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PubMed2006

The effects of dexfenfluramine administration on brain serotonin immunoreactivity and lipid peroxidation in mice.

Obesity continues to be an increasing health problem in worldwide and antiobesity drugs have commonly been used by obese patients. During the use of anorectic drugs, the antioxidant defense may be affected, especially by reactive oxygen species. It was decided to investigate the effects of dexfenfluramine on body weight, daily food intake, brain thiobarbituric acid-reactive substances (TBARS), glutathione (GSH) and nitric oxide (NO) levels, and 5-HT immunoreactivity. Mice were divided into two groups each containing 8 Swiss Albino adult (6 months) mice. Group 1, untreated, was used as a control; group 2 was treated with dexfenfluramine 0.4 mg/kg per day intraperitoneally for 7 days. Brain TBARS and GSH levels were assayed spectrophotometrically. The stable end-products of NO, nitrite and nitrate, were analyzed spectrophotometrically. Brain tissue 5-HT immunoreactivity was observed using an immunohistochemical method. There were significant decreases in body weight in the dexfenfluramine group (p < 0.05). Although brain GSH and NO(x) levels decreased significantly, brain TBARS levels increased in the dexfenfluramine group (p < 0.05). Brain 5-HT immunoreactivity also increased in the dexfenfluramine-treated group compared to control. In conclusion, our findings show that dexfenfluramine is effective in achieving weight loss and also increases lipid peroxidation in mouse brain.

Animals↗
PubMed2006

Dexfenfluramine does not worsen but moderates progression of chronic hypoxia-induced pulmonary hypertension.

This study shows for the first time, that dexfenfluramine, a 5-HT(2) receptor agonist, attenuates the development of chronic hypoxia-induced pulmonary hypertension. Chronic exposure to hypoxia, 4 weeks, induced hypoxic pulmonary hypertension in adult rat as haemodynamic and cardiac measurements showed significant modifications in right ventricle parameters (free wall right ventricle thickness; pulmonary acceleration time and velocity time integral) in chronic hypoxic control when compared to normoxic control animals. We observed that free wall right ventricle thickness and pulmonary velocity time integral were significantly less in chronic hypoxic rats treated with dexfenfluramine when compared to chronic hypoxic control rats. Similarly, rats exposed to chronic hypoxia exhibited an increase in both right ventricle pressure and weight by comparison to normoxic control animals but those variations were significantly diminished in dexfenfluramine-treated rats, indicating the moderating influence exerted by dexfenfluramine on chronic hypoxia-induced pulmonary hypertension and cardiac alterations. Thus, we report here the ability of dexfenfluramine to limit chronic hypoxia-induced pulmonary hypertension, emphasizing the importance of the time after the dexfenfluramine treatment discontinuation to assess the influence of this 5-HT receptor agonist on the development of chronic hypoxia-induced pulmonary hypertension.

Animals↗
PubMed2000

Dexfenfluramine-induced contraction of human and rat isolated pulmonary arteries.

Mechanisms of dexfenfluramine-induced vasoconstriction were studied in isolated pulmonary arteries suspended in organ baths for isometric tension recording. Dexfenfluramine (10(-7)-10(-4) M) caused concentration-dependent contractions in rat and human pulmonary arteries with and without endothelium. In pulmonary arteries of the rat, the response to dexfenfluramine was nearly abolished by treatment with the alpha-adrenoceptor antagonists, phentolamine (10(-6) M) or prazosin (10(-7) M). In human pulmonary arteries, the concentration-response curve to dexfenfluramine was unaltered by the presence of phentolamine (10(-6) M), prazosin (10(-7) M), ketanserin (10(-6) M), or indomethacin (3x10(-6) M). The results suggest that dexfenfluramine causes contraction of pulmonary vascular smooth muscle by multiple mechanisms, one of which involves activation of alpha-adrenoceptors within the blood vessel wall. The mechanisms by which dexfenfluramine causes pulmonary vasoconstriction may differ between rat and human pulmonary arteries.

Animals↗
PubMed1996

Repeated administration of escalating high doses of dexfenfluramine does not produce morphological evidence for neurotoxicity in the cortex of rats.

