bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of the pharmacokinetics of co‐administered maraviroc and raltegravir
Authors: Andrews Emma , Glue Paul , Fang Juanzhi , Crownover Penelope , Tressler Randall , Damle Bharat 
Published: September 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Maraviroc is a CCR5 receptor antagonist, while raltegravir is a HIV‐1 integrase inhibitor.• Based on the known metabolic pathways (CYP3A4 for maraviroc and UGT1A1 for raltegravir), interaction between the two drugs is unlikely. However, unexpected interactions have been reported for other antiretroviral drugs.• As both these drugs are likely to be used in combination, this study evaluated the pharmacokinetic interaction between them. WHAT THIS STUDY ADDS • Relative to individual monotherapy, co‐administration resulted in a 20% and 33% decrease in mean Cmax, and 14% and 37% decrease in mean AUC of maraviroc and raltegravir, respectively.• Co‐administration was generally safe and well tolerated in healthy subjects.• These changes are not likely to be clinically relevant, thus no dose adjustment is necessary.AIMS To assess the two‐way pharmacokinetic interaction between maraviroc and raltegravir.METHODS In this open‐label, multiple‐dose, fixed‐sequence study, 18 healthy, human immunodeficiency virus (HIV)‐seronegative subjects received the following: days 1–3 raltegravir 400 mg q12h, days 4–5 washout, days 6–11 maraviroc 300 mg q12h, and days 12–14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12‐h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters.RESULTS For maraviroc, the test/reference % ratio (95% CI) for AUCτ was 85.8 (78.7, 93.5), for Cmax was 79.5 (64.8, 97.5) and for Cmin was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUCτ was 63.3 (41.0, 97.6), for Cmax was 66.8 (37.1, 120.0) and for Cmin was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUCτ divided by 12) were >100 ng ml−1, the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean Cmin decreases >60% are considered to be clinically relevant for short‐term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance.CONCLUSIONS Co‐administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.
Adherence level of antihypertensive agents in coronary artery disease
Authors: Perreault Sylvie , Dragomir Alice , Roy Louise , White Michel , Blais Lucie , Lalonde Lyne , Bérard Anick 
Published: September 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Non‐adherence is probably an important source of preventable cardiovascular morbidity and mortality.• However, until now there have been very few large effectiveness studies assessing the relationship between adherence levels to antihypertensive medication and major cardiovascular outcomes for primary prevention of cardiovascular disease. WHAT THIS STUDY ADDS • The study results suggest that there is an association between better adherence to antihypertensive agents and a relative risk reduction of coronary artery disease.• Adherence to antihypertensive agents needs to be improved so that patients can benefit from the full protective effects of antihypertensive therapies.AIMS Antihypertensive (AH) agents have been shown to reduce the risk of cardiovascular events, including coronary artery disease (CAD). Previous surveys have shown that a substantial number of patients with diagnosed hypertension remain uncontrolled. Non‐adherence to AH agents may reduce the effectiveness. The aim was to evaluate the impact of better adherence to AH agents on the occurrence of CAD in a real clinical setting.METHODS A cohort of 83 267 patients was reconstructed using the Régie de l'assurance maladie du Québec databases. Patients were eligible if they were between 45 and 85 years of age without indication of cardiovascular disease, and had been newly treated with AH agents between 1999 and 2004. A nested case–control design was used to study the incidence of CAD. Every case of CAD was matched for age and duration of follow‐up to up to 15 randomly selected controls. The adherence level was measured by calculating the medication possession ratio. Cases' adherence was calculated from the start of follow‐up to the time of the CAD (index date). For controls, adherence was calculated from the start of follow‐up to the time of selection (index date). Rate ratios of CAD were estimated by conditional logistic regression adjusting for covariables.RESULTS The mean patient age was 65 years, 37% were male, 8% had diabetes and 18% had dyslipidaemia. High adherence level (96%) to AH therapy compared with lower adherence level (59%) was associated with a relative risk reduction of CAD events (rate ratios 0.90; 0.84, 0.95). Risk factors for CAD were male gender, diabetes, dyslipidaemia and developing a cardiovascular condition disease during follow‐up.CONCLUSION Our study suggests that better adherence to AH agents is associated with a risk reduction of CAD. Adherence to AH agents needs to be improved so that patients can benefit from the full protective effects of AH therapies.
New central targets for the treatment of obesity
Authors: Sargent Bruce J. , Moore Nicholas A. 
Published: September 2009

