bluuebunny/crossref_metadata_2025 huggingface dataset:
COMT inhibition with tolcapone does not affect carbidopa pharmacokinetics in parkinsonian patients in levodopa/carbidopa (Sinemet®)
Authors: Jorga Karin M. , Nicholl David J.
Published: March 2003

Aims Tolcapone is a novel catechol‐O‐methyltransferase (COMT) inhibitor used as an adjunct to levodopa/carbidopa or levodopa/benserazide therapy to improve treatment of Parkinson’s disease. The aim of the current study was to investigate the potential effect of tolcapone on the pharmacokinetics of carbidopa.

Methods This was an open‐label study in 12 parkinsonian patients receiving optimal levodopa/carbidopa therapy and tolcapone 200 mg three times daily for 6 weeks. Blood samples were taken at baseline (i.e. before the first tolcapone intake) and after 1–2 weeks and 6 weeks so that carbidopa pharmacokinetics before and during tolcapone treatment could be assessed.

Results No changes in any pharmacokinetic parameters of carbidopa were observed. The mean AUC(0,τ) and Cmax values at baseline were 0.39 μg ml−1 h and 0.14 μg ml−1, respectively. During tolcapone treatment these values were on average 0.35 μg ml−1 h (AUC(0,τ), week 1–2), 0.34 μg ml−1 h (AUC(0,τ), week 6 and 0.13 μg ml−1 (Cmax, weeks 1–2 and 6). tmax remained unchanged (approx. 2 h).

Conclusions These results indicate that tolcapone does not affect carbidopa elimination and that no interaction of any clinical relevance occurs between tolcapone and carbidopa.
Short‐term dose‐response relationships for the relative systemic effects of oral prednisolone and inhaled fluticasone in asthmatic adults
Authors: Wilson  , Lipworth
Published: March 2003

Aims To determine the systemic dose–response relationships with oral prednisolone and inhaled fluticasone propionate administered in a putative 11:1 mg equivalent basis, in terms of effects on adrenal, bone and haematological markers.

Methods Twelve asthmatic patients mean (s.e.) age, 28.8 [3.3] years, FEV1 94.7 [3.6]% predicted, FEF25–75 65.5 [6.1]% predicted were studied in a double‐blind, double dummy randomised crossover design comparing placebo, inhaled fluticasone propionate via volumatic spacer given twice a day (ex actuator dose 0.44 mg day−1, 0.88 mg day−1, 1.76 mg day−1 ) and oral prednisolone given once daily (5 mg day−1, 10 mg day−1, 20 mg day−1 ). All treatments were for 4 days at each dose level with a 7‐day washout at crossover. Measurements were made at 08.00 h after the last dose of each dose level for plasma cortisol, serum osteocalcin and blood eosinophil count.

Results There were significant dose‐related effects for suppression of all three endpoints with both prednisolone and fluticasone propionate. Parallel slope analysis revealed a calculated dose ratio for relative potency of 8.5:1 mg (95% CI 5.7–11.2) comparing Pred with FP for morning cortisol. The magnitude of suppression with FP was less for osteocalcin and eosinophils than for cortisol.

Conclusions Systemic tissues exhibit different dose–response relationships for the effects of inhaled and oral corticosteroids with suppression of cortisol being greater than osteocalcin or eosinophils. For cortisol suppression we observed an 8.5:1 mg relative potency ratio comparing prednisolone with fluticasone propionate. Patients taking high dose inhaled fluticasone propionate should therefore be screened for evidence of impaired adrenal reserve.
Fenoterol stimulates human erythropoietin production via activation of the renin angiotensin system
Authors: Freudenthaler  , Schenck  , Lucht  , Gleiter
Published: March 2003

Aims The present study assessed the hypothesis that the β2 sympathomimetic fenoterol influences the production of erythropoietin (EPO) by activation of the renin angiotensin system (RAS), i.e. angiotensin II.

Methods In an open, parallel, randomized study healthy volunteers received i.v. either placebo (electrolyte solution), fenoterol or fenoterol in combination with an oral dose of the AT1‐receptor antagonist losartan.

Results Compared with placebo treatment AUCEPO(0,24 h) was significantly increased after fenoterol application by 48% whereas no increase in the group receiving fenoterol and losartan could be detected. The rise of PRA was statistically significant under fenoterol and fenoterol plus lorsartan.

Conclusions Stimulation of EPO production during fenoterol infusion appears to be angiotensin II‐mediated. Thus, angiotensin II may be considered as one important physiological modulator of EPO production in humans.
Effect of chronic magnesium supplementation on magnesium distribution in healthy volunteers evaluated by 31P‐NMRS and ion selective electrodes
Authors: Wary  , Brillault‐Salvat  , Bloch  , Leroy‐Willig  , Roumenov  , Grognet  , Leclerc  , Carlier
Published: March 2003

Aims The role of magnesium (Mg) intake in the prevention and treatment of diseases is greatly debated. Mg biodistribution after chronic Mg supplementation was investigated, using state‐of‐the‐art technology to detect changes in free ionized Mg, both at extra‐ and intracellular levels.

Methods Thirty young healthy male volunteers participated in a randomised, placebo (P)‐controlled, double‐blind trial. The treated group (MgS) took 12 mmol magnesium lactate daily for 1 month. Subjects underwent in vivo31P‐NMR spectroscopy and complete clinical and biological examinations, on the first and last day of the trial. Total Mg was measured in plasma, red blood cells and 24 h urine ([Mg]U ). Plasma ionized Mg was measured by ion‐selective electrodes. Intracellular free Mg concentrations of skeletal muscle and brain tissues were determined noninvasively by in vivo31P‐NMR at 3T. NMR data were automatically processed with the dedicated software MAGAN.

