Pharmacogenetics of amfepramone in healthy Mexican subjects reveals potential markers for tailoring pharmacotherapy of obesity: results of a randomised trial.

Amfepramone (AFP) is an appetite-suppressant drug used in the treatment of obesity. Nonetheless, studies on interindividual pharmacokinetic variability and its association with genetic variants are limited. We employed a pharmacokinetic and pharmacogenetic approach to determine possible metabolic phenotypes of AFP and identify genetic markers that could affect the pharmacokinetic variability in a Mexican population. A controlled, randomized, crossover, single-blind, two-treatment, two-period, and two sequence clinical study of AFP (a single 75 mg dose) was conducted in 36 healthy Mexican volunteers who fulfilled the study requirements. Amfepramone plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed using real-time PCR with TaqMan probes. Four AFP metabolizer phenotypes were found in our population: slow, normal, intermediate, and fast. Additionally, two gene polymorphisms, ABCB1-rs1045642 and CYP3A4-rs2242480, had a significant effect on AFP pharmacokinetics (P < 0.05) and were the predictor factors in a log-linear regression model. The ABCB1 and CYP3A4 gene polymorphisms were associated with a fast metabolizer phenotype. These results suggest that metabolism of AFP in the Mexican population is variable. In addition, the genetic variants ABCB1-rs1045642 and CYP3A4-rs2242480 may partially explain the AFP pharmacokinetic variability.

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.

The use of appetite suppressants among health sciences undergraduate students in Southern Brazil.

OBJECTIVE: To investigate the prevalence of appetite suppressant use among health sciences students in Southern Brazil. METHODS: Undergraduate students (n=300) from seven health science undergraduate courses of the Universidade de Caxias do Sul completed a questionnaire about the use of substances to suppress appetite. RESULTS: A significant percentage (15%; n=45) of research participants used appetite suppressants at least once in their lives. The most commonly used substances were sympathomimetic stimulant drugs (5%), including amfepramone (3.3%) and fenproporex (1.7%). The lifetime use of appetite suppressants was more prevalent among Nursing (26.7%) and Nutrition (24.4%%) students. There was no reported use of appetite suppressants among medical students. The use of appetite suppressants was significantly more prevalent among women. The majority of those who used these substances did so under medical recommendation. Most of users took appetite suppressants for more than 3 months. CONCLUSION: Lifetime use of appetite suppressants was substantial, being sympathomimetic stimulant drugs the most commonly used agents. Students enrolled in Nursing and Nutrition courses presented a significantly higher prevalence of lifetime use of appetite suppressants.

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.

Effects of diethylpropion treatment and withdrawal on aorta reactivity, endothelial factors and rat behavior.

Diethylpropion (DEP) is an amphetamine-like compound used as a coadjutant in the treatment of obesity and which presents toxicological importance as a drug of abuse. This drug causes important behavioral and cardiovascular complications; however, the vascular and behavioral alterations during DEP treatment and withdrawal, have not been determined. We evaluated the effects of DEP treatment and withdrawal on the rat aorta reactivity to noradrenaline, focusing on the endothelium, and the rat behavior during DEP treatment and withdrawal. DEP treatment caused a hyporreactivity to noradrenaline in aorta, reversible after 2 days of withdrawal and abolished by both the endothelium removal and the presence of L-NAME, but not by the presence of indomethacin. Furthermore, DEP treatment increased the general activity of rats. Contrarily, DEP withdrawal caused a decrease in the locomotor activity and an increase in grooming behavior, on the 2nd and 7th days after the interruption of the treatment, respectively. DEP treatment also caused an adaptive vascular response to noradrenaline that seems to be dependent on the increase in the endothelial nitric oxide system activity, but independent of prostaglandins synthesis. The data evidenced chronological differences in the adaptive responses of the vascular and central nervous systems induced by DEP treatment. Finally, a reversion of the adaptive response to DEP was observed in the vascular system during withdrawal, whereas a neuroadaptive process was still present in the central nervous system post-DEP. These findings advance on the understanding of the vascular and behavioral pathophysiological processes involved in the therapeutic and abusive uses of DEP.

