TY - JOUR
T1 - Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials
T2 - Insights from mathematical modeling and meta-analysis
AU - Garami, Andras
AU - Shimansky, Yury P.
AU - Rumbus, Zoltan
AU - Vizin, Robson C.L.
AU - Farkas, Nelli
AU - Hegyi, Judit
AU - Szakacs, Zsolt
AU - Solymar, Margit
AU - Csenkey, Alexandra
AU - Chiche, Dan A.
AU - Kapil, Ram
AU - Kyle, Donald J.
AU - Van Horn, Wade D.
AU - Hegyi, Peter
AU - Romanovsky, Andrej A.
N1 - Funding Information:
The authors thank Dr. Arthur Gomtsyan for reading the manuscript and providing important feedback, Joshua J. Corrigan for editing the manuscript, and Nancy L. Romanovsky for graphics assistance. The authors’ research summarized in this review has been supported in part by the Hungarian National Research, Development and Innovation Office (grant FK 124483 to AG), the Medical School, University of Pecs (grant KA-2019-27 to AG), the New National Excellence Program of the Hungarian Ministry of Human Capacities (grant UNKP-19-4-PTE-236 to AG), the US National Institutes of Health (grants R01GM112077 to WVH and R01NS41233 to AAR), and the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (to AG). The meta-analysis was supported by GINOP “Stay alive – translational medicine for better healthcare” ( 2.3.2-15-2016-00048 to PH) and EFOP “Live longer” ( 3.6.2-16-2017-00006 to PH) grants.
Publisher Copyright:
© 2020 The Authors
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
KW - Drug development
KW - Hyperthermic
KW - Hypothermia
KW - Protons
KW - Thermoregulation
KW - TRPV1 blockers
UR - http://www.scopus.com/inward/record.url?scp=85078962027&partnerID=8YFLogxK
U2 - 10.1016/j.pharmthera.2020.107474
DO - 10.1016/j.pharmthera.2020.107474
M3 - Review article
C2 - 31926897
AN - SCOPUS:85078962027
SN - 0163-7258
VL - 208
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
M1 - 107474
ER -