Results Only [Mg]U changed significantly after treatment (in mmol/24 h, for P, from 4.2±1.4 before to 4.1±1.3 after and, for MgS, from 3.9±1.1 before to 5.1±1.1 after, t=2.15, P=0.04). The two groups did not differ, either before or after the trial, in any other parameter, whether clinical, biological or in relation with the Mg status.

Conclusions Chronic oral administration of Mg tablets to young healthy male volunteers at usual pharmaceutical doses does not alter Mg biodistribution. This study shows that an adequate and very complete noninvasive methodology is now available and compatible with the organization of clinical protocols which aim at a thorough evaluation of Mg biodistribution.
Myocardial region (right or left ventricle) and aetiology of heart failure can influence the inotropic effect of ouabain in failing human myocardium
Authors: Padrini  , Panfili  , Magnolfi  , Piovan  , Casarotto  , Ferrari
Published: March 2003

Aims To investigate whether the inotropic effect of ouabain in failing human myocardium varies according to the heart chamber tested (right or left ventricle) or the aetiology of the heart disease, i.e. ischaemic or idiopathic.

Methods The inotropic effect of ouabain was measured, as the percentage change in baseline tension, in myocardial strips isolated from right (RV; n=21) and left ventricles (LV; n=21) of hearts explanted from patients with idiopathic (IDC; n=11) and ischaemic cardiomyopathy (CAD; n=10). Concentration‐effect curves obtained with ouabain (0.05–1.6 μmol l−1 ) were analysed using the Emax sigmoidal model, and the following parameters were calculated: Emax, EC50, n and EC10 (threshold concentration). The influence of ventricular chamber and heart failure aetiology on these parameters was evaluated by means of a two‐way anova.

Results Age and baseline haemodynamic parameters did not differ between IDC and CAD patients. Baseline strip contractility was highly variable (range: 0.48–10.0 mN), but neither ventricular chamber nor aetiology could explain such variability. A two‐way anova showed that EC10 was greater in CAD than in IDC preparations (0.097±0.013 μmol l−1vs 0.059±0.009 μmol l−1; 95% C.I. for difference 0.043, 0.071) and Emax was lower in RV than in LV (121±21%vs 250±38%; 95% C.I. −221, −36), while EC50 and n were not significantly different between groups.

Conclusions The inotropic effect of ouabain in human myocardium may vary according to aetiology of heart failure and the ventricle being tested. Although our results do not support the hypothesis of increased sensitivity to cardiac glycosides in CAD patients, they may explain the diminished effect observed in patients with RV failure.
Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow‐up study
Authors: Lim  , Jung  , MacDonald
Published: March 2003

Aims Aldosterone/renin ratio is an index for inappropriate aldosterone activity, and it is increasingly being used to screen for primary aldosteronism within the hypertensive population. It may also be a good index to help predict the response to spironolactone. To assess the blood pressure response to oral spironolactone in hypertensive patients with primary aldosteronism identified with raised aldosterone to renin ratio.

Methods We conducted a prospective cohort study of hypertensive patients with raised aldosterone/renin ratio, who failed to suppress plasma aldosterone with salt loading and fludrocortisone suppression test. These patients were treated with spironolactone and were followed‐up for a period of up to 3 years.

Results We studied 28 (12 male) subjects with a mean age of 55 (s.d. 10) years who were followed up for a mean period of 12.9 (7) months. At baseline, the patients were taking a mean of 2.1 (1.2) antihypertensive drugs, but despite this 16/28 (57%) had diastolic BP >90 mmHg, 39% with systolic BP >160 mmHg. After commencing spironolactone, three patients complained of breast tenderness but continued treatment and one patient was intolerant of spironolactone and had to stop treatment. Of the remaining 27 patients, the mean number of antihypertensive drugs used dropped to spironolactone plus 0.7 (s.d. 0.9). All but one patient (96%) achieved a diastolic BP≤90 mmHg and 78% achieved a systolic BP≤160 mmHg. In total 48% had BP≤140/90 mmHg and 13/27 (48%) were treated with spironolactone monotherapy. Assessing only patients on drug treatment at baseline (n=24), spironolactone significantly reduced the need for antihypertensive drugs by −0.5 (CI 0.1–1.0), P=0.02, as well as reducing blood pressure [systolic BP −15 mmHg (CI 5–25), P=0.007 and diastolic BP (mmHg) by −8 mmHg (CI 4–13), P=0.001].

Conclusions Spironolactone was a highly effective antihypertensive agent in hypertensive patients who had a raised aldosterone/renin ratio. As a raised ratio was highly predictive of nonsuppression of plasma aldosterone suggesting primary aldosteronism, it might be worthwhile using spironolactone in this subgroup of hypertensive patients with raised aldosterone/renin ratios, provided that adrenal adenomas are excluded with imaging techniques.
Tacrine is not an ideal probe drug for measuring CYP1A2 activity in vivo
Authors: Larsen  , Hansen  , Brøsen
Published: March 2003

Aims The aim of the present study was to examine the CYP1A2 substrate tacrine as a possible alternative to caffeine for assessing CYP1A2 activity in vivo.

