Ivermectin is an anti-parasitic drug approved in humans for treatment of certain tropical diseases. For humans, ivermectin tablets are approved at very specific doses to treat some parasitic worms, and topical (on the skin) formulations are used for head lice and skin conditions like rosacea.
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Ivermectin is not approved for use to treat COVID-19.
According to the U.S. Food and Drug Administration (FDA), certain animal formulations of ivermectin are approved in the U.S. to treat or prevent parasites in animals.
Medications formulated or intended for use in animals should not be used by humans. Veterinary forms of this medication are highly concentrated for large animals and pose a significant toxicity risk for humans.
AMA opposes off-label use of ivermectin for COVID-19Ivermectin is reportedly being prescribed off label to treat those who have the COVID-19 virus. The AMA, American Pharmacists Association and American Society of Health-System Pharmacists strongly oppose the ordering, prescribing or dispensing of ivermectin to prevent or treat COVID-19 outside of a clinical trial.
Use of ivermectin for the prevention and treatment of COVID-19 has been demonstrated to be harmful to patients and causes adverse events, according to the CDC Health Advisory. Calls to poison control centers due to ivermectin ingestion have increased five-fold from their pre-pandemic baseline.
In the Sept. 9, , AMA COVID-19 video update, John Farley, MD, MPH, director, Office of Infectious Diseases in the Center for Drug Evaluation and Research&#;s Office of New Drugs, FDA, discusses why patients should not use ivermectin for COVID-19.
Dr. Farley cautions that physicians must consider the &#;&#;side effects from the drug itself and that could be worse in some patients and need to be monitored. These include stomach problems, skin rash and itching, and nervous system problems, including dizziness and tremors.&#;
Further, &#;&#;physicians also know with any drug, there are potential interactions with other drugs the patient might be taking and there's some patients who require a special kind of risk-benefit consideration when considering ivermectin.&#;
Prescribing medications responsiblyPhysicians are expected to prescribe drugs &#;based solely on medical considerations, patient need, and reasonable expectations of effectiveness for the particular patient,&#; according to the AMA&#;s Code of Medical Ethics.
When prescribing off label, however, physicians must determine what count as &#;reasonable expectations&#; under conditions of greater than usual uncertainty given the absence of relevant data for the intended use, in addition to determining appropriate dose and route of administration.
Responsibly prescribing an approved medication for a novel, off label use requires that the physician reflect critically on the evidence that is available, seek input from knowledgeable colleagues or other medical professionals, and attend carefully to minimizing the risks to the patients.
&#;(Opinion 1.2.11, &#;Ethically Sound Innovation in Medical Practice,&#; AMA Code of Medical Ethics).
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Reviewed by: Andrea Garcia, JD, MPH, director of science, medicine & public health, AMA
Perhaps more than any other drug, ivermectin is a drug for the world&#;s poor. For most of this century, some 250 million people have been taking it annually to combat two of the world&#;s most devastating, disfiguring, debilitating and stigma-inducing diseases, Onchocerciasis and Lymphatic filariasis. Most of the recipients live in remote, rural, desperately under-resourced communities in developing countries and have virtually no access to even the most rudimentary of medical interventions. Moreover, all the treatments have been made available free of charge thanks to the unprecedented drug donation program.
When the avermectins were discovered, they represented a completely new class of compounds, 'endectocides', so designated because they killed a diverse range of disease-causing organisms&#;as well as pathogen vectors&#;inside as well as outside the body. The first publications on avermectin appeared in , describing it as a complex mixture of 16-membered macrocyclic lactones produced by fermentation of the actinomycete Streptomyces avermitilis&#;later re-classified as S. avermectinius (Figure 2). The avermectin family displayed extraordinarily potent anthelmintic properties.15, 16, 17 Ivermectin is a safer, more potent semisynthetic mixture of two chemically modified avermectins, comprising 80% of 22,23-dihydroavermectin-B1a and 20% 22,23-dihydroavermectin-B1b (Figure 3).
