bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacogenetic interactions of three candidate gene polymorphisms with ACE‐inhibitors or β‐blockers and the risk of atherosclerosis
Authors: Schelleman H. , Klungel O. H. , Witteman J. C. M. , Hofman A. , Van Duijn C. M. , De Boer A. , Stricker B. H. CH. 
Published: February 2007

What is already known about this subject • To our knowledge, there are no prior studies which investigate whether there is a drug–gene interaction between the three genes involved in the renin–angiotensin system and ACE‐inhibitor therapy or β‐blocker therapy with these subclinical measurements of atherosclerosis.• Some studies have found an effect on blood pressure or stroke/myocardial infarction, although the results are not conclusive. What this study adds • The results do not indicate the presence of a strong drug–gene interaction between the use of ACE‐inhibitors or β‐blockers and the ACE insertion/deletion, AGT M235T or AGTR1573C/T polymorphism on the overall risk of atherosclerosis.Aims To investigate whether the angiotensin‐converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen M235T or angiotensin II receptor type 1 573C/T polymorphism modify the risk of atherosclerosis associated with β‐blocker or ACE‐inhibitor therapy.Methods Data were used from the Rotterdam Study, a population‐based prospective cohort study in the Netherlands, which started in 1990 and included 7983 subjects of ≥ 55 years. In this study, 2216 subjects with hypertension were included. Three subclinical measurements were used for atherosclerosis, i.e. peripheral arterial disease, carotid atherosclerosis and aortic atherosclerosis. The interaction between antihypertensive drugs and genetic polymorphisms on the risk of atherosclerosis was determined with binary logistic regression analysis.Results The risk of aortic atherosclerosis associated with long‐term (≥4 years) β‐blocker treatment compared with no use of β‐blockers was higher in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene [synergy index (SI) = 3.36; 95% confidence interval (CI) 1.14, 9.97]. The risk of carotid atherosclerosis associated with long‐term ACE‐inhibitor treatment compared with no use of ACE‐inhibitors was lower in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene (SI = 0.20; 95% CI 0.04, 0.95).Conclusion Overall, the risk of atherosclerosis in hypertensives taking a β‐blocker or ACE‐inhibitor‐based regimen was not strongly modified by any of the three candidate gene polymorphisms.
The use of mechanistic DM‐PK‐PD modelling to assess the power of pharmacogenetic studies –CYP2C9and warfarin as an example
Authors: Dickinson Gemma L. , Lennard Martin S. , Tucker Geoffrey T. , Rostami‐Hodjegan Amin 
Published: February 2007

What is already known about this subject• Many studies have shown that genetic polymorphisms of theCYP2C9gene contribute to some of the variability (around 20%) in warfarin dose requirements and therapeutic response to the drug.• It is also clear that this effect must be elicited through differences in the plasma (S)‐warfarin concentration between individuals of different genotypes, although assessing the effects of any single genotype ofCYP2C9on the kinetics of (S)‐warfarin has generally failed.What this study adds• The study aims to simulate the impact of genetic polymorphism in CYP2C9 on both the pharmacokinetics (PK) and pharmacodynamics (PD) of (S)‐warfarin using a mechanistic, population approach to modelling.• The outcomes with respect to the design of studies and their statistical power are compared against those of actual reported studies.• The exercise with warfarin is offered as an example of how prior information on thein vitroPK and PD of new drugs might be used in association with knowledge of relevant genetic polymorphisms and their frequencies to carry out virtual clinical studies as an aid to the design, optimization and powering of subsequent real clinical trials assessing the impact of specific genetic differences.AimTo assess the power ofin vivostudies needed to discern the effect of genotype on pharmacokinetics (PK) and pharmacodynamics (PD) usingCYP2C9and (S)‐warfarin as an example.MethodsInformation on thein vitrometabolism of (S)‐warfarin and genetic variation in CYP2C9 was incorporated into a mechanistic population‐based PK–PD model. The influence of study design on the ability to detect significant differences in PK (AUC0−12 h) and PD (AUEC0−12 hINR) betweenCYP2C9genotypes was investigated.ResultsA study size of 90 (based on the natural abundance of genotypes and uniform dosage) was required to achieve 80% power to discriminate the PK of (S)‐warfarin between wild type (*1/*1) and the combination of all other genotypes. About 250 subjects were needed to detect a difference in anticoagulant response. The power to detect differences between specific genotypes was much lower. Analysis of experimental comparisons of the PK or PD between wild‐type and other individual genotypes indicated that only 21% of cases (20 of 95 comparisons within 11 PD and four PK–PD studies) reported statistically significant differences. This was similar to the percentage expected from our simulations (20%, χ2test,P = 0.80). Simulations of studies enriched with specific genotypes indicated that only three and five subjects were required to detect differences in PK and PD between wild type and the *3/*3 genotype, respectively.ConclusionThe utilization of prior information (includingin vivoenzymology) in clinical trial simulations can guide the design of subsequentin vivostudies of the impact of genetic polymorphisms, and may help to avoid costly, inconclusive outcomes.
Do calcium antagonists contribute to gastro‐oesophageal reflux disease and concomitant noncardiac chest pain?
Authors: Hughes Jeff , Lockhart Judith , Joyce Andrew 
Published: February 2007

