Synthesis and Structure Elucidation of 5-Aminomethinimino-3-methyl-4-isoxazolecarboxylic Acid Phenylamides and Their Immunological Activity

A series of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides 4 has been prepared by condensation of 5-amino-3-methyl-4-isoxazolecarboxylic acid phenylamides 1 with trichloroacetic aldehyde. Alcoholysis of trichloro derivatives 2 gave 5-alkoxymethine derivatives 3 which, on reaction with an appropriate amine, formed the corresponding compounds 4 . The compounds obtained were evaluated for their immunological activity. The properties of three compounds, described in this report, permitted inhibition of the immune response in all possible ways: diminishing both types of immune response ( 4d ), humoral immune response ( 4a ), or cellular immune response ( 4c ). Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs. Two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.     

Immune function in cyclophosphamide-treated mice is restored by the T-cell-tropic isoxazole derivative R-13

Abstract

Reconstitution of the immune function in chemotherapy patients will lead to decreases in post-operative complications. A preliminary investigation showed that an isoxazole derivative R-13 (3,5-dimethyl-isoxazole[5,4-e]8H-triazepin-4-one) hydrochloride, given in a single oral dose to normal mice, induced significant increases in the content of CD4⁺ cells in the spleens and lymph nodes. That observation prompted the authors to assess the immune reconstituting effects of R-13 in mice pre-treated with cyclophosphamide (CP). Mice were given intraperitoneally (IP) a sublethal dose of CP (200?mg/kg) and then R-13 (as 20?µg IP doses, every 3 days post-CP treatment). Control mice, not treated with CP, received R-13 or the vehicle (DMSO in appropriate dilution). Blood leukocyte and splenocyte numbers, blood cell type levels, splenocyte spontaneous and ConA-induced proliferation, and delayed-type hypersensitivity (DTH) to ovalbumin (OVA) were investigated on day 15 post-CP treatment and five R-13 doses. The humoral immune response (antibody-forming cell development to sheep erythrocytes) was measured 30 days post-CP treatment and 10 R-13 doses. In CP-treated mice, five dosings with R-13 led to increases in numbers of splenocytes and blood leukocytes, as well as in spontaneous and ConA-induced splenocyte proliferation, relative to levels in mice that received only CP 15 days earlier. Blood analysis revealed decreases in neutrophil and eosinophil contents and an increased appearance of lymphocyte immature forms in all mice that received the R-13. Both cell-mediated responses to OVA and humoral immune response to sheep erythrocytes in CP-treated hosts were restored. Based on the data here, it is concluded that R-13 may be of potential value for reconstitution of the immune function of chemotherapy patients.     

雷抑素对大鼠移植肝Kupffer细胞的影响

目的探讨肝移植术前应用雷抑素对大鼠肝Ｋｕｐｆｅｒ细胞的影响方法以ＳＤ大鼠为供受体建立原位肝移植模型．受体移植术前３ｄ连续口服１％羧甲基纤维素１ｍｌ／ｄ（对照组）或雷抑素１０ｍｇ／ｋｇ·ｄ（用药组）．分别于术后１，２，３，２４ｈ采血并取肝组织，检测血清ＴＮＦ，ＡＬＴ及肝ＭＤＡ水平，观察肝超微结构及大鼠１周存活率变化．结果对照组移植术后３ｈ血清ＴＮＦ（５３ｋＵ／Ｌ±０４１ｋＵ／Ｌ），肝ＭＤＡ（４８４６ｎｍｏｌ／ｇ±２３６ｎｍｏｌ／ｇ）显著增加，ＴＮＦ表达呈强阳性；而且药组ＴＮＦ（０９ｋＵ／Ｌ±０１１ｋＵ／Ｌ）肝ＭＤＡ（３６１８ｎｍｏｌ／ｇ±１５４ｎｍｏｌ／ｇ）无明显变化，ＴＮＦ表达阴性，两者相差显著Ｐ＜００１）．电镜检查，对照组肝Ｋｕｐｆｅｒ细胞呈活化表现，而用药组肝Ｋｕｐｆｅｒ细胞呈非活化状态．对照及用药组术后１周存活率分别为０％和６０％．结论术前应用雷抑素可抑制移植肝ＴＮＦ和Ｏ２的产生，抑制Ｋｕｐｆｆｅｒ细胞活化，以减轻肝冷缺血再灌注损伤．     