Ivermectin was a revelation. It had a broad spectrum of activity, was highly efficacious, acting robustly at low doses against a wide variety of nematode, insect and acarine parasites. It proved to be extremely effective against most common intestinal worms (except tapeworms), could be administered orally, topically or parentally and showed no signs of cross-resistance with other commonly used anti-parasitic compounds. Marketed in , it quickly became used worldwide to combat filarial and other infections and infestations in livestock and pets.
Registered for human use in , ivermectin was immediately donated as Mectizan tablets to be used solely to control Onchocerciasis, a skin disfiguring and blinding disease caused by infection with the filarial worm Onchocerca volvulus, which afflicted millions of poor families throughout the tropics. Some 20&#;40 million people were infected prior to the launch of large-scale control interventions, with around 200 million more at risk of infection.18, 19, 20 Human infection has been tackled in endemic areas through annual or semi-annual mass drug administration of ivermectin and only 21&#;22 million people (almost exclusively in Africa) remain infected with O. volvulus.21
Since the prodigious drug donation operation began, 1.5 billion treatments have been approved. Latest figures show that an estimated 186.6 million people worldwide are still in need of treatment, with over 112.7 million people being treated yearly, predominantly in Africa.22 Actual treatments declined in / due to the planned closure of the highly successful and innovative African Programme for Onchocerciasis Control and a subsequent delay before the more comprehensive replacement, the Expanded Special Project for the Elimination of Neglected Tropical Diseases in Africa, became established and operational, plus deferment of some treatments until .
The African Programme for Onchocerciasis Control was created in to establish community-directed treatment with ivermectin to control Onchocerciasis as a public health problem in African nations that represented 80% of the global disease burden. For long the sole agent used in control efforts, ivermectin has been so successful that the goal has now switched from disease control to worldwide disease elimination. For most afflicted countries, nationwide Onchocerciasis elimination is within reach and there is hope that the global elimination target of will be achieved.23 Latest models indicate that if the target (or sooner) is to be achieved, 1.15 billion more treatments will be required,24 assuming that the absence of drug resistance continues.
In the mid-s, ivermectin was found to be an excellent treatment for Lymphatic filariasis, leading to the donation program being extended to cover this disease in areas where it co-exists with Onchocerciasis (Figure 4). In , almost 374 million people required ivermectin for Lymphatic filariasis, with 176.5 million being treated.25 In , 120.7 million ivermectin treatments were approved for Lymphatic filariasis, an accumulated 1.2 billion treatments being authorized since the drug donation program was extended to cover the second disease in .26
During , well over 900 million donated ivermectin tablets should be dispatched, representing more than 325 million treatments.22
Ivermectin mass drug administration also bestows significant secondary community-wide health and socioeconomic benefits due to its impact on non-target infections.13 During &#;, it was estimated that the disability-adjusted life years averted via the impact on these non-target diseases added a further 500&#;000 disability-adjusted life years to the African Programme for Onchocerciasis Control&#;s 19.1 million saved due to Onchocerciasis interventions.27
Surprisingly, despite 40 years of unmatched global success, plus widespread intensive scientific study in both the public and private sectors, scientists are still not certain exactly how ivermectin works. Moreover, whereas ivermectin-resistant parasites swiftly appeared in treated animals,28 as well as in ectoparasites, such as copepods parasitizing salmon in fish farms,29 somewhat bizarrely and almost uniquely, no confirmed drug resistance appears to have arisen in parasites in human populations, even in those that have been taking ivermectin as a monotherapy for over 30 years.
Ivermectin is already deployed to treat a variety of infections and diseases, most of which primarily afflict the world&#;s poor. But it is the new opportunities with respect to ivermectin usage, or re-purposing it to control a completely new range of diseases, that is generating interest and excitement in the scientific and global health research communities.
Ivermectin is registered for human use primarily to treat Onchocerciasis and strongyloidiasis, and, in combination with albendazole, to combat Lymphatic filariasis, as well as being increasingly used &#;off-label&#; to combat a variety of other diseases. Oral treatments are commonplace, but ivermectin doses have also been given successfully per rectum, subcutaneously and topically (Figure 5). Ivermectin has now been used for over three decades to treat parasitic infections in mammals, and has an extremely good safety profile, with numerous studies reporting low rates of adverse events when given as an oral treatment for parasitic infections.50 Several problematic reactions have been recorded, but they are generally mild and usually do not necessitate discontinuation of the drug.
