bluuebunny/crossref_metadata_2025 huggingface dataset:
Icehouse world sea‐level behaviour and resulting stratal patterns in late Visean (Mississippian) carbonate platforms: integration of numerical forward modelling and outcrop studies
Authors: Barnett A. J. , Burgess P. M. , Wright V. P.
Published: March 2003

Late Visean (Asbian–Brigantian) platform carbonates in the British Isles show a pronounced cyclicity marked by the alternation of mainly subtidal carbonates and subaerial exposure surfaces. Whereas the cyclicity of shallow‐water limestones of this age has been well‐documented, there has been little attempt to understand the controls on larger‐scale patterns such as those recognized in Pennsylvanian successions in the U.S.A. The principal aim of this study is to test two contrasting theories of cycle stacking via numerical forward modelling. Earlier studies of Pennsylvanian‐early Permian platform carbonates in south‐west U.S.A. suggest that cycle stacking patterns were controlled by the interaction of third‐ and fourth‐order sea‐level oscillations, with relatively uniform fourth‐order oscillations altered mainly by the harmonic effect of lower‐order sea‐level changes. An alternative model is based on an insolation curve for the Carboniferous calculated using Milankovitch parameters. This model predicts a considerable variability in levels of solar insolation that would have affected the amplitude of fourth‐order sea‐level changes and cycle composition. Both of these ideas were examined via numerous model runs using CARBONATE 6.0 and a new program, CARBOSMUT. Model results were evaluated through the use of 3 key criteria derived from well‐documented outcropping stratigraphies in the U.K.: (1) cycle stacking patterns and the stratigraphic position of major transgressions, (2) stratigraphic position of major faunal changes, (3) degree of development of subaerial exposure surfaces. Computer simulations and comparison with outcrop data suggest that a model invoking the interaction of relatively uniform fourth‐ (c.100 Kyr) and third‐order sea‐level oscillations is most appropriate for much of the late Visean, with major lowstands occurring at the mid‐Asbian and Asbian–Brigantian boundary. Late Visean cycles are important exploration targets in the Pri‐Caspian Basin, Kazakhstan and understanding the controls on stratal patterns is important as a potential exploration tool.
Adverse effects of a single dose of (+)‐sotalol in patients with mild stable asthma
Authors: Devereux G. , Fishwick K. , Aiken T. C. , Bourke S. J. , Hendrick D. J.
Published: March 2003

Aims
 To investigate the effect of (+)‐sotalol, which is not thought to possess clinically significant β‐adrenoceptor blocking activity, on airway responsiveness in subjects with mild asthma.

Methods
 A placebo controlled, double‐blind, single dose, cross over study, evaluating the effects of oral (+)‐sotalol 300 mg and oral (±)‐sotalol 240 mg, on airway responsiveness, FEV1, and heart rate in 18 asthmatic volunteers with quantifiable levels of airway responsiveness.

Results
 Compared with placebo, (+)‐sotalol induced a significant increase in airway responsiveness, and a significant decrease in FEV1, but there was no significant change in heart rate. Following (±)‐sotalol there was no significant effect on airway responsiveness, but there were significant decreases in FEV1 and heart rate. In one subject both (+)‐sotalol and (±)‐sotalol provoked a 49% decrement in FEV1, and in another there were decrements of 20% and 18%, respectively.

Conclusions
 Despite theoretical considerations, it cannot be assumed that (+)‐sotalol is safe in patients with asthma.
Dihydropyrimidine dehydrogenase pharmacogenetics in Caucasian subjects
Authors: Ridge Susan A. , Sludden Julieann , Brown Oliver , Robertson Leigh , Wei Xiaoxiong , Sapone Andrea , Fernandez‐Salguero Pedro M. , Gonzalez Frank J. , Vreken Peter , Van Kuilenburg Andre BP , Van Gennip Albert H. , McLeod Howard L.
Published: March 2003

Aims
 Dihydropyrimidine dehydrogenase (DPD) catalyses the reduction of pyrimidines, including the anticancer agent 5‐fluorouracil (5FU). Impaired 5FU degradation, through low DPD activity, has led to severe, life‐threatening or fatal toxicity after administration of 5FU. Complete DPD deficiency is associated with the inherited metabolic disease thymine uraciluria. Several mutations in the gene encoding DPD have recently been identified, but the phenotype‐genotype concordance of these alterations in the general population has not been reported.

Methods
 Mononuclear cells were isolated from whole blood and DPD activity was determined after ex vivo incubation with 14C‐5FU followed by h.p.l.c. analysis of 5FU metabolites. Analysis of mutations in the DPD gene at an exon splice site, codons 534, 543, and 732, and a deletion at base 1897 (ΔC1897) were performed in 30 subjects with the lowest and 30 subjects with the highest enzyme activity using PCR‐RFLP.

