胡 鐘,張 華,朱文莉,王 利,張榮嘎,周名磊,王 進
(安徽省馬鞍山十七冶醫(yī)院,安徽 馬鞍山 243000)
氟康唑為三唑類廣譜抗真菌藥,通過抑制真菌細胞P450酶來降低麥角固醇的合成,造成真菌細胞膜的缺損,通透性增加,從而抑制真菌的繁殖和生長[1],生物利用度高、半衰期長、水溶性好,可口服和靜脈給藥,廣泛用于治療淺表性和深部真菌感染,對全身性念珠菌病、隱球菌病、各種真菌引起的腦膜炎及艾滋病患者口腔、消化道念珠菌病等都均較好的抗菌作用[2]。近年,我國念珠菌血癥發(fā)病率明顯升高[3],氟康唑的使用也愈發(fā)廣泛,國內(nèi)外陸續(xù)有氟康唑相關(guān)不良反應(yīng)(ADR)的報道,筆者對氟康唑上市以來致ADR個案報道進行統(tǒng)計與分析,以期為臨床安全用藥提供參考?,F(xiàn)報道如下。
計算機檢索Elsevier數(shù)據(jù)庫、Springer Link、Ovid高影響因子核心藥學(xué)電子期刊全集、中國學(xué)術(shù)期刊全文數(shù)據(jù)庫(CNKI)和維普中文科技期刊數(shù)據(jù)庫,檢索文獻時間為1990年1月至2017年6月。中文檢索關(guān)鍵詞為“氟康唑”“不良反應(yīng)”“案例報道”;英文檢索關(guān)鍵詞為“fluconazole”“adverse reaction”“case report”,收集國內(nèi)外公開發(fā)表的醫(yī)藥期刊上關(guān)于氟康唑的ADR個案報道,逐篇查閱,剔除重復(fù)報道,得到符合條件的個案報道63篇,其中國內(nèi)11篇,國外52篇。采用回顧性研究方法,詳細閱讀63篇個案報道,對相關(guān)信息(包括患者性別、年齡、合并基礎(chǔ)疾病、聯(lián)合用藥及ADR發(fā)生的時間、臨床表現(xiàn)等)進行統(tǒng)計與分析。
63 例患者中,男 33 例(52.38%),女 30 例(47.62%);平均年齡46.55歲,最小為新生兒,最大89歲。詳見表1。
表1 患者性別與年齡分布
63例患者中,提示合并其他基礎(chǔ)疾病37例,其中糖尿病6例,艾滋病6例,器官移植5例,腫瘤4例,高脂血癥2例,精神異常2例,肝炎1例,肝硬化2例,肝性腦病1例,心臟系統(tǒng)疾病2例,腦梗死2例,高血壓2例,胃腸道出血史1例,肺源性心臟病1例。聯(lián)合應(yīng)用藥物有調(diào)血脂藥物辛伐他汀和阿托伐他汀,降糖藥物格列吡嗪,降壓藥物硝苯地平,免疫抑制劑西羅莫司、他克莫司和環(huán)孢素,其他藥物如呋喃妥因、地氯雷他定和秋水仙堿等。納入ADRs有18例明確指出ADR的發(fā)生與藥物相互作用有關(guān)。
氟康唑誘發(fā)ADR以皮膚及皮下組織疾病、肝膽系統(tǒng)和心臟疾病為主,ADR累及系統(tǒng)/器官及臨床表現(xiàn)見表2。
表2 ADR累及系統(tǒng)/器官及臨床表現(xiàn)(n=63)
63例ADR患者中,53例藥物減量或停用后癥狀好轉(zhuǎn)或消失,1例致死性尖端扭轉(zhuǎn)型室性心臟病,1例老年患者致死性肝壞死,1例致高鉀血癥心肺呼吸停止,1例芬太尼伴氟康唑相互作用致呼吸和循環(huán)衰竭,1例阿托伐他汀伴氟康唑相互作用致老年患者橫紋肌溶解癥和多器官功能衰竭,其余4例死亡病例與氟康唑無直接因果關(guān)系。
