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A M Nikaido

Publications and source records attributed to A M Nikaido.

10 recordsLinked to original sources
PubMed1990

Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines. I: Lorazepam.

This investigation compares the time course changes in the central nervous system (CNS) impairment effects on psychomotor and cognitive skills and relates these changes to the plasma lorazepam concentrations in a pharmacokinetic-pharmacodynamic (PK-PD) model. Six male subjects received a single oral dose of lorazepam or placebo. The CNS effects were measured by using computerized continuous tracking (TRKN), body sway with eyes open (SWAY OPEN), and digit symbol substitution (DSS) tests. Plasma lorazepam concentrations were best characterized by a two-compartment model with first-order absorption. Plotting the plasma lorazepam concentration and measured effect across time revealed a counterclockwise hysteresis loop. Fitting the time course of the effects in an integrated PK-PD model required an effect compartment with the equilibrium rate constant between it and the plasma compartment. The magnitude of the temporal lag was quantified by the half-time of equilibration between concentration in the hypothetical effect compartment and the plasma lorazepam level (t1/2keo). The CNS effect measured by TRKN was characterized by a mean estimate of maximum predicted effect (Emax) of 418 with a t1/2keo of 0.43 hr, an estimate of effect site drug level to produce 50% of Emax (EC50) of 35.8 ng/ml and a power parameter (gamma) of 6.29. Corresponding parameter mean estimates for SWAY OPEN and DSS as measures of drug CNS effect were quite similar.

Administration, Oral↗
PubMed1990

Age-related increase in CNS sensitivity to benzodiazepines as assessed by task difficulty.

The differential sensitivity of young and elderly healthy adults to the impairment effects of benzodiazepines was assessed by tasks with several levels of difficulty. Using a double-blind procedure, single doses of placebo, alprazolam (0.75 and 1.5 mg) and triazolam (0.25 and 0.5 mg) were ingested orally by 10 young men, 9 young women, 7 elderly men, and 10 elderly women. Order of drug administration was determined by a random Latin square design. Different versions of the subcritical tracking and digit symbol substitution tasks were characterized by three difficulty levels. Assessments of task performance were conducted at varying intervals for 7 h after drug administration. Both drugs induced a rapid initial onset of impairment in the two age groups. Evidence of increased drug sensitivity in the elderly was provided by the more prolonged duration of the pharmacologic effect in the older than young subjects, especially for the harder versions of the SCT and DSS tasks. In summary, the data provide support for the hypothesis of an age-related decline in the adaptive capacity to inhibit adverse drug effects.

Adult↗
PubMed1990

Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines. II. Triazolam.

This study compares the time course of triazolam effects on psychomotor and cognitive skills with triazolam plasma concentrations in a combined pharmacokinetic-pharmacodynamic (sigmoid-Emax) model. Ten male subjects received a single oral dose (1 mg) of triazolam or placebo. The CNS impairment effects were measured by using computerized tracking, body sway, and digit symbol substitution tests, and triazolam plasma concentration was measured by gas chromatography. The drug-induced effect changes lagged behind the plasma drug level changes. The magnitude of the time lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma triazolam levels (t 1/2 keo). Essentially the same t 1/2 keo (approximately 6 min) was found for subcritical tracking, body sway, and digit symbol substitution tests. When using the predicted drug concentrations at the effect site, the hysteresis of the plasma concentration-effect disappears, suggesting that the hysteresis is not caused by drug induced tolerance. Moreover, the model allows for estimation of the effect site concentration that causes one-half of the maximal predicted effect (EC50, approximately 5 ng/ml) which is a measure of an individual's sensitivity to triazolam. On the basis of the EC50 values of the effect measures, body sway was slightly less sensitive to triazolam than subcritical tracking and digit symbol substitution tests.

Adult↗
PubMed1990

Comparison of central nervous system and peripheral pharmacodynamics to atropine pharmacokinetics.

Two experiments were designed to examine the pharmacokinetic-pharmacodynamic relationship for the central nervous system and peripheral effects of atropine. According to a random Latin square design, healthy young male volunteers were given i.m. injections containing single doses of placebo or 0.5, 1.0, 2.0 or 4.0 mg of atropine. The central nervous system tests included wheel tracking, a coordination task, and digit symbol substitution, a memory-psychomotor speed task; the physiological variable was heart rate. The pharmacokinetics of atropine were best described by a two-compartment model with very rapid first order absorption. Changes in plasma atropine levels and heart rate closely overlapped for all four doses throughout most of the time course. In contrast, the differential time course of changes in atropine levels and behavioral impairment indicates that pharmacokinetics is not the primary rate-limiting mechanism for the central nervous system effects of atropine. Alternative explanations are discussed, including differential atropine effects on peripheral M2 receptors mediating a heart rate effect and on CNS M1 receptors mediating the memory-psychomotor effect.

Adult↗
PubMed1987

Comparison of the effects of quazepam and triazolam on cognitive-neuromotor performance.

