bluuebunny/crossref_metadata_2025 huggingface dataset:
Ketanserin in combination with beta‐adrenergic receptor blocking agents in the treatment of essential hypertension.
Authors: Hedner T , Persson B
Published: July 2012

The antihypertensive properties of ketanserin, a 5‐HT2 receptor antagonist, was investigated in combination with beta‐adrenoceptor blockade. Ketanserin was given 40 mg twice daily to 10 hypertensive patients during 4 weeks in a double‐blind placebo‐controlled trial. Ketanserin significantly reduced supine and erect blood pressure compared to double‐blind placebo, while no changes in heart rate were seen. When the blood pressure was assessed during 24 h at steady state conditions, the blood pressure reduction was maximal 1‐2 h after tablet intake, corresponding to peak plasma concentrations of ketanserin. The blood pressure remained significantly reduced until next tablet intake (12 h). At steady state, on a 40 mg twice daily regimen, Css was 41.6 +/‐ 4.22, 36.9 +/‐ 5.19 and 39.8 +/‐ 4.81 ng/ml, Cmax 102.4 +/‐ 15.64 ng/ml and tmax 1.6 +/‐ 0.32 h. A slight sedation was observed in six patients. This side effect occurred 1‐2 h after tablet intake and tended to subside with continued treatment.
Indobufen interacts with the sulphonylurea, glipizide, but not with the beta‐adrenergic receptor antagonists, propranolol and atenolol.
Authors: Elvander‐Stahl E , Melander A , Wahlin‐Boll E
Published: July 2012

This study assessed the possible interactions of the cyclooxygenase inhibitor indobufen with one sulphonylurea, glipizide, and with two beta‐adrenoceptor antagonists, one of which is extensively metabolised already in the first passage through the liver (propranolol) while the other essentially escapes biotransformation (atenolol). Indobufen was first given as a single 200 mg dose and then for a 5 day period in a dosage of 200 mg twice daily, to six healthy volunteers. Glipizide (5 mg), propranolol (80 mg) and atenolol (100 mg) were given as single doses before and during indobufen medication. The drug concentrations were measured by selective and sensitive h.p.l.c. methods. The findings suggest that the lipophilic acid indobufen can inhibit the metabolic inactivation of another lipophilic acid, glipizide, but does not interfere with the disposal of the two basic drugs, propranolol and atenolol. The increased glipizide concentrations following indobufen were associated with an enhanced blood glucose reduction. Hence, this interaction may be clinically relevant.
The effect of omeprazole on gastric emptying in patients with duodenal ulcer disease.
Authors: Horowitz M , Hetzel DJ , Buckle PJ , Chatterton BE , Shearman DJ
Published: July 2012

The effect of a single oral dose of omeprazole (90 mg) on gastric emptying was assessed with a dual isotope scintigraphic technique in eight patients with a history of duodenal ulcer disease. Omeprazole had no significant effect on solid or liquid gastric emptying. The bioavailability (AUC0‐2 h) of omeprazole in all patients was greater than that required for total suppression of acid secretion. No adverse clinical or laboratory effects were observed.
H2‐receptor blockade and exercise‐induced asthma.
Authors: Nogrady SG , Hahn AG
Published: July 2012

While in vitro studies suggest that H2‐receptor blockade enhances mediator release from bronchial mast cells and leads to bronchoconstriction, in vivo studies have given conflicting results. Eight asthmatic subjects were given cimetidine 800 mg and placebo double‐blind on different days. Baseline values of forced expiratory volume in one second (FEV1) were obtained before an 8 min standardized exercise test using a bicycle ergometer. Subjects inhaled cold, dry air and exercise on cimetidine and placebo days was matched for ventilation and thermal load. FEV1 was measured immediately, 5, 10, 15, and 20 min after exercise. No significant differences were observed between mean baseline FEV1, immediate post exercise FEV1, or maximum percentage fall from baseline after exercise on cimetidine or placebo days. Cimetidine does not appear to effect lung function or bronchial responses to cold air exercise challenge.
Nicotine from cigarette smoking enhances clonidine‐induced increase of serum growth hormone concentrations in men.
Authors: Coiro V , d'Amato L , Borciani E , Rossi G , Camellini L , Maffei ML , Pignatti D , Chiodera P
Published: July 2012

In order to determine whether nicotine exerts its stimulant effect on serum concentrations of growth hormone (GH) by interacting with an adrenergic pathway, we evaluated the effect of cigarette smoking on the response of GH to the administration of clonidine, a specific alpha‐ adrenoceptor agonist. In six normal volunteers, clonidine significantly increased serum levels of GH. When subjects smoked two non‐filter cigarettes, GH response to the alpha‐adrenoceptor agonist was greatly enhanced. These findings suggest that in man nicotinic cholinergic and adrenergic mechanisms might interact in the stimulation of GH secretion.
Alpha 1‐acid glycoprotein concentrations and propranolol binding in elderly patients with acute illness.
Authors: Paxton JW , Briant RH
Published: July 2012

