bluuebunny/crossref_metadata_2025_split huggingface dataset:
(−)‐Timolol is a more potent antagonist of the positive inotropic effects of (−)‐adrenaline than of those of (−)‐noradrenaline in human atrium
Authors: WANG T. , KAUMANN A. J. , BROWN M. J. 
Published: October 2003

1The affinity of (−)‐timolol for β1‐ and β2‐adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (−)‐adrenaline and (−)‐noradrenaline by (−)‐timolol were measured.2The antagonism of the positive inotropic effects of (−)‐adrenaline and (−)‐noradrenaline by (−)‐timolol (0.1–100 nm) was simple competitive in human atrium tissue. The slope of Schild‐plots was not significantly different from 1.0 [0.93±0.09 for (−)‐adrenaline, 0.97±0.09 for (−)‐noradrenaline].3The inotropic effects of (−)‐adrenaline were antagonized significantly more by each concentration of (−)‐timolol than those of (−)‐noradrenaline. KB‐values (‐log m) were 10.10±0.09 against (−)‐adrenaline and 9.43±0.07 against (−)‐noradrenaline (P<0.001).4Blocking kinetics of (−)‐timolol for the β‐adrenoceptor were relatively slow. Half‐times for the onset of blockade by 10 times KB of (−)‐timolol were approximately 30 min for both (−)‐adrenaline and (−)‐noradrenaline; offset times were similar.5It is concluded that (−)‐timolol has a higher affinity for the β2‐adrenoceptor than for the β1‐adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the β2‐adrenoceptor hypersensitivity induced by cardiac β1‐adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra‐ocular doses of the drug.
Suppression of vagus‐mediated pancreatic polypeptide release by the μ‐opiate receptor agonist loperamide in man
Authors: RIEPL RUDOLF L. , REICHARDT BÄRBEL , AUERNHAMMER CHRISTOPH J. , BEIER GERALD , SCHOPOHL JOCHEN , STALLA GÜNTER K. , LEHNERT PETER 
Published: October 2003

1Morphine suppresses the release of pancreatic polypeptide, a hormone under vagal cholinergic control. The intention of the study was to detect whether the μ‐opiate receptor agonist loperamide is also able to inhibit pancreatic polypeptide release, and to define its site of action. 2In groups of healthy subjects (n=6 each) stimulation of pancreatic polypeptide was assessed in five different tests: (i) insulin‐hypoglycaemia; (ii) modified sham feeding; (iii) intravenous infusion of the cholecystokinin analogue ceruletide; (iv) injection of corticotropin releasing hormone; (v) infusion of the muscarinic acetylcholine agonist bethanechol. All tests were performed after oral application of either a placebo or loperamide (16 mg), tests (ii) and (iii) were repeated with loperamide in smaller doses (2 and 6 mg), with loperamide plus naloxone, with naloxone alone, and with infusion of atropine. Plasma concentrations of pancreatic polypeptide were measured radioimmunologically. 3Release of pancreatic polypeptide in test (i) to (iv) was completely blocked by 16 mg loperamide, whereas bethanechol‐stimulated release (test 5) was not influenced. Tests (ii) and (iii) showed that the inhibition was dose‐dependent and could be attenuated by naloxone. The inhibitory effect of loperamide was comparable with that of atropine. 4We conclude that loperamide causes a dose‐dependent inhibition of pancreatic polypeptide release mediated by vagal‐cholinergic pathways, but does not have an atropine‐like peripheral action.
Measurement of total phospholipids in urine of patients treated with gentamicin
Authors: Saunders Darren A. , Begg Evan J. , Kirkpatrick Carl M. J. , Yeo James , Graham Garry G. , Bailey Ross R. 
Published: October 2003

