CHICAGO (EGMN) – Researchers are turning their attention from acid suppression to inhibition of transient lower esophageal sphincter relaxation as a new therapeutic approach for gastroesophageal reflux disease.
Proton pump inhibitors, which inhibit acid secretion from parietal cells in the gastric epithelium, are the mainstay of GERD therapy, but they’re unsuccessful in about 30% of patients. In those people, acid suppression is incomplete, or symptoms stem from weak- or non-acidic reflux. Basic and clinical studies have recently suggested that vagal mechanoreceptors that trigger transient lower esophageal sphincter relaxation (TLESR) may now be the most important cellular target in GERD, rather than the parietal cell.
“Gastric vagal afferent neurons are the new cellular target in GERD,” Ashley Blackshaw, Ph.D., head of the Nerve-Gut Research Laboratory at the Royal Adelaide Hospital in Adelaide, Australia, said at Neurogastroenterology and Motility 2009.
He explained that the primary etiology of GERD is disordered neural control of the gastroesophageal reflux barrier, which comprises an internal lower esophageal sphincter and an external sphincter. Both of these sphincters relax during TLESR, which is triggered by meals and gastric distension and stopped by sleep, anesthesia, and vagal blockade.
GABA B receptor agonists
Gamma-aminobutyric acid type B receptor (GABAB) agonists inhibit TLESR and thus reflux in animal models. The GABAB agonist baclofen is approved as an antispasmodic, but has been used to inhibit TLESR and reflux in humans. Its potential as a GERD treatment is limited, however, by marginal efficacy, the need for multiple dosing, and potential central nervous system side effects, as well as nausea and vomiting and cardiovascular contraindications, said Dr. Blackshaw, who has received grants from AstraZeneca and Australia’s National Health and Medical Research Council.
He noted that AZD3355, a GABAB receptor agonist in phase II development by AstraZeneca, is thought to have peripherally restricted actions and therefore considerably less central nervous system side effects than baclofen. It has shown limited uptake in human brain slices, binds to the GABA carrier better than baclofen has, and inhibits TLESR in dogs; the research was funded by AstraZeneca (J. Pharmacol. Exp.Ther. 2009 July 31. [Epub ahead of print]).
Dr. Blackshaw cited unpublished human research, also funded by AstraZeneca, indicating that AZD3355 0.8 mg/kg reduced TLESR by 40% and reflux episodes by 44% when compared with placebo and baclofen 40 mg in 21 patients. Side effects with the new drug were the same as with placebo.
Other GABAB receptor agonists in development include Xenoport’s XP19986 and AstraZeneca’s AZD9343. Unpublished data on AZD9343 at 60 mg and 320 mg demonstrates up to a 32% reduction in TLESRs and up to a 69% reduction in reflux episodes in patients with GERD, said Dr. Blackshaw at the meeting, hosted by the Functional Brain-Gut Research Group. Mild to moderate dizziness has been observed in the AZD9343 research, he said.
mGluR antagonists
In contrast to GABAB receptors, where activation with agonists reduces reflux, blockade of metabotropic glutamate 5 receptors (mGluR5) with antagonists reduces TLESR and reflux, Dr. Blackshaw said. mGluR5 antagonists also inhibit gastric vagal afferent signaling, mainly through peripheral actions, he added. Two experimental mGluR5 antagonists of interest are ADX10059, in phase II development by Addex Pharma SA, and AFQ056, in phase IB and II development by Novartis.
In a recently published proof-of-concept study in 24 patients with GERD, ADX10059 250 mg taken orally t.i.d. significantly reduced the subjects’ percentage of time with esophageal acid exposure from 7.2% to 3.6% and reduced the number and duration of symptomatic reflux episodes, when compared with placebo. ADX10059 at a dose of 50 mg t.i.d. was not significantly better than placebo (Gut 2009;58:1192-9)
Other vagal mechanoreceptor inhibitors
Dr. Blackshaw said that several other inhibitors of gastric vagal mechanoreceptors are being considered in GERD, including cannabinoid I receptor agonists, galanin 1 receptor agonists, ghrelin receptor agonists, mu and kappa opioid receptor agonists, nitric oxide donors, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists. The 5-hydroxytryptamine, opioid, and N-methyl d-aspartate (NMDA) receptors have all been shown to modulate triggering of TLESR, but either the effects are marginal or the target is associated with too many side effects, Dr. Blackshaw reported. Nitric oxide synthase inhibitors inhibit TLESR, but their site of action is not yet known.
“There is a wealth of opportunity,” he said.
