Dexfenfluramine

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Abstract
Dexfenfluramine stimulates serotoninergic activity by inhibiting serotonin reuptake into pre-synaptic neurons and by enhancing its release into brain synapses. Based on the serotonin hypothesis of appetite control these effects would be expected to reduce food intake and thus body-weight. Studies in animal models and severely overweight patients have confirmed the effectiveness of dexfenfluramine as a weight-reducing agent which appears to be well tolerated. Permanent weight loss is the goal of weight-reducing strategies and, based on current clinical evidence, dexfenfluramine appears to exert a weight reducing effect over periods of up to 12 months without development of tolerance, a problem that has limited the long term use of other pharmacological agents used in the treatment of this disorder. Dexfenfluramine facilitated weight loss in patients who had not responded satisfactorily to other weight-reducing strategies, prevented relapse in those patients who had achieved weight reduction by other methods, and corrected disturbed eating patterns (and therefore reduced weight gain) in small studies involving patients with premenstrual syndrome, seasonal affective disorder and nicotine withdrawal syndrome. Follow-up of the longest study reported with dexfenfluramine suggests that continued therapy is required in severely overweight patients if weight loss is to be maintained. Dexfenfluramine has not been directly compared with nonpharmacological measures of weight control such as behaviour modification or exercise programmes. The decision that pharmacological means are indicated in overweight patients must be highly individualised, and must consider the many complex factors that often contribute to overweight states, as well as the anticipated magnitude of drug effect. Despite such a cautionary note, and the expected need (at this stage of its development) for an expanded clinical study programme in certain areas, dexfenfluramine is a clear advance in the pharmacological approach to improved management of overweight individuals. Dexfenfluramine, the dextro-rotatory stereoisomer of fenfluramine, inhibits reuptake of serotonin (IC50 0.52 μmol/L) and stimulates serotonin release from rat brain synaptosomes (25% stimulation of release achieved with a concentration of 5 μmol/L). As a consequence, dexfenfluramine increases brain serotonin levels; in accordance with the serotonin hypothesis of appetite control this would be expected to selectively suppress food intake. Indeed, in normal weight volunteers, a single dose of dexfenfluramine 30mg reduced food intake by 40%, and decreased the size of large meals consumed, as well as the frequency of small meals and snacks. Evidence from animal studies indicates that dexfenfluramine may selectively reduce carbohydrate consumption, and in patients classified as carbohydrate cravers (individuals who consume about 60% of daily calories as carbohydrates) a 30mg daily dose reduced total mealtime calorie intake by 16%, mealtime carbohydrate calorie intake by 22%, snack carbohydrate intake by 41%, and had no significant effect on mealtime or snack protein intake. Dexfenfluramine also increases dietary-induced thermogenesis (particularly after a carbohydrate-rich meal), decreases lipogenesis in adipose tissue, reduces gastric emptying after a solid meal, and has been proposed to lower bodyweight ‘set-point’ (i.e. the hypothetical point around which bodyweight is maintained). The relative contribution of these effects to its weight-reducing activity remains to be established. The disposition of dexfenfluramine has been studied in normal weight healthy volunteers. Dexfenfluramine remains detectable in plasma for up to 48 hours after a single oral dose, and with multiple administration steady-state is reached within 4 to 8 days. The drug is lipophilic and is therefore extensively distributed, but does not appear to accumulate in tissues. An active metabolite, d-norfenfluramine, is detectable in plasma within 1 to 2 hours of dexfenfluramine administration and has a longer elimination half-life than its parent drug (31.2 vs 18.2 hours). Dexfenfluramine is virtually entirely eliminated in the urine. In clinical studies of 3 months’ duration, dexfenfluramine 15mg twice daily was effective in reducing bodyweight in severely overweight patients, including those refractory to other therapy. Weight loss ranged from 3 to 5kg in refractory patients and 8 to 10kg in de novo patients, was statistically significant compared with placebo after 1 month and had not levelled off after 3 months of treatment. Historically, continuous long term treatment (including pharmacotherapy) of obesity has been controversial. However, in the first well controlled, large multicentre study in which patients received dexfenfluramine 15mg twice daily or placebo for 12 months, the drug has shown encouraging efficacy. In dexfenfluramine recipients who completed the study (63% of initial cohort) weight loss was 9.8kg, representing 10.3% of initial bodyweight. In comparison, placebo recipients who completed the study (55% of initial cohort) lost an average of 7.2kg (7.2% of initial bodyweight) after 12 months. Further, almost twice as many patients treated with dexfenfluramine achieved a loss of > 10% of initial bodyweight, > 30% of initial overweight, or of > 10kg. All placebo versus drug differences in this study were statistically significant. After 2 months of discontinuing dexfenfluramine, mean bodyweight and caloric intake increased. Further weight loss in patients who had lost some weight through other means, but who could not exceed or maintain this achievement, was facilitated by dexfenfluramine, and in morbidly obese patients (body mass index 44) who achieved weight loss while on a very low calorie diet for 8 weeks, further weight loss was achieved with dexfenfluramine after the very low calorie diet was withdrawn. Dexfenfluramine reduced weight and carbohydrate craving, and improved mood in patients with seasonal affective disorder, and prevented excessive carbohydrate snacking and weight gain in patients with premenstrual syndrome or in those withdrawing from smoking. In addition, there is some evidence that dexfenfluramine reduces weight and improves glycaemic control in severely overweight patients with non-insulin-dependent diabetes mellitus. Tolerance to the initial weight-reducing effects of dexfenfluramine has not been noted during longer term administration, despite its occurrence in animal models. However, in the only study of > 6 months’ duration, most weight loss occurred during the first 6 months of treatment; thereafter dexfenfluramine appeared to prevent weight regain. Dexfenfluramine 15mg twice daily has been well tolerated in clinical studies when administered for up to 12 months. For many reported adverse events, the incidence rates for dexfenfluramine and placebo recipients were similar, exceptions being tiredness, diarrhoea, polyuria, drowsiness and dry mouth, which occurred significantly more frequently with dexfenfluramine than with placebo in the largest clinical trial reported to date. Adverse effects were generally of mild to moderate severity and resolved with continuing treatment. Withdrawal from therapy because of dissatisfaction with weight loss has been more common in placebo recipients than in dexfenfluramine recipients after 12 months of treatment. No significant changes in blood cell count, liver and renal function tests, fasting blood glucose or plasma cholesterol and triglyceride levels have been reported in patients treated with dexfenfluramine. Rare reports of pulmonary hypertension, including a fatal case, have been noted in patients during long term dexfenfluramine therapy; however, direct causality has not been established. The recommended dosage of dexfenfluramine for adjunctive management of overweight individuals, along with dietary restriction, is 15mg orally twice daily with meals. Treatment should be limited to 3 months although continued therapy appears to be required to maintain weight loss in severely overweight patients. Before treatment is initiated, organic causes of obesity should be excluded. Dexfenfluramine should be used with caution in patients with cardiac arrhythmias, and is contraindicated in patients with glaucoma, in those receiving monoamine oxidase inhibitors (a washout period of ≥15 days is advised), and in those with hepatic or renal failure.