bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of haemodialysis on metoclopramide kinetics in patients with severe renal failure.
Authors: Wright MR , Axelson JE , Rurak DW , McErlane B , McMorland GH , Ongley RC , Tam YK , Price JD
Published: July 2012

The kinetics of metoclopramide and the effects of haemodialysis on metoclopramide kinetics were examined in eight uraemic subjects 1 h and 24 h prior to the onset of dialysis. In spite of the relatively minor contribution of renal clearance to total body clearance in normals, metoclopramide kinetics were substantially altered in uraemia. The total body clearance was decreased by 2‐4 fold, terminal elimination half‐life proportionately increased, while the volume of distribution appeared to be unaffected compared with that previously demonstrated in normal healthy subjects. Haemodialysis does not appear to be effective in removing metoclopramide from the body and metoclopramide clearance subsequent to dialysis is unaltered. The kinetic parameters in the uraemic subjects are not significantly different between drug administrations 1 or 24 h prior to the time of onset of haemodialysis. Following kidney transplantation, in one subject, there appeared to be a rapid return to apparently normal kinetics from the uraemic state.
Topical minoxidil: cardiac effects in bald man.
Authors: Leenen FH , Smith DL , Unger WP
Published: July 2012

Systemic cardiovascular effects during chronic treatment with topical minoxidil vs placebo were evaluated using a double‐blind, randomized design for two parallel groups (n = 20 for minoxidil, n = 15 for placebo). During 6 months of follow‐up, blood pressure did not change, whereas minoxidil increased heart rate by 3‐5 beats min‐1. Compared with placebo, topical minoxidil caused significant increases in LV end‐ diastolic volume, in cardiac output (by 0.751 min‐1) and in LV mass (by 5 g m‐2). We conclude that in healthy subjects short‐term use of topical minoxidil is likely not to be detrimental. However, safety needs to be established regarding ischaemic symptoms in patients with coronary artery disease as well as for the possible development of LV hypertrophy in healthy subjects during years of therapy.
Regionally selective cholinergic stimulation by BRL 24924 in the human isolated gut.
Authors: Burke TA , Sanger GJ
Published: July 2012

1. The effects of BRL 24924 on cholinergic activity was studied in longitudinal muscle strips obtained from human stomach and colon (taenia). Contractions were evoked by exogenous acetylcholine (ACh) or by electrical field stimulation (EFS) of cholinergic neurones. Inhibitory nerve activity (predominantly non‐adrenergic, non‐ cholinergic; NANC) was detected by measuring the relaxations evoked by EFS in the presence of atropine 1.4 microM. 2. In the stomach, BRL 24924 0.28‐28 microM consistently increased the EFS‐evoked contractions; lower concentrations (0.0028 and 0.028 microM) increased the contractions in most, but not all of the specimens studied. Since BRL 24924 28 microM did not affect NANC‐mediated, EFS‐evoked relaxations, and since high concentrations of BRL 24924 (28 and 282 microM) were required to increase ACh‐evoked contractions, the increase in EFS‐evoked contractions caused by BRL 24924 may be due to a facilitation of ACh release. 3. In the colon, BRL 24924 0.0028‐282 microM did not affect EFS‐evoked contractions. 4. BRL 24924 may therefore be regionally selective in its ability to stimulate human gastrointestinal cholinergic activity.
A dose‐ranging study of the pharmacokinetics of hydroxy‐chloroquine following intravenous administration to healthy volunteers.
Authors: Tett SE , Cutler DJ , Day RO , Brown KF
Published: July 2012

1. The pharmacokinetics of hydroxychloroquine were studied in five healthy volunteers following an intravenous infusion of 155 mg (2.47 +/‐ 0.25 mg kg‐1) racemic hydroxychloroquine. Four of these volunteers also received a further 310 mg (4.92 +/‐ 0.45 mg kg‐1) infusion of hydroxychloroquine and evidence of nonlinearities in the pharmacokinetics of hydroxychloroquine were sought. 2. No nonlinear elimination or distribution processes appeared to be operating at the doses of hydroxychloroquine used in this study, supporting the hypothesis that in the therapeutic dosing range the pharmacokinetics of hydroxychloroquine are linear. 3. Half‐life and mean residence time were long (around 40 days) and large volumes of distribution were calculated (5,522 l from blood, 44,257 l from plasma). Sequestration into the tissues is an important feature of the disposition of hydroxychloroquine. The persistence of hydroxychloroquine in the body is due primarily to this extensive tissue distribution, rather than to low clearance (667 ml min‐1 based on plasma data, 96 ml min‐1 based on blood data). 4. Plasma data were more variable than blood data. Blood to plasma concentration ratios were not constant (mean +/‐ s.d.: 7.2 +/‐ 4.2). The data indicate that it is preferable to measure whole blood concentrations of hydroxychloroquine, rather than plasma concentrations, in pharmacokinetic studies. 5. The pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.
Plasma nitrendipine concentrations in elderly hypertensive patients after single and multiple dosing.
Authors: Crome P. , Baksi A. , MacMahon D. , Pandita‐Gunawardena ND , Edwards J. , Marley J.
Published: July 2012

Twenty‐three elderly hypertensive subjects received nitrendipine 10mg daily by mouth for 8 days. Plasma nitrendipine concentrations were measured after the first and last dose. There was no significant difference in plasma concentrations at any time point between the two days nor in derived pharmacokinetic measurements. Drug accumulation was not observed.
Beta‐adrenoceptor responses to high doses of inhaled salbutamol in patients with bronchial asthma.
Authors: Lipworth BJ , Clark RA , Dhillon DP , Brown RA , McDevitt DG
Published: July 2012

