bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose‐related pharmacokinetics after oral administration of a new formulation of erythromycin base.
Authors: Josefsson K , Bergan T , Magni L
Published: July 2012

1 Erythromycin concentrations in serum and urine were determined in 24 healthy male, fasting subjects after oral administration of 250, 500, or 1000 mg of erythromycin base (250 mg capsules containing enteric‐ coated pellets). The subjects also received a film‐coated erythromycin stearate tablet (equivalent to 500 mg base). 2 The mean +/‐ s.d. maximal serum erythromycin concentrations were 1.9 +/‐ 0.8, 3.8 +/‐ 1.4, 6.5 +/‐ 2.9 and 2.9 +/‐ 1.7 mg/l for 250, 500, or 1000 mg base and 500 mg stearate, respectively. The serum peaks usually occurred after 2 h irrespective of dosage form given. 3 The mean +/‐ s.d. areas under the serum concentration v time curves (AUC0‐infinity) were 4.5 +/‐ 1.7, 11.2 +/‐ 4.3, 27.2 +/‐ 10.6 and 7.5 +/‐ 3.4 mg l −1 . h after 250, 500, or 1000 mg base, and 500 mg stearate, respectively. 4 The urinary recoveries were 5.0, 6.7, 8.6% of the base doses given and 4.4% of the stearate dose given. 5 Dose‐dependent excretion of erythromycin occurred. The increase in AUC was larger than multiples of the lowest base dose.
A pharmacodynamic and pharmacokinetic assessment of a new alpha‐ adrenoceptor antagonist, doxazosin (UK33274) in normotensive subjects.
Authors: Elliott HL , Meredith PA , Sumner DJ , McLean K , Reid JL
Published: July 2012

1 Doxazosin is a quinazoline derivative, related to prazosin, recently developed for the treatment of hypertension. 2 The intravenous administration of doxazosin (12 micrograms/kg) to six healthy normotensive subjects resulted in significant fall in erect blood pressure, with a corresponding increase in heart rate, but there were no significant changes in supine blood pressure or heart rate. 3 The changes in blood pressure and heart rate were maximal at 6 h after intravenous dosing. With prazosin the maximum effects occurred within the first hours. 4 Pressor response studies with phenylephrine confirmed that doxazosin is a relatively selective postsynaptic alpha‐ adrenoceptor antagonist. 5 The mean elimination half‐life of doxazosin was 11 h. This compared with a T1/2 of 2.5 h for prazosin.
Rapid reduction of blood pressure with acute oral labetalol.
Authors: Davies AB , Subramanian Bala V , Gould B , Raftery EB
Published: July 2012

1 The effect of acute oral administration of labetalol on intra‐ arterial pressures in a group of ten hypertensive patients has been evaluated. 2 A single dose of 200 mg labetalol produced a significant reduction in systolic and diastolic pressures within 1 h of administration. 3 Within 24 h of initial administration, 200 mg three times daily produced a significant reduction in ambulant arterial levels of systolic pressure for 21 h and diastolic pressure for 14 h in the day. 4 Acute therapy lowered resting levels but there was no significant reduction in systolic pressure during either isometric or dynamic exercise. 5 Acute therapy was not associated with any significant postural hypotension.
Effect of cimetidine on gonadal function in man.
Authors: Wang C , Lai CL , Lam KC , Yeung KK
Published: July 2012

1 To study the effect of cimetidine on gonadal function in man, eleven male subjects with chronic duodenal ulcer were given cimetidine orally at a dosage of 1000 mg per day 3 months and 400 mg nocte for the subsequent 3 months. 2 Testosterone levels were found to be elevated during therapy when compared to pre‐ and post‐treatment periods. Serum LH remained unchanged but FSH was increased during therapy. In five out of eleven subjects serum PRL levels were increased. Mean sperm count was lower during cimetidine therapy when compared with that after drug withdrawal. The motility and morphology of the spermatozoa were not affected.
Nadolol in thyrotoxicosis.
Authors: Peden NR , Isles TE , Stevenson IH , Crooks J
Published: July 2012

1 Twenty outpatients with thyrotoxicosis received the non‐selective beta‐adrenoceptor antagonist nadolol as sole treatment for 3 weeks. 2 Clinical improvement as measured by reduction in thyrotoxicosis therapeutic index occurred during the first week of treatment and was continued thereafter, and was accompanied by a significant reduction in serum T3 and elevation of serum reverse T3. 3 As measured by reduction in exercise heart rate, during chronic dosing nadolol 160 mg once daily produced blockade of beta‐adrenoceptors for 12 h in all patients and 24 h in all but 2. 4 Wide interindividual variability was noted in steady state plasma nadolol concentrations, in part related to age and renal function. 5 Steady state plasma nadolol concentrations were related to reduction in heart rate.
Review of long‐term treatment with labetalol.
Authors: Waal‐Manning HJ , Simpson FO
Published: July 2012

1 Labetalol has been used to treat 163 patients at the Dunedin Hypertension Clinic for periods up to 6.5 y, and of 128 patients in a New Zealand multicentre study for 2 yr. 2 Labetalol was often effective when other anti‐hypertensive agents, including beta‐blockers, had failed. It was usually given with a diuretic. 3 Mean daily dose was 700 mg (range 100‐2400 mg). No tolerance to the anti‐hypertensive effect was seen. 4 Some postural‐induced decrease in blood pressure on labetalol was common. 5 Side‐effects led to withdrawal of labetalol in about 25% of patients, mainly during the first few months of therapy. Another 25% had minor side‐effects but could continue with the drug. 6 There were three types of side‐effects (in order of frequency): (a) non‐ specific, (b) related to alpha‐blockade and (c) related to beta‐ blockade. The latter were much less troublesome than on “pure” beta‐ blockers. 7 There was no significant evidence of renal haematological or hepatic toxicity. 8 Anti‐nuclear antibody tests became positive on labetalol in about 15%, usually at low titres but in one patient the titre increased to a high level and fell when labetalol was stopped. 9 In a subset of 25 patients who took labetalol for the longest time (up to 6.5 yr) there was a 16% incidence of anti‐mitochondrial antibodies.
Elimination kinetics of labetalol in severe renal failure.
Authors: Wood AJ , Ferry DG , Bailey RR
Published: July 2012

