bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: pharmacokinetic analysis and relationship to clinical response
Authors: HAAGSMA CEES J. , RUSSEL FRANS G. M. , VREE TOM B. , VAN RIEL PIET L. C. M. , VAN DE PUTTE LEVINUS B. A.
Published: October 2003

1The influence of sulphasalazine (SASP) on the pharmacokinetics of low dose methotrexate (MTX) and the relation between pharmacokinetic variables and clinical response was studied in 15 patients with active rheumatoid arthritis despite >6 months of SASP treatment.

2SASP was stopped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was administered after a standard breakfast. Blood was sampled initially every 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks the same procedure was repeated supplemented with concomitant administration of 1000 mg SASP. Clinical measurements included Ritchie articular index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two‐ compartment model with first order absorption and lag time. Results are given as mean (s.d.). Paired t‐test or signed rank test were applied in the statistical analysis.

3Pharmacokinetics of MTX without vs with SASP, means±s.d. were as follows: AUC: 673±179 vs 628±210 (95% confidence interval [CI] of the difference was −71 to 159) ng ml−1 h, MRT: 5.2±1.3 vs 5.2±1.1 (95% CI −0.4 to 0.4) h, t½,z: 4.3±1.1 vs 4.2±1.1 (95% CI −0.3 to 0.5) h, V /F: 59.3 ±29.3 vs 65.5±25.3 (95% ‐23.8 to 11.4) l, CL/F: 12.3±5.0 vs 13.5±4.8 (95% CI −4.5 to 2.3) l h−1. CLR/F: 6.2±1.3 vs 6.3±2.1 (95% CI −1.3 to 1.1) l h−1. All P values were ≥0.3.

4A weak correlation existed between the change of ESR and the MRT, the t½,z and the V /F (Spearman correlation coefficients of 0.43, 0.50 and 0.50 respectively, 0.05<P<0.1).

5There is no significant influence of chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consistently with some pharmacokinetic variables of MTX.
Lipid‐lowering drugs and mitochondrial function: effects of HMG‐CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio
Authors: DE PINIEUX G. , CHARIOT P. , AMMI‐SAÏD M. , LOUARN F. , LEJONC J. L. , ASTIER A. , JACOTOT B. , GHERARDI R.
Published: October 2003

1Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction.

2This study was designed to evaluate the effect of lipid‐lowering drugs on ubiquinone (coenzyme Q10) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio.

3Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels >6.0 mmol l−1) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects.

4Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls (P<0.05 and P<0.001). The difference was not significant between fibrate‐treated patients and untreated patients.

5Ubiquinone serum levels were lower in statin‐treated patients (0.75 mg l−1±0.04) than in untreated hypercholesterolaemic patients (0.95 mg l−1±0.09; P<0.05).

6We conclude that statin therapy can be associated with high blood lactate/pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.
The efficacy of ketoprofen and paracetamol (acetaminophen) in postoperative pain after third molar surgery
Authors: SEYMOUR R. A. , KELLY P. J. , HAWKESFORD J. E.
Published: October 2003

1A placebo‐controlled, double‐blind, randomized trial was carried out to evaluate the efficacy of single doses of racemic ketoprofen 12.5 and 25 mg and paracetamol 500 and 1000 mg in patients with post‐operative pain after third molar surgery over a 6 h investigation period.

2Outcome variables included overall pain scores (AUC(0,360 min), maximum pain relief, pain relief at 1 h after dosage and the number of patients taking escape analgesics.

3Overall pain scores (AUC(0,360 min) were significantly lower for all active treatments when compared to placebo (P<0.01).

4Both ketoprofen treatments and patients treated with paracetamol 1000 mg reported significantly greater pain relief (P<0.01) and a later time to taking escape analgesics (P<0.01) than patients medicated with placebo.

5At 1 h after dosage, pain scores were significantly less (P<0.01) after both doses of ketoprofen when compared with placebo.

6Single doses of ketoprofen 12.5 and 25 mg, together with paracetamol 1000 mg are effective analgesics for treating post‐operative pain after third molar surgery. These treatments provide up to 4 h of pain relief after this surgical procedure.
Diltiazem increases blood concentrations of cyclized cyclosporine metabolites resulting in different cyclosporine metabolite patterns in stable male and female renal allograft recipients
Authors: BLECK J. S. , THIESEMANN C. , KLIEM V. , CHRISTIANS U. , HECKER H. , REPP H. , FREI U. , WESTHOFF‐BLECK M. , MANNS M. , SEWING K. F.
Published: October 2003

1Six male and six female stable renal allograft recipients under cyclosporine immunosuppression and without concomitant therapy with drugs known either to induce or inhibit CYP3A enzymes were included in the study and received 180 mg day−1 diltiazem for 1 week in a two‐period cross‐over fashion. Cyclosporine (352±56 mg day−1) was given in two daily oral doses. The daily doses were not changed during the study. Blood samples were collected for 12 h after receiving cyclosporine alone and after receiving diltiazem in addition for 1 week. Cyclosporine and nine of its metabolites were quantified using h.p.l.c.

2Co‐administration of diltiazem caused a 1.6 fold increase of the AUC(0,12 h) of cyclosporine and a 1.7 fold increase of the AUC(0, 12 h) of its metabolites. Analysis of the metabolite patterns showed an over‐proportional increase of the AUC(0, 12 h) of the cyclized metabolites AM1c (2.6 fold) and AM1c9 (2.2 fold). The AUC(0, 12 h) values of cyclosporine and the hydroxylated metabolites increased less than two fold.