1. Fourteen asthmatics (mean +/‐ s.e. mean baseline FEV1 62 +/‐ 6% of predicted) were given cumulative doubling doses of salbutamol by metered‐dose inhaler as follows: 100 micrograms, 200 micrograms, 500 micrograms, 1000 micrograms, 2000 micrograms, 4000 micrograms. 2. Airways, tremor, haemodynamic and cyclic AMP responses were measured at each dose increment (made every 20 min). 3. There was a linear log dose‐ response relationship for each airways parameter (FEV1, VC, sGaw, FEF 50%). The plateau in the dose‐response curve was not reached within our dose range. These changes were also mirrored in cyclic AMP responses. 4. There was a wide range in maximum airways response expressed in terms of absolute increase over baseline (95% confidence intervals: delta FEV1 667‐1483 ml; delta VC 689‐1695 ml; delta sGaw 0.92‐4.50 s‐1 kPa‐1; delta FEF 50% 0.94‐2.15 l s‐1). Patients with a lower baseline showed a greater response in terms of percent increase in FEV1 (r = ‐ 0.83, P less than 0.001). There was however, no correlation between baseline airway calibre and the dose required for maximum bronchodilatation. 5. There were objective increases (mean +/‐ s.e. mean) in both heart rate (maximum delta HR of 14 +/‐ 5 beats min‐1 at 4000 micrograms) and tremor power (maximum delta Tr of 115 +/‐ 44% at 2000 micrograms). These were not dose limiting side‐effects as subjective symptoms were infrequent at higher doses. 6. Higher than conventional doses of salbutamol given by metered‐dose inhaler may produce a distinct improvement in airways response without significant side‐effects.(ABSTRACT TRUNCATED AT 250 WORDS)
A comparison of diazepam and midazolam as endoscopy premedication assessing changes in ventilation and oxygen saturation.
Authors: Bell GD , Morden A. , Coady T. , Lee J. , Logan RF
Published: July 2012

1. One hundred and two consecutive patients undergoing upper gastrointestinal endoscopy were randomised to be sedated with either intravenous diazepam (Diazemuls‐Kabi Vitrum) or intravenous midazolam (Hypnovel‐Roche). It was assumed that midazolam was likely to be approximately twice as potent as diazepam on the basis of previous work. 2. All patients had an ear oximeter attached throughout the procedure to record continuously their level of oxygen saturation. 3. All 102 patients had pre‐endoscopy respiratory function tests measured and 100 wore an induction plethysmograph vest to allow continuous estimation of respiratory rate and excursion. The plethysmograph was calibrated using a pneumotachygraph, so baseline, post‐injection and post‐endoscopy minute volumes could be estimated. 4. The age, sex ratio and pre‐endoscopy respiratory function tests of the 51 patients given intravenous diazepam in a mean dose (s.d.) of 11.5 (5.8) mg over a mean of 3.4 (0.9) min) were similar to that of the 51 patients sedated with intravenous midazolam (mean dose 6.0 (2.8) mg over 3.3 (0.9) min. 5. Both drugs significantly reduced minute volume (P less than 0.001) and oxygen saturation (P less than 0.001). Midazolam appeared to produce slightly greater hypoxaemia with 57% having falls in oxygen saturation of greater than 2.5% compared with only 35% given an equivalent dose of diazepam. 6. Ventilation was still less than baseline when re‐checked some minutes after removal of the gastroscope. The speed of recovery appeared faster after diazepam sedation which is in contrast to its longer pharmacological half‐life.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical pharmacology of sibutramine hydrochloride (BTS 54524), a new antidepressant, in healthy volunteers.
Authors: King DJ , Devaney N.
Published: July 2012

The cardiovascular, anticholinergic and central effects of single doses of 30, 45 and 60 mg of sibutramine hydrochloride (BTS 54524), a new potential antidepressant, were compared with amitriptyline (50 mg) and placebo given at weekly intervals in a randomised design to six healthy male volunteers. Sibutramine was associated with increases in both supine heart rate and systolic blood pressure at 1, 2 and 6 h after 60 mg (P less than 0.05). Amitriptyline caused a significant 50‐60% decrease in salivation compared with placebo at 2 and 6 h but there were no changes with sibutramine. No significant changes in pupil size were detected with either drug. Visual analogue rating scales (VARS) revealed significant drowsiness with amitriptyline but neither sedative nor stimulant effects with sibutramine. Impairments of simple auditory and visual reaction times, visual two‐choice reaction time, finger tapping and trail making, measured using an automated test battery, occurred with amitriptyline compared with sibutramine. If sibutramine proves to be an effective antidepressant it should be devoid of anticholinergic or central depressant effects. Chronic dosage studies are indicated to evaluate the clinical significance of its cardiovascular effects.
Plasma protein binding of amiodarone in a patient population: measurement by erythrocyte partitioning and a novel glass‐binding method.
Authors: Veronese ME , McLean S. , Hendriks R.
Published: July 2012

1. Amiodarone is an effective antiarrhythmic drug whose therapeutic usefulness is limited by variable pharmacokinetics and considerable toxicity. Total plasma concentrations are not reliably related to therapeutic effect, but if plasma protein binding varies between patients, then free drug concentrations may provide a better measure of drug effectiveness. 2. The plasma protein binding of amiodarone was measured by erythrocyte partitioning, and found to be the same in six healthy subjects and eight patients being treated for cardiac arrhythmias (mean = 99.98%; range 99.97‐99.99%). The free fraction of amiodarone was independent of the total drug concentration (r = ‐0.41, P greater than 0.50) and albumin level (r = ‐0.31, P greater than 0.50). 3. These data show no advantage in monitoring free concentrations of amiodarone. On the other hand, the patients in this study did not receive very high doses of amiodarone, and were free from drug side effects and biochemical abnormalities. Possibly a more heterogeneous group of patients would show variability in amiodarone binding. This should be examined, especially for patients with variations in alpha 1‐acid glycoprotein, a major ligand for basic drugs and a likely major binding protein for amiodarone.
Variability in response to nonsteroidal anti‐inflammatory analgesics: evidence from controlled clinical therapeutic trial of flurbiprofen in rheumatoid arthritis.
Authors: Preston SJ , Arnold MH , Beller EM , Brooks PM , Buchanan WW
Published: July 2012

