Munrocaspersen2071

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single ddecreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms.Introduction Antiplatelet therapy needs to be administered life-long in patients with peripheral arterial disease (PAD). Our study was aimed at 1) the analysis of non-persistence with antiplatelet medication in older PAD patients and 2) identification of patient- and medication-related characteristics associated with non-persistence. Methods The study data was retrieved from the database of the General Health Insurance Company. The study cohort of 9,178 patients aged ≥ 65 years and treated with antiplatelet medications was selected from 21,433 patients in whom PAD was newly diagnosed between 01/2012 and 12/2012. Patients with a 6 months treatment gap without antiplatelet medication prescription were classified as non-persistent. Characteristics associated with non-persistence were identified using the Cox regression. JAK inhibitor Results At the end of the 5 years follow-up, 3,032 (33.0%) patients were non-persistent. Age, history of ischemic stroke or myocardial infarction, clopidogrel or combination of aspirin with clopidogrel used at the index date, higher co-payment, general practitioner as index prescriber and higher overall number of medications were associated with persistence, whereas female sex, atrial fibrillation, anxiety disorders, bronchial asthma/chronic obstructive pulmonary disease, being a new antiplatelet medication user (therapy initiated in association with PAD diagnosis), and use of anticoagulants or antiarrhythmic agents were associated with non-persistence. Conclusion In patients with an increased probability of non-persistence, an increased attention should be paid to improvement of persistence.The ongoing loss of skeletal muscle is a central event of cancer cachexia, and its consequences include adverse effects on patient's quality of life and survival. Alpinetin (Alp), a natural plant-derived flavonoid obtained from Alpinia katsumadai Hayata, has been reported to possess potent anti-inflammatory and antitumor activities. This study aimed to explore the therapeutic effect and underlying mechanism of Alp in the prevention of cancer cachexia. We found that Alp (25-100 μM) dose-dependently attenuated Lewis lung carcinoma-conditioned medium-induced C2C12 myotube atrophy and reduced expression of the E3 ligases Atrogin-1 and MuRF1. Moreover, Alp administration markedly improved vital features of cancer cachexia in vivo with visible reduction of the loss of tumor-free body weight and wasting of multiple tissues, including skeletal muscle, epididymal fat, and decreased expression of Atrogin-1 and MuRF1 in cachectic muscle. Alp suppressed the elevated spleen weight and serum concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. Further, Alp treatment remained protective against cancer cachexia in the advanced stage of tumor growth. Molecular docking results suggested that Alp was docked into the active site of PPARγ with the docking score of -7.6 kcal/mol, forming a hydrogen bond interaction with PPARγ protein amino acid residue HIS449 with a bond length of 3.3 Å. Mechanism analysis revealed that Alp activated PPARγ, resulting in the downregulated phosphorylation of NF-κB and STAT3 in vitro and in vivo. PPARγ inhibition induced by GW9662 notably attenuated the improvement of Alp on the above cachexia phenomenon, indicating that PPARγ activation mediated the therapeutic effect of Alp. These findings suggested that Alp might be a potential therapeutic candidate against cancer cachexia.Osteoarthritis (OA) is a kind of degenerative disease, which is caused by many factors such as aging, obesity, strain, trauma, congenital joint abnormalities, joint deformities. Exosomes are mainly derived from the invagination of intracellular lysosomes, which are released into the extracellular matrix after fusion of the outer membrane of multi vesicles with the cell membrane. Exosomes mediate intercellular communication and regulate the biological activity of receptor cells by carrying non-coding RNA, long noncoding RNAs (lncRNAs), microRNAs (miRNAs), proteins and lipids. Evidences show that exosomes are involved in the pathogenesis of OA. In view of the important roles of exosomes in OA, this paper systematically reviewed the roles of exosomes in the pathogenesis of OA, including the roles of exosomes in OA diagnosis, the regulatory mechanisms of exosomes in the pathogenesis, and the intervention roles of exosomes in the treatment of OA. Reviewing the roles of exosomes in OA will help to clarify the pathogenesis of OA and explore new diagnostic biomarkers and therapeutic targets.Background Older people often receive multiple medications for chronic conditions, which often result in polypharmacy (concomitant use of 5‒9 medicines) and hyperpolypharmacy (concomitant use of ≥10 medicines). A limited number of studies have been performed to evaluate the prevalence of polypharmacy, hyperpolypharmacy, and potentially inappropriate medication (PIM) use in older people of developing countries. The present study aimed to investigate regional variations in the prevalence of polypharmacy, hyperpolypharmacy, and PIM use in older people (60 + years) in India. Methods Studies were identified using Medline/PubMed, Scopus, and Google Scholar databases published from inception (2002) to September 31, 2020. Out of the total 1890 articles, 27 were included in the study. Results Overall, the pooled prevalence of polypharmacy was 49% (95% confidence interval 42-56; p less then 0.01), hyperpolypharmacy was 31% (21-40; p less then 0.01), and PIM use was 28% (24-32; p less then 0.01) among older Indian adults.