Drug Treatment of ,2

Drug treatment of ,2

George A Bray

ABSTRACT The currently available drugs for treatment of with amphetamine, methamphetamine, ephedrine, and phen- obesity act on two pharmacologic systems in the central nervous rnetrazine but is minimal or absent with the others. Moreover, system: the noradrenergic system and the serotonergic system. weight loss may actually lower blood pressure. 3) Metabolic ef- There are clear and convincing clinical data that these drugs are fects expressed as a rise in the concentration of free fatty acids effective and safe. However, several types of barriers exist to and/or glycerol in plasma have been observed after administra- their proper and effective use, including public perceptions that tion of amphetamine, rnetharnphetarnine, and phenmetrazine. obesity is a disease resulting from lack ofwillpower, professional Methamphetamine has been found to antagonize the lipolytic expectations that anorexiant drugs should cure obesity, hindrance effects ofnorepinephrine in vitro but has no direct lipolytic effect by state licensing agencies, regulatory rigidity, limited research itself. Mazindol has been reported to increase the uptake of glu- funding, and legislative inaction. In spite of these limitations, cose after intraarterial administration in humans. Fenfluramine Downloaded from several new and potentially valuable drugs are under develop- reduces blood glucose through non-insulin-dependent mecha- ment, and given an appropriate clinical and therapeutic envi- nisms (4). ronment, the future is bright for treatment of obesity. Am The peak blood concentration of anorexiant medications J Clin Nuir l992;55:538S-44S. usually occurs shortly after oral administration. However, the half-life ofthe drugs in the serum varies considerably; benzphet- KEY WORDS Anorexiant drugs, noradrenergic drugs, se- amine and amphetamine have 2-5-h half-lives compared with www.ajcn.org rotonergic drugs, stigmatization, thermogenic drugs much longer ones for phentermine, fenflurarnine, and fluoxetine (a serotonergic antidepressant that has been reported to produce weight loss but has not been approved for that indication, see Introduction below). There are important pharmacologic differences among Drugs for the treatment of obesity can be classified by using the stereoisomers of these compounds. The dextro isomer of by on April 30, 2010 a feedback model to understand alterations in nutrient balance amphetamine, for example, is four times more potent than the (1). A feedback model consists of a control system of nutrient levo isomer. The d-isorner of fenfluramine appears to contain intake, digestion, absorption, storage, and oxidation, which sends most, ifnot all, ofthe appetite-suppressing effects ofthe racemic afferent messages of a hormonal, neural, or nutrient type to a (d, I) mixture with the /-isomer being ineffective in this regard. central controller in the brain, which in turn sends efferent signals Urinary excretion of several drugs is dependent upon urine pH to regulate digestion and metabolism offood and the partitioning and may increase in acidic urine (4). of nutrients between fat, protein, and energy utilization. A clas- Clinical use of noradrenergic appetite-suppressing drugs. In sification of treatments for obesity by use of this approach is evaluating the clinical usefulness of appetite suppressants, two shown in Table 1 (2). questions need to be answered: Are they effective? And are they safe? The Food and Drug Administration has provided one of the Drugs acting on the central nervous system largest reviews ofeffectiveness for noradrenergic drugs (5). They analyzed 105 new drug applications containing data on 4543 Drugs acting on noradrenergic neurotransmitters placebo-treated and 3 182 patients treated with active drugs. In Most appetite-suppressing drugs currently marketed for the studies comparing placebo and active drug, the dropout rate treatment of obesity are derivatives of phenethylamine (3, 4). after 4 wk of therapy was 18.5% for subjects on placebo and The exception is mazindol, which is an imidazoisoindole. The 24.3% for those receiving active drug. At the end of the study currently available drugs are listed in Table 2 according to the periods, lasting 3, 4, 8, or more weeks, equal percentages of Drug Enforcement Agency (DEA) Schedule. patients receiving placebo and active drugs remained in treat- Pharmacologic effects. The pharmacologic effects of appetite ment (49% for the placebo group vs 47.9% for the active-drugs suppressants can be divided into three categories. 1) Most of these medications can stimulate the central nervous system, but the degree is highly variable; and two ofthem, phenylpropanolamine and fenfluramine, appear almost devoid of this effect. I From the Pennington Biomedical Research Center, Baton Rouge, 2) Some appetite-suppressing drugs have cardiovascular effects, LA. which include a rise in heart rate and blood pressure, but most 2 Address reprint requests to GA Bray, Pennington Biomedical Re- do not. A rise in heart rate and blood pressure has been observed search Center, 6400 Perkins Road, Baton Rouge, LA 70808.