What is already known about this subject • Calcium antagonists (CA) are listed in textbooks as potential causes of gastro‐oesophageal reflux disease (GORD).• There have been two studies which have documented increased use of acid suppressant therapy amongst patients taking CAs. What this study adds • This study provides the first data on the frequency of exacerbation and precipitation of gastro‐oesophageal reflux symptoms amongst users of CAs.• It also provides evidence of the likely potential of the different CAs to cause such symptoms and highlights the need for a prospective study into CA therapy.• The data from the study should heighten prescribers' awareness of the potential of these agents to exacerbate/precipitate GORD, and to consider avoiding CAs in patients with GORD or withdrawing them in patients in whom GORD symptoms develop or worsen.Aims A cohort retrospective observational study was undertaken to determine the relationship between calcium antagonist (CA) use and gastro‐oesophageal reflux disease (GORD), as well the ability of CAs to precipitate or exacerbate noncardiac chest pain, an atypical symptom of GORD.Methods Eligible patients were those prescribed CAs for hypertension without a history of ischaemic heart disease or nitrate use. Patients were recruited through 15 pharmacies (hospital 1, community 14). Patients giving informed consent were administered a standard questionnaire to obtain information including history of reflux symptoms before and during treatment with CAs, and the management of these symptoms.Results Three hundred and seventy‐one participants were enrolled. Their mean age was 64 years (SD ± 12.7 years), 51.2% were females and 48.8% males. Of the 130 patients with pre‐existing gastrointestinal (GI) symptoms, 59 (45.4%) reported a worsening of reflux symptoms during CA therapy. Increases in both frequency and severity of symptoms were most common amongst patients on amlodipine (61.3%; P ≤ 0.0001) and least common amongst those taking diltiazem (12.5%). Reflux‐related symptoms developed in 85 (35.3%) of the 241 previously asymptomatic patients during CA therapy, with verapamil having the greatest number of reports (39.1%; P = 0.001) and diltiazem the least (30.7%).Conclusions Diltiazem appears the least likely of the CAs to precipitate or exacerbate reflux symptoms. Further research using a prospective design could test whether it may be more appropriate to use diltiazem in patients with ischaemic heart disease and could assess the appropriateness of CA therapy in patients with moderate to severe GORD. Increasing prescriber and pharmacist awareness of these adverse effects may result in better patient outcomes and potentially reduce treatment costs.
Gender, age, smoking behaviour and plasma clozapine concentrations in 193 Chinese inpatients with schizophrenia
Authors: Tang Yi‐lang , Mao Peixian , Li Feng‐Min , Li Wenbiao , Chen Qi , Jiang Feng , Cai Zhuo‐ji , Mitchell Philip B. 
Published: February 2007

