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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 127 records · Page 7Linked to original sources
PubMed1986

Systemic synthesis of prostaglandin I2 following sustained infusion of angiotensin II in conscious dogs.

Acute infusion of pharmacological doses of angiotensin II stimulates the release of prostaglandin I2 (PGI2), which may modulate the vasoconstrictor response. It is uncertain whether sustained small increases in the plasma concentration of angiotensin II has the same effect. To investigate this further, low doses of angiotensin II were infused into conscious sodium replete dogs for 3 h. PGI2 synthesis was assessed by measurement of a major metabolite of PGI2, 2,3-dinor-6-keto PGF1 alpha, in urine and plasma, using gas chromatography mass spectrometry. Angiotensin II infusion (15 ng/min per kg body weight) resulted in a 3-fold increase in plasma angiotensin II (50.8 +/- 5.4 to 149 +/- 11.2 pg/ml, P less than 0.01). Mean blood pressure increased (84.8 +/- 4.3 to 108 +/- 4.7 mm Hg, P less than 0.02) and renal blood flow decreased (201 +/- 46 to 127 +/- 13 ml/min, P less than 0.01) throughout the infusion. However there was no change in either the plasma concentration (11.3 +/- 2.5 to 9.1 +/- 1.0 pg/ml) or rate of urinary excretion of dinor-6-keto PGF1 alpha (1.75 +/- 0.28 to 1.85 +/- 0.41 ng/30 min) during the angiotensin II infusion. The results suggest that small sustained elevations of the plasma concentration of angiotensin II such as are likely to occur in conscious animals, do not persistently stimulate release of PGI2 in the systemic circulation.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Is carbaryl as safe as its reputation? Does it have a potential for causing chronic neurotoxicity in humans?

The observation of neurotoxicity in a subject with long-term exposure to high levels of carbaryl has prompted the review of the potential for carbaryl to cause toxicity. Short-term studies in animal species and humans confirm that carbaryl can cause toxicity due to cholinesterase inhibition. Wide variations in the dosage required to induce toxicity in either different species or in one species by different routes of administration can in part be explained by differences in drug disposition. However, the information available about carbaryl's disposition in humans is inadequate to interpret the relevance of animal studies to humans. Limited long-term exposure studies in rats and dogs have not demonstrated unexpected adverse effects. However, long-term exposure in pigs results in a progressive neuromyopathy that is associated with structural damage and is not acutely reversible with atropine. Published information on the effects of long-term exposure to carbaryl in humans is limited and has not identified any adverse effects. It is concluded that not enough information is available to exclude the possibility that sustained high levels of exposure to carbaryl could be associated with neurotoxic or myotoxic responses in humans.

Animals↗
PubMed1986

Subacute neurotoxicity following long-term exposure to carbaryl.

Carbaryl, a widely used insecticide, is reputed to have a wide safety margin. It can induce acute cholinesterase poisoning, which is rapidly reversible on discontinuation of exposure. Long-term sequelae from long-term exposure have not previously been described in humans. This report describes the experience of a 75-year-old man who had long-term excessive exposure to carbaryl and in whom a debilitating syndrome, including headaches, memory loss, proximal muscle weakness, muscle fasciculation, muscle cramps, and anorexia with marked weight loss, developed. At the time of diagnosis, serum pseudocholinesterase levels were low, and his major symptoms resolved on termination of exposure. Late clinical features were sleep apnea and progressive development of a peripheral neuropathy. The difficulty in diagnosing the cause of a group of relatively nonspecific symptoms raises the question of whether chronic carbaryl neurotoxicity might be occurring more frequently than previously suspected.

Aged↗
PubMed1986

Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital.

