bluuebunny/crossref_metadata_2025 huggingface dataset:
Nucleation of diamond by pure carbon ion bombardment—a transmission electron microscopy study
Authors: Yao Y. , Liao M. Y. , Wang Z. G. , Lifshitz Y. , Lee S. T.
Published: July 2005

A cross-sectional high-resolution transmission electron microscopy (HRTEM) study of a film deposited by a 1 keV mass-selected carbon ion beam onto silicon held at 800 °C is presented. Initially, a graphitic film with its basal planes perpendicular to the substrate is evolving. The precipitation of nanodiamond crystallites in upper layers is confirmed by HRTEM, selected area electron diffraction, and electron energy loss spectroscopy. The nucleation of diamond on graphitic edges as predicted by Lambrecht et al. [W. R. L. Lambrecht, C. H. Lee, B. Segall, J. C. Angus, Z. Li, and M. Sunkara, Nature, 364 607 (1993)] is experimentally confirmed. The results are discussed in terms of our recent subplantation-based diamond nucleation model.
Synthesis, Crystal Structures, and Reactions of 2-Oxomalonylbis(arylimidoyl) Chlorides and Hydroxymethane Tris(arylimidoyl) Chlorides
Authors: Bowen Richard J. , Caddy Judy , Coyanis Mabel E. , Fernandes Manuel A. , Layh Marcus , Linganiso Linda Z. , Maboya Winny K. , Omondi Bernard
Published: July 2005

The 2-oxomalonylbis(arylimidoyl) chlorides [C6H3(R2-2,6)N=CCl]2CO (R = Me, 3a; Pri, 3b; H, 3c) were synthesized from C6H3(R2-2,6)NHCHO and an excess of (COCl2)3 and their reaction with various nucleophiles was studied. Successive hydrolysis of 3a led to the formation of [C6H3(Me2-2,6)N=CCl]3COH 4a and [C6H3(Me2-2,6)NHCO]3COH 5a, while treatment of 3a with HAuCl4(H2O)x gave {[C6H3(Me2-2,6)N(H)=CCl][C6H3(Me2-2,6)NHCO]2COH}AuCl4 6a. All compounds were fully characterized by microanalysis, NMR spectroscopy, mass spectrometry, and, in the case of 3a, 4a, 5a, and 6a, by X-ray crystallography.
The 1,3-Diaxial Dibromo Interaction
Authors: Bernhardt Paul V. , Carman Raymond M. , Le Tri T.
Published: July 2005

The non-bonding interaction between two bromine atoms sited 1,3-diaxially on a simple cyclohexane ring is explored by X-ray crystallography. The ring is distorted to allow the bromine atoms an interatomic distance of 3.54 Å.
The Through-Bond Interaction of a Sulfur Lone Pair with Oxygenated Substituents in the Thiacyclohexane Framework
Authors: Andrau Laura , White Jonathan M.
Published: July 2005

Low-temperature X-ray crystal structures were determined on a range of derivatives of 4-thiacyclohexanol 5a of varying electron demand with a view to finding evidence for a through-bond interaction between the sulfur lone pair and the oxygenated substituent. In contrast to earlier suggestions, plots of C–OR bond distance versus pKa (ROH) showed that any interaction between the sulfur and the OR group is unlikely to be of a through-bond origin. Furthermore, unimolecular solvolysis rate measurements on the nosylate ester derivative 5g showed that the sulfur actually retards the reaction slightly in comparison with the corresponding sulfur-free analogue 6.
Identification of metaphase II-specific gene transcripts in porcine oocytes and their expression in early stage embryos
Authors: Cui Xiang-Shun , Song Hyuk , Kim Nam-Hyung
Published: July 2005

