bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of indoramin, labetalol and alinidine on sympathetic function in normal man.
Authors: Nicholls DP , McNeill J , O'Connor PC , Harron DW , Leahey WJ , Shanks RG
Published: July 2012

The effects of single oral doses of indoramin (mean dose 58 mg), abetalol (mean dose 150 mg), alinidine 80 mg and placebo on arterial pressure and heart rate in the supine and standing positions were studied in six normal volunteers. Doses were chosen to give equivalent reductions of arterial pressure in the standing position. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. In the supine position, alinidine produced a significant reduction of systolic arterial pressure from 124.0 +/‐ 3.0 mm Hg to 104.3 +/‐ 4.1 mm Hg at 2 h (P less than 0.01) and to 101.7 +/‐ 2.2 mm Hg at 4 h (P less than 0.01). Diastolic pressure was reduced from 74.7 +/‐ 2.6 mm Hg to 57.0 +/‐ 4.6 mm Hg at 4 h (P less than 0.01). Arterial pressure was unchanged after indoramin or labetalol administration. In the supine position, heart rate was unchanged after indoramin, and small reductions were observed after labetalol and alinidine. Indoramin produced a significant increase in plasma NA. A small increase of plasma NA was observed after labetalol, and a small decrease after alinidine. In the standing position, the three active drugs reduced systolic arterial pressure to a similar extent (indoramin, ‐26.7 mm Hg at 4 h after drug administration; labetalol, ‐21.3 mm Hg at 2 h; alinidine, ‐21.7 mm Hg at 4 h).(ABSTRACT TRUNCATED AT 250 WORDS)
Gender and oral contraceptive steroids as determinants of drug glucuronidation: effects on clofibric acid elimination.
Authors: Miners JO , Robson RA , Birkett DJ
Published: July 2012

The disposition of clofibric acid, a drug metabolised largely by glucuronidation, was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Clofibric acid plasma clearance was not significantly different in males compared to the control female group but was 48% greater (P less than 0.01) in women receiving OCS compared to non‐pill using females. This difference was due to an alteration in clofibric acid metabolic clearance as there were no differences between the groups in clofibric acid free fraction. Along with previous data the results suggest that induction of drug glucuronidation by OCS may be of clinical importance, although any sex‐ related differences are unlikely to be of clinical significance.
The role of the intestinal microflora in the reductive metabolism of acenocoumarol in man.
Authors: Thijssen HH , Baars LG , Hazen MJ , Van den Bogaard AE
Published: July 2012

Although the oral anticoagulant acenocoumarol (AC) is very effectively metabolized by the intestinal microflora to its amino metabolite, under clinical conditions this route of AC‐disposition is of no importance because the compound is rapidly absorbed from its pharmaceutical application form. Only when the gastro‐intestinal absorption is retarded, for instance by using a capsule as vehiculum, are appreciable amounts of reduced metabolites recovered in urine.
The stimulatory effects of caffeine, theophylline, lysine‐theophylline and 3‐isobutyl‐1‐methylxanthine on human sperm motility.
Authors: Jiang CS , Kilfeather SA , Pearson RM , Turner P
Published: July 2012

The potencies of caffeine, theophylline, lysine‐theophylline and 3‐ isobutyl‐1‐methylxanthine (IBMX) in stimulating sperm motility have been compared, and we have found IBMX to be significantly more potent than the other three compounds, which did not exhibit significant differences in potency from each other.
Effect on finger tremor of withdrawal of long‐term treatment with propranolol or atenolol.
Authors: Wharrad HJ , Birmingham AT , Wilson CG , Williams EJ , Roland JM
Published: July 2012

The effect of the withdrawal of long‐term beta‐adrenoceptor blockade on pulse rate and finger tremor was studied in 27 patients who had been treated for 2 years following an uncomplicated myocardial infarction with either atenolol, propranolol or placebo. During treatment, pulse rate was significantly lower in patients treated with propranolol or atenolol compared with placebo. Compared with the response in the placebo group the mean increase in tremor on withdrawal of propranolol was statistically significant for postural and for work tremor in both hands. A significant increase in tremor on withdrawal of atenolol occurred only in the postural position and in a narrow frequency band (left hand, 7‐11 Hz; right hand, 7‐9 Hz). The differences in the effect on tremor of withdrawal of treatment with propranolol or atenolol in doses which produced similar reductions in heart rate, emphasise the beta 2 classification of peripheral receptors associated with normal muscle tremor but do not exclude the involvement of beta 1‐ adrenoceptors.
The effects of enzyme induction and enzyme inhibition on labetalol pharmacokinetics.
Authors: Daneshmend TK , Roberts CJ
Published: July 2012

The oral and intravenous pharmacokinetics of labetalol were determined in five subjects before and after a 3 week course of glutethimide 500 mg/day. After glutethimide there was a significant reduction in the AUC after the oral dose of labetalol, from 40,596 +/‐ 11,534 (mean +/‐ s.e. mean) to 22,057 +/‐ 6,276 ng ml‐1 min (2P less than 0.05), and systemic bioavailability was reduced from 30.3 +/‐ 2.8 to 17.0 +/‐ 3.5% (2P less than 0.001). There was no significant change in labetalol plasma concentration‐time curve (AUC) following an intravenous dose, half‐ life, volume of distribution, and plasma clearance. The oral and intravenous pharmacokinetics of labetalol were determined in six subjects before and after a 3 day course of cimetidine 1.6 g/day. After cimetidine there was a significant reduction in the volume of distribution of labetalol, from 520 +/‐ 51 to 445 +/‐ 24 1 (2P less than 0.05). The AUC of labetalol after the oral dose increased by 66%, from 51,029 +/‐ 7,950 to 84,772 +/‐ 19,444 ng ml‐1 min (2P = 0.06). The systemic bioavailability of labetalol increased from 25.1 +/‐ 2.4 to 39.0 +/‐ 7.6% (2P = 0.06). There was no significant change in labetalol AUC after the intravenous dose, half life, and plasma clearance. There were no significant changes in resting heart rate and supine systolic and diastolic blood pressure following labetalol plus glutethimide, or labetalol plus cimetidine.(ABSTRACT TRUNCATED AT 250 WORDS)
The uricosuric action of azapropazone: dose‐response and comparison with probenecid.
Authors: Higgens CS , Scott JT
Published: July 2012

