bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of age on the pharmacokinetics of duloxetine in women
Authors: Skinner Michael H. , Kuan Han‐Yi , Skerjanec Andrej , Seger Mary E. , Heathman Michael , O'Brien Lisa , Reddy Shobha , Knadler Mary P. 
Published: December 2004

Aims  The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence.Methods  Twenty‐four healthy subjects (12 women 65–77 years, and 12 women 32–50 years) were given a single 40‐mg oral dose of duloxetine in Study 1. Plasma concentration‐time data were analysed by noncompartmental pharmacokinetic methods. Sparse plasma samples were obtained from patients with urinary incontinence treated in two phase II studies: 70 women (24–77 years) who received duloxetine 20 mg day−1, 30 mg day−1, or 40 mg day−1 in Study 2A and 128 women (28–64 years) who received duloxetine 20 mg day−1, 40 mg day−1, or 80 mg day−1 in Study 2B. Based upon the combined data, a model was developed to characterize population pharmacokinetics of duloxetine using the nonlinear mixed‐effects modelling program (NONMEM).Results  In Study 1, the elderly (≥ 65 years) exhibited a statistically significant slower elimination rate constant λz compared with younger subjects {elderly‐younger difference = −0.022 h−1[95% confidence interval (CI) − 0.036, − 0.008]}. However, no statistically significant differences in either CL/F [elderly‐younger difference = −17.4 l h−1 (95% CI − 41.1, 6.23)] or V/F [elderly‐younger difference = 115.9 l (95% CI − 168.6, 400.4)] were observed. The population pharmacokinetic analysis of Studies 2A and 2B revealed that the CL/F of duloxetine decreased with increasing age. Despite statistical significance, the age effect only accounted for 3% of the interindividual variability in CL/F and unexplained sources of the variation in clearance were still substantial (> 50%). Adverse events were generally mild to moderate, and the incidence of adverse events was generally similar in elderly and non‐elderly participants in these studies.Conclusions  Whereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower λz in the elderly, the magnitude of mean changes in CL/F, or V/F was small relative to the large interindividual variation in pharmacokinetics. Elderly participants had a safety profile of duloxetine comparable to their younger counterparts. Specific dose recommendations for duloxetine in the elderly are not warranted.
Influence of mild liver impairment on the pharmacokinetics of tezosentan, a drug excreted unchanged into bile
Authors: Dingemanse Jasper , Van Giersbergen Paul L. M. 
Published: December 2004

Aims  To investigate the effect of mild liver impairment on the pharmacokinetics of tezosentan.Methods  Eleven patients with mild liver impairment and eight healthy subjects received an intravenous infusion of 50 mg h−1 tezosentan for 1 h. Plasma and urine concentrations were determined during and following termination of the infusion.Results  The pharmacokinetic parameters presented as geometric means [95% confidence interval (CI)] for clearance, volume of distribution and terminal half‐life were 30 (22, 40) and 42 (36, 48) l h−1, 28 (19, 42) and 19 (16, 23) l, and 4.5 (2.9, 7.0) and 3.6 (2.9, 4.5) h in liver patients and healthy subjects, respectively. The ratios (liver patients/healthy subjects) of these geometric means (95% CI) were 0.71 (0.47, 1.1), 1.5 (0.87, 2.6), and 1.3 (0.69, 2.3), respectively. A two‐compartment model accurately fitted the concentration–time data. In both groups approximately 4% of the dose was excreted unchanged into urine.Conclusions  Although there was a slight trend towards a decreased clearance, the pharmacokinetics of tezosentan in patients with mild liver impairment were similar to those in healthy subjects. Therefore, no dose adaptation seems to be needed in this patient population.
Assessment of the relative in vivo potency of the hydroxylated metabolite of darifenacin in its ability to decrease salivary flow using pooled population pharmacokinetic–pharmacodynamic data
Authors: Kerbusch Thomas , Milligan Peter A. , Karlsson Mats O. 
Published: December 2004

