Analysis of unbound plasma concentration of oxcarbazepine and the 10-hydroxycarbazepine enantiomers by liquid chromatography with tandem mass spectrometry in healthy volunteers

This study describes the development and validation of a method for the analysis of unbound plasma concentrations of oxcarbazepine (OXC) and of the enantiomers of its active metabolite 10-hydroxycarbazepine (MHD) [S-(+)- and R-(−)-MHD] using liquid chromatography with tandem mass spectrometry (LC–MS/MS). Additionally, the free fraction of the drug is described in healthy volunteers (n = 12) after the oral administration of 300 mg OXC/12 h for 5 days. Plasma aliquots of 200 μL were submitted to ultrafiltration procedure and 50 μL of the ultrafiltrate were extracted with a mixture of tert-butyl methyl ether:dichloromethane (2:1, v/v). OXC and the MHD enantiomers were separated on a OD-H chiral phase column. The method was linear in the range of 4.0–2.0 μg/mL for OXC and of 20.0–6.0 μg/mL plasma for the MHD enantiomers. The limit of quantification was 4 ng for OXC and 20 ng for each MHD enantiomer/mL plasma. The intra- and inter-day precision and inaccuracy were less than 15%. The free fraction at the time of peak plasma concentration of OXC was 0.27 for OXC, 0.37 for S-(+)-MHD and 0.42 for R-(−)-MHD. Enantioselectivity in the free fraction of MHD was observed, with a higher proportion of R-(−)-MHD compared to S-(+)-MHD

Albendazole versus Praziquantel in the Treatment of Neurocysticercosis: A Meta-analysis of Comparative Trials

Neurocysticercosis is a parasitic disease caused by the pork tapeworm, Taenia solium, when the larval form of the parasite lodges in the central nervous system. This disease is most commonly found among members of agricultural societies with poor sanitary conditions and economies based on breeding livestock (especially pigs) with low hygiene standards. It is a disease with long history in humans, and the usual therapeutic intervention was surgery until the development of antiparasitic cysticidal agents, the most common being praziquantel and albendazole. T. solium infection can take many different forms in humans, but we concentrated on parenchymal neurocysticercosis with viable cysts. A consensus statement by a panel of experts on the subject supports the use of antiparasitic treatment, but does not indicate either albendazole or praziquantel as the drug of choice for this type of neurocysticercosis, because data from single relevant clinical trials are not conclusive. We conducted a meta-analysis to further evaluate the comparative effectiveness and safety of albendazole and praziquantel for this particular type of neurocysticercosis. The outcomes of our meta-analysis suggest that albendazole is more effective than praziquantel in controlling seizures in affected patients and in leading to the total disappearance of cysts and subsequently cure of patients with neurocysticercosis

Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects

Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(-)- and S-(+)-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n=12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300mg b.i.d. and 80mg t.i.d., respectively. Blood samples (n=185) were collected over a period of 12h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9L/h (69.5-100.3) for oxcarbazepine and 2.0L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131L (97-165)) as compared to R-(-)- and S-(+)-MHD (23.6L (14.4-32.8) vs. 31.7L (22.5-40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10-28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition