News article: Medical team in Bangladesh suggests combination of Ivermectin and Doxycycline for COVID-19 treatment

News article: Bangladesh Medical College Hospital Physician See ‘Astounding Results’ with Drug Combination Targeting COVID-19

Drug Repurposing

Drug repurposing occurs when a drug that is designed (and usually also approved) for use for one type of condition, is applied to a different type of condition. For example, azithromycin is an antibiotic, used to treat bacterial infections. It is FDA-approved for certain types of bacterial infections. But when azithromycin is used to treat Covid-19, a viral disease, it is not working as an antibiotic at all, but as an antiviral. This is drug repurposing.

The advantages of drug-repurposing, as opposed to searching for new drugs, include: lower research and development costs; faster time to market; and for FDA-approved drugs, the possibility of immediate or very prompt use in patients. Most of the drugs being considered for use against Covid-19 are a type of drug repurposing.

Doxycycline

Doxycycline is an antibiotic, which has recently been used to treat Covid-19. This example of drug repurposing has several grounds. First, molecular docking studies showed the potential of doxycycline to bind to Mpro [1] or PLpro [2], or both [3]. Then we know that doxycycline has been used to treat other viral infections, specifically Chikungunya and Dengue infections [4, 5]. And doxycycline has anti-inflammatory properties, which might reduce the risk of a cytokine storm. So these indications caused doxycycline to be prescribed for Covid-19 patients, with some success.

What is a molecular docking study? It is a study done entirely by computer, analyzing the three-dimensional structure of viral components, which are usually proteins, and the structure of some drug or other small molecules (perhaps a natural compound). The study looks for the ability of the drug to bind to the viral protein; this is termed inhibition, as the drug that binds, called the ligand, prevents that viral component from working. To inhibit the viral component in this way, the ligand or inhibitor needs to bind to just the right place, to the receptor binding domain (RBD) of the protein.

For example, when doxycycline binds to the main protease, Mpro, of SARS-CoV-2 (the virus that causes Covid-19), the doxycycline prevents that protease from doing its main task, which is to cut up long non-functional proteins into smaller working viral proteins. When that task is inhibited, the long proteins simply remain non-functional, and the virus cannot continue to replicate. So this inhibition occurs within an infected cell. Other types of inhibition of SARS-CoV-2 target the Spike protein, which the virus uses to infect cells. This type of inhibition prevents infection in the first place, which is perhaps better than the inhibition that occurs after infection. But since no type of inhibition is 100% effective, you need a set of inhibitors, which targets at least several different targets, before and after infection of the cell.

In addition to being a viral inhibitor and an anti-inflammatory, doxycycline is also a zinc ionophore [6]. So doxycycline has the ability to carry zinc through the lipid bilayer, which is the cell wall in human cells. Then, once inside the cell, the zinc ion is able to inhibit the replicase protein which is used by the virus to make copies of its RNA.

Doxycycline was tested, in vitro, against SARS-CoV-2 and found to have an EC50 of 5.6 µM [7]. The study authors suggested that doxycycline be used either as a prophylaxis against Covid-19 or a treatment: “Doxycycline, with its antiviral and anti-inflammatory activities, could be used in prophylaxis of COVID-19 at 100 mg day in combination with chloroquine, or in treatment at 200 mg day during 10 days in combination with hydroxychloroquine.” [7] It’s not clear why chloroquine would be used as prophylaxis and hydroxychloroquine as treatment, unless it is merely a question of the availability of the drugs and the priority for using the better medication for the patients who are sick.

Caution: “According to the FDA, doxycycline is unsafe for pregnant women and is generally not given to young children (under the age of 8). It is contraindicated in people who are allergic to any of the components of the drug. This drug can cause photosensitivity and cause sunburns so it’s best to stay out of the sun while you’re on it.” [10]

Ivermectin

Ivermectin is an important drug used to treat parasitic infections, including scabies. It is designed to kill invertebrates (parasites which lack vertebrae), so it has minimal side effects on humans (since we are vertebrates). The main side effects occur as a result of the sudden death of many parasites within the body, and the body’s reaction to that event. Without a parasitic infection, ivermectin would have very low risk of side effects [8]. “Ivermectin is widely available, due to its inclusion on the WHO model list of essential medicines.” [9]

It is possible that a patient might have an undiagnosed infection with parasites, so that the treatment of Covid-19 with ivermectin might have greater side effects than anticipated. But even in such a case, side effects are quite manageable.

A molecular docking study found that ivermectin may bind to the S2 subunit of the Spike protein in SARS-CoV-2 [11]. The Spike itself is three copies of the same protein, wrapped around one another asymmetrically. The first subunit binds to the ACE2 receptor on the cell, while the second subunit of the Spike initiates the merging of the viral membrane with the cell wall, so as to actually infect the cell with the viral RNA. Ivermectin appears to bind to the second part of the Spike, thereby stopping infection of the cell. “The free energy of stabilization upon ivermectin binding to SARS-CoV-2 spike (S) protein is -15 kcal/mol” — which is a good value for the binding of an inhibitor to a viral protein [11].

