bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of debrisoquine oxidation phenotype on exercise tolerance and subjective fatigue after metoprolol and atenolol in healthy subjects.
Authors: Lewis RV , Ramsay LE , Jackson PR , Yeo WW , Lennard MS , Tucker GT
Published: July 2012

1. The effects of single doses of metoprolol 50 mg, metoprolol 100 mg and atenolol 100 mg on exercise tolerance were compared with placebo in a double‐blind random cross‐over study in 12 healthy subjects. Nine subjects were extensive metabolisers of debrisoquine, and three were poor metabolisers. 2. Three hours after dosing beta‐adrenoceptor blocker treatments significantly reduced exercise heart rate, prolonged time to complete exercise, and increased subjective fatigue measured by visual analogue scale. 3. Scores for subjective fatigue did not correlate with reduction in exercise heart rate or prolongation of exercise time. Exercise time prolongation was weakly but not significantly correlated with exercise heart rate reduction. 4. When compared with placebo, prolongation of exercise time and increased fatigue with metoprolol were not significantly related to debrisoquine oxidation phenotype or to the debrisoquine/4‐hydroxydebrisoquine (D/4OH‐ D) ratio. 5. When metoprolol responses were compared with those for atenolol, changes in exercise time and fatigue scores were significantly related to oxidation phenotype. For metoprolol 100 mg, poor metabolisers required 20.8 s longer to complete exercise (P less than 0.05) and had higher fatigue scores by 78% (P less than 0.05) as compared with extensive metabolisers.(ABSTRACT TRUNCATED AT 400 WORDS)
Caffeine renal clearance and urine caffeine concentrations during steady state dosing. Implications for monitoring caffeine intake during sports events.
Authors: Birkett DJ , Miners JO
Published: July 2012

1. Relationships between the plasma and urine concentrations and clearances of caffeine over successive dosage intervals at steady‐state were investigated in six healthy volunteers administered caffeine, 150 mg 8 hourly for 6 days. 2. There was marked inter‐individual variability in the urine (15.9‐fold range) and steady‐state plasma (8.1‐ fold range) concentrations of caffeine. 3. Urine caffeine concentrations were similar to those in plasma, with mean ratios (plasma:urine) ranging from 1.10 to 1.74. There was a good correlation (r = 0.93, P less than 0.01) between caffeine urine and plasma concentrations. 4. There was a good correlation between caffeine renal clearance and urine flow rate (r = 0.89, P less than 0.01). Caffeine renal clearance was not significantly different from the product of fu and urine flow rate, where fu is the fraction of caffeine unbound in plasma. Urine caffeine concentration and urine flow rate were not correlated (r = 0.14, P greater than 0.05). 5. The results indicate that caffeine is reabsorbed from the renal tubule to equilibrium with unbound caffeine in plasma. 6. A regulatory urine caffeine concentration limit of 12 mg 1(‐1) may be exceeded by some individuals with coffee intake in the range 3 to 6 cups per day.
Cerebral blood flow and indomethacin drug levels in subjects with and without central nervous side effects.
Authors: Seideman P. , von Arbin M.
Published: July 2012

1. Central nervous system (CNS) side effects are observed during treatment with all nonsteroidal anti‐inflammatory drugs (NSAIDs) but their effects are more common during treatment with indomethacin. 2. The aim of the study was to elucidate the mechanism of the CNS related side effects of indomethacin. Two groups were obtained, one with (n = 11), and one without (n = 7), CNS symptoms. Cerebral blood flow was measured in these groups with Doppler equipment, indomethacin levels with h.p.l.c. and CNS symptoms graded on a VAS scale. 3. Blood flow was reduced by 18‐30% and was most marked 60 min after dose and did not differ between the two groups. The maximum CNS effect coincided with indomethacin peak levels 60‐70 min after dose. These results could implicate that CNS symptoms may be related to indomethacin levels in sensitive patients.
Acute reduction of TxA2 platelet binding sites after in vivo administration of a TxA2 receptor inhibitor.
Authors: Modesti PA , Colella A. , Cecioni I. , Gensini GF , Abbate R. , Neri Serneri GG
Published: July 2012

1. Picotamide has been shown to interfere competitively with the thromboxane A2 (TxA2) platelet receptor. In the present study the effect of in vivo administration of picotamide on TxA2 human platelet receptors was investigated in 10 healthy subjects. 2. Picotamide (300 mg x 3 daily) or placebo were administered in a double‐blind, cross‐ over, placebo controlled study, each treatment lasting 1 week with a 2 week interval period. TxA2 receptors were investigated by a direct radioligand binding assay method employing [125I]‐PTA‐OH as labelled ligand. Platelet studies were performed on the first day of treatment immediately before and 2, 4 and 8 h after the ingestion of the drug. The effects of chronic administration were assessed on the seventh day. 3. Two and 4 h after the administration of picotamide 300 mg orally platelet TxA2 receptors were significantly reduced from 1366 +/‐ 237 to 957 +/‐ 221 (P less than 0.05) and 753 +/‐ 119 receptors/platelet (mean +/‐ s.d.) (P less than 0.03). After 8 h platelet receptor population was restored (1362 +/‐ 324, NS). The same pattern was observed after 7 days of treatment. Thus picotamide seems to induce a short lasting down regulation of platelet TxA2 receptors.
A method for bioassay of potency and effectiveness of inhaled bronchodilators in normal subjects.
Authors: Foster RW , Atanga GK , Carpenter J.R. , Evans DE , Rakshi K. , Small RC
Published: July 2012

