bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives
Authors: Farmer R. D. T. , Lawrenson R. A. , Todd J.‐C. , Williams T. J. , MacRae K. D. , Tyrer F. , Leydon G. M. 
Published: March 2003

Aims
In October 1995 in response to the results of three studies, the Committee on the Safety of Medicines advised doctors and pharmacists that oral contraceptives containing desogestrel (DSG) and gestodene (GST) were associated with around a two‐fold increase in the risk of thromboembolism compared with those containing other progestogens. The objective of this study was to estimate the risk of idiopathic venous thromboembolic disease (VTE) in users of combined oral contraceptives (COCs), to compare the risk between formulations and to examine the effect of using age banding as opposed to matching by exact year of birth.
Methods
A nested case control study was conducted using the General Practice Research Database. Women with a VTE event recorded between 1992 and 1997, who were treated with an anticoagulant, from consideration of their prescription records were likely to have been using a COC prescription on the day of the event and also had no exclusion factors, were deemed cases. For comparison with the previous studies, two nested case control studies were undertaken. Study 1 used controls matched by practice and year of birth. Study 2 used controls matched by practice and within 5 years age bands.
Results
We found an incidence of idiopathic VTE amongst users of combined oral contraceptives of 3.8 per 10 000 exposed women years. Incidence rates increased markedly after 35 years of age. The nested case‐control study using controls matched by year of birth showed no significant difference in risk between the major COC formulations. With levonorgestrel (LNG) 150 µg and ethinyloestradiol (EE) 30 µg as the reference, the adjusted ORs for GST 75 µg and EE 30 µg was 1.3 (95% CI 0.8, 2.1), for DSG 150 µg and EE 30 µg it was 1.0 (95% CI 0.7, 1.7) and for DSG 150 µg and EE 20 µg it was 0.8 (95% CI 0.4, 1.6). Using less rigorous matching criteria, matching controls to cases within 5 years age bands, the ORs increased. When a mixed group of COCs, characterized by having LNG as the progestogen component was used as the reference category, there was an elevation in the ORs for the newer products. We found a significant association between idiopathic VTE and current smoking (OR 2.0 (1.4, 2.7)), BMI over 35 (OR 3.8 (1.8, 8.0)) and asthma (OR 1.9 (1.3, 2.9)). The OR for women who had proxy evidence of general ill health (indicated by the number of prescriptions issued) was 2.2 (1.7, 3.7).
Conclusions
The results of this study indicate that a number of the characteristics of the women taking COCs affect the risk of VTE. There is no evidence to support the hypothesis that there is any difference in risk between COC formulations containing under 50 µg ethinyloestradiol.
Absorption of lefradafiban from different sites of the gastrointestinal tract
Authors: Drewe Jürgen , Narjes Hans , Heinzel Günther , Brickl Rolf‐Stefan , Rohr Andrea , Beglinger Christoph 
Published: March 2003

Aims
Fibrinogen receptor antagonists show a close relationship between plasma concentrations and inhibitory effect. Optimal efficacy at an acceptable bleeding risk requires low inter‐ and intrasubject variability on low peak trough fluctuation in receptor occupancy and therefore also of plasma concentrations. Therefore, the enteral absorption of lefradafiban, an orally available fibrinogen receptor antagonist prodrug, was investigated after local administrations to different sites of the gastrointestinal tract in order to investigate the feasibility of an oral extended release formulation.
Methods
Twelve healthy male subjects received in a randomised, open‐labelled, four‐period crossover trial four consecutive administrations of lefradafiban: 1. orally; 2. administration into the jejunum, 3. administration into the lower jejunum/ileum (300 cm distally to the teeth), and 4. administration into the lumen of the sigmoid region (30 cm proximally to the anus). Local intestinal administrations were performed through a gastrointestinal tube.
Results
Compared with oral administration, ratios [mean (two‐sided 90% confidence intervals)] of maximum drug plasma concentrations and AUC(0,24 h) of fradafiban were 1.05 (0.80,1.39) and 1.06 (0.85,1.31) after jejunal, 0.98 (0.75,1.30) and 0.98 (0.79,1.21) after ileal, 0.52 (0.39,0.69) and 0.68 (0.55,0.85) after colonic administration. Urinary excretion of fradafiban was about 16% of the dose after oral, jejunal and ileal applications whereas after rectal administration about 11% were excreted.
Conclusions
Lefradafiban is absorbed throughout the entire gastrointestinal tract. Therefore, an extended release formulation seems to be feasible with regard to bioavailability.
The incidence of adverse events and risk factors for upper gastrointestinal disorders associated with meloxicam use amongst 19 087 patients in general practice in England: cohort study
Authors: Martin Richard M. , Biswas Pipasha , Mann Ronald D. 
Published: March 2003

