COVID-19: Ivermectin as a potential treatment drug

Numerous clinical trials are being reviewed for use of multiple drugs, biologics, and vaccines in COVID-19.

Ivermectin is one of the potential drugs that can be repurposed for use against SARS-CoV-2 infection.

Ivermectin, a drug used to fight parasites in third-world countries, could help reduce the length of infection for people who contract coronavirus for less than a $1 a day, according to recent research by Sheba Medical Center in Tel Hashomer.Prof. Eli Schwartz, founder of the Center for Travel Medicine and Tropical Disease at Sheba, conducted a randomized, controlled, double-blinded trial from May 15, 2020, through the end of January 2021 to evaluate the effectiveness of ivermectin in reducing viral shedding among nonhospitalized patients with mild to moderate COVID-19.

Nearly 72% of volunteers treated with ivermectin tested negative for the virus by day six. In contrast, only 50% of those who received the placebo tested negative.

As of 16-10-2020, 38 Ivermectin trials are registered with ClinicalTrials.gov and 8 with Clinical Trials Registry, India (CTRI) to validate its use in treatment of COVID-19. Table 1 provides details of clinical trials of ivermectin.

Table 1

Clinical trials of ivermectin (from ClinicalTrials.gov and CTRI as of 16-10-2020)

	Trial registration	Phase/status	Intervention/comparator	Study design	Size/location
1	NCT04343092	Phase 1Completed	Ivermectin	Randomized, parallelMasking: double	100Iraq
2	NCT04422561	Phase 2/phase 3Completed	Ivermectin	Randomized, sequentialMasking: none	340Egypt
3	NCT04434144	Completed	Ivermectin + doxycyclineHydroxychloroquine + azithromycin	Prospective, case-only	116Bangladesh
4	NCT04381884	Phase 2Completed	Ivermectin plus standard careControl arm will receive standard care	Randomized, parallelMasking: none	45Argentina
5	NCT04446104	Phase 3Completed	Hydroxychloroquine sulfate tabletsIvermectin 3 Mg TabZincPovidone-iodineSupplement: vitamin C	Randomized, parallelMasking: none	4257Singapore
6	NCT04523831	Phase 3Completed	Ivermectin and doxycyclineStandard of care	Randomized, parallelMasking: double	400Bangladesh
7	NCT04438850	Phase 2Recruiting	IvermectinPlacebo	Randomized, sequentialMasking: quadruple	102Italy
8	NCT04425707	Not applicableRecruiting	Ivermectin	Randomized, parallelMasking: none	100Egypt
9	NCT04429711	Not applicableRecruiting	Ivermectin oral product	Randomized, parallelMasking: quadruple	100Israel
10	NCT04405843	Phase 2| Phase 3Recruiting	Ivermectin oral productPlacebo	Randomized, parallelMasking: quadruple	400Colombia
11	NCT04445311	Phase 2|Phase 3Recruiting	Ivermectin	Randomized, parallelMasking: none	100Egypt
12	NCT04392713	Not applicableRecruiting	Ivermectin 6 MG oral tablet (2 tablets)	Randomized, parallelMasking: none	100Pakistan
13	NCT04351347	Phase 2|Phase 3Recruiting	IvermectinNitazoxanide with ivermectinIvermectin wth chloroquine	Randomized, parallelMasking: none	300Egypt
14	NCT04431466	Phase 2Recruiting	IvermectinStandard treatment for COVID-19	Randomized, parallelMasking: triple	64Brazil
15	NCT04529525	Phase 2|Phase 3Recruiting	IvermectinPlacebo	Randomized, parallelMasking: quadruple	500Colombia
16	NCT04384458	Not applicableRecruiting	HydroxychloroquineIvermectin	Randomized, parallelMasking: none	400Brazil
17	NCT04373824	Not applicableRecruiting	Ivermectin	Non-randomized, crossoverMasking: None	50India
18	NCT04403555	Phase 2|Phase 3Recruiting	IvermectinDoxycyclineChloroquine	Randomized, parallelMasking: None	200Egypt
19	NCT04447235	Phase 2Recruiting	PlaceboIvermectinLosartan	Randomized, parallelMasking: double	176Brazil
20	NCT04472585	Phase 1|Phase 2Recruiting	Nigella sativa/black cuminIvermectin injectable solutionPlaceboZinc	Randomized, parallelMasking: quadruple	40Pakistan
21	NCT04399746	Not applicableRecruiting	IvermectinAzithromycinCholecalciferol	Non-randomized, parallelMasking: none	30Mexico