Component Mechanism Example

Agents acting on controlled system Decrease nutrient density of food High-carbohydrate, low-fat diet Fiber Simplesse Olestra Reduce digestibility Tetrahydrolipstatin Olestra Disaccharidase Inhibitors Disrupt micelle formation Cholestyramine Increase energy expenditure Cold exposure Exercise Exercise Vasodilation Prazosin Calorigenic drugs Thyroid Growth hormone -3 Adrenergic agonists Ephedrine Caffeine Change nutrient partitioning fi-3 Adrenergic agonists Growth hormone Downloaded from Corticosteroids Androgens Estrogens Agents acting on afferent system Palatability Sweeteners Saccharin Aspartame

Topical anesthetic Benzocaine www.ajcn.org Taste altering drugs Capsaicin Gastric distention Gastric balloon Gastrointestinal peptides Aconitase Cholecystokinin Procolipase signal peptide by on April 30, 2010 Bombesin Nutrients 3-Hydroxybutyrate Lactate l-Butene-4-olide 3,4-Dihydroxybutyrate Agents acting on controller GABAergic antagonists (GABA-A receptors) Picrotoxin Adrenergic agonists (a-I, $-3) Phenethylamine derivatives Serotonergic agonists Fenfluramine Fluoxetine Sertraline Histaminergic (H-l) agonists Peptides Cholecystokinin agonists Opioid antagonists (Naloxone; Nalfemene; Kappa-receptor antagonists) NPY antagonists CRH-agonists Agents acting on efferent mechanisms Thermogenic drugs i-3 Agonists Jaw-wiring Steroid removal Adrenalectomy RU-486 blockade of steroid receptors Inhibit prolactin release Dopamine agonists

group). Drug-treated patients lost on average 0.25 kg/wk (0.56 of 1.4 kg/wk, achieved by 2% of those on active drugs com- lb/wk) more than subjects receiving placebos. pared with 1% ofthose on placebo. An examination ofthe weight The effectiveness of weight loss by anorexiant medications loss results after 4 wk of treatment shows 68% of patients on can also be evaluated in terms ofthe proportion ofsubjects who the active drugs lost 0.45 kg/wk compared with 46% patients lost given amounts of weight per week. A weight loss of 0.45 on placebo and 10% ofthe drug-treated subjects vs 4% of those kg/wk was almost twice as common in patients receiving active receiving placebo lost 1.4 kg/wk. In clinically effective doses drugs (44%) as in those on placebo (26%), as was a weight loss there was no basis on which to choose between these drugs in 540S BRAY

TABLE 2 Appetite-suppressing drugs

Excreted Peak blood unchanged Genetic and proprietary Common trade concentration Half-life in acidic names names Dosage Administration (h after po dose) in blood urine

mg mg h %

Over-the-counter Phenylpropanolamine Dexatrim 25, 75 25 tid, 75 in morning Schedule IV Diethylpropion Tenuate, propion 25, 75 25 before meals (tid), 1-2 8-13 24 (Noradrenergic) 75 in morning Fenfluramine Pondimin 20 20-40 before meals I 20 20 (Serotonergic) Mazindol Sanorex, mazanor 1, 2 1 before meals, 2 13 22 (Noradrenergic) 2 in morning Phentermine Ionamin 15, 30 15 tid, 30 in morning Free 7-8 75 (Noradrenergic) Fastin 1 20-24 Schedule 111*

Phendimetrazine Plegine, obalan 35 35 before meals - 4 7?

