bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of oral nitrendipine and propranolol, alone and in combination, on hypertensive patients with special reference to AV conduction.
Authors: Maltz MB , Davies DW , Lau CP , Creamer JE , Banim SO , Camm AJ
Published: July 2012

The effects of oral nitrendipine and oral propranolol, alone and in combination, on AV conduction have been examined in 11 patients with essential hypertension in whom arterial pressure was not adequately controlled despite treatment with thiazide diuretics. The study was performed double‐blind. After a drug free period of 1 week, the patients received two 7 day courses of drug therapy after initial control measurements. Five of the eleven patients were randomised to receive nitrendipine 20 mg daily, the other six patients received propranolol (Inderal LA 160 mg daily) for the first week of therapy. During week 2, 10 patients received combined therapy. In the 10 patients who completed the study, oral nitrendipine, given either alone or in combination with oral propranolol, had no significant effect on resting PR, QRS, QT intervals nor on AV conduction as assessed by ambulatory electrocardiography. Propranolol did not affect the resting PR interval but significantly increased PR intervals on the ambulatory ECG recordings during single and combined therapy. However the maximum PR intervals remained within normal limits.
Comparison of the effects of penbutolol and propranolol on glomerular filtration rate in hypertensive patients with impaired renal function.
Authors: van der Meulen J , Reijn E , Heidendal GA , Oe PL , Donker AJ
Published: July 2012

Penbutolol and propranolol were administered orally in a dosage of 40 mg once daily and 80 mg twice daily, respectively to 12 patients with hypertension and impaired renal function. Both drugs caused a significant decrease in mean arterial pressure and heart rate. Serum creatinine concentration increased significantly by 10% during therapy with propranolol without concomitant decrease in creatinine clearance. No such effect was seen with penbutolol. GFR measured with [125I]‐ iothalamate showed no significant changes with both drugs.
Effect of calcium antagonists on histamine release from human basophil leukocytes.
Authors: Miadonna A , Tedeschi A , Leggieri E , Lorini M , Froldi M , Zanussi C
Published: July 2012

The effect of calcium antagonists on basophil activation was investigated in 14 subjects. Verapamil, methoxyverapamil and diltiazem, in a concentration range of 1‐100 microM, exert a concentration‐ dependent inhibition on the human basophil histamine release induced by calcium ionophore A23187, zymosan activated human serum and grass pollen allergens. This inhibitory effect is highly variable from subject to subject and from drug to drug. At concentrations higher than 200 microM, verapamil, methoxyverapamil and diltiazem induce a calcium independent histamine secretion from basophil leukocytes. This mediator release is associated with an increase in LDH levels in the cell supernatant and seems to be due to a cytotoxic effect.
Plasma [3H]‐noradrenaline kinetics and blood pressure following regular, moderate ethanol consumption.
Authors: Howes LG , MacGilchrist A , Hawksby C , Sumner D , Reid JL
Published: July 2012

Normotensive male volunteers (n = 8) either abstained from ethanol for 4 days or consumed 66 g of ethanol per day in an open, crossed, random order study. Mean arterial pressures rose by an average of 5.4 mmHg following the ethanol phase of the study (P less than 0.001). Plasma noradrenaline (NA) concentration was higher during ethanol ingestion (P less than 0.01), principally because of a significant reduction in NA clearance of −1.51 l min−1 m−2 (P less than 0.05). In contrast, NA spillover or release rates did not significantly differ between the two study periods. Total plasma calcium levels were significantly lower (P less than 0.05) following the ethanol compared to the control period. These data do not appear to support the proposition that regular alcohol consumption raises blood pressure by producing a generalised increase in sympathetic activity.
Pharmacodynamic and pharmacokinetic studies on bufuralol in man.
Authors: Pringle TH , Francis RJ , East PB , Shanks RG
Published: July 2012

Observations were made in eight subjects who exercised before and at 1, 2, 4, 6, 8 and 24 h after the double‐blind oral administration of placebo, bufuralol 7.5, 15, 30, 60 and 120 mg and propranolol 40 and 160 mg. The exercise heart rate remained constant after placebo. Bufuralol 7.5 mg and propranolol 40 mg reduced exercise heart rate up to 6 and 8 h respectively after dosing but bufuralol 15, 30, 60 and 120 mg and propranolol 160 mg were still active at 24 h. The lowest exercise heart rate occurred at 2 h after all active treatments. Bufuralol 60 and 120 mg produced similar reduction in exercise tachycardia as propranolol 40 mg but less than propranolol 160 mg. Plasma levels of bufuralol and its two major metabolites were measured. The peak plasma concentrations of bufuralol occurred at 1.5 h after 7.5 mg and at 2 h after the other doses of bufuralol. In six subjects the plasma elimination half‐life of bufuralol was 2.61 +/‐ 0.18 h and in the other three subjects 4.85 +/‐ 0.35 h. There was a corresponding longer time to peak concentration and plasma elimination half‐life of the two metabolites in these three subjects. These findings show that bufuralol is a potent beta‐adrenoceptor antagonist with partial agonist activity. It has a long duration of action and there is bimodal metabolism of the drug in man.
A comparative study on the ventilatory and haemodynamic effects of xamoterol and atenolol in asthmatic patients.
Authors: Lammers JW , Muller ME , Folgering HT , Van Herwaarden CL
Published: July 2012