3Differences of the AUC(0, 12 h) values of cyclosporine with and without diltiazem were significantly higher in female than in male patients (P<0.02). The differences in the AUC(0, 12 h) values of the metabolites, especially AM1c, tended to be higher in female patients as well.

4It is concluded that coadministration of diltiazem not only increases the blood concentration of cyclosporine but also those of its metabolites, leads to a shift of the metabolite pattern towards cyclized metabolites, and that the pharmacokinetic changes under diltiazem administration are more prominent in female than in male patients.
Excursions in biomedical mass spectrometry
Authors: TAYLOR GRAHAM W. , DONNELLY LOUISE E. , MURRAY STEPHEN , RENDELL NIGEL B.
Published: October 2003

1Mass spectrometry (MS) has played a vital role in the research of the department of clinical pharmacology for over 25 years.

2MS has been used for trace analysis of endogenous compounds and xenobiotics in plasma and urine, and also for a wide range of structural studies.

3Examples of current applications are reported, including data from gas chromatography‐mass spectrometry (GC‐MS) assays for mevalonic acid, the identification of an antibiotic produced by Pseudomonas aeruginosa which is active against Helicobacter pylori, high pressure liquid chromatography (h.p.l.c)‐electrospray MS studies on steroid sulphates, the aspergillus ciliotoxin, gliotoxin, and ADP ribosyltransferase activity in human polymorphonuclear neutrophil leucocytes (PMNs). The value of electrospray MS in the molecular weight determination of proteins is exemplified by the analysis of human serum amyloid component P.
Objective measurement of activation of rigidity: diagnostic, pathogenetic and therapeutic implications in parkinsonism
Authors: KIROLLOS C. , CHARLETT A. , O'NEILL C. J. A. , KOSIK R. , MOZOL K. , PURKISS A. G. , BOWES S. G. , NICHOLSON P. W. , HUNT W. B. , WELLER C. , DOBBS S. M. , DOBBS R. J.
Published: October 2003

1Quantification of the effect on rigidity of its ‘activation’, by isometric grip, of standardized pressure, of the contralateral hand, was explored. Torque required to move the forearm through a fixed angle of 40°, at a controlled rate of 0.5 Hz, in a horizontal plane about a pivotal axis aligned to the elbow joint, was recorded before (12 ‘baseline’ recordings), during (10), and after (≥8) activation. Work required per unit displacement was calculated.

2Specificity: Pilot serial daytime measurements gave an overall mean ratio, work required on activation over baseline, of 2.94 (95% CI 2.53, 3.42) in two elderly untreated parkinsonians, and 3.19 (2.75, 3.71) in two elderly subjects with isolated, clinically activation phenomenon, compared with 1.90 (1.64, 2.21) in two elderly without (P<0.001), whilst two young adults did not activate, 0.98 (0.85, 1.14). In elderly subjects, work required under activation decreased during the day in health (−10 (−5, −14)% h−1, P=0.0002), showed no significant change in those with clinical activation (4 (−1, 9)% h−1), and increased in parkinsonians (6 (0, 12)% h−1, P=0.05): there appeared to be a transitionary state.

3Validation of methodology: Quantifying the same work ratio on a single occasion in 20 aged parkinsonians (P), their spouses (Ps), 20 index controls (C) without parkinsonism, matched to (P), and their spouses (Cs) gave corroborative evidence of a pre‐clinical state, defined by other measurements, in the spouses of sufferers. Values for C, Cs and Ps, 1.89 (1.42, 2.52), 2.38 (1.79, 3.17) and 2.93 (2.20, 3.90) respectively, were in consecutive positions, from health to (P, 2.96 (2.22, 3.95)) disease (P=0.001 for Ps c.f. C; P=0.1 for Ps c.f. Cs). Data on change over the day may enhance discrimination.

4Sensitivity to medicines was illustrated, in two parkinsonians, by randomised, placebo balanced and controlled challenges: 1 and 2 tablets, Sinemet CR (Du Pont Pharmaceuticals, each levodopa 200 mg/carbidopa 50 mg) and 1 tablet, Sinemet‐Plus (levodopa 100 mg/carbidopa 25 mg), then two 2 mg tablets, benzhexol. The dopaminergic effect (P<0.001) was selective for activation (treatment.test‐condition interaction, P=0.004), and showed the expected time profiles. The effect of benzhexol (P=0.008) lacked such selectivity. Its onset (>4, ≤6 h) was delayed, compatible with a gastrointestinal anti‐muscarinic action and the subjects' ages.

5Reliability (Fleiss's criterion) was shown to be good in 30 untreated parkinsonians.
Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol
Authors: VAN STEVENINCK A. L. , GIESCHKE R. , SCHOEMAKER R. C. , RONCARI G. , TUK B. , PIETERS M. S. M. , BREIMER D. D. , COHEN A. F.
Published: October 2003

1Interaction between alcohol and bretazenil (a benzodiazepine partial agonist in animals) was studied with diazepam as a comparator in a randomized, double‐blind, placebo controlled six‐way cross over experiment in 12 healthy volunteers, aged 19−26 years.

2Bretazenil (0.5 mg), diazepam (10 mg) and matching placebos were given as single oral doses after intravenous infusion of alcohol to a steady target‐blood concentration of 0.5 g l−1 or a control infusion of 5% w/v glucose at 1 week intervals.

3CNS effects were evaluated between 0 and 3.5 h after drug administration by smooth pursuit and saccadic eye movements, adaptive tracking, body sway, digit symbol substitution test and visual analogue scales.

