bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and haemodynamic effects of tocainide in patients with acute myocardial infarction complicated by left ventricular failure.
Authors: MacMahon B , Bakshi M , Branagan P , Kelly JG , Walsh MJ
Published: July 2012

The pharmacokinetics and haemodynamic effects of tocainide, an orally active structural analogue of lignocaine, were studied in patients with acute myocardial infarction complicated by left ventricular failure. Fourteen patients (mean age 65 years) with acute myocardial infarction complicated by mild left ventricular failure were studied, following a single dose of tocainide (250 mg) by intravenous infusion, over 30 min. Heart rate, systemic arterial pressure, pulmonary artery pressure and cardiac output were monitored. Plasma tocainide levels were estimated by gas chromatography. The mean plasma level of tocainide achieved was 2.95 micrograms/ml (15.37 mmol/l). The mean plasma half‐life was 15.6 h. The mean cardiac index was reduced 5 min after completion of the infusion, from 2.24 1 min‐1 m‐2 (+/‐ 0.40) to 2.07 1 min‐1 m‐2 (+/‐ 0.29) (P less than 0.01). At 90 min the cardiac index had returned to pre‐treatment levels. Small changes were seen in the heart rate, arterial blood pressure and the pulmonary artery pressure but these changes were not statistically significant. The pharmacokinetics of tocainide were not significantly altered in patients with acute myocardial infarction complicated by mild left ventricular failure.
A possible explanation for the absence of anti‐anginal properties of transdermal nitroglycerin units: an echocardiographic study.
Authors: Bennett ED , Davis AL
Published: July 2012

The failure of clinical trials to demonstrate any anti‐anginal properties of the transdermal nitroglycerin units has resulted in the re‐evaluation of one such product, Transiderm‐Nitro. Haemodynamic assessment following the application of 10, 20 and 40 cm2 units has been made in eight healthy volunteers over a 6 h period. Measurements of heart rate, blood pressure, stroke volume and left ventricular dimension (by ‘M’ mode echocardiography) were made 2 h after the application of the units. End diastolic dimension fell by 5.2% and stress by 12.6% implying a reduction in myocardial oxygen consumption. However this was offset by an increase in double product of 10.7% and in circumferential fibre shortening of 23.4%. These results imply that the doses used produce venodilatation leading to a reduction in myocardial oxygen consumption. However this is counterbalanced by the reflex induced increase in heart rate and inotropic state. It suggests therefore that much larger doses are required to produce significant anti‐anginal effects.
A comparison of the effects of lorazepam with those of propranolol on experimentally‐induced anxiety and performance.
Authors: File SE , Lister RG
Published: July 2012

In a double‐blind cross‐over study the effects of propranolol (80 mg) and of lorazepam (1 or 2.5 mg) were assessed in normal student volunteers using a number of performance tests and mood‐rating and bodily symptom questionnaires. Drug effects on experimentally‐induced anxiety were also studied. The high dose of lorazepam impaired performance in digit‐symbol substitution, symbol copying and verbal learning tests, and increased subjects' ratings of dizziness. Both lorazepam and propranolol increased simple reaction time. Lorazepam but not propranolol increased ratings of sedation. Although the stressor increased subjects' ratings of anxiety, neither drug altered anxiety ratings. Propranolol decreased and lorazepam increased subjects' pulse. These changes were not reflected in subjects' self‐ratings ‐ lorazepam caused a reduction in ratings of palpitations. The results suggest that if administered acutely, neither drug is beneficial in the treatment of short‐term anxiety associated with intellectual stress.
Increased platelet membrane [3H]‐LSD binding in patients on chronic neuroleptic treatment.
Authors: Schachter M , Geaney DP , Grahame‐Smith DG , Cowen PJ , Elliott JM
Published: July 2012

Using a [3H]‐lysergic acid diethylamide [(3H]‐LSD) binding technique, platelet 5‐hydroxytryptamine (5‐HT) receptor number and affinity were compared in schizophrenics treated with depot thioxanthenes and phenothiazines and controls. There was an approximately 30% increase in platelet receptor number (Bmax) in the patient group. There was a decrease in affinity (increase in Kd) of about 30% in the patient group. This was probably due to the persistence of the neuroleptic in the platelet membrane preparation. There was a weak positive correlation between receptor number and total neuroleptic dosage. The increased number of 5‐HT receptors is consistent with the previously reported enhancement of 5‐HT‐induced platelet aggregation in patients treated with long‐term phenothiazines and thioxanthenes. Our findings are compatible with 5‐HT up‐regulation in human platelets produced by depot neuroleptic therapy. It is not known whether parallel changes may be occurring in brain 5‐HT receptors.
Plasma concentrations of melatonin in man following oral absorption of different preparations.
Authors: Aldhous M , Franey C , Wright J , Arendt J
Published: July 2012

The plasma concentrations of melatonin in man, fasting and fed, were determined after ingestion of three different oral preparations. A dose of 2 mg was given as either a gelatine capsule, a solution in corn oil or as a slow‐release pill. Gelatine capsules and the corn oil preparation gave reproducibly timed peak plasma concentrations, 30 to 60 min after ingestion regardless of nutritional status, and plasma melatonin remained at or above endogenous night‐time levels for 3‐4 h with mean elimination half‐lives of 0.54 to 0.67 h. The slow‐release preparation usefully extended high plasma melatonin concentrations for 5‐7 h after ingestion but the timing of peak concentrations was very dependent on nutritional status. These preparations should be of use in the study of timed melatonin administration in man.
Acute haemodynamic effects of ibopamine in patients with severe congestive heart failure.
Authors: Ghirardi P , Brusoni B , Mangiavacchi M , Bianco L , Col J , Metra M , Dei Cas L
Published: July 2012

