31 mars 2020
Par Pierre-Jacques Raybaud- Docteur, médecin généraliste et CES Immunologie de recherche en biologie humaine- ARTICLE ORIGINAL.
Cet article se propose d’analyser la physiopathologie, les constats cliniques et biologiques et d’en tirer une conclusion thérapeutique.
Actuellement, la seule proposition concrète de traitement, en dehors des traitements symptomatiques, semble être celle du Pr Raoult. Son concept, fondé sur le constat d’une activité anti-virale et immuno-suppressive de l’Hydroxychloroquine, consiste à utiliser une molécule que l’on connait bien, et peu chère pour un traitement mondial le cas échéant, comparée aux anti-viraux. De nombreux anti-viraux ont été testés en Chine notamment avec des résultats mitigés selon les molécules.
Physiopathologie
Le COVID-19 a la particularité de déclencher une réponse immunitaire très forte, et d’activer tous les médiateurs cellulaires et biochimiques de l’inflammation ainsi que d’activer toute la chaîne de la coagulation. On assiste ainsi à l’apparition d’un œdème alvéolaire et interstitiel énorme, altérant très fortement la barrière alvéolo-capillaire. On observe aussi une élévation des D-dimères, marqueur majeur de la formation de thrombose, dans les formes bénignes ou débutantes et une très forte élévation dans les formes graves avec détresse respiratoire.
Son tropisme de prédilection est l’épithélium respiratoire. Par voie sanguine, il diffuse dans l’organisme et peut affecter plusieurs tissus en altérant par exemple les récepteurs neurologiques de l’odorat ou du goût, entraînant anosmie et dysgueusie, mais aussi céphalée. On le retrouve dans le liquide céphalo-rachidien (LCR), dans les muscles entraînant des myalgies et courbatures ou encore, dans l’intestin, avec des diarrhées possibles - on le retrouve aussi dans les selles.
Causes de mortalité du COVID-19
Il y a bien sûr les décompensations de pathologies pré-existantes: diabète, insuffisance cardiaque, hypertension artérielle, déficits immunitaires, insuffisances polyviscérales, susceptibles de basculer en phase d’hypoxie majeure et lors de l’utilisation délicates des drogues de réanimation, pour ajuster les fondamentaux de l’homéostasie.
Il y a les surinfection bactériennes, estimées à environ 10% dans les formes mineures et 30% à 40 %, selon les sources., en réanimation.
Il y a surtout les embolies pulmonaires, estimées entre 25% et 45%, les infarctus myocardiques et les AVC possibles par cette hypercoagulabilité.
De même, une proportion de l’ordre de 15% à 25% de myocardite virale, avec troubles du rythme, ACFA, FV et TDP torsade de pointe et / ou insuffisance cardiaque.
Proposition d’une trithérapie : anticoagulante, corticoïde et antibiotique / anti-viral proche de l’Hydroxychloroquine sans les inconvénients cardiaques.
- Les anticoagulants :
Il existe, pour l’essentiel, en ville, beaucoup de formes bénignes de l’infection par Covid-19.
Cependant, dès les premiers signes d’aggravation, il est important de connaitre le niveau des D-Dimères entre autres, qui, par leur élévation au-dessus de 0,6, annonce un processus d’hypercoagulabilité.
Il est capital de repérer le J1, premier jour des signes et de conseiller de faire un bilan biologique, en cas d’aggravation entre J5 et J1O. La dyspnée et la SatO2 en ville sont de bons repères. À l’approche des 90 et en-dessous, il parait souhaitable de déclencher l’analyse. Il semble logique de prescrire une HBPM à dose préventive à ce stade, Lovenox 0,4ml/j 14j ou un anticoagulant oral Xarelto 10mg/j ou Eliquis 5mg/j pour 14j, et il y en a d’autres, selon les antécédents et analyse des contre-indications des patients.
Cas du patient arrivé en réa : Outre les drogues habituelles des fondamentaux de l’homéostasie, les doses seront augmentées à l’appréciation des réanimateurs.
À ce stade, en hypoxie, chez des patients ventilés, ce processus entraine des micro-embolies diffuses, voir massives. La mortalité par EP est en moyenne de 35%. Il est donc légitime de durcir le traitement et d’ajouter, le cas échéant, des inhibiteurs des protéases à sérine comme le Camostat ou mieux le Nafamostat au Japon (Yamamoto- Mers-2016), dont on connait à la fois les propriétés anti-coagulantes mais aussi anti-virales par l’inhibition transmembranaire , notamment du gène TMPRSS2, qui est activé par le Sars-Cov 1 de 2003 ou le COVID-19 maintenant.