Results
 DPD activity was measured in 226 Caucasian subjects and was highly variable (range 19.1–401.4 pmol min−1 mg−1 protein). Mutations were frequently observed at codons 543 (allele frequency 28%), 732 (allele frequency 5.8%), and 534 (allele frequency 0.8%), but were not associated with low DPD activity. There were no splice site or ΔC1897 mutations found in this population.

Conclusions
 The five mutations analysed in this study are insufficient for identification of patients at risk for 5FU toxicity or thymine uraciluria. Both the splice site mutation and ΔC1897 are relatively rare in the general Caucasian population. Therefore, identification of further molecular alterations is required to facilitate the use of DPD analysis in genetic diagnosis and cancer therapeutics.
Paracetamol metabolism in patients with ulcerative colitis
Authors: Haderslev  , Sonne  , Poulsen  , Loft
Published: March 2003

Aims The capacity for sulphation of phenols appears to be impaired in the colonic mucosa of patients with ulcerative colitis. The aim of the present study wasto investigate the systemic capacity for sulphation of phenols in patients with ulcerative colitis assessed by the metabolic clearances of paracetamol to the sulphate, glucuronide and glutathione derived metabolites.

Methods Ten patients with ulcerative colitis and 10 control subjects received a single oral dose of paracetamol (1 g). Venous blood samples were collected frequently for pharmacokinetic determinations (one compartment model). Urine was collected for 24 h. Plasma samples were analysed for parent drug and urine samples for parent drug and metabolites by h.p.l.c. Partial metabolic clearances were calculated as the fractional urinary recovery of each conjugate multiplied by the apparent oral clearance of paracetamol.

Results The apparent oral clearance of paracetamol and the partial clearances of its metabolites were not significantly different between the two study groups. Median value and the corresponding 25th and 75th percentiles for the clearance of the sulphate metabolites were 93.6 (82.5–138.8) ml kg−1 h−1 and 77.4 (75.5–99.1), patients with ulcerative colitis and control subjects, respectively.

Conclusions These results do not indicate a general impairment of the systemic capacity for sulphation of paracetamol in patients with ulcerative colitis.
Endogenous angiotensin II and baroreceptor dysfunction: a comparative study of losartan and enalapril in man
Authors: Yee  , Struthers
Published: March 2003

Aims To assess the role of direct AT1 receptor antagonism in baroreceptor modulation in man, and to perform a direct comparison of Ang II blockade at the receptor level with that of ACE inhibition.

Methods Ten healthy male volunteers [mean age (s.d.) 23 (6.9)] pretreated with frusemide therapy (40 mg day−1 for 3 days prior to each visit) were studied on 3 separate days, 10 days apart, in a placebo‐controlled, randomized, double‐blind, cross‐over fashion. On each study day, subjects were randomly given either a single‐dose of enalapril 20 mg, losartan 50 mg or placebo. Baroreceptor function was assessed by measuring changes in blood pressure (BP), pulse interval (RR Int) and heart rate (HR) in response to incremental doses of intravenous phenylephrine infusions (0.2–3.6 μg kg−1 min−1 ).

Results In response to phenylephrine, no significant differences in BP responses were observed with any of the study medications but reflex heart rate responses were significantly increased with both enalapril and losartan compared with placebo (P<0.05). The (RR/ΔsBP ratio, taken as a measure of baroreceptor sensitivity (BRS) was significantly increased with enalapril [12.2+4.6 ms mmHg−1 (mean+s.d.)] and losartan [11.9+3.6 ms mmHg−1] compared with placebo [9.2+4.5 ms mmHg−1]; i.e. enalapril and losartan increased the (RR/(ΔsBP ratio by 3.0 ms mmHg−1 (95%CI 0.5, 5.6; P<0.05) and 2.8 ms mmHg−1 (95%CI 0.6, 5.0; P<0.038), respectively. There were however, no significant differences between losartan and enalapril [mean difference 0.25 (95%CI −1.6, 2.1)].

Conclusions The present study confirms observations from animal models that blocking endogenous angiotensin II in man improves baroreceptor function. Both strategies, AT1 receptor antagonism and ACE inhibition appear to be equally effective in restoring baroreceptor function in salt‐depleted normotensive subjects.
Concurrent administration of donepezil HCl and theophylline: assessment of pharmacokinetic changes following multiple‐dose administration in healthy volunteers
Authors: Tiseo  , Foley  , Friedhoff
Published: March 2003

Aim The aim of the study was to evaluate the pharmacokinetics of theophylline administered alone, and in combination with donepezil HCl, following multiple‐dose administration of both drugs in healthy volunteers.

Methods This was an open‐label, randomized, two‐period crossover study in healthy male volunteers (n=12). During each treatment period, subjects received either titrated‐dose theophylline alone, or in combination with donepezil (5 mg, once daily) for 10 consecutive days. On day 10 of each treatment period, serial blood samples for the determination of theophylline concentrations in plasma were measured up to 24 h. Treatment periods were separated by a 3‐week, drug‐free washout. Plasma concentrations of theophylline were determined by HPLC with UV detection.

