, '.
PUBLIC RECORD
UNITED STATES OF AMERICA 11\"1 BEFORE FEDERAL TRADE COMMISSION v.., I l U.) OFFICE OF ADMINISTRATIVE LAW JUDGES SECRETI\
In the Matter of
BASIC RESEARCH, L.L.C G. WATERHOUSE, L.L.C. KLEIN-BECKER USA, L.L.c. NUTRASPORT, L.L.C. SOVAGE DERMALOGIC LABORATORIES, L.L.c. d//a BASIC RESEARCH, L.L.C. OLD BASIC RESEARCH, L.L.c. BASIC RESEARCH, A. G. WATERHOUSE BAN, L.L.C. DOCKET NO. 9318 d/b/a KLEIN-BECKER USA, NUTRA SPORT, and SOV AGE DERMALOGIC LABORATORIES DENNIS GAY DANIEL B. MOWRY d/b/a AMERICAN PHYTOTHERAY RESEARCH LABORATORY, and MITCHELL K. FRIEDLANDER
Respondents.
RESPONDENTS' EMERGENCY MOTION TO STRIKE DR. ROBERT ECKEL AN DR. STEVEN HEYMSFIELD AS PETITIONER' S EXPERT WITNESSES AND FOR SANCTIONS AND OTHER RELIEF-EXPEDITED BRIEFING AND DECISION REQUESTED
During its pre-Complaint investigation and continuing into post-Complaint discovery in this case, the Federal Trade Commission ("FTC" or "the Commission ) and
Complaint Counsel propounded upon Respondents exhaustive discovery requests seeking, among other things, some of Respondents most private, confidential, valuable and proprietary information and work product. Given the extremely sensitive and privileged nature of many of these documents and materials, including product formulations, product research and substantiation, and other proprietary work-product Docket No. 9318
Respondents sought from this Court a pre-production protective order to ensure their
compliance with Complaint Counsels ' discovery requests would not result in the
dissemination of their most protected and valuable information-particularly to
competitors. To that end, the Court, early in this case, entered a Protective Order
Governing Discovery Material ("Protective Order ) specifically designed to protect against improper use or disclosure of Respondents' information.
Both before and after entry of the Order, Respondents, acting in good faith produced to the FTC thousands of highly sensitive documents. Many of these documents were designated as attorneys' eyes only.
Respondents rightfully believed that the Court' s August 2004 Protective Order would insulate Respondents ' proprietary and confidential information from improper disclosure and, potentially improper use by the Federal Trade Commission and or its experts. Unfortnately, Respondents ' faith that the Government would respect this
Court' s mandate was misplaced.
This Motion documents overwhelming evidence that Complaint Counsel ignored material provisions of the Protective Order prior to disseminating Respondents' attorneys eyes only documents to its experts. During the same time those experts improperly received and reviewed Respondents ' information, at least one of the experts was conducting and assisting in studies of potential weight-loss products for some of
Respondents' direct and indirect competitors. Moreover, one of those experts was, at the same time, in negotiations with a competitor for in-house employment to head a division devoted to the development and production of a new line of products specifically designed for weight-loss. Incredibly, that expert, while in actual possession of
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Respondents ' confidential , proprietary information, including formulas, and product
research and substantiation, negotiated a compensation package with a competitor that
provides financial incentives based upon his success in getting to market new products
that directly compete with Respondents ' products. 1
In clear violation of this Court' s Order, designed to preclude the very
dissemination that here occurred, Complaint Counsel provided Rcspondents' information to those two expcrts without providing Respondents advance notice. As a result
Respondcnts had no knowledge of thesc serious breaches and no opportunity to timely raise their concerns in advance of the incurable disclosures. These breaches by
Complaint Counsel were unknown to Respondents until they received reports from
Complaint Counsels ' experts , and even then were unconfirmed until Respondents had a chance to question the experts about these issues during their recent depositions.
Complaint Counsel has to the date of this filing never notified Respondents of these disclosures of Respondents' information or any disclosures to other individuals currently unkown to Respondents.
Complaint Counsels ' failure to comply with this Court' s Protective Order has caused Respondents incalculable har and prejudice, as their most private, confidential and valuable commercial information now rcsides with at least one direct competitor and was held by Complaint Counsels ' experts while conducting paid work for several of
Respondents' direct and indirect competitors. The harm is extraordinary and incurable.
1 While Respondents no longer sell ephedra/ephedrne based dietary supplements, the formulas for these products still have value as there is no bar on fiing a New Drug Application (NDA) for any ephedra/ephedrine based weight control compound.
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For these reasons , as discussed more fully below, Respondents Basic Research
LLC, A.G. Waterhouse, LLC , Klein-Becker USA, LLC, Nutrasport, LLC, Savage
Dermalogic Laboratories, LLC, Ban, LLC, Dennis Gay, Daniel B. Mowrey, and Mitchell
K. Friedlander (collectively "Respondents ), through undersigned counsel, jointly seek an Order pursuant to 16 C.F.R. 9 3. 38(b) and 16 C.F. R. 9 3.42(h), that: (I) sanctions
Complaint Counsel for their deliberate or grossly indifferent breach of this Court'
Protective Order by excluding from these proceedings the two expert witnesses , Dr.
Robert H Eckel ("Dr. Eckel") and Dr. Steven B. Heymsfield ("Dr. Heymsfield"), to whom Complaint Counsel improperly provided Respondents ' confidential information;
(2) commands the return to Respondents from Drs. Heymsfield and Eckel of all documents in their possession marked or designated confidential, together with sworn affidavits that reasonable efforts were made to confirm that no additional copies, either electronic or in hard form, exist, and that no other persons had access to the materials while in their possession; and (3) requires Complaint Counsel to fie a declaration or sworn affdavit detailing in specific terms; (a) their handling of Respondents ' protected confidential information, (b) the measures undertaken by Complaint Counsel to safeguard that information and comply with the Court' s Protective Order, (c) the identities of all individuals who were provided access to or copies of the protected information, and (d) dctailing the full scope of their violations of the Protective Order.
Alternatively, should the Court be disinclined to strike Dr. Heymsfield and/or Dr.
Eckel trom these proceedings, Respondents request the declaration from Complaint
Counsel described above in addition to an Order from the Court commanding: (I) Dr.
Heymsfield to make available immediately all documents in his possession responsive to
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the subpoena specifications this Court made clear in an earlier ruling were applicable to
this witness; (2) Complaint Counsel to make Dr. Heymsfield available for two days
following adequate opportunity for Respondents to review and digest the documents
Respondents have yet to rcceive from Dr. Heymsfield or Complaint counsel, to ensure
Respondents have a full and fair opportnity to resume and conclude their deposition; (3)
Complaint Counsel to reimburse Respondents ' costs and fees for having to conduct a
second out-of-state deposition; and (4) setting a new date, ten days after completion of
Dr. Heymsfield' s deposition, for Respondents to rcspond to Complaint Counscls motions for summary decision, in order to ensure a fair opportnity to respond to the arguments, issues and evidence presented therein, at least some of which wil, no doubt be based upon Dr. Heymsfield' s opinions.
The instant Motion is fied as an emergency motion due to the immediate and pressing nature ofthcsc issues , the fact that the discovery cut-off has now passed, and the impending summary decision fiing deadlines.2 Timely clarification from the Court concerning the relief available is needed in ordcr to properly plan for the rcsumption of
Dr. Heymsfield' s deposition, if the Court is reluctant to grant the relief requested and strike the FTC's experts. To that end, Respondents request an expedited briefing schedule and ruling from the Court.
In support ofthis Motion, Respondents state as follows:
FACTUAL BACKGROUND
A. The Protective Order Governing Discovery Material.
2 As a showing of good faith, the fiing of this Motion was shortly delayed due to settlement discussions between the parties.
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On August 11 2004, the Administrative Law Judge ("AU") entered a Protective
Order Governing Discovery Material ("Protective Order ) in this case to shicld the
parties and third parties against improper disclosure or use of confidential information
submittcd or produced in connection with this matter. Protective Order, p. I. The
Protective Order governs all confidential documents designated in the manner set fort in
the Order. See Order at 4 Those documents bearing the special designation
Restricted Confidential , Attorneys Eyes Only - FTC Docket No. 9318 " contain
competitively proprietary information and are subject to enhanced protection under the
Order. Id. at 5 2(b).
Under the express terms of the Protective Order, disclosure and dissemination of
material marked "Restricted Confidential - Attorneys Eyes Only - FTC Docket No.
9318" ("Confidential Material" ) is limited to the parties and the Court. !d. at 7 4(a),
(b), (c) and (e). Dissemination of Confidential Material to expert witnesses is subject to
the terms of Paragraphs 5 and 7 of the Protective Order. Id. at 9 , 'I,r 5 and 7. Even the process for copying the confidential information is spelled-out in the Order. Save for that which is "reasonably necessary to facilitate the conduct of this matter " Paragraph 7 prohibits copying or reproduction any of the Confidential Material, and any copies or reproductions that are reasonably necessary are afforded the same protections as originals
under the Order. Id. at 9 7. .
The express language of the Protective Order requires Complaint Counsel to provide advance notice to Respondents of its desire to disclose to a third-part any
Confidential Material. Id. at 5 2(c). Complaint Counsel's notice must include, at a minimum, the namc of the individual to whom disclosure is contemplated, together with
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his or her professional address and affliation. Id. Respondents then have five business
days in which to object to the proposed disclosure. Id. The reason for this is obvious-
provide Respondents an opportunity to challenge proposed disclosure to someone
connected directly or indirectly to a competitor. Complaint Counsel is also required by
the Court' s Order to obtain a written declaration from the proposed rccipient swearing
that he or she will comply with the terms of the Protective Order concerning the handling
of the Confidential Material prior to receipt of the same. Id. at 7 ~ 5.
The language of the Protective Order itself notes that disclosure of Confidential
Materials, including without limitation, customer names, consumer complaints, strategic
plans , trade secrets , customer specific evaluations or data, proprietary or engineering
information, market research and analysis, and the like would cause substantial
commercial harm or personal embarrassment to the disclosing part. Id. at 3 , ~ 20. It is
Complaint Counsels ' failure to comply with the mandatory provisions governing the disclosure of Respondents ' confidential information to third- parties that has caused the very irreparable harm contemplated by the Court' s Order, and which precipitates the instant Motion.
B. Respondents' Production of Confidential Material and Complaint Counsels' Subsequent Dissemination to Others in Contravention of the Protective Order.
In January 200 I , several Respondents first learned they were under investigation by the FTC. During the course of that investigation, and continuing through the discovery phase of this action, initiated in June 2004, Respondents produced to the FTC and Complaint Counsel, thousands of requested documents, including some
Respondents ' most valuable , confidential , and proprietary information and work
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product. The Protective Order clearly governs Respondents ' productions following
entry of the Order, but also expressly applies to documents produced in advance of the
Order:
All documents heretofore obtained by the Commission through compulsory process or voluntarily from any Part or Third Part, regardless of whether designated confidential by the Part or Third Party, and transcripts of any investigational hearings, interviews and depositions that were obtained during the pre-Complaint stage of this Matter shall be treated as "Confidential " in accordance with paragraph 2(a) ofthis Order.
Protective Order at 6, ~ 3.
Of course, Complaint Counsel also undertook responsibilities and duties as
custodians of the confidential documents produced by Respondents irrespective of the
Protective Order. Chief among the continuing responsibilities owed by Complaint
Counsel to Respondents is the duty to vigorously protect the confidentiality of the private, commercial, and proprietary information provided in response to numerous requests and demands by the FTC, and to prcvent the disclosure of that material in any manner that may injure or harm Respondents or their businesses.
3 Any challenge or dispute Complaint Counsel may now seek to raise concerning the propriety of any specific Confidential designation of documents here at issue should be summarily dismissed because Complaint Counsel has failed to raise any objection to the designation of any of the documcnts, as required under Paragraph 6 of the Protective Order. Moreover, Complaint Counsel is also barred from arguing the impropriety of any such designations based upon any such documents being otherwise available individually in the public domain, as the documents were produced to Complaint Counsel and the FTC as a collection or compilation, uniquely combined as they relate to the specific challenged products at issue here, thus justifying their status as trade secrets and giving Respondents a competitive advantage. Seeh Cir. 1969); seeWater also RestatementServices, Inc. v.of Tesco the Law Chemicals, 3d Inc. 410 F.2d 163 , 173 (5 , Unfair Competition (1995), 9 39(t), p. 432 (stating "the fact that some or all of the components of (aJ trade secret are well-known does not preclude protection for a secret combination compilation, or integration of the individual elements. Salsbury Laboratories, Inc. v. Merieux Laboratories, Inc. 735 F. Supp. 1555 , 1569 (M.D. Ga. 1989), affd 908 F. 2d 706 (11 Cir. 1990); Rivendell Forest Products v. Georgia-Pacifc Corp. 28 F.3d 1042 1042
(loth Cir. 1994); Essex Group, Inc. v. Southwire Co. 501 S. E.2d 501 503 (Ga. 1998).
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1. Dr. Heymsfield.
Pursuant to notice previously provided and subpoena to the witness, Respondents began the deposition of Dr. Heymsfield on January 11 2005, the date agreed upon by the parties. Prior to Complaint Counsel unilaterally suspending the deposition and walking out, over objection of all Respondents, it became clear from Dr. Heymsfield' s testimony that Complaint counsel had materially violated the terms of this Court' s Protective Order that Complaint counsel had conducted itself in bad faith with respect to allowing
Respondents suffcient access to Dr. Heymsfield, that Dr. Heymsfield had failed to meaningfully comply with Respondents ' subpoena, and that Complaint Counsel had failed to comply with the terms of the Court' s scheduling describing the documents to be
4 Each of exchanged by parties relating to experts these issues has caused Respondents actual prejudice and harm. Cumulatively, the injury to Respondents is incalculable and incurable, thus entitling Respondents to the relief sought.
Complaint Counsel's Disclosure of Confidential Materials to Dr. Heymsfield in Violation of the Protective Order.
As discussed more fully below, Dr. Heymsfield' s deposition testimony clearly establishes that Complaint Counsel provided Dr. Heymsfield with copies of Respondents
4 Because Complaint Counsel unilaterally suspended Dr. Heymsfield' s deposition in the middle of examination by counsel for the entity Respondents on the very issues discussed herein, it is impossible for Respondents to know whether there are additional material breaches or issues that may bear on this Motion. Complaint Counsel intentionally interfered with Respondents ' very ability to frame these issues for the Cour' consideration by unilaterally removing Dr. Heymsfield once it became clear there were serious problems with their failure to comply with the Court' s Order and Dr. Heymsfield' s failure to comply with the subpoena. Respondents believe the prejudice flowing from these violations requires briefing as soon as possible, even though Respondents were deprived of the opportnity to fully develop this issue for the Court and they submit this memorandum based upon the best information now available however incomplete it may be.
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confidential document and materials, and that Dr. Heymsfield reviewed those materials.
It is not disputed that Complaint Counsel failed to comply with the express requirements
of this Court' s Protective Order, that notice in advance of disclosure be provided to
Respondents for an opportunity to object. This failure led to extraordinary prejudice and
harm to Respondents when their confidential documents and materials were provided to
Dr. Heymsfield by Complaint Counsel.
During that portion of Dr. Heymsfield' s deposition that was later unilaterally
suspended by Complaint Counsel, counsel for Respondents started questioning Dr.
Heymsfield about certain documents he received from Complaint Counsel during the
course of his involvement in this case. During that questioning, Respondents' counsel
showed Dr. Heymsfield a letter addressed to him from Complaint Counsel
acknowledging the enclosure of documents pertaining to Respondents ' substantiation for
Anorex, bate stamp numbered R0332 through R181 L Tr. Depo. Steven B. Heymsfield p. 376 (January 11 2005), attached to this Motion hereto as Exhibit 1 (and is cited in this
Motion as "Heymsfield depo. at - Respondents ' counsel then removed a representative sample of documents from that bate stamp range, numbered R1l5l through R1252, and asked Dr. Heymsfield if the bottom of each of these documents read
Restricted Confidential Attorneys Eyes Only. !d. at 377. Dr. Heymsfield responded
with a simple yes. Id. Respondents ' counsel made the same inquiry with respect to two other document samples (bate stamped 826 through 1000, and 1094 through 1193) provided to Dr. Heymsfield with the September 27 2004, letter from Complaint counsel.
!d. at 378. Dr. Heymsfield again acknowledged that each page of these documents was marked "Restricted Confidential Attorneys Eyes Only. Id. at 378-
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Respondents ' counsel next asked if Dr. Heymsfield would agree that he had
received "many, many of(Respondcnts Restricted Confidential Attorneys Eyes Only
documents " to which Dr. Heymsfield concurred. Id. at 379.
Dr. Heymsfield' s testimony clearly establishcs Complaint Counsel provided him
with Confidential Material covered by the Court' s Protective Order. Respondents were never notified of this by Complaint Counsel, and given no opportnity to object. Had
Respondents been given such an opportunity there is no question but that they would have objected for the reasons that follow, among others.
Dr. Heymsfield's Obvious and Serious Conflct of Interest.
Dr. Heymsfield' s own deposition testimony proves that Complaint Counsel provided him with Respondents ' confidential information and materials , including product formulations and other highly valuable and secret commercial data and research at the same time Dr. Heymsfield was being paid by direct and indirect competitors of
Respondents to conduct and assist with studies of other competing weight loss products.
Even more astonishing is that Dr. Heymsfield was, while in possession of this same highly confidential, proprietary information and work product, negotiating with Merck &
Company for employment as head of a research division at Merck charged with the task of researching, developing and getting to market weight loss products-products that
5 To the extent Complaint Counsel may try to argue that no "new" documents were provided to Dr. Heymsfield after the Court issued the Protective Order, Respondents note that any such representation lacks merit. Among the documents provided Dr. Heymsfield in September 2004, after entry of the Order, were proprietary product formulations not produced by Respondents prior to discovery in this action. That is, Complaint Counsel did not have the formulation documents at the time they initially provided documents to Dr. Heymsfie1d before entr of the Order. There can be no serious dispute that Dr. Heymsfie1d received new, confidential documents and materials from Complaint Counsel following entr of the Protective Order.
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would obviously compete directly with Respondents ' products , the formulations for
many of which were in Dr. Heymsfield' s possession. Dr. Heymsfield' s negotiations with
Merck eventually led to his accepting a position as Executive Director of Clinical
Research in Metabolism, with a healthy compensation package that includes financial
bonuses directly tied to his success in creating and getting to market products that will
complete with those of Respondents. Id. at 205-06.
Dr. Heymsfield testified that negotiations between himself and Merck began
sometime during the summer of 2004. !d. at 351. He further testified that he formally accepted employment with Merck in early October and began working there on
November 1 2004. Id. When asked ifhe had disclosed to Complaint counsel that he was in negotiations with Merck, Dr. Heymsfield answered yes... as soon as I signed my contract with Merck, I disclosed it to them. Id. Respondents' counsel then asked Dr.
Heymsfield were you involved in any studies for any pharmaceutical or dietary supplement companies, any time during your tenure as an expert in this case, that is from the point where you were asked to act either in consulting or testifying capacity in this
case?" Id. at 355. Dr. Heymsfield answered during that time period, I was actively engaged in research projects related to at least two drugs. One happened to be a Merck drug, the other is a drug from a company called Regeneron. For sure. There are probably
many others, but those were two. Id. at 355-56.
As a follow-up, Respondents' counsel asked whether these two drugs were weight
loss studies, to which Dr. Heymsfield responded yes. !d. at 356. Dr. Heymsfield went on to list several other companies that he worked with or was approached by while retained as an expert in this case, including Kellogg , the National Dairy Counsel
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Healthy Tech, Tanita, Areron, American Home Products , and Wyeth. Id. at 357- 60.
Dr. Heymsfield also acknowledged previous relationships with numerous other direct and
indirect competitors of Respondcnts in the weight loss field. When asked for what other
pharmaceutical companies Dr. Heymsfield had been a consultant, he answered that he
had consulted for Hoffman LaRoche, Abbott Pharmaceuticals , Takida, Johnson &
Johnson, Sinofy Pharmaceuticals , and Servier. Id. at 9- 10. When asked specifically if he
had ever bccn a consultant to any dietary supplement companies, Dr. Heymsfield'
answered "1 have been a consultant to companies such as SlimFast, Neutra System. 1
think those are the main ones. And companies like Weight Watchers... I did work at one
point as a consultant for several dietary supplement companies. One is called Pacific
Health. Id. at 10.
Had Respondents known that Dr. Heymsfield was affliated in any way with these
companies (especially the contemporaneous engagements with competitors whilc
reviewing Respondents' confidential information), and had Respondents been provided
the opportnity to object to disclosure of its confidential documents and materials to Dr.
Heymsfield, as provided in the Court' s Protective Order, they would unquestionably have
6 Complaint Counsels done SO. ' failure to comply with the Protective Order and notify
Respondents of its desire to disclose Confidential Materials to Dr. Heymsfie1d deprived
Respondents of their opportnity to prevent their most valuable, proprietary, and confidential material from landing squarely in the hands of a direct competitor-and to
6 To the extent Complaint Counsel may suggest otherwise, Respondents note that Dr. Heymsfield' s historical and contemporaneous relationships with competitors was not necessarily a basis for seeking to exclude him as an expert in this case. It was Complaint Counsels' act of providing him with confidential proprietary documents and materials while so engaged that caused the extraordinary harm here, the significance of which was unkown to Respondents until his deposition.
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be sure, as the Executive Director of Clinical Research in Metabolism for Merck, a major
pharmaceutical company, Dr. Heymsfield is Merck for all intents and purposes-actively
engaged in developing weight loss products to bring to market to compete with
Respondents' products. The prejudice is extraordinary and obvious. It is also incurable.
Thc Court should grant Respondents Motion and provide the requested relief.
Post-Disclosure Breaches of the Protective Order by Dr. Heymsfield and Complaint Counsel.
Complaint Counsels ' breaches of the Court' s Protective Order did not end with
disclosure of Respondents ' Confidential Materials to an expert affiiated with direct and
indirect competitors of Respondents. Complaint Counsel failed even to ensure Dr.
Heymsfield, once he received from Complaint Counsel the documents he should not have received, was adcquately educated on how to properly protect the confidentiality of the materials. During his deposition, counsel for Respondents asked whether Complaint
Counsel had ever instructed Dr. Heymsfield on how to handle the Confidential Materials to which Dr. Hcymsfield responded they never gave me a lecture on how to handle
these documents. Id. at 379-80. Respondents counsel next posed the question they never asked you to sign a declaration, obtaining your agreement to abide by the
protective order that the court entered in this case; is that true?" !d. at 380. To this question, Dr. Heymsfield responded that is true. Id.
Additional questioning of Dr. Heymsfield also revealed he was completely unaware of the existence of a Protective Ordcr in this matter. During the course of the deposition, Respondents ' counsel asked and Dr. Heymsfield answered the following:
Q. Did you know at the time that you were given this document that there had been a protective order entered by the court in this case
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governing the handling and use of this document; do you know of that order yes or no? A. No, I didn t know of that order. Q. No one from the FTC told you about the order;... isn t that true? A. I don t think that anyone ever told me specifically about that order. Q. I'm showing you Exhibit 10 , the protective order. You have no- do you have any recollection of ever read (sic J this is (sic document? A. No.
Id. at 364-
As a result, Complaint Counsels ' own expert witness , Dr. Heymsfield, was provided access to Respondents' Confidential Materials and , without Dr. Heymsfield' appreciation for the confidentiality of these documents, he admittedly scanned these documents and saved them to a computer owned not by himself, but by St. Luke
Hospital , in clear violation of the Protective Order. Id. at 372. Dr. Heymsfield also testified that these documents and materials were left for months in his Hospital offce.
Dr. Heymsfield' s deposition demonstrates that Complaint Counsel provided Dr.
Heymsfield with numerous sensitive confidential documents belonging to Respondents and marked Restricted Confidential Attorneys Eyes Only without Dr. Heymsfield' appreciation of the importance of such a designation, whether or not he was aware of the
Protective Order, and that the failure to adequately counsel their witness led to additional
7 Despite Dr. Heymsfield' s plain testimony on this point, Complaint Counsel produced to Respondents, subsequent to the interrpted deposition, a copy of a declaration signed by Dr. Heymsfield acknowledging he was aware of and would comply with the terms of the Court' s Protective Order. Respondents note the document was not in the material provided them by the witness or Complaint Counsel prior to the deposition. Whatever possible explanation may exist for why Dr. Heymsfield testified unequivocally that he had not previously seen the declaration or the Court' s Protective Order, or even discussed either with Complaint Counsel, the testimony clearly establishes that Complaint Counsel failed to adequately educate their expert about the handling of the highly Confidential Materials. As discussed, this led to actual and harmful breaches of the Order by Dr. Heymsfield. Of course, whether or not Complaint Counsel obtained the signed declaration from Dr. Heymsfield, Complaint Counsel still breached the Protective Order by failng to provide Respondents advance notice of the disclosure, as noted herein.
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breaches of the Court' s Protective Order. Quitc aside from Complaint Counsel's and Dr.
Heymsfield' s mis-handling of Respondents' Confidential Materials , an obvious additional
concern to Respondents is that they cannot possibly know whether the confidentiality of
the material it produced to Complaint Counsel in good-faith, and in reliance on the
protections in the Protective Order, has been compromised by yet another party, causing
still further harm and prejudice.
Complaint Counsels ' Bad- Faith with Respect to Providing Respondents a Fair Opportunity to Depose Dr. Heymsfield.
Complaint Counsel has also acted in bad- faith with respect to allowing
Respondents a fair and full opportnity to depose Dr. Heymsfield, a key witness in these proceedings. On January 6, 2005, the week before Dr. Heymsfield' s deposition was to take place, Respondent Mitch Friedlander and counsel for corporate Respondents, Jeffrey
Feldman, had a conversation with Complaint Counsel wherein Complaint Counsel was asked to make Dr. Heymsfield available as long as was necessary to complete his deposition on the day designated. Tr. Depo. Mitch Friedlander, p. 247 (January 6, 2005), attached to this Motion hereto as Exhibit 2. The conversation took place in the middle of what was only one of several very lengthy depositions taken by Complaint Counsel that week, some of which went into the evening hours. Complaint Counsel responded that they would speak to Dr. Heymsfield about his availability. Friedlander depo. at 248.
Apprehensive about Complaint Counsel' s simple assertion only that they would speak with Dr. Heymsfield about being available for an extended deposition, corporate
Respondents' counsel made the following statement on the record:
let's go back and remind the court and the record that yesterday I had a conversation which was not the first time about Dr.
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Heymsfield (sic J availability, and I would ask not - at least over the last two days - for assurance that Dr. Heymsfield would make himself available and be available for as long as we need him next week because there are one, two, three, four people that need to question him.
I asked Ms. Kapin to call Dr. Hcymsfield - 1 asked this yesterday - to determine whether or not he would be available and would be able to stay late if necessary. I have not gotten anything back.
Id. at 248. Complaint Counsel Laureen Kapin s response, also on the record, was "what I said, Jeff, is that I would talk with him. I have not had the opportunity to do that. I will
do that." Id. Complaint Counsel apparently forgot that this conversation occurred on the record during Mr. Friedlander s deposition, as Complaint Counsel provided a completely different account of the conversation the next week during Dr. Heymsfield' s deposition in which Ms. Kapin stated that "for the record, we never talked about making Dr.
Heymsfield tomorrow. He is not available tomorrow. And when you say you had discussed that with me previously, that is incorrect." Heymsfield depo at 68-
Notwithstanding Complaint Counsel's earlier assertion that Dr. Heymsfield would be consulted about making himself available until all parties had completed their questioning, Dr. Heymsfield was directly asked during his deposition: "before yesterday, at any time during the past week did you have any discussions with Complaint Counsel
concerning the length of this deposition and your availability for the deposition?" !d.
80. Dr. Heymsfield responded not in the past week that I recall." Id. Complaint
Counsels' failure to consult Dr. Heymsfield about the need for him to remain until all parties had completed their questioning, together, it seems, with the testimony Dr.
Heymsfield had given to that point concerning his failures to comply with subpoenas and the Protective Order, led to Complaint Counsel unilaterally suspending Dr. Heymsfield'
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deposition in the middle of questioning by only the second Respondcnt with an
opportnity to pose any questions.
After returning from a recess during Dr. Heymsfield' s deposition, Complaint
Counsel rc-entered the deposition room and, at 7:11 p. , over Respondents' counsel'
objection, stated that they were going to recess Dr. Heymsfield' s deposition. !d. at 392-
93.
Complaint Counsel conducted many depositions during discovery in this case of much longer duration than Dr. Heymsfield' s and not once did Respondents attempt to foreclose Complaint Counsel from completing their deposition. To the contrar,
Respondents made their own offces available for an after-hours deposition after being forced to leave one location when it closed in thc evening. Respondents have not once interfered with Complaint Counsels' ability to conduct and complete a full and fair deposition of a witness.
As a result of Complaint Counsels' deliberate failure even to consult their expert witness to ensure his schedule provided for a full and fair opportnity for Respondents to take his deposition on the day mutually agreed upon, and Complaint Counsels misrepresentations on the record to Respondents about the same, Respondcnts are unable at this time even to adequately meet the allegations made by Dr. Heymsfield in his report as only one of four Respondents was provided leave to complete their questioning of Dr.
Heymsfield before Complaint Counsel simply walked-out with the witness. Of course even the questioning that took place was necessarily incomplete, as discussed below because Dr. Heymsfield elected to produce only about twenty percent of the documents in his fie that he reviewed in this case.
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Complaint Counsels ' bad faith with respect to allowing Respondents a fair chance
to fully question Dr. Heymsfield is ongoing. Even as of the date of this fiing, Complaint
Counsel is refusing to make Dr. Heymsfield available for deposition for any period
longer than four hours, despite the fact that Dr. Heymsfield has well over four binders of
documents he failed to previously produce, and despite that fact that only Respondent
Mowery has completed his direct examination of this witness. Moreover, though
Respondents believe that Dr. Heymsfield should be stricken, an adverse ruling on this
Motion will force Respondents to return to New York City to finish the deposition
Complaint Counsel unilaterally suspended, at a cost of many thousands of dollars in
additional time and travel expenses.
Despite all the foregoing, Complaint Counsel is still failing to act in good-faith
refuses to comply with the discovery rules and chooses not to extend to Respondents the
same courtesies extended to them. The Court should grant Respondents the relief
requested.
Dr. Heymsfield' s Intentional Failure to Comply with Respondents' Subpoena and this Court' Expert Witness Disclosure Requirements.
Heymsfie1d Deliberately Ignored the Respondents ' Subpoena for Documents.
As noted, it also became apparent during his deposition that Dr. Heymsfield simply chose not to comply with the subpoena issued by Respondents. On October 12
2004, Respondents issued a subpoena to Dr. Heymsfield, lawfully ordering him to produce certain specifically identified documents in advance of his deposition.s Among
8 The FTC fied a Motion for Protective Order as to a number of the document specit1cations in Dr. Heymsfield' s subpoena; however, the FTC had no objection to the
Page 19 Docket No. 9318 the documents requested were all documents Heymsfield reviewed in preparation of his expert witness report, all correspondence between Dr. Heymsfield and the FTC concerning this matter and Dr. Heymsfieid' s entire fie pertaining to this matter. Subp.
Steven B. Heymsfield, Exhibit A(1), (2), (6), (October 12, 2004), attached to this Motion as Exhibit 3. However, when questioned during his deposition about his production pursuant to the subpoena, Dr. Heymsfield acknowledged that he elected not to produce to
Respondents the requcsted materials.
Of particular concern was Heymsfield's decision to withhold documents that he considered in reaching his decisions in this case. Dr. Heymsfield' s stated in his expert report that he considered several categories of documents. One category encompassed documents the FTC sent to him for his review. Another category were documents that
Dr. Heymsfield pulled from his own fies. Indeed, Dr. Heymsfield's expert report states that: "My report is based on material provided to me by the Federal Trade Commission
(FTC) and on my own extensive fies and literature search. " Expert Report of Steven B.
Heymsfield, p. 9, ~ 40. Specification numbers 6 and 7 of Respondents' subpoena to Dr.
Heymsfield called for thc production of "All documents reviewed by you in connection with you work on this matter" and "All materials consulted by you or relied on by you in forming any opinion in connection with this matter. See Exhibit 3. Despite having an appreciation that the subpoena required production of all documents that he considered even those in his personal fies, Dr. Heymsfield decided to provide only those documents that he deemed "directly relevant" to his opinion.
first seven specifications. All of the documents withheld by Dr. Heymsfield were responsive to one of more of these first seven requests.
Page 20 , "
Docket No. 9318
Notably, Rcspondents' counsel asked Dr. Heymsfield ifhe " would agree that (he)
did not list the fies, (his) own fies that (he) considered." Heymsfield depo at 297. Dr.
Heymsfield responded simply, "that' s correct " later stating "I produced to (Respondents)
all the papers I relied often. I didn t produce my fies. Id. at 297, 299 (emphasis added).
Dr. Heymsfield also admitted that he "only provided the material that (he) thought was
directly relevant to (his) report , but there is other material." Id. at 318. Moreover, when
asked which documents Dr. Heymsfield produced apart from those provided to him by
Complaint Counsel, Dr. Heymsfield responded "likely... none of them, because the
FTC's was the most consolidated clear set of papers as opposed to mine which are pretty
worn. Id. at 302. Thus, Dr. Heymsfield' s production apparently consisted of no more
than a portion of Complaint Counsels ' own fie to Dr. Heymsfield, though Dr.
Heymsfield himself admittedly reviewed and relied upon other documents in his own
fies.
In attempting to determine the extent of Dr. Heymsfield' s breach of the subpoena
and disregard of Respondents ' right to fully and fairly examine him, Respondents
counsel asked approximately how many notebooks of material Dr. Heymsfield received
from Complaint Counsel and how much of that material he actually produced to
Respondents. Specifically, Respondents ' counsel asked of the total amount of
information that you received from the FTC... what percentage of it have you produced
to (Respondents)?" Id. at 324. Dr. Heymsfield' s response was remarkable, stating that he "provided to (Respondents)... a little more than one photo book. There s probably another four or five notebooks full of material which I did not specifically use in my
Page 21 , "
Docket No. 9318 report, and that r only reviewed in a very cursory way as a screening, which I did not
send. Id. at 324-
Thus, Dr. Heymsfield also admits to failing to produce the vast majority of documents provided to him by Complaint Counsel. Failure to produce all of the
documents Dr. Heymsfield received from Complaint Counsel and all of the documents
Dr. Heymsfield consulted in formulating his opinion, severely prejudices Respondents making it impossible for Respondents to have conducted a thorough examination of Dr.
Heymsfield, and rendering Respondents unable to adequately formulate rebuttal argument against Dr. Heymsfield and his report. It effectively nullifies even the effect of the testimony obtained during his partial deposition because Respondents' counsel could not possibly be adequately prepared to depose Dr. Heymsfield without knowing what documents he reviewed and relied upon.
This Court' s recent ruling concerning a single document the Respondents withheld (on the basis of privilege) from the production of Respondents' expert linguist
Professor Larr Solan, clearly establishes an expcrt' s responsibility to provide all data documents, or information considered by a testifying expert witness in forming the opinions to be proffered " including "documents considered but rejected by the testifying expert in reaching (the) opinions." Order on Complaint Counsel' s Motion to Compel a
Document from Respondents' Testifying Expert Solan , at 2 (citations omitted). This
Court was clear that each expert expected to testify at trial must provide "all documents reviewed, consulted, or examined. . . in connection with forming his or her opinion on the subject on which he or she is expected to testify.... Id.
Page 22 Docket No. 9318
These documents were requested by Respondents in the subpoena served on Dr.
Heymsfield. He was aware of the request and simply chose not to comply with
Respondents' lawful requcst and the Subpoena issued by this Court. His failure to
comply deprived Respondents (at least those who had any opportunity to examine Dr.
Heymsfield at all) of an opportunity to fully explore the basis for his opinions and the
materials considered. Respondents are now forced to prepare motions for summary
decision and prepare for the hearing in this matter having been deprived of a meaningful
opportunity to examine a key witness in this proceeding. The reason for that is simple-
the Commissions ' expert simply decided to not to comply with the terms of the valid and
lawful subpoena from this Court. As a matter of equity, and in the context of the
numerous other issues raised by the conduct of Complaint Counsel and Dr. Heymsfield, it
is only fair that Dr. Heymsfield should be stricken entirely from this proceeding.
Complaint Counsel and Heymsfield Violated this Court' s Expert Witness Disclosure Requirements.
Complaint Counsel also failed to disclose all cases in which Dr. Heymsfield has testified as an expert and, with respect to one of those cases, Complaint Counsel and Dr.
Heymsfield failed to disclose the full nature of Dr. Heymsfield' s testimony in that case.
For example, in Complaint Counsel' s expert witness disclosure, Complaint Counsel and
Dr. Heymsfield represented that Dr. Heymsfield had testified in five (5) cases, none of which involved the FTC as a party. However, during his deposition, Dr. Heymsfield disclosed, for the first time, that he had testified via deposition and at trial as an expert in a case for the FTC. See, e. Heymsfield Dep. at 41:21-42:3.
Additionally, in their expert witness disclosure, Complaint Counsel and Dr.
Heymsfield represented that Dr. Heymsfield had testified via deposition in the case of
Page 23 Docket No. 9318
Parks v. Cytodyne Technologies, Inc. However, Respondents independently learncd that
in addition to testifying via deposition in the Parks case, Dr. Heymsfield also testified at
the trial of that case.
Complaint Counsel's and Dr. Heymsfield' s failurc to fully disclose all cases in
which Dr. Heymsfield has testified as an expert is important because, aside from the fact
such failure is a violation of thc Court' s order, Dr. Heymsfield has offered testimony in this case which is irreconcilably inconsistent with testimony he has previously offered.
For example, Dr. Heymsfield has tcstified in this case that several of the studies that Rcspondents' rely on to support their ephedra, aspirin and caffeine products are irrelevant because the active ingredients in the studies did not include aspirin but rather a willow bark derivative called salicin. Dr. Heymsfield has opined in this case that aspirin and salicin are not the same thing and therefore studies that involve salacin cannot substantiate aspirin based products. In this regard, Dr. Heymsfield' s testified at his deposition as follows:
So is it your opinion that aspirin and salicin are the same thing?
A. No. I think there s some questions about comparable effcacy of willow bark compared to acetylsalicylic acid, which is aspirin.
Yet in direct contrast to that testimony, Dr. Heymsfield testified during the Parks trial that salicin and aspirin are herbal equivalents, and that salicin and aspirin are the same
thing. For example , during questioning at the Parks trial concerning the use of
ephedrne, caffeine , and aspirin in a scientific study conducted by, inter alia Dr. Patricia
Daly, and whether Cytodyne s Xenadrine product contained aspirin, the following colloquy occurred:
Page 24 Docket No. 9318
Q. Now Xenadrine RFA- , if we re to believe what's on the label says it has salicin, correct?
That's correct.
And that's a -- is that an herb?
A. Well , it s -- 1 believe there s an herbal source. It' s called white willow bark and it's salicin , that's right.
Is that an active ingredient?
A. Not by itself. It' s transformed in the body to acetylsalicylic acid which is aspirin.
Transcript of Proceedings Parks v. Cytodyne Technologies, Inc. March 13 , 2003 , at
1590: 15-23.
During Dr. Heymsfield' s testimony at the Parks trial, there was also testimony concerning a scientific study which Dr. Heymsfield had done involving a product which has ephedra, caffeine, and salicin from white wilow bark, but not aspirin. During that discussion, Dr. Heymsfield specifically testified that salicin (the source of which is white willow bark) is the same thing as aspirin: Q. And that product (the product which was the subject of Dr. Heymsfield' s study), I understand, did not have synephrine; is that correct?
That's correct.
Did not have tyrosine?
That's correct.
And did it have aspirin or-
Yes.
Okay.
It did.
Page 25 , " g.,
Docket No. 9318
It did have aspirin but did not have synephrine? A. Had the same thing. White willow bark, I believe. I could be wrong about that.
Id. at 1682:21- 1683:4
Dr. Heymsfield' s inconsistencies on the aspirinlsalacin dichotomy issue are
important because inter alia in his rebuttal expert report in this case Dr. Heymsfield
stated that "An average weight loss of 2 pounds/months for ephedrine/ephedra as
reported in the Rand Report is considered extremely weak effcacy. Heymsfield
Rebuttal Report at 8. Yet in his original expert report, Dr. Heymsfield characterized the
weight loss from ephedrine or ephedra products as " modest." See, e. Heymsfield
Expert Report at 10. Moreover, in his prcpared testimony to Congress, Dr. Heymsfield
characterized the weight loss resulting from ephedrine, caffeine and aspirin in a much
different light, testifying that:
The collective studies strongly support the premise that ephedrine particularly in combination with caffeine and also aspirin, promote
signifcant short-term (j( 3-6 months) weight loss when ingested as par of an intervention program including dietary and lifcstyle management. Long-term (?6 months) controlled trials with large and diverse subject
9 Similarly, in written testimony to Congress Dr. Heymsfield also expressly testified that salicin is an herbal equivalent of, and the same thing as, aspirin, testifying as follows:
Ephedrine and ephedra alkaloids alone have modest weight loss effects and their effcacy appears to be enhanced by addition of caffeine and aspirin either as the pharmaceutical grade ingredients or as their natural counterparts such as Guarana and Wilow-bark, respectively.
Addition of caffeine (i. Guarana ) arid aspirin (i. , Willow-bark) to MaHuang purportedly potentiates the actions of ephedrine.
Prepared Witness Testimony: Hcymsfield, Steven, presented to The Committee on Energy and Commerce W "Billy" Tauzin, Chairman, July 23 , 2003 ("Heymsfield Congressional Testimony ) at 3.
Page 26 Docket No. 9318
populations are lacking. The evidence for ephedra effcacy is summarized in the recent Rand Report.
Heymsficld Congressional Testimony at 3.
Given the clear and irreconcilable inconsistencies between Dr. Heymsfield'
testimony in this case and his testimony in other proceedings, Complaint Counsel' s and
Dr. Heymsfield' s failure to fully disclose all cases wherein Dr. Hcymsfield has testified
as an expert witness is prejudicial to Respondents, and warrants an appropriate remedial
order from the Court.
2. Dr. Eckel.
On or about October 21 , 2004, Respondents received the report of Dr. Eckel, an expert retained by Complaint Counsel to testify concerning the scientific validity of
certain representations allegedly made by Respondents in various of their advertisements.
Report of Robert H. Eckel, M. , ~ 13 , attached to this Motion hereto as Exhibit 4 (and is cited in this Motion as "Eckel Report ~ - ). Dr. Eckel' s report included a disclosure describing the documents that Complaint Counsel provided to him in his capacity as their expert:
The staff of the Federal Trade Commission (FTC) have provided the following materials for my review: Complaint and Exhibits A-L (product advertisements); Respondents ' CLAIM SUBSTANTIATION FOR TUMMY FLATTENING GEL"; Respondents CLAIM SUBSTANTIATION FOR DERMALIN Apg ; Respondents ' CLAIM SUBSTANTIATION FOR "CUTTING GEL"; DermTech report dated 6/11/03 titled "Evaluation of the Percutaneous Absorption of Aminophylline in vitro Using the Human Cadaver Skin Model" DermTech report dated 9/01/02 titled "Determination of the Percutaneous Absorption of Aminophylline in vitro Using the Human Cadaver Skin Model"; and DermTech report dated 12/06/01 titled "Evaluation of the Percutaneous Absorption of Aminophylline in vitro Using the Human Cadaver Skin Model". A hard copy and CD-Rom were both supplied.
Page 27 Docket No. 9318
Complaint Counsel ostensibly provided these documents to Dr. Eckel on or about July 1
2004. A letter reflecting Complaint Counsels' transmittal of these documents is sequentially numbered FTC 5426 and is attached to this Motion as Exhibit 5.
Among othcr things, Dr. Eckel's report states that the concentration of aminophylline in Dermalin-Apg, Cutting Gel, and Tummy Flattening Gel is and then, using the identical language used in the Protective Order, cites this formulation information as "('Restricted , Confidential-Attorneys Eyes Only " Eckel report , ~ 26.
This proprietary and trade secret formulation information was very clearly designated
RESTRICTED, CONFIDENTIAL - ATTORNEYS EYES ONLY, FTC DOCKET NO.
9318." It can be traced back to Exhibit "A" to respondents ' Answers to Complaint counsel' s First Set of Intcrrogatories on Behalf of Basic Research, LLC, A.
Waterhouse, LLC, Klein-Becker usa, LLC, Nutrasport, LLC, and Sovage Dermalogic
Laboratories, LLC, dated September 16, 2004 over a month after execution of the
Protective Order. A copy of Respondents ' Confidential formulation documents , as produced by Respondcnts, is filed under seal as Exhibit 6.
Dr. Eckel' s reference to the proper concentration of aminophylline, his reference to the same as confidential, combined with the date the formulation information was produced to Complaint Counsel, make clear that Complaint Counsel providcd Dr. Eckel with Confidential Material produced by Respondents and governed by the terms of the
Protective Order. However, just as they had failed to do with the highly confidential private, proprietar documents, and information provided to Dr. Heymsfield, Complaint
Counsel breached the express terms of the Protective Order by failing to provide
Page 28 Docket No. 9318
Respondents with any advance notice whatsoever that Confidential Material would be
disclosed to Dr. Eckel.
Had Complaint Counsel complied with the terms of the Protective Order and
provided Respondents with noticc of an intent to disclose Respondents ' confidential
documents and material to Dr. Eckel, Respondents would have timely objected and, if
necessary, would have pursued the issue with the Court, as Dr. Eckel is or has been
affiiated with several of Respondents , competitors in the weight loss industry, including
Merck and SlimFast. See , Dr. Eckel's curriculum vitae attached as Report 1 and
incorporated at Exhibit 4.
Respondents move, based upon these numerous instanccs of intentional deliberate and careless irregularities surrounding Complaint Counsels ' experts , Drs.
Heymsfield and Eckel, including several violations of the plain language of this Court'
Protective Order, and the severe prejudice flowing therefrom, that the Court grant
Respondents the relicf requestcd, including the striking of these witnesses. As explained below, this remedy is available and is the only fair way to deal with the incurable harm to
Respondents.
II. ARGUMENT SANCTIONS AGAINST COMPLAINT COUNSEL SHOULD BE IMPOSED FOR FAILING TO COMPLY WITH THE PROTECTIVE ORDER
Complaint Counsel should be sanctioned for violating the Protective Order. They should be held fully accountable for any acts, omissions or practices that violated the
Protective Order. The Court has this authority pursuant to 16 C.F.R. 93.38(b):
If a part or an offcer or agent of a party fails to comply... with an order including but not limited to , an order.. . of the Administrative Law
Page 29 Docket No. 9318
Judge,... the Administrative Law Judge or the Commission , or both... may take such action in regard thereto as is just, including but not limited to the following:
(1) Infer that the admission, testimony, documents or other evidence would have been adverse to the part;
(2) Rule that for the purposes of the proceeding the matter or matters concerning which the order or subpoena was issued be taken as established adversely to the part;
(3) Rule that the part may not introduce into evidence or otherwise rely, in support of any claim or defense, upon testimony by such party, offcer, or agent, or the documents or other evidence;
(4) Rule that the part may not be heard to object to introduction and use of secondary evidence to show what the withheld admission testimony, documents, or other evidence would have shown; and
(5) Rule that a pleading, or part of a pleading, or a motion or other submission by the part, concerning which the order or subpoena was issued, be stricken, or that a decision of the proceeding be rendered against the part, or both.
The AU plainly possess statutory authority to impose sanctions against
Complaint Counsel for violations of its Orders and the discovery rules. The Protective
Order herc violated by Complaint Counsel is a discovery order, and 16 C.F.R. 93.38(b)
, therefore, applicable. Failure to comply with an ALl's order may subject a violating part to contempt. 16 C. R. 9 3.42(h). There is wide latitude to determine whether there has been contemptuous behavior and wide latitude to determine proper sanctions.
Id.; Giford v. Heckler 741 F. 2d 263 , 266 (9th Cir. 1984).
The importance of protective orders and the role they serve in facilitating
discovery in litigation are widely acknowledged. Beam Sys., Inc. v. Checkpoint Sys.
1997 WL 364081 , *2 (C.D. Cal. 1997). Without such orders, litigants would be forced to choose between fully presenting their claims and/or defenses or forgoing such claims
Page 30 Docket No. 9318
and/or defenses in order to keep competitively sensitive, proprictary information
confidential. Id. Protective orders also preclude discovery materials from being used as
a sword through threats against a producing party that disclose confidential information.
Joy v. North 692 F. 2d 880, 893 (2d Cir. 1982). Accordingly, " it is essential that
protective orders be respected. Beam Sys. 1997 WL 364081 , *2. Whether a violation
of a protective order is merely careless or wilful is irrelevant. Improper disclosure
initiates potential loss of confidentiality. Carelessness cannot be tolerated when dealing
with protective orders and confidential information. In re Baycol Products Litgation
2004 WL 1052968 (D. Minn. 2004); see also Marrocco v. General Motors Corp. , 966
2d 220, 224-225 (7th Cir. 1992)(citing National Hockey League v. Metropolitan
Hockey Club, Inc. 427 U.S. 639 , 640 (1976) and noting "the Supreme Court has
expressly stated that sanctions may be appropriate in anyone of three instances--where
the noncomplying party acted either with wilfulness , bad faith or fault ). Parties must comply with the terms of (aJ protective order or subject themselves to possible
sanctions. American National Bank and Trust Co. of Chicago v. AX Client Solutions,
LLC 2002 WL 1067696, *3 (N.D. Il 2002) (emphasis added).
Respondents sought a Protective Order for a very specific and definite reason- protect valuable and confidential trade secrets and work product from being revealed to competitors. Complaint Counsels ' improper conduct , whether deliberate or merely the result of gross indiffcrence to the Court' s Order, caused the very harm Respondents sought to avoid and the Court sought to shield. Such serious and irreparable breaches should not be taken lightly. Complaint Counscls ' multiple violations of the Protective
Order justify sanctions, irrespective of whether the breaches were intentional or
Page 31 Docket No. 9318
incidental. The harm to Respondents is incalculable. The AU has the authority to
impose sanctions and they are unquestionably appropriate here. 16 C.F. R. 93.42(h).
Complaint Counsel violated a valid and binding Order that was clear and
unambiguous. As a result, Respondents have forever lost the opportnity to object
disclosure of the highly confidential and sensitive documents and materials provided in
good-faith to the Commission in response to its demands. Complaint Counsel failed to
exercise their responsibility and duty to restrict access to Respondents ' Confidential
Matcrials in accordance with the terms of the Protective Order when they provided those
materials to Drs. Eckel and Dr. Heymsfield. Moreover, had Complaint Counsel properly
complied with the Protective Order, Respondents would have objected to Drs. Eckel and
Heymsfield being permitted access to respondents' Confidential Material , as Drs. Eckel and Heymsfield have been and currently are affliated with Respondents' competitors in the weight loss product industry, including Merck, a pharmaceutical company with an entire division dedicated to obesity.
Due to Complaint Counsels ' grievous breaches of the Protective Order
Respondents' product formulations have been provided to at least one direct competitor of Respondent. Of course Complaint Counsels ' experts were also in possession of this same material when conducting or assisting in studies for other direct and indirect competitors of Respondents and involving products that may compete directly with
Respondents' products. This creates a clear conflict of interest for both Dr. Eckel and Dr.
Heymsfield and it is simply impossible to "un-ring the bell."
Even after violating the terms of the Protective Order and providing confidential documents and materials without notice to Respondents, Complaint Counsel clearly
Page 32 Docket No. 9318
failed to properly educate their own experts concerning the importance of the Order and
the gravity of potential breaches. Dr. Heymsfield' s testimony is evidence of that very
point.
Several potential sanctions are made available to the Court under 16 C.F.R. 9
38(b) for violations of discovery ordcrs. These provide some guidance to the AU, who
must ultimately dctcrmine exactly which sanctions are suitable here. Striking Drs. Eckel
and Dr. Heymsfield and entirely excluding them from these proceedings is appropriate and warranted, as Complaint Counsels' multiple violations and breaches of the Protective
Order and other discovery rules spccifically relate to these two witnesses. Moreover
Drs. Eckel and Heymsfield cannot be considered truly independent experts given their past and current affliations with Respondents ' direct and indirect competitors- including, as noted above, employment of one of the experts by a direct competitor for
the express purpose of getting competing products to market. See also Beam Sys. , 1997
WL 364081 (excluding plaintiffs expert witness after disclosure of defendant
Confidential Materials to expert who had a past and ongoing business relationship with
plaintiff); Pride v. BIC Corp 218 FJd 566 (6 Cir. 2000) (excluding expert witness testimony and staying discovery due to plaintiffs violation of protective order and late- disclosed expert testimony and staying discovery due to plaintiffs violation of protective order and late-disclosed expert testimony).
Given the gravity of the violations, the seriousness of the injury and the inability to fairly cure the harm, Respondents respectfully submit striking these witnesses is the only remedy adequate here.
Page 33 Docket No. 9318
COMPLAINT COUNSEL SHOULD BE ORDERED TO SUBMIT A SWORN DECLARATION.
The full scope of Complaint Counsels ' breaches of the Protective Order is
unclear and unkown to Respondents. Respondents werc unaware that Drs. Eckel and
Heymsfield would be provided access to their Confidential Materials. Additionally, it is
unclear exactly which confidential documents and other materials may have been
disclosed to them or to other third parties. From the face of Dr. Eckel' s report it is clear
that Complaint Counsel reproduced at least some of Respondents ' confidential
documents and materials, also in violation of Paragraph 7 of the Protection Order, which
prohibits unauthorized copying or reproduction of the same. Dr. Heymsfield' s deposition
conclusively establishes the same with respect to other documents, as Dr. Heymsfield
acknowlcdges that he received from Complaint Counsel many documents marked
Confidential" by Respondents. Complaint Counsels' carelessness must not be condoned
or ignored. Respondents ' confidence in Complaint Counsels ' ability to properly handle
and safeguard their Confidential Materials must be restored. The Court has and should
exercise the authority, under 16 C. R. 9 3.42(h) to restore that confidence and provide
some measure of certainty concerning the scopc and breadth of the violations.
In order to determne the extent of Complaint Counsels ' breaches of the
Protective Order to date, Respondents move that Complaint Counsel be required to submit a sworn declaration detailing in specific terms: (a) their handling of Respondents protected confidential information; (b) the measures undertaken by Complaint Counsel to safeguard that information and comply with the Court' s Protective Order; (c) the identities of all individuals who were provided access to or copies of the protected information; and (d) detailing the full scope of their violations of the Protective Order.
Page 34 Docket No. 9318
II. CONCLUSION Complaint Counsel clearly violated the plain, unambiguous language of the
Court' s Protective Order, and the FTC' s experts failed to comply with the discovery
rules. As a result, Respondents respectfully request an Order from the Court pursuant to
16 C.F. R. 9 3.38(b) and 16 C.F. R. 9 3.42(h), that: (1) sanctions Complaint Counsel for
their deliberate or grossly indifferent breach of this Court' s Protective Order by excluding
from these proceedings the two expert witnesses, Dr. Eckel and Dr. Heymsfield, to whom
Complaint Counscl impropcrly provided Respondents ' confidential information; (2) commands the return to Respondents from Drs. Heymsfield and Eckel of all documents in their possession marked or designated confidential, together with sworn affdavits affrming that reasonable efforts were made to confirm that no additional copies, either electronic or in hard form, exist, and that to their knowledge no other person has had access to the materials while in their possession; and (3) requires Complaint Counsel to fie a declaration or sworn affdavit detailing in specific terms; (a) their handling of
Respondents ' protected confidential information, (b) the measures undertaken by
Complaint Counsel to safeguard that information and comply with the Court' s Protective
Order, (c) the identities of all individuals who were provided access to or copies of the protected information, and (d) detailing the full scope of their violations of the Protective
Order.
Alternatively, should the Court be disinclined to strike Dr. Heymsfield and Dr.
Eckel from these proceedings, Respondents request the declaration from Complaint
Counsel described above in addition to an Order from the Court commanding: (1) Dr.
Heymsfield to make available immediately all documents in his possession responsive to
Page 35 Docket No. 9318
Respondents' subpoena as well as those documents this Court has required experts in this case to produce; (2) Complaint Counsel to make Dr. Heymsfield available for two days of questioning, following adequate opportunity for Respondents to review and digest the documents we have yet to receive from Dr. Heymsfield or Complaint Counsel, to ensure
Respondents have a full and fair opportunity to rcsume and conclude their deposition; (3)
Complaint Counsel to reimburse Respondents ' costs and fees for conducting a second deposition; and (4) setting a new date, ten days after completing Dr. Heymsfield' deposition, for Respondents to respond to Complaint Counsels ' motions for summary decision, in order to ensure a fair opportnity to respond to the arguments, issues and evidence presented therein, at least some of which will undoubtedly be based upon Dr.
Heymsfield' s opinions.
The relief requested is necessary to sanction Complaint Counsel for their improper conduct, and to remedy, to the extent possible, the harm and prejudice caused to
Respondents by Complaint Counsel and their witnesses.
Page 36 Respectfully submitted
Jef e' D. Feldman Todd M. Malynn Gregory L. Hillyer Christophcr P. Demetriades
Feldman Gale, P. Miami Center, 19 Floor 201 South Biscayne Blvd. Miami, Florida 33131 Tel: (305) 358-5001 Fax: (305) 358-3309
Attorneysfor Respondents Basic Research, LLC, A. G. Waterhouse, LLC, Klein-Becker USA , LLC, Nutrasport, LLC, Savage Dermalogic Laboratories, LLC and Ban LLC ' :, ;: :-=
DATED this ZiJ dayoLJc""jOl' 2005.
BURBIDGE & MITCHELL
Richard D. Burbidge Attorneys for Respondent Dennis Gay ,,/,
Respectfully Submitted
Ronald F. Price PETERS SCOFIELD PRICE A Professional Corporatio 340 Broadway Centre
111 East Broadway Salt Lake City, Utah 84111 Telephone: (80l) 322-2002 Facsimile: (801) 322-2003 E-mail: rfp(2psplawyers.com
Attorneys for Respondent Daniel B. Mowrey c//t:/ Mitchell K. Friedlander c/o Compliance Deparment 5742 West Harold Gatty Drive Salt Lake City, Utah 84116 Telephone: (801) 414- 1800 Facsimile: (801) 517-7108
Pro Se Respondent :," " ),/:. : '" " '" "
CERTIFICATE OF SERVICE
I HEREBY CERTIFY that a true and correct copy of the foregoing Motion to Strike was provided to the following parties this day of January, 2005 as follows:
(1) One (1) original and two (2) copies by Federal Express to Donald S. Clark Secretary, Federal Trade Commission, Room H- 159, 600 Pennsylvania Avenue, N. Washington, D. , 20580;
(2) One (1) electronic copy via e-mail attachment in Adobe pdf' format to the Sccretary of the FTC at Secretarv(cftc. gOv;
(3) Two (2) copies by Federal Express to Administrative Law Judge Stephen 1. McGuire, Fedcral Trade Commission, Room H- I04, 600 Pennsylvania Avenue N. Washington , D. C. 20580;
(4) One (I) copy via e-mail attachment in Adobe pdf' format to Commission Complaint Counsel , Laureen Kapin, Joshua S. Millard, and Laura Schneider, all care of lkapin(Ljjtlc. gov imillard(LiUkgov rrichardson(Luftc. gOv Ischneider(Luftc. gOv with one (1) paper courtesy copy via U. S. Postal Scrvice to Laureen Kapin, Bureau of Consumer Protection Fcderal Trade Commission, Suite NJ-2122 , 600 Pennsylvania Avenue , N. , Washington, D. 20580; (5) Onc (1) copy via U. S. Postal Service to Elaine Kolish, Associate Director in the Burcau of Consumer Protection, Federal Trade Commission, 600 Pennsylvania Avenue , N. Washington , D. C. 20580
(6) One (I) copy via United States Postal Service to Stephen Nagin , Esq. , Nagin Gallop & Figueredo, 3225 Aviation Avenue, Suite 301 , Miami, Florida 33131.
