不同剂量盐酸氨溴索对开胸手术围术期肺保护作用的研究
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摘要
目的
检测开胸手术围术期患者血清标志物肺表面活性物质相关蛋白-A (surfactant-associated protein A, SP-A)、细胞间粘附因子1(intercellular adhesion molecule, ICAM-1)、丙二醛(malondialdehyde, MDA).超氧化物歧化酶(superoxide dismutase, SOD)与肺功能(pulmonary function)、动脉血气(arterial blood gas)等指标,研究不同剂量盐酸氨溴索对上述指标变化的影响。为开胸手术围术期盐酸氨溴索剂量的临床应用提供新的依据。
方法
(1)收集湘雅2011年5月-2012年2月胸外科行开胸手术的患者80例。
(2)采用分组、双盲、空白对照的方法,以入选病人随机分为A、B、C、D四组,A组为空白对照组(不使用试验药物)；B组为小剂量组(3mg/(kg.d)组)；C组为中剂量组(9mg/(kg.d)剂量组)；D组为大剂量组(15mg/(kg.d)组)。试验组病人术前3天起采用相应剂量的盐酸氨溴索针(规格2m1：15mg)至术后3天。
(3)在试验前(T1a)、术中(T1b)、试验第六天(T1c)进行动脉血气分析,记录其氧分压(PaO2,mmHg)水平；在入院即刻(T2a)、术前即试验第三天(T2b)、术后第三天(T2c)对患者进行肺功能试验,记录一秒钟用力呼气容积(FEV1)与用力肺活量(FVC)比值(FEV1/FVC)(?)勺水平；在试验前(T3a)、术前即试验第三天(T3b)、术后30min(T3c)、术后第三天(T3d)测量静脉血中肺表面活性物质相关蛋白A(SP-A)的水平；在试验前(T4a)、术前即试验第三天(T4b)、术后120min(T4c)、术后第三天(T4d)测量静脉血中超氧化物歧化酶(SOD)、细胞间粘附因子(ICAM-1)和丙二醛(MDA)的水平。
(4)对所有血清标本用酶联免疫吸附试验法(enzyme-linked immunosorbent assay, ELISA)检测(?)SP-A、MDA、SOD、ICAM-1水平。
(5)对试验结果、临床资料等应用SPSS17.0软件进行统计学分析,P<0.05为差异有统计学意义。
结果
(1)PaO2:T1a, T1b时刻PaO2水平,ABCD组间两两比较无统计学差异(P>0.05)；T3c时刻Pa02水平,A组与B组比较、C组与D组比较无统计学差异(P>0.05),A组与C、D组比较有统计学差异(P<0.05)；B组与C、D组比较有统计学差异(P<0.05)。
(2) FEV1/FVC:T2a、T2b时刻FEV1/FVC水平,ABCD组间两两比较无统计学差异(P>0.05)；T3c时刻FEV1/FVC水平,B、C、D组高于A组(P>0.05),B组与C组比较无统计学差异(P>0.05)；D组高于B、C组(P<0.05)。
(3)SP-A：BCD组T3b、T3c、T3d时刻SP-A含量较A组低(P<0.05)；T3b、T3c时刻,B组与C组、C组与D组、B组与D组的SP-A水平相比无统计学差异(P>0.05)；Y3d时刻,D组SP-A水平明显低于B组与C组(P<0.05),C组SP-A水平与B组相比无统计学差异(P>0.05)。
(4) ICAM-1、SOD、MDA:BCD组T4b T4c T4d时刻ICAM-1、MDA含量与A组相比明显降低,SOD含量则相应明显升高(p<0.05)。D组T4b T4c T4d时刻ICAM-1、MDA含量与BC组相比明显降低,SOD含量则相应明显升高(P<0.05)。C组T4b T4c T4d时刻ICAM-1、 MDA、SOD含量与B组相比无统计学差异(P>0.05)。
结论
1.围术期小剂量盐酸氨溴索应用,对围术期患者动脉血氧分压水平无明显影响,应用中剂量与大剂量盐酸氨溴索可有效提高患者术后血氧分压水平,且效果相同。
2.围术期应用盐酸氨溴索可有效提高患者术后FEV1/FVC水平,从而改善肺顺应性,大剂量应用盐酸氨溴索,其改善效果更为明显。
3.围术期使用盐酸氨溴索可降低外周血中SP-A水平,大剂量盐酸氨溴索的应用对术前及术后30min降低SP-A水平的作用不明显,而在术后三天内,可显著降低SP-A水平,与其对炎性因子、抗炎因子的影响综合分析,炎性反应与外周血SP-A水平并非成正相关。
4.盐酸氨溴索可有效调控MDA、SOD、ICAM-1因子的含量,从而发挥其抗炎、抗氧化作用,且药物起效时间小于三天,其抗炎、抗氧化作用在大剂量应用时效果更为明显。
Objective Detect the serum markers (surfactant-associated protein A, intercellular adhesion molecule, malondialdehyde, superoxide dismutase) and clinical examination indexes (pulmonary function, arterial blood gas) of the postoperative thoracotomy patients, in order to research the relation between the markers above and the usage of mucosolvan with different dosage. So as to provide new evidence for the clinical usage of ambroxol in the patients undergoing thoracotomy.
Methods (1) Collected80cases of thoracotomy patients of XiangYahospital during2011.05-2012.02.