Aims
Meloxicam is a novel nonsteroidal anti‐inflammatory drug (NSAID) which may be associated with fewer adverse upper gastrointestinal events than other NSAIDs because it preferentially inhibits the inducible enzyme cyclo‐oxygenase‐2 relative to the constitutive isoform, cyclo‐oxygenase‐1. The aims of the study were to: determine the rate of adverse events associated with meloxicam in general practice, stratify these rates by selected risk factors, and to identify signals of previously unsuspected adverse events associated with meloxicam.
Methods
As part of the national prescription‐event monitoring pharmacovigilance system for newly launched drugs in general practice, all patients prescribed meloxicam in England between December 1996 and March 1997 were identified by the central Prescription Pricing Authority. We sent short questionnaires to all prescribers asking about adverse events experienced within 6 months of the first prescription.
Results
There were 19 087 patients in the study. The rate of dyspepsia during the first month of exposure was 28.3 per 1000 patient‐months. There were 33 reports of upper gastrointestinal haemorrhage during treatment (rate: 0.4 per 1000 months). A history of gastrointestinal disorder in the previous year was associated with an increased rate of dyspepsia (rate ratio: 3.0; 95% confidence interval: 2.6, 3.4), abdominal pain (2.1; 1.6, 2.6), and peptic ulcer (4.0; 1.4, 13.2). Prior NSAID use was associated with a 20–30% decrease in the rate of dyspepsia and abdominal pain in patients starting meloxicam, while patients prescribed concomitant gastroprotective agents had a two to three‐fold increased rate of dyspepsia, abdominal pain and peptic ulceration. Other rare events were thrombocytopenia (n = 2); interstitial nephritis (n = 1) and idiosyncratic liver abnormalities (n = 1).
Conclusions
In the absence of gastro‐intestinal risk factors the incidence of gastro‐intestinal disturbance was low. Such risk factors should be carefully reviewed prior to prescribing meloxicam.
Influence of asimadoline, a new κ‐opioid receptor agonist, on tubular water absorption and vasopressin secretion in man
Authors: Kramer H. J. , Uhl W. , Ladstetter B. , Bäcker A. 
Published: March 2003

