两性霉素B脂质体滴眼液在兔房水中的药动学

目的:探索兔眼局部应用生物黏附性两性霉素B脂质体(AmBL)滴眼液后,房水中的药动学状况。方法:32只新西兰白兔,在角膜上皮完整和刮除时,分别应用0．5％AmBL滴一眼,用0．5％两性霉素B滴眼液(AmBS)滴对侧眼作对照,于用药后0．25,0．5,1,2,3和4 h的6个时点,选取不同的白兔抽取房水,用高效液相色谱法测定房水中AmB的含量。结果:AmBL滴眼后,房水中AmB的有效抑菌浓度可维持2 h,AmBE S滴眼1 h后即近全部消除。角膜上皮完整时,AmBL的AUC和t1/2是AmBS的3．6倍和5倍;角膜上皮刮除后,AmBL的AUC和t1/2是AmBL S的3．9倍和3．2倍。结论:0．5％AmBL滴眼液具有较好的缓释作用和生物利用度,药物浓度较稳定,作用时间较长,是较有前途的局部治疗真菌性角膜炎的新型缓释制剂。     

格尔德霉素滴眼液在离体兔眼角膜的吸收与扩散

目的制备格尔德霉素 ( geldanamycin)滴眼液 ,进行离体兔眼角膜实验 ,检测角膜及人工房水中药物量。方法采用二室渗透池法 ,在不同时间点取人工房水及角膜 ,分别测定药物在角膜吸收量及角膜中药物扩散进入人工房水量 ,对累积数据进行方程模拟。结果药物易被角膜吸收 ,但不易渗透进入房水 ,药物在角膜中不同时间的吸收累积曲线符合Higuchi方程 ,吸收速率常数为10 2 1 9ng/h。角膜中的药物扩散进入人工房水符合零级方程 ,药物在角膜和人工房水中达到平衡的时间分别为 2h和 4h ,药物从角膜扩散进入人工房水有 2h时滞。结论格尔德霉素滴眼液易被兔眼角膜吸收 ,且在角膜中达到较高浓度 ,在治疗单纯疱疹性病毒性角膜炎方面具有良好的前景     

重组人角质细胞生长因子异构体对兔角膜碱烧伤的疗效观察

目的:观察重组人角质细胞生长因子异构体(简称K102)对实验性兔角膜碱烧伤的治疗作用。方法:60只新西兰大耳白兔,均选左眼为实验眼,随机分成5组,各组均以1mol·L-1的氢氧化钠溶液建立碱烧伤模型。其中,A、B、C组为治疗组(浓度分别为0.5、0.25、0.125mg·mL-1K102滴眼液),D组为阳性对照组(贝复舒滴眼液),E组为阴性对照组(K102滴眼液的溶媒)。镜下观察各组角膜上皮愈合速度(率)及血管新生(CNV)发生情况。结果:在碱烧伤24h内,A、B、C组的角膜上皮生长速率分别为1.52、1.57、1.46mm2·h-1,与E组(0.98mm2·h-1)比较具有显著性差异(P<0.01);各组上皮愈合率各时间点比较治疗组均优于阴性对照组并有显著性差异(P<0.01或<0.05)。治疗组低浓度可抑制CNV,高浓度可促进CNV。结论:K102滴眼液不同浓度均能够显著促进兔角膜碱烧伤后上皮愈合,抑制角膜CNV生长,改善角膜碱烧伤预后。     

不合理用药实例分析(30)

13单纯疱疹性角膜炎——可的松实例:患者,男,38岁。因左眼畏光、异物感2天就诊。体检:左眼角膜上皮呈树枝状浸润,角膜感觉减退。初步诊断:左侧单纯疱疹性角膜炎。应用阿昔洛韦滴眼液、可的松滴眼液治疗。处方:阿昔洛韦滴眼液2滴每日4次滴眼可的松滴眼液2滴每日4次滴眼分析:单纯疱疹性角膜炎患者局部应用可的松后,可使疾病进展加速,导致角膜不可逆损害。其他糖皮质激素(氢化可的松、泼尼松、地塞米松等)也有类似的影响。处置:单纯疱疹性角膜炎患者应避免应用糖皮质激素。14青光眼——泼尼松实例:患者,女,36岁。因双膝关节痛3周就诊。既往有青…     