The effects of single oral doses of atenolol 50 mg and xamoterol 200 mg (a recently developed partial beta 1‐adrenoceptor agonist) on lung function, heart rate and blood pressure were investigated in 11 patients with asthma. Xamoterol caused a significant increase in heart rate and systolic blood pressure, which changes are consistent with the partial beta 1‐adrenoceptor agonist activity of this drug. Atenolol induced a significant decrease in FEV1 and the forced vital capacity (FVC); there was a non‐significant change in FEV1 and FVC after xamoterol. There was no significant difference between the effects of atenolol and xamoterol of FEV1 and FVC. Bronchospasm induced by atenolol 50 mg and xamoterol 200 mg was completely reversed by inhalation of the beta 2‐adrenoceptor agonist terbutaline to a cumulative dose of 4.0 mg.
The effectiveness of ranitidine in reducing gastric acid‐secretion decreases with continued therapy.
Authors: Prichard PJ , Jones DB , Yeomans ND , Mihaly GW , Smallwood RA , Louis WJ
Published: July 2012

To examine whether changes in inhibition of gastric acid secretion occur during chronic ranitidine therapy, duodenal ulcer patients in remission were studied before and after 9 months of maintenance ranitidine therapy (150 mg nocte). At each time, the effect of a bolus i.v. dose of ranitidine (50 mg) on pentagastrin‐stimulated maximal acid output was measured. Oral and intravenous pharmacokinetic studies were also performed to examine whether changes in absorption or disposition occur during long‐term dosage. After 9 months' therapy, ranitidine inhibited pentagastrin‐stimulated secretion by a median of 62%, substantially less than the median inhibition of 95% pre‐treatment. Median acid output in the period 60‐120 min post‐ranitidine was six times the pretreatment value. Since pharmacokinetic parameters were unaltered, this reduced ability to inhibit acid output appears to indicate reduced sensitivity of acid secreting mechanisms to ranitidine after prolonged dosage.
A rest and exercise haemodynamic evaluation of a new cardio‐selective beta‐adrenoceptor blocker celiprolol alone and in combination with nitroglycerine in ischaemic heart disease.
Authors: Silke B , Verma SP , Frais MA , Reynolds G , Taylor SH
Published: July 2012

The symptomatic benefits of combining beta‐adrenoceptor blockers and nitrates in angina pectoris are well recognised. Their actions on cardiac haemodynamics and volumes when combined have been poorly characterized. Accordingly this study investigated a new cardioselective beta‐adrenoceptor blocking agent celiprolol and buccal nitroglycerine in 24 patients with angiographically documented coronary artery disease. Following a control period, with confirmed stable haemodynamics, three groups (n = 8/group) of prospectively matched patients, were studied following intravenous celiprolol (8 mg), buccal nitrate (10 mg) or their combination. Haemodynamics and left ventricular ejection fraction (nuclear probe) were determined following each intervention. The actions of each regimen on the haemodynamics of exercise‐induced angina were compared by exercise testing in the control state and following each regimen. At rest, celiprolol did not alter haemodynamic parameters. Nitrate therapy reduced left ventricular filling pressure (pulmonary artery occluded pressure‐PAOP) and volumes; the ejection fraction and heart rate increased. Combination therapy resulted in a highly significant reduction in left ventricular preload and afterload (PAOP and mean arterial blood pressure) at an increased left ventricular ejection fraction and reduced cardiac volumes; there was a trend to reduce cardiac double product (HR X SBP). During exercise celiprolol reduced systolic blood pressure, heart rate and cardiac index; systemic vascular resistance index increased. Nitrate therapy reduced blood pressure and PAOP, and increased ejection fraction. Combination therapy reduced all components of the triple product (heart rate, systolic blood pressure and PAOP) without affecting the other haemodynamic or radionuclide parameters. These data suggest improvements in cardiac function from the combination of celiprolol and nitrate therapy which were not achieved by either agent when used as monotherapy; they afford an interesting insight into the manner in which such widely utilised therapeutic modalities interact in coronary artery disease.
No effects on sleep of a histamine H1‐receptor antagonist: temelastine.
Authors: Adam K , Oswald I
Published: July 2012

Twelve volunteer poor sleepers of mean age 57 years took placebo on each of 3 consecutive nights, and temelastine 100 mg on 3 consecutive nights in a double‐blind balanced order study. Sleep in the EEG laboratory was unaffected by the drug.
Enantiomers of warfarin and vitamin K1 metabolism.
Authors: Choonara IA , Haynes BP , Cholerton S , Breckenridge AM , Park BK
Published: July 2012

The effect of the individual enantiomers of warfarin at steady state (1 mg daily) was investigated in five healthy volunteers. Both enantiomers produced a significant increase in prothrombin time, but the increase with S warfarin (1.8 +/‐ 0.8 s, mean +/‐ s.d.) was greater than with R warfarin (1.0 +/‐ 0.3 s), despite lower steady state plasma concentrations of S warfarin, due to its more rapid clearance. Following the administration of vitamin K1, the maximum plasma concentration and area under the plasma concentration time curve values for the metabolite vitamin K1 2,3‐epoxide were greater after S warfarin than after R warfarin. The greater anticoagulant potency of S warfarin is reflected by a greater degree of inhibition of vitamin K1 epoxide reductase.
Effects of locally administered anticholinesterase agents on the secretory response of human eccrine sweat glands to acetylcholine and carbachol.
Authors: Longmore J. , Jani B. , Bradshaw CM , Szabadi E.
Published: July 2012

