DOCSLIB.ORG

United States Patent 19 11 Patent Number: 5,409,690 Howell Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
United States Patent 19 11 Patent Number: 5,409,690 Howell Et Al USOO5409690A United States Patent 19 11 Patent Number: 5,409,690 Howell et al. (45) Date of Patent: Apr. 25, 1995 54 TREATMENT OF MULTIDRUG RESISTANT Primary Examiner-Raymond Henley, III DISEASES IN CANCER CELL BY Assistant Examiner-T. J. Criares POTENTATING WITH MASOPROCOL Attorney, Agent, or Firm-Weiser & Associates 75) Inventors: Stephen Howell, Del Mar, Calif.; Atul Khandwala, Edgewater, N.J.; Om P. 57 ABSTRACT Sachdev, New City, N.Y.; Charles G. Disclosed are: a method for reversing multidrug resis Smith, Rancho Santa Fe, Calif. tance in a mammal; and a composition to reverse multi 73) Assignee: Chemex Pharmaceuticals, Inc., Fort drug resistance comprising: Lee, N.J. 21 Appl. No.: 81,663 is is , is R9 22 Filed: Jun. 23, 1993 R1O g--- 51) Int. Cl. ..................... A61K 48/00; A61K 31/70; R10 R11 R12 R13 R8 A61K 31/045 R2O R7 52 U.S. C. ........................................ 424/10; 514/34; 514/727; 514/731 wherein 58 Field of Search ......................... 514/34, 7. R1 and R2 are independently H, lower alkyl or lower acyl; (56) References Cited R3, R4 and R5 are independently H or lower alkyl; U.S. PATENT DOCUMENTS R7, R8 and R9 are independently H, hydroxy, lower alkoxy or lower acyloxy; and 5,008,294 4/1991 Jordan et al. ....................... 514/73 R10, R11,y R12 and R13yIOXy are independently H or lower OTHER PUBLICATIONS alkyl, in a pharmaceutically acceptable vehicle. Carter et al; Chemotherapy of Cancer, Second Edition, A Wiley Medical Publication, 1981 pp. 361-365. 22 Claims, No Drawings 5,409,690 1. 2 brew tea which was the basis for a folk remedy that TREATMENT OF MULTIDRUG RESISTANT called for drinking the tea to cure colds, rheumatism DISEASES IN CANCER CELL BY POTENTIATING and other ailments. However, this remedy has not WITH MASOPROCOL proven to be successful. A clinical study was conducted by Smart et al, re BACKGROUND OF THE INVENTION ported in U.S. Pat. No. 4,880,637, in which human can Field of the Invention cer patients ingested either a tea made form the creosote This invention relates to a method of preventing bush or doses of pure NDGA. This study indicated that development of multidrug resistance (hereinafter neither NDGA nor the tea were effective anticancer MDR) and to a method of reversing MDR if one al 10 agents and in some cases caused stimulation of tumor ready exists thereby to prevent or correct drug accumu cell growth. This confirmed the earlier screening stud lation defect in drug resistant cells. More particularly, ies of NDGA conducted by Leiter et all of the Cancer the invention relates to the administration of maso Chemotherapy National Service Center of National procol along with antineoplastic/cytotoxic drugs to Cancer Institute which obtained negative results when which cells develop multidrug resistance (MDR), e.g. 15 NDGA was tested against several types of cancer cells. Doxorubicin, Daunorubicin, Amsacrine Mitoxantrone, It has been reported in U.S. Pat. No. 4,880,637 that Dactinomycin, Ellipticine, Etoposide, Teniposide, NDGA and its analogues in combination with ionic zinc Chlorambucil, Melphalan, Cyclophosphamide, Ni is effective in the treatment of benign, paramalignant trosoureas BCNU, CCNU, MeCCNU), Methotrexate, and malignant growth of the skin without detrimental Trimetrexate, 5-FU, Ara-C, Ara-A, Cisplatin, Carbo 20 side effects associated with chemotherapy or chemosur platin and Taxol. gical techniques. Reported Developments NDGA was also reported in U.S. Pat. No. 4,695,590, Patients having solid malignant tumors e.g., breast, as having efficacy in retarding senescence or aging in ovarian, lung, colon and hematological malignant disor mammals. ders, such as refractory myeloma, often develop MDR 25 To our knowledge, NDGA in combination with . MDR is associated with the overexpression of an other cytotoxic/antineoplastic