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Biomedical subjects

H E Barber

Publications and source records attributed to H E Barber.

At least 19 recordsLinked to original sources
PubMed1991

Disposition of gamma-glutamyl levodopa (gludopa) after intravenous bolus injection in healthy volunteers.

1. The pharmacokinetics of gludopa in healthy volunteers were studied at two doses, 250 micrograms kg-1 and 100 micrograms kg-1, after rapid intravenous bolus injection. 2. Gludopa had a clearance of 4.43 +/- 1.50 ml min-1 kg-1 and 4.92 ml min-1 kg-1 at the higher and lower doses, respectively. Corresponding half-lives were 29.2 +/- 3.7 min and 32.5 +/- 5.6 min, and volumes of distribution were 0.183 +/- 0.052 l kg-1 and 0.235 +/- 0.07/ l kg-1. 3. Urinary excretion of dopamine rose sharply after injection of gludopa at both doses, peaking at 30 min. At this time, amounts were over 215 and 60 times baseline values at the higher and lower dose of gludopa, respectively. Urinary dopamine rose in parallel with urinary levodopa excretion, supporting the view that levodopa is the precursor of urinary dopamine. 4. Less than 1% of the injected dose of gludopa was excreted unchanged in the urine. 5. These findings suggest that, in man, gludopa is an efficient pro-drug for dopamine. Gludopa may find therapeutic use in conditions where the beneficial renal effects of dopamine may be indicated.

Adult↗
PubMed1990

The pharmacokinetics of gamma-glutamyl-L-dopa in normal and anephric rats and rats with glycerol-induced acute renal failure.

1. The pharmacokinetics of gamma-glutamyl-L-dopa (gludopa) and its metabolite, L-dopa, have been studied in normal rats at three dose levels of gludopa: 2 mg kg-1, 5 mg kg-1 and 7.5 mg kg-1. The extent of metabolism in normal rats, and the pharmacokinetics in anephric rats and rats with glycerol-induced acute renal failure (ARF) were also studied at a gludopa dose of 2 mg kg-1. 2. Gludopa was extensively metabolised to L-dopa with only about 10% of an injected dose being excreted unchanged. Normal rats had a rapid gludopa clearance of 50.9 +/- 9.6 ml min-1 kg-1 and elimination rate constant of 2.99 +/- 0.27 h-1. The mean residence time and half-life were 20.9 +/- 1.4 and 14.4 +/- 1.0 min, respectively. The apparent volume of distribution at steady state was 1.05 +/- 0.18 l kg-1. 3. No statistically significant differences were found in the main pharmacokinetic parameters between ARF and controls for either gludopa or its metabolite L-dopa. 4. In anephric rats and controls the kidneys were found to contribute about 68.5% and 67.2% to the elimination of gludopa and the metabolite L-dopa, respectively. 5. These results confirm that gludopa is an efficient pro-drug for L-dopa, and that the kidneys are the major site of gludopa metabolism. It seems likely that the renal specificity of gludopa persists in ARF.

Acute Kidney Injury↗
PubMed1986

The kinetics of 4-nitrophenol conjugation by perfused livers and hepatic microsomes from streptozocin-induced diabetic rats.

The formation of both glucuronide and sulphate conjugates of 4-nitrophenol is deficient in perfused livers from male diabetic rats. Experiments with 'native' hepatic microsomes demonstrated that the defect in glucuronidation is due to a decrease in the maximal velocity of the reaction. There is no alteration in the affinity of the glucuronyltransferase for 4-nitrophenol. Non-linear regression analysis of the 4-nitrophenol liver perfusate concentrations showed that the elimination follows saturable Michaelis-Menten kinetics. Clearance values in 'native' microsomal preparations and in perfused livers were calculated and found to be similar in both systems. This provides evidence that glucuronyltransferase is 'native' in the intact liver.

Animals↗
PubMed1983

The protein binding of vinblastine in the serum of normal subjects and patients with Hodgkin's disease.

The protein binding of vinblastine was measured in the serum from 6 normal subjects and 9 patients with Hodgkin's disease. Cellulose acetate electrophoresis showed that the predominant binding protein fractions were the alpha 1- and alpha 2-globulins with little binding to albumin and beta- and gamma-globulins. At a serum concentration of 10 nM a significantly lower percentage bound was found in the patient group (p = 0.001). Binding to both groups was very high at 99.7% bound in the normal subjects and 98.9% bound in the patient group. Binding in both groups was best described by a two class protein binding model with higher and lower affinity binding sites. No significant difference was found on inter-group comparisons of binding parameter values.