What is already known about this subject • Plasma concentrations of clozapine (CLZ) and its active metabolite vary considerably at a given dosage.• A number of patient‐related factors have been reported to increase the variability of plasma CLZ concentrations, with gender, age and smoking behaviour representing some of the more important contributing variables• However, results of previous studies concerning these factors have been inconsistent and most studies were conducted in western populations. What this study adds • Using this ethnically unique, relatively large sample, we replicated some findings in western populations, including large interindividual variability of plasma CLZ concentrations, significant effects of gender on plasma CLZ concentrations.• Female patients had significantly higher levels than males and no significant differences in plasma CLZ concentrations were observed between male smokers and nonsmokers, despite the CLZ dosage for smokers being significantly higher.Aim To study the relationship between age, gender, cigarette smoking and plasma concentrations of clozapine (CLZ) and its metabolite, norclozapine (NCLZ) in Chinese patients with schizophrenia.Methods Data from a therapeutic drug monitoring programme were analysed retrospectively. One hundred and ninety‐three Chinese inpatients with schizophrenia were assessed using clinical data forms. Steady‐state plasma concentrations of CLZ and NCLZ were assayed using high‐performance liquid chromatography. Comparisons of dosage and plasma CLZ concentrations were undertaken between males (n = 116) and females (n = 77), younger (≤40 years, n = 82) and older patients (>40 years, n = 111) and current male smokers (n = 50) and nonsmokers (n = 66).Results (i) Plasma CLZ concentrations demonstrated large interindividual variability, up to eightfold at a given dose; (ii) there were significant effects of gender on plasma CLZ concentrations (relative to dose per kg of body weight) with female patients having significantly higher concentrations than males (30.09 ± 24.86 vs. 19.87 ± 3.55 ng ml−1 mg−1 day−1 kg−1; P < 0.001); (iii) there were no significant differences in plasma CLZ concentrations between those patients ≤40 years old and those >40 years; and (iv) there were no significant differences in plasma CLZ concentrations between male smokers and nonsmokers, despite the CLZ dosage for smokers being significantly higher.Conclusions Plasma CLZ concentrations vary up to eightfold in Chinese patients. Among the patient‐related factors investigated, only gender was significant in affecting CLZ concentrations in Chinese patients with schizophrenia, with female patients having higher levels.
Trends over 5 years in cardiovascular medicine use in Australian veterans with diabetes
Authors: Roughead Elizabeth E. , Pratt Nicole , Gilbert Andrew L. 
Published: February 2007

What is already known about this subject • Previous cross‐sectional studies have demonstrated underuse of cardiovascular medicines in the population with diabetes. What this study adds • Trends are changing over 5 years with increasing use of medicines affecting the angiotensin–renin system, lipid‐lowering medicines and antiplatelets in the Australian veteran population, in line with recommended practice.Aim To determine trends over 5 years in cardiovascular medicine use in the Australian veteran population with diabetesMethods An observational study. All veterans dispensed medicines indicative of diabetes between 2000 and 2005 were identified from the Veterans Affairs pharmacy claims dataset. Concurrent dispensings of angiotensin‐converting enzyme inhibitor (ACEI), lipid‐lowering medicines and antiplatelets were assessed.Results ACEI/angiotensin II receptor blocker use has risen from 46% to 67% in the veteran population dispensed medicines indicative of diabetes. Lipid‐lowering medicines have increased from 33% to 58% and antiplatelets from 28% to 50%.Conclusion The increasing use of cardiovascular medicines in the diabetes population is suggestive of improved treatment practices over time, consistent with guidelines and quality use of medicines initiatives.
The BPS Diploma in Advanced Pharmacology: a training opportunity for clinical pharmacologists
Authors: Hall Judith M 
Published: February 2007

AbstractCoinciding with its 75th anniversary, the British Pharmacological Society (BPS) has launched a Diploma in Advanced Pharmacology (BPS Dip Pharmacol). This award is open to clinical and non‐clinical scientists and those in related occupations. The Diploma is designed to appeal to those who want to further their pharmacological knowledge or gain an appreciation of basic and clinical aspects of the subject through participation in an advanced programme of non‐clinical and clinical pharmacological study. The Diploma is unique in the UK. It provides not only a mechanism for continuing and updating education in basic pharmacology, clinical pharmacology, and therapeutics, but also a range of networking opportunities for non‐clinical and clinical scientists in industry and academia.
Iron‐bearing phases in a peat‐derived duricrust from Brazil
Authors: Varajão A. F. D. C. , Da Costa G. M. , Varajão C. A. C. , Meunier J. D. , Colin F. 
Published: February 2007

