CN117017967A - 三丁酸甘油酯及其衍生物在制备预防和/或治疗放疗引起的消化道并发症药物中的应用 - Google Patents
三丁酸甘油酯及其衍生物在制备预防和/或治疗放疗引起的消化道并发症药物中的应用 Download PDFInfo
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Abstract
本发明涉及三丁酸甘油酯及其衍生物在制备预防和/或治疗放疗引起的消化道并发症中的应用,属于生物医药技术领域。本发明通过动物水平实验发现三丁酸甘油酯及其衍生物改善放疗引起的粘膜溃疡水肿、隐窝扭曲变形、炎症细胞浸润、黏膜下层增厚等病理现象,可刺激肠隐窝细胞增殖分化、促进放射后受损的结肠修复和维护肠粘膜屏障的完整性,从而治疗放疗引起的消化道并发症。
Description
技术领域
本发明涉及生物医药技术领域,尤其涉及三丁酸甘油酯及其衍生物在制备预防和/或治疗放疗引起的消化道并发症药物中的应用。
背景技术
放射性肠病(Radiation Enteropathy,RE)是指因盆腹腔恶性肿瘤患者接受放射治疗而出现的放射性肠道损伤,通常以放射后3个月作为急性期与慢性期病变的分界点,其中急性期病变的发病率约为75%,慢性期病变的发病率约为20%。急性期RE的常见症状包括腹泻、腹痛、里急后重等,大多具有自限性;部分症状迁延不愈发展为慢性期RE,以便血为主要特征,严重者出现肠梗阻、肠穿孔、肠瘘等并发症。RE的主要病理特征包括肠黏膜糜烂水肿、炎症浸润、血管异常增生、肠壁纤维化等,与RE的直肠出血等症状的发生发展密切相关。尽管RE发病率较高,其发生发展的具体机理尚不明确,目前临床仍缺乏切实有效的治疗方案。
短链脂肪酸(Short Chain Fatty Acids,SCFAs)由结肠部位的厌氧菌分解不可溶性纤维素产生,为肠上皮细胞提供营养,其中丁酸是最主要的产能SCFA。研究表明,丁酸及丁酸钠溶液可促进肠上皮细胞增殖,抑制炎症浸润,维护肠粘膜屏障的完整性。但在临床实际应用中,丁酸和丁酸钠灌肠处理对RE的治疗效果存在较大争议。尽管Vernia P等发现丁酸钠灌肠可减轻急性放射性肠炎的症状(Vernia,P.,etal.Topical butyrate for acuteradiation proctitis:Randomised,crossover trial.Lancet 356,1232-1235(2000).),但该队列样本量较小,结果的外推性有限。近年一项多中心大规模的临床研究显示,在辐照及辐照后2周连续进行丁酸钠灌肠处理,对放射性肠炎的发生率、严重程度及持续时间都无显著影响(Maggio,A.,et al.Daily sodium butyrate enema for the prevention ofradiation proctitis in prostate cancer patients undergoing radical radiationtherapy:results of a multicenter randomized placebo-controlled dose-findingphase 2study.)。丁酸及丁酸钠在临床放射性肠病治疗中效果不佳,其原因一方面是在于摄入的全部丁酸及大部分丁酸钠被小肠吸收,实际进入结肠发挥抗炎促修复作用的浓度很低;另一方面是由于丁酸和丁酸钠的气味具有刺激性,且灌肠操作复杂,体内有效作用时间短,极大地限制了治疗的接受度与依从性。因此,需要挖掘其他丁酸替代药物推动RE的治疗。
发明内容
本发明的目的在于克服现有技术的不足之处而提供一种能够减轻放疗引起的消化道并发症的三丁酸甘油酯及其衍生物,可在制备预防和/或治疗放疗引起的消化道并发症药物中应用。
为实现上述目的,本发明采取的技术方案为:
第一方面,本发明提供了三丁酸甘油酯及其衍生物在制备预防和/或治疗放疗引起的消化道并发症药物中的应用。
