DOCSLIB.ORG

Canton Final FDA Paper.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Canton Final FDA Paper.Pdf The Elusive Silver Bullet: FDA Failures, Rejected New Drug Applications, and the Search for an Obesity Cure The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Allison Nina Canton, The Elusive Silver Bullet: FDA Failures, Rejected New Drug Applications, and the Search for an Obesity Cure (March 2011). Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:8789607 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA The Elusive Silver Bullet: FDA Failures, Rejected New Drug Applications, and the Search for an Obesity Cure Allison N. Canton Class of 2012 March 2011 This paper is submitted in satisfaction of the course requirement for: Food and Drug Law Professor Peter Barton Hutt Winter 2011 Abstract: Over the past forty-five years, America has fallen victim to an obesity epidemic, affecting more than thirty percent of American adults. If the incidence of obesity continues at current rates, an estimated forty-percent of Americans will be obese by 2018. Despite its widespread prevalence, treatment is limited to lifestyle modification, surgery, and pharmacotherapy. With lifestyle modification proven to be largely ineffective, surgical options reserved only for the severely obese, and only one long-term drug on the market, there is a vacuum in obesity treatment options. Moreover, the Food and Drug Administration recently rejected three promising drugs. In this paper, I review the obesity problem facing America and describe the history of anti-obesity pharmaceuticals. After examining the three recently rejected drug applications, I bring to light FDA’s new priorities and offer an alternative framework for thinking about pharmacology to guide anti-obesity drug development and review. TABLE OF CONTENTS I. INTRODUCTION ................................................................................................................................ 1 II. OVERVIEW OF THE OBESITY PROBLEM IN THE US ........................................................... 1 A. DEMOGRAPHICS AND PREVALENCE .................................................................................................. 1 B. THEORIES BEHIND THE GROWING OBESITY RATES .......................................................................... 3 C. OBESITY’S TOLL: INCREASED MORBIDITY & MORTALITY AND INDIRECT COSTS ........................... 3 III. OVERVIEW OF THE CURRENT ANTI-OBESITY DRUG MARKET .................................... 4 A. THE CURRENT MARKET .................................................................................................................... 5 i. Phentermine ................................................................................................................................... 5 ii. Diethylpropion (Tenuate).............................................................................................................. 6 iii. Orlistat (Xenical/Alli)................................................................................................................... 7 B. FDA FAILURES .................................................................................................................................. 8 i. Fen-Phen (1997) and Dexfenfluramine (Redux) (1997) ................................................................ 9 ii. Sibutramine (Meridia) (2010) ..................................................................................................... 13 IV. AN EXAMINATION OF THREE RECENTLY-REJECTED WEIGHT LOSS NDAS .......... 16 A. THE LONG ROAD FROM DRUG DEVELOPMENT TO APPROVAL ....................................................... 16 B. GUIDELINES FOR APPROVAL OF A WEIGHT LOSS DRUG ................................................................. 17 C. RECENT REJECTED NEW DRUG APPLICATIONS............................................................................... 19 i. Qnexa (July 2010) ........................................................................................................................ 19 ii. Lorcaserin (September 2010)...................................................................................................... 24 iii. Contrave (December 2010)........................................................................................................ 28 V. THE IMPACT OF NON-APPROVAL ........................................................................................... 31 VI. LOOKING AHEAD......................................................................................................................... 33 VII. CONCLUSION ............................................................................................................................... 37 I. INTRODUCTION With FDA’s rejection of Contrave’s new drug application (NDA), the third anti-obesity drug rejected in the past nine months, the Internet was ablaze with predictions that the anti- obesity pharmaceutical market was effectively dead. Some incensed critics alleged that FDA didn’t care enough about obese Americans to let innovative new drugs come to the market. An exploration of the history of the anti-obesity pharmaceutical market in the US, however, leads one to the opposite conclusion. FDA’s hesitancy to approve a new drug is a manifestation of the agency’s deep concern over patient safety. And given the history of FDA-approved anti-obesity drugs that turned out to be harmful, including Meridia, which was withdrawn from the market in October 2010, it’s hard to say that their concern is not well founded. In this paper, I will provide an overview of the obesity problem today in order to illustrate why a solution is urgently needed. Then, I will describe the history of anti-obesity pharmaceuticals in the US, paying particular attention to instances where FDA ultimately turned out to be wrong about the safety and efficacy of an approved drug. Next, I will chronicle three promising anti-obesity pharmaceuticals whose new drug applications (NDAs) were rejected in rapid succession over the past nine months. Finally, I will discuss the aftermath of non-approval of these NDAs and forecast an alternative framework to guide anti-obesity drug development and review. II. OVERVIEW OF THE OBESITY PROBLEM IN THE US a. DEMOGRAPHICS AND PREVALENCE According to the 2008 National Health and Nutrition Examination Survey (NHANES), seventy-four percent of Americans aged twenty and older are overweight or obese.1 Of these, 1 Cynthia L. Ogden and Margaret D. Carroll, Prevalence of Overweight, Obesity, and Extreme Obesity Among Adults: United States, Trends 1976-1980 Through 2007-2008 (2010). 1 almost half were considered obese (body mass index [BMI]2 of thirty or higher).3 These rates are alarming not only for their extreme prevalence among the American population, but also for their rapid growth over the past forty-five years. Specifically, while the percentage of overweight Americans has not significantly changed since 1976, the prevalence of obesity among adults between ages twenty and seventy-four more than doubled between 1976 and 2008.4 If the current obesity trend continues, some studies have estimated that 43% of the U.S. population will be obese by 2018.5 Public health professionals have characterized the situation to be of “epidemic” proportions.6 The obesity epidemic has a disparate impact on minority communities, especially among women. Non-Hispanic black women and Mexican-American women are far more likely (50% and 45%, respectively) to be obese than non-Hispanic white women (33%).7 Evidence also suggests disparities along class lines; 15% of children aged two to four year old from low- income households are obese.8 The prevalence of obesity varies across the nation. While none of the states in 2009 met the 15% obesity target set forth in Healthy People 2010, 9 obesity rates 2 BMI is a measure of body fat based on height and weight. An adult’s BMI is calculated by dividing her weight in kilograms by the square of her height in meters. A normal BMI is between 18.5 and 24.9. An individual is considered overweight if her BMI is between 25 and 29.9 and is clinically obese if her BMI is over 30. See Centers for Disease Control and Prevention, Healthy Weight: Assessing Your Weight: About BMI for Adults (2009), available at http://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html. 3 Ogden, supra note 1. 4 Id. 5 United Health Foundation et al., The Future Costs of Obesity: National and State Estimates of the Impact of Obesity on Direct Health Care Expense 9 (2009), available at http://www.fightchronicdisease.org/pdfs/costofobesityreport-final.pdf. 6 See, e.g., Youfa Wang and May A. Beydoun, The Obesity Epidemic in the United States—Gender, Age, Socioeconomic, Racial/Ethnic, and Geographic Characteristics: A Systematic Review and Meta-Regression Analysis, 29 Epidemiological Reviews 6-28 (2007). 7 Ogden, supra note 1. 8 National Center for Chronic Disease Prevention and Health Promotion, Obesity: Halting the Epidemic by Making Health Easier (2010). 9 U.S. Dep’t of Health and Human Services, Healthy People 2010: Nutrition and Overweight 19-11, available at http://www.healthypeople.gov/2010/Document/pdf/Volume2/19Nutrition.pdf 2 across the country ranged from 19% in Colorado to 34% in Mississippi.10 At least thirty percent of people were obese in
