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Drug. Therapy for Obesity: An Update
Drug .Therapy for Obesity: An Update Drug therapy plays an important
cOfflpletnentary role in an integrated strategy for managing obesity. by Nicholas G. Popovich, PhD, and Olivia B. Wood, MPH
In troduction Obesity is fmally becoming recognized as a chronic disease process with adverse health consequences. Yet, in contemporary American society, despite numerous recent advances in our understanding of the physiology of obesity, the condition still carries a stigma. Obesity is still perceived by many as a failure of Willpower, and is considered more of a cosmetic problem than a medical problem. 1,2 Such misconceptions can and do result in discrimination, and actually cause social disability. Responding to complaints of widespread discrimination against obese persons, the U.S. Equal Opportunity Commission declared obesity a protected category 3 '> under the federal Americans with Disabilities Act. As a method of losing weight and maintaining the loss, calorie-restricted diets are proving ineffective and counterproductive, and have been associated with adverse effects. By them, selves, these diets do not ensure weight loss. Success at that goal is more likely with an inte, grated approach that includes proper food choices along with patient education, behavioral modification, and a regular aerobic exercise program. However, because obesity is a chronic disease, it requires lifelong management; treatment strategies must therefore be geared to long-term goals. Drug therapy can play an important complementary role in an integrated strategy for managing obeSity. The caveat is that drug therapy must be monitored closely because drugs used for this purpose have the potential for misuse, abuse, and/or adverse effects. In addition, a number of unproven drugs are being extolled for weight reduction. The first article in this two-part series (see the December Journal) focused on the prevalence and etiology of obesity, its role in chronic disease, and nbnpharmacologic approaches to the treatment of obesity. This article focuses on drug therapy for obesity and discusses both prescription and nonprescription drugs. j
This article is the second of a two-part series on obesity treatment.
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• As a method of losing weight and maintaining weight loss, calorie-restricted diets are proving ineffective and counterproductive. • The best candidates for drug therapy for obesity include patients with comorbidities that can be decreased with weight loss and those at risk for obesity-related comorbidities. • The central nervous system properties of the amphetamines have led to chemical alterations of the original molecule in the hope of creating an appetitesuppressant drug without the potential for abuse. • Studies demonstrate that serotonergic drugs can induce weight loss in / the short term. • Patients using nonprescription drugs for weight ' loss that have not been approved for that purpose · should be informed that efficacy is unproved and warned that, in some cases, adverse effects could be serious.
journal of the American Pharmaceu~ Association
Drug Therapy for Obesity The Committee to Develop Criteria for Evaluating the Outcomes of Approaches to Prevent and Treat Obesity (hereafter known as the Obesity Committee), under the auspices of the National Academy of Sciences' Institute of Medicine, considers anti-obesity drugs effective when they are coupled with a sound program of diet, behavior modification, and exercise. 4 A drug is considered effective in treating obesity when it results in weight loss of at least 5% of the initial body weight and maintenance of that loss; reduced body weight through a reduction of body fat with a sparing of body protein; reduction of comorbidities (e.g. , hyperglycemia, hypertension, dyslipidemias); and a minimum of tolerable side effects and low abuse potential. According to the Obesity Committee, the best candidates for drug therapy for obesity include those patients with comorbidities that can be decreased with weight loss and those at risk for obeSity-related comorbidities (e.g. , stroke).4 Ideally, drug therapy should accomplish its goal and then be discontinued. However, because obesity control is a longterm process, one school of thought is that a phYSician who prescribes appetite-suppressant drugs (ASDs) should plan to continue therapy for at least 5 to 10 years and treat the comorbidities of obeSity. Ideally, an ASD should be safe and acceptable for long-term administration. It should produce a dose-related reduction in body fat, and as mentioned, spare the body from protein loss and the loss of other tissue. Unfortunately, it appears that to Table 1
Barriers to the Use of Drugs that Treat Obesity • P~blic opinion that obesity is related to a lack of willpower. ' • Professional belief that weight regain after termination of drug therapy indicates a fai.lure of the drug; drugs are expec~ed to cure obesity. • Inflexibility of regulatory agencies to extend drug therapy for obesity beyond three months. • Scrutiny of physicians by licensing boards for alleged misuse of prescribed appetite-suppressing drugs. • Little incentive (Le., 16ss of patent rights) for pharmaceutical manufacturers to conduct long-term clinical trials. •
Lack of political leadership to encourage research.
Adapted from: Bray GA. Use and abuse of appetite-suppressant drugs in the treatment of obesity. Ann Intern Med. 1993;119:707-13.
Journal of the American Pharmaceutical Association
gain approval for use in the United States, ASDs may be held to a higher standard than drugs used for other diseases. Historically, this may have come about because the use of ASDs over long periods of time has been hindered by fears of the potential for abuse and because the public acceptance of new ~ drugs for obesity contradicts the general perception that obe· sity is a disorder of willpower. 5 Dextroamphetamine , discovered in the 1930s and ' serendipitously found to produce weight loss, contributed to \ this fear as a result of its misuse in the late 1960s and early 1970s, While it has demonstrated more weight loss in clinical ,> trials in the active drug group compared with placebo, weight loss was small and variable.6 1 Also of great concern was the amphetamines' apparent loss of effectiveness after a short period of time. Consequently,) medical practice review boards and boards of pharmacy insti· : tuted regulations relevant to ASDs and their medical use, These regulations vary from state to state. For example, some states (e.g. , Tennessee) prohibit prescribing ASDs for obesity ; control. Physicians can prescribe these drugs for other condi- . tions (e.g., narcolepsy) as long as the diagnosis is written on the face of the prescription order. Other states (e.g. , Indiana) t place specific time limits on the us~ of ASDs. Because of this time limitation (usually three months in a calendar year), once drug therapy is discontinued, recidivism (i.e. , weight regain) . is ascribed to the failure of the drugs. A more correct conclu· sion would be that drugs cannot work when not taken, and cannot work if the patient is not also following the additional diet and exercise protocols identified for the total integrated therapy. Insulin therapy for Type I diabetes mellitus provides an apt analogy. When insulin is not used, it obviously fails miserably at controlling diabetes, and if not used in conjunction with diet and exercise the condition will worsen. The same is true for drug therapy for hypertension, asthma, and gastro intestinal (GI) illnesses, to mention a few. Unfortunately," there are very few long-term trials of drugs for the treatment of obesity, and this lack of information, coupled with the \ aforementioned historical perspective and attitude toward / obeSity, has helped form the existing barriers to the use of drug therapy for obesity (Table 1).5 PhYSicians in these states who prescribe the restricted drugs are subjected to scrutiny by state medical review boards, with action possibly culminating in licensure revoca· ; tion. Some scrutiny is warranted. However, assuming that I most physicians prescribe these drugs appropriately for con· trol of chronic obesity, some have found innovative ways to allow their patients to continue to secure prescribed ASDs. For example, in a state that prohibits prescribing ASDs for longer than 90 days, a group of four physiCians may rotate prescribing ASDs for one patient for the legal period of time (i.e. , four 90-day periods within one year). It has been estimated that 14% of adults are using prescriPtion drug treatments for weight loss, while another 7% are using over-the-counter (OTC) weight loss 'medications. 7 The /1
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following sections review prescription and nonprescription pharmacologic modalities for weight foss and weight control.
