中华实验眼科杂志
中華實驗眼科雜誌
중화실험안과잡지
CHINESE JOURNAL OF EXPERIMENTAL OPHTHALMOLOGY
2014年
3期
200-205
,共6页
王丽曌%陈翔%王雨生%陈晓农%王庆伟
王麗曌%陳翔%王雨生%陳曉農%王慶偉
왕려조%진상%왕우생%진효농%왕경위
眼%抗生素/药代动力学%盐酸去甲万古霉素%眼内炎/药物治疗%注射/玻璃体内%聚N-异丙基丙烯酰胺-聚氧化乙烯%纳米微粒%色谱法,高效液相%革兰阳性细菌%毒理学%兔
眼%抗生素/藥代動力學%鹽痠去甲萬古黴素%眼內炎/藥物治療%註射/玻璃體內%聚N-異丙基丙烯酰胺-聚氧化乙烯%納米微粒%色譜法,高效液相%革蘭暘性細菌%毒理學%兔
안%항생소/약대동역학%염산거갑만고매소%안내염/약물치료%주사/파리체내%취N-이병기병희선알-취양화을희%납미미립%색보법,고효액상%혁란양성세균%독이학%토
Eye%Anti-bacterial agent/pharmacokinetics%Norvancomycin%Endophthalmitis/drug therapy%Injection/intreavenous%Poly (N-isopropyl acrylamide)-polyethylene oxide%Nanocomposite%Chromatography,high pressure liquid%Gram-positive bacteria%Toxicology%Rabbi
背景 传统给药方法治疗眼内炎症时,药物难以透过血-视网膜屏障而达到有效的治疗浓度,局部药物缓释系统可以减少用药剂量并降低药物的毒性作用,构建载药药物缓释系统对眼内感染性疾病的治疗具有重要意义. 目的 评价多聚体材料聚N-异丙基丙烯酰胺-聚氧化乙烯(PNIPAAm-PEO)构建的盐酸去甲万古霉素-PNIPAAm-PEO(NV-PNIPAAm-PEO)纳米粒在兔眼玻璃体腔内注射给药后的眼部毒理学和眼内药代动力学特征,为眼后节给药治疗感染性眼病提供依据. 方法 NV-PNIPAArn-PEO纳米粒平均载药量约为质量分数22％,用无菌生理盐水配成质量浓度为20 g/L的凝胶液.新西兰白兔41只采用随机数字表法分为实验组31只和对照组10只,将20 g/L NV-PNIPAAm-PEO凝胶液0.1 ml注射入实验组兔的一侧眼玻璃体腔内,对照组注入等容量的生理盐水.分别于给药后的第1、2、3、7、14、21和28天进行眼前后节裂隙灯显微镜和B型超声检查,记录实验眼的视网膜电图(ERG)反应,对角膜、虹膜、玻璃体和视网膜组织行组织病理学检查,以评价NV-PNIPAAm-PEO对眼部组织结构和功能的影响.将兔眼角膜和视网膜脉络膜制备组织匀浆,收集兔房水、玻璃体和血浆样本,用高效液相色谱分析(HPLC)法检测上述各组织中的药物质量浓度.结果 NV-PNIPAAm-PEO玻璃体腔内注射后1～28 d,裂隙灯显微镜下可见眼前后节组织正常,B型超声检查未见异常；最大混合ERG b波振幅、a波振幅和峰潜时在两组间的差异均无统计学意义(P＞0.05).视网膜组织病理学检查表明,两组兔玻璃体腔内注射后视网膜结构均正常.HPLC法分析表明,注射后1～28d,兔眼角膜组织中药物质量分数均低于检测水平下限,血浆药物质量浓度最高为(0.34±0.11) mg/L,房水药物质量浓度为(0.08±0.04)～(2.16±0.07) mg/L,视网膜脉络膜中药物质量分数为(0.11±0.02)～(2.54±0.38)μg/g,玻璃体药物质量浓度为(5.65±1.14) ～ (406.69±21.05) mg/L,21d内玻璃体腔内药物质量浓度高于大多数革兰阳性菌的最低抑菌质量浓度. 结论 载药量约为22％ NV-PNIPAAm-PEO纳米粒在兔眼玻璃体腔内注射未见明显眼内毒性反应,玻璃体腔内可维持有效药物质量浓度时间达21d,NV-PNIPAAm-PEO纳米粒是治疗眼内感染较好的缓释给药方法.
揹景 傳統給藥方法治療眼內炎癥時,藥物難以透過血-視網膜屏障而達到有效的治療濃度,跼部藥物緩釋繫統可以減少用藥劑量併降低藥物的毒性作用,構建載藥藥物緩釋繫統對眼內感染性疾病的治療具有重要意義. 目的 評價多聚體材料聚N-異丙基丙烯酰胺-聚氧化乙烯(PNIPAAm-PEO)構建的鹽痠去甲萬古黴素-PNIPAAm-PEO(NV-PNIPAAm-PEO)納米粒在兔眼玻璃體腔內註射給藥後的眼部毒理學和眼內藥代動力學特徵,為眼後節給藥治療感染性眼病提供依據. 方法 NV-PNIPAArn-PEO納米粒平均載藥量約為質量分數22％,用無菌生理鹽水配成質量濃度為20 g/L的凝膠液.新西蘭白兔41隻採用隨機數字錶法分為實驗組31隻和對照組10隻,將20 g/L NV-PNIPAAm-PEO凝膠液0.1 ml註射入實驗組兔的一側眼玻璃體腔內,對照組註入等容量的生理鹽水.分彆于給藥後的第1、2、3、7、14、21和28天進行眼前後節裂隙燈顯微鏡和B型超聲檢查,記錄實驗眼的視網膜電圖(ERG)反應,對角膜、虹膜、玻璃體和視網膜組織行組織病理學檢查,以評價NV-PNIPAAm-PEO對眼部組織結構和功能的影響.將兔眼角膜和視網膜脈絡膜製備組織勻漿,收集兔房水、玻璃體和血漿樣本,用高效液相色譜分析(HPLC)法檢測上述各組織中的藥物質量濃度.結果 NV-PNIPAAm-PEO玻璃體腔內註射後1～28 d,裂隙燈顯微鏡下可見眼前後節組織正常,B型超聲檢查未見異常；最大混閤ERG b波振幅、a波振幅和峰潛時在兩組間的差異均無統計學意義(P＞0.05).視網膜組織病理學檢查錶明,兩組兔玻璃體腔內註射後視網膜結構均正常.HPLC法分析錶明,註射後1～28d,兔眼角膜組織中藥物質量分數均低于檢測水平下限,血漿藥物質量濃度最高為(0.34±0.11) mg/L,房水藥物質量濃度為(0.08±0.04)～(2.16±0.07) mg/L,視網膜脈絡膜中藥物質量分數為(0.11±0.02)～(2.54±0.38)μg/g,玻璃體藥物質量濃度為(5.65±1.14) ～ (406.69±21.05) mg/L,21d內玻璃體腔內藥物質量濃度高于大多數革蘭暘性菌的最低抑菌質量濃度. 結論 載藥量約為22％ NV-PNIPAAm-PEO納米粒在兔眼玻璃體腔內註射未見明顯眼內毒性反應,玻璃體腔內可維持有效藥物質量濃度時間達21d,NV-PNIPAAm-PEO納米粒是治療眼內感染較好的緩釋給藥方法.
배경 전통급약방법치료안내염증시,약물난이투과혈-시망막병장이체도유효적치료농도,국부약물완석계통가이감소용약제량병강저약물적독성작용,구건재약약물완석계통대안내감염성질병적치료구유중요의의. 목적 평개다취체재료취N-이병기병희선알-취양화을희(PNIPAAm-PEO)구건적염산거갑만고매소-PNIPAAm-PEO(NV-PNIPAAm-PEO)납미립재토안파리체강내주사급약후적안부독이학화안내약대동역학특정,위안후절급약치료감염성안병제공의거. 방법 NV-PNIPAArn-PEO납미립평균재약량약위질량분수22％,용무균생리염수배성질량농도위20 g/L적응효액.신서란백토41지채용수궤수자표법분위실험조31지화대조조10지,장20 g/L NV-PNIPAAm-PEO응효액0.1 ml주사입실험조토적일측안파리체강내,대조조주입등용량적생리염수.분별우급약후적제1、2、3、7、14、21화28천진행안전후절렬극등현미경화B형초성검사,기록실험안적시망막전도(ERG)반응,대각막、홍막、파리체화시망막조직행조직병이학검사,이평개NV-PNIPAAm-PEO대안부조직결구화공능적영향.장토안각막화시망막맥락막제비조직균장,수집토방수、파리체화혈장양본,용고효액상색보분석(HPLC)법검측상술각조직중적약물질량농도.결과 NV-PNIPAAm-PEO파리체강내주사후1～28 d,렬극등현미경하가견안전후절조직정상,B형초성검사미견이상；최대혼합ERG b파진폭、a파진폭화봉잠시재량조간적차이균무통계학의의(P＞0.05).시망막조직병이학검사표명,량조토파리체강내주사후시망막결구균정상.HPLC법분석표명,주사후1～28d,토안각막조직중약물질량분수균저우검측수평하한,혈장약물질량농도최고위(0.34±0.11) mg/L,방수약물질량농도위(0.08±0.04)～(2.16±0.07) mg/L,시망막맥락막중약물질량분수위(0.11±0.02)～(2.54±0.38)μg/g,파리체약물질량농도위(5.65±1.14) ～ (406.69±21.05) mg/L,21d내파리체강내약물질량농도고우대다수혁란양성균적최저억균질량농도. 결론 재약량약위22％ NV-PNIPAAm-PEO납미립재토안파리체강내주사미견명현안내독성반응,파리체강내가유지유효약물질량농도시간체21d,NV-PNIPAAm-PEO납미립시치료안내감염교호적완석급약방법.
Background The penetration of bacterial agents into the vitreous cavity is difficult because of the existence of blood-retina barrier.So conventional drug therapy is not enough effective on endophthalmitis.Drug delivery systems can decrease drug dose and reduce the drug toxicity.To construct nano controlled-release system of anti-bacterial agents is very important for the treatment of intraocular infectious diseases.Objective This study was to investigate the toxicology and intraocular pharmacoklnetics of intravitreal PNIPAAm-PEO loaded norvancomycin nanoparticles (NV-PNIPAAm-PEO) in normal rabbit eyes.Methods NV-PNIPAAm-PEO was constructed with the drug-loading rate about 22％,and then the drug gelatin solution (20 g/L) was prepared using normal saline solution.Forty-one New Zealand albino rabbits were randomized divided into experimental group and control group.20 g/L drug gelatin solution 0.1 ml was monocularly injected into the vitreous cavity in the experimental group,and the equal volume of sterilized normal saline solution was used in the control group.In 1 day,2,3,7,14,21 and 28 days after injection,ocular anterior and posterior segments were examined by slit lamp microscope and Bsonography,and electroretinogram (ERG) was recorded and the histopathological examination was performed to evaluate the biotoxicity of the drug.Norvancomycin contents in the cornea homogenate,aqueous humor,vitreous,retinochoroid homogenate were detected by high performance liquid chromatography (HPLC) system.Results The anterior and posterior segments were normal by the slit lamp microscope and B-sonography 1-28 days after injection of NV-PNIPAAm-PEO.In 7,14,21 and 28 days after injection,there were no statistically significant difference in the a-wave latency and amplitude of max-ERG between the two groups,as well as the b-wave amplitude(P＞0.05).The histopathological examination showed that the retinal structure was normal in both groups.HPLC assay showed that the norvancomycin level was gradually declined in different eye tissues from 1 day through 28 days after injection.Norvancomycin was undetectable in the cornea during the observing duration.The maximal norvancomycin content in the blood plasma was (0.34 ± 0.11) mg/L in the second day,and norvancomycin content ranged (0.08 ± 0.04)-(2.16±0.07) mg/L in the aqueous humor,(0.11 ±0.22)-(2.54 ±0.38) μg/g in the chorioretina,respectively.The drug concentration was (5.65 ± 1.14)-(406.69 ± 21.05) mg/L in the vitreous,which was higher than the minimal inhibitory concentration (MIC) to the most gram-positive bacteria.Conclusions The intravitreal injection of 22％ NV-PNIPAAm-PEO maintains the therapeutic drug concentration till 21 days in vitreous without the toxic effect on eye tissues,suggesting a great treating potential for intraocular infecting diseases.