Aims  To describe the population pharmacokinetic–pharmacodynamic relationship between darifenacin (UK‐88,525) and its hydroxylated metabolite (UK‐148,993), and the reduction in salivary flow (SF, a M3‐mediated response). This enabled an estimation of the in vivo potency of the metabolite to decrease SF relative to that of the parent drug.Methods  A total of 262 individuals were pooled from 11 Phase 1 studies and one Phase 2 study. A comparison was made between a series of pharmacodynamic models (direct‐effect, indirect‐effect, link and binding model) using NONMEM.Results  The binding model yielded the best description of the decrease in SF by fully accounting for the time course of the pharmacodynamic effect. An internal validation exercise demonstrated the robustness of this model. Covariate analysis identified a circadian rhythm in SF. This model, with confidence intervals (CI) determined by likelihood profiling, indicated that the relative potency of the metabolite to darifenacin to reduce SF was 11.1% (95% CI 3.8, 19.6). This implied that the metabolite was ninefold less potent than darifenacin in vivo. Accounting for the unbound fraction of darifenacin (2%) and its metabolite (13%), the in vivo protein binding‐corrected relative potency was estimated to be 2.1%, indicating that the metabolite was 50‐fold less potent than the parent drug. The model supported the assumption that no other metabolites contributing to the impairment of the SF were formed during first‐pass, and that the development of sensitization or tolerance was not evident over time. The validation process indicated that the i.v.–oral crossover study was necessary for the estimation of the relative potency.Conclusions  Population modelling of darifenacin and its hydroxylated metabolite yielded individual pharmacokinetic predictions that could be used to assess the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. The metabolite had a negligible effect on SF.
The effect of rosuvastatin on oestrogen & progestin pharmacokinetics in healthy women taking an oral contraceptive
Authors: Simonson Steven G. , Martin Paul D. , Warwick Mike J. , Mitchell Patrick D. , Schneck Dennis W. 
Published: December 2004

AimsTo assess the effect of rosuvastatin on oestrogen and progestin pharmacokinetics in women taking a commonly prescribed combination oral contraceptive steroid (OCS); the effect on endogenous hormones and the lipid profile was also assessed.MethodsThis open‐label, nonrandomised trial consisted of 2 sequential menstrual cycles. Eighteen healthy female volunteers received OCS (Ortho Tri‐Cyclen®) on Days 1–21 and placebo OCS on Days 22–28 of Cycles A and B Rosuvastatin 40 mg was also given on Days 1–21 of Cycle B.ResultsCo‐administration did not result in lower exposures to the exogenous oestrogen or progestin OCS components. Co‐administration increased AUC[0–24] for ethinyl oestradiol (26%; 90% CI ratio 1.19–1.34), 17‐desacetyl norgestimate (15%; 90% CI 1.10–1.20), and norgestrel (34%; 90% CI 1.25–1.43), and increased Cmax for ethinyl oestradiol (25%; 90% CI 1.17–1.33) and norgestrel (23%; 90% CI 1.14–1.33). The increases in exposure were attributed to a change in bioavailability rather than a decrease in clearance. Luteinizing and follicle‐stimulating hormone concentrations were similar between cycles. There were no changes in the urinary excretion of cortisol and 6β‐hydroxycortisol. Rosuvastatin significantly decreased low‐density lipoprotein cholesterol [‐55%], total cholesterol [‐27%], and triglycerides [‐12%], and significantly increased high‐density lipoprotein cholesterol[11%]. Co‐administration was well tolerated.ConclusionsRosuvastatin can be coadministered with OCS without decreasing OCS plasma concentrations, indicating that contraceptive efficacy should not be decreased. The results are consistent with an absence of induction of CYP3A4 by rosuvastatin. The expected substantial lipid‐regulating effect was observed in this study, and there was no evidence of an altered lipid‐regulating effect with OCS coadministration.
Tizanidine is mainly metabolized by cytochrome P450 1A2 in vitro
Authors: Granfors Marika T. , Backman Janne T. , Laitila Jouko , Neuvonen Pertti J. 
Published: December 2004