Alpha 1‐acid glycoprotein (AAG) concentrations and propranolol binding were investigated in the serum of elderly hospitalized patients with acute illness, and healthy elderly and young subjects. Significantly greater AAG concentrations and reduced unbound propranolol fraction were observed in the elderly with acute disease compared to the elderly controls. The greatest changes (up to five‐fold) occurred with cancer, with lesser changes associated with myocardial infarction and ischaemic heart disease, acute infection, heart failure, chronic obstructive respiratory disease, and cerebrovascular accident. Various miscellaneous conditions were also associated with high AAG concentrations and enhanced propranolol binding. The healthy elderly had higher AAG concentrations and lower unbound propranolol fractions than the healthy young group. Overall there was a highly significant correlation between the propranolol binding ratio (bound/free) and the serum AAG concentration. These results suggest that the elderly population may be particularly susceptible to changes in AAG concentrations, and that during acute illness interpretation of serum concentrations of drugs which bind mainly to AAG, may require knowledge of their free fractions.
Effect of a new calcium antagonist, tiapamil, in hypertension of the elderly.
Authors: Balansard P , Elkik F , Levenson JA , Ciampi M , Sans P
Published: July 2012

The antihypertensive effect of a single oral dose of tiapamil (450 mg) and placebo were compared in a single blind randomized cross‐over study in 10 71‐86 year old hypertensive patients. Blood pressure (BP) and heart rate (HR) were recorded every 15 min for 12 h by an automatic device. Tiapamil led to a decrease in mean daytime systolic (SBP) and diastolic (DBP) BP from 171 +/‐ 12/98 +/‐ 10 mm Hg to 159 +/‐ 11/90 +/‐ 9 mm Hg (P less than 0.001) without significant variation in HR. Thereafter patients received tiapamil 450 twice daily; by the seventh day of treatment mean daytime SBP and DBP were 155 +/‐ 13/85 +/‐ 14 mm Hg (P less than 0.001 vs placebo). The hourly mean values of SBP recorded for 8/12 h (first tiapamil day) and 10/12 h (seventh tiapamil day) were significantly lower than the corresponding values after placebo. We conclude that tiapamil in the elderly exerts a sustained antihypertensive effect lasting 12 h or more, with only minor variations in HR. This effect predominates on systolic pressure and is significant from the first dose.
Nicardipine: pharmacokinetics and effects on carotid and brachial blood flows in normal volunteers.
Authors: Thuillez C , Gueret M , Duhaze P , Lhoste F , Kiechel JR , Giudicelli JF
Published: July 2012

The effects of nicardipine, 20 mg, three times daily, nicardipine slow release, 30 mg, twice daily and a placebo on brachial and carotid arteries diameters and flows have been investigated by the pulsed Doppler technique during a single blind and cross‐over study performed in six healthy volunteers. Simultaneously, nicardipine plasma levels and relative bioavailability were determined. Nicardipine significantly increased brachial and carotid arteries diameters (by 16 and 10% respectively) and flows (by 60 and 35% respectively). These effects peaked after 4 h and lasted no longer than 6 h. Forearm vascular resistance was significantly decreased. Hence nicardipine dilated both large and small arteries. Nicardipine slow release elicited the same effects on brachial and carotid arteries diameters and flows as nicardipine. These effects peaked at 6 h and lasted up to 10 h. Although the profiles of the pharmacodynamic effects and of the kinetics of nicardipine were almost parallel in each individual after administration of both nicardipine formulations, there was no correlation between the nicardipine plasma relative bioavailability and its effects on brachial and carotid arteries blood flows when considering all subjects together.
Cimetidine alters pethidine disposition in man.
Authors: Guay DR , Meatherall RC , Chalmers JL , Grahame GR
Published: July 2012

The effect of concurrent cimetidine administration on the disposition of pethidine was investigated in eight healthy male volunteers (18‐31 years). The subjects received 70 mg i.v. pethidine HCl doses before and during cimetidine treatment (1200 mg/day p.o.). During cimetidine treatment, pethidine total body clearance (CL) decreased by 22% (0.611 +/‐ 0.101 [mean +/‐ s.d.] to 0.474 +/‐ 0.098 1 kg‐1 h, P less than 0.05) and pethidine volume of distribution at steady state (Vss) decreased by 13% (4.79 +/‐ 0.82 to 4.16 +/‐ 0.75 l/kg, P less than 0.05). A cimetidine‐induced reduction in pethidine oxidation to norpethidine was suggested by a 23% reduction in norpethidine area under the curve from 0 to 24 h (472 +/‐ 93 to 362 +/‐ 38 ng ml‐1 h, P less than 0.05) and a 29% reduction in peak norpethidine concentration (26.7 +/‐ 5.3 to 18.9 +/‐ 1.9 ng/ml, P less than 0.05). There were no significant linear correlations of serum trough cimetidine concentration with percentage reductions in pethidine CL, pethidine Vss, norpethidine AUC (24), or norpethidine peak concentrations. It would appear that the cimetidine‐pethidine kinetic interaction may be of sufficient magnitude to be clinically significant. Caution is advised when patients are treated concurrently with these two agents.
Carbamazepine 10,11‐epoxide in children.
Authors: Rylance GW , Edwards C , Gard PR
Published: July 2012

Concentrations of carbamazepine (CBZ) and its 10,11‐epoxide metabolite (CBZ‐E) were measured in simultaneously collected plasma and mixed saliva samples from 15 children (aged 1‐13 years). Saliva concentrations of CBZ and CBZ‐E were measured in hourly samples taken from six of these children during dose intervals whilst on different dose or dose‐frequency regimens. Saliva and plasma CBZ (r = 0.91; P less than 0.001) and CBZ‐E (r = 0.91; P less than 0.001) concentrations were significantly correlated. The mean +/‐ s.d. steady state CBZ‐E/CBZ concentration ratio in the six children was 0.40 +/‐ 0.21 and was similar at all times within the 12 h dose interval. The mean +/‐ s.d. percentage fluctuation of the combined CBZ + CBZ‐E (103.0 +/‐28.9) was significantly less than that of CBZ‐E (145.5 +/‐ 52.8) but not CBZ (109.6 +/‐ 31.1). If CBZ and CBZ‐E have equipotent anticonvulsant activity in man, the contribution of CBZ‐E approximates to 30% of total anticonvulsant effect in children taking CBZ alone.
Dose‐response studies with pancuronium, vecuronium and their combination.
Authors: Ferres CJ , Mirakhur RK , Pandit SK , Clarke RS , Gibson FM
Published: July 2012

