【作者】 刘二刚；

【导师】 傅旭春；

【作者基本信息】 浙江大学 ， 药剂学， 2012， 硕士

【摘要】 痛风性关节炎是一种由于人体内尿酸含量异常升高,尿酸盐在关节等部位析出而引发的炎症反应。随着人类生活水平的提高,高尿酸血症及痛风性疾病的发病率呈升高趋势,迫切需要研究和开发药效好、副作用小的抗痛风性关节炎的新药。本文采用灌胃尿酸(400mg/kg/d建立高尿酸血症的鹌鹑模型；分别用灌胃次黄嘌呤(500mg/kg)+皮下注射尿酸酶抑制剂氧嗪酸钾(400mg/kg)法与皮下注射尿酸(400mg/kg)法建立了小鼠高尿酸血症模型。实验结果表明：本文采用的造模方法可以使动物血尿酸水平显著提高；黄嘌呤氧化酶抑制剂别嘌醇可以显著性降低由尿酸引起的鹤鹑血尿酸升高,对次黄嘌呤+氧嗪酸钾引起的小鼠血尿酸升高也有明显的抑制作用,但对皮下注射尿酸引起的小鼠血尿酸升高没有明显作用；促尿酸排泄药苯溴马隆可以显著性降低上述三种模型动物的血尿酸水平。本文对HPLC测定血尿酸含量进行了方法学考察,建立了准确、稳定、可靠的血尿酸测定方法。本文采用关节腔内注射尿酸钠结晶的方法诱导大鼠产生痛风性关节炎症状。与空白对照组动物相比,模型组动物4h时即可检测到显著肿胀,11h时达到峰值。之后肿胀现象开始逐渐消退,整个过程可持续30h以上。本文用鹌鹑高尿酸血症模型评价了中药TCM-1的降血尿酸作用。TCM-180%乙醇(V/V)提取物可以显著性降低高尿酸血症鹌鹑的血尿酸浓度,而其水提物的降血尿酸作用不明显。本文分别研究了穿山龙提取物对用次黄嘌呤+氧嗪酸钾法和注射尿酸法诱导产生的两种小鼠高尿酸血症模型的作用。结果表明穿山龙提取物对两种小鼠高尿酸血症模型均有降血尿酸作用。本文研究了黄酮类化合物落新妇苷对尿酸钠所致大鼠痛风性关节炎的作用,并探讨了可能的作用机理。研究结果显示：落新妇苷对尿酸盐引起的大鼠关节肿胀具有显著的抑制效果,而秋水仙碱对关节肿胀的抑制作用并不明显；落新妇苷和秋水仙碱均可以显著促进大鼠炎症部位抗炎因子IL-4的表达；落新妇苷还可以促进Th0细胞向Th2细胞分化,提示落新妇苷对尿酸盐引起的大鼠关节肿胀的抑制作用可能是通过抑制在炎症发展过程中具有增强血管通透性作用的Th1型细胞因子的表达而实现。更多还原

【Abstract】 Gouty arthritis is a kind of inflammation caused by deposits of monosodium urate acid (MSU) in the synovia of joint due to continual elevation of serum urate acid in human body. Owning to improvement of human living standard, prevalence of high purine diet leads to a rise of incidence of hyperuricemia and gout in those years, making it an urgent need for drugs that is more excellent in treating gouty arthristis with less adverse effects.In this research, quails were administratered with urate acid suspension (400mg/kg) to induce continual elevation of SUA; Hyperuricemia of mouse was induced by subcutaneous injection of urate acid (400mg/kg), or by gavage of hypoxanthine (500mg/kg) in coordination with subcutaneous injection of uricase inhibtor, i.e. potassium oxonate (400mg/kg). Allopurinol, a xanthine oxidase inhibitor, was found to be able to antagonize both the quails’SUA elevation induced with urate acid and the mouse hypreuricemia induced with hypoxanthine and potassium oxonate, but it was inactive to hyperuricemic mouse induced with urate acid. Benzbromarone, another commenly used drug promoting excretion of uric acid, significantly reduced SUA levels of all the animal models in this research.We established the accurate, robust and reliable method to detect the authentic concentration of serum uric acid with HPLC.Gouty arthritis was induced by injection of MSU into joint of rat’ s ankles. Compared with animals injected with saline, animal ankles injected with MSU can be detected swell since time 4h since artificial damage, Volume of the MSU treated ankles reach a peak at 11h, then decrease slowly in the following hours. The process may last for more than 30 hours.Hyperuricemic quails were used to assess TCM-1’s potential to decrease SUA concentration of the experimental animals.80% ethanol (V/V) extracts of TCM-1 can significantly reduced SUA concentrations of quails induced with uric acid.Dioscoreae Nipponicae Makino’s extracts were found to be able to decrease the level of SUA in hyperuricemia mice induced either by injection of uric acid or by coadministration of hypoxthine and potassium oxonate.Astilbin was found to be able to inhibit swell at rat’s ankle due to MSU-induced inflammation, and promote expression of IL-4 in inflammatory joints and differertiation of T helper cells from ThO phase to Th2 phase. Its inhibitory function to swell of inflammatory joints may owe to its ability to down regulate Thl-type cytokines that are pivotal to increase vascular permeability.更多还原