Methods Eighteen, healthy, nonsmoking men participated. Each volunteer was tested by caffeine (200 mg orally), and caffeine metabolic ratios were calculated. Subsequently, on two occasions, separated by at least 4 weeks, each volunteer was tested with tacrine (40 mg orally). The apparent oral clearance, partial clearances and different metabolic ratios of tacrine were determined.

Results The median oral clearances of tacrine in the two study periods were 1893 l h−1 (range: 736–3098) and 1890 l h−1 (range: 438–4175), respectively. The interindividual coefficient of variation was 42% and 49%, respectively. The intraindividual coefficients of variation ranged from 0.28% to 64% (median: 13%). In both study periods, the oral clearance of tacrine correlated with the caffeine urinary metabolic ratio. However, only modest magnitudes of correlation were observed (rs: 0.64–0.66, P<0.01). No tacrine metabolic ratio correlating with the oral clearance of tacrine was found.

Conclusion The applicability of tacrine as a probe drug for measuring CYP1A2 activity in vivo appears limited.
The haemodynamic effect of the 5HT1 agonist BMS‐180048: a class effect of triptans?
Authors: Swan  , Hood  , Birnie  , Muir  , McCann  , Hillis
Published: March 2003

Aims To investigate the effects of an intravenous infusion of BMS‐180048, a novel 5HT1‐like agonist, on the systemic, pulmonary and coronary circulations in patients undergoing diagnostic cardiac catheterisation.

Methods Ten patients (mean age 55 years (range 41–65)) were studied during diagnostic cardiac catheterisation. The haemodynamic response to an intravenous (i.v.) infusion for 30 min of BMS‐180048 (0.56 mg kg−1 h−1 for 10 min and 0.39 mg kg−1 h−1 for 20 min) was assessed via a 7F Swan Ganz catheter and thermodilution cardiac output system. Quantitative coronary angiography was performed at 10 min intervals.

Results BMS‐180048 caused a significant increase in systemic arterial systolic blood pressure (rise of 32.5 mmHg, 95% CI 24,44.5) P=0.009), pulmonary artery systolic (12.2 mmHg, 95% CI 6.8,18.5; P=0.009) and diastolic pressures (8.5 mmHg, 95% CI 5.0,13.8; P=0.009), right atrial pressure (4 mmHg, 95% CI 1.5,5.2; P=0.013) and pulmonary capillary wedge pressure (9.5 mmHg 95% CI 5.2, 14.0; P=0.009). There was no significant change in cardiac output (0.1 l  min−1, 95% CI −0.17, 0.57, P >0.05). Mean coronary artery diameter in the proximal coronary segments decreased by 0.73 mm (95% CI −1.22, −0.15; P=0.03) at 35 min. The corresponding reduction in middle segments was 0.26 mm (95% CI −0.395, −0.08; P=0.02). There was a non‐significant trend to constriction in the most distal segments of 0.28 mm (95% CI −0.68, 0.015); P=0.06). One patient experienced chest pain with ECG changes suggestive of ischaemia.

Conclusions BMS‐180048 displayed a cardiovascular profile similar to that previously reported for sumatriptan. These changes appear to reflect a class effect of these agents.
Pharmacokinetics of glycosylated recombinant human granulocyte colony‐stimulating factor (lenograstim) in healthy male volunteers
Authors: Houston  , Stevens  , Cour
Published: March 2003

Aims The aim of this open, randomised, crossover, parallel‐group study was to compare the pharmacokinetics and neutrophil responses of lenograstim when administered subcutaneously (s.c.) and intravenously (i.v.).

Methods A total of 27 healthy male volunteers was recruited. Lenograstim doses (0.5, 2, 5, or 10 μg kg−1 ) were administered s.c. or i.v. once‐daily for 5 days, and then, after a 10‐day washout period, vice versa for a further 5 days. Lenograstim concentrations and absolute neutrophil counts (ANCs) were measured predosing and postdosing on days 1 and 5.

Results Maximum serum concentrations of lenograstim were higher following i.v. dosing (mean 5.2–185.5 vs 0.7–30.0 ng ml−1 after s.c. dosing on day 1) and attained sooner (median 0.5–0.8 vs 4.7–8.7 h on day 1). However, apparent elimination half‐lives of lenograstim were longer following s.c. dosing (mean 2.3–3.3 vs 0.8–1.2 h after i.v. dosing on days 1 and 5). ANCs increased in a dose‐dependent manner with both routes of lenograstim, but more prolonged rises and higher ANC peaks were attained following s.c. doses. ANCs peaked on day 6 following 5 μg kg−1 s.c. doses (mean peak=26.3×109 cells l−1 ), but on day 2 after 5 μg kg−1 i.v. doses (mean peak=12.4×109 cells l−1 ). Irrespective of route, the most common adverse events were headaches and back/spine pain; at doses of up to 5 μg kg−1 these were mild and generally well tolerated.

Conclusions While supporting the use of both s.c. and i.v. administered lenograstim to treat neutropenia, these results demonstrate that neutrophil responses are more sustained and prolonged with the s.c. route.
Pharmacokinetic variability and strategy for therapeutic drug monitoring of saquinavir (SQV) in HIV‐1 infected individuals
Authors: Regazzi Mario B. , Villani Paola , Maserati Renato , Cocchi Laura , Giacchino Roberto , Burroni Daniela , Rettani Mauro
Published: March 2003

Aims To investigate the pharmacokinetic profile of the protease inhibitor saquinavir (SQV) after multiple doses in HIV‐positive patients and to evaluate the possibility of predicting total body exposure of SQV from concentrations determined at single time points.