Pancuronium, vecuronium and a combination of these were administered in an incremental fashion to study any potentiation of effect with the combination of the two relaxants. The ED95 (dose producing a 95% block) of the combination was 29 micrograms kg‐1 for each component in comparison to 57 micrograms kg‐1 for vecuronium and 59 micrograms kg‐1 for pancuronium. The dose‐response curves for the three groups did not differ from each other and no potentiation was demonstrated.
Domperidone and levodopa in Parkinson's disease.
Authors: Shindler JS , Finnerty GT , Towlson K , Dolan AL , Davies CL , Parkes JD
Published: July 2012

To study the absorption of levodopa and interaction with the extracerebral dopamine antagonist domperidone, 15 patients with idiopathic Parkinson's disease were given levodopa 500 mg p.o., alone, and with domperidone pre‐treatment. Domperidone pretreatment (10, 20, 40 mg, p.o., i.v. or i.m.) caused a mean 12% increase in peak plasma levodopa concentration, which occurred a mean of 10 min earlier than when levodopa was given alone. Parkinsonian disability scores were improved and peak clinical response occurred 16 min earlier with domperidone than without. Domperidone slightly increases the immediate bioavailability (over 4 h) and anti‐parkinsonian response to a given dose of levodopa.
Driving tests with patients.
Authors: de Gier JJ
Published: July 2012

Mental illness and the use of psychotropic drugs are considered to influence driving skills of patients. However, studies which indicate the relative contributions of these factors are rare. It is emphasized that for measuring the effects of psychotropic drugs on driving performance of patients, real driving tests are needed. Actual driving and psychomotor performance of patients receiving diazepam, and patients and healthy volunteers receiving mebhydrolin were measured to illustrate the use of real driving tests. The results of both studies are discussed in terms of problems associated with the application of these tests. Patient recruitment is considered to be a major problem. To draw conclusions under these circumstances is extremely difficult, but still acceptable in comparison with the limitations and methodological difficulties of the more commonly used laboratory tests. Some guidelines for driving tests with patients are given.
Enalapril in heart failure.
Authors: Nicholls MG , Ikram H , Espiner EA , Webster MW , Fitzpatrick MA
Published: July 2012

Serum MK‐422 and plasma angiotensin converting enzyme activity were measured during the introduction of enalapril therapy in eight patients with heart failure. In a second study of 16 patients, we recorded exercise tolerance, clinical status and haemodynamics before and after 12 weeks of placebo or enalapril treatment. Increasing doses of enalapril gave step‐wise increments in serum MK‐422. Plasma converting enzyme activity remained low for at least 24 h after each dose of enalapril (5, 10 and 20 mg). Compared to placebo patients (n = 8), those receiving enalapril (n = 8) tended to improve their exercise performance and clinical status, and showed a fall in right heart pressures after 12 weeks of treatment.
Effect of converting enzyme inhibition by enalapril on sodium homeostasis in the rat.
Authors: Jover B , Mimran A
Published: July 2012

The effect of oral treatment with the converting enzyme inhibitor enalapril on sodium homeostasis was investigated in the rat. Treatment by enalapril prior to and during a 6 day period following abrupt suppression of dietary Na+ was associated with a sodium wasting state (urinary Na+ always exceeded intake during the observation period) and blunting by 90% of the aldosterone response to Na+ restriction In rats on chronic low Na+ intake, enalapril produced a slight, transient natriuresis together with a marked increase in drinking volume. In Na+ replete rats, enalapril had no influence on sodium balance. Converting enzyme inhibition markedly impaired the systemic and renal response to Na restriction and enalapril had no natriuretic effect in the Na+ replete state.
An overview of the clinical pharmacology of enalapril.
Authors: Davies RO , Gomez HJ , Irvin JD , Walker JF
Published: July 2012

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half‐life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose‐response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once‐ or twice‐daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase.
Oxazepam pharmacokinetics in thyroid disease.
Authors: Scott AK , Khir AS , Bewsher PD , Hawksworth GM
Published: July 2012

The pharmacokinetics of oxazepam, a drug mainly eliminated by a single step glucuronidation reaction, were studied in seven hyperthyroid and six hypothyroid patients before and after treatment. Oxazepam elimination half‐life was shorter and apparent oral clearance higher in untreated hyperthyroid patients than after treatment. There was no significant change in oxazepam elimination in hypothyroid subjects. Time to peak concentration (tmax) was reduced in the hyperthyroid state. Hypothyroidism had no significant effect on tmax. Serum bilirubin concentration was lower in the patients while hyperthyroid before treatment than when euthyroid and also lower than in the hypothyroid patients. There was no significant correlation between serum bilirubin concentrations and oxazepam elimination. These results suggest that glucuronyl transferase activity is increased in hyperthyroidism but is not altered in most patients with hypothyroidism. The extent of increase in glucuronyl transferase activity is similar to that produced by enzyme inducing drugs.
Nicotine and cotinine concentrations in serum and milk of nursing smokers.
Authors: Luck W. , Nau H.
Published: July 2012