1. A clinical trial was conducted with flurbiprofen 100 mg three times a day by mouth in rheumatoid arthritis to determine variability in response. 2. Forty patients entered the study, but only 32 completed it. Patients were treated with flurbiprofen on two occasions at a month's interval, each being preceded by a 3 day wash out period. Pain relief and a Ritchie articular index of joint tenderness was assessed at the beginning and end of each treatment period. 3. Flurbiprofen produced significant improvement in both pain relief and articular tenderness. No significant differences were observed between the two trial periods in the mean of these outcome measures. 4. No evidence was found to support the concept of responders and non‐responders.
Pharmacokinetic and pharmacodynamic comparison of two doses of long acting propranolol (80 and 160 mg) in healthy subjects.
Authors: Flouvat B , Berlin I , Cournot A , Robinet D , Duchier J , Sarmini H , Rossi A
Published: July 2012

1. The kinetics and dynamics of long acting propranolol 80 mg and 160 mg were examined after single oral doses to 12 healthy volunteers. 2. Long acting propranolol 160 mg produced a twofold increase in mean peak blood propranolol concentration and AUC compared with the lower dose. There was no difference in elimination half‐life, bioavailability and mean residence time of propranolol between the two doses. 3. Resting pulse rate was decreased by long acting propranolol 160 mg but not by the lower dose. 4. Both preparations blocked exercise induced tachycardia during the entire observation period of 29 h. Percentage inhibition of exercise tachycardia was significant at all time points but long acting propranolol 160 mg exhibited a greater reduction at 24 h and 29 h. 5. Increase in systolic blood pressure during exercise was inhibited by both preparations during the entire observation period with no differences between them. 6. The doubling of the dose administered was reflected in blood concentrations but not in pharmacodynamic parameters. Few pharmacodynamic differences were found between the two doses.
Comparative analgesic and anti‐inflammatory properties of sodium salicylate and acetylsalicylic acid (aspirin) in rheumatoid arthritis.
Authors: Preston SJ , Arnold MH , Beller EM , Brooks PM , Buchanan WW
Published: July 2012

1. Enteric coated sodium salicylate 4.8 g daily was compared with the same dose of enteric coated aspirin in 18 patients with rheumatoid arthritis. 2. After an initial washout period lasting 3 days, patients were randomly allocated to treatment with sodium salicylate or aspirin. After 2 weeks the two treatments were crossed over. 3. Pain relief, reduction in articular index of joint tenderness, increase in grip strength, decrease in digital joint circumference and patients' assessment showed significant improvement with both treatments compared with the washout period. No significant differences were found between the two therapies. 4. No correlation was found in the degree of improvement in any of the clinical outcomes and the salicylate concentrations at steady state.
Glyceryl trinitrate and platelet aggregation: effects of N‐acetyl‐ cysteine.
Authors: Hogan JC , Lewis MJ , Henderson AH
Published: July 2012

The concentration range of GTN causing inhibition of platelet aggregation in vitro is much higher than the plasma concentrations achieved clinically. This action is potentiated by the sulphydryl donor N‐acetylcysteine. We have investigated the effects of GTN given with and without N‐acetylcysteine on ex vivo platelet aggregation in man. In a double‐blind randomised crossover trial eight healthy volunteers were treated with 20 mg of transdermal GTN/24 h, together with N‐ acetylcysteine 200 mg three times daily or matching placebo. Platelet aggregation, measured ex vivo by whole blood impedance aggregometry in response to adenosine diphosphate, was not significantly altered by GTN acutely or after 4 days' treatment with or without N‐acetylcysteine. Platelet cyclic guanosine monophosphate levels were not significantly altered by GTN either in the absence or presence of N‐acetylcysteine. This result implies that previously reported beneficial effects of GTN in myocardial infarction or unstable angina are unlikely to be attributable to direct pharmacological inhibition of platelet aggregation.
Pharmacodynamic and pharmacokinetic study of propranolol in patients with cirrhosis and portal hypertension.
Authors: Cales P , Grasset D , Ravaud A , Meskens C , Blanc M , Vinel JP , Cotonat J , Pascal JP
Published: July 2012

1. The aim of this study was to investigate the pharmacokinetics and the beta‐adrenoceptor blocking activity according to time of conventional (C) and long acting (LA) propranolol in cirrhotic patients. Twenty‐four patients with alcoholic cirrhosis and oesophageal varices were randomly assigned to receive either 160 mg C propranolol, 160 mg LA propranolol or placebo acutely and then following repeated administration (acute and chronic phases). Thereafter propranolol concentrations and beta‐adrenoceptor blockade (resting and exercise heart rates) were measured at different intervals. 2. The Cmax was significantly higher with C propranolol in both phases. The time of Cmax was significantly later with LA propranolol in both phases. The AUCs were significantly higher after chronic administration with both formulations of propranolol. 3. The exercise peaks of beta‐adrenoceptor blockade were similar between the two formulations and between the two phases of administration of propranolol. The duration of effective beta‐ adrenoceptor blockade was significantly longer in the chronic phase and seemed to be longer with LA than with C propranolol although this was not significant (72 +/‐ 31 vs 48 +/‐ 18 h, respectively). 4. There was a significant correlation between the log propranolol concentration and exercise heart rate but not with resting heart rate. No correlation could be demonstrated between pharmacological data and the Child Pugh score. 5. We conclude that in cirrhotic patients exercise testing was a reliable method in the assessment of beta‐adrenoceptor blockade. Pharmacology of propranolol was found to be different according to the formulation or to the phase of administration.
Effects of alpha‐interferon on theophylline pharmacokinetics and metabolism.
Authors: Jonkman JH , Nicholson KG , Farrow PR , Eckert M , Grasmeijer G , Oosterhuis B , De Noord OE , Guentert TW
Published: July 2012