Methods Twenty HIV‐positive patients on steady‐state treatment with SQV (Hard‐Gel‐Capsule, Invirase®) were enrolled in this study. Serial blood samples were obtained during a dosing interval. SQV plasma concentrations were determined by high performance liquid chromatography (h.p.l.c.) and pharmacokinetic parameters were determined by noncompartmental techniques.

Results There was a marked interindividual variability in SQV pharmacokinetic parameters with a 11‐fold variability in total systemic exposure to SQV, as expressed by AUC(0,8h) values (range: 268–3009 ng ml−1 h, CV: 69%). The oral clearance shows an interindividual CV of 75%. A strong correlation (r=0.94) was found between SQV plasma concentration at 3 h (C3 h ) and AUC(0,8h).

Conclusions This study shows that C3 h is a good predictor for total body exposure of SQV and might be useful to predict SQV disposition in HIV‐positive patients on steady‐state treatment.
Use of dexfenfluramine, fenfluramine and phentermine and the risk of stroke
Authors: Derby Laura E. , Myers Marian W. , Jick Hershel
Published: March 2003

Aims To estimate the incidence of newly diagnosed idiopathic stroke among users of fenfluramine, dexfenfluramine and phentermine compared to obese nonusers.

Methods We conducted a cohort study with nested case‐control analysis utilizing data from the General Practice Research Database in the UK. Eight thousand four hundred and twenty‐three subjects aged 69 years or less at the start of follow‐up were exposed to at least one of the three study drugs and 17 225 similarly obese subjects were not exposed to any of the study drugs.

Results We identified 45 incident cases of idiopathic CVA in this cohort of subjects. The incidence of CVA among all current users of a diet drug was 1.3/1000 person‐years (95% CI 0.5, 3.5). The incidence for current fenfluramine users (n=2) was 2.6/1000 person‐years (95% CI 0.7, 9.6), for current dexfenfluramine users (n=1) 1.1/1000 person‐years (95% CI 0.3, 3.8), and for current phentermine users 0/1000 person‐years (95% CI 0.0, 12.9). The incidence in obese nonusers was 0.6/1000 person‐years (95% CI 0.4, 0.9). The adjusted matched odds ratio (OR) for thrombotic stroke from the case‐control analysis comparing current use of a diet drug to nonuse was 2.4 (95% CI 0.6, 9.1). There was only one exposed subject among seven who had haemorrhagic stroke.

Conclusions The incidence of CVA in generally young obese subjects during use of fenfluramine, dexfenfluramine or phentermine is low. Although we found an OR of 2.4 comparing users of any of the anorexiants with nonusers, this is based on only three exposed cases and the confidence limits are wide. We conclude that our study does not support a substantial increased risk of stroke attributable to the use of fenfluramine, dexfenfluramine or phentermine.
Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily
Authors: Kirkpatrick  , Duffull  , Begg
Published: March 2003

Aims 1. To determine the population pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. 2. To see if current starting doses for once daily aminoglycoside dosing are appropriate. 3. To test whether calculating creatinine clearance using an adjusted Cockcroft and Gault method (CLCr,adjusted ) was a better predictor of gentamicin clearance than the standard Cockcroft and Gault method (CLCr,unadjusted ).

Methods Nine hundred and fifty‐seven patients were dose‐individualized for gentamicin using SeBA‐GEN, a Bayesian dosing method. This method returns estimates of the values of gentamicin CL and V d from which the 24 h AUC can be estimated. The goal of therapy was to attain an AUC of 70–100 mg l−1 h depending on the severity of the infection. The population was divided into four groups of differing renal function. Linear regression analysis was performed to determine the relationship between V d and various indices of weight, and gentamicin CL and either CLCr,adjusted or CLCr,unadjusted.

Results The mean V d (±s.d.) and CL (±s.d.) of gentamicin in our total population were 17.4 (±4.1) l and 4.0 (±1.8) l h−1, respectively. There was a decrease in V d with reducing renal function when comparing patients with normal renal function and patients with poor renal function. The lower of total body weight (TBW) and lean body weight (LBW), termed dosing weight (DWT), was a slightly better predictor of V d (r2=0.28) than either TBW (r2=0.21) or LBW (r2=0.21). CLCr,adjusted (r2=0.80) was a better predictor of gentamicin CL than CLCr,unadjusted (r2=0.57).

Conclusions The mean population values of V d and CL of gentamicin dosed once daily are similar to those described by others in relation to multiple daily dosing. Given that previous methods have been based on population values of V d and CL from multiple daily dosing, the currently recommended starting doses for once daily aminoglycoside dosing would seem appropriate. The V d reduced with decreasing renal function, with a maximum of 23% difference between patients with normal and poor renal function. The Cockcroft and Gault method of calculating creatinine clearance does not appear to perform well at low values of serum creatinine concentration. An adjustment of the Cockcroft and Gault method is proposed to allow for this.
Systemic availability of budesonide after nasal administration of three different formulations: pressurized aerosol, aqueous pump spray, and powder
Authors: Thorsson  , Borgå  , Edsbäcker
Published: March 2003

The present study was undertaken to determine the absolute systemic availability of budesonide from three different devices for nasal administration: pressurized aerosol, aqueous pump spray, and powder.

