CN101884781B - 用于对器官或组织的移植的排异反应或骨髓移植的移植物抗宿主反应预防或治疗的药物组合物 - Google Patents
用于对器官或组织的移植的排异反应或骨髓移植的移植物抗宿主反应预防或治疗的药物组合物 Download PDFInfo
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Abstract
本发明涉及用于对器官或组织的移植的排异反应或骨髓移植的移植物抗宿主反应预防或治疗的药物组合物。通过本发明可提供一种有效发挥免疫抑制剂或抗炎剂的效果,且减少副作用的出现的医药。其是由具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物与免疫抑制剂和/或抗炎剂组合而成的医药。
Description
本发明申请是PCT专利申请PCT/JP2005/013113,申请日为2005年7月15日发明名称为“有效的医药使用方法及与副作用发生的防御相关的方法”的发明专利申请的分案申请,母案进入中国的申请号为200580023859.3。
技术领域
本发明涉及一种具有减少末梢循环的淋巴细胞的作用的,含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物与免疫抑制剂和/或抗炎剂组合而成的医药,还涉及一种有效发挥免疫抑制作用或抗炎作用且减少副作用发生的方法。
背景技术
开发抑制免疫应答的方法,对于防止脏器及细胞移植中的排异反应、各种自身免疫疾病的治疗及预防均有极为重大的意义。目前使用于抑制免疫应答的化合物为具有下述作用机理的化合物,即通过(1)攻击特定的免疫细胞并将细胞从免疫***内除去,或(2)抑制免疫细胞的细胞因子应答功能,以减少与免疫应答相关的细胞数量的作用机理。免疫应答的细胞数量减少时,免疫***无法发生与正常情况相同的应答反应,其结果为抑制免疫应答。
具体而言,具有第一类作用机理的化合物群抑制免疫细胞中核苷酸合成并阻止该细胞的代谢及免疫活性。该化合物群中,可举出硫唑嘌呤(非专利文献1)、咪唑立宾(非专利文献2)、霉酚酸(以下有时简称为“MPA”,非专利文献3)、布喹那(非专利文献4)、来氟米特、甲基蝶啶胺。但是,上述化合物存在易发生毒性副作用的问题。
具有第二类作用机理的化合物群中,可举出环孢菌素A(以下有时简称为“CsA”)、泰克利玛(以下有时简称为“FK506”)、雷帕霉素(非专利文献5)等。上述化合物通过抑制IL-2等细胞因子的合成,使效应细胞的增殖和分化不能被诱导从而阻碍免疫反应的发生。另一方面,雷帕霉素还阻断细胞因子对免疫细胞的作用。
为了减轻各种免疫抑制剂的副作用,CsA或FK506的任一种和硫唑嘌呤或咪唑立宾(非专利文献6)、(非专利文献7)等其它的免疫抑制剂或类固醇类的联用治疗法被广泛使用,但现状仍未能达到在不显示毒副作用的情况下发挥充分的免疫抑制效果。
作为具有免疫抑制作用的氨基丙二醇衍生物的FTY720和钙调神经磷酸酶抑制剂的联用的效果已众所周知(专利文献1)。但是,为了发挥更优秀的作用及降低副作用,很有必要开发新型药物。
非专利文献1:Nature,183:1682(1959).
非专利文献2:J.Clin.Invest.,87:940(1991).
非专利文献3:Pharm.Res.,7:161(1990).
非专利文献4:Transplantation,53:303(1992).
非专利文献5:N.Eng.J.Med.,321:1725(1989);Transplant.Proc.,23:2977(1991).
非专利文献6:Transplant.Proc.,17:1222(1985).
非专利文献7:Clin.Transplant.,4:191(1990).