SummaryThe formation of aluminium‐substituted iron‐minerals is still subject to debate. We report a case study in a Humic Gleysol soil profile, developed on a sedimentary saprolite, from a basin floor on the Uberaba Plateau (Minas Gerais State, Brazil) where iron‐phases are crystallized by a ferruginization process. The mineralogical and chemical properties were investigated by X‐ray diffraction, thermogravimetric analysis, differential scanning calorimetry and Mössbauer spectroscopy. The specific surface area (BET method) and cation exchange capacity (CEC) were also determined. The soil profile is mainly composed of gibbsite, kaolinite and amorphous alumino‐silicate phases, the latter being more frequent in the H horizon where the organic carbon content is greater. The surface area and CEC values are also greater in the H horizon (58.6 m2g−1 and 4.65 molckg−1, respectively) which indicates an increase in porosity caused by the presence of 20.8% of organic matter and amorphous materials. Goethite occurs as a secondary mineral in the H horizon and as the main mineral in the duricrust in association with haematite. The omnipresence of aluminium in the environment (24.6–46.2% of Al2O3) resulted in Al‐substitution in all iron‐bearing phases but the goethite from the H horizon has the greatest Al‐for‐Fe substitution, with at least 20 mole per cent of aluminium. In spite of the greater microporosity and wetness of the H horizon, the immediate contact with the richest Al‐source (gibbsite) favours the precipitation of unusually greatly Al‐substituted goethite instead of haematite in this horizon.
Inter‐annual variation in responses of water chemistry and epilithon to Pacific salmon spawners in an Alaskan stream
Authors: CHALONER D. T. , LAMBERTI G. A. , CAK A. D. , BLAIR N. L. , EDWARDS R. T. 
Published: February 2007

Summary1. Pacific salmon (Oncorhynchus spp.) deliver salmon‐derived nutrients (SDN) to the streams in which they spawn. However, many stream parameters, such as discharge and spawner abundance, can vary from year to year, which could alter the quantity and flux of SDN.2. Over six consecutive years, we studied responses in streamwater chemistry and epilithon (i.e. the microbial community on submerged rocks) to salmon spawners in Fish Creek, southeastern Alaska, U.S.A. The lower reach of Fish Creek receives spawners of several salmon species, while the upper reach does not receive spawners because of an intervening waterfall.3. We estimated salmon spawner biomass, analysed water chemistry [ammonium, nitrate, soluble reactive phosphorus (SRP) and dissolved organic carbon (DOC)], and measured epilithon abundance [as chlorophyll a (chl a) and ash‐free dry mass (AFDM)] in Fish Creek. Measurements were made in both the upper and lower reaches, before, during and after the major salmon runs.4. Absolute values and relative differences indicated that the presence of salmon spawners consistently increased dissolved ammonium (by 58 μg L−1 on average, 41× over background), SRP (by 6 μg L−1, 14×), epilithon chl a (by 35 mg m−2, 16×), and epilithon AFDM (by 3 g m−2, 8×). Salmon spawners did not increase nitrate or DOC in either absolute or relative amounts. The persistence and magnitude of spawner effects varied among years and appeared to reflect weather‐driven hydrology as well as spawner biomass.5. Salmon‐derived nutrients can stimulate the growth of primary producers by increasing streamwater nutrient concentrations, but this positive influence may be modulated by other factors, such as water temperature and discharge. To better assess the ecological influence of SDN on stream biota, future studies should explicitly consider the role of key environmental factors and their temporal and spatial dynamics in stream ecosystems.
Sub‐lethal effects of disturbance on a predatory net‐spinning caddisfly
Authors: BEVERIDGE OLIVER S. , LANCASTER JILL 
Published: February 2007