chemotherapeutic drugs MDR-1 gene that codes for a plasma membrane P glycoprotein. The expression of the MDR-1 gene is is not known, nor have been reported to inhibit multi believed to be associated with a decreased cellular accu drug resistance associated with the treatment of solid mulation of drug due to an active energy dependent 30 malignant tumors or hematological disorders in mam efflux mechanism. The active efflux of drug is believed mals. to be mediated by the P-glycoprotein efflux pump. In the modern clinical oncology practice, it has been Attempts have been made to reverse MDR and to established that overexpression of P-glycoprotein (Pgp) correct the drug accumulation defect in drug resistant in cancer patients is directly related to the increase in cells. Among the agents which show promise in vitro 35 the multidrug resistance (MDR) to treatment with pres are verapamil, quinidine, amioderone, cyclosporin and ently available chemotherapies. The present inventors certain phenothiazines. It appears, however, that in have discovered that masoprocol (NDGA) overcomes vivo concentrations necessary to reverse MDR cannot the Pgp mediated resistance and Pgp antagonism of the be achieved without substantial toxicity to patients. cells, thereby increasing the levels of chemotherapeutic drugs which accumulate in the cancer cells. SUMMARY OF THE INVENTION The present invention provides a method and compo Masoprocol is new MDR modulating agent. We have sition for the inhibition and/or reversal of multidrug discovered that the combination of masoprocol known resistant phenomenon in a patient and thereby treatment as nordihydroguaiaretic acid (hereinafter sometimes of solid malignant tumors and hematological malignan referred to as NDGA) or certain analogues thereof in 45 cies comprising the administration of NDGA to said combination with cytotoxic agents, e.g. Doxorubicin, patient preferably in a pharmaceutically acceptable Daunorubicin, Amsacrine, Mitoxantrone, Dactinomy vehicle. cin, Ellipticine, Etoposide, Teniposide, Chlorambucil, The general formula comprises of from about 0.1% to Melphalan, Cyclophosphamide, Nitrosoureas (BCNU, about 25% NDGA or an analogue thereof in a pharma CCNU, MeCCNU), Methotrexate, Trimetrexate, 5-FU, 50 ceutically acceptable vehicle for topical application or Ara-C, Ara-A, Cisplatin, Carboplatin and Taxol can of from about 1 mg NDGA to about 500 mg of NDGA overcome multidrug resistance of certain diseased cells per kg of body weight for systemic administration. and has the potential of being effective in the treatment NDGA and its analogues used in the present inven of solid malignant tumors e.g., brain, breast, colon, lung, tion have the following Formula (I): ovarian cancers and hematological malignant disorders 55 including lymphoma, leukemia (acute nonlymphocytic leukemia, acute myelocytic leukemia), or increase the is is , is /y-R. " therapeutic effectiveness of the above-mentioned cyto toxic agents. R1O-(U)---- The naturally occurring meso form of the nordihy R10R11 R12 R13 R8 droguaiaretic acid meso- 1,4-bis (3,4-dihydroxy R2O R7 phenyl)-2,3-dimethylbutane ("NDGA') was reported as providing a positive result against malignant mela wherein noma. C. R. Smart, et al, Rocky Mountain Medical Jour R1 and R2 are independently H, lower alkyl or lower nal, November 1970, pp.39-43. (Unless otherwise indi 65 acyl; cated, NDGA is used herein to refer to the meso form R3, R4, R5, and Ré are independently H or lower of nordihydroguaiaretic acid). NDGA is found in the alkyl; R7, R8 and R9 are independently H, hydroxy, creosote bush, and this plant was used for centuries to lower alkoxy or lower acyloxy; and 5,409,690 3 4 R10, R11, R12 and R13 are independently H or lower be adjusted by methods well known in the art, for exam alkyl. ple, by the use of a higher molecular weight polyethyl Lower alkyl is intended to generally mean C1-C6 ene glycol. alkyl, and preferably R3 and R4 are C1-C3 alkyl. Lower In addition to NDGA, the formulation can contain