奧曲肽治療化療相關(guān)性腹瀉最終版

1、Octreotide in chemotherapy induced diarrhoea in colorectal cancer: a review article奧曲肽治療直腸癌患者化療相關(guān)性誘發(fā)腹瀉：綜述Abstract 摘要Background: Chemotherapy-induced diarrhea(CID)is well known in cancer management. The riskis greater when the primary cancer is colorectal. The article aims towards assessing the role

2、of octreotide in CID through an extensive literature search.背景：化療相關(guān)性誘發(fā)腹瀉(CID)在癌癥治療中比較常見。特別是原發(fā)灶位于直腸 的癌癥則風險更大。本文旨在通過全面的文獻檢索評價奧曲肽治療CID的作用。Methods： After searching through PUBMED,MEDLINEd the Cochrane library, only those studies which were published over the last 20 years in English and where at least t

3、he majority of the cohort were colorectal patients, were included. Tworandomized trials, four non-randomized studies and two case-series publications were thus considered.方法：檢索PUBMED,MEDL和循證醫(yī)學圖書館，選出最近 20年用英文發(fā)表的、 并且至少所選的主要觀察隊列為結(jié)腸病人的研究論文。符合條件的共有兩項隨機 對照試驗，四項非隨機研究和兩篇系列案例研究文獻。Results: It was seen in both

4、 the randomized studies, that octreotide had much better outcome as compared to loperamide in treating severe CID.Among 88 patients from the non-randomized studies with severe CID, the primary cancer was colorectal in 79 patients.61 patients had drug-resistant CID. Within a maximumof 96 hours, octre

5、otide reduced CID by 2 grades in 91% of 88 patients and in 88.52% patients with drug-resistant CID.結(jié)果：隨機對照試驗研究結(jié)果顯示，奧曲肽治療嚴重CID的療效比咯哌丁胺好很 多。非隨機研究結(jié)果顯示，88例嚴重CID病人中，原發(fā)是結(jié)腸癌的有79例。其 中61例病人有CID抗藥性。用奧曲肽治療最長時間為96個小時后，88例嚴重 CID病人中，抗藥性降低的患者為91%抗藥性患者中88.52%患者的CID評分至少2級。Conclusion: Octreotide is effecti ve in trea

6、ting severe CID, resistant to other modes of treatment. It is associated with a few minor adverse effects. Though expensive, octreotide could be considered as first line medication in CID of grades 3 or above. Its use in lower grades of CID would not be cost effective.結(jié)論：奧曲肽對其他治療方式無效的嚴重CID患者有效，且不良反應(yīng)

7、較少。 盡管價格比較昂貴，奧曲肽仍可考慮作為 CID評分3級以上患者的一線藥物。在低級別的CID治療中，奧曲肽的作用并不是很大。Key words: octreotide, chemotherapy induced diarrhoea, octreotide in diarrhoea.關(guān)鍵詞：奧曲肽，化療導(dǎo)致的腹瀉，奧曲肽治療腹瀉Abbreviations 縮寫CID = Chemotherapy induced diarrhoea 化療相關(guān)性 誘發(fā)腹瀉5FU = 5 Fluorouracil5-氟尿 口密咤UFT=Uracil 優(yōu)福定NCI=National Cancer Institute

8、 國際腫瘤研究所NICE=National Institute of Clinical Excellence 國家臨床優(yōu)化研究所Introduction 介紹Colorectal cancer is the second commonest cause for cancer related mortality inEngland and Wales and the third commonest cause in the United States.In the UK,there are 30000 new cases each year, a quarter of which are Duk

9、es C or Stagem atpresentation. （please refer to （a） NICE Guidance on Cancer Service: ImprovingOutcomes in Colorectal Cancer, Manual Improving Outcomes in Colorectal Cancers,Manual Update 2000 and （b） Cancer Stats monograph 2004 cancer incidence survivaland mortality in the UKand EU. Bowel Cancer Sta

