bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of the post‐marketing safety of four selective serotonin re‐uptake inhibitors including the investigation of symptoms occurring on withdrawal
Authors: PRICE JOHN S. , WALLER PATRICK C. , WOOD SUSAN M. , MACKAY ANGUS V. P. 
Published: October 2003

1We have addressed the question of whether there is a ‘serotonin withdrawal syndrome’ by analysis of spontaneous reports of suspected adverse drug reactions (ADRs) associated with four SSRIs. A comparison of the post‐marketing safety profiles of the four SSRIs has also been made. 2The UK database of ADRs was examined for reactions associated with fluoxetine, fluvoxamine, paroxetine and sertraline. The safety profiles of the four SSRIs were similar. However, withdrawal reactions with paroxetine constitute a greater proportion of reports (5.1%) than with the other SSRIs (0.06–0.9%). They have been reported more often with paroxetine (0.3 reports per thousand prescriptions) than with sertraline and fluvoxamine (0.03), and least often with fluoxetine (0.002). 3Descriptions of withdrawal reactions received and further details of 217 reports of withdrawal reaction with paroxetine obtained by mailing a questionnaire to the reporting doctor were examined. Withdrawal symptoms were diverse but most commonly comprised dizziness, paraesthesia, tremor, anxiety, nausea and palpitation. They usually occurred after 2 days and lasted for an average of 10 days. There was no evidence of a physical drug dependency syndrome. 4Symptoms different from the previous depressive illness occur after discontinuing an SSRI, and are reported most often with paroxetine. Paroxetine is the most pharmacologically specific of the SSRIs, but it is not clear whether the reactions constitute a ‘serotonin withdrawal syndrome’.
Stimulatory as well as inhibitory effects of ethinyloestradiol on the metabolic clearances of propranolol in young women
Authors: WALLE T. , FAGAN T. C. , WALLE U. K. , TOPMILLER M. J. 
Published: October 2003

1 The metabolism of a single 80 mg oral dose of propranolol was determined in nine young women before and after administration of ethinyloestradiol alone (EE2) or in combination with norethindrone (OC). 2 Whereas the total clearance of propranolol (2713±404 ml min−1 (mean±s.e.mean)) was not significantly altered by either EE2 (3365±347 ml min−1) or the combined OC (2905±345 ml min−1), significant changes in all three primary metabolic pathways were observed. 3 The clearance through side‐chain oxidation decreased from 345±55 ml min−1 to 262±33 ml min−1 after EE2 (P<0.05). A similar reduction of cytochrome P450 metabolism by EE2 has been observed for other drugs. 4 The clearance through glucuronidation increased from 364±61 ml min−1 to 625±117 ml min−1 after EE2 (P<0.01). Similar stimulation of glucuronic acid conjugation by EE2 has also been observed for other drugs. 5 The clearance through ring oxidation increased from 697±109 ml min−1 to 1280±162 ml min−1 after EE2 (P<0.01). This observation appears to be a novel finding with EE2 and cytochrome P450 metabolism. 6 The treatment with OC produced changes in propranolol's metabolic clearances which were qualitatively similar to those generated by EE2.
Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers
Authors: DEMOLIS J.‐L. , CHARRANSOL A. , FUNCK‐BRENTANO C. , JAILLON P. 
Published: October 2003

1Sparfloxacin, a new fluoroquinolone, slightly increases the duration of the QT interval. Reverse rate‐dependence of QT interval prolongation has been shown for many agents that are known to prolong QT interval duration, and QT prolongation at slow heart rates may be a risk factor for torsades de pointes. 2A double‐blind, randomized, placebo controlled, crossover study was performed in 15 healthy volunteers to determine the effects of single oral doses of sparfloxacin (200 and 400 mg) on the QT interval at various heart rates. 312‐lead ECGs were recorded at rest and during exercise tests 5 h after sparfloxacin or placebo administration. QT intervals were calculated at predetermined RR intervals (1000, 800, 700, 600, 500 and 400 ms) after individual QT‐RR curve fitting. 4Sparfloxacin at both doses induced prolongation of the QT interval which was around 4% greater than placebo. No significant reverse rate‐dependence of QT interval prolongation was observed. 5Oral administration of sparfloxacin appears unlikely to be associated with marked QT interval prolongation.
Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes
Authors: ZOMORODI K. , HOUSTON J. B. 
Published: October 2003

1The metabolism of diazepam to its primary metabolites 3‐hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a Vmax /Kmratio of 0.50–7.26 μl min−1 mg −1 protein.2Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a Ki of 201±89 μm was obtained for the 3HDZ pathway (Km/Ki ratio of 3.0±0.9).3Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar Kis of 121±45 and 188±73 μm respectively (Km/Ki ratios of 5.2±2.3 and 3.3±1.5 respectively).4These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam‐omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.
Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients
Authors: GIACCONE M. , BARTOLI A. , GATTI G. , MARCHISELLI R. , PISANI F. , LATELLA M.A. , PERUCCA E. 
Published: October 2003

