AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity.

BACKGROUND & AIMS: Pharmacological management of obesity improves outcomes and decreases the risk of obesity-related complications. This American Gastroenterological Association guideline is intended to support practitioners in decisions about pharmacological interventions for overweight and obesity. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis of the following agents: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 oral superabsorbent hydrogel. The guideline panel used the evidence-to-decision framework to develop recommendations for the pharmacological management of obesity and provided implementation considerations for clinical practice. RESULTS: The guideline panel made 9 recommendations. The panel strongly recommended the use of pharmacotherapy in addition to lifestyle intervention in adults with overweight and obesity (body mass index ≥30 kg/m2, or ≥27 kg/m2 with weight-related complications) who have an inadequate response to lifestyle interventions. The panel suggested the use of semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, and naltrexone-bupropion ER (based on moderate certainty evidence), and phentermine and diethylpropion (based on low certainty evidence), for long-term management of overweight and obesity. The guideline panel suggested against the use of orlistat. The panel identified the use of Gelesis100 oral superabsorbent hydrogel as a knowledge gap. CONCLUSIONS: In adults with overweight and obesity who have an inadequate response to lifestyle interventions alone, long-term pharmacological therapy is recommended, with multiple effective and safe treatment options.

Detection of amfepramone and its metabolite cathinone in human hair: Application to a uthentic cases of amfepramone use.

In recent years, overseas anti-obesity drugs including amfepramone have flowed into China through the internet or personal import by travelers. Amfepramone is controlled in China and is not available as a pharmaceutical product. It is obtainable either through the internet or imported by individuals across the border. The abuse of amfepramone is causing serious health problems. A method for the detection and quantification of amfepramone and its metabolite cathinone in human hair was developed and fully validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Approximately 10 mg of hair was weighed and pulverized with extraction solvent (a mixture of methanol: acetonitrile: 2 mM ammonium formate [pH 5.3] [25:29:46, v/v/v]). The limit of detection (LOD) and the limit of quantitation (LOQ) were 5 and 10 pg/mg, respectively. The method was linear over a concentration range from 10 to 10,000 pg/mg. The accuracy varied from -9.3% to 2.3%, with acceptable intra- and inter-day precision. The validated method was successfully applied to 17 authentic cases. The amfepramone concentrations ranged from 11.7 to 209 pg/mg, with a median of 30.2 pg/mg, and the hair cathinone concentrations ranged from 11.9 to 507 pg/mg, with a median of 54.0 pg/mg. This is the first report of amfepramone concentrations in human hair from amfepramone users. Cathinone can be incorporated into hair after amfepramone use.

Anorectic interaction and safety of 5-hydroxytryptophan/carbidopa plus phentermine or diethylpropion in rat.

Drug combinations are being studied as potential therapies to increase the efficacy or improve the safety profile of weight loss medications. This study was designed to determine the anorectic interaction and safety profile of 5-hydroxytryptophan (5-HTP)/carbidopa + diethylpropion and 5-HTP/carbidopa + phentermine combinations in rats. The anorectic effect of individual drugs or in combination was evaluated by the sweetened milk test. Isobologram and interaction index were employed to determine the anorectic interaction between 5-HTP/carbidopa and diethylpropion or phentermine. Plasma serotonin (5-HT) was measured by ELISA. Safety of repeated doses of both combinations in rats was evaluated using the tail sphygmomanometer, cardiac ultrasound, hematic biometry and blood chemistry. A single oral 5-HTP, diethylpropion or phentermine dose increased the anorectic effect, in a dose-dependent fashion, in 12 h-fasted rats. A dose of carbidopa at 30 mg/kg reduced the 5-HTP-induced plasmatic serotonin concentration and augmented the 5-HTP-induced anorectic effect. Isobologram and interaction index indicated a potentiation interaction between 5-HTP/30 mg/kg carbidopa + diethylpropion and 5-HTP/30 mg/kg carbidopa + phentermine. Chronic administration of experimental ED40 of 5-HTP/30 mg/kg carbidopa + phentermine, but not 5-HTP/30 mg/kg carbidopa + diethylpropion, increased the mitral valve leaflets area. Moreover, there were no other significant changes in cardiovascular, hematic or blood parameters. Both combinations induced around 20% body weight loss after 3 months of oral administration. Results suggest that 5-HTP/30 mg/kg carbidopa potentiates the anorectic effect of diethylpropion and phentermine with an acceptable safety profile, but further clinical studies are necessary to establish their therapeutic potential in the obesity treatment.

