CN114533739B - 核苷类似物在制备预防或治疗胃肠道疾病药物中的应用 - Google Patents
核苷类似物在制备预防或治疗胃肠道疾病药物中的应用 Download PDFInfo
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Abstract
本发明涉及医药技术领域,具体涉及核苷类似物在制备预防或治疗胃肠道疾病药物中的应用,核苷类似物选自胞嘧啶核苷类似物、胸腺嘧啶核苷类似物、腺嘌呤核苷类似物和鸟嘌呤核苷类似物中的任一种,实验结果显示,所述的核苷类似物对消化性溃疡病和炎症性肠病疗效显著,比现有临床药物活性高40倍,能够有效的改善黏膜完整度、促进组织形态改善、恢复动物体重,具有良好的临床应用前景。
Description
技术领域
本发明涉及医药技术领域,具体涉及核苷类似物在制备预防或治疗胃肠道疾病药物中的应用。
背景技术
胃肠道疾病涵盖食管、胃、小肠、结肠和直肠等疾病,常见的主要症状包括节律性、周期性上腹痛、腹泻、饥饿性腹痛、反酸、发烧、黑便血便、消化道出血和肠梗阻等。胃肠道疾病是人类最常见的疾病之一,其中最常见的包括吞咽障碍、胃溃疡、消化性溃疡、胃轻瘫、胃排空延迟、肠易激综合征(IBS)和炎症性肠病(IBD)。消化性溃疡主要包括胃溃疡、十二指肠溃疡和复合型溃疡等,目前认为胃溃疡的形成因素较多着重于胃粘膜屏障的削弱和胃泌素分泌的增加,而十二直肠溃疡的形成因素则较多着重于壁细胞总体积的增大。此外,过度饮酒、进食无规律、长期精神紧张和长期服用非甾体抗炎药(如阿司匹林)、糖皮质激素、氯吡格雷等药物等外源性因素均与消化性溃疡病的形成有关。炎症性肠病可由细菌、真菌、病毒、寄生虫、原虫等生物引起,亦可由变态反应及理化因子引起。根据病因不同,可分为特异性炎性病变和非特异性炎性病变,前者指感染性结肠炎、缺血性结肠炎和伪膜性结肠炎等,后者主要包括溃疡性结肠炎(Ulcerative Colitis,UC)与结肠克罗恩病(Crohn’sDisease,CD)。UC是一种炎症性疾病(Inflammatory bowel disease,IBD),作为消化内科常见的病症,可引起消化道发生长期炎症和溃疡,以慢性复发性肠道炎症和肠上皮细胞损伤为主要特征,多发于20-30岁,临床症状主要有腹泻、腹痛、血便和肠梗阻等。已有许多研究表明,UC的发病与免疫因素、炎症、环境遗传和压力及感染等因素有关。胃炎由慢性胃炎、急性胃炎等组成。
目前主要治疗胃肠道疾病的西药类型有促胃肠动力药、解痉药、止吐药、消化性溃疡药物、胃黏膜保护剂、助消化药、微生态制剂等。其中治疗消化性溃疡的药物主要包括质子泵抑制剂、H2-受体拮抗剂、铋制剂和前列腺素类等,其主要是通过含有钙质的原料来中和胃酸,虽能改善缓解症状,但很难彻底治愈,疗效无法令人满意,易反复发作。炎症性肠病被世界卫生组织列为现代难治病之一,且发病率在全球均呈上升趋势,结肠炎的发病机制尚未完全阐明,临床治疗常用的药物包括氨基水杨酸类制剂、糖皮质激素和免疫抑制剂等,短期使用可控制结肠炎的症状,但治愈率极低,长时间使用可诱发多种不良反应,且停药可复发等问题,严重者可引起癌变,因此,开发出一种治疗胃肠道疾病的新药物是目前亟需解决的技术问题。
核苷类似物具有一些特殊的作用,2’-脱氧核苷药物能特异性的感染病毒的复制。目前临床上用于治疗肝炎、艾滋病、疱疹等病毒性疾病的药物有很大一部分都是核苷类化合物,它们一般都是作为病毒复制过程中酶的抑制剂,阻断病毒对于靶细胞的浸染,常见的核苷类抗病毒化合物主要包括拉米夫定(Lamivudine,3-TC)、替比夫定(Telbivudine,LDT)、齐多夫定(Zidovudine,AZT)、泛昔洛韦(Famciclovir,FCV)、替洛福韦(PMPA)、阿德福韦酯(PMEA)等药物。替比夫定,用于有病毒复制证据以及有血清转氨酶(ALT或AST)持续升高或肝组织活动性病变证据的慢性乙型肝炎成人患者;齐多夫定,别名叠氮脱氧胸苷,用于艾滋病或与艾滋病有关的综合征患者及免疫缺陷病毒(HIV)感染的治疗,齐多夫定是世界上第一个获得美国FDA批准生产的抗艾滋病药品,其作用机制主要是与病毒的DNA聚合酶结合,中止DNA链的增长,从而阻止病毒的复制;拉米夫定,抗病毒药物,对病毒DNA链的合成和延长有竞争性抑制作用,其主要用于乙型肝炎和肝胆疾病的治疗,是目前临床应用中疗效最好、最具代表性的核苷类似物;阿昔洛韦,是一种高效、低毒、广谱的抗病毒药物,目前是治疗疱疹的首选药物;泛昔洛韦,是第一个在美国获准用于艾滋病患者复发性单纯疱疹病毒感染的口服药,不仅人体吸收率高,而且药物持续时间长,是减少疱疹后神经痛唯一有效的药物;阿德福韦,具有广谱抗病毒活性的腺嘌呤类核苷衍生物,可以有效地抑制逆转录病毒基因的复制和表达。
除了常见的抗病毒的核苷类化合物,据报道,一些2’和3’-脱氧核苷类药物能特异性的干扰病毒复制,并且可以选择性的引导病变癌细胞向正常细胞分化。
