bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropsychological and neurophysiological findings in individuals suspected to be at risk for schizophrenia: preliminary results from the Basel early detection of psychosis study – Früherkennung von Psychosen (FEPSY)
Authors: Gschwandtner U. , Aston J. , Borgwardt S. , Drewe M. , Feinendegen C. , Lacher D. , Lanzarone A. , Stieglitz R.‐D. , Riecher‐Rössler A. 
Published: June 2003

Objective: Our study aims to establish a scientific basis for the very early detection of patients at risk for schizophrenia during the nonspecific prodromal phase of the disorder and to predict its outbreak.Method: A multidomain approach is used. After screening, approved psychopathological, neurophysiological, neuropsychological and neuroradiological investigations are used to assess a sample of individuals suspected to be at risk for schizophrenia.Results: Neuropsychological and fine motor functioning tests as well as eye movement measurements showed statistically significant differences (P<0.01) between individuals suspected to be at risk for schizophrenia and healthy controls.Conclusion: Individuals suspected to be at risk for schizophrenia show specific impairments in various investigations including neuropsychological and fine motor functioning tests as well as eye movement measurements. A set of methods sensitive to even subtle changes in normal functioning may prove useful in predicting the subsequent outbreak of schizophrenia.
Serious psychiatric and neurological adverse effects of herbal medicines – a systematic review
Authors: Ernst E. 
Published: June 2003

Objective: Psychiatric and neurological patients frequently try herbal medicines often under the assumption that they are safe. The aim of this systematic review was to provide a summary of recent data on severe psychiatric and neurological adverse effects of herbal remedies.Method: Computerized literature searches were carried out to identify all reports of psychiatric and neurological adverse effects associated with herbal medicines. These data were subsequently extracted, validated and summarized in narrative and tabular form.Results: Numerous case reports comprise a diverse array of adverse events including cerebral arteritis, cerebral oedema, delirium, coma, confusion, encephalopathy, hallucinations, intracerebral haemorrhage, and other types of cerebrovascular accidents, movement disorders, mood disturbances, muscle weakness, paresthesiae and seizures. Several fatalities are on record. They are caused by improper use, toxicity of herbal ingredients, contamination and adulteration of preparations and herb/drug interactions.Conclusion: Herbal medicines can cause serious psychiatric and neurological adverse effects.
Topical ascorbic acid on photoaged skin. Clinical, topographical and ultrastructural evaluation: double‐blind study vs. placebo
Authors: Humbert Philippe G. , Haftek Marek , Creidi Pierre , Lapière Charles , Nusgens Betty , Richard Alain , Schmitt Daniel , Rougier André , Zahouani Hassan 
Published: June 2003

Abstract:  Vitamin C is known for its antioxidant potential and activity in the collagen biosynthetic pathway. Photoprotective properties of topically applied vitamin C have also been demonstrated, placing this molecule as a potential candidate for use in the prevention and treatment of skin ageing.A topically applied cream containing 5% vitamin C and its excipient were tested on healthy female volunteers presenting with photoaged skin on their low‐neck and arms in view to evaluate efficacy and safety of such treatment. A double‐blind, randomized trial was performed over a 6‐month period, comparing the action of the vitamin C cream vs. excipient on photoaged skin. Clinical assessments included evaluation at the beginning and after 3 and 6 months of daily treatment. They were performed by the investigator and compared with the volunteer self assessment. Skin relief parameters were determined on silicone rubber replicas performed at the same time‐points. Cutaneous biopsies were obtained at the end of the trial and investigated using immunohistochemistry and electron microscopy. Clinical examination by a dermatologist as well as self‐assessment by the volunteers disclosed a significant improvement, in terms of the ‘global score’, on the vitamin C‐treated side compared with the control. A highly significant increase in the density of skin microrelief and a decrease of the deep furrows were demonstrated. Ultrastructural evidence of the elastic tissue repair was also obtained and well corroborated the favorable results of the clinical and skin surface examinations.Topical application of 5% vitamin C cream was an effective and well‐tolerated treatment. It led to a clinically apparent improvement of the photodamaged skin and induced modifications of skin relief and ultrastructure, suggesting a positive influence of topical vitamin C on parameters characteristic for sun‐induced skin ageing.
Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects
Authors: De Jong Jeroen C. F. , Van Den Berg Paul B. , Tobi Hilde , De Jong Lolkje T. W. , Van Den Berg ‐ 
Published: June 2003