The review focuses on the central neuronal circuits involved in energy homeostasis and the opportunities these offer for pharmacological intervention to decrease feeding behaviour and reduce weight. This article is based on the presentation ‘New central targets for the treatment of obesity’ (Sargent, British Pharmacological society, Clinical Section Symposium, December 2008).Central neuronal substrates controlling weight offer numerous opportunities for pharmacological intervention. These opportunities range from non‐specific enhancement of monoamine signalling (triple reuptake inhibitors) to targeting specific monoamine receptor subtypes (5‐HT2c and 5‐HT6). The data reviewed suggest that these approaches will lead to weight loss; whether this is sufficient to produce clinically meaningful effect remains to be determined. Combination therapy targeting more than one mechanism may be a means of increasing the magnitude of the response. Preclinical studies also suggest that novel approaches targeting specific neuronal pathways within the hypothalamus, e.g. MCH1 receptor antagonism, offer an opportunity for weight reduction. However, these approaches are at an early stage and clinical studies will be needed to determine if these novel approaches lead to clinically meaningful weight loss and improvements in co‐morbid conditions such as diabetes and cardiovascular disorders.
The impact of SLCO1B1 polymorphisms on the plasma concentration of lopinavir and ritonavir in HIV‐infected men
Authors: Kohlrausch Fabiana B. , De Cássia Estrela Rita , Barroso Paulo F. , Suarez‐Kurtz Guilherme 
Published: September 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • There is large interindividual variability in the pharmacokinetics of protease inhibitors (PIs) among human immunodeficiency virus (HIV)‐infected individuals under highly active antiretroviral therapy.• Protease inhibitor have been recently reported to be substrates of the SLCO1B1/OATP1 drug transporter.• A single nucleotide polymorphism (SNP) in the SLCO1B1 gene (521T→C) was associated with plasma levels of lopinavir in HIV‐infected individuals. WHAT THIS STUDY ADDS • Data on the impact of three SLCO1B1 SNPs (521T→C, 388A→G, 463C→A) on the trough plasma concentration of lopinavir and ritonavir in a cohort of 99 adult HIV‐infected Brazilian men under stable highly active antiretroviral therapy.• Evidence that carriers of the 521C allele display significantly higher lopinavir, but not ritonavir plasma concentrations relative to the wild‐type TT genotype.• No effect of either 388A→G or 463C→A SNPs on lopinavir or ritonavir plasma concentrations.• Further studies are required to confirm the clinical significance of the association between the SLCO1B1521T→C polymorphism and lopinavir pharmacokinetics.AIMS To investigate possible associations between three SLCO1B1 single nucleotide polymorphisms (388A→G, 463C→A, 521T→C) and lopinavir/ritonavir plasma concentrations.METHODS The study included 99 human immunodeficiency virus‐infected men on stable highly active antiretroviral therapy containing lopinavir/ritonavir. Trough concentrations of lopinavir and ritonavir in plasma were quantified using liquid chromatography–tandem mass spectrometry. Genotyping of SLCO1B1388A→G, 463C→A and 521T→C polymorphisms was performed by allelic discrimination using real‐time polymerase chain reaction.RESULTS The trough concentration of lopinavir in plasma is significantly associated with SLCO1B1521T→C genotypes (P= 0.03). There is a significant trend for increasing concentrations of lopinavir from TT to TC to CC genotypes (P= 0.02). Carriers of the 521C allele display significantly higher lopinavir plasma concentrations relative to the wild‐type TT genotype (P= 0.03).CONCLUSIONS Reduced uptake of lopinavir by hepatocytes in carriers of the 521C allele may account for these results, but further studies to confirm the clinical importance of SLCO1B1 polymorphisms in lopinavir pharmacokinetics are warranted.
Soil metaproteomics: a review of an emerging environmental science. Significance, methodology and perspectives
Authors: Bastida F. , Moreno J. L. , Nicolás C. , Hernández T. , García C. 
Published: September 2009

