Utilizing the crosstalk among aerosolized phenformin, methylene blue, photodynamictherapy , zinc and potassium for treating severe COVID-19 infection and its inflammatorycomplicationAmr 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 UnitedStates and globally during this pandemic. Here, we will use combination therapy whichinvolve agents with significant activity and different mechanisms of action againstcovid-19 and its inflammatory complication. Excessive activities of cysteinyl cathepsins(CysCts) contribute to the progress of many diseases. however, therapeutic inhibition hasbeen problematic. Cathepsin L are crucial in terms of the endocytosis by cleaving thespike protein, which permits viral membrane fusion with endosomal membrane, and succeededby the releasing of viral genome to the host cell. Thereby, inhibition of cathepsin L maybe advantageous in terms of decreasing infection caused by SARS-CoV-2. It is well knownthat zinc (Zn) possesses a variety of direct and indirect antiviral properties, which arerealized through different mechanisms. Administration of Zn supplement has a potential toenhance antiviral immunity and to restore depleted immune cell function, in particular inimmunocompromised patients. It has been found that Zn 2+ deficiency leads to anexaggerated activity of Cysteine cathepsin increasing the autoimmune/inflammatoryresponse. . Zn2+ is a natural inhibitor of proteases with CysHis dyads or CysHis(Xaa)triads. cysteine protease Cathepsin L (CatL) involvement with severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2) and COVID-19 from different points of view. At thispurpose Zn 2+ metal can be safely combined with phenformin a drug that increases theanti-proteolytic effect of endogenous Zn 2+ lowering the excessive activity of someCysCts.; A study found that phenformin-Zn2+ complex is identified as a modifiablepharmacophore for synthesis of therapeutic CysCt inhibitors with a wide range ofpotencies and specificities. Phenformin stabilizes a "Zn2+ sandwich" between the drug andprotease active site. Additionally, phenformin was found to be potent inhibitor of IL-6R, 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 topotentially and strongly bind to ACE2 receptors, according to a docking research beingconducted by the principle investigators of this clinical study therefore, Phenformin isexpected to potentially attach to ACE2 receptors and lead to its downregulation, aninhibitory mechanism which may combat and block COVID-19 infection in lung epithelialcells. Phenformin may induce lactic acidosis therefore according to the principalinvestigator The phenformin will be utilized as aerosolized by inhalation for COVID-19treatment and this may be an effective novel treatment strategy that would limit the riskof systemic side-effects associated with biguanides due to the low inhaled dose. Inaddition, we will use aerosolized phenformin in combination with methylene blue. A studyfound that a very marked improvement in lactate and pyruvate concentrations occurredwithin six hours of the beginning of méthylène blue administration in human . It has beenknown for some time that méthylène blue is a moderately efficient hydrogen acceptor inseveral enzyme sys¬ tems and significantly reduce oxidative stress by scavenging ROS.Moreover, Methylene Blue has antiviral activity and was found to Inhibit the Spike-ACE2Protein-Protein Interaction-a Mechanism that can contribute to its Antiviral ActivityAgainst COVID-19 For many reasons, methylene blue is a promising drug for an activetreatment against SARS-CoV-2 . Since methylene blue can work as a photosensitizer,photodynamic therapy as an antiviral treatment has great potential in the treatment ofCOVID-19.. This clinical study will investigate the effectiveness of SARS-CoV-2 infectedpeople treatment using methylene blue and the following photodynamic therapy after thatour clinically approved patients will receive phenformin and zinc . But methylene bluemay lead to lowering in potassium concentration.Therefore, we will add potassiumsupplement to this combination.
The study is a randomized interventional comparative Phase I/II trial. 360 adult male and
female patients with positive COVID-19 diagnosis and fulfilling the below outlined
inclusion criteria will be enrolled into the study.
--Promising features of our clinical trial
-Il-6 inhibition strategy
1. 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.
2. Methylene blue inhibited IL-6 levels and attenuated Lung Injury Induced by Hindlimb
Ischemia Reperfusion in Rats.
3. For many reasons, methylene blue is a promising drug for an active treatment against
SARS-CoV-2 infected patients. 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 investigated the effectiveness of SARS-CoV-2
infected people treatment using methylene blue and the following photodynamic
therapy
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
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
- A history of renal failure (unless recovered for at least 6 months), lactic
acidosis, recurrent or severe hypoglycemia.
- A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- Other uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements
- Allergic to experimental drugs and patients have the following conditions:
- Medical records of cirrhosis
- Myocardial infarction, developed after the patient was included in the study, but
before the intervention
- bleeding, developed after the patient was included in the study, but before the
intervention
- connection to artificial lung ventilation developed after the patient was included
in the study, but before the intervention
- Active infection, or chronic or persistent infection that might worsen with
immunosuppressive treatment (e.g., HIV, hepatitis B virus, hepatitis C virus,
tuberculosis [TB])
- Liver disease
- Renal disease
- Pregnancy
- Lactation
- Depressive disorder
- Body mass index less than 18 points or higher than 25 points
- Contraindications for hormonal contraception or intrauterine device.
- Autoimmune diseases
- A history of organ, bone marrow or hematopoietic stem cell transplantation
- Patients receiving anti-hcv treatment
- The competent physician considered it inappropriate to participate in the study
Ministry of health.First health cluster ,Riaydh
Riyadh, Saudi Arabia
Amr Ahmed
00966597310032
drmedahmed@gmail.com
Mahmoud Elkazzaz,
00201090302015
mahmoudramadan2051@yahoo.com