bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do we need a new gastro‐oesophageal reflux disease questionnaire?
Authors: Stanghellini V. , Armstrong D. , Mönnikes H. , Bardhan K. D. 
Published: December 2004

SummaryBackground : Gastro‐oesophageal reflux disease (GERD) is highly prevalent in Western countries. Because the majority of patients do not present with endoscopic abnormalities, the assessment of the symptom severity and quality of life, and their response to treatment, has become increasingly important. Self‐assessed symptom questionnaires are now key instruments in clinicaltrials.Aim : To evaluate the validity of available GERD measurement tools.Methods : An ideal GERD symptom assessment instrument, suitable as a primary end‐point for clinical trials, should possess the following characteristics: (i) be sensitive in patients with GERD; (ii) cover the frequency and intensity of typical and atypical GERD symptoms; (iii) be multidimensional (cover all symptom dimensions); (iv) have proven psychometric properties (validity, reliability and responsiveness); (v) be practical and economical; (vi) be self‐assessed; (vii) use ‘word pictures’ which are easy to understand for patients; (viii) respond rapidly to changes (responsiveness over short time intervals); (ix) be used daily to assess changes during and after therapy; and (x) be valid in different languages for international use.Results : A literature review revealed five scales that met some of the above characteristics, but did not fulfil all criteria.Conclusion : There is a need for a new evaluative tool for the assessment of GERD symptoms and their response to therapy.
The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti‐migraine drug zolmitriptan (311C90) in healthy volunteers
Authors: Dixon* Ruth , Gillotin Catherine , Gibbens Michael , Posner John , Peck Richard W. 
Published: December 2004

Aims Zolmitriptan (311C90), a novel, selective, centrally and peripherally acting 5‐HT1D‐receptor agonist is under development as an acute treatment for migraine. The tolerability, pharmacokinetics and effects on blood pressure and heart rate of multiple doses of 5 or 10 mg (5 doses administered over 24 h) were compared, in healthy adult volunteers, with those after placebo and single doses of zolmitriptan. Methods Twelve subjects participated in a randomized, balanced, crossover comparison. Plasma and urine concentrations of zolmitriptan and its metabolites, pulse rate and blood pressure were measured at intervals after drug. Ten volunteers completed the study. Results Zolmitriptan was well tolerated after single and multiple doses throughout the study. There was no evidence of significant changes in the pharmacokinetic parameters of zomitriptan or its metabolites after the last dose compared to the first, except for an expected rise in peak concentrations and a small, apparent increase in the amount of drug excreted in urine and hence in CLR. After the last 10 mg dose, mean dosing interval zolmitriptan AUC was 80.3 ng ml−1 h compared with 86.5 ng ml−1 h after the single 10 mg dose (95% CI for ratio 0.76–1.13). There was no evidence of changes in the pharmacokinetic parameters of zolmitriptan and its metabolites after 10 mg compared with 5 mg, except a small increase in zolmitriptan CLR. There were no statistically significant increases in peak systolic or diastolic blood pressure after the last doses of zolmitriptan compared to placebo or in peak blood pressure after the last dose compared to the first. There were no significant differences between blood pressure immediately before the first and last doses of each multiple dose regimen. Peak erect systolic blood pressure after the last 10 mg dose (137 mmHg) was significantly lower than that after placebo (147 mmHg, 95% CI for difference −18, −2) and that after the last 5 mg dose (148 mmHg, 95% CI −19, −3). Conclusions Repeated doses of 5 or 10 mg zolmitriptan are well tolerated despite higher plasma concentrations than expected from single doses.
Evidence for involvement of human CYP3A in the 3‐hydroxylation of quinine
Authors: Zhang H. , Coville P. F. , Walker R. J. , Miners J. O. , Birkett D. J. , Wanwimolruk S. 
Published: December 2004

Aims Our previous studies using in vitro hepatic microsomal preparations suggested that the hepatic metabolism of quinine to form the major metabolite 3‐hydroxyquinine is most likely catalysed by human P450 3A (CYP3A). The present study was carried out to investigate the kinetics and to identify and further characterise the human liver CYP isoforms involved in the metabolism of quinine. Methods In vitro human microsomal techniques were employed. Results The mean apparent Km value for 3‐hydroxyquinine formation was 83±19 (s.d.) μm, ranging from 57 μm to 123 μm in microsomes from ten human livers. There was a 6.7‐fold variation in Vmax values (mean 547±416 pmol min−1 mg−1 ). Quinine 3‐hydroxylation was inhibited by the specific CYP3A inhibitors, troleandomycin, midazolam and erythromycin. Inhibitors selective for CYP1A1/2, CYP2D6, CYP2E1, CYP2C9/10 or CYP2C19 had little or no effect on quinine 3‐hydroxylation. Using microsomes from a panel of livers, significant correlations were found only between 3‐hydroxyquinine activity and other CYP3A activities (caffeine 8‐oxidation, omeprazole sulphoxidation, midazolam 1′‐hydroxylation and midazolam 4‐hydroxylation) and immunoreactive CYP3A content. There were no statistically significant correlations with activities selective for CYP1A2, CYP2C9 and CYP2E1. Competitive inhibition of quinine 3‐hydroxylation was observed with a substrate known to be specifically metabolized by human CYP3A, i.e. midazolam, with an apparent Ki value of 11.0 μm. Conclusions The present results strongly indicate that the conversion of quinine to 3‐hydroxyquinine is the major metabolic pathway in human liver in vitro and that the reaction is catalysed by CYP3A isoforms.
Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler
Authors: Hindle M. , Peers E. M. , Parry‐Billings M. , Chrystyn H. 
Published: December 2004

