Ivermectin Effect on In-Hospital Mortality and Need for Respiratory Support in COVID-19 Pneumonia: Propensity Score-Matched Retrospective Study.

INTRODUCTION: There is negligible evidence on the efficacy of ivermectin for treating COVID-19 pneumonia. This study aimed to assess the efficacy of ivermectin for pre-emptively treating Strongyloides stercoralis hyperinfection syndrome in order to reduce mortality and the need for respiratory support in patients hospitalized for COVID-19. METHODS: This single-center, observational, retrospective study included patients admitted with COVID-19 pneumonia at Hospital Vega Baja from 23 February 2020 to 14 March 2021. Because strongyloidiasis is endemic to our area, medical criteria support empiric administration of a single, 200 µg/kg dose of ivermectin to prevent Strongyloides hyperinfection syndrome. The outcome was a composite of all-cause in-hospital mortality and the need for respiratory support. RESULTS: Of 1167 patients in the cohort, 96 received ivermectin. After propensity score matching, we included 192 patients. The composite outcome of in-hospital mortality or need for respiratory support occurred in 41.7% of the control group (40/96) and 34.4% (33/96) of the ivermectin group. Ivermectin was not associated with the outcome of interest (adjusted odds ratio [aOR] 0.77, 95% confidence interval [CI] 0.35, 1.69; p = 0.52). The factors independently associated with this endpoint were oxygen saturation (aOR 0.78, 95% CI 0.68, 0.89, p < 0.001) and C-reactive protein at admission (aOR: 1.09, 95% CI 1.03, 1.16, p < 0.001). CONCLUSIONS: In hospitalized patients with COVID-19 pneumonia, ivermectin at a single dose for pre-emptively treating Strongyloides stercoralis is not effective in reducing mortality or the need for respiratory support measures.

Impact of short-term discontinuation of ivermectin-based chemoprevention on onchocerciasis transmission in endemic settings with long history of mass drug administration.

BACKGROUND: The control of onchocerciasis currently relies on annual distribution of single dose ivermectin. Because ivermectin has minimal effects on the adult parasite, mass drug administration (MDA) campaigns against onchocerciasis require at least 15 years of annual uninterrupted ivermectin distribution. Mathematical models have predicted that short-term disruption of MDA (as was seen during COVID-19) could impacted the microfilaridermia prevalence depending on the pre-control endemicity and the histories of treatment, requiring corrective measures (such as biannual MDA) to mitigate the effect on onchocerciasis elimination. Field evidence supporting this prediction, however, has yet to be gathered. This study aimed to assess the impact of ~2 years disruption of MDA on onchocerciasis transmission indicators. METHODOLOGY: A cross-sectional survey was carried out in 2021 in seven villages of Bafia and Ndikinimeki, two health districts located in the Centre Region, Cameroon, where MDA has been ongoing for two decades, but interrupted in 2020 as a response to the COVID-19 pandemic. Volunteers aged 5 years and above were enrolled for clinical and parasitological examinations for onchocerciasis. Data were compared with pre-COVID-19 prevalence and intensity of infection from the same communities to measure changes over time. PRINCIPAL FINDINGS: A total of 504 volunteers (50.3% males), aged 5-99 years (Median: 38; IQR: 15-54) was enrolled in the two health districts. The overall prevalence of microfilaridermia in 2021 was similar in Ndikinimeki health district (12.4%; 95% CI: 9.7-15.6) and Bafia health district (15.1%; 95% CI: 11.1-19.8) (p-value = 0.16). Microfilaridermia prevalences were either similar between 2018 and 2021 in the communities of Ndikinimeki health district (19.3% vs 12.8% (p = 0.057) for Kiboum 1; and 23.7% vs 21.4% (p = 0.814) for Kiboum 2), or higher in 2019 compared to 2021 in the communities of Bafia health district (33.3% vs 20.0% (p = 0.035) for Biatsota). The mean microfilarial densities in these communities dropped from 5.89 (95% CI: 4.77-7.28) mf/ss to 2.4 (95% CI: 1.68-3.45) mf/ss (p-value < 0.0001), and from 4.81 (95% CI: 2.77-8.31) mf/ss to 4.13 (95% CI: 2.49-6.86) mf/ss (p-value < 0.02) in Bafia and Ndikinimeki health districts, respectively. Community Microfilarial Load (CMFL) dropped from 1.08-1.33 mf/ss in 2019 to 0.052-0.288 mf/ss in 2021 in Bafia health district while remaining stable in the Ndikinimeki health district. CONCLUSION/SIGNIFICANCE: The continued decline in prevalence and CMFL observed ~2 years after MDA disruption is consistent with mathematical predictions (ONCHOSIM) and shows that additional efforts and resources are not needed to mitigate the effects of short-term MDA disruption in highly endemic settings prior to intervention with long treatment histories.