Aims
The purpose of the study was to investigate the effects of asimadoline, a new κ‐opioid agonist, on renal function and on hormones related to body fluid balance as well as its tolerability in healthy subjects.
Methods
In a placebo‐controlled, randomised, double‐blind crossover design we studied the effects of single oral doses of 1, 5, and 10 mg of asimadoline, in 24 healthy volunteers. Two hour control urine collections were followed by 2 h postdose urine collections and subsequently 2.5% saline was given i.v. at a rate of 0.3 ml min−1 kg−1 during another 2 h urine collection. Blood was obtained hourly. Arginine‐vasopressin (AVP), atrial natriuretic peptide (α‐hANP), endothelin (ET‐1) and cAMP were determined by r.i.a. or ELISA.
Results
GC‐MS measurements revealed Cmax values of asimadoline in plasma ranging from 18 ng ml−1 at the 1 mg dose, 91 ng ml−1 at the 5 mg dose, to 214 ng ml−1 at the 10 mg dose after an average of 1.1–1.4 h. Without effects on blood pressure, heart rate, GFR or urine electrolyte excretion, urine volume increased after 1–2 h after administration of 5 and 10 mg asimadoline from 3.3 ± 1.3 to 5.6 ± 1.4 (P < 0.05) and from 3.2 ± 1.6 to 5.5 ± 2.2 ml min−1 (P < 0.01), respectively. CH2O rose from 0.2 ± 1.5 to 2.0 ± 1.6 (P < 0.05) and from 0.6 ± 1.6 to 3.0 ± 1.6 ml min−1 (P < 0.01). Urinary excretion of AVP was suppressed only with the 10 mg dose from 46 ± 23 to 25 ± 15 fmol min−1 (P < 0.05) without and from 410 ± 206 to 181 ± 125 fmol min−1 (P < 0.05) with stimulation by 2.5% saline. Plasma AVP was suppressed only by the 10 mg dose of asimadoline in six of eight subjects during the 2.5% saline infusion. Changes in the α‐hANP or ET‐1 systems were not affected by asimadoline.
Conclusions
Asimadoline is diuretic in man after single doses of 5 or 10 mg probably through a direct effect at the renal tubular level. Suppression of AVP secretion was observed only at the highest dose level of 10 mg of asimadoline.
The xenobiotic inhibitor profile of cytochrome P4502C8
Authors: Ong Chin‐Eng , Coulter Sally , Birkett Donald J. , Bhasker C. Ramana , Miners John O. 
Published: March 2003

Aims   To investigate inhibition of recombinant CYP2C8 by: (i) prototypic CYP isoform selective inhibitors (ii) imidazole/triazole antifungal agents (known inhibitors of CYP), and (iii) certain CYP3A substrates (given the apparent overlapping substrate specificity of CYP2C8 and CYP3A).Methods   CYP2C8 and NADPH‐cytochrome P450 oxidoreductase were coexpressed in Spodoptera frugiperda (Sf21) cells using the baculovirus expression system. CYP isoform selective inhibitors, imidazole/triazole antifungal agents and CYP3A substrates were screened for their inhibitory effects on CYP2C8‐catalysed torsemide tolylmethylhydroxylation and, where appropriate, the kinetics of inhibition were characterized. The conversion of torsemide to its tolylmethylhydroxy metabolite was measured using an h.p.l.c. procedure.Results   At concentrations of the CYP inhibitor ‘probes’ employed for isoform selectivity, only diethyldithiocarbamate and ketoconazole inhibited CYP2C8 by > 10%. Ketoconazole, at an added concentration of 10 µm, inhibited CYP2C8 by 89%. Another imidazole, clotrimazole, also potently inhibited CYP2C8. Ketoconazole and clotrimazole were both noncompetitive inhibitors of CYP2C8 with apparent Ki values of 2.5 µm. The CYP3A substrates amitriptyline, quinine, terfenadine and triazolam caused near complete inhibition (82–91% of control activity) of CYP2C8 at concentrations five‐fold higher than the known CYP3A Km. Kinetic studies with selected CYP3A substrates demonstrated that most inhibited CYP2C8 noncompetitively. Apparent Ki values for midazolam, quinine, terfenadine and triazolam ranged from 5 to 25 µm.Conclusions   Inhibition of CYP2C8 occurred at concentrations of ketoconazole and diethyldithiocarbamate normally employed for selective inhibition of CYP3A and CYP2E1, respectively. Some CYP3A substrates have the capacity to inhibit CYP2C8 activity and this may have implications for inhibitory drug interactions in vivo.
Frequency of cytochrome P450 2C9 mutant alleles in a Korean population
Authors: Yoon Young‐Ran , Shon Ji‐Hong , Kim Moon‐Kyung , Lim Young‐Chai , Lee Hye‐Rang , Park Ji‐Young , Cha In‐June , Shin Jae‐Gook 
Published: March 2003

