The story of ivermectin begins with its discovery in the mid-1970s thanks to Satoshi Omura, a microbiologist at Tokyo’s Kitasako Institute [4]. He sampled soil in search of new antibacterial properties and sent them to Merck Research Labs in New Jersey where his collaborator, William Campbell, tested their effectiveness against various parasitic worms [4]. One culture grew Streptomyces avermitilis which demonstrated a potent response against helminthes substances. The biologically active component, avermectin, needed minor chemical modifications to increase its safety and activity. It was later renamed the compound we know today, ivermectin. Ivermectin was initially only used by veterinarians to treat parasitic infections in animals. It wasn’t until 1987, when William Campbell urged for a trial of ivermectin as a treatment for onchocerciasis, that ivermectin began being prescribed for humans [4]. Since it’s initial utilization for onchocerciasis, ivermectin continues to be used in unique ways to treat a variety of conditions and now is known as the mainstay treatment for head lice and scabies.

Apart from its antiparasitic activity, ivermectin has several other effects including anti-inflammatory, antibacterial, and anticancer properties. Among these various actions, ivermectin’s antiviral properties continue to gain traction for further investigation due to the continued prominence of the COVID-19 global pandemic.

The fundamental mechanism of ivermectin and its treatment of parasitic infections, scabies, and lice, stems from its ability to inhibit glutamate Cl− channels. Glutamate Cl− channels are expressed in the musculature of invertebrates, and consequently inhibition of these channels causes paralysis and eventual organism death [7]. Fortunately, for humans, as vertebrates, these channels are not present in the core musculature and are only accessible after crossing the blood-brain barrier, which ivermectin is unable to do. In addition to paralysis, other mechanisms surrounding the effects of glutamate Cl− channel inhibition have been identified. Specifically, with microfilarial infections such as onchocerciasis, inhibition of glutamate Cl− channels demonstrated a decrease in excretory-secretory vesicle secretion of proteins which resulted in the parasite’s inability to evade the host’s natural immunologically mediated TH2 response [7]. Thus, demonstrating ivermectin’s versatility in treatment with its fundamental mechanism.

The treatment of another skin condition, dermatitis, led to the discovery of the anti-inflammatory mechanisms of ivermectin. Studies performed by Ventre et al. and Barańska-Rybak & Kowalska-Olędzka applied topical ivermectin to various inflammatory skin conditions, including allergic dermatitis and perioral dermatitis, and successfully demonstrated sustained decreases in inflammation [8, 9]. The proposed mechanism involves the reduction in the activation of allergen-specific T-cells, and diminished production of inflammatory cytokines. Ivermectin accomplishes this by inhibiting phosphorylation of the mitogen-activated protein kinases (MAPK) p38, extracellular -signal-regulated kinase (ERK) n1/2, and c-Jun N-terminal kinase (JNK). Consequently, this results in inhibition of iNOS, and COX2 gene expression, which suppresses the inflammatory mediator’s NO and prostaglandin E2 (PGE2) [9].

In addition to the mechanisms of treating dermatological conditions, researchers have successfully discovered the utilization of ivermectin in anti-bacterial and anti-cancer treatments. Lim et al. found that ivermectin, as well as other avermectins, elicits a bactericidal effect that successfully treats most drug-resistant M. tuberculosis clinical isolates and M. tuberculosis laboratory strains [10]. Ashraf et al. provided findings that further support this notion with their demonstration of ivermectin’s potent anti-staphylococcal activity [11]. More recently, Juarez et al. identified ivermectin’s anti-cancer properties that included its ability to modulate multidrug resistance proteins (MDR), the Akt/mTOR and WNT-TCF pathways, the purinergic receptors, the PAK-1 protein, certain cancer-related epigenetic deregulators such as SIN3A and SIN3B, RNA helicase activity, and the ability to down-regulate stemness genes to preferentially target cancer stem-cell like populations [12]. All of these innovations demonstrate ivermectin’s untapped potential as a therapeutic modality.

These studies support the future of ivermectin and its antiviral properties, as well as highlight its ability to fight against COVID-19. One known antiviral property of ivermectin is its ability to inhibit nuclear transport mediated by the importin α/β1 heterodimer, and consequently prevent the translocation of viral proteins necessary for replication [13]. This mechanism directly affect several RNA viruses including Dengue Virus 1-4 (DENV), West Nile Virus (WNV), and Venezuelan Equine Encephalitis Virus (VEEV), and Influenza [14-17]. Therefore, with the identification of COVID-19 as an RNA virus, it was inferred a similar mechanism might apply. Errecalde et al. recently confirmed this mechanism to be true in COVID-19 with their pig model assessment of intranasal ivermectin [6]. Furthermore, preliminary studies in humans identify an earlier clearance of COVID-19 in those treated with a 5-day course of ivermectin compared to placebo [18]. Thus, supporting the claim of ivermectin’s ability to combat COVID-19 successfully, and warranting continued investigation of harnessing ivermectin’s importin α/β1 heterodimer antiviral mechanism to combat the virus in other ways.