Another study of ivermectin, this one in vitro, found a high degree of effectiveness against Covid-19. The study infected Vero cells with the SARS-CoV-2 virus. After infection, ivermectin was added to the mix. The result was a sharp decrease in the viral RNA detected, indicating a reduction of viral replication within the infected cells. By 48 hours, there was about a 5000-fold reduction in viral RNA. And this was caused by a single addition of ivermectin at only

Note: Vero cells are a type of cell sold by research companies to be used in studies as an analog for human cells. Tests on Vero cells are known to yield very similar results to the same tests on human cells. For the first several months of the Covid-19 pandemic, all of the in vitro studies were of SARS-CoV-1 (the virus that causes SARS), not SARS-CoV-2. Only recently have in vitro studies of the SARS-CoV-2 virus, done in a biosafety level 3 lab, been available.

“As above, a >5000 reduction in viral RNA was observed in both supernatant and cell pellets from samples treated with 5 µM ivermectin at 48 h, equating to a 99.98% reduction in viral RNA in these samples. Again, no toxicity was observed with ivermectin at any of the concentrations tested. The IC50 of ivermectin treatment was determined to be ~2 µM under these conditions.” [9]

This is a particularly low concentration for an IC50, only 2 µM. And even at 5 or 10 µM, the concentration is low enough to be attainable in vivo, without having to use a dosage so high that major side effects would be feared. So the study indicates that the usual dosage of ivermectin might be sufficient to inhibit SARS-CoV-2 substantially.

Clinical Trial: Doxycycline and Ivermectin

As far as I could determine, the first clinical study of doxycycline against Covid-19 was done in Bangladesh, and recently announced by the study authors in the media, prior to scientific publication. The study combined doxycycline with ivermectin, with remarkable results:

“the team tested a combination of the antiparasitic drug Ivermectin and the antibiotic Doxycycline on a group of 60 COVID-19 patients, all of whom were cured within four days of treatment with the combo. The patients had reported breathing problems and other symptoms of the coronavirus disease and were confirmed to be COVID-19 positive. None of the patients showed any side effects and all of them tested negative for the virus in the repeated or the second test.” [10]

The study has not yet been published. The clinicians are preparing an article for publication in an international medical journal. An article by a physician, Dr. Kamal Kant Kohli, on the therapy is found at: MedicalDialogues.in.

The Bangladeshi study is discussed at length by Dr. Mobeen Syed in this video “COVID-19 Insights: Bangladeshi Doctors Use A Drug Combo Successfully” on the “Drbeen Medical Lectures” YouTube channel. His explanation is both accessible to the non-medical layperson and has substantial technical depth and breadth. Recommended.

Summary

Doxycycline and Ivermectin have both shown promise against Covid-19 in molecular docking studies and in vitro studies. The combination makes sense as doxycycline inhibits the two SARS-CoV-2 proteases, while ivermectin inhibits the Spike protein, and both are effective at modest doses. In addition, the two drugs do not conflict with one another, when combined (as happens when hydroxychloroquine is used with azithromycin). And each medication is widely available, inexpensive, and has known safely profiles. Doxycycline also has anti-inflammatory effects, and is a zinc ionophore [6].

This last point suggests that a triple therapy: ivermectin, doxycycline, and zinc. In addition, since hydroxychloroquine, chloroquine, and doxycycline, are each zinc ionophores, a reasonable prophylaxis would be to take a zinc supplement, so that zinc levels in the body are already high, in preparation for whichever therapy might be used, should the person become ill with Covid-19.

Please note that doxycycline is contraindicated in pregnant women and in children younger than eight years of age. Ivermectin is in pregnancy category C; the manufacturer of ivermectin cautions against its use in pregnancy. However, large scale distributions of ivermectin have not found any adverse affects on pregnant women [12].

Ronald L Conte Jr
Covid.us.org
Note: the author of this article is not a doctor, nurse, or healthcare provider.

1. Wafa, Tachoua, and Kabrine Mohamed. “Molecular Docking study of COVID-19 Main Protease with Clinically Approved Drugs.” (2020).

2. Choudhury, Shuvasish, et al. “In search of drugs to counter the countermeasures of SARS-CoV-2 in evading host’s innate immune defense: a Molecular modeling approach.” (2020).

3. Wu C, et al. “Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods”, Acta Pharmaceutica Sinica B.

4. Rothan, Hussin A., et al. “A combination of doxycycline and ribavirin alleviated chikungunya infection.” PloS one 10.5 (2015).

5. M Fredeking, Terry, et al. “Dengue patients treated with doxycycline showed lower mortality associated to a reduction in IL-6 and TNF levels.” Recent patents on anti-infective drug discovery 10.1 (2015): 51-58.

6. Te Velthuis, Aartjan JW, et al. “Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture.” PLoS pathogens 6.11 (2010).

7. Gendrot, Mathieu, et al. “In vitro antiviral activity of doxycycline against SARS-CoV-2.”

8. Antimicrobe.org, Ivermectin

9. Caly, Leon, et al. “The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro.” Antiviral research (2020): 104787.

10. FirstPost.com, “Medical team in Bangladesh suggests combination of Ivermectin and Doxycycline for COVID-19 treatment”; 18 May 2020.

11. Dasgupta, Jhimli, et al. “Nsp7 and Spike Glycoprotein of SARS-CoV-2 are envisaged as Potential Targets of Vitamin D and Ivermectin.” (2020).

12. Pacque, M., et al. “Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution.” The Lancet 336.8729 (1990): 1486-1489.