Azapropazone is an anti‐inflammatory agent with reported uricosuric properties. The aim of the present study was to extend these observations, by examining the dose‐response and to compare the uricosuric effect of azapropazone with that of probenecid. Patients were given varying doses of azapropazone from 900‐2400 mg daily for 4‐ day periods at separated intervals. Plasma uric acid levels were measured before and at the end of each treatment period. Three other patients maintained on low purine diets were given a 4‐day course of 1200 mg azapropazone daily followed at an interval by a 4‐day period of probenecid 1 g daily. Plasma uric acid levels and 24 h urinary uric acid excretion were compared. The mean fall in plasma uric acid level after four days of 900 mg azapropazone daily was 31.4% (n = 9) compared with 33.9% (n = 12) on 1200 mg daily; 42.3% (n = 10) on 1800 mg daily; and 46% (n = 6) on 2400 mg daily, indicating a graded dosage response. In the three patients on low purine diets the falls in plasma uric acid levels on probenecid 1 g daily were 50.5%, 46% and 29% compared with 33.5%, 32% and 20% respectively on azapropazone 1200 mg daily. Similarly the total amount of uric acid excreted in the urine by each patient during the 4‐day period on probenecid 1 g daily was 14.01; 13.03 and 8.97 mmol compared with 23.53, 10.9 and 7.69 mmol on azapropazone 1200 mg daily.(ABSTRACT TRUNCATED AT 250 WORDS)
Thiazide‐induced hypokalaemia; prevalence higher in women.
Authors: Toner JM , Ramsay LE
Published: July 2012

In 193 hypertensive patients taking bendrofluazide 5 mg daily, the mean serum potassium concentration was lower in women than in men (3.77 vs 3.99 mmol/l, P less than 0.001) and the prevalence of hypokalaemia (less than 3.5 mmol/l) was higher (25% vs 12%, P less than 0.05). This difference between the sexes was independent of age, body weight, renal function, the use of other antihypertensive drugs and compliance with treatment as judged by tablet counts. Severe hypokalaemia (less than 3.0 mmol/l) was uncommon and showed no difference between the sexes.
Effect of age and sex on acenocoumarol requirements.
Authors: Arboix M , Laporte JR , Frati ME , Rutllan M
Published: July 2012

A group of 690 patients (337 males and 353 females) on long‐term acenocoumarol therapy was studied. 62.8% of the values of the prothrombin ratio were within the chosen therapeutic range (1.8 to 2.7), 21.9% were below 1.8 and 15.3% were above 2.7. The daily maintenance dose, expressed on a weight basis, was found to significantly decrease with increasing age. The daily maintenance dose taken by females was significantly higher than the dose taken by males (P less than 0.05); the differences between males and females were maximal among patients aged between 21 and 50 years, and disappeared at older ages. Two hundred and twenty‐eight haemorrhagic episodes in 160 patients were recorded during a total of 7797 months of follow‐up. No lethal haemorrhages were observed. The overall incidence of bleeding episodes among females (3.6%) was higher than among males (2.2%) (P less than 0.001), even if menorrhagia was excluded (P less than 0.01).
The effect of etretinate on the cyclo‐oxygenase and lipoxygenase products of arachidonic acid metabolism in psoriatic skin.
Authors: Wong E , Barr RM , Brain SD , Greaves MW , Olins LA , Mallet AI
Published: July 2012

Eight psoriatic patients were treated with etretinate (50 mg daily) for 6 weeks. Skin chamber exudates from involved and uninvolved skin were assayed for arachidonic acid, 12‐HETE, PGE2 and for neutrophil chemokinetic activity co‐chromatographing with leukotriene B4, before and at weekly intervals during therapy. Pre‐treatment concentrations of arachidonic acid, 12‐HETE and leukotriene B4‐like chemokinetic activity but not of PGE2 were elevated in involved skin when compared to uninvolved skin. The concentrations of arachidonic acid and 12‐HETE declined during therapy but changes in PGE2 were minimal. LTB4‐like activity was detectable in involved skin both before and after etretinate treatment. Clinically, scaling and infiltration improved but erythema was still evident.
Omeprazole inhibition of nocturnal gastric secretion in patients with duodenal ulcer.
Authors: Hetzel DJ , Shearman DJ
Published: July 2012

We studied the effect of single 08.00 h doses of omeprazole or placebo on gastric acid secretion during the following night, 14 to 23 h after administration, in seven male subjects with duodenal ulcer. The drug was given orally, double‐blind, in randomized order. Omeprazole 20 mg, 40 mg and 80 mg reduced mean total overnight acid output by 43%, 73% and 91% respectively and median pH increased from 1.4 with placebo to 1.6, 3.1 and 7.0 respectively. The inhibitory effect was maintained throughout the study period. No clinical side effects or abnormalities of laboratory screening tests were seen. Omeprazole is well tolerated and administration at 08.00 h produces prolonged dose related inhibition of acid output during the following night.
Is N‐acetylation of 5‐aminosalicylic acid reversible in man?
Authors: Meese CO , Fischer C , Klotz U
Published: July 2012