4Compared with placebo all treatments caused significant decrements in performance. Overall, the following sequence was found for the magnitude of treatment effects: bretazenil+alcohol>diazepam+alcohol≥bretazenil> diazepam>alcohol>placebo.

5There were no consistent indications for synergistic, supra‐additive pharmacodynamic interactions between alcohol and bretazenil or diazepam.

6Bretazenil with or without alcohol, and diazepam+alcohol had marked effects. Because subjects were often too sedated to perform the adaptive tracking test and the eye movement tests adequately, ceiling effects may have affected the outcome of these tests.

7No significant pharmacokinetic interactions were found.

8Contrary to the results in animals, there were no indications for a dissociation of the sedative and anxiolytic effects of bretazenil in man.
The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance
Authors: KERR J. S. , POWELL J. , HINDMARCH I.
Published: October 2003

Reboxetine is a novel antidepressant that has been shown to be effective in the treatment of major depressive disorders. The present experiment was designed to assess whether it affects the cognitive and psychomotor skills necessary for optimum function in everyday life. Ten healthy male volunteers received reboxetine 0.5 mg, 1 mg or 4 mg, amitriptyline 25 mg, or matched placebo with and without alcohol (0.6 mg kg−1) in a double‐blind 10‐way crossover study. A psychometric test battery was administered at baseline and at 1, 2.25, 3.5, 6 and 9 h post‐dose. The results showed that reboxetine had little or no effect on performance at any dose, compared with placebo. Amitriptyline, however, with and without alcohol, lowered critical flicker fusion threshold compared with placebo and/or reboxetine at all test points (e.g. at 3.5 h: 28.51 vs 30.33 Hz; P<0.05); increased reaction time (e.g. 619 vs 540 ms; P<0.05); increased tracking error (e.g. 16.34 vs 8.54 RMS units; P<0.05); and slowed short‐term memory scanning (e.g. 742 vs 590 ms; P<0.05). It is concluded that reboxetine at doses of 4 mg and below is free from disruptive effects on cognitive function and psychomotor performance, and that it does not act synergistically with alcohol, in contrast to amitriptyline.
(−)‐Timolol is a more potent antagonist of the positive inotropic effects of (−)‐adrenaline than of those of (−)‐noradrenaline in human atrium
Authors: WANG T. , KAUMANN A. J. , BROWN M. J.
Published: October 2003

1The affinity of (−)‐timolol for β1‐ and β2‐adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (−)‐adrenaline and (−)‐noradrenaline by (−)‐timolol were measured.

2The antagonism of the positive inotropic effects of (−)‐adrenaline and (−)‐noradrenaline by (−)‐timolol (0.1–100 nm) was simple competitive in human atrium tissue. The slope of Schild‐plots was not significantly different from 1.0 [0.93±0.09 for (−)‐adrenaline, 0.97±0.09 for (−)‐noradrenaline].

3The inotropic effects of (−)‐adrenaline were antagonized significantly more by each concentration of (−)‐timolol than those of (−)‐noradrenaline. KB‐values (‐log m) were 10.10±0.09 against (−)‐adrenaline and 9.43±0.07 against (−)‐noradrenaline (P<0.001).

4Blocking kinetics of (−)‐timolol for the β‐adrenoceptor were relatively slow. Half‐times for the onset of blockade by 10 times KB of (−)‐timolol were approximately 30 min for both (−)‐adrenaline and (−)‐noradrenaline; offset times were similar.

5It is concluded that (−)‐timolol has a higher affinity for the β2‐adrenoceptor than for the β1‐adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the β2‐adrenoceptor hypersensitivity induced by cardiac β1‐adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra‐ocular doses of the drug.
Suppression of vagus‐mediated pancreatic polypeptide release by the μ‐opiate receptor agonist loperamide in man
Authors: RIEPL RUDOLF L. , REICHARDT BÄRBEL , AUERNHAMMER CHRISTOPH J. , BEIER GERALD , SCHOPOHL JOCHEN , STALLA GÜNTER K. , LEHNERT PETER
Published: October 2003

1Morphine suppresses the release of pancreatic polypeptide, a hormone under vagal cholinergic control. The intention of the study was to detect whether the μ‐opiate receptor agonist loperamide is also able to inhibit pancreatic polypeptide release, and to define its site of action.

2In groups of healthy subjects (n=6 each) stimulation of pancreatic polypeptide was assessed in five different tests: (i) insulin‐hypoglycaemia; (ii) modified sham feeding; (iii) intravenous infusion of the cholecystokinin analogue ceruletide; (iv) injection of corticotropin releasing hormone; (v) infusion of the muscarinic acetylcholine agonist bethanechol. All tests were performed after oral application of either a placebo or loperamide (16 mg), tests (ii) and (iii) were repeated with loperamide in smaller doses (2 and 6 mg), with loperamide plus naloxone, with naloxone alone, and with infusion of atropine. Plasma concentrations of pancreatic polypeptide were measured radioimmunologically.

3Release of pancreatic polypeptide in test (i) to (iv) was completely blocked by 16 mg loperamide, whereas bethanechol‐stimulated release (test 5) was not influenced. Tests (ii) and (iii) showed that the inhibition was dose‐dependent and could be attenuated by naloxone. The inhibitory effect of loperamide was comparable with that of atropine.