The effects of locally administered physostigmine and di‐ isopropylphosphorofluoridate (DFP) were compared on the secretory response of sweat glands to intradermally injected acetylcholine and carbachol in healthy male volunteers (physostigmine: six subjects; DFP: one subject). The response to acetylcholine reached its peak within 10 s of injection and then rapidly declined, whereas the response to carbachol increased steadily reaching a peak between 5 and 7 min after injection. The response to acetylcholine was potentiated in the presence of both physostigmine and DFP, whilst the response to carbachol was not significantly affected by either of these drugs. The difference in the time‐course of responses to acetylcholine and carbachol may be attributed to differences in the susceptibility of the two drugs to metabolism by acetylcholinesterase; carbachol, unlike acetylcholine, being virtually immune to metabolism by this enzyme. It is concluded that the response to carbachol is mediated by a direct stimulatory action on post‐synaptic muscarinic receptors rather than by activation of pre‐synaptic nicotinic receptors leading to the release of endogenous acetylcholine.
A comparison of the clinical and bronchodilating effects of plain and slow‐release tablets of terbutaline at steady state.
Authors: Pauwels R. , Elinck W. , Lamont H. , van der Straeten M. , Ljungholm K.
Published: July 2012

The clinical efficacy, the bronchodilating effect and the side effects of two oral forms of terbutaline were compared in a double‐blind, cross‐ over study involving ten patients with chronic reversible airways obstruction. The administration of plain‐tablets, containing 2.5 mg terbutaline sulphate, three times daily at 6 h intervals was compared to the administration of slow‐release (SR) tablets, containing 5 mg terbutaline sulphate, every 12 h. Each course of treatment lasted for 7 days. Treatment with SR‐tablets resulted in significantly higher lung function values in the morning (PEFR at home and FEV1 at the lung function laboratory on day 7). There were no significant differences between the two forms with regard to symptom score, extra use of rimiterol aerosol, heart rate or blood pressure. The plasma terbutaline concentration in the morning of the seventh treatment day was significantly higher during SR‐tablet treatment. The plasma terbutaline concentration curve showed a smaller peak/trough ratio for the SR‐ tablets.
Quantitation of dose and concentration‐effect relationships for fenclofenac in rheumatoid arthritis.
Authors: Dunagan FM , McGill PE , Kelman AW , Whiting B.
Published: July 2012

Response to non‐steroidal anti‐inflammatory drugs (NSAIDs) is not usually assessed on the basis of concentration measurements: identification of a concentration‐effect relationship has proved difficult to achieve. Dose and concentration‐effect relationships of fenclofenac have been determined in a group of 18 patients with rheumatoid arthritis at three dose levels (600, 1200 and 1800 mg day‐ 1). The study was double‐blind and treatments were randomised according to a Latin square design. A multiple linear regression technique (GLIM) was used in the analysis. The best model to describe the change in effect in terms of dose and concentration incorporated an average slope and an individual subject intercept for each effect measurement. On average, an improvement in grip strength of 20 mm Hg could be obtained with an increase in fenclofenac (trough) concentration of 100 micrograms ml‐1.
The effect of moderate urine alkalinisation on low dose diethylcarbamazine therapy in patients with onchocerciasis.
Authors: Awadzi K. , Adjepon‐Yamoah KK , Edwards G. , Orme ML , Breckenridge AM , Gilles HM
Published: July 2012

Twenty‐one patients with moderate to heavy infections with O. volvulus were treated with 25 mg of diethylcarbamazine (DEC) citrate twice daily for 10 days. In 11 patients the urine was made alkaline with sodium bicarbonate, 2 g, administered 6 hourly for three doses daily beginning 1 day before DEC was started and continued throughout the DEC therapy. Ten patients served as controls. The mean pre‐dose plasma DEC concentration during treatment and the mean plasma DEC half‐life were significantly higher in bicarbonate treated patients as compared to controls. Total urinary excretion of DEC was significantly less in the bicarbonate treated group than in controls. Mean overall total reaction was higher in bicarbonate‐treated patients but the difference was not significant. The bicarbonate‐treated group achieved a significantly greater reduction in skin microfilarial counts than the control group as assessed 1 week after completion of therapy, but there was little difference at 1 month. Microfilarial killing was associated with microfilarial mobilisation, alteration in peripheral leucocytes and elevation in serum aminotransferases in both groups. There was no effect of DEC on the number of adult worms recovered in nodules removed at the end of the therapy. This study indicates that moderate urinary alkalinisation alters the kinetics of DEC and the therapeutic response. However the severity of clinical reaction coupled with the inadequate level of microfilarial killing achieved make it unlikely that manipulation of urinary pH will be of practical value in onchocerciasis chemotherapy.
Inhibition of human gastric secretion by ICI 162,846‐a new histamine H2‐receptor antagonist.
Authors: Wilson JA , Johnston DA , Penston J. , Wormsley KG
Published: July 2012

The inhibitory effect of ICI 162,846, a new histamine H2‐receptor antagonist, on gastric secretion of acid and pepsin was studied in 10 healthy male volunteers, aged 21‐30 years. Single doses of 0.5, 1.0, 2.5 and 5.0 mg were given orally at 18:00 h. Overnight 12 h gastric secretion of acid was reduced by 69, 81, 91 and 95%, respectively. The inhibition of nocturnal output of pepsin was less than acid, with median decreases of 21, 42, 73 and 87%, respectively, of the output after administration of placebo. Intragastric concentration of acid, and values of intragastric pH, during the following 12 h of the day were not significantly affected by any of the doses of the drug. We conclude that ICI 162,846 is a powerful inhibitor of gastric secretion, with potential for use in the treatment of peptic diseases.
Accumulation of caffeine in healthy volunteers treated with furafylline.
Authors: Tarrus E , Cami J , Roberts DJ , Spickett RG , Celdran E , Segura J
Published: July 2012