Aims  To investigate the relationship between the use of antidepressants with or without NSAIDs and the risk of gastrointestinal side‐effects.Methods  This was a population‐based cohort study. Medication data of 180 000 patients from 16 pharmacies in The Netherlands were studied. The subjects were a group of 15 445 new users of antidepressants with or without NSAIDs. A review of patient profiles for cases of gastrointestinal adverse effects caused by first time use of antidepressants with or without NSAIDs was carried out. The number of first prescriptions for peptic ulcer drugs (Anatomical Therapeutic Chemical classification A02B) in the period from day 2 after starting antidepressants with or without NSAIDs until 10 days after the last dose was the main outcome measure.Results  In the reference group of 619 new users of nonselective antidepressants (TCAs), the incidence of first prescriptions for peptic ulcer drugs was 0.051 (95% confidence interval 0.021, 0.105). The use of SSRIs (n = 1181) caused a slightly higher incidence rate ratio (IRR) of 1.2 (0.5, 2.8). The combined use of SSRIs and NSAIDs (n = 86) increased the IRR to 12.4 (3.2, 48.0). In contrast, the combination of nonselective antidepressants and NSAIDs (n = 74) increased the IRR to 2.5 (0.3, 20.3).Conclusions  SSRIs increase the risk of gastrointestinal adverse effects in first time users as compared with nonselective antidepressants. The combined use of SSRIs and NSAIDs strongly increases the risk of gastrointestinal adverse effects and should be avoided. The combination of nonselective antidepressants and NSAIDs does not have this effect.
Population pharmacokinetics of levosimendan in patients with congestive heart failure
Authors: Jonsson E. Niclas , Antila Saila , McFadyen Lynn , Lehtonen Lasse , Karlsson Mats O. 
Published: June 2003

Aims  The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and β‐blocking agents.Methods  Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed‐effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one‐, two‐ or three‐compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined.Results  A two‐compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and β‐blocking agents, influenced the pharmacokinetics. In the final model, a 76‐kg patient was estimated to have a clearance ± s.e. of 13.3 ± 0.4 l h−1 and a central volume of distribution of 16.8 ± 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg.Conclusions  The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and β‐blocking agents, significantly influenced the pharmacokinetics of levosimendan.
Comparison of the micro‐ and macro‐vascular effects of glimepiride and gliclazide in metformin‐treated patients with Type 2 diabetes: a double‐blind, crossover study
Authors: Dhindsa Pash , Davis Karl R. , Donnelly Richard 
Published: June 2003

