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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 217 records · Page 12Linked to original sources
PubMed1976

A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)-propranolol.

The pharmacokinetics, following i.v. administration of (+)-propranolol (40 mg) have been compared to in vitro measurement of protein binding and biochemical parameters of liver function in six normal subjects and twenty patients with stable chronic liver disease. The clearance of (+)-propranolol decreased with evidence of increasing severity of impairment of liver function correlating significantly with a fall in serum albumin, a rise in bilirubin and a prolongation in prothrombin index. The clearance of (+)-propranolol correlated with and was numerically similar to the clearance of indocyanine green in normal subjects and also in patients with chronic liver disease. Protein binding was decreased in chronic liver disease, but this change was not related to changes in plasma proteins. In normal subjects and patients without ascites the volume of distribution increased with decreases in protein binding. Ascites was associated with a further increase in the volume of distribution. The considerable variation in half-life largely depends on changes in liver blood flow, the degree of protein binding and the plasma protein pool size.

Adult↗
PubMed1976

The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man.

Liver volume and the clearances of antipyrine and indocyanine green have been measured before and after administration of phenobarbitone (180 mg/day) for 3 weeks to ten healthy subjects. The measurement of liver volume by an ultrasound scanning technique yielded reproducible results which were consistent with predictions of liver size by allometric methods. Before phenobarbitone, antipyrine clearance correlated with liver volume, but there was no correlation between indocyanine green clearance and liver volume. Phenobarbitone administration increased the clearance of antipyrine significantly by 90 +/- 14% but there was no significant change in indocyanine green clearance or liver volume. After phenobarbitone the correlation between antipyrine clearance and liver volume persisted. There was no correlation between indocyanine green clearance and liver volume. These results suggest that in non-medicated subjects some of the difference in antipyrine clearance is due to difference in functional hepatic parenchymal mass and that phenobarbitone increases the drug metabolising capacity per unit of hepatic mass but not total liver size.

Adult↗
PubMed1976

Intravenous administration of diazepam in patients with chronic liver disease.

The EEG response and drug kinetics after intravenous infusion of diazepam at 1-0 mg/min until nystagmus, dysarthria, and moderate sedation developed, has been investigated in five normal subjects and 17 patients with chronic liver disease. Diazepam induced adequate premedication with a similar clinical response in all subjects with no adverse reactions. Maximal response was during or within five minutes of infusion. The dose of diazepam required in liver chronic disease was 17-9 +/- 1-4 mg (M +/- SEM) compared with 27 +/- 5-4 mg in controls (p less than 0-01). Dose correlated significantly with serum albumin (p less than 0-05). Baseline mean dominant frequency (MDF) and slow wave index (SWI) significantly correlated with albumin (p less than 0-01). After diazepam, the MDF decreased and SWI increased. The change was greatest at the time of maximal clinical response. It was greater in liverdisease and was greatest in patients with previous hepaticencephalopathy. In spite of reduced dose requirements in liver disease, there was no significant difference in plasma concentration at the end of drug infusion...

Chronic Disease↗
PubMed1976

Prolactin, diuretics and urinary electrolytes in normal subjects.

The relationship of plasma prolactin concentration and renal electrolyte excretion has been investigated in six normal male volunteers. In two studies, 80 mg frusemide were administered at 18.00 h on Day 1 and followed by dietary sodium restriction. In study A, after 38 h of sodium depletion, a second dose of frusemide was administered at 08.00 h on Day 3. In study B, after 14 h of sodium depletion, the effect of administration of 100 mg spironolactone or 45 mg prorenoate potassium (another aldosterone antagonist) at 08.00 h on Day 2 was compared with that of a placebo. After the first dose of frusemide in study A, the mean plasma prolactin concentration correlated negatively with the urinary Na and K excretion over 5 h. After 38 h sodium depletion, the plasma prolactin concentration correlated positively with urinary Na excretion following the second dose of frusemide. In study B, after Na depletion for 14 h the plasma prolactin concentration of 08.00 h on Day 2 had a positive correlation with the 24 h urinary log10 Na:K ratio following placebo administration and had negative correlations with the true urinary log10 Na:K ratio following spironolactone and prorenoate potassium administration. Neither acute Na deprivation nor the administration of single doses of frusemide, spironolactone or proprenoate potassium appeared to affect the normal circadian rhythm of plasma prolactin concentrations which remained constant for each subject throughout the 3 months covered by the investigation. The correlations of plasma prolactin concentration to renal excretion of electrolytes, with no evidence for a negative feedback control mechanism, suggest an indirect relationship between prolactin and renal function.

Adult↗
PubMed1976

Propranolol disposition in chronic liver disease: a physiological approach.

The pharmacokinetics of propranolol can be quantitatively explained on a physiological basis from a knowledge of the effects of four biological determinants: (1) the activity of the drug metabolising enzymes (intrinsic clearance); (2) hepatic blood flow; (3) drug binding, and (4) the anatomical arrangement of the hepatic circulation. Distrubances of all these determinants can occur in chronic liver disease and result in predictable changes in propranolol disposition. These changes, as well as those occurring with other drugs in chronic liver may be explained by 'intact hepatocyte theory' which postulates that the major pathophysiological change occurring in compensated chronic liver disease is a reduction in relatively normally perfused and functioning cell mass with the development of intrahepatic portasystemic vascular shunts.

Administration, Oral↗
PubMed1976

Familial interstitial nephritis.

We report a family in whom sixteen members in three consecutive generations have died or currently suffer from chronic renal failure. Histology revealed an interstitial nephritis. One patient also had medullary cysts. The condition appears to be similar to familial juvenile nephronophthisis.

Adult↗
PubMed1976

The elimination of ethyl, n-propyl, n-butyl and iso-amyl alcohols by the isolated perfused rat liver.

The elimination of ethyl, n-propyl, n-butyl and iso-amyl alcohols has been investigated over a dose range in the isolated perfused rat liver. The elimination of ethanol was saturable with a zero-order phase being succeeded below a concentration of 5 mmol by an exponential phase. The elimination of n-propyl, n-butyl and iso-amyl alcohols was similar. There was an increasing affinity of the alcohol to the rate-limiting process with increasing carbon chain length of the alcohol. The apparent Michaelis constants for the alcohols were similar to those determined in vitro with the enzyme alcohol dehydrogenase. The addition of ethanol simultaneously with either n-propyl, n-butyl or iso-amyl alcohol was associated with a reduction in the rate of elimination of both ethanol and the higher alcohol. Changes in the apparent Michaelis constant (KM) in the absence of changes in the apparent maximal velocity (Vmax) suggested competitive inhibition for the elimination process.

1-Propanol↗
PubMed1975

Plasma uric acid concentration related to the urinary excretion of aldosterone and of electrolytes in normal subjects.

1. The relations between the concentration of plasma uric acid and urinary excretion of aldosterone, sodium and potassium, were studied in ten healthy males on a diet containing 160 mmol of sodium and 90 mmol of potassium per day. 2. Plasma uric acid correlated positively with aldosterone excretion and this correlation was statistically independent of sodium and potassium excretion. 3. Plasma uric acid correlated positively with potassium excretion and negatively with the urinary sodium/potassium ratio. There was no significant simple correlation with sodium excretion but the partial correlation of plasma uric acid and sodium excretion was negative and significant when excretion of aldosterone and potassium were held constant.

Adult↗
PubMed1974

Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Relative contributions of enzyme induction and increased hepatic blood flow.

The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179+/-15 to 239+/-27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value.

Animals↗