(7) One (I) copy via United States Postal Service to Richard Burbidge , Esq. Jefferson W. Gross, Esq. and Andrew J. Dymek, Esq., Burbidge & Mitchell, 215 South State Street, Suite 920, Salt Lake City, Utah 84111 , Counsel for Dennis Gay.
(8) One (I) copy via United States Postal Service to Ronald F. Price, Esq. , Peters ScofielcrPrice, A Professional Corporation, 340 Broadway Centre, 111 East Broadway, Salt Lake City, Utah 84111 , Counsel for Daniel B. Mowrey.
(9) One (I) copy via United States Postal Service to Mitchell K. Friedlander, 5742 West Harold Gatty Drive, Salt Lakc City, Utah 84111 Pro Se.
CERTIFICATION FOR ELECTRONIC FILING I HEREBY CERTIFY that the electronic version of the foregoing is a true and correct copy of the original document being filed this same day of January, 2005 via Federal Express with the Offce of the Secretary, Room H- 159 , Federal T?de Commission, 600 Pennsylvania Avenue, N. , Washington, D. C. 20580. ------
UNITED STAT S OF AMERICA
BEFORE THE FEDERAL TRADE COMMISSION
OFnCE OF ADMINISTRATIVE LAW JUDGES
Tn the Matter of
BASIC RESEARCH , L. A. G. WATERHOUSE, L. L. C. , KLEIN- BECKER USA , L. NUTRASPORT, L. L. C., SOVAGE DERMALOGIC Docket No. 9318 LABORATORIES, L. L. C. / BAN, L. L . C . DENNIS GAY, DANIEL B. MOWREY , and MITCHELL K. FRIEDLANDER
Respondents. - - X
VIDEOTAPED DEPOSITION OF
STEVEN B. HEYMSFIELD
New York , New York
Tuesday, January 11, 2005
Reported by: Thomas R. Nichols, RPR Toni Allegrucci JOB NO. 168691
EXHIBIT January 2005
9:25
Videotaped Deposition of Expert
Witness, STEVEN B. HEYMSFI held
at the offices of Esquire Deposition
Services, 216 East 45th Street
New York , New York , pursuant to
Subpoena, before Thomas R. Nichols,
Registered Professional Reporter and
Toni Allegrucci Notaries Public of the
State of New York. A P PEA RAN C S S:
UNITED STATES FEDERAL TRADE COMMISSlON
BUREAU OF CONSUMER PROTECT ION
DIVISION OF ENFORCEMENT
600 Pennsylvania Avenue, NW
Washington, DC 20580
BY: ROBIN M. RICHARDSON , ESQ.
LAUREEN KAPIN , ESQ.
WALTER C. GROSS , III , ESQ.
JOSHUA S. MILLARD, ESQ.
FELDI",AN GALE
Attorneys for Respondents
201 South Biscayne Boulevard
Miami , Florida 3313J
BY: JEFFREY D. FELDMAN, ESQ.
BURBIDGE & MITCHELL
Attorneys for Respondent Dennis Gay
215 South State Street
Salt Lake City, Utah 84111
BY: ROBERT J. SHELBY, FSQ. APPEARANCES (CONT' D.
PETERS SCOFIELD PRICE
Attorneys for Respondent Daniel B. Mowrey
340 Broadway Centre
111 Eas t Broadway
Salt Lake City, Utah 84111
BY: RONALD F. PRICE, ESQ.
ALSO PRESENT:
MITCHELL K. FRIEDLANDER, PRO SE
DANIEL MOWREY ._- " , - - . "
SUBPOENA DUCES TECUM Issued Pursuant to Rule 3.34(b), 16 C. R. !: 3. 34(b)(1997)
1. TO 2. FROM Steven B. Heymsfield , M. St. Luke ' s- Roosevel t Hospital UNITED STATES OF AMERlCA Obesi ty Research Center FEDERA TRAE COMMISSION 1090 Amsterdam Avenue # 14C ew York NY 10025 This subpoena requires you to produce and permit inspection and copying of designated books , documents (as defined in Rule 3.34(b)), or tangible things - or to permit inspection of premises - at the date and time specified Item 5 , at the request of Counsel listed in Item 9, in the proceeding described in Item 6.
3. PLACE OF PRODUCTION 4. MATERIAL WILL BE PRODUCED TO Peters Scofield Price Peters Scofield Price 111 East Broadway, Suite 340 A Professional Cor oration Salt Lake City, Utah 84111 5. DATE AND TIME OF PROOUCTION OR INSPECTION Monday, December 6, 2004
6. SUBJECT OF PROCEEDING
In the Matter of Basic Research, LLC, et. al., Docket No. 9318
7. MATERIAL TO BE PRODUCED SEE EXHIBIT A In lieu of production at the above place, documents may be produced by return mail bn or before December 6 , 2004 , to Ronald F. Price at Peters Scofield Price , 111 East Broadway, Suite 340, Salt Lake City, UT 84111-
B. ADMINISTRATIVE LAW JUDGE 9. COUNSEL REOUESTING SUBPOENA Peters Scofield Price The Honorable Stephen J. McGuire A Professional Corporation
Federal Trade Comm1$ 16rl Washington C:\ 20580 " . l 7' DATE ISSUED "
6!t2,!i R 0 , t 95; n , GENERAL INSTRUCTIONS
APPE;ARANCE. 1\1 TRAVEL EXPENSES J. The deliveryof'hls subpoena to you by, ,,riY method The Commission s Rules of Practice require that fees and prescribed by- the Commission s R les' Qf,Practice is mileage be paid by the part that requested your legal service and may'subject you to ;3 penalty appearance. You should present your claim to counsel imposed by law forfailuie td comply. listed in Item 9 for payment. If you are permanently or temporarily living somewhere other Ihan the address on MOTION TO LIMIT OR QUASH this subpoena and it would require excessive travel for you to appear, you must get prior approval from counsel The Commission s Rules of Practice require that any listed in Item 9. motion to limit or quash this subpoena be fied within the earlier of 10 days after service or the time for compliance. The original and ten copies of the petition must be fied with the Secretary of the Federal Trade Commission, accompanied by an affdavit of service of tneaiicumenfupon counsel liS-tea ;nltem. upOri---...-1'fifs- ;;bpoen adoesnot qui reapproval byOf",fs under ail other parties prescribed by the Rules of Practice. the Paperwork Reduction Act of 1980.
FTC Form 70.8 (rev. 1/97) + ------___ ------___.--,,-----
RETURN OF SERVICE
I hereby certify that duplicate original of the within subpoena was duly served: (check Ite melhrJd used)
in person.
by registered mai!o
by leaving copy at principal offce or place of business, to wi
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on the person named herein on:
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(Namearpe Dn.rrakingsErVce)
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Docket No. 9318
EXHIBIT A
Your complete file relafed to fhis matter. 2. All correspondence with the Federal Trade Commission concerning this matter regardless of whether you were the aufhor, addressee or copy recipient.. 3. All correspondence with any individual or entity of her than the Federal Trade Commission concerning this matter regardless of whefher you were the author, addressee or copy recipient.
All reports prepared by you in connecfion with your work on this matter. 5. All drafts of all reports prepared by you in connection with your work on this matter.
All documents reviewed by you in connecfioh with your work on this matter. 7. All maferials consulted by you or relied on by you in forming any opinion in connection with this matter.
All documents thaf you have ever authored or confributed to regarding:
obesity weighf loss falloss fhe Federal Trade Commission clinical trial protocol or procedures the definifion of " competent and reliable scienfific evidence Federal Trade Commission advertising rules' and regulafions dietary supplements eightioss-oriatioss" advertsing . 9. All documenfs relating to lecfures, speeches or tesfimony that you have ever given relafing to:
obesity weighf loss fat loss clinical frial protocol or procedures the Federal Trade Commission ------_._ -"- . -.. .- - - - -, - - , - . - _.__._ _- _._- , _. ------. -. --- - .. --,---_._ --- _.- --.-.----
Docket No. 9318
the definifion of "compefent and reliable scienfific evidence Federal Trade Commission advertising rules and regulafions dietary supplements weight loss or faf loss advertising. 10 All documents relafing to medical or clinical studies or fesfs that you have conducted or contributed fon or participated relating fo or involving:
obesity weighf loss fat loss dietary supplements
11. All patents and patent applications (whefher or not published or pending review by the United Sfafes Pafent and Trademark Offce) in which you are named as an inventor or pafent owner or assignee of any invenfion relating to:
obesity weight loss , c. fat loss dietary supplements
12. All documents relating to lawsuits, whether criminal or civil , in which you were named as a party.
13. All documents pertaining fo work that you have performed for any company that manufactures , markets or sells pharmaceuficals or dietary supplements relating. fo:
obesity weighf loss faf loss
14. All documents relating to weight loss or faf loss advertisements that yrnrilave-QuflTred ewu-uppTOVB1:1181atingtoyweig1o- s or af 10ss product.
15. All documents relating fo requesfs for approval that you have made fo the FDA, FTC or any ofher regulatory body, eifher on behalf of yourself or some other third party, relating to advertising or package labeling claims thaf you soughf to make in relation fo any weight loss or faf loss product.
16. All documents relafing to efforts by you, either on your own behalf or on behalf of any other fhird party or parties, to justify or substanfiafe -_._ - - - -
Docket No. 9318
advertising claims made in relation ,to any weight loss or faf loss product including but not limited to pharmaceutical products or dietary supplements.
17. All documents pertaining to work that you have periormed for the Federal Trade Commission , The Food and Drug Administration or any other federal agency, whether as an expert, consultant or in any other capacity, relating to: ,
obesity weight loss fat loss the Federal Trade Commission clinical trial protocol or procedures the definition of "competent and reliable scientific evidence Federal Trade Commission advertising rules and regulations dietary supplements weight loss or fat loss advertising.
18. All scientific and/or medical testing protocols you have authored.
19. All scienfific and/or medical testing protocols on which you have provided comments, including your comments.
20. All documents which the Federal Trade Commission , including Complaint Counsel in this matter, has provided to you in connection with this matter.
21. All documents , including drafts, which you have provided to the Federal Trade Commission , including Complaint Counsel in this matter , in connection with fhis matter.
22. All notes of any meefings and/or telephone conversations and/or any other communicafions you have had with fhe Federal Trade Commission including Complaint Counsel in this matter, and/or any of her entity or person , in connection with this matter.
23. All records and documents of whatever kind reflecting side effects experienced by subjects in control or placebo groups during the sfudy fifled Weight Control and Risk Factor Reduction in Obese Subjects Treated for 2 Years with Orlistat: A Randomized Confrolled Trial a copy of which is attached as Exhibit A. You may provide redacted records or documents redacting identifying information concerning the tesf subjects including but not limited to name address, telephone number, social security number or similar. Docket No. 9318 24. All records and documents of whatever kind reflecting comments by subjects concerning or related to any side effects experienced by subjects in the control or placebo group during the study titled Weight Control and Risk Factor Reduction in Obese Subjects Treated for 2 Years with Orlistat: A Randomized Confrolled Trial a copy of which is attached as Exhibit A. You may provide redacted records or documents redacting identifying information concerning fhe test subjecfs including but not limited to name , address , telephone number social security number or similar. REPORT OF ROBERT H. ECKEL, M.
To thc mattcr of Basic Rcsearch ct aI, Dockct #9318
Robert H. Eckel , MD. hereby rcports as follows:
QUALIFICA TlONS r am a Doctor of Mcdicine and am board certified in both Internal Medicine and Endocrinology and Mctabolism. I rcceived my M.D. dcgree from the University of Cincinnati in 1973 graduating as a membcr of the honorary medical socicty Alpha Omcga Alpha. I am licensed to practice medicine in the state of Colorado.
My current appointment is Professor of Medicinc in thc DIvision of Endocrinology, Metiibolism and Diabetes and in the Di vision of Cardiology at the Uni vcrsity of Colorado Health Sciences Centcr (UCHSC) in Denver/Aurora, Colorado. I also have a joint appOintment in the Department of Physiology and Biophysics at UCHSC and an adjunct appointment as Professor of Food Sciencc and Human Nutrition at
Colorado State University i n Ft Collins, Colorado.
I receivcd my undergraduatc degree (BS) in Bacteriology in 1965 (with Honors) from thc Uni versity of Cincinnati. Following medical school I trained (internship and residency) in Internal Medicine at the Univcrsity of Wisconsin Hospitals in Madison Wisconsin (1973- 1976) with a research and clinical fellowship in Endocrinology and Metabolism at the University of Washington in Seattle, Washington (1976- 1979).
My research has focused predominantly on fat metabolism. For almost 30 years of academic pursuit, my science has included studies in the laboratory at the level of: a) DNA and RNA
b) biochemistry
c) cell biology
d) animals e) human subjects and
f) human populations , nutrition g) Related studies have included investigations on weight regulation , and diabetes obesity, insulin resistance, lipid and lipoprotein metabolism mellitus. In my years of research, I have been eontinuousl y funded by the National Institutes of Health (NIH) in addition to support from other professional organizations (Juvenile , American Diabetes Association) Diabetes Foundation , American I-Icar Association doctoral fellows for 27 consecutive years , trained 29 graduate students or post- . published 138 peer reviewed aricles, numerous editorials, book chapters and reviews entitled and near' y 200 abstracts'- Among the most quoted articles is a paper Enzyme Related to Common Metabolic Lipoprotein Lipase: Multifnctional
Seminar from the Beth Israel Hospital Diseases that was published as an invited in 1989. New England Journal of Medicine Harvard Medical School in the
, Journal 1 presentl y serve on the editorial boards of the American Journal of Medicine , Thrombosis and Vascular of Endocrinology and Metabolism, Arteriosclerosis
and Obesity Research. 1 have reviewed Biology, The International Journal of Obesity, Nature, Science, Proceedings of the journal articles for 69 medical journals including and the National Academy of Sciences, Journal of the American Medical Association
New England Journal of Medicine. I have been asked to write many editorials, book Obesity: Mechanisms and chapters , and am proud to have recently edited a book on , Williams and Wilkins, 2003. This Clinical Management published by Lippincott book has been widely circulated and also received reviews in major medical
and Tne Lancei. periodicals, i. e. the New England Journal of Medicine
Over my career, there have been increasing examples of recognition of my accomplishments in the fields of weight regulation, obesity and nutrition. the last 25 years by the a) Again, 1 have been continuously supported by for NU-r This funding has been in the form of at least one, and sometimes up to
three RO 1 grants. RO 1 grants through the NIH are the major mechanism by which biomedical research scientists are supported by the Federal reviewed by government. These grants are highly competitive being peer- specific study sections prior to further consideration by one or more of the 27 scientific institutes at the NUL Typically, award rates are in the range of 20- 25%. b) In 1987, I was promoted to Professor of Medicine at UCHSC and also elected two very prestigious societies - The American Society for Clinical Investigation in 1987 and The Association of American Physicians in 1999. c) In 1989 , I was asked to join the NIl! Nutrition Study Section and became their
chairman from 1991- 1993 d) Since 1991 , I have been the Program Director of the National Center for Research Resources (NCCR) of the NIH funded Adult General Clinical Research Center at the UCHSC. e) From 1997 to the present, I have been the Associate Director of the UCHSC Center for Human Nutrition. f) I have been the Vice Chair for Research in the Department of Medicine since 1998. g) In 200 I I was honored as the recipient of the Charles A. Boettcher II Endowed Chair in Atherosclerosis.. h) In 1996, Ijoined thc Nutrition Commttee of the American Hear Association (AHA) and in 1999 became chairman of the committee. In 2002 I would becomc the second chairperson of the Scientific Council on Nutrition , I Physical Activity and Metabolism (NPAM) of the Al-I and in July 2004 assumed the penultimate position as President Elect of the AHA with my Presidency to begin in July 2005. i) In 2001, I was asked by the National Hear, Lung and Blood Institute (NHI) and National Institutes of Diabetes, Digestive and Kidney Diseases (NIDK) at the NIH to chair a working group on the pathophysiology of (Circulation 2002). In 2002 I obesity- associated cardiovascular diseases joined the NIDDK Advisory Council, a term that lasts until 2006. In this position, I am one of twelvc extramural academicians providing advice about NIDDK grants to be awarded and programmatic dcvelopment in fields related , I was also appointed to the mission of the institute including obesity. In 2002 , a working group that helps to the NIDK Clinical Obesity Rescarch Pancl cstablish policy relating obcsity science to the populati
j) (n 1996 , I was Prcsident of thc North American Association for the Study of Obesity (NAASO), an organization that 1 continue to support with my scicncc.
of the uptake and My rcsearch has focuscd on the tissue spccific regulatio metabolism of circulating fatty acids into tissucs including adipose tissue (fat) and skeletal muscle. Once thc circulating fatty acids are stored in tissucs as triglycerides Once these depots of fat can breakdown (lipolysis) and again produce fatty acids. generated, fatty acids can again bc released into the circulation (from adipose tissue) or burned (from musclc). In my laboratory, we havc uscd cultured fat cells and muscle cells , fat pieces obtained from whole animals (mice and rats) and humans to study this process. In this regard, I feel that ( am in a strong position to comment on how body fat is regulated.
This Perhaps thc most exciting observation in my research carecr was in thc J 980s. lived in animals and rclated to thc important fact that weight loss is often short- humans. Whcn my group examined obese subjccts three months aftcr a 13% wcight reduction, we discovered that the enzymc that controls thc uptake of lipoprotei (LL) was not only not derivcd fatty acids into adipose tissuc, lipoprotein lipase decreased, but increased with an exaggerated increase to the infusion of insulin and 1987). Subsequent studies would document that LPL in meal ingestion (1 Clin InVlst,
(Eur Clin Invest skeletal muscle was decreased in humans aftcr weight reduction 1995). These observations would establish one mechanism by which an incrcase in of the fat mass and weight food intake in the reduced state could lead to expansio regain. These studies complemented existing knowledge from animal experiments and helped to establish the current recognition of obesity as a lifelong disease. 10) For nearly 30 years now , I have designed numerous experiments that are aimed at testing hypotheses. Studies in animals and humans are similar in that control groups , drug or other clinical perturbati are necessary to determine the effect of any diet the outcome. To be successful, studies must be designed based on the number of is a pre- animals or humans needed to satisfy statistical significance. Built into this existing knowledge of the varability of the measurements that will be employed. Only with careful consideration of all of these scientific principles will hypothes rigorously tested.
s attached (Report 1). 11) A copy of my most recent Currculum Vitae i
12) In summary, I believe my career in biomedical research provides a strong foundation of education, training, and experience in the area of fat metabolism and weight regulation including the biology of adipose tissue to serve as an expert witness in this case. My science has extended from DNA to molecules to cells to animals to human subjects to populatio . The quality of my work has been recognized by years of , and consecutive funding, numerous peer reviewed publications and leadership roles on the election to a number of prestigious professional societies. My positio AH are recent NlDDK Advisory Council and upcoming Presidency of the reflections of this credibility.
INFORMATION ANALYSIS OF PRODUCT
13) I have been asked by attorneys from the Division of Enforcement of the Federal scientific validity of Trade Commission (FfC) to assist them in dererrning the doing business claims made by BasicResearch LLC, a limited liability corporatio with other corporations and laboratories, that a) "Dermalin-Apg causes rapid and visibly obvious fat loss in areas of the body to which it is applied" (Complaint 'l14); b) "Cutting Gel causes rapid and visibly obvious fat loss in areas of the body to which it is applied" (Complaint 'l17); c) ' 'Tummy Flattening Gel causes rapid and visibly obvious fat loss in areas of the body to which it is applied" (Complamt 'J20); d) "Published, clinical testing provcs that Cutting Gel causcs rapid and visibly obvious fat loss in areas of the body to which it is applied" (Complaint 'J23); and e) "Published, clinical testing provcs that Tummy Flattening Gcl causes rapid and visibly obvious fat loss in areas of the body to whieh it is applied" (Complaint 'J25)-
provided the following 14) The staff of thc Fedcral Trade Commssion (FC) have L (product advertisemcnts); materials for my review: Complaint and Exhibits A- TUMM FLATTENING GEL" Respondents' CLAIM SUBSTANTIATION FOR " ; Respondents Respondents' CLAIM SUBSTANTIATION FOR DERMALlN Apg ; DermTcch report dated CLAIM SUBSTANTIATION FOR "CUTING GEL" in vitro 6111/03 titled "Evaluation of the Percutaneous Absorption of Aminophylline Using the Human Cadaver Skin Model"; DennTech report dated 9/01102 titled in vitro, Using thc Detennnation of the Percutaneous Absorption of Aminophylline Human Cadaver Skin Model"; and DermTech repOlt dated 12/06/01 titled in vitro, Using the Evaluation of the Percutaneous Absorption of Aminophylline Rom were both supplied. Human Cadaver Skin Model" - '\ hard copy and CD-
15) The report to follow is based on my review of the materials provided to me by the , published aricles that I FTC including documents from Basic Research LLC et aI have retrieved following my review of the relevant medical literature through the
(PubMed), and my knowledge and cxpn-ience in the National Library of Medicinc scientific field of regional and whole body fat metabolism. I reserve the right to review additional documents that become available and modify my rcport accordingly. My compensation is $500.00 per hour.
Reviewed articles: Caruso MK, Pekarovic S , Raum WJ , and Greenway F. Topical fat reduction from the waist. Manuscript status unclear. Collis N, Elliot L- , Sharpe C , ani: Sharpe DT. Cellulite treatment: A myth or reality: A prospective randomizcd, controlled trial of two therapies, Endermologic and 104: 1110- 1114, 1999. aminophylline cream. Plastic and Reconstructive Surg Obesity: Eckel RH. Obesity: A disease or a physiologic adaptation for survival? In: , Williams and Mechanisms and Clinical Management Eckel RH, editor; Lippincott Wilkins , pp 3- , 2003. Greenway FL and Bray GA. Rcgional fat loss from the thigh in obcse women after
adrcnergic modulation. Clin Ther9:663-6(j9 , 1987.
Ohes Res 3:561S-568S Greenway FL, Bray GA , and Heber D. Topical fat reduction. 1995. Lesser T, Ritvo E, and Moy LS. Modification of subcutaneous adipose tissuc by a DennalOl Surg 25:455- methylxanthine formulation: A double- blind controlled study. 462, 1999. TM - A lecithin- based Mowery D. Evaluation of the pcrcutaneous absorption pf Epidril
aminophylline gel in vitro, using thc human skin model: A review of research conducted by Paul Lchman , M.Sc. Manuscript status unclear. , metabolism and site of Muller B , Kasper M, Surber C , and lmanidis G. Permeation action concentration of nicotinic deri vati ves in human skin. Correlation with topical 20: 181- 195 , 2003. pharacological effect. Eur Journal Phannaceut Sci
SUMRY OF HNDlNGS
16) I find no evidence to support that a) "Dermalin-Apg causes rapid and visibly obvious fat loss in areas of the body to which it is applied" b) "Cutting Gel causes rapid and visibly obvious fat loss in areas of the body to which it is applied" c) "Tummy Flattening Gel causes rapid and visibly obvious fat loss in areas of the body to which it is applied" d) "Published, clinical testing proves that Cutting Gel causes rapid and visibly ; or obvious fat loss in areas of the body to which it is applied" e) "Published, clinical testing proves that Tummy Flattening Gel causes rapid and visibly obvious fat loss in areas of thc body to which it is applied"
DETAILED ANALYSIS
17) I'd like to set the stagc for my review of whether the evidence supports the claims of Basic Rcsearch LLC by an ovcrview of adipose tissuc (fat) metabolism. This summary will provide support for thc concept that body fat is rcgulated and defendcd against depletion.
- Adipose Tissue Metabolism
(8) Adiposc tissuc (fat) is formed in the fetus during thc 3'" trimcstcr of prcgnancy, and throughout life has a number of critical roles. Ccrtain pcriods of development such as puberty arc dcpendcnt on thc presence and quantity of adipose tissue. The defense of body fat speaks to thc Importance of adipose tissue fuel reservcs in providing the nccdcd energy when food deprivation occurs. Although this role of adipose tissue " century, even in the may be less rclevant in the increasingly obesc world of the 21 th century data from the famines of the world wars support the contention that the
Obesity, Eckel, Lippincott amount of adipose tissue is a survival advantage (Eckel , In
Williams and Wilkins, 2003).
, i.e. an organ a) Today, adipose tissue is also recognized as an endocrine organ that secretcs hormones or proteins that have cffects on other tissues. Substances that are made by fat that have an impact elsewhere in the body plasminogen activator inhibitor- include leptin, adiponectin , angiotensin
(P AI- I), and cytokines. Leptin communicatcs information to thc brain about the amount of adipose tissue , adiponectin increases the effects of insulin in muscle and liver, angiotensin II produces constriction of blood vessels, P Al- , and cytokines are impedes the process by which blood clots are dissolved involved in the inflammatory response to forcign organisms and/or injury. relate to the function of adipose Thus , impO!1ant aspccts of the biology of life , many of tissuc. Moreover, when fat mass increases in amount and volume these functions become disrupted and/or contribute to the adverse , hypc!1ensio . an consequcnces of obesity including insulin resistance increased tendency to clot blood, and tissue damage (livcr diseasc athcrosclerosis - coronary hear disease, stroke - as a result of the cytokine burden).
of Adipose Tissue Regionalization
19) The regionalization of body fat is sex depcndent and controlled by the relative
quantity of sex steroids , i.e. estrogcns and androgcns. Othcr hormones may also be influential, e. g. the adrenal hormone conisol (hydrocortisone). Whcn high levels of as a drug, cortisol are produccd by the adrenal gland or by taking hydrocortiso , with depletion of excessive fat is deposited centrally, i.e. around the waist and trunk fat stores in the ars and legs. This type of excessivc fat distribution is also seen in other conditions, e. g. in patients with human immunodeficiency virus infection, paricularly when treatment with anti-rctroviral drugs cnsues. Genetics also appear to be involved. Recently, up to 30 genes have been identified in humans that relate to body fat distribution. At present, the genetic influence is at the level of association only, however, I'm sure that in the next few years more science will add to the
relevance of man y of these genes.
Regulation of fat cells
20) Fat cells are filled with triglycerides, storage molecules produced from fatty acids and glucose. These fatty acids are for thc most par delivered to fat from circulating paricles called lipoproteins that are produced by the liver and the intestine after
eating. This uptake of lipoprotein-derived fatty acids by fat tissue is controlled in par , thes triglyceride molecules are acted by insulin. During periods without food intake upon by the enzyme honnone sensitive lipase that facilitates the breakdown of the triglyccrides back to fatly acids. These fatly acids then leave the fat cells and travel to othcr organs to be utilized for criergy. This proccss is regulated by a number of honnones such as adrenaline (epinephrine).
21) The numbcr of fat cells is determined during critical periods throughout life including in utero during mfant fecding, pubcrty and after largc amounts of weight gain. What , but when fat cells reach a maximum regulates the number of fat cells is not clear volume, new cells are fonned.
Defense of body fat
. man or woman and 22) Body fat is maximized by the important interaction between a their environment. Today, thc environment has been sufficiently modified to morc easily enhance thc dcvelopment of obesity with the appropriate genetic predispositi . The failure of forced overfeeding studies to cause obesity in humans 322: 1477- , 1990) and the lack of (Bouchard C et ai New England Journal Med
Int.J Obes 21:941-947 1997) sustained weight loss in most dietcrs (Millcr WC et ai, ons for this recidivism support the biology of body fat maintenance. Many explanati , increase in appetitc and after weight reduction include the fall in basal metabolic rate , rcduction in physical activity, and a preference for fat and sugar containing foods change in mctabolism that favors carbohydrate (not fat) burning, and therefore fat , Lippincott, Williams and Wilkins, 2003). The storage (Eckel , In Obesity, Eckel long-tenn success of a weight loss program depends on continuous attention to the Obes Res 7:334-341 amount of food intake and physical activity (McGuire MT et ai 1999).
23) Alternatively, the surgical removal of adipose tissue in rodents is typically followed Neurosis Biobehav Rev by re-accumulation of adipose tissue (Mauer MM et ai,
25: 15- , 2001). In humans, it is unclear whether surgical removal of subcutaneous fat has lasting effects, but in studies we did in which regional subcutaneous fat was removed by liposuction , re-accumulation of subcutaneous fat occurred locally or elsewhcre by onc year if a lifestyle modification (diet and/or excrcise) was not 92: 1101- 1108, 1993). employed (Yost ct ai Plast Recon';tr Surg
CLINICAL TRIAL DESIGN
24) To dctennne whether a drug works to favorably modify a dtseasc state or a physiologi paramcter, pre-clinical studics in animals need to establish the efficacy of the compound, in addition to a safety profilc ovcr a rcasonable dosage range. In Phase I clinical trials in humans, drug safety is thc focus. Phase I studics also include measurements of drug absorption, distribution, mctabolism and excretion over a prc- , Phasc II studies can be determned dosage range. Once successfully completed initiated. Thcse studies are intended to provide additional evidence of drug safcty, but whether or not the drug works in humans as in animals (effcacy) noW becomcs relevant In Phase III studies , randomization of human subjects to a drug group vs no-drug (placebo) group is neccssary for valid conclusions to be madc. Studies are typically double-blinded, a study design whcrcin neither the subject nor physician/scientist know to which group the subject has bcen assigned. This strategy is needed to avoid any bias on bchalf of thc subject or treating physician/scientist as , a placeb arm is expccted to to whcthcr the drug works. In thesc typcs of studies the drg determne whether or not simply taking or applying a substance or ' produces an effect. Data from Phase II studies should be able to allow the Phase m trial to focus in on dosagc and treatment interval necessary to produce the desired the sample effect. Studies should be powcred bascd on preliminar data to predict , and investigators should r main size necessary to achieve the desired response blinded to thc data until the study is completed or stopped due to an unexpected treatment outcome and/or adverse event.
Apg, Cutting Gel, 25) Placebo-controlled trials as just described are lacking for Dennalin- and Tummy Flattening Gel. There are actually no trials of any type presented to indicate Dennalin-Apg, Cutting Gel, and Tummy Flattening Gel work. More Apg, Cutting Gel or Tummy specifically, there is no evidence that Dennalin- Flattening Gel produce rapid and visibly obvious fat loss in areas of the body to which they are applied.
Product.
Apg, Cutting Gcl, and Tummy Flattening Gel are all aminophylli 26) Dennalip- e. in containing skin prcparations designed for the purposes of removing fat locally, i. in all of the the areas to which it is applied. Thc concentration of aminophylli
:\-cd.l f RCdo.
From this point forward, commcnts will be bascd on the
scientific evidence that support or fail to support the validity of the claims of Basic Reseaarch LLC et al related to all 3 of the aforementioned products unless specifically otherNise stated (Attachment 2).
Relevant Science
) results in lipolysi (the 27) The scientific fact that the drug aminophylline (theophylli release of fatty acids from lipid stores) in adipose tissuc and adipocytes (fat cells) phanacologicalliterature outside the body is supported by the medical and 11:497-511, 1986). This effect J Cyclic Nucl Pmt Phosphor Res - (Manganiello et al is related to the ability of amnophylline to inhibit the breakdown of cyclic- (cAMP), the biochemical mediator of lipolysis, after stimulation of fat cells by
- or adrcnergic agonists). Basic Research LLC has no appropriate stimulants ( and fat cell shrnkage in data to indicatc that any of their products stimulates lipolysi
fat cells in vitro. Nor is therc any evidence that Dennalin Apg, Cutting Gel or Tummy Flattening Gel cause rapid and visibly obvious fat loss in areas of the body to which they are applied. 28) The effectiveness of amnophylline-containing products to produce regional fat loss Clin Ther 9:663- in humans in vivo exists from peeneviewed (Greenway and Bray, Obes Res 3:5615- 669, 1987) and non-peer reviewed publicatIOns (Greenway et ai 5685, 1995). These reports indicate that the topical application of a product containing aminophylline cream, not Dermalin Apg, Cutting Gel or Tummy Flattening Gel , reduces thigh circumference in women.
Clin Ther (1987) paper, 28 obcse women were put on a 29) In the Greenway and Bray 600-800 calorie diet and encouraged to engage in a walking program. Five groups were differentially assigned, but only two used aminophylline cream. One of the to one thigh aminophylline cream groups applied the cream + forskolinlyohimbi and placebo to the other 5 days/week for 4 weeks; the other aminophylline cream group applied the cream without forskolinlyohimbine in an identical manner. Measurements were made 2/3 of the distance between the knee and greater trochanter.
subjects (2 groups combined) 30) ' Variable amounts of weight loss occurred in 9110 whereas all 10 subjects receiving an aminophylline-containing cream lost more circumference in the thigh in which the cream was applied than the one to which placebo was applied. In thc study in which aminophylline/forskolinlyohimbine cream treated and placebo-treated thighs was applied, the mean difference between the drug-
was 2.03 :t 1.36 cm. The difference was 1. 50:t 0. 77 cm when amnophylline cream
only was compared with placebo. The only adverse effect was a rash in one subject in the aminophylline/forskolinlyohimbine group.
, however, in an extremcly 31) This study documents the benefit of aminophylline cream small sample. Clearly, validation is needed in larger populatio
Obes Res paper (1995) - which was not peer reviewed, 6 study 32) In the Greenway et'al Cfin groups were id, ntified , 3 of which appear to be studies previously reported in the Thei (1987) paper. The 3 additional groups were treated with one of three aminophylline-containing creams, 0. , 2% and 10% (5 grams each) to one thigh and placebo to the other. Unlike the previous studies, two measurements were made: , and a 2 one at half the distance between the fibular head and the greater trochanter 5 cm above the I . Only the 10% aminophylline cream group was placed on a 900- , modest to 1100 calorie diet without encouragement to exercise. In all 3 groups moderate decreases in thigh circumference were seen. In the 10% aminophylline- 3 :! 2.2 treated study wherein 23 of 30 women completed the study, weight loss was 3. kg with a girth loss greater in the aminophylline-treated thigh than in the placebo- 78 :t 0.89 cm at treated thigh, 0.77 :t 0.66 cm at the lower girth measurement and 0. the upper girth measurement (p OO I) after 6 weeks of treatment. The 2% aminophylline application study was cared out over 5 weeks in women who claimed their thighs were ' undesirably fat and dimpled' . One subject developed a rash. Again the aminophylline-treated thigh was reduced more in circumference than the placebo-
treated thigh, 1.21 :t 0. 31 cm (p OI). Finally, in the 0.5% aminophylline vs placebo cream study, the difference between thighs was 3.08 :i 0.27 cm over 5 weeks.
33) Unfortunately, no analyses were carred out to examine whether or not the apparent greater reduction in thigh circumference occurred on 0.5% aminophylline cream (:0 0 cm) vs. the other two concentrations (- 1.5 cm on 10% and - 1.3 em on 2%) was true statistically. Does this suggest that at higher doses the effect of aminophylline is treated parially lost? This is of paricular interest because the 10% aminophyllne- group was placed on a reduced calorie diet and actually lost weight over the 6 weeks of observation. This relationship between the amount of weight loss and the It is also reduction in thigh circumference with aminophylline requires further study. Clin Ther 1987 unclear why the additional data presented in this manuscript vs. the , peer paper were never subjected to a peer-review process. In science and medicine review is accepted as an honored process by which the value of scientific discovery is weighed. Whenever possible, publications that have been peer-reviewed are cited before those that have not been so examined. 34) More recently, r have been provided with a copy of a manuscript from the Grcenway group that is either intended to be submitted for publication or has bccn already submitted (Carso et al). In this study, 50 overweight and obese men and women with a body mass index (BMI) of:o 27 kg/m' (mean of28. 2 and 28. 5, respectively) betwecn the agcs of21 and 65 ycars paIicipated. A male pattcrn fat distribution
characterizcd by a waist to hip ratio 94 was present in the study subjccts. The presence or absence of co-morbidities associated with obesity, i.c. diabetes . lipid disorders , and heart diseasc, or medications that the subjects were taking, wcre not dcscribed. Nor was thcre any dctail provided about the measurement of the thigh
circumferences , i.e. what sites (anatomical landmarks) were used, what was the variability of measurement, did one or more individuals cary out these dctcnnnations? All subjects wcre treated with a 1200-calorie diet and were encouraged to follow a walking program throughout the 12 week study. Subjects were either given a 0.5% aminophylline cream to apply vs no topical application to thcir abdomen twice a day ovcr the study period. This is an inadequate study design bccause of the absence of a placebo cream application. Thus, neither the subjects nor thc investigators were blinded. This raiscs substantial conccl1.
a) Athough the data were not provided, the reduction in weight and BMI was stated to be similar between the 2 groups. In the 0.5% amnophylline group, the waist circumference was reduced by 11.0:t 1.0 cm whereas in the no-
treatment group the reduction was 5.0:t 0. 6 cm (p"= 0.001). Waist. circumference reductions were seen in both men and women, but the waist
circumference decline was greater in womcn than men, 11.6 :t 0.6 vs 9.4 :t 0. , respectively.
35) It is extremely difficult to understand how with this much reduction in waist circumference that weight reduction was not different between the groups.
Aminophylline levels were undetected in the plasma of paricipants, and there were no adverse effects of the cream. With this amount of surface- area of application aminophylline, it's difficuJt to believe that no drug was measurable in the plasma. Unfortunately, the assay utilized is not dcscribed, Also notcworthy is the very brief bibliography, with no citations related to thc effect of aminophylline cream on regional subcutaneous body fat other than those of the senior author (Grecnway) listed,
36) In the stufIy of Lesser ct al (Denn Surg 25:455-462, 1999), soft supportive cvidence of the benefit of a topical caffeine cream is provided. Caffeine is a methylxanthine compound in the same drug class as aminophyllinc, and therefore could produce fat cell lipolysis, This study was carried out over 2 months in 49 subjects, 41 of whom finished the study, Herc, a ! % or 2% cream was applied to one side of the body including abdomcn , thighs, tliceps and hips with a placebo-containing cream administercd to the opposite side. Caliper measuremcnts in addition to circumferenccs wcre utilizcd in the various fat regions to quantify bcnefit.
a) The 2% caffeine-containing cream reduced caliper thickness in all areas, with a rangc from 3.0 to 5.4 mm (p = 0,001 for all). There was also a benefit using
the 1 % crcam ranging from 2. 1 - 3.4 mm (I' = 0, 005 for the triceps area and p = 001 for thc remaindcr of regions). ' Dcspitc the statistical significancc of
these data, this amount of changc in caliper thickncss might wcll be too small to bc delected by the subjccts, This is supported by the tapc mcasurements that failed to show any differcnces between the 1 % and 2% creams and placebo.
(Clin Ther 1987) and 37) Dcspitc the evidcnce presented from the Greenway and Bray
Greenway et al (Obes Res 1995) aricles , data are lacking for any clinical benefit of Dennalin-Apg, Cutting Gel and Tummy Flattening Gel. Specifically, there is no indication that any of these products produce rapid and visibly obvious fat loss in areas of the body to which they are applied. Moreover, there is no e idence these products or the aminophylline creams used by Greenway et al affect ' resistant body fat' any differently. 38) Basic Research LLC claims that ' exercise or dccrcased caloric content is needed bum off rcleased fat : This statcment suggests that even if decrcascs in regional fat did ensue subsequcnt to the applt ation of Dermalin-Apg. Cutting Gel and Tummy Flattening Gel, that to sustain the effect a diet and/or cxercise is needed, Although this statement in general supports the scientific dogma that body fat is regulated and defended against reduction/dcpletion, there arc no data provided to spcak to thc specific claim of Basic Research, LLC
39) In the advertisements provided by Basic Research LLC, repcatcdl y stated is that
studies wherein adipocytes are incubated with aminophylline in vitro there is a loss in adipocyte volumc. This contention is simply stated; there are no data to support the claim. Even if such data werc available, it would be important to know whether these studies were carricd out in acutely preparcd or cultured isolated fat ceIls, in 3T3-
cells or in othcr culturcd cclls after fat cell diffcrcntiation ) If isolated adipocyte:.
wcre used, it would be important to know whether these cclls were sourced from rodcnts or humans,
40) With the epidemic of overweight/obesity and the overzealous conccrn (cven among normal weight individuals) about the unacceptable cosmetic effects of exccss fat in certain anatomic regions , it is hard to cxplain the paucity of published science in this area. Why at this timc is thcre only one peer-reviewed report in the literature on the value of topically applied aminophylline-containing products to selected fat- containing regions? Certainly, the development and implementation of scientifically sound randomizcd double blind controlled clinical studies would appear straightforward. The lack of adventure by Basic Research LLC into this area of opportunity is without explanation. Yet, the Greenway group appears to among the few participants in this area of clinical science. However, still there remains the
major issue, that there are no data to support that Derralin Apg, Cutting Gel or Tummy Flattening Gel cause rapid and visibly obvious fat loss in areas of the body to which they are applied, 41) The only other report to my knowledge provtdes no evidence to document the benefit of a product containing 2% aminophylline on regional fat (Collis et ai Plasl Reconstr
Surg 104: lllO- 1114, 1999). In this study, 52 women with 'cellulite' deposits on their thighs and/or buttocks were studied. The age of the study population ranged from 19- 2 Subjects were 70 years , the weight from 53. 93. 7 kg and BMI from 21 -38. 5 kg/m divided i1!to 3 groups: only one group used a 2% aminophylline cream + 10% glycolic acid which was applied to one thigh/buttock with placebo applied to the other. These applications were caried out twice a day for 12 weeks. Measurements included physical examination, photographs , thigh girth at two points, and thigh fat depth by ultrasound. After 12 weeks of application, there was no statistical difference in any of the measurements between the aminophylline-containing and placebo- containing creams. Only 3 of the 35 research subjects who finished the study believed that their cellulite had been favorably modified at the study s terminus. Of note, skin reactions were seen in 9 subjects treated with aminophylline cream that finished the study and 11 of the 45 subjects so treated if subject withdrawals are included.
42) Overall , the data of Collis et al are in conflict with the data of Greenway et al. explanation for these diffcrenees could be related to study design. Perhaps more disturbing is the absence of any fm1her scientific experiments to validate this area of science.
Drug Absorption
43) Using tbe report of Mowrey, rates of absorption for aminophylline were carred out in a human skin model using a lecithin-based aminophylline gel -Epidril . The active ingredient was measured over 48 hours after elution byhigh performance liquid chromatography (HPLC) in the ' subcutaneous fatty layer' of human cadaver skin.
The peak rate of delivery was 0.795 llg/em /hr with a peak time of absorption of 26.
:t 2. 9 hours and total absorption of 48.22 :t 4. 16%. In studies described under DP02-
618 and DPOl-645 , rates for the Cutting Gel' were - 8 /-g/cm Ihr and for the ranged from a Ripping Gel' 379 fJgIcm /hr. Peak absorption for thc Cutting Gel'
time of 10 to 26. 3 hours and for the Ripping Gel' 27.6 hours. In addition, total
absorption for thc Cutting Gel' was 48- 56% and 11.7% for the Ripping Gel'.
44) Despite the potential value of these studies, thc human cadaver skin technique may have limitations in assessing the subcutaneous absorption of dmgs in living human subjects. First it remains unclear how decply thc products of discussion would have pcnetratcd into human skin in living subjects. The science of skin penctration of dmgs topically applied is dependent on thc drug itsclf, its fonnulation, and thc skin to which it is applied. The metabolism of the drug by the skin and the blood supply to thc area of application arc both important factos in thc local effcct of drugs and their absorption. Of course both of thcse issues would not be applicable to cadavcr skin. This arca of science and medicine is complex, with an optimal system to evaluate drug pcnctration, metabolism, and absorption still lacking (Mulier et ai Eur J l'harm
Sci 20:181- 195 , 2003).
45) As notcd above, the repeatcd claims of the Greenway group that no aminophylline was found in the blood stream of subjccts to whom the crcams were applied is
surprising. With greater penetration, the blood supply is more extensivc; thus , it would seem likely that levels of aminophyllinc would be measurable in the blood stream. We have no studies with Dermalin-Apg, Cutting Gel or Tummy Flattening Gel to know whether or not this is true.
Lack gf Ph3n!!!!Ceutical Comp my Activity
46) Even in the absence of much or any principal invcstigator-initiated pursuit of the effcacy and safety of aminophyllne-containing creams or similar products on subcutaneous adipose tissue, the apparcnt reluctance of industry efforts in this cosmetic arena appears to speak for itself. Since the prevalence of overweight/obesity affects 65% of the US population and more than a few in the
normal weight group' seek cosmetic surgery for ' cellulite' or related undesirable fat , '
depoStts, there must be some rcason for the lack of enthusiasm and development by the pharmaceutical industry. Thcrc certainly appears to be a largc markct place out therc waiting for such an innovation. Y ct, sincc the conflicting publications of Greenway and Bray in 1987 and that of Collis et a! in 1999, there is no evidcnce of any further such research and dcvclopment.
Conclusions
47) Based on my over 25-year experience as a rcsearch physician in thc area of fat metabolism, r feel strongly that the cvidenee to support that Dennalin-Apg, Cutting Gel, and Tummy Flattening Gel arc effective in rcducing undesirable deposits of subcutaneous fat is unfounded. There are no data that speak to the claim that Dcnnalin-Apg Cutting Gel' and ' Tummy Flattening Gel' cause rapid and visibly obvious fat loss in areas of the body to which they are applied. Competent and reliable randomized double blindtlials are lacking, and thc intended value of thcsc products is based on a limited expericnce by others using aminophylline-containing creams that differ from those of Basic Rcseareh LLC. An additional problem here is that these ' success' stories have bcen carred out almost entirely by one group (Greenway et al) with validation wanting. Although Dcrmalin-Apg, Cutting Gel, and Tummy Flattening Gel may not be harful, there are no data to support even this claim. I believe that the task before Basic Research LLC remains to provide support for what at present appear to be unfounded claims. Oct. 19. 2004 3:49PM No8431 p. 2
!?o/
Robert H. Eckel, M.
October 19 2004 REPORT , .
ROBERT H. ECKEL, M.
University of Colorado Health Sciences Center Division of Endocrinology, Metabolism and Diabetes . Box 6511 , M. S. 8106 Aurora, CO 80045 Phone: (303) 724-3923 Fax: (303) 724-3924 (E-mail) Robert. eckel (g uchsc.edu
EDUCATION , Ohio 1969 Bachelor of Sciences, Bacteriology, University of Cincinnati, Cincinnati , Cincinnati , Ohio 1973 Doctor of Medicine, University of Cincinnati College of Medicine POSTGRADUATE TRAINING Madison, Wisconsin 1973-74- Internship in Medicine, University of Wisconsin Hospitals , Wisconsin 1974-" Medical Residency, University of Wisconsin Hospitals, Madison
1976- Senior Fellowship in Metabolism and Endocrinology, Deparment of Medicine University of Washington School of Medicine, Seattle, Washington
LlCENSURE TO PRACTICE Wisconsin, July 10, 1974, License No. 18866 Washmgton, July 10, 1976, Certificate No. 25209 Colorado, July 10, 1979, License No. 22425 APPOINTMENTS 1979-85 Assistant Professor of Medicine University of Colorado Health Sciences Center, Denvcr, Colorado 1981- Associatc Program Director, Adult Gcneral Clinical Research Center University of Colorado Health Sciences Center, Denver, Colorado 1983- 1985 Acting Chairman, Division of Endocrinology, University of Colorado Hcalth Sciences Center, Denver, Colorado 1984-present Graduate Faculty Appointmcnt University of Colorado Health Sciences Center, Denver, Colorado 1985-1989 Associate Professor of Medicine University of Colorado Health Sciences Center, Denver, Colorado 1989- Faculty Affiliate, Deparment of Food Science and Human Nutrition Colorado State University, Fort Collns, Colorado 1989-present Professor of Medicine University of Colorado Health Sciences Center, Denver, Colorado 1989- Professor of Biochemistry, Biophysics and Gcnetics University of Colorado Health Sciences Center, Denver, Colorado 1990-present Graduate Faculty Appointment, Deparment of Food Science and Human Nutrition, Colorado State University, Fort Collins, Colorado 1991-1997 Co-Director, Center for Human Nutrition University of Colorado Health Sciences Center, Denver, Colorado Kooert M. Eckci, Ivi. 1993-present Program Director, Adult General Clinical Rcsearch Center University of Colorado Health Sciences Ccnter, Denver, Colorado 1995-present Professor of Physiology and Biophysics University of Colorado Health Sciences Center, Denver, Colorado 1997-present Co-Director, Clinical Nutrition Research Unit University of Colorado Health Sciences Center, Denver, Colorado 1997.preseni Associate Director, Center for Human Nutrition University of Colorado Health Sciences Center, Denver, Colorado 1998-present Vice-Chairman, Research Affairs , Deparment of Medicine University of Colorado Health Sciences Center, Denver, Colorado 2000-present Charles A. Boettcher Endowed Chair in Atherosclerosis, Department of Medicine University of Colorado Health Sciences Center, Denver, Colorado 2002-present Professor of Medicine, Division of Cardiology University of Colorado Health Sciences Center, Denver, Colorado BOARDS Diplomate, National Board of Medical Examiners, July 1974 Diplomate, American Board of Internal Medicine, June 16 , 1976 Diplomate, American Board of Endocrinology and Metabolism, June 19, 1979 HONORS 1969 - Bachelor of Sciences Cum Laude in Bacteriology, University of Cincinnati , Cincinnati, Ohio
1973 Alpha Omega Alpha University of Cincinnati College of Medicine, Cincinnati, Ohio
1987 American Society for Clinicallnvestigation
1987- Full-Time Faculty Housestaff Teaching A ward, Department of Medicine University of Colorado Health Sciences Center, Denver, Colorado
1990 Moses Barron Award, American Diabetes Association , Minnesota Affiliate
1991 A ward of Excellence, Colorado Dietetic Association
1994- Best (Top) Doctors in America Recognition 2001-2004
1997 Association of American Physicians
1998 Excellence in Teaching, Medical Student Councii 1999 OutstandingSciences Teaching Award, Clinical Center Science Program, University of Colorado Health' 2000 Charles A. Boettcher Endowed Chair in Atherosclerosis, Deparment of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
2000 Robert H. Willams-Rachmiel Levine Award, Western Metabolisrn Club
2001 Robert W. Schrier A ward of Excellence, Deparment of Medicine, University of Colorado School of Medicine ft I. ;- .;L r 2002 The Alexander Marble Lecturer at the Elliott P. Joslin Research Laboratory, Harard Medical School
2003 Fellow of the American Heart Association and the Council on Nutrition, Physical Activity and Metabolism, April 20, 2003 .
2004 rank and Sheila Thompson Lectureship in Endocrinology, Scott & White Clinic, Temple Texas, Januar 9 2004 GRANTS 7/77 -6/79 Juvenile Diabetes Foundation Research Fellowship. Cultured Fibroblasts as a Cellular Model of Diabetes Mellitus and its Complications.
4/79-3/80 University of Colorado Research Assistance, BRS699 Grant: Hormonal Control of Adipose Tissue Lipoprotein Lipase.
12/79-5/05 NIDDK, Grant:DK26356, Hormonal Control of Adipose Tissue Lipoprotein Lipase.
09/80-08/82 Juvenile Diabetes Foundation Research, Grant: 80R055Pathophysioiogy of Adipose Tissue Lipoprotein Regulation in Diabetes: Use of Cultured Human Preadipocytes.
7/82- Cambridge Quest Foundation. Adipose Tissue Lipoprotein Lipase Regulation after Weight Reduction in Obese Humans.
1J84- 1O/86 Mead Johnson, Nutritional Division. Regulation of Adipose Tissue Lipoprotein Lipase Before and After Weight Loss in Obese Subjects. Response to Variable Fatty Acid Chain Length Formula Diets. 04/86-03/89 NIDK, Grant: AM30747. Diabetes Mellitus in the San Luis Valley, Colorado. Principal Investigator: Richard F. Hamman , MD
02/87-01/90 N1Cl-HD, Grant: HD19547. Physiological Factors Affecting 1.1uman Lactation. Principal Investigator: Margaret C. Neville, PhD. A 03/89-02/90 Procter and Gamble Co. Effect of Medium Chain Triglycerides on Glucose and Lipid Metabolism in Type II Diabetes Mellitus. 12/89-11/92 NlDK, Grant: DK42266. Nutrition, Lipoprotein Lipase and Body Weight Regulation.
09/92-08/94 USDA , Grant: 92-37200-7522. Transcriptional Control of Lipoprotein Lipase by Cytokines. 07/94-06/99 NIDK, Grant: DK46881. Diet, Lipoprotein Lipase, Insulin Action and Weight Gain. 01/95-09/02 NIDDK, Grant: Clinical Nutrition Research Unit, Metabolic Core Director.
04/95-04/02 NIDDK, Grant: DK42266. Nutrition, Lipoprotein Lipase and Body Weight Regulation.
12/96-06/98 Amgen, The Effect of Leptin on Postprandial Lipid Metabolism.
09/97-present Merck Unrestricted Grant 97-033 , Assessment of Coronar Atherosclerosis in Young Adults with Type 1 Diabetes by Ultrafast Computerized Tomography.
03/98-02/04 Slim-Fast Nutrition Institute, Effects of Weight Loss with Reduced-Weight Maintenance and Sub"equent High-Carbohydrate vs. High-Fat Macronutrient Feeding on Neck Morphology, Whole-Body Energy Metabolism, Sleep Dynamics, Pulmonar Function, and Insulin Sensitivity in Severely Obese Humans. ?,!???
RODen N. r:cKci . lvi. i).
02/99-06/02 Abbott, Effect of Triglyceride-Lowcring on Endothelial-Dependent and Endothelial- Independent Arterial Vasodilation, Independent of the Known Effects of Hypcrcholesterolemia on Endothelial Function.
07/99-06/04 NHLBI, K-30 Grant: Co PI, Advanccd Training for Clinical Investigators.
07/00-07/04 American Diabetes Association , Mentor Based Postdoctoral Fellowship, Title?'
12/01-03/04 Mcrck and Co. , PNOlll-057 Grant: The Impact of HMG Co-A Inhibitors on C-Rcactive Prot in in Patients with Type 2 Diabetes.
08/02-07/04 Eli Lilly and Company, The Acute Effects of Fceding High Fal Diels on Insulin Clearance.
08/03-07/08 NUl DK61668: Grant: Mechanisms Defending Fat Mass in Humans After Lipectomy.
10/03-09/04 National Multiplc Sclerosis Society. Lipoprotein Lipase and Nervc Myelination.
TRAINEES Past Trainees PrelPost . Name Doctorate Dates in Lab ree Current Position Craig Sadur Post 07/80-06/82 Pri vate practice Phil Kcrn Post 07/81-06/85 Prof of Mcdicine Univ. of Arkansas, Little Rock Arkansas Mary O'Shea Post 07/84-06/85 Privatc practice Tammi Gregg Pre 1988- 1989 Dietitian, Madison , Wisconsin Paul Rudolf Post 07/85-06/87 Pri vale practicc Daniel Rule Post 09/86-07/87 Ph. Assoc Prof, Animal Sciences Univ. of WY, Laramie, Wyoming Daniel Besscsen Post 07/87- 12/90 Assoc. Prof of Medicine, Div. of Endocrinology, Metab & Diabetes UCHSC, Denver, CO Mar Kay Post 07/88-06/90 Private Practice Rozmyslovicz Mar Raynolds Post 05/88-07/92 h Ph. Asst. Prof., Division of Cardiology, UCHSC, Denver, CO
Jamie Erskine Pre 09/90-09/92 .. Ph. Asst. Prof, Human Nutrition Univ of Northern Colorado Greeley, CO Jackie Berning Pre 09/90- 12/94 Ph. Asst Prof, Kinesiology Univ. of Colorado, Denver, CO Sharon Travers Post 07/92-07/94 Assoc. Prof, Division of Endocrinology, Dept of Pediatrics UCHSC, Denver, CO' Hong Liu Pre 09/92-06/94 Ph. Graduate Student, Dept. Nutrition Univ. of Texas, Austin, Texas ODen i-L Eckei. ivi.