Aims  To compare the metabolic and vascular effects of two sulphonylureas (SU), gliclazide (specific for the pancreatic [SUR1] receptor) and glimepiride (a nonspecific agent that also binds to vascular and cardiac [SUR2] receptors), during chronic administration in metformin‐treated patients with Type 2 diabetes (T2DM).Methods  A randomized, double‐blind, crossover study of gliclazide 80 mg BID and glimepiride 2 mg OD, each for 4 weeks as add‐on therapy to metformin, with a 4‐week washout period. Patients attended four study mornings after first dose and 4 weeks’ SU treatment for measurements of arterial distensibility (Ax), pressor responsiveness to i.v. angiotensin II (ANGII), and cutaneous microvascular vasodilator responses to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP).Results  Glycaemic responses were similar (e.g. serum fructosamine was 315 vs 329 µmol l−1 after 4 weeks), and there was no change in augmentation index during treatment with either SU (9.1 vs 9.8 mmHg after 4 weeks [95% confidence interval −8.1, 10.5]). Similarly, there were no differences between treatments in pressor responsiveness (e.g. PD10[dose of agonist required to increase mean BP by 10 mmHg] for ANGII was 1.37 vs 1.68 ng kg−1 min−1[−4.3, 6.9]) or cutaneous microvascular vasodilator responses (peak ACh response 68 ± 36 vs 63 ± 34 perfusion units [−82.7, 79.1]).Conclusions  There is no evidence that SUR1‐specific and nonspecific SUs have differential effects on arterial distensibility, endothelial function or vasodilator mechanisms in metformin‐treated patients with T2DM.
Population pharmacokinetics of netilmicin in short‐term prophylactic treatment
Authors: Jauregizar Nerea , Wald Jeff A. , Astobieta Ander , Sasiain Jose M. Rodriguez , Lukas John C. , Calvo Rosario 
Published: June 2003

Aims  To characterize the population pharmacokinetics of netilmicin, an aminoglycoside antibiotic, in adult urology patients and to develop a covariate model for improved dose titration.Methods  Data from 62 adult patients (55 male, seven female), undergoing urological surgery and treated with netilmicin for short‐term prophylaxis, were evaluated retrospectively. The group had (median, range) ages 68, 31–92 years, weights 72, 43–106 kg and heights 167, 148–182 cm. No patient showed renal impairment before netilmicin treatment (serum creatinine ≤1.9 mg dl−1). Netilmicin (100 mg) was administered as a maximum of four successive intravenous infusions of 30 min, at 8‐h intervals. A total of five blood samples were collected from each patient. Prior to analysis, the dataset was divided into ‘index’ (n = 44) and ‘validation’ (n = 18) groups at random. The time courses of netilmicin concentrations from all subjects were analysed using a mixed effects, population, nonlinear modelling package (WinNonMix). For covariate model development, a stepwise procedure was used with backward elimination followed by forward inclusion based on age, sex, weight, height, creatinine clearance and type of surgery. The final covariate model parameters from the index group were used to simulate concentrations in the validation group and the bias and precision were compared with the observations.Results  A bi‐compartmental open model with a proportional residual error best described the data. The population parameters for central and peripheral volumes of distribution were (typical population value [interindividual CV%]) Vc = 14.5 l [56%] and Vp = 10.2 l [not estimated], and the systemic and intercompartmental clearances were CL = 3.9 l h−1[42%] and CLQ = 10.1 l h−1[not estimated], respectively. The final population covariate relationships were based on sex (SEX) and creatinine clearance (CrCL): (Vc, l) = 18.9 − 5.9 × SEX [29%] and (CL, l h−1) = 0.06 × CrCL [33%]. Compared with the observations in the validation group, this model showed a bias (95% confidence interval) of −0.028 (−0.28, 0.25) and precision of 1.22 (0.78, 1.34).Conclusion  Bi‐compartmental pharmacokinetic parameters of netilmicin have been estimated from clinical data in urological surgery patients using a population approach. A given single dose results in large variability in plasma concentrations and thus the population covariate final model can be used for direct estimation of initial dosing in patients.
Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1 and MDR‐1 in the Egyptian population
Authors: Hamdy Samar I. , Hiratsuka Masahiro , Narahara Kaori , Endo Naomi , El‐Enany Mervat , Moursi Nadia , Ahmed Mohammed S.‐E. , Mizugaki Michinao 
Published: June 2003