AimsTo identify the cytochrome P450 (CYP) enzyme(s) that catalyze the metabolism of tizanidine in vitro.MethodsThe effect of CYP isoform inhibitors on the elimination of tizanidine was studied using pooled human liver microsomes. The metabolism of the drug by a range of human recombinant CYP isoforms was then investigated.ResultsIncubation of tizanidine (80 nm) with human liver microsomes resulted in time‐ and NADPH‐dependent substrate consumption with a half‐life of 50 min, initial reaction velocity of 1.1 pmol min−1 mg−1 protein and intrinsic clearance of 17 ml min−1 kg−1. The predicted in vivo hepatic clearance (CLh) of tizanidine using the well‐stirred and parallel‐tube model was close (68% and 82%, respectively) to its estimated in vivo CLh. Fluvoxamine and furafylline strongly inhibited tizanidine metabolism. Inhibitors specific to isoforms other than CYP1A2 had no substantial effect. Recombinant CYP1A2 metabolized tizanidine to a substantial degree (35% in 45 min), but other recombinant CYPs had little metabolic capacity for the drug.ConclusionsCYP1A2 is primarily responsible for the metabolism of tizanidine. CYP1A2 inhibitors may inhibit its metabolism also in vivo.
Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese
Authors: Fukazawa Ichiro , Uchida Naoki , Uchida Eiji , Yasuhara Hajime 
Published: December 2004

AimsTo investigate the effects of repeated grapefruit juice (GFJ) intake on the pharmacokinetics of atorvastatin and pravastatin in Japanese subjects.MethodsTwo randomized, two‐way crossover studies were performed. GFJ or water was given to two groups of 10 subjects each three times daily for 2 days. On the third day, single 10 mg doses of atorvastatin or pravastatin were orally administered with GFJ or water, and an additional 250 ml of GFJ or water was taken before lunch and dinner. Plasma concentrations of atorvastatin and its metabolites were determined over 48 h postdosing and of pravastatin and its metabolites over 24 h postdosing.ResultsCompared with in the water group, the AUC(0,48 h) of atorvastatin acid significantly increased by 1.40 fold (95% CI 1.02, 1.92; P < 0.05) when atorvastatin was taken with GFJ. AUC(0,48 h) and Cmax of atorvastatin lactone significantly increased by 1.56 (95% CI 1.33, 1.83; P < 0.001) and 1.29 fold (95% CI 1.09, 1.51; P < 0.01), respectively, when atorvastatin was taken with GFJ. No significant changes were detected in any pravastatin pharmacokinetic parameter examined when pravastatin was taken with GFJ. However, AUC(0,24 h) of pravastatin lactone increased 1.31 fold (95% CI 1.01, 1.71; P < 0.05) with GFJ intake.ConclusionsGFJ was confirmed to significantly affect the pharmacokinetics of atorvastatin but had little or no effect on those of pravastatin in Japanese subjects.
Protein binding and α : β anomer ratio of dihydroartemisinin in vivo
Authors: Batty Kevin T. , Ilett Kenneth F. , Davis Timothy M. E. 
Published: December 2004

AimsTo determine the ratio of α : β anomers and the protein binding of dihydroartemisinin (DHA) in vivo.Methods10‐[3H]‐DHA was synthesized by reduction of artemisinin with sodium boro‐[3H]‐hydride and purified with preparative thin layer chromatography. A solution of 3H‐DHA (2000 ng in 20 µl) was added to 2 ml whole blood from 15 healthy volunteers and 22 Vietnamese patients with falciparum or vivax malaria. The blood was centrifuged and the plasma stored at −25 °C until analysed by HPLC with radiochromatographic detection. Protein‐free ultrafiltrate of the plasma was assayed to determine the free fraction of DHA and the in vivo ratio of α‐DHA : β‐DHA.ResultsThe DHA fraction unbound (mean ± SD) was 0.068 ± 0.032 in Vietnamese patients with falciparum malaria (n = 17), 0.065 ± 0.009 in Vietnamese patients with vivax malaria (n = 5), 0.117 ± 0.015 in Vietnamese volunteers (n = 7) and 0.092 ± 0.020 in Caucasian volunteers (n = 8). The ratios of α‐DHA : β‐DHA for the four groups were 6.3 ± 0.9, 6.9 ± 0.8, 6.9 ± 0.6 and 5.4 ± 0.8, respectively.ConclusionsDHA is approximately 93% protein‐bound in patients with malaria infection and there is a preferential existence in vivo of the α‐DHA anomer. Knowledge of this stereochemistry may be valuable in elucidation of the mechanisms of DHA action and/or toxicity, and in the synthesis of new trioxane antimalarials.
Biological diagnosis of primary intraocular lymphoma
Authors: Merle‐Béral Hélène , Davi Frédéric , Cassoux Nathalie , Baudet Sylvie , Colin Chantal , Gourdet Thomas , Bodaghi Bahram , LeHoang Phuc 
Published: December 2004