10、tistics. Cancer Research UK; 2004）.在英國和威爾士，結(jié)、直腸癌的死亡率是位居所有癌癥死亡率的第二位，在美國是 所有癌癥死亡率的第三位（1）。英國每年新增30000例結(jié)直腸癌患者，其中四分之一是DukesC期或腫瘤III期。（請參考（a） NICE癌癥服務(wù)指導(dǎo)原則：提高結(jié)直腸癌病愈率，提高結(jié)直腸癌病 愈率手冊，2000補充資料手冊和（b）英國和歐盟2004年癌癥死亡率和生存率統(tǒng)計專題論文集。腸癌統(tǒng)計資料，癌癥研究，英國；2004)All Dukes C, high risk Dukes B and metastatic colorectal cancers ar

11、e likely to be considered for either post operative (Dukes B/C) or palliative chemotherapy (Dukes D/ metastatic disease)(2,3). Chemotherapy induced diarrhea(CID) is commonand could be as high as 82%.Nearly a third of these patients have severe grade 3-4 diarrhoea(Fig.1), which is frequently responsi

12、ble for hospitalization, chemotherapy dose modification and early termination of treatment. Chemotherapy regimens used in adjuvant(4,5) and metastatic(6,7) colorectal disease and respective incidences of CID are summarized in the charts(Fig.2.3).所有的杜克斯C期，高危的杜克斯B期和轉(zhuǎn)移的結(jié)直腸癌似乎都可考慮手術(shù)后化療(DukesB/C期)或姑息性化療(

13、杜克斯D期/癌轉(zhuǎn)移)(2,3)。化療相關(guān)性 誘發(fā)腹瀉(CID)非常普遍，可能高達 82%。 其中大約三分之一患有比較嚴重的 3-4 級腹瀉 (見表 1 ) ， 這往往是由于住院治療、 化療劑量改變和治療較早結(jié)束引起的。 輔助化療方案(4,5)和轉(zhuǎn)移性結(jié)直腸癌疾病( 6,7)及其CID發(fā)病率請見圖表(表2,3)中的匯總。Capecitabine, irinotecan, cetuximab and 5FU bolus regimens are often associated with higher incidences of diarrhea(8-12). Primary colorectal

14、 cancer is an independent risk factor for CID. Other independent risk factors reported in the literature are diarrhea with chemotherapy in earlier cycles, chemotherapy in summer months(13), older age group females(14,15), dihydropyrimidine dehydrogenase (DPD) deficiency, uridine diphosphate glucoron

15、yl transferase (UGT) deficiency(16-20) and adjuvant chemotherapy as compared to palliative therapy(16). Diarrhoea can cause dehydration, electrolyte imbalance, renal impairment ,nutritional deficiency and can have negative impact on the management of cancer itself. Severe diarrhea decreases patient

16、s tolerance towards chemotherapy often resulting in dose reduction or early termination of the treatment. Increased morbidity increases the cost of care and leads to poorer clinical outcomes. Diarrhoea can be associated with chemotherapy induced neutropenia, which can be serious or even fatal. The s

17、everity of the CID is assessed by the National Cancer Institute(NCI) criteria(16).Dranitsaris and colleagues reported an incidence of 54.2% diarrhoea after the first cycle of chemotherapy in a retrospective study and this resulted in a median dose reduction by 20% and median delay in treatment by 7

18、days. 32.3% cases in this study neededhospitalization and their median length of hospital stay was 8 days （21）.卡培他濱，伊立替康，西妥昔單抗和5-氟尿喀咤推注方案通常導(dǎo)致高腹瀉率（8-12）。原發(fā)性結(jié)直腸癌是CID的獨立的危險因素。文獻報道的其他的獨立的危險因素有化療早期療程導(dǎo)致的腹瀉、夏季化療相關(guān)性 誘發(fā)腹瀉以及老年組女性（14,15）、雙氫喀咤脫氫酶（DPD）缺乏，尿甘二磷酸葡萄糖醛酸基轉(zhuǎn)移酶缺乏（UGT） （16-20）以及與姑息性治療相比較的輔助化療（16）。腹瀉會導(dǎo)致脫水、

