Anorectic efficacy and safety of the diethylpropion-topiramate combination in rats.

Preclinical Research & Development Current drugs for obesity treatment have limited efficacy and considerable adverse effects. Combination of drugs with complementary mechanisms of action at lower doses may produce a greater efficacy with a better safety profile. This study was designed to assess the anorectic effect and safety of a diethylpropion + topiramate mixture in rats. The anorectic effect of drugs was measured using a sweetened milk consumption model, and the corresponding interaction was determined by isobolographic analysis, interaction index and confidence intervals. Additionally, blood pressure was measured using a sphygmomanometer in the rat tail. Diethylpropion and topiramate alone or in combination increased the anorectic effect in a dose-dependent fashion in either nondeprived or 12 hr food-deprived rats. All theoretical ED30 values of diethylpropion + topiramate combinations at 1:1, 1:3, and 3:1 dose ratios were significantly higher than experimental ED30 values. In addition, interaction indices and confidence intervals confirmed the potentiation between both drugs. Theoretical ED30 of diethylpropion + topiramate combination did not affect the blood pressure. Data suggests that low doses of the diethylpropion + topiramate combination can potentiate the anorectic effect of individual drugs with a better safety profile, which deserves further investigation in clinical trials.

The efficacy of the appetite suppressant, diethylpropion, is dependent on both when it is given (day vs. night) and under conditions of high fat dietary restriction.

Obesity is a public health problem caused by excessive consumption of high caloric diets and/or lack of physical activity. Although treatments for obesity include low caloric diets and exercise programs, these activities frequently are supplemented with appetite suppressants. For the short-term treatment of weight loss, diethylpropion (DEP) is a commonly used appetite suppressant. However, little is known with regard to how to improve its weight loss efficacy. We therefore evaluated, in rats, two administration protocols where the animals received daily injections of DEP. First, when these nocturnal animals were normally active (at night) and when they were normally inactive (daytime), and second, with or without high fat dietary restriction (HFDR). We observed that DEP induced a greater weight-loss administered when the animals were in their active phase than in their inactive phase. Moreover, DEP's administration during the inactive phase (and to a lesser degree in the active phase) promotes the consumption of food during normal sleeping time. In addition, we found that DEP-induced weight loss under ad libitum access to a HF diet, but its efficacy significantly improved under conditions of HFDR. In summary, the efficacy of DEP, and presumably other like appetite suppressants, is enhanced by carefully controlling the time it is administered and under dietary restriction of HF diets.

Six-month efficacy and safety of amfepramone in obese Mexican patients: a double-blinded, randomized, controlled trial.

Amfepramone, also known as diethylpropion, is an anorectic drug used for the short-term treatment of obesity; however, its efficacy and safety during periods greater than 3 months has been scarcely studied. To evaluate the 6-month efficacy and safety of amfepramone treatment in obese adult Mexican patients resistant to diet and exercise, a double-blinded, randomized, and placebo-controlled clinical trial study was designed on 156 volunteers with a body mass index (BMI) greater than 30 kg/m2 and less than 45 kg/m2. Patients were randomized to receive a 75 mg tablet of amfepramone or placebo daily for 6 months. Primary outcome was the absolute body weight loss, whereas secondary outcomes were the percentage of patients who achieved at least 5% or 10% weight loss, as well as the improvement of anthropometric and metabolic parameters. Amfepramone treatment produced a superior efficacy to decrease body weight than placebo at 3 months (-4.9±0.25 kg vs. -0.7±0.32 kg) and 6 months (-7.7±0.52 kg vs. -1.1±0.7 kg). In addition, 64 and 34 patients achieved at least 5% or 10% weight loss, respectively, with amfepramone at 6 months, compared with 8 and 0 patients on placebo. Amfepramone also significantly improved BMI and waist circumference, but it only showed a favorable tendency in the waist-hip index (WHI), glucose, total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides, heart rate, systolic blood pressure, and diastolic blood pressure at 3 and 6 months. Amfepramone produced only mild adverse events, and they were presented in a greater number than placebo only at 3 months, dry mouth being the the main adverse event. Data suggest that amfepramone is effective and well tolerated in obese Mexican patients during a 6-month regimen.

D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell.

Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to short-term treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds.

Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse.

