一种有效治疗冠状病毒(COVID-19)的方法

2020年3月20日13:35:52一种有效治疗冠状病毒(COVID-19)的方法已关闭评论 1.1K32972字阅读109分54秒

Presented by:James M.Todaro,MD(Columbia MD,jtodaro2@gmail.com)and Gregory J.Rigano,Esq.(grigano1@jhu.edu)

In consultation with Stanford University School of Medicine,UAB School of Medicine and National Academy of Sciences researchers.

与斯坦福大学医学院,UAB 医学院和国家科学院的研究人员协商。

March 13,2020

2020313

SPANISH:https://docs.google.com/document/d/e/2PACX-1vR1adodKPhWalV9djnerI2x_v1LGgGyhZZxpl0O5r-ZNyDdagqFq1rTCxXBqaeicfxgvypDOqKCZVyV/pub

西班牙语:

https://docs.google.com/document/d/e/2pacx-1vr1adodkphwalv9djneri2x_v1lgggyhzzxpl0o5r-znyddagqfq1rtcxxbqaeicfxgvypdoqkczvyv/pub

Translation by:Celia Martínez-Aceves(Yale B.S.Candidate 2021;celia.martinez-aceves@yale.edu),Martín Martínez(MIT B.S.2017;martin.martinez.mit@gmail.com)

翻译:Celia mart nez-aceves(Yale b.s.Candidate 2021;Celia.martinez-aceves@Yale.edu)mart n mart nez(MIT b.s.2017;martin.martinez.MIT@gmail.com)

ITALIAN:https://docs.google.com/document/d/e/2PACX-1vSjPNh_WX6FXUIE3OaA3ScsW7yIH3-SpZyYzElNQUNuJvDmD9eFzM29mVXeaYRY-rjGv52wkrZNa7tb/pub

意大利:

https://docs.google.com/document/d/e/2pacx-1vsjpnh_wx6fxuie3oaa3scsw7yih3-spzyyzelnqunujvdmd9efzm29mvxeayry-rjgv52wkrzna7tb/pub

Translation by:Google Translate and edited by Ross Shulman,Cornell University MS'20 ross.shulman@gmail.com

Summary

摘要

Recent guidelines from South Korea and China report that chloroquine is an effective antiviral therapeutic treatment against Coronavirus Disease 2019.Use of chloroquine(tablets)is showing favorable outcomes in humans infected with Coronavirus including faster time to recovery and shorter hospital stay.US CDC research shows that chloroquine also has strong potential as a prophylactic(preventative)measure against coronavirus in the lab,while we wait for a vaccine to be developed.Chloroquine is an inexpensive,globally available drug that has been in widespread human use since 1945 against malaria,autoimmune and various other conditions.

来自韩国和中国的最新指导方针报告说,氯喹是2019年对抗冠状病毒病的有效抗病毒治疗药物。使用氯喹(片剂)对感染冠状病毒的人类显示出良好的效果,包括更快的康复时间和更短的住院时间。美国疾病控制和预防中心的研究表明,氯喹也有很大的潜力作为预防措施,对冠状病毒在实验室,而我们等待疫苗开发。氯喹是一种廉价的全球可用的药物,自1945年以来已被广泛用于治疗疟疾、自身免疫性疾病和各种其他疾病。

一种有效治疗冠状病毒(COVID-19)的方法

Background

背景

The U.S.CDC and World Health Organization have not published treatment measures against Coronavirus disease 2019("COVID-19").Medical centers are starting to have issues with traditional protocols.Treatments,and ideally a preventative measure,are needed.South Korea and China have had significantly more exposure and time to analyze diagnostic,treatment and preventative options.The U.S.,Europe and the rest of the world can learn from their experience.According to former FDA commissioner,board member of Pfizer and Illumina,Scott Gotlieb MD,the world can learn the most about COVID-19 by paying closest attention to the response of countries that have had significant exposure to COVID-19 before the U.S.and Europe.[1]

美国疾病预防控制中心和世界卫生组织尚未公布2019年对抗冠状病毒病的治疗措施。医疗中心开始对传统的协议产生了问题。治疗,以及最理想的预防措施是必要的。韩国和中国有更多的机会和时间来分析诊断、治疗和预防措施。美国、欧洲和世界其他地区可以从他们的经验中学习。根据前 FDA 专员、辉瑞公司董事会成员、Illumina 公司董事会成员 Scott Gotlieb MD 的说法,世界可以通过密切关注那些在美国和欧洲之前接触过 COVID-19的国家的反应来了解最多的 COVID-19[1]

As per the U.S.CDC,"Chloroquine(also known as chloroquine phosphate)is an antimalarial medicine…Chloroquine is available in the United States by prescription only…Chloroquine can be prescribed for either prevention or treatment of malaria.Chloroquine can be prescribed to adults and children of all ages.It can also be safely taken by pregnant women and nursing mothers."[2]

根据美国疾病控制和预防中心的说法,"氯喹(也称为磷酸氯喹)是一种抗疟疾药物......氯喹在美国只能通过处方获得......氯喹既可用于预防疟疾,也可用于治疗疟疾。氯喹可以处方给所有年龄的成人和儿童。孕妇和哺乳期的母亲也可以安全服用。"[2]

CDC research also shows that"chloroquine can affect virus infection in many ways,and the antiviral effect depends in part on the extent to which the virus utilizes endosomes for entry.Chloroquine has been widely used to treat human diseases,such as malaria,amoebiosis,HIV,and autoimmune diseases,without significant detrimental side effects."[3]

疾病预防控制中心的研究还表明,"氯喹可以通过多种方式影响病毒感染,抗病毒效果部分取决于病毒利用内涵体进入的程度。氯喹已被广泛用于治疗人类疾病,如疟疾、变形虫病、艾滋病毒和自身免疫性疾病,没有明显的副作用[3]

The treatment guidelines of both South Korea and China against COVID-19 are generally consistent,outlining chloroquine as an effective treatment.

