小剂量长时间口服罗红霉素治疗常年性变应性鼻炎的临床研究
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摘要
目的：近年，罗红霉素（ roxithromycin，RXM）等十四元环大环内酯类抗生素的抗炎活性及免疫调节作用的研究取得了很大进展，虽然作用机制不清，但目前研究工作初步证实的一些机制与包括常年性变应性鼻炎 （ perennial allergic rhinitis , PAR）在内的变应性疾病密切相关, 临床上已应用小剂量大环内酯类抗生素治疗支气管哮喘, 并取得了理想疗效。尚未见有用于治疗PAR的报道, 本文通过观察小剂量长时间口服RXM治疗PAR后患者症状体征改善情况，并通过检测鼻分泌物嗜酸性粒细胞（EOS）计数﹑ 血清细胞因子浓度变化的情况, 探讨RXM是否对PAR有治疗作用 及可能的作用机制，为临床治疗PAR探索一种新途径。
材料与方法: 按照 PAR 诊断标准自门诊选择 111例 PAR患者, 随机分为三组：常规免疫治疗对照组， RXM 治疗试验组，RXM并常规免疫治疗试验组。 除去患者因故失访外，追踪观察资料全的常规免疫治疗组21例，RXM治疗组22例，RXM并常规免疫治疗组30例。RXM治疗组：成人患者自确诊之日起口服 RXM(大连美罗大药厂生产)150mg，儿童患者按体重2.5~5mg/kg，日1次，共12周。常规免疫治疗组：病例使用的变应原均为北京协和医院提供的吸入组变应原液20种，依据病史、皮试、体外特异性 IgE 检测确定患者变应原种类。脱敏起始浓度根据皮试反
应强弱确定，“+”者用1:106，“++” 者用1:108,“+++” 者用 1:1012，脱敏采用皮下注射，每周2次。起始量 0.1ml皮下注射，以后每次递增 0.1ml，当注射量达到 1.0ml 时，如无不良反应，下一疗程浓度增加10倍，直至12周结束随访，之后患者仍接受以后疗程的脱敏治疗。RXM并常规免疫治疗组：在患者常规免疫治疗的同时,给予成人口服RXM(大连美罗大药厂生产)150mg,儿童患者按体重2.5~5mg/kg，日1次，共12周。三组患者均嘱其每1个月来复诊1次，以保证其按试验设计要求用药。三组患者于治疗前后分别进行临床症状﹑体征打分，治疗效果按下列公式评定：治疗前后症状、体征积分改善百分率=（治疗前总分—治疗后总分）/治疗前总分×100%,其结果≥51%为显效,50% ~21%为有效，≤20%为无效。在光镜下对经Wright染色的鼻分泌物进行EOS计数，并应用 ELISA 法检测血清细胞因子IL-5﹑IL-8浓度值。 所采用数据用美国 SAS公司生产的SAS统计软件THE SAS SYSTEM FOR WINDOWSTMRELEASE 6.12进行分析。
结果：应用RXM治疗组一般25~35天症状减轻，12周疗程结束时， 大多数患者症状体征得到改善, 不良反应轻微。1. 治疗12周后, RXM治疗组总有效率为 72.73%; RXM并常规免疫治疗组总有效率为80%；常规免疫治疗组总有效率为19.05%。可见，有RXM治疗组效果显著，有效率差异具有统计学意义（P<0.01）； 应用RXM治疗组症状、体征记分明显下降， 三组记分差异显著（均为 P<0.01）； 应用RXM 治疗组治疗前后症状﹑ 体征记分下降明显 （ 均为P<0.01）。 2 . 治疗后，应用 RXM治疗组鼻分
泌物EOS计数明显下降，三组EOS计数差异显著（P<0.05）,应用RXM 治疗组治疗前后 EOS 计数降低明显 （P<0.01， P<0.01）。3. 治疗后， 应用RXM治疗组血清IL-5浓度明显下降，三组IL-5浓度值差异显著（P<0.05）; 应用RXM治疗组治疗前后IL-5浓度降低明显（P<0.01， P<0.01）。4.治疗后，应用 RXM 治疗组血清 IL-8 浓度明显下降，三组IL-8浓度值差异显著（P<0.01）；应用RXM治疗组治疗前后IL-8浓度降低明显（P<0.01， P<0.01）。5. 单用RXM治疗组症状体征记分减少的百分率与EOS计数减少的百分率无明显相关性（r = 0.1599，P=0.4887）；单用RXM治疗组症状体征记分减少的百分率与血清IL-5浓度值减少的百分率有相关性（r = 0.4674，P=0.0326）；单用RXM治疗组症状体征记分减少的百分率与血清 IL-8 浓度值减少的百分率无明显相关性（r = 0.1644，P=0.4764）。
结论：本研究从RXM对PAR患者治疗效果出发，通过应用光镜观察EOS数量的变化情况 , 应用免疫学检测与PAR发病相关的细胞因子含量的变化情况, 观察到RXM治疗12周后， 患者症状体征记分明显下降， 鼻分泌物EOS及血清 IL-5﹑IL-8 含量均明显下降， 单用RXM治疗组症状体征记分减少的百分率与血清IL-5浓度值减少的百分率有明显相关性。 这些结果提示： 小剂量长时间口服 RXM可能治疗 PAR 有效 , 可能通过减少机体细胞因子 IL-5﹑IL-8，尤其是IL-5的生成， 抑制EOS在鼻黏膜的募集而发挥其抗炎﹑调节免疫的作用，进而能够有效控制PAR的症状及体征。
Objective: Lately, the study of roxithromycin (RXM) and other 14-membered macrolide antibiotics’ anti-inflammatory and immunoregulatory activity has made much progress. Although the precise mechanisms remain unclear, some mechanism verified were correlated with allergy diseases, inculding perennial allergic rhinitis(PAR). Long-term low-dose macrolide antibiotics had been successfully used to treat asthma patients, while nothing had been reported about using it to treat PAR. To determine whether RXM is effective in the management of patients with PAR, the changs of symptoms and rhinoscopic findings were observed; To investigate the possible mechanisms, the amount of eosinophils (EOS) in nasal secrection and concentration of serum cytokine were measured.
Materials and methods: 111 outpatients with PAR wererandomly divided into 3 groups: immunotherapy control group,RXM group and RXM/immunotherapy group. Except somepatients failed to follow-up, the immunotherapy group wasconsisted of 21 patients, the RXM group comprised 22 patients,the RXM/immunotherapy group was composed of 30 patients.The patients in RXM group were treated with 150mg (children
with 2.5~5mg/kg) of RXM once a day orally for 12 weeks. Themethod of immunotherapy: 20 sorts of allergen used for patientscame from Beijing Xiehe Hospital. The allergen was verified bymedical history, skin test and special IgE test in vitro.The initialconcentration was chose according to the result of skin test: “+” ---- 1:106,“++” ---- 1:108,“+++” ---- 1:1012, hypodermic injection,twice a week. Injection began with 0.1ml, added 0.1ml in thenext time until 1.0ml. The concentration was added up to 10times for the next course, follow-up was not terminated until 12weeks, then the patients continued to receive the subsequentimmunotherapy. When patients in the third group received immunotherapy, they were administered with 150mg (childrenwith 2.5~5mg/kg) of RXM once a day orally at the same time.All the patients in the three groups were told to come to hospitalonce a month. All the patients were given symptom and rhinoscopic findings scores before and after therapy,respectively.The efficacy of therapy was assessed as the formula:
(total score pretreatment — total score post-treatment) /total score pretreatment × 100%
the result ≥ 51% indicated significant effect, 50% ~21% indicated effect, ≤20% indicated no effect, The amount ofEOS in the nasal secretion was counted under microscope(×400) after Wright’s staining, and the concentration of serumIL-5 and IL-8 were detected by ELISA. All the data wereanalyzed by THE SAS SYSTEM FOR WINDOWSTM RELEASE 6.12
Result: Most patients in the two experimental groups feltsymptoms decrease after treating for 25~35 days. 12 weeks later,improvement of symptoms and signs was noted in most patients.No significant side effects were noted. 1. The effective rate of immunotherapy group, RXM group, and RXM/immunotherapy group was 19.05%, 72.73%, 80%, respectively. The efficacy of the two experimental groups was more significant (P<0.01); Thescores of symptoms and rhinoscopic findings were significantlylower than that before treatment (all P<0.01). 2. After treatment,the amount of EOS in the two experimental groups wassignificantly lower than that in immunotherapy group(P<0.05); The amount of EOS in RXM group andRXM/immunotherapy group was significantly lower thanthat before treatment(P<0.01, P<0.01, respectively ). 3. Aftertreatment, the levels of serum IL-5 in the two experimentalgroups were significantly lower than that in immunotherapygroup (P<0.05); The levels of serum IL-5 in RXM group andRXM/immunotherapy group significantly decreased comparedwith pretreatment ( P<0.01, P<0.01, respectively ). 4. Aftertreatment, the concentration of serum IL-8
材料与方法: 按照 PAR 诊断标准自门诊选择 111例 PAR患者, 随机分为三组：常规免疫治疗对照组， RXM 治疗试验组，RXM并常规免疫治疗试验组。 除去患者因故失访外，追踪观察资料全的常规免疫治疗组21例，RXM治疗组22例，RXM并常规免疫治疗组30例。RXM治疗组：成人患者自确诊之日起口服 RXM(大连美罗大药厂生产)150mg，儿童患者按体重2.5~5mg/kg，日1次，共12周。常规免疫治疗组：病例使用的变应原均为北京协和医院提供的吸入组变应原液20种，依据病史、皮试、体外特异性 IgE 检测确定患者变应原种类。脱敏起始浓度根据皮试反
应强弱确定，“+”者用1:106，“++” 者用1:108,“+++” 者用 1:1012，脱敏采用皮下注射，每周2次。起始量 0.1ml皮下注射，以后每次递增 0.1ml，当注射量达到 1.0ml 时，如无不良反应，下一疗程浓度增加10倍，直至12周结束随访，之后患者仍接受以后疗程的脱敏治疗。RXM并常规免疫治疗组：在患者常规免疫治疗的同时,给予成人口服RXM(大连美罗大药厂生产)150mg,儿童患者按体重2.5~5mg/kg，日1次，共12周。三组患者均嘱其每1个月来复诊1次，以保证其按试验设计要求用药。三组患者于治疗前后分别进行临床症状﹑体征打分，治疗效果按下列公式评定：治疗前后症状、体征积分改善百分率=（治疗前总分—治疗后总分）/治疗前总分×100%,其结果≥51%为显效,50% ~21%为有效，≤20%为无效。在光镜下对经Wright染色的鼻分泌物进行EOS计数，并应用 ELISA 法检测血清细胞因子IL-5﹑IL-8浓度值。 所采用数据用美国 SAS公司生产的SAS统计软件THE SAS SYSTEM FOR WINDOWSTMRELEASE 6.12进行分析。
结果：应用RXM治疗组一般25~35天症状减轻，12周疗程结束时， 大多数患者症状体征得到改善, 不良反应轻微。1. 治疗12周后, RXM治疗组总有效率为 72.73%; RXM并常规免疫治疗组总有效率为80%；常规免疫治疗组总有效率为19.05%。可见，有RXM治疗组效果显著，有效率差异具有统计学意义（P<0.01）； 应用RXM治疗组症状、体征记分明显下降， 三组记分差异显著（均为 P<0.01）； 应用RXM 治疗组治疗前后症状﹑ 体征记分下降明显 （ 均为P<0.01）。 2 . 治疗后，应用 RXM治疗组鼻分
泌物EOS计数明显下降，三组EOS计数差异显著（P<0.05）,应用RXM 治疗组治疗前后 EOS 计数降低明显 （P<0.01， P<0.01）。3. 治疗后， 应用RXM治疗组血清IL-5浓度明显下降，三组IL-5浓度值差异显著（P<0.05）; 应用RXM治疗组治疗前后IL-5浓度降低明显（P<0.01， P<0.01）。4.治疗后，应用 RXM 治疗组血清 IL-8 浓度明显下降，三组IL-8浓度值差异显著（P<0.01）；应用RXM治疗组治疗前后IL-8浓度降低明显（P<0.01， P<0.01）。5. 单用RXM治疗组症状体征记分减少的百分率与EOS计数减少的百分率无明显相关性（r = 0.1599，P=0.4887）；单用RXM治疗组症状体征记分减少的百分率与血清IL-5浓度值减少的百分率有相关性（r = 0.4674，P=0.0326）；单用RXM治疗组症状体征记分减少的百分率与血清 IL-8 浓度值减少的百分率无明显相关性（r = 0.1644，P=0.4764）。
结论：本研究从RXM对PAR患者治疗效果出发，通过应用光镜观察EOS数量的变化情况 , 应用免疫学检测与PAR发病相关的细胞因子含量的变化情况, 观察到RXM治疗12周后， 患者症状体征记分明显下降， 鼻分泌物EOS及血清 IL-5﹑IL-8 含量均明显下降， 单用RXM治疗组症状体征记分减少的百分率与血清IL-5浓度值减少的百分率有明显相关性。 这些结果提示： 小剂量长时间口服 RXM可能治疗 PAR 有效 , 可能通过减少机体细胞因子 IL-5﹑IL-8，尤其是IL-5的生成， 抑制EOS在鼻黏膜的募集而发挥其抗炎﹑调节免疫的作用，进而能够有效控制PAR的症状及体征。
Objective: Lately, the study of roxithromycin (RXM) and other 14-membered macrolide antibiotics’ anti-inflammatory and immunoregulatory activity has made much progress. Although the precise mechanisms remain unclear, some mechanism verified were correlated with allergy diseases, inculding perennial allergic rhinitis(PAR). Long-term low-dose macrolide antibiotics had been successfully used to treat asthma patients, while nothing had been reported about using it to treat PAR. To determine whether RXM is effective in the management of patients with PAR, the changs of symptoms and rhinoscopic findings were observed; To investigate the possible mechanisms, the amount of eosinophils (EOS) in nasal secrection and concentration of serum cytokine were measured.
Materials and methods: 111 outpatients with PAR wererandomly divided into 3 groups: immunotherapy control group,RXM group and RXM/immunotherapy group. Except somepatients failed to follow-up, the immunotherapy group wasconsisted of 21 patients, the RXM group comprised 22 patients,the RXM/immunotherapy group was composed of 30 patients.The patients in RXM group were treated with 150mg (children
with 2.5~5mg/kg) of RXM once a day orally for 12 weeks. Themethod of immunotherapy: 20 sorts of allergen used for patientscame from Beijing Xiehe Hospital. The allergen was verified bymedical history, skin test and special IgE test in vitro.The initialconcentration was chose according to the result of skin test: “+” ---- 1:106,“++” ---- 1:108,“+++” ---- 1:1012, hypodermic injection,twice a week. Injection began with 0.1ml, added 0.1ml in thenext time until 1.0ml. The concentration was added up to 10times for the next course, follow-up was not terminated until 12weeks, then the patients continued to receive the subsequentimmunotherapy. When patients in the third group received immunotherapy, they were administered with 150mg (childrenwith 2.5~5mg/kg) of RXM once a day orally at the same time.All the patients in the three groups were told to come to hospitalonce a month. All the patients were given symptom and rhinoscopic findings scores before and after therapy,respectively.The efficacy of therapy was assessed as the formula:
(total score pretreatment — total score post-treatment) /total score pretreatment × 100%
the result ≥ 51% indicated significant effect, 50% ~21% indicated effect, ≤20% indicated no effect, The amount ofEOS in the nasal secretion was counted under microscope(×400) after Wright’s staining, and the concentration of serumIL-5 and IL-8 were detected by ELISA. All the data wereanalyzed by THE SAS SYSTEM FOR WINDOWSTM RELEASE 6.12
Result: Most patients in the two experimental groups feltsymptoms decrease after treating for 25~35 days. 12 weeks later,improvement of symptoms and signs was noted in most patients.No significant side effects were noted. 1. The effective rate of immunotherapy group, RXM group, and RXM/immunotherapy group was 19.05%, 72.73%, 80%, respectively. The efficacy of the two experimental groups was more significant (P<0.01); Thescores of symptoms and rhinoscopic findings were significantlylower than that before treatment (all P<0.01). 2. After treatment,the amount of EOS in the two experimental groups wassignificantly lower than that in immunotherapy group(P<0.05); The amount of EOS in RXM group andRXM/immunotherapy group was significantly lower thanthat before treatment(P<0.01, P<0.01, respectively ). 3. Aftertreatment, the levels of serum IL-5 in the two experimentalgroups were significantly lower than that in immunotherapygroup (P<0.05); The levels of serum IL-5 in RXM group andRXM/immunotherapy group significantly decreased comparedwith pretreatment ( P<0.01, P<0.01, respectively ). 4. Aftertreatment, the concentration of serum IL-8
引文
1 顾之燕。 认识和诊治变应性鼻炎的指导性文件。中华耳 鼻咽喉科杂志，2002，37（3）：163~164
2 变应性鼻炎诊断标准及疗效评定标准。 中华耳鼻咽喉科 杂志，1998, 33（3）: 134~135
3 顾之燕， 韩子刚，刘志连。耳鼻咽喉科变应性和免疫性 疾病。天津：天津科学技术出版社。2000, 7: 11~14
4 黄江菊，洪苏玲，杨玉成。变应性鼻炎病人 IL-4， IL-5 和GM-CSF的水平观察。免疫学杂志, 2002, 18（ 2）： 161
5 侯穗波，戴勇，刘明等。 变应性鼻炎特异性免疫治疗对 细胞因子的影响。广东医学，2001，22（1）：44~45
6 肖琪， 赖乃揆， 周立红。 变应性鼻炎患者血浆中白细 胞介素4和白细胞介素8的研究。 广州医学院学报， 2000，28（1）：65~68
7 顾之燕，呼吸道炎症反应。中华耳鼻炎喉科杂志， 2001, 36(5): 397~399
8 Simons FE. Allergic rhinobronchitis: the asthma-allergic rhinitis link. J Allergy Clin Immunol, 1999, 104 (3 pt 1): 534~540
9 Komoi H, Kurihara N, Fujiwara H, et al. The macrolide antibacterial roxithromycin reduces bronchial hyperresponsiveness and superoxide anion production by polymorphonuclear leukocytes in patients with asthma. J Asthma, 1995, 32: 191~197
10 Amayasu H, Yoshida S, Ebana S, et al. Clarithromycin suppresses bronchia hyperresponsiveness associated with eosinophilic inflammation in patients with asthma. Ann Allergy Asthma Immunol, 2000 , 84(6): 594~598
11 Garey KW, Rubinstein I, Gotfried MH, et al. Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma. Chest, 2000, 118(6): 1826~1827
12 陶仲为。 小剂量长期红霉素治疗哮喘12例及其有效机 理。医师进修杂志，1995, 18: 10~11
13 Konno S, Asano K, Kurokawa M, et al. Antiasthmatic activity of a macrolide antibiotic , roxithromycin: analysis of possible mechanisms in vitro and in vivo. Int Arch Allergy Immunol, 1994, 105(3): 308~316
14 Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin modulates IL-8 expression in normal and inflamed human bronchial epithelial cells. Am J Respir Care Med, 1997 , 156(1): 266~271
15 Morikawa K, Zhang J, Nonaka M, et al. Mudulatory effect of macrolide antibiotics on the Th1-and Th2-type cytokine production. Int J Antimicrob Agents, 2002 , 19(1): 53~59
16 Kohyama T, Takizawa H, Kawasaki S. Fourteen-member macrolides inhibit interleukin-8 release by human eosinophils from atopic donors. Antimicrob Agents Chemother, 1999 , 43(4): 907~911
17 Miyanohara T, Ushikai M, Marsune S, et al. Effect of clarithromycin on cultured human nasal epitheial cells and fibroblasts. Laryngoscope, 2000 , 110(1): 126~131
18 Abe S, Nakamura H, Znoue S, et al. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial cells. Am J Respir Cell Mol Biol, 2000 , 22(1): 51~60
19 Rhee CS, Majima Y, Arima S, et al. Effects of clarithromycin on rheological properties of nasal mucus in patients with chronic sinusitis. Ann Otol Rhinol Laryngol, 2000 , 109(5): 484~487
20 Feldman C, Anderson K, Theron AJ, et al. Roxithromycin, clarithromycin, and azithromycin attenuate the injurious effects of bioactive phospholipids on human respiratory epithelium in vitro. Inflammation, 1997 , 21(6): 655~ 66521 Feldman C, Anderson R, Theron A, et al. The effects of ketolides on bioactive phospholipid-induced injury to human respiratory epithelium in vitro. Eur Respir J, 1999, 13: 1022~1028
22 Tamaoki J, Tagaya E, Sakai A, et al. Effects of macrolide antibiotics on neurally mediated contraction of human isolated bronchus. J Allergy Clin Immunol, 1995, 95: 853~ 859
23 Miyatake H, Taki F, Taniguchi H, et al. Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma. Chest, 1991, 99: 670~673
24 Spector S. Pathophysiology and Pharmacotherapy of Allergic Rhinitis. J Allergy Clin Immunol, 1999, 103(3): S377~S400
25 顾之燕，韩子刚, 刘志连。耳鼻咽喉科变应性和免疫性 疾病。天津：天津科学技术出版社。2000, 7: 23
26 Anderson R, Theron AJ, Feldman C. Membrane-stabilizing anti-inflammatory interactions of macrolides with human neutrophils. Inflammation, 1996, 20(6): 693~705
27 Nakajima T, Yoshizawa I, Kawano Y, et al. Suppressive effect of roxithromycin on the induction of IL-2 responsiveness by DF-stimulated lymphocytes from patients with bronchial asthma. Arerugi, 1996 , 45(6): 554~ 561
28 Noma T, Aoki K, hayashi M, et al. Effect of roxithromycin on T lymphocyte prolifer and cytokine production elicited by mite antigen. Int Immunopharmacol, 2001, 1(2): 201~ 210
29 张罗，韩德民， 张波。 IL-5在鼻息肉发病机制中的作 用。 国外医学耳鼻咽喉科学分册， 2000， 24（4）： 223
30 Barnes PJ, Adcock IM. Transcription factors and asthma. Eur Respir J, 1998, 12: 221~234
31 Antoon J, Njikamp F. Effect of anti-IL-5 and IL-5 on airway hyperactivity and eosnophils in guinea pigs. Am Rev Respir Dis , 1993, 147: 548~552
32 Noah TL, Henderson FW, Henry MM, et al. Nasal lavage cytokines in normal, allergic, and asthmatic school-age children. Am J Respir Crit Care Med, 1995, 152: 1290~ 1296
33 Feather IH, Wilson SJ. Eosinophils in rhinitis. In: Busse WW, Holgate ST, editors. Asthma and rhinitis. Oxford, England: Blackwell Scientific, 1995: 347~366
34 James N, Baraniuk MD, Washington DC. Pathogenesis of allergic rhinitis, J Allergy Clin Immunol, 1997; 99: S768~ S769
2 变应性鼻炎诊断标准及疗效评定标准。 中华耳鼻咽喉科 杂志，1998, 33（3）: 134~135
3 顾之燕， 韩子刚，刘志连。耳鼻咽喉科变应性和免疫性 疾病。天津：天津科学技术出版社。2000, 7: 11~14
4 黄江菊，洪苏玲，杨玉成。变应性鼻炎病人 IL-4， IL-5 和GM-CSF的水平观察。免疫学杂志, 2002, 18（ 2）： 161
5 侯穗波，戴勇，刘明等。 变应性鼻炎特异性免疫治疗对 细胞因子的影响。广东医学，2001，22（1）：44~45
6 肖琪， 赖乃揆， 周立红。 变应性鼻炎患者血浆中白细 胞介素4和白细胞介素8的研究。 广州医学院学报， 2000，28（1）：65~68
7 顾之燕，呼吸道炎症反应。中华耳鼻炎喉科杂志， 2001, 36(5): 397~399
8 Simons FE. Allergic rhinobronchitis: the asthma-allergic rhinitis link. J Allergy Clin Immunol, 1999, 104 (3 pt 1): 534~540
9 Komoi H, Kurihara N, Fujiwara H, et al. The macrolide antibacterial roxithromycin reduces bronchial hyperresponsiveness and superoxide anion production by polymorphonuclear leukocytes in patients with asthma. J Asthma, 1995, 32: 191~197
10 Amayasu H, Yoshida S, Ebana S, et al. Clarithromycin suppresses bronchia hyperresponsiveness associated with eosinophilic inflammation in patients with asthma. Ann Allergy Asthma Immunol, 2000 , 84(6): 594~598
11 Garey KW, Rubinstein I, Gotfried MH, et al. Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma. Chest, 2000, 118(6): 1826~1827
12 陶仲为。 小剂量长期红霉素治疗哮喘12例及其有效机 理。医师进修杂志，1995, 18: 10~11
13 Konno S, Asano K, Kurokawa M, et al. Antiasthmatic activity of a macrolide antibiotic , roxithromycin: analysis of possible mechanisms in vitro and in vivo. Int Arch Allergy Immunol, 1994, 105(3): 308~316
14 Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin modulates IL-8 expression in normal and inflamed human bronchial epithelial cells. Am J Respir Care Med, 1997 , 156(1): 266~271
15 Morikawa K, Zhang J, Nonaka M, et al. Mudulatory effect of macrolide antibiotics on the Th1-and Th2-type cytokine production. Int J Antimicrob Agents, 2002 , 19(1): 53~59
16 Kohyama T, Takizawa H, Kawasaki S. Fourteen-member macrolides inhibit interleukin-8 release by human eosinophils from atopic donors. Antimicrob Agents Chemother, 1999 , 43(4): 907~911
17 Miyanohara T, Ushikai M, Marsune S, et al. Effect of clarithromycin on cultured human nasal epitheial cells and fibroblasts. Laryngoscope, 2000 , 110(1): 126~131
18 Abe S, Nakamura H, Znoue S, et al. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial cells. Am J Respir Cell Mol Biol, 2000 , 22(1): 51~60
19 Rhee CS, Majima Y, Arima S, et al. Effects of clarithromycin on rheological properties of nasal mucus in patients with chronic sinusitis. Ann Otol Rhinol Laryngol, 2000 , 109(5): 484~487
20 Feldman C, Anderson K, Theron AJ, et al. Roxithromycin, clarithromycin, and azithromycin attenuate the injurious effects of bioactive phospholipids on human respiratory epithelium in vitro. Inflammation, 1997 , 21(6): 655~ 66521 Feldman C, Anderson R, Theron A, et al. The effects of ketolides on bioactive phospholipid-induced injury to human respiratory epithelium in vitro. Eur Respir J, 1999, 13: 1022~1028
22 Tamaoki J, Tagaya E, Sakai A, et al. Effects of macrolide antibiotics on neurally mediated contraction of human isolated bronchus. J Allergy Clin Immunol, 1995, 95: 853~ 859
23 Miyatake H, Taki F, Taniguchi H, et al. Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma. Chest, 1991, 99: 670~673
24 Spector S. Pathophysiology and Pharmacotherapy of Allergic Rhinitis. J Allergy Clin Immunol, 1999, 103(3): S377~S400
25 顾之燕，韩子刚, 刘志连。耳鼻咽喉科变应性和免疫性 疾病。天津：天津科学技术出版社。2000, 7: 23
26 Anderson R, Theron AJ, Feldman C. Membrane-stabilizing anti-inflammatory interactions of macrolides with human neutrophils. Inflammation, 1996, 20(6): 693~705
27 Nakajima T, Yoshizawa I, Kawano Y, et al. Suppressive effect of roxithromycin on the induction of IL-2 responsiveness by DF-stimulated lymphocytes from patients with bronchial asthma. Arerugi, 1996 , 45(6): 554~ 561
28 Noma T, Aoki K, hayashi M, et al. Effect of roxithromycin on T lymphocyte prolifer and cytokine production elicited by mite antigen. Int Immunopharmacol, 2001, 1(2): 201~ 210
29 张罗，韩德民， 张波。 IL-5在鼻息肉发病机制中的作 用。 国外医学耳鼻咽喉科学分册， 2000， 24（4）： 223
30 Barnes PJ, Adcock IM. Transcription factors and asthma. Eur Respir J, 1998, 12: 221~234
31 Antoon J, Njikamp F. Effect of anti-IL-5 and IL-5 on airway hyperactivity and eosnophils in guinea pigs. Am Rev Respir Dis , 1993, 147: 548~552
32 Noah TL, Henderson FW, Henry MM, et al. Nasal lavage cytokines in normal, allergic, and asthmatic school-age children. Am J Respir Crit Care Med, 1995, 152: 1290~ 1296
33 Feather IH, Wilson SJ. Eosinophils in rhinitis. In: Busse WW, Holgate ST, editors. Asthma and rhinitis. Oxford, England: Blackwell Scientific, 1995: 347~366
34 James N, Baraniuk MD, Washington DC. Pathogenesis of allergic rhinitis, J Allergy Clin Immunol, 1997; 99: S768~ S769