|
 
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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 22
| Issue : 3 | Page : 27-31 |
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Role of ivermectin in COVID-19: Wishful thinking or scientific optimism
Prafull Mohan, Sharmila Sinha, Rajdeep Uppal
Department of Pharmacology, AFMC, Pune, Maharashtra, India
| Date of Submission | 29-Sep-2020 |
| Date of Decision | 03-Oct-2020 |
| Date of Acceptance | 05-Oct-2020 |
| Date of Web Publication | 02-Nov-2020 |
Correspondence Address:
Col (Dr) Prafull Mohan
Department of Pharmacology, AFMC, Pune - 411 040, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jmms.jmms_146_20
Ivermectin is routinely used for indications such as strongyloidiasis, onchocerciasis, and scabies. It is also known to possess antimicrobial, anticancer, antimitotic, anti-allergic, and antiviral properties. It has been found to inhibit SARS-COV-2 in an in-vitro study, following which, a lot of interest has been generated regarding its role in the treatment of COVID-19. However, as per extrapolation from in vitro study, the current approved dose of ivermectin may not result in sufficient concentration in the lungs to have an anti-COVID-19 effect. However, a large number of trials using different ivermectin doses are underway to generate conclusive data. If ivermectin fails to show clinical benefit in ongoing trials, additional studies to address its safety at much higher doses, additional mechanisms of its action, and different routes of administration/formulations may be required. As of now, ivermectin shows promise against SARS-CoV-2, but the dose and context of its use remains nebulous.
Keywords: Antiviral effects, COVID-19, ivermectin, SARS-CoV-2
How to cite this article:
Mohan P, Sinha S, Uppal R. Role of ivermectin in COVID-19: Wishful thinking or scientific optimism. J Mar Med Soc 2020;22, Suppl S1:27-31 |
| Introduction | |  |
An effective and dependable therapeutic intervention against COVID-19 still eludes us while the disease has already infected more than 34 million individuals and claimed more than a million lives globally.[1] Ivermectin, an established and relatively safe antihelminthic drug, has generated hope as a possible agent against COVID-19. Besides its effect against various ecto- and endoparasites, ivermectin has also displayed antibacterial, anticancer, antiviral, antimitotic, and anti-allergic properties.[2],[3],[4],[5],[6] In the current pandemic, hopes have been put in ivermectin due to findings reported by Caty et al. revealing its anti-COVID-19 property in a singlein vitro study. Although conclusive clinical evidence regarding its efficacy in COVID-19 is still not available, there are several clinical trials which are underway. This review attempts to understand the role of ivermectin in COVID-19, along with the available evidence.
| Current Use of Ivermectin | | |
Ivermectin has broad-spectrum activity having action against multiple parasites not only of humans but also of livestock and pets. It has activity against cattle tick (Rhipicephalus microplus), barber's pole worm (Haemonchus contortus), and mange (Sarcoptes scabiei) to name a few.[7] In humans, it is the drug of choice for river blindness (onchocerciasis) and strongyloidiasis. The main current indications are summarized in [Table 1].
| Pharmacokinetics and Safety | | |
Ivermectin is absorbed from the gastrointestinal tract following oral administration and reaches a peak plasma concentration of 20–50 ng/dl following the doses of 6 and 12 mg.[9] It is primarily metabolized in the liver by CYP3A4 hepatic microsomal enzyme system to numerous metabolites and is a substrate for P-glycoprotein.[10] It does not cross an intact blood–brain barrier and takes approximately 4 h to reach maximum concentration in plasma. It is reported to be 93% plasma protein bound and has a plasma elimination half-life of about 12–24 h. It is chiefly excreted in feces over a period of 12 days, with <1% of the dose excreted in urine.[11] In routine dose, ivermectin is largely safe, giving rise to minor side effects only, such as pruritus, giddiness, nausea, and lethargy.[8]
| Mechanism of Action | | |
Ivermectin acts on gamma aminobutyric acid-gated chloride channels which cause increased conductance of the electrolyte, causing hyperpolarization of the cell membrane, and blocking inhibitory neurotransmission in neurons and myocytes, thereby resulting in paralysis and death of the infesting organism.[12] Invertebrates are 100 times more sensitive for this action as compared to vertebrates. It also acts on various receptors such as Cys-loop receptors, P2 ×4 receptors, and fernesoid × receptors.[13] Ivermectin has also been postulated to have immunomodulatory effect by activation of neutrophils, C-reactive protein, and iterleukin-6.[14]
Ivermectin is also known to possess antiviral effects against a number of viruses. Postulated mechanisms of antiviral effect consist of inhibiting nuclear transport mediated by importin α/β1 heterodimer which is responsible for incorporating viral protein into host cell nucleus.[15] Ivermectin also exerts antiviral effect by virtue of it being an ionophore.[3],[16],[17] The list of viruses against which ivermectin has effect (in vitro and/or in vivo) is given in [Table 2]. | Table 2: List of viruses against which ivermectin has been found to be having anti-viral action[25]
Click here to view |
As is apparent, there is evidence ofin vitro antiviral effects of ivermectin against a number of viruses.In vivo evidence of antiviral effect is limited and is contradictory in some cases.[19],[20]
| Ivermectin in Covid-19 | | |
Due to its broad-spectrum antiviral activity, ivermectin was also investigated for its anti-COVID-19 action.In vitro results reported a 5000-fold reduction in viral.