Consumo de anorexígenos tipo-anfetamina (dietilpropiona, fenproporex, mazindol) e de fenfluramina no Brasil: Prejuízo ou benefício para a saúde / Consumption of amphetamine-like anorectic drugs (diethylpropion, fenproporex and mazindol) and of anorectic d.1-fenfluramine in Brazil: Harm or benefit to health

O consumo brasileiro das drogas anorexígenas tipo-anfetamina (dietilpropiona, fenproporex, mazindol e de d.1-fenfluramina), obtido através de dados oficiais do Ministério da Saúde, foi avaliado expessando-se resultados em doses diárias definidas por 1.000 habitantes por dia. Esta medida calcula o número de doses terapêuticas que säo utilizadas por dia para cada 1.000 habitantes, permitindo assim comparaçöes independentes da quantidade de princípio ativo e de suas preparaçöes comerciais; é por esta razäo recomendada pela Organizaçäo Mundial da Saúde (DDDs/1.000 habitantes/dia). Em 1988 o Brasil consumia essas drogas equivalentes a 4,59DDDs/1.000 habitantes/dia e no ano seguinte houve um aumento de 43,8//. Esses valores podem ser triplicados quando se leva em consideraçäo apenas a populaçäo que tem acesso a medicamento. Estes números revelam um elevado consumo de drogas tipo-anfetamina, em constraste com outros países onde o mesmo quase inexistente. Constatou-se que 68,6//do consumo em 1988 e 39,4//em 1989 processaram-se através de receitas magistrais aviadas em farmácias de manipulaçäo, sendo o restante consumido através de produtos acabados manufaturados pelas industrias farmacêuticas. A d.l-fenfluramina foi a droga menos utilizadas nos dois anos e o mazindol e o fenproporex foram as mais utilizadas, respectivamente, em 1988 e 1989. Discute-se as razöes do uso exagerado destas drogas, as possíveis reaçöes adversas que podem resultar do mesmo e a ausência de providência das autoridades de saúde do país em controlar adequadamente a situaçäo

Re-evaluation of the metabolism and excretion of diethylpropion in non-sustained and sustained release formulations.

A direct gas chromatographic method for unstable amino ketones, using a neutral column and moderately alkaline conditions during extraction has been developed. Its application has given a new perspective to the relative importance of the metabolic routes in the complex metabolism of diethylpropion which after oral administration in man is rapid and extensive (only 3-4% of the drug remains unchanged). Mono-N-de-ethylation is the main pathway (about 35% of the dose). N-De-ethylation is more important than carbonyl-reduction, occurring mainly with the unchanged drug (about 20% of the dose). Norephedrine, thought previously to be one of the main metabolites, has been shown to be present only in negligible amounts. About 30% of the dose, which cannot be accounted for as the sum of the amines recovered in urine, is probably metabolized by deamination, followed by oxidation and conjugation to give hippuric acid.

Bioavailability of amfepramone hydrochloride sustained release pellets formulation in healthy subjects.

The relative bioavailability and pharmacokinetic profile of two amfepramone (diethylpropion) hydrochloride oral preparations were evaluated in 12 normal volunteers using a newly developed gas-liquid chromatographic procedure to monitor the unchanged drug and its two major metabolites in urine, plasma and saliva. The sustained release pellets formulation (Regenon retard) provided excellent bioavailability and gave broad plateau levels extending over 6 to 8 h after administration, which were intermediate between the "peaks and troughs" shown by the same total dose of the free drug in three equal portions at 4-h intervals.

Formula diet in the treatment of moderate obesity.

To evaluate the effect of the popular use of formula diets in the treatment of moderate obesity two regimens have been standardized: (1) formula diet replacing three of five daily meals (partial meal replacement (PMR, 1000 kcal (4.19 MJ] and (2) formula diet taken as five pre-meals (pre-meal satiation, PMS greater than or equal to 565 kcal (greater than or equal to 2.37 MJ]. Weight loss and compliance have been evaluated in a prospective 12 weeks randomized clinical trial with allocation to one of the two regimens or to a control group treated with a 1000 kcal (4.19 MJ) conventional diet (CD). CD and PMR were supported by diethylpropion (Dobesin) individually dosaged by the patient. No anorexic drugs was given to the PMS-group. Of 136 consecutively admitted patients 120 were included. After 12 weeks the median weight loss was 7.0, 8.4 and 6.1 kg in the CD-, PMR- and PMS-group, respectively (no significant differences between the groups (P much greater than 0.02]. Thirteen percent dropped out. Consumption of diethylpropion was significantly lower in the PMR-group compared with the CD-group (median 0.15 and 0.60 tablets of 25 mg per d, respectively). Even among selected sub-groups only few subjects obtained a relevant weight loss through continued treatment after the initial 12 weeks. No serious side-effects to the treatments were observed.

Controlled-release diethylpropion hydrochloride used in a program for weight reduction.

In a double-blind, placebo-controlled evaluation in obese adults given comparable dietary and exercise recommendations, controlled-release diethylpropion hydrochloride promoted significantly more weight loss than matching placebo. The mean reduction in 12 weeks was 15.9 lb (average 1.32 lb/week) for 12 patients taking diethylpropion hydrochloride, 10.0 lb (0.84 lb/week) for 13 taking placebo, and 12.2 lb for 13 taking drug for two four-week periods separated by four weeks of placebo (1.38 lb/week on active drug and 0.30 lb/week on placebo). Amphetamine-like side effects were virtually absent. Diethylpropion hydrochloride is an effective adjunct to caloric restriction in therapy of obesity.