Aims The excretion of phospholipids in urine may be a marker of the early renal toxicity of the aminoglycoside antibiotics. Urinary phospholipids are formed in myeloid bodies which develop in the lysosomes of proximal tubules during treatment with the aminoglycosides, and overflow into the urine.
Methods Published assays were modified in order to measure the total phospholipid concentrations in human urine. Phospholipids were extracted from freeze‐dried urine samples, digested in concentrated sulphuric acid, and the inorganic phosphorus content determined by complexing with ammonium molybdate and measuring the absorbance at 820 nm. Ten septicaemic patients treated with gentamicin for 5–7 days had significantly higher urine phospholipid concentrations than 10 healthy untreated control subjects (P<0.0001). There was a negative linear relationship between phospholipid excretion and creatinine clearance (r
2=0.71).
Results In 34 patients with acute pyelonephritis, increased phospholipid concentrations were observed prior to treatment compared with healthy controls (P<0.001) and did not alter during treatment with gentamicin. However, the phospholipid concentrations decreased significantly after treatment was completed (P<0.03).
Conclusions These studies suggest that urinary phospholipids may indicate early aminoglycoside toxicity but with poor specificity, as many of the infections being treated may themselves be associated with phospholipiduria.
Stereoselective 4′‐hydroxylation of phenytoin: relationship to (S)‐mephenytoin polymorphism in Japanese
Authors: Ieiri I. , Mamiya K. , Urae A. , Wada Y. , Kimura M. , Irie S. , Amamoto T. , Kubota T. , Yoshioka S. , Nakamura K. , Nakano S. , Tashiro N. , Higuchi S. 
Published: October 2003

Aims The aim of this study was to clarify whether phenytoin (PHT) stereoselective hydroxylation cosegregates with (S)‐mephenytoin phenotype.
Methods A single dose of PHT (100 mg) was administered orally to six healthy Japanese subjects in whom the genotype and phenotype of CYP2C19 had been determined previously. The urinary excretion profiles of the metabolites of PHT, (R)‐ and (S)‐p‐HPPH [
5‐(4‐hydroxyphenyl)‐5‐phenylhydantoin] up to 36 h postdose were compared between the two groups of poor metabolizers (PMs, n=3) and extensive metabolizers (EMs, n=3) with respect to CYP2C19. CYP2C9 genotype was also determined.
Results All the alleles were found to be wild type (Arg144Tyr358Ile359Gly417 ) in each subject. The mean value for cumulative urinary excretion of unchanged PHT was not significantly different between the PMs and the EMs. However, recovery of (R)‐p‐HPPH at 36 h was 3.5‐fold lower and that of (S)‐p‐HPPH 1.3‐fold lower in PMs than in EMs. Although the mean urinary excretion values for both metabolites were significantly lower in the PMs than in the EMs, the difference between the two groups was larger for (R)‐p‐HPPH. A significant negative correlation was observed between the hydroxylation index of omeprazole (the ratio between the serum concentrations of omeprazole and hydroxyomeprazole in blood samples drawn 3 h after drug intake) and the log10 0–12 h urinary recovery of (R)‐p‐HPPH.
Conclusions In humans, the 4′‐hydroxylation of PHT is highly stereoselective towards formation of the (S)‐enantiomer. Thus, (S)‐hydroxylation by CYP2C9 might be the major determinant of the disposition of PHT. However, these results support the hypothesis that the stereoselective hydroxylation pathway of PHT to form (R)‐p‐HPPH cosegregates with the CYP2C19 metabolic polymorphism.
Enhanced effect of triazolam with diltiazem
Authors: Kosuge Kazuhiro , Nishimoto Masahiko , Kimura Masahiko , Umemura Kazuo , Nakashima Mitsuyoshi , Ohashi Kyoichi 
Published: October 2003

Aims Triazolam, a triazolobenzodiazepine hypnotic agent, is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme. The aim of this study was to determine if diltiazem affects plasma concentrations of triazolam in humans.
Methods We investigated the interaction between triazolam and diltiazem in a randomized, three‐phase crossover study. Seven healthy male volunteers received orally either a single 0.25 mg dose of triazolam, a 0.25 mg dose of triazolam after a 3‐day treatment of diltiazem (180 mg day−1), or a placebo. Plasma samples were collected to determine triazolam concentration over a 24 h period. The pharmacodynamic effects of triazolam were investigated using the peak saccadic velocity of eye movements (PSV), electroencephalogram (EEG), and visual analogue scale (VAS) through 8 h.
Results Diltiazem pretreatment significantly increased the area under the triazolam concentration‐time curve (8.0±2.4 to 18.2±3.1 ng ml−1 h; P<0.001; mean±s.d.). Peak triazolam concentration was increased (2.1±0.7 to 3.6±1.0 ng ml−1, P<0.05) and the elimination half‐life prolonged (4.1±2.1 to 7.6±1.9 h; P<0.01). The PSV, EEG, and VAS of the triazolam plus diltiazem group revealed significant differences from the triazolam alone group or the control placebo group.
Conclusions Diltiazem markedly affects the pharmacokinetics of triazolam and increases the intensity of its sedative effects. Inhibition of CYP3A isozyme by diltiazem may explain the observed pharmacokinetic interaction. Therefore, triazolam should be avoided when patients are using diltiazem.
Use of sumatriptan in Denmark in 1994–5: an epidemiological analysisof nationwide prescription data
Authors: Gaist David , Andersen Morten , Aarup Ann‐Lisbeth , Hallas Jesper , Gram Lars Freng 
Published: October 2003

Aims We describe the use of medication with symptomatic relief of migraine as specific indication by analysing prescription data from the entire Danish population in 1994 and 1995.
Methods The data for sumatriptan were analysed at the level of the individual user. We used aggregated data for ergotamine drugs.
Results Sumatriptan constituted 46% of the total amount of defined daily doses (DDD) sold and 94% of the total pharmacy retail price expenses in the drug‐group studied. In total, 43 389 users of sumatriptan were identified who presented 340 148 prescriptions, corresponding to 2.2 million DDD of sumatriptan. The quarterly consumption increased by 50% during the study period. Tablets accounted for 92% of consumption. The 1 year period prevalence of use of sumatriptan among persons 16 years and older was 7.8 per 1000 in 1995 with a female to male prevalence ratio of 3.8:1. Use was most common in the age interval 35–54 years. Regional differences in use, which were not large, were positively correlated to the degree of urbanization. The incidence of use of sumatriptan was estimated at 3.6 per 1000 person‐years. The intensity of use of sumatriptan varied greatly with 1.1% of patients (n=507) using 60 DDD or more within 30 days at some time during the observation period. Long‐term high use of tablets was common in this group.
Conclusions We conclude that sumatriptan had a considerable impact on the treatment of migraine with prescription drugs in Denmark. The underlying reasons for high use of the drug in a smaller fraction of the patients deserve further study.
Pharmacokinetic and pharmacodynamic interaction trial after repeated oral doses of imdapril and digoxin in healthy volunteers
Authors: Harder Sebastian , Thürmann Petra A. 
Published: October 2003

Aims  To investigate the potential pharmacokinetic and pharmacodynamic interaction between imidapril and digoxin. Methods
AUC, Cmax and tmax of imidapril, imidaprilat and digoxin were calculated and evaluated in a randomized, doubleblind three‐period cross‐over design in 12 healthy volunteers after 8 days treatment with the following combinations: digoxin 0.25 mg day−1+placebo (D+P); imidapril 10 mg day−1+placebo (I+P); imidapril 10 mg day−1+digoxin 0.25 mg day−1 (I+D). Results
Mean AUC (0, 24 h) of digoxin was 10.4 (±4.9 s.d.) ng ml−1 h (D+P) and 10.7 (±3.9 s.d.) ng ml−1 h (I+D), respectively (90%‐confidence intervals [
CI] for the ratio of (D+P) and (I+D): 0.91–1.27, point estimator [PE]: 1.06). Mean AUC (0, 24 h) of imidapril was 133 (±86 s.d.) ng ml−1 h (I+P) and 108 (±52 s.d.) ng ml−1 h (I+D), respectively (90%‐CI: 0.76–0.94, PE 0.85). AUC (0, 24 h) of imidaprilat was 215 (±91 s.d.) ng ml−1 h (I+P) and 194 (±54 s.d.) ng ml−1 h (I+D), respectively (90%‐CI: 0.80–1.08, PE 0.93). Cmax was 19.9 (±8.7 s.d.) ng ml−1 (I+P) and 15.9 (±5.3 s.d.) ng ml−1 (I+D) (90%‐CI: 0.67–1.00, PE 0.82). The results indicate a slight reduction of imidapril and imidaprilat plasma levels when coadministered with digoxin without any effect on digoxin plasma levels. Maximal ACE‐inhibition was 79% (I+P) and 67% (I+D). Conclusions
Grouped data analysis of imidaprilat plasma levels vs ACE‐activity showed that for maximal inhibition of plasma ACE activity, imidaprilat plasma levels should exceed 10 ng ml−1. Under digoxin and imidapril, more plasma concentrations of imidaprilat were seen under this level as after imidapril alone, this reduces the integral of the ACE‐inhibition/time curves by about 20 to 30%.
Pharmacokinetic and pharmacodynamic assessment of bioavailability for two prodrugs of methylprednisolone
Authors: Daley‐Yates P. T. , Gregory A. J. , Brooks C. D. 
Published: October 2003

Aims The aim of this study was to establish whether pharmacokinetic differences between two pro‐drugs of methylprednisolone (MP) are likely to be of clinical significance.Methods This study was a single‐blind, randomized, crossover design comparing the bioequivalence of MP released from the pro‐drugs Promedrol (MP suleptanate) and Solu‐Medrol (MP succinate) after a single 250 mg (MP equivalent) intramuscular injection to 20 healthy male volunteers. Bioequivalence was assessed by conventional pharmacokinetic analysis, by measuring pharmacodynamic responses plus a novel approach using pharmacokinetic/pharmacodynamic modeling. The main measure of pharmacodynamic response was whole blood histamine (WBH), a measure of basophil numbers.Results The MP Cmax was less for MP suleptanate due to a longer absorption half‐life of the prodrug from the intramuscular injection site. The bioavailability of MP was equivalent when based on AUC with a MP suleptanate median 108% of the MP succinate value (90% CI: 102–114%). For Cmax the MP suleptanate median was 81% of the MP succinate value (90% CI: 75–88%). The tmax for MP from MP suleptanate was delayed relative to MP succinate. The median difference was 200% (90% non‐parametric CI: 141–283%). The area under the WBH effect‐time curve (AUEC) and the maximum response (Emax ) were found to be equivalent (90% CI: 98–113% and 93–109% respectively). The maximum changes in other white blood cell counts, blood glucose concentration and the parameters of the pharmacodynamic sigmoid Emax model (EC50, Emax and γ) were also not significantly different between prodrugs.Conclusions MP suleptanate is an acceptable pharmaceutical alternative to MP succinate. The use of both pharmacokinetic and pharmacodynamic response data together gives greater confidence in the conclusions compared with those based only on conventional pharmacokinetic bioequivalence analysis.
Comparison of the effects of a selective muscarinic receptor antagonist and hyoscine (scopolamine) on motion sickness, skin conductance and heart rate
Authors: Golding J. F. , Stott J. R. R. 
Published: October 2003

Aims Hyoscine (scopolamine), which is effective in the prophylaxis of motion sickness, shows similar binding affinities to all of the five known muscarinic receptor sub‐types. The effectiveness of hyoscine was compared with zamifenacin (UK‐76654), which binds selectively to the muscarinic M3 and m5 receptors.Methods Eighteen subjects received hyoscine hydrobromide 0.6 mg, zamifenacin 20 mg, or placebo (double‐blind cross‐over design). Sessions were 1 week apart and the drug (oral) was given 90 min prior to a motion sickness test. Motion sickness was elicited by cross‐coupled stimulation on a turntable. The rotational velocity was incremented by 2° s−1 every 30 s, and a sequence (seq) of eight head movements of 45° was completed every 30 s. Motion tolerance was assessed as the number of sequences of head movement required to achieve moderate nausea. Pulse rate was recorded before and at 1 and 2 h after drug administration. Skin conductance activity in the frequency band 0.005–0.48 Hz, an index of sweat gland activity, was measured using Ag/AgCl electrodes on the palmar surfaces of fingers and across the forehead.Results Both zamifenacin and hyoscine produced an increase in tolerance to the motion challenge (P<0.01) with no significant difference between the two drugs (5.0±1.6 vs 5.7±1.6 seqs. respectively, mean±s.e.mean). Compared with placebo or zamifenacin, pulse rate fell following hyoscine administration (9 beats min−1, P<0.01). Skin conductance was reduced following hyoscine compared with zamifenacin or placebo (P<0.001).Conclusions These results suggest that compounds with selective M3 and/or m5 antagonism possess activity against motion sickness. Antagonism at these receptors may be the basis of the anti‐motion sickness action of hyoscine.
The mechanism of the carbamazepine‐valproate interaction in humans
Authors: Bernus I. , Dickinson R. G. , Hooper W. D. , Eadie M. J. 
Published: October 2003

Aims The study investigated the mechanism of the interaction between valproate and carbamazepine which causes raised plasma carbamazepine‐10,11‐epoxide concentrations with unchanged plasma carbamazepine concentrations. This interaction has usually been attributed to valproate inhibiting epoxide hydrolase, the enzyme that catalyses the biotransformation of carbamazepine‐10,11‐epoxide to carbamazepine‐10,11‐trans‐diol. Methods Clearances of plasma carbamazepine, carbamazepine‐epoxide and carbamazepine‐diol to relevant carbamazepine metabolites present in urine were measured under steady‐state conditions in 17 adults receiving carbamazepine as anticonvulsant monotherapy, and in 10 adults taking the drug together with valproate. Results Plasma carbamazepine‐epoxide concentrations were higher, relative to carbamazepine dose, in the co‐medicated patients. Plasma apparent clearances of carbamazepine, relative to drug dose, were similar whether or not valproate was taken. Formation clearances of carbamazepine‐10,11‐trans‐diol conjugate, and probably of carbamazepine‐10,11‐trans‐diol, were lower in subjects co‐medicated with valproate, and a higher proportion of the carbamazepine dose was excreted in urine as carbamazepine‐10,11‐epoxide. Conclusions Valproate appears to inhibit the glucuronidation of carbamazepine‐10,11‐trans‐diol, and probably also inhibits the conversion of carbamazepine‐10,11‐epoxide to this trans‐diol derivative, rather than simply inhibiting the latter reaction only.
Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics*
Authors: Dingemanse Jasper , Kleinbloesem Cornelis H. , Zürcher Gerhard , Wood Nolan D. , Crevoisier Charles 
Published: October 2003

Aims The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple‐dose regimens. Methods Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100 mg three times daily and 12.5, 50, 200 mg three times daily, respectively. Plasma levels of levodopa, 3‐O‐methyldopa (3‐OMD) and 3,4‐dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250 mg levodopa. Results Endogenous concentrations of levodopa and 3‐OMD increased dose‐dependently (from 8 up to 52 μg l−1 and from 0.02 up to 0.50 mg l−1, respectively, at doses of 200 mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration‐time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9 mg l−1 h at benserazide doses of 100–200 mg three times daily. Benserazide caused a dose‐dependent increase in the AUC of 3‐OMD from 7.4 to 106 mg l−1 h at doses of 200 mg. Formation of DOPAC was dose‐dependently suppressed, with benserazide 5 mg three times daily already halving its AUC. Conclusions The benserazide‐dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.
Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non‐case study in the French pharmacovigilance system database
Authors: Moore Nicholas , Kreft‐Jais Carmen , Haramburu Françoise , Noblet Catherine , Andrejak Michel , Ollagnier Michel , Bégaud Bernard 
Published: October 2003

Aims To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database. Methods The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non‐case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA). Results 428 of 93338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33–48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25–2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57–112)), disopyramide (OR 32 (22–46)), nifedipine (OR 2.16 (1.32–3.51)), diltiazem (OR 1.76 (1.01–3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16–3.16)) and frusemide (OR 1.89 (1.31–1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5–1.4) and 1.2 (0.7–2.2), respectively). The same was found for other drugs except cibenzoline. Conclusion The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.
Reporting of adverse drug reactions by hospital doctors and the response to intervention
Authors: McGettigan P. , Golden J. , Conroy R. M. , Arthur N. , Feely J. 
Published: October 2003

Aims In Ireland there are relatively fewer adverse drug reaction (ADR/yellow card) reports from doctors in hospital than in general practice. The aim of this study was to review the attitudes to reporting of ADRs of hospital doctors and to determine the effect of making yellow cards freely available. Methods A postal survey of actively practising doctors with follow‐up of non‐responders was undertaken. We addressed the single most frequently claimed deterrent to reporting, unavailability of yellow cards, by making cards prominently available and placing one in patient’s chart upon admission. In addition, doctors were regularly reminded that ADRs should be reported. Results Of 118 hospital based doctors, only 45% had ever reported an ADR. Fewer than 5% of pre‐registration house officers had reported an ADR and the likelihood of reporting increased with seniority and was greater among physicians than surgeons. We found no evidence that doctors had published case reports in place of submitting ADR reports. Over 3 months, the greater availability of yellow cards and reminders about reporting ADRs led to an approximate five‐fold increase in reports but reporting declined rapidly thereafter when verbal reminders were withdrawn, despite continued ready availability of cards suggesting that making cards available alone does not significantly increase reporting. Conclusions This study indicates there may be more fundamental constraints to reporting than attitudinal surveys would suggest and we need to explore additional avenues to ensure a ‘reporting culture’.