- Les corticoïdes :
Il s’agit d’un traitement à la fois anti-inflammatoire puissant, anti-oedémateux et aussi immunosuppresseur, pour restaurer la barrière alvéolo-capillaire. Il est très important et capital de les éviter de J1 à J7.
En revanche, ils constituent une molécule facile et bien connue à l’usage. L’étude chinoise de Shang montre, sur 401 cas de COVID-19, une réduction de mortalité de 38% à la dose de 0,5mg/kg à 1 mg/kg pendant au moins 7j. Il semble logique, autant que faire se peut, d’attendre le début de la montée des anticorps vers J14, afin d’éviter de la freiner, pour démarrer le traitement.
- La Doxycycline :
Il faut saluer l’initiative du Pr Raoult, de l’IHU de Marseille, d’avoir proposé un premier traitement avec un médicament peu onéreux et dont il avait lui-même prouvé l’action anti-virale in vitro. Il semble que, sur une faible cohorte, puis confirmée par une autre étude chinoise sur 10 personnes, l’Hydroxychloroquine (HCQ) soit efficace. Attendons les résultats de ses études, et plus tard les études en double aveugle contre placebo. On ne peut contester son protocole devant l’urgence de la situation, et le drame qui se joue pour la population mondiale.
Cependant, et on peut le comprendre, à une dose de 500mg/j, les réanimateurs peuvent craindre le risque accru de troubles du rythme et notamment la TDP, de l’HCQ, a fortiori, en situation d’hypoxie, signalé d’ailleurs par le groupe pharmaceutique qui les commercialise.
Dans son deuxième protocole, l’association HCQ+Azithromycine est encore plus problématique pour la toxicité cardiaque.
Attention, outre son risque accru de troubles du rythme en détresse respiratoire, ce macrolide, l’azithromycine seule, pourtant efficace sur les bactéries, inventé par les croates en 1980, n’a pas montré de réduction de la mortalité sur le MERS, le coronavirus de 2012 ( 3) lors d’une étude portant sur 349 patients. Pour autant, l’azitrhomycine est couramment utilisée pour des infections respiratoires sans problème , en dehors de quelques rares cas et des conditions délicates de la réa.
Le risque de TDP semble encore plus élevé avec l’association HCQ+Azithromycine en terrain fortement hypoxique qui est potentialisatrice dans ce sens.
Tout dépendra du mode de sélection des patients et de leur stade.
Quand un patient présente des effets secondaires à L’HCQ (Plaquenil) ou à la Chloroquine sulfate (Nivaquine), ou encore une intolérance à la Malarone, pour une prévention anti-paludéenne, il reste le choix de la Doxycycline.
Cet antibiotique, de la famille, des cyclines, bien connu et peu onéreux aussi, a également une action anti-virale et même anti-inflammatoire. Il a de plus, le gros avantage de ne pas avoir d’effet sur l’allongement de QT et donc de ne pas déclencher ou d’aggraver les troubles du rythme chez des patients fragilisés par l’hypoxie, les micro-embolies, et l’atteinte du myocarde et du tissu de conduction. En outre, il existe 10% de surinfections bactériennes dans les formes moyennes et 35%, voire plus, en réanimation: son action antibiotique est donc salutaire, même si en réa, on le sait, il existe beaucoup de souches résistantes, nécessitant souvent des antibiotiques de dernière génération.
- L’utilisation d’anti-viraux spécifiques comme le Favipiravir (Avigan), Remdevisir ou encore le Lopinavir associé au Ritonavir ( Kaletra) semble donner aussi beaucoup d’espoir, mais sont beaucoup plus chers, et ils peuvent aussi avoir une toxicité sur les cardiomyopathies comme la myocardite provoquée par le COVID-19 avec des blocs auriculo-ventriculaires.
Au final,
Il conviendrait en ville de ne prescrire que Paracétamol, au début, associé à deux inhalations d’air chaud humide au-dessus de 56 degrés de 6mn, selon le protocole précis détaillé dans le premier article de Mediapart ( https://blogs.mediapart.fr/pierre-jacques-raybaud/blog/020320/coronavirus-recommandations-et-inhalation)
et aucun AINS ni corticoïdes les 7 premiers jours.
Se discute à ce stade, le choix de donner tout de suite ou pas un anti-viral car il agit dans les 4 premiers jours surtout, mais moins après, ou d’attendre. Car en effet, primum non nocere, 99% des cas n’évolue pas vers une forme très grave.
