Kamm Michael A
Physiology Unit, St Mark's Hospital, London, UK.
Eur J Surg Suppl. 2002(587):10-5.
Functional gastrointestinal disorders are characterised by central and peripheral physiological changes, associated with psychological factors. Successful drug development has been hindered by lack of adequate characterisation of the nature of symptoms and their physiological and psychological correlates. Animal models of chronic stress are lacking. High levels of drug safety are now demanded for treating non-life threatening conditions. Once close to market, patient pressure groups, health care providers and insurers, government, and the internet can all influence a drug's success. Serotonin-modifying drugs have been the main recent focus of development, with mixed results. Cisapride has been withdrawn because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists have been developed on the questionable assumption that they modify visceral sensation in patients. Problems have arisen with alosetron being associated with ischaemic colitis and a high incidence of constipation. The 5-HT4 agonists have their major effect on inducing peristalsis, and may modify gut secretion and sensory function. Tegaserod and prucalopride show promise in patients with constipation and related symptoms. 5-HT1 agonists may play a role in treating functional dyspepsia, partly by improving impaired gastric accommodation to a meal. Antidepressants, often found to be clinically beneficial in these disorders, also affect serotonin metabolism. Past successes, such as loperamide or the somatostatin analogue octreotide, involved targeting end organ receptors influencing motor function or secretion. Modifying sensory function is much more challenging. Future research with novel compounds need to keep these recent lessons in mind.
功能性胃肠疾病的特征是中枢和外周生理变化，并伴有心理因素。症状本质及其生理和心理关联缺乏充分的特征描述，这阻碍了药物研发的成功。目前缺乏慢性应激的动物模型。对于治疗非危及生命的疾病，现在要求药物具有高度的安全性。一旦药物接近上市，患者压力团体、医疗保健提供者和保险公司、政府以及互联网都可能影响药物的成功。5-羟色胺调节药物是近期主要的研发重点，但结果不一。西沙必利因与QT间期延长和心律失常有关而被撤市。5-羟色胺3拮抗剂是基于它们能改变患者内脏感觉这一有疑问的假设而研发的。阿洛司琼出现了问题，它与缺血性结肠炎和高便秘发生率有关。5-羟色胺4激动剂主要作用于诱导蠕动，并可能改变肠道分泌和感觉功能。替加色罗和普芦卡必利在便秘及相关症状患者中显示出前景。5-羟色胺1激动剂可能在治疗功能性消化不良中发挥作用，部分原因是改善胃对进餐的适应性受损。抗抑郁药在这些疾病中往往具有临床益处，它们也会影响5-羟色胺代谢。过去的成功案例，如洛哌丁胺或生长抑素类似物奥曲肽，涉及靶向影响运动功能或分泌的终末器官受体。改变感觉功能则更具挑战性。未来对新型化合物的研究需要牢记这些近期的经验教训。