Ten patients with congestive heart failure (CHF), in III and IV NYHA Class, were treated orally with a single dose of ibopamine ranging from 1.2‐3.3 mg/kg, and were studied using the Swan‐Ganz catheter and thermodilution technique. Cardiac index (CI) and stroke volume index (SVI) were increased, and mean pulmonary pressure (PAP), systemic vascular resistances (SVR) were lowered. Ibopamine increased CI (+33%) and SVI (+26%), and decreased PAP (‐17%) and SVR (‐24%). All changes were statistically significant. The maximum haemodynamic effect occurred 180 min after ibopamine administration. Blood pressure and heart rate were unaffected. Tolerability was good. This study shows that ibopamine when orally administered to human subjects improves cardiac performance and further investigations on its use as a therapeutic agent in the long term treatment of CHF are recommended.
Inhibition of histamine release from dispersed human lung and tonsillar mast cells by nicardipine and nifedipine.
Authors: Kim YY , Holgate ST , Church MK
Published: July 2012

Calcium entry blocking drugs attenuate antigen‐induced bronchoconstriction in asthma which is mast cell mediated. We have investigated the effects of two calcium uptake blockers, nicardipine and nifedipine on histamine secretion from human mast cells dispersed from lung and tonsillar tissue. Mast cells were activated for secretion with anti‐human IgE or calcium ionophore, A23187. Nicardipine and nifedipine caused a concentration‐related inhibition of IgE‐dependent histamine release from both lung (IC30 10 microM and 4.4 microM) and tonsillar (IC30 21 microM and 47 microM) mast cells. Nicardipine and nifedipine also inhibited mast cell histamine release induced by A23187 with IC30 values of 14 microM and 67 microM for lung and 15 microM and 30 microM for tonsillar mast cells. In the absence of drugs, increasing the extracellular calcium concentrations from 0.2 to 5 mM caused a concentration related increase in IgE‐dependent histamine release from tonsillar mast cells. Both nicardipine and nifedipine (50 microM) displaced the concentration‐effect curve to the right. Nicardipine (0.01‐100 microM) caused a concentration related inhibition of rat kidney histamine methyltransferase activity used in the radioenzymatic assay of histamine (ki of 7.5‐12 microM) whereas nifedipine was only a weak inhibitor. Nicardipine also interfered with the spectrofluorimetric assay after exposure to ultraviolet light. These observations demonstrate that nicardipine and nifedipine inhibit IgE‐ dependent and ionophore stimulated mediator secretion from human mast cells. The lack of stimulus‐related specificity and the high drug concentrations required suggest that classical calcium channel blockade is not responsible for inhibition of mast cell mediator release. Furthermore, we suggest that inhibition of mast cell mediator release is unlikely to be the mechanism by which these drugs alleviate asthma.
Specific antagonism of adenosine‐induced bronchoconstriction in asthma by oral theophylline.
Authors: Mann JS , Holgate ST
Published: July 2012

The airway response to increasing concentrations of inhaled‐adenosine and histamine after oral theophylline or matched placebo was studied in nine asthmatic subjects. Changes in airway calibre were followed as sGaw and FEV1 and concentration‐response curves constructed. Inhaled adenosine caused concentration‐related bronchoconstriction and was four‐ five times less potent than inhaled histamine. Theophylline, which achieved a mean plasma level of 15.9 and 16.6 micrograms/ml on the histamine and adenosine study days respectively, caused significant increases in FEV1 (17%) and sGaw (41‐53%) whereas placebo had no effect. Theophylline also protected the airways against histamine‐and adenosine‐induced bronchoconstriction. However theophylline had a greater protective effect against adenosine (concentration‐ratio 17.4 for FEV1 and 12.8 for sGaw) than against histamine (concentration ratio 5.6 for FEV1 and 5.4 for sGaw (P less than 0.05]. At therapeutic concentrations theophylline is a specific antagonist of the airway effects of adenosine in addition to being a bronchodilator and a functional antagonist.
Posture and theophylline kinetics.
Authors: Warren JB , Cuss F , Barnes PJ
Published: July 2012

The effect of posture on theophylline kinetics was examined in six healthy men who took 450 mg slow‐release aminophylline orally at the same time of day on two separate occasions. On one day they remained standing and on the other supine throughout. Plasma theophylline was measured hourly for 6 h from ingestion. Mean theophylline levels were significantly higher in the standing position at all times (P less than 0.01). We conclude that diurnal variation in theophylline kinetics can be explained, at least in part, by differences in posture.
Differential effect of platelet inhibitors in normal and in hypercholesterolaemic subjects.
Authors: Aviram M , Winterstein G , Brook JG
Published: July 2012

Dibutyryl cyclic AMP, forskolin, dipyridamole and butyl imidazole inhibited platelet aggregation (induced by ADP or collagen) in washed platelets more than in platelet‐rich plasma preparations. Aspirin, indomethacin and epoprostenol (prostacyclin, PGI2) showed no preferential inhibition of these platelet preparations. When platelet‐ rich plasma from either normal or familial hypercholesterolaemic (FH) subjects was used, aspirin, indomethacin and dipyridamole (but not forskolin) inhibited platelet aggregation in normal subjects more than in FH patients. When low doses of aspirin (75 mg daily for 7 days) or dipyridamole (250 mg, single dose) were administered in vivo, platelet aggregation was inhibited more in the normal subjects in comparison to the patient group.
Pharmacokinetics of primaquine in man. I. Studies of the absolute bioavailability and effects of dose size.
Authors: Mihaly GW , Ward SA , Edwards G , Nicholl DD , Orme ML , Breckenridge AM
Published: July 2012

