Assessment the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatment of COVID-19 ( Isotretinoin in Treatment of COVID-19) (Randomized)

• Status: Not yet recruiting
• Trial end date: 2021-11-01
• Target enrollment: 0
• Participant gender: All

Summary

Assessment the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatment of COVID-19

Mahmoud ELkazzaz(1),Tamer Haydara(2), Mohamed Abdelaal(3), Abedelaziz Elsayed(4) ,Yousry Abo-amer(5), Hesham Attia(6), Quan Liu(7)' Tim Duong(8) and Heba Sahyon(9)

1. Department of chemistry and biochemistry, Faculty of Science, Damietta University, 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 Pharmaceutical Biotechnology, Faculty of Pharmacy, Tanta University, Egypt.

5. Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Egypt

6. Department of Immunology and Parasitology, Faculty of Science, Cairo University, Egypt.

7. School of Life Sciences and Engineering, Foshan University, Laboratory of Emerging Infectious Disease, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.

8. Montefiore Health System and Albert Einstein College of Medicine, New York, United States of America.

9. Chemistry Department, Faculty of Science, Kafrelsheikh University, Egypt.

• This clinical study is the first clinical study in literature (submitted on 20 April, 2020) which demonstrated that Isotretinoin will provide complete protection against COVID-19

Abstract

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. There is an urgent need for targeted and effective COVID-19 treatments which has put great pressure on researchers across the world for developing effective drugs. In this clinical study we attempt to demonstrate Isotretinoin could be an effective and promising treatment for SARS-CoV-2 based on the intracellular mechanism of SARS-CoV-2 transmission and consequences caused. Isotretinoin could strongly inhibit both inflammation and viral entry in severe acute respiratory syndrome coronavirus 2 infection via decreasing the overproduction of early response proinflammatory cytokines (interleukin-6 ) which are over expressed in COVID-19 and contributed to disease progression, poor outcomes, vascular hyper permeability and multiorgan failure in patients infected with COVID-19. It could also block the entry of COVID-19 by inhibiting androgenic factors that induce serine 2 transmembrane protease (TMPRSS2) expressions.. In addition to inhibiting of Angiotensin-converting enzyme-2 (ACE2), Angiotensin T1 protein and Angiotensin II-mediated intracellular calcium release pathway which is responsible for COVID-19 cell fusion and entry, ACE2-expressing cells are prone to SARS-CoV-2 infection as ACE2 receptor facilitates cellular viral entry and invasion. Moreover, isotretinoin is a potential repressor and inhibitor of papain-like protease (PLpro), which is a lethal protein expressed by COVID-19 genes and is an enzyme of dubiquitination which facilitates virus replication in patients with COVID-19.The genome of Middle East Respiratory Syndrome Coronavirus is recognized by melanoma differentiation-associated protein-5 (MDA5), retinoic acid inducible gene-1 (RIG-1) and endosomal toll-like receptor 3 (TLR3) as pathogen-associated molecular patterns. This recognition resulted in the formation of type-1 interferon (IFN1). As an evasion mechanism, virus synthesize proteins that hinder the production IFN1 in the pathway. 13-cis retinoic acid induced significant upregulation of toll-like receptor 3 (TLR3), mitochondrial antiviral-signaling protein (MAVS) and IFN regulatory factor 1 expression in a time-dependent. Furthermore, 13 cis Retinoic Acid (13 cis RA) could be an effective and promising treatment for SARS-CoV-2 owing to its ability to increase CD4 cells and induce mucosal IgA antibodies that are less prone to Antibody Dependent Enhancement process (ADE) and responsible for passive mucosal immunity in the respiratory tract. ADE is a phenomenon in which antiviral antibodies facilitate viral infection of target immune cells and, in some cases, make a second infection worse, such as dengue fever (dengue virus), By inducing IgA antibodies, 13 cis retinoic acid enhances mucosal immunity and is known to be a potent IgA isotype.13 Cis retinoic acid induced significant upregulation of toll-like receptor 3 an immune boosting action that may result in an immune response to dsRNA intermediate leading to the production of type I IFNs which is important to enhance the release of antiviral proteins for the protection of uninfected cells. Isotretinoin therapy has furthermore proven anti-platelet and fibrinolytic activities which may protect patients infected with covid-19 from widespread blood clots. From this point, we suggest that isotretinon will be the Immunity passport" in the context of COVID-19

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Kafrelsheikh University
• Collaborators: 1-Foshan University Laboratory of Emerging Infectious Disease Institute of Translational Medicine The First Hospital of Jilin University China; 2-Faculty of Science, Kafrelsheikh University, Egypt.; 2-Montefiore Health System and Albert Einstein College of Medicine, Newyork, United States of America (U.S.A).
• Treatments: Isotretinoin; Tretinoin

Criteria

Inclusion Criteria:

Adult SARI patients with 2019-ncov infection confirmed by PCR; Absolute value of lymphocytes < 0. 6x 109/L; Severe respiratory failure within 48 hours and requires admission to ICU. (severe respiratory failure was defined as PaO2/FiO2 < 200 mmHg and was supported by positive pressure mechanical ventilation (including non-invasive and invasive mechanical ventilation, PEEP>=5cmH2O))

Exclusion Criteria:

Age < 18 Pregnant Allergic to experimental drugs and patients have the following conditions:

1. Hypercholesterolemia

2. Hypertriglyceridemia

3. Liver disease

4. Renal disease

5. Sjögren syndrome

6. Pregnancy

7. Lactation

8. Depressive disorder

9. Body mass index less than 18 points or higher than 25 points

10. Contraindications for hormonal contraception or intrauterine device.

11. Autoimmune diseases A history of organ, bone marrow or hematopoietic stem cell transplantation

12. Patients receiving anti-hcv treatment

13. Permanent blindness in one eye

14. History of iritis, endophthalmitis, scleral inflammation or retinitis 15-90 days of retinal detachment or eye surgery

16-The competent physician considered it inappropriate to participate in the study

------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------- ----------------------------------------------------------

Safety and promising features of isotretinoin in tne era of COVID 2019 according Principal Investigator Protocol:

1. This medication have the feature of Aerosolized Drug Delivery to increase its efficacy beside Oral administration, Which makes it distinct from other medication in which should dose be only given orally. A study demonstrated that treating with 13 cis retinoic acid aerosolized via inhalation rout did not cause any damage in lung cells.

2. Repeated high doses of 13 cis retinoic by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lung.

3. Inhaled isotretinoin might provide sufficient drug to the target cells for efficacy while avoiding systemic toxicity.

4. A study demonstrated that 13 cis retinoic is used in treating Emphysema (emphysema is a lung condition that causes shortness of breath)

5. RA has been reported to induce formation of new alveoli and returns elastic recoil in the lung to approximately normal values in animal models of emphysema.

6. Strong expectation of complete COVID -19 blockade from cell entry and infection depending on strong ethics, researches and references.

7. Availability of our compounds.

8. Ease of application.

9. Expectation of COVID -19 treating by isotretinoin via more than one distinct mechanism.

10. Expectation of High induction of anti- inflammatory T cells and significant inhibition of IL-6 at low concentrations of isotretinoin.

11. Controlling Accompanying cytokine storm.

12. No interactions with Egyptian protocol drugs were found.

13. (13- cis -Retinoic acid ) can be given in the form of aerosol to avoid these systemic side effects. A clinical trial conducted on 148 subject from 5 university hospitals to evaluate the possibility of retinoids in the treatment of emphysema. The patients, were randomized to receive 13-cis retinoic acid (1 mg/kg/day, daily or ATRA at either low dose (1 mg/kg/day for 4 days/wk) or high dose (2 mg/kg/day for 4 days/wk), placebo for six months, followed by a three-month crossover phase. then, they were observed for an additional nine months before the final evaluation. In the trial, retinoids(13 cis retinoic acid ) were proven to be safe as the drug-related AEs were generally mild[188]. A study reported that the application of aerosolized RA system led to a rise of RA levels in lung, but not plasma. or liver. In lung concentration and levels of retinol, retinyl palmitate and retinyl stearate also showed to be unchanged [189] A study on rabbits demonstrated that 13 cis retinoic acid can be given in the form of aerosol without serious side effects In this study repeated elevated doses of 13 cis retinoic acid by inhalation caused moderate loss of body weight, but microscopic examination of ten tissues including oesophagus and lung did not found any significant inhalation-induced injury or damage therefore aerosolized 13 cis retinoic acid might provide sufficient therapy to the target cells in lung for efficacy while avoiding systemic toxicity © 2000 Cancer Research Campaign[190]