Published: 15 February 2017
Review Article
Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and
exceed expectations
Andy Crump
The Journal of Antibiotics volume 70, pages 495–505 (2017)
Cite this article
Abstract
Over the past decade, the global scientific community have begun to recognize
the unmatched value of an extraordinary drug, ivermectin, that originates from
a single microbe unearthed from soil in Japan. Work on ivermectin has seen its
discoverer, Satoshi Ōmura, of Tokyo’s prestigious Kitasato Institute, receive the
2014 Gairdner Global Health Award and the 2015 Nobel Prize in Physiology or
Medicine, which he shared with a collaborating partner in the discovery and
development of the drug, William Campbell of Merck & Co. Incorporated. Today,
ivermectin is continuing to surprise and excite scientists, offering more and
more promise to help improve global public health by treating a diverse range
of diseases, with its unexpected potential as an antibacterial, antiviral and anti-
cancer agent being particularly extraordinary.
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Introduction
The unique and extraordinary microorganism that produces the avermectins
(from which ivermectin is derived) was discovered by Ōmura in 1973 (Figure 1).
It was sent to Merck laboratories to be run through a specialized screen for
anthelmintics in 1974 and the avermectins were found and named in 1975. The
safer and more effective derivative, ivermectin, was subsequently
commercialized, entering the veterinary, agricultural and aquaculture markets in
1981. The drug’s potential in human health was confirmed a few years later and
it was registered in 1987 and immediately provided free of charge (branded as
Mectizan)—‘as much as needed for as long as needed’—with the goal of
helping to control Onchocerciasis (also known as River Blindness) among
poverty-stricken populations throughout the tropics. Uses of donated
ivermectin to tackle other so-called ‘neglected tropical diseases’ soon followed,
while commercially available products were introduced for the treatment of
other human diseases.
Figure 1
figure 1
Satoshi Ōmura collecting soil from the very site where the fateful sample
containing Streptomyces avermectinius (S. avermitilis) was taken in 1973.
(Photo credit: Andy Crump).
Full size image
Many excellent, eloquent and comprehensive reviews covering the discovery,
advent, development, manufacture and distribution of ivermectin have been
published by those intimately involved with the various stages.1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14 It would be folly to replicate those here. Instead, it is the
current status, beneficial global health impact and exciting future potential that
ivermectin has to offer to human health worldwide that will be the focus of
attention.
Today, ivermectin remains a relatively unknown drug, although few, if any, other
drugs can rival ivermectin for its beneficial impact on human health and welfare.
Ivermectin is a broad-spectrum anti-parasitic agent, primarily deployed to
combat parasitic worms in veterinary and human medicine. This
unprecedented compound has mainly been used in humans as an oral
medication for treating filarial diseases but is also effective against other worm-
related infections and diseases, plus several parasite-induced epidermal
parasitic skin diseases, as well as insect infestations. It is approved for human
use in several countries, ostensibly to treat Onchocerciasis, lymphatic filariasis
(also known as Elephantiasis), strongyloidiasis and/or scabies and, very
recently, to combat head lice. However, health workers are increasingly utilizing
it in an unsanctioned manner to treat a diverse range of other diseases, as
shown in Appendix 1.
The past: unmatched successes
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 1979, 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).
Figure 2
figure 2
S. avermitilis, sole source of the avermectins: (a) colony and (b)
photomicrograph. (Photo credits: Kitasato Institute).
Full size image
Figure 3
figure 3
The molecular structure of avermectin, a complex of several compounds, which
then underwent chemical modification to produce ivermectin, a combination of
two dihydroderivatives.
Full size image
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 1981, it quickly became
used worldwide to combat filarial and other infections and infestations in
livestock and pets.
Registered for human use in 1987, 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
2014/2015 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 2016.