Prescription Drugs Noradrenerg.c Drugs The abuse of amphetamine, methamphetamine, and phenmetrazine has given noradrenergic drugs a bad reputation, and no clinical need exists for these drugs in the treatment of obesity. All are classified as Schedule II. However, the central nervous system (CNS) properties of the amphetamines have led to chemical alterations of the original molecule in the hope of creating a drug with appetite-suppressant activity without the potential for abuse. Thus medicinal chemistry alterations of the side chain and ring structure of amphetamine have produced drugs with appetite-suppressing effects (e.g., benzphetamine, phendimetrazine, diethylpropion, phentermine) but markedly lower risks for CNS stimulation and abuse. The nonamphetamine anorexiants, also called anorectics or anorexigenics, are indirect-acting sympathomimetic amines. Except for mazindol (an imidazoline), phenmetrazine, and phendimetrazine (morpholines), all are phenethylamine (amphetamine-like) analogs. Mechanistically, it is thought that these drugs suppress appetite by direct stimulation of the satiety center in the hypothalamic and limbic regions of the brain. Diethylpropion and phentermine act primarily on adrenergic pathways, whereas mazindol acts on both adrenergic and dopaminergic pathways. Secondarily, these drugs produce eNS stimulation and blood pressure elevation. Because these drugs are chemically and pharmacologically related to amphetamines, they do possess the potential for abuse. Long-term therapy or abuse can lead to intense psychological or physical dependence and severe social dysfunction. This has hindered the ability to accrue any substantial information about each of these drugs' potential to cause dependence. Therefore, reviews of short-term clinical trials, such as the review by Stahl and Imperiale, 8 must be carried out. These authors, for example, studied relevant short-term clinical trials of mazindol for the treatment of obesity. After reviewing 16 trials, their conclusion was that mazindol had no drug addiction or severe adverse drug effects, suggesting that it should be studied in long-term trials. The more common adverse effects of the anorexiants include a false sense of well-being, irritability, nervousness or restlessness, and insomnia. After these stimulant effects have Worn off, unusual fatigue or weakness, drowsiness, trembling, or fi?ental depression may occur. Less common adverse effects of the anorexiants, including fenfluramine, include blurred vision, impotence, heart palpitations, and dizziness or lightheadedness. Vol. NS37, No.1
January/February 1997
Serotonergic Drugs Serotonergic drugs (e.g., fenfiuramine, dexfenfiuramine) offer another approach for the treatment of obesity. These drugs act by partially inhibiting the reuptake of serotonin and releasing serotonin from nerve endings. The process of satiation is believed to begin with the ingestion of dietary starch from foodstuffs that are converted to sugar. Sugar in tum stimulates the pancreas to secrete insulin, and, subsequently, insulin raises the levels of the amino acid tryptophan in the brain. Tryptophan is a precursor of serotonin, and serotonin regulates mood, producing a sense of well-being. The increased serotonin in the neuronal cleft is thought to be responsible for satiation, thereby reducing food intake. 5 Fluoxetine
The link between serotonin and eating disorders was serendipitously observed during clinical trials of the serotonin reuptake inhibitor fiuoxetine when patients who took it demonstrated weight loss. 5 In addition, high-carbohydrate snacks are known to improve mood, and premenstrual women and smokers trying to quit also tend to eat more carbohydrates, which seems to increase mood. Studies have demonstrated that serotonergics help overeaters reduce snacking and can induce weight loss in the short term. Weight loss slows after the first few months of therapy, is minimal by months 6 to 10, and is maintained only as long ~s the patient remains on the drug. Weight gain usually occurs when the drug is discontinued, again highlighting the need for an integrated program of behavioral modification through diet and exercise. The recommended daily dose of fluoxetine for obesity is 60 mg, triple that recommended for depression. Thus the possibility clearly exists for toxicity (which would cause anxiety, nervousness, diarrhea, drowsiness). The manufacturer of fluoxetine (Eli Lilly) has indicated no intention at this time to seek approval of the drug for obesity control. But, if the drug were approved for obesity control, it would be used for serious medical cases. Realistically, however, as in the case of depression, it is possible that fluoxetine would be overprescribed for those who need it least-that is, mildly obese patients who want to shed a few pounds for cosmetic purposes. More likely is the development of chemically modified forms of existing serotonergic drugs that would be capable of increasing weight loss. II
Fen-Phen"
A pharmacologic approach of the early 1990s (known as "fen-phen ") has been to treat obese patients using lower doses of the serotonergic drug fenfluramine (PondiminRobins) 60 mg, plus the noradrenergic drug phentermine resin (lonamin-Pennwalt) 15 mg, rather than usual doses when given alone (i.e. , fenfluramine 120 mg or phentermine 30 mg). The fenfluramine stimulates the release of serotonin and inhibits its reuptake by afferent neurons, reducing the journal of the American Pharmaceutical Association
feelings of agitation and deprivation often associated with hunger. The phentennine enhances levels of dopamine and norepinephrine, which affect blood flow, heartbeat, movement, and reactions to stress. Because these drugs are classified as Schedule IV controlled substances, they can be prescribed for 30 days of treatment and refilled five times within a six-month period. However, as mentioned previously, some states (e.g., Indiana) have more stringent regulations (i.e., no more than a 9O-day supply within one calendar year). The use of this drug combination for obesity therapy was originally described by Weintraub et aJ.9-16 The study initially enrolled 121 men and women between the ages of 18 and 60 who were 30% to 80% above their ideal body weights. None of the subjects had hypertension, diabetes mellitus, other longterm conditions, or were taking chronic medications. Participants were randomly assigned to two groups-one group used the combination fenfluramine/phentermine; the other group used a placebo. All subjects began an exercise program, diet, and behavior modification before starting the medication. After 34 weeks, the group taking the combination therapy lost an average of 32 pounds (about 16% of their body weight), while the placebo group lost an average of 9 pOlmds (about 4.6% of their body weight). Those subjects who lost weight in the study did so in the first 24 weeks of treatment. The most troublesome adverse effect of "fen-phen " was dry mouth, which some patients experienced for four months of therapy. The severity of this effect and the number of complaints diminished over time, however. GI symptoms (e.g. , abdominal pain, nausea, metallic taste, diarrhea, constipation) were also common during treatment. However, after four weeks of "fen-phen " therapy, complaints of diarrhea diminished. Fatigue was also reported in the first two weeks, but then diminished to low levels. Other CNS complaints (e.g., drowsiness, dizziness, nervousness, sadness, increased dreaming) persisted up to six weeks before decreasing. Some participants did not experience any adverse effects. Weintraub reported that, in general, patients on intermittent therapy suffered a recurrence of adverse effects each time the drugs were restarted, suggesting a disadvantage to this approach. 16 From weeks 190 to 210 of the overall clinical trial, Weintraub et al. discontinued anorexiant medications in the 48 participants who remained in the program. 13 The results demonstrated that the participants had difficulty maintaining weight loss without the medications. Despite long periods of time at weights much lower than at baseline, permanent resetting of weight control mechanisms could not be shown for most participants. This supported previous fmdings about cessation of weight control interventions in humans; that is, weight returns toward its baseline value when the intervention (diet, exercise, drug therapy) is stopped. These studies9-16 demonstrated that ASDs retained their effectiveness for more than three and a half years without serious adverse effects in some patients. While only 48/121 (40%) of the original participants remained in the study at its conclusion, the Journal. of the American Phannaceutical Association
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study demonstrated that drug therapy effectively enhances weight loss when integrated into an action plan with other inter· I ventions. Weintraub further concluded that the weight loss I would be maintained for several years if the medications are used ( continuously in conjunction with these interventions that are ) periodically reinforced as part of a total weight loss program. 16 However, Weintraub et al. reported that, for some patients, , increased doses of ASDs were needed to maintain or develop , effectiveness. II In addition, some patients demonstrated no 1\ benefit from the medications. Very importantly, too, there ( was no evidence for nontherapeutic use or any misuse/abuse ! of the ASDs.16 As mentioned earlier, ASDs are optimally prescribed for patients with comorbidities (e .g ., hypertension, dysJipi· demias, diabetes) that can be decreased with weight loss. If ! fenfluramine is prescribed for weight loss in a patient with \ diabetes (typically Type m, increased skeletal muscle uptake of glucose effected by the drug may increase hypoglycemic effects. 17 Thus, under a physician's guidance, the patient must I monitor blood glucose levels and adjust the insulin or oral I antidiabetic agent drug dosage as necessary. Also , fenflu· l ramine is not to be used in combination with mood-altering ,I drugs, such as antidepressants, or drugs that cause drowsiness (e.g., antihistamines, sedatives, tranquilizers).
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Dexfenfluramine
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Dexfenfluramine (Redux-Wyeth-Ayerst), is the dextro is(} mer of fenfluramine, and in November 1995, in a less than overwhelming vote (6 pro and 5 con), the Food and Drug Administration (FDA) Metabolism and Endocrine Drugs AdVi' l sory Committee concluded that its benefits for treating obesi· ty outweighed its potential risks. Subsequently, FDA formally 1 approved the drug for use in the treatment of obesity, which \ was the frrst time a drug had been approved for this indica· I tion in 23 years. It became available for use in June 1996. like ; that of fenfluramine, dexfenfluramine's mechanism of action appears to be influencing serotonin pathways that effect ser(} tonin release and slow its depletion. As a consequence, carb(} hydrate craving is reduced and patients feel satiated. In contrast to the CNS stimulation by the noradrenergic I agents, fenfluramine produces CNS depression. Fenflu-I' ramine's abuse potential is qualitatively different, also. Doses of 80 to 400 mg have been associated with euphoria, derea!- , ization, and perceptual changes. The most common adverse I effects associated with fenfluramine and dexfenfluramine are ' diarrhea, drowsiness, and dry mouth. It is thought that dexfenfluramine might supplant "fenphen" therapy because its adverse effects are milder. However, caution is still advised because data in humans are limited. Even in the relatively short time dexfenfluramine has been studied, a rare adverse effect, primary pulmonary hypertension, has been observed. 18 ,19 The incidence of this serioUS condition in the general population is estimated at 1 to 2 cases per million adults per year,20 and the current labeling of
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Redux estimates the risk at 18 cases per million for patients using the drug for longer than three months. The symptoms of this complication include vague chest discomfort or shortness of breath. Stopping the medication mayor may not stop the disease process because primary pulmonary hypertension obliterates the lung's ability to get oxygen to the heart. Therefore, the possibility exists that a lung or heart -lung transplant might be necessary for survival. Primary pulmonary hypertension has an estimated four-year mortality rate of 45%. Even though dexfenfluramine is indicated for obese patients whose initial body mass index (BM1)21 is at least 30 (e.g., someone 5'6" weighing> 185 pounds), much like fluoxetine, it has the potential to be overprescribed and used by mildly obese persons for cosmetic weight loss. Even though the incidence of pulmonary hypertension remains small, the disorder is serious. Therefore, it is important that dexfenfluramine not be prescribed for cosmetic weight loss. In addition, this drug is indicated for obese patients with other risk factors (e.g. , hypertension, diabetes) if their BMI is >27 (e.g., someone 5'6 " weighing >167 pounds). Another point of contention in the FDA AdviSOry Committee's approval vote for dexfenfluramine was the theoretical risk of brain damage. Dexfenfluramine has demonstrated neurologic toxicity in primates and rodents. 22 Historically, in some species, high doses of some drugs (e.g., 3,4-methylenedioxymethamphetamine) have caused a massive release of serotonin from neurons, and when so much is reabsorbed back into the neuron and metabolized at once, neurotoxic oxidation intermediates are produced. These destroy the neuron. Consequently, serotonin depletion in primates caused by dexfenfluramine has caused concern, but the relevance of the finding to humans remains unknown. Experience with the racemic mixture of fenfluramine gives credence to its safety, although without the levo enantiomorph present in the dosage form, different results may occur in vivo. Because no long-range safety and efficacy data are available for dexfenfluramine for more than one year, the drug is only approved for one year's use. In all studies, the drug was used as an adjunct to a reduced-calorie diet, increased exercise regimen, and other behavioral modifications. A key point is that not all patients respond to the drug. Physicians should discontinue its use in any patient who does not demonstrate a loss of at least four pounds within one month of taking the drug. Tables 2 and 3 provide an overview of ASDs and serotonergic drugs.
