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

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

The ALICE Transition Radiation Detector: construction, operation, and performance

The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/ c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection