bluuebunny/crossref_metadata_2025_split huggingface dataset:
M2 and M3 muscarinic receptor‐mediated contractions in longitudinal smooth muscle of the ileum studied with receptor knockout mice
Authors: Unno Toshihiro , Matsuyama Hayato , Sakamoto Takashi , Uchiyama Mai , Izumi Yusuke , Okamoto Hiroyuki , Yamada Masahisa , Wess Jürgen , Komori Seiichi 
Published: June 2005

Isometric contractile responses to carbachol were studied in ileal longitudinal smooth muscle strips from wild‐type mice and mice genetically lacking M2 or M3 muscarinic receptors, in order to characterize the mechanisms involved in M2 and M3 receptor‐mediated contractile responses.
Single applications of carbachol (0.1–100 μM) produced concentration‐dependent contractions in preparations from M2‐knockout (KO) and M3‐KO mice, mediated via M3 and M2 receptors, respectively, as judged by the sensitivity of contractile responses to blockade by the M2‐preferring antagonist methoctramine (300 nM) or the M3‐preferring antagonist 4‐DAMP (30 nM).
The M2‐mediated contractions were mimicked in shape by submaximal stimulation with high K+ concentrations (up to 35 mM), almost abolished by voltage‐dependent Ca2+ channel (VDCC) antagonists or depolarization with 140 mM K+ medium, and greatly reduced by pertussis toxin (PTX) treatment.
The M3‐mediated contractions were only partially inhibited by VDCC antagonists or 140 mM K+‐depolarization medium, and remained unaffected by PTX treatment. The contractions observed during high K+ depolarization consisted of different components, either sensitive or insensitive to extracellular Ca2+.
The carbachol contractions observed with wild‐type preparations consisted of PTX‐sensitive and ‐insensitive components. The PTX‐sensitive component was functionally significant only at low carbachol concentrations.
The results suggest that the M2 receptor, through PTX‐sensitive mechanisms, induces ileal contractions that depend on voltage‐dependent Ca2+ entry, especially associated with action potential discharge, and that the M3 receptor, through PTX‐insensitive mechanisms, induces contractions that depend on voltage‐dependent and ‐independent Ca2+ entry and intracellular Ca2+ release. In intact tissues coexpressing M2 and M3 receptors, M2 receptor activity appears functionally relevant only when fractional receptor occupation is relatively small.

British Journal of Pharmacology (2005) 146, 98–108. doi:10.1038/sj.bjp.0706300
Power bounded operators and supercyclic vectors II
Authors: Müller V. 
Published: June 2005

We show that each power bounded operator with spectral radius equal to one on a reflexive Banach space has a nonzero vector which is not supercyclic. Equivalently, the operator has a nontrivial closed invariant homogeneous subset. Moreover, the operator has a nontrivial closed invariant cone if

1
1

belongs to its spectrum. This generalizes the corresponding results for Hilbert space operators. For non-reflexive Banach spaces these results remain true; however, the non-supercyclic vector (invariant cone, respectively) relates to the adjoint of the operator.
Levocetirizine has a longer duration of action on improving total nasal symptoms score than fexofenadine after single administration
Authors: Horak Friedrich , Zieglmayer Petra U. , Zieglmayer R. , Kavina A. , Lemell P. 
Published: June 2005

AimsTo compare the onset and duration of action of the new antihistamine levocetirizine with that of the second‐generation antihistamine fexofenadine using the Vienna Challenge Chamber (VCC). The latter is an environment where subjects can be exposed to specific aeroallergens in controlled and reproducible conditions allowing for precise comparisons of anti‐allergic drugs.MethodsNinety‐four subjects received a single dose of levocetirizine 5 mg, fexofenadine 120 mg or placebo in a random order using a three‐way cross‐over design. On day 1, subjects were exposed to grass pollens (1500 grains/m3) in the VCC over a period of 4 h. Treatment was given 2 h after the start of challenge. On day 2, 22 h after drug intake, subjects were again exposed to pollens for 6 h. Specified symptoms were assessed by the subjects every 15 min using 5‐point scales. The main efficacy parameter was the change from baseline in the Major Symptom Complex Score (MSCS = sum of rhinorrhea, sneezing, itchy nose and eyes).ResultsBaseline characteristics, including symptoms scores, were similar in the three study groups. During the first 2 h after drug intake both antihistamines achieved clinically relevant and significant (P < 0.001) improvements in symptom scores. Twenty‐two to 24 h after drug intake, mean (SEM) MSCS reductions were: 1.9 (0.3) after placebo (baseline of 9.7), 3.8 (0.3) after fexofenadine (baseline of 9.9), and 5.1 (0.3) after levocetirizine (baseline of 9.8). Levocetirizine was significantly (P < 0.001) more effective than fexofenadine with a score difference of 1.3 (95% CI 0.7, 1.9). This was maintained until the end of the study (up to 28 h).ConclusionsA rapid onset of action in alleviating seasonal allergic rhinitis (SAR) symptoms of subjects exposed to grass pollens in the VCC was observed after levocetirizine and fexofenadine. Levocetirizine was more effective than fexofenadine at and later than 22 h after drug intake, an indication of the longer‐duration of action of levocetirizine.
Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents
Authors: Holstein A. , Plaschke A. , Ptak M. , Egberts E.‐H. , El‐Din J. , Brockmöller J. , Kirchheiner J. 
Published: June 2005

