Avermectin compounds share a similar structure with Milbemycin. The major difference between the two classes of compounds is at the position number 13 of the macrolide ring, where a bisoleandrosyloxy group is substituted. Other alterations include attachment of alkyl group of a different type at C-25 in both classes. Deleting the hydroxyl group at position number 12 results in the production of 13-deoxyavermectin (avermectin aglycone), which is very similar to some milbemycins and they can therefore be referred to as glycosylated milbemycins [ 8 ]. The bisoleandrosyl group at C-13 position is lipophilic and it is not important for the biological activity and is therefore often a target for chemical modification [ 9 ]. The easy accessibility to 4-position of avermectin has made it one of the most studied site for modification. Different chemical groups such as acyl, amino, or thio groups have been inserted at this position to alter the chemical properties of the drugs (solubility, stability distribution) without altering the potency of the parent drug [ 10 , 11 ]. Different derivatives of the parent drug have been produced by modifying the terminal sugar of avermectin to enhance the potency and biological activity, and improve its efficacy as an anthelmintic drug [ 5 , 6 ]. 24-hydroxymethyl-H 2 B 1a and 3&#;-O-desmethyl-H 2 B 1a are the two major metabolites of ivermectin that are found in the liver of cattle and swine. It was also observed that the concentrations of the metabolites were lower than the parent compounds. Also, the transformation of the drug in the soil produced a more polar by-product of ivermectin, which is less toxic than the parent drug to daphnids [ 12 ]. With respect to the physical and chemical properties of avermectin, they are less volatile, and poorly soluble in water, as 50% of ivermectin takes less than 6 h to be dissolved in water, while 90% of the drugs takes more than 16.8 days to be dissolved in water. They have a high vapor pressure, which makes it difficult for them to be distributed in the atmosphere [ 13 ]. Avermectins are generally soluble in organic solvents, such as ethanol, chloroform, diethyl ether, ethyl acetate. They have a high adsorption coefficient, which makes them less likely to accumulate in the water column. The hydrophobic properties (log K ow = 3.2) and high-affinity organic matter make ivermectin to accumulate in the environment [ 9 , 14 ]. Experimental data obtained from field and laboratory research have shown that ivermectin residues are strongly attached to soil particles [ 15 ]. The high K oc of ivermectin makes it immobile in the environment. Ivermectin is lipophilic, which may make it bio accumulate in animal tissues. However, the lipophilic nature of the drug is countered by the high molecular weight, which prevents it from crossing the biological membrane [ 10 ].
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The mechanism of avermectin biosynthesis from S. avermitilis is present in a cluster of gene and has been sequenced. This cluster of genes encodes all the enzymes involved in various steps in the avermectin synthesis pathway [ 8 ]. The first step is the synthesis of avermectin aglycone catalyzed by polyketide synthases, followed by aglycone modification, synthesis of modified sugar and the avermectin aglycone is glycosylated with the modified sugar. Eight different types of avermectins are synthesized from these clusters of gene [ 16 ]. The polyketide synthase complex activity requires four proteins (AVES 1, AVES 2, AVES 3, and AVES 4) for the synthesis of the initial avermectin aglycone. There is a strong similarity between the activity of the enzyme and type I polyketide synthases [ 16 ]. The enzyme uses either isobutyrl CoA 2-methylbutyrl CoA as a substrate, after which seven acetate units and five propionate units are added to produce avermectin &#;A&#; or &#;B&#; series, respectively [ 16 ]. The first substrate is now removed from the enzyme complex (thioesterase domain of AVES4), via the cyclization to form cyclic esters. The other enzymatic activity involved the modification of the avermectin aglycone includes: (1) AveE which contains a Cyt P450 monooxygenase activity and catalyzes the cyclization between C6 and C8 to form a furan ring, (2) AveF which has a keto reductase activity that catalyzes the reduction of keto group on C5 to a hydroxyl group, using NAD(P)H as an electron donor, (3) The mechanism by which AveC acts as a dehydratase between C22&#;C23 in module 2 is not well understood, AveD possesses a methyltransferase activity that requires SAM [ 17 , 18 ]. Whether AveC or AveD acts on the aglycone determines whether the resulting avermectin aglycone produces avermectin series &#;A&#; or &#;B&#; and series 1 or 2, respectively. Downstream of AveA4 are none open reading frames (orf1, aveB-BVIII) that are involved in the synthesis of the sugar and glycosylation [ 17 ]. Analysis of orf1 sequence shows that it might probably possess a reductase activity that is active but might not be needed in the avermectin synthesis. AveBI is involved in avermectin aglycone glycosylation with an activated sugar (dTDP-sugar). AveBII-BVIII are involved in the synthesis of dTDP-L-oleandrose [ 19 ]. The summary of avermectin biosynthesis has been shown in .
The mode of action of milbemycins is not well understood compared to avermectin although its anti-parasitic properties have been discovered and described more than two decades ago [ 62 ]. Nemadectin is the most potent milbemycin that has unsaturated long-chain C at its 25-position. Nemadectin has been shown to possess insecticidal and nematocidal activities. It also serves as a substrate for moxidectin (MOX) synthesis, a commercial endectocide [ 63 ]. As with other macrocyclic lactones, there is a high affinity for invertebrates-specific glutamate-gated ion channels. The glutamate-gated binding site exists in juxtaposed to GABA-gated chloride channels, therefore, there is a possibility of macrolide endectocides enhancing GABA-gated chloride channels. MOX also binds to the myroneural junctions of anthropoids and neuronal membrane of nematodes [ 64 ]. Hyperpolarization of the postsynaptic cells occurs as a result of the influx of chloride ion, which decreases the resistance of the cell membrane. This disrupts the neurotransmission processes, causing disability, death, and elimination of the parasite [ 65 ]. It has also been reported that MOX inhibits the release of dopamine from the striatum due to the activation of the GABAergic system, leading to reduced motor coordination in rats [ 66 ].