目前用于临床和正在研究的核苷类抗肿瘤药物有数十种,他们的主要作用是干扰肿瘤的DNA合成,或者影响核酸的转录过程,抑制蛋白质的合成,从而达到治疗肿瘤的效果。例如阿糖胞苷,主要作用于细胞S增殖期的嘧啶类抗代谢药物,通过抑制细胞DNA的合成,干扰细胞的增殖,主要用于急性白血病,对急性粒细胞白细胞疗效最好,对急性单核细胞白血病及急性淋巴细胞白血病也有效。对恶性淋巴瘤、肺癌、消化道癌、头颈部癌有一定的疗效,对病毒性角膜炎及流行性结膜炎等也有一定的疗效。吉西他滨,为一种新的胞嘧啶核苷衍生物,作用机制和阿糖胞苷相同,其主要代谢物在细胞内掺入DNA,主要作用于G1/S期。在临床上,吉西他滨和阿糖胞苷的抗瘤谱不同,对多种实体瘤有效,用于晚期胰腺癌患者在氟尿嘧啶类失败后作为二线用药,能改善患者的生活;其次是对局部晚期和已经有转移的非小细胞肺癌作为一线应用。近有资料说明本品对卵巢癌、乳腺癌、膀胱癌、子宫颈癌、肝癌、胆道癌、鼻咽癌、睾丸肿瘤、淋巴瘤及头颈部癌也具有姑息性疗效。
目前,研究人员针对核苷及其类似物的研究中,更多的是关于其剂型、检测方法、制备方法、结构修饰以及癌症治疗等方面研究,例如专利CN201880077576.4公开了核苷酸类似物的制备方法及其在核酸序列测定等方面的应用;专利CN201780039312.5公开了使用可逆封闭核苷类似物进行核酸检测的方法;专利CN201810489585.6公开了一种骨架整合有核苷类似物药物的功能性核酸及其衍生物及其制备方法;专利CN201410169585.X公开了环磷酰化基团修饰后并连接脂肪链的磷酸N-脂肪酸用于病毒性肝炎和肝癌的治疗;专利CN201910892040.4公开了核苷类似物药物分子构建的药物适配体、制备方法及其应用等;专利CN201810077674.X公开了1,4-二取代1,2,3-三氮唑核苷类似物在抗肿瘤药物尤其是胃癌中的应用;然而没有研究者针对核苷类似物治疗胃肠道疾病的相关研究,亦没有相关的文献或者专利公开其具有治疗胃肠道疾病的新用途。发明人在研究过程中意外的发现,核苷类似物对胃肠道疾病具有显著的疗效,在临床上具有广阔的应用前景。
发明内容
针对上述技术问题,本发明公开了核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式,及其可药用盐在制备预防和/或治疗胃肠道疾病药物中的应用,所述的胃肠道疾病不包括胃癌。
优选地,所述的核苷类似物选自胞嘧啶核苷类似物、胸腺嘧啶核苷类似物、腺嘌呤核苷类似物和鸟嘌呤核苷类似物中的任一种。
优选地,所述的胞嘧啶核苷类似物选自拉米夫定、脱氧胞苷、盐酸吉西他滨、盐酸阿糖胞苷、西多福韦、依曲西他平、艾夫他滨、恩曲他滨、阿卡地新、阿扎胞苷、地西他滨、Thiarabine、Ethynylcytidine、卡培他滨、艾西拉滨、安西他滨、4-S-β-D-阿糖胞嘧啶核苷、5-氮杂-4-硫代-2-脱氧胞苷、顺式-1-[4-(羟基-甲基)-环戊-2-烯基]-5-I-碘胞嘧啶和顺式-1-[4-(羟基-甲基)-环戊-2-烯基]-5-(2-I-碘乙烯基)胞嘧啶中的任一种;所述的胸腺嘧啶核苷类似物选自齐多夫定、替比夫定、索非布韦、5-氟尿嘧啶、脱氧尿苷、克来夫定、司他夫定、氟铁龙、双呋氟尿嘧啶、替加氟、氟尿嘧啶、卡莫氟、4-硫代胸腺嘧啶、5-牛磺酸甲基-2-S-尿苷、2’-氟-5-甲基-β-L-阿糖呋喃尿苷、2,3-胸腺嘧啶二脱氧碳环核苷衍生物、3-苯甲酰胸腺嘧啶和三氟胸苷中的任一种;所述的腺嘌呤核苷类似物选自腺苷、脱氧腺苷、脱氧腺苷酸、泛昔洛韦、替洛福韦、替洛福韦酯、富马酸替洛福韦二吡呋喃、阿德福韦、阿德福韦酯、二磷酸阿德福韦、阿地福韦、氯法拉滨、克拉屈滨、曲沙他滨、Aristeromycin和Neplanocin A中的任一种;所述的鸟嘌呤核苷类似物选自8-羟基-2-脱氧鸟嘌呤核苷、阿昔洛韦、更昔洛韦、恩替卡韦、三磷酸恩替卡韦、LB80380/ANA380、奈拉滨、9-β-D-阿糖呋喃糖鸟嘌呤、Forodesine hydrochloride、巯鸟嘌呤、6-巯基鸟嘌呤、6-硫基鸟嘌呤、6-硫代鸟嘌呤核苷酸、2-脱氧鸟苷一磷酸和5-(2-呋喃基)-2-脱氧鸟苷中的任一种。
优选地,所述的胞嘧啶核苷类似物选自拉米夫定或盐酸吉西他滨;所述的胸腺嘧啶核苷类似物选自齐多夫定或替比夫定;所述的腺嘌呤核苷类似物选自泛昔洛韦、替洛福韦酯或阿德福韦酯;所述的鸟嘌呤核苷类似物选自阿昔洛韦或6-硫基鸟嘌呤。
优选地,所述的胃肠道疾病为消化性溃疡。
优选地,所述的消化性溃疡为胃溃疡、十二指肠溃疡、球后溃疡、幽门管溃疡、复合溃疡和对吻溃疡中的一种或几种。
优选地,所述的消化性溃疡为胃溃疡和十二指肠溃疡。
优选地,所述的胃肠道疾病为炎症性肠病。
优选地,所述的炎症性肠病为溃疡性结肠炎和克罗恩病。
优选地,所述核苷类似物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体及其混合物形式,及其可药用盐和一种或多种药学上可接受的载体组成药物组合物,所述药物组合物的剂型为注射剂、片剂、胶囊剂、颗粒剂、丸剂。