The African Programme for Onchocerciasis Control was created in 1995 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 2025 will be achieved.23 Latest models indicate
that if the 2025 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-1990s, 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 2015,
almost 374 million people required ivermectin for Lymphatic filariasis, with
176.5 million being treated.25 In 2015, 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 1998.26
Figure 4
figure 4
(a) An African man with blindness, skin damage and disfigurement due to
Onchocerciasis and Lymphatic filariasis. (b) A community-directed distributor
of ivermectin recording the administration of a combination of ivermectin with
albendazole, used to treat and protect individuals in areas where the two
diseases co-exist—both diseases being poised for elimination as public health
problems within a decade. (Photo credits: Andy Crump).
Full size image
During 2016, 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 1995–2010, 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.
The present: a puzzle
The avermectins potentiate neurotransmission by disrupting glutamate-gated
chloride channels, as well as having minor effects on γ-aminobutyric acid
(GABA) receptors. They disrupt neurotransmission in nerve and muscle cells,
causing hyperpolarisation of the neuronal membrane, inducing paralysis of
somatic muscles, particularly the pharyngeal pump, killing the parasites. GABA-
related channels are commonplace throughout nematodes and insects,
whereas in mammals, GABA receptors and neurons are restricted to the central
nervous system. Ivermectin is therefore very safe for vertebrates, as it cannot
cross the blood–brain barrier. Adult filarial worms (macrofilariae), once paired,
do not require substantial movement or pharyngeal pumping. Consequently,
ivermectin treatment results in a rapid and almost total (98%) reduction in
dermal-dwelling immature worms (microfilariae),30 but has only a limited
sterilizing effect on female macrofilariae.31
Ivermectin’s mode of action against parasites in the human body remains to be
clarified. There is a substantial disparity between maximum plasma
concentrations after ivermectin administration and the concentrations needed
to induce paralysis in microfilariae. Support has been accumulating for the
evidenced-based hypothesis that the clearance of microfilariae is governed by
immunoregulatory processes.
Ivermectin treatment causes microfilariae to quickly disappear from the
peripheral skin lymphatics, with long-lasting effect, the high lipid solubility of
ivermectin resulting in it being widely distributed throughout the body.
Following oral administration, mean peak plasma concentration occurs
approximately 4 h after dosing, a second peak at 6–12 h probably arising
because of enterohepatic recycling of the drug, with the plasma half-life of
ivermectin being around 12 h.32, 33, 34 Dermal microfilarial loads are reduced
by 78% within 2 days, and by some 98% within 2 weeks of treatment,
remaining at extremely low levels for about 12 months. As lowest levels of
microfilariae occur well after ivermectin administration, they are not necessarily
killed when plasma drug levels are highest.
Ivermectin’s primary target is glutamate-gated chloride channels, although it
also active against other invertebrate neurotransmitter receptors, including
GABA-, histamine- and pH-sensitive chloride channels.35, 36, 37 In addition,
ivermectin exposure alters expression of genes involved in the reproduction
mechanism of female worms, even at low concentrations.38, 39
Latterly, research has indicated that glutamate-gated chloride channels activity
is solely expressed in musculature surrounding the filarial excretory–secretory
vesicle, suggesting that chemicals originating from the excretory–secretory
vesicle are regulated by the activity.40 It is increasingly believed that the rapid
microfilarial clearance following ivermectin dosing results not from the direct
impact of the drug but via suppression of the parasite’s ability to evade the
host’s natural immune defense mechanism.41, 42, 43, 44, 45, 46, 47, 48, 49
Immunomodulatory agents often display fewer side effects than drugs, as well
as producing less opportunity for creation of resistance in target
microorganisms, which helps explain the absence of drug resistance in
humans.
The future: new potential/new target diseases
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 5
figure 5
Ivermectin 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.
Full size image
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
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
Trichinosis
Globally, approximately 11 million individuals are infected with Trichinella
roundworms. Ivermectin kills Trichinella spiralis, the species responsible for
most of these infections.53
Disease vector control
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
Malaria
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
Leishmaniasis
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
African trypanosomiasis (sleeping sickness)
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
American trypanosomiasis (Chagas disease)
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
Schistosomiasis
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
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
Rosacea
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.
