A randomized, double-blind, positive-controlled, 3-way cross-over human experimental pain study of a TRPV1 antagonist (V116517) in healthy volunteers and comparison with preclinical profile

Abstract

This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus-response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.

Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome

“…Several second generation modality specific antagonists have been developed, as it has been observed that hyperthermia is less severe with compounds that are full antagonists for capsaicin, but not for protons . Two recent phase‐I trials reported no side effects of two modality‐selective TRPV1 antagonists . Their potency as analgesics however remains to be established in future studies.…”

Antinociceptive Effects of Isosakuranetin in a Rat Model of Peripheral Neuropathy

“…Many of these channels, such as TRP Vanilloid one, have been shown to be critically involved in pain signal transmission and are the targets of many drug-development endeavors, some of which have advanced to clinical trials [8]. Transient receptor potential melastatin 3 (TRPM 3) is a relatively newly discovered member of the TRP family and is a calcium-permeable nonselective cation channel.…”

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

“…As for PHE377, no data regarding this compound have been published in the peer‐reviewed literature. Yet another compound, V116517, while potently blocking TRPV1 activation by protons and causing hyperthermia in rats, caused no hyperthermia in a clinical trial in humans . However, at doses used, V116517 showed no or low efficacy in some capsaicin pain tests in this trial, while being a slightly more potent blocker of human TRPV1 activation by capsaicin than by protons.…”

“…Hence, it is possible that the doses of V116517 used were insufficient to block the proton mode and cause hyperthermia. Furthermore, no data on T b were presented in the report whatsoever, thus leaving the authors’ statement about the lack of effect on T b open to questions.…”