The pharmacokinetics of primaquine have been examined in five healthy volunteers who received single oral doses of 15, 30 and 45 mg of the drug, on separate occasions. Each subject received an i.v. tracer dose of [14C]‐primaquine (7.5 microCi), simultaneously with the 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absolute bioavailability of 0.96 +/‐ 0.08. Elimination half‐life, oral clearance and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size, or route of administration. The relationships between area under the curve and dose size were linear for both primaquine (r = 0.99, P less than or equal to 0.01) and its carboxylic acid metabolite (r = 0.99, p less than or equal to 0.01). The mean whole blood to plasma concentration ratios were determined for primaquine (0.81), and for the carboxylic acid metabolite of primaquine (0.84). Primaquine is a low clearance compound (CL = 24.2 +/‐ 7.4 l h‐1), is extensively distributed into body tissues (V = 242.9 +/‐ 69.5 l) and is not subject to extensive first pass metabolism.
Pharmacokinetics of primaquine in man. II. Comparison of acute vs chronic dosage in Thai subjects.
Authors: Ward SA , Mihaly GW , Edwards G , Looareesuwan S , Phillips RE , Chanthavanich P , Warrell DA , Orme ML , Breckenridge AM
Published: July 2012

We have investigated the pharmacokinetics of primaquine after acute and chronic administration of the drug to five healthy Thai volunteers. After acute dosage (15 mg p.o.) mean (+/‐ s.d.) peak plasma concentrations of 65.0 +/‐ 34.7 ng ml‐1 were achieved within 2 +/‐ 1h. Thereafter plasma drug concentrations declined monoexponentially with a mean elimination half life of 4.4 +/‐ 1.4 h. The mean (+/‐ s.d.) oral clearance was 37.6 +/‐ 15.5 1 h‐1. These values are in broad agreement with values obtained in healthy Caucasians after administration of an equivalent dose of primaquine. Repeated dosing with primaquine had no effect on the mean pharmacokinetic parameters calculated for this drug. In contrast, individual pharmacokinetic parameters for some subjects exhibited gross and unpredictable changes after chronic dosage. The carboxylic acid metabolite of primaquine accumulated in plasma after repeated dosing such that by day 14 of chronic dosing the mean AUC (0,24) for this metabolite was 74% greater than that obtained after acute administration of primaquine.
Hyper‐responsiveness of eccrine sweat glands to carbachol in anxiety neurosis: comparison of male and female patients.
Authors: Buceta JM , Bradshaw CM , Szabadi E
Published: July 2012

The responsiveness of eccrine sweat glands to intradermally injected carbachol was studied in six male and six female healthy volunteers and six male and six female patients suffering from anxiety neurosis. Consistently greater responses to carbachol were obtained in the healthy males than in the healthy females. Analysis of the dose‐ response curves showed that this was reflected in a higher value of Emax in the males. Consistently greater responses to carbachol were obtained in the anxious males than in the healthy males, this being reflected in a higher value of Emax for the anxious subjects. Consistently greater responses to carbachol were obtained in the anxious females than in the healthy females, this being reflected in a higher value of Emax for the anxious subjects. In contrast to the results obtained with the healthy subjects, there was no sex‐related difference in responsiveness to carbachol among the anxious patients. It is suggested that the hyper‐responsiveness of sweat glands in anxiety states involves the sensitization of normally 'dormant' sweat glands by impulse flow in sudomotor sympathetic fibres. The upper limit to the value of Emax for carbachol, which may be determined by the number of potentially responsive glands, may be similar in the two sexes.
A placebo controlled comparison of the effects of pirenzepine and amitriptyline on the tyramine pressor test in healthy volunteers.
Authors: Wilkins MR , Wynne RD , Kendall MJ
Published: July 2012

The possibility of an interaction between pirenzepine, an antimuscarinic drug structurally similar to the tricyclic antidepressants, and sympathomimetic agents was investigated in a group of healthy volunteers. The effect of pirenzepine on response to intravenous tyramine was compared with that of placebo and amitriptyline. The mean dose of tyramine required to elevate systolic blood pressure by 30 mm Hg was 5.0 mg (+/‐ s.d. 0.8) after placebo, 5.1 mg (+/‐ 1.0) after pirenzepine and 11.3 mg (+/‐ 1.8) after amitriptyline. These results suggest that pirenzepine will not potentiate the effects of concurrently administered sympathomimetic drugs.
The effect of activated charcoal and hyoscine butylbromide alone and in combination on the absorption of mefenamic acid.
Authors: el‐Bahie N , Allen EM , Williams J , Routledge PA
Published: July 2012

Mefenamic acid 500 mg orally was administered to nine healthy volunteers on four occasions 7 days apart. On two occasions allocated at random, activated charcoal (2.5 g of medicoal) was administered 1 h after the drug. Hyoscine butylbromide (20 mg intramuscularly) was given immediately after mefenamic acid on one of these occasions, and on one occasion after mefenamic acid without charcoal. Hyoscine significantly delayed the time to maximum mefenamic acid concentrations but did not affect the area under the plasma concentration‐time curve. Charcoal reduced the area under the plasma concentration curve by 36% and charcoal and hyoscine reduced the area under the plasma concentration curve by 42% from their respective control values. We conclude that early charcoal administration in a ratio of 5 g to 1 g of drug effectively reduces the area under the plasma concentration‐time curve after oral mefenamic acid administration. Early charcoal administration may be of value therefore in reducing the toxicity of mefenamic acid after deliberate or accidental overdosage.
The use of benzodiazepines in depression.
Authors: Johnson DA
Published: July 2012

