喹诺酮类药物对离体兔软骨细胞的毒性

目的 :评价几种喹诺酮类药物对幼龄兔软骨细胞的相对毒性 ,软骨毒性与浓度、时间、年龄的关系。方法 :采用兔软骨细胞体外培养的技术 ,观察细胞形态 ,四氮甲基唑蓝 (MTT)法评价细胞的增殖 ,二甲基亚甲蓝 (DMB)法评价细胞蛋白多糖的含量。观察环丙沙星、左氧氟沙星、氟罗沙星、帕珠沙星对 1月龄兔软骨细胞的影响 ,及环丙沙星对 1,3,5月龄兔软骨细胞的影响。结果 :喹诺酮类药物使细胞形态发生改变 ;抑制细胞的增殖的作用依次为环丙沙星 >左氧氟沙星 >氟罗沙星 >帕珠沙星 ;对蛋白多糖含量的作用为环丙沙星 >左氧氟沙星 >氟罗沙星、帕珠沙星 ;环丙沙星的抑制作用随作用时间的延长和浓度的增加而增加 ,随兔年龄的增大而减少。结论 :喹诺酮类几种药物的软骨毒性存在着差异 ,且随浓度、时间、年龄不同而不同。     

Are chondrocytes damaged when rheumatologic inflammation is suppressed?

Aim: The use of biological agents (BAs) for treating diseases such as rheumatoid arthritis (RA), spondyloarthropathy, and systemic lupus erythematosus to reduce inflammation has been fruitful. Especially as part of the increasing number of studies on the intra-articular application of BAs, the effects of BAs on cartilage have been widely investigated. In the present study, the effects of rituximab, abatacept, and adalimumab, all approved antirheumatic agents, on human primary chondrocytes were investigated comparatively and on the molecular level through viability, proliferation, and toxicity analyses. Materials and methods: Osteochondral tissues from the distal femur and proximal tibia were resected during total knee arthroplasty from patients (n?=?3) with confirmed gonarthrosis in whom all medical or conservative treatments had failed. Standard human primary chondrocyte cell culturing was carried out. Immunophenotyping was performed on the cells that adhered to the flask, and their chondrotoxicity was observed using a flow cytometry device. Images of the cells showing chondrotoxicity were analyzed using invert and environmental scanning microscopes, and microimages were obtained. The MTT-enzyme linked immunosorbent assay was performed to observe the toxic effects of BAs on the proliferation of chondrocytes at 24 and 48?h. The results were analyzed using the number of cells and proliferation; statistical comparisons among the groups were carried out using one-way ANOVA. The alpha significance level was set at <0.01. Results: These pharmaceutical agents were chondrotoxic, especially on viability and proliferation (p?=?0.0000). Conclusion: BAs are generally used during active inflammation, and following the management of inflammation, their dosage should be determined taking into consideration their cellular-level toxic effects on chondrocytes.     

Preclinical safety evaluation of levonadifloxacin,a novel anti-methicillin-resistant Staphyloccocus aureus benzoquinolizine fluoroquinolone by intravenous and oral administration

Fluoroquinolone (FQ) antibacterials have drawn heightened attention from various international regulatory agencies due to their class-specific side effects. Levonadifloxacin is a novel broad spectrum benzoquinolizine FQ active against methicillin-resistant Staphyloccocus aureus (MRSA). Owing to FQ-associated safety concerns, extensive preclinical safety pharmacology (central nervous system and cardiac safety) and toxicology studies (subacute repeat-dose toxicity, genotoxicity, phototoxicity and chondrotoxicity) of levonadifloxacin were performed at relatively high doses. Intravenous (IV) and oral studies were conducted using WCK 771 (l -arginine salt of levonadifloxacin) and WCK 2349 (l -alanine ester prodrug of levonadifloxacin), respectively. Safety pharmacology studies following single dose revealed no adverse effects on central nervous system (including seizure) in mice and cardiovascular system (hERG and monkey telemetry). In repeat-dose toxicity studies, except for IV bolus dosing related effects in rat (hyperactivity, mild convulsion, polypnoea and injection site irritation) and dog (emesis and salivation), no other adverse findings limiting the dosing duration were observed. No major biochemical, haematological, gross or histopathological changes suggestive of damage to vital organs were observed in either WCK 771- or WCK 2349-treated groups. WCK 771 and WCK 2349 were found to be nongenotoxic; however, they showed weak phototoxicity that was comparable with levofloxacin. WCK 771 showed chondrotoxicity in the Beagle dog pups on repeat-dose administration; however, the severity level was lower than ofloxacin. Overall, preclinical safety studies helped establish wider safety margin for WCK 771 and WCK 2349 that supports administration of higher therapeutic doses in humans by both IV and oral routes, thereby enabling safe anti-MRSA treatment.     

西那沙星对幼龄大鼠的软骨毒性

目的:观察西那沙星(sinafloxacin)静脉注射对幼龄大鼠关节软骨的影响。方法:40只大鼠,雌雄各半,按照体重随机分为西那沙星低、高剂量组(iv,10和60 mg·kg~(-1))、加替沙星阳性对照组(iv,60 mg·kg~(-1))和空白对照组(iv生理氯化钠溶液10 mL·kg~(-1))。各组连续给药7 d。d7给药后24 h处死动物取完整膝、髋关节进行病理组织学检查。结果:西那沙星可使幼龄大鼠膝、髋关节软骨表层幼稚软骨细胞数量减少,骨骺软骨细胞变性坏死,且存在量效关系。结论:西那沙星10～60 mg·kg~(-1)连续iv 7 d对幼龄大鼠关节软骨有破坏作用。