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Heart Failure Reviews - This review summarizes and describes the current evidence addressing how sodium-glucose cotransporter 2 (SGLT2) inhibitors alter the function of sodium-hydrogen exchanger 1... 相似文献
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Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d9-methadone.The pharmacokinetic profiles of d9-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d9-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD50 value for a single intravenous dose of d9-methadone was 2.1-fold higher than that for methadone. Moreover, d9-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy. 相似文献
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Toxicity resulting from off-target effects, beyond acetylcholine esterase inhibition, for the commonly used organophosphate (OP) insecticides chlorpyrifos (CPS) and malathion (MA) was investigated using Saccharomyces cerevisiae and Caenorhabditis elegans model systems. Mitochondrial damage and dysfunction were observed in yeast following exposure to CPS and MA, suggesting this organelle is a major target. In the C. elegans model, the mitochondrial unfolded protein response pathway showed the most robust induction from CPS and MA treatment among stress responses examined. GABAergic neurodegeneration was observed with CPS and MA exposure. Impaired movement observed in C. elegans exposed to CPS and MA may be the result of motor neuron damage. Our analysis suggests that stress from CPS and MA results in mitochondrial dysfunction, with GABAergic neurons sensitized to these effects. These findings may aid in the understanding of toxicity from CPS and MA from high concentration exposure leading to insecticide poisoning. 相似文献
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《Revue d'épidémiologie et de santé publique》2022,70(1):9-16
BackgroundIn the Sub-Saharan African region, data on Arterial Hypertension (AHT) from longitudinal studies are scattered.This work analyzes the prevalence and incidence of AHT and its associated factors in an open cohort of Congolese adults in South Kivu.MethodsBetween 2012 and 2019, 2,633 subjects aged ≥ 15 years were monitored for at least 3 years. Baseline and follow-up included blood pressure (BP) measurements. AHT was defined as BP of at least 140/90 mmHg or intake of antihypertensive medication in patients with known AHT. Cox regression was used to analyze the association between risk factors and risk of AHT.ResultsThe prevalence of AHT increased from 24.8% to 29.0% and the proportion of controlled hypertensive participants rose from 46.9% to 56.6% (p=0.03). During the 7,525 person-years observation period, the incidence of AHT among 1,981 participants without AHT at baseline was 19.4/1000 person-years. The annual incidence of AHT (2.4% per year) was higher in urban (5.0% per year) than in rural areas (2.0% per year). The strongest determinants for incident AHT (p<0.05) were male gender [adjusted HR (aHR)=1.67 (1.08-2.59)], age between 40-59 years [aHR=2.26 (1.48-3.45)], age ≥ 60 years [aHR=3.53 (2.11-5.93)], urban residence [aHR=3.37 (2.07-5.50)], pre-hypertension [aHR=1.77 (1.16-2.70)], abdominal obesity [aHR=1.99 (1.29-3.07)] and smoking [aHR=2.01 (1.12-3.60)].ConclusionThe present study shows that the prevalence and incidence of AHT are increasing in the Congolese general population. Consequently, improved strategies for the prevention and management of non-communicable diseases are very important in Sub-Saharan Africa. 相似文献