Efficacy and Safety of Drug Combination Therapy of Isotretinoin and Some Antifungal Drugs as A Potential Aerosol Therapy for COVID-19 : An Innovative Therapeutic Approach COVID-19

• Status: Not yet recruiting
• Trial end date: 2020-11-20
• Target enrollment: 0
• Participant gender: All

Summary

Efficacy and safety of Drug combination therapy of Isotretinoin and some Anti fungal Drugs as A potential Aerosol therapy for COVID-19 : An innovative therapeutic approach

The pandemic of COVID-19 which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has infected over 2,000,000 people causing over 150,000 deaths.It hasno currently approved treatments.. Airborne SARS-CoV-2 infections in humans initiate from the virus entering nasal and airway epithelial cells through binding to angiotensin-converting enzyme 2 (ACE2). TMPRSS2, a cellular protease that activates the SARS-CoV-2 spike protein, colocalizes with ACE2 and can prime SARS-CoV-2 fusion directly at the plasma membrane. In the lungs, SARS-CoV-2 infects type I and type II alveolar epithelial cells, as well as alveolar macrophages that are among the first producers of pro-inflammatory cytokines. As key components of the immediate antiviral response, type I interferons (here after referred to as IFNs) are crucial for restricting viral replication and spread, through autocrine and paracrine type I IFN receptor (IFNAR) signalling. However, minimal amounts of IFNs have been detected in the peripheral blood or lungs of patients with severe COVID-19 In a mouse model of SARS-CoV infection, local IFN responses in the lungs were delayed relative to peak viral replication, which impeded virus clearance and was associated with the development of CRS . SARS-CoV-2 ORF3b is a potent interferon inhebitor and antagonist Here, we review the molecular mechanisms by which Retinoic acid (isotretinoin) and antifungal drugs can cooperate to induce interferon in covid-19 infected patients A 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 (Interferon-regulatory factor 1 (IRFs) and Nuclear factor-κB (NFκB) activation, respectively) are activated to produce type I interferons. The production of type I IFNs is important to enhance the release of antiviral proteins for the protection of uninfected cells. RA can be generated in multiple forms as all-trans, 9-cis,and 13-cis retinoic acid. A study reported that Retinoic acid induces directly the expression of two transcription factors, Stat1 and IRF-1 which play central roles in the IFN signal transduction. In addition, RA induces IFN-a synthesis, IFNs can serve as the first line of immune defense against viral infections. IFNs are very powerful cytokines, which play a key role in combatting pathogenic infections by controlling inflammation and immune response by directly inducing antipathogen molecular countermeasures. There are three classes of IFNs: type I, type II, and type III. Antifungal drug. Fluconazol or itraconazol can inhibit cytochrome P450 enzymes, especially cype 26 which control retinoic acid concentration into human cells enhance both isotretinoin effect and Concentrations in Target Tissues This in turn lead to hyper interferon induction and synthesis in case of COVID-19. Also a study demonstrated that isotretinoin can be given as aerosolized via inhalation rout without any damage in lung cells. 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 therefore inhaled isotretinoin might provide sufficient drug to the target cells in lung for efficacy while avoiding systemic toxicity. In conclusion,isotretinoin therapy has furthermore a proven anti-inflammatory, anti-platelet and fibrinolytic activities which may protect patients infected with covid-19 from widespread blood clots. From this point, we suggest that isotretinoin will be the immunity passport" in the context of COVID-19.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Kafrelsheikh University
• Treatments: Isotretinoin; Itraconazole; 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

• The underlying disease is very serious and the expected survival time is less than 6 months (such as advanced malignant tumor);

• COPD or end-stage lung disease requires home oxygen therapy

• Expected survival time not exceeding 48 hours

• Participated in other clinical intervention trials within the last 3 months

• Autoimmune diseases

• A history of organ, bone marrow or hematopoietic stem cell transplantation

• Received radiotherapy and chemotherapy for malignant tumor within 6 months

• HIV infected patients or diagnosed with acquired immunodeficiency within the past year (CD4 T cells <=200/mm3)

• Patients receiving anti-hcv treatment

• 90 days of retinal detachment or eye surgery

• Permanent blindness in one eye

• History of iritis, endophthalmitis, scleral inflammation or retinitis

• The competent physician considered it inappropriate to participate in the study