Clinical implications of appetite suppressants

Clinical Implications of Appetite Suppressants Edward Saltzman and Paul M. Hassoun CASE REPORT A

41-YEAR-OLD woman with a past medical history significant for asthma, tubal ligation, and mild systemic hypertension presented with the chief complaint of severe exertional dyspnea. She was essentially well until 6 weeks before presentation when she began to experience exertional dyspnea that progressed rapidly over the next few weeks. Her systemic hypertension had been wellcontrolled by lisinopril 10 mg/d and she was using inhaled bronchodilators and occasional steroid therapy to treat her asthma. Approximately 7 months before presentation, the patient, who was a long-time smoker (10 pack-year), had asked her primary care physician to prescribe an appetite suppressant. Although not markedly overweight, she intended to quit smoking and was concerned about possible weight gain following smoking cessation. Fen-phen (fenfluramine with phentermine) was prescribed, which the patient took daily for approximately 4 months. The drug was discontinued by the patient when she began experiencing nausea and vomiting, which she associated with drug intake. There was no history of illicit drug use, human immunodeficiency virus risk factors, connective tissue disease, or liver disease. Physical examination revealed a moderately overweight woman (92 kg and 163 cm), but was otherwise normal. A chest x-ray film revealed clear lungs and a significantly enlarged cardiac silhouette compared with a normal examination obtained 1.5 years previously. An echocardiogram revealed a markedly dilated right atrium and ventricle, septal paradoxical motion, 3+ tricuspid regurgitation, and an estimated pulmonary systolic pressure greater than 80 mm Hg. The left ventricular function was normal. The diagnosis of pulmonary hypertension was confirmed by right heart catheterization. Mean pulmonary arterial pressure was 50 mm Hg and pulmonary vascular resistance index 824 dynes, s/cmS/m2. A ventilation-perfusion scan and Doppler studies of the lower extremities were normal. Acute drug testing with oral calcium channel blocker, performed under hemodynamic monitoring, resulted in a 30% reduction in mean pul-

monary artery pressure and pulmonary vascular resistance index. The patient was given 120 mg of diltiazem slow release twice a day, which significantly improved her tolerance to exercise as assessed by a 6-minute walk test. She was also given warfarin daily. She remains stable on therapy 10 months after diagnosis, although a repeat echocardiogram has revealed no change in estimated pulmonary artery pressure.

TREATMENT OF OBESITY The treatment of obesity is the subject of considerable controversy. The prevalence of this condition is increasing, yet substantial recidivism is observed with most dietary and behavioral approaches. More recently, this controversy has been fueled by the debate surrounding pharmacologic treatments, their potential short- and longer-term benefits, and evolving knowledge of their risks. While a comprehensive review of obesity is well beyond the scope of this report, a compilation of recent trends in its prevalence, etiology, health consequences, and treatment has been recently published, l We primarily focus on the pharmacologic treatment of obesity, including previous and currently available drugs as well as investigational agents. Central to the issue of drug therapy for obesity is the balance between potential benefit versus potential risk; therefore, the risks and benefits of each agent, when known, are discussed.

From the Division of Clinical Nutrition and the Pulmonary and Critical Care DivisionlTupper Research Institute, Department of Medicine, New England Medical Center, Tufts University School of Medicine, and the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA. The contents of this publication do not necessarily reflect the views or policies of the United States Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States government. Address reprint requests to Paul 114, Hassoun, MD, New England Medical Center, Pulmonary and Critical Care Division, 750 Washington St, NEMC #128, Boston, MA 02111. Copyright 9 1998 by W.B. Saunders Company 0277-0326/98/1704-000258.00/0

Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 17, No 4 (December),1998: pp 273-286

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274

OBESITY: DEFINITION AND PREVALENCE Obesity is characterized by an excess of body fat, and the adverse health consequences of obesity are directly attributable to the excess and distribution of adipose tissue. Body fat is typically expressed as a percentage of body weight and can be measured by a number of simple or bedside methods, such as anthropometry, bioelectrical impedance, or by more complicated methods such as hydrodensitometry (underwater weighing), dual energy x-ray absorbtrometry, computed tomography, etc. Although not a direct measure of body fat, body weight is often used to categorize individuals as overweight. For decades, weight-for-height tables derived from actuarial data have been used as standards of ideal weight. A recently popularized method to classify weight for height is the body mass index (BMI). Use of the BMI allows classification without reference to specific weightfor-height tables. The BMI is calculated as BMI (kg/m 2) = weight (kg)/[height (m)] 2. Technically, the BMI describes weight in a relatively heightindependent manner, and the positive correlation between BMI and percent body fat permits assumptions regarding adiposity to be made based on BMI. In general, as BMI increases, so does body fat, except in the case of very muscular individuals or bodybuilders. While obesity and being overweight are technically different constructs, the terms will be used interchangeably in this review. The BMI at which overweight is defined is a matter of controversy. The US National Health and Nutrition Examination Surveys2 originally defined overweight using statistical criteria based on population norms: for women 27.3 kg/m 2 and for men 27.8 kg/m 2. It is in the range of these BMIs that weight-related comorbidity such as diabetes and hypertension is shown to dramatically increase, so these criteria remain clinically useful. Obesity is by far the most prevalent nutritional disease in the industrialized world. In 1991, approximately one in three Americans was overweight; in some United States subpopulations, the prevalence of overweight approaches or exceeds 50%. 2 Increases are also evident in many other industrialized and some developing countries. The reason for a worldwide increasing prevalence of obesity is the focus of considerable scrutiny. Clearly, dietary factors play a role and are likely to include the availability of an enormous

SALTZMAN AND HASSOUN selection of energy-dense and conveniently consumed foods, as well as the ever-enlarging portion size. Inadequate energy expenditure is also a substantial contributor. Leisure time spent participating in sedentary activities (such as television viewing) predicts overweight in both adults 3"4 and children. 5 Genetic factors are clearly implicated in the etiology of obesity in both animal models and studies of human heritance. 6'7 It must be noted, however, that the increase in prevalence of obesity outpaces the changes in our gene pool; genes may confer susceptibility to obesity, but we must look to environmental and behavioral factors to explain recent secular trends, s

EFFECTS OF OBESITY ON MORTALITY AND MORBIDITY There is a large body of evidence indicating that obesity is a major risk factor for cardiovascular disease, diabetes mellitus, and certain cancers, 9 and that it may be the second leading cause of preventable death in the United States after cigarette smoking-related conditions. Obesity is thought to be responsible for 300,000 annual deaths in the United States. 9 On the other hand, modest weight loss (approximately 10% of initial body weight) is often associated with improvement in blood pressure, serum lipid, and glucose disturbances, lo That this modest weight loss has beneficial effects on cardiovascular and metabolic morbidity and that larger losses are exceptionally difficult to maintain serve as the basis for recommendations concerning weight loss goals. With or without the use of anorectic drugs, weight loss of 5% to 15% of initial weight is a goal likely to reduce morbidity risk and to be sustainable over time. In addition, a 20% reduction in mortality has been reported in certain patient groups (ie, obese women with primarily diabetes mellitus and hypertension) after intentional weight loss. 11 However, this reported improvement in mortality has not been consistently demonstrated in all epidemiologic trials, lz However, while there is no doubt that significant weight reduction can be achieved by treatment with anorectic drugs, ~3 there is currently no known evidence that drug-induced weight reduction will prevent mortality in the obese population. Instead, the possible reduction in mortality has been inferred from data on the beneficial effects of inten-

ANORECTIC AGENTS tional weight reduction on comorbid conditions or from limited mortality data from some populations.