acyl is intended to generally mean C1-C6 acyl, with pharmacologically-acceptable additives or adjuvants C2-C6 acyl being preferred. The formula is directed to such as antimicrobial agents, e.g. methyl, ethyl, propyl both the phenolic compounds and the conventional and butyl esters of parahydroxybenzoic acid as well as esters and ethers thereof. chlorobutanol, phenol, ascorbic acid, etc. The formula tion can also contain thickening or gelling agents, emul DETAILED DESCRIPTION OF THE 10 sifiers, wetting agents, coloring agents, buffers, stabiliz INVENTION ers and preservatives including antioxidants such as NDGA and its analogues (also referred to herein as butylhydroxyanisole in accordance with the practice of catecholic butanes) according to the present invention, the art. The formulation can also contain penetration may be made by the synthetic methods provided in U.S. enhancers such as dimethylsulfoxide, long-chain alco Pat. Nos. 4,562,298 and 4,954,659 which are incorpo 15 hols such as nonoxynol, long-chain carboxylic acids, rated herein by reference in their entirety. propylene glycol, N-(2-hydroxyethyl)pyrrolidone, 1 Examples of catecholic butanes include: the d-, 1 dodecyl-azacycloheptan-2-one, and the like. Depending racemic mixture of d- and 1-, meso-isomers of 1,4- on the method of application and the disease being bis(3,4-dihydroxyphenyl)-2,3-dimethylbutane; 1,4- treated, it may be desirable to use absorption-delaying bis(3,4-dihydroxyphenyl)butane; 1,4-bis(3,4-dimethoxy 20 agents such as aluminum monostearate and gelatin. phenyl)-2,3-dimethylbutane; 1,4-bis(3,4-diethoxy The compositions of the formulation can be adjusted phenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipropoxy using components well-known in the formulation art to phenyl)-2,3-dimethylbutane; 1-(3,4-dihydroxyphenyl)- provide a pharmaceutical formulation which is a gel, 4-(3',4',5'-trihydroxyphenyl)butane; 1,4-bis(3,4- cream, ointment, solid, liquid, semi-solid, etc. The par diacetoxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4-dipro 25 ticular physical form of the formulation depends on the pionyloxyphenyl)2,3-dimethylbutane; 1,4-bis(3,4- desired method of treatment and the patient to be dibutyroyloxyphenyl)-2,3-dimethylbutane; 1,4-bis(3,4- treated.
Load more

Recommended publications
  • Title 16. Crimes and Offenses Chapter 13. Controlled Substances Article 1
    TITLE 16. CRIMES AND OFFENSES CHAPTER 13. CONTROLLED SUBSTANCES ARTICLE 1. GENERAL PROVISIONS § 16-13-1. Drug related objects (a) As used in this Code section, the term: (1) "Controlled substance" shall have the same meaning as defined in Article 2 of this chapter, relating to controlled substances. For the purposes of this Code section, the term "controlled substance" shall include marijuana as defined by paragraph (16) of Code Section 16-13-21. (2) "Dangerous drug" shall have the same meaning as defined in Article 3 of this chapter, relating to dangerous drugs. (3) "Drug related object" means any machine, instrument, tool, equipment, contrivance, or device which an average person would reasonably conclude is intended to be used for one or more of the following purposes: (A) To introduce into the human body any dangerous drug or controlled substance under circumstances in violation of the laws of this state; (B) To enhance the effect on the human body of any dangerous drug or controlled substance under circumstances in violation of the laws of this state; (C) To conceal any quantity of any dangerous drug or controlled substance under circumstances in violation of the laws of this state; or (D) To test the strength, effectiveness, or purity of any dangerous drug or controlled substance under circumstances in violation of the laws of this state. (4) "Knowingly" means having general knowledge that a machine, instrument, tool, item of equipment, contrivance, or device is a drug related object or having reasonable grounds to believe that any such object is or may, to an average person, appear to be a drug related object.
