Metabolism,Distribution, and Transdermal Permeation of a Soft Corticosteroid,Loteprednol Etabonate

The soft corticosteroid, loteprednol etabonate (chloromethyl 17-ethoxycarbonyloxy-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylate), I, was designed based on the inactive metabolite approach. Accordingly, I should be metabolized by hydrolysis to the corresponding inactive cortienic acid derivative, II. The in vitro and in vivo metabolism of I indeed yielded mainly this inactive metabolite, which is more hydrophilic and thus readily eliminated from the body. Relatively high levels of I were found in tissues after intravenous administration of the drug in rats. The permeability of I through hairless mouse skin was comparable to what has been found for related hard steroids, without significant metabolism taking place in the skin.     

氯替泼诺控制眼部炎症的安全性和有效性的荟萃分析(英文)

目的 :对氯替泼诺控制眼部炎症的有效性和安全性进行系统评价。方法 :检索MEDLINE获得 8篇以往发表的论文 ,并根据临床和统计标准进行合并分析。通过计算优势比来评估氯替泼诺治疗的安全性和有效性 ,并按照固定效应模型对优势比进行合并。结果 :总计 1 660例病人纳入荟萃分析。与安慰剂和泼尼松龙相比 ,眼内压升高的合并危险差分别为 1 % (95 %可信区间 ,-1 % ,3 % ) ,-5 % (95 %可信区间 ,-9% ,0 % )。与安慰剂相比 ,炎症控制的合并危险差分别为 :术后炎症 3 1 %(95 %可信区间 ,2 2 % ,40 % ) ,春季结膜炎 2 8%(95 %可信区间 ,1 9% ,3 7% ) ,过敏性结膜炎 2 6%(95 %可信区间 ,1 8% ,3 5 % ) ;而与泼尼松龙相比 ,急性前葡萄膜炎控制的合并危险差为 -1 5 %(95 %可信区间 ,-2 5 % ,-4% )。结论 :氯替泼诺可以控制眼部炎症 ,如 :术后炎症、春季结膜炎、过敏性结膜炎、急性前葡萄膜炎 ,是既有效又安全的糖皮质激素     

Management of seasonal allergic conjunctivitis: guide to therapy

Seasonal allergic conjunctivitis (SAC) is an inflammatory response of the conjunctiva triggered by exposure to seasonal allergens. Treatment options for SAC include artificial tears, antihistamines, decongestants, mast cell stabilizers, nonsteroidal anti‐inflammatory drugs, dual antihistamine/mast cell stabilizers, immunotherapy and corticosteroids. Topical, intranasal and systemic formulations of corticosteroids have traditionally provided the most effective relief of the inflammation and signs and symptoms associated with severe, acute exacerbations of SAC. However, steroid‐induced ocular and systemic side‐effects have limited the prescribing of these agents. This limitation of traditional corticosteroids led to the development of modified corticosteroids that retain the anti‐inflammatory mechanism of action of traditional corticosteroids with a much‐improved safety profile because of their rapid breakdown to inactive metabolites after exerting their activity. The development of one such novel corticosteroid, loteprednol etabonate (LE), led to the insertion of an ester (instead of a ketone) group at the carbon‐20 (C‐20) position of the basic corticosteroid structure. Clinical trials assessing this C‐20 ester corticosteroid have demonstrated similar efficacy to C‐20 ketone corticosteroids in the prevention or treatment of the signs and symptoms of SAC but with a greatly improved safety profile, as the C‐20 ester corticosteroid is less likely to elevate intraocular pressure. In addition, the ketone at the C‐20 position has been implicated in the formation of cataract, while nonketolic corticosteroids do not form Schiff base intermediates with lens proteins, which is a common first step in cataractogenesis. The clinical relevance of the C‐20 ester corticosteroid class, as modelled by LE, is that they provide both effective and safe treatment of the inflammation associated with SAC and relief of its signs and symptoms. Loteprednol etabonate offers a well‐tolerated treatment option for patients with debilitating acute exacerbations as well as chronic forms of the disease.     