4We conclude that loperamide causes a dose‐dependent inhibition of pancreatic polypeptide release mediated by vagal‐cholinergic pathways, but does not have an atropine‐like peripheral action.
Variable contribution of CYP2D6 to the N‐Dealkylation of S‐(‐)‐propranolol by human liver microsomes
Authors: ROWLAND K. , WYNNE ELLIS S. , LENNARD M. S. , TUCKER G. T.
Published: October 2003

Recombinant cDNA expression systems for CYP2D6 have been shown to have significant catalytic activity with respect to the N‐dealkylation of propranolol. However, the involvement of CYP2D6 in this reaction in human liver is inconclusive. We have re‐evaluated the role of CYP2D6 in the dealkylation of S‐(‐)‐propranolol using a bank of 10 human livers characterized for their specific CYP2D6 and CYP1A2 activities, the latter enzyme being known to be involved substantially in the formation of N‐desisopropylpropranolol. Using quinidine (1 μm) or LKM‐1 antibodies as selective inhibitors of CYP2D6, the contribution of this enzyme to net N‐desisopropylation of S‐(‐)‐propranolol (10 μm) by microsomes from the range of livers was found to vary from nil (poor metabolizer genotype) to 60%. N‐desisopropylpropranolol formation inhibitable by quinidine was highly correlated with specific CYP2D6 activity, as measured by the α‐hydroxylation of metoprolol (rs=0.90; P<0.001). The two livers with the highest proportion of CYP2D6‐mediated N‐dealkylation had relatively high ratios of specific CYP2D6 to CYP1A2 activity. These findings emphasize that data obtained using microsomes from single human livers or pooled microsomes from several livers may be misleading inasmuch as the relative contribution of different isoenzymes to the same metabolic reaction may show considerable between‐subject variation.
Measurement of total phospholipids in urine of patients treated with gentamicin
Authors: Saunders Darren A. , Begg Evan J. , Kirkpatrick Carl M. J. , Yeo James , Graham Garry G. , Bailey Ross R.
Published: October 2003

Aims The excretion of phospholipids in urine may be a marker of the early renal toxicity of the aminoglycoside antibiotics. Urinary phospholipids are formed in myeloid bodies which develop in the lysosomes of proximal tubules during treatment with the aminoglycosides, and overflow into the urine.

Methods Published assays were modified in order to measure the total phospholipid concentrations in human urine. Phospholipids were extracted from freeze‐dried urine samples, digested in concentrated sulphuric acid, and the inorganic phosphorus content determined by complexing with ammonium molybdate and measuring the absorbance at 820 nm. Ten septicaemic patients treated with gentamicin for 5–7 days had significantly higher urine phospholipid concentrations than 10 healthy untreated control subjects (P<0.0001). There was a negative linear relationship between phospholipid excretion and creatinine clearance (r
2=0.71).

Results In 34 patients with acute pyelonephritis, increased phospholipid concentrations were observed prior to treatment compared with healthy controls (P<0.001) and did not alter during treatment with gentamicin. However, the phospholipid concentrations decreased significantly after treatment was completed (P<0.03).

Conclusions These studies suggest that urinary phospholipids may indicate early aminoglycoside toxicity but with poor specificity, as many of the infections being treated may themselves be associated with phospholipiduria.
Stereoselective 4′‐hydroxylation of phenytoin: relationship to (S)‐mephenytoin polymorphism in Japanese
Authors: Ieiri I. , Mamiya K. , Urae A. , Wada Y. , Kimura M. , Irie S. , Amamoto T. , Kubota T. , Yoshioka S. , Nakamura K. , Nakano S. , Tashiro N. , Higuchi S.
Published: October 2003

Aims The aim of this study was to clarify whether phenytoin (PHT) stereoselective hydroxylation cosegregates with (S)‐mephenytoin phenotype.

Methods A single dose of PHT (100 mg) was administered orally to six healthy Japanese subjects in whom the genotype and phenotype of CYP2C19 had been determined previously. The urinary excretion profiles of the metabolites of PHT, (R)‐ and (S)‐p‐HPPH [
5‐(4‐hydroxyphenyl)‐5‐phenylhydantoin] up to 36 h postdose were compared between the two groups of poor metabolizers (PMs, n=3) and extensive metabolizers (EMs, n=3) with respect to CYP2C19. CYP2C9 genotype was also determined.

Results All the alleles were found to be wild type (Arg144Tyr358Ile359Gly417 ) in each subject. The mean value for cumulative urinary excretion of unchanged PHT was not significantly different between the PMs and the EMs. However, recovery of (R)‐p‐HPPH at 36 h was 3.5‐fold lower and that of (S)‐p‐HPPH 1.3‐fold lower in PMs than in EMs. Although the mean urinary excretion values for both metabolites were significantly lower in the PMs than in the EMs, the difference between the two groups was larger for (R)‐p‐HPPH. A significant negative correlation was observed between the hydroxylation index of omeprazole (the ratio between the serum concentrations of omeprazole and hydroxyomeprazole in blood samples drawn 3 h after drug intake) and the log10 0–12 h urinary recovery of (R)‐p‐HPPH.

Conclusions In humans, the 4′‐hydroxylation of PHT is highly stereoselective towards formation of the (S)‐enantiomer. Thus, (S)‐hydroxylation by CYP2C9 might be the major determinant of the disposition of PHT. However, these results support the hypothesis that the stereoselective hydroxylation pathway of PHT to form (R)‐p‐HPPH cosegregates with the CYP2C19 metabolic polymorphism.
Enhanced effect of triazolam with diltiazem
Authors: Kosuge Kazuhiro , Nishimoto Masahiko , Kimura Masahiko , Umemura Kazuo , Nakashima Mitsuyoshi , Ohashi Kyoichi
Published: October 2003

Aims Triazolam, a triazolobenzodiazepine hypnotic agent, is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme. The aim of this study was to determine if diltiazem affects plasma concentrations of triazolam in humans.

