I From the Pennington Biomedical Research Center, Baton Rouge, LA. 2 Address reprint requests to GA Bray, Pennington Biomedical Research

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1 Drug tretment of,2 George A Bry ABSTRACT The currently vilble drugs for tretment of obesity ct on two phrmcologic systems in the centrl nervous system: the nordrenergic system nd the serotonergic system. There re cler nd convincing clinicl dt tht these drugs re effective nd sfe. However, severl types of brriers exist to their proper nd effective use, including public perceptions tht obesity is disese resulting from lck ofwillpower, professionl expecttions tht norexint drugs should cure obesity, hindrnce by stte licensing gencies, regultory rigidity, limited reserch funding, nd legisltive inction. In spite of these limittions, severl new nd potentilly vluble drugs re under development, nd given n pproprite clinicl nd therpeutic environment, the future is bright for tretment of obesity. Am J Clin Nuir l992;55:538s-44s. KEY WORDS Anorexint drugs, nordrenergic drugs, serotonergic drugs, stigmtition, thermogenic drugs Introduction Drugs for the tretment of obesity cn be clssified by using feedbck model to understnd ltertions in nutrient blnce (1). A feedbck model consists of control system of nutrient intke, digestion, bsorption, storge, nd oxidtion, which sends fferent messges of hormonl, neurl, or nutrient type to centrl controller in the brin, which in turn sends efferent signls to regulte digestion nd metbolism offood nd the prtitioning of nutrients between ft, protein, nd energy utilition. A clssifiction of tretments for obesity by use of this pproch is shown in Tble 1 (2). Drugs cting on the centrl nervous system Drugs cting on nordrenergic neurotrnsmitters Most ppetite-suppressing drugs currently mrketed for the tretment of obesity re derivtives of phenethylmine (3, 4). The exception is mindol, which is n imidoisoindole. The currently vilble drugs re listed in Tble 2 ccording to the Drug Enforcement Agency (DEA) Schedule. Phrmcologic effects. The phrmcologic effects of ppetite suppressnts cn be divided into three ctegories. 1) Most of these medictions cn stimulte the centrl nervous system, but the degree is highly vrible; nd two ofthem, phenylpropnolmine nd fenflurmine, pper lmost devoid of this effect. 2) Some ppetite-suppressing drugs hve crdiovsculr effects, which include rise in hert rte nd blood pressure, but most do not. A rise in hert rte nd blood pressure hs been observed with mphetmine, methmphetmine, ephedrine, nd phenrnetrine but is miniml or bsent with the others. Moreover, weight loss my ctully lower blood pressure. 3) Metbolic effects expressed s rise in the concentrtion of free ftty cids nd/or glycerol in plsm hve been observed fter dministrtion of mphetmine, rnethrnphetrnine, nd phenmetrine. Methmphetmine hs been found to ntgonie the lipolytic effects ofnorepinephrine in vitro but hs no direct lipolytic effect itself. Mindol hs been reported to increse the uptke of glucose fter intrrteril dministrtion in humns. Fenflurmine reduces blood glucose through non-insulin-dependent mechnisms (4). The pek blood concentrtion of norexint medictions usully occurs shortly fter orl dministrtion. However, the hlf-life ofthe drugs in the serum vries considerbly; benphetmine nd mphetmine hve 2-5-h hlf-lives compred with much longer ones for phentermine, fenflurrnine, nd fluoxetine ( serotonergic ntidepressnt tht hs been reported to produce weight loss but hs not been pproved for tht indiction, see below). There re