 Sixteen healthy, non‐smoking, volunteers participated in this open, randomized, and crossover study. All subjects received budesonide as an intravenous dose of 400 μg, and as three, single‐dose, intranasal administrations: pressurized aerosol 800 μg, aqueous pump spray 400 μg, and powder 800 μg. Blood was sampled for 10 h after each administration and budesonide was assayed in plasma by liquid chromatography plus mass spectrometry.

 The mean [95% CI] systemic availability of budesonide with reference to the metered dose was: 13 [10; 15]%, 29 [23; 37]%, and 20 [16; 23]%, and the maximum plasma concentration (Cmax ) was attained at (tmax ) 2.0, 0.7, and 0.4 h after administration for the pressurized aerosol, aqueous pump spray, and powder, respectively.

 The uptake of budesonide was more rapid and more complete, and the systemic availability of the drug was significantly higher from the aqueous pump spray and powder than from the pressurized aerosol.
The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing
Authors: Begg Evan J. , Robson Richard A. , Saunders Darren A. , Graham Garry G. , Buttimore Rona C. , Neill Alister M. , Town G. Ian
Published: March 2003

Aims To examine the pharmacokinetics of ciprofloxacin and fleroxacin in plasma and sputum of patients with an acute exacerbation of chronic bronchitis or bronchiectasis following the first dose and again during the third day of treatment.

Methods Twelve patients, aged >35 years, with acute infective exacerbation of bronchitis or bronchiectasis were allocated randomly to treatment with either fleroxacin 400 mg daily or ciprofloxacin 500 mg twice daily in an open, parallel group design. Plasma and sputum were collected during the first and third days of treatment. The time course of concentrations in sputum was modelled assuming that it acted as a negligibly small compartment of distribution.

Results The mean sputum to plasma ratios of both ciprofloxacin and fleroxacin were approximately 1 on both days 1 and 3. Peak concentrations of ciprofloxacin in sputum were achieved 1.6 (95% CI on mean difference 0.8–2.3) and 1.2 (0.4–1.9) h later than in plasma on day 1 and day 3, respectively (mean difference±95% confidence interval). For fleroxacin, the corresponding delay in time to peak concentrations was less marked and not significant. Fleroxacin accumulated in plasma (accumulation index 1.52±0.07) and sputum (accumulation index 1.79±0.39) from day 1 to day 3. Accumulation did not occur for ciprofloxacin because the dose interval (12 h) was considerable longer than its half life (3–4 h).

Conclusions The sputum to plasma ratio of ciprofloxacin and fleroxacin is approximately 1. The time to peak concentrations of ciprofloxacin in sputum is slightly delayed compared with plasma. Fleroxacin accumulates over time in both plasma and sputum consistent with its longer half‐life.
Effectiveness of delayed activated charcoal administration in simulated paracetamol (acetaminophen) overdose
Authors: Yeates P. J. A. , Thomas S. H. L.
Published: March 2003

Aims Oral activated charcoal is used to treat drug overdose and is effective at reducing drug absorption when administered within 1 h of drug ingestion. There are fewer data on efficacy when the delay is longer, as is the case in most drug overdoses. This study investigated the efficacy of activated charcoal at preventing paracetamol (acetaminophen) absorption after simulated overdose when administration was delayed between 1 and 4 h.

Methods An open randomized‐order four‐way crossover study was performed in healthy volunteers comparing the effect of activated charcoal 50 g on the absorption of 3 g paracetamol tablets when administered after an interval of 1, 2 or 4 h or not at all. Plasma paracetamol concentrations were measured over 9 h after paracetamol ingestion using h.p.l.c. and areas under the curve between 4 and 9 h (AUC(4,9 h)) calculated as a measure of paracetamol absorption.

Results Activated charcoal significantly reduced paracetamol AUC(4,9 h)when administered after 1 h (mean reduction 56%; 95% Confidence intervals 34, 78; P<0.002) or 2 h (22%; 6, 39; P<0.03) but not after 4 h (8%; −8, 24). When administered after 1 h activated charcoal reduced individual plasma paracetamol concentrations significantly at all times between 4 and 9 h after paracetamol administration. Administration at 2 or 4 h had no significant effect.

Conclusions These results in healthy volunteers cannot be extrapolated directly to poisoned patients. However, they provide no evidence of efficacy for activated charcoal when administered after an interval of more than 2 h.
Effect of caffeine on clozapine pharmacokinetics in healthy volunteers
Authors: Hägg Staffan , Spigset Olav , Mjörndal Tom , Dahlqvist Rune
Published: March 2003

Aims To assess the effects of caffeine on the pharmacokinetics of clozapine in healthy volunteers.

Methods This was an open label randomized crossover study in 12 nonsmoking healthy male volunteers. The subjects received a single oral dose of 12.5 mg clozapine in each phase with or without concomitant intake of caffeine (mean dose: 550 mg day−1, range: 400–1000 mg day−1 ). Serum concentrations of clozapine and its metabolites desmethyl‐clozapine and clozapine‐N‐oxide were measured during a 48 h period in each phase. In addition, serum concentrations of caffeine and the metabolite paraxanthine were monitored.