Came Ganong Post 07/94- 1997 AssL Prof, Pediatrics Ohio State Univ. , Columbus, OH Cathy Morin Post 09/92-06/98 Ph. Asst Prof, Preventive Medicine UCHSC, Denver, CO
Angie McGinnis Pre 07/96-06/98 Pre doc Post 09/96-09/99 Ph. Assistant Professor of Medicine Patricia Uelmen , GA Huey Emory University, Atlanta , Cardiovascular Paul Poi rier Post 02/98- 12/99 MD. Scientific Director Rehabilitation Program Quebec Hear InstitutefLaval Hospital Quebec , Canada Luis Ferreira Post Ilf98 - 10/0 I PhD. Instructor of Medicine University of Perth , Perth, Australia William Troy Post 07/95-02/04 AssL Prof of Medicine Donahoo University of Vermont
Current Trainees LIsa Kosmiski Post 07/93-present Asst. Professor of Medicine UCHSC, Denver, Colorado
Bakary J. Sonko Post IlfOO-present Ph. Postdoc Waren H. Capell Post 07/0l-present Postdoc Alison M. Moms Post 09/0 I-present Ph. Postdoc Dean J. Calsbeek Post 07/02-present Ph. Postdoc Linda Barbour Post 09/02-present Assoc. Professor of Medicine OB/GYN, UCHSC Leigh Perreault Post Ilf02,present Assistant Professor of Medicine Boulder GCRC Paul Wischmeyer Post Ilf02"present Assistant Professor of Anesthesiology Bryan C. Bergman Post 04/03-present Ph. Assistant Professor
PROFESSIONAL ORGANIZA nONS Adipocytes: An International Journal Devoted to Basic and Clinical Research on Adipocyte and Adipose Tissue Biology, Editorial Board American College of Physicians, Fellow American Diabetes Association American Federation for Clinical Research American Hear Association, FAH Council on Arteriosclerosis, Thrombosis, and Vascular Biology Council on Nutrition, Physical Activity, and Metabolism American Society for Clinical Investigation American Society for Clinical Nutrition American Society for Nutritional Sciences Association of American Physicians Association for Patient-Oriented Research Endocrine Society North American Association for the Study of Obesity Raben M- r:cKel , IVl.u. Western Association of Physicians Western SOCiety for Clinical Investigation COMMITTEES - LOCAL Animal Care Control Committee , Colorado 1980- 1983 University of Colorado Health Scienc s C , 9cnver , Deparment of Medicine 2. Intern Selection Committee , Colorado 1980-present Uni versity of Colorado Health Sciences Center, Denver , Organizational Committee, 1980- 1985 American Diabetes Association, Colorado Affiliate , 1980- 1981 Juvenile Diabetes Foundation, Denver, Colorado Denver Medical Advisory Board , Department of Medicine Attending Physiciiln , Gordon Meiklejohn Service , 1993-present. University of Colorado, Denver, Colorado 1980- 1993; Ward Darley Service , Adult General Clinical Research Center 6. Scientiftc Advisory Committee present University of Colorado Health Sciences Center, 1981- , 1983- 1987 Grant Review Committee, Colorado Heart Association Centers of Excellence" in Cardiovascular Disease Dean s Subcommittee on " , Colorado 1984 University of Colorado Health Sciences Center, Denver Faculty Senate 9. , Denver, Colorado 1985- 1987 , 1989-present Uni versity of Colorado Health Sciences Center , Denver, Colorado 10. Research and Development Committee, Veterans Administration Medical Center Dean s Committee Representati , 1985- 1988 II. Currculum Review Committee University of Colorado College of Medicine 1986- 1994. 12. Inter-Deparmental Steering Committee on Nutrition, University of Colorado College of Medicine 1987- 1990. 13. University of Colorado/Colorado State University Consortium for Human Nutrition present Board Member, 1988- , Department of Medicine 14. Nutrition Support Subcommittee, University of Colorado Hospital . Representative , 1990- 1992. , Barbara Davis Childhood Diabetes Center, 1991- 1992. 15. Search Conunittee, Executive Director , University of 16. Metabolic Regulation of Fetal Growth Center Grant: Internal Advisory Committee Colorado lISC , 1991- 1997. 17. Faculty Communications Committee , 1991- 1993. University of Colorado College of Medicine , 1992- 1994. 18. University of Colorado School of Medicine Faculty Council Representati 19. Clinical Trials Office Committee 1997. University of Colorado Health Sciences Center, Denver, Colorado 1995- Committee 20. Graduate School Governance present. University of Colorado Health Sciences Center, Denver, Colorado 1996- 21. Doctor of Philosophy in Biology, Clinical Investigation Track Curriculum Committee , 1997-present. University of Colorado Health Sciences Center , 1997. 22. The Robert W. Schrier A ward of Excellence Commi ttee Committee on Planning and FisC::l! Policy, 1997- 1999. 23. University of Colorado Health Sciences Center , Colorado Affiliate, 1997- 24. Denver Metro Physicians Advisory Council, American Hear Association 1998. , 1998-present. 25. American Hear Association of Colorado, Public Affairs Commttee, 1999-present 26. Electives Committee, University of Colorado School of Medicine Chair, 2001 27. Cliniealrrranslational Research Committee, University of Colorado School of Medicine, Co- 28. Veterinaran Pathologist Search Commttee, 2002-2003. 29. University Hospital Research Committee, 20OZ-present. , University of Colorado College of Medicine, 2004- 30. Co-Chair Advanced Studies Currculum Commttee present. , 2004 - present. 31. Research Advisory Committee, University of Colorado College of Medicine Roben n. GCKCl , ivl.u. CQMMITTEES - NA TlONALflNTERNA TlONAL 1. National Eye Institute, Diabetes Retinopathy Study II, Medical Therapy Committee, 1977- 1978. 2. Councilor, American Federation for Clinical Research (Western Section), 1982- 1984. 3. National Councilor, American Federation for Clinical Research, 1984- 1988 1988. 4. Secretary-Treasurer, American Federation for Clinical Research (Western Section), 1985- 5. Councilor, North American Association for the Stl'c1:' "f f)'J"s;t y, 1987- 1990. 6. Technical Advisory Board, Institute for Creation Research, EI Cajon, California, 1988-present. 7. Progrm Committee, Council on Nutritional Sciences and Mctabolism, American Diabetes Association 1989- 1991. 8. Education Committee, North American Association for the Study of Obesity, 1991- 1992. 9. Chairman , Publi ations Committee, North American Association for the Study of Obesity, 1991- 1994. 10. External Advisory Committee , Nutrition Training Grant: University of California, Davis , 1990- 1995. 11. Vice-President, N0I1h American Association for the Study of Obesity, 1993- 1994. 12. Program Committee , International Association for the Study of Obesity, Toronto, August 1994. 13. President , North American Association for the Study of Obesity, 1995- 1996. 14. Executive Commttee, General Clinical Research Center Program Directors, 1995-present. 15. Nutrition Committee, American Hear Association , 1996-present; Vice-Chairman 1997- 1998 , Chairman July 1998- present. 16. Co-Chairman, Annual Meeting of the North American Association for the Study of Obesity, 1996. 17. Program Commttee , International Association for the Study of Obesity, October 1996. Obesity, 1996- 18. President s Commttee, North American Association for the Study of. present. 19. LtJng Range Planning Committee, North American Association for the Study of Obesity, 1996-prcsent. 20. President , Western Society for Clinical Investigation , 1997- 1998. 21. Co-Chairman, Planning Committce, General Clinical Research Program Directors Mccting, 1998. 22. Chairman , Nutrition Committee, American Hear Association, July 1998-present. 23. Executive Board, Kern Aspen Lipid Confcrence, 1997 -present. 24. Boston Obesity Nutrition Research Center, Scientific Advisory Committee , 1998-200 I. 25. Board of Directors , Association for Patient-Oriented Research , 1998-present. 32. Co-Chairman, Program Committee, Association for Paticnt-Oriented Research, 1999-2001. 33. Vice-Chairman, Council on Nutrition, Physical Activity and Metabolism, American lIear Association 2000-2002. 34. Secretar-Treasurer, Association of Patient-Oriented Research , 2001-2003. 35. Chair, Prevcntion VI: Obesity, A Worldwide Epidemic Related to Hear Disease and Stroke, American Hear Association, Honolulu, Hawaii, April 26- , 2002 36. Chairman , Council on Nutrition, Physical Activity and Metabolism, American Hear Association, 2002- 2004. 37. Chair, Kern Aspen Lipid Conference, Fatty Acid Transport and Metabolism: Impact on Insulin Action/Secretion and Body Weight Regulation, 2002 38. Member, Science AdvisOlY and Coordinating Commttee, American Heart Association, 2002-present. 39. University of North Carolina Chapel Hill , Member of External Advisory Committee for Mentored Clinical Research Scholar Program, NIH K- 12 Award RR-02-2001 , 2002 - present. 38. CNRU NIDDK sponsored "National Task Force 011 Prevention and Treatme:ot of Obesity," 2003-present. 39. NIDK Advisory Council , 2003-2006. 40. American Board of Internal Medicine Endocrinology Subspecialty Writing Commttee 2003-2006. 41. Chairman, Nutrition, Physical Activity and Metabolism Council, American Hear Association, 2002- present. 42. Keystone Symposia Scientific Advisory Board, 2003-2006. 43. Program Committee, L.J Filer Symposium, American Hear Association, March 2004, San Francisco CA. 44. President, Kern Aspen Lipid Conference, 2002-present. 45. President-Elect, Association for Patient Oriented Research, 05/03-04/04. 46. President, Association for Patient Oriented Research 05104-04/05. 47. President-Elect. American Hear Association, 07/04-06/05. DUGll i. akti, iii. JOURAL REVIEWS Acta Endocrinologica American Hear Journal American Journal of Clinical Nutrition , Editorial Board, 1997- 1999 American Journal of Medicine, Editorial Board, 1998-present American Journal of Physiology Applied Physiology Anthropology Endocrinology and Metabolism Hear and Circulatory Regulatory Integrative Comparative Annals of Epidemiology Annals of Intemal Medicine Archives of Biochemistry and Biophysics Archives of Internal Medicine present Areriosclerosis, Thrombosis and Vascular Biology, Editorial Board, 200l- Arhrtis and Rheumatology Atherosclerosis Biochimica Biophysica Acta Chemical Reviews Circulation Circulation Research Cleveland Clinic Joumal Clinical Chemistry Clinical Endocrinology Clinical Science Diabetes, Editorial Board, 1988- 1992 Diabetes Care Diabetes, Obesity and Metabolism DiabeteslMetabolism Research and Rcviews Diabetologia Endocrine Endocrinology European Journal of Clinical Investigation Gene Hepatology Hormone and Metabolic Rescarch Human Gene Therapy Hypertension In Vitro International Journal of Obesity, Editorial Board, 1989-present . Joumal of the American Society of Nephrology Joumal of Biological Chemistry Journal of Cardiopulmonar Rehabilitation Journal of Cardiovascular Research Journal of Cellular Physiology Journal of Clinical Endocrinology and Metabolism, Editorial Board, 2003-present Journal of Clinical Investigation Journal of Epidemiology and Community Health Journal of Gerontology Journal of Hepatology Journal of Investigative Dermatology Journal of Laboratory and Clinical Medicine Journal of Lipid Research Journal of Nutritional Biochemistry Journal of Obesity and Weight Regulation, Editorial Board, 1984-present rtOOtIl n. c.L:r.ci r\' Journal of Pediatric Gastroenterology Journal of Pediatlics Mayo Clinic Proceedings Mechanisms of Ageing and Development Metabolism Metabolic Syndrome and Related Disorders, Edttorial Board Neuroendocrinology Ncw England Journal of Medicine Nutrition Obesity Research, Editorial Board, 1992-present Obstetrics and Gynecology Proceedings of the National Academy of Sciences Procecdings of the Society for Experimental Biology and Medicine Science The Online Joumal of Current Clinical Trials
INVITED I'ARTICIPANT 1. Adipose Tissue Development and Metabolism Satellite Symposium to the Third International Congress on Obesity; Gothenburg, Sweden; October 4- 6, 1980. , Switzerland; October 8- , 1981. 2. First International Symposium on Acarbose; Montreux , New York 3. National Institutes of Health Workshop on the Classification of Obesity; Poughkeepsie October 17- , 1983. 4. American Diabetes1982. Research Symposium; Denver , Colorado; Januar 10- , Marland; August 9 , 1983. 5. 'National Institutes of Health Special Study Section; Bethesda , 1985. 6. National Institutes of Health Site Visit; East Carolina University; July 23- , Ontaro, Canada; 7. Joint Confcrence on Obesity and Non-Insulin Dependent Diabetes Mellitus; Toronto October 30 - November 1 , 1985. Reverse Site Visit; Bethcsda, Maryland; October 8- , 1986. 8. Nationallnstitutcs of Health , 1986. 9. General Clinical Research Center Site Visit; Stanford University; December 3- 10. Council on Nutritional Sciences and Metabolism of the American Diabetes, 1987. Association: Program on Obesity and Exercise in Type II Diabetes; IndIanapolis, Indiana; June 6 11. American Diabetcs Association, Northern Dlinois Affiliate, Thirtieth Professional Symposium; Chicago Ilinois; October 14 1987. , Massachusetts; December 12. Seminars in Medicine , Beth Isracl Hospital, Harard Mcdical School; Boston , 1987. 13. The Endocrine Society National Meeting, Symposium on Hormonal Control of the Adipose Cell; New Orleans, Louisiana; June 9, 1988. 14. American Diabetes Association Symposium on Current Issues in Nutrition and Metabolism; San , 1988. Francisco, California; October 7 , Marland; October 6- 15. National Institutes of Health Nutrition Study Section , Special Reviewer; Bethesda 17, 1988. , 1988. 16. General Clinical Research Center Site Visit; University of Cincinnati; Decembcr 1- , Marland: 17. National Institutes of Health Metabolism Study Section, Specia! Reviewer; Bethesda , 1988.. Dccember 15 1993; 18. National Institutes of Health Nutrition Study Section; July 1 1989 - June 30 , 1991 - June 30, 1993. Chairman; July 1 , 1989. 19. General Clinical Research Center Site Visit; Brown University; April 5- C.; April 27- , 1989. 20. American Society for Clinical Nutrition Postgraduate Course; Washington, D. 21. American Diabetes Association National Meeting. Symposium: Issues in the Nutritional Management of Patients with Diabetes; Detroit, Michigan; June 6 1989. 22. FASEB Summer Conference on the Regulation of Energy Balance; Vermont Acadcmy; July 31 - August 1989. 23. National Institutes of Health Workshop on Basic and Clinical Aspects of Regional Fat Distribution; Bethesda, Maryland; September 9- 11, 1989. 24. International Symposium on Lipoprotein Metabolism and Lipid Lowering Agents; Nctherlands; February 27 - March 2, 1990. -. . -
.. 4'- KUOen 11- c.Cr.n lV1.u. , Genetics of Obesity; Phoenix, Arizona; March 26- , 1990. 25- National Institutes of Health , 1990. 26- General Clinical Research Center Site Visit; University of Florida; April 10- 27. The Endocrine Society National Meeting. Symposium on Control of Regional Fat Distribution; Atlanta Georgia; June 21 , 1990. 28- The Aspen Bile Acid/Cholesterol Conference- Hepatic Cholesterol and Postprandial Lipoproteins; August 18- , 1990- , i 990- , Japan; Ocluber 18- 29. International Symposium on Obesity and Diabetes Mellitus; Nagoya 30. North American Association for the Study of Obesity Symposium on the Treatment of the Patient with Medically Significant Obesity; Atlanta, Georgia; December 1 , 1990- 31. Keystone Symposta. The Adipose Cell: A Model for Integration of Hormone Signaling in the Regulation of Cellular Function; Park City, Utah; January 18- , 199 I. 32- The Science of FQod Regulation Symposium- Pennington Biomedical Rcsearch Center; Louisiana Statc University; Baton Rouge, Louisiana; March 14- , 1991. 33. North American Association for the Study of Obesity/Society for the Study of Ingestive ilchavior National Meeting; Sacramento, California; ' October 20- , 1991. 34. FASEB Summer Conference on Regulation of Energy l3alance: From Organism to Gene; Copper Mountain , Colorado; August 2- 1992- 35- North American Association for the Study of Obesity Symposium Obesity Update: Pathophysiology, , Georgia; August 31-September 2 , 1992- Clinical Consequences and Therapeutic Options; Atlanta Resistance Syndrome and 36. American Heart Association Scientific Conference on Central Obesity/Insulin , DC; April 22- , 1993- Coronary Artery Disease; Washington Adele 37- International Symposium on Insulin Resistance as a Risk Factor for Cardiovascular Disease; Ste- , June 22- Quebec , 1993. Meeting; Milwaukee, Wisconsin; 38. North American Association for the Study of Obesity. National October 17- , 1993. , 1994- 39. International Symposium on Atherosclerosis; Montreal , Ontaro; October 9- 12 , 1995- 40. Master Clinical Dieticians; Key Biscayne; Januar 14 , Columbia 41. NIDK Program Project on Body Composition Site Visit, St. Luke Roosevelt Hospital , New York; April 5- , 1995. University; New York , Louisiana; 42- North American Association for the Study of Obesity- National Meeting; Baton Rouge October 14- 17, 1995. , Washington 43. NIDK Program Project on Body Composition , Columbia University; Reverse Site Visit C.; March 24- , 1996- 44. NIDK Symposium on Transgenic Animals in Nutrition Research , FASEB Meeting; Washington, D. Apri114, 1996- 3, 1996. 45. I\TIDK Metabolism Study Section, Special Reviewer; Bethesda, Marland; July 2 , Ilinois; October 9, 1996. 46. The Endocrine Society Clinical Endocrinology Update; Chicago , Alabama; December 47. General Clinical Research Center Site Visit, University of Alabama; Birmingham 17- , 1996- 1997. 48. Kern Aspen Lipid Conference; Aspen, Colorado; August 15- 49. Satellite Symposium of the Annual International Symposium on Atherosclerosis; SL Malo, France; 5, 1997 - October.3- , Florida; NovemberlO- 13, 1997 50. American Heart Association Annual Sessions , Plenar speaker; Orlando , Louisiana; March 1- , 1998 51. Pennington Biomedical Research Symposium on Obesity; Baton Rouge , Florida; May 22- 52. American Hear Association, Obesity: Impact on Cardiovascular;, Amclia Island 1998 53. American College of Sports Medicine; Orlando, Florida; June 3- , 1998 54- American Diabetes Meeting; Chicago; June 13- , 1998 Conference on Behavioral and Metabolic Sub-phenotypes in Obesities, Genetic and 55. FASEB Summer , Colorado; June 20-25, Molecular Aspects, Pathophysiology and Therapeutic Implications; Snowrnass 1998 56. NIDK Metabolism Study Section, Special Reviewer; Julyl-2, 1998 57. Gencral Clinical Research Center Site Visit, Beth Israel Deaconess, Harvard Medical School; July 13- , 1998 - 58. NIDK Diabetes Complications Special Study Section, Chairman; July 30-31, 1998 th International Congress on Obesity, Sept 3 , 1998 59. 8 Plenar speaker; Pars, France; Aug 29- , " , ' , " , "
KaDett 11. t'cKci. ivLD. , CO; 60. American Association of Cardiovascular and Pulmonar Rehabilitation Annual Meeting; Denver Oct 15 1998 1998. 61. Joslin Diabetes Center lOO'" Anniversary; Boston, Mass; Oct 22- t!' Anniversar of NIDDK, San Diego Convention Center, April 17 , 2000. 62. F ASEB , 50 , 19 2000 Special Study Section on Lipids and Lipoproteins, Chair, June 18 63 NIDK s Health and Obesity Across the Life 64. North American Association for the Study of Obesity, Women , Oct 31 2000 Span Symposium speaker Secondar Prevention in the 65. American I-icart Association Annual Sessions, Cardiovascular Seminar on , 2000 Eldcrly, Nov 13 s Time to Treat Obesity, Nov 15 66. Amcrican Hear Association Annual Sessions, Special Session on It 2000 , Orlando 67. Amcrican Hem1 Association Prevention VI on Cardiovascular Disease and Diabetes Mellitus Jan 18- , 2001 Special2001 Study Section on Lipids and .Lipoproteins , Chair, I'eb 21 68. NIDK Associated Cardiovascular 69. NHBI-NlDK Working Group on The Pathophysiology of Ohesity- , 24 , 200 I. Disease, Chair, May 23 2001. Special Study Section on Lipids and Lipoproteins, Chair, June 18 70. NIDK Professor on Hyperlipidemi , June 20 , 2001. 71. The Endocrine Society Annual Meeting, Meet the , St. Louis, Oct 22, 2001 Dietetics Annual Meeting, ' Beyond the AI-I Guidclines 72. The American , Arizona, Dcc 6- 2001. 73. American Diabetes Association Meeting on Insulin Resistance. Tempe 74. American Hear Association Prevention Vil: Obesity, a Worldwide Epidemic Related to Heart Disease and Stroke, Honolulu, April 26- , 2002, Chair. 75. The Kern Aspen Lipid Conference Fatty Acid Transport and Metabolism: Irnpact on Insulin , Aspen, Aug 17- 2002, Co-Chair. Action/Secretion and Body Weight Regulation , Japan Octobcr 11- 76. MSDM (Multiclinical Study for Diabetic Macrovascular Complication) Tokyo 2002 , Japan October 13 , 2002. 77. U.S. Japan Panel on Nutrition and Metabolism Tokyo , Moderator "Emerging Epidcmics, Obesity, Diabetcs 78. American Heart Association Scientific Sessions " and "Curbing the Diabetic Epidemic " Chicago, IL, November 17, 2002. Mellitus, Sedentar Lifestyle Metabolic Association Scientific Sessions, November 18 2002, Plenar Session " 79. American Heart " Chicago, lL, Novembcr 17 Syndrome: Pathogenesis of CVD in Metabolic Syndrome and Diabetes 2002. . , IL, November 18, 2002 Role of Diet in the 80. American Hear Association Scientific Sessions, Chicago Statin Era s Role in Translational Medicine , January 14 2003. 81. Keystone Symposia 2003. 82. 2005 Keystone Symposia Planning Committee, Januar 15, 83. NPAM and ATVB Councils of American Hear Association "Skeletal Muscle Lipoprotein Lipase " Washington, DC, May, 2003. Nutrient Paritioning and Insulin Action. , Nutrient Paritioning and Insulin 84. UCLA SCOR Atherosclerosis Grant Review, Lipoprotein Lipase Action." Lake Arowhead, California, September, 2003. , DC. "Obesity and its Metabolic Complications 85. Metabolic Syndrome Clinical Conference, Washington Skeletal Muscle 86. Frontiers in Cardiovascular Science Meeting, Israel Atherosclerosis Society, " " Eilat, Israel , October, 2003. Lipoprotein Lipase, Nutrient Paritioning and Insulin Action. " Orlando, PL, 87. American Hear Association Scientific Sessions "The Skinny on Weighr Reduction Diets November 2003. " Orlando, FL, 88. American Heart Association Scientific Sessions Postprandial Lipemia and Diet November 2003.Associated Co-Morbidities 89. Co-Chair, NI, Adipose Tissuc Secretory Function and Its Role in Obesity- Washington, DC, 2003. Experience to Date Emerging Therapeutic 90. Duke CRI Confercnee Medical Problem- Medical Approach, , V A Targets, McLean , January 2004. , May, 2004. 91. Lipids and the Pathophysiology of Obesity , Washington, DC NIDK, " , Bethesda, MD, May, 2004. 92. FDNNDK, Joint Symposium on Diabetes , Washington 93. AHA Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke DC, May, 2004. Coronar heart 94. Endocrine Society, "The Metabolic Syndrome: The Most Important Risk Factor for Disease?", New Orleans LA, June 17, 2004. , " , ," " , "
RODen 11. cCKci. lvi. Muscle Lipoprotein Lipase, Energy Balance and Insulin 95. Oregon Health & Science University, " . Portland OR. June 28- , 2004. Resistance" and "The Metabolic Syndrome: Therapeutic Options . Denver CO 96. Clinical Science Course Sessions General Clinical Research Opportunities for Research" August 7 , 2004. 97. Kaplan Lectureship Program: Obesity, "Translation of Basic SCIence to Clinical Research & Practice in Obesity Management . Cincinnati OH, August 27- , 2004. Weight Loss Principles Used in Practice . Dallas TX 98. American Mean: Associalion: Weight Loss Book September 3 , 2004. Association: Prevention of Vascular Disease The Current National Epidemics of 99. American Hear , Including the Effects and Relationships of These Obesity, Diabetes and the Metabolic Syndrome 2004. Diseases on Cardiovascular Disease . Detroit MI, September 9 The Metabolic Syndrome: Therapeutic Consideration 100. Fall Symposium on Atherosclerosis Prevention , October 15- , 2004. for Major Modifiable Risk factor(s) for CHO". Blowing Rock NC IHBLIOGRAPHY PUBLICA nONS Eckel RlI, Crowell EB Jr, Waterhouse BE, Bozdcch MJ. Platelet inhibiting drugs in thrombotic Arch Int Med 37:735-737, 1977. thrombocytopenic purpura. 11 cells. . Eckel RH, Fujimoto WY, Brunzell JD. Development of lipoprotein lipase in cultured 3T3- , 1977. Biochem Biophys Res Comm; 78:288-293 Eckel RII. fujimoto WY , Brunzell fl). Insulin regulation of lipoprotelllipase in cultured 3T3- 84: 1069- 1075 , 1978. cells. Biochem Biophys Res Comm; (gip) enhanced lipoprotein Eckel RH. Fujimoto WY, Brunzell JD. Gastric inhibitory polypeptid Diabetes; 28: 1141- 1142 1979. lipase activity in cultured preadipocytes. Eckel RH, Green WL. Postpartum thyrotoxicosis in a patient with Graves disease association with , 1980. JAm Med Assoc; 243: 1454- 1456 low radioactive iodine uptake. , Bierman EL. High density lipoprotein Eckel RH, Albers JJ, Cheung MC, Wahl PW, Lindgren rl Diabetes; 30: 132- 138 , 198 L composition in insulin- dependent diabetes mellitus. , leucine incorporation into protein and Eckel RI-I, FUjimoto WY. lnsulin stimulated glucose uptake uridine incorporation into RNA in skin fibroblast cultures from patients with diabetes mellitus.
Diabetologia; 20:186- 189 1981. Eckel RH, Albers JJ, Cheung MC, McLean EG, Bierman EL Plasma lipids and microangiopathy in Diabetes Care; 4:447-493 , 1981. insulin- dependent diabetes mellitus. Eckel RH, Fujimoto WY. Quantification of cell death in human fibroblast by measuring the loss of Anal Biochem; 114: 118- 124, 1981. (14C ) thymadine from prelabeled cell monolayers. in vitro lifespan of 3T3-l1 cells on hormonal 10. Eckel RI-I, Fujimoto WY , Brunzell JD. Effect of Int J Obesity; 5:571-578, 1981. responsiveness of lipoprotein lipase activity. ii. Brunzell JD, Schwartz RS , Eckel RH. Goldberg AP. Insulin and adipose tissue lipoprotein lipase , 1981 activity in humans. Int J Obesity; 5:685-694 12. Sadur CN, Eckel RH. Insulin stimulation of adipose tissue lipoprotein lipase: use of the euglycemie 1125, 1982. clamp technique. J Clin Invest; 69: 1119- 13. Kern P A, Knedler; Eckel RH. Isolation and culture of microvascular endothelium from human 1829 1983. adipose tissue. J Clin Invest 71(6):1822- 14. Sadur CN, Eckel RH. Insulin-mediated increases in the HOL cholesterol/cholesterol ratio in
Arteriosclerosis; 3:339-343, 1983. humans. of lipoprotein lipase in cultured 15. Eck,el RH, Prasad JE, Kern P A, Marshall S: Insulin regulation 114: 1665- 1671 , 1984. isolated rat adipocytes. Endocrinology; 16. Kern PA, Eckel RI-I. Absence of lipoprotein lipase in cultured human adipose stromal cells. Arteriosclerosis 4:232-237, 1984. Robert H. Eckel , Iv.
17- Sadur CN, Yost TJ, Eckel RH. Fat feeding decreascs insulin responsiveness of adipose tissuc
lipoprotein lipasc- Metabolism; 33: 1043- 1047 , 1984-
, regulated and functional in rat brain- Proc 18- Eckel RH, Robbins RJ: Lipoprotein lipasc is produccd
Natl Acad Sci USA; 81:7604-7607 1984. 19- Sadur CN , Yost TJ, Eckel RH. Insulin responsivcness of adipose tissue lipoprotein lipase is delayed 1182 , 1984. but prcservcd in obesity- J Clin Endocr Metab; 59: 1176- primar cultnres of isolated 20. Kern PA , Marshall S , Eckel RH. Rcgulation of lipoprotein lipase in
human adipocytes. J Clin Invest; 75:199-208 1985. 21. Berr F, Eckel RH, Kern F Jr. Plasma dccay of chylomicron remnants is not affected by heparin- J Lipid Res; 26:852-859 1985- stimulated plasma lipolytic activity in nonnal fasting men. 22- Berr F, Eckel IUl Kern F Jr. Contraceptivc stcroids incrcase hepatic uptake of chylomicron 651 , 1986- rcmnants in healthy young women. J Lipid Res; 27:645- Garvcy WT, Grundy SM. Eckel RH. Xanthogranulomatosis in an adult: lipid analysis of xanthomata
and plasma- JAm Acad Derm; 16: 183- 187 , 1987- glucosidasc 24. Baron AD, Eckel RI- Schmeiser L, Kolterman OG. The effect of short term a- Metabolism; 36:409-415 , 1987- inhihition on carbohydratc and lipid metaholism in typc II diabetics. Kern PA, Mandic A, Eckel RI-I- Regulation of lipoprotein lipase by glucose in primary cultures of Diabetes; 36: 1238- isolated human adipocytes: rclevance to the hypertriglyceridemia of diabetes- 1245 , 1987. 26. Eckel RH , Yost TJ. Weight reduction increases adiposc tissue lipoprotein lipase rcsponsivcness in
obese women. J Clin Invest 80:992-997 , 1987- Eckel RH, Goldberg D , Steincr L, Yost TJ , Patcrniti JR,Jr. Plasma lipolytic activity: relationship to Diabetes; 37:610-615 1988- postheparin lipolytic activity and evidence for metabolic regulation. Eckel RH, Sadur CN, Yost TJ- Deficicncy of the insulin/glucose-mediated decrcase in senlm Int J Obesity; 12:369-376 1988. triglyccrides in nonnolipidemic obese subjccts. obese womcn: a permissivc 29. Yost TJ, Eckel RIl Fat calories may be preferentially stored in reduccd- , 1988- J Clin Endocr Metab; 67:259-264 pathway for resumption of the obcse state. Draznin B , Sussman KE, Eckel RH, Kao M, Yost TJ , Shennan N. Possihle role of cytosolic free 30- J Clin calcium concentrations in mediating insulin rcsistance of obcsity and hyperinsulinemi Invest. 82:1848- 1852 1988. 31. Yost TJ, Eckel RH. Hypocaloric feeding in obese womcn: metabolic effects of medium-chain
triglyceride substitution. Am J Clin Nutr; 49:326-330 1989. obese state- 32. Eckel RlI, Yost TJ. HDL subfractions and adipose tissuc metabolism in the reduced-
J Phys- 256:E740-746 , 1989- like growth factor action and 33- Kern PA, Svoboda ME, Graves D , Eckel RH, Van Wyk n. Insulin- Diabetes 38:710-717 production in adipocytes and endothelial cclls from human adipose tissue. 1989.
34. - Eckel RH. Lipoprotein lipase: A multifunctional cnzymc relevant to common metabolic diseases.
Engl J Med; 320:1060- 1068 1989- 35. Samuels MH, Eckel RH: Massi ve insulin. overdosage: Detailed studies of free insulin levels and
glucose requirements. Clin Tox J Tox; 26:157- 168, 1989. , Klecker RW, Flexner C, Eckel Lorentsen KJ, Hendrix CW, Collins JM, Kornhauser PM, Perr BG 36. Ann Int RH, Barlett JG , Leitman PS. Dextran sulfate is poorly absorbed after oral administration.
Med; 111:561- 566, 1989. chain or 37. Brass EP, Tserng K- Y, Eckel RI-I. Urinar organic acid excretion during feeding of medium- Am J Clin long-chain triglyceride diets in patients with non- insulin dependent diabetes mellitus.
Nutr, 52:923-926, 1990. KODen n. c.cKei. ivi.l). , Ohtake A, Yost TJ- Lipoprotein lipase: 38. Eckel Raynolds MV, Bessesen DH, Farese R V Jr , 1990- hormonal and nutritional regulation- J Drug Devel; 3 Suppl 1:91- , Wood WM , Eckel RH. 39- Raynolds MV, Awald PD, Gordon OF, Gutierrez-Hartmann A , Rule DC Lipoprotein lipase gene expression in rat adipocytes is regulated by isoproterenol and insulin through
different mechanisms- Mol Endocr; 1416- 1422, 1990- 40- Farese RV Jr, Yost '11 , Eckel RH- Tissue- specific regulation of lipoprotein lipase activity by Insulin
in normal weight humans. Metabolism; 40:214-216 1991. 41. Neville MC , Waxman LJ , Jensen DR, Eckel RH. Lipoprotein lipase in human J Lipid Res; 32:251-257 1991. milk:compartmentalization and effect of fasting, insulin and glucose. 42- Iensen DR , Besscsen DR Etienne J , Eckel RII. Neville Me. Distribution and source of lipoprotcin
lipase in mouse mammary glands- J Lipid Res: 32:733-742, 1991. , Haskell WL, Marshall JA, Baxter J, Hamman 43. Regensteiner Mayer El' , Shetterly SM , Eckel RH diabetic men RF. Relationship between habitual physical activity and hyperinsulinemia among non- Diabetes Care; 14: 1066- 1074 , 1991- and women: Thc San Luis Valley Diabetes Study. 44- Bcssesen DH, Robertson AD , Eckel RH. Weight reduction increases adipose but decrcascs cardiac , 1991. LPL in reduced- obcse Zuckcr rats- Am J Phys; 261 :E246-E25I 45. Mayer EJ , Burchfiel CM, Eckel RH, Marshall JA, Haskell WL, Hamman RF. The role of insulin and body fat in associations of physical activity with lipids and lipoproteins in a bi-ethnic population: 11:973-984 1991. The San Luis Valley Diabetes Study- Arteriosclerosis and Thrombosis;
46. - Yost TJ , Eckel RH. Regional similarities in the metabolic regulation of adipose tissue lipoprotein
lipase. Metabolism; 41 :33- , 1992- Sniderman A , Cianflone K, Eckel RH- Levels of acylation stimulating protein in obese women , 1991. before and after moderate weight loss. Int J Obesity; 15:327-332 Surv Ophthalmol 48. Barchiesi BJ, Eckel RH , Ellis PP- The cornea and disorders of lipid metabolism 36: 1- , 1991. 49- Glaser DS , YostTJ, Eckel RH- Preheparin lipoprotein lipolytic activities: Relationship to plasma 214 , 1992- lipoproteins andpostheparin lipolytic activities. J Lipid Res; 33:209- 50. Eckel RH , Hanson AS , Chen A Y, Berman IN, Yost TJ, Brass EP- Dietary substitution of medium- chain triglycerides improves insulin-mediated glucose metabolism in non-insulin dependent
diabetics- Diabetes; 41:641-647, 1992. 51. Fulton-Kehoe DL, Eckel RH, Shetterly S , Hamman RF. Detennnations of total HDL and HOL subfraction cholesterol levels among Hispanic and non-lIispanic white subjects with normal glucose 1200 1992. tolerance- The San Luis Valley Diabetic Study. J Clin Epidemiol; 45:1191- 52. Curre RA, Eckel RH. Characterization of a high affinity octamer transcription factor binding site in 298:630-639, 1992- the human lipoprotein lipase promoter. Arch Biochem Biophys; 53. Yost TJ, Jensen DR, Eckel RH. Tissue-specific lipoprotein lipase: Relationship to body composition Obesity Res; , 1993. and body fat distribution in normal weight humans. 1:1-- Lancet; 340: 1452- 1453, 1992. 54. Eckel RH. Insulin Resistance: An adaptation for weight maintenance. 55. Bessesen DH, Richards CL, Etienne J, Goers JW, Eckel RH. The spinal cord is the most abundant J Lipid Res; 238 1993. source of lipoprotein lipase in the central nervous system. 34:229- specific lipoprotei 56. Yost TJ, Rodgers CM, Eckel RH. Suction lipectomy: Outcome relates to region- 1108, 1993. lipase activity and interval weight change. Plastic Reconstr Surg; 92:1101- , Ravussin E. Relationship 57. Ferraro RT, Eckel Larson DE, Fontvieille A-M, Rising R, Jensen DR J Clin Invest; bctween skeletal muscle lipoprotein lipase activity and 24-hr macronutricnt oxidation- 92:441-445 1993. Rubctt ; ;.c;; . rv
58- Jensen DR, Gavigan S , Sawicki V, Witsell DL, Eckel RI-, Neville Me. Regulation of lipoprotein Biochem J; 98;321-327 lipase1994- activity and MRNA in the manu-nary gland of the lactating mouse- 59. Erskine 1M, Jensen DR, Eckel RIt Macronutrient regulatIOn of lipoprotein lipase is
posttranslationaL J Nutrition; 124:500- 507 , 1994- 60. Yost TJ, Erskine JM , Gregg 1'S , Pod!ecki DL, Brass EP, Eckel RH. Dietary substitution of medium chain triglycerides (met) in non-insulin dependent diabetes mellitus in an ambulatory setting: impact JAm Col Nutrition; 13:615-622 , 1994- on control and insulin- mediated glucose metabolism- 61. Bagdade ID , Dunn 1-1., Eckel RH, Ritter Me. Intraperitoneal insulin thcrapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activity in insulin-dependent diabetes mellitus-
Arterioscler Thromb; 14: 1933- 1939 , 1994. 62. Yost 1'1 , Froyd KK, Jensen DR, Eckel RH- Change in skeletal muscle lipoprotein lipase activity in Metabolism; 44:786-790 response to insulinlglucose in non-insulin- dependent diabetes mellitus- 1995- 63. Travers SH, Jeffers BW, Bloch CA, Hill 10, Eckel RH. Gender and Tanner Stage differences in J Cfin Endocr Metab; 80: 172- body composition and insulin sensitivity in early pubertal children. 178 , 1995. 64. Eckel RH, Yost T, Jensen DR. Sustained weight reduction in moderately obese women results in Eur J Cfin Invest; 25:396-402 , 1995- decreased activity of skeletal muscle lipoprotein lipase. Obesity Res; 3: 191-204 - Bessesen DH, Rupp CL, Eckel RH- Trafficking of dietar fat in lean rats- 1995. Bessesen DH, Rupp CL, Eckel RH- Dietary fat is shunted away from oxidation towards storage in
obese Zucker rats- Obesity Res; 3: 179- 190 , 1995- 67- Morin CL, Schlaepfer IR, Eckel RIL Tumor necrosis-a climinates binding of NF- Y and an octamer- 1689 binding protein to the lipoprotein lipase promoter in 3T3-Ll adipocytes_ .I Clininvest; 95:1684- 1995. , Hamman RF- 68. Regensteiner JG, Shctterly SM, Mayer El, Eckel RH, Haskell WR, Baxter J Relationship between habitual physical activity and insulin area among persons with impaired Diabetes Care; 18:490-497, 1995. glucose tolerance: Thc San Luis Valley Diabetes Study 69- Yost TJ, Sadur CN, Eckel RH- Glycohemoglobin levels relate to the response of adipose tissue Metabolism; lipoprotein lipase to insulin/glucose in obese non-insulin- dependent diabetes mellitus. 44: 1475- 1480, 1995. 70. Yost TJ, Jensen DR, Eckel RH. Weight regain following sustained weight reduction is predicted by
relative insulin sensitivity. Obesity Res; 3:583-587, 1995. activity in Coppack SW, Yost TJ, Fisher RM, Eckel RH, Miles JM. Peri prandial and regionallipase
nonral men. Am J Physiol; 270:E718-E722, 1996. Gnudi L, Jensen DR, Tozzo E, Eckel RH, Kahn BE. Adipose specific Gverexpressian of the GLUT4 glucose transporter in transgenic mice alters lipoprotein lipase acti vity in muscle and Am Physiol; 270 (Rcgu1atory adipose tissue: Implications for regulation of nutrient paritioning. Integrative Compo Physio1.9):R785-R792, 1996. 73. Eckel RH, Jensen DR, Schlaepfer IR, Yost TJ. Tissue-specific regulation of lipoprotein lipase by
isoproterenol in normal weight humans. Am.l Physiol; (Regulatory Integrative Compo Physiol. 40):RI280-RI286, 1996. 74. Bagdade , JD, Kelley DE, Henry RR, Eckel RH, Ritter Me. Effects of multiple daily insulin injections and intraperitoneal insulin therapy on cho1esteryl ester transfer and lipoprotein lipase Diabetes; 420 1997- activities in no" insulin- dependent diabetes mellitus. 46:414- Raben M. t:CKCI, lvi- 221 Mehler PS , Lezotte , D, Eckel RH- Lipid levels in anorexia nervosa- Int J Eating Dis; 24:217- 1998. 76. Morin CL, Pagliassotti MJ , Windmiller D, Eckel RH. Adipose tissue-derived tumor necrosis factor-
a is elevated in older rats. J Gerantol; 52:B 190-B 195 , 1997. Hartmann Jensen DR , Schlaepfer lR, Morin CL, Pennington DS, Marcell T, Ammon SM, Gutierrez- , Eckel Rlt Prevention of diet-induced obesity in transgenic mice overexpressing skeletal muscle 273:R683-R689 , 1997. lipoprotein lipase. Am J Physiol (Regulatory Integrative Comp- PhysioI42_ derived tumor 78. Morin CL, Eckel RH, Marcel T, Pagliassotti MJ. High fat diets elevate adipose tissue- , 1997- necrosis factor- a activity. Endocrinology; 138:4665-4671 79. Morin CL, Eckel RH- Transgenic and knockout animals: Novel mechanisms of body weight /Nutr Biochem; 8:702-706 rcgulation. , 1997. 80- Donahoo WT, Jensen DR, Yost T, Eckel RH- Isoproterenol and somatostatin decrease plasma leptin 4143 in humans: A novcl mechanism regulating leptin secretion- J Clin Endocrinol Metab; 82:4139- 1997. 81. Eckel RII. Obesity and heart disease: a statement for healthcare professionals from the Nutrition , 1997. Committee , American Heart Association- Circulation. Nov 4;96(9):3248- like growth - 83. Travers SH, Labarta JI, Gargosksy SE, Rosenfeld RG, Jeffers BW, Eckel RH- Insulin- factor binding protein- l (lGFBP- l) levels are strongly associated with insulin sensitivity and obesity , 1998- in early pubertal children. J Clin Endocrinol Metab; 83: 1935- 1939 - Bagdade JD, Teuscher A , Ritter MC, Eckel RH, Robertson RP- Alterations in cholesterol ester transfer, lipoprotein lipase, and lipoprotein composition following combined pancreas-kidney
transplantation- Diabetes; 47: 113- , 1998. 85. Yost TJ , Jensen DR, Haugen B , Eckel RI-t Effect of dietar macronutrient composition on tissuc- specific lipoprotein lipase activity and insulin action in normal- weight subjects. Am J Clin Nutr; 68:296-302, 1998. , Smith S 86. Regensteiner JG, Bauer T A , Reusch J EB , Brandenburg SL, Sippel JT, Vogelsong AM Wolfel EE, Eckel RI-I, Hiatt WR- Abnormal oxygen uptake kinetic responses in women with type IT
diabetes mellitus- J Applied Physiol; 85; 1 310- , 1998. 87. Huey PU, Marcell T, Owens GC, Etienne J , Eckel RH. Lipoprotein lipase is expressed in cultured J Lipid Res; 39 2135- 2142 1998. Sehwann cells and functions in lipid synthesis and utilization- 88- Donahoo WT, Eckel RH. Lipid management post-myocardial infarction: Outcomes and cost.
Primary Care Case Reviews; 1:4, 158- 167, 1998. 89. Schlaepfer lR, Eckel RH. Plasma triglyceride reduction in mice following direct injections of muscle-
specific lipoprotein lipase DNA. Diabetes; 48:223-227, 1999. , Jensen 90. Ginzinger DG, Clee SM, Dallongeville J, Lewis ME, Henderson HE, Bauje E, Togers QR DR, Eckel RH, Dyer R, Innis S , Jones B , Fruchar JC, Hayden MR- Lipid and lipoprotein analysis of 29; 1: 17- cats with lipoprotein iipase deficiency. Eur J Clin Jnve3t; , 1999. 91. Grundy SM, Benjamin IJ, Burke GL, Chait A. Eckel RH, Howard BV, Mitch W, Smith SC, Sowers JR. Diabetes and cardiovascular disease: a statement for healthcare professionals from the council on Diabetes Care; arerioselerosis, thrombosis and vascular biology of the American Hear Association. , C21- , 1999. Int J Eat 92. Mehler PS, Eckel RH , Donahoo WT, Leptin levels in restricting and purging anorectics. Disord- Sep;26(2):189- , 1999. 93. Shepard TY, Jensen DR, Blotner S. Zhi J, Guerciolini R, Pace D, Eckel RH. Orlistat fails to alter Int J postprandial plasma lipid excursions or plasma lipases in norn1al weight male volunteers. (2): 187- Obesity RelatMetab Disord; 2000. RoDen t1. cCKti , lvi. , B , Sanan DA, Raber J, Eckel RH, Farese 94. Smith SJ, Cases S, Jensen DR , Chen HC , Sande E, Tow Jr. R V, Obesity Resistanee and multiple mechanisms of triglyceride synthesis in mice lacking DGA T Nature Genetics 25:87- 2000, , Jensen DR, Eckel RI'!. Increascd 95, Poirier P, Marcell T, Uclmen Huey P: Schlacpfcr fR , Owens GC Intracellular Triglyceride in C2C 12 Musclc Cells Transfectcd with Human Lipoprotein Lipase Biochem Riophys Res 270:997 - I 001 , 2000, , Jenscn DR, Eckel RH Brown NS , Smart A, Sharma V, Bonkmeicr ML, Greenlee L, Camper SA KrczeI W, Chambon P and Haugen BR, Thyroid honnone rcsistance and increased metabolic rate in 79, 2000, thc RXy deficient mousc, J Cfin Invest 106:73- lIpoprotein lipase and Donahoo WT Jensen DR, Shcpard TY, Eckel RH, Seasonal varation in J Cfin Endo Metab 85:9: 3065-3068 2000. plasma lIpids in physically active nOlmal weIght humans. Shepard TY, Weil KM, Shar TA, Grunwald GK, Bell ML, Hill JO, Eckel RH, Occasional physical inactivity combined with a high- fat dict may be important in thc dcvelopment and maintcnance of , 200!. obesity in human subjccts. Am J Clin Nutr 73:703-708 , Clec SM, Hayden MR, Eckel RH, Hickman 99. Backus RC, Ginzinger DG, Ashbourne Excoffon KJD A, Rogers QA. Maternal expression of functional lipoprotein lIpase and effects on body fat mass and Am J Vet Res 62:264-269, 200!. condition scores of mature cats with lipoprotein lipase deficiency, Correcting Indirect Calorimeter tOO. Jensen DR, Gayles EC, Ammon S , Phillips R, Eckel RH, A Self- J ApI' Phys 90:912-918 2001. System for the Measurement of Energy Balance in Small Animals , Deckelbaum RJ, Erdman JW, Krs- 101. 'Krauss RM , Eckel RH , Howard B , Appel U , Daniels SR , Mullis R, Robinson K, Wylie- Etherton P, Goldberg I, Kotchen TA, Lichtenstein AH, Mitch WE Revision 2000: A , Suttie J, Tribble DL, Bazzare TL. AHA Dietar Guidelincs Rosett J, SI. Jeor S Hear statement for Healthcare Professionals From the Nutrition Committce of the American
Association, J Nutr 131 :1; 132- 146 200 L , Kris- , Eckel RH , Howard B , Appcl U , Daniels SR, Dcckelbaum RJ, Erdman JW 102. Krauss RM , Wylie- Etherton P, Goldberg I, Kotchen TA, Lichtcnstein AH, Mitch WE, Mullis R, Robinson K 2000: A , St. Jeor S , Suttic J, Tribblc DL, Bazzarc TL. AlIA Dietar Guidelincs: revision Rosctt J Hear statcment for healthcare professionals from the Nutrition Committec of the American
Stroke, Nov;31 (11 ):2751- , 2000. Association. , Peinado- t03, Davies PJ, Berr SA, Shipley GL , Eckel RII Hcnnuycr N, Crombie DL, Ogilvie KM Onsurbe J, Fievet C. Leibowitz MD, Hcyman RA, Auwerx J. Mctabolic effects of rexinoids: tissue- Mol Phannacol Feb; 59(2): 170- 2001. specific regulation of lipoprotein lipase activity. 104. Ferreira LDMC- , Pulawa LK, Jensen DR, Eckel RH. Overexpressing human lipoprotein lipase in Diabetes 50: 1064- 1068 , 2001. mouse skeletal muscle is associated with insulin resistance. Kris-Etherton P, Eckel RII, Howard BV, SI. Jeor S , Bazzare 1' The Lyon Hear Study: Bencfits of a 105. Circulation Mediterranean stylc NCEP/ AHA Step 1 dictar pattern for cardiovascular disease. 103:13; 1823- 1825 , 200!. depleted, low density 106. Monks J, Hl.ey PC, Hanson L, Eckel RH, Neville MC, Gavigan S. Cholesterol- J Lipid Research, 42:686-696, lipoprotein- sized paricles are present in the milk of lactating mice. 2001. , Stamm ER, Scherzinger AI., 107. Kosmiski LA, Kuritzkes DR, Lichtenstein KA, Glueck DR. Gourley PJ Eckel RH. Fat Distribution and Metabolic Changes arc Strongly Correlated and Energy Expenditure 15:1993-2000 2001. is Increased in the HI Lipodystrophy Syndrome. AiDS , Krauss RM, Lichtenstein AH, Sacks 108. Krs-Etherton P, Daniels SR, Eckel RH, Engler M, Howard BV , Denke MA , Stampfer M, Grundy SM, Appel U, Byers T, Campos H, Cooney G , St. Jeor S , Tracy RP Kennedy E, Marckmann P, Pearson TA, Riccardi G, Rudel LL, Rudrum M, Stein DT of the Ursin V, Vogel RA. Zock PI., Bazzare TL, Clark J. AH scientific statement: summar summar from Scientific Conference on Dietary Fatty Acids and Cardiovascular Health. Conference KODen 11. aKei , lvi. i).
Circulation. Feb 20; 103(7): 1034- the Nutrition Committee of the American Hcart Association. 2001. , Eckel RH. Dietary Protein and Weight 109. St. Jeor S , Howard BV, Prcwitt, TE, Bovee V. Bazzare T 2001. Reduction. Circulation 104: 1869- 1874 lipase is cxprcsscd in rat sciatic ncrve and 110. Huey PU, Waugh KC, Etienne J. Eckel'RH. Lipoprotcin 43: 19- , 2002. regulated in rcsponse to crush injury. 1. Lipid Research , Huey PU, Pulford BE, Ishii DN and Eckel RH. Sciatic nerve lipoprotein lipase is Ill. Ferreira LOMC- 143(4): 1213- Endocrinology, reduced in streptozotocin- induced diabetes and correctcd by insulin. 1217 2002. , Erlich HA, Ehrlich J, Eckel RH , Cheng S, Sncll-Bergeon JK, Grow MA, Hung C 112. Hokanson JE 480C;o T) is Rewers M. A conunon promotcr polymorphism in the hepatic lipase gcne (LIPC- Diabetes. Diabete. Apr. 51:4; 1208- associated with an increase in coronar calcification in Type I 1213 2002. lipase and insulin sensitivity. Curr 113. Pulawa LK and Eckel RH. Overexpression of musclc lipoprotci 5:569-574, 2002. Opin Clin Nutr Mctab Care NlDK Working Group on the 114. Eckel RI-I, Ershow AG , and Barouch WW. Report of the NHBI- Circulation 105:2923-2928 , 2002. . Associated Cardiovascular Discase. Pathophysiology of Obesity- , Pitas RE , Eckel RH 115. Chen HC, Smith S1, Ladha Z, Jensen DR, Ferreira LO, Pulawa LK McGuirc JG and Farese RV Jr Incrcased insulin and leptin scnsitivity in micc lacking acyl CoA:diacylglycerol 2002. . acyltransferase. J Clin Invest. 109(8): 1049- 116. Travers SH, Jcffers BW , and Eckel RH. Insulin Rcsistancc During Puberty and Future Fat 3818 , 2002. Accumulation. J Clin Endo and Metab 87:8; 3814- , Lopes- Virella M , Rcusch J, Rudcnnan N, 117. Eckel RH, Wassef M, Chait A, Sobel B, Barrett E, King G Steiner G, and Vlassar H. Prevention Conference VI Diabetes and Cardiovascular Disease Wnting Circulation 105:el38-eI43, 2002. Group II: Pathogenesis of Atherosclcrosis in Diabetes. 118. Grundy SM, Smith S Jr., Eckel RH, Redberg R, and Bonow RO. Prevention Conference VI: Diabetcs proceeding for healthcare professionals and Cardiovascular Disease: Executive summar: conference Circulation 105:2231-9, 2002. from a special writing group of the American Heart Association. , Marcovina SM and Eckel RH. 119. Plenge JK, Hernandez 1'1., Weil KM, Poirier P, Grunwald GK Simvastatin lowers C-reactive protein within fourteen days: An effect independent of LOL cholesterol , 1447- 1452 2002. reduction. Circulation Sept 17 , 106:12; 12 lM, Fortmann SP, Franklin BA, Goldstein LB , Blair SN, Daniels SR , Eckel RH, Fair 120. Pearson l' A , Sallis , 1r, JF, , Houston-Miller N, Lauer RM, Ockene IS , Sacco R Greenland P, Grundy SM, Hong Y Cardiovascular , Stone NJ, Taubert KA. AHA Guidelines for Primar Prevention of Smith SC, Jr Risk Reduction for Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensi Adult Paticnts Without Coronar or Other Atherosclerotic Vascular Diseases. American Hear Circ:.atio.' July 16, 106:3; 388-391 Association Science Advisory and Coordinating Cui:mruttee. 2002. 121. Eckel RH, Barouch WW, Ershow AG. Report of the National Hear, Lung, and Blood Institute- National Institute of Diabetes and Digestive and Kidney Diseases Working Group on the Circulation. Jun 18; 105(24):2923- pathophysiology of obesity-associated cardiovascular disease. 2002. , lipid uptake and regulation. J Lipid 122. Merkel M, Eckel RH, Goldberg U. Lipoprotein lipase: genetics Res 43:12: 1997-2006 2002. 123. Capell WH, DeSouza CA, Poirier P, Bell ML, Stauffer BL, Wei1 KM, Hernandez 1'L and Eckel RH. Short-tenn triglyceride lowering with fenofibrateimproves vasodilator function in subjects with 13, 2003. hypertriglycerid Arterioscler Throm Vasc Bio Feb. 1; 23(2):307- - .
RODcn n. r.cKd. lvi. , Jr. Obesity resistance and enhanced 124. Chen HC , Jensen DR, Myers HM, Eckel RH, and Farese RY. glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA:diacylglycerol 2003. acyltransferase I. J Clin Invest III: 1715- 1722 , James DE, Capell WI-, and Eekel RH. Increased 125. Schlaepfer IR, Pulawa LK. Ferreira fDM C- J Lipid expression of the SNARE accessory protein Munc 18c in lipid- mediated insulin resistance. Res 44: 1174- 1181 2003. 126. Duncan GE, Perr MG, Theriaque DW, Hutson AD, Eckel RH, Stacpoole PW. Exercise training, without weight loss, increases insulin sensitivity and postheparn plasma lipase activity in previously , 2003. Diabetes Care. Mar;26(3):557- sedentary adults. derived hormone levels in HlY 127. Kosmiski L, Kurtizkes D , Lichtenstein K, Eckel RH. Adipocyte- , 2003. lipodystrophy. Antivir Ther. Feb; 8( 1):9- , Kamboh MI, Scarboro S, Eckel RH, and Hamman RF Effects of the Hepatic Lipase 128. Hokanson JE 158(9); 836-843 Gene and Physical Activity on Coronar Hear Disease Risk Am. 1. Epidemiology, 2003. , Lichtenstein KA, Mosca CL, Grunwald GK 129. Kosmiski LA, Kuritzkes DR, Shar T A, Hamilton JT Eckel RH, Hill JO. Tolal- energy expenditure and carbohydrate oxidation are increased, 2003. in the human Metabolism. May; 52(5):620- immunodeficiency virus lipodystrophy syndrome. Fat distribution , Hamilton J, Sharp '1 , Lichtenstien K. Hill JO, Eckel RH. 130. Kosmiski L, Kuritzkes D HTV Med. is altered in HIV-infected men without clinical evidence of Ill lipodystrophy syndrome. 40, 2003. Jul; 4(3):235- induced weight , Weil KM, Shepard TJ and Eckel RH. The impact of diet- 131. Poirier P, Hernandez TL Obesity loss on cardiac autonomic nervous system and arrhythmias in subjects with severe obesity. 11(9); 1040- 1047 2003. Research. , Ehrlich J, Garg S , Hamman RF Dabelea D, Kinney G, Snell-Bergeon JK, Hokanson JE, Eckel RII 132. Coronar Artery Calcification: and Rewers M. Effect of Type I Diabetes on the Gender Difference in 1 Diabetes (CACTI) A Role for Insulin Resistance? The Coronar Artery Calcification in Type , 2003. Study. Diabetes Nov; 52(11):2833-2839 , Kinney G, Dabclea D, Eckel RH, Ehrlich 133 Snell-Bergeon JK, Hokanson JE, Jensen L, MacKenzie '1 Diabetes. Diabetes J, Garg S. and Rewers M. Progression of Coronar Artcry Calcification in Typel
Care 26:2923-2928, 2003. , Ehrlich J, Eckel RH, and Rewers M. 134. Hokanson JE, MacKenzie '1 , Kinney G, Snell-Bergeon JK approach that accounts for inter-scan Evaluating changes in coronar arery calcium: An analytical
Am J Roentgenology, 182:1327- 1332 2004. varability. , Parks JS, Eckel RH, Schaefer EJ Matthan NR , Welty FK, Baret HR, Harausz C, Dolnikowski GG 135. l catabolism and decreases LDL and Lichtenstein AH. Dietary hydrogenated fat increases HDL apoA- 24(6): 1092- Arterioscler Throm Vasc Bio apoB- IOO catabolism in hypercholesterolemic women. 2004. ' , Eckel RH. 136 Haugen BR, Jensen DR, Sharma V, Pulawa LK, Hays WR, Wojciech K, Chambon P RXy Deficient Mice Have Increased Skeletal Muscle Lipoprotein Lipase Activity and Less Weight 2004. Endocrinology, 145(8):3679- Gain When Fed a High Fat Diet. , Pi-Sunyer X, Hong Y, Eckel RH. Clinical 137. Klein S , Burke LE, Bray GA, Blair S, Allison D Implications of Obesity With Specific Focus on Cardiovascular Disease: A Statement for and Professionals From the American Hear Association Counsil on Nutrition, Physical Activity, In Press Metabolism. Circulation. , 2004. , St. Jeor ST, Hayman LL, Mullis RM, Blair 138. Eckel RH, York DA, Rossner S, Hubbard V, Caterson I SM. Prevention Conference VII: Obesity, a Worldwide Epidemic Related to Hear Disease and , 2004. Stroke Executive Summar. Circulation. In Press . " l\u0Cfl I-. EckeL r"
LETTERS AND EDITORIALS New 1. Eckel RIf, Sadur CN , Yost TJ. Smoking, weight change and lipoprotein lipase (Correspondence).
Eng/J Med; 311 :259- 260, 1984.
Diabetes Spectrum; 1:33- , 1987. 2. Eckel RH Very low Calorie Diets. 3. Knedler A, Eckel RII, Kcrn PA, Ham RG. Microvascular endothelial cell cultures from human omental Oct;25(I0):863- , 1989. adipose tissue. In Vitro Cell Dev BioI. J Nutr Immunol 3. Eckel RH and Kim SK. Workshop on nutrition , immunity, and infection: Introduction. 2:71- 1994. AmJ Clin Nutr; 65:164- 165 1997. 4. Eckel RH. Insulin resistance in atherosclerosis. , 1998. New Engl J Med; 338( 16): 1156 6 Krauss RM , Eckel RH. The Obesity Problem. Association. American Heart 7. Eckel RH, Krauss RM. For the Nutrition Committee of the American Hear Circulation Association Call to Action: Obesity as a major risk factor for coronary artery disease. 7:2099-2100 1998. 8. Eckel RH. The five-to-ten percent weight loss: Long-tenn changes in lipids and lipoprotcins and some 228, 1999. unanswered questions. Obesity Res 7; 227- 9. Eckel RIt Natural history of macrovascular disease and classic risk factors for atherosclerosis Diabetes Care 22: C21-C24, 1999. session summary. Diabetes 10. Ec,!el RIt Advanced glycation end products and coronar heart disease in type 2 diabetes. Care 23:1441- 2000. Invest Med; 49: 100- 103 2001. 11. Eckel RH. Perspectives on Vascular Biology and Diabetes. j 21 :1977- 1983 2001. I Mutant Increases Atherosclerosis. Arterio Thromb Vasc Bioi 12. Eckel RH. ApoA- J Cardiopulm Rehabil May- 13. Francis CC, Eckel Rll. Assessing dietar fat intake in cardiac rehabilitation. June; 22(3): 168- 2002. 14. Eckel RH. Familial combined hyperlipidemia and insulin resistance: distant relatives linked by intra- April 21 , 4:469-470, 2001. abdominal fan Arterioscler Throm Vasc Bioi Am J Clin Nutr; 78:671- , 2003. dietar protein in diabetes. 15. Eckel RH. A new look at May 22;348(21 ):2057- 16. Bonow RO and Eckel RH. Diet, Obesity and Cardiovascular Risk N Engl J Med. 2003. 17. Eckel RH Seasonal variation in scrum cholcsterollevels: Treatmcnt implications and possible mechanisms Arch Int Med In Press. all that bad? Amer J Clinical Nutrition, 18. Eckel RH Diabetes and dietar macronutrients: Is carbohydrate In Press.