In clinical practice the benzodiazepines are prescribed almost as frequently as the tricyclic antidepressants for the treatment of depression. The therapeutic effects of the benzodiazepines and tricyclic antidepressants in depression have been compared in only 29 double‐blind studies. The antidepressants proved overwhelmingly superior with only one study (alprazolam) even suggesting a possible parity of action. A symptom response analysis failed to show any true antidepressant action for the benzodiazepines. No clear indication for the use of a combination of drugs was revealed, although certain symptoms may show a more rapid response initially with combination therapy.
Influence of food intake on plasma oxprenolol concentrations following oral administration of conventional and Oros preparations.
Authors: John VA , Smith SE
Published: July 2012

Plasma concentrations of oxprenolol have been measured in six healthy volunteers following single‐dose oral administration of the drug in conventional and Oros dosage forms in fasting and postprandial states. After the Oros system, plasma concentrations reached peaks in most subjects at 3‐8 h after dosing and were approximately 25% of those achieved with the conventional tablet. Plasma concentrations were well sustained for at least 24 h. A secondary peak occurred consistently at 12 h, possibly reflecting a transient change in clearance and/or distribution of the drug following the evening meal. With each formulation, plasma drug concentration profiles following administration in the fasting state did not differ significantly from those obtained when the drug was given postprandially. Drug absorption in vivo corresponded reasonably closely with in vitro drug release from the Oros system.
A multiple dose pharmacokinetic and pharmacodynamic evaluation of conventional and 19/285 Oros formulations of metoprolol in healthy volunteers.
Authors: Grainger SL , John VA , Shotton PA , Smith SE
Published: July 2012

Plasma metoprolol concentrations and haemodynamic effects have been measured in six healthy male volunteers during once daily dosing with a 19/285 Oros system and twice daily dosing with 100 mg conventional tablets, on two separate occasions. Plasma drug concentrations throughout the day varied less with the Oros than with the conventional tablet regimen. Predosing concentrations were also higher with Oros but areas under the curve, after correcting for the differences in dose, were similar for the two preparations. Inhibition of exercise tachycardia was drug concentration dependent and was smoothly controlled through the day only with the Oros preparation. Predosing effects at steady‐state were also greater for the Oros regimen. The decline in mean blood pressure, however, showed the same daily pattern for both regimens, and no significant differences were detected between Oros and conventional tablet treatments. The smoothness of the plasma profiles after Oros confirmed the controlled‐release performance of the system in vivo and indicates its potential in the treatment of angina, cardiac arrhythmias and wherever it is important not to jeopardize steady selective beta‐adrenoceptor blockade.
The effect of captopril on the reflex control heart rate: possible mechanisms.
Authors: Ajayi AA , Campbell BC , Meredith PA , Kelman AW , Reid JL
Published: July 2012

Angiotensin converting enzyme inhibitors reduce blood pressure without reflex tachycardia, possibly as a result of enhanced hypothesis that this results from the removal of the parasympathetic activity. We examined the vagolytic action of angiotensin II or alternatively by acetylcholinesterase inhibition. Both captopril and [Sar1ala8] angiotensin II, (saralasin), caused modest falls in blood pressure, without increasing heart rate in normotensive subjects. Captopril and saralasin significantly attenuated the vagally mediated heart rate slowing after facial immersion in water. There was a close correlation between the effects produced by captopril and saralasin on the diving reflex. Infusion of subpressor doses of angiotensin II, reversed the hypotensive effect of captopril and returned the bradycardia after facial immersion to placebo level. In vitro neither captopril nor enalapril or lisinopril affected bovine erythrocyte acetylcholinesterase activity. The parasympathetic effect of angiotensin converting enzyme inhibitors appear to reflect a direct consequence of the removal of angiotensin II.
A dose‐response study of HOE 498, a new non‐sulphydryl converting enzyme inhibitor, on blood pressure, pulse rate and the renin‐ angiotensin‐aldosterone system in normal man.
Authors: Manhem PJ , Ball SG , Morton JJ , Murray GD , Leckie BJ , Fraser R , Robertson JI
Published: July 2012

The effect of different oral doses of HOE 498, a new non‐sulphydryl containing converting enzyme inhibitor, was investigated in a double‐ blind, placebo‐controlled study in normotensive volunteers. Dose‐ related reductions in serum converting enzyme activity, plasma angiotensin II and aldosterone were seen, greater at 4 h than at 12 h after drug ingestion. Converse dose‐related increases in blood angiotensin I and plasma active renin concentration occurred. Falls of angiotensin II were as great with 20 mg as with 50 mg of HOE 498, although the effect was more prolonged with 50 mg. The reductions in concentrations of plasma angiotensin II and serum converting enzyme activity and the increases in plasma renin concentration were correlated with the concentration of HOE 498 ‐ diacid in plasma. Dose‐ related falls in both supine and erect blood pressure were maximal 2‐ 3.5 h after dosing. Pulse rate increased marginally but insignificantly in the supine; slightly and significantly in the upright position, concomitantly with the blood pressure reduction at all doses of active drug. We conclude that effects of single doses of HOE 498 on the renin‐ angiotensin system are maximal within 4 h, but are still apparent after 24 h. Thus it is likely that once daily administration will be adequate for treatment of high blood pressure in patients.
Lack of effect of highly purified subunit influenza vaccination on theophylline metabolism.
Authors: Winstanley PA , Tjia J , Back DJ , Hobson D , Breckenridge AM
Published: July 2012

