Tonini Marcello, De Giorgio Roberto, De Ponti Fabrizio
Department of Physiological and Pharmacological Sciences, University of Pavia, Pavia, Italy.
Drugs. 2004;64(4):347-61. doi: 10.2165/00003495-200464040-00001.
Gastro-oesophageal reflux disease (GORD) is a chronic disorder characterised by an increased exposure of the oesophagus to intragastric contents. Currently, GORD symptoms are maintained under control with antisecretory agents, mainly gastric proton pump inhibitors (PPIs). Although impaired oesophageal motility may partly underlie the pathophysiology of GORD, the use of prokinetic agents has been found to be unsatisfactory. To date, novel pharmacological approaches for GORD are mainly related to the control of transient lower oesophageal sphincter (LOS) relaxations (TLOSRs). The majority of patients with GORD have reflux episodes during TLOSRs, which are evoked by gastric distension, mainly occurring after ingestion of a meal. Patients with reflux disease with normal peristalsis and without or with mild erosive disease could potentially benefit from anti-TLOSR therapy. This therapy might also be of value to treat some severe forms of esophagitis in combination with PPIs. GABA-B-receptor agonists are the most promising class of agents identified so far for TLOSR control. The GABA-B-receptor agonist, baclofen, is the most effective compound in inhibiting TLOSRs in humans. Since baclofen has several CNS adverse effects, novel orally available GABA-B agonists are needed for effective and well tolerated treatment of GORD. Endogenous or exogenous cholecystokinin (CCK) causes a reduction in LOS pressure, an increase in TLOSR frequency and a reduction in gastric emptying. In healthy volunteers and patients with GORD, loxiglumide, a selective CCK1-receptor antagonist, was found to reduce the rate of TLOSRs, although its effect on postprandial acid reflux may be modest. Orally effective CCK antagonists are not marketed to date. The anticholinergic agent atropine, given to healthy volunteers and patients with GORD, markedly reduced the rate of TLOSRs. Because of severe gastrointestinal (and other) adverse effects of anticholinergics, including worsening of supine acid clearance and constipation, it is unlikely that this class of drugs will have a future as anti-TLOSR agents on a routine basis. In spite of their effectiveness in reducing TLOSR rate, untoward adverse effects, such as addiction and severe constipation, currently limit the use of morphine and other opioid mu-receptor agonists. The same applies to nitric oxide synthase inhibitors, which are associated with marked gastrointestinal, cardiovascular, urinary and respiratory adverse effects. Animal studies provide promising evidence for the use of cannabinoid receptor 1 agonists, by showing potent inhibition of TLOSRs in the dog, thus opening a new route for clinical investigation in humans. A better understanding of TLOSR pathophysiology is a necessary step for the further development of novel drugs effective for anti-reflux therapy.
胃食管反流病（GORD）是一种慢性疾病，其特征是食管暴露于胃内物质的时间增加。目前，GORD症状通过抗分泌药物（主要是胃质子泵抑制剂（PPI））得以控制。尽管食管动力障碍可能是GORD病理生理学的部分原因，但已发现使用促动力剂效果不佳。迄今为止，治疗GORD的新型药理学方法主要与控制一过性下食管括约肌（LOS）松弛（TLOSR）有关。大多数GORD患者在TLOSR期间会出现反流发作，这是由胃扩张诱发的，主要发生在进食后。蠕动正常且无糜烂性疾病或仅有轻度糜烂性疾病的反流病患者可能会从抗TLOSR治疗中获益。这种治疗联合PPI治疗某些严重形式的食管炎可能也有价值。γ-氨基丁酸B（GABA-B）受体激动剂是迄今为止已确定的用于控制TLOSR最有前景的一类药物。GABA-B受体激动剂巴氯芬是抑制人类TLOSR最有效的化合物。由于巴氯芬有多种中枢神经系统不良反应，因此需要新型口服有效的GABA-B激动剂来有效且耐受性良好地治疗GORD。内源性或外源性胆囊收缩素（CCK）可导致LOS压力降低、TLOSR频率增加以及胃排空减少。在健康志愿者和GORD患者中，已发现选择性CCK1受体拮抗剂洛昔咕胺可降低TLOSR发生率，尽管其对餐后酸反流的作用可能较小。迄今为止，口服有效的CCK拮抗剂尚未上市。给健康志愿者和GORD患者使用抗胆碱能药物阿托品可显著降低TLOSR发生率。由于抗胆碱能药物有严重的胃肠道（及其他）不良反应，包括仰卧位酸清除能力恶化和便秘，这类药物不太可能常规用作抗TLOSR药物。尽管吗啡和其他阿片μ受体激动剂在降低TLOSR发生率方面有效，但成瘾和严重便秘等不良副作用目前限制了它们的使用。一氧化氮合酶抑制剂也是如此，它们与明显的胃肠道、心血管、泌尿和呼吸系统不良反应有关。动物研究通过显示对犬TLOSR有强效抑制作用，为使用大麻素受体1激动剂提供了有前景的证据，从而为人类临床研究开辟了一条新途径。更好地理解TLOSR病理生理学是进一步开发有效抗反流治疗新药的必要步骤。