专利文献1:特开平11-80026号公报
发明内容
发明所要解决的技术问题
本发明的目的为提供一种自身毒性较低可进行安全的使用,同时不产生副作用的与现有的免疫抑制化合物或抗炎症药物进行联用的,能最大限度的发挥出作为其功效的免疫抑制作用或抗炎症作用,以及减少免疫抑制剂或抗炎剂的副作用的方法。
解决技术问题的手段
本发明人发现,通过联用具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物与免疫抑制剂和/或抗炎剂,可有效的发挥联用的药物的免疫抑制作用或抗炎作用,进一步通过减少发挥与其联用的其它药物的效果所需的足够的量可以期待降低副作用,从而完成了本发明。
也即,本发明包括以下内容:
1)医药,由具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物、与免疫抑制剂和/或抗炎剂组合而成。
2)如1)所记载的医药,其中,具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物为通式(1)所表示的化合物或其可药用盐及水合物,
[化1]
[式中,R1表示卤原子、三氟甲基、羟基、碳原子数为1~7的低级烷基、也可以具有取代基的苯基、芳烷基、碳原子数为1~4的低级烷氧基、三氟甲氧基、苯氧基、环己基甲氧基、也可以具有取代基的芳烷氧基、吡啶甲氧基、肉桂酰氧基、萘甲氧基、苯氧甲基、羟甲基、羟乙基、碳原子数为1~4的低级烷基硫基、碳原子数为1~4的低级烷基亚硫酰基、碳原子数为1~4的低级烷基磺酰基、苄硫基、乙酰基、硝基或氰基;R2表示氢原子、卤原子、三氟甲基、碳原子数为1~4的低级烷氧基、碳原子数为1~7的低级烷基、苯乙基或苯甲氧基;R3表示氢原子、卤原子、三氟甲基、碳原子数为1~4的低级烷氧基、羟基、苯甲氧基、碳原子数为1~7的低级烷基、苯基、碳原子数为1~4的低级烷氧甲基或碳原子数为1~4的低级烷氧硫基;X表示O、S、SO或SO2;n表示1~4的整数]
3)如2)所述的医药,所述通式(1)表示的化合物为2-氨基-2-[4-(3-苯甲氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇。
4)如2)所述的医药,所述通式(1)表示的化合物为2-氨基-2-[4-(3-苯甲氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇盐酸盐。
5)如1)所述的医药,免疫抑制剂为钙调神经磷酸酶抑制剂。
6)如5)所述的免疫抑制剂,钙调神经磷酸酶抑制剂为环孢菌素A或泰克利玛。
7)如1)所述的医药,免疫抑制剂为甲基蝶啶胺或霉酚酸或霉酚酸吗啉乙酯。
8)方法,其特征为通过组合使用具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物、与免疫抑制剂和/或抗炎剂而构成的医药,增强相互的药效,并通过减少用量防止副作用的发生。
发明效果
虽然具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物单独用药也可以发挥优秀的免疫抑制效果,但通过和钙调神经磷酸酶抑制剂的CsA或FK506的联用,可相互增强两药物的免疫抑制效果。其结果为可减少钙调神经磷酸酶抑制剂的使用量,因此在临床中可避免针对CsA或FK506的肾毒性或肝毒性设定的使用限制,提供安全性高而有效的治疗方法。另外,与具有抑制核苷酸合成阻止免疫细胞的代谢及免疫活性作用的霉酚酸(MPA)联用也可以互相增强两种药物的免疫抑制效果,通过减少MPA的用量可以避免腹泻、胀气等消化器官的症状、全血细胞减少或嗜中性粒细胞减少、二次感染症、淋巴瘤的发生,提供安全性足够高的治疗。另外,风湿症的治疗中的第一选择药物的甲基蝶啶胺与本申请的化合物联用也有同样的协同促进效果。即,具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物,在佐剂型关节炎模型中即使以单独用药也显示了优秀的关节炎抑制效果,而通过与甲基蝶啶胺的联用,可互相增强它们的效果,可以更少量的两种药物的组合抑制关节炎的发展。甲基蝶啶胺为副作用很强的药物,在风湿治疗中以少量的脉冲式疗法进行,但通过本申请的方法可减少甲基蝶啶胺的给药量,提供一种可避免副作用和安全性高的治疗方法。总而言之,通过以少量的甲基蝶啶胺发挥其效果,可期待使安全的长期使用变为可能,并有效且持续的抑制风湿病情的发展或复发。
附图说明
[图1]表示大鼠佐剂型关节炎模型中的KNF-299的单独用药效果的图表。◆:正常对照◇:佐剂对照■:KNF-2990.03mg/kg.p.o.□:KNF-2990.1mg.kg.p.o.
