It has been more than a year since the world declared war on COVID. Quarantines, lock-downs, social distancing, separation and loneliness, masks and face shields. spikes, surges and flattening of the curve, new infections and rising death counts, herd immunity, the new ways of grieving, dying and death—they became the language of the "new normal."
While the world anxiously waited for the vaccine, while politics battled with science, there was a desperate search for treatments and supplements to stave off the raging virus: hydroxychloroquine saw fleeting use; zinc, D3, and vitamin C continue as popular vitamin/mineral supplements; virgin coconut oil and barley as natural alternative options; prescription colchicene as anti-inflammatory; drugs for re-purposing, compassionate use or off-label use; convalescent plasma for the connected; remdesivir for the rich, leronlimab monoclonal antibody for the richer.
Despite the recent availability of the vaccine, its distribution has been hampered by politics and realities of poor nation status:
the rich and powerful stay in front of the line, the poor and
the lowly at the back. Despite vaccination efforts, the virus is far from being vanquished—it continues to threaten with surges, waves, mutations and variants, and augurs the possibility that it is here to stay, seasonally hibernating, or constantly mutating into variants that are vaccine resistant, that will need a continuing search for therapies that are both preventive and therapeutic.
One such drug with preventive and therapeutic promise for COVID-19 is ivermectin. It didn't come out from the blue. A repurposed drug, it has been around for 40 years, an FDA-approved antinematode drug, well-studied, off-patent, inexpensive, with an excellent safety profile. (Early records of adverse reactions in the human field tainted its safety profile, but the majority of reactions were attributable to interaction between drug and disease, not the drug itself.) It has been used by more than three billion people, with immeasurable benefits to humankind.
Ivermectin was listed in the Philippine National Formulary way back 2006. Then, its inclusion in the Formulary was hailed by no other than, then and now, Secretary of Health Francisco Duque. Mysteriously, ivermectin disappeared from the Formulary. The once "essential" medicine for Filipinos is now deemed a "threat" by some guardians of healthcare in the DOH and FDA.
Fueled by the "animal drug" denigration, disinformation, and uncertain political or financial agendas of the powers that be, it has stirred polarized chaotic debates in social media, political circles, and even the medical profession.
While the scientific institutions refuse to endorse ivermectin, their positions are invariably delivered in "soft" language. The DOH and FDA do not recommend it for COVID care because the drug "did not significantly reduce" the risk of death in patients with moderate to severe COVID. The WHO's hesitance is expressed as "absence of statistically relevant evidence of effectiveness. . . harmful because it instills false confidence. Others are just as exasperating: "evidence for benefit is not sufficiently robust" or "inconclusive."
For now, the drug is caught in limbo, in a tug of war between naysayers and fearmongers intent on keeping it out of the formulary and practicing physicians desperate for its return to prescription accessibility and off-label use until clinical trials can "scientifically" justify recommending or debunking it.
For the meantime, there seems to be an efficient underground market that provides for ivermectin access, with social media, texting, and word-of-mouth sharing of information on dosage and usage. However, this unregulated trade runs the risks of black marketing of prices, fake drugs and distribution of veterinary formulations.
Ivermectin is a semi-synthetic anthelmintic agent, derived from avermectins, a class of highly active, broad-spectrum antiparasitic agent,discovered in the late 1970s and isolated from the fermentation products of Saccharomyces avermitilis from the Japanese soil at the Kitasato Institute in Tokyo. Collaborating with Merck Sharpe and Dohme (MSD), avermectin and the derivative ivermectin were isolated from biologic isolates. Ivermectin was found extremely safe and more effective than avermectin. While it was originally introduced as a veterinary drug and introduced as a commercial product for Animal Health in 1981, and found effective against a wide range of parasites including gastrointestinal worms (Strongyloides stercoralis), mites (scabies), lice (pediculosis), and ticks. An antimalarial potential is being evaluated on mosquitoes feeding on humans and livestock treated with ivermectin to reduce malaria transmission. It is also used off-label, illegally, to treat fish lice in aquaculture.