Load more

Recommended publications
  • Investigating Interactions Between Phentermine, Dexfenfluramine, and 5-HT2C Agonists, on Food Intake in the Rat
    Psychopharmacology DOI 10.1007/s00213-014-3829-2 ORIGINAL INVESTIGATION Investigating interactions between phentermine, dexfenfluramine, and 5-HT2C agonists, on food intake in the rat Andrew J. Grottick & Kevin Whelan & Erin K. Sanabria & Dominic P. Behan & Michael Morgan & Carleton Sage Received: 2 October 2014 /Accepted: 20 November 2014 # The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Conclusions Dex-phen synergy in the rat is caused by a Rationale Synergistic or supra-additive interactions between pharmacokinetic interaction, resulting in increased central the anorectics (dex)fenfluramine and phentermine have been concentrations of phentermine. reported previously in the rat and in the clinic. Studies with 5- HT2C antagonists and 5-HT2C knockouts have demonstrated Keywords Synergy . BELVIQ® . Lorcaserin . Isobologram . dexfenfluramine hypophagia in the rodent to be mediated by Fen-phen actions at the 5-HT2C receptor. Given the recent FDA approv- al of the selective 5-HT2C agonist lorcaserin (BELVIQ®) for weight management, we investigated the interaction between Introduction phentermine and 5-HT2C agonists on food intake. Objectives This study aims to confirm dexfenfluramine- Fenfluramine (Pondimin) and dexfenfluramine (Redux) are phentermine (dex-phen) synergy in a rat food intake assay, anorectic agents which act to enhance serotonergic transmission to extend these findings to other 5-HT2C agonists, and to both through inhibition of 5-HT reuptake by the parent com- determine whether pharmacokinetic interactions could ex- pounds, and through their major circulating des-ethylated me- plain synergistic findings with particular drug combinations. tabolite, (dex)norfenfluramine, which is a 5-HT reuptake inhib- Methods Isobolographic analyses were performed in which itor, a 5-HT and noradrenaline releasing agent, and a potent phentermine was paired with either dexfenfluramine, the 5- agonist at postsynaptic 5-HT2 receptors (Curzon et al.
    [Show full text]
  • Downloaded Popular in Europe, and the “Rave” (An All Night Dance Party) from the Web [4]
    The Open Forensic Science Journal, 2011, 4, 20-24 20 Open Access A Historical Review of MDMA Steven B. Karch* Berkeley, California 94705, USA Abstract: In less than 50 years the number of MDMA (3,4-Methylenedioxymethamphetamine or Ecstasy) users in the United States has gone from zero to nearly three million. For all of its popularity, very little is known about MDMA’s probable mechanism of action, or the mechanisms by which it causes death and disability. Even less is known about this drug’s checkered past, including dangerous plans by various government agencies to “weaponize” MDMA, and misleading research sponsored and propagated by the U.S. government. Recently, evidence has begun to emerge that MDMA may cause valvular heart disease and possibly myocardial disease as well. These issues have not yet appeared on the media radar. For that reason, an historical review of this fascinating drug was undertaken here. Keywords: Ecstacy, Shulgin, history, MK-Ultra, psychoactive, serotonin, empathogen, myocardial fibrosis, neurotoxicity. MDA, Club drugs, Raves. INTRODUCTION as a precursor compound, and never even evaluated MDMA’s basic physiologic properties until years after the Estimates of the United Nations suggest that in North patent for MDMA was actually awarded. America there are approximately 2.6 million MDMA (3,4- Methylenedioxymethamphetamine or Ecstasy) users, mostly Fifteen years passed before Merck made any effort to in the United States. The annual prevalence of MDMA use systematically evaluate MDMA’s pharmacologic effects in within the general U.S. population is approximately 0.9%, animals. The first experiments were carried out in 1927.