1 The pharmacokinetics of intravenously administered labetalol were studied in four patients with severe renal failure and in three normal subjects. 2 A new and sensitive method for the assay of plasma labetalol concentrations using high performance liquid chromatography is described. 3 Labetalol has a relatively large apparent volume of distribution (3.3‐7.9 l/kg, two‐compartment open model) and a relatively high plasma clearance (0.3‐1.6 1 h‐1 kg‐1). 4 There were no significant differences between the patients with severe renal failure and the controls for any of the pharmacokinetic parameters measured. 5 In the presence of renal functional impairment, no modification of labetalol dosage is required. 6 In another study of 31 patients, glomerular filtration rate was measured at 3‐month intervals for 3‐18 months. In ten patients there was no change, in ten there was an improvement and in 11 there was deterioration, but in only three was this attributable to treatment. 7 In our experience with over 300 patients, we conclude that labetalol plus diuretic treatment is efficacious and safe in all grades of hypertension including those with all degrees of renal insufficiency.
Role of labetalol in acute myocardial infarction.
Authors: Timmis AD , Fowler MB , Jaggarao NS , Vincent R , Chamberlain DA
Published: July 2012

1 The role of labetalol in managing acute myocardial infarction is reviewed. 2 After intravenous infusion labetalol lowers blood pressure in patients with increased blood pressure associated with acute myocardial infarction. 3 Although average heart rate was decreased, cardiac index fell only slightly and stroke index was substantially unchanged. 4 In patients whose pretreatment pulmonary artery end‐ diastolic pressures were increased, labetalol induced decreases, whereas in the presence of normal pressures, these were unchanged. 5 It is concluded that labetalol infusion in patients with acute myocardial infarction is unlikely to precipitate heart failure and is likely to be of value in reducing myocardial oxygen requirement.
Pindolol‐the pharmacology of a partial agonist.
Authors: Clark BJ , Menninger K , Bertholet A
Published: July 2012

1 Pindolol is a non‐selective beta‐adrenoceptor blocking agent; its affinity to adrenoceptors in guinea pig atria (beta 1) is not significantly different from that in guinea pig trachea (beta 1 + beta 2) and canine vascular smooth muscle (beta 2). 2 Pindolol displays a striking diversity of agonist activities in isolated tissues. Stimulant effects correspond to 40–50% of the maximum effects of isoprenaline in isolated kitten atria and guinea pig trachea and to only 10% in guinea pig atria. Effects in canine isolated mesenteric vessels are those of a full agonist, maximum responses equaling those of isoprenaline. These findings suggest that the stimulant effects of pindolol are exerted principally on beta 2‐adrenoceptors. 3 Cardiac stimulation produced by pindolol in the dog is sufficient to compensate for the cardiac depression resulting from blockade of beta‐adrenoceptors in the heart. Reductions in cardiac output and compensatory increases in total peripheral resistance do not occur or are much smaller than those produced by beta‐adrenoceptor blocking agents lacking sympathomimetic activity. 4 Pindolol‐induced relaxation of bronchial smooth muscle prevents or minimizes the bronchoconstrictor effects of injected spasmogens in the cat. 5 Pindolol has marked vasodilator activity, small doses reducing femoral and mesenteric vascular resistance by approximately 30%. Doses comparable to those used in hypertensive patients lower blood pressure by 20 mmHg in non‐anaesthetized dogs.
Relevance of selectivity and non‐selectivity in beta‐adrenoceptor blocking drugs.
Authors: Bonelli J
Published: July 2012

1 The heart rate responses to increasing doses of isoprenaline (n = 6) (during infusion with atropine 0.5 mg/min i.v.) and noradrenaline (n = 5), (during infusion with phentolamine 160 mg/h i.v.) were recorded before and after the intravenous administration of propranolol (15 mg) or metoprolol (15 mg). 2 In the doses used, metoprolol was less potent than propranolol in antagonizing isoprenaline‐induced tachycardia, during atropine infusion. 3 In volunteers treated with phentolamine both metoprolol and propranolol produced similar inhibition of noradrenaline‐induced tachycardia, indicating comparable beta 1‐ adrenoceptor blockade in the doses used. 4 The fact that the shift of the dose‐response curve of isoprenaline‐induced tachycardia was smaller after metoprolol than after propranolol supports the hypothesis that beta 2‐adrenoceptors are present in the heart.
Haemodynamic effects of metoprolol and pindolol: a comparison in hypertensive patients.
Authors: Svensson A , Gudbrandsson T , Sivertsson R , Hansson L
Published: July 2012