Nonprescription Drugs PhenylpropanolalTline As a sympathomim,e tic , phenylethylamine derivative, phenylpropanolamine (PPA) is a direct agonist of postsynapVol. NS37, No.1
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tic alpha- and beta-adrenoreceptors and acts indirectly by increasing norepinephrine concentrations from sympathetic nerve endings. It is well absorbed from the GI tract and has an elimination half-life that ranges between three and four hours. Although 80% of an oral dose is excreted unchanged in urine, a portion of the drug is hepatically converted to norephedrine. The exact mechanism by which PPA exerts its anorexic effect is unknown. One theory is that it may activate postsynaptic alpha-I-adrenergic receptors within the medial hypothalamic paraventricular nucleus. 23 Stimulation of this nucleus may activate the human satiety mechanism. Other research has noted that PPA can increase energy by accelerating the breakdown of fat tissue, an effect similar to that of ephedrine, which may account for its efficacy in weight loss.24 Recently, a meta-analysis of PPA clinical trials for obesity was reported. 25 In placebo-controlled trials since 1985, PPA has demonstrated a net greater weight loss of 0.14 kg/week · compared with placebo. Overall, PPA demonstrated an incidence of adverse effects of 19% compared with 14% for placebo. 25 There was no mention of addiction or abuse potential. There has been considerable attention in the literature to the safety of PPA in view of case reports of serious adverse effects such as cerebral infarction, intracerebral hemorrhage, seizures, acute interstitial nephritis, and cardiac arrhythmias. Because these case reports demonstrate a variability of PPA dosage and dosage form, it is very difficult to interpret the findings. However, the serious nature of the reported reactions to PPA make them a concern. FDA permits a PPA dose of up to 37.5 mg in immediaterelease products and up to 75 mg in sustained-release products with a maximum daily dose of 75 mg. It is prudent, therefore, to warn patients not to exceed the immediate dose of 37.5 mg or the maximum dose of 75 mg per day, because most of the adverse effects reported appear to result from higher-than-recommended doses. When serious toxicity is suspected, the most common presenting symptom is a persistent, severe headache or other sign of elevated arterial pressure. Thus those at risk for adverse reactions to PPA would include patients with hypertension or anorexia/bulimia, women who take oral contraceptives (risk of hypertension is higher), the elderly, those concomitantly using other sympathomimetic agents, and those who demonstrate autonomic insufficiency. Adverse effects (e.g., nervousness, restlessness, insomnia, dizziness , perspiration , anxiety, headache , increased blood pressure) can occur in previously normotensive individuals. Serious cardiovascular adverse effects (including hypertensive episodes, tremor, increased motor activity, agitation, hallucinations, stroke) have occurred following doses of PPA exceeding that of product labeling (Le., abuse situations). To avoid problems with sustained-release PPA, patients should be told not to crush or chew the dosage form. To avoid
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Table 2
Overview of Noradrenergic Drugs Used to Treat Obesity DEA Schedule
Phendimetrszine
HalfLife, t'lz (hours)
Dosage Regimen
Trade Name (Manufacturer)
Dosage Form, Strength (mg)
III
6-12
25-50 mg once daily; range 25-50 mg, once daily to three times daily
Didrex (Upjohn)
Tablets: 25, 50
III
5-12.5
35 mg twice or three times daily, 1 hour before meals. Sustained release: 105 mg once daily before breakfast
80ntril (Carnrick)
Tablets: 35 Capsules: 35 Sustainedrelease capsules: 105
Anorex (Dunhall) Prelu-2 (8-1)
Diethylpropion
IV
4-6
25 mg three times daily, 1 hour before meals, and in mid-evening if needed. Sustained-release 75 mg once daily, mid-morning
Tenuate (Lakeside)
Tablets: 25
Tepanil (Riker)
Dospan: 75
Tenuate (Lakeside)
Ten-Tab: 75
Tepanil (Riker) IV
10
19-24
3-4
1 mg three times daily, 1 hour before meals or 2 mg once daily, 1 hour before lunch. Take with meals to avoid GI upset 8 mg three times daily; ~ hour before meals, or 15 to 37.5 mg as a single daily dose before breakfast or 10 to 14 hours before bedtime
25 mg three times daily, not to exceed 75 mg in 24 hours or 75 mg once daily (as sustained-release adm i nistration)
excessive CNS stimulation, patients should be instructed to avoid highly caffeinated beverages. Benzocaine
One factor in overeating is the need to satisfy the sense of taste. In many obese persons, constant snacking is characteristic of the "oral syndrome. ,, 23 The rationale for using benzocaine for weight loss lies in its ability to decrease taste sensations by numbing the oral cavity and the gastric mucosa. Manufacturers have claimed that the drug can decrease sensitivity to sweetness, discouraging snacking and decreasing caloric consumption. Benzocaine is delivered in the form of Journal of the American pharmaceutical Association
Mazanor (Wyeth-Ayerst)
Tablets: 1
Sanorex. (Sandoz) Tablets: 1, 2 Phentermine (various manufacturers)
Tablets: 8 Capsules: 8
Fastin (Beecham)
Sustainedrelease capsules: 30
lonamin (Pennwalt)
Sustainedre lease capsules: 15,30
Dexatrim Pre-Meal (Thompson)
Capsules: 25
Prolamine (Thompson)
Capsules: 37.5
Acutrim 16 Hour (Ciba)
Tablets: 75
gum, wafers, or hard candy to be used between meals. TIlis keeps the patient orally active. The FDA Advisory Review Panel on aTC Miscellaneous Internal Drug Products classified benzocaine as generally I effective and safe for short-term weight control. The panel I also determined that a dose of 3 to 15 mg in gu m , lozenges , or candy just prior to a meal was generally appropriate. A daily dosage of greater than 45 mg is discouraged for fear that topical anesthesia may impair swallowing, increasing .the danger of aspiration. Also , numbness of the tongue or buccal mucosa may increase the risk I of biting trauma. January/February 1997
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Table 4
Serotonergic Drugs Used to Treat Obesity
Unapproved Nonprescription Drugs for Weight Reduction Aminophylline Cream
Although not officially approved for this purpose, aminophylline cream has been extolled in the lay media for its supposed weight reduction capability. In women, it is usually applied to the thighs, where it supposedly effects a reduction in thigh circumference. Pharmacists who receive prescription orders for a 2% aminophylline cream for weight reduction may want to read about a method for preparing a 2% aminophylline powder in an oil/water (OIW) emulsion base26 (e.g. , Dermabase [Paddock], Velvachol [Owen/Galderma], and Unibase [Warner Chilcott]). In addition, several topical aminophylline products are being advertised over the Internet for application to the thighs and buttocks (e.g., Thigh High) by women or, by men, to the stomach area (e.g., Belly Buster). FDA has not approved aminophylline for topical use. It is likely that the products are being marketed without listing aminophylline as the active ingredient on the .label. This practice, which many consider unethical, will probably continue until FDA issues a "cease and desist" order. Topical aminophylline products can cause skin sensitivity, manifested by skin rash or hives. The ethylenediamine component of the aminophylline molecule has been implicated as the offending agent. With oral aminophylline, an allergic reaction to the ethylenediamine moiety may appear 12 to 24 hours after initial administration. There is no information about how soon this could occur after topical application. Although no information is available on this, of concern is the amount of theophylline (from the aminophylline) that could be percutaneously absorbed, especially when applied (or overapplied) to a large area. Therefore , patients preVol. NS37, No.1
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scribed a topical dosage form of this drug must be monitored for potential toxicities (e.g., eNS stimulation [nervousness or restlessness], nausea) and drug interactions with other medications (e.g., cimetidine, lithium, phenytoin) and instructed to use the drug only as directed. Also, a patient who has obtained a topical commercial product may complain of theophylline adverse effects without understanding the source of the problem; unless the pharmacist or physician questions the patient thoroughly, one would not know that a "cosmetic," unregulated product is causing the toxicity. Glucomannan
Glucomannan is a hydrophilic hemicellulose composed of glucose and mannose linked through beta-glycoside bonds. Human digestive enzymes cannot break down polysaccharides of this nature. Being hydrophilic, glucomannan absorbs up to about 60 times its weight in water. Thus, when in the stomach, it creates a sense of fullness. Unforttmately, however, it has not produced substantial effects when used by dieters and it has proven largely ineffective in weight control. 23 Like other bulk-producing agents (e.g. , psyllium mucilloid), the ability of glucomannan to produce feelings of satiety is poor. Theoretically, sustaining the sensation of fullness might help curb one's appetite. However, radiographic studies have demonstrated that little of a bulk-forming compound remains in the stomach 30 minutes after ingestion. 23 Consequently, taking substances like glucomannan 30 to 60 minutes prior to a meal as directed by the product instructions for weight control is unlikely to prove beneficial. Chromium Picolinate
Chromium deficiency supposedly results in impaired glucose tolerance because the chromium ion is thought to be a
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journal of the American Pharmaceutical Association
part of a complex called glucose tolerance factor (GTF). 27 Deficiency of GTF may result in elevated blood glucose levels, hypercholesterolemia, and aortic plaques. Impaired glucose tolerance has been reported to be improved with elemental chromium (found in brewer's yeast, bread, beef, liver, cheese, nuts, prunes, asparagus). One study reported that chromium supplementation reversed impaired glucose tolerance and neuropathy in a patient receiving longterm total parenteral nutrition.28 Oral chromium ion is poorly absorbed from the GI tract (most individuals absorb < 1% to 3% from dietary sources), although it has been shown that patients with diabetes absorb two to four times more chromium ion than normal subjects. Chromium is available as chromium picolinate because picalinic acid (a metabolite of tryptophan) forms stable complexes with transitional metals such as chromium and enhances the bioavailability of the ion. The average American diet contains 5 to 115 mcg/day of chromium, with recommended levels established at 50 to 200 mcg/day.27 The evidence to date of chromium picolinate causing weight reduction is for the most part anecdotal, although case - reports have described the effects of GTF in patients with diabetes. The usefulness of chromium picolinate as a weight loss product has been extrapolated from its role in regulating glucose metabolism. That is , in chromium-deficient tissue, chromium will increase glucose uptake by cells and effect oxidation of glucose to carbon dioxide, thus potentiating the incorporation of glucose into fatty acids and cholesterol. To date, little, if any, toxicity has been associated with the use of chromium picolinate. In this compound, chromium is present as a trivalent ion, Cr+. With more widespread use, it is possible that toxicities may be reported. The hexavalent chromium compounds can be extremely harmful and have been demonstrated in animal studies to produce nausea, vomiting, convulsions, and coma.
