COVID-19: PROPOSAL FOR A NEW TREATMENT AND PROTOCOL USING TRIPLE THERAPY

Given the extreme urgency of the current situation, this article is intended for health professionals, not for the general public. Mass media is however the quickest way, in the current context, to disseminate information to specialists and scientists, whom I would urge to initiate studies.

March 31, 2020

By Pierre-Jacques Raybaud - Doctor, General Practitioner, Post-Graduate Diploma in General Immunology, research in human biology. -  ORIGINAL ARTICLE.

The purpose of this article is to analyze the pathophysiology, clinical and biological findings and to reach a therapeutic conclusion.

 At present, the only concrete proposal for treatment, apart from symptomatic treatments, would seem to be that of Professor Raoult of the Faculty of Medicine of Aix-Marseille University in France. His concept, based on the anti-viral and immuno-suppressive activity of Hydroxychloroquine, consists in using a molecule that is well known and inexpensive, compared to anti-viral drugs, with a view to providing a worldwide treatment, if required. Numerous anti-virals have been tested in China, with mixed results depending on the molecule.

 Pathophysiology

 COVID-19 has the particularity of triggering a very strong immune response, activating all the cellular and biochemical mediators of inflammation as well as the entire coagulation chain. Thus, an enormous alveolar and interstitial edema appears, strongly altering the alveolar-capillary barrier. There is also an increase in D-dimer, a major marker of thrombosis formation, in benign or early forms, and a very strong increase in severe forms with respiratory distress.

 The COVID-19 tropism of choice is respiratory epithelium; it enters the body via the bloodstream and can affect several tissues by altering, for example, the neurological smell or taste receptors, causing anosmia and dysgeusia, but also headaches. It has been found in the cerebrospinal fluid (CSF), in the muscles causing myalgia and aches and pains, or in the intestine, with possible diarrhea. It can also be found in the stool.

 Causes of mortality from COVID-19

 We have, of course, decompensations of pre-existing pathologies: diabetes, heart failure, high blood pressure, immune deficiencies, polyvisceral insufficiencies, which are likely to fall into a phase of major hypoxia and during the difficult administration of resuscitation drugs, impacting homeostasis fundamentals.

 We have bacterial superinfections, estimated at about 10% for minor cases and 30% to 40%, depending on the source, for cases in resuscitation.

 Especially, we have pulmonary embolisms, estimated at between 25% and 45%, myocardial infarction and possibly strokes due to this hypercoagulability.

 Similarly, we note 15% to 25% viral myocarditis, with rhythm disorders, atrial fibrillation, ventricular fibrillation, TdP and/or heart failure.

 Proposal for a triple therapy: Anticoagulants, Corticosteroids and Antibiotics – An anti-viral similar to Hydroxychloroquine, but without the cardiac inconveniences.

 - Anticoagulants:

 Many mild forms of the COVID-19 infection have been observed, mainly under conditions of ambulatory care.

 However, as soon as the first signs of aggravation appear, one of the first things we need to know is the level of D-Dimer, which, if above 0.6, indicates hypercoagulability.

 It is essential to identify D1, the first day of signs of infection, and to recommend a biological examination in the event of aggravation between D5 and D10. Dyspnea and O2Sat, measured under conditions of ambulatory care, are good indicators; on falling to 90 or lower, we are of the opinion that the examination should be started. At this stage, we would consider it logical to prescribe LMWH at a preventive dose, Lovenox 0.4 ml/d 14d or an oral anticoagulant Xarelto 10 mg/d or Eliquis 5 mg/d for 14d, and there are others, depending on the patient's history and an analysis of contraindications.                                

 Case of a patient entering intensive care: In addition to the usual homeostasis drugs, the doses will be increased at the discretion of resuscitation unit personnel.

 At this stage, in hypoxia, with ventilated patients, this process leads to diffuse, or even massive, microembolisms. Mortality due to Pulmonary Embolism (PE) averages 35%. It is therefore justified to boost the treatment adding, if necessary, serine protease inhibitors such as Camostat or, even better, Nafamostat in Japan (Yamamoto-Mers-2016), whose anticoagulant and antiviral properties are known through transmembrane inhibition, particularly of the TMPRSS2 gene, which was activated by SARS-CoV-1 in 2003, and now, by COVID-19.

 - Corticosteroids:

 This is a powerful anti-inflammatory, anti-edematous and immunosuppressant treatment administered in other to restore the alveolar-capillary barrier. It is absolutely vital that Corticosteroids not be used from D1 to D7.

 The molecule has the advantage of being well-known and easy to use. The Chinese study of Shang showed, for 401 cases of COVID-19, a 38% reduction in mortality at a dose of between 0.5 mg/kg and 1 mg/kg for at least 7 days. To the extent that doing so is possible, we recommend, before starting the treatment to wait until about D14, so as not to interfere with the antibodies-formation process.

 - Doxycycline:

 The initiative taken by Professor Raoult, proposing a first treatment using an inexpensive drug whose anti-viral action he himself has proven in vitro, is to be commended. Tests run on a small cohort, later confirmed by another Chinese study on 10 people, would seem to show that Hydroxychloroquine (HCQ) is effective. Let us wait now for the results of his studies, and later the double-blind, placebo-controlled studies. We cannot however reasonably question his protocol given the urgency of the situation and the tragedy currently unfolding worldwide.