importnt phrmcologic differences mong the stereoisomers of these compounds. The dextro isomer of mphetmine, for exmple, is four times more potent thn the levo isomer. The d-isorner of fenflurmine ppers to contin most, ifnot ll, ofthe ppetite-suppressing effects ofthe rcemic (d, I) mixture with the /-isomer being ineffective in this regrd. Urinry excretion of severl drugs is dependent upon urine ph nd my increse in cidic urine (4). Clinicl use of nordrenergic ppetite-suppressing drugs. In evluting the clinicl usefulness of ppetite suppressnts, two questions need to be nswered: Are they effective? And re they sfe? The Food nd Drug Administrtion hs provided one of the lrgest reviews ofeffectiveness for nordrenergic drugs (5). They nlyed 15 new drug pplictions contining dt on 4543 plcebo-treted nd ptients treted with ctive drugs. In studies compring plcebo nd ctive drug, the dropout rte fter 4 wk of therpy ws 18.5% for subjects on plcebo nd 24.3% for those receiving ctive drug. At the end of the study periods, lsting 3, 4, 8, or more weeks, equl percentges of ptients receiving plcebo nd ctive drugs remined in tretment (49% for the plcebo group vs 47.9% for the ctive-drugs I From the Pennington Biomedicl Reserch Center, Bton Rouge, LA. 2 Address reprint requests to GA Bry, Pennington Biomedicl Reserch Center, 64 Perkins Rod, Bton Rouge, LA S Am J C/in Nuir l992;55:538s-445. Printed in USA Americn Society for Clinicl Nutrition

2 TABLE 1 A nutrient blnce pproch to tretment of obesity DRUG TREATMENT OF OBESITY 539S Component Mechnism Exmple Agents cting on controlled system Agents cting on fferent system Agents cting on controller Agents cting on efferent mechnisms Decrese nutrient density of food Reduce digestibility Disrupt micelle formtion Increse energy expenditure Exercise Vsodiltion Clorigenic drugs Chnge nutrient prtitioning Pltbility Sweeteners Topicl nesthetic Tste ltering drugs Gstric distention Gstrointestinl peptides Nutrients GABAergic ntgonists (GABA-A receptors) Adrenergic gonists (-I, $-3) Serotonergic gonists Histminergic (H-l) gonists Peptides Thermogenic drugs Jw-wiring Steroid removl Inhibit prolctin relese High-crbohydrte, low-ft diet Fiber Simplesse Olestr Tetrhydrolipsttin Olestr Discchridse Inhibitors Cholestyrmine Cold exposure Exercise Prosin Thyroid Growth hormone -3 Adrenergic gonists Ephedrine Cffeine fi-3 Adrenergic gonists Growth hormone Corticosteroids Androgens Estrogens Scchrin Asprtme Benocine Cpsicin Gstric blloon Aconitse Cholecystokinin Procolipse signl peptide Bombesin 3-Hydroxybutyrte Lctte l-butene-4-olide 3,4-Dihydroxybutyrte Picrotoxin Phenethylmine derivtives Fenflurmine Fluoxetine Sertrline Cholecystokinin gonists Opioid ntgonists (Nloxone; Nlfemene; Kpp-receptor ntgonists) NPY ntgonists CRH-gonists i-3 Agonists Adrenlectomy RU-486 blockde of steroid receptors Dopmine gonists group). Drug-treted ptients lost on verge.25 kg/wk (.56 lb/wk) more thn subjects receiving plcebos. The effectiveness of weight loss by norexint medictions cn lso be evluted in terms ofthe proportion ofsubjects who lost given mounts of weight per week. A weight loss of.45 kg/wk ws lmost twice s common in ptients receiving ctive drugs (44%) s in those on plcebo (26%), s ws weight loss of 1.4 kg/wk, chieved by 2% of those on ctive drugs compred with 1% ofthose on plcebo. An exmintion ofthe weight loss results fter 4 wk of tretment shows 68% of ptients on the ctive drugs lost.45 kg/wk compred with 46% ptients on plcebo nd 1% ofthe drug-treted subjects vs 4% of those receiving plcebo lost 1.4 kg/wk. In cliniclly effective doses there ws no bsis on which to choose between these drugs in