In addition to the gradual appreciation of the diverse and invaluable health and socioeconomic benefits that ivermectin use can provide, research is currently shedding light on the promise that the drug still harbors and the prospects of it combatting a new range of diseases or killing vectors of various disease-causing parasites.
The following are an indication of the divergent disease-fighting potential that has been identified for ivermectin thus far:
Myiasis is an infestation of fly larvae that grow inside the host. Surgical removal of parasites is often the only remedy but unavailable to many of the needful people who live in poor, rural tropical communities where myiatic flies thrive. Oral myiasis has been successfully treated with ivermectin,51 which has also been used effectively as a non-invasive treatment for orbital myiasis, a rare and preventable ocular morbidity.52
Globally, approximately 11 million individuals are infected with Trichinella roundworms. Ivermectin kills Trichinella spiralis, the species responsible for most of these infections.53
Ivermectin is highly effective in killing a broad range of insects. Comprehensive testing against 84 species of insects showed that avermectins were toxic to almost all the insects tested, including the vectors of malaria and critical neglected tropical diseases such as leishmaniasis and trypanosomiasis (see below). At sub-lethal doses, ivermectin inhibits feeding and disrupts mating behavior, oviposition, egg hatching and development.54, 55
Mosquitoes (Anopheles gambiae) that transmit Plasmodium falciparum, the most dangerous malaria-causing parasite, can be killed by the ivermectin present in the human bloodstream after a standard oral dose.56, 57, 58, 59 Meanwhile, it has been demonstrated that even at sub-micromolar levels, ivermectin inhibits the nuclear import of polypeptides of the signal recognition particle of P. falciparum (PfSRP), thereby killing the parasites. Consequently, in combination with other anti-malarial agents, ivermectin could become a useful, novel malaria transmission control tool.60, 61 The use of ivermectin as an additional malaria control weapon is now receiving increased attention, driven by the growing importance of outdoor/residual malaria transmission and the threat of insecticide resistance. One outcome has been the creation of the &#;Ivermectin Research for Malaria Elimination Network&#;.62
Ivermectin has been proposed as a possible rodent-bait feed-through insecticide to help control the Phlebotomine sandfly vectors that transmit Leishmania parasites.63, 64 Experiments to test the impact of ivermectin on one blood-feeding sandfly vector, Phlebotomus papatasi, demonstrated that they die if the blood feed is 1&#;2 days post treatment. Although Leishmania major promastigotes have been shown to die or lose their infectivity after exposure to ivermectin, it does not have a major impact against L. major. Nevertheless, ivermectin is more effective in killing promastigotes than rifampicin, nystatin and erythromycin.65, 66 For cutaneous leishmaniasis, ivermectin is more effective than other drugs (including pentostam, rifampicin, amphotericin B, berenil, metronidazole and nystatin) in killing Leishmania tropica parasites in vitro and by subcutaneous inoculation, with accelerated skin ulcer healing.60 When combined with proper surgical wound dressing, ivermectin shows significant promise for curing cutaneous leishmaniasis.67
Tsetse flies (Glossina palpalis) fed on ivermectin-treated animals die within 5 days, demonstrating that ivermectin has promise to help control these African trypanosomiasis vectors.68, 69 Effective in killing tsetse flies, experiments in mice infected with Trypanosoma brucei brucei parasites have also shown that ivermectin treatment doubled their survival time, suggesting that there is scope for investigating the use of ivermectin in the treatment of African trypanosomiasis from several aspects.70
When dogs infected with Trypanosoma cruzi parasites suffered a tick infestation, ivermectin treatment eliminated the ticks but had no impact on either the dogs or their infection. Triatomine bug vectors of T. cruzi feeding on the dogs relatively soon after treatment displayed high mortality, which declined rapidly as the interval between ivermectin treatment and blood feed increased.71