RNA in 48 h compared with control in Vero/hSLAM cells infected with SARS-CoV-2 when exposed to 5 μM ivermectin.[15] This meant that treatment with ivermectin effectively killed almost all viral particles in 48 h. It was postulated that this effect may be due to the same inhibitory effect on importin a/b1 which reduces the translocation of viral RNA into host cell nucleus.[15] As of now, the authors have not come across anyin vivo animal study reflecting ivermectin's use in COVID-19.
Clinical evidence of ivemectin use in COVID-19 is limited. Ivermectin–doxycycline combination was found to be superior in a study conducted on patients with mild-to-moderate COVID-19 disease. However, the difference in time to becoming symptom-free and the difference in time to negative PCR were not statistically significant.[26] Similarly, ivermectin doxycycline–combination was found to be very effective in viral clearance of mild-to-moderately sick COVID-19 patients in a case series.[27] Nevertheless, ivermectin is being used across the world as prophylaxis or as a part of treatment protocol for COVID-19. In addition, some state governments in India, namely Uttar Pradesh, Punjab, and Bihar, have included ivermectin in their official treatment protocols.[28],[29],[30] The Government of Uttar Pradesh is also prescribing ivermectin to possible contacts of patients of COVID-19.[30] Similar use in the form of prophylaxis and/or treatment protocols also seen in other countries (Brazil, Peru, and Bolivia to name a few).[31]
| Issues in Using Ivermectin for Covid-19 | | |
Caty et al. in theirin vitro study used a concentration of 5 μM, which leads to a 5000-fold reduction in viral load. On the basis of this finding, it was estimated that IC50 of ivermectin against SARS Cov-2 is 2 μM. This IC50 corresponds to an effective plasma concentration of 1750 ng/ml. This estimated plasma concentration is approximately 25 times higher than the plasma concentration of 46.6 ng/ml which is achieved after the maximum approved dose (i.e., 200 μg/kg) in humans.[10] Even considering differential distribution into the lungs as seen in cattle (lung homogenate: plasma concentration: 2.7:1),[10] the concentration in lung tissue is likely to be much less as compared to anti-SARS CoV-2 effective concentration of 1750 ng/ml. Pharmacokinetic studies in healthy individuals have suggested that use of single doses up to 120 mg can be safe and well tolerated.[32] The maximum plasma concentration reported with even this dose is around 250 ng/ml, which is quite lower than the effectivein vitro concentration against SARS-CoV-2.
