bluuebunny/crossref_metadata_2025_split huggingface dataset:
General practitioners’ adoption of new drugs and previous prescribing of drugs belonging to the same therapeutic class: a pharmacoepidemiological study
Authors: Dybdahl Torben , Andersen Morten , Kragstrup Jakob , Kristiansen Ivar Sønbø , Søndergaard Jens 
Published: October 2005

AimTo test the hypothesis that general practitioners (GPs) with high prescribing levels of certain drugs will adopt new drugs belonging to the same therapeutic group faster than those with low prescribing levels.MethodsThe adoption of four new drugs: esomeprazol, selective cyclo‐oxygenase‐2 inhibitors, new triptans, and angiotensin‐II receptor blockers were analysed using population‐based prescription data. We used the preference proportion (prescriptions for new rather than older alternatives for the same indication) to measure GPs’ adoption rate. Annual prescribing volume and prevalence were used to measure previous prescribing of older drug alternatives. We modelled the preference proportion using multiple linear regression analysis and the prescribing of older drugs as independent variables. We controlled for the GPs’ general prescribing level and weighted for practice size. In the first three analyses, we dichotomized data using the median, lower and upper quartile as cut‐off point. Next, we grouped data into quartiles and finally, we used continuous data.ResultsFor esomeprazol and new triptans there was a higher preference for new drugs among ‘high prescribers’, but only when this term was defined as the upper quarter and the upper half of previous prescribing levels, respectively (mean difference in preference proportion: 10.2% (99% confidence interval = 1.3%, 19.1%) and 8.2% (0.2%, 16.2%)). For the remaining two drug classes the associations were weak and almost all statistically nonsignificant.ConclusionThere is no consistent association between GPs’ level of drug prescribing and their adoption of new drugs of the same therapeutic group.
Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment
Authors: Holmes Gregory , Galitz Lawrence , Hu Peter , Lyness William 
Published: October 2005

AimsTo assess the effects of body mass index, renal impairment (creatinine clearance), and hepatic impairment (Child‐Pugh Score) on the pharmacokinetics of insulin aspart.MethodsPharmacokinetics of insulin aspart (injected subcutaneously in the abdomen immediately before a Boost® standardized meal) were characterized in: (1) diabetic subjects with four ranges of BMI values (n = 23); (2) diabetic subjects with varying degrees of renal impairment (normal, n = 6 vs. two ranges of impairment, n = 12); and (3) nondiabetic patients with varying degrees of hepatic impairment (normal, n = 6 vs. three ranges of impairment, n = 18).ResultsThere was no correlation between any pharmacokinetic variable and the degree of renal or hepatic impairment. Increasing obesity was associated with a decreased apparent clearance per kg body weight (β = −0.0005, SE = 0.0001; P = 0.002), an increased t½ (β = 3.513, SE = 1.636; P = 0.044), and an increased ln(AUC0−360) and ln(AUC0−1440) (β = 0.030, SE = 0.013; P = 0.032 and β = 0.039, SE = 0.0132; P = 0.006, respectively). However, obesity‐related changes were smaller than individual variations in parameters.ConclusionsRenal impairment, hepatic impairment, or BMI do not affect the pharmacokinetics of insulin aspart in a clinically significant manner.AbbreviationsAUC0–1440, area under the plasma concentration curve; BMI, body‐mass index; CLcr, renal clearance of creatinine; CL/F, apparent clearance; CL/F/kg, body weight‐adjusted apparent clearance; Cmax, maximal plasma concentration; FBG, fasting blood glucose; GFR, glomerular filtration rate; HI, human insulin; MRT, mean residence time; PK, pharmacokinetics; t½, half life; tmax, time to maximum concentration; Vz/F, apparent volume of distribution.
Trends in prescribing and utilization of statins and other lipid lowering drugs across Europe 1997–2003
Authors: Walley T. , Folino‐Gallo P. , Stephens P. , Van Ganse E. ,   EuroMedStat group
Published: October 2005

