bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancement of physiological finger tremor by intravenous isoprenaline infusions in man: evaluation of its role in the assessment of beta‐ adrenoceptor antagonists.
Authors: Arnold JM , McDevitt DG
Published: July 2012

Graded intravenous isoprenaline infusions produce dose‐related increases in finger tremor. The dose‐response curves constructed with intra‐arterial or intravenous isoprenaline behave similarly in the presence of both atenolol 50 mg and propranolol 40 mg. In Five subjects, practolol 120 mg, atenolol 50 mg, propranolol 40 mg and sotalol 200 mg reduced exercise heart rate by 20.2 +/‐ 2.3, 21.4 +/‐ 1.8, 17.4 +/‐ 2.5, 23.9 +/‐ 3.6% respectively: the differences were not significant. The corresponding dose‐ratios for reduction of an isoprenaline tachycardia were 2.8, 2.3, 19.1 and 16.9 respectively. At doses which had comparable effects on an exercise tachycardia, the non‐ selective beta‐adrenoceptor antagonists, propranolol 40 mg and sotalol 200 mg, attenuated the finger response to isoprenaline (dose ratios 33.3 and greater than 25.0 respectively) more than the beta 1‐selective adrenoceptor antagonists, practolol 120 mg and atenolol 50 mg (dose ratios 1.0 and 2.3 respectively). In two out of five subjects, dose‐ response curves could not be constructed with sotalol, either at a dose of 200 or 100 mg. The enhancement of physiological finger tremor by intravenous infusions of isoprenaline may be useful in the investigation of beta 2‐adrenoceptors and their antagonists in man.
Omeprazole: effects on oxidative drug metabolism.
Authors: Henry DA , Somerville KW , Kitchingman G , Langman MJ
Published: July 2012

Omeprazole, a substituted benzimidazole, and a potent inhibitor of gastric parietal cell H+/K+ ATPase, was tested for drug interactions at two dose levels (30 mg and 60 mg/day) in man using the model drugs [14C]‐aminopyrine and antipyrine. Elimination of both models was assessed before and after 15 days treatment with omeprazole. In addition [14C]‐aminopyrine metabolism was assessed on day 2 of treatment to investigate the rapidity of onset of any effect. In 10 healthy male volunteers omeprazole 60 mg/day for 14 days prolonged aminopyrine 14CO2 half life (t1/2), measured on the 15th day, by 21% (P less than 0.05), and reduced percent dose demethylated in 2 h (ABT2) by 19% (P less than 0.005). No effect was seen on day 2 of therapy. After 14 days treatment antipyrine half‐life was prolonged by 10% (P less than 0.025) and clearance was reduced by 14% (P = 0.063). In nine healthy male volunteers omeprazole 30 mg/day for 14 days prolonged aminopyrine 14CO2 by 13% and reduced ABT2 by 11%. Both changes just failed to reach statistical significance. At this dose antipyrine metabolism was unaltered. As the dose of omeprazole used in clinical practice may be less than 30 mg/day it is unlikely that metabolic inhibition will occur during routine use, although it will be necessary to test for interactions with therapeutically more important compounds. Interactions should be looked for when large doses of omeprazole are being used to treat hypersecretory states.
The short term effects of bezafibrate on the hypertriglyceridaemia of moderate to severe uraemia.
Authors: Williams AJ , Baker F , Walls J
Published: July 2012

Hypertriglyceridaemia, an atherogenic risk factor, is a well recognised complication of uraemia, and is present in the earliest stages of the disease. Bezafibrate is an effective hypolipidaemic agent, and its effect in moderate to severe uraemia is documented in this study. Significant reductions in serum triglyceride and cholesterol have been achieved after 1 month's therapy with a reduced dosage of bezafibrate. A reduction in the hyperinsulinaemia was also seen, but no change in the fractional removal rate of injected lipid emulsion (K2) was observed. An accelerated decline in some patients' renal function was observed, which was partially reversed on cessation of treatment. Reversible elevations in the serum creatinine phosphokinase were also seen, but no patient exhibited the myositis‐like syndrome associated with clofibrate.
Metabolic effects of high dose amiloride and spironolactone: a comparative study in normal subjects.
Authors: Millar JA , Fraser R , Mason P , Leckie B , Cumming AM , Robertson JI
Published: July 2012

Amiloride (75 mg daily) and spironolactone (300 mg daily) were given to five normal subjects for 7 days in order to compare metabolic effects at maximal doses. Blood pressure, body weight, Na+ and K+ balance, and plasma concentrations of Na+, K+, active and total renin, angiotensin II, aldosterone, 11‐deoxycorticosterone (DOC), 18‐ hydroxydeoxycorticosterone (18‐OH DOC), corticosterone (B), 18‐ hydroxycorticosterone (18‐OH B) and cortisol were measured before and on each day of treatment. Natriuresis and K+ retention were significantly greater with amiloride. Plasma K+ increased from 4.1 +/‐ 0.2 to 4.9 +/‐ 0.2 mmol/l (mean +/‐ s.d.) on amiloride and from 4.0 +/‐ 0.2 to 4.4 +/‐ 0.2 mmol/l with spironolactone. Stimulation of renin, angiotensin II, aldosterone and 18‐OH B occurred with both drugs but was greater with amiloride in each case. A transient decrease in systolic and diastolic blood pressure was observed after 2 days of spironolactone treatment but not with amiloride. The slope of the regression of aldosterone on angiotensin II during spironolactone treatment was less than that with amiloride, consistent with partial blockade of aldosterone synthesis by spironolactone. These data suggest that the maximum metabolic effects of amiloride exceed those of spironolactone.
A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients.
Authors: Perucca E , Hedges A , Makki KA , Ruprah M , Wilson JF , Richens A
Published: July 2012