(Noradrenergic) Downloaded from

Benzphetamine Didrex 25, 50 25-50 before meals 1-2 - 7? (Noradrenergic) Schedule II Amphetamine Dexedrine 5, 10, 15 5-10 before meals (tid) 1-2 5 55 (Noradrenergic) Methamphetamine Desoxyn 5, 10, 15 2.5 or S before meals (tid), 1-2 13 45 www.ajcn.org (Noradrenergic) 10 or 15 in morning

Phenmetrazine Preludin 25, 50, 75 25 (bid or tid) - - 19

* The Federal Controlled Substances Act of 1970 places the prescription anorexiants into five schedule categories. Appetite suppressants in schedule

II are most likely to be abused whereas those in schedule IV have little or no risk of abuse. by on April 30, 2010

terms of their rates of weight loss or the duration over which including food intake. Drugs modulating serotonin metabolism this weight loss occurred (5). The data from one 20-wk trial are influence body weight (4). Food intake is reduced by the ad- shown in Figure 1. ministration of tryptophan or 5-hydroxytryptophan, two pre- Additional data are available from trials lasting from 6 to 52 cursors that are converted to serotonin after entering the brain. wk (4). Weight loss continued at a decelerating rate for the du- Similarly, drugs that release serotonin from nerve endings (fen- ration of treatment. Tolerance did not appear to develop, since fluramine) and/or block its reuptake (fluoxetine or sertraline) increased amounts ofdrug were not required to maintain weight decrease food intake and body weight. Fenflurarnine was the loss. first clinically useful appetite-suppressant medication ofthis type Phenylpropanolamine is the only noradrenergic drug that is (Table 2). It both releases and prevents reuptake of serotonin. available for weight control over-the-counter (Table 2). It is also Fluoxetine, a serotonin reuptake inhibitor (7), has been shown sold in many nasal decongestants. In a review of this drug, an to produce weight loss in both depressed and normal people. advisory panel to the Food and Drug Administration concluded Clinical trials with serotonergic drugs. Trials with serotonergic that it was probably safe and effective. At high doses (75 mg) it drugs have lasted up to 52 wk. In one trial (8, 9), fenfluramine has been reported to increase blood pressure. A critical review was administered continuously for 1 y, followed by a second of published and unpublished studies with this drug supports year ofplacebo (Fig 2). A plateau ofweight loss occurred between this contention (6). In one group offive clinical trials with phen- the 8th and 12th month and weight remained 10-1 1 kg lower ylpropanolamine alone, the drug-treated individuals lost an av- for the remainder of the year. When transferred to placebo, pa- erage of 0.24 kg/wk more than the placebo-treated group. This tients regained weight as would be expected when treatment for is very similar to the extra weight loss of 0.25 kg/wk reported a chronic disease is stopped. when prescription appetite-suppressing drugs and placebo are A second year-long trial with d-fenfluramine vs placebo shows compared. A more recent study (6) illustrated the effectiveness that a nadir occurred after a weight loss of 1 1% of initial weight of phenylpropanolamine with minor adverse effects, particularly (10). Those in the placebo group plateaued after a weight loss over the critical holiday period. of 8% (Fig 3). A third study has compared the combined effect of a seroto- Drugs acting on serotonin neurotransmitters nergic drug, dI-fenfluramine, plus a noradrenergic drug, phen- Pharmacology. One of the general biobehavioral properties termine. After a single blind run-in period of 4 wk, the drug- of serotonin is a reduction in the physiological level of activity, treated patients reached a nadir that was 17 kg below the placebo DRUG TREATMENT OF OBESITY 54 1 S

