Antiparasitic Drug Ivermectin Research Articles

Pathophysiology and Potential Therapeutic Candidates for COVID-19: A Poorly Understood Arena.

Coronavirus disease 2019 (COVID-19), an acute onset pneumonia caused by a novel Betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in the Wuhan City of China in December 2019 and evolved into a global pandemic. To date, there are no proven drugs or vaccines against this virus. Hence, the situation demands an urgent need to explore all potential therapeutic strategies that can be made available to prevent the disease progression and improve patient outcomes. In absence of clinically proven treatment guidelines, several repurposed drugs and investigational agents are currently being evaluated in clinical trials for their probable benefits in the treatment of COVID-19. These include antivirals (remdesivir, lopinavir/ritonavir, umifenovir, and favipiravir), interferon, antimalarials (chloroquine/hydroxychloroquine), antiparasitic drugs (ivermectin and nitazoxanide), biologics (monoclonal antibodies and interleukin receptor antagonist), cellular therapies (mesenchymal stem cells and natural killer cells), convalescent plasma, and cytokine adsorber. Though several observational studies have claimed many of these agents to be effective based on their in vitro activities and extrapolated evidence from SARS and Middle East respiratory syndrome (MERS) epidemics, the currently available data remains inconclusive because of ill-defined patient selection criteria, small sample size, lack of concurrent controls, and use of intermediary outcomes instead of patient-relevant outcomes. Moreover, there is a need to clearly define the patient populations who warrant therapy and also the timing of initiation of treatment. Understanding the disease pathology responsible for the clinical manifestations of COVID-19 is imperative to identify the potential targets for drug development. This review explains the pathophysiology of COVID-19 and summarizes the potential treatment candidates, which can provide guidance in developing effective therapeutic strategies.

Need for a sustainable use of medicinal products: environmental impacts of ivermectin.

It is worldwide recognized that the use of pharmaceuticals for human and veterinary purposes could lead to unsustainable effects on the environment. A strategy to reduce the impact of pharmaceuticals on the environment has been recently established at European level, where guidelines to evaluate the impacts of veterinary drugs used to treat animal diseases are in place. The aim of this article is to focus on the worldwide used antiparasitic drug ivermectin (IVM) and its potential impact on the environment. A specific section is related to the IVM resistance that the massive use of this drug could generate enhancing the risk scenarios also for human health. The application of stringent measures for the veterinary use of this substance, in line with the recommendations provided by International frameworks such as One Health and EcoHealth, is recommended.

Ivermectin and Moxidectin Can Incapacitate Different Strains of the Common Bed Bug Cimex lectularius L.: A Study.

The common bed bug Cimex lectularius L. (C. lectularius) is a hematophagous ectoparasite that has recently resurged in many western industrialized nations, in part due to pesticide resistance. Using a laboratory feeding system, we found that the antiparasitic drugs ivermectin and moxidectin did not show higher incapacitation rates in pyrethroid-resistant strains of C. lectularius compared to a pyrethroid-susceptible strain. Additionally, we developed a high-performance liquid chromatography (HPLC) and mass spectroscopy (MS) assay to measure the concentrations of ivermectin inside C. lectularius and found that ivermectin persists in the insects for up to one month. HPLC/MS will be useful in understanding the pathophysiology behind the long-term morbidity observed in C. lectularius that consumes a sublethal dose of ivermectin.

Current status of drug development against SARS CoV-2 infections

SARS CoV-2 and its associated disease Covid-19 first occurred in China at the end of 2019 and conquered the world in a storm. As of June 24, 2020, the World Health Organization listed 9,129,146 confirmed cases, accompanied by 473,797 deaths. An initial response by many countries was to lock down their economies, which helped flattening the curve at a high economic cost. The long-term solution will be vaccines to prevent infection and treatment drugs.             This minireview focuses on drugs against the virus itself. Among the drugs that interfere with the virus’ ability to attach to and invade the human cell, camostat mesylate looks promising in vitro, but clinical trials have not been completed yet. A phase II trial has been completed for recombinant human angiotension converting enzyme 2 that blocks the spike protein from binding to cellular ACE-2. Hydroxychloroquine is probably the most controversial of all drugs; after initial excitement, the Federal Drug Administration revoked the emergency use of this drug against SARS CoV-2. Among the inhibitors of the RNA dependent RNA polymerase of the virus, remdesivir, faripiravir which is already in a phase IV trial, and tenofovir will be discussed. Additional drugs included in this study are lopinavir/ritonavir that have previously been used against HIV and the antiparasitic drug ivermectin. Many of the presented drugs have previously been used for a different disease and are currently being trialed against SARS CoV-2.