    [Show full text]
  • 212102Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212102Orig1s000 OTHER REVIEW(S) Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research | Office of Surveillance and Epidemiology (OSE) Epidemiology: ARIA Sufficiency Date: June 29, 2020 Reviewer: Silvia Perez-Vilar, PharmD, PhD Division of Epidemiology I Team Leader: Kira Leishear, PhD, MS Division of Epidemiology I Division Director: CAPT Sukhminder K. Sandhu, PhD, MPH, MS Division of Epidemiology I Subject: ARIA Sufficiency Memo for Fenfluramine-associated Valvular Heart Disease and Pulmonary Arterial Hypertension Drug Name(s): FINTEPLA (Fenfluramine hydrochloride, ZX008) Application Type/Number: NDA 212102 Submission Number: 212102/01 Applicant/sponsor: Zogenix, Inc. OSE RCM #: 2020-953 The original ARIA memo was dated June 23, 2020. This version, dated June 29, 2020, was amended to include “Assess a known serious risk” as FDAAA purpose (per Section 505(o)(3)(B)) to make it consistent with the approved labeling. The PMR development template refers to the original memo, dated June 23, 2020. Page 1 of 13 Reference ID: 46331494640015 EXECUTIVE SUMMARY (place “X” in appropriate boxes) Memo type -Initial -Interim -Final X X Source of safety concern -Peri-approval X X -Post-approval Is ARIA sufficient to help characterize the safety concern? Safety outcome Valvular Pulmonary heart arterial disease hypertension (VHD) (PAH) -Yes -No X X If “No”, please identify the area(s) of concern. -Surveillance or Study Population X X -Exposure -Outcome(s) of Interest X X -Covariate(s) of Interest X X -Surveillance Design/Analytic Tools Page 2 of 13 Reference ID: 46331494640015 1.
    [Show full text]
  • Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans
    molecules Review Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans Paul Cumming 1,2,* , Milan Scheidegger 3 , Dario Dornbierer 3, Mikael Palner 4,5,6 , Boris B. Quednow 3,7 and Chantal Martin-Soelch 8 1 Department of Nuclear Medicine, Bern University Hospital, CH-3010 Bern, Switzerland 2 School of Psychology and Counselling, Queensland University of Technology, Brisbane 4059, Australia 3 Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, CH-8032 Zurich, Switzerland; [email protected] (M.S.); [email protected] (D.D.); [email protected] (B.B.Q.) 4 Odense Department of Clinical Research, University of Southern Denmark, DK-5000 Odense, Denmark; [email protected] 5 Department of Nuclear Medicine, Odense University Hospital, DK-5000 Odense, Denmark 6 Neurobiology Research Unit, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark 7 Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, CH-8058 Zurich, Switzerland 8 Department of Psychology, University of Fribourg, CH-1700 Fribourg, Switzerland; [email protected] * Correspondence: [email protected] or [email protected] Abstract: Hallucinogens are a loosely defined group of compounds including LSD, N,N- dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), Citation: Cumming, P.; Scheidegger, which can evoke intense visual and emotional experiences. We are witnessing a renaissance of re- M.; Dornbierer, D.; Palner, M.; search interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. Quednow, B.B.; Martin-Soelch, C. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and Molecular and Functional Imaging ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or Studies of Psychedelic Drug Action in single photon emission computer tomography (SPECT).
    [Show full text]
  • Neural Control of Dieting Counting Species Names
    SCIENTIFIC CORRESPONDENCE supersensitivity, and also by acting, via its Neural control of dieting principal metabolite ( + )norfenfluramine, as an agonist at 5-HT2c receptors and SIR - Tecott et al. 1 have shown that trans­ 100 thereby directly inducing satiety. The genic mice lacking the receptor for 0 effects of dexfenf!uramine as an anorectic the 5-hydroxytryptamine neurotransmitter 75 agent in humans are abolished by the co­ subtype 5-HT2c become obese through administration of ritanserin 7• overeating, indicating a primary role for ~ These findings emphasize the role of this receptor in the satiety response; these dr 50 5-HT2c receptors in controlling food () animals do not respond to the 5-HT2c intake and satiety, and suggest that dex­ receptor agonist m-chlorophenylpiperazine 25 fenfluramine might reset the balance 2 (mCPP). Cowen et al. emphasized that between 5-HT release and 5-HT2c recep­ antagonists for this receptor, such as cloza­ tor stimulation. Further work is required 0 pine and mianserin, cause troublesome - 5 to define how control of this receptor weight-gain in people; clozapine abolishes system parallels other, recently described, the endocrine responses to mCPP in Cytosolic calcium levels in CHO cells trans­ sytems such as glucagon-like peptide-1 fected with the human recombinant 5-HT2c 3 9 10 humans • These authors showed that diet­ receptor. The concentration-response cu rve (ref. 8) and leptin • , to modulate satiety ing may be difficult because of an imbal­ for (+)norfenfluramine for increase in intracel­ and obesity. In this respect, both the ance of brain 5-HT release and 5-HT2 c lular calcium is expressed as a percentage of leptin receptor and 5-HT2c receptors are receptors: dieting lowers plasma trypto­ the final response to 5-HT (3 µM).