Aims  To determine the frequencies of CYP2C9 variants in the Korean population and compare them with the frequencies in other ethnic populations.Methods  Genotyping of CYP2C9*2 and CYP2C9*3 allelic variants was carried out in 574 Korean subjects by PCR and restriction fragment length pattern analysis.Results  Thirteen of 574 subjects (2.3%) were heterozygous for CYP2C9*3 (Ile359Leu), but no subjects with a CYP2C9*2 allele or homozygous for CYP2C9*3 were identified. The allele frequency of CYP2C9*3 in Korean subjects (0.0113, 95% CI 0.0066–0.0193) was similar to that of other East Asian populations, but was considerably lower than that of Caucasian populations.Conclusions  CYP2C9*3 seems to be an allelic variant related to the functional polymorphism of CYP2C9, but this variant is rarely seen among Koreans compared with Caucasians. Routine genotyping of the CYP2C9*2 allele is considered to be unnecessary in Korean and East Asians, because this allele appears to be extremely rare or absent in these populations.
Outcomes of a randomized controlled trial of a clinical pharmacy intervention in 52 nursing homes
Authors: Roberts Michael S. , Stokes Julie A. , King Michelle A. , Lynne Teresa A. , Purdie David M. , Glasziou Paul P. , Wilson D. Andrew J. , McCarthy Sean T. , Brooks Geoffrey E. , De Looze Ferdinandus J. , Del Mar Christopher B. 
Published: March 2003

Aims  To evaluate whether a year long clinical pharmacy program involving development of professional relationships, nurse education on medication issues, and individualized medication reviews could change drug use, mortality and morbidity in nursing home residents.Methods  A cluster randomised controlled trial, where an intervention home was matched to three control homes, was used to examine the effect of the clinical pharmacy intervention on resident outcomes. The study involved 905 residents in 13 intervention nursing homes and 2325 residents in 39 control nursing homes in south‐east Queensland and north‐east New South Wales, Australia. The outcome measures were: continuous drug use data from government prescription subsidy claims, cross‐sectional drug use data on prescribed and administered medications, deaths and morbidity indices (hospitalization rates, adverse events and disability indices).Results  This intervention resulted in a reduction in drug use with no change in morbidity indices or survival. Differences in nursing home characteristics, as defined by cluster analysis with SUDAAN®, negated intervention‐related apparent significant improvements in survival. The use of benzodiazepines, nonsteroidal anti‐inflammatory drugs, laxatives, histamine H2‐receptor antagonists and antacids was significantly reduced in the intervention group, whereas the use of digoxin and diuretics remained similar to controls. Overall, drug use in the intervention group was reduced by 14.8% relative to the controls, equivalent to an annual prescription saving of $A64 per resident (approximately £25).Conclusions  This intervention improved nursing home resident outcomes related to changes in drug use and drug‐related expenditure. The continuing divergence in both drug use and survival at the end of the study suggests that the difference would have been more significant in a larger and longer study, and even more so using additional instruments specific for measuring outcomes related to changes in drug use.
Trans‐3′‐hydroxycotinine: Disposition kinetics, effects and plasma levels during cigarette smoking
Authors: Benowitz N. L. , Jacob P. 
Published: March 2003

Aims
(3′R,5′S)‐trans‐3′‐hydroxycotinine (3‐HC) is a major metabolite of nicotine. The aim of this study was to characterize the disposition kinetics of 3‐HC in healthy smokers, including metabolism to (3′R,5′S)‐trans‐3′‐hydroxycotinine glucuronide (3‐HC‐Gluc). We also studied pharmacologic responses to 3‐HC and plasma levels of 3‐HC in a group of smokers.
Methods
Eight cigarette smokers were studied on a clinical research ward. After 5 days of supervised nonsmoking, each subject received an intravenous infusion of 3‐HC, 4 µg kg−1 min−1 for 60 min. Plasma and urine levels of 3‐HC and 3‐HC‐Gluc and cardiovascular and subjective responses were examined. Plasma levels of 3‐HC, nicotine, and cotinine were measured in 62 smokers on up to three occasions.
Results
The total plasma clearance of 3‐HC averaged 1.3 ml min−1 kg−1, of which 63% was renal excretion of unchanged drug. An average of 29% of the dose was excreted as 3‐HC‐Gluc. 3‐HC did not have nicotine‐like cardiovascular effects.
Conclusions
These findings extend our understanding of the quantitative nature of nicotine metabolism. Such data may be of use in quantitating human exposure to nicotine from tobacco and in studying individual variability in nicotine metabolism.
Carbamazepine is not a substrate for P‐glycoprotein
Authors: Owen Andrew , Pirmohamed Munir , Tettey Justice N. , Morgan Paul , Chadwick David , Park B. Kevin 
Published: March 2003

Aims  To determine whether the anticonvulsant carbamazepine (CBZ), a known CYP3A4 substrate, is also a substrate for the multidrug efflux transporter P‐glycoprotein (Pgp).Methods  The role of Pgp in the transport of CBZ was assessed in three systems: (a) in mdr1a/1b(−/−) and wild‐type mice after administration of 2 mg kg−1 and 20 mg kg−1, which served as a model for brain penetration; (b) in Caco‐2 cells, an in vitro model of the intestinal epithelium that is known to express high Pgp levels; and (c) by flow cytometry in lymphocytes using rhodamine 123, a fluorescent substrate for PgP.Results  Brain penetration of both doses of CBZ at 1 h and 4 h was comparable in wild‐type and mdr1a/1b(−/−) mice. Transport across the Caco‐2 cell monolayer was Pgp‐independent, and was not affected by the Pgp inhibitor PSC‐833. CBZ had no effect on rhodamine 123 efflux from lymphocytes, in contrast to verapamil, which increased fluorescence intensity fivefold.Conclusion  CBZ is not a substrate for Pgp. Its efficacy is unlikely to be affected by Pgp over‐expression in the brain. Furthermore, the interaction of CBZ with drugs that modulate both CYP3A4 and Pgp function such as verapamil is probably due to inhibition of CYP3A4 and not Pgp.
Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p‐aminohippuric acid and pindolol
Authors: Gross A. S. , McLachlan A. J. , Minns I. , Beal J. B. , Tett S. E. 
Published: March 2003

Aims  Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect changes in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers, to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption.Methods  Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p‐aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac‐pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (mean± s.d.) was calculated as the ratio of the amount excreted in urine and the area‐under‐the‐concentration‐time curve. Statistical comparisons were made using a paired t‐test and 95% confidence intervals were reported.Results  The renal clearances of sinistrin (M: 119 ± 31 ml min−1; M + F: 130 ± 40 ml min−1; P = 0.32), PAH (M: 469 ± 145 ml min−1; M + F: 467 ± 146 ml min−1; P = 0.95), R‐pindolol (M: 204 ± 41 ml min−1; M + F: 190 ± 41 ml min−1; P = 0.39; n = 11), S‐pindolol (M: 225 ± 55 ml min−1; M + F: 209 ± 60 ml min−1; P = 0.27; n = 11) and fluconazole (F: 14.9 ± 3.8 ml min−1; M + F: 13.6 ± 3.4 ml min−1; P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F).Conclusions  This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes can be used to simultaneously investigate pathways of renal drug elimination.
Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers
Authors: Knoester P. D. , Jonker D. M. , Van Der Hoeven R. T. M. , Vermeij T. A. C. , Edelbroek P. M. , Brekelmans G. J. , De Haan G. J. 
Published: March 2003

Aims  To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects.Methods  Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross‐over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1‐hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. β‐band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model.Results  Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (±s.d.) peak plasma concentration of midazolam of 71 (±25 ng ml−1) was reached after 14 (±5 min). Mean bioavailability following intranasal administration was 0.83±0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11±0.25 l kg−1, mean systemic clearance 16.1±4.1 ml min−1 kg−1 and harmonic mean initial and terminal half lives 8.4±2.4 and 79±30 min, respectively. Formation of the 1‐hydroxymetabolite after intranasal administration did not exceed that after intravenous administration.Conclusions  In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.