(2) Based on the method of randomized grouping double-blind,blank control.Divided the patients sellected into four groups (A、B、C、D). group A is blank controled group (without using drugs); group B is small dosage group (3mg/(kg.d)); group C is middle dosage group (9mg/(kg.d)); group D is large dosage group (15mg/(kg.d)).To use corresponding dosage of ambroxol (2ml:15ml) on three days before the surgery to three days after the surgery, altogether six days.
(3) Testing the arterial blood gas on pre-test (T1a),intraopration (T1b),the sixth days of the test (T1c), and record the level of oxygen partial pressure (PaO2, mmHg); Testing the pulmonary function on pre-test (T2a),intraopration (T2b),the sixth days of the test (T2c), and record the level of FEV1/FVC; Testing the SP-A on pre-test (T3a)、 intraopration (T3b)、30minutes after the surgery (T3c), the sixth days of the test (T3d); Testing the level of MDA,SOD,ICAM-1on pre-test (T4a),intraopration (T4b),two hours after surgery (T4c),the sixth days of the test (T4d)
(4) Test the level of SP-A,MDA,SOD by the mean of Enzyme-linked Immunosorbent Assay.
(5) Stafistical analysis was performed using SPSS statistical software package (17.0). P values≤0.05indicated statistically significant difference.
Results (1) PaO2:At the moment of T1a and T1b, the level of PaO2in ABCD group is no significant difference with each other(P>0.05); at T3c, there is no significant difference (P>0.05) at the level of PaO2in group A compared with group B and group C compared with group D, group A compared with group C and group D had statistical differences (P<0.05); group B compared with group C and D had statistical differences (P<0.05).
(2) FEV1/FVC:Between any two of the T2a, T2b time the FEV1/FVC level, group ABCD had no significant difference with each other (P>0.05); the FEV1/FVC level at T3c time, Group BCD was higher than that in group A (P>0.05), Group B had no significant difference compared with group C (P>0.05); group D was higher than group BC(P <0.05).
(3) SP-A:At T3b T3c and T3d, the SP-A of group BCD was lower compared with group A (P<0.05); at T3b and T3c, the level of SP-A in group B and group C, group C and group D, group B and group D had no significant difference (P>0.05); at T3d, the level of SP-A in group D was significantly lower than group B and group C (P<0.05), there was no significant difference between group C and group B (P>0.05).
(4) ICAM-1、SOD. MDA:At T4b T4c T4d, the content of MDA and ICAM-1in group A was significantly higher than that of group BCD,and the level of SOD was significantly higher (P<0.05). At T4b T4c T4d,the content of MDA and ICAM-1in group D was lower than that of group BC, and the level of SOD was significantly higher (P<0.05). At T4b T4c T4d moment,there was no significant difference of ICAM-1、 MDA. SOD between group C and group B (P>0.05).
Conclusion (1) Small dose ambroxol application in perioperation had no significant effect on the perioperative period in patients with arterial oxygen tension levels, while medium dose and high-dose application of ambroxol can improve the postoperative blood oxygen levels, and has the same effect both.(2) Perioperative application of ambroxol can effectively improve the level of FEV1/FVC postoperative, thereby improving lung compliance, the improvement is more obvious while use large dose of ambroxol.(3) The perioperative ambroxol may reduce the level of SP-A in peripheral blood, large doses of ambroxol application preoperative and postoperative30min to reduce the role of SP-A levels is not obvious, and within three days after surgery, can significantly reduce SP-A level, and the analysis of the inflammatory factors, anti-inflammatory factors and peripheral blood SP-A levels indicates that the Inflammatory response and SP-A in peripheral blood are not positively correlated.(4) Ambroxol can regulate the content of MDA,SOD and ICAM-1effectively, thus play the role of anti-inflammatory and antioxidant, its onset time is less than three days, the anti-inflammatory, anti-oxidation effect is more obvious while large dose application.
检测开胸手术围术期患者血清标志物肺表面活性物质相关蛋白-A (surfactant-associated protein A, SP-A)、细胞间粘附因子1(intercellular adhesion molecule, ICAM-1)、丙二醛(malondialdehyde, MDA).超氧化物歧化酶(superoxide dismutase, SOD)与肺功能(pulmonary function)、动脉血气(arterial blood gas)等指标,研究不同剂量盐酸氨溴索对上述指标变化的影响。为开胸手术围术期盐酸氨溴索剂量的临床应用提供新的依据。
