Daniel L. Azarnoff

Correlation between plasma diphenhydramine level and sedative and antihistamine effects

The sedative and antihistamine effects of diphenhydramine were assessed in relation to plasma concentration after placebo, diphenhydramine 50 mg intravenously, and diphenhydramine 50 mg orally to each of 6 healthy volunteers on three separate occasions. Diphenhydramine plasma elimination t½ was 3.0 to 4.3 hr, volume of distribution was 188 to 336 L, and clearance was 637 to 1,014 mllmin. Systemic bioavailability of the oral preparation ranged from 0.26 to 0.60. The sedative effect of intravenous diphenhydramine differed from that of placebo only during the first 3 hr. Antihistamine effect, as measured by reduction of histamine provoked skin wheal diameter, was significantly different from that of placebo for at least 8 hr. There was a positive correlation between plasma diphenhydramine level and sedative and antihistamine effects, but wide variation in the extent and rate of change of these effects were observed between the subjects. There appears to be a concentration range of 25 to 50 ng/ml, within which there is significant antihistamine effect without significant sedation.

The Effects of Urine pH and Plasma Protein Binding on the Renal Clearance of Disopyramide

SummaryTo ascertain whether the renal clearance of disopyramide (pKa = 8.36) is affected by urine pH, the disposition kinetics of disopyramide were compared during excretion of acidic and alkaline urine following both single dose intravenous (2 mg/kg) and oral (5mg/kg) administration to 4 healthy male volunteers. No significant difference was observed in the plasma concentration-time curve of disopyramide. The mean 72 hour recovery of disopyramide and its N-deisopropyl metabolite (MND) in urine was 55.1 and 20.3% of the dose respectively, with no apparent difference between the two routes of administration or pH of urine. Renal clearance of disopyramide was found to vary with time, which is partly the result of a concentration dependent change in plasma protein binding. The unbound fraction of drug in plasma varied from 0.32 to 0.72 between 0.4 to 4μg/ml concentration. However, time-dependent change in renal clearance of disopyramide persists even after correction for plasma protein binding.

Gynecomastia induced in normal males by spironolactone.

The short‐term (1 week) and long‐term (10 month) effects of spironolactone have been determined in normal males. There were no adverse effects or changes in plasma testosterone, luteinizing hormone, or progesterone levels during one week of treatment with spironolactone (200 mg/day) in 6 normal men. A continuous 4‐hr sampling technique to provide an integrated plasma sample resulted in plasma hormone concentrations similar to the mean values for intermittent sampling. There was considerable intraindividual variability in the levels of each hormone. To evaluate the long‐term effects of spironolactone, 30 normal males were randomly divided into three groups: placebo, 100 mg spironolactone per day (low dose), and 100 mg spironolactone per day increased at two months to 200 mg spironolactone per day (high dose). The study was double blind and lasted 10 months. The presence of gynecomastia was determined clinically and confirmed by thermography. Two metabolic clearance studies with either 3H‐testosterone or 3H‐androstenedione were obtained (1) just before spironolactone treatment and (2) again with the same steroid either the last day of the 10‐month treatment period or with the development of gynecomastia. The concentrations of testosterone, estradiol, estriol, luteinizing hormone, follicle stimulating hormone, progesterone, and prolactin were also determined before treatment and at two‐month intervals during treatment. Eighteen individuals received spironolactone (10 in the low‐dose group and 8 in the high‐dose group); of these, 8 developed gynecomastia. There were none in the placebo group. The incidence of gynecomastia was 30% in the low‐dose group and 62% in the high‐dose group. In addition, one individual in the high‐dose group discontinued taking the drug early because of decreased libido, bringing the incidence of adverse effects in this high‐dose group to 75%. Spironolactone induced no significant changes in the metabolic clearance of androstenedione or testosterone. Plasma concentrations of the various hormones did not change as a result of either spironolactone or the development of gynecomastia. Inhibition of testosterone synthesis or alteration in its metabolic clearance by spironolactone does not appear to be the cause of spironolactone‐induced gynecomastia in man.

Metabolic responses to plasma concentrations of theophylline

We investigated the effect of intravenous infusions of aminophylline on plasma glucose, insulin (IRI), glucagon (IRG), growth hormone (HGH), cortisol, and free fatty acid (FFA) levels in healthy young subjects. Six received an intravenous loading dose of aminophylline (6.0 mg/kg over 20 min) followed by a maintenance dose (0.9 mg/kg/hr) for 100 min. Another 7 subjects initially received smaller loading (3.0 mg/kg) and maintenance (0.45 mglkg/hr) doses, and after 60 min they received a second loading dose (3.0 mg/kg) followed by a larger maintenance dose (0.9 mg/kg/hr) over 120 min. In these fasting volunteers, infusion of aminophylline, which produced theophylline levels in the usual therapeutic range (10 to 20 µg/ml), caused small increases in plasma glucose levels without changing IRI, IRG, HGH, or cortisol. There were rapid, pronounced, and prolonged rises in FFA associated with the aminophylline infusion. Increases in FFA paralleled the rise in theophylline levels. It is concluded that routine therapeutic doses of theophylline, i.e., doses that achieve serum levels normally encountered in treatment for bronchial asthma, cause a marked rise in FFA and a slight rise in glucose (8 ± 3 mg/dl) without changing levels of IRI, IRG, HGH, or cortisol.