CHAPTER.'! AND BOOKS, REVIEWS
the aged. IN: Clinicallntemal Medicine in 1. Eckel RH, Hofeldt FD. Endocrinology and metabolism in 255 , 1982. the Aged. Schrier RW, ed. New York, NY: WB Saundcrs; 222- Sussman KE, Draznin 2. Eckel RH. Diabetes and hyperlipidemia. IN: Clinical Guide to Diabetes Melltus , 1987. B, James WE, eds. New York, NY Alan R. Liss , Inc.; 209-222 3. Eckel RH, Kern PA, Sadur CN, Yost TJ. Methods for studying lipoprotein lipase in human adipose , Clarke WL, Lamer J, eds. Poughkeepsie, New York tissue. IN: Methods in Diabetes Research SL Pohl : 259c273, 1986. John Wiley and Sons, Inc. , ed. Chicago, IL, Lipoprotein Lipase Borensztajn J 4. Eckel RH. Adipose tissue lipoprotein lipase. IN: Evener Publishing, Inc., 79- 132, 1987. , p.
RoLcrl . cct.t;;
Current Medical Therapy. Schrier RW 5. Sadur CN, Eckel RH. Diabetes mcllitus and hyperlipidcmia. IN: ed. New York, NY: Raven Press , 486 509 1989. 6. Eckel RH, Bcssesen DB, Yost TJ. Molecular regulation of lipoprotein lipase in obcsity and diabetes
mellitus. IN: New Directions in Research and Clinical Works for Obesity and Diabetes Mellitus. , 1991. Sakamoto N, Angel A, Hatta H , cds. Elsevier-Scicncc, Amsterdam: 71- 7. Eckel RH, Bessesen DH, Raynolds MV , Jcnscn DR , Fox D , Yost TJ. Lipoprotein lipase and nutrient , Food Intake, Taste, Nutrient Par1itioning and Energy partitioning. IN: Ihe Science of Food Regulation , LA LSD Press: 187- 192, 1992. Expenditure Bray GH, Ryan DH, eds. Baton Rougc Diabetes and Atherosclerosis Draznin B 8. Eckel RH. Lipoprotein lipases and diabctes mellitus. IN: Eckel RH, eds. New York, NY; Elsevier-Science: 77- 102 , 1993 Intem J Obesity 9. Eckel RH, Yost TJ , Jensen DR. Alterations in lipoprotein lipase in insulin resistancc. 19:516-521; Supplement I , 1995: , ed. Primary Care Secrets Mladenovic J 10. Estacio R , Eckel RH. Abnormalities of lipids. IN: Philadelphia, PA Hanley and Bclfus, Inc. 134- 140 , 1995- Atherosclerosis; X:231- 11. Morin CL, Eckel RIf. Transcriptional regulation of the lipoprotein lipase gene. 235 , 1995. , Steffens 12. Eckel RH, Ailhaud G, Astrup A, Flatt J- , Hauner H, Levine AS, Prenticc AM, Ricquier D , Woods se. What are the metabolic and physiological mechanisms associated with the regulation of Bray GA body weight? IN: Regulation of Body Weight: Biological and Behavioral Mechanisms , 1996. BCfchard C, eds. Dahlcm Workshop Report LS 57. Chichester: John Wiley & Sons Ltd- Current Opinions in Endocrinology D. Donahoo WT , Eckel RH. Adipocytc metabolism in obesity. IN:
and Diabetes; 3:501-508 1996. 14. Kosmiski L, Eckel RH. Dyslipidcmia, atherosclerosis and non-insulin dependent diabetes mellitus. IN: , Rizza R, eds. Humana Press Clinical Research in Diabetes Melltus and Obesity Volume II. Draznin B 159- 185 , 1997 15. Kosmiski L, Eckel RH. The use of anorectic agents in non-insulin dependent diabetes mellitus. IN: 1998ln Press. Current Opinions in Endocrinology and Diabetes Bray CA, Bouchard 16. Arer P, Eckel RII. Adipose tissue as a storage organ. IN: Handbook of Obesity. , James WPT, cds. Marcel Dekker, lnc. 379-396 1998- . IN. Endocrinology Clinics 17. Donahoo WT, Kosmiski LA, Eckel RH. Drugs causing dyslipoproteinemi of North America J Hoeg, ed, WE Saunders, Inc. ; 27: 677-698, 1998. 18. Eckel RH. The importnce of timing and accurate interpretation of the benefits of weight reduction on
plasma lipids. Obes Res - Mar; 7(2):227- 1999. 19. Poirier P, Eckel RH, Adipose tissue metabolism and obesity IN Physical Activity and Obesity Bouchard , ed. Human Kinetics publisher, Chapter 9 181-200, 2000. Progress in Obesity Research 20. Eckel RH. Substrate trafficking and the regulation of adipose mass- IN: , 1999. B Guy-Grand and G Ailhaud, eds, John Libbey & Company, Ltd.;50:415-422 21. Eckel RH. Late breaking advances in the biological understanding of obesity and its sequelae IN: , NY, Futura publishing,: 205- Obesity: Impact on Cardiovascular Disease Fletcher GF MD, ed. Armonk 218, 1999. Hil: 2289- HURST'S THE HEART. NY, NY McGraw- 22. Poirier P , Eckel RH. The Hear in Obesity IN: 2303 2001. Cardiology Special Edition 7: 17- 23. Poirier P , Eckel RI.I. Management of Diabetes and Hear Disease. 2001. s The Heart: Manual of Cardiology. McGraw 24. Poirier P , Eckel RH. The Hear and Obesity. IN: Hurst Hill, NY: 733-749, 2001. .., . ,- ' '- - - * , , p. 1 'If I'OUCl 11. L,.."- . j.v'!.L'.
25. Donahoo WT, Stephens E, Eckel RHo The Evaluation of Dyslipidemia and Obesity, IN: The Handbook of Diagnostic Endocrinology. Humana Press, 2002 In Press. , 2002. 26. Donahoo WT and Eckel RH. Leptin. McGraw Hill Yearbook of Science Am.l Clin Nutr 76(suppl):264S-265- , 2002. 27. Ludwig DS and Eckel RHo The Glycemic Index at 20 y 1. Lipoprotein Lipase and Insulin Sensitivity. 28. Pulawa LK and Eckel RH. Overexpression of Muscle 5: 569-5742002 Current Opinion in Clinical Nutrition and Metabolic Care Nov;4(6):448- 29. Poirier P and Eckel RHo Obesity and Cardiovascular Disease Curr Atheroscler Rep. 2002- , Taylor JA, Eckel RH, Jenscn DR 30 Cooke PS , Naaz A, Heine PA, Zakroczymski MA , Saunders P1'K Helferich WG , and Lubahn DB. Chapter 179 Effects of Estrogen and phytoestrogen signaling through Progress in Obesity estrogen receptor a IER a) and ERp on adipose tissuc in males and females. IN:
Re. earch. In Press, 2003. . IN: Obesity Mechanisms and , RII. Obesity: A disease or a Physiologic Adaptation for Surviva 31. Eckel , Philadelphia, PA, p. 3- Clinical Management. ed, Eckel, RH , Lippincott , Williams and Wilkins 2003. Primary Care Secrets 3'd Edition 32. Wolfert AL and Eckel RHo Abnormalities of Lipids. Chapter 31 IN: , 2004. , M. , ed. Hanley & Belfus, Philadelphia, PA 176- 180 Jeanette Mladenovic Strategies. 33. Morrs AM, Calsbeek DJ and Eckel RII. Lipid Metabolism and Nutrient Paritioning 3; 411-430, 2004. CNS Neurological Disorders Current Drug Targets- Drug Discovery 34. Capell WH and Eckel RH. Therapeutic Targets in Severe Hypertriglyceridemi In Press, 2004. Today: Disease Mechanisms. Metabolic 35. Sutherland lP , McKinley B and Eckel RJi. The Metabolic Syndrom" and Inflammation. , 2004. Syndrome and Related Disorders. 2; 82- 104
ABSTRACTS Presented; ** at both regional and national meetings) Eckel RH, Waterhouse BE, Bozdech MJ , Crowell EB , Jr Antiplatelet drugs in thrombotic Dallas , Texas American Society of Hematology Annual Meeting thrombocytopenic purpura (TIP). December, 192, 1975. Eckel RH, Fujimoto WY, Brunzell JD. The development of lipoprotein lipase (LPL) in cultured 31'3-
Ll cells. Clin Res; 25:495A, 1977. Eckel RII, Fujimoto WY, Brunzell JD. The development of lipoprotein lipase (LPL) in cell culture.
Diabetes; 26; SuppLl :373 1977. Eckel RII, Albers JJ, Wahl PW, Bierman EL. Alterations of high density lipoprotein cholesterol in 26:560A, 1978. juvenile onset diabetes. Clin Res; Clin Res Eckel RH, Fujimoto WY , Brunzell JD. Insulin regulation of lipoprotein lipase in culture. 26:413A, 1918, pool of cultured cells. Eckel RH and Fujimoto WY. Quantitation of cell death in the proliferati , 189 1979* Annual Meeting of the Tissue Culture Association Abstracts Eckel RH, Albers JJ, McLean EB , Wahl PW and Bierman EL. High density lipoprotein cholesterol Diabetes; 27(Supp1.2):67, 1978. and microangiopathy in juvenile onset diabetes mellitus. Eckel RH, Fujimoto WY. Abnormalities in insulin stimulated leucine incorporation into protein and Clin Res; 27:85A, 1979. uridine incorporation into RNA in diabetic fibroblasts. Eckel RH, Albers JJ, Cheung MC, Wahl PW, Bierman EL Antiatherogenic high density lipoprotein Clin Res; 27:44A, 1979. composition in juvenile onset diabetes melltus. enhanced lipoprotein lipase 10. Eckel RII, Fujimoto WY, Brunzell JD. Gastric hhibitory polypeptid , 1979. * activity in cultured cells. Clin Res; 27:354A ,; . .
Kobert n. teke!, /vi. . Bierman EL. Antiatherogenic high density lipoprotein 11. Eckel RH. Albers JJ, Cheung MC, Wahl PW Diabetes; 28 (Supp1.:94), 1979* compositio in juvenile onset diabetes mellitus. 12. Eckel RH, Fujimoto WY. The decreased growth capacity of fibroblasts from diabetes donors is not Clin Res; 28:48A, 1980* attributable to enhanced ccll death. Sadur CN, Eckel RH. Insulin-induced ,alterations in lipoprotein lipase activity: Usc of the 1981* euglycemic clamp technique. CLin Res;29:59A 14. Sadur CN , Eckel RIL Insulin stimulation of adiposc tissue lipoprotein lipase activity in man: a Clin Res; 29:421 A, 1981.* definite , but dclayed effect. 15. Eckel RH, Gwinner DA. Varability in lipoprotein lipase regulation in cultured prcadipocytes also CLin Res;29:404A , 1981. occurs in primar cultures. lipoprotein 16. Eckel RH, Gwinner DA. primary cultures of rat adipocytes also demonstrate varability in 108:370, 1981. lipase regulation. The Endocrine Society Abstracts; 17. Sadur CN, Eckel RH. Insulin-mediated decreases in plasma cholesterol in man: use of the Diabetes; 30; (SuppI.2): 189 , 1981* euglycemic clamp technique. 18. Sadur CN, Eckel RH. Alterations in insulin stimulation of adiposc tissue lipoprotein lipase in obesity.
Clin Res; 30:64A, 1982. * 19. Sadur CN, Eckel RH. Insulin stimulation of adipose tissue lipoprotein lipase in obesity: A deviation CLin Res; , 1982. from insulin resistance. 30:403A Marshall S. Adipose tissue lipoprotein lipase regulation by insulin in 20. Eckel RlI , Kern PA, Prasad Cfin Res; 30:390A, 1982. Jhe cultured rat adipocyte: A sclective protein synthesis dependenreffect. Diabetes; 31 21. . Sadur CN , Eckel RH, Insulin- mediated lipoprotcin metabolism in obesity. (Supp1.):596, 1982. 22. Kern PA , Eckel Rlf. Lipoprotein lipase activity is measurable in cultured isolated human adipocytes.
Diabetes; 31 SuppI.2:228, 1982* 23. Kern PA, Knedler A, Eckel RlL The isolation and culture of human microvascular endothelium.
Circulation; 66:II:204, 1982* , Jr. Plasma lipolytic activity in humans: evidencc for 24. Eckel RH, Steiner L, Kern PA , Paterniti JR 66: 11:282 , 1982* hormone regulation. Circulation; 25. Sadur CN, Yost TJ, Eckel RH. Fat feeding decreases insulin responsiveness of adipose tissue , 1983** lipoprotein lipase. Clin Res; 31 :60A and 244A3 26. Eckel RlI, Prasad IE, Kern PA, Marshall S. Cultured isolated rat adipocytes. a novel system for CLin Res; 31 :54A , 1983. * investigation of lipoprotein lipase regulation by insulin. lipase in cultured isolated human 27. Kern PA, Marshall S, Eckel RH. Regulation of lipoprotci
adipocytes. Diabete. , Suppl.:55, 1982. 28. Clark RAP, Folkvord JM, Kern PA, Eckel RH. Human endothelial cells from both large and small J Cell BioI; 97 ;327 A, 1983. blood vessels demonstrate fibronectin dependent inherence. lipoprotein lipase than insulin in 29. Kern PA, Eckel RH. Glucose is a more impoIT..01t regulatar of Clin Res; 32:49A and 400A , 1984. ** cultured isolated human adipocytes. Cfin Res; 32:74A 30. Eckel RH, Robbins RJ. Lipoprotein lipase is produced and regulated in the brain. and 394A, 1984* 31. Sadur CN, Yost TJ, Eckel RII. Glucose is the major detennnant of the early response of adipose Cfin Res; 32:86A and 407 A, 1984. tissue lipoprotein lipase acti vity to insulin. 32. Berr F, Eckel RH, Kern F, J r. Plasma disappearance of retinol palmitate labeled chylomicrons is Cfin Res; 32:45A, 1984. independent of enhanced plasma lipolytic activity. 33. Berr F, Eckel RH, Kern F, Jr. Plasma clearance of retinol palmitate labeled chylomicrons is not Gastroenterology 1984. affected by enhanced plasma lipolytic activity. KuoCn ri. Eckei. lvi.
Clin Res1986; 34:543A resistance: Elevated fasting (basal), yet diminishcd sensitivity of response. 1986* Eckel RH, A wald PO, O' Shea AM, Edwards DP. Heparin treatment of cultured rat adipocytes results Clin Res; 34:543A, 1986* in a quantitative and highly purified preparation of lipoprotein lipase. Kern PA , Eckel RH. Effect of glucose on lipoprotein lipase and lipolysis in cultured human
Clin Res; . 1986. adipocytes: Reievance to diabetes. 34:547 A 36. Eckel RH, Yost TJ. Weight reduction increases adipose tissue lipoprotein lipasc responsiveness in Diabetes; 35: lOA obcse womcn: A potential mcchanism for resumption of the obese state. is deficient in 37. Sadur CN , Yost TJ , Eckel RI.t Insulin stimulation of adiposc tissue lipoprotein lipase 1984. typc II diabeti s. Diabetes 33 (Suppl.): , 623 C may bc a local regulator of 38. Kern PA , Graves D , Baskin J, Eckel RH. Van Wyk JJ. Somatomcdin- Clin Res; 33:62A and 434A, 1985** lipoprotein lipase in human adipose tissuc. 39. Eckel RH. Glucosc and protein synthesis dependcncy of thc insulin effcct on lipoprotein lipase in Clin Res; , 1985** cultured isolated rat adipocytes. 33: 102A and 429A , glucose mediated incrcase in the HDL 40. Eckel RH, Sadur CN, Yost TJ. Deficicncy of the insulin Clin Res; 33:429A, 1985. cholesterol/cholesterol ratio in normolipidemic obese subjccts. 41. Eckel RH, Sadur CN , Yost TJ. The increase in adipose tissue lipoprotein lipase activity in obese , 1985; women is luteal phasc- depcndent. Int J Obesity 9:A27 Eckel RII. Prasad JM. Impainnent of tubulin polymerization incrcases intracellular lipoprotein lipase Int J Obesity; -activity in culturcd rat adipocytes. 9:A281985* 43. . Eckel RH, Sadur CN, Yost TJ. Low-dosc insulin increases adiposc tissue lipoprotein lipase in normal . 1986* weight but not obese women. Cfin Res; 34:58A 44. Eckel RH, Awald PD , O'Shea AM, Edwards DP. Lipoprotein lipase is the major protein released by Clin Res; 34:57 A , 1986* heparin from cultured rat adipocytcs. , a paradox of 45. Eckel RH, Sadur CN, Yost TJ. Adipose tissue lipoprotein lipasc in obese women
insulin. Clin Res 1987. obesc women: A permissive 46. Yost TJ , Eckel RH. Fat calories may be preferentially stored in reduced- Cfin Res; , 1987. * pathway for resumption of the obcse state. 35: 160A and 520A 47. Rulc DC, Cook C, Ridgway EC, Eckel RH. Lipoprotein lipase may playa role in the rcgulation of
pituitary hormone secretion. Cfin Res; 35:516A, 1987* 48. Rudolf PM, Horwitz KB , Eckel RH. Thc mctabolic effects of progesterone on parametrial adipose
tissue must be indirect. Cfin Res; 35:401A, 1987. 49. Draznin B, Sussman KE, Eckel RH. Role of cytosolic free calcium concentration in mcdiating insulin Diabetes; 36:573, 1987. resistance of obesity and hyperinsulinemia. dependent 50. Eckel RH, Yost TJ Increasing pounds off may predict increasing pounds on: Weight loss- 36:691, 1987. adipose tissue lipoprotein lipase responsiveness in reduccd- obese women. Diabetes; , Sussm;:n Y.E, Draznin B. !'!ech2.ni 51. Lewis D Kao M, Yost TJ, Eckei RH, Leitner JW, Sherman N Cfin Res; 36: 155A of glucose- and insulin- induced insulin resistance in human and rat adipocytes. 1988. 52. Berman IN, Yost TJ, Eckel RH. Dietary substitution of medium chain triglycerides for long chain Cfin Res; 36:148A, 1988* triglycerides enhances insulin action. , Peters JH, Clark 53. Coleman-Smith A, Steiner Z, Tonnensen M, Viders D, Moo-Young GA, Chase P RAF, Eckel RII. Dermal capillar basement membrane thickness is increased in Type I diabetics and Cfin Res; 36:491A, 1988* correlated with the duration of diabetes and diabetic retinopathy. mediated 54. Awald PD, Gordon DF, Wood WM, Rule DC, Gutierrez-Harmann A, Eckel RH. Insulin- increases in lipoprotein lipase specific mRNA precede increases in lipoprotein lipase acti vity in
cultured rat adipocytes. Clin Res; 36:477A, 1988. (---
Robert Ke1
, Smith AC , Eckel RH, Clark RAE Thickened 55. Viders D , Tonnensen MG, Steiner Z , Couchman IR blood vessel walls in patients with type I diabetes mellitus consist of glycoproteins conjugated with n- , 198R* linked man nose- type oligosaccharides. Clin Res; 36:380A 56. Christiansen C , Eckel RfL Is " sliding scale" insulin the optimal approach to the management of hospitalized diabetics Diabetes; 37:6&2 , 198R. 57. Eckel RH. insulIn regulation of lipoprotein lipase in adipose cells: relevance to common metabolic 115: 12 , 1988* disease states. The Endocrine Society Abstracts; Hanson AS , Chen A Y , Bennan Yost TJ, Brass EP, Eckel RH. Medium chain triglycerides: 58. Clin Res; Implications for their use in the treatment of non- msulin dependent diabetcs mellitus. 37:526A 1989* Farese RV, Yost TJ, Awa1d I'D , Eckel RH. The rcgulation of lipoprotein lipase actIvity and mRNA , 1989* by insulIn is tissue- specific Clin Res; 37:570A Clin Res; 60. Lang CA, Pcarson JR, Eckel RH, Byyy RL. The effectivcness of cholesterol screening. 37:318A 1989. 61. Bessesen D1'I, Eckel RH. Maintenance of rcduced obesity incrcases adipose tissue but decreases Int J Obesity; 13:545, 1989* cardiac muscle lipoprotcin lipase in the obese Zucker rat. derived , Arend WP, Eckel RH. Gamma interferon decrcases human monocyte- 62. Schneider DJ lipopolysacchard macrophage lipoprotein lipasc activity and mRNA: An effect distinct from that of
Arteriosclerosis; 9:762A, 1989. 63. Raynolds MV, Awald PD, Eckel RH. Lipoprotein lipase gene expression in cultured adipocytes is Circulation 1989; 80:II-78* . regulated by insulin and isoproterenol through different mcchanisms. The Endocrine Society 64. Eckel RlI. Regional regulation of adipose tissue lipoprotein lIpase activity. Abstracts; , Hamman , Mayer1990* EJ , Shettcrly SM, Eckel RI-I, Haskell WL, Marshall JA, Baxter J 65. Regensteiner diabctic men and RF. Relationship betwcen physical activity and hyperinsulInemia among non-
women: The San Luis Vallcy Study. Socfor Epid Res Abstracts 1990* Mayer EJ , Burchfiel CM, Eckel RH, Marshall JA, Hamman RF. The role of insulin in the association of physical activity with HDL cholesterol (HDL-c) and HDL subfractions: Thc San Luis Valley
Diabetes Study. Socfor Epid Res Abstracts 1990* 67. Currie RA, Eckel RH. Transciiption control of lipoprotein lipase by octamer transcription factor- Arteriosclerosis; 1O:781A , 1990* Raynolds MY, Eckel RH. Isoproterenol-induced decreases in lipoprotein lipase in adipocytes rnay be 68. The Endocrine mediated by inhibitory effects of cyclic amp on lipoprotein lipase gene expression.
Society Abstracts; 171,1991 * Mammar Lipoprotei 69. Neville MC, Jensen DR, Witsell DC, Eckel RH. Metabolic Rcgulation of
Lipase. FASEB, 1991.* neoL\s regions: Similarties in 70. Yost n, Eckel RH. Adipose tissue lipoprotein lipasc in twc subsut Clin Res; enzyme regulation by insulin may mean more metabolically than basal differences. 39:277A, 1991* cron triglyceride 71. Bessesen DH, Fox D, Erskine J, Eckel RH. In obcsity, the metabolism of chylomi Clin Res; 39:277 A, 1991.* fatty acids factors storage over oxidation. Bessesen DH, Etienne J, Goers J, Eckel RI-I. Lipoprotein lipase mRNA and protein in the brain: Clin Res; 39:330A, 1991.* discrepancies in co localization predict a novcl regulation.
73. Curre RA, Eckel RH (SPON: Wood WM). Transcriptional Control of Human Lipoprotein Lipase , 1991* During Differentiation. The Endocrine Society Abstracts; ...... ,,--..
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74. Raynolds MV, Jensen DR, Eckel RH. C2 Skeletal Myoblasts: A New Model for Studying The Endocrine Society Regulation of Muscle Specific Lipoprotein Lipase Gene Expression.
Abstracts; 475 1991* 75. Eckel RH, Bessesen DH, Raynolds MV. Tissue-specific Regulation of Lipoprotein Lipase in Adipose J Cell Biochem; 1513:9 , 1991. Tissue and Muscle. Lipase Gene Expression by 76. Raynolds MV, Eckel RH. Tissue-specific iZegulation of Lipoprotei
J Cell Biochem; 15B:32, 1991* cAMP. lipase: Regulation by octamer Eckel RH, Curre RA. Transcriptional regulation of human lipoprotei Gene Expression During Liver transcription Factor- l and TATA box factor interactions.
Diferentiation and Disease; 104 , 1991. 78. Raynolds MV, Jensen DR, Eckel RIL Divergent effects of cAMP on lipoprotein lipase gene Arteriusclerosis; 11: 1392a, 1991.* transcription in adipocytes and myocytes. regulation of human lipoprotein lipase during 79. Slaughter JL, Eckel RH, CUITie RA. Transcriptional ; 191 , 1991.* differentiation. Cancer cells: Regulation of eucaryottC mRNA transcription. specific changes in 80. Yost TJ , Rodgers CM, Eckel RH. Results of suction lipectomy relate to region- Clin Res; , 1992* adipose tissue lipoprotein lipase. 39: 104A , Raynolds MV, Eckel RH. Responses of lipoprotein lipase mRNA and 81. Erskine lM, Jensen DR , 1992. FASEB Journal; 6:AI938 activity to high carbohydrate and high fat diets are tissue- specific. , FelineLS , Dunn F Jr. Insulin therapy Bagdade J, Ritter M, Eckel RH, Rodby R, Thistlewaite R 82. dependent diabetes mellitus (lDDM). pathologically alters cholesteryl ester transfer (CET) in insulin-
Clin Res; 40:208A , 1992. * , Eckel RH. Identification and localization of a muscle-specific CAMP response 83. Raynolds MY 572, 1992* element in the human lipoprotein lipase promoter. 17Je Endocrine Society Abstracts; 84. Ferraro RT, Jensen DA, Eckel RH, Ravussin E. Relationship between skeletal muscle lipoprotei 41: 188A, 1992. lipase activity and 24- hr regulatory quotient Diabetes; 85. Dunn FL, Thompson MJ, Eckel RII, Howard BV. Intraperitoneal insulin therapy in IDDM normalizes very low density lipoprotein composition independent of improved glycemic control.
Diabetes; 4l:26A, 1992* 86. Raynolds MV, Eckel RH. Cyclic AMP-mediated induction of lipoprotein lipase gene transcription in response clement binding protein. myocytes may be transduced by the nuclear factor cyclic AM
Circulation 86:291 1992. 87. Ferraro RT, Jensen DR, Eckel RH, Ravussin E. Relationship between skeletal muscle/adipose tissue Obesity Res; 1:059, 1993* LPL activity and whole-body substrate oxidation. lipase 88. Jensen DR, Eckel RH. Differences in the regulation of muscle and adipose tissue lipoprotei Obesity Res; 1:075, 1993. * by short and long- term isoproterenol infusions. central nervous system and 89. Bessesen DR, Richards CL, Eckel RH. Uptake of dietar fat by the l:() J 6 , J 993. * pituitar of lean, obese and reduced- obese ralS. Obesity Res; 90. Yost TJ, Jensen DR, Eckel RH. Divergent responses of skeletal muscle lipoprotein lipase to insulin Clin Res; 41:391A, 1993. in obese and lean women: relationship to insulin resistance. 91. Morin CL, Schlaepfer lR, Eckel RH. Transcriptional control of lipoprotein lipase in 3T3- adipocytes by tumor necrosis factor-a. is mediated by DNA:protein interactions at the proximal
promoter. Circulation 1993. 92. Yost TJ, Jensen DR, Eckel RII. Sustained weight reduction in obese women decreases skeletal Obesity Res; Supplmuscle jipoprotein lipase: another2:77S, metabolic predictor of subsequent1993* weight gain. 93. Eckel RH. Tissue specific regulation of lipoprotein lipase: relationship to obesity and insulin
resistance. Obesity Res; 1 Suppl 2: 66S, 1993*' .,,".._ - - - - . - . - - ' . ,"... ",-
HJC.,- ,,,,. "-'-'''''' L/- Obesity Res 3 Suppl 3:322S, 1995* 94. Eckel RH- Lipoprotein lipase and dyslipidemia. lipoprotei lipasc , Kosmiski L, Lowell BB , Flicr JS , Eckel RIL Divergent and altered 95. Jensen DR Int J Obesity; 18; and hormonc-sensitive lipasc activitics in brown adipose- deficicnt transgenic mice. Suppl 2: 4 1994* 96. Gnudi L, Jensen DR, Tozzo E, Bliss JL, Eckel Rll, Kahn BB. Regulation of adipose mass in Int J Obesity; 18; Suppl 2: 81 transgcnic mice overexpressing GLUT - 4 selectively it\ adipocytes. 1994* Int J Obe" ity; 8; 97. Eckel RH. Tissue specific rcgulation of lipoprotein lipase and nutrient paritioning. Suppl 2: 41 1994* , Hill JO , Eckel RIL Gender diffcrenccs in the relationship between insulin 98. Travers SH. Bloch CA , 1994. * Int J Obesity; 18 Suppl 2: 34 sensitivity and ' body composition in early pubertal children a eliminates binding of NF- Y and an Morin CL, Schlacpfcr IR , Eckel, RH. Tumor necrosis factor- 99. J Clin Invest; octamer binding protein to the lipoprotein lipasc promotcr in 3T3- Ll adipocytcs. 95: 1684, 1995* , Ratliff KA, Lcenders NL, Clem KL, Troup JP, Eckel RH. The effects of ingested 100. Berning JR Med Sci Sports Exerc, mcdium chain triglyccridcs on muscle glycogen preservation during exercise. 1995* 101. Morin CL, Sundquist KO, Eckel RH, Pagliassotli MJ. A high fat diet (HF) elevates adipose tissue- Diabetes: 44; Suppl l:203A, 1995* derived tumor necrosis factor-a (A T-TNF) activity. , Marcell T, Gutierrez-Harmann A, Eckel RH- 102. Jensen DR , Morin CL, Schlaepfer IR, Pennington DS . Transgenic mice with overcxpression of skeletal musele lipoprotein lipase: divergent effects of Obesity Res; 3:36IS, 1995. differential overexpression on body lipid. lnsulin-like growth factor binding 103. Travers SH, Labaran, Gargosky SE, Roscnfeld RG, Eckel RH. protein- 1 (IGFBP- I) levels are strongly associated with insulin sensitivity and obesity in early
pubertal children. Obesity Res; 3; Suppl 3: 403S, 1995* 104. Yost TJ, Jensen DR, Eckel RH- Weight regain following sustained weight reduction is predicted by , 1995* Obesity Res; 3; Suppl 3: 367S relative insulin sensitivity. , Eckel RH. Transgenic mice with 105. Jensen DR, Morin CL, Schlaepfer IR, Pennington DS , Marcell T ovcrexpression of skeletal muscle lipoprotein lipase: Divergent effects of differential overexprcssion , 1996* of body lipid. Obesity Res; 4; Suppl1: 2S 106. Donahoo WT, Jensen DR, Yost TJ, Eckel RH. Tissue specific seasonal varation in lipoprotein lipase Obesity Res; , 1996. in fasted, normal weight humans. 4; Suppl1: 29S 107. Donahoo WT, Jensen DR, Yost TJ , Eckel RI-I. Isoproterenol and somatostatin decrease plasma leptin
in humans. Obesity Res; 4; Suppl1: 395, 1996. , Jensen DR, Kosmiski LA, Makovsky NJ, Eckel RH- Tissue specific overexpression of 108. Schlaepfer IR mediated gene transfer: A hormone sensiti ve lipase (HSL) in adipose tissue using a cationic liposome- Obe:;ity Res; 4; Supp! 1: 5056, promising approach for changing body weight and composition. 1996* , Gutierrez-Harmann A, Eckel RH. 109. Jensen DR, Schlaepfer lR, Pennington DS , Marcell T, Morin CL High fat feeding induced obesity is prevented by skeletal muscle overexpression of lipoprotein lipase , 1996. in transgenic mice. Circulation; 94; Suppl1:266 110. Donahoo WT, Berg CL, Marcell T, Eckel RH. The effect of rnacronutrient composition and a meal
on serum leptin in humans. J Invest Med; 45,1:152A, 1997* 111. Ganong CA. Schlaepfer IR, Marcell T, Jensen DR, Eckel RH. Cellular localization of hormone J Invest Med; 45;1:106A, 1997* sensitive lipase mRNA in rat cardiac and skeletal muscle. of hormone sensitive lipase 112. Makovsky NJ . Schlaepfer IR, Eckel RH. Tissue specific overexpressio
in adipose tissue mediated by gene therapy. J Invest Med;45(1):14lA, 1997. . .
KOUCll L L. CA!lCI, IVI- L"".
113. Yost TJ , Jensen DR, Eckel RH. The effect of dietary macronutrient composition on skeletal muscle J Invest Med; 45(1): 105A , 1997* lipoprotein lipasc activity reflects the oxidative fuel mix. , Reusch JEB Rcgensteiner JG, BauerTA, Brandenburg SL, Sippel J, Wolfel EE, Eckel RH 114. insulin Vogelsong AM, Hiatt WR. Slowed oxygen uptake kinctic responses in women with non- , 1997* dependent diabctcs (NlDDM). J Invest Med; 45:215A liS. Davy BM, Seagle HM, Kealcy EH, Yost TJ, J;ckd an, Hil1 JO. A comparison of three prediction JAm Dietetic Assn; 97 Suppl9: A- , 1997. equations for estimating energy requiremcnts. TNF) 116. Morin C , Eckel RH' Pagliassotti MJ. Adiposc tissue- derived tumor necrosis factor (AT- Diabetes; 46: Supp I; 965-965, 1997* activity is relatcd to cell size and glucose uptake. Trouillot TE, Eckel RH' McKinley CL, Showalter RE , Yost TJ, Everson GT. The link Betwecn. 117. Hepatology, 1997* weight loss , gallstones and insulin action: A pathophysiologic study in humans , Everson GT. Hepatic and total body 118. Trouillot TE, Eckel RII, McKinley CL, Showalter RB , Yost TJ insulin sensitivitics are disassociatcd in obese subjects after diet-induccd wcight loss followed by IJepatology, 1997* isocaloric wcight maintenance. , Eckel RII. Diet and age 119. McGinnis AR, Jensen DR, Ammon SM, Pennington DS , Schlaepfer IR induced increases in body weight prevented by overexpression of skeletal muscle lipoprotein lipase.
Obesity Res; 5; Supp I, 25S, 1997 * 120. Yost TJ, Jensen DR, Hill JO, Eckel RH' The effects of dietaIY macronutrient composition on fuel J Invest Med In Press ubstrate utilization and balance in normal weight humans. Schlacpfer IR, McGinnis AR, Marcell T, Eckel RH. Human lipoprotein lipase (hLPL) is 12L. Obesity overexpressed in mouse skeletal muscle following direct injection of naked plasmid DNA.
Res; , Supp 1; 78S , 1997. * 122. Yost TJ, Jensen DR, Hill JO, Eckel RI-I. The effects of dietary macronutrient composition on fuel Obesity Res 1999; 5 , Supp 1; substrate utilization and balance in normal weight human subjects. 87S* , Eckel RH. High 123. Rewcrs M, Ehrlich J, Jenscn L, Seigel R, Barga K, Garg S , Janowitz W prevalence of asymptomatic coronary atherosclerosis detccted by electron beam computed Diabetes; 47; Suppll: A12, 1998* tomography in young adults with lDDM. induced 124. Fcrreira LDMC- , Huey PU, Waugh KC , Eckel RH. The effect of acutc stretozotocin- Diabetes; 48 Suppll: A2, 1999* diabetes on rat sciatic nerve lipoprotein lipasc expression. in vitro model for the Poirier P, Marcell T, Schlaepfer I, Owens GC , Waugh KC, Eckel RH. A new 125. paritioning. study of the rolc of lipoprotein lipase in skeletal muscle metabolism and substrate Circulation 1999. 126. Capell WH, Poirier P, DeSouza CA, Eckel RI-I. Lowering triglycerides with fenofibrate , 1999. improves vascular reflctivity; impact of free fatty acids. Circulation 127. Weil , KM, Shepard TY, Eckel RH. A diet high in fat versus carbohydrate increases Obesity Res, 7:(1),325 insulin sensitivity in weight-maintained , reduced severely obese subjects. 1999;. 128. Kosmiski L, Kuritzkes D, Lichenstein K, Greenberg K, Ehrlich J, Eckel RH. An increase in abdominal girth on protease inhibitor therapy is associated with visceral obesity and metabolic
disturbances that closely resemble syndrome X. Obesity Res;7:(l),126S, 1999* 129. Smith SJ, Jensen DR, Ammon S, Cases S, Eckel RI-I, Farese RV. Increases in metabolic rate Obesity Res; 7:(1), 128S explain the protection from obesity in high fat fed DGAT Knockout mice. 1999. 130. Donahoo WT, Rothman R, Ammon S, Grunwald G, Davis J, Levin N, Eckel RH. Chronic leptin administration alters postprandial lipid metabolism by decreasing postprandial triglyceride Obesity Res 7:(1),28S, 1999. excursion and increasing skeletal muscle lipoprotein lipase. KoiJt;n n. at.c , j'v
, Eckel Rll. Evidencc for glucose intolerance 131. Ferreira LDMC- , Jensen DR, Schlaepfer I, Ammon S Obesity Res; 7:(1),80S , 1999* in mice overcxpressing lipoprotein lipase in skeletal muscle. , Sanan D, Jensen DR, Ammon S , Eckel RH 132. Smith , SJ Cases S. Sande E, Tow B, Yu T, Newland D Farcse, RV Jr DGAT Knockout Mice: Resistance and evidencc for an altcrnative tricylglycerot Vol 100; 18 1609 1999. synthcsis pathway. AHA Scientific Scssions Circulation , Scrwiler Eckel, RI-I. Thc effcct of crush 133. Huey PJU, Waugh KC , Marcell T, Ferreira LDMC- Soc Neurosci 1999; 25:(Partl),l00I. injury on lipoprotein lipasc expression in rat sciatic nerve. 134. Schlacpfer IR, Jensen DR, Eckel RH. Potential Mcchanisms for Increased Substrate Oxidation in Obesity Res White Skeletal Muscle of Micc Overexpressing Human Lipoprotein Lipase. 8:t;130S,(NA'ASO) 2000* 135. Ferreira LDMC- , Pulawa LK, Schlacpfer IR, Jenscn DR and Eckel RH. Musclc Spccific Overexpression of Lipoprotein Lipasc Protects Diabetic Transgenic Mice from Hypertriglyceridemi Obe,' iIY Res 8: I; 130S (NAASO) 2000* Pulawa LK, Fcrreira LDMC- , Jensen DR and Eckel RH. The Overexprcssion of Human 136 1 130S Lipoprotein Lipase in Murine Skeletal Muscle Results in Insulin Resistance Obcsity Res 8: (NAASO) 2000* 137. Sharma V, Jensen DR, Chambon P, Eckel RlI, Haugen BR. RXR (Gamma) Dcficient Mice Havc Lower Body Fat , Lower Serum Triglyceride Levels and Incrcascd Skeletal Muscle Lipoprotein Lipase Activity. Endocrine Society Meeting 2001* , Eckel RH, Farese RV, Farcse RV, Jr Increased 1380 Chen HC, Jensen DR, Ferrcira LDMC- , Pu1awa L Insulin Scnsitivity in DGAT-Dcficient Mice. Endocrine Society Meeting 2001* , Cooke PS. Estrogen Rcceptor Alpha (ER' 139. Heinc PA, Jensen DR, Tayor JA, Eckel RH, Lubahn DB Regulates the Effcct of Estrogen on Metabolic Ratc (MR). Endocrine Society Meeting 2001 * Capell WH, Poirier P, Desouza CA, Weil KM, Stauffer BL, Eckel RH. Effect of Triglyceridc 140. . Clinical Rescarch Lowering on Endothclial Dysfunction in Patients with Hypertriglyceridcmi 2001* 141. Schlaepfer lR, Ramanathan M, James DE and Eckel RH. Skeletal Muscle Lipoprotein Lipase- Mcdiated Resistancc to Obesity and Insulin Action Results in Increased Expression of Munc 18c. 2001 Thc American Diabetes Association 61 st Scientific Sessions 142. Ferreira LDMCB, Pulawa LK , Schlaepfer IR, Jensen DR and Eckel RH. Overexpression of Related Lipoprotein Lipasc in Skeletal Muscle Protects Transgenic Mice from Diabetes- , 2001.* Hypertriglyceridemia, The American Diabetes Association 61st Scientific Sessions , Eckel RH and Rewers MJ. Coronar 143. Snell Bergeon J, Hokanson JE, Ehrlich J, Garg S , Quaifc R , Increasing Total and Atherosclerosis Progression in Type 1 Diabetes: ImpOitance of Age Cholesterol and Pre-existing Disease. The American Diabetes Association 61st Scientific Sessions, 200 1. * , Eckel RH and , Cheng S , Snell-Bergeon JK, Grow MA, Hung C, Erlich HA, Ehrlich J 144. Hokanson JE Coronar Arery Rewers M. The Hepatic Lipase Gene Promoter Polymorphism is associated with Classification in Type 1 Diabetes, The American Diabetes Association 61st Scientific Sessions 2001.* 145. Hokanson JE, Kamboh MI, Eckel RH and Hamman RF. The hepatic lipase promoter polymorphism is associated with genetic susceptibility to coronary heart disease. 2001 146. Donahoo WT, Melanson EL, Pistone B , Hamilton J and Eckel RH. Excrcise Following Weight Loss Helps Prevent the Fall in Skeletal Muscle Lipoprotein Lipase: A Potential Mechanism for Maintenance of the Reduced Obese State. NAASO, 2001* 147. Jensen DR, Pulawa LK, Lerman I, and Eckel RH. Transgenic Mice Overexpressing "keletal Muscle Lipoprotein Lipase Have Reduced Exercise Performance. NAASO, 2001.* :;0 KODen ri. r:ckei , iVl.
, Bell ML, Grunwald GK, Shar TA , Hill and Eckel RH. Carbohydrate 148. Weil KW, Shepard TY 2001* balance on a high carhohydrate diet predicts fat gain over 4 ycars. NAASO, Modest weight loss 149. Weil KW, Shepard TY, Scherzinger AL, Stamm ER, Ballard R and Eckel RH. in the severely obese improves the upp',r airway as well as sleep efficiency and oxygenation. N AASO 2001* , Kanoh Y, Sajan IvJ, Eckel RH, Farese 150. Chen HC, Jensen DR, Ferreira L, Pulawa LK, Standaert ML , Jr RV. Increased Insulin Sensitivity in DGAT-Deficient Mice. Endo 2001* RV and Farese RX (Gamma) Deficient 15 I. Shara V, Jensen DR, Krezel W, Chambon P, Eckel RI-I and Haugen BR. Mice Have Lower Body Fat, Lower Scrum Triglyceride Levels and Incrcased Skcletal Muscle Lipoprotein Lipase Activity. Ehdo 2001* , Jensen DR , Taylor Lubahn DB , Eckel RH and Cooke PS. Estrogcn Receptor Alpha 152. Heine PA 2001* (ERa) Regulates The Effcct Of Estrogen On Metabolic Ratc (MR). Endo , Snell-Bergeon JK, Dabe1ca D, Eckel RII, Ehrlich J, Rewers M. Visceral Adiposity is 153. Hokanson JE Diahetic Associated with the Presence of Coronary Artery Calcium in Type I Diabetes and Non- Subjects. Endo 2001. 154. Morrs AM, Donahoo wr and Eckel RII. Plasma Adiponectin Concentrations Are Not Acutely Affected By Diet Composition. AI-I Scientific Sessions 2002. Submitted. , Weil KM, Shepard TY, Bell ML, Grunwald GK, Francis CC, Sharp T A, Hill JO, and 155. Hernandez TL 106; 19 May Predict Obesity Circulation jickel RH. The Responsc to High Carbohydrate Feeding . Supp. IT, 468. AHA Scientific Sessions 2002* , Chambon P, Eckel RH, and Haugen B. f56. Jensen DR, Shara V, Pulawa LK, Morrs AM, Krezel W RXy Dcficient Mice Havc Lower Body Fat and Highcr Skeletal Muscle Lipoprotein Lipase Activity When Fed A High Fat Diet 106: 19 Supp. IT , 122. AH Scientific Sessions 157. Pulawa LK, Sch1aepfer IR, Ferrcira LDMC- , and Eckel RH. Effects of diahetes and lipoprotein lipase on munc18c gene expression in skeletal muscle. AHA Scientific Sessions. Submitted. , Eckel RH, Olson S , Turck F, Bass J. Diet 158. - Emily L, Laposky A, Horton T, Easton A, Jensen DR Induced Obesity in Clock Mutant Mice: Circadian Regulation of Sleep, Food Intake and Metabolism. Kcystone Symposia 2002. Suhmitted. , Rewers M. Abdominal Fat by CT Is 159. Snell-Bergeon J, Hokanson , JE, Eckel RH, Ehrlich J, Ogden LG Not Superior to Anthropometric Measures As A Predictor Of Subclinical Atherosclerosis. American Hear Association Epidemiology Meetings 2002. Submitted. , Eckel RH and Haugen BR. , Shara V, Pulawa LK, Morrs AM, Krezel W, Chambon P 160. Jenscn DR Activity RXRy Deficient Mice Have Lower Body Fat and Higher Skelctal Muscle Lipoprotein Lipase When Fed a High Fat Diet. American Hear Association Scientific Sessions 2002. , Eckel RH, and Rewers M. The 159. Hokanson, JE, Cheng S , Snell-Bergeon JK, Erlich HA, Ehrlich J Coronar Calcium Type 1 Diabetes Heptic Lipase Promoter Pclymarphism Predicts Progression of American Diabctes Association, Submitted. RH, Ehrlich J, Rewers M and 160. Chen MY, Bhola R, Snell-Bergeon JK, Kinney GL, Fisher AD, Eckel Quaife RA. Myocardial Perfusion Reservc in Patients with Longstanding Type 1 Diabetes Mellitus Association, Submitted. and Coronar Artery Calcification. American Diabetes Induced Weight 161. Poirier, P, Hernandez TL, Weil KM, Shepard TJ and Eckel RH. The Impact of Diet- Subjects with Severe Obesity. Loss on Cardiac Autonomic Nervous System and Arhmias in American Diabctes Association, Submitted. TA, Hill JO, and 162. Hernandez TL, Weil KM, Shepard TY, Bell, ML, Grunwald GK, Francis CC, Shar Term Inactivity Predicts Eckel RH. The Response to High Carbohydrate Feeding During Short- Changes in Fat Mass. Baltimore Clinical Research, 2003, Submitted. Robert h. L:c . IvLu- Fat and Low- 163. Eckel RH. Dietary and Endogenous Fat Oxidations are Similar for Mixed Meal Hjgh- Fat Maintenance Treatments: A Potential Recipe for Long-TeI1 Obesity Development NAASO. 164. Eckel RH. Carbohydrate overfeeding decreases endogenous but not ingested fat oxidation U and Eckel RH. Is Hernandez T, Jensen D , Donahoo W; Costa J, Brennan M, Hochgeschwend 165. , 2003. Alpha-Melanocyte Stimulating HOI1otle (a-MSH) Important in Human Obesity" NAASO 166. Dietar Fat Fails to Alter Endogenous Ingested Fat Oxidation: A Mechanism for Fat Storage When , Hernandez T, Hill J , Fennessey Fat Balance is Positive. Sonko B, Grunwald G , Sharp T, Perreault L P and Eckel RH NAASO, 2003* Morrs A, Travers Sand 167. Plasma Adiponectin Is Related to Measures of Adiposity Only in Girls. Eckel RH. NAASO, 2003. Fat and Low-Fat 168 Dietar and Endogenous Fat Oxidations are Similar for Mixed Meal High- Maintenance Treatments: A Potential Recipe for Long-TeI1 Obesity Development. Hernandez TL Eckel RH NAASO 2003* Hernandez TL, Eckel 169. Carbohydrate overfeeding decreases endogenous but not ingested fat oxidation. RH AHA Scientific Sessions 20m. * , Awareness, Treatment and Control in Type 1 Diabetes and Comparable 170. Hypertension Prevalence , Eckel RH and General Population. Maahs DM, Wadwa P, Kinney GL, Snell-Bergeon JK, Garg S Rewers M. American Heart Association Epi Program, 2004. 171. Low Plasma Adiponcctin Levels Predict Progression of Coronary Arery Calcification. Maahs DM Kinney GL, Wadwa P, Snell-Bergeon JK, Ehrlich J , Eckel RH and Rewers M. American Hear Association Epi Program, 2004. Diabetes. Hokanson JE 172. Lp(a) Levels Predict Progression of Coronar Artery Calcum in Type 1 Marcovina SM, Snell-Bergeon JK, Dabelea D, EckcI RH and Rewers M. American Hear Association Epi Program, 2004. Hokanson JE, Cheng S l73. The Hepatic Lipase Gene Predicts Progression of Coronary Artery Calcium. Kinney GL, Hughes R, Snell-Bergeon JK, Eckel RH, Erlich HA and Rewers M. American Hear Association Epi Program, 2004. Coronar Arery Calcium. Pratte KA. 174. Association between Plasminogen Activator Inhihitor - I and Hokanson JE, Eckel RH and Rewers M. American Hear Association Epi Program 2004. in Adults with Type 1 Diabetes 175. Prevalence, Awareness Treatment and Control of Dyslipidemi , Maahs , DM, Snell-Bergeon Mellitus and Comparable General Population. Wadwa RP, Kinney GL , 2004. , Garg S , Eckel RH and Rewers M. American Hear Association Epi Program 176. Obesity is a Strong, Independent Risk Factor for Subclinical Atherosclerosis in Young Adults: The Coronar Arery Calcification in Type 1 Diabetes Study. American Hear Association Epi Program 2004. 177 Carbohydrate Overfeeding Decreases Endogenous but not Ingested Fat Oxidation, Sonko BJ Hernandez TL, Grunwald GK, Perreault L, Shar T, Hill JO, Fennessey PV and Eckel RH. Circulation 108, 17 , IV-762, 2003. AHA Scientific Sessions. 178. Glucose Metabolism on a High Carbohydratc Diet Independent of Insulin Sensitivity is a Predictor of Weightlat Gain in Adults. Hernandez TL, Weil KM, Shepard TY, Bell ML, Grunwald GK, Francis 108, 17, IV-306, 2003. * AH Scientific , Sharp TA , Hill JO and Eckel RH. Circulation Sessions. 179. Dietar Fat Fails to Alter Endogenous and Ingested Fat Oxidation: A Mechanism for Fat Storage , Hernandez TL, Hill When Fat Balance is Positive. Sonko BJ, Grunwald GK, Shar T A, Perreault L VoL 11 supplement, Pg. A18 , 2003. * NAASO JO, Fennessey PV , and Eckel RH. Obesity Res. Annual Meeting. Robert H. r"t0. ? Hernandez TL 180. Is Alpha-Melanocyte Stimulating Honnone (a-MSH) Important in Human Obesity Jensen DR . Donahoo WT. Costa JL. Brennan MS , Hochgeschwender U , and Eckel RH. Obesity Res VoL 11 supplement, Pg A 72 2003. NAASO Annual Meeting- , Kinney GL 181. Aclponectin Levels Predict Coronar Arery Calcification Progression. Maahs DM Wadwa, RP. Snell-Bergeon JK, Ehrlich J, Eckel RH, and Rewers, M .American Diabetes Association, 64th Scientific Sessions, 2004. 182. Typ I Diabetes and Insulin Resistance Increase the Risk of Coronar Calcium Progression: The Coronar Arery Calcification in Type I Diabetes Study- Snell-Bergeon JK. Kinney GL, Hokanson JE Eckel RH, Dabelea D , Ehrlich J, and Rewers M. , Baghian S 183. Subtyping Diabesity: an Adipose Tissue Perscpective. Smith SR, Xie H, Bogacka I McNeil M, Morris AM, Eckel RH, and Bray GA. * NAASO 2004 Annual Scientific Meeting.
October 18 . 2004. revised by JM ARTICLES Topical Fat Reduction from the Waist
Mary Katherine Caruso
Susan Pekarovic
Wiliam J. Raum
Frank Greenway
Louisiana State University Division of Human Ecology Baton Rouge , LA 70803
Harbor-UCLA Medical Center Torrance , CA 90509
LSU Health Sciences Center and SI. Charles General Hospital
New Orleans , LA 70115
Pennington Biomedical Research Center
Baton Rouge Louisiana 70808
Corr€sDondinc Author:
Frank L. Greenway. M_ Medical Director and Professor Pennington Biomedical Research Center 6400 Perkins Road Baton Rouge, LA 70808
Email: qreenwflrcpbrc_ 3022 Tel: (225) 763-2576 Fax: (225) 763-
Running Title: Tor'lcal Fat R ductio Abstract
Objective: Topicai fat reduciion from the thigh in women using aminophyllne cream has been or in men by lowering the local demonstrated, but the loca1 fat reduction in other body areas
lipolytic threshold ith aminophyllne cream has not. This study is designed to test the hypothesis that aminophyllne cream application to the waist will reduce waist circumference compared to a controL
65 years of age with a 8MI Research Methods and Procedures: Fifty men and women 21- 5% aminophyllne :027 kg/m and a waist to hip ratio c: 094 were randomized in a 1:1 ratio to 0. All subjects were instructed to Bream to the waist twice a day or no treatment to the waist. follow a 1200 kcal balanced diet, participate in a walking program and return biweekly to , BMI and waist to encourage compliance. A theophylline level was drawn monthly and the waist
hip ratio were re-measured at 12 weeks.
Results: At week 12 there was a significant reduction in 8MI from baseline that was not 0 cm in the different between the groups. The reduction in waist circumference was 11 :' 1. 001). The reduction in aminophyllne cream group and 5. 0:, 0. 6 cm in the control group (p",0. , but the women lost significantly waist circumference was significant for both women and men
more waist girth, and the waist to hip ratio also declined significantly. Aminophylline levels were
undetectable, and were no adverse events.
Discussion: Aminophylline cream offers a safe and effective alternative to invasive surgical
procedures for local fat reduction.
Key Words: Aminophyllne , Cellulite , Waist to Hip Ratio ackground
The influence of endogenous stimulators and inhibitors of the lipolytic process determine the threshold for lipol sis at the fat cell in the human body. The relative lipolytic thresholds of the body s fat cells , therefore, determine a person s fat distribution. The greater abundance of lipolytically inhibitory alpha-2-adrenergic receptors on the thigh fat cells of women under the cteristic lower body fat distribution influence of estrogen is felt to be responsible for the chara , fat is stored in typical for women (1). Fat is a dynamic storage organ. When weight is stable fat cells during the day as people eat and used during the night to sustain the body until breakfast the next morning. Fat is quantitatively mobilized from the individual fat cells in , therefore, logical proportion io the individual lipolytic thresholds of the regional fat deposits. It is to assume that lowering the lipolytic threshold in a local fat deposit will cause its fat stores to be
preferentially depleted through dynamic process of body lipid turnover.
can inject a There are several methods to lower the local lipolytic threshold at the fat cell. One
lipolytic stimulator locally or deliver the lipolytic stimulator transdermally using ointments or
creams (2). Aminophylline 0. 5% cream has been shown to reduce thigh girth compared to a
vehicle control (2). Aminophyllne , two theophylline molecules joined by ethylenediamine
inhibits the breakdown ofcyc!ic-/"JJ!P in the fat cell amplifying the lipolytic signal and lowering
the lipolytic threshold.
gynoid" and "android" . A major cosmetic concern Fat is distributed in two different patterns
for women with a gynoid fat distribution is the size of their thighs, while for women and men with
an android fat distribution , it is the size of their waist. Since thigh fat reduction with , the same principle aminophylline cream occurs due to a reduction in the local lipolytic threshold should apply to other local body areas. This study is designed to test the hypothesis that 0.
")il aminophyllne cream applied to the waist cause preferential fat loss from that location
Methods
kg/m between the ages of 21 and Fifty overweight and obese men and women with a 8MI '" 27 :: 0. 65 years of age and with an android fat distribution characterized by a waist to hip rat
were included in this study. Subjects using aminophyllne, theophyllne or having a known
allergy to either were excluded.
At baseline all subjects were instructed to follow a balanced 1200 kcalld diet and encouraged to
follow a walking program throughout the 12-week study. The subjects were randomized with 5% aminophyllne cream and blocking for gender into two groups of 25 subjects , one receiving 0.
the other receiving no topical treatment served as a control. All participants in the 0.
aminophylline cream group were instructed to rub 15 cc of the cream on their waist twice a day , encouraged to follow for the duration of the 12-week trial. Subjects were seen every 2 weeks
their diet, encouraged to continue their walking program, encouraged to apply the cream twice
daily and asked about any adverse events. Each month, blood was drawn to measure the measured at theophylline level. The 8MI , waist circumference and hip circumference were re-
the endofthe 12-week study The 8MI , waist circumference and the waist to hip ratio were
analyzed by t-test
Results
Twenty females and 5 males were in both groups, and groups were well matched for body mass 2 vs. 28. index at baseline, 28. 2 kg/m kg/m (p = NS), for the aminophylline cream and the control groups , respectively The average waist circumference was 101 cm confirming that the study population had an android fat distrib\Jtion. The waist circumference of the two groups was
8d h2 study. not different at baseline All 50 subjects complE
kg/m (SEM) and 26. At week 12, the 810 in the aminophyllne cream group was 26.
kg/m in the control group, a significant reduction in 8MI from baseline that was not different O cm in the between the groups The reduction in waist circumference was 11 001). The reduction in aminophyllne cream group and 5 0:, 06 cm in the control group (p"0 6 cm in the aminophylline group waist circumference was significant for both women (11. 7 cm in the aminophyllne group and 4 and 56 6 cm in the control group) and men (9.4
:' 0. 6 cm in the control group) (p"0. 001). Women treated with 05% aminophylline cream lost 001) The waist to hip ratio more girth (11 6 cm vs. 9.4:, 0.7 cm) than the men (p"0
declined more in the 9rouP treated with 0 5% aminophyllne cream than the control group (0.
:' 0 05 vs 92:, 0. , p"0001) see Table 1 All monthly aminophylline levels were
undetectable There were no adverse events or allergic reactions to the cream
Discussion
This trial demonstrates that reducing the local lipolytic threshold with topical aminophyllne
cream results in a reduction of waist circumference in both men and women. Local girth
reduction of the waist in android body types is consistent with the principle that lowering the Thus, one can extend the local lipolytic threshold causes fat reduction in the area of application
principle of local fat reduction with aminophylline cream to both genders and to a body area
different from the thigh , two theophyllne In developing aminophylline cream it was appreciated that aminophyllne molecules joined by ethylenediamine , is a ,skin sensitizer and chemically reactive due to the ethylenediamine it contains. A standard cream b se Lr:1ed yellow from a chemical reaction with aminophyllne. This yellow cream was ineffective and caused rashes in some subjects.
, the safety and effcacy Using a specially formulated cream base to stabilize the aminophylline of local thigh fat reduction was demonstrated (2). The same cream base was used in this study.
Not only was the aminophylline cream effective for reduction of waist circumference in this study, but it was also safe. The undetectable aminophyllne levels confirmed that the cream was acting locally, and there were no rashes or adverse events during the trial.
