拉坦前列素滴眼液诱发支气管哮喘

1例65岁女性患者，因右眼青光眼给予拉坦前列素滴眼液0．1ml，1次／d点眼，首次用药2h后患者出现呼吸困难、发绀、大汗淋漓，HR120次／min，P160／100mmHg，双肺闻及哮鸣音。立即给予患者沙美特罗替卡松粉吸入剂，10min后症状缓解。以后改用1％布林佐胺滴眼液，支气管哮喘未再出现。     

HPLC法测定拉坦前列素滴眼液中15S-拉坦前列素的含量

目的：建立拉坦前列素滴眼液中杂质15S-拉坦前列素的含量测定方法。方法：色谱柱为ZORBAX SB- C18(4.6 mm′250 mm,5 mm),流动相为甲醇-乙腈-水(用冰乙酸调节pH3.0)(56∶14∶30),流速为1.0 ml.min_-1,检测波长为210 nm,进样量为100 ml。结果：在选定的色谱条件下,15S-拉坦前列素杂质与主成分可以有效分离,在0.04994～0.9988 mg.mL_-1质量浓度范围内呈良好的线性关系(r=0.9993),平均回收度为99.03%(n=9)。结论：所建立的方法可以用于拉坦前列素滴眼液中15S-拉坦前列素的含量测定。     

拉坦前列素脂质体滴眼液的眼表毒性

目的研究拉坦前列素(latanoprost,LAT)脂质体滴眼液对眼表的毒性。方法采用薄膜分散法制备拉坦前列素脂质体,平均粒径为(98.7±34.4)nm;采用随机数字表法将新西兰白兔15只分为3组,分别为Xalatan组、LAT Liposome组和无抑菌剂组,右眼给予试验滴眼液,左眼采用无菌生理盐水作为对照,1次/d给药,连续使用28 d;在每日给药前以及最后一次给药后的1、2、4、24、48、72 h进行眼刺激反应和角膜荧光素染色评分。结果 LAT Liposome组与无抑菌剂组在实验第28天刺激反应平均分值分别为0.96和2.24,属于无刺激,而Xalatan组评分值为4.17,属于轻度刺激;角膜荧光素染色实验中,给药后第21天,与对照组比较,Xalatan组评分开始显著升高(P<0.01);给药后第28天,与对照组比较,Xalatan组、无抑菌剂组评分均显著增加(P<0.01);与Xalatan组比较,LAT Liposome组评分显著降低(P<0.01),说明LAT Liposome对眼表刺激性最小,角膜损伤最轻。结论 LAT Liposome的毒性最小,更有利于长期使用。     

拉坦前列素滴眼液对兔眼的刺激性研究

目的探讨拉坦前列素滴眼液对正常兔眼的刺激性。方法使用眼睛检查合格的4只新西兰白兔用于试验。采用自身对照,左眼给予供试品,右眼给予等量的空白。每天用药1次,0.1 ml/次/眼,供试品原液给药,浓度50μg/ml,连续14 d眼部给药。每天给药前以及最后1次给药后1、2、4、24、48和72 h对眼部进行检查,采用双盲法用裂隙灯观察兔眼刺激情况并评分,试验结束,取眼球作病理组织学检查。结果连续14 d给药,药物对正常兔眼无明显影响,与空白组比较,无显著差异。结论拉坦前列素滴眼液对兔眼无刺激性。     

拉坦前列素滴眼液抑菌剂抑菌效力研究

目的 探索拉坦前列素滴眼液中抑菌剂的合理添加量。方法 根据药物成分的特征,选择合适的抑菌剂,依照中国药典2015年版抑菌剂效力检查法,采用试验菌株金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌、白色念珠菌、黑曲霉,对合用防腐剂苯扎氯铵和苯氧乙醇按照不同加入量,配置后进行抑菌效果检查。结果 A、B、C组联合应用防腐剂都能达到规定的抑菌效果。0.03%苯扎氯铵和0.015%羟苯乙酯联合应用防腐剂对上述5种试验菌的生长有良好的抑制作用,且为最低有效浓度。结论 确定0.04%苯扎氯铵和0.03%羟苯乙酯作为拉坦前列素滴眼液的抑菌剂。     