    [Show full text]
  • 2015 Schmid LSD Biol Psych Athor Copy
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by edoc Schmid et al. Effects of LSD Archival report Acute effects of LSD in healthy subjects Yasmin Schmid, Florian Enzler, Peter Gasser, Eric Grouzmann, Katrin H. Preller, Franz X. Vollenweider, Rudolf Brenneisen, Felix Müller, Stefan Borgwardt, Matthias E. Liechti From Psychopharmacology Research, Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Switzerland (YS, FE, MEL), Practice for Psychiatry and Psychotherapy, Solothurn, Switzerland (PG), Biomedicine Service, University Hospital Lausanne, Lausanne, Switzerland (EG) Neuropsychopharmacology and Brain Imaging and Heffter Research Center, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry Zurich, Switzerland (KHP, FXV), Department of Clinical Research, University of Bern, Bern, Switzerland (RB), and Department of Psychiatry, University of Basel, Basel, Switzerland (FM, SB). Short title: Effects of LSD Address correspondence to Prof. Matthias E. Liechti, MD, Clinical Pharmacology, University Hospital Basel, Hebelstrasse 2, Basel, CH-4031, Switzerland; E-mail: [email protected]; Phone: +41 61 328 68 68; Fax: +41 61 265 45 60 Word counts: Abstract: 250; Manuscript: 3940 References : 90 Tables and Figures : Tables: 0; Figures: 6 Supplemental material online: 1 file with 3 tables and 4 figures Keywords: LSD, prepulse inhibition, subjective effects, hormones, adverse effects, sympathomimetic effects 1 Schmid et al. Effects of LSD Summary Background: After no research in humans for more than 40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD and its endocrine effects are unknown.
    [Show full text]
  • Revisão Pharmacological Treatment of Obesity
    Pharmacological Treatment of Obesity revisão ABSTRACT Marcio C. Mancini This review offers an overview of physiological agents, current therapeu- Alfredo Halpern tics, as well as medications, which have been extensively used and those agents not currently available or non-classically considered anti-obesity drugs. As obesity — particularly that of central distribution — represents an important triggering factor for insulin resistance, its pharmacological treatment is relevant in the context of metabolic syndrome control. The authors present an extensive review on the criteria for anti-obesity man- agement efficacy, on physiological mechanisms that regulate central and/or peripheral energy homeostasis (nutrients, monoamines, and pep- tides), on β-phenethylamine pharmacological derivative agents (fenflu- ramine, dexfenfluramine, phentermine and sibutramine), tricyclic deriva- tives (mazindol), phenylpropanolamine derivatives (ephedrin, phenyl- propanolamine), phenylpropanolamine oxytrifluorphenyl derivative (flu- oxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials — over ten-week long — is also presented for medications used in the management of obesity, as well as data about future medications, such as a the inverse cannabinoid agonist, rimonabant. (Arq Bras Endocrinol Metab 2006;50/2:377-389) Keywords: Obesity; Treatment; Anfepramone; Mazindol; Sibutramine; Endocrinology and Metabology Orlistat; Rimonabant Division, Hospital das Clínicas, University of São Paulo Medical