date, clinical trials have demonstrated its clinical efficacy for weight loss when used adjunctively to caloric restriction, behavioral modification, and exercise.31 Although patients taking sibutramine have shown a dose-dependent reduction in body weight, they have also experienced increased heart rate and blood pressure. Because of these adverse effects, in September 1996 the FDA's Metabolism and Endocrine Drugs AdviSOry Committee refused to approve sibutramine for weight loss. However, this committee recommended further studies to determine the drug's cardiovascular effects. Orlistat (tetrahydrolipstatin, Xenical-Roche) is a chemically produced derivative of the natural product lipstatin. Lipstatin, a potent, irreversible lipase inhibitor, effects a decrease in the amount of ingested dietary fat (i.e. , the product resulting from the dividing of free fatty acids from the glycerol backbone) that is absorbed systemically. Orlistat inhibits pancreatic lipase, the primary enzyme for fat metabolism in the gut. Consequently, fecal fat excretion is increased, and this characterizes the GI complaints associated with the drug (e.g. , loose bowel movements, oily appearing stools, abdominal cramps, fecal incontinence, nausea). Clinical trials to date have demonstrated the weight loss abilities of this drug as well as the dose-dependency for its effect. 32 Several other entities are also being studied for possible weight reduction activity. Chlorocitrate has been shown to inhibit gastric emptying, causing a sense of fullness. Also, the hormone leptin has been postulated as a substance that helps to set the body's weight, and recently scientists discovered receptors for that protein in the brain. Leptin triggers the production of glucagon-like peptide-1 (GLP-1). This substance is known to help digest sugars in the human intestine. However, an animal study involving rats demonstrated that after a large meal, GLP-1 is also released in the brain to signal that the stomach is full. 33
Syrup of Ipecac
The use of syrup of ipecac to induce vomiting and avoid weight gain is a dangerous and illegitimate practice and should be avoided. The pharmacist must be wary of requests for the drug, especially from young adults and teenagers. Chronic use of syrup of ipecac has resulted in several fatalities in patients with eating disorders (e.g. , bulimia, anorexia) who used it regularly.29,30 Ipecac can demonstrate cardiotoxic effects when absorbed, and can cause cardiac conduction disturbances, bradycardia, atrial fibrillation, hypotension, and fatal myocarditis.
Drugs Under Investigation Sibutramine (Meridia-Knoll), a new monoamine antidepressant, is also being studied as a weight loss agent. To Journal of the American phannaceutical Association
Patient/Consumer Education Advertisements and testimonials in the media can be confusing and misleading, and the phannacist can provide patients with infonned advice on weight loss products and programs. In desperation, patients frequently turn to outrageous schemes claiming to offer cures for obesity. Commercial weight loss programs have counselors (some trained and qualified, some not) with a variety of backgrounds and whose experience may vary widely. Indeed, one's credentials may be limited to personal experience in lOSing pounds in that program. Thus, patients can get less than optimal advice and guidance. Optimally, weight loss and maintenance requires an individualized, interdisciplinary approach. The pharmacist must be alert to comments that may indicate that a patient is seeking information or attempting to determine whether a weight loss approach is likely to be sueJanuary/February 1997
Vol. NS37, No.1
cessful. When an approach involves drugs, the pharmacist must be attuned to patient comments that might indicate suspected adverse effects or misuse. Medications for obesity will work best in patients who need them the least; for example, in motivated patients with mild .J obesity. A weight management program is considered successful when the weight loss is maintained for up to five years after program initiation. 34 This means that morbidly obese patients who are prescribed medications will need constant support and reinforcement while they attempt to lose weight, probably over a period of years. Patients are certain to become frus) trated with current approaches to the treatment of obesity, and health care professionals, including phannacists, will feel pressured to embrace each newly reported treatment (often accompanied by media attention). As Weintraub pointed out, I "We must teach ourselves and our patients to measure success by prevention of weight gain and maintenance of a significant but perhaps more modest weight loss than we or they would fmd 'desirable.' ,, 16 When opportune, pharmacists must reinforce this notion and continue to encourage patients to abide by their integrated weight loss program of diet modification, behavioral modification, exercise, and drug therapy. In the end, the patient will prosper from this encouragement. Mildly obese patients without significant medical risk factors for obeSity-related disease should be advised to consume foods low in fat and high in complex carbohydrates. Also, they should be encouraged to increase their daily physical activity, with weight maintenance as a long-term goal. For the patient with significant obesity or the risk factors for obesity-related disease, the problem is much more complex. Those who are motivated should be guided to programs targeted to their needs that emphasize long-term changes in behavior, diet, and physical activity. This approach coupled with ASD therapy might be indicated in patients with long-standing obesity who have been unable to lose sufficient weight to decrease their medical risks. Ideally,' pharmacists should identify centers (locally if possible) that specialize in conducting clinical trials that evaluate the long-term safety and effectiveness of ASDs. When no such centers are identifiable, a pharmacist may take the prerogative to work with a physician and dietitian (perhaps through a managed-care organization) who may wish to begin an ASD regimen in conjunction with other established dietary and behavioral methodologies. Again, patient success is related to monitoring and reinforcement coupled with careful documentation that justifies continued use of the ASD; in other words, pharmaceutical care. I
Conclusion From a research standpoint, data on the long-term efficacy of drug therapy for obesity are sorely needed. Further studies Vol. NS37, No.1
January/February 1997
are also needed to examine the effects of variables such as sex, race, age, and other eating behaviors (e.g., binging, purging) on the effectiveness and safety of ASDs. Knowledge is also lacking in how drug therapy affects other aspects of a weight loss program (e.g., behavioral modification, diet, exercise). Although no "magic bullet" now exists to treat obeSity, molecular biology may eventually provide a cure. In the meantime, the reality is that the pharmacologic approaches to obesity control and management pose a serious threat to the billion dollar commercial weight loss industry. Gratefully, obesity is ftnally being recognized as a long-term problem requiring integrated long-term care, including drug therapy. Nicholas G. Popovich, PhD, is professor, Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, and Olivia B. Wood, MPH, RD, is associate professor, Department of Foods and Nutrition, School of Consumer and Family Sciences, Purdue University, West Lafayette, Ind.
References 1. Frank A. Futility and avoidance. Medical professionals in the treatment of obesity. JAMA. 1993;269:2132-3. Commentary. 2. Yanovski SZ. Are anorectic agents the 'magic bullet' for obesity? Arch Fam Med. 1993;2:1025-7. 3. Gortmaker SL, Must A, Perrin JM, et al. Social and economic consequences of overweight in adolescence and young adulthood. N Engl J Med. 1993:329:1008-12. 4. Committee to Develop Criteria for Evaluating the Outcome of Approaches to Prevent and Treat Obesity. Thomas PR, ed. Weighing the Optians. Criteria far Evaluating Weight-Management Programs. Washington, D.C.: National Academy Press; 1995. 5. Bray GA. Use and abuse of appetite-suppressant drugs in the treatment of obesity. Ann Intern Med. 1993;119:707-13. 6. Bray GA. The obese patient. WB Saunders Company; 1976:1-450. 7. Levy AS, Heaton AW. Weight control practices of U.S. adults trying to lose weight. Ann Intern Med. 1993;119:661-6. 8. Stahl KA, Imperiale TF. An overview of the efficacy and safety of fenfluramine and mazindol in the treatment of obesity. Arch Fam Med. 1993;2:1033-7. 9. Weintraub M, Sundaresan PR, Madan M, et al. Long-term weight control study I (weeks 0 to 34). Clin Pharmacal Ther. 1992;51:586-94. 10. Weintraub M, Sundaresan PR, Schuster B, et al. Long-term weight control study II (weeks 34 to 104). Clin Pharmacal Ther. 1992;51 :595-601. 11 . Weintraub M, Sundaresan PR, Schuster B, et al. Long-term weight control study III (weeks 104-156). Clin Pharmacal Ther. 1992;51:602-7. 12. Weintraub M, Sundaresan PR, Schuster B, et al. Long-term weight control study IV (weeks 156to 190). Clin Pharmacal Ther. 1992;51:608-14. 13. Weintraub M, Sundaresan PR, Schuster B, et al. Long-term weight control study V (weeks 190 to 210). Clin Pharmacol Ther. 1992;51 :615-8. 14. Weintraub M, Sundaresan PR, Cox C. Long-term weight control study VI. Clin Pharmacal Ther. 1992;51:619-33. 15. Weintraub M, Sundaresan PR, Schuster B. Long-term weight control study VII (weeks 0 to 210). Clin Pharmacal Ther. 1992;51:634-41. 16. Weintraub M. Long-term weight control study: Conclusions. Clin Pharmacal Ther. 1992;51 :642-6. 17. Olin BR, editor-in-chief. Facts and Camparisons. St. Louis: Facts and Comparisons; 1996. 18. Pouwels HM, Smeets JL, Cherlex EC, et .al. Pulmonary hypertension and fenfluramine. Eur Respir J. 1990;3:606-7. 19. McMurray J , Bloomfield P, Miller HC. Irreversible pulmonary hypertension after treatment with fenfluramine. BMJ. 1986:292:239-40.
