Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.

Possible Herb-Drug Interaction Risk of Some Nutritional and Beauty Supplements on Antiretroviral Therapy in HIV Patients.

This study was carried out to assess the drug interaction potential of a variety of beauty and sports/nutritional supplements when co-administered with antiviral drug therapy, especially anti-HIV drugs. Ethanolic extracts of seven dietary supplements (two beauty products, three nutritional protein supplement products and two weight loss/body building products) were examined in human liver cells (HepG2 cells and primary hepatocytes) for their influence on the hepatic metabolism of five antiviral drugs (elvitegravir, rilpivirine, tenofovir, dolutegravir, and cobicistat), all of which are substrates for a key drug metabolizing enzyme CYP3A4. Our results showed that six of the seven supplements caused a 1.5 - 2 fold induction in PXR transcriptional activity in HepG2 cells. PXR regulates the expression of key drug metabolizing enzymes including CYP3A4. Follow up studies indicated a 1.5 - 3 fold induction in CYP3A4 enzyme activity in HepG2 cells treated with these supplements. We further investigated the effects of the supplement on the metabolism of above mentioned anti-viral drugs in HepG2 cells and primary hepatocytes. Of the five drugs, rilpivirine and dolutegravir metabolism was increased by up to 2-folds over the no supplement control by some of the supplements. Our findings indicate that concomitant consumption of these products with anti-HIV drugs may compromise the efficacy of antivirals therapy due to supplement-induced metabolism via induction of CYP3A4 activity.

Trends in Utilization of Statin Therapy and Contraindicated Statin Use in HIV--Infected Adults Treated With Antiretroviral Therapy From 2007 Through 2015.

Background HIV is associated with an increased risk for atherosclerotic cardiovascular disease, which may result in many people living with HIV taking a statin. Some statins are contraindicated with certain antiretroviral therapies ( ART ) and other medications commonly used by HIV -infected patients. Methods and Results We analyzed trends in the use of statins, including contraindicated statins, between 2007 and 2015 among HIV -infected patients aged ≥19 years taking ART who had employer-sponsored or Medicare supplemental health insurance in the Marketscan database (n=186 420). Statin use was identified using pharmacy claims. Contraindicated statin use was defined by a pharmacy claim for HIV protease inhibitors, cobicistat, hepatitis C protease inhibitors, anti-infectives, calcium channel blockers, amiodarone, gemfibrozil, or nefazodone followed by a fill for a contraindicated statin type and dosage within 90 days. The percentage of beneficiaries with HIV taking a statin remained unchanged between 2007 (24.6%) and 2015 (24.7%). Among those taking a statin, the percentage taking a contraindicated statin declined from 16.3% in 2007 to 9.0% in 2014 and then increased to 9.8% in 2015. The proportion of contraindicated statin fills attributable to HIV protease inhibitors declined from 63.9% in 2007 to 51.0% in 2015, while those attributable to cobicistat increased from 0% before 2012 to 20.6% in 2015. Conclusions Changes in ART regimens resulted in a decline in contraindicated statin use from 2007 to 2014, but this favorable trend was attenuated in 2015 because of increased use of cobicistat-containing ART regimens.