CN111358775A - 促进亚精胺体内水平的产品及其在骨关节炎中的应用 - Google Patents
促进亚精胺体内水平的产品及其在骨关节炎中的应用 Download PDFInfo
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Abstract
本发明其中一个目的在于提供一种含亚精胺成分的产品,将其应用于骨关节炎的防治。本发明还涉及一种可促进机体内亚精胺水平的产品,用于关节炎的防治。机体中腐胺在亚精胺合酶作用下转变成亚精胺,而后又在精胺合成酶作用下转变成精胺。因此可通过调控参与亚精胺生成的底物和/或调控亚精胺转化的产物,从而调控亚精胺在机体内的水平。本发明所述可促进亚精胺体内水平的产品,可将机体整体或局部亚精胺水平调控至相当于含亚精胺成分制剂剂量为0.0011‑110.0 mg/kg的产品产生的有效水平,并达到骨关节炎的有效防治。本发明所述的骨关节炎防治,包括药物制剂对骨关节炎的治疗作用和保健食品对骨关节炎的保健功能。
Description
技术领域
本发明属于生化药物制剂技术及应用领域,具体涉及亚精胺体内水平上调的产品及其在骨关节炎中的应用。
背景技术
骨关节炎(osteoarthritis, OA)多发于膝、髋、踝等负重大、活动多的关节,是一种严重危害人类身体健康的慢性疾病。OA原发性病因主要与年龄、性别、肥胖、积累性劳损、内分泌及代谢异常等因素相关,病理特点为关节透明软骨细胞变性,细胞外基质变异、降解,炎性细胞因子释放粘附,诱发关节炎性反应,最终引起关节软骨损失和其他关节结构损伤,导致关节疼痛、功能丧失。
亚精胺广泛分布在生物体内,参与生物体内许多的生物学过程,如调控细胞增殖、细胞衰老、器官发育、免疫以及癌症等生理和病理过程。随着年龄的增长,体内亚精胺水平会逐渐下调。近年来,亚精胺被应用于神经损伤、减肥、预防脱发、美白等领域的研究。专利CN02828213.2公开了多胺的组成、合成及其治疗用途,公开了多胺的多种可能用途,包括用于治疗神经性、心血管、内分泌获得性和遗传性线粒体损伤等疾病及炎症治疗方面应用等。但是通过调控体内亚精胺水平的相关研究寥寥无几。公开技术中没有一种方案是通过促进体内亚精胺水平的相关作用应用于关节炎治疗。虽然亚精胺及其相关成分被广泛应用于临床研究中,研究结果也显示亚精胺对多种类型炎症反应起到关键性作用,但是目前还未有已批准的亚精胺相关药物进入临床治疗,现有技术还未曾公开过亚精胺在OA防治中的研究。因此,本发明的一个关键构思是开发一种含有亚精胺成分的产品,并用于OA的防治。
此外,本发明的另一个发明点是通过调控体内多胺水平调节机制(相互转化、氧化及外流等)对亚精胺水平进行调节,即发现一种可促进亚精胺在体内局部或整体水平的有效物质,以此对OA起到防治作用。根据公开文献所知,机体中有重要生理功能的多胺是腐胺、亚精胺、精胺等。腐胺在亚精胺合酶作用下转变成亚精胺,而后又在精胺合成酶作用下转变成精胺。多胺在机体中的是动态平衡可逆的转化过程,参与多胺水平调控的酶的活性是受到精确调控的:生长因子和其他刺激因素使其水平上升,而多胺本身则使其活性下降。这些因素共同作用,将多胺调整至细胞生长和发育所需的水平。在控制多胺水平诸多因素中,鸟氨酸脱羧酶和S-腺苷甲硫氨酸脱羧酶的活性是最主要的两个因素。亚精胺合成酶和精胺合成酶的活性主要是通过其底物利用度进行调节的。因此,可通过增加/减少合成亚精胺底物浓度,或者提高/降低相关合成酶或脱羧酶活性对体内多胺,尤其是亚精胺水平进行调控。
本发明研究发现亚精胺对OA的有效防治作用,并且发现一种可促进亚精胺在体内局部或整体水平上升的有效物质,本发明有望弥补骨关节炎临床治疗的空缺,给OA患者带来新的希望。
发明内容
本发明其中一个目的在于提供一种含亚精胺成分的产品,将其应用于骨关节炎的防治。为实现上述目的,本发明通过小鼠普通喂食和高脂饮食模型的内侧半月板游离手术(DMM)造模,研究亚精胺对骨关节炎的炎症缓解情况。
实验包括以下步骤:
1)C57BL6/J小鼠周龄在10周至12周间进行内侧半月板游离手术(DMM),术后立即予以一定剂量亚精胺饮水,以普通饮水为对照,隔天换一次水;在造模后第4周、8周取造模侧膝关节进行切片、番红O/快绿染色以评估造模实验性小鼠OA模型的进展情况。