Lisdexamfetamine dimesylate (LDX) is the first prodrug stimulant and is indicated for the treatment of attention-deficit/hyperactivity disorder. A single-centre, double-blind, randomised, placebo-controlled, 6-period crossover study evaluated the abuse potential of single oral doses of 50, 100 (equivalent to 40 mg d-amphetamine), and 150 mg LDX, 40 mg d-amphetamine and 200 mg diethylpropion in 36 individuals with a history of stimulant abuse. On the primary abuse liability measure, maximum change of the Drug Rating Questionnaire-Subject Liking Scale compared with placebo, d-amphetamine and diethylpropion showed significant differences of 4.5 and 4.0 units, respectively (P < 0.001 for both vs placebo). LDX, administered at 50, 100 and 150 mg, showed nonsignificant differences of 2.0 and 2.1 units, respectively, at the two lower doses but a significant (P < 0.001 vs placebo) difference of 6.1 units at the highest dose. Subjects significantly favoured d-amphetamine 40 mg versus LDX 100 mg (2.4 units difference; P < 0.05). There was no significant difference in liking scores between d-amphetamine 40 mg and LDX 150 mg. Drug Rating Questionnaire-Subject Feel-Drug-Effect score was significantly lower for 100 mg LDX than for 40 mg d-amphetamine. There were no statistically significant differences between LDX and diethylpropion hydrochloride, a Schedule IV amphetamine-like stimulant, on abuse-related liking scores. Cardiovascular responses of LDX and d-amphetamine were similar at equivalent doses. In conclusion, at an equivalent amount of amphetamine base taken orally, LDX 100 mg had attenuated responses on measures of abuse liability compared with immediate-release d-amphetamine 40 mg. Abuse-related liking scores of LDX at a dose corresponding to a 50% higher amphetamine base (LDX 150 mg) were similar to d-amphetamine 40 mg.

[Drug treatment of obesity]. / Medikamentel behandling af fedme.

Acceptable adverse effects and a clinical relevant weight loss of 3 to 5 kilograms have been found in long-term randomized clinical trials for sibutramine (Reductil) and orlistat (Xenical); these drugs may be prescribed for treatment of obesity for a duration of one and four years, respectively. This also seems to be the case for rimonabant (Acomplia), which is expected to receive approval in 2005 or 2006. However, until data on morbidity and mortality are available from RCTs, there is no absolute indication for prescribing drugs for treatment of obesity.

Homeopathic products, not as innocent and safe as they seem? A case report.

Although homeopathic and other alternative products are very popular and are supposed to be safe and harmless they are not free of risks. We present the case of a 29-year-old woman who had to be treated for a state of extreme agitation after using speed, alcohol and homeopathic slimming droplets (LOCO X112). Toxicological analysis of these droplets revealed the presence of thyroid extract and diethylpropione, an amphetamine-like noradrenergic anorectic agent banned in Belgium. This case among other reports in the literature proves that homeopathic products are not as safe and harmless as they seem. Medical professionals as well as the public should be aware of this.

Primary pulmonary hypertension after amfepramone (diethylpropion) with BMPR2 mutation.

Primary pulmonary hypertension (PPH) is characterised by sustained elevations of pulmonary arterial pressure without a demonstrable cause, leading to right ventricular failure and death. Hereditary mutations in the bone morphogenetic protein receptor type II (BMPR2) gene result in familial PPH transmitted as an autosomal dominant trait, albeit with low penetrance. The causes in cases without a BMPR2 mutation are unknown, but a syndrome of pulmonary arterial hypertension (PAH) similar to hereditary PPH is associated with systemic connective tissue disease, congenital heart disease, portal hypertension, and human immunodeficiency virus infection, or with the use of appetite-suppressant drugs. The authors identified a BMPR2 gene mutation in a 27-yr-old female who developed PAH after a short course of the appetite-suppressant drug amfepramone (diethylpropion). This allowed molecular genetic counselling and prevention of potentially harmful drug exposure in the patient's son treated for attention deficit disorder with methylphenidate, an amphetamine-related drug. No BMPR2 mutation was found in four additional, unrelated patients with appetite suppressant-related PPH. The findings provide strong evidence that amfepramone can trigger primary pulmonary hypertension in a bone morphogenetic protein receptor type II gene mutation carrier, and indicate that other genes are probably implicated in genetic susceptibility to appetite suppressants.