目前,氟康唑上市近30年,有關(guān)引起ADR公開發(fā)表的個案報道中,皮膚及皮下組織疾病最多見,其中罕見不良反應(yīng)包括Stevens-Johnson綜合征、中毒性表皮壞死松解、皮疹和面部水腫、重癥剝脫性皮炎和鱗狀皮膚綜合征。黑甲為新的嚴(yán)重ADR,在氟康唑藥品說明書中未提及,該患者在用氟康唑治療甲癬后發(fā)展為黑甲,在患病指甲中產(chǎn)生縱向色素帶,其他正常指甲并未出現(xiàn),停藥3個月后逐漸減退、消失。
氟康唑致肝膽系統(tǒng)損害共10例(15.87%),其中罕見不良反應(yīng)8例(80.00%,包括3例罕見性致死性病例、1例肝毒性、1例肝功能障礙加重、1例藥物性肝炎和2例肝損害)。本研究中,1例罕見老年患者致命性肝壞死尸檢分析發(fā)現(xiàn)大量肝細胞變性壞死伴有單核淋巴細胞浸潤和重度膽汁淤積,血清肝轉(zhuǎn)氨酶急劇增加與氟康唑劑量呈正相關(guān),故醫(yī)務(wù)人員在對老年人基礎(chǔ)疾病的進行藥物治療時更應(yīng)重視ADR的觀察監(jiān)測。
氟康唑致心臟疾病共8例(12.70%),其中罕見不良反應(yīng)7例,包括1例QT間期延長和室性心動過速、5例尖端扭轉(zhuǎn)型室性心臟病、1例QT間期綜合征。1例室性心律失常和心臟驟停為新的嚴(yán)重ADRs,在氟康唑藥品說明書中未提及,該患者用藥22 h后出現(xiàn)心臟室性異位、尖端扭轉(zhuǎn)型室性心動過速(TDP)和多次心臟驟停,隨后用兩性霉素B替代氟康唑后,在隨后的24 h內(nèi),癥狀得到明顯改善。此外,氟康唑引起的嚴(yán)重低鈉血癥、血尿、聽力損傷、膜性腎病、腎上腺功能不全、全身性膿皰瘡和呼吸困難均為新的ADRs,雖然發(fā)生率低,但也需要引起重視。
本研究中納入ADR有18例明確指出ADRs的發(fā)生與藥物相互作用有關(guān),其中說明書中涉及的藥物12例,包括調(diào)血脂藥(3例橫紋肌溶解癥)、他克莫司(1例谷氨酸轉(zhuǎn)氨酶升高和1例腎臟損傷)、環(huán)孢素(2例腎臟損傷)、西羅莫司(1例高鉀血癥)、華法林(1例胃腸道出血)、硝苯地平(1例血壓升高)、潑尼松(1例腎上腺功能不全)和芬太尼(1例呼吸循環(huán)衰竭)。藥品說明書中未涉及的藥物6例,包括格列吡嗪(1例低血糖昏迷)、地氯雷他定(1例肝毒性)、呋喃妥因(1例肺纖維化和肝損害)、左氧氟沙星(1例尖端扭轉(zhuǎn)型室性心臟?。?、秋水仙堿(1例神經(jīng)肌肉毒性)和氯氮平(1例氯氮平毒性)。
綜上所述,氟康唑所致ADR涉及到全身多個器官和系統(tǒng),且嚴(yán)重和新的ADR并不少見,相關(guān)醫(yī)務(wù)人員要加強認識,在臨床合理使用氟康唑的同時,還應(yīng)警惕氟康唑的ADR,并關(guān)注藥物的相互作用,加強監(jiān)測,減少ADR的發(fā)生,保障臨床用藥安全有效。
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