The antipyrine clearance and the urinary excretion of D‐glucaric acid (D‐GA) were determined in 122 patients receiving chronic anticonvulsant drug treatment and in 21 drug‐free control subjects. Patients treated with carbamazepine (CBZ), phenytoin (DPH), primidone (PMD) and phenobarbitone (PB), either alone or in combination, showed higher values of antipyrine clearance and excreted larger amounts of D‐GA as compared to controls. While antipyrine clearance values did not differ significantly from one drug group to another, D‐GA excretion was significantly higher in patients treated with CBZ than in those treated with DPH. In patients treated with sodium valproate antipyrine clearance did not differ from control values. There was a trend for D‐ GA excretion to be higher in these patients but the difference was not statistically significant. Significant positive correlations were found between the dosage of CBZ, DPH, PMD and PB and both indices of enzyme induction. These data demonstrate a dose‐dependent degree of enzyme induction in patients receiving therapeutic doses of these anticonvulsants. The relative potency at average dose levels for antipyrine clearance was PB (1), DPH (0.92), CBZ (0.84), PMD (0.82) and for log D‐GA excretion was PB (1), CBZ (0.96), PMD (0.95), DPH (0.90).
Determinants of carbamazepine and carbamazepine 10,11‐epoxide binding to serum protein, albumin and alpha 1‐acid glycoprotein.
Authors: MacKichan JJ , Zola EM
Published: July 2012

The binding of carbamazepine and carbamazepine 10,11‐epoxide to serum, albumin and alpha 1‐acid glycoprotein (AAG) was determined and compared at drug concentrations ranging from 0.5 to 400 mg/l using equilibrium dialysis and liquid chromatography. The total binding of carbamazepine in serum was determined primarily by albumin and to a lesser extent (20‐ 30%) by AAG. Modified Scatchard plots for carbamazepine binding in serum were biphasic, suggesting the presence of two binding sites on serum protein. Association constants characterizing the first (k1 = 2.4 X 10(4) l/mol) and second (k2 = 4.6 X 10(2) l/mol) binding sites agreed with those measured for AAG and albumin respectively. Modified Scatchard plots for carbamazepine 10,11‐epoxide binding in serum were linear and serum binding was largely accounted for by binding to albumin. The epoxide metabolite did not bind to AAG. Carbamazepine binding to AAG was drug concentration‐dependent over the concentration range considered to be therapeutic, while the percent binding values for carbamazepine and epoxide binding to albumin and serum from a normal individual were constant over this range. Computer simulations showed that physiological extremes in AAG and albumin concentrations can result in a range of carbamazepine unbound fractions of 0.17 to 0.47. These data suggest that normal variations in concentrations of both proteins may be the principal cause of interpatient variability in serum protein binding of carbamazepine.
Bronchodilator effect of disodium cromoglycate administered as a dry powder in exercise induced asthma.
Authors: Horn CR , Jones RM , Lee D , Brennan SR
Published: July 2012

A double‐blind, placebo controlled study of the effects of disodium cromoglycate (DSCG), administered as a dry powder via the spinhaler, in established exercise‐induced asthma, was carried out. DSCG resulted in an increase in the rate of recovery compared with placebo. The findings confirm that DSCG has bronchodilator properties.
Benzodiazepines and memory.
Authors: Roth T , Roehrs T , Wittig R , Zorick F
Published: July 2012

Benzodiazepines possess anterograde amnesic properties, disrupting both short‐term and long‐term memory function. The amount of amnesia is systematically related to dose effects and half‐life differences among the benzodiazepines. Memory deficits are found for episodic, semantic, and iconic memory function. The deficits in long‐term memory are probably the result of a disruption of consolidation of information in memory and not retrieval from memory. The disruption is produced by rapid sleep onset. Thus the long‐term amnesia is really a retrograde effect of sleep and not the anterograde effect of the drug.
Prediction of response to theophylline in chronic bronchitis.
Authors: Whiting B. , Kelman AW , Struthers AD
Published: July 2012

In chronic bronchitis, intersubject variability in both theophylline pharmacokinetics and pharmacodynamics must be taken into account if the drug is to be used to its best advantage. Both kinds of variability can be integrated into a model which relates the steady state concentration of theophylline to simultaneously measured ventilatory response (most conveniently, the FVC). In a group of 56 patients with chronic bronchitis, the mean +/‐ s.d. linear response to increasing steady state concentrations of theophylline was 0.04 +/‐ 0.012 1 microgram‐1 ml, starting from a mean +/‐ s.d. pretreatment FVC of 1.58 +/‐ 0.791. Using these population parameter values, with or without a pretreatment FVC and/or one steady state concentration ‐FVC observation, it was possible to predict the degree of response which would be achieved by a smaller group of 20 similar patients. These estimates were obtained using a mathematical procedure based on Bayesian Probability Theory and Maximum Likelihood Estimation. Estimates of the overall response in individual patients allowed prediction of the response at any steady state concentration. These estimates were unbiased and accurate enough for clinical use when they were based on a pretreatment FVC and/or one paired steady state concentration ‐FVC observation.
Do saliva concentrations predict plasma unbound theophylline concentrations? A problem re‐examined.
Authors: Knott C. , Bateman M. , Reynolds F.
Published: July 2012