Results A 19% increase in mean clozapine AUC(0,∞) (P=0.05) and a 14% decrease of mean oral clearance of clozapine were observed during concomitant intake of caffeine (P=0.05) compared with intake of only clozapine. Statistically significant decreases of mean ratios between AUC(0,12h) for desmethyl‐clozapine and AUC(0,12h) for clozapine (−18%), and between AUC(0,12h) for clozapine‐N‐oxide and AUC(0,12h) for clozapine (−23%) were observed during the caffeine phase (P=0.03 and 0.02, respectively). Oral clearance of clozapine and the ratio AUC(0,12h) for desmethyl‐clozapine/AUC(0,12h) for clozapine were correlated with the paraxanthine/caffeine ratio in serum after intake of caffeine (rs=0.62; P=0.03 and rs=0.77; P=0.003, respectively).

Conclusions These results suggest that caffeine in daily doses of 400–1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals.
Pharmacokinetics and pharmacodynamics of R‐ and S‐gallopamil during multiple dosing
Authors: Gross Annette S. , Eichelbaum Michel , Mörike Klaus , Mikus Gerd
Published: March 2003

Aims Using a stable isotope technique we investigated the pharmacokinetics and pharmacodynamics of gallopamil after administration of 50 mg pseudoracemic gallopamil every 12 h for 7 doses (72 h).

Methods Six male healthy volunteers were studied. After the seventh dose the pharmacokinetics and pharmacodynamics were assessed. Serum levels of gallopamil were measured by gas chromatography/mass spectrometry. Effects of gallopamil were measured by ECG recording.

Results The apparent oral clearances (R: 4.8 l min−1 (95% CI: 2.9–6.8); S: 5.5 l min−1 (95% CI: 2.5–8.5)) and half‐lives (R: 6.2 h; S: 7.2 h) of R‐ and S‐gallopamil were similar (P >0.05). The serum protein binding (fu R: 0.035 (95% CI: 0.026–0.045); S: 0.051 (95% CI: 0.033–0.069)) and the renal elimination (% of dose R: 0.49%; S: 0.71%) were enantioselective. Gallopamil had a potent effect on the PR interval (% prolongation 35.7% (95% CI: 14.0–57.3)). No changes in other electrocardiographic or cardiovascular parameters were observed.

Conclusions The pharmacokinetics and bioavailability of the racemic drug gallopamil are not stereoselective at steady‐state and are therefore not substantially altered compared with the single dose administration of gallopamil.
The effect of staggered dosing of sucralfate on oral bioavailability of sparfloxacin
Authors: Kamberi Marika , Nakashima Hajime , Ogawa Keita , Oda Naomi , Nakano Shigeyuki
Published: March 2003

Aims To investigate the effect of sucralfate on sparfloxacin absorption when administered concurrently or at strategically spaced dosing times designed to avoid the potential interaction.

Methods The study was a four‐way crossover design where eight healthy Japanese volunteers were randomized to one of four treatment sequences at entry. A 300 mg dose of sparfloxacin was administered alone for treatment A (control). Treatments B, C and D included sucralfate 1.5 g every 12 h for five doses. For treatment B, the fifth dose of sucralfate was administered concurrently with sparfloxacin 300 mg. For treatment C, 300 mg sparfloxacin was given 2 h prior to the fifth dose of sucralfate. Treatment D consisted of sparfloxacin 300 mg given 4 h prior to the fifth dose of sucralfate. Blood and urine samples were collected at predetermined time intervals for 72 h. Sparfloxacin concentrations in plasma and urine and the concentrations of sparfloxacin metabolite in urine were determined by high performance liquid chromatography assays.

Results Sucralfate administrated concurrently with sparfloxacin decreased the mean AUC(0,∞) of sparfloxacin 2‐fold (P<0.001) and the mean Cmax 2.1‐fold (P<0.001) compared with sparfloxacin alone. When sucralfate was administrated 2 h after sparfloxacin, the mean AUC(0,∞) was decreased 1.5‐fold (P<0.01) and the mean Cmax 1.4‐fold (P<0.01). Sucralfate did not alter the extent of absorption of sparfloxacin when it was given 4 h after the administration of sparfloxacin. The relative bioavailabilities for treatments B, C and D were 0.50 (95% CI: 0.35–0.65), 0.64 (95% CI: 0.51–0.77), and 0.92 (95% CI: 0.81–1.03), respectively, relative to sparfloxacin alone. The mean percentage of the sparfloxacin dose recovered in urine was significantly lower after sparfloxacin was administered with sucralfate than after sparfloxacin was administered alone or 2 h before the sucralfate dose (P<0.001). Treatments B, C and D were demonstrated to be equivalent to treatment A in the rate of absorption. The tmax, CLr and t1/2 were not significantly affected by sucralfate. The metabolism of sparfloxacin was not altered in the presence of sucralfate.

Conclusions Oral administration of sucralfate with sparfloxacin or 2 h after sparfloxacin, decreased the extent of sparfloxacin absorption. When both drugs are to be administered together, sucralfate should be administered 4 h after sparfloxacin, allowing thus sufficient time for sparfloxacin absorption prior to the sucralfate dose and thereby minimizing the chance of a significant interaction.
Comparative oral bioavailability of azimilide dihydrochloride in the fed and fasted states
Authors: Corey Alfred E. , Agnew Jeffrey R. , Valentine Suzanne N. , Nesbitt John D. , Wagner Dan L. , Powell James H. , Thompson Gary A.
Published: March 2003

Aims
 This study investigated the relative oral bioavailability of azimilide dihydrochloride following administration in the fed (high‐fat meal) and fasted states.