Although a placebo cream was not used in the control group, the two groups were well matched
at baseline, and the BMlloss was similar in both groups. The purpose of the 1200 kcal/d weight
loss diet was twofold: 1) to address the subject's overweight problem and 2) to lower the lipolytic
threshold through negative caloric balance.
The waist to hip ratio has been used as a surrogate measure of insulin resistance due to its insulin resistance (5). Since the correlation with visceral fat (3 4). Visceral fat correlates with , it presumably does not reduce local fat reduction reduced the subcutaneous abdominal fat
insulin resistafjce despite the reduction in the waist to hip ratio. The change in waist to hip ratio
in this study is confirmation that the fat shifted away from the waist.
The most common cosmetic concern for those with a gynoid fat distribution is the size of their study thighs and for those with the android fat distribution is the size of their waist. This
demonstrates that fat can be preferentially and safely mobilized from the waist during weight
loss in those with an android fat distribution Subjects in this study volunteered that they felt better about themselves after the aminaphyllne cream allawed them to cause preferential fat loss in their area af maximal cosmetic cancern. Since cosmetic surgical procedures like , a;ninaphyllne cream affers lipasuctian and abdominoplasty are naw used for local fat reGuction a non-surgical alternative that is safe and non-invasive.
References
Lafontan M , Dang-Tran L, Serlan M. Alpha-adrenergic antilpolytic effect af adrenaline in
human fat cells of the thigh: comparison with adrenaline responsiveness of different faf
deposits. Eur J Clin Invest. 1979 Aug;9(4):261-
Greenway FL , Bray GA, Heber D Topical Fat Reduction. Obes Res. 1995; 3: 561S-
568S
Peiris AN , Mueller RA, Struve MF , Smith GA, Kissebah AH. Relationship af androgenic
activity to splanchnic insulin metabolism and peripheral glucase utilization in
premenopausal wamen. J Clin Endocrinol Metab 1987 Jan;64(1):162-
Peins AN , Hennes MI , Evans OJ, Wilson CR Lee MS, Kissebah AH. Relationship af
anthropometric measurements of body fat distribution to metabolic profie in 88. premenopausal women. Acta Med Scand Suppl. 1988;723:179- , Suzzigoli E, Ghione S , Turchi S Sironi AM , Gastaldelli A, Mari A, Ciociaro 0 , Postano V
Lombardi M, Ferrannini Eh Visceral fat in hypertension: influence on insulin resistance 33. Epub 2004 Ju119. and beta-cell function. Hypertension. 2004 Aug;44(2):127- Table 1.
WaisUHip Group Waist Male Waist Female Waist
86:, 0. 5% aminophylline (cm) 11 :' 1. 9.4 :' 116:, 06" 6 :' 0. 92 :' 0. Control (cm) 0:, 0. -4.7 :' 0.
Legend
Table 1 shows the changes in waist circumference (cm) from baseline in the two groups and
separately for men and women. The waist to hip ratio is also shown. Different superscript 001). show values that are significantly different from one another (p"=O. :... :.. ...,' - :;, :: - ' ' :, , ' :.- :.::," ' ' " : ' :: :.:: : :" - ::-::;'::? :,,:: --- --.-- -::j -~~~ --- ~~~------: - Ovid: '-ollis: Plast Reconstr Surg. Volume \ 04(4 ). Seotember 1999. 1110- 1114 Page 1 of7
n ' in; Plastic Rec nstrtcfi\f Stl.i
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1999 Lippincott Wiliams Wilkins, Inc.
Volume 104(4) Scptember 1999 pp 1110- 1114 Cellulite Treatment: A Myth or Reality: A Prospective Randomized Controlled Trial of Two Therapies, Endermologie and Aminophyllne Cream (Cosmeticl
Collis, Nicholas SSc., F. R.e.S.(Ed.); Elliot, Lee-Anne M. e.P. , F. e.R. ; Share, Caroline; Sharpe, David 1' a. , M.A , F.R.e.S.
Bradford, West Yorkshire, England 4 Reedling Drive; Morley; Leeds; West Yorkshire; 1.527 8GQ; U.K. nicollis aol.com (Collis) From the Department of Plastic Surgery, I3radford Royal Infirmary. Received for publication Dccember 11 , 1998; revised February 22 1999. Presented at the joint winter meeting of The British Association of Aesthetic Plastic Surgeons and the Plastic Surgery d1Tcational Fou dation of America, Royal College of Surgeons England, December I , 1998.
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TABLE I Patient Excl. Abstract Com pi ete Reference . . IABLE1I PI t(,,_qtI1en . TABLE I1 Pretreatrne... Help . fu Logoff . I'K2 History... . IAB.1EJYW ight Chafl"" TABLEYl1!.rasQ !ld . TABLE yr Changes in Icellulite Treatment
Abstract.!
Cellulite is a common phenomenon that particularly affects the thighs and buttocks of women. Little scientific evidence exists to support any of the many advertised treatments for it. A total of
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52 of69 women, who were divided into three groups, completed a 12-week, randomized controlled trial in which the effectiveness of two different treatments for cellulite was assessed. The patients acted as their own controls. The treatments investigated were twice-daily 1. Group application of aminophylline cream and twice-weekly treatment with Endermologie ES I (double blind) reccivcd aminophyllinc to one thighluttock and a placebo cream to the other. Group 2 (singly blind) received Enderrologie to onc thighl ttock. Grot- 3 received Enderrologie to both sides and used the same cream rcgimen as group I. Results were assessed subjectively by the paticnt and by clinical examination and photographic assessment by the , thigh surgeon (before and after the trial). Morphologic assessment included body mass index girt at two points , and thigh fat depth measurement by ultrasound. No statistical difference test ;0 0.4). The existed in measurements bctween legs for any of thc treatment groups (paired best subjective assessment, by thc patients themselves, rcvealed that only 3 of 35 aminophylline- treated legs and 10 of 35 Endermologie-treatcd legs had their cellulite appearance improvcd. The authors do not believe that eithcr of these two treatments is effective in improving thc appearance of cellulitc.
Cellulite is a common phenomcnon that causes embarrassment to even the most fit of women. Its cause is unclear, and buttocks and thighs seem to be paricularly affectcd. The scientific and meical press has scant information on cellulite and its treatment; howevcr, women s magazines oftcn feature articlcs and advertiscments advocating thcrapies that havc littlc, if any, scicntific validation, some of which cost sevcral hundred dollars for a course of treatment. The aim of this study was to test the clinical effectiveness of two different methods of treatment for cellulite in a variable, blind, randomized trial in which the patients acted as their own controL Topically applicd aminophylline is a pharmacological treatment, and Endermologie ES 1 (LPG Systcms Valence, France) is a mechanical mcthod of "aspirated hypodermal mobilization" that claims to mobilize subcutaneous fat and is now licensed for usc in the Unitcd States.
Although the LS 1 machine was purchased for use in the private scctor, we felt an ethical obligation to assess its effectivcness before markcting the trcatment.
Patients and Methods.!
Women over the age of 18 with cellulite of the thighs and buttocks were invited to take part in the l2-week trial. A detailed medical history was followed by physical examination. I!lblc.. shows patient exclusion criteria. After acceptance onto the trial, a series of morphologic measurements were made on each patient. Body mass index was calculated (weight (kg)/height 2 )),l and bilateral thigh circumferences were measured (while standing) at 15 and 25 cm (arbitrarily chosen) above the superior pole of the patella by the first author using a single tape measure. Lateral thigh subcutaneous fat depth was measured midway between these two points using a Toshiba SSA-270A ultrasound machirie with a 7. MHz linear aray probe by the second author. Stadardized photographic documentation (anterior, right, left, lateral, and posterior views) of the cellulite was done in a semicircular booth specifically designed for this purpose by LPG Systems. The appearance of the cellulite was best documented without using the camera flash. A total of 69 patients were randomized into one ofthree groups (23 patients in each) to receive one or both treatments.
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Group I patients received two tubs of cream marked left leg and right leg. One contained the glycoaminophylline cream (2% aminophylline with 10% glycolic acid to aid skin penetration), and the other contained a placebo , which did not contain aminophylline but was in every other respect identical to the aminophylline cream. Each was applied twice a day to the respective thigh and buttock for 12 weeks. Using a placebo negated any effect from massaging during application of the creams. This group was double-blind.
Group 2 patients received twice-weekly lO-minute Enderrologie sessions for 12 weeks on , therefore, received one thighluttock only; the contralateral side acted as a control. Each patient 24 unilateral treatments. This group was single-blind with respect to the investigator. , they Group 3 patients received the same creams and instructions as group 1. In addition received twice-weekly 10-minute Enderrologie sessions to both thighslbuttocks. The same operator was responsible for all of the Enderrologie treatment sessions and had attended their training course in France, as recommended by LPG Systems.
Patients were instructed to maintain their lifestyles to minimize any effect of changes in weight and fitness levels on the appearance of the cellulite. After 12 weeks, morphologic measurements and photographs were repeated. In addition, the cellulite was assessed by the first author to discover any difference in the appearance of the cellulite between legs. The patient was then asked whether she thought there had been any improvement in the appearance ofthe cellulite on either or both legs. Results.!
A total of 52 patients completed the 12-week trial, 17 from group 1 (aminophylline cream), 17 from group 2 (Endermologie), and 18 from group 3 (both treatments). Seventeen patients failed to complete the course of treatment (five, seven, and five for groups 1 , and 3 , respectively). Of these, two developed a dermatologic reaction to the aminophylline cream (not placebo), three , and in found the Enderrologie treatment painful, two felt that the treatments were ineffective one patient, Enderrologie made the superficial veins in her thigh more prominent. There were also two pregnancies, three unrelated intercurent illnesses, and four patients for whom the 12- week commitment proved to be too much.
Table IU Table Ii shows the ages and morphologic data for the patient group as a whole, and shows the distribution of the body mass indexes with reference to normal ranges and obesity. Figures I a d2 show that when patient photographs were simply ordered according to the severity of cellulite , a spread of body mass indexes and fat depths existed across the range of cellulite providing evidence that cellulite is not simply related to the amount of subcutaneous fat. LajJle I\I throughVI show the changes in weight, ultrasound-determined fat depth, and thigh girth for each = 0.4 to 0.9) in the fat depth treatment group. There was no significant difference (paired t test
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and thigh girth between legs in any of the three groups. However, the same trend for di fferences in weight change between the three treatment groups was rcpeated in the fat depth and thigh girth changes. The results indicate that the changes in these measurements are simply a result of weight loss and not the treatment
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TABLE V Ultrasound Fa! Depth Changes (mm) I , f: 5 JIL .Y. .il1gJ
TABLE VI Changes in Th;gh Girth (em) :f. T--- (1: lp\Vjt.hirilg i"-,,i!1;1
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Subjective assessment of the cellulite by both the paticnt and investigator (clinical examination and photographic assessment) revealed poor results from both treatments. Any improvements wcre slight, and in no paticnts did the ccllulite disappear- Of 17 patients in group , only three thought that the appearance of the cellulite in the aminophylline-treated leg had improved. None thought that the placebo leg had improved. The photographs of only two , blind cc patients shcwcd ;l :: ight improvement in thc aminophylline-treated leg. Thc investigator to which wcre treatmcnt and placebo legs, could detect no obvious difference between thcm in any members of this group. In group 2, five patients (of 17) thought that the Endermologie- treated leg improved. The investigator could only dctect a similar difference in two patients; photographic assessment discovcred a difference in only one. In group 3 , five paticnts (of 18) thought that both.lgs had improved. None thought that either only one leg, or both differentially, had improved. Clinical examination showed a differential improvement in favor of thc aminophylline cream in two cascs and the placebo in one case- There was photographic improvement in one patient (both legs). In only one patient was thcre a consensus of agrcement of improvemcnt among the patient, thc investigator, and thc photographs.
Problems with both treatments were encountered. Nine patients (of35) developed a dennatologic reaction to the aminophylline cream (none had a reaction to the placebo). This rises to 11 of 45 if patient withdrawals are included. Thread veins developed in two of 35 patients (three of 53 legs) treated with Endennologie. Two patients also withdrew for this reason- Three paEents withdrew because the Endennologie treatment was too uncomfortable.
The results, at best, using thc patients' own cvaluations of trcatment efficacy, indicatc that only three of 3 5 legs improved with topically applied aminophylline and 10 of 35 improvcd with Endermologie. Discussion.!
Cellulitc is a common and diffcult problem that predominantly affects the buttocks and thighs of postpubertal women- Its cause is unclear, although it may rcsult from fatt distension of the superficial fascial system, which connects the dermis to the deep fascia- Points of attachment to the dermis are tethered while surrounding areas bulge, producing the "cobblestonc" appearance. Whether the fat storage in these areas is abnormal or merely represents one end of a spectrum is not known. It has also been suggested from ultrasonic analysis of the upper thigh and buttock that there is hernation of subcutancous fat into the reticular and papilar dcrmis. Increases in water-binding dermal glycosaminoglycans have also been reported.2 Cellulite is not exclusivcly related to obesity but may be accentuated by it. The range of body mass indexes and subcut3.!"cous fat depths across the ranges of cellulite appearance in our study group confrms this observation. Of the varous treatments available, only aminophylline and Enderrologie have medical literatue to support claims for their use. Studies published to date are small nomandomized, and often without controls. Results tend to focus on morphologic measurements rather than cellulite appearance. In none of the studies have all the initial patients finishcd the treatment protocol, and reasons for withdrawal are not given. An unpublished Endermologie study was recently used as evidence to persuade the Food and Drug Administration of the United States to grant a license for "temporary improvement in the appearance of cellulite" Thcre are no published studies to support this claim.
Topically applied aminophylline has been reported to be a safe, pharmacological, and nonivasive treatment for cellulite. 4 Aminophyllne is an inhibitor of phosphodiesterase, the enzme responsible for breaking down cyclic adenosine monophosphate. Its use in treating
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increased asthma stems from the bronchial smooth-muscle relaxation that results from the tubular levels of cyclic adenosine monophosphate. It also acts as a diuretic by reducing renal activity, reabsorption. Although these and other possible methods of action for its anticellulite , none have been proven. S In 1995 , Arz and Dinner 4 including fat lipolysis, have been proposed treatment showed that systcmic absorption of topicalfy applied 2% aminophyllineimprovement for cellulite in the appearance was minimal. All l ie:1ts (no controls) in their study had an , and eight showed a thinning of the subcutaneous fat at 3 months. Weight of their cellulite 5 cm. However, no actual remained static, and thigh circumerence decreased by an average of 0. figures wcre featued in the results. In 1993, Hamilton et aU measured a reduction of between , these figures arc small in relation to 73 and 2.27 cm in all six patients in their study. However or thc actual thigh girth mcasurements. Our results do not support these morphologicaminophylline changes are cffectiveness of aminophylline in cellulite treatment. Adverse reactions to the , although the Food and Drug Administration is apparently not mentioned in these or othcr studies aminophylline- aware of some patients developing a rash after using the cream; 24 percent of our treated patients developed a rash.
1 is a mechanical method of treatment for ccllulite. It was developed in The Endennologie ES soften burn France in the 1970s and initially used to relieve muscular achcs and" essentially to massage sucks and up a fold of scars. The proposcd method aspirated hypodennal mobilization , progrcssively disorganizing the adipose tissue skin and rolls it between two revolving rollers , sublethal and-gradually smoothing it out over thc course of several treatments. 'this,. Aprogressive nylon body stocking damage is similar to the shoulder indentation caused by brassiere straps. Administration is worn to reduce friction between the rollers and the skia. The Food and Drug as effective in the temporary reduction in the appearancc of recently licensed Endennologie " , particularly after the cellulite" Its use has also been recommended as an adjunct to liposuctio tumescent technique. " Only six of their 22 Ersek et aL6 used Endermologie for "noninvasive body contouring patients completed fourteen 45-minute sessions. All completed at least seven treatments and were encouraged to drink water and maintain a low-fat diet. A mean loss in body circumferencc measurements was related to the number of treatments, regardless of weight loss or gain although the results were better if weight was lost. However, no controls were used and the appearance of cellulite was not mentioncd. A follow-up study by the same group reported the same conclusion. Only 39 of 85 patients in the latter study managed to complete the course of , the reasons for withdrawal were not given. Our results suggest that changes in 14 sessions; again weekly, localized morphologic measurements are related to weight loss alone and not a twice- week 10-minute encounter with an Endermologie machine. Patients willing to complete a 12- twice-weekly treatment are much more likely to modify their diet and exercise regimens , only 10 patients who consciously or otherwise, to tr and gain maximum dfest. However received Endermologie treatment in the curent study pcrceived any improvement in the appearance of their cellulite, and only three of these patients had lost wcight. Adcock ct al.9 analyzed the effects of Endermologie in a porcine model and found no decrease in subcutaneous tissue thickness after up to 20 treatments.
We do not believe that either aminophylline or Endermologie is effective in the, dietary treatment . cellulite. Most of the benefits are probably derived from the adjuncts of exercise modification, and increased water intake that most treatments recommend.
Nick Colls, B.Sc., F. C.S.(Ed. ; nicollis!EaoI.com 4 Reedling Drive; Morley; Leeds; West Yorkshire; LS27 8GQ; U.
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REFERENCES.!
, 1981. rCllntcx!_ (1kJ 1. Garrow , J. Treat Obesity Seriously. Edinburgh: Churchill Livingstone
Dermato!. Surg. 23: 1177 , 1997. 2. Draelos, Z.- D. , and Marenus , K. D. Cellulite: Etiology and purported treatment. (CQ.Hc: (jbC'I'_ lloldi(1gs Ri!l_I!o rapNcJ.ink J.if1k
3. Hamilton, E. c., Greenway, F. L, and Bray, G. A. Regional fat loss from the thigh in women using 2% aminophylline. t1--.(lkJ Obesity Res I(SuppL 2): 95S, 1993. ( \!!nJ; Can J. 4. Art, J. S., and Dinner , M. L Treatment of cellulite deformities of the thighs with topical aminophylline gel. Pfost Surg. 3: 190 , 1995. (Conlcxt L!(!h.
Ann. Pharmacuther. 30: 292 1996. 5. Dickinson, B. , and Gora-Harper , M. L. Aminophylline for cellulite removaL .ii!nl a'. HQldJ!lg-' m b1iog(~pJli Lill (C91).IJ:ot.I- .bJ
, R. A., Mann , G. E, II, Salisbury, S., and Salisbury, A. V. Noninvasive mechanical body contouring: A 6. Ersek I!ogr l,i !1I. lCflXllG ! l)nk . Surg. 21: 61 , 1997. !,ihptry HoldJ!1gs B! preliminary clinical outcome study. Aesthetic Pla:i
1997. (CQl1tf;KtJ-i Aesthetic Plast. Surg. 21: 68 7. Fodor , P. B. Endermologie (LPG): Does it work? , R. A. Noninvasive mechanical body contouring: 8. Chang, P. , Wiseman, J., Jacoby, T., SaJisbury, A. V , and Ersek Aesthetic Plm. t. Surg. 22: 145 , 1998. U.tJrll!J I:olcJillgs dCnnologi ) A one-year clinical outcome study update. i.bi()gr rbh iJ1k IC()!!
, D. , Paulsen, S., Davis, S., Nanney, L , and Shack, R. B. Analysis of the cutaneous and systemic effects of an 9. Adcock mkj Aesthetic Surg. J. 18: 414, 1998. (C;on!\:xt endennologic device in the porcine model.
Accession Number 00006534- 199909040-00034
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NAME : DH ECKEL"
49969 FAX NUMBER 912023262559
PAGE
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T ABLE II
BMI Age Weigh! (kg) (kg/m
44. 67. 25. Mean 25. Median 45.5 64. d deviation 11.2 Standal- 21-38-5 Range 19-70 536-93.
l\1' (. body mass inde".
T ABLE II Pretreatment Patient Data September 1999. 1110- 1114 From: Collis: Plast Rcconstr Surg, Volume 104(4).
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TABLE I
Pregnancy Breast feeding Cardiac disease Hepatic disease Peptic ulcer Porphyri HyperthyroidisIl therapy . Hematologic disorders/anticuaguiatiu Aminophyll / theophylli therapy Drugs with potential interactions with aminophylli Dermatoses/severe thread or varicose veins Dieting/recent weight loss Recent u-auma/surgery to thighs/buttocks
TABLE I Patient Exclusion Criteria Septemb 1999. 1110- 1114 From: Collis: Plast Reconstr Surg, Volume 104(4).
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T ABLE III No. of l'atieo.t. Obesity B!vII(kg/m Normal 20- Grade 25- Grade 2 30- ::40 Grade
BMI , body mass index.
III Pretreatment Body Mass index Distribution TABLE Septemb 1999. 1110- 1114 From: Collis: Plast Reconstr Surg, Volume 104(4).
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Fig. 1
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Fig. 2
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Fig. 2. Body mass indcx and severity of ccllulite appearance. Patients were simply ranked by photographs. September 1999. 1110- 1114 From: Collis: Plast Reconstr Surg, Volume 104(4).
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TABLE IV
Group 1 Group 2 Group 3 l\kan 1.0 -0. -0. Median 1.2 - 0.45 1.53 . Standard deviation 1.47 1.63 Range 7 to 4.5 - 2. 3 to 3. - 4. 3 to 1.5
TABLE IV Weight Change (kg) Septcmb 1999. 1110- 11\4 From: Collis: Plast Reeonstr Surg, Volume 104(4).
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TABLE V
Group 1 Group
!\minophyilline Placebo Endermologie Mean Median Standa. d deviation 7 to :J.i Rano' 23 to 7. - '!.3 to 5.
TABLE V Ultrasound Fat Depth Changes (mm) 04(4 ). September 1999. 1110- 1114 From: Collis: Plast Reconstr Surg, Volume 1
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T ABLE VI Group 2 (IIJp I
!'lacebo Endenl101ogie Aminophyilline
Mean 0.5 Median 1.3 Standard deviation 3 to 3 - 4 to Range :) to '2
VI Changes in Thign Girth (cm) T ABLE Septemb 1999. 1110- 1114 From: Collis: Plast Reconstr Surg, Volume l04(4)
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199909040-00034jTT6&.. 7/26/2004 http://gateway2.ovid.com/ovidweb.cgi?VieW+Image=00006534- -.- -. ", Obesity: A Disease or a Physiologic Adaptation for Survival?
Robert If Eckel
, animal, or human that Impairs normal func- A disease is a condition of a living plant a positio that is sup- tioning and nnp1ies a condition of ill health- If obesity is a disease- nces (2), and ported by many, including a number of organizations (I), consensus confer it has now rcached epidemic proportions- Using the definition experts in the field (3 )- ) and obesity as equal of overweight as 25. 0 to 29. 9 kilograms per meter squared (kgim to or more than 30.0 kgim ' tI adults (4 5), Flegal and Troiano (6) estimate that 26% of 1 % is overweight. Moreover, the the population of the United States is obese and that problem of relative adiposity is increasing throughout the world (4)- ,According 40% of the to UnrtedKopel- man (4), If the current trend in hody mass mdex (13M!) continues Stales population will be labeled obese by 2025 at risk" and Adolescents in the 85th and 95th percentllcs have been representedin both as " children and overweight " respectively (7). However, because the 85th percentil kg/m and the 95th percentile apPI:oxiolatcs a BNU :idolcsccnts approximates a 8M! of25 10 chil- of 30 kg/rn , the most recent recommendation is to use a simtiar range of 8M!sl are belo\v , BMIs of 25 and 30 kg/m dren as in adults (8). For both adults and children . Native Americans the mean for many segments of the population, including Htspanics and African Americans (9 , I 0)- If this "disease" were virally induced as was suggested by Ohurandhar et al. (1t), by now Congress would have funded research for developmg antiviral drugs , analogous to the funds which it provided for human immunodeficiency virus and the related acquired immune deficiency syndrome in the last decadc. IIowever disease" of increasmg prevalence , the despite the increasing attention to obesity as a " solutions seem even further away-
OBESITY AS A DISEASE?
Definition of the Disease storage pool in the Adipose tissue is the body s largest energy reservoir. The trglycerid 0 adipose tissue; respectively, average nonnal-weight man and woman with 15% and 25 weight man and woman, total amounts to 10 and 15 kg, respectively. In the average noma i- 000 and 132 000 kcal (about 370 and 555 MJ), body fat stores amount to approximately 88 000 respectively. This is about three to six times the amount stored as protein (roughly 24 kcal or 100 MJ). These fuel depots are used to meet the needs of tissues during exercise 13). stress, and periods of food deprivation tasting from 60 to 90 days (12 To classify a condition as a disease, typically a pathologic basis is needed. However , conditions for unlike pulmonary thromboembolism, rheumatoid arthritis, or hepatitis C . which criteria for diagnosis are reasonably well established, the definition of obesity is .."'
I ETiOLOG1: PATfiOPHYSIOIDGY. AND ASSESS:\JENT
(hypertroph ) and/or cell num- limited fa the 81\11 a110 to increases In adipocytc cell size volume alone would be considered diag- ber (hyrerplasia) (3)- Ifan lHcrease in adipocyte over, even if criteria nostic , corresponding criteria have not yet bcC'n estflhlished. rvlor "vith an acceptable level of sensitivity were established, increases In adipocytes volume BrvU IS might be present in some regions of adipose tissue even thoughassessment the individual' is even morc less than 25 kg:'m The use of adipocytc number for diagnosti difficult because hyperplasia is ty)lcally preceded by hypertrophy (14). a generalizatio that is open to question- Examples to the contrary from transgenic rodents include mice specific ovcrexpresSlOn of the lnsulin-medlated glucose transporter with adipose tissue- criteria tha.t GLUT-4 (! 5) or the a adrenergic receptor (t6). In summary. the pathologi are needed to label obesity as a disease have not yet been establlshed-
Singtc Gene Defects
Substantial evidence indicates that obesity rarely results from single gene mutations; it is lnstcad polygenic. However, in this genetic age, an increasing number of single gene defects responsibl for the obese phenotype have been identified in humans- As Chapterphenorypes 2 outlines , most of th knm-v11 single genc defects Jrc associated \vith other II more detail , and/or malformations , endocrine (reproductive) disorders including mental retardation \vith (see Table 2.4 Hl Chapter 2)- Today, the most common single gene mutation4 receptor associated (tvIC4R) obesity in the absence ofmeotal retardation is that of the mclanocortin- (17)- A number of other mutations have also been identified, and the related hyperphagi obesity can present with either domlIant or recessive pauerns of inhcrit3nce (18)- The can. sequences of mutations in MC4R do not appear to he accompanied by other pathophysi, represents logic defects. Because of the high pr valence of tills genetic modificarion (i. about 4% of patienrs \vith severe obesity (17)) and in the absence or accompanywg bene-mor- , this mutation could perhaps be viewed as " rbologic and/or functional abnormalities , this advantage 1S appreciated only in ficial" for survival rather than as harmful. Of course cllvirorunents in which adequate sources of energy intake are not available
Comorhidities as Diseases , the consequences of excess \Vhen lifespan continues into the eighth and ninth decade , obesity is body fat are anything but advantageous. As other chapters in this text relate either directly or indirectly associated with an increased incidence and prevalence of heart disease and stroke (Chapter 8), obstructive sleep apnea (Chapter 9), type II diabetes mellitus (Chapter 10), dyslipidemia (Chapter 16), hyperterlSon (Chapler 11), hepatobll- iary dtsease (Chapter 12). cancer (Chapter 13), endocrine disorders (Chapter 14), psy- chosocial disturbances (Chapter 15). and orlhopedic complications (Chaptcr 17) Clearly- 5o pa hologically i.n-borh gross. these outcomes aremeasurabk not only ciinically but a and microscopic examinations. Usif!g relative hazards associated with elevated Brvn Jl six United States studics (Alameda Community Health Study, Framiogham Heart Study, Tecumseh, National Community Health and Health Study. American Cancer Society Cancer Protection Study I Up Study 1. and Nurses Health Study), the Nutrition Survey I Epidemiological Follow- national dIstributIOn of adult BM1 , and the estimates of population size and total deatbs from the same period, Allison et aL (19) calculated that tbe annual number of deaths 000. When hazard ratios were calculated from dala for attributable to obesity was 280 /0 and 9Y 34% in nonsmokers or neyer-smokers only, this figure was increased by 16 I. OBtSfrL DfSE4SF. OR PHL')/oLOGICADAPTATfON"
TABLE 1. 1. Estimates of obesity-attributable mortality in United States adults Role 01 Number obesity Rank Cause of death 725, 192 Diseases of Ihe heart 549. 838 Malignant neoplasms 167 366 Cerebrovascular diseases 124 181 Chronic lower respiratory diseases 860 Accidellis 399 Diabetes melli1us 63. 730 .Influenza and pneumonia 536 Alzheimer disease phrosis 35.525 Nephritis . nephrotic syndrome . and ne 680 Septicemia 199 Intentional self- harm (suicide) 259 Chronic liver disease and cirrhosis 16. 968 Essential (primary) hypertension and hypertensive renal disease 889 Assault (homocid 15.807 15- Aortic aneurysm and dissection 378. 970 Other 391 399 TOTAL , In the pathophysiology lor each oj the causes of deattl The approximate role 01 obesity, from 0 10 +-++t- is simply an estimate Other" in 1999 and the estimated contribution of Data are for the 15 most common causes of death + " obesity based on the prevalence of obesity in each of the categories of disease.National Vital Statislics Reporls Data from Hoyen DL Arias E , Smith BL . et al Deaths: final data for 1999. 2001 ;49:1- 113. with permissio
" Although these deaths ostensibly healthy weight- stable nonsmokers or never smokers. , such as coronary heart disease , stroke were variably attributable to underlying diseases ;V3S and diabetes in Framingham (20), obesity was rarely listed as the cause of death; it more likely to be noted as the associated comorbidity. based and gendcr- When the prevalence of obesity-related comorbiditics is examined, age- based distrbutions must be considered. In addition, the criteria used to stlpulate the specific comorbidity must be specified. Nevertheless, when estimates of the contrbutory role of obe- sity are made for the causes of death in 1999 (Table 1.), the importance of obesity in con- tributing to mortality through a number of different patbophysiologic mechanisms may be identified. Recently, criteria for tbe metabolic syndrome were developed by, threethe National or more Cholesterol Education Program Adult Treatment Panel 11 (21). For diagnosis i 02 of the following five components must be present: (a) a waist circumference greater thall level higher than 150 cm for men and more than 88 cm for women; (b) a fasting trglycerid mg per dL; (c) a high-density lipoprotein (HDL) cholcsterollevelless than 40 mg per dL for men and less than 50 mg per dL for women; (d) blood pressure higher than 130/85; and (e) a fasting serum glucose concentration greater than 110 mg per dL Based on these criteria the age-adjusted prevalence of the metabolic syndrome in adults 20 years or older is 23. (22). Based on data from the 2000 census, 47 million United States citizens are thus afficted. All of the criteria for the metabolic syndrome point to obesity as an uoderlying disorder
:1: Basis for the Definition of Obesity as a Disease Development Conference on the The National Institutes of Health held a ConS"-Tl5US Health Implications of Obesity in 1985. After presentations by 19 experts II relevant ;Ii level professionals came to the areas of obesity science , a panel of 15 impartial senior- cooclusion that obesity is a disease (2) AHhough the panelists agreed that the amount of I; . . "";. --'"
r ETIOLOGY PATHOPHYSfQLOC1: AND ASSESSiVlENT
, the conclusion that was reached was that an bod ! fat is a continuUIl! within populations increase !( body \velght of 20% or more above the desirabk body weight is associated
with a plethora of cornorbiditJes in addition to excess mortality and thatQ:- it thusc cac1y consti- fat tut s a health haLaru. The panel did note that the precise d2tc;:::: requires tcchnically sophisticated methodologies that are not readily available to most clinicians and that BMi as an assessment of body fat has limitatioos- Despite this limita- , diabetes, hypertensi , heart disease , and oth- tion , because si!:Tniflcant health risks (c_ , Clinical ers) can occur in some mdividuals at lower percentages of increased body fat concern about excess adiposity was extended to this population. (Even though, the term this disease man- uscript is frequentJy cited in support of approaching obesity as a disease IS never mentioned Hl the rnanuscnpL) fhc value of this decision by a group of "unbiased" professionals centers in the cur- rent thrust of the " sity as a disease" argument regardmg health care reimbursement 5% to 7. 8% of total health care fora disorder that was estimated in 1998 to amount to 5. , earty therapeutic and prevemive expenditures (23). If obesity were considered a disease Presently, strategies to diminish this epidemic would be implemented and reimbursed. reimbursement almost always relates to the comorbiditics of obesity, such as hyperten- sion, obstructive sleep apnea, and dyslipidemia. Recently, the metabolic syndrome has es corle. (m the ninth revision), pro- been given an Il1ternational Classifcation oj Diseas viding yet another disease category under which reimbursements for some obese patients may be filed. Moreover, even though the Internal Revenue Service now considers the sjty evaluation and treatment to be medically rdated tax deductions (24), cxr nse:s for ob deductions IS the high level of expenditures tbat is necessary for health clairns to receive . cessary for most obese individuals to unlikely to provide the financial incentive that IS ne seek additiona! attention- \-vas highlighted in , the importance of obesit)-' as a health problem In the United States promotio and disease Healthy People 2010 a comprehensive nationwide health- s Department of Health and Human prevention program orchestrated by the United Stat , the Surgeon General's call to action notably highlights the ServIces (25). In late 2001 I (26) need to prevent an increase IT overweight individuals and ohesity II late 200 Clearly, the lobbymg effort of both professional organizations and lay groups is directed towards future reimbursement for obesity as a disease. The bigger concern is whether the health .care system can absorb these costs. Presemly the health care budget in the United States is about $190 billion (27). Using 7% of this budget is obesity rclated, obesity- these figures and an average estimate that 6. 7 billion. Of course, some of these expenses related expenses could result in a cost of $12. , but many arc not. These would are presently covered under obesity-related co morbidities , aboul then be added to the economic burden indicated by the following ftgures. Each year loss programs, mcluding dietary, exer- $33 billion is spent in the United States on weight- , a recent bilt to prevent obes'itythat was pro- cise, and behavior modifications (28). In fact posed by Senators Frist, I3ingaman. and Dodd ("Improved nntrtion and physical activity att" or " Impact " aVailable in May 2002) estimated the alliual cost of obesity in the, incorpo- United States as $1\7 billion. Although the source for this amount is not stated in the bill rating even a small proportion of such costs into health care reimbursement is unthinkable. I f obesity is not a disease but rather a metabolic adaptation for survival in settings) The of food deprivation , would this fact affect the view of health care economists answer may be yes; however, if a preventive strategy is accompanied by sufficient evi- denced-based documentation that obesity prevention or treatment modifies hard out- , stroke, and type II diabetes), the result may comes (e. . death. myocardial infarction ORESfTJ DISEASE OR PHYSIOLOGfC ADAPTATION? be not only climcally effective but also cost sa\'ing. Ultimately, this may translate into the same type or "quality- adjusted life-year saved" assessments that have been applied 983 per life-year saved for in other areas of me'dicine. Recent ex.amples include $10 repeated colonoscopy for colorectal carci.noma screening beginning at 50 yearspatients of age 256 per life-year saved for hepatitis A vacClOCS administered to (19) and $22 acceptable" median level with chronic hepatitis C at 30 years of age (30)- To reach an '" 000 per life-year saved (31) for obesity using the assumption of the pre- afcost of $42 000 for each life-year sent 26% prevalence of obesity, the cost would be about $14 'Yvhether /Q of thc obese population were henefitted. The debate about saved if only IO approach to obesity obcsity is a disease may then be lrrelcvant when this outcome-related expenditures is used.
OBESITY AS A SURVIVAL ADVANTAGE Despite rhe magnitude of the health problem of obesity and its comorbidities today, substantial evidence from history illustrates that the consequences of obesity are far from unfavorable- Adipose tissue remains the predommant storage depot of energy as as noted above , if typical fat depots of 10 and 15 kg for the aver- triacylglyceroL As v.' suf- age adult man and woman, respectiveJy, are assumccL the energy stored therein is ficient for 60 to 90 days of starvation at a level of cnergy expenditure of 6 MJ a day , but the amount of stored proton can pro- ,13). Energy is also available from protein life- vide only approxnnately one- half of the stored quantity of protcin before , expanded adipose tissue mass pre threatening loss of lean tlSSllC ensues (32). However serves protem mass (33) (Fig- 1. 1).
8 c 8 c c c
FIG. 1.1. The eHect of starvation in lean subjects (solid squares) from the Benedict study (179) and from versus other studies (open squares) from obese subjects (open circles groups of subjects and small
squares from individual subjects) in the studies of Elia (32) and Elia Stubbs. and Henry (128). (From Elia M. Hunger disease. Clin Nutr 2000; , with permission. Period of staration (days) 19:379 386 I UIOLOGJ': PATHOPHYSIOLOGY. AND ASSESSMENT
Adipose Tissue Functions
Adipose tissue has other Important functions that are both related to and independent 1). These include the synthesis and secretion of various of cn rgy storage (34) (Table 1_ , ct prlJems Lilat regulate adipose tissu fuel flux, insulin sensitivity, vasomotor tone turnover, inf1ammation , coagulation, and conversion of androgens to estrogens. fVlanyof , cell proliferatio , thrombosis , vas- these protC!TS (i. , those that regulate lrsulin action cular r activlty, and the inflammatory response) may be related to the survival advantage of obesIty In addition to periods of food deprivation, other important periods of energy provision pregnancy and poor weight include pregnancy and lactation. LOlA' maternal weight before birth-weight infants (35 36) gain during pregnancy mcrease the prevalence of low- , energy Although lactation does occur in the absence of abundant adipose tissueto maintain stores breast intakes mllst mcrease \vith a body composition of this tye in order n1l1k quantity and qualIty (37). (n addition, adipose tissue acts as insulation and protects against the adverse effects of cold air or water (3S). It also has an important role in fertility- The age at40), which and, menar- as fat che occurs is at least partially attributable to adipose tissue content (39 mass decreases with exercise or cating disorders, oligomenorrhea and amenorrhea may llctive function of adipose tissue result (4iJ. Although the mechanisms for the reprod remain controversial, leptin appears to be important. Not only is leptin able to induce decrcase mleptin that occurs with reproductl.!e maturation m female rodents (42), but th weight reducticI' and loss of adipose tissue mass appears to be partially responsible for the alIered function of the hypothalamic-pituitary- ovarian (testicular) axis (43). Bone
TABLE 1. 2. RoJes of proteins secreted from human adipose tissue
Rcgljlation of adipose tissue fuel flux Kather et ai. (182) Adenosine Friedman and Halaas (150) Leptin Sniderman et aL (183) Acylation- stirnulatinq protein Regulation of insulin action Weyer et aL (184) Adiponectin Moller (185) TNF-a t soluble receptor Regulation of vasomotor tone Van Harme!en et al. (186) Angiotensinogen Gorzelniak ct ai , (187) Angiotensin-converting enzyme Fink et aL (188) PGlz Regulation of ceJllurnover Negrel et a1. (189) PGI Alessi e! al. (190) TGF- Wabitsch et at. (1 91 ) JGF- Regulation of coagu1ation Cranda!! et al. (192) Plasminogen activator inhibitor- McCarty (1931 PGb Regulation of inflammation McDermott (194) TNF-a + soluble recepto Hirano et al. (195) Inlerleukin. Esterbauer et aL (196) Adipsin , reproduction , bone mass Steroid conversion Su/un et aL (197) Cytochrome P450-dependent aromatase Crobould et aL (198) 17p- hydroxysteroid oxidoreductase Other Voisey e1 aL (199) Agouti signa! protein
Abbreviations: IGF. insulin-like growth factor; PGI. prostaglandin I; TGF, transforming growth factor; TNF, tumor necrosis factor / OBESITY D/SEASF OR PHYSIOLOG/CADAPTATlON? mass and adipose mass are also high1y related (44), and obesity protects against the , a workup de\relopment of osteoporosis (45). \1.,ihen osteoporosis occurs in obese patients for Cushing' syndrome is mandatory-
Environmental Influences on Adipose Tissue !\1ass The present environment of food availability and decreased physical activity favors an tlldies sup- increase in adipose tIssue mass. Although evidence from adoption and twin , so this port a genetic basis for body fatness (46- 48), the gene pool has changed little does not explain the epidemic of overweight individuals and obesiry that has been encountered In the last two decades. Even if genetics could explain a large percentage of the overvveight and obesity epidemic , the literature is mixed regarding which component erati()ns of energy balance is etiologic. Moreover, variable data on the contributions of al in .energy expenditure to changes In fat mass over time do not clarify the mechanism of the genetic impact (49). Thus , the cnvirOlunent must be examined as the cause Influences of the environment on body fatness could work through llcrcases in energy , data on food Intake mtake and/or decreases in energy expenditLUe. As Chapter 3 revic\"'s 51) are contradictory, with. some studies shO\\'ing 110 change \l calonc consumption (50 and others demonstrating increases (52 53)- Endencc supporting a higher consumptioJl of dietary fat as etiologic is equa!ly as unconvincing as that which demonstrates no rela- O\'efCOll- !ionshlP betwecn dietary fat and \\'eight change (54 55). Some believe that the sumption of dietary carbohydrates resulting from the '. fat is bad" mentality of rhe late n\'enticth century is etiologic (56 57). However, when e:.amllling intakes for populatio , using caiitlOn must be used In making conclusions about cause and effect: for example such an approach, the increase in overweight and obese muividuals can be attributed to the consumption of diet beverages. Reductions in physical activity also contrihute to the positive energy balance that, in turn, results in increases 1I VI'eight and adipose tissue over time (58). Activity data, which have been collected only tI the United States Stice 1985 reveal that 60% of the United States population has no regular pattern of physical activ- ity and that 25% reports nn physical activity (59). Many people in the United States, and in the rest of the civilized world are increasingly "desk bound" in their occupations this lifestyle is supported by the many advances of the modern world. Substantial evidence from migratory patterns of populations indicates not only that .food is more available and more energy dense but also that the physical acti'irity profiles of past generations have been exchanged for a more sedentary lifestyie. Examples frail: these include the Samoans within the Samoan archipelago and Hawaii (60), the Pima Indians of Mexico and Arizona (61). the Japanese-American immigrants (62), and the West African Diaspora and its migrations out of Africa to the United Kingdom and the United States (63). In these instances. fatness results when the stresses of life in a more deprived setting are replaced by the conveniences of the modern \vorld. One conclusion that seems tenable is that the body creates an excess adipose tissue reservoir in prepara- tion for less favorable environmental conditions. Another relatively recent example of the impact of the environment on body weight during the regulation and obesity prevalence was the experience of the Dutch populatio famme of World War II (1944 to 1945). During this 6-month period of food rationing in the Nctherlands, infant size was substantially decreased and infant mortality was signif- . icantly increased (64). A similar experience was seen in Leningrad and Odessa at the :as greatest during same time (65). .Moreover, when food deprivation in the Netherlands the third trimester, the incidence of obesity in the offspring \\'as decreased, whereas food r ETlOLOGY PATHOPHrS/OLOCY AND ASSESSMENT
offspnng deprivatIOn In the firsUrirnester produced a much higher rate of obesity In the (66). The authors concluped that the early deprivation likely caused damage tooccurs the hypo- later thalamic centers , which regulate food mtake and grow1h; when deprivati in gestatIon, a defect in adipogeileslS may be responsIble. This expenence suggests tbat the regulatlon of adipose tissue mass at least partially relates to the intrauterine envrron- nt and that it may differ during the course of the prenatal period-
Overfeeding and Obesity , remains one The response to forced overfeeuing, \vhich is somewhat unrealistic way to determine the genetic predIsposition to overweight and/or obesity. (n general overfeeding rodents resu ts in weight gain and adipose tissue accumulatIOn; however this response is typical1y dependent on the rodent strain (67) and likely on the ther- mogenic response of the rodent to overfeeding (68)- In female baboons that arc overfed during infancy, hypertrophic obesity deve10ps after puberty (69). However
ad libitUm food intake variable amounts of intragastric overfeeding in adultreductIOns male in rhesus monkeys resulted in weight gain , but this was also accompamcd by overfeedrng period was discontinued in these monkeys (70) When the intragastnc several months and their body normal energy intake stabilized over a period of , whereas weights dropped rapidly Some monkeys returned to tneir iniual body weight some net weight galn occurred in others perfOITI1Cd in humans. Bouchard et A number of overfeeding experiments have been aJ. (7\) performed one of the the longest and best sludies for determining the genetic basis of the metabolic and anatomic resronse to excess calories- In his study, 12 pairs of 000 kcal over 100 days. The average \'veight gaw was identical twins were ov rfed by 84 3 kg to 13. 3 kg was observed. Although 63% of the excess calo- 81 kg. but a range 01'4. of weight maintenance at an expanded body ries \A'ere stored, predicting an increased cost weight (72), about one- third of the excess calones were not stored, tbus implying tbat thermogentc mechanisms tn response to overfeeding also occurred Twin pairs were sim- ilar in their response , with three times more variance in weight gain and in the increase II adipose tissue among pairs than wlthm pairs. An eventissue greater mass. srnularity Moreover within, within tWII 4 parrs was noted in the changes in regIonal adipose , fat , and 100% of the overfeeding gain in body weight monthsof overfeeding, 82 , 74% free mass , respectively, were lost (72). mass, and fat- a1. (73) also demonstrated that massive The classic overfeeding studies of Sims et , was accompanied by substantial caloric overfeeding, which , in tius experiment increases in physical activity, resulted in, variableresumption weight of their gain; initial an increased body weight thermo- after genic response; and, for most participants overfeeding was discontinued. More recently, research subjects at the Mayo Clmie who were ovetf d 1 000 kca! per day for 8 weeks experienced increases in fat fromexpenchture, 58g tp. free mass from 17 g to 78: g (74). Although energy. 687 g and in fat- 100 kcal to +360 keaL The greatest pre- increased m most subjects, tbis ranged from - dictor of the change in weight and fat masS during exereise-this relativelyassociated brief periodthermogenesis of over- feeding was the individual's increase in non , but (NEAT), or fidgeting. Presently the genetic basis of NEAT remains undefined NEAT may be extremely important in determining the response to the environmentalof one factors that lead to obesity regardless of whether it results from the expressi or many genes. I. OBESIrY DISEASE OR PH,SJOI"OGIC ADAPTATION?
Reduced Obesity Predicts Resumption of the Obese State , and it may be more difficult Achieving weight reduction is difficult for obese patients to sustain (75-77). The term reduced obesity defines the behavioral and metabolic status of an obese person Of animal after weight reduction and isocaloric weight maintenance. reduced normal-weight organisms. Although Similar responses may also occur in weight- these variables and intervals are probably mflucncect by the amount, they of are weight poody reJuction defined and the duration of the weight-reduced stale among other factors and thus they require additional elucidation. In general, the adaptations of the reduced obese state appear to work in a manner that 3)- After successful weight reduction predicts resumption of the obese weight (Table 1_ , increases in appetite (78, 79) and and months of maintenance of the reduced obese state , those containing fat and sugar) (80) are a preference for energy- dense foods (i. , which observed. This increase in appetite may be partially related to decreasesv.reight in leptin reduction: in at east one study (81) predicted the increase in body weight after , Cummings et other studies (82 83) have not reported the same effect. In a recent report a1. (84) suggest that changes in the gastrointestinal hormone ghrelin may also contribute lIduced weighl reduction. Normally, levels of ghre- to weight regain after successful dict- , Cummings et aL (84) found lin increase before the meal and fall after the meal; however, 24-hour areas under the curve for that during maintenance of the reduced obese state ghreli were actually increased, rather than decreased, compared to the baseline. Regain of weight is also favored by changes Hl energy' expenditure- bodyWith weightmass (85)- reduc- In tion, the basallletabolic rate falls in proportion to the loss of 1ean , the energy expended in the form of physical activity docs not increase many subjects succcssfnl" reduced obese (86- 88)- Klem et aL (89) gathered a nonrandom sample of " , a subjects into the National Weight Loss Registry- In more than 90% of these subjects combination of a diet restricted in fat and exercise of more than 500 kcal daily was nec- essary to maintain a BM! of25 kg/m' (90 91) Finally, isocaloric maintenance of the reduced obese state modifies the physiologi93), processes that promote fat storage. This includes increases in insulin sensitivity (92lipase decreases in fat oxidation (94 95), and tissue-specific changes in lipoprotein- (LPL) activity. Although increases in insulin sensitivity after weight reduction and the maintenance of the reduced obese state have been shown to predict weight regain (96), conflicting reports have been made (5,97).
of weight regain TABLE 3. The reduced obese state: possible predicto Doucet et a1. (78) Increased appetite Mavri et al. (81) Decreased leptin Cummings et aL (84) Increased ghrelin Orewnowski and Holden-Wilse (80) Preference lor energy-dense loads Reductions in energy expenditure Astrup et al. (85) Basal metabolic rate Weigle (B7) Physical activity Yost et al. (96) Increased insulin sensitivity Froidevaux ei aJ. (94) Increased respiratory quotient Changes in LPL Schwartz and BrunzeIL(100) Increased adipose tissue LPL Eckel et al. (101) Decreased skeletal muscle LPL Abbreviation: LPL, lipoprotein lipase. . ,:( !;.-,:" , '-..'. , '(. ',:- ., . . "-. p-- t.,* r ETlOUJG1: PATIiOPHYSlOWGY. AND ASSESSlvIENT
Lean (\Z:;'c l \:f ( TG ;FA juM1
Reduced-Obese FIG. 1.2. Tissue- specific changes in lipoprotein lipase (LPL) in the reduced obese state. LPl, which is shown bound to. the glycocaJyx of LPL capillary endothelial cells, hydrolyzes the triglyceride (TG) core of circulat- r , L . mMj ing TG-rich lipoproteins. very low , and chylomi- ';TG ;61 density lipoproteins 1 . crOflS, resulting in the productiOIl of f-F.I\ (uMj free fatty acids (FFA) and monoacyl. glycerol , which are then taken up by adipose tissue and muscle- There the 1 0, FFAs are either stored (adipose tis- t-- 17;- sue) or stored and/or oxidized (mus- cle)
rich lipoprotei LPI. hydrolyzes the triglyceride core of circulating triglycende- producing ttssues of the body, iocluding adipose tis- provide fatty aerd fuels for the LPL- , the activity of the fasting 100), and the sue and muscle- After 3 months of sustainedunchaoged weight reductlon or increased (98- enzyme in adtpose tissue either remains , LPL levels arc response of LPL to insulin aod meals is iocreased (98). In skeletal muscle reduced in compariso to the levels that were present before weight reduction2) do (99). not Theseoccur changes in macro nutrient partitioning and presumably in storage (Fig. 1. in a vacuum; instead, they arc permined by a setting in which energy intake is greater t fo explain- than energy expenditure. J!"C probably importa !1_ Overall, these changes In behavior and mctabotis: , and they point to the ing the relatively low success rate of sustamed weight reduction potential role of obesity in defending the organism during food deprivatio
Evidence that Obesity Promotes Survival accompanied by marked, if not complete Death from starvation is almost always loss of adipose tissue (102). This is illustrated by adult necropsies performed during the Irish famine of 1847 (103), World War I (104), and World War II (105), as well as in . .. -- iiii\f-..r
ADAPr,TlON' I. OBESITL DISEASE OR PlirSIOLOGIC
, the loss of sub 3tion 11 Kharkov (106). In general chIldren who were victims of st3f\' cutaneous adipose tissue precedes the loss of fat located elsewhere, the oramount of muscle of weight mass (105) (Ftg. (3) Dunng prolonged periods of food deprivatio reduction varied from 15% over 5 months (107) to nearly 25% over 3 years (l08) in World War! , from 22% to 26% dunng the Russian famine of 1920 to \922 (l09), and from 9. 3% to 13_ o among Parisian civilians during \Vorld \Var II (110)- tvlore/0 andrecent in , for men , a reduction in hody fat to less than 4(\ studies have ascertained that (Ill). 5 kg reaches a level that is inconsistent with good health fat mass to less than 2_ kg/m a level of estimated fatness that sep- Generally. this results in a BM! of ahout i3 , a much greater variability in arates survivors from Ilonsurvtvors in men. In women , more recent 8Ml is seen in survivors versuS nOllsurvivors (13) (Fig. lA). However kg/m can
data provided by the famme in Samaha suggest that a BM! of less than 10 , in Soma- support life as long as the individual receives specialized care (12). However lia , starvmg male patients had more severe edema and a poorer prognosis than females atian- at auy given level of seventy of stan' ,,'ome/1 appear to withstand semistarvation and As th, prevIous statement suggests , other examples men. In addition to the experience in Somalia starvation better than include the 1941 to 1942 famine in the Greek1941 cities to 1942of Athens (113), and and Piraeus the Dutch (112) famine (Fig. 5), the German siege of Leningrad from in 1945 (114) (Fig- \.6)- Although the data accrued from these unfortunaterelated incidents mortal- of history are far from satisfactory, the percentage increase in starvation-the peak incIdence of and ity in Greece was lower in women tban in men. in Leningra :2 to 5 months in \\lomen versuS men- In the the rise in death mortality were delayed by 169%, while that for women was only Netherlands , the mortality for men increased by
100
-0 Body Weiohi Mulde Mall Fat
Weeks of Semi-Starvatio starvation in FIG. 1.3. Percentage changes in body weight. muscle mass, and fat3 duringkg with semi a body composi- the Minnesota experiment. In this experiment, 32 men weighing 69. 570 kca! per day for 24 tion of 13. 9% fat a baseline vo!untarily ingested an average of. BrozelCJ. 1 Henschel A. ef aL weeks. Body fat was estimated by specificVaLL gravity. Minneapolis: (From Keys UniversityA of Minnesota Press, Body tat in biology of human starvation. 1950:161 183. with permission. - - ,- .------.- - _--- -
1. ETI01.0GY. PATHOPHYSIOLOGY. AND ASSESSMENT
"" da.ad dOlad star"ad 3(\On,'''\ nar"as Q 0= somt-starved star"..d . = lam;n6 )ndia,UOIOcl ."",..a"value .." mean \,al,,'"
3' 14 ;: 16-
;;15 002
Alive Dead Oead AI".... (Data from FIG. 1.4- Body masS index (BMI) and limitstrlOSe of survival of non in survivorsmen and arewomen. portrayed Comparisons of Eur Clin Nutr 1990;44. BMls 01 male and female survivors versuS 01 human survival Henry CJK Body masS Index and the limits 329-335 , with permission.
, the smaller fat 72%- One of the factors rhat most likely contributes to the relative survival advantagea survival abdominai fat provid of women versUS men is the increased fat stores in women- Moreover seque- cells and reduced metabolrc activity, and of theypclvic could versUS protect against the patholog advantage in periods of starvation iae of cettral adipose ttSSue deposition that is more typical in men during period , of Keys et at. (\02), the caloric excess-" or scmistarvatio experiment In the " Minnesota Experiment adipose ttSsue dramatically responded to refeeding, , predictingthe pattern the of followinglean and fatreturn tissue of body weight (Fig- l. 7)- In more recent experiments depositio during the refeeding period appears to be due to individual difTerences in energy partitioning; in other words, the disproportionate gain inthat fat enhances versus lean energy tissue effi- is a consequence of a relative greater reduction in thermogenesi ciency (115). This metabolic efficiency may actually, \occur 18)- in response to low energy intakes (116), although this view is controversial (117 Until the late eighteenth century, individual life expectancy was only 25 to 35 years (119)- Even at the beginning of the twentieth century, the, survivalaverage increasedlifespan in to the 55 United years States was less than 50 years (120)- By the early 1900s, Canada, France, Germany, Italy, (12\), and for those born in the G7 countries today (i_ decline in mortality predicts a Japan, United Kingdom, United States), the progressi report by Geppen years (122). In fact, in a recent and provocati longevity of nearly 80 '.. .. .--..------..., -....-_. = ".. g :: ,; :: .: :;....:; .;g. ;:'" ~~~ ,.,= "" ..
.:..allw..
1,4) ,,.0 ,.oQ
FIG. 1. 5. Effects of famine on the population of Greece. Shown is the number of deaths, 1940- by1943- age for men and women in Athens and Piraeus during the period of World WarMilbank 11 Memo6al tFrom Va1aoras VG. Some effects of famine on the population of Greece. Fund Quarterly 1946;24:215-234 . with permissio
Under 1 Year 2.400 - 1 3 Years 200 - - 4- 13 Years (From June 3 , 1945 : 4-5 Years) 000 -- 14- 17 Years (From June 3 , 1945: 6- 17 Years) 800 18 Years and Over 1.00 1.400 200 000 800 600 400 200
1' = .. u; q '" ;:2!;: en :: C3 :: = a 1945 1944
groups. The data portrayed represent the FIG. 1. 6. Average calories per day far various age - average calories per day by weekly periods for food rations distributed daily to various age groups in the Western Netherlands trom September 3. 194410 AuguS15. 1945. (From Dots MJL. van Arcken DJAM. Food supply and nutrition in the Netherlands during and after World War II. Milbank Memorial Fund Ouarterly1946;24:319-355, with permission. ASSESSi'vIENT r ETlOLOGY PATILOPHYSLOLOC): AND
t50
. BOy WEGHT o BODY FAT
RZO R?3 o I SIZ SZ4 R1Z FIG. 1.7. The recovery of body weight and body fat expressed as a percentage of contro!' 570 kcal per day) !t 32 men in the Minnesota Experiment alier 24 weeks of semistarvation (1 R 12), subjects were dIvided into four groups During the first 12 weeks of rehabilitation (R1- 378 to 3 392 kcal per day (average consisting of four different caloric !evels ranging fmm 2 . Brozek 896 kcal per day) with or without protein and vitamin supplementation-Vol 1. Minneapolis: (From Keys University A of J. Henschel A , et aL Body fat in biology of human starvation Minnesota Press , 1950:161-183 , with permissio
, by 2070 and Vaupel (123), they indicate that, if the current trends lI survival continue the average lifespan could be extended by 12 to 15 years. AlthoughtreneL the the !rlcreasing data availah!e inCI- dence and prevalence of obesity may ultimately modify this today for obese individuals older than 65 years of age may not indicate an e3rlier8), demise death , because a maximum lifespan exists for all mammals (Fig. 1_ (124). However natural or degenerati causes- rarely occurs without it being attrihuted to onc or more " Although senescence is accepted as the biology of aging, death is still attributed to the failure of one or more organs , and the increased survivorship of these times is largely a function of medical intervention (l20). of food deprivati Evidence indicates that obesity prolongs survival in period , the lifespan ranged from 45 to 73 days (32). in (102 125). In the Irish hunger stfikes which longevity could be predicted by a normal amount of fat mass before starvation. Howeyer, prolonged fasts of up to 400 days have been accomplished by obese subjectsexpla 127)- A number of metahoJicfact9 who fasted for therapeutic reasons (i26 1.), obese indi- these results (Table 1.4). As has already been noted and portrayed (Fig., but during starva- free mass) than lean individuals viduals have more body protein (fat- , within tion they excrete less nitrogen than their lean counterparts (128). in addition weeks of the onset of starvation, the energy contribution from protein remains the same
in lean subjects , but it progressively decreases in obese individuals (33). Other metabolic differences observed in the obese versus the lean include a decreased rate of.protein oxi- dation (128), a decreased rate in the rise of circulating ketoneof bodies glucose and from of the gluconeo- indices of the mitochondrial redox state (129), a greater productio . -- . .--.