Asthma
A 2011 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
Epilepsy
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 1997. 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 2012 has coincided with a
substantial drop in the number of new NS cases. No new cases were reported
in 2013, although there is no conclusive evidence to prove any connection.91
Neurological disease
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 2007, Belgian
scientists applied for a patent, ‘Use of ivermectin and derivates thereof for the
treatment of amyotrophic lateral sclerosis’ (Publication No.:
WO/2008/034202A3), 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
Antiviral (e.g. HIV, dengue, encephalitis)
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
Antibacterial (tuberculosis and Buruli ulcer)
Up until recently, avermectins were also believed to lack antibacterial activity.
However, in 2012, 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 2013, 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
Anti-cancer
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
Novel delivery systems
Drug delivery mechanisms can affect drug pharmacokinetics, absorption,
distribution, metabolism, duration of therapeutic effect, excretion and toxicity.
As new therapeutics appear, there is an accompanying necessity for improved
chemistries and novel materials and mechanisms to target their delivery
(including to currently impractical/inaccessible locations), at efficacious
therapeutic concentration, and for the required period of time.119 Ivermectin is
one of the most extensively used anti-parasitic agents worldwide. However, as
with most drugs, minor variations in formulation may change the plasma
kinetics, the biodistribution, and consequentially, its efficacy. It has already
been demonstrated that oral solutions produce twice the systemic availability
than solid forms (tablets or capsules).34 As shown in Appendix 2, the
possibility of novel systems for delivering ivermectin opens up a plethora of
opportunities for usage of the drug against currently targeted diseases, as well
as realizing its potential to combat a totally new range of diseases and
conditions. It may therefore be likely that novel formulations and delivery
systems, such as those in Appendix 2, as well as ivermectin-containing skin
patches, slow-release formulations, oral solutions, ivermectin-impregnated
clothing or newly discovered time-sensitive shape-shifting materials, may
become innovative and effective means of delivering the drug in the near
future. They may well also create innovative, cost-effective delivery
mechanisms to revitalize existing uses of ivermectin.
As a further indication of the increasing attention being paid to ivermectin, in
2013, Chinese scientists applied for an international patent ‘Use of ivermectin
and derivatives thereof’ (Publication No.: WO/2014/059797) for new uses in
the ‘development and manufacture of medicaments for human use in treating
metabolic related diseases, such as hyperglycemia, insulin resistance,
hypertriglyceridemia, hypercholesterolemia, diabetes, obesity and so on, and
Famesoid X receptor-mediated diseases, such as cholestasia, gallstones, non-
alcohol fatty liver disease, atherosclerosis, inflammation and cancer’.
Essentially, a unique, multifaceted ‘wonder’ drug of the past and present may
yet become an even more exceptional drug of the future.
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Acknowledgements
Having spent a good deal of time during the past 25 years among remote rural
communities in Africa while following the ivermectin story, I wish to convey to
Satoshi Ōmura the grateful thanks of millions of men, women and children in
such communities whose health, nutrition, education, economic situation and
social status have been immeasurably improved by their access to ivermectin.
Without his innovation, vision, drive and unwavering commitment, their lives
and livelihoods would still be blighted by disease and misery. I also wish to
convey my profound thanks to him for the opportunity of working alongside him
and for his personal friendship, chivalry and tutelage in the art of interpersonal
respect and understanding in the pursuit of all partnerships and collaborative
endeavors.
Author information
Authors and Affiliations
Graduate School of Infection Control Sciences, Kitasato University, Minato-Ku,
Japan
Andy Crump
Corresponding author
Correspondence to Andy Crump.
Ethics declarations
Competing interests
The author declares no conflict of interest.
Appendices
Appendix 1
Current ivermectin usage
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.
Appendix 2
Novel delivery systems for ivermectin
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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