Safety ofappetite suppressants

The safety of appetite suppressant drugs has been the subject ofconsiderable discussion (4). Griffiths et al (12), using baboons as subjects, examined the reinforcing properties of intravenous preparations ofseveral appetite-suppressing drugs and compared them to the reduction in food intake. The reinforcing property is the effect of a drug that leads the animal to seek additional amounts ofthe drug. The ratio ofanorexiant dose to reinforcing dose, a measure of abuse potential, is shown for several drugs in Figure 4. At one extreme is diethylpropion and amphetamine, which show a small reinforcing effect; at the other extreme is fenfluramine and phenylpropanolamine, which have no reinforcing effect. Although the ratio of appetite-suppressant dose to reinforcing dose may help predict abuse potential, it does not always correlate with clinical experience. For example, diethylpropion has been widely used as an appetite-suppressing drug, with few reported episodes of abuse. However, its ratio of appetite-suppressant to reinforcing is greater than that of amphetamine or phenmetrazine, which have both been abused with addictive results and are appropriately classified in Schedule II. There is no indication for use of drugs in Schedule II for the Downloaded from treatment of obesity (3, 4). Drugs in Schedule IV are obviously WEEKS OF TREATMENT preferred, but drugs in Schedule III also have a low abuse potential. FIG 1. Comparison ofplacebo and amphetamine-like drug. The drug- treated group consisted of 30 patients and the placebo group consisted of 15 patients, all ofwhom finished the 20-wk trial. (To convert pounds Barriers to use of current drugs to kilograms divide by 2.2.) (Copyright 1976, George A Bray). www.ajcn.org Clinical and experimental data suggest that anorexiant drugs have little risk (3, 4). Drug abuse with amphetamine, meth- weight level and that was maintained until the end of the 34- amphetamine, and phenmetrazine is well-known and these drugs wk trial (M Weintraub, personal communication, 1991). have no place in the treatment of obesity and are not approved by on April 30, 2010 Three clinical findings from these studies would argue against for this purpose. However, the other drugs have little abuse po- tolerance. 1) Weight loss continued for 4-6 mo until a new pla- tential and in studies that use drug reinforcement protocols two teau was reached. 2) Hunger did not increase during treatment. drugs, phenylpropanolamine and fenfluramine, have been shown 3) Subjects regained weight when fenfluramine was discontinued. to have no reinforcing properties, indicating essentially complete One interpretation of this is that the drug had readjusted the freedom ofabuse potential. Likewise, side effects other than dry weight-control mechanism to a lower level, which ceased when mouth, alterations in bowel habits, and insomnia are relatively the drug was stopped (I I). mild.

-J z

p.- I 0 w

MONTHS

FIG 2. Mean weight change during 1 y oftreatment with dl-fenfluramine. A total of 176 patients were followed for 1 y of drug treatment and for a second year after discontinuation of the drug. (To convert pounds to kilograms divide by 2.2.) (Adapted from reference 8 and published in reference 9). 542S BRAY