The simultaneous dosing of two drugs with co-regulated genetic polymorphisms determined by a single cytochrome P-450 isozyme could result in competitive inhibition of metabolism. We investigated this hypothesis in vivo by studying the interaction of mephobarbital and mephenytoin in eight normal subjects with wide variability in S-mephenytoin 4-hydroxylation. Each received oral racemic mephenytoin (100 mg) alone and, on a separate occasion, 1 hour after oral racemic mephobarbital (200 mg). After mephenytoin dosing alone, the 8-hour urinary enantiomeric (R/S) ratio indicated one poor (PM), one intermediate (IM), and six extensive (EM) metabolizers. Total intrinsic clearance of S-mephenytoin varied more than 100-fold, whereas the range for R-mephenytoin was only twofold. The urinary R/S ratio correlated (r = 0.92) with the enantiomeric ratio of the plasma AUCs over the same period, indicating no stereoselectivity in renal clearance. When mephenytoin was taken in the presence of mephobarbital, peak levels and AUC of S-mephenytoin increased while those of the R-enantiomer remained unchanged. Accordingly, the R/S ratios in both plasma and urine were reduced, with the change rank order-related to the control value of the total intrinsic clearance of S-mephenytoin (i.e., greatest in the most extensive EM). Thus the urinary R/S ratio can be used as a measure of the enantiomeric ratio of the plasma concentrations over the same time period of collection. Moreover, this ratio may be used to detect drug interactions that involve the cytochrome P-450 isozyme(s) responsible for the polymorphic 4-hydroxylation of mephenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Furosemide kinetics and dynamics in patients with cirrhosis.

Factors that influence intersubject variability in response to furosemide have been investigated in normal subjects and patients with cirrhosis. Furosemide pharmacokinetics and pharmacodynamics were measured in eight normal subjects and 14 patients with cirrhosis, eight of whom were resistant to diuretic therapy. Furosemide renal clearance decreased in proportion to creatinine clearance, whereas nonrenal clearance and volume of distribution were unchanged. These pharmacokinetic changes were, however, minimal and resulted in an only marginal alteration in the plasma concentration-time curve. The maximal rate of urinary sodium excretion decreased with reductions in creatinine clearance (r = 0.77). However, the extent of reduction in urinary excretion of sodium was proportionally greater than the reduction in creatinine clearance, whereas the rate of urinary furosemide excretion required to achieve 50% of maximal response did not change. Furosemide's pharmacokinetics were not, therefore, appreciably altered by cirrhosis. However, cirrhosis was associated with a reduction in pharmacodynamic response to this diuretic.

Adult↗
PubMed1986

Hemodynamic effects of adenosine in conscious hypertensive and normotensive rats.

Mean arterial pressure and heart rate were measured during intra-aortic arch (i.a.a.), intravenous, and suprarenal artery (s.r.a.) infusions of adenosine in conscious, unrestrained normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in the absence and presence of ganglionic blockade. In both groups, i.a.a. and i.v. infusions of adenosine induced comparatively larger dose-dependent reductions in mean arterial pressure than did s.r.a. infusions. In WKY, i.a.a. and i.v. infusions of adenosine were equipotent in reducing mean arterial pressure. In contrast, i.a.a. infusion of adenosine was approximately twice as potent as i.v. infusion in SHR. Also, SHR were approximately 6.5 and 2.6 times more sensitive to i.a.a. and i.v. infusions of adenosine, respectively, than were WKY. Further, i.a.a. and s.r.a. infusions of adenosine caused tachycardia in WKY, while i.v. infusions did not alter heart rate. In SHR, neither i.a.a. nor s.r.a. infusion of adenosine altered heart rate, but i.v. infusion induced a profound bradycardia. In ganglionic-blocked WKY that received a norepinephrine infusion to restore blood pressure and heart rate to pre-ganglionic blockade levels, depressor responses to i.a.a. infusion of adenosine were unchanged while the increase in heart rate was abolished. In SHR, ganglionic blockade markedly decreased the depressor response to i.a.a. and i.v. infusions of adenosine and abolished the bradycardic response to i.v. infusion. These results suggest that adenosine is an effective hypotensive agent in both WKY and SHR; however, marked between-strain differences exist in the cardiovascular response to adenosine. These differences most likely are due to changes in adenosine-pulmonary interactions and increases in the importance of adenosine-autonomic interactions in SHR.