19、電解質(zhì)失衡、腎損害、營養(yǎng)缺乏，并且對癌癥治療本身有負面影響。嚴重的腹瀉降低患者對于化療的耐受能力，從而導(dǎo)致劑量的減少和治療結(jié)束過早。發(fā)病率增加提高了治療成本，并且導(dǎo)致不良的治療結(jié)果。腹瀉可能與化療誘發(fā)的嗜中性白血球減少癥有關(guān)，可能非常嚴重甚至致命。NCI劃分了 CID的嚴重性等級。Dranitsaris及其同事在一項回溯性研究中報道， 第一個療程后腹瀉發(fā)生率為54.2%,這導(dǎo)致治療劑量平均降低 20%, 治療時間平均延長 7天。此項研究中32.3%的患者需要住院治療，并且平均住院期為8天。Fig.1.-NCI grading of diarrheaNational Cancer Institu

20、te Criteria for assessing the severity of chemotherapy-induced diarrhoeaGrades of CIDFrequency of DiarrhoeaStoma outputNeed for intravenous fluidresuscitationInterfering with dailyActivities1 4 times/dayMildNoneNone24-6 times/dayModerate 7 times/daysevere24 hrsYes4Diarrhoea resulting into life threa

21、tening consequences like haemodynamic collapse or shock.5Death due to consequences of diarrhoea表1.一美國國立癌癥研究所（NCI）腹瀉分級美國國立癌癥研究所評價化療相關(guān)性腹瀉嚴重性的標準CID等級腹瀉頻率造痿病人排泄量需要靜脈輸液復(fù)日常活動干擾蘇14次/天輕無無24-6次/天中度7次/天嚴重24小時有4腹瀉導(dǎo)致生命危險，例如血液動力學衰竭或休克5腹瀉導(dǎo)致死亡Fig2Chemotherapy-induced diarrhea in colorectal cancer in adjuvant setti

22、ngChemotherapy-induced diarrhea in colorectal cancer in adjuvant settingNoChemotherapy/RegimensIncidence of CIDNCI gradew 3Reference/Trial/Citation1FOLFOX 411%MOSAIC trial, AndreT., et al.N.Engl.J.Med.,20042FLOX38%NSABP trial,Kuebler J.P, etal,.J.Clin.Oncol.,2007Reference-(5)3CapO/OxCap11%X-ACT Tria

23、l.Twelves C.,etal.Clin.ColorectalCancer,2006 Reference-(9)4Capecitabine+Oxaliplatin(XELOXA)19%Schmoll et al.Journal ofClinical ofOncology,2007.January;25Reference-。)5Mayo Clinic Regimen(FU/LV)16%6Roswell Park Regimen(FU/LV)29%表2.一采用輔助療法的結(jié)直腸癌患者的化療相關(guān)性腹瀉采用輔助療法的結(jié)直腸癌患者的化療相關(guān)性腹瀉編R化療/方家CID發(fā)生率NCI等級w 3參考文獻/試驗

24、/弓1文1奧沙利鉗、氟尿喀咤和甲酰四氫11%MOSAIC trial, AndreT., et al.葉酸鈣方案N.Engl.J.Med.,20042FLOX38%NSABP trial,Kuebler J.P, etal,.J.Clin.Oncol.,2007Reference-(5)3CapO/OxCap11%X-ACT Trial.Twelves C.,etal.Clin.Colorectal Cancer,2006Reference-(9)4卡培他濱+奧沙利鉗(XELOXA)19%Schmoll et al.Journal of Clinical ofOncology,2007.Jan

