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Biomedical subjects

J A Oates

Publications and source records attributed to J A Oates.

At least 163 records · Page 9Linked to original sources
PubMed1981

A second pathway of leukotriene biosynthesis in porcine leukocytes.

Incubation of suspensions containing polymorphonuclear and eosinophilic leukocytes with arachidonic acid led to the formation of two pairs of diastereomeric 8,(15S)-dihydroxy-5,9,11,13-icosatetraenoic acids and two erythro-14,15-dihydroxy-5,8,10,12-icosatetraenoic acids. The structures were elucidated by ultraviolet spectroscopy and gas chromatography--mass spectrometric analysis of several derivatives of each compound, catalytic hydrogenation, oxidative ozonolysis with steric analysis of alcohols, and comparison to reference compounds prepared by chemical synthesis. Experiments with 18O2 and H218O indicated that in all six compounds the hydroxyl group at C-15 was derived from molecular oxygen. Two of the diastereomeric 8,15-dihydroxy acids incorporated H218O at C-8, while the other two 8,15-dihydroxy products (also diastereomers) and the 14,15-dihydroxy compounds (geometric isomers) incorporated 18O2 at C-8 and C-14, respectively, in addition to C-15. Two of the 8,15-dihydroxy acids are formed by reaction of water with an unstable allylic epoxide intermediate, (14S,15S)-oxido-5,8,10,12-icosatetraenoic acid; the two 14,15-dihydroxy acids are proposed to be formed by reaction of activated molecular oxygen with the same epoxide, which in turn originates via 15S oxygenation of arachidonic acid.

Animals↗
PubMed1981

Recurrent ventricular tachycardia in the absence of overt heart disease: clinical characteristics and response to drug therapy.

Eight patients, seven of them women, have been followed up for a mean of 8.1 years (range, three to 18) with the uncommon syndrome of recurrent frequent episodes of ventricular tachycardia in the absence of overt cardiac abnormality. The mean age at diagnosis was 25 years (range, 12 to 44). Serious symptoms were common: five patients had syncope, cardiac arrest, and/or cerebrovascular accidents. Multiple measures to characterize this population, including study of symptoms, response to exercise, degree of prematurity of ventricular ectopic depolarizations, and response to antiarrhythmic drugs, showed little uniformity. An individualized approach to therapy, taking into account age and symptoms as well as frequency of arrhythmia, was used. Excellent control of arrhythmia was eventually achieved in four patients, but only after multiple drug trials (mean 5.3, range two to eight trials per patient) had been ineffective. Prognosis in this syndrome is generally good, but serious complications occur frequently enough that vigorous therapy is justified in selected patients.

Adolescent↗
PubMed1981

Indomethacin decreases arterial blood pressure and plasma renin activity in rats with aortic ligation.

Severe renovascular hypertension was produced in rats by complete aortic ligation between the origin of the renal arteries. Six days after coarctation, a carotid cannula was implanted and mean arterial blood pressure (MABP) and plasma renin activity (PRA) were determined. Subsequently, indomethacin (5 mg/kg in oil) or vehicle was administered subcutaneously three times in the following 24-hour period. On day 7, MABP and PRA were again determined. Indomethacin reduced MABP from 179.0 +/- 6.7 to 156.5 +/- 8.8 mm Hg (P less than 0.002, n = 11) and PRA from 21.2 +/- 7.3 to 9.3 +/- 2.9 ng AI/ml per hr (P less than 0.045, n = 10), whereas vehicle treatment did not alter either MABP or PRA (n = 6). There was a significant association between the decrease in MABP and the percentage decrease in PRA following indomethacin treatment (r = 0.766, P less than 0.016). A similar study was performed in aortic ligated rats in which the left kidney was removed at the time of ligation. In these animals, 6 days after surgery, MABP and PRA were 128.0 +/- 5.9 mm Hg and 0.11 +/- 0.06 ng AI/ml per hr (n = 6), respectively, and indomethacin had no effect on either MABP or PRA. These data provide evidence that the prostaglandin system is involved in the release of renin and in the pathogenesis of elevated blood pressure in this model of renin-dependent hypertension.

Animals↗
PubMed1981

Tolerance to the humoral and hemodynamic effects of caffeine in man.

Acute caffeine in subjects who do not normally ingest methylxanthines leads to increases in blood pressure, heart rate, plasma epinephrine, plasma norepinephrine, plasma renin activity, and urinary catecholamines. Using a double-blind design, the effects of chronic caffeine administration on these same variables were assessed. Near complete tolerance, in terms of both humoral and hemodynamic variables, developed over the first 1-4 d of caffeine. No long-term effects of caffeine on blood pressure, heart rate, plasma renin activity, plasma catecholamines, or urinary catecholamines could be demonstrated. Discontinuation of caffeine ingestion after 7 d of administration did not result in a detectable withdrawal phenomenon relating to any of the variables assessed.