方法
(1)收集湘雅2011年5月-2012年2月胸外科行开胸手术的患者80例。
(2)采用分组、双盲、空白对照的方法,以入选病人随机分为A、B、C、D四组,A组为空白对照组(不使用试验药物)；B组为小剂量组(3mg/(kg.d)组)；C组为中剂量组(9mg/(kg.d)剂量组)；D组为大剂量组(15mg/(kg.d)组)。试验组病人术前3天起采用相应剂量的盐酸氨溴索针(规格2m1：15mg)至术后3天。
(3)在试验前(T1a)、术中(T1b)、试验第六天(T1c)进行动脉血气分析,记录其氧分压(PaO2,mmHg)水平；在入院即刻(T2a)、术前即试验第三天(T2b)、术后第三天(T2c)对患者进行肺功能试验,记录一秒钟用力呼气容积(FEV1)与用力肺活量(FVC)比值(FEV1/FVC)(?)勺水平；在试验前(T3a)、术前即试验第三天(T3b)、术后30min(T3c)、术后第三天(T3d)测量静脉血中肺表面活性物质相关蛋白A(SP-A)的水平；在试验前(T4a)、术前即试验第三天(T4b)、术后120min(T4c)、术后第三天(T4d)测量静脉血中超氧化物歧化酶(SOD)、细胞间粘附因子(ICAM-1)和丙二醛(MDA)的水平。
(4)对所有血清标本用酶联免疫吸附试验法(enzyme-linked immunosorbent assay, ELISA)检测(?)SP-A、MDA、SOD、ICAM-1水平。
(5)对试验结果、临床资料等应用SPSS17.0软件进行统计学分析,P<0.05为差异有统计学意义。
结果
(1)PaO2:T1a, T1b时刻PaO2水平,ABCD组间两两比较无统计学差异(P>0.05)；T3c时刻Pa02水平,A组与B组比较、C组与D组比较无统计学差异(P>0.05),A组与C、D组比较有统计学差异(P<0.05)；B组与C、D组比较有统计学差异(P<0.05)。
(2) FEV1/FVC:T2a、T2b时刻FEV1/FVC水平,ABCD组间两两比较无统计学差异(P>0.05)；T3c时刻FEV1/FVC水平,B、C、D组高于A组(P>0.05),B组与C组比较无统计学差异(P>0.05)；D组高于B、C组(P<0.05)。
(3)SP-A：BCD组T3b、T3c、T3d时刻SP-A含量较A组低(P<0.05)；T3b、T3c时刻,B组与C组、C组与D组、B组与D组的SP-A水平相比无统计学差异(P>0.05)；Y3d时刻,D组SP-A水平明显低于B组与C组(P<0.05),C组SP-A水平与B组相比无统计学差异(P>0.05)。
(4) ICAM-1、SOD、MDA:BCD组T4b T4c T4d时刻ICAM-1、MDA含量与A组相比明显降低,SOD含量则相应明显升高(p<0.05)。D组T4b T4c T4d时刻ICAM-1、MDA含量与BC组相比明显降低,SOD含量则相应明显升高(P<0.05)。C组T4b T4c T4d时刻ICAM-1、 MDA、SOD含量与B组相比无统计学差异(P>0.05)。
结论
1.围术期小剂量盐酸氨溴索应用,对围术期患者动脉血氧分压水平无明显影响,应用中剂量与大剂量盐酸氨溴索可有效提高患者术后血氧分压水平,且效果相同。
2.围术期应用盐酸氨溴索可有效提高患者术后FEV1/FVC水平,从而改善肺顺应性,大剂量应用盐酸氨溴索,其改善效果更为明显。
3.围术期使用盐酸氨溴索可降低外周血中SP-A水平,大剂量盐酸氨溴索的应用对术前及术后30min降低SP-A水平的作用不明显,而在术后三天内,可显著降低SP-A水平,与其对炎性因子、抗炎因子的影响综合分析,炎性反应与外周血SP-A水平并非成正相关。
4.盐酸氨溴索可有效调控MDA、SOD、ICAM-1因子的含量,从而发挥其抗炎、抗氧化作用,且药物起效时间小于三天,其抗炎、抗氧化作用在大剂量应用时效果更为明显。
Objective Detect the serum markers (surfactant-associated protein A, intercellular adhesion molecule, malondialdehyde, superoxide dismutase) and clinical examination indexes (pulmonary function, arterial blood gas) of the postoperative thoracotomy patients, in order to research the relation between the markers above and the usage of mucosolvan with different dosage. So as to provide new evidence for the clinical usage of ambroxol in the patients undergoing thoracotomy.
Methods (1) Collected80cases of thoracotomy patients of XiangYahospital during2011.05-2012.02.
(2) Based on the method of randomized grouping double-blind,blank control.Divided the patients sellected into four groups (A、B、C、D). group A is blank controled group (without using drugs); group B is small dosage group (3mg/(kg.d)); group C is middle dosage group (9mg/(kg.d)); group D is large dosage group (15mg/(kg.d)).To use corresponding dosage of ambroxol (2ml:15ml) on three days before the surgery to three days after the surgery, altogether six days.
(3) Testing the arterial blood gas on pre-test (T1a),intraopration (T1b),the sixth days of the test (T1c), and record the level of oxygen partial pressure (PaO2, mmHg); Testing the pulmonary function on pre-test (T2a),intraopration (T2b),the sixth days of the test (T2c), and record the level of FEV1/FVC; Testing the SP-A on pre-test (T3a)、 intraopration (T3b)、30minutes after the surgery (T3c), the sixth days of the test (T3d); Testing the level of MDA,SOD,ICAM-1on pre-test (T4a),intraopration (T4b),two hours after surgery (T4c),the sixth days of the test (T4d)
(4) Test the level of SP-A,MDA,SOD by the mean of Enzyme-linked Immunosorbent Assay.
(5) Stafistical analysis was performed using SPSS statistical software package (17.0). P values≤0.05indicated statistically significant difference.
Results (1) PaO2:At the moment of T1a and T1b, the level of PaO2in ABCD group is no significant difference with each other(P>0.05); at T3c, there is no significant difference (P>0.05) at the level of PaO2in group A compared with group B and group C compared with group D, group A compared with group C and group D had statistical differences (P<0.05); group B compared with group C and D had statistical differences (P<0.05).
(2) FEV1/FVC:Between any two of the T2a, T2b time the FEV1/FVC level, group ABCD had no significant difference with each other (P>0.05); the FEV1/FVC level at T3c time, Group BCD was higher than that in group A (P>0.05), Group B had no significant difference compared with group C (P>0.05); group D was higher than group BC(P <0.05).