Aims  The goal of this study was to determine the frequencies of important allelic variants in the TPMT, NAT2, GST, SULT1A1 and MDR‐1 genes in the Egyptian population and compare them with the frequencies in other ethnic populations.Methods  Genotyping was carried out in a total of 200 unrelated Egyptian subjects. TPMT*2 was detected using an allele‐specific polymerase chain reaction (PCR) assay. TPMT*3C and NAT2 variants (*5,*6 and *7) were detected using an allele‐specific real‐time PCR assay. Detection of GSTM1 and GSTT1 null alleles was performed simultaneously using a multiplex PCR assay. Finally, a PCR‐restriction fragment length polymorphism assay was applied for the determination of TPMT*3A (*3B), SULT1A1*2 and MDR‐1 (3435T) variants.Results  Genotyping of TPMT revealed frequencies of 0.003 and 0.013 for TPMT*3A and TPMT*3C, respectively. No TPMT*2 or *3B was detected in the analysed samples. The frequencies of specific NAT2 alleles were 0.215, 0.497, 0.260 and 0.028 for *4 (wild‐type), *5 (341C), *6 (590A) and *7 (857A), respectively. GSTM1 and GSTT1 null alleles were detected in 55.5% and 29.5% of the subjects, respectively. SULT1A1*2 was detected at a frequency of 0.135. Finally, the frequencies of the wild‐type allele (3435C) and the 3435T variant in the MDR‐1 gene were found to be 0.6 and 0.4, respectively.Conclusions  We found that Egyptians resemble other Caucasians with regard to allelic frequencies of the tested variants of NAT2, GST and MDR‐1. By contrast, this Egyptian population more closely resemble Africans with respect to the TPMT*3C allele, and shows a distinctly different frequency with regard to the SULT1A1*2 variant. The predominance of the slow acetylator genotype in the present study (60.50%) could not confirm a previously reported higher frequency of the slow acetylator phenotype in Egyptians (92.00%), indicating the possibility of the presence of other mutations not detectable as T341C, G590A and G857A. The purpose of our future studies is to investigate for new polymorphisms, which could be relatively unique to the Egyptian population.
Effect of carbocysteine on cough reflex to capsaicin in asthmatic patients
Authors: Ishiura Yoshihisa , Fujimura Masaki , Yamamori Chihiro , Nobata Kouichi , Myou Shigeharu , Kurashima Kazuyoshi , Michishita Yasukatsu , Takegoshi Tadayoshi 
Published: June 2003

Aims  Cough, one of the main symptoms of bronchial asthma, is a chronic airway inflammatory disease with functionally damaged bronchial epithelium. Recently, we established an animal model with cough hypersensitivity after antigen challenge and clearly showed the protective effect of carbocysteine in this model. This study was designed to investigate the clinical effect of carbocysteine for cough sensitivity in patients with bronchial asthma.Methods  The effects of the two orally active mucoregulatory drugs, carbocysteine and ambroxol hydrochloride, on cough response to inhaled capsaicin were examined in 14 patients with stable asthma. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough sensitivity.Results  Geometric mean values of the cough threshold at run‐in (baseline) and after 4 weeks’ treatment of placebo, 1500 mg day−1 of carbocysteine and 45 mg day−1 of ambroxol hydrochloride were 12.8 µM (95% confidence interval [CI] 5.5, 29.6), 11.0 µM (95% CI 4.4, 27.5), 21.0 µM (95% CI 8.8, 50.2) and 11.6 µM (95% CI 5.8, 23.3), respectively. The cough threshold for carbocysteine was significantly greater than those of ambroxol hydrochloride (P = 0.047) and placebo (P = 0.047), respectively.Conclusions  These findings indicate that carbocysteine administration may be a novel therapeutic option for asthmatic patients, especially with cough variant asthma.
A novel metabolic pathway of morphine: formation of morphine glucosides in cancer patients
Authors: Chen X. Y. , Zhao L. M. , Zhong D. F. 
Published: June 2003

