bluuebunny/crossref_metadata_2025_split huggingface dataset:
Review article: extraoesophageal manifestations of gastro‐oesophageal reflux disease
Authors: RICHTER J. E. 
Published: July 2005

SummaryAlthough recent studies suggest that gastro‐oesophageal reflux disease may frequently contribute to ear, nose and throat and respiratory diseases, the cause‐and‐effect relationship is far from proven. The review will address this controversial topic emphasizing recent literature raising concerns about the credibility of this association and our tests to make this diagnosis. The author believes these extraoesophageal symptoms suspected to be secondary to gastro‐oesophageal reflux disease are an unresolved issue, but selective use of aggressive proton‐pump inhibitor therapeutic trials may help to resolve this problem in our individual patients.
Inhibition of the metabolism of brotizolam by erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in brotizolam metabolism
Authors: Tokairin Takaki , Fukasawa Takashi , Yasui‐Furukori Norio , Aoshima Toshiaki , Suzuki Akihito , Inoue Yoshimasa , Tateishi Tomonori , Otani Koichi 
Published: July 2005

AimsTo obtain in vivo evidence for the involvement of cytochrome P450 (CYP) 3A4 in the metabolism of brotizolam.MethodsFourteen healthy male volunteers received erythromycin 1200 mg day−1 or placebo for 7 days in a double‐blind randomized crossover manner. On the 6th day they received a single oral 0.5‐mg dose of brotizolam, and blood samplings were performed for 24 h.ResultsErythromycin treatment significantly increased the peak plasma concentration (P < 0.05), total area under the plasma concentration‐time curve (P < 0.01), and elimination half‐life (P < 0.01) of brotizolam.ConclusionsThe present study provides in vivo evidence for the involvement of CYP3A4 in brotizolam metabolism.
Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide
Authors: Niemi Mikko , Backman Janne T. , Juntti‐Patinen Laura , Neuvonen Mikko , Neuvonen Pertti J. 
Published: July 2005

Background and aimsGemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration‐time curve [AUC(0, ∞)] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro, gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil‐itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4.MethodsIn a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30‐mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h.ResultsDuring the gemfibrozil‐itraconazole phase, the AUC(0, ∞) and Cmax of nateglinide were 47% (range 23–74%; P < 0.0001) and 30% (range − 8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the tmax and t1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole.ConclusionsThe combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.
Do nonsteroidal anti‐inflammatory drugs affect the risk of developing ovarian cancer? A meta‐analysis
Authors: Bonovas Stefanos , Filioussi Kalitsa , Sitaras Nikolaos M. 
Published: July 2005

AimThe relationship between the use of nonsteroidal anti‐inflammatory drugs (NSAIDs), including aspirin, and the risk of ovarian cancer has been controversial. This study examines the strength of this association by conducting a detailed meta‐analysis of the studies published in peer‐reviewed literature on the subject.MethodsA comprehensive search for articles published up to April 2004 was performed, reviews of each study were conducted and data were abstracted. Prior to meta‐analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated.ResultsTen reports (six case–control and four cohort studies), published between 1998 and 2004, were identified. There was no evidence of an association between aspirin use and ovarian cancer risk either assuming a random‐effects model (RR = 0.92, 95% CI 0.80, 1.06), or a fixed‐effects model (RR = 0.93, 95% CI 0.81, 1.06). Similarly, we did not find evidence of an association between non‐aspirin NSAID use and ovarian cancer, both on the basis of a random‐effects model (RR = 0.86, 95% CI 0.68, 1.08), and on the basis of a fixed‐effects model (RR = 0.88, 95% CI 0.76, 1.01). When the analyses were stratified into subgroups, there was no evidence that study design substantially influenced the estimate of effects. Furthermore, our analysis did not show decreasing risks with increasing frequency or duration of use, features often associated with causal relationships.ConclusionsOur meta‐analysis findings do not support that NSAID use plays a role in the chemoprevention of ovarian cancer. Future research should examine potential relationships between specific NSAIDs and ovarian cancer, taking into account the possible biases that may have affected this meta‐analysis.
Pharmaceutical care of patients with heart failure
Authors: Sadik A. , Yousif M. , McElnay J. C. 
Published: July 2005