本发明的有益效果是:本发明提供了核苷类似物在制备预防或治疗胃肠道疾病药物中的应用,具体提供了部分经典的核苷类似物拉米夫定、替比夫定、泛昔洛韦、替洛福韦酯、阿德福韦酯、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤,在不同饲喂条件下,对结肠炎小鼠进行DAI评分和结肠形态测定,结果显示拉米夫定、替比夫定、泛昔洛韦、替洛福韦酯、阿德福韦酯、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤等药物对溃疡性结肠炎均有效。同时,在不同饲喂条件下,对胃溃疡小鼠进行溃疡指数和抑制率及组织形态学检查,实验结果显示拉米夫定、替比夫定、泛昔洛韦、替洛福韦酯、阿德福韦酯、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤均具有防治胃溃疡的效果,且大部分药物效果强于现有临床用药西咪替丁的疗效,即本发明所述的核苷类似物拉米夫定、替比夫定、泛昔洛韦、替洛福韦酯、阿德福韦酯、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤等药物同时对溃疡性结肠炎和胃溃疡均有效,治疗效果比现有临床药物活性高40倍,具有良好的临床应用前景。
附图说明
图1拉米夫定对C57BL/6N结肠炎小鼠体重和DAI评分的影响;
图2拉米夫定对C57BL/6N结肠炎小鼠结肠形态及结肠长度的影响;
###p<0.001vs.Control组;*p<0.05、**p<0.01和***p<0.001vs.DSS组。
图3拉米夫定对胃溃疡小鼠胃组织形态的影响;
图4拉米夫定对胃溃疡指数、胃溃疡面积及胃溃疡抑制率的影响;
###p<0.001vs.Control组;**p<0.01和***p<0.001vs.Ethanol组。
图5阿德福韦酯、替洛福韦酯、泛昔洛韦和替比夫定对KM结肠炎小鼠体重、DAI评分、结肠形态和结肠长度的影响;
###p<0.001vs.空白对照组;*p<0.05、**p<0.01和***p<0.001vs.DSS模型组。
图6阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤对KM结肠炎小鼠体重、DAI评分、结肠形态和结肠长度的影响;
###p<0.001vs.空白对照组;*p<0.05、**p<0.01和***p<0.001vs.DSS模型组。
图7替比夫定、盐酸吉西他滨和齐多夫定对KM胃溃疡小鼠胃组织形态、溃疡指数、溃疡面积和溃疡抑制率的影响;
###p<0.001vs.空白对照组;*p<0.05、**p<0.01和***p<0.001vs.乙醇模型组。
图8阿德福韦酯、替洛福韦酯、阿昔洛韦、泛昔洛韦和6-硫基鸟嘌呤对KM胃溃疡小鼠胃组织形态、溃疡指数、溃疡面积和溃疡抑制率的影响;
###p<0.001vs.空白对照组;*p<0.05、**p<0.01和***p<0.001vs.乙醇模型组。
具体实施方式
以下结合具体实施例对本发明的保护范围进行详细说明,但应当指出的是,本发明的保护范围并不限于以下实施例,同时保护核苷类似物的一类化合物在所有胃肠道疾病尤其是消化性溃疡病和炎症性肠病中的治疗效果,包括不同剂型、剂量、联合用药等。凡本领域技术人员按照本发明的思路在现有技术上通过逻辑分析、推断和实验得出的技术方案,均属于本发明所请求保护的范围。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本文发明主题做任何限制。在本申请中,必须注意,除非文中另有清楚的说明,否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其他形式,例如“包含”、“含”和“含有”并非限制性。
本发明所述的C57BL/6N小鼠是小鼠中使用最广泛的品系之一,也是基因工程中最常用作转基因或基因敲除小鼠的母本。
本发明所述的KM小鼠是指昆明小鼠。
本发明以下实施例使用葡聚糖硫酸钠用于小鼠结肠炎的造模。
本发明以下实施例中,柳氮磺吡啶肠溶片的适应症为(1)溃疡性结肠炎治疗轻至中度的溃疡性结肠炎;在重度溃疡性结肠炎中可作为辅助疗法。亦可用于溃疡性结肠炎缓解期的维持治疗;(2)Crohn’s病用于治疗活动期的克隆病,特别是那些累及结肠的患者;(3)类风湿性关节炎对水杨酸类或其他非甾体抗炎药疗效不显著的类风湿性关节炎和幼年类风湿性关节炎(多关节型),本发明实施例一中将柳氮磺吡啶肠溶片作为阳性药物使用。
本发明以下实施例中的西咪替丁,也称甲氰咪胍,是一种组胺H2受体阻抗剂,主要用于抑制胃酸的分泌,能明显抑制基础和夜间胃酸分泌,也能抑制由组胺、分肽胃泌素、胰岛素和食物等刺激引起的胃酸分泌,并使其酸度降低,对因化学刺激引起的腐蚀性胃炎有预防和保护作用,对应激性胃溃疡和上消化道出血也有明显疗效。本发明实施例将西咪替丁作为阳性药物使用。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药物组合物”是指任选的混合有至少一种药学上可接受的化学成分或试剂的生物活性化合物,所述药学上可接受的化学成分或试剂即为“载体”,其有助于将化合物引入到细胞或组织中,包括但不限于稳定剂、稀释剂、悬浮剂、增稠剂和/或赋形剂。