OBESITY DISEASE OR PHrSIOI.cjc;IC AIJAPf4T!ON'
tOO man
- r;..phGn'
- '0 Kc/ - hlppopotOlYu.! (SMA) (MLP1 . 200
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".or.I! li:: dD- cC'm toyolt . - galollo "toi. . -k Inoloui . d... mou" Qt:n.t held mou5t . - raccoo plliJ . - chipmunlo If ,hod- i cUed shr(!W' QUincCi hlJm!ler shrrw Iounk . ret fUfopeol' colicin fa! 100 100 200
SMR le/g/d)
(MLP) and specific metabolic rate FIG. 1. 8. Re\ationship between maximum lifespan potentia! (SMR) expressed as calories consumed per gram of body weight per day in a variety of mam- malian species (180). (From Weiss KM. Are the known 319chronic, with diseases permission_ related to the human Am Hum 810/1989;1 :307- lifespan and its evolution?
genesis by the kidney (130), and a lower deterioration in glucose tolerance (131). The reduced rise in ketogenesis and in the indices of the mitochondrial redox state indicate the relative preservati of glucose as the dominant energy source for the brain in the --bose individual. The experiments ofElia et a1. (128) portIE)' this nicely '.ers,"s(Fig. 1.9). !eaD Over- indi- all, these differences in the meuiboJic response to starvalion '" 0bcs viduals are not trivial , and they most likely contribute to the prolonged survival that is seen in those with expanded adipose tissue mass.
TABLE 1.4. Metabolic differences between lean and obese individuals during starvation Lean :; obese Rate of rise of ketone bodies over 3-4 days Lean /- obese Ketone body concentration at 3-- days Lean /- obese Rate of rise of 3-hydroxybutyrate/acetoacetate ratio Lean:; obese Concentration of 3-hydroxybutyratelacetoacetate ratio Lean :; obese Deterioration of glucose tolerance Lean /- obese Protein oxidation at 60 h Lean:; obese Nitrogen excretion Lean.: obese Rena! gluconeogenesis , with permission. Clin Nutr 2000:19:379-386 From Elia M. Hunger disease. ." . ,. " (j
r ETIOLOCY PITHOPHYSlOLOCY AND ASSESSMENT
Jean adults + children CD' 7 e m OJ 6 E iU gj 5 TI '" .. en 4
obese adults
72 96 120 144 period of staNation: hours hydroxybutyrate to ace- F!G. 1.9. The effect 01 total starvation on HIe plasma molar ratio of 3- and obese (open symbols) adults. (From Elia and lean (solid symbols) toacetate in children , and protein metabolism between M. Stubbs R , Henry CJK. Differences in fat. carbohydrate Obes Res 1999;7:597-604 , with permis- lean and obese subjects undergoing total starvation siG
The Thrifty Genotype , obesity has bl As DrilY (132 133) has repeatedly pointed out In historical reviews 000 to 25 000 years ago (134). exemp\Jfied since the Paleolithic period, approximately 23, , Venus figunnes portraying female ohesity have been located in As fig, 1, 10 demonstrates Venus many Sites throughout Furope and the Middle East. The most famous of these lS the .' of Willendorf" made of limestone , which IS the only one that has been discovered in i\us- tria. These figurines have been viewed as representing primordial deities reflecting the bounty of the earth, These artistic records of history may also represent the longevity asso- ciated with obesity at a time when the lifespan was only two decades (125). The concept of the "thrifty genotype" was initially proposed by Neel (135) in 1962 and his initial interpretatIOn of genes was revisited in 1982 (136) and 1998 (13 n Although " type of enviromnent related more to diabetes beneficial to survival in a ""huhter-gatherer than to obesity, the most recent view focuses more on obesity and it also includes hyper- tension (137), The putative genes would operate such that carriers are predisposed to extract scalee i e.'uufC8S :n:Jr t'ff!ciE', nrly from the environment. In the modern woiId in gatherer" concept is fading and the lifespan extends far past the repro- which the "hunter- , be detrimental. , these genes are no longer beneficial and they can, in fact ductive age ners to physiologic Now called pleiotropic, these genes may also predispose their car degeneration or loss of function during their middle or later years of life (138). This model thus provides a theoretical basis for explaining aging and the many degenerati diseases that accompany the extended lifespan, " model of degenerati As Gerber and Crews (121) outline, the "thrfty and/or pleiotropic , specific risk factors associated with diseases with aging can be appli d at two levels, First :,.. ~~~.' j?' .. .~~~:.,;:;
IOLOGIC ADAPTATiON:' 1 OBES17T DfSEA.\E OR PHfl.
\lV
:;iCeo
Venus" figurines in Europe and the lJ\idd\e East FIG. 1.10. Approximate location of Paleolithic " about obe- 000 8G. (From Bray G. Historical framework for tile developmentNew York:of ideas Marcel Dekker about 22 Handbook of obesity- sity- In: Bray GA, Bouchard C , James WPT. cds Inc, 1998:1- , Wlttl permission.
degenerati diseases fonow either the accumulation (thrifty) or the scarcity or loss (non-dis- , stores , or deposits. Second, some degenerati thrifty) of specific nutnents , metabolites eases result from the antagonistic effects of thnfty genotypes that have high selective value during development. These effects then predispose their carriers to the risk factors associated diseases. The transition from obesity to type II diabetes and then to the with degenerati , such as dyslipidemi , the prothromboti additional risk factors for cardiovascular disease docwnented example of the proposed modcL state, and hypertension, is a \vell- Genotype BioLogic Considerations of the Thrifty or Pleiotropic A gene or genes that favorably modify energy storage during periods of food depriva- tion and that could ultimately result in degenerative diseases during midlife and late life generally are genes that at least have some influence on energy balance. Ideally, candi- date genes would operate to enhance energy intake and metabolic efficiency in a way that partitions fuels for storage rather than for oxidative metabolism. Because of the limitedand capacity for carbohydrate storage, these genes would need to influence lipid uptak , so storage mechanisms. The plethora of metabolic effects of insulin satisfy these criteria a gene or genes that enhance insulin sensitivity in the periphery is worthy of serious con- sideration. , anabolism is the rule. This is related to the multi- In an insulin-sensitive environment ple effects of insulin that promote fuel uptake and storage in peripheral !lssues (Tabl 1.5). In protein metabolism, insulin increases amino acid uptake and protein synthesis AND ASSESSlvlENT r ETiOLOGY PATf!OPf!YSIOLOC I:
tissues TABLE 1.5- Insulin action in insulin-sensiti
P,otein metabolism Lerner (200) Increases amino acid uptake Miers et aL (201) Inhibits proteotysis Kimball et a1. (202) Increases protein syn!l1€SIS Ryder et a1. (203) Glucose metabolism musclE!) Increases glucose transport (adipose tissue, SrivastaVa and Pandey (204) Increases glycogen syntll( siS Cherrington et al. (205) Inhibits hepatic and renal glucose production Lipid metabolism Bergman (206) Sparks and Sparks (207) Inhibits 1ipolysis Increases fatty aCid and Irig1yceridfo synthesis (liver) Sadur and Eckel (208) Farese et aL (209) Increases adipose tissue lipoproteinin lipase lipase Inhibits skeletal muscle lipoprot( Lewis and Steiner (210) Inhibits very low density 11poprotein secretion
and inhibits proteolysIs Insulin modifies carbohydrate metabolism by increasmg glucose uptake and glycogen synthesis in musele and adipose tissue and by increasing glycogen synthests and mhlbltmg glucose production m the liver and kidney. Finally, in lipid , insulin mhibits adipose tissue lipolysIs of stored triacylglycerol (the most metabolism mcreases lipoprotcm-denved fatty acid uptak sensitive parameter of rnsulin actlon) mhlhlts the sccretion of very low density lipoprotei Its effect on adipose tissue LPL from the liver and mhiblts skeletal muscle LPL modestly, thns decreasing the availabrl- denved fatty aCids to muscle. All of these effects ofof insulin nutri- Ity of clrculatmg lipoprotcm- work to enhance energy storage and thus to protect the O'gamsmuod wtake against whcn period it is infused . insulin is also known to whiblt t ent deprivation. However 1401 How this parameter of msulin baboons and rodents (\39 wto the third vcntnele action rdates to energy balance 10 the periphery remalOS unclear. A substantial amount of evidence providesmsulin resistancesupport for protects the concept agamst that insulmweight sensi- gam tiVity promotes weight gain and 146) indicate that fastmg hypennsul (141- 144). Some epidemiologic studies-Dr (145 more likely insuhn resistance itself predicts nua- a marker of mSlllin reslstance- . sev- , not all studies (147 1481 support this. Nevertheless weight mamtenance , however eral recent studies have demonstrated that mcreased msulmul sensitivity weight reductiOn is a predictor (96) Inof wClght (fat) gam or of the rehound of obesity afier successf' , alternative data do exist (97). these cases as wcll , when the thnfty gene effects of msulm Graphical depictions (fig. I II) mdieate that sensttivity are manifested, increases in adlpocyte number and/or size and insulin resis-
of insulin sen5itivity in leanness (A) to obesity (8), which repre- FIG. 1. 11. The progressio . to the insulin resistance af type II diabetes mell- and gf)'cf)gen depo- sents the intermedIate metabolic oaradigm mediated glucose uptake tus (C). In the setting of insulin sensitivity. insulin- mediated sup- sition in skeletal muscle is enhanced with relative sparing of fatty acid oXidation and the uptake of lipids with slorage in adipose tissue. The liver remains responsiVe to insulin- pressio of hepatic glucose production. fn obesity. defects in all hyperinSuIinemlaaspects of insulin butaction preser- ulti- mately result however, insulin secrefion increases. resultrng 10 failure. insulin vation of glucose tolerance. With persistence of insulin resistance and islet" mediated glu- secretion fails. In this mefabolic setting, insulin resistance. and further increases. defects inincluding insulin- resistance to insulin suppression of hepatic glucose production cose disposal and hyperglycemia result. Because of persistent and worsening insulin action in adipose tissue, fat mass fails to increase further. \--.- -, ,.'/\ .( '\ ., /. );', .',-/;. . .)'/:" . .. ., ,..-', (j . ,/
OBESITY DISEASE OR PHYSIOLOGIC ADAPTATION" fat Cells L - i , PTG:fFA TG1 1",i/ . / fTA
' 1--
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INS Pa012reas
Skeletal Muscle
fat Cells ' LI"L TG:FFA
, 8 '0 j:t(irAK FFA :i):.
L') CtlO
Glu Pancreas ffA
Skeletal Muscle (coDtinued on next page) ': -\ --- , )- - - '--/ -)--\/y;\. - \
r ETIOLOGY. PATHOPHYSIOLOGY AND ASSESSMENT
rat Cells- - - v' - LI" TG:rfl\
ii'"
FFA
r-- ,I .r\-
CHO
"'i frA 'C'"
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FIG. 1. 11. Continued.
. insulin , ullmJatcly result. In adipose tissue tance , as mamfested by hypennsulinerma resistarlce to the aotilipolytic, y.ritheffects the of development insulin and theof obesity, insulin insulinstimulatory resistance effects in on tissues LPL become apparent. Moreover , with mediated glucose transport and glycogen synthesis lllso results in defects in insulin- tncreases In lriacylglycerol accumulation and fatty acid oxidation in muscle, the and conlmuen lack of suppresslon of glucose production by the lIver and kIdney. Over years stress of (he Insulin- resistant environment on the pancreas produces an inability to main- tain insulin secretion , and type II diabetes results. Of interest is reccnt evidence from insulin receptor knockout mice suggesting that the islet defect may also be a consequence of insulin resistance (149)- Whether the propenslty to develop diabetes, or relatesto a separate to the func-gene tion of the same gene , thus demonstrating -its pleiotropic qualities must sttll be elucidated. gene Several genes have been entertained as candidates for the thrifty or pleiotropisecreted by thrifty" component Leptin is a cytokine hypothesi or at least for the " adipocy1es that regulates energy balance at the levelsexplored of intake factor and thatexpenditure communicates (150). Moreover, although leptin appears to be the long-hypothalamus regarding fat mass (adipo- between the peripherY (adipose tissue) 3;1d th reproduCti stat), "favorable" mut tions of \eptin result not only in obestty but also in
incompetence and infertility (151). in the regulation of energy MC4R is expressed in hypothalamic nuclei and is: involved balance (152,153). Indirect evidence for this was provided when the agouti obesity syn- drome in mice was found to be a consequence of chronic inhibition of MC4R signaling (152). furthennore, mice with a deletion of the MC4R gene have a phenotype indistin- guishable from the agouti, and mice with heterozygous knockouts of MC4R have an intermediate phenotype (154). A recent discovery mdicates that up to 4% of obesity in / OBESITY DfSEASE OR PH\S!O!OGIC ADAPljU1CN?
over, those with het- some populations may be related to mutations m MC4R (17). Mor erozygous mutations of MC4R are predisposed to obesity, likely as a result of haploin-that suffIciency (155 )- The variab1e pcnetrancc of obesity in heterozygotes indicates olher genes and/or environmental influences arc important in the development of the obese phenotype. Presently, the gene that best meets the qualificztlons for the thnfry or pleiotropic gene activatcd receptor y (PPARy). This gene is the nuclear receptor peroxisome proliferator- allves and forms heterodimers with product 15 activated by fatty acids or fatty acid dcu\ other nuclear receptors , such as the retinoid X receptor (RXR), to modify the gene tran- scnption of numerous target genes ,-"ith specific PilAR response elements (157).activaticJn The PPARy gene product is particularly relevant because one of the ligands for its , which are currently used to improve is the class of drugs caJled thiazolidincdiones resistant states insulin sensitivity in the treatment of type U diabetes and other insulin- show that thiazohdinediones enhance adlpocyte dif- (58). Studies in cultured adipocytes in vil'o they produce weIght gain to both animals and humans TerentiatioJ1 (159) and that ht oam can be attributed to fluid retention (161), - (160- 162). Although some of the wei 11 adipose tissue. the predominant explanation is an increase PPARy action is not only reflected by increasing adipocyte differentiation and insulin action but also by a number of other effects Cfable i.6t ,These inflammation. include itsatherosclerosis- influence on Ilsutin secretion , cell cycle control , immunomodulation myocardiaJ function, and carcilogenesis (157). Of added relevance is the fact thatheterozy- natu' y and induced haploinsufflCiency i11" mice rally occurnng mutations :n PPAR , the gous for PPARy produce interesting modifications in receptor biology- For example pro12Ala PPARy mutation in humans has variably been associated with obesity (163); 165), reductions in glucose and arginine- diabetes (164); protection from diabetes (163 , including a mediated insulin secretion (166); and diverse effects on atherosclerotic risk (167), lipid and lipoprotein phenotype consistent with familial comhined hyperlipidemi reductions in total and non-high-density lipoprotein cholesterol (168) and pnsthepari LPL (169), and reductions in coronary heart disease (170).). HowC\:er Alten1atively,, other this mutations mutation in has had no metabolic effect in some populations (171)directly 71 (173) or via their influence PPAR)' have also been hnked to human obesity, either , such as !cptin (174). on other obesity-related proteins ) or normal mice treated Serendipitously, mice heterozygous for PPAR)' (PPAR)' +/- with PPARy or RXR antagonIsts are spared adipocyte hypertrophy, they are morc insulin reouctiOLlS ;i '.cle and liver triacyl- sensitive , they are relatively hyperlcptlOcrnic with , and they have enhanced immune (T- glycerol levels and increases in fatty acid oxidation mice arc treated wIth a PPAR)' or cell and 8-cell) function (175- 178). When PPAR)' +I a RXR antagonist, a dramatic metabolic effect characterized by marked reductions in white adipose tissue, leptin, and energy expenditure; increases in triacylglycerol accu-
TABLE 6. . Paroxisome proliferator-aGtivated receptor yactions Fajas et aL (211) Increased adipocyte differentiation Saad et at. (212) Increased insulin sensitivity Kawai et a!. (213) Increased insulin secretion A1tiok et al. (214) Celt cycle regulation Clarket al. (215) Immunomodutation Molavi et aL (216) Reduced atherosclerosis Khandoudi et aL (217) Enhanced myocardiallundion Fajas et a1. ( 11) Carcinogenesis 11-'-'
r ETIOLOGY. PATHOPHrSTOLOGY. AND ASSESSMENT
, and decreases In msulm sensitivIty is observed (1IS). mu\altOn m muscle andltver rule for RXR m this resppnse is supported by the relative kanness and the increased energy expenditure found in mice with a knockout of"1 RXRy role In(90). .dtpose tissue biology and Together these data suggest that PPAR Y has a pr.o alleles The crillcal role of thaltill msu\m acllOn thal is modified by the number of PPARy on survival . the gene IS also exempltfied by embryonic lethalityPPARy m its gene absence exprcssi (175). With a lifespan beneficial" effects of exlends pasl the " , atherosclerosi , or malignancy. Much pleiotrop"c downside may be metabolic disorders gene remains to be learned. about this fascmating candidate, with for the the human thnfty genome or pleiotropi sequence now m hand, many more Moreover, the hope lS that genes that act alone or m concert to produce obesity wIll likely be uncovered.
CONCLUSIONS " The , the Is obesIty a d,sease or an adaptation for survivaP Does this even make a difference answer IS yes The impact of the environment is the same with either view; however , health care reimburse atmosphere In which health care professionals and their patients operate may be profoundly, weight and differentially influenced by the opinion, which of science.includes pharmaceutICalgovernent companies meat organ,zations, and the marketplace the counter products Although referring to obesity as a disease is loss programs, and over- , the criteria for obesity to be called a disease are insufficientlyoccur delineated;, obesity pnlttlcally correct . when famine or senllstarvatio moreover, abundant evidence indicates tbt , the complicat\Ons of obesity are dlS- s best friend. W,thout question could be a partlclpant importance of obesity over the hIStory of caseS However. an acknowledgment of the humankmd helps the health care proressional and the pauent to develop an understanding about the facts of excess body fat. This newfound knowledge can modifyof treatment the behavior with of a . what was once both so that gUilt is removed and both can now approach the Mlicuitics of the barners With some degree of ambivalence greater appreciati pleiotropi " and potentIally harmfuL nOW be accepted as " thrifty" and bencfictal must
REFERENCES demK Albany. NY World Health Db"itr p, ece"nog aod maoago'" th, glouol 'lo t Wmld He,I'h Olgom"ti ", of Ob"ity ttea\lb Organization, 2000- D,velopmen' "wet 00 the Hoa\lb Impheati , Nanonal In,,iruoo of Health Con"n'"' 15l A.led 1985;l03:147- 15. ofob sity- Alwin/em storlf 1999;2: 1- implications sity- Clin. Comel' :3 Bray GA. Etiology and pathogenesis of ob Na/!re 2000;404:635--- wveigbt . evalnolion . and "eatmen' nf o,. -4 Kopelman PG. Obesity as a medical problem. gmdehn" on the iden'iri'oIion 109S. j NoIio,,l to",tot" of Health Clini,al Qbes Res 1998;6:5 j S- the evidence report. and obesity in adults- v m"; index ot adote; and children in the US pop' 6. Flegal KM. Troiano RP Chang" in the di;"ibntioo2000;24:807- of 818bod ! Mernh DisQrd ""ti' ,e ,,;vi"" ",ommendan",,; from ao ulatimi.- ira.i 0&':5 R::! Dietz Wli Guideline; for oveweighl m adolmenl pre. 7 Him" JH. 1994;59307- orus growth chart' Am J Clin Nuw Am J exp'" commilt". . el a!. p"vakne, of316 ove,weigh' io US ,hildleo; 'ompan;on . , Wei R "fecoce valne; for hody ma" index. , Flegal KM. Ogden CL ConICol and p"ven,ion with olher fenm Ihe Center; fot Di"a" . by mce and CIin jlil/lr 2001;73:\086- 1093 nce of ;elected health beh.-i"c; . powell-G,inel EE. et a!. State-;pecifi' prevale 2000;491-'O 9 Boleo JC. Rhode' L . 1997. MMIVR Moo'b MOt,,,l Wkly Rep 2848 Su"dbn,e System JAMA 200 1 ;2862845.- Behaviorat Ri;k FactOl . 1986- 1998 ethniccly- in",a" in chddhood ",,weight Db" 10. SICau" RS . pollack IIA Ep,demic of adennvirus iofe"",n with human ob"i!y. NY. Kulkam' PR, AJinkya SM. et al A"o,iolron I t Dhnrandh" 814 "\64--469, Nal ,\-ed 1995;\:810- Res 1997;5- t990,"" 329-335 limit of human adaptation to starvation- Eu, J Clin Nut' \?. Collins S. Th the timits of human s",viva! 1976;5;299 -3 t L Clio Endo"i.ol Merab tJ Henry CJK. Body m'" iodeX and t" Hi,,,h J . BoI,hclor B Adipose tis,"e "ItulanlY in human ob,;ity. :'.
OBESITY DISEASE OR PHYSiOLOGIC ADAPTATION"
11 transg:tmc - Shepherd PR, Gnudi L. Tozzo E , et al Adipose cell nyp6plasia and enhanced glucose disposal Rio! Chclt 1993;268:22243- 22246 kctiveJy in adipose tissue. J mice U\"crexpressl!g GLUT4 s , et aJ. Expression of human alpha 2-adrenergic receptors in adipose tissue ofhela 3 1(, Vale! P, GruJic D, Wade J 34802 induced obesity. J BioI ChenJ 2000:275:34797- adrenergic receptor-deficient mice plOITotes diel- Cill a frequent aud heterogenouS c"lUse of morbid obesIty J ! 7 Yaisse C. Melanoconin-4 receptor mutations an 262- s'Ki;Jted \\"th esr 2000:106:253- inheritilrlce 01 mor111G obesity a IS- Fa!Ooql IS , \co (;5. Keogh Jl\t ct al. Dominant and rccessi\c C5! 2000; 106:271-279 mebnocorlin -' reee-plOT defiCiency J ChI! III' ./-L\JA , ct al. Annual deaths attibutable to obesiry Ii the Unitcd States. 19 Allison DO , Fontaine KR. Manson JE 1999:282:15JO-- 1538 J ?uhhc 20 Dawber TR. Mome FE. 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Ild cd \\a ::5 Uuited States Depanment of Health and Human Serl'ices , 2000 Uni!ed Sta!es (J0\'crrnll.:1l Ptinting Office 26 f)ei1t j M. Tbe Surgeon-Genera!'s caU to actioll to prevent an increase ill overweight and obesity: r,,!cas;:d D:.:: , 200 lObes Surg 2002: 12:3-- lnd 27 L(lvern E , Gardner J Too link or JUS! nghf) Bush lays his healthcan: Dud get on the laUIt. but Democrats - s;J)" $190 billion falls short,Jfu del'l Health Core 2002::32:6- some Repub!icans- en ol1ce-oh' se people go from hefty tel lleJ!II1\' h :::- Espinoza G. SCOI! S. The rea! skinny: forgoing fad dlels- sc Tille 2002 Feh I! :88 cultiug calories and gaining resolve ctJ.! cancer 2'- S(mnClberg _ , Deleo F Cosl-effec:llvene% of a single w!onosCopy il1 screening for color II1/erl1 Mcd 2002: 162:163. 168 p;Jrll:'IJts .1gainst of \"acciOaTing chronic hepatitis C ::U Jacobs RJ. KotT RS , 1'v1eyerhoff AS. 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Fntscne A H;.niI1g H, ct a1. Effect of t'xper-imcmal ele auoli of fl ee fatty aCIds on insulm sec!f:tiol1 and insuhn sensitl\Jt) II healthy caniers of (he Pro!lA.la pulymorphism uf the peroxisome proiifcraIO! :1ui- ated receptor- garmna2 gene. Dillbt!cs 2001 ;50 11. - 1 I '-S Cl\'L rvfcQuillan 8M, (1 al. A Pro12Ala poh' morphisl! in the human pem'\isolne pro- 167 S\\arbndc MM. Chapman fndiJoilioi liferaror-activa!cd receptor-gamma 2 is associated \\itn l 0UlhuJed hYr, riipidat:mia in obesi:v fw .. 2001.. !44:277-2!\L 168 1w2ta E- !vJ;muda H , fu\cudJ T el a1. Mutations of The peroxisome prolifaalOr- acti\iItt:d receptu! g,J!1nl;1 /PPAR gamma) gene'!f a Japanese population: the Pro 12Ala muLltion.!i1 PPi\R gamma 2 IS associated with !o\\'cr con ccntrations of Sf'Urn total and non- HDL ch01:;sterol DwbclOfogia 2001 ;44:1 35' 1355 aC!\'.ll 169 Schneider 1. KreuI.er 1, Ha1lJon A et al. The proline 1 Z alanine sub5lilution ill the pero."iS(111C rrolifel,JtO!- 2002:5 I :86'7 - 870 reccptor. ga!T!la2 gene is ;:ssociared \\' ith lower lipoprotein !lpi15C :\cli\ ity in \'ivoDwhclCS .. T poh,'!lorp!u':!1 170. \\'ang XL, Oosterhof 1. Duane N. Peroxisome proltferator- activatcd receptor gamma C16! - and coronary artery disease. Card/ovQsc Res 1999:44:588- 594 ! 71. Clement K , Hercberg S , Pas singe B , et aL Thc Prol J SGln and pwl2Ala Pl', A"R gamma gcne mutation,: in obe- sity and type 2 diabetes Int J Oves Re!at Metah Disnrd 2000:24391-- 393 172 Mari Y, Ki-Mot oyama H , Katakura T, et aL Effect of the Pro12A\a "Briant of the hUITJn peroxIsome prolif- erator-activated receptor gamma 2 gene on adiposity, f;JI dIstribution, and insulin senslIi\'lt)' in bpanese n1en B!uchem Biophys R('. CommU/1 f99f\;251 :195- 198. 173. RistO".' M , Muller-Wieland D. Pfeiffer A , et aL Obesity associated with a TTutation in " genetic regulator of N EI1g1 Med 1998;339:953-959- adipocyte differentiariOIL ac!ivaled 174- Meirhaeghe A, Fajas L , Hdbecque N, et a!. A genetic polymorphism orthe peroxisome proliferatm Hum MDI Genel 1998;7:435- 440 receptor g.amma gene influences plasma Jeptin levels in obese humans, g:muna deficiency 175 Miles PD, BarakY, He W ct a1. Improved insulin-sensitivilJ' in mice heterozygous for PPAR- J Clill 1n.l':SI2DOD;105:287--292 " 176- Sctoguchi K. Misaki y, Terduchi Yet a!. Peroxisome proliferator- activated receptor- gamma haploinsuffiuellcy J Clin II1H!sl 200 I; enhances B cen proliferative responses and exacerbates experimental1y induced arthritis. 108:1667- 1675. 177 Yamauchi T Kaman J, Waki H, et al The mechanisms by \\ hich both heterozygous peroxisome prohfer3t(H- activated receptor ganuna (PPARgamma) deficiency and Pl'ARgamrna agonist improve insulin resistance. BioI Chem 2001:276:41245--1254 induced obesity and 178.. Yamauchi T, Waki H, Kaman J, et aL Inhibition of RXR and PPARgarmna ameliorates diet- type 2 diabetes J Cli/) Invest 2001; I 08: I 00 I- I 013. 178a. Brown NS. Smart A. Sharma V, et al Thyroid hormone resistance and increased metabolic rate i:l tbe RXR- ganuna-deficiem mouse. J Clin invest 2000; I 06:73-79- , nc.. Carnegie Institution . 1915- 179. Benedict FG. A swdy of prolongedJasting. Publication no. 20 I. Washington
1--16-senescence. In: Behnke J, Finch C. Moment G , eds. The bio logy of agillg 180 Cutler RG, Evo!Ulionary biology of New YorkPlenu1T Publishing, 1978:311- 2001 :49: (- I! J 181. Hayen DL Arias E, Smith BL et al. Deaths:360 final d La for 1999. Nat/olla! Vita! SWti5/ics Reports 182- Kathe.r H, Wieland E, Scheurer A, et at Influences of variation in ittal energy intake and dietary composition on regulation offat cell lipolysis in ideal- weight subjects. J Chn 1l1vcst 1987;gO 56(j-572. 183 SflidennanAD, Maslowska M , Cianflone K. Of mice and men (and women) and the acyJation-stimuJating prQ. (ein pathway. Cun Opin Lip/dol :2000: 11 :291-296 . ." j. _ ') ./ ')
AND ASSESSJtENT r ETrorOC!: P4THOPHysrorOCY
ccrincmlJ. in obesity and Iype "2 diaoett:s: close assoCIation , Tlflaka S , et OIL Hypoadipo \9.35. 18.. Weyer C , Funahashi T docrmol .Hcwb 2001;86: I gJO - -and hyperinsltlwemia. CIln Ell diabetes. Tren with \!slIlin resl"t:l!1Ce finsu!Ul resistance and type a\pha in tbe pathugenes!s o 5 l\lo1kr DE. Potentia! roiel ofTNf- OOO:!! :212-217 fo:douJl1o! Mewn iotens!f\Ogef1 gene es.prr:sslon in humJ.!1 , HoffsH:dt J , et al ll\crcased adipose a!l :1" J-L::rf:_den V Ariar:nt P J41 renin-angiotensi sys- obesity Obes Res 2000;!U J 7 -- ssue , et aL Horrnonal regulati of the bUlIan adipose- ISi Ciofzelmak K. Engel! S , hnke J 973 J HvperletlS 2002:20:965- atment of cardlUvas tem: rdalionship to obesiry and hypertension, et al Us . of prostacyclin and lrs analogllcs in the tr 8 rmk AN , Frishman WH , Aziad M 40- Blochi'm J cular dist:ase- Heart DL, 1999;t:29- cell differentlation , Ailhaud G Pros!Jcycll! as a potent effcctm of adipose- IR!) Negrd rc Gai!lard 0 beta I ! 989;257 :399-405 , tIansforrning groV.1h factor- , t\:1omngc P, et at Plasminogen activator inhjhltor I 2000;49:\374- 1380 190 Alessi Me. Basle!ica D Dwbetes and BMI are closely associated HI human adipose tIssue durwg morbid obesity- lik grov.rth factors in adipocyre , Hauner H , Heinze E. et aL The role (Jf growth hoo!1one':insulin- 19! Wabitsch M I by '.Ie/abu/lsm 1995; :L45 40 ditfcrwr;atiou , Mor'dal\ GA, et .II. Synthesis and secretion of plasminogen activator inhibiwr- 192 Crandall OL , QU!!let EM 1999;8-:13222 3217 j ChI! t:/lducrHwl jI!oaD 193 human preadipocytes Med Hypothcses 1995;4.:: \ 79- 63 5 193 McCarty MF Hemostatic concomitants or syndrome X- Cell/Hal BioI 200 1;4 7:619 - i 94 McDermott rvlF TNF and TNfR blology l! health and dIsease rowth , differentiation and survival signals , Hibi M- Roks of STAT3 in mediatIng the cdl 195 Hirano T, lshihJra K Oncogene 2000:19:25'18- 6 bmily ofcywkine !cceplors .) linking host ddense aod relayed through tbe (L- complement system: a path ! 96 Esterbauer H , Kttmpkr f. Oherkofler H, et at. The est \ 999;29:653-656 adipocyte blOlogy- Eur J Clirl Irl ill adipose tissue: relallonship to brc3.st , t\-Iahendroo !v(S, Simpson ER- AromJ.tase genc expressi \ 97 BullIn SE !994;49:319- 316 cancr:( J Steroid Bioc!1em (viol Biol , 2. and 3 17 beta- hydrmystemid dehydrogenase in sub- 1998:83: t87- 19,t 198 Corbould AM, Judd 51 Rodgers RJ Expression of ryes \ J Clin El!dvcrillJ/ ,Hew.b abdominal adipose tissue of worncn ll R s 2002;15_ 10- cutaneoUS abdomi!lil and inrra- Pig/lien l1)85 199 VOlsey J , van Daal A- Agouti from mouse 10 man. from skin to fat- Camp Biochem Phl'srol A port processes in J.nlffal cell membranes 200 Lerntr 1 Effectors oJfat,ll:10 ac!c! !rafj 817\3-739 of amino actd and protein , Barret! EJ. The role of 1IsL!iin and other honnont's in the25 regulatio3 201 !\litrs \-VR 5101 PharnlOco! ! 998;9:135 - .J BasIc Ult! Ph l0l 199'156- 32 1 merJholisll in humans. !nIJu Rev Pil) ascs in gtucosc uptak 202 Kiwb::1!1 SR. Vary TC, Jefferson LS- RegulationInu:H:e\ln!a1 of protcin 1l synrhesischJnlS(15 by insulin-lmdedying incr , Chibalin Av' Zierath JR- 2001: l) 1 :2 1:57 1.03 Ryder JW Acta PhYSlO1 Scand response to losullo or exercise 1\ skdet31 muscle, of glycogen synthesis by insulin 204 Sri\-:!sta\' \K, Pandey SIC PotefHia\ mcchanlsm(S) in\-o\vtd in the !egulario 1995. 1S2:IJ5- 1:.1 Mol Cell Blochem , Sindelar OK Thc dlrect and in,1\l ect efkcts of insulin on hepatic glu:.ose pro. 205- Chernngton AD, Edgenon D 1998;'11 :987-996 Djab.:wlog ductl\Jf ill VlVO DUJbt'ologln - why is insultn sccreted into the pomi! vein lO(j 13ergm,m rzN- Non-cstetified fally aCids and tbe liver 2000; 1:946- 9"):2 rich llpoprotctG synthesis :md secrction- BlociurH 207 Sparks JO, Spark CE. Insulin regnlaTion of !riacylglycero!- 1215:9- clamp Bivplr)'sA. cta 1994 tissuc lipoprotei lipase Use of thc euglycemi 208 Sadur eN, Eckel RH- (nsulin stimulation of adipos 19R2;69: \ 1 \ 9- 1125 technique- ChlJ Invest lipase activity by insulin/glucosc in specific regulation of lipoprotei 209 Farese RV Jr, Yost TJ, Eeke! RH- Tissue- 1991 :40:2.14- 2 1 G ons for wcight hurnaas- 11"Ietabolism in hllmans- Implicati norm31- ;n the contrul ofVLDL productio 210 l.ewis GE Steiner G. Acute effectS ofinsl1lin 391 Dlaber s Care 1996; 19:390- to car- the insulin-resistant state- activated rcceptor-gamma: from adipogenesi 211 rajas L , Oebril MB, Auwerx 1 Peroxisome proliferator- 2001;27: 1- Diabetes Teclmol cinogenesis. J ,Hol EJIdocrillol e review of approved U5CS. ?'12 Soad V, r:olleran K, Burge MR- Thiazolidinediones: a comparali :.:.o Ther2G00;2:c:2() , et aL Troglitazone amdioratt's IipotOxicity in the bda-ceH line rNS- t expressing., 213- Kawai T, Hirose H, SeW Y 92- PPAR gaIIma- Dinbe1es Res Clill Pract 2002;56:83- , Xu M, Spiegelman BM. PPARgamma induccs cell cycle withdrawal:- 1998 inhibition of Elf/DP DNA- 214- A!twk S Genes Del' \ 997; 1t: 1987 - regulation of PP2A- binding activity via down- , et aL The nuclear receptor PPAR gamma and immunoregu. Hernandez T 137 L 115 Clark RB, Bishop- Bailey 0. Estrada- J ImmunoJ 2000;164: 1364-- agenL larion: PPAR gamma. mediates inhibition of helper T cell responses-activated receptor ligands as antiatherogeni , Rasouli N, Mehta JL Peroxisome prolife,at'Jr- 216 Mo!avi B J Cardiovasc Pharmacol Ther 2002:7:1- panacea or another Pandora s box , a peroxisome proliferator-activated receptor- Bertrand L et aL Rosiglitazone , Berrebl- 1 path\'iay and protects the heart from 2\ 7. Khandoudi N, De\erive P terminal kinase/activating protei gamma, inhibits the JUri NH(2)- 2002 51: 1 S07- 151 ischemia. rep.orfusi injury. Diabetes ,--"._.=-"=' . - "", :""' ,," ",,,,,,j,,,$=,",,,_--. :;: ------""- ----~~~ ",f" .i,*""4 -:14?
9. NO- 6. 1987 CLINICAL THERAEUT CLI1CAL TIIERAPEU'lCSrvO
Obese
WK, ber:on D. Exacerbation of an peri bv proprnolo jRegiomu Fat Loss from tbe Thigh in CJrculatfon 1982; 65:281-285. Women after Adrcnerg'i Modulati
0- Uchida Y Car oV'as a. effect of dihydr8-(2-bydrxy-1-;spwpyl 1- Greenway. M. Medicine. aropropoxy) - 3- wtrn1o-2 H beuzo- Pran Jpn Henrc J 1982- 23- Medicine, ucLA School oj pyran)(K351). Deportent oj , Californi 981-988- 1.os Angeles l. Uchida Y. Nabur. M. ShirD1ZU - . ct George A. Bray, M. then! California al Vas. oasve and bela-adrelloceptor ihydr0--t 1- Departmenf oj Medicine. Universiry aJ Soil blocki pn:pertie, of3 h !drry-J-lsopropylamino) - propoxy- J School of Medicine, Los Allgeles, Califonii llu-oxy- benzoPYIlm (K351 ' a h flll new anypertns\Vc agent Plzamwcad Thr 1983; 262:132- 149- smgery. \ Studies offal cells haveca showndi- =- C". irasaw9. , Kawada M Fujii lY eta!. taadnecgic ngoni ABSTRACT !lt roonophO&- ct of rnprilol on the carovascular ly incrcase cydic adcnosin lipolysi - .,nl Phnrmacometris 1985- 30' alld alphaz- Betaadrencrgic stimulati phatc levels aDd stiulate 1027- 104 C . absa:act in inhibitio increase lipolysi regional dierence in this Englsh). . 1I apane- adrenergi wOIIcn There is a Fat Iwen!Y: responsivencss to betO:RgOrtts.sen.sifIve . hA from fat cell. ' estrictd diet Shirasawa Y F Ju.. iU., Nakamura M. ;;a calori;r abmen ar rorc were placed o lis froro the !.3' !lergc Ve . . 'il3tig Guon of niprailo1 (K- t:ff"!Jsj)I l:_ and onc of five treatmcnts was applied(OC to ';JiP9 Jhe 35- i) il the plthed rat pretrate with ulatioIl than ar thos Jpn J Plwrmacof one thigh three to five urnes per wcek ons there ar dihydrrgotamlac. This appear to be because 1985; 39;77- four weeks: (1) isoP.tefcnol injecti(fqr3J!Q\i). l ce (2) cram cotHoig I;fors more alph receptors on Kondo S, ct at , !ld yohimbine; (3)LD- oflle a&lcime';! Rasing the Fujii M, Shi raswa J arnIopbyll thgh than ation in the Cardiovasar effect. of niprailo cream (4) C9orsill cream; or ;-rneI1t1 va. hiin opJOsite (cpinephri frm the betaa.drenoe.ptor blocker with (5) aminophyllnesrea The medium suspending the rat cells Jpn Heart J 1986- placebo (inject ditig prpertes. thghwas treate with a thgh increnses in vitro lipolysis frmrate 27,233- treate thgb los sigc ' The roaxallipolyte 250. or cr)- The both Ihese cells. . locations. is afr tfcatmCt1t Robiison'"F. RelaUol1 ofh a.-- tr" canny more girth in fat ,:cHs ftom the two blood pressur to the onset cl by injection and by cream Noeither adve-se the equal but higher COIlQentrstiO!l of nor-that pectoris. Cimilation Il needed to reach il angia reactoll were attrbutable to cluded inep tion...- It is con when rat cell froOl the thgh ar ; 35:1073-1083. cream or the injec fr theth maum receptoIS on used. Blockig the alpha,- Kinoshita. Yamnguchi S, Takashi that local fat reduct c'fces liolysi frm the thgh L-4 , etal omparative effects ofniprdi- can be safely accomplished fat cells 101 and nItrglyceri on lare and small in the presence of norepinep c.ronnr arries in coou do J 1 n-nriRODUCnON We hypothesized that (betaby incre..ing Coil AngioI 1986; ' 26;271-275 the local conceIltrtioIl o e ab Japanese). pid1Y ;-tl"hitig phosphodiesterae or F a!. ore rby thethgP .ii1st b)ass . dU from ?r" 5 00 3 3 37
't..= ::,::'c; '_0 'T" "CC" -i",="-'"'." j\
'Or; 1 \T(:S r:L 1."rI(:''L TIp7U
the COtro1 1.2 X 10' moVL colforsin (forskolin). fr . tOW groUl. the alpha.- adrnergic receptors to fat cells 5 X 10'" moVL yohimbin , and \,3 X fatf cou1d be rcle prterenollost 3 facas 10-1 moVL aminophyllin in ripamde th: '" ,,eadiy. We report the results of a reived (!0'" th (aquaph ) hase. The other thgh No cbgCS m p series of small tral to test ths hypthesis- ripumide base oPly in a .mable-blind or other clica dcsigl1 In Study 2 , 11 IViJ\TEiULS AND METHODS the four week SWfly ( one los weight Sfudy I 03 :. meoll of 2. Eighteen womell (mean weight, 197 Fi VI: women who were morc than above - thgh trated lb) who were more than 209 colfor -yo 20% above their desirable body weight desirablc body weight and wished to lose (mean weigh 209 Ib) and wished to JQS6 than frmn the ( recrute weight frm. the thighs were rccruted (Figure2). Th' weight from their thighs were and placed 00 a liquid formwa diet of rash th and placed on n diel of 6(jQJU!aily ruti f;L a1 daily and encouraged to engage were seen in one 5t1bjcc and encouraged to engage ill a walking in a waHdog progr They ",taIed to th, progr They received injections of 0. .1 muVL isoproterenol at inter- five days per week for four weeks- At dressing. ill ot" iO each visi warm wraps of 600 to gOO val of 4 ern arund the circumference of rno TlvI. of magnesiwn sulfate. solution one tlligb, two thrds of the way frm the niinute , three days were applied to each thigh for 30 IUlCC 10 the greater trochanter followed by cr npplication. One thgb pEr wf:ek for four weeks- The 4-cm was treated in each patient with one of inlerval was chosn because calculations the three creams in 1'ipamdc: colforsin, from the area ofvasodi1auon on the skin 25 X lO- ' JIoVL(six patients); yohim- sugeested that the spheres of diffusion WfL'1 bine, 5 X 10-4 moVL (six patients); or would overlap when this distance amophyllinc. 1.3 )( 10- ' moVL (six kepL The opposite thigh was treated P'! salic iJl a . patients). The other thgh in each subject simi.lm\y, but using nonnal was trated with xipanude only, ill a double-bliad desigr double-blid design In each study, tratment effectveness mellurg the thgh cir Srnri 2 was judged by the cufercncc two th of th way fr Five women (mean weight, lfl2 Ib) knee to the greater trochanter, using the wbo wer more th 20% above desrnlc saluo- or ripamido-trated thgh as the body weight and wished to lose weight contrl Dierece were copared with from their thgh were reCruled und Student's f. test for paied observations. placed on a diel of 6DQkcnl daily und encouraged to engage in a waling prO-- IRESULTS gram. They were seen five days a week INITI for four weeks At eah viit, Wan wrps In Study 1 , al five women compteted the WEIGl of 600 to 900 ilosm/L of magesi four weeks of tratment and al but onp. sulfate soluton -wcre applied to each iost weight The four subjects who lost Figure L C thgh for 30 minutes , followed by an thgh weigbt lost more girt from the application of cream and plastic wrap, with isoproteol injeruous than The cream appli to one thigh contaned trte G3338 , L. C. 10 Fedefal pfod uced by Basic Resemch 012113/02 664 Tra e COmmission Pursu301 C. I. 0. ,:---- , . " p - - - ;-.\.
AN GA. BRAY C!JNICAL TIIERA.PFf;n.-.. - n ENWAY 18 wo,men In Study 3, l30f the ' rnol!L colforsin (forsknl' ) frm the conaol thgh (Figue 1). In the completd the traL In the four su1,cc 1.2 X 10- trated with iso yohibine (Figu 3). ni 5 X 10- rnnl!L yohibine and 1 ta grou.p, the thigh 89 cm who received an all butane lostrnoJ,,g 10- mnl!L amphylle ,; xi - prterenollost a mean of 1.8:: 0.-c 0.05). lost weigt thgh (P treated with yob1iin (aqphor) bae. The other reIVed more than the control preure, from the th The X1p de base only in a doublebl' No chages in pule rate, blooo croam than frm the C01Jtr frm the cliica parameters were noted lost roorc . or other woman wh -'.. the fit dcslgI In Study 2, al five women completed thgh treate with place Aftr her fit r w eks of trfltncnt and all but Study 3 ; the subject to enler the tral one lost -Weight. The five subjects lost a visit it was found that having subject 03 :! 1.36 crn more from the Eighteen women (mean weigh (97 mean of2. tIg support their body weightreproilty. on the thgh b) whn were mnre than 20% ah - thighs aeated with cream con bein mea m= the yohine, and aminopyll Unfortuately, this was not done in irbl body weighr and wisbed t0 1 0'" ve colforsin, thgh (P -c 0.05) have been velght fr 00; e thgh wen: recruted - than froff the conaol first patient, and thi may for the aberrant results in hcr nd placed on a liquid formula diet of (Figure 2). The only adve",e effect was a responsibl rash that occum:d on both thghs whole lost a mean of 00 keal datly and encouraged to engage pruriti to be cae. The group bi- 1 a wal"rng-progr They- were Seen in onc subject, which was judged 75 ::o.35 cmmorefrtheyothe conaol il the occlusive plastic-wrap . da!: -pr week: for four weeks. At related trated thgh than from "lcn V1S1 warm wraps of 600 to " drC$SL1' LOS magnesIUm sulfate unn ro applied to each tJgb for. 30 minu '"'
Uowed b ap Icanon. One thgh 1ated in each patient with one of lC creams in xipamide- colruors . X 10- (SIX patents); yohim- PLACE80 - ' 5 X 10 mol!L (six patients Ie !! ACTIVE uno. hp y ne 3 X 10-' mo sue: tlents . c other thI in ach 5U ect s trated WIth xipmndon y,I .1l a bI6-blid dosign Zil n eacb std cut effectIveness trat UJ :; 'Judged by measur the thgh CJr- CJ:: e",ne twnthrd of th way fr the 2:0 at 4: a: e to the rester trchanter, using the n!) or JUmndetreatc thi.&'' as the ernces wer compared with trt7 , Di ient test for paied observa nns- t-- ;ULTS rIL277 281 185 116 180 all five wamCQ completed the iNITIAL WEIGHT (lb) 5 -2. dy 1- WEIGHT CHANGE (lb) - eks of treatment and "al but one weIght The four subjects whn (nst umerence and tota body weight in five subjects 1. Changes in thigh circ ht lost more gith from e Uti,c' Figu tratmcnt "witb isoproterenol injecton or placebo. xiWI '\h' ISoproterenol injections 5003339 665 Produce by Basic RB36arch , LLC- to Federal C I. D- of 2I13i02 Tra1e CommissIon Pursuan) '""'
CLICAL THERAEUTCS
1hhighS, but the 'icay signcant ,. Al foU! subjec UJ 1:- o PLACEBO fo weeks of tI II ACTIVE los weighl 'Ty OC l' - 61 em more I =wd with coif, W:!IL e thgi eJ:: 5 the cotrol All five ,ubjec foU!weeksoftrea 00 lie lost weig!l. :I 0.71 em mme trated with am fr the contro (Figoe 5). No adverse re iNHUAl WEIGHT (Ib) 203 129 250 188 the ti-eo par of : WEiGHT CHIINGE (ITI) - -4. +2 -H. 5 +1. 25' changes in blood
FiL'1In Changes in thgh circumference and totnI body weight in five subjects after treatment 'with a cream containg colforsin. aminophylline, and yohimbine or placebo-
,OlACEilO
l1 ACTiVE
",1.
5! 2
IN1TA DMTDAL WEIG, T iDb) 151 205 ;2 '1. 5 235 WlEiQiH CHArIG'" qab) -6 -13 - 2.75 WEIGHl
Figu Changes in thgh circuference and tota body weight in four subjects afr Figu 4- Cha treatment with yohimbinc cream Df placebo. traIL
roduced b Y Basic Re'ealct, . L. C to Cedelol 666 . Trade Commission Pursuanl C L 0- or 2113/02 ::. ..' - . . . _ ~~~ . '
A. BRAY Ct.lNICA TIRAEUcs 'L vREEtAY AN v. The five allY evidence of ski rash. Jl; (\pped oat &1 "0 "jer patients who dRys of ghs, but the differeace ,,"" nst "'en,, six, and the en eight, ;e the five . Sticay signcanl subjects who complete the treatment, rectvelY. Fou of , AJ fOUI gi frm the drpout had los morethe contrl thgh .- fOUI weeks of trstIent with colforinof 1.0 :t th frm o PUCEBO trealed thgh frm the st. lost weigl 'Tey los a meanthe thgh tie of dep day o II ACTIVE gi frm by the th f: / 61 em mor The HII drPped out 00 the trated with colfors cream05) (Figure than frm 4). tie there (P.( treatment, at which the control thgh ifereocc. AjK1ve e subjecs who copletedphyl- the change in thgh e tne of tJl fi dropouts had los weight at the four weeks oftreatmenl w\tll1unin their depar thigh )ie lost weight. They lost a mean of 1.5 lo \fm the tr from the thghs When :! 0.71 em more gi crm th amophyllin is compard with loss from tho untrated trated wi 01. tm- studies combin the . the control thghs (P .( 0. thigh in al nvenlge of 1.33 :! from treated thgh lost an (Figure 5). 12 em more thob did the control thigh No ad"lcrse reactions were Doted in (P.( 0.001). , 166 162 the three part of dStudy pressure 3. There Of pulse, were norno changes in bloo -11. 5 +"1.
)Oy cight in fi e sujecL, afr 1. amophyllie, and yohimbine
pUciieo PLACEBO III\CTIlE II ACTIVE II 1 -\.zUJ 6 UJ :: C);: 5 4;a:Xuo . ..
I- 1 5 144 201 ZEli 206. INiTAL WEIGHT (lb) (11))-10 6 - 5 235 WEIGHT CHAIM)I!: 3 -12. bq weight in four subject afer in thgh circuerence and tota Figu 4. Changes ody weight in fOUI subjec af treatment with colforSin cream or placebo. 50G3341 boo 661 rouca by Basic Research L L to Federal rade CommissIon ursuant C. LOof2113f02 -=- ",- =,p-- - ':-
Cilr:C/. . TI APC;UTICS
. ibiIDr and an effecve. ( PlACEBO the phosl
II ACTIVE W83 tnosteffcct o 8- srlatr. an t il 1 . Th numbe of however, wa SI ZW abut the relali1 COpanent of ( teUOUS- The onl .6:!! of the trtc wa IO thigh in one v when plastic wn il 2 '" sive dressin TI I =n in Study 3 ! J H\JI'fJAL WEiGHT (I b) 191 228 i58 212 HiS WEKHrr CHANGE (I b) '- 15. ,0.25.- 25 -12. REFERENCES
Figmc 5- Changes in tlle-h circmufcTence aDd total hody weight in five sujcct afr Krll JG, Bj treatment with aminophylline -cream or placebo. SjO&troro L I po tisue c jej\10ileo:!t01 jecs. Ear SCVS.SION of adrenergjc modulators The rcgults of the fut studydernonsated thtlncal fat 419. safely H has. been gcnuaUy believed fOI same reducton can be accomplished Smith D, Hi time that thgh fat in women is bard to aud effectvely. KrllJG. Reg and 3 suppor! c;on of weight (CI mobilize. OthC0' , bowcvc(, have becn Studic f . Jhc accpt th cocept, beliving that topical_ ;pplicatioo oLadr-1_c,gic metalim. reluctant il 9,327-332. that al rat cells are metabolically the odulatrs ca enhanc,,lipa)Yflis. It sae- In vitro work, however, ha sug- might hav !;'; Postated tht yohi Monllsky II geoted that the adenergic thsholds to ine, the alph inibitor, would ha reptors in : lipolysis ar inde d1e--ent in Clcrent been the most effecve agent, since the ph)"iologc " rat atns N.. Sites, and that thigIfis more dicult higher thshold for lipolysis in thgh 29. bdome fatVS cell appear il be a result of a higher -wany Htteml: have been . .made to oontroo of inl'bitoy al- achieve loc or spot fat recton tlnugh tors I'O f1atualy.o"curg alpha,- nonsurgical meam but none have Slle- hibitorn circulate in human systems, but t3stulatg care- ceeded 6 The use of injections in dy, ar alwa chats present In these two stues, data clij ii.LJ:practica1 did support the concet of loca adrnergic on the aver los ofthigh ciumerence modultion of lipolysis in vivo and en- suggest that the cream containing a bem- courged us to try the topical application stiulator with a phosphodiesterae
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AN G.A 1IRA Y QREENW A Y wrp V1 CLICA THERAPE the was used Clearly, \he plasti inbitO is not essential to the effecvenesstratmel1t of the bitOr an IJ the compo ffecv . Of thes trcatment. The safety sinceof ths v ry s:a! v: inibit was not unexpctd uld PLACEBO IIodultoJ: co enu; th yl! '!db thebeta ""aunts of adrnergc inbitor, intO the bloodtf . ACTIE n t!e be absorb aI- albR patients ii 'fe nUIber of conclus sxti an thus CONCLUSIONS ho",e"er. wa arC abOut the relatie potenCY of the It is concluded that reults of fatthe ca the be cOJDnents of the corobiDed cream th loc nly side effcct seen. in any stdies demonstrate surely an t&u-ou.c:. The o ski ras on both ce Wi a crlU bo f the tr1l13 wll Il reu r o woman durS Stuy 2 effectively, \ thghs in one occ1u- plastic wrP waS used 8- 8IW3S not
111 sivcdrCS.'Iing. This corop\icilti WIP \ ,een in Study 3 when no pillsti
158 212 158 25 -12. jJ\n J. Alpta 25- mn,NCES RP-f-- 4, LRootnn M.antipoc Daog 1 effec of ! toW bov we' gbt .m.fve subjects nttr , Bjorotorp P. Schcr.tc T, fat cell of the thgh Kr JG line in hUJ m or plac bo. \ 1. Body cOmpono" and ad' J Clirt Sjos Cmar wi adnJ Eur die-rl fat depoitS posc tiSl1C cellularityseverely before obes and sub-afer aesS of '266. jej\Joile-stY in 1911; 1:413- Invest 1979; 9:'261- Clin Invest 1t.1Tfl ject. Eur Cellulite Thos ,ergic modulw couldn t lose 419, 5. RDn, N. you lstudydemonstrated rs. The that reull'iof local fat . BjornlOrp P b-ps al1 d blliges it U. l-laIIlInersleo. J uction 1"01 aceo mplih s cd safely rwdierences ttdeffecl beJore New Y Of\: Beauty and flealth 3d effecvely, lZal JG. R. eduction 00. huntaD fat cell l'ublisbig Corp. 1913. of wei.ght r ofroasSRgc in the Studies 2 and 3' support the concept Clin Inverl 1919 Th.e fal Eur taolim. 6. Rs SW. J Med Sac N ppllcahon of 8.wl;nergk..- obeity. at topical a 332, trtmcut of odulators can nhce hpolysi:L. It 9:327, AdeIfC Jerey 1944; 41:4D6-01. ight have beC'T e that yomar Motlh;\oy il. Inset P A. tication /te jJ Dire iden ne, the alPha, , would have receptors in !:l ",guion an clirral alte' :en the most effe ti"e 1OOr ag since the f- 3 physiologc IJ Me 1982; 30B;I ' ,Lr ationre New Eng gher thshold r c ,or pol slS gh fat 0 a higher '29. , appea t o e a rest f ucention of inhilitto aJbare rs. No natual ocum al P ",- Jttors cirnIat. in' umanh systems J ut re ar B.wa em-sum U1 llUjg" cait ois present In ese two stu data
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Topical Fat Reduction : Bray. Dm'jiHeber Fra1.k L. dreemvay. George A The thighs and bultock area seem specif art:a oflheir body , n, This"desire ofmoslfrequcnt cooc-:rU forWom Abstrad AN DAVID to be: the area L,GEORGEABRA Y chan c has been the basi5 t"ormucb popu'ar I\ad GREEN A V, FRA 1995;J(Suppl forcosllcti Dbes Res. ona\ writing (10). Ronsard (13) popularized the h'tWl HEBER. Topic.1 (at red"ction- profe$si 568S. cdluWe . to describe the dimpling and orange :okiI look of 4):561S. iff(cu1t to mobile due orangc). Bayard (3) attribUted it to the , thighs i5 more Ihe: thigh (peau d' . the,e e lOi (The raton women acti" ' induced hy Our images. or to 2 adrenergic re.eeph,r aging process Regardless of the ca"seII)'. " " (11) . Lipoly!i! caD be initiated through adipocyte re- concern:- are widespread, As Ohrhach1 synonymouS with Ihiness anood are 81mo c tissue ac. ceptorstimulatlon(P adrenergk) or lnhibUion (adenode5tera.c. ' inhibition of I1h The tr..ElUr Qf the subcutaneoll- adipoorange appear- OT u-2 adrenergic) 0 r b a !crie! of \"dopU\ent of the p':iiU d ' women desire regional thigh fat lou, cou :, for tht: d Since maD 8. duuble- o li,"ue seplae smTol1d gro"pScdb uf clinical trlab were initiated udng one thigh a:l aoco- FL Jou, cmmecti\' e overweight women had tho. JjJ cdls aod .nach to OlC uodcrside of the donnis- As r.t blinded control. Trial IH: Fh' ;,cj!t t: ar 5tn tc-hed and puU do\'.-n on cn1(\g... th injections of hO(1rotereno\ at intervab aroundaUdnl!' the thighTrial procesS is an indentation or with diet and \'' skin, Th r6ult orthi llrn three time a week fer.! week ;1yin d buuock area in '\ HtW cigbt ,,"oman had olntmwt cuntaining dimpling ofl11c skinovcrlht: thigh 81 #2: five o ap pUed to the thigh cn th nl1meeellulit.;( 13)- Although (0 \\hi h Ronsard ha. gh' Gdurt::) for cdlulito.. no fo r. kolin.yohimbIne ..nd aminophJU ann oak Roosard has proposed treatmenl pro to support the five time a weekfor.t weelu after hypertonichteen "' o, crweight with a ilet and walkng, Trial #3: Eig oxpcrinlCntal evidence has boen puhli,hod ing.. (arly women weredh' ided into three groupS of ,ix andngfonko\in, trial#2 wa dlicacv of her.sugg..sti :.a.l1iued spot rcdu ral - stUdies havt: repeated with each agent alone V5. placebo u'i gc might han: effeds on local Uine in sCflarate ointments, Trial ohimbin or 1\J1lnoph,. smdies suggc:,l.:d lhat ulas:HI. amino(1hyni 14). A carcfully controHed :)wdy by KHlb\e to #4: Thirty Oyt(" eight women haulO% eck. fat distribuliun (5, H times a week fo.-6 er. domonstrated that ",,,sage wa.' uoa rc; ointment applied to the tbigb H' tt,- (7). howo\ (: ioeal fat rcJuction, In his study - 4.0 patient: w with diet and walking, Chembtr)" panet, theoph ewomen achie\ and patcbtesting were performed. Trial#5: Twd, ithout placed on an 800 calorie diet'ing with as unma..:;;aged20 subjecls rocoivingl:outrols. necreamw mId 20 subjecb s became bad trial #: repealed with 1% aminopb ith 0. ma:,:;ag All pati u1S lost weight and their 3rm5 and m.,," a dietorwalking. Trial #6: Trial#SwOU repeatedohimbineointment ,, of aon cream, AU triah excel1t smaller. but Ihere were no ditTerenee, between the aminophyll ' from the treated thigh ga'r' C Jiv;nifcantly more girth lo grn"p aod the umnassaged control gtOUP in the 10 . panelsbowed no toxicitl' rO g ion 0 fthe (p":O.OS to p.cO, OOl), Chemi:dl" or kg fat. :And patch te:.tingwa, nega- Theophyllewas undetectalJ Ad ipo,e ti ""e metabo\ ism v.riesd frumKral onOot ul. (8). dcmon- th' e. W conclude that topical fat reductionforwomen bod, to .o"ther Smith el at (IS). .n dh:t cr !.crcbe, ;; absnrbed mote slowly in the femoral ;ed that fat "- in \\ou,cn 105in5 thigh! can be 1\chicyed witil0ti stra e\'crc: regi Ihan from the .bdominal rogi for . adipocyte amintJph)"Uine, 1ipol weighl after th juno-ileal bypa..;s op(:r .. I Key words: ohe'U adrenergic recepto r-:! obesity - Tht:st: observation:, suggested - reg.ionald 10 diffcn:nCt::: the 10e.1 in thc lipolyti processe" that might respon Introduction .pplicatio oflipolyli agents. Tho lipolylic process h., boons;S. fat from a J ' decti,'elllos de:eribed in great detail in tho past 20 year' (16)-glycero!.nd Lipol)' Many pcoph: would like to \" t the proce55 of hydrolyzing triacylglyccrol into sensiti " 3 Ir: Oiyt lon of Ender - Ot;parC111 of MC?I cdl'al Ffom Hllt.r-l.CLA. Mcd:c,,l Co!lIlcr pCllmgforl Bl.ol\ rally acid" is mcdialed by the onzyme honno , L.\.. "- UCl. Cenle! ,cn,itive lipaso is activo in the pho;phory' ,ol\ology, UCL\ Schoal of Mcd"u\c, T -orrancc BilOn Rouge lip.;e. Honno , Louisiar SUile Unt'lCf"lt). , o"",on.,f Chn.ul KutUOI\ RC1Cuch Ca.t.r . Ocp;Vmrnl of Medicine bound 8dcny (or the H.alih Scienct' lated fonn This .ctiv'lion isAtv prod"ced - Membrane- by protein kin.,e. lcjlC,r, . Lo! AnGel.:'" C CCilv:r, 641)0 atcd by cydic eCL,\ Schol co Rcs:uc wh!ch i5 acli\. fl.","1 u:quutI :0 0. GrccnWlr- pI:II"nglc1n ft\ClmCdLCII 5003344 ckilU RJ. BalCln",,,\50 Rouge. LA 1QI!Oll ;:I!f' n&ht 0I9q Suppl. 4 No"- 1 995 5615 Pruce by Basic Research, Ll.C. to fedeCt ESITY RESEARCH Vol. 3 Trado CommIssion pursuant C, L D. of 2113/02 0 ,; ' .("". ;; :"(.