本发明通过动物水平实验证实三丁酸甘油酯及其衍生物能够有效缓解放疗引起的肠道黏膜溃疡水肿、隐窝扭曲变形、炎症细胞浸润和黏膜下层增厚,有效治疗放疗引起的消化道并发症。
三丁酸甘油酯(tributyrin)是丁酸的酯化物,可被结肠上皮细胞内的酯酶催化分解为1分子甘油和3分子丁酸。作为丁酸的前体药物,三丁酸甘油酯在肠道内缓慢释放,易于在结肠富集。研究表明,三丁酸甘油酯与丁酸钠的结肠上皮细胞渗透速率相近,在相同浓度的情况下,前者释放丁酸发挥促细胞增殖修复的效果是后者的3倍。同时,三丁酸甘油酯无刺激性气味,无毒副作用,在动物和人体内耐受性良好。
作为本发明所述应用的优选实施方式,所述预防和/或治疗放疗引起的消化道并发症药物为预防和/或治疗放射性肠病药物。
作为本发明所述应用的优选实施方式,所述三丁酸甘油酯衍生物包括丁酸单酯、丁酸二酯、β-羟基丁酸、丁酸甘油酯、二丁酸甘油酯、三醋精、乙酸甘油酯、二乙酸甘油酯、三丙酸甘油酯、乙酰乙酸中的至少一种。
作为本发明所述应用的优选实施方式,所述三丁酸甘油酯及其衍生物占预防和/或治疗放疗引起的消化道并发症药物总重量的20%。
作为本发明所述应用的优选实施方式,所述三丁酸甘油酯及其衍生物以固态或液态的形式存在。
作为本发明所述应用的优选实施方式,所述三丁酸甘油酯及其衍生物可刺激肠隐窝细胞增殖分化、促进放射后受损的结肠修复和维护肠粘膜屏障的完整性。
作为本发明所述应用的优选实施方式,所述三丁酸甘油酯及其衍生物可抑制炎症细胞浸润。
作为本发明所述应用的优选实施方式,所述预防和/或治疗放疗引起的消化道并发症药物的剂型为胶囊剂、片剂、口服制剂、微囊制剂、注射剂、栓剂、喷雾剂、软膏剂、凝胶剂、溶液剂、粉剂、洗剂、酊剂、油剂、乳膏剂和气雾剂中的至少一种。
作为本发明所述应用的优选实施方式,所述预防和/或治疗放疗引起的消化道并发症药物给药途径包括口服、静脉内、肌内、动脉内、髓内、鞘内、心室内、透皮、皮下、腹膜内、鼻内、肠、局部、舌下和直肠方式中的至少一种。
第二方面,本发明提供了一种治疗放疗引起的消化道并发症药物,所述药物包括三丁酸甘油酯及其衍生物和药学上可接受的承载体。
与现有技术相比,本发明的有益效果为:
本发明通过动物水平实验发现三丁酸甘油酯及其衍生物具有改善放疗引起的粘膜溃疡水肿、隐窝扭曲变形、炎症细胞浸润、黏膜下层增厚,同时调节了肠道菌群平衡、协助抵抗放疗引起的氧化损伤,从而治疗放疗引起的消化道并发症。
附图说明
图1为实验例中小鼠给药方案;
图2为实验例中各实验组HE染色结果;
图3为实验例中各实验组的放射性肠损伤组织病理评分(RIS),图中“***”表示两组间具有统计学差异,p<0.001,“n.s.”表示两组间不具有统计学差异。
具体实施方式
为更好地说明本发明的目的、技术方案和优点,下面将结合具体实施例对本发明作进一步说明。
下述实验例中所用的试剂、耗材无特别说明均可通过商业途径获得。
健康雄性SPF级C57BL/6J小鼠由江苏集萃药康生物科技有限公司提供。
实验用鼠维持饲料由协同医药生物工程有限公司提供。
实验例
为了验证三丁酸甘油酯及其衍生物在放疗引起的消化道并发症中的治疗效果,通过动物实验评估三丁酸甘油酯及其衍生物治疗放射性肠病的效果,具体方案如下:
(1)动物模型选择及分组
选择体重为16-18g的C57BL/GJ雄性小鼠,随机分为3组,每组10只。实验共设置3个组别,具体处理见表1。
表1各实验组的处理
组别 | 药物处理 |
对照组 | 正常实验用鼠维持饲料 |
三丁酸甘油酯组 | 含20%(g/g)三丁酸甘油酯的实验用鼠维持饲料 |
丁酸钠组 | 含20%(g/g)丁酸钠的实验用鼠维持饲料 |
(2)药物处理
如图1所示,按照表1分组的饲料连续喂养小鼠2周,对小鼠盆腔局部照射X射线,具体操作如下:照射当天提前腹腔注射1%戊巴比妥钠溶液进行麻醉,麻醉剂量为40mg/kg。将麻醉后的小鼠俯卧位平放于3.5×6cm的铅盒内,上方可滑动的铅盖下缘移动至小鼠肛门上约1cm的位置,使小鼠肛门及上方1cm肠段暴露在X射线照射范围内,将铅盒置于RS2000小动物辐射仪内进行照射,设定辐射总剂量为25Gy,剂量率为2.95Gy/min。
