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作者：Kristina Rebelo  
出處：WebMD醫學新聞

　　November 18, 2009（加州聖地牙哥訊）－根據一項發表在美國腸胃科醫學會2009年年會上理事長壁報發表會的新研究結果，不同於預期，治療胃食道逆流疾病（GERD）相關的心灼熱，並未隨著質子幫浦抑制劑（PPI）esomeprazole劑量上升而增加。
　　
　　這是一項多中心、雙盲、隨機分派研究，對象是使用esomeprazole magnesium（Nexium，阿斯特捷利康藥廠）的18至75歲（平均年齡為45歲）有6個月以上心灼熱病史，以制酸劑或是抑制胃酸治療且食道酸灌流檢查呈陽性病患。試驗參加者都是停經後或是正在使用荷爾蒙藥物、幽門螺旋桿菌檢驗陰性、且能夠持續記錄症狀日記。
　　
　　這項研究收納368位GERD相關中度心灼熱病患，這些病患被隨機分派接受4週的esomeprazole每天20 mg（共121位）、每天40 mg（共121位）、或一天兩次40 mg（共126位）。
　　
　　使用之esomeprazole劑量高於此項研究的病患排除在外。
　　
　　病患在試驗期間每天將以下問題的回應記錄在電子日記上，包括「請評分過去24小時間最密集的心灼熱嚴重度」，以及「在正常的睡眠時間是否感覺到睡眠中的心灼熱」。
　　
　　主要試驗評量是4週治療期間心灼熱持續消退，以心灼熱評估電子日記「無反應」定義。次要評量包括4週治療間心灼熱緩解，以及4週治療間累積每日持續緩解率。
　　
　　3位每天使用兩次40 mg esomeprazole（21%）的受試者，不良反應（AE）的發生率些微高於每天使用20 mg與40 mg組（分別為17%與18%）。3位每天使用40 mg的病患，因為AE而停止參與試驗，每天使用兩次40 mg的病患有2位退出試驗。這些AE包括嚴重疲倦、關節疼痛、冒汗、視力模糊（僅有1例）、輕微噁心與腹瀉（1例）、中度腹瀉（1例），有1位病患發生中度非心因性胸痛。
　　
　　症狀緩解並未隨著PPI劑量增加或是調整PPI給藥時間而增加。研究者們的結論是，這三種劑量都提供相仿的心灼熱持續緩解率，且三種劑量之間並無統計上顯著差異。研究者與共同作者，德拉威州阿特捷利康藥廠美國Nexium產品醫療主任Marta Illueca醫師在一項壁報展示的訪談中向Medscape腸胃醫學表示，一直以來，PPI劑量加倍或是在睡前投予是否可以提供胃酸抑制上額外的好處都是個公開的議題。
　　
　　Illueca醫師聲稱，根據這些數據，對於這些有GERD相關心灼熱的病患，以胃酸灌流檢查確認，並沒有差異；因此最高效應的觀念，至少在這項研究中，對esomeprazole的症狀反應率並未隨著劑量增加而上升。
　　
　　她指出，其他研究顯示，有30% GERD患者即使接受PPI治療仍然有症狀。她表示，這是在任何劑量下可以達到的胃酸抑制作用。改變生活型態及飲食習慣必須與藥物治療並行。
　　
　　Illueca醫師表示，未來研究的領域將會包括研究不同劑量的PPI與投藥時機對胃酸抑制緩解心灼熱感的效果。
　　
　　未參與此項研究的賓州費城Thomas Jefferson大學醫學臨床教授與Albert Einstein醫學中心腸胃科主任、新科美國腸胃科醫學會理事長Philip O. Katz醫師向Medscape腸胃醫學表示，治療心灼熱或是ESRD病患是很複雜的。
　　
　　Katz醫師指出，逆流病患的心灼熱症狀成因很多。由於敏感度的差異，實際上的逆流症狀如何表現是有差異的，顯然地，對個體病患而言，有一個持續增加劑量但不會更有幫助的限制。有最高效應嗎？合起來看可能有，但不是那麼明顯。因此，總體而言，對某些人來說更多將會更好，但對某些人來說，增加劑量並沒有幫助。每個病患都該視為一個個體來看待。
　　
　　這項研究由Nexium製造商阿斯特捷利康藥廠贊助。Illueca醫師是阿斯特捷利康的員工。Katz醫師表示已無相關資金上的往來。
　　  


Ceiling Effect Noted With Esomeprazole Dosing for GERD

By Kristina Rebelo
Medscape Medical News

November 18, 2009 (San Diego, California) — Contrary to expectations, there was no evidence of an increased response in gastroesophageal reflux disease (GERD)-associated heartburn relief to increased dosages of the proton pump inhibitor (PPI) esomeprazole, according to new study results presented here in a 2009 Presidential Poster presentation at the American College of Gastroenterology 2009 Annual Scientific Meeting.