DRUG THERAPYOF OBESITY The use of pharmacologic adjuncts in the treatment of obesity has become immensely popular because of the growing number of individuals who are overweight and the perception that drugs will substantially facilitate weight loss efforts. Feasibility of drug-facilitated weight reduction is supported by numerous clinical trials, as presented below. Furthermore, in some trials, while an individual remains on a medication, beneficial effects on weight have persisted for years. 13 However, use of these drugs is now highly controversial due to recent reports of toxicity, such as cardiac valvular disease TM and pulmonary hypertension) 5 Aside from obvious concerns related to the risk to benefit ratio, use of drugs for weight loss is controversial given the current lack of data concerning long-term health benefit of weight lost with the assistance of drugs. Pharmacologic agents can be grouped by mechanism of action, whether (1) acting on the central nervous system to decrease food intake, (2) acting peripherally to increase energy expenditure (thermogenesis), or (3) by action in the gastrointestinal tract to limit digestion and/or absorption of ingested food. Table 1 summarizes important members of each class. While the mechanisms of action differ greatly, several features are common to all classes. No drug permanently cures obesity, and as with most chronic diseases, relapse (here manifested as weight gain) occurs when drugs are discontinued. For some patients, medications may facilitate behavioral and cognitive changes useful in the longer term (ie, post-drug), but this phenomenon has been neither well-studied nor widely documented. Another common feature of drug therapy is the amount of weight loss achieved in clinical trials. Most drugs have been roughly equivalent in facilitating an average weight loss in the range of 5% to 15% of initial weight when administered over 3 to 6 months. Medications do not, however, routinely promote massive weight loss, and their use should not modify weight loss goals based on moderate losses toward a healthier, but not ideal, weight. A cautionary note must accompany comparison of clinical trials involving medications. Trials differ dramatically in terms of the dietary, exercise, and behavioral interventions; therefore,

275 in many cases it is inappropriate to compare weight lost in one trial versus another.

Indications for Drug Treatment of Obesity Increased risks for morbidity and mortality are associated with a BMI greater than 30 kg/m2.16 Existing comorbidities such as hypercholesterolemia, diabetes mellitus, or hypertension at lower levels of BMI may increase mortality risk. These observations provide the rationale for consideration of drug therapy for individuals with a BMI -> 30 kg/m 2, or for those with existing comorbid conditions, a BMI of ---27 kg/m 2. It is important that patients understand that medication will serve only as an adjunct to a plan of dietary and lifestyle changes. Drug use is best considered to catalyze or reinforce efforts to modify food intake and related behavior. Drug use may augment weight loss in partial responders to dietary and lifestyle intervention or render responders from otherwise nonresponders. However, if an individual is already fully able to meet dietary and physical activity goals, the addition of a medication would likely be superfluous, as risks would outweigh the potential small benefit.

A Historical Note The human use of substances influencing appetite and body weight appears to predate written history, 17 although the exact time when the intended use of such compounds became focused on control of body weight (as opposed to other actual or imagined purposes) remains speculative. In more recent history, several substances have been incidentally found to decrease food intake and have been used as appetite suppressants. For example, industrial dyes were found to uncouple oxidative phosphorylation and were effective for weight loss, but were also unfortunately related to the development of neuropathy, l Thyroid hormones and extracts also have been used to induce weight loss. The potential cardiovascular toxicity, as well as the longer-term destructive effects on lean body mass and bone mass, make thyroid hormone use unacceptably risky. Amphetamine, introduced over 50 years ago, is perhaps the best known anorectic. The potent effects of amphetamine on body weight are accompanied by equally potent and addictive effects of central nervous system stimulation and induction of euphoria, which render this agent unacceptable for clinical use in

276

SALTZMAN A N D HASSOUN Table 1. PharmacologicAgents Available/Proposed to Treat Obesity

Class Centrally acting noradrenergic

Serotonergic

Agent (Trade Name) Phentermine* (Ionamin, Adipex-P, Fastin) Diethlyproprion* (Tenuate, Tepanil) Mazindol* (Mazanor, Sanorex) Phenylpropanolamine* (Acutrim, Dexatrim) Benzphetamine* (Didrex) Phendimetrazine* (Adipost, Bontril)

Usual Dose

Comments

15.0-37.5 mg qd

DEA schedule IV

25 mg tid/75 mg qdt

DEA schedule IV

1-2 mg qd

DEA schedule IV

25 mg bid-tid/75 mg qdt

OTC

25-50 mg qd

DEA schedule III

17.5-35 mg bid-tid/105 mg qdt

DEA schedule III

20 mg tid

Withdrawn September 1997 (see text) Withdrawn September 1997 (see text)

dI-Fenluramine (Pondimin) d-Fenfluramine (Redux) Fluoxetine (Prozac)

20-60 mg qd

Noradrenergic and serotonergic

Sibutramine* (Meridia)

5-15 mg qd

Thermogenic

Ephedrine

15 mg bid

Ephedra(ma-huang,

Monitor for increased blood pressure and heart rate Often accompanied by methylxanthine Use not recommended.

"herbal fen-phen') /32 and/33 agonist Inhibitors of digestion/ absorption

Others Opiod antagonists Peptides Nutrient partitioning

Tetrahydrolipstastin (Xenical) Acarbose (Precose)

Awaiting FDA review for approval April 1997. ?Long-term effect on weight demonstrated

Naloxone, naltrexone

?Long-term effect on weight demonstrated. Undergoing phase II clinical trials.

Leptin Cholecystokinin Growth hormone Testosterone

Abbreviations: qd, everyday; tid, three times a day; bid, two times a day; DEA, Drug EnforcementAgency; OTC, over the counter; FDA, Food and Drug Administration * Approved by the Food and Drug Administration for weight loss (as of March 1998). t Sustained release preparation.

weight control. The search for drugs capable of inducing anorexia, but without central nervous system stimulation and abuse potential, has led to the identification of a number of compounds structurally related to amphetamine but having substantially less, or no, abuse potential. Review of the chemical structures in Fig 1 illustrates that small

changes in structure can result in large differences in biological and behavioral effects.

Drugs Primarily Acting on the Central Nervous System The most numerous drugs, and the only drugs approved by the Food and Drug Administration,

277

ANORECTIC AGENTS Phentermine

Amphetamine

CH3 CHr~- NH3 CHz

D~thylpropion

Fenfluramine

Fsc ~ . _

O /CH2CH 3 C-CH-NH I ~, CH3 CH~CHa

Phenylpropanolamine

~CI-P-OH-NH 3

Sibutraraine CH~.--~cH~ I CH3 Cl'~(,"

Fig 1. Chemical structures of some anorectic drugs.

r

-4-3

9

"-CH2-- ?H"N H2---H2C-CH 3 CH3

Fluoxetine

F3C~

(~--CH'--CH,/"CH2-'NH

Aminorex

-~

~-C ~ C H 2 H=C~CH=

for the treatment of obesity (as of March 1998) are the centrally acting class. Drugs in this class promote weight loss by decreasing food intake, an effect presumably mediated by the central nervous system. Drugs can be classified by the primary neurotransmitter(s) affected, either serotonin or catecholamines, or both.