SummarySoil is a dynamic system in which microorganisms perform important tasks in organic matter transformations and nutrient cycles. Recently, some studies have started to focus on soil metaproteomics as a tool for understanding the function and the role of members of the microbial community. The aim of our work was to provide a review of soil proteomics by looking at the methodologies used in order to illustrate the challenges and gaps in this field, and to provide a broad perspective about the use and meaning of soil metaproteomics. The development of soil metaproteomics is influenced strongly by the extraction methods. Several methods are available but only a few provide an identification of soil proteins, while others extract proteins and are able to separate them by electrophoresis but do not provide an identification. The extraction of humic compounds together with proteins interferes with the latter's separation and identification, although some methods can avoid these chemical interferences. Nevertheless, the major problems regarding protein identification reside in the fact that soil is a poor source of proteins and that there is not enough sequence‐database information for the identification of proteins by mass spectrometric analysis. Once these pitfalls have been solved, the identification of soil proteins may provide information about the biogeochemical potential of soils and pollutant degradation and act as an indicator of soil quality, identifying which proteins and microorganisms are affected by a degradation process. The development of soil metaproteomics opens the way to proteomic studies in other complex substrates, such as organic wastes. These studies can be a source of knowledge about the possibility of driven soil restoration in polluted and degraded areas with low organic matter content and even for the identification of enzymes and proteins with a potential biotechnological value.
An inverse abundance approach to separate soil nitrogen pools and gaseous nitrogen fluxes into fractions related to ammonium, nitrate and soil organic nitrogen
Authors: Stange C. F. , Spott O. , Müller C. 
Published: September 2009

SummaryThe soil nitrogen (N) cycle exhibits a variety of complex biochemical reactions in which N species such as NO2−, NO and N2O are produced and consumed by co‐existing processes that respond differently to the local environmental conditions. Key to understanding the soil N cycle in its full complexity is the development and application of methods that allow a quantification of individual pathways and processes that are responsible for the build‐up and/or emission of N compounds. Triplet 15N tracer experiments (TTE) have been developed and applied to allow a source‐related quantification of N species such as NO2−, and N2O by different biochemical pathways (e.g. ammonia oxidation and nitrate reduction) that are related to multiple N sources (NH4+, NO3− and Norg). An analysis of a TTE requires the application of either a numerical or analytical model. Because of the ease of application it is desirable to use analytical models. However, available analytical solutions suffer from serious drawbacks concerning the quantification of N fluxes related to soil organic N. In this paper we describe the development and application of a new inverse abundance approach (IAA) to analyse a TTE. Theoretical and experimental data sets of soil N2O release were analysed by the new method. The IAA was also applied to an already existing data set to identify fractions of the soil nitrite pool related to NH4+, NO3− and Norg. We show that the IAA provides a reliable and comprehensive data evaluation of a TTE.
Land use and climatic factors structure regional patterns in soil microbial communities
Authors: Drenovsky Rebecca E. , Steenwerth Kerri L. , Jackson Louise E. , Scow Kate M. 
Published: September 2009

