Effective Concentration-Based Serum Pharmacodynamics for Antifungal Azoles in a Murine Model of Disseminated Candida Albicans Infection.

Effective concentration-based serum pharmacodynamics for antifungal azoles in a murine model of disseminated Candida albicans infection.

Eur J Drug Metab Pharmacokinet. 2013 Mar 29;
Maki K, Kaneko S

An assessment of the effective in vivo concentrations of antifungal drugs is important in determining their pharmacodynamics, and therefore, their optimal dosage regimen. Here we establish the effective in vivo concentration-based pharmacodynamics of three azole antifungal drugs (fluconazole, itraconazole, and ketoconazole) in a murine model of disseminated Candida albicans infection. A key feature of this study was the use of a measure of mycelial (m) growth rather than of yeast growth, and pooled mouse sera rather than synthetic media as a growth medium, for determining the minimum inhibitory concentrations (MICs) of azoles for C. albicans (denoted serum mMICs). The serum mMIC assay was then used to measure antifungal concentrations and effects as serum antifungal titers in the serum of treated mice. Both serum mMIC and sub-mMIC values reflected the effective in vivo serum concentrations. Supra-mMIC and mMIC effects exhibited equivalent efficacies and were concentration-independent, while the sub-mMIC effect was concentration-dependent. Following administration of the minimum drug dosage that inhibited an increase in mouse kidney fungal burden, the duration periods of these effects were similar for all drugs tested. The average duration of either the mMIC effect including the supra-mMIC effect, the sub-mMIC effect, or the post-antifungal effect (PAFE) were 6.9, 6.5 and 10.6 h, respectively. Our study suggests that the area under the curve for serum drug concentration versus time, between the serum mMIC and the sub-mMIC, and exposure time above the serum sub-mMIC after the mMIC effect, are major pharmacodynamic parameters. These findings have important implications for effective concentration-based pharmacodynamics of fungal infections treated with azoles. HubMed – drug


Antipsychotic and psychostimulant drug combination therapy in attention deficit/hyperactivity and disruptive behavior disorders: a systematic review of efficacy and tolerability.

Curr Psychiatry Rep. 2013 May; 15(5): 355
Linton D, Barr AM, Honer WG, Procyshyn RM

This systematic review examines treatment guidelines, efficacy/effectiveness, and tolerability regarding the use of antipsychotics concurrently with psychostimulants in treating aggression and hyperactivity in children and adolescents. Articles examining the concurrent use of antipsychotics and psychostimulants to treat comorbid attention deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBDs) were identified and their results were summarized and critically analyzed. Antipsychotic and stimulant combination therapy is recommended by some guidelines, but only as a third-line treatment following stimulant monotherapy and stimulants combined with behavioral interventions to treat aggression in patients with ADHD. Some studies suggest efficacy/effectiveness for an antipsychotic and stimulant combination in the treatment of aggression and hyperactivity in children and adolescents. However, the data do not clearly demonstrate superiority compared to antipsychotic or psychostimulant monotherapy. Most studies were performed over short time periods, several lacked blinding, few studies used any placebo control, and no comparisons were made with behavioral interventions. There are concerns about the tolerability of combination therapy, but data do not suggest significantly worse adverse effects for combination compared to either antipsychotic or stimulant monotherapy. Conversely, and contrary to speculation, use of a stimulant does not significantly reduce metabolic effects of antipsychotics. Combination treatment with antipsychotics and psychostimulants is used frequently, and increasingly more often. Few studies have directly examined this combination for the treatment of ADHD and DBDs. Further studies are necessary to confirm the efficacy and tolerability of the concurrent use of antipsychotics and psychostimulants in children and adolescents. HubMed – drug


Investigation of the Pharmacokinetic Interaction between Ritonavir and CMDCK, a New Non-nucleoside Reverse Transcriptase Inhibitor.

Drug Res (Stuttg). 2013 Mar 28;
Zhuang XM, Shen GL, Yuan M, Li H

The aim of this study was to investigate the pharmacokinetic interaction between ritonavir (RTV) and an anti-HIV agent 3-cyanomethyl-4-methyl-DCK (CMDCK). CMDCK was administered orally (8 mg/kg) and intravenously (2 mg/kg) to rats in the absence or presence of RTV (1 or 2.5 mg/kg). By comparing the pharmacokinetic parameters between the control and the RTV treated groups, it was found that co-administration with RTV could significantly increase the plasma exposure of CMDCK, through improving the hepatic and intestinal availabilities. The AUCinf of CMDCK was increased by 2.4 or 8.7 times for intravenous or oral route, respectively. The oral bioavailability of CMDCK was increased from 15% of the control group to 45% of the RTV concomitant group (2.5 mg/kg). In the in vitro studies with liver and intestinal microsomes, the K i values of RTV on the CMDCK metabolism were determined and found to be 0.22 and 0.48 µM for human, 0.33 and 1.60 µM for rat, respectively. Caco-2 cells study showed that CMDCK is not a P-glycoprotein (P-gp) substrate and its transepithelial transport is mainly through passive diffusion. The in vitro and in vivo results indicate that RTV could improve the bioavailability of CMDCK by inhibiting CYP3A mediated metabolism in both liver and intestine. HubMed – drug