Ivermectin as a possible treatment for COVID-19: a review of the 2022 protocols.

Ivermectin is a safe and effective drug in humans and has been approved for use in numerous parasitic infections for over 50 years. In addition, many studies have already shown its antiviral activity. Ivermectin is generally well tolerated, with no indication of central nervous system-associated toxicity at doses up to 10 times the highest FDA-approved dose of 200 µg/kg. The in vitro results of ivermectin for reducing SARS-CoV-2 viral load are promising and show that Ivermectin kills SARS-CoV-2 within 48 hours. A hypothesized mechanism of action for this drug is a likely inhibition of IMPα/ß1-mediated nuclear import of viral proteins as demonstrated for other RNA viruses. However, controlled and randomized studies are needed to prove its effectiveness in COVID-19 in humans. In a single in vivo study with published results, patients confirmed to be infected with SARS-CoV-2 received at least one dose of ivermectin at any time during hospitalization. The use of ivermectin was associated with lower mortality during treatment with COVID-19, especially in patients who required increased inspired oxygen or ventilatory support. Additionally, 81 studies with the clinical use of ivermectin in humans are being carried out worldwide according to ClinicalTrials.gov. However, none of these data has been published so far. However, private and public entities in Brazil have been adopting this drug in their protocols as prophylaxis and in the initial phase of the disease. In addition, ivermectin has been used in mass treatment to prevent onchocerciasis and lymphatic filariasis in sub-Saharan Africa for many years. Surprisingly, this region has the lowest proportional mortality rate among the continents, despite the increasing numbers of infected people released by the World Health Organization.

Is the antiparasitic drug ivermectin a suitable candidate for the treatment of epilepsy?

There are only a few drugs that can seriously lay claim to the title of "wonder drug," and ivermectin, the world's first endectocide and forerunner of a completely new class of antiparasitic agents, is among them. Ivermectin, a mixture of two macrolytic lactone derivatives (avermectin B1a and B1b in a ratio of 80:20), exerts its highly potent antiparasitic effect by activating the glutamate-gated chloride channel, which is absent in vertebrate species. However, in mammals, ivermectin activates several other Cys-loop receptors, including the inhibitory γ-aminobutyric acid type A and glycine receptors and the excitatory nicotinic acetylcholine receptor of brain neurons. Based on these effects on vertebrate receptors, ivermectin has recently been proposed to constitute a multifaceted wonder drug for various novel neurological indications, including alcohol use disorders, motor neuron diseases, and epilepsy. This review critically discusses the preclinical and clinical evidence of antiseizure effects of ivermectin and provides several arguments supporting that ivermectin is not a suitable candidate drug for the treatment of epilepsy. First, ivermectin penetrates the mammalian brain poorly, so it does not exert any pharmacological effects via mammalian ligand-gated ion channels in the brain unless it is used at high, potentially toxic doses or the blood-brain barrier is functionally impaired. Second, ivermectin is not selective but activates numerous inhibitory and excitatory receptors. Third, the preclinical evidence for antiseizure effects of ivermectin is equivocal, and at least in part, median effective doses in seizure models are in the range of the median lethal dose. Fourth, the only robust clinical evidence of antiseizure effects stems from the treatment of patients with onchocerciasis, in which the reduction of seizures is due to a reduction in microfilaria densities but not a direct antiseizure effect of ivermectin. We hope that this critical analysis of available data will avert the unjustified hype associated with the recent use of ivermectin to control COVID-19 from recurring in neurological diseases such as epilepsy.