    [Show full text]
  • Pharmaceuticals As Environmental Contaminants
    PharmaceuticalsPharmaceuticals asas EnvironmentalEnvironmental Contaminants:Contaminants: anan OverviewOverview ofof thethe ScienceScience Christian G. Daughton, Ph.D. Chief, Environmental Chemistry Branch Environmental Sciences Division National Exposure Research Laboratory Office of Research and Development Environmental Protection Agency Las Vegas, Nevada 89119 [email protected] Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Why and how do drugs contaminate the environment? What might it all mean? How do we prevent it? Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada This talk presents only a cursory overview of some of the many science issues surrounding the topic of pharmaceuticals as environmental contaminants Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada A Clarification We sometimes loosely (but incorrectly) refer to drugs, medicines, medications, or pharmaceuticals as being the substances that contaminant the environment. The actual environmental contaminants, however, are the active pharmaceutical ingredients – APIs. These terms are all often used interchangeably Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Office of Research and Development Available: http://www.epa.gov/nerlesd1/chemistry/pharma/image/drawing.pdfNational
    [Show full text]
  • Photodynamic Therapy for the Treatment of Actinic Keratoses and Other Skin Lesions
    Photodynamic Therapy for the Treatment of Actinic Keratoses and Other Skin Lesions Policy Number: Current Effective Date: MM.02.016 March 22, 2019 Lines of Business: Original Effective Date: HMO; PPO; QUEST Integration April 01, 2008 Place of Service: Precertification: Office Not Required I. Description Photodynamic therapy (PDT) refers to light activation of a photosensitizer to generate highly reactive intermediaries, which ultimately cause tissue injury and necrosis. Photosensitizing agents are being proposed for use with dermatologic conditions such as actinic keratoses and nonmelanoma skin cancers.For individuals who have nonhyperkeratotic actinic keratoses on the face or scalp who receive PDT, the evidence includes randomized controlled trials (RCTs). The relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. Evidence from multiple RCTs has found that PDT improves the net health outcome in patients with nonhyperkeratotic actinic keratoses on the face or scalp compared with placebo or other active interventions. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. For individuals who have low-risk basal cell carcinoma who receive PDT, the evidence includes RCTs and systematic reviews of RCTs. The relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. Systematic reviews of RCTs have found that PDT may not be as effective as surgery for superficial and nodular basal cell carcinoma. In the small number of trials available, PDT was more effective than placebo. The available evidence from RCTs has suggested that PDT has better cosmetic outcomes than surgery.
    [Show full text]
  • Wo 2010/068920 A2
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 17 June 2010 (17.06.2010) WO 2010/068920 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 239/78 (2006.01) A61P 31/04 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/51 7 (2006.01) A61P 35/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) Number: International Application DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2009/067749 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 11 December 2009 ( 11.12.2009) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (26) Publication Language: English TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/121,965 12 December 2008 (12.12.2008) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): AUS- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, PEX PHARMACEUTICAL, INC.
    [Show full text]
  • Aacr Cancer Progress Report
    AACR CANCER PROGRESS REPORT CANCER PROGRESS AACR 615 Chestnut Street, 17th Floor, Philadelphia, PA 19106-4404 2017 AACR CANCER PROGRESS REPORT 2017 Harnessing Research Discoveries to Save Lives AACR.org CancerProgressReport.org #CancerProgress17 For your FREE copy of the full report, go to www.CancerProgressReport.org AACR CANCER PROGRESS REPORT 2017 Harnessing Research Discoveries to Save Lives AACR.org CancerProgressReport.org #CancerProgress17 Please cite this report as: cancerprogressreport.org [Internet]. Philadelphia: American Association for Cancer Research; ©2017 [cited year month date]. Available from http://www.cancerprogressreport.org/. HARNESSING RESEARCH TABLE OF DISCOVERIES TO SAVE LIVES 48 Biomedical Research 48 CONTENTS Progress across the Clinical Cancer Care Continuum 54 Cancer Prevention, Detection, and Diagnosis 54 Simplifying the HPV Vaccination Schedule 54 Enhancing Cancer Detection AACR CANCER PROGRESS and Diagnosis with Technology 54 REPORT 2017 STEERING COMMITTEE iii Treatment with Surgery, Radiotherapy, and Cytotoxic Chemotherapy 56 AACR STAFF iv Improving Outcomes by Combining Existing Treatments 56 Reducing the Adverse Effects of Surgery 56 A MESSAGE FROM THE AACR 1 Tailoring Radiotherapy: Less Is Sometimes More 57 EXECUTIVE SUMMARY 3 Treatment with Molecularly Targeted Therapeutics 57 Cancer in 2017 3 Adding Precision to Treatment for Acute Myeloid Leukemia 61 Targeting Soft Tissue Sarcoma 62 Preventing Cancer: Understanding Risk Factors 4 Increasing Options for Patients with Ovarian Cancer 64 Screening for
    [Show full text]
  • 2.01.44 Dermatologic Applications of Photodynamic Therapy
    Medical Policy 2.01.44 Dermatologic Applications of Photodynamic Therapy Original Policy Date: June 1, 2001 Effective Date: February 1, 2021 Section: 2.0 Medicine Page: Page 1 of 30 Policy Statement Photodynamic therapy may be considered medically necessary as a treatment of any of the following: I. Nonhyperkeratotic actinic keratoses of the face and scalp (see policy guidelines) II. Nonhyperkeratotic actinic keratoses of the upper extremities (see policy guidelines) III. Low-risk (e.g., superficial and nodular) basal cell skin cancer only when surgery and radiation are contraindicated IV. Cutaneous squamous cell carcinoma in situ (Bowen disease) only when surgery and radiation are contraindicated Photodynamic therapy is considered investigational for other dermatologic applications, including, but not limited to: I. Acne vulgaris II. Hidradenitis suppurativa III. High-risk basal cell carcinomas IV. Mycoses Photodynamic therapy is considered not medically necessary as a technique of any of the following: I. Altering normal structures of the body in order to improve appearance II. Hair removal III. Skin rejuvenation NOTE: Refer to Appendix A to see the policy statement changes (if any) from the previous version. Policy Guidelines Surgery and radiation are the preferred treatments for low-risk basal cell cancer and Bowen disease (see Rationale section). If photodynamic therapy is selected for these indications because of contraindications to surgery or radiation, patients and physicians need to be aware that it may have a lower cure rate than surgery or radiation. Photodynamic therapy typically involves 2 office visits: 1 to apply the topical aminolevulinic acid and a second visit to expose the patient to blue light.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2002/0010208A1 Shashoua Et Al
