Etravirine (formerly TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant strains of HIV-1. Etravirine has been approved in several ...countries for use as part of highly active antiretroviral therapy in treatment-experienced patients. In vivo, etravirine is a substrate for, and weak inducer of, the hepatic cytochrome P450 (CYP) isoenzyme 3A4 and a substrate and weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. An extensive drug-drug interaction programme in HIV-negative subjects has been carried out to assess the potential for pharmacokinetic interactions between etravirine and a variety of non-antiretroviral drugs. Effects of atorvastatin, clarithromycin, methadone, omeprazole, oral contraceptives, paroxetine, ranitidine and sildenafil on the pharmacokinetic disposition of etravirine were of no clinical relevance. Likewise, etravirine had no clinically significant effect on the pharmacokinetics of fluconazole, methadone, oral contraceptives, paroxetine or voriconazole. No clinically relevant interactions are expected between etravirine and azithromycin or ribavirin, therefore, etravirine can be combined with these agents without dose adjustment. Fluconazole and voriconazole increased etravirine exposure 1.9- and 1.4-fold, respectively, in healthy subjects, however, no increase in the incidence of adverse effects was observed in patients receiving etravirine and fluconazole during clinical trials, therefore, etravirine can be combined with these antifungals although caution is advised. Digoxin plasma exposure was slightly increased when co-administered with etravirine. No dose adjustments of digoxin are needed when used in combination with etravirine, however, it is recommended that digoxin levels should be monitored. Caution should be exercised in combining rifabutin with etravirine in the presence of certain boosted HIV protease inhibitors due to the risk of decreased exposure to etravirine. Although adjustments to the dose of clarithromycin are unnecessary for the treatment of most infections, the use of an alternative macrolide (e.g. azithromycin) is recommended for the treatment of Mycobacterium avium complex infection since the overall activity of clarithromycin against this pathogen may be altered when co-administered with etravirine. Dosage adjustments based on clinical response are recommended for clopidogrel, HMG-CoA reductase inhibitors (e.g. atorvastatin) and for phosphodiesterase type-5 inhibitors (e.g. sildenafil) because changes in the exposure of these medications in the presence of co-administered etravirine may occur. When co-administered with etravirine, a dose reduction or alternative to diazepam is recommended. When combining etravirine with warfarin, the international normalized ratio (INR) should be monitored. Systemic dexamethasone should be co-administered with caution, or an alternative to dexamethasone be found as dexamethasone induces CYP3A4. Caution is also warranted when co-administering etravirine with some antiarrhythmics, calcineurin inhibitors (e.g. ciclosporin) and antidepressants (e.g. citalopram). Co-administration of etravirine with some antiepileptics (e.g. carbamazepine and phenytoin), rifampicin (rifampin), rifapentine or preparations containing St John's wort (Hypericum perforatum) is currently not recommended as these are potent inducers of CYP3A and/or CYP2C and may potentially decrease etravirine exposure. Antiepileptics that are less likely to interact based on their known pharmacological properties include gabapentin, lamotrigine, levetiracetam and pregabalin. Overall, pharmacokinetic and clinical data show etravirine to be well tolerated and generally safe when given in combination with non-antiretroviral agents, with minimal clinically significant drug interactions and no need for dosage adjustments of etravirine in any of the cases, or of the non-antiretroviral agent in the majority of cases studied.
Objectives
Preclinical studies have suggested that the mechanism of the analgesic action of acetaminophen (INN, paracetamol) is linked to the serotonergic system and that it is inhibited by ...tropisetron, a 5‐hydroxytryptamine type 3 antagonist. The aim of this study was to confirm these findings in humans.
Methods
Twenty‐six rapid metabolizers of tropisetron were included in this double‐blind crossover study. After ethical approval, at weekly intervals, the subjects took a single oral dose of 1 g acetaminophen combined with either intravenous tropisetron (5 mg), granisetron (3 mg), or placebo (saline solution). For each session, the analgesic effect of acetaminophen was assessed by use of a pain self‐evaluation instrument, the Pain Matcher. The pain detection threshold was determined 5 times over the period of the 4 postdosing hours. The area under the curve (0–4 hours) (mean ± SD) of acetaminophen/tropisetron and the area under the curve of acetaminophen/granisetron were compared with the effect of acetaminophen/placebo. Blood samples for acetaminophen concentration measurements were taken to evaluate a pharmacokinetic interaction.
Results
The analgesic effect of acetaminophen/placebo (expressed as the area under the curve of the percentage of the individual pain score reported at baseline along time % · min) (2145 ± 2901 % · min) was totally inhibited by both tropisetron (89 ± 1747 % · min, P = .007) and granisetron (45 ± 2020 % · min, P = .002). Acetaminophen concentration was not significantly different when associated with tropisetron (P = .919) or granisetron (P = .309).