术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力,并且在生物学或其它方面上没有不良作用的盐。除特别指示外,本发明中的盐可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状,预防其它症状,改善或预防导致症状的潜在代谢原因,抑制疾病或病症,例如阻止疾病或病症的发展,缓解疾病或病症,使疾病或病症好转,缓解由疾病或病症导致的症状,或者中止疾病或病症的症状,此外,该术语还可包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外,对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果,例如尽管患者可能仍然受到潜在疾病的影响,但观察到患者情况改善。就预防效果而言,可向具有患特定疾病风险的患者施用所述组合物或化合物,或者即便尚未做出疾病诊断,但向出现该疾病的一个或多个生理症状的患者施用所述组合物或化合物。
本发明以下实施例中,具体涉及小分子活性化合物如表1所示。
表1 实施例中活性小分子一览表
实施例一、拉米夫定对C57BL/6N结肠炎小鼠的治疗效果
1.动物饲喂
SPF级健康雄性C57BL/6N雄性小鼠,体重18-22g,实验前未用过任何药物,由中国农业科学院兰州兽医研究所提供。实验动物于温度为24~26℃,12h/12h的白昼规律交替的环境中适应饲养一周,给予动物饮食并自由饮水,然后分组进行实验。
2.药物及试剂
拉米夫定(Lamivudine,3-TC,HPLC≥98%),购自麦克林生物科技有限公司,批号:C10102050,分子量为229.25;柳氮磺吡啶肠溶片(Salazosulfapyridine,SASP)购自上海信谊天平药业有限公司;葡聚糖硫酸钠(Dextran Sulfate sodium,DSS),MW:40000,购自阿拉丁生物科技有限公司。
3.实验分组和灌胃给药剂量
取8周龄雄性C57BL/6N小鼠40只,按体重随机分为5组,每组8只,分组和给药剂量如下:
正常对照组(Control,口服给予等体积0.9%生理盐水);
正常鼠给予拉米夫定组(C+3-TC,给药剂量为2mg/kg/day)
DSS模型对照组(DSS,口服给予等体积0.9%生理盐水);
阳性药组(SASP,口服给予柳氮磺吡啶,80mg/kg/day);
模型鼠给予拉米夫定组(D+3-TC,给药剂量为2mg/kg/day)。
4.溃疡性结肠炎模型的制备
配制4%的DSS蒸馏水溶液,DSS模型组小鼠自由饮用DSS水溶液造模,并保持常规饲料喂养,连续造模7天。
5.给药时间及方法
DSS模型对照组小鼠自由饮用DSS水溶液造模、DSS+3-TC组小鼠自由饮用DSS水溶液造模同时给予2mg/kg/day的3-TC;DSS+SASP组小鼠自由饮用DSS水溶液造模同时给予80mg/kg/day的SASP;空白对照组小鼠自由饮用蒸馏水,空白对照组+3-TC组小鼠自由饮用蒸馏水的同时给予2mg/kg/day的3-TC,所有小鼠保持常规饲料喂养,连续给药7天。第七天末次给药2h后,分离血清及结肠组织备用。
6.溃疡性结肠炎临床指标检测
6.1体重降低情况
按每只鼠降低体重的百分比(%)计算,无体重减轻为0分,体重减轻1%-5%记为1分,体重减轻6%-10%为2分,体重减轻11%-15%记为3分,体重减轻大于15%为4分。
6.2大便粘稠度
正常大便评分记为0分,松散便记为2分、腹泻记为4分。
6.3便血及隐血情况
正常大便评分记为0分,隐血出血记为1分(按隐血检测结果进行判断),肉眼可见血便为3分、以上三项均值即为DAI。
6.4结肠长度的测量
处死小鼠后分离小鼠结肠,从回肠和结肠结合处剪断回肠,再在结肠近肛门处剪断,分离结肠外的筋膜,使结肠完全伸展开,用直尺测量小鼠结肠自回结肠处至肛门的长度,并拍照记录。
7.数据处理
实验数据采用SPSS23.0软件进行统计学分析,数据以(x±s)表示,组间比较采用单因素方差分析(One-way ANOVA)和LSD-t法进行两两比较。p<0.05认为具有统计学意义。
8.结果分析
8.1拉米夫定对C57BL/6N结肠炎小鼠体重和疾病活动指数的影响
上述小鼠在实验过程中,对其体重、粪便粘稠度、便血及隐血情况进行监测,数据统计用SPSS23.0软件进行单因素方差分析。
各组小鼠体重差异和DAI评分的显著性差异表示为*p<0.05、**p<0.01和***p<0.001。不同品系UC小鼠的各组小鼠的体重差异和DAI评分检测结果见图1。