拉坦前列素滴眼液的抑菌效力研究

目的:考察拉坦前列素滴眼液的抑菌效力,以确定处方中抑菌剂苯扎氯铵的使用量。方法:根据2010年版《中国药典》二部抑菌剂效力检查法指导原则,采用平皿菌落计数法对处方Ⅰ、处方Ⅱ、处方Ⅲ、处方Ⅳ[分别含0.005%(0.005g/100ml)、0.01%、0.015%、0.02%苯扎氯铵的拉坦前列素滴眼液]供试品中5种标准菌株(铜绿假单胞菌、大肠埃希菌、金黄色葡萄球菌、白色念珠菌、黑曲霉)进行计数,考察其对标准菌株的抑菌效力。结果:处方Ⅰ、处方Ⅱ对铜绿假单胞菌的抑菌效力不符合《中国药典》要求;处方Ⅲ、处方Ⅳ对5种标准菌株的抑菌效力符合《中国药典》要求,7d下降3.4个lg值,14～28d内菌数不再增加。结论:拉坦前列素滴眼液中苯扎氯铵的处方量建议为0.015%。     

拉坦前列素滴眼液治疗青光眼

目的 :观察用降眼压药物而眼压不能控制的病人 ,加用拉坦前列素滴眼液治疗的临床疗效。方法 :2 4例病人 (共 2 4只病眼 ) ,男性 10例 ,女性 14例 ,年龄 (5 0±s12 )a ,共 2 4只病眼用 2种以上降眼压药物而眼压不能控制 ,加用 0 .0 0 5 %拉坦前列素滴眼液滴病眼 ,每晚 1次 ,疗程至少 3mo。结果 :用2种降眼压药有 9例 (38% ) ,用 3种以上降眼压药15例 (6 2 % ) ,其中有 8例 (33% )需口服乙酰唑胺片降眼压。 2 4例病人加用 0 .0 0 5 %拉坦前列素滴眼液 1wk ,1mo和 3mo后 ,眼压由 (3.6 4± 0 .18)kPa降至 (2 .19± 0 .11)kPa ,(2 .18± 0 .11)kPa ,(2 .14 0± 0 .0 10 )kPa ,均P <0 .0 1。眼压降至正常 15例 (6 2 % ) ,眼压降低但未至正常 7例 (2 9% ) ,无效为 2例 (8% )。结论 :对用降眼压药物而眼压不能控制的病人 ,加用拉坦前列素滴眼液可以有效的控制眼压 ,防止青光眼对视功能的进一步损伤     

HPLC测定拉坦前列素滴眼液复杂系统中的有关物质及含量

目的 建立HPLC测定拉坦前列素滴眼液复杂系统中的有关物质及含量的方法。方法 采用糖涂敷型手性色谱柱（4.6 mm×250 mm,5 μm）,有关物质测定以0.005 mol·L^-1磷酸二氢钠溶液（用磷酸调节pH值至2.7）-乙腈（56：44）为流动相,含量测定以0.005 mol·L^-1磷酸二氢钠溶液（用磷酸调节pH值至2.7）-乙腈（54：46）为流动相,检测波长为200 nm,流速为0.5 ml·min^-1。结果 有关物质测定中2个已知杂质与主峰之间的分离度良好,线性关系良好,5,6-反式-拉坦前列素和15S-拉坦前列素的平均回收率分别为101.5%和99.5%,拉坦前列素、5,6-反式拉坦前列素和15S-拉坦前列素的定量限（S/N≈10）分别为0.12,0.13和0.12 μg·mL^-1;含量测定线性关系良好,重复性RSD=0.90%,拉坦前列素平均回收率为98.8%。结论 建立的方法准确可靠,可用于拉坦前列素滴眼液的质量控制。     

拉坦前列素滴眼液中有关物质的NP-HPLC法测定

建立了正相-高效液相色谱法测定拉坦前列素滴眼液中的有关物质,采用Zorbax Rx-SIL硅胶柱,以正己烷-无水乙醇(96∶4)为流动相,检测波长210nm.拉坦前列素的最低检测限为8ng.     

反相高效液相色谱法测定拉坦前列素滴眼液的含量

目的建立RP-HPLC测定拉坦前列素滴眼液含量的方法。方法采用Chiralcel OD-R色谱柱(4.6mm×250 mm,5μm),以0.025 mol·L-1磷酸盐缓冲液-乙腈(55:45)为流动相,检测波长为200 nm,流速0.5mL·min-1。结果拉坦前列素质量浓度在0.999⁸.991μg·mL-1与峰面积呈良好的线性关系(r=0.999 9,n=5);定量限为2.0 ng;平均回收率分别为102.2%、100.7%、101.9%;RSD分别为0.19%、0.31%、0.02%(n=3)。结论该方法灵敏度高,操作简便,可满足本品含量测定。     