25、uary;25(1)Reference-。)5Mayo Clinic Regimen(FU/LV)16%6Roswell Park Regimen(FU/LV)29%Fig.3. - Chemotherapy-induced diarrhea in advanced/metastatic colorectal cancerChemotherapy-induced diarrhea in advanced/metastatic colorectal cancerNo.Chemotherapy/RegimensIncidence of CIDNIC graded 3Reference/Trial/

26、Citation1Capecitabine/Oxaliplatin16%Cao Y.,et al. Journal ofColouectal Disease, 2009Reference-(11)25-FU+Oxaliplatin12.5%3OxMdG Fegimen6%Adams R.A.,et al.BritishJournal of Cancer (2009)100,251-8Reference-(12)4OxMdG+Cetuximab13%5XELOX15%6XELOX+ Cetuximab25%7FOLFIRI14%Tournigand C., et al. GERCOR study

27、. Journal of Clinical Oncology, Jan 2004,24(2)Reference-(6)8FOLFOX 611%9FOLFOX 4+Bevacizumab7.8%Emmanouilides C.,et al. BMCCancer,2007,7(91)Reference-表3.晚期/轉(zhuǎn)移性結(jié)直腸癌患者的化療相關(guān)性腹瀉晚期/轉(zhuǎn)移性結(jié)直腸癌患者化療相關(guān)性腹瀉編R化療/方家CID發(fā)生率NCI等級w 3參考文獻/試驗/引文1卡培他濱/奧沙利柏16%Cao Y.,et al. Journal ofColouectal Disease, 2009Reference-(11)25

28、-氟尿口咤+奧沙利鉗12.5%3OxMdG Fegimen6%Adams R.A.,et al.BritishJournal of Cancer (2009)100,251-8Reference-(12)4OxMdG+西妥昔單抗13%5XELOX15%6XELOX的妥昔單抗25%7氟尿喀咤、亞葉酸和伊立替康聯(lián)合用約14%Tournigand C., et al. GERCOR study. Journal of Clinical Oncology, Jan 2004,24(2)Reference-(6)8奧沙利鉗、氟尿喀咤和甲酰四氫葉酸鈣方案（FOLFOX 611%9氟尿喀咤、亞葉酸和伊立替康

29、聯(lián)合用約（FOLFOX 4 +貝伐單抗7.8%Emmanouilides C.,et al. BMCCancer,2007,7(91)Reference-Aim of the study 研究目的Octreotide has often been used to treat CID. In the absence of a fixed protocol, treatment has been purely empirical. This review article aims towards assessing the role of octreotide in CID through an

30、extensive literature search.奧曲肽經(jīng)常被用來治療CID。由于沒有固定的方案，完全是憑經(jīng)驗來進行治療。本綜述的目的在于通過全面的文獻研究來評估奧曲肽治療CID的作用。Methods and materials 方法和材料We have searched PUBMED, MEDLINE and Cochrane library for relevant published articles over the last 25years from 1984 to 2009.The phrases like octreotide CID”, colorectal cancer

31、 CID and octreotide and chemotherapy induced diarrhea in colorectal cancer and octreotide were used to search for relevant articles . We included those studies, which were published in English and where the whole cohort or at least a major proportion of it were colorectal cancer patients. We have in

32、cluded two randomized trials, four non-randomized controlled studies and two case series publications in our review.我們檢索了從1984到2009年25年間PubMed , MEDLINE和循證醫(yī)學圖書館中的有關(guān)文獻。檢索用詞有 octreotide CID 以及colorectal cancer CID and octreotide、chemotherapyinduced diarrhea in colorectal cancer and octreotide(結(jié)直腸癌患者化療

33、相關(guān)性腹瀉和奧曲肽)”。入選文獻均用英文撰寫而且樣本人群中至少大部分是結(jié)直腸癌患者。綜述包括了兩組隨機對照臨床試驗、四組非隨機對照研究和兩篇系列病例報道。The articles related to patients having chemotherapy solely for cancers other than colorectal carcinoma and solitary case reports regarding use of octretide or other modes of medications to control CID were excluded. We hav