1 In a double‐blind study, 36 patients with essential hypertension were randomly allocated to treatment with either metoprolol, 100–300 mg/day, or pindolol, 5–15 mg/day for 6 months. Haemodynamic investigations were made on three separate occasions. Blood flow in the calves and in the forearm was determined by venous occlusion plethysmography after 6 weeks of placebo, after 6 weeks and again after 6 months of active therapy. 2 Both drugs reduced blood pressure significantly, by 17.1/11.8 mm Hg with metoprolol and 21.9/10.9 mm Hg with pindolol after 6 weeks (P less than 0.005). No further changes were seen after 6 months. 3 Heart rate after 6 weeks was significantly reduced by metoprolol (10.7 +/‐ 2.4 beats/min, P less than 0.001) but not by pindolol (4.4 +/‐ 2.3 beats/min, NS). After 6 months a significant reduction was seen also in the pindolol group (5.2 +/‐ 2.1 beats/min, P less than 0.05). 4 The vascular resistance in the calves at rest was reduced by pindolol (P less than 0.05), whereas resistance tended to increase with metoprolol. 5 Resting vascular resistance in the forearm after 6 months was significantly reduced in the metoprolol group (P less than 0.001) as well as in the pindolol group (P less than 0.02). The increase in forearm vascular resistance seen during leg exercise was not influenced by either drug. 6 Vascular resistance at maximal vasodilatation was unchanged in the calves, but a significant reduction (‐17.4 +/‐ 5.7%, P less than 0.01) in the forearm vascular bed was seen after 6 months of pindolol. No change was observed with metoprolol. 7 It is concluded that pindolol reduces elevated blood pressure partly through peripheral vascular mechanism. Metoprolol, on the other hand, probably acts mainly via central cardiac mechanisms.
The influence of beta‐adrenoceptor antagonists with and without intrinsic sympathomimetic activity on local wall motion abnormalities in patients with coronary heart disease.
Authors: Gleichmann U , Fassbender D , Trieb G , Mannebach H , Ohlmeier H
Published: July 2012

1 A single‐blind randomized study of the effects of a beta‐adrenoceptor antagonist with intrinsic sympathomimetic activity (pindolol 0.4 mg i.v., n = 10) and a drug lacking this property (metoprolol 5 mg i.v., n = 11) on local wall motion abnormalities was carried out in 21 patients with coronary heart disease and anterior wall hypokinesia. 2 The drugs produced similar changes in left ventricular end diastolic pressure (LVEDP) and end diastolic volume index (EDVI) but differed in their effects on heart rate and ejection fraction. Pindolol did not exert any marked effect on heart rate or ejection fraction whereas after metoprolol treatment both were significantly decreased. 3 Shortening of the hypokinetic wall segments was improved by both drugs. Shortening of the non‐hypokinetic contralateral segments was unchanged after pindolol administration but was decreased after metoprolol. 4 The differing effects of beta‐adrenoceptor antagonists on regional wall motion appear to be dependent on the presence or absence of intrinsic sympathomimetic activity.
Abrupt withdrawal of pindolol or metoprolol after chronic therapy.
Authors: Szecsi E , Kohlschutter S , Schiess W , Lang E
Published: July 2012

1 In an open controlled study a group of 18 healthy volunteers received either pindolol 10 mg three times daily or metoprolol 100 mg three times daily for 4 weeks. Before treatment, and after abrupt withdrawal the resting heart rate, the blood pressure, the exercise heart rate and the isoprenaline CD25 (dose of isoprenaline to increase the heart rate of 25 beats/min) were determined. Heart rates were continuously monitored by an ECG‐coupled computer. The CD25 values were calculated by an off line computer procedure from the on line recorded data. 2 After metoprolol we found 6 out of 12 patients with a CD25 below baseline, in one case with a corresponding increase in heart rate during exercise. After pindolol we observed a CD25 below baseline only in one case with no corresponding reaction in the exercise test. In both groups we observed a reactive increase in resting heart rate and systolic blood pressure around day 5 after withdrawal. 3 We conclude that abrupt withdrawal of metoprolol in contrast to pindolol is associated with a higher risk of developing beta‐adrenergic receptor hypersensitivity.
Beta‐adrenoceptor blockade in stress due to oral surgery.
Authors: Brisse B , Tetsch P , Jacobs W , Bender F
Published: July 2012

1 The effects of a single oral dose of 5 mg pindolol (P) and 100 mg metoprolol (M) were assessed in a double‐blind study in 30 patients undergoing oral surgery. 2 Systolic and diastolic blood pressures and heart rate were reduced 90 min after oral medication and did not exceed initial values at rest during the procedure. 3 Noradrenaline, adrenaline and c‐AMP concentrations did not differ at any time from the control values at rest after P, but were increased after local anaesthesia and during oral surgery after M as were the metabolic responses reflected by plasma concentrations of glucose and free‐fatty acids. 4 Plasma levels of ACTH and cortisol showed the typical increase during the procedure, being independent of beta‐adrenoceptor blockade. In contrast to the cardioselective antagonist M, prophylactic administration of the non‐selective drug P prevented the sympathetic and metabolic responses to the stress of oral surgery. 5 Hypothalamic and adrenal stimulation were not reduced by either selective or non‐ selective beta‐adrenoceptor blockade.
Effects of pindolol and metoprolol on plasma lipids and lipoproteins.
Authors: Pasotti C , Capra A , Fiorella G , Vibelli C , Chierichetti SM
Published: July 2012

1 The effects of two beta‐adrenoceptor blocking drugs, pindolol and metoprolol, on plasma lipids and lipoproteins were studied in sixteen hypertensive patients (WHO I‐I) by a cross‐over design, with two active treatment periods of 12 weeks each. 2 Neither pindolol nor metoprolol had any effect on total plasma cholesterol (total‐C), triglycerides (TG) or low‐density lipoprotein cholesterol (LDL‐C). 3 Pindolol significantly increased high‐density lipoprotein cholesterol (HDL‐C). After metoprolol, HDL‐C levels remained similar to those in the placebo period. 4 The ratio of total‐C to HDL‐C was significantly reduced by pindolol only. 5 Compared with the placebo period, both pindolol and metoprolol significantly reduced heart rate (HR) and systolic (SBP) and diastolic (DBP) blood pressure. The decreases in HR were significantly greater after metoprolol. No differences between the effects of the two drugs on SBP and/or DBP were observed.
Antihypertensive drugs and blood lipids: the Oslo study.
Authors: Leren P , Eide I , Foss OP , Helgeland A , Hjermann I , Holme I , Kjeldsen SE , Lund‐ Larsen PG
Published: July 2012