Timolol + latanoprost: new preparation. Last-resort eye drops

(1) First-line drug treatment of chronic open-angle glaucoma or intraocular hypertonia is based on monotherapy with timolol eye drops. Patients in whom several single-agent treatments have failed can use combinations of timolol + dorzolamide (a carbonic anhydrase inhibitor) or a betablocker + pilocarpine (a parasympathomimetic agent). (2) An eye-drop preparation is now available in which 0.5% timolol is combined with 0.005% latanoprost, a prostaglandin F2alpha analogue. (3) A clinical trial indicated that the timolol + latanoprost combination was more effective than the timolol + dorzolamide combination on intraocular pressure, but the report of this study is too scanty to accept these results at face value. Once-a-day dosing with timolol + latanoprost has not been compared with a betablocker + pilocarpine combination. (4) Patients using the timolol + latanoprost combination are exposed to the adverse effects of both latanoprost (especially ocular irritation and brown iris discoloration) and the betablocker. (5) It is not known whether the once-a-day dosing of the timolol + latanoprost combination is a significant advantage, especially in terms of adherence to treatment. (6) In practice, the arrival of the timolol + latanoprost combination changes virtually nothing for patients with chronic open-angle glaucoma, except for those with no other alternative.     

Cardiovascular disorders due to latanoprost eye drops?

(1) Several cases of cardiovascular disorders linked to latanoprost eye drops were reported in post-marketing surveys, whereas none were noted in clinical trials.     

两种无防腐剂滴眼液的研究

目的：探讨无防腐剂的磺胺醋酰钠滴眼液和氧氟沙星滴眼液的可行性。方法配制不含防腐剂的磺胺醋酰钠滴眼液、氧氟沙星滴眼液，依据《中国药典》进行微生物限度检查。结果不含防腐剂的磺胺醋酰钠滴眼液、氧氟沙星滴眼液的微生物限度检查结果符合《中国药典》规定。结论无防腐剂的磺胺醋酰钠滴眼液、氧氟沙星滴眼液是可行的。     

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.     

Preservative-free versus preserved latanoprost eye drops in patients with open-angle glaucoma or ocular hypertension

Objective: This study compared the efficacy, safety, and pharmacokinetics of a preservative-free latanoprost formulation to an established, benzalkonium chloride (BAK) containing formulation for the treatment of open-angle glaucoma or ocular hypertension.

Methods: This was a phase II, randomized, cross-over, investigator-masked, multi-center, pilot study (NCT01494753). A total of 30 untreated adult patients (aged ≥18 years) with primary open angle glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, or ocular hypertension received either preservative-free or preserved latanoprost once daily in both eyes for 6 weeks, before crossing over to receive the other treatment. Efficacy (intraocular pressure [IOP] at 8 am, midday, 4?pm and 8?pm, and global efficacy assessment by investigator), safety (adverse events, ocular symptoms and global tolerance, slit lamp examination, funduscopy, visual field examination, visual acuity, and heart rate), and pharmacokinetics were assessed at Days 0, 42, and 84.

Results: Both treatments resulted in a reduction in IOP that was similar for the preservative-free and the preserved formulation at all time points. Similarly, the overall diurnal reduction was similar in both groups (6.3?mmHg [27.9% reduction] and 6.4?mmHg [28.1% reduction] for preserved and preservative-free latanoprost, respectively). There were no differences in global efficacy assessment or in the safety and tolerance of each treatment. Systemic concentrations of latanoprost were very low; AUC_0–30 and C_max were lower and t_max was longer for preservative-free latanoprost.

Conclusions: Preservative-free latanoprost showed similar efficacy at all time points compared to BAK preservative containing formulation, with no difference in tolerance, allowing progression to phase III clinical development.     

加替沙星滴眼液的稳定性研究

用高效液相方法研究加替沙星滴眼液的稳定性。加替沙星滴眼液对热相对稳定 ,室温放置 1年亦是稳定的 ,但光照 10 d后 HPL C测定表明增加一个光降解峰 ,经 L C- MS分析此降解峰为 N- 1脱环丙基物 ,含量约 0 .12 % ,提示加替沙星滴眼液应避光贮存     

氟哌酸滴眼液稳定性的研究

本文采用紫外分光光度法测定氟哌酸及其滴眼液的含量,操作方法简便、快速。同时用初均速法对其稳定性进行了初步研究,结果表明本品稳定性较好,室温(25℃)t_(0.9)=3.5a,E=20.833kcal·mol~(-1)。