[图2]表示佐剂型关节炎模型中的甲基蝶啶胺(MTX)的单独用药效果的图表。●:佐剂对照□:正常对照△:MTX 0.03mg/kg◇:MTX 0.1mg/kg
[图3]表示佐剂型关节炎模型中的KNF-299和MTX的联用效果的图表。○:佐剂对照△:KNF-2990.01mg/kg□:MTX 0.025mg/kg◇:MTX 0.05mg/kg■:KNF-299(0.01mg/kg)+MTX(0.025mg/kg)◆:KNF-299(0.01mg/kg)+MTX(0.05mg/kg)
具体实施方式
本发明的具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物为下述通式(1)所表示的化合物或其可药用盐及水合物:
[化2]
[式中,R1表示卤原子、三氟甲基、羟基、碳原子数为1~7的低级烷基、也可以具有取代基的苯基、芳烷基、碳原子数为1~4的低级烷氧基、三氟甲氧基、苯氧基、环己基甲氧基、也可以具有取代基的芳烷氧基、吡啶甲氧基、肉桂酰氧基、萘甲氧基、苯氧甲基、羟甲基、羟乙基、碳原子数为1~4的低级烷基硫基、碳原子数为1~4的低级烷基亚硫酰基、碳原子数为1~4的低级烷基磺酰基、苄硫基、乙酰基、硝基或氰基;R2表示氢原子、卤原子、三氟甲基、碳原子数为1~4的低级烷氧基、碳原子数为1~7的低级烷基、苯乙基或苯甲氧基;R3表示氢原子、卤原子、三氟甲基、碳原子数为1~4的低级烷氧基、羟基、苯甲氧基、碳原子数为1~7的低级烷基、苯基、碳原子数为1~4的低级烷氧甲基或碳原子数为1~4的低级烷氧硫基;X表示O、S、SO或SO2;n表示1~4的整数。]
本发明中的通式(1)表示的化合物的可药用盐中,可举出盐酸盐、氢溴酸盐、醋酸盐、三氟醋酸盐、甲磺酸盐、柠檬酸盐、酒石酸盐等酸加成盐。
在本发明的通式(1)中,“卤原子”表示氟原子、氯原子、溴原子、碘原子,“三卤代甲基”表示三氟甲基、三氯甲基,“碳原子数为1~7的低级烷基”可举出例如甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基、庚基等直链或支链状的碳原子数1~7的烃基。“也可具有取代基的苯氧基”可举出在苯环上的任意位置上具有氟原子、氯原子、溴原子、碘原子等卤原子、三氟甲基、碳原子数为1~4的低级烷基、碳原子数为1~4的低级烷氧基的基团。“芳烷基”、“芳烷氧基”的“芳烷基”可举出苄基、联苯甲基、苯乙基、苯丙基。另外“碳原子数为1~4的低级烷氧基”、“碳原子数为1~4的低级烷基硫基”、“碳原子数为1~4的低级烷基亚硫酰基”、“碳原子数为1~4的低级烷基磺酰基”等的“低级烷基”可举出例如甲基、乙基、丙基、异丙基、丁基等直链或支链状的碳原子数1~4的烃基,“也可具有取代基的芳烷基”可举出在苯环上的任意位置上具有氟原子、氯原子、溴原子、碘原子等卤原子、三氟甲基、碳原子数为1~4的低级烷基、碳原子数为1~4的低级烷氧基的基团。
更具体而言可举出2-氨基-2-[4-(3-苯甲氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇或其盐酸盐。
通式(1)中表示的本发明的化合物已在例如WO03/029184及WO03/029205等中公开,可通过上述公报中的方法进行制造。
本发明与具有免疫抑制剂和/或抗炎作用的药物的联用中发挥其效果。需要说明的是,本发明的免疫抑制剂中,不包括具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物。
可以联用的物质为,具有用于同种或异种移植的急性或慢性排异、炎症性疾病、自身免疫疾病的治疗或预防的免疫抑制、免疫调节作用的免疫抑制剂和/或、显示抗炎症、抑制恶性细胞增殖作用的抗炎剂。