雷帕霉素纳米粒滴眼液兔眼部药物分布研究

目的:比较雷帕霉素纳米粒滴眼液及其一般滴眼液滴眼后,在兔眼房水及角膜组织中药物分布。方法:将健康无眼疾新西兰白兔随机分为试验组与对照组,分别每眼结膜囊内单次给雷帕霉素纳米粒滴眼液及其一般滴眼液50μL。于滴眼后15、30、60、360和720min取材,采用高效液相色谱法(HPLC)测定兔眼不同时间房水及角膜组织中雷帕霉素浓度。结果:在用药后15～720min内实验组各时间点房水和角膜组织中的药物浓度均明显高于对照组。实验组内30～720min各时间点房水和角膜组织中的药物浓度比较无统计学差异。结论:雷帕霉素纳米粒滴眼液同一般滴眼液相比明显延长药物在眼部的停留时间,增加房水和角膜组织中的药物浓度,且能够维持组织中药物浓度的平稳。     

纤维细胞生长因子滴眼液治疗外伤性角膜上皮缺损的临床观察

目的:探讨重组牛碱性成纤维细胞生长因子滴眼液(bFGF)治疗外伤性角膜上皮缺损的临床效果和安全性。方法:将2007年1月-2008年7月在我院就诊的100例(100眼)外伤性角膜上皮缺损患者随机分成治疗组50例和对照组50例,治疗组给予bFGF滴眼,qid,每次1～2滴;对照组给予玻璃酸钠滴眼液(爱丽滴眼液)点眼,qid,每次1～2滴。并根据病情给予清创缝合、抗炎及对症处理,观察滴眼后2,4d角膜上皮缺损修复情况。结果:滴眼后2d和4d,bFGF治疗组外伤性角膜上皮缺损的治愈率均明显高于对照组,经χ2检验,治疗组与对照组在滴眼后2,4d差异均有极显著性(P<0.01)。结论:bFGF能很好地促进角膜上皮再生和修复,缩短病程,是一种治疗外伤性角膜上皮缺损的有效方法。     

妥布霉素滴眼液对兔眼金葡菌、绿脓杆菌性角膜炎的治疗作用

通过损伤兔眼浅层角膜,感染金黄色葡萄球菌和绿脓杆菌造成角膜炎动物模型;考察妥布霉素滴眼液的治疗作用。结果表明:妥布霉素滴眼液对金黄色葡萄球菌及绿脓杆菌感染的兔角膜炎具有较好的治疗作用,尤其对于绿脓杆菌感染的兔角膜炎,其作用明显优于硫酸庆大霉素滴眼液。     

还原型谷胱甘肽滴眼液对迁延不愈浅层角膜病变的临床疗效观察

目的:了解还原型谷胱甘肽滴眼液对迁延不愈的浅层角膜病变治疗的临床疗效。方法:浅层角膜病变包括点状角膜炎、点状上皮糜烂、丝状角膜炎、持续性上皮缺损、浅层角膜溃疡患者曾经治疗一个月以上病情未愈者,应用还原型谷胱甘肽(天亿)等治疗,观察治疗前后症状及体征的变化,并进行统计学分析。结果:门诊共收集迁延不愈浅层角膜病变31例,男性14例,女性17例,平均年龄49.6岁,平均病程2.7月。治疗前后症状平均积分分别为2.64±1.3及1.03±0.71分,差异有显著性(P﹤0.05);角膜病变治疗后总有效率74.19%。结论:还原型谷胱甘肽滴眼液对迁延不愈的浅层角膜病变治疗安全有效。     

