卡泊芬净雾化吸入防治侵袭性肺曲霉病药效学与安全性的动物实验研究
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摘要
侵袭性肺曲霉病(invasive pulmonary aspergillosis, IPA)多发生于重度免疫缺陷人群,死亡率高。抗真菌药通过雾化吸入给药近来受到广泛关注。与系统用药相比,雾化给药少量药物即可达到肺部高药物浓度,并且因较少入血降低了药物系统毒性。
本研究的目的是建立免疫抑制小鼠IPA模型,并评价雾化吸入卡泊芬净在预防和治疗IPA的疗效及安全性。主要分为以下三个部分：
1.免疫抑制小鼠侵袭性肺曲霉病模型的建立
目的：动物实验被广泛的应用于侵袭性肺曲霉病(IPA)诊断及治疗方面的研究,本文利用气管插管法建立免疫抑制小鼠IPA模型。
方法：以环磷酰胺及地塞米松对小鼠进行免疫抑制处理后,气管插管气管内滴入烟曲霉孢子悬液,通过组织病理进行验证,并观察小鼠生存-时间曲线。同时运用平板菌落计数方法比较气管插管法与传统滴鼻法造模实际进入鼠肺的孢子量。
结果：气管插管法可成功建立小鼠IPA模型。小鼠1周内死亡率55%,接种24小时后肺组织匀浆平板菌落计数显示气管插管法所造成的孢子入肺量为5.17±0.32CFU(1g)/g肺组织,而传统滴鼻法仅为3.82±0.49CFU(1g)/g肺组织。
结论：气管插管法成功建立小鼠IPA模型,较滴鼻法更适于进行IPA相关研究。
2.卡泊芬净雾化吸入给药防治侵袭性肺曲霉病药效学研究
目的：通过动物实验对雾化吸入卡泊芬净对IPA的防治效果做初步探讨。
方法：免疫抑制小鼠IPA模型,分别给予卡泊芬净腹腔注射及雾化用药,用药策略分为单纯治疗及预防+治疗,同时设置标准治疗——两性霉素B腹腔注射组及对照组,持续用药至感染后第7天。比较各组小鼠生存率及肺组织真菌负荷。
结果：与标准治疗——两性霉素B腹腔注射相比,雾化吸入卡泊芬净作为单纯治疗性用药、或预防+治疗用药均能有效降低小鼠肺组织真菌负荷；但只有作为预防+治疗给药时才能有效提高小鼠生存率,且对IPA预防效果与腹注给药相当。
结论：动物实验证明卡泊芬净雾化吸入给药是一种有效的预防IPA的给药方式。
3.卡泊芬净雾化吸入给药局部安全性研究
目的：观察连续多次雾化吸入卡泊芬净后小鼠肺组织病理学及局部炎症因子表达。
方法：ICR小鼠分为三组,高剂量组每天雾化2小时,低剂量组每天雾化时间为1小时,设置生理盐水对照组,各组小鼠连续用药7天。各组小鼠行肺组织病理学检查并予以评分；提取肺组织RNA行荧光定量PCR,检测各组小鼠肺组织炎症因子表达。
结果：雾化给药结束后各组肺组织病理评分无明显差异,荧光定量PCR检测显示雾化吸入卡泊芬净并未导致肺组织IL-1β、IL-6、TNF-α等炎症因子的活化。
结论：动物实验证明卡泊芬净雾化吸入给药对肺组织刺激性小,安全性较好。
综上所述,抗真菌药物雾化吸入用药在肺组织局部形成较高药物浓度,作为预防性用药时可显著增强抗真菌效果,且避免了高血药浓度导致的副作用。本研究利用动物实验观察了雾化卡泊芬净用于预防和治疗IPA疗效和安全性,与标准治疗药物——两性霉素B治疗相比,雾化卡泊芬净作为预防性用药时可提高小鼠生存率,并降低肺真菌负荷。雾化用药易于操作且安全性较好,有潜在的临床应用前景。
Invasive aspergillosis is a significant cause of morbidity and mortality in heavily immunocompromised patients and is associated with significant hospital costs and therapy complications in those with multiple comorbidities. Targeted pulmonary delivery by aerosolization of antifungals has recently gained attention, The use of aerosols for targeting medication to the receptor sites in the lung has multiple advantages compared to systemic administration, including the use of less drug to provide the same therapeutic effect and the reduction in the likelihood of systemic side effects.
Our objective was to establish the mice model of IPA and assess the Efficacy and safety of caspofungin inhalations for prevention and treatment of invasive pulmonary aspergillosis in mice.Three parts of this research are as following:
1. Establishment of animal model of invasive pulmonary aspergillosis in immunosuppressed mice
Objective Animal experiments are widely used in the diagnosis and treatment of invasive pulmonary aspergillosis (IPA). We establish an experimental model of IPA in neutropenic ICR mice with method of tracheal intubation.
Methods Female ICR mice was immunosuppressed with cyclosphamide and Dexamethasone and inoculated with1×107conodia of Aspergillus fumigates.Patholigic examination were evaluated to determine whether the IPA model was successfully constructed. survival curves was draw,Fungal burden analysis following24h inoculation to compare these two methods.
Results IPA was confirmed in neutropenic ICR mice with method of tracheal intubation based on pathologic examination. Mortality of mice was55%within7d after inculation,Numbers of CFU from homogenized lung tissues of IPA mice were5.17±0.32and3.82±0.49(log/gram lung) with these two methods of tracheal intubation and intranasal challenge, respectively.
Conclusion The IPA model in immunosuppressed ICR mice is constructed successfully,and tracheal intubation was better than intranasal challenge.
2. Efficacy of caspofungin inhalations for prevention and treatment of invasive pulmonary aspergillosis in mice
Objective To evaluated the effectiveness of aerosolizing caspofungin as prophylaxis and treatment against invasive pulmonary aspergillosis caused by Aspergillus fumigates in an established model.
Methods Immunocompromised ICR mice received either caspofungin by intraperitoneal injection or by aerosolization.dosing began2days prior or after pulmonary incoculation with A. fumigates and continued until7days after pulmonary incoculation. Survival and pulmonary fungal burden were assessed.
Results The use of aerosolization of caspofungin,either as a prophylactic or therapeutic agent, is effective in reducing pulmonary fungal burden of immunosuppressed animals with pulmonary aspergillosis. But only caspofungin inhalations for prevention, is effective in reducing mortality of immunosuppressed animals.
Conclusion Aerosol administration of caspofungin, especially used as prophylactic,could be an additional approach to optimizing treatment of invasive pulmonary aspergillosis.
3. safety of caspofungin inhalations in mice
Objective To evaluated the histologic effects, immunogenic potential after servel inhalations of caspofungin.
Methods ICR mice received caspofungin by aerosolization dosing for1h/day(LD group),2h/day(HD group), or saline control for up to7days. Coronal sections of the entire lung were stained,viewed by light microscopy, and the histopathologic inflammatory score was obtained for each lobe. Cytokine induction of IL-1β、IL-6、TNF-α was assessed by Real-time PCR.
Results The lung histopathologic scores for HD group, LD group, and saline control on days7did not differ between groups. Real-time PCR analysis showed no cytokine induction of IL-1β、IL-6、TNF-α.
Conclusion Aerosol administration of caspofungin for up to7days do not apper to be immunogic and do not cause changes in pulmonary histology. Aerosolization of caspofungin is a safe method of pulmonary delivery.
In conclusion, Targeted airway delivery of antifungals as prophylaxis against invasive aspergillosis may lead to high lung drug concentrations while avoiding toxicities associated with systemically administered agents. We evaluated the effectiveness of aerosolizing caspofungin as prophylaxis and treatment against invasive pulmonary aspergillosis caused by Aspergillus fumigatus in an established murine model. Inhaled caspofungin significantly improved survival and limited the pulmonary fungal burden, as assessed by histopathology, compared to control and amphotericin B treatments. Inhalations were easy to administer and were well tolerated. This experience suggests The physiologic profile of the response to inhaled caspofungin is acceptable and is well tolerated. It merits further assessment in the treatment of pulmonary fungal disease.
本研究的目的是建立免疫抑制小鼠IPA模型,并评价雾化吸入卡泊芬净在预防和治疗IPA的疗效及安全性。主要分为以下三个部分：
1.免疫抑制小鼠侵袭性肺曲霉病模型的建立
目的：动物实验被广泛的应用于侵袭性肺曲霉病(IPA)诊断及治疗方面的研究,本文利用气管插管法建立免疫抑制小鼠IPA模型。
方法：以环磷酰胺及地塞米松对小鼠进行免疫抑制处理后,气管插管气管内滴入烟曲霉孢子悬液,通过组织病理进行验证,并观察小鼠生存-时间曲线。同时运用平板菌落计数方法比较气管插管法与传统滴鼻法造模实际进入鼠肺的孢子量。
结果：气管插管法可成功建立小鼠IPA模型。小鼠1周内死亡率55%,接种24小时后肺组织匀浆平板菌落计数显示气管插管法所造成的孢子入肺量为5.17±0.32CFU(1g)/g肺组织,而传统滴鼻法仅为3.82±0.49CFU(1g)/g肺组织。
结论：气管插管法成功建立小鼠IPA模型,较滴鼻法更适于进行IPA相关研究。
2.卡泊芬净雾化吸入给药防治侵袭性肺曲霉病药效学研究
目的：通过动物实验对雾化吸入卡泊芬净对IPA的防治效果做初步探讨。
方法：免疫抑制小鼠IPA模型,分别给予卡泊芬净腹腔注射及雾化用药,用药策略分为单纯治疗及预防+治疗,同时设置标准治疗——两性霉素B腹腔注射组及对照组,持续用药至感染后第7天。比较各组小鼠生存率及肺组织真菌负荷。
结果：与标准治疗——两性霉素B腹腔注射相比,雾化吸入卡泊芬净作为单纯治疗性用药、或预防+治疗用药均能有效降低小鼠肺组织真菌负荷；但只有作为预防+治疗给药时才能有效提高小鼠生存率,且对IPA预防效果与腹注给药相当。
结论：动物实验证明卡泊芬净雾化吸入给药是一种有效的预防IPA的给药方式。
3.卡泊芬净雾化吸入给药局部安全性研究
目的：观察连续多次雾化吸入卡泊芬净后小鼠肺组织病理学及局部炎症因子表达。
方法：ICR小鼠分为三组,高剂量组每天雾化2小时,低剂量组每天雾化时间为1小时,设置生理盐水对照组,各组小鼠连续用药7天。各组小鼠行肺组织病理学检查并予以评分；提取肺组织RNA行荧光定量PCR,检测各组小鼠肺组织炎症因子表达。
结果：雾化给药结束后各组肺组织病理评分无明显差异,荧光定量PCR检测显示雾化吸入卡泊芬净并未导致肺组织IL-1β、IL-6、TNF-α等炎症因子的活化。
结论：动物实验证明卡泊芬净雾化吸入给药对肺组织刺激性小,安全性较好。
综上所述,抗真菌药物雾化吸入用药在肺组织局部形成较高药物浓度,作为预防性用药时可显著增强抗真菌效果,且避免了高血药浓度导致的副作用。本研究利用动物实验观察了雾化卡泊芬净用于预防和治疗IPA疗效和安全性,与标准治疗药物——两性霉素B治疗相比,雾化卡泊芬净作为预防性用药时可提高小鼠生存率,并降低肺真菌负荷。雾化用药易于操作且安全性较好,有潜在的临床应用前景。
Invasive aspergillosis is a significant cause of morbidity and mortality in heavily immunocompromised patients and is associated with significant hospital costs and therapy complications in those with multiple comorbidities. Targeted pulmonary delivery by aerosolization of antifungals has recently gained attention, The use of aerosols for targeting medication to the receptor sites in the lung has multiple advantages compared to systemic administration, including the use of less drug to provide the same therapeutic effect and the reduction in the likelihood of systemic side effects.
Our objective was to establish the mice model of IPA and assess the Efficacy and safety of caspofungin inhalations for prevention and treatment of invasive pulmonary aspergillosis in mice.Three parts of this research are as following:
1. Establishment of animal model of invasive pulmonary aspergillosis in immunosuppressed mice
Objective Animal experiments are widely used in the diagnosis and treatment of invasive pulmonary aspergillosis (IPA). We establish an experimental model of IPA in neutropenic ICR mice with method of tracheal intubation.
Methods Female ICR mice was immunosuppressed with cyclosphamide and Dexamethasone and inoculated with1×107conodia of Aspergillus fumigates.Patholigic examination were evaluated to determine whether the IPA model was successfully constructed. survival curves was draw,Fungal burden analysis following24h inoculation to compare these two methods.
Results IPA was confirmed in neutropenic ICR mice with method of tracheal intubation based on pathologic examination. Mortality of mice was55%within7d after inculation,Numbers of CFU from homogenized lung tissues of IPA mice were5.17±0.32and3.82±0.49(log/gram lung) with these two methods of tracheal intubation and intranasal challenge, respectively.
Conclusion The IPA model in immunosuppressed ICR mice is constructed successfully,and tracheal intubation was better than intranasal challenge.
2. Efficacy of caspofungin inhalations for prevention and treatment of invasive pulmonary aspergillosis in mice
Objective To evaluated the effectiveness of aerosolizing caspofungin as prophylaxis and treatment against invasive pulmonary aspergillosis caused by Aspergillus fumigates in an established model.
Methods Immunocompromised ICR mice received either caspofungin by intraperitoneal injection or by aerosolization.dosing began2days prior or after pulmonary incoculation with A. fumigates and continued until7days after pulmonary incoculation. Survival and pulmonary fungal burden were assessed.
Results The use of aerosolization of caspofungin,either as a prophylactic or therapeutic agent, is effective in reducing pulmonary fungal burden of immunosuppressed animals with pulmonary aspergillosis. But only caspofungin inhalations for prevention, is effective in reducing mortality of immunosuppressed animals.
Conclusion Aerosol administration of caspofungin, especially used as prophylactic,could be an additional approach to optimizing treatment of invasive pulmonary aspergillosis.
3. safety of caspofungin inhalations in mice
Objective To evaluated the histologic effects, immunogenic potential after servel inhalations of caspofungin.
Methods ICR mice received caspofungin by aerosolization dosing for1h/day(LD group),2h/day(HD group), or saline control for up to7days. Coronal sections of the entire lung were stained,viewed by light microscopy, and the histopathologic inflammatory score was obtained for each lobe. Cytokine induction of IL-1β、IL-6、TNF-α was assessed by Real-time PCR.
Results The lung histopathologic scores for HD group, LD group, and saline control on days7did not differ between groups. Real-time PCR analysis showed no cytokine induction of IL-1β、IL-6、TNF-α.
Conclusion Aerosol administration of caspofungin for up to7days do not apper to be immunogic and do not cause changes in pulmonary histology. Aerosolization of caspofungin is a safe method of pulmonary delivery.
In conclusion, Targeted airway delivery of antifungals as prophylaxis against invasive aspergillosis may lead to high lung drug concentrations while avoiding toxicities associated with systemically administered agents. We evaluated the effectiveness of aerosolizing caspofungin as prophylaxis and treatment against invasive pulmonary aspergillosis caused by Aspergillus fumigatus in an established murine model. Inhaled caspofungin significantly improved survival and limited the pulmonary fungal burden, as assessed by histopathology, compared to control and amphotericin B treatments. Inhalations were easy to administer and were well tolerated. This experience suggests The physiologic profile of the response to inhaled caspofungin is acceptable and is well tolerated. It merits further assessment in the treatment of pulmonary fungal disease.
引文
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[12]吕沛华,赵蓓蕾,施毅,等.侵袭性肺部真菌感染动物模型制作及血浆β-葡聚糖检测的诊断价值[J].中华医院感染学杂志,2007,(11)：1328-1331.
[13]荣令,周新.米卡芬净单药及联合两性霉素B对小鼠侵袭性肺曲霉病的治疗作用[J].实用临床医药杂志,2008,(12)：12-15+25.
[14]刘金辉,杨芬,罗闳丹,等.NF-κB启动的炎症反应在小鼠侵袭性肺曲霉病肺损伤中的作用[J].微生物学通报,2008,(11)：1769-1773.
[15]张冬梅,宋泽庆.侵袭性肺曲霉病动物模型的研究进展[J].国际呼吸杂志,2011,31(6)：468-470.
[16]Gavalda J, Martin MT, Lopez P, et al. Efficacy of nebulized liposomal amphotericin B in treatment of experimental pulmonary aspergillosis. Antimicrob Agents Chemother,2005,49(7):3028-3030.
[1]Denning DW.Echinocandins:a new class of antifungal. [J]. J Antimicrob Chemother,2002,49:889-891.
[2]Diekema DJ,Messer SA,Hollis RJ, et al. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol 2002; 41(8):3623-3626.
[3]Lafaurie M, Lapalu J, Raffoux E, et al. High rate of breakthrough invasive aspergillosis among patients receiving caspofungin for persistent fever and neutropenia. Clin Microbiol Infect 2010;16(8):1191-1196.
[4]Groll AH, Silling G, Young C,et al. Randomized comparison of safety and pharmacokinetics of caspofungin, liposomal amphotericin B, and the combination of both in allogeneic hematopoietic stem cell recipients. Antimicrob Agents Chemother 2010;54(10):4143-4149.
[5]Hiemenz JW, Raad Ⅱ, Maertens JA, et al. Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort. Eur J Clin Microbiol Infect Dis 2010;29(11):1387-1394.
[6]Herbrecht R, Maertens J, Baila L, et al. Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study. Bone Marrow Transplant 2010;45(7):1227-1233.
[7]Ruijgrok EJ, Fens MH, Bakker-Woudenberg IA, et al. Nebulization of four commercially available amphotericin B formulations in persistently granulocytopenic rats with invasive pulmonary aspergillosis:evidence for long-term biological activity. J Pharm Pharmacol,2005,57:1289-1295.
[8]Wong-Beringer A, Lambros MP, Beringer PM, et al. Suitability of caspofungin for aerosol delivery:physicochemical profiling and nebulizer choice. Chest. 2005.128(5):3711-3716.
[9]Tolman JA, Wiederhold NP, McConville JT, et al. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2009.53(6):2613-2615.
[10]de Sande WW v, van VW, ten KMT, et al. Caspofungin prolongs survival of transiently neutropenic rats with advanced-stage invasive pulmonary aspergillosis. Antimicrob Agents Chemother.2008.52(4):1345-1350.
[11]Singh G, Imai J, Clemons KV, et al. Efficacy of caspofungin against central nervous system Aspergillus fumigatus infection in mice determined by TaqMan PCR and CFU methods. Antimicrob Agents Chemother.2005.49(4): 1369-1376.
[12]Shi S, Ashley ES, Alexander BD, et al. Initial characterization of micafungin pulmonary delivery via two different nebulizers and multivariate data analysis of aerosol mass distribution profiles [J]. AAPS PharmSciTech, 2009,10(1):129-137.
[13]Denning DW. Invasive aspergillosis. Clin Infect Dis,1998,26(4):781-803.
[14]Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital [J]. J Infect, 1996,33(1):23-32.
[15]Hagerman JK, Hancock KE, Klepser ME. Aerosolised antibiotics:a critical appraisal of their use [J]. Expert Opin Drug Deliv,2006,3(1):71-86.
[16]Corcoran TE, Venkataramanan R, Mihelc KM, et al. Aerosol deposition of lipid complex amphotericin-B (Abelcet) in lung transplant recipients [J]. Am J Transplant,2006,6(11):2765-2773.
[17]Lambros MP, Bourne DW, Abbas SA, et al. Disposition of aerosolized liposomal amphotericin B [J]. J Pharm Sci,1997,86(9):1066-1069.
[18]Yang W, Johnston KP, Williams RO 3rd. Comparison of bioavailability of amorphous versus crystalline itraconazole nanoparticles via pulmonary administration in rats [J]. Eur J Pharm Biopharm,2010,75(1):33-41.
[19]Yang W, Tam J, Miller DA, et al. High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers [J]. Int J Pharm,2008,361(1-2):177-188.
[20]Shi S, Ashley ES, Alexander BD, et al. Initial characterization of micafungin pulmonary delivery via two different nebulizers and multivariate data analysis of aerosol mass distribution profiles [J]. AAPS PharmSciTech, 2009,10(1):129-137.
[21]张敏,张莉,陈树.两性霉素B雾化吸入治疗老年糖尿病患者下呼吸道真菌感染的临床观察[J].现代临床医学,2009,35(6)：414-415.
[22]乔亚红.氟康唑雾化吸入治疗老年肺部真菌感染的疗效观察[J].中国误诊学杂志,2004,4(8)：1274-1275.
[23]张国范.雾化吸入氟康唑治疗AIDS合并系统性真菌感染67例分析[J].传染病信息,2004,17(4)：175-176.
[24]Gavalda J, Martin MT, Lopez P, et al. Efficacy of nebulized liposomal amphotericin B in treatment of experimental pulmonary aspergillosis. Antimicrob Agents Chemother,2005,49(7):3028-3030.
[25]Shah SP, Misra A. Liposomal amphotericin B dry powder inhaler:effect of fines on in vitro performance [J]. Pharmazie,2004,59(10):812-813.
[26]Vaughn JM, McConville JT, Burgess D, et al. Single dose and multiple dose studies of itraconazole nanoparticles [J]. Eur J Pharm Biopharm, 2006,63(2):95-102.
[27]McConville JT, Overhoff KA, Sinswat P, et al. Targeted high lung concentrations of itraconazole using nebulized dispersions in a murine model [J]. Pharm Res,2006,23(5):901-911.
[28]Hoeben BJ, Burgess DS, McConville JT, et al. In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis [J]. Antimicrob Agents Chemother, 2006,50(4):1552-1554.
[29]Tolman JA, Nelson NA, Bosselmann S, et al. Dose tolerability of chronically inhaled voriconazole solution in rodents [J]. Int J Pharm,2009,379(1):25-31.
[30]Ho KM, Duff O, Chambers D, et al. Meta-analysis of nebulized amphotericin B to prevent or treat pulmonary aspergillosis in immunosuppressed animals. Transpl Infect Dis.2008.10(3):168-176.
[31]Hiemenz JW, Raad Ⅱ, Maertens JA, Hachem RY, Saah AJ, Sable CA, et al. Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort. Eur J Clin Microbiol Infect Dis2010;29(11):1387-1394.
[32]Lamaris GA, Lewis RE, Chamilos G, May GS, Safdar A, Walsh TJ, et al. Caspofungin-mediated beta-glucan unmasking and enhancement of human polymorphonuclear neutrophil activity against Aspergillus and non-Aspergillus hyphae. J Infect Dis 2008; 198(2):186-192.
[33]Alvarez CA, Wiederhold NP, McConville JT, et al. Aerosolized nanostructured itraconazole as prophylaxis against invasive pulmonary aspergillosis [J]. J Infect,2007,55(1):68-74.
[1]Wong-Beringer A, Lambros MP, Beringer PM, et al. Suitability of caspofungin for aerosol delivery:physicochemical profiling and nebulizer choice. Chest. 2005.128(5):3711-3716.
[2]卢鑫,孙文逵,高伟,等.雾化吸入两性霉素B对侵袭性肺曲霉病预防效果的Meta分析[J].中国呼吸与危重监护杂志,2012,11(1)：28-36.
[3]Vaughn JM, McConville JT, Burgess D, et al. Single dose and multiple dose studies of itraconazole nanoparticles [J]. Eur J Pharm Biopharm, 2006,63(2):95-102.
[4]Tolman JA, Nelson NA, Bosselmann S, et al. Dose tolerability of chronically inhaled voriconazole solution in rodents [J]. Int J Pharm,2009,379(1):25-31.
[5]Tolman JA, Wiederhold NP, McConville JT, et al. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis [J]. Antimicrob Agents Chemother,2009,53(6):2613-2615.
[6]乔亚红.氟康唑雾化吸入治疗老年肺部真菌感染的疗效观察[J].中国误诊学杂志,2004,4(8)：1274-1275.
1. Denning DW. Invasive aspergillosis. Clin Infect Dis,1998,26(4):781-803.
2 Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital [J]. J Infect,1996,33(1):23-32.
3 Scott LJ, Simpson D. Voriconazole:a review of its use in the management of invasive fungal infections [J]. Drugs,2007,67(2):269-298.
4 Bolland MJ, Bagg W, Thomas MG, et al. Cushing's syndrome due to interaction between inhaled corticosteroids and itraconazole [J]. Ann Pharmacother, 2004,38(1):46-49.
5 Naef R, Schmid C, Hofer M, et al. Itraconazole comedication increases systemic levels of inhaled fluticasone in lung transplant recipients [J]. Respiration, 2007,74(4):418-422.
6 Hagerman JK, Hancock KE, Klepser ME. Aerosolised antibiotics:a critical appraisal of their use [J]. Expert Opin Drug Deliv,2006,3(1):71-86.
7 Corcoran TE, Venkataramanan R, Mihelc KM, et al. Aerosol deposition of lipid complex amphotericin-B (Abelcet) in lung transplant recipients [J]. Am J Transplant,2006,6(11):2765-2773.
8 Lambros MP, Bourne DW, Abbas SA, et al. Disposition of aerosolized liposomal amphotericin B [J]. J Pharm Sci,1997,86(9):1066-1069.
9 Ruijgrok EJ, Fens MH, Bakker-Woudenberg IA, et al. Nebulization of four commercially available amphotericin B formulations in persistently granulocytopenic rats with invasive pulmonary aspergillosis:evidence for long-term biological activity [J]. J Pharm Pharmacol,2005,57(10):1289-1295.
10 Yang W, Johnston KP, Williams RO 3rd. Comparison of bioavailability of amorphous versus crystalline itraconazole nanoparticles via pulmonary administration in rats [J]. Eur J Pharm Biopharm,2010,75(1):33-41.
11 Yang W, Tam J, Miller DA, et al. High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers [J]. Int J Pharm,2008,361(1-2):177-188.
12 Shi S, Ashley ES, Alexander BD, et al. Initial characterization of micafungin pulmonary delivery via two different nebulizers and multivariate data analysis of aerosol mass distribution profiles [J]. AAPS PharmSciTech,2009,10(1):129-137.
13.张敏,张莉,陈树.两性霉素B雾化吸入治疗老年糖尿病患者下呼吸道真菌感染的临床观察[J].现代临床医学,2009,35(6)：414415.
14.乔业红.氟康唑雾化吸入治疗老年肺部真菌感染的疗效观察[J].中国误诊学杂志,2004,4(8)：1274-1275.
15.张国范.雾化吸入氟康唑治疗AIDS合并系统性真菌感染67例分析[J].传染病信息,2004,17(4)：175-176.
16 Shah SP, Misra A. Liposomal amphotericin B dry powder inhaler:effect of fines on in vitro performance [J]. Pharmazie,2004,59(10):812-813.
17 Vaughn JM, McConville JT, Burgess D, et al. Single dose and multiple dose studies of itraconazole nanoparticles [J]. Eur J Pharm Biopharm, 2006,63(2):95-102.
18 McConville JT, Overhoff KA, Sinswat P, et al. Targeted high lung concentrations of itraconazole using nebulized dispersions in a murine model [J]. Pharm Res, 2006,23(5):901-911.
19 Hoeben BJ, Burgess DS, McConville JT, et al. In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis [J]. Antimicrob Agents Chemother,2006,50(4):1552-1554.
20 Tolman JA, Nelson NA, Bosselmann S, et al. Dose tolerability of chronically inhaled voriconazole solution in rodents [J]. Int J Pharm,2009,379(1):25-31.
21 Ho KM, Duff O, Chambers D, et al. Meta-analysis of nebulized amphotericin B to prevent or treat pulmonary aspergillosis in immunosuppressed animals [J]. Transpl Infect Dis,2008,10(3):168-176.
22 Alexander BD, Dodds Ashley ES, Addison RM, et al. Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation [J]. Transpl Infect Dis,2006,8(1):13-20.
23 Alvarez CA, Wiederhold NP, McConville JT, et al. Aerosolized nanostructured itraconazole as prophylaxis against invasive pulmonary aspergillosis [J]. J Infect, 2007,55(1):68-74.
24 Takazono T, Izumikawa K, Mihara T, et al. Efficacy of combination antifungal therapy with intraperitoneally administered micafungin and aerosolized liposomal amphotericin B against murine invasive pulmonary aspergillosis [J]. Antimicrob Agents Chemother,2009,53(8):3508-3510.
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27 Rijnders BJ, Cornelissen JJ, Slobbe L, et al. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia:a randomized, placebo-controlled trial [J]. Clin Infect Dis, 2008,46(9):1401-1408.
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30 Abe M, Kondo K, Fujino S, et al. Lipoid pneumonia combined with pulmonary nocardiosis caused by inhalation of amphotericin-B after renal transplantation [J]. Nihon Kyobu Shikkan Gakkai Zasshi,1996,34(6):737-740.
31 Tolman JA, Wiederhold NP, McConville JT, et al. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis [J]. Antimicrob Agents Chemother,2009,53(6):2613-2615.
[2]Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital [J]. J Infect, 1996,33(1):23-32.
[3]Scott LJ, Simpson D. Voriconazole:a review of its use in the management of invasive fungal infections [J]. Drugs,2007,67(2):269-298.
[4]Bolland MJ, Bagg W, Thomas MG, et al. Cushing's syndrome due to interaction between inhaled corticosteroids and itraconazole [J]. Ann Pharmacother,2004,38(1):46-49.
[5]Naef R, Schmid C, Hofer M, et al. Itraconazole comedication increases systemic levels of inhaled fluticasone in lung transplant recipients [J]. Respiration,2007,74(4):418-422.
[6]Keating G, Figgitt D. Caspofungin:a review of its use in oesophageal candidiasis, invasive candidiasis and invasive aspergillosis. Drugs 2003;63(20):2235-2263.
[7]Lafaurie M, Lapalu J, Raffoux E, Breton B, Lacroix C, Socie G, et al. High rate of breakthrough invasive aspergillosis among patients receiving caspofungin for persistent fever and neutropenia. Clin Microbiol Infect 2010;16(8):1191-1196.
[8]Groll AH, Silling G, Young C, Schwerdtfeger R, Ostermann H, Heinz WJ, et al. Randomized comparison of safety and pharmacokinetics of caspofungin, liposomal amphotericin B, and the combination of both in allogeneic hematopoietic stem cell recipients. Antimicrob Agents Chemother 2010;54(10):4143-4149.
[9]Hiemenz JW, Raad Ⅱ, Maertens JA, Hachem RY, Saah AJ, Sable CA, et al. Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort. Eur J Clin Microbiol Infect Dis 2010;29(11):1387-1394.
[10]Herbrecht R, Maertens J, Baila L, Aoun M, Heinz W, Martino R, et al. Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients:an European Organisation for Research and Treatment of Cancer study. Bone Marrow Transplant 2010;45(7):1227-1233.
[11]Ruijgrok EJ, Fens MH, Bakker-Woudenberg I A, et al. Nebulization of four commercially available amphotericin B formulations in persistently granulocytopenic rats with invasive pulmonary aspergillosis:evidence for long-term biological activity [J]. J Pharm Pharmacol,2005,57(10):1289-1295.
[12]Shah SP, Misra A. Liposomal amphotericin B dry powder inhaler:effect of fines on in vitro performance [J]. Pharmazie,2004,59(10):812-813.
[13]Ho KM, Duff O, Chambers D, et al. Meta-analysis of nebulized amphotericin B to prevent or treat pulmonary aspergillosis in immunosuppressed animals [J]. Transpl Infect Dis,2008,10(3):168-176.
[14]Paniagua Martin MJ, Marzoa Rivas R, Barge Caballero E, et al. Efficacy and tolerance of different types of prophylaxis for prevention of early aspergillosis after heart transplantation. Transplant Proc,2010,42(8):3014-3016.
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[16]Slobbe L, Boersma E, Rijnders BJ. Tolerability of prophylactic aerosolized liposomal amphotericin-B and impact on pulmonary function:data from a randomized placebo-controlled trial. Pulm Pharmacol Ther,2008, 21(6):855-859.
[17]Rijnders BJ, Cornelissen JJ, Slobbe L, et al. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia:a randomized, placebo-controlled trial. Clin Infect Dis, 2008,46(9):1401-1408.
[18]Behre GF, Schwartz S, Lenz K, et al. Aerosol amphotericin B inhalations for prevention of invasive pulmonary aspergillosis in neutropenic cancer patients. Ann Hematol,1995,71(6):287-291.
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[26]卢鑫,孙文逵,高伟,等.雾化吸入两性霉素B对侵袭性肺曲霉病预防效 果的Meta分析[J].中国呼吸与危重监护杂志,2012,11(1)：28-36.
[27]Tolman JA, Nelson NA, Bosselmann S, et al. Dose tolerability of chronically inhaled voriconazole solution in rodents [J]. Int J Pharm,2009,379(1):25-31.
[28]Alvarez CA, Wiederhold NP, McConville JT, et al. Aerosolized nanostructured itraconazole as prophylaxis against invasive pulmonary aspergillosis [J]. J Infect,2007,55(1):68-74.
[29]Shi S, Ashley ES, Alexander BD, et al. Initial characterization of micafungin pulmonary delivery via two different nebulizers and multivariate data analysis of aerosol mass distribution profiles [J]. AAPS PharmSciTech, 2009,10(1):129-137.
[30]Wong-Beringer A, Lambros MP, Beringer PM, et al. Suitability of caspofungin for aerosol delivery:physicochemical profiling and nebulizer choice. Chest. 2005.128(5):3711-3716.
[1]Yang W, Johnston KP, Williams RO 3rd. Comparison of bioavailability of amorphous versus crystalline itraconazole nanoparticles via pulmonary administration in rats [J]. Eur J Pharm Biopharm,2010,75(1):33-41.
[2]Tolman JA, Nelson NA, Bosselmann S, et al. Dose tolerability of chronically inhaled voriconazole solution in rodents [J]. Int J Pharm,2009,379(1):25-31.
[3]Ho KM, Duff O, Chambers D, et al. Meta-analysis of nebulized amphotericin B to prevent or treat pulmonary aspergillosis in immunosuppressed animals [J]. Transpl Infect Dis,2008,10(3):168-176.
[4]陈志平,刘金辉,罗宏丹,等.NF-κB和TNF-α在烟曲霉菌感染小鼠肺组织中的表达[J].江西医学院学报,2008,(06)：11-13.
[5]李祥,罗闳丹,石青,等.小鼠侵袭性肺曲霉病发病过程中TLRs/NF-κB信号通路的激活[J].中国免疫学杂志,2010,(10)：881-884.
[6]罗闳丹,杨芬,施旻,等.四君子汤对小鼠侵袭性肺曲霉病作用的实验研究[J].中国中医基础医学杂志,2010,(04)：300-302.
[7]于利玲,肖永红.免疫抑制小鼠侵袭性肺曲霉病动物模型的建立[J].中国抗生素杂志,2009,(04)：259-263.
[8]荣令,周新.中性粒细胞减少小鼠侵袭性肺曲霉病模型的构建[J].中国感染与化疗杂志,2008,(05)：373-376.
[9]李军,席丽艳,李希清.实验大鼠侵袭性肺曲霉病早期诊断的研究[J].中华检验医学杂志,2005,(09)：68-71.
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[5]Tolman JA, Wiederhold NP, McConville JT, et al. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis [J]. Antimicrob Agents Chemother,2009,53(6):2613-2615.
[6]乔亚红.氟康唑雾化吸入治疗老年肺部真菌感染的疗效观察[J].中国误诊学杂志,2004,4(8)：1274-1275.
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2 Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital [J]. J Infect,1996,33(1):23-32.
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6 Hagerman JK, Hancock KE, Klepser ME. Aerosolised antibiotics:a critical appraisal of their use [J]. Expert Opin Drug Deliv,2006,3(1):71-86.
7 Corcoran TE, Venkataramanan R, Mihelc KM, et al. Aerosol deposition of lipid complex amphotericin-B (Abelcet) in lung transplant recipients [J]. Am J Transplant,2006,6(11):2765-2773.
8 Lambros MP, Bourne DW, Abbas SA, et al. Disposition of aerosolized liposomal amphotericin B [J]. J Pharm Sci,1997,86(9):1066-1069.
9 Ruijgrok EJ, Fens MH, Bakker-Woudenberg IA, et al. Nebulization of four commercially available amphotericin B formulations in persistently granulocytopenic rats with invasive pulmonary aspergillosis:evidence for long-term biological activity [J]. J Pharm Pharmacol,2005,57(10):1289-1295.
10 Yang W, Johnston KP, Williams RO 3rd. Comparison of bioavailability of amorphous versus crystalline itraconazole nanoparticles via pulmonary administration in rats [J]. Eur J Pharm Biopharm,2010,75(1):33-41.
11 Yang W, Tam J, Miller DA, et al. High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers [J]. Int J Pharm,2008,361(1-2):177-188.
12 Shi S, Ashley ES, Alexander BD, et al. Initial characterization of micafungin pulmonary delivery via two different nebulizers and multivariate data analysis of aerosol mass distribution profiles [J]. AAPS PharmSciTech,2009,10(1):129-137.
13.张敏,张莉,陈树.两性霉素B雾化吸入治疗老年糖尿病患者下呼吸道真菌感染的临床观察[J].现代临床医学,2009,35(6)：414415.
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16 Shah SP, Misra A. Liposomal amphotericin B dry powder inhaler:effect of fines on in vitro performance [J]. Pharmazie,2004,59(10):812-813.
17 Vaughn JM, McConville JT, Burgess D, et al. Single dose and multiple dose studies of itraconazole nanoparticles [J]. Eur J Pharm Biopharm, 2006,63(2):95-102.
18 McConville JT, Overhoff KA, Sinswat P, et al. Targeted high lung concentrations of itraconazole using nebulized dispersions in a murine model [J]. Pharm Res, 2006,23(5):901-911.
19 Hoeben BJ, Burgess DS, McConville JT, et al. In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis [J]. Antimicrob Agents Chemother,2006,50(4):1552-1554.
20 Tolman JA, Nelson NA, Bosselmann S, et al. Dose tolerability of chronically inhaled voriconazole solution in rodents [J]. Int J Pharm,2009,379(1):25-31.
21 Ho KM, Duff O, Chambers D, et al. Meta-analysis of nebulized amphotericin B to prevent or treat pulmonary aspergillosis in immunosuppressed animals [J]. Transpl Infect Dis,2008,10(3):168-176.
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31 Tolman JA, Wiederhold NP, McConville JT, et al. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis [J]. Antimicrob Agents Chemother,2009,53(6):2613-2615.