The pharmacokinetics and tolerance of repeated oral doses of furafylline were investigated in normal volunteers. In accord with predictions from single dose studies, steady state was achieved on the first day following the administration of 90 mg and maintained by subsequent daily doses of 30 mg. When corrected for body weight there were no significant differences in minimum and maximum plateau levels of furafylline between males (1.2‐2.0 micrograms ml‐1; mean body weight 67.2 kg) and females (1.6‐2.6 micrograms ml‐1; mean body weight 54.9 kg). The half‐life of elimination was less when the plasma concentration was lower than 600 ng ml‐1 than during the stationary phase of treatment. Despite constant plasma levels the repeated administration of furafylline appeared to be associated with the onset of adverse xanthine‐like side effects, a finding which was subsequently traced to the presence of, and possible synergism with, accumulating serum levels of caffeine in those volunteers drinking caffeine containing beverages. Subsequent studies showed that a single dose (90 mg) of furafylline results in a rapid accumulation of caffeine given orally (100 mg twice daily) and that this is accompanied by an elimination half‐life of some 50 h and an abrupt decrease in metabolite levels. The furafylline‐induced accumulation of caffeine was not influenced by the smoking habits of the subjects, implying that the metabolite pathway blocked by furafylline is the demethylation of caffeine in position 3, an implication confirmed by the reduced formation of paraxanthine. This demonstration of an unacceptable level of adverse side effects resulting from a potent inhibiting effect of furafylline on the metabolism of a normal dietary constituent has obvious implications in the interpretation of drug‐induced toxicity.
Immediate haemodynamic effects of a novel partial agonist, beta 1‐ adrenoceptor blocking drug ICI 141,292 after intravenous administration to healthy young volunteers and patients with ischaemic heart disease.
Authors: Bonde J , Svendsen TL , Lyngborg K , Mehlsen J , Trap‐Jensen J
Published: July 2012

ICI 141,292 is a new beta 1‐adrenoceptor blocking drug. The beta 1‐ adrenoceptor antagonistic effect of ICI 141,292 was examined in a double‐blind, randomised crossover study in eight healthy young volunteers and compared with atenolol. Three doses of ICI 141,292 (1, 2 and 4 mg) and atenolol 5 mg were administered intravenously. The attenuation in exercise induced tachycardia varied between 16.0 and 21.2% (P less than 0.01). A significant reduction in blood pressure could be demonstrated following all three doses of ICI 141,292 and atenolol during exercise. At rest in the sitting position HR decreased approximately 8% following all three doses of ICI 141,292 and 14.9% after atenolol 5 mg. No changes in blood pressure were observed under resting conditions after any of the drugs. In six patients with ischaemic heart disease the intrinsic sympathomimetic activity following intravenous administration of four sequential doses (0.5, 0.5, 1.0 and 2.0 mg) of ICI 141,292 was examined. HR decreased 7% (P less than 0.05) following ICI 141,292 1 mg with no further decrease following the succeeding doses. Cardiac output decreased 5.2% (P less than 0.05) following a cumulative dose of 4 mg. No significant changes were observed in mean arterial blood pressure, stroke volume or total peripheral resistance whereas an increase in supine resting mean pulmonary arterial pressure of 3.4 mm Hg (P less than 0.05) could be demonstrated. ICI 141,292 seems to be a potent (at least five times as potent as atenolol) beta 1‐adrenoceptor blocking agent possessing moderate intrinsic sympathomimetic activity.
Effects of time of dosing and age on intravenous aminophylline pharmacokinetics.
Authors: Rodgers A , Woodhouse KW , Bateman DN
Published: July 2012

The elimination kinetics of theophylline were investigated following intravenous administration of aminophylline in 12 subjects (six fit young, and six healthy hospitalised elderly volunteers) at 09.00 h and 21.00 h on separate occasions at least 5 days apart to determine whether time of administration had significant effects on clearance in young and elderly subjects. We were unable to demonstrate a significant change in kinetic parameters between morning and evening administration in either young or elderly subjects. Our results also demonstrated no difference in kinetics between young and elderly subjects. We conclude that neither time of dosing nor age are important determinants of theophylline elimination kinetics in healthy subjects.
The pharmacokinetics of enalapril in hospitalized patients with congestive heart failure.
Authors: Dickstein K , Till AE , Aarsland T , Tjelta K , Abrahamsen AM , Kristianson K , Gomez HJ , Gregg H , Hichens M
Published: July 2012

The pharmacokinetics of the converting enzyme inhibitor, enalapril, were studied in an open, randomized, balanced crossover design in 12 hospitalized patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril maleate 10 mg orally, enalapril maleate 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72 h period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of enalaprilat, before and after sample hydrolysis. Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first‐pass effect 10%. The results were compared with available data in normal subjects. After oral administration of 10 mg enalapril maleate, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normals with differences less than 10%. The rate of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF and maximal concentrations were reached at 6 h in CHF as compared to 4 h in normal subjects. We conclude that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.
Evidence for polymorphic oxidation of sparteine in Japanese subjects.
Authors: Ishizaki T , Eichelbaum M , Horai Y , Hashimoto K , Chiba K , Dengler HJ
Published: July 2012