Et en cas d’aggravation de prescrire :
-Un bilan biologique avec le dosage des D-Dimères.
-Puis, de surveiller entre autres la Sat02.
-Enfin, selon l’appréciation du médecin prescripteur et après avoir pris connaissance des antécédents et contre-indications du patient :
- prescrire des HBPM ou Rivaroxan (Xarelto) per os 10mg par jour, ou Apixaban (Eliquis) 5mg par jour pour la prévention des EP, TVP et ETEV, et il y en a d’autres.
- prescrire de la Doxycycline 2 fois 100mg par jour pour un adulte de plus de 60kg pour 14 jours. En revanche, si c’est pour une utilisation anti-virale, comme tous les antiviraux, c’est la précocité de mise en œuvre du traitement qui compte.
- prescrire un corticoïde, Cortancyl par exemple, après le septième jour à la dose de 20 à 25mg par jour pour une personne de 50 à 60kg, pendant 7 jours, avec un spray local de béclométhasone ( Bécotide) ou avec broncho-dilatateur associé si présence de bronchospasme (Sérétide par ex, ou ajout de salbutamol si pas de contre-indication.
- évacuer le patient aux urgences sous oxygène 4l/mn, si satO2 inférieure à 85 et /ou dyspnée mal tolérée.
En Réa ou USI :
Seront discutés, outre le contrôle polyviscéral classique, la majoration du traitement anticoagulant, le niveau de la corticothérapie générale et locale ( Béclomethasone par exemple), l’adjonction des inhibiteurs de protéases à sérine, la dose de Doxycycline ou de l’HCQ, l’adjonction d’anti-viraux spécifiques.
Cette proposition thérapeutique, en âme et conscience, est destinée aux professionnels de santé, en respectant notre déontologie. Tout doit rester sous le contrôle d’un médecin et en aucun cas, il ne doit y avoir auto-médication. J’insiste sur ce point.
L’objectif est de proposer des études sur ce nouveau traitement par trithérapie séquentielle, logique scientifiquement.
Dr. Pierre-Jacques RAYBAUD
Bibliographie :
1 --Sci China Life Sci. 2019 Feb;62(2):187-202. doi: 10.1007/s11427-018-9385-3. Epub 2018 Dec3.
Chinese society of cardiology expert consensus statement on the diagnosis and treatment of adult fulminant myocarditis.
Wang D1, Li S2, Jiang J2, Yan J2, Zhao C2, Wang Y2, Ma Y2, Zeng H2, Guo X2, Wang H2, Tang J2, Zuo H2, Lin
L2, Cui G2; Section of Precision Medicine Group of Chinese Society of Cardiology; Editorial Board of Chinese Journal of Cardiology; Working Group of Adult Fulminant Myocarditis.Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China. dwwang@tjh.tjmu.edu.cn.Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College,Huazhong University of Science & Technology, Wuhan, 430030, China.
2 ---Lancet. 2020 Feb 29;395(10225):683-684. doi: 10.1016/S0140-6736(20)30361-5. Epub 2020 Feb 12.
On the use of corticosteroids for 2019-nCoV pneumonia.
Shang L1, Zhao J2, Hu Y3, Du R4, Cao B5.Beijing University of Chinese Medicine, Beijing, China; Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing 100029, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.Department of Pulmonary and Critical Care Medicine, The Central Hospital of Wuhan, Wuhan, China.Department of Pulmonary and Critical Care Medicine, Wuhan Pulmonary Hospital, Wuhan, China.Department of Pulmonary and Critical Care Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing 100029, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China; Department of Respiratory Medicine, Capital Medical University, Beijing, China; Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, China.
3 -- Int J Infect Dis. 2019 Apr;81:184-190. doi: 10.1016/j.ijid.2019.01.041. Epub 2019 Jan 25.
Macrolides in critically ill patients with Middle East Respiratory Syndrome.