Aims The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI. Methods A randomized, double‐blind, two way crossover study compared the amount of salbutamol in the urine 30 min following inhalation of 2×100 μg salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin® (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24 h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body. Results The mean (s.d.) 30 min post‐treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9) μg, respectively (P<0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24 h period after inhalation was 187.9 (77.6) and 137.6 (40.0) μg (P<0.05). Conclusions The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.
Phenotyping CYP3A using midazolam in cancer and noncancer Asian patients
Authors: Lee How Sung , Goh Boon Cher , Fan Lu , Khoo Yok Moi , Wang Lingzhi , Lim Robert , Ong Ai Bee , Chua Charlotte 
Published: December 2004

Aims
To investigate CYP3A activity in cancer and noncancer Asian patients using midazolam and to reveal possible alternative traits for phenotyping CYP3A.
Methods
Intravenous midazolam 2.5 mg or 2.5–8 mg was administered to 27 cancer and 24 noncancer patients, respectively. Plasma was sampled at 0, 0.25, 0.5, 1, 1.5, 2, 3.5 and 5 h after intravenous ultrashort, 30 s infusion. Plasma midazolam and 1′‐hydroxymidazolam concentrations were determined using GCMS. The disposition of midazolam and 1′‐hydroxymidazolam in these patients was compared. Midazolam clearance was correlated with dose‐normalized plasma midazolam concentrations (concentration/per dose).
Results
Clearance (CL) and steady state volume of distribution (Vss) of midazolam (mean ± SD, 95% confidence level) in cancer (424 ± 155, 61.3 ml min−1; 1.21 ± 0.46, 0.18 l kg−1) and noncancer (407 ± 135, 57.1 ml min−1; 1.15 ± 0.33, 0.155 l kg−1) patients, respectively, were not different and comparable with published data. Clearance variability was 4–5 fold in both groups. Midazolam clearance correlated significantly with all plasma concentration/per dose at and after the  1‐h time point, with a minimum correlation coefficient of r = 0.752, P < 0.001.
Conclusions
CYP3A activities determined with different doses of midazolam in cancer and noncancer Asian patients showed variability of 4–5‐fold and were not different between groups. One to two‐fold plasma midazolam concentrations per dose may be feasible as a simple alternative phenotypic trait for hepatic CYP3A activity determination.
Planning and monitoring of placebo‐controlled survival trials: comparison of the triangular test with usual interim analyses methods
Authors: Hulot Jean‐Sébastien , Cucherat Michel , Charlesworth Andrew , Van Veldhuisen Dirk J. , Corvol Jean‐Christophe , Mallet Alain , Boissel Jean‐Pierre , Hampton John , Lechat Philippe 
Published: December 2004

Aims
For ethical and economic reasons, interim analysis of phase III clinical trials is essential. This study was conducted to compare the efficiency of two interim analysis procedures, which could be used to allow early termination of a clinical trial.
Methods
We made a post hoc application of two interim analysis methods (Lan & DeMets with O’Brien–Flemming modification, and the triangular test according to Whitehead) by using individual patient data from four published placebo‐controlled survival trials. We determined the date the trial would have been stopped had each method been used, and we estimated consequent results in terms of events and patient numbers included in the trial, the duration of the trial, and on treatment effect.
Results
The triangular test provided the lowest number of events required to reach a conclusion of the trials while providing an accurate estimate of experimental treatment effects. The triangular test thus indicated the smallest number of patients that would have been enrolled, and the shortest trial duration. The difference between the methods was most important with a detrimental effect of experimental treatment: the number of required events was reduced by 75% and the trial duration was shortened by 48% with the triangular test compared to the Lan & DeMets method.
Conclusions
Stopping a trial early must depend on the clinical context. It is most important to stop a placebo‐controlled trial as soon as possible when the experimental treatment can be shown deleterious. In such a situation the triangular test is more appropriate than the Lan & DeMets method. When a treatment effect is no different from, or better than, placebo the triangular test is also superior but the importance of premature termination of the trial in such cases has to be balanced against the inevitable reduction of information that the trial can provide.
Influence of captopril on symptomatic and hormonal responses to hypoglycaemia in humans
Authors: Oltmanns Kerstin M. , Deininger Eva , Wellhoener Peter , Schultes Bernd , Kern Werner , Marx Esther , Dominiak Peter , Born Jan , Fehm Horst L. , Peters Achim 
Published: December 2004