Results No statistically significant differences in theophylline pharmacokinetics (Cmax, AUC or tmax ) were observed between theophylline administered alone and in combination with donepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed in any subject during any treatment period.

Conclusions Concurrent administration of donepezil HCl does not alter the pharmacokinetic profile of theophylline following multiple‐dose administration of both drugs in healthy volunteers. These findings suggest that donepezil may be safely co‐administered with theophylline without a need for dose modification or additional monitoring procedures.
An evaluation of the pharmacokinetics of donepezil HCl in patients with impaired hepatic function
Authors: Tiseo  , Vargas  , Perdomo  , Friedhoff
Published: March 2003

Aim The aim of this study was to evaluate the pharmacokinetic profile of donepezil HCl (5 mg) in patients with impaired hepatic function, following the administration of single oral doses.

Methods This was an open‐label, non‐randomized study comparing the pharmacokinetic profile of donepezil in male volunteers with chronic compensated cirrhosis of the liver (n=10) to that in healthy age‐ and sex‐matched controls (n=10). Each subject received a single 5 mg oral dose of donepezil. Blood samples for pharmacokinetic analyses were taken at specified intervals up to 120‐h post‐dose. Concentrations of donepezil in plasma were determined by HPLC with UV detection.

Results No statistically significant differences in donepezil pharmacokinetics were observed between hepatically impaired patients and normal subjects, with the exception of Cmax. The hepatically impaired patients showed a statistically significant, but not clinically significant, higher mean Cmax value of 6.6 ng ml−1 compared with the control group, which had a mean Cmax value of 4.8 ng ml−1 (P=0.022). This represented an increase of 37.5%. The observed changes in AUC values were smaller and not statistically different. The AUC(0–120) and AUC(0–∞) were 7% and 21% larger in the hepatically impaired patients than in the normal subjects, respectively, although clearance and volume of distribution were almost identical in the two groups. The t½ increased by 20%, but this change was also not statistically significant. Donepezil was equally well tolerated by all subjects.

Conclusions This study demonstrates that compromised hepatic function does not produce clinically significant changes in the pharmacokinetics of donepezil following single‐dose administration. These results suggest that the administration of donepezil to patients with hepatic disease in clinical practice should not require any dosing modifications.
An evaluation of the pharmacokinetics of donepezil HCl in patients with moderately to severely impaired renal function
Authors: Tiseo  , Foley  , Friedhoff
Published: March 2003

Aim The aim of this study was to evaluate the pharmacokinetics of donepezil HCl (5 mg) in patients with moderately to severely impaired renal function (creatinine clearance: <30 ml min−1 1.73 m−2 ), following the administration of single oral doses.

Methods This was an open‐label, non‐randomized study in patients with compromised renal function (n=11), and in age‐ and gender‐matched healthy controls (n=11). Each subject received a single oral dose of 5 mg donepezil. Blood samples for pharmacokinetic measurements were taken at specified intervals for 17 days post‐dose. Concentrations of donepezil in plasma were measured by HPLC with UV detection.

Results There were no statistical differences between the two groups for any of the pharmacokinetic parameters evaluated (ANOVA ). Cmax (mean±SD) was 7.7±1.2 ng ml−1 in healthy subjects and 8.3±3.2 ng ml−1 in renally impaired patients. AUC(0–∞) in healthy subjects and in renally impaired patients was 539±115 ng h ml−1 and 640±150 ng h ml−1, respectively. The mean half‐life of donepezil was 86.7±23.3 h in healthy subjects and 91.3±40.9 h in the renally impaired patients. The drug was well tolerated by all study participants. There were no clinically significant changes in vital signs, clinical chemistry or ECG parameters.

Conclusions These findings suggest that the pharmacokinetics of donepezil do not change in patients with moderately to severely impaired renal function.
Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions
Authors: Naldi Luigi , Conforti Anita , Venegoni Mauro , Grazia Troncon Maria , Caputi Achille , Ghiotto Elisabetta , Cocci Alfredo , Moretti Ugo , Velo Giampaolo , Leone Roberto
Published: March 2003

Aims Cutaneous manifestations are frequently reported in association with drug use. The aim of this study was to analyse the skin reactions reported to the spontaneous surveillance systems of four Italian regions (Friuli Venezia Giulia, Lombardy, Sicily and the Veneto), and correlate the reports with estimated drug consumption during the same period, paying particular attention to the reactions to antimicrobial agents and nonsteroidal anti‐inflammatory drugs (NSAIDs).

Methods All of the adverse drug reactions (ADRs) reported spontaneously between January 1996 and December 1997 to the surveillance systems of four Italian regions (a total population of about 20 million people) were analysed by a panel of experts including dermatologists. On the basis of the Critical Term List of the World Health Organization (WHO), the reactions were classified as either serious or nonserious events. Drug consumption was expressed as a daily defined dose (DDD)/1000 inhabitants/day.