韩国和中国针对 COVID-19的治疗指南大体上是一致的,氯喹是一种有效的治疗方法。

Specifically,according to the Korea Biomedical Review,in February 2020 in South Korea,the COVID-19 Central Clinical Task Force,composed of physicians and experts treating patients agreed upon treatment principles for patients with COVID-19.[4] In China,the General Office of the National Health Commission,General Office of the State Administration of Traditional Chinese Medicine as well as a Multi-Center Collaborative Group of Guangdong Provincial Department of Science and Technology and Guangdong Provincial Health Comp and the China National Center for Biotechnology Development have established effective treatment measures based on human studies.[5]

具体而言,根据《韩国生物医学评论》,20202月在韩国,COVID-19中央临床工作队,由治疗患者的医生和专家组成,就 COVID-19患者的治疗原则达成一致。[4]在中国,国家卫生委员会办公厅、国家中医药管理局办公厅、广东省科学技术厅、广东省卫生厅多中心合作小组和中国国家生物技术开发中心制定了基于人体研究的有效治疗措施。[5]

According to their research(reported in Clinical Trials Arena),

根据他们的研究(发表在临床试验竞技场上),

"Data from the drug's[chloroquine]studies showed'certain curative effect'with'fairly good efficacy'…patients treated with chloroquine demonstrated a better drop in fever,improvement of lung CT images,and required a shorter time to recover compared to parallel groups.The percentage of patients with negative viral nucleic acid tests was also higher with the anti-malarial drug…Chloroquine has so far shown no obvious serious adverse reactions in more than 100 participants in the trials…Chloroquine was selected after several screening rounds of thousands of existing drugs.Chloroquine is undergoing further trials in more than ten hospitals in Beijing,Guangdong province and Hunnan province."[6]

"来自药物[氯喹]研究的数据显示,'某些疗效''相当好的疗效'......与平行组相比,用氯喹治疗的患者表现出更好的退烧、肺部 CT 图像改善,并需要更短的恢复时间。病毒核酸检测阴性的病人百分比在抗疟疾药物方面也更高...到目前为止,在100多名试验参与者中没有显示出明显的严重不良反应...经过数千种现有药物的几轮筛选后,选出了氯喹。氯喹正在北京、广东和 Hunnan 的十多家医院进行进一步试验。"[6]

Treatment Guidelines from South Korea[7]

韩国的治疗指南[7]

According to the Korea Biomedical Review,the South Korean COVID-19 Central Clinical Task Force guidelines are as follows:

根据《韩国生物医学评论》,韩国 COVID-19中央临床工作队的指导方针如下:

1.If patients are young,healthy,and have mild symptoms without underlying conditions,doctors can observe them without antiviral treatment;

1.如果患者年轻、健康,并且症状轻微,但没有潜在病症,医生可以在不使用抗病毒药物的情况下观察他们;

2.If more than 10 days have passed since the onset of the illness and the symptoms are mild,physicians do not have to start an antiviral medication;

2.如果发病后超过10天,症状轻微,医生不必开始使用抗病毒药物;

3.However,if patients are old or have underlying conditions with serious symptoms,physicians should consider an antiviral treatment.If they decide to use the antiviral therapy,they should start the administration as soon as possible:

3.然而,如果患者年龄较大或有严重症状的潜在疾病,医生应考虑使用抗病毒治疗。如果他们决定使用抗病毒疗法,他们应该尽快开始管理:

…chloroquine 500mg orally per day.

每天口服氯喹500毫克。

4.As chloroquine is not available in Korea,doctors could consider hydroxychloroquine 400mg orally per day(Hydroxychloroquine is an analog of chloroquine used against malaria,autoimmune disorders,etc.It is widely available as well).

4.由于韩国没有氯喹,医生可以考虑每天口服羟氯喹400毫克(羟氯喹是氯喹的类似物,用于治疗疟疾、自身免疫性疾病等。它也被广泛使用)

5.The treatment is suitable for 7-10 days,which can be shortened or extended depending on clinical progress.

5.治疗时间为7-10天,可根据临床进展缩短或延长。

Notably,the guidelines mention other antivirals as further lines of defense,including anti-HIV drugs.

值得注意的是,指南提到其他抗病毒药物作为进一步的防线,包括抗艾滋病毒药物。

Treatment Guidelines from China[8]

中国的治疗指南[8]

According to China's Novel Coronavirus Pneumonia Diagnosis and Treatment Plan,7th Edition,the treatment guidelines are as follows:

根据中国新型冠状病毒肺炎诊断和治疗计划第7版,治疗指南如下:

1.Treatment for mild cases includes bed rest,supportive treatments,and maintenance of caloric intake.Pay attention to fluid and electrolyte balance and maintain homeostasis.Closely monitor the patient's vitals and oxygen saturation.

1.轻度病例的治疗包括卧床休息、支持性治疗和维持热量摄入。注意体液和电解质平衡,保持体内平衡。密切监测病人的生命体征和氧饱和度。

2.As indicated by clinical presentations,monitor the hematology panel,routine urinalysis,CRP,biochemistry(liver enzymes,cardiac enzymes,kidney function),coagulation,arterial blood gas analysis,chest radiography,and so on.Cytokines can be tested,if possible.

2.根据临床表现,监测血液学、尿常规、CRP、生化(肝酶、心肌酶、肾功能)、凝血、动脉血气分析、胸片等。如果可能的话,可以检测细胞因子。

3.Administer effective oxygenation measures promptly,including nasal catheter,oxygen mask,and high flow nasal cannula.If conditions allow,a hydrogen-oxygen gas mix(H2/O2:66.6%/33.3%)may be used for breathing.