Adenosine↗
PubMed1986

Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats.

The purpose of this study was to determine whether or not caffeine would exacerbate renovascular hypertension. Therefore, we examined the effects of chronic caffeine administration on arterial blood pressure in rats subjected to either unilateral renal artery clipping (2K-1C rats) or sham-operation. Animals in each group were randomly assigned to receive either 0.1% caffeine in their drinking water or normal drinking water, and systolic blood pressure was monitored for 6 wk. Caffeine markedly exacerbated the severity of hypertension in 2K-1C rats and caused histological changes consistent with malignant hypertension. 6 wk after surgery, systolic blood pressure, plasma renin activity, and creatinine clearance in control 2K-1C rats were 169 +/- 5 mmHg (mean +/- SEM), 4.4 +/- 0.5 ng AI X ml-1 X h-1, and 2.9 +/- 0.2 ml/min, respectively; as compared with 219 +/- 4 mmHg, 31.8 +/- 7.8 ng AI X ml-1 X h-1, and 1.4 +/- 0.3 ml/min, respectively, in 2K-1C rats receiving caffeine (all values were significantly different compared with control 2K-1C). Chronic caffeine administration did not alter systolic blood pressure, plasma renin activity, or creatinine clearance in sham-operated rats or spontaneously hypertensive rats. Chronic treatment with enalapril (a converting enzyme inhibitor) prevented the development of hypertension in control 2K-1C rats and caffeine-treated 2K-1C rats; however, withdrawal of enalapril precipitated a rapid rise in systolic blood pressure in caffeine-treated 2K-1C rats, but not in control 2K-1C rats. These experiments indicate that caffeine specifically exacerbates experimental renovascular hypertension and might worsen the hypertensive process in patients with renovascular hypertension.

Animals↗
PubMed1985

Attenuation of cisplatinum-induced nephrotoxicity in the rat by high salt diet, furosemide and acetazolamide.

The influence of variations in sodium chloride diet, furosemide and acetazolamide on nephrotoxicity induced by cisplatinum have been investigated in the rat by measuring serum creatinine concentrations 5 days after cisplatinum (5 mg/kg, ip) administration. Sodium chloride depletion enhanced, while sodium chloride loading minimized changes in renal function. Increases in urine flow rate following a dextrose water load failed to alter the nephrotoxic response. Both furosemide and acetazolamide, given 30 min before cisplatinum, attenuated the nephrotoxic response. In contrast, neither sodium chloride loading, furosemide, nor acetazolamide influenced the change in renal function when given 30 min after cisplatinum. These observations indicate that renal damage due to cisplatinum can be modified by alterations in dietary salt and by diuretics and that the extent of ultimate renal damage is dependent on factors occurring immediately after cisplatinum administration.

Acetazolamide↗
PubMed1985

Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations.

Interethnic differences in debrisoquin and mephenytoin hydroxylation have been compared between normal white (n = 183) and Japanese (n = 100) subjects with the 8-hour urinary metabolic ratio of debrisoquin and the urinary S/R enantiomeric ratio of mephenytoin to identify extensive (EM) and poor (PM) metabolizers. In white subjects the frequency of PMs was 8.7% and 2.7% for debrisoquin and mephenytoin, respectively. In contrast, in Japanese subjects no PMs of debrisoquin were identified, while the incidence of PMs of mephenytoin was 18%. These substantial differences (P less than 0.001) in polymorphic distributions of oxidative drug metabolizing ability have implications for interethnic efficacy and toxicity of drugs and other xenobiotics that are metabolized by the involved cytochrome P-450 isozymes.

Administration, Oral↗
PubMed1985

Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation.

