Vortioxetine is a new treatment for MDD, and its adverse event profile is similar to that of other SSRIs.

No abstract

Although it is widely recognised that measurement of metabolite concentrations is crucial to understanding the clinical pharmacology characteristics of a new molecular entity, a clear consensus on the role of metabolites in the assessment of bioequivalence has never been achieved within the scientific community. However, a regulatory policy for the role of metabolites in bioavailability and bioequivalence has been established by the US FDA. One school of thought believes that the parent drug alone is sensitive to picking up formulation differences, whereas another school of thought believes that establishing bioequivalence criteria on all the species that contribute to safety and efficacy is the only way to ensure the switchability of two products. In this paper, a brief review of the pharmacokinetics of metabolites under different scenarios is presented and the history of the role of metabolites in the assessment of bioequivalence is summarised. Relevant examples from the literature illustrating conflicting opinions on the need for the measurement of metabolites in bioequivalence studies are given. Cases from the literature in which the parent drug is able to meet the 90% confidence intervals while the metabolite(s) fail to do so, and vice versa, are presented to illustrate the difficulty in choosing the pertinent entity to measure. The relevant current US FDA policy and guidelines related to bioavailability and bioequivalence are discussed and contrasted with the rules and regulations applicable in Canada and Europe.

The pharmacokinetics of atropine (dl-hyoscyamine) was studied in six normal volunteers following a single 1-mg intravenous dose of atropine. Atropine plasma levels were collected for 24 hours and analyzed by radioimmunoassay. Pulse rates were monitored and compared with predose values in each subject. Atropine plasma concentrations were fitted by least-squares regression analysis. The observed maximal increase in pulse rate, at 12 to 16 minutes after the dose, correlated with the maximum predicted tissue levels of atropine based on the computer fit of the plasma atropine concentration-time data. No correlation between the time of maximum response and atropine plasma concentrations was observed. The average half-life of atropine was 4.125 hours. This data may be used to design a multiple-dosing regimen for intravenous atropine in patients.

A high-pressure liquid chromatographic method has been developed that allows for the simultaneous analysis of dacarbazine (DTIC), 5-aminoimidazole-4-carboxamide (AIC), and 2-azahypoxanthine (2-AZA) in plasma or urine. Plasma samples were prepared by ultrafiltration, whereas urine samples were filtered and diluted for analysis. Chromatography was done with a C18 ,uBondapak column along with gradient elution of the drugs. The mobile phase consisted of 100% 0.5 M sodium acetate (pH 7.0) and 25% acetonitrile in 0.05 M sodiumf acetate (pH 5.5) with detection at 280 nm. Linearity was observed up to 500 ,ug/ml for DTIC and up to 53 ,ug/ml for AIC and 2-AZA. The assay methodology was reproducible, with a lower limit of detection of 5.0, 0.5, and 0.5 ,Lg/ml for DTIC, AIC, and 2-AZA, respectively. Interday and intraday coefficients of variation ranged between 4 to 14% and 2 to 16%, respectively. The analytical method was applied to the analysis of plasma and urine samples resulting from the isolation perfusion chemotherapy of an extremity with 57 mg of DTIC per kg in a patient with melanoma.The pharmacokinetics of dacarbazine (DTIC), a cytotoxic agent, has recently been studied in animals and humans (1-5) by a specific high-pressure liquid chromatographic (HPLC) assay. Assays used in these studies involved different chromatographic conditions for the determination of DTIC and its metabolite, 5-aminoimidazole-4-carboxamide (AIC). In addition, neither of the methods uses an internal standard. The methods also describe the analysis of 2-azahypoxanthine (2-AZA), a photolytic degradation product of DTIC, but again, the analysis is a separate assay with either DTIC or AIC and never with all three being simultaneously determined, which indeed would be the most efficient methodology.To facilitate pharmacokinetic studies in animals and humans, a gradient elution HPLC assay for the simultaneous determination of DTIC, AIC, and 2-AZA in plasma and urine was developed that uses an internal standard.Sodium acetate and phosphoric acid were obtained from J. T. Baker Chemical Co., Phillipsburg, N.J. Acetonitrile (HPLC grade) and 3-methylxanthine (internal standard) were purchased from Fisher Scientific Co., Fairlawn, N.J., and Aldrich Chernical Co., Inc., Milwaukee, Wis., respectively. DTIC, AIC, and 2-AZA were obtained from Miles Pharmaceuticals, West Haven, Conn. The DTIC was dessicated for 2 h over phosphorus pentoxide under vacuum before being used. Subsequently, all three compounds were stored at 22°C in a dessicator until used. DTIC solutions were kept covered with aluminum foil whenever they were handled to prevent exposure to UV light and possible degradation. The detector output was monitored with a model 3390 integrator-plotter (Hewlett-Packard Co., Rockville, Md.) set at an attenuation of 6 and a chart speed of 0.2 cm/mm. Analysis was done by gradient elution with solvent systems designated as solvent A, which was 100% 0.5 M sodium acetate adjusted to pH 7.0 with 10% concentrated phosphoric acid in Water and a solvent system, a...