3 54S BRAY TABLE 2 Appetite-suppressing drugs Genetic nd proprietry nmes Common trde nmes Dosge Administrtion Pek blood concentrtion (h fter po dose) Hlf-life in blood Excreted unchnged in cidic urine mg mg h % Over-the-counter Phenylpropnolmine Dextrim 25, tid, 75 in morning Schedule IV Diethylpropion Tenute, propion 25, before mels (tid), (Nordrenergic) 75 in morning Fenflurmine Pondimin before mels I 2 2 (Serotonergic) Mindol Snorex, mnor 1, 2 1 before mels, (Nordrenergic) 2 in morning Phentermine Ionmin 15, 3 15 tid, 3 in morning Free (Nordrenergic) Fstin Schedule 111* Phendimetrine Plegine, obln before mels - 4 7? (Nordrenergic) Benphetmine Didrex 25, before mels ? (Nordrenergic) Schedule II Amphetmine Dexedrine 5, 1, before mels (tid) (Nordrenergic) Methmphetmine Desoxyn 5, 1, or S before mels (tid), (Nordrenergic) 1 or 15 in morning Phenmetrine Preludin 25, 5, (bid or tid) * The Federl Controlled Substnces Act of 197 plces the prescription norexints into five schedule ctegories. Appetite suppressnts in schedule II re most likely to be bused wheres those in schedule IV hve little or no risk of buse. terms of their rtes of weight loss or the durtion over which this weight loss occurred (5). The dt from one 2-wk tril re shown in Figure 1. Additionl dt re vilble from trils lsting from 6 to 52 wk (4). Weight loss continued t decelerting rte for the durtion of tretment. Tolernce did not pper to develop, since incresed mounts ofdrug were not required to mintin weight loss. Phenylpropnolmine is the only nordrenergic drug tht is vilble for weight control over-the-counter (Tble 2). It is lso sold in mny nsl decongestnts. In review of this drug, n dvisory pnel to the Food nd Drug Administrtion concluded tht it ws probbly sfe nd effective. At high doses (75 mg) it hs been reported to increse blood pressure. A criticl review of published nd unpublished studies with this drug supports this contention (6). In one group offive clinicl trils with phenylpropnolmine lone, the drug-treted individuls lost n verge of.24 kg/wk more thn the plcebo-treted group. This is very similr to the extr weight loss of.25 kg/wk reported when prescription ppetite-suppressing drugs nd plcebo re compred. A more recent study (6) illustrted the effectiveness of phenylpropnolmine with minor dverse effects, prticulrly over the criticl holidy period. Drugs cting on serotonin neurotrnsmitters Phrmcology. One of the generl biobehviorl properties of serotonin is reduction in the physiologicl level of ctivity, including food intke. Drugs modulting serotonin metbolism influence body weight (4). Food intke is reduced by the dministrtion of tryptophn or 5-hydroxytryptophn, two precursors tht re converted to serotonin fter entering the brin. Similrly, drugs tht relese serotonin from nerve endings (fenflurmine) nd/or block its reuptke (fluoxetine or sertrline) decrese food intke nd body weight. Fenflurrnine ws the first cliniclly useful ppetite-suppressnt mediction ofthis type (Tble 2). It both releses nd prevents reuptke of serotonin. Fluoxetine, serotonin reuptke inhibitor (7), hs been shown to produce weight loss in both depressed nd norml people. Clinicl trils with serotonergic drugs. Trils with serotonergic drugs hve lsted up to 52 wk. In one tril (8, 9), fenflurmine ws dministered continuously for 1 y, followed by second yer ofplcebo (Fig 2). A plteu ofweight loss occurred between the 8th nd 12th month nd weight remined kg lower for the reminder of the yer. When trnsferred to plcebo, ptients regined weight s would be expected when tretment for chronic disese is stopped. A second yer-long tril with d-fenflurmine vs plcebo shows tht ndir occurred fter weight loss of 1 1% of initil weight (1). Those in the plcebo group plteued fter weight loss of 8% (Fig 3). A third study hs compred the combined effect of serotonergic drug, di-fenflurmine, plus nordrenergic drug, phentermine. After single blind run-in period of 4 wk, the drugtreted ptients reched ndir tht ws 17 kg below the plcebo