    US 2002001 0208A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0010208A1 Shashoua et al. (43) Pub. Date: Jan. 24, 2002 (54) DHA-PHARMACEUTICAL AGENT Related U.S. Application Data CONJUGATES OF TAXANES (63) Continuation of application No. 09/135,291, filed on (76) Inventors: Victor Shashoua, Brookline, MA (US); Aug. 17, 1998, now abandoned, which is a continu Charles Swindell, Merion, PA (US); ation of application No. 08/651,312, filed on May 22, Nigel Webb, Bryn Mawr, PA (US); 1996, now Pat. No. 5,795,909. Matthews Bradley, Layton, PA (US) Publication Classification Correspondence Address: Edward R. Gates, Esq. (51) Int. Cl." ............................................ A61K 31/337 Wolf, Greenfield & Sacks, P.C. (52) U.S. Cl. .............................................................. 514/449 600 Atlantic Avenue Boston, MA 02210 (US) (57) ABSTRACT The invention provides conjugates of cis-docosahexaenoic (21) Appl. No.: 09/846,838 acid and pharmaceutical agents useful in treating noncentral nervous System conditions. Methods for Selectively target 22) Filled: Mayy 1, 2001 ingg pharmaceuticalp agents9. to desired tissues are pprovided. Patent Application Publication Jan. 24, 2002 Sheet 1 of 14 US 2002/0010208A1 1 OO 5 O -5OO - 1 OO-9 -8 -7 -6 -5 -4 LOG-10 OF SAMPLE CONCENTRATION (MOLAR) CCRF-CEM-o- SR ----- RPM-8226----- K-562- - -A - - HL-60 (TB) -g- - MOLT4: ... O Fig. 1 1 OO 5 O -5OO -1 O O -8 -7 -6 -5 -4 -- 9 LOGo OF SAMPLE CONCENTRATION (MOLAR) A549/ATCC-o-NS326. NCEKVX 28. --Q-- NCI-H322M-...-a---Eidsf8::... NC-H522--O-- HOP-62---Fig. 2 a-- NC-H460.-------- Patent Application Publication Jan.
    [Show full text]
  • Pharmaceutical Compositions and Dosage Forms of Thalidomide
    (19) & (11) EP 2 277 512 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 26.01.2011 Bulletin 2011/04 A61K 9/48 (2006.01) A61K 9/20 (2006.01) A61K 31/454 (2006.01) (21) Application number: 10175930.6 (22) Date of filing: 13.11.2003 (84) Designated Contracting States: (72) Inventor: D’Angio, Paul AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Basking Ridge, NJ 07929 (US) HU IE IT LI LU MC NL PT RO SE SI SK TR Designated Extension States: (74) Representative: Ritter, Thomas Kurt AL LT LV MK Jones Day Prinzregentenstraße 11 (30) Priority: 14.11.2002 US 426016 P 80538 München (DE) (62) Document number(s) of the earlier application(s) in Remarks: accordance with Art. 76 EPC: This application was filed on 09-09-2010 as a 03783567.5 / 1 562 556 divisional application to the application mentioned under INID code 62. (71) Applicant: CELGENE CORPORATION Summit New Jersey 07901 (US) (54) Pharmaceutical compositions and dosage forms of thalidomide (57) Pharmaceutical compositions and single unit not limited to, leprosy, chronic graft-vs-host disease, dosage forms of thalidomide and pharmaceutically ac- rheumatoid arthritis, sarcoidosis, an inflammatory condi- ceptable prodrugs, salts, solvates, hydrates, or clath- tion, inflammatory bowel disease, and cancer using the rates are disclosed. Also disclosed are methods of treat- novel dosage forms disclosed herein. ing and preventing diseases and conditions such as, but EP 2 277 512 A2 Printed by Jouve, 75001 PARIS (FR) EP 2 277 512 A2 Description [0001] This application claims priority to provisional application no.
