2021年11月26日,世界卫生组织(WHO)召开紧急会议向全世界通报,一种令人担忧的新型冠状病毒(SARS-CoV-2)变异株正在世界各地传播,各国亟需采取应对措施。WHO定性为最高级别的、值得关切的“变异株”(variants of concern,VOC),并命名为...2021年11月26日,世界卫生组织(WHO)召开紧急会议向全世界通报,一种令人担忧的新型冠状病毒(SARS-CoV-2)变异株正在世界各地传播,各国亟需采取应对措施。WHO定性为最高级别的、值得关切的“变异株”(variants of concern,VOC),并命名为奥密克戎(omicron),距离该变异株被发现仅2 d时间。已观察到奥密克戎在支气管中感染速度和繁殖速度比SARS-CoV-2德尔塔变异株及SARS-CoV-2原始毒株快70倍,传播力为德尔塔的3~4倍。至2022年2月24日,时隔3个月,WHO最新实时统计指出,自SARS-CoV-2暴发以来,已扩散至全球各个角落,累计确诊新型冠状病毒肺炎病例4.30亿例,死亡近97万人,95%以上是由德尔塔和奥密克戎变异株感染引起的。全球范围内已有超过100多个国家发现奥密克戎新变异毒株BA.2,其传染性比奥密克戎高30%,患者临床症状更严重,成为危害全球人类身心健康的严重传染疾病的病原体,可使多种疫苗的防疫机制失效。美国当地时间2021年11月23日,美国食品药品管理局(FDA)紧急授权,批准美国默克制药集团公司(除美国和加拿大外,均称为默沙东制药公司)与美国Ridgeback公司合作开发的第3款治疗COVID-19新药:莫努匹韦(molnupiravir)胶囊上市,商品名lagevrio。根据Ⅲ期临床试验研究的中期分析,莫努匹韦胶囊治疗SARS-CoV-2轻至中度成人和≥12岁,体质量≥40 kg的儿科患者,及具有较高重症风险的住院人群,推荐剂量为每12小时口服莫努匹韦胶囊800 mg(4粒),连续服用5 d。可使住院率或死亡风险率减低约50%。该文对莫努匹韦(商品名:lagevrio)胶囊的非临床和临床药理毒理学、临床研究、不良反应、适应证、剂量与用法、用药注意事项及知识产权状态和国内外研究进展等进行介绍。展开更多
Background: Molnupiravir, N4-hydroxycytidine-5’-isopropyl ester, is an oral prodrug of N4-deoxycytidine (NHC), a nucleoside analog, which has in vitro activity against SARS-CoV-2. NHC is phosphorylated in cells to NH...Background: Molnupiravir, N4-hydroxycytidine-5’-isopropyl ester, is an oral prodrug of N4-deoxycytidine (NHC), a nucleoside analog, which has in vitro activity against SARS-CoV-2. NHC is phosphorylated in cells to NHC triphosphate (NHC-TP), which is incorporated into viral RNA, leading to epigenetic catastrophe of the viral genome and inhibition of viral replication. The antiviral activity against SARS-CoV-2 is dependent on the number of molecules of NHC-TP incorporated into viral RNA. Clinical studies in patients with COVID-19 showed that treatment with molnupiravir for 5 days decreases the risk of hospitalization and death as compared with placebo. Objective: It should be possible to enhance the antiviral activity of NHC-TP against SARS-CoV-2 by the use of the biochemical modulator, 3-deazauridine (3DU). 3DU is an inhibitor of CTP synthetase. Inhibition of this enzyme results in a reduction in the intracellular pool size of CTP. Since NHC-TP competes with CTP for incorporation into viral RNA in the reaction catalyzed by the SARS-CoV-2 viral RNA-dependent RNA polymerase, the reduction in the level of CTP should result in a significant enhancement of the incorporation of NHC-TP into viral RNA and an enhancement of its antiviral activity. Methods: Analysis of the publications of 3DU and cytosine nucleoside analogues support the hypothesis that 3DU enhances the pharmacological action of the analogues. Results: 3-DU increased the incorporation of 5-azacytidine into RNA and 5-aza-deoxycytidine into DNA of leukemic cells with an enhancement of their antineoplastic action. 3-DU potentiated the antiviral activity against HIV-1 activity by the cytosine nucleoside analogues: 2’-deoxy-3’-thiacytidine (3TC;lamivudine) and 2’,3’-dideoxycytidine (ddC). This anti-HIV-1 activity of 3DU was associated with a reduction in the intracellular pool size of dCTP and increased incorporation of triphosphates of 3TC and ddC into DNA by the HIV-1 reverse transcriptase. The reduction of CTP levels in cells by 3-DU also leads to a reduction in dCTP since CTP is its precursor. Conclusion: The preclinical studies on 3-DU indicate that it can enhance the pharmacological activity of both ribo- and deoxyribonucleoside analogues against neoplastic cells and viral infected cells. These observations suggest that 3-DU also has the potential to enhance the antiviral activity of molnupiravir and arrest the progression of the disease in patients with COVID-19.展开更多
