Dietary supplement for energy and reduced appetite containing the ß-agonist isopropyloctopamine leads to heart problems and hospitalisations.

In 2013 the Dutch authorities issued a warning against a dietary supplement that was linked to 11 reported adverse reactions, including heart problems and in one case even a cardiac arrest. In the UK a 20-year-old woman, said to have overdosed on this supplement, died. Since according to the label the product was a herbal mixture, initial LC-MS/MS analysis focused on the detection of plant toxins. Yohimbe alkaloids, which are not allowed to be present in herbal preparations according to Dutch legislation, were found at relatively high levels (400-900 mg kg(-1)). However, their presence did not explain the adverse health effects reported. Based on these effects the supplement was screened for the presence of a ß-agonist, using three different biosensor assays, i.e. the validated competitive radioligand ß2-adrenergic receptor binding assay, a validated ß-agonists ELISA and a newly developed multiplex microsphere (bead)-based ß-agonist assay with imaging detection (MAGPIX(®)). The high responses obtained in these three biosensors suggested strongly the presence of a ß-agonist. Inspection of the label indicated the presence of N-isopropyloctopamine. A pure standard of this compound was bought and shown to have a strong activity in the three biosensor assays. Analysis by LC-full-scan high-resolution MS confirmed the presence of this 'unknown known' ß3-agonist N-isopropyloctopamine, reported to lead to heart problems at high doses. A confirmatory quantitative analysis revealed that one dose of the preparation resulted in an intake of 40-60 mg, which is within the therapeutic range of this compound. The case shows the strength of combining bioassays with chemical analytical techniques for identification of illegal pharmacologically active substances in food supplements.

Development and validation of sensitive methods for determination of sibutramine hydrochloride monohydrate and direct enantiomeric separation on a protein-based chiral stationary phase.

Sibutramine hydrochloride monohydrate, chemically 1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl) hydrochloride monohydrate (SB.HCI.H20), was approved by the U.S. Food and Drug Administration for the treatment of obesity. The objective of this study was to develop, validate, and compare methods using UV-derivative spectrophotometry (UVDS) and reversed-phase high-performance liquid chromatography (HPLC) for the determination of SB.HCI.H20 in pharmaceutical drug products. The UVDS and HPLC methods were found to be rapid, precise, and accurate. Statistically, there was no significant difference between the proposed UVDS and HPLC methods. The enantiomeric separation of SB was obtained on an alpha-1-acid glycoprotein column. The R- and S-sibutramine were eluted in < 5 min with baseline separation of the chromatographic peaks (alpha = 1.9 and resolution = 1.9).

Sibutramine--a review of clinical efficacy.

Controlled studies have shown that sibutramine produces dose-related weight loss when given in the range 5-30 mg per day, with optimal doses of 10 and 15 mg per day. Weight loss with sibutramine is 3-5 kg better than placebo at 24 weeks, and weight loss is maintained to 52 weeks at doses of 10 and 15 mg. By six months, 69% of patients treated with sibutramine 15 mg achieve a 5% or greater reduction in their baseline weight. The weight loss achieved with sibutramine was similar to that achieved with dexfenfluramine over 12 weeks (4.5 kg compared with 3.2 kg). Sibutramine-induced weight loss has been found to be accompanied by a significant reduction in waist/hip ratio, and decreases in plasma triglycerides, total cholesterol and low density lipoprotein (LDL) cholesterol. There were also increases in high density lipoprotein (HDL) cholesterol. In patients with type II diabetes, sibutramine-induced weight loss was accompanied by a shift towards improved glycaemic control. In controlled studies, 84% of sibutramine-treated patients reported adverse events, compared with 71% of patients receiving placebo. The most frequently reported adverse events are related to pharmacological actions of sibutramine, and include dry mouth, decreased appetite, constipation and insomnia.

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.