Multiple-dose halazepam kinetics.

Halazepam is a benzodiazepine used in the management of anxiety disorders or short-term relief of anxiety. Our study was undertaken to evaluate its steady-state kinetics and those of its major active plasma metabolite N- desalkylhalazepam . Eleven healthy men aged 19 to 35 yr were given oral, 40-mg halazepam tablets every 8 hr for 14 days. Plasma samples were analyzed by gas chromatography to determine levels of halazepam and N- desalkylhalazepam . Halazepam kinetics can best be described by a two-compartment open model with first-order absorption kinetics. The elimination phase t1/2s of halazepam and N- desalkylhalazepam were 34.7 and 57.9 hr. Steady-state levels were predictable from kinetic data and were reached by the third day for halazepam and by the eleventh day for N- desalkylhalazepam .

Multiple-dose quazepam kinetics.

Quazepam, a benzodiazepine hypnotic, was studied in normal subjects to evaluate steady-state kinetics of quazepam and of its major active plasma metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam, after 15 mg once daily by mouth for 14 days. The kinetics of quazepam and 2-oxoquazepam can be best described by a two-compartment open model with first-order absorption/formation kinetics. Quazepam was rapidly absorbed and its two major plasma metabolites appeared very quickly in systemic circulation. The elimination t 1/2s of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were 41, 43, and 75 hr. Steady-state levels were predictable from the kinetic data and were reached by the seventh dose for quazepam and 2-oxoquazepam and by the thirteenth dose for N-desalkyl-2-oxoquazepam. These kinetic profiles may explain the clinical hypnotic effect of quazepam--rapid induction of sleep and long duration of clinical action without appreciable rebound insomnia.

Excretion of quazepam into human breast milk.

Previous metabolic studies have established that two major metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam, are present in plasma after dosing with quazepam, a new benzodiazepine hypnotic. The excretion of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam into human breast milk was studied in four lactating nonpregnant volunteers. Each volunteer received one 15-mg quazepam tablet following an overnight fast. Nursing of offspring was discontinued after drug administration. Milk and blood samples were collected prior to and at specified times (up to 48 hours) after dosing. Plasma and milk levels of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were determined by specific GLC methods. The concentrations of the three compounds found in milk appeared to depend on their relative lipophilicities, which were determined by log P values. The mean milk/plasma AUC ratios of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were 4.19, 2.02, and 0.091, respectively. Levels of quazepam and 2-oxoquazepam declined at about the same rate in plasma and in milk. The total amount of the administered quazepam dose found in the milk as quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam through 48 hours was only 0.11 per cent.

Rising multiple-dose pharmacokinetics of labetalol in hypertensive patients.

Labetalol, a drug possessing both alpha- and beta-adrenergic blocking activities, is used in the treatment of hypertension. The current study was undertaken to elucidate the steady-state pharmacokinetics of labetalol following a rising oral multiple-dosage regimen. Twelve patients received oral labetalol every 12 hours for 18 days. An initial dose of 100 mg was increased at three-day intervals to 200, 300, 400, and 600 mg q12h. Selected blood samples were taken at various times following drug administration at each dose level and analyzed for labetalol levels by a specific high-performance liquid chromography assay. The pharmacokinetics of labetalol are best described by a two-compartment open model with first-order absorption. The half-lives of the absorption, distribution, and elimination phases are 0.6, 1.3, and 8.3 hours, respectively. The steady-state plasma drug concentrations are predictable from the pharmacokinetic data and are in good agreement with the observed values. Steady-state levels are reached by the third day at each dose level studied and increase proportionally with dose.

Phenytoin I: in vitro-in vivo correlation for 100-mg phenytoin sodium capsules.

Dissolution profiles for 11 brands of phenytoin sodium capsules were carried out by the basket and paddle methods (USP) and the spin-filter method. The results from the dissolution studies have been correlated with observed differences in in vivo parameters (Cmax and tmax). The dissolution by the basket method at 50 rpm in water gave a correlation greater than 0.9. The results suggest the existence of two types of phenytoin sodium products on the market.

Factors affecting serum oxytetracycline levels in beef calves.