    [Show full text]
  • Download Supplementary
    Supplementary table 1: List of drugs and their binding energies to ACE1 and ACE2. Human ACE1 Human ACE2 Binding energy Binding energy Ligand (kcal/mol) (kcal/mol) (S)-NICARDIPINE -8.6 -6.0 (S)-NITRENDIPINE -7.5 -6.5 17-BETA ESTRADIOL -8.2 -5.7 4-AMINOPYRIDINE -3.9 -4.0 4-PHENYLAMINO-3-QUINOLINECARBONITRILE -8.2 -6.5 ABACAVIR -8.2 -6.3 ABARELIX -6.0 -4.4 ABEMACICLIB -9.1 -6.7 ABIRATERONE ACETATE -9.8 -7.0 ACALABRUTINIB -9.6 -7.2 ACAMPROSATE -5.7 -4.5 ACARBOSE -8.2 -6.0 ACEBUTOLOL -7.3 -5.6 ACETAMINOPHEN -5.5 -5.6 ACETAZOLAMIDE -6.2 -5.1 ACETOHEXAMIDE -8.6 -6.3 ACETOHYDROXAMIC ACID -3.9 -3.5 ACETOPHENAZINE -8.0 -6.2 ACETYLCHOLINE -4.3 -3.5 ACETYLCYSTEINE -4.7 -3.9 ACETYLDIGITOXIN -10.0 -7.1 ACRISORCIN -5.9 -5.8 ACYCLOVIR -6.7 -5.2 ADAPALENE -9.2 -7.3 ADEFOVIR DIPIVOXIL -7.6 -4.8 ADENOSINE -7.0 -5.5 ALATROFLOXACIN -10.6 -6.4 ALBENDAZOLE -6.9 -5.2 ALBUTEROL -6.6 -5.2 ALCAFTADINE -9.0 -5.8 ALCLOMETASONE DIPROPIONATE -8.6 -6.5 ALFENTANIL -7.4 -4.9 ALFUZOSIN -7.7 -5.6 ALISKIREN -7.5 -5.9 ALITRETINOIN -7.4 -5.6 ALLOPURINOL -5.6 -5.1 ALMOTRIPTAN -7.0 -6.0 ALOSETRON -8.3 -6.4 ALPELISIB -8.7 -6.6 ALPHA-TOCOPHEROL -7.4 -5.8 ALPHA-TOCOPHEROL ACETATE -7.8 -5.6 ALPRAZOLAM -8.6 -5.9 ALPROSTADIL -6.2 -5.3 ALTRETAMINE -5.1 -4.1 ALVIMOPAN -8.3 -6.4 AMANTADINE -5.5 -4.6 AMBENONIUM -7.6 -5.5 AMBRISENTAN -7.8 -5.2 AMCINONIDE -10.7 -7.4 AMDINOCILLIN -7.1 -5.8 AMIFAMPRIDINE -4.1 -4.2 AMIFOSTINE -4.8 -3.8 AMIKACIN -7.2 -5.4 AMILORIDE -6.4 -5.9 AMINOCAPROIC ACID -4.9 -4.4 AMINOGLUTETHIMIDE -7.4 -5.7 AMINOLEVULINIC ACID -4.7 -5.3 AMINOMETHYLBENZOIC ACID -6.4 -3.9
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9.468,603 B2 Mcchesney Et Al
    USOO9468603B2 (12) United States Patent (10) Patent No.: US 9.468,603 B2 McChesney et al. (45) Date of Patent: Oct. 18, 2016 (54) NANOPARTICULATE COMPOSITIONS FOR A61 K3I/7076 (2013.01); A61K 45/06 TARGETED DELIVERY OF ACID LABILE, (2013.01); A61K 47/48061 (2013.01) LIPOPHILIC PRODRUGS OF CANCER (58) Field of Classification Search CHEMOTHERAPEUTICS AND THEIR CPC ........... A61K 47/48061; A61K 45/06; A61 K PREPARATION 9/0019; A61K 9/5123; C07D 305/14: CO7D 314/24: CO7D 407/12: C07D 487/04; C07D (71) Applicant: Arbor Therapeutics, LLC, Etta, MS 491/14: CO7D 493/06; C07D 493/08: C07D (US) 519700 See application file for complete search history. (72) Inventors: James D. McChesney, Etta, MS (US); Igor Nikoulin, San Diego, CA (US); (56) References Cited Steve J. Bannister, Tampa, FL (US); Douglas L. Rodenburg, Thaxton, MS U.S. PATENT DOCUMENTS (US) 4,762,720 A * 8/1988 Jizomoto ............. A61K9/1277 264/4.1 (73) Assignee: ARBOR THERAPEUTICS, LLC, 8.440,714 B2 * 5/2013 McChesney ......... CO7D 305,14 Etta, MS (US) 514,449 2004/0213837 A1* 10/2004 Mantripragada ...... A61K 9,127 424/450 (*) Notice: Subject to any disclaimer, the term of this 2011 0077291 A1* 3, 2011 Chen .................... A61K9/0019 patent is extended or adjusted under 35 514,449 U.S.C. 154(b) by 0 days. 2012/030861.6 A1* 12/2012 Liu ...................... A61K9/0019 424/400 (21) Appl. No.: 14/485,713 2012/0309819 A1 12/2012 McChesney 2015,0297749 A1* 10, 2015 Hahn ................. A61K 49, 1839 (22) Filed: Sep. 13, 2014 424, 1.37 (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2015/OO79189 A1 Mar.