On the assumption that plasma unbound drug concentrations are therapeutically active, the value of saliva concentrations in predicting plasma unbound theophylline concentrations was investigated in 25 ambulatory adults (aged 27 to 84 years) receiving theophylline (225‐1350 mg aminophylline daily) for asthma or chronic bronchitis. Plasma samples from all patients were ultrafiltered, and the plasma unbound theophylline (F) concentrations were compared with the corresponding total plasma (P), citric acid stimulated saliva (S) and non‐stimulated saliva (Ns) theophylline concentrations. Plasma unbound theophylline concentrations correlated significantly with P (r = 0.97) and S (r = 0.973), but less well with Ns (r = 0.883), emphasising the benefit of saliva stimulation. The ability of S to predict F theophylline concentrations was assessed using the mean ratio of 0.7297. In 92% of the patients, predicted F concentrations were within +/‐ 1 microgram/ml of the measured concentrations. Similarly, using the mean F/P ratio of 0.418, predicted P were within +/‐ 1 microgram/ml of obtained P in 84% patients, and using the mean S/P ratio of 0.568, predicted P were within +/‐ 1 microgram/ml of obtained P in 81%. An accuracy of +/‐ 1 microgram/ml in estimating F from S concentrations would be sufficient to indicate appropriate dose adjustments, and we therefore advocate the use of stimulated saliva samples for routine monitoring of theophylline therapy.
Clofibrate enhances the affinity of insulin receptors in non‐insulin dependent diabetes mellitus.
Authors: Murakami K. , Nambu S. , Koh H. , Kobayashi M. , Shigeta Y.
Published: July 2012

Glucose‐lowering mechanism by clofibrate was studied in non‐insulin dependent diabetics managed with dietary therapy alone. Clofibrate 1500 mg was administered for 1 month to 15 patients, and 75 g oral glucose tolerance test and insulin tolerance test were carried out before and after 1 month of the treatment. Fasting plasma glucose values were decreased from 9.34 +/‐ 0.53 mmol/l to 7.58 +/‐ 0.33 mmol/l (P less than 0.01), and fasting insulin levels were decreased from 13.8 +/‐ 1.7 microunits/ml to 10.1 +/‐ 1.5 microunits/ml (P less than 0.05). However, insulinogenic index and sigma IRI/sigma glucose ratio during 75 g oral glucose tolerance test were not changed. Enhanced glucose fall in insulin tolerance test was also observed. As these results suggested the enhanced tissue sensitivity to insulin, we examined the insulin binding to erythrocytes before and at 3 months' treatment of clofibrate in 10 non‐insulin dependent diabetics. Insulin bindings were increased from 3.41 +/‐ 0.17% to 4.11 +/‐ 0.20% in the presence of 1 ng/ml of native insulin (P less than 0.01). This increased binding was due to an increased affinity without a change in the number of insulin receptors. These results suggest that improved glucose tolerance by clofibrate might be derived from the enhanced tissue sensitivity to insulin, probably through an enhanced affinity of insulin receptors.
Decreased serum protein binding of diazepam and its major metabolite in the neonate during the first postnatal week relate to increased free fatty acid levels.
Authors: Nau H. , Luck W. , Kuhnz W.
Published: July 2012

The protein binding of diazepam (D) and its major active metabolite N‐ desmethyl diazepam (DD) was investigated in vitro in the serum of 14 mothers at birth, 21 foetuses at birth, in 100 neonates between 1 and 11 days of age and in 16 control subjects. The free (unbound) fractions of D and DD in the foetus were similar to those in the controls, but lower than those in the mothers. During the first day of life the free fractions of D and DD doubled in the neonates and subsequently declined slowly to reach near control levels at 1 week of age. The sharp increase and slow decrease of the free fractions of D and DD during the first postnatal week was closely paralleled by sharply increasing and decreasing free fatty acid (FFA) concentrations. Bilirubin and albumin levels were of lower importance in regard to the protein binding of D and DD. These results indicate that the greatly increased FFA levels shortly after birth result in increased free fractions of D and DD. Because of the known immaturity of the neonatal hepatic elimination capacity, these elevated free fractions may result in elevated free concentrations of the two compounds, which may help to explain the adverse effects observed clinically in some D‐exposed neonates.
The effect of dose form on the bioavailability of mebendazole in man.
Authors: Dawson M , Watson TR
Published: July 2012

Four different dose forms of mebendazole were administered to human volunteers, and urine was collected and assayed for mebendazole and unconjugated metabolites of mebendazole. Oral administration of mebendazole as an oily suspension slightly enhances the bioavailability of the drug, however mebendazole is not absorbed following rectal administration. The major urinary metabolite of mebendazole in humans is 2‐amino‐5(6)[alpha‐hydroxybenzyl]benzimidazole (IV), not 2‐amino‐ 5(6) benzoylbenzimidazole (II), as previously reported.
Pharmacokinetics of metronidazole in patients with varying degrees of renal failure.
Authors: Houghton GW , Dennis MJ , Gabriel R
Published: July 2012

Twenty‐nine patients with varying degrees of renal insufficiency were given a single intravenous dose of metronidazole (500 mg). Plasma and urinary concentrations of metronidazole and two major metabolites were determined using a specific high performance liquid chromatographic assay. The pharmacokinetic parameters of metronidazole elimination half‐ life, area under the metronidazole concentration against time curve, apparent volume of distribution, metronidazole clearance and predicted degree of accumulation of metronidazole on repeated dosing were not statistically significantly affected by renal inadequacy of any degree. The urinary excretion of metronidazole in patients with moderate or severe renal insufficiency was approximately half the value in healthy volunteers. The renal clearance of metronidazole was significantly greater in healthy volunteers compared to renally insufficient patients, but accounted for less than 10% of the total metronidazole clearance in all groups. The elimination half‐life and predicted accumulation (on three times daily dosing) of metabolite I [1‐(2‐ hydroxyethyl)‐2‐hydroxymethyl‐5‐nitroimidazole] were significantly increased with decreasing renal function from 9.2 h and 2.3, respectively, in healthy volunteers to 34 h and 6.7, respectively, in patients with total renal failure. The degree of accumulation of this metabolite on repeated dosing is probably of limited clinical significance in all patients except those with severe or total renal failure for reasons detailed in the text. The elimination half‐life and predicted accumulation on three times daily dosing of metabolite II, [2‐ methyl‐5‐nitroimidazole‐1‐acetic acid] increased rapidly with decreasing renal function.(ABSTRACT TRUNCATED AT 250 WORDS)
Treatment with beta‐adrenoceptor blockers reduces plasma melatonin concentration.
Authors: Cowen PJ , Bevan JS , Gosden B , Elliott SA
Published: July 2012