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Initial Wt. (I 287 185 116 180 227 Weight Change - 4 - 2 - 4. - 2. figurl. l:Changesin thghcircumfer n.x and total body w ighl in tivesubjects afcrlreatent with isoproterenol ectionorplacbo.
Jak t;ydase t;an be: inhibited or :;tinmtah:d by tht: action of lor. on the other hand tirnulate GTP inibitory binding inhibitoryorstimula(oryGTPhindingprotems(G:i-pru(l:ins). proteins (G, proh:ins) which inhibit adcnylat cyclase and acting on adenylah cyclase. A numher of honnones react thusinibitthc:lipolytcprocess. Thcrdalivenumberofpand with ceU surace receptors on the: adipocyte to iufluence adrenergic reccptors on the surface of the fat cells lipolysis. SlimLllation of the p- adrenergic receplor S!1mU- dctermill the lipolytic baf81ce of those ceUs. Hormon s can lates1he GTP stimulatory hinding prokin (G, protein) which have long-krmeffects on the lipof)1ic procc:;scs by tnuenc. activates adcnyiare cyclase which. in mIl. actinlfe:: cyc:ic ing the nUllb rof a-2 and p rCl;eptors on the fal cd1.Ih AMP The (',. 2 adrenergic receplof and the adnlO5.tnr: r cep- con lroHinl! linolvs.is- hfJrmfJp. o;s C-;.!l uC!l:rmine PQdy f di5-
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Initial Wt. (I 203 129 250 166 162 Weight Change - 4 - 4. 11. +1. 5003345 FigUre 2: Changes in thigh circumference and total body weight in five subjects afler treutment with omlment cootai.g focskoli, amophylline and yohimhine or placebo.
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.c 1 .f= 210. 235 157 205 12. i\- Initial Wt. (Ib) - 16 - 6 ointment or placb Weight Change ur,ubjects .rerlTeablleotWi!h yohimhin thigh circwnferell"" nnd total body weight ill fo 'Figue): Changes in re a- a control and tho other treated. Soeond. reduced lipolyti ributinn. Womell. through the erfect ofestrogon. ha\'o mo receptor acti,'ity made this an c",y area to test. ",1.o r lIs of thm h.p' "nd th.ghs This a.-c receptors o causeS the conce gi"'" a h.gher hpolVihreshold and nt".Methods and Experimental ProtoCOls wo,"en(I.. tioo of fat in !hat area in \2). of a P adreuergic any women are distressed as they lose wcight that The lirst study compared injectio 2 p l (l0" 1I'v .e 6) Isoprotereno against placeb their hips and thighs remain undesi,abl, fat. ccor b, modulat. agonist t,,d in 0.2 mL of ypnthesi that loeal rat reduction could highly selective P agonist, w mfer' . we chose wotHen , !hig s as the nomtal fat ccll function at 4 em intervals oround the circu o reasons. Fir't . thigh' otler a key ad- antage phy,iological saline te" area for tw' cnce of d.e thigh two. thirds of the waY from the knee tu the in that each woman hIl a matched se"O that one can be used
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228 158 212 158 Initial Wt. (I 191 b) 10. - 4 12. Weight Change -15. nl with alUinophyHin uinum.1\1 Of Figu 5: Changes in thgh circumference and total body weig.t in five :mbjt.b; after treatrn plBcbo. Llbjecl" had their Ihigh girhs measur u \\(:ckt - greal r trm:ha.tcr. This dose of i5opraterenol was seledt:d es ma.ximal lipolysi in ...itro. The sphcr6 of since it gi\.' judged by the diffusion of th isoproterenol m;crlappc:LI a The second srud y t ,jh:d whdh.:r fat loss could b vasodilatation al the skin :,urface. Five ",'"omen par1icipakd produc tI using a to p(cal preparation (-L6) In thi srud\. in ths single b1id study. 'me paricipant:' were more than eights we women more than % abo..e Iheir desirabk \\ 200/0 above their desirable weights (mt:an wt:ight 95 kg) and given a GOO kcaVday di t and .:ncouragcd in I) walking. wert: placed on 3600 kcalfd:1Y diet and asked to participuh: in outJ afccl th program. A j.ombinnlion of compound:, Ihat a walking program. injedion.s were given three times a week injedcd control. The lipolyti process by di ffcrent mechanisms \\ a., compoum1t:d for weeks using one (high as a 5alin --Control 67. -- Treated 66.70 . 66. 66. E 65. ;; 65. 65. 64. P -c . 001 64. ANOVA 64. 64. Weekr ointmt:nl or placebo. Figure 6: Changes in thigh circumference in ZJ subjccls after trealment with 10% aminophyllin to Federal Produced by BaSIC Research. LLC 50D3347 564S OBESITY RESEARCH Vol. J Suppl. 4 Nov. 199 Tl4do Commlss1on pursuant C. 1. O. of 2113/02 )' .. p= . ,,"' --" -
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001 001 2 - OZ p= 001 ANOVA Time (week crellm or placeb r treatment with 2% BJIDophynin . and six womenhadondhigh trellted Figure 1: Cbanges in thigh circumference in 11 subjects aft mo1/ ,ohimbin ",iooph,nin . The Ilcccpt com- g \3 10' 010111. ontrol with u;otmcnt vehide as Ihe This necessitated ",ing a carior that would as treated with aquaph with diverse ;olubility characteristics. The fmal other tl1igh w pound bl!e were 1. 2 " 10" mo1/ nlind fa.,hion. Evidence ofloca\ fallo," was againtwo- in adoub\c- 10';'; 01 thigh girth al concentrations in the aquaph 10' moVL , !'himninelaofL. can1 (p4)05) r). 25 laken to be a ;ignifi forskolinlaOstUnulatll inophvllnc(KI adenosine 3 x 10' mol/ am thirds the distance between the knee and the greatertroch ".ta.ooi I). and 1. f phusp hibi"" o tcr on the treatod versUS the untrcated 1high blind study. the subjects' thighs were wrapped In th double- tllagn sulfot olutions ' h"el,t 900 mO:mJL UdY antlnupl" II, with war 600 to e dav/wcek uintnlent to each of the r,, fo\, id, lor 30 minutes prio . An oc- A Medic,,1 Center. Thir" d was performed at the U erweight.participatcd in applicati to mllximizc transcutaneooSer the absoIJti area to which the an womCO. who ,,"re morelh"n 20%0, loOkcaVdsv elusive pla;ti wrap wa; placed o,' eek ;tody pcriud. 'i1 to 1. week trial They were placcd plied throughoot the 4- recouuueud"lions regarding exor- ointment thirds o f the waV between the this6. any specifi tudy. five p-ar. o Measurements of girth two. localfat did withoot were omitted in this s .gb ei,e. War \li!s 10 one t knee and the greater trochanter wac used to judgevehic k and in aqua horwas appli 10'" of Ibe Ihigh treated with the aqoaph the 10% amino hyllin ebide wa,; applied to the blinded and compared to the Ihigb receiving active treatment. Five women and an equa\ amount of aquaph other thigb a. a control. The trial waS double- greaterthan20%overwdghl(meanweighI83 kilogram"'l 82 sO that 50%.. of the: subjedS had acri\" pou.d ) participated in Ihe study. countL:rbalanc ointmeut to tbo rightthigh and 50%10withweighlsupportedontbe tbe lell. Thigh circum- es which ferenceswerem"asuredweekl, Study hree smaller stu!! h. Two mo.,urements were taken. one at balf Study 3 was divided into t measured thig distance betVveon the tihulathe head first. and Body the greator weight. trochan- hlood tested the dTect of each cOlnponen! whetbaof this combinalion they were the ,;ccond 5 cm abov for ointme t used in Stud)' 2 10 detennin recorded weekly. Patch tcsL 6). Atotalof18WOmCngreaterthan teL a effecliveindividUally(4. pres,ore. and pol,e wcr participa1 d in these Ihroe studies (mean 20% ovoreigbt allergy 01 the active ointment and Ihe vehide were done ThewomenwerePlllcedonan m. during the I""t week of the study. A chemistrshld\'. Theophylli pand was Weigbt90kiIOgrIlS). w.&king pcncra the begining and end 01 the a" d and enc'Ouraged 10 engage in a solfate dr",'" at kvels were me""ored during the Ihird week of tbc study. At Warm Wf." with 60010900 mOrnlL of magnesi level; were drawn at eitber nt. An oedu- the elld of the study. theophyllin solulion were agai applied to theoftbe thighs for JO minotes five times per week bdore applicati 30 and 60 minotcsural60 and I 20 minote;at'tr the application of the acti,' e ointnient 10 hoth thigbs. Patients were ,een 5 sive plasti wrap was not u;ed. Six WOlllen hadl/ forskoli'! Olle thigb vs per w,, k during tho ,tud)" at "hich tin,e nintments were treatcdwithanointmenlcontaining 25 x 10" mo t containing do 5003348 six women bad one thigh treated with an ointmC. to Feder.I Bastc Research. L.L. 012113102 4 Nov. 1995 565S pruced by OBES:TY RESEARCH Vol. 3 SuppL Trada comISsion pu",u.n1 C. L 0 \.. "'''"$::::.j::;.:::\:-
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Weeks
5% -aminophyllin cream or p18c nce in 12 subjccl$ an r trcatm nt with 0. Figun: H Changes in thigh circLUn.rer U5 by paied 1- treated 'high than on the control (high (poCU. app.!ed to the thghs by study pe,,o","1. 1101 many women lest) This (esult was encouraging. althongh wanted to haH multiple inj.:tions thce 'in,es, week ..ound entration of aminophvl1ine in a cream base the J:nllrC Lircumference of their thighs. .A 2% cnn as used. Twelve women who f lt that their thighs were Study 1 undesirably fat and dimpled were en( r(:d inlo the study. An live paricipant510st more girth un Lhe treated thigh Som wonlen wW1ted 10 lose. weight while others wen:: satIs- diferal(; of2. ecifi diet Was than the t;ontrol thigh with a mean :i SEM fied with their present weight. TItUS Th study T 1.6 em (p OU5 bv paired ,.test) (Figme 2). 't:. reeommcnded. A chemistry panel wasrlrawn at the bcginning showed that locat fat reduction could be produced without and end of the study. Skin palch testing was done during tht: weight lo s. During this study, which was conducted during lasl week onhe study and thcophy1linc Ic..dswere drawn on the summer. one Clt'lhc women developed a heat rash under the final day, 90 minutes after the cream containing the occ1l1si'\ plastic wrap on bolb legs that disappeared with aminophyllin had been applied to botl (highs. An .Iliquotof continuation of the plastic wrap. Was applied b ' stUdy pcr:;onnel in a double-blind and counterbalanced fashion so that 50% of the sl.bjec1s bad Study 3 acth' e cream applied 10 the rig.ht thi h and 50% had active trial. Four of the five subjects completed lhc yohimbin am applied 10 the ten thigh. Subjecfs were seen five day girh on the treated AU lo:,t weight and all but one 10st more a week for six wt:ks. Thigh circumference was measured at thanon theconlro\ thigh (Figue J). The woman who iostffore the beginng. of each study week with wcight supported on half girt on th ptacebo thigh was the flrstentrant ioto the study. the measured thigh. Circwnerence wasm.:a.ured alone. Aftcrher nrst visit it was found that girhmeasurt:cnts were Iht: distance from the fibular head to the greilier trochanter. more reproduciblt: if the subject supported her weight on the . a reproducibl muscle thigh being meased so as to give . the tension. Since !.is was not done in ths one patic:l Twetve women volunteered for a study usin 5o/ sult. The omission may account for her unexpected r Lino hy1l crgI. This clinical trial used the same the orthe yohimbin group 10sl more on the treated thgh than methotodolog)' as Study 5 with on'-)" the concentralion control thgh. 0.75 '" 0. 35 em. although this did not reach cream being changed. statistical signifcance due to the small nwnben. The four 1!. subjects who completed the forskoli tral altlost weight and Results 0:: 0. lostmoregirh on the treated than thecontrotlhigh. 1. Study 1 em (p-c .05 by paired l- test)(Figure 4). The lIve subjects who AU five wom n completed this study and four lost weight t more giril from completed the aminophylline tral all lost weigh' and 105'1. (Figure I). The women who lost weighllo ;i0.77 em more gir on the treated thigh thao the contcot thigh rhe rreated than the control thigh. For lh group a.s a whole (p.ct02 by paircd I-test) (Figure 5). There were no rashe rherewasa 1. 8i O. 89cmgrealer girhlossofl th isuprotcrcnol- Pruce by Ba$lc Research. LL.C. to Fedorl Trude Commls9kx Pursuanl C. I. D. of 2/13102 500334 566S OBESITY RESEARCH Vol. 3 Suppl. 4 Nov. 1995 nwd.' "" ;: 0 Regiondl L'POlysi:;, Grc
Studf 6 d thigh than irh on th ots. Tht:r Were uo changt:s in blood other adversc c.\' A-U 12 5ubjccis \o;;IIlQrt: 08 :i 0_21 cm fivc patie.nts who dropped out of the prc:ssun: or pulse. Th the: control thigh at S \\eeks or treatment. 6. 7 8 and IOdays. Fourofthe five patienl, A)(Figure8). ThechemistIJpandshowcd stUdy did so after 1. (p""O.UO I by ANOV trc:ah:d rhan the placebothigb at , LDH. Jobuli and creariin had lost more gir from the signifi.cant decreases in AL T futh patient dropped out O I by paired I-tesl). but these were felt to be clinicaly the time Ibat they left Ibe study The (p""O. 11-.;; nonn:! range :; fuc d y of the study and there had been (10 change insignificant since the changes were wllci.i" On the basi$ of these studies. it was no. n.shes. pstuh It:stlnf!was negati in her thgh gir. for Utcte::l.lncrt: \,.;crc detc.ctablc: theshold. d tht:ophyHin levds wer!: bdow tht: concluded that each agent ,"ould produce:furter a change :;tlulic:s in for lhigh two girth. AminophyUine\\ as sdectcd for o nd. Discussion reasons. Firt. it is more: soluble than othcr xanthines. s a.q there ho.." been a 1ong"tt."t experience with aminophyllin The$C six trial$ demonstrate that looal fal reduction a., I.W bcproduced by topical appti\lu- a dwg for treating astnma in which its low toxicity has bc:en measured by thigh girh. . Although we wdldeflled. lion of compounds that stimulate lipolysi. ilscen1sunlikclylh made nodired measun::mcnloffat los:; Study 4 week the girth change could be attibutable to any other compo- three of the 30 women completed thig (i- , since the physiology of these compound T wenly- wel seen in the nent of the thigh s. and fat cells are trial (Figure 6). No significanl cbange rides fr is known to affecl the lipolytic proce1tcli"\c ingrt:di nt (;ould except for a uction in tTidvc hcrc tht cbemitr resuUs m./dL(p41.05) and an increase diredly \lndel the :;kin \.. 45 '" 121 mg/dUo 1)9 x 57 nonnal rates of lipolysis. q/ to 0. 5 2 x 0. rnodu'at fromO.3 "0. 24 thigb girlh lo =, with \opicallipol;-tic Ire in freefal! Oitlerentia\ hnJcrtqpil; salin could have been due to thceffecto -;nocQuire w cight loss. war 05) which could be nt doc erc' s ro raRl. Since Ihe Ss- No theophyUin ivr: dressin s. or an e rcslrcted diet s.cc timuhited first. the: thigh dt:lcctcd at any time point, Hnd patch testinger showed th-: comst no fa.t cell,: direcd.. under the s.kin a.n: ubcut 3 :l 2 -2 kg o,,' g ..' tension is relieved on tbe , sensitivity. Weight d.:lincd by 3. s in \''-.:rO; no significant chang s to the undersurfoco; of the denms. of the si:,, wedi. study. Ther:: as great r in neoUS hssue tbat 8tt8ch puIs.: rate or blood pressure. Thigh girth loss TI\is occur Ycn before 5igniHcaJ1t girth changes)' that can W1de=r be the treah:d than in the control thigh atglrthmea:ur the t'nd or theTTtnt study and mca:mred. WithoUl weight loss. the possibiH (Figun:6). 77 1: 0.66 em for the lower OOI by nt fat may be n:.distributcd from tht: lhighsand lipo- lo asurclUent (p-:O_ topica( In:atm unlikdy. Lipolysi 89 ern for tht: upper girth 78:1 0. the intra-abdominal area seelU=' . and the topic4t1 trc:atmcn.t ANOV A). genesi arc: ongoing processes rmis. oo!\' conla!,ts the L:dls irnmediatclyd wouid presumablY bc10w or ir redislributhe d St"dy5 amount orfalllobiliz d to sludy (fig.ure 7) There . Thu,. the amount parition EIe.. en women compklcd thi wet:ks aftcr the 1I other rat depo" was no skin iritation with patch testing. Thr::. any sing\c area is likely to bt: vanishingly smail. Oe-rim"\'cT or MR woman developed a rash 01\ the kg ~ions. however. wil requir start of the study. on answers to thc"t: qu(; being tceated \,.. j(h active cream. Inc cream waS sloppedd into and the scans. the rash resolved, This p::ticnt was thcn re-enlt:r e indication for topical iipolv11C trealment is co:,m..i aminophyUin cream- She did not rede- $ludy using O. 5o/Q Man.. wornc:n are concemed aboUI the appearance ofdving thdr m roor in gjrt o1l1he treated Ihan velop the: rash and lost 2 hs wheth r or not they are obese. The women rec eeks of treatment. Prob1em:' thig image whichcan on the control thigh after tive \\ this cream experienced II improved self- with freezing and thawing made chemistry pant:except anaty:;i:; for result in tangible improvements in their percdved quality of levels wereundeteclabl unre1iablc- Theophylln for lift'. Tht:ywereoffered 2 to 3 months of free aclivecreamaft one subject who violaled protocol and took theophyUi level tbey cQ( ple: d Ihe study and all wanted it. it is easiersc about to phym womcn who arc $0 di:,tres an asthma attack on the night prior io her lhe omen lost more girth from the O1Ca."ure the benefilto bdng drawn. The group of 11 ",, L21 ,,0.3 I cm (p""O. O I the appearance of the fal on their thighs that they resort to treated than from the control thigh carr with it i1 wmuen lost more girt on a surgical procedure sucb as liposuction for tberapy. Topical ANDV A) (Figure 7). Ten ofthe The lipolv,i' is almost certaily sat;,r and docs not arng the treated than the control thigh at the end of the study.gir on the ;ttendant risks of a surgical procedure with itsthc:sia. sc a... wd1as the-risks of 3le:; one woman who. at the end of the study, lost (TOre and risks of infection thgh had lost more girth on tRc treated thigh tht the placeb an error. Attempt: ha\'t: been made over many yearsmethods.. to affect Ofthcse local measement could have bc:n week 'before und the fmal in one fat reduction by" variety of nODsmgical Sint;e the 2% aminophylline cream caused a rash atlhe methods. none have he(;o shown 10 be effective:. Nowwpic:a1IY Ihere subje t and that subject !'howcd 3:2 em girth differcnfia1 is an cfft:ctive mdhod 10 achieve local fat reduction end of flve v..eek of In:atmcnl without a rash on 0. hy manipulating the lipolytic mechanism and obviating tbe secred prudcntlO investigate further aminophylli cream. it need - for mon: risky surgical interventio o 0 3350 the lowl'r cceam I;ont;t:plralion in Study 6. 1995 5675 BasiC R6363fCh. LL.C. to Fedef3\ prouce by 2113102 08ESITY RESEARCH Vol. J SuppL 4 Nov. Trade Comrnlss\cnPucsuant C- I. O. of \!' ~~~
P.eg! , C r:' N:-_ \r ;': ::L
it; reccptorsandthc L3fontBn M . Berbn 1. FlilCCUtidrc References Lipid Rf!s and bro\hn flit cell functiop.- J ArnerP. Adren gictcceptorrunctioninf&ll.ellj..-tJCli" control ofwhit VU/. 199U5:218S- 1993:H: 1057. 10. Morini S. BoJ.vSculplure.1O9\. Plastic Surgery From Head Arncr P, HeUstrom236S. L. Wahrenberg H. Bronnegard M. . New York: Ddacot1e Pn::)s 1972. Bc1Ii-ddrenoc plor :\'-pression inhumanfalcdlsfromdiffer- ro DietGuide..o II. Ohrbach, S. FatisaFf!millisl/ssue.. . TJleAlJli- ntr gion.... Clill/llvesl. 1990;86(5): 1595-1600. s:;. Lttl: Pennout'rrllFe.ight Loss- New York: P ingtun Pr Bapud E. ne. TllifiGame.: DietillgScanualldDif'rarvSmse. 1978' New York: Avon Books: 1979. ctue: inadr.:ergic dirc:di.ons for 12. Pretta E. uibelR4 HfnchJ. Regiona Bray GA. Greenw.)" FL. Obesity: Future rec ptnr ::tntu... during hypoca1oric intake do not predict seo.ch. (11: Bouchard C.Johnton f. cds. Fat Di,tribu(io1t A/clabo/ism. chang in adipocyte .:(Z': or body .:lupe. and.\/f!.abolicRiskFaclorsDuringGro'Kth(JldLate llt!CJlth 350. 1990:39:307-)15. Outcomes. New York: AlAR R. Liss. (oe: 198H:3JJ- . Q1fdBulge. rOil D. Ronsard N. Cellulite: Those Lumps. Bllmp:r Tnt: effect ofmli:lsag:,on mdllbolism of 5. Curhberbon UP. Could" 'fLM Bl!fore New York: B utyandHelitthPublish- \/ed. 1932: 1:387-400. l\onnlilindi,..iduab. QJ, ing Co 1973. Bra)" GA. Rcgionat fat los... frnmthe thigh in 6'- GreenwayFl. 14. ShortJJ , CarnegieJD. An attemptto mobilze lipoidsfrom Clill Ther. obese women after adrenergic modu(ation. slollge depot.: by dee massage and increao;ed lissue temperu- 1 9S7;9(6);G6J.669. Lab Clin A-fed. 19J9 24:J95-J97. treatlUC:llt ofob siry. ture . J . KalbSW. The fal\acy of massage in Ih 1:5. SmitbJ, HammentenJ. BJorntorp p. KralJG. Regional \/edSoc tV J. 1944:41:406- 401. differem:esintheefii:ctofweightreductioninhumanfatcdl R. Kral JG , Bjorntorp P. Schcden T. Sjostrom L otlv mc:abohsm. EllrJClinlll"est. 1979 9:J17 332. composition in adipos tissue cdhtlarity before and nt: 119 regutation. 16. Vernon RG. EfTetts of diet on lipolysis and ilcostomrin:;e\" rBlob Scsubjects. EurJCli,r!t,vest. jejuno. ProcN/lIrSoc. 1992:51:397-408. 1977;7:41-1-419.
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Permeation, metabolism and site of action concentration . of nicotinic acid derivatives in human skin Correlation with topical pharmacological effect
Beat MUller , Marlis Kaspcr , Christian Surber , Georgios lmanidis , Klingdncrysrnu.se 50. 4056 8osd. Switzerland " Instilufe ofPhamwceulicul Technology. Deparlmen( of Pharmacy, University of Basel , Switzerland Institute oj Pathology, UniversilJ' of Basc!. 4003 Basel . Swilz('r/and fl1Hill/le of Hospital Pharmucy. UIJjyel-.lrJ) Hospital. 4(J31 Basel
Received 29 OctOber 2002; received in revised form 10 June 200); accepled 24 June 2003
Abstrat effect relationship ofmethy1 nicotinate, hexyl nicotinatc and mcotinic acid A novel methodology for establishing a pharmacological dose - i'S investIgated. This methodology involves the estimation of the acting as peripher 1 vasodilators in the skin fol1owing topical application , termed which was evaluated as the perlinent unbound drug concentration in the aqueolls compartment at the site of action in tissuc dennis boundary were postulated to be concentration responsible for the phannacological effccL Blood capillaries next to the epidermis- the relevant site of action. C' was estimated from drug transport parameters for different layers of human cadaverccn skin the detennincd basal ce1I in; vitro-of the Immunohistochemical sludies showed that the plane of separation of skin achieved hy heat treatmentif1 the experiments- was beh\' The permeation rate for epidcnnis aod the lamina lucida, confirming the integrity of the epidermis and the dennis used epidennis increased drastically with increasing lipophilicity of the drug. Dermis permeability was roughly the same for nicotinate,al1 three compounds The estcrs The epidermis represented the major transport baTTier in Vitro for methyl nicotinate and nicotinic acid but not for hexy! for the were metabohsed to nicotinic acid during tissue pcrmeation to an extent Ihat was rather limited, forwhich the wasepidem,is in agrcement but very with pronounced the metabolism dcnnis. Nonspecifica-naphthylacctate-esterase activity was predominately located in the dennis volunteers and vasodilation results- The drugs were applied each at three different concentrations in vivo to the ventral offoreaml reflected ofhea!thy light. Areahuman under the curve of the change was evaluated based on skin eT),thcma which was quantified by measuring colour change of colour co-ordinates as a function of time was used as a measure of pharmacological effect The pharmacological effect of aU three drugs , evcn though the concentrations applied to the skin differed by oiders of magnitude. was comparable when similar C. values were considered , nearly sigmoidal effect/C. profiles The effect showed a strong positive dependence on Methyl and hexyl nicotinate showed identical while the profile for nicotinic acid was linear, suggesting a possible difference in the intrinsic phannacological potency between the estersof the and the acid- These results demonstrate the validity of C. as the relevant drug concentration for the cutaneous pharmacological effect topically applied drugs and underline the usefulness of the presented methodology for establishing dose-response relationships in dermal therapy and expressing bioavailability, (Q 2003 Elsevier RV AU rights reserved. relationship; Site ofactiou KI? \lIord.i: Nicotinic acid esters; Tr:msdermal pemleation; MeTabolism: Topical application; In vivo pharmacological dose-effect drg concentration
L Introduction a transport barrier and can be influenced by the applied for- mulation (Leopold and Maibach. 1996; Bach and Lippold 1998). These factors, along with skin first-pass metabolism Skin penetration and pemleation of drug after topical ad- , de- ministration depend on the physicochemical properties of and haemodynamic parameters of the cutaneous tissue tenl1ine the bioavailability of topically applied dDlgS. The the drug molecule as well as on the function of the skin as experimental detennination of bioavailabitity and, hence bioequivale ce of dermal fonnulations presents a formidable . Com:sponding autbor. Tel- : +41-61-267- 1513; challenge because of the diffculty entailed in the measure- fax: +41-61-267- 1516. ch (G, ment of drug concentration in a compartment of cutaneous E.mail address: georgios.imanidis uniba;- Imanidis).
0928-0981/$ - see front matter 2003 Elsevier B.Y All rights reserved. doi: 1 0. 1 0 16fS0928- 0987(03 JOG i 79- 195 / Ev, opean Jour/wi afPharmaceutical Sciences 20 (2003) /81- 182 B Muller et a1. the drug. Nicotinic acid derivatives are used as model drugs- tissue that is relevant for the pharmacologic action of the The estimation of the drug concentration at the site of ac- cderal RegulatIons , 1999). The site- of phar- drug (Code of (: tion is based on the C con(:ept that was proposed earlier. macologic activity of the drug may vary In Lenos of depth trnsport This utilizes a mechanistic model to describe drug within the skin and the subcutaneous tissue depending on the through successive tissue layers and permeation parameters treatment. ALso , specifying a mode of administration wit.h , in of the drug for these layers for calculating drug concentra- 100% dermal bioavailabiiity to be used as a reference tion at the interface between epidermis and dermis (Su et aI. analogy to the intravenous holus administration in systemic , 1994)- This concept was applied to , neither is the definition of 1991; Imanidis ct at delivery, is not straightforward the estimation of the active site concentration of Acyclovir the dose ofa dermal fOimulation given as the amount of drug used in the treatment of cutaneous Herpes Simplex Virus- released by the vehicle and taken up by the skin or as the , this concept aUows infections in mice. As outlined below total drug amount applied with the formulation to the skin the estimation of the free, i- e. unbound (rather than the total) surface. Determination of bioavailability based on pharma- drug concentration in the tissue which represents the phar- cologic effect is complicated by the factthat the relationship macologically active fraction and takes into account that a between drug concentration and pharmacologic effect is not concentration gradient prevails as one moves from the sur- linear. face to deeper skin layers. These characteristics arc not af- These issues are related to the diffculty of establishing , punch forded by other te hniques involving, for example rcsponse relationships in , suction bllster meaningful pharmacologic dosc- biopsy, tape stripping, dennatomed layers dermal drug therapy- Approaches taken to this end include and microdlalysis (Surber, 1996) used partty in conjunction using (i) the entire drug amount applied topically (Ryatt , 1995), (ii) the drug amount (flux) with the multicompartment models mentioned above. These et aI., 1986; Realdon et aI. techniques yield total tissue drug amount with the excep- which is released by the formulation in vitro (Real don et aI. tion of microdialysis and suction blister and have all a lim- f6) or in vivo (Leopold and Maibach, 1999) and (iii) the ited spatial resolution, which for microdialysis specifically drug amount measured in stratum corneum by tape stlipping is related to the positioning of the tuhe. Implications ofof der- the (Pershing et aI., 1994) considered to corrcspond to the drug present study for the assessment ofthe bioavatlability amount in plasma in case of transdennal medication (Shah mal formulations are discussed with respect to estimating , 1993), as the dose to be related with the phar- and Maibach active site drug concentration utilising the outlined method macological effect. While topical bioavailability may corre- as compared with other proposed methods. late with the applied drug amount or the amount released The pharmacological effect of topically applied nicotinic from the formulation when dealing with the same drug, and acid derivatives is a vasodilation of the peripheral blood the amount determined by tape stripping may give a good capillari which are located in the dermal papillae of up- indication of skin penneation of the drug, bioavailability in per demlis layers adjacent to the epidennis-cem1is junc- general may be influenced by processes at the lower tissue tion. The mechanism of this action involves the release of layers, skin first-pass metabolism and haernodynamic ef- uncer- prostaglandi Dl as an important step it is still , linear multi-compartment models were proposed fects. Thus tain which cell type of the skin exactly is responsible for to describe the distribution and micropharmacokincti , subcutis , un prostaglandi release. However;prostaglandins have a very drug in skin. One model encompassing dermis life being rapidly metabolised and therefore act , blood microcirculation and contralat- short half- derlying tissue layers strictly locally on cells by which they are released or on eral tissue (Singh and Roberts, 1993; Singh et aI., 1998) was , it is neighbouring cells (Roberton, 1995). Considering this validated for the steady state situation using hairless mice postulated that the C* concentration of nicotinic acid deriva- with and without blood supply and analysing dermatomed , which is tives estimated at the epidcfflis-dermis interface tissue layers. Differences were identified between lipophilic , represents in the immediate vicinity of the blood capillaries compounds , which were found to penetrate by direct diff- the active site drug concentration. sion into subcutaneous tissue located below the application Nicotinic acid and its hexyl and methyl esters were cho- site - and hydrophilic compounds, which were taken up by sen as drug compounds because of the differences in their the peripheral blood circulation. Another model describing lipophilicity which should provide different in vitro and) 991; in the interaction between skin and topically applied fonTlu- vivo penneab1lities through skin (Dal Pozzo ct al. lation and drug biotransformation during percutaneousab- Le and Lippold, 1995; Guy et aI., 1986). Metabolism ofthe sorption was experimentally validated using the jsolated per- drug esters during permeation through different skin layers fused porcine skin ftap model (IPPSF) combined with tape resulting in nicotinic acid is . investigated since it may af- stripping and sectioning of skin punch biopsies for deter- fect bioavailability. Cutaneous esterases were reported to be mining drug concentration in the skin (Riviere et a1. 1995). mostly located in the epidermis and in skin assoclated glands The goal of the present work is to evaluate a novel method such as hair follicles and perspiratory glands. It was shown for establishing a dose-response relationship for topically esterase activity for hydrolysing esters of corticos- that total , but applied dennatological fonnulations in humans in vivo. This teroids was equal between the epidermis and the dennis method entails that the drug concentration at the site of ac- it was 20 times higher in the epidermis than in the dennis tion in the skin is related to the pharmacological effect of 195 tSJ B Miiller ef af. J European Journal of Phnrmacewica/ Science$ 20 (2003) /8/- when refcITcd to tissue weight (Tauber and Rost, 1987). to 400 mosm/I. The above phosphate buffer with appropri- ately adjusted osmolarity to match that of the dnlg solution There was no esterase activity in the strahnn corneum- lnves- was used as receiver solution tigations with mono- and diesters of salicylic acid in cryostat sections of human skin transplanted onto hairless mice and 2- Human skill for in vitro studies of human cadaver skin have shown a higher activity of es- terases in the upper skin layers (Guzek el a1. 1989)- Fur1her Cadaver skin from the abdominal region of female donors ethyl nicotinate was shown to be incompletely metabolised to nicotinic acid during skin transport (Rittirod d aI., 1999a). with no skin diseases or serious internal illnesses (Insti- approach are tute of Pathology of the University of Basel) was isolated Pem1cation parameters required in the C , freed of subcutaneous fat, placed detennined in vitTo using human cadaver sbtL Permeation within 24 h from death tight container and immediately stored in a freezer and simultaneous metabolism of the three drugs is stud- in an air- c. Before use, skin specimens with no visible hair ied in the epidermis, the demlis and full thickness skin and at - 70 " permeability parameters of parent drug and, where applica- were thawed at room temperature and soaked in receiver so- lution for 30 min. When the epidermis or the dermis were ble, metabolite for the different skin layers are detemlined. investigated separately, they were separated fTom each other The exact plane of separation between epidermis and der- mis achieved experimentally by heat treatment is determined by heat treatment of the skin for 60 s in receiver solution C and subsequent mechanical peeling (Kligman and histochemically. This is crucial for accurately assigning the at 60 . 1963) and then they were -soaked in receiver determined parameters to tissue layers and forms the basis Christophers for the estimation of the active site dmg concentration using medium for 30 min. Intactness of the baTTer function of pre- pared tissue was verified in previous studies by transepider- these parameters. Fllrthennore, localisation of esterase activ- mal water loss (Betz ct aL. 200 t) and nlembrane electrical ity in the epidennis and the demlis is canied out histochem- , 2003). ically and is used to interpret the transpor1 and metabolism resistance measurements (Kochhar and Imanidis results. The pham\acologicai effect is measured in vivn in 3- In vitro permeatioYl erperiment5 healthy human volunteers. The skin erythema caused by vasodilation is scaled using the tristimulus skin colour rc- A novel glass diffusion celt was developed (Fig. 1). In thjs , the skin membrane was damped between donor and flectance (SCR) technique (Wilhelm and Maibach , 1989). This technique is well qualified for quantification of ef- receiver compartment against rims with ground glass sur- fects on the peripheral blood circulation in comparison to face that were sphCilcal in fonn (rather than plane) with a radius of curvature of 14. 3 mm. With this geometry, the other non-invasive methodologies such as laser Doppler vc- , prevent- membrane was positioned far below the fluid kvel locimetry, photopulse plethysmography and visual scoring (Guy et ai , 1983; WlIheim ct al . 1989) ing the accumulation of gas bubbles at the membrane upon withdrawal of sample volumes as large as onc third of the l11e employed derivatives have all the same phannacolog- ical effect (RoberL" and Monow, 1997) but they should differ volume of the receiver solution- It was therefore possible by vaiying sampling volume and sampling frequency over a greatly in their skin penneability which cxpectedly affects wide range and taking advantage of the fairly small volume the concentration level they reach at the site of their phar- , to attain a high sensitivity of flux macological action. Each of them was applied to the skin of the receiver solution at different concentrations. This made possible to study the measurement while maintaining sink conditions. The highly relationship between pharmacological effect and concentra- flexib1e sampling regimen made possible to imitate condi- tions prevailing in flow-through aITangements. The surface tion at the site of action with the same compound but also 69 cm for different compounds. area of diffsion was 2. Two ml of drug solution were added occ1usively to the donor compar.:n nt 3!ld 14 mt of receiver solution were used 2. Materials and methods providing identical fluid levels in both compartments. Oc- c1usion was used in order to eliminate effects arising from r Dmgs and solutions the evaporation of vehicle and simulate the conditions of the in- vivo study in which drug was applied in Finn chambers. Nicotinic acid (NA) and its methyl and hexyl esters (MN Three diffsion cells mounted on a support base were kept in a water bath at 37 o C and run simu1taneously, the receiver and IIN , respectively) (Sigma. St. Louis, MO. USA) were used as received. For the in vitro permeation experiments solutions stirred at 500 rev.lmin with Teflon paddles inter- connected with a bead string. The materials comprising the donor solutions were prepared in phosphate buffer (pH 6. cells were inert, showing a maximaLconcentration decrease fi = 0.03) in concentrations of365mM and I mM for methyl for a 0.2 mM solution of hexyl nicotinate of 22% over a nicotinate, 145 rnM for nicotinic acid and 0. 7 mM for hexyl h period due to sorption on the Teflon paddle. nicotinate. The osmolarity of the solutions was adjusted to 48- of 1-4 ml were drawn from the receiver com- the physiological level of 285 mosmll with NaCI except for Samples . partment at predetennined time intervals and replaced with the 365 mM methyl nicotinate solution whlch was adjusted - - - .,.: ,'
195 184 B Miil!er f't 01.1 European Journal of Pharmaceutical Sciences 20 (2001) 181-
I 23. 2 mm . 70 mm I, 23.2 In':. 4 27.3 mm . 34. 0 mm , membranc. (B) Frontal view of , donor compartment; 3 , mechanical stirrer; 4 Fig L (A) Cross section of the diffusion ceil; I , receiV!;r compa,tment; 2 the receiver compartment; dunor compartmcnt in the foreground nol shown. (C) Tup view of the receiver compartment a mixture of this phosphate buffer and acetonitrile with a ra- fresh buffer. Samples from the donor solution were drawn acetonitriJc tio of 50:50 (v/v); 4 to 14 min , phosphate buffer- in the beginning and the end of the permeation experiment. phosphate 50:50 (v/v); 14 to \6 min , linear change to Chemical stability ofhcxyl and methyl nicotinate was invcs 20 min. Nicotinic buffer (pH 3. , /3= 01); stop time= tigated in separate experiments under conditions identical to acid was dctected at "A = 262 om and hexyl nicotinate at those of the permeation studies with samples taken at 1 "A= 219 om. , 12 24 and 48 h- All samples were analyscd for nicotinic acid, hexyl or methyl nicotinate by HPLC. 5- !listochemical investigations of skin 2.4- HPLC assay To determine the exact plane of separation of the skin after heat treatment, pieces of skin were fixed in formalde- Samples were centrifuged for 10 min (3500 to IS 800xg) hyde, embedded in paraffn and sections with a thickness and the supernatant was analyscd at room temperature by background staining of 10 j.ff were prepared. A general HPLC (Hewlett Packard, scries 1050, Hewlett Packard of van with haematoxylin-cosin and with the triple dye Waldbom, Gennany)- A reversed-phase RP- 18 column Subsequently, Giessen (Rome is, 1989) was applied first. (Spherisorb ODS2 , 5 125x4 mm) with precolumn was jlm sections were preliminarily treated with pronase tye 14 used and a flow rate of I mllmin. F6r analysis of nicotinic the mobile far 10 min and the protejn collagen IV and the glycopro- acid alone, the - injection volume was jO~ tein laminin, which are present in the basal membrane of phase was phosphate buffer (pH 7.5 = 0. 06) containing the epidermal-iermal junction, were stained immunohis- 5 roM tetrabutylammonium-hydrogensulphate and detection Q! ABC tochemically. For this purpose, the Vectostain Elite was perfonned UV -spectrophotometrically at A = 219 um- (Avidine Biotin Complex) standard kit (Vector Laboratories For simultaneous assay of methyl nicotinate and nicotinic Burlingame, CA, USA) was used. Laminin was labelled acid, the injection volume was 10 jll, the mobile phase was a using a polyclonal IgG antibody from rabbits (Eurodiag- mixture of aqueous phosphate buffer (pH 7. , fJ = 0.06 with nostica, Amhem, The Netherlands) as a primary antibody, 5 roM tetrabutylammonium-hydrogensulphate) and acetonl- an antirabbit IgG antibody from goats (Vector Laboratories) tri1e at a ratio of 97:3 (v/v) and detection was perfonned simultaneous associated with biotin as secondary antibody, a chromogen spectrophotometrically at A = 219 nff. For complexed with avidin converting biotinylated peroxidase - assay of hexyl nicotinate and nicotinic acid, the injection and diaminobenzidine (Vector Laboratories) as chromogen. volume was 1.0 jll and the composition of the mobile phase Collagen IV was revealed using an IgG antibody from was varied in a gradiem mode as follows: 0 to 2 min, phos- mouse (Daco , Glostrp, Denmark) as a primary antibody, phate buffer (pH 3. , fJ = 0.0); 2 to 4 min, \inear change to (j) =- - = + -- - - -
18/-195 '85 lJ- Muller el a1./Europeu/I Journal ojPharmo.ceulica! Sc;eflces 20 (20D1)
The degradation rate of the drug during the penneation an antimouse IgG antibody from goat (Vector Laboratories) experiment was defined as the nonnalised flux of metabolite associated with biotin as secondary antibody, a chromogen into the receiver compartment expressed in percent of the converting biotinylated peroxidase cornplexed with avidin sum of nonnalised fluxes of parent drug and metabolite in and diaminobenzidine (Vector Laboratories) as chromogen. the same compartiUl'.tL Ti1e same methods without primary antibody were used as If only chemical hydrolysis 1n the dOllor and the receiver controL , then the solutions of the permeation ceil were considered To investigate the distribution of a naphthylacetate ratio of nicotinic acid (degTadation product) to parent drug esterase (ANAE), skin samples were fixed in 4% forrnaldc- phos- in the receiver compartment would be: hyde- sucrose for 4 h followed by 12 h in 30% sucrose- phate buffered saline. Cryostat sections with a thickness of A er kt + expC kl) dried. The sections were PMN/HN 8 to JO I-m were prepared and air- CNA. (3) incubated at room temperature under the microscope for 5 CMN/ttN.R I - exp(- kt) to 30 min with a mixture of (1) 40 ml of a 0_ 1 M phosphate buffer pH 7. 5 containing 0. 5% of a 4% pararosaniline so- where CNA R is nicotinic acid concentration in the receiver lution and 0. 5% of a 4% sodium nitrite solution and (II) I compartment, CMN/HN R is concentration of methyl nicoti- ml of a 1% a-naphthylacetate solution in acetone. Subse nate or hexyl nicotinate in the receiver compartment first order chemical degradation constant is time PNA quently the sections werc rinsed under nmning water for 5 PMN/HN min, air-dried, and incubated with lIarris haematoxylin for skin permeability coeffcient of nicotinic acid and 4 min to stain the nuclei of the cells. After 12 h the scc- is skin permeability coeffcient of methyl nicotinate or hexyl . The tions were covered with a cover glass using Eukitt nicotinate. For the derivation of Eq. (3) insignificant deple- d of parent drug in the donor solution incub medium without a-naphthylacetate was used as tion ofr.icotinic acid an a control (Leder. 1967). was assumed
6- Analysis of the permeation data 7. Selection of volunteers for in vivo stu.dy
into the receiver compartment The in vivo investigation was carried out with 20 heallhy Normalised skin fluxes vohmteers, seven males and 13 females aged between 21 were calculated for the parent drug, i-e. the drug initially , the and 37 years. The volunteers had neither florid skin diseases added to the donor compartment and, whe.;e applicable nor severe internal illnesses, were not smokers and were not , i.e. nicotinic acid and their SHm using the steady metabolite treated by corticosteroids- No extraneous local therapy of state portion of the permeation curve according to Eq (1) any kind on the application site was allowed. One week be- /t\1 (I) fore starting the investigation, no treatment with nonsteroidal J= _ b.l anti-inflammatory drugs was accepted- The consumption of coffee or black tea and the washing of the application site , like lo- where I"m/ St is the slope of the amount versus time curve with detergents or the use of skin care products obtained by linear regression L\l is the mean donor con- tions or cremes, on the application site was not allowed for t'1 t2 - centration of the parent drug in the time interval 12 h before starting the expcriment. Lack of effect of the , 11 is lag time and II, S is the surface area of diffsion smallest applied concentration led to the drop out of the par- marks the end of the linear segment of penneatioo. Using a ticular subject. The volunteers participated in the study with- longer time interval and non- linear fitting to calculate nor- out financial compensation and signed a written infonned maliscd fluxes introduced a larger variability to the results. consent.
L\I Was calculated from the initial drug. amount and the lransport data fiJ parer.t d:-g an.d degradation product based 8. In viilO st dy design on mass balance considerations. For the back diffusion of metabolite in the donor com- Solutions of hexyl nicotinate (HN), methyl nicotinate partment , a nonnalised flux (jNA D) was calculated using (MN) and Olcotinic acid (NA) were prepared in the same Eq. (2) assuming that the flux remained constant over the buffer used for the in vitro experiments. The solutions were entire duration of the experiment applied to skin on the ventral side of the foreann of the subjects occlusively in order to minimise environmental in- t'mNAltlot (2) oo application sys- jNA fluences using Finn Chambers on Scanpor - S tems (Epitest, Tuusula, Finland). Each chamber contained of 8 mm (applicatio a filter paper disk with a diameter _ where I"mNA is the difference of nicotinic acid amount In the surface area 0.5 cm ) which was soaked with 20 lll of drug donor between the end and the beginning of the experiment f is average solution. B1Jffer was used as placebo. ttot is the duration of the experiment and CD The vasodilatation of peripheral blood vessels after topi- donor concentration of the parent drug between time zero cal application of nicotinates follows a circadian rhythm, the and ttal that was calculated in analogy to CD 6/' !'" - ",( (!), . . + + +++++. . . .
186 B. Muller er nl. European Journal of P/wrmaceu/icu/ Sciences 10 (2001) J 81- maximal effect being observed during the day with peaks . latcd as follows' around noon and the minimal at night (Reinberg et aI. , 1995). ;,c (5) For this rcason, the investigations were carried out con- 1\0 (1) (t) sistently within a short time period in the morning hours
(08:00 to 11 :00 h) guaranteeing reproducibi:ity of the results oo at the time and a nearly maximal pharmacologic response. The volun- where (t) is the reading of coordinate oo (t 23 = 0) is the reading of the same coordi- teers were acclimatised to the room conditions (20- - point and 50-60% relative humidity) for half an hour prior to the ex- nate at time zero for the same application point. Natural perment. Each volunteer participated twice in the study, the changes of the skin colour during the experiment were cor- first time hc/she received hcxyl nicotinate and the second rectcd for using the mean value of the four control points at time nicotinic acid and methyl nicotinate. A washout inter- the time , a and at the beginning of the experiment LOO and val of at least 2 weeks was applied between the first and (I = 0). The changes of the colour coordi.nates the second time. Three different concentrations of HN and h* 'were calculated in an analogous manner. a placebo solution were applied in duplicate randomly on The arithmetic mean of the colour change of all applica- each foreann. NA and MN were applied each on a foreann tion sites with the same drug concentration was calculated at three different concentrations along with a placebo so- at each time point. The AUC (cumulative area under the curve) of the skin colour change versus time curve was rep- lution in triplicate in a random fashion. HN included more OO b.a and 6.E" as a function oftimc. test points than the other two drugs because of its rather resented graphically for low concentration. To exclude differences between right and An example is shawn in Fig. 2. The AUC of the placebo left foreaml, the test solutions were applied with equal fre- was subtracted from the AUC of the test solutions and the quency on both forearms among all the subjects. resulting corrected AUC was used for further analysis. In . Drug solutions were applied for 20 mirL For HN, which this work, the AUC between 0 min and 95 mio (AUC95 mill had the highest skin permeation rate, the fi Iter paper disc after removal of the drug solution from the skin was used as was replaced every 5 min to prevent drug depletion. :\ftcr a measure of pharmacological cifect because in more than removing the application system, the remaining test solu- 80% of the measurements a maximum AUC was reached , 1993). After dis- tion drops were dabbed off with paper tissue- Twenty-five at this time point (Chao and Lt Wan Po minutes after drug application commenced , the fi.rst read- carding dropoul", outliers in each concentration group, both , wen:: eliminated by a statistical ing of skin colour was taken. Measurements of skin colour low and high responders continued every 10 min for the following 120 min. Mea- test (Sakal and Roh!f, 198\). The differences in colour nts and at four change between the means of the different concentration surements were made at the application poi way ANOVA control points located dista!1y, proximally, and laterally of groups were tcstcd for significance by a one- sided i-test (com- the arca containing the test points- These controls were used using AUC95min as a factor and a two- , SPSS , Chicago , IL to COITect for skin colour changes during the test time. Prior puter software: SPSS 8.0 for windows to the application of the drug solutions, the application and USA) control points were marked and a baseline measurement of skin colour was made. 500 000 9. Recording and analysis. of the. in vivo data 400 The measurement of skin colour was carred out using a Minolta Chroma Meter CR-300 (Minolta Camera, Osaka 300 Japan) '.'/ith a sin::ular measurement field with a diameter of 8 mm and the data were processed online. The colour of light reflected by the skin after emission of white light was 200 :5. + * b* system recorded three-dimensionally based on the L* (lu- (Commission International d' Eclairage , 1976) with Q+.. minance) expressing the relative brightness, a* the colour 100
range from green to red and b* the colour range from blue to yellow, all on a - 100 to + I 00 scale. The absolute colour change I:EOO was calculated as follows: 100 150
time (minJ .2 (4) b.E' b.L.2 b.a absolutL colour change Fig- 2. Typical AUC versus time curve of the 50 mM (x), f'E- after 20 mill occlusive application of 100 mM (0), The change of colour coordinate for each application and 5 mM (+) of nicotinic acid (NA) solutions- point and at each lime point , denoted as 6.a (t), was calcu- =--
187 195 B- MrilJer el aL I European Journal of Pharmaceutical Sciences 20 (2003) 181- In Eq (6) (and Fig. 3), two tissue layers are considered Dermis for the sake of simplicity although the stratum corneum rep- resents a distinct layer in terms of penneability propelties , however within the epidennis. For the ensuing calculations which deal with the concentration at me epiaermis-dennis barriers be- interface, the presence of additional penneati tween the ' viable ' epidermis and the donor compartmcnt is inconsequential. With respect to the drug concentration at the epioermis- dennis interface, Eq. (7) holds
Cder epi (7) - = Kder/epi Cepi dGr between dermis where Kdcr/epi is drug partition coeffcient Distance and epidermis. The phannacologicaHy active , i.e. unbound drug concen- d Circ laiiOil: 9-= tration C.. at the site of action is calculated as follows:
relevant (8) Fig J. Schematic representatIon of concentration profile and concentrations durmg steady state flux of drug across skin .Tder/20
gh the skin at steady state and der /20 where is the flux throu lation of the dntg concentration at the site of is the normalised flux for isolated dermis corresponding to action and of the application lime in vivo the effective in vivo diffusion path length in the dermis. The steady state mass flux in vivo may be controlled ac- The epidennal-dennal junction constitutes the site of cording to Eq. (6) by penneation through both the epidennis tan us phannacological activity of topicaHy applied and tbe dermis- The in vitro skin pcmlcation experiments con- nICotiniC aCId derivatives. For the calculation of drug demonstrate that the permeation rate of nicotinic acid and centration a this interface , the permeation of drug through methyl nicotinate is controlled by the transport through the the epldenms and the dennis , i. e. the tissue layers bordering epidermis. This is even more so in vivo if one considers that on this interface, at steady state conditions is considered. only one part of the dcnnis thickness contributes to diffu- , flux in vivo is shown Assuming that the drug penneability differs between the sional transport. For hexyl nicotinate two layers, the concentration profile of drug depicted in to be controlled by diffusion within the donor reservoir when Fig. 3 will result. The steady state nux , .1, for both tissue the shorter diffsion path length in the dermis compared to , mass flux layers is given by Eq (6) its anatomical thickness is considered. Therefore /)dcr in vivo was calculated according to Eq. (9) Depi Cder (6) (Cepi D - Cepi. der epi (9) hepj hderj20 CO. '/epi where Ccpi D and Ccpi.der is the drug concentration at the where epi is nonnalised flux detennined in vitro for the borders of the epidermis facing the donor compartment and epidermis and Co is donor drug concentration. the dennis, respectively, Cdcr.cpi is the drug concentration in Norrnalised flux for the dermis calculated according to , Dcpi and Dder dennis at. the boundary to the epidennis Eq. (1) from in vitro data and corrected for the difference IS drug dIffusIon coeffcient in the epidermis and the dermis between the anatomical thlckness and the effective m vivo respectively, and hepi and hderj20 is diffusion path length in diffSion path length can be expressed by Eq. (l0) , respectively. the epidennis and the dennis Dder . Kder/O (10) Jder/20= epi corresponds to diffsion through the enlire thickness hdcr/20 of the epidermis. In the dermis, the drug enters the sys- , i.e. where temic circulation where sink conditions prevail where Kder/D is the partition coeffcient between dermis and the drug concentration is practically equal to zero. Since en- donor solution. tering of the drug lnto the highly branched network of the By substituting the last tenn of Eq. (6) and Eq. (10) into , an syste blood capillaries represents a random process Eq. (8) and taking into account firstly, Eq. (7) and secondly, effectIve length of its diffusion pathway in the dennis prior that Kder/epi X Kepi/D= Kder/D. where KepijD is the parti- ' epidermis and donor , the to reaching the sinkofthe circulation is defined. Previous es- tion coeffcient between ' viable lat s (Imanidis et a1., 1994) have indicated that for drugs following expression for C* results: with mtermediate hydrophilic1ty/lipophilicity balance, this epi der (1\) length (hder is approximately equal to one twentieth of C* = 120) - Kepi/D the anatomical thickness oUhe dermis. ---
195 188 8. Miiler er al.lEuropeanJoumalojPharmat.uticalSClcnccs 20(2003) 18/-
Table 1 Normahscd l1u)Ies into the reccwu compartment for different skin lay Full thickrJ(ss skin LJt:f1IS Flux Epidermi .Drug 213xlO- 38 x 10- H :: 1.22 X IO- 114 x \0- 1.97 x IO- 1.9 x \0- 58 x 10 6 :i 2. 12.41 x !o- 04 X lO- 1.08 X IO- h.fN \2 x \0- 25 x 10- 1.68 X 10- 1: 8. 'Ie X \0- 52 X IO- 'Jc 71 X 10- .: 3.46 x 10 - 07 x 1O- 52 x 10 9J 98 x 10 It 1: 2. :: 2.90 X 10- -J 2.04 X \O- 250 X 10- 06 X 1O- !O )(10. J'OI 212)( 10- :1 2. ,-7) x !0. 6 1: 8.44 x 1O- 5 1: 4.45 x 10- JHN L36 x 10- 1.'57 X 10- L19x 10- '1 + 4.48 x 10- 30 X 10- .: 7.53 X 10- 79 X 10- L57 X 10 - 39 X \0- 5 1: 4. 1.0 X 10- :! 7. 53 X \0- 57 x 10- 68 x \0- , methyl nicotinate; i-IN , hexyl nicotinate. , Drug applied in the dOf1r compartment; NA , nicotinic acid; MN M!\ ejMN). HN (1HN) and the total of parent drug plus NA (1'0' Normalised fJuxcs . mean :: S.D. in cm/s (n "- 2-7) of NA (jNA). " Drug donor cuncentration, 165 mM d Drug donor concentration . I roM. , Concentration in the receiver was not detectable.