Results A total of 2224 adverse skin reaction reports (44.7% of all of the reported ADRs) were identified, making a reporting rate of about 5.5 per 100 000 inhabitants/year. The female/male ratio was 1.58, and the reporting rate progressively increased with age. The drug categories with the highest number of cutaneous reactions were antimicrobials, followed by NSAIDs, analgesics and radiology contrast media. There was a total of 372 (16.9%) serious reaction reports, the most frequent being angioedema (171 cases), erythema multiforme (68 cases) and photosensitivity (37 cases). Co‐trimoxazole, followed by the cephalosporins and fluoroquinolones, were associated with the highest consumption‐related reporting rate among the antimicrobials, and aspirin and dipyrone among the NSAIDs and analgesics.

Conclusions Spontaneous reports from four Italian regions revealed that the skin was the organ most frequently affected by ADRs. The paper shows the validity of a regional decentralized system in Italy.
Pharmacokinetics of intravenous and oral L‐arginine in normal volunteers
Authors: Tangphao† Oranee , Grossmann‡ Matthias , Chalon§ Stephan , Hoffman Brian B. , Blaschke Terrence F.
Published: March 2003

Aims Recent studies in patients with cardiovascular diseases suggest potential for the use of orally administered l‐arginine, the precursor of nitric oxide, as a therapeutic agent. This crossover study was designed to examine the pharmacokinetics of single i.v. and oral doses of l‐arginine in healthy volunteers (n=10).

Methods A preliminary control study (n=12) was performed to assess the variation in plasma l‐arginine concentrations when ingesting a normal diet. The observed variation was taken into account when interpreting the pharmacokinetic data obtained after exogenous administration.

Results The mean baseline plasma concentration of l‐arginine in the control study was 15.1±2.6 μg ml−1. After intravenous administration (30 g over 30 min), the plasma concentration reached 1390±596 μg ml−1. The disappearance of l‐arginine appeared biphasic, with an initial rapid disappearance due to concentration‐dependent renal clearance followed by a slower fall in plasma concentrations due to nonrenal elimination. The peak concentration after oral administration (10 g) was 50.0±13.4 μg ml−1, occurring 1 h after administration. Renal elimination was not observed after oral administration of this dose. The absolute bioavailability of a single oral 10 g dose of l‐arginine is ≈20%.

Conclusions This study provides basic knowledge of l‐arginine pharmacokinetics in healthy humans. Intravenous and oral administrations show at minimum a biphasic pattern. Further studies will assess whether a similar profile is observed when the drug is administered to patients.
Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs
Authors: José de Abajo Francisco , Rodríguez Luis Alberto García
Published: March 2003

Aims To quantify and compare the incidence of ventricular arrhythmias associated with the use of five nonsedating antihistamines: acrivastine, astemizole, cetirizine, loratadine and terfenadine. The effects of age, sex, dose, duration of treatment, and the interaction with P450 inhibitor drugs were also examined.

Methods We carried out a cohort study with a nested case‐control analysis using the UK‐based General Practice Research Database (GPRD). The study cohort included persons aged less than 80 years old who received their first prescription for any of the five study drugs between January 1, 1992 and September 30, 1996. We estimated relative risks and 95% confidence intervals of idiopathic ventricular arrhythmias with current use of antihistamines as compared with non use.

Results The study cohort included 197 425 persons who received 513 012 prescriptions. Over the study period 18 valid cases of idiopathic ventricular arrhythmias were detected. Nine occurred during the current use of any antihistamine, resulting in a crude incidence of 1.9 per 10 000 person‐years (95%CI: 1.0–3.6) and a relative risk of 4.2 (95%CI: 1.5–11.8) as compared with non use. Astemizole presented the highest relative risk (RR=19.0; 95%CI: 4.8–76.0) of all study drugs, while terfenadine (RR=2.1; 95%CI:0.5–8.5) was in the range of other nonsedating antihistamines. Older age was associated with a greater risk of ventricular arrhythmias (RR=7.4; 95%CI: 2.6–21.4) and seemed to increase the effect of antihistamines (RR=6.4; 95%CI: 1.7–24.8). The proportions of high dose terfenadine and the concomitant use with P450 inhibitors among current users of terfenadine were 2.7% and 3.4%, respectively over the study period with no single case of ventricular arrhythmias occurring in the presence of these two risk factors.

Conclusions The use of nonsedating antihistamines increases the risk of ventricular arrhythmias by a factor of four in the general population. Yet, the absolute effect is quite low requiring 57 000 prescriptions, or 5300 person‐years of use for one case to occur. The risk associated with terfenadine was no different from that with other nonsedating antihistamines.
Impaired β‐adrenoceptor mediated venodilation in patients with diabetes mellitus
Authors: Harada Kazuhiro , Ohmori Masami , Kitoh Yasuhiko , Sugimoto Koh‐ichi , Fujimura Akio
Published: March 2003

Aims We investigated whether venoconstriction by α‐adrenoceptor stimulation, and venodilation by β‐adrenoceptor stimulation and nitroglycerin are altered in patients with diabetes mellitus (DM).

Methods Eight male patients with non insulin‐dependent DM and eight age‐matched control subjects were included. The patients had neither hypertension nor hyperlipidaemia. Noradrenaline (1 to 512 ng min−1 ), isoprenaline (1 to 256 ng min−1 ) and nitroglycerin (0.5 to 128 ng min−1 ) were infused into a dorsal hand vein and its diameter was measured using a linear variable differential transformer.

Results The venoconstricting response to noradrenaline and the venodilating response to nitroglycerin in DM patients were similar to those in control subjects, while the venodilation by isoprenaline was significantly (P<0.05) smaller in DM patients than in control subjects at the dose of 32 ng min−1 or more [32 ng min−1: 11.5%vs 29.8% (DM vs control subjects), 64 ng min−1: 19.0%vs 40.1%, 128 ng min−1: 25.2%vs 49.0%, 256 ng min−1: 34.3%vs 56.7%].

Conclusions These data suggested that venoconstriction by α‐adrenoceptor stimulation and venodilation by nitroglycerin are not altered, whereas venodilation by β‐adrenoceptor stimulation might be impaired in patients with DM.
The influence of CYP2D6 activity on the kinetics of propafenone enantiomers in Chinese subjects
Authors: Cai  , Chen  , Cai  , Chen  , Zhang
Published: March 2003

Aims To determine role of CYP2D6 activity in the pharmacokinetics of propafenone (PPF) enantiomers in native Chinese subjects.

Methods Sixteen extensive metabolizers (EMs) and one poor metabolizer (PM), whose phenotype had been previously assessed with dextromethorphan metabolic phenotyping, were enrolled. Blood samples (0~15 h) were taken after oral administration of a single dose (400 mg) of racemic‐propafenone hydrochloride. A reverse‐phase h.p.l.c. method with pre‐column derivatization was employed to quantitate enantiomeric concentrations of propafenone in plasma.

Results For the EM subjects, S‐PPF was less rapidly metabolized and had higher peak plasma concentrations than R‐PPF (413±143 vs 291±109 ng ml−1, P<0.001). The AUC was markedly higher for S‐PPF than for R‐PPF (2214±776 vs 1639±630 μg h l−1, P<0.001), whereas the clearance of S‐PPF was significantly lower than that of R‐PPF (96.0±39.0 vs 138±78 l h−1, P<0.01). There were no differences in t1/2, and Cmax between the two isomers (P >0.05). In the one PM subject, not only did S‐PPF appear to undergo less rapid metabolism than R‐PPF, but the subject also showed 2~3 fold differences in Cmax, CL and AUC compared with EMs. The correlation coefficients (rs ) between dextromethorphan metabolic ratio (lg MR) and pharmacokinetic parameters (Cmax, CL and AUC) were 0.63, −0.87, 0.87 for S‐PPF and 0.57, −0.73, 0.86 for R‐PPF, respectively.

Conclusions Our results suggest that CYP2D6 activity contributes to the pharmacokinetic variability of propafenone enantiomers in Chinese subjects.
Signalling possible drug–drug interactions in a spontaneous reporting system: delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole
Authors: Van Puijenbroek Eugène P. , Egberts Antoine C. G. , Meyboom Ronald H. B. , Leufkens Hubert G. M.
Published: March 2003

Aims In spontaneous adverse drug reaction reporting systems, there is a growing need for methods facilitating the automated detection of signals concerning possible adverse drug reactions. In addition, special attention is needed for the detection of adverse drug reactions resulting from possible drug‐drug interactions. We describe a method for detecting possible drug‐drug interactions using logistic regression analysis to calculate ADR reporting odds ratios.

Methods To illustrate this method, we analysed the adverse drug reaction ‘delayed withdrawal bleeding’ resulting from a possible interaction between itraconazole and oral contraceptives in reports received by the Netherlands Pharmacovigilance Foundation LAREB between 1991 and 1998.

Results In total 5,503 reports were included in the study. The odds ratio, adjusted for year of reporting, age and source of the reports, for a delayed withdrawal bleeding in women who used both drugs concomitantly compared with women who used neither oral contraceptives, nor itraconazole, was 85 (95% CI: 32–230).

Conclusions Since spontaneous reporting systems can only generate signals concerning possible relationships, this association needs to be analysed by other methods in more detail in order to determine the real strength of the relationship. This approach might be a promising tool for the development of procedures for automated detection of possible drug‐drug interactions in spontaneous reporting systems.
Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide
Authors: Abel Samantha , Nichols Donald J. , Brearley Christopher J. , Eve Malcolm D.
Published: March 2003

Aims The aim of this open‐label, placebo‐controlled, randomized, four‐period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide.

Methods Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 μg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1–2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three‐lead electrocardiograms.

Results Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose‐dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration‐time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide‐induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml−1 increase in plasma dofetilide concentration produced a 17–19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment‐related adverse events or laboratory abnormalities.

Conclusions These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H2‐receptor antagonist class effect but is specific to cimetidine. If therapy with an H2‐receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative.
The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine
Authors: Stuart‐harris R. , Joel S. P. , McDonald P. , Currow D. , Slevin M. L.
Published: March 2003

Aims
 To investigate the pharmacokinetics of morphine, morphine‐6‐glucuronide (M6G) and morphine‐3‐glucuronide (M3G) in healthy volunteers after the administration of morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c.i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of morphine.

Methods
 Six healthy volunteers each received 5 mg morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for morphine, M6G and M3G.

Results
 After i.v. morphine, the concentrations of morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l− 1, for a 10 mg dose to a 70 kg subject). After s.c.b. morphine, similar results were obtained except that the median tmax values for morphine and M3G were significantly longer than after i.v. morphine (P< 0.001 and P< 0.05, respectively), with a trend to a longer tmax for M6G (P= 0.09). The appearance half‐lives after s.c.b. morphine for M6G and M3G were also significantly longer than after i.v. morphine (P= 0.03 and P< 0.05, respectively). Comparison of log‐transformed AUC values indicated that i.v. and s.c.b. administration of morphine were bioequivalent with respect to morphine, M6G and M3G. In comparison with i.v. morphine, morphine by s.c.i. was associated with significantly longer median tmax values for morphine (P< 0.001), M6G (P< 0.001) and M3G (P< 0.05), and the mean standardized Cmax values significantly lower than after both i.v. and s.c.b. morphine (morphine P< 0.001, M6G P< 0.001 and M3G P< 0.01 for each comparison). Comparison of log‐transformed AUC values after i.v. and s.c.i. morphine indicated that the two routes were not bioequivalent for morphine (log‐transformed AUC ratio 0.78, 90% CI 0.66–0.93), M6G (0.72, 90% CI 0.63–0.82), or M3G (0.65, 90% CI 0.54–0.78). A small stability study indicated no evidence of adsorptive losses from morphine infused over 4 h using the infusion devices from the study.

Conclusions
 Although bioequivalence was demonstrated between the s.c.b. and i.v. routes of morphine administration, the bioavailabilities of morphine, M6G and M3G after s.c.i. were significantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of morphine.
The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function
Authors: Everson G. , Lasseter K. C. , Anderson K. E. , Bauer L. A. , Carithens R. L. , Wilner K. D. , Johnson A. , Anziano R. J. , Smolarek T. A. , Turncliff R. Z.
Published: March 2003

Aims  To assess whether hepatic impairment influences the pharmacokinetics of ziprasidone.

Methods  Thirty subjects with normal hepatic function or a primary diagnosis of clinically significant cirrhosis (Child‐Pugh A or B) were enrolled into an open‐label, multicentre, multiple‐dose study. The subjects with chronic, stable hepatic impairment and the matched control subjects received ziprasidone 40 mg day− 1, given orally with food, as two divided daily doses for 4 days and a single 20 mg dose on the morning of day 5. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 5. Liver function was evaluated quantitatively using antipyrine.

Results  On day1 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax) of ziprasidone between the two groups. On day 5 there were no statistically significant differences in the Cmax or tmax for ziprasidone between the two groups. The mean AUC(0,12 h) for ziprasidone was statistically significantly greater in the hepatically impaired subjects compared with the normal subjects (590 ng ml− 1 h vs 467 ng ml− 1 h, P= 0.042). However, the AUC(0,12 h) increased by only 26% in the cirrhotic group compared with the matched control group. The ziprasidone λz in the subjects with normal hepatic function was statistically significantly greater than that in the hepatically impaired subjects (P< 0.001). There was no correlation between antipyrine λz and ziprasidone λz in the subjects with normal hepatic function or in those with hepatic impairment.

Conclusions  The findings of this study indicate that mild to moderate hepatic impairment does not result in clinically significant alteration of ziprasidone pharmacokinetics.
Interaction between the LMWH reviparin and aspirin in healthy volunteers
Authors: Klinkhardt, Ute , Breddin, Hans Klaus , Esslinger, Heinz Ulrich , Haas Silvia , Kalatzis Andreas , Harder Sebastian
Published: March 2003

Aims
To investigate potential interactions between reviparin and acetylsalicylic acid (ASA 300 mg o.d. from day 1–5).

Methods
In an open, randomized, three‐way‐cross over study nine healthy volunteers received reviparin (s.c. injection of 6300 anti‐Xa units) or placebo from days 3 to 5 and acetylsalicylic acid (ASA 300 mg) or placebo from days 1 to 5. Assessments included bleeding time (BT), collagen (1 µg ml−1) induced platelet aggregation (CAG), heptest, plasma antifactor Xa‐activity and activated partial thromboplastin time (aPTT).

Results
Median bleeding time at day 5 was 5.5 min after reverparin alone and after ASA alone and was 9.6 min after the combination of reviparin and ASA. ASA treatment reduced CAG from 84% to 40 to 50% of Amax; values after combined treatment of reviparin with ASA were not different from those after ASA alone. aPTT was prolonged to 32 s after reviparin; this effect was not modified if subjects received ASA. Combined treatment with ASA and reviparin had no effect on plasma anti‐Xa‐activity and heptest compared with reviparin alone.

Conclusions
We could not entirely exclude a small interaction between reviparin and ASA on bleeding time, but the effect is probably without clinical significance.
Nonprescription medicine use in a multiple sclerosis clinic population
Authors: Tremlett H. L. , Wiles C. M. , Luscombe D. K.
Published: March 2003

Aims
To determine the use of nonprescription medicines in a cohort of multiple sclerosis (MS) patients and to identify a subgroup of patients liable to spend more on nonprescription medicines

Methods
A questionnaire was given to MS patients attending a neurology out‐patients clinic during the previous year. Medicines from a General Practitioner (GP), pharmacy and ‘other’ sources utilized in the last month were determined, along with demographic data. Additional information was obtained from hospital notes.

Results
One hundred and seventeen MS patients responded to the questionnaire, giving a response rate of 79% (117/148). Responders differed from nonresponders only in age, with responders being significantly older than nonresponders (P = 0.011). Over one‐third of medicines taken in the last month were nonprescription medicines (35%; 219/627). A gamolenic acid containing preparation was the most popular, purchased by 28% of patients. Fifteen percent (17/117) of MS patients had exceeded the recommended daily allowance of a vitamin (frequently vitamins A, D and E), and one exceeded the upper safe level for daily self‐supplementation of vitamin A and D. Females spent significantly more than males in the previous month (£10.09 compared with £5.53, respectively; P = 0.022). Patients who were older, reported worsening MS symptoms in the last year and those who exhibited greater disability were more likely to have been prescribed medicines by a GP (P < 0.0005), although they were not more likely to self‐prescribe or take alternative remedies (P > 0.05). However, those with poorer mobility were significantly less likely to have purchased a pharmacy medicine in the last month (P = 0.033).

Conclusions
MS patients were high users of nonprescription medicines. A typical subgroup of MS patients that spent more on nonprescription medicines could not be identified, aside from females. Furthermore, the strong predictors for increased use of prescription medicines (increasing age, severity of symptoms in the last year and poorer mobility) were not found for nonprescription medicines. Excessive intake of the fat soluble vitamins could lead to hypervitaminosis, the effects of which could exacerbate or mimic MS symptoms. Health professionals should be aware of these issues and counsel the MS patient accordingly, particularly as the majority purchased products from ‘other’ sources where typically there is no health‐professional available to give advice. The limited use of pharmacy medicines by the more disabled patient could indicate a problem with access to the pharmacy, or could reflect the greater use of prescription medicines.
The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies
Authors: Martin Richard M. , Dunn Nicholas R. , Freemantle Shayne , Shakir Saad
Published: March 2003

Aims
To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England.

Methods
In prescription‐event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied.

Results
The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0.18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0.17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age‐response relationship.

Conclusions
Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly.
Effects of high ambient temperature on parasympathetically mediated cardiovascular reflexes in normal man
Authors: Banjar W. M. A. , Gazzaz J. , Langley R. W. , Bradshaw C. M. , Szabadi E.
Published: March 2003

Aims
To examine the effects of high ambient temperature (‘heat stressor’) on parasympathetically mediated cardiovascular reflexes (power of respiratory sinus dysrhythmia; change in heart rate elicited by change in posture from lying to standing [‘30 : 15 ratio’]).

Methods
Twelve healthy male volunteers participated in four weekly sessions, each of which was associated with one treatment condition (placebo at an ambient temperature of 22 °C; propranolol 40 mg at 22 °C; placebo at 40 °C; propranolol 40 mg at 40 °C), according to a balanced double‐blind design. Heart rate was recorded by ECG, finger tremor (7–12 Hz) with an accelerometer strapped to the middle finger of the nondominant hand, and sublingual temperature by a mercury thermometer. Power of finger tremor and the variations of the R‐R intervals of the ECG were obtained from Fourier transformations of the data. Data were analysed by analysis of variance, with repeated measures using a significance criterion of P < 0.05; individual comparisons of active treatment with placebo and of data obtained at 40 °C with those obtained at 22 °C were made with Fisher's Least Significant Difference test.