AimsThe genetically polymorphic cytochrome P450 (CYP) enzyme CYP2C9 metabolizes most sulphonylurea oral hypoglycaemic agents. The aim of this study was to test the hypothesis that individuals with genotypes predicting low CYP2C9 activity may be at a higher risk of severe drug‐associated hypoglycaemia.MethodsIn a case‐control study, 20 diabetic patients admitted to the emergency department with severe hypoglycaemia during sulphonylurea drug treatment were compared with a control group of 337 patients with type 2 diabetes but without a history of severe hypoglycaemia. A large sample of 1988 healthy Caucasian subjects served as a second control group.ResultsThe CYP2C9 genotypes *3/*3 and *2/*3 that are predictive of low enzyme activity were more common in the hypoglycaemic group than in the comparison groups (10%vs <2%, respectively: odds ratio 5.2; 95% confidence interval 1.01, 27). Furthermore, the diabetic patient group with severe hypoglycaemia exhibited lower body mass indexes, higher rates of renal failure, were older compared with the diabetic group without severe hypoglycaemia, and were being treated with higher doses of glibenclamide.ConclusionsThese findings suggest that among other factors, individuals with genetically determined low CYP2C9 activity are at an increased risk of sulphonylurea‐associated severe hypoglycaemia. Thus, genotyping might be a tool for the better prediction of adverse effects caused by oral hypoglycaemic agents.
The role of CYP2C and CYP3A in the disposition of 3‐keto‐desogestrel after administration of desogestrel
Authors: Korhonen Tuomas , Tolonen Ari , Uusitalo Jouko , Lundgren Stefan , Jalonen Jorma , Laine Kari 
Published: June 2005

AimsOur objective was to study in vivo the role of CYP2C and CYP3A4 in the disposition of 3‐keto‐desogestrel after administration of desogestrel, by using the selective inhibitors fluconazole (CYP2C) and itraconazole (CYP3A4).MethodsThis study had a three‐way crossover design and included 12 healthy females, the data from 11 of whom were analyzed. In the first (control) phase all subjects received a single 150 µg oral dose of desogestrel alone. In the second and third phases subjects received a 4 day pretreatment with either 200 mg fluconazole or 200 mg itraconazole once daily in a randomized balanced order. Desogestrel was given 1 h after the last dose of the CYP inhibitor. Plasma 3‐keto‐desogestrel concentrations were determined for up to 72 h post dose.ResultsPretreatment with itraconazole for 4 days significantly increased the area under the plasma concentration‐time curve (AUC) of 3‐keto‐desogestrel by 72.4% (95% confidence interval on the difference 12%, 133%; P = 0.024) compared with the control phase, whereas fluconazole pretreatment had no significant effect (95% CI on the difference −42%, 34%). Neither enzyme inhibitor affected significantly the maximum concentration (95% CI on the difference 14%, 124% for itraconazole and −23%, 40% for fluconazole) or elimination half‐life (95% CI on the difference −42%, 120% for itraconazole and −24%, 61% for fluconazole) of 3‐keto‐desogestrel.ConclusionsAccording to the present study, the biotransformation of desogestrel to 3‐keto‐desogestrel did not appear to be mediated by CYP2C9 and CYP2C19 as suggested earlier. However, the further metabolism of 3‐keto‐desogestrel seems to be catalyzed by CYP3A4.
Dexamethasone as a probe for vinorelbine clearance
Authors: Puisset Florent , Dalenc Florence , Chatelut Etienne , Cresteil Thierry , Lochon Isabelle , Tisnes Pierre , Roché Henri 
Published: June 2005