3- Results and discussion Eq. (11) shows that C. calculated according to Eq- (8) prffides the drug concentration in a location of the epider- 3 I Normalisedjiuxes and mefabolism in vifro mis inmlediately bordering the epidennis-dcrmis boundary. When an aqueous donor solution is used, Kepi/Di: I will domains of the epi- Nonnalised fluxes into the receiver compartment for the be due to drug partitioning in lipid three drugs and different skin layers are given in Table 1. dermis or binding to tissue components. Consequently, , both the When methyl and hexyl nicotinate were applied C'" provides the free drug concentration in the aque- parent drug and nicotinic acid were detected in the receiver ous compartment of the epidennis and , sensibly, of the , C'" cor- solution. The conversion rate of the esters to nicotinic acid dermis at the epidermis-dennis interface. Thus is given in Table 2- Nicotinic acid was also detectable in the responds to the free drug concentration at the site of donor solution when methyl and hexyt nicotinate were used action of the nicotinic acid derivatives which is consid- product was identified by , to be as dmgs (Tahle 3). No other by- , in analogy to systemic pharmacodynami IIPLC. Under the conditions of the permeation experiments responsible for pharacologic activity- C can be calcu- lated from quantities that are experimentally accessible in vitro. Table 2 The .time required to reach steady state flux across epi Mean degradation rates during permeation for different skin layers dermis, which is relevant for the calculation of C* in the in Epidermis Dermis Full thickness skin vivo experiments, was estimated as follows. The mass per 2%1. 32_ Methyl nicotinate O.4%a.l' unit area Q" that flows at the epidennis-dermis interface 7%C 100% 100% as a function of time is given by Eq. (12), considering that Hexyl nicotinate 3.4% initially the concentration throughout the membrane is equal a Amount within chemical degradation range. to zero (Crank, (975) b Donor concentration, 365 rnM. :; Donor concent,ation, I mM. - Depj' 2 00 (- I)" Table 3 hcpi - Cepi 6- comparent for difierent op' 11= NorTIalised fluxes of metabolite into the donor skin layers DOPi . (12) Dcnnis Full thickness skin .exp h . Drug" Flux Epidermis iNh. 1.04 X 1O- 73 X 10- 60 x 1O- Cepi O is related to Co through the partition coeffcient 18 x \0- 7" 71: L90 X 10- Kepi/D. Eq. (12) was differentiated numerically with respect lNA 1.40 x 10- 52 X 10- , Waterloo to time (computer softare: Maple V Retease a Drug applied in the donor comparment; MN, methyl nicotinate; HN Maple Ontario, CA, USA) in order to calculate the mass hexyl nicotinate. flux at the epidermis-dermis interface as a function oftime. - b Mean norroalised fluxes in emls (Ii = 2--6) of nicotinic acid (iNh, O)' Steady state conditions were defined to be reached when Dmg donor concentration. 365 mM. d Drug donor concentration, 1 mM. flux exceeded 80% of its maximum (asymptotIc) value , Amounts in the range of chemical degradation. (Fig. 6). /95 189 B. Miiller et a'-I European Journal of Pharmaceutical Sciences 20 (20GJ) /8/-
d to 2% and roughly 1% of the fOrvard nux for hexyl nicotinate. chemical hydrolysis over a 24-h period arnount , which .- Ba$ed This is because back flux entails that nicotinic acid for methyl nicotinate and 1.5% for hexyl nicotinate. , transverses the epidermis norma!ised fluxes of Table 1 are is mostly generated io the dennis on Eq (3), for which the compound used as approximation for permeability coeffcients and the which represenl') a major tTansport baITicr for this . Back fluxes in pcnneation experiments chemical staiJility data are used to estimate the first order as outlined below , a nicotinic acid fraction of through isolated dennis were considerable in relation to the chemical hydrolysis constant , which is consistent with the 5% in the receiver solution is found to be attributable to forward fluxes for both esters absence of the epidermal transport baITier. chemical hydrolysis for t,- \2 h. degradation ofhexy1 nicotinate was more pro- The degradation rate measured - in the receiver solution Enzyatic generally exceeded chemical hydrolysis, evidencing that en- nounced than that of methyl nicotinate which is probably zyatic hydrolysis of the nicotinic acid esters takes place related to the higher concentration of methyl nicotinate com- during penneation through cutaneous tissue. Back fluxes of pared to hexyl nicotinate used in most experiments. In ad- metabolite into the donor compartment also yielded levels dition, however, studies in hairless mice have shown that esterases had a higher affnity for lipophilic than for hy- above chemical hydrolysis in some instances although the , 1999a). The high concentration of parent drug produced accordingly high drophilic nicotinic acid esters (Riltirod ct aL levels of nicotinic acid by chemical hydrolysis which inter- difference in the activity of cutaneouS csterases between fered with the determination of small back fluxes. mice and humans found during transport of ethyl nicotinate For penneation of methyl nicotinate through isolated epi- through skin was much smaller than between other species such as rats and humans (Rittirod et aI. , 1999b). dermis, enzymatic hydrolysis was measurable at a donor averaged concentration of 1 mM but nol of 365 mM, probably be- The degradation rates given in Table 2 are time- cause of a saturable system of esterases in the tissue in the values derived from normalised fluxes cOITesponding to the linear part of the permeation curve. For methyl nicotinate conce1ftration range used. Accordingly, the methyl nicoti- thick- natc flux was at I mM smaller than at 365 rnM in agreement degradation rate decreased fTom 37% to 32% for full ness skin and from 8% to 5% for dennis during this pemle- with the higher metabolic rate at the low compared to the , degradation high concentration , while the smaller variability f the flux ation time. For penneation through epidemlis values at I mM compared to 365 mM is likely related to the rates were rather constant. The observed changes are rela- fact that the fonner were detem1incd with skin specimens tively small but may refke! some change in the enzymatic , in particular, during the experiment. from the same subject compared to different subjects used activity of the dermis for the latter. For permeation ofhexyl nicotinate through iso- When skin was subjected to the heat treatment protocol used lated epidennis, enzymatic hydrolysis was detectable from for skin separation and then used in flIlt thickness for the , a degradation rate of 32% was ob- the flux into the receiver solution but not from the back flux. penneation experiment The enzymatic degradation rate of methyl and of hexyl tained for methyl nicotinate throughout. This indicates that nicotinate during permeation through isolated dcnnis was the applied treatment did not seriously impair this particular esterase activity of the skin. It is possible however, that a much larger than during penneation through epidennis as inactivation evidenced by both forward and back fluxes of metabolite. small frae-tion of enzymes is susceptible to heat , leading to the observed reduction of This can be related to the larger thickness and a higher as a function of time enzymatic activity of the dennis compared to the epidermis. degradation rate. These factors overshadow the effect of the larger diffivity of drug in the dermis (see below) which acting alone would 3-2. Skin permeation control have caused a reduction of degradation rate. The largest rate of metabolite appearance in the receiver The permeation rate of nicotinic acid through full thick- ution for methyl nicotinate was found with full thickness ness skin is controlled by the penneation through the epi- nce between the j NA values for the two sbu. This is the result of the lower penneation rate and, sec- denni5. The diff ondarily, the larger thickness of full thickness skin compared tissue membranes was not statistically significant. Similarly, tot values to the isolated skin layers. Thus , transport through the epi- no statistical difference was found betwecn the dennis, whiie it does not contribute markedly to metabolism of epidennis and fuU thickness skin for methyl nicotinate. Here, the total forward flux values are used since there was reduces the drug concentration reaching the dCITis where tissue membranes. degradation mainly takes place. Consequentiy, this concen- no measurable back diffsion for these tration is lower than the one obtained for the isolated der- Hence, the epidennis controls skin penneation rate of methyl mis, leading to a higher percentage of degradation in the full nicotinate. Dermis flux values of nicotinic acid and methyl nicotinate were considerably higher than flux values for the thickness skin compared to isolated dennis due to sahtrable , on the other , complete metaboli other tissue membranes. For hexyl nicotinate enzyme kinetics. For hexyl nicotinate COITcsponding was obtained during permeation through full thickness skin hand , J101. for epidermis was higher than the as well as through isolated dennis. flux for full thickness skin indicating that dermis played a tot for full Back flux of metabolite into the donor compartment for rate contrall jng role in skin penneation. Here full thickness skin was not measurable for methyl nicotinate thickness skin is calculated from the influx of nicotinic acid .,- .. -', - "": ...:,:"" ..,
maceutical Science.. 20 (2003) /81- /95 190 B- Muller et ar/European JourTal ajPhw
4 h of permeation. This calculation demonstrates that the into the receiver and reflccl') the amount of parent drug per experimentally detennined permeability of hexyl nicotinate mcating through the epidermis in the full thickness: skin ar- diffsion for the epidennis is predominately controlled by rangemenL The smaller ito! of the dermis compared to full in the donor compartment. Even if one considers that the thickness skin is because of the milch greater back flux of values calculated with Eq- (13) may underestimate the true metabolite observed for Cut: "'(;Ilit i:;. (ltO! of the three CQm values because of agitation taking place in the donor so Comparable nonnalised fluxes lution due to thermal convection and mechanical vibration pounds were obtained for the dermis. The lotal dermis flux the contribution of transport across the tissue to the overali reflects permeation of the parent drug for nicotinic acid and permeatio rate ofhexyl nicotinate measured for the epider- to a very large extent (95%), for methyl nicotinate, while for mis over 3 to 4 h is still expected to be negligible because hcxyl nicotinate it reflects the permeation of the parent drug of the of the overwhelming efTect of the high lipophilicity and of the resulting metabolite. The fact that i lot is almost compound. the same in aU cases suggests the thee compounds have comparable pcnneability coeffcients for the dermis, which 3. Immunohistological investigations of skin separation is probably because ofthcir similar molecular size resulting plane and esterase focalization in roughly the same diffusion coeffcient, while their differ- ent lipophilicities do not playa roie since the partition co- The epidennal--derral junction is made of three differ- effcient between the donor solution and the predominantly , (ii) the ent components: (i) the basal cell plasma membrane aqueous dennis tissue should for all of them be around unity. basal lamina composed of lamina lucida and lamina densa lo contrast, normalised fluxes for the epidermis varied and (iii) fibres of connective tissue below the basal lam- considerably between the three dnJgs. This is attributed ina. The lamina luciJa contains the glycoprotein laminin to differences in partitioning between the donor solution . 1983; , the and the lamina dens a the protein collagen rv (Weiss and the lipid domains of the stratum corneum. Thus Woodley et aI. , 1983). 1mmunohistochemical staining of ':IOO- fold smaller flux of nicotinic acid compared to laminin (Fig. 4) and collagen tV (not shown) showed that methyl nicotinate is in tal1dem with the lipophihcity of following skin separation by heat treatment these remained the compounds which, in tenns of the isopropyl myris- on the outermost surface of the dennis. Consequently, the tate/water partition coefficient, differs by a factor of 65 separation plane is located between the basal lamina and (K!PMjH 0 = 0.035 and 2. 29 for nicotinic acid and methyl , 1991). Hexyl the basal cell membrane of the stratum basalc of the epi- nicotinate , respectively; Oat Pazza et at , on the other hand, showed only a lO-fold higher dermis. This result is in agreement with that of studies in r:icotinate which a different protocol for heat separation of skin was 1!01 than methyl nicotinate even though its partition cocff- used (Woodley et a\., t 983). Thus, the in vitro determined cient (KLPM/Hl() =- 2089; Dal Pozzo et at. , 1991) is "- 1000 drug fluxes for epidermis and dermis can be safely assigned timcs grcater. 1n the following, it is examined whether this could be related to a shift oUhe control of the permeation to these tissue layers. rate from the lipid membrane to the diffusion boundary Esterase activity was locahsed predominately in the der- mis as evidenced by the red-brown granules sUfmunding layer as this was reported elsewhere for nicolinates with the nuclei ofhisteocytes and cells which are in contact with increasing lipophiticity (Lc and Lippold, ! 998). Assuming for the sake of the argument that the epidermis permeability coeffcient of hexyl nicotinate is entirely due to the diffu- sion boundary layer in the donor compartment, a thickness of this layer of 2. 8 mm is calculated using an aqueous dif- nin fusion coeffcient of hexyl nicotinate (DHN 0) at 32 of 7. 22 x \0- /s (Le and Lippold, 1998). This is re- alistic since the total height of the solution column in the donor compartment is 9.9 mm. The release of drug from an unstined donor solution in the direction of the skin cor- ed as a function of responds to a flux (1r which is expres time by Eq. (13) assuming an jnfinite donor volume and sink conditions in the skin (Crank; 1975)
- DHN H:!O. CD (13) IT' DHN H,O . I , fluxes J; . For an initial donor concentration, CD. O, of 0. 7 mM 5 x \0- 5 flmol/(em' s) and of 4. 3 x 10- flmol/(cm' s), 2. 2 s) alc calculated for 1= 10, 30 and 1.8 x 10- ILmol/(em Fig- 4. immunohistochemica1 preparation of epidermis (A) afld dermis 60 min, respectively. In the in vitro experiments, a constant (8) after heat separation of skin. Laminin is stained on the dermis surface 2 s) was obtained during 3 to facing the epidermis. flux of 1.8 x 10- mol!(cm ,/ .,
t9t (2003) 181-195 B. Muller el al /European Journal ofPharmauulical Sciences 20
68-
5 e-
4 e- :'1t 38- 2 e-
1 8- Fig- 5. Distribution of u-llaphlhylacctatf: esterase (ANAE) in skin- (A) and , respectively- (B) is the stained (C) arc controls. of dennis and epideris granu\es (red-brown 2000 3000 4000 5000 full- thickness. skin -, shows the ANAE positive 1000 staining) ((51 peripheral vessels (Fig- 5). No such granules were found Fig- 6 Computer simu!atlOn of nonnalised mass flux( differentiationover lime at the of activity reflects the cpidennis- is intcrface for NA based on f1Urnerica in the epidermis. This enzymatic Eq (12) . non-specific a-naphthylacetate esterase bound to cell con- stituents while dissolved enzyes may be released during centage points and that back flux of metabolite is barely9 and preparatio . No differences in the enzyme localisation were 5 x \0- detectable. Depi values for NA and MN of 2_ seen between freshly thawed skin and skin subjected to wet 9 cm C (not shown)- Hence 3 x 10- , respectively, were obtained- This calcula- heat treatment for 1 and 3 Olin at 60 o cpi. IOI measured this histochemical- study is in f lI! agreement with the per- tion is not applicable to HN because the for this compound is due to the diffsion boundary layer in meation and metabolism experiments with respect to the through epi- the donor compartment rather than penneatio localisation of and the effect of heat on enzymatic activity dermis. From the numerical differentiation of Eq. (12), flux in the tissue. It further supports the notion that the increased , as an enzymatic degradation rate of methyl and hexyl nicotinate as a function of time is calculated and plotted for NA , in Fig- 6. The time required to reach steady state found for the dermis may, in addition to the difference in example flux was defined as the time at which at least 80% of the tissue mass, be due to a higher abundance of enzymes in -- 00 was reached. maximum flux value corresponding to the dermis compared to the other tissue layers. It should , the be noted, however, that these results may be unique to the This was arollnd 20 min for NA and MN. Therefore system studied here since for corticoid esters and a rather drug application time in vivo was fixed at 20 min. This was different skin treatment protocol, esterase activity was de- expected to be suitable also for HN which has a similar size tcctcd in the epidennis as well as in the demlis and heat was and should therefore have a comparable diffsivity 1n the found to have an adverse effect on the enzymes (Tauber cpidennis as the other compounds. It is noted that the lag time of permeation does not correspond to the lag time of and Rost, 1987). , 1984) the pharmacological effect of nicotinates (Guy et at , therefore, cannot be deduced from it. The fraction of , applied concentration and and 3.4. Application time the applied dose that is released from the donor solution dur- il1 vivo C* ing the 20 min of application can be calculated using Eq. (9) and the epi lot values of Table 1 and taking into account the The in vivo application time of the drug was detcrmined applied solution volume and the surface area of the applica- 7% for MN based on the 6me required to attain steady state flux across tion device. This fraction was 0.06% for NA, 5. the epidermis. This was estimated using Eq. (12) which gives , in order to prevent excessive interface and 77. 1 % for HN. Therefore the amount of drug crossing the epidermis-denni , the applied HN dose was renewed every 5 min. , as a function of time. depletion e. the site of pharmacologlc action applied drug concentration , Depj, Range finding of the in vivo The diffsion coeffcient of drug for the epidermis was carried out in preliminary studies with five male vol- was calculated from the total normalised flux for epidennis unteers aged between 26 and 29 years complying with the jepiJot (Table I; I mM for MN, using the isopropyl my tis- inclusion criteria of the in vivo investigation. The AUC of tate/water partition coeffcient of the compounds as an ap- skin colour change over lOO min after application was used of the partition coeffcient between epidermis proximation, as a scale of the phannacotogical effect Test solutions were and donor solution and an epidermis thickness of 4 x 10- ' of total applied for 2.5 , 10 20 and 180 min. During the 180 min ap- cm which was determined experimentally. The use plication kin colour was measur d andfTesh drug solution 1 and nonnalised flux introduces only a small inaccuracy since it apPlied every 15 min. For MN, concentrations of 10 is demonstrated in the in vitro studies that enzymatic degra- 1 mM were used. Both drug concentration and applicatio dation during epidennis penneation amounts to a few per- /95 ojPhormUCfUliCal Sciellce. lU (lOOJ) 18J - 8 Miiller ef of. /European.JlJurnol 192 macological dlect as the parcnt compounds (RObC11s and Tank: 4 Mon , 1997)- Therefore, for the calculation of C* total Applitd and site of action drug concentratiofl normalised fluxes for the epidermis epi lOj. were used- Even Drug .lcP'JO' jdc,/lU tut /cn LmoLI if the potency of pharmacological effect of these compounds (emfs) (cOlis) , which is not known with certainty, the 100 Lr" j,j- were not the same 1.97 x: 10 28 x: \0 30 x: 10 . introduced inaccuracy would be rather small., whichThe determi. is also 30 x: !O- nation of nonnalised flux for isolated dermis , quan- 86)( 10 Co- is affectcd by metabolism 73)( \0- 2.20 )( 1O- required for calculating 93)( 10- titatively not so much for MN , for which roughly 5% of 86 x: \0 , but markedly more for L17 )( 1O- metabolic conversion was measured 257 x IO- 3:30 x \0- 67 x: 10 , for which degradation was 100%. In case ofsimultanc- 00\5 1.7 x: \0- ous transport and metabolism, the normahsed flux of drug, bioconversion per- . hexyl flico(inatc. lcpi.!ut corresponding to a combined transport- , nicotinic acid; MN . methyl nicotinate; !IN wt is the: tulJI meability, is equal to the sum of fluxes of parent drug and is the total normalised flux for epidermis in vitro jdcr/lH metabolite both in the receiver and the donor compartments. normaliscd flux lor dennis correspondmg 10 the reduced diffusIOn path , for the calculations with Eq- (8), the totai nor- length in vivo- Co is the applied conct:ntratiun in vivo. C. is the unbound Therefore dcr, tot. considering flux drug concentration in !ht: aqueous compartment of the site of phannaco- maliscd fluxes for isolated dem\is logte activity in both compartments were used (Table 4)- The values in diffsion path Table 4 are additionally adjusted to an in vivo time affected the pharmacological response in a saturable length equal to one twentieth of the anatomical thickness of and interdependent fashion. The difference of the effecttime be-in- the dennis (see also Se:ction 2). tween O. 1 and I mM was reduced as the applicatio , no increase of the c!e ed. Forconcentratioos above 1 !TM C"' times 5. Pharmacological response and correlation with phannacologieal effect was observed for applicatio ::2.5 min. This flnding is confirmed by studies in which a Table 5 shows the results or the measurement of the phar- substantially higher concentration of 100 mM was applied , 1984). This saturation of the phar- macological effect expressed by the colour coordinate for 5 to 30 s (Guy eta\. and the absolute colour E* for different applied concentra- macological effect is probably related to the mechanism of tions of the three dmgs. The difference of the effect between06 roM the vasodilatation of the peripheral blood vessels involving 5 and 50 mM for NA and between 0_ 015 and 0_ 005 and P--5 x 10- the secretion of prostaglandin Dl as a primary transmitter for HN was highly significant and possibly nitrogen monoxide as a secondary transmitter respectively). The difference between 50 and 100 mM for , 1997) and thc nature of the effect it- IN was significant (Roberts and Monow NA and between 0_06 and 0. 15 mM for I. ar concentration dependence of the pharmacolog- self A cle (P.oO_05). Solely, the difference of the effect benvcen 0, ical effect for the employed application lime of 20 min was (P 11). 1 and 1 mM for MN and I mM ofMN was not statistically significant observed for concentrations between 0. Thus, overall, a strong positive dependence of the pharma- and 10 and 100 mM for NA. cologic response on the applied concentration is evident, The concentrations of the different dJllgS applied in vivo The low concentrations were close to the minimal effective were defined based on this preliminary range finding study concentrations while towards the high concentrations a lev- and taking into account the pharmacologically active drug , C* C* is calculated us- elling off of the effect seemed to take place, The concentra- concentration at the site of action tion range in which a clear concentration dependence of the ing Eq. (8). For all three drugs the applied concentrations effect could be measured was rather nanow. The colour co- were chosen in a way that they produced values of C* ly- log in the same range. These concentrations are shown in Table 5 Table 4. This choice of concentrations served the purpose CUlUu!ative area under the colour change versus time curve (AUC9Sm;n of testing the hypothesis that C* represents a relevant con- of the co!our coordinatt: a . and the absolute colour AUC95,,,in 6.E AUC95miro centration parameter that correlates with the phannacologi Dmg and number tJ(l effect, resting on the background that the different nicotinic (mM) Meall:!S. Mcan-iS- of action (Robert of volunteers acid derivatives have the same mechanism 239.0 1: 28. 279. 5 :i 3). Nicotinic acid 100 189.4 :i 25.5 and Morrow, 1997). 160.2 1: 2\.6 70.5 I 15. 92.61: 18. It was shown in the in vitro experiment." using drug con- 371.8:i 18. Methyl nicotinate 304. 3 1: 13. centrations of the same order of magnitude as in the in vivo 277. 3 1: 15, 341.4 :t t7. 11=13 study, that metabolic degradation of nicotinic esters was 162. 81: 16- 221.01:22- epidermis and took place predominately :f 18. 424 9:i 21. quite small in th Hexyl nicotinate )65. , the drug con- 2 :I 19. 356. 2 :i 22. during permeation through the dennis. Thus --13 302- dermi 70. 3:i 71 centration reaching the site of action at the epidennis- 015 49. 0 :i 4. interface is not greatly affected by metabolism. In addi- II is the l1umber of dala sets without dropouts and outliers. tion, the resulting metabolite has reportedly the same ph 193 181 - 195 B Muller el all f;urop( U" Journal of l'harmoceu!ical Sciences 10 (1003) cutaneous Herpes Simplex Vims- I infections in mice , in- 500 dependent validation of C'" was possible (Imanidis et aI. was in good 1994)- (n that study, the estimated active C 400 agreement with the antiviral IC 0 of the drug determined In ceil cullure in vitro. Also, the topically attained C* was con- 300 stslent with free serum conccntTations of the drug showing a systemic antiviral effect The data points ofMN and HN in Fig- 7 follow an identical 200 + activity of pattern indicating that the intrinsic pharmacologi these compounds is the same. This is in agreement with sug- 1 00 gestions made eadier according to which all nicotinic acid tl! esters have the same pharmacological potency (Roberts and off MorTOw, 1997). The AUC95 mill versus C* curve levels 005 0. 015 for MN and HN at high concentrations , which is tyical for C'(mMJ a saturablc pharmacologic response. The NA response curve runs somewhat lower than that of MN and HN and seems ,;,,,," as a function of Fig. 7. Phanacological effect expressed as AUC to be linear. Comparing the activity at the highest used con- , a significant difference drug concenlration al the site of action Filled and empty symbols centrations between NA and MN . 0) NA; (8 0) UN; correspond to 6.e and tJa respectively. Key (+ was found (P-:O_ 05). These data indicate a lower intrinsic , 0) MN. Points and bars denote mea11 and S. potency ofNA compared to MN and HN- Whether the max- imal attainable effect of NA at higher concentrations would corresponding to the red-green dimension was ordinate be comparable to that of the two esters is rather diffcult to the rrst sensitive measure of pharmacological effect reflect- predict Overall , these results demonstrate that the presented ing obviously the increased presence of red blood ceils in b* was model can be used as a tool for comparative studies of top- the skin , while no response of the colour coordinate ica! bioavailability and effcacy of drugs with very different L' was also influenced by the recorded. Colour brightness , MN and HN. b.a physicochemical properties such as NA drugs giving rise to lhe observed difference bctveen , a qualitative In addition to the quantitative evaluation and b. E' _ however, seemed to be more sensitive to drug difference of the colour change reaction between NA on activity than the absolute colour onc hand and MN and HN on the olhcr was observed. MN In Fig. 7 the pharmacological effect is plotted against the and IIN caused a regular and on the application area limited concentration at the site of action For the same value colour change while for NA, colour change was irregularly of the same or a very similar effect is obtained for all dottcd and extended over the application area in some of three drugs. Also , a similar effect/C relationship results for , a lhe subjects (Fig. 8). Also , in II out of 20 volunteers these drugs. This is remarkable considering that the applied secondary colour reaction occurred 24 h after the end of concentrations varied between the drugs by orders of magni- NA application, the colour change re-emerging and lasting tude and demonstrates that C" is the relevant parameter that for 2 to 3 days followed by a brown coloration resembling correlates with the effcacy of the lopically applied nicotinic a pigmentation , possibly due to increased melanin resulting acid derivatives. This further implies the potential utility of the model approach yielding C. for estimating bioavailabil- ity as well as establishing dose-response relationships of topical formulations. Validation of the estimated absolute values of C* as the concentration that is responsible for the pharmacological ef- fect in this study represents an unanswered chaHenge. No independent data about the concentration of pharmacologi action of nicotinic acid derivatives on blood capillaries are available. Direct intradennal inj'ection of nicotinates pro- duced a vasodibtatory effect at drug concentrations of the order of 0. 1 fJM (Stoughton et aI. , 1960). The concentra- tion of the injected solution, however, cannot be converted reliably to a site-of aclion concentration because of an un- known volume of distribution of the tissue. Therefore, this Furthermore, the ofasubject showing concentration cannot be compared to Fig. 8. Photograph of the ventrat side of the lower arm cOITespond to experimental determination of drug concentration at the site change of skin colour in vivo after drug application. Dots bOHom) NA 5 mM, of action in the skin with suffcient resolution is with our application au:as of (from left to right and top to , NA 50 mM , MN 0. 1 mM, present means not possible. Nevertheless, in a previous study placeb , MN 0. 5 mM, placebo , NA 100 ruM that dealt with the topical antiviral effect of Acyclovir in MN I roM- 20 (200J) 181 195 1')4 B. Miifer ef aL/European Journal ofPharmm:ellficol Sciences Stipcndienfond cler Basler from inflammatory response, that was visible for 1 to 2 in Basel (SENGLET)' and the ' Chemischen (ndustrie zur UntcrstUtzung von Doktoranden weeks- It appears therefore, fmm the quantitative as well , cler Uiotechnologie wId der as the phenomenological effect assessment that the pattern auf clem Gebietc der Chemic ' is thankfully acknowledged. The authors wish to of phannacologicaI activity of nicotinic acid ditTers from Phannazic thank Prof. Fred Gudat, Institute of Pathology, University of that of its esters, this being in contrast with the commoniy Basel for his support with the histochemical investigations. accepted notion to date Supply of human cadaver skin by the Institute of Pathology To fully appreciate the meaning of the correlation be- , was greatly of the University of Basel, Prof. M.J. Mihatsch tween pharmacologic effect and site of action concentration found for the three nicotinic acid derivatives , the as- aprreciated. sumptions involved in' setting up this cOITelation should be discussed. C. is calculated on the basis of steady state flux References across the skin. The effect of the drugs, on the other hand is evaluated not only at one time point after steady state flux Albery, W , Hadgraft, L , 1979. Percutaneous absOtptioll: theoretical removal of des-criptioll L Pharm. Pharwaco\. 31 , 129- 139- is established but cumulatively for 95 min post- enhancement the drug, that, , until the effect completely receded. These Bach , M. , Lippo!d , B_ , 1998. Percutaneous penetrati and its quantification Em 1. l'harm Bwpharrn. 46 . 1- measurements provided the most reproducible results in the , IL , hnal1idis, G.. 2001. Heparin pen- Ektz, G.. Nowbakht , P., Imboden present study, while momentary measur.ements for example etration into and penneation through human skin ITom aqueous and . 147- 159- at the time point of removal of the application device did liposomal formulations in vitro. (nL L PharTI. 218 not provide useful data. This may be because the phannaco- Chan, So . Ll Wan Po, A., 1993. Quantitative evaluation of drug. induced logic effect of nicotinates recorded here, i.e. vasodilatation eryhema by using a rristimulus colour analyzer: experimental design and d;:Ia analysis. Skil1 PhamlacoJ. 6, 298 - 3! 2. is primarily brought about by intennediate events of their of Fed. Oioequivalence and Bioavailability Requiremcnts. Title 2!. Code , Washington owntime sca!e involving the action of prostaglandins (see era! Regulations, Vol 5 US Governmen1 Printmg Offce aoove). Thus, recording of the full effect elicited by the DC. pp. 190- 191. drug may better be achieved with a prolonged rather than a Crank . J . !975. In: Tht: Mathematics of Diffusion. Clarendon Press , drug reaching the site Oxford . pp. 47- momentary measurement. Moreover , L. , 199! Percutaneous Ua! Puzzo, A., Oonzcl1i, G. , Liggeri , E., Rodriguez of action prior to the establishment of steady state flux and absorption of nICotinic acid derivatives in vitro. J. PhanT. Sci. 80 drug still present at the site of action after removal of the ap- 54--57. , c., Sheint:, L.B_ . M,libach , HJ. plication device may also elicit an effect if its concentration Guy. R. , Tm, E., Bugatto , B. . Gaebd exceeds the minimal active level. \Vith the present measure- 1984- Pharmacodynamic measuremellts of methyl nicotinatE percuta- . 76-81. ment protocol, an integral effect is recorded. An attempt ncuus absorption. I'harm. Res. I , Wester, R. , Tur. E-, Maibach, ILl. , 1983. Noninvasive assess. to cone late the measured integra! effect with an " integral Guy. R. nicotinate in humans- Il1ents of tht: pt:rcutant:ous absorption of methyl concentration ' over time at the site of action would entail J. Pharm. Sci. 72 , 1077 1079 , O. , Hinz, R. , Maibach . H. the assumption that the effect of progressively increasing 01 Guy, R. , Carlstrom , E. , Bucks decreasing concentration is additive. In view of the mecha- 1986. Percutan.coUS pcndration of nicotinates: in vivo and in vitro . 75 . 968- 972. measurements. J. Phaml. Sci , R. nism of action of the nicotinates and the fact that the phar- , S. , WakshuH , E.. Potts , D. , Kennedy, A.H. , McNeill macologic response of a pulse delivery of drug 1S not known Guzek 1989- Transderml drug transport and metabolism- L ComparisOit of ascertain. , 33- 39. the validity of this assumption is diffcult to in vitro and in vivo results. Pharm. Res. 6 , M. , Kern , E. , Higuchi Therefore, this approach was not taken in the present wor Imanidis Song, W.- , Lee, PJL , Su The approach of corrclating the cumulative drug flux with . 1994. Estimation of skin targel site acyclovir concentration fol. . 1979) is lowing controHed (trans)dcrmal drug ddivel) in topical and systemic the pharmacological effect (Albery and Hadgraft I infections in hairless mice. Pharm- Res. confounded by the diffculty of converting flux values into treatment of cutaneoUS HSY- . 1035- 1041. , 1963. Prepardtion of isolated sheets of tissue concentration and by the fact that it disregards the Kligrran , A_ , Christophers, E. circuiation. C. used here , 702-705. removal of drg by the systemic human stratum comeum. Arch. Dennato\. 88 de- to establish an effect-concentratlon relationship is a repre- Kochhar, c.. Imanidis , G. , 2003. In vitro transdennal iontophoreti mechanisms under constant voltage applicati sentative concentration reflecting the drug level reached in livery of leuprolide 84-96. , notably at the site of pharmacologi J. Phann. Sci. 92 deeper tissue layers , v.1-, Lippold, B. , 1995. Influence of physicochemical properties of action. Its use is in line with the emphasis widely placed on homologous esters of nicotinic acid on skin permeability and maximal concentration, rather than dose, as the relevant predictor of lime Int 1. Phar. 124 285-192- pharmacologic effect. This simplifying approach is shown , V.B. , Lippold , B. , 1998- The influence ofpnysico-chemica! proper- establishing an ties of homologue nicotinic acid esters on the permeability and max. to provide very good results in tenns of , 11-22. imal flux through an octanol membrane. InL J- Pharm. 163 , Herkunfl, Funk- effect-concentration relationship in topical drug therapy. , 1967 . 1n: Ocr Blutmonocyt. Morphologie Leder, L- , Berlin lion und prospektive polenz. Monocylenleubimie. Springer Acknowledgements 226. Leopold , C. , Maibach , H. , 1996. Effect of lipophilic vehicles on in Support of this project by scholarships to B.M. from the vivo skin penetration of methyl nicotinale in different races. Iflt. J. Pharm. 139 , 161- 167. Stiftng zur F6rdcrung des phannazeutischen Nachwuchses 1 - 195 t9' B Miiller et ar Eumpean Journal uf f'harmm:.eufical Scie/lces 20 (2001) lli
Hioe- , v.P , Maibach, H. , 1993. In: Topical Drug Bioavailability, Leopold, CS.. Maibach . H. , 1999. Percutanwus penetration of loca! Shah . and Penetration. Plenurn Press , New York, pp 161-- ao.csthetic bases pharmacodynamic measurement': , J - Inv st ()ennalo! quiva1ence 113 104- - 1St , Po, Maibach, H. , Roberts 1998, Site of effects. In: Robert Pershiug, L.K-307. Corlett, L, Jorgensen , C , 1994. In vivo phannacokioetics Singh , Walters. KA., (Eds. ), Delmal Absmption and Toxicity Assess- and pharmacodynamics of lopical ketoconazole and micOllazole in , Ncw York, pp- 351- 366. human stratum comellm. AntimiciOb. Agents Chemolner. 38 . 90-95. fllen!. MJn:eI Dekker , P. , Robert, M- , 1993- DemJaI and underlying tissue pharmacoki- Rea\don, N. , Ragazzi , E., Dal lotto . 1995. Innuence of ointment Singh fomlU!atioo on skin erythema induct:d by Ilicotioatc esters. Pharmazie netics of salicylic acid after lopical application- 1. Phann. Biopharm. , 603 606 337-373 . R. . Rohlf, FJ. , 1981 In: Biomctry: The Principles and Practice Rea!doIl , N.. Ragazzi , E., Dal Zotln , M. . 1996. Kinetics of release and Sakal Research W_ H- Freeman, San Franciso simulated absorption of rneilyl nicotinate from diffcren.t omtrnent of Statistics in Biological 23 I. in vivo com:lations- Pharmazie 5 I , 113- 116. pp. 229 - formulations: In vitro- , 1960- Percutaneous ab- , R. . Clendenning, W , Krse, D. , Kou!banis, C , Buiu , R. , Nicolai , A. , Mechk, Stoughton Reinberg, A-E- , Soudant, L . Dermatol. 35 , J37- 341. ouri, M. , Touitou, Y, J 995- Circadian dosing tilTc dependen.cy in. the sorption of nicotinic aCId derivalives. J- Invest , PJt , Ghanem, A. , Higuchi, W . )991. A nove) method forearm skin penetration of methyl and hexyl nicotinatc- Life Sci- 57 , M- . Lee to assess bioavailahility and to predict efficacy for dennato1ogical 1507- 1513. , 265-274 Riuirod, T. , Hatanaka, T, Kagami, N" Katayama, K., Koizumi , T , 1999;1. formulations- Chin. Phant- 1. 41 Sirnultaneous lransport and metabolism of nicotinic acid derivatives Surber, C , 1996. In: Bioavailabi\iry and Bioequivalence of Topic a! Dcrma- , Basel , pp. 114- 115. 9- in hairless mouse skin- BioI. Pharm. Hull. 22 , 305- 309. wlogic Fonnulatiol1s. University of Basel Rittirod, T., Halanaka, T, U'dki , A- , HinD , K , Katayama, K., Koimmi, T. 30-3J. Tauber, U- , Rost , K. , 1987. Esterdsc activity of the skin including I 999b. Species difference in simultaneous transport and metabolism , 8., Schaefer, H. , (Eds.). Pharmacology of ethyl nicotinate in skin- Int J. Pharm- 178 , 161- 169. species variations. In Shroot , Basel, pp. 171- 183. Riviere, LE. , Moteiro- Rivicre , N_, Williams , P , 1995. Isolated perfsed of the Skin. Karger porcine skin flap as an in vitro model for predicting transdermal Weiss, L., 1983. In: Histology: Cell and Tissue Biology Elsevier Biomed- , pp. 582-'583. pham1acokinetics. Ear. J. Phann. Uiopharm- 41 , !52- !62- ical. New York Wilhelm , K_ . Maibach, HI. . 1989, Skin color reflectance measurements Roberls;-J- , MOITOw, 1.D., 1997. Prostaglandin D2 mediates contact urticaria caused hy sorbic acid, be!Lcoic acid, and csters of nicoli(lic for objective quantification of erythema in human beings- J- Am- Acad , 1306- 1308 acid. In: Amin , S. , Lahti, A., Maihach, H. t (Eds- ), Contact Urticaria DcrmalOL 21 , Surber, C . Maibach, H_ T. 1989- Quantification of sodium Syndrome. CRC Press , Boca Ralon, pp 77-88. Wilhelm , K- Roberton, P. , 1995- Eikosanoide und Erkrankungen. In: Hamson, T.R. lauryl sulfate; irrtant dermatitis in man comparison of four techniques: skin co!or reflecUincc , transepidermal water loss, !aser Doppler flow Issdbacher, K_ , Schmailzl, K-LG- (Eds. ), HaITisons Ionere Mcdiz.in , 293-295 rneasurement and visual scores, Arch. DemlJ!ol. Res. 28! B1ackwell , Berlin, pp- 511-515. , G- , p- 757 Woodley, 0-, Sauder, D. , Talley, M.1. , Silver, M. , Grotendorst , Qwam. ROIneis , 8.. 1989- In: Mikroskopische Technik. Btick , Munchen after , 1986. PhJrma- strom . E. , 1983. Lucaliz.1.tio:l of basemen I rnembrane componellL Ryaa, K. , Stevenson , 1M., Maibach, ILL, Guy, R. , 149- codynamic measurement of percu!i\neous penetration enhancement in denna! -epidermal junction separation. J- Invest. Dermato!. 81 vivo- 1. Ph.mn. Sci, 75 374-377 - -
UNITED STATES OF AMERICA FEDERAL TRADE COMMISSION W ASHlNGTON . O. C 20580
lJureau of Consumer Protection Laura Schneider Attorney
Direct Dial 202.326. 2604
July 1 2004
Via Federal Express Robcrt H. Eckel M. University of Colorado Health Scienccs Center Division of Endocrinology, Metabolism, and Diabetes 4200 East Ninth Avenue, B- 151 Denver, Colorado 80262 3300 - Re: Basic Research LLe. FTC Matter No. 002-
Dear Dr. Eckel: , than you for agreeing Pursuant to your conversation with Jonathan Cowen of our office assist the Division of Enforcement staff in the above matter. Enclosed for your review please find thc following materials:
Complaint and Exbibits A-L (product advcrtisements) TUMMY FLATTENING GEL" Respondents' CLAIM SUBSTANTIATION FOR " DERMALIN Apg Respondents' CLAI SUBSTANTIATION FOR "
Respondents' CLAIM SUBSTANTIATION FOR/CUTTING GEL"
DermTech report dated 6/11/03 titled "Evaluation of the Percutaneous Absorption of Aminophyllinc in vitro Using thc Human Cadaver Skin Model."
DermTech report dated 9/1102 titled "Determination of the Pcrcutaneous Absorption of Aminophylline in vitro Using the Human Cadaver Skin Model."
DermTech report dated 12/6/01 titled "Evaluation of the Percutaneous Absorption of Aminophylline in vitro, Using the Human Cadaver Skin Model." Rom. P1easc note that We have supplied both a hard copy and a copy of all of the above on CD- thercfor is a certaineach amount of of overlap the among gels.the claim substantiation that Respondents submittcd EXHIBIT
FTC 5426 I will contact you in two weeks to discuss these materials. Please let me know via email telephone ifthere are any paricular convenient times for you to discuss this mattcr. Thank you F:: for your assistance.
chneiderlei Attorney (202) 326-2604 Lschneider((ftc.gov
enc.
FTC 5427 UNITED STATES OF AMERICA BEFORE THE FEDERAL TRADE COMMISSION OFFICE OF ADMfNISTRATlVE LAW JUDGES
In the Matter of Docket Na 9318 BASIC RESEARCH, LLC PUBLIC DOCUMENT a limited liability company,
AG. WATERHOUSE, LLC a limited liability corporation;
KLEIN-BECKER USA, LLC a limited liability company;
NUTRASPORT, LLC a limited liability company;
.-OV AGE DERMALOGIC LABORATORIES , LLC a limited liability company,
BAN. LLC, a limited liability corporation, also doing business as BASIC RESEARCH, L.L C , OLD BASIC RESEARCH, LL C BASIC RESEARCH, AG. WATERHOUSE KLEIN-BECKER USA, NUTRA SPORT, and SOVAGE DERMALOGIC LABORATORIS DHiNISGAY individually and as an offcer of the limited liability corporations
DANfEL B. MOWREY, PhD Also doing business as AMRICAN PHYTOTHERAY RESEARCH LABORATORY, and MITCHELL K FRIEDLANDER
Respondents
RESPONSE TO COMPLAINT COUNSEL' S FIRST SET OF INTERROGA TORneS
Pursuant to Rule 3. 35 of the Federal Trade Commission s Rules af Practice. Respondents
Basic Research, LLC, AG. Waterhouse, LLC. Klein Becker usa. LLC , Nutrasport. LLC, Savage 1-6EXHIBIT Dockct No 93 I
Dermalogic Laboratories, LLC , Ban, L!,C (collectively, "Respondents ) object and respond to
Complaint Counsel' s First Set of Interrogatories ("Request ) as follows
General Obiections Respondents object to the Interrogatories as overbroad and unduly burdensome on
the grounds and to the extent that they call for responses that are neither relcvant to the suhJect
matter of the pending action nor reasonably calculated to lead to the discovery of admissible evidence
Respondents object to the Interrogatories on the grounds and to the extent that they seek responses that are subject to (i) the attorney-client privilege; (ii) the attorney and/or party work product immunity, and (iii) any other privilege or immunity, including common law and constitutional right of privacy and/or trade secret protection Respondents hereby claim such privileges and immunities. Any disclosure of any such privileged or immunized information is inadvertent and is not, and is not intendcd , as a waiver of those privileges and immunities
Respondents object to the Interrogatories and to the Definitions and Instructions on the grounds and tD the extent that they are overbroad, unduly burdensome and oppressive, and purport tD impDse obligations on RespDndents that are beyond the scope of the Rules of Practice Dr other applicable law
Respondents object to the Interrogatories on the grounds and to the extent that they are va!,'le , ambi!,'lous and unintelligible , particularly in light of the inherent vagueness and ambiguity in the standards employed by the Commission as well as in the charges that have been levied in this matter, which is the subject of Respondents' pending motion for an interlocutory appear and more definite statement by the Commission
Respondents incorporate by this reference Respondents' Motion to Quash in Par and to Limit Subpoenas on Non-Parties and each response, objection and basis therefore in the motion, and further objects to each IntcITogatory 011 those grounds.
RespDndents ' objections and responses to the Interrogatories are not intended tD waive or prejudice any objections that Respondents may assert now or in the future. including, Docket No 9318
without limitation, objections as to the rplcvancc of the subject matter of any interrogatory, or
the admissibtlily of any response or document or category of responses or documents, at hearing, trial or any other time Respondents expressly reserve any and all rights and privileges under the
Rules of Practice, applicable evidentiary rules, and any other law or rule, and the failure to assert such rights and privileges or the inadvertent disclosure by Respondents of information protected
by such rights or privileges shall not constitute a waiver thereof, either with respect to these
responses or with respect to any future discovery responses or objections.
Specific Obiections and Responses
Based on , subject to , and without waiving its General Objections, Respondents specitically and additionally respond to each of the Specifications contained in Complaint Counsel's Interrogatories as follows:
Interrogatory No 1
Identify and describe in detail the current and former duties, responsibilities, or work performed by each person relating to the promotional materials for each of the challenged products. (This request includes, but is not limited to, the creation, development, evaluation approval, modification. and dissemination of promotional materials. Response
Respondents incorporate by reference each General Objection as set forth here in fulL
Respondents further objects to this interrogatory on the following grounds: (a) it is vague and ambiguous, (b) it is overly broad and unduly burdensome, (c) it seeks irrelevant information and information not reasonably calculated to lead to the discovery of admissible evidence; and (d) it seeks information protected (rom disclosure by the attorney-client privilege, work product doctrine, and/or right of privacy Based on, subject to, and without waiving the foregoing responses and objections, Respondents responds as follows Respondents interpret this interrogatory as requesting the identity of persons and descriptions of duties, responsibilities and work performed In providing the following response Docket No. 93 18
Respondents do not discuss or imply, or iptend to dIscuss or imply, any relationship between any of the parties and/or any of the persons identtfied below
Dan Mowrey, Ph . D, researched and developed product ideas, concepts and
ingredients, performed ad substantiation research, and reviewed ads for
substantiation
Mitch Friedlander, determined commercial viability of products, wrote copy,
directed ad layout, and assisted with marketing,
Gina Gay, placed advertisements with media;
Jeff Davis, proof read advertisements;
Brett Madsen, assisted with copy layout;
Ned Simpson, assisted with copy layout;
John Swallow, reviewed ad copy,
Nathalie Chevreau, PhD , PediaLean project director; assisted with website
development for PediaLean; performed PediaLean safety tests
Carla Fobbs, facilitated and obtained substantiation review from outside counsel;
Dennis Gay, final approval of products and advertisements, and
Stephen Nagin, Esq. , perfonned substantiation review.
Interrogatory NO.
Identify and describe in detail the currenl and fonner duties, responsibilities, or work performed by each pcrson consulted by you, or upon who advise, opinion, or expertise you relied in the production of each of the challenged products (This request includes, but it not limited to , the creation, development, evaluation, approval, and manufacture of the challenged products. Response Respondents incorporaie by reference each General Objection as set forth here in full Respondents further objects to this interrogatory on the following grounds: (a) it is vague and - -
Docket No. 9318
ambiguous, (b) it is overly broad and unduly burdensome, (c) it seeks irrelevant information and information not reasonably calculated to lead to the discovery of admissible cvidence , and (d) it seeks information protected from disclosure by the attorney- client privilege, work product doctrine, and/or right of privacy Based on, subject to, and without waiving the foregoing responses and' objections , Respondents respond by referring to their Response to Interrogatory No. J , which includes the persons consulted.
Intermgatorv NO.
Describe in detail the composition of each of the challenged products (This request iucludes but is not limited to, the identity of each ingredient and the amount of each ingredient contained in a single capsule , application , and serving If any challenged product has becn relormulated, provide a separate answer for each version of the product that has been marketed
and sold identifying the time period(s) in which each version was marketed and sold Response
Respondents incorporate by reference each Gencral Objection as set forth here in full.
Based on, subject to, and without waiving the foregoing objections, Respondents refer to
Attachment "A," which has been designated pursuant to the Protective Order as "Restricted Confidential, Attorney Eyes Only-FTC Docket No 9318"
Interrogatorv NO.
Disclose the total amount of sales, in terms of units and dollars that each Respondent has
achieved for each of the challeuged products for each year from 2001 to the present. ReSDonse
Respondents incorporate by reference each General Objection as set forth here in full Respondents further objects to this interrogatory on the following grounds: (a) it is vague and ambiguous; (b) it is overly broad and unduly burdensome; (c) it seeks irrelevant information and
information not reasonably calculated to lead to the discovery of admissible evidence (the . ;;
Docket No. 9318
requested information has no relationship to the alleged false or misleading advertising claims
that Complaint Counsel pursues in this matter), and (d) it seeks information protected fTOm
disclosure by the attorney-client privilege, work product doctrine, and/or right of privacy, including financial privacy
InterrogatoryJ'o
To the extent a challenged product is a substantially similar product to others products, identify each other product
Response
Respondents incorporate by reference each General Objectionas set forth here in full
-Respondents further objects to this interTOgatory on the following grounds: (a) it is vaf,'Ue and ambiguous; (b) it is overly broad and unduly burdensome, (c) it seeks irrelevant information and information not reasonably calculated to lead to the discovery of admissible evidence (the
requested information has no relationship to the alleged false or misleading advertising claims
that Complaint Counsel pursues in this matter); and (d) it seeks information protected from
disclosure by the attorney-client privilege , work product doctrine, and/or right of privacy, including financial privacy
Interrogatory No.
Disclosc all payments that each Respondent has received, directly or indirectly, in connection with the advertising, marketing, promotion, and sale of ach of the challenged products for each year from 2001 to the prescnt. (This request includes the total dollar amount
and source of all payments For consumer sales, it is not necessary to disclose names, addresses or telephone numbers. Response
Respondents incorporate by reference each General Objection as set forth here in full
Respondents further objects to this interrogatoJj Oil the following grounds: (a) it is vague and ambiguous; (b) it is overly broad and unduly burdensome; (c) it seeks irrelevant information and Dockct No. 9318
information not reasonably calculatcd tolcad to the discovery of admissiblc cvidcnce (thc
requestcd information has no relationship to the alleged false or mislcading advertising claims
that Complaint Counsel pursues in this matter); and (d) it seeks information protected tfom
disclosure by thc attorney-client privilcge, work product doctrine, and/or right of privacy, including financial privacy
Interrogatory No 7
Disclose the total amount of dollars that each Respondent has spent to advertise, market
or otherwise promote each of the challenged products lor each year fTOm 2001 to the present
broken down by each medium used (ie_ television, print, internet, radio, or other means). (This request includes, but is not limited to, all expenditures attributable to the creation, development evaluation, approval, modification, and dissemination of promotional materials). Response
Respondents incorporate by reference each General Objection as set forth here in lull
Respondents further objects to this interrogatory on the following grounds: (a) it is vague and ambiguous, (b) it is overly broad and unduly burdensome, (c) it seeks irrelevant information and information not reasonably calculated to lead to the discovery of admissible evidence (the rcquested information has no relationsrup to the alleged lalse or misleading advertising claims that Complaint Counsel pursues in this matter), and (d) it seeks information protected from disclosure by the attorney-client privilege, work product doctrine, and/or right of privacy, including financial privacy-
Interrogatory NO.
Provide a dissemination schedule that descrihes in detail how each item of promotional
materials submitted in response to the Requests for Production was disseminated OT otherwise exposed to consumers.
Response
Respondents incorporate by refeience each Gencral Objection as set forth here in fuIi
Respondents further objects to this interrogatory on the following grounds' (a) it is vague and Docket No 9318
ambilo'1ouS , (b) it is overly broad and unduly burdensome; (c) it seeks irrelevant information and
information not reasonably calculated to lead to the discovery of admissible evidence (the
requested information has no relationship to the alleged false or misleading advertising claims
that Complaint Counsel pursues in this matter), and (d) it seeks information protected ITom
disclosure by the attorney-client privilege, work product doctrine, and/or right of privacy, including financial privacy
Interrogatorv No 9
Dcscribe in detail the actions each Respondent has taken to comply with the US Food and Drug Administration s prohibition on the sale of dietary supplements containing ephedrine alkaloids, effective April 12 , 2004. (This request includes but is not limited to identification of any product formulations that have been created, modified, or removed trom distribution identification of any promotional materials that have been created, revised, or removed !Tom dissemination, and the date(s) on which all of the actions described in your answer took place; and how orders for Leptoprin or Anorex or in response to existing promotional materials Leptoprin or Anorex have been fulfilled.
Response
Respondents incorporate by reference each General Objection as set forth here in full
Respondents further objects to this interrogatory on the following grounds (a) it is val,'1e and ambiguous. (b) it is overly broad and unduly burdensome; (c) it seeks irrelevant information and information not reasonably calculated to lead to the discovery of admissible evidence (the requested information has no relationship to the alleged false or misleading advertising claims that Complaint Counsel pursues in this matter); and (d) it seeks information protected !Tom disclosure by the attorney-client privilege, work product doctrine, and/or right of privacy, including financial privacy-
Based on, subject to, and without waiving the foregoing responses and objections
Respondents state that during the first par"! of April 2004 Basic Research staIled the process of identifying all products that considered to be " adulterated" according to 21 CFR Part 119, which Docket No. 9318
states all d,etmy supplemellts COlltOlllflg ephedrine alkaloids are adulierated under the
Pederal food, f)rug, and Cosmetic Act "
April I " through April 6 of 2004 all products and raw materials containing a source
of ephedrine a!kaloids, such as ephedra, Ma huang and pinellia were gathered together and
quarantined along with all boxes, labels, advertising brochures and other artwork containing
information rclative to ephedrine containing products
On April 7''' , 2004 Basic Research prepared Material Destruction Forms, which
contained all necessary information for tracking the materials through all steps of the
destruction process The Material Destruction Forms included approval signatures, raw
material lot numbers, finished good lot numbers, label revision numbers, persons responsible for destruction and all other pertinent information required to conform to the regulation.
On April 8 , 2004 Basic Research conducted one last search throughout the facility to ensure that every product considered adulterated by the FDA, had been properly identified and quarantined . All adulterated materials discovered during this comprehensive search were quarantined and Material Destruction Fonns filled out
On Friday the 9 of April 2004, all adulterated materials were destroyed prior to the
April 12 , 2004 deadline. During the destruction process, each item was verified by two separate individuals who immediately thereupon affxed their signatures to the Material
Destruction F onns
In accordance with 21 CFR part 119, Basic Research immediately destroyed every product containing a source of ephedrine alkaloid (such as ephedra, Ma huang and pinellia) returned to our facility by customers of Basic Research subsequent to the April 12, 2004 deadline y _ ):,, , - -
Docket No ',3 l8
gator No).9
Disclose the total amOlt!\t ofrciimds to consumers, 11 tcrms of units and dollars, that each
Respondent has made fen each of the challenged produc!s for each year Lrom 200 I to the prescnt.
Res pOD"-C
Respondents incorporate by reCerence each General Objection as set f0I1h here in lull
Respondents ntt1her objects to this interrogatory on the Ic)llowLng grounds (a) it is vabruc and ambiguous: (b) it is overly broad and unduly burdensome: (c) it seeks irrelevant iniormation and information not reasonably calculated to lead to the discovery of admissible evidence (the
!equestcd information has no relationsbip to the alleged false or misleading advertising claims that Complaint Counsel pursues in this matter), and (d) it seeks information protected from disclosure by the attorney-cliettt privilege, work pr oduct doctrinc , andlor right of privacy, including fmanciaJ privacy
Rcspectfully submLtted this /1 , day of August, 2004
(- 5- iJ.!;!fREY D FELDMAN . (j) - - - "'., -
Docker No 'JJ 1 B
CERTIFICATE OF SERVICE
I IIEREBY CERTIFY that a true and cOr/eet copy of the foregoing was provided to the f(dlowing parlies lilL . ddY of August, 2004 as 1(,llows
One (I) copy via e-mail attachment in Word document format to Commission Complaint Counsel , Laureen lCapin, Joshua S Millard , and Laura Schneider, all care of !i;;H;1Hi :d"t(. i;l dr(1)nr (h: !i5- m((fiJ1C. ischneiden( Ht\ l: with one (l) paper courtesy copy via U S Mail , First Class Postage Prepaid to Laureen Kapin, Bureau ol'Conslimer l'roteCl1OIl , Federal Trade Commission , Suite NJ-2122 , GOO Pennsylvania Avenue, N W Washington . D . 20580
(2) Onc (I) copy via U S MaIl, First Class Postage Prepaid to Stephen Nagm , Esq, Nagin Gallop & Figueredo , 3225 Aviation Avenue, Suite 301 , Miami , Florida 33131
(3) One (I) copy via U. S. Mail, First Class Postage Prepaid to Richard Burbidge Esq. Jefferson W . Gross, Esq and Andrew J. Dymek, Esq. , Burbidge & Mitchell . 215 South ';tate Street , Suite 920, Salt Lake City, Utah &4111 , Counsel 1(" Dennis Gay
(4) One (1) copy via U SMail, Firsl Class Postage Prepaid to Ronald F Price, Esq, Peters Scotield Price , A Professional Corporation , 340 Broadway Cenlre, II t East Broadway, Salt Lake City, Utah 1111 Counsel for Daniel B Mowrey
(5) One (I) eopy via U S Mati, First Class Postage Prepaid to Mitchell K Fnedlander, 5742 West Harold Gatty Drive, Salt Lake City, Utah 84116, Pro Se
J9f.frey Feldman RESTRICTED, CONFIDENTI ATTORNEYS EYES ONL Y FTC DOCKET NO. 9318
EXHIBIT A __-
Culliu!' ' .!r 9.edjent % per Formula
1. -'- - "
'M : Ucrmali APg
- Ir J. % perFormula j ummv FI4Ittening. Gci
Ingredient - - - Yo !:ula
e-\e .-- - -
Anorcx Raw Amount ofElcmcntallngredients Ingredient raw (caffeine, ephedrine alkaloids ingredient !JIll DaiiyVaiue Raw ingredient my/serving vitamin &. mineral) pcrserl/ing (mg) for mg/capsulc forlabel roduction _.- " -
jent; LcotoPrin nOU ;;Ele;nentat I"gre Raw raW - (carfeine, ePI1edrinea1kaIOid oj,0 0 al IY V- due ingredient Ingredient vitamin & mineral) per serving Raw ingredient rug/serving mg/capsule Imq) - . - - " -- ..-- -"-"--_ ._------
;R:' Pedia11 mqfC Raw ingr dient 1- mgfserving --/,;- .)--- /'' . --\,-:=-,.-'- _._---.. :\~~~:,- . ---.,j.--.- -'_.-.. -;/; ...... _: :-- ,_.:::'_--- -_..-..-' .--,/,. , / " - , :-) - -
VERIFICATION
Answers to I Carla R Fobbs bein" dulv authorlled 10 execute the aroresaid . LLC , AG Complaint Counsel' s First Set or InterrogatoficS on behalf of Basic Research , LLC , Nutrasport, L.LC , and Savage Dermalogic Waterhouse, LLC, Klein- Becker usa , hereby state that foregoing Laboratories. LLC, having read and reviewed said answers answers arc true and correct to the best or my knowJcdge and beliet-
FURTHER AFFIANT SA YETI- NAUGHT
CHC("L l:i:y\-- CARLAR FOBBS
STA TJ, 011 UTAU :ss. COUNTY OF SALT LAKE) , 2004 by CARl SWORN TO AND SUBSCRIBED before me this 16th day or August
has produced J2LU1fiLj R. FOBBS , who is personally known to me ):J! /f.'-.3 f7'- 3 ( Identification
rli/! 1):. ,, l/ '''i L-, . Notary Public, State of Utah
//"J 7'::/ l//7 I- My Commission Expires. L/
)-(11,\10 PUBLIC i ,- D. IL MICHAELIS iV;." :IU:1SPLdJOOI1WJ\' !fJ. i: td LM,F ri !n!\tI) 'i" Q,:Q:2ik' )Jj"' 1"" 1'. :tP:"I: "1!' . r: I' I C I.r i. I! I: . :"'1) 7 l-_