ABSTRACTAim Although patterns are emerging for macroorganisms, we have limited understanding of the factors determining soil microbial community composition and productivity at large spatial extents. The overall objective of this study was to discern the drivers of microbial community composition at the extent of biogeographical provinces and regions. We hypothesized that factors associated with land use and climate would drive soil microbial community composition and biomass.Location Great Basin Province, Desert Province and California Floristic Province, California, USA.Methods Using phospholipid fatty acid analysis, we compared microbial communities across eight land‐use types sampled throughout the State of California, USA (n= 1117).Results The main factor driving composition and microbial biomass was land‐use type, especially as related to water availability and disturbance. Dry soils were more enriched in Gram‐negative bacteria and fungi, and wetter soils were more enriched in Gram‐positive, anaerobic and sulphate‐reducing bacteria. Microbial biomass was lowest in ecosystems with the wettest and driest soils. Disturbed soils had less fungal and more Gram‐positive bacterial biomass than wildland soils. However, some factors known to influence microbial communities, such as soil pH and specific plant taxa, were not important here.Main conclusions Distinct microbial communities were associated with land‐use types and disturbance at the regional extent. Overall, soil water availability was an important determinant of soil microbial community composition. However, because of the inclusion of managed and irrigated agricultural ecosystems, the effect of precipitation was not significant. Effects of environmental and management factors, such as flooding, tillage and irrigation, suggest that agricultural management can have larger effects on soil microbial communities than elevation and precipitation gradients.
Vigabatrin but not valproate prevents development of age‐specific flexion seizures induced byN‐methyl‐d‐aspartate (NMDA) in immature rats
Authors: Kubová Hana , Mareš Pavel 
Published: September 2009

SummaryIn immature rats,N‐methyl‐d‐aspartate (NMDA) induces several seizure types: flexion seizures (FS; in rats younger than 3 weeks), clonic seizures (in animals older than 3 weeks), and clonic–tonic seizures (CTS; in rats of all ages). FS represent a model of human infantile spasms. Effects of vigabatrin and valproate against all types of NMDA‐induced seizures were studied in rats at postnatal days 12 (P12) and 25 (P25). NMDA (60 or 300 mg/kg) was injected to animals pretreated with vigabatrin (300–1,200 mg/kg; 24 h before NMDA) or valproate (100–400 mg/kg; 15 min before NMDA). Vigabatrin suppressed FS in P12 rats, but was ineffective against CTS in both age groups. Valproate suppressed CTS in P12, but not in P25 rats. Clonic seizures were rare in NMDA‐treated P25 rats, but valproate pretreatment increased their incidence significantly. Neither drug decreased NMDA‐induced mortality, which occurred within ∼15 min after NMDA administration and reached almost 100% in all groups.
Does concurrent renin‐angiotensin‐aldosterone blockade in (older) chronic kidney disease patients play a role in the acute renal failure epidemic in US hospitalized patients?—Three cases of severe acute renal failure encountered in a northwestern Wisconsin Nephrology practice
Authors: ONUIGBO Macaulay A. C. 
Published: September 2009

AbstractFollowing the publication of several large multicenter randomized placebo‐controlled trials showing reno‐protection with renin‐angiotensin‐aldosterone (RAAS) blockade, the last 2 decades have witnessed an escalating use of the angiotensin‐converting enzyme inhibitors and the angiotensin receptor blockers. Simultaneously, we continue to experience an increasing epidemic of acute renal failure (ARF) both in community‐based and in hospital‐based studies. Even though other factors would be contributing to this ARF epidemic, recent published data have raised concerns of a plausible connection between increased use of the RAAS blocking agents and this ARF epidemic. In our 4‐nephrologist northwestern practice, we have, in recent years, anecdotally encountered an increasing number and severity of ARF, often with hyperkalemia, sometimes requiring dialysis intervention, in patients concurrently on these agents. Over the 3‐day Christmas weekend in 2007, we treated 3 cases of severe ARF (peak serum creatinine of 7.0 (3.3–9.2) mg/dL), all on RAAS blockade. Renin‐angiotensin‐aldosterone blockade was promptly discontinued. All patients received intravenous fluid repletion. Kidney function rapidly normalized in 2 within 1 week. One patient required hemodialysis for 14 days before his serum creatinine returned to normal after 5 weeks. All 3 patients have continued to maintain baseline serum creatinine several months later, still off RAAS blockade. The mean baseline eGFR for the 3 patients was 46 (41–51) mL/min/1.73 m2 body surface area. This phenomenon of ARF exacerbation, which may have implications for chronic kidney disease progression to ESRD especially in the elderly, merits further study. We support the recommendation that (older, >65 years old) chronic kidney disease patients on RAAS blocking agents should have the medications temporarily suspended during any acute illness, before major surgical procedures, and before iodinated contrast or oral phosphate sodium administration.
The biofuel potential of municipal solid waste
Authors: SHI ALLEN ZIHAO , KOH LIAN PIN , TAN HUGH T. W. 
Published: September 2009