2)对于高脂模型小鼠,于小鼠周龄4周时予以60%高脂模型饲料喂养,于小鼠10周龄时进行DMM手术造模,术后立即予以一定剂量亚精胺给水喂养,以普通饮水为对照,隔天换一次水;在造模后第4周、8周取造模侧膝关节进行切片、番红O/快绿染色以评估造模实验性小鼠OA模型的进展情况。
进一步地,实验方案中小鼠重量约20 g/只,每天饮水量约为4-7 mL,其中所述的一定剂量的亚精胺,可选剂量为:0.010 -1000 mg/kg。按《药理实验方法学》附录实验动物用药剂量换算公式:小鼠的剂量=X mg / kg×70 kg×0.0026 / 20 g=X mg / kg×70kg×0.0026 / 0.02 kg= 9.1 X mg / kg,其中小鼠(20 g)可选剂量为:0.010 -1000 mg/kg,推算成人(70 KG)剂量范围为:0.0011-110.0 mg/kg。
更进一步地,为优化亚精胺对骨关节炎的较低剂量范围,将实验方案中所述的一定浓度的亚精胺,其剂量优选范围在0.10-10.0 mg/kg,成人剂量相当于0.011-1.10 mg/kg。更优选剂量为:0.1 mg/kg、1.0 mg/kg、2.0 mg/kg、3.0 mg/kg、4.0 mg/kg、5.0 mg/kg、6.0 mg/kg、7.0 mg/kg、8.0 mg/kg、9.0 mg/kg、10.0 mg/kg。相当于成人剂量:0.011 mg/kg、0.110 mg/kg、0.220 mg/kg、0.330 mg/kg、0.440 mg/kg、0.550 mg/kg、0.660 mg/kg、0.770 mg/kg、0.880 mg/kg、0.990 mg/kg、1.10 mg/kg。
更进一步地,为研究低剂量亚精胺对骨关节炎的有效剂量范围,将实验方案中所述的一定剂量的亚精胺,其剂量范围选择为0.01 -0.10 mg/kg,成人剂量相当于1.10-11.0µg/kg。更优选剂量为:0.01 mg/kg、0.02 mg/kg、0.030 mg/kg、0.040 mg/kg、0.050 mg/kg、0.060 mg/kg、0.070 mg/kg、0.080 mg/kg、0.090 mg/kg、0.10mg/kg。相当于成人剂量:1.10 µg /kg、2.20 µg /kg、3.30 µg /kg、4.40 µg/kg、5.50µg /kg、6.60 µg /kg、7.70 µg/kg、8.80 µg /kg、9.90 µg /kg、11.0 µg /kg。
更进一步地,为研究中剂量亚精胺对骨关节炎的有效剂量范围,将实验方案中所述的一定浓度的亚精胺,其剂量范围选择为10 -100 mg/kg,成人剂量相当于1.10 -11.0mg/kg。更优选剂量为:10 mg/kg、20 mg/kg、30 mg/kg、40 mg/kg、50 mg/kg、60 mg/kg、70mg/kg、80 mg/kg、90 mg/kg、100 mg/kg。相当于成人剂量:1.10 mg/kg、2.20 mg/kg、3.30mg/kg、4.40 mg/kg、5.50 mg/kg、6.60 mg/kg、7.70 mg/kg、8.80 mg/kg、9.90 mg/kg 、11.0mg/kg。
更进一步地,为研究高剂量亚精胺对骨关节炎的有效剂量范围,将实验方案中所述的一定浓度的亚精胺,其剂量范围选择为100 -1000 mg/kg,成人剂量相当于11.0 -110.0 mg/kg。更优选剂量为:100 mg/kg、200 mg/kg、300 mg/kg、400 mg/kg、500 mg/kg、600 mg/kg、700 mg/kg、800 mg/kg、900 mg/kg、1000 mg/kg。相当于成人剂量:11.0 mg/kg、22.0 mg/kg、33.0 mg/kg、44.0 mg/kg、55.0 mg/kg、66.0 mg/kg、77.0 mg/kg、88.0 mg/kg、99.0 mg/kg 、110.0 mg/kg。
