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Biomedical subjects

A H Hayes

Publications and source records attributed to A H Hayes.

18 recordsLinked to original sources
PubMed1979

Determination of propranolol and six metabolites in human urine by high-pressure liquid chromatography.

A method for the determination of propranolol and six of its metabolites, as well as their glucuronide and/or aryl sulfate conjugates in human urine is described. Propranolol and its basic and neutral metabolites are extracted into ether at pH 9.8, evaporated to dryness, reconstituted, separated on a reversed-phase, high-pressure liquid chromatographic system and quantitated using fluorescence detection. The aqueous urine aliquot is then made acidic and the acid metabolites extracted and measured using similar methods. The presence of 2% sodium metabisulfite in all urines collected is essential to ensure the stability of 4-hydroxy-propranolol during collection and storage. Preliminary data is presented from 24-h urine samples collected from three patients chronically receiving propranolol.

Chromatography, High Pressure Liquid↗
PubMed1979

Effect of coadministration of procainamide and isoniazid on each other's acetylation pathway.

The effect of isoniazid (INH) and procainamide (PA) on each other's acetylation pathway was studied in 7 normal subjects (3 rapid acetylators, 3 slow acetylators, 1 of indeterminate phenotype). Oral PA (6 mg/kg) was administered every 4 h for a total of seven doses. Following the final dose subjects received a single 300-mg oral dose of INH. Analysis of the parent drugs and their acetylated metabolites in plasma and urine revealed no effect on the acetylation of either drug. In 2 subjects (1 rapid, 1 slow acetylator) increasing doses of PA were given and the effect on INH (300 mg) acetylation measured. High mean circulating levels of PA (7.1 microgram/ml) appeared to inhibit acetylation of INH in the rapid acetylator whereas a mean PA plasma level of 8.6 microgram/ml had no effect on INH acetylation in the slow acetylator. However, the results from this study suggest that alterations of INH acetylation by PA are unlikely to be of clinical significance.

Administration, Oral↗
PubMed1979

Measurement of propranolol, 4-hydroxypropranolol and propranolol glycol in human plasma.

An HPLC method for the quantitative determination of propranolol, 4-hydroxypropranolol, and propranolol glycol in human plasma is described. The limits of sensitivity for the method were: 1 ng/ml propranolol; 5 ng/ml 4-hydroxypropranolol; and 1 ng/ml propranolol glycol. Data obtained from 6 healthy volunteers given a single 160 mg oral dose of propranolol revealed mean (+/- SEM) peak plasma levels of 31 +/- 10 ng/ml for 4-hydroxypropranolol and 9 +/- 2 ng/ml for propranolol glycol. These plasma levels were less than the peak concentrations recorded for propranolol (123 +/- 34 ng/ml. The rates of plasma decay of these two metabolites were greater than that observed for propranolol.

Chromatography, High Pressure Liquid↗
PubMed1978

Propranolol rebound--a retrospective study.

To assess the effects of sudden withdrawal of propranolol on inpatients with coronary artery disease, 102 patients admitted for cardiac catheterization were evaluated. Criteria for inclusion in the study were angiographically documented coronary artery disease, propranolol therapy at a mean daily dose of at least 80 mg and abrupt discontinuation of propranolol therapy before catheterization. There were 55 patients (mean age 52.5) who discontinued propranolol therapy (mean daily dose 127 mg) and a control group of 47 patients (mean age 53) who continued to receive propranolol (mean daily dose 143 mg). The criteria for morbidity were death, myocardial infarction or change in pain pattern. In the withdrawal group there were no deaths, one myocardial infarction judged to be related to catheterization and only one instance of a change in pain pattern. Thus, propranolol rebound appears to occur infrequently among hospitalized patients with reduced activity.

Adult↗
PubMed1978

The contribution of propranolol metabolites to the fluorometric assay of propranolol in human plasma.

1. Studies were undertaken to determine the fluorescent properties of several propranolol metabolites under the conditions of the fluorometric propranolol assay. Of the metabolites studied, propranolol glycol and N-desisopropylpropranolol had significant molar fluorescent coefficients relative to propranolol (72 and 79% respectively). N-desisopropylpropranolol was extracted with the same efficiency as propranolol (greater than 90%) wheras the glycol metabolite had only 34% extraction efficiency. Addition of each metabolite to samples of human plasma containing propranolol produced the predicted increase in fluorescent intensity. 2. Gas chromatographic analysis of plasma collected from 22 hypertensive patients chronically receiving oral propranolol revealed low concentrations of propranolol glycol and N-desisopropylpropranolol relative to propranolol. The results of these studies indicate that fluorescent metabolites of propranolol are not present in sufficient concentration to significantly interfere with the fluorometric assay of propranolol.

Chromatography, Gas↗
PubMed1978

The effect of hydralazine and other drugs on the kinetics of procainamide acetylation by rat liver and kidney N-acetyltransferase.

The objectives of this study were to investigate 1) the tissue distribution of procainamide acetylase activity in the rat and 2) the kinetics of procainamide acetylation by rat liver and kidney N-acetyltransferase and 3) to determine the effect of drugs thought to be similarly acetylated on procainamide acetylation. The cytosol fraction (100,000 X g) of tissue homogenates served as the source of N-acetyltransferase. Of the tissues studied the liver possessed the greatest acetylase activity followed by the kidney, lung, intestine and spleen. The apparent procainamide Michalis constant (Km) for liver and kidney was 2.03 X 10(-4) and 2.09 X 10(-4) M in the presence of 4.2 X 10(-4) M acetyl CoA. The liver Km for procainamide with "infinite" acetylCoA concentration was 4.36 X 10(-3) M. The liver Km for acetyl CoA in the presence of "infinite" PA concentration was 2.44 X 10(-3) M. Hydralazine, para-aminobenzoic acid, isoniazid, and sulfapyridine competitively inhibited procainamide acetylation by liver and kidney N-acetyltransferase.

Acetylation↗
PubMed1978

The quantitative disposition of procainamide and N-acetylprocainamide in the rat.

The objectives of this study were to investigate: 1) the rat acetylator phenotype, 2) the systemic availability of oral procainamide (PA), 3) the kinetic disposition of PA and its N-acetyl metabolite (NAPA) and 4) the relationship between PA dose and steady-state blood PA and NAPA levels. The rat acetylator phenotype seems to be monomorphic in type. The systemic availability of PA was estimated to be 78%. The half-life (T 1/2) of PA elimination was 55 minutes and that of NAPA was 51 minutes. PA clearance was 64 ml/kg/min and NAPA clearance 22.4 ml/kg/min. The apparent distribution volume for PA was 4.92 liters/kg and for NAPA 1.64 liters/kg. Acetylation accounted for 38% of PA disposition, urinary excretion 34% and other metabolism 28%. Urinary excretion of NAPA accounted for 72% of administered drug. Steady-state blood PA levels showed a linear increase with dose whereas NAPA did not. The latter observation suggests saturation of PA acetylation at higher PA doses.

Acetylation↗
PubMed1978

The effect of isoniazid and other drugs on the acetylation of procainamide in the intact rat.

The effects of isoniazid (INH), hydralazine, salicylazosulfapyridine, and sulfapyridine on the quantitative disposition of procainamide (PA) in the intact rat were examined. A dose-dependent inhibition of PA acetylation was observed after coadministration of PA with INH via nasogastric intubation. The 24-hr urinary excretion of N-acetylprocainamide was noted to decline in the presence of INH whereas that of the unchanged drug exhibited a coincident rise. A reduction in the systemic clearance of PA and a prolongation in its half-life of elimination was also observed. INH increased PA hepatic levels and decreased N-acetylprocainamide hepatic content. In contrast hydralazine affects not only PA acetylation but also its absorption rate and transformation by other metabolic pathways. Salicylazosulfapyridine did not affect PA acetylation whereas high doses of sulfaphridine did.

Acetylation↗
PubMed1977

Studies on the uptake and binding of propranolol by rat tissues.

The tissue distribution of propranolol after i.v. administration (1.5 and 7.5 mg/kg) was studied in rats. Lung, brain and kidney showed extensive propranolol tissue binding. Propranolol uptake by lung seemed to be a saturable process. In contrast to the above tissues, liver propranolol concentrations remained low over the time period of study. An increase in the propranolol T1/2 was noted at the high dose and seemed to result from reduced systemic clearance and an increase in the apparent volume of distribution. Microsomal and mitochondrial fractions from several tissues contained substantial amounts of propranolol after i.v. administration and in vitro incubation with homogenates. Cytosol proteins did not bind significant amounts of propranolol. Equilibrium dialysis studies with rat liver mitochondrial and microsomal fractions revealed both high affinity, low capacity propranolol binding sites and low affinity, high capacity sites. At low concentrations, propranolol interaction with rat liver microsomes produced a type I difference spectrum with high affinity binding of similar magnitude to that observed with equilibrium dialysis. Higher concentrations of propranolol produced a saturable shift in the difference spectra with reduced binding affinity for propranolol. Results from these studies indicate that particulate fractions from several tissues contribute to the extensive tissue binding of propranolol.

Animals↗
PubMed1976

Plasma and urinary aldosterone measurement in healthy subjects with a radioimmunoassay kit not requiring chromatography.

We examined the application of a radioimmunoassay kit, not requiring chromatography, to the measurement of aldosterone in healthy human subjects. Plasma aldosterone, urinary aldosterone, and plasma renin activity measurements were performed on samples from 47 subjects under conditions in which dietary sodium intake, posture, and times of sample collection were rigidly controlled. Nomograms are presented to illustrate the continuous, rather well defined, inverse relationship between 24 h sodium excretion and aldosterone measurements in plasma and urine. Mean plasma and urinary aldosterone values for subjects on normal sodium diets were 0.332+/-0.211 nmol/liter and 36.6+/-18.6 nmol/24 h and agreed well with previously reported values. A significant (p less than 0.05 increase in 24 h urinary aldosterone, plasma aldosterone and plasma renin activity resulted with decreased dietary sodium intake and conversely, a significant (p less than 0.05) decrease in each hormone occurred with increased dietary sodium intake. Rising from the supine to upright position resulted in a 230% increase in plasma aldosterone concentrations and a 284% increase in plasma renin activity.

Aldosterone↗
PubMed1976

Persistence of biologic activity after disappearance of propranolol from the serum.

In order to evaluate the duration of the biologic effects of propranolol after the drug was discontinued, we evaluated a variety of noninvasively determined hemodynamic parameters. Significant depression was found in the heart rate (18 per cent), cardiac output (13 per cent) (determined echocardiographically), and the triple product of blood pressure, heart rate, and systolic ejection time (16 per per cent) during administration or propranolol (200 mg. per day) to 9 normal volunteers. Significant depression of these parameters was present 12 hours after discontinuing the drug. By 12 hours, serum propranolol levels had returned 90 per cent toward their base line; however, at the same time, the heart rate and cardiac output had returned only 19.4 and 14.3 per cent toward their base-line values, and the triple product had returned 41 per cent toward its baseline. By 36 hours no biologic effect was seen. Thus if propranolol were discontinued 2 days prior to cardiac surgery, no significant biologic effect would remain to complicate the patient's postoperative course.

Adult↗