34、e also looked at the pharmaco-economic aspects relating to octreotide, its recommended safe dose and its adverse effects in the treatment of CID only.排除了僅使用化療治療癌癥的非結(jié)直腸癌患者、使用奧曲肽治療的單個病例報告以及其他控制CID的用藥方案。本文也從藥物經(jīng)濟學的角度審視了單獨使用奧曲肽治療CID時的推薦安全劑量和副作用。Results 結(jié)果Octreotide VS other medications in CID奧曲肽和其他藥物治療 C

35、ID的對比A randomized trial (22) established the effectiveness of octreotide , against loperamide in controlling severe CID (NIC grades 2 and above) in a cohort of 41patients(68.3% colorectal cancer)(P 0.005).在41個患者的隊列研究(68.3%的結(jié)直腸癌患者)(P0.005)的隨機臨床試驗(22) 中，證明了奧曲肽相對比洛哌丁胺在控制嚴重CID (NIC級別2級和以上)的效果。Gebbia et

36、al. performed a similar randomized trial(23), where the group of patients receiving octreotide had much better results, compared to those receiving loperamide (Fig.4).Gebbia等進行了類似的隨機試驗（23）,證明患者使用奧曲肽比使用洛哌丁胺效果更好（見表4）。A prospective study (26) reporting the effects of octreotide in a cohort with opioid-

37、resistant CID, demonstrated 94% success rate with no serious side effects. Cascinu et al.(27) has reported a better success rate (96.3% complete response within 72hours of onset of treatment) with octreotide in a cohort of 27 patients (21 patients with advanced colorectal cancer and rest with advanc

38、ed pancreatic cancer). When we combined the results of all these non-randomized studies, in a cohort of 88 patients (colorectal cancer in 79 out of 88 cases) with severe CID (NCI grades 3 and above), 61 patients (69.32%) with opioids or loperamide resistant CID were treated with octreotide, which wa

39、s effective in controlling diarrhea in 54(88.52%) patients within a maximum of 4 days.在一個前瞻性研究中(26),報道了奧曲肽在治療一個對阿片樣物質(zhì)有抗藥性的CID患者隊列的有效性為94%,且沒有嚴重的副作用。Cascinu et al.(27)在一個27名患者(其中21名患者有晚期直腸癌，其余的是晚期胰腺癌)的隊列中報道了更高的有效率(在開始治療72小時完全有效率達到了96.3%)。當我們將所有的隨機研究的結(jié)果綜合起來，發(fā)現(xiàn)在一個88名嚴重CID ( NCI級別為三家或者以上)患者(79名為結(jié)直腸癌患者)的

40、 隊列中，61名患者(69.32%)為阿片樣物質(zhì)或者洛哌丁胺抵抗性CID患者使用奧曲肽，在至少4天之內(nèi)有54名患者(88.52%)有效控制腹瀉。In a prospective non-randomized study(24), colorectal cancer patients with grade 3-4, loperamide resistant CID were treated with octreotide. In this cohort, nearly 16% of patients had complete resolution of diarrhea and about 29

41、% experienced reduction of diarrhea by at least two grades. In the remaining 25% of cases, diarrhea ,was reduced by one grade.在一個前瞻性非隨機研究中(24), 3-4級、對洛哌丁胺有抗藥性的結(jié)直腸癌患者， 使用奧曲肽來治療CID=在這個隊列中，大約16%的患者的腹瀉癥狀完全消退，大約29%的患者癥狀減輕了至少兩個級別。剩下的25%的病例中，腹瀉減輕了1個級別。A similar prospective multicentre trial by Zidan et al.