Low concentration of ivermectin does not destroy the worms by its effect on GluCls expressed in the neurons, as hyperpolarization caused by ivermectin spreads through gap junctions encoded by unc-7 and unc-9 to other excitable cells important for the worm&#;s activity. A study in GluClα3 (AVR-14) and GluClα1 (GLC-1) to confer sensitive gap junction to ivermectin has shown that it is important for hyperpolarization to spread from the extra pharyngeal nervous system to the pharynx [ 53 ]. This process occurs by connecting neurons, such as I1 and RIP, which may not be expressed by GluCls [ 28 , 54 ]. The information on the role of avermectins on chloride channels opening, decreasing muscle fiber&#;s resistance to input, GABA-like effects, and nerve signal transmission has been well documented [ 55 ]. Some early results on different species, various model systems, and at varying concentrations are as follows: stimulation of high-affinity binding of GABA and benzodiazepine to rat brain membranes. Listed below are some of the experiments that were conducted using various types of species, different experimental designs, with different doses. A quick disabling of nematodes devoid of hypercontraction or soft disability. A very low concentration of avermectin induced a quick and fast irreversible inhibition of inhibitory postsynaptic potential in the nerve of crustacean and delay reducing the excitatory potential amplitude and elevating the chloride ion entry. High avermectin induced by membrane conduction was inhibited using GABA antagonists (e.g., bicuculline and picrotoxin) [ 56 ]. The signal transmission between ventral interneurons and motor neurons of Ascaris was blocked. The nanomolar concentration of avermectin in the extensor tibiae muscle of the locust Schistocerca gregaria has been reversibly increased by the chloride ion in the GABA sensitive fibers. Micromolar concentrations of avermectin also reversibly prevent muscle fibers from Schistocerca gregaria that are either sensitive or insensitive to GABA [ 57 ]. Another study showed that subpicomolar concentration of avermectin induced reversible opening of multi-transmitter-gated chloride channels isolated from the stomach muscle of crayfish using a patch-clamp technique. It should be noted that the chloride channel can be activated using GABA, glutamate, or acetylcholine [ 58 ]. This experimental design was able to distinguish between two different conductance states, the first being activated by carbachol, glutamate, ibotenic and quisqualic acid, while the second was activated by GABA and muscimol (a GABA agonist). Avermectin was not effective in activating the second conductance like GABA. This is because the effect is direct and thus it does not require a second messenger pathway. However, a huge non-reversible increase in the opening of chloride channels occurs when the avermectin concentration increased to or above 10 pmol and this reversible or nonreversible opening of the chloride channels was blocked by picrotoxin [ 58 ]. Further studies were carried out on the effect of ivermectin on the electrophysiology of the oocytes obtained from Xenopus laevis. A 1&#;2.5 kb size of poly (A+) RNA obtained from C. elegans was injected into the oocytes. The results showed that the induction of inner-bound membrane stream associated with high ivermectin concentration as well as increasing the entry of chloride ion across the membrane [ 59 ]. The result also shows that GABA, muscimol, benzodiazepam or bicuculline do not alter the effect of ivermectin, while picrotoxin does. Based on the above-mentioned results, it can be concluded that ivermectin can directly induce the GABA-insensitive chloride channels opening [ 59 , 60 ]. To understand the mechanism by which avermectin acts against different species of insects, arthropods, nematodes and immature worms such as flukes, tapeworms and filarial worms, couples with good tolerance by the host animals. It is necessary to isolate the binding site of avermectin in various species and study how it induces the opening of chloride channels and increases hyperpolarization, since it has been established that its binding site is specific to other effector molecules [ 61 ].
A commonly used therapy in recent times has been based on oral, parenteral, topical, or spot topical (as in veterinary flea repellant &#;drops&#;) administration of avermectin. They show activity against a broad range of nematodes and arthropod parasites of domestic animals at doses of 300 μg/kg or less than 200 μg/kg of ivermectin appears to be the common interspecies standard, from humans to horses to house pets, unless otherwise indicated. Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activity [ 40 ]. Taylor et al. [ 41 ] illustrated an annual single oral dose of 150 μg/kg of ivermectin was given to prevent microfilarial production and inhibit disease progression. In humans, the most commonly used dose of ivermectin varies from 150 to 200 µg/kg for the treatment of enterobiasis onchocerciasis, and strongyloidiasis, while a higher dose of 400 µg/kg was used for lymphatic filariasis. It is worth noting that ivermectin was administered twice a week, up to 1.6 mg/kg subcutaneously, for patients with spinal damage and muscle spasms, for 12 weeks [ 42 ]. Avermectin IB1 demonstrated the potential to minimize tumor growth at a dose of 1 mg/kg in SHK male mice with a strong Ehrlich carcinoma as well as human acute myeloblastic leukemia, breast and colon carcinoma, glioblastoma, and murine lymphosarcoma cell line. The median dose used was 5 mg/kg (2.4&#;40 mg/kg), equivalent to 0.40 mg/kg in humans [ 43 , 44 , 45 , 46 ]. A dose of 150 μg/kg of ivermectin was reported to be linked to reduce mortality rates and lower healthcare resource use in COVID-19 patients. [ 47 , 48 ]. Laing et al. documented that a single dose of 30 µg/kg of ivermectin significantly reduced the number of skin microfilariae, and that effect continued for at least 6 months without any significant adverse effects [ 49 ].
Ivermectin is the most common avermectin derivative. It is available in numerous forms and can be applied through different routes of administration. It is used by humans to treat gastrointestinal strongyloidiasis in the United States and other countries and has been used to treat onchocerciasis and strongyloidosis [ 10 ]. In animals, it is used to prevent heartworm, treat ectoparasite, and as a microfilaricide. Its dosage is dependent on the kind of treatment, i.e., 0.006 to 0.012 mg/kg has been used for heartworm prevention in dogs and 0.024 mg/kg in cats, 0.05 to 0.2 mg/kg as a macrofilaricide in dogs and 0.3 to 0.6 mg/kg to treat ectoparasites [ 20 ]. It is administered at high concentration in animals (10&#;18.7 mg/mL) that may lead to overdose due to wrong calculation or exposure [ 10 ]. Exposure may also be from the remnants of the de-wormer or drippings or droplets of the horse&#;s mouth when dewormed, or from the excreta of treated animals. For example, a study showed that the peak amount of ivermectin was 2.5 mg/kg of horse excreta after 2.5 days post-exposure [ 21 ]. This meant that for a collie to be exposed to a mild toxic level of ivermectin (0.1 mg/kg), a 27.3 kg (60 lb) collie homozygous for ABCB1-1Δ would ingest about 1.1 kg (2.4lb) of excreta [ 22 ]. Some breeds of dogs have been shown to develop clinical symptoms following ivermectin ingestion. However, it was not known whether dogs have defects in the ABCB1 gene, particularly when the dose was between 0.08&#;0.34 mg/kg [ 23 ]. It was also shown that dose higher than 0.2 mg/kg resulted in mild symptoms in normal animals and developed severe signs when the dose was above 1 mg/kg [ 23 , 24 ]. The study also found that German shepherds are sensitive to low doses of ivermectin, with a small percentage having a defect in ABCB1 gene, which could be correlated with clinical signs observed in normal dogs at low doses [ 25 ]. However, these problems have not been encountered with therapeutic doses to avoid heartworm in normal or ABCB1 gene defective dogs. No clinical signs were observed when collies sensitive to ivermectin administered at a high dose of 0.06 mg/kg [ 26 ]. Patients with ABCB1 gene defect can develop clinical signs when administered a high dose of ivermectin as a microfilaricide or for demodicosis. Sometimes dogs with normal ABCB1 genotype can develop clinical signs when administered a high dose of ivermectin. Other clinical symptoms have been observed including bradycardia, tremors, hypersalivation, lethargy, ataxia, and blindness [ 26 , 27 ]. Several derivatives were developed including eprinomectin, which shows prolonged activity and no milk withdrawal and selamectin with a greater margin of safety than IVM in MDR1 mutated dogs [ 28 ].