1 The report presents the effects on blood lipids and uric acid of six different antihypertensive drugs, used alone and of five different combinations of two antihypertensive drugs. 2 Prazosin significantly lowered serum LDL + VLDL cholesterol and total triglycerides. Atenolol lowered LDL + VLDL cholesterol to a smaller but significant extent. Both pindolol and hydrochlorothiazide (HCTH) were without effect, while oxprenolol significantly increased total triglycerides. Propranolol significantly lowered HDL cholesterol and increased total triglycerides and uric acid. 3 The combination prazosin and pindolol had a favourable effect on the lipid profile, while the combination propranolol and HCTH lowered HDL cholesterol but increased total triglycerides. Propranolol and prazosin lowered HDL cholesterol, while methyldopa and HCTH, and HCTH and amiloride were without effect on blood lipids. 4 It is suggested that the metabolic effects of antihypertensive drugs could be of special importance in long‐term treatment of mild hypertension.
Side effects occurring during administration of epoprostenol (prostacyclin, PGI2), in man.
Authors: Pickles H , O'Grady J
Published: July 2012

1 Fifty infusions of epoprostenol (PGI2) were made, usually increasing the infusion rate until adverse effects were encountered. The volunteers were appraised that they might experience headache and facial flushing. 2 Facial flushing, headache, tachycardia and decrease in diastolic blood pressure were seen in almost all subjects. Erythema over the venous infusing site was also encountered in 13 infusions. Less common effects were sudden bradycardia, pallor and sweating–the vagal reflex–(seven times) and chest pain (twice). Other complaints included restlessness, abdominal discomfort, nausea and drowsiness. 3 The literature on side effects reported during PGI2 infusion is reviewed and recommendations are made concerning administration of PGI2.
Ranitidine: single dose pharmacokinetics and absolute bioavailability in man.
Authors: van Hecken AM , Tjandramaga TB , Mullie A , Verbesselt R , De Schepper PJ
Published: July 2012

1 Ranitidine single dose pharmacokinetics and absolute bioavailability have been studied in five healthy male volunteers. Following an overnight fast, 150 mg was given intravenously as a bolus injection or orally as a tablet formulation to each subject on separate occasions. 2 Following intravenous administration, plasma levels declined biexponentially. The mean (+/‐ s.d.) distribution half‐life (t 1/2 alpha) was 6.6 +/‐ 1.6 min; plasma half‐life (t 1/2 beta) was 1.7 +/‐ 0.2 h; the volume of distribution (V) was 96 +/‐ 9 1; total body clearance (CL) was 647 +/‐ 94 ml/min and renal clearance (CLR) 520 +/‐ 123 ml/min. 3 Following oral administration plasma levels showed a bimodal pattern with a first peak at 1.1 +/‐ 0.4 h and a second peak at 3 +/‐ 0 h. The absolute availability was 60 +/‐ 17%. The plasma half‐ life (t 1/2) of 2.3 +/‐ 0.4 h was significantly longer (P less than 0.05) after oral than after i.v. administration. 4 Renal excretion of unchanged ranitidine accounted for 79 +/‐ 9% of the dose after i.v. administration and for 27 +/‐ 7% after oral administration. 5 Our results suggest a more extensive biotransformation of ranitidine and biliary excretion of metabolites after oral administration while i.v. administration ranitidine is preferentially excreted unchanged in the urine.
The effect of intravenous cimetidine on the absorption of orally administered diazepam and lorazepam.
Authors: McGowan WA , Dundee JW
Published: July 2012

1 The effect of intravenous cimetidine 200 mg or 400 mg on the absorption of lorazepam 2.5 mg tablet and diazepam 10 mg tablet and capsule was studied. 2 Considerable individual variation in plasma concentrations was found with all preparations. 3 Cimetidine increased the absorption of diazepam and lorazepam. 4 Capsule preparations of diazepam generally produced higher drug plasma concentrations than the tablets.
Enhanced metabolism of mexiletine after phenytoin administration.
Authors: Begg EJ , Chinwah PM , Webb C , Day RO , Wade DN
Published: July 2012

1 Unexpectedly low plasma concentrations of mexiletine were observed in three patients treated with mexiletine and concurrently taking phenytoin. 2 Six healthy volunteers were given a single oral dose of mexiletine (400 mg), before and after 1 week of phenytoin administration (300 mg/day). 3 The mean +/‐ s.d. area under the plasma mexiletine concentration‐time curve decreased from 17.67 +/‐ 6.21 to 8.01 +/‐ 3.64 micrograms ml‐1 h (P less than 0.003). 4 The mean +/‐ s.d. half‐life of elimination of mexiletine decreased from 17.2 +/‐ 5.26 to 8.4 +/‐ 4.17 h (P less than 0.02) 5 The suggested mechanism of the interaction is hepatic mixed‐function oxidase enzyme induction by phenytoin. 6 The interaction is likely to be clinically significant.
Effect of nitroglycerin on peripheral large arteries in hypertension.
Authors: Simon AC , Levenson JA , Levy BY , Bouthier JE , Peronneau PP , Safar ME
Published: July 2012

