【作者】 胡成穆；

【导师】 李俊； 金涌；

【作者基本信息】 安徽医科大学 ， 药理学， 2002， 硕士

【摘要】 美洛昔康是治疗类风湿性关节炎和骨关节炎的非甾体抗炎药，对环氧酶-2具有选择性抑制作用，胃肠道反应较其它非甾体抗炎药小，但有关Mel口服和静脉用药的不良反应也有报道。外用制剂，可以避开口服和静脉用药引起的血药浓度过高造成的全身不良反应，可能是一种疗效好、不良反应小的局部用药剂型。为研究美洛昔康凝胶的有效性和安全性以及外用后药物在体内的动态规律，本文采用大鼠佐剂性关节炎（AA）模型，研究美洛昔康凝胶对AA大鼠的治疗作用，结果发现Mel G(3.75、7.5和15mg·kg^-1)对AA大鼠原发性和继发性炎症均有抑制作用。与Mel 7.5mg·kg^-1ig相比，Mel G组不良反应相对较小（溃疡指数较小，对动物体重增长影响较少）。 为研究美洛昔康凝胶的药代动力学，本研究建立了血及组织中美洛昔康的高效液相色谱（HPLC）检测方法。高效液相色谱条件：流动相：甲醇：水：冰乙酸：乙腈（600：500：20：50）v/v；流速：1.0ml·min^-1，柱温40℃，定量管：50μl；检测波长：355nm。血清中Mel能得到很好的分离，最低检测浓度为0.039μg·ml^-1，检测限1.95ng，线性范围为0.039～10μg·ml^-1，r为0.9998，P＜0.05，回收率在85.67％～95.09％，足爪局部回收率在80.13％～94.56％，本方法符合生物样品分析要求。在此基础上采用AA大鼠模型，研究Mel G治疗AA大鼠的药效与药物浓度间的关系，以同剂量Mel 3.75mg·kg^-1ig作对照，每4天测定AA大鼠的足爪肿胀度，同时用HPLC检测血和足爪局部组织的药物浓度，观察Mel G治疗AA大鼠的治疗效果与其血药浓度和局部药物浓度的关系。结果发现，与Mel ig相比，Mel G治疗AA大鼠疗效相当，Mel G血药浓度较低而足爪局部药物浓度明显增高，将AA大鼠继发性足爪肿胀度与Mel G的药物浓度作相关分析，结果显示AA大鼠继发性足爪肿胀度与Mel G的足爪局部组织药物浓度之间呈显著负相关，r为-0.7459，P＜0.05。不良反应小可能与其血中药物浓度低有关，而其治疗效果则 安徽医科大学硕士学位论文 与足爪局部药物浓度高有关。k 为进一步探讨 MelG在体内的动态变化过程，本研究通过家兔单次皮肤外用 美洛昔康凝胶，观察美洛昔康凝胶的透皮吸收及药代动力学情况，估算药代动力 学参数。采用高效液相色谱法测定家兔单次皮肤外用 Mel后的血中药物浓度。 药物浓度－时间数据作房室模型分析，并求出相应的药动学参数。Mel三个剂量 组家兔单次皮肤外用的血药浓度其数据均适合一级吸收的二房室模型。Mel的 TI。k。短，说明其吸收快，透皮吸收好；主要药动学参数分别为： Mki G 3．75k＊．吟－1：TIok。O．1刀5川．1506h，T！0ke7．97十2。56卜，几ulh， Cm拙 1．42＋0．38 P g．二1＊，AUCO－24 5＊5＋1．47 119．h．4lJ： MCIG7．sffig．kg－！：TI／Zk。0．2051＋0．二769h，TIQke12．88＋10．38h，T＊ulh， 乙肌2．3附0了lpg．ml1，＊＊＊o2412＊8＋5．08卜g．h．41＊； M dG15＊g．叱I：TIQk。0．＊＊92＋0＊9＊gb，T！ohe22．13＋32．18h，＊m肛1，2＋0．＊sh ＊＿皿6回15＋147pg．＊11，＊＊C口－24二2．16十6．52vg．h．D口卜。’、。＿＿、。＿＿、。、。＿＿＿＿。，；＿＿＿＿＿。＿、＿＿＿。，＿。L。。。＿＿、。一 总之，美洛昔康凝胶具有疗效好、不良反应少和透皮吸收快的特点，是美洛 昔康治疗类风湿关节炎的局部用药剂型。更多还原

