Pharmacokinetics and pharmacodynamics of multiple-dose terbinafine.

Data from clinical trials of terbinafine for the treatment of onychomycosis were analyzed with the following two objectives: 1) to identify demographic predictors of the duration and extent of systemic drug exposure; and 2) to explore whether increased systemic exposure or demographic predictors of increased exposure were associated with altered safety or efficacy. Demographic predictors of exposure were identified by a model-free, nonparametric approach applied to the sparse pharmacokinetic data from the onychomycosis studies. Those covariates were then incorporated into a multicompartmental nonlinear mixed effects model. Post hoc parameter estimates from the nonlinear mixed effects model provided individual measures of exposure. Safety scores were derived for adverse events that were frequently attributed to drug exposure and for liver function tests. Terbinafine was found to have an average terminal half-life (t1/2) of approximately 3 weeks. That terminal elimination phase contributed so little to the total exposure, however, that average concentrations accumulated only approximately two-fold at steady state with once daily dosing. Age and concomitant hypertension were predictors of higher plasma concentrations of terbinafine; smokers had lower levels than nonsmokers. Although some statistically significant associations between adverse events and systemic exposure were found, in all cases the actual frequency of the adverse events and systemic exposure were found, in all cases the actual frequency of the adverse events was low, and there were no trends in severity with respect to exposure. Above-normal levels of gamma-glutamyl transferase were associated with exposure, but there was no trend in severity with respect to exposure. No other liver function test abnormalities were associated with exposure, nor were there any significant associations between adverse events or liver function abnormalities and demographic subgroups that differed with respect to exposure. Among patients taking the active drug there were no significant associations between exposure levels and efficacy, nor were there differences in efficacy between demographic subgroups that differed with respect to exposure.

The pharmacokinetics of a microemulsion formulation of cyclosporine in primary renal allograft recipients. The Neoral Study Group.

This study was a randomized, double-blind, 12-week comparison of the pharmacokinetics, safety, and tolerability of two cyclosporine (CsA) formulations, cyclosporine emulsion capsules and oral solution for microemulsion and cyclosporine, in the postoperative management of renal transplant patients. Of the 101 patients, aged 18 to 65, who entered the study, 89 were evaluable for pharmacokinetics. Initial dosage was 10 mg/kg per day, administered twice daily in two equal doses. Dosages were adjusted to achieve target CsA concentrations. The pharmacokinetic (PK) parameters (dose-normalized) of greatest interest were maximum blood concentration (C(max)/dose), time to reach maximum concentration (t(max), area under the blood concentration-vs.-time curve (AUC/dose), and trough blood concentrations (Co h/dose). The relative CsA bioavailabilty was found to be significantly enhanced with cyclosporine emulsion compared with cyclosporine with a 16% to 31% increase in AUC and a 32% to 42% increase in C(max). Intrapatient variability of PK parameters was significantly lower with cyclosporine emulsion than with cyclosporine for AUC, C(oh), t(max), and C(max) in many instances. This indicates a more consistent, rapid, and more complete total absorption of CsA. Despite higher CsA C(max) levels and AUCs with cyclosporine emulsion, safety and tolerability (detailed in a parallel report) were comparable to those of cyclosporine. The PK advantages of cyclosporine emulsion over cyclosporine are either independent of food conditions or possibly reflective of more consistent absorption of CsA with cyclosporine emulsion. The findings suggest that de novo use of cyclosporine emulsion may simplify and improve management of organ transplant recipients and that the PK advantages of cyclosporine emulsion may translate into clinical benefits.

A nonlinear mixed-effects pharmacokinetic model comparing two formulations of cyclosporine in stable renal transplant patients.

A nonlinear mixed-effects model simultaneously modeled two pharmacokinetic (PK) variables in patients administered cyclosporine twice daily: (i) concentration of drug in blood at the end of the 12-hr dosing interval (C12) and (ii) area under the concentration-time curve within the dosing interval (AUC). For two formulations (Neoral and Sandimmune), the model assessed the following: nonlinearity with respect to dose, interoccasion (intraindividual) variability, interindividual variability, and within- and across-individual correlation between C12 and AUC. Data were pooled from six clinical studies in stable renal transplant patients administered each formulation. PK samples on two occasions were taken usually for each formulation. Each individual's random effect was eight-dimensional consisting of two PK variables for each formulation on two occasions. An ANOVA-like partitioning worked well and reduced the variance matrix for the random effect to a known function of 13 parameters to be estimated, thereby making a numerically intensive computation feasible. Simulations were used to check the model fit, to compute standard errors, and to account for peculiarities in the residual analysis. Outcomes of tests comparing formulations, most of which were statistically significant, favored Neoral (dose proportional, lower interoccasion variability, lower interindividual variability, and higher correlation between C12 and AUC).

A cytosolic cyclic AMP-dependent protein kinase in Dictyostelium discoideum. I. Properties.

A cAMP-dependent protein kinase was isolated and partially purified from Dictyostelium discoideum. The cytosolic holoenzyme has an apparent Mr = 160,000-180,000; its activity was stimulated significantly by cAMP when Kemptide served as substrate. The enzyme was dissociated and the regulatory subunit purified by affinity chromatography on 8-aminoethylamino-cAMP. Only one type of regulatory subunit was found; it has an apparent Mr = 41,000 and is a substrate for the in vitro phosphorylation by the homologous catalytic subunit and by purified bovine catalytic subunit. Antibody against the regulatory subunit was prepared. The D. discoideum catalytic subunit was separated from cAMP-independent protein kinase by chromatofocusing. The apparent molecular weight of the catalytic subunit of the D. discoideum cAMP-dependent protein kinase is 33,000 and its pI is 6.4. The enzyme catalyzed the phosphorylation of bovine RII but not of RI regulatory subunit and was inhibited by high concentrations of the inhibitor of mammalian cAMP-dependent protein kinase. The evolution of the functional domains of cAMP-dependent protein kinases is discussed on the basis of a comparison of the analogous D. discoideum and vertebrate enzymes.

Norepinephrine attenuation of amnesia produced by diethyldithiocarbamate.

Rats given 680 mg/kh diethyldithiocarbamate, approximately one half hour before training in an inhibitory avoidance task, had impaired retention performance when tested one week after training. Intracerebroventricular or subcutaneous injections of norepinephrine administered shortly after training attenuated the disruptive effects of DDC on retention performance. The effect depended upon the footshock intensity used during training. NE(0.01 microgram) administered centrally attenuated the DDC induced retention deficit when animals were trained with a high (2 mA) but not a low footshock (0.5 mA). The effect of peripherally administered NE also varied with intensity of footshock. The lowest dose of subcutaneously administered NE (5 microgram/kg) was effective in attenuating DDC induced retention deficits only when animals were trained with higher footshock. Higher doses of NE (50 microgram/kg, 500 microgram/kg) were more effective when animals were trained with lower footshock.