Methods
 This was a single‐dose, randomized, two‐way crossover study in 30 healthy, Caucasian, male subjects. Following oral administration, blood samples were collected over 27 days and analysed for azimilide using h.p.l.c. with u.v. detection. Pharmacokinetic parameters were determined using ‘noncompartmental’ analysis and compared using an ANOVA and 90% or 95% confidence intervals.

Results
 The extent of absorption was equivalent in the fed and fasted states (ratio = 96.2%; 90% CI=90.5%−102.4%). However, Cmax was decreased 19% following a high‐fat meal (ratio=81.4%; 90% CI= 76.2%−87.0%). No difference in tmax or t½,z was observed.

Conclusions
 Azimilide dihydrochloride may be orally administered to patients without regard to the prandial state.
Pharmacokinetics of bambuterol during oral administration of plain tablets and solution to healthy adults
Authors: Rosenborg, Johan , Larsson Per , Nyberg Lars
Published: March 2003

Aims 
The pharmacokinetics of orally administered bambuterol were investigated in healthy adult subjects, with particular regard to time to steady state, pharmacokinetic linearity, intraindividual variability for the parent drug and its active β2‐adrenergic metabolite terbutaline and bioequivalence between tablet and solution.

Methods 
Twenty‐six healthy Caucasian subjects were included and 23 (12 women) completed this open, randomised, crossover study. Racemic bambuterol hydrochloride was administered orally as 10 mg, 20 mg, and 10 + 20 mg tablets, and as a solution once daily for 2 weeks at about 19.00 h. Plasma concentrations and urinary recoveries of bambuterol and terbutaline were measured after single doses and during repeated treatments.

Results 
Absorption of bambuterol was biphasic. The initial rate could not be assessed directly, but it was faster than that during the second phase where absorption was rate‐limiting for elimination (mean terminal half‐life: 16 h). Steady‐state AUC(0,24 h) of bambuterol, reached within 1 week, was not dose‐linear. Mean terminal half‐life of terbutaline was 22 h and steady‐state was reached within one week of bambuterol treatment. Contrary to bambuterol, overall pharmacokinetics of terbutaline indicated dose‐linearity. Day‐to‐day intraindividual variation in AUC(0,24 h) of terbutaline, 15% with the tablet, was half that of bambuterol. Urine data indicated that intraindividual variability was slightly smaller with the solution. Tablets were bioequivalent with the solution with regard to terbutaline (90% confidence interval: 87–100%).

Conclusions 
With oral bambuterol steady state was reached within 1 week. Regarding generated terbutaline, pharmacokinetics judged to be were linear, intraindividual variability of AUC at steady state was on average 15% with the tablet, and tablets were bioequivalent with the solution.
Single‐ and multiple‐dose pharmacokinetics of ziprasidone in healthy young and elderly volunteers
Authors: Wilner K. D. , Tensfeldt T. G. , Baris B. , Smolarek T. A. , Turncliff R. Z. , Colburn W. A. , Hansen R. A.
Published: March 2003

Aims  To compare the pharmacokinetics of ziprasidone in healthy young (18–45 years) men and women, and healthy elderly ( ≥ 65 years) men and women.

Methods  Eight young men, 11 young women, 8 elderly men and 8 elderly women were given oral ziprasidone 40 mg day− 1, in two evenly divided daily doses, for 7 days, followed by a single 20 mg dose on day 8. Serum samples were collected immediately before the morning dose on days 1–8, for up to 12 h after dosing on day 1 and for up to 96 h after dosing on day 8. The resulting data were used to derive pharmacokinetic parameters of ziprasidone in each age and gender group.

Results  Steady‐state serum concentrations of ziprasidone were achieved within 2–3 days. The steady‐state pharmacokinetics of ziprasidone, determined 8 days after the initiation of treatment, were similar in the young men, elderly men and young women. Assessment of gender effects by analysis of variance revealed statistically significant differences in Cmax (85 vs 69 ng ml− 1) and tmax (3.19 vs 4.81 h) but no differences in AUC(0,12 h) or λz. Assessment of age effects by analysis of variance revealed statistically significant differences in AUC(0,12 h) (560 vs 465 ng  ml− 1 h), Cmax (85 vs 69 ng ml− 1) and λz (0.126 vs 0.197 l h− 1) but no difference in tmax. Assessment of age and gender effects by analysis of covariance, with body weight as the covariate, did not reveal any significant differences. The mean t½,z in the young men, young women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 h, respectively. Standard deviations of the means for the pharmacokinetic parameters for the elderly women tended to be large.

Conclusions  The influence of age and gender on the pharmacokinetics of ziprasidone is not clinically significant.
Paracetamol, alcohol and the liver
Authors: Prescott Laurie F.
Published: March 2003

It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with ‘therapeutic intent’ had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol–alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic.

The paracetamol–alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short‐lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol–ethanol interaction is not specific for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical.

In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the first few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insufficient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestion‐ingly accepted this supposed interaction in man for so long with such scant regard for scientific objectivity.
In vitro sensitivity of Plasmodium falciparum and clinical response to lumefantrine (benflumetol) and artemether
Authors: Tanariya Peerapan , Tippawangkoso Pongsri , Karbwang Juntra , Na‐bangchang Kesara , Wernsdorfer Walther H.
Published: March 2003

Aims  To assess the sensitivity of 103 Plasmodium falciparum isolates to a combination of lumefantrine (benflumetol) and artemether (CGP 56697), with the objective of determining a correlation between in vitro drug sensitivity and therapeutic outcome.