1To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine. 2Compared with controls, epileptic patients showed markedly shorter ethosuximide half‐lives (29.0±7.8 vs 53.7±14.3 h, means±s.d., P<0.001) and higher apparent oral clearance (CL/F) values (15.3±3.8 vs 9.2±1.9 ml kg−1 h−1, P<0.001). The apparent volume of distribution (V/F) of ethosuximide was slighty lower in the patients than in controls (0.6±0.1 vs 0.7±0.1 l kg−1, P<0.05). 3These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity. 4The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.
Pathophysiology of asthma
Authors: BARNES PETER J. 
Published: October 2003

1Our understanding of asthma and its therapy has changed markedly over the last few years, particularly with the application of molecular and cell biology and the discovery of new and more specific pharmacological tools. 2Many inflammatory cells participate in the inflammatory process in asthma and mediate a complex mixture of mediators. Cytokines are of particular importance as mediators of chronic inflammation and the means by which cytokines amplify and perpetuate the inflammatory process is now emerging. Airway epithelial cells may be a particularly important source of cytokines and other mediators, such as nitric oxide and endothelin, and may be a major target cell for inhaled steroids, which are the most effective therapy for asthma currently available. 3The inflammatory process in asthma results not only in bronchoconstriction, but also plasma exudation, the activation of neural mechanisms, mucus secretion. The chronic inflammation may lead to structural changes, including an increase in airway smooth muscle and fibrosis, that are essentially irreversible. There is increasing evidence that transcription factors, such as NF‐κB, play a pivotal role in the expression of inflammatory genes in asthma and may be the major molecular target for glucocorticoids.
Racial differences in propranolol enantiomer kinetics following simultaneous i.v. and oral administration
Authors: SOWINSKI KEVIN M. , LIMA JOHN J. , BURLEW BRAD S. , MASSIE JAMES D. , JOHNSON JULIE A. 
Published: October 2003

1Racial differences in propranolol enantiomer kinetics following oral dosing were previously documented in our laboratory. The purpose of this study was to more completely describe propranolol kinetics in black and white subjects with the goal of gaining a better understanding of the mechanism(s) responsible for racial differences in oral propranolol kinetics. 2Twelve white and 13 black healthy males were included in the study. Poor metabolizers of dextromethorphan and mephenytoin were excluded. Subjects took oral propranolol 80 mg every 8 h for 16 doses and received an intravenous dose of radiolabelled propranolol with the 16th dose. Serum and urine samples were collected for 24 h after the 16th dose. Serum concentrations of R‐ and S‐propranolol and urine concentrations of its three primary metabolites were determined by h.p.l.c. 3Apparent oral clearances of R‐ and S‐propranolol were higher (P<0.05) in blacks than whites (R‐propranolol: 5036±4175 ml min−1vs 2854±879 ml min−1; S‐propranolol 3255±1723 ml min−1vs 2125±510 ml min−1; blacks vs whites). 4R‐ and S‐propranolol clearances were higher in blacks than whites (R‐propranolol 1069±316 ml min−1vs 841±161 ml min−1; S‐propranolol 947±271 ml min−1vs 771±142 ml min−1; blacks vs whites, P<0.05). 5There were trends (P >0.05<0.10) toward higher side chain oxidation, 4‐hydroxylation and R‐propranolol glucuronidation in blacks compared with whites. Ethnic differences in the enantiomeric ratios of partial metabolic clearance values were not observed. 6We conclude the higher propranolol oral clearances in black subjects are explained by blacks having slightly higher hepatic metabolism via all three of its major metabolic pathways. Higher propranolol clearances among black subjects were also observed and we conclude this finding is explained largely by the higher hepatic metabolism, but also by slightly higher liver blood flow among black subjects.
Pharmacokinetics of bismuth and ranitidine following single doses of ranitidine bismuth citrate
Authors: KOCH K. M. , DAVIS I. M. , GOODING A. E. , YIN Y. 
Published: October 2003

1The pharmacokinetics of bismuth and ranitidine derived from ranitidine bismuth citrate given in single oral doses ranging from 200 mg to 1600 mg were evaluated in healthy subjects.2Bismuth was only minimally absorbed (<0.5% of the amount dosed) after administration of ranitidine bismuth citrate, and peak plasma concentrations never exceeded 33 ng ml−1 in any subject. Plasma concentrations and urinary recoveries of bismuth at doses up to and including 800 mg were relatively constant and not proportional to dose. Bismuth absorption was increased more than proportionally with the dose at 1600 mg.3The pharmacokinetics of ranitidine after administration of ranitidine bismuth citrate were dose‐proportional and consistent with previous observations for ranitidine administered alone.4Ranitidine bismuth citrate was well‐tolerated in single oral doses of up to 1600 mg.
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.