Hollow-fiber liquid-phase microextraction and chiral LC-MS/MS analysis of venlafaxine and its metabolites in plasma.

BACKGROUND: An enantioselective analytical method was developed and validated for determination of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in plasma samples. The method employed LC-MS/MS analysis and hollow-fiber liquid-phase microextraction (HF LPME) for sample preparation. RESULTS: After HF LPME optimization the following condition was established: sample volume of 4 ml, sample agitation at 1750 rpm, 20 min of extraction, 0.1 mol/l acetic acid as acceptor phase, 1-octanol as organic phase and donor phase pH adjustment to 10. Under these conditions, the method was linear over the concentration range of 5-500 ng/ml with quantification limits of 5 ng/ml. CONCLUSION: The use of HF LPME for sample preparation provided suitable recoveries, efficient clean-up and low consumption of organic solvent.

Corrected QT interval changes during electroconvulsive therapy-antidepressants-atypical antipsychotics coadministration: safety issues.

Both old and newer antidepressants and some atypical antipsychotics, such as ziprasidone and quetiapine, used as augmentation agents in severe major depression, are known to increase corrected QT (QTc) interval. We investigated the safety of the coadministration of electroconvulsive therapy with an antidepressant-ziprasidone-quetiapine combination with respect to QTc interval in 6 female patients with severe major depression resistant to pharmacotherapy alone. Each patient underwent a series of 10 to 11 sessions of bilateral electroconvulsive therapy. Corrected QT intervals were calculated at baseline and several times up to 10 minutes after seizure cessation. Overall, QTc interval changes remained within normal limits, without the occurrence of any cardiac adverse events. Our findings suggest that the coadministration of these treatments might be safe, at least with respect to QTc interval changes.

Bupropion for the treatment of tobacco dependence: guidelines for balancing risks and benefits.

Tobacco use, particularly cigarette smoking, is now a global pandemic. The expected morbidity and mortality from smoking-attributable diseases will continue to rise for the next 30 years. In order to reduce this negative impact on worldwide health, effective therapy to aid smoking cessation must be provided to current smokers. Treatment for tobacco dependence involves the combination of behavioural therapies and pharmacological treatment. The most common pharmacological treatments include nicotine replacement therapy and non-nicotine medications, including antidepressants. The antidepressant with the greatest weight of evidence for efficacy in the treatment of tobacco dependence is bupropion. Sustained-release bupropion is approved for the treatment of tobacco dependence in over 50 countries worldwide. The efficacy of bupropion for the treatment of tobacco dependence is attributed to the blockage of dopamine reuptake in the mesolimbic dopaminergic system. This area of the brain is believed to mediate reward for nicotine use and for other drugs of dependence. Randomised, controlled clinical trials have shown that bupropion approximately doubles abstinence rates compared with placebo. In addition, long-term treatment with bupropion may reduce or delay smoking relapse. Bupropion also appears to be effective in the treatment of smokers who have recently relapsed and smokers with other comorbid psychiatric conditions. Bupropion has a good adverse events profile, but the risk exists for serious adverse effects such as seizures. Recent postmarketing surveillance reports have raised safety concerns about bupropion, although no causal relationship between bupropion and the reported serious adverse events or death has been established.

Selective liquid chromatographic method for determination of fluoxetine in plasma.

A selective and sensitive liquid chromatographic method was developed for the determination of fluoxetine (FLU) in plasma. FLU was isolated from plasma by liquid-liquid extraction. The chromatographic separation was performed on an analytical 250 x 3.9 mm id Novapak C18 column (4 microm particle size) with an isocratic mobile phase consisting of phosphate buffer-acetonitrile-methanol -triethylamine (58 + 30 + 10 + 2, v/v) adjusted to pH 7. Using UV detection at 226 nm, the detection limit for FLU in plasma was 3 ng/mL. No interferences were found with tricyclic antidepressant drugs, which allows this method to be used in clinical studies. The calibration curve was linear over the concentration range of 10-200 ng/mL. The average recovery was about 80% for plasma. The inter- and intraday assay coefficients of variation were <8%.