    [Show full text]
  • 1 441 702 B1
    (19) TZZ__Z _T (11) EP 1 441 702 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4045 (2006.01) A61P 25/20 (2006.01) 10.05.2017 Bulletin 2017/19 A61K 9/20 (2006.01) (21) Application number: 02760523.7 (86) International application number: PCT/IL2002/000662 (22) Date of filing: 12.08.2002 (87) International publication number: WO 2003/015690 (27.02.2003 Gazette 2003/09) (54) METHOD FOR TREATING PRIMARY INSOMNIA VERFAHREN ZUR BEHANDLUNG PRIMÄRER INSOMNIA METHODE DE TRAITEMENT DE L’INSOMNIE PRIMAIRE (84) Designated Contracting States: • ROTH T ET AL: "Consensus for the AT BE BG CH CY CZ DE DK EE ES FI FR GB GR pharmacological management of insomnia in th IE IT LI LU MC NL PT SE SK TR enew millennium", INTERNATIONAL JOURNAL Designated Extension States: OF CLINICAL PRACTICE, MEDICON LT LV RO SI INTERNATIONAL, ESHER, GB, vol. 55, no. 1, 1 January 2001 (2001-01-01), page 10PAGES, (30) Priority: 14.08.2001 IL 14490001 XP002990688, ISSN: 1368-5031 • PERLIS M L ET AL: "Psychophysiological (43) Date of publication of application: insomnia: the behavioural model and a 04.08.2004 Bulletin 2004/32 neurocognitive perspective", JOURNAL OF SLEEP RESEARCH, BLACKWELL SCIENTIFIC, (60) Divisional application: OXFORD, GB, vol. 6, 1 January 1997 (1997-01-01), 16172415.8 / 3 103 443 pages 179-188, XP002990686, ISSN: 0962-1105, DOI: DOI:10.1046/J.1365-2869.1997.00045.X (73) Proprietor: NEURIM PHARMACEUTICALS (1991) • SILVA J A C E ET AL: "Special report from a LIMITED symposium held by the WHO and the World Tel Aviv 69710 (IL) Federation of sleep research societies: an overview of insomnias and related disorders - (72) Inventor: ZISAPEL, Nava recognition, epidemiology and rational 69355 Tel Aviv (IL) management", SLEEP, ALLEN PRESS, LAWRENCE, KS,US, vol.
    [Show full text]
  • Pharmacotherapies for Obesity: Past, Current, and Future Therapies
    Hindawi Publishing Corporation Journal of Obesity Volume 2011, Article ID 179674, 18 pages doi:10.1155/2011/179674 Review Article Pharmacotherapies for Obesity: Past, Current, and Future Therapies Lisa L. Ioannides-Demos, Loretta Piccenna, and John J. McNeil Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Centre, Commercial Road, Melbourne, VIC 3004, Australia Correspondence should be addressed to Lisa L. Ioannides-Demos, [email protected] Received 4 August 2010; Accepted 24 September 2010 Academic Editor: A. Halpern Copyright © 2011 Lisa L. Ioannides-Demos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie- controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long- term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta- analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7 kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months.
