Investigating the Potential Role of Aerosolized Retinoic Acid, a Potent Vitamin A Metabolite for Treating COVID-19 Anosmia and Retinoic Acid Insufficiency .A Novel Approach for Regaining Sense of Smell.

Summary

Investigating the potential role of Aerosolized retinoic acid, a potent Vitamin A metabolite for treating COVID-19 Anosmia and retinoic acid insufficiency .A novel approach for regaining Sense of Smell.

Mahmoud ELkazzaz(1),Tamer Haydara(2), Abedelaziz Elsayed(3) ,Yousry Abo-amer(4), Hesham Attia(5), Quan Liu(6) and Amr Ahmed(7)

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 Pharmaceutical Biotechnology, Faculty of Pharmacy, Tanta University, Egypt.
4. Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Egypt
5. Department of Immunology and Parasitology, Faculty of Science, Cairo University, Egypt.
6. 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.
7. Director of tuberculosis program Ghubera, public health department ,First health cluster ,Ministry of health ,Saudia Arabia.

* Very important Note: This clinical study is the first clinical study in literature (First posted August 12, 2021) which demonstrated depending on molecular findings that Vitamin A /Retinoic Acid will treat smell loss resulted by COVID-19

Recent rapidly accumulating evidences and reports indicate that partial loss of the sense of smell or even total anosmia are early markers of SARS-CoV-2 infection and frequently reported symptoms associated with the COVID-19 pandemic (Lechien J. R et al., 2020) However, the cellular mechanisms of this phenomenon are unknown. The rates of insomnia and depression were 26.45% and 9.92% in the COVID-19 patients after recovery. Therefore, finding an effective treatment for COVID-19 Anosmia is a critical point. Although, ACE2 has been identified as the principal host cell receptor of 2019-nCoV, and it is thought to play a critical role in the virus's entrance into the cell and subsequent infection, many cells can be infected by COVID-19 while also expressing little or no ACE2. Even though the COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its synthesis is limited to to a minor fraction of these neurons.of these neurons, COVID-19 infection causes a loss of smell (anosmia) (Katarzyna Bilinska et al.,2021). Our recent findings showed that COVID-19 binds directly to STRA6 receptors of retinol leading to retinol depletion and retinoic acid insufficiency (M Elkazzaz et al,. 2021) . Retinoic acid insufficiency in the olfactory epithelium, both in mouse and chick models, causes progenitor cell maintenance failure and, consequently, olfactory neurons differentiation is not maintained . An explant system, showed that renewal of olfactory neurons is inhibited if retinoic acid synthesis was failed in the olfactory epithelium (Paschaki M et al., 2013) . It's worth noting that vitamin A shortage also causes olfactory and taste problems, In a study by Garrett-Laster et al., (1984), the patients had vitamin A deficiency because of malnutrition and alcoholic liver cirrhosis; they lost their sense of smell after that disorder. LaMantia and Rawson et al.,( 2007) reported that administration of retinoid acid after the damage of olfactory system motivates an immune response and produces a more quick recovery of olfactoryguided behavior. It was showed that Isotretinoin improved the significantly performance of patients in the olfactory test(Demet Kartal et al.,2017) Moreover, there is increasing evidence that retinoic acid (atRA) influences gene expression of components of renin-angiotensin system (RAS), which plays a pivotal role in the pathophysiology of essential hypertension. Retinoic acid induced ACE2 expression in different animal models. Moreover, a study suggests that topical retinoids may have applicability in promoting sinus regeneration and wound healing. In a study comparing treated and untreated nasal mucosa ,untreated regenerated mucosa showed expected changes of submucosal gland loss, basal lamina and lamina propria fibrosis and loss of cilia. Reinoic acid treatment appeared to result in better mucosal regeneration marked by less cellular atypia and fibrosis(Mendy S. Maccabee et al,. 2003).. Aerosolized retinoic acid will have an effective role in treating post COVID-19 anosmia (loss of smell) via upregulating ACE2, STRA 6 and regenerating of olfactory receptors and olfactory sensory cells and neurons.

Conditions

• Post COVID-19 Anosmia (Loss of Smell)

Interventions

DRUG

Aerosolized 13 cis retinoic acid plus Vitamin D

Patients with Post COVID-19 Anosmia (Loss of Smell) will receive one dose daily of Aerosolized 13 cis retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 3 weeks. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

DRUG

Aerosolized All trans retinoic acid plus Vitamin D

Patients with Post COVID-19 Anosmia (Loss of Smell) will receive one dose daily of Aerosolized All trans retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 3 weeks. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

OTHER

Standard therapy

Standard therapy

Sponsors & Collaborators

• Ministry of Health, Saudi Arabia

  collaborator OTHER_GOV

• Foshan University Laboratory of Emerging Infectious Disease Institute of Translational Medicine , Jilin University China

  collaborator UNKNOWN

• Montefiore Health System and Albert Einstein College of Medicine, Newyork, United States of America (USA)

  collaborator UNKNOWN

• Faculty of Science, Kafrelsheikh University, Egypt.

  collaborator UNKNOWN

• Kafrelsheikh University

  lead OTHER

Principal Investigators

• Tamer Haydara, Ass/Prof of Internal medicine · Faculty of Medicine Kafrelshiekh university

• Mahmoud Elkazzaz, M.Sc of Biochemistry · Faculty of Science, Damietta university

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-11-30

Primary Completion

2021-12-31

Completion

2022-01-31

Countries

• China
• Egypt
• Saudi Arabia

Study Locations