Rats were treated for 28 days with increasing doses of dexfenfluramine (0.5, 1, 1.5, 2, 3, 4 and 5 mg/kg bid ip, each dose given for 4 days before being increased) and subsequently studied at intervals between 1 and 60 days following the cessation of treatment. Control rats received vehicle and were allowed food ad libitum or were pair fed with dexfenfluramine-treated animals. Immediately following drug treatment 5-HT immunoreactivity was increased in cortical areas compared to control animals. Subsequently, there was a persistent decrease in fine fibre density and the appearance of coarse truncated fibres. 5-HT levels in cortex were decreased 1 day following dexfenfluramine treatment but recovered to control values by 15 days. GFAP and GAP 43 immunoreactivity was unaffected by dexfenfluramine treatment compared to control animals, indicating a lack of evidence for neuronal degeneration and regeneration. Dexfenfluramine treatment decreased the density of 5-HT uptake sites in the cortex, labelled with [3H]-citalopram, but this partially recovered towards control values at 60 days. These alterations in 5-HT terminal networks conflict with the return of 5-HT levels to normal and the lack of evidence for degenerative changes or neuronal regrowth. On the basis of these results, it cannot be concluded that dexfenfluramine is neurotoxic.

Animals↗
PubMed1991

Haemodynamic, metabolic and endocrine effects of short-term dexfenfluramine treatment in young, obese women.

Seventeen normotensive, premenopausal women were treated with the 5-hydroxytryptamine-reuptake inhibitor dexfenfluramine 30 mg per day, for 4 days in a randomised double-blind, cross-over, placebo controlled trial. Energy intake was held constant during the study as the aim was to study the endocrine and metabolic effects of dexfenfluramine dissociated from its weight-lowering properties. Body weight, blood glucose, plasma insulin, cholesterol triglycerides and C-peptide after an overnight fast and during an oral load of 100 g glucose did not change after dexfenfluramine compared to placebo. Supine and standing systolic and diastolic blood pressures were significantly decreased, while heart rate remained unchanged. Plasma noradrenaline and plasma renin were markedly reduced by dexfenfluramine, and cortisol, beta-endorphin and thyroid hormones were not changed. Thus, dexfenfluramine has a significant hypotensive effect in normotensive, obese women after 4 days of treatment, independent of a negative energy balance. This was associated with decreased circulating plasma noradrenaline, indicating decreased sympathetic nerve activity. Dexfenfluramine may be a candidate drug for longer-term trials in the treatment of primary hypertension associated with obesity.

Adult↗
PubMed1995

Further studies to examine the nature of dexfenfluramine-induced suppression of heroin self-administration.

The present series of experiments sought to investigate further the mechanism by which dexfenfluramine, a selective 5-HT releaser/reuptake inhibitor, reduces heroin self-administration by male Wistar rats. In experiment 1, the effect of combined intravenous heroin and intraperitoneal dexfenfluramine injections on operant responding for food was examined. In experiment 2, the maintenance of dexfenfluramine suppression of heroin self-administration following chronic (7 day) treatment was evaluated. Finally, in experiment 3, the ability of various 5-HT antagonists to block the dexfenfluramine suppression was examined. The results from experiment 1 suggest that sensorimotor deficits/malaise potentially associated with heroin/dexfenfluramine combinations are unlikely to account for the reductions in heroin self-administration. Experiment 2 suggested that the suppressant effect of dexfenfluramine on heroin responding may diminish rapidly following chronic treatment. Finally, central 5-HT1 and/or 5-HT2, but not 5-HT3, receptors may underlie the suppressant effects of dexfenfluramine on heroin self-administration.

Animals↗
PubMed1994

8-OH-DPAT attenuates the dexfenfluramine-induced increase in extracellular serotonin: an in vivo dialysis study.

Rats with frontocortical microdialysis probes were treated with dexfenfluramine or dexfenfluramine with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) pretreatment. Dexfenfluramine (10 mg/kg i.p.) increased extracellular serotonin (5-hydroxytryptamine, 5-HT) (calculated area under the curve (AUC) for the 0 to 105-min period after dexfenfluramine treatment = 8.22 +/- 2.66 pmol 5-HT). Systemic (0.025 mg/kg i.p.) or local (0.01 microM into the dorsal raphe nucleus) 8-OH-DPAT pretreatement decreased the dexfenfluramine response (AUC: 1.03 +/- 0.07 and 0.44 +/- 0.04 pmol 5-HT, respectively). This result might be explained by the decrease in 5-HT neuronal discharge caused by somatodendritic 5-HT1A autoreceptor activation, and suggests that the 5-HT releasing effect of dexfenfluramine in vivo depends on nerve terminal depolarization.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Preliminary findings with the indirect 5-HT agonist dexfenfluramine on heroin discrimination and self-administration in rats.