本发明还涉及一种可促进机体内亚精胺水平的产品,用于关节炎的防治。机体中腐胺在亚精胺合酶作用下转变成亚精胺,而后又在精胺合成酶作用下转变成精胺。因此可通过调控参与亚精胺生成的底物和/或调控亚精胺转化的产物,从而调控亚精胺在机体内的水平。此外,还可通过调控参与亚精胺生成和/或亚精胺转化的酶活性,从而调控亚精胺在机体内的水平。
第一方面,本发明促进机体内亚精胺水平的产品中包含有参与机体中亚精胺生成的底物。
进一步地,所述参与亚精胺生成的底物是一种或者两种以上多胺化合物。
更进一步地,所述参与亚精胺生成的多胺化合物选自:腐胺、脱羧化S-腺苷甲硫氨酸、精胺、或其组合;和药学上可接受的载体。
第二方面,本发明促进机体内亚精胺水平的产品中包含有参与机体中亚精胺生成的生物酶。
进一步地,所述参与机体中亚精胺生成的生物酶包含有鸟氨酸脱羧酶,S-腺苷甲硫氨酸,腐胺氨丙基转移酶(亚精胺合酶)其中的一种或两种以上组合。
第三方面,本发明可促进机体内亚精胺水平的产品中包含有参与机体中亚精胺转化成精胺的酶活性抑制剂,该抑制剂可抑制亚精胺转化为精胺。
进一步地,所述亚精胺转化成精胺的酶活性抑制剂是亚精胺丙基转移酶抑制剂。
第四方面,本发明可促进机体内亚精胺水平的产品,所述体内水平包括整体水平和局部水平。
第五方面,本发明所述的产品包括含有亚精胺成分的药物制剂、保健食品和医疗器械,其中药物制剂的剂型包括液体剂型、固体剂型和半固体剂型。
更进一步地,当活性成分为多胺化合物时,在制备这些组合物时,通常将活性成分(多胺化合物)与赋形剂混合,或用赋形剂稀释,或包在可以胶囊或药囊形式存在的载体中。当赋形剂起稀释剂作用时,它可以是固体、半固体或液体材料作为赋形剂、载体或活性成分的介质。因此,组合物可以是片剂、丸剂、粉剂、溶液剂、糖浆剂、灭菌注射溶液等。合适的赋形剂的例子包括:乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、等。制剂还可包括:湿润剂、乳化剂、防腐剂(如羟基苯甲酸甲酯和丙酯)、甜味剂等。
第六方面,本发明所述可促进机体内亚精胺水平的产品,其中成分选自底物和生物酶成分时,可将机体整体或局部亚精胺水平调控至达到骨关节炎的有效防治水平。其中所述体内亚精胺水平相当于剂量为:0.0011-110.0 mg/kg的亚精胺产品产生的有效水平。
进一步地,所述可促进机体内亚精胺水平的产品,可将机体整体或局部亚精胺水平调控至达到骨关节炎的有效防治水平。成人剂量相当于0.011-1.10 mg/kg的较低剂量亚精胺产品产生的有效水平。
进一步地,所述可促进机体内亚精胺水平的产品,可将机体整体或局部亚精胺水平调控至达到骨关节炎的有效防治水平。相当于剂量为0.0011-0.011 mg/kg的低剂量亚精胺产品产生的有效水平。
更进一步地,所述可促进机体内亚精胺水平的产品,可将机体整体或局部亚精胺水平调控至达到骨关节炎的有效防治水平。其中所述体内亚精胺水平相当于摄入浓度为1.10 -11.0 mg/kg的中剂量亚精胺产品产生的有效水平。
进一步地,所述可促进机体内亚精胺水平的产品,可将机体整体或局部亚精胺水平调控至达到骨关节炎的有效防治水平。其中所述体内亚精胺水平相当于摄入浓度为11.0-110.0 mg/kg的高剂量亚精胺产品产生的有效水平。
第七方面,本发明所述的骨关节炎防治,包括药物制剂对骨关节炎的治疗作用和保健食品对骨关节炎的保健功能。
附图说明
图1 普通饮食小鼠给予剂量90 mg/kg亚精胺喂养后膝OA进展,图为番红O/快绿染色评估小鼠膝关节软骨破坏情况。
图2 高脂饮食肥胖模型小鼠给予剂量90 mg/kg亚精胺喂养后膝OA进展,番红O/快绿染色评估小鼠膝关节软骨破坏情况;
图3普通饮食小鼠给予剂量10 mg/kg、50 mg/kg、100 mg/kg亚精胺喂养后膝OA进展,图为番红O/快绿染色评估小鼠膝关节软骨破坏情况。
具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此:
实施例1
在广东省实验动物中心订购C57BL6/J雄性小鼠,在南方医科大学动物实验中心进行动物饲养及动物实验。C57BL6/J小鼠周龄在10周至12周间进行内侧半月板游离手术(DMM),术后立即予以亚精胺(Spd,#S0266, Sigma,剂量90 mg/kg)饮水,以普通饮水为对照,隔天换一次水;在造模后第4周、8周取造模侧膝关节进行切片、番红O/快绿染色以评估造模实验性小鼠OA模型的进展情况。结果表明膝OA进展较对照组显著缓解,结果见图1。