Schistosoma species are the causative agent of schistosomiasis, a disease afflicting more than 200 million people worldwide. Praziquantel is the sole drug available for controlling schistosomiasis, with schistosome-resistant parasites now becoming an increasingly worrying problem.72, 73 Ivermectin is a potent agonist of glutamate-gated chloride channels and as glutamate signaling has been recorded in schistosomes,74, 75 there may be an ivermectin target in the tegument. Workers in Egypt evaluating the effect of ivermectin on mice infected with Schistosoma mansoni, concluded that ivermectin has promising anti-schistosomal effects. It has potential due to its schistosomicidal activity on adult worms, especially females, and its ovicidal effect, in addition to its impact in improving hepatic lesions.76, 77 It has also been reported that ivermectin can kill Biomphalaria glabrata, intermediate host snails involved in the schistosomiasis re-infection cycle, reinforcing the prospect of using ivermectin to help control one of the world&#;s major neglected tropical diseases.78, 79
Bedbugs are parasitic insects of the Cimicidae family that feed exclusively on blood. Cimex lectularius, the common bedbug, feeds on human blood, with infestations increasing significantly in poor households across North America and Europe. Ivermectin is highly effective against bedbugs, capable of eradicating or preventing bedbug infestations.80
Although the broad-spectrum anti-parasitic effects of ivermectin are well documented, its anti-inflammatory capacity has only relatively recently been identified. Ivermectin is used &#;off-label&#; to treat diseases associated with Demodex mites, such as blepharitis and demodicosis, oral ivermectin, in combination with topical permethrin, being a safe and effective treatment for severe demodicosis.81 Demodex mites have also been linked to rosacea, a chronic skin condition that manifests as recurrent inflammatory lesions. Long-term treatment is required to control symptoms and disease progression, with topical medicaments being the first-line choice. Ivermectin 1% cream is a new once-daily topical treatment for rosacea lesions, more effective and safer than all current options,82 which has recently received approval from American and European authorities for the treatment of adults with rosacea lesions.
A study investigated the impact of ivermectin on allergic asthma symptoms in mice and found that ivermectin (at 2&#;mg&#;kg&#;1) significantly curtailed recruitment of immune cells, production of cytokines in the bronchoalveolar lavage fluids and secretion of ovalbumin-specific IgE and IgG1 in the serum. Ivermectin also suppressed mucus hypersecretion by goblet cells, establishing that ivermectin can effectively curb inflammation, such that it may be useful in treating allergic asthma and other inflammatory airway diseases.83
Nodding syndrome (NS) is a mysterious and problematic form of epilepsy that occurs in parts of South Sudan and northern Uganda. It is also endemic in a locus in Tanzania but, there, the prevalence is low and stable.84, 85 The condition has serious socioeconomic implications and, like other forms of epilepsy, generates profound social stigma.86 The obvious outward feature of NS, which afflicts children and adolescents, is a paroxysmal bout of forward and downward head movement, the nodding episodes representing epilepsy seizures.87 Children with NS display varying levels of mental retardation, often alongside notable stunted growth and failure to develop secondary sexual characteristics (hyposexual dwarfism). Affected children are outwardly healthy until the nodding episodes begin, with several dying due to uncontrolled seizures.84 The cause of NS remains unknown but there appears to be an unexplained link with Onchocerciasis infection.88, 89, 90 The African Programme for Onchocerciasis Control, which operated in the three afflicted countries, adopted mass drug administration of ivermectin in . However, it was not always possible to operate in conflict-affected regions. After the civil war in northern Uganda ceased, biannual ivermectin distribution in districts affected by both Onchocerciasis and NS since has coincided with a substantial drop in the number of new NS cases. No new cases were reported in , although there is no conclusive evidence to prove any connection.91
Many neurological disorders, such as motor neurone disease, arise due to cell death initiated by excessive levels of excitation in central nervous system neurons. A proposed novel therapy for these disorders involves silencing excessive neuronal activity using ivermectin. Because of its action on P2X4 receptors, ivermectin has potential with respect to preventing alcohol use disorders92 as well as for motor neurone disease.93 Indeed, in , Belgian scientists applied for a patent, &#;Use of ivermectin and derivates thereof for the treatment of amyotrophic lateral sclerosis&#; (Publication No.: WO//A3), to cover &#;the use of ivermectin and analogs, to prevent, retard and ameliorate a motor neuron disease such as amyotrophic lateral sclerosis and the associated motor neuron degeneration&#;.
Recent work has elucidated how ivermectin binds to target receptors and helped explain its selectivity for invertebrate Cys-loop receptors. Combined with emerging genomic information, species sensitivity to ivermectin can now be predicted and the molecular basis of ivermectin resistance has become clearer. In humans, Cys-loop neurotransmitter receptors, particularly those activated by GABA, mediate rapid synaptic transmission throughout the nervous system and are crucial for intercellular communication. They are key factors in fundamental physiological processes, such as learning and memory, and in several neurological disorders, making them attractive drug targets.94 Improved understanding of the stereochemistry of ivermectin binding will facilitate the development of new lead compounds, as anthelmintics as well as treatments for a wide variety of human neurological disorders.95, 96
Recent research has confounded the belief, held for most of the past 40 years, that ivermectin was devoid of any antiviral characteristics. Ivermectin has been found to potently inhibit replication of the yellow fever virus, with EC50 values in the sub-nanomolar range. It also inhibits replication in several other flaviviruses, including dengue, Japanese encephalitis and tick-borne encephalitis, probably by targeting non-structural 3 helicase activity.97 Ivermectin inhibits dengue viruses and interrupts virus replication, bestowing protection against infection with all distinct virus serotypes, and has unexplored potential as a dengue antiviral.98
Ivermectin has also been demonstrated to be a potent broad-spectrum specific inhibitor of importin α/β-mediated nuclear transport and demonstrates antiviral activity against several RNA viruses by blocking the nuclear trafficking of viral proteins. It has been shown to have potent antiviral action against HIV-1 and dengue viruses, both of which are dependent on the importin protein superfamily for several key cellular processes. Ivermectin may be of import in disrupting HIV-1 integrase in HIV-1 as well as NS-5 (non-structural protein 5) polymerase in dengue viruses.99, 100
Up until recently, avermectins were also believed to lack antibacterial activity. However, in , reports emerged that ivermectin was capable of preventing infection of epithelial cells by the bacterial pathogen Chlamydia trachomatis, and to do so at doses that could be used to counter sexually transmitted or ocular infections.101 In , researchers confirmed that ivermectin was bactericidal against a range of mycobacterial organisms, including multidrug resistant and extensively drug-resistant strains of Mycobacterium tuberculosis, the authors suggesting that ivermectin could be re-purposed for tuberculosis treatment. Although other researchers found that ivermectin does not possess anti-tuberculosis activity, the results were later shown to be non-comparable due to differences in testing methods, with the original findings being confirmed by further work in Japan.102, 103, 104 Unfortunately, the potential use of ivermectin for tuberculosis treatment is doubtful due to possible neurotoxicity at high dosage levels. Ivermectin was also reported to be bactericidal against M. ulcerans,105 although other researchers found no significant activity against this bacterium.106
There is a continuously accumulating body of evidence that ivermectin may have substantial value in the treatment of a variety of cancers. The avermectins are known to possess pronounced antitumor activity,107 as well as the ability to potentiate the antitumor action of vincristine on Ehrlich carcinoma, melanoma B16 and P388 lymphoid leukemia, including the vincristine-resistant strain P388.108
Over the past few years, there have been steadily increasing reports that ivermectin may have varying uses as an anti-cancer agent, as it has been shown to exhibit both anti-cancer and anti-cancer stem cell properties. An in silico chemical genomics approach designed to predict whether any existing drugs might be useful in tackling glioblastoma, lung and breast cancer, indicated that ivermectin may be a useful compound in this respect.109
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In human ovarian cancer and NF2 tumor cell lines, high-dose ivermectin inactivates protein kinase PAK1 and blocks PAK1-dependent growth. PAK proteins are essential for cytoskeletal reorganization and nuclear signaling, PAK1 being implicated in tumor genesis while inhibiting PAK1 signals induces tumor cell apoptosis (cell death).