But while debunkers delight in denigrating it as an "animal" drug, Merck recognized ivermectin's potential for human use, particularly in combating two of the world's most devastating and disfiguring diseases which have plagued the world's poor for centuries: onchocerciasis and lymphatic filariasis. For onchocerciasis, it has been successful in preventing blindness and visual disability in millions of the afflicted. From its huge success as an "animal drug" to widespread use in humans, it subsequently earned the designation of "Wonder Drug." (In 2015, for his contributions to the discovery of avermectin and ivermectin, Omura received the Nobel Prize for Physiology or Medicine.)
Two other drugs that can claim the title of "wonder drug" are penicillin and aspirin. Ivermectin can also be considered alongside these two, based on versatility, safety, and beneficial impact worldwide— especially for hundreds of millions of the world's poorest people. (3)
|| A VACCINE ASIDE
Deeply disturbing is the vaccination refusal among certain urban populations and the rural poor—a resistance attributed to the Dengvaxia fiasco, with consequent deep and lingering distrust for vaccine science. Sadly, it is a dismal failure of education and information dissemination on the life-saving and health promoting benefits of a panoply of vaccines in use i.e. measles, mumps, polio, diphtheria, pertusis, tetanus, influenza, and hepatitis B, along with other essential travel vaccinations.
• Proposed Mechanisms of Action: (1) Reduces viral entry into cells by preventing the spike protein of the SARS-CoV-2 virus from binding to the enzyme on the host cell surface giving the immune system an opportunty to mount a response. (2) Inside the cell, IVM disrupts viral RDRP (RNA dependent RNA polymerase) to reduce viral replication. (4) Disruption of another enzyme, 3-chymotrypsin-like protease to further reduce viral replication. (4) IVM blocks the viral message to cell nucleus. (5) IVM blocks the pathway of NF-kB reducing cytokine and inflammatory response. (Dr Mobeen Syed)
• Neurologic Adverse Events Beyond Onchocerciasis: Serious neurologic events have been reported from large community-based ivermectin treatment campaigns against Onchocerciasis volvulus in Africa. A series of serious neurological adverse events occurring with the use of ivermectin outside of onchocerciasis are extremely rare. Potential mechanisms may be interactions with concomitantly administered drugs which inhibit CYP3A4 and polymorphisms in the mdr-1 gene. Some cases reported concomitant used of drugs such as statins, HIV protease inhibitors, calcium channel blockers, and benzodiazepines. (2) There have been few case reports of neurologic disorders in humans after ivermectin treatment. A case report of ivermectin induced encepalopathy in a 13-year old boy. ABCB1 sequencing identified the child as a compound heterozygote for two nonsense mutations. The loss of ABCB1 activity could have induced high exposure of the CNS to ivermectin and its toxic side effects. (19)
• Inhibitor of SARS-CoV-2: Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum antiviral activity in vitro, is an inhibitor of the causative virus (SARS-Cov-2), with single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 with about a 5000-fold reduction in viral RNA at 48 h. Results warrant further investigation for possible benefits in humans. (5)
• Pharmacokinetic Studies: Pharmacokinetic studies in healthy volunteers suggested single doses up to 120 mg of ivermectin can be safe and well tolerated. This dose is 10-fold greater than those approved by USFDA, the Cmax values reported were about 250 ng/mL, one order of magnitude lower than effective invitro concentrations against SARS-CoV2. Although the results may seem to discourage follow-up clinical trials, an invivo effect may be possible despite physiologically unattainable efficacious invitro concentrations. (6) While ivermectin has been shown to inhibit replication of SARS-CoV-2 in cell cultures, pharmacokinetics and phamacodynamic studies suggest achieving the plasma concentrations necessary for antiviral efficacy detected invitro would require administration of doses up to 100-fold higher than those approved for use in humans. (8)
• Trials: One systematic review of controlled clinical trials showed ivermectin did NOT SIGNIFICANTLY reduce the risk of mortality among COVID-19 patients. Some studies have reported shorter time to resolution of disease manifestations that were attributed to COVID-19, greater reduction in inflammatory marker levels, shorter time to viral clearance, or lower mortality rates in patients in patients who received ivermectin than in patients who received comparable drugs or placebo. However, most of the studies had incomplete information and significant methodological limitations, which made it difficult to exclude bias. (8)
• Approved Dose (200 µg/kg) Not Ideal for COVID19 Treatment: Caly et al. reported ivermectin inhibited severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) in vitro up to 48 hours using ivermectin at 5µM. The concentration requiring 50% inhibition (IC50: 2 µM) was > 35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved oral dose when given fasting. Plasma ivermectin concentrations of total and unbound do not reach the IC50 even at dose level 10X higher than the approved dose. Even at high lung:plasma ratio ivermectin is unlikely to reach the IC50 in the lungs after single oral approved dose or at dose 10X higher. In summary, the likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. (7)