AbstractThe world in the 21st century is facing a dual crisis of increasing waste and global climate change. Substituting fossil fuels with waste biomass‐derived cellulosic ethanol is a promising strategy to simultaneously meet part of our energy needs, mitigate greenhouse gas (GHG) emissions, and manage municipal solid waste (MSW). However, the global potential of MSW as an energy source is as yet unquantified. Here, we report increasing trends of MSW generation, and waste biomass‐derived cellulosic ethanol potentials in relation to socio‐economic development across 173 countries, and show that globally, up to 82.9 billion litres of waste paper‐derived cellulosic ethanol can be produced worldwide, replacing 5.36% of gasoline consumption, with accompanying GHG emissions savings of between 29.2% and 86.1%.
Phenylbutyrate Induces Antimicrobial Peptide Expression
Authors: Steinmann Jonas , Halldórsson Skarphéđinn , Agerberth Birgitta , Gudmundsson Gudmundur H. 
Published: September 2009

ABSTRACT

Antimicrobial peptides (AMPs) are important components of our first line of defense. Induction of AMPs such as LL-37 of the cathelicidin family might provide a novel approach in treating bacterial infections. In this study we identified 4-phenylbutyrate (PBA) as a novel inducer of AMP expression and investigated affected regulatory pathways. We treated various cell lines with PBA and assessed mRNA expression by real-time reverse transcriptase PCR (RT-PCR). Cathelicidin AMP (CAMP) gene expression was found to be upregulated in all four cell lines tested. Additionally, we found that the beta-defensin 1 gene was upregulated in the lung epithelial cell line VA10 while being downregulated in the monocytic cell line U937. Further we found that PBA induced CAMP gene expression synergistically with 1,25-dihydroxyvitamin D
3
at both protein and mRNA levels. The general mechanism of induction of CAMP gene expression by PBA was found to be dependent on protein synthesis. Results from quantitative chromatin immunoprecipitation experiments challenge the common view that histone deacetylase inhibitors directly increase CAMP gene expression. Furthermore, we have demonstrated that inhibition of the mitogen-activated protein kinases MEK1/2 and c-Jun N-terminal kinase attenuate PBA-induced CAMP gene expression. Similarly, α-methylhydrocinnamate (ST7), an analogue of PBA, increases CAMP gene expression. Our findings contribute to understanding of the regulation of AMP expression and suggest that PBA and/or ST7 is a promising drug candidate for treatment of microbial infections by strengthening the epithelial antimicrobial barriers.
Characterization of aCampylobacter jejuniVirK Protein Homolog as a Novel Virulence Determinant
Authors: Novik Veronica , Hofreuter Dirk , Galán Jorge E. 
Published: September 2009

ABSTRACTCampylobacter jejuniis a leading cause of food-borne illness in the United States. Despite significant recent advances, its mechanisms of pathogenesis are poorly understood. A unique feature of this pathogen is that, with some exceptions, it lacks homologs of known virulence factors from other pathogens. Through a genetic screen, we have identified aC. jejunihomolog of the VirK family of virulence factors, which is essential for antimicrobial peptide resistance and mouse virulence.