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Ivermectin proposes many potentials effects to treat a range of diseases, with its antimicrobial, antiviral, and anti-cancer properties as a wonder drug. It is highly effective against many microorganisms including some viruses. In this comprehensive systematic review, antiviral effects of ivermectin are summarized including in vitro and in vivo studies over the past 50 years. Several studies reported antiviral effects of ivermectin on RNA viruses such as Zika, dengue, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome, Human immunodeficiency virus type 1, and severe acute respiratory syndrome coronavirus 2. Furthermore, there are some studies showing antiviral effects of ivermectin against DNA viruses such as Equine herpes type 1, BK polyomavirus, pseudorabies, porcine circovirus 2, and bovine herpesvirus 1. Ivermectin plays a role in several biological mechanisms, therefore it could serve as a potential candidate in the treatment of a wide range of viruses including COVID-19 as well as other types of positive-sense single-stranded RNA viruses. In vivo studies of animal models revealed a broad range of antiviral effects of ivermectin, however, clinical trials are necessary to appraise the potential efficacy of ivermectin in clinical setting.

Unchecked ivermectin use in the region is making it difficult to test the anti-parasite drug’s effectiveness against the coronavirus. Latin America’s embrace of unproven COVID treatment hinders drug trials Unchecked ivermectin use in region is making it difficult to test anti-parasite drug’s effectiveness against the coronavirus.

The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders, including autism and hyperekplexia. Understanding of molecular mechanisms and pharmacology of glycine receptors has been hindered by a lack of high-resolution structures. Here we report electron cryo-microscopy structures of the zebrafish α1 GlyR with strychnine, glycine, or glycine and ivermectin (glycine/ivermectin). Strychnine arrests the receptor in an antagonist-bound closed ion channel state, glycine stabilizes the receptor in an agonist-bound open channel state, and the glycine/ivermectin complex adopts a potentially desensitized or partially open state. Relative to the glycine-bound state, strychnine expands the agonist-binding pocket via outward movement of the C loop, promotes rearrangement of the extracellular and transmembrane domain ‘wrist’ interface, and leads to rotation of the transmembrane domain towards the pore axis, occluding the ion conduction pathway. These structures illuminate the GlyR mechanism and define a rubric to interpret structures of Cys-loop receptors. A high-resolution electron cryo-microscopy structure of the zebrafish α1 glycine receptor bound to agonists or antagonists reveals the conformational changes that take place when the channel transitions from closed to open state. Glycine receptor mechanism Eric Gouaux and colleagues have determined the high-resolution electron cryo-microscopy structure of strychnine-sensitive glycine receptor (GlyR) from zebrafish, bound to agonists or antagonists to reveal the conformational changes that take place when the channel opens. GlyRs mediate neurotransmission throughout the spinal cord and brainstem and their dysfunction is linked to multiple neurological disorders, including autism and hyperekplexia. Also in this issue of Nature , Xin Huang et al . report the X-ray crystal structure of the human GlyR in the presence of the antagonist strychnine.

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.

AbstractUpdatesThis is the second version (first update) of the living systematic review, replacing the previous version (available as a data supplement). When citing this paper please consider adding the version number and date of access for clarity.ObjectiveTo determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19).DesignLiving systematic review and network meta-analysis (NMA).Data sourcesWHO covid-19 database, a comprehensive multilingual source of global covid-19 literature to 4 March 2022.Study selectionRandomised trials in which people at risk of covid-19 were allocated to prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.MethodsAfter duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach.ResultsThe second iteration of this living NMA includes 32 randomised trials which enrolled 25 147 participants and addressed 21 different prophylactic drugs; adding 21 trials (66%), 18 162 participants (75%) and 16 (76%) prophylactic drugs. Of the 16 prophylactic drugs analysed, none provided convincing evidence of a reduction in the risk of laboratory confirmed SARS-CoV-2 infection. For admission to hospital and mortality outcomes, no prophylactic drug proved different than standard care or placebo. Hydroxychloroquine and vitamin C combined with zinc probably increase the risk of adverse effects leading to drug discontinuation—risk difference for hydroxychloroquine (RD) 6 more per 1000 (95% credible interval (CrI) 2 more to 10 more); for vitamin C combined with zinc, RD 69 more per 1000 (47 more to 90 more), moderate certainty evidence.ConclusionMuch of the evidence remains very low certainty and we therefore anticipate future studies evaluating drugs for prophylaxis may change the results for SARS-CoV-2 infection, admission to hospital and mortality outcomes. Both hydroxychloroquine and vitamin C combined with zinc probably increase adverse effects.Systematic review registrationThis review was not registered. The protocol established a priori is included as a supplement.FundingThis study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321).

The antiparasitic drug ivermectin plays an essential role in human and animal health globally. However, ivermectin resistance is widespread in veterinary helminths and there are growing concerns of sub-optimal responses to treatment in related helminths of humans. Despite decades of research, the genetic mechanisms underlying ivermectin resistance are poorly understood in parasitic helminths. This reflects significant uncertainty regarding the mode of action of ivermectin in parasitic helminths, and the genetic complexity of these organisms; parasitic helminths have large, rapidly evolving genomes and differences in evolutionary history and genetic background can confound comparisons between resistant and susceptible populations. We undertook a controlled genetic cross of a multi-drug resistant and a susceptible reference isolate of Haemonchus contortus , an economically important gastrointestinal nematode of sheep, and ivermectin-selected the F2 population for comparison with an untreated F2 control. RNA-seq analyses of male and female adults of all populations identified high transcriptomic differentiation between parental isolates, which was significantly reduced in the F2, allowing differences associated specifically with ivermectin resistance to be identified. In all resistant populations, there was constitutive upregulation of a single gene, HCON_00155390 : cky-1 , a putative pharyngeal-expressed transcription factor, in a narrow locus on chromosome V previously shown to be under ivermectin selection. In addition, we detected sex-specific differences in gene expression between resistant and susceptible populations, including constitutive upregulation of a P-glycoprotein, HCON_00162780 : pgp-11 , in resistant males only. After ivermectin selection, we identified differential expression of genes with roles in neuronal function and chloride homeostasis, which is consistent with an adaptive response to ivermectin-induced hyperpolarisation of neuromuscular cells. Overall, we show the utility of a genetic cross to identify differences in gene expression that are specific to ivermectin selection and provide a framework to better understand ivermectin resistance and response to treatment in parasitic helminths.

Ivermectin is an antiparasitic drug that has shown also an effective pharmacological activity towards various infective agents, including viruses. This paper proposes an alternative mechanism of action for this drug that makes it capable of having an antiviral action, also against the novel coronavirus, in addition to the processes already reported in literature.

This study solved structures of the glutamate-gated chloride channel (GluCl), a Cys-loop receptor from C. elegans , in an apo , closed state and in a lipid-bound state — comparison of these structures with a previously published structure of GluCl in an ivermectin-bound state reveals what conformational changes probably occur as this membrane protein transitions from the closed/resting state towards an open/activated state. Resting-to-activated state of a Cys-loop receptor Depending on their ligand and ion selectivity, Cys-loop receptors are neurotransmitter-activated ion channels that mediate either excitatory or inhibitory neurotransmission. In this paper the authors solve the structures of the glutamate-gated chloride channel (GluCl), a Cys-loop receptor from Caenorhabditis elegans , in an apo or closed state and in a lipid-bound state. Comparison of these structures with the previously published structure of GluCl in an ivermectin-bound state reveals the conformational changes involved as this membrane protein transitions between the closed/resting and an open/activated state. Cys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections 1 , 2 , 3 , 4 . Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor 5 , high-resolution X-ray structures of extracellular domains 6 and X-ray structures of bacterial orthologues 7 , 8 , 9 , 10 . In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding 11 . However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids.