AimsTo describe trends in utilization and prescribing of statins and other lipid lowering drugs across Europe from data in routine administrative databases.MethodsObservational study in EU member states and Norway. Comparison of annual utilization data for lipid lowering agents by class and drug from national administrative databases for reimbursement over the period 1997–2003, measured in DDDs per 1000 inhabitants/day. Prescribed daily doses (PDD) of statins obtained from a commercial database (IMS Health) for 2000 and 2003, and used to calculate numbers of ‘patient treatment days’ (PTD) in each country in each year. Analysis of PTD to explain increased utilization of statins.ResultsUse of lipid lowering agents varied among countries (in 2003, highest in Ireland and Norway, and lowest in Italy), but increased in all countries studied (between 2000 and  2003  by  274% in  Ireland  and  by  56% in  France).  This  increase  was  entirely  due to increases in statin use. Prescribed daily doses of statins increased in all countries for which data was available between 2000 and 2003, but still usually fell below the doses used in the major trials of statins. As a result, the numbers of PTDs increased to a lesser extent than suggested by utilization (e.g. by 192% in Ireland and by 35% in France). One‐third of the total rise in utilization was explained by increased PDD, and two‐thirds by an increase in numbers of PTDs. Statins dominated the markets in all countries, although fibrates remained strong in France and Belgium (approximately 25% of all lipid lowering agents) and to a lesser extent Germany (10%).ConclusionsUse of statins across Europe has increased hugely over the study period. Some of the increase in use is due to higher prescribed daily doses, but two‐thirds is due to increases in numbers of patient days of treatment, either due to more patients treated or less likely to better compliance.
Mirtazapine‐induced arthralgia
Authors: Passier Anneke , Van Puijenbroek Eugène 
Published: October 2005

AimWith this article, we intend to corroborate the assumed association between mirtazapine and arthralgia by presentation of eight case reports, and we describe a possible mechanism of action.Methods and resultsThe Netherlands Pharmacovigilance Centre Lareb received eight case reports on arthralgia associated with use of mirtazapine. These case reports are presented in short. We also present worldwide data on this association.ConclusionsThe Lareb reports support the association between mirtazapine and arthralgia. A comparison is made between mirtazapine, mianserin and nefazodone, as these antidepressants show similarities in their mode of action and are all associated with arthralgia. We suggest that this adverse drug reaction may be induced by enhanced 5HT1‐mediated neurotransmission.
Calcium antagonists and deep gingival pockets in the population‐based SHIP study
Authors: Meisel Peter , Schwahn Christian , John Ulrich , Kroemer Heyo K. , Kocher Thomas 
Published: October 2005

AimGingival overgrowth is a common undesired side‐effect in patients taking calcium channel blockers. Different reports have suggested that the drug‐induced gingival hyperplasia may aggravate inflammatory periodontal disease. However, representative epidemiological data are lacking. We investigated the association between the intake of calcium antagonists and periodontitis in a population‐based analysis including the most important risk factors of periodontitis.MethodsIn a cross‐sectional epidemiological investigation involving 4290 subjects aged 20–80 years, we recorded periodontal risk factors and identified participants using calcium antagonists. Periodontal parameters, attachment loss, probing depth and number of teeth were assessed. In a subgroup analysis with matched pairs, 456 subjects using calcium antagonists and 456 without were compared for periodontal status.ResultsSubjects treated with calcium antagonistic drugs had significantly deeper gingival pockets than their drug‐free counterparts. This was observed in the total population of 4290 and confirmed by logistic regression analyses (P < 0.001) controlled for the known risk factors of periodontitis (age, sex, smoking, education). In the matched‐pair analysis only the probing depth was increased: extent probing depth ≥ 4 mm median 23.5 vs. 17.0% (P < 0.001); mean probing depth 3.0 ± 0.8 vs. 2.7 ± 0.9 mm (P < 0.001). No differences were found in extent and severity of clinical attachment loss and in the number of teeth. The risk of gingival overgrowth was aggravated in smokers.ConclusionIn the general population, treatment with calcium antagonists leads to gingival overgrowth without an aggravation of periodontal disease. Interaction with smoking indicates the multifactorial background of the undesired effect of calcium antagonists.
Population plasma pharmacokinetics of 11C‐flumazenil at tracer concentrations
Authors: Van Rij Catharina M. , Huitema Alwin D. R. , Swart Eleonora L. , Greuter Henricus N. J. M. , Lammertsma Adriaan A. , Van Loenen Arie C. , Franssen Eric J. F. 
Published: October 2005

ObjectiveThe objectives of the study were to develop a population pharmacokinetic model for 11C‐flumazenil at tracer concentrations, to assess the effects of patient‐related covariates and to derive an optimal sampling protocol for clinical use.MethodsA population pharmacokinetic model was developed using nonlinear mixed effects modelling (NONMEM) with data obtained from 51 patients with either depression or epilepsy. Each patient received ∼370 MBq (1–4 µg) of 11C‐flumazenil. The effects of selected covariates (gender, weight, type of disease and age) were investigated. The model was validated using a bootstrap method. Finally, an optimal sampling design was established.ResultsThe population pharmacokinetics of tracer quantities of 11C‐flumazenil were best described by a two compartment model. Type of disease and weight were identified as significant covariates (P < 0.002). Mean population pharmacokinetic parameters (percent coefficient of variation) were: CL 1530 mL min−1 (6.6%), V1 24.8 × 103 mL (3.8%), V2 27.3 × 103 mL (5.4%), and Q 2510 mL min−1 (6.5%). CL was 20% lower in patients with epilepsy, and the influence of weight on V1 was 0.55% kg−1. For the prediction of the AUC, a combination of two time points at t = 30 and 60 min post injection was considered optimal (bias −0.7% (95% CI −2.2 to 0.8%), precision 5.7% (95% CI 4.5–6.9%)). The optimal sampling strategy was cross‐validated (observed AUC = 296 MBql−1 min−1 (95% CI 102–490), predicted AUC = 288 MBql−1 min−1 (95% CI 70–506)).ConclusionsThe population pharmacokinetics of tracer quantities of 11C‐flumazenil are well described by a two‐compartment model. Inclusion of weight and type of disease as covariates significantly improved the model. Furthermore, an optimal sampling procedure may increase the feasibility and applicability of 11C‐flumazenil PET.
Circulating microparticles are elevated in haemophiliacs and non‐haemophilic individuals aged <18 years
Authors: Proulle Valérie , Hugel Bénédicte , Guillet Benoit , Grunebaum Lélia , Lambert Thierry , Freyssinet Jean‐Marie , Dreyfus Marie 
Published: October 2005

SummaryPlatelet and cell stimulation lead to plasma membrane remodelling, resulting in phosphatidylserine (PS) externalisation in the outer leaflet of the membrane, associated with the shedding of PS‐rich microparticles (MPs), and contributes to thrombin generation by promoting the assembly of coagulation enzyme complexes. A previous study assessed MP levels in haemophiliacs after haemostatic treatment. To further investigate in vivo membrane remodelling, MP levels and characteristics were studied in 79 haemophiliacs and in 62 non‐haemophiliacs. Both groups showed heterogeneity in MP levels, with higher values in individuals <18 years. This finding should be considered when studying MP levels in individuals <18 years.
Circulating CD10−/CD16low neutrophils provide a quantitative index of active bone marrow neutrophil release
Authors: Orr Y. , Taylor J. M. , Bannon P. G. , Geczy C. , Kritharides L. 
Published: October 2005

SummaryCirculating neutrophil phenotype and function are altered during neutrophilia associated with acute inflammatory states, however, the contribution of bone marrow neutrophil release to these changes has been difficult to quantify in humans. Accelerated release of neutrophils, with potentially distinct attributes, from the bone marrow and their dilution within the circulating pool may produce these apparent changes. Unfortunately selective analysis of these newly emergent neutrophils is difficult given their morphologic similarity to those already in the circulation and the coincident effect of soluble inflammatory mediators on circulating neutrophil phenotype and function. Using whole blood flow cytometry and cardiac surgery as an inflammatory stimulus, we demonstrate the emergence of a unique subpopulation of circulating neutrophils characterised as CD10−/CD16low, indicative of active bone marrow neutrophil release peri‐operatively. CD10−/CD16low neutrophils emerge at the same operative stages as band forms and a left shift, yet represent over 40% of circulating neutrophils postoperatively, and generate a greater stimulus‐induced [Ca2+]i flux than their CD10+ counterparts. We conclude that CD10−/CD16low neutrophils represent a significant proportion of the circulating pool after cardiac surgery and that bone marrow release, a major contributor to neutrophilia, influences the phenotype and functional activity of circulating neutrophils following this acute inflammatory stimulus.
The synthetic furanonaphthoquinone induces growth arrest, apoptosis and differentiation in a variety of leukaemias and multiple myeloma cells
Authors: Desmond Julian C. , Kawabata Hiroshi , Mueller‐Tidow Carsten , Simamura Eriko , Heber David , Hirai Kei‐Ichi , Phillip Koeffler H. 
Published: October 2005