PAK1 is essential for the growth of more than 70% of all human cancers, including breast, prostate, pancreatic, colon, gastric, lung, cervical and thyroid cancers, as well as hepatoma, glioma, melanoma, multiple myeloma and for neurofibromatosis tumors.110
Globally, breast cancer is the most common cancer among women but treatment options are few. Ivermectin suppresses breast cancer by activating cytostatic autophagy, disrupting cellular signaling in the process, probably by reducing PAK1 expression. Ivermectin-induced cytostatic autophagy also leads to suppression of tumor growth in breast cancer xenografts, causing researchers to believe there is scope for using ivermectin to inhibit breast cancer cell proliferation and that the drug is a potential treatment for breast cancer.111 Triple-negative breast cancers, which lack estrogen, progesterone and HER2 receptors, account for 10&#;20% of breast cancers and are associated with poor prognosis. Tests using a peptide corresponding to the SIN3 interaction domain (SID) of MAD, found that the SID peptide selectively blocks binding of SID-containing proteins to the paired α-helix domain of SIN3, resulting in epigenetic and transcriptional modulation of genes associated with epithelial&#;mesenchymal transition. An in silico screen identified ivermectin as a promising candidate as a paired α-helix domain-binding small molecular weight compound to inhibit SID peptide, ivermectin phenocopying the effects of SID peptide to block SIN3-paired α-helix interaction with MAD, inducing expression of CDH1 and ESR1, and restoring tamoxifen sensitivity in mass drug administration-MB-231 human and MMTV-Myc mouse triple-negative breast cancers cells in vitro. Ivermectin addition led to transcriptional modulation of genes associated with epithelial&#;mesenchymal transition and maintenance of a cancer stem cell phenotype in triple-negative breast cancers cells, resulting in impairment of clonogenic self-renewal in vitro and inhibition of tumor growth and metastasis in vivo.112
It has been reported that ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells and it has also been suggested that ivermectin synergizes with the chemotherapy agents cytarabine and daunorubicin to induce cell death in leukemia cells, with researchers claiming that ivermectin could be rapidly advanced into clinical trials.113 This potential has been supported by reports that ivermectin displays bioactivity against chronic lymphocytic leukemia cells and against ME-180 cervical cancer cells.114 Additionally, ivermectin has been shown to potentiate doxorubicin-induced apoptosis of drug-resistant leukemia cells in mice.115 Cancer stem cells are a key factor in cancer cells developing resistance to chemotherapies and these results indicate that a combination of chemotherapy agents plus ivermectin could potentially target and kill cancer stem cells, a paramount goal in overcoming cancer.
Ivermectin inhibits proliferation and increases apoptosis of various human cancers. Over-expression of P2X7 receptors correlates with tumor growth and metastasis. However, ATP release is linked to immunogenic cancer cell death, in addition to inflammatory responses caused by necrotic cell death. Exploiting ivermectin as a prototype agent to allosterically modulate P2X4 receptors, it should be possible to disrupt the balance between the pro-survival and cytotoxic functions of purinergic signaling in cancer cells. Ivermectin induces autophagy and release of ATP and HMGB1, key mediators of inflammation. Potentiated P2X4/P2X7 signaling can be further linked to ATP-rich tumor environments, providing an explanation of the tumor selectivity of purinergic receptor modulation, confirming ivermectin&#;s potential to be used for cancer immunotherapy.116 Activation of WNT-TCF signaling is implicated in multiple diseases, including cancers of the lungs and intestine, but no WNT-TCF antagonists are in clinical use. A new screening system has found that ivermectin inhibits the expression of WNT-TCF targets. It represses the levels of C-terminal β-catenin phosphoforms and of cyclin D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases. In vivo, ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without side effects. Because ivermectin has an exemplary safety record, it could swiftly become a useful tool as a WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases, encompassing multiple cancers.117
Researchers have recently reported a direct interaction between ivermectin and nematode and human tubulin, even at micromolar concentrations. When added to human HeLa cells, ivermectin stabilizes tubulin against depolymerizing effects and prevents replication of the cells in vitro, although the inhibition is reversible. This suggests that ivermectin binds to and stabilizes mammalian microtubules. Ivermectin thus affects tubulin polymerization and depolymerization dynamics, which can cause cell death. Again, given that ivermectin is already approved for use in humans, its rapid development as an anti-mitotic agent offers significant promise.118
Every year, more uses for the avermectins, and ivermectin in particular, are being found in human and animal health. Mectizan is the donated form of ivermectin manufactured by Merck & Co. for use in human health, while Stromectol is the commercially available form. Besides donated ivermectin being the sole or primary tool in the two global disease elimination programs to conquer Onchocerciasis and Lymphatic filariasis, commercial preparations of ivermectin-based drugs are also being put to ever increasing uses.