A double-blind controlled study of the use of diethylpropion hydrochloride (Tenuate) in obese patients in a rural practice.

A double-blind, placebo-controlled, cross-over study has been carried out to compare long-acting diethylpropion hydrochloride (Tenuate Dospan, Wm. S. Merrell Company, hereafter referred to as TD) in a rural general practice. TD was found to produce significantly more weight loss than placebo and side effects were not significantly greater. The need for the treatment of obese patients in general practice is discussed, as is the role of anorexiant therapy.

Cardiovascular effects of amphepramone.

The i.v. administration of amphepramone in dogs induced a dose-related depressor reaction. This effect was due to a peripheral myotropic vasodilatation. When the drug was administered intracerebroventricularly it elicited a marked pressor response, due, to the release of catecholamines with its subsequent action on alpha-adrenergic receptors. Small doses of amphepramone administered in dogs, rats and rabbits, induced a sinus tachycardia. Larger doses brought about a sinus bradycardia, bradyarrhythmias, extrasystoles, ventricular bradycardia and ventricular fibrillation or asystolia. The respiratory movements as well as the EEG tracings were depressed by larger doses of amphepramone.

Self-administration of psychomotor stimulant drugs: the effects of unlimited access.

Rhesus monkeys surgically prepared with intravenous catheters were given 23 hr daily access to injection of either cocaine, d-amphetamine, 1-amphetamine, d-methamphetamine or diethylpropion on a fixed ratio 1 schedule of reinforcement for a maximum of 30 days. Responding was maintained by all these drugs but showed both day-to-day and hour-to-hour variability. The two animals self-administering 0.2 mg/kg/infusion cocaine died in less than 5 days. All 6 animals given access to 0.05 mg/kg/infusion d-amphetamine or 0.025 mg/kg/infusion d-methamphetamine also died, but tended to survive more days than animals exposed to cocaine. Three of the 5 animals whose responding was maintained by 0.5 mg/kg/infusion diethylpropion and one of the two animals whose responding was maintained by 0.05 mg/kg/infusion 1-amphetamine survived the entire 30 days despite high rates of intake. Food intake was initially decreased, but often returned to predrug levels and was not related to level of drug intake.

Self-administration of amphetamine analogues in rats.

In rats self-injecting amphetamine (0.25 mg/kg/injection) at a stable level during daily 3 hr sessions, three different amphetamine analogues )phenmetrazine, diethylpropion and fenfluramine) were substituted for amphetamine, one at a time on different experimental days. Phenmetrazine (1.0 mg/kg/injection) and diethylpropion (2.0 mg/kg/injection) were self-administered but not fenfluramine (in doses of 0.1, 0.5 and 2.0 mg/kg/injection). It is concluded that amphetamine, phenmetrazine and diethylpropion have reinforcing properties, whereas fenfluramine has not.

The objective and timing of drug disposition studies, appendix III. Diethylpropion and its metabolites in the blood plasma of the human after subcutaneous and oral administration.

Diethylpropion hydrochloride is an effective anorexiant at the recommended dose of 25 mg three times a day. Previous work in volunteers to evaluate the effects of much larger doses showed that 400 mg given orally was equipotent with 600 mg subcutaneously in terms of subjective and physiologic effects, i.e., the drug was more potent orally than subcutaneously. In one volunteer, blood level studies after a 600-mg subcutaneous dose showed concentrations of unchanged diethylpropion in the plasma about three times as high as those found after the equipotent 400 mg oral dose. In nine other volunteers, the plasma concentrations of unchanged diethylpropion found after a 75-mg oral dose was less than 1/100 of that observed after a 400-mg oral dose. These observations suggest a rapid but limited metabolic capacity for conversion of diethylpropion to its metabolites. The data indicate that the metabolites, rather than the parent drug, are responsible for the pharmacologic responses seen with doses much larger than those necessary for inducting anorexia.

Double blind evaluation of long acting diethylpropion hydrochloride in obese patients from a general practice.

Obese patients encountered in general practice were studied in order to determine whether a long-acting form of diethylpropion hydrochloride (Tenuate Dospan) was more effective than placebo for weight loss. One hundred and two patients completed this double blind, 16-week crossover study. During the first eight weeks, the patients treated with diethylpropion hydrochloride lost significantly (P smaller than 0.001) more weight than the patients treated with placebo (an average of 11-1 lb or 6-4% of their initial weight as compared with 6-2 lb or 3-6% of their initial weight). When the group taking diethylpropion hydrochloride crossed over to placebo for a second eight weeks, they lost an average of 1-5 lb (0-9% of their weight at the start of the second period), while the group who crossed from placebo over to diethylpropion hydrochloride lost an average of 6-7 lb (3-8%). The advantages of diethylpropion hydrochloride over placebo are statistically significant.