4 DRUG TREATMENT OF OBESITY 54 1 S Sfety ofppetite suppressnts WEEKS OF TREATMENT FIG 1. Comprison ofplcebo nd mphetmine-like drug. The drugtreted group consisted of 3 ptients nd the plcebo group consisted of 15 ptients, ll ofwhom finished the 2-wk tril. (To convert pounds to kilogrms divide by 2.2.) (Copyright 1976, George A Bry). weight level nd tht ws mintined until the end of the 34- wk tril (M Weintrub, personl communiction, 1991). Three clinicl findings from these studies would rgue ginst tolernce. 1) Weight loss continued for 4-6 mo until new plteu ws reched. 2) Hunger did not increse during tretment. 3) Subjects regined weight when fenflurmine ws discontinued. One interprettion of this is tht the drug hd redjusted the weight-control mechnism to lower level, which cesed when the drug ws stopped (I I). mild. The sfety of ppetite suppressnt drugs hs been the subject ofconsiderble discussion (4). Griffiths et l (12), using bboons s subjects, exmined the reinforcing properties of intrvenous preprtions ofseverl ppetite-suppressing drugs nd compred them to the reduction in food intke. The reinforcing property is the effect of drug tht leds the niml to seek dditionl mounts ofthe drug. The rtio ofnorexint dose to reinforcing dose, mesure of buse potentil, is shown for severl drugs in Figure 4. At one extreme is diethylpropion nd mphetmine, which show smll reinforcing effect; t the other extreme is fenflurmine nd phenylpropnolmine, which hve no reinforcing effect. Although the rtio of ppetite-suppressnt dose to reinforcing dose my help predict buse potentil, it does not lwys correlte with clinicl experience. For exmple, diethylpropion hs been widely used s n ppetite-suppressing drug, with few reported episodes of buse. However, its rtio of ppetite-suppressnt to reinforcing is greter thn tht of mphetmine or phenmetrine, which hve both been bused with ddictive results nd re ppropritely clssified in Schedule II. There is no indiction for use of drugs in Schedule II for the tretment of obesity (3, 4). Drugs in Schedule IV re obviously preferred, but drugs in Schedule III lso hve low buse potentil. Brriers to use of current drugs Clinicl nd experimentl dt suggest tht norexint drugs hve little risk (3, 4). Drug buse with mphetmine, methmphetmine, nd phenmetrine is well-known nd these drugs hve no plce in the tretment of obesity nd re not pproved for this purpose. However, the other drugs hve little buse potentil nd in studies tht use drug reinforcement protocols two drugs, phenylpropnolmine nd fenflurmine, hve been shown to hve no reinforcing properties, indicting essentilly complete freedom ofbuse potentil. Likewise, side effects other thn dry mouth, ltertions in bowel hbits, nd insomni re reltively U, -J p.- I w 2 MONTHS FIG 2. Men weight chnge during 1 y oftretment with dl-fenflurmine. A totl of 176 ptients were followed for 1 y of drug tretment nd for second yer fter discontinution of the drug. (To convert pounds to kilogrms divide by 2.2.) (Adpted from reference 8 nd published in reference 9).

