CN116270618A - 褪黑素和维生素e药物组合物及其应用 - Google Patents
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Abstract
本发明涉及一种褪黑素和维生素E药物组合物及其应用。本发明首次证实了褪黑素和维生素E结合在制备卵巢抗辐射药物或治疗卵巢电离辐射损伤药物中的新用途，在动物模型中证实本发明的的药物组合物可改善辐照小鼠的动情周期紊乱、增加辐照小鼠的卵巢器官系数、改善辐照引起的小鼠卵巢激素水平紊乱以及增加辐照小鼠卵泡。表明褪黑素和维生素E可以用来治疗辐射诱导的卵巢组织损伤，为减轻卵巢的辐射损伤防护带来了新希望。
Description
技术领域
本发明医药技术领域，具体地说，是关于褪黑素和维生素E药物组合物及其应用。
背景技术
一项最新的统计数据显示，全世界每年约有120万例恶性肿瘤新发病例在15至39岁的年轻患者中得到诊断，该年龄段新发人数约占全年所有癌症诊断人数的6％左右。以放化疗为主的肿瘤综合治疗措施的不断发展，使得肿瘤患者的生存率不断提高。得以幸存的肿瘤患者，在很长一段时间内均需面临肿瘤综合治疗副反应的影响。对于年轻女性肿瘤患者，包括放疗在内的肿瘤治疗手段往往会对卵巢功能产生影响，出现卵巢功能紊乱，严重时可能发生卵巢早衰。在儿童肿瘤幸存者中，有研究提示她们的卵巢早衰的发生率约为8％，与之相对应的是，她们的姐妹发生卵巢早衰的比例小于1％。尽管肿瘤治疗的益处包括缓解和治愈，但卵巢功能过早丧失的后遗症无疑会对女性产生不良影响。除了丧失生育能力外，卵巢功能下降还可能导致更年期提前，这与潮热、骨密度降低和心血管不良事件相关。卵巢功能减退或卵巢功能衰竭的总体效应还包括可能导致生活质量下降，甚至过早死亡。
现阶段，仅有少数年轻肿瘤患者在治疗前或治疗过程中接受了遗传咨询，生育力保留已经成为此类人群继生存之后第二大需要考虑的问题。“Oncofertility”在此情况下逐渐发展起来，并逐渐成为近些年来相对热门的话题，吸引了越来越多的临床肿瘤医生及生育专家们的注意，使越来越多的学者致力于肿瘤患者的生育力保留措施的相关研究。
放疗可通过直接效应对卵巢功能产生影响，也可通过间接效应造成卵巢损伤。直接效应是指放射线对生物大分子的直接损伤，如蛋白质、脂类以及DNA等，特别是DNA，它是放疗引起卵巢损伤的主要效应物，一旦被破坏，可以引起细胞分裂和增殖延缓，甚至导致细胞凋亡乃至坏死的发生。间接效应是指放疗产生的氧自由基对生物大分子的影响，主要是水电解之后产生的活性氧(ROS)的效应。最常见的活性氧(ROS)包括超氧化物阴离子(O2-)、过氧化氢(H2O2)和羟基自由基(OH-)。ROS在低浓度和中等浓度下对细胞反应和免疫功能表现出有益的作用。然而，在中等浓度以上，这些自由基会破坏身体的抗氧化防御系统，从而导致氧化应激。这些ROS与不同的生物分子，即脂质、DNA和蛋白质反应，并在其中引起氧化损伤，导致生物分子的结构损伤，如DNA的单链断裂(SSBs)或双链断裂(DSBs)以及DNA–DNA或DNA–蛋白质的交联，导致细胞死亡。ROS还可以通过破坏生物分子和激活相关信号通路来增加卵巢颗粒细胞的凋亡。氧自由基有两个不成对的电子，可以迅速添加到许多其他自由基中，进一步增加生物大分子的损伤，产生新的反应性自由基，并促进连锁反应。