To reach the desired concentrations, ivermectin would have to be given in very high doses, safety of which is not established. Although generally considered as a safe drug, it has the potential of crossing blood–brain barrier, especially in people with hyperinflammatory states which might lead to neurotoxicity. There are concerns regarding ocular and cutaneous adverse events as well.[33],[34] The bioavailability of ivermectin can increase when co-administered with CYP3A4 enzyme inhibitors, thereby leading to higher plasma concentration. This coupled with P-glycoprotein inhibition can further increase the entry of the drug past blood–brain barrier.[35],[36]
Furthermore, any indiscriminate use can have ecological consequences with ivermectin entering into the food chain. This can have a detrimental effect on its antihelminthic use with a high possibility of development of resistance.[37]
| Emerging Evidence | | |
As per the clinicaltrials.gov, there are a total of 39 ongoing clinical trials concerning ivermectin use in COVID-19 at different stages, at the time of writing. Four clinical trials have been completed, with one clinical trial displaying its efficacy in protective use in contacts of COVID-19 when compared to the control group.[38] The dose instituted is mentioned only in some trials. The highest reported dose which is being tested is 600 μg/kg OD. However, even this high dose will lead to plasma concentration which is much lower as compared to plasma concentration derived by Caly et al. In clinical trials, ivermectin has been used in combination with other investigational anti-COVID-19 drugs such as azithromycin, doxycycline, and chloroquine. The rationale/pharmacological logic behind such combination is nebulous, except in case of hydroxychloroquine where a combination of ivermectin and hydroxychloroquine may exert a synergistic effect against SARS CoV-2. Hydroxychloroquine acts by inhibiting SARS-COV-2 into the host cells, whereas ivermectin would further enhance antiviral activity by inhibiting viral replication.[39]
| Way Forward | | |
As per the estimated IC50 values (by Caty et al.), doses currently used (off label) and doses used in ongoing trials are unlikely to produce a significant anti-COVID-19 effect. However, in view of its use in combinations, other unknown antiviral mechanisms, and physiological differences betweenin vitro andin vivo environment, the possibility of ivermectin exhibiting anti-COVID-19 effects in clinical trials cannot be ruled out. If currently used doses are unable to produce clinical benefit, further investigation including safety studies at much higher doses, proof of concept studies in animal model, and dose ranging in humans shall be warranted. Establishing the safety of ivermectin in pregnant women and children is another priority research area.[40]
Inhalational preparation of ivermectin is another proposed strategy to get increased local concentrations of the drug in lung tissue.[10] One preclinical study has been done on inhaled ivermectin on Sprague–Dawley rats, in which no-observed-adverse-effect-level after 28 days of inhaled ivermectin was identified to be 380 mg/m3.[41] Inhalational toxicity studies in suitable animal models are required to establish the safety and efficacy of inhalational ivermectin.
There has also been interesting in various liposomal delivery systems where ivermectin could be given as nanocarriers. If rendered useful, then the dose to be delivered of the drug could be increased without any rise in the chance of adverse drug reactions such as neurotoxicity.[42]
Many vaccine candidates are in pipeline, with few of them showing early promising results. However, the effectiveness of any future approved vaccine remains to be seen. Till it happens, our best hope can be to limit the virus spread and have reasonably effective treatment protocols if not a straight shot individual drug. Ivermectin has shown promise in studies mentioned in this article, it has a robust safety profile, and if proven useful in clinical trials, it will help reduce the burden of COVID-19.
| Conclusion | | |
Ivermectin is a widely used drug with established safety. Its repurposing for treatment/prophylaxis of COVID-19 appears promising, especially in light of its demonstratedin vitro efficacy. However, pharmacokinetic imperative of its use in COVID-19 warrants that robust clinical evidence be generated a priori. Using higher than usual doses, using it in combinations, administering by different routes are some of the research areas that need to be explored if already approved doses fail to exhibit efficacy against COVID-19.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | |
| 2. | Lim LE, Vilchèze C, Ng C, Jacobs WR Jr., Ramón-García S, Thompson CJ. Anthelmintic avermectins kill Mycobacterium tuberculosis, including multidrug-resistant clinical strains. Antimicrob Agents Chemother 2013;57:1040-6.  |
| 3. | Juarez M, Schcolnik-Cabrera A, Dueñas-Gonzalez A. The multitargeted drug ivermectin: From an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res 2018;8:317-31. |