In two healthy male subjects the disposition of deuterated N‐(2H3) acetyl‐5‐aminosalicylic acid (d3‐ac‐5‐AS) was investigated after a single rectal dose of 500 mg d3‐ac‐5‐AS. Urine and plasma were analysed by h.p.l.c. and gas chromatography mass‐spectrometry. Peak concentrations of around 0.5 microgram/ml occurred within 6 h and plasma concentrations declined thereafter with a half‐life (t1/2) of about 6 h which was confirmed by urinary excretion data. Renal clearance of d3‐ac‐5‐AS ranged between 200 and 300 ml/min and only 4.4‐ 11.2% of the dose could be recovered in the 48 h urine. Since no undeuterated ac‐5‐AS could be detected in any of the plasma and urine samples an irreversible acetylation of 5‐AS is assumed in man.
Plasma disposition of vitamin K1 in relation to anticoagulant poisoning.
Authors: Park BK , Scott AK , Wilson AC , Haynes BP , Breckenridge AM
Published: July 2012

The disposition of vitamin K1, after intravenous (10 mg) and oral doses (10 mg and 50 mg) was studied in six healthy male subjects. After intravenous administration, the plasma concentration‐time profile was adequately fitted with an average terminal half‐life of 1.7 h. After oral administration (10 mg and 50 mg) the availability of vitamin K showed marked inter‐individual variation (10‐63%). With the higher dose intra‐individual variation was also observed. Experiments in brodifacoum‐anticoagulated rabbits demonstrate that the duration of action of a pharmacological dose (10 mg/kg) is short (9 h) and that high plasma concentrations (ca 1 microgram/ml) of the vitamin are required to drive clotting factor synthesis during maximum coumarin anticoagulation. Taken collectively, these data indicate that the short duration of action of vitamin K, frequently observed in cases of coumarin poisoning, is a consequence of requirements for high vitamin K concentrations and rapid clearance of the vitamin.
Do gastric contents modify antidotal efficacy of oral activated charcoal?
Authors: Olkkola KT , Neuvonen PJ
Published: July 2012

The effect of food on the antidotal efficacy of activated charcoal was studied in six healthy volunteers, who ingested aspirin 1000 mg, mexiletine 200 mg and tolfenamic acid 400 mg in a randomized cross‐over study. Activated charcoal 25 g, suspended in water, was administered 5 min or 60 min after the drugs were taken on an empty stomach or after a standard meal. The serum concentrations and the cumulative excretion into urine of the drugs were followed for 48 h. When the drugs were taken on an empty stomach, activated charcoal given 5 min or 60 min afterwards reduced the bioavailability of the drugs by 75‐98% or 10‐ 60%, respectively. Food moderately weakened the effect of activated charcoal administered 5 min after the drugs, but when the charcoal was given 1 h later the effect was still practically the same, the reduction of absorption varying in both cases in the range of 45‐85%. Thus the efficacy of charcoal given 60 min after the drugs was better after a standard meal than on an empty stomach. Presence of food in the stomach of patients with drug overdosage modifies the efficacy of activated charcoal and gives it more time to adsorb drugs in the gastrointestinal canal, possibly by slowing gastric emptying rate.
Pharmacokinetics and efficacy of high‐dose metoclopramide given by continuous infusion for the control of cytotoxic drug‐induced vomiting.
Authors: Taylor WB , Proctor SJ , Bateman DN
Published: July 2012

To avoid the accumulation of metoclopramide that occurs with repeated i.v. bolus doses, a new regimen for the administration of high‐dose metoclopramide consisting of a loading dose followed by a continuous infusion was investigated to determine the pharmacokinetics and antiemetic efficacy of the drug when given in this manner. Nine patients with non‐Hodgkin's lymphoma entered the study, of whom six completed the study, receiving each of three dosage schedules of metoclopramide during three consecutive courses of chemotherapy. In these six patients plasma metoclopramide half‐life was 5.9 +/‐ 0.4 h (mean +/‐ s.e. mean) and plasma clearance was 25.4 +/‐ 4.8 l/h (mean +/‐ s.e. mean). Neither half‐life nor clearance were dose‐related. Steady‐ state was achieved during 9/18 infusions. Nausea and vomiting were completely controlled in 13/24 treatment courses (57%) and adverse effects were minimal. We conclude that steady‐state plasma concentrations of metoclopramide can be achieved using a weight‐related infusion regimen, though the optimum plasma concentration remains to be determined.
Haemodynamic dose‐response effects of i.v. nicardipine in coronary artery disease.
Authors: Silke B , Verma SP , Nelson GI , Hussain M , Taylor SH
Published: July 2012