The metabolism of sparteine which exhibits a genetic polymorphism in Caucasians was studied in 84 unrelated Japanese subjects. In contrast to a recent study where debrisoquine was used as a probe and no poor metabolizers could be observed in Japanese involving 100 subjects, two subjects had a urinary metabolic ratio of sparteine greater than 20 and thus were poor metabolizers of sparteine. The incidence of poor metabolizer phenotype of sparteine oxidation of 2% seems to be lower in Japanese as compared with various Caucasian populations where 5 to 10% are poor metabolizers of sparteine. However, this is not conclusive, because the 95% confidence interval of the observed frequency, 0.6 to 8%, covers the range reported in the literature for Caucasians.
The effects of beta‐adrenoceptor blockade on breathing during progressive exercise in normal man.
Authors: Pearson SB , Morrison JF , Simpson FG
Published: July 2012

1 We have studied the effects of single oral doses of 80 mg propranolol and 100 mg atenolol on breathing during progressive exercise in nine healthy men in a double‐blind, placebo‐controlled experiment. As judged by their effects on exercise heart rate significant levels of beta‐ adrenoceptor blockade were achieved. 2 At the two lower levels of work rate (50 watts and 100 watts) minute ventilation on atenolol was lower than on placebo while at the highest level of work (200 watts) minute ventilation was higher on atenolol than on placebo. The regression of VE atenolol on VE placebo was 1.28 which is significantly different from unity (P less than 0.001). The results with propranolol were more scattered and failed to reach the 5% level of significance. 3 Effects on the pattern of breathing are small but when minute ventilation is matched with placebo, atenolol results in larger tidal volumes and prolonged inspiratory and expiratory time. 4 These observations are discussed in relation to other work in the literature.
Psychomotor, pulmonary and exercise responses to sleep medication.
Authors: Charles RB , Kirkham AJ , Guyatt AR , Parker SP
Published: July 2012

1 Athletes may use benzodiazepines before events to improve sleep, but these drugs may adversely affect performance. 2 Nitrazepam (10 mg) and temazepam (30 mg) were compared with placebo in 27 physical education students, (14 males, 13 females). Treatments were administered at night, using a double‐blind, double dummy protocol, for 9 nights. Observations were made in the morning after night 2 and night 9. At least 2 weeks interval was allowed between each treatment. 3 At each examination lung mechanics were measured, a Leeds Sleep Evaluation Questionnaire completed, recognition reaction time, choice reaction time and the critical flicker fusion threshold test were used to assess psychomotor activity and an exercise test was performed. The subject exercised to exhaustion on a bicycle ergometer while ventilation, gas exchange and heart rate were recorded on an FM tape unit for off‐line digital analysis. 4 The questionnaire indicated that both drugs were equally effective in promoting and maintaining sleep, but nitrazepam had a marked ‘hangover’ effect. The psychomotor activity and lung mechanics however seemed unaffected. On day 2, maximum exercise levels attained using either drug were comparable to placebo whilst on day 9 temazepam and placebo were significantly higher than nitrazepam. 5 Heart rate was significantly increased at each exercise level with both drugs. 6 Although there may be some effect of these drugs on athletic performance this is likely to be small especially with temazepam.
Circulatory and respiratory effects of infused adenosine in conscious man.
Authors: Fuller RW , Maxwell DL , Conradson TB , Dixon CM , Barnes PJ
Published: July 2012

1. The nucleoside, adenosine, was infused into six conscious healthy male subjects at rates up to 100 micrograms kg‐1 min‐1. 2. Compared with a control 0.9% saline infusion, adenosine in all subjects caused dose dependent increases in heart rate, skin temperature and minute ventilation with corresponding falls in PaCO2, estimated transcutaneously. 3. There were no changes in systemic blood pressure, airways resistance (measured by forced partial expiratory manoeuvres), or plasma catecholamines. At the top infusion rates subjects experienced tolerable chest and abdominal discomfort. 4. These findings conflict with some previous studies in anaesthetised man and animals, in which higher doses of adenosine and its long acting analogues have caused hypotension and central respiratory depression. 5. Although some of these changes may have been due to symptoms, the cardiovascular changes may have been due to a vasodilator action and the respiratory stimulation may have been due to an action on peripheral chemoreceptors.
Platelet activation following intravenous injection of a conventional heparin: absence of effect with a low molecular weight heparinoid (Org 10172).
Authors: Mikhailidis DP , Fonseca VA , Barradas MA , Jeremy JY , Dandona P
Published: July 2012

1. The effects of an intravenous injection of a conventional high molecular weight heparin (HMWH) were compared with those of a low molecular weight heparinoid (Org 10172). A bolus injection of HMWH (5000 iu) was associated with: (a) a small but significant prolongation of bleeding time (BT); (b) a significant fall in PRP platelet count; (c) significantly enhanced platelet aggregation; and (d) significantly increased platelet thromboxane A2 (TXA2) release. These changes were not observed following the intravenous injection of Org 10172 (3200 anti Xa U). 2. These experiments were repeated following the oral administration of acetylsalicylic acid (ASA). HMWH again caused some enhancement of platelet aggregation despite the ASA‐mediated inhibition of platelet aggregation and TXA2 release. Administration of Org 10172 to subjects taking ASA did not alter any of the platelet function indices. 3. In additional control experiments the injection of 5000 iu of HMWH was associated with a significant fall in PRP but not whole blood platelet counts. This finding suggests that the fall in PRP platelet count is a methodological artefact. 4. The HMWH also induced a significantly greater increase in serum non‐esterified fatty acid (NEFA) concentrations than Org 10172. 5. The present findings indicate that Org 10172 is a less potent stimulator of platelet aggregation and lipolysis than HMWH. 6. The minor prolongation of the BT after HMWH is not compatible with enhanced aggregation but may be a consequence of alterations in the activity of coagulation factors and vascular‐ platelet interactions or of ongoing platelet activation accompanied by granule depletion. 7. The different effects of the two anticoagulants assessed suggests a therapeutic advantage in favour of Org 10172, especially in patients with hyperactive platelets.
Adenosine causes transient dilatation of coronary arteries in man.
Authors: Watt AH , Penny WJ , Singh H , Routledge PA , Henderson AH
Published: July 2012

We investigated the effects of i.v. adenosine on coronary blood flow in 10 normal subjects undergoing investigation for chest pain. Coronary flow transiently doubled after greater than or equal to 3.5 mg adenosine without increase in perfusion pressure, systolic load or inotropic state at a constant, paced heart rate. The data provide direct evidence that adenosine dilates coronary arteries in man. The transience of the effect suggests a possible role for adenosine in repeated estimations of coronary flow reserve.
Theophylline and antipyrine disposition in smoking and non‐smoking epileptic subjects.
Authors: Acheson DW , Uden S , Braganza JM , Brown SW , Houston JB
Published: July 2012

Theophylline and antipyrine disposition has been compared in smoking epileptic patients, non‐smoking epileptic patients and non‐smoking healthy volunteers. Although clear differences in drug clearance and half‐life were evident as a result of anticonvulsant drug therapy, no effect of smoking was discernible. Thus, additive effects from induction of the hepatic microsomal monooxygenase system in man by anticonvulsant drugs and polycyclic aromatic hydrocarbons (in cigarette smoke) were not evident.
Dipipanone and nifedipine in cold induced pain; analgesia not due to skin warming.
Authors: Holland RL , Harkin NE , Coleshaw SR , Jones DA , Peck AW , Telekes A
Published: July 2012

The mechanism of the pain relief produced by opiates in normal volunteers in the cold induced pain test has been investigated. In a double‐blind placebo controlled study, hand skin temperature during a 3 min immersion in water at 1 degree C was not affected by either the opioid dipipanone 8 mg or the vasodilator nifedipine 10 and 20 mg. During this immersion, dipipanone produced significant pain relief. Nifedipine reduced pre‐immersion blood pressures and raised heart rates, however, it did not significantly alter pain scores. It is concluded that vasodilatation and local warming do not play a role in the relief of pain by opiates in the cold immersion test.
Bioavailability of rectally administered carbamazepine mixture.
Authors: Neuvonen PJ , Tokola O
Published: July 2012

The relative bioavailability of carbamazepine mixture was studied after oral and rectal administration to healthy subjects. The absorption was significantly slower after the rectal than after the oral route but the total bioavailability was similar provided the mixture was not defaecated within 2 h of administration. We conclude that carbamazepine can be administered rectally, e.g. to postoperative patients in doses corresponding with oral doses.
Evaluation of the antimuscarinic activity of atropine, terfenadine and mequitazine in healthy volunteers.
Authors: Brion N , Beaumont D , Advenier C
Published: July 2012

1 The anticholinergic effects of atropine and two antihistamines (terfenadine and mequitazine) were investigated vs placebo in a double‐ blind study. 2 Salivary secretion, basal pupil diameter, pilocarpine (0.25%) induced miosis and heart rate were determined in eight healthy volunteers, seven male and one female, aged between 23 and 35 years. Each volunteer received all four separate courses of treatment: i.e. terfenadine 60 mg or mequitazine 5 mg twice daily for 3 days, and one single dose on the day of the trial; for the placebo or atropine courses they received the placebo twice daily during 3 days and, on the morning of test day, either the placebo again or atropine 1 mg. Pupillary diameter was measured under standardized conditions using a pupil gauge (Smith and Nephew Pharmaceuticals Ltd). 3 Atropine significantly reduced salivary output (‐2.25 +/‐ 0.36 ml from control values of 4.17 +/‐ 0.42 ml, P less than 0.001) and heart rate (‐9.7 +/‐ 3.7 beats min‐1 from 77.5 +/‐ 2.7, P less than 0.05). These maximal effects were observed 3 h after atropine dosing for salivary secretion and 1 h for heart rate. Atropine did not affect basal pupil diameter or pilocarpine‐induced miosis. 4 Mequitazine and terfenadine did not affect salivary flow, heart rate or pilocarpine‐induced miosis. 5 Terfenadine and mequitazine had no anticholinergic effect in these tests involving a limited number of subjects.
The influence of beta‐adrenoceptor blockers with and without intrinsic sympathomimetic activity on heart rate, arrhythmias and ST‐T segments, using ambulatory electrocardiography.
Authors: Northcote RJ , Ballantyne D
Published: July 2012

1. Ambulatory electrocardiography was used to compare the effects of propranolol and pindolol on symptoms, heart rate, arrhythmias and ST segments. Seventeen males (mean age 54 years) with a diagnosis of chronic stable angina pectoris (New York Heart Association Class II‐ III) were studied. Patients were treated on a double‐blind cross‐over basis with propranolol 80 mg three times daily or pindolol 5 mg three times daily for 14 days each. During the last 48 h of each treatment period ambulatory electrocardiography was performed. 2. Propranolol resulted in a significantly lower mean hourly, mean 24 h and minimum heart rate. Likewise propranolol caused a lower mean daytime and nocturnal heart rate. There was no significant difference in the frequency of angina between the treatments. The number of episodes of ST segment depression was not significantly different between the two drugs, although there was a trend in favour of propranolol. 3. Both the mean 24 h ST level and the maximum ST segment depression were lower during treatment with pindolol. Propranolol was associated with a total of 117 nocturnal pauses or episodes of asystole ranging in length from 1.5 to 2.8 s. During treatment with pindolol only one such period occurred. The number of premature ventricular contractions occurring during treatment with pindolol (1316 beats) was less than on propranolol (2010) and the mean hourly frequency of premature ventricular contractions was significantly lower during pindolol administration. 4. Pindolol is not significantly different from propranolol in the control of symptomatic and asymptomatic myocardial ischaemia and is associated with fewer premature ventricular contractions. However, there is no advantage in using pindolol in chronic stable angina.
Intravenous enoxacin for the treatment of acute pyelonephritis: pharmacokinetic and clinical study.
Authors: Bailey RR , Walker RJ , Lynn KL , Donaldson IM , Peddie BA , Dobbs BR
Published: July 2012

1. Eight women with acute pyelonephritis were treated with i.v. enoxacin for 5 days. All were clinically cured and five had a bacteriological cure. Five women reported side effects. 2. During treatment there was no significant accumulation of enoxacin and the total clearance of the drug did not alter with repeated dosing. Drug elimination half‐life (mean 4.3 h, s.d. 2.1) was similar to that reported in healthy volunteers. 3. Enoxacin should be compared with the aminoglycosides and beta‐lactam antibiotics for the treatment of severe or complicated urinary tract infections.
Effects of resins and activated charcoal on the absorption of digoxin, carbamazepine and frusemide.
Authors: Neuvonen PJ , Kivisto K , Hirvisalo EL
Published: July 2012

1. The interference of resins and activated charcoal with the absorption of digoxin, carbamazepine and frusemide was studied. 2. In a cross‐over study consisting of four phases, single doses of colestipol hydrochloride (10 g), cholestyramine (8 g), activated charcoal (8 g) or water only were given to six healthy volunteers immediately after the simultaneous ingestion of digoxin (0.25 mg), carbamazepine (400 mg) and frusemide (40 mg). Plasma and urine concentrations of the test drugs and the urine volumes were determined up to 72 h. 3. The absorption of digoxin was not reduced by colestipol, moderately (30‐40%, P less than 0.05) reduced by cholestyramine and greatly (96%) by charcoal. 4. The absorption of carbamazepine was not decreased by cholestyramine, slightly (10%) by colestipol and greatly (90%) by activated charcoal. 5. The absorption and the diuretic effect of frusemide were significantly diminished by all agents. The bioavailability was reduced by colestipol 80%, by cholestyramine 95% and by activated charcoal 99.5%. 6. The interference with the gastrointestinal absorption of most of the basic drugs by colestipol and cholestyramine seems to be minimal. On the other hand, the resins may seriously impair the absorption of certain acidic drugs, for example frusemide.
Lack of effect of nitrendipine on the pharmacokinetics and pharmacodynamics of midazolam during steady state.
Authors: Handel J , Ziegler G , Gemeinhardt A , Stuber H , Fischer C , Klotz U
Published: July 2012

1. The possible interaction (as indicated by rat experiments) between calcium channel blocking agents and benzodiazepines has been evaluated in nine healthy subjects. 2. Subsequently to an intravenous loading dose (0.07 mg kg‐1) midazolam was infused for 6 h (0.035 mg kg‐1 h‐1) and steady state plasma levels between 54 to 114 micrograms l‐1 were achieved. Two hours after the bolus of midazolam a solution of 20 mg nitrendipine or placebo was administered in a randomized, double‐blind crossover fashion. 3. The marked sedative‐hypnotic effects of midazolam as assessed by visual analogue scales (about four fold increase in the sedation index) and choice reaction time (100% prolongation) indicated some form of adaptation or tolerance towards the end of the infusion. However, the midazolam‐induced impairments were not affected by nitrendipine. 4. EEG‐data indicated stabile benzodiazepine‐like effects during the complete infusion period of midazolam (e.g. decrease in alpha activity, increase in sigma, delta 2 and beta 1 activity). Again, these alterations were not modified by nitrendipine. 5. There was also no pharmacokinetic interaction between both agents, since elimination of midazolam (t 1/2 = 2.5 +/‐ 0.8 h; CL = 548 +/‐ 143 ml min‐1) was in close agreement with control values (t 1/2 = 2.4 +/‐ 0.6 h; CL = 512 +/‐ 102 ml min‐1). Likewise, plasma levels of nitrendipine were comparable to literature data. 6. Thus, it could be concluded that nitrendipine does not affect the action of midazolam and therefore a direct involvement of calcium at the benzodiazepine receptor site is unlikely under our clinical conditions.
Continuous intragastric delivery of fenoldopam: relationship between plasma concentration and effects on renal function.
Authors: Ziemniak JA , Boppana VK , Cyronak MJ , Beck TR , Familiar RG , Dubb JW , Allison NL , Stote RM
Published: July 2012

1. The pharmacodynamics of the dopamine DA1 agonist fenoldopam were examined in six healthy male volunteers after constant intragastric infusions of fenoldopam at dosages of 0, 10, 25, 50 and 75 mg h‐1 for 6 h. 2. Hourly p‐aminohippurate (PAH) clearance was used to assess fenoldopam induced renal plasma flow changes. Marked dose‐related increases in renal plasma flow were noted with a maximal increase of 65% over baseline values of 711 ml min‐1 being seen at the 75 mg h‐1 rate. No changes in sodium excretion and glomerular filtration rate were observed. 3. Mean steady‐state fenoldopam plasma concentrations were related to mean PAH clearance based on an Emax model (r = 0.996) with an Emax of 1350 ml min‐1 and an EC50 of 6.2 ng ml‐1. 4. Mean steady‐state plasma concentrations of fenoldopam‐7‐sulphate and fenoldopam‐8‐sulphate failed to increase with dose but were linearly correlated to mean PAH changes (r = 0.998, r = 0.981 respectively). 5. These results support the concept of extending fenoldopam's duration of action through the development of an oral sustained delivery system.
Effect of acute and chronic oral administration of alfuzosin on baroreflex function and tremor in man.
Authors: Deering AH , Riddell JG , Harron DW , Shanks RG
Published: July 2012