In treated hypertensive patients plasma melatonin levels were lower in subjects receiving beta‐adrenoceptor blockers than those treated with diuretics. Melatonin concentrations in middle‐aged and young control subjects were similar to each other and to those of the diuretic‐ treated patients. The results suggest that treatment with beta‐ adrenoceptor blockers causes a persistent reduction in plasma melatonin but it is unclear if this finding has clinical implications.
The plasma noradrenaline and growth hormone response to alpha‐ methyldopa and clonidine in hypertensive subjects.
Authors: Struthers AD , Brown MJ , Adams EF , Dollery CT
Published: July 2012

The mechanism of the antihypertensive effect of alpha‐methyldopa was compared with clonidine by administering equipotent single doses of clonidine (0.2 mg) and alpha‐methyldopa (750 mg) to nine hypertensive patients. Plasma noradrenaline was followed for 8 h thereafter as an index of peripheral sympathetic activity. alpha‐Methyldopa and clonidine produced the same hypotensive response at 6 and 8 h after dosing with a similar fall in plasma noradrenaline levels at these times. Linear regression analysis between the systolic blood pressure fall and the corresponding plasma noradrenaline fall, showed that the slopes of the two regression lines were similar for alpha‐methyldopa as for clonidine. Equipotent doses of alpha‐methyldopa and clonidine produce the same fall in plasma noradrenaline. This supports the current hypothesis that an alpha‐methyldopa metabolite acts centrally, like clonidine, to reduce peripheral sympathetic activity.
Pharmacokinetics of potassium chloride in wax‐based and syrup formulations.
Authors: Toner JM , Ramsay LE
Published: July 2012

The effect on plasma potassium of 64 mmol potassium chloride (KCl) in two oral formulations was compared against placebo in five healthy men, and their bioavailability was calculated from urinary data. Mean plasma potassium varied between 4.0‐4.6 mmol/l during the placebo phase and mean (s.d.) urinary potassium excretion was 84.4 (18.5) mmol over 36 h. KCl syrup produced a significant change in plasma potassium over 24 h (P less than 0.02) with a marked elevation in the first 3 h after dosing and a mean (s.d.) peak plasma potassium 1.72 (0.52) mmol/l higher than placebo (P less than 0.05). By 36 h an excess of 55.9 (23.9) mmol potassium, equivalent to 87.3% of the stated dose, was excreted in the urine. KCl in wax base had a less consistent effect on plasma potassium (P greater than 0.5) and its effect was no more prolonged. The mean peak increment in plasma potassium was 1.03 (0.42) mmol/l (P less than 0.01) and the total potassium excretion was 50.5 (17.7) mmol higher than placebo values giving a bioavailability of 78.8% calculated from the stated dose.
Enalapril (MK421) activation in man: importance of liver status.
Authors: Larmour I , Jackson B , Cubela R , Johnston CI
Published: July 2012

The in vitro conversion of enalapril (MK421) to enalaprilic acid (MK422) in human autopsy tissues was examined. MK422 was measured by radioimmunoassay. Human cadaver liver was the only tissue in which significant conversion was demonstrated. The esterase activity was stable after post mortem. Autopsy liver tissues from patients with elevated ante mortem liver function tests were found to have a reduced rate of deesterification.
Central effects during the continuous osmotic infusion of a benzodiazepine (triazolam).
Authors: Breimer DD , Jochemsen R , Kamphuisen HA , Nicholson AN , Spencer MB , Stone BM
Published: July 2012

The effects of relatively constant plasma levels of a rapidly eliminated benzodiazepine (triazolam) were studied in young healthy males to determine whether tolerance to certain effects may develop over a relatively short period of time. The drug was given over a period of 30 h (2 days and 1 night) at zero‐order rate using a rectal osmotic pump. Performance was measured at 2 hourly intervals during the day and was continuously impaired during the infusion, though there was a rapid recovery when the infusion ceased. All tasks were affected, in particular mental arithmetic and letter cancellation, but there was some improvement in performance during the second day. The normal circadian improvement in performance may have contributed to this effect, but some degree of tolerance to the effect of the drug cannot be excluded. Overnight there was a marked reduction in wakefulness, suppression of slow wave sleep, and delay to the onset and reduction in the duration of rapid eye movement sleep. During the night after infusion there was less slow wave sleep and increased wakefulness. The experimental design may prove useful in the study of tolerance to drugs.
Fenfluramine delays gastric emptying of solid food.
Authors: Horowitz M , Collins PJ , Tuckwell V , Vernon‐Roberts J , Shearman DJ
Published: July 2012

The effect of a single dose of (+/‐)‐fenfluramine hydrochloride (40 mg) on gastric emptying of a mixed solid and liquid meal was assessed with a dual isotope scintigraphic technique in eight obese patients. Fenfluramine significantly delayed gastric emptying of solid food (approximately a 15% reduction in the solid linear emptying rate), but had no effect on gastric emptying of liquid.
Computers working for medicine.
Authors: Richmond G
Published: July 2012