Serotonergic Drugs Two types of serotonergic agents have been widely used: the fenfluramines and the serotoninspecific reuptake inhibitors. Fenfluramines. dl-Fenfluramine and dexfenfluramine (the active d-isomer of fenfluramine) are phenethylamine derivatives primarily acting as serotonin releasers and possibly reuptake inhibitors.~S These drugs were widely used until September 1997, after which they were withdrawn due to concerns regarding cardiac valve disease (discussed in detail below). The drugs were shown to be efficacious in promoting weight loss in multiple

trials. In one trial involving dexfenfluramine, 64% of 404 patients treated with the drug over a period of 12 months achieved at least a 5% weight loss, with more than 20% of patients losing 15% of their body weight, 20% losing 10% to 14%, and another 20% losing 5% to 9%. w The combination of fenfluramine with phentermine (fen-phen) was shown to augment weight control in a trial lasting over 3 years, 13 which in large part stimulated the widespread use of this combination. Fenfluramine has been rarely associated with anesthetic complications, primarily hypotension, on induction. 2~ The cardiac and pulmonary problems associated with the fenfluramines are discussed in detail below.

Serotonin-specific

reuptake inhibitors.

The

use of serotonergic antidepressants has become popular worldwide. There has been considerable research effort aimed at demonstrating a beneficial effect of these agents on weight loss, and while none are approved for weight loss, off-label use for

278 this purpose is believed to be common. The serotonin-specific reuptake inhibitors used most in research has been fluoxetine, followed by sertraline. Fluoxetine is a bicyclic monoamine derivative of phenylpropanolamine (PPA), which acts as a highly specific serotonin reuptake inhibitor. The elimination half-life of fluoxetine is 1 to 4 days, while that of its active hepatic metabolite norfluoxetine is 7 to 15 days. 21 Fluoxetine has been used at doses up to 80 mg/d in placebo-controlled trials and weight loss occurs in dose-dependent fashion at doses up to 60 mg. 22 Many trials, 23-26 but not all, 27 have demonstrated superior weight loss with fluoxetine versus placebo. Fluoxetine appears to influence weight loss by mediating a decrease in food intake. While specific inhibition of carbohydrate has resulted in animals given fluoxetine, no clear macronutrient-specific effect has been consistently demonstrated in humans. 28 There are sparse and inconsistent reports that fluoxetine may effect small but meaningful increases in body temperature and energy expenditure. 29'3~ Also of interest are reports that fluoxetine may improve insulin sensitivity independent of its effect on body weight, 31'32 a phenomenon of potential importance in the monitoring of glycemia in diabetic patients.

Catecholaminergic Drugs The centrally acting catecholaminergic agents can be divided into (1) those agents whose mechanism of action is believed to be release or reuptake inhibition of norepinephrine and (2) those agents that act as alpha-adrenergic agonists.

Phentermine, mazindol, and diethylpropion. The noradrenergic agents phentermine, diethylpropion and mazindol are available in the United States and other countries. Although structurally different, the drugs are considered together, as their common mechanism of action is considered to be secondary to alterations in synaptic norepinephrine. Phentermine and diethylpropion are phenethylamine derivatives whose mechanism of action appears to be norepinephrine release, while mazindol is a tricyclic imidazo-isoindole compound whose mechanism of action appears to be reuptake inhibition of norepinephrine and, to a lesser extent, serotonin and dopamine. Most research documenting efficacy of these agents was conducted before 1980 (with the exception of mazindol, which appears to remain a

SALTZMAN AND HASSOUN subject of research effort in Japan), and has been reviewed by Scoville33 and more recently by Bray. TM These agents appear to be similarly efficacious and, as a class, can be considered to augment dietary and lifestyle interventions to a moderate extent (approximately 0.25 kg/wk lost beyond placebo), as was noted by Scoville. 33 Tolerance to these drugs, as to amphetamine, does develop and the anorectic effect wanes over several weeks. Some individuals, however, appear to derive longer-term benefit from stable doses, as demonstrated in trials up to 1 year. 33 Delayed gastric emptying with mazindol has been reported, 35 which may contribute to its beneficial effect in decreasing food intake. All three compounds are capable of central nervous system stimulation, but euphoria is rarely experienced and abuse potential is low (reflected in Drug Enforcement Agency schedule IV, in contrast to other adrenergic schedule III agents, such as phendimetrazine and benzphetamine). Increased blood pressure and heart rate may occur, although clinically significant hypertension and tachycardia are rare; caution in the setting of coronary artery disease and existing hypertension is suggested. Mazindol may especially potentiate the effect of pressor amines when given simultaneously. 36 Common side effects include dry mouth, insomnia, and constipation. There are rare reports of these agents inducing psychosis, 37 which has been reversible with withdrawal of the drug; depression (both during administration and following withdrawal) has been reported as well. While we are unaware of reports linking these agents specifically to hypotension with induction of anesthesia, this complication has been reported in patients taking the combination of phentermine and fenfluramine. The potential for catecholamine depletion secondary to use of releasing agents suggests that these agents be discontinued before anesthesia whenever possible. Phenylpropanolamine. Phenylpropanolamine is a phenethylamine consisting of a racemic mixture of the two enantiomers d- and 1-norephedrine. Unlike amphetamine, the levo-rotatory form appears to have considerably greater effect on food intake. 38 Phenylpropanolamine is available in the United States as an over-the-counter weight loss aid as well as a decongestant. While mechanisms by which PPA influence body weight in humans remain unclear, animal studies suggest that central

ANORECTIC AGENTS alpha-adrenergic stimulation, and resultant anorexia, is most likely to mediate the major effect. 38 An inhibitory effect on gastric emptying also has been noted ss and also may contribute to decreased food intake. No effect of PPA on basal metabolic rate, 24-hour energy expenditure, or respiratory quotient (indicating no greater utilization of fat for thermogenesis), after both 4 days and 7 weeks of treatment, was found in a small number of overweight women losing weight. 39 Thermogenesis and increased lipolysis, however, may underlie a portion of the effect of PPA in non-human species endowed with greater amounts of brown fat. 3s Elimination of PPA is primarily renal excretion of the unchanged drug, with a half-life of 2.7 to 3.4 hours; sustained release forms are available. Human trials of weight loss using PPA have been conducted for several decades and have been reviewed (for trials before 198540 and after 198541). Combined analysis suggests that trials conducted before 1985 demonstrated comparable efficacy to the prescription drugs evaluated by Scoville, s3 with a weight loss benefit of PPA beyond placebo of 0.27 kg/wk. 4~ As reviewed by Greenway, 41 trials conducted between 1985 and 1990 demonstrated a benefit of PPA beyond placebo of 0.14 kg/wk, and trials since 199039.42 demonstrate weight loss intermediate to the two previous analyses. It is likely that these upper and lower values describe the range of average weight loss to be reasonably expected with PPA. Phenylpropanolamine also has been found to diminish weight gain, but not other withdrawal phenomena, associated with smoking cessation. 43 While the stimulatory and euphoric effects of PPA do not appear to promote significant risk for abuse, hypertension with PPA remains a concern. While a well-designed large multicenter study indicated that the average acute effect of PPA on blood pressure may be in the range of 2 to 4 mm Hg, 42'44 other reports of blood pressure changes range from no increase to 22 mm and even to 50 m m Hg. 39'45 The balance of evidence appears to suggest that PPA will not adversely influence blood pressure in a clinically meaningful way for most patients. Given the possible risk of such occurrences, however, monitoring of blood pressure in patients taking PPA seems prudent.