The 8-hour urinary recovery of 4-hydroxy-mephobarbital has been measured after oral administration of racemic mephobarbital (90 mg) in 17 extensive (EM) and six poor (PM) metabolizer phenotypes of mephenytoin. The recovery of this metabolite was measurable in every EM and ranged from 2.5% to 48% (10.9% +/- 1.9% of dose), but was not detected in any PM (less than 1% of dose). In EMs, the 8-hour urine recovery of 4-OH-mephobarbital after mephobarbital was approximately half that of 4-OH-mephenytoin over the same time after mephenytoin administration. One EM received similar doses of R- and S-mephobarbital on separate occasions. Urinary recovery of 4-OH-mephobarbital was 33% and less than 1%, respectively. These results suggest that mephobarbital is stereoselectively hydroxylated by the same drug metabolizing enzyme that is responsible for the stereoselective aromatic hydroxylation of mephenytoin.

Administration, Oral↗
PubMed1985

Effects of age on meperidine disposition.

Elderly patients appear to be more sensitive to meperidine than younger ones; however, the contributions of altered dynamic and kinetic factors are not clear. Accordingly, seven healthy normal men aged 60 to 79 yr were simultaneously given 25 mg meperidine HCl intravenously and the same dose of deuterium-labeled drug either orally or intramuscularly (deltoid). Blood and urine samples collected over 24 hr were analyzed by gas chromatography-mass spectrometry and kinetic data were compared to those previously obtained in a young cohort. Systemic clearance (8.61 +/- 2.22 ml/min/kg), apparent oral clearance (17.5 +/- 5.5 ml/min/kg), terminal t1/2 (6.98 +/- 1.86 hr), and the blood/plasma concentration ratio (0.97 +/- 0.12) in the elderly did not differ from those in younger subjects. In the elderly, however, the initial (2.4 +/- 0.8 l/kg) and the steady-state (4.6 +/- 0.9 l/kg) volumes of distribution were 300% and 135% values in the young. No age differences were found in absorption profiles or bioavailability after oral (F = 0.49 +/- 0.08) or intramuscular (F = 0.94 +/- 0.04) dosing. It appears that age-related alterations in drug disposition per se do not account for changes in clinical efficacy of meperidine in the elderly.

Administration, Oral↗
PubMed1985

Unilaterally nephrectomized rat with aortic ligation: a uremic model of severe hypertension.

The purpose of this study was to characterize a new animal model of severe hypertension with azotemia. Hypertension was induced in rats by complete ligation of the aorta between the origin of the renal arteries. One month later chronic renal failure was induced by removing the right kidney. The serum creatinine concentration, mean arterial blood pressure (MABP), plasma renin activity (PRA) and plasma angiotensin II levels were monitored over the next two weeks. One month after aortic ligation, but before removal of the right kidney, the MABP, PRA, and plasma angiotensin II levels were significantly greater than in controls (P less than 0.05). Following nephrectomy serum creatinine concentration rose from 0.65 +/- 0.03 mg/100 ml (X +/- SEM) to 2.75 +/- 0.40 mg/100 ml and 1.78 +/- 0.22 mg/100 ml (P less than 0.05), 3 and 14 days after the right nephrectomy, respectively. Although the elevated MABP remained unchanged, the PRA and plasma angiotensin II concentrations significantly declined to levels indistinguishable from normotensive controls. These data indicate that combining aortic ligation with right nephrectomy produces a uremic model of severe hypertension in the rat. This model may facilitate studies designed to determine the best choice of antihypertensive drugs in the situation of severe hypertension and renal insufficiency.

Angiotensin II↗
PubMed1985

Phenotypic differences in mephenytoin pharmacokinetics in normal subjects.

