甲氨蝶呤对佐剂性关节炎大鼠免疫器官重量的影响

目的观察大鼠佐剂性关节炎（adjuvant arthritis,AA）模型免疫器官重量（胸腺、脾脏）的变化,探讨甲氨蝶呤（MTX）的免疫药效学。方法将SD大鼠随机分为正常组、模型组、MTX组,模型组和MTX组用弗氏完全佐剂（FCA）造模,正常组和模型组给予5%的葡萄糖注射液2 ml/d腹腔注射,MTX组每日MTX 0.3mg·kg^-1·d^-1（溶于5%的葡萄糖注射液2 ml）腹腔注射,正常饲养;15天后将大鼠处死,取胸腺、脾脏,电子天平称重,计算重量指数。结果MTX组胸腺重量和指数较模型组低且差异有统计学意义（P〈0.05）,而对脾脏影响不大（P〉0.05）。结论MTX可以减低AA大鼠模型胸腺重量和胸腺指数,从而对细胞免疫有一定作用。     

Nitroflurbiprofen, a nitric oxide-releasing cyclooxygenase inhibitor, improves cirrhotic portal hypertension in rats

BACKGROUND & AIMS: We studied whether administration of nitroflurbiprofen (HCT-1026), a cyclooxygenase inhibitor with nitric oxide (NO)-donating properties, modulates the increased intrahepatic vascular tone in portal hypertensive cirrhotic rats. METHODS: In vivo hemodynamic measurements (n = 8/condition) and evaluation of the increased intrahepatic resistance by in situ perfusion (n = 5/condition) were performed in rats with thioacetamide-induced cirrhosis that received either nitroflurbiprofen (45 mg/kg), flurbiprofen (30 mg/kg, equimolar concentration to nitroflurbiprofen), or vehicle by intraperitoneal injection 24 hours and 1 hour prior to the measurements. Additionally, we evaluated the effect of acute administration of both drugs (250 micromol/L) on the intrahepatic vascular tone in the in situ perfused cirrhotic rat liver (endothelial dysfunction and hyperresponsiveness to methoxamine) and on hepatic stellate cell contraction in vitro. Typical systemic adverse effects of nonsteroidal anti-inflammatory drugs, such as gastrointestinal ulceration, renal insufficiency, and hepatotoxicity, were actively explored. RESULTS: In vivo, nitroflurbiprofen and flurbiprofen equally decreased portal pressure (8 +/- 0.8 and 8.4 +/- 0.1 mm Hg, respectively, vs 11.8 +/- 0.6 mm Hg) and reduced the total intrahepatic vascular resistance. Systemic hypotension was not aggravated in the different treatment groups (P = .291). In the perfused cirrhotic liver, both drugs improved endothelial dysfunction and hyperresponsiveness. This was associated with a decreased hepatic thromboxane A(2)-production and an increased intrahepatic nitrate/nitrite level. In vitro, nitroflurbiprofen, more than flurbiprofen, decreased hepatic stellate cells contraction. Flurbiprofen-treated rats showed severe gastrointestinal ulcerations (bleeding in 3/8 rats) and nefrotoxicity, which was not observed in nitroflurbiprofen-treated cirrhotic rats. CONCLUSIONS: Treatment with nitroflurbiprofen, an NO-releasing cyclooxygenase inhibitor, improves portal hypertension without major adverse effects in thioacetamide-induced cirrhotic rats by attenuating intrahepatic vascular resistance, endothelial dysfunction, and hepatic hyperreactivity to vasoconstrictors.     

甲氨蝶呤微乳的制备与质量评价

目的:制备甲氨蝶呤微乳并评价其质量。方法:选用无水乙醇作助表面活性剂,以甲氨蝶呤在各种油相组分中的溶解度、不同体系的最大载油量为指标,通过滴定法绘制伪三元相图,确定微乳区,筛选甲氨蝶呤微乳的最佳处方;以外观、平均粒径及其分布、Zeta电位、含量、pH值为指标进行质量评价。结果:微乳的最佳处方为聚氧乙烯氢化蓖麻油RH-40、大豆磷脂、无水乙醇、油酸乙酯(3∶1.5∶1.5∶3),其中甲氨蝶呤在大豆磷脂中的溶解度为585.95μg·mL-1,在聚氧乙烯氢化蓖麻油RH-40/大豆磷脂体系中的最大载油量为42.8%;其外观均一透明,平均粒径为25.1nm,多分散指数为0.273,Zeta电位为-1.723mV,pH值为6～7,含药量均大于94%。结论:所制制剂理化性质稳定,制备工艺简单,质量稳定易控。     