由上述数据可见,与空白对照组相比,空白对照+拉米夫定给药组在体重指标和DAI评分指标中均显示无统计学差异,表明拉米夫定对正常小鼠无毒副作用;与空白对照组相比,DSS模型组体重大幅度降低,符合结肠炎患者体重减少的规律,DAI评分呈显著的上升趋势(###p<0.001),表明DSS模型是制备成功的;与DSS模型对照组相比,柳氮磺吡啶给药组和拉米夫定给药组均能显著的改善体重减低和DAI评分(*p<0.05),且拉米夫定的的疗效强于临床用药柳氮磺吡啶的疗效。
8.2拉米夫定对C57BL/6N结肠炎小鼠结肠形态及结肠长度的影响
上述各组小鼠处死后,迅速摘除其结肠组织,观察其形态改变,同时测量其长度,对各组数据进行统计分析。各组小鼠结肠长度的显著性差异表示为*p<0.05、**p<0.01和***p<0.001。UC结肠炎小鼠的各组小鼠的结肠形态及结肠长度监测结果见图2。
与空白对照组相比,空白对照+拉米夫定给药组小鼠结肠长度无明显的变化,表明拉米夫定对正常小鼠无毒副作用;与空白对照组相比,DSS模型组结肠长度显著的缩短(###p<0.001),表明DSS模型是制备成功的;与DSS模型对照组相比,柳氮磺吡啶给药组和拉米夫定给药组均能显著的改善结肠水肿及缩短情况,并具有显著性差异(*p<0.05和***p<0.001),且拉米夫定的疗效强于临床用药柳氮磺吡啶的疗效。
所述体重差异、DAI评分、结肠形态及结肠长度测定表明,拉米夫定对DSS诱导的结肠炎小鼠有治疗效果,无明显的毒副作用,且疗效显著强于临床用药柳氮磺吡啶的疗效。实施例二、拉米夫定对KM胃溃疡小鼠的治疗效果
1.实验动物来源
实验动物:8周龄SPF级昆明(Kunming,KM)雄性小鼠,体重为18~22g,实验前未使用任何药物,购自中国农业科学院兰州兽医研究所。实验动物于温度为24~26℃,12h/12h的白昼规律交替的环境中适应饲养一周,给予动物饮食并自由饮用蒸馏水,然后分组进行实验。
2.药物及试剂
拉米夫定(Lamivudine,3-TC,HPLC≥98%),购自麦克林生物科技有限公司;无水乙醇,天津大茂化学试剂公司;西咪替丁片(Cimetidine,CIM)购自上海信谊天平药业有限公司。
3.KM小鼠酒精性胃溃疡模型的制备
40只KM雄性小鼠(20-25g),饲养于兰州大学实验动物房,小鼠适应性饲养一周后,随机分为5组,每组8只小鼠,分组情况及给药量如表2所示;
表2 KM雄性小鼠实验分组及各组的给药剂量
组别 | 给药剂量 |
空白对照组 | 0.3mL/只灌胃0.9%生理盐水 |
空白+拉米夫定 | 2mg/kg/day 3-TC注射给药,2h后0.3mL/只灌胃生理盐水 |
乙醇模型组 | 0.3mL/只灌胃无水乙醇 |
西咪替丁阳性组 | 80mg/kg/day西咪替丁灌胃给药,2h后0.3mL/只灌胃无水乙醇 |
拉米夫定给药组 | 2mg/kg/day 3-TC注射给药,2h后0.3mL/只灌胃无水乙醇 |
上述各组小鼠刺激2h后结束实验,分离血清和胃组织测定各项指标。
4.溃疡面积、溃疡指数与抑制率
将胃取出,沿胃大弯剪开,冲洗干净内容物,观察胃粘膜溃疡情况,用直尺测量溃疡的横径与纵径,两者乘积为溃疡面积(mm2),如公式1所示;然后计算整个胃组织的溃疡面积,从而计算溃疡抑制率(%),见公式2。同时以各组鼠溃疡点数之和的均值作为溃疡指数(愈合记0分、表浅性黏膜糜烂记1分、深陷性溃疡或透壁性坏死记2分、穿孔或穿透性溃疡记3分)
溃疡面积(mm2)=溃疡最大长径*垂直于最大长径的最大宽径 (1)
5.数据处理
实验数据采用SPSS23.0软件进行统计学分析,数据以(x±s)表示,组间比较采用单因素方差分析(One-way ANOVA)和LSD-t法进行两两比较。p<0.05认为具有统计学意义。
6.拉米夫定对胃溃疡小鼠胃组织形态、溃疡指数、溃疡面积及溃疡抑制率的影响
上述各组小鼠处死后,迅速取其胃组织,观察其形态改变及溃疡损伤情况,并对其溃疡面积和溃疡指数进行统计分析,实验结果如图3和图4所示。由图3可知,正常组小鼠和正常组给予拉米夫定药物组胃组织宏观形态正常,未出现明显出血性病变,而乙醇模型组小鼠胃组织出血性病变明显,溃疡最为严重,表明乙醇胃溃疡模型制备成功,同时拉米夫定对健康小鼠胃组织无明显的损伤作用;与乙醇模型组相比,拉米夫定和西咪替丁各给药组均能显著的改善胃粘膜的损伤程度,减少溃疡面积,且拉米夫定的溃疡抑制率(79.2%)高于临床用药西咪替丁(CIM)的溃疡抑制率(73.25%)。以上所述溃疡面积、溃疡指数与抑制率,及胃组织形态学测定表明,拉米夫定防治胃溃疡有效,且疗效显著强于临床用药西咪替丁的疗效。
实施例三、阿德福韦酯、替洛福韦酯、泛昔洛韦和替比夫定对KM结肠炎小鼠的治疗效果1.药物及试剂
替洛福韦酯(PMPA,HPLC≥98%)、阿德福韦酯(PMEA,HPLC≥98%)、泛昔洛韦(Famciclocir,FCV,HPLC≥98%)和替比夫定(Telbivudine,LDT,HPLC≥98%)均购自阿拉丁生物科技有限公司;柳氮磺吡啶肠溶片(Salazosulfapyridine,SASP)购自上海信谊天平药业有限公司;葡聚糖硫酸钠(Dextran Sulfate sodium,DSS),MW:40000,购自阿拉丁生物科技有限公司。