279

Combined Catecholaminergic and Serotoninergic Sibutramine is the only drug used for weight loss in this class. Sibutramine is a phenethylamine derivative that inhibits reuptake of both serotonin and norepinephrine, and to a lesser extent, dopamine. It is of note that in animal studies, sibutramine has not been found to be associated with cerebral catecholamine depletion. 46 Approved by the Food and Drug Administration in 1997, sibutramine is now available in the United States at 5, 10, and 15 mg doses. Sibutramine is rapidly absorbed and undergoes extensive first-pass metabolism to two active metabolites, with elimination half-lives of 14 and 16 hours. Active drug is hepatically metabolized to two inactive forms, which are conjugated and primarily excreted in urine. In humans and animals, the effect of sibutramine on body weight appears to be mediated through central inhibition of food intake. Several placebocontrolled double-blind trials have demonstrated greater weight loss with sibutramine over placebo in obese humans. In a trial lasting 8 weeks, Weintraub et 8147 reported dose dependent weight loss with sibutramine 5 mg and 20 mg, both surpassing placebo. In a 12-week trial, 4s sibutramine 10 mg was comparable to dexfenfluramine 15 mg twice a day in promoting weight loss. Bray et al49 gave 173 overweight subjects sibutramine ranging from 1 mg to 30 mg or placebo, and demonstrated a significant weight loss benefit beyond placebo in doses greater than 10 mg. At the 15 mg dose (the maximum marketed dose in the United States), weight loss at 24 weeks was 6.9 kg or 7.8% of initial weight for women and 7.65 kg or 7.3% of initial weight for men, while the placebo groups experienced less than 1 kg loss. In that trial and others, a significant benefit of sibutramine over placebo was found in promoting a 5% to 10% weight loss. 49'50

The most common reported side effects of sibutramine include dry mouth, insomnia, constipation, and headache. The sympathomimetic properties of sibutramine result in risk for increases in blood pressure and heart rate, and in some individuals, clinically significant increases have been noted. While at multiple doses the average increase in systolic blood pressure or diastolic blood pressure was 1 to 3 mm, and the average increase in pulse was 4 to 5 beats/min (data on file, Knoll Pharmaceutical Co, Mount Olive, N J), a number of

280 individuals had substantially greater responses. At a dose of 15 mg, systolic blood pressure increases of -> 15 mm occurred in 13%, diastolic blood pressure increases of ->10 mm occurred in 17%, and increases in heart rate of --10 beats/min occurred in 24% (data on file, Knoll Pharmaceutical Co). As such, blood pressure and heart rate require monitoring, and use in those with uncontrolled hypertension is not advised. At this time, after limited premarketing exposure and very early clinical use, no reports of sibutramine-related pulmonary hypertension or cardiac valve disease are known. Given the potential for the rare but serious serotonin syndrome, the manufacturers of sibutramine recommend that the drug not be used simultaneously with other serotonergic antidepressants, with agents for headache that influence serotonin, and with some narcotic analgesics such as meperidine.

Thermogenic Drugs Ephedrine. Ephedrine is not approved for weight loss in the United States, but is available as such in some European countries and is available for the treatment of asthma and other respiratory maladies in the United States. Ephedrine is sometimes paired with methylxanthines or aspirin, which potentiate its effectsSl; doses of a common preparation are ephedrine 20 nag/caffeine 200 mg taken three times a day. Like other adrenergic drugs, concerns exist due to stimulatory effects on the cardiovascular system and central nervous system. Ephedrine appears to contribute to weight loss by both suppression of food intake and by stimulating thermogenesis. The thermogenic benefit may be as much as 5% to 10% of 24-hour energy expenditure. 52 Effects appear to be mediated via alpha- and beta-adrenergic receptors, and direct and indirect (releasing) effects may be involved as well. Ephedrine with caffeine has been shown to result in weight loss beyond placebo or either substance alone52 and has been equally as efficacious as dexfenfluramine when directly compared. 53 Buemann et al54 have reported that a hypocaloric diet combined with ephedrine did not result in diminished high-density lipoprotein cholesterol compared with a significant decrease seen in high-density lipoprotein cholesterol with diet alone. The investigators suggest that the beta-adrenergic stimulation may prevent the declines in high-density lipoprotein cholesterol observed with

SALTZMAN AND HASSOUN weight loss as well as with use of beta-adrenergic blocking agents. 54 Herbal sympathornimetics. In the United States, the regulation of dietary supplements is less rigorous than that for drugs. A number of products containing naturally occurring sympathomimetic compounds are readily available. Indeed, before, and especially since, the withdrawal of the fenfluramines, "herbal fen-phen" (a combination of Ephedra and St John's Wort) has been widely advertised. One of the most popular substances marketed for weight loss is Ephedra, also known as ma-huang. Interestingly, Ephedra was found among collected plants in a paleolithic grave dating to 60,000 Bc and has been used in traditional Chinese medicine for millenniaJ 7 The available Ephedra preparations usually contain E sinica, but also may contain E intermedia and E equisentia. Ephedra contains variable amounts of ephedrine as well as norpseudoephedrine, norephedrine, and methylephedrine. Often combined with other stimulants such as methylxanthines, Ephedra may result in reduced food intake, thermogenesis, and central nervous system and cardiovascular effects. The central nervous system stimulatory effects of Ephedra combined with other central nervous system-active substances have made some preparations popular as "energy pills. ''55 A number of serious adverse events and deaths have been associated with use of Ephedra products, including myocardial infarction, stroke, and psychosis. At this time, three factors prohibit recommendation of these compounds for use in weight loss: few data exist concerning the amounts of ephedrine-like compounds in preparations, combinations of substances found in compounds or taken along with compounds may potentiate the risk for adverse events, and there are few data identifying patient characteristics or pre-existing medical problems that increase risk or adverse events. Accordingly, many states and the Food and Drug Administration have cautioned against use of these compounds. [33 Adrenergic agonists. A third type of betaadrenergic receptor, the [33-adrenergic receptor, has been characterized, and [33 stimulation appears to play roles in thermogenesis, lipolysis, and insulin sensitivity in some animal species. 56'57 The simultaneous publication in 1995 of three studies linking a human [33-adrenergic receptor mutation with proclivity to weight gain 58 and early onset of diabetes 59"6~ brought the [33-adrenergic receptor

ANORECTIC AGENTS into the spotlight. Whether, and how, the /33-adrenergic receptor plays an important role in human energy regulation remains unclear. /33-Adrenergic receptors in humans are found in white fat (visceral more than subcutaneous) and in the small amounts of brown fat present, and in the intestine.56 Administration of/33-specific compounds to humans has met with mixed success in stimulating thermogenesis, lipolysis, and altered substrate oxidation, and also has been reported to induce side effects such as tremor. 57"61"63 It remains unclear whether the metabolic effects noted with agonists are attributable specifically to/33 (v other/3) stimulation. The/33 story is far from resolved and considerable advances are likely in the near future. The colonic antimotility effects of/33 agonists also may hold promise for disorders of intestinal hypermotility such as irritable bowel syndrome.56

