In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Xueting Yao, Fei Ye, Miao Zhang, Cheng Cui, Baoying Huang, Peihua Niu, Xu Liu, Li Zhao, Erdan Dong, Chunli Song, Siyan Zhan, Roujian Lu, Haiyan Li, Wenjie Tan, Dongyang Liu
Abstract: Background. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquinehas been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use ofhydroxychloroquine in SARS-CoV-2 infection. Methods. The pharmacological activity of chloroquine and hydroxychloroquine wastested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokineticmodels (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug’s safety profile. Results. Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading doseof 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by amaintenance dose of 200 mg given twice daily for 4 days is recommended forSARS-CoV-2 infection, as it reached three times the potency of chloroquinephosphate when given 500 mg twice daily 5 days in advance. Conclusions. Hydroxychloroquine was found to be more potent than chloroquine to 4 / 25inhibit SARS-CoV-2 in vitro
之前看文章提到过，氯喹这个用来对付sars是很久之前香港就做过实验，只是后来sars很快结束了。所以这次很多人首先想到的是用氯喹来实验。 这是2008年香港学者发表的paper。 https://academic.oup.com/jac/article/62/3/437/734735 Strategies of therapy and therapeutic options Traditionally, there were no effective antiviral agents for coronaviruses and initial efforts focused on the use of currently available drugs, either conventional antiviral agents or non-antivirals with inhibitory effects on SARS-CoV. When SARS-CoV was better characterized in terms of virology and pathogenesis, attempts were made to target specific pathways or viral molecules using novel compounds. Another approach to therapy was the use of agents that augment the immune system or provide specific antibodies using passive immunization (Table 1). Summaries of the agents that had been tested or undergone clinical trials were recently published.3–8 It has to be noted that none of the potential antiviral agents has undergone randomized controlled clinical trials to assess their efficacies. Table 1 Strategies for antiviral treatment of SARS-CoV infection Currently available drugs for human use Investigational agents Viral targets viral entry and fusion chloroquine convalescent plasmaa, monoclonal antibodies, peptides representing different regions of ACE2, luteolin, other small molecules, peptides targeting S protein viral replication chloroquine calpain inhibitors viral protease protease inhibitors (lopinavir/ritonavira and nelfinavir) quercetin viral RNA synthesis and gene expression ribavirina and indomethacin siRNA Immunomodulation interferon alfacon-1a interferon-α and interferon-β Unknown or other mechanisms nitric oxidea, niclosamide and reserpine glycyrrhizin, baicalin, valinomycin, nitric oxide donors (e.g. S-nitroso-N-acetylpenicillamine) aHave been used in human subjects for the treatment of infection.
Strategies of therapy and therapeutic options Traditionally, there were no effective antiviral agents for coronaviruses and initial efforts focused on the use of currently available drugs, either conventional antiviral agents or non-antivirals with inhibitory effects on SARS-CoV. When SARS-CoV was better characterized in terms of virology and pathogenesis, attempts were made to target specific pathways or viral molecules using novel compounds. Another approach to therapy was the use of agents that augment the immune system or provide specific antibodies using passive immunization (Table 1). Summaries of the agents that had been tested or undergone clinical trials were recently published.3–8 It has to be noted that none of the potential antiviral agents has undergone randomized controlled clinical trials to assess their efficacies.
Table 1 Strategies for antiviral treatment of SARS-CoV infection
Currently available drugs for human use Investigational agents Viral targets viral entry and fusion chloroquine convalescent plasmaa, monoclonal antibodies, peptides representing different regions of ACE2, luteolin, other small molecules, peptides targeting S protein viral replication chloroquine calpain inhibitors viral protease protease inhibitors (lopinavir/ritonavira and nelfinavir) quercetin viral RNA synthesis and gene expression ribavirina and indomethacin siRNA Immunomodulation interferon alfacon-1a interferon-α and interferon-β Unknown or other mechanisms nitric oxidea, niclosamide and reserpine glycyrrhizin, baicalin, valinomycin, nitric oxide donors (e.g. S-nitroso-N-acetylpenicillamine) aHave been used in human subjects for the treatment of infection. ray_golden 发表于 4/20/2020 9:01:34 PM
Abstract We report on chloroquine, a 4-amino-quinoline, as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro. Chloroquine is a clinically approved drug effective against malaria. We tested chloroquine phosphate for its antiviral potential against SARS-CoV-induced cytopathicity in Vero E6 cell culture. Results indicate that the IC50 of chloroquine for antiviral activity (8.8 +/- 1.2 microM) was significantly lower than its cytostatic activity; CC50 (261.3 +/- 14.5 microM), yielding a selectivity index of 30. The IC50 of chloroquine for inhibition of SARS-CoV in vitro approximates the plasma concentrations of chloroquine reached during treatment of acute malaria. Addition of chloroquine to infected cultures could be delayed for up to 5h postinfection, without an important drop in antiviral activity. Chloroquine, an old antimalarial drug, may be considered for immediate use in the prevention and treatment of SARS-CoV infections. Copyright 2004 Elsevier Inc. 中文的机器翻译： 氯喹体外抑制重症急性呼吸综合征冠状病毒。 Keyaerts E1，Vijgen L，Maes P，Neyts J，Van RanstM。 作者信息 抽象 我们报告氯喹，一种4-氨基喹啉，作为一种有效的抑制剂，可在体外复制严重急性呼吸系统综合症冠状病毒（SARS-CoV）。氯喹是临床上有效的抗疟疾药物。我们测试了氯喹磷酸酯在Vero E6细胞培养物中针对SARS-CoV诱导的细胞病变的抗病毒潜力。结果表明，氯喹对抗病毒活性的IC50（8.8 +/- 1.2 microM）明显低于其抑制细胞活性。 CC50（261.3 +/- 14.5 microM），选择性指数为30。氯喹在体外抑制SARS-CoV的IC50近似于急性疟疾治疗期间达到的血浆氯喹浓度。在感染后5个小时内，向感染的培养物中添加氯喹的时间最多可以延迟，而抗病毒活性不会明显下降。氯喹是一种古老的抗疟药，可以考虑立即用于预防和治疗SARS-CoV感染。 版权所有2004 Elsevier Inc.
Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2)
Xueting Yao, Fei Ye, Miao Zhang, Cheng Cui, Baoying Huang, Peihua Niu, Xu
Liu, Li Zhao, Erdan Dong, Chunli Song, Siyan Zhan, Roujian Lu, Haiyan Li,
Wenjie Tan, Dongyang Liu
Clinical Infectious Diseases, ciaa237, https://doi.org/10.1093/cid/ciaa237
Abstract:
Background. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquinehas been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use ofhydroxychloroquine in SARS-CoV-2 infection. Methods. The pharmacological activity of chloroquine and hydroxychloroquine wastested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokineticmodels (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug’s safety profile. Results. Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading doseof 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by amaintenance dose of 200 mg given twice daily for 4 days is recommended forSARS-CoV-2 infection, as it reached three times the potency of chloroquinephosphate when given 500 mg twice daily 5 days in advance. Conclusions. Hydroxychloroquine was found to be more potent than chloroquine to 4 / 25inhibit SARS-CoV-2 in vitro
全文:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108130/pdf/ciaa237.pdf
这个只是提出个假说.不是investigation. 整个文章是review, 也不是主要讲chloroquine, 只是带了一句话
北医三院那个是第一次 investigative文章
你看看你写的标题：
北医三院的科学家首先证明氯喹和羟氯喹的作用
跑北美网站上来吹嘘来了
你看看2004年的sars研究报告，16年后当人们遇到跟sars类似的传染病的时候想到用之前的研究来实验是太正常不过的事情了，氯喹、克立芝都在之前的研究报告里写着。
自己玩出火来了还吹嘘自己先研究出成果，给你个面子不想喷你们，不会英文看着中文假新闻就自嗨，没见过这么不要脸的。
https://www.ncbi.nlm.nih.gov/pubmed/15351731
In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine.Keyaerts E1, Vijgen L, Maes P, Neyts J, Van Ranst M.
Author information
Abstract We report on chloroquine, a 4-amino-quinoline, as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro. Chloroquine is a clinically approved drug effective against malaria. We tested chloroquine phosphate for its antiviral potential against SARS-CoV-induced cytopathicity in Vero E6 cell culture. Results indicate that the IC50 of chloroquine for antiviral activity (8.8 +/- 1.2 microM) was significantly lower than its cytostatic activity; CC50 (261.3 +/- 14.5 microM), yielding a selectivity index of 30. The IC50 of chloroquine for inhibition of SARS-CoV in vitro approximates the plasma concentrations of chloroquine reached during treatment of acute malaria. Addition of chloroquine to infected cultures could be delayed for up to 5h postinfection, without an important drop in antiviral activity. Chloroquine, an old antimalarial drug, may be considered for immediate use in the prevention and treatment of SARS-CoV infections. Copyright 2004 Elsevier Inc.
中文的机器翻译： 氯喹体外抑制重症急性呼吸综合征冠状病毒。 Keyaerts E1，Vijgen L，Maes P，Neyts J，Van RanstM。 作者信息 抽象 我们报告氯喹，一种4-氨基喹啉，作为一种有效的抑制剂，可在体外复制严重急性呼吸系统综合症冠状病毒（SARS-CoV）。氯喹是临床上有效的抗疟疾药物。我们测试了氯喹磷酸酯在Vero E6细胞培养物中针对SARS-CoV诱导的细胞病变的抗病毒潜力。结果表明，氯喹对抗病毒活性的IC50（8.8 +/- 1.2 microM）明显低于其抑制细胞活性。 CC50（261.3 +/- 14.5 microM），选择性指数为30。氯喹在体外抑制SARS-CoV的IC50近似于急性疟疾治疗期间达到的血浆氯喹浓度。在感染后5个小时内，向感染的培养物中添加氯喹的时间最多可以延迟，而抗病毒活性不会明显下降。氯喹是一种古老的抗疟药，可以考虑立即用于预防和治疗SARS-CoV感染。
版权所有2004 Elsevier Inc.
这是最简单的临床用药方式，去年得流感了用达菲，今年新流感类型来了，继续用达菲试试，哦，这次也管用，我们厉害国第一个证明的。
你怎么不吹嘘一下，河南村艾滋病多，中国乙肝多，哪个特效药是中国研制的，跟美国现在几个生物厂商的药来比比。别说用中药上莲花清瘟，靠数据造假和洗脑天天编假新闻，也就蒙骗国内的韭菜，还有看不懂英文的小红粉。
你有毛病
看看，被揭穿了，理屈词穷就开始骂人。假装还转paper吹牛，没素质就不要装。你看看你huaren和买买提上连发两个一样的文章，排版都一样，就是动作有点慢，一个是20:38:35 ，华人上是 20:48