A demonstration of the use of Viewdata Systems in clinical trials is presented. The potential of these systems in several areas of medicine is shown and related to their speed of development in the last 2 years. Particular reference is made to the use of computers in the assessment of patients with affective disorders.
The gastrointestinal absorption of drugs in man: a review of current concepts and methods of investigation.
Authors: Hirtz J
Published: July 2012

The various mechanisms which have been advanced to explain drug absorption are critically reviewed and the limitations of current theories are discussed. Various techniques for investigating drug absorption and transit through the gut are presented, and the results obtained with metoprolol are briefly considered to illustrate the potential of some of these methods.
Gastric, intestinal and colonic absorption of metoprolol in the rat.
Authors: Domenech J , Alba M , Morera JM , Obach R , Pla Delfina JM
Published: July 2012

The absorption of metoprolol from the stomach, small intestine and colon of anaesthetized rats has been evaluated using an in situ technique. Absorption rates were measured in terms of the rate of disappearance of metoprolol fumarate from the lumen between 5 and 30 min after dosing. Adsorption was estimated from the initial rapid fall in luminal content within the first 5 min after drug administration. The rate of drug absorption from the stomach was low or negligible. In the small intestine, the absorption rate constants, ka, at pH 6.2 and 7.5 were 0.66 and 0.81 h‐1, respectively. In the colon, the rate of drug absorption at pH 7.5 was faster (ka = 1.21 h‐1) than in other segments of the gut. Drug adsorption in the stomach amounted to 11% of the administered dose. In the small intestine adsorption was greater (16‐22%), presumably because of the larger surface area in this segment of the gut, but in the colon adsorption was negligible.
Pharmacokinetic investigation of the absorption of oxprenolol from Oros delivery systems in healthy volunteers: comparison of in vivo and in vitro drug release.
Authors: Bradbrook ID , John VA , Morrison PJ , Rogers HJ , Spector RG
Published: July 2012

The absorption kinetics of oxprenolol have been investigated in eight healthy volunteers after single dosing with 16/260 Oros drug delivery systems. Oxprenolol disposition kinetics in individual subjects were estimated from intravenous dose data. Loo‐Riegelman analysis of the plasma concentration data indicated an extended duration of drug absorption for the Oros system. Initially, the in vivo absorption rate was similar to the in vitro release rate but after 5‐6 h it slowed perceptibly. However, at later times similar in vivo and in vitro rates were again observed. The absolute bioavailabilities for prototype and clinical trial systems were shown to be similar, at approximately 42%, and no significant differences in plasma profiles or pharmacokinetic constants were detected between the two Oros forms. A comparison of plasma concentration data in seven subjects who received the prototype system on two occasions in separate studies indicated a consistent level of drug absorption from this preparation. Approximately 10‐15% of the administered dose was found in Oros systems recovered from faeces. The quantity of drug remaining was poorly correlated with the observed areas under the plasma concentration‐time curve.
Single‐dose pharmacokinetic and pharmacodynamic comparison of polymer‐ matrix (Slow Trasicor) and Oros dosage forms of oxprenolol in healthy volunteers.
Authors: Bennett PN , Bennett J , Bradbrook I , Francis J , John VA , Rogers H , Turner P , Warrington SJ
Published: July 2012

Oxprenolol was administered in single doses by mouth to healthy volunteers either in a polymer‐matrix slow‐release formulation (Slow Trasicor) or in osmotic drug‐delivery systems (oxprenolol Oros). Plasma oxprenolol concentrations and heart rates after exercise were measured. Plasma concentrations of the drug were maximal at 3 h but negligible at 24 h after administration of Slow Trasicor. Following ingestion of the Oros systems measurable concentrations were maintained throughout 24 h. Significant reduction of exercise‐induced tachycardia persisted for 24 h after administration of oxprenolol Oros. With Slow Trasicor heart rate responses had returned to baseline values by this time. The osmotic drug‐delivery systems appear to sustain significant beta‐ adrenoceptor blockade for 24 h after a single oral dose.
Influence of site of drug delivery on the systemic availability of metoprolol: comparison of intragastric infusion and 14/190 Oros administration.
Authors: Warrington SJ , Barclay SP , John VA , Shotton PA , Wardle HM , Good W
Published: July 2012

The influence of the site of drug delivery on the systemic availability of metoprolol has been evaluated by measuring plasma drug concentrations in six healthy volunteers after administration of a continuous 13.5 h intragastric infusion and a 14/190 Oros controlled‐ release dosage form, on two separate occasions. The same total amount of drug was administered at the same rate on both occasions but the Oros system moved through the gut whereas the site of the infusion was constant. The differences between treatments were confined largely to the period 6‐15 h after dosing when lower plasma concentrations were obtained after administration of the Oros system. The levels after 20 h were higher for Oros, however, reflecting its longer duration of drug release. The amount of drug reaching the circulation was 19.8% less for the Oros preparation compared with intragastric infusion but this was not due to incomplete release since the residual amounts of drug in three systems recovered from faeces corresponded to less than 12% of the administered dose. Analysis of the plasma profiles by the Wagner‐ Nelson method indicated a reasonable agreement between in vitro release and in vivo absorption. The appearance of drug in plasma was delayed for both treatments, and for Oros the apparent absorption rate slowed 6 h after dosing. Plasma profiles after 14/190 metoprolol Oros were consistent with prolonged in vivo delivery and absorption from the gut. The absorption process, however, was associated with some reduction both in the rate, after 6 h, and in the total amount reaching the circulation.
Effects of locally and systemically administered cholinoceptor antagonists on the secretory response of human eccrine sweat glands to carbachol.
Authors: Longmore J , Bradshaw CM , Szabadi E
Published: July 2012

Eleven healthy male volunteers participated in a study comparing the effects of locally and systemically administered cholinoceptor antagonists on the secretory response of sweat glands to intradermally injected carbachol chloride. Atropine sulphate administered locally into the skin antagonised the response to carbachol: the dose‐response curve for carbachol was shifted to the right without any depression of the maximum of the curve. The nicotinic receptor antagonists hexamethonium bromide and (+)‐tubocurarine chloride, however, had little effect on the response to carbachol. Atropine sulphate, administered systemically by intramuscular injection, caused a non‐ surmountable antagonism of the response to carbachol: the maximum of the dose‐response curve was depressed with little change in the value of ED50. Atropine methonitrate (a mixed muscarinic/nicotinic receptor antagonist), and hexamethonium bromide (a nicotinic receptor antagonist), both with poor access to the central nervous system, were injected intramuscularly: both caused non‐surmountable antagonism of the response to carbachol. It is concluded that the response to carbachol is mediated by muscarinic rather than nicotinic receptors. The effect of atropine sulphate on the response to carbachol depends on the route of administration: while locally applied atropine sulphate appears to act as a competitive antagonist, systemically applied atropine sulphate, like atropine methonitrate and hexamethonium bromide, appears to act in a non‐competitive manner. It is suggested that the systemically administered cholinoceptor antagonists reduce the response to carbachol by interacting with cholinoceptors in sympathetic ganglia: such an interaction would reduce the impulse flow in sudomotor fibres resulting in decreased sensitivity of the sweat glands to carbachol.
Phenacetin O‐deethylase: an activity of a cytochrome P‐450 showing genetic linkage with that catalysing the 4‐hydroxylation of debrisoquine?
Authors: Kahn GC , Boobis AR , Brodie MJ , Toverud EL , Murray S , Davies DS
Published: July 2012

Phenacetin O‐deethylase activity was impaired, both in vivo and in vitro, in poor metabolisers of debrisoquine, consistent with the work of others. No impairment was observed in the oxidation of acetanilide, amylobarbitone or antipyrine in the PM phenotype. There was a good correlation (r = 0.804) between the high affinity component of phenacetin O‐deethylase and debrisoquine 4‐hydroxylase activities. No such correlation was observed with the low affinity component of phenacetin O‐deethylase activity. Although debrisoquine was a competitive inhibitor of phenacetin O‐deethylase activity, phenacetin was without effect on debrisoquine 4‐hydroxylation. There was also marked differences in the effects of sparteine, guanoxan and alpha‐ naphthoflavone on the two activities. Cigarette smoking was associated with a significant, two‐fold, increase in phenacetin O‐deethylase activity whilst debrisoquine 4‐hydroxylase activity was not affected. It is concluded that the high affinity component of phenacetin O‐ deethylase and debrisoquine 4‐hydroxylase activities are catalysed by different isozymes of cytochrome P‐450 but that these are most probably regulated by closely linked genes.
Discovery of altered pharmacokinetics of CGP 15 210 G in poor hydroxylators of debrisoquine during early drug development.
Authors: Gleiter CH , Aichele G , Nilsson E , Hengen N , Antonin KH , Bieck PR
Published: July 2012

The pharmacokinetics of CGP 15 210 G, a new 5‐HT uptake inhibitor in poor and extensive metabolisers of debrisoquine, give indirect evidence of an association between its metabolism and polymorphic hydroxylation of the debrisoquine type.
The effects of long‐acting pinacidil on intra‐arterial blood pressure.
Authors: Caruana MP , Al‐Khawaja I. , Royston P. , Raftery EB
Published: July 2012

We have tested the efficacy of a new long‐acting preparation of pinacidil, an arterial vasodilator, using continuous intra‐arterial ambulatory blood pressure recording. An acute dose produced a measurable effect lasting for 12 h. The duration of this effect was less during chronic twice daily drug administration. Side effects were common, causing two out of nine patients to withdraw from the study. Tilt testing produced no postural hypotension and there was no evidence of rebound hypertension on the withdrawal day.
Effects of long‐acting propranolol on blood pressure and heart rate in hypertensive Chinese.
Authors: Oh VM , Chia BL , Taylor EA
Published: July 2012

In a double‐blind, balanced and randomised study we used treadmill exercise to assess the effects of long‐acting propranolol (LA propranolol) 160 or 320 mg or placebo, given once daily for 4 weeks, on heart rate (HR) and blood pressure (BP) in 15 Chinese subjects with mild primary hypertension (PHT). We used 24 h ECG monitoring to assess drug effects on HR. Another 18 patients were similarly assessed without exercise. Steady‐state plasma propranolol concentrations after LA propranolol 160 and 320 mg were comparable to those after ordinary propranolol 80 and 160 mg daily measured in 11 and 12 separate patients. LA propranolol 160 and 320 mg reduced HR and BP before and during vigorous exercise. LA propranolol 160 and 320 mg reduced HR for 17.6 and 21.4 h of the day, and 320 mg significantly reduced the mean 24 h HR, and the mean maximum HR. The drug effects on BP and HR, and the average plasma propranolol levels after LA propranolol were similar to those reported in European subjects.
Pharmacokinetics of ranitidine in quadriplegics.
Authors: More DG , Watson CJ , Boutagy JS , Shenfield GM
Published: July 2012

