Role of neutrophils and mast cells in acute indomethacin-induced small bowel injury in the rat

The aim of this study was to determine whether the injury to the rat jejunum during the first 4.5h exposure to indomethacin is due to an influx of neutrophils or degranulation of resident mast cells. Indomethacin and vehicle both caused changes in villous morphology (length, width, etc.) while only indomethacin injured the small bowel, as indicated by increased histological lesion score and⁵¹Cr-ethylene diamine tetraacetate (EDTA) flux across the intestinal epithelium. Immunohistochemical staining showed the same small increase in neutrophil density (predominantly in the submucosa) following exposure to vehicle as following exposure to indomethacin. Chronic oral administration of indomethacin for 48 h did cause increased tissue neutrophil density compared to that in vehicle-fed controls. Mast cell depletion (using dexamethasone) did not alter either the indomethacin-induced increase in⁵¹Cr-EDTA clearance or the increase in neutrophil density caused by the vehicle and by indomethacin. However, the lesion score following exposure to indomethacin was significantly lower in mast-cell-depleted animals than in control animals. We conclude that the acute phase of indomethacin-induced intestinal injury is not associated with neutrophil influx. Increased neutrophils seen after chronic indomethacin may result from injury rather than be causative. Mast cells appear to exacerbate the initial stages of indomethacin-induced intestinal injury.     

Hyaluronan-modified transfersomes based hydrogel for enhanced transdermal delivery of indomethacin

Hyaluronic acid (HA), as a hygroscopic and biocompatible molecule, has displayed unique permeation enhancement in transdermal delivery systems. Hence, indomethacin (IND) was encapsulated in HA-modified transfersomes (IND-HTs) to enhance transdermal IND delivery to reduce adverse effects in this study. The physiochemical properties of IND-HTs were characterized. Results showed that the prepared IND-HTs were spherical and revealed good entrapment efficiency (87.88 ± 2.03%), with a nanometric particle size (221.8 ± 93.34 nm). Then, IND-HTs were further incorporated into a carbopol 940 hydrogel (IND-HTs/Gel) to prolong retention capacity on the skin. The in vitro release and skin permeation experiments of IND-HTs/Gel were carried out with the Franz diffusion cells. It was found that IND-HTs/Gel exhibited sustained drug release, as well as superior drug permeation and flux across the skin. Confocal laser scanning microscopy showed improved penetration of HTs/Gel with a wider distribution and higher fluorescence intensity. The hematoxylin–eosin stained showed that HA improved the transdermal effect by changing the microstructure of skin layers and decreasing skin barrier function. In addition, IND-HTs/Gel showed significant analgesic activity in hot plate test and no potentially hazardous skin irritation. This study indicated that the developed IND-HTs/Gel could be a promising alternative to conventional oral delivery of IND by topical administration.     

复方吲哚美辛栓对取环镇痛及宫口松弛的作用

[目的]比较三种不同药物肛门内置入后对取环手术镇痛及宫口松弛的作用.[方法]将90例择期行取环手术的妇女随机分为三组,分别于肛门内置入复方吲哚美辛栓1粒(A组),或0.4 mg米索前列醇(B组),或者安慰荆甲硝唑片200 mg(C组),1 h后行取环手术.术中判断宫颈软化程度及阴道出血量,记录手术时间和各种副反应以及最终能否取出宫内节育器,术毕患者评价术中疼痛视觉模拟评分(VAS).[结果]三组一般资料差异无显著性,宫颈软化程度C组显著低于A、B两组,C组较其他两组手术时间显著为长、手术成功率显著为低,术中疼痛VAS评分A组＜B组＜C组.[结论]复方吲哚美辛栓在取环手术前直肠内应用,可在一定程度上软化宫颈、缩短手术时间、提高手术成功率,并且可以减轻术中疼痛.     

经颅多普勒观察消炎痛治疗兔急性脑外伤的实验研究

为探讨消炎痛（ＩＤＴ）对急性实验性颅脑损伤后脑血流速度的早期影响，采用直接打击法建立具有临床闭合性颅脑损伤特点的兔急性实验性颅脑损伤模型。在该模型的基础上，静脉注射ＩＤＴ（４ｍｇ／ｋｇ），应用经颅多普勒超声（ＴＣＤ），观察其对大脑中动脉（ＭＣＡ）血流速度的影响，并结合颅内压（ＩＣＰ）监护，综合评定消炎痛在脑外伤治疗中的作用。结果表明：ＩＤＴ对脑外伤后脑血流速度有明显影响（Ｐ＜０．０５）。具体表现为ＭＣＡ收缩期血流速度（Ｖｓ）和血流速度时间平均值（ＴＡＭ）降低，而舒张末期血流速度（Ｖｄ）保持相对恒定。随着脑血流速度的下降，动物ＩＣＰ升高的速度及幅度也明显低于对照组。结果提示：ＩＤＴ在不影响脑氧代谢的基础上，可以减少脑血流量，从而有效地控制ＩＣＰ升高，改善脑外伤的预后。     