1 Blood pressure, systemic arterial compliance, and diameter, blood flow velocity, volumic flow and impedance of the brachial artery were measured before and after intravenous administration of nitroglycerin (15 micrograms/min during 15 min) in 11 patients with sustained essential hypertension. 2 For the evaluation of the diameter of the brachial artery, a bidimensional pulsed Doppler was used, enabling the angle of the ultrasound beam relative to the flowing stream of blood to be measured with an error of less than 2%. 3 After nitroglycerin, systolic pressure significantly decreased (P less than 0.01) without significant change in diastolic and mean arterial pressures, cardiac index, stroke index and total peripheral resistance. 4 Systemic arterial compliance and brachial artery diameter significantly increased (P less than 0.001; P less than 0.01) while velocity and blood flow of the brachial artery were unchanged. 5 The pattern of the input impedance of the brachial artery was consistent with a predominant effect of nitroglycerin on the viscoelastic properties of peripheral large arteries. 6 The study provided evidence that, in hypertensive patients, nitroglycerin has a direct effect on peripheral large arteries, causing an increase in arterial diameter and compliance, thus leading to a predominant decrease in systolic pressure.
OPT: a package of computer programs for parameter optimisation in clinical pharmacokinetics.
Authors: Kelman AW , Whiting B , Bryson SM
Published: July 2012

1 OPT is a series of computer programs designed to assist dose optimisation for individual patients. It is based on Bayesian Statistical Theory and Maximum Likelihood Estimation. 2 OPT uses prior information on the distribution of population pharmacokinetic parameters and plasma drug concentration measurements to obtain the ‘most likely’ set of parameters for the individual. 3 Complex dosage regimes and non‐steady state conditions can be handled. 4 OPT is designed for use in a Clinical Pharmacokinetics Laboratory where informed interpretation of results is essential. 5 The drugs for which the system is currently available include theophylline, digoxin, lignocaine, disopyramide, gentamicin and phenytoin (steady state data only).
Sample size for short‐term trials of antihypertensive drugs.
Authors: Freestone S , Silas JH , Ramsay LE
Published: July 2012

1 Controlled trials of antihypertensive drugs published in the British Journal of Clinical Pharmacology during 1979 and 1980 were examined. Studies comparing two or more active drugs or dosage regimens nearly always failed to separate and treatments significantly. The sample size (mean 19 patients) and power of these studies were too low. 2 When planning such studies the aims should be a power of at least 0.8; significance 0.05 or less; and to detect a difference between treatments of 10/5 mmHg, or 6.7 mmHg mean arterial pressure (MAP). The sample size needed can be derived readily from a nomogram if the standard deviation of differences (SDD) between BP measurements under trial conditions is known. 3 In five studies the SDDs were fairly constant despite different observers, patient groups and measuring devices, at approximately 14 mmHg systolic, 9 mmHg diastolic, and 9 mmHg MAP. Use of three BP measurements at each visit reduced the SDD by about 1 mmHg, and would reduce the sample size required by about 20%. Replicate BP measurements at separate visits would be expected to have a larger effect on the power of the study. 4 Published studies with negative results should give an estimate of the power of the study.
Atenolol in the treatment of essential hypertension during pregnancy.
Authors: Rubin PC , Butters L , Low RA , Reid JL
Published: July 2012

Atenolol has been studied prospectively in the management of ten patients with essential hypertension during pregnancy. Median supine BP fell significantly from 156/98 mmHg before treatment to 128/82 mmHg at term. Atenolol did not suppress cardiotocographic signs of foetal distress. Although there was one intrauterine death, the remaining nine babies had a median Apgar score at birth of 9 and a median weight which was 82% of the gestational mean. There were no cases of neonatal bradycardia or respiratory depression and the only case of hypoglycaemia was in a dysmature baby. These findings justify a formal study of beta‐adrenoceptor blocker therapy in hypertensive diseases of pregnancy.
Defective metabolism of metoprolol in poor hydroxylators of debrisoquine.
Authors: Lennard MS , Silas JH , Freestone S , Trevethick J
Published: July 2012

Eight healthy volunteers received oral metoprolol 200 mg once daily for a week. The AUC, half‐life and duration of beta‐adrenoceptor blockade on day 7 was much greater in two subjects than in the remaining six. This suggested that the metabolism of metoprolol was impaired in two and the effect was therefore prolonged. Subsequent testing of oxidation phenotype with oral debrisoquine showed that the subjects with high metoprolol availability were also poor hydroxylators of debrisoquine. The urinary debrisoquine/4‐hydroxydebrisoquine ratio was highly correlated with metoprolol AUC, half‐life and beta‐adrenoceptor blockade at 24 h. Thus patients with a genetic defect in drug oxidation, when treated with metoprolol, are likely to have high plasma concentrations and a prolonged effect.
In vitro studies on the hydrolysis of frusemide in gastrointestinal juices.
Authors: Andreasen F , Botker HE , Lorentzen K
Published: July 2012

To elucidate a possible explanation for a relatively low bioavailability, the hydrolysis of frusemide in gastrointestinal juices was studied in vitro at concentrations likely to be present in vivo. Between 1.0 and 4.4% of the frusemide molecules were hydrolyzed to 4‐ chloro‐N‐furfuryl‐5‐sulphamoyl‐antranilic acid (CSA) after 1 h at 37 degrees C in gastric juices. The rate of hydrolysis was inversely connected to pH. No fall in frusemide concentration was observed and no CSA was found in duodenal juices after 4 h at 37 degrees C. In three buffer solutions with the same pH as three gastric juices frusemide was hydrolyzed to CSA at a lower rate than in the gastric juices (pH 1.2, P less than 0.15;pH 1.4, P less than 0.001; pH 1.6, P less than 0.001). The solubility of frusemide was significantly higher in gastric juice from two fasting subjects (83‐104 mg l‐1) than in buffer solutions with the same pH (52‐58 mg 1‐1). The solubility of frusemide was significantly increased (by 40‐50%) in gastric juice obtained after pentagastrin stimulation compared with its solubility in the mixed gastric secretion obtained after fasting. The binding of frusemide to macromolecules was 28.0 +/‐ 9.7% in ventricular secretion after fasting while it was 1.4 +/‐ 2.6% in the fluid obtained after pentagastrin stimulation. It is concluded that a hydrolysis of frusemide in the stomach prior to absorption cannot explain the relatively low bioavailability of the drug observed after oral intake.
Disopyramide and its N‐monodesalkyl metabolite in breast milk.
Authors: Barnett DB , Hudson SA , McBurney A
Published: July 2012