SummaryPrimary intraocular lymphoma (PIOL) is a rare presentation of lymphoma that is particularly difficult to recognize. In our institution, 36 cases of PIOL were diagnosed between March 1997 and July 2002. The recognition of lymphoma cells by cytology with or without immunophenotyping on slides generated a strong suspicion of the diagnosis in 34 of 36 cases. The diagnosis was confirmed by measurement of interleukin‐10 (IL‐10) in the vitreous humour or aqueous humour; high levels were observed in 35 of 36 cases, all were of B‐cell origin. As expected, the only case with T‐cell lymphoma had a very low level of IL‐10. Furthermore, IL‐10 levels excluded this diagnosis in two cases that were incorrectly suspected of PIOL after cytological examination. Finally, detection of clonality by polymerase chain reaction techniques, performed in 29 cases, represented a helpful tool in diagnosing PIOL as this approach definitively confirmed the diagnosis of B‐ or T‐cell lymphoma in 17 cases.
Computer‐assisted training system for pars plana vitrectomy
Authors: Jonas Jost B. , Rabethge Stefan , Bender Hans‐Joachim 
Published: December 2004

Abstract.Purpose:  To evaluate whether microsurgical steps in vitreoretinal surgery can be taught by a computer‐assisted training system. Methods:  This prospective, randomized experimental study included 14 ophthalmic residents and medical students who were completely inexperienced in microsurgery. They were randomized into two groups. The study group underwent training programmes in a computer‐assisted training system for simulation of pars plana vitrectomy. The control group did not participate in any in vitro training. In the second phase of the study, participants of both groups performed a pars plana vitrectomy in three pig eyes, which included picking a metallic foreign body from the retinal surface. Results:  The amount of retinal detachment and the number of retinal defects at the end of the vitrectomies were smaller, the time needed to remove the foreign body was shorter, the number of retinal lesions associated with the foreign body removal was lower, and the mark given was better in the trained study group than in the untrained group. The relatively small number of study participants did not allow the differences between the study and control groups to reach the 5% level of error probability. Conclusions:  In an animal model, training by a computer‐based medical work station for simulation of pars plana vitrectomy showed better outcome measures for trained study participants compared with untrained study participants. Future studies may show whether further refinements of such training programmes will result in statistically significantly better results in surgical outcome parameters.
Myopia and natural lighting extremes: risk factors in Finnish army conscripts
Authors: Vannas Antti E. , Ying Gui‐Shuang , Stone Richard A. , Maguire Maureen G. , Jormanainen Vesa , Tervo Timo 
Published: December 2004

Abstract.Purpose:  To establish whether features of environmental lighting in far northern latitudes might be associated with prevalence of myopia. Methods:  Using both questionnaires and military medical examinations, this cross‐sectional survey of Finnish conscripts assessed both light exposure and conventional risk factors for myopia. Results:  While myopia was not associated with the month of birth, there was a trend towards a higher prevalence of myopia among conscripts living above the Arctic Circle, consistent with the hypothesis that ambient lighting might influence refractive development. Other novel associations with myopia were decreased sunglasses use and brown iris colour. As indicated by other reports, myopia was found to be associated with family history, education and nearwork. Conclusion:  Although constraints inherent in surveying this military population may have limited our ability to detect associations, the positive findings suggest that studying northern populations may prove useful in clarifying any potential role of the light/dark cycle in refractive development.
Elevated homocysteine levels in euthymic bipolar disorder patients showing functional deterioration
Authors: Osher Yamima , Sela Ben‐Ami , Levine Joseph , Belmaker Robert H 
Published: December 2004