Ivermectin Attenuates CCl4-Induced Liver Fibrosis in Mice by Suppressing Hepatic Stellate Cell Activation.

Liver fibrosis, a common liver dysfunction with high morbidity and mortality rates, is the leading cause of cirrhosis and hepatocellular carcinoma, for which there are no effective therapies. Ivermectin is an antiparasitic drug that also has been showing therapeutic actions in many other diseases, including antiviral and anticancer actions, as well as treating metabolic diseases. Herein, we evaluated the function of ivermectin in regulating liver fibrosis. Firstly, carbon tetrachloride (CCl4)-injected Balb/c mice were used to assess the antifibrosis effects of ivermectin in vivo. Further, CFSC, a rat hepatic stellate cell (HSC) line, was used to explore the function of ivermectin in HSC activation in vitro. The in vivo data showed that ivermectin administration alleviated histopathological changes, improved liver function, reduced collagen deposition, and downregulated the expression of profibrotic genes. Mechanistically, the ivermectin treatment inhibited intrahepatic macrophage accumulation and suppressed the production of proinflammatory factors. Importantly, the ivermectin administration significantly decreased the protein levels of α-smooth muscle actin (α-SMA) both in vivo and in vitro, suggesting that the antifibrotic effects of ivermectin are mainly due to the promotion of HSC deactivation. The present study demonstrates that ivermectin may be a potential therapeutic agent for the prevention of hepatic fibrosis.

The effect of ivermectin on the viral load and culture viability in early treatment of nonhospitalized patients with mild COVID-19 - a double-blind, randomized placebo-controlled trial.

OBJECTIVES: Ivermectin, an antiparasitic agent, also has antiviral properties. In this study, we aimed to assess whether ivermectin has anti-SARS-CoV-2 activity. METHODS: In this double-blinded trial, we compared patients receiving ivermectin for 3 days versus placebo in nonhospitalized adult patients with COVID-19. A reverse transcriptase-polymerase chain reaction from a nasopharyngeal swab was obtained at recruitment and every 2 days for at least 6 days. The primary endpoint was a reduction of viral load on the sixth day as reflected by cycle threshold level >30 (noninfectious level). The primary outcome was supported by the determination of viral-culture viability. RESULTS: Of 867 patients screened, 89 were ultimately evaluated per-protocol (47 ivermectin and 42 placeboes). On day 6, the odds ratio (OR) was 2.62 (95% confidence interval [CI]: 1.09-6.31) in the ivermectin arm, reaching the endpoint. In a multivariable logistic regression model, the odds of a negative test on day 6 were 2.28 times higher in the ivermectin group but reached significance only on day 8 (OR 3.70; 95% CI: 1.19-11.49, P = 0.02). Culture viability on days 2 to 6 was positive in 13.0% (3/23) of ivermectin samples versus 48.2% (14/29) in the placebo group (P = 0.008). CONCLUSION: There were lower viral loads and less viable cultures in the ivermectin group, which shows its anti-SARS-CoV-2 activity. It could reduce transmission in these patients and encourage further studies with this drug.

Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations.