• Proposed Mechanism of Action and Rationale of Use in COVID19: In vitro studies have suggested ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host's antiviral response. Ivermectin may also interfere with attachment of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein to human cell membrane. Ivermectin is thought to be a host-directed agent, which may be the basis for its broad-spectrum activity in vitro against viruses that cause dengue, Zika, HIV, and yellow fever. However, despite invitro activity, no clinical trials have reported clinical benefit for ivermectin in patients with these viruses. Some studies have also reported anti-inflammatory properties for ivermectin, possibly beneficial for patients with COVID19. (8)
• Prevention and Treatment / Regimens and Dosing: The FLCCC (Frontline COVID-19 Critical Care) alliance provides links to scientific studies on prophylaxis and treatment protocols for COVID-19. (11) The I-MASK+ prophylaxis and early out-patient protocol for high risk individuals and post COVID-19 exposure prophylaxis consists of ivermectin 0.2 mg/kg per dose, repeated in 48 hours, then one dose every two weeks, along with vitamin D3, vitamin C, quercetin, zinc, and melatonin. For early out-patient protocol, recommended regimen consists of ivermectin 0.2 mg/kg per daily for 2 days (minimum) or daily until recovered (max 5 days), along with D3, vitamin C, quercetin, zinc, melatonin, and aspirin, with monitoring of oxygen saturation by pulse oximeter. (Many advise taking ivermectin with a meal or just following a meal for better absorption and bioavailability.) (10)
• Pharmacokinetics and Tolerability: Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 2,000 mcg/kg, 10 times the highest FDA-approved dose of 200 mcg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. (in other studies, patients given doses of 800 mcg/kg described transient visual disturbances. Smit et al safely administered 600 mcg/kg for three days.) (13) .
• Lack of Efficacy of Standard IVM Dose in Severe COVID-19 patients: Ivermectin has shown efficacy against SARS-CoV-2 in vitro. Study retrospectively reviewed severe COVID-19 patients receiving standard doses of IVM and compared clinical and microbiological outcomes with a similar group not receiving IVM. No differences were found between groups. Study recommend the evaluation of high-doses of IVM in randomized trials against SARS-CoV-2. (14)
• Ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A hospital-based matched case-control study explored the association between ivermectin and the development of SARS-CoV-2 infection among 186 case-control pairs of healthcare workers. Cases and controls were healthcare workers who tested positive and negative, respectively. Exposure was defined as intake of ivermectin and/or hydroxychloroquine and/or vitamin C and/or other prophylaxis for COVID-19. Results showed two-dose ivermectin prophylaxis at dose of 200 µg/kg with a gap of 72 hours was associated with a 73% reduction of SARS-CoV-2 infection among healthcare workers for the following month. (16)
• Inadvertent Anti-COVID Campaign / The African Enigma: Study evaluated SARS-CoV-2 infection and death rates in African countries that participated in an intensive ivermectin mass campaign carried out to control onchocerciasis and compared with countries that did not participate. APOC (African Programme for Onchocerciasis Control) showed 28% lower mortality and 8% lower rate of infection. The incidence in mortality rates and number of cases were significantly lower among APOC countries compared to non-APOC countries. Study suggests a mass public health preventive campaign against COVID-19 may have taken place, inadvertently in some African countries with massive community ivermectin use is an attractive hypothesis that needs to be confirmed by additional studies. (The effort to reduce the risk of COVID-19 mass treatment campaigns was suspended, after an interim WHO guidance on April 1, 2020) (17)
• Effect of Early Treatment with Ivermectin on Viral Load / Clinical Trial: Pilot placebo-controlled, double-blind, randomized clinical trial evaluated the efficacy of a single dose of ivermectin (400 mcg/kg) to reduce the transmission of SARS-CoV-2 when administered early after disease onset in patients (median age 26) with non-severe COVID-19 and no risk factors for complicated disease. Results showed among patients with non-severe COVID-19 and no risk factors for severe disease receiving the ivermectin single dose within 72 hours of fever or cough onset, there was no difference in the proportion of PCR positives. However, there was marked reduction of self-reported anosmia/hyposmia, reduction of cough and tendency to lower viral load and lower IgG titers, which warrant assessment in larger trials. (21)
WONDER DRUG REDUX
If there is a war being waged, victory is far from being won. The deaths and case counts continue to rise. The pandemic threatens to bring the healthcare system to its knees. Hospitals are jammed; There are horror stories of patients waiting in tents or cars, or consigned to die at home. Vaccine access is restricted, hesitancy abounds, as variants threaten vaccine efficacy.