Analysis of 44 milk samples from 23 nursing smokers revealed that there was a linear correlation between nicotine concentrations in serum and in milk (r = 0.70). The nicotine concentrations in milk were considerably higher than the corresponding serum concentrations: milk/serum concentration ratio = 2.92 +/‐ 1.09; (n = 44). There was also a linear correlation between the cotinine concentrations in serum and in milk (r = 0.89). The cotinine concentrations in milk were lower than the corresponding serum concentrations: milk/serum concentration ratio = 0.78 +/‐ 0.19; (n = 44). The direct comparison between the half‐ lives of nicotine in serum and in milk was possible in five nursing smokers. The half‐life of nicotine in milk was determined in four additional smoking mothers. The half‐life of nicotine in milk t 1/2 = 97 +/‐ 20 min slightly exceeded the half‐life of nicotine in serum t 1/2 = 81 +/‐ 9 min; the difference between these two values was not statistically significant (P greater than 0.05). Cotinine concentrations remained fairly consistent during a 4 h interval without smoking.
Effect of valproate on free plasma phenytoin concentrations.
Authors: Tsanaclis LM , Allen J. , Perucca E. , Routledge PA , Richens A.
Published: July 2012

The plasma protein binding of phenytoin was studied in nine epileptic patients before and during addition of sodium valproate to the drug therapy. The free phenytoin fraction in plasma was significantly greater during sodium valproate treatment. The mean free fraction rose from 0.135 +/‐ 0.019 (s.d.) to 0.182 +/‐ 0.030. Total plasma phenytoin concentration fell significantly from a range of 4.3‐26.2 micrograms/ml to 3.4‐19.8 micrograms/ml during sodium valproate treatment. Neither the free plasma concentration nor the saliva concentration of phenytoin was significantly altered by sodium valproate. No significant correlation was found between plasma valproic acid concentrations and the change in phenytoin binding. We conclude that valproic acid displaces phenytoin from plasma protein binding sites but does not inhibit its metabolism.
Pharmacodynamics and pharmacokinetics of digoxin in the presence of lithium.
Authors: Cooper SJ , Kelly JG , Johnston GD , Copeland S. , King DJ , McDevitt DG
Published: July 2012

Previous biochemical and clinical data suggest there may be an interaction between digoxin and lithium. The pharmacodynamics and pharmacokinetics of an intravenous infusion of digoxin were studied in six male subjects before and after 2 weeks treatment with lithium carbonate. The effects of lithium on sodium pump activity, intracellular electrolytes and extracellular electrolytes were studied. No significant interaction between digoxin and lithium was found. No significant effects of lithium on sodium pump activity or electrolyte concentrations were found.
Effects of chronic metoprolol and sulphinpyrazone on human lymphocyte beta‐adrenoceptors.
Authors: De Blasi A. , Cortellaro M. , Costantini C.
Published: July 2012

Multiple (100 mg twice daily for 21 days) but not single (100 mg) oral doses of metoprolol significantly reduced the number (Bmax) and the KD of beta‐adrenoceptors on intact lymphocytes from nine healthy volunteers. Sulphinpyrazone (400 mg twice daily for 21 days) did not change lymphocyte beta‐adrenoceptors and did not modify their reaction to chronic metoprolol. In vitro sulphinpyrazone (10‐4M) increased [3H]‐ DHA specific binding on intact lymphocytes. This effect was not modified by metoprolol, sulphinpyrazone or the two combined. Metoprolol and sulphinpyrazone did not interact in the experimental model of beta‐ adrenoceptors on intact lymphocytes in conditions mimicking long‐term treatment.
Antihypertensive and renal effects of nicardipine.
Authors: van Schaik BA , van Nistelrooy AE , Geyskes GG
Published: July 2012

Both the acute blood pressure lowering and renal effects of the calcium antagonist nicardipine and those after 1 week's treatment were investigated in 10 normotensive volunteers and in 10 patients with mild to moderate essential hypertension. After 1 week of placebo, nicardipine was administered orally for 1 week (20 mg three times daily), Investigations, done on the first and last day of nicardipine treatment were compared with those on the last day of placebo. During water loading, nicardipine increased urinary volume and urinary excretion of sodium significantly after 1 week nicardipine treatment. In the normotensive group the natriuretic effect was caused by a decrease of fractional proximal and distal reabsorption of sodium. In the hypertensive group the natriuresis was achieved mainly by an increase of the rate of glomerular filtration (GFR) and also by a slight distal effect. Our results show that nicardipine had natriuretic effects. There were trends suggesting that the renal effects may differ between patients with essential hypertension and normotensive volunteers, but the findings might also be related to differences in age between the groups.
The influence of age on renal and extrarenal effects of frusemide.
Authors: Andreasen F. , Hansen U. , Husted SE , Mogensen CE , Pedersen EB
Published: July 2012