Obesity continued on p . 56
JOumal of the American Pharmaceutical Association
cOfflpletnentary role in an integrated strategy for managing obesity. by Nicholas G. Popovich, PhD, and Olivia B. Wood, MPH
In troduction Obesity is fmally becoming recognized as a chronic disease process with adverse health consequences. Yet, in contemporary American society, despite numerous recent advances in our understanding of the physiology of obesity, the condition still carries a stigma. Obesity is still perceived by many as a failure of Willpower, and is considered more of a cosmetic problem than a medical problem. 1,2 Such misconceptions can and do result in discrimination, and actually cause social disability. Responding to complaints of widespread discrimination against obese persons, the U.S. Equal Opportunity Commission declared obesity a protected category 3 '> under the federal Americans with Disabilities Act. As a method of losing weight and maintaining the loss, calorie-restricted diets are proving ineffective and counterproductive, and have been associated with adverse effects. By them, selves, these diets do not ensure weight loss. Success at that goal is more likely with an inte, grated approach that includes proper food choices along with patient education, behavioral modification, and a regular aerobic exercise program. However, because obesity is a chronic disease, it requires lifelong management; treatment strategies must therefore be geared to long-term goals. Drug therapy can play an important complementary role in an integrated strategy for managing obeSity. The caveat is that drug therapy must be monitored closely because drugs used for this purpose have the potential for misuse, abuse, and/or adverse effects. In addition, a number of unproven drugs are being extolled for weight reduction. The first article in this two-part series (see the December Journal) focused on the prevalence and etiology of obesity, its role in chronic disease, and nbnpharmacologic approaches to the treatment of obesity. This article focuses on drug therapy for obesity and discusses both prescription and nonprescription drugs. j
This article is the second of a two-part series on obesity treatment.
Vol. NS37, No.1
January/February 1997
II
• As a method of losing weight and maintaining weight loss, calorie-restricted diets are proving ineffective and counterproductive. • The best candidates for drug therapy for obesity include patients with comorbidities that can be decreased with weight loss and those at risk for obesity-related comorbidities. • The central nervous system properties of the amphetamines have led to chemical alterations of the original molecule in the hope of creating an appetitesuppressant drug without the potential for abuse. • Studies demonstrate that serotonergic drugs can induce weight loss in / the short term. • Patients using nonprescription drugs for weight ' loss that have not been approved for that purpose · should be informed that efficacy is unproved and warned that, in some cases, adverse effects could be serious.
journal of the American Pharmaceu~ Association
Drug Therapy for Obesity The Committee to Develop Criteria for Evaluating the Outcomes of Approaches to Prevent and Treat Obesity (hereafter known as the Obesity Committee), under the auspices of the National Academy of Sciences' Institute of Medicine, considers anti-obesity drugs effective when they are coupled with a sound program of diet, behavior modification, and exercise. 4 A drug is considered effective in treating obesity when it results in weight loss of at least 5% of the initial body weight and maintenance of that loss; reduced body weight through a reduction of body fat with a sparing of body protein; reduction of comorbidities (e.g. , hyperglycemia, hypertension, dyslipidemias); and a minimum of tolerable side effects and low abuse potential. According to the Obesity Committee, the best candidates for drug therapy for obesity include those patients with comorbidities that can be decreased with weight loss and those at risk for obeSity-related comorbidities (e.g. , stroke).4 Ideally, drug therapy should accomplish its goal and then be discontinued. However, because obesity control is a longterm process, one school of thought is that a phYSician who prescribes appetite-suppressant drugs (ASDs) should plan to continue therapy for at least 5 to 10 years and treat the comorbidities of obeSity. Ideally, an ASD should be safe and acceptable for long-term administration. It should produce a dose-related reduction in body fat, and as mentioned, spare the body from protein loss and the loss of other tissue. Unfortunately, it appears that to Table 1
Barriers to the Use of Drugs that Treat Obesity • P~blic opinion that obesity is related to a lack of willpower. ' • Professional belief that weight regain after termination of drug therapy indicates a fai.lure of the drug; drugs are expec~ed to cure obesity. • Inflexibility of regulatory agencies to extend drug therapy for obesity beyond three months. • Scrutiny of physicians by licensing boards for alleged misuse of prescribed appetite-suppressing drugs. • Little incentive (Le., 16ss of patent rights) for pharmaceutical manufacturers to conduct long-term clinical trials. •
Lack of political leadership to encourage research.
Adapted from: Bray GA. Use and abuse of appetite-suppressant drugs in the treatment of obesity. Ann Intern Med. 1993;119:707-13.
Journal of the American Pharmaceutical Association
gain approval for use in the United States, ASDs may be held to a higher standard than drugs used for other diseases. Historically, this may have come about because the use of ASDs over long periods of time has been hindered by fears of the potential for abuse and because the public acceptance of new ~ drugs for obesity contradicts the general perception that obe· sity is a disorder of willpower. 5 Dextroamphetamine , discovered in the 1930s and ' serendipitously found to produce weight loss, contributed to \ this fear as a result of its misuse in the late 1960s and early 1970s, While it has demonstrated more weight loss in clinical ,> trials in the active drug group compared with placebo, weight loss was small and variable.6 1 Also of great concern was the amphetamines' apparent loss of effectiveness after a short period of time. Consequently,) medical practice review boards and boards of pharmacy insti· : tuted regulations relevant to ASDs and their medical use, These regulations vary from state to state. For example, some states (e.g. , Tennessee) prohibit prescribing ASDs for obesity ; control. Physicians can prescribe these drugs for other condi- . tions (e.g., narcolepsy) as long as the diagnosis is written on the face of the prescription order. Other states (e.g. , Indiana) t place specific time limits on the us~ of ASDs. Because of this time limitation (usually three months in a calendar year), once drug therapy is discontinued, recidivism (i.e. , weight regain) . is ascribed to the failure of the drugs. A more correct conclu· sion would be that drugs cannot work when not taken, and cannot work if the patient is not also following the additional diet and exercise protocols identified for the total integrated therapy. Insulin therapy for Type I diabetes mellitus provides an apt analogy. When insulin is not used, it obviously fails miserably at controlling diabetes, and if not used in conjunction with diet and exercise the condition will worsen. The same is true for drug therapy for hypertension, asthma, and gastro intestinal (GI) illnesses, to mention a few. Unfortunately," there are very few long-term trials of drugs for the treatment of obesity, and this lack of information, coupled with the \ aforementioned historical perspective and attitude toward / obeSity, has helped form the existing barriers to the use of drug therapy for obesity (Table 1).5 PhYSicians in these states who prescribe the restricted drugs are subjected to scrutiny by state medical review boards, with action possibly culminating in licensure revoca· ; tion. Some scrutiny is warranted. However, assuming that I most physicians prescribe these drugs appropriately for con· trol of chronic obesity, some have found innovative ways to allow their patients to continue to secure prescribed ASDs. For example, in a state that prohibits prescribing ASDs for longer than 90 days, a group of four physiCians may rotate prescribing ASDs for one patient for the legal period of time (i.e. , four 90-day periods within one year). It has been estimated that 14% of adults are using prescriPtion drug treatments for weight loss, while another 7% are using over-the-counter (OTC) weight loss 'medications. 7 The /1
January/ February 1997
Vol. NS37, No. 1
following sections review prescription and nonprescription pharmacologic modalities for weight foss and weight control.