Arabi YM1, Deeb AM2, Al-Hameed F3, Mandourah Y4, Almekhlafi GA5, Sindi AA6, Al-Omari A7, Shalhoub S8, Mady A9, Alraddadi B10, Almotairi A11, Al Khatib K12, Abdulmomen A13, Qushmaq I14, Solaiman O15, Al-Aithan AM16, Al-Raddadi R17, Ragab A18, Al Harthy A19, Kharaba A20, Jose J21, Dabbagh T22, Fowler RA23, Balkhy HH24, Merson L25, Hayden FG26; Saudi Critical Care Trials group.College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; Intensive Care Department, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia. Electronic address: arabi@ngha.med.sa.Research Office, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia. Electronic address: rn_a_deeb@hotmail.com.College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia; Department of Intensive Care, Ministry of the National Guard - Health Affairs, Jeddah, Saudi Arabia. Electronic address: Hameedf@ngha.med.sa.Department of Intensive Care Services, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Electronic address: Yasser.mandourah@me.com.Department of Intensive Care Services, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Electronic address: gmekhlafi@yahoo.com.Department of Anesthesia and Critical Care, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: ansindi@gmail.com.College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Intensive Care, Dr Sulaiman Al-Habib Group Hospitals, Riyadh, Saudi Arabia. Electronic address: dr_awad_ksa@yahoo.com.Department of Medicine, Division of Infectious Diseases, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia; Department of Medicine, Division of Infectious Diseases, University of Western Ontario, London, Canada. Electronic address: sarah.shalhoub@googlemail.com.Intensive Care Department, King Saud Medical City, Riyadh, Saudi Arabia; Department of Anesthesiology and Intensive Care, Tanta University Hospitals, Tanta, Egypt. Electronic address: afmady@hotmail.com.College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Medicine, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia. Electronic address: basemalraddadi@gmail.com.Department of Critical Care Medicine, King Fahad Medical City, Riyadh, Saudi Arabia. Electronic address: aalmotairi@kfmc.med.sa.Intensive Care Department, Al-Noor Specialist Hospital, Makkah, Saudi Arabia. Electronic address: kasimalkhatib@yahoo.com.Department of Critical Care Medicine, King Saud University, Riyadh, Saudi Arabia. Electronic address: aturk@ksu.edu.sa.Department of Medicine, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia. Electronic address: iqushmaq@kfshrc.edu.sa.King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Electronic address: omsmd@yahoo.com.Intensive Care Department, Ministry of the National Guard - Health Affairs, Al Ahsa, Saudi Arabia; King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Al Ahsa, Saudi Arabia. Electronic address: AithanA@ngha.med.sa.King Abdulaziz University, Department of Family and Community Medicine, Jeddah, Saudi Arabia. Electronic address: saudiresearcher@yahoo.com.Intensive Care Department, King Fahd Hospital, Jeddah, Saudi Arabia. Electronic address: ahmadragab63@hotmail.com.Intensive Care Department, King Saud Medical City, Riyadh, Saudi Arabia. Electronic address: a_almshal@hotmail.com.Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah Al-Monawarah, Saudi Arabia. Electronic aDepartment of Biostatistics and Bioinformatics, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia. Electronic address: joseje@ngha.med.sa.Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Department of Critical Care Medicine and Department of Medicine, Sunnybrook Hospital, Toronto, Ontario, Canada. Electronic address: rob.fowler@sunnybrook.ca.College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; Department of Infection Prevention and Control, Ministry of the National Guard - Health Affairs, Riyadh, Saudi Arabia. Electronic address: BalkhyH@ngha.med.sa.5International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), Infectious Diseases Data Observatory, Oxford University, Oxford, United Kingdom. Electronic address: laura.merson@ndm.ox.ac.uk.6International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States. Electronic address: fgh@virginia.edu.
4 --Lancet. 2020 Feb 15;395(10223):473-475. doi: 10.1016/S0140-6736(20)30317-2. Epub 2020 Feb 7.
Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
Russell CD1, Millar JE2, Baillie JK3.University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute Edinburgh, Edinburgh, UK.Genetics and Genomics, Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UKGenetics and Genomics, Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK.Electronic address: j.k.baillie@ed.ac.uk.
5 --Autoimmun Rev. 2020 Mar 20:102523. doi: 10.1016/j.autrev.2020.102523. [Epub ahead of print]
COVID-19 infection and rheumatoid arthritis: Faraway, so close!
Favalli EG1, Ingegnoli F2, De Lucia O3, Cincinelli G4, Cimaz R5, Caporali R2.Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy. Electronic address: enniofavalli@me.com.Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy; Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milano, Italy.Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy.Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milano, Italy.Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milano, Italy; Division of Pediatric Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy.
6 --JAMA Intern Med. 2020 Mar 13. doi: 10.1001/jamainternmed.2020.0994. [Epub ahead of print]
Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in PatientsWith Coronavirus Disease 2019 Pneumonia in Wuhan, China.