Toxicological effect of ivermectin on the survival, reproduction, and feeding activity of four species of dung beetles (Coleoptera: Scarabaeidae and Geotrupidae) in Japan.

We investigated the effects of the antiparasitic drug ivermectin on the dung beetles Copris acutidens Motschulsky, Onthophagus bivertex Heyden, O. lenzii Harold and Phelotrupes auratus auratus Motschulsky in Japan. Ivermectin was detected in cattle dung from 1 to 3 or 7 days post-treatment, with a peak at 3 days post-treatment in two pour-on administrations (500 µg kg-1). In C. acutidens, adult survivals and numbers of brood balls were significantly reduced in dung collected at 3 and 7 days post-treatment, and adult emergence rates were significantly decreased in dung collected at 7 and 14 days post-treatment. Feeding activity of C. acutidens was inhibited in dung collected at 3 days post-treatment, but was not significantly different from that seen in control dung at 7 and 14 days post-treatment. In O. bivertex and O. lenzii, there were no effects of ivermectin on adult survival or feeding activities, but the numbers of brood balls of O. bivertex constructed in dung collected at 3 and 7 days post-treatment were significantly lower than observed with control dung. The adult emergence rates of O. bivertex and O. lenzii were significantly reduced in dung collected at 1 to 3 and 1 to 7 days post-treatment, respectively. In P. auratus, there were no effects of ivermectin on adult survival, oviposition, feeding activity, or larval survival (until the third instar) in dung at 3 days post-treatment. The environmental risks affecting the populations of dung beetles in Japan are discussed.

Clinical picture, diagnosis and treatment of rosacea, complicated by Demodex mites.

The article analyzes the clinical picture and course of rosacea in patients with Demodex mites. It presents the advantages of using the method of confocal laser scanning microscopy over the method of light microscopy of facial skin scrapes. The aimes were to study the influence of Demodex mites on the clinical picture and course of rosacea; to compare laboratory and instrumental diagnostic methods for detecting Demodex mites; to evaluate the effectiveness of external therapy aimed at eliminating Demodex mites. 212 people were examined. The study included healthy patients, patients with a diagnosis of rosacea with the presence and absence of Demodex. The presence of Demodex mites was confirmed by two methods of study (light microscopy of skin scrapes and confocal laser scanning in vivo microscopy). Demodex mites promote the development of acute-inflammatory morphological elements, increase the duration of the condition (more than 5 years, P<0.01) and the probability of recurrence (from 1 to 3 relapses in 39.5% of patients, P<0.05), resulting in a decrease in the quality of life of patients (dermatology life quality index is 12.5±4.5, P<0.05). Antiparasitic drug ivermectin, in the form of an external form, at a concentration of 1% has a high therapeutic efficacy (in 93.3% of cases). Demodex folliculorum shows signs of parasitism, while Demodex folliculorum brevis is a saprophyte. The severity of the condition does not depend on the quantitative load of the mites in the scrape. As an antiparasitic drug, it is recommended to use 1% ivertmectin.

Acute behavioural and physiological responses of sheep to S/C ivermectin injection

Acute behavioural and physiological responses of sheep to S/C ivermectin injection

Xenointoxication of a Rabbit for the Control of the Common Bed Bug Cimex lectularius L. Using Ivermectin.