具体而言为钙调神经磷酸酶抑制剂的CsA或FK506、mTOR抑制剂的雷帕霉素、40-O-(2-羟甲基)-雷帕霉素、CCI779、ABT578、具有免疫抑制作用的子囊霉素类的ABT-281、ASM981及霉酚酸(MPA)、霉酚酸吗啉乙酯、硫唑嘌呤、咪唑立宾、环磷酰胺等。另外还有叶酸代谢拮抗药物的甲基蝶啶胺、显示广谱抗炎症作用的副肾皮质甾体、具有免疫调节作用的金诺芬、阿克他利、美沙拉秦或柳氮磺吡啶等或抗TNF-α抗体的英利昔单抗、抗IL-6受体抗体的MRA、抗整合素抗体的那他珠单抗等。
联用时可以分别或同时对患者进行给药。另外,可以混合物或单独的形式进行给药。化合物的剂型可以根据化合物的性状进行改变,制成口服制剂或非口服制剂。也即,可以将有效成分分别或同时的,与生理学允许的载体、赋形剂、粘合剂、稀释剂等混合,制成颗粒剂、粉末剂、片剂、胶囊剂、糖浆剂、栓剂、混悬剂、溶液剂等,以口服或非口服的形式进行给药。在分别将有效成分进行制剂化的时候,可分别在使用时混合后给药,或同时、或有时间差的连续向同一患者进行给药。用于上述组合的制剂可通过通常的方法进行制备。
组合使用的各种有效成分的给药量,可根据含有的各种有效成分、给药方法或治疗对象的状态而制定。通常,以通式(1)的化合物为例,在与钙调神经磷酸酶抑制剂的CsA或FK506、mTOR抑制剂的雷帕霉素、40-O-(2-羟甲基)-雷帕霉素、CCI779、ABT578、具有免疫抑制作用的子囊霉素类的ABT-281、ASM981及霉酚酸(MPA)等组合使用时,可以成人每日0.01mg~100mg的剂量1次或数次分开给药。另外,与叶酸代谢拮抗药物的甲基蝶啶胺组合使用时,也可以成人每日0.01mg~100mg的剂量1次或数次分开给药。
如上述获得的本申请的免疫抑制剂用于下述疾病的预防和治疗:对器官或组织(例如心脏、肾脏、肝脏、肺、骨髓、角膜、胰脏、小肠、四肢、肌肉、神经、脂肪髓、十二指肠、皮肤或胰岛细胞等,包含异种移植)的移植的抵抗性或移植排异反应、骨髓移植的移植物抗宿主反应(GVHD)、风湿性关节炎、全身性红斑狼疮、肾变病综合症、桥本甲状腺瘤、多发性硬化症、重症肌无力症、I型糖尿病、II成人发病型糖尿病、虹膜炎、甾体依赖性及甾体抵抗性肾变病、手掌脚底脓胞症、过敏性脑脊髓炎、丝球体肾炎等自身免疫疾病及病原微生物引起的炎症。
另外,还可以用于干藓、关节症性干藓、特异性湿疹(特异性皮炎)、接触性皮炎及湿疹性皮炎、脂溢性皮炎、扁平苔藓、天疱疮、水疱性类天疱疮、表皮水疱症、荨麻疹、血管浮肿、皮肤过敏性血管炎、红斑、皮肤嗜酸性细胞增加症、痤疮、圆形脱发、嗜酸细胞性筋膜炎、以及粥样动脉硬化症等炎症、增殖性及高增殖性皮肤病及皮肤上出现的免疫介导性疾病的预防及治疗。
本发明进一步可用于呼吸疾病例如类肉瘤症、肺纤维化症、特发性间质性肺炎及以支气管哮喘为代表的可逆性闭塞型气管疾病、支气管炎等的治疗。
另外,本发明还可用于结膜炎、角结膜炎、角膜炎、春季粘膜炎、伴随贝切特病的虹膜炎、疱疹性角膜炎、圆锥角膜、角膜上表皮营养不良、角膜白斑、眼天疱疮、蚕蚀性角膜溃疡、巩膜炎、凸眼性甲状腺肿引起的眼肌肉麻痹、重症眼内膜炎等眼病的治疗。
另外,本发明还可用于粘膜或血管的炎症(例如胃溃疡、缺血性疾病及血栓症引起的血管损伤、缺血性肠道疾病、炎症性肠道疾病(例如克隆氏症、溃疡性大肠炎)、坏死性肠炎)或伴随烫伤的肠障碍的预防及治疗。
本发明还可用于下述疾病的预防及治疗:肾疾病(例如间质性肾炎、肺出血肾炎综合症、溶血性***症候群及糖尿病性肾病等)、神经疾病(多发性肌炎、格林-巴利综合症、梅尼尔氏病及神经根症等)、内分泌性疾病(甲状腺功能亢进症及凸眼性甲状腺肿病等)、血液疾病(再生障碍性贫血、再生低下性贫血、特发性血小板减少性紫癜病、自身免疫性溶血性贫血、粒细胞减少症、红细胞形成缺乏等)、骨骼疾病(骨质疏松症等)、呼吸疾病(肉瘤症、肺纤维症、特发性间质性肺炎等)、皮肤病(皮肤肌肉炎、白癜风、寻常性鱼鳞癣、光过敏性过敏症、皮肤T细胞淋巴肿瘤等)、循环器官疾病(动脉硬化症、大动脉炎、结节性多发性动脉炎、心肌炎等)、胶原质病(硬化症、韦格纳肉芽肿、舍格伦综合症等)、肥胖症、嗜酸性细胞肌膜炎、牙周病、肾变病综合症、溶血性***综合症及肌肉营养不良的预防及治疗。