The origin of ivermectin use in the treatment of human diseases started in , in an effort by the united nation to tackle the challenges posed by tropical diseases, which have become endemic in various areas of Africa. Some of these diseases that are treated with ivermectin, including onchocerciasis, caused by a filarial nematode, Onchocerca volvulus [73]. Presently ivermectin is used to treat strongyloidiasis, scabies, pediculosis, gnathostomiasis, myiasis, and leishmaniasis [74,75]. In addition, other studies have shown that ivermectin can be used to reduce the prevalence and spread of other infectious diseases linked to a helminthic parasites transmitted through soil such as strongyloidiasis, ascariasis, trichuriasis, and enterobiasis hookworm, Trichuris and Ascaris. These diseases have been identified as major cause of death for underdeveloped children with poor nutrition and retarded growth [76,77]. Topical administration of ivermectin to children also reduced the prevalence of head lice and scabies [78]. Moreover, ivermectin has also been shown to be effective in the treatment of Papulopustular rosacea (PPR), a human skin disease characterized by transient pustules and facial erythema [79]. In order to enhance the efficacy of ivermectin in the treatment of infectious diseases in human, it has been administered with other drugs. For example, ivermectin is combined with doxycycline to inhibit onchocerciasis transmission in humans [80]. Other study showed that ivermectin combined with doxycycline has also been shown to improve the efficacy of ivermectin in suppressing microfiladerma, as it has been shown to reduce the symbiotic endobacteria of filariae, Wolbachia spp. that is important for the reproduction and survival of mature female worms [81]. Moreover, another study stated that the daily administration of ivermectin-antibiotic combination for six weeks was more effective in reducing the microfiladerma levels in infected patients than ivermectin alone. The antiparasitic activity of ivermectin in the treatment of onchocerciasis was also improved when combined with amorcazine compared to ivermectin itself [82]. The study also showed that ivermectin has the potential to be used in the treatment of mites and human lice infestation [83]. Ivermectin has also been reported to possess other therapeutic properties such as filaricidal in the lymphatic system and as an anticonvulsant against lidocaine- and strychnine-induced convulsion [84]. The anticonvulsant properties of ivermectin is linked to the activation of a receptor-ion channel that is independent in the glycine and strychnine pathway [85]. Moreover, Kane et al. [86] revealed that the anticonvulsant effect of ivermectin is mediated by GABAA receptors. The summary of human uses of ivermectin is shown in .
One of the commercially available forms of avermectin is abamectin, which contains 80% avermectin B1a and 20% avermectin B1b. It is reportedly to be used either as an insecticide or acaricide in several countries, mostly in countries that depend on agriculture and animal husbandry for preservation and protection, respectively [87,88]. In addition, Khalil et al. [32] reported its use as a protective agent against plant nematodes that feed on the roots, during seed germination, coupled with its long shelf-life, while Hussein and Sabry [89] reported its molluscicides activity against matured E. vermiculata in the growth of wheat. Another avermectin product, emamectin benzoate, a semi-synthetic product of avermectin has been shown to be very active as a nematocide in destroying root-knot nematodes when administered at the nursery bed of chili. It significantly reduced the population of nematodes meloidogyne spp.) in a dose-dependent manner. Avermectin has been reported to be effective against other nematodes including: Hoplolaimus galeatus and Tylenchorynchus dubius [90]. Several reports have confirmed the efficacy of avermectin as a nematocides against various nematodes that attack plants. Jayakumar et al. [90] reported the effectiveness of avermectin in the treatment of seed against reniform nematode, and Rotylenchulus reniformis used crude avermectin to treat seed. Blackburn et al. [91] also reported the nematocide effect of avermectin B1 in reducing the population of H. galeatus and T. dubius. In an experiment conducted by Das et al. [92], the efficacy of emamectin benzoate as a nematocide in the reduction of root-knot nematode (Meloidogyne spp.) populations was reported when used in the nursery bed of chili.
An observed non-prescriptive activity of avermectins is its antibacterial activity. The primary pharmacological activity of avermectins is its use as insecticides, nematocides, antihelminthic and arachnicides [93]. However, recent studies have shown that avermectin is not effective against broad spectrum bacteria, others have shown it is effective against some bacteria species [93]. Some avermectins have been evaluated for antibacterial activities include ivermectin, selamectin, doramectin, and moxidectin. Using the approved standard methods based on the gold standard proportion, glycerol reuptake or nitrate reductase, resazurin of viable colony forming unit after exposure [94]. The 3 (4, 5-dimethylthiazol-2-yl) 2, 5 diphenyl tetrazolium bromide (MTT) assay method was used to test the antibacterial activity of four different avermectins in different Mycobacterium species. All four were effective against both Mycobacterium bovis and M. tuberculosis laboratory strains (H37Rv, CDC , and Erdman) in a concentration-dependent manner. While all of them were effective against M. smegmatis apart from doramectin. They showed a lower inhibitory effect against M. avium [95]. With a recent study showing that the presence of glycerol in the assay medium plays an important role in the antibacterial activity of some drugs on some mycobacterium species, the inhibitory activities of selamectin, moxidectin, and ivermectin were only slightly affected in the absence of glycerol in the assay medium [93,96,97]. Lim et al. [93] also tested the antibacterial activity of avermectins on some M. tuberculosis that are resistant to drugs (multidrug-resistance [MDR] and extensive drug-resistance [XDR]. Twenty-seven MDR and XDR isolated from different geographical location have been confirmed to be resistant to anti-TB drugs such as kanamycin, ethambol, rifampin, ethionamide, rifabutin, isoniazid, p-aminosalicyclate (PAS), streptomycin and pyrazinamide. All were sensitive to MIC activity of avermectins except three MDR and two drug susceptibility. Clinical trials of selamectin, moxidectin, and ivermectin have shown that their antibacterial activity is bactericidal against M. tuberculosis strain H37Rv and mc2 587. They all reduce the number of the initial bacteria viability up to six orders of magnitude [93]. Selamectin is the most potent with respect to bactericidal activity, while ivermectin was the most potent bactericidal avermectin against MDR strain. The sensitivity of Mycobacterium spp. to avermectin as compared to other bacteria might be linked to the nature and complexity of their cell wall envelope [98]. As stated earlier by Wolstenholme and Rogers [99], avermectin causes paralysis and fecundity by binding to glutamate-gated chloride channels on the muscles and nerves of the parasite, which does not occur in humans due to the lack of different channels that bind to avermectins. Observations that selamectin and moxidectin, majorly used as an antiparasitic drugs in animals with a report of no toxic effect, showed a strong activity against M. bacterium. This shows that avermectins, with their high specificity for some mycobacterium can be selected for some pathogens that are resistance to antibacterial drugs, without any concern for side effect on the intestinal gut flora when administered orally. The study also showed that ivermectin and moxidectin can also inhibit the growth of different strains of M. ulcerans at concentrations ranging from 4 to 8 μg/mL. While they are not effective in M. marinum which shares similar features with M. ulcerans. They also found out that IVM performed better than the standard drug rifampicin at the administered MIC concentration. And when the two drugs were combined (IVM and rifampicin), a better activity was observed as compared to individual activity in eliminating the parasite [99]. It was suggested that the induction of P-glycoprotein/ABCB1 in human by rifampicin may reduce the plasma concentration of IVM. Of all the types of avermectin tested against M. ulcerus, that causes Buruli ulcer (BU) in vitro, selamectin and milbemycin were the most potent with MIC concentrations of 2 to 4 μg/mL and 2 to 8 μg/mL, respectively, while IVM and moxidectin were not significantly active (MIC > 32 μg/mL) overall, it was concluded that selamectin had the best potential in the treatment of BU. Besides, of all the tested isolates of Staphylococcus aureus (>20) using IVM, only 2 isolates were sensitive to IVM [94]. The LD50 of IVM in animals is 50 mg/kg, while the administered dose in animals and humans is 200 μg/kg and peaked at the concentration of 52 ng/mL in plasma. The potential of IVM in the treatment of methicillin-resistance and methicillin-sensitive S. aureus isolates can make IVM a good antibiotic in addition to its anti-helminthic properties [94].
