水飞蓟宾胶囊联合多烯磷脂酰胆碱治疗抗结核药物所致药物性肝损伤患者疗效研究.pdf

基金项目:海南省自然科学基金面上项目(编号:818MS163)作者单位:570103 海口市 海南省第五人民医院药剂科(莫俊俏);制剂科(林景);海南医学院第二附属医院药学部(羊莉)第一作者:莫俊俏,女,34 岁,大学本科,主管药师。E-mail:药物性肝损伤水飞蓟宾胶囊联合多烯磷脂酰胆碱治疗抗结核药物所致药物性肝损伤患者疗效研究莫俊俏,林 景,羊 莉【摘要】目的 观察应用水飞蓟宾胶囊联合多烯磷脂酰胆碱治疗抗结核药物所致药物性肝损伤(DILI)患者的疗效。方法 2018 年 6 月 2021 年 6 月我院收治的 118 例肺结核患者,经标准抗痨治疗后,发生 DILI 者 63 例,采用随机数字表法将其分为对照组 30 例和观察组 33 例,在继续抗痨的基础上,在对照组给予多烯磷脂酰胆碱治疗,在观察组给予多烯磷脂酰胆碱联合水飞蓟宾胶囊治疗,两组均护肝治疗至抗痨结束。采用 ELISA 法检测血清白介素 2(IL-2)、IL-6、IL-1 和肿瘤坏死因子-(TNF-)水平,采用放射免疫法检测血清超氧化物歧化酶(SOD)水平,采用生化比色法检测血清还原型谷胱甘肽(GSH)和丙二醛(MDA)水平。结果 在治疗后,观察组血清 ALT、AST 和 GGT 水平分别为(32.86.1)U/L、(41.28.3)U/L 和(36.16.5)U/L,显著低于对照组【分别为(48.68.4)U/L、(53.89.2)U/L 和(53.89.6)U/L,P0.05】;观察组血清 IL-6、IL-1 和 TNF-水平为(6.31.0)ng/L、(11.02.3)g/L 和(6.81.5)ng/L,均显著低于对照组【分别为(9.51.2)ng/L、(19.23.6)g/L 和(9.91.3)ng/L,P0.05);观察组血清 SOD 和 GSH 水平分别为(597.371.6)U/L 和(7.61.5)mol/L,显著高于对照组【分别为(542.868.2)U/L 和(6.21.3)mol/L,P0.05】,而血清 MDA 水平为(4.00.7)nmol/L,显著低于对照组【(5.80.9)nmol/L,P0.05】。结论 应用水飞蓟宾胶囊联合多烯磷脂酰胆碱治疗抗结核药物所致的 DILI 患者能很好地保护肝功能,维持抗痨治疗,可能与减轻了炎症和氧化应激反应有关。【关键词】药物性肝损伤;抗结核药物;水飞蓟宾;多烯磷脂酰胆碱;治疗 DOI:10.3969/j.issn.1672-5069.2023.05.016 Improvement of liver function tests by silibinin and polyene phosphatidylcholine combination therapy in patients with anti-tuberculosis drugs-induced liver injury Mo Junqiao,Lin Jing,Yang Li.Department of Pharmacy,Fifth Peoples Hospital,Haikou 570103,Hainan Province,China【Abstract】ObjectiveThe aim of this study was to observe the efficacy of silibinin and polyene phosphatidylcholinecombination therapy in patients with anti-tuberculosis drugs-induced liver injury(DILI).Methods 118 patients with pulmonarytuberculosis were encountered in our hospital between June 2018 and June 2021,and all received standardized anti-tuberculosistreatment by 2HRS(E)Z/4HR for six months.During the process,63 patients were found having DILI,and were randomlydivided into control(n=30)and observation(n=33)groups,receiving polyene phosphatidylcholine or silibinin capsule andpolyene phosphatidylcholine combination therapy until the anti-tuberculosis regimen ended.Serum interleukin-2(IL-2),IL-6,IL-1 and tumor necrosis factor-(TNF-)levels were detected by ELISA,serum