5 542S BRAY I- I Li -4 p -6 U) U) -8 I- I 9-1#{149} Li Dexfenfluromine (.-.) n=256 Plcebo (o-o) n-227.:n;ii#{247}.-+j: p (.5 C p ( FIG 3. Comprison ofplcebo nd d-fenflurmine tretment for 1 y. Weight loss of the noted number of ptients followed in multicenter study is shown. Dt re men ± SEM. (Reproduced from reference 1). This profile ofreltively sfe drugs with long-term effectiveness leds one to sk why they re not more widely used (3). There re number ofbrriers to the effective use ofnorexint gents. First, obesity is stigmtied condition. Tht is, the public perceives obesity not s disese, s proposed by the 1985 NIH Consensus Conference ( 13), but rther condition ssocited with lck of willpower nd gluttony. Willpower, the power to push oneself wy from the tble, is ll tht is needed to tret obesity. This simplistic public perception of obesity is reflected in professionl ttitudes of helth-cre workers s well (14). The fct tht obesity ptients regin weight fter tretment is terminted is lmost universlly ttributed to filure of the drugs becuse helth professionls expect tht fter drug tretment of obesity there should be no weight regin. Tht is, the drugs re expected to cure obesity. These professionl ttitudes hve led to demnd for higher therpeutic stndrds for modictions used in treting obesity thn for medictions used in treting other chronic conditions. In recent review, Weintrub nd Bry (3) described this unrelistic expecttion s follows: We ccept the fct tht serum cholesterol vlues will rise following the cesstion oftherpy with hypocholesterolemic drugs. We lso ccept tht peptic ulcers will lso recur following cesstion of H2-blocking medictions. We understnd rising introculr pressure when pilocrpine tretment is stopped, mening tht glucom hs been controlled but not cured. Even in the bsence of cure, ptients nd physicins still view oculr hypotensive gents, cholesterol lowering medictions nd H2- blockers s vluble. All of these filures to cure problem of mlregultion in the humn orgnism re cceptble. Yet, for obesity, this is uncceptble (3). Bthers to the effective use ofnoretic drugs re lso provided by stte licensing gencies. Mny physicins hve been questioned nd disciplinry ction brought for using ppetite suppressnt drugs for more thn few weeks. Yet the vilble dt reviewed bove rgue they re effective for s long s they re used. Regultory rigidity in scheduling nd lbeling norexint drugs is lso brrier to their effective use. The Food nd Drug Administrtion hs lbeled these drugs for the mngement ofexogenous obesity s short term ( few weeks) djunct to the tretment ofobesity. There is no definition of exogenous, term of dubious nd outmoded merit in describing obesity. The dt do not support few weeks unless this mens wk or more. Clerly, regultions do not mke truth, nd current regultions pper to ber little reltionship to the relities ssocited with these medictions. Even worse, unrelistic regultions cn serve s the bsis for criminl prosecutions, without the perpetrtors ofthe regultions being lible for the negligence tht they hve produced. Moreover, current regultions inhibit future developments becuse they indicte closed nd unresponsive leglistic mentlity from regultory uthorities. Another limittion in the use of norexint drugs hs been the reltively limited number of clinicl trils possible becuse of limited reserch funding. Few, if ny, of the current rnedictions hve ptent protection nd thus there is no incentive for compnies to conduct long-term trils. Government spending is limited: $35 million spent on obesity reserch ginst expenditures by the public of more thn $35 billion in its quest for lenness. There is only single Obesity Reserch Center where trils could effectively be done. Finlly, the legisltive process hs produced hering reports on the diet-pill industry in 1967, on the liquid-diet fisco in 1977, nd the obesity tretment progrms in 199, but it hs produced little increse in funding. Other drugs, nd drugs under development Centrlly ctive drugs Nloxone, drug which blocks the ction of opioids nd decreses food intke in experimentl nimls, hs lso been demonstrted to decrese food intke cutely in norml-weight nd overweight subjects (1 5), but the longer cting nltrexone hs not been effective ( 1 6). A number of peptides cn increse or decrese food intke in experimentl nimls (17). Of these, E.., U. C 3 C E U. -I 1..5 ANORECTIC - REINFORCEMENT RATIO UOh FIG 4. Comprison of norectic-reinforcement rtio for severl ppetite-suppressing drugs. The higher the number the greter the potentil for hbitution to ppetite-suppressnt effect, s determined in studies with primtes. Two drugs hd no pprent reinforcement potentil (Adpted from reference I 2).