The plasma and breast milk were sampled from a woman who was breastfeeding whilst taking disopyramide (200 mg three times daily). Paired samples taken on the fifth to eighth day of treatment showed that disopyramide was present in breast milk in a similar concentration to plasma (mean +/‐ s.d. milk; plasma ratio 0.9 +/‐ 0.17). The estimated dose likely to be ingested by an infant is less than 2 mg kg‐ 1 day‐1. The active N‐monodesalkyl metabolite of disopyramide (NMD) although present in plasma in much smaller concentrations than the parent compound, was excreted in breast milk (mean +/‐ s.d. milk: plasma ratio 5.6 +/2.9) in concentrations similar to those of disopyramide. The pharmacological and toxicological properties of the disopyramide metabolite need to be considered when assessing likely effects on the infant. No adverse effects were noted in the infant in this case. Maternal plasma and breast milk were sampled again along with infant plasma after 28 days. Disopyramide and NMD were undetectable in the infant's serum. No evidence was found to indicate that the concentrations of disopyramide or NMD in breast milk might be sufficient to pose a definite risk to the infant. Whenever disopyramide is prescribed in a breast feeding mother, close observation of the baby and measurement of both disopyramide and its active metabolite NMD in breast milk or infant plasma is recommended, pending further investigation.
Pharmacokinetics of mexiletine in renal insufficiency.
Authors: El Allaf D , Henrard L , Crochelet L , Delapierre D , Carlier J , Dresse A
Published: July 2012

1 The aim of this study was to evaluate the influence of renal insufficiency on the plasma pharmacokinetics of mexiletine, a new antiarrhythmic agent, in human beings. 2 Mexiletine was administered orally three times daily for 10 days to 15 patients with chronic renal failure (creatinine clearance lower than 30 ml/min) and to 9 subjects with normal renal function. 3 The use of low doses of mexiletine was possible owing to the development of a new fluorescence h.p.l.c. method with a limit of sensitivity lower than 20 gn/ml. 4 Our results clearly indicate that the plasma kinetics of mexiletine are not modified when the renal clearance of creatinine is higher than 10 ml/min.
Patient subsets and variation in therapeutic efficacy.
Authors: Simon R
Published: July 2012

1 The determination of what treatment is best for what kinds of patients is a general objective of clinical research. We consider here the extent to which this objective can be accomplished reliably in a single clinical trial. 2 The reliability of subset analyses is often poor due to problems of multiplicity and limitations in numbers of patients studied. Implications for the design of clinical trials are presented. 3 Statistical approaches to subset analysis are reviewed in a general manner. In order to obtain the degree of reliability usually demanded of clinical therapeutic evaluations, ‘statistically significant’ interactions between relative treatment efficacy and subsets should be demonstrated. Exploratory analyses of subset differences are important but should be reported as hypotheses to be tested in separate studies.
Pharmacokinetic interaction between theophylline and erythromycin.
Authors: Iliopoulou A , Aldhous ME , Johnston A , Turner P
Published: July 2012

1 The pharmacokinetics of a single intravenous dose of theophylline alone and during the fifth day of treatment with 500 mg erythromycin every 8 h was studied in six healthy subjects. 2 At the same time the pharmacokinetics of erythromycin at steady‐state on the fourth day of the treatment (alone) and the fifth day (during the theophylline co‐ administration) were also studied. 3 Mean +/‐ s.d. theophylline clearance was decreased from 62 +/‐ 15.4 to 53 +/‐ 10.3 ml min‐1 (P less than 0.05) and elimination half‐life rose from 7.1 +/‐ 1.9 to 7.7 +/‐ 2 h (P less than 0.05) when erythromycin was co‐administered. 4 Mean +/‐ s.d. erythromycin area under the curves (0‐8 h) and (0‐oc) were reduced from 6.09 +/‐ 3.2 to 3.8 +/‐ 2.5 micrograms ml‐1 h and 7.2 +/‐ 3.6 to 5.0 +/‐ 2.9 micrograms ml‐1 h (P less than 0.05) in the presence of theophylline. Mean steady state and maximum steady state concentrations were also reduced from 0.75 +/‐ 0.4 to 0.47 +/‐ 0.3 microgram ml‐1 (P less than 0.05) and 1.45 +/‐ 0.87 to 0.85 +/‐ 0.51 microgram ml‐1 (P less than 0.05) respectively. 5 The potential clinical implications of this indication should be considered.
Ventilatory and cardiovascular effects of BHT 933 in volunteers.
Authors: Pleuvry BJ , Redpath JB
Published: July 2012

In 12 healthy volunteers BHT 933 in doses of 5 and 10 mg had minimal effects on ventilation, a small fall in total volume occurred with the highest dose. BHT 933 (5 mg) reduced both systolic and diastolic blood pressure, but had little effect on autonomic reactivity tests, whereas the 10 mg dose reduced the response to these tests. Both doses of BHT 933 caused marked sedation. It is concluded that 5 mg BHT 933 orally presents the most suitable profile of activity for further studies into its usefulness as an anti‐tussive and antihypertensive.
Pharmacokinetics of theophylline: a dose‐range study.
Authors: Rovei V , Chanoine F , Benedetti Strolin M
Published: July 2012