0 2 4 6 8 19 12 The data do not support a few weeks unless this means 34-52 wk or more. Clearly, regulations do not make truth, and current I- I Dexfenfluromine (.-.) n=256 regulations appear to bear little relationship to the realities as- Lai Placebo (o-o) n-227 sociated with these medications. Even worse, unrealistic regulations can serve as the basis for criminal prosecutions, without -4 p the perpetrators ofthe regulations being liable for the negligence z that they have produced. Moreover, current regulations inhibit -6 future developments because they indicate a closed and unre- U) U) .:N;ii#{247}.-+j: sponsive legalistic mentality from regulatory authorities. -8 p ( 0.05 Another limitation in the use of anorexiant drugs has been I- I the relatively limited number of clinical trials possible because 9 -10#{149} of limited research funding. Few, if any, of the current rnedi- Li C 0 p ( cations have patent protection and thus there is no incentive for -12 companies to conduct long-term trials. Government spending FIG 3. Comparison ofplacebo and d-fenfluramine treatment for 1 y. is limited: $35 million spent on obesity research against expen- Weight loss of the noted number of patients followed in a multicenter ditures by the public of more than $35 billion in its quest for study is shown. Data are mean ± SEM. (Reproduced from reference leanness. There is only a single Obesity Research Center where 10). trials could effectively be done. Finally, the legislative process has produced hearing reports on the diet-pill industry in 1967, on the liquid-diet fiasco in 1977, and the obesity treatment pro- This profile ofrelatively safe drugs with long-term effectiveness grams in 1990, but it has produced little increase in funding. leads one to ask why they are not more widely used (3). There Downloaded from are a number ofbarriers to the effective use ofanorexiant agents. First, obesity is a stigmatized condition. That is, the public per- Other drugs, and drugs under development ceives obesity not as a disease, as proposed by the 1985 NIH Centrally active drugs Consensus Conference ( 13), but rather a condition associated with a lack of willpower and gluttony. Willpower, the power to Naloxone, a drug which blocks the action of opioids and de- push oneself away from the table, is all that is needed to treat creases food intake in experimental animals, has also been dem- www.ajcn.org obesity. This simplistic public perception of obesity is reflected onstrated to decrease food intake acutely in normal-weight and in professional attitudes of health-care workers as well (14). overweight subjects (1 5), but the longer acting naltrexone has The fact that obesity patients regain weight after treatment is not been effective ( 16). A number of peptides can increase or

terminated is almost universally attributed to a failure of the decrease food intake in experimental animals (17). Of these, by on April 30, 2010 drugs because health professionals expect that after drug treatment of obesity there should be no weight regain. That is, the drugs are expected to cure obesity. These professional attitudes ANORECTIC - REINFORCEMENT RATIO have lead to a demand for higher therapeutic standards for mod- C ications used in treating obesity than for medications used in 0 0 treating other chronic conditions. In a recent review, Weintraub 3 C and Bray (3) described this unrealistic expectation as follows: 1.00 “We accept the fact that serum cholesterol values will rise fol- E lowing the cessation oftherapy with hypocholesterolemic drugs. 0 E a Ui Ui We also accept that peptic ulcers will also recur following ces- 0 z 0 sation of H2-blocking medications. We understand rising intra- 0 a 0 0 ocular pressure when pilocarpine treatment is stopped, meaning 0 z Ui a that glaucoma has been controlled but not cured. Even in the 0.50 0. 0 0. U. absence of a cure, patients and physicians still view ocular hy- z 0, Ui potensive agents, cholesterol lowering medications and H2- a 0 blockers as valuable. All of these failures to cure a problem of 0 0 U. Ui malregulation in the human organism are acceptable. Yet, for 0 obesity, this is unacceptable” (3). -I 0 UOh Bathers to the effective use ofanoretic drugs are also provided by state licensing agencies. Many physicians have been ques- tioned and disciplinary action brought for using appetite suppressant drugs for “more than a few weeks”. Yet the available data reviewed above argue they are effective for as long as they are used. Regulatory rigidity in scheduling and labeling anorexiant drugs is also a barrier to their effective use. The Food and FIG 4. Comparison of anorectic-reinforcement ratio for several ap- Drug Administration has labeled these drugs for “the manage- petite-suppressing drugs. The higher the number the greater the potential ment ofexogenous obesity as a short term (a few weeks) adjunct” for habituation to appetite-suppressant effect, as determined in studies to the treatment ofobesity. There is no definition of exogenous, with primates. Two drugs had no apparent reinforcement potential a term of dubious and outmoded merit in describing obesity. (Adapted from reference I 2). DRUG TREATMENT OF OBESITY 543S