Malaria is one of the top diseases that cause death among infants, especially in India and Africa. It is caused by Plasmodium falciparum in Africa and transmitted to humans by female anopheles. Progress has been made in reducing malaria deaths since [100]. However, recent data showed that there is substantial rise in the number of malaria deaths. It was noticed that the major challenge in the management of malaria is the complexity in the life cycle of the parasite, which often develops resistance to various approved drugs [101]. The insecticidal activity of ivermectin and its specific effect on Anopheles mosquito prompted an investigation into its antiplasmodial activity against the malaria parasite in order to use it for malaria treatment [102]. The antiplasmodial and insecticidal effects of ivermectin often depend on the concentration, route of administration, duration, species type, and experimental design [103]. Ivermectin was reported to inhibit the development of P. falciparum at the asexual stage with IC50 in the range of 1&#;10 µg/mL, however, ivermectin had no effect at concentrations of 3.9&#; ng/mL on P. vivax [104]. However, incubation of ivermectin with a different dilution of P. vivax with plasma from healthy individuals (4.28&#;34.24 ng/mL) for 4 h, ivermectin was able to inhibit the growth of P. vivax. It is reported that the metabolite of ivermectin may be responsible for the inhibitory activity of ivermectin at low concentration. The lack of ivermectin effect on P. falciparum in vitro might be due to the absence of the glutamate-gated chloride channel and GABA-gated chloride channels in P. falciparum where ivermectin binds to insects [104,105] it was also reported that ivermectin has no significant effect on P. falciparum at the blood stage of development in vitro, while the possible mechanism of ivermectin in inhibiting the parasite at the blood stage might be by blocking nucleo-cytoplasmic shuttling of P. falciparum signal transduction particle (SRP) components [104]. This process takes place through a cascade of events involving the induction of chloride dependent polarization of the Plasmodium nuclear membrane then altering the shuttling of importin α/β, which leads to the inhibition of SRP polypeptides [106]. It is believed that the importin α/β might be karyophyrin α/β as it is the only importin present in P. Falciparum. A different observation on the process by which ivermectin inhibits the growth of mosquitoes when infected with P. falciparum [106]. Kobylinski et al. [103] reported that ivermectin decreased the intensity and prevalence of oocyst in different mosquitoes, while de Carvalho et al. and Perez-Garcia et al. [104,107] reported a reduction in the prevalence of oocyst without affecting the intensity in mosquito infected with P. falciparum and P. vivax. Three different avermectins were also tested with respect to the hepatic effect of Plasmodium. Ivermectin, eprinomectin, emamectin were orally administered into mice at 10 mg/kg thrice, using soybean oil as a vehicle before infection with P. berghei 24 h later. The parasite load was determined between 44&#;46 h post infections. It has been found that ivermectin has been shown to be effective with approximately 88% protection against liver infection while the other two have been shown to be ineffective compared to primaquine, the standard drug [106]. Of note is the mild neurotoxicity of ivermectin in some of the mice treated. One of the major observation in a mouse-model of antimalarial activity of ivermectin showed mild neurotoxicity as impairment in infection and behavior were observed in the mice. With the potent insecticidal activity of ivermectin against female Anopheles mosquitoes, it was concluded that the ability of ivermectin to prevent parasite invasion of the liver could be central to malaria treatment and prevention as it decreases the level of Plasmodium in the blood and other tissues [108]. A study by Mekuriaw et al. [109] showed that ivermectin has anti-plasmodial activity in humans infected with An. Arabiensis which might be linked to the delay effect on fecundity. More experiments still need to be conducted on the efficacy of ivermectin in treating malaria.
New discovery on the pharmacological activity of ivermectin is its potential usage as an anti-inflammatory drug. Ivermectin has been reported to modulate immune activity in mast cells and macrophages that are important in T-cell mediated skin inflammation through the following process: (1) priming of T cell through skin emigration of allergen-loaded DC [110]. (2) Recruitment of effector T cells by the skin, and (3) generating a cluster of T-cell/DC through macrophage, this is important in dermal skin inflammation [111]. Ventre et al. [112], using murine, showed that application of ivermectin topically delays skin inflammation as a result of allergy prompted by regular contact with Dermatophagoides farina (an allergen), slowing the synthesis of inflammatory cytokines, priming and activation of allergen-specific T-cells. They also showed that ivermectin did not have a significant effect on dendritic cells functions, either in an in vivo or in vitro, but caused impairment in the activation of T-cells, production and proliferation of cytokines by stimulating antigen-specificity and polyclonal activity. Nörenberg et al. [113] and Wareham et al. [114] showed that ivermectin possess immunomodulatory activity in mast cells and macrophages in various in vitro models. Thus, the anti-inflammatory effect of ivermectin can be linked to its regulatory effect in T- cells, skin mast cells and macrophages. Leyva-Castillo et al. [115] also showed that ivermectin -induced modulation of T-cells does not involve some target expressed by T cells such as P2XR4 (involved in the regulation of Ca2+metabolism) and FXR (a receptor for which ivermectin has a strong affinity for). However, other receptors involved in T-cell proliferation and screened in vitro showed that they were also not involved in IVM-immunomodulatory effect on T-cell. Some of these receptors include Ryanodine receptors (RyRs), gamma aminobutyric acid (GABAARs) type A receptors, type 3, 5-hydroxytryptamine receptors (5-HT3Rs) [116]. In addition, Ci et al. [117] showed that the mechanism of anti-inflammatory activity of avermectin might involve a reduction in the pathway of mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa B (NFkB).
