Many studies suggest opioid receptor (OPr) dimerization modulates the pharmacological properties of opiates. Specifically, heteromerization between OPr types has been reported to lead to changes in intracellular signaling.  https://www.selleckchem.com/products/BIBF1120.html  Thus, ligands targeting heteromers are expected to be novel therapeutic targets with reduced side effects. The heteromers of mu (MOPr) and delta (DOPr) are detected in brain regions involved in pain processing. The bivalent ligand or small molecule were identified as a MOPr-DOPr targeting ligand. These ligands exhibit antinociceptive properties similar to that of morphine with lesser antinociceptive tolerance as compared to morphine. Studies exploring the in vivo regulation of MOPr-DOPr heteromers, showed chronic morphine administration leads to an upregulation of these heteromers in select brain regions. Exploration of mechanisms underlying this phenomenon led us to the G protein-coupled receptor chaperone, RTP4, that is induced by chronic morphine and facilitates the heteromerization of MOPr and DOPr. In this review, I will introduce the simulated structure or property of MOPr-DOPr heteromer, its targeting ligands, and its intracellular regulatory mechanism that include a key molecule like RTP4 that could serve as a scaffold for the development of novel therapeutic drugs with reduced adverse effects, and hence may take place of the conventional clinical opioids.In Japan, 14 opioids with a variety of dosage forms, such as oral preparation, injection, transdermal patch, transmucosal and suppository are clinically available as analgesics, and their use properly depends on the type and degree of pain and patient condition. Fundamentally, strong opioids are restricted to only treatment of cancer pain, while the indication of fentanyl transdermal patch and oxycodone tamper resistant tablet has been expanded for the treatment of non-cancer chronic pain. In US, the additional indication of opioids to chronic pain has led to prolongation and generalization of opioid use, which may contribute to "opioid crisis" in which opioid-related death strikingly increased due to opioid abuse and overdose-induced respiratory depression. Currently, opioid-related abuse and death have not been evident in Japan, while abuse of antitussive opioids (codeine and dihydrocodeine) are recently seen as a problem, which may suggest the sense of guilt to abuse legally-uncontrolled drugs (ex. weak opioids, antitussives or hypnotics) may be low in Japanese. In this review, I will summarize current status and issues in clinical use of opioid analgesics, and will talk about the necessity and expectation for development of novel analgesics without serious adverse reactions such as addiction and respiratory depression.
  The effect of treatment with paclitaxel-containing devices (PTXD) on mortality in patients with peripheral artery disease remains controversial.Methods and ResultsAn independent patient-level meta-analysis of 12 clinical trials (1,389 PTXD patients and 1,192 non-PTXD patients) was conducted. This study included 7 pivotal trials and 5 post-marketing surveillance studies on endovascular treatment for femoropopliteal artery by 6 companies. The primary endpoint was all-cause death, and 5-year cumulative mortality was estimated by a Kaplan-Meier curve. Cox proportional hazard model was used to calculate the hazard ratio (HR) and confidential interval (CI). During the median follow up of 3.0 years, 459 patients died. The cumulative 5-year mortality for the entire cohort was significantly lower in the PTXD than in the non-PTXD group (24.4% vs. 27.4%, respectively; HR, 0.81; 95% CI, 0.67-0.97; P=0.023), but this difference was no longer significant after adjustment for relevant covariates (HR, 1.01; 95% CI, 0.39-2.58; P=0.987). The Cox proportional hazard model revealed that sex, hyperlipidemia, Type 2 diabetes, hemodialysis, Rutherford category, and age above 75 years were significantly associated with 5-year mortality, but treatment with PTXD was not.
 
  This large individual meta-analysis of patients with femoropopliteal artery disease found that the use of PTXD does not have a negative effect on 5-year mortality.
 This large individual meta-analysis of patients with femoropopliteal artery disease found that the use of PTXD does not have a negative effect on 5-year mortality.
  This study investigated the effects of age on the outcomes of coronavirus disease 2019 (COVID-19) and on cardiac biomarker profiles, especially in patients with cardiovascular diseases and/or risk factors (CVDRF).Methods and ResultsA nationwide multicenter retrospective study included 1,518 patients with COVID-19. Of these patients, 693 with underlying CVDRF were analyzed; patients were divided into age groups (<55, 55-64, 65-79, and ≥80 years) and in-hospital mortality and age-specific clinical and cardiac biomarker profiles on admission evaluated. Overall, the mean age of patients was 68 years, 449 (64.8%) were male, and 693 (45.7%) had underlying CVDRF. Elderly (≥80 years) patients had a significantly higher risk of in-hospital mortality regardless of concomitant CVDRF than younger patients (P<0.001). Typical characteristics related to COVID-19, including symptoms and abnormal findings on baseline chest X-ray and computed tomography scans, were significantly less prevalent in the elderly group than in the younger groups. However, a significantly (P<0.001) higher proportion of elderly patients were positive for cardiac troponin (cTn), and B-type natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP) levels on admission were significantly higher among elderly than younger patients (P<0.001 and P=0.001, respectively).
 
  Elderly patients with COVID-19 had a higher risk of mortality during the hospital course, regardless of their history of CVDRF, were more likely to be cTn positive, and had significantly higher BNP/NT-proBNP levels than younger patients.
 Elderly patients with COVID-19 had a higher risk of mortality during the hospital course, regardless of their history of CVDRF, were more likely to be cTn positive, and had significantly higher BNP/NT-proBNP levels than younger patients.