    [Show full text]
  • The Pyramid of Recent Trials
    Endoscopic and Minimally Invasive Bariatrics: Medical Management of Obesity September 25, 2017 Judith Korner, MD, PhD Professor, Department of Medicine Division of Endocrinology Director, Weight Control Center Columbia University Medical Center Cornerstone of Weight Loss Treatment • Behavior Therapy, Diet, Exercise Long-Term Weight Loss with Non-Pharmacologic Treatment VLCD: ≤800 kcal/day BMOD: behavior + 1200kcal/day Combined: VLCD + behavior Wadden Annals of Int Med 119:688 1993 Neurohormonal Changes Associated with Weight Loss Korner & Aronne, J Clin Invest 111:565-570 (2003) A Guide to Selecting Treatment: National Institutes of Health (NIH) Guidelines* Body Mass Index (BMI) (kg/m2) Treatment 25–26.9 27–29.9 30–34.9 35–39.9 ≥40 Diet, physical activity, Yes with Yes with Yes Yes Yes behavior comorbidities comorbidities therapy Pharmaco- Yes with Yes Yes Yes therapy comorbidities Weight-loss Yes with *** Yes surgery comorbidities *Yes alone indicates that the treatment is indicated regardless of the presence or absence of comorbidities. The solid arrow signifies the point at which therapy is initiated. *** The FDA has approved use of LAGB for patients with BMI > 30 who also have at least one condition linked to obesity, such as heart disease or diabetes. NIH/NHLBI, NAASO. The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Bethesda, Md: NIH; 2000. History of Drugs for Weight Loss • 1947: Methamphetamine Phendimetrazine (Bontril) • 1957: Phentermine (Adipex, Suprenza) • 1982: Diethylpropion
    [Show full text]
  • Boris Quednow: Brain Serotonin Function in MDMA (Ecstasy) Users
    BrainBrain serotoninserotonin functionfunction inin MDMAMDMA (( ““ecstasyecstasy ””)) usersusers Boris B. Quednow 1, Felix Hasler 1, Valerie Treyer 2, Matthias T. Wyss 2, Katharina M. Rentsch 3, Gerrit Westera 4, Schubiger PA 4, Alfred Buck 2, Franz X. Vollenweider 1 1University Hospital of Psychiatry, Zurich, Switzerland 2Department of Nuclear Medicine, University Hospital Zurich, Switzerland 3Department of Clinical Chemistry, University Hospital Zurich, Switzerland 4Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland EcstasyEcstasy • The use of Ecstasy is increasingly spreading since the end of the 1980s. • Lifetime prevalence of Ecstasy use in European adolescents and young adults is about 4-5%. • In Europe, Ecstasy is the second most popular illicit drug in adolescents and young adults following cannabis. • Over the past 15 years, in Germany and Switzerland more than 90% of the confiscated Ecstasy pills contained exclusively the substituted amphetamine derivative MDMA. • Ecstasy pills comprise of 60-65 mg MDMA on average, but with a great range (0-360 mg). SerotonergicSerotonergic neurotransmissionneurotransmission Holmes, Neurosci Biobehav 2008 MDMA SelectiveSelective serotonergicserotonergic neurotoxicityneurotoxicity ofof MDMAMDMA Sagittal plane of 5-HT immunoreaktive axons in the frontal cortex of squirrel monkeys after a treatment of 5 mg/kg MDMA 2x/die for 4 days. Control 2 weeks after MDMA 7 years after MDMA Hatzidimitriou et al., J Neurosci 1999 TheThe serotoninserotonin systemsystem
    [Show full text]
  • Introduction Obesity Is a Major Health Problem in Most Developed
    Introduction Obesity is a major health problem in most developed countries around the world. It is estimated that there are approximately 76 million obese people in the United States, thus making 1 in every 3 people obese (1). Furthermore, obesity has bee n labeled the second leading cause of preventable death (the first being smoking) in the United States, contributing to 300,000 deaths annually (1). Health problems associated with obesity primarily involve the cardiovascular system, such as hypertension, hypercholestrolemia, stroke, and myocardial infarction. Physicians are accordingly motivated to help their patients lose weight in order to minimize the impact of obesity on their health. Consequently, many diets, regimens, herbs, and drugs have been intro duced to help in this common endeavor, however none have been as potent as the combination drug therapy commonly known as "fen -phen". Two landmark studies Fen -phen is a combination of fenfluramine or dexfenfluramine (fenfluramine’s d-isomer) and phenterm ine, all of which have been individually approved by the Food and Drug Administration (FDA) as appetite suppressants for short -term use in the medical management of obesity. Fenfluramine is a serotonergic agonist that performs its action of appetite suppre ssion via the activation of serotonergic pathways in the brain, thus giving one the sensation of fullness. Fenfluramine and dexfenfluramine promote the rapid release of serotonin, inhibit its reuptake, and may have receptor-agonist activity, thus making se rotonin more susceptible to metabolism and breakdown (2). Phentermine, on the other hand, is a noradrenergic agent that interferes with the pulmonary clearance of serotonin and also helps in appetite suppression (2).
    [Show full text]