大剂量甲氨蝶呤在急性淋巴细胞白血病患儿体内血药浓度的相关因素分析

目的:研究大剂量甲氨蝶呤在急性淋巴细胞白血病(ALL)患儿体内血药浓度与水化量、碱化量、尿量、体质量及各生化指标的相关性。方法:采用回顾性调查方法,查阅我院儿科2003～2006年住院接受甲氨蝶呤抗肿瘤治疗的ALL患儿病历,记录甲氨蝶呤血药浓度值及相应的生化检验值、水化量、碱化量、尿量及体质量等数据,应用SPSS10.0统计软件对数据进行多元线性回归分析。结果:甲氨蝶呤单位剂量血药浓度对数值与大部分生化检验值、水化量、碱化量及尿量间不存在明显的相关性,但24h甲氨蝶呤单位剂量血药浓度的对数值与体质量呈负相关,与总胆红素呈正相关(P<0.05),42h甲氨蝶呤单位剂量血药浓度的对数值与体质量及总蛋白均呈负相关(P<0.01)。结论:甲氨蝶呤血药浓度与患儿自身因素具有一定相关性,应根据每位患儿的具体情况制定个体化给药方案。     

Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters

Nilotinib, a BCR-Abl tyrosine kinase inhibitor (TKI), was developed to surmount resistance or intolerance to imatinib in patients with Philadelphia positive chronic myelogenous leukemia. Recently, it was shown that several human multidrug resistance (MDR) ATP-binding cassette (ABC) proteins could be modulated by specific TKIs. MDR can produce cancer chemotherapy failure, typically due to overexpression of ABC transporters, which are involved in the extrusion of therapeutic drugs. Here, we report for the first time that nilotinib potentiates the cytotoxicity of widely used therapeutic substrates of ABCG2, such as mitoxantrone, doxorubicin, and ABCB1 substrates including colchicine, vincristine, and paclitaxel. Nilotinib also significantly enhances the accumulation of paclitaxel in cell lines overexpressing ABCB1. Similarly, nilotinib significantly increases the intracellular accumulation of mitoxantrone in cells transfected with ABCG2. Furthermore, nilotinib produces a concentration-dependent inhibition of the ABCG2-mediated transport of methotrexate (MTX), as well as E₂17βG a physiological substrate of ABCG2. Uptake studies in membrane vesicles overexpressing ABCG2 have indicated that nilotinib inhibits ABCG2 similar to other established TKIs as well as fumitremorgin C. Nilotinib is a potent competitive inhibitor of MTX transport by ABCG2 with a K_i value of 0.69 ± 0.083 μM as demonstrated by kinetic analysis of nilotinib. Overall, our results indicate that nilotinib could reverse ABCB1- and ABCG2-mediated MDR by blocking the efflux function of these transporters. These findings may be used to guide the design of present and future clinical trials with nilotinib, elucidating potential pharmacokinetic interactions. Also, these findings may be useful in clinical practice for cancer combination therapy with nilotinib.     

曲安奈德联合甲氨喋呤关节腔注射治疗类风湿关节炎

目的探讨联合使用甲氨喋呤(MTX)和曲安奈德(TA)关节腔注射治疗类风湿关节炎(RA)的疗效。方法选择2006年1月-2007年4月我院门诊对称性腕或膝关节炎的RA患者37例。选择一对炎症程度相当的膝或腕关节,随机确定一侧,以曲安奈德针(TA)1mL:40mg溶解MTX针(MTX)5mg混匀后关节腔注射(TM组)。对侧作为对照,以相同剂量曲安奈德针关节腔注射(TA组),整体治疗不变,继续按原来方法服用NSAIDs及DMARDs治疗。分别于注射后第1个月、3个月、6个月末观察注射关节的肿胀数、疼痛数、压痛数及相应指数。结果TM组与TA组关节腔注射后,肿胀关节明显减少,而不同时间点两组间差异均有统计学意义(P<0.01)。随访6个月,两组均未发现明显不良反应。结论曲安奈德针联合MTX针关节腔注射治疗类风湿关节炎,其消炎、止痛、消肿和改善患者关节功能的疗效优于单用曲安奈德针关节腔注射,可显著减少复发机会,延迟复发时间,是类风湿关节炎有效的控制方法之一。     