照射结束后,待小鼠自然苏醒后带回饲养间按照表1分组的饲料连续喂养小鼠8周,每天观察小鼠状态,每天称量体重。
(3)检测小鼠放射性肠病情况
照射X射线后连续喂养至第8周,将小鼠进行颈椎脱臼处死,取出小鼠结肠,以刚尺为参照,截取肛门及上方1cm结直肠,剖开肠断纵向分为2等份,1份用于制作病理切片,置于1ml 4%中性福尔马林中,随后进行HE染色。
HE染色具体步骤如下:将置于4%中性福尔马林固定液中24h的结直肠组织取出,流水冲洗、脱水、透明、石蜡包埋,制备为4μm后的连续石蜡切片,再经过脱蜡、脱水处理,苏木素室温染10min,冲洗30s,1%盐酸酒精分化3s,冲洗1min,伊红室温染5-10min,梯度酒精脱水,二甲苯透明,中性树脂封片。HE染色结果见图2。
根据HE染色切片进行放射性肠损伤组织病理评分(RIS),评分细则见表2,评分结果见图3。
如图2~3所示,与对照组小鼠相比,三丁酸甘油酯组小鼠肠道组织病理损伤明显减轻,RIS评分显著降低,具体表现为对照组黏膜溃疡水肿,隐窝扭曲变形,炎症细胞浸润,黏膜下层显著增厚;三丁酸甘油酯组小鼠粘膜层无明显水肿,轻度糜烂且仅局限于表层,肠上皮细胞排列较为整齐,肠隐窝无明显扭曲变形,炎症浸润轻微且局限于固有层,黏膜下层未见明显纤维化。
与对照组小鼠相比,丁酸钠组小鼠未能有效减轻病损程度,两组的RIS无显著差异,具体表现为对照组黏膜糜烂,隐窝扭曲变形,炎症细胞浸润,黏膜下层显著增厚;丁酸钠组黏膜层糜烂水肿,隐窝几乎全丢失,炎症细胞浸润于固有层,黏膜下层胶原纤维玻璃样变性。
以上结果表明,三丁酸甘油酯能够通过刺激肠隐窝细胞增殖分化、促进放射后的结肠修复和维护肠粘膜屏障的完整性,同时抑制炎症细胞浸润、调节肠道菌群平衡和协助抵抗放疗引起的氧化损伤,从而起到治疗放射性肠病的效果。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
Claims (10)
1.三丁酸甘油酯及其衍生物在制备预防和/或治疗放疗引起的消化道并发症药物中应用。
2.如权利要求1所述的应用,其特征在于,所述预防和/或治疗放疗引起的消化道并发症药物为预防和/或治疗放射性肠病药物。
3.如权利要求1所述的应用,其特征在于,所述三丁酸甘油酯衍生物包括丁酸单酯、丁酸二酯、β-羟基丁酸、丁酸甘油酯、二丁酸甘油酯、三醋精、乙酸甘油酯、二乙酸甘油酯、三丙酸甘油酯、乙酰乙酸中的至少一种。
4.如权利要求1所述的应用,其特征在于,所述三丁酸甘油酯及其衍生物占预防和/或治疗放疗引起的消化道并发症药物总重量的20%。
5.如权利要求1所述的应用,其特征在于,所述三丁酸甘油酯及其衍生物以固态或液态的形式存在。
6.如权利要求1所述的应用,其特征在于,所述三丁酸甘油酯及其衍生物可刺激肠隐窝细胞增殖分化、促进放射后受损的结肠修复和维护肠粘膜屏障的完整性。
7.如权利要求1所述的应用,其特征在于,所述三丁酸甘油酯及其衍生物可抑制炎症细胞浸润。
8.如权利要求1所述的应用,其特征在于,所述预防和/或治疗放疗引起的消化道并发症药物的剂型为胶囊剂、片剂、口服制剂、微囊制剂、注射剂、栓剂、喷雾剂、软膏剂、凝胶剂、溶液剂、粉剂、洗剂、酊剂、油剂、乳膏剂和气雾剂中的至少一种。
9.如权利要求1所述的应用,其特征在于,所述预防和/或治疗放疗引起的消化道并发症药物给药途径包括口服、静脉内、肌内、动脉内、髓内、鞘内、心室内、透皮、皮下、腹膜内、鼻内、肠、局部、舌下和直肠方式中的至少一种。
10.一种治疗放疗引起的消化道并发症药物,其特征在于,所述药物包括三丁酸甘油酯及其衍生物和药学上可接受的承载体。
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CN1843508A (zh) * | 2005-04-07 | 2006-10-11 | 安成制药科技股份有限公司 | 治疗胃肠不适的医药组合物 |
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