在“Oncofertility”具体实践过程中主要包含以下三方面措施，物理防护、生物防护、药物防护。物理防护主要是通过屏障作用来减少放射线引起的损伤，但不能有效避免类似于头颅放疗，通过影响下丘脑-垂体-性腺轴，进而导致卵巢功能障碍，效果不甚理想。近些年来，卵巢移位术的开展为需要接受盆腔放疗的育龄期女性肿瘤患者卵巢功能的保留提供了一个新的选择，但同样面临着一些条件的限制，例如卵巢储备能力差、有卵巢转移的高风险、只单纯进行化疗等。包括胚胎冷冻保存和移植、卵母细胞冻存和移植、卵巢组织冻存和移植及卵巢移植等在内的生物防护是现阶段育龄期女性肿瘤患者生育力保留实践过程中开展最多的项目。但该类防护手段同样面临着诸多的挑战和限制，例如，该类项目在具体实践过程中技术操作的难度较大、开展此类技术的医疗机构较少、社会家庭经济因素以及相关医疗禁忌症等。药物防护手段因其操作过程相对简便，与肿瘤的治疗极少产生冲突，得到了众多学者的关注，并取得一定进展。
在药物防护方面，目前国际上效果最佳的药物为FDA批准的WR-2721，但其在实践过程中被证实毒性较大，副反应较多，一定程度上限制了其的使用。国内目前配备的辐射损伤防治药物包括雌激素类和茜草提取物等，在实践过程中均被证实疗效不佳。近些年来，我国学者在中医药领域开展了多项基础研究结果提示多种中药或汤剂可以减轻辐射诱导的卵巢组织损伤，为减轻卵巢的辐射损伤防护带来了新希望，但均面临着效应不明确、具体机制不清晰、毒副反应较大等多重挑战。因此，亟需开发高效低毒、针对电离辐射作用新靶点的药物。
前期，我们从放疗引起卵巢损伤的具体机制出发，从部分国内外有报道过的抗氧化食品、药品中开展筛选试验并进行配对组合，从而得到了一个较为安全且效果显著的组合：维生素E联合褪黑素组合。据报道，褪黑素可对顺铂诱导的小鼠卵巢损伤发挥改善作用[1]，减小其卵巢早衰风险。维生素E的额外补充可以改善卵巢功能不全妇女的症状，表现为抗缪勒管激素水平及窦状卵泡数目上升[2]。
而目前关于如本发明的褪黑素和维生素E药物组合物及其应用还未见报道。
发明内容
本发明的第一个目的是，针对现有技术中的不足，提供一种药物组合物。
本发明的第二个目的是，提供药物组合物的用途。
为实现上述第一个目的，本发明采取的技术方案是：
一种卵巢抗辐射或治疗卵巢电离辐射损伤的药物组合物，所述的药物组合物由褪黑素和维生素E组成。
作为一个优选例，所述药物组合物给予治疗对象的褪黑素给药浓度为10mg/Kg，所述维生素E的给药浓度为50mg/Kg。
更优选地，所述的药物组合物还包括一种或多种药学上可接受的载体或赋形剂。
更优选地，所述药学上可接受的载体或赋形剂选自溶剂、增溶剂、助溶剂、乳化剂、矫味剂、矫嗅剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、pH调节剂、稳定剂、表面活性剂或防腐剂中的一种或几种。
更优选地，所述剂型为固体制剂、半固体制剂或液体制剂。
更优选地，所述固体制剂包括片剂、胶囊剂、颗粒剂和/或丸剂；所述半固体制剂包括凝胶剂、栓剂和/或膏剂；所述液体制剂包括乳剂、合剂、混悬剂和/或溶液剂。
为实现上述第二个目的，本发明采取的技术方案是：
上述任一所述的药物组合物在制备卵巢抗辐射药物或治疗卵巢电离辐射损伤药物中的应用。
作为一个优选例，所述辐射为γ射线或X射线辐射。
本发明优点在于：
本发明提供了褪黑素和维生素E药物组合的新用途，该药物组合物可以减轻辐射诱导的卵巢组织损伤，为减轻卵巢的辐射损伤防护带来了新希望。
附图说明
附图1为辐照后小鼠卵巢组织器官系数变化(IR+NS：单纯辐照组；IR+Vit E：维生素E给药辐照组；IR+Mel：褪黑素给药辐照组；IR+Vit E+Mel：维生素E+褪黑素给药辐照组)(***：P＜0.001)。
附图2为褪黑素及维生素E给药可有效改善辐照引起的小鼠卵巢激素水平紊乱。(A)小鼠抗缪勒管激素AMH水平；(B)小鼠雌激素E2水平；(C)小鼠卵泡刺激素FSH水平；(D)小鼠黄体生成素LH水平。(IR+NS：单纯辐照组；IR+Vit E：维生素E给药辐照组；IR+Mel：褪黑素给药辐照组；IR+Vit E+Mel：维生素E+褪黑素给药辐照组)(*：P＜0.05，**：P＜0.01，***：P＜0.001)。