The pharmacological activity of quazepam, a BZ1 specific benzodiazepine, was compared to the effects of triazolam, a BZ1, BZ2 nonspecific benzodiazepine. Using a double-blind procedure, single oral doses of quazepam (15 or 30 mg), triazolam (0.5 or 1.0 mg) and placebo were administered to 21 healthy young men according to a random Latin square design balanced for order of drug administration. The drug effects on the performance of motor coordination and cognitive tasks were monitored for 7 h following drug ingestion. The results did not indicate any differential effects on cognitive-neuromotor performance for the BZ1 specific quazepam and 2-oxoquazepam compared with the BZ1, BZ2 nonspecific N-desalkylflurazepam metabolite. The impairment magnitude for 30 mg quazepam was closer to that of 0.5 mg triazolam. The onset of the initial drug effect was considerably slower for quazepam than for triazolam. The time course of the impairment profiles for the tasks was compared to pharmacokinetic data from previous studies and suggested that published pharmacokinetic rate constants explain only a limited portion of the impairment time course. In particular, the performance scores were already showing recovery from peak impairment 2 h post-drug ingestion, although quazepam's potent N-desalkylflurazepam metabolite has been found to maintain a maximum plateau level from 2 to 24 h.

Adult↗
PubMed1987

Benzodiazepine pharmacodynamics: evidence for biophase rate limiting mechanisms.

Pharmacokinetics do not adequately reflect recovery from cognitive neuromotor impairment induced by most benzodiazepines. This paper examines across time the nature of the relationship of effect to serum concentration of three benzodiazepines. Using the same protocol lorazepam, alprazolam, diazepam and placebo were administered to eight healthy males at doses of 0.057, 0.029, 0.286 and 0.000 mg/kg, body weight, respectively for the first study and at 0.028, 0.014, 0.143 and 0.000 mg/kg, respectively, for the second study. After each dose administration multiple measurements were made over a period of 5.5-11.5 h using two different psychomotor performance tests. Serum drug concentrations were also measured. The profiles for diazepam and alprazolam effects demonstrate a stepwise decrement in the slopes of the concentration versus response curves across time, illustrating the rapid development of acute tolerance. In contrast, lorazepam induced a remarkably constant relationship between concentration and effect across testing intervals.

Adult↗
PubMed1987

Differential CNS effects of diazepam in elderly adults.

The present study examines the effects of 0.07, 0.14 and 0.21 mg/kg of diazepam on the performance of several cognitive and neuromotor tasks, including wheel tracking, digit symbol substitution and standing steadiness. The drug or placebo was administered at 3-week intervals to healthy elderly men (N = 8) and women (N = 8). Both medium and high doses significantly impaired performance on the cognitive tasks, whereas only the latter dose induced similar impairment effects on the neuromotor tasks. Wheel tracking and standing steadiness displayed rapid onset and offset of the drug effect, while acute tolerance developed at a considerably slower rate on the digit symbol substitution tasks. Specifically, the subjects continued to show poorer cognitive performance for over 3 hours after dosing, but were no longer impaired on the basically neuromotor skills at 3 hours.

Aged↗
PubMed1985

Comparative pharmacokinetics and pharmacodynamics of lorazepam, alprazolam and diazepam.

The contribution of differential absorption-distribution pharmacokinetics to drug activity can be partially determined by comparing simultaneous estimates of drug serum level with pharmacodynamic effects. In the present paper we have contrasted the effects of clinically equipotent doses of lorazepam, alprazolam, and diazepam on the performance of tracking and digit symbol substitution tasks. Eight young males were tested for 12 h after ingesting the drug. The three benzodiazepines and placebo were administered to each subject according to a balanced double-blind Latin square design. A model is presented that describes the relationship between drug concentration and the degree of impairment across time after the final peak effect. Exponential rate constants were determined for each drug using a Marquardt nonlinear fit of the pooled data. Basically, the constants relate offset serum drug values to the impairment curves at a time when serum-brain equilibrium is assumed to have occurred. The values indicate markedly rapid acute tolerance for alprazolam and diazepam but relatively little acute tolerance for lorazepam. Whether these constants reflect adaptation or differential association-dissociation receptor rate constants cannot be determined, but they do highlight the need to consider receptor kinetics as an important factor in benzodiazepine pharmacodynamics.

Adult↗
PubMed1979

Hemispheric efficiency in middle and later adulthood.

Right and left hemisphere efficiency, as measured by dichotic memory for numbers, was assessed in a sample of older adults in Experiment I. Right hemisphere efficiency dropped off sharply with age, while left hemisphere efficiency did not show a significant decline. A second group of subjects was tested on a musical note recognition task in Experiment II. Regression analyses revealed significant age decrements in performance, regardless of ear/hemisphere involved. The writers suggested that the reported decline with age in spatial ability may result from an age related decline in right hemispheric functioning, even on tasks that are right hemisphere dominant. The lack of decline reported for verbal ability may be a consequence of the lack of decline in left hemisphere efficiency with regard to left hemisphere dominant tasks.

Adult↗