Adult↗
PubMed1981

Estimated rate of prostacyclin secretion into the circulation of normal man.

The rate of secretion of prostacyclin (PGI2) into the circulation of normal man was estimated by measurement of the 2,3-dinor-6-keto-PGF1 alpha (D) and 15-keto-13,14-dihydro-2,3-dinor-6-keto-PGF1 alpha (KDD) urinary metabolites of PGI2. Subjects received 6-h intravenous infusions of vehicle alone and PGI2 at 0.1, 0.4, and 2.0 ng/kg per min in random order. The fractional elimination of the metabolites was independent of the rate of PGI2 infusion. 6.8 +/- 0.3% of the infused PGI2 appeared as D and 4.1 +/- 0.4% as KDD. The regression of infused PGI2 upon the quantities of the two metabolites excreted in excess of control values permitted estimation of the rate of entry of endogenous PGI2 into the circulation corresponding to a given quantity of metabolite excreted. Using the quantities excreted in the 24 h from commencement of the infusions the estimated rates were 0.08 +/- 0.02 ng/kg per min from D and 0.10 +/- 0.03 from KDD. Studies with exogenous PGI2 suggest that infusion rates 2--4 ng/kg per min are required to achieve the threshold for inhibition of platelet function (ex vivo) in man. Although not precluding a role for PGI2 in local platelet-vessel wall interactions, the much lower estimates obtained in this study suggest that endogenous PGI2 is unlikely to act as a circulating antiplatelet agent in healthy man.

Adult↗
PubMed1981

Intravenous prostacyclin in thrombotic thrombocytopenic purpura.

A therapeutic trial of prostacyclin (PGI), was done in a patient with thrombotic thrombocytopenic purpura resistant to treatment with antiplatelet drugs and plasmapheresis. Despite marked thrombocytopenia and continued treatment with aspirin, sulfinpyrazone, and dipyridamole, the urinary excretion of 2,3-dinor-thromboxane B2, a major thromboxane urinary metabolite, was within the normal range (90.3 to 368 pg/mg creatinine) at 96 pg/mg creatinine. Because of its potent antiaggregatory properties and the possibility of a defect in endogenous PGI2 production in thrombotic thrombocytopenic purpura, synthetic PGI2 (4 to 10 ng/kg-1 . min-1) was infused intravenously, first for 72 hours and then continuously for 18 days. Prostacyclin markedly reduced the excretion of 2,3-dinor-thromboxane B2, and the platelet count rose steadily to reach 100 000/mm3 by the eighth day of the second infusion. The patient remains in clinical remission, on no therapy, 7 months later. A controlled evaluation of PGI2 in thrombotic thrombocytopenic purpura is warranted. Apparent therapeutic failure in previous cases may have resulted from inadequate prolongation of PGI2 infusion.

Adult↗
PubMed1981

6-Keto-prostaglandin E1 is more potent than prostaglandin I2 as a renal vasodilator and renin secretagogue.

Several studies indicate that prostaglandin (PG) I2 is involved in the control of renin release. This investigation was performed to determine if the active possible metabolite of PGI2, 6-keto-PGE1, is also a renin secretagogue. The relative potencies of PGI2, 6-keto-PGE1 and 6-keto-PGF1 alpha on renin secretion rate (RSR) and renal blood flow (RBF) were assessed in nonfiltering, beta adrenoreceptor blocked kidneys of seven anesthetized dogs. Intrarenal infusions of both PGI2 and 6-keto-PGE1 significantly augmented RSR in a dose-related fashion. However, 6-keto-PGE1 was approximately 5 times more potent than PGI2, producing significantly greater increases in RSR at doses from 3 X 10(-9) to 3 X 10(-8 g/kg/min (P < .03). At low infusion rates (less than 3 X 10(-8) g/kg/min), 6-keto-PGE1 enhanced RBF to a greater extent than PGI2. However, with infusion rates of 3 X 10(-8) g/kg/min, these eicosanoides enhanced RBF to an equal extent. Thus, in comparison to PGI2, 6-keto-PGF1 induced a greater increase in RSR for equivalent increases in RBF. 6-keto-PGF 1 alpha had no effect on either RSR or RBF at any of the doses infused. We conclude that, in the canine kidney, 6-keto-PGE1 is more potent than PGI2 in stimulating the juxtaglomerular cells to secrete renin.

Alprostadil↗
PubMed1980

Total suppression of ventricular arrhythmias by encainide. Pharmacokinetic and electrocardiographic characteristics.

We studied the antiarrhythmic effect of a range of oral doses of encainide in 11 patients with stable high-frequency ventricular arrhythmias. Total suppression of arrhythmia was documented in 10 patients at a wide range of doses and plasma concentrations, and the suppression was subsequently verified in a placebo-controlled crossover study. Drug elimination was rapid (the half-life was 1.9 to 3.8 hours), but the margin between efficacy and side effects was sufficiently wide for therapy every six to 12 hours to be feasible in all 10 patients, with continuing outpatient treatment at six to 12 months. Marked prolongation of PR (mean, 44 per cent) and QRS (mean, 47 per cent) durations coincided with abolition of arrhythmia, but no evidence that these effects were detrimental was observed in radionuclide ventriculograms, exercise testing, or prolonged monitoring. A single patient whose arrhythmia and electrocardiogram were unchanged during therapy eliminated the drug much more slowly than the others and was the only patient in whom no O-demethyl form could be detected in plasma, suggesting that this metabolite may be active. In this study, encainide was a highly effective, well-tolerated antiarrhythmic agent.

Adult↗
PubMed1980

Metabolic effects and pharmacokinetics of intravenously administered dichloroacetate in humans.

Dichloroacetate decreases plasma glucose, lactate, and alanine concentrations in normal and diabetic subjects, and lowers lactate concentrations and increases survival in animals with experimentally induced lactic acidosis. The relationship between these effects and plasma dichloroacetate concentrations have not been previously studied in man. Dichloroacetate (1-50 mg/kg) was infused over 30 min to 16 healthy subjects and plasma drug concentrations were followed by gas chromatography over the next 8 h. Peak plasma concentrations were linearly related to the dose (r = 0.98, p < 0.001) up to 30 mg/kg, above which 4 of 7 subjects had disproportionately high plasma drug concentrations. Nonlinear disposition was also indicated by the convex decreasing plasma elimination curves; levels declining less rapidly initially than later. At plasma concentrations below 10 micrograms/ml, elimination was monoexponential with a half-life of 32 +/- 11 min (mean +/- SD). Plasma drug clearance also decreased with doses greater than 20 mg/kg. Within 2 h of administration of the maximally effective dichloroacetate dose of 35 mg/kg, plasma lactate concentrations fell 75% below baseline and alanine fell 50% below baseline, while blood glucose was unaffected.

Acetates↗
PubMed1980

Tocainide therapy for refractory ventricular arrhythmias.

Tocainide, a congener of lidocaine, was used to treat symptomatic ventricular arrhythmias in 19 patients resistant to or unable to tolerate conventional agents. In this highly selected group, 15 showed good initial responses to oral therapy. Ventricular tachycardia was suppressed to a greater extent than isolated ventricular ectopic depolarizations at any plasma concentration, and upward dose-ranging showed progressive suppression of both. Arrhythmia responsiveness to lidocaine was found to be an excellent predictor of tocainide response. Of the 15 responders, one died 24 hours after stopping therapy, three died while receiving tocainide, nine stopped because of adverse reactions (five allergic), and two continue on therapy at 1 and 4 years. We conclude that tocainide is an effective agent for the short-term suppression of ventricular arrhythmias, particularly ventricular tachycardia sensitive to lidocaine, but a high incidence of adverse effects limits its application to chronic therapy in many patients.

Adult↗
PubMed1980

Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide.

The antiarrhythmic efficacy and pharmacokinetics of N-acetylprocainamide (NAPA), the major metabolite of procainamide, were investigated in 23 patients with chronic, high frequency ventricular ectopic depolarizations. An extensive trial design incorporated the approaches of (1) generation of dose-response relations, (2) randomized crossover, and (3) prolonged electrocardiographic monitoring. Seven patients with reproducible suppression of arrhythmias (70 percent or greater reduction in frequency) were thus identified. The mean plasma concentration of acecainide associated with efficacy was 14.3 micrograms/ml (range 9.4 to 19.5) and with side effects (primarily gastrointestinal) was 22.5 micrograms/ml (10.6 to 37.9). The antiarrhythmic response to procainamide did not predict response to acecainide; this finding implies that estimates of the antiarrhythmic contribution of acecainide concentrations achieved during long-term procainamide therapy are unlikely to be meaningful in a given person. The mean half-life of elimination after a single 500 mg dose of acecainide was 7.5 hours; this had prolonged significantly (p < 0.05) to 10.3 hours after higher dosages. No variable examined (including acetylator phenotype) was found to be a predictor of responsiveness to acecainide. Outpatient therapy (2 to 20 months) was not associated with the development of antinculear antibodies or the lupus syndrome; one patient's procainamide-induced arthritis resolved during therapy. Acecainide, unlike procainamide, is an agent whose pharmacokinetics allow long-term therapy on a practical schedule. It is effective in a subset of patients with ventricular arrhythmias yet appears much less likely to induce the lupus syndrome seen with the parent compound.

Acecainide↗