Summary2‐Methyl‐naphtho[2,3‐b]furan‐4,9‐dione (FNQ3), a synthetic analogue of the quinone kigelinone, has demonstrated a real potential for use in the treatment of a variety of solid tumours. Unlike other quinones, such as mitomycin‐C and adriamycin, the cytotoxicity of FNQ3 is often 10‐ to 14‐fold more potent towards the tumour cells than their normal counterparts. We report, for the first time, that the drug had activity against a broad spectrum of leukaemias and multiple myeloma cells. It decreased the growth of acute myeloid leukaemia (AML) and multiple myeloma cell lines in a dose‐dependent fashion (50% inhibitory concentration ≈1·25 μg/ml against most of the leukaemia cell lines). This dose apparently initiated mitochondrial collapse as measured by depolarisation of the mitochondrial membrane. FNQ3 potentiated the differentiation of HL‐60 myeloid cells in the presence of either 1α, 25(OH)2 dihydroxyvitamin D3 [1α,25(OH)2D3] or all‐trans‐retinoic acid (ATRA). FNQ3 inhibited the proliferation of primary AML cells while inducing apoptosis. Eleven of 14 (79%) AML marrow samples had a prominent decrease in their clonogenic growth when cultured in the presence of the drug. In summary, this drug has growth inhibitory, apoptotic and differentiative effects against myeloid leukaemias and multiple myeloma cells. FNQ3 may represent a new therapeutic approach to these malignancies.
Management of Evans syndrome
Authors: Norton Alice , Roberts Irene 
Published: October 2005

SummaryEvans syndrome is an uncommon condition defined by the combination (either simultaneously or sequentially) of immune thrombocytopenia (ITP) and autoimmune haemolytic anaemia (AIHA) with a positive direct antiglobulin test (DAT) in the absence of known underlying aetiology. This condition generally runs a chronic course and is characterised by frequent exacerbations and remissions. First‐line therapy is usually corticosteroids and/or intravenous immunoglobulin, to which most patients respond; however, relapse is frequent. Options for second‐line therapy include immunosuppressive drugs, especially ciclosporin or mycophenolate mofetil; vincristine; danazol or a combination of these agents. More recently a small number of patients have been treated with rituximab, which induces remission in the majority although such responses are often sustained for <12 months and the long‐term effects in children are unclear. Splenectomy may also be considered although long‐term remissions are less frequent than in uncomplicated ITP. For very severe and refractory cases stem cell transplantation (SCT) offers the only chance of long‐term cure. The limited data available suggest that allogeneic SCT may be superior to autologous SCT but both carry risks of severe morbidity and of transplant‐related mortality. Cure following reduced‐intensity conditioning has now been reported and should be considered for younger patients in the context of controlled clinical trials.
Up‐regulation of the T cell quiescence factor KLF2 in a leukaemic T‐cell line after expression of the inositol 5′‐phosphatase SHIP‐1
Authors: García‐Palma Lizet , Horn Stefan , Haag Friedrich , Diessenbacher Philip , Streichert Thomas , Mayr Georg W. , Jücker Manfred 
Published: October 2005

SummaryInositol 5′‐phosphatase SHIP‐1 (SHIP) is a negative regulator of signal transduction in haematopoietic cells. SHIP inactivation may be involved in the pathogenesis of leukaemia. An inducible expression system was combined with microarray analysis to identify target genes regulated by SHIP in the human T‐cell leukaemia cell line Jurkat. One gene identified was Krüppel‐like factor 2 (KLF2), which was up‐regulated two to threefold at the RNA and protein level after the induced expression of SHIP. KLF2, a negative regulator of T cell proliferation, has been implicated in T cell quiescence. KLF2 or SHIP expression in Jurkat cells caused 45% or 60% reduction of proliferation, respectively. SHIP can up‐regulate KLF2 expression, implicating KLF2 in the SHIP‐mediated growth inhibition of a human leukaemic T‐cell line.
Can the evolutionary‐rates hypothesis explain species‐energy relationships?
Authors: EVANS K. L. , GASTON K. J. 
Published: October 2005