3.及时采取有效的氧合措施,包括鼻导管、氧气面罩和高流量鼻插管。如果条件允许,氢氧混合气体(h2/o2:66.6%/33.3%)可用于呼吸。

4.Antiviral therapies:

4.抗病毒疗法:

...chloroquine phosphate(adult 18-65 years old weighing more than 50kg:500mg twice daily for 7 days;bodyweight less than 50kg:500mg twice daily for day 1 and 2,500mg once daily for day 3 through 7)…

磷酸氯喹(18-65岁体重超过50公斤的成年人:500毫克,每日两次,连续7;体重超过50公斤的人:500毫克,每日两次,连续1;2,500毫克,连续3天至7)

Additionally,the Guangdong Provincial Department of Science and Technology and the Guangdong Provincial Health and Health Commission issued a report stating"Expert consensus on chloroquine phosphate for new coronavirus pneumonia:…clinical research results show that chloroquine improves the success rate of treatment and shortens the length of patient's hospital stay."[9] The report further goes on to cite research from the US CDC from 2005 as well as research from the University of Leuven University in Belgium regarding chloroquine's effectiveness against SARS coronavirus at the cellular level.[10]

此外,广东省科学技术厅及广东省衞生和卫生委员会发表报告,指出「专家对磷酸氯喹治疗新型冠状病毒性肺炎的共识:...临床研究结果显示,氯喹可提高治疗成功率,缩短病人住院时间。」报告进一步引用了2005年美国疾病预防控制中心的研究以及比利时荷语天主教鲁汶大学关于氯喹在细胞水平上对抗 SARS 冠状病毒的有效性的研究。[10]

Like the South Korean guidelines,notably,other antivirals(e.g.anti-HIV drugs)are listed as further lines of defense.The most research thus far has been around chloroquine.

与韩国的指导方针一样,值得注意的是,其他抗病毒药物(如抗艾滋病毒药物)也被列为进一步的防线。到目前为止,最多的研究是关于氯喹的。

Chloroquine as a prophylactic(preventative)measure against COVID-19[11]

氯喹作为预防措施对 COVID-19[11]

According to research by the US CDC,chloroquine has strong antiviral effects on SARS coronavirus,both prophylactically and therapeutically.SARS coronavirus has significant similarities to COVID-19.Specifically,the CDC research was completed in primate cells using chloroquine's well known function of elevating endosomal pH.The results show that"We have identified chloroquine as an effective antiviral agent for SARS-CoV in cell culture conditions,as evidenced by its inhibitory effect when the drug was added prior to infection or after the initiation and establishment of infection.The fact that chloroquine exerts an antiviral effect during pre-and post-infection conditions suggest that it is likely to have both prophylactic and therapeutic advantages."

根据美国疾病预防控制中心的研究,氯喹对 SARS 冠状病毒有很强的预防和治疗作用。Sars 冠状病毒与 COVID-19有显著的相似性。具体而言,CDC 的研究是在灵长类动物细胞中利用氯喹提高内涵体 ph 值的众所周知的功能完成的。结果表明:"我们已经确定,在细胞培养条件下,氯喹是 SARS-CoV 的一种有效抗病毒药物,当药物在感染前或感染开始和建立后加入时,其抑制作用就证明了这一点。氯喹在感染前后发挥抗病毒作用的事实表明,氯喹可能具有预防和治疗的双重优势。"

The study shows that chloroquine is effective in preventing SARS-CoV infection in cell culture if the drug is added to the cells 24 h prior to infection.

研究表明,如果在感染前24小时将药物加入细胞内,氯喹能有效防止细胞培养中的严重急性唿吸综合症。

一种有效治疗冠状病毒(COVID-19)的方法

1

Prophylactic effect of chloroquine.Vero E6 cells pre-treated with chloroquine for 20 hrs.Chloroquine-containing media were removed and the cells were washed with phosphate buffered saline before they were infected with SARS-CoV(0.5 multiplicity of infection)for 1 h in the absence of chloroquine.Virus was then removed and the cells were maintained in Opti-MEM(Invitrogen)for 16–18 h in the absence of chloroquine.SARS-CoV antigens were stained with virus-specific HMAF,followed by FITC-conjugated secondary antibodies.(A)The concentration of chloroquine used is indicated on the top of each panel.(B)SARS-CoV antigen-positive cells at three random locations were captured by using a digital camera,the number of antigen-positive cells was determined,and the average inhibition was calculated.Percent inhibition was obtained by considering the untreated control as 0%inhibition.The vertical bars represent the range of SEM.

氯喹的预防作用。用氯喹预处理 Vero E6细胞20小时。含有氯喹的培养基被去除,细胞在感染 SARS-CoV(0.5倍感染)前用磷酸盐缓冲生理盐水清洗,在没有氯喹的情况下持续1小时。然后去除病毒,在没有氯喹的情况下,细胞在 Opti-MEM(Invitrogen)中维持16-18小时。用病毒特异性 HMAF 染色 SARS-CoV 抗原,然后用 fitc 结合的二级抗体染色。(a)所用氯喹的浓度在每个面板的顶部标明。(b)用数码相机捕获3个随机位置的 sars 冠状病毒抗原阳性细胞,测定抗原阳性细胞数,计算平均抑制率。将未经处理的对照作为0%抑制剂,可获得抑制率。竖条代表扫描电镜的范围。

In the case of chloroquine treatment prior to infection,the impairment of terminal glycosylation of ACE2 may result in reduced binding affinities between ACE2 and SARS-CoV spike protein and negatively influence the initiation of SARS-CoV infection.The cell surface expression of under-glycosylated ACE2 and its poor affinity to SARS-CoV spike protein may be the primary mechanism by which infection is prevented by drug pretreatment of cells prior to infection.

在感染前使用氯喹治疗的情况下,ACE2的末端糖基化受损可能导致 ACE2 SARS-CoV s 蛋白之间的结合亲和力降低,并对严重急性唿吸综合症的启动产生负面影响。在感染前对细胞进行药物预处理可能是预防感染的主要机制。

In addition,the study also shows that chloroquine was very effective even when the drug was added 3–5 h after infection,suggesting an antiviral effect even after the establishment of infection.