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Another non-prescription discovery for ivermectin is as an anticancer drugs. The ability of ivermectin to stimulate the intracellular influx of chloride ion in cells from a leukemia patient and induction of oxidative stress leading to the death of the leukemia cells without having any effect on normal cells [43]. The anticancer effect of ivermectin against leukemia was also tested in mice using three different models, all of which demonstrated the ability of ivermectin to inhibit or slow the growth of tumor cells. Most tissue cancers in human have a deregulated WNT-TCF (WNT-T cell factors) signaling pathway. This pathway regulates cell proliferation and metastasis. The antitumor effect of ivermectin in human colon cancer and lung carcinoma xenograft is dependent on WNT-TCF signaling pathway, it is effective if the cancer is WNT-TCF-dependent and ineffective if it is not [118]. The potency of ivermectin as an anticancer in a glioma xenograft is also observed by inhibiting DEAD-vox RNA helicase DDX23 [119]. This type of helicase is linked to miR-21 processing, a microRNA associated with glioma the proliferation and metastasis of glioma cells. One of the key pathways in colon cancer is the inhibition of TGFβ-R2 (a WNT-TCF repressor) by miR-21, leading to the overexpression of WNT-TCF [120]. This shows that ivermectin can play a dual role in preventing tumor growth and metastasis. Ivermectin can also inhibit the depolymerization of microtubules, thus preventing mitosis in tumor cells as well as increasing the polymerization of microtubules [121].
Ivermectin has also been reported to affect lipid and carbohydrate metabolism in mammals by targeting farnesoid X receptor (FXR), a nuclear hormone receptor that is involved in glucose, cholesterol, and bile control. Ivermectin binds to FXR to initiate its transcriptional function and the recruitment of other metabolic regulators. An experimental model of diabetes using mice shows that ivermectin significantly reduced serum glucose and cholesterol concentrations and enhanced the sensitivity of insulin, however, ivermectin had no effect in FXR-null mice [122]. C. elegans, a nematode in which ivermectin is active against, possesses a DAF-12 (a nuclear hormone receptor that regulates its life cycle), that shares almost similar homologue with FXR [123]. However, there is no proof if ivermectin elicits its nematocidal activity through this receptor.
Four different types of AVM were tested for their potential as anti-alcohol therapy, namely selamectin (SEL), abamectin (ABM), ivermectin (IVM) and moxidectin (MOX). IVM modulates the action of ethanol on P2X4Rs in an in vivo study, which may be associated with a decrease in alcohol intake [124]. Also in both male and female mice of the C57BL/6J strain. IVM at a dose between 1.25&#;10 mg/kg reduces alcohol intake in various models mimicking different types of alcohol intake in human such as binge drinking, social drinking, and alcohol-induced behaviour [125,126]. IVM elicits its anti-alcohol effectively at 9 h post-administration, a time that us close to the half-life of IVM in the plasma [127]. It also showed that the least effective dose of IVM (2.5 mg/kg) is in proximity to the level of IVM in the brain, which is 0.28 ng/h/mg tissue. This shows the decrease in alcohol intake can be linked to the administration of IVM. IVM does not have any significant effect on water and food intake as well as weight change and general physiology of the mice. Using a self-operant chamber technique designed by Yardley et al. [127], IVM also caused a reduction in preference for alcohol bottle and appetite for alcohol consumption. This same observation was reflected in another experiment using both male and female rats of HAD-1 and HAD-2 strains [128]. Proving that IVM can be effective as an anti-alcohol therapy in different animal models of alcohol intake. Another model representing the long-term exposure of IVM to alcohol intake was conducted by [127,129]. IVM was administered intraperitoneally to female C57BL/6J mice strain at a dose of 2.5 mg/kg for seven consecutive days and resulted in a substantial decrease in alcohol intake as well as the option to drink alcohol bottle or another bottle, the mice preference reduced with respect to alcohol bottle [127]. Yardley et al. [129] using the same female mice strain as Yardley et al. [127], also administered IVM at 3 mg/kg for 10 consecutive days and also reported a reduction in alcohol intake without affecting fluid intake or body weight. The various models used a dose extrapolated from the approved pharmacology dose for humans. Another experiment to see whether modifying the route of administration of IVM would still produce the same anti-alcohol effect of IVM was conducted by [126]. The oral administration of IVM for 30 days also shows similar findings with i.p administration. They also show that IVM did not cause any histological changes in the kidney, liver, and brain tissues of the animals. Neurobehavioral effect of IVM has also shown that the drug does not have any neurological deficits, such as perceptual, cognitive, and emotional functions, however, mild anxiolytic activity was observed, which is likely linked to the GABAARs potentiation [130]. A clinical study involving administration of 120 mg of IVM to humans did not induce any adverse reaction or toxicity [131]. In summary, IVM has shown a great potential to be used as an anti-alcohol drug with minimal adverse effects. To study the mechanism by which IVM can act as an anti-alcohol drug, Natsuaki et al. [111] conducted various in vitro and in vivo experiments. It has been discovered the rate of alcohol consumption significantly reduced in male P2X4R knock-out mice, hypothesizing that the anti-alcohol potential of IVM may be related to the potentiation of P2X4R. Jin et al. [132] showed that ethanol addiction can be linked to its ability to inhibit pre-synaptic P2XRs in the synaptic terminals that releases GABA in the VTA, preventing the release of GABA into the DA neurons, which inadvertently lead to an increased firing of VTA and DA neurons, suggesting that the addictive effect of ethanol can be countered by DA system inhibition. Khoja et al. [133] also provided more evidence of a link between DA system and IVM. Their findings showed that IVM can play a role in the phosphorylation of cAMP response element binding protein (CREB) and DARP-32 (a 32 KDa phosphoprotein) as well as dopamine in the ventral striatum though P2X4R potentiation. Based on a previous study by [134,135] that reported a link between coordination of ethanol-linked behavior and phosphorylation of CREB and DARPP-32, Khoja et al. [133] concluded that the mechanism by which IVM acts as an anti-alcohol effect of IVM might be by controlling steps linked to dopamine signaling in the brain area involved in drug reward circuitry. Abamectin, another type of AVM, shares similar structure with IVM, the difference being the presence of a double bond between the carbon atom at positions 22 and 23 of the spiroketal unit. Asatryan et al. [125] showed that ABM had similar effect on Xenopus oocytes as observed with IVM. They also find out that ABM enhanced P2X4R potentiation more than IVM at higher concentrations and acting as a direct agonist in P2X4R potentiation in comparison with IVM, as it enhances P2X4R activity in the absence of ATP. There was no difference in the potentiation of GABAARs-mediated current between ABM and IVM, however, the potency reduced with increased concentration when compared to IVM. Their results also showed that ABM reverses the inhibition of ATP-activated current by ethanol, decreased ethanol intake and enhanced water intake. The variance between the anti-alcohol effects of ABM and IVM was not well explained, suggesting more research on their mechanism. SEL, another type of AVM showed low ow P2X4R potency and reversed ethanol inhibitory activity compared to IVM and ABM. Lespine et al. [136] reported that the poor activity of SEL can be linked to its structural variation. SEL contains only one saccharide group, which is believed to limit its affinity for p-glycoprotein [136]. Apart from this, other differences between SEL and IVM includes, replacing the isobutyl and alicyclic hydroxyl groups in IVM with a cyclohexyl ring and an unsaturated ketoxime group in SEL respectively. Asatryan et al. [125] reported that very high amount of SEL (10 µM) was required to potentiate P2X4R as compared to IVM (0.5 µM), a weaker action on GABAARs as compared to IVM and ABM, leading to its inability to antagonized the inhibitory effect of ethanol on P2X4Rs. They also reported the inability of SEL to affect appetite or preference for ethanol intake. MOX is a type of AVM that is structurally different from IVM [137]. The isopropyl group in IVM is substituted by dimethyl butyl group and MOX contains a methoxime group from which its name was derived. These features are believed to enhance its lipophilicity and might increase its ability to cross the blood brain barrier (BBB). Another difference between MOX and IVM is that P-gp has low affinity for MOX, which means that MOX does not allow P-gp to be extracted from the brain. In addition, it also does not have a significant effect on GABAARs [138,139]. The advantage of these differences is that it reduces the potential toxicity as a result of accumulation from long-term usage in brain deficient in P-gp and effect that IVM has on the brain and interaction of MOX with other drugs that stimulate GABAARs which might lead to depression and coma. Result also showed that MOX at varying concentration induces currents in Xenopus oocytes via the potentiation of P2X4Rs significantly and reverse the inhibitory effect of ethanol at low concentration but had no effect at high concentrations [139]. In vivo study also showed that MOX reduced the desire for ethanol consumption in C57BL/6J mice of both sexes in different models of alcohol intake [139]. Comparing the various doses used for IVM, it has been shown that MOX was more efficient on reducing ethanol consumption as it takes 4 h for MOX to reduce ethanol intake, while IVM takes a longer period to exert similar effect.
Drinyaev et al. [140] were the first to confirm the antitumor activity of AVM. They tested the combination effect of AVM C and AVM B on tumor growth using experimental mice. It inhibits the growth of 755, ascites Ehrlich and solid Ehrlich carcinoma and P388 lympholeukemia, and the highest inhibition of tumor growth (70&#;80%) observed when administered intraperitoneally. AVM have also been shown to improve some anticancer drugs (e.g., vincristine) as they synergistically increase the suppression of the growth of EC, P388 lympholeukemia, and melanoma B16 when administered after vincristine injection. IVM has been identified as one of the avermectin group of drugs that has the potential to treat leukemia cells [43]. IVM was reported to be effective in cell death induction of myeloid leukemia at low concentration without affecting normal hematopoietic cells. In three independent experiments involving the induction of leukemia in mice, IVM slows the growth of tumor cells at a dosage that seems replicable in humans. This antitumor activity is believed to be linked to the established ability of IVM to increase chloride influx in parasite and nematodes, as IVM increased the concentration of chloride ion and cell polarization in leukemic cells. In addition, IVM increases reactive oxygen species (ROS) in leukemic cells, which may contribute to the cytotoxicity observed in leukemic cells [141]. It was also reported that IVM enhances the antitumor effect of established drugs such as cytarabine and daunorubicin. A low concentration of IVM has been reported to alter the tumor growth through a constitutive mechanism involving direct activation of transcriptional activity of TCF, repressing the phosphorylation of β-catenin and cyclin D at the C-terminal [142]. IVM was also revealed to be active as an antitumor agent in human colon cancer xenograft and lung cancer in an in vivo experiment through inhibition of TCF and blocking of WNT-TCF pathway without any side effects [142]. There are reports that the mode of action of avermectin in tumor cells might be different from that of nematodes and parasites. As stated earlier, the antitumor activity of AVM drugs may be due to the transcription pathway of TCF, phosphorylation of cyclin D and β catethin, whereas, in the parasite, it is through the chloride-gated ion channels. Some AVM, such as moxidectin, have been reported to be ten times more active than IVM as nematocides, whereas this same moxidectin is less active or not active at all in human cancer cells. A particular concentration to cause behavior is observed for each measurable effect of IVM. Cytotoxicity of tumor cells is achieved at a concentration above 10 μM or longer while for 48 h or longer if the concentration is above 5 μM. For the inhibition of TCF transcription and cell death induction through apoptosis, the concentration is lower at different durations [43]. With respect to a brain tumor, the use of IVM may require caution as the blood brain barrier features might have been lost, leading to the entry of IVM into the brain. The brain contains the gated-chloride ion and GABA-channels that IVM binds to in nematodes, thus IVM might bind to them in the brain leading to brain injury and death in normal cells [143]. Melotti et al. [144] summarizes the mechanism of antitumor activity of AVM, such as ivermectin, selamectin, and other types as follows: detects the role of avermectin B1 in inhibiting the activation of WNT-TCF reporter activity by N-terminal mutant (APC-insensitive) β-CATENIN as detected in their screen; detects the ability of AVM B1, IVM, doramectin, MOX and SEL to parallel the modulation of WNT-TCF targets by dnTCF; the finding that the specific WNT-TCF response blockade by low doses of Ivermectin and Selamectin is reversed by constitutively active TCF; the repression of key C-terminal phospho-isoforms of β-CATENIN resulting in the repression of the TCF target and positive cell cycle regulator CYCLIN D1 by IVM and SEL; the specific inhibition of in vivo-TCF-dependent, but not in vivo-TCF-independent cancer cells by IVM in xenograft. The study showed that the regulation of phosphorylation of β catenin may be by a ser-552 or ser-675 on the catenin polypeptide chain. The PP2A/PP1 protein phosphatase-blocked situation may be used by IVM or selamectin to improve this step either directly or indirectly to dephosphorylate P-ser552 / P-ser675. This can be further explained in the relationship between β-catenin and TCF factors as an important step in WNT signaling in human colon cancer cells [145]. The decrease in the concentration of phosphorylated β-catenin in colon cancer cells also requires the Bα (PR55α) subunit of PP2A [146]. This shows the complex nature involved in the inhibition of β-catethin phosphorylation and a potential multiple targets of IVM as an anticancer agent in colon cancer [147]. One of the important information from these findings is that the human colon cancer cell lines are TCF-dependent [148]. For cancer cells deficient in the APC destruction complex, it is predicted that the pathway involved in the IVM-induced enhancement of PP2A is silent. IVM treatment is also reported to reduce some important markers of colon cancer cells, such as ASCL2 andLGR5 [149,150]. The dependent of cells on TCF also on the environment of the cell. For example, it was reported by [148] that Ls174T and primary CC14 cells are TCF-dependent in vitro, while in an in vivo condition, they turn to TCF-independent cells. Although the mechanism involved is not yet understood, de Sousa et al. [151] reported the role of DNA methylation in the process involved in the switch over. However, some colon cancer cells, such as DLD1 remain TCF-dependent either in vitro or in vivo [148]. This is one of the proofs of IVM safety as an anticancer drug, as it only targets TCF-sensitive cancerous cells in vivo and not normal cells at the administered dose. However, non-specific toxicity might be developed at higher dosages. Apart from anticancer usage of IVM, it can also be used as a prophylactic drug against some TCF-dependent intestinal tumor and sporadic colon tumor in an aging population.