【Abstract】 Meloxicam is a non-steroidal anti-inflammatory drug which was widely used to treatpatients with rheumatoid arthritis and osteoarthritis. Selective COX-2 inhibitors suchas me1oxicam are thought to hav’e feYVer adverse gastrointestinal reactions than othernon-steroidal anti-inflammatory drugs. But adverse reactions induced by meloxicamorally or intravenously administered recently could aIso be found. Meloxicam gel(Me1 G) adrninistered thIough cutaneously (tc ) could avoid over-high serum drugconcentration, which is relevant to adverse reactions, and may be a new preparationx"ith less toxic and more effective. The therapeutic effect of Mel G was studied by’means of adjuvant arthritis(AA) model which was induced by intradermal injection ofFreund’s complete adjuvant(FCA). The effects of Mel G on rat AA were observedfOllowing Mel G tc. Me1 G (3.75’ 7.5’ l5 mg. kg-’ ) significantly inhibited primaIyand secondary inflanunation of AA rats. Compared with intragastric injection (ig)Me1, Mel G had less adver5e reactions (such as ulcer index) and no effect tvereobseri!ed on tx-eight gain of AA rats.A high perfOrmance liquid cbIomatography (HPLC ) method t’ith ultraviolet detectionwas set up to determine the concentration of Mel in serum and local tissue, the mobilephase consisted of methanol: Water f Acetic acid t Acetonitrile = 600: 500: 20f 50 witha flow rate of l .0 ml. min-1 ) a constan temperature oven was set at 40C and the UVabsorbance detector was set at 355nm, Under this condition, Mel in serum could bewell separated. The limit of detection was l.95 ng. A good linearity of Mel tt’asobtained from 0.039 ng. ml-I to l0ng. m1-1 t’-ith r=0.9998 (P (0.05 ), The recovery inserum was between 85.67% and 95.09%, and the recovery in local tissue was betWeen4%4tt a f}k4xz + 4tisak80. l 3% and 94.56%. All of these showed HPLC method fitted for ana1ytic requirementof Mel preparation. Then AA model t’as used to study the relationship betxveentherapeutic effect and serum or local tissue concentration of Mel G in rats. The resultsshot’.ed that the concentration of NIel G t"as lower in serum and higher in local tissuethan that of Mel tablets. A significant 1inear correlation in a negative manner existedbettt’een local tissue concentration of Mel G and hindpaw sxx.el1ing volume, xx1ith thecorrelation coefficient rv -0.7459, P<0.05.The pharmacokinetics of Mel G in rabbits after a single dose of 3.75, 7.5 and1 5mg. kg-’ tc was also studied, HPLC method xtas used to determine the concentrationof Mel in serum, The results of the pharmacokinetic study of Me1 G showed that itexhibited first order kinetic characteristics. The profile of the serum concentration-timecurves of Me1 G after a sing1e dose of 3.75, 7.5 and l5rng. kg-’ tc was fitted tott’-o-compartment model. Short T1,2ka indicated that Mel G t"as ea5y to be absorbed.Main pharmacokinetic parameters of MeI G after singIe dose transdermaladministration in five rabbits as follow:Mel G 3.75mg. kg-’: Tl/2k. 0’ 12l5i0. l506h, T1/2k, 7.97f2.56h, T.. 1 h,C.,. l .42t0.38 ll g. ml-1, AUCo~:4 5’9521 .47 P g. h. ml-’:Mel G 7.5 mg. kg-’: Tl/2k. 0’205lr0.2769 h, Tl;2k, l2’88i10.38 h, T... l h,C.. 2’30I0.7l ll g. ml-l, AUCo--24 l2’98I5.08 ll g. h. ml-l:Mel G l 5 mg. kg-’: Tl/2k, 0’2792I0.2929 h, Tl/2k, 22’ l3f32.l8 h, T..l ’210.45 h,C.. 6’ 151l .47 ll g. ml-l, AUCo~24 22’ l6I6.52 ll g. h. ml-1.In a t’.ord, Mel G is a new preparation for treatment rheurnatoid arthIitis xx’ith less toxicand more effecti1’e.更多还原