Dexfenfluramine

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EDITORIALS

Dexfenfluramine Fenfluramine, originally produced as a drug of similar chemical structure to amphetamine but without the stimulant effects, is an effective anorexic agent with little risk of habituation.1 After oral ingestion, about half the dose is absorbed in 1 hour; plasma half-life is slow, at 24 hours. Fenfluramine is converted, mainly in the liver, to norfenfluramine, whose plasma half-life is twice as long. It is excreted in the urine, mostly as 3-trifluoromethylhippuric acid. In man, plasma concentrations of about 200 ng/ml (ljmol/1) correlate with the best rate of weight loss. Fenfluramine is taken up by adipose tissue, and this may be the basis for the long washout periods that occur after the drug is stopped in patients with obesity. The dose is usually 60-120 mg/day, although higher doses of 2 mg/kg per day have been recommended. Weight loss occurs over about 20 weeks but reaches a steady state at about that time; the amount lost is no more than can be achieved from equivalent food restriction, so the drug does not increase energy consumption. Fenfluramine enhances glucose uptake by peripheral tissues, and may reduce hepatic gluconeogenesis without increasing insulin release. The effects may be mediated through changes in insulin receptor binding or sensitivity. Fenfluramine is a racemic mixture of D and L stereoisomers. The L stereoisomer has its predominant effects on catecholamines and leads to raised striatal concentrations of the dopamine metabolites dihydroxyphenyl acetic acid and homovanillic acid and to reduced concentrations of dopamine. There is increased release of dopamine that lasts some hours. D-fenfluramine has little or no effect on the dopaminergic system but increases presynaptic output and decreases postsynaptic uptake of serotonin.2

Food intake is reduced by promoting or prolonging satiety; some of this effect may be the result of slowed gastric emptying. Fenfluramine also stimulates ileal contractions, which can be blocked by serotonin antagonists, and perhaps the release of serotonin from such peripheral sites. The drug may result in selective reduction of carbohydrate ingestion, but since the studies supporting this idea concentrated mainly on the effect on snacking, and the snacks were high in carbohydrate, the reduction may not have been as specific as at first seemed. Nevertheless, the idea is interesting because carbohydrate intake results in increased brain uptake of tryptophan; this serotonin precursor, through its neurotransmitter effects on the brain, produces a calming effect. The unwanted effects of DL-fenfluramine include gastrointestinal complaints, especially diarrhoea, and also drowsiness, dizziness, lethargy, dry mouth, headache, sleep disturbances, visual disorders, hypotension, urinary frequency, impotence, and loss of libido. Rashes, blood disorders, and pulmonary hypertension have been reported occasionally. One of the most worrying side-effects is depression, which may be precipitated by sudden withdrawal of the drug—eg, when a patient forgets to take the tablets while on holiday. With a slimming industry already worth 1:1billion and growth at 20% per annum to maintain in the UK alone,3investment in anorectic drugs continues. Evidence that the anorectic effect of fenfluramine is confined to the D enantiomer made it logical to try to isolate this from the L form, especially because the latter may be responsible for many of the side-effects. Thus dexfenfluramine4 is newly marketed as "a turning point for your overweight patients". That the serotoninergic D isomer is primarily anorectic accords with results of animals studies in which, dose for dose, weight loss with pure dexfenfluramine may be twice that with fenfluramine.s The L enantiomer has a longer half-life6 and produces some of the untoward side-effects of the racemate. The appropriate dose of dexfenfluramine seems to be 15-30 mg twice daily-ie, half that of DL-fenfluramine. Controlled trials have compared dexfenfluramine only with placebo in combination with dietary intervention or counselling. Enzi et aF reported a significant loss of body weight in the dexfenfluramine group compared with placebo over 3 months. Silverstone and Goodall8 used dexfenfluramine and diet in twenty-nine overweight schizophrenic patients maintained on depot neuroleptic injections who wished to lose weight. Dropout rate was almost half in both groups, mainly due to adverse effects in the dexfenfluramine group. However, the rate of weight loss was significantly greater with dexfenfluramine. Finer et al9 found that dexfenfluramine resulted in increased weight loss after 3 months. In an open trial, some of the

subjects who had earlier been on placebo were given 3 months of dexfenfluramine. 10 In contrast to an

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weight gain of 07 kg during placebo, these subjects lost 2-9 kg after 3 months of dexfenfluramine. Patients who had already received dexfenfluramine for 3 months were maintained on the drug for a further 3.10 Although the rate of weight loss diminished in the second 3 months, it remained significant and did not plateau.