6 DRUG TREATMENT OF OBESITY 543S neuropeptide-y, glnin, corticotropin-relesing hormone, nd cholecystokinin hve received the most emphsis. Thermogenic drugs Thyroid hormone. Thyroid hormone is one prototype of thermogenic drug. It produces log-dose increse in metbolic expenditure. However, phrmcologic doses, nd even high physiologicl doses, of thyroid hormone re ssocited with incresed brekdown of protein, incresed clcium loss from bone, nd n incresed risk of crdiovsculr dysfunction. There is thus no current indiction for use ofthyroid hormone for tretment of obesity, except s replcement therpy for clinicl nd lbortory-documented hypothyroidism. Ephedrine. Ephedrine is synthetic drenergic drug hving both - nd fl-gonist properties. Ephedrine my increse blood pressure, hert rte, nd peripherl vsculr resistnce. Centrl nervous system stimultion my occur. Some people cnnot tolerte the centrl nervous system effect, complining of insomni nd nervousness. However, ephedrine cn increse energy expenditure when dministered orlly. At present the dt re insufficient to conclude tht ephedrine lone is useful in treting obesity (1 1). A recent report by Astrup et l (18) showed tht when ephedrine is combined with cffeine significnt weight loss cn be induced. Bet-drenergic gonists. The observtion tht fl-drenergic drugs could enhnce thermogenesis in experimentl nimls hs led to the development of other thermogenic compounds (19). Tretment ofexperimentl nimls with these drugs will decrese body weight nd body ft content without reducing food intke, suggesting tht they work by incresing energy expenditure. Two of three clinicl trils with fl-gonist (BRL2683A) hve resulted in desirble weight loss (2, 21). Results in the other were equivocl (2). The presence of tremor of the hnds ( fl2-drenergic effect) nd n increse in hert rte hve led to the serch for drugs with better phrmcologic profile (22). Growth hormone. Growth hormone is clorigenic (3) nd hs been shown to reduce protein loss during low-clorie dieting (3). However, growth hormone remins controversil nd experimentl. The dverse effects of growth hormone, including development of crornegly, mke its use problemtic. Drugs ffecting the gstrointestinl trct Becuse the tste of food, its digestibility, nd its metbolism re relted to the control of food intke, it is not surprising tht pproches tht lter these fctors hve been selected for developrnent ofmedictions for tretment ofobesity. Severl different drugs tht modify the tste, digestion, or bsorptive processes in the gstrointestinl trct hve been tested. Enyme inhibitors. Inhibition of ft digestion or bsorption induces mlbsorption nd thus reduces the vilble energy from fts in the diet. The ntibiotic neomycin will increse the fecl excretion of ft, but the chnges in the intestinl rnucos cused by this drug mke it uncceptble for clinicl use in obesity (3). Cholestyrmine is resin tht binds bile slts nd thus disturbs rnicelle formtion. When given to obese ptients in lrge doses this drug does not increse ft loss significntly nd is thus ineffective in obesity (3). Drugs tht inhibit discchridse enyrnes in the intestine hve lso been tried but hve not been shown to increse weight loss over diet lone. Finlly, lipse inhibitor, tetrhydroliposttin, hs recently been described. In niml studies it ppers promising nd clinicl trils re underwy (23). Indigestible food. Sucrose polyester (Olestr, Procter nd Gmble, Cincinnti) is n indigestible ft produced by esterifying sucrose with ftty cids of pproprite length to give it chrcteristics of norml cooking oil. Addition of this gent to the diet will reduce the bsorption of cholesterol nd vitmin A by 67% nd 42%, respectively. In one clinicl tril with sucrose