22	NCT04374019	Phase 2Recruiting	Hydroxychloroquine and azithromycinIvermectinCamostat mesilateArtemesia annua	Randomized, parallelMasking: none	240US
23	NCT04391127	Phase 3Active, not recruiting	HydroxychloroquineIvermectinPlacebo	Randomized, parallelMasking: double	108Mexico
24	NCT04390022	Phase 2Active, not recruiting	IvermectinPlacebo	Randomized, parallelMasking: double	24Spain
25	NCT04425863	Active, not recruiting	Ivermectin 5 mg/mL	Prospective, cohort	100Argentina
26	NCT04425850	Active, not recruiting	Iota carrageenanIvermectin	Prospective, cohort	70Argentina
27	NCT04407130	Phase 2Enrolling by invitation	Ivermectin + doxycycline + placeboIvermectin + placeboPlacebo	Randomized, parallelMasking: double	72Bangladesh
28	NCT04510233	Phase 2Not yet recruiting	Ivermectin nasalIvermectin oralStandard care	Randomized, parallelMasking: none	60
29	NCT04360356	Phase 2| Phase 3Not yet recruiting	Ivermectin plus NitazoxanideStandard Care	Randomized, parallelMasking: double	100
30	NCT04407507	Phase 2Not yet recruiting	IvermectinPlacebo	Randomized, parallelMasking: single	66
31	NCT04392427	Phase 3Not yet recruiting	Nitazoxanide, ribavirin and ivermectin for 7 days	Randomized, sequentialMasking: single	100Egypt
32	NCT04435587	Phase 4Not yet recruiting	Ivermectin pillCombined ART/hydroxychloroquine	Randomized, parallelMasking: single	80Thailand
33	NCT04382846	Phase 3Not yet recruiting	NitazoxanideIvermectinChloroquineAzithromycin	Randomized, parallelMasking: none	80
34	NCT04460547	Not yet recruiting	Convalescent plasma transfusionHydroxychloroquineDAS181IvermectinInterferon beta-1A	Retrospective, cohort	200
35	NCT04482686	Phase 2Not yet recruiting	IvermectinDoxycycline HclZincVitamin D3Vitamin C	Randomized, parallelMasking: triple	300US
36	NCT04551755	Phase 2Not yet recruiting	Ivermectin and doxycyclinePlacebo	Randomized, parallelMasking: triple	188
37	NCT04530474	Phase 3Not yet recruiting	Ivermectin pillPlacebo	Randomized, parallelMasking: triple	200US
38	NCT04527211	Phase 3Not yet recruiting	Ivermectin	Randomized, parallelMasking: quadruple	550Argentina
39	CTRI/2020/04/024858	Not yet recruiting	Ivermectin (200–400 mcg/kg on day 1 and 2 in addition to standard treatment)Standard treatment	Non-randomized, active controlled	50New Delhi, India
40	CTRI/2020/04/024948	Phase 2Not yet recruiting	Ciclesonide (200 mcg twice a day for 7 days)Hydroxychloroquine (400 mg twice a day, Day1 followed by 200 mg twice a day on Days 2–7)Ivermectin (12 mg once a day for 7 days)Standard of care	Randomized, parallel	120New Delhi, India
41	CTRI/2020/05/025224	Phase 2Not yet recruiting	Ivermectin (12 mg once a day at night, oral for 2 days with standard of care)Standard of care	Randomized, parallel	50Madhya Pradesh, India
42	CTRI/2020/06/025960	Not yet recruiting	Ivermectin (12 mg, per orally, once a day for 3 days)Standard of care	Randomized, parallel, active controlled	100Maharashtra, India
43	CTRI/2020/06/026232	Phase 3Not yet recruiting	Ivermectin (single oral dose of 200 mcg/kg)	Single arm	50Andhra Pradesh, India
44	CTRI/2020/08/027225	Not yet recruiting	Ivermectin (12 mg orally on days 1 and 2)Placebo tablets	Randomized, parallel, placebo controlled	90Bihar, India
45	CTRI/2020/08/027282	Phase 3Not yet recruiting	Ivermectin 12 mg or 36 mg one dose orally one time a day (two intervention arms)Two multivitamin tablets	Randomized, parallel, multiple arm	180Uttar Pradesh, India
46	CTRI/2020/09/027944	Phase 3Not yet recruiting	Cefixime 200 mg (BD, 5 days), Ivermectin 12 mg (OD, day 1), Montelukast 10 mg (OD, 5 days), Ascoril LS 5 ml (TID, 5 days)Cefixime 200 mg, vitamin C, MVBC, antacids	Randomized, parallel group, active controlled	30Maharashtra, India

Ivermectin belongs to class ‘avermectins’ consisting of 16-membered macrocyclic lactone compounds [1]. It is approved by FDA for use as an anti-parasitic drug [2] and is known to have nematocidal, insecticidal, and acaracidal properties.

