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Biomedical subjects

W A Mahon

Publications and source records attributed to W A Mahon.

At least 37 records · Page 2Linked to original sources

Approach to drug therapy for hypertension.

Prevention of complications of hypertension requires the lowering of blood pressure. The therapeutic goal is to achieve and maintain a diastolic pressure of less than 90 mm Hg with minimal adverse effects. The treatment of patients with established diastolic blood pressures between 90 and 104 mm Hg (determined from three separate readings) should be individualized; general measures such as weight loss and salt restriction should be tried first as an alternative to drug therapy. Patients with diastolic pressure in excess of 104 mm Hg should be treated with antihypertensive drugs; the first step should be the use of a thiazide diuretic in addition to general measures. Patients with diastolic pressures of 90 to 115 mm Hg may require the addition of a beta-adrenergic-receptor antagonist, methyldopa or clonidine if the therapeutic goal is not achieved; rarely they require the further addition of hydralazine or prazosin. Patients with diastolic pressures of 116 to 129 mm Hg usually require initially both a thiazide diuretic and a beta-blocker, methyldopa or clonidine; if the therapeutic goal is not achieved, hydralazine or prazosin is added, and if a further hypotensive effect is required guanethidine can be added. Patients with severe hypertension (diastolic pressures greater than 130 mm Hg) may require urgent treatment with combinations of drugs of all three levels. Emphasis should be placed on individualized therapy and patient compliance in the assessment of therapeutic failures. These "step-care" guidlines represent a framework for antihypertensive therapy devised from information available in 1977. It is not a rigid scheme and should be adjusted to the individual patient to ensure as normal a life as possible.

Adrenergic beta-Antagonists↗

High performance liquid chromatographic analysis of cimetidine in serum.

A rapid and reliable micro procedure for the high pressure liquid chromatographic analysis of cimetidine. N"-cyano-N-methyl-N'-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]guanidine, in serum or plasma is described. The percentage analytical recovery of cimetidine and internal standard (beta-hydroxypropyl-theophylline) was 65 and 99%, respectively. The between-day precision of the method at cimetidine serum concentrations of 2,000, 1,000, and 500 microgram/liter yielded coefficients of variation of 10.6, 11.5, and 10.6%, respectively. The method has been used in preliminary studies to determine the serum concentrations in patients receiving the drug by both the oral and intravenous route.

Chromatography, High Pressure Liquid↗

Phenacetin concentrations in portal and hepatic venous blood in man.

After intra-gastric or intra-duodenal administration of phenacetin (200 mg in solution), concentrations of phenacetin and its 0-dealkylated metabolite, acetaminophen, in portal and hepatic veins and in peripheral blood were monitored. A sharp increase in the portal concentration of phenacetin indicated rapid absorption. The concentration ratio of acetaminophen to phenacetin in early portal blood was 0.01--0.11 and lower than the ratio in hepatic vein. The hepatic extraction ratio of phenacetin was calculated to be 0.59--0.78. It is concluded that 0-dealkylation occurs mainly in the liver and only to a limited extent in the gastrointestinal wall.

Acetaminophen↗

Metabolism of flurazepam by the small intestine.

The metabolism of flurazepam-5-14C has been studied in man following catheterization of the portal and hepatic veins. Flurazepam was administered through a tube into the stomach in one patient and into the duodenum in two patients. Thin-layer chromatographs of portal vein blood showed that there was a rapid and early appearance of metabolites of flurazepam consistent with the metabolism of the flurazepam by the intestinal mucosa and at times when the concentrations in the hepatic vein and peripheral blood were very much lower than those in the portal vein. The major metabolites identified in portal vein blood were the mono- and didesetyl metabolies of flurazepam. Considerable hepatic uptake of flurazepam and its metabolites occurred, as evidenced by the lower concentrations of the parent compound and metabolites in the hepatic vein. Thus, "first-pass" metabolism of flurazepam following oral administration occurs in the small bowel mucosa of man as well as in the liver.

Adult↗

Hemagglutination inhibition assay for gentamicin.

A rapid and simple hemagglutination inhibition test for measuring gentamicin concentrations in serum has been developed. Correlation coefficients for this assay with the radioimmunoassay and microbiological assay were r = 710 and r = 0.864, respectively. Measurements of gentamicin levels in serum by the three methods showed no statistically significant differences. The hemagglutination inhibition assay is fast, reliable, and relatively inexpensive, and should prove valuable for laboratory use.

Biological Assay↗

Prinzmetal's angina with coronary artery spasm. Angiographic, pharmacologic, metabolic and radionuclide perfusion studies.

We studied the effects of coronary artery spasm on perfusion of the microvasculature in a patient with Prinzmetal's angina. Intracoronary injections of 99mTc and 131I-labelled macroaggregated human serum albumin were performed (1) at rest, (2) during spontaneous angina, (3) after the administration of nitroglycerin and (4) during pacing-induced spasm and the resultant scans compared. The resting scan was normal. Pain and spasm were associated with a perfusion defect that was localized to the anterior and inferior walls of the left ventricle. The localization of the perfusion defect corresponded with angiographically demonstrated spasm involving left anterior descending and distal circumflex coronary arteries. A subsequent myocardial infarction was localized by 43K scanning to the same perfusion area. Metabolic and parasympathetic stimulation studies were performed but were inconclusive. The patient's recurrent pains were ultimately controlled with large oral doses of isosorbide dinitrate.

Angina Pectoris↗

Biliary elimination of diazepam in man.

The metabolism of 14C-5-diazepam has been studied in 5 patients with T tube biliary drainage. A single bolus of 40 to 50 muCi was given intravenously and blood, urine, and bile were analyzed from 5 to 14 days. The mean half-life of elimination from blood was 93.2 hr; the major metabolite noted in blood was N-desmethyl-diazepam. In urine the average recovery of radioactivity was 48.9% and consisted of 3 OH-diazepam, 4'OH-diazepam, and oxazepam. In bile the average recovery of radioactivity was 5.35% (corrected to a bile flow of 700 ml was 15.0%) and consisted of the same metabolites as in the urine. Essentially no diazepam or N-desmethyl-diazepam was found, and therefore an enterohepatic circulation cannot be held to account for the prolonged half-life of these substances in man.

Adult↗

Disposition kinetics of two oral forms of quinidine.

There are relatively few studies on the disposition properties of quinidine. We have studied in 10 normal subjects conventional quinidine sulfate and a slow-release quinidine bisulfate. Single and repetitive doses were given; blood and urine concentrations were measured by the method of Cramer and Isaakson. After a single dose of two tablets of quinidine sulfate (400 mg), the average peak concentration was 2.13 +/-0.22 mug/ml (+/-SEM); following two tablets of the slow-release form, the average peak concentration was 1.17 +/-0.12 mug/ml. T-max was approximately 2 hr with quinidine sulfate and 4 hr with quinidine bisulfate. One fourth of both forms of the drug was recovered in the urine. Total body clearance was 0.36 L/kg-hr and renal clearance was 117 +/-22ml/min for both. With multiple dosing the serum quinidine concentration was higher than these predicted from the results of the single-dose study. Based on the mean estimates of quinidine half-life of 6 hr, a rapid method for achieving steady-state levels of quinidine would be to give an initial dose twice that of the maintenance dose. With the slow-release product if an equivalent dose was given every 12 hr, the mean steady-state quinidine serum concentration would be approximately the same.

Adult↗

The elimination of tritiated doxycycline in normal subjects and in patients with severely impaired renal function.

Tritiated doxycycline was administered to four normals, four patients with renal failure interdialysis, and three patients in renal failure who were not on dialysis. Elimination was followed by collection of urine and feces up to eight days. It was demonstrated that renal failure reduced the urinary excretion of doxycycline. In normal individuals the total of 86% of the radioactivity was eliminated in five days, half in the urine and half in the feces. In patients, with renal failure on dialysis, 32% of the radioactivity was eliminated in that time, 9.3% in the urine and 23% in the feces. In renal failure patients not on dialysis 49% was eliminated in that time, 4% in the urine and 45% in the feces; when followed up to eight days a total of almost 70% of the radioactivity was eliminated and the increase elimination was accounted for by fecal elimination such that 64% was eliminated in the feces and 5% in the urine. The disappearance from the plasma compartment in all three groups was similar. Thus, although the plasma half-life of doxycycline is not significantly prolonged in renal failure, it appears likely that the drug is taken up into a compartment from which it may slowly be eliminated and when followed for a continual period of time a significant percentage can be recovered from the feces. There remains however, up to 30% of the administered dose which was not recovered and it must be assumed that a significant per cent of doxycycline would accumulate in a compartment, as yet unidentified, in patients with renal failure.

Administration, Oral↗

Control of therapy.

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Drug Prescriptions↗

Radioimmunoassay for measurement of gentamicin in blood.

Gentamicin toxicity has been shown to be related to high concentrations in serum. Because there is a narrow range between its therapeutic and toxic levels, serial monitoring of gentamicin is the most reliable method of guiding therapy. Microbiological assays commonly in use do not afford the desired speed and accuracy, and results may be difficult to interpret in the presence of other antimicrobials. Hence, a rapid, sensitive, and highly specific radioimmunoassay for measurement of gentamicin in serum has been developed. Antibody to gentamicin was raised in rabbits by using a gentamicin-albumin conjugate. Tritiated gentamicin (specific activity 1.0 Ci/mM) competes with unlabeled gentamicin for binding sites on the antibody. Dextran-coated charcoal separates the unbound from antibody-bound gentamicin. Serum levels of gentamicin are determined by comparison with a standard curve. This method can detect concentrations as low as 0.01 mug/ml. Results of a 24-tube run can be obtained in 1 h, thus allowing modification of gentamicin dosage to advantage.

Aged↗

Bretylium tosylate in the management of refractory ventricular fibrillation.

Nine patients who had recurrent ventricular fibrillation following acute myocardial infarction or angina were given bretylium tosylate in a dose of 5 mg./kg. intramuscularly every eight hours after other measures had proved ineffective. Provided the patients were not in shock or in heart failure, there was a considerable reduction in the episodes of ventricular fibrillation.A second group of nine patients who developed recurrent ventricular fibrillation following open heart surgery were given bretylium intravenously, which controlled the arrhythmia in every instance.Bretylium did not completely abolish ventricular premature beats but the latter did not initiate ventricular fibrillation even when they occurred on the T wave.

Adult↗