1. The influence of alpha‐interferon (Roferon‐A) on the pharmacokinetics and metabolism of theophylline was studied in healthy adults. Roferon‐A was administered as an intra‐muscular injection (3 x 10(6) iu) once‐a‐day over 3 days. One week prior to and immediately after this course a single 20 min aminophylline infusion (4 mg kg‐1) was given. 2. Blood samples for theophylline analysis were taken over 48 h. Urine was collected up to 72 h and assayed for theophylline and its major metabolites 3‐methylxanthine, 1,3‐dimethyluric acid and 1‐ methyluric acid. 3. Pharmacokinetic parameters for theophylline in plasma were calculated. From urinary excretion data the overall metabolic clearance of theophylline and clearances for formation of the metabolites were calculated. 4. After interferon administration, there was a significant increase of approximately 15% in the mean values of the terminal elimination half‐life, area under the curve and mean residence time of theophylline in association with a similar decrease in plasma clearance (P less than 0.05). Formation clearances of the metabolites tended to be smaller after treatment, but only the change in the overall clearance of theophylline was significantly different (P less than 0.05). There was no systematic shift in the metabolic pattern of theophylline. 5. Additional investigations of the influence of the duration of alpha‐interferon treatment are necessary before definite conclusions can be drawn about the mechanism and the clinical relevance of the described interaction.
Systemic beta‐adrenoceptor responses to salbutamol given by metered‐ dose inhaler alone and with pear shaped spacer attachment: comparison of electrocardiographic, hypokalaemic and haemodynamic effects.
Authors: Lipworth BJ , McDevitt DG , Struthers AD
Published: July 2012

1. Seven normal subjects were given cumulative doubling doses of inhaled salbutamol either by metered‐dose inhaler (MDI) alone, or in conjunction with a pear shaped spacer attachment (PSS). Dose increments were made every 20 min from 100 micrograms to 2000 micrograms. 2. Plasma potassium (K), electrocardiographic (ECG) and haemodynamic (HR, SBP and DBP) responses were measured at each dose increment. 3. There were falls in K (as mean and 95% CI) in response to salbutamol (P less than 0.001): 3.70 mmol l‐1 (3.46‐3.95) to 3.20 mmol l‐1 (2.91‐3.49) MDI, 3.78 mmol l‐1 (3.61‐3.95) to 3.18 mmol l‐1 (3.06‐3.30) PSS. 4. Salbutamol produced marked ECG effects including T wave flattening (P less than 0.001): 0.46 mV (0.24‐0.68) to 0.22 mV (0.07‐0.37) MDI, 0.50 mV (0.23‐0.77) to 0.24 mV (0.07‐0.41) PSS; and Q‐Tc interval prolongation (P less than 0.001): 0.382 s (0.372‐0.392) to 0.409 s (0.397‐0.421) MDI, 0.378 s (0.358‐0.398) to 0.410 s (0.388‐0.432) PSS. U waves occurred in five subjects with MDI and in four with PSS. S‐T segment depression was present in two subjects with MDI and in three with PSS. These changes were not however associated with ventricular extrasystoles. There were also significant chronotropic effects (P less than 0.001): 63 beats min‐1 (57‐70) to 79 beats min‐1 (69‐89) MDI, 58 beats min‐1 (53‐63) to 75 beats min‐1 (69‐81) PSS. 5. Comparison of dose‐response curves for MDI alone and with PSS showed no significant differences, for any of the variables measured.(ABSTRACT TRUNCATED AT 250 WORDS)
Deep inspiration increases the absorption of inhaled sodium cromoglycate.
Authors: Richards R , Fowler C , Simpson SF , Renwick AG , Holgate ST
Published: July 2012

The plasma concentrations of sodium cromoglycate were measured for 4 h following a single dose of 20 mg given by inhalation to six normal volunteers. A series of forced expiratory manoeuvres was performed 2 h after the dose, which resulted in a rapid and marked increase in the plasma concentrations of the drug. A similar increase was found in three volunteers who undertook a single deep inspiration at 4 h. These data indicate that the absorption of cromoglycate from the airways can be affected by manoeuvres used to assess lung function.
The effect of vigabatrin on brain and platelet GABA‐transaminase activities.
Authors: Bolton JB , Rimmer E , Williams J , Richens A
Published: July 2012

1. The inhibition profiles of GABA‐transaminase (GABA‐T) in rat brain and platelet have been compared following a single intraperitoneal dose of vigabatrin. The inhibition profiles exhibit similarities. The inhibition produced by the drug is dose‐dependent and, in the dose range used in man, the dose‐response curves are comparable. The pharmaco‐dynamic effects of the drug (inhibition of central and peripheral GABA‐T) remain after the drug has been eliminated from plasma. It is suggested that the measurement of rat platelet GABA‐T may be used as a non‐invasive assessment of the efficacy of GABA‐T inhibitors in the rat CNS. 2. Human blood platelet GABA‐T was significantly inhibited by the administration of a single oral dose of vigabatrin. Chronic administration also produces a significant inhibition of platelet GABA‐T. As with rats, the pharmacodynamic effects on the platelet enzyme remained after the drug had been eliminated from plasma. If the situation in man is assumed to parallel that found in the rat then measurement of platelet GABA‐T inhibition could prove to be a useful indicator of central inhibition.
Effects of vigabatrin and of GABA on myelinated rat cerebellar cultures: preliminary data.
Authors: Hauw JJ , Boutry JM , Sun P , Sazdovitch V , Duyckaerts C
Published: July 2012