neuropeptide-Y, galanin, corticotropin-releasing hormone, and animal studies it appears promising and clinical trials are un- cholecystokinin have received the most emphasis. derway (23). Indigestible food. Sucrose polyester (Olestra, Procter and Thermogenic drugs Gamble, Cincinnati) is an indigestible fat produced by esterifying sucrose with fatty acids of appropriate length to give it charac- Thyroid hormone. Thyroid hormone is one prototype of a teristics of a normal cooking oil. Addition of this agent to the thermogenic drug. It produces a log-dose increase in metabolic diet will reduce the absorption of cholesterol and vitamin A by expenditure. However, pharmacologic doses, and even high 67% and 42%, respectively. In one clinical trial with sucrose physiological doses, of thyroid hormone are associated with in- polyester, overweight subjects did lose weight (24). A subsequent creased breakdown of protein, increased calcium loss from bone, study by Mellies et al (25) failed to demonstrate any significant and an increased risk of cardiovascular dysfunction. There is effect on body weight ofsubstituting sucrose polyester for fat in thus no current indication for use ofthyroid hormone for treat- the diet of five obese subjects. The reasons for the reduction in ment of obesity, except as replacement therapy for clinical and caloric intake in one study and the failure to detect a reduction laboratory-documented hypothyroidism. in the second study remain unclear. Recent data show that in Ephedrine. Ephedrine is a synthetic adrenergic drug having normal-weight subjects, adaptation does occur (26). both a- and fl-agonist properties. Ephedrine may increase blood Inhibitors of gastric emptying. Another area for potential pressure, heart rate, and peripheral vascular resistance. Central therapeutic intervention is gastric emptying. Medications such nervous system stimulation may occur. Some people cannot as threo-chlorocitric acid or its derivatives, which inhibit gastric tolerate the central nervous system effect, complaining of in- emptying, may increase satiety directly and via intestinal hor- somnia and nervousness. However, ephedrine can increase en- mones (4). ergy expenditure when administered orally. At present the data are insufficient to conclude that ephedrine alone is useful in Miscellaneous Downloaded from treating obesity (1 1). A recent report by Astrup et al (18) showed that when ephedrine is combined with caffeine significant weight Human chorionic gonadotropin (HCG). The treatment of loss can be induced. obesity with diet and injections of HCG has been proposed for Beta-adrenergic agonists. The observation that fl-adrenergic more than 30 years. There have been three double-blind, placebo- drugs could enhance thermogenesis in experimental animals has controlled parallel studies (27) comparing injections of HCG led to the development of other thermogenic compounds (19). and placebo added to a low-calorie diet. In no instance was there www.ajcn.org Treatment ofexperimental animals with these drugs will decrease a statistically significant improvement in the rate of weight loss body weight and body fat content without reducing food intake, during treatment with HCG compared with placebo. Thus, HCG suggesting that they work by increasing energy expenditure. Two is not effective in the treatment of obesity. of three clinical trials with a fl-agonist (BRL26830A) have re- Regionalfat mobilization. Lipolysis in human adipose tissue sulted in desirable weight loss (20, 21). Results in the other were is stimulated by drugs that act on fi-adrenergic receptors and is by on April 30, 2010 equivocal (20). The presence of tremor of the hands (a fl2-ad- inhibited by drugs that act on a2-adrenergic receptors. These renergic effect) and an increase in heart rate have led to the clinical observations suggested that it might be possible to mo- search for drugs with a better pharmacologic profile (22). bilize fat locally by /3-adrenergic stimulation or inhibition of a2- Growth hormone. Growth hormone is calorigenic (3) and has adrenergic receptors. This possibility has received tentative sup- been shown to reduce protein loss during low-calorie dieting (3). port by finding that local injection of isoproterenol, a 3-adren- However, growth hormone remains controversial and experi- ergic agonist, into one thigh of wornen on a diet increased the mental. The adverse effects of growth hormone, including de- rate of fat loss from the treated thigh. Local applications of a velopment of acrornegaly, make its use problematic. cream containing aminophylline to increase -adrenergic-like effects of yohimbine, an a2-adrenergic blocking drug, also in- Drugs affecting the gastrointestinal tract creased the mobilization of fat from the treated thigh. The possibility oftreating regional fat deposits by topical means has thus Because the taste of food, its digestibility, and its metabolism been proposed and awaits further testing (28). are related to the control of food intake, it is not surprising that approaches that alter these factors have been selected for devel- oprnent ofmedications for treatment ofobesity. Several different Conclusions drugs that modify the taste, digestion, or absorptive processes in the gastrointestinal tract have been tested. In spite of the daunting regulatory hurdles and widespread Enzyme inhibitors. Inhibition of fat digestion or absorption negative attitudes toward obesity, quite a few potentially useful induces malabsorption and thus reduces the available energy agents are under development and this may lead to changes in from fats in the diet. The antibiotic neomycin will increase the attitude and changes in methods of treatment (Table 3). Oem- fecal excretion of fat, but the changes in the intestinal rnucosa onstration of a role for the sympathetic nervous system in reg- caused by this drug make it unacceptable for clinical use in obe- ulation of energy expenditure has led to development of ther- sity (3). Cholestyramine is a resin that binds bile salts and thus mogenic drugs by several companies. At the present time, a din- disturbs rnicelle formation. When given to obese patients in large ical trial is available for only one such compound. Additional doses this drug does not increase fat loss significantly and is thus clinical trials with thermogenic drugs are awaited. These drugs ineffective in obesity (3). Drugs that inhibit disaccharidase en- are ofparticular interest because they can modify the distribution zyrnes in the intestine have also been tried but have not been ofenergy between fat and protein. They are biologically similar shown to increase weight loss over diet alone. Finally, a lipase to the effect observed with physical activity, ie, they increase inhibitor, tetrahydrolipostatin, has recently been described. In muscle and decrease fat stores. 544S BRAY