BACKGROUND: COVID-19 pandemic has claimed millions of lives and devastated the health service system, livelihood, and economy in many countries worldwide. Despite the vaccination programs in many countries, the spread of the pandemic continues, and effective treatment is still urgently needed. Although some antiviral drugs have been shown to be effective, they are not widely available. Repurposing of anti-parasitic drugs with in vitro anti-SARS-CoV-2 activity is a promising approach being tested in many clinical trials. Combination of these drugs is a plausible way to enhance their effectiveness. METHODS: The in vitro anti-SARS-CoV-2 activity of combinations of niclosamide, ivermectin and chloroquine were evaluated in Vero E6 and lung epithelial cells, Calu-3. RESULTS: All the two-drug combinations showed higher potency resulting in up to 4-fold reduction in the half maximal inhibitory concentration (IC50) values compared to individual drugs. Among these combinations, niclosamide-ivermectin achieved the highest inhibitory level of over 99%. Combination synergy analysis showed niclosamide-ivermectin combination to have the best synergy score with a mean Loewe synergy score of 4.28 and a peak synergy score of 24.6 in Vero E6 cells and a mean Loewe synergy score of 3.82 and a peak synergy score of 10.86 in Calu-3 cells. CONCLUSIONS: The present study demonstrated the benefit of drug combinations on anti-SARS-CoV-2 activity. Niclosamide and ivermectin showed the best synergistic profile and should be further tested in clinical trials.

Potential therapeutic effects of Ivermectin in COVID-19.

COVID-19 is a critical pandemic that affected communities around the world, and there is currently no specific drug treatment for it. The virus enters the human cells via spikes and induces cytokine production and finally arrests the cell cycle. Ivermectin shows therapeutic potential for treating COVID-19 infection based on in vitro studies. Docking studies have shown a strong affinity between Ivermectin and some virulence factors of COVID-19. Notably, clinical evidence has demonstrated that Ivermectin with usual doses is effective by both the prophylactic and therapeutic approaches in all phases of the disease. Ivermectin inhibits both the adhesion and replication of the virus. Local therapy of the lung with Ivermectin or combination therapy may get better results and decrease the dose of the drug.

Community-based trial assessing the impact of annual versus semiannual mass drug administration with ivermectin plus albendazole and praziquantel on helminth infections in northwestern Liberia.

We assessed the impact of three annual vs five semiannual rounds of mass drug administration (MDA) with ivermectin plus albendazole followed by praziquantel for the control or elimination of lymphatic filariasis (LF), onchocerciasis, soil-transmitted helminth (STH) infections and schistosomiasis in Lofa County, Liberia. The study started in 2012 and was interrupted in 2014 during the Ebola virus outbreak. Repeated cross-sectional surveys were conducted in individuals 5 years and older to measure infection markers. Wuchereria bancrofti antigenemia prevalences decreased from 12.5 to 1.2% (90% reduction) and from 13.6 to 4.2% (69% reduction) one year after three rounds of annual or five rounds of semiannual MDA, respectively. Mixed effects logistic regression models showed decreases in odds of antigenemia positivity were 91 and 74% at that time in the annual and semiannual treatment zones, respectively (p < 0.001). Semiannual MDA was slightly more effective for reducing Onchocerca volvulus microfiladermia prevalence and at follow-up 3 were 74% (from 14.4 to 3.7%) and 83% (from 23.6 to 4.5%) in the annual and semiannual treatment zones, respectively. Both treatment schedules had similar beneficial effects on hookworm prevalence. Thus, annual and semiannual MDA with ivermectin and albendazole had similar beneficial impacts on LF, onchocerciasis, and STH in this setting. In contrast, MDA with praziquantel had little impact on hyperendemic Schistosoma mansoni in the study area. Results from a long-term follow-up survey showed that improvements in infection parameters were sustained by routine annual MDA provided by the Liberian Ministry of Health after our study endpoint.

Could the COVID-19-Driven Increased Use of Ivermectin Lead to Incidents of Imbalanced Gut Microbiota and Dysbiosis?

The microfilaricidal anthelmintic drug ivermectin (IVM) has been used since 1988 for treatment of parasitic infections in animals and humans. The discovery of IVM's ability to inactivate the eukaryotic importin α/ß1 heterodimer (IMPα/ß1), used by some viruses to enter the nucleus of susceptible hosts, led to the suggestion of using the drug to combat SARS-CoV-2 infection. Since IVM has antibacterial properties, prolonged use may affect commensal gut microbiota. In this review, we investigate the antimicrobial properties of IVM, possible mode of activity, and the concern that treatment of individuals diagnosed with COVID-19 may lead to dysbiosis.

Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes.

Patients with coronavirus disease 2019 (COVID-19) commonly have manifestations of heart disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 27 proteins. Currently, SARS-CoV-2 gene-induced abnormalities of human heart muscle cells remain elusive. Here, we comprehensively characterized the detrimental effects of a SARS-CoV-2 gene, Orf9c, on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) by preforming multi-omic analyses. Transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with Orf9c overexpression (Orf9cOE) identified concordantly up-regulated genes enriched into stress-related apoptosis and inflammation signaling pathways, and down-regulated CM functional genes. Proteomic analysis revealed enhanced expressions of apoptotic factors, whereas reduced protein factors for ATP synthesis by Orf9cOE. Orf9cOE significantly reduced cellular ATP level, induced apoptosis, and caused electrical dysfunctions of hPSC-CMs. Finally, drugs approved by the U.S. Food and Drug Administration, namely, ivermectin and meclizine, restored ATP levels and ameliorated CM death and functional abnormalities of Orf9cOE hPSC-CMs. Overall, we defined the molecular mechanisms underlying the detrimental impacts of Orf9c on hPSC-CMs and explored potentially therapeutic approaches to ameliorate Orf9c-induced cardiac injury and abnormalities.

Remdesivir-ivermectin combination displays synergistic interaction with improved in vitro activity against SARS-CoV-2.

A key element for the prevention and management of coronavirus disease 2019 is the development of effective therapeutics. Drug combination strategies offer several advantages over monotherapies. They have the potential to achieve greater efficacy, to increase the therapeutic index of drugs and to reduce the emergence of drug resistance. We assessed the in vitro synergistic interaction between remdesivir and ivermectin, both approved by the US Food and Drug Administration, and demonstrated enhanced antiviral activity against severe acute respiratory syndrome coronavirus-2. Whilst the in vitro synergistic activity reported here does not support the clinical application of this combination treatment strategy due to insufficient exposure of ivermectin in vivo, the data do warrant further investigation. Efforts to define the mechanisms underpinning the observed synergistic action could lead to the development of novel treatment strategies.

Ivermectin in COVID-19 Management: What is the Current Evidence?

Ivermectin (IVM), an approved anthelminthic drug, has been reported to have antiviral, antibacterial, and anticancer activities. Antiviral activity is due to the inhibition of nuclear cargo importin (IMP) protein. The anti-SARS CoV-2 activity through in vitro study was first reported by an Australian team. Later, many studies were conducted, and most of the study results were available as non-peer-reviewed preprints. In this narrative review, literature on the clinical studies conducted with ivermectin from published articles, preprints, and unpublished evidence was collected until 13th June 2021. They are discussed based on the severity of COVID-19 disease. Out of the 23 peer-reviewed published articles, 13 studies were randomized controlled trials. The remaining were either prospective interventional, prospective observational, retrospective cohort, cross-sectional, or case series type of studies; additionally, there were 10 randomized controlled trials available as preprints. In most studies, ivermectin was used in combination with doxycycline, azithromycin, or other drugs. Some studies suggested that a higher dose or increased duration of ivermectin usage was required to achieve favorable effects. In this review, articles on the prophylactic role of ivermectin in COVID-19 are also discussed - wherein the results are more promising. Despite accumulating evidence suggesting the possible use of ivermectin, the final call to incorporate ivermectin in the management of COVID-19 is still inconclusive.

Moxidectin and Ivermectin Inhibit SARS-CoV-2 Replication in Vero E6 Cells but Not in Human Primary Bronchial Epithelial Cells.

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 µM. These limited in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. However, in April 2021, the World Health Organization stated the following: "The current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive." It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to-head comparison of the antiviral activity of ivermectin and the structurally related, but metabolically more stable moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that these compounds predominantly act on the steps following virus cell entry. Surprisingly, however, in human-airway-derived cell models, both moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at concentrations of 10 µM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on their activity in Vero cells. Altogether, these findings suggest that even using a high-dose regimen of ivermectin, or switching to another drug in the same class, is unlikely to be useful for treatment of SARS-CoV-2 in humans.

