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What is the therapeutic response of hydroxycholoroquine on coronavirus

What is the therapeutic response of Hydroxychloroquine on corona virus

The novel corona virus disease (COVID-19),officially known as severe acute respiratory syndrome –corona virus -2(SARS –CoV-2),initially originated in Hubei province in the Chinese city of Wuhan on November 17th 2019, which is currently an ongoing threatening to the whole world is also declared as a global pandemic by the World health organization on March 11, 2020.

It was at the midst of crisis WHO launched global megatrial of four most promising coronavirus treatments.A drug combo used against HIV,A malaria treatment first tested during world war II, A new antiviral that promised against Ebola virus; Which are Ritonavir/Loponavir and Ritonavir,Lopinavir ,Interferon Beta combination,Chloroquine/Hydroxychloroquine and Remdesivir respectively.

Hydroxychloroquine sulfate has been used extensively for Malaria treatment and because of the immunomodulatory role it is used in various autoimmune diseases like rheumatoid arthritis ,systemic lupus erythematosus etc. Expirimental studies reveal that chloroquine/HCQ is a proven anti-malarial drug that inhibhits the replication of several intracellular micro-organisms including corona viruses in vitro.


MECHANISM OF ACTION IN HUMANS

• The chemical structure and mechanism of action of chloroquine and hydroxychloroquine (HCQ) are exactly same except for an additional hydroxy moiety in one terminal in HCQ.

• Both are weakly basic in nature which can change the pH of intracellular organelles like endosomes/lysosomes that are acidic and essential for the viral membrane fusion.

• It is studied that both these agents could be effective tools against SARSCoV-1 and SARS-CoV-2.

• CQ/HCQ inhibits the quinone reductase-2 which is a structural neighbour of UDP- N -acetylglucosamine 2- epimerases( uridine diphosphate)enzyme involved in sialic acid biosynthesis (an acidic monosaccharides of cell transmembrane proteins required for ligand recognition) that makes this a broad antiviral agent.

• While the CQ/HCQ changes the pH of intracellular organelles, it results in the inhibhition of cathepsins ,hence the formation of autophagosome which cleaves SARS-CoV-2 spike protein is hindered.

• Another mechanism by which CQ/HCQ impede with the action of SARS-CoV-2 is by inhibiting MAP-kinase(Mitogen activated protein kinase pathway) and disrupting biological and molecular crosstalk.

• CQ/HCQ acts by altering the assembly of virion in the vector stage , budding and interfering with the proteolytic synthesis of the viral matrix protein( M-protein).

• Previous experimental studies have also demonstrated that action of chloroquine can combat against in vitro effects of SARS-CoV-1 , which initially causes a paucity in the glycosylation receptors of virus cell surface, that makes it unable to bind to the angiotensin-converting enzyme 2 (ACE-2) expressed in lung, heart, kidney and intestine, thus prevents SARS-CoV-2 attachment to the target cells

• Addition of hydroxyl molecule makes HCQ less permeable to blood-retinal barrier and allows comparatively rapid clearance from retinal pigment cell, thereby chances of lesser risk of retinal toxicity with HCQ.

• Absorption of HCQ is rapid and complete and takes 1-3 hours to reach peak plasma concentration.55% is bound to protein and 60% excreted in urine.


THERAPEUTIC OUTCOMES:-

A study conducted in china with more than 100 patients with COVID-19 found chloroquine effective in causing symptomatic relief, radiological improvement in patients with exacerbation of pneumonia and promoting virus-negative seroconversion. This is the first human trial ever conducted with chloroquine against COVID-19.The dose of chlorquine used is 500mg and HCQ 400mg ,200mg in varied frequency and intervals in different studies. The mechanism of action of some antimalarial drugs with antiviral property depicts their potential role in the chemoprophylaxis of the COVID-19 epidemic. Based on the preliminary reports , 100 infected patients who were treated with chloroquine experienced a more rapid abatement in fever and improvement in the computed tomography (CT) images of lungs lesions.


Clinical investigational report from the critically ill patients infected with SARS-CoV-2 revealed high concentration of cytokines in the plasma and it is associated with disease severity. Other than its antiviral activity, HCQ is a successful anti-inflammatory agent that can markedly decrease pro-inflammatory factors particularly cytokinines, interleukin-1 and tumour necrosis factor.Therefore, inflammatory response in COVID-19 patients can be attenuated using HCQ .


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