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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the COVID-19 pandemic, is rapidly evolving. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), including the currently most prevalent Delta variant, orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that adenosine analogue 69-0 (also known as GS-441524), possesses potent anti-SARS-CoV-2 activity. Herein, we report that esterification of the 5-hydroxyl moieties of 69-0 markedly improved the antiviral potency. The 5-hydroxyl-isobutyryl prodrug, ATV006, showed excellent oral bioavailability in rats and cynomolgus monkeys and potent antiviral efficacy against different VOCs of SARS-CoV-2 in cell culture and three mouse models. Oral administration of ATV006 significantly reduced viral loads, alleviated lung damage and rescued mice from death in the K18-hACE2 mouse model challenged with the Delta variant. Moreover, ATV006 showed broad antiviral efficacy against different mammal-infecting coronaviruses. These indicate that ATV006 represents a promising oral drug candidate against SARS-CoV-2 VOCs and other coronaviruses.
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Objective To establish a rapid,specific and sensitive TaqMan real-time fluorescence quantitative PCR assay for detection of murine polyomavirus ( MPyV) .Methods The specific primers and TaqMan probe were designed based on genome sequence of MPyV.The primers amplified a 69 bp fragment.After optimizing the reaction system and reaction condition, the standard curve was plotted by detecting recombinant plasmid standards.The specificity, sensitivity and reproducibility of this method were evaluated.In addition, samples of lungs, spleens and feces obtained from experimentally infected mice and 86 clinical samples were used to validate the efficacy of this real-time PCR assay.Results The specificity assay showed that this assay could specifically detect MPyV and the sensitivity for MPyV was about 100 copies/well.The coefficients of variation ( CV) of both intra-assay and inter-assay were less than 1.13%.All of the samples from experimentally infected mice were positive for MPyV and 3 out of 86 clinical samples were positive by this TaqMan-PCR detection with a positive rate of 3.5%.Conclusions The real-time fluorescence quantitative TaqMan-PCR assay established in this study has high specificity, sensitivity and stability.It can be used for clinical diagnosis, routine detection and epidemiological investigation of murine polyomavirus infections.
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OBJECTIVE:To observe the efficacy and safety of amitriptyline combined with carbamazepine in the treatment of postherpetic neuralgia(PHN). METHODS:80 patients with PHN were randomly divided into observation group and control group. Control group was orally given Carbamazepine tablets 100 mg,bid,then increased to 100 mg,tid after 3 d. Observation group was additionally given Amitriptyline tablets 12.5 mg every night before bed,d1~3;then increased to 25 mg after 3 d every night be-fore bed,d4~5;and 12.5 mg every morning from 6th d+25 mg every night before bed,and the dose could be adjusted based on the pain and adverse reactions of 2 groups. The treatment course for 2 groups was 4 weeks. Visual analogue scale score(VAS),sleep-ing time,pain disappearing time and clinical efficacy in 2 groups were compared,and the incidence of adverse reactions were re-corded. RESULTS:The total effective rate in observation group was higher than control group,VAS was lower than control group, sleeping time was longer than control group and pain disappearing time was shorter than control group,the differences were statisti-cally significant(P0.05). CON-CLUSIONS:Amitriptyline combined with carbamazepine has obvious efficacy in the treatment of PHN,with good safety.
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Objective To observe changes of plasma thrombinogen segment 1+2(FI+2)and D-dimer(D-D)in multiple trauma patients and exphlore their relations with traumatic disseminated intra-vascular coagulation(DIC). Methods A total of 66 multiple trauma patients were divided into minor injury group(ISS＜16 points,21 patients)and severe multiple trauma group(ISS≥16 points,45 pa-tients).Then.severe multiple trauma group were divided into DIC group(12 patients)and non-DIC group(33 patients).Another 10 healthy pemons were served as control group.Venous blood was collect-ed once in the control group and that collected from other groups at days 1,3 and 7 after injury.The F1 +2 concentrarion was detetrained with ELISA.and the D-D concentration was measured by automated la-tex enhanced immunoassay. Results The F1+2 and D-D levels in the minor injury group and sever multiple trauma group were both higher than that of the control group.In the meantime.the F1+2 and D-D levels in severe injury group were remarkably higher than that in the minor injury group.The plasma F1 +2 and D-D levels were elevated continuously in traumatic DIC group and remarkably higher than that in the non.DIC group.in which the plasma F1+2 and D-D levels gradually declined.Plasma F1+2 and D-D levels had significantly positive correlations at days 1,3 and 7 after injury. Conclusions Hiigher levels of F1+2 and D.D at acute stage is not only relevant to the injury severity,but also closely to the occurrence of traumatic DIC after injury.Detection of plasma F1+2 and D-D levels may play an impor-taut role in early prediction of DIC.
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Objective To investigate the effect of fibroblast growth factor receptor 3(FGFR3) in development phase of murine small intestine.Methods Wild type mice and their littermate FGFR3+ mice were used to observe their morphology and proliferation characteristics of epithelia of small intestinine in development phase and changes of FGFR3 expression.Results Mutant mice had lower density and their villa were lower than those of the controls.But to the depth of crypt,the results were conversely.Cells in proliferation mainly located in intestine crypt.Mutant mice had more proliferation than the controls at every time point.Expression of FGFR3 was detected at birth(day 1),and the expression was maximal from day7 to day 21,decreasing rapidly thereafter to reach the relatively low at day35.And the expression of FGFR3 also located in intestine crypt,overlapping with that of Brdu.Conclusion FGFR3 improves formation of murine intestine crypt in development phase.
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Objective To explore the relation between traumatic disseminated intravascular coagulation (DIC) and the level of plasma thrombomodulin (TM) in severe multiple-injury patients. Methods Sixty-six multiple-injury patients were divided into minor-injury group (ISS