polyester, overweight subjects did lose weight (24). A subsequent study by Mellies et l (25) filed to demonstrte ny significnt effect on body weight ofsubstituting sucrose polyester for ft in the diet of five obese subjects. The resons for the reduction in cloric intke in one study nd the filure to detect reduction in the second study remin uncler. Recent dt show tht in norml-weight subjects, dpttion does occur (26). Inhibitors of gstric emptying. Another re for potentil therpeutic intervention is gstric emptying. Medictions such s threo-chlorocitric cid or its derivtives, which inhibit gstric emptying, my increse stiety directly nd vi intestinl hormones (4). Miscellneous Humn chorionic gondotropin (HCG). The tretment of obesity with diet nd injections of HCG hs been proposed for more thn 3 yers. There hve been three double-blind, plcebocontrolled prllel studies (27) compring injections of HCG nd plcebo dded to low-clorie diet. In no instnce ws there sttisticlly significnt improvement in the rte of weight loss during tretment with HCG compred with plcebo. Thus, HCG is not effective in the tretment of obesity. Regionlft mobilition. Lipolysis in humn dipose tissue is stimulted by drugs tht ct on fi-drenergic receptors nd is inhibited by drugs tht ct on 2-drenergic receptors. These clinicl observtions suggested tht it might be possible to mobilie ft loclly by /3-drenergic stimultion or inhibition of 2- drenergic receptors. This possibility hs received tenttive support by finding tht locl injection of isoproterenol, 3-drenergic gonist, into one thigh of wornen on diet incresed the rte of ft loss from the treted thigh. Locl pplictions of crem contining minophylline to increse -drenergic-like effects of yohimbine, n 2-drenergic blocking drug, lso incresed the mobilition of ft from the treted thigh. The possibility oftreting regionl ft deposits by topicl mens hs thus been proposed nd wits further testing (28). Conclusions In spite of the dunting regultory hurdles nd widespred negtive ttitudes towrd obesity, quite few potentilly useful gents re under development nd this my led to chnges in ttitude nd chnges in methods of tretment (Tble 3). Oemonstrtion of role for the sympthetic nervous system in regultion of energy expenditure hs led to development of thermogenic drugs by severl compnies. At the present time, dinicl tril is vilble for only one such compound. Additionl clinicl trils with thermogenic drugs re wited. These drugs re ofprticulr interest becuse they cn modify the distribution ofenergy between ft nd protein. They re biologiclly similr to the effect observed with physicl ctivity, ie, they increse muscle nd decrese ft stores.

7 544S BRAY TABLE 3 Tretments under development I. Centrlly cting drugs 1. Agents cting on opioid receptors 2. Peptide gonists or ntgonists II. Thermogenic drugs I. -3 Adrenergic gonists Adrenergic ntgonists 3. Growth hormone gonists III. Gstrointestinl drugs 1. Enyme inhibitors 2. Inhibitors of bsorption 3. Synthetic foods Additionl drugs re under development, including centrlly cting metbolites nd drugs tht ffect lipid digestion. Comprtive studies ofdrugs vs behviorl tretment hve been crned out for fenflurmine but re needed for other gents. Most of the currently vilble drugs re sfe nd re underutilied becuse ofperceptul, regultory, nd reserch brriers. Development of new drugs nd use of old ones is hmpered by public, professionl, regultory, reserch, nd legisltive brriers. Conceptully, ll forms of experimentl obesity cn now be treted by drugs. Only more reserch nd n improved regultory environment will bring their potentil vlue to the public. fl References 1. Bry GA. Obesity- disese of nutrient or energy blnce? Nutr