Search

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Lunsekimig is a novel, bispecific NANOBODY® molecule that inhibits both thymic stromal lymphopoietin (TSLP) and interleukin (IL)‐13, two key mediators of asthma pathophysiology. In this first‐in‐human study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of lunsekimig in healthy adult participants. Participants received single ascending doses (SAD) of lunsekimig (10–400 mg intravenous [IV] or 400 mg subcutaneous [SC]) (SAD part) or multiple ascending doses (MAD part) of lunsekimig (100 or 200 mg, every 2 weeks [Q2W] for three SC doses), or placebo. Overall, 48 participants were randomized 3:1 in the SAD part and 4:1 in the MAD part for lunsekimig or placebo. The primary endpoint was safety and tolerability. The secondary endpoints included PK, antidrug antibodies (ADAs) and total target measurement. Lunsekimig was well tolerated and common treatment‐emergent adverse events were COVID‐19, nasopharyngitis, injection site reactions, and headache. Lunsekimig showed dose‐proportional increases in exposure and linear elimination. Mean t1/2z of lunsekimig was around 10 days across all IV and SC doses of the SAD and MAD parts of the study. Increases in the serum concentration of total TSLP and IL‐13 for lunsekimig versus placebo indicated target engagement. ADA of low titers were detected in four (11.1%) participants who received lunsekimig in the SAD, and seven (43.8%) in the MAD. In conclusion, lunsekimig was well tolerated in healthy participants with a linear PK profile up to single 400 mg IV and SC dose and multiple doses of 100 and 200 mg SC Q2W, with low immunogenicity. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) signaling has been implicated in human inflammatory diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Lorpucitinib (JNJ‐64251330) is an oral, small molecule, pan‐JAK inhibitor. Unlike systemic JAK antagonists, lorpucitinib was found to have enteric (gut)‐selective properties, providing possible applications in diseases of the human gastrointestinal tract. Here, lorpucitinib was evaluated in a phase I, two‐part, dosing study (NCT04552197) to assess pharmacokinetics, pharmacodynamic biomarkers, and safety in healthy participants. In part 1, 24 participants were randomized to 1 of 4 treatment arms receiving either lorpucitinib (30 mg daily, 30 mg every 12 hours (q12h), or 75 mg q12h) or tofacitinib (5 mg q12h) for 5 days. Part 2 was a food‐effect study in which 12 participants received a single 75‐mg dose of lorpucitinib under either fasting or fed conditions. In part 1, plasma and gut tissue concentrations of lorpucitinib showed approximately dose‐proportional increases. At all doses, lorpucitinib concentrations were significantly higher (392‐ to 1928‐fold) in the gut mucosal biopsies vs. the corresponding plasma samples, demonstrating high enteric selectivity and significantly exceeding both the tissue concentrations (> 200‐fold) and tissue/plasma ratios observed with tofacitinib. JAK inhibition in biopsies was confirmed via reduction in pSTAT‐3 levels. In part 2, lorpucitinib plasma concentrations were detectable but at low levels, with no statistical differences in PK parameters between the fed and fasted groups. Lorpucitinib was safe and well‐tolerated, and the data may be useful in designing studies to evaluate lorpucitinib in patients with JAK/STAT‐driven gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

Abstract: Chronic visceral pain, altered motility and bladder dysfunction are common, yet poorly managed symptoms of functional and inflammatory disorders of the gastrointestinal and urinary tracts. Recently, numerous human channelopathies of the voltage‐gated sodium (NaV) channel family have been identified, which induce either painful neuropathies, an insensitivity to pain, or alterations in smooth muscle function. The identification of these disorders, in addition to the recent utilisation of genetically modified NaV mice and specific NaV channel modulators, has shed new light on how NaV channels contribute to the function of neuronal and non‐neuronal tissues within the gastrointestinal tract and bladder. Here we review the current pre‐clinical and clinical evidence to reveal how the nine NaV channel family members (NaV1.1–NaV1.9) contribute to abdominal visceral function in normal and disease states. [ABSTRACT FROM AUTHOR]

α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABAB receptor (GABABR) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABABR activation. Remarkably, all disulfide isomers of the active α-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs. [ABSTRACT FROM AUTHOR]

Objectives: Experiments using P2X3 knock-out mice or more general P2X receptor antagonists suggest that P2X3 receptors contribute to visceral hypersensitivity. We aimed to investigate the effect of the selective P2X3 antagonist A-317491 on visceral sensitivity under physiological conditions, during acute colitis and in the post-inflammatory phase of colitis. Methods: Trinitrobenzene sulphonic-acid colitis was monitored by colonoscopy: on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Visceral sensitivity was assessed by quantifying visceromotor responses to colorectal distension in controls, rats with acute colitis and post-colitis rats. A-317491 was administered 30 min prior to visceral sensitivity testing. Expression of P2X3 receptors (RT-PCR and immunohistochemistry) and the intracellular signalling molecules cdk5, csk and CASK (RT-PCR) were quantified in colonic tissue and dorsal root ganglia. ATP release in response to colorectal distension was measured by luminiscence. Results: Rats with acute TNBS-colitis displayed significant visceral hypersensitivity that was dose-dependently, but not fully, reversed by A-317491. Hypersenstivity was accompanied by an increased colonic release of ATP. Post-colitis rats also displayed visceral hypersensitivity that was dose-dependently reduced and fully normalized by A-317491 without increased release of ATP. A-317491 did not modify visceral sensitivity in controls. P2X3 mRNA and protein expression in the colon and dorsal root ganglia were similar in control, acute colitis and post-colitis groups, while colonic mRNA expression of cdk5, csk and CASK was increased in the post-colitis group only. Conclusions: These findings indicate that P2X3 receptors are not involved in sensory signaling under physiological conditions whereas they modulate visceral hypersensitivity during acute TNBS-colitis and even more so in the post-inflammatory phase, albeit via different mechanisms of sensitization, validating P2X3 receptors as potential new targets in the treatment of abdominal pain syndromes. [ABSTRACT FROM AUTHOR]

Chronic visceral pain, altered motility and bladder dysfunction are common, yet poorly managed symptoms of functional and inflammatory disorders of the gastrointestinal and urinary tracts. Recently, numerous human channelopathies of the voltage-gated sodium (Na V ) channel family have been identified, which induce either painful neuropathies, an insensitivity to pain, or alterations in smooth muscle function. The identification of these disorders, in addition to the recent utilisation of genetically modified Na V mice and specific Na V channel modulators, has shed new light on how Na V channels contribute to the function of neuronal and non-neuronal tissues within the gastrointestinal tract and bladder. Here we review the current pre-clinical and clinical evidence to reveal how the nine Na V channel family members (Na V 1.1-Na V 1.9) contribute to abdominal visceral function in normal and disease states., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABA(B) receptor (GABA(B)R) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABA(B)R activation. Remarkably, all disulfide isomers of the active α-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)