1. Bioassay of inhaled bronchodilator drugs for potency and effectiveness in normal human subjects is rendered difficult and imprecise because bronchomotor tone is low. When attempting to determine log dose‐effect relationships for inhaled, nebulised bronchodilator drugs and measuring increased specific airways conductance (sGaw), the coefficient of variation of each mean response is likely to be so large that an intermediate response is not significantly different from either the maximum or no response. 2. A method is described by which inhaled, nebulised bronchodilator drugs can be bioassayed for potency and effectiveness with high precision. The method involves the use of inhaled, nebulised bronchoconstrictor agents (methacholine or histamine) to provide a highly reproducible, near‐constant, background reduction in airway conductance in normal human subjects. The activity of bronchodilators is assessed against this background reduction in airway conductance. 3. Log specific airway conductance (log sGaw) was chosen as the response metameter on grounds of normality of distribution and relative homoscedasticity. A central straight line segment of the bronchoconstrictor drug dose‐effect curve extending over a 10‐fold dose multiple could be found easily; the upper end of this segment occurred near 67‐75% reduction in sGaw and was reproducible. 4. The effect of a dose bronchoconstrictor drug causing 67‐75% reduction in sGaw waned linearly with time at first, over the effect segment corresponding to the linear segment of the drug's log dose‐effect curve. The rate constant of local elimination of bronchoconstrictor drug from its site of action, in inhaled dose equivalents, was deduced from the ratio of the slopes of the linear segments of the log dose‐effect and time‐effect curves. 5. The maintenance dose rate to maintain the peak effect (67‐75% reduction in sGaw) of the loading dose was calculated. The repeated administration of maintenance doses at regular short intervals, at this calculated dose rate, created a steady state of bronchoconstriction equal in extent to the effect of the loading dose. This steady state bronchoconstriction occurred without undue discomfort for the subject and was reproducible. 6. Against this background bronchoconstriction, inhaled, nebulised salbutamol produced a rapidly developing and slowly waning increase in sGaw. Reproducible log dose‐effect curves for the bronchodilator drugs salbutamol and reproterol allowed measurement of their potency and effectiveness; the potency of reproterol relative to salbutamol was 0.082 with 95% confidence limits of 0.0504 and 0.131. 7. Estimation of the subject's pharmacodynamic and pharmacokinetic parameters for inhaled methacholine from just three dosage individualising sessions provides estimates accurate enough to be of practical value.
Skin irritation induced by topically applied timolol.
Authors: Kubota K. , Koyama E. , Yasuda K.
Published: July 2012

1. Erythema induced by topically applied timolol, a non‐selective beta‐ adrenoceptor blocker, was assessed in six male volunteers. Intensity of erythema developed on the inner surface of the left forearm where timolol free base was applied for 10 h was measured by a visual score, laser doppler flowmeter and reflectance spectrophotometry. Plasma timolol concentrations collected from the left and right arms were also measured. 2. The mean values for blood volume and blood flow per unit volume of tissue both of which were assessed by a laser doppler flowmeter, haemoglobin index measured by reflectance spectrophotometry, and magnitude of erythema graded by a visual score significantly increased after the application of an acrylic co‐polymer adhesive patch containing 20% (w/v) timolol free base. 3. Plasma timolol concentrations collected from the left antecubital vein were 2.4 to 10.7 times greater than those from the right arm and had significant correlations (rs = 0.55 to 0.76) with the parameters indicating the extent of erythema developed where a patch containing timolol was applied. 4. The inter‐individual variation of timolol was attributed to that of the diffusivity of timolol through skin rather than that of the skin reactivity to topically applied timolol because the plasma timolol concentrations drawn from the left arm in the subjects who did not develop erythema were very low.(ABSTRACT TRUNCATED AT 250 WORDS)
Subjective and objective assessment of enalapril in primary Raynaud's phenomenon.
Authors: Challenor VF , Waller DG , Hayward RA , Griffin MJ , Roath OS
Published: July 2012

1. The efficacy and acceptability of enalapril were assessed in a double‐blind, randomised, placebo controlled cross‐over study in 21 patients with primary Raynaud's phenomenon. 2. Skin temperature was assessed by thermocouples in response to a 15 degrees C cold water challenge as an index of digital blood flow. 3. Following enalapril there were no significant changes in the number and severity of Raynaud's attacks, and no subjective benefit from treatment as measured by visual analogue scales, 5 point rating scales, and skin temperature response to cold challenge when compared with placebo. 4. Enalapril in a dose of 20 mg daily is ineffective in the management of primary Raynaud's phenomenon.
Effect of zinc supplementation on oxidative drug metabolism in patients with hepatic cirrhosis.
Authors: Barry MG , Macmathuna P. , Younger K. , Keeling PW , Feely J.
Published: July 2012

The pharmacokinetics of antipyrine were studied in seven zinc deficient patients with hepatic cirrhosis, before and after zinc supplementation. Each patient received zinc sulphate 660 mg daily for 30 days, restoring zinc status to normal as assessed by leucocyte zinc concentration. Antipyrine clearance was significantly reduced (P less than 0.05) and antipyrine elimination half‐life increased (P less than 0.05) following administration of zinc sulphate without significant alteration in the apparent volume of distribution. It is concluded that supplementation of the zinc deficiency associated with hepatic cirrhosis impaired the hepatic oxidative metabolism of antipyrine.
Pharmacokinetic and pharmacodynamic effects of UK‐68,798, a new potential class III antiarrhythmic drug.
Authors: Sedgwick M. , Rasmussen HS , Walker D. , Cobbe SM
Published: July 2012

1. The pharmacokinetic and pharmacodynamic properties of UK‐68,798, a novel selective potential class III antiarrhythmic agent, were studied in 18 patients with coronary artery disease. Three groups of four patients received intravenous doses of 1.5, 3.0 and 4.5 micrograms kg‐1 respectively over 10 min. 2. UK‐68,798 caused a mean increase in electrocardiographic QTc interval of 41, 40 and 81 ms, and in uncorrected QT interval of 36, 52 and 83 ms at the three dose levels. There were no significant effects on heart rate, blood pressure, PR interval and QRS duration. UK‐68,798 was well tolerated with no significant adverse effects. 3. A dosing regimen using a loading infusion of two thirds of the total dose over 15 min with the remainder given over the following 45 min in six patients produced stable plasma concentrations and lengthening in QTc during the maintenance infusion. 4. There was a linear correlation between plasma concentration and change in QTc. The drug exhibited first‐order kinetics with a mean clearance of 4.7 +/‐ 1.2 ml min‐1 kg‐1 and a mean terminal plasma half‐ life of 9.7 h. 5. UK‐68,798 warrants further study as a selective potential Class III antiarrhythmic agent.
Evaluation of drug information for cardiology patients.
Authors: Baker D. , Roberts DE , Newcombe RG , Fox KA
Published: July 2012

1. Cardiologists and pharmacists at the University Hospital of Wales collaborated to write 20 individual leaflets incorporating guidelines for a range of drugs used in the treatment of cardiology patients. The Plain English Campaign advised on the intelligibility and presentation of the information. 2. One hundred and twenty‐five patients from the Regional Cardiology Unit, University Hospital of Wales were randomly allocated to receive usual verbal counselling about their drug treatment with or without an individualised drug information wallet. Two weeks after discharge from hospital patients completed a postal questionnaire to determine their satisfaction with the information about their drug treatment and their understanding of it. Forty‐nine questionnaires were returned from the leaflet group and 52 from the control group. 3. The provision of written guidelines resulted in significant improvements in patients' satisfaction with their drug treatment (chi 2 = 33.3, P less than 0.001) and their understanding of it (P less than 0.001, Mann‐Whitney test). Overall, patients who received leaflets were more likely to be aware of the potential side effects of their drugs but less likely to be apprehensive about them. Succinct guidelines concerning drug therapy can be assimilated by cardiology patients and provide them with a permanent record for future reference.
Lack of a relationship between the polymorphism of debrisoquine oxidation and lung cancer.
Authors: Duche JC , Joanne C. , Barre J. , de Cremoux H. , Dalphin JC , Depierre A. , Brochard P. , Tillement JP , Bechtel P.
Published: July 2012

1. Determination of debrisoquine oxidation phenotype was carried out in 119 healthy subjects, 135 patients with chronic bronchitis and 153 patients with lung cancer, all of Caucasian origin. 2. A non‐Gaussian distribution of the log D/HD ratio was observed in the three groups. 3. Assuming an antimode of 1.12, the proportion of PMs was found to be 6.7% in healthy subjects, 8.9% in chronic bronchitics and 6.5% in patients with lung cancer. These differences were not significant. 4. The presence of a lung tumour itself had no influence on phenotype in a group of 14 patients who were phenotyped before and after surgery. 5. We conclude that a link between debrisoquine phenotype and lung cancer is unlikely.
Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease.
Authors: Radermacher J. , Jentsch D. , Scholl MA , Lustinetz T. , Frolich JC
Published: July 2012

1. Ten patients with bilateral knee joint effusions were treated topically with a gel containing 1 g diclofenac/100 g (80 mg three times daily). They were randomized to receive diclofenac gel to one knee and a placebo gel preparation to the other knee. 2. Diclofenac was assayed in synovial fluid and blood plasma by GC/ECD as the pentafluorobenzyl‐ ester derivative. 3. Total concentrations of diclofenac in synovial fluid (day 4) were significantly higher in the diclofenac gel treated knee than in the contralateral placebo treated knee (25.5 +/‐ 3.6 ng ml‐ 1 vs 21.6 +/‐ 2 ng ml‐1; P less than 0.05). These concentrations were lower than total plasma drug concentrations (40.6 +/‐ 4.7 ng ml‐1, n = 10, P less than 0.01). Unbound concentrations of diclofenac in synovial fluid from either the diclofenac gel treated or the placebo treated knee were not significantly different from each other or from plasma free concentrations (115 +/‐ 16 and 99 +/‐ 12 vs 108 +/‐ 19 pg ml‐1). 4. Clinical parameters showed improvement of joint mobility and a small reduction of swelling (circumference) in both knees with time. However, the differences between knees were not significant. 5. We conclude that direct transport of diclofenac from the skin into the ipsilateral knee joint after cutaneous application is minimal. Distribution seems to be predominantly via the blood. Whether the observed improvements of clinical parameters were due to drug effects or to the spontaneous course of the underlying disease cannot be distinguished.
The comparative pharmacokinetics of acemetacin in young subjects and elderly patients.
Authors: Jones RW , Collins AJ , Notarianni LJ , Sedman E.
Published: July 2012

Single and multiple dose pharmacokinetics of acemetacin in 10 young healthy subjects and 10 elderly patients with osteoarthritis were studied. Peak plasma concentrations of acemetacin and its metabolite, indomethacin, were found between 2.4 and 4 h after an oral dose of the drug. After dosing to steady state (7 days), the mean plasma elimination half‐life for acemetacin was 1.1 h and 1.0 h, and for indomethacin 7.1 h and 7.2 h in the young and elderly groups respectively. Statistical analysis of tmax, AUC, plasma t1/2 and residual drug concentrations for acemetacin or indomethacin revealed no significant differences (P greater than 0.05) between young subjects and elderly patients after acute or chronic dosing. The results suggest that drug accumulation did not occur in the elderly subjects over the time period studied and that, on pharmacokinetic grounds, dose adjustment in the elderly is unlikely to be required.
A comparison of drug protein binding and alpha 1‐acid glycoprotein concentration in Chinese and Caucasians.
Authors: Feely J. , Grimm T.
Published: July 2012

alpha 1‐acid glycoprotein (AAG) concentration and the binding of both lignocaine and warfarin were compared in 15 healthy Chinese and age and sex matched Irish (Caucasian) subjects. Both the extent of lignocaine binding and AAG concentrations were significantly (P less than 0.05) lower in Chinese subjects. No difference was shown in warfarin binding. These results suggest that the binding of basic drugs may be significantly less in Chinese than Caucasians, and lower concentrations of the binding protein AAG are a major determinant of this difference.
A comparison of serum and saliva paracetamol concentrations.
Authors: Smith M. , Whitehead E. , O'Sullivan G. , Reynolds F.
Published: July 2012

The relationship between serum and saliva paracetamol concentrations was investigated in twenty healthy volunteers. The plasma and saliva drug concentrations showed a significant correlation (r = 0.67). However the agreement between the two methods of measurement was poor with limits of agreement of −15.3 mg l‐1 to +15.9 mg l‐1 with mean sample values of 19.2 and 19.5 mg l‐1 for plasma and saliva, respectively.
Mefloquine pharmacokinetics and resistance in children with acute falciparum malaria.
Authors: Nosten F. , ter Kuile F. , Chongsuphajaisiddhi T. , Na Bangchang K. , Karbwang J. , White NJ
Published: July 2012

The pharmacokinetic properties of mefloquine hydrochloride (15 mg base kg −1) were studied in 12 Karen children (five girls, seven boys) aged between 5 and 10 years presenting with uncomplicated falciparum malaria. The drug was well tolerated. Mean (s.d.) peak blood drug concentrations of 2031 (831) ng ml‐1 were reached in a median of 8 (range 6‐24) h. Mean (s.d.) estimates for oral clearance and mean residence time were 0.52 (0.27) ml min −1 kg −1 and 15.3 (4.7) days, respectively. These values are similar to those reported previously in adults. In one child parasitaemia failed to clear despite whole blood mefloquine concentrations which peaked at 1744 ng ml −1; parasitaemia rose and fever recurred when blood drug concentrations had fallen to 442 ng ml −1. The prevalence of highly mefloquine resistant parasites such as this can be expected to increase under drug pressure in this area.
Transdermal nitrate therapy: bioavailability during exercise increases transiently after the daily change of patch.
Authors: Gjesdal K. , Klemsdal TO , Rykke EO , Bredesen JE
Published: July 2012

Ten volunteers carried a 10 mg 24 h −1 transdermal glyceryl trinitrate (GTN) patch for 24 h before moderate exercise. Plasma GTN‐concentration increased significantly (P less than 0.05) by 19% to peak value at 15 min. Two hours after patch renewal repeat exercise increased GTN concentration by 56% (P less than 0.001). The two nitrate‐concentration curves differed significantly (P less than 0.0001). Thus, change of patch augmented nitrate availability during exercise.
Interindividual variability in the glucuronidation and sulphation of ethinyloestradiol in human liver.
Authors: Temellini A. , Giuliani L. , Pacifici GM
Published: July 2012

1. Glucuronidation and sulphation of ethinyloestradiol (EE2) was studied in human liver. Microsomal glucuronyltransferase activity was measured in 110 livers whose donors were 71 women and 39 men. Enzyme activity ranged between 12.6 and 242 pmol min‐1 mg‐1 protein, i.e. over a 19‐fold range and the mean (+/‐ s.d.) glucuronyltransferase activity was 96.8 +/‐ 47.9 pmol min‐1 mg‐1 protein. 2. Cytosolic sulphotransferase activity was measured in 138 livers whose donors were 90 women and 48 men. Enzyme activity ranged between 14.4 and 98.2 pmol min‐1 mg‐1 protein, i.e. over a 7‐fold range, and the mean (+/‐ s.d.) sulphotransferase activity was 43.7 +/‐ 18.6 pmol min‐1 mg‐1 protein. 3. Human liver glucuronyltransferase and sulphotransferase activities showed a unimodal distribution pattern. Enzyme activities were neither sex‐related nor age‐dependent. Sulphotransferase activity did not correlate with glucuronyltransferase activity (n = 80) suggesting that the two enzymes are independently regulated. The ratio of specific glucuronyltransferase to sulphotransferase activity ranged between 0.15 and 8.0 (mean +/‐ s.d., 2.44 +/‐ 1.51) and was unimodally distributed.
The effect of cisapride on gastro‐oesophageal dysfunction in systemic sclerosis: a controlled manometric study.
Authors: Kahan A. , Chaussade S. , Gaudric M. , Freitag B. , Amor B. , Menkes CJ , Strauch G. , Guerre J. , Couturier D.
Published: July 2012

1. Cisapride is a novel prokinetic drug which facilitates or restores motility throughout the gastrointestinal tract. Its mechanism of action is thought to involve enhancement of acetylcholine release in the myenteric plexus of the gut. 2. The effect of intravenous cisapride 10 mg on gastro‐oesophageal dysfunction was investigated in 20 patients with systemic sclerosis, using a double‐blind, randomised, cross‐over, placebo‐controlled manometric study design. 3. The increase in lower oesophageal sphincter pressure was significantly higher after cisapride (mean +/‐ s.e. mean, 8.3 +/‐ 2.1 cm H2O) than after placebo (mean +/‐ s.e. mean. 0.1 +/‐ 0.3 cm H2O) (P less than 0.001). The increase in the number of fundic gastric contractions during the 30 min study period was significantly higher after cisapride (mean +/‐ s.e. mean, 7.7 +/‐ 2.3) than after placebo (mean +/‐ s.e. mean, 0.9 +/‐ 0.6) (P less than 0.01). 4. No serious clinical adverse effects were observed. 5. The study demonstrates that intravenous cisapride induces a significant increase in lower oesophageal sphincter pressure and in the number of fundic gastric contractions, which may be beneficial in the treatment of scleroderma gastro‐oesophageal dysfunction. Further long‐term studies of the effect of oral cisapride in patients with systemic sclerosis are warranted.
The activation of the biguanide antimalarial proguanil co‐segregates with the mephenytoin oxidation polymorphism‐a panel study.
Authors: Ward SA , Helsby NA , Skjelbo E. , Brosen K. , Gram LF , Breckenridge AM
Published: July 2012

The activation of the antimalarial drug proguanil (PG) to the active metabolite cycloguanil (CG) has been evaluated in a panel of 18 subjects. These subjects had previously been screened and classified as mephenytoin poor (PMm) or extensive metabolisers (EMm) and sparteine poor (PMs) or extensive metabolisers (EMs). Five subjects had the phenotype PMm/EMs, one was PMm/PMs, six subjects were EMm/PMs and six were EMm/EMs. The PG/CG ratio in urine (8 h) was significantly higher in PMm than in EMm (P = 0.0013). This study shows that the P450‐isozyme involved in the polymorphic oxidation of mephenytoin is of critical importance in the activation of PG to CG and this may explain the large intersubject variability in CG concentrations in man. PMm make up about 3% of Caucasians, but up to about 20% of Orientals. From the present study, it may be anticipated that the antimalarial effect of PG is absent or impaired in this phenotype. The sparteine polymorphism appeared not to influence the activation of PG to CG significantly.
The effect of renal impairment on the pharmacokinetics and metabolism of bopindolol.
Authors: MacDonald NJ , Grant AC , Rodger RS , Meredith PA , Elliott HL
Published: July 2012

The pharmacokinetics of the non‐selective beta‐adrenoceptor antagonist, bopindolol, have been studied in 18 hypertensive patients with varying degrees of renal impairment following single and multiple oral dosing. Bopindolol, which undergoes extensive hepatic metabolism, was found to accumulate in patients with chronic renal failure but the disposition in patients on regular haemodialysis did not differ significantly from patients with normal renal function. The mechanism underlying these changes in pharmacokinetics is not clear but suggests the presence of metabolic inhibitors in uraemic plasma which are removed by regular haemodialysis.
Renal and neurohumoral effects of ibopamine and metoclopramide in normal man.
Authors: Girbes AR , van Veldhuisen DJ , Smit AJ , Drent‐Bremer A. , Meijer S. , Reitsma WD
Published: July 2012

The effects of 100 mg ibopamine, an orally active nonselective dopamine agonist on renal haemodynamics, sodium excretion, blood pressure (BP), heart rate (HR) and neurohumoral parameters were investigated in 10 healthy volunteers, with and without metoclopramide pretreatment. A small and temporary rise of glomerular filtration rate (GFR) was found after ibopamine without but not with metoclopramide pretreatment. No differences in effective renal plasma flow (ERPF) but a small rise in sodium excretion were observed comparing ibopamine with control. Metoclopramide induced a fall in sodium excretion which was not reversed by ibopamine. Ibopamine failed to affect BP and HR and no changes of PRA or plasma aldosterone concentration (PAC) were found. Metoclopramide induced a pronounced increase of PAC which was blunted by ibopamine. Plasma and urinary catecholamines were unchanged for all study days. We conclude that ibopamine induces natriuresis probably not by the observed small and temporary renal haemodynamic effects but by direct stimulation of DA1 dopamine receptors in the proximal tubule.
Pentoxifylline stimulates human sperm motility both in vitro and after oral therapy.
Authors: Shen MR , Chiang PH , Yang RC , Hong CY , Chen SS
Published: July 2012

Pentoxifylline is a haemorrheologic agent often used in the treatment of peripheral vascular disorders. In this study, we measured sperm motility with a trans‐membrane migration method and investigated the effect of this drug in the treatment of male infertility. We found that pentoxifylline increased motility of ejaculated spermatozoa in vitro from both normal and asthenozoospermic samples. After giving pentoxifylline to patients with asthenozoospermia for 3 months, sperm motility significantly increased, but sperm concentration did not increase. From the above results, it can be concluded that pentoxifylline is a useful drug in the treatment of normogonadotropic asthenozoospermia.
Ponalrestat does not cause a protein binding interaction with warfarin in diabetic patients.
Authors: Moulds RF , Fullinfaw RO , Bury RW , Plehwe WE , Jacka N. , McGrath KM , Martin FI
Published: July 2012

Ponalrestat (Statil, ICI; Prodiax, Merck Sharp and Dohme) is an aldose reductase inhibitor which is highly protein bound. Ponalrestat markedly displaced warfarin from its protein binding in vitro at a concentration of 500 micrograms ml‐1, but not at a concentration of 50 or 100 micrograms ml‐1. Twelve diabetic patients (six males), age range 38‐65 years, in receipt of chronic stable warfarin therapy, were given ponalrestat (600 mg daily) for 2 weeks in an open trial. A matching placebo tablet was administered for 1 week before and after the active treatment period. Patients were seen ten times (four times during the ponalrestat phase), and during the ponalrestat phase, plasma samples were also taken before and at 3 h after the daily dose of ponalrestat. At none of the visits was there any significant change in prothrombin ratio (INR), plasma total or unbound warfarin concentrations, or percentage protein binding of warfarin. No clinical complications of combination treatment were detected. The maximum ponalrestat concentration observed in the patients was approximately 100 micrograms ml‐1. We conclude that no significant interaction between these drugs occurs at the doses of ponalrestat studied.
Stereoselective pharmacokinetics of oral and intravenous nitrendipine in healthy male subjects.
Authors: Soons PA , Breimer DD
Published: July 2012

1. Stereoselectivity in the pharmacokinetics of nitrendipine was investigated by reanalysing plasma samples of a previously published study (Soons et al., 1989). 2. Racemic nitrendipine was administered intravenously (40 micrograms kg‐1) and orally, both as plain tablet (20 mg) and in an osmotic pump device (40 mg Osmet) to nine healthy male subjects. Nitrendipine enantiomers were measured with a stereoselective assay. 3. Upon oral administration (tablet) the bioavailability of (S)‐ (−)−nitrendipine (13.4% +/‐ 5.6%) was 75% (50% ‐ 98%) higher than that of (R)‐nitrendipine (7.9% +/‐ 4.0%) (mean +/‐ s.d. (95% confidence interval)). Values of AUC and Cmax for (S)‐nitrendipine were 90% (55% ‐ 121%) and 77% (51% ‐ 100%) higher respectively, than those for (R)‐ nitrendipine. Similar results were obtained with the osmotic system. 4. The clearance of intravenously administered (S)‐nitrendipine was slightly (7%) lower than that of (R)‐nitrendipine, but elimination half‐ lives and volumes of distribution were similar. 5. The difference in disposition of nitrendipine enantiomers is most likely related to a difference in activity of the cytochrome P‐450 system towards the enantiomers, giving rise to a two‐fold difference in first‐pass elimination. 6. Stereoselectivity in the first pass metabolism of nitrendipine exhibited little intersubject variability and therefore is not a major factor in the wide variability in systemic availability of the more‐potent (S)‐enantiomer.
The effect of various drugs on the glucuronidation of zidovudine (azidothymidine; AZT) by human liver microsomes.
Authors: Sim SM , Back DJ , Breckenridge AM
Published: July 2012

1. Zidovudine (3'‐azido‐3'‐deoxythymidine; AZT) is the drug of proven efficacy available for the treatment of patients with AIDS or ARC. It is eliminated mainly by hepatic glucuronidation. Therefore, interference with this metabolic pathway may lead to enhancement of AZT effect or to increased toxicity of the drug. We have examined the effect of a number of drugs which themselves undergo glucuronidation on AZT conjugation by human liver microsomes in vitro. 2. AZT glucuronidation followed Michaelis‐Menten kinetics. The apparent Km and Vmax values (mean +/‐ s.d., n = 5), were 2.60 +/‐ 0.52 mM and 68.0 +/‐ 23.4 nmol h‐1 mg‐1, respectively, as determined from Eadie‐Hofstee plots. 3. Dideoxyinosine, sulphanilamide and paracetamol were essentially non‐inhibitory at concentrations up to 10 mM (4 times the concentration of AZT in the incubation). The most marked inhibitory effects were seen with indomethacin, naproxen, chloramphenicol, probenecid and ethinyloestradiol, with enzyme activity decreased by 97.7, 94.9, 88.7, 83.4% and 79.0%, respectively, at a concentration of 10 mM. Other compounds producing some inhibition of AZT conjugation were oxazepam, salicylic acid and acetylsalicylic acid. 4. Further studies are necessary to characterise the inhibition observed but the method described enables a screen of potentially important drug interactions to be carried out.
Morphine kinetics after diamorphine infusion in premature neonates.
Authors: Barrett DA , Elias‐Jones AC , Rutter N. , Shaw PN , Davis SS
Published: July 2012

1. The pharmacokinetics of morphine were studied in 26 newborn premature neonates (26‐38 weeks gestational age) who were given a loading dose of 50 micrograms kg‐1 of diamorphine followed by an intravenous infusion of 15 micrograms kg‐1 h‐1 of diamorphine. Plasma concentrations of morphine were measured during the infusion at steady‐ state and for 24 h after the cessation of the diamorphine infusion. 2. The mean steady‐state plasma morphine concentration (+/‐ s.d.) for a diamorphine infusion rate of 15 micrograms kg‐1 h‐1 was 62.5 +/‐ 22.8 ng ml‐1. 3. Morphine clearance was 3.6 +/‐ 0.9 ml min‐1 kg‐1, the elimination half‐life was 8.9 +/‐ 3.3 h and the volume of distribution was 2.7 +/‐ 1.01 kg‐1. 4. Morphine elimination kinetics were described by a mono‐exponential function. 5. There was a direct relationship between the gestational age of the patients and the clearance (r2 = 0.31, P = 0.003) and half‐life (r2 = 0.35, P = 0.01) of morphine, but no relationship was found between gestational age and volume of distribution. 6. The results suggest that the currently used dosing regimen of diamorphine achieves a safe and effective morphine concentration in the premature newborn but that the loading dose could be modified to achieve a more rapid onset of analgesia.
Cardiovascular effects of cromakalim (BRL 34915) in healthy volunteers.
Authors: Fox JS , Whitehead EM , Shanks RG
Published: July 2012

1. The effect of oral doses of cromakalim 0.5, 1.0, 1.5 and 2.0 mg on several cardiovascular parameters was studied in healthy male volunteers. 2. In the first study, no dose of cromakalim reduced systolic or diastolic blood pressure in the supine or standing position. Reductions of diastolic blood pressure after exercise (P less than 0.01) were observed 4 h after administration of 2.0 mg. 3. There was a trend towards increased heart rate after 2.0 mg at all time intervals, and significant changes were observed in supine and standing heart rate at 2 and 4 h (P less than 0.01). No significant change was observed in exercise heart rate. 4. In the second study small increases in forearm blood flow were observed from 3 h to 5 h after oral administration of 1.0 and 2.0 mg of cromakalim. Forearm vascular resistance was significantly reduced after 2.0 mg (P less than 0.025) when compared with placebo. No change was observed in forearm venous capacitance after either dose of cromakalim, or placebo. Supine heart rate was significantly increased 4 h after 2.0 mg of cromakalim (P less than 0.025). 5. These results show that oral administration of cromakalim decreases diastolic blood pressure and forearm vascular resistance. A hypotensive effect is probably attenuated by reflex tachycardia.
No effect of probenecid on the renal and biliary clearances of digoxin in man.
Authors: Hedman A. , Angelin B. , Arvidsson A. , Dahlqvist R.
Published: July 2012

1. The cardiac glycoside digoxin is subject to a number of pharmacokinetic interactions. This study concerns the influence of the anionic transport inhibitor probenecid on the steady‐state kinetics of digoxin. 2. Six healthy young men were enrolled in the study. After an administration period of 6 days with digoxin only (0.5 to 1 mg p.o. day‐ 1) or digoxin in combination with probenecid (2 g p.o. day‐1; 8 days), digoxin was administered intravenously (0.7 oral dose) on day 7. Plasma and urine samples were taken over 48 h. The biliary clearance of digoxin was measured during day 8 by a duodenal perfusion technique. 3. Probenecid did not affect the plasma clearance (mean +/‐ s.d.: 255 +/‐ 80 vs 266 +/‐ 40 ml min‐1), renal clearance (166 +/‐ 17 vs 155 +/‐ 10 ml min‐1), biliary clearance (106 +/‐ 40 vs 111 +/‐ 50 ml min‐1), elimination half‐life (34.4 vs 35.2 h) or volume of distribution (538 +/‐ 241 vs 566 +/‐ 60 l) of digoxin. 4. Our results suggest that different systems exist in man for the renal and biliary secretion of probenecid and digoxin.
Dose‐related analgesic effects of flupirtine.
Authors: Hummel T. , Friedmann T. , Pauli E. , Niebch G. , Borbe HO , Kobal G.
Published: July 2012

1. Flupirtine is a novel and, in all probability, centrally acting, analgesic. The present investigation was conducted in order to investigate dose‐related effects of perorally administered flupirtine in man, with special regard to specifically analgesic actions, employing a model based on pain‐related chemosomatosensory evoked potentials and subjective intensity estimates of painful stimuli. 2. Plasma concentrations of flupirtine measured 2 h after dosing linearly increased as a function of the administered dose. 3. It was possible to reproduce our own previously obtained results, which established the analgesic action of 200 mg flupirtine administered perorally. 4. Intensity estimates linearly decreased as a function of the administered dose, whereas chemosomatosensory evoked potential amplitudes non‐linearly changed in relation to the administered dose. 5. In the spontaneous EEG, a dose‐dependent increment in the power‐ spectra was observed, and this mainly in the alpha‐ and beta‐range.
The role of histamine in the acute inflammatory responses to intradermal platelet activating factor.
Authors: Sciberras DG , Jordan S. , Gill D. , Baber NS , James I.
Published: July 2012

1. The role of histamine in PAF‐induced acute inflammatory responses (flare and weal) in the skin has been evaluated in a series of three separate studies. 2. Terfenadine, a potent H1‐selective histamine antagonist virtually abolished the flare response and significantly inhibited the weal response. 3. Histamine depletion in the skin using compound 48/80 resulted in similar effects on the flare and weal response. Two consecutive daily injections of compound 48/80 were found to deplete comprehensively skin sites of histamine and the ability of skin to respond to PAF was completely restored within 2 weeks of compound 48/80 treatment. 4. Intradermally injected PAF was associated with acute rises in plasma histamine in blood drawn from a draining vein with peak concentrations occurring within 5 min of injection. 5. No difference in PAF‐induced flare and weal response was found between atopic and non‐atopic subjects and this was reflected in the peak plasma histamine results. A significantly higher baseline plasma histamine was found in the atopic group, however, when compared with the non atopic group. 6. It is concluded that histamine has an important role in the acute inflammatory responses to intradermally injected PAF, although there does appear to be a significant direct vascular component in the PAF‐induced weal response.
Pharmacodynamic effects of buspirone and clobazam.
Authors: Alford C. , Bhatti JZ , Curran S. , McKay G. , Hindmarch I.
Published: July 2012

1. The pharmacodynamic effects of buspirone and clobazam were compared in two volunteer studies. Acute doses of buspirone 5 mg, 10 mg and clobazam 10 mg were contrasted with placebo and a verum (lorazepam 1 mg), in a repeated measures design with 10 subjects assessed on a battery of psychometric tests at 1.5, 3.5, and 5.5 h post dose. For the combined results clobazam and the lower dose of buspirone (5 mg) were significantly contrasted with lorazepam on measures of subjective sedation, memory and choice reaction time (CRT). The higher dose of buspirone was not statistically different from lorazepam for all measures except memory; whilst contrasting significantly with placebo and clobazam on movement and total reaction time components respectively. Though failing to achieve significance, a similar trend was seen for critical flicker fusion (CFF) with buspirone 10 mg and lorazepam producing the lowest scores indicative of increased sedation. 2. Repeated doses of buspirone 5 mg twice daily, clobazam 10 mg twice daily, or placebo twice daily for 8 consecutive days were compared on the same battery of psychometric tests in a repeated measures design. Nine subjects were assessed on days 1, 3, and 8 of the study. Overall, memory performance significantly decreased with buspirone 5 mg in contrast to both clobazam and placebo whilst the opposite trend was seen with CFF. Clobazam significantly improved TRT in contrast to both placebo and buspirone. 3. These results indicate improved reaction time and memory performance with repeated dosing of clobazam in contrast to buspirone. Impairment following acute administration of buspirone appears limited to the higher (10 mg) dose.
Monotherapy with conventional and controlled‐release carbamazepine: a double‐blind, double‐dummy comparison in epileptic patients.
Authors: McKee PJ , Blacklaw J. , Butler E. , Gillham RA , Brodie MJ
Published: July 2012

1. Twenty‐one epileptic patients completed a double‐blind, double‐ dummy, random order, crossover comparison of conventional carbamazepine (CBZ, Tegretol, Ciba‐Geigy) with a new controlled‐release formulation (CBZ‐CR, Tegretol Retard). All participants were stabilised on maximally tolerated doses of CBZ as monotherapy (one twice daily, twelve three times daily, eight four times daily). Each preparation was taken with a matched placebo of the other for 4 weeks. 2. Peak serum CBZ concentrations (mean +/‐ s.e. mean) were lower (CBZ 11.4 +/‐ 0.4 mg l‐1; CBZ‐CR 10.4 +/‐ 0.5 mg l‐1; P less than 0.01) and times to peak longer (CBZ 3.6 +/‐ 0.5 h, CBZ‐CR 5.2 +/‐ 0.7 h, P less than 0.01) during CBZ‐CR treatment. Mean CBZ concentrations, however, were also slightly reduced with the new formulation (CBZ 9.9 +/‐ 0.3 mg l‐1; CBZ‐ CR 9.1 +/‐ 0.5 mg l‐1, P less than 0.05) and this was associated with greater seizure frequency (CBZ 2.8 +/‐ 1.2, CBZ‐CR 3.8 +/‐ 0.9; P less than 0.05) during the CBZ‐CR treatment phase. 3. Diurnal fluctuations (CBZ 41 +/‐ 3%, CBZ‐CR 28 +/‐ 2%, P less than 0.01) and variations (CBZ 53 +/‐ 5%, CBZ‐CR 33 +/‐ 3%; P less than 0.01) in serum CBZ concentration were substantially less with CBZ‐CR and were similar to those calculated during a 6 or 8 hourly dosage interval with conventional CBZ (fluctuation 33 +/‐ 3%, variation 42 +/‐ 5%).(ABSTRACT TRUNCATED AT 250 WORDS)
Does treatment with beta‐adrenoceptor antagonists in vivo alter human adenylate cyclase responsiveness in vitro?
Authors: Michel MC , Kluppel M. , Philipp T. , Brodde OE
Published: July 2012

1. Treatment with beta‐adrenoceptor antagonists in vivo can alter adenylate cyclase responsiveness in the human heart. We have determined the effects of treatment with four different beta‐adrenoceptor antagonists in vivo on the responsiveness of lymphocyte and platelet adenylate cyclase in vitro in healthy volunteers. 2. Propranolol (non‐ selective, 4 x 40 mg day), bisoprolol (beta 1‐selective, 1 x 10 mg day), and ICI 118.551 (beta 2‐selective, 3 x 25 mg day) were tested as drugs without and pindolol (non‐selective, 2 x 5 mg day) as a drug with intrinsic sympathomimetic activity. Adenylate cyclase stimulation by GTP, prostaglandin E1 and forskolin was determined before, after a 7 day treatment period and 7 days after drug withdrawal. 3. Neither treatment with or withdrawal of any of the beta‐adrenoceptor antagonists altered adenylate cyclase responsiveness. 4. We conclude that adenylate cyclase responsiveness in circulating blood cells underlies different regulatory mechanisms than that in solid tissues such as the human heart. Our data suggest that circulating blood cells do not always reflect alterations in solid tissues.
Regular nebulised terbutaline in chronic obstructive airways disease: dose‐response studies fail to detect tolerance.
Authors: Teale C. , Pearson SB
Published: July 2012

1. To determine the effects of high dose terbutaline on the possible development of tolerance we have examined the influence on dose‐ response of regular nebulised terbutaline. 2. We studied 10 subjects with severe chronic obstructive airways disease (COAD), mean age 63 years mean (s.e. mean) PEFR 142 l min‐1 (19), FEV1 0.77 1 (0.12) and FVC 1.93 (0.19). Cumulative dose‐response curves were measured (PEFR, FEV1 and FVC) to six incremental doses of terbutaline (0.5‐8 mg) before and 1, 4, 8 and 12 weeks after starting nebulised terbutaline 5 mg four times a day. 3. Maximal bronchodilatation (Emax) was calculated by polynomial regression. Responses were examined by analysis of variance. 4. Mean baseline PEFR increased by 32 l min‐1 (P less than 0.05), FEV1 by 0.16 1 (NS) and FVC by 0.54 l (P less than 0.05) after 12 weeks. Initial mean Emax PEFR was maintained throughout the study. The percentage of mean Emax PEFR achieved by each cumulative dose of terbutaline either increased (0.5 mg, 1 mg and 2 mg, P less than 0.01) or was maintained (4 mg, 6 mg and 8 mg) throughout the study. 5. We conclude that in severe COAD regular nebulised terbutaline 5 mg four times a day produces a sustained improvement in baseline lung function without changes in dose‐response which would suggest tolerance.
Once vs twice daily administration of a fixed combination of captopril plus hydrochlorothiazide in essential hypertension: a double‐blind crossover study in known responders to a standard combination.
Authors: Lacourciere Y. , Poirier L. , Provencher P. , Guivarc'h PH
Published: July 2012

The purpose of this randomized, double‐blind, crossover trial was to compare the hypotensive effects of a fixed combination of captopril (C) 50 mg and hydrochlorothiazide (HCTZ) 25 mg (C 50/HCTZ 25) once daily with those of a fixed combination of C 25 mg and HCTZ 12.5 mg (C 25/HCTZ 12.5) twice daily. We studied 199 patients (108 M, 91 F) with mild to moderate essential hypertension whose BP was already controlled by the co‐administration of C 25 mg and HCTZ 12.5 mg twice daily. They were randomly assigned to either C 25/HCTZ 12.5 twice daily during the first 6 weeks and C 50/HCTZ 25 once daily during the second 6 weeks or C 50/HCTZ 25 once daily followed by C 25/HCTZ 12.5 twice daily. Both regimens showed comparable efficacy on office diastolic BP (91.6 vs 91.3 mm Hg). Systolic BP was slightly but significantly higher (P = 0.02) with the once daily formulation (141.2 vs 139.1 mm Hg). Fixed combinations once daily and twice daily resulted in identical working ambulatory BP (133.7 +/‐ 13/83.6 +/‐ 8 mm Hg vs 132.4 +/‐ 11/83.3 +/‐ 7 mm Hg) without affecting heart rate. Adverse events were reported by 16% of patients and cough was the most common occurring in 7%. In conclusion, these results indicate that the fixed combination of C 50/HCTZ 25 given once daily controls office and working BP as well as the fixed combination C 25/HCTZ 12.5 given twice daily in patients with mild to moderate hypertension.