The haemodynamic dose‐response effects of the slow channel blocking agent nicardipine were evaluated in 10 male patients with angiographically confirmed coronary artery disease. At rest, following a similar control saline period, four doses of the drug (log cumulative dosage: 1.25, 2.5, 5.0 and 10.0 mg) were administered by i.v. infusion over a total duration of 40 min; haemodynamic variables were recorded in the 3‐5 min following each 5 min infusion. During steady‐state exercise the haemodynamic effects of the drug were evaluated by comparison of a control exercise period with observations made at the same workload (200‐500 kpm) following the maximum cumulative dose (10 mg). Following the four i.v. infusions, the plasma nicardipine level increased log‐linearly with the infused dose (r = 0.68). Compared with control measurements at rest after saline, these plasma concentrations (35 +/‐ 8 to 141 +/‐ 24 micrograms/l) resulted in a linear decrease in systemic blood pressure and vascular resistance with significant increase in cardiac index (maximum delta CI + 1.6 l min(‐1) m(‐2); P less than 0.01), stroke index (maximum delta SI + 11 ml/m2; P less than 0.01) and in pulmonary artery occluded pressure (maximum delta PAOP + 2 mm Hg; P less than 0.01). There was a significant increase in heart rate; the stroke work index was unchanged. During upright bicycle exercise the reduction in systemic blood pressure was accompanied by an increased exercise cardiac output without change in stroke index. The exercise pulmonary artery occluded pressure was unchanged compared with control observations, the stroke work index fell significantly (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Prophylaxis against ventricular arrhythmias in suspected acute myocardial infarction: a comparison of tocainide and disopyramide.
Authors: Allen‐Narker RA , Roberts CJ , Marshall AJ , Jordan SC , Barritt DW , Goodfellow RM
Published: July 2012

Five hundred and seventy one patients admitted to a coronary care unit with suspected acute myocardial infarction were considered for entry into a double‐blind study. Two hundred and eighty‐three patients were excluded, mainly because of recent treatment with beta‐adrenoceptor blocking agents, life threatening arrhythmias requiring specific treatment and left ventricular failure presenting with hypotension or pulmonary oedema. Two hundred and eighty‐eight entered the trial of whom 202 were subsequently confirmed to have had myocardial infarction. The effects of tocainide and disopyramide on ventricular arrhythmias were compared with placebo over the first 48 h period. The three treatments were given by a combination of intravenous infusion and oral administration. The doses used were tocainide 500 mg intravenously over 30 min plus 2800 mg orally over 48 h and disopyramide 150 mg intravenously over 30 min plus 1050 mg orally over 48 h. As judged by counts of ventricular premature beats, tocainide and disopyramide exerted a similar and significant antiarrhythmic effect. The median number of ventricular premature beats over the first 24 h of treatment was 58 on placebo compared with 30 on tocainide (P less than 0.05) and 19 on disopyramide (P less than 0.05). The corresponding figures for the second 24 h were 9, 6 and 2, respectively. There were eight deaths and three episodes of ventricular fibrillation with no significant differences between the three treatment groups. Sustained ventricular tachycardia was observed in one patient in the tocainide group.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of atenolol and nifedipine on digoxin‐induced inotropism in humans.
Authors: Hansen PB , Buch J , Rasmussen OO , Waldorff S , Steiness E
Published: July 2012

Short term effect of digoxin on left ventricular performance was studied in six healthy volunteers before and during atenolol or nifedipine administration. Left ventricular function was evaluated by systolic time intervals and echocardiography. No changes in left ventricular end diastolic or systolic dimensions occurred throughout the study, indicating unchanged ventricular pre‐ and afterload. Thus, changes in the systolic time intervals must be attributed to changes in cardiac contractility. Changes in the pre‐ejection period index (PEPI) obtained from the systolic time intervals were used as a measure of digoxin‐induced inotropism. A concentration‐response relationship between plasma digoxin level and changes in PEPI was revealed when digoxin was given alone. Atenolol did not influence the digoxin‐induced inotropism at a given serum digoxin level. During nifedipine administration no inotropic effect of digoxin could be demonstrated. Thus, it is concluded that nifedipine attenuates digoxin‐induced inotropism, while atenolol seems without this effect. These results are in accordance with previous experiments and reflect the different pharmacological sites of action of beta‐adrenoceptor antagonists and calcium channel blocking agents. Plasma digoxin concentration, renal digoxin clearance and creatinine clearance did not change during atenolol or nifedipine.
Propranolol concentrations in blood serum, seminal plasma and saliva in man after a single oral dose.
Authors: Mahajan P , Grech ED , Pearson RM , Ridgway EJ , Turner P
Published: July 2012

A single dose of 80 mg racemic propranolol hydrochloride was administered by mouth to six healthy male volunteers. The mean concentration achieved in seminal plasma at 2 h after dosing was almost identical to that in blood serum. The concentrations of propranolol in seminal plasma and saliva were much less than those known to reduce sperm motility by 50% in vitro. The concentrations in saliva did not reflect those in blood serum. Propranolol in the dose administered in this study is unlikely to affect fertility by its presence in saliva or semen.
Flurbiprofen interaction with single doses of atenolol and propranolol.
Authors: Webster J , Petrie JC , McLean I , Hawksworth GM
Published: July 2012

In patients with mild hypertension, flurbiprofen in a dose of 100 mg daily for 7 days attenuated the hypotensive effect of a single dose of propranolol 80 mg but not of atenolol 100 mg. The attenuation was not due to an effect on the pharmacokinetic profile of either propranolol or atenolol. An alternative explanation is required.
Evaluation of cyclosporin‐phenytoin interaction with observations on cyclosporin metabolites.
Authors: Freeman DJ , Laupacis A , Keown PA , Stiller CR , Carruthers SG
Published: July 2012