Liability in prescribing choice: the example of the antidepressants.

OBJECTIVE: The aim of this study is to review issues of legal liability in prescribing choice. Prescribing not only occurs in a medical setting, but also in a social and legal context in this era of evidence-based medicine and greater consumer awareness. Prescribers may be unaware of the legal consequences of medical decision-making and prescribing choice. This issue affects all areas of medicine and can be illustrated by antidepressant choice for major depression. METHOD: A review was undertaken of liability issues that may arise in the context of prescribing, with particular reference to prescribing antidepressants. RESULTS: There are legal precedents which illustrate prescribers' potential liability. These impose duties on the prescriber including those of care, to inform, and to respond to patients' wishes. In particular, the duty of care requires that if medicines are of equal efficacy, one should prescribe the best tolerated and least toxic medicine that is most likely to be taken at an effective dose for an adequate duration. While older and newer antidepressants are generally of equal efficacy, the newer agents have higher tolerability, lower toxicity and are less likely to be associated with treatment failure (due to sub-therapeutic dose regimens, or the patient discontinuing medication), disabling psychomotor impairment, dietary interaction or fatal overdose. CONCLUSIONS: There needs to be compelling reasons for prescribing medicines with a greater likelihood of adverse outcomes such as the older antidepressants (e.g. tricyclics) rather than the newer antidepressants such as RIMAs, SSRIs, SNRIs and 5HT2 receptor antagonists. The higher likelihood of an adverse outcome of treatment where an older antidepressant has been prescribed raises the potential for professional negligence claims to be brought against medical practitioners who prescribe such medicines for reasons other than established medical need.

Analytical methods for the quality control of Prozac capsules.

Some analytical methods (two spectrophotometric and two chromatographic procedures) for the determination of fluoxetine in Prozac capsules are described. All of them are applied to the samples after extracting the drug with a methanol water mixture. The direct and derivative spectrophotometric methods are simple and reliable; the derivative method gives better recovery and lessens interference. Both methods show linearity in the 5-30 microg ml(-1) range of the fluoxetine concentration range. Both HPLC methods (spectrophotometric and spectrofluorimetric detection) use a tetramethylammonium perchlorate buffer-acetonitrile mixture as the mobile phase and a C8 reversed phase column. The UV detection is performed at 226 nm, while the fluorimetric detection is performed by exciting at 230 nm and revealing the emission at 290 nm. The HPLC method with UV detection is more precise, but the procedure with fluorimetric detection is more sensitive.

Analysis of venlafaxine by capillary zone electrophoresis.

Capillary electrophoresis has been used for the separation of venlafaxine and two of its impurities deriving from the synthesis process. The electrophoretic experiments were performed using background electrolytes at different pHs in the 2.5-9.2 range in order to study the effective mobilities and resolution of the three examined compounds. The optimum experimental conditions for the baseline resolution of the three analytes was found at pH 6.5. Very good repeatability for both migration time and corrected peak areas was achieved. The calibration curve was studied for venlafaxine (concentration range 26-224 micrograms/mL), and the plot of the peak area ratio (sample/internal standard [IS]) versus venlafaxine concentration was linear with a correlation coefficient of 0.9991. The effect of different cyclodextrins (CDs), namely, gamma-cyclodextrin (gamma-CD), hydroxypropyl-beta-CD (HP-beta-CD), and alpha-cyclodextrin (alpha-CD), on effective mobility and enantiomeric resolution (R) of venlafaxine (Wy45030) and its impurities (imp1 and imp2) was studied at different pHs, and the best results were obtained at pH 9.2. Venlafaxine was baseline resolved in its enantiomers using gamma-CD or HP-beta-CD, while imp1 (Wy45494) was baseline resolved using alpha-CD.