The role of IVM in inhibiting RNA helicase has led to research on the potential of AVM in the treatment of viral-related diseases. IVM has been reported to inhibit the replication of most flavivirus through blocking viral helicase [152]. Some of the diseases caused by flavivirus include dengue, yellow fever, tick-borne encephalitis, and West Nile virus. This led to the submission of a patent application for IVM as an off-label for antiviral therapy in humans. A study also showed that consistent passaging of IVM for a six months duration did not induce resistance in the yellow fever virus, suggesting that the helicase domain may not be able to undergo mutation [28]. In addition, the report revealed that IVM had no activity against other types of virus, though it inhibits the replication of HIV-1 and dengue virus at high concentrations of IVM (25&#;50 μM) in an in vitro experiment. Nuclear import of viral proteins is critical to the life cycle of many viruses, including many RNA viruses that replicate exclusively in the cytoplasm such as DENV, respiratory syncytial virus, and rabies [153,154,155,156]. The mechanism of inhibition of viral replication is linked to its inhibition of importin α/β-mediated transport, leading to the alteration of the trafficking of viral protein between the host cell cytoplasm and the nucleus [157,158]. Forwood and Jans. [159] also discovered that IVM prevents the ability of SV40T-ag to recognize Impα/β1.,this observation led investigators to subject IVM to various nuclear-localizing proteins such as IN, T-ag, hCMV UL44, p54, Impα/β-recognized protein, and Impβ1-recognized proteins in HeLa cells and compared with a standard drug (mifepristone). The result showed that IVM inhibited the accumulation of IN nuclear and T-ag nuclear, while mifepristone inhibited the accumulation of IN nuclear only [160]. They also showed that IVM only inhibits nuclear protein that contains Impα/β1-recognized, as it did not inhibit TRF1 SRY or PTHrP which are transported in the nucleus dependent of Impα/β1 [161,162]. From their results, it can be suggested that IVM is specific for a particular type of Impβ-recognized nuclear import, called Impα/β1-recognized nuclear import cargoes, and has no effect on other nuclear import pathways. In addition to the above report, IVM does not affect histone H2B and SUMO-conjugating enzyme UBC9 which are both imported into the nucleus by multiple different Impβ homologues and Imp13 respectively [163,164]. The antiviral activity of IVM and ribavirin was also tested against Newcastle disease virus (NDV) using a 9-day old chicken [165]. They observed that IVM and ribavirin were cytotoxic at concentrations above 50 μg/mL and 12.5 μg/mL, respectively. However, the most potent concentration of IVM to inhibit virus growth is from 100 μg/mL and above, while the antiviral activity of ribavirin was experienced at all concentrations (6.25&#;200 μg/mL). The antiviral activity of IVM against HIV is also linked to an importin (IN) protein. HIV produces a complex called PIC (pre-integration complex), made up of a newly transcribed viral cDNA, IN, host proteins, and other HIV proteins. It is believed that the transportation of PIC requires the action of IN [166], for the integration of viral cDNA into the host cell genome, an important step in HIV infection [167]. The inhibitory activity of IVM on IN was tested and compared with mifepristone (a standard drug that works by inhibiting IN) using HeLa cells infected with VSV-G-pseudotyped NL4-3.Luc.R-E-HIV. IVM at 25 µM significantly inhibits the growth of the virus. The inhibition of importin this is consistent with ivermectin being able to generally inhibit Impα/β1-mediated nuclear import, which is essential for HIV infection and the first demonstration that inhibitors of nuclear import can have potent antiviral activity. DENV NS5 protein is critical in the viral replication of DENV in the host cytoplasm. Most DENV Ns5 proteins are found in the nucleus at a specific stage of the life cycle of viral infection [154]. NS5 contains another NLS recognized by Impβ1 alone that is not important for the accumulation of NS5nuclear [154]. It was concluded that IVM significantly inhibits the binding of Impα/β1 to NS5 and not the binding of Impβ1 to NS5, showing that the inhibitory activity of IVM was specific, a situation not observed with mifepristone. With respect to dengue virus (DENV) infection, IVM was also studied on its antiviral status against DENV [153,168]. Ivermectin can block the DENV 2 at any anatomical barrier, like midgut or salivary gland the transmission rate of the virus by a mosquito is usually lower than the infection. It is believed that the transmission rate is low as it involves several anatomical barriers such as the midgut and glands. Thus, research is often conducted on the effect of IVM on infection status rather than transmission [169]. They find out that IVM significantly reduced the DENV infection when the vector is pretreated with IVM. IVM could work either in preventing the transport of DENV to the salivary gland or reducing the number of mosquitoes that carry the virus [43]. This means that IVM could be a potential drug used to control DENV infection by acting as an insecticidal [170] in killing A. albopictus [171], or as an antiviral drug for the treatment of dengue [169]. IVM prevents the growth of the virus in Aedes albopictus as well as destroys several blood-sucking vectors. More research are still been done to decipher the mechanism involved in how IVM affects the transmission and infection rate of DEN through Aedes albopictus. One of the mechanisms that IVM might be probably linked to inhibiting the growth of DENV might be by preventing the interaction of NS5 and Impα/β1 [152]. On the basis of the available structures of DENV bound to ssRNA (PDB 2JLU) it is not possible to predict a plausible interaction site or a model of the ternary complex. Reasonably, during activity the helicase/RNA complex changes its structure [172], allowing ivermectin to interact with the identified amino acids to block dsRNA unwinding. IVM has also been reported to be effective against another flavivirus, the yellow fever virus (YFV) [173,174].