Rev l987;452: Bry GA. Tretment for obesity: nutrient blnce/nutrient prtition pproch. Nutr Rev 199 1;49: Bry GA. The obese ptient: mjor problems in internl medicine. Vol 9. Phildelphi: WB Sunders, Weintrub M, Bry GA. Drug tretment ofobesity. Med Clin North Am l989;73: Scoville BA. Review of mphetmine-like drugs by the Food nd Drug Administrtion: clinicl dt nd vlue judgments. In: Bry GA, ed. Obesity in perspective. Bethesd, MD: Ntionl Institutes of Helth, 1975: [DHEW publiction (NIH) ] 6. Weintrub M. Phenylpropnolmine s norexint gent in weight control: review ofpublished nd unpublished studies. In: Morgn JP, Kgn DV, Brody is, eds. Phenylpropnolmine. Risks, benefits, nd controversies. New York: Preger Scientific, 1985: Levine LR, Rosenbltt 5, Bosomworth J. Use of serotonin reuptke inhibitor, fluoxetine, in the tretment ofobesity. mt j Obes 1987; 1 1: Hudson KD. The norectic nd hypotensive effect of fenflurmine in obesity. J R Coll Gen Prct l977;27: Munro if. Clinicl spects of the tretment of obesity by drugs: review. Int i Obes 1979;3: I Guy-Grnd B, Apfelbum M, Crepldi, Gries A, Lefebvre P, Turner P. Interntionl tril oflong-term dexfenflurmine in obesity. Lncet 1989:2: Bry GA, Gry OS. Tretment of obesity: n overview. Dibetes Metb Rev 1988;4: Griffiths RR, Brdy iv, Brdford LD. Predicting the buse libility of drugs with niml drug self-dministrtion procedures: psychomotor stimulnts nd hllucinogens. Adv Behv Phrmcol 1979;2: NIH Consensus Development Conference Sttement. Helth implictions of obesity. Ann Intern Med l985;13:l Mddox GL, Liedermn V. Overweight s socil disbility with medicl implictions. J Med Educ I 969;44: Cohen MR, Cohen RM, Pickr, Murphy DL. Nloxone reduced food intke in humns. Psychosom Med l985;47: Atkinson RC, Berke LK, Drke CR, Bibbs ML, Willims FL, Kiser DL. Effects oflong-term therpy with nltrexone on body weight in obesity. Clin Phrmcol Ther 1985;38:4l Morley JE. Neuropeptide regultion of ppetite nd weight. Endocrinol Rev l987;8: Astrup A, Toubro 5, Christensen NJ, Qude F. Phrmcology of Thermogenic Drugs. Am J Clin Nutr l992;55(suppl):s-s. 19. Arch irs, Ainsworth AT, Cwthorne MA. Atypicl fl-drenoceptor on brown dipocytes s trget for nti-obesity drugs. Nture l984;39: Munro if, Chpmn BJ, Robb GH, Zed C. Clinicl studies with thermogenic drugs. In: Berry EM, Blondheim SH, 5hfrir E, eds. Recent dvnces in obesity reserch V. London: John Libbey, 1987: Conncher AA, Mitchell PEG, Jung RT. Weight loss in obese subjects on restricted diet given BRL 2683A, new typicl fl-drenoceptor gonist.brmedj l988;26:l2l Hollowy BR, Howe R, Ro B5, Stribling D. ICID7 1 14: novel selective fl-drenoceptor gonist of brown ft nd thermogenesis. Am J Gin Nutr l992;55(suppl):s Huptmn JB, Jeunet FS, Hrtmnn D. Initil studies in mn with the novel gstrointestinl lipse inhibitor, Ro (tetrhydrolipsttin). Am J Clin Nutr 1992;55(suppl):S-S. 24. Glueck Ci, Jndcek R, Hogg E, Allen C, Behler L, Trucksbury M. Sucrose polyester: substitution for dietry fts in hypocloric diets in the tretment of fmilil hypercholesterolemi. Am i Clin Nutr l983;37: Mellies MJ, Vitle C, Jndcek Ri, Lmkin GE, Glueck Ci. The substitution of sucrose polyester for dietry ft in obese, hypercholesterolemic outptients. Am J Clin Nutr l985;4l:l-l Rolls BJ, Pirrgli P, Jones M, Peters J. Effect ofcovert ft replcement with Olestr on 24-hour food intke in len dults. FASEB i 199 1;5:A l77(bstr). 27. Greenwy FL, Bry GA. Humn chorionic gondotrophin (HCG) in the tretment of obesity- criticl ssessment of the Simeons method. West J Med l977;127:46l Greenwy FL, Bry GA. Regionl ft loss from the thigh in obese women fter drenergic modultion. Clin Ther 1987;9:663-9.

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