High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial.

High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. The aim of this study was to assess the safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. This was a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants were adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection. Exclusion criteria were: pregnant or lactating women; CNS disease; dialysis; severe medical condition with prognosis <6 months; warfarin treatment; and antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned (ratio 1:1:1) according to a randomised permuted block procedure to one of the following arms: placebo (arm A); single-dose ivermectin 600 µg/kg plus placebo for 5 days (arm B); and single-dose ivermectin 1200 µg/kg for 5 days (arm C). Primary outcomes were serious adverse drug reactions (SADRs) and change in viral load at Day 7. From 31 July 2020 to 26 May 2021, 32 participants were randomised to arm A, 29 to arm B and 32 to arm C. Recruitment was stopped on 10 June because of a dramatic drop in cases. The safety analysis included 89 participants and the change in viral load was calculated in 87 participants. No SADRs were registered. Mean (S.D.) log10 viral load reduction was 2.9 (1.6) in arm C, 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (P = 0.099 and 0.122 for C vs. A and B vs. A, respectively). High-dose ivermectin was safe but did not show efficacy to reduce viral load.

Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication.

Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but have also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/ß1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein, disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.

Identification of the metabolites of ivermectin in humans.

Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the major metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure, defined by LC-MS/MS and NMR, indicated that M1 is 3″-O-demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O-demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1, M3, and M6 were produced primarily by CYP3A4, and that M1 was also produced to a small extent by CYP3A5. Demethylated (M1) and hydroxylated (M3) ivermectin were the main human in vivo metabolites. Further studies are needed to characterize the pharmacokinetic properties and mosquito-lethal activity of these metabolites.

Molecular Docking and Dynamics Simulation Revealed Ivermectin as Potential Drug against Schistosoma-Associated Bladder Cancer Targeting Protein Signaling: Computational Drug Repositioning Approach.

Urogenital schistosomiasis is caused by Schistosoma haematobium (S. haematobium) infection, which has been linked to the development of bladder cancer. In this study, three repurposing drugs, ivermectin, arteether and praziquantel, were screened to find the potent drug-repurposing candidate against the Schistosoma-associated bladder cancer (SABC) in humans by using computational methods. The biology of most glutathione S-transferases (GSTs) proteins and vascular endothelial growth factor (VEGF) is complex and multifaceted, according to recent evidence, and these proteins actively participate in many tumorigenic processes such as cell proliferation, cell survival and drug resistance. The VEGF and GSTs are now widely acknowledged as an important target for antitumor therapy. Thus, in this present study, ivermectin displayed promising inhibition of bladder cancer cells via targeting VEGF and GSTs signaling. Moreover, molecular docking and molecular dynamics (MD) simulation analysis revealed that ivermectin efficiently targeted the binding pockets of VEGF receptor proteins and possessed stable dynamics behavior at binding sites. Therefore, we proposed here that these compounds must be tested experimentally against VEGF and GST signaling in order to control SABC. Our study lies within the idea of discovering repurposing drugs as inhibitors against the different types of human cancers by targeting essential pathways in order to accelerate the drug development cycle.

Harnessing autophagy to fight SARS-CoV-2: An update in view of recent drug development efforts.

Drug repurposing is an attractive option for identifying new treatment strategies, in particular in extraordinary situations of urgent need such as the current coronavirus disease 2019 (Covid-19) pandemic. Recently, the World Health Organization announced testing of three drugs as potential Covid-19 therapeutics that are known for their dampening effect on the immune system. Thus, the underlying concept of selecting these drugs is to temper the potentially life-threatening overshooting of the immune system reacting to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This viewpoint discusses the possibility that the impact of these and other drugs on autophagy contributes to their therapeutic effect by hampering the SARS-CoV-2 life cycle.

Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients.

Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations.