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研究生:凌家珊
研究生(外文):KAR-SAN LING
論文名稱:血管收縮素轉換酶阻斷劑和其他抗高血壓藥物引發咳嗽副作用的比較
論文名稱(外文):Association between cough and Angiotensin converting enzyme inhibitor versus
指導教授:林中生林中生引用關係
指導教授(外文):Chung-Sheng Lin, M.D., Ph.D.
學位類別:碩士
校院名稱:中山醫學院
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:27
中文關鍵詞:血管收縮素轉換酶阻斷劑血管收縮素-II接受器阻斷劑咳嗽
外文關鍵詞:Angiotensin converting enzyme inhibitorangiotensin-II receptor antagonistcough
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背景 :
有顯著數量的病人在使用血管收縮素轉換酶阻斷劑 (Angiotensin converting enzyme inhibitors, ACEI) 後, 引發無法解釋的、且持續性咳嗽的副作用, 這惱人的副作用也限制了血管收縮素轉換酶阻斷劑 (ACEI) 的使用。 血管收縮素轉換酶阻斷劑 (ACEI) 引發咳嗽副作用的機制可能跟抑制激呔素-II (Kininase-II) 的活性有關, 因抑制了激呔素-II (Kininase-II) 的活性, 將會使激呔 (Kinins), 物質-P (Substance-P) 和前列腺素 (Prostaglandins) 的累積, 而這些累積的物質將引發咳嗽的副作用。 新發展出來的選擇性血管收縮素-II接受器阻斷劑 (Selective angiotensin-II receptor antagonist, AII blockers) 雖然和血管收縮素轉換酶阻斷劑 (ACEI) 同樣作用在腎活素-血管收縮素系統 (Renin-angiotensin system), 但不影響緩激呔系統 (Bradykinin system), 故理論上應不會有咳嗽的副作用。 所以, 我們設計本研究, 以評估血管收縮素-II接受器阻斷劑 (AII blockers) 與其他傳統抗高血壓藥物發生咳嗽的比率作比較。
目的 :
為探討作用於同樣腎活素-血管收縮素系統 (Renin-angiotensin system, RAS) 的血管收縮素-II接受器阻斷劑 (AII blockers) 是否有類似血管收縮素轉換酶阻斷劑 (ACEI) 的咳嗽副作用。 我們比較血管收縮素-II接受器阻斷劑 (AII blockers) 與其他非作用於腎活素-血管收縮素系統 (RAS) 的抗高血壓藥物產生咳嗽副作用的比較。
研究設計及方法 :
有63 位因服用血管收縮素轉換酶阻斷劑 (Angiotensin converting enzyme inhibitors, ACEI) 引發咳嗽副作用的病人, 被隨機分配在兩組使用不同藥物治療的組別, 分別為同樣作用在腎活素-血管收縮素系統 (Renin-angiotensin system, RAS) 的血管收縮素-II 接受器阻斷劑 (Angiotensin-II receptor antagonist agents, Valsartan or Losartan) 或 其他非作用於腎活素-血管收縮素系統 (RAS) 的抗高血壓藥物, 如鈣離子阻斷劑 (Calcium channel antagonist agents), 貝他-腎上腺素阻斷劑 (Beta-adrenergic antagonist agents) 及利尿劑 (Diuretic agents), 以比較兩組病人咳嗽的發生率。 並使用 Fisher’s exact test 來計算兩組病人咳嗽的發生率, 以及使用百分比來表示當服用血管收縮素轉換酶阻斷劑 (ACEI) 引發咳嗽副作用的病人在轉換服用其他抗高血壓藥物後的咳嗽發生率。
結論 :
新發展出來的選擇性血管收縮素-II接受器阻斷劑 (Selective angiotensin-II receptor antagonist agents, AII blockers), 雖然和血管收縮素轉換酶阻斷劑 (Angiotensin converting enzyme inhibitors, ACEI) 同樣作用於腎活素-血管收縮素系統 (Renin-angiotensin system, RAS) 上, 但選擇性血管收縮素-II 接受器阻斷劑 (AII blockers) 比較不會產生像血管收縮素轉換酶阻斷劑所引發的咳嗽副作用 (ACE inhibitor-induced cough)。 另外, 選擇性血管收縮素-II接受器阻斷劑 (AII blockers) 和其他抗高血壓藥物, 如鈣離子阻斷劑 (Calcium channel antagonist agents), 貝他-腎上腺素阻斷劑 (Beta-adrenergic antagonist agents) 及利尿劑 (Diuretic agents)一樣沒有咳嗽的副作用。