2.实验分组和给药剂量:标准体重KM雄性小鼠,随机分为7组,每组8只,分组和给药剂量如下:
正常对照组(Control,口服给予等体积0.9%生理盐水);
DSS模型对照组(DSS,口服给予等体积0.9%生理盐水);
阳性药组(SASP,口服给予柳氮磺吡啶,80mg/kg/day);
替洛福韦酯组(PMPA,给药剂量为2mg/kg/day,腹腔注射);
阿德福韦酯组(PMEA,给药剂量为2mg/kg/day,腹腔注射);
泛昔洛韦组(FCV,给药剂量为2mg/kg/day,腹腔注射);
替比夫定组(LDT,给药剂量为2mg/kg/day,腹腔注射)。
3.溃疡性结肠炎模型的制备和临床指标检测方法如实施例一中“4-6实验方法”所示。
4.结果分析
上述各组小鼠在实验过程中,对其体重、粪便粘稠度、便血及隐血情况、结肠形态及长度进行监测,数据统计用SPSS23.0软件进行单因素方差分析。由图5可知,与空白对照组相比,DSS模型组体重大幅度降低,符合结肠炎患者体重减少的规律,DAI评分呈显著的上升趋势(###p<0.001),结肠长度显著的缩短(###p<0.001),表明DSS模型是制备成功的;与DSS模型对照组相比,替洛福韦酯、阿德福韦酯、替比夫定和泛昔洛韦给药组均能显著的改善体重减低、DAI评分、结肠水肿和缩短情况,表明替洛福韦酯、阿德福韦酯、替比夫定和泛昔洛韦对溃疡性结肠炎有治疗作用,其中替比夫定的疗效强于临床用药柳氮磺吡啶的疗效。
实施例四、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤对KM结肠炎小鼠的治疗效果
1.药物及试剂
盐酸吉西他滨(Gemzar,HPLC≥98%)、齐多夫定/3-叠氮-3-脱氧胸苷(AZT,HPLC≥98%)和6-硫基鸟嘌呤(6-TG,HPLC≥98%)购自阿拉丁生物科技有限公司;阿昔洛韦(Acyclovir,ACV,HPLC≥97%)购自麦克林生物科技有限公司;柳氮磺吡啶肠溶片(Salazosulfapyridine,SASP)购自上海信谊天平药业有限公司;葡聚糖硫酸钠(DextranSulfate sodium,DSS),MW:40000,购自阿拉丁生物科技有限公司。
2.实验分组和给药剂量:标准体重KM雄性小鼠,随机分为7组,每组8只,分组和给药剂量如下:
正常对照组(Control,口服给予等体积0.9%生理盐水);
DSS模型对照组(DSS,口服给予等体积0.9%生理盐水);
阳性药组(SASP,口服给予柳氮磺吡啶,80mg/kg/day);
盐酸吉西他滨组(Gemzar,给药剂量为2mg/kg/day,腹腔注射);
齐多夫定组(AZT,给药剂量为2mg/kg/day,腹腔注射);
阿昔洛韦组(ACV,给药剂量为2mg/kg/day,腹腔注射);
6-硫基鸟嘌呤组(6-TG,给药剂量为2mg/kg/day,灌胃给药)。
3.溃疡性结肠炎模型的制备和临床指标检测方法如实施例一中“4-6实验方法”所示。
4.结果分析
上述各组小鼠在实验过程中,对其体重、粪便粘稠度、便血及隐血情况、结肠形态及长度进行监测,数据统计用SPSS23.0软件进行单因素方差分析。
由图6可知,与空白对照组相比,DAI评分呈显著的上升趋势(###p<0.001),结肠长度明显缩短(###p<0.001),表明DSS模型是制备成功的;与DSS模型对照组相比,阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤各给药组均能显著的增加DAI评分(***p<0.001、**p<0.01、*p<0.05和*p<0.05)、改善结肠水肿和缩短情况(***p<0.001、**p<0.01、**p<0.01和**p<0.01),表明阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤对溃疡性结肠炎有治疗作用,其中阿昔洛韦的疗效强于临床用药柳氮磺吡啶的疗效,各给药组疗效对比为:阿昔洛韦>柳氮磺吡啶>6-硫基鸟嘌呤>盐酸吉西他滨>齐多夫定。
实施例五、替比夫定、盐酸吉西他滨和齐多夫定对KM胃溃疡小鼠的保护效果
1.实验动物来源
实验动物:8周龄SPF级昆明(Kunming,KM)雄性小鼠,体重为18~22g,实验前未使用任何药物,购自中国农业科学院兰州兽医研究所。
2.药物及试剂
盐酸吉西他滨(Gemzar,HPLC≥98%)、齐多夫定/3-叠氮-3-脱氧胸苷(AZT,HPLC≥98%)和替比夫定(Telbivudine,LDT,HPLC≥98%)购自阿拉丁生物科技有限公司;无水乙醇,天津大茂化学试剂公司;西咪替丁片(Cimetidine,CIM)购自上海信谊天平药业有限公司。
3.KM小鼠酒精性胃溃疡模型的制备