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2. Peptide agonists or antagonists 1 1. Bray GA, Gray OS. Treatment of obesity: an overview. Diabetes II. Thermogenic drugs Metab Rev 1988;4:653-79. I. -3 Adrenergic agonists 12. Griffiths RR, Brady iV, Bradford LD. Predicting the abuse liability 2. a-2 Adrenergic antagonists of drugs with animal drug self-administration procedures: psycho- 3. Growth hormone agonists motor stimulants and hallucinogens. Adv Behav Pharmacol 1979;2: III. Gastrointestinal drugs 163-208. 1. Enzyme inhibitors 13. NIH Consensus Development Conference Statement. Health im- 2. Inhibitors of absorption plications of obesity. Ann Intern Med l985;103:l073-7. 3. Synthetic foods 14. Maddox GL, Liederman V. Overweight as a social disability with medical implications. J Med Educ I 969;44:2 14-20. 15. Cohen MR, Cohen RM, Pickar 0, Murphy DL. Naloxone reduced food intake in humans. Psychosom Med l985;47:132-8. Additional drugs are under development, including centrally 16. Atkinson RC, Berke LK, Drake CR, Bibbs ML, Williams FL, Kaiser DL. Effects oflong-term therapy with naltrexone on body weight in acting metabolites and drugs that affect lipid digestion. Com- obesity. Clin Pharmacol Ther 1985;38:4l9-22. parative studies ofdrugs vs behavioral treatment have been car- 17. Morley JE. Neuropeptide regulation of appetite and weight. Endo- ned out for fenfluramine but are needed for other agents. crinol Rev l987;8:256-87. Most of the currently available drugs are safe and are under- 18. Astrup A, Toubro 5, Christensen NJ, Quaade F. Pharmacology of