Soft Drugs 19. Pharmacokinetics,Metabolism and Excretion of a Novel Soft Corticosteroid,Loteprednol Etabonate,in Rats

Purpose. Pharmacokinetics, metabolism and excretion of loteprednol etabonate (LE) were investigated in rats. Methods. The pharmacokinetic studies were performed by iv injections of LE (1-20 mg/ kg). In the metabolism and excretion studies, 0.5-10 mg/kg of LE were iv administered, bile and urine samples were collected for 6 hr. Results. The pharmacokinetic of LE showed a rapid, dose-dependent elimination with a total blood clearance (CL_total) of higher than 60 ml/min/kg. The metabolism and excretion of LE also showed a marked dose-dependency. At 6 hr after iv of LE (0.5-10 mg/kg), the total recoveries (LE and the metabolites, AE & A, in bile and urine) were 99.35-26.72%. However, only about 2% of LE was excreted from the body through the urine. There were 0.93-2.12% and 0.66-0.26% of AE, and 75.67-19.69% and 20.74-2.77% of A excreted in the bile and urine, respectively. The excretion of A was dose dependent, and significantly higher at the lower dose. Using the (% of total excretion) vs. (log dose) plots, it could be predicted that almost all of the administered LE will be metabolized, and excreted as A when the systemic dose is lower than 0.25 mg/kg. Conclusions. The results indicate that LE absorbed systemically, after topical administration, can be rapidly transformed to the inactive metabolites, and eliminated from the body mainly through the bile and urine.     

Comparison of tobramycin 0.3%/dexamethasone 0.1% and tobramycin 0.3%/loteprednol 0.5% in the management of blepharo-keratoconjunctivitis

In this clinical trial, investigators compared the effectiveness of 2 commercially formulated antibiotic/steroid combinations - tobramycin 0.3%/dexamethasone 0.1% (Tobradex; Alcon, Fort Worth, Tex) and tobramycin 0.3%/loteprednol 0.5% (Zylet; Bausch & Lomb Inc., Rochester, NY) - for rapidly controlling inflammation in patients with blepharo-keratoconjunctivitis. Investigators in this randomized, parallel-group, double-masked study examined 40 eyes of 40 patients with blepharo-keratoconjunctivitis. Patients received tobramycin 0.3%/dexamethasone 0.1% or tobramycin 0.3%/loteprednol 0.5% twice daily in the test eye, according to the randomization schedule. At baseline, the ocular surface was graded on a scale of 3 (extensive) to 0 (minimum) for 4 components: blepharitis, conjunctivitis, ocular discharge, and corneal punctate epithelial keratopathy (PEK). Only those patients with moderate to extensive inflammation (cumulative score >6) were included in the study. At follow-up 3 to 5 d later, the ocular surface was regraded so that treatment response could be evaluated. No statistically significant difference was noted between groups in pretreatment scores for blepharitis (P=.31), discharge (P=.62), conjunctivitis (P=1.0), and PEK (P=.57), or for total ocular inflammation (P=.87). Mean posttreatment scores were as follows: total ocular surface scores, 1.8 and 3.4 (P=.002); blepharitis scores, 0.9 and 1.35 (P=.017); discharge scores, 0.2 and 0.6 (P=.025); and conjunctivitis scores, 0.15 and 0.6 (P=.013) for tobramycin/dexamethasone and tobramycin/loteprednol, respectively. Corneal PEK scores were not significantly different between treatments. Tobramycin 0.3%/dexamethasone 0.1% significantly decreased clinical signs of ocular inflammation (ie, blepharitis, discharge, conjunctivitis) and total ocular inflammation scores when compared with tobramycin 0.3%/loteprednol 0.5% in patients with moderate to severe blepharo-keratoconjunctivitis. The 2 regimens also provided comparably rapid decreases in corneal PEK.     

Symptomatic Treatment of Subepithelial Infiltrates after Viral Conjunctivitis: Loteprednol or Dexamethasone?

Purpose: To compare the efficiency and ocular side-effect profile of topical loteprednol applied to one eye and topical dexamethasone applied to the other eye in the early period on the same patient who has subepithelial infiltrates (SEI).

Methods: The patients who developed bilateral SEI following epidemic keratoconjunctivitis (EKC) were applied topical loteprednol on one eye (group 2) and topical dexamethasone on the other (group 1).