48只KM雄性小鼠(20-25g),饲养于兰州大学实验动物房,小鼠适应性饲养一周后,随机分为6组,每组8只小鼠,分组情况及给药量如表3所示;
表3 KM雄性小鼠实验分组及各组的给药剂量
组别 | 给药剂量 |
空白对照组 | 0.25mL/只灌胃0.9%生理盐水 |
乙醇模型组 | 0.25mL/只灌胃无水乙醇 |
西咪替丁阳性组 | 80mg/kg/day西咪替丁灌胃给药,2h后0.25mL/只灌胃无水乙醇 |
吉西他滨给药组 | 2mg/kg/day Gemzar注射给药,2h后0.25mL/只灌胃无水乙醇 |
齐多夫定给药组 | 2mg/kg/day AZT注射给药,2h后0.25mL/只灌胃无水乙醇 |
替比夫定给药组 | 2mg/kg/day LDT注射给药,2h后0.25mL/只灌胃无水乙醇 |
上述各组小鼠乙醇刺激2h后结束实验,分离血清和胃组织测定各项指标。
4.溃疡面积、溃疡指数与抑制率
将胃取出,沿胃大弯剪开,冲洗干净内容物,观察胃粘膜溃疡情况,用直尺测量溃疡的横径与纵径,两者乘积为溃疡面积(mm2),如公式1所示;然后计算整个胃组织的溃疡面积,从而计算溃疡抑制率(%),见公式2。同时以各组鼠溃疡点数之和的均值作为溃疡指数(愈合记0分、表浅性黏膜糜烂记1分、深陷性溃疡或透壁性坏死记2分、穿孔或穿透性溃疡记3分)
溃疡面积(mm2)=溃疡最大长径*垂直于最大长直径的最大宽径 (1)
5.数据处理
实验数据采用SPSS23.0软件进行统计学分析,数据以(x±s)表示,组间比较采用单因素方差分析(One-way ANOVA)和LSD-t法进行两两比较。p<0.05认为具有统计学意义。
6.替比夫定、盐酸吉西他滨和齐多夫定对胃溃疡小鼠胃组织形态、溃疡指数、溃疡面积及溃疡抑制率的影响
上述各组小鼠处死后,迅速取其胃组织,观察其形态改变及溃疡损伤情况,并对其溃疡面积和溃疡指数进行统计分析,实验结果如图7所示。由图7可知,正常组小鼠胃组织宏观形态正常,未出现明显出血性病变,而乙醇模型组小鼠胃组织出血性病变明显,溃疡最为严重,表明乙醇胃溃疡模型制备成功;与乙醇模型组相比,替比夫定、盐酸吉西他滨、齐多夫定和西咪替丁各给药组均能显著的改善胃粘膜的损伤程度,减少溃疡面积,其中盐酸吉西他滨的溃疡抑制率(91.02%)和齐多夫定的溃疡抑制率(84.47%)高于临床用药西咪替丁(CIM)的溃疡抑制率(65.25%)。以上所述溃疡面积、溃疡指数与抑制率,及胃组织形态学测定表明,替比夫定、盐酸吉西他滨和齐多夫定防治胃溃疡有效。
实施例六、阿德福韦酯、替洛福韦酯、阿昔洛韦、泛昔洛韦和6-硫基鸟嘌呤对KM胃溃疡小鼠的保护效果
1.实验动物来源
实验动物:8周龄SPF级昆明(Kunming,KM)雄性小鼠,体重为18~22g,实验前未使用任何药物,购自中国农业科学院兰州兽医研究所。
2.药物及试剂
替洛福韦酯(PMPA,HPLC≥98%)、阿德福韦酯(PMEA,HPLC≥98%)、泛昔洛韦(Famciclocir,FCV,HPLC≥98%)和6-硫基鸟嘌呤(6-TG,HPLC≥98%)购自阿拉丁生物科技有限公司;阿昔洛韦(Acyclovir,ACV,HPLC≥97%)购自麦克林生物科技有限公司;无水乙醇,天津大茂化学试剂公司;西咪替丁片(Cimetidine,CIM)购自上海信谊天平药业有限公司。
3.KM小鼠酒精性胃溃疡模型的制备
64只KM雄性小鼠(20-25g),饲养于兰州大学实验动物房,小鼠适应性饲养一周后,随机分为8组,每组8只小鼠,分组情况及给药量如表4所示;
表4 KM雄性小鼠实验分组及各组的给药剂量
组别 | 给药剂量 |
空白对照组 | 0.25mL/只灌胃0.9%生理盐水 |
乙醇模型组 | 0.25mL/只灌胃无水乙醇 |
西咪替丁阳性组 | 80mg/kg/day西咪替丁灌胃给药,2h后0.25mL/只灌胃无水乙醇 |
阿德福韦酯组 | 2mg/kg/day PMEA注射给药,2h后0.25mL/只灌胃无水乙醇 |
替洛福韦酯组 | 2mg/kg/day PMPA注射给药,2h后0.25mL/只灌胃无水乙醇 |
阿昔洛韦组 | 2mg/kg/day ACV注射给药,2h后0.25mL/只灌胃无水乙醇 |
泛昔洛韦组 | 2mg/kg/day FCV注射给药,2h后0.25mL/只灌胃无水乙醇 |
6-硫基鸟嘌呤组 | 2mg/kg/day 6-TG注射给药,2h后0.25mL/只灌胃无水乙醇 |
上述各组小鼠乙醇刺激2h后结束实验,分离血清和胃组织测定各项指标。
4.溃疡面积、溃疡指数与抑制率
将胃取出,沿胃大弯剪开,冲洗干净内容物,观察胃粘膜溃疡情况,用直尺测量溃疡的横径与纵径,两者乘积为溃疡面积(mm2),如公式1所示;然后计算整个胃组织的溃疡面积,从而计算溃疡抑制率(%),见公式2。同时以各组鼠溃疡点数之和的均值作为溃疡指数(愈合记0分、表浅性黏膜糜烂记1分、深陷性溃疡或透壁性坏死记2分、穿孔或穿透性溃疡记3分)
溃疡面积(mm2)=溃疡最大长径*垂直于最大长径的最大宽径 (1)