Conclusion
These results clearly show for the first time in humans that the coadministration of tropisetron or granisetron with acetaminophen completely blocks the analgesic effect of acetaminophen. They support the hypothesis that the mechanism of the analgesic action of acetaminophen might involve the serotonergic system. Furthermore, they demonstrate a pharmacodynamic interaction between these 2 types of drugs, which are frequently coadministered, especially in cancer patients.
Clinical Pharmacology & Therapeutics (2006) 79, 371–378; doi: 10.1016/j.clpt.2005.12.307
Drylands are home to more than 38% of the world's population and are one of the most sensitive areas to climate change and human activities. This review describes recent progress in dryland climate ...change research. Recent findings indicate that the long‐term trend of the aridity index (AI) is mainly attributable to increased greenhouse gas emissions, while anthropogenic aerosols exert small effects but alter its attributions. Atmosphere‐land interactions determine the intensity of regional response. The largest warming during the last 100 years was observed over drylands and accounted for more than half of the continental warming. The global pattern and interdecadal variability of aridity changes are modulated by oceanic oscillations. The different phases of those oceanic oscillations induce significant changes in land‐sea and north‐south thermal contrasts, which affect the intensity of the westerlies and planetary waves and the blocking frequency, thereby altering global changes in temperature and precipitation. During 1948–2008, the drylands in the Americas became wetter due to enhanced westerlies, whereas the drylands in the Eastern Hemisphere became drier because of the weakened East Asian summer monsoon. Drylands as defined by the AI have expanded over the last 60 years and are projected to expand in the 21st century. The largest expansion of drylands has occurred in semiarid regions since the early 1960s. Dryland expansion will lead to reduced carbon sequestration and enhanced regional warming. The increasing aridity, enhanced warming, and rapidly growing population will exacerbate the risk of land degradation and desertification in the near future in developing countries.
Key Points
Drylands are one of the most sensitive areas to climate change and human activities
Attribution of major drivers and processes to dryland climate change has been summarized
Enhanced warming, increasing aridity, and expanding drylands pose a threat to developing countries
1. Evolutionary adaptations in interactions between plants, microbes and arthropods are generally studied in interactions that involve only two of these groups, that is, plants and microbes, plants ...and arthropods or arthropods and microbes. 2. We review the accumulating evidence from a wide variety of systems, including plant- and arthropod-associated microbes, and symbionts as well as antagonists, that selection and adaptation in seemingly two-way interactions between plants and microbes, plants and arthropods and arthropods and microbes are often driven by the biotic context of a third partner. 3. We extend the concept of local adaptation from two-way interactions to scenarios for three-way interactions. We show that consumers can locally adapt to specific host phenotypes that are induced by a third species with which they do not directly interact. This emphasizes that indirect interactions have not only ecological but also important evolutionary consequences, and stresses the need to conduct studies of local adaptation in the proper ecological context of the species involved. 4. Overall, our review underlines the importance of three-way interactions in the evolution of plant—microbe, plant—arthropod and arthropod—microbe interactions, and we outline some promising directions for future research.
A search for narrow resonances in the dijet mass spectrum is performed using data corresponding to an integrated luminosity of 2.9 pb⁻¹ collected by the CMS experiment at the Large Hadron Collider. ...Upper limits at the 95% confidence level are presented on the product of the resonance cross section, branching fraction into dijets, and acceptance, separately for decays into quark-quark, quark-gluon, or gluon-gluon pairs. The data exclude new particles predicted in the following models at the 95% confidence level: string resonances, with mass less than 2.50 TeV, excited quarks, with mass less than 1.58 TeV, and axigluons, colorons, and E6 diquarks, in specific mass intervals. This extends previously published limits on these models.
Transition metals are required cofactors for many proteins that are critical for life, and their concentration within cells is carefully maintained to avoid both deficiency and toxicity. To defend ...against bacterial pathogens, vertebrate immune proteins sequester metals, in particular zinc, iron, and manganese, as a strategy to limit bacterial acquisition of these necessary nutrients in a process termed “nutritional immunity.” In response, bacteria have evolved elegant strategies to access metals and counteract this host defense. In mammals, metal abundance can drastically shift due to changes in dietary intake or absorption from the intestinal tract, disrupting the balance between host and pathogen in the fight for metals and altering susceptibility to disease. This review describes the current understanding of how dietary metals modulate host-microbe interactions and the subsequent impact on the outcome of disease.
Transition metals are necessary nutrients and key players at the host-pathogen interface. In their review, Lopez and Skaar describe the multi-faceted ways in which dietary metal availability influences bacterial virulence and the host response to infection.
New precise results of a measurement of the elastic electron-proton scattering cross section performed at the Mainz Microtron MAMI are presented. About 1400 cross sections were measured with negative ...four-momentum transfers squared up to Q² = 1 (GeV/c)² with statistical errors below 0.2%. The electric and magnetic form factors of the proton were extracted by fits of a large variety of form factor models directly to the cross sections. The form factors show some features at the scale of the pion cloud. The charge and magnetic radii are determined to be <r²E>½ = 0.879(5)stat(4)syst(2)model(4)group fm and <r²M>½ = 0.777(13)stat(9)syst(5)model(2)group fm.