前列腺素E_1与实验性晶体过敏性色素膜炎的免疫学研究

通过实验性晶体过敏性色素膜炎(PAU)动物模型,观察了血中抗晶体抗体(ALAb)、血和房水中免疫复合物(IC)和前列腺素E_1(PGE_1)的动态变化;探讨了虹膜PGE_1和眼球病理改变的关系以及局部点滴消炎痛对PAU的作用。结果表明:PAU的发病和病理过程与全身和局部PGE_1水平下降、晶体蛋白的释放量、机体的致敏程度和IC的局部沉积有关;PAU的病理变化为非肉芽肿性炎症或Arthus反应:PGE_1可能作为重要的免疫或炎症抑制因子参与其病理过程:1％消炎痛局部应用未显示出对PAU的良好治疗作用。     

中西医结合治疗单纯性疱疹病毒角膜炎206例

单纯疱疹病毒性角膜炎,是一种常见的致盲眼病,其发病率和致盲率均占角膜病的首位.且病程迁延,易反复发作,给患者躯体及精神造成严重伤害.2001年12月～2005年11月,笔者采用中西医结合的方法治疗该病206例,取得满意疗效,现总结如下.     

A Phase I Study Evaluating the Pharmacokinetic Profile of a Novel,Proprietary, Nano-formulated,Lower-Dose Oral Indomethacin

Abstract

Background: Safety and tolerability concerns associated with nonsteroidal anti–inflammatory drugs (NSAIDs) have prompted the development of lower–dose formulations. This phase 1 clinical study characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano–formulated, lower–dose oral indomethacin (nano–formulated indomethacin) compared with standard oral indomethacin in healthy subjects. Methods: Forty healthy subjects were enrolled in a single–dose, randomized, 5-period, 5-treatment crossover study. Subjects received nano–formulated indomethacin 20 mg (fasted), or nano–formulated indomethacin 40 mg or standard indomethacin 50 mg (fed and fasted). Pharmacokinetic parameters, including maximum measured plasma concentration (C_max), time to maximum measured concentration (T_max), elimination half–life (T_1/2), and area under the concentration–time (AUC) curve, along with safety and tolerability, were assessed. Results: There was a more rapid mean (± standard deviation) T_max for nano–formulated indomethacin 20 mg (1.11 ± 0.55 h) and 40 mg (1.25 ± 0.60 h) compared with indomethacin 50 mg (1.97 ± 0.81 h) under fasting conditions, demonstrating faster absorption for the nano–formulated indomethacin. The T_1/2 was similar for nano–formulated indomethacin 40 mg and indomethacin 50 mg. The C_max for nano–formulated indomethacin 40 mg was higher compared with indomethacin 50 mg in fasted subjects (3115 ± 900 ng/mL vs 2759 ± 936 ng/mL, respectively), and slightly lower in fed subjects (1360 ± 424 ng/mL vs 1408 ± 469 ng/mL, respectively). There was a 26% reduction in drug exposure (AUC_0-∞) when subjects received nano–formulated indomethacin 40 mg compared with indomethacin 50 mg under fasting conditions (6861 ± 1585 h*ng/mL vs 9306 ± 2234 h*ng/mL, respectively). Safety and tolerability were comparable between formulations. Conclusion: The nano–formulated, lower–dose indomethacin had an improved PK profile compared with indomethacin. Under the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may support use of lower–dose NSAID formulations that improve safety/tolerability while maintaining pain relief similar to standard NSAID formulations.     

Gastrointestinal Protection by Low-Dose Oral Prostaglandin E2 in Rheumatic Diseases

In a previous study oral prostaglandin E₂ (PGE₂) was shown to protect against indomethacin-induced gastrointestinal bleeding in patients with rheumatic diseases. This study examined whether a lower oral dose of PGE₂, without acid antisecretory effect, is protective. Its methylated analogue 15(R)15 Me PGE₂, which has effect on the acid secretion given orally, was also tested. Indomethacin, 50 mg three times daily, induced an increase in gastrointestinal bleeding measured by the ⁵¹Cr technique. PGE₂, 0.33 mg three times daily, taken concomitantly significantly reduced fecal blood loss. 15(R)15 Me PGE₂, 40 μg three times daily, was also effective. The prostaglandins did not increase joint symptoms and had no significant side effects. It is suggested that the combination of nonsteroidal anti-inflammatory drugs with a low oral dose of E₂ prostaglandins could be used clinically, especially in patients with rheumatic diseases.