Summary1. The sub‐lethal effects of hydrologic disturbances on stream invertebrates are poorly understood, but integral to some models of how disturbances influence population and community dynamics. Carnivorous larvae of a net‐spinning caddisfly, Plectrocnemia conspersa, have a strong predatory impact in some streams. Their silken nets, however, are vulnerable to high flow disturbance and the consequent destruction of nets could reduce predatory impacts and have life history consequences.2. In a laboratory experiment, we manipulated the frequency of disturbances that destroyed the nets of P. conspersa, in the presence and absence of potential prey. Animals were housed individually and each trial lasted 8 days. We estimated net size, cumulative mass of silk produced, net allocation (net mass expressed as a proportion of body mass), per capita prey consumption and growth or mass loss of larvae.3. In the absence of prey, increased disturbance frequency was accompanied by increased loss of body mass, a reduction of net size and an increase in the cumulative mass of silk produced. At the highest disturbance frequency, larvae eventually gave up producing nets. The ratio of net mass to body mass decreased with increasing disturbance, suggesting a trade‐off in the allocation of resources, with a decreasing proportion of resources available for foraging. In the presence of prey, increased disturbance frequency was accompanied by a reduction in per capita prey consumption. Although foraging success offset the costs of silk production, growth rate decreased with increasing disturbance and could eventually lead to reduced body size and fecundity of adults.4. These sub‐lethal effects suggest that hydrologic disturbances could impose metabolic costs and reduce foraging efficiency of this predator. Thus, disturbances may reduce predator impact on prey populations and reduce predator population size without any direct mortality or loss of individuals.
Variation in body size and trophic morphology within and among genetically differentiated populations of the cichlid fish, Metriaclima zebra, from Lake Malawi
Authors: TODD STREELMAN J. , ALBERTSON R. C. , KOCHER T. D. 
Published: February 2007

Summary1. The cichlid fish Metriaclima zebra, common in Lake Malawi, feeds by filtering plankton from the water and by brushing items from sediment covered substrata. It inhabits isolated rocky reefs among which community structure, resource availability and gene pools are likely to differ. We speculated that body size and trophic morphology of M. zebra might vary concomitantly.2. We quantified the extent of genetic, body size and trophic variation within and between populations of M. zebra from southern Lake Malawi. Specifically, we tested the hypotheses that: (i) local populations are genetically differentiated, (ii) local populations differ in jaw morphology, dentition and standard length (SL), and (iii) variation in size is correlated with variation in trophic morphology.3. Local populations of M. zebra differed in mean SL and were genetically differentiated. Moreover, populations exhibited dissimilar oral jaw morphologies and dentitions, perhaps related to differences in feeding biology. Variation in jaw shape was largely restricted to the curvature of the distal tip of the dentary. Populations were characterised by individuals with oblique, upward or downward directed gapes. Dental patterns differed in the proportion of unicuspid teeth in all rows of each jaw (dentaries and premaxillae) and the spacing of teeth in affected rows.4. Within populations, jaw and tooth shapes were correlated with body size. Smaller individuals possessed upward curving jaws and closely packed multicusped teeth, while larger individuals exhibited relatively downward‐directed jaws with increasing numbers of widely spaced unicuspid teeth.5. Metriaclima zebra populations have increased in mean SL over the last decade, in contrast to a decline among Lake Malawi pelagic cichlids. Differences in size may contribute to variation in trophic morphology and may track local environmental dynamics in this lacustrine system.
Spatio‐temporal genetic variability in sea trout (Salmo trutta) populations from north‐western Spain
Authors: CAMPOS JOSÉ L. , POSADA DAVID , CABALLERO PABLO , MORÁN PALOMA 
Published: February 2007

Summary1. Genetic variation at five microsatellite loci was investigated in six sea trout (Salmo trutta) populations to describe their spatio‐temporal genetic variation in north‐western Spain. We observed significant genetic variation between river basins, and isolation by distance with restricted gene flow between neighbouring rivers, which suggests an important homing behaviour.2. Despite these populations suffering a serious demographic decline during 1998, we did not detect any reduction in their genetic variation, suggesting a reasonably high effective population size and temporal stability.3. Genetic differences among rivers should be taken into account in future management activities. Given the high genetic variability and the temporal stability observed, we believe that no supportive breeding programmes are presently needed in these populations.