Methods  Patients suffered from uncomplicated falciparum malaria and came from areas of Thailand affected by multidrug resistance. CGP 56697 was given in the form of tablets containing 20 mg artemether and 120 mg lumefantrine. The standard dose regimen, 4 doses of 4 tablets over 48 h, was compared with two lower dose regimens (4 × 2 tablets and 3 × 4 tablets).

Results  The parasites showed high resistance to chloroquine, fairly advanced resistance to mefloquine and compromised sensitivity to quinine. Sensitivity to artemisinin and lumefantrine prior to treatment was similar in all treatment groups. The 4 × 4 tablet regimen was more effective than the other regimens in coping with infections with relatively low sensitivity to artemisinin and/or lumefantrine. The EC90 for artemisinin is an important determinant of treatment success. Parasite density at the start of treatment was identified as another critical predictor of treatment outcome.

Conclusions  The results indicate that parasite exposure to the drugs may have been inadequate and/or too short in the cases of treatment failure, particularly marked in the lower dose regimens. This could probably be remedied by expanding the dose regimen in areas affected by multidrug resistance and in the case of relatively high parasitaemia.
Influence of hydroxychloroquine on the bioavailability of oral metoprolol
Authors: Somer Mika , Kallio Jaana , Pesonen Ullamari , Pyykkö Kaija , Huupponen Risto , Scheinin Mika
Published: March 2003

Aims
Hydroxychloroquine (HCQ) is used widely in the treatment of chronic inflammatory diseases such as rheumatoid arthritis. Since there is great interindividual variability in the pharmacokinetics of HCQ and chloroquine is a potent inhibitor of CYP2D6‐catalysed pathways in vitro, we wished to study the interaction of HCQ with CYP2D6‐mediated metabolism of other drugs in vivo.

Methods
Metoprolol and dextromethorphan (DM) were selected as probe drugs because they are well‐studied and widely used test substrates of CYP2D6. In this randomized, double‐blind crossover study, seven healthy volunteers with extensive metabolizer phenotype for CYP2D6 ingested either 400 mg hydroxychloroquine or placebo daily for 8 days after which single oral dose pharmacokinetics of metoprolol were investigated. Dextromethorphan metabolic ratio (DM‐MR) was also determined at baseline and after the ingestion of HCQ or placebo.

Results
Concomitant administration of HCQ increased the bioavailability of metoprolol, as indicated by significant increases in the area under the plasma concentration‐time curve (65 ± 4.6%) and maximal plasma concentrations (72 ± 6.9%) of metoprolol. While the DM‐MR values were not significantly changed, the phenotypic classification of one individual, who was heterozygous for a mutant CYP2D6 allele, was converted to a poor metabolizer by HCQ administration.

Conclusions
HCQ inhibits metoprolol metabolism most probably by inhibiting its biotransformation by CYP2D6. The inhibitory effect of HCQ on dextromethorphan metabolism was not apparent when DM‐MR was used as an indicator, except in an individual with limited CYP2D6 capacity.
Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O‐demethylation in different CYP2D6 genotypes
Authors: Kubota T. , Yamaura Y. , Ohkawa N. , Hara H. , Chiba K.
Published: March 2003

Aims
To determine the frequencies of 11 CYP2D6 mutant alleles (CYP2D6*2,*3,*4,*5,*8,*10,*11,*12,*14,*17 and *18), and their relation to the metabolic capacity of CYP2D6 in Japanese subjects.

Methods One hundred and sixty‐two unrelated healthy Japanese subjects were genotyped with the polymerase chain reaction amplification method and 35 subjects were phenotyped with dextromethorphan.

Results
The frequencies of CYP2D6*2,*5, *10 and *14 were 12.9, 6.2, 38.6 and 2.2% in our Japanese subjects, respectively. CYP2D6*3, *4, *8, *11, *12, *17 and *18 were not detected. The mean log metabolic ratio of dextromethorphan in subjects with genotypes predicting intermediate metabolizers was significantly greater than that of heterozygotes for functional and defective alleles.

Conclusions CYP2D6*5 and CYP2D6*14 are the major defective alleles found in Japanese subjects. In addition, CYP2D6*10 may play a more important role than previously thought for the treatment of Japanese patients with drugs metabolized by CYP2D6.
The link between sunshine and phototoxicity of sparfloxacin
Authors: Pierfitte Corinne , Royer René Jean , Moore Nicholas , Bégaud Bernard
Published: March 2003

Aims
To test the association between reporting rates for sparfloxacin‐induced phototoxicity and sunlight u.v. exposure, and the effects of regulatory action.

Methods
The reporting rates for phototoxicity with sparfloxacin to the French Pharmacovigilance System or to the Drug Manufacturer were compared with concurrent national mean u.v. exposure obtained from Météo‐France, before and after the regulatory restrictions and warnings.

Results
There were 371 severe phototoxic reaction reports during the first 9 months of marketing (reporting rate of 0.4 per thousand treated patients), approximately four to 25 times that reported for other fluoroquinolones. The reporting rate correlated highly (r = 0.873, P < 0.001) with the mean monthly u.v. exposure from sunlight (from Météo‐France). Regulatory action including warnings for physicians, and restricted indications dramatically decreased the number of reports, but not the reporting rate.

Conclusions
This is the first demonstration of a strong association between sunlight exposure in a population and drug‐induced phototoxicity. Regulatory action had no effect on the reporting rate (individual exposed patient risk), though it solved the public health issue.