Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-3 (of 3 Records) |
Query Trace: Schinazi RF[original query] |
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Potent in vitro activity of beta-D-4'-chloromethyl-2'-deoxy-2'-fluorocytidine against Nipah virus
Lo MK , Amblard F , Flint M , Chatterjee P , Kasthuri M , Li C , Russell O , Verma K , Bassit L , Schinazi RF , Nichol ST , Spiropoulou CF . Antiviral Res 2020 175 104712 Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that continues to cause outbreaks in humans characterized by high mortality and significant clinical sequelae in survivors. Currently, no therapeutics are approved for use in humans against NiV infection. Here, we report that 4'-chloromethyl-2'-deoxy-2'-fluorocytidine (ALS-8112) inhibits NiV. ALS-8112 is the parent nucleoside of lumicitabine, which has been evaluated in phase I and II clinical trials to treat pediatric and adult respiratory syncytial virus infection. In this study, we tested ALS-8112 against NiV and other major human respiratory pneumo- and paramyxoviruses in 2 human lung epithelial cell lines, and demonstrated the ability of ALS-8112 to reduce infectious wild-type NiV yield by over 6 orders of magnitude with no apparent cytotoxicity. However, further cytotoxicity testing in primary cells and bone marrow progenitor cells indicated cytotoxicity at higher concentrations of ALS-8112. Our results warrant the evaluation of lumicitabine against NiV infection in relevant animal models. |
Long-term virological and adherence outcomes to antiviral treatment in a 4-year cohort chronic HBV study
Abreu RM , Bassit LC , Tao S , Jiang Y , Ferreira AS , Hori PC , Ganova-Raeva LM , Khudyakov Y , Schinazi RF , Carrilho FJ , Ono SK . Antivir Ther 2019 24 (8) 567-579 BACKGROUND: Chronic hepatitis B (CHB) treatment adherence has been poorly studied worldwide. We evaluated long term virological and adherence outcomes to antiviral treatment in CHB patients. METHODS: A prospective 183 Brazilian CHB patients cohort treated with monotherapy or combination adefovir dipivoxil, entecavir, lamivudine and / or tenofovir disoproxil fumarate was studied in a reference tertiary center. Treatment adherence was evaluated by a validated questionnaire named "Assessment of Adherence to Antiviral Therapy Questionnaire" (CEAT-HBV) within three year-periods (2010/2011, 2013/2014 and 2014/2015). RESULTS: CEAT-HBV identified 43% (79/183) patients with non-adherence to antiviral treatment and among them, 67% (53/79) were viral load positive. The main causes associated with non-response to antiviral treatment were drug resistance variants followed by non-adherence, insufficient treatment duration and other causes. Single-dose pharmacokinetics demonstrated 35% (23/65) antiviral non-adherence. Two years after the first assessment, the CEAT-HBV indicated that 71% (101/143) subjects adhered to treatment (per-protocol population). However, 21% (40/183) of the patients could not be evaluated and were excluded. The main reasons for exclusion were death (20/183), 11 out 20 deaths due to hepatocellular carcinoma. Hepatitis B virus (HBV) booklet was used for medical education. The third CEAT-HBV assessment (2014/2015) showed that 83% (112/135) patients were compliant with treatment adherence (per-protocol population). Long-term evaluation showed that adherence rate based on CEAT-HBV continue to increase after 4-years (p<0.001). CONCLUSIONS: The results highlight the importance of CHB therapy adherence assessment monitoring. Long-term adherence outcomes were dynamic and it is possible to increase the migration rate to adherence/HBV DNA negative group. |
Antiviral activity of nucleoside analogues against norovirus.
Costantini VP , Whitaker T , Barclay L , Lee D , McBrayer TR , Schinazi RF , Vinje J . Antivir Ther 2012 17 (6) 981-91 BACKGROUND: Norovirus (NoV) is the leading cause of epidemic gastroenteritis worldwide. The lack of a cell culture has significantly hampered the development of effective therapies against human NoV. Clinically approved nucleoside and non-nucleoside analogues have been used successfully against RNA viruses. METHODS: In this study, we evaluated the efficacy of four nucleoside analogues (2'-C-MeC, 2'-F-2'-C-MeC, beta-D-N(4)-hydroxycytidine [NHC] and lamivudine) on Norwalk virus (NV) RNA levels and protein expression in NV replicon-harbouring cells (HG23 cells), and their efficacy in blocking murine norovirus (MNV) replication in RAW 264.7 cells. RESULTS: 2'-C-MeC and 2'-F-2'-C-MeC reduced MNV RNA levels and infectivity in RAW 264.7 cells in a concentration- and time-dependent manner. The median effective concentrations (EC(50)) of 2'-C-MeC and 2'-F-2'-C-MeC were 6.9 mcM and 12.7 mcM, respectively. 2'-C-MeC, 2'-F-2'-C-MeC and NHC reduced NV RNA levels and protein expression in HG23 cells. For the NV replicon, the EC(50) of 2'-C-MeC (1.3 mcM) was comparable to the antiviral activity of NHC (1.5 mcM) and twofold more potent than 2'-F-2'-C-MeC (3.2 mcM). The combination of 2'-C-MeC/ribavirin resulted in modest synergistic activity, whereas NHC/ribavirin was antagonistic for NV replication in HG23 cells. CONCLUSIONS: The antiviral activity of 2'-C-MeC against strains of two different NoV genogroups and the low EC(50) suggest that this nucleoside analogue may be effective against the more prevalent GII NoVs. In the absence of a vaccine, antiviral agents could be an effective intervention to control the spread of human NoV in populations at a high risk for NoV disease. |
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