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).
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ABSTRACT: Electrical excitation of peripheral somatosensory nerves is a first step in generation of most pain signals in mammalian nervous system. Such excitation is controlled by an intricate set of ion channels that are coordinated to produce a degree of excitation that is proportional to the strength of the external stimulation. However, in many disease states this coordination is disrupted resulting in deregulated peripheral excitability which, in turn, may underpin pathological pain states (i.e. migraine, neuralgia, neuropathic and inflammatory pains). One of the major groups of ion channels that are essential for controlling neuronal excitability is potassium channel family and, hereby, the focus of this review is on the K+ channels in peripheral pain pathways. The aim of the review is threefold. First, we will discuss current evidence for the expression and functional role of various K+ channels in peripheral nociceptive fibres. Second, we will consider a hypothesis suggesting that reduced functional activity of K+ channels within peripheral nociceptive pathways is a general feature of many types of pain. Third, we will evaluate the perspectives of pharmacological enhancement of K+ channels in nociceptive pathways as a strategy for new analgesic drug design.Current Neuropharmacology 12/2013; 11(6):621-40. DOI:10.2174/1570159X113119990042 · 2.35 Impact Factor
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ABSTRACT: A reported mixed opioid agonist – neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3′,5′-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat.European Journal of Medicinal Chemistry 03/2015; 92. DOI:10.1016/j.ejmech.2014.12.033 · 3.43 Impact Factor
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ABSTRACT: Chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV) can negatively impact patient quality of life, functional performance and activities of daily living. Although the development of serotonin receptor antagonists has greatly improved the control of acute emesis, delayed CINV remains a significant clinical issue. Aprepitant (Emend(®)) is the first commercially available drug from a new class of agents, the neurokinin-1 receptor antagonists. Elucidation of its mechanism of action has produced a greater understanding of the pathophysiology of nausea and vomiting. Oral aprepitant, in combination with a selective serotonin (5-HT3) receptor antagonist and corticosteroids, is indicated for the prevention of acute and delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy in adults. Aprepitant alone or in combination only with dexamethasone does not optimally control acute emesis compared with triple combination therapy. By contrast, aprepitant as monotherapy is indicated for the prevention of PONV. Aprepitant represents an emerging class of agents and its addition to standard therapy provides an advanced benefit in the prevention and treatment of CINV and PONV. Investigations of aprepitant for other indications are ongoing.Expert Review of Clinical Pharmacology 01/2008; 1(1):27-37. DOI:10.1586/17512422.214.171.124