SummaryThere is growing consensus that much of the marked broad‐scale spatial variation in species richness is associated with variation in environmental energy availability, but at least nine principal mechanisms have been proposed that may explain these patterns.The evolutionary‐rates hypothesis suggests that high environmental energy availability elevates rates of molecular evolution, promoting faster speciation, so that more species occur in high‐energy areas because more evolve there. Direct tests of this hypothesis are rare and their conclusions inconsistent. Here we focus on assessing the support for its underlying assumptions.First, the evolutionary‐rates hypothesis assumes that high energy levels promote mutation. There is certainly evidence that high levels of ultraviolet radiation increase mutation rates. High temperatures may also reduce generation times and elevate metabolic rates, which may promote mutation. On balance, data support a link between rates of metabolism and mutation, but a link between the latter and generation time is more equivocal and is particularly unlikely in plants.Second, the evolutionary‐rates hypothesis assumes that mutation rates limit speciation rates. This may be true if all else was equal, but correlations between mutation and speciation are probably very noisy as many other factors may influence rates both of sympatric and allopatric speciation, including the occurrence of physical isolation barriers, the magnitude of selection and population size.Third, the evolutionary‐rates hypothesis assumes that there is a strong correlation between current and historical energy levels. Factors such as tectonic drift may weaken such relationships, but are likely to have had negligible effects over the time period during which the majority of extant species evolved.Fourth, the evolutionary‐rates hypothesis assumes that changes in species ranges following speciation do not sufficiently weaken the correlation between the rate of speciation in an area and species richness. The ranges of many species appear to alter dramatically following speciation, and this may markedly reduce the strength of the relationship, but to what extent is unclear.In sum, the degree to which the evolutionary‐rates hypothesis can explain spatial variation in species richness remains surprisingly uncertain. We suggest directions for further research.
Effect of food level and rearing temperature on burst speed and muscle composition of Western Spadefoot Toad (Spea hammondii)
Authors: ARENDT J. , HOANG L. 
Published: October 2005

SummaryPast studies on phenotypic plasticity usually focus on ultimate (evolutionary) issues. More recently, proximate (developmental) factors explaining how plasticity is achieved are starting to be addressed.Here, we examine the importance of resource level and temperature on growth rate and burst swimming speed in tadpoles ofSpea hammondii(Western Spadefoot Toad).Food and temperature manipulations alter growth rate via different developmental processes (cell growth and cell recruitment, respectively) and these processes appear to have consequences for swimming performance in tadpoles.Tadpoles reared at warm temperatures were slower swimmers than those reared at cooler temperatures while food level had no effect on size‐specific burst speed. Tadpoles reared at warm temperatures also had more fibres in the tail muscle, probably due to an earlier onset of recruitment. Tadpoles reared at higher food levels had larger muscle fibres, but little differences in fibre number compared to those reared at low food levels.These results indicate that growth by adding cells comes at a performance cost not seen when growth is due to increasing cell size. This developmental difference also has implications for how body size manipulations are carried out in behavioural and ecological studies.
Compensatory growth of Festuca rubra after grazing: can migratory herbivores increase their own harvest during staging?
Authors: VAN DER GRAAF A. J. , STAHL J. , BAKKER J. P. 
Published: October 2005

Summary

The grazing optimization hypothesis predicts increased production and quality of plants grazed at intermediate grazing pressures. Following this hypothesis, herbivores will be able to increase their own harvest by repeated grazing. We tested the predictions of this hypothesis for Barnacle Geese, Branta leucopsis.
We manipulated the grazing intensity of Festuca rubra swards through trials with captive geese in early spring. Levels on experimental grazing matched levels of natural grazing pressure. The growth response of individually marked tillers was measured over 6 weeks.
Above‐ground biomass production of individual tillers was not different among different grazing intensities. Lost biomass in grazed tillers was compensated by a lower rate of senescence.
Grazing affected sward characteristics significantly: the proportion of dead biomass in the vegetation was reduced, and production of additional axillary tillers increased.
When extrapolating the experimental findings to foraging opportunities for staging geese, we calculate an increase in potential harvest for grazed compared with ungrazed swards at levels of natural spring grazing.
This experiment demonstrates an increase in the carrying capacity of the staging site for migratory geese through grazing. When comparing the experiment with grazing levels of wild Barnacle Geese, it is clear that current goose densities maximize potential harvest.