The effect of frusemide 80 mg i.v. was compared during 24 h in 10 young and eight elderly healthy male volunteers following a 24 h control period in the ward. During the 30 min following the injection the increments in excretion of urine, sodium, potassium and frusemide were significantly smaller in the elderly. The 24 h increase in sodium excretion was significantly larger in the 0 young and eight elderly healthy male volunteers following a 24 h control period in the ward. During the 30 min following the injection the increments in excretion of urine, sodium, potassium and frusemide were significantly smaller in the elderly. The 24 h increase in sodium excretion was significantly larger in the 0 young and eight elderly healthy male volunteers following a 24 h control period in the ward. During the 30 min following the injection the increments in excretion of urine, sodium, potassium and frusemide were significantly smaller in the elderly. The 24 h increase in sodium excretion was significantly larger in the elderly. The endogenous 24 h creatinine clearance was reduced by 12% (P less than 0.01) in both age groups. The frusemide induced changes in the 8 h serum concentration curves for albumin differed significantly between the two groups (analysis of variance, P less than 0.01). The drug induced increase in albumin concentration became significant in the young 5 min after the injection. In the elderly it took more than 15 min before the increase in serum albumin reached significance. The average maximal increase in albumin concentration was 14.3% in the young and 9.7% in the elderly (P less than 0.05). No difference was seen between the two age groups in the significant frusemide induced increases in the 24 h albumin excretion but in the elderly a significantly larger decrease in the 24 h excretion of beta 2‐ microglobulin was observed (P less than 0.05). No significant age difference was observed in the initial significant increases in diastolic blood pressure observed in both age groups or between the later changes in systolic blood pressure which was significantly reduced in the young only. The slower haemoconcentration response in the elderly seemed associated with the slower secretion rate of frusemide to the tubular lumen. We found no evidence of an age related difference in tubular cell response to frusemide. It is emphasized that a maximal initial frusemide response in the elderly, in contrast to what was found in the young, probably was not achieved by the 80 mg i.v.
The dose‐response characteristics of the acute non‐diuretic peripheral vascular effects of frusemide in normal subjects.
Authors: Johnston GD , Nicholls DP , Leahey WJ
Published: July 2012

The peripheral venous and arterial effects of frusemide, plasma renin activity and plasma frusemide concentrations were examined during the 15 min period following the i.v. administration of 0, 5, 10, 20, 40 and 80 mg of frusemide in a group of nine salt depleted volunteers. The responses to 80 mg frusemide given orally during the 1 1 h period after administration were also examined. Increases in venous capacitance 5 min after administration of 5 and 10 mg frusemide were observed (P less than 0.05) but no significant increases were apparent after the higher doses. At 10 min, the increases in venous capacitance showed a flat dose response effect with significant increases throughout the dose range (5‐80 mg). Decreases in forearm blood flow occurred at 5 and 10 min after frusemide administration at all the doses studied (P less than 0.05) while blood pressure responses at 10 min showed increasing effect with increasing dose. An oral dose of 80 mg frusemide produced a rise in venous capacitance 15 min after administration and a decrease in forearm blood flow during the period 15‐60 min without any alteration in heart rate or blood pressure.
Chronic effects of metoprolol and methyldopa on calf blood flow in intermittent claudication.
Authors: Lepantalo M.
Published: July 2012

In a placebo‐controlled double‐blind study 14 hypertensive patients with intermittent claudication were treated with metoprolol (100‐200 mg daily) and methyldopa (500‐1000 mg daily) for 3 weeks and their effects on heart rate, blood pressure as well as on resting and hyperaemic calf blood flow and vascular resistance were compared. In their antihypertensive effect metoprolol and methyldopa did not differ significantly. In 23 diseased limbs the calf blood flow and vascular resistance remained unchanged at rest during the trial. The active drugs reduced hyperaemic flow (P less than 0.05). The peak flow was reduced by 20% (P greater than 0.01) with metoprolol and by 15% with methyldopa below the initial level and by 17% and by 12% below the level recorded on placebo, respectively. Neither of the drugs influenced vascular resistance during reactive hyperaemia. Thus, in patients with intermittent claudication antihypertensives should be used with care.
Cortisol and dexamethasone elimination during treatment with cimetidine.
Authors: Peden NR , Rewhorn I. , Champion MC , Mussani R. , Ooi TC
Published: July 2012

In a randomised cross‐over study of treatment for 7 days with cimetidine 600 mg twice daily and placebo, cimetidine had no effect on the pharmacokinetics of a single intravenous dose of dexamethasone sodium phosphate. Likewise the elimination characteristics of endogenous cortisol in the dexamethasone suppressed state were not affected by cimetidine.
The effects of dazoxiben, an inhibitor of thromboxane synthetase, on cold‐induced forearm vasoconstriction and platelet behaviour in different individuals.
Authors: Cowley AJ , Jones EW , Carter AJ , Hanley SP , Heptinstall S
Published: July 2012

The effect of dazoxiben, a thromboxane synthetase inhibitor, on cold‐ induced forearm vasoconstriction was determined in two groups of human volunteers, those in whom dazoxiben abolished the platelet aggregation and release reaction induced by sodium arachidonate (group I) and those in whom it did not (group II). Dazoxiben abolished cold‐induced forearm vasoconstriction in group I volunteers but not in those of group II. These results imply a correlation between platelet behaviour and cold‐ induced changes in vascular tone. In the group I volunteers the effect of dazoxiben on cold‐induced vasoconstriction was abolished by 1800 mg of aspirin, but not by 40 mg. Since the lower dose of aspirin inhibits platelet cyclo‐oxygenase but has no effect on cyclo‐oxygenase in blood vessel walls, it is possible that platelets play no part in the modulation of vascular tone by dazoxiben. It is more likely that the effects of dazoxiben are confined to the vessel wall.
Inhibition of food stimulated acid secretion by misoprostol, an orally active synthetic E1 analogue prostaglandin.
Authors: Ramage JK , Denton A , Williams JG
Published: July 2012