Blood Proteins↗
PubMed1982

Binding of vinblastine to recrystallized human alpha 1-acid glycoprotein.

The binding of vinblastine (VLB) to recrystallized human alpha 1-acid glycoprotein (alpha 1-AGP) dissolved in phosphate-buffered saline (pH 7.4) was determined at different drug concentrations using the technique of continuous ultrafiltration. Vinblastine was extremely highly bound (greater than 99.0%) at a drug concentration of 4.0 mumol X l-1, dropping to under 60% at 65.0 mumol X l-1. Binding was best described by a two-class model with higher- (9.4 microM-1) and lower- (0.1 microM-1) affinity sites but with a similar number of binding sites (1.5 as against 1.1 lower-affinity sites). These results strongly suggest that alpha 1-AGP would be a major binding protein for VLB in plasma.

Crystallization↗
PubMed1982

The effect of propranolol on luteinising hormone and prolactin plasma concentrations in hypertensive women.

1 Chronic propranolol treatment has been previously shown to lower the plasma concentrations of LH and prolactin in normal male volunteers. 2 The effect of 2 weeks treatment with propranolol (80 mg twice daily) on the plasma concentrations of LH and prolactin has now been investigated in five post menopausal hypertensive women. 3 There was no significant effect of propranolol treatment on the basal plasma concentrations of either hormone. Both hormones showed significant increases in plasma concentration following GnRH stimulation and these increases were also unaffected by propranolol treatment.

Female↗
PubMed1982

The binding of prednisolone in human serum and to recrystallized human albumin in vitro.

1 Prednisolone binding in human serum and to recrystallized human serum albumin was measured by continuous ultrafiltration. 2 At serum concentrations of prednisolone up to 0.6 micron, 95.0% was bound but at higher concentrations the binding became non-linear falling to 80.5% at 1.8 microns. At even higher concentrations binding in serum became linear again and paralleled the binding to albumin which was linear throughout the entire range of prednisolone concentrations. 3 A binding model was proposed which included a saturable component attributable to binding to transcortin and a non-saturable binding to albumin. 4 Computer simulations using the experimentally determined binding parameters of the model indicated that binding in serum was critically dependent on transcortin concentration and almost independent of albumin concentration.

Adult↗
PubMed1982

The effect of chlorpromazine, metyrapone, imipramine and SKF 525-A on the hepatic first pass elimination of propranolol in the pithed rat.

1 The effect of chlorpromazine, metyrapone, imipramine and SKF 525-A on the hepatic first pass elimination of propranolol has been studied in the pithed rat. 2 The effect of chlorpromazine, metyrapone, imipramine and SKF 525-A on the inhibition caused by propranolol of an elicited electrically induced tachycardia has also been studied. 3 The hepatic first pass elimination of propranolol was reduced following pretreatment with chlorpromazine, imipramine and SKF 525-A but was not affected by pretreatment with metyrapone. 4 Chlorpromazine, imipramine and SKF 525-A all resulted in an increased propranolol blood concentration after hepatic portal vein administration which was associated with decreased formation of metabolites and an enhanced inhibition of an electrically induced tachycardia.

Animals↗
PubMed1981

Cimetidine-a clinical and pharmacokinetic study.

1 The effect of six months therapy with cimetidine (800 mg or 1600 mg/day) and subsequent withdrawal was studied in 19 patients with duodenal ulceration. 2 The overall rates of healing were 63% and 79% of patients after 3 and after 6 months of treatment respectively. The longer course (6 months) or the higher dose (1600 mg) did not result in significantly increased rates of ulcer healing. 3 Abrupt withdrawal of cimetidine resulted in the recurrence of severe symptoms in 15 patients (79%). 4 Pharmacokinetic studies showed the mean elimination half-life of cimetidine to be 100 +/- 25 min, the total body cimetidine clearance 652 +/- 223 ml/min, the mean volume of distribution at steady state 65 +/- 181 and the overall bioavailability 78%. 5 Long term cimetidine treatment does not result in drug accumulation or changes in its pharmacokinetic profile. 6 Inter-individual differences in clinical and endoscopic response to cimetidine cannot be explained by pharmacokinetic differences.

Cimetidine↗
PubMed1981

Withdrawal of long-term therapy with atenolol in hypertensive patients.

