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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 181 records · Page 10Linked to original sources
PubMed1981

Normal metabolism of morphine in cirrhosis.

Morphine disposition and elimination was studied in 6 healthy male subject s and 6 male patients with cirrhosis, to assess the role of differences, if any, on the reported intolerance of morphine in cirrhosis. In addition the elimination of indocyanine green was studied in the same subjects on a separate occasion. The elimination half-life of indocyanine green was increased and its plasma clearance was markedly reduced in patients with cirrhosis as compared with controls (p less than 0.05). In contrast the disposition and elimination of morphine were unaffected by moderate to severe cirrhosis. Furthermore, while marked sedation was observed in normal subjects, the cirrhotics demonstrated mild sedation with no clinical evidence of hepatic coma. The normal elimination of morphine in cirrhosis is in contrast to the decreased elimination of high clearance drugs metabolized by oxidation, such as lidocaine and meperidine. Morphine is also normally a high clearance drug that is detoxified by conjugation with glucuronic acid. Since intra- or extrahepatic shunting, or both, in cirrhosis do not significantly impair morphine clearance, we postulate that significant extrahepatic morphine conjugation may occur in both normal subjects and in patients with cirrhosis. Furthermore, the reported morphine intolerance to the central effects of morphine cannot be explained by impaired drug elimination and increased availability of morphine to cerebral receptors.

Adult↗
PubMed1980

The influence of sodium status and furosemide on canine acute amphotericin B nephrotoxicity.

The influence of sodium balance and furosemide administration on acute amphotericin B-induced nephrotoxicity has been investigated in the anesthetized dog. In sodium-depleted dogs, amphotericin B (1 mg/kg i.v.) reduced renal blood flow by 32% and glomerular filtration rate by 90% 40 min after the infusion and 32 and 65%, respectively, 140 min after infusion. Although filtration fraction was reduced, fractional sodium excretion increased 13-fold. Renal renin secretion rate decreased by 64%. Prior sodium loading abolished the acute response to amphotericin B. Pretreatment of sodium-depleted dogs with furosemide (5 mg/kg bolus followed by 260 micrograms/kg/min i.v.) attenuated the reduction in renal blood flow and glomerular filtration rate produced by amphotericin B. The data indicate that acute reductions in renal blood flow and glomerular filtration rate in response to amphotericin B infusion are not direct but related to sodium status. The changes do not seem to be mediated by the renin-angiotensin system and can be inhibited by sodium loading and attenuated by concurrent furosemide administration. These observations are consistent with the hypothesis that the acute response is mediated by tubulo-glomerular feedback.

Amphotericin B↗
PubMed1979

Effect of aging and cigarette smoking on antipyrine and indocyanine green elimination.

The plasma clearances of antipyrine (AP) and indocyanine green (ICG) have been measured after intravenous administration in each of 20 normal male subjects aged 22 to 72 yr. An additional 4 subjects aged 65 to 73 yr received only ICG. AP clearance fell with age in the group as a whole (r = 0.56; p less than 0.01), but when cigarette smoking habits were considered the relationship was apparent only in smokers (r = 0.68; p less than 0.02). In the under 40 yr group. AP clearance was higher in smokers than nonsmokers (p less than 0.02). There was no such difference in men over 40 yr of age. These observations suggest that the enzyme-inducing effect of smoking diminishes with advancing years. In contrast, and consistent with a reduction in liver blood flow, the clearance of the highly extracted ICG fell with age, irrespective of smoking habits (r = 0.57; p less than 0.004). These findings suggest that while hepatic drug clearance may be impaired in elderly people, the outcome depends not only on the effects of the aging process on the physiologic determinants of hepatic clearance (liver blood flow and the activity of the drug-metabolizing enzymes) but also on the effects of environmental factors, such as smoking.

Adult↗
PubMed1979

Antipyrine clearance per unit volume liver: an assessment of hepatic function in chronic liver disease.