AimTo assess the value of using dexamethasone as an in vivo probe for predicting vinorelbine clearance (CL).MethodsA population approach (implemented with NONMEM) was used to analyse blood vinorelbine pharmacokinetic data from 20 patients who received a 20‐min intravenous infusion of vinorelbine (from 20 to 30 mg m−2). Selected patient clinical data as well as known functional single CYP3A5 and ABCB1 genotype were also tested as covariates.ResultsThe best covariate model (with ± 95% confidence intervals) was based on dexamethasone plasma clearance (DPC) and alkaline phosphatase (ALP): vinorelbine blood CL (l h−1) = 39.8(± 4.0) × (DPC/13.2)0.524(±0.322) × (ALP/137)−0.198(±0.158). Interindividual variability in vinorelbine CL decreased from 29.7% (model without covariate) to 14.7% when including DPC and ALP. Vinorelbine CL was not correlated with body surface area (BSA) or associated with CYP3A5 and ABCB1 genotype.ConclusionsThese results indicate that individualization of vinorelbine dose would be improved by using dexamethasone clearance rather than BSA. Dexamethasone merits further evaluation as a probe of CYP3A metabolism.
Queen Mary Utilization of Antihypertensive Drugs Study: use of antihypertensive drug classes in the Hypertension Clinic 1996–2004
Authors: Cheung Bernard M. Y. , Wong Yuk Lin , Lau Chu Pak 
Published: June 2005

BackgroundUtilization of antihypertensive drugs in the hypertension outpatient clinic is surveyed periodically in the Queen Mary Utilization of Antihypertensive Drugs Study (QUADS).MethodsTwo hundred and fifty‐one patients (123 men, 128 women) were interviewed in April to December 1996, 439 patients (232 men, 207 women) in January to December 99 and 228 patients (109 men, 119 women) in April to May 2004. Their case notes were reviewed.ResultsThe percentages of patients receiving no drug (lifestyle modification), one, two, three and over three drugs were 7%, 48%, 36%, 7%, 3%, respectively, in 1996; 14%, 34%, 36%, 13% and 1%, respectively, in 1999; and 3%, 30%, 40%, 22% and 6%, respectively, in 2004. The number of drugs correlated with age and overweight. In 1996, 51% patients received calcium channel blockers (CCB); 46%β‐blockers (BB); 32% angiotensin‐converting enzyme inhibitors (ACEI); 15% thiazide diuretics; 5%α‐blockers; and 0% angiotensin receptor blockers (ARB). In 1999, the respective figures were 52% CCB, 49% BB, 24% ACEI, 22% thiazide diuretics, 4%α‐blockers and 2% ARB. In 2004, the respective figures were 65% CCB, 64% BB, 33% ACEI, 24% thiazide diuretics, 4%α‐blockers and 7% ARB. Fewer patients on BBs reported side‐effects. Only 11% were on α statin and 9% on aspirin. Blood pressure on treatment was 147 ± 21/84 ± 11 mmHg in 1999 and 144 ± 21/82 ± 11 mmHg in 2004.ConclusionsIncreasingly, multiple drugs were used for blood pressure control. Blood pressure control needs improvement, especially in diabetics. CCBs and BBs were consistently popular. Thiazide diuretics, ARBs, statins and aspirin were underused, despite favourable clinical trial evidence.
Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract
Authors: Thörn Mari , Finnström Niklas , Lundgren Stefan , Rane Anders , Lööf Lars 
Published: June 2005