As viruses continue to pose risks to global health, having a better understanding of virus⁻host protein⁻protein interactions aids in the development of treatments and vaccines. Here, we introduce ...Viruses.STRING, a protein⁻protein interaction database specifically catering to virus⁻virus and virus⁻host interactions. This database combines evidence from experimental and text-mining channels to provide combined probabilities for interactions between viral and host proteins. The database contains 177,425 interactions between 239 viruses and 319 hosts. The database is publicly available at viruses.string-db.org, and the interaction data can also be accessed through the latest version of the Cytoscape STRING app.
1. Plants mediate multiple interactions between below‐ground (BG) and above‐ground (AG) heterotrophic communities that have no direct physical contact. These interactions can be positive or negative ...from the perspective of each player, can go from the BG to the AG community or vice versa, and comprise representatives of different phyla. Here we highlight emerging general patterns and discuss future research directions. 2. Ecologists initially postulated that root herbivores induce general stress responses, which increase the levels of primary (nutritional) compounds in the undamaged plant compartment and thereby facilitate future attack by AG herbivores. However, damage can also reduce the levels of primary compounds or increase contents of secondary (defensive) metabolites. Both effects may cause resistance phenotypes that play an important role in mediating BG-AG interactions. Systemically induced resistance does not only affect other herbivores but also pathogens in the AG and BG compartment and may inhibit beneficial organisms such as natural enemies of herbivores, microbial root symbionts and pollinators. Conversely, symbiotic mutualists such as mycorrhiza and rhizobia may affect AG and BG defence levels. Finally, BG-AG interactions may be costly if they impede optimal defence strategies in the undamaged compartment. 3. Synthesis. In order to better understand the adaptive value of BG-AG induced responses for the players involved and to identify the driving evolutionary forces, we need a better integration of studies at the community level with experiments on model systems that allow unravelling the genetic and physiological mechanisms of BG-AG interactions. Experiments preferably should be carried out at realistic densities and using the natural temporal sequence at which the various associations are established, because we can expect plants to be adapted only to events that are common over evolutionary time spans. Detailed mechanistic knowledge will help to reproduce relevant interactions in experiments that study multiple species in the field. This step will ultimately allow us to evaluate the importance of plant‐mediated interactions between BG and AG communities for the fitness of the species involved and for the structuring of natural communities.
The Arctic region is a harbinger of global change and is warming at a rate higher than the global average. While Arctic warming is driven by increases in anthropogenic greenhouse gases' in ...combination with local feedback mechanisms, short‐lived climate forcing agents, such as tropospheric aerosol, are also important drivers of Arctic climate. Arctic aerosol‐climate impacts vary seasonally as a result of the interplay between aerosol and different cloud types, available solar radiation, sea ice, surface albedo, Arctic and lower latitude removal processes, and atmospheric transport patterns. Photochemistry and efficient wet aerosol removal have low impact in winter but become important in spring to summer, dramatically altering aerosol chemical composition, and driving the size distribution from a pronounced accumulation mode toward a dominance of smaller particles. Retreating sea ice, increasing solar insolation and warmer temperatures in summer result in enhanced emissions from Arctic marine and terrestrial ecosystems, and anthropogenic sources, with impacts on the composition of gas and particle phases. Fractional cloud cover reaches a maximum in Arctic summer, in parallel with decreasing sea ice extent and surface albedo. This seasonal variation corresponds to significant changes in the net cloud radiative effect; changes that are affected by aerosol. This review summarizes our current knowledge of processes that control Arctic aerosol properties. We highlight both natural and anthropogenic processes that will be impacted by current and future sea ice loss. Efforts are needed to better constrain aerosol removal rates, characterize aerosol precursors, and constrain the seasonality and magnitude of aerosol‐cloud‐climate impacts.
Plain Language Summary
The Arctic environment is changing rapidly. While Arctic climate change is mostly driven by increases in greenhouse gases produced by human activity, other human‐induced and natural emissions also influence climate. We focus on the role of atmospheric aerosol in Arctic regions. In this article, we summarize the current state of knowledge of the various processes that drive the climate‐relevant properties of aerosol in the Arctic. We emphasize the processes that arise from interactions between the atmosphere, ocean, land, and ice‐covered areas and the impact of aerosol on clouds at high latitudes. These processes are all being impacted by Arctic warming and sea ice loss. We need to understand these processes in order to understand past and future changes in Arctic climate.
Key Points
Very strong seasonal variations in radiation, sea ice, oxidants, transport, and removal mechanisms drive Arctic aerosol properties
Decreasing sea ice extent is impacting Arctic aerosol through increases in natural and anthropogenic emissions and changes in meteorology
Aerosol removal within the Arctic and at mid‐latitudes during transport is a primary driver of aerosol properties in all seasons
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