Aims  To characterize directly the conjugated metabolites of morphine in urine samples of cancer patients.Methods  Urine samples from the patients were treated by solid‐phase extraction method and chromatographed using three high‐performance liquid chromatography systems. Conjugated metabolites were directly detected with liquid chromatographic/ion trap mass spectrometric (LC/MSn) technique by selected ion monitoring, full scan MS/MS and MS3 modes.Results  Six conjugated metabolites including two new metabolites M5 and M6 were found. Morphine‐3‐glucuronide (M‐3‐G) and morphine‐6‐glucuronide (M‐6‐G) were identified by comparing their l.c. retention times and multistage mass spectra with those of the reference substances. Two novel metabolites, morphine‐3‐glucoside and morphine‐6‐glucoside, as well as normorphine glucuronides were identified by comparing their mass fragment patterns and l.c. retention times with those of M‐3‐G and M‐6‐G. Hydrolysis of urine samples with β‐glucosidase and β‐glucuronidase provided further evidence of the metabolites M5 and M6 as morphine glucosides. The excretion amounts of morphine conjugates in urines were in the order of morphine glucuronides, morphine glucosides and normorphine glucuronides.Conclusions  In the present study, the applications of l.c. separation and multistage mass spectra have permitted the direct identification of conjugated metabolites of morphine. To our knowledge, this is the first report about O‐linked glucosides of morphine at 3‐aromatic and 6‐aliphatic hydroxyl groups.
Central nervous system effects of moxonidine experimental sustained release formulation in patients with mild to moderate essential hypertension
Authors: Kemme Michiel J. B. , Post Jeroen P. vd , Schoemaker Rik C. , Straub Matthias , Cohen Adam F. , Van Gerven Joop M. A. 
Published: June 2003

Objectives  The primary aim was to demonstrate that moxonidine, given in an experimental sustained release (SR) formulation, had no clinically relevant central nervous system (CNS) effects after 4 weeks of treatment. A clinically relevant CNS effect was predefined as more than 45° s−1 reduction in saccadic peak velocity (SPV), corresponding to the effects of one night's sleep deprivation.Methods  In a randomized, double‐blind fashion, 35 patients with mild to moderate essential hypertension received placebo run‐in medication for 2 weeks, followed by 4 weeks’ moxonidine sustained release (1.5 mg o.d.) or placebo. On the first day and 1 and 4 weeks following the start of treatment, blood pressure was measured and CNS effects were assessed using SPV, visual analogue scales and EEG.Results  On day 1 there was a significant, but not clinically relevant, reduction in the time‐corrected area under the effect curve (AUEC) for SPV in the moxonidine group compared with placebo [difference of 38° s−1; 95% confidence interval (CI) 23, 52]. This difference was no longer significant after one (9° s−1; 95% CI −17, 35) and 4 weeks (6.9° s−1; 95% CI −16, 30). Visual analogue scales for alertness showed similar results. A decrease in EEG α‐ and β‐power and an increase in δ‐power were only found on day 1 of moxonidine treatment. The AUEC for systolic/diastolic blood pressure relative to placebo was 23 (95% CI 17, 29)/13 (9, 16) mmHg lower on day 1 and remained reduced by 20 (11, 30)/12 (6, 17) and 15 (6, 25)/9 (3, 15) mmHg after 1 and 4 weeks’ moxonidine treatment.Conclusions  Four weeks’ treatment with an experimental SR formulation resulted in tolerance to CNS effects (equivalence to placebo) while blood pressure‐lowering effects remained adequate. The tolerance to CNS effects was already observed after 1 week of treatment.
Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis
Authors: Tomaselli Florian , Dittrich Peter , Maier Alfred , Woltsche Michael , Matzi Veronika , Pinter Johannes , Nuhsbaumer Stephan , Pinter Hans , Smolle Josef , Smolle‐Jüttner Freyja M. 
Published: June 2003

Objectives  The pharmacokinetic profile of antibiotics at the site of anti‐infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis‐based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma.Patients and methods  The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra‐, or post‐operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20‐min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam.Results  The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 ± 105.0 mg l−1 and 326.0 ± 60.6 mg l−1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 ± 167.0 mg.h l−1 and for serum 470.0 ± 142.0 mg.h l−1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4–6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis‐associated side‐effects were observed.Conclusion  This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti‐infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.