One‐year trials with halofenate, clofibrate, and placebo

The hypolipidemic as well as other laboratory and clinical effects of halofenate, clofibrate, and placebo were compared in 29 patients with type IV hyperlipoproteinemia in a double‐blind, controlled, therapeutic trial of 1 yr duration. Plasma drug levels were obtained to monitor compliance. Clofibrate and halofenate lowered serum triglycerides to a similar extent. The hypotriglyceridemic effect of halofenate was significant only when data from noncompliant patients were discarded. Only clofibrate lowered baseline levels of plasma cholesterol. Very low density lipoproteins were decreased and low density lipoproteins were increased by clofibrate but not by halofenate. Halofenate had a marked hypouricemic effect that was greater than that of clofibrate. The hypouricemic effect of halofenate and clofibrate was paralleled by a concomitant decrease in serum bilirubin. Abnormal increases in serum creatine phosphokinase were observed with both drugs primarily in patients who had abnormal initial levels.

Methapyrilene kinetics and dynamics

A study was undertaken to characterize the H1 receptor blockade, central nervous system depressant properties, and kinetic parameters of methapyrilene in man. Eight healthy subjects received, in random order at weekly intervals, placebo and methapyrilene 20 mg intravenously and 50 mg and 25 mg orally. Methapyrilene exhibited a moderate antihistaminic effect as measured by the reduction of histamine‐provoked skin wheals. Sedation and drowsiness were detected only at the first sampling time (0.75 hr) after intravenous doses. The terminal plasma half‐life ranged from 1.1 to 2.1 hr, apparent volume of distribution from 2.14 to 6.61 l/kg, and plasma clearance from 0.013 to 0.048 l/min/kg. Systemic bioavailability was low and showed large interindividual differences, ranging from 4% to 46%. Recovery of unchanged drug from the 24‐hr urine was under 2% of the doses.

Glutethimide and 4‐0H glutethimide: Pharmacokinetics and effect on performance in man

The relationship between the plasma concentration of glutethimide (G) and the change from baseline of the standard error of the mean (ΔSDE) of a tracking test was determined in 7 volunteers. There was excellent positive correlation (r = 0.9/) between log G and log ΔSDE and good correlation between log G and ΔSDE (r = 0.77). The metabolite, 4 hydroxyglutethimide, did not contribute significantly to the effect of G administered in therapeutic doses. No trend in performance versus level was found with 5 other tests (finger tapping, card sorting, digit substitution, subtraction, and subjective perception of drowsiness). Although the numbers were small, when the volunteers were divided into smokers (3) and nonsmokers (4) G decreased tracking ability to a greater extent in smokers than in nonsmokers.

The interaction between halofenate and propranolol

The effect of halofenate on beta adrenergic blockade by propranolol was studied in 4 subjects during chronic drug administration in a randomized, double‐blind study. The plasma propranolol concentration was significantly lower during treatment with halofenate than with placebo. The reduction in propranolol levels correlated with a decrease in beta adrenergic blockade. The mechanism for the decrease in plasma concentration has not been determined.

Insecticides: effect on drug metabolism.

The effects of chlorinated organic insecticides on the half‐life and rate of elimination of a variety of drugs were studied in laboratory animals; observations were made in humans occupationally exposed and in birds environmentally exposed to pesticides. Species differences are reported depending on the insecticide tested: DDT decreased hexobarbital sleep time of rats but had no effect in mice, which did respond similarly when treated with chlordane. All isomers of DDT as well as their metabolites were potent inducers of hepatic microsomal drug‐metabolizing enzymes in rats. In treated dogs, plasma elimination half‐life of hexobarbital was shortened, but the half‐life of pentobarbital was lengthened. Exterminators exposed to a mixture of chlorinated organic pesticides, showed significantly shorter antipyrine plasma elimination half‐lives as contrasted to office personnel from the same company. Similar observations were made on workers in a DDT factory, with decreasing plasma half‐lives of phenylbutazone as compared with findings in a control group. Induction of mixed Junction oxidase (MFO) activity by chlorinated insecticides was associated with frequency of eggshell breakage and decreased eggshell weight in breeding birds, e.g., falcon, sparrow hawks, and others with a declining population. It was postulated that the eggshell defects resulted from altered metabolism due to excess steroid inactivation secondary to induction of MFO activity.

Quantitation of chlordiazepoxide and its metabolites in biological fluids by thin-layer chromatography

Chlordiazepoxide and its 4 major metabolites were assayed after separation by thin-layer chromatography following extraction from biological fluids. The compounds become intensely fluorescent in the presence of red, fuming nitric acid. The resulting compounds are quantitated with a spectrodensitometer with a fluorescent attachment. The sensitivity varies between 0.05 and 0.1 microgram. The coefficient of variation is 1.4% for assays in urine and 6.4% in serum.