The pharmacokinetics of pramiracetam, a new, investigational, cognition activator, were assessed in normal male volunteers as part of a clinical tolerance study. In a double-blind, randomized design, two groups of six subjects each received alternating placebo and single 400, 800, 1,200, and 1,600 mg oral doses of pramiracetam after an overnight fast. Mean (+/- SD) peak plasma concentrations of the four dose groups (2.71 +/- 0.54, 5.40 +/- 1.34, 6.13 +/- 0.71, 8.98 +/- 0.71 micrograms/mL) were attained between two to three hours following drug administration. The harmonic mean elimination half-life (4.5-6.5 hours), the mean total body clearance (4.45-4.85 mL/min/kg), the mean renal clearance (1.83-3.00 mL/min/kg), and the mean apparent volume of distribution (1.82-2.94 L/kg) were independent of dose, whereas the peak plasma concentrations and area under the curves increased as a linear function of dose. No significant side effects were observed at any dose level.

Administration, Oral↗

PubMedDate not supplied

Discriminating deterministic versus stochastic dynamics in neuronal activity.

An approach to discriminating deterministic versus stochastic dynamics from neuronal data is presented. Direct tests for determinism are emphasized, as well as using time series with clear physical correlates measured from small ensembles of neurons. Surrogate data are used to provide null hypotheses that the dynamics in our data could be accounted for by linear stochastic systems. Algorithms are given in full, and the analysis of an experimental example is given.

Algorithms↗

PubMedDate not supplied

Metabolic disposition of Rolziracetam in laboratory animals.

The metabolic disposition of [14C]-labeled Rolziracetam (CI-911) was studied in rhesus monkeys, beagle dogs, and Wistar rats after both p.o. and i.v. doses. Intravenously administered CI-911 was rapidly eliminated from systemic circulation with an apparent elimination half-life of less than 25 min. Plasma radioactivity was 10-20 times higher than that of parent drug and persisted much longer. After oral doses, only traces of intact drug were detected in plasma, whereas total radioactivity reached peak concentrations within 0.5-1 h indicating rapid absorption. The extent of absorption determined from plasma radioactivity and urinary excretion data was 90% or better. Tissue distribution of radioactivity in rats showed the highest concentrations in the liver and kidneys (12-30 times greater than plasma levels) with decreasing levels in the lungs, gonads, heart, spleen, muscle, and brain. Urinary excretion accounted for nearly 90% of the administered dose while fecal recovery was less than 5%. The sole metabolite present in plasma, tissues, and urine was identified as 5-oxo-2-pyrrolidinepropanoic acid (PD 106,687).

Administration, Oral↗

PubMedDate not supplied

Metabolic disposition of the non-steroidal anti-inflammatory agent isoxicam in man.

The metabolic fate of isoxicam, a long half-life non-steroidal anti-inflammatory agent, in human subjects was investigated using isoxicam labelled with 14C in the N-methyl position. Three healthy male subjects were each administered a single oral 200 mg dose (90.7 microCi) with plasma and urine collected. Total plasma radioactivity peaked between 8 and 24 h postdose with mean 14C plasma radioactivity half-life of 36.1 h. Low levels of plasma radioactivity precluded plasma metabolic profiling. In urine, 37% of the administered radioactivity was recovered through 168 h. Metabolic profiling of urine confirmed the major oxidative excretion product as the hydroxymethylisoxazole metabolite. Identified and confirmed as minor urinary metabolites were radiolabelled open-ring sulfonamide and N-methylsaccharin. Non-labelled saccharin formed by oxidative loss of the 14C N-methyl group from N-methylsaccharin, was also observed. The role of this 'saccharin pathway' in the overall human disposition of isoxicam remains to be elucidated.

Adult↗