Human bed bug infestations have undergone a recent global resurgence. The human antiparasitic drug ivermectin has been proposed as a strategy to help control bed bug infestations, but in vivo data are lacking. We allowed separate populations of the common bed bug, Cimex lectularius L., to feed once on a rabbit before and after it was injected subcutaneously with 0.3 mg/kg of ivermectin, and bed bug morbidity and mortality were recorded. Ivermectin levels in the rabbit were measured using high-performance liquid chromatography and mass spectroscopy. Ivermectin blood levels of ∼2 ng/mL caused reductions in bed bug fecundity, and levels of >8 ng/mL caused bed bug death and long-term morbidity including reductions in refeeding, mobility, reproduction, and molting. Gut bacterial cultures from the fed bed bugs showed that ivermectin altered the bed bug gut microbiome.

Beauveria bassiana is a potential effective biological agent against Psoroptes ovis var. cuniculi mites

Beauveria bassiana is an entomopathogenic fungus known for its high efficacy against many agricultural insect pests, and is considered to be safe to the environment. Previous studies showed that B. bassiana is also capable of infection and horizontal transmission between Psoroptes ovis mites, but we still lack information on the clinical efficacy of B. bassiana against P. ovis. In this study, we evaluated the acaricidal efficacy of B. bassiana against Psoroptes ovis var. cuniculi, both in vitro and in vivo. Tests consistently showed that B. bassiana caused high mortality against P. ovis var. cuniculi in vitro with dose- and time-dependent susceptibility responses; applying 4.26 × 109 conidia/ml resulted in 100% mortality of P. ovis var. cuniculi within 9 days with an LT50 of 2.50. In vivo, rabbits infected with P. ovis var. cuniculi that were treated with 4.26 × 109 conidia/ml B. bassiana fungal suspension showed a 100% therapeutic response 3 days later, an efficacy greater than that of the anti-parasitic drug ivermectin. Moreover, no rabbits treated with B. bassiana showed symptoms of disease recurrence by 60 days post-treatment. Taken together, these results show that B. bassiana has high efficacy against P. ovis var. cuniculi; hence, it may be a potentially effective biological insecticide for use against psoroptic mange.

Reaction plays favorites in polyols

Chemists would like to be able to modify compounds containing multiple hydroxyl groups, such as the antiparasitic drug ivermectin, to generate useful new molecules. One way to do this would be to selectively oxidize individual hydroxyls to ketones, which are synthetically versatile groups in that they can be readily converted to nitrogen-based groups. As described at the ACS national meeting last week, John F. Hartwig and Christopher K. Hill of the University of California, Berkeley, have now designed a catalyst capable of such a feat (Nat. Chem. 2017, DOI: 10.1038/nchem.2835). Dehydrogenating selected hydroxyls to ketones in multihydroxylated compounds known as polyols has been difficult. A common strategy is to add protecting groups to the hydroxyls you don’t want to react and then deprotect them later. But this is laborious, requiring multiple reactions instead of just one. The Berkeley team developed a catalyst that oxidizes polyol secondary alcohol groups—hydroxyls on carbon

In vitro susceptibility of nematophagous fungi to antiparasitic drugs: interactions and implications for biological control.

The fast anthelmintic resistance development has shown a limited efficiency in the control of animal's endoparasitosis and has promoted research using alternative control methods. The use of chemicals in animal anthelmintic treatment, in association with nematophagous fungi used for biological control, is a strategy that has proven to be effective in reducing the nematode population density in farm animals. This study aims to verify the in vitro susceptibility of the nematophagous fungi Arthrobotrys oligospora, Duddingtonia flagrans and Paecilomyces lilacinus against the antiparasitic drugs albendazole, thiabendazole, ivermectin, levamisole and closantel by using the Minimum Inhibitory Concentration (MIC). MICs ranged between 4.0 and 0.031 µg/mL for albendazole, thiabendazole and ivermectin, between 0.937 and 0.117 µg/mL for levamisole, and between 0.625 and 0.034 µg/mL for closantel. The results showed that all antiparasitic drugs had an in vitro inhibitory effect on nematophagous fungi, which could compromise their action as agents of biological control. D. flagrans was the most susceptible species to all drugs.

