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What do penicillin, aspirin and ivermectin have in common? Apart from the fact that they rhyme, all three belong to a very select group of drugs that can claim to have had the &#;greatest beneficial impact on the health and well-being of humanity&#;.
They have at least two other things in common: all three were found in nature and all three led to a Nobel prize. Aspirin is derived from salicin, a compound found in a variety of plants such as willow trees. Its use was first mentioned by Hippocrates in 400 BC, but was isolated only in as salicylic acid and synthesised some years later as acetylsalicylic acid. The discovery of the mechanisms underlying aspirin&#;s effects gave Sir John Vane the Nobel prize in . Penicillin was isolated from mold that grew by accident on a Petri dish in Alexander Fleming&#;s laboratory. Its discovery changed the course of medicine, and earned Fleming the Nobel prize in , which he shared with Howard Florey and Ernst Chain.
And this brings us to ivermectin- not likely a drug you will have in your first-aid kit, like aspirin or penicillin, but definitely a drug that has improved the lives of millions of people since its discovery in .
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The long journey of a Japanese soil sample
The story of how ivermectin was discovered is quite incredible. In the late s, Satoshi Ōmura, a microbiologist at Tokyo&#;s Kitasako Institute, was hunting for new antibacterial compounds and started to collect thousands of soil samples from around Japan. He cultured bacteria from the samples, screened the cultures for medicinal potential, and sent them 10,000 km away to Merck Research Labs in New Jersey, where his collaborator, William Campbell, tested their effect against parasitic worms affecting livestock and other animals. One culture, derived from a soil sample collected near a golf course southwest of Tokyo, was remarkably effective against worms. The bacterium in the culture was a new species, and was baptised Streptomyces avermictilis. The active component, named avermectin, was chemically modified to increase its activity and its safety. The new compound, called ivermectin, was commercialised as a product for animal health in and soon became a top-selling veterinary drug in the world. Remarkably, despite decades of searching, S. avermictilis remains the only source of avermectin ever found.
Remarkably, despite decades of searching, S. avermictilis remains the only source of avermectin ever found.
Campbell urged his colleagues to study ivermectin as a potential treatment for onchocerciasis (also known as river blindness), a devastating disease caused by worms and transmitted by flies, that left millions of people blind, mostly in sub-Saharan Africa. The first clinical trials in Senegal showed that the treatment worked, and ivermectin was approved for human use in . Since then, more than 3.7 billion doses (donated by Merck laboratories) have been distributed globally in mass drug administration campaigns against onchocerciasis and lymphatic filariasis (another disease caused by worms, which causes severe swelling of limbs). The impact of ivermectin in decreasing the burden of these devastating diseases is immeasurable. Deservedly, Ōmura and Campbell won the Nobel prize for physiology and medicine in &#;for their discoveries concerning a novel therapy against infections caused by roundworm parasites&#; (they shared it with Youyou Tu, who discovered the antimalarial drug artemisinin). But ivermectin&#;s story of success does not end here.
A game-changing drug with many potential uses
Ivermectin, in fact, was the world&#;s first &#;endectocide&#; &#; a drug with activity against a wide variety of internal and external parasites, from nematodes to arthropods. It has also proved to be astonishingly safe for humans. This is because the drug acts by binding to special channels on the cell membrane (called glutamate-gated ion channels) that play a fundamental role in nematodes and insects. In mammals, however, the drug has no effect since the neurons expressing these channels are protected by the blood brain barrier. In addition to its high safety profile, no convincing evidence of drug resistance has been found to date among Onchocerca worms, despite 30 years of continued use and billions of doses administered.
All this explains why ivermectin is becoming increasingly attractive to treat other diseases in humans. For example, long-term treatment with ivermectin to control onchocerciasis was shown to reduce the prevalence of other parasitic worms called soil-transmitted helminths, which infect up to one fifth of the world&#;s population and are a major cause of malnutrition and growth impairment in children. Furthermore, ivermectin is very effective against Strongyloides, a roundworm that infects up to 35 million people every year. This has motivated studies - such as the STOP project led by ISGlobal - to test the efficacy of adding ivermectin to the current recommended treatment against these intestinal worms.
Ivermectin has also proved to be effective against external parasites such as head lice and the tiny Sarcoptes mite, which causes scabies (an itchy skin condition, of which there are 3oo million cases every year).
But that is not all. The observation that mosquitoes feeding on individuals treated with ivermectin have a shorter lifespan, inspired the innovative idea of using the drug as a &#;weapon&#; against malaria-transmitting mosquitoes. The BOHEMIA project, also led by ISGlobal, will test the impact of giving ivermectin to entire communities, and their livestock, on mosquito populations and malaria prevalence in two highly endemic areas for the disease.
The BOHEMIA project, also led by ISGlobal, will test the impact of giving ivermectin to entire communities, and their livestock, on mosquito populations and malaria prevalence in two highly endemic areas for the disease.
Because of its impact, safety and versatility, ivermectin has earned the title of &#;wonder drug&#; among public health specialists. Treating entire communities with the drug could represent a safe and effective means of &#;hitting several birds with one stone&#;; in other words, reducing the prevalence of several disabling parasitic diseases and improving overall community health in the developing world. Whether ivermectin lives up to these great expectations, remains to be seen. Meanwhile, its trip from a Japanese sample soil to improving the lives of millions of people affected by parasitic worms, is definitely worth a story.
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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.
Figure 5Ivermectin has been formulated in a variety of ways, for example, as an injectable solution for livestock (a); donated as tablets for human use to treat Onchocerciasis (b); and as a commercial tablet preparation for scabies and strongyloidiasis (c). (Photo credits: Andy Crump). A full color version of this figure is available at The Journal of Antibiotics journal online.
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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
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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
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
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