Objective:  Previous studies have found elevated plasma homocysteine levels in schizophrenic patients. This study examined homocysteine levels in euthymic bipolar patients.Methods:  Homocysteine levels in 41 euthymic outpatients with bipolar disorder (DSM IV) were compared with 305 comparison subjects from a large employee health screening program. Homocysteine levels were assessed using high‐pressure liquid chromatography by fluorescence detection following labeling of homocysteine with monobromobimane. Functional deterioration in patients was rated as ‘present’ or ‘absent’ by consensus of two treating clinicians.Results:  Data were analyzed by two‐way (sex, patient versus control) ANCOVA, with age as the covariant. Significant effects were found for age (p < 0.001) and for sex (p < 0.001) and a significant two‐way interaction was found for group by sex (p < 0.001). One‐way (by group) ANCOVAs were then performed separately for each sex. For the male subjects, a main effect was found for group (p = 0.001) and for age (p < 0.001): young male bipolar patients have higher homocysteine levels than controls. Among the females, bipolar patients had homocysteine levels, which were lower than controls across all age groups (p < 0.05) with homocysteine levels increasing with age for both groups (p < 0.001). ANCOVA, which divided subjects into three groups – bipolar patients with and without functional deterioration versus comparison subjects – found a significant group by sex interaction (p < 0.05). Sheffe’post‐hoc comparisons revealed that among the male subjects, bipolar patients showing deterioration had homocysteine levels which were significantly higher than those of comparison subjects, while bipolar subjects without deterioration had homocysteine levels which were almost identical to the comparison subjects.Conclusion:  Bipolar patients who show functional deterioration have plasma levels of homocysteine, which are significantly elevated as compared with controls.
Biochemical and psychiatric predictors of Li+ response and toxicity in Li+‐treated bipolar patients
Authors: Layden Brian T , Minadeo Nicole , Suhy Joyce , Abukhdeir Abde M , Metreger Tabitha , Foley Kathleen , Borge George , Crayton John W , Bryant Fred B , Freitas Duarte Mota de 
Published: December 2004

Background:  It has not been determined whether biochemical or psychological variables predict clinical response and toxicity to Li+ treatment.Methods:  From 30 Li+‐treated bipolar patients, we measured biochemical variables in red blood cells (RBCs) that encompassed the cell membrane abnormality and the Li+/Mg2+ competition mechanism. Psychiatric measures of depression, mania, and side effects of Li+ toxicity were correlated with these biochemical variables. Physician classification of Li+ response and toxicity for each patient were used for determining whether significant differences in biochemical variables and psychiatric measures existed between full and partial responders, and as well as toxic and non‐toxic Li+‐treated bipolar patients.Results:  Serum [Li+] ([Li+]e), the ratio of intracellular RBC to serum Li+, [Li+]i/[Li+]e, and phosphatidylcholine shared moderate proportions of variance (10–15%) with several of the psychiatric measures. Physician assessment of full response was predicted by higher levels of [Li+]e and lower scores on the Hamilton Slowing subscale (95.6% accuracy), whereas higher lithium‐binding constants and higher Hamilton total scores perfectly predicted physician classification of partial response. Higher scores on Hamilton Slowing subscale and General Side Effects (GSE) scale were strongly predictive of physician classified Li+ toxicity (80% accuracy), whereas lower levels of [Li+]e and lower scores on the Hamilton Symptom Severity subscale perfectly predicted physician rated non‐toxicity in these patients.Conclusions:  We found distinct [Li+]e levels that predict response and/or toxicity. Specifically, when [Li+]e was in the range of 0.93–1.42 mM, full response without toxicity was predicted; higher values predicted toxicity; lower values predicted partial response.
Occupational therapists report a low level of knowledge, skill and involvement in evidence‐based practice
Authors: McCluskey Annie 
Published: December 2004

This study was conducted to collect information about Australian occupational therapists’ involvement in evidence‐based practice. The study aimed to document: (i) respondents’ level of knowledge and skills; (ii) their level of participation in continuing education; and (iii) perceived barriers to evidence‐based practice. A purposive sample of 85 occupational therapists was invited to complete a questionnaire prior to attending an introductory workshop on evidence‐based practice. Sixty‐seven questionnaires were returned and analysed (78.8% response rate). Half of the respondents rated their level of knowledge and skills required for evidence‐based practice as low (conducting database searches = 50.7%; critically appraising literature = 53.0%). The majority of respondents (79.1%) reported a low level of knowledge about electronic databases. Few respondents had attended education sessions on evidence‐based practice (15.0%). The six most commonly reported barriers to adopting evidence‐based practice were lack of time, a large caseload, limited searching skills, limited appraisal skills, difficulty accessing journals and a perceived lack of evidence to support occupational therapy intervention. The majority of occupational therapists in this sample were entering the first phase of continuing professional development in relation to evidence‐based practice.