Since early in the pandemic, ivermectin surfaced from mainstream pharmaceutical anonymity as a drug with both preventive and therapeutic potential against COVID19. In the face of the deepening crisis, the resistance against it by some powers that be and political guardians of our healthcare is inexplicable. The definitive results of well-designed clinical trials that will hopefully establish its efficacy or disprove its claims might be a long time coming.
Is safety a primary concern?
Ivermectin's safety profile is supported by more than 40 years of use in more than 3 billion people. Like any other drug, there have been reports of adverse reactions, but the severe ones like hepatitis and neurologic events are extremely rare. Its potential benefits—from mass-prevention, contact and post-exposure treatment, shorter clinical course, prevention of disease progression to increase survival—far outweigh the risks. Comparing its toxicity to aspirin—another "wonder drug"— the number of deaths attributed to NSAID/aspirin use was 21.0 and 24.8 cases/million users, respectively, or 15.3 deaths/100,000 NSAID/aspirin users, with up to one-third of the deaths attributed to low-dose aspirin. (20) Alas—and a word of caution—the inclusion of low-dose daily aspirin in some anti-COVID19 preventive regimens is likely to cause more toxicity than ivermectin.
No drug or therapeutic approach—remdesivir, steroids, ventilators, convalescent plasma, monoclonal antibodies—can assure 100% efficacy—failures are inevitable. Ivermectin is no different—it will have failures, side effects, and occasional adverse reactions. But it offers another option for prevention, treatment and survival.
As an off-patent drug with no windfall profit potential, BIG PHARMA has no further interest in ivermectin. In the Philippines, Pascual and Lloyd laboratories—small pharma making affordable generic drugs and phytomedicines for the poor and underserved—have expressed interest in applying for registration and production of ivermectin for human use, but only pursuant to the DOH's approval for its inclusion in a COVID-19 treatment plan.
With rising counts of daily deaths and new cases, ivermectin should not sit idle. It should be immediately released to practicing physicians for off-label, emergency, or compassionate use. The accumulation of studies and use in clinical settings suggest the likelihood of benefit for prevention and treatment. Its safety profile makes compelling argument for a public health policy to use a 15 mg dose as prophylaxis to healthy adult populations, or use treatment regimens for high-risk exposure or outpatient treatment protocols for mildly infected patients. (see study above:10)
In the marginalized rural communities and boondocks, barangay health care workers can help in dispensing the drug to high risk contacts and do appropriate follow-up and record keeping. This inexpensive drug could be a godsend to the management of COVID19 among the rural poor. Ivermectin-based preventive programmes can be an alternative to rural poor refusing vaccination.
While most vaccines claim almost 100% protection against death or severe disease, there are lingering concerns on their duration of efficacy and degree of protecton against mild to moderate disease. Furthermore, with increasing concerns on the vaccines' diminished efficacy against COVID-19 variants, ivermectin could be an attractive component of a drug-supplement maintenance regimen.
If the re-purposed drug delivers on its potential, it can save thousands of lives, and validate and further cement its status as a "wonder drug."