1. The aim of this study was to evaluate the effect of high concentrations of vigabatrin (gamma‐vinyl GABA) and of GABA on myelin of the central nervous system cultures. 2. Explants of rat cerebellum were cultured for 14‐19 days in vitro on collagen‐coated coverslips in Leighton tubes. They were exposed for up to 14 days to 500 nmol ml‐1 vigabatrin or to 1000 nmol ml‐1 GABA. 3. Qualitative and quantitative blind examination of living cultures and of Sudan black B‐stained slides showed mild toxicity of both drugs for myelinated fibres. No clear‐cut differences could be demonstrated between the two compounds, although vigabatrin seemed slightly more toxic than GABA at these doses. 4. In electron microscopy, no patent intramyelinic oedema nor primary demyelination were seen. On the contrary, some degenerating myelinated fibres and astrocytic gliosis were seen in both experimental conditions. The changes involved axons as well as myelin sheaths. 5. The toxicity of GABA and vigabatrin was surprisingly mild in this very sensitive model.
A multicentre study of vigabatrin for drug‐resistant epilepsy.
Authors: Browne TR , Mattson RH , Penry JK , Smith DB , Treiman DM , Wilder BJ , Ben‐ Menachem E , Miketta RM , Sherry KM , Szabo GK
Published: July 2012

1. Vigabatrin (GVG) was given in a single‐blind fashion to 89 patients with complex partial seizures (CPS) refractory to conventional drugs. 2. The median number of CPS per month decreased from 11.0 to 5.0 after addition of GVG, and 51% of patients had a 50% or greater decrease in CPS frequency (P less than 0.001). 3. Side effects (principally drowsiness, ataxia, headache) occurred mainly during the initiation of therapy and decreased during therapy. After 12 weeks on GVG side effects significantly interfered with functioning in only 13% of patients, and the efficacy: toxicity ratio warranted continued administration in 74% of patients. 4. Co‐administration of GVG resulted in a mean decrease of 20% in phenytoin serum concentration (P less than 0.001). 5. Sixty‐six patients having a favourable response to GVG during the single‐blind study have been followed for 6‐54 (median 33) months on GVG. Only 17 patients have dropped out of long‐term follow‐up due to break through seizures and/or side effects. No serious systemic or neurological toxicity has been detected.
Meta‐analysis of European placebo controlled studies of vigabatrin in drug resistant epilepsy.
Authors: Mumford JP , Dam M
Published: July 2012

1. A meta‐analysis has been performed on nine placebo controlled trials of vigabatrin (GVG) administered as add‐on therapy to patients suffering from drug resistant epilepsy. 2. There were two pilot placebo‐ controlled dose ranging studies, six double‐blind crossover studies and a multicentre response controlled study. 3. There were a total of 398 patients entered and 390 have been evaluated for safety and 337 for efficacy. 4. In spite of the difficulties in the clinical evaluation of new antiepileptic drug, a reduction in seizure frequency was reported following the addition of vigabatrin to the concomitant medication in all studies. This was statistically significant in the larger of the two pilot studies, the multicentre study and three of the six double‐ blind studies. 5. There was a statistically significant reduction in seizures of in all six double‐blind studies when the 98 patients suffering from complex partial seizures with or without generalisation were considered. Seventy two percent of these patients showed a greater than 25% reduction in seizure frequency. 6. Vigabatrin was well tolerated. The frequency of adverse events was similar to that reported elsewhere.
Efficacy and safety of vigabatrin in the long‐term treatment of refractory epilepsy.
Authors: Remy C , Beaumont D
Published: July 2012

1. The long term safety and efficacy of vigabatrin has been studied in 254 patients with refractory epilepsy (82% with partial seizures) in 23 different clinics in eight European countries. 2. This was an open multicentre study in which patients who had experienced a significant benefit from vigabatrin and had continued to take the drug for 1 year or longer were eligible for evaluation. The mean duration of therapy in the 254 patients was 22.7 months; 72 patients received vigabatrin for more than 2 years. 3. Patients were severely affected by epilepsy with a median monthly seizure frequency of 15.7 despite taking an average of 2.2 antiepileptic drugs. On vigabatrin, the median seizure frequency was about 35% of baseline, remaining stable over time despite a 10% reduction in the number of concurrent medications. 4. The lack of tachyphylaxis to the antiepileptic effect of vigabatrin is shown by the small number of patients who discontinued for insufficient efficacy (11%), two thirds of them during the first 6 months of follow‐up. Maintenance of efficacy is also clearly demonstrated by analysis of 2 year and 3 year cohorts of patients. 5. Clinical and biological tolerability was excellent. There was a very low rate of drop out for adverse events (1.6%). Adverse events, mainly sedation, irritation and weight gain were mostly mild and transient. 75% of patients reported no adverse event at all. 6. Safety evaluation included serial neurological, ophthalmological and general examinations: no new abnormal clinical feature or adverse event emerged with long term therapy.
Safety and pharmacokinetics of the low molecular weight heparinoid Org 10172 administered to healthy elderly volunteers.
Authors: Stiekema JC , Wijnand HP , Van Dinther TG , Moelker HC , Dawes J. , Vinchenzo A. , Toeberich H.
Published: July 2012

1. In a cross‐over study a new low molecular weight heparinoid Org 10172 was administered to 12 elderly male and female volunteers. It was well tolerated and no adverse effects occurred. 2. The absolute bioavailability of Org 10172 as measured by plasma anti‐Xa activity, glycosaminoglycuronans with no affinity to antithrombin III (NoA‐GAG) and thrombin generation inhibiting activity approached 100% in both sexes. 3. The half‐life of elimination of its anti‐Xa activity (19.2 +/‐ 6.1 h) was similar to that found previously in young volunteers. Org 10172 was further characterised by a rapid disappearance from the circulation of its anti‐thrombin activity (t1/2 1.8 +/‐ 0.6 h) and of the NoA‐GAG (t1/2 3.5 +/‐ 2.1 h). 4. Its thrombin generation inhibiting activity was of intermediate duration (t1/2 elimination 6.2 +/‐ 4.0 h).
Treatment of quinine overdosage with repeated oral charcoal.
Authors: Prescott LF , Hamilton AR , Heyworth R.
Published: July 2012

In five symptomatic patients with acute quinine poisoning the mean admission plasma concentration was 11.1 mg l‐1. After treatment with repeated oral charcoal 50 g 4 hourly, plasma quinine concentrations fell rapidly with a mean half‐life of 8.1 +/‐ 1.1 h (s.d.) compared with more than 24 h in a previous report in similarly poisoned patients. The visual impairment which was expected in a patient with cardiotoxicity and a plasma quinine concentration of 12.6 mg l‐1 did not occur, but late treatment with charcoal was of no obvious benefit in another patient who was already blind. Repeated oral charcoal has been shown to increase the rate of elimination of a therapeutic dose of quinine in healthy volunteers. It appears to be the only practical means of enhancing the removal of this drug after overdosage and should reduce the risk of potentially disastrous complications.
Healthy volunteer studies in Great Britain: the results of a survey into 12 months activity in this field.
Authors: Orme M. , Harry J. , Routledge P. , Hobson S.
Published: July 2012

1. A survey has been conducted amongst 459 members of the Clinical Section of the British Pharmacological Society to ascertain facts about the administration of drugs to healthy volunteers over the period October 1986 to September 1987. 2. A response rate of 87.1% was obtained with 114 individuals being involved in healthy volunteer studies. After exclusion of duplicate returns from the same unit 98 questionnaires were analysed. 3. Drugs were given in the year under review to 8163 healthy volunteers for research purposes. Minor adverse effects were reported in 565 (6.9%), moderately severe adverse effects in 45 (0.55%) and potentially life threatening adverse effects in 3 (0.04%). No lasting sequelae were reported. 4. Drugs were given to 7607 healthy student volunteers as part of class teaching practicals. Minor adverse effects were reported in 6.0% of student exposures but no moderately severe or life threatening adverse effects were reported. 5. The risk involved in healthy volunteer studies is very small indeed but some suggestions are made as a result of the questionnaire to improve further the safety of these studies.
The effect on motion sickness and oculomotor function of GR 38032F, a 5‐ HT3‐receptor antagonist with anti‐emetic properties.
Authors: Stott J.R. , Barnes GR , Wright RJ , Ruddock CJ
Published: July 2012

1. The 5‐hydroxytryptamine (5‐HT3) receptor antagonist, GR 38032F, which possesses potent anti‐emetic properties in vomiting induced by cancer chemotherapeutic drugs, has been tested to determine its value in the prophylaxis of motion sickness induced by cross‐coupled stimulation. The double‐blind trial compared GR 38032F with both a placebo (lactose) and with hyoscine. In addition, studies of ocular pursuit and saccadic eye movements were carried out following the administration of each drug. 2. The prophylactic effect of GR 38032F on motion‐induced nausea was indistinguishable from that of placebo, whereas following hyoscine subjects showed a highly significant (P less than 0.001) increase in tolerance to cross‐coupled stimulation. Tests of oculomotor function showed no effect on saccadic eye movement from either drug. However, both drugs produced a significant (P less than 0.05) though small reduction in eye velocity gain during pursuit eye movement. 3. These findings suggest that the 5‐HT3 receptor is not involved in the neural pathways that bring about motion sickness, but that it may have a role in the control of ocular pursuit. The absence of an anti‐motion sickness effect from a drug that is effective in the treatment of vomiting induced by cancer chemotherapy serves to emphasize that different neural mechanisms are involved in the generation of motion sickness.
Effect of infused adenosine on cardiac output and systemic resistance in normal subjects.
Authors: Bush A. , Busst CM , Clarke B. , Barnes PJ
Published: July 2012

1. The purine nucleoside adenosine relaxes smooth muscle in vitro and is a vasodilator in animals, but its effects on cardiac output and systemic vascular resistance have not been measured in normal conscious human subjects. 2. We have studied the effects of infused adenosine in doses of 0.005, 0.03 and 0.07 mg kg‐1 min‐1 on pulmonary blood flow and systemic vascular resistance in eight healthy volunteers, using a non‐ invasive, inert gas method and mass spectrometry. 3. At a dose of 0.07 mg kg‐1 min‐1, there was a rise in effective pulmonary blood flow (which is approximately equivalent to cardiac output) of 0.52 +/‐ 0.08 l min‐1 m‐2 (mean +/‐ s.e. mean) and a fall in estimated systemic vascular resistance of 357 +/‐ 44 dyn s cm‐5. Despite this marked systemic vasodilation, there was no significant change in mean heart rate. 4. The effects of this dose of adenosine were maximal 2 min after starting the infusion, and had disappeared within 5 min of stopping it. 5. Adenosine may be therapeutically useful in the reduction of left ventricular afterload, where the absence of reflex tachycardia may be advantageous. We suggest that adenosine in doses of 0.03 mg kg‐1 min‐1 should be evaluated as a selective pulmonary vasodilator.
Importance of beta 2‐adrenoceptor stimulation in the suppression of intradermal antigen challenge by adrenaline.
Authors: Warren JB , Pixley FJ , Dollery CT
Published: July 2012