In the present study, the effect of the 5-HT releaser/reuptake inhibitor dexfenfluramine in heroin self-administration and morphine (3 mg/kg) drug discrimination paradigms was examined. Dexfenfluramine (1 mg/kg) reduced heroin self-administration (heroin dose 0.03 mg/kg/infusion; FR5 schedule; 1-h session/day). This effect was antagonised by the 5-HT1/2 receptor antagonist metergoline (1 mg/kg). In the drug discrimination model, dexfenfluramine (0.5-2.5 mg/kg) produced no significant generalisation to a morphine cue, and also failed to modify the generalization curve to heroin. Dexfenfluramine (1 mg/kg) produced a slight decrement in response rate in the drug discrimination model and this effect was potentiated by heroin. The mechanism(s) by which dexfenfluramine reduces heroin self-administration remain to be determined, however substitution for heroin would seem unlikely. Furthermore, this effect of dexfenfluramine is probably mediated by either 5-HT1 or 5-HT2 receptors.

Animals↗
PubMed1998

Aminorex, dexfenfluramine, and primary pulmonary hypertension.

BACKGROUND: In the late 1960s, an epidemic of primary pulmonary hypertension (PPH) occurred in Europe shortly after the introduction of aminorex fumarate, a potent anorexigen. A recently published case-control study from Europe reported that use of other anorexigens (the most prevalent of which was dexfenfluramine) was also associated with an increased risk of PPH. This led to warnings of a repeat epidemic, especially after the introduction of dexfenfluramine on the North American market. OBJECTIVE: To compare the epidemiologic associations of PPH with aminorex and dexfenfluramine, both with respect to strength of association (estimate of relative risk) and public health impact (etiologic fraction) and thus to assess the potential for a new epidemic of PPH. METHODS: We constructed a "synthetic" case-control study for aminorex based on reported case series from Berne and Basel, Switzerland, and a random population sample from Hanover, Germany, and compared the results with those recently reported for dexfenfluramine. Control rates of exposure were used to estimate population exposure prevalences and, hence, etiologic fractions. RESULTS: The estimated odds ratio (and 95% confidence interval) for the association between PPH and any exposure to aminorex was 97.8 (78.9-121.3), with a corresponding etiologic fraction of 77%. The corresponding figures for dexfenfluramine were 3.7 (1.9-7.2) and 17%, respectively. CONCLUSION: The strong association between aminorex and PPH probably led to a 5-fold increase in PPH incidence, and thus a very noticeable epidemic. The association with dexfenfluramine would result in an increase in incidence of only 20%. Based on the available evidence, a repeat PPH epidemic seems unlikely.

Adult↗
PubMed1995

Efficacies of dexfenfluramine and fluoxetine in preventing weight gain after smoking cessation.

We tested whether 14 wk of dexfenfluramine (30 mg) or fluoxetine (40 mg) treatment would prevent weight gain after subjects quit smoking. Normal-weight women (n = 144) were randomly assigned to drug or placebo on a double-blind basis for 2 wk before quitting smoking and 12 wk thereafter. The fluoxetine group had more dropouts (28/49, 57.1%) than the dexfenfluramine group (17/47, 36.2%), with an intermediate number of dropouts from the placebo group (21/48, 43.8%). All groups gained weight during treatment, but their amount and pattern of weight gain differed. In the first month after quitting smoking, the placebo group gained more weight than either the dexfenfluramine or fluoxetine group (P < 0.05). By 2 mo postcessation, dexfenfluramine still suppressed weight gain in comparison with placebo (P < 0.05); weight gain with fluoxetine was not differentiable from either dexfenfluramine or placebo. By 3 mo postcessation, the dexfenfluramine group had gained 1.0 +/- 0.7 kg, significantly less than either the placebo (3.5 +/- 0.7 kg) or fluoxetine (2.7 +/- 0.5 kg) groups. Three months after drug discontinuation, formerly medicated, but not placebo patients, showed additional weight gain, eliminating differences between groups. Results indicate that weight gain, an adverse accompaniment of smoking cessation, can be minimized to some degree by serotoninergic drugs, although only for the duration of drug treatment.