0.5%莫西沙星滴眼液和0.3%加替沙星滴眼液预防眼科术后感染有效性的系统评价

目的:系统评价0.5%莫西沙星(MXFX)滴眼液和0.3%加替沙星(GTF)滴眼液预防眼科术后感染的有效性。方法:计算机检索PubMed、EMbase、西文生物医学期刊文献数据库和中国期刊全文数据库,收集以0.5%MXFX滴眼液和0.3%GTF滴眼液作为眼科清洁手术预防用药的随机对照试验(RCT),按照Cochrane系统评价方法对符合纳入标准的文献提取房水药物浓度和药物不良反应资料,对提取的房水药物浓度与眼内炎常见病原菌最小抑菌浓度(MIC)进行对比,采用Rev Man 4.2统计软件对有效数据进行Meta分析。结果:共纳入9篇文献14项RCT,合计747例患者。Meta分析结果显示,0.5%MXFX滴眼液和0.3%GTF滴眼液的房水药物浓度比较差异有统计学意义[SMD=1.26,95%CI(1.03,1.48),P<0.000]。0.5%MXFX的房水药物浓度可以达到眼内炎常见病原菌的MIC,而0.3%GTF只能达到凝固酶阴性葡萄球菌和金黄色葡萄球菌的MIC。结论:0.5%MXFX滴眼液可有效预防眼科术后感染,其房水药物浓度显著高于0.3%GTF滴眼液,能达到眼内炎常见致病菌的MIC。由于纳入文献的数量较少,质量较低,该结论还需大样本、多中心、高质量的RCT进一步证实。     

2种更昔洛韦滴眼液在家兔眼部的生物等效性比较

目的:比较更昔洛韦壳聚糖滴眼液与不含壳聚糖的相同处方更昔洛韦滴眼液的眼部药动学与相对生物利用度。方法:取日本大耳兔分为实验组(更昔洛韦壳聚糖滴眼液)与对照组(更昔洛韦滴眼液),双侧眼分别滴入相应的更昔洛韦滴眼液50μL,分别于不同时间取泪液、角膜、房水,采用高效液相色谱法测定药物浓度并计算药动学参数。结果:实验组与对照组给药后泪液药物t1/2分别为15.41、16.22min,角膜t1/2分别为45.21、32.55min,房水t1/2为59.43、48.53min,房水Cmax分别为2.03、1.22μg·mL-1,实验组泪液、角膜与房水中药物AUC0→240分别是对照组的1.66、1.89、2.77倍。结论:与不含壳聚糖滴眼液比较,更昔洛韦壳聚糖滴眼液生物利用度显著提高。     

Effect of fluoroquinolones on the expression of matrix metalloproteinase in debrided cornea of rats

Matrix metalloproteinases (MMPs) are implicated in regenerative and healing processes in corneal injuries. Based upon reports that topical fluoroquinolones (FQs) may cause perforations during corneal healing by modulating MMPs, this study evaluated the comparative effects of commercially available FQs eye drops on the expression of MMP-2 and MMP-9 in the cornea after ethanol injury. Uniform corneal epithelial defects were created using 70% ethanol in the right eye of the rats (n = 6). The groups studied were (I) sham, (II) normal saline with benzalkonium chloride (NS-BKC), (III) norfloxacin 0.3%, (IV) ciprofloxacin 0.3%, (V) lomefloxacin 0.3%, (VI) sparfloxacin 0.3%, (VII) gatifloxacin 0.3%, and (VIII) moxifloxacin 0.5%. Each treatment was instilled six times/day up to 48 h and rats were sacrificed using excess of anesthesia. The corneas were excised to study the expression of MMP-2 and MMP-9 using gelatin zymography and real-time PCR. All the FQs significantly increased the expression of MMP-2 and MMP-9 as compared to the sham and NS-BKC-treated group. NS-BKC did not show a significant effect on MMPs expression compared to the sham group. Among the studied FQs, ciprofloxacin was observed to exhibit maximal induction of MMP-2 and MMP-9, whereas lomefloxacin exhibited an equivocal effect on both MMP-2 and MMP-9 expression. Findings of the present study demonstrate that topical application of FQs may induce the expression of MMP-2 and MMP-9 in debrided corneal epithelium and, therefore, may delay corneal wound healing. Thus, it can be concluded that selecting a FQ for ophthalmic use having minimal effect on MMPs may impact wound healing in injured or vulnerable cornea.     