Prescription Drugs Noradrenerg.c Drugs The abuse of amphetamine, methamphetamine, and phenmetrazine has given noradrenergic drugs a bad reputation, and no clinical need exists for these drugs in the treatment of obesity. All are classified as Schedule II. However, the central nervous system (CNS) properties of the amphetamines have led to chemical alterations of the original molecule in the hope of creating a drug with appetite-suppressant activity without the potential for abuse. Thus medicinal chemistry alterations of the side chain and ring structure of amphetamine have produced drugs with appetite-suppressing effects (e.g., benzphetamine, phendimetrazine, diethylpropion, phentermine) but markedly lower risks for CNS stimulation and abuse. The nonamphetamine anorexiants, also called anorectics or anorexigenics, are indirect-acting sympathomimetic amines. Except for mazindol (an imidazoline), phenmetrazine, and phendimetrazine (morpholines), all are phenethylamine (amphetamine-like) analogs. Mechanistically, it is thought that these drugs suppress appetite by direct stimulation of the satiety center in the hypothalamic and limbic regions of the brain. Diethylpropion and phentermine act primarily on adrenergic pathways, whereas mazindol acts on both adrenergic and dopaminergic pathways. Secondarily, these drugs produce eNS stimulation and blood pressure elevation. Because these drugs are chemically and pharmacologically related to amphetamines, they do possess the potential for abuse. Long-term therapy or abuse can lead to intense psychological or physical dependence and severe social dysfunction. This has hindered the ability to accrue any substantial information about each of these drugs' potential to cause dependence. Therefore, reviews of short-term clinical trials, such as the review by Stahl and Imperiale, 8 must be carried out. These authors, for example, studied relevant short-term clinical trials of mazindol for the treatment of obesity. After reviewing 16 trials, their conclusion was that mazindol had no drug addiction or severe adverse drug effects, suggesting that it should be studied in long-term trials. The more common adverse effects of the anorexiants include a false sense of well-being, irritability, nervousness or restlessness, and insomnia. After these stimulant effects have Worn off, unusual fatigue or weakness, drowsiness, trembling, or fi?ental depression may occur. Less common adverse effects of the anorexiants, including fenfluramine, include blurred vision, impotence, heart palpitations, and dizziness or lightheadedness. Vol. NS37, No.1
January/February 1997
Serotonergic Drugs Serotonergic drugs (e.g., fenfiuramine, dexfenfiuramine) offer another approach for the treatment of obesity. These drugs act by partially inhibiting the reuptake of serotonin and releasing serotonin from nerve endings. The process of satiation is believed to begin with the ingestion of dietary starch from foodstuffs that are converted to sugar. Sugar in tum stimulates the pancreas to secrete insulin, and, subsequently, insulin raises the levels of the amino acid tryptophan in the brain. Tryptophan is a precursor of serotonin, and serotonin regulates mood, producing a sense of well-being. The increased serotonin in the neuronal cleft is thought to be responsible for satiation, thereby reducing food intake. 5 Fluoxetine
The link between serotonin and eating disorders was serendipitously observed during clinical trials of the serotonin reuptake inhibitor fiuoxetine when patients who took it demonstrated weight loss. 5 In addition, high-carbohydrate snacks are known to improve mood, and premenstrual women and smokers trying to quit also tend to eat more carbohydrates, which seems to increase mood. Studies have demonstrated that serotonergics help overeaters reduce snacking and can induce weight loss in the short term. Weight loss slows after the first few months of therapy, is minimal by months 6 to 10, and is maintained only as long ~s the patient remains on the drug. Weight gain usually occurs when the drug is discontinued, again highlighting the need for an integrated program of behavioral modification through diet and exercise. The recommended daily dose of fluoxetine for obesity is 60 mg, triple that recommended for depression. Thus the possibility clearly exists for toxicity (which would cause anxiety, nervousness, diarrhea, drowsiness). The manufacturer of fluoxetine (Eli Lilly) has indicated no intention at this time to seek approval of the drug for obesity control. But, if the drug were approved for obesity control, it would be used for serious medical cases. Realistically, however, as in the case of depression, it is possible that fluoxetine would be overprescribed for those who need it least-that is, mildly obese patients who want to shed a few pounds for cosmetic purposes. More likely is the development of chemically modified forms of existing serotonergic drugs that would be capable of increasing weight loss. II
Fen-Phen"
A pharmacologic approach of the early 1990s (known as "fen-phen ") has been to treat obese patients using lower doses of the serotonergic drug fenfluramine (PondiminRobins) 60 mg, plus the noradrenergic drug phentermine resin (lonamin-Pennwalt) 15 mg, rather than usual doses when given alone (i.e. , fenfluramine 120 mg or phentermine 30 mg). The fenfluramine stimulates the release of serotonin and inhibits its reuptake by afferent neurons, reducing the journal of the American Pharmaceutical Association
feelings of agitation and deprivation often associated with hunger. The phentennine enhances levels of dopamine and norepinephrine, which affect blood flow, heartbeat, movement, and reactions to stress. Because these drugs are classified as Schedule IV controlled substances, they can be prescribed for 30 days of treatment and refilled five times within a six-month period. However, as mentioned previously, some states (e.g., Indiana) have more stringent regulations (i.e., no more than a 9O-day supply within one calendar year). The use of this drug combination for obesity therapy was originally described by Weintraub et aJ.9-16 The study initially enrolled 121 men and women between the ages of 18 and 60 who were 30% to 80% above their ideal body weights. None of the subjects had hypertension, diabetes mellitus, other longterm conditions, or were taking chronic medications. Participants were randomly assigned to two groups-one group used the combination fenfluramine/phentermine; the other group used a placebo. All subjects began an exercise program, diet, and behavior modification before starting the medication. After 34 weeks, the group taking the combination therapy lost an average of 32 pounds (about 16% of their body weight), while the placebo group lost an average of 9 pOlmds (about 4.6% of their body weight). Those subjects who lost weight in the study did so in the first 24 weeks of treatment. The most troublesome adverse effect of "fen-phen " was dry mouth, which some patients experienced for four months of therapy. The severity of this effect and the number of complaints diminished over time, however. GI symptoms (e.g. , abdominal pain, nausea, metallic taste, diarrhea, constipation) were also common during treatment. However, after four weeks of "fen-phen " therapy, complaints of diarrhea diminished. Fatigue was also reported in the first two weeks, but then diminished to low levels. Other CNS complaints (e.g., drowsiness, dizziness, nervousness, sadness, increased dreaming) persisted up to six weeks before decreasing. Some participants did not experience any adverse effects. Weintraub reported that, in general, patients on intermittent therapy suffered a recurrence of adverse effects each time the drugs were restarted, suggesting a disadvantage to this approach. 16 From weeks 190 to 210 of the overall clinical trial, Weintraub et al. discontinued anorexiant medications in the 48 participants who remained in the program. 13 The results demonstrated that the participants had difficulty maintaining weight loss without the medications. Despite long periods of time at weights much lower than at baseline, permanent resetting of weight control mechanisms could not be shown for most participants. This supported previous fmdings about cessation of weight control interventions in humans; that is, weight returns toward its baseline value when the intervention (diet, exercise, drug therapy) is stopped. These studies9-16 demonstrated that ASDs retained their effectiveness for more than three and a half years without serious adverse effects in some patients. While only 48/121 (40%) of the original participants remained in the study at its conclusion, the Journal. of the American Phannaceutical Association
I
study demonstrated that drug therapy effectively enhances weight loss when integrated into an action plan with other inter· I ventions. Weintraub further concluded that the weight loss I would be maintained for several years if the medications are used ( continuously in conjunction with these interventions that are ) periodically reinforced as part of a total weight loss program. 16 However, Weintraub et al. reported that, for some patients, , increased doses of ASDs were needed to maintain or develop , effectiveness. II In addition, some patients demonstrated no 1\ benefit from the medications. Very importantly, too, there ( was no evidence for nontherapeutic use or any misuse/abuse ! of the ASDs.16 As mentioned earlier, ASDs are optimally prescribed for patients with comorbidities (e .g ., hypertension, dysJipi· demias, diabetes) that can be decreased with weight loss. If ! fenfluramine is prescribed for weight loss in a patient with \ diabetes (typically Type m, increased skeletal muscle uptake of glucose effected by the drug may increase hypoglycemic effects. 17 Thus, under a physician's guidance, the patient must I monitor blood glucose levels and adjust the insulin or oral I antidiabetic agent drug dosage as necessary. Also , fenflu· l ramine is not to be used in combination with mood-altering ,I drugs, such as antidepressants, or drugs that cause drowsiness (e.g., antihistamines, sedatives, tranquilizers).
I
!
I
Dexfenfluramine
I
Dexfenfluramine (Redux-Wyeth-Ayerst), is the dextro is(} mer of fenfluramine, and in November 1995, in a less than overwhelming vote (6 pro and 5 con), the Food and Drug Administration (FDA) Metabolism and Endocrine Drugs AdVi' l sory Committee concluded that its benefits for treating obesi· ty outweighed its potential risks. Subsequently, FDA formally 1 approved the drug for use in the treatment of obesity, which \ was the frrst time a drug had been approved for this indica· I tion in 23 years. It became available for use in June 1996. like ; that of fenfluramine, dexfenfluramine's mechanism of action appears to be influencing serotonin pathways that effect ser(} tonin release and slow its depletion. As a consequence, carb(} hydrate craving is reduced and patients feel satiated. In contrast to the CNS stimulation by the noradrenergic I agents, fenfluramine produces CNS depression. Fenflu-I' ramine's abuse potential is qualitatively different, also. Doses of 80 to 400 mg have been associated with euphoria, derea!- , ization, and perceptual changes. The most common adverse I effects associated with fenfluramine and dexfenfluramine are ' diarrhea, drowsiness, and dry mouth. It is thought that dexfenfluramine might supplant "fenphen" therapy because its adverse effects are milder. However, caution is still advised because data in humans are limited. Even in the relatively short time dexfenfluramine has been studied, a rare adverse effect, primary pulmonary hypertension, has been observed. 18 ,19 The incidence of this serioUS condition in the general population is estimated at 1 to 2 cases per million adults per year,20 and the current labeling of
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Redux estimates the risk at 18 cases per million for patients using the drug for longer than three months. The symptoms of this complication include vague chest discomfort or shortness of breath. Stopping the medication mayor may not stop the disease process because primary pulmonary hypertension obliterates the lung's ability to get oxygen to the heart. Therefore, the possibility exists that a lung or heart -lung transplant might be necessary for survival. Primary pulmonary hypertension has an estimated four-year mortality rate of 45%. Even though dexfenfluramine is indicated for obese patients whose initial body mass index (BM1)21 is at least 30 (e.g., someone 5'6" weighing> 185 pounds), much like fluoxetine, it has the potential to be overprescribed and used by mildly obese persons for cosmetic weight loss. Even though the incidence of pulmonary hypertension remains small, the disorder is serious. Therefore, it is important that dexfenfluramine not be prescribed for cosmetic weight loss. In addition, this drug is indicated for obese patients with other risk factors (e.g. , hypertension, diabetes) if their BMI is >27 (e.g., someone 5'6 " weighing >167 pounds). Another point of contention in the FDA AdviSOry Committee's approval vote for dexfenfluramine was the theoretical risk of brain damage. Dexfenfluramine has demonstrated neurologic toxicity in primates and rodents. 22 Historically, in some species, high doses of some drugs (e.g., 3,4-methylenedioxymethamphetamine) have caused a massive release of serotonin from neurons, and when so much is reabsorbed back into the neuron and metabolized at once, neurotoxic oxidation intermediates are produced. These destroy the neuron. Consequently, serotonin depletion in primates caused by dexfenfluramine has caused concern, but the relevance of the finding to humans remains unknown. Experience with the racemic mixture of fenfluramine gives credence to its safety, although without the levo enantiomorph present in the dosage form, different results may occur in vivo. Because no long-range safety and efficacy data are available for dexfenfluramine for more than one year, the drug is only approved for one year's use. In all studies, the drug was used as an adjunct to a reduced-calorie diet, increased exercise regimen, and other behavioral modifications. A key point is that not all patients respond to the drug. Physicians should discontinue its use in any patient who does not demonstrate a loss of at least four pounds within one month of taking the drug. Tables 2 and 3 provide an overview of ASDs and serotonergic drugs.
