Selecting a stable solid form of remdesivir using microcrystal electron diffraction and crystal structure prediction.

Therapeutic options in response to the coronavirus disease 2019 (COVID-19) outbreak are urgently needed. In this communication, we demonstrate how to support selection of a stable solid form of an antiviral drug remdesivir in quick time using the microcrystal electron diffraction (MicroED) technique and a cloud-based and artificial intelligence implemented crystal structure prediction platform. We present the MicroED structures of remdesivir forms II and IV and conclude that form II is more stable than form IV at ambient temperature in agreement with experimental observations. The combined experimental and theoretical study can serve as a template for formulation scientists in the pharmaceutical industry.

Renin-angiotensin system inhibitor attenuates oxidative stress induced human coronary artery endothelial cell dysfunction via the PI3K/AKT/mTOR pathway.

INTRODUCTION: The renin-angiotensin system is associated with blood pressure regulation, inflammation, oxidative stress and insulin resistance. It can decrease intracellular oxidative stress. Stimulation with H2O2 leads to increased oxidative stress and activation of the AKT/mTOR pathway. However, the role of renin-angiotensin system inhibitors in oxidative stress-induced endothelial cell dysfunction and H2O2-induced AKT activation remains unclear. MATERIAL AND METHODS: Human coronary artery endothelial cells (HCAECs) were used. The cells were treated with H2O2, captopril, the AKT inhibitor MK-2206, and the AKT activator SC79, either separately, or in combination. p53 and ICAM-1 expression, and p-eNOS, p-Akt and mTOR activation were measured by Western blot. Cell viability was assessed by MTT assay. Levels of reactive oxygen species (ROS) were assayed by flow cytometry. Proliferation was monitored by BrdU labeling, while cell migration and invasion were determined by wound healing and Transwell assays, respectively. RESULTS: The renin-angiotensin system inhibitor captopril reversed H2O2-induced oxidative stress and apoptosis in HCAECs. Co-treatment with captopril and the AKT inhibitor MK-2206 reduced the H2O2-induced P53 and ICAM-1 protein expression (p < 0.05). The proliferation, migration and invasion of HCAECs were significantly enhanced by co-treatment with captopril and MK-2206 (p < 0.05). CONCLUSIONS: The study revealed the protective effect of captopril against H2O2-induced endothelial cell dysfunction through the AKT/mTOR pathway, and its enhancement of cell survival. These findings provide new insights into the protective effects of captopril and novel therapeutic approaches to treatment of cardiovascular disease.

[Efficacy of cardiac resynchronization therapy for patients with refractory congestive heart failure].

OBJECTIVE: To observe the efficacy of cardiac resynchronization therapy for patients with refractory congestive heart failure. METHODS: Thirty-one patients with refractory congestive heart failure received cardiac resynchronization therapy. Before operation, all patients received standard drug therapy (28 cases) or integrated with CRRT (3 cases). Coronary sinus and its branches were shown by direct angiography with hollow angiographic catheter (11 cases) and by balloon angiographic catheter (20 cases). Left ventricle and right ventricle electrodes were implanted to 3 patients with atrial fibrillation, 4 patients with paroxysmal ventricular tachycardia or ventricular fibrillation received CRT-D implantation. electrocardiogram, 24 hours Holter, echocardiography and physical clinical examinations were made at baseline, 6, 12, 18 and 24 months post resynchronization therapy. RESULTS: Pacemakers were successfully implanted in all 31 patients. One patient implanted with CRT-D died of multiple organ failure on third day after operation, 1 patient suffered sudden cardiac death 5 months after therapy and 2 patients were lost to fellow up 6 and 12 months after operation, respectively. Results from the remaining 27 patients showed that QRS duration was significantly decreased (153 +/- 8.4 at baseline vs. 132 +/- 9.8 at 24 months follow up) and cardiac function significantly improved (LVEF 0.29 +/- 0.10 at baseline vs. 0.41 +/- 0.11 at 24 months follow up, P < 0.05 vs. baseline) during follow up compared to baseline. Malignant ventricular arrhythmia occurred in 3 patients with CRT-D and successfully terminated and converted to sinus rhythm. CONCLUSIONS: Cardiac resynchronization therapy could improve cardiac function for patients with refractory congestive heart failure. CRT-D can effectively terminate the malignant ventricular arrhythmia.