1. The effects of the acute and chronic administration of the alpha 1‐ adrenoceptor antagonist alfuzosin (5 mg twice daily for 7 days) on baroreflex function, physiological tremor and sedation (visual analogue scale) were investigated in six healthy volunteers. 2. Phenylephrine‐ systolic pressure dose‐response curves were shifted (P less than 0.05) to the right by alfuzosin compared with placebo on day 1, and on day 8 prior to the administration of alfuzosin indicating significant alpha‐ adrenoceptor blockade over 24 h with 5 mg twice daily administration. 3. Baroreflex sensitivity (delta R‐R ms mmHg‐1 systolic arterial pressure) was reduced (P less than 0.05) by alfuzosin compared with placebo on day 1 (13.8 +/‐ 2.6 vs 20.6 +/‐ 3.6 ms mmHg‐1) and on day 8 (13.4 +/‐ 1.7 vs 21.1 +/‐ 2.7 ms mmHg‐1). 4. Maximum power (microV2) or frequency (Hz) of physiological tremor did not change 2 h after alfuzosin administration on day 1 (13.7 +/‐ 4.4 microV2, 9.2 +/‐ 0.3 Hz) or day 8 (11.5 +/‐ 4.3 microV2, 10.0 +/‐ 0.4 Hz) compared with placebo on day 1 (16.9 +/‐ 7.5 microV2, 10.0 +/‐ 0.4 Hz) and day 8 (17.3 +/‐ 5.7 microV2, 10.2 +/‐ 0.8 Hz). 5. Alfuzosin 5 mg twice daily did not cause sedation on day 1 or day 8. 6. In conclusion the reduction in baroreflex sensitivity with the alpha‐adrenoceptor antagonist alfuzosin may contribute to its antihypertensive activity in reducing the reflex tachycardia associated with its hypotensive action.
N‐acetylation polymorphism of dapsone in a Japanese population.
Authors: Horai Y , Ishizaki T
Published: July 2012

1. The N‐acetylation of dapsone (DDS) was studied in 182 unrelated healthy Japanese subjects. The frequency of slow acetylators determined using the plasma monoacetyldapsone (MADDS) to DDS ratio (MADDS/DDS, slow acetylators less than 0.30 and rapid acetylators greater than 0.35) at 3 h after an oral dose of DDS (100 mg) was 6.6% (12 of the 182 subjects) with a 95% confidence interval of 3.8 to 11.2%. 2. The frequency distribution histogram of the plasma MADDS/DDS ratio showed an apparent trimodal pattern. However, the numbers of heterozygous (n = 105) and homozygous rapid acetylators (n = 65) derived from the observed data did not agree with those predicted for the respective rapid acetylators (n = 70, and n = 100) by applying the Hardy‐Weinberg Law, when the suggested antimode of 0.85 discriminating these two rapid acetylators was employed. 3. The incidence of slow acetylators was unexpectedly lower in the males (1.4%, 1 of the 69 subjects, with a 95% confidence interval of 0.2 to 7.7%) compared with the incidence in the females (9.7%, 11 of the 113 subjects, with a 95% confidence interval of 5.5 to 16.6%). The difference reached a marginally significant level (Fisher's exact probability test, P = 0.02). 4. The mean plasma concentration of MADDS was significantly (P less than 0.001) lower in the slow compared to the rapid acetylators and there was a highly significant correlation (rs = 0.757, P less than 0.001) between plasma MADDS levels and MADDS/DDS ratios. 5. Slow acetylators showed a significantly (P less than 0.001) lower urinary MADDS/DDS ratio and excreted less (P less than 0.001) MADDS than rapid acetylators.(ABSTRACT TRUNCATED AT 250 WORDS)
Respiratory and cardiovascular effects in relation to plasma levels of midazolam and diazepam.
Authors: Sunzel M , Paalzow L , Berggren L , Eriksson I
Published: July 2012

1. In the present study possible relationships between cardiovascular and respiratory effects and plasma concentrations were investigated after administration of midazolam and diazepam. Eight healthy volunteers were given three injections at 20 min intervals of equipotent sedative doses of midazolam (0.05 mg kg‐1) and diazepam (0.15 mg kg‐1) in a randomized double‐blind cross‐over design. Blood pressure, blood‐gases and respiration measured nonivasively, were monitored throughout the experimental session of 160 min, and frequent blood samples were collected during the session. 2. Correlations between the blood pressure reduction, the increase of PaCO2 in blood, and plasma concentrations were found for both drugs. A maximal reduction of blood pressure and PaCO2 was produced after sedative doses of midazolam and diazepam. 3. A possible acute tolerance development towards the blood pressure reduction was found after the repeated administration of diazepam but not after the midazolam administration. 4. The plasma concentrations producing half the maximal effects after administration of midazolam was 50‐60 ng ml‐1, indicating that the influence on blood pressure and PaCO2 after drug administration is evoked at lower plasma concentrations than sedation. 5. No correlation between the respiratory effects and plasma concentrations was found for either drug.