(3) SP-A:At T3b T3c and T3d, the SP-A of group BCD was lower compared with group A (P<0.05); at T3b and T3c, the level of SP-A in group B and group C, group C and group D, group B and group D had no significant difference (P>0.05); at T3d, the level of SP-A in group D was significantly lower than group B and group C (P<0.05), there was no significant difference between group C and group B (P>0.05).
(4) ICAM-1、SOD. MDA:At T4b T4c T4d, the content of MDA and ICAM-1in group A was significantly higher than that of group BCD,and the level of SOD was significantly higher (P<0.05). At T4b T4c T4d,the content of MDA and ICAM-1in group D was lower than that of group BC, and the level of SOD was significantly higher (P<0.05). At T4b T4c T4d moment,there was no significant difference of ICAM-1、 MDA. SOD between group C and group B (P>0.05).
Conclusion (1) Small dose ambroxol application in perioperation had no significant effect on the perioperative period in patients with arterial oxygen tension levels, while medium dose and high-dose application of ambroxol can improve the postoperative blood oxygen levels, and has the same effect both.(2) Perioperative application of ambroxol can effectively improve the level of FEV1/FVC postoperative, thereby improving lung compliance, the improvement is more obvious while use large dose of ambroxol.(3) The perioperative ambroxol may reduce the level of SP-A in peripheral blood, large doses of ambroxol application preoperative and postoperative30min to reduce the role of SP-A levels is not obvious, and within three days after surgery, can significantly reduce SP-A level, and the analysis of the inflammatory factors, anti-inflammatory factors and peripheral blood SP-A levels indicates that the Inflammatory response and SP-A in peripheral blood are not positively correlated.(4) Ambroxol can regulate the content of MDA,SOD and ICAM-1effectively, thus play the role of anti-inflammatory and antioxidant, its onset time is less than three days, the anti-inflammatory, anti-oxidation effect is more obvious while large dose application.
引文
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[16]Guan RN.Treatment of different doses of ambroxol compare the efficacy of lower respiratory tract infections. Guangzhou Medical Journal,,2006,37(3):25-26[关瑞宁.不同剂量沐舒坦治疗下呼吸道感染的疗效比较.广州医药,2006,37(3)：25-26.]
[17]Zhang Q,Yuan SY.The effect of high dose ambroxol on the antioxidant activity in patients with ARDS. The Journal of Clinical Anaesthesiology,2004,20(3)：135-137.[张清,袁世荧.大剂量沐舒坦对急性呼吸窘迫综合征患者抗氧化能力的影响.临床麻醉学杂志,2004,20(3)：135-137.]
[18]Cai X,Chen SR. Effect of high dose ambroxol on the pulmonary function of patients with ARDS. China Modern Medicine,2011,18(1):75-76[蔡茜,陈思睿.大剂量盐酸氨溴索对ARDS患者呼吸功能的影响.药物与临床,2011,18(1)：75-76.]
[19]He L. Therapeutic Effect of Large Dose of Mucosolvan on Respiratory Distress Syndrome in Premature Children. Journal of Kunming Medical University,2011,32(2)：121-123.[合力.大剂量盐酸氨溴索治疗早产儿呼吸窘迫综合征疗效观察.昆明医学院学报,2011,32(2)：121-123.]
[20]Liang YF,Hu RB. Clinical Application of Ambroxol to Patients with Heart Operations in Perioperative Period. Chinese Journal of Modern Drug Application,2010,4(18):28-29.[梁永福,胡荣波.氨溴索在心外科手术围术期的临床应用.中国现代药物应用,2010,4(18)：28-29.]
[21]Wu JF,Duan JF. The effect of treatment using larger dose of ambroxol on lung trauma with thoracic wound. Journal of Clinical Pulmonary Medicine,2008,13(11):1420-1422.[吴俊峰,段俊峰.大剂量沐舒坦对胸部创伤所致肺损伤的治疗的作用.临床肺科杂志,2008,13(11)：1420-1422.]
[22]Liu X,Wang ZQ. High dose ambroxol in patients with severe traumatic brain injury in the application of lung infection. Chinese Journal of Neurosurgical Disease Research,2010,9(6):551-552[刘鑫,王周勤.大剂量沐舒坦在重型颅脑损伤患者肺部感染中的应用.中华神经外科疾病研究杂志,2010,9(6)：551-552.]
[23]Fegiz G. Prevention by ambroxol of bronchopulmonary complications after upper abdominal surgery:double-blind Italian multicenter clinical study versus placebo.Lung.1991;169(2):69-76.
[24]Drewa T, Wolski Z, Gruszka M, Misterek B, Lysik J. Uric acid plasma level and urine pH in rats treated with ambroxol.Acta Pol Pharm.2007;64(6):565-7.
[25]Liu J.Cui F. High dose ambroxol in minimally invasive thoracic surgery and postoperative clinical results. The Journal of Practical Medicine,2006,22(16)：1930-1931.[刘君,崔飞.大剂量沐舒坦在微创胸外科术后的临床应用效果.实用医学杂志,2006,22(16)：1930-1931.]
[26]何国均,邹学超.胸外科领域肺功能测定与评价.见穆魁津,林友华主编.肺功能测定原理与临床应用.第一版.北京,北京医科大学和中国协和医科大学联合出版社,1992,319-329.
[27]WIRTZ H R.Effect of ambroxol on surfactant synthesis and secretion in isolated type Ⅱ alveolar cells [J]. Pneumologie,2000,54(7):278-283.