1. Seven atopic subjects received two injections of antigen and one of saline intradermally in the back on each of 4 separate days. They were pretreated with four different drug combinations: (a) adrenaline 0.3 mg subcutaneously over the deltoid muscle (b) subcutaneous adrenaline preceded by 5 mg of the specific beta 2‐adrenoceptor antagonist ICI 118,551 orally (c) 8 mg of salbutamol orally (d) placebo. Tablets were given 2 h before and subcutaneous injections 15 min before the intradermal injections of saline and antigen. 2. The median flare response to intradermal low dose antigen and high dose antigen after pretreatment with adrenaline was 4% and 49% of the response seen following pretreatment with placebo (P less than 0.001). When adrenaline was preceded by ICI‐118,551, the corresponding median flare responses were 2% and 44% (P less than 0.001) of the placebo response. The flare response after pretreatment with salbutamol was not significantly different from placebo. 3. Adrenaline suppressed the median weal response to the higher dose of antigen to 52% of the response after pretreatment with placebo (P less than 0.05). This suppression by adrenaline was blocked by pretreatment with ICI 118,551. The median weal response after the highest dose of antigen was suppressed by salbutamol to 66% of the response seen after placebo, although this was not significant even when a further three subjects were studied with either salbutamol or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetics of lisinopril in hospitalized patients with congestive heart failure.
Authors: Till AE , Dickstein K. , Aarsland T. , Gomez HJ , Gregg H. , Hichens M.
Published: July 2012

1. The pharmacokinetics of the angiotensin converting enzyme inhibitor, lisinopril, were studied in an open, randomized, balanced, two‐period, crossover design in 12 in‐patients with stable, chronic congestive heart failure (CHF). 2. To evaluate the pharmacokinetics of lisinopril in CHF, lisinopril was administered orally (10 mg) and intravenously (5 mg) in each patient. Each dose was followed by a 72 h period with frequent blood sampling and fractional urine collections for radioimmunoassay of lisinopril. 3. Mean urinary recovery of lisinopril was 15 and 88% following oral and intravenous administration, respectively; absorption/bioavailability of lisinopril based on urinary recovery ratios was 16%, less than that found in normal subjects. 4. Serum concentrations of lisinopril following intravenous administration were higher in this study than those previously observed in normal subjects. 5. The results of this study suggest a reduced absorption of lisinopril in CHF and altered disposition, possibly associated with age as well as the disease state.
Bayesian derived predictions for twice daily theophylline under outpatient conditions and an assessment of optimal sampling times.
Authors: Chrystyn H. , Ellis JW , Mulley BA , Peake MD
Published: July 2012

1. The accuracy of a computerised method of pharmacokinetic interpretation of a single serum theophylline concentration, employing the statistical technique of Bayesian analysis, has been evaluated for an oral slow release form of theophylline using twice daily dosing. 2. Twenty‐four hour steady state serum theophylline concentration‐time profiles of one Uniphyllin Continus 400 mg tablet (Napp Laboratories) every 12 h were measured in 15 patients. These profiles demonstrated a diurnal variation of theophylline absorption which was faster during the day. 3. Revised predictions of the profiles were generated by Bayesian analysis using a single serum theophylline concentration taken during a previous outpatient appointment. Comparing the predicted and measured profiles, the accuracy of the Bayesian method is considered more than adequate for clinical purposes. 4. The predictions produced by the revised estimates were statistically less biased and more precise than those derived by a theophylline algorithm using population data. 5. The mean prediction errors of the revised estimates of the day and night‐peak drug concentrations were ‐0.55 mg l‐1 and ‐0.21 mg l‐1 whilst those of the evening and morning troughs were 1.17 mg l‐1 and 0.41 mg l‐1, respectively. 6. Analysis of the predictive and relative performance of the samples drawn during the profile revealed that the sample taken prior to a morning dose produced the most accurate predictions. 7. There was no statistical difference in the relative predictive performance of samples drawn up to 4 h before or 2 h after the morning dose. It is, therefore, recommended that all serum theophylline concentrations to be used in Bayesian analysis, should be drawn within this period.
Lack of effect of treatment with human recombinant‐tumour necrosis factor (HrTNF) on the binding of quinidine to alpha 1‐acid glycoprotein (AGP).
Authors: Barnett JA , Brenner DE , Creaven PJ , Lalka D.
Published: July 2012

Tumour necrosis factor (TNF) is known to be a key mediator in the acute phase response and its administration has been shown to cause a five fold increase in serum alpha 1‐acid glycoprotein (AGP) concentration in the rat. Since, in man, plasma AGP level determines the protein binding of many important drugs (e.g. narcotic analgesics, phenothiazines, antiarrhythmics, calcium channel blockers) likely to be given to patients who will be treated with TNF, it is important to determine if TNF treatment of humans causes a similar increase in AGP concentration and drug binding. Therefore, the plasma protein binding of quinidine and the serum level of AGP were studied over a 4 day period in each of five cancer patients who were treated with human recombinant‐tumour necrosis factor (HrTNF) using a dosage schedule of 6‐8 x 10(+5) units/m2 daily for 5 days. It was observed that the quinidine binding ratio (the quotient of bound and free concentration in plasma) was highly correlated with the plasma concentration of AGP (r = 0.818) and that the mean pretreatment AGP concentration in the patients was about three times that found in normal subjects. However, no effects of the TNF treatment regime used in the present study could be demonstrated on either plasma AGP concentration or quinidine free fraction. These observations allow the tentative conclusion that HrTNF does not cause a significant increase in serum AGP level in cancer patients whose baseline AGP concentration is high. However, further study of the relationship between TNF treatment and serum AGP level is needed.
Methylprednisolone pharmacokinetics after intravenous and oral administration.
Authors: Al‐Habet SM , Rogers HJ
Published: July 2012