AimThe aim of this study was to quantify the mRNA expression of three cytochromes P450 (CYP) and P‐glycoprotein (P‐gp) in the human gastrointestinal (GI) tract.MethodBiopsies were obtained from gastric, duodenal, colonic and rectal mucosa during routine gastro‐colonoscopy in 27 patients. The biopsies were snap‐frozen in liquid nitrogen. Real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR) was used for the quantitative analyses of mRNA expressed by the CYP2E1, CYP3A4 and CYP3A5 genes, and the MDR1 gene coding for P‐gp protein. The mRNA expression of b‐actin was used as an internal standard for comparisons between samples.ResultsAll CYP genes were expressed at all locations throughout the GI tract, although all showed substantial interindividual variation. CYP2E1 had the highest expression at all locations (P < 0.05 to P < 0.0001), except in the right colon. CYP3A4 and CYP3A5 had their highest mRNA expression in the duodenum (P < 0.001 and P < 0.000 001, respectively) and CYP2E1 in the stomach (P < 0.01). MDR1 mRNA concentrations increased along the GI tract with the highest expression being in the left colon (P < 0.000001).ConclusionMultiple sampling within the same individual enabled us to study the intraindividual variation in expression of CYP and MDR1 genes along the GI tract. We find that CYP2E1 mRNA expression is higher than that of the other CYPs. CYP3A expression is highest in the duodenum and that of MDR1 increases from stomach and duodenum to colon.
The effects of growth hormone status on circulating levels of vascular growth factors
Authors: Silha Josef V. , Krsek Michal , Hana Vaclav , Marek Josef , Weiss Vladimir , Jezkova Jana , Rosicka Martina , Jarkovska Zuzana , Murphy Liam J. 
Published: June 2005

SummaryBackground  Vascular growth factors are important not only in angiogenesis but also for the maintenance of normal endothelial integrity and function. Elevated levels of vascular endothelial growth factor (VEGF), angiopoietin‐2, hepatocyte growth factor (HGF), endostatin and angiogenin have been associated with endothelial dysfunction and atherosclerosis. Both acromegaly and growth hormone deficiency (GHD) are associated with endothelial dysfunction and changes in blood vessel morphology.Aim  To investigate the effect of GH status on the circulating levels of angiogenic factors.Design  We measured the levels of six endothelial growth modulators, four angiogenic growth factors and two inhibitors of angiogenesis in 35 untreated acromegalics, 36 untreated GH‐deficient subjects and 101 normal control subjects. Fifteen GH‐deficient subjects were also studied before and 1 year after treatment with GH.Results  Mean angiogenin concentrations were increased in acromegaly and decreased in GH‐deficient subjects compared to control subjects. Endostatin levels showed a similar pattern although the elevated levels in acromegalic subjects did not achieve statistical significance. Angiogenin and endostatin levels both correlated significantly with IGF‐I levels (R = 0·61, P < 0·001 and R = 0·22, P < 0·01, respectively). The relationship between angiogenin and IGF‐I levels remained significant even after correction for gender, age, body mass index (BMI) and insulin resistance. There were no significant differences in the levels of HGF, VEGF, VEGF‐C or angiopoietin‐2 between the three groups. VEGF‐D levels were elevated in both acromegalic and GH‐deficient male subjects. A similar pattern was apparent in female subjects. After GH treatment, a significant reduction in VEGF‐D levels and a significant rise in endostatin levels were observed in GH‐deficient subjects. A nonsignificant increase in angiogenin levels was also observed.Conclusion  These data indicate that significant perturbations in the levels of vascular growth modulators are present in both acromegaly and GHD. While changes in endostatin and angiogenin levels appear to correlate with IGF‐I levels, VEGF‐D levels show similar perturbations in both acromegaly and GHD. Further studies are required to determine the relationship of the perturbations to endothelial dysfunction in these conditions.
Quality of life of patients having renal replacement therapy
Authors: Niu Shu‐Fen , Li I.‐Chuan 
Published: June 2005

Aim.  This paper reports a study to compare the quality of life and its correlates for patients undergoing various types of renal replacement therapy.Background.  Patients with end stage renal disease need renal replacement therapy as a substitute for their original kidneys. Different renal replacement therapies have different levels of impact on physical, psychological and social health. Quality of life as perceived by patients with end‐stage renal disease is an important measure of patient outcome.Methods.  A cross‐sectional, descriptive, correlational study was carried out in 2002. A total of 240 patients were recruited from two medical centres in northern Taiwan. These patients were currently undergoing one of following types of renal replacement therapies: haemodialysis, continuous ambulatory peritoneal dialysis or transplantation. The study instrument used was the WHOQOL‐BREF‐TAIWAN. Data were analysed using descriptive and inferential statistics.Results.  The scores for quality of life of transplantation patients were higher than those for both haemodialysis and continuous ambulatory peritoneal dialysis patients. The lowest scores for all three groups were in the psychological domain. The mean age for haemodialysis and continuous ambulatory peritoneal dialysis patients was significantly higher than that for transplant patients. The educational level, proportion of single people, and employment status of transplant patients were significantly higher than those of haemodialysis and continuous ambulatory peritoneal dialysis patients. Perception of economic status as ‘balanced’ or ‘proficient’ for transplant patients was significantly higher than for continuous ambulatory peritoneal dialysis and haemodialysis patients.Conclusion.  Information about the quality of life of patients having various types of renal replacement therapy will assist physicians, nurses, patients and their families to make decisions on treatment selection. There is a need to establish support groups for patients having renal replacement therapy in order to enhance their quality of life, especially in the psychological domain.
The development of a new measure for the assessment of psychopathology in adults with intellectual disability
Authors: Mohr C. , Tonge B. J. , Einfeld S. L. 
Published: June 2005