Results: Decrease in the symptoms was faster in the dexamethasone group, but this difference between the groups was not statistically significant (p = 0.073). Both groups were found to have substantial recurrence. However, the difference between the groups was not statistically significant (p = 0.131).

Conclusions: The study has found that in the treatment of SEI, which developed after EKC, statistically similar results can be obtained with loteprednol, which is known to have fewer adverse effects.     

Loteprednol and tobramycin in combination: a review of their impact on current treatment regimens

Importance of the field: The treatment of ocular inflammation continues to be a challenge. Topical corticosteroids are effective in reducing ocular inflammation but are limited by adverse events including elevation of intraocular pressure, development of cataracts, glaucoma and inhibition of wound healing with associated risk of infection. Loteprednol etabonate (LE) is a unique C-20 ester corticosteroid designed to produce a predictable therapeutic effect with a low incidence of side effects. Zylet^® (LE/T) a combination of LE and tobramycin (T) is indicated for the treatment of steroid-responsive ocular inflammatory conditions in which there exists either superficial bacterial ocular infection or a potential risk of bacterial infection.

Areas covered in this review: The current review of the literature (Medline and the Cochrane Library, 1996 – 2009) examines the safety and efficacy of LE/T in the treatment of ocular inflammation.

What the reader will gain: Studies with either LE or LE/T indicate that LE has a lower risk of IOP elevation compared with C-20 ketone corticosteroids owing to its rapid de-esterification to inactive metabolites. LE also lacks the ability to form Schiff base intermediates with lens proteins, a common first step in cataractogenesis. LE/T was noninferior to dexamethasone 0.1%/tobramycin 0.3% in the treatment of blepharokeratoconjunctivitis.

Take home message: LE/T may be a safer treatment option for ocular inflammation in which there is risk of superficial bacterial infections.     

氯替泼诺的合成工艺改进

以泼尼松龙为原料，经氧化、酰化、水解成盐、氯甲基化成酯制得氯替泼诺。用氯甲酸乙南将17位醇羟基和羧羟基同时酰化；水解时用碳酸钠溶液代替氢氧化钠甲醇溶液，提高反应的选择性。改进后的工艺副反应少，操作简便，成本降低，总收率45％。     

氯替泼诺治疗中重度干眼抗炎作用的临床分析

目的观察0．5％氯替泼诺滴眼液治疗中重度干眼病的临床疗效。方法按标准纳入中重度千眼患者40例,回顾性分两组：联合用药组予0．5％氯替泼诺滴眼液和新泪然滴眼液联合用药;单用药组用新泪然滴眼液。在治疗前及治疗后2、4、6周观察眼表疾病指数（OSDI）、泪膜破裂时间（BUT）、泪液分泌实验（SchirmerI试验）、眼表染色评分（OSS评分）、眼压;ELISA测泪液中炎症介质白介素-6（IL-6）的表达。结果治疗2周后,联合用药组OSDI评分均值明显降低,较治疗前差异有显著性（P〈0．05）;治疗2周联合用药组眼表炎症体征减轻;联合用药组BUT均较治疗前延长;两组各时间点的SehirmerI及眼压值无明显变化。结论0．5％氯替泼诺滴眼液通过下降IL-6表达,减轻中重度干眼眼表炎症,安全有效。     

氯替泼诺混悬眼液联合小牛血去蛋白提取物眼用凝胶治疗角膜云翳

目的:观察氯替泼诺混悬眼液联合小牛血去蛋白提取物眼用凝胶治疗各类眼科炎症及外伤导致角膜云翳的临床疗效。方法:采用自身对照的方法,选择我院门诊2009-02/2010-10各类角膜疾病导致角膜云翳的97例120眼患者,在不同阶段使用氯替泼诺混悬眼液联合小牛血去蛋白提取物眼用凝胶后,对云翳消退情况进行疗效分析。结果:角膜云翳形成0～1mo内治疗24例30眼,治愈80%,有效20%。1～2mo治疗23例30眼,有效53.3%,无效46.7%;2～3mo治疗25例30眼,有效13.3%,无效86.7%;3mo以上治疗25例30眼,无效100%。结论:氯替泼诺混悬眼液联合小牛血去蛋白提取物眼用凝胶治疗各种早期角膜云翳,具有积极有效地提高视力和促进角膜恢复透明的作用。