With the global pandemic nature of COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-COV-2), there is an urgency for scientists to discover drugs or compounds to treat the disease. The reported antiviral potential of IVM has made it a potential drug to be investigated for the treatment of COVID-19 [175]. Caly et al. [176] earlier reported the potential of IVM to inhibit the replication of SARS-CoV-2 in an in vitro experiment. Such findings were obtained by incubating 2.19 mg/mL of IVM with a Vero/hSLAM-cells infected with SAES-CoV-2. Extrapolating this dose into human models shows that this dose well exceeds tolerable dose for humans approved by the US food and Drug administration. However, Guzzo et al. [131] showed that administration of 120 mg of IVM to healthy humans was safe and well tolerated by volunteers. The results showed the peak plasma concentration of 250 ng/mL, which was just a bit lower than the effective concentration of IVM that inhibits replication of SARS-COV-2 in Vero/hSLAM cells. The results might have been a setback in further clinical trial of IVM. With the respiratory destructive nature of SARS-CoV-2 and Lespine et al. [177] showing a higher concentration of IVM in the respiratory system as compared to the plasma, one week after administration of IVM, shows that all hope might not be lost in the investigation of IVM as a potential antiviral drug. However, some care must be considered before the continuity of the investigation. Based on the reported neurotoxicity and metabolic pathway of IVM, caution should be taken to conduct clinical trial on its antiviral potentials. The GABA-gated chloride channels in the human nervous system might be a target for IVM, this is because the BBB in disease-patient might be a weakened as a result of inflammation and other destructive processes, allowing IVM to cross the BBB and gain access to the CNS where it can elicit its neurotoxic effect (II) IVM is metabolized by CYP3A4 enzyme that is repeatedly inhibited by ritonavir and cubocistat, two drugs used to treat COVID-19 patients. Furthermore, the two drugs are also reported to impair BBB. Thus care should be taken in the administration of IVM with antiviral drugs [178]. Data obtained from the WHO-supported International Drug Monitoring Program are essential in the combination therapy of IVM with other antiviral drugs. They reported that out of data on co-administration of IVM as an antiviral drugs, only one is linked to its neurotoxicity. (III). the third point is based on the evidenced stated earlier that the potency of IVM to treat SARS-CoV-2 infection might require a dosage that might be toxic to humans [178].
The role of IVM in regulating lipid and glucose level was investigated using a high-fat diet animal of two types- FXR wild type and FXR &#;/&#; mice. Animals were administered IVM intraperitoneally daily for 14 days and concomitantly exposed to a high-fat diet. All the markers of liver injury (aspartate aminotransferase and alanine transferase) along with tissue histology showed no toxicity of IVM [179]. IVM significantly reduced the serum level of cholesterol, low-density cholesterol, very low-density cholesterol, and glucose only in FXR-wild type mice without any change in appetite and weight gained. It is reported that IVM-induced glucose decrease might be due to increased insulin sensitivity to glucose [122]. The role of IVM as an FXR ligand in metabolic regulations was further confirmed by its ability to regulate the expression of some genes that are targeted either directly or indirectly by FXR. mRNA that codes for the expression of SHP, CYP7A1 and CYP8B1. IVM suppresses the expression of CYP7A1, and CYP8B1 mRNA but induces the expression of SHP mRNA. IVM also regulates some key regulatory enzymes in glucose synthesis such as G6Pase and PEPCK. However IVM was only active in FXR wild mice when it was not effective in FXR&#;/&#; mice. In this mice (FXR wild type), IVM suppresses the expression of genes involved in G6Pase and PEPCK synthesis, leading to their low concentration [180]. This also confirms the importance FXR in the metabolic activity of IVM. Duran-Sandoval et al. [181] also showed that IVM does not have any effect on the expression of L-PK mRNA levels as compared to GW in hepatic cells and tissues. Apart from regulating genes involved in glucose metabolism, IVM also affects genes involves in cholesterol metabolism. Important regulatory enzymes, such as mRNA that codes for hydroxymethylglutaryl CoA reductase and hydroxymethylglutaryl Coenzyme A synthase, are suppressed by IVM in an FXR-dependent pathway [182]. In addition to these regulatory enzymes, IVM also induced the expression of mRNA that codes multidrug resistance genes, bile salt excretory pumps, and type I scavenger receptor. In another study, IVM caused a significant reduction in the serum cholesterol levels when administered to animal fed high-fat diet and a decrease in body weight was also observed despite the fact that IVM did not influence the animal feed intake rate. IVM also regulates the level of glucose and insulin levels. Their results also corroborated the reported hyperglycaemic and hyperlipidemic effects of IVM. In comparison to the above result, Jin et al. [122] using diabetic mice fed with a high-fat diet, showed that IVM had no significant effect on some regulatory enzymes involved in cholesterol metabolism. That is the mRNA gene that codes for FDFT1 (farnesyl-diphosphate farnesyltransferase 1), hydroxymethylglutaryl coenzyme A synthase, LDL receptor, and hydroxymethylglutaryl coenzyme A reductase were not affected. However IVM alters the mRNA expression of key glucose synthesis enzymes (G6Pase and PEPCK). The summary of pharmacological activities of avermectins are shown in .
Ivermectin is a semi-synthetic antiparasitic medication derived from avermectins, a class of highly-active broad-spectrum antiparasitic agents isolated from the fermentation products of Streptomyces avermitilis.8 Ivermectin itself is a mixture of two avermectins, comprising roughly 90% 5-O-demethyl-22,23-dihydroavermectin A1a (22,23-dihydroavermectin B1a) and 10% 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A1a (22,23-dihydroavermectin B1b).8
Ivermectin is mainly used in humans in the treatment of onchocerciasis, but may also be effective against other worm infestations (such as strongyloidiasis, ascariasis, trichuriasis and enterobiasis). Applied topically, it may be used in the treatment of head lice infestation.
With the advent of and the COVID-19 pandemic, ivermectin began garnering notoriety due to its off-label use for the prophylaxis and treatment of COVID-19. While studies are still ongoing, much of the evidence for ivermectin in COVID-19 relies on pre-print in vitro data, and the clinical utility of this data remains unclear. Due to a number of factors - for example, the relatively low number of patients per trial and the speed at which these trials were conducted - studies on the use of ivermectin in COVID-19 have been fraught with statistical errors and accusations of plagiarism.9,5 In addition, the use of aggregate patient data in large-scale meta-analyses (as opposed to individual patient data (IPD)) has been shown to disguise otherwise blatant data errors, such as extreme terminal digit bias and the duplication of blocks of patient records.5
Until high-quality, peer-reviewed data regarding both the safety and efficacy of ivermectin for COVID-19 in humans becomes available, the use of ivermectin for these purposes should be avoided in favour of thoroughly-vetted therapies (e.g. COVID-19 vaccines like Comirnaty).
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