Results
Heart rate was increased by the heat stressor, and this increase was abolished by propranolol. The heat stressor reduced the power of respiratory sinus dysrhythmia and the 30 : 15 ratio, and increased the power of physiological finger tremor. Propranolol did not affect heat stressor‐induced changes in the parasympathetic cardiac reflexes, but reduced the heat stressor‐induced enhancement of finger tremor.

Conclusions
The increase in the power of physiological finger tremor at high ambient temperature is consistent with sympathetic activation, whereas the reduction in the power of respiratory sinus dysrhythmia and 30 : 15 ratio indicates a decrease in parasympathetic activity. These results demonstrate that high ambient temperature may induce vagal withdrawal in the heart.
Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease
Authors: Cullberg Marie , Eriksson Ulf G. , Larsson Marita , Karlsson Mats O.
Published: March 2003

Aims  The purpose of this study was to characterize the relationship between the degree of anticoagulation, assessed by APTT, and the plasma concentration of inogatran in healthy subjects and in patients with coronary artery disease.

Methods  Data from five phase I studies in 78 healthy males and two phase II multicentre studies in 948 patients of both sexes with unstable angina pectoris or non‐Q‐wave myocardial infarction were evaluated. A total of 3296 pairs of concentration‐APTT samples were obtained before, during, and after intravenous infusions of inogatran. Mixed effects modelling was used for population pharmacodynamic analysis of the drug effect and for describing the variability in baseline APTT.

Results  The population mean baseline APTT was 29 s, but large variations between individuals (s.d. 3.6 s) were observed. The variability between studies (1.3 s) and centres (1.8 s) were of less importance, though statistically significant. APTT increased in a nonlinear manner with increasing inogatran concentration and the relationship was well described by a combined linear and Emax model. A significant part of the overall variability could be ascribed to the APTT reagent and equipment used at the different study centres. These method‐dependent differences were compensated for by including the lower limit of the normal reference range as a covariate, affecting both baseline and Emax, in the model. For the typical healthy subject and patient, the method‐corrected population mean parameters were: APTTbaseline 35 and 31 s, slope 8.0 and 5.8 s l µmol−1, Emax 36 and 34 s, and EC50 0.54 and 0.72 µmol l−1, respectively. The model predicted plasma concentration needed to double the APTT from the baseline value was 1.25 and 1.45 µmol l−1 in the healthy volunteer and patient, respectively.

Conclusions  The nonlinear relationship between APTT and inogatran concentration in plasma was well described by a combined linear and Emax model. Pooling of data was made possible by incorporating a centre‐specific characteristic of the assay method in the model. Patients had lower baseline APTT and appeared to have less pronounced effect of inogatran than young healthy subjects.
Effects of nociceptin and endomorphin 1 on the electrically stimulated human vas deferens
Authors: Bigoni Raffaella , Calo Girolamo , Guerrini Remo , Strupish James W. , Rowbotham David J. , Lambert David G.
Published: March 2003

Aims  To examine the effects of nociceptin (NC) and endomorphin 1 (EM1) on electrical field stimulation (EFS)‐induced contractions of the human vas deferens (hVD).

Methods  Concentration‐response curves to NC and EM1 were constructed in the absence and in presence of peptidase inhibitors (PI). In some experiments a NC receptor antagonist, [Phe1ψ(CH2‐NH)Gly2]NC(1–13)NH2 [F/G], 10 µm) or naloxone (1 µm) were included.

Results  All data are mean(95%CI). In the presence of PI, NC inhibited twitches (Emax=67(44,90)%; pEC50 = 7.28(6.95,7.61)). NC inhibition was sensitive to [F/G]. EM1 also inhibited twitches both in the absence (Emax=82(73,91)% pEC50 = 7.07(6.92,7.22)) and presence (Emax=83(76,90)%; pEC50 = 7.00(6.91, 7.09)) of PI. EM1 inhibition was sensitive to naloxone.

Conclusions  These data suggest that hVD express NC and opioid receptors that inhibit neurogenic contractions.
Frequencies of thiopurine S‐methyltransferase mutant alleles (TPMT*2, *3A, *3B and *3C) in 151 healthy Japanese subjects and the inheritance of TPMT*3C in the family of a propositus
Authors: Kubota T. , Chiba K.
Published: March 2003

Aims  To determine the frequencies of four thiopurine S‐methyltransferase (TPMT) mutant alleles, TPMT*2, *3A, *3B and *3C in a normal Japanese population.

Methods  Genotypes were determined in 151 Japanese subjects and in six family members of a propositus using polymerase chain reaction (PCR)‐restriction fragment length polymorphism and allele‐specific PCR assays.

Results  Only one TPMT*3C heterozygote was identified (gene frequency 0.3%). TPMT*2,*3A and *3B were not detected. In addition, TPMT*3C was found to have been inherited from the mother and passed on to the son of the propositus.

Conclusions  TPMT*3C appears to be most prevalent among the known mutant allele of TPMT in a Japanese population which may have some relevance for the treatment of Japanese patients with thiopurine drugs.