average

Dexfenfluramine was tried over 1 year in a multicentre trial in eight hundred adults weighing 120 % or more of their ideal weight in Western Europe." Drop-out rate, although high in both groups, was significantly less in the dexfenfluramine group (45% vs 37%) because of dissatisfaction with weight loss in the placebo group (20% vs 12%). Patients in the dexfenfluramine group had significantly more tiredness, diarrhoea, dry mouth, polyuria, and drowsiness, especially in the early stages of treatment. Significant weight loss occurred in both groups at each time point in the first 6 months, with body weight maintained in the second 6 months in the dexfenfluramine group but regained significantly in the placebo group. At the end of the year mean weight loss was 9-82 kg and 7-15 kg in the dexfenfluramine and placebo groups, respectively, or 10.26% and 7-18% of the inital weight (p < 0-001). Thus the clinical question is whether an extra 3 kg weight loss is worth the treatment, its side-effects, and its costs. It is not yet possible to determine which obese patients will benefit most from dexfenfluramine. Initial body weight does not seem to be important. We should restrict the use of this drug to patients at risk from their obesity-eg, those with associated metabolic, rheumatic, or cardiorespiratory diseases and those in whom dietary manipulation has failed. Patients with organic causes of obesity should be excluded. Obesity associated with compulsive hyperphagia, stress-induced compulsive feeding behaviour, and atypical depression such as seasonal affective disorder may respond to dexfenfluramine. It has been suggested that the presence of a mild atypical depression may be a predictor ofresponsiveness,12 although great care will be needed when the drug is withdrawn in such patients. The possible selective reduction in carbohydrate intake may be important in some obese women who crave carbohydrate probably in response to low serotonin concentrations.13 Monoamine oxidase inhibitors should be stopped for several weeks before starting dexfenfluramine because they prevent metabolism of the drug. Dexfenfluramine may potentiate the actions of central nervous system depressants, antihypertensives, and sulphonylureas and the hypotensive effects of tricyclic antidepressants.4It should be used cautiously in those with cardiac arrhythmias and should be avoided during pregnancy and in patients with renal or hepatic

impairment. Since there is some evidence that dexfenfluramine maintain weight loss, the drug could be considered for long term use to prevent relapse in dietary restriction of up to a year, although the current licence can

does not allow for use beyond 3 months. The drug is a small adjunct to dietary restriction and long-term modification, but could boost the morale of a dieter whose weight had "stuck" and be used as a "reward" in treatment strategies after initial weight loss had been achieved by dieting. Dexfenfluramine may well be more of a turning point for neuropharmacologists than for patients. NE, Carlton J. Neurobiology of an anorectic drug: fenfluramine. Prog Neurobiol 1986; 27: 16-62. 2. Garattini S, Bizzi A, Caccia S, Mennini T, Samanin R. Progress in assessing the role of serotonin in the control of food intake. Clin Neuropharmacol 1988; 11 (suppl 1): S8-S32. 3. Dietplan 2000. Observer Magazine; Jan 13, 1991. 4. Turner P. Dexfenfluramine: its place in weight control. Drugs 1990; 39 (suppl 3): 53-62. 5. Le Douarec JC, Schmitt H, Laubie M. Pharmacologic study of fenfluramine and its optical isomers. Arch Int Pharmacodyn 1966; 161: 206-32. 6. Campbell DB, Richards RP, Caccia S, Garattini S. Stereoselective metabolism and the fate of fenfluramine in animals and man. In: Gorrod JW, Gibson GG, Mitchard M, Eds. Development of drugs and modern medicine. Chichester: Ellis Horwood, 1986: 298-311. 7. Enzi G, Crepaldi G, Inelman EM, Bruni R, Baggio B. Efficacy and safety of dexfenfluramine in obese patients: a multicentre study. Clin Neuropharmacol 1988; 11 (suppl 1): S173-78. 8. Silverstone T, Goodall E. The efficacy and acceptability of d-fenfluramine (Isomeride) in neuroleptic induced obesity. In: Ferrari E, Brambilla F, eds. Disorders of eating behaviour; a psychoneuroendocrine approach. Adv Biosci 1986; 60: 361-66. 9. Finer N, Craddock D, Lavielle R, Keen H. Dexfenfluramine in the treatment of refractory obesity. Curr Therap Res 1985; 38: 847-54. 10. Finer N, Craddock D, Lavielle R, Keen H. Prolonged weight loss with dexfenfluramine treatment in obese patients. Diahete Metab 1987; 13: 598-602. 11. Guy-Grand B, Apfelbaum M, Crepaldi G, Gries A, Lefebvre P, Turner P. International trial of long-term dexfenfluramine in obesity. Lancet 1989; ii: 1142-45. 12. O’Rourke D, Wurtman J, Bryezinski A, Abou-Nader T, Marchant P. Treatment of seasonal affective disorder with D-fenfluramine. Ann NY Acad Sci 1987; 499: 329-30. 13. Wurtman J, Wurtman R, Mark S, Tsay R, Gilbert W, Growdon J. D-fenfluramine selectively suppresses carbohydrate snacking by obese subjects. Int J Eating Dis 1985; 4: 89-99. 1. Rowland

Teratogenesis with carbamazepine That antiepileptic drugs are potentially teratogenic has been known since 1968.1 The overall risk of congenital anomalies is 2-3 times that in unexposed babies-ie, about 6%.zPolypharmacy increases the proportion of malformed infants in relation to the number of antiepileptic drugs taken.3,4The incidence with individual agents is harder to determine. The fetal hydantoin syndrome was first described in 1975;5 many affected babies exposed in utero to phenytoin alone have some of the components but not all.6 Sodium valproate is associated with spina bifida; the overall frequency is about 1 -5 %, but this association is more common in some countries than in others.8 A fetal valproate syndrome has also been proposed,9 as has a primidone embryopathy. 10 Carbamazepine (CBZ) has been used clinically for more than 20 years, but has been acknowledged as a first-line antiepileptic drug only in the past decade." Early studies were reassuring with respect to teratogenesis, and CBZ was therefore suggested as the