Adult↗
PubMed1992

The effects of dexfenfluramine on blood glucose control in patients with type 2 diabetes.

Dexfenfluramine has been shown to promote weight loss in overweight people. The present double-blind study was designed to test whether the addition of dexfenfluramine to conventional oral hypoglycaemic treatment would promote weight loss and improve blood glucose control in overweight patients with Type 2 diabetes. The 34 patients studied were randomly assigned to dexfenfluramine or placebo therapy which was added for 12 weeks to their existing treatment regimens of metformin with or without a sulphonylurea. Dexfenfluramine treatment was associated with a significant reduction in weight (98.7 +/- 5.0 (+/- SE) vs 94.9 +/- 5.2 kg; p less than 0.001), BMI (35.0 +/- 1.2 vs 33.6 +/- 1.9 kg m-2; p less than 0.001), HbA1c (7.5 +/- 0.3 vs 6.3 +/- 0.2%; p less than 0.001), fructosamine (313.9 +/- 17.6 vs 274.3 +/- 10.4 mumol l-1; p less than 0.01), systolic (137 +/- 5 vs 128 +/- 6 mmHg; p less than 0.05), and diastolic blood pressure (85 +/- 2 vs 73 +/- 3 mmHg; p less than 0.001). At the end of the study period, the dexfenfluramine treated group had a significantly lower HbA1c (6.3 +/- 0.2 vs 7.2 +/- 0.4; p less than 0.05), fructosamine level (274.3 +/- 10.4 vs 313.3 +/- 16.1 mumol l-1; p less than 0.05) and diastolic blood pressure (73 +/- 3 vs 81 +/- 3 mmHg; p less than 0.03) when compared with the placebo group. In those patients treated with dexfenfluramine, the reduction in HbA1c and blood pressure did not correlate with the decrease in BMI (r = 0.44 and 0.12, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗
PubMedDate not supplied

Obese patients with type 2 diabetes poorly controlled by insulin and metformin: effects of adjunctive dexfenfluramine therapy on glycaemic control.

Dexfenfluramine is well known for its weight reducing action and has been reported to improve glycaemic control in obese Type 2 diabetic patients not adequately controlled on conventional oral hypoglycaemic therapy. In this double-blind placebo-controlled study, 20 obese Type 2 diabetic patients with mean HbA1c of 8.8 +/- 0.5% (normal range 3.5-6.0%), and mean body mass index (BMI) of 34.4 +/- 1.0 kg m-2, who were poorly controlled on insulin (mean dosage 58.0 +/- 6.1 units day-1) were randomized to receive either additional dexfenfluramine or placebo for 12 weeks. Seventeen of these patients were already taking maximum tolerated metformin therapy (mean dosage 1.6 +/- 0.2 g day-1) and the other three were unable to tolerate any at all. At baseline, the dexfenfluramine and placebo groups were similar in all parameters studied. After the 12-week treatment period, median HbA1c had fallen in dexfenfluramine treated patients from 8.5 (interquartile range (IR): 7.5-10.3) to 7.1% (IR: 6.7-7.5; p < 0.02). The fall in HbA1c in individual patients after treatment with dexfenfluramine was strongly associated with weight loss (r = 0.69; p < 0.04), although as a group the changes in weight and BMI were not statistically significant. Placebo was without effect. These results show that in the obese patient with Type 2 diabetes who is poorly controlled despite large daily doses of insulin and metformin, adjunctive dexfenfluramine can improve glycaemic control without exacerbating weight gain.

Biomarkers↗
PubMed1996

Effects of chronic dexfenfluramine treatment on pulmonary hemodynamics in dogs.