We have observed that patients on concurrent cyclosporin and phenytoin therapy required increased doses of cyclosporin to maintain therapeutic concentrations of this novel immunosuppressive drug. We have, therefore, studied the influence of phenytoin on the pharmacokinetics of oral cyclosporin in six healthy male subjects. Cyclosporin concentrations in serum and whole blood were measured by high pressure liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA). Concentrations of cyclosporin in whole blood were consistently higher than corresponding values in serum. Concentrations of cyclosporin determined by RIA were also consistently higher than those determined by h.p.l.c. Irrespective of the biological fluid (serum or whole blood) or the type of drug analysis (h.p.l.c. or RIA), changes in cyclosporin kinetics following phenytoin administration exhibited similar patterns. Phenytoin significantly reduced the maximum concentration and the area under the concentration‐time curve and significantly increased total body clearance of cyclosporin. There was a statistically significant reduction of cyclosporin half‐life (t 1/2) in whole blood using h.p.l.c. analysis. However, there was no significant change in cyclosporin t 1/2 in serum following phenytoin administration, using either form of drug analysis. Cyclosporin metabolites 17 and 18 were measured by h.p.l.c. in whole blood samples only, since these metabolites were found almost entirely in red blood cells. Phenytoin significantly reduced the Cmax and AUC of both metabolites, but no significant change was observed in the t 1/2 of either. Phenytoin enhanced the metabolism of antipyrine which was co‐administered with cyclosporin to assess oxidative enzyme activity. We conclude that patients undergoing organ transplantation should be carefully monitored if they require phenytoin or other drugs known to accelerate oxidative metabolism.
Location of vascular alpha 2‐adrenoceptors in man.
Authors: Murphy MB , Brown MJ , Dollery CT
Published: July 2012

To determine whether vascular postsynaptic alpha 2‐adrenoceptors are innervated by sympathetic nerves in man, normal volunteers were infused for 90 min with angiotensin II (A II) and the alpha 2‐adrenoceptor agonist alpha‐methylnoradrenaline (MNA) in a double‐blind cross‐over study. Whilst systolic blood pressure returned to baseline within 5 min of terminating the A II infusion it remained elevated 40 min after stopping MNA. The prolongation of the pressor response to MNA, a substrate for neuronal uptake, was probably due to activation of alpha 2‐adrenoceptors by MNA re‐released from contiguous sympathetic nerve endings. The proximity of alpha 2‐adrenoceptors to sympathetic nerve terminals suggests that they could contribute to blood pressure regulation in man.
Investigating drug‐ethanol interactions.
Authors: Starmer GA , Bird KD
Published: July 2012

Methodology developed in our laboratories for testing the interactive effects of ethanol and drugs on human psychomotor performance is discussed. An attempt has been made to relate the findings of our studies to the results of real‐life impairment, particularly in traffic crashes. Proposals for more comprehensive testing of drug‐ethanol interactions have been put forward which may increase the predictive value of such tests.
Effects of antidepressants on skilled performance.
Authors: Linnoila M , Johnson J , Dubyoski K , Buchsbaum MS , Schneinin M , Kilts C
Published: July 2012

Effects of amitriptyline 50 mg, desipramine 100 mg, and zimelidine 200 mg alone and in combination with ethanol 0.8 g/kg were investigated in healthy, male volunteers. Amitriptyline increased body sway and impaired tracking as well as information processing. It had an additive deleterious pharmacodynamic interaction with ethanol. Desipramine and zimelidine were free of adverse effects on performance and did not have significant interactions with ethanol. The dose of ethanol used in the present study did not inhibit biotransformation of the antidepressants.
Angiotensin converting enzyme inhibition in heart failure.
Authors: Cleland JG , Dargie HJ , Robertson JI
Published: July 2012

Captopril, the first orally effective converting enzyme inhibitor, was administered to 14 patients with chronic heart failure for 6 week periods, in a double‐blind crossover comparison with placebo. Captopril improved symptoms and exercise performance, while left ventricular internal dimensions were reduced. The fall in blood pressure induced by captopril was well tolerated. Glomerular filtration rate was reduced and effective renal plasma flow increased on captopril. No decline in body weight or total body sodium was seen, suggesting that a natriuresis had not occurred. Serum and total body potassium rose. Ventricular arrhythmias declined.
Acute and long‐term response to enalapril in congestive failure.
Authors: Kjekshus JK , Soyland E , Dickstein K , Abrahamsen AM , Gundersen T
Published: July 2012

Enalapril, a novel long acting angiotensin converting enzyme (ACE) inhibitor, was given orally to 12 patients with chronic heart failure (NYHA functional class III and IV) and cardiomegaly. The optimal dose averaged 17 mg given once‐daily. Heart rate, systemic arterial blood pressure, pulmonary arterial pressure, right and left ventricular filling pressures and cardiac index were monitored during dose efficacy titration. Eleven patients were recatheterised 3 months later. After stabilisation of cardiac filling pressures, all patients had left ventricular filling pressures in excess of 20 mmHg. Enalapril increased cardiac index acutely by 34% but at 12 weeks follow‐up, cardiac index was not different from control levels. Left ventricular filling pressure was reduced acutely by 36% and by 41% at 3 months. Heart rate, systemic arterial and right atrial pressures and plasma concentrations of aldosterone were reduced during the observation period. ACE activity was inhibited at the time of peak haemodynamic effect from 25.3 +/‐ 9.8 to 4.9 +/‐ 3.4 U/ml (P less than 0.01). Renin was markedly elevated. These changes were accompanied by marked and sustained clinical improvement and subjective well‐being.
Factors affecting the reporting of symptoms by hypertensive patients.
Authors: Vandenburg MJ , Evans SJ , Kelly BJ , Bradshaw F , Currie WJ , Cooper WD
Published: July 2012