Ivermectin was discovered in Japanese Kitasato Institute in the year 1967 and first got approval in 1987 for treatment of onchocerciasis (river blindness) caused by Onchocerca volvulus and transmitted by blackfly in humans.

It is efficacious in filarial infections and eradicates parasites of gastrointestinal tract. It is also used for treatment of malaria, trypanosomiasis, head lice, scabies, and leishmaniasis [1]. Moreover, it also exhibits antibacterial and anticancer activities [3]. Ivermectin is safe at higher doses and frequent regimens. Guzzo et al. showed that higher doses of ivermectin 120 mg (up to 2,000 µg/kg) taken once or at 180 mg (up to 3,000 µg/kg) taken in split doses over 1 week is well-tolerated and safe [4].

Furthermore, ivermectin has shown antiviral activity against various RNA as well as DNA viruses [5] and is now being evaluated for use in COVID-19. Moreover, it can be used in cases, where use of hydroxychloroquine is not feasible. Hydroxychloroquine in COVID-19 is limited in some cases, because it can occasionally cause QTc prolongation and effective antiviral tissue levels need 5–10 days to accrue at maximum safe daily dosage [6]. Ivermectin is not found to be associated with such side effects and treatment with it can also be more cost-effective [7]. Following is an in tuned study about the clinical and molecular attributes of ivermectin.

Mechanism of action of ivermectin

Ivermectin enhances the activity of GABA receptors or glutamate-gated chloride ion channels in parasites and helminths which blocks the signal between neuron and muscle. GABA sensitive neurons of mammals are protected by blood brain barrier (BBB), and thus protect vertebrates from possible adverse effects of ivermectin. However, invertebrates are dose-dependently susceptible because of extensive distribution of chloride ion channels, where ivermectin generates Cl− influx, resulting in hyperpolarization which impedes myosin II light chain’s phosphorylation.

This promotes paralysis of somatic muscles with concomitant uncoordinated movement, starvation because pharyngeal pumping is inhibited, and death. Ivermectin’s affinity for parasite is 100 times more than for brain of mammals [1]. Immunomodulation of host response is another mechanism by which ivermectin can act achieved by activation of neutrophils, increased C-reactive protein and interleukin-6 levels [8].

For its antiviral activity, ivermectin is believed to act through inhibition of nuclear import of proteins of virus as well as of host. Majority of the RNA virus depend on IMPα/β1 at the time of infection, and ivermectin inhibits this import and enhances the antiviral response [9].

Another mechanism of action by which ivermectin is believed to act involves transmembrane receptor CD147. CD147 along with ACE-2 has been recognized as a key binding site for SARS-CoV-2 spike protein. The potential for major dose–response gains is assessed on the basis of studies that indicate that ivermectin shields SARS-CoV-2 spike protein which binds to CD147 and ACE-2 [6]. Furthermore, Rizzo suggested that ivermectin may have a possible ionophore role. Ionophores have been appreciated for their antibiotic activity and their role as antiviral and anticancer agents is also hypothesized [10].

Another, mechanism of action of ivermectin which needs consideration involves the allosteric modulation of the P2X4 receptor. P2X receptors are the channels selective to cation and are gated by extracellular ATP [11]. They mediate a number of functions in health and disease through extracellular ATP [12, p. 4]. From the seven subunits of P2X receptors, P2X4 is most sensitive to ivermectin. Priel et al. studied the effect of ivermectin on whole cell as well as single channel currents of P2X4 receptors of humans expressed in HEK293 cells.

Authors observed that at low ivermectin concentrations maximal current activated by ATP is predominantly activated and at high concentrations rate of current deactivation is predominantly slowed and potency of ATP is enhanced. Hence, ivermectin possibly binds to different extracellular sites (higher and lower affinity sites) on the receptor and modulate the amplitude of current and rate of deactivation of current [11].

Positive allosteric modulation of P2X4 by ivermectin enhances ATP-mediated secretion of CXCL5 (pro-inflammatory chemokine). CXCL5 is a chemo-attractant molecule expressed in inflammatory cells in different tissues and modulates neutrophil chemotaxis and chemokine scavenging [13]. Furthermore, ivermectin (2 mg/kg) was shown to have anti-inflammatory effects in animal model of allergic asthma. Immune cell recruitment, cytokine production in broncho-alveolar lavage fluid, IgE and IgG1 secretion in serum as well as hyper-secretion of mucus by goblet cells was reduced significantly by ivermectin [14].

Moreover, ivermectin blocked inflammatory cytokine production induced by LPS in mice. Production of IL-6, IL-1ss, and TNF-α was reduced considerably both in vitro and in vivo and LPS induced translocation of NF-κB was curbed too [15]. Quantitative proteomics study by Li et al. had revealed broad-spectrum antiviral property of ivermectin which can be of use in treatment of COVID-19 [16].

Figure 1 describes possible mechanism of actions of ivermectin.

Evidence available for use of Ivermectin in COVID-19
In silico, in vitro as well as clinical studies have been carried out to check the efficacy of ivermectin against SARS-CoV-2 infection and are summarized in the subsequent paragraphs.

In silico

Abdel-Mottaleb et al. reported that ivermectin, hydroxychloroquine and favipiravir are the strongest binding drugs to ACE-2 as well as S protein [17] and molecular modeling study by Dayer demonstrated that ivermectin is one of the most efficient agent that shields SARS-CoV-2 spike protein from host cell receptors [18]. According to another study by Lehrer et al. ivermectin docked in the region of leucine 91 of the spike and histidine 378 of the ACE2 receptor. Furthermore, a study by Daghir Janabi reported high binding affinity of ivermectin to RNA dependent RNA polymerase (RdRp) [19].

In vitro

Caly et al. showed that when 5 µM of ivermectin was added to Vero/hSLAM cells with SARS-CoV-2 isolate Australia/VIC01/2020, viral RNA in the supernatant (indicated virions that were released) was reduced by 93% and RNA of virus associated with cell was reduced by 99.8% (indicated virions that were not released and packaged). Furthermore, it was stated that by 48 h ivermectin brought about 5000 fold reduction of viral RNA and the IC50 was found out to be ∼ 2 μM [2].

Clinical

Rajter et al. carried out a retrospective cohort study (n = 280) of patients confirmed with SARS-CoV-2 infection hospitalized at a hospital in South Florida. They reviewed 173 patients who received treatment with ivermectin (at least one dose of ivermectin 200 mcg/kg orally along with usual clinical care) and 107 who received usual care and found out that treatment with ivermectin was related to lower mortality particularly in patients needing higher inspired oxygen or ventilator support. [20]. Another study by Alam et al. reported that ivermectin and doxycycline’s combination is very efficacious in SARS-CoV-2 clearance in patients with mild to moderate disease. In their observational/cross-sectional study, they included 100 mild and moderate RT-PCR confirmed COVID-19 patients from Bangladesh.

They were treated with combination of ivermectin (0.2 mg/kg single dose) and doxycycline (100 mg daily for 10 days) in addition to supportive treatment. Symptoms of all the patients improved within 72 h, no side effects were observed, intensive care admission was not required, no deaths were reported, and all of them tested negative [21].

Furthermore, Gorial et al. conducted a pilot clinical trial to evaluate the efficacy of ivermectin as additional treatment to hydroxychloroquine and azithromycin in mild to moderate hospitalized COVID-19 patients. 16 patients who were given ivermectin (200 mcg/kg on day of admission) as additional treatment to hydroxychloroquine and azithromycin were compared to control group (n = 71) who were given hydroxychloroquine and azithromycin.

Cure rate was 100% in case of ivermectin group and 97.2% (69 out of 71 patients) in case of control group. Also the mean time to stay in the hospital was considerable less for the ivermectin group. No side effects were seen [22]. In another prospective comparative study by Rahman et al. (n = 400; patients with mild to moderate disease), effect of ivermectin in combination with doxycycline was compared to hydroxychloroquine in combination with azithromycin. 200 patients were administered ivermectin (18 mg on day 1) and doxycycline (100 mg two times a day for 5 days), whereas the another 200 were administered hydroxychloroquine (800 mg on day 1 and after that 400 mg every day for 10 days) and azithromycin (500 mg on day 1 and after that 250 mg every day for 4 days).

According to the results ivermectin combined with doxycycline was safe and efficacious in early viral clearance in patients with mild to moderate disease and took less time than hydroxychloroquine and azithromycin combination for viral clearance [23]. Chowdhury et al. also compared combination of ivermectin and doxycycline to hydroxychloroquine and azithromycin in mild to moderate COVID-19 patients.

Patients were categorized into 2 groups. The first group (n = 60) received ivermectin (200 mcg/kg one dose) and doxycycline (100 mg two times a day for 10 days) and the second (n = 56) received hydroxychloroquine (400 mg on day 1 and after that 200 mg two times a day for 9 days) and azithromycin (500 mg every day for 5 days).

According to the study, ivermectin and doxycycline were superior to hydroxychloroquine and azithromycin in mild to moderate COVID-19 patients but the variation in time to become symptom free and time to negative PCR was not significant statistically [24]. Furthermore, Wijaya and Salim reported that there was significant clinical and radiological improvement in 3 confirmed COVID-19 patients after one dose of ivermectin [25].

