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阿利吉崙(絡舒樂適®)

Aliskiren (Rasilez ®)

摘要


腎素-血管收縮素-皮質醛固酮系統為人體高血壓形成的一個重要的生物機轉,腎素將血管收縮素原轉化為血管收縮素Ⅰ,再由血管收縮素轉換酵素轉化血管收縮素Ⅰ成為血管收縮素Ⅱ。腎素、血管收縮素原、及血管收縮素Ⅰ並沒有血管收縮作用,但是血管收縮素Ⅱ擁有強力血管收縮的能力及促進皮質醛固酮釋放。在高血壓治療之藥品工業發展上,血管收縮素轉換酵素抑制劑初被使用,後來成功研發出血管收縮素接受體阻斷劑,確實帶來降低血壓、回歸心臟肥大、減少心血管疾病之利益。然而,由於血管收縮素Ⅱ可由其他途徑生成及血管收縮素接受體種類多樣性,發展腎素抑制劑為最理想之方向。在早期曾研發出腎素抑制劑,功能卻不理想。阿利吉崙是第一個直接作用在腎素的非肽胜抑制劑,它可以在腎素上之遠脂性S1/S3囊,結合腎素S33p,改變腎素構造進而抑制其功能,是其他肽胜腎素抑制劑所沒有之功能。當腎素被阿利吉崙結合後其即被抑制,無法轉化血管收縮素原。阿利吉崙對腎素是一個競爭型抑制劑,結合腎素之力度是其他阿斯巴肽胜酶的10,000倍。阿利吉崙主要經由肝膽吸收,它在口服後1至3小時後血中濃度即可達到最高濃度,血漿蛋白結合率為47%-51%。阿利吉崙在人體內於口服後,約有81%並沒有被代謝由肝膽腸道被排除在體內,腎臟約只有排出1%以下。其他經由肝臟代謝的部份,重要途徑為經由細胞色素P450同種酵素CYP3A4所催化。直至目前,阿利吉崙在肝或腎功能異常病人使用時並無建議調整藥量之必要,對老人、女性或不同種族人士之降血壓功能上亦無明顯差別。阿利吉崙初步被認為有心管血管及腎臟保護功能,但是對於腻部並不清楚。其副作用類似血管收縮素轉換酵素抑制劑及血管收縮素接受體阻斷劑,例如腸胃不適、皮疹、咳嗽、血管性水腫等,大致上其安全性和耐受性高。臨床上建議劑量為每日一次服用150毫克,視需要再調整至300毫克,人體試驗上至600毫克時其效果較300毫克相差不多。除了單方治療外,阿利吉崙亦有作複方治療之研究,初期結果顯示有加乘作用,需要更多結果來證實其安全性。在臺灣,應該在上市後監視其不良事件,確定對國民之有效性及安全性。

並列摘要


The renin-angiotensin-aldosterone system has been established for its essential role of hypertension in human body. Renin converts angiotensinogen into angiotensin Ⅰ, which is further into angiotensin Ⅱ by the angiotensin converting enzyme. Renin, angiotensinogen, and angiotensin Ⅰ do not possess vasoconstricting property, but angiotensin Ⅱ can powerfully constrict artery and enhance aldosterone release. In pharmacopeutical industry, angiotensin converting enzyme inhibitor and angiotensin receptor blocker are subsequently developed. Indeed, they effectively reduce blood pressure, regress heart failure, and decrease cardiovascular mortality. As angiotensin can be produced through alternative pathway and different angiotensin receptors are discovered, a development of renin inhibitor is the most ideal agent. In earlier, a few peptidergic renin inhibitors have been developed but their pharmacological efficiency is not satisfied. Aliskiren (Rasilez ®) is the first direct, nonpeptidergic, renin inhibitor. It mainly targets to the hydrophobic S1/S3 pocket of renin and competitively binds with S33p. After binding, the biological activity of renin is rapidly suppressed. The binding capacity of aliskiren is 10, 000-fold more potent than other peptidergic renin inhibitor. Aliskiren is chiefly absorbed by hepatobiliary tract, reaches the maximal concentration in blood 1 to 3 hours after oral administration, and binds with proteins in 47% to 51%. In body, 81% of aliskiren is excreted through fecal route without change. Renal excretion constitutes less than 1%. The CYP3A4 of cytochrome P450 can metabolize other aliskiren. Until now, aliskiren is considered a safe and tolerable drug. The dosage is not needed to adjust in hepatic or renal impairment patient. The antihypertensive effect does not differ in elderly, female gender, or different racial groups. Whereas aliskiren is thought to have cardiovascular and renal protection, the role of brain protection is unknown. The side effect of aliskiren is similar to angiotensin converting enzyme inhibitor and angiotensin receptor blocker, such as alimentary tract discomfort, rash, cough, angioedema and others. Clinically, aliskiren is recommended 150 mg in once single dose, and increases to 300 mg in once single dose according to therapeutic effect. The antihypertensive effect does not differ between 150 mg and 300 mg of aliskiren. Besides of monotherapy, aliskiren has been tested in combination therapy. A synergic effect is found in a few studies but further study is warranted for conclusion. In order to elucidate the effectiveness and safety in our society, a close monitor of adverse event should be done.

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