喹诺酮类药物在儿科的临床使用及实验性软骨毒性研究
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摘要
喹诺酮类药物(Quinolones, QNs)抗菌谱广、抗菌活性强、组织渗透性好,在临床上广泛应用于治疗成人的各种感染性疾病,而在儿科的应用却受到限制。动物实验表明各种QNs均可在幼年动物中诱发关节损害,提示可能对未成年人也具有相同的毒性,也有临床资料显示未成年人服用QNs后引起关节疼痛肿胀,从而导致了该类药物在儿童中应用的限制。但另有较多资料表明儿童接受治疗后并未出现动物实验所引起的关节损害,再加上QNs在治疗一些疾病上的优势,因此在某些情况下,QNs仍在儿科中使用。然而儿科医生认为,使用该类药物也冒着一定的风险,所以在应用的同时也带着一定的矛盾心理。因此QNs在儿科中的安全性评价则显得尤为重要,一直受到广大儿科医生与药学工作者的关注。
本研究通过对儿科临床QNs的使用情况和不良反应进行医院内集中监测,确定临床常用QNs应用现状和不良反应发生情况;研究QNs对幼龄大鼠的软骨毒性和毒代动力学;研究种属、年龄、作用时间和药物品种对软骨毒性的影响以及应用分子生物学方法探讨QNs 软骨毒性机制。主要结果如下:
1. QNs在儿科使用情况调查。通过在复旦大学附属儿科医院病房,江西省儿童医院病房内集中监测方法,对14周岁以下住院患儿进行药物应用情况和安全性评价。监测期(2002年7月18日至2004年2月28日,为期19个月)有101例住院患儿入选,平均年龄为8.16±4.20 (0.01~13.64)岁;其中,小于1岁,9例(8.91%);1～4岁,11例(10.89%);4～7岁,19例(18.81%);7～10岁,22例(21.78%);10～14岁,41例(39.60%)。监测期间所涉及的QNs有环丙沙星,氧氟沙星。其中主要为环丙沙星,93例,占92.08%。监测期间用药持续时间为5.80±3.94 (1~24) d;其中,1～3 d,26例(25.74%);4～7 d,43例(42.57%);7～10 d,19例(18.81%);大于10 d,13例(12.87%)。主要用于胃肠道(33例,32.67%)、呼吸系统(32例,31.68%)、泌尿系统(12例,17.82%)、耳鼻喉科(6例,5.94%)及中枢神经系统(3例,2.97%)感染。药物不良反应总发生率 8.91 %(9/101),胃肠道反应3.96%(4/101),中枢神经系统2.97%(3/101),
过敏反应1.0%(1/101),静脉炎1.0%(1/101)。不良反应主要发生在环丙沙星,8例,氧氟沙星仅1例。均为轻、中度不良反应, 停药后可自行恢复。按卫生部ADR监测中心颁发的标准进行因果关系评价为可能3例,很可能6例。
2. 研究环丙沙星在幼龄大鼠的体内和体外毒性。
(1)软骨毒性和毒代动力学。将4周龄大鼠随机分为4组,每组6只,分别ig 环丙沙星0,400,800和1200 mg/kg,连续7天。第1、6天给药后收集尾静脉血,第7天给药后4 h左侧膝关节做光镜切片,并行软骨厚度测量,右侧膝关节软骨组织制成匀浆,用微生物法测定血清及软骨匀浆上清液药物浓度。结果显示:①环丙沙星的药时曲线符合一室模型,呈线性动力学;第1天与第6天Cmax 和AUC0→∞无显著性差异;Cmax 和AUC0→∞和软骨内药物浓度随剂量成比例递增。② 环丙沙星使软骨层变薄,软骨细胞、软骨基质减少;经图像分析,环丙沙星800和1200 mg/kg使软骨厚度显著减少。③以软骨厚度为效应的定量指标,与剂量,Cmax 和AUC0→∞、软骨内药物浓度进行线性拟合,与Cmax 和AUC0→∞、软骨内药物浓度相关性较好。④根据实验所得的软骨正常厚度的95%的可信期间推测,引起4周龄大鼠软骨损伤的临界Cmax、AUC0→∞和软骨内药物浓度分别为665.90 mg/kg、14.16 mg/L、84.86 mg.h/L和11.95 μg/g。结果提示Cmax、AUC0→∞和软骨内药物浓度可作为毒性效应判定和预测的客观指标。
(2)体外软骨细胞毒性。4周龄大鼠软骨细胞体外与环丙沙星共培养5天,以MTT法评价细胞的增殖,以DMB法评价蛋白多糖的含量。环丙沙星浓度在20 mg/L以上可抑制软骨细胞增殖,浓度在10 mg/L以上可减少蛋白多糖含量。结果表明体内实验与体外实验有较好的相关性。
3. 研究种属、年龄、作用时间、药物品种对QNs体外软骨毒性的影响。(1) QNs对离体大鼠软骨细胞的毒性:将4,8,12周龄大鼠的软骨细胞在各含不同药物的培养基中培养一定时间后,以MTT法和DMB法测定增殖和蛋白多糖分泌。4种QNs对4周龄大鼠软骨体外增殖和蛋白多糖分泌均有抑制作用,其顺序为环丙沙星>左氧氟沙星>氟罗沙星>帕珠沙星。环丙沙星对大鼠软骨细胞体外增殖的抑制作用随大鼠周龄的增大而减弱,随培养时间的延长而增强。(2) QNs对离体兔软骨细胞的毒性:结果与在大鼠上相似。(3) QNs对儿童软骨细胞的毒性:骨外科手术获得的3、6和10岁儿童软骨细胞在各含不同药物的培养基中培养一定时间后测定增殖和蛋白多糖分泌。4种QNs对3岁儿童软骨体外增殖和蛋白多糖分泌均有抑制作用,环丙沙星和左氧氟沙星毒性大于氟罗沙星和帕珠沙星。环丙沙星对儿童软骨细胞体外增殖的抑制作用随儿童年龄的增大而减弱,随
培养时间的延长而增强。(4) 不同种属的比较。对于增殖和蛋白多糖分泌,1月龄兔>4周龄大鼠>3岁儿童。结果表明种属、年龄、作用时间、药物品种对QNs体外软骨毒性均具有影响。
4. 环丙沙星对离体大鼠软骨细胞IL-1β、TNF-α含量的影响。将4周龄大鼠的软骨细胞在含环丙沙星0,5,20,80 mg/L的培养液中,分别培养24、48、72 h后,收集细胞以RT-PCR方法检测IL-1β,TNF-α的mRNA含量,细胞培养上清液以ELISA方法检测
Quinolones (QNs) are rapidly bactericidal and have an extended antimicrobial spectrum, and they have advantageous pharmacokinetic properties such as absorption from gastrointestinal tract, excellent penetration into many tissues and good intracellular diffusion. Thus, they have been showed to be effective in the treatment of a large variety of bacterial infection in adults. A major drawback of QNs is the potential to induce arthropathy in juvenile animals. The extraordinary form of age-related drug toxicity has been determined with various QNs. In the same time, arthropathy has been reported in rare case reports in pediatricts. Thus, the toxicity potential has led to important restrictions of the use of QNs in children. on the other hand, many investigations showed no evidences of increase chondrotoxicity with QNs in pediatric patients. So in some occasions, many children have received treatment with QNs. Thus, it is necessary to evaluate QNs safety in children.
The present studies evaluated the clinical drug utinization in children by hospital intensive monitoring and determined the incidence rates of ADR. Secondly, the chondrotoxicity and toxicokinetics of ciprofloxacin in 4-week old rats were studied. Thirdly, we evaluated the chondrotoxicity of four kinds of QNs (ciprofloxacin, levofloxacin, fleroxacin, pazufloxacin) in animal and child, and evaluated the influence of animal or children age, treatment duration. Finally, the underlying mechanisms of chondrotoxicity were investigated using molecular biological techniques. The results are summarized as follows:
1. The clinical investigation in children hospital
The clinical investigation was eaccomplished by hospital intensive monitoring. The main outcome measures were patient background factors, including age, sex, underlying disease, complications, history, etc. 101 hospitalized patients who took QNs were monitored between July 2002 and February 2002. The children were
8.16±4.20 (0.01~13.64) years old, including 9 patients below 1a (8.91%), 11 patients between1～4 a (10.89%), 19 patients between 4～7 a (18.81%), 22 patients between 7～10 a (21.78%) and 41 patients between 10～14 a (39.60%). The drug involed ciprofloxacin and ofloxacin, and the most commonly used QNs was ciprofloxacin (93 patients, 92.08%). The treatment periods were 5.80±3.94 (1~24) d, including 26 patients between 1～3 d (25.74%), 43 patients between 4～7 d (42.57%), 19 patients between 7～10 d (18.81%) and 13 patients over 13 d (12.87%), respectively. The systems or tissues for treatment category included gastrointestinal tract (33, 32.67%), respiratory system (32, 31.68%), urinary tract (12, 17.82%), otolaryngology (6, 5.94%) and central nerves system (3, 2.97%). The overall ADR rate was 8.91% (9/101). Gastrointestinal, CNS, allergic reaction and phlebitis accounted for 3.96% (4/101), 2.97% (3/101), 1.0%(1/101) and 1.0%(1/101) of the ADR, respectively. The ADR rates of ciprofloxacin were 8.60% (8/93). The symptoms of ADR were gentle or moderate and reversible after drawback.
2. In vivo and in vitro chondrotoxicity of ciprofloxacin in juvenile rats (1) The chondrotoxicity and toxicokinetics of ciprofloxacin were studied in 4-week old rats. Rats were randomly assigned to treatment groups (each including 6 animals) and treated with 0, 400, 800, and 1200 mg/kg ciprofloxacin ig once daily on seven consecutive days. Venous blood on d 1 and d 6 were collected. Four hours after final dosing the rats were killed, the left knee joint was removed for the histopathological examination and the thickness of the cartilage of the femoral condyle was measured with Image Analysis System. Cartilage was obtained from the right knee joint was homogenized. Concentration in serum and cartilage was determined by a validated agar diffusion microbioassay. Results: ① Drug serum concentration-time curves of different doses conformed to one compartment model. The maximum serum concentrations (Cmax), the areas under the concentration-time curve(AUC0→∞) and the concentration in cartilage of ciprofloxac
本研究通过对儿科临床QNs的使用情况和不良反应进行医院内集中监测,确定临床常用QNs应用现状和不良反应发生情况;研究QNs对幼龄大鼠的软骨毒性和毒代动力学;研究种属、年龄、作用时间和药物品种对软骨毒性的影响以及应用分子生物学方法探讨QNs 软骨毒性机制。主要结果如下:
1. QNs在儿科使用情况调查。通过在复旦大学附属儿科医院病房,江西省儿童医院病房内集中监测方法,对14周岁以下住院患儿进行药物应用情况和安全性评价。监测期(2002年7月18日至2004年2月28日,为期19个月)有101例住院患儿入选,平均年龄为8.16±4.20 (0.01~13.64)岁;其中,小于1岁,9例(8.91%);1～4岁,11例(10.89%);4～7岁,19例(18.81%);7～10岁,22例(21.78%);10～14岁,41例(39.60%)。监测期间所涉及的QNs有环丙沙星,氧氟沙星。其中主要为环丙沙星,93例,占92.08%。监测期间用药持续时间为5.80±3.94 (1~24) d;其中,1～3 d,26例(25.74%);4～7 d,43例(42.57%);7～10 d,19例(18.81%);大于10 d,13例(12.87%)。主要用于胃肠道(33例,32.67%)、呼吸系统(32例,31.68%)、泌尿系统(12例,17.82%)、耳鼻喉科(6例,5.94%)及中枢神经系统(3例,2.97%)感染。药物不良反应总发生率 8.91 %(9/101),胃肠道反应3.96%(4/101),中枢神经系统2.97%(3/101),
过敏反应1.0%(1/101),静脉炎1.0%(1/101)。不良反应主要发生在环丙沙星,8例,氧氟沙星仅1例。均为轻、中度不良反应, 停药后可自行恢复。按卫生部ADR监测中心颁发的标准进行因果关系评价为可能3例,很可能6例。
2. 研究环丙沙星在幼龄大鼠的体内和体外毒性。
(1)软骨毒性和毒代动力学。将4周龄大鼠随机分为4组,每组6只,分别ig 环丙沙星0,400,800和1200 mg/kg,连续7天。第1、6天给药后收集尾静脉血,第7天给药后4 h左侧膝关节做光镜切片,并行软骨厚度测量,右侧膝关节软骨组织制成匀浆,用微生物法测定血清及软骨匀浆上清液药物浓度。结果显示:①环丙沙星的药时曲线符合一室模型,呈线性动力学;第1天与第6天Cmax 和AUC0→∞无显著性差异;Cmax 和AUC0→∞和软骨内药物浓度随剂量成比例递增。② 环丙沙星使软骨层变薄,软骨细胞、软骨基质减少;经图像分析,环丙沙星800和1200 mg/kg使软骨厚度显著减少。③以软骨厚度为效应的定量指标,与剂量,Cmax 和AUC0→∞、软骨内药物浓度进行线性拟合,与Cmax 和AUC0→∞、软骨内药物浓度相关性较好。④根据实验所得的软骨正常厚度的95%的可信期间推测,引起4周龄大鼠软骨损伤的临界Cmax、AUC0→∞和软骨内药物浓度分别为665.90 mg/kg、14.16 mg/L、84.86 mg.h/L和11.95 μg/g。结果提示Cmax、AUC0→∞和软骨内药物浓度可作为毒性效应判定和预测的客观指标。
(2)体外软骨细胞毒性。4周龄大鼠软骨细胞体外与环丙沙星共培养5天,以MTT法评价细胞的增殖,以DMB法评价蛋白多糖的含量。环丙沙星浓度在20 mg/L以上可抑制软骨细胞增殖,浓度在10 mg/L以上可减少蛋白多糖含量。结果表明体内实验与体外实验有较好的相关性。
3. 研究种属、年龄、作用时间、药物品种对QNs体外软骨毒性的影响。(1) QNs对离体大鼠软骨细胞的毒性:将4,8,12周龄大鼠的软骨细胞在各含不同药物的培养基中培养一定时间后,以MTT法和DMB法测定增殖和蛋白多糖分泌。4种QNs对4周龄大鼠软骨体外增殖和蛋白多糖分泌均有抑制作用,其顺序为环丙沙星>左氧氟沙星>氟罗沙星>帕珠沙星。环丙沙星对大鼠软骨细胞体外增殖的抑制作用随大鼠周龄的增大而减弱,随培养时间的延长而增强。(2) QNs对离体兔软骨细胞的毒性:结果与在大鼠上相似。(3) QNs对儿童软骨细胞的毒性:骨外科手术获得的3、6和10岁儿童软骨细胞在各含不同药物的培养基中培养一定时间后测定增殖和蛋白多糖分泌。4种QNs对3岁儿童软骨体外增殖和蛋白多糖分泌均有抑制作用,环丙沙星和左氧氟沙星毒性大于氟罗沙星和帕珠沙星。环丙沙星对儿童软骨细胞体外增殖的抑制作用随儿童年龄的增大而减弱,随
培养时间的延长而增强。(4) 不同种属的比较。对于增殖和蛋白多糖分泌,1月龄兔>4周龄大鼠>3岁儿童。结果表明种属、年龄、作用时间、药物品种对QNs体外软骨毒性均具有影响。
4. 环丙沙星对离体大鼠软骨细胞IL-1β、TNF-α含量的影响。将4周龄大鼠的软骨细胞在含环丙沙星0,5,20,80 mg/L的培养液中,分别培养24、48、72 h后,收集细胞以RT-PCR方法检测IL-1β,TNF-α的mRNA含量,细胞培养上清液以ELISA方法检测
Quinolones (QNs) are rapidly bactericidal and have an extended antimicrobial spectrum, and they have advantageous pharmacokinetic properties such as absorption from gastrointestinal tract, excellent penetration into many tissues and good intracellular diffusion. Thus, they have been showed to be effective in the treatment of a large variety of bacterial infection in adults. A major drawback of QNs is the potential to induce arthropathy in juvenile animals. The extraordinary form of age-related drug toxicity has been determined with various QNs. In the same time, arthropathy has been reported in rare case reports in pediatricts. Thus, the toxicity potential has led to important restrictions of the use of QNs in children. on the other hand, many investigations showed no evidences of increase chondrotoxicity with QNs in pediatric patients. So in some occasions, many children have received treatment with QNs. Thus, it is necessary to evaluate QNs safety in children.
The present studies evaluated the clinical drug utinization in children by hospital intensive monitoring and determined the incidence rates of ADR. Secondly, the chondrotoxicity and toxicokinetics of ciprofloxacin in 4-week old rats were studied. Thirdly, we evaluated the chondrotoxicity of four kinds of QNs (ciprofloxacin, levofloxacin, fleroxacin, pazufloxacin) in animal and child, and evaluated the influence of animal or children age, treatment duration. Finally, the underlying mechanisms of chondrotoxicity were investigated using molecular biological techniques. The results are summarized as follows:
1. The clinical investigation in children hospital
The clinical investigation was eaccomplished by hospital intensive monitoring. The main outcome measures were patient background factors, including age, sex, underlying disease, complications, history, etc. 101 hospitalized patients who took QNs were monitored between July 2002 and February 2002. The children were
8.16±4.20 (0.01~13.64) years old, including 9 patients below 1a (8.91%), 11 patients between1～4 a (10.89%), 19 patients between 4～7 a (18.81%), 22 patients between 7～10 a (21.78%) and 41 patients between 10～14 a (39.60%). The drug involed ciprofloxacin and ofloxacin, and the most commonly used QNs was ciprofloxacin (93 patients, 92.08%). The treatment periods were 5.80±3.94 (1~24) d, including 26 patients between 1～3 d (25.74%), 43 patients between 4～7 d (42.57%), 19 patients between 7～10 d (18.81%) and 13 patients over 13 d (12.87%), respectively. The systems or tissues for treatment category included gastrointestinal tract (33, 32.67%), respiratory system (32, 31.68%), urinary tract (12, 17.82%), otolaryngology (6, 5.94%) and central nerves system (3, 2.97%). The overall ADR rate was 8.91% (9/101). Gastrointestinal, CNS, allergic reaction and phlebitis accounted for 3.96% (4/101), 2.97% (3/101), 1.0%(1/101) and 1.0%(1/101) of the ADR, respectively. The ADR rates of ciprofloxacin were 8.60% (8/93). The symptoms of ADR were gentle or moderate and reversible after drawback.
2. In vivo and in vitro chondrotoxicity of ciprofloxacin in juvenile rats (1) The chondrotoxicity and toxicokinetics of ciprofloxacin were studied in 4-week old rats. Rats were randomly assigned to treatment groups (each including 6 animals) and treated with 0, 400, 800, and 1200 mg/kg ciprofloxacin ig once daily on seven consecutive days. Venous blood on d 1 and d 6 were collected. Four hours after final dosing the rats were killed, the left knee joint was removed for the histopathological examination and the thickness of the cartilage of the femoral condyle was measured with Image Analysis System. Cartilage was obtained from the right knee joint was homogenized. Concentration in serum and cartilage was determined by a validated agar diffusion microbioassay. Results: ① Drug serum concentration-time curves of different doses conformed to one compartment model. The maximum serum concentrations (Cmax), the areas under the concentration-time curve(AUC0→∞) and the concentration in cartilage of ciprofloxac
引文
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11. Chubinskaya S, Huch K, Schulze M, et al. Gene expression by human articular chondrocytes cultured in alginate beads. J Histochem Cytochem. 2001;49(10): 1211-20.
12. Cuzzolin L, Fanos V. Safety of fluoroquinolones in paediatrics. Expert Opin Drug Saf. 2002; 1(4): 319-24
13. Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Ann N Y Acad Sci. 2001;933:222-34.
14. Dominique G, Florence M. Fluoroquinolones in paediatrics. Paediatr drugs. 2001; 3(5):365-77
Stahlmann R, Lode H. Toxicity of quinolones. Drugs. 1999; 58( Suppl 2): 37-42.
15. Egerbacher M, Edinger J, Tschulenk W. Effects of enrofloxacin and ciprofloxacin hydrochloride on canine and equine chondrocytes in culture. Am J Vet Res. 2001; 62(5): 704-8.
16. Egerbacher M, Wolfesberger B, Gabler C. In vitro evidence for effects of magnesium supplementation on quinolone-treated horse and dog chondrocytes. Vet Pathol 2001; 38(2): 143-8
17. Egerbacher M; Edinger J; Tschulenk W. Effects of enrofloxacin and ciprofloxacin hydrochloride on canine and equine chondrocytes in culture. Am J Vet Res. 2001; 62(5): 704-8
18. Enobakhare BO, Bader DL, Lee DA. Quantification of sulfated glycosaminoglycans in chondrocyte/alginate cultures, by use of 1,9-dimethylmethylene blue. Anal Biochem. 1996; 243(1): 189-195
19. Kato M, Takada S, Ogawara S, et al. Effect of levofloxacin on glycosaminoglycan and DNA synthesis of cultured rabbit chondrocytes at concentrations inducing cartilage lesions In Vitro. Antimicrob Agents and Chemother. 1995; 39(9): 1979-1987
20. Enobakhare BO, Bader DL, Lee DA. Quantification of sulfated glycosaminoglycans in chondrocyte/alginate cultures, by use of 1,9-dimethylmethylene blue. Anal Biochem. 1996; 243(1): 189-91.
21. Li GC, Chen CY, Wang YH. Comparative pharmacokinetic study on ciprofloxacin in healthy volunteers of the han, uigur and kazak nationalities. Chin J Clin Pharmacol 1997; 13(3): 145-148
22. Fernandes J C; Martel Pelletier J; Pelletier J P. The role of cytokines in osteoarthritis pathophysiology. Biorheology. 2002; 39(1-2): 237-46
23. Fernandes JC, Martel Pelletier J, Pelletier JP, et al. The role of cytokines in osteoarthritis pathophysiology. Biorheology. 2002; 39(1-2): 237-46
24. Finch RG. Ciprofloxacin: efficacy and indications. J Chemother. 2000;12(Suppl 1):5-7
25. Egerbacher M, Seiberl G, Wolfesberger B, et al. Ciprofloxacin causes cytoskeletal changes and detachment of human and rat chondrocytes in vitro. Arch Toxicol. 2000; 73(10-11):557
26. Gendrel D, Chalumeau M, Moulin F, et al. Fluoroquinolones in paediatrics: a risk for the patient or for the community. Lancet Infect Dis. 2003;3(9):537-46
27. Gendrel D, Chalumeau M, Moulin F, et al. Fluoroquinolones in paediatrics: a risk
for the patient or for the community? Lancet Infect Dis. 2003; 3(9):537-46.
28. Grady R. Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J. 2003; 22(12):1128-32
29. Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use--safety report. Pediatr Infect Dis J. 1997; 16(1):127-9
30. Henrotin YE, De Groote DD, Labasse AH. Effects of exogenous IL-1 beta, TNF alpha, IL-6, IL-8 and LIF on cytokine production by human articular chondrocytes. Osteoarthritis Cartilage. 1996; 4(3):163-73.
31. Hildebrand H, Kempka G, Schluter G, et al. Chondrotoxicity of quinolones in vivo and in vitro. Arch Toxicol. 1993; 67(6): 411-5.
32. Iannone F, Lapadula G. The pathophysiology of osteoarthritis. Aging Clin Exp Res. 2003;15(5):364-72
33. Jafri HS, McCracken GH Jr. Fluoroquinolones in paediatrics. Drugs. 1999;58 (Suppl) 2:43-8
34. Jian XL, Prudhommeaux F, Meunier A, et al. Effects of chitosan on rat knee cartilages Biomaterials. 1999;20: 1937-1944
35. Kato M, Takada S, Ogawara S, et al. Effect of Levofloxacin on Glycosaminoglycan and DNA Synthesis of Cultured Rabbit Chondrocytes at Concentrations Inducing Cartilage Lesions In Vivo. Antimicrob Agents Chemother 1995; 39(9): 1979-83
36. Koyle MA, Barqawi A, Wild J, et al. Pediatric urinary tract infections: the role of fluoroquinolones. Pediatr Infect Dis J. 2003;22(12):1133-7.
37. Kunihisa O, David P, Martin D, et al. Pro- and Anti-inflammatory Cytokine Gene Expression in Rat Sciatic Nerve Chronic Constriction Injury Model of Neuropathic Pain. Experimental Neurology. 2001;169: 386–391
38. Lotz M, Terkeltaub R; Villiger PM. Cartilage and joint inflammation. Regulation of IL-8 expression by human articular chondrocytes. J Immunol. 1992; 148(2): 466-73
39. Lozo E, Riecke K, Schwabe R, et al. Synergistic effect of ofloxacin and magnesium deficiency on joint cartilage in immature rats. Antimicrob Agents Chemother. 2002; 46(6): 1755-9.
40. Lozo E, Riecke K, Schwabe R, et al. Synergistic Effect of Ofloxacin and Magnesium Deficiency on Joint Cartilage in Immature Rats. Antimicrob Agents
Chemother. 2002; 46(6):1755
41. Marchetti F, Candusso M, Faraguna D, et al. Early Pseudomonas aeruginosa colonisation in cystic fibrosis patients. Lancet. 2002;359(9306):626-7
42. Margerie D, Flechtenmacher J, Buttner FH,Complexity of IL-1 beta induced gene expression pattern in human articular chondrocytes.Osteoarthritis Cartilage. 1997;5(2):129-38..
43. Nagai A, Miyazaki M, Morita T, et al. Comparative articular toxicity of garenoxacin, a novel quinolone antimicrobial agent, in juvenile beagle dogs. J Toxicol Sci 2002; 27(3): 219-28.
44. Nazmul A H, Rasul C H. Quinolone induced arthropathy in adolescents and adults. Pak J Med Sci. 2000; 16(5): 271-275
45. Nieha S, Fub E, Hsieh Y D, et al. Effects of cyclosporin A on the mandibular condylar cartilage in rats. Archives of Oral Biology. 1999;44(8):693-700
46. Patel IR, Attur MG, Patel RN, et al. TNF-alpha convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-alpha.J Immunol. 1998;160(9):4570-9
47. Pulsatelli L, Dolzani P, Piacentini A, et al. Chemokine production by human chondrocytes. J Rheumatol. 1999;26(9):1992-2001.
48. Redmond A, Sweeney L, MacFarland M, et al. Oral ciprofloxacin in the treatment of pseudomonas exacerbations of paediatric cystic fibrosis: clinical efficacy and safety evaluation using magnetic resonance image scanning. J Int Med Res. 1998;26(6):304-12
49. Reigner BG, Williams PE, Patel IH, et al. An evaluation of the integration of pharmacokinetic and pharmacodynamic principles in clinical drug development. Experience within Hoffmann La Roche. Clin Pharmacokinet. 1997; 33(3):142-52
50. Richardson DW, Dodge GR. Dose-dependent effects of corticosteroids on the expression of matrix-related genes in normal and cytokine-treated articular chondrocytes. Inflamm Res. 2003;52(1):39-49.
51. Roland PS, Anon JB, Moe RD, et al. Topical ciprofloxacin/dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media and otorrhea through tympanostomy tubes. Laryngoscope. 2003;113(12):2116-22.
52. Rouveix, B. Antibiotic safety assessment. Int J Antimicrob Agents, 2003; 21(3):215-21
53. Rubinstein E. History of quinolones and their side effects. Chemotherapy, 2001, 47
(Suppl 3): 3, discussion 44
54. Rude RK, Gruber HE, Wei LY, et al. Magnesium deficiency: effect on bone and mineral metabolism in the mouse. Calcif Tissue Int. 2003;72(1):32-41..
55. Schaad UB, abdus Salam M, Aujard Y, et al. Use of fluoroquinolones in pediatrics: consensus report of an International Society of Chemotherapy commission. Pediatr Infect Dis J. 1995;14(1):1-9.
56. Schaad UB, Stoupis C, Wedgwood J, et al. Clinical, radiologic and magnetic resonance monitoring for skeletal toxicity in pediatric patients with cystic fibrosis receiving a three-month course of ciprofloxacin. Pediatr Infect Dis J. 1991;10(10):723-9
57. Schuerwegh AJ, Dombrecht EJ, Stevens WJ,et al. Influence of pro-inflammatory (IL-1 alpha, IL-6, TNF-alpha, IFN-gamma) and anti-inflammatory (IL-4) cytokines on chondrocyte function. Osteoarthritis Cartilage. 2003; 11(9): 681-7
58. Shakibaei M; Kociok K; Forster C. Comparative evaluation of ultrastructural changes in articular cartilage of ofloxacin-treated and magnesium-deficient immature rats. Toxicol-Pathol. 1996; 24(5): 580-7
59. Sharma AK, Khosla R, Kela AK, Mehta, et al. Fluoroquinolones: antimicrobial agents of the 90’s. Indian J Pharmacol. 1994; 26(4):249-61
60. Stahlmann R, Forster C, Shakibaei M, et al. Magnesium Deficiency Induces Joint Cartilage Lesions In Juvenile rats which are identical to quinolone-induced arthropathy. Antimicrob Agents Chemother. 1995; 39(9) :2013-8.
61. Stahlmann R, Kuhner S, Shakibaei M, et al. Chondrotoxicity of ciprofloxacin in immature beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations. Arch Toxicol, 2000 ,73(10-11):564.
62. Stahlmann R, Kuhner S, Shakibaei M, et al. Effects of magnesium deficiency on joint cartilage in immature beagle dogs: immunohistochemistry, electron microscopy, and mineral concentrations. Arch Toxicol. 2000; 73(10-11): 573-80
63. Stahlmann R, Lode H. Toxicity of quinolones. Drugs. 1999;58 Suppl 2:37-42
64. Stahlmann R, Zippel U, Forster C, et al. Chondrotoxicity and toxicokinetics of sparfloxacin in juvenile rats. Antimicrob Agents Chemother, 1998, 42(6): 1470.
65. Stahlmann R. Children as a special population at risk--quinolones as an example for xenobiotics exhibiting skeletal toxicity. Arch Toxicol. 2003; 77(1): 7-11.
66. Stahlmann R, Zippel U, Forster C, et al. Chondrotoxicity and Toxicokinetics of Sparfloxacin in Juvenile Rats. Antimicrob Agents Chemother. 1998; 42(6): 1470-5
67. Stahlmann R. Clinical toxicological aspects of fluoroquinolones. Toxicol Lett. 2002;127(1-3): 269.
68. Takafuji VA, McIlwraith CW, Howard RD. Effects of equine recombinant interleukin-1alpha and interleukin-1beta on proteoglycan metabolism and prostaglandin E2 synthesis in equine articular cartilage explants. Am J Vet Res. 2002; 63(4): 551-8
69. Takayama S, Hirohashi M, Kato M, et al. Toxicity of quinolone antimicrobial agents. J Toxicol Environ Health. 1995; 45(1):1-45
70. Takizawa T; Hasimoto K; Itoh N; et al. A comparative study of the repeat dose toxicity of grepafloxacin and a number of other fluoroquinolones in rats. Hum Exp Toxicol. 1999; 18(1): 38-45
71. Thuong Guyot M, Domarle O, Pocidalo JJ, et al. Effects of fluoroquinolones on cultured articular chondrocytes flow cytometric analysis of free radical production. J Pharmacol Exp Ther. 1994;271(3):1544-9
72. Tiku K, Thakker Varia S, Ramachandrula A, et al. Articular chondrocytes secrete IL-1, express membrane IL-1, and have IL-1 inhibitory activity. Cell Immunol. 1992; 140(1): 1-20
73. Van den Berg W. Cytokines in bone and cartilage destruction and repair. J Clin Rheumatol . 2001; 7(3): S8-S11
74. Visnapuu V, Peltomaki T, Isotupa K, et al. Distribution and characterization of proliferative cells in the rat mandibular condyle during growth. Eur J Orthod. 2000; 22(6): 631-8.
75. Walter I; Egerbacher M; Wolfesberger; et al. Confocal laser scanning microscopy of chondrocytes in vitro: cytoskeletal changes after quinolone treatment. Scanning. 1998; 20(7): 511-5
76. Wang L, Verbruggen G, Almqvist KF, et al. Flow cytometric analysis of the human articular chondrocyte phenotype in vitro. Osteoarthritis Cartilage. 2001;9(1):73-84
77. Warren RW. Rheumatologic aspects of pediatric cystic fibrosis patients treated with fluoroquinolones. Pediatr Infect Dis J. 1997; 16(1): 118-22; discussion 123-6
78. Yoon YM, Kim SJ, Oh CD, Ju JW, et al. Maintenance of differentiated phenotype of articular chondrocytes by protein kinase C and extracellular signal-regulated protein kinase. J Biol Chem. 2002; 277(10): 8412-20.
79. Zhang LR, Wang YM, Chen BY, et al. Neurotoxicity and toxicokinetics of norfloxacin in conscious rats. Acta Pharmacol Sin. 2003; 24(6): 605-9
80. 冯云云, 王新华, 安文. 氧氟沙星与环丙沙星治疗小儿伤寒的临床观察. 河南医药信息. 1999; 7(9):22-23
81. 姜天俊, 虞爱华. 喹诺酮类药物对儿童关节软骨的影响. 中华儿科杂志. 1998; 36(8): 506.
82. 李国昌, 陈春雁, 王玉华. 环丙沙星在中国汉族、维吾尔族、哈萨克族正常人体中的药代动力学比较. 中国临床药理学杂志. 1997; 13(3): 145-148
83. 虞爱华, 韩铁铮, 杨生, 等. 氟哌酸对儿童安全性观察. 中华儿科杂志. 1991; 29(3): 223-224
84. 虞爱华, 苏淑惠, 韩铁铮, 等. 吡哌酸对儿童骨关节的远期影响. 中国抗生素杂志. 1996; 21(3): 239-240
85. 周红梅, 张智. 环丙沙星治疗小儿伤寒. 儿科药学. 2002; 8(1):53
2. kizawa T, Hasimoto K, Itoh N, et al. A comparative study of the repeat dose toxicity of grepafloxacin and a number of other fluoroquinolones in rats. Hum Exp Toxicol. 1999; 18(1): 38-44
3. Ball P. Future of the quinolones. Semin Respir Infect. 2001; 16(4): 215-224
4. Beluche LA; Bertone AL; Anderson DE; et al. In vitro dose-dependent effects of enrofloxacin on equine articular cartilage. Am J Vet Res. 1999; 60(5): 577-82
5. Burkhardt J E, Walterspiel JN, Schaad U B. Quinolone arthropathy in animals versus children. Clin Infect Dis, 1997; 25(5): 1196-1204
6. Burkhardt JE, Walterspiel JN, Schaad UB. Quinolone arthropathy in animals versus children. Clin Infect Dis, 1997; 25(5): 1196-1175
7. Chalumeau M, Tonnelier S, D'Athis P, et al. Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France. Pediatrics. 2003;111(6 Pt 1): 714-9.
8. Cheung WH, Lee KM, Fung KP, et al. Growth plate chondrocytes inhibit neo-angiogenesis -- a possible mechanism for tumor control. Cancer Lett. 2001; 163(1): 25-32
9. Chowdhury TT, Bader DL, Lee DA, et al. Dynamic compression counteracts IL-1 beta-induced release of nitric oxide and PGE2 by superficial zone chondrocytes cultured in agarose constructs. Osteoarthritis Cartilage. 2003; 11(9): 688-96
10. Christ, W., Central nervous system toxicity of quinolones: human and animal findings. J Antimicrob Chemother 1990; 26(Suppl B):219-25
11. Chubinskaya S, Huch K, Schulze M, et al. Gene expression by human articular chondrocytes cultured in alginate beads. J Histochem Cytochem. 2001;49(10): 1211-20.
12. Cuzzolin L, Fanos V. Safety of fluoroquinolones in paediatrics. Expert Opin Drug Saf. 2002; 1(4): 319-24
13. Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Ann N Y Acad Sci. 2001;933:222-34.
14. Dominique G, Florence M. Fluoroquinolones in paediatrics. Paediatr drugs. 2001; 3(5):365-77
Stahlmann R, Lode H. Toxicity of quinolones. Drugs. 1999; 58( Suppl 2): 37-42.
15. Egerbacher M, Edinger J, Tschulenk W. Effects of enrofloxacin and ciprofloxacin hydrochloride on canine and equine chondrocytes in culture. Am J Vet Res. 2001; 62(5): 704-8.
16. Egerbacher M, Wolfesberger B, Gabler C. In vitro evidence for effects of magnesium supplementation on quinolone-treated horse and dog chondrocytes. Vet Pathol 2001; 38(2): 143-8
17. Egerbacher M; Edinger J; Tschulenk W. Effects of enrofloxacin and ciprofloxacin hydrochloride on canine and equine chondrocytes in culture. Am J Vet Res. 2001; 62(5): 704-8
18. Enobakhare BO, Bader DL, Lee DA. Quantification of sulfated glycosaminoglycans in chondrocyte/alginate cultures, by use of 1,9-dimethylmethylene blue. Anal Biochem. 1996; 243(1): 189-195
19. Kato M, Takada S, Ogawara S, et al. Effect of levofloxacin on glycosaminoglycan and DNA synthesis of cultured rabbit chondrocytes at concentrations inducing cartilage lesions In Vitro. Antimicrob Agents and Chemother. 1995; 39(9): 1979-1987
20. Enobakhare BO, Bader DL, Lee DA. Quantification of sulfated glycosaminoglycans in chondrocyte/alginate cultures, by use of 1,9-dimethylmethylene blue. Anal Biochem. 1996; 243(1): 189-91.
21. Li GC, Chen CY, Wang YH. Comparative pharmacokinetic study on ciprofloxacin in healthy volunteers of the han, uigur and kazak nationalities. Chin J Clin Pharmacol 1997; 13(3): 145-148
22. Fernandes J C; Martel Pelletier J; Pelletier J P. The role of cytokines in osteoarthritis pathophysiology. Biorheology. 2002; 39(1-2): 237-46
23. Fernandes JC, Martel Pelletier J, Pelletier JP, et al. The role of cytokines in osteoarthritis pathophysiology. Biorheology. 2002; 39(1-2): 237-46
24. Finch RG. Ciprofloxacin: efficacy and indications. J Chemother. 2000;12(Suppl 1):5-7
25. Egerbacher M, Seiberl G, Wolfesberger B, et al. Ciprofloxacin causes cytoskeletal changes and detachment of human and rat chondrocytes in vitro. Arch Toxicol. 2000; 73(10-11):557
26. Gendrel D, Chalumeau M, Moulin F, et al. Fluoroquinolones in paediatrics: a risk for the patient or for the community. Lancet Infect Dis. 2003;3(9):537-46
27. Gendrel D, Chalumeau M, Moulin F, et al. Fluoroquinolones in paediatrics: a risk
for the patient or for the community? Lancet Infect Dis. 2003; 3(9):537-46.
28. Grady R. Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J. 2003; 22(12):1128-32
29. Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use--safety report. Pediatr Infect Dis J. 1997; 16(1):127-9
30. Henrotin YE, De Groote DD, Labasse AH. Effects of exogenous IL-1 beta, TNF alpha, IL-6, IL-8 and LIF on cytokine production by human articular chondrocytes. Osteoarthritis Cartilage. 1996; 4(3):163-73.
31. Hildebrand H, Kempka G, Schluter G, et al. Chondrotoxicity of quinolones in vivo and in vitro. Arch Toxicol. 1993; 67(6): 411-5.
32. Iannone F, Lapadula G. The pathophysiology of osteoarthritis. Aging Clin Exp Res. 2003;15(5):364-72
33. Jafri HS, McCracken GH Jr. Fluoroquinolones in paediatrics. Drugs. 1999;58 (Suppl) 2:43-8
34. Jian XL, Prudhommeaux F, Meunier A, et al. Effects of chitosan on rat knee cartilages Biomaterials. 1999;20: 1937-1944
35. Kato M, Takada S, Ogawara S, et al. Effect of Levofloxacin on Glycosaminoglycan and DNA Synthesis of Cultured Rabbit Chondrocytes at Concentrations Inducing Cartilage Lesions In Vivo. Antimicrob Agents Chemother 1995; 39(9): 1979-83
36. Koyle MA, Barqawi A, Wild J, et al. Pediatric urinary tract infections: the role of fluoroquinolones. Pediatr Infect Dis J. 2003;22(12):1133-7.
37. Kunihisa O, David P, Martin D, et al. Pro- and Anti-inflammatory Cytokine Gene Expression in Rat Sciatic Nerve Chronic Constriction Injury Model of Neuropathic Pain. Experimental Neurology. 2001;169: 386–391
38. Lotz M, Terkeltaub R; Villiger PM. Cartilage and joint inflammation. Regulation of IL-8 expression by human articular chondrocytes. J Immunol. 1992; 148(2): 466-73
39. Lozo E, Riecke K, Schwabe R, et al. Synergistic effect of ofloxacin and magnesium deficiency on joint cartilage in immature rats. Antimicrob Agents Chemother. 2002; 46(6): 1755-9.
40. Lozo E, Riecke K, Schwabe R, et al. Synergistic Effect of Ofloxacin and Magnesium Deficiency on Joint Cartilage in Immature Rats. Antimicrob Agents
Chemother. 2002; 46(6):1755
41. Marchetti F, Candusso M, Faraguna D, et al. Early Pseudomonas aeruginosa colonisation in cystic fibrosis patients. Lancet. 2002;359(9306):626-7
42. Margerie D, Flechtenmacher J, Buttner FH,Complexity of IL-1 beta induced gene expression pattern in human articular chondrocytes.Osteoarthritis Cartilage. 1997;5(2):129-38..
43. Nagai A, Miyazaki M, Morita T, et al. Comparative articular toxicity of garenoxacin, a novel quinolone antimicrobial agent, in juvenile beagle dogs. J Toxicol Sci 2002; 27(3): 219-28.
44. Nazmul A H, Rasul C H. Quinolone induced arthropathy in adolescents and adults. Pak J Med Sci. 2000; 16(5): 271-275
45. Nieha S, Fub E, Hsieh Y D, et al. Effects of cyclosporin A on the mandibular condylar cartilage in rats. Archives of Oral Biology. 1999;44(8):693-700
46. Patel IR, Attur MG, Patel RN, et al. TNF-alpha convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-alpha.J Immunol. 1998;160(9):4570-9
47. Pulsatelli L, Dolzani P, Piacentini A, et al. Chemokine production by human chondrocytes. J Rheumatol. 1999;26(9):1992-2001.
48. Redmond A, Sweeney L, MacFarland M, et al. Oral ciprofloxacin in the treatment of pseudomonas exacerbations of paediatric cystic fibrosis: clinical efficacy and safety evaluation using magnetic resonance image scanning. J Int Med Res. 1998;26(6):304-12
49. Reigner BG, Williams PE, Patel IH, et al. An evaluation of the integration of pharmacokinetic and pharmacodynamic principles in clinical drug development. Experience within Hoffmann La Roche. Clin Pharmacokinet. 1997; 33(3):142-52
50. Richardson DW, Dodge GR. Dose-dependent effects of corticosteroids on the expression of matrix-related genes in normal and cytokine-treated articular chondrocytes. Inflamm Res. 2003;52(1):39-49.
51. Roland PS, Anon JB, Moe RD, et al. Topical ciprofloxacin/dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media and otorrhea through tympanostomy tubes. Laryngoscope. 2003;113(12):2116-22.
52. Rouveix, B. Antibiotic safety assessment. Int J Antimicrob Agents, 2003; 21(3):215-21
53. Rubinstein E. History of quinolones and their side effects. Chemotherapy, 2001, 47
(Suppl 3): 3, discussion 44
54. Rude RK, Gruber HE, Wei LY, et al. Magnesium deficiency: effect on bone and mineral metabolism in the mouse. Calcif Tissue Int. 2003;72(1):32-41..
55. Schaad UB, abdus Salam M, Aujard Y, et al. Use of fluoroquinolones in pediatrics: consensus report of an International Society of Chemotherapy commission. Pediatr Infect Dis J. 1995;14(1):1-9.
56. Schaad UB, Stoupis C, Wedgwood J, et al. Clinical, radiologic and magnetic resonance monitoring for skeletal toxicity in pediatric patients with cystic fibrosis receiving a three-month course of ciprofloxacin. Pediatr Infect Dis J. 1991;10(10):723-9
57. Schuerwegh AJ, Dombrecht EJ, Stevens WJ,et al. Influence of pro-inflammatory (IL-1 alpha, IL-6, TNF-alpha, IFN-gamma) and anti-inflammatory (IL-4) cytokines on chondrocyte function. Osteoarthritis Cartilage. 2003; 11(9): 681-7
58. Shakibaei M; Kociok K; Forster C. Comparative evaluation of ultrastructural changes in articular cartilage of ofloxacin-treated and magnesium-deficient immature rats. Toxicol-Pathol. 1996; 24(5): 580-7
59. Sharma AK, Khosla R, Kela AK, Mehta, et al. Fluoroquinolones: antimicrobial agents of the 90’s. Indian J Pharmacol. 1994; 26(4):249-61
60. Stahlmann R, Forster C, Shakibaei M, et al. Magnesium Deficiency Induces Joint Cartilage Lesions In Juvenile rats which are identical to quinolone-induced arthropathy. Antimicrob Agents Chemother. 1995; 39(9) :2013-8.
61. Stahlmann R, Kuhner S, Shakibaei M, et al. Chondrotoxicity of ciprofloxacin in immature beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations. Arch Toxicol, 2000 ,73(10-11):564.
62. Stahlmann R, Kuhner S, Shakibaei M, et al. Effects of magnesium deficiency on joint cartilage in immature beagle dogs: immunohistochemistry, electron microscopy, and mineral concentrations. Arch Toxicol. 2000; 73(10-11): 573-80
63. Stahlmann R, Lode H. Toxicity of quinolones. Drugs. 1999;58 Suppl 2:37-42
64. Stahlmann R, Zippel U, Forster C, et al. Chondrotoxicity and toxicokinetics of sparfloxacin in juvenile rats. Antimicrob Agents Chemother, 1998, 42(6): 1470.
65. Stahlmann R. Children as a special population at risk--quinolones as an example for xenobiotics exhibiting skeletal toxicity. Arch Toxicol. 2003; 77(1): 7-11.
66. Stahlmann R, Zippel U, Forster C, et al. Chondrotoxicity and Toxicokinetics of Sparfloxacin in Juvenile Rats. Antimicrob Agents Chemother. 1998; 42(6): 1470-5
67. Stahlmann R. Clinical toxicological aspects of fluoroquinolones. Toxicol Lett. 2002;127(1-3): 269.
68. Takafuji VA, McIlwraith CW, Howard RD. Effects of equine recombinant interleukin-1alpha and interleukin-1beta on proteoglycan metabolism and prostaglandin E2 synthesis in equine articular cartilage explants. Am J Vet Res. 2002; 63(4): 551-8
69. Takayama S, Hirohashi M, Kato M, et al. Toxicity of quinolone antimicrobial agents. J Toxicol Environ Health. 1995; 45(1):1-45
70. Takizawa T; Hasimoto K; Itoh N; et al. A comparative study of the repeat dose toxicity of grepafloxacin and a number of other fluoroquinolones in rats. Hum Exp Toxicol. 1999; 18(1): 38-45
71. Thuong Guyot M, Domarle O, Pocidalo JJ, et al. Effects of fluoroquinolones on cultured articular chondrocytes flow cytometric analysis of free radical production. J Pharmacol Exp Ther. 1994;271(3):1544-9
72. Tiku K, Thakker Varia S, Ramachandrula A, et al. Articular chondrocytes secrete IL-1, express membrane IL-1, and have IL-1 inhibitory activity. Cell Immunol. 1992; 140(1): 1-20
73. Van den Berg W. Cytokines in bone and cartilage destruction and repair. J Clin Rheumatol . 2001; 7(3): S8-S11
74. Visnapuu V, Peltomaki T, Isotupa K, et al. Distribution and characterization of proliferative cells in the rat mandibular condyle during growth. Eur J Orthod. 2000; 22(6): 631-8.
75. Walter I; Egerbacher M; Wolfesberger; et al. Confocal laser scanning microscopy of chondrocytes in vitro: cytoskeletal changes after quinolone treatment. Scanning. 1998; 20(7): 511-5
76. Wang L, Verbruggen G, Almqvist KF, et al. Flow cytometric analysis of the human articular chondrocyte phenotype in vitro. Osteoarthritis Cartilage. 2001;9(1):73-84
77. Warren RW. Rheumatologic aspects of pediatric cystic fibrosis patients treated with fluoroquinolones. Pediatr Infect Dis J. 1997; 16(1): 118-22; discussion 123-6
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