In a cross-sectional study by Malik et al., majority of health care professionals were treated with ivermectin either in combination with azithromycin or with doxycycline and favorable outcomes were observed [26].

Table ​Table22 provides data on clinical efficacy and safety of ivermectin.

Table 2

Clinical efficacy and safety of ivermectin

References	Population	Intervention	Control	Outcome of intervention	Outcome of control	Adverse Event in intervention arm	Adverse Event in control arm
Rajter et al. [20]	280 COVID-19 patients	Ivermectin (at least one oral dose of ivermectin 200 mcg/kg) along with usual clinical careN = 173	Usual careN = 107	Overall mortality—15.0%Mortality in patients with severe illness—38.8%	Overall mortality—25.2%Mortality in patients with severe illness—80.7%	–	–
Alam et al. [21]	100 RT-PCR confirmed COVID-19 patients with mild to moderate disease	Ivermectin (0.2 mg/kg one dose) and doxycycline (100 mg every day for 10 days) in addition to supportive treatment	–	Symptoms of all the patients improved within 72 h, no side effects were observed, intensive care admission was not required, no deaths were reported, and all of them tested negative	–	–	–
Gorial et al. [22]	87 mild to moderateCOVID-19 diagnosed patients	16 patients were given ivermectin (200 mcg/kg on day of admission) in addition to hydroxychloroquine and azithromycin	71 patients were given hydroxychloroquine and azithromycin	Cure rate—100%Mean time to stay in the hospital—7.62 ± 2.75 days	Cure rate—97.2% (69 out of 71 patients)Mean time to stay in the hospital—13.22 ± 5.90 days	–	–
Rahman et al. [23]	400 mild to moderate COVID-19 patients	Ivermectin (18 mg on day 1) and doxycycline (100 mg two times a day for 5 days)N = 200	Hydroxychloroquine (800 mg on day 1 and after that 400 mg every day for 10 days) and azithromycin (500 mg on day 1 and after that 250 mg every day for 4 days)N = 200	66% viral clearance at day 5 and 83.5% at day 6. 16.5% remained PCR positive after 6th day of taking Ivermectin	77.0% viral clearance at day 11 and 81.5% at day 12 of taking hydroxychloroquine. 18.5% remained PCR positive after day 12	Anorexia (23.5%), diarrhea (12%), skin rash (10%)	Anorexia (31%), diarrhea (7%),Skin rash (1%)
Chowdhury et al. [24]	COVID-19 patients with mild to moderate illness	Ivermectin (200 mcg/kg one dose) and doxycycline (100 mg two times a day for 10 days)N = 60	Hydroxychloroquine (400 mg on day 1 and after that 200 mg two times a day for 9 days) and azithromycin (500 mg every day for 5 days)N = 56	All patients of reached negative PCR at 8.93 days (mean), symptomatic recovery, at 5.93 days (mean)	96.36% reached a negative PCR at 6.99 days (mean) and were having no symptoms at 9.33 days	Seen in 31.67% patients (comprising lethargy: 23.3%; nausea: 18.3%; and infrequent vertigo: 11.66%)	Seen in 46.43% (comprising mild blurring of vision and headache: 23.21%; enhanced lethargy and dizziness: 39.2%; infrequent palpitation: 17.85%; nausea and vomiting:

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History of ivermectin

In 1975, Professor Satoshi Omura at the Kitsato institute in Japan isolated an unusual Streptomyces bacterium from the soil near a golf course along the southeast coast of Honshu, Japan. Omura, along with William Campbell, found that the bacterial culture could cure mice infected with the roundworm Heligmosomoides polygyrus. Campbell isolated the active compounds from the bacterial culture, naming them “avermectins” and the bacterium S. avermitilis for the compounds’ ability to clear mice of worms.7

Despite decades of searching around the world, the Japanese microorganism remains the only source of avermectin ever found. Ivermectin, a derivative of avermectin, then proved revolutionary. Originally introduced as a veterinary drug, it soon made historic impacts in human health, improving the nutrition, general health, and well-being of billions of people worldwide ever since it was first used to treat onchocerciasis (river blindness) in humans in 1988. It proved ideal in many ways, given that it was highly effective, broad-spectrum, safe, well tolerated, and could be easily administered.7

Although it was used to treat a variety of internal nematode infections, it was most known as the essential mainstay of 2 global disease elimination campaigns that has nearly eliminated the world of two of its most disfiguring and devastating diseases. The unprecedented partnership between Merck & Co. Inc, and the Kitasato Institute combined with the aid of international health care organizations has been recognized by many experts as one of the greatest medical accomplishments of the 20th century.