Background  People with intellectual disability (ID) and untreated psychiatric disorder lead unnecessarily difficult and unhappy lives. The prevalence of mental illness in children and adults with ID is greater than that found in the general population. A carer‐completed checklist of psychopathology that could be used with both children and adults would help identify those individuals with ID most likely to have a mental health problem, help ensure that they receive the limited services that are usually available and also assist the process of clinical assessment, diagnosis and management.Method  This research aimed to develop a reliable and valid carer‐completed checklist of psychopathology for adults with ID by redeveloping an existing measure for children with ID, the Developmental Behaviour Checklist (DBC‐P). The new checklist, The Developmental Behaviour Checklist for Adults (DBC‐A) was devised by changing, deleting and adding to DBC‐P items. Reliability studies were conducted with paid and family carers, and DBC‐A scores were compared with the results from two other measures of psychopathology.Results  One DBC‐P item was deleted, seven items changed and 12 items added. The psychometric properties of this new checklist, the DBC for Adults with ID (DBC‐A), were investigated and found to be satisfactory. Intraclass correlations for test‐retest and inter‐rater reliability ranged from 0.72 to 0.85, and concurrent validity with two measures of emotional and behavioural disturbance was satisfactory.Conclusions  The carer‐completed DBC‐A provides a broad and comprehensive survey of the emotional and behavioural problems of adults with ID. It has satisfactory psychometric properties and therefore can be used with confidence in clinical, research and service settings, and its development allows continuous assessment of psychopathology across the lifespan for all people with ID.
Is Post‐Traumatic Stress Disorder a helpful concept for adults with intellectual disability?
Authors: Mitchell A. , Clegg J. 
Published: June 2005

AbstractBackground  Research using the concept of Post‐Traumatic Stress Disorder (PTSD) with adults with intellectual disability (ID)assumes they perceive and react to traumatic events in a similar way to non‐disabled adults. Reactions to trauma displayed by children may be relevant to adults with ID as well.Methods  Two focus groups were held with professionals and practitioners to explore the relevance of criteria from child as well as adult literature to adults with ID who experience trauma. Descriptive thematic analysis was carried out.Results  Abuse, parental bereavement, and having children removed were considered common sources of trauma. Similarities identified between disabled and non‐disabled adults were flashbacks and nightmares; distressed by reminders; avoidance; hypervigilance and increased arousal. Differences were the frequent occurrence of multiple rather than single events, which were considered significant in generating chronic problems similar to those described as PTSD; also the occurrence of physical health problems and behavioural re‐enactments.Discussion and conclusions  Experienced professionals and practitioners considered most of the ideas from PTSD research with non‐disabled adults to be relevant to adults with ID who experience trauma, but that some behaviour reported in research with children was also relevant. Topics and questions for use in clinical and research practice with individuals who have experienced trauma were proposed.
Randomized controlled trial of assertive community treatment in intellectual disability: the TACTILD study
Authors: Oliver P. C. , Piachaud J. , Tyrer P. , Regan A. , Dack M. , Alexander R. , Bakala A. , Cooray S. , Done D. J. , Rao B. 
Published: June 2005

AbstractBackground  There has been a policy shift away from hospital to community in the services of all those with psychiatric disorders, including those with intellectual disability (ID), in the last 50 years. This has been accompanied recently by the growth of assertive outreach services, but these have not been evaluated in ID services.Method  In a randomized controlled trial we compared assertive outreach with ‘standard’ community care, using global assessment of function (GAF) as the primary outcome measure, and burden and quality of life as secondary measures.Results  We recruited 30 patients, considerably less than expected; no significant differences were found between the primary and secondary outcomes in the two groups. The differences were so small that a Type II error was unlikely.Conclusions  Reasons for this lack of specific efficacy of the assertive approach are discussed and it is suggested that there is a blurring of the differences between standard and assertive approaches in practice.