| 4. | Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J 2012;443:851-6. |
| 5. | Ashraf S, Prichard R. Ivermectin exhibits potent antimitotic activity. Vet Parasitol 2016;226:1-4. |
| 6. | Ventre E, Rozières A, Lenief V, Albert F, Rossio P, Laoubi L, et al. Topical ivermectin improves allergic skin inflammation. Allergy 2017;72:1212-21. |
| 7. | Molento MB. COVID-19 and the rush for self-medication and self-dosing with ivermectin: A word of caution. One Health 2020;10:100148. |
| 8. | |
| 9. | González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans A mini-review. AAPS J 2008;10:42-6. |
| 10. | Schmith VD, Zhou JJ, Lohmer LR. The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19. Clin Pharmacol Ther 2020;108:762-5. |
| 11. | Canga AG, Prieto AM, Liébana JD, Martínez NF, Veja MS, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans A mini-review. Am Assoc Pharm Sci J 2008;10:42-6. |
| 12. | Geary TG. Ivermectin 20 years on: Maturation of a wonder drug. Trends Parasitol 2005;21:530-2. |
| 13. | Chen IS, Kubo Y. Ivermectin and its target molecules: Shared and unique modulation mechanisms of ion channels and receptors by ivermectin. J Physiol 2018;596:1833-45. |
| 14. | Njoo FL, Hack CE, Oosting J, Luyendijk L, Stilma JS, Kijlstra A.C-reactive protein and interleukin-6 are elevated inonchocerciasis patients after ivermectin treatment. J Infect Dis 1994;170:663-8. |
| 15. | Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020;178:104787. |
| 16. | Krenn BM, Gaudernak E, Holzer B, Lanke K, Van Kuppeveld FJ, Seipelt J. Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. J Virol 2009;83:58-64. |
| 17. | Sandler ZJ, Firpo MR, Omoba OS, Vu MN, Menachery VD, Mounce BC. Novel Ionophores Active against La Crosse Virus Identified through Rapid Antiviral Screening. Antimicrob Agents Chemother. 2020 May 21;64(6):e00086-20. doi: 10.1128/AAC.00086-20. |
| 18. | Ketkar H, Yang L, Wormser GP, Wang P. Lack of efficacy of ivermectin for prevention of a lethal Zika virus infection in a murine system. Diagn Microbiol Infect Dis 2019;95:38-40. |
| 19. | Surnar B, Kamran MZ, Shah AS, Basu U, Kolishetti N, Deo S, et al. Orally administrable therapeutic synthetic nanoparticle for Zika virus. ACS Nano 2019;13:11034-48. |
| 20. | Xu TL, Han Y, Liu W, Pang XY, Zheng B, Zhang Y, et al. Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus. PLoS Negl Trop Dis 2018;12:e0006934. |
| 21. | Azeem S, Ashraf M, Rasheed MA, Anjum AA, Hameed R. Evaluation of cytotoxicity and antiviral activity of ivermectin against Newcastle disease virus. Pak J Pharm Sci 2015;28:597-602. |
| 22. | Wang X, Lv C, Ji X, Wang B, Qiu L, Yang Z. Ivermectin treatment inhibits the replication of Porcine circovirus 2 (PCV2) in vitro and mitigates the impact of viral infection in piglets. Virus Res 2019;263:80-6. |
| 23. | Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antivir Res 2018;159:55-62. |
| 24. | Nguyen KY, Sakuna K, Kinobe R, Owens L. Ivermectin blocks the nuclear location signal of parvoviruses in crayfish, Cherax quadricarinatus. Aquaculture 2014;420-421:288-94. |
| 25. | Heidary F, Gharebaghi R. Ivermectin: A systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot (Tokyo) 2020;73:593-602. |
| 26. | Chowdhury ATMM, Shahbaz M, Karim MR, Islam J, Guo D, He S. A Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients. Research Square; 2020. DOI: 10.21203/rs.3.rs-38896/v1 |
| 27. | Alam MT, Murshed R, Bhiuyan E, Saber S, Alam R, Robin R. A Case Series of 100 COVID-19 Positive Patients Treated with Combination of Ivermectin and Doxycycline. Journal of Bangladesh College of Physicians and Surgeons, 2020;38:10-5. |
| 28. | |
| 29. | |
| 30. | |
| 31. | |
| 32. | Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol 2002;42:1122-33. |
| 33. | Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun 2017;60:1-12. |
| 34. | Navarro M, Camprubí D, Requena-Méndez A, Buonfrate D, Giorli G, Kamgno J, et al. Safety of high-dose ivermectin: A systematic review and meta-analysis. J Antimicrob Chemother 2020:75;827-34. |
| 35. | |
| 36. | Drewe J, Gutmann H, Fricker G, Török M, Beglinger C, Huwyler J. HIV protease inhibitor ritonavir: A more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol 1999;57:1147-52. |
| 37. | Molento MB. Parasite control in the age of drug resistance and changing agricultural practices. Vet Parasitol 2009;163:229-34. |
| 38. | |
| 39. | Patrì A, Fabbrocini G. Hydroxychloroquine and ivermectin: A synergisticcombination for COVID-19 chemoprophylaxis and/or treatment? J Am Acad Dermatol 2020;82:e221. |
| 40. | King CL. Is ivermectin safe in pregnancy? Lancet Glob Health 2020;8:e12-3. |
| 41. | Ji L, Cen J, Lin S, Hu C, Fang H, Xu J, et al. Study on the subacute inhalation toxicity of ivermectin TC in rats. Chin J Comp Med 201626:70-4. |
| 42. | Croci R, Bottaro E, Chan KW, Watanabe S, Pezzullo M, Mastrangelo E, et al. Liposomal systems as nanocarriers for the antiviral agent ivermectin. Int J Biomater 2016;2016:8043983. |
[Table 1], [Table 2]
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