Methods We investigated the interaction between triazolam and diltiazem in a randomized, three‐phase crossover study. Seven healthy male volunteers received orally either a single 0.25 mg dose of triazolam, a 0.25 mg dose of triazolam after a 3‐day treatment of diltiazem (180 mg day−1), or a placebo. Plasma samples were collected to determine triazolam concentration over a 24 h period. The pharmacodynamic effects of triazolam were investigated using the peak saccadic velocity of eye movements (PSV), electroencephalogram (EEG), and visual analogue scale (VAS) through 8 h.

Results Diltiazem pretreatment significantly increased the area under the triazolam concentration‐time curve (8.0±2.4 to 18.2±3.1 ng ml−1 h; P<0.001; mean±s.d.). Peak triazolam concentration was increased (2.1±0.7 to 3.6±1.0 ng ml−1, P<0.05) and the elimination half‐life prolonged (4.1±2.1 to 7.6±1.9 h; P<0.01). The PSV, EEG, and VAS of the triazolam plus diltiazem group revealed significant differences from the triazolam alone group or the control placebo group.

Conclusions Diltiazem markedly affects the pharmacokinetics of triazolam and increases the intensity of its sedative effects. Inhibition of CYP3A isozyme by diltiazem may explain the observed pharmacokinetic interaction. Therefore, triazolam should be avoided when patients are using diltiazem.
Use of sumatriptan in Denmark in 1994–5: an epidemiological analysisof nationwide prescription data
Authors: Gaist David , Andersen Morten , Aarup Ann‐Lisbeth , Hallas Jesper , Gram Lars Freng
Published: October 2003

Aims We describe the use of medication with symptomatic relief of migraine as specific indication by analysing prescription data from the entire Danish population in 1994 and 1995.

Methods The data for sumatriptan were analysed at the level of the individual user. We used aggregated data for ergotamine drugs.

Results Sumatriptan constituted 46% of the total amount of defined daily doses (DDD) sold and 94% of the total pharmacy retail price expenses in the drug‐group studied. In total, 43 389 users of sumatriptan were identified who presented 340 148 prescriptions, corresponding to 2.2 million DDD of sumatriptan. The quarterly consumption increased by 50% during the study period. Tablets accounted for 92% of consumption. The 1 year period prevalence of use of sumatriptan among persons 16 years and older was 7.8 per 1000 in 1995 with a female to male prevalence ratio of 3.8:1. Use was most common in the age interval 35–54 years. Regional differences in use, which were not large, were positively correlated to the degree of urbanization. The incidence of use of sumatriptan was estimated at 3.6 per 1000 person‐years. The intensity of use of sumatriptan varied greatly with 1.1% of patients (n=507) using 60 DDD or more within 30 days at some time during the observation period. Long‐term high use of tablets was common in this group.

Conclusions We conclude that sumatriptan had a considerable impact on the treatment of migraine with prescription drugs in Denmark. The underlying reasons for high use of the drug in a smaller fraction of the patients deserve further study.
Pharmacokinetic and pharmacodynamic interaction trial after repeated oral doses of imdapril and digoxin in healthy volunteers
Authors: Harder Sebastian , Thürmann Petra A.
Published: October 2003

Aims  To investigate the potential pharmacokinetic and pharmacodynamic interaction between imidapril and digoxin.

Methods
 AUC, Cmax and tmax of imidapril, imidaprilat and digoxin were calculated and evaluated in a randomized, doubleblind three‐period cross‐over design in 12 healthy volunteers after 8 days treatment with the following combinations: digoxin 0.25 mg day−1+placebo (D+P); imidapril 10 mg day−1+placebo (I+P); imidapril 10 mg day−1+digoxin 0.25 mg day−1 (I+D).

Results
 Mean AUC (0, 24 h) of digoxin was 10.4 (±4.9 s.d.) ng ml−1 h (D+P) and 10.7 (±3.9 s.d.) ng ml−1 h (I+D), respectively (90%‐confidence intervals [
CI] for the ratio of (D+P) and (I+D): 0.91–1.27, point estimator [PE]: 1.06). Mean AUC (0, 24 h) of imidapril was 133 (±86 s.d.) ng ml−1 h (I+P) and 108 (±52 s.d.) ng ml−1 h (I+D), respectively (90%‐CI: 0.76–0.94, PE 0.85). AUC (0, 24 h) of imidaprilat was 215 (±91 s.d.) ng ml−1 h (I+P) and 194 (±54 s.d.) ng ml−1 h (I+D), respectively (90%‐CI: 0.80–1.08, PE 0.93). Cmax was 19.9 (±8.7 s.d.) ng ml−1 (I+P) and 15.9 (±5.3 s.d.) ng ml−1 (I+D) (90%‐CI: 0.67–1.00, PE 0.82). The results indicate a slight reduction of imidapril and imidaprilat plasma levels when coadministered with digoxin without any effect on digoxin plasma levels. Maximal ACE‐inhibition was 79% (I+P) and 67% (I+D).

Conclusions
 Grouped data analysis of imidaprilat plasma levels vs ACE‐activity showed that for maximal inhibition of plasma ACE activity, imidaprilat plasma levels should exceed 10 ng ml−1. Under digoxin and imidapril, more plasma concentrations of imidaprilat were seen under this level as after imidapril alone, this reduces the integral of the ACE‐inhibition/time curves by about 20 to 30%.
Pharmacokinetic and pharmacodynamic assessment of bioavailability for two prodrugs of methylprednisolone
Authors: Daley‐Yates P. T. , Gregory A. J. , Brooks C. D.
Published: October 2003

Aims The aim of this study was to establish whether pharmacokinetic differences between two pro‐drugs of methylprednisolone (MP) are likely to be of clinical significance.