In a previous study we observed that quadriplegic patients were unresponsive to ranitidine given in high dose (600 mg day‐1 intravenously) for prophylaxis of stress ulceration. The pharmacokinetics of 100 mg of intravenous ranitidine have therefore been studied in six male quadriplegic patients. Plasma drug concentrations declined in a biexponential fashion. The mean (+/‐ s.e. mean) distribution half‐life was 9.42 (+/‐ 1.04) min. The terminal plasma elimination half‐life 1.79 (+/‐ 0.12) h, the volume of distribution 103 (+/‐ 17) litres and total body clearance 663 (+/‐ 86) ml/min. These values are similar to those described in two published studies performed in normal male volunteers. This suggests that there is no pharmacokinetic reason for the quadriplegics to be resistant to ranitidine and the defect is likely to be related to vagal control of acid secretion.
The effect of ranitidine on the disposition of lignocaine.
Authors: Robson RA , Wing LM , Miners JO , Lillywhite KJ , Birkett DJ
Published: July 2012

The effect of pretreatment with ranitidine (150 mg twice daily for 5 days) on the disposition of lignocaine was examined in 10 healthy volunteers (five male, five female). Each subject received separate oral (250 mg) and intravenous (1.5 mg/kg) doses of lignocaine hydrochloride before and after ranitidine. Lignocaine systemic clearance was reduced by 9% (1.11 to 0.99 1 h‐1 kg‐1; P less than 0.01) following ranitidine pretreatment. The volume of distribution at steady‐ state was reduced by 15% (3.34 to 2.85 1 kg‐1; P less than 0.005). Lignocaine oral clearance, elimination half‐life and oral bioavailability were unchanged after ranitidine pretreatment. There was no sex difference in the effects of ranitidine pretreatment on lignocaine disposition. These results are consistent with small reductions in blood flow to the splanchnic and other vascular beds due to ranitidine.
Lack of effect of nizatidine on hepatic drug metabolism in man.
Authors: Secor JW , Speeg KV , Meredith CG , Johnson RF , Snowdy P. , Schenker S.
Published: July 2012

The effect of nizatidine, a new H2‐receptor antagonist, on the hepatic metabolism of three probe drugs was studied in normal volunteers. The drugs studied were chlordiazepoxide and theophylline which are metabolized in part by N‐demethylation by the hepatic microsomal cytochrome P‐450 system and lorazepam which is conjugated to lorazepam glucuronide. A 7 day course of nizatidine did not interfere with the disposition of any of these therapeutic agents in man.
Effects of nicardipine on aldosterone release and pressor mechanisms.
Authors: Elliott HL , Pasanisi F. , Reid JL
Published: July 2012

This study evaluated the effects of nicardipine, following intravenous infusion and oral administration, on the pressor and aldosterone responses to infused angiotensin II. Six healthy, normotensive male subjects were studied. Following administration of nicardipine, no significant change in blood pressure was seen. Nicardipine attenuated the pressor response produced by intravenous administration of angiotensin. Nicardipine did not inhibit the aldosterone response to angiotensin.
Effects of nicardipine on cardiac volume at rest and during exercise‐ induced angina.
Authors: Silke B. , Verma SP , Frais MA , Hafizullah M. , Taylor SH
Published: July 2012

The action of nicardipine on cardiac volume, both at rest and during exercise‐induced angina, was evaluated in 12 patients with angiographically‐proven coronary artery disease. Nicardipine given to patients at rest reduced systemic vascular resistance and mean arterial pressure and increased heart rate and cardiac index. The left ventricular filling pressure, ejection fraction (EF), end‐diastolic and end‐systolic volumes were unchanged. During supine bicycle exercise, the reduction in systemic arterial blood pressure following nicardipine increased cardiac and stroke index and attenuated the rise in left ventricular filling pressure observed in the control exercise. The effects of nicardipine on EF, end‐diastolic and end‐systolic cardiac volumes were dependent on the baseline cardiac reserve. In patients with EF less than 50%, nicardipine improved EF and left ventricular exercise volumes.
Short‐ and long‐term treatment of stable effort angina with nicardipine, a new calcium channel blocker: a double‐blind, placebo‐ controlled, randomised, repeated cross‐over study.
Authors: Gheorghiade M. , St Clair C. , St Clair J. , Freedman D. , Schwemer G.
Published: July 2012

This study evaluated 1 year the efficacy of therapy with nicardipine in patients with chronic stable angina pectoris. Twenty‐five male patients were entered. After a placebo run‐in phase, the patients received nicardipine 30 mg, nicardipine 40 mg, and placebo, three times daily given in random, double‐blind manner for 8 weeks. A double‐blind, cross‐ over study comparing nicardipine with placebo was then undertaken. After 5 months of open treatment with nicardipine 90 or 120 mg day‐1, patients received either placebo or nicardipine for 3 weeks, each followed by the alternative treatment for an additional 3 weeks and further open‐label treatment with nicardipine for another 3‐5 months. There were no significant changes in the PR, QRS or QT intervals, or in the QRS pattern during the short‐term and long‐term studies. There were no significant differences in mean heart rate after nicardipine compared with baseline. During treatment with nicardipine 120 mg day‐1, patients reported significantly fewer anginal attacks compared with placebo, and nitroglycerin consumption also decreased. Nicardipine increased treadmill time, time to onset of angina, and time to one mm ST segment depression. These effects were maintained after 6 months of continued nicardipine therapy. Adverse effects were minor and well tolerated and included headache, dizziness, gastrointestinal upset, flushing paraesthesia and pedal oedema. Abrupt withdrawal of nicardipine at the end of the study resulted in a rapid return of the original symptoms but without further deterioration from the baseline measurements. Nicardipine was effective in the treatment of stable effort angina pectoris; this benefit was maintained for the entire year of treatment.
Pharmacokinetics of enalapril in normal subjects and patients with renal impairment.
Authors: Kelly JG , Doyle G , Donohue J , Laher M , Vandenburg MJ , Currie WJ , Cooper WD
Published: July 2012