Ivermectin (systemic) dosing regimens for the four &#;official&#; target diseases and 10 so-called &#;off-label&#; diseases are as follows:
1. Onchocerciasis (due to Onchocerca volvulus):
Oral: 150&#;200&#;μg&#;kg&#;1 body weight as a single dose (optimal dose=150&#;μg&#;kg&#;1); retreatment may be required every 3&#;12 months for 9&#;15 years until asymptomatic.
2. Lymphatic filariasis (due to Wuchereria bancrofti):
Oral: 150&#;200&#;μg&#;kg&#;1 body weight (in combination with albendazole) twice annually or 300&#;400&#;μg&#;kg&#;1 as a single dose annually.
3. Strongyloidiasis (due to Strongyloides stercoralis):
Oral: 200&#;μg&#;kg&#;1 as a single dose; perform follow-up stool examinations.
Alternative dosing: 200&#;μg&#;kg&#;1per day for 2 days.
4. Scabies (due to Sarcoptes scabiei):
Oral: 200&#;μg&#;kg&#;1 as a single dose (repeat dose in 7&#;14 days (for immunocompromised or immunocompetent patients).
Crusted scabies (Norwegian Scabies)Oral: 200&#;μg&#;kg&#;1 as a single dose on days 1, 2, 8, 9 and 15 in combination with topical permethrin 5% cream. Severe cases may require additional ivermectin treatment on days 22 and 29.
&#;Off-Label&#; uses
5. Pediculosis (due to Pediculus capitis, Pediculus corporis, Pediculus pubis):
Oral: Treatment generally requires >1 dose.
Pediculus humanus capitis: Oral: 400&#;μg&#;kg&#;1 per dose every 7 days (2 doses).
Pediculus humanus corporis: Oral: 200&#;μg&#;kg&#;1 per dose every 7 days (3 doses).
Pediculosis pubis: Oral: 250&#;μg&#;kg&#;1 dose every 7 days (2 doses) or 250&#;μg&#;kg&#;1per dose every 14 days (2 doses).
6. Demodicosis (due to Demodex folliculorum and Demodex brevis):
Oral: 200&#;μg&#;kg&#;1 as a single dose, followed by topical permethrin.
7. Blepharitis (due to Demodex folliculorum):
Oral: 200&#;μg&#;kg&#;1 as a single dose, repeat dose once in 7 days.
8. Filariasis (due to Mansonella ozzardi):
Oral: 6&#;mg as a single dose.
9. Filariasis (due to Mansonella streptocerca):
Oral: 150&#;μg&#;kg&#;1 as a single dose.
10. Gnathostomiasis (due to Gnathostoma spinigerum):
Oral: 200&#;μg&#;kg&#;1 as a single dose.
11. Cutaneous larva migrans (due to Ancylostoma braziliense):
Oral: 200&#;μg&#;kg&#;1 as a single dose.
12. Trichuriasis (due to Trichuris trichiura):
Oral: 200&#;μg&#;kg&#;1 as a single dose on day 1; may repeat dose on day 4.
13. Ascariasis (due to Ascaris lumbricoides):
Oral: 200&#;μg&#;kg&#;1 as a single dose.
14. Enterobiasis (due to Enterobius vermicularis):
Oral; 200&#;μg&#;kg&#;1 single dose followed by second dose 10 days later.
(Data sources): ref. 120, (https://www.drugs.com/monograph/ivermectin.html#r1) and refs 121, 122.
The oral route is the primary delivery mechanism for ivermectin, although it has been shown that liquid formulations provide twice the bioavailability.