Liver size has been estimated clinically and by a non-invasive ultrasound technique in 16 normal subjects, 16 patients with cirrhosis, 10 patients with chronic biliary obstruction, and three patients with primary hepatoma. Antipyrine disposition was also measured in each subject. Hepatomegaly was not clinically detectable until there was approximately a 20% increase in liver size. Additional increases in size correlated significantly with clinical estimates of hepatomegaly. Antipyrine clearance had a three-fold range in normal subjects. Its mean value was significantly reduced in each subgroup of patients with liver disease. However, 48% of patients with liver disease had values within the normal range. In normal subjects there was a significant correlation between antipyrine clearance and liver volume. Thus, intersubject variation in clearance normalised for liver volume was less than clearance alone. Antipyrine clearance normalised for liver volume in patients with liver disease was significantly lower than in normal subjects and there was no overlap with normal subjects. In conclusion, assessment of drug metabolising efficiency per unit volume of liver increased the discrimination in differentiating subjects with normal from abnormal livers.

Aged↗
PubMed1979

Intact hepatocyte theory of impaired drug metabolism in experimental cirrhosis in the rat.

The elimination of propranolol by perfused livers of rats made cirrhotic by chronic carbon tetrachloride inhalation during phenobarbital treatment has been compared with control animals receiving only phenobarbital. Cirrhosis reduced propranolol clearance at a constant flow of 20 ml/min from 1.43 +/- 0.08 to 1.12 +/- 0.08 ml/min/g liver (P less than 0.025). In addition, an increase in intrahepatic shunting of 15-micron microspheres from 0.41 +/- 0.01 to 9.4 +/- 4.1% was found in cirrhotic livers (P less than 0.05). Finally, in cirrhotic livers, reducing blood flow did not produce the normal rise in hepatic extraction ratio, which actually fell from 0.873 +/- 0.021 at 20 ml/min to 0.836 +/- 0.025 at 15 ml/min and 0.823 +/- 0.026 at 10 ml/min. At each flow the observed extraction was significantly lower than that predicted to result from a reduced enzyme activity alone, consistent with the development of functionally significant intrahepatic shunts. An operational model is proposed that explains impaired drug metabolism in cirrhosis on the basis of the development of intrahepatic shunts which perfuse nonfunctioning tissue, while the remaining blood flow is exposed to a reduced mass of hepatocytes with an apparently normal amount of drug metabolizing enzyme (the intact hepatocyte theory).

Animals↗
PubMed1978

Effects of an oral contraceptive on hepatic size and antipyrine metabolism in premenopausal women.

Liver volume and antipyrine disposition have been investigated in healthy premenopausal women who received 30 microgram ethinyl oestradiol + 500 microgram dl-norgesterol as an oral contraceptive. Six months' treatment was associated with a 17% increase in liver volume while no change occurred in age-matched control subjects. In the same subjects the contraceptive decreased antipyrine clearance by 21%. Thus the contraceptive markedly reduced drug-metabolizing activity per unit volume of liver by 33%. In additional subjects, discontinuation of the contraceptive resulted in a 30% increase in antipyrine clearance. These observations confirm that conventional oral contraceptive therapy to premenopausal women increases hepatic size and that it is a potent inhibitor of drug-metabolizing activity.

Adolescent↗
PubMed1978

Racial differences in drug metabolizing ability: a study with antipyrine in the Sudan.

The kinetic disposition of antipyrine following oral administration of 1,200 mg has been investigated in 11 normal Sudanese subjects living in Sudan, 9 Sudanese subjects living in England for at least 2 yr, and 19 normal English subjects living in England. Sudanese subjects living in Sudan had significantly lower mean antipyrine clearance and higher volume of distribution than the English group (-28% and +30%, respectively). There was no significant difference for antipyrine clearance between English and Sudanese subjects living in England, but the volume of distribution of antipyrine was higher (16%) in the Sudanese subjects. The mean half-lives of the three groups differed significantly. We conclude that differences in disposition of antipyrine between native English and Sudanese populations was predominantly due to environmental factors.

Adolescent↗