实施例2
对于高脂模型小鼠,购买地点和实验场地同实施例1,于小鼠周龄4周时予以60%高脂模型饲料喂养,于小鼠10周龄时进行DMM手术造模,术后术后立即予以亚精胺给水(S0266,Sigma,剂量90 mg/kg)喂养,以普通饮水为对照,隔天换一次水;在造模后第4周、8周取造模侧膝关节进行切片、番红O/快绿染色以评估造模实验性小鼠OA模型的进展情况。结果表明膝OA进展较对照组显著缓解,结果见图2。
实施例3
中剂量亚精胺喂养对关节炎症状缓解的有效性研究。
实验条件如实施例1,术后立即予以亚精胺(使用剂量分别为10 mg/kg、50 mg/kg、100 mg/kg)饮水,以普通饮水为对照,隔天换一次水;在造模后第8周取造模侧膝关节进行切片、番红O/快绿染色以评估造模实验性小鼠OA模型的进展情况。结果见图3,图中亚精胺#1、亚精胺#2、亚精胺#3分别表示亚精胺剂量10 mg/kg、50 mg/kg、100 mg/kg。结果表明膝OA进展较对照组显著缓解,不同亚精胺剂量对炎症缓解效果无显著差异。
实施例4
低剂量亚精胺喂养有效范围研究。
实验条件如实施例1,术后立即予以亚精胺(使用剂量分别为0.01 mg/kg、0.02mg/kg、0.030 mg/kg、0.040 mg/kg、0.050 mg/kg、0.060 mg/kg、0.070 mg/kg、0.080 mg/kg、0.090 mg/kg、0.10mg/kg)饮水,以普通饮水为对照,隔天换一次水;在造模后第4周、8周取造模侧膝关节进行切片、番红O/快绿染色以评估造模实验性小鼠OA模型的进展情况。结果表明不同剂量亚精胺喂养实验组膝OA进展较对照组有缓解。
实施例5
高剂量亚精胺喂养有效范围研究。
对于高脂模型小鼠,购买地点和实验场地同实施例1,于小鼠周龄4周时予以60%高脂模型饲料喂养,于小鼠10周龄时进行DMM手术造模,术后立即予以亚精胺(使用剂量分别为:100 mg/kg、200 mg/kg、300 mg/kg、400 mg/kg、500 mg/kg、600 mg/kg、700 mg/kg、800mg/kg、900 mg/kg、1000 mg/kg)饮水,以普通饮水为对照,隔天换一次水;在造模后第4周、8周取造模侧膝关节进行切片、番红O/快绿染色以评估造模实验性小鼠OA模型的进展情况。结果表明不同剂量亚精胺喂养实验组膝OA进展较对照组有缓解。
Claims (10)
1.一种促进亚精胺体内水平的产品,所述产品应用于骨关节炎防治。
2.如权利要求1所述的产品,其特征在于所述促进亚精胺体内水平的产品含有亚精胺成分。
3.如权利要求2所述的产品,其特征在于所述亚精胺剂量为0.0011-110.0 mg/kg。
4.如权利要求3所述的产品,其特征在于所述亚精胺浓度为0.011-11.0 mg/kg。
5.如权利要求4所述的产品,其特征在于所述亚精胺浓度为0.11 -1.10 mg/kg。
6.如权利要求1所述的产品,其特征在于所述促进亚精胺体内水平的产品含有参与机体中亚精胺生成的底物。
7.如权利要求6所述的产品,其特征在于所述参与亚精胺生成的底物是多胺化合物,其中多胺化合物选自:腐胺、脱羧化S-腺苷甲硫氨酸、精胺中的一种或两种及以上的组合。
8.如权利要求1所述的产品,其特征于促进机体内亚精胺水平的产品中包含有参与机体中亚精胺生成的生物酶,所述生物酶选自鸟氨酸脱羧酶、S-腺苷甲硫氨酸、腐胺氨丙基转移酶(亚精胺合酶)中的一种或两种及以上的组合。
9. 如权利要求6-8其中一项所述的产品,其特征在于所述体内亚精胺水平相当于含亚精胺成分制剂剂量为0.0011-110.0 mg/kg的产品产生的有效水平,并达到骨关节炎的有效防治。
10.如权利要求9所述的产品,其特征在于所述体内亚精胺水平相当于含亚精胺成分制剂剂量为0.011-11.0 mg/kg的产品产生的有效水平,并达到骨关节炎的有效防治。
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