Lipid nanocapsules have been prepared by a new phase inversion procedure and characterized in terms of size, surface potential, encapsulation efficiency and physical stability. An activation assay and uptake experiments by THP-1 macrophage cells were used to assess the &#;stealth&#; characteristics of the nanocarrier in vitro. A pharmacokinetics and biodistribution study were also undertaken as a &#;proof of concept&#; following subcutaneous injection in a rat model. The final ivermectin-lipid nanocapsules suspension had a narrow size distribution and an encapsulation rate >90% constant over a 60-day period. Flow cytometry and blood permanence confirmed the ability of these particles to avoid macrophage uptake. Moreover, the disposition of ivermectin in the subcutaneously administered lipid nanocapsules was higher compared to treatment with a commercial formulation, with no significant differences in the biodistribution pattern. This novel delivery system is a promising therapeutic approach in anti-parasitic control and may help delay the appearance of resistance.123
Poly(d,l-lactic-co-glycolic) acid is a safe and effective biodegradable material and has been used as a drug delivery matrix for extended release applications. Results from experiments in pets and livestock indicate that poly(d,l-lactic-co-glycolic) acid containing ivermectin, either as microparticles or an injectable microsphere formulation, facilitated long-lasting delivery of the drug.124 The injectable microsphere formulation of ivermectin should be useful in a variety of other applications, including the control of external and internal parasites.125
In China, a novel microsphere drug delivery system of ivermectin using hydrophobic zein protein has been investigated. Releases of the drug from zein microspheres, tabletted microspheres and from pepsin degradation of tabletted microspheres were performed in vitro to investigate the mechanism of model drug release. The results indicate that the zein microspheres and tabletted microspheres are suitable for use as a sustained-release form of ivermectin.126
Another project developed an ivermectin nanoemulsion for investigation of transdermal drug delivery, whereby the physicochemical property, stability, in vitro drug release and transdermal property were all evaluated. The ivermectin nanoemulsion was stable when stored at 4°C and at room temperature for 1 year. The cumulative permeation and retention of ivermectin nanoemulsion in 24&#;h were 3.24 and 2.05 times, respectively, more than commercially available preparations. These results indicated that the ivermectin nanoemulsion had the advantages of simple preparation process, excellent stability and efficacious transdermal delivery, and so had good application prospects.127
A range of serious challenges confronts the task of eliminating malaria, including emerging insecticide resistance in vector mosquitoes and by vectors with outdoor and/or nocturnal or crepuscular activity. Ivermectin has the potential to overcome such challenges by killing mosquitoes taking a blood feed, at any time, on animals and humans that have enough ivermectin in their blood following treatment. Unfortunately, a single oral dose generates only short-lived mosquitocidal plasma levels. To investigate the possibilities of increased mosquitocidal activity, three different slow-release formulations of ivermectin were tested to discover whether long-term mosquitocidal levels of ivermectin in the blood could be sustained for advantageous periods of time. All formulations steadily released ivermectin over a period of more than 12 weeks. Sustained plasma levels capable of killing 50% of Anopheles gambiae feeding on a treated subject lasted for up to 24 weeks and no apparent adverse effects attributable to the drug were identified. Modeling predicts a 98% reduction in infectious vector density based on an ivermectin formulation with a 12-week drug release duration. These results indicate that relatively stable mosquitocidal plasma levels of ivermectin can be safely sustained for up to 6 months using a silicone-based subcutaneous formulation, such that modifying the formulation of ivermectin could be a suitable strategy for malaria vector control.128
As a novel method aimed at improving the safety of conventional oral ivermectin for scabies treatment, a &#;whole-body bathing method&#; was conceived. In this method, patients bathe themselves in a fluid containing ivermectin at an effective concentration. Measurement of ivermectin concentration in the skin and plasma after bathing rats in a fluid containing 100&#;ng&#;ml&#;1 of ivermectin, found the concentration of ivermectin was clearly higher than that measured in patients taking ivermectin by mouth. Consequently, the method would be a preferable drug delivery system for topical skin application of ivermectin compared with administration per os.129 A similar initiative found that the use of another promising alternative dosage form, namely fast-dissolving oral films, worked well with ivermectin.130
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