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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 199 records · Page 11Linked to original sources
PubMed1978

The lack of an effect of furosemide on uterine prostaglandin metabolism in vivo.

We determined the effect of 2 mg/kg intravenous furosemide on the production and metabolism of prostaglandin E2 in the utero-placental unit of pregnant dogs. Uterine venous prostaglandins E2 and 15-keto-13,14-dihydro E2 were measured by gas chromatography-mass spectrometry. Even though the dose of furosemide was adequate to effect a good diuresis, neither the production nor the metabolism of prostaglandin E2 by the uterus was altered by that dose of the drug. Using radioactive microspheres to measure hemodynamic parameters, we observed no change in uterine vascular resistance while renal vascular resistance decreased. Although the renal concentration of furosemide may be higher than the uteroplacental concentration, there is so far no evidence in vivo that usual doses of furosemide enhance the production or inhibit the metabolism of prostaglandin E2.

Animals↗
PubMed1978

The effect of PGI2 on canine renal function and hemodynamics.

The effect of prostaglandin I2 (prostacyclin) on renal and intrarenal hemodynamics and function was studied in mongrel dogs to elucidate the role of this novel prostaglandin in renal physiology. Starting at a dose of 10(-8) g/kg/min, PGI2 decreased renal vascular resistance and redistributed the blood flow away from the outer cortex (zone 1) and towards the juxtamedullary cortex (zone 4). At 3 X 10(-8) g/kg/min, the renal vascular resistance decreased even further, but at this dose the mean arterial blood pressure also declined 13% indicating recirculation of this prostaglandin. PGI2 infusion at a vasodilatory dose resulted in natriuresis and kaliuresis. With a decline in filtration fraction, these changes were most likely secondary to the hemodynamic effects of this prostaglandin. Unlike PGE2, PGI2 had no direct effect on free water clearance indicating lack of activity at the collecting duct. PGI2 may be the important renal prostaglandin involved in modulating renal vascular resistance and intrarenal hemodynamics as well as influencing systemic blood pressure.

Animals↗
PubMed1978

Prostaglandins and renin release: II. Assessment of renin secretion following infusion of PGI2,E2 and D2 into the renal artery of anesthetized dogs.

The influence of intra-renal infusions of prostaglandin (PG) I2, PGE2 and PGD2 on renin secretion and renal blood flow was investigated in renally denervated, beta-adrenergic blocked, indomethacin treated dogs with unilateral nephrectomy. All three prostaglandins when infused at doses of 10(-8) g/kg/min and 10(-7) g/kg/min resulted in marked renal vasodilation. Renin secretory rates increased significantly with both PGI2 and PGE2 at the 10(-8) g/kg/min and 10(-7) g/kg/min infusion rates in a dose dependent manner. However, PGD2 was inactive. At 10(-7) g/kg/min, PGI2 infusions resulted in systemic hypotension indicated recirculation of this prostaglandin. These findings suggest that PGI2 should be included among the cyclooxygenase derived metabolites of arachidonic acid to be considered as possible mediators of renin release.

Animals↗
PubMed1978

The influence of sodium and potassium supplements on the diuretic responses to frusemide administration in normal subjects.

1 Twelve normal subjects received (1) normal diet, (2) normal diet with 100 mmol supplementary sodium chloride and (3) normal diet with 96 mmol supplementary potassium chloride, each for 10 days, in a balanced cross-over study according to a Latin Square design. At the end of each study period, the subjects received 80 mg frusemide orally. Each study period was separated from the other by 10 days. 2 Changes in urinary electrolyte excretion occurred within the first four days of each dietary period then remained constant, with significant differences in urinary Na/K ratio between the dietary regimes. 3 Between-subject correlations, using the mean values over the three study periods, demonstrated significant associations between plasma uric acid and urinary Na/K ratio and between plasma prolactin and urinary potassium excretion. 4 Urinary potassium excretion and Na/K ratio following frusemide were influenced significantly by alteration of diet but there was no change in sodium excretion. 5 Between-subject correlations of pretreatment variables with diuretic response, using the mean values over the three study periods, demonstrated significant associations between both pretreatment urinary Na/K ratio and plasma uric acid and respectively the urinary potassium excretion and urinary Na/K ratio in response to frusemide. 6 While the response to frusemide was altered by short-term changes in dietary sodium and potassium, the difference was less than expected from observations in two populations with customary diets differing in similar manner.