Annealing control primer (ACP)-based GeneFishing polymerase chain reaction (PCR) was used to identify the genes that are specifically or prominently expressed in porcine oocytes at the metaphase II (MII) and germinal vesicle (GV) stages. By using 60 ACPs, 13 differentially expressed genes (DEGs) were identified. The cloned genes or expressed sequence tags (ESTs) showed sequence similarity with known genes or ESTs of other species in GenBank. The mRNA expression during oocyte maturation and early embryonic development in both pigs and mice of four of these genes (namely transcription factor TZP, annexin A2, hypoxia-inducible protein 2, and ATPase 6) was further characterised by real-time quantitative reverse transcription–PCR. All four genes were markedly upregulated in pig and mouse MII oocytes compared with GV-stage oocytes. The expression levels of the four genes decreased gradually during early cleavage. Thus, these genes may play important roles during oocyte maturation and/or early cleavage in mammals. Although the detailed functions of these genes remain to be determined, their identification in the present study provides insights into meiotic maturation and fertilisation.
Principal parametric resonance of axially accelerating viscoelastic strings with an integral constitutive law
Authors: Chen Li-Qun
Published: July 2005

The steady-state transverse responses and the stability of an axially accelerating viscoelastic string are investigated. The governing equation is derived from the Eulerian equation of motion of a continuum, which leads to the Mote model for transverse motion. The Kirchhoff model is derived from the Mote model by replacing the tension with the averaged tension over the string. The method of multiple scales is applied to the two models in the case of principal parametric resonance. Closed-form expressions of the amplitudes and the existence conditions of steady-state periodical responses are presented. The Lyapunov linearized stability theory is employed to demonstrate that the first (second) non-trivial steady-state response is always stable (unstable). Numerical calculations show that the two models are qualitatively the same, but quantitatively different. Numerical results are also presented to highlight the effects of the mean axial speed, the axial-speed fluctuation amplitude, and the viscoelastic parameters.
Antitumor and antimetastatic actions of eicosapentaenoic acid ethylester and its by‐products formed during accelerated stability testing
Authors: Kimura Yoshiyuki , Sumiyoshi Maho
Published: July 2005

The aim of the present work was to compare the effects of eicosapentaenoic acid (EPA) ethylester and EPA derivatives (EPAD) on tumor growth and metastasis to the lung in tumor‐bearing mice. Because EPA is very unstable during long‐term storage, the EPAD were subjected to accelerated testing under storage conditions of 60 ± 5% relative humidity at 37°C for 30 days. EPAD are composed of a mixture of a newly identified EPA ethylester dimer and EPA hydroxyethylester, and known EPA and EPA ethylesters. The inhibitory effects of EPAD, the EPA ethylester dimer and EPA hydroxyethylester on Matrigel‐induced capillary‐like network formation were stronger than the effect of EPA ethylester. The oral administration of EPAD (300 or 1000 mg/kg) inhibited angiogenesis in gels containing Matrigel supplemented with vascular endothelial growth factor (VEGF) and heparin in an in vivo model, but EPA ethylester had no effect. EPA ethylester (300 or 1000 mg/kg) or EPAD (1000 mg/kg) inhibited tumor growth in mice with subcutaneously implanted LLC. Furthermore, EPAD inhibited metastasis to the lung in mice implanted with LLC subcutaneously, but EPA had no effect. EPAD increased the CD8+ T‐cell population in the spleen compared with mice with subcutaneously implanted LLC. EPA ethylester increased the natural killer cell population in the spleen. Thus, it is suggested that the mechanisms of the antitumor and/or antimetastatic actions of EPAD and EPA ethylester involve different immune functions, and that the EPA ethylester dimer and the EPA hydroxyethylester of EPAD may contribute to these actions. (Cancer Sci 2005; 96: 441–450)
Lamivudine therapy in chronic delta hepatitis: a multicentre randomized‐controlled pilot study
Authors: NIRO G. A. , CIANCIO A. , TILLMAN H. L. , LAGGET M. , OLIVERO A. , PERRI F. , FONTANA R. , LITTLE N. , CAMPBELL F. , SMEDILE A. , MANNS M. P. , ANDRIULLI A. , RIZZETTO M.
Published: July 2005

Background:  Delta virus (HDV)‐related chronic hepatitis is difficult to treat.