1. The pharmacokinetics of methylprednisolone (MP) were studied in five normal subjects following intravenous doses of 20, 40 and 80 mg methylprednisolone sodium succinate (MPSS) and an oral dose of 20 mg methylprednisolone as 4 x 5 mg tablets. Plasma concentrations of MP and MPSS were measured by both high performance thin layer (h.p.t.l.c.) and high pressure liquid chromatography (h.p.l.c.). 2. The mean values (+/‐ s.d.) of half‐life, mean residence time (MRT), systemic clearance (CL) and volume of distribution at steady state (Vss) of MP following intravenous administration were 1.93 +/‐ 0.35 h, 3.50 +/‐ 1.01 h, 0.45 +/‐ 0.12 lh‐1 kg‐1 and 1.5 +/‐ 0.63 1 kg‐1, respectively. There was no evidence of dose‐related changes in these values. The plasma MP concentration‐time curves were superimposable when normalized for dose. 3. The bioavailability of methylprednisolone from the 20 mg tablet was 0.82 +/‐ 0.11 (s.d.). 4. In vivo hydrolysis of MPSS was rapid with a half‐life of 4.14 +/‐ 1.62 (s.d.) min, and was independent of dose. In contrast, in vitro hydrolysis in plasma, whole blood and red blood cells was slow; the process continuing for more than 7 days. Sodium fluoride did not prevent the hydrolysis of MPSS.
Metabolism of the contraceptive steroid desogestrel by the intestinal mucosa.
Authors: Madden S. , Back DJ , Martin CA , Orme ML
Published: July 2012

1. The intestinal mucosal metabolism of the progestogen oral contraceptive desogestrel (Dg) has been studied in vitro using the Ussing chamber technique. Histologically normal ileum or colon was obtained from eight patients undergoing various resections. The mucosal sheets were mounted between two perspex chambers. 2. Two hours after addition of [3H]‐Dg (0.2 microCi; 100 ng) to the mucosal chamber, more than 90% of the steroid was present in that chamber. In studies with colon, metabolite analysis showed that 55.4 +/‐ 11.7% (mean +/‐ s.d.; n = 6) of drug present was Dg, 28.9 +/‐ 11.4% as unconjugated Phase I metabolites, 13.3 +/‐ 2.6% as sulphate conjugates and 2.5 +/‐ 1.5% as glucuronide conjugates. 3. By co‐chromatography with authentic metabolites and mass spectrometry, it was shown that 3‐keto desogestrel is formed in the mucosa. This is the active metabolite of desogestrel. A large peak of radioactivity did not co‐chromatograph with any known metabolites and has been tentatively identified as ring hydroxylated products of 3‐keto desogestrel. 4. The effect of the synthetic oestrogen ethinyloestradiol (EE2) on the metabolite profile of Dg was studied. In the presence of increasing concentrations of EE2 (100 ng, 1 and 10 micrograms), there was competition for sulphation such that the sulphate fraction decreased by 32, 49 and 48% respectively. 5. The results of this study indicate substantial first pass metabolism of desogestrel by the gut mucosa with evidence for the formation of the active metabolite. The extent of phase I metabolism is unusual.
Pharmacokinetics of acitretin and its 13‐cis metabolite in patients on haemodialysis.
Authors: Stuck AE , Brindley CJ , Busslinger A. , Frey FJ
Published: July 2012

1. Plasma concentrations of acitretin and its metabolite (13‐cis acitretin) were measured in six patients on haemodialysis and six subjects without renal failure following a single oral dose of 50 mg of acitretin. 2. The mean areas under the plasma concentration vs time curves of acitretin and its metabolite were about 50% lower in patients on haemodialysis. 3. No retinoids were detectable in the dialysate.
A double‐blind comparison of conventional and controlled‐release carbamazepine in healthy subjects.
Authors: Larkin JG , McLellan A. , Munday A. , Sutherland M. , Butler E. , Brodie MJ
Published: July 2012

1. Eight healthy subjects took part in a balanced, double‐blind, crossover comparison of conventional carbamazepine (Tegretol, Ciba‐ Geigy Ltd, CBZ‐C) and a novel controlled‐release formulation (Tegretol CR Divitabs, Ciba‐Geigy Ltd; CBZ‐CR). An initial single dose of either preparation was followed 1 week later by a 2 week course of 200 mg twice daily. 2. Following the single dose, CBZ‐CR produced a concentration plateau from 6‐56 h at 50‐60% of the CBZ‐CR peak. 3. After 2 weeks' treatment, CBZ daytime levels measured as area under the concentration‐time curve over a dosage interval were 7% lower with CBZ‐ CR, but this difference was not statistically significant. 4. CBZ‐CR showed less diurnal fluctuation (12%) of CBZ than CBZ‐C (24%; P less than 0.025) with less rapid changes in concentration (P less than 0.02). 5. Diurnal fluctuation of free CBZ and of CBZ 10,11 epoxide, the active metabolite, did not differ significantly between the two preparations. 6. Auto‐induction of CBZ metabolism resulted from the administration of both formulations. The mean elimination half‐life was 23 h (CBZ‐C) and 25 h (CBZ‐CR) after dose 29 compared with a base‐line value of 37 h (both P less than 0.02). Antipyrine metabolism was also induced to a similar extent in both legs of the study (P less than 0.01). 7. No significant alteration in psychomotor function was demonstrated with either preparation. 8. CBZ‐CR fulfils the criteria for a controlled‐release preparation with comparable apparent bioavailability to CBZ‐C. Further pharmacokinetic and, more importantly, pharmacodynamic studies are required in epileptic patients to confirm a clinical advantage over the currently available formulation.