superoxide dismutase(SOD)was detected byradioimmunoassay and serum reduced glutathione(GSH)and malondialdehyde(MDA)levels were assayed by biochemicalcolorimetry.Results After treatment,serum ALT,AST and GGT levels in the observation group were(32.86.1)U/L,(41.28.3)U/L and(36.16.5)U/L,all significantly lower than(48.68.4)U/L,(53.89.2)U/L and(53.89.6)U/L,respectively,P0.05 in the control;serum IL-6,IL-1 and TNF-levels in the observation were(6.31.0)ng/L,(11.02.3)g/L and(6.81.5)ng/L,all much lower than(9.51.2)ng/L,(19.23.6)g/L and(9.91.3)ng/L,respectively,P0.05);serumSOD and GSH levels in the observation group were(597.371.6)U/L and(7.61.5)mol/L,both significantly higher than(542.868.2)U/L and(6.2 1.3)mol/L,P0.05,while serum MDA level was(4.00.7)nmol/L,much lowerthan(5.80.9)nmol/L,P0.05),具有可比性。在对照组,给予多烯磷脂酰胆碱赛诺菲(北京)制药有限公司,国药准字H20059010456 mg 口服,2 次/d;在观察组,在同上服用多烯磷脂酰胆碱的同时,给予水飞蓟宾胶囊(天津天士力圣特制药有限公司,国药准字 H20040299)140 mg 口服,2 次/d。两组均连续用药至抗结核治疗结束。1.3 指标检测 使用山东博科医疗器械有限公司提供的全自动生化分析仪检测血生化指标;采用ELISA 法检测血清白介素 2(interleukin 2,IL-2)、IL-6、IL-1 和肿瘤坏死因子(tumor necrosis factor,TNF-)水平(艾迪康生物科技有限公司);采用放射免疫法检测血清超氧化物歧化酶(superoxidedismutase,SOD)水平(上海恒远生物科技有限公司);采用生化比色法检测血清还原型谷胱甘肽(glu-tathione,GSH)和丙二醛(malondialdehyde,MDA)水平(上海极威生物科技有限公司)。1.4 统计学方法应用 SPSS Statistics 21.0 软件行统计学分析,对正态分布的计量资料以(xs)表示,采用 t 检验。计数资料以%表示,采用 x2检验。P0.05 表示差异有统计学意义。2 结果2.1 两组肝功能指标变化的比较 治疗后,观察组血清 ALT、AST 和 GGT 水平显著低于对照组(P0.05,表 1)。2.2 两组血清细胞因子水平比较 治疗后,观察组血清 IL-6、IL-1 和 TNF-水平显著低于对照组(P0.05,表 2)。2.3 两组血清氧化应激指标水平比较 治疗后,观察组血清 SOD 和 GSH 水平显著高于对照组,而血清MDA 水平显著低于对照组(P0.05,表 3)。2.4 转归情况 在本组 188 例肺结核患者中,经过半年抗痨治疗,125 例患者治愈;在并发 DILI 患者,大多经护肝和继续抗结核治疗,也获得病愈,5 例患者因肝损伤严重而停止抗结核治疗,经综合护肝治疗,病情稳定后继续抗痨治疗,在治疗8 个月时也获得治愈。766实用肝脏病杂志 2023 年 9 月第 26 卷第 5 期 J Prac Hepatol,September.2023.Vol.26 No.5表 1 两组肝功能指标(xs)比较例数ALT(U/L)AST(U/L)TBIL(mol/L)GGT(U/L)观察组治疗前33147.325.4135.723.620.43.893.813.6治疗后3332.86.141.28.312.33.236.16.5对照组治疗前30145.723.8131.921.519.63.490.511.7治疗后3048.68.453.89.213.54.153.89.6 与对照组比,P0.05表 2 两组血清细胞因子水平(xs)比较例数IL-2(ng/L)IL-6(ng/L)IL-1(g/L)TNF-(ng/L)观察组治疗前3352.38.620.43.659.310.414.92.8治疗后3330.55.86.31.011.02.36.81.5对照组治疗前3050.99.319.53.856.89.714.32.6治疗后3028.76.49.51.219.23.69.91.3 与对照组比,P0.05表 3 两组血清氧化应激指标水平(xs)比较例数SOD(U/L)MDA(nmol/L)GSH(mol/L)观察组治疗前33326.847.27.91.35.31.1治疗后33597.371.64.00.77.61.5对照组治疗前30329.549.37.51.65.51.0治疗后30542.868.25.80.96.21.3 与对照组比,P0.053 讨论当前,临床尚未完全明确抗结核药物引起肝损伤的具体机制。一般认为与药物毒性反应及机体过敏反应作用存在密切的联系8-10。选择合适、快速、安全并且有效的护肝药物能减轻药物所致的肝损伤。多烯磷脂酰胆碱为现今治疗 DILI 的主要选择药物,该药可以结合并有效修复肝细胞膜,增加肝细胞结构和功能的稳定性,保护肝功能,已经得到临床广泛的认可11。尽管应用多烯磷脂酰胆碱能够恢复大多数患者的肝功能指标,然而其单独应用效果并未达到人们理想的水平。水飞蓟宾可发挥抗脂质氧化作用,同时还能加快细胞 DNA 和结构蛋白的合成,具有保护肝细胞作用12,13。以往研究表明,在多烯磷脂酰胆碱治疗的同时予以水飞蓟宾胶囊能够获得更好的肝功能保护效果14。本研究发现,经过治疗,观察组血清 ALT、AST 和 GGT 水平均较对照组显著降低,与上述研究结果相符,提示水飞蓟宾胶囊联合多烯磷脂酰胆碱可发挥较佳的肝功能修复作用。水飞蓟宾可以稳定肝细胞膜,并对肝细胞酶系统产生保护作用,有效清除肝细胞内多余的氧自由基,增强肝脏解毒功能15。水飞蓟宾能够清除异烟肼相关代谢产物增加的氧自由基,抑制利福平诱导 P450酶生成过程或在异烟肼治疗过程中有毒代谢产物的形成,利用“膜效应”抑制利福平药物结合 P450 酶受体,下调 P450 酶的表达,降低异烟肼代谢速率,有效减少患者体内肝毒性代谢产物,达到减少对肝组织毒副作用的目的。水飞蓟宾胶囊与多烯磷脂酰胆碱联合应用,在保护肝功能方面可起到协同作用。以往研究指出,抗结核药物所致的肝损伤患者肝细胞损伤和体内炎症反应激活引起细胞因子大量分泌有关16,17。在 DILI 发生时,肝脏残留药物能够引起特异性免疫应答,激发炎症反应,导致单核细胞合成促炎因子增多,比如 TNF-、IL-6 和 IL-1 等18-20。本研究治疗后观察组血清 IL-6、IL-1 和 TNF-水平均较对照组显著降低,提示该联合用药方案能够有效减轻机体的炎症状态,可能与水飞蓟宾能阻止Wnt/-catenin 通路激活,降低炎症介质释放的作用有关21。也有报道称,肝脏局部产生氧化应激反应属于抗结核药物引起肝损伤时主要的病理学变化。随着抗结核药物大量聚集于肝细胞中,线粒体功能受到损害,导致氧化呼吸链电子出现传递障碍,形成氧化性剧烈活性氧,最终损害肝细胞22,23。人体抗氧化系统主要包括 GSH 和 SOD 等物质,其中 GSH可以清除体内过多的氧自由基,至于 SOD,则可维持氧化还原状态24。研究认为,氧自由基能够对多不饱和脂肪酸产生刺激作用,形成 MDA 代谢物,通过检测血清 MDA 水平,能够反映机体的氧化应激状866实用肝脏病杂志 2023 年 9 月第 26 卷第 5 期 J Prac Hepatol,September.2023.Vol.26 No.5态25。当发生 DILI 时,大量的氧自由基能够消耗各种抗氧化物质,比如 GSH 和 SOD 等,促使多不饱和脂肪酸出现过氧化反应,提高 MDA 水平。本研究显示,治疗后观察组血清 MDA 水平较对照组显著降低,而血清 SOD 和 GSH 水平显著升高,表明水飞蓟宾胶囊联合多烯磷脂酰胆碱能够更好地调控氧化应激反应,减轻氧化应激损伤。多烯磷脂酰胆碱可以保护对磷脂存在依赖性的相应酶系统,减轻脂质过氧化26。水飞蓟宾胶囊为由水飞蓟宾和磷脂酰胆碱制作而成的复合物,能够提高水飞蓟宾成分的脂溶性,使得药物生物利用率显著升高,发挥良好的抗脂质过氧化作用。因此,两药联合使用可起到更显著的抗氧化应激功效。综上所述,对抗结核药物所致的 DILI 患者应用水飞蓟宾胶囊联合多烯磷脂酰胆碱治疗能够有效减轻机体的炎症反应,发挥良好的抗氧化作用,促进肝功能恢复,具有积极的临床应用价值。【参考文献】1Natarajan A,Beena PM,Devnikar AV,et al.A systemic review ontuberculosis.Indian J Tuberc,2020,67(3):295-311.2Snow KJ,Cruz AT,Seddon JA,et al.Adolescent tuberculosis.Lancet Child Adolesc Health,2020,4(1):68-79.3Pan Y,Tang P,Cao J,et al.Lipid peroxidation aggravates anti-tu-berculosis drug-induced liver injury:Evidence of ferroptosis induc-tion.Biochem Biophys Res Commun,2020,533(4):1512-1518.4Lei X,Zhang J,Xu Q,et al.Exploring the efficacy and safety ofpolyene phosphatidylcholine for treatment of drug-induced liverinjury using the Roussel Uclaf causality assessment method:a pro-pensity score matching comparison.J Int Med Res,2021,49(8):3000605211039810.5Islam A,Mishra A,Siddiqui MA,et al.Recapitulation of evidenceof phytochemical,pharmacokinetic and biomedical application of si-lybin.Drug Res(Stuttg),2021,71(9):489-503.6Zhang Y,Biao Y,Chu X,et al.Protective effect of Chushizi(Fructus Broussonetiae)on acetaminophen-induced rat hepatitis byinhibiting the Toll-like receptor 3/c-Jun N-terminal kinase/c-jun/c-fos/janus protein tyrosine kinase/activators of transcription 3pathway.J Tradit Chin Med,2020,40(6):965-973.7中华医学会结核病学分会.抗结核药物性肝损伤诊治指南(2019 年版).中华结核和呼吸杂志,2019,42(5):343-356.8Banerjee R,Ali RAR,Wei SC,et al.Biologics for themanagementof inflammatory bowel disease:A review in tuberculosis-endemiccountries.Gut Liver,2020,14(6):685-698.9Liu X,Ren S,Zhang J,et al.The association between cytochromeP450 polymorphisms and anti-tuberculosis drug-induced liver inju-ry:a systematic review and meta-analysis.Ann Palliat Med,2021,10(6):6518-6534.10 Moosa MS,Maartens G,Gunter H,et al.A randomized controlledtrial of intravenous N-acetylcysteine in the management of anti-tu-berculosis drug-induced liver injury.Clin Infect Dis,2021,73(9):e3377-e3383.11 魏明禄,刘建民,陈南清,等.滋肾益肝方联合多烯磷脂酰胆碱治疗抗结核药物所致急性肝损伤的有效性与安全性研究.中华中医药学刊,2018,36(1):45-48.12 Zhang R,Xu D,Zhang Y,et al.Silybin restored CYP3Aexpression through the sirtuin 2/nuclear factor -B pathway inmouse nonalcoholic fatty liver disease.Drug Metab Dispos,2021,49(9):770-779.13 Cui S,Pan XJ,Ge CL,et al.Silybin alleviates hepatic lipid accu-mulation in methionine-choline deficient diet-induced nonalcoholicfatty liver disease in mice via peroxisome proliferator-activated re-ceptor.Chin J Nat Med,2021,19(6):401-411.14 Duan RL,Sun X,Liu J,et al.Mixed micelles loaded with silybin-polyene phosphatidylcholine complex improve drug solubility.ActaPharmacol Sin,2011,32(1):108-115.15 Li X,Wang Y,Xing Y,et al.Changes of gut microbiota during si-lybin-mediated treatment of high-fat diet-induced non-alcoholicfatty liver disease in mice.Hepatol Res,2020,50(1):5-14.16 Naidoo K,Hassan-Moosa R,Mlotshwa P,et al.High rates of drug-induced liver injury in people living with HIV coinfected with tu-berculosis(TB)irrespective of antiretroviral therapy timing duringantituberculosis treatment:Results from the starting antiretroviraltherapy at three points in TB trial.Clin Infect Dis,2020,70(12):2675-2682.17 Zhang D,Hao J,Hou R,et al.The role of NAT2 polymorphism andmethylation in anti-tuberculosis drug-induced liver injury in Mon-golian tuberculosis patients.J Clin Pharm Ther,2020,45(3):561-569.18 Ambade A,Lowe P,Kodys K,et al.Pharmacological inhibition ofCCR2/5 signaling prevents and reverses alcohol-induced liver dam-age,steatosis,and inflammation in mice.Hepatology,2019,69(3):1105-1121.19 Sun Y,Gu J,Liu R,et al.IL-2/IL-6 ratio correlates with liverfunction and recovery in acute liver injury patients.APMIS,2019,127(6):468-474.20 Serrya MS,Nader MA,Abdelmageed ME.Hepatoprotective effectof the tyrosine kinase inhibitor nilotinib against cyclosporine-A in-duced liver injury in rats through blocking the Bax/Cytochrome C/caspase-3 apoptotic signaling pathway.J Biochem Mol Toxicol,2021,35(6):1-13.21 刘俊平,郭新忠,李晓敏,等.水飞蓟宾胶囊对慢性 HBV 感染患者肝纤维化 Wnt/-catenin 信号通路的影响.中华医院感染学杂志,2022,32(3):336-340.22 Santos EA,Gonalves JCS,Fleury MK,et al.Relationship of anti-tuberculosis drug-induced liver injury and genetic polymorphisms inCYP2E1 and GST.Braz J Infect Dis,2019,23(6):381-387.23 Jiang F,Yan H,Liang L,et al.Incidence and risk factors of anti-tuberculosis drug induced liver injury(DILI):Large cohort studyinvolving 4652 Chinese adult tuberculosis patients.Liver Int,2021,41(7):1565-1575.24 El-Hussieny M,Mohammed EM,Zenhom NM,et al.Possible roleof TGF-1,MMP-2,E-CAD,-catenin and antioxidants inpathogenesis of placenta accreta.Fetal Pediatr Pathol,2021,40(3):222-232.25 Sri Iswari R,Dafip M,Purwantoyo E.Malondialdehyde(MDA)production in atherosclerosis supplemented with steamed tomato.Pak J Biol Sci,2021,24(3):319-325.26 陈靓,黄强,刘三海,等.五苓散联合多烯磷脂酰胆碱对非酒精性脂肪性肝病的临床观察.中华中医药学刊,2020,38(6):190-193.(收稿:2022-11-25)(本文编辑:刘波)966实用肝脏病杂志 2023 年 9 月第 26 卷第 5 期 J Prac Hepatol,September.2023.Vol.26 No.5