1 The offset of effects on blood pressure and heart rate after cessation of long-term therapy (19 +/- 3.6 months) with atenolol (200 mg once/daily) was studied in six hypertensive patients. 2 Withdrawal of atenolol resulted in a gradual return of lying, standing and post-exercise systolic and diastolic blood pressure levels and heart rate towards the baseline value. The offset of effect greatly exceeded the time for elimination of atenolol. 3 No significant differences in the pharmacokinetic profile of atenolol were evident between the values obtained following chronic dosing and an acute single-dose study. 4 The lack of clinical evidence of increased cardiac adrenergic sensitivity or rebound hypertension following withdrawal of atenolol contrasts with reports of a withdrawal syndrome following cessation of therapy with propranolol. Nevertheless until the mechanism of the propranolol-withdrawal syndrome is better understood caution is required when stopped therapy with atenolol in patients with severe coronary artery disease.

Adult↗
PubMed1981

The effect of frusemide and piretanide on the renal clearance of gentamicin in man.

1 Gentamicin alone (dose 1 mg/kg) or in combination with frusemide (dose 0.25 mg/kg) or piretanide (dose 0.1 mg/kg) was administered intravenously to six healthy male volunteers. 2 Blood samples were collected at various times for 24 h and urine for up to 48 h. 3 Both diuretics increased the renal clearance of gentamicin during the period of the diuresis, without influencing either the glomerular filtration rate or the distribution of the antibiotic. 4 The results are discussed in relation to gentamicin-induced nephrotoxicity.

Adult↗
PubMed1979

The relationship between the pharmacokinetics, cholinesterase inhibition and facilitation of twitch tension of the quaternary ammonium anticholinesterase drugs, neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethylammonium.

1 The relationship between the concentration of drug in plasma, the inhibition of erythrocyte acetylcholinesterase and the facilitation of neuromuscular transmission has been studied in the rat after the administration of neostigmine, pyridostigmine, edrophonium and 3-hydroxyphenyltrimethyl-ammonium (3-OH PTMA). 2 After the administration of neostigmine or pyridostigmine, acetylcholinesterase activity recovered only slowly due to the covalent nature of the inhibition. In contrast, recovery from the reversible inhibition caused by edrophonium or 3-OH PTMA was rapid and showed a direct relationship to the plasma concentration of these drugs. 3 There was a statistically significant linear correlation between the logarithm of the plasma concentration of the drugs and the increase in the tibialis twitch tension. 4 The relationship between the inhibition of acetylcholinesterase and the facilitation of neuromuscular transmission was complex. When the enzyme was less than 85% inhibited no facilitation occurred. Between 85% and 98% inhibition, facilitation was linearly related to enzyme inhibition. Above 98% inhibition, facilitation was unrelated to inhibition of the enzyme.

Acetylcholinesterase↗
PubMed1976

Plasma concentration of edrophonium in man.

The plasma concentration of edrophonium was measured in man after intravenous administration. In 5 patients, the clearance of edrophonium from the circulation during the 1-hr period of sampling was invariably resolved into 2 exponential components. An initial rapid phase of elimination from plasma (T/2 = 0.54 TO 1.92 Min) was followed by a much slower decline (T/2 = 24.23 to 45.00 Min), corresponding to the fall in concentration between 10 and 60 min. In parallel experiments in the rat, the clearance of 14C-edrophonium was resolved into 3 exponential components, although the final component could not be reliably defined until 1 to 3 hr after intravenous injection. It is suggested that the rapid fall in the plasma concentration of edrophonium in both species is not dependent on metabolism or excretion, but is due to the rapid uptake of the drug by the liver and kidneys.

Acetylcholinesterase↗
PubMed1976

The effect of edrophonium on erythrocyte acetylcholinesterase and neuromuscular function in the rat.

1. The relation between the concentration of edrophonium in plasma, inhibition of red cell acetylcholinesterase, and neuromuscular transmission was studied in the rat. 2. In both in vivo and in vitro conditions, red cell acetylcholinesterase activity was predictably related to the concentration of the quaternary amine. 3. After low doses of edrophonium (1.0 mumol/kg) there was a significant correlation between the monophasic potentiation of twitch tension and the plasma concentration of the drug. In contrast, with higher doses of edrophonium (4.0 or 10.0 mumol/kg) a biphasic potentiation of twitch tension was observed; this was only correlated with the plasma concentration of the drug during the secondary decline in neuromuscular facilitation. Subsequent recovery of normal neuromuscular transmission invariably occurred at a constant plasma concentration of edrophonium.

Acetylcholinesterase↗