As we look to integrate ivermectin into the arsenal of treatment methods for COVID-19, it is imperative to learn from current indications of ivermectin use. In dermatology, ivermectin treats scabies with a 200 mcg/kg single oral dose and may be repeated in 14 days if necessary. It can also be prescribed for Gnathostomiasis, a parasitic infection with creeping eruptions, a 200 mcg/kg as a single oral dose. Off-label ivermectin treats head lice with a 200 mcg/kg single oral dose that may require 1-2 additional doses repeated after 7 days. Another off-label use of ivermectin treats blepharitis with a 200 mcg/kg single oral dose followed by a repeat dose once in 7 days. Topical 1% ivermectin cream off-label treats resistant rosacea and resistant dermatitis.

Other indications for ivermectin use include strongyloidiasis of the intestinal tract and river blindness (Onchocerciasis) and off-label uses for filariasis due to Mansonella Ozzardi and filariasis due to Mansonella Streptocerca. Dosing for strongyloidiasis ranges from 3-200mcg/kg single oral dose and only needs a repeat dose if stool examinations demonstrate a lack of eradication of infection. Dosing for onchocerciasis ranges from 3-150mcg/kg single oral dose that can be repeated in 3-12 months based on clinical symptoms. Dosing for filariasis due to Mansonella Ozzardi is 6mg as a single oral dose and for filariasis due to Mansonella Streptocerca 150mcg/kg as a single oral dose.

Suggested indications for ivermectin use in the treatment of COVID-19 should originate with its mechanism of impeding viral replication. One possible indication is an immediate one-time oral dose in newly infected individuals to suppress further increases in viral load, which in turn would reduce the duration and severity of infection. Another possible indication for ivermectin utilization in COVID-19 is for individuals suffering from a severe inflammatory response due to the infection. These individuals could benefit from one or more oral doses of ivermectin to not only diminish the viral load but also exploit the anti-inflammatory properties of the drug to lower cytokine levels. Although administration of parenteral ivermectin is not approved yet, intranasal use of ivermectin provides another unique vector that needs to be considered. Errecalde et al. found in a 60 kg body weight person, higher ivermectin concentrations in nasopharyngeal tissue were attained with 4 mg intranasally (2 spray doses 12 h apart) than giving 12 mg orally (1 dose 0.2 mg/kg) [6]. They also found two sprays elicited significantly higher concentrations of ivermectin than one spray. This suggests that the intranasal administration of ivermectin in humans can provide faster and higher levels of ivermectin for longer periods when compared to oral administration. As a result, intranasal treatment could potentially provide enhanced protection against COVID-19, a virus that enters through the nasopharynx. COVID-19 patients treated with intranasal ivermectin had a greater rate of two consecutive negative PCR nasopharyngeal swabs (94.7% vs. 75.4% P=0.004) and shorter periods for a nasopharyngeal swab to be negative (8.3± 2.8 days versus 12.9 ± 4.3 days; P = 0.0001) compared to COVID-19 patients treated as per the standard Egyptian protocol [19]. They also found shorter durations of fever, cough, dyspnea, and anosmia between the two groups (fever, 5 ± 1.7 days versus 13.6 ± 2.7 days; cough, 5 ± 1.9 days versus 14 ± 2.6; dyspnea, 4.4 ± 2.7 days versus 10.1 ± 3.4; anosmia, 0.5 ± 0.9 versus 1.6 ± 3.2, with P = 0.0001 for all) [19].This evidence supports a new application of ivermectin as a treatment for COVID-19. It is important to note that some studies demonstrate dissimilar and contradictory results. However, the intent of this article is not to evaluate the merit of ivermectin’s effectiveness as a treatment in the literature, but rather to highlight a potential new treatment modality for COVID-19. More specifically, we suggest a once-daily administration of intranasal ivermectin for health care workers to ensure protection against COVID-19 in the nasopharyngeal tissue. Errecalde et al. also assessed intranasal ivermectin concentrations in the lung, and found that although there is notable distribution in the lung after intranasal administration, concentrations measured at 6h post-treatment were higher in those receiving oral ivermectin [6]. Therefore, we also suggest that an indication of oral ivermectin might be preferred for protection against more severe pulmonary infections, while intranasal administration might be prioritized for rapid preventative purposes and nasal mucosa protection. Nevertheless, parenteral uses of ivermectin and warrant further investigation, especially when considering many patients suffering from COVID-19 are intubated and cannot receive oral ivermectin. Furthermore, the plethora of possible indications of ivermectin as a modality of treatment for COVID-19 identifies the value it can bring to healthcare as a proactive defense against the global pandemic.