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.

Systematic review and meta-analysis of the efficacy and safety of amfepramone and mazindol as a monotherapy for the treatment of obese or overweight patients.

The aim of this study was to evaluate efficacy and safety of amfepramone, fenproporex and mazindol as a monotherapy for the treatment of obese or overweight patients. A systematic review of primary studies was conducted, followed by a direct meta-analysis (random effect) and mixed treatment comparison. Medline and other databases were searched. Heterogeneity was explored through I2 associated with a p-value. Of 739 identified publications, 25 were included in the meta-analysis. The global evaluation of Cochrane resulted in 19 studies with a high level of bias and six with unclear risk. Due to the lack of information in primary studies, direct meta-analyses were conducted only for amfepramone and mazindol. Compared to placebo, amfepramone resulted in higher weight loss in the short-term (<180 days; mean difference (MD) -1.281 kg; p<0.05; I2: 0.0%; p=0.379) and long-term (≥180 days; MD -6.518 kg; p<0.05; I2: 0.0%; p=0.719). Only studies with long-term follow up reported efficacy in terms of abdominal circumference and 5-10% weight reduction. These results corroborated the finding that the efficacy of amfepramone is greater than that of placebo. Treatment with mazindol showed greater short-term weight loss than that with placebo (MD -1.721 kg; p<0.05; I2: 0.9%; p=0.388). However, metabolic outcomes were poorly described, preventing a meta-analysis. A mixed treatment comparison corroborated the direct meta-analysis. Considering the high level of risk of bias and the absence of important published outcomes for anti-obesity therapy assessments, this study found that the evaluated drugs showed poor evidence of efficacy in the treatment of overweight and obese patients. Robust safety data were not identified to suggest changes in their regulatory status.

Diethylpropion and mazindol: An end to the discussion?

Antiobesity pharmacotherapy remains the main point of disagreement among both scientists and regulators. This is probably due to small sample sizes, high levels of heterogeneity, and low methodological quality. For many years, Brazil was one of the largest consumers of appetite suppressants worldwide, with evidence of irrational use of this drug class. Therefore, the country was the scene of a debate that divided the Brazilian Health Surveillance Agency (Anvisa - Agência Nacional de Vigilância Sanitária) and medical societies over the maintenance record of diethylpropion, mazindol and fenproporex. In this context, this commentary presents new arguments to contribute to the discussion, as well as recommendations for future studies.

Initial dual oral combination therapy in pulmonary arterial hypertension.

Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment.

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.

Mechanisms involved in the vasorelaxant effects produced by the acute application of amfepramone in vitro to rat aortic rings.

Amfepramone (diethylpropion) is an appetite-suppressant drug used for the treatment of overweight and obesity. It has been suggested that the systemic and central activity of amfepramone produces cardiovascular effects such as transient ischemic attacks and primary pulmonary hypertension. However, it is not known whether amfepramone produces immediate vascular effects when applied in vitro to rat aortic rings and, if so, what mechanisms may be involved. We analyzed the effect of amfepramone on phenylephrine-precontracted rat aortic rings with or without endothelium and the influence of inhibitors or blockers on this effect. Amfepramone produced a concentration-dependent vasorelaxation in phenylephrine-precontracted rat aortic rings that was not affected by the vehicle, atropine, 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. The vasorelaxant effect of amfepramone was significantly attenuated by NG-nitro-L-arginine methyl ester (L-NAME) and tetraethylammonium (TEA), and was blocked by removal of the vascular endothelium. These results suggest that amfepramone had a direct vasorelaxant effect on phenylephrine-precontracted rat aortic rings, and that inhibition of endothelial nitric oxide synthase and the opening of Ca2+-activated K+ channels were involved in this effect.

A versatile and one-pot strategy to synthesize α-amino ketones from benzylic secondary alcohols using N-bromosuccinimide.

A metal-free one-pot strategy has been developed for the first time to synthesize pharmaceutically important α-amino ketones from readily available benzylic secondary alcohols and amines using N-bromosuccinimide. This new reaction proceeds via three consecutive steps involving oxidation of alcohols, α-bromination of ketones, and nucleophilic substitution of α-bromo ketones to give α-amino ketones. Importantly, this novel one-pot greener reaction avoids direct usage of toxic and corrosive bromine. This methodology has been employed efficiently to synthesize pharmaceutically important amfepramone and pyrovalerone in a single step.