Effect of fluoroquinolones on the expression of matrix metalloproteinase in debrided cornea of rats

Matrix metalloproteinases (MMPs) are implicated in regenerative and healing processes in corneal injuries. Based upon reports that topical fluoroquinolones (FQs) may cause perforations during corneal healing by modulating MMPs, this study evaluated the comparative effects of commercially available FQs eye drops on the expression of MMP-2 and MMP-9 in the cornea after ethanol injury. Uniform corneal epithelial defects were created using 70% ethanol in the right eye of the rats (n?=?6). The groups studied were (I) sham, (II) normal saline with benzalkonium chloride (NS-BKC), (III) norfloxacin 0.3%, (IV) ciprofloxacin 0.3%, (V) lomefloxacin 0.3%, (VI) sparfloxacin 0.3%, (VII) gatifloxacin 0.3%, and (VIII) moxifloxacin 0.5%. Each treatment was instilled six times/day up to 48?h and rats were sacrificed using excess of anesthesia. The corneas were excised to study the expression of MMP-2 and MMP-9 using gelatin zymography and real-time PCR. All the FQs significantly increased the expression of MMP-2 and MMP-9 as compared to the sham and NS-BKC-treated group. NS-BKC did not show a significant effect on MMPs expression compared to the sham group. Among the studied FQs, ciprofloxacin was observed to exhibit maximal induction of MMP-2 and MMP-9, whereas lomefloxacin exhibited an equivocal effect on both MMP-2 and MMP-9 expression. Findings of the present study demonstrate that topical application of FQs may induce the expression of MMP-2 and MMP-9 in debrided corneal epithelium and, therefore, may delay corneal wound healing. Thus, it can be concluded that selecting a FQ for ophthalmic use having minimal effect on MMPs may impact wound healing in injured or vulnerable cornea.     

不同剂型双氯芬酸钠的眼部抗炎效果比较

目的：研究不同剂型的双氯芬酸钠对兔眼炎症的抗炎效果。方法：36只新西兰大白兔按抛币法随机分为对照组和实验组,进行前房穿刺,对照组给予生理盐水,实验组分别给予眼药水、眼膏、眼用膜剂,观察疗效,以房水中蛋白含量为指标,使用SPSS统计软件进行结果分析。结果：双氯芬酸钠不同制剂的抗炎效果：膜剂组 > 眼用软膏剂组 > 眼药水组（P<0.05）。结论：膜剂在眼科中的抗炎作用较好,适宜眼科患者术后选用。     

Pharmacokinetic and pharmacodynamic evaluation of the anti-cataract effect of eye drops containing disulfiram and low-substituted methylcellulose using ICR/f rats as a hereditary cataract model