When considering repurposing ivermectin as a treatment for COVID-19, one must assess drug interactions. Of particular interest, drug interactions with other medications currently being used to treat COVID-19. Dexamethasone is one of the drugs widely used to treat COVID-19 due to its anti-inflammatory properties. Areskog et al. assessed dexamethasone’s interactions with ivermectin in calves and demonstrated significantly lower plasma levels of ivermectin in the group concomitantly treated with dexamethasone compared to the group treated with only ivermectin [20]. They concluded that dexamethasone altered the pharmacokinetics of ivermectin and impaired its efficacy. Therefore, optimal treatment of COVID-19 with ivermectin likely requires cessation of dexamethasone.

Another medication that currently treats COVID-19 patients is the antiviral agent, remdesivir. Remdesivir had been previously thought to depend on p-glycoprotein for transportation, which posed a concern if used in conjunction with ivermectin. These concerns included inhibitory effects causing increased plasma concentration of either ivermectin or remdesivir, as well as alterations of the pharmacokinetics of remdesivir due to ivermectin’s functionality as both a substrate and an inducer of p-glycoprotein [21]. However, alternative preclinical studies indicate that remdesivir is not a substrate of CYP2C8, CYP2D6, or CYP3A4, and is not “significantly” transported by ABCB1/Pgp or the OATP type drug transporters [22]. This conclusion alleviates concerns that ivermectin and remdesivir will have drug-drug interactions. Telbisz et al. also addressed concerns of other antivirals inhibiting ivermectin’s P-glycoprotein efflux pumps at the blood-brain barrier and potentially causing neurotoxicity [22]. To do this, they identified a recent analysis of ivermectin-related neurotoxic adverse events reported to the WHO Program for International Drug Monitoring that showed only one case out of 1,668 reports in which, concomitant use of antivirals and ivermectin was associated with neurotoxicity [22]. Consequently, one can surmise that ivermectin and remdesivir are safe to utilize together in the treatment of COVID-19. Of note, Telbisz et al. brings to light concerns that the ivermectin plasma concentrations required to reach an in vitro antiviral efficacy (about 2–10 μM) are highly toxic, and very high oral doses would be needed for antiviral use. These concerns were previously identified but left with the caveat that animal models show up to a 3-fold higher ivermectin level in pulmonary tissue than in plasma, and leave the potential for targeted increases in concentration to possibly circumvent toxic level doses [23]. Thus, illuminating the recommendation of an ivermectin nasal spray since it can reach these required antiviral concentration levels in the nasopharynx without inducing toxic plasma levels. Further investigation into whether or not the same P-glycoprotein transporters and pharmacokinetics apply to nasal administration of ivermectin is recommended for optimal safety.

Other pertinent interactions to consider with the use of ivermectin to treat COVID-19 include alcohol and fruit juices. The data of the pharmacokinetic effects of these beverages on ivermectin, although minimal, demonstrates significantly elevated plasma concentrations of ivermectin when co-administered with 750ml of beer when compared to water, and a decreased plasma concentrations when co-administered with orange juice when compared to water [24, 25]. The drug interference mechanism is suggested to be related to GABA with regards to the alcohol and the effect of fruit juices on drug transporters. Although not direct medications administered in a hospital, the general population commonly consumes both of these beverages, and practitioners should make a note when assessing the appropriate administration of ivermectin.

Drug resistance and safety are the final aspects to address in the discussion of repurposing ivermectin as a modality to treat COVID-19. Despite 40 years of continued use of ivermectin, and billions of doses administered for various parasitic and dermatological conditions, there is minimal evidence of drug resistance. This is not to say that expanding ivermectin’s use as a treatment modality will not potentially lead to the development of drug resistance. However, until the prominent evidence of drug resistance develops, safety precautions against possible effects of ivermectin should be the primary focus. The main safety concern with ivermectin use is neurotoxicity due to high doses causing the activation of GABA-gated chloride channels in the mammalian central nervous systems [23]. In addition, patients with genetic defects in p-glycoprotein channels are at a higher risk of neurotoxicity [22]. Another effect to monitor is prolonged prothrombin times due to the reduced factor II and factor VII levels [5]. Although patients in this study did not suffer any bleeding complications, and mass treatment was deemed unjustified, it is suspected that ivermectin interferes with Vitamin K metabolism and therefore requires monitoring in higher risk populations. The involvement of other organ systems is minimal, but mild to moderate ocular events were noted in patients receiving higher doses of ivermectin [26]. The safety concerns with ivermectin use are not entirely negligent, but low enough to consider it as a safe drug to use in the treatment of COVID-19 and even possibly the drug of choice to treat the new variants due to its non-existent drug resistance profile.