Evaluation of the toxic activity of anorectic diethylpropion in Chinese hamster ovary cells.

Diethylpropion has been available in the market for treating obesity for over 50 years. Refined studies are lacking to fully elucidate its action spectrum. The aim of our study was to evaluate possible toxic effects of anorectic diethylpropion in Chinese hamster ovary (CHO) cells. Comet assay (detects breaks in the DNA strand), micronucleus test (detects clastogenic/aneugenic damage), and cell survival test (detects cytotoxic damage) were used to evaluate the toxic effects. In comet assay, we found that the damage scores with diethylpropion treatments at the concentrations of 20 and 40 µg/mL were more significant ( p < 0.05) than that of the negative control. When assessing the possible aneugenic and/or clastogenic damage caused by the drug in CHO cells, we found no difference ( p > 0.05) in the values of micronucleated cells when comparing different diethylpropion treatments and the negative control. Regarding the cell viability, for all the diethylpropion concentrations tested, higher values ( p < 0.05) of apoptosis were found compared with those of the negative control. In relation to the number of necrotic cells, no difference ( p > 0.05) was noted between the means of the three concentrations of diethylpropion evaluated and the negative control. In the experimental conditions, we conclude that diethylpropion has weak genotoxic and cytotoxic activities.

Simultaneous analysis of amphetamine-type stimulants in plasma by solid-phase microextraction and gas chromatography-mass spectrometry.

Brazil is considered one of the countries with the highest number of amphetamine-type stimulant (ATS) users worldwide, mainly diethylpropion (DIE) and fenproporex (FEN). The use of ATS is mostly linked to diverted prescription stimulants and this misuse is widely associated with (ab)use by drivers. A validated method was developed for the simultaneous analysis of amphetamine (AMP), DIE and FEN in plasma samples employing direct immersion-solid-phase microextraction, and gas chromatographic/mass spectrometric analysis. Trichloroacetic acid 10% was used for plasma deproteinization. In situ derivatization with propylchloroformate was employed. The linear range of the method covered from 5.0 to 100 ng/mL. The detection limits were 1.0 (AMP), 1.5 (DIE) and 2.0 ng/mL (FEN). The accuracy assessment of the control samples was within 85.58-108.33% of the target plasma concentrations. Recoveries ranged from 46.35 to 84.46% and precision was <15% of the value of relative standard deviation. This method is appropriate for screening and confirmation in plasma forensic toxicology analyses of these basic drugs.

Stimulant mechanisms of cathinones - effects of mephedrone and other cathinones on basal and electrically evoked dopamine efflux in rat accumbens brain slices.

Mephedrone, an erstwhile "legal high", and some non-abused cathinones (ethcathinone, diethylpropion and bupropion) were tested for stimulant effects in vitro, through assessing their abilities to increase basal and electrically evoked dopamine efflux in rat accumbens brain slices, and compared with cocaine and amphetamine. We also tested mephedrone against cocaine in a dopamine transporter binding study. Dopamine efflux was electrically evoked and recorded using voltammetry in the rat accumbens core. We constructed concentration response curves for these cathinones for effects on basal dopamine levels; peak efflux after local electrical stimulation and the time-constant of the dopamine decay phase, an index of dopamine reuptake. We also examined competition between mephedrone or cocaine and [(125)I]RTI121 at the dopamine transporter. Mephedrone was less potent than cocaine at displacing [(125)I]RTI121. Mephedrone and amphetamine increased basal levels of dopamine in the absence of electrical stimulation. Cocaine, bupropion, diethylpropion and ethcathinone all increased the peak dopamine efflux after electrical stimulation and slowed dopamine reuptake. Cocaine was more potent than bupropion and ethcathinone, while diethylpropion was least potent. Notably, cocaine had the fastest onset of action. These data suggest that, with respect to dopamine efflux, mephedrone is more similar to amphetamine than cocaine. These findings also show that cocaine was more potent than bupropion and ethcathinone while diethylpropion was least potent. Mephedrone's binding to the dopamine transporter is consistent with stimulant effects but its potency was lower than that of cocaine. These findings confirm and further characterize stimulant properties of mephedrone and other cathinones in adolescent rat brain.

