The effect of mild or moderate hepatic impairment (cirrhosis) on the pharmacokinetics of zileuton.

The pharmacokinetics of zileuton and its R(+) and S(-) glucuronide metabolites were determined after single and multiple (400mg every 8 hours) oral dose administration in healthy subjects (n = 5) and patients with mild or moderate hepatic impairment (cirrhosis; n = 8). The clearance of total zileuton (unbound plus bound to plasma proteins) in patients with hepatic impairment (approximately 350 ml/min) was approximately half than in healthy subjects (approximately 670 ml/min), with similar values in patients with mild or moderate cirrhosis. However, the clearance of unbound zileuton in patients with moderate hepatic impairment was nearly half that in patients with mild hepatic impairment, and one quarter that in healthy subjects. On the basis of these findings, it may be necessary to reduce the dose in patients with impaired hepatic function to maintain levels similar to those in healthy subjects.

Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans.

A double-blind parallel randomised study was conducted to assess the effects of multiple oral doses of zileuton (600mg every 6 hours) or matching placebo on the steady-state pharmacokinetics and pharmacodynamics of warfarin titrated to a prothrombin time of 14 to 18 seconds in 24 healthy adult male volunteers. Serial blood samples were collected for assessment of prothrombin times and R- and S-warfarin plasma concentrations. Coadministration of zileuton and warfarin had no effect on S-warfarin pharmacokinetics but statistically significantly increased mean R-warfarin plasma concentrations and decreased mean R-warfarin total oral plasma clearance compared with warfarin alone (by 15%). This stereoselective interaction was accompanied by an increase in mean morning (predose) and evening (12-hour postdose) prothrombin times from 17.5 to 19.8 seconds and 17.1 to 19.1 seconds, respectively; the corresponding changes in the placebo group were from 18.1 to 18.8 seconds and 17.3 to 17.5 seconds. Thus, multiple dose administration of zileuton appears to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics. Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfarin.

Pharmacologic effects of A-56234, a new high-ceiling diuretic.

The pharmacokinetic characteristics, the diuretic, saluretic, and uricosuric properties, and the safety of single, rising, oral doses of A-56234, a new high-ceiling diuretic, were evaluated in this double-blind, placebo-controlled, cross-over study. Each of three groups of eight subjects received placebo and three different single doses of the diuretic at 1-week intervals. Doses ranged from 0.5 to 80 mg. Significant, dose-related increases in urine volume and in urinary excretion of sodium and chloride were produced during the 24 hours after administration of 20, 40, 60, and 80 mg of the drug. Uricosuria was not observed at any dose. The drug was rapidly absorbed and displayed linear pharmacokinetics within the dose range studied. The elimination-phase plasma half-life was approximately 6 hours. Hepatic clearance was the main route of excretion in humans; only 2 to 10% of the parent drug was excreted in the urine. The drug was well tolerated and no clinically important adverse events were noted.

Pharmacologic effects of A-49816, a new high-ceiling diuretic.

The pharmacologic effects of A-49816, a high-ceiling, loop diuretic, were evaluated in a single-blind, placebo-controlled, randomized trial. Eighteen (18) normal volunteers aged 19 to 40 years were divided into three groups. The subjects in each group received either placebo or three increasing doses of A-49816 with at least a one-week washout between doses. Nine doses of A-49816 (0.5 to 20 mg) were administered during the entire study. Urine volume and excretion of electrolytes were measured at timed intervals following dosing. A-49816 increased urine volume and excretion of sodium and chloride. Significant saluresis, chloruresis and diuresis were seen in most time periods following administration of the highest doses (12.5, 15 and 20 mg) of A-49816. Kaluresis was not consistently seen at any dose. The mean rates of urine output and sodium and chloride excretion were increased relative to placebo within 2 hours of drug administration. The mean rates of urine formation and sodium and chloride excretion peaked at 2-4 hours and often remained elevated at the 6-12 hour interval.

Effect of infusion duration on valproate pharmacokinetics.

The pharmacokinetics of intravenously administered valproic acid (VPA) were investigated in 16 healthy male volunteers in a single-dose, fasting, four-period, randomized, double-blind, placebo-controlled, parallel design study. Subjects were randomly assigned to be infused a single dose of sodium valproate equivalent to 1000 mg VPA or placebo over each of four different time periods. Valproate concentrations in plasma were determined using gas chromatography with flame ionization detection. The pharmacokinetic parameters were determined by both non-compartmental and model-dependent techniques. Analyses of variance (ANOVAs) were performed to detect any statistical differences among the regimens. Overall, the pharmacokinetic of valproate were similar after infusions of 5, 10, 30, and 60 min, with an average terminal-phase half-life of 15.9 h. There were modest differences in overall clearances among the regimens, with the 5 min infusion producing a mean area under the plasma concentration-time curve (AUC; 1877 micrograms.h ml-1) that was significantly (13 to 16 per cent) higher than the means for the longer infusions (1614-1656 micrograms.h ml-1). Differences in distribution were also noted as a function of infusion duration. The shortest duration produced a significantly smaller terminal volume of distribution (12.8 vs 14.2-15.1 l) and more rapid tissue equilibration. The alpha-phase rate constant declined from a mean of 5.1 h-1 after the 5 min infusion to a mean of 0.9 h-1 after the 60 min infusion. The distributional differences are almost certainly related to the saturable protein binding of valproate. However, the lower clearance after the 5 min infusion indicates that there may have also been partial saturation of one of the metabolic pathways of valproate during the distributive phase, and that the increase in fu was smaller than the decrease in CL'int, such that the product of fu.CL'int showed a net decrease.

Capacity limitations in short-term memory in schizophrenia: tests of competing hypotheses.

BACKGROUND: Capacity limitation theories have proved to be surprisingly resilient in characterizing some of the cognitive deficits in schizophrenia. However, this perspective has not generally been applied to short-term verbal memory tasks. We explored this issue by first attempting to ascertain if gross misallocations of processing resources might explain impairments in short-term memory in schizophrenia on a classic digit span task and in a second study by attempting to determine what effects delay and memory set size had on a divided attention short-term verbal memory paradigm. METHODS: In the first study 16 patients with schizophrenia and 21 normal controls received 40 trials of a three digit task and 20 trials of a six digit span task. As the absolute number of digits presented and duration of presentation in two conditions were identical, subjects thus had equivalent 'opportunities' to make errors if distraction, in the sense of misallocation of cognitive resources, were at the root of poor performance. In the second study 15 patients with schizophrenia and 15 normal controls were tested in conditions in which two, four or six words were presented and in which rehearsal was prevented by an interference task (colour naming) for delays of 5, 10 or 15 s. RESULTS: Patients had disproportionate difficulty on the six digit rather than the three digit condition, suggesting that deficits in the verbal working memory short-term store may not be the result of attentional factors. In the second study, patients' performance was differentially worsened by the interference task, by memory set size (i.e. a capacity limitation) and by delay, a measure of decay rate. CONCLUSIONS: In concert, these studies demonstrate that schizophrenia patients have difficulties on verbal short-term memory span tasks not because of misallocation of resources, but rather because of limitations in 'representational capacity' and maintenance of information over delays.