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芝加哥(EGMN)——在胃食管反流病的新治疗方法方面，研究者已将他们的注意力从抑制胃酸分泌转移到抑制一过性食管下段括约肌松弛(TLESR)。
质子泵抑制剂可以抑制胃上皮壁细胞的酸分泌，这是目前治疗GERD的主要方法，但其对大约30%患者的治疗效果欠佳。对于这部分患者来说，疗效欠佳的原因可能与对胃酸的抑制并不彻底有关，或者反流症状由非酸反流产生或仅部分与酸反流相关。迷走神经机械感受器可以诱发TLESR，最近的基础和临床研究已经表明，它可能成为治疗GERD的最重要的细胞靶点，而非壁细胞。
澳大利亚皇家阿德莱德医院神经与胃肠研究实验室主任Ashley Blackshaw博士在2009年神经胃肠病学与胃肠动力学术会议上说：“胃迷走神经传入神经元是治疗GERD的新细胞靶点。”
他解释说，GERD的主要病因在于胃食管反流屏障的神经控制功能紊乱，而此屏障主要由食管下段内、外括约肌构成。当发生TLESR时，这些括约肌均处于松弛状态，这种情况可由进食及胃扩张触发，而由睡眠、麻醉及迷走神经阻滞终止。
B型γ-氨基丁酸(GABA)受体激动剂
Blackshaw说，动物模型显示，B型GABA受体激动剂(GABAB)可抑制TLESR及反流的发生。巴氯芬是一种B型GABA受体激动剂，被批准作为解痉剂使用，但在人类已被用于抑制TLESR及反流。然而，由于疗效并不理想、需要多次服药以及存在潜在的中枢神经系统副作用（如恶性、呕吐、心血管系统禁忌证）等原因，巴氯芬治疗GERD的潜力有限。Blackshaw的研究获得了来自阿斯利康公司及澳大利亚国家健康与医疗研究委员会的资助。
他指出，由阿斯利康公司开发的一种B型GABA受体激动剂AZD3355已进入II期临床阶段，由于AZD3355的外周作用较小，因此认为其中枢神经系统副作用明显较巴氯芬小。以人类脑组织切片为对象的研究表明，人类脑组织摄取AZD3355较少，与GABA转运载体的结合力也强于巴氯芬，并且在狗类的实验中显示出可抑制TLESR；此项研究受到阿斯利康公司的资助。(J. Pharmacol. Exp.Ther. 2009 July 31. [Epub ahead of print])。
Blackshaw博士引用一项尚未发表的以人类为对象的研究(也受到阿斯利康公司资助)表明，与21例使用安慰剂和40 mg巴氯芬的患者相比，0.8 mg/kg剂量的AZD3355可以减少40%的TLESR以及44%的反流事件。而AZD3355 的副作用与安慰剂相当。
正在研制的其他B型GABA受体激动剂包括Xenoport公司的XP19986和阿斯利康公司的AZD9343。Blackshaw博士在一次由功能性脑-肠研究组主办的会议上报道了一项尚未发表研究的数据，60 mg和320 mg的AZD9343可减少GERD患者32%的TLESR以及69%的反流事件。他说，AZD9343研究中曾观察到患者出现轻至中度的头晕症状。
亲代谢性谷氨酸盐受体（mGluR）拮抗剂
Blackshaw说，不同于B型GABA受体被其激动剂激活而减轻反流程度，mGluR5可被其拮抗剂阻滞而减轻TLESR和反流程度。他补充说，mGluR5拮抗剂也抑制胃迷走神经传入通路，主要是通过外周作用起效。ADX10059和AFQ056是目前比较有前景的实验性mGluR5拮抗剂。前者由Addex Pharma SA公司开发，处于II期临床研究阶段；后者由诺华制药公司开发，处于IB和II期临床研究阶段。
最近发表的一项包含24例GERD患者的概念验证研究表明，与安慰剂比较，每日3次口服250 mg ADX10059可以使受试者食管酸暴露时间的百分比从7.2%显著减少至3.6%，并且可减少有症状反流事件的数量和持续时间。而每日3次口服50 mg ADX10059与安慰剂相比并无优势(Gut 2009;58:1192-9)。
其他迷走神经机械感受器抑制剂
Blackshaw医生说，目前正在研制几种其他的胃迷走神经机械感受器抑制剂用于GERD的治疗，如大麻素I受体激动剂、促生长激素神经肽1 受体激动剂、生长激素释放肽受体激动剂、μ型和κ型阿片样物质受体拮抗剂、一氧化氮供体、α氨基羟甲基噁唑丙酸(AMPA)拮抗剂。Blackshaw博士报告，虽然已知5-羟色胺、阿片样物质、N-甲基-D-天冬氨酸(NMDA)受体可调控TLESR的发生，但不是其效应太微弱，就是其靶点与太多的副作用相关。一氧化氮合酶抑制剂可以抑制TLESR的发生，但其作用位点仍然未知。“这值得进一步研究”，他说。
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