Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis
| Autor: | Margit Solymár, Donald J. Kyle, Zsolt Szakács, András Garami, Robson Cristiano Lillo Vizin, Nelli Farkas, Wade D. Van Horn, Dan A. Chiche, Ram P. Kapil, Yury P. Shimansky, Zoltan Rumbus, Judit Hegyi, Andrej A. Romanovsky, Alexandra Csenkey, Péter Hegyi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Hyperthermia TRPV1 TRPV Cation Channels Pharmacology Models Biological 03 medical and health sciences Transient receptor potential channel chemistry.chemical_compound 0302 clinical medicine Drug Development medicine Animals Humans Pharmacology (medical) musculoskeletal neural and ocular physiology Antagonist Hypothermia Thermoregulation medicine.disease 030104 developmental biology nervous system chemistry Capsaicin 030220 oncology & carcinogenesis lipids (amino acids peptides and proteins) medicine.symptom Vasoconstriction |
| Zdroj: | Pharmacology & Therapeutics. 208:107474 |
| ISSN: | 0163-7258 |
| DOI: | 10.1016/j.pharmthera.2020.107474 |
| Popis: | Antagonists 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-antithermogenic and acido-antivasoconstrictor reflexes - modulates thermogenesis and skin vasoconstriction. In this work, we used a mathematical model to analyze Tb data from human clinical trials of TRPV1 antagonists. The analysis suggests that, in humans, the hyperthermic effect depends on the antagonist's potency to block TRPV1 activation not only by protons, but also by heat, while the CAP activation mode is uninvolved. Whereas in rats TRPV1 drives thermoeffectors by mediating pH signals from the trunk, but not Tb signals, our analysis suggests that TRPV1 mediates both pH and thermal signals driving thermoregulation in humans. Hence, in humans (but not in rats), TRPV1 is likely to serve as a thermosensor of the thermoregulation system. We also conducted a meta-analysis of Tb data from human trials and found that polymodal TRPV1 antagonists (ABT-102, AZD1386, and V116517) increase Tb, whereas the mode-selective blocker NEO6860 does not. Several strategies of harnessing the thermoregulatory effects of TRPV1 antagonists in humans are discussed. |
| Databáze: | OpenAIRE |
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