Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis

Publication date: Available online 9 January 2020Source: Pharmacology &TherapeuticsAuthor(s): Andras Garami, Yury P. Shimansky, Zoltan Rumbus, Robson C.L. Vizin, Nelli Farkas, Judit Hegyi, Zsolt Szakacs, Margit Solymar, Alexandra Csenkey, Dan A. Chiche, Ram Kapil, Donald J. Kyle, Wade D. Van Horn, Peter Hegyi, Andrej A. RomanovskyAbstractAntagonists of the transient receptor potential vanilloid-1 (TRPV1) channel alter body temperature (Tb) in laboratory animals and humans: most cause hyperthermia; some produce hypothermia; and yet others have no effect. TRPV1 can be activated by capsaicin (CAP), protons (low pH), and heat. First-generation (polymodal) TRPV1 antagonists potently block all three TRPV1 activation modes. Second-generation (mode-selective) TRPV1 antagonists potently block channel activation by CAP, but exert different effects (e.g., potentiation, no effect, or low-potency inhibition) in the proton mode, heat mode, or both. Based on our earlier studies in rats, only one mode of TRPV1 activation – by protons – is involved in thermoregulatory responses to TRPV1 antagonists. In rats, compounds that potently block, potentiate, or have no effect on proton activation cause hyperthermia, hypothermia, or no effect on Tb, respectively. A Tb response occurs when a TRPV1 antagonist blocks (in case of hyperthermia) or potentiates (hypothermia) the tonic TRPV1 activation by protons somewhere in the trunk, perhaps in muscles, and – via the acido-antithermog...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research

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