Background Ivermectin mass drug administration to humans or livestock is a potential vector control tool for malaria elimination. Racemic ivermectin is composed of two components, namely a major component (> 80%; ivermectin B 1a ), which has an ethyl group at C-26, and a minor component (< 20%; ivermectin B 1b ), which has a methyl group at C-26. There is no difference between the efficacy of ivermectin B 1a and ivermectin B 1b efficacy in nematodes, but only ivermectin B 1b has been reported to be lethal to snails. The ratios of ivermectin B 1a and B 1b ratios in ivermectin formulations and tablets can vary between manufacturers and batches. The mosquito-lethal effects of ivermectin B 1a and ivermectin B 1b have never been assessed. As novel ivermectin formulations are being developed for malaria control, it is important that the mosquito-lethal effects of individual ivermectin B 1a and ivermectin B 1b compounds be evaluated. Methods Racemic ivermectin, ivermectin B 1a or ivermectin B 1b , respectively, was mixed with human blood at various concentrations, blood-fed to Anopheles dirus sensu stricto and Anopheles minimus sensu stricto mosquitoes, and mortality was observed for 10 days. The ivermectin B 1a and B 1b ratios from commercially available racemic ivermectin and marketed tablets were assessed by liquid chromatography-mass spectrometry. Results The results revealed that neither the lethal concentrations that kills 50% (LC 50 ) nor 90% (LC 90 ) of mosquitoes differed between racemic ivermectin, ivermectin B 1a or ivermectin B 1b for An. dirus or An. minimus , confirming that the individual ivermectin components have equal mosquito-lethal effects. The relative ratios of ivermectin B 1a and B 1b derived from sourced racemic ivermectin powder were 98.84% and 1.16%, respectively, and the relative ratios for ivermectin B 1a and B 1b derived from human oral ivermectin tablets were 98.55% and 1.45%, respectively. Conclusions The ratio of ivermectin B 1a and B 1b does not influence the Anopheles mosquito-lethal outcome, an ideal study result as the separation of ivermectin B 1a and B 1b components at scale is cost prohibitive. Thus, variations in the ratio of ivermectin B 1a and B 1b between batches and manufacturers, as well as potentially novel formulations for malaria control, should not influence ivermectin mosquito-lethal efficacy. Graphical abstract

The review presents metabolic properties of Ivermectin (IVM) as substrate and inhibitor of human P450 (P450, CYP) enzymes and drug transporters. IVM is metabolized, both in vivo and in vitro, by C-hydroxylation and O-demethylation reactions catalyzed by P450 3A4 as the major enzyme, with a contribution of P450 3A5 and 2C9. In samples from both in vitro and in vivo metabolism, a number of metabolites were detected and as major identified metabolites were 3″-O-demethylated, C4-methyl hydroxylated, C25 isobutyl-/isopropyl-hydroxylated, and products of oxidation reactions. Ivermectin inhibited P450 2C9, 2C19, 2D6, and CYP3A4 with IC50 values ranging from 5.3 μM to no inhibition suggesting that it is no or weak inhibitor of the enzymes. It is suggested that P-gp (MDR1) transporter participate in IVM efflux at low drug concentration with a slow transport rate. At the higher, micromolar concentration range, which saturates MDR1 (P-gp), MRP1, and to a lesser extent, MRP2 and MRP3 participate in IVM transport across physiological barriers. IVM exerts a potent inhibition of P-gp (ABCB1), MRP1 (ABCC1), MRP2 (ABCC2), and BCRP1 (ABCG2), and medium to weak inhibition of OATP1B1 (SLC21A6) and OATP1B3 (SLCOB3) transport activity. The metabolic and transport properties of IVM indicate that when IVM is co-administered with other drugs/chemicals that are potent inhibitors/inducers P4503A4 enzyme and of MDR1 (P-gp), BCRP or MRP transporters, or when polymorphisms of the drug transporters and P450 3A4 exist, drug–drug or drug–toxic chemical interactions might result in suboptimal response to the therapy or to toxic effects.