附图3为各组小鼠卵泡计数。(A)各组小鼠原始卵泡计数；(B)各组小鼠初级卵泡计数；(C)各组小鼠窦前卵泡计数；(D)各组小鼠窦卵泡计数；(E)各组小鼠闭锁卵泡计数；(F)各组小鼠总卵泡计数。(IR+NS：单纯辐照组；IR+Vit E：维生素E给药辐照组；IR+Mel：褪黑素给药辐照组；IR+Vit E+Mel：维生素E+褪黑素给药辐照组)(*：P<0.05，**：P<0.01，***：P<0.001)。
具体实施方式
下面结合具体实施方式，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
1实验材料：
实验动物：本实验所选用的小鼠遗传背景为：C57BL/6J，购置于上海吉辉实验动物饲养有限公司，周龄为6-8周，养于日夜交替采光、20℃恒温动物房中。
试剂：褪黑素，α-维生素E(MedChemExpress公司)；小鼠雌激素(E2)、黄体生成素(LH)、卵泡刺激素(FSH)及抗缪勒管激素，(AMH)ELISA检测试剂(上海茁彩生物科技有限公司)；苏木素染料，伊红染料，吉姆萨染料(珠海贝索生物技术有限公司)
2实验方法：
(a)实验动物的造模：雌性小鼠分为单纯辐照组及维生素E给药辐照组，褪黑素给药辐照组以及维生素E+褪黑素给药辐照组，所有给药辐照组雌性小鼠在辐照前3周开始腹腔注射褪黑素和/或维生素E(给药浓度：维生素E50mg/Kg，褪黑素10mg/Kg)，在辐照后继续腹腔注射褪黑素和/或维生素E(给药浓度：维生素E 50mg/Kg，褪黑素10mg/Kg)2周，单纯辐照组小鼠腹腔注射同等体积的生理盐水。所有雌性小鼠均接受总剂量2Gy(1Gy/次*2次)的盆腔局部放疗。
(b)实验安排：雌性小鼠32只分为4组，经给药、辐照后进行后续器官系数、卵泡计数、动情周期及卵巢激素水平检测等实验。
(c)动情周期：小鼠辐照+给药均结束后24小时开始，在每天的08:00及20:00，通过检测各组小鼠的阴道脱落细胞形态学变化，从而判断小鼠具体动情周期的阶段，完整评估21天并进行统计学分析。
(d)激素水平：在动情周期评估实验结束之后，将小鼠麻醉后，眼球取血制得血清，并采用ELISA方法检测小鼠的AMH、E2、FSH、LH水平。
(e)器官系数：在麻醉结束后对各组小鼠的体重进行称量，并在眼球取血结束后解剖小鼠双侧卵巢组织进行称重，进行器官系数计算及分析。
(f)卵泡计数：取小鼠的卵巢组织进行石蜡标本制作，并对标本进行及卵泡计数，评估各级卵泡数目及总卵泡数目变化。
3统计分析
采用GraphPad Prism 9.0和SPSS 22.0软件进行分析，所有数据都采用平均值±标准差(Means±SD)来表示。计量资料间的差异性分析采用了不配对的t检验进行，P<0.05被认为在统计学上具有显著性差异。
4实验结果
4.1褪黑素及维生素E给药均对辐照小鼠的动情周期紊乱的影响
褪黑素及维生素E给药均可改善辐照小鼠的动情周期紊乱，且两者连用效果更佳：辐照组及各辐照给药组在三批次实验过程中均有部分小鼠出现了动情周期紊乱，相比于单纯辐照组小鼠有70.83±4.17％的小鼠出现了动情周期紊乱，维生素E给药辐照组及褪黑素给药辐照组小鼠动情周期紊乱率均有所下降，且维生素E及褪黑素联用组的小鼠动情周期紊乱率下降更明显，与单纯辐照组相比，二者在统计学上存在差异，见表1。
表1各组小鼠的动情周期紊乱率
注：(IR+NS：单纯辐照组；IR+Vit E：维生素E给药辐照组；IR+Mel：褪黑素给药辐照组；IR+Vit E+Mel：维生素E+褪黑素给药辐照组)(*：P＜0.05)
4.2褪黑素及维生素E给药对辐照小鼠的卵巢器官系数的影响
褪黑素及维生素E给药均可增加辐照小鼠的卵巢器官系数，且两者连用效果更佳：在卵巢器官系数方面，单纯辐照组小鼠的卵巢器官系数明显减轻，在辐照前后给予小鼠腹腔注射维生素E和/或褪黑素均会一定程度逆转这个趋势，且二者连用效果更佳。与单纯辐照组相比，均具有统计学差异。见图1。
4.3褪黑素及维生素E给药对辐照引起的小鼠卵巢激素水平的影响
褪黑素及维生素E给药均可有效改善辐照引起的小鼠卵巢激素水平紊乱，且二者连用效果更佳：与单纯辐照组相比，在辐照前后给予小鼠应用褪黑素和/或维生素E均会显著升高辐照小鼠的抗缪勒管激素(图2A)及雌激素(图2B)水平，同时可明显降低辐照小鼠的卵泡刺激素(图2C)及黄体生成素(图2D)水平。见图2。
4.4褪黑素及维生素E给药对辐照小鼠卵泡的影响
褪黑素及维生素E给药可以增加各级效应卵泡数量(图3A/B/C/D)，降低闭锁卵泡数量(图3E)，并增加总卵泡数量(图3F)，且二者联用效果更佳。见图3。
参考文献
[1]HUANG J,SHAN W,LI N,et al.Melatonin provides protection againstcisplatin-induced ovarian damage and loss of fertility in mice[J].Reproductive biomedicine online,2021,42(3):505-19.
[2]SAFIYEH F D,MOJGAN M,PARVIZ S,et al.Theeffect of selenium andvitamin E supplementation on anti-Mullerian hormone and antral follicle countin infertile women with occult premature ovarian insufficiency:A randomizedcontrolled clinical trial[J].Complementary therapies in medicine,2021,56(102533.
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (8)
1.一种卵巢抗辐射或治疗卵巢电离辐射损伤的药物组合物，其特征在于，所述的药物组合物由褪黑素和维生素E组成。
2.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物给予治疗对象的褪黑素给药浓度为10mg/Kg，所述维生素E的给药浓度为50mg/Kg。
3.根据权利要求1所述的药物组合物，其特征在于，所述的药物组合物还包括一种或多种药学上可接受的载体或赋形剂。
4.根据权利要求3所述的药物组合物，其特征在于，所述药学上可接受的载体或赋形剂选自溶剂、增溶剂、助溶剂、乳化剂、矫味剂、矫嗅剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、pH调节剂、稳定剂、表面活性剂或防腐剂中的一种或几种。
5.根据权利要求4所述的药物组合物，其特征在于，所述剂型为固体制剂、半固体制剂或液体制剂。
6.根据权利要求5所述的药物组合物，其特征在于，所述固体制剂包括片剂、胶囊剂、颗粒剂和/或丸剂；所述半固体制剂包括凝胶剂、栓剂和/或膏剂；所述液体制剂包括乳剂、合剂、混悬剂和/或溶液剂。
7.权利要求1-6任一所述的药物组合物在制备卵巢抗辐射药物或治疗卵巢电离辐射损伤药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述辐射为γ射线或X射线辐射。
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