AimThe aim of this study was to investigate the impact of a pharmacist‐led pharmaceutical care programme, involving optimization of drug treatment and intensive education and self‐monitoring of patients with heart failure (HF) within the United Arab Emirates (UAE), on a range of clinical and humanistic outcome measures.MethodsThe study was a randomized, controlled, longitudinal, prospective clinical trial at Al‐Ain Hospital, Al‐Ain, UAE. Patients were recruited from the general medical wards and from cardiology and medical outpatient clinics. HF patients who fulfilled the entrance criteria, and had no exclusion criteria present, were identified for inclusion in the study. After recruitment, patients were randomly assigned to one of two groups: intervention group or control group. Intervention patients received a structured pharmaceutical care service while control patients received traditional services. Patient follow‐up took place when patients attended scheduled outpatient clinics (every 3 months). A total of 104 patients in each group completed the trial (12 months). The patients were generally suffering from mild to moderate HF (NYHA Class 1, 29.5%; Class 2, 50.5%; Class 3, 16%; and Class 4, 4%).ResultsOver the study period, intervention patients showed significant (P < 0.05) improvements in a range of summary outcome measures [AUC (95% confidence limits)] including exercise tolerance [2‐min walk test: 1607.2 (1474.9, 1739.5) m·month in intervention patients vs. 1403.3 (1256.5, 1549.8) in control patients], forced vital capacity [31.6 (30.8, 32.4) l·month in the intervention patients vs. 27.8 (26.8, 28.9) in control patients], health‐related quality of life, as measured by the Minnesota living with heart failure questionnaire [463.5 (433.2, 493.9) unit·month in intervention patients vs. 637.5 (597.2, 677.7) in control patients; a lower score in this measure indicates better health‐related quality of life]. The number of individual patients who reported adherence to prescribed medications was higher (P < 0.05) in the intervention group (85 vs. 35), as was adherence to lifestyle advice (75 vs. 29) at the final assessment (12 months). There was a tendency to have a higher incidence of casualty department visits by intervention patients, but a lower rate of hospitalization.ConclusionsThe research provides clear evidence that the delivery of pharmaceutical care to patients with HF can lead to significant clinical and humanistic benefits.
Inappropriate drug prescribing in older adults: the updated 2002 Beers criteria – a population‐based cohort study
Authors: Van Der Hooft Cornelis S. , Jong Geert W.’t , Dieleman Jeanne P. , Verhamme Katia M. C. , Van Der Cammen Tischa J. M. , Stricker Bruno H. CH. , Sturkenboom Miriam C. J. M. 
Published: July 2005

BackgroundIn 1997, Beers and colleagues developed explicit criteria for potentially inappropriate drug prescribing in ambulatory older adults aged 65 years and over. Several studies have been performed to estimate the prevalence of inappropriate drug prescribing based on these criteria. In 2002, the criteria were updated.AimsTo examine the extent and trend of inappropriate drug prescribing to ambulatory older adults in the Netherlands between 1997 and 2001, according to the 1997 and the updated Beers criteria.MethodsData were retrieved from the Integrated Primary Care Information (IPCI) project, a general practice research database with data from computer‐based patient records of a group of 150 general practitioners in the Netherlands. All subjects aged 65 and over were included. Prescriptions were classified as inappropriate if they fulfilled the Beers criteria of prescriptions that generally should be avoided in older adults because of a high risk of adverse effects, while also considering dose and comorbidity.ResultsBetween 1997 and 2001, the 1‐year risk of receiving at least one inappropriate drug prescription for older adults ranged between 16.8% (95% CI: 16.3–17.3%) and 18.5% (18.3–18.7%) according to the 1997 criteria and between 19.1% (18.6–19.6%) and 20.0% (19.5–20.5%) according to the updated Beers criteria. According to the updated criteria, the most frequently prescribed inappropriate drugs were nitrofurantoin, long‐acting benzodiazepines, amitriptyline, promethazine and cimetidine. Temazepam and zolpidem were mostly prescribed in supratherapeutic dose. Conventional NSAIDs in persons with a history of gastric/duodenal ulcer were the most frequently prescribed contra‐indicated drugs.ConclusionsPrescribing potentially inappropriate prescriptions to ambulatory older people in the Netherlands is substantial. Compared with other studies using the 1997 Beers criteria, inappropriate prescribing to the elderly is lower than in the USA but similar to Finland. Despite a restrictive medication policy and a growing attention for medication surveillance in Europe, inappropriate drug prescribing is still a substantial problem.
Meta‐analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression
Authors: Chowbay Balram , Li Huihua , David Machin , Bun Cheung Yin , Lee Edmund J. D. 
Published: July 2005