Patients diagnosed as hypertensive have a high complaint rate, both on and off treatment and this has been postulated to be due to either their disease process, their being labelled as hypertensive, or to their treatment. Data from 6637 hypertensive patients being entered into clinical trials in general practice have been analysed to determine the relationship between the patient's age, sex, concurrent illnesses, concurrent medication, whether they were on antihypertensive treatment and the frequency of their reporting symptoms. The analysis was conducted using a multivariate technique. The frequency of reporting symptoms was greater in females than males. Those receiving antihypertensive therapy reported more symptoms than those who were not. This was notable with those receiving a beta‐adrenoceptor blocker (47% of such patients complaining). Patients receiving concurrent medication were more likely to report a symptom than those not (48 compared to 37%). This was particularly noticeable if central nervous system‐acting drugs were prescribed where the prevalence of symptoms was 52%. Patients already on antihypertensive treatment were more likely to be taking other medication for other conditions (37 vs 31%) than those not receiving antihypertensive treatment. Females were more likely to be taking other tablets than males (38 compared to 30%). The only symptoms which were less prevalent in those receiving treatment were headache, dizziness and breathlessness. All other symptoms were increased or unchanged in patients on antihypertensive therapy. This study indicates that present treatment for hypertension produces a high complaint rate from patients and that, when patients so complain, the possibility of their symptoms being due to their concurrent medication should be considered.
Plasma enalapril levels and hormonal effects after short‐ and long‐term administration in essential hypertension.
Authors: Johnston CI , Jackson BJ , Larmour I , Cubella R , Casley D
Published: July 2012

Enalapril lowers blood pressure both acutely and during long‐term therapy in patients with essential hypertension. After a single 10 mg dose of enalapril a close relationship between plasma enalaprilic acid (MK‐422) levels, angiotensin converting enzyme (ACE) inhibition and the acute hypotensive and hormonal effects was demonstrated. During long‐ term administration of enalapril, a similar relationship between the plasma enalaprilic acid level, ACE inhibition and the hypotensive effect was shown, although the dose‐response curve for plasma enalaprilic acid to ACE inhibition was displaced to the right compared to the acute dose‐response curve. Several weeks' administration of enalapril was needed to reach stable plateau levels of plasma enalaprilic acid and ACE inhibition. During long‐term treatment with enalapril in essential hypertension, there was sustained inhibition of ACE and the associated hormonal changes.
Tolerance and safety of enalapril.
Authors: McFate Smith W , Davies RO , Gabriel MA , Kramsch DM , Moncloa F , Rush JE , Walker JF
Published: July 2012

Enalapril is the result of a targeted research programme to develop a non‐mercapto converting enzyme inhibitor with a long duration of action and an improved safety profile for use in the therapy of hypertension and congestive heart failure. Over 3500 patients world‐wide have received enalapril or enalaprilat. Long‐term experience at present includes over 2500 patients. While enalapril and captopril produce similar efficacy, enalapril is better tolerated and appears not to be associated with occurrence of captopril‐type side‐effects, particularly the skin rash, taste loss, leukopenia and proteinuria. Enalapril and other converting enzyme inhibitors may be associated with renal insufficiency when given to patients with bilateral renovascular hypertension.
Patient compliance with oral theophylline therapy.
Authors: Taylor DR , Kinney CD , McDevitt DG
Published: July 2012

Day‐to‐day variations in plasma theophylline concentrations at steady‐ state have been assessed in 29 hospital inpatients who required theophylline for obstructive airways disease. Plasma concentrations were measured at 09.00h and 14.00h for four consecutive days in the equilibrium state in 13 patients taking 350 mg/day and 16 patients taking 700 mg/day. Analysis of variance gave 95% confidence limits for day‐to‐day variation of +/‐ 2.9 micrograms/ml at 350 mg/day and +/‐ 4.8 micrograms/ml at 700 mg/day. In a separate study, compliance with sustained‐release theophylline therapy has been assessed in a group of 63 patients receiving the drug in general practice but not attending hospital. Compliance was estimated by comparing plasma theophylline concentrations before and after a 7‐day period of measured theophylline consumption and by tablet counting. Of the 63 patients, 16 had discontinued their theophylline prior to being contacted and two did so during the first week: these were considered non‐compliant. Three patients had plasma concentrations which increased by more than the day‐ to‐day variation for their dose level during monitored intake and one other took less than 80% of his tablets. These patients were also considered non‐compliant. A further four patients in whom plasma theophylline levels were zero on at least one occasion during the study were also adjudged non‐compliant. Thus non‐compliance with prescribed theophylline dosage occurred in 26 (41.3%) of the patients studied. In the majority of these, treatment had been discontinued and the non‐ compliance was gross.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of ICI 118,587 and atenolol on the responses to exercise and on breathlessness in healthy subjects.
Authors: O'Neill PA , Morton PB , Sharman P. , Marlow HF , Stark RD
Published: July 2012

The effects of ICI 118,587 and atenolol on the responses to submaximal exercise and on breathlessness were studied in six healthy subjects. Atenolol reduced heart rate at rest and during exercise whereas ICI 118,587 increased resting heart rate but caused a small reduction in the highest heart rate achieved during exercise. Neither ICI 118,587 nor atenolol significantly changed minute ventilation or oxygen uptake either at rest or during exercise. There were no effects on bronchomotor tone. The assessment of breathlessness was validated for the subjects participating in the study. Atenolol increased the intensity of breathlessness in relation either to ventilation or to oxygen uptake. This effect was not secondary to a change in bronchomotor tone but was possibly related to changes in pulmonary haemodynamics. On the other hand, the relationships of breathlessness to ventilation or to oxygen uptake were unchanged by ICI 118,587. The effects of ICI 118,587 on exercise tolerance and dyspnoea in patients with impaired cardiac function should now be determined.
Plasma cortisol delivery from oral cortisol and cortisone acetate: relative bioavailability.
Authors: Heazelwood VJ , Galligan JP , Cannell GR , Bochner F. , Mortimer RH
Published: July 2012

