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IBS is a disorder of the brain-gut axis, with altered motility, heightened sensation or hypersensitivity, and psychosocial disorders as key factors. However, there are several other perturbations that impact these three main factors, including prior infection, luminal irritants and genetics. This lecture focuses on colonic motility. The unit of motor function in the gut is the peristaltic reflex which, in its simplest rendition, involves an intrinsic primary afferent neuron or multimodal neurons that sense distension by intraluminal content and has ascending contractile and descending relaxatory components. The main excitatory transmitters are acetylcholine and substance P, and the main relaxatory substances are nitric oxide, somatostatin, and vasoactive intestinal peptide. Afferent signals from the gut transmit sensation to the central nervous system along vagal and splanchnic (visceral) afferents. Sensory transmitters include serotonin (5-hydroxytryptamine (5-HT), substance P, calcitonin gene-related peptide, and norepinephrine. Novel approaches are in development to treat lower functional gastrointestinal disorders: IBS, functional constipation, and functional diarrhea, which arise from abnormalities in motility, sensation, brain-gut axis, or immune activation. These treatment approaches include new serotonergic type 4 (5-HT4) agonists (prucalopride, velusetrag, naronapride), chloride ion secretagogues (lubiprostone, linaclotide, plecanatide), inhibition of 5-HT synthesis (LX-1031) and 5-HT3 receptors (ramosetron), bile acid modulators (colesevelam and elobixibat), GLP-1 analog, drugs that target immune activation (5-ASA compounds and mast cell stabilizers), and drugs that modify sensation (asimadoline, dextofisopam, pregabalin). The therapeutic options for constipation, which appear safe and efficacious, activate diverse mechanisms to induce increased motility (new-generation 5-HT4 receptor agonists) or secretion in both the small bowel and the colon (e.g., lubiprostone, linaclotide, plecanatide) or predominantly in the colon (e.g., A3309). The studies to date have not categorized the constipation by cause and type: abnormal secretion, normal colonic transit, or delayed colonic transit. Therefore, after the new drugs are approved, practitioners will have a choice, but patient responsiveness will be based on trial and error. A commonly observed colonic motility disorder results from administration of mu-opiates. New approaches to treat these conditions include mu-opioid antagonists and PAMORA (peripherally restricted mu-opioid receptor antagonists), as well as mu-opioid agonist plus norepinephrine reuptake inhibitor. The development of this wide spectrum of medications augurs well for satisfactory treatment of these common clinical indications in the future. |