The effect of 200 micrograms misoprostol (a synthetic prostaglandin E1 analogue) on food stimulated intragastric acidity has been monitored over a 9 h period in 16 normal volunteers. Misoprostol caused a significant inhibition of intragastric acidity for 2 h post‐dosing, but no significant effect was seen thereafter on either basal or food stimulated acidity.
Calcium antagonists stimulate sperm motility in ejaculated human semen.
Authors: Hong CY , Chiang BN , Ku J , Wei YH , Fong JC
Published: July 2012

Three calcium antagonists, diltiazem, flunarizine and verapamil stimulated human sperm motility in vitro. Among them, diltiazem induced the largest amplitude of motility increase. The concentration‐response curve of diltiazem was similar in shape to those of calcium chelators. EGTA, a calcium chelator, potentiated the stimulatory effect of diltiazem while A23187, a calcium ionophore, antagonized it. These observations supported our previous hypothesis that an increased concentration of calcium ion was detrimental to human sperm motility. Whether calcium antagonists could be used in the treatment of subfertile patients awaits further investigation.
Metoclopramide reduces carbohydrate absorption in man.
Authors: Holgate AM , Read NW
Published: July 2012

The effect of metoclopramide (20 mg p.o) on the times taken for a radiolabelled liquid starch meal to empty from the stomach and to reach the ileum (230 cm from the mouth), the ileal flow rates and the degree of carbohydrate absorption were studied in five normal male volunteers, intubated with a four lumen intestinal tube. Administration of metoclopramide significantly reduced the time taken for delivery of 50% and 80% of the meal to the ileal aspiration site, but had no significant effect on the half time for gastric emptying. Administration of metoclopramide did not affect the average flow rate or the total postprandial volume, which passed the ileal aspiration site. Administration of metoclopramide reduced carbohydrate absorption in every subject by between 8 and 30%. This study is consistent with the hypothesis that metoclopramide may reduce the degree of absorption in the human small intestine by decreasing the contact time between food and small intestinal epithelium, though it could also act by reducing the area of mucosa in contact with nutrients.
Lack of inhibition of purine nucleoside phosphorylase and adenosine deaminase in patients treated with azathioprine.
Authors: Maddocks JL , Al‐Safi SA
Published: July 2012

Deficiency of the purine salvage enzymes purine nucleoside phosphorylase (PNP) and adenosine deaminase (ADA) are known causes of immunodeficiency. Evidence for inhibition of these enzymes was sought in 16 patients on azathioprine therapy by testing for deoxyguanosine (PNP deficiency) and deoxyadenosine (ADA deficiency) in urine using a novel phosphorescence method. These abnormal nucleosides were not found in urine of azathioprine treated patients or in 30 normal controls but were easily detected in urine from proven cases of PNP and ADA deficiency suggesting lack of in vivo inhibition of PNP and ADA by azathioprine.
Ethnic differences in human lymphocytic cyclic AMP production after isoprenaline stimulation and propranolol blockade.
Authors: Venter CP , Daya S , Joubert PH , Strydom WJ
Published: July 2012

The stimulatory effects of isoprenaline on human lymphocytic cyclic AMP (cAMP) and blockade by propranolol were studied in vitro in healthy Black and White volunteers. Basal levels of lymphocytic cAMP were significantly higher in Blacks than in Whites. Stimulation with isoprenaline caused a dose‐related increase in cAMP, which was in concentrations of 10(‐9) to 10(‐5)M significantly greater in Blacks than in Whites. Blockade by 10(‐4)M propranolol did not affect basal cAMP levels significantly, but increases in cAMP levels were significantly smaller in both groups after 10(‐9) to 10(‐2)M isoprenaline, while differences between cAMP levels in Blacks and Whites were still significant at concentrations 10(‐9) to 10(‐3)M. The increased cAMP concentration in lymphocytes of Blacks probably reflects a higher degree of beta 2‐adrenoceptor activity which could be due to either a greater number and/or greater sensitivity of lymphocytic beta 2‐adrenoceptors in Blacks than in Whites.
Comparison of the urinary metabolite profile of caffeine in young and elderly males.
Authors: Blanchard J , Sawers SJ , Jonkman JH , Tang‐Liu DD
Published: July 2012

The urinary metabolite profile of caffeine was compared in a group of seven healthy young men aged 18‐29 years and in a group of five healthy elderly men aged 66‐71 years. All subjects were given 5 mg/kg doses of caffeine as an aqueous oral solution or an intravenous infusion on two separate occasions in a randomized crossover design. Urine samples were collected for 24 h after dosing and analysed for caffeine and eleven of its metabolites by high‐performance liquid chromatography. The effects of age, route of administration, and order of administration by route on the metabolite profile of caffeine were examined. The route of administration and the order of administration by the two routes were found not to influence the urinary metabolite pattern significantly. The urinary metabolite profile did not vary substantially with age except for the observation that significantly greater amounts of 1‐ methyluric acid, 7‐methyluric acid and 1,7‐dimethyluric acid were excreted by the elderly subjects.
Lack of effect of tenoxicam on glibornuride kinetics and response.
Authors: Stoeckel K , Trueb V , Dubach UC , Heintz RC , Ascalone V , Forgo I , Hennes U
Published: July 2012

The pharmacokinetics of glibornuride (25 mg i.v.) and the accompanying insulin and glucose responses were characterized in eight human subjects in the presence and absence of steady‐state tenoxicam (20 mg p.o./day for 2 weeks). Tenoxicam affected neither the pharmacokinetic parameters of glibornuride (systemic clearance, volume of distribution and biological half‐life) nor the responses of plasma insulin and blood glucose to glibornuride. The single i.v. dose of glibornuride had no detectable effect on the kinetics of tenoxicam.
Side‐effects of beta‐adrenoceptor blocking drugs assessed by visual analogue scales.
Authors: Lewis RV , Jackson PR , Ramsay LE
Published: July 2012