Methods This study was a single‐blind, randomized, crossover design comparing the bioequivalence of MP released from the pro‐drugs Promedrol (MP suleptanate) and Solu‐Medrol (MP succinate) after a single 250 mg (MP equivalent) intramuscular injection to 20 healthy male volunteers. Bioequivalence was assessed by conventional pharmacokinetic analysis, by measuring pharmacodynamic responses plus a novel approach using pharmacokinetic/pharmacodynamic modeling. The main measure of pharmacodynamic response was whole blood histamine (WBH), a measure of basophil numbers.

Results The MP Cmax was less for MP suleptanate due to a longer absorption half‐life of the prodrug from the intramuscular injection site. The bioavailability of MP was equivalent when based on AUC with a MP suleptanate median 108% of the MP succinate value (90% CI: 102–114%). For Cmax the MP suleptanate median was 81% of the MP succinate value (90% CI: 75–88%). The tmax for MP from MP suleptanate was delayed relative to MP succinate. The median difference was 200% (90% non‐parametric CI: 141–283%). The area under the WBH effect‐time curve (AUEC) and the maximum response (Emax ) were found to be equivalent (90% CI: 98–113% and 93–109% respectively). The maximum changes in other white blood cell counts, blood glucose concentration and the parameters of the pharmacodynamic sigmoid Emax model (EC50, Emax and γ) were also not significantly different between prodrugs.

Conclusions MP suleptanate is an acceptable pharmaceutical alternative to MP succinate. The use of both pharmacokinetic and pharmacodynamic response data together gives greater confidence in the conclusions compared with those based only on conventional pharmacokinetic bioequivalence analysis.
Comparison of the effects of a selective muscarinic receptor antagonist and hyoscine (scopolamine) on motion sickness, skin conductance and heart rate
Authors: Golding J. F. , Stott J. R. R.
Published: October 2003

Aims Hyoscine (scopolamine), which is effective in the prophylaxis of motion sickness, shows similar binding affinities to all of the five known muscarinic receptor sub‐types. The effectiveness of hyoscine was compared with zamifenacin (UK‐76654), which binds selectively to the muscarinic M3 and m5 receptors.

Methods Eighteen subjects received hyoscine hydrobromide 0.6 mg, zamifenacin 20 mg, or placebo (double‐blind cross‐over design). Sessions were 1 week apart and the drug (oral) was given 90 min prior to a motion sickness test. Motion sickness was elicited by cross‐coupled stimulation on a turntable. The rotational velocity was incremented by 2° s−1 every 30 s, and a sequence (seq) of eight head movements of 45° was completed every 30 s. Motion tolerance was assessed as the number of sequences of head movement required to achieve moderate nausea. Pulse rate was recorded before and at 1 and 2 h after drug administration. Skin conductance activity in the frequency band 0.005–0.48 Hz, an index of sweat gland activity, was measured using Ag/AgCl electrodes on the palmar surfaces of fingers and across the forehead.

Results Both zamifenacin and hyoscine produced an increase in tolerance to the motion challenge (P<0.01) with no significant difference between the two drugs (5.0±1.6 vs 5.7±1.6 seqs. respectively, mean±s.e.mean). Compared with placebo or zamifenacin, pulse rate fell following hyoscine administration (9 beats min−1, P<0.01). Skin conductance was reduced following hyoscine compared with zamifenacin or placebo (P<0.001).

Conclusions These results suggest that compounds with selective M3 and/or m5 antagonism possess activity against motion sickness. Antagonism at these receptors may be the basis of the anti‐motion sickness action of hyoscine.
The mechanism of the carbamazepine‐valproate interaction in humans
Authors: Bernus I. , Dickinson R. G. , Hooper W. D. , Eadie M. J.
Published: October 2003

Aims The study investigated the mechanism of the interaction between valproate and carbamazepine which causes raised plasma carbamazepine‐10,11‐epoxide concentrations with unchanged plasma carbamazepine concentrations. This interaction has usually been attributed to valproate inhibiting epoxide hydrolase, the enzyme that catalyses the biotransformation of carbamazepine‐10,11‐epoxide to carbamazepine‐10,11‐trans‐diol.

Methods Clearances of plasma carbamazepine, carbamazepine‐epoxide and carbamazepine‐diol to relevant carbamazepine metabolites present in urine were measured under steady‐state conditions in 17 adults receiving carbamazepine as anticonvulsant monotherapy, and in 10 adults taking the drug together with valproate.

Results Plasma carbamazepine‐epoxide concentrations were higher, relative to carbamazepine dose, in the co‐medicated patients. Plasma apparent clearances of carbamazepine, relative to drug dose, were similar whether or not valproate was taken. Formation clearances of carbamazepine‐10,11‐trans‐diol conjugate, and probably of carbamazepine‐10,11‐trans‐diol, were lower in subjects co‐medicated with valproate, and a higher proportion of the carbamazepine dose was excreted in urine as carbamazepine‐10,11‐epoxide.

Conclusions Valproate appears to inhibit the glucuronidation of carbamazepine‐10,11‐trans‐diol, and probably also inhibits the conversion of carbamazepine‐10,11‐epoxide to this trans‐diol derivative, rather than simply inhibiting the latter reaction only.
Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics*
Authors: Dingemanse Jasper , Kleinbloesem Cornelis H. , Zürcher Gerhard , Wood Nolan D. , Crevoisier Charles
Published: October 2003

Aims The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple‐dose regimens.