Plasma cortisol levels were measured before and for 6 h after the intravenous injection of 50 mg cortisol as sodium succinate and oral administration of 50 mg cortisol and 50 mg cortisone acetate in 10 subjects with primary or secondary adrenal failure and in two normal volunteers. Peak cortisol levels of 1518 +/‐ 190 nmol 1(‐1) (mean +/‐ s.e. mean) and 739 +/‐ 74 nmol 1(‐1) were found 1.46 +/‐ 0.25 and 1.79 +/‐ 0.16 h after oral cortisol and cortisone acetate respectively. The relative bioavailability of oral cortisol and cortisone acetate varied widely (cortisol 26‐91%, mean 54 +/‐ 6.9%, cortisone acetate 21‐95%, mean 44 +/‐ 6.5%) but despite this wide variation there was, in individual subjects, a highly significant correlation between the bioavailability of the two steroids (r = 0.870, P less than 0.001). This suggests that the wide interindividual variations in plasma cortisol levels seen after oral cortisone acetate are not related to variations in bioconversion of cortisone.
Sulphate conjugation of beta 2‐adrenoceptor stimulating drugs by platelet and placental phenol sulphotransferase.
Authors: Sodha RJ , Schneider H.
Published: July 2012

A possible route of metabolism of beta‐adrenoceptor stimulating drugs used in obstetrics consists of conjugation by the enzyme phenol sulphotransferase. The substrate specificities of the platelet and the placental enzymes towards these drugs were tested. The specific activities of the beta‐adrenoceptor agonists were found to be relatively similar to those obtained with the catecholamine dopamine but their Km values were considerably higher.
Effect of levamisole and azathioprine on the human mixed lymphocyte reaction (MLR).
Authors: Al‐Safi SA , Maddocks JL
Published: July 2012

Levamisole (1.25‐4.15 microM) had no effect on tritiated thymidine incorporation into DNA of mixed lymphocyte cultures. Moreover, it did not cause any reversal of azathioprine (18‐36 microM) inhibitory effects on the MLR.
Enzyme induction by phenobarbitone and vitamin K1 disposition in man.
Authors: Park BK , Wilson AC , Kaatz G. , Ohnhaus EE
Published: July 2012

The plasma disposition of an intravenous pharmacological dose of vitamin K1 was determined in seven healthy volunteers before and after chronic administration of phenobarbitone (100 mg nocte). Phenobarbitone produced a significant increase in antipyrine clearance and 6 beta‐ hydroxycortisol excretion in all volunteers, indicating induction of hepatic microsomal mixed‐function oxidase enzymes. However, phenobarbitone administration had no effect on the plasma disposition of vitamin K1. We conclude therefore, that vitamin K1 is not metabolized to any significant extent, by phenobarbitone‐inducible mixed‐function oxidase enzymes.
Interaction of propoxyphene with diazepam, alprazolam and lorazepam.
Authors: Abernethy DR , Greenblatt DJ , Morse DS , Shader RI
Published: July 2012

Healthy volunteers received single doses of three benzodiazepines (diazepam, 10 mg i.v.; alprazolam, 1.0 mg orally; lorazepam, 2 mg i.v.) on two occasions in random sequence. One trial was a control; for the other, subjects ingested propoxyphene, 65 mg every 6 h, for the duration of the benzodiazepine study. The kinetics of each benzodiazepine were determined from multiple plasma concentrations measured following each dose. For diazepam, propoxyphene produced a small and statistically insignificant prolongation of elimination half‐ life (43 vs 38 h) and reduction of total clearance (0.41 vs 0.47 ml min‐ 1 kg‐1). Propoxyphene significantly prolonged alprazolam half‐life (18 vs 12 h, P less than 0.005) and reduced total clearance (0.8 vs 1.3 ml min‐1 kg‐1, P less than 0.005). Propoxyphene had no apparent influence on lorazepam half‐life (13.4 vs 13.5 h) or clearance (1.5 vs 1.4 ml min‐ 1 kg‐1). Thus propoxyphene significantly impairs the clearance of alprazolam, biotransformed mainly by the oxidative reaction of aliphatic hydroxylation. Propoxyphene has far less effect on the oxidation of diazepam by N‐demethylation, and has no apparent influence on lorazepam conjugation.
Lack of effect of amoxicillin on theophylline pharmacokinetics.
Authors: Jonkman JH , van der Boon WJ , Schoenmaker R , Holtkamp A , Hempenius J
Published: July 2012

The effect of the antibiotic drug amoxicillin on steady state pharmacokinetics of theophylline was studied in healthy adults by comparing the pharmacokinetic parameters as found during a 9 day course of theophylline alone and as obtained during comedication with amoxicillin. Theophylline plasma concentrations were measured by means of h.p.l.c. analysis. On the ninth day of each of the two periods of drug administration a concentration‐time curve was evaluated. It showed no influence of amoxicillin on absorption, elimination and volume of distribution of theophylline, as a result of which mean steady state plasma concentrations were not significantly different during both treatments. It is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.
Thrombocytopenia and leucopenia with mianserin‐dependent antibodies.
Authors: Stricker BH , Barendregt JN , Claas FH
Published: July 2012

By indirect immunofluorescence specific mianserin‐dependent antibodies were detected against platelets but not against granulocytes in the serum of a patient with thrombocytopenic purpura and mild leucopenia. A complement‐mediated cytotoxicity assay demonstrated 70% lysis of granulocytes but no lysis of platelets, only when mianserin was added to the medium. We suggest that, at least in some patients, mianserin may cause blood disorders by an immunologically‐mediated mechanism.
A class experiment in clinical pharmacology using beta‐adrenoceptor antagonist drugs.
Authors: Kumana CR , Ogle CW
Published: July 2012