Anorexígenos: indicaciones e interacciones / Anorexigens: indications and interactions

Antecedentes: Los anorexígenos generalmente no suelen ser de manejo habitual en la práctica clínica psiquiátrica. Sin embargo, es frecuente indicar una amplia gama de psicofármacos a pacientes a los cuales se les ha prescrito medicamentos supresores del apetito por otros profesionales. Esta combinación farmacológica implica una serie de aspectos a considerar en relación a las indicaciones, efectos adversos y fundamentalmente las interacciones propias de los agentes anorexígenos que en algunos casos pueden llegar a provocar complicaciones irreversibles y fatales. Objetivo. Puesta al día de los principales fármacos anorexígenos disponibles en Chile describiendo su clasificación, características, farmacocinética, indicaciones, contraindicaciones, efectos adversos e interacciones. Material y métodos. Revisión actualizada de la literatura especializada. Resultados. Los anorexígenos son coadyuvantes en el tratamiento integral de pacientes obesos. El resultado del tratamiento es mejor si se acompaña de una recuperación de los hábitos alimentarios. Poseen un alto potencial de abuso, dependencia, tolerancia y síndrome de privación. Sus principales efectos son cardiovasculares, gastrointestinales y en el sistema nervioso central. Los más utilizados en Chile entre 1997 y 1998 fueron fetermina, dietilpropión, fenproporex y dexfenfluramina. Discusión. La principal indicación de los anorexígenos es la obesidad. Deben ser prescritos exclusivamente por médicos. Se recomienda su indicación a corto plazo. Poseen importantes interacciones a considerar con IMAOs, ISRSs, descongestionantes, antitusígenos, antialérgicos, anestésicos generales, sustancias ilícitas, alcohol y otras drogas metabolizadas por citocromo P450. Se enfatiza la posibilidad de la producción del síndrome serotoninérgico. Chile, Argentina y Brasil se encuentran entre los principales países consumidores de estimulantes

Efeitos da dietilpropiona, energia da dieta e sexo sobre o ganho de peso corporal, peso dos órgäos e deposiçäo de tecidos em ratos / Effects of diethylpropion, diet energy and sex on the corporal weight gain, organs weight and tissues deposition in rats

O objetivo deste trabalho foi avaliar a dietilpropiona (DEP), um derivadoo fenetilamínico utilizado como anorexígeno, e dietas de diferentes densidades calóricas, utilizando ratos de ambos os sexos. O experimento contou com 72 ratos Wistar distribuídos por sexo, bloqueados por peso inicial e alocados dois a dois em 36 gaiolas experimentais. As dietas e a água foram fornecidas ad libitum e atenderam a todas as exigências dos animais, sendo que a dieta de alta energia continha 3.700kcal de energia metabolizável (EM)/kg, a média 3.350kcal EM/Kg e a baixa 3.000Kcal EM/Kg de raçäo. A droga foi administrada com uma dose diária de 20mg/kg, durante 36 dias, por via intraperitonial. A análise estatística considerou os efeitos da droga, energia da dieta, sexo, triplicata e a interaçäo entre essas variáveis. Os resultados mostraram que houve interaçäo entre dieta e droga (p<0,0195) e que o uso da droga dimunuiu o consumo alimentar apenas em dietas de baixa e média energias. A interaçäo entre sexo e droga (p<0,0253) mostrou que a droga reduziu o ganho de peso em ambos os sexos. Conclui-se que a DEP reduziu o ganho de peso dos machos e das fêmeas, com reduçäo de gordura depositada em ambos os sexos, sndo que as percentagens de deposiçäo de gordura foram maiores nas fêmeas do que nos machos, os quais depositaram mais proteína. A DEP foi responsável pela reduçäo no consumo de diatas de baixa e média energia metabolizáve, näo havendo efeito em dietas de alta energia.

WHO Expert Committee on Drug Dependence. Thirty-second report.

This report presents the recommendations of a WHO Expert Committee responsible for reviewing information on dependence-producing drugs to assess the need for their international control. The first part of the report contains a general discussion of the new guidelines for the review of dependence-producing psychoactive substances and their implications for the scheduling of ephedrine and of the guidelines that were drafted to clarify the scope of control of stereoisomers. A summary follows of the Committee's evaluations of six substances (4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-methylthioamphetamine (4-MTA), gamma-hydroxybutyric acid (GHB), N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MDBD), diazepam and zolpidem), four of which (2C-B, 4-MTA, GHB and zolpidem) were recommended for international control. The report also discusses the substances that were pre-reviewed by the Committee, five of which (amfepramone, amineptine, buprenorphine, dronabinol and tramadol) were recommended for critical review at a future meeting.

Valve disease and pulmonary arterial hypertension due to appetite suppressants (update).

(1) The unfavourable risk-benefit ratio of amphetamine appetite suppressants has led the French medicines agency to withdraw their marketing authorisation.