Drugs Affecting Digestion and Absorption Tetrahydrolipstatin. Inhibition of digestion and/or absorption of ingested food is another mechanism that limits positive energy balance. Tetrahydrolipstatin is an inhibitor of gastric and pancreatic lipase and results in fecal excretion of approximately 30% of dietary fat.64 Approximately 1% of the drug is systemically absorbed; since the drug likely inhibits multiple lipases in addition to intestinal lipases, minimal systemic absorption is an important feature in preventing inhibition of lipid metabolism outside the gut. The inhibition of fat digestion and assimilation accounts for both the effects and side effects of the drug. If a diet of approximately 2,000 calories/d was consumed, and fat constituted 33% of dietary energy, approximately 200 calories/d would be excreted and would theoretically lead to a loss of approximately 9 kg over 1 year. Another potential but as yet unproven effect of the drug is to inhibit overeating of a high-fat diet, as this would lead to increased fecal excretion of fat with attendant unpleasant symptoms. James et al65 reported a yearlong trial of tetrahydrolipstatin versus placebo and found that at 6 months the drug group lost 8.6 kg (v 5.5 with placebo); this loss was maintained at 1 year in the drug group while the placebo group had significantly regained. Small decreases in some fat-soluble vitamin concentrations have been noted with use of tetrahydrolipstatin, but the magnitude of these decreases is likely to be clinically unimportant (data on file, Roche Laboratories Inc);

281 however, it remains prudent to instruct patients to take an additional multivitamin while using the drug. Concomitant use with lipid-based drugs such as cyclosporine is contraindicated due to the potential for irregular absorption of these drugs.

ANORECTIC DRUGS AND PRIMARY PULMONARY HYPERTENSION Pulmonary hypertension is defined as an increase in the systolic pulmonary artery pressure above 25 mm Hg at rest or 30 mm Hg with exertion or an increase in the mean pulmonary artery pressure above 18 mm Hg at rest. Significantly less common than secondary pulmonary hypertension in which an identifiable etiology is present (eg, chronic thromboembotic disease and cardiac malformations such as atrial septal defect), primary pulmonary hypertension (PPH) affects predominantly young women without apparent cause. 66 Reports of familial PPH suggest a genetic susceptibility.67 Other predisposing factors include portal hypertension and chronic liver disease, 6s'69 pregnancy, and human immunodeficiency virus infection.7~ Exogenous factors such as cocaine use, oral contraceptive pills, 71 and appetite suppressants 72-74 also have been identified. Despite the identification of associated, but apparently unrelated, clinical syndromes or the presence of exogenous factors, the resulting pulmonary hypertension is conventionally referred to as primary since clinical and histologic findings are indistinguishable from PPH. Primary pulmonary hypertension is clinically characterized by progressive dyspnea, an increase in pulmonary vascular resistance leading to right cardiac failure, cor pulmonale, and, ultimately, death. 66 The median life expectancy is usually less than 3 years after the onset of symptoms.75 The pathologic findings include pulmonary vascular remodeling with medial hypertrophy and the characteristic plexogenic arteriopathy.TM

Primary Pulmonary Hypertension Related to Appetite-Suppressant Drugs The most notorious outbreak of severe pulmonary hypertension related to appetite suppressants occurred approximately 1 year after the drug aminorex fumarate was released in Austria, Switzerland, and Germany.73 Between the years 1967 and 1972, the incidence of severe pulmonary hypertension increased sharply in these countries. A retrospective cooperative study reported 582 cases as-

282 sociated with the use of this drug. 73 The causeeffect relationship of aminorex and PPH was confirmed by epidemiologic data, although no animal model of aminorex-induced PPH could ever be established. Half of the patients had died within a decade of the report. 77 Half of the patients who were still alive after 10 years had evidence of normal hemodynamics at rest, but a significant increase in pulmonary vascular resistance with exercise when restudied with cardiac catheterization. 77 Sadly, half of the patients affected with the disease weighed only 10% over their ideal body weight. 77 This fact, as also illustrated by our introductory clinical case, underlines the dramatic consequence of misuse of such drugs when liberally prescribed.

Primary PulmonaryHypertension AssociatedWith Fenfluramine and Related Drugs The first single case reports of PPH related to the intake of fenfluramine emerged in 1981 and 1982. 72,78 Other sporadic cases (a total of 10) followed, which were associated with the use of fenfluramine derivatives (including eight cases related to the use of dl-fenfluramine and two related to dexfenfluramine). 79-83 These cases were initially thought to have a better survival than PPH in general, and reversal of disease was described in some patients. 72 Five of the 10 cases of fenfluramine-related PPH showed spontaneous clinical and hemodynamic remission that was partial or complete 72'78-8~ 1 to 3 months after withdrawal of therapy. However, in a 5-year retrospective study, Brenot et a l TM not only linked the development of pulmonary hypertension to fenfluramine use in an additional 15 patients, but also demonstrated that prognosis in these patients was not significantly better than that of patients with classic PPH. TM Eight of the 15 patients described developed symptoms within 12 months after the start of treatment, a time interval similar to that described by Gurtner for the aminorex epidemic. 73 It is noteworthy that all users of fenfluramine in this report were female, TM a finding ascribed to the higher likelihood of women using appetite suppressants and consistent with the epidemiologic finding of increased susceptibility to PPH in this gender. 75 Only three of the 15 patients had clinical and hemodynamic improvement after withdrawal of the drug; however, one of these three patients later experienced worsening and eventually died. TM Overall survival

SALTZMAN AND HASSOUN in this group was no different (42% survival at 3 years) from that of a control group of patients with PPH unrelated to appetite suppressants (50% survival at 3 years), after exclusion in each group of a few patients who received therapy with lung transplantation. TM Histologic examination of lung tissue in patients with fenfluramine-induced PPH (from three autopsy and two heart and lung transplantations) showed features of advanced plexogenic pulmonary arteriopathy, indistinguishable from those of control patients with PPH unrelated to drug intake. In a recent retrospective case-control study conducted in four countries (France, Belgium, the United Kingdom, and the Netherlands), the use of anorectic drugs (mainly fenfluramine and its derivative dexfenfluramine, as well as amphetaminelike anorectic agents) was associated with a significantly increased risk of PPH, with an odds ratio of 23:1 when these drugs were used for more than 3 months. 15 The odds ratio increased sharply with the duration of the exposure starting with a 1.8 odds ratio for a period of -<3 months. Therefore, even a short duration of exposure (<3 months) was associated with the development of PPH, similar to a report from Switzerland related to aminorex intake in which one patient took the drug for only 3 weeks, three patients took the drug for 1 month, and the remaining patients took the drug for ->3 months. 84 In a recent report of fatal pulmonary hypertension related to the intake of fen-phen, duration of therapy was only 23 days and the patient died 8 months after initiation of treatment. 85 Although pre-existing disease could not be ruled out in this particular case, the histologic age of the pulmonary lesions (ie, plexogenic arteriopathy) were thought to be consistent with the time elapsed between the patient's death and ingestion of the drug combination. In the European study by Abenhaim et al, 15 the effect of anorectic agents was the same whether the patients had a high BMI or not, 15 but cases were not specifically matched by degree of overweight with controls. This study also confirmed an association between PPH and predisposing factors such as human immunodeficiency virus infection, cirrhosis, and the use of cocaine or intravenous drugs. In an eloquent and, retrospectively, perhaps daring, editorial 86 published before the report of valvular pathology associated with the use of fenphen, 14 and the voluntary withdrawal by the man-