Methods Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100 mg three times daily and 12.5, 50, 200 mg three times daily, respectively. Plasma levels of levodopa, 3‐O‐methyldopa (3‐OMD) and 3,4‐dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250 mg levodopa.

Results Endogenous concentrations of levodopa and 3‐OMD increased dose‐dependently (from 8 up to 52 μg l−1 and from 0.02 up to 0.50 mg l−1, respectively, at doses of 200 mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration‐time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9 mg l−1 h at benserazide doses of 100–200 mg three times daily. Benserazide caused a dose‐dependent increase in the AUC of 3‐OMD from 7.4 to 106 mg l−1 h at doses of 200 mg. Formation of DOPAC was dose‐dependently suppressed, with benserazide 5 mg three times daily already halving its AUC.

Conclusions The benserazide‐dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.
Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non‐case study in the French pharmacovigilance system database
Authors: Moore Nicholas , Kreft‐Jais Carmen , Haramburu Françoise , Noblet Catherine , Andrejak Michel , Ollagnier Michel , Bégaud Bernard
Published: October 2003

Aims To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database.

Methods The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non‐case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA).

Results 428 of 93338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33–48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25–2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57–112)), disopyramide (OR 32 (22–46)), nifedipine (OR 2.16 (1.32–3.51)), diltiazem (OR 1.76 (1.01–3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16–3.16)) and frusemide (OR 1.89 (1.31–1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5–1.4) and 1.2 (0.7–2.2), respectively). The same was found for other drugs except cibenzoline.

Conclusion The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.
Reporting of adverse drug reactions by hospital doctors and the response to intervention
Authors: McGettigan P. , Golden J. , Conroy R. M. , Arthur N. , Feely J.
Published: October 2003

Aims In Ireland there are relatively fewer adverse drug reaction (ADR/yellow card) reports from doctors in hospital than in general practice. The aim of this study was to review the attitudes to reporting of ADRs of hospital doctors and to determine the effect of making yellow cards freely available.

Methods A postal survey of actively practising doctors with follow‐up of non‐responders was undertaken. We addressed the single most frequently claimed deterrent to reporting, unavailability of yellow cards, by making cards prominently available and placing one in patient’s chart upon admission. In addition, doctors were regularly reminded that ADRs should be reported.

Results Of 118 hospital based doctors, only 45% had ever reported an ADR. Fewer than 5% of pre‐registration house officers had reported an ADR and the likelihood of reporting increased with seniority and was greater among physicians than surgeons. We found no evidence that doctors had published case reports in place of submitting ADR reports. Over 3 months, the greater availability of yellow cards and reminders about reporting ADRs led to an approximate five‐fold increase in reports but reporting declined rapidly thereafter when verbal reminders were withdrawn, despite continued ready availability of cards suggesting that making cards available alone does not significantly increase reporting.

Conclusions This study indicates there may be more fundamental constraints to reporting than attitudinal surveys would suggest and we need to explore additional avenues to ensure a ‘reporting culture’.
Clinical Pharmacology and Therapeutics—past, present and future
Authors: Reid John L.
Published: October 2003

Aims To obtain information about the speciality of clinical pharmacology and therapeutics in the United Kingdom.

Methods A survey of the views of 26 individuals in academic posts in clinical pharmacology and therapeutics was carried out by postal questionnaire. Response rate was 100%.

Results Of 25 assessable responses of 25 centres, there were 35 academic staff of professorial status (median 2, range 0–5) and 61 staff of reader/senior lecturer status (median 2, range 0–5) but only 20 clinical staff in training grades in 19 institutions. All had extensive clinical commitments. Two‐thirds of respondents considered that the speciality was stable locally and nationally. However, recruitment of trainees was poor with only 8% of responders having several good applicants for each post and 90% reported that recruitment had deteriorated in the last 5–10 years. Likely good future careers for clinical pharmacologists in training were considered by 75–80% of respondents to likely lie in the pharmaceutical industry or regulatory authorities. Greater flexibility is required to facilitate training in clinical pharmacology and therapeutics.

Conclusions Clincal pharmacology and therapeutics in the United Kingdom has a strong academic base but a sub‐optimal age structure. Recent experience in recruitment into training posts was disappointing. This may reflect wider problems of recruitment into academic medicine in this country.
Regional metabolism of articaine in 10 patients undergoing intravenous regional anaesthesia during day case surgery
Authors: Vree Tom B. , Simon Marc A. M. , Gielen Mathieu J. M. , Booij Leo H. D. J.
Published: October 2003

Aims To study the pharmacokinetics of articaine and its metabolite articainic acid, in patients undergoing intravenous regional anaesthesia.

Methods Ten patients (three male, seven female, ASA class 1–2), scheduled for surgery of the hand or forearm were included in the study. Articaine (40 ml, 0.5% solution (200 mg) was injected over 30 s. In total fifteen arterial blood samples were taken; one before injection and then at 10 min intervals, starting 10 min after completion of injection, until the tourniquet was released; thereafter blood samples were drawn at intervals of 1, 5, 10, 15, 20, 25, 30, 45, 60, 75 and 90 min. The tourniquet was released 30 min after completing the injection.