1 Pharmacokinetics of theophylline were investigated in a group of healthy adult volunteers (non smokers and on xanthine‐free diet) following single oral administration of 125, 250, 375 and 500 mg doses as tablets (Theodel). 2 Absorption of theophylline was rapid and followed first‐order kinetics. Plasma curves were fitted according to a one compartment open model. 3 There was a linear relationship (P less than 0.001) between plasma Cmax or AUCx values and the administered dose. The analysis of variance showed that the pharmacokinetic parameters of theophylline (t1/2 abs, tmax, t1/2 beta, CL, CLR, Vd and F) were not modified at any dose. 4 Absorption of the drug was complete since the recovery in urine of theophylline (13.7 to 16.8% of the dose) and its major metabolites, 1,3‐dimethyluric acid (35 to 42%), 1‐ methyluric acid (21.3 to 26.7%) and 3‐methylxanthine (11.5 to 13.7%), accounted for the administered dose. Some impairment of demethylation to 3‐methylxanthine was observed in two subjects, however the percentage of theophylline and its major metabolites excreted in urine was constant for all the four doses. 5 On the basis of these results, after single oral administration, elimination of theophylline followed first‐order kinetics in the range of doses investigated (1.62 to 10.42 mg/kg).
A placebo controlled study of the cardiovascular effects of fluvoxamine and clovoxamine in human volunteers.
Authors: Robinson JF , Doogan DP
Published: July 2012

1 Fluvoxamine and clovoxamine, two new potential antidepressants were given to 27 healthy male volunteers in a double‐blind, placebo controlled, three‐way crossover study. 2 Neither compound affected the electrical intervals of 24 h ambulant electrocardiographic monitoring with the exception of a small increase in R‐R interval. 3 There were no changes in blood pressure measurements. 4 The only notable unwanted symptom was nausea for both fluvoxamine and clovoxamine.
Cimetidine, but not oxmetidine, penetrates into the cerebrospinal fluid after a single intravenous dose.
Authors: Jonsson KA , Eriksson SE , Kagevi I , Norlander B , Bodemar G , Walan A
Published: July 2012

1 Thirty‐six patients with various neurological diseases or symptoms received single intravenous doses of either cimetidine 400 mg (n = 19) or oxmetidine 200 mg (n = 17), 15 or 60 min before a diagnostic lumbar puncture. 2 In the 15 min CSF samples concentrations of cimetidine were detectable but not measurable in 5 and non‐detectable in 3 patients. 3 In the 60 min CSF samples the concentrations of cimetidine were detectable in all 11 patients and were measurable in 8 of these patients with a mean +/‐ s.e. mean of 0.12 +/‐ 0.01 microgram/ml. These CSF concentrations were correlated to simultaneously measured plasma concentrations (P less than 0.01). The mean ratio CSF/plasma concentration was 0.03. 4 No detectable concentrations of oxmetidine were found either in the 15 min (n = 9) or in the 60 min (n = 8) liquor samples. 5 Cimetidine penetrates the blood‐drain barrier slowly and not freely after a single dose. Our data suggest that the new histamine H2‐ receptor antagonist oxmetidine does not cross this barrier.
Effect of beta‐adrenoceptor antagonists on prevalence of peripheral vascular symptoms in hypertensive patients.
Authors: Steiner JA , Cooper R , McPherson K , Riley AJ
Published: July 2012

1 Eight hundred patients were approached by questionnaire to give details of side effects of their antihypertensive medications. The response rate was 72.8%. The percentage of those questioned who were taking beta‐adrenoceptor antagonists at the time was 54.6%. 2 Raynaud's phenomenon (P less than 0.05) and complaints of cold extremities (P less than 0.001) were significantly more frequent in women than in men, 74.8% of women complained of cold extremities. 3 Exposure to beta‐ adrenoceptor antagonists did not increase the prevalence of Raynaud's phenomenon in either men or women in the study, but did increase the prevalence of cold extremities in men (P less than 0.001). Propranolol, labetalol, oxprenolol and possibly atenolol were likely to produce such side effects. Smoking and the addition of vasodilators did not alter the effect of beta‐adrenoceptor blockers on peripheral vascular symptoms. Complaints of cold extremities were not associated with an excess of complaints of other side effects.
Heart rate control in hypertensive patients treated by captopril.
Authors: Sturani A , Chiarini C , Degliesposti E , Santoro A , Zuccala A , Zucchelli P
Published: July 2012

1 The effect of captopril on autonomic reflex functions has been investigated in fifteen patients with essential hypertension by examining their responses to tests of baroreceptor function (Valsalva's manoeuvre and upright posture), sympathetic nervous system reactivity (cold pressor and mental stress tests) and parasympathetic reactivity (diving test) before and after 3 weeks' treatment with captopril. 2 Captopril significantly reduced arterial blood pressure and resting heart rate but did not affect cardiovascular responses to Valsalva's manoeuvre, upright posture, cold pressor and mental stress tests. 3 The bradycardia associated with the diving reflex test was significantly enhanced by captopril (P less than 0.01). 4 These results indicate that treatment with captopril is associated with increased parasympathetic tone but without inhibition of baroreceptor or sympathetic reflexes.
Long‐term captopril treatment in moderate to severe hypertension.
Authors: Santucci A , Aguglia F , de Mattia G , Ficara C , Balsano F
Published: July 2012

1 The long‐term effects of the oral angiotensin‐converting enzyme inhibitor captopril with the addition of a diuretic (chlorthalidone) were examined in 16 patients with moderate or grave hypertension. Of these, 14 had essential hypertension and two renovascular hypertension. 2 Blood pressure fell sharply in all patients and this antihypertensive effect was maintained during 2, 4, 6, 12, and 24‐month follow‐up periods. The efficacy of treatment was not predicted by basal values of plasma renin activity. 3 Urinary excretion of sodium and potassium increased, but the increases were never such as to modify significantly sodium and potassium serum concentration. 4 The long‐term treatment was generally well tolerated.
Maintenance of the antihypertensive efficacy of captopril despite consistent reduction in daily dosage.
Authors: Mimran A , Jover B
Published: July 2012