    [Show full text]
  • Emerging Strategies for Cancer Immunoprevention
    Oncogene (2015) 34, 6029–6039 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW Emerging strategies for cancer immunoprevention JC Roeser1, SD Leach2 and F McAllister3 The crucial role of the immune system in the formation and progression of tumors has been widely accepted. On one hand, the surveillance role of the immune system plays an important role in endogenous tumor prevention, but on the other hand, in some special circumstances such as in chronic inflammation, the immune system can actually contribute to the formation and progression of tumors. In recent years, there has been an explosion of novel targeted immunotherapies for advanced cancers. In the present manuscript, we explore known and potential various types of cancer prevention strategies and focus on nonvaccine- based cancer preventive strategies targeting the immune system at the early stages of tumorigenesis. Oncogene (2015) 34, 6029–6039; doi:10.1038/onc.2015.98; published online 14 September 2015 INTRODUCTION Differences between chemoprevention and immunoprevention. As cancer is a collection of multiple complex individual diseases Whereas immunoprevention focuses on directly or indirectly that happen in different sites of the body and progress in different targeting the immune system, chemopreventive strategies utilize ways, a large amount of information is required to understand drugs or natural compounds to prevent cancer development.3 how to prevent each cancer type. Existing interventions for cancer Less than a dozen chemopreventive agents have been FDA prevention focus on the use of chemopreventive agents or approved: tamoxifen and raloxifene for breast cancer fi prevention,4,5 celecoxib for colorectal polyps prevention in vaccines designed and tested for prevention of speci c cancer 6,7 8,9 types.
    [Show full text]
  • Review Article
    Review Article Photodynamic therapy in dermatology Chitra S. Nayak Department of Dermatology, BYL Nair Hospital and TN Medial College, Mumbai, India Address for correspondence: Chitra S. Nayak, 302, Arun, 6th Road, Santacruz East, Mumbai - 400055, India. E-mail: [email protected] ABSTRACT Photodynamic therapy is a new modality of therapy being used for the diagnosis and treatment of many tumors. It is now being increasingly used for skin tumors and other dermatological disorders. With its range of application it is certainly the therapy of the future. Its mechanism of action is by the Type II photo-oxidative reaction. The variables are the photosensitizer, the tissue oxygenation and the light source. It has been used to treat various disorders including Bowen’s disease, actinic keratoses, squamous cell carcinomas, basal cell carcinomas, and mycosis fungoides. The side-effects are fortunately mild and transient. Newer photosensitisers like methyl aminolevulinate hold a lot of promise for better therapy. Key Words: Photosensitizer, Light source, Aminolevulinate HISTORY in the target cells followed by selective irradiation of the lesion with visible light. The drug and light are The use of sunlight for the treatment of various skin individually non-toxic, but in combination destroy disorders (heliotherapy) was known to ancient Indians tissues. and Greeks. In the modern era, Oscar Raab, a German medical student first reported the death of Paramecium MECHANISM OF ACTION caudatum (a protozoan) after light exposure in the presence of acridine orange in the year 1900.[1] His The efficacy of PDT depends on all the following professor, von Tappeiner, coined the term mechanisms which are inter-linked: direct cytotoxicity, “photodynamic” to describe oxygen-consuming vascular damage, inflammation and immune host chemical reactions in vivo.
    [Show full text]