Aims  Hypoglycaemic symptoms and hormonal counter‐regulation are of high importance to avoid the risk of severe hypoglycaemia in patients with diabetes mellitus. Various antihypertensive drugs, such as angiotensin‐converting enzyme (ACE) inhibitors, have been suspected for a long time to reduce this response to hypoglycaemia in diabetic subjects. Although ACE inhibitors are approved for controlling diabetic complications, previous investigations regarding this putative side‐effect are controversial.Methods  We performed clamp experiments in 16 healthy men lasting for 6 h each. The subjects were pretreated for 7 days with captopril 3 × 25 mg day−1vs placebo in a randomized, double‐blind, crossover study. Plasma glucose was decreased in a stepwise manner during a hypoglycaemic clamp session and counter‐regulatory hormones [epinephrine (adrenaline), norepinephrine (adrenaline), ACTH, cortisol, glucagon], symptoms, and haemodynamic parameters (blood pressure, heart rate] were measured.Results  Counter‐regulatory hormone concentrations significantly increased in both sessions (ACE inhibitor vs placebo) during hypoglycaemia. The rise of counter‐regulatory hormones as well as symptom scores were equal under both ACE inhibitor and placebo treatment. Systolic blood pressure and heart rate increased (from 110 ± 3 vs 115 ± 3 mmHg to 132 ± 4 vs 133 ± 4 mmHg) whereas diastolic blood pressure slightly decreased (from 63 ± 2 vs 70 ± 3 mmHg to 61 ± 2 vs 64 ± 2 mmHg) independent of pretreatment. Systolic and diastolic blood pressure were significantly lower in the captopril session vs placebo (P < 0.05).Conclusions  Our results demonstrate that subchronic treatment with captopril does not attenuate symptomatic and hormonal response to hypoglycaemia. Thus, to patients at risk of hypoglycaemia who require antihypertensive or nephroprotective treatment, we would continue giving an ACE inhibitor.
Aspirin for the prevention of cardiovascular disease: calculating benefit and harm in the individual patient
Authors: Loke Yoon Kong , Bell Alastair , Derry Sheena 
Published: December 2004

Aims
To estimate the absolute reduction in the risk of cardiovascular events and absolute increase in gastrointestinal haemorrhage associated with aspirin for individuals with different baseline risks.
Methods
Calculation of absolute treatment effects from estimates of: (i) baseline risks for cardiovascular event and gastrointestinal haemorrhage; and (ii) relative risks of these events with treatment. Baseline cardiovascular risks were derived from existing risk scores, and baseline risk of gastrointestinal haemorrhage from an observational cohort study. Changes in relative risks were obtained from clinical trial data. The effects of aspirin treatment were calculated in examples of two individuals with very different baseline risks.
Results
Treatment of a healthy  74‐year‐old man (blood pressure 144/88 mm Hg and no history of gastrointestinal disorder) would reduce his annual risk of a cardiovascular event from 2% to 1.74% (absolute risk reduction 0.26%, number needed to treat 385), but increase the gastrointestinal haemorrhage risk from 0.3% to 0.51% (absolute risk increase 0.21%, number needed to harm 476). In a  66‐year‐old obese man, following a transient ischaemic attack, and with a history of hospital treatment for a peptic ulcer, the annual risk of a cardiovascular event would be reduced from 5% to 4.35% (absolute risk reduction 0.65%, number needed to treat 153), but the risk of gastrointestinal haemorrhage would increase from 1.08% to 1.83% (absolute risk increase 0.75%, number needed to harm 133).
Conclusions
Estimating benefit and harm by taking into account the baseline risks in each individual allows patients and doctors to judge for themselves the magnitude of the trade‐offs involved in taking aspirin.
Time effects of food intake on the pharmacokinetics and pharmacodynamics of quazepam
Authors: Yasui‐Furukori Norio , Takahata Takenori , Kondo Tsuyoshi , Mihara Kazuo , Kaneko Sunao , Tateishi Tomonori 
Published: December 2004