Aims:  To evaluate the efficacy of lamivudine 100 mg daily on serum HDV‐RNA, hepatitis D virus antibodies and alanine aminotransferase levels, liver histology, and on hepatitis B surface antigen seroconversion.

Methods:  Thirty‐one hepatitis B surface antigen‐positive, HDV‐RNA‐positive patients with ALT ≥ 1.5 upper normal level and compensated liver disease were randomized (1:2 ratio) to placebo (group A, n = 11) or lamivudine (group B, n = 20) for 52 weeks; thereafter, all patients were given lamivudine for 52 weeks and followed up for 16 weeks.

Results:  Twenty‐five patients (81%) completed the study. No patient was HDV‐RNA‐negative at week 52; three patients (11%) were negative at week 104. Two of them remained HDV‐RNA‐negative at week 120, and one lost the hepatitis B surface antigen without seroconversion. Paired pre‐treatment and week 104 liver biopsies were available from 19 patients: of which three of seven (43%) from group A and two of 12 patients (17%) from group B had a ≥2 point decrease in the Ishak necroinflammatory score.

Conclusion:  A sustained complete response was achieved in 8% of hepatitis D virus‐infected patients treated with lamivudine and a partial histological response in 26% of them. Hepatitis D virus viraemia was unaffected, even in patients when hepatitis B virus replication was lowered by lamivudine therapy.
Trends in the management and survival of digestive tract cancers among patients aged over 80 years
Authors: BOUVIER A. M. , LAUNOY G. , LEPAGE C. , FAIVRE J.
Published: July 2005

Background:  Advances have occurred in the management of digestive tract cancers, but it is not known how much they have benefited the elderly.

Aims:  To determine trends in treatment, stage at diagnosis and prognosis of digestive tract cancers among patients aged ≥80 years in two well‐defined French populations.

Design:  Time trends were studied in three age classes and in 5 four‐year time intervals. A multivariate relative survival analysis was performed to estimate the independent effect of both age and period on prognosis.

Results:  Five‐year relative survival rates were 1.9% for oesophageal cancer, 12% for stomach cancer, 41% for colon cancer and 37% for rectal cancer. The survival rates improved between the first and the fifth period for all cancer sites except for oesophageal cancer. This improvement remained significant after adjustment for age, sex, site and treatment. It was associated with an increase in the proportion of patients who underwent curative resection. Very few patients received adjuvant chemotherapy. The use of adjuvant radiotherapy for rectal and oesophageal cancers did not significantly increase over time.

Conclusions:  Except for oesophageal cancers, substantial advances in the care of digestive tract cancers in the elderly have been achieved. Surgery should not be restricted on the basis of age alone. Further improvements can be made in particular to enhance adjuvant therapy whenever possible.
Review article: gastro‐oesophageal reflux disease – the extent of the problem
Authors: MOAYYEDI P. , AXON A. T. R.
Published: July 2005

There have been little review data on the period prevalence of heartburn symptoms in the community. We analysed reflux symptom data from a test‐and‐treat trial that evaluated community Helicobacter pylori levels and added these to data identified from a literature search. We found 31 papers reporting on 77 671 subjects who provided information on the frequency of heartburn symptoms in the community. Pooled data from these papers suggested that, in Western populations, 25% had symptoms at least once per month, 12% had symptoms at least weekly and 5% had heartburn daily. Reflux symptoms were less common in East Asian populations with only 7% having heartburn at least once per month. Heartburn is a significant problem in Western societies.
Review article: gastro‐oesophageal reflux disease – the health economic implications
Authors: MASON J. , HUNGIN A. P. S.
Published: July 2005

For the vast majority of patients with gastro‐oesophageal reflux disease appropriate care involves the management of symptoms with lifestyle advice and drugs. However, there is dissension about the appropriate use of endoscopy, whether drugs should be stepped up or down according to potency, how long drugs should be used for, the role of lifestyle advice, and, related to this, the role of patients’ lifestyle choices.