ANORECTIC AGENTS ufacturer of the drug, Manson and Faich argued that the benefit to risk ratio of treatment with appetite-suppressant drugs was 20:1, based on the assumption that 280 lives might be saved by weight reduction (a figure extrapolated from data related to the Nurses' Health Study 87) as opposed to an estimated 14 deaths per million person-years for drug treatment. The latter figure was also extrapolated from the recent European study linking appetite-suppressant drugs and primary pulmonary hypertension 15 assuming a very conservative 50% mortality rate in patients afflicted with the complication. However, the investigators appropriately concluded that appetite suppressants should be used with caution and only in patients with marked obesity. 86

FENFLURAMINE DERIVATIVES AND VALVULAR HEART DISEASE A recent report from the Mayo Clinic linking an outbreak of serious valvular disease to the intake of fenfluramine-phentermine raised significant concern about toxicity of these agents, an This report shortly preceded the motion by the Food and Drug Administration to ask the manufacturer to voluntafily withdraw the drug from the market. Because this study raised an important public health issue, the editors of the New England Journal of Medicine made the rather unusual decision to allow the findings of the study to be released to the general public more than 7 weeks before publication of the study in their journal, as Twenty-four women with no prior history of cardiovascular disease presented with cardiac symptoms or a heart murmur an average of 12 months after treatment with fen-phen. The patients had unusual echocardiographic findings with fightsided and left-sided heart valve changes thought to be unusual for rheumatic, congenital, or degenerative lesions and that were consisted mainly of thickening and shortening of the chordae tendinae (mitral valve) and thickening and retraction of the leaflets (aortic and tricuspid valves). Regurgitation was present in all cases. Five patients required cardiac surgical intervention that revealed plaquelike encasement of the leaflets and chordal structure with intact valve architecture, findings that were thought to be identical to those seen in carcinoid or ergotamine-induced valve disease. Of note is that eight of the 24 patients described had either Doppler echocardiographic or catheter evi-

283 dence of pulmonary hypertension that had not been documented previously. TM A report from the Food and Drug Administration published in the form of a letter simultaneously with this study described an additional 28 patients who developed similar valvular disease a mean of 10 months after initiation of therapy with fenfluramine-phentermine.89 The patients were also all female and all had valvular insufficiency, and fenfluramine or phentermine doses of more than 30 mg/d were associated with multivalvular disease. Two patients required valve replacement surgery within 1.5 years. 89 Another letter in the same issue of the New England Journal of Medicine described severe mitral valve regurgitation and thickening in a 32-year-old woman who had been taking dexfenfluramine for a period of 10 months. 9~ As more reports emerge that are related to the toxic effects of appetite suppressant drugs on cardiac valves, the exact impact of these drugs and the prevalence of the cardiac disease in these patients will become clearer. The prevalence of cardiac abnormalities (significant aortic insufficiency or mitral regurgitation) is reported to be as high as 45%. 91 However, newer data (unpublished) suggest that these initial reports of valve disease may considerably overstimate valve disease found in other centers. 92 Many questions remain about the true risk of valvular disease and susceptible populations at this time.

PATHOGENIC MECHANISMS OF APPETITE SUPPRESSANT-RELATED DISEASES The mechanisms involved in the development of PPH after fenfluramine and dexfenfluramine use remain unclear. It is noteworthy that these compounds, as well as the chemically related aminorex drug, inhibit potassium current in rat pulmonary vascular smooth muscle causing pulmonary vasoconstriction through membrane depolarization. 93 Increased level of serotonin by these drugs has been incriminated in the pathogenesis of the vascular remodeling. 94 This increase is secondary to blockade of serotonin reuptake during neurotransmission, excessive release of serotonin into synapses, and activation of serotonin 5HT2 receptors. Serotonin has mitogenic activity on smooth muscle cells in vitro95 and has been shown to be spontaneously elevated in family members with a platelet storage disorder who are afflicted with pulmonary hypertension. 96 However, despite circumstantial

SALTZMAN AND HASSOUN

284 evidence incriminating serotonin in the development of PPH, the exact role of this neurotransmitter remains elusive. The valvular heart lesions that have been related to fen-phen intake are also of unclear etiology. The lesions are very reminiscent of those seen in the malignant carcinoid syndrome, which is characterized by high levels of circulating serotonin. 97 However, it should be noted that high levels of serotonin are not consistently seen in patients taking fenfluramine.

CONCLUSION There can be no doubt that obesity is a common condition associated with multiple serious health risks. The use of medications to promote and maintain weight loss is in principle an attractive strategy to combat this widespread problem. To date, medications have been shown to be useful in promotion of weight loss and maintenance. However, demonstration that these changes in body weight translate to improved long-term morbidity and mortality are currently lacking. There appears to be a risk of pulmonary hypertension associated with appetite suppressant medications, but the exact nature of this risk and the medication most likely to produce this complication remain unclear given the low incidence of disease. Fenfluramine and its active isomer dexfenfluramine have been associated with valvular heart disease; the true incidence and pathogenesis of this valvular disease is unclear at present, but these issues will likely be much better defined in the very near future. The use of appetite suppressant drugs remains a potentially useful modality to accompany more traditional obesity interventions, but both the practitioner and patient should recognize that knowledge concerning benefits and risks of these agents is still accumulating rapidly.

REFERENCES 1. Bray GA: Pharmacological treatment of obesity, in Bray GA, Bouchard C, James WP (eds): Handbook of obesity. New York, NY, Marcel Dekker, 1998, pp 953-974 2. Kuczmarski RJ, Flegal KM, Campbell SM, et al: Increasing prevalence of overweight among US adults: The National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA 272:205-211, 1994 3. Gardner AW, Poehlman ET: Physical activity is a significant predictor of body density in women. Am J Clin Nutr 57:8-14, 1993