此外,研究还表明,即使在感染后3-5小时内加入氯喹,氯喹仍然非常有效,表明即使在感染确立后仍然有抗病毒作用。

一种有效治疗冠状病毒(COVID-19)的方法

2

Post-infection chloroquine treatment reduces SARS-CoV infection and spread.Vero E6 cells were seeded and infected as described for Fig.1 except that chloroquine was added only after virus adsorption.Cells were maintained in Opti-MEM(Invitrogen)containing chloroquine for 16–18 h,after which they were processed for immunofluorescence.(A)The concentration of chloroquine is indicated on the top.(B)Percent inhibition and SEM were calculated as in Fig.1B.(C)The effective dose(ED50)was calculated using commercially available software(Grafit,version 4,Erithacus Software).

感染后使用氯喹治疗可减少严重急性唿吸综合症和传播。如图1所示,接种和感染 Vero E6细胞,但只有在吸附病毒后才加入氯喹。细胞在含有氯喹的 Opti-MEM(Invitrogen)中维持16-18小时,然后处理免疫荧光。(a)氯喹的浓度显示在顶部。(b)抑制率和扫描电镜计算如图1B 所示。(c)有效剂量(ED50)采用市售软件(Grafit,版本4Erithacus Software)计算。

When chloroquine is added after infection,it can rapidly raise the pH and subvert on-going fusion events between virus and endosomes,thus inhibiting the infection.When added after the initiation of infection,it likely affects the endosome-mediated fusion,subsequent virus replication,or assembly and release.Specifically,rapid elevation of endosomal pH and abrogation of virus-endosome fusion may be the primary mechanism by which virus infection is prevented under post-treatment conditions.

当感染后加入氯喹,可迅速提高 pH 值,破坏病毒与内涵体之间持续的融合事件,从而抑制感染。当感染开始后加入时,它可能影响内部体介导的融合,随后的病毒复制,或组装和释放。具体地说,内体 pH 值的迅速升高和病毒-内体融合的消失可能是在治疗后条件下预防病毒感染的主要机制。

The US CDC study goes on to conclude that:

美国疾病控制与预防中心的研究得出结论:

"The infectivity of coronaviruses other than SARS-CoV are also affected by chloroquine,as exemplified by the human CoV-229E[15].The inhibitory effects observed on SARS-CoV infectivity and cell spread occurred in the presence of 1–10μM chloroquine,which are plasma concentrations achievable during the prophylaxis and treatment of malaria(varying from 1.6–12.5μM)[26]and hence are well tolerated by patients.Chloroquine,a relatively safe,effective and cheap drug used for treating many human diseases including malaria,amoebiasis and human immunodeficiency virus is effective in inhibiting the infection and spread of SARS CoV in cell culture."

" sars 冠状病毒外,冠状病毒的传染性也受到氯喹的影响,例如人类的 CoV-229E[15]。观察到的对 SARS-CoV 感染和细胞传播的抑制作用发生在1-10m 氯喹的存在下,这是疟疾预防和治疗期间可达到的血浆浓度(1.6-12.5 m)[26],因此患者耐受性良好。氯喹是一种相对安全、有效和廉价的药物,用于治疗包括疟疾、阿米巴病和人类免疫缺陷病毒在内的许多人类疾病,它能有效地抑制细胞培养中 SARS CoV 的感染和传播。"

COVID-19 and Chloroquine:Mechanisms of Action[12]

Covid-19和氯喹:作用机理[12]

COVID-19 in a single stranded,positive strain RNA virus with a protein shell and membrane.The genome is of the same sense of the mRNA.It goes through a lifecycle where incoming viral COVID genome has to become double stranded RNA and the new strand becomes the new strand for the new mRNA.There are significant similarities between COVID-19 and SARS coronavirus.Both COVID-19 and SARS-like coronaviruses have machinery for regulating their own replication and production of their proteins.Coronavirus depends on the breakdown of macromolecules such as proteins.Specifically,the virus depends on turning over the host proteins to trigger response for available building blocks to make their own proteins or nucleic acids.They break down due to low PH catalyzed by hydrolysis.Additionally,coronaviruses have non-structural proteins that are not part of the capsid(protein shell of the virus).These non-structural proteins are regulatory proteins that take over the host cell and suppress the immune system of the host(similar to HIV).Coronavirus can create growth factor like mechanisms(e.g.cytokines)to optimize the growth environment in the cell to favor it.

Covid-19在一个单链,阳性菌株 RNA 病毒的蛋白质外壳和膜。基因组与信使核糖核酸具有相同的意义。它经历了一个病毒输入的 COVID 基因组成为双链 RNA 的生命周期,而新链成为新 mRNA 的新链。Covid-19 SARS 冠状病毒有显著的相似性。Covid-19 sars 样冠状病毒都具有调节自身蛋白质复制和生产的机制。冠状病毒取决于蛋白质等大分子的分解。具体来说,病毒依赖于翻转宿主蛋白质来触发可用的构建模块的反应,从而制造自己的蛋白质或核酸。由于水解作用的催化剂 PH 值较低,它们会分解。此外,冠状病毒具有不属于衣壳(病毒的蛋白外壳)的非结构蛋白。这些非结构性蛋白质是调节蛋白,它们接管宿主细胞并抑制宿主的免疫系统(类似于艾滋病毒)。冠状病毒可以产生类似生长因子的机制(例如细胞因子)来优化细胞内的生长环境以利于生长因子的产生。

It is this part of the coronavirus'replicative path that chloroquine inhibits.Notably,because of its nitrogen structure,chloroquine has the unique ability to get into cells and cross endosomal membranes.Once inside,nitrogens in chloroquine(and quinines in general)prevent acidification by absorbing a high amount of hydrogens that simply then interact with nitrogen and then chloroquine becomes positively charged-an ionic interaction which makes it harder for the endosome to become acidified.The result is a buffer that holds it at the higher pH and prevents it from becoming acidic enough to be functional.To summarize,because chloroquine has a multitude of extra nitrogens,once it crosses the membrane and enters an organelle,the organelle is prevented from reaching a lower pH.The organelle's enzymes cannot work because the donor group will be a hydrogen ion,disabling the hydrolysis required for coronavirus replication.This means that all kinds of events in the cell are incapable of performing optimally,including viral replication.