另外,本发明还可用于肠炎或过敏症(乳糜泻、直肠炎、嗜酸性细胞肠胃炎、红皮疹、克隆氏症、溃疡性大肠炎)、以及除了胃肠道之外的显示综合症的病状(例如偏头痛、鼻炎、湿疹)的食物关联过敏症的治疗。
本发明,具有促进肝脏再生作用和/或肝细胞的肥大及过形成的作用。因此,还可以用于免疫原性的疾病(例如自我免疫性肝炎、原发性胆汁性肝硬化、硬化性胆管炎的慢性自身免疫肝脏疾病等)、部分肝脏切除、急性肝脏坏死(例如毒素、病毒性肝炎、休克或缺氧引起的坏死)、B型肝炎、C型肝炎、以及肝病变等肝脏病的预防及治疗。
进一步,本发明还可用于下述疾病的预防及治疗:恶性类风湿关节炎、淀粉症、恶性肝炎、直立性低血压综合症、脓疱型银屑病、贝切特病、全身性红斑狼疮、内分泌性眼肌肉麻痹、进行性全身性硬化症、混合***病、大动脉炎综合症、韦格纳肉芽肿、活动性慢性肝炎、EVANS综合症、花粉症、特发性上皮小体功能低下症、原发性慢性肾上腺皮质功能减退症(自身免疫性肾上腺炎)、自身免疫性***、自身免疫性***、寒冷红血球凝集素病、发作性寒冷红血球凝集素病、恶性贫血、成人T细胞白血病、自身免疫性萎缩性胃炎、类狼疮性肝炎、输尿管间质性肾炎、膜性肾病、肌萎缩性侧索硬化症、风湿热、心肌梗塞后综合症及交感性眼炎。
实施例
以下举出实施例对本发明进行具体说明。本实施例中对特别是通式的化合物中的2-氨基-2-[4-(3-苯甲氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇(以下简称为“KNF-299”)及环孢菌素A(CsA)、泰克利玛(FK506)、甲基蝶啶胺(MTX)及霉酚酸(MPA)的组合进行叙述,但本发明并不受上述实施例的任何限定。
实施例1
主要组织相容性基因复合物(MHC)相容大鼠***间的同种皮肤移
植片的存活延长效果
参考文献(A.m.J.Med.Technol.;36,149-157,1970,Transplant.Proc.;28,1056-1059,1996)等,以下述方法进行使MHC一致的大鼠同种异系皮肤移植。以5只1组进行研究,所有的大鼠分别在不同的笼子里饲养。选择LEW(RT1)作为移植提供者,选择F344(RT1V1)作为移植接受者。在接受者的背部制作移植床,在滴下数滴青霉素溶液(4万U/mL,生理盐水中)后,放置从提供者的腹部取下制备的整层植皮片(1.8×1.8cm)。以急救绷带(30×72mm)的中央部分贴附在移植片之上,再用透气胶带(粘合包带,3.8×15cm)进行包裹。在第5天使用剪刀将绷带和透气胶带剪开除去。
药物的给药,从移植皮肤当天开始,以1天1回,每天0.5mL/100gB.W.的剂量进行口服给药。给予对照组以蒸馏水。CsA以蒸馏水稀释山地明注射液(50mg/mL)进行给药。FK506以蒸馏水混悬泰克利玛胶囊(藤泽药品)的内容物进行给药。KNF-299以蒸馏水溶解进行给药。另外,对于联合给药组,在给药前混合各给药液进行给药。
移植物排异的判定通过如下方法进行:从取下绷带的移植后5天开始,每天观察移植物,移植物上皮的90%以上发生坏死成为褐色的状态被视为排异。以从移植到确认排异的天数作为存活期间。
以各组的存活期间的平均值作为平均存活天数(MST)计算。另外,以各组(n=5)中第3长的存活期间作为中间值。
KNF-299在其3mg/kg的单独给药中具有使平均存活天数延长至27天以上的效果。另外,CsA、FK506分别以30mg/kg、10mg/kg进行单独给药观察到了30天以上的存活期间的延长。
以比确认单独给药有存活延长作用的给药量更低的用量进行联用效果实验的结果在表1中表示。