4. Gardner AW, Poehlman ET: Leisure time physical activity is a significant predictor of body density in men. J Clin Epidemiol 47:283-291, 1994 5. Obarzanek E, Schreiber GB, Crawford PB, et al: Energy intake and physical activity in relation to indexes of body fat: The National Heart, Lung, and Blood Institute Growth and Health Study. Am J Clin Nutr 60:15-22, 1994 6. Bouchard C: The genetics of obesity. Boca Raton, FL, CRC Press, 1994 7. Ravussin E, Tataranni PA: Dietary fat and human obesity. J Am Diet Assoc 97:$42-$46, 1997 8. Flatt JP: McCollum award lecture, 1995: Diet, lifestyle, and weight, maintenance. Am J Clin Nutr 62:820-836, 1995 9. McGinnis JM, Foege WH: Actual causes of death in the United States. JAMA 270:2207-2212, 1993 10. Daly PA, Solomon CG, Manson JE: Risk modification in the obese patient, in Manson JE, Ridker PM, Gaziano JM, et al (eds): Prevention of myocardial infarction. New York, NY, Oxford University Press, 1996, pp 203-240 11. Williamson DF, Pamuk E, Thun M, et al: Prospective study of intentional weight loss and mortality in never-smoking overweight US white women aged 40-64 years. Am J Epidemiol 141:1128-1141, 1995 12. Blair SN, Lee I-M: Weight loss and risk of mortality, in Bray GA, Bouchard C, James JPT (eds): Handbook of obesity. New York, NY, Marcel Dekker, 1998, pp 805-818 13. Weintraub M, Hasday JD, Mushlin AI, et al: A doubleblind clinical trial in weight control: Use of fenfluramine and phentermine alone and in combination. Arch Intern Med 144: 1143-1148, 1984 14. Connolly HM, Crary JL, McGoon MD, et al: Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 337:581-588, 1997 15. Abenhaim L, Moride Y, Brenot F, et al: Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 335:609-616, 1997 16; Stevens J, Cal J, Pamuk ER, et al: The effect of age on the association between body-mass index and mortality. N Engl J Med 338:1-7, 1998 17. Lietava J: Medicinal plants in a middle paleolithic grave shanidar IV? J Ethnopharmacol 35:263-266, 1991 18. Sugrue MF: Neuropharmacology of drugs affecting food intake. Pharmacol Ther 32:145-182, 1987 19. Guy-Grand B, Apfelbaum M, Crepaldi G, et al: International trial of long-term dexfenfluramine in obesity. Lancet 2:1142-1145, 1989 20. Jeffers LA: Anesthetic considerations for the new antiobesity medications. J Am Assoc Nurs Anesthetists 64:541544, 1996 21. Altamura AC, Moro AR, Percudani M: Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet 26:201-214, 1994 22. Levine LR, Enas GG, Thompson WL, et al: Use of fluoxetine, a selective serotonin-uptake inhibitor, in the treatment of obesity: A dose-response study. Int J Obes 13:635-645, 1989 23. O'Kane M, Wiles PG, Wales JK: Fluoxetine in the treatment of obese type 2 diabetic patients. Diabetic Med 11: 105-110, 1994 24. Visser M, Seidell JC, Koppeschaar HPF, et al: The effect of fluoxetine on body weight, body composition and visceral fat accumulation. Int J Obes 17:247-253, 1993

ANORECTIC AGENTS 25. Goldstein DJ, Rampey AH, Enas GG, et al: Fluoxetine: A randomized clinical trial in the treatment of obesity. Int J Obes 18:129-135, 1994 26. Connolly VM, Gallagher A, Kesson CM: A study of fluoxetine in obese elderly patients with type 2 diabetes. Diabetic Med 12:416-418, 1995 27. Fernandez-Soto ML, Gonzalez-Jimenez A, BarredoAcedo F, et al: Comparison of fluoxetine and placebo in the treatment of obesity. Ann Nutr Metab 39:159-163, 1995 28. Silverstone T: Appetite suppressants. Drugs 43:820-836, 1992 29. Bross R, Joffer LJ: Fluoxetine increases resting energy expenditure and basal body temperature in humans. Am J Clin Nutr 61:1020-1025, 1995 30. Stinson JC, Murphy CM, Andrews JF, et al: An assessment of the thermogenic effects of fluoxetine in obese subjects. Int J Obes 16:391-395, 1992 31. Maheux P, Ducros F, Bourque J, et al: Fluoxetine improves insulin sensitivity in obese patients with non-insulindependent diabetes mellitus independently of weight loss. Int J Obes 21:97-102, 1997 32. Breum L, Bjerre U, Bak JF, et al: Long-term effects of fluoxetine on glycemic control in obese patients with noninsulin-dependent diabetes mellitus or glucose intolerance: Influence on muscle glycogen synthase and insulin receptor kinase activity. Metabolism 44:1570-1576, 1995 33. Scoville B: Review of amphetamine-like drugs by the Food and Drug Administration: Clinical data and value judgements, in Obesity in perspective. DHEW Publication No. (NIH) 75-708, pp 441-443 34. Bray GA: Use and abuse of appetite-suppressant drugs in the treatment of obesity. Ann Intern Med 119:707-713, 1993 35. Jonderko K, Kucio C, Skrzypek D: Slowed gastric evacuation accounts for the reduction of food intake by anorectic drugs. Eur J Clin Nutr 42:627-631, 1988 36. American Medical Association: Drug evaluations annual. Chicago, IL, American Medical Association, 1995 37. Carney MWP: Diethylpropion and psycosis. Clin Neuropharmacol 11:!83-188, 1988 38. Wellman PJ: A review of the physiological bases of the anorexic action of phenylpropanolamine (d,l-norephedrine). Neurosci Biobehav Rev 14:339-355, 1990 39. Alger S, Larson K, Boyce VL, et al: Effect of phenylpropanolamine on energy expenditure and weight loss in overweight women. Am J Clin Nutr 57:120-126, 1993 40. Weintraub M: Phenylpropanolamine as an anorexiant agent in weight control: A review of published and unpublished studies, in Morgan JP, Kagan DV, Brody JS (eds): Phenylpropanolamine--Risks, benefits, and controversies. Clinical Pharmacology and Therapuetic Series. Vol 5. New York, NY, Prager Scientific, 1985 41. Greenway FL: Clincal studies with phenylpropanolamine: A metaanalysis. Am J Clin Nutr 55:203S-205S, 1992 42. Schteingart DE: Effectivesness of phenylpropanolamine in the management of moderate obesity. Int J Obes 16:487-493, 1992 43. Klesges RC, Klesges LM, DeBon M, et al: Effects of phenylpropanolamine on withdrawal symptoms. Psychopharmacology (Bed) 119:85-91, 1995

