A novel gamma-aminobutyric acid (GABA)B receptor agonist, lesogaberan, combined with proton pump inhibitor therapy led to a 25% reduction in postprandial transient lower esophageal sphincter relaxations, compared with placebo, reported Dr. Guy E.E. Boeckxstaens and colleagues in the August issue of Gastroenterology.
And unlike baclofen, another GABAB receptor agonist used to treat gastroesophageal reflux, lesogaberan carries fewer central nervous system side effects, wrote Dr. Boeckxstaens and his coauthors (Gastroenterology 2010 [doi: 10.1053/j.gastro.2010.04.051]).
The primary end point of the phase II, randomized, placebo-controlled study – funded by the maker of lesogaberan, AstraZeneca – was a reduction in the number of transient lower esophageal sphincter relaxations (TLESRs), “considered to be a major mechanism behind acid, weakly acidic, and weakly alkaline reflux episodes in both healthy individuals and those with gastroesophageal reflux disease (GERD),” wrote the authors.
“TLESRs are triggered in response to the activation of stretch receptors in the stomach and are thought to be mediated by a vasovagal reflex pathway,” they explained. “By targeting this pathway, it should be possible to reduce the number of TLESRs and hence inhibit all types of reflux.”
The study enrolled men and postmenopausal women who had at least a 6-month history of reflux. Patients could not weigh more than 100 kg and had to have reported symptoms of at least mild intensity on at least 3 of the 7 days prior to enrollment.
Out of 42 patients who enrolled, only 21 completed the study and were included in the final analysis; the remainder had a fasting lower esophageal sphincter pressure that was too low to give accurate manometry (pressure) readings; dropped out because of nausea, dosing errors, or for other reasons; or had symptoms too infrequently.
The resulting cohort was 100% white, included 16 males and 5 females, and had a mean age of 51.6 years.
Patients were randomized to receive three doses of either lesogaberan (65-mg capsules) or placebo. The first two doses were in the morning (9 a.m.) and evening (9 p.m.) on day 1, and the third was at 9 a.m. on day 2. Patients ate a standardized meal after the first dose and continued on their preexisting proton pump inhibitor therapy throughout the study.
Patients underwent ambulatory impedance-pH recording during the 24 hours following the first treatment dose on day 1 to determine the frequency and type of reflux.
“A stationary combined manometric and impedance-pH recording was performed over the 4 hours following the third treatment dose,” given on day 2. Then after a washout period of 5-28 days, patients crossed over to the opposite treatment arm, and received placebo, explained Dr. Boeckxstaens of the Academic Medical Center in Amsterdam and also of the department of gastroenterology at the University Hospital Leuven, Belgium.
The researchers found that while in the treatment arm, patients experienced a 25% reduction in the number of transient lower esophageal sphincter relaxations in the 3 postprandial hours after the third dose, compared with placebo (11.6 TLESRs vs. 15.5, respectively).
“Overall, 16/21 patients had fewer TLESRs with lesogaberan than [they did] with placebo, 2 patients had the same number with both interventions, and 3 patients had fewer TLESRs with placebo than with lesogaberan,” they added.
They also found that lower esophageal sphincter pressure increased with lesogaberan by an average of 28%, compared with placebo during the 3 postprandial hours.
“Increases in [lower esophageal sphincter] pressure with lesogaberan peaked around 1 hour after the meal,” they added, and persisted for at least 3 hours.
Lesogaberan’s side effect profile, according to the researchers, was good. “Headache and transient, mostly mild, paraesthesia were the most frequently reported adverse events during study treatment,” they wrote.
Dizziness and somnolence also were reported, with similar frequency by both the active and control treatment groups. No serious adverse events were reported.
Dr. Boeckxstaens disclosed that he has received an unrestricted grant from AstraZeneca and has participated on advisory boards or has been a consultant for AstraZeneca as well as several other drug companies. Four other researchers are employees of AstraZeneca, and a fifth has received research and grant support from the company.
Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
Guy E.E. Boeckxstaens博士及其同事在《胃肠病学》8月刊上撰文指出，与安慰剂比较，新型γ-氨基丁酸(GABA)B受体激动剂lesogaberan与质子泵抑制剂联合应用，使餐后一过性下食管括约肌松弛的发生次数减少25%。
Boeckxstaens博士及其同事写道，与已经用于治疗胃食管反流病的另一GABAB受体激动剂巴氯芬(baclofen)不同，lesogaberan中枢神经系统不良反应较小(Gastroenterology 2010 [doi: 10.1053/j.gastro.2010.04.051])。
这项随机、安慰剂对照II期临床研究(由lesogaberan制造商阿斯利康公司资助)的主要终点是一过性下食管括约肌松弛(TLESRs)次数的减少。作者写道：“TLESRs被认为是健康者和胃食管反流病(GERD)患者酸、弱酸以及弱碱反流症状的主要机制。”
他们解释道：“TLESRs是由胃牵张感受器活化引起的反应，并认为是由迷走反射通路介导的。以此通路作为靶点，就有可能减少TLESRs次数，进而抑制各种类型的反流。”
该研究纳入至少有6个月反流病史的男性和绝经后女性患者，体重低于100 kg，在入组前7天内必须至少有3天出现轻微症状。
在42例入组患者中，仅有21例完成研究并纳入最终结果分析，其他病例或因空腹下食管括约肌压力太低而不能准确读取压力数值，或因恶心、给药剂量错误或其他原因脱落，或症状出现过于频繁等。
最终纳入结果分析的病例均为白人，男性16例，女性5例，平均年龄51.6岁。
患者随机分组，服用3次lesogaberan (65 mg胶囊)或安慰剂。前两次服药分别在第一天的上午9点和晚上9点，第三次服药在次日上午9点。患者首次给药后给予标准饮食，在研究期间并继续接受质子泵抑制剂治疗。
患者第一天首次服药后24 h内接受移动式阻抗-pH检测，以测定反流次数及类型。
阿姆斯特丹大学医学研究中心、比利时鲁汶大学医院胃肠病学系Boeckxstaens博士解释称，稳定的、结合压力和阻抗-pH检测持续至次日第三次服药后4 h，然后经5～28天洗脱期后，患者交叉分组接受治疗和服用安慰剂。
研究者发现，治疗组患者第三次服药后餐后3 h TLESRs次数较安慰剂组减少25%(11.6对15.5)。
他们补充道：“总的说来，21例患者中有16例服用lesogaberan后比服用安慰剂TLESRs次数较少，2例次数相同，3例次数较多。”
他们还发现，与服用安慰剂相比，服用lesogaberan餐后3 h下食道括约肌压力平均增加28%。
“服用lesogaberan患者下食道括约肌压力增加峰值出现在餐后约1 h，”并持续至少3 h。他们补充道。
据研究者称，lesogaberan不良反应较小。“研究期间，头痛和一过性轻微感觉异常是最常见的不良反应。”
眩晕和嗜睡也有报告，治疗组和对照组发生率相似。无严重不良事件报告。
Boeckxstaens博士披露他接受了阿斯利康公司无限制资助，并参加阿斯利康公司和其他几家制药公司咨询委员会或作为顾问。其他四位研究者为阿斯利康公司雇员，第五位研究者得到该公司研究和基金支持。
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