An epidemic of primary pulmonary hypertension occurred in Europe in the 1960s, after the introduction of the appetite suppressant aminorex. Recently, a cluster of cases of pulmonary hypertension was observed in France in relation to the intake of the appetite suppressant dexfenfluramine. We previously reported that intravenous dexfenfluramine enhances hypoxic pulmonary vasoconstriction in dogs. We therefore investigated the pulmonary hemodynamic effects of chronic oral intake of this drug. Twenty-four dogs with a strong (n = 12) and a weak hypoxic pulmonary vasoconstriction (n = 12) respectively were randomly allocated in a double blind manner to a twice daily oral intake of either a placebo or dexfenfluramine 1.5 mg/kg for 20 d. A strong hypoxic vasoconstriction was defined as a hypoxia-induced increase in pulmonary artery pressure by more than 3 mm Hg at a standardized cardiac output of 3 L/min/m2. Pulmonary hemodynamics were studied in hyperoxia (fraction of inspired O2 [F(I)O2] 0.4) and in hypoxia (F(I)O2 0.1) before and after treatment. Venous return was manipulated at post-treatment evaluation for isoflow comparisons of pulmonary vascular pressures. Dexfenfluramine had no effect on systemic hemodynamics or blood gases, but increased pulmonary vascular resistance from 155 +/- 17 to 192 +/- 14 dyne x s x cm(-5) in hyperoxia (mean +/- SE, p < 0.05) and from 237 +/- 27 to 293 +/- 47 dyne x s x cm(-5) in hypoxia (p < 0.01). Dexfenfluramine, and not placebo, increased the isoflow pulmonary vascular pressure gradient in hyperoxia and in hypoxia. This effect was unrelated to the magnitude of pretreatment hypoxic vasoconstriction. We conclude that the chronic intake of dexfenfluramine in dogs is associated with a moderate increase in pulmonary vascular resistance which is unrelated to pulmonary vasoreactivity to hypoxia.

Administration, Oral↗
PubMed1993

Influence of short-term dexfenfluramine therapy on glucose and lipid metabolism in obese non-diabetic patients.

In a short-term (eight days) double-blind crossover study involving 10 obese patients, the effects of dexfenfluramine on glucose and lipid metabolism were examined. The protocol comprised whole body in vivo measurements (hyperinsulinemic euglycemic clamp in combination with indirect calorimetry) and in vitro studies of isolated adipocytes (lipolysis and glucose transport). All study participants were weight stable during the study period (103.1 +/- 3.2, placebo vs 103.3 +/- 3.1 kg, dexfenfluramine, NS). The following parameters were significantly reduced after dexfenfluramine treatment: fasting levels of plasma glucose (6.2 +/- 0.2 vs 5.7 +/- 0.2 mmol/l, p < 0.01), serum insulin (168.0 +/- 14.5 vs 138.9 +/- 7.9 pmol/l, p < 0.05), serum C-peptide (0.68 +/- 0.03 vs 0.58 +/- 0.02 nmol/l, p < 0.05) and total serum cholesterol (6.07 +/- 0.41 vs 5.48 +/- 0.38 mmol/l, p < 0.01). In the basal state glucose oxidation rate was significantly reduced by 36% (p < 0.001), whereas non-oxidative glucose disposal was significantly increased by 41% (p < 0.01), following dexfenfluramine treatment. Insulin-stimulated (2 mU.kg-1 x min-1) glucose disposal rate tended to be increased (18%, p = 0.10) after dexfenfluramine. In conclusion, dexfenfluramine possesses beneficial regulatory effects on glucose and lipid metabolism in non-diabetic obese patients, independently of weight loss.

Adipose Tissue↗
PubMed1995

[Effect of dexfenfluramine on eating behavior and body weight of obese patients: results of a field study of Isomeride in Austrian general practice].

In a multicenter study by 243 practicing physicians in Austria 819 severely obese subjects of both sexes without overt disease were encouraged to keep a calorie-restricted diet to reduce weight. After a run-in period of more than two weeks of dieting patients started taking 15 mg dexfenfluramine (Isomeride) twice daily for three month. While their weight was fairly stable during the run-in period progressive weight loss occurred during taking dexfenfluramine due to obvious changes in eating habits and appetite allowing to keep the reducing diet more strictly. Females lost 7.7 +/- 3.9 kg while obese men lost 9.32 +/- 4.6 kg. Laboratory tests obtained before starting dexfenfluramine and after 3 months at termination of medication showed blood glucose, cholesterol, LDL and triglycerides to decrease while HDL-cholesterol increased moderately. Dexfenfluramine was well tolerated by the majority of patients. Side effects such as fatigue, sedation, flatulence or diarrhea occurred in only 7.9% of the probands initially and dropped to 2.1% during the third month of the medication. It is concluded that Dexfenfluramine modifies eating habits and appetite thus making weight reducing diets easier acceptable and resulting in weight loss. It is suggested that Dexfenfluramine has a role in treatment regimes for morbid and refractory obesity.