We attempted to develop anti-cataract eye drops using disulfiram (DSF) and low-substituted methylcellulose (MC), and evaluated their anti-cataract effect in terms of the lens opacification vs. age-profile curves using a one-exponential equation. The eye drops were prepared using 0.5% DSF and 2% MC (DSF eye drops), and ICR/f rats, a recessive-type hereditary cataractous strain, were used as the experimental model. Gelation of DSF eye drops containing MC was first observed at about 35°C, close to body temperature. In in vivo transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while DSF was not detected. The DDC penetration level of DSF eye drops containing MC was approximately 1.3-fold higher than that of DSF eye drops. The opacification rate constant (k) of ICR/f rat instilled with DSF eye drops with or without MC was lower, and the initial time of opacification (τ) was longer than those of ICR/f rats instilled with saline. Furthermore, the k of ICR/f rats instilled with DSF eye drops with MC was lower than that of ICR/f rats instilled with DSF eye drops without MC. In conclusion, the analysis of kinetic parameters including k and τ using a one-exponential equation provided useful information for clarifying the anti-cataract effect of eye drops. ICR/f rats instilled with DSF eye drops using a low-substituted MC-based drug delivery system demonstrated a delay in cataract development, probably resulting from an increase in the retention of DSF eye drops on the cornea.     

Safety of sodium hyaluronate eye drop with C12-benzalkonium chloride

Purpose: In this study, we investigated the effects of commercially available multi-dose sodium hyaluronate 0.1% (Hyalein^®; Santen, Osaka, Japan) containing 0.003% C12-benzalkonium chloride (BAC) on the Corneal epithelium and its degree of safety.

Methods: Japanese white male rabbits were divided into four groups. The corneas of each group exposed to one of the following solutions: sodium hyaluronate 0.1%, C12-BAC, C12, 14, 16-BAC Mixture, and Hank’s Balanced Salt Solution (HBSS) (as control), respectively. Corneal transepithelial electrical resistance (TER) changes after 60?s of exposure to the above solutions were measured in living rabbits. TER reflects the barrier function of the epithelium. In addition, scanning electron microscopy was used to examine the acute effects of the above solutions on the integrity of the corneal epithelium of four groups.

Results: There was no significant decrease in the corneal TER after exposure of the cornea to Hyalein^® eye drops as compared to HBSS control eyes. Also, BAC mixture solution and C12-BAC did not produce any significant decrease in the corneal TER as compared to HBSS control eyes. All the corneal epithelium exposed to Hyalein^®, 0.003% C12-BAC and 0.003% BAC mixture exhibited a regular appearance of the superficial cells with a high density of microvilli.

Conclusion: This study confirms that Hyalein^® has no acute hazardous effect on corneal epithelium.     

Corneal damage and its recovery after instillation of preservative-free versus preserved latanoprost eye drops

Abstract

Purpose: Latanoprost ophthalmic solution is highly effective as a therapeutic agent for glaucoma and is applied worldwide. However, harmful effects on the corneal surface have been reported regarding the commercially available latanoprost ophthalmic solution. Corneal surface toxicity may be caused by the added preservative of the ophthalmic solution. In order to ascertain whether latanoprost itself can damage the cornea or if this is solely due to the added preservatives, this study attempted to determine the corneal changes that occur at different time periods following usage of preservative-free versus preserved latanoprost eye drops.

Materials and methods: Preservative-free latanoprost eye drops (Monoprost^®) or preserved latanoprost eye drops (Xalatan^®) containing 0.02% benzalkonium chloride (BAC) were instilled in the corneas of rabbits. For each of the two different eye drop solutions, the rabbits used in this experiment were divided into three exposure groups: 1?minute, 24?hour, and 1?week groups. Corneal transepithelial electrical resistance (TER) and scanning electron microscopy (SEM) were examined immediately (1?minute) after instillation, at 24?hours after instillation, and at 24?hours after 1?week of daily instillations of latanoprost. Hank’s balanced salt solution was used in the control group.

Results: The mean corneal TER of the control group was 933.8?±?279.0 Ω cm². In preservative-free latanoprost instilled corneas, there was no significant decrease in the TER or morphological changes at any of the time points, with the relative TER values of 117?±?38%, 100?±?34%, and 93?±?21% for 1?minute, 1?day, and 1?week time points, respectively. In preserved latanoprost instilled corneas, SEM showed that only the immediate group exhibited superficial cell damage and a significant decrease in the corneal TER compared to the controls and other time points and to the immediate preservative-free latanoprost corneas. In the preserved latanoprost groups, the relative TER values were 18?±?5%, 110?±?28%, and 92?±?10%, for the three respective observation time points.