One example was the decision by Merck & Co to donate ivermectin doses to support the Mectizan Donation Program that then provided more than 570 million treatments in its first 20 years alone.8 Ivermectin’s impacts in controlling onchocerciasis and lymphatic filariasis, diseases which blighted the lives of billions of the poor and disadvantaged throughout the tropics, is why its discoverers were awarded the Nobel Prize in Medicine in 2015 and the reason for its inclusion on the World Health Organization’s (WHO) “List of Essential Medicines.” Furthermore, it has also been used to successfully overcome several other human diseases and new uses for it are continually being found.7

Preclinical studies of Ivermectin’s activity against SARS-CoV-2

Since 2012, a growing number of cellular studies have demonstrated that ivermectin has antiviral properties against an increasing number of RNA viruses, including influenza, Zika, HIV, Dengue, and most importantly, SARS-CoV-2.9–17 Insights into the mechanisms of action by which ivermectin both interferes with the entrance and replication of SARS-CoV-2 within human cells are mounting.

Caly et al18 first reported that ivermectin significantly inhibits SARS-CoV-2 replication in a cell culture model, observing the near absence of all viral material 48 hours after exposure to ivermectin. However, some questioned whether this observation is generalizable clinically given the inability to achieve similar tissue concentrations used in their experimental model using standard or even massive doses of ivermectin.19,20 It should be noted that the concentrations required for an effect in cell culture models bear little resemblance to human physiology given the absence of an active immune system working synergistically with a therapeutic agent, such as ivermectin.

Furthermore, prolonged durations of exposure to a drug likely would require a fraction of the dosing in short-term cell model exposure. Furthermore, multiple coexisting or alternate mechanisms of action likely explain the clinical effects observed, such as the competitive binding of ivermectin with the host receptor-binding region of SARS-CoV-2 spike protein, as proposed in 6 molecular modeling studies.21–26

In 4 of the studies, ivermectin was identified as having the highest or among the highest of binding affinities to spike protein S1 binding domains of SARS-CoV-2 among hundreds of molecules collectively examined, with ivermectin not being the particular focus of study in 4 of these studies.27 This is the same mechanism by which viral antibodies, in particular, those generated by the Pfizer and Moderna vaccines contain the SARS-CoV-2 virus.

The high binding activity of ivermectin to the SARS-CoV-2 spike protein could limit binding to either the ACE-2 receptor or sialic acid receptors, respectively, either preventing cellular entry of the virus or preventing hemagglutination, a recently proposed pathologic mechanism in COVID-19.21,22,26–28 Ivermectin has also been shown to bind to or interfere with multiple essential structural and nonstructural proteins required by the virus to replicate.26,29 Finally, ivermectin also binds to the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), thereby inhibiting viral replication.30

Arevalo et al investigated in a murine model infected with a type 2 family RNA coronavirus similar to SARS-CoV-2, (mouse hepatitis virus), the response to 500 μg/kg of ivermectin versus placebo.31 The study included 40 infected mice, with 20 treated with ivermectin, 20 with phosphate-buffered saline, and then 16 uninfected control mice that were also given phosphate-buffered saline. At day 5, all the mice were killed to obtain tissues for examination and viral load assessment.

The 20 nonivermectin-treated infected mice all showed severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158), whereas in the ivermectin-treated mice a much lower viral load was measured (23,192; P < 0.05), with only few livers in the ivermectin-treated mice showing histopathological damage such that the differences between the livers from the uninfected control mice were not statistically significant.

Dias De Melo et al32 recently posted the results of a study they did with golden hamsters that were intranasally inoculated with SARS-CoV-2 virus, and at the time of the infection, the animals also received a single subcutaneous injection of ivermectin at a dose of 0.4 mg/kg on day 1. Control animals received only the physiologic solution.

They found the following among the ivermectin-treated hamsters: a dramatic reduction in anosmia (33.3% vs. 83.3%, P = 0.03), which was also sex dependent in that the male hamsters exhibited a reduction in clinical score while the treated female hamsters failed to show any sign of anosmia. They also found significant reductions in cytokine concentrations in the nasal turbinates and lungs of the treated animals, despite the lack of apparent differences in viral titers.

Despite these mounting insights into the existing and potential mechanisms of action of ivermectin both as a prophylactic and treatment agent, it must be emphasized that significant research gaps remain and that many further in vitro and animal studies should be undertaken to better define not only these mechanisms but also to further support ivermectin’s role as a prophylactic agent, especially in the optimal dose and frequency required.

