Summary
The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A ...PubMed literature search was performed for perampanel. Congress data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5–2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co‐ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2–12 mg); perampanel is 95% protein‐bound to albumin and α1‐acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half‐life is ~105 h, whereas the calculated effective half‐life is 48 h. These half‐life values allow for once‐daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half‐life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4‐inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use.
How We Reason Johnson-Laird, Philip
2008, 2006, 2008-10-23
eBook
Good reasoning can lead to success; bad reasoning can lead to catastrophe. Yet, it's not obvious how we reason, and why we make mistakes. This new book by one of the pioneers of the field, Philip ...Johnson-Laird, looks at the mental processes that underlie our reasoning. It provides the most accessible account yet of the science of reasoning.
Estimates of the global population of humans living at high altitude vary widely, and such data at the country level are unavailable. Herein, we use a geographic information system (GIS)-based ...approach to quantify human population at 500-m elevation intervals for each country. Based on georeferenced data for population (LandScan Global 2019) and elevation (Global Multiresolution Terrain Elevation Data), 500.3 million humans live at ≥1,500 m, 81.6 million at ≥2,500 m, and 14.4 million at ≥3,500 m. Ethiopia has the largest absolute population at ≥1,500 m and ≥2,500 m, while China has the greatest at ≥3,500 m. Lesotho has the greatest percentage of its population above 1,500 m, while Bolivia has the greatest at ≥2,500 m and ≥3,500 m. High altitude presents a myriad of environmental stresses that provoke physiological responses and adaptation, and consequently impact disease prevalence and severity. While the majority of high-altitude physiology research is based upon lowlanders from western, educated, industrialized, rich, and democratic countries ascending to high altitude, the global population distribution of high-altitude residents encourages an increased emphasis on understanding high-altitude physiology, adaptation, epidemiology, and public health in the ∼500 million permanent high-altitude residents.
Nonalcoholic fatty liver disease (NAFLD) has an estimated prevalence of 25% in the general population, and cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is predicted to become the ...leading cause of liver transplantation, yet there is a lack of effective licensed treatments for these conditions. There is a close relationship between insulin resistance (IR) and NAFLD, with prevalence of NAFLD being 5‐fold higher in patients with diabetes compared to those without. IR is implicated both in pathogenesis of NAFLD and in disease progression from steatosis to NASH. Thus, modulation of IR represents a potential strategy for NAFLD treatment. This review highlights key proposed mechanisms linking IR and NAFLD, such as changes in rates of adipose tissue lipolysis and de novo lipogenesis, impaired mitochondrial fatty acid β‐oxidation (FAO), changes in fat distribution, alterations in the gut microbiome, and alterations in levels of adipokines and cytokines. Furthermore, this review will discuss the main pharmacological strategies used to treat IR in patients with NAFLD and their efficacy based on recently published experimental and clinical data. These include biguanides, glucagon‐like peptide 1 receptor (GLP‐1) agonists, dipeptidyl peptidase 4 (DPP‐4) inhibitors, peroxisome proliferator‐activated receptor (PPAR‐γ/α/δ) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors, and farnesoid X receptor (FXR) agonists, with further novel treatments on the horizon. Ideally, treatment would improve IR, reduce cardiovascular risk, and produce demonstrable improvements in NASH histology—this is likely to be achieved with a combinatorial approach.
The stem cell niche and the size of the root meristem in plants are maintained by intercellular interactions and signalling networks involving a peptide hormone, root meristem growth factor 1 (RGF1)
.... Understanding how RGF1 regulates the development of the root meristem is essential for understanding stem cell function. Although five receptors for RGF1 have been identified
, the downstream signalling mechanism remains unknown. Here we report a series of signalling events that follow RGF1 activity. We find that the RGF1-receptor pathway controls the distribution of reactive oxygen species (ROS) along the developmental zones of the Arabidopsis root. We identify a previously uncharacterized transcription factor, RGF1-INDUCIBLE TRANSCRIPTION FACTOR 1 (RITF1), that has a central role in mediating RGF1 signalling. Manipulating RITF1 expression leads to the redistribution of ROS along the root developmental zones. Changes in ROS distribution in turn enhance the stability of the PLETHORA2 protein, a master regulator of root stem cells. Our results thus clearly depict a signalling cascade that is initiated by RGF1, linking this peptide to mechanisms that regulate ROS.
Purpose
Humanity has been modifying the planet in a measurable way for thousands of years. Recently, this influence has been such that some feel we are in a new geological epoch, the Anthropocene. ...This review will describe how soil erosion and sediment dynamics have (i) been used to assess the impact of humans on the planet and (ii) affected the global climate and influenced water security. Emphasis is placed on changes since the middle of the twentieth century, as this coincides with what many suggest is the start of the Anthropocene Epoch.
Results and discussion
The use of sediment archives has been instrumental in our understanding of how environmental systems have developed over time, both naturally and in response to anthropogenic activities. Additional information has come from measurement and monitoring programs, and tracing and fingerprinting studies. In turn, models have been developed that enable forecasting. Some of the main global impacts of enhanced soil erosion and changes in sediment dynamics and sediment composition include: changes in radiative energy balances and impacts on the cryosphere; the global carbon cycle; and greenhouse gas emissions. Impacts on water security include: effects on freshwater biota, including wild salmon populations; fluxes of contaminants, including microplastics; and reservoir and river channel sedimentation, including flooding. Sediment archives and monitoring programs have also been used to document the effect of mitigation measures and environmental policies.
Conclusion
Sediment archives enable us to assemble information over a variety of timescales (i.e., 10
0
to 10
5
years and longer) and a range of spatial scales (from sub-watershed to continental), in addition to environments ranging from arid to tropical to polar. Often the temporal resolution is better than other paleoenvironmental reconstruction approaches. As such, sedimentary records, when combined with measurement and monitoring approaches and other sources of information, have enabled us to determine changes in atmospheric, terrestrial, and aquatic systems, especially over the last 100 years. While soil erosion and sediment dynamics have provided a wealth of information and greatly enhanced our understanding of the role of humanity in modifying the planet, suggestions are given for further research.
Abstract Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and the incidence of which is rising rapidly due to the increasing epidemic of obesity in ...both adults and children. The initial accumulation of fat followed by subsequent inflammation is central to the development of liver damage, and is critically influenced by host factors including age, gender, presence of diabetes, genetic polymorphisms and more recently by the gut microbiome. An increasing body of data suggest that NAFLD is also an independent risk factor of cardiovascular disease, which remains the commonest cause of mortality in such patients. This review focusses on the pathogenesis of NAFLD, and the evolution of new approaches to the management and treatment of NAFLD.
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