Utilizing the Crosstalk Among Aerosolized Phenformin , Methylene Blue, Photodynamic Therapy , Zinc and Potassium for Treating Severe COVID-19 Infection and Its Inflammatory Complication

Summary

Utilizing the crosstalk among aerosolized phenformin, methylene blue, photodynamic therapy , zinc and potassium for treating severe COVID-19 infection and its inflammatory complication

Amr Ahmed(1), Mahmoud Elkazzaz(2), Tamer Haydara(3), and Abdullah Alkattan(4)

1. Director of tuberculosis program Ghubera, public health department ,First health cluster ,Ministry of health ,Saudia Arabia.
2. Department of chemistry and biochemistry, Faculty of Science, Damietta University, Egypt.
3. Department of Internal Medicine, Faculty of Medicine, Kafrelsheikh University, Egypt.
4. Ministry of Health, Riyadh, Saudi Arabia.

SARS-CoV-2 represents the largest current health challenge for the society. Moreover, numerous variants of the virus that causes COVID-19 are being tracked in the United States and globally during this pandemic. Here, we will use combination therapy which involve agents with significant activity and different mechanisms of action against covid-19 and its inflammatory complication. Excessive activities of cysteinyl cathepsins (CysCts) contribute to the progress of many diseases. however, therapeutic inhibition has been problematic. Cathepsin L are crucial in terms of the endocytosis by cleaving the spike protein, which permits viral membrane fusion with endosomal membrane, and succeeded by the releasing of viral genome to the host cell. Thereby, inhibition of cathepsin L may be advantageous in terms of decreasing infection caused by SARS-CoV-2. It is well known that zinc (Zn) possesses a variety of direct and indirect antiviral properties, which are realized through different mechanisms. Administration of Zn supplement has a potential to enhance antiviral immunity and to restore depleted immune cell function, in particular in immunocompromised patients. It has been found that Zn 2+ deficiency leads to an exaggerated activity of Cysteine cathepsin increasing the autoimmune/inflammatory response. . Zn2+ is a natural inhibitor of proteases with CysHis dyads or CysHis(Xaa) triads. cysteine protease Cathepsin L (CatL) involvement with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 from different points of view. At this purpose Zn 2+ metal can be safely combined with phenformin a drug that increases the anti-proteolytic effect of endogenous Zn 2+ lowering the excessive activity of some CysCts.; A study found that phenformin-Zn2+ complex is identified as a modifiable pharmacophore for synthesis of therapeutic CysCt inhibitors with a wide range of potencies and specificities. Phenformin stabilizes a "Zn2+ sandwich" between the drug and protease active site. Additionally, phenformin was found to be potent inhibitor of IL-6 R, with phenformin (100 µM) treatment for 48 h, decreased IL-6R expression in ANBL6, RPMI, U266, MM1S, and JJN3 was 5.51 (p = 0.0025), 3.03 (p = 0.0005), 1.55 (p \< 0.05), 2.09 (p = 0.0082) and 1.19-fold, respectively. Furthermore, phenformin was discovered to potentially and strongly bind to ACE2 receptors, according to a docking research being conducted by the principle investigators of this clinical study therefore, Phenformin is expected to potentially attach to ACE2 receptors and lead to its downregulation, an inhibitory mechanism which may combat and block COVID-19 infection in lung epithelial cells. Phenformin may induce lactic acidosis therefore according to the principal investigator The phenformin will be utilized as aerosolized by inhalation for COVID-19 treatment and this may be an effective novel treatment strategy that would limit the risk of systemic side-effects associated with biguanides due to the low inhaled dose. In addition, we will use aerosolized phenformin in combination with methylene blue. A study found that a very marked improvement in lactate and pyruvate concentrations occurred within six hours of the beginning of méthylène blue administration in human . It has been known for some time that méthylène blue is a moderately efficient hydrogen acceptor in several enzyme sys¬ tems and significantly reduce oxidative stress by scavenging ROS. Moreover, Methylene Blue has antiviral activity and was found to Inhibit the Spike-ACE2 Protein-Protein Interaction-a Mechanism that can contribute to its Antiviral Activity Against COVID-19 For many reasons, methylene blue is a promising drug for an active treatment against SARS-CoV-2 . Since methylene blue can work as a photosensitizer, photodynamic therapy as an antiviral treatment has great potential in the treatment of COVID-19.. This clinical study will investigate the effectiveness of SARS-CoV-2 infected people treatment using methylene blue and the following photodynamic therapy after that our clinically approved patients will receive phenformin and zinc . But methylene blue may lead to lowering in potassium concentration.Therefore, we will add potassium supplement to this combination.

Conditions

• COVID-19

Interventions

COMBINATION_PRODUCT

Combination therapy plus Standard therapy

Methylene Blue 1 mg/kg water solution. Participants will orally receive Methylene Blue solution of 1 mg/kg concentration one time if any. After 3 hours of Methylene Blue administration irradiation of chest using 650 nm laser source with 18 J/cm\^2 energy dose will be performed. Patients will be administered study medication (Inhaled 100-150 mg phenformin per day; or, if broken into 3 doses/day, 30-50 mg/dose. this dose well be once daily for 5 days, for a maximum of 7 days for those who remain hospitalized. Patients will receive an Enriched Grape Juice containing 234.5 mmol microcrystalline KCl (a total of 6000 mg of K in 2 EGJ, but split into 2 intakes daily) Patients received will receive Zinc gluconate capsule 15 mg x 2 per day during 14 days

RADIATION

Photodynamic therapy

After 3 hours of Methylene Blue administration irradiation of chest using 650 nm laser source with 18 J/cm\^2 energy dose will be performed.

DRUG

Standard therapy

Infected patients will receive the standard therapy for COVID-19 for 14 days

Sponsors & Collaborators

• Faculty of Medicine , Kafrelshiekh University, Egypt.

  collaborator UNKNOWN

• Amr kamel khalil Ahmed

  lead OTHER_GOV

Principal Investigators

• Amr Ahmed · Ministry of Health

• Mahmoud Elkazzaz · 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

2021-09-30

Primary Completion

2021-10-31

Completion

2021-11-30

Countries

• Saudi Arabia

Study Locations