The NK₁‐receptor antagonist TKA731 in painful diabetic neuropathy: A randomised, controlled trial

Abstract

Substance P is one of the neurotransmitters released by primary nociceptive neurons in the dorsal horn of the spinal cord and it binds postsynaptically to NK(1)-receptors. This receptor is therefore an obvious target for analgesic drugs. The aim of this multicenter, randomised, double-blind, placebo-controlled and parallel-group study was to test if the non-peptide NK(1)-receptor antagonist TKA731 would relieve painful diabetic polyneuropathy. Eighty-seven patients completed a treatment period of 2 weeks' duration with TKA731 (150 mg daily) or placebo preceded by one week for baseline observations. There was no significant difference between TKA731 and placebo in change in pain rating from baseline to study end neither for rating of total pain (mean -13.4 mm vs. -11.6 mm, p = 0.664) nor for change in ratings of different pain symptoms (touch- or pressure-evoked pain, pain paroxysms, steady burning or deep aching pain) (p = 0.169-0.834).

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

“…Despite promising preclinical results on rodents, NK-1 antagonists have been shown to lack efficacy in human neuropathy. 46, 47 Nonetheless, NK-1 antagonists may prove useful in combination therapies or by use of hybrid compounds that contain both opioid and NK-1 pharmacophores, as this may ensure simultaneous drug action and may improve therapy as compared to the administration of a single general analgesic.…”

“…46, 47 The right sciatic nerve was exposed under sodium pentobarbital anaesthesia (60 mg/kg; ip). Four ligatures (4/0 silk) were made around the nerve distal to the sciatic notch with 1 mm spacing until a brief twitch in the respective hind limb was observed.…”

Substance P in heart failure: The good and the bad

“…Further, they continue to be trialed clinically with promising results for numerous other uses including, prevention of pruritus related to cancer treatment (78), the prevention of post-operative nausea and vomiting (79;80), and depression (81). NK-1 receptor antagonists have also been trialed with little success for migraine (82;83) and painful diabetic neuropathy (84). We would argue that there is a need to aggressively pursue this avenue of research, and should the experimental evidence continue to demonstrate the importance of sensory nerves and substance P in particular, modulation of this pathway may represent a treatment strategy for the prevention of heart failure in the foreseeable future.…”

Evidence for anti-inflammatory and putative analgesic effects of a monoclonal antibody to calcitonin gene-related peptide

“…Previous studies from our laboratory, using the same model of pulpal inflammation and stimulation, have found a reduction in Fos expression following treatment with clinically effective analgesics, for example ibuprofen and paracetamol (Worsley et al, 2008a,b). Furthermore, classes of compound with little clinical analgesic efficacy eg neurokinin-1 receptor antagonists (Goldstein et al, 1997(Goldstein et al, , 2000(Goldstein et al, , 2001Reinhardt et al, 1998;Sindrup et al, 2006) do not affect Fos expression in this model (Worsley et al, 2008a). Thus the data from the current study suggest that the monoclonal antibody to CGRP may be eliciting an analgesic effect.…”