[28]朱光发,钮善福.急性肺损伤患者血清肺表面活性物质蛋白A的变化及其意义.中国危重病急救医学,2000,12(1)：15-17.
[1]Morgenroth K, Bolz J. Morphological features of the interaction between mucus and surfactant on the bronchial mucosa. Respiration 1985;47(3):225-231.
[2]Kranicke R. Results of a clinical trial with ambroxol as to postoperative therapy of bronchitis (author's transl). Arzneimittelforschung.1978;28(5a):934-5.
[3]Fraschini. Effects of a mucolytic agent on the bioavaility of antibiotics in patients with chronic respiratory diseaes[J].Current Therapeutic Research.1997,8:5.
[4]Farkhutdinov UR, Farkhutdinov RR, Petriakov VV, Farkhutdinov ShU, Mirkhaidarov AM. Effect of mucolytic therapy on the production of reactive oxygen species in the blood of patients with an exacerbation of chronic obstructive pulmonary disease. Ter Arkh.2010;82(3):29-32.
[5]Ottonello L, Arduino N, Bertolotto M, Dapino P, Mancini M, Dallegri F. In vitro inhibition of human neutrophil histotoxicity by ambroxol:evidence for a multistep mechanism.Br J Pharmacol.2003;140(4):736-42.
[6]ZHAO Zhong-jiang; MENG Xin-ke; YAN Jing. Study of predictive effect of ambroxol on acute lung injury. China Journal of Modern Medicine.2004; 14(22):106-108.[赵中江,孟新科,杨径.沐舒坦对急性肺损伤肺保护作用的研究[J].中国现代医学杂志,2004：14(22)：106-108.]
[7]Zhou HY, Chang YY. The protective effect of ambroxol for valve replacement in patients with perioperative lung injury. Journal of Central South University(Medical Sciences).,2004,29 (6):723-724.[周海洋,常业怡.盐酸 氨溴索对瓣膜置换患者围术期肺损伤的保护作用.中南大学学报(医学版),2004,29(6)：723-724.]
[8]Fischer J, Pschorn U, Vix JM, Peil H, Aicher B, Miiller A, de Mey C.Arzneimittelforschung. Efficacy and tolerability of ambroxol hydrochloride lozenges in sore throat. Randomised, double-blind, placebo-controlled trials regarding the local anaesthetic properties.2002;52(4):256-63.)
[9]Xia DH, Xi L, Xv C,etc.The protective effects of ambroxol on radiation lung injury and influence on production of transforming growth factor betal and tumor necrosis factor alpha.Med Oncol.2010;27(3):697-701.
[10]Hasegawa I, Niisato N, Iwasaki Y, Marunaka Y. Ambroxol-induced modification of ion transport in human airway Calu-3 epithelia.Biochem Biophys Res Commun.2006;343(2):475-82.
[11]Yang HD.Xu B.Mechanism and clinical application of action of ambroxol. Chin Hosp Pharm J,2002,22(1):44-45[杨惠娣,徐彬.氨溴索的作用机制及临床应用.中国医院药学杂志,2002,22(1)：44-45.]
[12]Stetinova V, Smetanova L, Kholova D, Svoboda Z, Kvetina J. Ambroxol-induced modification of ion transport in human airway Calu-3 epithelia.Gen Physiol Biophys.2009;28(3):309-15.
[13]Ren YC, Wang L, He HB, Tang X. Pulmonary selectivity and local pharmacokinetics of ambroxol hydrochloride dry powder inhalation in rat.J Pharm Sci.2009;98(5):1797-803.
[14]Ren Y, Yu C, Meng K, Tang X. Influence of formulation and preparation process on ambroxol hydrochloride dry powder inhalation characteristics and aerosolization properties.Drug Dev Ind Pharm.2008;34(9):984-91.
[15]Liu JY Different doses of ambroxol adjuvant treatment efficacy in children with bronchial pneumonia. Guide of China Medicine,2011,9(7):82-83.[刘景燕.不同剂量盐酸氨溴索辅助治疗小儿支气管肺炎疗效观察.中国医药指南,2011,9(7)：82-83.]
[16]Guan RN.Treatment of different doses of ambroxol compare the efficacy of lower respiratory tract infections. Guangzhou Medical Journal,,2006,37(3):25-26.[关瑞宁.不同剂量沐舒坦治疗下呼吸道感染的疗效比较.广州医药,2006,,37(3)：25-26.]
[17]Zhang Q,Yuan SY.The effect of high dose ambroxol on the antioxidant activity in patients with ARDS. The Journal of Clinical Anaesthesiology,2004,20(3)：135-137.[张清,袁世荧.大剂量沐舒坦对急性呼吸窘迫综合征患者抗氧化能力的影响.临床麻醉学杂志,2004,20(3)：135-137.]
[18]Cai X.Chen SR. Effect of high dose ambroxol on the pulmonary function of patients with ARDS. China Modern Medicine,2011,18(1):75-76.[蔡茜,陈思睿.大剂量盐酸氨溴索对ARDS患者呼吸功能的影响.药物与临床,2011,18(1)：75-76.]
[19]He L. Therapeutic Effect of Large Dose of Mucosolvan on Respiratory Distress Syndrome in Premature Children. Journal of Kunming Medical University,2011,32(2)：121-123.[合力.大剂量盐酸氨溴索治疗早产儿呼吸窘迫综合征疗效观察.昆明医学院学报,2011,32(2)：121-123.]
[20]Liang YF,Hu RB. Clinical Application of Ambroxol to Patients with Heart Operations in Perioperative Period. Chinese Journal of Modern Drug Application,2010,4(18):28-29[梁永福,胡荣波.氨溴索在心外科手术围术期的临床应用.中国现代药物应用,2010,4(18)：28-29.]
[21]Wu JF,Duan JF. The effect of treatment using larger dose of ambroxol on lung trauma with thoracic wound. Journal of Clinical Pulmonary Medicine,2008,13(11)：1420-1422.[吴俊峰,段俊峰.大剂量沐舒坦对胸部创伤所致肺损伤的治疗的作用.临床肺科杂志,2008,13(11)：1420-1422.]
[22]Liu X,Wang ZQ. High dose ambroxol in patients with severe traumatic brain injury in the application of lung infection. Chinese Journal of Neurosurgical Disease Research,2010,9(6):551-552.[刘鑫,王周勤.大剂量沐舒坦在重型颅脑损伤患者肺部感染中的应用.中华神经外科疾病研究杂志,2010,9(6)：551-552.]
[23]Fegiz G. Prevention by ambroxol of bronchopulmonary complications after upper abdominal surgery:double-blind Italian multicenter clinical study versus placebo.Lung.1991; 169(2):69-76.
[24]Drewa T, Wolski Z, Gruszka M, Misterek B, Lysik J. Uric acid plasma level and urine pH in rats treated with ambroxol.Acta Pol Pharm.2007;64(6):565-7.
[25]Liu J.Cui F. High dose ambroxol in minimally invasive thoracic surgery and postoperative clinical results. The Journal of Practical Medicine,2006,,22(16)：1930-1931,[刘君,崔飞.大剂量沐舒坦在微创胸外科术后的临床应用效果.实用医学杂志,2006,22(16)：1930-1931.]
[2]Kranicke R. Results of a clinical trial with ambroxol as to postoperative therapy of bronchitis (author's transl). Arzneimittelforschung.1978;28(5a):934-5.
[3]Fraschini. Effects of a mucolytic agent on the bioavaility of antibiotics in patients with chronic respiratory diseaes[J].Current Therapeutic Research.1997,8:5.
[4]Farkhutdinov UR, Farkhutdinov RR, Petriakov VV, Farkhutdinov ShU, Mirkhaidarov AM. Effect of mucolytic therapy on the production of reactive oxygen species in the blood of patients with an exacerbation of chronic obstructive pulmonary disease. Ter Arkh.2010;82(3):29-32.
[5]Ottonello L, Arduino N, Bertolotto M, Dapino P, Mancini M, Dallegri F. In vitro inhibition of human neutrophil histotoxicity by ambroxol:evidence for a multistep mechanism.Br J Pharmacol.2003;140(4):736-42.
[6]ZHAO Zhong-jiang; MENG Xin-ke; YAN Jing. Study of predictive effect of ambroxol on acute lung injury. China Journal of Modern Medicine,2004; 14(22): 106-108[赵中江,孟新科,杨径.沐舒坦对急性肺损伤肺保护作用的研究[J].中国现代医学杂志,2004；14(22)：106-108.]
[7]Zhou HY,Chang YY. The protective effect of ambroxol for valve replacement in patients with perioperative lung injury. Journal of Central South University(Medical Sciences).,2004,29(6):723-724[周海洋,常业怡.盐酸氨溴索对瓣膜置换患者围术期肺损伤的保护作用.中南大学学报(医学版),2004,29(6)：723-724.]
[8]Fischer J, Pschorn U, Vix JM, Peil H, Aicher B, Muller A, de Mey C.Arzneimittelforschung. Efficacy and tolerability of ambroxol hydrochloride lozenges in sore throat. Randomised, double-blind, placebo-controlled trials regarding the local anaesthetic properties.2002;52(4):256-63.)
[9]Xia DH, Xi L, Xv C.etc.The protective effects of ambroxol on radiation lung injury and influence on production of transforming growth factor betal and tumor necrosis factor alpha.Med Oncol.2010;27(3):697-701.
[10]Hasegawa I, Niisato N, Iwasaki Y, Marunaka Y. Ambroxol-induced modification of ion transport in human airway Calu-3 epithelia.Biochem Biophys Res Commun.2006;343(2):475-82.
[11]Yang HD.Xu B.Mechanism and clinical application of action of ambroxol. Chin Hosp Pharm J,2002,22(1):44-45.[汤惠娣,徐彬.氨溴索的作用机制及临床应用.中国医院药学杂志,2002,22(1)：44-45.]
[12]Stetinova V, Smetanova L, Kholova D, Svoboda Z, Kvetina J. Ambroxol-induced modification of ion transport in human airway Calu-3 epithelia.Gen Physiol Biophys.2009;28(3):309-15.
[13]Ren YC, Wang L, He HB, Tang X. Pulmonary selectivity and local pharmacokinetics of ambroxol hydrochloride dry powder inhalation in rat.J Pharm Sci.2009;98(5):1797-803.
[14]Ren Y, Yu C, Meng K, Tang X. Influence of formulation and preparation process on ambroxol hydrochloride dry powder inhalation characteristics and aerosolization properties.Drug Dev Ind Pharm.2008;34(9):984-91.
[15]Liu JY. Different doses of ambroxol adjuvant treatment efficacy in children with bronchial pneumonia. Guide of China Medicine,2011,9(7):82-83[刘景燕.不同剂量盐酸氨溴索辅助治疗小儿支气管肺炎疗效观察.中国医药指南,2011,9(7)：82-83.]
[16]Guan RN.Treatment of different doses of ambroxol compare the efficacy of lower respiratory tract infections. Guangzhou Medical Journal,,2006,37(3):25-26[关瑞宁.不同剂量沐舒坦治疗下呼吸道感染的疗效比较.广州医药,2006,37(3)：25-26.]
[17]Zhang Q,Yuan SY.The effect of high dose ambroxol on the antioxidant activity in patients with ARDS. The Journal of Clinical Anaesthesiology,2004,20(3)：135-137.[张清,袁世荧.大剂量沐舒坦对急性呼吸窘迫综合征患者抗氧化能力的影响.临床麻醉学杂志,2004,20(3)：135-137.]
[18]Cai X,Chen SR. Effect of high dose ambroxol on the pulmonary function of patients with ARDS. China Modern Medicine,2011,18(1):75-76[蔡茜,陈思睿.大剂量盐酸氨溴索对ARDS患者呼吸功能的影响.药物与临床,2011,18(1)：75-76.]
[19]He L. Therapeutic Effect of Large Dose of Mucosolvan on Respiratory Distress Syndrome in Premature Children. Journal of Kunming Medical University,2011,32(2)：121-123.[合力.大剂量盐酸氨溴索治疗早产儿呼吸窘迫综合征疗效观察.昆明医学院学报,2011,32(2)：121-123.]
[20]Liang YF,Hu RB. Clinical Application of Ambroxol to Patients with Heart Operations in Perioperative Period. Chinese Journal of Modern Drug Application,2010,4(18):28-29.[梁永福,胡荣波.氨溴索在心外科手术围术期的临床应用.中国现代药物应用,2010,4(18)：28-29.]
[21]Wu JF,Duan JF. The effect of treatment using larger dose of ambroxol on lung trauma with thoracic wound. Journal of Clinical Pulmonary Medicine,2008,13(11):1420-1422.[吴俊峰,段俊峰.大剂量沐舒坦对胸部创伤所致肺损伤的治疗的作用.临床肺科杂志,2008,13(11)：1420-1422.]
[22]Liu X,Wang ZQ. High dose ambroxol in patients with severe traumatic brain injury in the application of lung infection. Chinese Journal of Neurosurgical Disease Research,2010,9(6):551-552[刘鑫,王周勤.大剂量沐舒坦在重型颅脑损伤患者肺部感染中的应用.中华神经外科疾病研究杂志,2010,9(6)：551-552.]
[23]Fegiz G. Prevention by ambroxol of bronchopulmonary complications after upper abdominal surgery:double-blind Italian multicenter clinical study versus placebo.Lung.1991;169(2):69-76.
[24]Drewa T, Wolski Z, Gruszka M, Misterek B, Lysik J. Uric acid plasma level and urine pH in rats treated with ambroxol.Acta Pol Pharm.2007;64(6):565-7.
[25]Liu J.Cui F. High dose ambroxol in minimally invasive thoracic surgery and postoperative clinical results. The Journal of Practical Medicine,2006,22(16)：1930-1931.[刘君,崔飞.大剂量沐舒坦在微创胸外科术后的临床应用效果.实用医学杂志,2006,22(16)：1930-1931.]
[26]何国均,邹学超.胸外科领域肺功能测定与评价.见穆魁津,林友华主编.肺功能测定原理与临床应用.第一版.北京,北京医科大学和中国协和医科大学联合出版社,1992,319-329.
[27]WIRTZ H R.Effect of ambroxol on surfactant synthesis and secretion in isolated type Ⅱ alveolar cells [J]. Pneumologie,2000,54(7):278-283.
[28]朱光发,钮善福.急性肺损伤患者血清肺表面活性物质蛋白A的变化及其意义.中国危重病急救医学,2000,12(1)：15-17.
[1]Morgenroth K, Bolz J. Morphological features of the interaction between mucus and surfactant on the bronchial mucosa. Respiration 1985;47(3):225-231.
[2]Kranicke R. Results of a clinical trial with ambroxol as to postoperative therapy of bronchitis (author's transl). Arzneimittelforschung.1978;28(5a):934-5.
[3]Fraschini. Effects of a mucolytic agent on the bioavaility of antibiotics in patients with chronic respiratory diseaes[J].Current Therapeutic Research.1997,8:5.
[4]Farkhutdinov UR, Farkhutdinov RR, Petriakov VV, Farkhutdinov ShU, Mirkhaidarov AM. Effect of mucolytic therapy on the production of reactive oxygen species in the blood of patients with an exacerbation of chronic obstructive pulmonary disease. Ter Arkh.2010;82(3):29-32.
[5]Ottonello L, Arduino N, Bertolotto M, Dapino P, Mancini M, Dallegri F. In vitro inhibition of human neutrophil histotoxicity by ambroxol:evidence for a multistep mechanism.Br J Pharmacol.2003;140(4):736-42.
[6]ZHAO Zhong-jiang; MENG Xin-ke; YAN Jing. Study of predictive effect of ambroxol on acute lung injury. China Journal of Modern Medicine.2004; 14(22):106-108.[赵中江,孟新科,杨径.沐舒坦对急性肺损伤肺保护作用的研究[J].中国现代医学杂志,2004：14(22)：106-108.]
[7]Zhou HY, Chang YY. The protective effect of ambroxol for valve replacement in patients with perioperative lung injury. Journal of Central South University(Medical Sciences).,2004,29 (6):723-724.[周海洋,常业怡.盐酸 氨溴索对瓣膜置换患者围术期肺损伤的保护作用.中南大学学报(医学版),2004,29(6)：723-724.]
[8]Fischer J, Pschorn U, Vix JM, Peil H, Aicher B, Miiller A, de Mey C.Arzneimittelforschung. Efficacy and tolerability of ambroxol hydrochloride lozenges in sore throat. Randomised, double-blind, placebo-controlled trials regarding the local anaesthetic properties.2002;52(4):256-63.)
[9]Xia DH, Xi L, Xv C,etc.The protective effects of ambroxol on radiation lung injury and influence on production of transforming growth factor betal and tumor necrosis factor alpha.Med Oncol.2010;27(3):697-701.
[10]Hasegawa I, Niisato N, Iwasaki Y, Marunaka Y. Ambroxol-induced modification of ion transport in human airway Calu-3 epithelia.Biochem Biophys Res Commun.2006;343(2):475-82.
[11]Yang HD.Xu B.Mechanism and clinical application of action of ambroxol. Chin Hosp Pharm J,2002,22(1):44-45[杨惠娣,徐彬.氨溴索的作用机制及临床应用.中国医院药学杂志,2002,22(1)：44-45.]
[12]Stetinova V, Smetanova L, Kholova D, Svoboda Z, Kvetina J. Ambroxol-induced modification of ion transport in human airway Calu-3 epithelia.Gen Physiol Biophys.2009;28(3):309-15.
[13]Ren YC, Wang L, He HB, Tang X. Pulmonary selectivity and local pharmacokinetics of ambroxol hydrochloride dry powder inhalation in rat.J Pharm Sci.2009;98(5):1797-803.
[14]Ren Y, Yu C, Meng K, Tang X. Influence of formulation and preparation process on ambroxol hydrochloride dry powder inhalation characteristics and aerosolization properties.Drug Dev Ind Pharm.2008;34(9):984-91.
[15]Liu JY Different doses of ambroxol adjuvant treatment efficacy in children with bronchial pneumonia. Guide of China Medicine,2011,9(7):82-83.[刘景燕.不同剂量盐酸氨溴索辅助治疗小儿支气管肺炎疗效观察.中国医药指南,2011,9(7)：82-83.]
[16]Guan RN.Treatment of different doses of ambroxol compare the efficacy of lower respiratory tract infections. Guangzhou Medical Journal,,2006,37(3):25-26.[关瑞宁.不同剂量沐舒坦治疗下呼吸道感染的疗效比较.广州医药,2006,,37(3)：25-26.]
[17]Zhang Q,Yuan SY.The effect of high dose ambroxol on the antioxidant activity in patients with ARDS. The Journal of Clinical Anaesthesiology,2004,20(3)：135-137.[张清,袁世荧.大剂量沐舒坦对急性呼吸窘迫综合征患者抗氧化能力的影响.临床麻醉学杂志,2004,20(3)：135-137.]
[18]Cai X.Chen SR. Effect of high dose ambroxol on the pulmonary function of patients with ARDS. China Modern Medicine,2011,18(1):75-76.[蔡茜,陈思睿.大剂量盐酸氨溴索对ARDS患者呼吸功能的影响.药物与临床,2011,18(1)：75-76.]
[19]He L. Therapeutic Effect of Large Dose of Mucosolvan on Respiratory Distress Syndrome in Premature Children. Journal of Kunming Medical University,2011,32(2)：121-123.[合力.大剂量盐酸氨溴索治疗早产儿呼吸窘迫综合征疗效观察.昆明医学院学报,2011,32(2)：121-123.]
[20]Liang YF,Hu RB. Clinical Application of Ambroxol to Patients with Heart Operations in Perioperative Period. Chinese Journal of Modern Drug Application,2010,4(18):28-29[梁永福,胡荣波.氨溴索在心外科手术围术期的临床应用.中国现代药物应用,2010,4(18)：28-29.]
[21]Wu JF,Duan JF. The effect of treatment using larger dose of ambroxol on lung trauma with thoracic wound. Journal of Clinical Pulmonary Medicine,2008,13(11)：1420-1422.[吴俊峰,段俊峰.大剂量沐舒坦对胸部创伤所致肺损伤的治疗的作用.临床肺科杂志,2008,13(11)：1420-1422.]
[22]Liu X,Wang ZQ. High dose ambroxol in patients with severe traumatic brain injury in the application of lung infection. Chinese Journal of Neurosurgical Disease Research,2010,9(6):551-552.[刘鑫,王周勤.大剂量沐舒坦在重型颅脑损伤患者肺部感染中的应用.中华神经外科疾病研究杂志,2010,9(6)：551-552.]
[23]Fegiz G. Prevention by ambroxol of bronchopulmonary complications after upper abdominal surgery:double-blind Italian multicenter clinical study versus placebo.Lung.1991; 169(2):69-76.
[24]Drewa T, Wolski Z, Gruszka M, Misterek B, Lysik J. Uric acid plasma level and urine pH in rats treated with ambroxol.Acta Pol Pharm.2007;64(6):565-7.
[25]Liu J.Cui F. High dose ambroxol in minimally invasive thoracic surgery and postoperative clinical results. The Journal of Practical Medicine,2006,,22(16)：1930-1931,[刘君,崔飞.大剂量沐舒坦在微创胸外科术后的临床应用效果.实用医学杂志,2006,22(16)：1930-1931.]