Ivermectin, Famotidine, and Doxycycline: A Suggested Combinatorial Therapeutic for the Treatment of COVID-19

Abstract

At times, combination therapy has proven to be very effective. While no cure is available to date, herein we put forward with rationale and supporting evidence that if administrated simultaneously, a combination of FDA-approved drugs comprising ivermectin, famotidine, and doxycycline may provide robust chemoprophylaxis effective against COVID-19.

The outbreak of SARS-CoV-2 (COVID-19) causing innumerable death and infections across 216 countries/territories has turned into the biggest pandemic of the century. Moreover, the lack of any approved cure to date insinuates health, social, and economic debacles globally. While the search for preventive cures perseveres, two less expensive and safer FDA-approved drugs ivermectin and famotidine were noticed to be effective against SARS-CoV-2.^1,2 Similarly, doxycycline, a class of tetracycline antibiotics, aids to reduce COVID-19-induced inflammation.³ At times, combination therapy has proven to be very effective as a combination of interferon-beta-1b, lopinavir–ritonavir, and ribavirin was found to alleviate symptoms and shorten the duration of viral shedding and hospital stay of patients with mild to moderate COVID-19 infections.⁴ Herein, we hypothesized that if administrated simultaneously, the combination of ivermectin and famotidine with doxycycline may provide robust chemoprophylaxis effective against COVID-19.

Inhibition of the targets responsible for RNA synthesis and replication of SARS-CoV-2 is crucial for inhibitor design. SARS-CoV-2 PLpro aids in replication as well as subverts cellular ubiquitination machinery to facilitate viral survival. Similarly, the RNA-dependent RNA polymerase (RdRp) is vital for the replication/transcription of coronavirus. For these indispensable roles, both are a promising drug target for SARS-CoV-2. Our recent studies^5,6 unraveled PLpro and RdRp of SARS-CoV-2 as plausible targets for famotidine and ivermectin, respectively.

Doxycycline was previously found in a plaque-formation assay to be effective against the dengue virus by inhibiting its serine protease.⁷ It was reported that cytokines are significantly elevated when coronavirus is exposed to lung tissues, inducing the proliferation of mast cells within the respiratory submucosa to produce inflammatory agents.³ Having well-known antimicrobial and anti-inflammatory capabilities, doxycycline thus could be effective against COVID-19.

Ivermectin, an antiparasitic drug, has shown in vitro antiviral activity previously against a broad range of viruses, including HIV, dengue, influenza, and Zika virus.⁸ In breakthrough research at Monash University, Australia, scientists have reported that ivermectin can kill SARS-CoV-2 within 48 h, which has gained considerable attention worldwide.¹ Recently, a medical team from Bangladesh has claimed that a combination of two widely used drugs ivermectin and doxycycline have had “astounding” results in curing patients with acute symptoms of SARS-CoV-2.⁹ Moreover, a recent study from the USA found that the use of ivermectin is associated with lower mortality in hospitalized patients with COVID-19.¹⁰ In the same line, famotidine has also received significant attention.

Famotidine is a histamine-2 receptor antagonist that blocks the action of histamine in parietal cells, ultimately blocking acid secretion in the stomach.² Recently, scientists from the USA have reported that the use of famotidine in 1620 hospitalized patients with COVID-19 was associated with improved clinical outcomes and a reduced risk of intubation or death.² In the past, famotidine has demonstrated its in vitro antiviral properties by inhibiting the replication of HIV.¹¹

On the basis of the evidence, we firmly believe that famotidine and ivermectin would act in a sequential manner with a synergistic effect and doxycycline will augment it by reducing any inflammation. Famotidine would act as a first-level barrier by inhibiting the entry of the virus, subsequently ivermectin would act as a second-level barrier by inhibiting the replication of the virus inside cells, thereby ascertaining a sheer inhibition of the virus. Besides, the safety, easy availability, and low-cost will make these drugs more desirable. With the above rationale, the suggested combination of drugs is thus deemed to be an effective therapy for COVID-19 in this pandemic situation. Herein, we are requesting and inviting all the researchers and clinicians to explore the suggested drugs within permissible levels in clinical trial to unearth their potential in combination therapy for the better treatment of COVID-19.

The authors declare no competing financial interest.