Preclinical studies of ivermectin’s anti-inflammatory properties

Given that little viral replication occurs in the later phases of COVID-19, nor can virus be cultured, and only in a minority of autopsies can viral cytopathic changes be found,33–35 the most likely pathophysiologic mechanism is that identified by Li et al36 where they showed that the nonviable RNA fragments of SARS-CoV-2 lead to a high mortality and morbidity in COVID-19 through the provocation of an overwhelming and injurious inflammatory response.

Based on these insights and the clinical benefits of ivermectin in the late phase of disease to be reviewed below, it seems that the increasingly well-described in vitro properties of ivermectin as an inhibitor of inflammation are far more clinically potent than previously recognized. The growing list of studies demonstrating the anti-inflammatory properties of ivermectin include its ability to inhibit cytokine production after lipopolysaccharide exposure, downregulate transcription of NF-kB, and limit the production of both nitric oxide and prostaglandin E2.37–39

Exposure prophylaxis studies of ivermectin’s ability to prevent transmission of COVID-19

Data are also now available showing large and statistically significant decreases in the transmission of COVID-19 among human subjects based on data from 3 randomized controlled trials (RCTs) and 5 observational controlled trials (OCTs) with 4 of the 8 (2 of them RCTs) published in peer-reviewed journals.40–46

Elgazzar and colleagues45 at Benha University in Egypt randomized 200 health care and household contacts of patients with COVID-19 where the intervention group consisted of 100 patients given a high dose of 0.4 mg/kg on day 1 and a second dose on day 7 in addition to wearing personal protective equipment, whereas the control group of 100 contacts wore personal protective equipment alone. They reported a large and statistically significant reduction in contacts testing positive by Reverse Transcriptase Polymerase Chain Reaction (PCR) when treated with ivermectin versus controls, 2% versus 10%, P < 0.05.

Shouman conducted an RCT at Zagazig University in Egypt, including 340 (228 treated and 112 control) family members of patients positive for SARS-CoV-2 through PCR.44 Ivermectin (approximately 0.25 mg/kg) was administered twice, on the day of the positive test and 72 hours later. After a two-week follow-up, a large and statistically significant decrease in COVID-19 symptoms among household members treated with ivermectin was found, 7.4% versus 58.4%, P < 0.001.

Recently, Alam et al from Bangladesh performed a prospective observational study of 118 patients who were evenly split into those who volunteered for either the treatment or control arms, described as a persuasive approach. Although this method, along with the study being unblinded, likely led to confounders, the difference between the 2 groups was so large (6.7% vs. 73.3%, P <0.001) and similar to the other prophylaxis trial results that confounders alone are unlikely to explain such a result.47

Carvallo et al also performed a prospective observational trial where they gave healthy volunteers ivermectin and carrageenan daily for 28 days and matched them to similarly healthy controls who did not take the medicines.40 Of the 229 study subjects, 131 were treated with 0.2 mg of ivermectin drops taken by mouth 5 times per day. After 28 days, none of those receiving ivermectin in the prophylaxis group had tested positive for SARS-COV-2 versus 11.2% of patients in the control arm (P < 0.001).

In a much larger follow-up prospective, observational controlled trial by the same group that included 1195 health care workers, they found that over a 3-month period there were no infections recorded among the 788 workers who took weekly ivermectin prophylaxis, whereas 58% of the 407 controls had become ill with COVID-19. T

his study demonstrates that remarkable protection against transmission can be achieved among high-risk health care workers by taking 12 mg once weekly.40 The Carvallo IVERCAR protocol was also separately tested in a prospective RCT by the Health Ministry of Tucuman, Argentina, where they found that among 234 health care workers, the intervention group that took 12 mg once weekly, only 3.4% contracted COVID-19 versus 21.4% of controls, P < .0001.46

The need for weekly dosing in the Carvallo study over a 4-month period may not have been necessary given that, in a recent RCT from Dhaka, Bangladesh, the intervention group (n = 58) took 12 mg once monthly for a similar 4-month period and also reported a large and statistically significant decrease in infections compared with controls, 6.9% versus 73.3%, P < 0.05.47 Then, in a large retrospective observational case–control study from India, Behera et al41 reported that among 186 case–control pairs (n = 372) of health care workers, they identified 169 participants who had taken some form of prophylaxis, with 115 participants that had taken ivermectin.

After matched pair analysis, they reported that in the workers who had taken 2 dose ivermectin prophylaxis, the odds ratio for contracting COVID-19 was markedly decreased (0.27, 95% confidence interval (CI) 0.15–0.51). Notably, one dose prophylaxis was not found to be protective in this study. Based on both their study finding and the Egyptian prophylaxis study, the All India Institute of Medical Sciences instituted a prophylaxis protocol for their health care workers where they now take two 0.3 mg/kg doses of ivermectin 72 hours apart and repeat the dose monthly.

