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Absorption, tissue distribution, and excretion of tritium-labeled ivermectin in cattle, sheep, and rat

Chiu et al., J. Agric. Food Chem., doi:10.1021/jf00101a015
Nov 1990  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now known with p < 0.00000000001 from 100 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
Animal study showing that lung tissue concentration of ivermectin may be ~20 times higher than plasma concentration.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), inhibits SARS-CoV-2 3CLpro Mody, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing Fauquet, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, Scheim, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation Liu (C), shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), increases Bifidobacterium which plays a key role in the immune system Hazan, has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.
Chiu et al., 1 Nov 1990, peer-reviewed, 7 authors.
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Abstract: 2072 J. Agric. Food Chem. 1990, 38, 2072-2078 Absorption, Tissue Distribution, and Excretion of Tritium-Labeled Ivermectin in Cattle, Sheep, and Rat Shuet-Hing Lee Chiu,' Marilyn L. Green, Francis P. Baylis, Diana Eline, Avery Rosegay, Henry Meriwether, a n d Theodore A. Jacob Department of Animal and Exploratory Drug Metabolism, Merck Sharp and Dohme Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065 Tritium-labeled ivermectin was studied in cattle, sheep, and rat for absorption, tissue residue distribution, and excretion at doses of 0.3 mg/ kg of body weight. The drug was absorbed by various dosing routes. By intraruminal and subcutaneous dosing routes, highest tissue residues were present in fat and liver of cattle, with half-lives of 6-8 and 4-5 days, respectively. Shorter half-lives (1-2 days) were observed in sheep and rat. The tissue residue distribution pattern was essentially the same for all species studied and similar in male and female rats. With doses of tritium-labeled avermectin B1, ranging from 0.06 to 7.5 mg/kg of body weight, plasma and tissue residue concentrations increased proportionally with the dose. When ivermectin was administered by various routes (ip, sc, iv, oral, and intraruminal), blood residue levels converged to 20-50 ppb 4 h after dosing and then depleted a t a similar rate regardless of the dosing route. Ivermectin was excreted primarily in the feces, with only less than 25;) of the doses being eliminated in the urine in all three species studied. Ivermectin is the 22,23-dihydro derivative of avermectin B1, a macrocyclic lactone produced by a n actinomycetes, Streptomyces avermitilis (Chabala et al., 1980; Burg et al., 1979; Miller e t al., 1979; Egerton et al., 1979). It is active a t extremely low dosage against a wide variety of nematode and arthropod parasites. I t is widely used for the treatment and control of parasites in cattle, horses, sheep, swine, and dogs (Campbell et al., 1983). Ivermectin consists of two closely related homologues containing no less than 80!( 22,23-dihydroavermectin B1, (H2Bla)and no more than 20 22,23-dihydroavermectin Blb ( H & , ) as shown in Figure 1. In vivo metabolism and in vitro metabolism of ivermectin have been studied previously in cattle, sheep and rat (Chiu et al., 1986, 1988) and by hepatic microsomes from cattle and rat (Miwa et al., 1982). A similar in vitro study was also carried out with swine hepatic microsomes (Chiu et al., 1984, 1987). Pharmacokinetics of ivermectin using various formulations have also been reported in various species, e.g., swine, dog, sheep, and cattle (Lo et al., 1985; Wilkinson et al., 1985; Prichard et al., 1985; Fink and Porras, 1989). The biological half-lives (t1p) of the drug increase among these species in the same order, ranging from 0.5 day (swine) to 1.8 (dog), 2.7 (sheep), and 2.8 days (cattle). T h e studies herein described were carried out with the radiolabeled drug in target animals of drug use (cattle, sheep) as well as the laboratory animal (rat) mainly for tissue residue levels, distribution, a n d excretion of t h e radioactive dose. Absorption of the radioactive dose was also studied for comparison with tissue residue levels. '( MATERIALS AND METHODS Radiolabeled Chemicals. [22,23-3H]Ivermectinconsisting of [22,23-3H]H2B1,and [22,23-3H]H2Blb(4:l) was prepared by reduction of avermectins B1, and Blb separately with tritium in the presence of Wilkinson's catalyst [PhaPJsRhCl (Chabala et al.,..
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