utilized because ofperceptual, regulatory, and research barriers. Thermogenic Drugs. Am J Clin Nutr l992;55(suppl):000S-000S. Downloaded from Development of new drugs and use of old ones is hampered by 19. Arch iRS, Ainsworth AT, Cawthorne MA. Atypical fl-adrenoceptor public, professional, regulatory, research, and legislative barriers. on brown adipocytes as target for anti-obesity drugs. Nature Conceptually, all forms of experimental obesity can now be l984;309: 163-5. treated by drugs. Only more research and an improved regulatory 20. Munro iF, Chapman BJ, Robb GH, Zed C. Clinical studies with thermogenic drugs. In: Berry EM, Blondheim SH, 5hafrir E, eds. environment will bring their potential value to the public. fl Recent advances in obesity research V. London: John Libbey, 1987:

155-9. www.ajcn.org 21. Connacher AA, Mitchell PEG, Jung RT. Weight loss in obese subjects References on a restricted diet given BRL 26830A, a new atypical fl-adrenoceptor agonist.BrMedJ l988;26:l2l7-20. 1. Bray GA. Obesity-a disease of nutrient or energy balance? Nutr 22. Holloway BR, Howe R, Rao B5, Stribling D. ICID7 1 14: a novel Rev l987;452:33-43. selective fl-adrenoceptor agonist of brown fat and thermogenesis. by on April 30, 2010 2. Bray GA. Treatment for obesity: a nutrient balance/nutrient partition Am J Gin Nutr l992;55(suppl):000S-0005. approach. Nutr Rev 199 1;49:33-45. 23. Hauptman JB, Jeunet FS, Hartmann D. Initial studies in man with 3. Bray GA. The obese patient: major problems in internal medicine. the novel gastrointestinal lipase inhibitor, Ro 18-0647 (tetrahydro- Vol 9. Philadelphia: WB Saunders, 1976. lipstatin). Am J Clin Nutr 1992;55(suppl):000S-000S. 4. Weintraub M, Bray GA. Drug treatment ofobesity. Med Clin North 24. Glueck Ci, Jandacek R, Hogg E, Allen C, Baehler L, Trucksbury Am l989;73:237-50. M. Sucrose polyester: substitution for dietary fats in hypocaloric 5. Scoville BA. Review of amphetamine-like drugs by the Food and diets in the treatment of familial hypercholesterolemia. Am i Clin Drug Administration: clinical data and value judgments. In: Bray Nutr l983;37:347-54. GA, ed. Obesity in perspective. Bethesda, MD: National Institutes 25. Mellies MJ, Vitale C, Jandacek Ri, Lamkin GE, Glueck Ci. The of Health, 1975:441-3. [DHEW publication (NIH) 75-708.] substitution of sucrose polyester for dietary fat in obese, hypercho- 6. Weintraub M. Phenylpropanolamine as a anorexiant agent in weight lesterolemic outpatients. Am J Clin Nutr l985;4l:l-l2. control: a review ofpublished and unpublished studies. In: Morgan 26. Rolls BJ, Pirraglia P, Jones M, Peters J. Effect ofcovert fat replace- JP, Kagan DV, Brody is, eds. Phenylpropanolamine. Risks, benefits, ment with Olestra on 24-hour food intake in lean adults. FASEB i and controversies. New York: Praeger Scientific, 1985:53-79. 199 1;5:A l077(abstr). 7. Levine LR, Rosenblatt 5, Bosomworth J. Use ofa serotonin reuptake 27. Greenway FL, Bray GA. Human chorionic gonadotrophin (HCG) inhibitor, fluoxetine, in the treatment ofobesity. mt j Obes 1987; 1 1: in the treatment of obesity-a critical assessment of the Simeons 185-90. method. West J Med l977;127:46l-3. 8. Hudson KD. The anorectic and hypotensive effect of fenfluramine 28. Greenway FL, Bray GA. Regional fat loss from the thigh in obese in obesity. J R Coll Gen Pract l977;27:497-501. women after adrenergic modulation. Clin Ther 1987;9:663-9.