Adult↗
PubMed1978

Drug metabolism in hepatosplenic schistosomiasis in the Sudan: a study with antipyrine.

The disposition of antipyrine following oral administration of 1200 mg has been investigated in 10 patients with histologically confirmed hepatosplenic schistosomiasis and 11 normal subjects living in Sudan. Drug metabolising activity as assessed by antipyrine clearance was similar in patients when compared with normal controls. We conclude that antipyrine disposition is normal in patients with clinically compensated hepatosplenic schistosomiasis.

Adolescent↗
PubMed1978

Indomethacin is a placental vasodilator in the dog. The effect of prostaglandin inhibition.

The effect of 8 mg/kg of indomethacin on uterine blood flow, prostaglandin production, and intraamniotic fluid pressure was examined in late pregnant dogs. Uterine blood flow was measured with 15 mum radiolabeled microspheres. Because we found that a significant percentage of the microspheres shunted through the placental circulation into the lungs, we calculated placental blood flow by adding the shunted microspheres through the placenta to the nonshunted microspheres in the placenta. Total uterine blood flow significantly increased from 271+/-69 ml/min during control period to 371+/-72 ml/min (P < 0.01) 30 min after indomethacin. This increase was attributable to the change in blood flow to the placental circulation (222+/-58 to 325+/-63 ml/min; P < 0.01). Associated with these hemodynamic changes we found an almost complete suppression of uterine prostaglandin E(2) production (1,654+/-305 to 51+/-25 pg/ml; P < 0.01) as measured by gas chromatography-mass spectrometry. In addition, we found that indomethacin treatment resulted in uterine relaxation as measured by intraamniotic fluid pressure changes (11.2+/-1.3 mm Hg to 8.5+/-1.2 mm Hg; P < 0.001). We conclude that indomethacin causes an increase in placental blood flow without any change in flow to the rest of the uterus, and that this dose of the drug inhibits greater than 95% of uterine prostaglandin production. In addition, indomethacin is responsible for uterine relaxation. The increase in placental blood flow after indomethacin is probably a result of uterine relaxation, which is secondary to prostaglandin synthesis inhibition.

Amniotic Fluid↗
PubMed1978

Effect of age and parenchymal liver disease on the disposition and elimination of chlordiazepoxide (librium).

There is an increased incidence of unwanted sedation associated with chlordiazepoxide usage in the elderly and in patients with liver disease. To determine whether pharmacokinetic alterations could account in part for these observations we studied the disposition and elimination of intravenously administered chlordiazepoxide in 27 healthy controls aged 16 to 86 years, 8 patients with cirrhosis, and 5 patients with acute viral hepatitis. Both increasing age and parenchymal liver disease led to similar changes in chlordiazepoxide pharmacokinetics. Over the age range 20 to 80 years, elimination half-life (t1/2(beta)) increased from 7 to 40 hr (r, 0.67; P less than 0.001) attributable to a decrease in plasma clearance from 30 ml per min to 10 ml per min (r, -0.71; P less than 0.001) and an increase in volume of distribution from 0.26 to 0.38 liters per kg (r, 0.60; P less than 0.05). Similarly, a decrease in plasma clearance in cirrhosis (7.7 +/- 2.1 compared to 15.3 +/- 4.4 ml per min, P less than 0.01) and acute viral hepatitis (6.1 +/- 4.3 compared to 18.1 +/- 7.1 ml per min, P less than 0.01) relative to age-matched controls and an increase in the volume of distribution resulted in a prolongation of the elimination half-life in both forms of liver disease. Impaired elimination of chlordiazepoxide may account in part for the increased incidence of oversedation seen in the elderly and in patients with liver disease.

Adolescent↗
PubMed1978

The influence of indomethacin on the pharmacokinetics, diuretic response and hemodynamics of furosemide in the dog.