42、(25) in a cohort of patients, (the majority of which were colorectal cancer patients) with severe loperamide resistant CID, octreotide was used as a failsafe and complete resolution of diarrhea was noted in 94% caseswithout any major adverse effects. This study did not specify the exact percentage o

43、fcolorectal cancer patients who were among this complete resolution group.Zidan等(25)以對洛哌丁胺有嚴重抗藥性的CID患者群(大多數(shù)為結(jié)直腸癌患者)為研究對象，進行了一個類似的前瞻性多中心試驗，將奧曲肽作為一種特效藥，發(fā)現(xiàn)94%的患者腹瀉痊愈且沒有任何嚴重副作用。 該研究沒有給出痊愈患者中直結(jié)腸癌患者的確 切百分比。A prospective study (26) reporting the effects of octreotide in a cohort with opioid-resistant CID,

44、demonstrated 94% success rate with no serious side effects. Cascinu et al.(27) has reported a better success rate (96.3% complete response within 72hours of onset of treatment) with octreotide in a cohort of 27 patients (21 patients with advanced colorectal cancer and rest with advanced pancreatic c

45、ancer). When we combined the results of all these non-randomized studies, in a cohort of 88 patients (colorectal cancer in 79 out of 88 cases) with severe CID (NCI grades 3 and above), 61 patients (69.32%) with opioids or loperamide resistant CID were treated with octreotide, which was effective in

46、controlling diarrhea in 54(88.52%) patients within a maximum of 4 days.一項前瞻性研究報道了奧曲肽對具有阿片樣物質(zhì)抗藥性的CID患者群的作用(26)證實了其治愈率為94%，且沒有嚴重副作用。Cascinu 等 (27)對27 名患者( 21 名患者為比較嚴重的結(jié)直腸癌，其余為比較嚴重的胰腺癌患者)用奧曲肽治療，獲得了更高的治愈率(在 72 小時的治療時間內(nèi)96.3%完全有效)。綜合所有這些非隨機研究的結(jié)果，在88名患有嚴重CID (NCI評級為3以上)的患者(其中結(jié)直腸癌患者為79例)中，61名具有鴉片樣物質(zhì)或洛哌丁胺抗藥性

47、的CID患者( 69.32%)使用奧曲肽治療，54名患者( 88.52%)在4 天內(nèi)腹瀉得到有效控制。Two case series publications by Rosenoff (28,29) reported successful treatment of severe CID (NCI grades 3 and above), refractory to loperamide and/or diphenoxylate atropine, by octreotide LAR(long acting release preparation). Both these publication

48、s demonstrated improvement in patient s quality of life and tolerance towards chemotherapy. No serious adverse effects were reported in either of them.Rosenoff (28,29)發(fā)表的兩個病例系列報道了使用長效奧曲肽治愈對洛哌丁胺和/或地芬諾脂阿托品有抗藥性的嚴重的CID （NCI級別3以上）患者。這兩篇論文都表明，奧提高了對化療的耐受能力， 均未報道嚴重的不良反應(yīng)。Dose of octreotide in CID治療CID時奧曲肽的劑量

49、In the absence of fixed dose related guidelines, the use of octreotide in CID has been purely empirical. The Canadian Working Group on CID has recommended that patients with grade 2 CID (NCI grading) refractory to loperamide or opioids and grade 3 or 4 CID should have octreotide at a dose of 100-150

50、 micrograms subcutaneously thrice daily. In refractory diarrhea, doses may be increased up to 500 micrograms thrice daily (16,30).由于沒有固定劑量的相關(guān)指導(dǎo)，奧曲肽治療CID完全憑經(jīng)驗。加拿大 CID工作小組對抗洛哌丁胺或鴉片的CID2級患者(NCI分級)和3或4級CID患者的推薦劑量是皮下注射奧曲肽 100-150 微克，一天三次。對頑固性腹瀉患者，劑量可以增加到 500 微克，一天 三次( 16,30 ) 。The Canadian working group

51、also recommends that octreotide LAR 30 mg (intramuscularly, once every 28 days) can be used prophylactically in any patient with colorectal cancer receiving chemotherapy who had experienced CID with the previous cycles(16).該小組還推薦使用長效奧曲肽30mg (肌肉注射，每28 天一次)對任何接受化療的在以前的療程中有CID病史的結(jié)直腸癌患者進行預(yù)防性的治療(16)。Dose

