Zsa Zsa Weerts

TRP channels as therapeutic targets in IBS 91 4 animals, its first human clinical trial was prematurely halted as hyperthermia was observed in three out of four patients. 82 Interestingly, while TRPV1 has been identified as a thermosensor, its temperature threshold is well above physiological body temperature. It is possible that adverse effects are not TRPV1 related and represent an off-target effect. Additionally, classical TRPV1 antagonists impair the noxious heat sensation and may therefore increase burn risk. Together, these results disfavoured the development of non-selective TRPV1 antagonists. Therefore, new strategies are being explored in order to tackle thermoregulation related adverse events in TRPV1 targeted therapy. 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. 83 Two recent phase-I trials reported no side effects of two modality-selective TRPV1 antagonists. 84,85 Their potency as analgesics however remains to be established in future studies. Table 4.3 Summary of therapeutic strategies in relation to the TRP channels discussed in this paper. TRPV1 TRPV4 TRPA1 Antagonists Potent analgesics, but thermoregulation interference with first generation compounds 80-82 Modality-selective antagonists currently being developed 108 Reduction of human nociceptor mechanosensitivity ex vivo 41 Tested in neuropathies with good safety profiles 105 Several antagonists currently evaluated in clinical trials 105 Desensitization Six weeks of chilli treatment effective in IBS-D patients, but short-term adverse effects may limit adherence 87 Evidence currently lacking Repeated TRPA1 stimulation results in desensitization 52 Cross- desensitization Inhibition of chemo- and mechanosensory responses with peppermint oil* Inhibition of chemo- and mechanosensory responses with peppermint oil* Reduced mechanosensitivity through repeated capsaicin administration 52 Downstream targets NK1 antagonists may provide anti-hyperalgesic effects 96 Improved abdominal pain and stool pattern in female IBS-D patients with NK2 antagonist ibodutant 94 Somatostatin analogues may provide anti-hyperalgesic effects 98-101 Improved abdominal pain scores in IBS patients with HRH1 antagonist ebastine 34 Evidence currently lacking Evidence currently lacking RNA-based therapy Plausible 102 Plausible 102 Plausible 102