The urinary metabolic profile of mephenytoin and its oxidative metabolites indicates significant stereoselective metabolism of its two enantiomers. Also, polymorphic oxidation, which is present in about 2 to 5% of the Caucasian population, has been demonstrated by an impaired ability to 4-hydroxylate this anticonvulsant. In order to determine the consequences of such metabolism, the plasma concentration/time profiles of the enantiomers of mephenytoin and its N-demethylated metabolite, phenylethylhydantoin (PEH), were investigated after a single p.o. dose of racemic mephenytoin in normal subjects with different metabolizing ability for mephenytoin [extensive metabolizer (EM) vs. poor metabolizer (PM) phenotypes]. In the EM subjects, the disposition of S- and R-mephenytoin was markedly different with a 100- to 200-fold difference in mean oral clearance (4.7 vs. 0.027 liters/min) and a 30- to 40-fold difference in elimination half-life (2.1 vs. 76 hr). In these same subjects, R-PEH concentrations significantly accumulated over several days and then very slowly declined with an apparent half-life of about 200 hr. Plasma levels of S-PEH were essentially negligible. In contrast, the stereoselective elimination of mephenytoin was reduced markedly in subjects of the PM phenotype, with the disposition of the S-enantiomer being the same as that for R-mephenytoin, which in turn was similar to that observed for this enantiomer in EMs. Almost comparable plasma levels of S- and R-PEH were also present in PMs. Only a small amount (less than 5%) of unchanged mephenytoin was excreted in the urine regardless of phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Attenuation of noradrenergic neurotransmission by the thromboxane synthetase inhibitor, UK 38,485.

The purpose of this study was to determine the effects of chronic administration of the thromboxane synthetase inhibitor, UK 38,485, on noradrenergic neurotransmission. Male Sprague Dawley rats (n = 14) were treated once daily with either UK 38,485 (100 mg/kg; n = 7) or the vehicle of UK 38,485 (olive oil; n = 7) by gavage. The dose of UK 38,485 chosen was sufficient to inhibit ex vivo platelet TXB2 production by greater than 90% for 24 hours. One week into the treatment animals were prepared for in situ perfusion of their mesenteric vascular beds. Vasoconstrictor responses to both exogenous norepinephrine and periarterial nerve stimulation were determined both before and during an infusion of angiotensin II (9 ng/min) into the superior mesenteric artery. UK 38,485 significantly (P less than 0.02) attenuated the vascular response to periarterial nerve stimulation without altering the vascular response to either norepinephrine or angiotensin II. UK 38,485 did not influence the baseline perfusion pressure, the mean arterial blood pressure or the potentiation of neurotransmission by angiotensin II. These data indicate that in the in situ rat mesentery UK 38,485 attenuates the release of neurotransmitter from sympathetic nerve terminals.

Angiotensin II↗
PubMed1984

Direct enantiomeric resolution of mephenytoin and its N-demethylated metabolite in plasma and blood using chiral capillary gas chromatography.

A gas chromatographic method was developed for the determination of the R- and S- enantiomers of the anticonvulsant, mephenytoin, and its N-demethylated metabolite, 5-phenyl-5- ethylhydantoin ( PEH ), in plasma and blood. Direct enantiomeric separation of mephenytoin and its internal standard was obtained using a chiral capillary column ( Chirasil -Val) followed by nitrogen specific detection. However, resolution of the enantiomers of PEH and its internal standard required propylation at the 3-position of the hydantoin ring prior to analysis. Similar linear and reproducible standard curves were obtained from both plasma and blood over the concentration range 50 ng/ml to 5 micrograms/ml, and above 100 ng/ml the reproducibility was less than 8% (coefficient of variation). Pronounced stereoselective differences in the plasma concentration--time curves for both mephenytoin and PEH were observed in a normal subject who received a single oral dose of 300 mg racemic mephenytoin. The peak plasma level of S-mephenytoin was only one-fifth that of the R-enantiomer and its elimination half-life was less than 3 h compared to over 70 h for R-mephenytoin. Similarly, S- PEH levels were barely detectable whereas concentrations of R-metabolite steadily increased over 4-6 days before slowly declining.

Anticonvulsants↗