KNF-299在3mg/kg的单独给药中确认有明确的延长移植物的存活的作用。另外,也确认了CsA30mg/kg即使单独使用也具有延长存活作用。CsA 10mg/kg,KNF-2990.03mg/kg的给药与对照相比,虽然是只有1~4天的存活延长的给药量,但是两者联用时在所有例子中均观察到30天以上的存活延长,诱发了优秀的抑制排异的效果。另外,与FK506相同,低用量的单独给药几乎并未发现有任何效果,但是FK5063mg/kg和KNF-299在0.1mg/kg的联用组中的平均存活日期达到26天以上,确认有明确的联用效果。
[表1]
表1大鼠***间的同种皮肤移植物的存活延长效果
如上所示,证明了通过KNF-299的联用,可增强CsA或FK506的钙调神经磷酸酶抑制剂的效果。钙调神经磷酸酶抑制剂的使用量的降低,使避免在临床上的肾毒性或肝毒性带来的使用限制的可能性大大增加,可提供有效的治疗方法。
实施例2
与大鼠佐剂型关节炎模型中的甲基蝶啶胺(MTX)的联用效果
在LEW/Crj系雌性大鼠(日本CHARLES RIVER)6或7周龄的右后肢脚跟部皮内,每只以0.05ml(0.6mg/只)注射以流动石蜡混悬的M.Butyricum死菌(12mg/mL),引发关节炎(Day0)。供试化合物以纯水溶解或混悬,每只以每100g大鼠的体重0.5ml口服给药。对佐剂对照组给予纯水。另外,联合给药组以KNF-299的水溶液和MTX(Sigma)的水溶液在给药前进行混合后给药。给药从Day0开始连续1天1次给药,直至实验结束。
关节炎的评价使用容积测定仪(MK-550,室町机械),在Day0,3,8,14,17,21时测定左右后肢的容积,求得相对Day0的后肢容积的增加量。
KNF-299的佐剂型关节炎的发病预防效果具有浓度依赖性,大约在0.1mg/kg达到最大(图1)。另外,MTX的发病预防效果在0.03mg/kg时未确认有效果,在0.1mg/kg时达到最大(图2)。
然后,在分别的单独给药无法期待具有效果的给药量的组合中,研究其联用的效果。以KNF-299的给药量为0.01mg/kg,MTX的给药量为0.025mg/kg及0.05mg/kg。结果在图3中表示。
MTX在0.025mg/kg及0.05mg/kg单独给药中显示20%及35%的抑制率,但并非具有显著性作用(Day21)。KNF-299在0.01mg/kg单独给药中显示36%(Day21)的抑制率。KNF-299在0.01mg/kg和MTX的联用确认具有联用的效果,与MTX0.05mg/kg的联用显示了84%的抑制率。
MTX为叶酸代谢拮抗剂,已知具有发生骨髓抑制、间质性肺炎等的副作用。KNF-299通过与作为临床上有效性最高的首选药物的MTX联用,显示了对于AA模型的优秀的联用效果。因此,对于不显示MTX的效果的难治性风湿患者通过与KNF-299联用,可显示出有效性。另外,MTX为副作用强的药物,在风湿治疗中进行少量脉冲式疗法。在这种情况下也会发生副作用,可同时联用叶酸减轻其副作用。而通过MTX与KNF-299的联用可减少MTX或KNF-299的给药量,避免副作用,提供安全性高的治疗方法。
实施例3
与主要组织相容性基因复合物(MHC)不相容大鼠***中的霉酚酸
(MPA)的联用带来的心脏移植物的存活延长效果
在MHC不一致的大鼠同种异系间的心脏移植中研究KNF-299的作用。参考文献(Micro surgery;21,16-21,2001)等如下实施异位性心脏移植,即,组合为以DA(RT1a)大鼠作为移植提供者,以LEW(RT11)大鼠作为移植接受者,将提供者的心脏以血管周围套接合至接受者的颈部血管处。
药物的给药,从心脏移植当天开始,以1天1次进行口服给药。MPA为由和光纯药购进的产品,以含有0.5%羧甲基纤维素、0.4%Tween80、及0.9%苄醇的生理盐水配制为20mg/mL,以0.1mL/100gB.W.进行给药。KNF-299在蒸馏水中溶解为0.06mg/mL,以0.5mL/100g B.W.进行给药。给予对照组MPA给药液中使用的溶剂。
