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Biomedical subjects

J S Harmatz

Publications and source records attributed to J S Harmatz.

At least 19 recordsLinked to original sources
PubMed1992

The pharmacokinetics and pharmacodynamics of sublingual and oral alprazolam in the post-prandial state.

We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study. The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes. Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography. Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P less than 0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng.ml-1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h.ng.ml-1. Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h. In general the two routes were significantly different from placebo but not from each other.

Administration, Oral↗
PubMed1992

Pharmacokinetics and pharmacodynamics of oral diazepam: effect of dose, plasma concentration, and time.

Eleven healthy subjects received single oral doses of placebo, 2 mg diazepam, 5 mg diazepam, and 10 mg diazepam in a randomized four-way crossover study. Plasma diazepam levels, the Digit Symbol Substitution Test (DSST), and fraction of total electroencephalographic (EEG) amplitude falling in the sigma plus beta (13 to 31 Hz) frequency range were determined during the 12 hours after drug administration. Peak plasma diazepam concentration and area under the 12-hour curve were proportional to dose; time of peak was independent of dose. Baseline percentage of EEG amplitude falling in the 13 to 31 Hz range averaged 15.7% and did not differ among the four trials. The percentage of EEG amplitude falling in the 13 to 31 Hz range did not change over baseline with placebo or 2 mg diazepam but was increased 1/4 to 2 1/2 hours after 5 mg diazepam, (maximum, +7.3%) and 3/4 to 12 hours after 10 mg diazepam (maximum, +15.2%). The increase in the percentage of EEG amplitude falling in the 13 to 31 Hz range was highly correlated with plasma diazepam concentration. DSST scores for placebo and 2 mg diazepam were nearly identical. DSST decrements with 5 and 10 mg diazepam paralleled and were correlated with the changes in the percentage of EEG amplitude falling in the 13 to 31 Hz range and with plasma diazepam levels. Thus the EEG analysis provides objective quantitation of benzodiazepine central nervous system effects, in turn reflecting plasma levels and other clinical measures.

Administration, Oral↗
PubMed1992

Fluoxetine impairs clearance of alprazolam but not of clonazepam.

Volunteer male subjects received single 1.0 mg oral doses of alprazolam and of clonazepam on two occasions, during coadministration of 40 mg/day fluoxetine or of placebo. When the sequence of trials was placebo first and fluoxetine second, fluoxetine coadministration significantly prolonged alprazolam half-life (20 versus 17 hours) and reduced clearance (48 versus 61 ml/min). No effect of fluoxetine was seen when fluoxetine was given first and placebo second, because norfluoxetine persisted into the placebo phase even though fluoxetine had been discontinued 2 weeks earlier. Fluoxetine had no significant effects on clonazepam elimination half-life or clearance regardless of the sequence of fluoxetine and placebo administration. In the fluoxetine-placebo sequence, fluoxetine significantly increased the rate of clonazepam absorption. Thus fluoxetine appears to impair clearance of alprazolam by way of microsomal oxidation but does not alter clearance of clonazepam by way of nitroreduction. The very slow elimination of norfluoxetine should be considered in the design of clinical or pharmacokinetic studies that involve fluoxetine.

Adolescent↗
PubMed1979

Lorazepam kinetics in the elderly.

Lorazepam is a 3-hydroxy-1,4-benzodiazepine derivative biotransformed by glucuronide conjugation, followed by urinary excretion of the glucuronide metabolite. The kinetic properties of single 1.5- to 3.0-mg doses of intravenous lorazepam were assessed in 15 healthy elderly subjects, 60 to 84 yr of age, and in 15 healthy young subjects, 19 to 38 yr of age. Volumes of distribution for lorazepam in the elderly group (mean, 0.99 1/kg), were slightly but significantly smaller than in the young group (1.11 1/kg), suggesting less extensive drug distribution in the elderly. Values of elimination half-life (t1/2beta) in the elderly (15.9 hr) did not differ significantly from those in the young group (14.1 hr), but total clearance in the elderly (0.77 ml/min/kg) was 22% less (p less than 0.05) than in the young subjects (0.99 ml/min/kg). Age differences in lorazepam clearance were partly explained by more frequent cigarette smoking in the young subjects. Gender had no apparent relationship to kinetics. The rate and completeness of absorption of intramuscular (IM) and oral loraxepam was assessed in 10 of the elderly subjects. Deltoid IM injection and oral administration of tablets in the fasting state led to rapid absorption of lorazepam into the systemic circulation. Peak plasma lorazepam concentrations were always reached within 2.5 hr, and values of absorption half-life (t1/2a) did not exceed 45 min. Absorption of IM and oral lorazepam was 80% to 100% complete. Thus, the aging process is associated with small changes in the kinetics of lorazepam. IM and oral administration of lorazepam in elderly persons, as in the case of young individuals, leads to rapid and nearly complete absorption into the systemic circulation.

Absorption↗
PubMed1979

Self-rated sedation and plasma concentrations of desmethyldiazepam following single doses of clorazepate.

Plasma concentrations of desmethyldiazepam (DMDZ) and intensity of self-rated sedation (SRS) were measured at multiple points in time during 6 h after a single 15 mg oral dose of clorazepate dipotassium. Mean plasma DMDZ levels and mean SRS scores both became maximal at 1.0--2.5 h after drug dosage. By 6 h, however, mean SRS had returned to the predrug baseline score while mean DMDZ concentration fell only slighty from the maximum value. Disappearance of SRS despite persistence of high DMDZ levels might be due to adaptation or tolerance. If this is the case, subjective effects of benzodiazepines may depend upon duration of drug exposure as well as dose and concentration.

Adult↗
PubMed1979

Diagnosis and lithium treatment of affective disorder in the retarded: five case studies.

The authors report on five institutionalized retarded patients who had symptoms strongly suggestive of manic-depressive illness and who showed significant symptom reduction in a single-blind placebo-controlled three-year trial of lithium. The number of illness episodes was reduced, and symptoms decreased in all major illness dimensions. These findings indicate that major affective disorder can be both diagnosed and treated in individuals with primary mental retardation.

Adult↗
PubMed1979

Correlates of outcome following acute glutethimide overdosage.

Potential predictors of outcome following acute glutethimide overdosage were assessed in 63 patients hospitalized with this diagnosis at a large urban medical center between 1962 and 1975. Their mean age was 34 years (range, 15 to 84 years) and 62% were female. Assisted ventilation was required in 59% of cases, and 32% developed hypotension. Six patients died, including all three aged 60 years or older. Multiple regression analysis confirmed that age was the major identifiable determinant of survival, regardless of other factors. Among identifiable determinants of coma grade, glutethimide dose, glutethimide plasma concentration, and coingestion of barbiturates were the most important. An ingested dose of 10 g or more, or a plasma concentration exceeding 30 microgram/ml, was almost always associated with deep coma. However, a relatively small ingested dose or a low plasma level by no means ruled out development of serious intoxication, particularly in those patients who also ingested barbiturates. Thus elderly individuals are at high risk for fatal outcome following glutethimide overdosage and should receive priority for intensive care and monitoring. Glutethimide dose, plasma concentration, and history of coingestion of barbiturates are of value in predicting development of deep coma. These items of information should be obtained on admission whenever possible.

Adolescent↗
PubMed1978

Impaired absorption of desmethyldiazepam from clorazepate by magnesium aluminum hydroxide.

Ten healthy volunteers ingested single 15-mg doses of clorazepate dipotassium (CZP) with 60 ml of water, or with 60 ml of magnesium aluminum hydroxide (Maalox), on two occasions in a randomized, two-way crossover study. Plasma concentrations of desmethyldiazepam (DMDZ) were determined in multiple samples drawn during 48 hr after each dose. Mean kinetic variables for DMDZ in CZP-water and CZP-magnesium aluminum hydroxide treatment conditions, respectively, were: peak measured concentration, 273 and 188 ng/ml (p 0.001); time of peak concentration, 1.8 and 2.8 hr after dose (p less than 0.01); apparent absorption half-life, 14.8 and 30.7 min (p less than 0.02); area under the 48-hr plasma concentration curve, 6,028 and 5,433 ng/ml X hr (p less than 0.02). Self-rated sensations of feedling "spacey," "thinking slowed down," and of generalized sedation, were reported with both treatment conditions, but these subjective effects occurred earlier and were more profound when CZP was taken with water as opposed to magnesium aluminum hydroxide. Thus administration of single doses of CZP with usual doses of a commonly prescribed antacid reduces the rate and extent of appearance in blood of DMDZ (the compound responsible for clinical activity) and attenuates self-rated clinical effects.

Adult↗
PubMed1978

Dose-independent pharmacokinetics of digoxin in humans.