Results During tourniquet application and regional analgesia of 30 min duration, 55% of articaine was hydrolysed by plasma (20%) and tissue (35%) esterase activity to the metabolite articainic acid. After releasing the tourniquet, articaine and its metabolite appeared in the blood; articaine was rapidly eliminated with a t1/2z of approximately 60 min. The plasma concentration of the metabolite articainic acid was the sum of the amount formed during IVRA (55%) and the amount formed after tourniquet release (45%).

Conclusions Articaine is a safe agent for intravenous regional anaesthesia (IVRA) with rapid onset of good surgical anaesthesia. During tourniquet application and regional analgesia, 55% of the administered dose is already hydrolysed, thus reducing the chance of side effects after tourniquet release.
The effect of pharmacological supplementation with vitamin C on low‐density lipoprotein oxidation
Authors: Wen Y. , Cooke T. , Feely J.
Published: October 2003

Aims Vitamin C (ascorbic acid) is a powerful antioxidant but there is limited information on its ability to prevent LDL oxidation and its interaction with other natural antioxidants in vivo. We assessed the effect of 4 weeks pharmacological supplementation with vitamin C 1 g day−1 on copper induced LDL oxidation and lipid peroxidation.

Methods Blood samples were obtained at baseline and at the end of 4 weeks supplementation from 11 healthy non‐smokers and also from nine control subjects. Plasma lipid peroxides were measured as malondialdehyde (MDA) by h.p.l.c. The relationship between vitamin C and two other important antioxidants, vitamin E and glutathione, was also studied.

Results There was no difference in baseline values between the two groups and the oxidizability of LDL, assessed as the lag phase of conjugated dienes production and the formation of thiobarbituric acid reactive substances (TBARS), remained unchanged after 4 weeks. In the vitamin C supplemented group only, there was a 2.2‐fold increase in plasma ascorbic acid level and a 28% increase in red cell reduced glutathione (GSH) (P<0.001). Vitamin E, measured as α‐tocopherol, in red cells increased significantly (P<0.02) and plasma MDA was reduced (P<0.01).

Conclusions Vitamin C did not alter LDL oxidation but it may have a protective role against lipid peroxidation as shown by decreased plasma MDA levels and enhanced vitamin E and GSH status.
Effects of oral and inhaled corticosteroid on lymphocyte β2‐adrenoceptor function in asthmatic patients
Authors: Tan Kia Soong , McFarlane Lesley C. , Lipworth Brian J.
Published: October 2003

Aims We have previously demonstrated that a single dose of oral prednisolone but not single doses of inhaled fluticasone had facilitatory effects on lymphocyte β2‐adrenoceptor (AR) function. To address possible differences in steady‐state time‐course, the aim of this study was to determine if repeated dosing with inhaled fluticasone would have facilitatory effects on lymphocyte β2‐AR. Plasma cortisol was also evaluated as a measure of systemic bioactivity.

Methods Ten asthmatic subjects, mean (s.e.mean) age 29 (3) years, FEV1 89 (5) % predicted, were randomised in a double‐blind crossover study to receive inhaled placebo (PL), inhaled fluticasone 1000 μg day−1 (F1000) and inhaled fluticasone 2000 μg day−1, each for 4 days and also a single dose of oral prednisolone 50 mg (PRED). Prednisolone was given as open medication. The last dose of study drug was taken at 22.00 h and subjects attended the laboratory at 08.00 h the following day.

Results β2‐AR density (Bmax; fmol/106 cells) was significantly increased after PRED compared with PL and inhaled fluticasone. Bmax (geometric mean) after each treatment were: PL 1.51, F1000 1.20, F2000 1.20 and PRED 2.14 (a 1.4 fold difference PRED vs PL; 95% CI 1.05 to 1.95; P<0.001). There was significant (P<0.001) suppression of plasma cortisol (nmol l−1 ) following F2000 and PRED compared with PL: 393.8, F1000 302.1, F2000 205.0 (95% CI F2000 vs PL 58.1 to 319.4) and PRED 87.0 (95% CI PRED vs PL 176.2 to 437.5). The estimated milligram equivalence ratio for adrenal suppression was calculated at 1:11 for fluticasone vs prednisolone.

Conclusions Repeated dosing with high‐dose inhaled fluticasone did not up‐regulate lymphocyte β2‐AR as compared with a single dose of oral prednisolone, despite having significantly suppressed early morning plasma cortisol. This study confirms our previous finding of a dissociation in sensitivity between effects of inhaled corticosteroid on adrenal suppression and lymphocyte β2‐AR regulation, at least for doses up to 2 mg day−1 of fluticasone.
Enantioselective pharmacokinetics of mefloquine during long‐term intake of the prophylactic dose
Authors: Hellgren Urban , Berggren‐Palme Ingela , Bergqvist Yngve , Jerling Markus
Published: October 2003

Aims To investigate the kinetics of the (+)RS‐ and (−)SR‐enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers.

Methods Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250 mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method.

Results A two‐compartment model adequately described the disposition of (+)RS‐MQ. CL/F was 6.5±1.8 l h−1, Vss/F 815±165 l, and k 0.0081± 0.0023 h−1. The kinetics of (−)SR‐MQ were time‐ and/or concentration dependent with a lower oral clearance (0.92±0.25 vs 2.14±0.63 l h−1, 95% CI for the difference 0.86–1.60 l h−1 ) and a longer half‐life (345 vs 185 h, 95% CI for the difference 47–291 h) after the last dose compared with the first dose. Clearance of (+)RS‐MQ and (−)SR‐MQ was significantly correlated within subjects (r=0.69, P<0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS‐MQ and 12.3% for (−)SR‐MQ. The elimination of MMQ was disposition rate‐limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound.

Conclusions The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.