A series of visual analogue scales (VAS) was used to examine the prevalence of side‐effects among hypertensive patients taking beta‐ adrenoceptor blocking drugs. When compared to untreated non‐ hypertensive control subjects, patients taking beta‐adrenoceptor blockers had a greater prevalence of tired legs (P less than 0.001), cold digits (P less than 0.01), insomnia (P less than 0.01) and loss of overall wellbeing (P less than 0.01). Side‐effects did not differ significantly between patients taking atenolol (n = 30), oxprenolol (n = 16), propranolol (n = 15) or metoprolol (n = 10). If there is an important difference in the prevalence of side‐effects between different beta‐adrenoceptor blockers, a much larger study will be needed to demonstrate it.
Drug metabolising activity of freshly isolated human hepatocytes.
Authors: Tee LB , Seddon T , Boobis AR , Davies DS
Published: July 2012

Hepatocytes have been isolated from samples of adult human liver by removal of extracellular calcium followed by perfusion with collagenase. The hepatocytes were isolated with a yield of up to 39 × 10(6) cells/g and with a viability of up to 74%. The cells were active in the oxidation of aldrin and 7‐ethoxycoumarin. They also catalysed the conjugation of 7‐hydroxycoumarin. Monooxygenase activity of the hepatocytes was linear for at least 60 min. Maintenance of the hepatocytes in suspension at 4 degrees C for 19 h resulted in a 15% loss in viability. This was accompanied by a 50% decrease in monooxygenase activity expressed per viable cell. It is concluded that human hepatocytes can be isolated in sufficient yield and with satisfactory viability for use in a range of studies on drug metabolism and toxicity.
Comparison of the effects of binodaline and amitriptyline on peripheral autonomic functions in healthy volunteers.
Authors: Longmore J , Szabadi E , Bradshaw CM
Published: July 2012

Twelve healthy male volunteers participated in five experimental sessions separated by weekly intervals. At the beginning of each session the subjects received one single oral dose of the following drugs, according to a double‐blind, balanced cross‐over design: binodaline hydrochloride (50 mg or 100 mg); amitriptyline hydrochloride (50 mg or 100 mg); lactose placebo. Salivation and resting pupil diameter were assessed before and 2 h after the ingestion of the drugs; baseline sweating, carbachol‐ or phenylephrine‐evoked sweating were measured 2 h following drug taking. Binodaline, like placebo, had little effect on salivary output, whereas amitriptyline caused a dose‐ dependent decrease in salivation. None of the drugs caused any significant change in resting pupil diameter or in baseline sweating. Carbachol‐evoked sweating did not differ significantly following the ingestion of binodaline or placebo; on the other hand responses to carbachol were significantly reduced following amitriptyline. Phenylephrine‐evoked sweating was reduced by both binodaline and amitriptyline. The lack of effect of binodaline on salivation, resting pupil diameter, baseline and carbachol‐evoked sweating is in agreement with the results of animal experiments indicating the lack of an interaction of this drug with cholinergic mechanisms. The reduction in phenylephrine‐evoked sweating would be indicative of an alpha‐ adrenoceptor blocking property of this drug.
The evaluation of domperidone and metoclopramide as antiemetics in day care abortion patients.
Authors: Waldmann CS , Verghese C , Short SM , Goldhill DR , Evans SJ
Published: July 2012

A randomised double‐blind investigation was undertaken to assess the value of domperidone and metoclopramide as prophylactic anti‐emetics in unpremedicated patients undergoing general anaesthesia for therapeutic abortion on a day care basis. Sixty patients were divided into three groups, and received, at induction, one of three drugs intravenously. The incidences of postoperative nausea and vomiting were 35% in the group receiving normal saline as placebo, 30% in the group receiving 10 mg domperidone and 25% in the group receiving 10 mg metoclopramide; these were not statistically significantly different. Furthermore, there was no statistically significant difference in the incidence of postoperative nausea and vomiting as influenced by age, weight, length of gestation, anaesthetic time and a history of nausea and vomiting during the pregnancy.
Human pharmacokinetic and pharmacodynamic studies on Ro31‐1118, a new beta‐adrenoceptor antagonist.
Authors: O'Connor PC , Arnold JM , Brown AN , Francis RJ , Finch MB , Galloway DB , Harron DW , McDevitt DG , Shanks RG
Published: July 2012

The pharmacokinetic and pharmacodynamic effects of Ro31‐1118 were examined in groups of healthy volunteers. In three subjects given 10 mg of [14C]‐Ro31‐1118 orally, peak levels of radioactivity (84 +/‐ 5 ng/ml) were 16 times those of the parent drug (approximately 5 ng/ml). Very little parent drug was recovered in the urine, although recovery of total radioactivity was nearly 80% in the urine by day 5. In five subjects studied after both oral and intravenous administration of 20 mg Ro31‐1118 the average bioavailability was 57% (range 41‐73%). Following intravenous infusion the apparent volume of distribution for the five subjects averaged 590 1 (range 510‐700 1). The elimination half‐life averaged 18 h (range 17‐26 h). In eight subjects who received 40, 80, 160 and 320 mg of Ro31‐1118 orally there was a linear relationship between dose and plasma concentration (r = 0.999) and between dose and AUC (r = 0.996). Ro31‐1118 had no effect on resting heart rate whereas atenolol reduced resting heart rate up to 6 h after all doses. The maximum reduction of an exercise tachycardia after Ro31‐ 1118 (320 mg) was 23.13 +/‐ 0.7% and compared with atenolol (100 mg) was 28.2 +/‐ 1.25%. At 24 h the percentage reduction after Ro31‐1118 was 21.5 +/‐ 1.7%, while after atenolol the percentage inhibition had decreased to 11.1 +/‐ 1.6%. In three subjects Ro31‐1118 (160 mg) orally had no effect on resting heart rate, forearm blood flow and systolic blood pressure, while atenolol (50 mg) reduced all three parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics.
Authors: Lewis RV , Lennard MS , Jackson PR , Tucker GT , Ramsay LE , Woods HF
Published: July 2012