Fifteen Aberdeen Angus steers, 295-364 kg, were dosed with either 4.4 or 11 mg of oxytetracycline hydrochloride/kg im. The antimicrobial activity of the serum was determined periodically, and the resulting data were treated statistically to determine the sources of variation. Variance in serum levels of oxytetracycline activity was attributed to dose, time of bleeding, order of dosing, animal, and assay. The total variance component was proportionately greater for the 11-mg/kg dose than for the 4.4-mg/kg dose. Animal variance increased with the higher dose level of oxytetracycline. The influence of dose on serum level was tested by applying a t test to the mean serum levels and their standard deviations at each bleeding time. The 4.4- and 11-mg/kg serum levels were significantly different (p less than 0.01) at all bleeding times. The 4.4-mg/kg serum levels mutliplied by 2.5 were not significantly different (p less than 0.05) from the 11-mg/kg serum levels at all bleeding times.

Dose-dependent absorption of disodium etidronate.

The gastrointestinal absorption of disodium etidronate (as [14C]disodium etidronate) was investigated in the rat proximal jejunum in-situ. Studies using various initial concentrations of the drug suggested that etidronate absorption occurred by passive diffusion at initial concentrations below 0.08 M. At initial concentrations above 0.08 M, the rate of absorption was significantly greater than would be expected if passive diffusion was the only mechanism responsible for absorption. Etidronate absorption is not mediated by the carrier mechanism responsible for phosphate ion absorption.

Disposition of sulfonamides in food-producing animals: pharmacokinetics of sulfamethazine in lambs.

Previously reported plasma and urine concentrations of unchanged sulfamethazine and 3 metabolites following intravenous administration of sodium sulfamethazine to young ewe lamb were fitted to a linear pharmacokinetic model in which sulfamethazine itself obeyed 1-compartment phamacokinetics. The average rate constant for overall elimination of sulfamethazine was 0.096 +/- 0.023 hours-1, corresponding to a biological half-life of 7.2 +/- 1.7 hours. The results of residue analysis of 8 tissues obtained at slaughter showed that tissue and plasma concentrations and urine output of unchanged sulfamethazine fell parallel throughout the experiment. The results indicate that determination of the plasma concentration or urinary output of sulfamethazine can be substituted for tissue residue analysis to determine contamination of carcasses above specified tolerance limits.

Suppression of histamine-induced wheal response by loratadine (SCH 29851) over 28 days in man.

Five groups of 12 healthy volunteers each received in double-blind, randomized fashion oral b.i.d. doses of 10, 20, or 40 mg loratadine, 12 mg chlorpheniramine maleate (CTM), or placebo for 28 days. Histamine and saline were injected intradermally into opposite arms at baseline and at specified times following treatment on days 1, 3, 7, 14, 21, and 28. Notable suppression of adjusted wheal formation (histamine-induced minus saline-induced) occurred within two hours after the first dose of each active treatment on day 1. In general, throughout the treatment period, suppression of adjusted wheal formation by all doses of loratadine was significantly greater than by placebo. Suppression by 10 mg loratadine was comparable to CTM, and 20 and 40 mg loratadine were significantly greater than CTM. Suppression of wheal formation by loratadine during the treatment period and during five days posttreatment were dose related. The continued effectiveness of loratadine throughout the 28 days suggests that tolerance to loratadine did not develop in this study. Sedation occurred in 8 of 12 subjects receiving CTM, 1 of 12 receiving 10 mg loratadine, and 1 of 12 receiving placebo.

Interspecies pharmacokinetic scaling of Sch 34343.

Pharmacokinetic parameters of Sch 34343 have been determined for mice, rats, rabbits, monkeys, dogs and humans and correlated among species as an exponential function of body weight. The pertinent pharmacokinetic parameters tested are apparent and steady-state volumes of distribution, total body clearance, elimination phase half-life, and mean residence time. This study showed that the extrapolation of animal data to humans on a new investigational drug, Sch 34343, can be potentially useful.

Pharmacologic evaluation of loratadine (SCH 29851), chlorpheniramine and placebo.

The antihistaminic effect of loratadine (160 mg) was compared in twenty-four normal male volunteers to chlorpheniramine maleate (4 mg) and placebo in a double blinded 3-way cross-over study of latin square design. After receiving single oral doses of each medication, the wheal response to serial 0.1 ml intradermal histamine (2 micrograms) and saline (control) injections were recorded over a 24-h period. The calculated wheal areas were compared to base-line measurements. The results were analyzed by analysis of variance. Loratadine exhibited a more pronounced inhibition of histamine wheal formation than placebo or chlorpheniramine maleate (p less than 0.003). In contrast to chlorpheniramine maleate which had a duration of action of only 3 h, loratadine inhibited the response for the entire observation period between 1 and 24 h post-dose. Although sedation was observed less frequently with loratadine (Placebo, n = 2; chlorpheniramine, n = 3; and loratadine, n = 1), the relative incidence were not statistically significant.