帕瑞昔布钠超前镇痛对妇科术后自控硬膜外镇痛效果的影响

目的 探讨帕瑞昔布钠超前镇痛对妇科术后患者自控硬膜外镇痛(PCEA)效果的影响.方法 90例择期妇科手术的患者随机分成三组,均采取硬膜外阻滞麻醉方式,Ⅰ组于切皮前10 min静脉注射帕瑞昔布钠40 mg,Ⅱ组于手术结束时静脉注射帕瑞昔布钠40 mg;Ⅲ组不应用帕瑞昔布钠.三组术毕均留置硬膜外导管以0.12%罗哌卡因行患者自控硬膜外镇痛(PCEA).记录术后4、8、12、24、48 h的VAS评分及术后48 h内罗哌卡因用量及不良反应.结果 Ⅰ组48 h镇痛满意度(8.3±2.1)、Ⅱ组镇痛满意度(7.2±1.8)明显高于Ⅲ组镇痛满意度(5.7±2.6)(P<0.05).Ⅰ组VAS评分分别为8 h(2.64±0.18)、12 h(1.33 ±0.52)、24 h(1.08±0.57),明显低于Ⅲ组8 h(4.65±0.54)、12 h(3.86±0.77)、24 h(3.09±0.67)(P<0.05)三个时点的VAS评分.Ⅲ组有效按压次数(9.69±8.68)明显高于Ⅰ组(5.56±6.34)(P<0.05);Ⅲ组实际按压次数(18.36±12.59)明显多于Ⅰ组的实际按压次数(11.67±15.16)(P<0.05).Ⅲ组罗哌卡因总用药量(239.78±19.31)明显高于Ⅰ组(187.46±22.59)和Ⅱ组(209.39±19.12)(P<0.05)的用药量.Ⅲ组患者恶心、呕吐发生率明显高于Ⅰ组(P<0.05).结论 帕瑞昔布钠超前镇痛在一定程度上能提高妇科术后患者硬膜外自控镇痛效果,并减少硬膜外自控镇痛期间局麻药的用量.     

来氟米特对急性化学性肝损伤小鼠肝Cyt.P450酶含量及CYP2E1 mRNA表达的影响

目的观察来氟米特(Lef)作用前后急性化学性肝损伤小鼠肝微粒体细胞色素P450(Cyt.P450)、细胞色素b5(Cyt.b5)含量及P4502E1(CYP2E1)mRNA表达水平的变化,进一步研究其治疗机制。方法采用CCl4诱导小鼠急性化学性肝损伤模型,检测血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)活性,肝匀浆丙二醛(MDA)、谷胱甘肽(GSH)含量以及肝微粒体细胞色素P450(Cyt.P450)和细胞色素b5(Cyt.b5)含量,RT-PCR法检测小鼠肝脏细胞色素P4502E1(CYP2E1)mRNA表达水平,并作肝组织切片病理观察。结果Lef明显降低CCl4急性肝损伤小鼠血清ALT、AST水平;降低肝匀浆MDA含量;提高GSH含量并提高肝微粒体Cyt.P450、Cyt.b5含量;抑制CYP2E1 mRNA表达;减轻肝脏病理损伤。结论Lef治疗CCl4所致小鼠急性化学性肝损伤,可能与其诱导肝微粒体Cyt.P450表达,抑制CYP2E1 mRNA转录及抗脂质过氧化有关。     

Leflunomide抑制大鼠角膜移植排斥反应的免疫病理学研究

目的：研究角膜移植排斥反应的免疫病理学变化，阐明Ｌｅｆｌｕｎｏｍｉｄｅ的免疫抑制机理。方法：应用免疫组织化学染色方法检测环孢霉素Ａ、Ｌｅｆｌｕｎｏｍｉｄｅ及对照组角膜移植片中ＣＤ４＾＋细胞、ＣＤ８＾＋细胞、白细胞介素－２受体及主要组织相容性Ⅱ类抗原的表达。结果：排斥的角膜组织大量表达上述免疫细胞和分子，Ｌｅｆｌｕｎｏｍｉｄｅ可以对这些细胞和分子产生明显的抑制作用。结论：迟发型超敏反应和细胞毒性Ｔ细     

来氟米特联合糖皮质激素治疗IgA肾病的研究

目的 观察来氟米特( leflunomide,LEF)与激素治疗IgA肾病患者的疗效及其对尿转化生长因子β1(TGFβ1)的影响.方法 选取符合条件的60例IgA肾病患者,将其分为LEF组和激素组各30例,LEF组给予口服LEF联合泼尼松治疗,激素组予口服泼尼松治疗,采用酶联免疫吸附试验(ELISA)检测尿TGF1,检测值均用尿肌酐(Cr)进行校正.用药期间检测尿TGFβ1/Cr的排泄水平、24 h尿蛋白定量、血清白蛋白、血常规、肝肾功能等指标,进行统计学分析.结果 LEF组治疗后尿TGFβ1/Cr水平、24 h尿蛋白定量均显著下降(P＜0.01),总有效率为85.7％.两组治疗后尿TGFβ1/Cr水平差异有统计学意义(P＜0.05).与激素组比较疗效存在显著差异(P＜0.01),不良反应轻微.结论 LEF联合中小剂量激素治疗IgA肾病比单纯应用激素的临床疗效好,抑制TGFβ1的表达可能是其治疗机制之一.     

随机、双盲、安慰剂对照、多中心研究唑尼沙胺添加用药治疗部分性癫(癎)发作的有效性和安全性

目的 评价唑尼沙胺(ZNS)作为添加用药治疗部分性癫(癎)发作的有效性和安全性.方法 采用多中心、随机、双盲、安慰剂对照、平行组、添加治疗设计.240例确诊为癫(癎)部分性发作的受试者按照1:1的比例随机分配到ZNS治疗组或安慰剂组.在前4周加鼋期内受试者自100 mg/d逐渐加量至300 mg/d,随后进入12周的稳定治疗期.在稳定期内可根据患者情况酌情减量,或加量至最大剂量400 mg/d.有效性评价的主要指标为稳定期部分性癫(癎)发作频率较基线值减少百分数的中位值,重要的次要评价指标为有效率,即部分性癫(癎)发作次数减少≥50%者的比例.同时对药物的安全性进行评价.结果 ZNS组受试者稳定期部分性癫(癎)发作频率较基线期减少百分数(48.4%)显著高于安慰剂组(26.6%),组间差异有统计学意义(F=4.904,P=0.028);ZNS组治疗部分性癫(癎)发作的有效率(48.6%)高于安慰剂组(34.9%),差异有统计学意义(X2=4.046,P=0.044),其中以复杂部分性癫(癎)的组间差异最为显著(分别为52.2%和33.3%,X2=5.607,P=0.018).ZNS组与安慰剂组不良事件发生率相当,与ZNS相关的不良事件多为头晕、头痛、嗜睡、食欲下降、恶心等.结论 ZNS能有效治疗部分性癫(癎),降低癫(癎)发作频率,对复杂部分性癫(癎)发作治疗效果尤为突出.ZNS耐受性良好,受试者用药安全性较高.     

来氟米特和甲氨蝶呤联合治疗幼年类风湿性关节炎21例报告

目的　探讨来氟米特和甲氨蝶呤联合治疗幼年类风湿性关节炎的疗效及其安全性。方法　 40例多关节型幼年类风湿性关节炎 (JRA) ,分为治疗组和对照组。治疗组 (来氟米特和甲氨蝶呤 ) 2 1例 ,对照组 (甲氨蝶呤 ) 1 9例 ,各自接受相应药物治疗 2 6周。参与疗效综合评估的指标有关节压痛数、关节压痛指数、关节肿胀数、关节肿胀指数、关节整体功能评分、家长及医生评分、血沉、C 反应蛋白、类风湿因子水平。以总改善百分率对疗效进行综合评估。参与安全性评估的指标有黏膜、皮肤损害、胃肠反应、神经系统反应、血象、肝、肾功能。结果　治疗组用药后 1 2、2 6周的总平均改善率分别为 39 6 %、71 9% ;对照组的总平均改善率分别为 2 7 5 %、49 5 % ,两组差异有显著性 (P <0 0 1 )。治疗组用药后 1 2、2 6周的缓解率分别为 4 76 %、38 1 0 % ;对照组分别为 0、0 ,两组差异有显著性 (P <0 0 1 )。治疗组不良反应的发生率为 9 5 % ,主要表现为轻度白细胞减少和转氨酶升高 ;对照组不良反应发生率为 5 3 % ,主要表现为头晕、皮疹 ,症状轻微 ,两组差异无显著性 (P >0 0 5)。结论　来氟米特和甲氨蝶呤联合治疗幼年类风湿性关节炎的临床疗效显著优于单独使用甲氨蝶呤。但来氟米特有白细胞减少、转氨酶升高的不良反     

Synthesis and antioxidant activity of a new class of bis and tris heterocycles

A series of novel heterocycles, bisbenzoxazolyl/benzothiazolyl/benzimidazolyl pyrazoles/isoxazoles/pyrimidines were synthesized and evaluated for their antioxidant activity. The bisbenzoxazolylisoxazole 10 exhibited good antioxidant activity when compared with the standard ascorbic acid.