Cardiac beta‐adrenoceptor blocking activity was evaluated in a between‐ subject study carried out as a class experiment with pre‐clinical medical students participating in a practical pharmacology course. From each of 10 groups of students, three healthy male volunteers, took oral propranolol 80 mg, pindolol 10 mg or placebo, according to a double‐ blind randomised protocol. Pre‐treatment, and 45‐60 min (1 h) and 105‐ 120 min (2 h) post‐treatment heart rate (HR) was determined electrocardiographically in the last 15 s during periods of rest (sitting for 5 min), isometric exercise (applying a standardized hand grip to a rolled sphygmomanometer cuff to elevate pressure from 50 to 150 mm Hg; 2 min) and dynamic exercise (bicycle ergometry with a load of 150 W for 3 min). Reductions from pre‐treatment HR yielded statistically significant differences during exercise (isometric and dynamic) between all corresponding changes on placebo and active drugs (P less than 0.05‐0.01), except with the 1 h post‐propranolol hand grip HR. At rest, only the difference between 2 h HR changes on placebo and propranolol achieved statistical significance (P = 0.05); presumably, the partial agonist activity of pindolol overcame any minimal HR slowing liable to occur at rest. Cardiac beta‐adrenoceptor blocking activity as judged by reductions in HR from pretreatment values, was more evident during cycling than during hand grip; and during hand grip than at rest.
The effect of a week's beta‐adrenoceptor antagonism on daytime heart‐ rates, subjective responses to exercise, and physical activity in normal subjects.
Authors: Patrick JM , Wharrad HJ , Wilson CG , Birmingham AT
Published: July 2012

The effects on heart rate (HR) and physical activity of 1 week's treatment with three different beta‐adrenoceptor antagonists (20 mg betaxolol (Lorex); 160 mg propranolol LA; or 100 mg atenolol daily) have been compared with placebo in a double‐blind study of 12 normal men. On the fifth day of each treatment a body‐borne tape‐recorder was worn during waking hours for recording of ECG and footfall signals. Each record was calibrated in terms of the subject's response to laboratory ergometer exercise, and a computer analysis provided objective indices of physical activity. While on beta‐adrenoceptor antagonists the subjects perceived standard exercise as significantly harder than on placebo and reported more side‐effects (albeit mild and transient). Ambulatory monitoring of HR showed that subjects spent 13% of their waking day at heart rates below 50 beats min‐1 while on propranolol, compared with 1% on placebo and 20% on atenolol and betaxolol. On these latter drugs, the group spent as much as 10% of their waking time with HR below 45 beats min‐1. The lowest individual heart‐rates recorded were below 35 beats min‐1. Objective indices of physical activity, such as the duration of periods spent with heart rates above the HR found at 100 W in the ergometer test, showed no differences between the treatments. This negative finding was confirmed by pedometer step counts over the whole week.
Pharmacokinetics of ornidazole in patients with renal insufficiency; influence of haemodialysis and peritoneal dialysis.
Authors: Merdjan H , Baumelou A , Diquet B , Chick O , Singlas E
Published: July 2012

The pharmacokinetics of ornidazole (Tiberal) was studied after intravenous administration of a single 500 mg dose in eight patients with advanced chronic renal failure (ACRF) (creatinine clearance 2‐16 ml/min), in seven patients treated by haemodialysis (residual renal creatinine clearance 0‐5 ml/min) and in five patients treated by continuous ambulatory peritoneal dialysis (CAPD) (residual renal creatinine clearance 0‐6 ml/min). In ACRF patients, the half‐life of ornidazole was 10.8 +/‐ 1.4 h, the total plasma clearance 46.3 +/‐ 2.3 ml/min and the volume of distribution 0.73 +/‐ 0.06 l/kg. During haemodialysis, ornidazole was partly removed: the dialyser extraction ratio was 42 +/‐ 5% and the dialysis clearance 64 +/‐ 7 ml/min. During CAPD, peritoneal excretion was low: the dialysis clearance was 3.0 +/‐ 0.4 ml/min and in 48 h 6.0 +/‐ 1.1% of the administered dose was found in the peritoneal fluids. In these patients, the half‐life of ornidazole was 11.8 +/‐ 0.8 h and total plasma clearance was 48.3 +/‐ 5.5 ml/min, values which were close to those determined in non dialysed patients. In patients with end‐stage renal disease, the half‐life of ornidazole is comparable to that of subjects with normal renal function. This is due to the predominantly extra‐renal elimination of the drug. Therefore, there is no need to modify the usual dosage of ornidazole for these patients. Because of the large elimination of the drug during haemodialysis it is necessary to administer the drug after the dialysis session.
The effects of age and smoking on the plasma protein binding of lignocaine and diazepam.
Authors: Davis D , Grossman SH , Kitchell BB , Shand DG , Routledge PA
Published: July 2012

In 63 healthy ambulant subjects 18 to 88 years of age, the plasma protein binding of diazepam (principally bound to albumin) decreased with age. Diazepam binding in plasma correlated positively with plasma albumin concentration which also decreased with age. In contrast, the plasma protein binding of the basic drug, lignocaine (predominantly bound to alpha 1‐acid glycoprotein [AAG]), tended to increase slightly with age. Lignocaine binding in plasma correlated positively with plasma AAG concentration which also increased slightly with age. Smoking did not affect the plasma protein binding of diazepam or lignocaine or the plasma concentrations of albumin, AAG or nonesterified fatty acids. These results suggest that age‐related changes in plasma protein binding of lignocaine and diazepam are determined in part by age‐related changes in the concentrations of the binding proteins in plasma. The ageing process alone causes only small changes in the plasma protein binding of these drugs compared with the effect of disease states, however.