This was a multicenter, double-blind, randomized trial of esomeprazole magnesium (Nexium, AstraZeneca LP) in patients aged 18 to 75 years (mean age, 45 years) with a history of 6 months or more of heartburn responsive to antacids or acid suppression therapy who were also positive for an esophageal acid perfusion test. Study participants were postmenopausal or on birth control, negative for Helicobacter pylori infection, and capable of keeping a symptoms diary.

The study consisted of 368 patients with GERD-associated moderate heartburn randomly assigned to 4 weeks of treatment with esomeprazole 20 mg once daily (n = 121), 40 mg once daily (n = 121), or 40 mg twice daily (n = 126).

Patients on esomeprazole doses higher than those under study were excluded.

Patients recorded responses to the following questions periodically throughout the study on an e-diary: "Please rate the severity of your most intense heartburn episode during the previous 24 hours," and "Did you experience nocturnal heartburn during your normal sleeping hours?"

Primary outcome measures were a sustained resolution of heartburn during the fourth week of treatment, defined as a "none" response in their heartburn assessment e-diary. Secondary outcome measures included relief of heartburn during the fourth week of treatment and cumulative daily sustained resolution rate through 4 weeks' treatment.

There was a slightly higher incidence of adverse events (AEs) in 3 patients who were in the 40-mg-twice-daily esomeprazole group (21%) than in patients in the 20-mg-once-daily and in the 40-mg-once-daily groups (17% and 18%, respectively). Study medication was withdrawn because of AEs in 3 patients who were in the 40-mg-once-daily group and in 2 patients who were in the 40-mg-twice-daily group. AEs included severe fatigue, arthralgia, myalgia, hyperhidrosis, blurred vision (1 case), mild nausea and diarrhea (1 case), moderate diarrhea (1 case), and moderate noncardiac chest pain in one patient. Symptomatic relief did not increase with higher PPI dosages or modified timing of PPI administration. The researchers concluded that treatment at all 3 doses provided similar rates of sustained heartburn relief with no statistically significant differences among the 3 doses."There's always the open question of whether doubling the PPI dose or using nighttime dosing could provide additional degrees of acid suppression," coauthor and investigator Marta Illueca, MD, FAAP, US Nexium brand medical director, AstraZeneca LP, Wilmington, Delaware, told Medscape Gastroenterology in an interview at the poster's presentation.

"According to these data, in these patients with GERD-associated heartburn, as determined by the acid perfusion test, there were no differences," Dr. Illueca asserted. "So the concept of a ceiling effect, at least in this study, is that an incremental symptomatic response to esomeprazole was not seen with increased dosage."

She pointed out that other studies have suggested that 30% of patients with GERD are still symptomatic despite PPI treatment. "There's just so much acid suppression that is achievable at any dose," she said. "Lifestyle modification and diet have to go hand in hand with pharmacological treatment."

Future areas of research, Dr. Illueca said, will include studying the effects of varying PPI dose and timing of the drug's administration on acid suppression for resolution of nighttime heartburn.

Philip O. Katz, MD, FACG, the newly elected president of the American College of Gastroenterology and chairman of the Division of Gastroenterology at Albert Einstein Medical Center and clinical professor of Medicine at Thomas Jefferson University in Philadelphia, Pennsylvania, who was not associated with the study, told Medscape Gastroenterology that treating the heartburn or GERD patients was "complex."

"The symptoms of heartburn in the reflux patient come in multiple forms," Dr. Katz said. "In reality, because of the differences in sensitivity, the differences in how reflux is expressed, it appears that there's a point at which increasing the dose is not going to be helpful in individual patients. Is there a ceiling effect? Perhaps in aggregate, but in individual patients, it is not quite as clear. So to round this out, in some people, more is better, and in some, increasing the dose will not be helpful. Everybody needs to be taken as an individual."

This research was supported by an industry grant from AstraZeneca LP, maker of Nexium. Dr. Illueca is an employee of AstraZeneca LP. Dr. Katz has disclosed no relevant financial relationships.

American College of Gastroenterology 2009 Annual Scientific Meeting: Abstract 15. Presented October 25, 2009.