Submitted by Mahmoud Elkazzaz Assessment the Activity Value of 13- cis-Retinoic Acid(Isotretinoin) in the Treatment of COVID-19 Mahmoud ELkazzaz(1),Tamer Haydara(2), Mohamed Abdelaal(3), Ahmed M. Kabel(4), Abedelaziz Elsayed(5) ,Yousry Abo-amer(6) ,Hesham Attia(7) 1. Department of chemistry and biochemistry, Faculty of Science, Damietta University,GOEIC,Egypt. 2. Department of Internal Medicine,Faculty of Medicine, Kafrelsheikh University, Egypt 3. Department of Cardiothoracic Surgery,Faculty of Medicine, Kafrelsheikh University, Egypt 4. Department of Clinical Pharmacy, Faculty of Medicine , Tanta University,Egypt. 5. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy,Tanta University,Egypt. 6. Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital,Egypt 7. Department of Immunology and Parasitology, Faculty of Science, Cairo University, Egypt. - Study Chair ((( Dr.Tamer Hydara))), Department of Internal Medicine,Faculty of Medicine, Kafrelsheikh University, Egypt - Contact: Dr.Tamer Hydara-Tel: 00201142233340 Mail: tamerhydara@yahoo.com - Principal Investigator (((Mahmoud Elkazzaz))), Faculty of Science, Damietta University,GOEIC,Egypt. - Contact:Tel: 00201090302015 Mail: mahmoudramadan2051@yahoo.com - Study coordinator ((Prof/Dr Mohamed Abdelaal)), Department of Cardiothoracic Surgery,Faculty of Medicine, Kafrelsheikh University, Egypt - Contact:Tel: 00201001422577 Mail: Malaal2@hotmail.com Abstract The COVID-19 pandemic caused by SARS-COV-2 has infected over 2,000,000 people causing over 150,000 deaths. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 and for which there are currently no approved treatments. Here, the principal investigator reported according to previous studies and research findings that Isotretinoin can strongly affect both inflammation and viral entry in severe acute respiratory syndrome coronavirus 2 infection via inhibiting the overproduction of early response proinflammatory cytokines (IL- 6 and tumor necrosis factors alpha ) which are over expressed in COVID-19 and contributed to disease progression, poor outcomes, vascular hyperpermeability and multiorgan failure in patients infected with severe acute respiratory syndrome(SARS-CoV-2) and also, via blocking COVID-19 entry by inhibiting androgenic factors which induce transmembrane protease, serine 2 (TMPRSS2) expression, In addition to inhibiting of Angiotensin-converting enzyme 2(ACE2) ,AT1 protein and Ang II-mediated intracellular calcium release pathway which is responsible for SARS-CoV-2 cell fusion and entry as opposed to ACE inhibitors (ACEIs) or angiotensin II type-I receptor blockers (ARBs) that upregulate ACE-2 receptors which might increase the risk of infection and subsequent complications Moreover, another study demonstrated that isotretinoin is a potential inhibitor of papain like protease (PLpro) which is a protein expressed by SARS-CoV-2 RNA and considered one of the proteins that should be targeted in COVID-19 treatment. And also,more than one study reported that 13 cis Retinoic Acid induces CD4+CD25+FOXP3+ Regulatory T Cells which their absence during acute infection alters the ability of the host to limit tissue damage In addition, isotretinoin was reported to increase CD4 counts and markedly decrease viremia in HIV positive patients suffering from acne vulgaris and retinoic acid inducible gene-1 (RIG-1) expression. And also, another study reported that 13 Cis retinoic acid induced significant upregulation of toll-like receptor 3 resulting in an immune response to dsRNA intermediate which can be partially generated during CoV-2 replication . TLR3 sensitized by dsRNA and cascades of signaling pathways (IRFs and NFκB activation, respectively) are activated to produce type I IFNs. The production of type I IFNs is important to enhance the release of antiviral proteins for the protection of uninfected cells. Isotretinoin therapy has furthermore proven anti-inflammatory, anti-platelet and fibrinolytic activities. which may protect patients infected with covid-19 from widespread blood clots. From this point, the principal investigator expects that isotretinoin will be the Immunity passport" in the context of COVID-19 Keywords: COVID 2019 , Retinoic acid, Endosomal toll-like receptor 3,T Cells, IFN type1, AT1, ACE2,TMPRSS2,RIG-1.

NCT04353180

Conditions

1. COVID19

Interventions

1. Drug: Drug Isotretinoin (13 cis retinoic acid ) capsules+standard treatment
2. Drug: Isotretinoin(Aerosolized 13 cis retinoic acid) +standard treatment
3. Drug: Standard treatment