5.数据处理
实验数据采用SPSS23.0软件进行统计学分析,数据以(x±s)表示,组间比较采用单因素方差分析(One-way ANOVA)和LSD-t法进行两两比较。p<0.05认为具有统计学意义。
6.阿德福韦酯、替洛福韦酯、阿昔洛韦、泛昔洛韦和6-硫基鸟嘌呤对胃溃疡小鼠胃组织形态、溃疡指数、溃疡面积及溃疡抑制率的影响
上述各组小鼠处死后,迅速取其胃组织,观察其形态改变及溃疡损伤情况,并对其溃疡面积和溃疡指数进行统计分析,实验结果如图8所示。由图8可知,正常组小鼠胃组织宏观形态正常,未出现明显出血性病变,而乙醇模型组小鼠胃组织出血性病变明显,溃疡最为严重,表明乙醇胃溃疡模型制备成功;与乙醇模型组相比,阿德福韦酯、替洛福韦酯、阿昔洛韦、泛昔洛韦、6-硫基鸟嘌呤和西咪替丁各给药组均能显著的改善胃粘膜的损伤程度,减少溃疡面积,抑制溃疡程度达50%以上,各药物组与阳性药西咪替丁对比结果为:6-硫基鸟嘌呤>替洛福韦酯>泛昔洛韦>阿昔洛韦>西咪替丁>阿德福韦酯。以上所述溃疡面积、溃疡指数与抑制率,及胃组织形态学测定表明,阿德福韦酯、替洛福韦酯、阿昔洛韦、泛昔洛韦和6-硫基鸟嘌呤防治胃溃疡有效。
综上所述,本发明所述的核苷类似物拉米夫定、替比夫定、泛昔洛韦、替洛福韦酯、阿德福韦酯、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤,在不同饲喂条件下,对结肠炎小鼠进行DAI评分和结肠形态测定,结果显示拉米夫定、替比夫定、泛昔洛韦、替洛福韦酯、阿德福韦酯、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤等药物对溃疡性结肠炎均有效。同时,在不同饲喂条件下,对胃溃疡小鼠进行溃疡指数和抑制率及组织形态学检查,实验结果显示拉米夫定、替比夫定、泛昔洛韦、替洛福韦酯、阿德福韦酯、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤具有防治胃溃疡的效果,且大部分药物效果强于现有临床用药西咪替丁的疗效,即本发明所述的核苷类似物拉米夫定、替比夫定、泛昔洛韦、替洛福韦酯、阿德福韦酯、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤等药物同时对溃疡性结肠炎和胃溃疡均有效,具有良好的临床应用前景。
本发明在研究过程中意外的发现,拉米夫定治疗胃肠道疾病具有显著的疗效,实验结果如上述实施例一和实施例二所示,而拉米夫定属于经典的胞嘧啶核苷类似物,因此发明人推断,所有的胞嘧啶核苷类似物均具有治疗胃肠道疾病的疗效,为了验证上述结论,发明人又选取了另外一种胞嘧啶核苷类似物盐酸吉西他滨进行相关实验,实验结果显示,盐酸吉西他滨也具有治疗胃肠道疾病的效果。由此,发明人进一步推断,所有的核苷类似物均具有治疗胃肠道疾病的效果。同时,核苷类似物又可分为胞嘧啶核苷类似物、胸腺嘧啶核苷类似物、腺嘌呤核苷类似物和鸟嘌呤核苷类似物,发明人选取了胸腺嘧啶核苷类似物选自齐多夫定或替比夫定;所述的腺嘌呤核苷类似物选自泛昔洛韦、替洛福韦酯或阿德福韦酯;所述的鸟嘌呤核苷类似物选自阿昔洛韦或6-硫基鸟嘌呤。并进行胃肠道疾病的相关实验,实验结果显示,替比夫定、泛昔洛韦、替洛福韦酯、阿德福韦酯、阿昔洛韦、盐酸吉西他滨、齐多夫定和6-硫基鸟嘌呤均具有显著的治疗胃肠道疾病的效果,实验结果如上述实施例所示,发明人证实了上述推断,并得出所有的核苷类似物治疗胃肠道疾病均具有效果,能够用于制备治疗胃肠道疾病药物,为核苷类似物的药物提供了一种新用途,这是本领域技术人员所能够认可的。
Claims (2)
1.拉米夫定在制备预防和/或治疗酒精性胃溃疡药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述的拉米夫定和一种或多种药学上可接受的载体组成药物组合物,所述药物组合物的剂型为注射剂、片剂、胶囊剂、颗粒剂或丸剂。
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KonstantinosH.Katsanos等.Inflammatory bowel disease and hepatitis B and C in Western Balkans: A referral centre study and review of the literature.《Journal of Crohn's and Colitis》.2010,第2010卷(第4期),第450-465页,尤其是第452页表2、第456页2.5和3.1-3.2、第460页左栏第1-4行. * |
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CN114533739A (zh) | 2022-05-27 |
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