This exploration of the economics of gastro‐oesophageal reflux disease reviews its cost burden to the UK, assesses published economic models for their strengths and weaknesses and examines current recommendations for gastro‐oesophageal reflux disease management from a socioeconomic perspective. Drugs prescribed predominantly for dyspepsia cost the UK National Health Service a projected £625 million in 2004, 7% of the primary care prescribing budget. When general practitioners consultations, endoscopies, over‐the‐counter sales and sickness absences are included the UK cost rises to £1.5 billion: approximately half of this cost can be ascribed to gastro‐oesophageal reflux disease. Emphasis upon regular review and stepping down treatment (while maintaining adequate symptom relief) is both clinically appropriate and resource efficient. Other cost‐effectiveness issues largely lack objective answers because investment in treatment for gastro‐oesophageal reflux disease depends upon how much more, at the margin, society wishes to invest for further but diminishing symptom relief.
Review article: Helicobacter pylori and gastro‐oesophageal reflux disease
Authors: DELANEY B. , McCOLL K.
Published: July 2005

Epidemiological studies demonstrate a negative association between Helicobacter pylori infection and gastro‐oesophageal reflux disease and its complications. This might represent a protective effect because of the tendency for H. pylori infection to lower gastric acid secretion with advancing age. However, studies of the effect of H. pylori eradication on gastro‐oesophageal reflux disease have failed to show any worsening of gastro‐oesophageal reflux disease symptoms. Several interactions between H. pylori and proton‐pump inhibitor therapy used to treat gastro‐oesophageal reflux disease need to be considered. Helicobacter pylori infection improves the control of gastric acidity by proton‐pump inhibitors and this produces a small advantage in clinical control of reflux disease. The infection prevents rebound acid hypersecretion occurring when proton‐pump inhibitor therapy is discontinued. However, concerns have been expressed that the body gastritis induced by proton‐pump inhibitor therapy in H. pylori‐infected subjects might increase the risk of gastric cancer. At present, it is unclear whether H. pylori should be eradicated in gastro‐oesophageal reflux disease patients.
Review article: quality‐of‐life issues in gastro‐oesophageal reflux disease
Authors: QUIGLEY E. M. M. , HUNGIN A. P. S.
Published: July 2005

The purpose of this review is to explore issues relating to quality of life in gastro‐oesophageal reflux disease, examining the range of generic and disease‐specific instruments available, their applicability and limitations and to overview the effect of gastro‐oesophageal reflux disease on quality of life. Whereas instruments have been developed to assist researchers, there is a paucity of reliable instruments for pragmatic use in the clinical setting. The situation is complicated because there is not necessarily a direct correlation between endoscopic findings and symptom severity and non‐erosive reflux disease is now recognized as an important manifestation of gastro‐oesophageal reflux disease. However, quality‐of‐life instruments are useful in evaluating the impact of therapies and interventions, although these are limited, particularly in surgical interventions. Impaired quality of life now forms part of a definition of gastro‐oesophageal reflux disease, the impact of which goes beyond the symptoms alone. While the symptoms themselves have a negative effect on sufferers’ lives, there are secondary effects caused by impaired physical, emotional and social functioning on productivity. Non‐gastrointestinal problems caused by gastro‐oesophageal reflux disease also impair quality of life. There is an ongoing need to develop instruments which truly measure the impact of gastro‐oesophageal reflux disease and which are readily interpretable to the individual patient and clinician.
Review article: role of pepsin and bile in gastro‐oesophageal reflux disease
Authors: TACK J.
Published: July 2005

Gastro‐oesophageal reflux disease is defined as the presence of symptoms or lesions that can be attributed to the reflux of gastric contents into the oesophagus. Aspiration and prolonged monitoring studies in humans have shown that reflux of gastric contents is comprised of both acid and non‐acid components, in healthy as well as diseased people. Methods to monitor the non‐acid component of the refluxate are described in detail. Experimental models suggest that synergism between acid and pepsin and conjugated bile acids have the greatest damaging potential for oesophageal mucosa, although unconjugated bile acids may be caustic at a more neutral pH. Human studies are compatible with a synergistic action between acid and duodenogastric reflux in inducing lesions. During prolonged monitoring studies, typical gastro‐oesophageal reflux disease symptoms are more related to acid reflux events than to non‐acid reflux events. However, symptoms that persist during acid‐suppressive therapy are often related to non‐acid reflux events. The therapeutic options for the non‐acid component of the refluxate, including acid suppression, prokinetics, baclofen and surgery, are discussed.
Review: What do we mean by GERD? – definition and diagnosis
Authors: JONES R. , GALMICHE J. P.
Published: July 2005

Gastro‐oesophageal reflux disease (GERD) is a condition in which the gastro‐oesophageal reflux provokes symptoms or complications. Since the majority of patients with heartburn do not have mucosal breaks, expressions such as ‘endoscopy‐negative reflux disease’ (ENRD), ‘non‐erosive reflux disease’ (NERD), or even ‘reflux‐like dyspepsia’ and ‘functional heartburn’ are frequently employed despite the lack of consensus concerning their exact meaning. Moreover, definition of a disease does not mean that precise diagnostic criteria exist. Diagnostic approaches to GERD differ considerably between primary and secondary care. The primary care physician's role is to decide, on the basis of symptoms and clinical examination, if it is likely that the patient has some serious problem which requires urgent investigation and intervention. In practice, a symptom‐based diagnosis can often be made reliably because heartburn and regurgitation are very specific for GERD. The secondary care physician has to make a full evaluation of an already highly‐selected patient and, as far as possible, to make a comprehensive, accurate diagnosis, using whatever investigative tools are required. However, there is no ‘gold standard’ for the diagnosis of GERD and 24‐hour pH monitoring lacks sensitivity in NERD. Recently, impedance‐pH monitoring has been introduced and promising results have been reported. However, this new technology needs further validation and technical improvement before being employed in routine clinical investigation.
Review article: the long‐term use of proton‐pump inhibitors
Authors: RAGHUNATH A. S. , O'MORAIN C. , MCLOUGHLIN R. C.
Published: July 2005

More than 15 years after the launch of omeprazole in 1988, proton‐pump inhibitors remain central to the management of acid‐suppression disorders and are unchallenged with regard to their efficacy and popularity among doctors and patients. They are considered safe despite early concerns about the possibility of an association with cancer and gastric atrophy; current concerns about long‐term proton‐pump inhibitor therapy are centred mainly on a possible association with fundic gland polyps and between Helicobacter pylori and gastric atrophic changes. Long‐term proton‐pump inhibitor usage accounts for the majority of the total proton‐pump inhibitor usage. Long‐term usage is difficult to define and most patients take proton‐pump inhibitors non‐continuously. Data indicate that a substantial proportion of long‐term users do not have a clear indication for their therapy and there is thus room for reduction or rationalization of treatment. Overall, on‐demand therapy is more cost‐effective than continuous therapy and should be considered wherever possible.
Review article: how valuable are proton‐pump inhibitors in establishing a diagnosis of gastro‐oesophageal reflux disease?
Authors: VAKIL N.
Published: July 2005

Diagnostic studies for gastro‐oesophageal reflux disease (endoscopy, pH testing) have significant limitations. A short trial of acid suppression with a proton‐pump inhibitor is often used in clinical practice as a diagnostic test for gastro‐oesophageal reflux disease. If there is a significant improvement in symptoms, the patient is considered to have gastro‐oesophageal reflux disease. Several studies have evaluated the administration of proton‐pump inhibitors as a diagnostic test for gastro‐oesophageal reflux disease. A recent meta‐analysis found that response to a proton‐pump inhibitor had limited value as a diagnostic test. Likelihood ratios for a positive test ranged from 0.45 to 1.86. The positive predictive value of the test ranged from 0.17 to 0.90 and the negative predictive value from 0.17 to 1, depending on the gold standard against which comparisons were made. These results may be explained by the inadequacy of the gold standard against which the proton‐pump inhibitor test is compared or by the inability of acid suppression to differentiate between gastro‐oesophageal reflux disease, peptic ulcer disease or dyspepsia. Although a trial of acid suppression may have pragmatic value in clinical practice, the proton‐pump inhibitor test is not an accurate test for the diagnosis of gastro‐oesophageal reflux disease.
Review article: extraoesophageal manifestations of gastro‐oesophageal reflux disease
Authors: RICHTER J. E.
Published: July 2005