Nonprescription Drugs PhenylpropanolalTline As a sympathomim,e tic , phenylethylamine derivative, phenylpropanolamine (PPA) is a direct agonist of postsynapVol. NS37, No.1
January/February 1997
tic alpha- and beta-adrenoreceptors and acts indirectly by increasing norepinephrine concentrations from sympathetic nerve endings. It is well absorbed from the GI tract and has an elimination half-life that ranges between three and four hours. Although 80% of an oral dose is excreted unchanged in urine, a portion of the drug is hepatically converted to norephedrine. The exact mechanism by which PPA exerts its anorexic effect is unknown. One theory is that it may activate postsynaptic alpha-I-adrenergic receptors within the medial hypothalamic paraventricular nucleus. 23 Stimulation of this nucleus may activate the human satiety mechanism. Other research has noted that PPA can increase energy by accelerating the breakdown of fat tissue, an effect similar to that of ephedrine, which may account for its efficacy in weight loss.24 Recently, a meta-analysis of PPA clinical trials for obesity was reported. 25 In placebo-controlled trials since 1985, PPA has demonstrated a net greater weight loss of 0.14 kg/week · compared with placebo. Overall, PPA demonstrated an incidence of adverse effects of 19% compared with 14% for placebo. 25 There was no mention of addiction or abuse potential. There has been considerable attention in the literature to the safety of PPA in view of case reports of serious adverse effects such as cerebral infarction, intracerebral hemorrhage, seizures, acute interstitial nephritis, and cardiac arrhythmias. Because these case reports demonstrate a variability of PPA dosage and dosage form, it is very difficult to interpret the findings. However, the serious nature of the reported reactions to PPA make them a concern. FDA permits a PPA dose of up to 37.5 mg in immediaterelease products and up to 75 mg in sustained-release products with a maximum daily dose of 75 mg. It is prudent, therefore, to warn patients not to exceed the immediate dose of 37.5 mg or the maximum dose of 75 mg per day, because most of the adverse effects reported appear to result from higher-than-recommended doses. When serious toxicity is suspected, the most common presenting symptom is a persistent, severe headache or other sign of elevated arterial pressure. Thus those at risk for adverse reactions to PPA would include patients with hypertension or anorexia/bulimia, women who take oral contraceptives (risk of hypertension is higher), the elderly, those concomitantly using other sympathomimetic agents, and those who demonstrate autonomic insufficiency. Adverse effects (e.g., nervousness, restlessness, insomnia, dizziness , perspiration , anxiety, headache , increased blood pressure) can occur in previously normotensive individuals. Serious cardiovascular adverse effects (including hypertensive episodes, tremor, increased motor activity, agitation, hallucinations, stroke) have occurred following doses of PPA exceeding that of product labeling (Le., abuse situations). To avoid problems with sustained-release PPA, patients should be told not to crush or chew the dosage form. To avoid
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journal of the American pharmaceutical Association
Table 2
Overview of Noradrenergic Drugs Used to Treat Obesity DEA Schedule
Phendimetrszine
HalfLife, t'lz (hours)
Dosage Regimen
Trade Name (Manufacturer)
Dosage Form, Strength (mg)
III
6-12
25-50 mg once daily; range 25-50 mg, once daily to three times daily
Didrex (Upjohn)
Tablets: 25, 50
III
5-12.5
35 mg twice or three times daily, 1 hour before meals. Sustained release: 105 mg once daily before breakfast
80ntril (Carnrick)
Tablets: 35 Capsules: 35 Sustainedrelease capsules: 105
Anorex (Dunhall) Prelu-2 (8-1)
Diethylpropion
IV
4-6
25 mg three times daily, 1 hour before meals, and in mid-evening if needed. Sustained-release 75 mg once daily, mid-morning
Tenuate (Lakeside)
Tablets: 25
Tepanil (Riker)
Dospan: 75
Tenuate (Lakeside)
Ten-Tab: 75
Tepanil (Riker) IV
10
19-24
3-4
1 mg three times daily, 1 hour before meals or 2 mg once daily, 1 hour before lunch. Take with meals to avoid GI upset 8 mg three times daily; ~ hour before meals, or 15 to 37.5 mg as a single daily dose before breakfast or 10 to 14 hours before bedtime
25 mg three times daily, not to exceed 75 mg in 24 hours or 75 mg once daily (as sustained-release adm i nistration)
excessive CNS stimulation, patients should be instructed to avoid highly caffeinated beverages. Benzocaine
One factor in overeating is the need to satisfy the sense of taste. In many obese persons, constant snacking is characteristic of the "oral syndrome. ,, 23 The rationale for using benzocaine for weight loss lies in its ability to decrease taste sensations by numbing the oral cavity and the gastric mucosa. Manufacturers have claimed that the drug can decrease sensitivity to sweetness, discouraging snacking and decreasing caloric consumption. Benzocaine is delivered in the form of Journal of the American pharmaceutical Association
Mazanor (Wyeth-Ayerst)
Tablets: 1
Sanorex. (Sandoz) Tablets: 1, 2 Phentermine (various manufacturers)
Tablets: 8 Capsules: 8
Fastin (Beecham)
Sustainedrelease capsules: 30
lonamin (Pennwalt)
Sustainedre lease capsules: 15,30
Dexatrim Pre-Meal (Thompson)
Capsules: 25
Prolamine (Thompson)
Capsules: 37.5
Acutrim 16 Hour (Ciba)
Tablets: 75
gum, wafers, or hard candy to be used between meals. TIlis keeps the patient orally active. The FDA Advisory Review Panel on aTC Miscellaneous Internal Drug Products classified benzocaine as generally I effective and safe for short-term weight control. The panel I also determined that a dose of 3 to 15 mg in gu m , lozenges , or candy just prior to a meal was generally appropriate. A daily dosage of greater than 45 mg is discouraged for fear that topical anesthesia may impair swallowing, increasing .the danger of aspiration. Also , numbness of the tongue or buccal mucosa may increase the risk I of biting trauma. January/February 1997
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I
Table 4
Serotonergic Drugs Used to Treat Obesity
Unapproved Nonprescription Drugs for Weight Reduction Aminophylline Cream
Although not officially approved for this purpose, aminophylline cream has been extolled in the lay media for its supposed weight reduction capability. In women, it is usually applied to the thighs, where it supposedly effects a reduction in thigh circumference. Pharmacists who receive prescription orders for a 2% aminophylline cream for weight reduction may want to read about a method for preparing a 2% aminophylline powder in an oil/water (OIW) emulsion base26 (e.g. , Dermabase [Paddock], Velvachol [Owen/Galderma], and Unibase [Warner Chilcott]). In addition, several topical aminophylline products are being advertised over the Internet for application to the thighs and buttocks (e.g., Thigh High) by women or, by men, to the stomach area (e.g., Belly Buster). FDA has not approved aminophylline for topical use. It is likely that the products are being marketed without listing aminophylline as the active ingredient on the .label. This practice, which many consider unethical, will probably continue until FDA issues a "cease and desist" order. Topical aminophylline products can cause skin sensitivity, manifested by skin rash or hives. The ethylenediamine component of the aminophylline molecule has been implicated as the offending agent. With oral aminophylline, an allergic reaction to the ethylenediamine moiety may appear 12 to 24 hours after initial administration. There is no information about how soon this could occur after topical application. Although no information is available on this, of concern is the amount of theophylline (from the aminophylline) that could be percutaneously absorbed, especially when applied (or overapplied) to a large area. Therefore , patients preVol. NS37, No.1
January/February 1997
scribed a topical dosage form of this drug must be monitored for potential toxicities (e.g., eNS stimulation [nervousness or restlessness], nausea) and drug interactions with other medications (e.g., cimetidine, lithium, phenytoin) and instructed to use the drug only as directed. Also, a patient who has obtained a topical commercial product may complain of theophylline adverse effects without understanding the source of the problem; unless the pharmacist or physician questions the patient thoroughly, one would not know that a "cosmetic," unregulated product is causing the toxicity. Glucomannan
Glucomannan is a hydrophilic hemicellulose composed of glucose and mannose linked through beta-glycoside bonds. Human digestive enzymes cannot break down polysaccharides of this nature. Being hydrophilic, glucomannan absorbs up to about 60 times its weight in water. Thus, when in the stomach, it creates a sense of fullness. Unforttmately, however, it has not produced substantial effects when used by dieters and it has proven largely ineffective in weight control. 23 Like other bulk-producing agents (e.g. , psyllium mucilloid), the ability of glucomannan to produce feelings of satiety is poor. Theoretically, sustaining the sensation of fullness might help curb one's appetite. However, radiographic studies have demonstrated that little of a bulk-forming compound remains in the stomach 30 minutes after ingestion. 23 Consequently, taking substances like glucomannan 30 to 60 minutes prior to a meal as directed by the product instructions for weight control is unlikely to prove beneficial. Chromium Picolinate
Chromium deficiency supposedly results in impaired glucose tolerance because the chromium ion is thought to be a
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journal of the American Pharmaceutical Association
part of a complex called glucose tolerance factor (GTF). 27 Deficiency of GTF may result in elevated blood glucose levels, hypercholesterolemia, and aortic plaques. Impaired glucose tolerance has been reported to be improved with elemental chromium (found in brewer's yeast, bread, beef, liver, cheese, nuts, prunes, asparagus). One study reported that chromium supplementation reversed impaired glucose tolerance and neuropathy in a patient receiving longterm total parenteral nutrition.28 Oral chromium ion is poorly absorbed from the GI tract (most individuals absorb < 1% to 3% from dietary sources), although it has been shown that patients with diabetes absorb two to four times more chromium ion than normal subjects. Chromium is available as chromium picolinate because picalinic acid (a metabolite of tryptophan) forms stable complexes with transitional metals such as chromium and enhances the bioavailability of the ion. The average American diet contains 5 to 115 mcg/day of chromium, with recommended levels established at 50 to 200 mcg/day.27 The evidence to date of chromium picolinate causing weight reduction is for the most part anecdotal, although case - reports have described the effects of GTF in patients with diabetes. The usefulness of chromium picolinate as a weight loss product has been extrapolated from its role in regulating glucose metabolism. That is , in chromium-deficient tissue, chromium will increase glucose uptake by cells and effect oxidation of glucose to carbon dioxide, thus potentiating the incorporation of glucose into fatty acids and cholesterol. To date, little, if any, toxicity has been associated with the use of chromium picolinate. In this compound, chromium is present as a trivalent ion, Cr+. With more widespread use, it is possible that toxicities may be reported. The hexavalent chromium compounds can be extremely harmful and have been demonstrated in animal studies to produce nausea, vomiting, convulsions, and coma.