The pharmacokinetics of enalaprilat were studied after administration of single and multiple doses of enalapril maleate to people with normal and impaired renal function. Renal impairment was associated with higher serum concentrations of enalaprilat, longer times to peak concentrations, slower decline of serum concentrations and with reduced urinary elimination. Urinary elimination of enalaprilat was closely related to renal function. In patients with severe renal impairment (GFR values below 30 ml min‐1 1.73 m‐2) significantly smaller doses of enalapril maleate will be required than in patients with normal or less severely impaired renal function.
Alpha‐adrenergic receptors in human blood vessels.
Authors: Van Brummelen P , Jie K , Van Zwieten PA
Published: July 2012

The evidence for the presence of postjunctional alpha 1‐ and alpha 2‐ adrenoceptor subtypes in human blood vessels is reviewed. Experiments in healthy subjects are described that show that alpha 1‐ as well as alpha 2‐adrenoceptor mediated vasoconstriction contribute to vascular smooth muscle tone and that adrenaline and noradrenaline have similar affinities for each subtype. In addition, evidence is presented for a preferential intrajunctional location of alpha 1‐adrenoceptors and a preferential extrajunctional location of alpha 2‐adrenoceptors in human blood vessels. It is concluded that at present postjunctional alpha‐ adrenoceptors in human blood vessels can be classified as alpha 1 and alpha 2. Despite the fact that both subtypes mediate vasoconstriction, these receptors are likely to subserve different physiological functions.
Multicentre 12‐week double‐blind comparison of doxazosin, prazosin and placebo in patients with mild to moderate essential hypertension.
Authors: Torvik D , Madsbu HP
Published: July 2012

A 12‐week double‐blind study was performed to compare the safety and efficacy of doxazosin, prazosin and placebo in 172 patients with essential hypertension. According to response, patients received doxazosin 1‐16 mg once daily, prazosin 0.5‐10 mg twice daily, or placebo. Mean final daily doses were doxazosin 11.3 mg and prazosin 13.8 mg. Doxazosin once daily and prazosin twice daily both produced statistically significant reductions in both standing and supine blood pressures when compared with placebo. No significant differences between treatments were recorded for standing and supine heart rates. Doxazosin, prazosin and placebo all had a similar effect on plasma lipid profiles, i.e. an increase in HDL/total cholesterol of approximately 10%. The differences between treatments were not statistically significant. The HDL/total cholesterol ratio significantly increased from baseline to the end of treatment for all three groups, the decrease in triglycerides being statistically significant only in the doxazosin‐treated group.
In vivo cation transport during short‐term and long‐term digoxin therapy.
Authors: Boon NA , Pugh SE , Hallis KF , Aronson JK , Grahame‐Smith DG
Published: July 2012

We have studied the effects of digoxin on cation transport in vivo by measuring the changes in plasma and red cell rubidium concentrations following an oral load of rubidium chloride. In eight patients who had been taking digoxin for 7 to 10 days (mean plasma digoxin concentration 1.3 ng ml‐1) the rise in plasma rubidium concentrations was enhanced and the rise in red cell rubidium concentrations was attenuated following the oral load of rubidium chloride, by comparison with the changes in well‐matched controls. In contrast, the disposition of rubidium was not altered in 12 patients who had been taking digoxin for more than 3 months (mean plasma digoxin concentration 1.1 ng ml‐1). These results suggest that the inhibitory effects of digoxin on cation transport are detectable in vivo during short‐term therapy, but not during long‐term therapy, and confirm our previous in vitro findings.
Acute haemodynamic effects of pinacidil in man.
Authors: Nicholls DP , Murtagh JG , Scott ME , Morton P , Shanks RG
Published: July 2012

The acute haemodynamic effects of i.v. pinacidil 0.2 mg kg‐1 infused over 8 min were studied in 10 normotensive patients undergoing cardiac catheterisation. Mean arterial pressure fell from 94 +/‐ 3 mmHg (mean +/‐ s.e. mean) before infusion to 74 +/‐ 3 mmHg at 10 min after commencing infusion (P less than 0.001) and during this time heart rate increased from 75 +/‐ 4 to 106 +/‐ 7 beats min‐1 (P less than 0.001). Significant changes were recorded until the end of the observation period (70 min after commencing infusion). Cardiac index increased from 3.2 +/‐ 0.2 to 4.0 +/‐ 0.2 l min‐1 m‐2 (P less than 0.001) and systemic vascular resistance fell from 16 +/‐ 1 to 10 +/‐ 1 units (P less than 0.001) at 10 min after commencing infusion. By the end of the observation period, the values had returned to pre‐infusion levels. Only small changes in pulmonary haemodynamics were observed. These results indicate that pinacidil acts as a peripheral arteriolar vasodilator, and as such may have a role in the treatment of arterial hypertension and of cardiac failure.
Paracetamol metabolism in pregnancy.
Authors: Miners JO , Robson RA , Birkett DJ
Published: July 2012

Paracetamol disposition was studied in groups of pregnant and non‐ pregnant women of comparable age. Paracetamol apparent oral clearance was 58% higher and elimination half‐life was 28% lower in the pregnant women compared to the control group. The higher clearance in the pregnant women was due to increased activity of the glucuronidation (75% higher) and oxidative (88% higher) pathways of paracetamol metabolism. There was no difference between the two groups in paracetamol sulphation or renal clearance of unchanged drug.