The pharmacokinetics and pharmacodynamics of atenolol and timolol were studied in six extensive and four poor metabolisers of debrisoquine. There was a significant correlation between the debrisoquine to 4‐ hydroxydebrisoquine ratio and the area under the plasma concentration time curve (AUC) for timolol (rs = 0.75, P less than 0.02). The mean of the AUC values for timolol was significantly greater in the poor metabolisers than in the extensive metabolisers (P less than 0.05). There was a significant correlation between the debrisoquine to 4‐ hydroxydebrisoquine ratio and beta‐adrenoceptor blockade 24 h after dosing with timolol (rs = 0.66, P less than 0.05). The mean degree of beta‐adrenoceptor blockade was significantly greater in the poor metabolisers than in the extensive metabolisers 24 h after dosing with timolol (P less than 0.01). There was no relation between the debrisoquine to 4‐hydroxydebrisoquine ratio and the pharmacokinetics or pharmacodynamics of atenolol.
Effects of repeated doses of enalapril on renal function in man.
Authors: McNabb WR , Noormohamed FH , Brooks BA , Till AE , Lant AF
Published: July 2012

Ten healthy subjects received 10 mg oral enalapril (MK 421) daily for a period of 8 days. Renal clearances of electrolytes, urate and phosphate were monitored and factored for glomerular filtration rate, as measured by creatinine clearance, with particular emphasis on the first and eighth day of treatment. Apart from a fall of around 10% in creatinine clearance between 1‐2 h on both days 1 and 8, GFR remained unchanged throughout the study. Fractional sodium excretion increased in a biphasic manner by approximately 50% over control between 1‐2 h and 4‐8 h on day 1. Significant chloruresis (+39.0 +/‐ 12.9%) and kaluresis (+26.5 +/‐ 10.3%) occurred between 4‐8 h. Urinary pH increased between 0‐1 h (+0.29 +/‐ 0.12; P less than 0.05), and between 4‐8 h (+0.50 +/‐ 0.08; P less than 0.01). The biphasic saluretic effect was also seen between 1‐2 h and 4‐8 h on day 8. Enalapril caused significant increases in urate and phosphate excretion on day 8 of therapy. There was a biphasic increase in fractional urate excretion at 1‐2 h (+28.1 +/‐ 6.9%; P less than 0.05) and at 4‐8 h (+21.0 +/‐ 6.0% P less than 0.01). Significant phosphaturia (+36.8 +/‐ 5.2%; P less than 0.05) was also observed at 4‐8 h on day 8. Urinary drug excretion was also biphasic; over the first 2 h the predominant drug form was unchanged enalapril, whilst the peak excretion of the diacid metabolite, enalaprilat, occurred at 4‐8 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Oxaprozin pharmacokinetics in the elderly.
Authors: Greenblatt DJ , Matlis R , Scavone JM , Blyden GT , Harmatz JS , Shader RI
Published: July 2012

A series of 42 healthy male and female volunteers aged 21 to 89 years received a single 1200 mg oral dose of oxaprozin. Kinetics were determined from multiple plasma oxaprozin concentrations measured by h.p.l.c. during 14 days after the dose. Peak plasma oxaprozin concentrations were reached between 3 and 6 h after dosage the majority of subjects, probably reflecting slow absorption from the gastrointestinal tract. Elimination also was slow with a mean half‐life of 59 h (range 36 to 92 h). Owing in part to extensive protein binding (mean free fraction 0.0023%), oxaprozin distribution was limited, with apparent volume of distribution averaging 0.25 l/kg. Apparent volume of distribution declined with increasing age, probably reflecting the reduction in lean mass relative to total weight that occurs in the elderly. Total apparent oxaprozin clearance declined with age in men (r = −0.58, P less than 0.01), but was not significantly related to age in women (r = −0.25, NS). This is consistent with the previously described gender‐specific reduction in hepatic oxidizing capacity association with increasing age. Thus oxaprozin is a slowly eliminated nonsteroidal anti‐inflammatory agent that should be suitable for once daily or every other day administration.
Pharmacokinetic interaction of acetylsalicylic acid and dipyridamole.
Authors: Nitelius E , Melander A , Wahlin‐Boll E
Published: July 2012

It is often recommended that acetylsalicylic acid (ASA) and dipyridamole should be given together in order to obtain secondary prophylaxis against certain ischaemic diseases. Therefore, the possible pharmacokinetic interactions between these agents were assessed following single‐dose exposures in 14 healthy volunteers. The plasma concentrations of ASA, salicylic acid (SA) and dipyridamole were measured by selective h.p.l.c. techniques. It was found that, while dipyridamole kinetics were unaffected by concurrent ASA, concurrent dipyridamole significantly enhanced the peak concentration (24%) and AUC (27%) of ASA. Thus, co‐administered dipyridamole might influence the anti‐platelet effect of ASA.