Although 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

Aims

To obtain in vivo evidence for the involvement of cytochrome P450 (CYP) 3A4 in the metabolism of brotizolam.

Methods

Fourteen 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.

Results

Erythromycin 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.

Conclusions

The 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 aims

Gemfibrozil, 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.

Methods

In 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.

Results

During 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.

Conclusions

The 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

Aim

The 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.

Methods

A 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.

Results

Ten 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.

Conclusions

Our 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

Aim

The 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.

Methods

The 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%).

Results

Over 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.

Conclusions

The 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

Background

In 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.

Aims

To 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.

Methods

Data 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.

Results

Between 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.

Conclusions

Prescribing 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

Aims

Studies 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.

Methods

Meta‐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.

Results

The 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.

Conclusions

Our 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

Aims

The 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.

Methods

After 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.

Results

Hepatic 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.

Conclusions

We 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

Aims

To compare the degree of taste disturbance by candesartan and valsartan.

Methods

Candesartan 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.

Results

Detection 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.

Conclusion

Both 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

Aims

Telithromycin 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.

Methods

Twenty‐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.

Results

Mean 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.

Conclusion

Our 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

Aim

The 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.

Methods

This 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).

Results

CNS 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.

Conclusion

NAALADase 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

Aim

To identify experience with and attitudes towards paediatric off‐label prescribing in primary care

Method

A prospective questionnaire survey was sent to a sample of Scottish primary care practices (346 doctors in 80 general practices located throughout Scotland).

Results

Two 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.

Conclusions

Despite 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.
Profound weight loss associated with reboxetine use in a 44‐year‐old woman
Authors: Lu T. Y.‐T. , Kupa A. , Easterbrook G. , Mangoni A. A.
Published: July 2005

We report a case of significant weight loss experienced by a 44‐year‐old Caucasian woman treated with reboxetine. She was treated with this drug at 12 mg daily for a total duration of 11 months. During the corresponding period her body mass index (BMI) decreased from a baseline of 21.4 kg m−2 to a low of 16.8 kg m−2. Withdrawal of the drug led to a full recovery of her BMI. The strongest evidence linking reboxetine to this woman's weight loss laid in the fact that the re‐introduction of the drug subsequently caused a similar negative impact in her BMI.
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

Aims

To study outpatient statin use after first acute myocardial infarction (AMI) in Denmark between 1995 and 2002 and to determine the predictors of statin use.

Methods

This 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.

Results

Statin 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.

Conclusions

In 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.
A distance‐learning programme in pharmacovigilance linked to educational credits is associated with improved reporting of suspected adverse drug reactions via the UK yellow card scheme
Authors: Bracchi Robert C. G. , Houghton Jane , Woods Fiona J. , Thomas Simon , Smail Simon A. , Routledge Philip A.
Published: July 2005

Aims

The effect of a distance‐learning package linked to educational credits on the rate and quality of spontaneous adverse drug reaction (ADR) reporting by general practitioners (GPs) and pharmacists in Wales was investigated.

Methods

In April 2000, 477 GPs and 261 pharmacists enrolled in the 12 month programme.

Results

The number and quality of yellow card reports improved compared with those of a control region in England (Northern Region).

Conclusions

We conclude that an educational initiative in drug safety linked to incentives may be associated with a significant but perhaps short‐lived improvement in the rate and quality of ADR reporting.