Plasma concentrations of theophylline, and urinary recovery of theophylline and its metabolites [1, 3‐dimethyluric acid, 3‐methyl xanthine and 1‐methyluric acid] were measured before and after highly purified subunit influenza vaccination in seven healthy subjects, and five subjects with chronic obstructive bronchitis. No cases of theophylline toxicity were seen, and there was no increase in mean plasma theophylline concentration or significant decrease in urinary metabolite concentration after vaccination. An antibody response to vaccination was demonstrated in all subjects. Highly purified subunit influenza vaccination may be given with safety to patients on theophylline.
Verapamil pharmacokinetics and apparent hepatic and renal blood flow.
Authors: Meredith PA , Elliott HL , Pasanisi F. , Kelman AW , Sumner DJ , Reid JL
Published: July 2012

The effect of acute and continued administration of verapamil on pharmacokinetics and regional blood flow has been studied in eight normotensive subjects. Continued administration resulted in a significant decrease in verapamil clearance, compared to that following acute dosing, as assessed by increases in both terminal elimination half‐life (from a mean +/‐ s.d. of 5.2 +/‐ 2.3 h to 6.7 +/‐ 2.0 h) and AUC (from a mean +/‐ s.d. of 800 +/‐ 353 ng ml‐1 h to 1455 +/‐ 244 ng ml‐1 h). The relative clearance of norverapamil was not changed. Acute administration of verapamil resulted in a significant increase (P less than 0.005) in apparent liver blood flow which with continued administration fell significantly (P less than 0.01) towards placebo values. Effective renal plasma flow similarly increased with acute verapamil administration (P less than 0.05) and with chronic administration reduced again to be not significantly different from placebo. Acute and chronic verapamil administration did not significantly alter glomerular filtration rates. These results suggest that there may be a relationship between the acute increase in liver blood flow and the relatively increased clearance of verapamil following acute dosing.
Effect of interleukin‐2 on the inhibition of the human mixed lymphocyte reaction (MLR) by azathioprine.
Authors: Szawlowski PW , Maddocks JL
Published: July 2012

The effect of interleukin‐2 on the response of the human MLR to azathioprine was studied. Azathioprine (36 microM) inhibited the MLR by 86% and interleukin‐2 (25%) stimulated the MLR by 99%. Only partial relief (16%) of azathioprine (36 microM) inhibition was found in the interleukin‐2 treated MLR compared with azathioprine treatment alone. However, [3H]‐thymidine incorporation by azathioprine (36 microM) + interleukin‐2 treated MLR was 4.3 times greater than that exposed to azathioprine alone. As the residual number of immunocompetent cells after drug exposure is pathologically more important than the fraction suppressed, this result may be of clinical relevance. These results show that the major mode of action of azathioprine is not the inhibition of interleukin‐2 production.
L‐643.441: an H2‐receptor antagonist with potent and long‐lasting effects in man.
Authors: Henry DA , Somerville KW , Kitchingman GK , Holmes IB , Tobert JA , Langman MJ
Published: July 2012

Submaximal dose pentagastrin tests conducted in normal male volunteers with L‐643.441, a novel histamine H2‐receptor antagonist, indicate that it is a potent and long‐acting inhibitor of gastric acid secretion. The effect appears dose‐dependent and single doses of 50 mg are sufficient to reduce secretory potential by at least 50% when examined 24 h after drug administration. No adverse effects attributable to treatment were observed.
Antisecretory effect and oral pharmacokinetics following low dose omeprazole in man.
Authors: Howden CW , Forrest JA , Meredith PA , Reid JL
Published: July 2012

The effects of single and repeated doses of omeprazole 10 mg on gastric secretion were studied in a group of six healthy subjects. Single doses had no significant effect on basal or stimulated acid output. After 7 days of treatment, there was a 93.1% reduction in basal acid output (P less than 0.02) and a 66.5% reduction in stimulated output (P less than 0.01). Pepsin output was not affected. Systemic availability of omeprazole, as reflected in the AUC, increased significantly (P less than 0.05) with repeated dosing. Low doses of omeprazole can produce substantial reductions in acid output after repeated dosing.
Effect of trimetazidine on membrane damage induced by oxygen free radicals in human red cells.
Authors: Maridonneau‐Parini I. , Harpey C.
Published: July 2012

The effect of trimetazidine, 1‐(2, 3, 4 trimethoxybenzyl)piperazine di‐ hydrochloride, on membrane damage induced by oxygen free radicals in red cells was studied in seven healthy volunteers after oral administration. Red cells collected prior to and after a 7 day treatment period with trimetazidine were incubated in the presence of phenazine methosulphate (an intracellular oxygen free radical generator) and diethyldithiocarbamate (a Cu‐Zn superoxide dismutase inhibitor). The loss of intracellular K+ induced by oxygen free radicals and the membrane content of peroxidated lipids were significantly reduced in red cells collected after the period of treatment. These results indicate a potent antioxidant activity of trimetazidine which could explain its cardioprotective role during ischaemic and reperfusion phases in which oxygen free radicals are generated and probably implicated in the genesis of cardiac cell injury.
The effects of sucralfate upon phenytoin absorption in man.
Authors: Smart HL , Somerville KW , Williams J. , Richens A. , Langman MJ
Published: July 2012