1 After a period of 7 +/‐ 1.4 months of good control of hypertension by thrice daily administration of captopril (85 +/‐ 9 mg three times a day), captopril was given twice daily and the total dose was progressively reduced to sometimes very low levels in 12 patients. Twice daily administration of captopril 85 +/‐ 9 mg did not modify blood pressure control. 2 During reduction of captopril dosage to a minimum of 36 +/‐ 4 mg twice a day, the acute effect of the morning dose of captopril (last dose taken at least 12 hours before study) was assessed. Administration of the morning dose induced a decrease in mean arterial pressure from 112 +/‐ 4 mm Hg (104 +/‐ 3 mm Hg during administration of 85 +/‐ 9 mg) three times a day to 106 +/‐ 4 mm Hg, an increase in plasma renin activity, and a decrease in plasma aldosterone concentration. 3 These acute effects of captopril suggest that blood pressure was well controlled in the presence of a non‐blocked circulating angiotensin‐converting‐enzyme activity, thus raising the possibility of alternate mechanisms by which captopril reduces arterial pressure. 4 The daily dosage of captopril needed to control hypertension may be reassessed after a certain period of good blood pressure control with 50 to 100 mg captopril three times a day.
Captopril in essential hypertension.
Authors: Estrada Rabinad E , Morin Ingelmo M , Amenos Martinez A , Alsina J , Gorina Balcells A
Published: July 2012

1 Forty‐one patients with essential hypertension, stages I, II, and III, were treated with captopril alone or in combination with hydrochlorothiazide. Forty two percent were responsive to captopril alone, while the remaining 58% also required the diuretic. The need for the diuretic was related to the phase of hypertension. 2 There was no significant relation between drug response and plasma renin activity. Serum concentrations of creatinine and potassium remained normal, and there were no pathological changes in serum glucose, cholesterol, uric acid concentrations, erythrocyte count, packed cell volume, haemoglobin, or heart rate. 3 Captopril was well tolerated. One patient developed a rash and another ageusia, which disappeared spontaneously. A third, who was also taking allopurinol, developed leucopenia but it disappeared after treatment was withdrawn. There were no cases of proteinuria attributable to captopril; and proteinuria disappeared in four of five patients who were proteinurin before the start of treatment. 4 These findings suggest that doses of captopril of 150 mg to 300 mg (with or without a diuretic) may be adequate for controlling the blood pressure of most patients with essential hypertension.
Captopril and atenolol combined with hydrochlorothiazide in essential hypertension.
Authors: Andren L , Karlberg B , Ohman P , Svensson A , Asplund J , Hansson L
Published: July 2012

1 Fifty‐seven patients with mild or moderate essential hypertension, mean age 50 (range 31‐69) were randomised to treatment with either captopril or atenolol. Twenty‐six patients in each group completed the study. 2 Captopril (25‐50 mg three times daily) and atenolol (50‐100 mg once daily) caused a highly significant fall in blood pressure both supine and standing. 3 When hydrochlorothiazide (25‐50 mg once daily) was added a further fall in blood pressure was observed in both groups. 4 Captopril as single drug caused no significant change in heart rate, while atenolol significantly reduced heart rate both supine and standing. 5 Two patients were excluded from the captopril group, one because of a reversible loss of taste and the other because of dizziness. Three patients were excluded from the atenolol group, two because of bradyarrhythmias and one because of inadequate blood pressure response. 6 Both captopril and atenolol were found to be effective antihypertensive agents, suitable for the treatment of essential hypertension.
Long‐term efficacy of angiotensin‐converting‐enzyme inhibition with captopril in mild‐to‐moderate essential hypertension.
Authors: Stumpe KO , Overlack A , Kolloch R , Schreyer S
Published: July 2012

1 Thirty‐one patients with mild‐to‐moderate essential hypertension were treated with captopril for 30 months. 2 Captopril effectively lowered raised blood pressure in hypertensive patients with high, low, and normal renin concentrations. There was no significant change in heart rates. Captopril alone normalised blood pressure (diastolic pressure below 95 mm Hg) in 11 patients. In the other patients the addition of hydrochlorothiazide produced a further hypotensive effect. Blood pressure control could be maintained without any signs of tachyphylaxis. 3 Plasma concentrations of aldosterone and angiotensin II were significantly lower after 30 months of therapy than pretreatment values whether captopril was associated with diuretics or not. No relevant symptomatic or biochemical adverse reactions were observed. 4 These data establish the long‐term potential of captopril for outpatient therapy in mild‐to‐moderate forms of essential hypertension.
Long‐term experience of captopril in the treatment of primary (essential) hypertension.
Authors: Karlberg BE , Asplund J , Wettre S , Ohman KP , Nilsson OR
Published: July 2012

1 Forty‐one patients with primary (essential) hypertension were treated with captopril alone or in combination with hydrochlorothiazide for 12‐ 36 months. 2 During an initial dose‐titration period mean blood pressure fell from 174/111 mm Hg to 134/88 mm Hg supine and from 170/116 mm Hg to 126/93 mm Hg standing after 3 months' treatment. 3 During long‐term treatment with unchanged or reduced doses of captopril or hydrochlorothiazide, or both, blood pressure remained substantially reduced. Mean supine blood pressure at 24 months was 136/90 mm Hg and at 36 months 138/90 mm Hg. 4 In 12 patients with clearly defined low renin (essential) hypertension initial blood pressure reduction was less than in patients with normal renin hypertension after 1 month's treatment (162/102 mm Hg v 143/92 mm Hg). After 24 months of treatment, however, the treatment results were similar in the two groups. 5 Except for one case of reversible proteinuria no serious side effects were seen during treatment periods of up to three years. 6 Captopril alone or in combination with hydrochlorothiazide seems to be an effective and safe drug in the long‐term treatment of primary hypertension.