Indomethacin has the potential to interact with furosemide in a number of different fashions. We have investigated some of these possibilities in seven mongrel dogs that received furosemide (2 mg/kg i.v.). Plasma and urinary concentration of furosemide were measured by high performance liquid chromatography, diuretic response was assessed by urinary sodium excretion and renal blood flow and its distribution were estimated using the radioactive microsphere technique. Furosemide induced a prompt diuresis associated with a 50% increase in total renal blood flow. Intrarenal blood flow was preferentially increased in the inner cortical zones. Furosemide was rapidly eliminated with a renal clearance that was 35% of the total systemic clearance. Maximal sodium excretion was attained at plasma furosemide concentrations greater than 0.8 microgram/ml; below this concentration there was a linear relationship between plasma concentration and rate of sodium excretion. The ratio of sodium/furosemide concentration in urine rose to a plateau, then remained constant. Indomethacin pretreatment inhibited the hemodynamic response to furosemide. In addition, indomethacin reduced the renal and extrarenal clearance of furosemide by approximately 30%, but did not change the proportion of unchanged drug excreted in the urine. Although the diuretic response for any given plasma concentration of furosemide was reduced, the ratio of urinary sodium/furosemide concentration was not changed by indomethacin. Since the amount of furosemide reaching the urine was not altered, the total diuretic response was not significantly affected by indomethacin. From these observations we conclude that indomethacin alters the pharmacokinetics of the disposition of furosemide and furosemide-induced renal hemodynamic changes. However, our data indicate that the response of the renal tubule to furosemide secreted into tubular fluid is not changed by indomethacin.

Animals↗
PubMed1977

Pharmacokinetics and pharmacodynamics of ethanol, whiskey, and ethanol with n-propyl, n-butyl, and iso-amyl alcohols.

Plasma ethanol concentration, reaction time, and electroencephalogram (EEG) were recorded in 6 normal men after ingestion of ethanol along (Group 1), whiskey (Group 2), or a mixture of ethanol, n-propanol, n-butanol, and iso-amyl alcohol (Group 3). The peak plasma ethanol concentration and the total area under the plasma concentration:time curve of ethanol did not depend upon the type of drink given, but the half-life of the terminal exponential phase of ethanol elimination was longer in Group 3. In each study period reaction time increased, there was a relative increase in delta activity (2 to 3 Hz) and a fall in mean dominant frequency in EEG activity. The extent of increase in reaction time depended on the rate of increase in plasma ethanol concentration and correlated with the concentration of ethanol while the plasma concentration of ethanol was falling. Differences in the effects of ethanol between study periods were minimal.

1-Propanol↗
PubMed1977

Influence of probenecid and spironolactone on furosemide kinetics and dynamics in man.

The pharmacokinetics and pharmacodynamics following administration of furosemide (40 mg intravenously) have been studied before and after treatment with probenecid (0.5 gm orally every 6 hr for 3 days) and spironolactone (200-mg initial oral dose followed by 50 mg every 6 hr for 3 days) in 6 normal male subjects. Urine losses during each study period were replaced with saline-dextrose-KCl intravenously. The study was performed with the use of a Latin-square design. Probenecid pretreatment induced significant reductions in renal clearance of furosemide by 78%, the extrarenal clearance by 56%, and the volume of distribution by 52%. As a consequence, furosemide half-life was increased by 54%. Probenecid significantly reduced the rate of sodium excretion at all plasma concentrations of furosemide, but the ratio between urinary furosemide concentration and urinary sodium concentration was not altered. Since the proportion of furosemide excreted unchanged in the urine was not markedly changed, total diuretic response was not influenced by probenecid. There was no evidence of any pharmacokinetic interaction between spironolactone and furosemide. The relationship of furosemide kinetics to dynamics observed in these studies confirms that, in man, the diuretic response is determined by drug that reaches the renal tubule rather than the drug level in plasma.

Adult↗
PubMed1977

The urinary sodium: potassium ratio and response to diuretics in resistant oedema.

