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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
2.
Ivermectin for preventing and treating COVID‐19 Weibel, Stephanie; Popp, Maria; Stegemann, Miriam ...
Cochrane database of systematic reviews,
07/2021, Volume:
2021, Issue:
10
Journal Article
Peer reviewed
Open access
Background
Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action ...suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS‐CoV‐2 infection and COVID‐19 treatment is conflicting.
Objectives
To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID‐19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS‐CoV‐2 (postexposure prophylaxis).
Search methods
We searched the Cochrane COVID‐19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021.
Selection criteria
We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID‐19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS‐CoV‐2 infection.
Co‐interventions had to be the same in both study arms.
We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy.
Data collection and analysis
We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate‐to‐severe COVID‐19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID‐19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS‐CoV‐2 infection: SARS‐CoV‐2 infection, development of COVID‐19 symptoms, adverse events, mortality, admission to hospital, and quality of life.
Main results
We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID‐19 in inpatient settings and four treating mild COVID‐19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS‐CoV‐2 infection. Eight studies had an open‐label design, six were double‐blind and placebo‐controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias.
Ivermectin doses and treatment duration varied among included studies.
We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies.
Ivermectin compared to placebo or standard of care for inpatient COVID‐19 treatment
We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low‐certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low‐certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low‐certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low‐certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low‐certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low‐certainty evidence) and duration of hospitalization (mean difference (MD) −0.10 days, 95% CI −2.43 to 2.23; 1 study; 45 participants; low‐certainty evidence). No study reported quality of life up to 28 days.
Ivermectin compared to placebo or standard of care for outpatient COVID‐19 treatment
We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low‐certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low‐certainty evidence) or non‐IMV or high flow oxygen requirement (0 participants required non‐IMV or high flow; 1 study, 398 participants; very low‐certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low‐certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low‐certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low‐certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days.
Ivermectin compared to no treatment for prevention of SARS‐CoV‐2 infection
We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low‐certainty evidence). The study reported results for development of COVID‐19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS‐CoV‐2 infection, hospital admission, and quality of life up to 14 days.
Authors' conclusions
Based on the current very low‐ to low‐certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID‐19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use of ivermectin for treatment or prevention of COVID‐19 outside of well‐designed randomized trials.
The synthesis, reactions and medicinal applications of the 1,3,4-thiadiazole ring in solution and the solid phase were investigated. The physical and chemical properties of biosostere and the ...reactions of aromatic and heterocyclic hydrazides with triethyl orthoformate were also explored.
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The continuous demand of medicinally important scaffolds has prompted the synthetic chemists to identify simple and efficient routes for their synthesis. 1H-1,2,3-triazole, obtained by highly ...versatile, efficacious and selective “Click Reaction” has become a synthetic/medicinal chemist’s favorite not only because of its ability to mimic different functional groups but also due to enhancement in the targeted biological activities. Triazole ring has also been shown to play a critical role in biomolecular mimetics, fragment-based drug design, and bioorthogonal methodologies. In addition, the availability of triazole containing drugs such as fluconazole, furacyclin, etizolam, voriconazole, triozolam etc. in market has underscored the potential of this biologically enriched core in expediting development of new scaffolds. The present review, therefore, is an attempt to highlight the recent synthetic/biological advancements in triazole derivatives that could facilitate the in-depth understanding of its role in the drug discovery process.
The review describes the synthetic/biological potential of 1H-1,2,3-triazoles appeared lately (2017–19) in the scientific literature. Display omitted
•The use of Click reaction for affording new hybrids with varied biological potential.•Recently reported anti-plasmodial, anti-TB, anti-microbial and anti-proliferative triazoles.•Structure-Activity Relationship of the synthesized hybrids along with mechanism of action.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Porphyrins and analogous macrocycles exhibit interesting photochemical, catalytic, and luminescence properties demonstrating high potential in the treatment of several diseases. Among them can be ...highlighted the possibility of application in photodynamic therapy and antimicrobial/antiparasitic PDT, for example, of malaria parasite. However, the low efficiency generally associated with their low solubility in water and bioavailability have precluded biomedical applications. Nanotechnology can provide efficient strategies to enhance bioavailability and incorporate targeted delivery properties to conventional pharmaceuticals, enhancing the effectiveness and reducing the toxicity, thus improving the adhesion to the treatment. In this way, those limitations can be overcome by using two main strategies: (1) Incorporation of hydrophilic substituents into the macrocycle ring while controlling the interaction with biological systems and (2) by including them in nanocarriers and delivery nanosystems. This review will focus on antiparasitic drugs based on porphyrin derivatives developed according to these two strategies, considering their vast and increasing applications befitting the multiple roles of these compounds in nature.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Four new series of arctigenin derivatives were designed, synthesised, and evaluated for their anti-Toxoplasma gondii activity in vitro and in vivo. Among the synthesised compounds, ...4-(3,4-dimethoxybenzyl)-3-(4-((1-(2-fluorobenzyl)-1H- 1,2,3-triazol-4-yl)methoxy)-3-methoxybenzyl)dihydrofuran-2(3H)-one (D4) exhibited the most potent anti-T. gondii activity and low cytotoxicity (IC50 in T. gondii: 17.1 μM; IC50 in HeLa cells: ≥ 600.0 μM; Selectivity: 35.09), demonstrating better results than the lead compound arctigenin (IC50 in T. gondii: 586.4 μM; IC50 in HeLa cells: 572.7 μM; Selectivity: 0.98) and the clinically applied positive-control drug spiramycin (IC50 in T. gondi: 262.2 μM; IC50 in HeLa cells: 189.0 μM; Selectivity: 0.72) in vitro. Furthermore, 2-(4-((4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2- methoxyphenoxy)N-phenylacetamide (E5) had better inhibitory effects on T. gondii in vivo than spiramycin did. Compound D4 and E5 not only significantly reduced the number of tachyzoites in the peritoneal cavity of mice, but also resulted in their partial malformation (P < 0.05) in vivo. The determination of liver and spleen index and biochemical parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione (GSH) and malondialdehyde (MDA), were comprehensively evaluated for compound D4 and E5's anti-T. gondii activity and some damage to the liver. In addition, the results of a docking study of D4 into the T. gondii calcium-dependent protein kinase 1 (TgCDPK1) receptor protein-binding site revealed that its mode of action was possibly as a TgCDPK1 inhibitor. Overall, the results revealed that D4 and E5 are promising lead compounds for the further development and identification of arctigenin derivatives as anti-T. gondii agents.
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•Four novel series of arctigenin derivatives were designed and synthesised.•Compound D4 and E5 were found to have the better anti-Toxoplasma gondii activity than the lead compound and the reference drug in in vitro and in vivo.•The determination of liver and spleen index and biochemical parameters were comprehensively evaluated for compound D4 and E5's anti-T. gondii activity and some damage to the liver.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane ...feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1–0.2μg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.
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