Aims  There is little information on interaction between food and the hypnotic agent quazepam. We therefore studied the effects of food and its time interval on the pharmacokinetics and pharmacodynamics of quazepam.Methods  A randomized three‐phase crossover study with 2‐week intervals was conducted. Nine healthy male volunteers took a single oral 20 mg dose of quazepam under the following conditions: 1) after fasting overnight; 2) 30 min after eating standard meal; or 3) 3 h after eating the same meal. Plasma concentrations of quazepam and its metabolite, 2‐oxoquazepam and psychomotor function using the Digit Symbol Substitute Test (DSST), Stanford Sleepiness Scale (SSS) and Visual Analogue Scale were measured up to 48 h.Results  During the food treatments at 30 min and 3 h before dosing, the peak concentrations (Cmax) were 300% (95% CI 260, 340%; P < 0.001) and 250% (95% CI 210, 290%; P < 0.01) of the corresponding value during the fasting phase. For quazepam, the area under the plasma concentration–time curve from 0 to 8 h measured at 30 min and 3 h before dosing was significantly increased, with the food treatments by 2.4‐fold (95% CI 2.0; 2.8‐fold; P < 0.001) and 2.1‐fold (95% CI 1.7; 2.4‐fold; P < 0.01), respectively. In response to pharmacokinetic changes, some of the pharmacodynamics (DSST, P < 0.05; SSS, P < 0.05) differed significantly between fasted status and fed status. No difference was found in any pharmacokinetic or pharmacodynamic parameters between the two food treatment phases.Conclusions  A food effect on quazepam absorption is evident and continues at least until 3 h after food intake. The dosing of quazepam after a long period of ordinary fasting might reduce its efficacy because a 3 h interval between the timing of the evening meal and bedtime administration of hypnotics is regarded as normal in daily life.
A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment
Authors: Shiran M. R. , Chowdry J. , Rostami‐Hodjegan A. , Ellis S. W. , Lennard M. S. , Iqbal M. Z. , Lagundoye O. , Seivewright N. , Tucker G. T. 
Published: December 2004

Aims  To assess CYP2D6 activity and genotype in a group of patients undergoing methadone maintenance treatment (MMT).Methods  Blood samples from 34 MMT patients were genotyped by a polymerase chain reaction‐based method, and results were compared with CYP2D6 phenotype (n = 28), as measured by the molar metabolic ratio (MR) of dextromethorphan (DEX)/dextrorphan (DOR) in plasma.Results  Whereas 9% of patients (3/34) were poor metabolizers (PM) by genotype, 57% (16/28) were PM by phenotype (P < 0.005). Eight patients, who were genotypically extensive metabolizers (EM), were assigned as PM by their phenotype. The number of CYP2D6*4 alleles and sex were significant determinants of CYP2D6 activity in MMT patients, whereas other covariates (methadone dose, age, weight) did not contribute to variation in CYP2D6 activity.Conclusions  There was a discordance between genotype and in vivo CYP2D6 activity in MMT patients. This finding is consistent with inhibition of CYP2D6 activity by methadone and may have implications for the safety and efficacy of other CYP2D6 substrates taken by MMT patients.
Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil
Authors: Shum B. , Duffull S. B. , Taylor P. J. , Tett S. E. 
Published: December 2004

Aim  To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between‐ and within‐subject variability and to evaluate the influence of covariates on the pharmacokinetic variability.Methods  Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration–time points were available. Data were analysed using the first‐order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler.Results  The best base model was a two‐compartment model with a lag time (apparent oral clearance was 27 l h−1, and apparent volume of the central compartment 98 l). There was visual evidence of complex absorption and time‐dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined.Conclusions  The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between‐subject and between‐occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.
Elimination of ephedrines in urine following multiple dosing: the consequences for athletes, in relation to doping control
Authors: Chester Neil , Mottram David R. , Reilly Thomas , Powell Mark 
Published: December 2004

Aims  To study the elimination of ephedrines with reference to the International Olympic Committee (IOC) doping control cut‐off levels, following multiple dosing of over‐the‐counter decongestant preparations.Methods  A double‐blind study was performed in which 16 healthy male volunteers were administered either pseudoephedrine or phenylpropanolamine in maximal recommended therapeutic doses over a 36‐h period. Urine was collected every two hours between 08:00 and 24:00 h and at 04:00 h throughout the testing period of three days. Urine drug levels were quantified using high performance liquid chromatography. Side‐effects were assessed, including heart rate and blood pressure, every four hours between 08:00 and 20:00 h.Results  Mean (95% CI) total phenylpropanolamine and pseudoephedrine eliminated unchanged was 75 (88, 61) and 81 (92, 71)%, respectively. Maximum urine concentrations of phenylpropanolamine and pseudoephedrine were 112.1 (164.2, 59.9) and 148.5 (215.0, 82.1) mg.l−1, respectively. A peak in drug urine concentration occurred four hours following the final dose. There were no adverse cardiovascular effects and only mild CNS stimulation was evident.Conclusions  Following therapeutic, multiple dosing, drug levels remain above the IOC cut‐off levels for a minimum of 6 h and 16 h following final doses of phenylpropanolamine and pseudoephedrine, respectively. Athletes require informed advice on this from their healthcare professionals.