Lors d’un échange (sur Facebook) avec un disciple de MONTAIGNE qui pratique le doute (c’est son droit) et scepticisme (ça l’est aussi) sur les résultats bénéfiques de l’usage de la chloroquine et de l’hydroxychloroquine pour traiter la Covid-19, j’ai essayé par tous les moyens d’amener mon interlocuteur à plus d’ouverture d’esprit, et surtout à un peu plus d’humilité devant la réalité des faits. Devant un échange parfaitement improductif, dans lequel du reste, se sont introduits des statisticiens, de très haute volée, je n’en doute pas, mais des statisticiens ignorants de la pratique de la recherche clinique et préclinique et qui voulaient à toute force faire intervenir les statistiques bayésiennes, et non pas les bonnes vieilles méthodes éprouvées (qui consistent à évaluer la probabilité que deux valeurs appartiennent à la même distribution), j’ai cessé de participer à ce débat. Je me propose ici de vous donner un extrait d’un article très objectif de BRUFSKY reprenant de manière exhaustive les résultats obtenus avec la chloroquine et l’hydroxychloroquine pour le traitement des patients atteints de Covid-19.
Hyperglycemia, hydroxychloroquine, and the COVID‐19 pandemic
Adam Brufsky MD, PhD
13 avril 2020. Journal of medical virology
"4 INHIBITION OF PROTEIN GLYCOSYLATION TO BOTH MODULATE VIRUS‐ACE2 INTERACTION AND BLUNT M1 MACROPHAGE POLARIZATION IN THE VIRAL IMMUNE RESPONSE
It is a tribute to the ingenuity and effort of the medical and scientific community that we currently have multiple agents in clinical trials to help treat COVID‐19, all of which have a rational basis. However, for an agent to have an effect in blunting the medical complications of a widespread pandemic, where hundreds of thousands of infected pa- tients are at risk of fatal progression of disease, this agent needs to be cheap, relatively nontoxic, and rapidly scalable. Only one of the agents being considered at this point meets these criteria.
Hydroxychloroquine has been used of the treatment of rheumatoid arthritis and other autoimmune conditions for nearly 70 years. It has also been used as malaria prophylaxis and treatment for nearly 50 years. It is extremely safe and has been used widely in underdeveloped countries for these conditions, in children and in pregnant women, with little to no monitoring. While there are po- tential concerns for rare drug interactions with other agents that prolong the QT interval, and there are concerns with retinopathy with long term use, neither of these uncommon complications should be clinically significant if appropriate caution (an electrocardiogram [EKG] before therapy) is employed.
There is a possible rational basis for the development of hy- droxychloroquine in the treatment of COVID‐19 in clinical trials of treatment and prophylaxis. Hydroxychloroquine inhibits SARS‐CoV‐2 in vitro at concentrations achievable in human lung tissue. Chloroquine, a related compound, inhibits SARS‐CoV replication and spread in cell culture, possibly through reducing glycosylation of the ACE2 receptor. Interestingly, computer simulations suggest that hydroxychloroquine and chloroquine are predicted to bind to the active site of the enzyme UDP‐N‐acetylglucosamine 2‐epimerase, which catalyzes the rate determining step in the sialic acid bio- synthesis pathway, and thus there is a rational basis to assume hydroxychloroquine can interfere in terminal glycosylation of proteins in the Golgi apparatus.
In a small unrandomized clinical cohort of 80 patients the combi- nation of hydroxychloroquine and azithromycin has been shown to ra- pidly reduce viral load in COVID‐19 patients and ameliorate clinical symptoms in the majority of patients. In another small randomized unpublished study of 62 COVID‐19 patients, undertaken after the observation that none of a cohort 80 lupus patients in Wuhan on chronic hydroxychloroquine therapy developed COVID‐19 infection, 62 patients with mild COVID‐19 symptoms and signs of COVID‐19 pneumonia on CT scan were randomized to 200mg of hydroxychloroquine orally twice daily for 5 days and usual care or usual care alone. In the hydroxychloroquine arm of this study, 80.6% of subjects had improvement of COVID‐19 pneumonia findings on CT scan vs 50.8% of controls after 5 days of therapy (P=.0476) and 0% of patients on hydroxychloroquine progressed to severe disease vs 12.9% of control patients (P=not done).
Hydroxychloroquine also can act as an oral hypoglycemic agent, as patients with diabetes taking hydroxychloroquine for rheumato- logic diseases had a significant reduction in hemoglobin A1c when compared to methotrexate, and thus can serve to reduce hyperglycemia, a possible COVID‐19 risk factor for disease severity.
While studies are mixed on this topic, and the balance of M1 to M2 macrophage polarization may differ depending on the local microenvironment, hydroxychloroquine has been shown in at least one study to block the polarization of macrophages to an M1 in- flammatory subtype, and it is predicted to interfere with glycosy- lation of a number of proteins involved in the humoral immune response, possibly including the macrophage FcR gamma IgG re- ceptor and other immunomodulatory proteins, potentially through inhibition of UDP‐N‐acetylglucosamine 2‐epimerase. In combination with potential other immunomodulatory effects, this could possibly blunt the progression of COVID‐19 pneumonia all to way up to ARDS where a potential over‐conversion to an inflammatory M1 macrophage subtype occurs in response to a postulated brisk humoral immune response to the SARS‐CoV‐2 spike protein around day 8 to 10 after symptom onset.
5 CONCLUSION AND SUMMARY
While we await larger randomized studies and more analysis of pa- tient subtypes to determine who, if anyone, will benefit from hy- droxychloroquine, in the context of this theoretical framework for COVID‐19 infection the results to date are supportive, although much caution should be used in interpretation of these early small clinical trials.
Regardless of the results of larger clinical trials of hydroxy- chloroquine in COVID‐19, it is hoped that the above analysis can provide a testable theoretical framework to allow for advances in our understanding and control of this deadly viral epidemic."
BRUFSKY fait état des résultats de plusieurs essais, randomisés ou non, montrant l’intérêt de ces molécules. Très judicieusement, en se fondant sur ce qu’on sait des mécanismes moléculaires de l’interaction entre le virus et son récepteur, il explique que si les diabétiques ont un risque accru, toutes les autres situations où la glycémie dépasse (pour des raisons diverses dont par exemple une atteinte du pancréas par le virus) la valeur normale de 1 g/l, il y a des risques de voir une glycosylation excessive du récepteur du virus (l’ACE2) et une glycosylation également importante des spicules d’enveloppe qui vont favoriser l’interaction virus-cellule. Or, entre autre action, la chloroquine inhibe une enzyme responsable de la glycosylation des protéines.
Par ailleurs, un autre résultat produit par le Pr PERONNE montre d’une manière absolument démonstrative le bénéfice du traitement du Pr RAOULT.
En somme, devant ces résultats absolument convaincants, les détracteurs du traitement me font penser à ces pharisiens qui demandent à Jésus « Quel signe vas-tu nous donner pour justifier que tu agisses ainsi ? », alors même qu’ils savent par le détail les guérisons et les miracles accomplis par lui.
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