A comparative study of five centrally acting drugs on the pharmacological treatment of obesity.

CONTEXT: No long-term studies have compared centrally acting drugs for treating obesity. OBJECTIVE: To compare the efficacy and safety of diethylpropion (DEP), fenproporex (FEN), mazindol (MZD), fluoxetine (FXT) and sibutramine (SIB) in promoting weight loss. DESIGN AND SETTING: A prospective, randomized, placebo (PCB)-controlled study conducted at a single academic institution. PATIENTS: A total of 174 obese premenopausal women. INTERVENTION: Participants randomly received DEP 75 mg (n=28), FEN 25 mg (n=29), MZD 2 mg (n=29), SIB 15 mg (n=30), FXT 20 mg (n=29) or PCB (n=29) daily over 52 weeks. Diet and physical activity were encouraged. MAIN OUTCOME MEASURES: The primary endpoints were changes in body weight and the proportion of women who achieved at least 5% weight loss by week 52 in the intent-to-treat population. Other measurements included anthropometry, safety, metabolic and cardiovascular parameters. RESULTS: Weight loss was greater than PCB (-3.1±4.3 kg) with DEP (-10.0±6.4 kg; P<0.001), SIB (-9.5±5.9 kg; P<0.001), FEN (-7.8±6.9 kg; P<0.01) and MZD (-7.4±4.9 kg; P<0.01) but not with FXT (-2.5±4.1 kg). Ten (33.3%) women lost⩾5% of their initial weight with PCB, compared with 20 (71.4%; P<0.001) with DEP, 20 (69%; P<0.02) with FEN, 21 (72.4%; P<0.01) with MZD, 22 (73.3%; P<0.001) with SIB and 10 (35.5%) with FXT. Each medically treated group experienced more adverse events compared with PCB (P<0.001). Compared with PCB, constipation was more prevalent with DEP, SIB and MZD (P<0.01); anxiety was more prevalent with DEP (P=0.01); and irritability occurred more frequently with DEP and FEN (P=0.02). Significant improvements in the depression and anxiety scores, binge-eating episodes and quality of life correlated with weight loss. CONCLUSION: The centrally acting drugs DEP, FEN, MZD and SIB were more effective than PCB in promoting weight loss in obese premenopausal women, with a satisfactory benefit-risk profile.

Use of buccal micronucleus assay to determine mutagenicity induced by amfepramone in humans and the protective effects of vitamin C.

The abusive use of amfepramone in Brazilian population has grown in recent years. Few studies have been conducted on amphetamine with respect to DNA damage, and there have been no apparent investigations examining the influence of amfepramone on humans. The aim of this study was to determine the possible mutagenic actions of amfepramone on humans using the micronucleus (MN) assay with buccal cells and the effects of supplementation with vitamin C as a potential protective agent. The study included 108 females with 52 as control and 56 taking amfepramone at 120 mg/d for at least the whole previous month. All women were intentionally selected to be nonsmokers and nondrinkers. After 30 d of amfepramone women were given amfepramone plus vitamin C use at 1000 mg/d for another month. Results showed a marked increase in the number of MN in amfepramone users in both basal and differentiated cells, indicating a mutagenic action. After vitamin C supplementation, a significant decrease in the frequency of MN and apoptosis was observed. Evidence indicates that the main mechanism of action of amfepramone in inducing DNA damage occurs through formation of reactive oxygen species (ROS), intercalation and topoisomerase binding, attributed to the presence of an N-dialkyl group. In addition, data demonstrated that vitamin C effectively inhibited amfepramone-induced DNA damage.

Simple catalytic mechanism for the direct coupling of α-carbonyls with functionalized amines: a one-step synthesis of Plavix.

The direct α-amination of ketones, esters, and aldehydes has been accomplished via copper catalysis. In the presence of catalytic copper(II) bromide, a diverse range of carbonyl and amine substrates undergo fragment coupling to produce synthetically useful α-amino-substituted motifs. The transformation is proposed to proceed via a catalytically generated α-bromo carbonyl species; nucleophilic displacement of the bromide by the amine then delivers the α-amino carbonyl adduct while the catalyst is reconstituted. The practical value of this transformation is highlighted through one-step syntheses of two high-profile pharmaceutical agents, Plavix and amfepramone.

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.