Wu C1,2,3, Chen X3, Cai Y2, Xia J4, Zhou X2, Xu S2, Huang H4, Zhang L4, Zhou X4, Du C1, Zhang Y3, Song J3, Wang S3, Chao Y3, Yang Z5, Xu J6, Zhou X7, Chen D8, Xiong W9, Xu L10, Zhou F1, Jiang J3, Bai C3,11, Zheng J12, Song Y1,3,11,13.Department of Pulmonary Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.Infection Division, Wuhan Jinyintan Hospital, Wuhan, China.Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.Tuberculosis and Respiratory Department, Wuhan Jinyintan Hospital, Wuhan, China.Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.Department of Infectious Diseases, Fengxian Guhua Hospital, Shanghai, China.Department of Pulmonary Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.Department of Respiratory Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.Department of Emergency Medicine, Shanghai Pudong New Area Gongli Hospital, Shanghai, China.Shanghai Respiratory Research Institute, Shanghai, China.Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
7 --Arch Virol. 2014 Apr;159(4):711-8. doi: 10.1007/s00705-013-1880-7. Epub 2013 Oct 19.
Inhibitory effect of doxycycline against dengue virus replication in vitro.
Rothan HA1, Mohamed Z, Paydar M, Rahman NA, Yusof R.Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia, rothan@um.edu.my.
8 --PLoS One. 2015 May 13;10(5):e0126360. doi: 10.1371/journal.pone.0126360. eCollection 2015.
A combination of doxycycline and ribavirin alleviated chikungunya infection.
Rothan HA1, Bahrani H1, Mohamed Z2, Teoh TC2, Shankar EM3, Rahman NA4, Yusof R1.Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.Institute of biological sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.Department of Medical Microbiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
9 --Zhao Y, Wang X, Li L, Li C.Can J Physiol Pharmacol. 2016 May;94(5):526-33. doi: 10.1139/cjpp-2015-0481. Epub 2016 Feb 25.
10 --Antimicrob Agents Chemother, 60 (11), 6532-6539 2016 Oct 21
Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay
Mizuki Yamamoto 1, Shutoku Matsuyama 2, Xiao Li 3, Makoto Takeda 2, Yasushi Kawaguchi 1 4, Jun-Ichiro Inoue 5 6, Zene Matsuda 5 31Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, People's Republic of China.4Division of Molecular Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.5Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan jun-i@ims.u-tokyo.ac.jp zmatsuda@ims.u-tokyo.ac.jp.6Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
11 --J-STAGE home BioScience Trends Volume 14 ( 2020) Issue 1
Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies
Jianjun Gao, Zhenxue Tian, Xu Yang
Jianjun GaoDepartment of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China.Zhenxue Tian
Department of pharmacy, qingdao municipal Hospia, Qingdao, China Xu Yang
12 --Int J Antimicrob Agents, 105933 2020 Mar 6
Arguments in Favour of Remdesivir for Treating SARS-CoV-2 Infections
Wen-Chien Ko 1, Jean-Marc Rolain 2, Nan-Yao Lee 1, Po-Lin Chen 1, Ching-Tai Huang 3, Ping-Ing Lee 4, Po-Ren Hsueh 5Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center for Infection Control and Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.Aix-Marseille Université, Institut de Recherche pour le Développement (IRD), Assistance 7 Publique-Hôpitaux de Marseille (AP-HM), MEPHI, 27 boulevard Jean Moulin, 13005 8 Marseille, France; IHU Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France.Department of Infectious Diseases, Chang Gung Memorial Hospital, Taoyuan, Taiwan.Department of Pediatrics, National Taiwan University Children's Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: hsporen@ntu.edu.tw.
13 --J Respir Crit Care Med, 197 (6), 757-767 2018 Mar 15
Corticosteroid Therapy for Critically Ill Patients With Middle East Respiratory Syndrome
Yaseen M Arabi 1 2, Yasser Mandourah 3, Fahad Al-Hameed 4, Anees A Sindi 5, Ghaleb A Almekhlafi 3, Mohamed A Hussein 6, Jesna Jose 6, Ruxandra Pinto 7, Awad Al-Omari 8 9, Ayman Kharaba 10 11, Abdullah Almotairi 12, Kasim Al Khatib 13, Basem Alraddadi 8 14, Sarah Shalhoub 15, Ahmed Abdulmomen 16, Ismael Qushmaq 14, Ahmed Mady 17 18, Othman Solaiman 19, Abdulsalam M Al-Aithan 20, Rajaa Al-Raddadi 21, Ahmed Ragab 22, Hanan H Balkhy 1 23, Abdulrahman Al Harthy 17, Ahmad M Deeb 24, Hanan Al Mutairi 24, Abdulaziz Al-Dawood 1 2, Laura Merson 25, Frederick G Hayden 25 26, Robert A Fowler 27 28
14 --Aging (Albany NY) 2020 Mar 30
COVID-19 and Chronological Aging: Senolytics and Other Anti-Aging Drugs for the Treatment or Prevention of Corona Virus Infection?