Data that further illuminates the potential protective role of ivermectin against COVID-19 come from a study of nursing home residents in France which reported that in a facility that suffered a scabies outbreak where all 69 residents and 52 staff were treated with ivermectin,41 they found that during the period surrounding this event, 7 of the 69 residents fell ill with COVID-19 (10.1%). In this group with an average age of 90 years, only one resident required oxygen support and no resident died. In a matched control group of residents from surrounding facilities, they found 22.6% of residents fell ill and 4.9% died.

Further evidence supporting the efficacy of ivermectin as a prophylaxis agent was published recently in the International Journal of Antimicrobial agents where a group of researchers analyzed data using the prophylactic chemotherapy databank administered by the WHO along with case counts obtained by Worldometers, a public data aggregation site used by among others, the Johns Hopkins University.42 When they compared the data from countries with active ivermectin mass drug administration programs for the prevention of parasite infections, they discovered that the COVID-19 case counts were significantly lower in the countries with recently active programs, to a high degree of statistical significance, P < 0.001.

Figure ​1 presents a meta-analysis performed by the study authors of the controlled ivermectin prophylaxis trials in COVID-19.

Further data supporting a role of ivermectin in decreasing transmission rates can be found from South American countries where, in retrospect, large “natural experiments” seem to have occurred. For instance, beginning as early as May, various regional health ministries and governmental authorities within Peru, Brazil, and Paraguay initiated “ivermectin distribution” campaigns to their citizen populations.48

In one such example from Brazil, the cities of Itajai, Macapa, and Natal distributed massive amounts of ivermectin doses to their city’s population, where in the case of Natal, 1 million doses were distributed. The distribution campaign of Itajai began in mid-July, in Natal they began on June 30th, and in Macapa, the capital city of Amapa and others nearby, they incorporated ivermectin into their treatment protocols in late May after they were particularly hard hit in April.

The data in Table 1 were obtained from the official Brazilian government site and the national press consortium and show large decreases in case counts in the 3 cities soon after distribution began compared with their neighboring cities without such campaigns.

Table 1.

Comparison of case count decreases among Brazilian cities with and without ivermectin distribution campaigns.

Region	New cases	June	July	August	Population 2020 (1000)	% Decline in new cases between June and August 2020
South	Itajaí	2123	2854	998	223	– 53%
	Chapecó	1760	1754	1405	224	– 20%
North	Macapá	7966	2481	2370	503	– 70%
	Ananindeua	1520	1521	1014	535	– 30%
North East	Natal	9009	7554	1590	890	– 82%
	João Pessoa	9437	7963	5384	817	– 43%

Bolded cities distributed ivermectin, neighboring regional city below did not.

The decreases in case counts among the 3 Brazilian cities given in Table ​1 were also associated with reduced mortality rates as summarized in Table ​2.

Table 2.

Change in death rates among neighboring regions in Brazil.

Region	State	% Change in average deaths/week compared with 2 weeks before
South	Santa Catarina	–36%
	PARANÁ	–3%
	Rio Grande do Sul	–5%
North	Amapá	–75%
	AMAZONAS	–42%
	Pará	+13%
North East	Rio Grande do Norte	–65%
	CEARÁ	+62%
	Paraíba	–30%

Bolded regions contained a major city that distributed ivermectin to its citizens, the other regions did not.

Ivermectin in post-COVID-19 syndrome

Increasing reports of persistent, vexing, and even disabling symptoms after recovery from acute COVID-19 have been reported and that many have termed the condition as “Long COVID” and patients as “long haulers,” estimated to occur in approximately 10%–30% of cases.71–73

Generally considered as a postviral syndrome consisting of a chronic and sometimes disabling constellation of symptoms which include, in order, fatigue, shortness of breath, joint pains, and chest pain. Many patients describe their most disabling symptom as impaired memory and concentration, often with extreme fatigue, described as “brain fog,” and is highly suggestive of the condition myalgic encephalomyelitis/chronic fatigue syndrome, a condition well reported to begin after viral infections, in particular with Epstein–Barr virus.

Although no specific treatments have been identified for Long COVID, a recent manuscript by Aguirre-Chang et al from the National University of San Marcos in Peru reported on their experience with ivermectin in such patients.74 They treated 33 patients who were between 4 and 12 weeks from the onset of symptoms with escalating doses of ivermectin; 0.2 mg/kg for 2 days if mild and 0.4 mg/kg for 2 days if moderate, with doses extended if symptoms persisted.

They found that in 87.9% of the patients, resolution of all symptoms was observed after 2 doses with an additional 7% reporting complete resolution after additional doses. Their experience suggests the need for controlled studies to better test efficacy in this vexing syndrome.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088823/

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reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778723/