宫腔镜技术保守治疗宫颈妊娠9例分析

目的探讨宫腔镜在保守治疗宫颈妊娠中的临床应用价值。方法9例经超声诊断宫颈妊娠的患者,予宫腔镜下妊娠物清除术,或MTX全身或局部注射后再行宫颈妊娠物电切术。结果9例采用宫腔镜保守治疗的病例均获得成功,术后2周复查血β-HCG均下降至正常。结论宫腔镜技术可直视下明确胚胎着床部位,彻底清除妊娠物,结合MTX全身或局部使用,是一种有效的保守治疗宫颈妊娠的方法。     

血清β-HCG<1000U/L的异位妊娠治疗方案及相关因素分析

目的:探讨血清β-HCG<1 000 U/L的异位妊娠治疗方案及相关影响因素。方法:回顾性分析血清β-HCG<1000 U/L的异位妊娠202例,其中102例采用肌肉注射MTX 50 mg+口服米非司酮150 mg(A组),100例采用期待疗法(B组)。所有病例治疗前测定血清β-HCG并做彩超检查,于第4天和第7天复查β-HCG和B超。结果:A组第4天有29例患者β-HCG上升,但幅度<30%,第7天β-HCG均下降;B组第4天有34例患者β-HCG上升,其中21例患者上升幅度>30%,第7天有17例患者上升超过一倍,这些患者停经时间均<40天,彩超提示包块周围有丰富的彩流信号。包块周边有丰富彩流信号者β-HCG水平相对较高,用杀胚药物治疗后下降幅度较大;少或无彩流信号者用杀胚药治疗后血清β-HCG水平与期待治疗组无明显差别。结论:对于血清β-HCG<1 000 U/L的异位妊娠患者不能一律采用期待疗法,若患者停经时间<40天,彩超提示包块周围有丰富的彩流信号应积极采取杀胚治疗,在治疗过程中第4天β-HCG和B超表现略有加重不能视为治疗无效。     

剖宫产术后43例瘢痕妊娠的治疗的探讨

目的:探讨瘢痕妊娠的诊断及治疗。方法:对上海市第一妇婴保健院2003年~2007年收治的43例瘢痕妊娠患者进行回顾性分析,并对不同的治疗方法进行比较。结果:43例患者均通过超声明确诊断,2例行全子宫切除术,1例行次全子宫切除术,其余患者均保守治疗成功。方法包括25例患者使用甲氨喋呤(MTX)与经阴道超声孕囊穿刺术相结合治疗,18例患者使用MTX与介入治疗相结合。结论:超声可以在孕早期明确诊断,早期诊断及治疗可以获得满意的治疗效果。     

ACNU和三尖杉酯碱分别联合MTX超选择性脑动脉灌注治疗恶性脑瘤的疗效比较

比较超选择性脑动脉灌注嘧啶亚硝脲（ＡＣＮＵ）加氨甲喋呤（ＭＴＸ）（Ａ组）以及三尖杉酯碱加ＭＴＸ（Ｂ组）治疗恶性脑胶质细胞瘤的疗效。方法将ＡＣＮＵ２～３ｍｇ／ｋｇ，三尖杉酯碱０１～０５ｍｇ／ｋｇ，ＭＴＸ０１～０２ｍｇ／ｋｇ按Ａ、Ｂ两组各１２例方案，采用超选择性脑动脉联合灌注化疗，并于化疗后１～１５个月以ＣＴ检查评定疗效。结果Ａ组肿瘤体积缩小４８３２％，Ｂ组缩小４６２１％；Ａ组有效者占４／１２，Ｂ组占３／１２；平均生存期分别为２５３个月和２３３个月；两组治疗前后肿瘤体积变化均有显著性差异，但两组疗效则无明显差异；并均无眼部及严重脑部并发症。结论ＡＣＮＵ加ＭＴＸ以及三尖杉酯碱加ＭＴＸ超选择性脑动脉灌注对恶性脑胶质细胞瘤的疗效相似，毒副作用小。