Objectives : Unexplained persistent cough limits the use of angiotensin-converting enzyme (ACE) inhibitors in a significant number of patients. The mechanisms underlying ACE inhibitor-induced cough are probably linked to suppression of kininase-II activity, which may be followed by an accumulation of kinins, substances P and Prostaglandins. The other type of anti-hypertension agents, especially the selective angiotensin-II receptor antagonist agents are not expected to influence other systems (kinin, prostaglandins) affected by ACE inhibitors. We explored the hypothesis that antihypertensive therapy with selective angiotensin-II receptor antagonist agents will not be associated with cough at a similar frequency or quality to that seen angiotensin converting enzyme inhibitor agents (ACEI).
Design and methods : Sixty three hypertensive patients with a history of cough on any angiotensin converting enzyme inhibitor were recruited into a randomly allocated, to be treated with angiotensin-II receptor antagonist agents (Valsartan or Losartan) or non-angiotensin-II receptor antagonist agents (Calcium channel antagonist agents, beta-adrenergic antagonist agents and diuretic agents). The presence of a dry, persistent cough, was determined using a symtoms questionnaire at each visit after enrollment. The patient had to respond ‘Yes’ or ‘No’ to the general question: ‘Have you felt any kind of discomfort during the past week?’, and if ‘Yes’, describe ‘what kind of discomfort’ they felt. The patients who responded positively (An ACE inhibitor-induced cough was defined as a nonproductive cough that persisted for at least 3 consecutive day and for which no other etiology could be determined) were considered coughers.
Conclusions : Dry cough is now recognized as a side effect of ACE inhibitors therapy. When this cough becomes bothersome, there is no better alternative than substituting a different class of antihypertensive agents for the offending ACE inhibitors. The selective angiotensin-II receptor antagonist agents (AII blockers) selectively block the AT1-receptor subtype, and do not affect the metabolism of other ACE substrates such as bradykinin and substance P. Both bradykinin and substance P may be involved in the development of ACE inhibitor-induced cough. The antihypertensive efficacy of an AII blocker is similar to that of the ACE inhibitors, but AII blockers offer the distinct advantage of a decreased incidence of cough. AII blockers represent useful alternatives to ACE inhibitors for the treatment of hypertension, particularly in patients who have experienced cough while taking ACE inhibitors.

中文摘要--------------------------------------I~IV
英文摘要------------------------------------V~VII
壹、 緒論---------------------------------------1~6
一、 前言---------------------------------------1
二、 血管收縮素轉換酶阻斷劑 (Angiotensin converting enzyme inhibitors, ACEI)----------------------2~4
三、 血管收縮素-II接受器阻斷劑 (Angiotensin-II receptor antagonists, AII blockers)---------------------------5~6
貳、 研究目的------------------------------------7
參、 材料與方法-----------------------------8~11
一、 研究對象---------------------------------8
二、 研究設計----------------------------9~10
三、 統計方法---------------------------10~11
肆、 研究結果------------------------------11~17
伍、 討論------------------------------------18~22
陸、 總結------------------------------------23~24
柒、 參考文獻------------------------------25~27

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3. Robert Y.L. Zee, V.S. Rao, Robert Z, et al. Three candidate genes and angiotensin-converting enzyme inhibitor-related cough. Hypertension 1998; 31: 925-928.
4. N.R. Levens, M.D. Gasparo, Jeanette M., et al. Could the pharmacological differences observed between angiotensin II antagonists and inhibitors of angiotensin converting enzyme be clinically beneficial? Pharmacol Toxicol 1992; 71: 241-249.
5. Y Lacourciere, J Lefebvre, G Nakhle, et al. Association between cough and angiotensin converting enzyme inhibitors versus angiotensin II antagonists. J Hypertens 1994; 12 (2): S49-S53.
6. LE Ramsay and WW Yeo. ACE inhibitors, angiotensin II antagonists and cough.. J Hum Hypertens 1995; 9(5): S51-S54.
7. J Benz, C Oshrain, D Henry, et al. Valsartan, a new angiotensin II receptor antagonist: A double-blind study comparing the incidence of cough with Lisinopril and Hydrochlorothiazide. J Clin Pharmacol 1997; 37: 101-107.
8. Ilkka Tikkanen, Per Omvik and Henrik AE. Jensen. Comparison of the angiotensin II antagonist losartan with the angiotension converting enzyme inhibitor enalapril in patients with essential hypertension. J Hypertens 1995; 13: 1343-1351.
9. WJ Elliott. Double-blind comparison of eprosartan and enalapril on cough and blood pressure in unselected hypertensive patients. J Hum Hypertens 1999; 13: 413-417.
10. Allan l. Goldberg, Mary C, Dunlay, et al. Safely and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension. Am. J. Cardiol. 1995; 75(15): 793-796.
11. F.J. Mackay, G.L. Pearce & R.D. Mann. Cough and angiotensin II receptor antagonists: cause or confunding? J Clin Pharmacol 1999; 47: 111-114.
12. Bonn, Germany. ACE Inhibitor-induced cough and bronchospasm. Drug safely 1996; 15(1): 72-78.
13. Faison EP, Nelson EB, Irvin JD. Profile of angiotensin converting enzyme inhibitor associated with cough: incidence and clinical characteristics. Am. J. Hypertens 1991; 4(suppl): 28A.
14. Morice AH, Lowry R, Brown MJ, et al. Angiotensin-converting enzyme and the cough reflex. Lancet 1987; ii: 1116-1118.
15. Tikkanen I, Omvik P, Jensen HE. Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patient with essential hypertension. J hypertens 1995; 13: 1342-1351.
16. Messerli FH, Weber MA, Brunner HR. Angiotensin II receptor inhibition. A new therapeutic principle. Arch Intern Med 1996; 156: 1957-1965.
17. Chan P et al. Double blind comparison of losartan, lisinopril, and metolazone in elderly hypertensive patients with previous angiotensin-converting enzyme inhibitor-induced cough. J Clin Pharmacol 1997; 37: 253-257.
18. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. Ann Intern Med 1992; 117: 234-242.

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