以视诊或触诊确认移植心脏的心跳动,以心脏停止跳动时判断为排异。从移植开始至确认排异的天数作为存活期间。以平均存活天数(MST)作为各组的存活期间的平均值进行计算。在引起强烈排异反应的***间的组合中,研究移植心脏的排异抑制作用的结果在表2中表示。
[表2]大鼠***间的移植心脏的存活延长效果
结果显示,确认KNF-299的0.3mg/kg单独给药中为7.0天的平均存活天数,与对照组相比仅有1.2天的延长作用。而MPA在20mg/kg单独给药中虽然是高剂量给药,其存活天数中的个体差异大移植排异的作用不充分。在两者联用的情况中,所有例子中均确认有100天以上的存活天数的延长,显示出了明显的联用作用。
产业实用性
脏器移植的时候,具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物以单独用药可显示出优秀的免疫抑制效果,但通过与钙调神经磷酸酶抑制剂的CsA或FK506、核苷合成抑制的酶酚酸(MPA)等的免疫抑制剂或抗炎剂的联用,可增强其效果。因此,可以减少临床使用中的CsA、FK506、霉酚酸吗啉乙酯的给药量,可避免钙调神经磷酸酶抑制剂的肾毒性或肝毒性或核苷合成抑制剂的嗜中性粒细胞减少等带来的使用限制,提供一种安全性高的有效的治疗方法。另外,在治疗风湿时,根据本申请的方法可减少甲基蝶啶胺的给药量,提供避免副作用的安全性高的治疗方法。总之,组合使用的药剂即使以少量也可显现充分的抗炎效果,可以期待安全的长期使用,并有效且持续的抑制风湿的病情的发展或复发。
因此,本发明的具有减少末梢循环的淋巴细胞的作用的含有2-氨基-1,3-丙二醇结构的二芳基硫醚或二芳基醚化合物和免疫抑制剂和/或抗炎剂组合而成的医药,可用于显示出有效的免疫抑制作用或抗炎作用,且作为减少副作用的发生的方法。此类医药可用于自身免疫疾病及病原微生物、外来抗原、外源性物质引起的炎症的预防或治疗或炎症性、增殖性及高增殖性的皮肤病及在皮肤处出现的免疫介导性疾病的预防和治疗。
Claims (4)
1.2-氨基-2-[4-(3-苯甲氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇或其盐或它们的水合物、与
环孢菌素A、泰克利玛或霉酚酸
在制备用于对器官或组织的移植的排异反应或骨髓移植的移植物抗宿主反应预防或治疗的药物组合物中的应用。
2.2-氨基-2-[4-(3-苯甲氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇、与
环孢菌素A、泰克利玛或霉酚酸
在制备用于对器官或组织的移植的排异反应或骨髓移植的移植物抗宿主反应预防或治疗的药物组合物中的应用。
3.2-氨基-2-[4-(3-苯甲氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇盐酸盐、与
环孢菌素A、泰克利玛或霉酚酸
在制备用于对器官或组织的移植的排异反应或骨髓移植的移植物抗宿主反应预防或治疗的药物组合物中的应用。
4.2-氨基-2-[4-(3-苯甲氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇或其盐或它们的水合物、与
环孢菌素A或泰克利玛
在制备用于对器官或组织的移植的排异反应或骨髓移植的移植物抗宿主反应预防或治疗的药物组合物中的应用。
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EP1431284A1 (en) * | 2001-09-27 | 2004-06-23 | Kyorin Pharmaceutical Co., Ltd. | Diaryl sulfide derivative, addition salt thereof, and immunosuppressant |
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