 However, and understandably, at a dose of 500 mg/d, resuscitation unit personnel may be concerned about the increased risk of rhythm disturbances, including TdP and necessarily HCQ, especially in hypoxic situations. In its second protocol, the HCQ+Azithromycin combination is even more problematic for cardiac toxicity.

Please note, in addition to its increased risk of rhythm disturbances in respiratory distress, this macrolide, azithromycin alone, however effective on bacteria, invented by the Croats in 1980, has not shown any reduction in mortality on MERS, coronavirus 2012 (3) in a study involving 349 patients.

.Moreover, the risk of TdP seems to be even higher, and the association HCQ+Azithromycin in highly hypoxic conditions acts as a potentiator.

 It will all depend on how patients are selected and on their stage of development.

 If a patient develops side effects to HCQ (Plaquenil) or Chloroquine sulfate (Nivaquine), or is intolerant to Malarone (malaria prevention), we still have the option of using Doxycycline.

 This antibiotic, of the cyclins family, well known and moreover inexpensive, also has an anti-viral and even anti-inflammatory action.  It also presents the great advantage of not having any effect on QT prolongation and therefore not triggering or aggravating rhythm disorders in patients weakened by hypoxia, microembolisms, and damage to the myocardium and conduction tissue. In addition, there are 10% of bacterial superinfections with moderate cases and 35% or more with cases in resuscitation: its antibiotic action is therefore beneficial, even though, under conditions of resuscitation, we do note many resistant strains, often requiring the latest generation of antibiotics.

 - The use of specific anti-virals such as Favipiravir ( Avigan), Remdevisir or Lopinavir also seems rather promising, but these are much more expensive, and they may also have toxicity on cardiomyopathies such as COVID-19-induced myocarditis with atrioventricular blocks.

 To resume:

 Under conditions of ambulatory care, only Paracetamol (Acetaminophen) should be prescribed at the beginning, combined with two inhalation sessions of humid hot air heated to above 56°C (133°F), each session lasting 6 minutes, using the protocol detailed in the first Mediapart article (https://blogs.mediapart.fr/pierre-jacques-raybaud/blog/020320/coronavirus-recommandations-et-inhalation)

 and no NSAIDs or corticosteroids for the first 7 days. And in case of aggravation, to prescribe:

 -A biological examination with D-Dimer assay.

 -Then, monitor O2Sat, amongst other factors.

 - Lastly, as decided by the prescribing physician and after having read the patient's history and contraindications:

 - prescribe LMWH or Rivaroxan (Xarelto) by mouth 10 mg per day, or Apixaban (Eliquis) 5 mg per day for the prevention of PE, DVT and VTE, and there are others.

 - prescribe Doxycycline 2 times 100 mg per day for an adult weighing more than 60 kg for 14 days. On the other hand, if it is for anti-viral use, like all antivirals, it is important to use it from an early stage.    

 - prescribe a corticosteroid (Cortancyl, for example) after the seventh day at a dose of 20 mg to 25 mg per day for a person weighing 50 kg to 60 kg, for 7 days, and with a local beclomethasone spray (Becotide) or with associated bronchodilator if presence of bronchospasm (Seretide for example), or addition of Salbutamol (Ventoline) if no contraindication.

 - Dispatch the patient to the Emergency department on 4 liters/minute oxygen, if O2Sat is less than 85 and/or dyspnea is poorly tolerated.

 Resuscitation Unit or Intensive Care Unit:

 In addition to classical polyvisceral control, the following will be discussed: increase in anticoagulant treatment, level of corticosteroid therapy, addition of serine protease inhibitors, dose of Doxycycline or HCQ, addition of specific anti-virals.

 This therapeutic proposal, made in good faith, is intended for health professionals, respecting our deontology. Everything must remain under the control of a doctor and under no circumstances must there be self-medication.  This is essential.

 The objective is to propose studies for this new treatment using sequential triple therapy.

 

I am of the opinion that this new treatment makes scientific sense.

 

Dr Pierre-Jacques Raybaud

 Translator   Samuel Young

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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 1Shutoku Matsuyama 2Xiao Li 3Makoto Takeda 2Yasushi Kawaguchi 1 4Jun-Ichiro Inoue 5 6Zene 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 GaoZhenxue TianXu 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 1Jean-Marc Rolain 2Nan-Yao Lee 1Po-Lin Chen 1Ching-Tai Huang 3Ping-Ing Lee 4Po-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 2Yasser Mandourah 3Fahad Al-Hameed 4Anees A Sindi 5Ghaleb A Almekhlafi 3Mohamed A Hussein 6Jesna Jose 6Ruxandra Pinto 7Awad Al-Omari 8 9Ayman Kharaba 10 11Abdullah Almotairi 12Kasim Al Khatib 13Basem Alraddadi 8 14Sarah Shalhoub 15Ahmed Abdulmomen 16Ismael Qushmaq 14Ahmed Mady 17 18Othman Solaiman 19Abdulsalam M Al-Aithan 20Rajaa Al-Raddadi 21Ahmed Ragab 22Hanan H Balkhy 1 23Abdulrahman Al Harthy 17Ahmad M Deeb 24Hanan Al Mutairi 24Abdulaziz Al-Dawood 1 2Laura Merson 25Frederick G Hayden 25 26Robert 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 1Federica Sotgia 1Michael 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.Jianjun 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 1Philippe ColsonDidier 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]. »

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