AimsStudies revealing conflicting results of the functional significance of MDR1 exon 26 C3435T SNP on the disposition of digoxin in different ethnic groups led us to perform a meta‐analysis on published data investigating the influence of C3435T SNP on the pharmacokinetics of digoxin and the expression of MDR1.MethodsMeta‐analysis was performed on data from published studies investigating the influence of MDR1 C3435T SNP on digoxin pharmacokinetics, as well as MDR1 expression in Caucasian and Japanese populations. The following outcomes were included: exposures to digoxin measured by area under the concentration–time curve and maximum concentration, the mean intestinal MDR1 mRNA expression and P‐gp expression in the absence of digoxin administration.ResultsThe overall results of the meta‐analysis in Caucasian and Japanese subjects suggested no major influence of the C3435T SNP on exposure levels of digoxin as determined by AUC0−4 h or AUC0−24 h although Cmax values for digoxin were lower in wild‐type (CC) subjects compared with subjects harbouring TT genotypes. Subgroup analysis by ethnic populations showed the oral availability of digoxin to be lower in wild‐type Caucasian populations compared with wild‐type Japanese subjects. No causal relationships were detected between the C3435T SNP and MDR1 mRNA or protein expression.ConclusionsOur meta‐analysis of available studies indicates that the synonymous MDR1 C3435T SNP does not affect the pharmacokinetics of digoxin and the expression of MDR1 mRNA. Future studies should focus on the impact of MDR1 haplotypes on the pharmacokinetics of MDR1 substrates rather than the C3435T SNP alone.
Kidneys contribute to the extrahepatic clearance of propofol in humans, but not lungs and brain
Authors: Hiraoka Haruhiko , Yamamoto Koujirou , Miyoshi Soutarou , Morita Toshihiro , Nakamura Katsunori , Kadoi Yuuji , Kunimoto Fumio , Horiuchi Ryuya 
Published: July 2005

AimsThe principal site for the metabolism of propofol is the liver. However, the total body clearance of propofol is greater than the generally accepted hepatic blood flow. In this study, we determined the elimination of propofol in the liver, lungs, brain and kidneys by measuring the arterial‐venous blood concentration at steady state in patients undergoing cardiac surgery.MethodsAfter induction of anaesthesia, propofol was infused continuously during surgery. For measurement of propofol concentration, blood samples were collected from the radial and pulmonary artery at predetermined intervals. In addition, blood samples from hepatic and internal jugular vein were collected at the same times in 19 patients in whom a hepatic venous catheter was fitted and the other six in whom an internal jugular venous catheter was fitted, respectively. In six out of 19 patients fitted with a hepatic venous catheter, blood samples from the radial artery and the renal vein were also collected at the same time, when the catheter was inserted into the right renal vein before insertion into the hepatic vein.ResultsHepatic clearance of propofol was approximately 60% of total body clearance. The hepatic extraction ratio of propofol was 0.87 ± 0.09. There was no significant difference in the concentration of propofol between the radial, pulmonary arteries and internal jugular vein. However, a high level of propofol extraction in the kidneys was observed – the renal extraction ratio being 0.70 ± 0.13.ConclusionsWe have demonstrated substantial renal extraction of propofol in human. Metabolic clearance of propofol by the kidneys accounts for almost one‐third of total body clearance and may be the major contributor to the extrahepatic elimination of this drug.
Angiotensin II receptor blocker‐induces blunted taste sensitivity: comparison of candesartan and valsartan
Authors: Tsuruoka Shuichi , Wakaumi Michi , Ioka Takashi , Yamamoto Hisashi , Ando Hitoshi , Sugimoto Kohichi , Fujimura Akio 
Published: July 2005