Nine healthy male volunteers received single 0.5, 1.0, and 1.5 mg. doses of intravenous digoxin in a randomized three-way crossover study. Multiple venous blood samples were drawn during 35 hours after each dose, and all urine was collected for 6 consecutive days. Concentrations of digoxin in serum and urine were determined by radioimmunoassay. Over-all mean values for kinetic variables were: distribution half-life, 0.35 hours; elimination half-life, 27.9 hours; volume of distribution, 5.46 liters/Kg; total clearance, 2.51 ml./min./Kg. The mean projected cumulative urinary excretion of digoxin was 70.1% of the dose; mean renal clearance of digoxin was 1.71 ml./min./Kg., not significantly different from creatinine clearance (1.50 ml./min./Kg.). None of the identifiable pharmacokinetic variables was significantly influenced by dose, suggesting that digoxin disposition is dose-independent in healthy individuals.

Adult↗
PubMed1978

Sex differences in diazepam protein binding in patients with renal insufficiency.

Sex differences in the extent of binding of diazepam to plasma protein were assessed in a series of patients with renal insufficiency previously described by Kangas et al. Among identifiable independent variables, sex alone accounted for the greatest proportion of variability in percent unbound diazepam (r = 0.33), whereas age and serum creatinine accounted for practically none. The mean (+/- SE) percent unbound among females (10.8 +/- 2.8%) was larger (p less than 0.1) than among males (5.8 +/- 1.3%). Since only the unbound fraction of diazepam in plasma is available for pharmacologic activity, the intensity and duration of diazepam's clinical action in patients with renal insufficiency might differ between males and females.

Adolescent↗
PubMed1978

Factors influencing diazepam pharmacokinetics: age, sex, and liver disease.

Published data on the effect of cirrhosis on diazepam pharmacokinetics were reanalyzed to determine how age, sex, and body weight might have influenced the conclusions. Diazepam elimination half-life (t1/2beta) and weight-corrected volume of distribution (Vd) were significantly larger in patients with cirrhosis (n = 9) than in controls (n = 4). Weight-corrected diazepam clearance was significantly reduced in cirrhotics as compared with controls. Multiple stepwise regression analysis, however, revealed that age and liver disease were of approximately equal importance as determinants of t1/2beta. Age, sex, and liver disease all influenced Vd, but liver disease by far was the most important determinant of diazepam clearance. Thus age, sex, and body size can have an important influence on the pharmacokinetics of drugs, and should be included as independent variables in pharmacokinetic studies.

Adult↗
PubMed1978

Pharmacokinetics of chlordiazepoxide and metabolites following single and multiple oral doses.

Three healthy volunteers (2 male and one female) participated in single- and multiple-dose pharmacokinetic studies of oral chlordiazepoxide (CDX) hydrochloride. Following single 50-mg oral doses of CDX.HCl, absorption and elimination proceeded as apparent first-order processes. Values of absorption half-life were: 14.5, 189, and 18.9 minutes; elimination half-lives were: 7.6, 9.8, and 12.6 hours. Disappearance of CDX was mirrored by appearance of its first active metabolite, desmethylchlordiazepoxide (DMCDX). During once-daily ingestion of 50 mg of CDX.HCl, observed values of CDX accumulation half-life (0.0, 5.8, and 52.5 hours) differed substantially from values predicted based upon the single-dose study; pre-dose steady-state CDX blood concentrations also differed from the predicted values. Accumulation half-lives for the metabolite DMCDX were: 17.7, 9.9, and 15.8 hours. Accumulation in blood of a second active metabolite, demoxepam (DMX), proceeded with half-life values of 21.1, 34.2, and 78.5 hours. Minimum steady-state concentrations of DMCDX and DMX exceeded those of the parent compound. Thus accumulation and persistence of at least two active metabolites during long-term treatment with chlordiazepoxide renders the drug suitable for single-daily dose therapy of anxiety.

Adult↗
PubMed1977

Factors influencing blood concentrations of chlordiazepoxide: a use of multiple regression analysis.

Three groups of male and female subjects aged 24-74 years received 25, 100, or 200 mg of chlordiazepoxide hydrochloride by mouth as a single dose or as two divided doses. The relation of plasma or whole blood concentrations for chlordiazepoxide (CDX) and its metabolite, desmethylchlordiazepoxide (DMCDX), to time since the last dose, weight, age, and sex were determined by simple and multiple regression analyses. Both CDX and DMCDX levels were negatively correlated with weight. Concentrations of CDX decreased, while those of DMCDX increased, with the time since the last dose. Lower levels of both drugs were associated with female sex, and lower levels of DMCDX were noted with increasing age. In the largest sample group, age and weight were more important variables than sex in accounting for CDX and DMCDX. Sex was of significance, and more important than time or age in explaining the variance of CDX in one series of observations. Multiple regression analysis is a useful approach to assessing interrelated factors influencing blood levels of drugs, especially when combined with a consideration of the interactive components of variance. Age and sex, in addition to weight and time, may be important factors that deserve further attention.

Adult↗