正是这部分冠状病毒的复制途径被氯喹抑制。值得注意的是,由于其氮结构,氯喹具有进入细胞和跨内涵体膜的独特能力。氯喹中的亚硝基(一般是奎宁)通过吸收大量的氢来防止酸化,这些氢只是与氮相互作用,然后氯喹就带正电荷——这种离子相互作用使内胚体更难酸化。其结果是形成一种缓冲液,使其保持在较高的 pH 值,并防止其变得足够酸性以发挥功能。总而言之,由于氯喹含有大量多余的亚硝基,一旦它穿过细胞膜进入细胞器,细胞器就无法达到较低的 ph 值。这意味着细胞中的所有事件都无法达到最佳状态,包括病毒复制。

Chloroquine's entrance into the organelle likely constipates the whole system.An analogy is that the virus is like a garbage facility which has to break down and burn up the garbage and if it cannot,the garbage piles up and the city becomes paralyzed.This is likely the case for any virus,cancer cells or any other condition that is dependent on turning over the worn out or incorrectly synthesized proteins.

氯喹进入细胞器后可能导致整个系统便秘。一个类比是,病毒就像一个垃圾设施,它必须分解和焚烧垃圾,如果它不能,垃圾堆积起来,城市瘫痪。这可能是任何病毒,癌细胞或任何其他条件,是依赖于翻转磨损或不正确合成的蛋白质。

The UK has banned the export of Chloroquine[13]

英国已经禁止出口氯喹[13]

As of February 26,2020,the UK government has added chloroquine to the list of medicines that cannot be parallel exported from the UK.Chloroquine was never on this list before.This likely happened because of the growing body of evidence of chloroquine's effectiveness against coronavirus.

截至2020226日,英国政府已将氯喹列入不能从英国平行出口的药物名单。氯喹以前从未出现在这个名单上。这可能是因为越来越多的证据表明氯喹对冠状病毒有效。

China prioritizes internal use of Active Pharmaceutical Ingredients(APIs)including Chloroquine[14]

中国优先使用包括氯喹在内的国内有效药物成分(api)

In early February,Chongqing Kangle Pharmaceutical was requested by the Ministry of Industry and Information Technology,Consumption Division to promptly increase the manufacturing and production of the active pharmaceutical ingredients chloroquine phosphate despite slowed production during the Chinese New Year.

2月初,重庆康乐制药有限公司应工业和信息化部消费司的要求,尽管农历新年期间磷酸氯喹的生产放缓,但仍迅速增加了有效药物成分的生产和生产。

Key Risks and Tradeoffs

主要风险与权衡

There has been massive de-stabilization of society due to COVID-19.

由于 COVID-19,社会出现了大规模的去稳定化。

Mutations[15]

突变[15]

RNA viruses are subject to fairly high mutation rates as RNA based genomes do not copy themselves faithfully,thereby accumulating mutations quickly which can lead to failure of the virus(analogy:unaudited software code will often eventually fail due to a critical error)or can lead to a stronger mutation-which is likely what has happened in 2020(when coronavirus"jumped"from animal to human;it is doubtful that this has occurred because of the use of chloroquine)as we have have two forms of COVID-19("more aggressive"and"less aggressive").If the replication quality of RNA virus like coronavirus can be destabilized this will likely cause it to self destruct,but there is always the risk that the virus mutates to become more aggressive.

Rna 病毒的突变率相当高,因为基于 RNA 的基因组不能忠实地复制自己,从而迅速积累突变,这可能导致病毒失败(类比:未经审计的软件代码通常最终会因一个严重错误而失败),或者可能导致更强的突变——这很可能就是2020年发生的情况(当时冠状病毒从动物"跳跃"到人类;这种情况是否发生是因为使用了氯喹),因为我们有两种形式的 COVID-19("更具侵略性""更不具侵略性")。如果 RNA 病毒的复制质量像冠状病毒可以不稳定,这将有可能导致它自毁,但总是有风险,病毒变异变得更具攻击性。

Treating COVID-19 with chloroquine,as is being done in South Korea and China does have the potential to lead to a mutation.The mutation can either be beneficial or harmful to humans.In this particular case,chloroquine is likely being used to destabilize the replication quality of COVID-19,providing significant potential for COVID-19 to self-destruct,which would likely bide more time for health systems worldwide to increase capacity and equipment as well as allow time for the public release of a vaccine.All precaution must be taken into account for the risk of escape where COVID-19 comes out stronger.

用氯喹治疗 COVID-19,就像韩国和中国正在做的那样,确实有可能导致突变。这种突变可能对人类有益,也可能有害。在这种特殊情况下,氯喹很可能被用来破坏 COVID-19的复制质量,为 COVID-19的自毁提供了巨大的可能性,这可能使世界各地的卫生系统有更多的时间来增加能力和设备,并为公开发放疫苗留出时间。所有的预防措施必须考虑到逃跑的风险,COVID-19出来更强。

Manufacturing

制造业

Chloroquine and its analogs has been manufactured and distributed at global scale since approximately 1945.While there has recently been a shortage of N95 protective masks,medical systems can adjust and dramatically increase the supply of chloroquine in the world.Chloroquine tablets and intravenous formulations are generic and easy to produce.

氯喹及其类似物自1945年左右开始在全球范围内生产和分布。虽然最近 N95防护口罩短缺,但医疗系统可以调整并大幅度增加世界上氯喹的供应。氯喹片剂和静脉配方是通用的,易于生产。

Safety[16]

安全[16]

Chloroquine is a prescription drug.It can have side effects and has contraindications.One often cited side effect is chloroquine retinopathy,which can result in permanent vision loss after high cumulative doses of chloroquine.However,retinal damage is extremely rare in patients with a total dosage under 400g(dosage level only reached after years of treatment).Medical professionals must be consulted before use of chloroquine.Chloroquine tablets are readily available in the U.S.and have never been removed from the market.Intravenous chloroquine was taken off the market in the USA pre-2000 because of the absence of acute malarial infections in the USA-there was no use for the intravenous form.It can easily be brought back to the market.

氯喹是一种处方药。它可能有副作用和禁忌症。一个经常提到的副作用是氯喹视网膜病变,它可以导致永久性失明后,高累积剂量氯喹。然而,视网膜损伤是极其罕见的患者的总剂量低于400(剂量水平只达到后多年的治疗)。在使用氯喹之前必须咨询医务人员。氯喹药片在美国很容易买到,而且从未从市场上撤下。由于美国没有出现急性疟疾感染,氯喹静脉注射在2000年前就已经停止在美国市场上销售——这种静脉注射剂没有任何用处。它可以很容易地被带回市场。

Formulation Optimizations[17]

Tablet vs.Intravenous

Currently chloroquine is most widely administered in tablet form(chloroquine phosphate.While readily available,the issue is that when the tablet is ingested,it must be processed through the stomach and be taken up by the small intestine,for which then it enters the blood and subsequently the respiratory system.Because of the metabolism,this takes time and there is a loss of chloroquine delivery to the respiratory system(where COVID-19 replicates).

目前氯喹是最广泛使用的片剂形式(磷酸氯喹。虽然药物很容易获得,但问题是当药片被摄取时,它必须通过胃进行处理,然后被小肠吸收,为此它进入血液,随后进入唿吸系统。由于新陈代谢的关系,这需要时间,而且氯喹的输送会流失到唿吸系统(COVID-19在那里复制)

When chloroquine is used intravenously against malaria(chloroquine hydrochloride),it is being mainlined directly into the blood stream so that it is distributing around the body within seconds,likely encountering the virus faster and at a higher concentration in the respiratory system.Intravenous formulations are readily available and should be studied accordingly.

当氯喹通过静脉注射用于治疗疟疾(盐酸氯喹)时,它会直接注入血液中,以便在几秒钟内分布于人体各处,很可能在唿吸系统中遇到病毒的速度更快,浓度也更高。静脉注射配方很容易获得,应相应地加以研究。

Further research should be carried out using chloroquine in nanoparticles and various fast,slow and sustained released formulations,as well as combinations of chloroquine and other molecules.

进一步的研究应该使用氯喹的纳米粒子和各种快速,缓慢和持续释放的配方,以及氯喹和其他分子的组合。

Repurposing other FDA approved drugs

As per Steve Schow PhD,Professor of Chemical and Systems Biology at Stanford University School of Medicine and Lead Advisor to Stanford's SPARK Translational Research Program:

斯坦福大学医学院化学与系统生物学教授、斯坦福大学 SPARK 转化研究项目首席顾问 Steve Schow 博士表示:

"There are a number of related isoquinoline and quinoline drug family members who might exhibit the same general acid neutralizing effects.In addition certain antidepressants and antipsychotic drugs are known to accumulate in lysosomes via this acid-base process and might be effective here if the doses needed aren't too high."[18]

"有许多相关的异喹啉和喹啉药物家族成员可能表现出相同的一般酸中和作用。此外,已知某些抗抑郁药和抗精神病药物通过这种酸碱过程在溶酶体中积累,如果所需剂量不太高,可能在这里有效。"[18]

New Molecular Entity:Chloroquine analogs with more nitrogens

新分子实体:含更多亚硝基的氯喹类似物

The nitrogens in chloroquine and quinines in general prevent acidification by absorbing a high amount of hydrogens that then interact with nitrogen,and,in turn,transfer a positive charge to chloroquine.This ionic interaction makes it harder and harder for the endosome to become acidified,therefore disrupting viral replication.If more nitrogens are added,either by making extra branches of ionizable nitrogens or lengthening one of the chains by putting extra carbons and other nitrogens around it,this may have even greater effect.The key issue will be whether there is a heavy change in bioavailability-will the new molecule be able to enter the cell and reach the right place with similar efficiency.

氯喹和奎宁中的亚硝基通常通过吸收大量的氢来防止酸化,这些氢随后与氮相互作用,并反过来将正电荷转移到氯喹上。这种离子相互作用使内胚体越来越难酸化,因此破坏了病毒的复制。如果加入更多的氮原子,或者通过制造更多的离子化氮原子的分支,或者通过在其周围放置更多的碳和其他氮原子来延长其中一个分支,这可能会产生更大的影响。关键问题是生物利用度是否会发生重大变化——新分子能否以类似的效率进入细胞并到达正确的位置。

Conclusion

Chloroquine can both both prevent and treat malaria.Chloroquine can prevent and treat coronavirus in primate cells(Figure 1 and Figure 2).According to South Korean and China human treatment guidelines,chloroquine is effective in treating COVID-19.Given chloroquine's human safety profile and existence,it can be implemented today in the U.S.,Europe and the rest of the world.Medical doctors may be reluctant to prescribe chloroquine to treat COVID-19 since it is not FDA approved for this use.The United States of America and other countries should immediately authorize and indemnify medical doctors for prescribing chloroquine to treat COVID-19.We must explore whether chloroquine can safely serve as a preventative measure prior to infection of COVID-19 to stop further spread of this highly contagious virus.

氯喹既可以预防疟疾,也可以治疗疟疾。氯喹可以预防和治疗灵长类动物细胞中的冠状病毒(1和图2)。根据韩国和中国的人体治疗指南,氯喹对 COVID-19有效。考虑到氯喹的人体安全状况和存在,它今天可以在美国、欧洲和世界其他地方实施。医生可能不愿意开氯喹治疗 COVID-19,因为它没有得到 FDA 的批准。美利坚合众国和其他国家应立即授权和赔偿开氯喹治疗 COVID-19的医生。我们必须探索氯喹是否可以安全地作为感染 COVID-19之前的预防措施,以阻止这种高度传染性病毒的进一步传播。

More Sources

Griffero-Diaz's F.,Hoschander SA,Brojatsch J.Endocytosis IS A Critical entry in STEP B of subgroup Avian leukosis viruses[J].J Virology,2003,76(24):12866-12876.The DOI: 10.1128/jvi.76.24.12866-12876.2002.

格里菲罗-迪亚兹的 f。内吞作用是禽白血病病毒亚群 STEP b 的关键入口[j]J Virology2003,76(24):12866-12876.Doi:10.1128/jvi.76.24.12866-12876.2002.

Rodrigo D,Luiza H,Paula P,et al.Chloroquine,an Endocytosis Blocking Agent,Inhibits Zika Virus Infection in Different Cell Models[J].Viruses,2016,8(12):322-.DOI: 10.3390/v8120322.

罗德里戈·dLuiza hPaula p,等。内吞阻断剂氯喹抑制不同细胞模型中的兹卡热。病毒,2016,8(12):322-Doi:10.3390/v8120322.

Zhang S,Yi C,of Li C,et Al.Chloroquine inhibits the endosomal Viral an RNA Release and autophagy in-dependent Viral Replication and Effectively Prevents CARE OF to Fetal Transmission of Zika Virus.[J]Antiviral Res.2019;169:104 547.The DOI: 10.1016/j.antiviral.2019.104547

s,易 c,李 c,等。氯喹抑制内涵体病毒 RNA 释放和自噬依赖性病毒复制并有效预防寨卡病毒对胎儿的传播。2019;169:104547.Doi:10.1016/j.antiviral.2019.104547

Kono M,Tatsumi K,Imai AM,et al.Inhibition of human coronavirus 229E infection in human epithelial lung cells(L132)by chloroquine:involvement of p38 MAPK and ERK[J].Antiviral Res,2008,77(2):150-152.DOI: 10.1016/j.antiviral.2007.10.011.

河野,Tatsumi kImai AM 等。氯喹对人肺上皮细胞(L132)感染人冠状病毒229E 的抑制作用:p38 MAPK ERK 参与[j]。抗病毒药物,2008,77(2):150-152Doi:10.1016/j.antiviral.2007.10.011.

Didier Raoult,et.al.,Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 International Journal of Antimicrobial Agents

等,氯喹和羟氯喹是对抗 COVID-19国际抗菌药物杂志的有效武器

Available online 4 March 2020,https://www.sciencedirect.com/science/article/pii/S0924857920300820?via%3Dihub#!

202034日可在网上查阅,https://www.sciencedirect.com/science/article/pii/s0924857920300820?via%3dihub#

Next Steps from the Community

社区的下一步计划

1.Disseminate this publication amongst the medical community.Get more feedback.

在医学界传播这个出版物,获得更多的反馈

2.Send this publication to your scientific contacts in South Korea and China-lets get more data,details,etc.Science never ends.

把这份出版物发给你在韩国和中国的科学联系人——让我们获得更多的数据、细节等等。科学永无止境

3.Translate this paper into all languages.

把这篇论文翻译成各种语言

4.Explore all options for use of chloroquine against any medical condition that depends on the turnover of worn out or incorrectly synthesized proteins.

探索使用氯喹的所有选择,以应对任何医疗条件,这取决于磨损或不正确合成的蛋白质的更替

Acknowledgements

鸣谢

Special thanks to Stanford University School of Medicine,SPARK Translational Research Program,Steve Schow,PhD,The Lab of Louise T.Chow,PhD and Thomas R.Broker,PhD,Bruce Bloom DDS,JD of HealX and Adrian Bye.

特别感谢斯坦福大学医学院,SPARK 转化研究项目,Steve SchowPhDThe Lab of Louise t.ChowPhD and Thomas r.BrokerPhDBruce Bloom DDSJD of HealX and Adrian Bye

License

许可证

Due to urgency,certain parts of this publication are taken directly from their attributed source.Cite them accordingly.

由于情况紧急,本出版物的某些部分直接取自其来源。相应地引用它们。

In all other circumstances,the GNU General Public License v3.0 applies.

在所有其他情况下,GNU通用公共许可协议版本3.0都适用。

Disclaimer

免责声明

This paper is for information purposes only.The authors and or its affiliates does not guarantee the accuracy of or the conclusions reached in this white paper,and this white paper is provided"as is".The authors and or its affiliates not make and expressly disclaims all representations and warranties,express,implied,statutory or otherwise,whatsoever,including,but not limited to:(i)warranties of merchantability,fitness for a particular purpose,suitability,usage,title or noninfringement;(ii)that the contents of this white paper are free from error;and(iii)that such contents will not infringe third-party rights.The authors and or its affiliates shall have no liability for damages of any kind arising out of the use,reference to,or reliance on this white paper or any of the content contained herein,even if advised of the possibility of such damages.In no event will the authors and or its affiliates be liable to any person or entity for any damages,losses,liabilities,costs or expenses of any kind,whether direct or indirect,consequential,compensatory,incidental,actual,exemplary,punitive or special for the use of,reference to,or reliance on this white paper or any of the content contained herein,including,without limitation,any loss of business,revenues,profits,data,use,goodwill or other intangible losses.All translations are done voluntarily by third-parties for which the authors have no affiliation-we do not attest to their accuracy.

本文仅供参考。作者及其附属机构不能保证本白皮书的准确性或得出的结论,本白皮书是按原样提供的。作者及其附属机构不作出或明确否认所有明示、暗示、法定或其他形式的陈述和保证,包括但不限于:(i)保证适销性、适用于特定目的、适宜性、用途、所有权或不侵权;(ii)本白皮书的内容不会出错;以及(iii)这些内容不会侵犯第三方权利。对于因使用、提及或依赖本白皮书或本白皮书所载任何内容而造成的任何种类的损害,即使被告知可能造成这种损害,提交人及其附属机构也不承担任何赔偿责任。在任何情况下,作者及其附属机构均不对任何个人或实体因使用、参考或依据本白皮书或本白皮书所载任何内容,包括但不限于任何业务、收入、利润、数据、使用、商誉或其他无形损失的任何直接或间接、间接、补偿、附带、实际、示范、惩罚性或专门的任何种类的损害、损失、赔偿责任、成本或费用负责。所有的翻译都是由第三方自愿完成的,对此作者没有从属关系——我们不能证明其准确性。

Informational Purposes Only

仅供参考

一种有效治疗冠状病毒(COVID-19)的方法

[1] https://www.cnbc.com/video/2020/03/02/coronavirus-testing-emergency-room-doctor-cdc-department-health-squawk-box.html

[2] https://www.cdc.gov/malaria/resources/pdf/fsp/drugs/Chloroquine.pdf

[3] Vincent, Martin J et al. "Chloroquine is a potent inhibitor of SARS coronavirus infection and spread." Virology journal vol. 2 69. 22 Aug. 2005, doi:10.1186/1743-422X-2-69 ,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/#B15.  Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3:722–727. doi: 10.1016/S1473-3099(03)00806-5.

[4] http://www.koreabiomed.com/news/articleView.html?idxno=7428

[5] https://www.ncbi.nlm.nih.gov/pubmed/32075365/ ; http://www.nhc.gov.cn/yzygj/s7653p/202002/0293d017621941f6b2a4890035243730.shtml translated as https://www.chinalawtranslate.com/en/chloroquine-phosphate/ ; Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 7th Edition)

 translated as https://www.chinalawtranslate.com/en/coronavirus-treatment-plan-7/ ; https://www.clinicaltrialsarena.com/news/coronavirus-covid-19-choroquine-data/ .

[6] https://www.clinicaltrialsarena.com/news/coronavirus-covid-19-choroquine-data/ .  This research must be confirmed and furthermore ruled out that the subjects that had negative viral nucleic acid tests might not have been infected with C-19.

[7] http://www.koreabiomed.com/news/articleView.html?idxno=7428

[8] Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 7th Edition)translated as https://www.chinalawtranslate.com/en/coronavirus-treatment-plan-7/

[9] https://www.ncbi.nlm.nih.gov/pubmed/32075365/ Guangdong Provincial Science and Technology Department and Guangdong Provincial Health and Health Commission's Multicenter Collaboration Group on Chloroquine Phosphate for New Coronavirus Pneumonia. Expert Consensus on Chloroquine Phosphate for New Coronavirus Pneumonia [J / OL]. Chinese Journal of Tuberculosis and Respiratory Medicine, 2020,43 (2020-02-20) .http: //rs.yiigle.com/yufabiao/1182323.htm.

[10] US CDC, Vincent MJ , Bergeron E , Benjannet S , et Al .Chloroquine IS A potent inhibitor of SARS coronavirus Infection and Spread of[J].Virology Journal,2005,2(. 1):69.The DOI: 10.1186 / 1743-422X-2-69 . Keyaerts E , Vijgen L , Maes P , et Al .The In Journal Severe acute Inhibition of Respiratory syndrome coronavirus by chloroquine[J].Biochem Biophys Res Communications,2004,323(. 1):0-268.The DOI:  10.1016 / j.bbrc .2004.08.085 .  

[11] All research from this section is from: US CDC, Vincent MJ , Bergeron E , Benjannet S , et Al .Chloroquine IS A potent inhibitor of SARS coronavirus Infection and Spread of[J].Virology Journal,2005,2(. 1):69.The DOI: 10.1186 / 1743-422X-2-69 

[12] All research from this section is from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147684/ , https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1182-0#citeas ,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/#B15 , https://www.nature.com/articles/s41422-020-0282-0 , Thomas R. Broker, PhD, Stanford University School of Medicine, Telephone discussion March 12, 2020 , https://www.sciencealert.com/genetic-analysis-shows-wuhan-coronavirus-is-similar-to-sars .

[13] https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/872567/medicines_that_cannot_be_parallel_exported_from_the_uk_13_march_2020.csv/preview

[14] http://doc.irasia.com/listco/hk/tfkf/announcement/a224851-e_01312ann_20200203(20200203_1952).pdf

[15] All information in this section is from: https://www.sciencealert.com/genetic-analysis-shows-wuhan-coronavirus-is-similar-to-sars , https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147684/ ,https://virologyj.biomedcentral.com/articles/10.1186/s12985-019-1182-0#citeas , Thomas R. Broker, PhD, Stanford University School of Medicine, Telephone discussion March 12, 2020.

[16] https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/006002s044lbl.pdf , https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=006002 ,https://www.cdc.gov/malaria/resources/pdf/fsp/drugs/Chloroquine.pdf

[17] See Safety citations.

[18] Steve Schow PhDhttps://sparkmed.stanford.edu/about-spark/who-we-are/ .  Email correspondence March 2020

来源:https://docs.google.com/document/d/e/2PACX-1vTi-g18ftNZUMRAj2SwRPodtscFio7bJ7GdNgbJAGbdfF67WuRJB3ZsidgpidB2eocFHAVjIL-7deJ7/pub

zhunbeizhuanbian
  • 本文由 发表于 2020年3月20日13:35:52
  • 除非特殊声明,本站文章均来自网络,转载请务必保留本文链接