AimsTo compare the degree of taste disturbance by candesartan and valsartan.MethodsCandesartan cilexetil (4 mg day−1), valsartan (40 mg day−1), or vehicle was given to subjects (n = 8) for 13 days in a randomized, placebo‐controlled, three‐way crossover design with a 14‐days washout period. Gustometry by filter‐paper test and electrogustometry were performed before and at the end of each trial. Plasma renin activity and zinc concentrations in serum and saliva were measured.ResultsDetection thresholds of four basic tastes (sweet, salty, sour and bitter) by paper‐disc test and electrogustometry were significantly worsened and plasma renin activity was elevated after the test, while the effects of two drugs did not significantly differ. These drugs did not affect zinc concentrations.ConclusionBoth candesartan and valsartan similarly alter taste sensitivity after the repeated dosing of the drug.
Assessment of the effect of a single oral dose of telithromycin on sotalol‐induced qt interval prolongation in healthy women
Authors: Démolis Jean‐Louis , Strabach Soraya , Vacheron Françoise , Funck‐Brentano Christian 
Published: July 2005

AimsTelithromycin belongs to ketolides, a new class of macrolide antibiotics. Macrolides are known to have the potential to prolong QT interval duration. Previous studies have shown that telithromycin did not induce significant QT interval prolongation in healthy subjects compared with placebo. The main objective of this study was to demonstrate the absence of amplification of QT interval prolongation induced by sotalol, when telithromycin and sotalol were co‐administered. The secondary objective was to correlate the QT interval changes induced by the study drugs to plasma concentrations during the elimination phase.MethodsTwenty‐four women received sotalol (160 mg) together with placebo or telithromycin (800 mg) in a two‐period, double‐blind, randomized study. Electrocardiograms were recorded at rest. Comparison of maximal corrected QT interval (QTcmax) with sotalol in the presence or absence of telithromycin was performed. The relation between sotalol concentration and QTc was studied using linear regression.ResultsMean difference (95% CI) between QTcmaxwith sotalol‐placebo and QTcmaxwith sotalol‐telithromycin was −15.5 ms (−27.7 to −3.2 ms). QTcmaxinterval prolongation was lower (P < 0.05) with sotalol‐telithromycin than with sotalol‐placebo, in relation to decreased sotalol plasma concentrations. Regression analysis showed that the relationship between sotalol plasma concentration and QTc interval duration was not modified by telithromycin co‐administration.ConclusionOur results do not support a potential synergistic effect on QT interval prolongation between sotalol and telithromycin. The decrease of mean QTc interval in subjects taking telithromycin and sotalol may be explained by a decrease of sotalol concentration.
The central nervous system effects, pharmacokinetics and safety of the NAALADase‐inhibitor GPI 5693
Authors: Van Der Post J. P. , De Visser S. J. , De Kam M. L. , Woelfler M. , Hilt D. C. , Vornov J. , Burak E. S. , Bortey E. , Slusher B. S. , Limsakun T. , Cohen A. F. , Van Gerven J. M. A. 
Published: July 2005