Adult↗
PubMed1998

Dexfenfluramine enhances striatal dopamine release in conscious rats via a serotoninergic mechanism.

The effects of dexfenfluramine on the release of brain dopamine and serotonin into striatal dialysates were measured in freely moving rats. Samples collected every 20 min were assayed for dopamine and serotonin by high-performance liquid chromatography in a single run. The administration of a lower anorectic dose of dexfenfluramine (0.5 or 1.0 mg/kg intraperitoneally) significantly increased dialysate serotonin concentrations without affecting those of dopamine. A higher dexfenfluramine dose (2.5 mg/kg intraperitoneally) increased both serotonin and dopamine. The increase in dopamine could be blocked by administering the mixed-acting serotonin antagonist methiothepin (20 microM), and was reproduced by applying serotonin (3-10 microM) directly to striatal neurons. Tetrodotoxin (1 microM) added to the striatal perfusates decreased the basal release of dopamine and serotonin; it also blocked the effect of dexfenfluramine (2.5 mg/kg intraperitoneally) on dopamine release and decreased the increment in serotonin release (by approximately 70%). Amphetamine (1 mg/kg subcutaneously) or phentermine (2 mg/kg intraperitoneally) increased dialysate dopamine concentrations without affecting those of serotonin, and tetrodotoxin (1 microM) failed to block the response to amphetamine. These findings suggest that (1) lower anorectic doses of dexfenfluramine release serotonin but not dopamine, and (2) higher doses of dexfenfluramine also increase dopamine release by an indirect mechanism mediated via serotonin.

Animals↗
PubMed2001

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine.

OBJECTIVE AND DESIGN: This study examined the effects of the anti-obesity agents, phentermine and dexfenfluramine given alone or in combination, on in vitro and in vivo 5HT release from rat brain tissue. RESULTS: In vitro, phentermine was without effect on basal [3H]5HT efflux from hypothalamic slices whereas dexfenfluramine (10 microM) evoked a 131% increase in [3H]5HT release. In combination, the two drugs did not alter [3H]5HT release beyond that caused by dexfenfluramine alone. At pharmacologically equivalent doses, phentermine (5.7 mg/kg, i.p.) caused a rapid, modest elevation, and dexfenfluramine (3 mg/kg, i.p.) a larger but equally rapid elevation of extracellular 5HT in the microdialysates from the rat anterior hypothalamus. In combination, the increase in extracellular 5HT evoked by these drugs was not significantly greater than the sum of their individual effects. CONCLUSIONS: This study provides evidence that phentermine's actions are not restricted to catecholamine systems and indicates that combining phentermine with dexfenfluramine results in an additive increase in neuronal 5HT release.

Animals↗
PubMed2004

Increased release of serotonin from rat ileum due to dexfenfluramine.

Plasma levels of serotonin are elevated in primary pulmonary hypertension even after bilateral lung transplantation, suggesting a possible etiologic role. Serotonin is released primarily from the small intestine. Anorectic agents, such as dexfenfluramine, which can cause pulmonary hypertension, are known to inhibit potassium channels in vascular smooth muscle cells. We examined the hypothesis that dexfenfluramine may stimulate release of serotonin from the ileum by inhibition of K+ channels. In an isolated loop of rat ileum perfused with a physiological salt solution, the administration of dexfenfluramine, its major metabolite D-norfenfluramine, the potassium channel blocker 4-aminopyridine (5 mM), and caffeine (30 mM) increased serotonin levels in the venous effluent. Potassium chloride (60 mM) tended to increase serotonin levels. In genetically susceptible individuals, dexfenfluramine may induce pulmonary hypertension by increasing cytosolic calcium in enterochromaffin cells of the small intestine, thus releasing serotonin and causing vasoconstriction. This work indicates that dexfenfluramine and its major metabolite d-norfenfluramine can increase serotonin release from the small intestine.

4-Aminopyridine↗