date, clinical trials have demonstrated its clinical efficacy for weight loss when used adjunctively to caloric restriction, behavioral modification, and exercise.31 Although patients taking sibutramine have shown a dose-dependent reduction in body weight, they have also experienced increased heart rate and blood pressure. Because of these adverse effects, in September 1996 the FDA's Metabolism and Endocrine Drugs AdviSOry Committee refused to approve sibutramine for weight loss. However, this committee recommended further studies to determine the drug's cardiovascular effects. Orlistat (tetrahydrolipstatin, Xenical-Roche) is a chemically produced derivative of the natural product lipstatin. Lipstatin, a potent, irreversible lipase inhibitor, effects a decrease in the amount of ingested dietary fat (i.e. , the product resulting from the dividing of free fatty acids from the glycerol backbone) that is absorbed systemically. Orlistat inhibits pancreatic lipase, the primary enzyme for fat metabolism in the gut. Consequently, fecal fat excretion is increased, and this characterizes the GI complaints associated with the drug (e.g. , loose bowel movements, oily appearing stools, abdominal cramps, fecal incontinence, nausea). Clinical trials to date have demonstrated the weight loss abilities of this drug as well as the dose-dependency for its effect. 32 Several other entities are also being studied for possible weight reduction activity. Chlorocitrate has been shown to inhibit gastric emptying, causing a sense of fullness. Also, the hormone leptin has been postulated as a substance that helps to set the body's weight, and recently scientists discovered receptors for that protein in the brain. Leptin triggers the production of glucagon-like peptide-1 (GLP-1). This substance is known to help digest sugars in the human intestine. However, an animal study involving rats demonstrated that after a large meal, GLP-1 is also released in the brain to signal that the stomach is full. 33
Syrup of Ipecac
The use of syrup of ipecac to induce vomiting and avoid weight gain is a dangerous and illegitimate practice and should be avoided. The pharmacist must be wary of requests for the drug, especially from young adults and teenagers. Chronic use of syrup of ipecac has resulted in several fatalities in patients with eating disorders (e.g. , bulimia, anorexia) who used it regularly.29,30 Ipecac can demonstrate cardiotoxic effects when absorbed, and can cause cardiac conduction disturbances, bradycardia, atrial fibrillation, hypotension, and fatal myocarditis.
Drugs Under Investigation Sibutramine (Meridia-Knoll), a new monoamine antidepressant, is also being studied as a weight loss agent. To Journal of the American phannaceutical Association
Patient/Consumer Education Advertisements and testimonials in the media can be confusing and misleading, and the phannacist can provide patients with infonned advice on weight loss products and programs. In desperation, patients frequently turn to outrageous schemes claiming to offer cures for obesity. Commercial weight loss programs have counselors (some trained and qualified, some not) with a variety of backgrounds and whose experience may vary widely. Indeed, one's credentials may be limited to personal experience in lOSing pounds in that program. Thus, patients can get less than optimal advice and guidance. Optimally, weight loss and maintenance requires an individualized, interdisciplinary approach. The pharmacist must be alert to comments that may indicate that a patient is seeking information or attempting to determine whether a weight loss approach is likely to be sueJanuary/February 1997
Vol. NS37, No.1
cessful. When an approach involves drugs, the pharmacist must be attuned to patient comments that might indicate suspected adverse effects or misuse. Medications for obesity will work best in patients who need them the least; for example, in motivated patients with mild .J obesity. A weight management program is considered successful when the weight loss is maintained for up to five years after program initiation. 34 This means that morbidly obese patients who are prescribed medications will need constant support and reinforcement while they attempt to lose weight, probably over a period of years. Patients are certain to become frus) trated with current approaches to the treatment of obesity, and health care professionals, including phannacists, will feel pressured to embrace each newly reported treatment (often accompanied by media attention). As Weintraub pointed out, I "We must teach ourselves and our patients to measure success by prevention of weight gain and maintenance of a significant but perhaps more modest weight loss than we or they would fmd 'desirable.' ,, 16 When opportune, pharmacists must reinforce this notion and continue to encourage patients to abide by their integrated weight loss program of diet modification, behavioral modification, exercise, and drug therapy. In the end, the patient will prosper from this encouragement. Mildly obese patients without significant medical risk factors for obeSity-related disease should be advised to consume foods low in fat and high in complex carbohydrates. Also, they should be encouraged to increase their daily physical activity, with weight maintenance as a long-term goal. For the patient with significant obesity or the risk factors for obesity-related disease, the problem is much more complex. Those who are motivated should be guided to programs targeted to their needs that emphasize long-term changes in behavior, diet, and physical activity. This approach coupled with ASD therapy might be indicated in patients with long-standing obesity who have been unable to lose sufficient weight to decrease their medical risks. Ideally,' pharmacists should identify centers (locally if possible) that specialize in conducting clinical trials that evaluate the long-term safety and effectiveness of ASDs. When no such centers are identifiable, a pharmacist may take the prerogative to work with a physician and dietitian (perhaps through a managed-care organization) who may wish to begin an ASD regimen in conjunction with other established dietary and behavioral methodologies. Again, patient success is related to monitoring and reinforcement coupled with careful documentation that justifies continued use of the ASD; in other words, pharmaceutical care. I
Conclusion From a research standpoint, data on the long-term efficacy of drug therapy for obesity are sorely needed. Further studies Vol. NS37, No.1
January/February 1997
are also needed to examine the effects of variables such as sex, race, age, and other eating behaviors (e.g., binging, purging) on the effectiveness and safety of ASDs. Knowledge is also lacking in how drug therapy affects other aspects of a weight loss program (e.g., behavioral modification, diet, exercise). Although no "magic bullet" now exists to treat obeSity, molecular biology may eventually provide a cure. In the meantime, the reality is that the pharmacologic approaches to obesity control and management pose a serious threat to the billion dollar commercial weight loss industry. Gratefully, obesity is ftnally being recognized as a long-term problem requiring integrated long-term care, including drug therapy. Nicholas G. Popovich, PhD, is professor, Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, and Olivia B. Wood, MPH, RD, is associate professor, Department of Foods and Nutrition, School of Consumer and Family Sciences, Purdue University, West Lafayette, Ind.
References 1. Frank A. Futility and avoidance. Medical professionals in the treatment of obesity. JAMA. 1993;269:2132-3. Commentary. 2. Yanovski SZ. Are anorectic agents the 'magic bullet' for obesity? Arch Fam Med. 1993;2:1025-7. 3. Gortmaker SL, Must A, Perrin JM, et al. Social and economic consequences of overweight in adolescence and young adulthood. N Engl J Med. 1993:329:1008-12. 4. Committee to Develop Criteria for Evaluating the Outcome of Approaches to Prevent and Treat Obesity. Thomas PR, ed. Weighing the Optians. Criteria far Evaluating Weight-Management Programs. Washington, D.C.: National Academy Press; 1995. 5. Bray GA. Use and abuse of appetite-suppressant drugs in the treatment of obesity. Ann Intern Med. 1993;119:707-13. 6. Bray GA. The obese patient. WB Saunders Company; 1976:1-450. 7. Levy AS, Heaton AW. Weight control practices of U.S. adults trying to lose weight. Ann Intern Med. 1993;119:661-6. 8. Stahl KA, Imperiale TF. An overview of the efficacy and safety of fenfluramine and mazindol in the treatment of obesity. Arch Fam Med. 1993;2:1033-7. 9. Weintraub M, Sundaresan PR, Madan M, et al. Long-term weight control study I (weeks 0 to 34). Clin Pharmacal Ther. 1992;51:586-94. 10. Weintraub M, Sundaresan PR, Schuster B, et al. Long-term weight control study II (weeks 34 to 104). Clin Pharmacal Ther. 1992;51 :595-601. 11 . Weintraub M, Sundaresan PR, Schuster B, et al. Long-term weight control study III (weeks 104-156). Clin Pharmacal Ther. 1992;51:602-7. 12. Weintraub M, Sundaresan PR, Schuster B, et al. Long-term weight control study IV (weeks 156to 190). Clin Pharmacal Ther. 1992;51:608-14. 13. Weintraub M, Sundaresan PR, Schuster B, et al. Long-term weight control study V (weeks 190 to 210). Clin Pharmacol Ther. 1992;51 :615-8. 14. Weintraub M, Sundaresan PR, Cox C. Long-term weight control study VI. Clin Pharmacal Ther. 1992;51:619-33. 15. Weintraub M, Sundaresan PR, Schuster B. Long-term weight control study VII (weeks 0 to 210). Clin Pharmacal Ther. 1992;51:634-41. 16. Weintraub M. Long-term weight control study: Conclusions. Clin Pharmacal Ther. 1992;51 :642-6. 17. Olin BR, editor-in-chief. Facts and Camparisons. St. Louis: Facts and Comparisons; 1996. 18. Pouwels HM, Smeets JL, Cherlex EC, et .al. Pulmonary hypertension and fenfluramine. Eur Respir J. 1990;3:606-7. 19. McMurray J , Bloomfield P, Miller HC. Irreversible pulmonary hypertension after treatment with fenfluramine. BMJ. 1986:292:239-40.
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