Camillo Sargiacomo 1, Federica Sotgia 1, Michael P Lisanti 1
Abstract : COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is ACE-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease.
15 --Drug Discov Ther. 2020;14(1):58-60. doi: 10.5582/ddt.2020.01012.
Discovering drugs to treat coronavirus disease 2019 (COVID-19)
Liying Dong Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong, China.Shasha Hu Department of Pathology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.ianjun Gao Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong, China
Abstract : The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.
16 --Int J Antimicrob Agents 30 (4), 297-308 Oct 2007
Recycling of Chloroquine and Its Hydroxyl Analogue to Face Bacterial, Fungal and Viral Infections in the 21st Century
Jean-Marc Rolain 1, Philippe Colson, Didier Raoult
Abstract :
Chloroquine (CQ) and its hydroxyl analogue hydroxychloroquine (HCQ) are weak bases with a half-century long use as antimalarial agents. Apart from this antimalarial activity, CQ and HCQ have gained interest in the field of other infectious diseases. One of the most interesting mechanisms of action is that CQ leads to alkalinisation of acid vesicles that inhibit the growth of several intracellular bacteria and fungi. The proof of concept of this effect was first used to restore intracellular pH allowing antibiotic efficacy for Coxiella burnetii, the agent of Q fever, and doxycycline plus HCQ is now the reference treatment for chronic Q fever. There is also strong evidence of a similar effect in vitro against Tropheryma whipplei, the agent of Whipple's disease, and a clinical trial is in progress. Other bacteria and fungi multiply in an acidic environment and encouraging in vitro data suggest that this concept may be generalised for all intracellular organisms that multiply in an acidic environment. For viruses, CQ led to inhibition of uncoating and/or alteration of post-translational modifications of newly synthesised proteins, especially inhibition of glycosylation. These effects have been well described in vitro for many viruses, with human immunodeficiency virus (HIV) being the most studied. Preliminary in vivo clinical trials suggest that CQ alone or in combination with antiretroviral drugs might represent an interesting way to treat HIV infection. In conclusion, our review re-emphasises the paradigm that activities mediated by lysosomotropic agents may offer an interesting weapon to face present and future infectious diseases worldwide.
Extract from this article :
« 5.2. Activity of HCQ/CQ on hepatitis viruses
In a recent study, Blanchard et al. [45] found that pre-treating target cells with CQ inhibited hepatitis C virus (HCV) clone JFH-1 propagation in cell culture, which suggests that HCV, like flaviviruses and pestiviruses, enters cells through clathrin-mediated endocytosis and fusion within an acidic endosomal compartment. CQ was also found to be active against hepatitis B virus (HBV) and duck HBV [43], [44], [123], contrasting with another study in which infection of human hepatocyte cultures with HBV was found to be unaffected by CQ [124]. Seven patients with histologically proven chronic active hepatitis B have been treated with 150–450 mg of CQ for a median of 12 months [125]. In all patients, alanine aminotransferase (ALT) returned to normal values and prothrombin time improved. Interestingly, ALT increased in three patients following inadvertent CQ withdrawal and returned to prior levels on re-administration. In four patients, a repeat liver biopsy 1 year later revealed inactive cirrhosis. Recently, an enhancement by CQ of human CD8+ T-cell cell response to HBV antigen has been observed [126]. Inhibition by CQ of hepatitis A virus (HAV) uncoating and replication has also been described [42], [60].
5.3. Toxicity and therapeutic range
A major advantage of CQ/HCQ is their limited and preventable toxicity. Long experience of the use of these drugs in the treatment of malaria has already demonstrated the safety of short-term administration to humans. Moreover, CQ/HCQ have been widely used for chronic administration in rheumatic diseases, chronic Q fever and for antimalarial prophylaxis for up to several years with only a low incidence of adverse effects even during pregnancy [114], [127], [128], [129]. The main adverse effect reported in long-term administration of these drugs was macular retinopathy due to the cumulative dose, which could be prevented with regular visual monitoring during the course of treatment [6], [130]. »
