UHPLC-MS/HRMS method for the quantitation of pyrithione metabolites in human urine.

Pyrithione glucuronide (PTG) and 2-thiopyridine glucuronide (ThPG) have been reported to be the major urinary metabolites in multiple animal species following administration of zinc pyrithione (ZnPT). However, the formation of these metabolites has never been confirmed in humans. A simple and rugged ultra-high-performance liquid chromatography high resolution mass spectrometry (UHPLC-MS/HRMS) method was developed and validated for the quantification of PTG and ThPG to investigate human metabolism of pyrithione following topical application of ZnPT as a shampoo. A UHPLC-MS/HRMS method was required due to the matrix interferences that were observed with the typical industry standard HPLC/tandem mass spectrometry (LC-MS/MS) methodology based on nominal mass triple quadrupole (QQQ) platform approach. Using UPLC-MS/HRMS, both PTG and ThPG were identified in human urine following topical application of ZnPT. The presence of these human urinary metabolites of pyrithione are consistent with findings from earlier studies in multiple animal species and suggest the metabolism of pyrithione is similar amongst those mammalian species studied.

Systematic Review and Meta-Analyses Assessment of the Clinical Efficacy of Bismuth Subsalicylate for Prevention and Treatment of Infectious Diarrhea.

BACKGROUND: A large number of studies have evaluated the pharmacology, safety, and/or efficacy of bismuth subsalicylate for the relief of common gastrointestinal symptoms, diarrhea and vomiting due to acute gastroenteritis. In addition, short-term (48 h) medication with bismuth subsalicylate is known to be effective against infectious gastroenteritis such as travelers' diarrhea. AIMS: Previous studies have documented the bacteriostatic/bactericidal effects of bismuth subsalicylate against a variety of pathogenic gastrointestinal bacteria. However, meta-analyses of the clinical efficacy of bismuth subsalicylate for both prevention and treatment of travelers' diarrhea have not yet been published. METHODS: A total of 14 clinical studies (from 1970s to 2007) comprised the core data used in this assessment of efficacy of bismuth subsalicylate against infectious (including travelers') diarrhea. These studies allowed for statistical meta-analyses regarding prevention (three travelers' diarrhea studies) and treatment of infectious diarrhea (11 studies [five travelers' diarrhea]). RESULTS: The results show that subjects treated with bismuth subsalicylate for up to 21 days have 3.5 times greater odds of preventing travelers' diarrhea compared with placebo (95% CI 2.1, 5.9; p < 0.001). In addition, subjects with infectious diarrhea treated with bismuth subsalicylate had 3.7 times greater odds of diarrhea relief (recorded on diaries as subjective symptomatic improvement) compared to those receiving placebo (95% CI 2.1, 6.3; p < 0.001). CONCLUSIONS: This systematic review and meta-analysis suggests that bismuth subsalicylate can be beneficial for those at risk or affected by food and waterborne diarrheal disease such as traveler's (infectious) diarrhea, and may decrease the risk of inappropriate antibiotic utilization.

Doxylamine pharmacokinetics following single dose oral administration in children ages 2-17 years.

To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages ∼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (∼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ∼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%.

Pharmacokinetics of glucarpidase in subjects with normal and impaired renal function.

Glucarpidase (formerly known as carboxypeptidase G2 or CPG2) is being evaluated for the adjunctive treatment of patients experiencing, or at risk of, methotrexate toxicity attributable to its delayed elimination. Delayed elimination of methotrexate can occur in patients with methotrexate-induced renal toxicity. In this study, glucarpidase pharmacokinetics were assessed in volunteer subjects with normal (n = 8) and severely impaired (n = 4) renal function. Each subject received a single intravenous dose of glucarpidase 50 U/kg (equivalent to 114.5 microg/kg) infused over 5 minutes. The mean maximum serum concentration (C(max)) for glucarpidase in renally impaired subjects was 2.9 microg/mL, the mean half-life (t(1/2)) was 10.0 hours, and the mean area under the serum concentration-time curve from time zero to infinity (AUC(0-infinity)) was 24.5 microg x h/mL. Similar values were found in subjects with normal renal function (mean C(max) 3.1 microg/mL, mean t(1/2) 9.0 hours, and mean AUC(0-infinity) 23.4 microg x h/mL). The results indicated little effect of renal impairment on the serum pharmacokinetics of glucarpidase.

Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers.

Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A-mediated metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single-dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645+/-236 mL/h/kg, 546+/-101 mL/h/kg (P = .01), and 540+/-104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.