52、 efficacy of octreotide LAR ( Long acting 40 mg VS 30mg) has been assessed by Rosenoff and colleagues in a multicentre, randomized, open-label study (31). The mean duration of anti-diarrhoeal treatment was found to be shorter for octreotide. Statistical significance was reached with both these resul

53、ts (p 0.001). In this trial, although fewer patients in the 40 mg group experienced severe (grades 3-4) diarrhea and unscheduled healthcare support as compared to the 30 mg group, none of these differences were statistically significant.Rosenoff 及其同事在一項多中心隨機標簽公開的研究中已對長效奧曲肽(長效40mg 對比30mg)的劑量效果進行了評價(3

54、1),發(fā)現(xiàn)奧曲肽組治療腹瀉所需的平均時間周期更 短。兩項結(jié)果都具有顯著的統(tǒng)計學意義 (pv 0.001)。在該項試驗中，盡管相對于30mg組， 40mg 組患有嚴重腹瀉(3 4 級)癥狀和得到額外健康護理支持的患者均少，這些差別沒有顯著的統(tǒng)計學意義。But this trial introduced the possibility of secondary prevention of CID by octreotide.Octreotide has a positive dose- response effect in CID, as shown by Goumas et al. in a r

55、andomized study, where patients with severe, loperamide resistant, CID were treated by thrice daily doses of either 100ug or 500ug of (subcutaneous) octreotide. Complete resolution was reported in 90.32% patients in the 500-microgram arm as compared to 60.71% in the 100-microgram arm (p0.05) (30). I

56、n a phase I trial performed to demonstrate the safe dose of octreotide in fluoropyrimidine-induced diarrhea in 35 patients, the maximum tolerated dose was found to be 2000 micrograms (subcutaneous) thrice daily (32).但是這個試驗提出了奧曲肽對于CID二級預(yù)防的可能性。正如 Goumas等指出，奧曲肽對CID患者具有正性的劑量響應(yīng)效果。在一項隨機研究中，每天三次100ug或500ug

57、奧曲肽(皮下注射)治療嚴重的、對洛哌丁胺抗藥患者的CID。結(jié)果顯示，500mg劑量組患者的治愈率為 90.32%, 100mg患者組的治愈率為60.71%(pv0.05) (30)。在35名患者參加的 I 期臨床試驗中證明奧曲肽治療氟嘧啶誘導(dǎo)的腹瀉的安全劑量，發(fā)現(xiàn)最大耐量是 每天三次 2000mg (皮下注射) ( 32) 。Adverse effects related to the use of octreotide in CID 治療 CID時奧曲肽的副作用An extensive literature search has revealed that octreotide is saf

58、e, well-tolerated drug and effective with minimal adverse effects within the therapeutic range when used in CID (26,32)(Fig.5). Local pain at the injection site was reported by Gebbia et al.(23) and Barbounis et al.(24)(incidences of 15% and 38%) in their respective studies. But none of these were s

59、evere enough for cessation of therapy. Local pain was short lived and no longer than 15 minutes. This can be avoided if the vial is warmed prior to drug administration(33).大量的文獻檢索結(jié)果顯示，奧曲肽是安全和耐受良好的藥物，在有效濃度范圍內(nèi)治療CID有效而且副作用極少 (26,32)(圖5.)。Gebbia等(23)和Barbounis等(24)在其各自的 研究中提到了注射部位的局部疼痛(發(fā)生率分別為15%和 38%) 。

60、但這些副作用都未嚴重到中止治療。局部疼痛的時間短暫，不超過15 分鐘。而且在注射之前將安瓶加熱即可以避免(33 ) 。Symptoms like increased diarrhea or looseness of stools, vitamin B12 deficiency andpotential risk of gallstone formation (12-60%) are associated with long-term octreotide use in CID, because of the short duration of therapy in the latter.長期使