The possible influence of sucralfate on phenytoin absorption was investigated in a double‐blind, placebo controlled study. Concomitant administration of 1 g sucralfate reduced the absorption of 300 mg phenytoin capsules by 20% as measured by the area under the curve from 0‐48 h. This could be of significance in epileptic patients stabilised on phenytoin in whom sucralfate is used in ulcer treatment.
Influence of rifampicin and isoniazid on the kinetics of phenytoin.
Authors: Kay L. , Kampmann JP , Svendsen TL , Vergman B. , Hansen JE , Skovsted L. , Kristensen M.
Published: July 2012

Clearance of phenytoin after i.v. injection of 100 mg was studied in six patients before and after 2 weeks daily treatment with 450 mg rifampicin, and in 14 patients with tuberculosis receiving standard treatment with 450 mg rifampicin, 300 mg isoniazid, and 1200 mg ethambutol daily. Acetylator status was measured by urinary acetylated sulphadimidine. Clearance of phenytoin in patients receiving only rifampicin increased from 46.7 ml min‐1 +/‐ 20.6 ml min‐1 to 97.8 ml min‐1 +/‐ 33.4 ml min‐1 (P less than 0.01), while clearance in patients on three drugs increased from 47.1 +/‐ 23.4 ml min‐1 to 81.3 ml min‐1 +/‐ 41.6 ml min‐1 (P less than 0.01). No significant differences were observed between the six fast acetylators and the eight slow acetylators. Phenytoin kinetics were unchanged after further 3 months of combined treatment. Rifampicin is a strong inducer of the elimination of phenytoin. Combined treatment with isoniazid has no counter‐acting effect in either fast or slow acetylators.
Displacement of bilirubin from cord serum by sulphadimethoxine, amoxycillin, clavulanic acid in combination with either amoxycillin or ticarcillin, temocillin and cloxacillin.
Authors: Davies BE
Published: July 2012

The displacement of bilirubin from its binding sites in cord serum by sulphadimethoxine and various penicillins was studied using Sephadex gel filtration. Sulphadimethoxine displaced bilirubin at concentrations well within the normal therapeutic range of sulphonamide concentrations. Amoxycillin, clavulanic acid in combination with either amoxycillin or ticarcillin, temocillin and cloxacillin displaced bilirubin at concentrations much higher than those found clinically. It was concluded that the primary binding site/s of sulphadimethoxine and the secondary binding site/s of the penicillins were at or near the primary bilirubin binding site.
Comparison of two slow‐release formulations of metoprolol with conventional metoprolol and atenolol in hypertensive patients.
Authors: Silas JH , Freestone S. , Lennard MS , Ramsay LE
Published: July 2012

We have compared the beta‐adrenoceptor blocking and antihypertensive effects of chronic once daily treatment with conventional metoprolol 200 mg, two 'long‐acting' formulations of metoprolol 200 mg and atenolol 100 mg in a cross‐over study in 12 hypertensive patients concurrently receiving diuretic therapy. The peak effects of all compounds were similar, with significant reductions in exercise heart rate and blood pressure. Twenty‐four hours after dosing only atenolol treatment was consistently associated with a reduction in both exercise heart rate (P less than 0.001) and blood pressure (P less than 0.02) when compared with placebo. Once daily treatment of hypertension with metoprolol, even in 'long‐acting' formulations, cannot be recommended because of waning antihypertensive effect which would be missed at routine clinic attendance. Metoprolol should be prescribed twice daily in hypertension. So‐called long‐acting formulations do not always confer benefits over conventional dose forms.
A comparison of single doses of bucindolol and oxprenolol in hypertensive patients.
Authors: Webster J. , Petrie JC , Robb OJ , Jamieson M. , Verschueren J.
Published: July 2012

Single doses of bucindolol 50, 100 and 200 mg were compared to placebo and single doses of oxprenolol 40, 80 and 160 mg in seven patients with mild hypertension, in a double‐blind randomized study. Both bucindolol and oxprenolol inhibited exercise induced tachycardia. The mean maximum inhibition of exercise heart rate was similar after each dose of both drugs (20%, P less than 0.001). Bucindolol produced a significantly greater reduction in blood pressure than either oxprenolol or placebo. This was most apparent in standing systolic and diastolic and post‐ exercise systolic blood pressures between 1 and 2 h after dosing and was dose‐related. All seven patients experienced adverse effects related to hypotension within the first 2 h after ingestion of bucindolol 200 mg. Plasma concentrations of oxprenolol, bucindolol or 5‐ hydroxy‐bucindolol, sampled 2 h after dosing, could not be related to either the changes in blood pressure or to the occurrence of symptoms. The results emphasise the need for careful dose‐finding of new drugs prior to their more widespread evaluation in phase 3 studies.
Effects of nadolol and propranolol on renal function in hypertensive patients with moderately impaired renal function.
Authors: Pun KK , Yeung CK , Chan MK
Published: July 2012

Effects of oral administration of equipotent antihypertensive doses of propranolol and nadolol on renal function were examined in 20 hypertensive patients with moderately impaired renal function. Creatinine clearance increased, and serum beta 2‐microglobulin concentrations decreased, when patients were switched from propranolol to nadolol therapy (creatinine clearance = 46.7 +/‐ 4.9 ml min‐1 on propranolol and 52.7 +/‐ 5.9 on nadolol; beta 2‐microglobulin = 6.14 +/‐ 0.66 mg l‐1 on propranolol and 5.62 +/‐ 0.62 on nadolol). When patients were put back on propranolol, their creatinine clearances (45.9 +/‐ 5.0 ml min‐1) and serum beta 2‐microglobulin concentrations (6.51 +/‐ 0.67 mg l‐1) returned to values comparable to those obtained before the change to nadolol was made. Serum beta 2‐microglobulin concentrations correlated significantly with creatinine clearance (r = ‐0.819, P less than 0.001).
CSF and plasma levels of nortriptyline and its 10‐hydroxy metabolite.
Authors: Nordin C. , Bertilsson L. , Siwers B.
Published: July 2012

After 3 weeks' nortriptyline (NT) treatment the mean plasma concentration of its 10‐hydroxy metabolite (10‐OH‐NT) (599 +/‐ 207 nmol l‐1) was higher than that of the parent drug (433 +/‐ 199 nmol l‐1) in 25 depressed patients. Also in the cerebrospinal fluid (CSF) the mean level of 10‐OH‐NT (67 +/‐ 20 nmol l‐1) was higher than that of NT (39 +/‐ 23 nmol l‐1). There was a strong correlation (P less than 0.001) between the CSF and plasma concentration of both NT (r = 0.92) and 10‐ OH‐NT (r = 0.77). The interindividual variation in the CSF/plasma ratio of both compounds was small, compared to the variation in plasma levels. These results show that 10‐OH‐NT passes the blood‐brain barrier as it is present in concentrations higher than those of NT in the CSF. 10‐OH‐NT has previously been shown to be a potent blocker of noradrenaline uptake and to have much less affinity for muscarinic receptors than NT itself. This active metabolite might therefore be a potential antidepressant with less disturbing anticholinergic side‐ effects.
Bronchial beta‐adrenoceptor blockade following eyedrops of timolol and its isomer L‐714,465 in normal subjects.
Authors: Richards R. , Tattersfield AE
Published: July 2012

The R‐enantiomer of timolol, L‐714,465, is considerably less potent as a beta 1‐ and beta 2‐adrenoceptor antagonist in animals than timolol, whilst only slightly less potent in reducing intraocular pressure. If the same was true in man L‐714,465 would have potential benefits over timolol in the treatment of glaucoma. The extent of bronchial beta‐ adrenoceptor blockade following one eyedrop in each eye of timolol 1% and L‐714,465 1% was compared in six normal subjects, by measuring the displacement of the bronchodilator dose‐response curve to isoprenaline following each drug compared to the isoprenaline dose‐response curve after placebo eyedrops (methyl‐cellulose). There was no significant difference between the dose‐response curves to L‐714,465 and placebo, but a significant displacement of the dose‐response curve following timolol. The geometric mean dose ratio following timolol (21) differed significantly from that following L‐714,465 (1.6). Heart rate at the end of the isoprenaline dose‐response study was lower after timolol, despite the fact that subjects had received higher doses of isoprenaline. The trend was in the same direction after L‐714,465 when compared with placebo though less marked. L‐714,465 clearly causes less beta‐adrenoceptor blockade than timolol when given as 1% eyedrops. The effects of L‐714,465 1% on the airways and heart rate did not differ significantly from placebo in these six subjects but the pattern of response would be most consistent with L‐714,465 having some beta‐ adrenoceptor blocking activity though considerably less than timolol.
Stereoselective disposition of indoprofen in surgical patients.
Authors: Bjorkman S.
Published: July 2012

The pharmacokinetics of the enantiomers of indoprofen were determined after intravenous administration of the racemate to 10 surgical patients. The mean volume of distribution was 8.97 +/‐ 2.21 (s.d.) 1 for the pharmacologically active S(+)‐enantiomer and 12.60 +/‐ 4.21 1 for the R(−)−enantiomer (P less than 0.001). The corresponding values for clearance were 32.2 +/‐ 11.1 ml min‐1 and 48.8 +/‐ 15.5 ml min‐1 (P less than 0.001). There was no significant difference in mean terminal half‐life between the enantiomers.
The pharmacokinetics of mefloquine in man: lack of effect of mefloquine on antipyrine metabolism.
Authors: Riviere JH , Back DJ , Breckenridge AM , Howells RE
Published: July 2012

A method is described for the determination of the new antimalarial agent, mefloquine, in plasma and urine. After oral administration of 750 mg mefloquine to six volunteers, absorption, was apparently slow, with plasma mefloquine concentrations at 24 h (559 +/‐ 181 ng ml‐1; mean +/‐ s.d.) higher than at 6 h (459 +/‐ 166 ng ml‐1). The elimination half‐life was 373 +/‐ 249 h, oral clearance was 5.09 +/‐ 2.7 1 h‐1, and apparent volume of distribution was 35.7 +/‐ 30.7 l kg‐1 (assuming 100% bioavailability). Mefloquine (750 mg) had no significant effect on salivary kinetics of antipyrine or on the metabolic clearance of antipyrine to its three main metabolites, 3‐hydroxymethylantipyrine, 4‐hydroxyantipyrine and norantipyrine, when antipyrine was administered either 2 h or 2 weeks after dosing with mefloquine.
Evaluation of gastrointestinal motility using the hydrogen breath test.
Authors: Van Wyk M. , Sommers DK , Steyn AG
Published: July 2012