目的系统评价莫诺拉韦治疗新型冠状病毒感染(COVID-19)的疗效与安全性。方法计算机检索CNKI、VIP、WanFang Data、PubMed、Web of Science、Cochrane Library和Epistemonikos COVID-19 L OVE数据库,搜集莫诺拉韦治疗COVID-19的随机对照...目的系统评价莫诺拉韦治疗新型冠状病毒感染(COVID-19)的疗效与安全性。方法计算机检索CNKI、VIP、WanFang Data、PubMed、Web of Science、Cochrane Library和Epistemonikos COVID-19 L OVE数据库,搜集莫诺拉韦治疗COVID-19的随机对照试验(RCT),检索时限均从建库至2023年7月。由2名研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan 5.4软件进行Meta分析。结果共纳入9个RCT,包括30675例患者。Meta分析结果显示,两组患者的28~29天住院率、28~29天死亡率、14~15天PCR检测结果转阴率和不良事件发生率的差异均无统计学意义(P>0.05)。莫诺拉韦组显著增加4类系统性器官疾病的不良事件发生率。结论当前证据显示,莫诺拉韦的安全性和对伴有进展为重症高风险COVID-19患者的益处尚不明确。受纳入研究数量和质量的限制,上述结论尚待更多高质量研究予以验证。展开更多
Despite the global decline in the severity of the coronavirus disease 2019(COVID-19)cases,the disease stillrepresents a major concern to the relevant scientific and medical communities.The primary concern of drug scie...Despite the global decline in the severity of the coronavirus disease 2019(COVID-19)cases,the disease stillrepresents a major concern to the relevant scientific and medical communities.The primary concern of drug scientists,virologists,and other concerned specialists in this respect is to find ready-to-use suitable and potent anticoronaviraltherapies that are broadly effective against the different species/strains of the coronaviruses in general,not only againstthe current and previous coronaviruses(e.g.,the recently-appeared severe acute respiratory syndrome coronavirus 2“SARS-CoV-2”),i.e.,effective antiviral agents for treatment and/or prophylaxis of any coronaviral infections,includingthose of the coming ones from the next species and strains(if any).As an expert in this field,I tried,in this up-to-dateperspective“viewpoint”article,to evaluate the suitability and applicability of using the currently-availableanticoronaviral agents for the next coronavirus diseases(COVIDs)and coronaviral pandemics,highlighting the mostimportant general guidelines that should be considered in the next pandemics from the therapeutic points of view.展开更多
文摘Background: Molnupiravir, N4-hydroxycytidine-5’-isopropyl ester, is an oral prodrug of N4-deoxycytidine (NHC), a nucleoside analog, which has in vitro activity against SARS-CoV-2. NHC is phosphorylated in cells to NHC triphosphate (NHC-TP), which is incorporated into viral RNA, leading to epigenetic catastrophe of the viral genome and inhibition of viral replication. The antiviral activity against SARS-CoV-2 is dependent on the number of molecules of NHC-TP incorporated into viral RNA. Clinical studies in patients with COVID-19 showed that treatment with molnupiravir for 5 days decreases the risk of hospitalization and death as compared with placebo. Objective: It should be possible to enhance the antiviral activity of NHC-TP against SARS-CoV-2 by the use of the biochemical modulator, 3-deazauridine (3DU). 3DU is an inhibitor of CTP synthetase. Inhibition of this enzyme results in a reduction in the intracellular pool size of CTP. Since NHC-TP competes with CTP for incorporation into viral RNA in the reaction catalyzed by the SARS-CoV-2 viral RNA-dependent RNA polymerase, the reduction in the level of CTP should result in a significant enhancement of the incorporation of NHC-TP into viral RNA and an enhancement of its antiviral activity. Methods: Analysis of the publications of 3DU and cytosine nucleoside analogues support the hypothesis that 3DU enhances the pharmacological action of the analogues. Results: 3-DU increased the incorporation of 5-azacytidine into RNA and 5-aza-deoxycytidine into DNA of leukemic cells with an enhancement of their antineoplastic action. 3-DU potentiated the antiviral activity against HIV-1 activity by the cytosine nucleoside analogues: 2’-deoxy-3’-thiacytidine (3TC;lamivudine) and 2’,3’-dideoxycytidine (ddC). This anti-HIV-1 activity of 3DU was associated with a reduction in the intracellular pool size of dCTP and increased incorporation of triphosphates of 3TC and ddC into DNA by the HIV-1 reverse transcriptase. The reduction of CTP levels in cells by 3-DU also leads to a reduction in dCTP since CTP is its precursor. Conclusion: The preclinical studies on 3-DU indicate that it can enhance the pharmacological activity of both ribo- and deoxyribonucleoside analogues against neoplastic cells and viral infected cells. These observations suggest that 3-DU also has the potential to enhance the antiviral activity of molnupiravir and arrest the progression of the disease in patients with COVID-19.
文摘目的系统评价莫诺拉韦治疗新型冠状病毒感染(COVID-19)的疗效与安全性。方法计算机检索CNKI、VIP、WanFang Data、PubMed、Web of Science、Cochrane Library和Epistemonikos COVID-19 L OVE数据库,搜集莫诺拉韦治疗COVID-19的随机对照试验(RCT),检索时限均从建库至2023年7月。由2名研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan 5.4软件进行Meta分析。结果共纳入9个RCT,包括30675例患者。Meta分析结果显示,两组患者的28~29天住院率、28~29天死亡率、14~15天PCR检测结果转阴率和不良事件发生率的差异均无统计学意义(P>0.05)。莫诺拉韦组显著增加4类系统性器官疾病的不良事件发生率。结论当前证据显示,莫诺拉韦的安全性和对伴有进展为重症高风险COVID-19患者的益处尚不明确。受纳入研究数量和质量的限制,上述结论尚待更多高质量研究予以验证。
文摘Despite the global decline in the severity of the coronavirus disease 2019(COVID-19)cases,the disease stillrepresents a major concern to the relevant scientific and medical communities.The primary concern of drug scientists,virologists,and other concerned specialists in this respect is to find ready-to-use suitable and potent anticoronaviraltherapies that are broadly effective against the different species/strains of the coronaviruses in general,not only againstthe current and previous coronaviruses(e.g.,the recently-appeared severe acute respiratory syndrome coronavirus 2“SARS-CoV-2”),i.e.,effective antiviral agents for treatment and/or prophylaxis of any coronaviral infections,includingthose of the coming ones from the next species and strains(if any).As an expert in this field,I tried,in this up-to-dateperspective“viewpoint”article,to evaluate the suitability and applicability of using the currently-availableanticoronaviral agents for the next coronavirus diseases(COVIDs)and coronaviral pandemics,highlighting the mostimportant general guidelines that should be considered in the next pandemics from the therapeutic points of view.