AimThe aim was to assess the central nervous system (CNS) effects, pharmacokinetics and safety of GPI 5693, an inhibitor of a novel CNS‐drug target, NAALADase which is being evaluated for the treatment of neuropathic pain.MethodsThis was a double‐blind, placebo‐controlled, exploratory study in healthy subjects receiving oral GPI 5693 single ascending doses of 100, 300, 750, 1125 mg with a placebo treatment randomly interspersed. An open‐label, parallel extension examined the effects of food and sex on the pharmacokinetics of 750, 1125 and 1500 mg doses. Blood samples were collected for pharmacokinetic and biochemical/haematological safety analysis, vital signs, ECG and adverse event checks were performed regularly up to 48 h postdose. Postdose CNS effects were assessed using eye movements, adaptive tracking, electroencephalography (EEG), body sway and Visual Analogue Scales (VAS).ResultsCNS effects were mainly observed after the 1125 mg dose, showing a significant decrease of adaptive tracking performance, VAS alertness and VAS mood, and an increase of EEG occipital alpha and theta power. Gastro‐intestinal (GI) adverse effects were frequent at higher doses. No clinically significant changes in vital signs or ECG were noted during any of the treatments. The therapeutically relevant concentration range (950–11 100 ng ml−1) as determined from animal experiments was already reached after the 300 mg dose. Cmax after the 300 mg and 750 mg dose was 2868 and 9266 ng ml−1 with a t1/2 of 2.54 and 4.78 h, respectively. Concomitant food intake (with the 750 mg and 1125 mg doses) reduced Cmax by approximately 66% and AUC by approximately 40%. With concomitant food intake, the dose‐normalized Cmax also decreased significantly by −5.6 (CI: −2.6 to −8.7) ng ml−1 mg−1. The pharmacokinetic variability was largest after the 300 mg and 750 mg dose, resulting in a SD of approximately 50% of the Cmax.ConclusionNAALADase inhibition with GPI 5693 was safe and tolerable in healthy subjects. Plasma concentrations that were effective in the reversal of hyperalgesia in the chronic constrictive injury animal model of neuropathic pain were obtained at doses of 300, 750 and 1125 mg in the fasted state. Comcomitant food intake reduced Cmax and AUC. CNS effects and GI AEs increased in incidence over placebo only at the 1125 mg dose.
Off‐label prescribing to children: attitudes and experience of general practitioners
Authors: Ekins‐Daukes Suzie , Helms Peter J. , Taylor Michael W. , McLay James S. 
Published: July 2005

AimTo identify experience with and attitudes towards paediatric off‐label prescribing in primary careMethodA prospective questionnaire survey was sent to a sample of Scottish primary care practices (346 doctors in 80 general practices located throughout Scotland).ResultsTwo hundred and two (58%) completed questionnaires were returned. Over 70% of GPs admitted to being familiar with the concept, and 40% to knowingly prescribing off‐label. The most important sources of paediatric prescribing information were the British National Formulary (81%), personal experience (71%) and previous prescription notes (45%). The most common reason given by GPs for off‐label prescribing was prescribing for a younger age than recommended, although prescribing data confirm that age is the least important and dose the most important reason for such prescribing. When asked to comment upon different causes for off‐label prescribing, 80% of respondents expressed appropriate awareness of and concern for the described scenarios. Over 97% of GPs ranked development of paediatric formulations and clearer dosage information more highly than clinical trials as a means to reducing off‐label prescribing.ConclusionsDespite high levels of off‐label prescribing in primary care in the UK, the majority of GPs claimed to be familiar with the concept, although less than half were aware of this common practice. A clear disparity between perceived and actual reasons for off‐label prescribing was noted, possibly due to a reliance on personal experience, colleague experience or previous patient prescription notes as a guide to prescribing.
Statin use after acute myocardial infarction: a nationwide study in Denmark
Authors: Rasmussen Jeppe N. , Gislason Gunnar H. , Abildstrom Steen Z. , Rasmussen Søren , Gustafsson Ida , Buch Pernille , Friberg Jens , Køber Lars , Torp‐Pedersen Christian , Madsen Mette , Stender Steen 
Published: July 2005

AimsTo study outpatient statin use after first acute myocardial infarction (AMI) in Denmark between 1995 and 2002 and to determine the predictors of statin use.MethodsThis is a nationwide population‐based study using administrative registries. Patients with first AMI between 1995 and 2002 older than 30 years of age and alive 6 months after discharge (n = 45 219) were identified through the National Patient Registry. The statins purchased by these patients within 6 months after discharge were determined using the Registry of Medicinal Product Statistics, a nationwide prescription database.ResultsStatin use following AMI increased from 13% in 1995 to 61% in 2002. In 2002, 81% of patients aged 30–64 years used statins. Older patients used fewer statins, but use increased more among patients aged 75–84 years: from 1.3% to 43%. Use in elderly patients did not differ according to gender in 2000–02, but young men used more than younger women. In 2000–02, patients with diabetes (odds ratio (OR): 0.84; 95% confidence interval (CI): 0.74–0.95) and with heart failure (OR: 0.70; 95% CI: 0.64–0.76) were undertreated; this trend was present throughout the period.ConclusionsIn this nationwide study, younger patients after AMI had high statin use in 2002, but high‐risk patients such as those with diabetes and heart failure were still being undertreated.