The purpose of the study was to evaluate the validity of a model where intestinal transit is increased and decreased by motility modifying drugs. The measurement of breath hydrogen concentrations after ingestion of lactulose was used to estimate small intestinal transit time. After obtaining base‐line values, eight healthy volunteers were pretreated on separate occasions with loperamide, diphenoxylate, metoclopramide and cisapride. Diphenoxylate caused a significant increase in small bowel transit time, whereas both metoclopramide and cisapride significantly shortened it. The H2 breath test therefore seems to accurately reflect the expected transit time. Loperamide did not alter significantly intestinal transit. Possibly this drug counteracts its own delaying influence on small bowel transit by hurrying gastric emptying. Alternatively, not enough time was allowed for it to exert its full effect.
Determinants of plasma alpha 1‐acid glycoprotein (AAG) concentrations in health.
Authors: Blain PG , Mucklow JC , Rawlins MD , Roberts DF , Routledge PA , Shand DG
Published: July 2012

The concentration of alpha 1‐acid glycoprotein (AAG) was measured in plasma from 200 healthy subjects belonging to 78 family units. The AAG concentration varied markedly between individuals (mean 0.77, range 0.36‐1.46 g 1(‐1]. When the genetic contribution to the variability was assessed, the only significant correlation observed was that between husband and wife and this was weak. We conclude that in addition to the known effects of age and gender, environmental (rather than genetic) factors largely determine the variance of AAG concentrations.
Pharmacokinetic profile of controlled release ketoprofen in elderly patients.
Authors: Dennis MJ , French PC , Crome P. , Babiker M. , Shillingford J. , Hopkins R.
Published: July 2012

The pharmacokinetics of ketoprofen following the administration of the first and final dose of a controlled release formulation (200 mg ketoprofen) once daily for 10 days to nine elderly patients have been studied. Plasma ketoprofen concentrations were measured by h.p.l.c. The data were compared to previously reported studies in young male volunteers. Mean +/‐ s.d. peak plasma concentrations (5.6 +/‐ 1.75 micrograms ml‐1 and 6.3 +/‐ 2.7 micrograms ml‐1 on day 1 and day 10, respectively) were higher than those reported in young volunteers given similar treatment, but similar to those reported in young volunteers following 50 mg four times daily of conventionally formulated ketoprofen, and markedly lower than reported following a single 100 mg dose of ketoprofen. The half‐life for drug release (mean +/‐ s.d.) from the controlled release formulation (8.5 +/‐ 7.4 h) and accumulation upon repeated dosing (28%) were essentially the same as reported for young volunteers. The area under the plasma concentration‐time curve was about 65% greater than reported in young volunteers following administration of controlled release ketoprofen. This increase in exposure to ketoprofen is probably partly due to the lower volume of distribution in the elderly and partly due to a reduced renal excretion of the glucuronide metabolite of ketoprofen. It was concluded that controlled release ketoprofen may be administered in standard doses (200 mg once daily) to elderly patients whose elimination processes are not severely impaired (i.e. severe renal failure or hepatic disease).(ABSTRACT TRUNCATED AT 250 WORDS)
The rise and fall of serum theophylline concentration: a comparison of sustained‐release formulations in volunteers with rapid theophylline clearance.
Authors: Mucklow JC , Kuhn S.
Published: July 2012

The pharmacokinetics of four sustained‐release formulations of theophylline have been examined after single doses (Nuelin SA, Phyllocontin, Slo‐phyllin and Theo‐Dur) and at steady‐state (Phyllocontin, Theo‐Dur) in six healthy adult volunteers, selected because they all eliminated theophylline rapidly after an intravenous dose of aminophylline. After a single dose of Theo‐Dur, the peak concentration of theophylline was smaller and occurred later than after single doses of Nuelin SA, Phyllocontin and Slo‐phyllin, suggesting that absorption occurs over a longer period. The systemic availability of theophylline was virtually complete after all four formulations. After repeated 12‐hourly dosing to steady‐state, and adjustment of dose to achieve trough concentrations of between 5 and 10 mg l‐1 (28‐55 mumol l‐1), theophylline concentration fluctuated to a significantly greater extent within a dose interval when the subjects were taking Phyllocontin than when they were taking Theo‐Dur.
Comparison of venous and capillary blood sampling for the clinical determination of tobramycin serum concentrations.
Authors: Lewis AS , Taylor G. , Williams HO , Lewis MH
Published: July 2012

Tobramycin concentrations have been determined in serum from capillary, venous and arterial blood samples taken from 16 patients during and after surgery. In 73 paired samples the concentrations in capillary samples were not significantly different from those measured in venous samples. The small concentration differences were neither dependent upon sampling time nor core‐peripheral temperature differences. In 26 paired samples, concentrations in capillary samples were not significantly different from those determined in arterial samples. We conclude that concentrations in capillary samples are precise and unbiased estimators of venous concentrations and may be used in the adjustment of tobramycin dosage regimens.
Antipyrine metabolite kinetics in healthy human volunteers during multiple dosing of phenytoin and carbamazepine.
Authors: Shaw PN , Houston JB , Rowland M. , Hopkins K. , Thiercelin JF , Morselli PL
Published: July 2012

Antipyrine total clearance and the formation clearance of its major metabolites were studied in normal, healthy male volunteers before and after multiple dosing for approximately three weeks with phenytoin (six subjects) and carbamazepine (six subjects). Total antipyrine clearance increased on average by 91% after phenytoin dosing and by 61% after carbamazepine and individual increases correlated well with mean plasma concentrations of the anti‐epileptic drug. The increase in total clearance resulted largely from increased formation clearances of the 4‐ hydroxy and 3‐hydroxymethylantipyrine metabolites with minimal effect on the norantipyrine pathway, following treatment with both enzyme‐ inducing drugs. It is concluded that both phenytoin and carbamazepine have similar effects on antipyrine metabolism and that these effects are mediated by induction of specific forms of cytochrome P450.