JC, It seems that it is the metabolites of Mara
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Posted On: 10/28/2020 5:28:44 PM
JC,
It seems that it is the metabolites of Maraviroc and the like generating hepatotoxicity. Chemically very different than leronlimab, which may thereby avoid toxicity.
Interesting that of a myriad of cytokines released by injured endothelial cells, two are chemokine (CCL2 and CCL5). Both are blocked by Maraviroc, which therefore has a shot at efficacy. Leronlimab has room for much higher/repeated dosing, as has been discussed here with frustrations over dosing only at day 0 and 7.
An old article discussing cytokines from endothelial injury:
https://www.liebertpub.com/doi/10.1089/107999099314234
Human Endothelium as a Source of Multifunctional Cytokines: Molecular Regulation and Possible Role in Human Disease
"Endothelial cells, by virtue of their capacity to express adhesion molecules and cytokines, are intricately involved in inflammatory processes. Endothelial cells have been shown to express interleukin-1 (IL-1), IL-5, IL-6, IL-8, IL-11, IL-15, several colony-stimulating factors (CSF), granulocyte-CSF (G-CSF), macrophage CSF (M-CSF) and granulocyte-macrophage CSF (GM-CSF), and the chemokines, monocyte chemotactic protein-1 (MCP-1), RANTES, and growth-related oncogene protein-alpha (GRO-alpha ). IL-1 and tumor necrosis factor-alpha (TNF-alpha) produced by infiltrating inflammatory cells can induce endothelial cells to express several of these cytokines as well as adhesion molecules. Induction of these cytokines in endothelial cells has been demonstrated by such diverse processes as hypoxia and bacterial infection. Recent studies have demonstrated that adhesive interactions between endothelial cells and recruited inflammatory cells can also signal the secretion of inflammatory cytokines. This cross-talk between inflammatory cells and the endothelium may be critical to the development of chronic inflammatory states. Endothelial-derived cytokines may be involved in hematopoiesis, cellular chemotaxis and recruitment, bone resorption, coagulation, and the acute-phase protein synthesis. As many of these processes are critical to the maturation of an inflammatory and reparative state, it appears likely that endothelial-derived cytokines play a crucial role in several diseases, including atherosclerosis, graft rejection, asthma, vasculitis, and sepsis. Genetic and pharmacologic manipulation of endothelial-derived cytokines provides an additional approach to the management of chronic inflammatory diseases."
Toxicity will continue to be an issue for Maraviroc.
It seems that it is the metabolites of Maraviroc and the like generating hepatotoxicity. Chemically very different than leronlimab, which may thereby avoid toxicity.
Interesting that of a myriad of cytokines released by injured endothelial cells, two are chemokine (CCL2 and CCL5). Both are blocked by Maraviroc, which therefore has a shot at efficacy. Leronlimab has room for much higher/repeated dosing, as has been discussed here with frustrations over dosing only at day 0 and 7.
An old article discussing cytokines from endothelial injury:
https://www.liebertpub.com/doi/10.1089/107999099314234
Human Endothelium as a Source of Multifunctional Cytokines: Molecular Regulation and Possible Role in Human Disease
"Endothelial cells, by virtue of their capacity to express adhesion molecules and cytokines, are intricately involved in inflammatory processes. Endothelial cells have been shown to express interleukin-1 (IL-1), IL-5, IL-6, IL-8, IL-11, IL-15, several colony-stimulating factors (CSF), granulocyte-CSF (G-CSF), macrophage CSF (M-CSF) and granulocyte-macrophage CSF (GM-CSF), and the chemokines, monocyte chemotactic protein-1 (MCP-1), RANTES, and growth-related oncogene protein-alpha (GRO-alpha ). IL-1 and tumor necrosis factor-alpha (TNF-alpha) produced by infiltrating inflammatory cells can induce endothelial cells to express several of these cytokines as well as adhesion molecules. Induction of these cytokines in endothelial cells has been demonstrated by such diverse processes as hypoxia and bacterial infection. Recent studies have demonstrated that adhesive interactions between endothelial cells and recruited inflammatory cells can also signal the secretion of inflammatory cytokines. This cross-talk between inflammatory cells and the endothelium may be critical to the development of chronic inflammatory states. Endothelial-derived cytokines may be involved in hematopoiesis, cellular chemotaxis and recruitment, bone resorption, coagulation, and the acute-phase protein synthesis. As many of these processes are critical to the maturation of an inflammatory and reparative state, it appears likely that endothelial-derived cytokines play a crucial role in several diseases, including atherosclerosis, graft rejection, asthma, vasculitis, and sepsis. Genetic and pharmacologic manipulation of endothelial-derived cytokines provides an additional approach to the management of chronic inflammatory diseases."
Toxicity will continue to be an issue for Maraviroc.
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