Conclusions: Preservative-free latanoprost can be safely instilled to the corneal epithelium. Latanoprost with 0.02% BAC has an immediate deleterious impact on the corneal epithelium; however, it disappears within 24?hours after instillation.     

格尔德霉素滴眼液兔眼角膜吸收的研究

目的：制备格尔德霉素滴眼液．进行兔眼角膜吸收实验．检测角膜及房水中药物量。方法：以健康新西兰大白兔为实验对象．单剂量给药．在不同时间点取房水及角膜．用HPLC法分别测定药物在角膜及房水中药物吸收量．用3p87药动学程序进行房室模型模拟和参数拟合。并进行体内外相关性考察。结果：药物易被角膜吸收，但不易渗透进入房水．药物在体角膜吸收符合血管外给药一级吸收一室模型。药物在眼部滞留时间较长．平均滞留时间为3.07h．有一定的缓释作用．利于提高药物生物利用度。体内外实验具较好的相关性(r=0．9086)、结论:格尔德霉素滴眼液易被兔眼角膜吸收，且在角膜中达到较高浓度．在治疗单纯疱疹性病毒性角膜炎方面具有良好的前景。     

Pharmacokinetics and efficacy of a ketorolac-loaded ocular coil in New Zealand white rabbits

Eye drops are considered standard practice for the delivery of ocular drugs. However, low patient compliance and low drug levels compromise its effectiveness. Our group developed a ketorolac-loaded ocular coil for sustained drug delivery up to 28 days. The aim of this study was to gain insight into the pharmacokinetics and efficacy of the ocular coil. The pharmacokinetics of the ketorolac-loaded ocular coil versus eye drops were tested in New Zealand White rabbits by repetitive sampling for 28 days. Efficacy of the ocular coil was also tested in New Zealand White rabbits. Ocular inflammation was induced where after the ocular coil was inserted, or eye drops, or no treatment was provided. The total protein concentration and cytokine levels were measured in tears, aqueous humor, and plasma at 4 h, 8 h, 24 h, 4 d, 7 d, 14 d, 21 d, and 28 d. Four h after inserting the ocular coil in the eye, ketorolac levels in aqueous humor and plasma were higher in the ocular coil group than in the eye drop group. Ketorolac released from the ocular coil could be detected up to 28 d in tears, up to 4 d in aqueous humor and up to 24 h in plasma. After inducing inflammation, both the ocular coil and eye drops were able to suppress prostaglandin E₂, TNFα and IL-6 levels in aqueous humor and plasma as compared to the group that received no treatment. To conclude, the ocular coil facilitated a sustained release of the drug and showed similar therapeutic benefit in suppressing post-operative inflammation as eye drops.     

Topical carbonic anhydrase inhibitors IV: Relationship between excised corneal permeability and pharmacokinetic factors

Ethoxzolamide (1) and two analogues, representing a hydroxyethoxy and a hydrogen substitution on the 6-position of the benzene ring (2 and 3), were applied to rabbit eyes using a topical infusion method designed to provide a constant rate into aqueous humor. Statistical-moment theory was applied to the topical infusion data to describe disposition of each compound within the rabbit eye. For each analogue, it was possible to compare the corneal absorption rate constant (ka), aqueous humor elimination rate constant (k10), disposition mean residence time (MRTd), apparent steady-state volume of distribution (Vdss), and total ocular clearance (Qe). In vivo ocular ka values were related to maximum in vitro corneal penetration rates determined across excised rabbit corneas. In particular, 2 had a much longer residence time and a slower clearance than 1 and 3, which may be responsible for its ability to lower intraocular pressure when dosed topically to the rabbit eye, whereas 1 and 3 show no activity.