Co-Opting the Genetic Redundancy of the Pax Family to Treat PAX5 Mutated Pre-B ALL

Pre-B cell ALL is the most common pediatric malignancy. More than a third of cases acquire loss-of-function mutations of PAX5, a regulatory transcription factor which is required for the differentiation of B lymphocytes. Additionally, germline loss of function PAX5 mutation is a cause of familial pre-B cell ALL. These observations indicate that loss of PAX5 activity drives leukemogenesis. We have seen that PAX5 re-expression in PAX5 -mutated pre-B cell ALL restores differentiation capacity and promotes apoptosis. However, because the gene is deleted or otherwise mutated it may not be possible to easily repair or restore PAX5 expression in leukemic cells. Nevertheless, PAX5 possesses two closely related paralogs, PAX2 and PAX8, which are structurally and functionally similar to PAX5, yet are neither expressed in lymphocytes nor mutated in ALL. Toward the goal of exploiting PAX family genomic redundancy for therapeutic purposes, we have tested the ability of PAX2 and PAX8 to replace PAX5 in pre-B ALL cell lines. Preliminary results indicate that both PAX2 and PAX8 rescue B cell differentiation and function similarly to PAX5 in this context. These results include modulation of B cell developmental markers, CD10, CD19 and CD22, as well as induction of PAX5 target genes, CD79a and BACH2. Cells also display a reduction in size which may be indicative of the large to small B cell transition and importantly show increased levels of cell death following PAX2 and PAX8 expression. We have further investigated the epigenetic status of PAX2 and PAX8 promoters in B cells and find that both loci are hypermethylated, suggesting that demethylation with agents such as methotrexate, may represent a therapeutic entry point for activating expression of PAX5 paralogs. Finally, based on observations that electrical polarization during early embryogenesis regulates developmental transcription factor expression, including for PAX genes, we have tested the ability of approved drugs targeting ion channels for their ability to induce PAX factor expression and thereby complement for loss of PAX5 in pre-B cell ALL. The anti-parasitic drug ivermectin, which activates chloride channels, is one of several compounds that appear promising in early studies. DisclosuresNo relevant conflicts of interest to declare.

Ivermectin exposure leads to up-regulation of detoxification genes in vitro and in vivo in mice

The biodisposition of the antiparasitic drug ivermectin in host and parasite is decisive for its efficacy and strongly depends on the efflux by ATP-Binding Cassette (ABC) transporters and on its biotransformation by cytochromes P450. The purpose of this study was to evaluate, in vitro and in vivo, the ivermectin ability in modulating the expression of the most important genes involved in drug detoxification. Gene expression of ABC transporters and cytochromes was evaluated by RT-qPCR in murine hepatic and intestinal cell lines exposed to increasing ivermectin doses, and in liver and intestine of mice orally administered with single or repeated therapeutic doses of ivermectin (0.2mg/kg). Plasma, brain, liver and intestinal concentrations of ivermectin and its main metabolite were measured by HPLC in ivermectin-treated mice. In hepatocyte cell line, ivermectin up-regulated expression of Abcb1a, Abcb1b, Abcc2, Cyp1a1, Cyp1a2, Cyp2b10; while Abcb1a, Abcb1b, Abcg2, Cyp1a1, Cyp1a2, Cyp2b10 and Cyp3a11 levels were induced in intestinal cell line. In mice, repeated administration of ivermectin induced the expression of Abcb1a, Abcc2, Cyp1a1 and Cyp2b10 in intestine while only Cyp3a11 was induced in liver. Compared with single administration, repeated ivermectin administration lowered plasma, liver and intestine drug concentration, while increasing main metabolite content in plasma and intestine. These findings can be regarded as a warning that repeated ivermectin exposure is able to induce detoxification systems in mammals that may lead to subtherapeutic drug concentration. This may also be an important consideration in the assessment of drug−drug interaction and toxicity for other ABC transporters and CYP450s substrates.