Nineteen patients with severe oedema due to either cirrhosis of the liver or to congestive cardiac failure, who had failed to respond to previous diuretic therapy, were treated with either increasing doses of frusemide (Group A), or with frusemide in a fixed dose of 80 mg daily and increasing doses of spironolactone (Group B). In Group A there was an inverse correlation between the baseline 24-hr urinary sodium: potassium (Na : K) ratio and the 24-hr urinary potassium excretion during diuresis, and a direct correlation between the urinary Na : K ratio before and after diuresis. Thus, in patients of this group during diuresis, there was a significantly higher urinary potassium excretion in those with a baseline urinary Na : K ratio of less than 1, as compared with those with a ratio of greater than 1. In Group B a satisfactory diuresis was achieved without marked urinary potassium loss in those patients with a baseline urinary Na : K ratio of less than 1, whereas no diuresis was obtained in the two patients with a baseline urinary Na : K ratio of greater than 1. These results suggest that the measurement of the baseline urinary Na : K ratio is of help in determining the potential value of spironolactone in patients with resistant oedema.

Adult↗
PubMed1976

Furosemide and bumetanide: a study of responses in normal English and German subjects.

Diuretic responses to oral administration of 1 mg bumetanide and 40 mg furosemide were determined in double-blind, crossover balanced trials in 10 normal English subjects and 6 normal German subjects. In each experiment the 0- to 8-hr urine volume and sodium excretion were significantly higher after bumetanide, potassium excretion did not differ, and the Na/K ratio, although higher after bumetanide, was not significantly different by analysis of variance. In German subjects the diuretic and natriuretic responses to both drugs were greater and the potassium excretion less than in English subjects. In the English, the pretreatment 24-hr urinary Na/K ratio correlated with the urinary Na/K ratio response to both drugs and with the potassium excretion after furosemide. The mean plasma uric acid before treatment correlated with the Na/K ratio and potassium excretion after furosemide. Aldosterone excretion did not correlate with response to either diuretic. The mean pretreatment 24-hr log10 Na/K ratio in the two treatment periods of the English and German subjects correlated with the mean sodium excretion, potassium excretion, and log10 Na/K after the two diuretics, thus providing a partial explanation for intersubject and interstudy variation. Pretreatment log10 Na/K could also explain intrasubject variation, justifying its use as a covariate in covariance analysis. This demonstrated that at this dose ratio the urinary log10 Na/K ratio response to bumetanide was significantly higher than that to furosemide.

Aldosterone↗
PubMed1976

The clearance of antipyrine and indocyanine green in normal subjects and in patients with chronic lever disease.

The pharmacokinetics after oral administration of 1,200 mg antipyrine and intravenous administration of 0.5 mg/kg indocyanine green have been investigated in 6 normal subjects and in 20 patients with chronic liver disease of varying etiology. Severe impairment of liver function associated with a decrease in serum albumin, elevation in serum bilirubin, or prolongation in prothrombin time correlated with a fall in the clearance of both drugs. The clearance of the two drugs correlated well in normal subjects and in patients with chronic liver disease. The presence of a surgical portacaval anastomosis was associated with a lower indocyanine green clearance for comparable clearance of antipyrine. The concept of functioning hepatic parenchymal mass is proposed as a common rate-limiting parameter for the elimination of the two drugs.

Adult↗
PubMed1976

Effect of phenobarbitone on plasma lipids in normal subjects.

1. Phenobarbitone in a dose of 180 mg daily was administered to ten normal subjects for 3 weeks. There was a significant increase in total plasma cholesterol, plasma low-density-lipoprotein cholesterol, plasma low-density-lipoprotein (LDL) triglycerides and plasma LDL protein. The increase in plasma LDL cholesterol accounted for the increase in total plasma cholesterol. There was a significant reduction in the ratio of LDL cholesterol to LDL protein. 2. No significant changes were observed in total plasma triglycerides, plasma very-low-density-lipoprotein (VLDL) triglycerides, plasma VLDL cholesterol or plasma VLDL protein. 3. Evidence that drug-metabolizing enzymes were induced by phenobarbitone was provided by an increase in antipyrine clearance. No relationship was observed between changes in plasma cholesterol and changes in antipyrine clearance. Serum gamma-glutamyl transpeptidase was also increased after phenobarbitone administration, the increase being unrelated to changes in antipyrine clearance or plasma cholesterol.

Adult↗