285 44. Blackburn GL, Morgan JP, Lavin PT, et al: Determinants of the pressor effect of phenylpropanolamine in healthy subjects. JAMA 261:3267-3272, 1989 45. Morgan JP, Funderburk FR: Phenylpropanolamine and blood pressure: A review of prospective studies. Am J Clin Nutr 55:206S-210S, 1992 46. Buckett WR, Thomas PC, Luscombe GP: The pharmacology of sibutramine hydrochloride: (BTS 54 524), a new antidepressant which induces rapid noradrenergic down-regulation. Prog Neuropsychopharmacol Biol Psychiaty 2:575-584, 1988 47. Weintraub M, Rubio A, Golik A, et al: Sibutramine in weight control: A dose-ranging, efficacy study. Clin Pharmacol Ther 50:330-337, 1991 48. Kelly F, Wade AG, Jones SP, et al: Sibutramine hydrochloride vs dexfenfluramine: Weight loss in obese subjects. Int J Obes 18:61, 1994 (suppl 2) 49. Bray GA, Ryan DH, Gordon D, et al: A double-blind randomized placebo-controlled trial of sibutramine. Obes Res 4:263-270, 1996 50. Jones SP, Smith IG, Kelly F, et al: Long term weight loss with sibutramine. Int J Obes 19:41, 1995 (suppl 2) 51. Atkinson RL, Blank RC, Loper JF, et al: Combined drug treatment of obesity. Obes Res 3:497S-500S, 1995 (suppl 4) 52. Astrup A, Breum L, Toubro S: Pharmacological and clincal studies of ephedrine and other thermogenic agonists. Obes Res 3:537S-540S, 1995 (suppl 4) 53. Breum L, Pedersen JK, Ahlstrom F, et al: Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice. Int J Obes 18:99-103, 1994 54. Buemann B, Marckmann P, Christensen NJ, et al: The effect of ephedrine plus caffeine on plasma lipids and lipoproteins during a 4.2 MJ/day diet. Int J Obes 18:329-332, 1994 55. White LM, Gardner SF, Gurley BJ, et al: Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults. J Clin Pharmacol 37:116-122, 1997 56. Lipworth BJ: Clincal pharmacology of/33-adrenoceptors. Br J Clin Pharmacol 42:291-300, 1996 57. Arch JRS, Wilson S: Prospects for 133-adrenoceptor agonists in the treatment of obesity and diabetes, lnt J Obes 20:!91-199, 1996 58. Clement K, Valsse C, Manning BS, et al: Genetic variation in the/33-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med 333:352-354, 1995 59. Walston J, Silver K, Bogardus C, et al: Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the/33-adrenergic-receptor gene. N Engl J Med 333:343-347, 1995 60. Widen E, Lehto M, Kanninen T, et al: Association of a polymorphism in the/33-adrenergic-receptor gene with features of the insulin resistance syndrome in finns. N Engl J Med 333:348-351, 1995 61. Connacher AA, Bennet WM, Jung RT: Clincal studies with the/3-adrenoceptor agonist BRL 26830A. Am J Clin Nutr 55:258S-261S, 1992 62. Cawthorne MA, Sennitt MV, Arch JRS, et al: BRL 35135, a potent and selective atypical/3-adrenoceptor agonist. Am J Clin Nutr 55:252S-257S, 1992

286 63. Goldberg GR, Prentice AM, Murgatroyd PR, et al: Effects on metabolic rate and fuel selection of a selective /3-3 agonist (ICI D7114) in healthy lean men, Int J Obes 19:625631, 1995 64. Guerciolini R: Mode of action of orlistat. Int J Obes 21:S12-$23, 1997 (suppl 3) 65. James WPT, Avenell A, Broom J, et al: A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes 21:$24-$30, 1997 (suppl 3) 66. Rubin LJ: Primary pulmonary hypertension. Chest 104: 236-250, 1993 67. Loyd JE, Slovis B, Phillips JAI: The presence of genetic anticipation suggests that the molecular basis of familial primary pulmonary hypertension may be a trinucleotide repeat expansion. Chest 111:82S-83S, 1997 (suppl) 68. Hadengue A, Benhayoun MK, Lebrec D, et al: Pulmonary hypertension complicating portal hypertension: Prevalence and relation to splanchnic hemodynamics. Gastroenterology 100:520-528, 1991 69. McDonnell PJ, Toye PA, Hutchins GM: Primary pulmonary hypertension and cirrhosis: Are they related? Am Rev Respir Dis 127:437-441, 1983 70. Legoux B, Piette AM, Bouchet PE, et al: Pulmonary hypertension and HIV infection. Am J Med 89:122, 1990 71. Kleiger RE, Boxer M, Ingham RE, et al: Pulmonary hypertension in patients using oral contraceptives: A report of six cases. Chest 69:143-147, 1976 72. Douglas JG, Munro JF, Kitchin AH, et al: Pulmonary hypertension and fenfluramine. BMJ 283:881-883, 1981 73. Gurtner HP: Pulmonary hypertension, "plexogenic pulmonary arteriopathy" and the appetite depressant drug aminorex: Post or propter? Bull Eur Physiopath Resp 15:897-923, 1979 74. Brenot F, Herve P, Petitpretz P, et al: Primary pulmonary hypertension and fenfluramine use. Br Heart J 70:537-541, 1993 75. Rich S, Dantzker DR, Ayres SM, et al: Primary pulmonary hypertension: A national prospective study. Ann Intern Med 107:216-223, 1987 76. Wagenvoort CA, Wagenvoort N: Primary pulmonary hypertension. A pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 42:1163-1184, 1970 77. Gurtner HP: Aminorex pulmonary hypertension, in Fishman AP (ed): The pulmonary circulation. Philadelphia, PA, University of Pennsylvania Press, 1990, pp 397-411 78. Gaul G, Blazek G, Deutsch E, et al: Ein fall von chronischer pulmonaler hypertonie nach Fenfluramineinahme. Wien Klin Wochenschr 22:618-621, 1982 79. Pouwels HMM, Smeets JLRM, Cheriex EC, et al: Pulmonary hypertension and fenfluramine. Eur Respir J 3:606-607, 1990 80. Atanassof PG, Weiss BM, Schmid ER, et al: Pulmonary hypertension and dexfenfluramine. Lancet 339:436, 1992

SALTZMAN AND HASSOUN 81. McMurray J, Bloomfield P, Miller HC: Irreversible pulmonary hypertension after treatment with fenfluramine. BMJ 292:239-240, 1986 82. Fotiadis I, Apostolou T, Koukoulas A, et al: Fenfluramine-induced irreversible pulmonary hypertension. Postgrad Med J 67:776-777, 1991 83. Roche N, Labrune S, Braun JM, et al: Pulmonary hypertension and dexfenfluramine. Lancet 339:436-437, 1992 84. Follath F, Burkart F, Schweizer W: Drug-induced pulmonary hypertension. BMJ 1:265-266, 1971 85. Marks EJ, Patalas ED, Chang HT, et al: Brief report: Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl J Med 337:602-606, 1997 86. Manson JE, Faich GA: Pharmacotherapy for obesity--Do the benefits outweigh the risks. N Engl J Med 335:659-660, 1996 (editorial) 87. Manson JE, Willett WC, Stampfer MJ, et al: Body weight and mortality among women. N Engl J Med 333:677-685, 1995 88. Curfman GD: Diet pills Redux. N Engl J Med 337:629630, 1997 89. Graham DJ, Green L: Further cases of valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 337:635, 1997 (letter) 90. Cannistra LB, Davis SM, Banman AG: Valvular heart disease associated with dexfenfluramine. N Engl J Med 337: 636, 1997 (letter) 91. Griffen L, Anchors M: Asymptomatic mitral and aortic valve disease is seen in half of the patients taking 'phen-fen.' Arch Intern Med 158:102, 1998 92. Rosen MD, Takeuchi M, Teupe C, et al: Are dexfenfluramine, fenfluramine and phentermine associated with valvular heart disease? Blinded analysis of 107 patients with matched controls. J Am Soc Echocardiogr (in press) 93. Weir KE, Reeve HL, Huang JMC, et al: Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation 94:22162220, 1996 94. Herve P, Launay J-M, Scrobohaci M-L, et al: Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99:249-254, 1995 95. Fanburg BL, Lee SL: A new role for an old molecule: Serotonin as a mitogen. Am J Physiol 272:L795-L806, 1997 96. Herve P, Drouet L, Dosquet C, et al: Primary pulmonary hypertension in a patient with a familial storage pool disease: Role of serotonin. Am J Med 89:117-120, 1990 97. Robiolio PA, Rigolin VH, Wilson JS, et al: Carcinoid heart disease: Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 92:790-795, 1995