Twelve-week ravidasvir plus ritonavir-boosted danoprevir and ribavirin for non-cirrhotic HCV genotype 1 patients: A phase 2 study.

BACKGROUND AND AIM: The need for all-oral hepatitis C virus (HCV) treatments with higher response rates, improved tolerability, and lower pill burden compared with interferon-inclusive regimen has led to the development of new direct-acting antiviral agents. Ravidasvir (RDV) is a second-generation, pan-genotypic NS5A inhibitor with high barrier to resistance. The aim of this phase 2 study (EVEREST study) was to assess the efficacy and safety of interferon-free, 12-week RDV plus ritonavir-boosted danoprevir (DNVr) and ribavirin (RBV) regimen for treatment-naïve Asian HCV genotype 1 (GT1) patients without cirrhosis. METHODS: A total of 38 treatment-naïve, non-cirrhotic adult HCV GT1 patients were enrolled in this multicenter, open-label, single-arm phase 2 study (NCT03020095). All patients received a combination of RDV 200 mg once daily (q.d.) plus DNVr 100 mg/100 mg twice daily (b.i.d.) and oral RBV 1000/1200 mg/day (body weight < 75/≥ 75 kg) for 12 weeks. The primary endpoint was the rate of sustained virologic response 12 weeks after the end of treatment (SVR12). RESULTS: Of 38 patients, all (100%) achieved SVR12. During the study, no treatment-related serious adverse events, no patients discontinued treatment due to adverse events, and no deaths were reported. Six of 37 (16%) patients with available sequences had HCV NS5A resistance-associated variants at baseline. All patients (6/6) with baseline NS5A resistance-associated variants achieved SVR12. CONCLUSIONS: Twelve-week RDV and DNVr in combination with RBV for 12 weeks achieves the SVR12 rate of 100% in treatment-naïve non-cirrhotic Asian patients with HCV GT1 infection. This interferon-free regimen is also safe and well tolerated.

Novel selective antagonist of the cannabinoid CB1 receptor, MJ15, with prominent anti-obesity effect in rodent models.

MJ15, a novel cannabinoid CB(1) receptor selective antagonist was discovered. In receptor binding assays, MJ15 displayed a high affinity for rat cannabinoid CB(1) receptor (K(i)=27.2 pM, and IC(50)=118.9 pM), but a much lower affinity for rat cannabinoid CB(2) receptor (only 46% inhibition at 10 microM). At the cellular level, the IC(50) values against activation of cannabinoid CB(1) and CB(2) receptors induced by Win55212-2 in specially designed EGFP-CB(1)_U2OS and EGFP-CB(2)_U2OS cells were 0.11 microM and >10 microM, respectively. In addition, MJ15 dose-dependently blocked Win55212-2 mediated increase of intracellular Ca(2+) levels in hippocampal cells and reversed the inhibitory effects of cannabinoid CB(1) receptor agonist on forskolin-stimulated adenylyl cyclase activity in CHO cells expressing the human cannabinoid CB(1) receptor. In animal experiments, MJ15 demonstrated remarkable effects from 20 to 40 mg/kg, including promoted the small intestine peristalsis in ICR mice and inhibited food intake and body weight increase in diet-induced obesity (DIO) rat and mouse. 40 mg/kg MJ15 significantly reduced food intake at initial 2 weeks of treatment, prevented the increase of body weight and adipose by 46% and 28% respectively in DIO rats, and reduced body weight and adipose gain by 70% and 23% respectively in early onset obesity DIO mice after 4 weeks treatment. Meanwhile, dyslipidemia were ameliorated in both models. Taken together the in vitro and in vivo data, MJ15 is demonstrated to be a potent and selective cannabinoid CB(1) receptor antagonist and holds a prominent potency in obesity and dyslipidemia treatment.

Evaluation of the cardiovascular function of older adult Rhesus monkeys by ultrasonography.

OBJECTIVE: To evaluate the cardiovascular structure and function of older adult Rhesus monkey by utrasonography. METHODS: Sixteen monkeys aged from 17 to 20 years and weighing from 8.2 to 15.3 kg, six adults aged 7-8 years and weighing from 8.1 to 9.2 kg. All monkeys were determined to be free from hypertension, hyperglycaemia and cardiac disease. The normal values of index related to heart and blood vessels including structure, haemodynamics and systolic or diastolic function were detected by 2D, M-mode, pulsed Doppler and tissue Doppler echocardiography respectively under ketamine hydrochloride sedation. Meanwhile, blood pressures were also measured by electronic sphygmomanometer. Each monkey underwent repeated detections in 2 weeks and all data were analysed with statistical methods. RESULTS: Compared with young adult monkeys, the older's heart rate (HR), the left ventricular diastolic function and the compliance of big artery including right and left common carotid artery, bulbus caroticus, internal carotid artery and abdominal aorta were decreased and the associated indexes changed significantly (P < 0.05 or P < 0.01). Meanwhile, older monkeys exhibited significant increase in the aorta diameter (AO), amplitude of aortic wall (AAO), left atrial diameter (LAD), end diastolic volume of left ventricle (EDV), stroke volume (SV), left ventricular mass (LVM) (P < 0.05 vs. young adult monkeys); however, cardiac output (CO) only slightly increased but the difference did not reach the statistical significance (P = 0.418, P = 0.644 respectively). CONCLUSIONS: The present results demonstrated the profiles of cardiovascular function and structure in the older Rhesus monkeys. Older monkey is accompanied by diminished left ventricular diastolic function and big artery compliance. Ultrasonography provides a means to non-invasively evaluate the anatomy and function of the heart and blood vessel, and plays an increasingly important role in the drug evaluation against cardiovascular dysfunction.