In the NEWS: A ROUNDUP OF NEWS AND INFORMATION FROM OUR COMMUNITY

In <i>the</i> NEWS: A ROUNDUP OF NEWS AND INFORMATION FROM OUR COMMUNITY

The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism

Farnesoid X receptor (FXR) has important roles in maintaining bile acid and cholesterol homeostasis. Here we report that the antiparasitic drug ivermectin is a ligand for nuclear FXR. We identify ivermectin using a high-throughput compound library screening and show that it induces the transcriptional activity of the FXR with distinctive properties in modulating coregulator recruitment. The crystal structure of ivermectin complexed with the ligand-binding domain of FXR reveals a unique binding mode of ivermectin in the FXR ligand-binding pocket, including the highly dynamic AF-2 helix and an expanded ligand-binding pocket. Treatment of wild-type mice, but not of FXR-null mice, with ivermectin decreases serum glucose and cholesterol levels, suggesting that ivermectin regulates metabolism through FXR. Our results establish FXR as the first mammalian protein targeted by ivermectin with high selectivity. Considering that ivermectin is a widely used clinical drug, our findings reveal a safe template for the design of novel FXR ligands.

Positive allosteric modulation by ivermectin of human but not murine P2X7 receptors

In mammalian cells, the anti-parasitic drug ivermectin is known as a positive allosteric modulator of the ATP-activated ion channel P2X4 and is used to discriminate between P2X4- and P2X7-mediated cellular responses. In this paper we provide evidence that the reported isoform selectivity of ivermectin is a species-specific phenomenon. Complementary electrophysiological and fluorometric methods were applied to evaluate the effect of ivermectin on recombinantly expressed and on native P2X7 receptors. A biophysical characterization of ionic currents and of the pore dilation properties is provided. Unexpectedly, ivermectin potentiated currents in human monocyte-derived macrophages that endogenously express hP2X7 receptors. Likewise, currents and [Ca(2+) ](i) influx through recombinant human (hP2X7) receptors were potently enhanced by ivermectin at submaximal or saturating ATP concentrations. Since intracellular ivermectin did not mimic or prevent its activity when applied to the bath solution, the binding site of ivermectin on hP2X7 receptors appears to be accessible from the extracellular side. In contrast to currents through P2X4 receptors, ivermectin did not cause a delay in hP2X7 current decay upon ATP removal. Interestingly, NMDG(+) permeability and Yo-Pro-1 uptake were not affected by ivermectin. On rat or mouse P2X7 receptors, ivermectin was only poorly effective, suggesting a species-specific mode of action. The data indicate a previously unrecognized species-specific modulation of human P2X7 receptors by ivermectin that should be considered when using this cell-biological tool in human cells and tissues.

Moxidectin has a lower neurotoxic potential but comparable brain penetration in P‐glycoprotein‐deficient CF‐1 mice compared to ivermectin

The anti-parasitic drugs ivermectin (IVM) and moxidectin (MOX) normally show limited brain penetration in vertebrates because of effective drug efflux at the blood-brain barrier by P-glycoprotein, encoded by the multi-drug resistance (MDR1) gene. However, dogs with homozygous nt230(del4) mutation in the MDR1 gene do not express a functionally active P-glycoprotein and show increased brain penetration of these drugs, resulting in neurological toxicity to different degrees. Thus, whereas IVM provokes neurological toxicity at 0.1 mg/kg, MOX is tolerated at this dosage. To investigate whether this difference is attributable to lower brain penetration of MOX in the absence of P-glycoprotein or to their neurotoxic potential, we applied IVM and MOX to P-glycoprotein-deficient CF-1 mice and comparatively analysed the absolute drug concentrations in the brain. Furthermore, we quantified drug-induced neurotoxicity by measuring the walking performance of the mice on a rotarod setup. We found that at a dosage of 0.2 mg/kg, representing 0.23 μmol/kg IVM and 0.31 μmol/kg MOX, the absolute drug concentrations in the brain were comparable with 100.8 pmol/g and 140.2 pmol/g, respectively. However, MOX induced the same degree of neurotoxicosis at the higher dosage of 1.09 μmol/kg (0.7 mg/kg) compared with IVM at 0.40 μmol/kg (0.35 mg/kg), demonstrating the 2.7-fold lower neurotoxic potential of MOX compared to IVM. This could be explained by a lower binding affinity or lower intrinsic activity of MOX at the relevant central nervous system receptors compared with IVM.

Mutation of the Highly Conserved Pore-Lining Leucine Residue Increases Agonist Sensitivity of a Glutamate-Gated Chloride Channel

The glutamate-gated chloride channel (GluCl) is an invertebrate, ligand-gated anion channel of the Cys-loop receptor family. It is activated by the endogenous neurotransmitter L-glutamate and by the antiparasitic drug ivermectin. The crystal structure of the Caenorhabditis elegans GluCl alpha homopentamer (3.3A resolution; Hibbs & Gouaux, 2011) shows the location of the glutamate binding site, the separate ivermectin site, and the highly conserved leucine residue at the 9’ position of the pore-lining M2 transmembrane domain. Mutation of this L9’ residue in other Cys-loop receptors dramatically increases agonist sensitivity. Using whole-cell patch clamp, we found that six of seven mutations at this position (L9's, A, F, I, T, V, but not G) increased the glutamate sensitivity of the heteromeric GluCl channel by factors of 5- to 80-fold. Beta-branched amino acids (Ile, Thr, Val) gave the greatest reductions in EC50. Analysis of side chain properties revealed that helix-destabilizing energy correlated with increased glutamate sensitivity. Except for WT and the L9’F mutation, we were unable to detect glutamate- and/or ivermectin-induced changes in membrane potential using a fluorescent membrane potential assay (FlexStation, Molecular Devices), probably because the spontaneous activity of the mutant channels obscured the fluorescence changes. However, whole-cell patch clamp and fluorescent membrane potential experiments confirmed that the L9’F mutation increased both the glutamate and ivermectin sensitivity of the GluCl channel. Increasing GluCl sensitivity to ivermectin will benefit its use as a neuronal silencing tool.

Δ2,3 -Ivermectin ethyl secoester, a conjugated ivermectin derivative with leishmanicidal activity but without inhibitory effect on mammalian P-type ATPases

Looking at a new putative target for the large spectrum antiparasitic drug ivermectin, we recently showed that avermectin-derived drugs are active against promastigote and amastigote forms of Leishmania amazonensis at low micromolar concentrations. However, we then reported that at this concentration range ivermectin is also able to inhibit three important mammalian P-type ATPases so that unacceptable adverse effects could occur if this drug were used at such high doses therapeutically. The present work aimed to test the activity of ten ivermectin analogs on these rat ATPases in search of a compound with similar leishmanicidal activity but with no effect on the mammalian (host) ATPases at effective concentrations. We synthesized three new ivermectin analogs for testing on rat SERCA (1a and 1b), Na+, K+-ATPase (α₁ and α₂/α₃ isoforms) and H+/K+-ATPase activity, along with seven analogs already characterized for their leishmanicidal activity. Our main finding is that one of the prepared derivatives, Δ²,³-ivermectin ethyl secoester 8, is equipotent to ivermectin 1 for the in vitro leishmanicidal effects but is nearly without effect on the rat ATPases, indicating that it could have a better therapeutic index in vivo and could serve as a candidate for hit-to-lead progression. This conclusion is further supported by the fact that compound 8 produced only 6% (vs 77% for ivermectin) inhibition of the human kidney enzyme at 5 μM, a concentration corresponding to the IC₅₀ for the activity against L. amazonensis amastigotes.

Seguridad de la ivermectina: toxicidad y reacciones adversas en diversas especies de mamíferos

La ivermectina es un fármaco antiparasitario muy utilizado en Medicina Veterinaria, dado su espectro de actividad que abarca tanto endo como ectoparásitos, elevada eficacia y amplio margen de seguridad. No obstante, su administración puede dar lugar a efectos tóxicos. La mayoría de ellos derivan de la sobredosificación del compuesto, aunque también se han descrito, a dosis terapéuticas, casos de susceptibilidad extrema a los efectos neurotóxicos del fármaco en determinadas razas o subpoblaciones de animales, así como reacciones anafilácticas por la destrucción masiva de parásitos.