CN113730546B - 一种治疗帕金森病的药物组合物及其用途 - Google Patents
一种治疗帕金森病的药物组合物及其用途 Download PDFInfo
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Abstract
本发明提供了一种治疗帕金森的药物组合物及其用途，本发明还提供了一种改善帕金森症状的保健品、食品及其用途。该药物组合物、保健品、食品可以全面改善帕金森的运动及非运动症状。
Description
技术领域
本发明涉及一种治疗帕金森的药物组合物及其用途。
背景技术
帕金森病是第二常见的神经退行性疾病。表现为震颤、肌强直、动作迟缓、姿势平衡障碍的运动症状和睡眠障碍、嗅觉障碍、自主神经功能障碍、认知和精神障碍等非运动症状。流行病学调查研究显示我国65岁以上人群患病率为1.7％，几乎占到全球帕金森病患病人数的一半。目前的治疗以药物和手术为主。
帕金森病早期对药物治疗反应较好，但随着疾病的进展，药物疗效明显减退，常有严重的症状波动如异动症和剂末现象。旨在补充多巴胺的经典用药，并不能完全缓解患者症状，尤其对于步态障碍、姿势平衡障碍、语言和(或)吞咽障碍等轴性症状及非多巴胺能运动症状(如便秘、睡眠障碍、言语、吞咽问题、精神障碍和痴呆)，药物对于这些症状疗效甚微。
近年大量证据表明肠道微生物可能在帕金森病的发病机制中发挥关键作用。有学者提出：帕金森病始于肠道的理论(Gershanik OS.Gershanik.Does Parkinson's diseasestart in the gut？Arq Neuropsiquiatr.2018Feb；76(2):67-70)。因此，基于微生物群的疗法，例如抗生素，益生菌和粪菌移植，可能抑制帕金森病的进展。这一领域的研究已经成为热点。
尽管人们对通过干预肠道微生态来治疗帕金森病抱有很大的期待，但是目前很少使用微生态治疗帕金森的临床及临床前证据。全世界仅仅有一项2019年伊朗的研究，报道随机，双盲，安慰剂对照的临床试验评估帕金森患者对三个月益生菌摄入的运动和代谢反应，为患者提供了含有嗜酸乳杆菌，双歧杆菌，罗伊氏乳杆菌和发酵乳杆菌的胶囊，结果提示对帕金森氏病评分量表(MDS-UPDRS)评分有有利影响，(Omid RezaTamtaji，etal.Clinical and metabolic response to probiotic administration in peoplewith Parkinson's disease:A randomized,double-blind,placebo-controlledtrial.Clinical Nutrition.Volume 38,Issue 3,June 2019,Pages 1031-1035)。与对照组相比，试验组降低MDS-UPDRS为(-4.8±12.5vs.+3.8±13.0,P＝0.01)。该研究证实了补充益生菌可以改善帕金森患者的症状。但是，该研究的标准差太大，影响了试验结果的准确性，且未提及长期疗效，以及对MDS-UPDRS评分量表之外的其它症状如焦虑、抑郁及排便等非运动症状的改善。一个人的肠道菌株有500余种，可能存在更为有效的菌株。我们需要开发更多基于肠道共生菌的、真实有效的微生态治疗方法去治疗帕金森病。
另外，脑血流量(CBF)不足是人类和动物模型中大多数神经退行性疾病的共同早期发现。为了保持神经元在大脑正常工作，需要充足的血液供应，不管是营养物质，还是抗炎物质或代谢废物，均需要通过血管进行运输，因此，改善血液循环成为神经退行性变的基础治疗策略之一。该研究也没有使用改善循环的治疗策略。
发明内容
本发明的目的在于提供一种治疗帕金森的药物组合物及其用途，本发明还提供了一种改善帕金森症状的保健品、食品及其用途。
为实现上述目的，所采取的技术方案：一种治疗帕金森的药物组合物，所述药物组合物包括脆弱拟杆菌BF839、乳酸乳球菌乳亚种AD-839、格氏乳杆菌TTys-839和地龙蛋白。
优选地，每12g药物组合物含106CFU脆弱拟杆菌BF839活菌量、106CFU的乳酸乳球菌乳亚种AD-839活菌量、106CFU的格氏乳杆菌TTys-839活菌量和0.3g的含地龙蛋白。
优选地，所述药物组合物为口服制剂。
本发明提供了上述所述的药物组合物在制备治疗帕金森的药物中的用途。
本发明提供了一种改善帕金森症状的保健品或食品，所述保健品或食品包括脆弱拟杆菌BF839、乳酸乳球菌乳亚种AD-839、格氏乳杆菌TTys-839和地龙蛋白。
优选地，每12g保健品或食品含106CFU脆弱拟杆菌BF839活菌量、106CFU的乳酸乳球菌乳亚种AD-839活菌量、106CFU的格氏乳杆菌TTys-839活菌量和0.3g的地龙蛋白。
优选地，所述保健品或食品为口服制剂。
本发明提供了上述所述的保健品或食品在制备改善帕金森症状的保健品中的用途。
有益效果：
本发明提供了一种治疗帕金森的药物，本发明还提供了一种改善帕金森症状的保健品、食品，该药物组合物、保健品、食品可以全面改善帕金森的运动及非运动症状。
具体实施方式
为更好的说明本发明的目的、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。
本发明将脆弱拟杆菌BF839、乳酸乳球菌乳亚种AD-839、格氏乳杆菌TTys-839和地龙蛋白进行组合，它们协同作用来治疗帕金森病。通过菌群-肠-脑轴的相互作用以及改善脑部循环，能全面改善帕金森病的运动和非运动症状。
脆弱拟杆菌BF839是我公司自主研发的第二代益生菌，是从儿童粪便中分离出的菌株，生理生化鉴定以及动物毒力试验的研究结果认定该细菌是一株无毒的脆弱拟杆菌，1997年被国家批准为新资源食品，由其发酵制得的图腾益生液，填补了拟杆菌作为益生菌的空白，具有增强免疫、预防肠道和呼吸道疾病、促进儿童身体生长发育等功效。
乳酸乳球菌乳亚种是公认安全的食品级微生物[Camperio C,Armas F,Biasibetti E,et al.A mouse mastitis model to study the effects of theintramammary infusion of a food-grade Lactococcus lactis strain[J].PloS One,2017,12(9):e0184218..]，也属于2010年我国卫生部批准了可用于食品的益生菌种中的一种，乳酸乳球菌乳亚种AD-839是我公司健康人肠道中筛选、分离出一株乳酸乳球菌乳亚种(Lactococcus lactis subsp.Lactis)菌株，它保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.22117，分类命名为AD-839。其可将大分子营养物质降解成易被人体消化吸收的小分子营养物质，同时产生的乳酸等还可抑制有害菌生长。
格氏乳杆菌(Lactobacillus gasseri)属于2010年我国卫生部批准了可用于食品的益生菌种中的一种，它是一种普遍存在的人体共生细菌，广泛存在于正常人的口腔、小肠、大肠、阴道粘膜上，该微生物已在健康的人类中确立了安全性(Kurt Selle,ToddR.Klaenhamme，Genomic and phenotypic evidence for probiotic influences ofLactobacillus gasseri on human health.FEMS Microbiology Reviews,Volume 37,Issue 6,November 2013,Pages 915–935)。亦是美国食品药品监督管理局(FDA)表列安全菌种之一。经研究发现：它能够维持人类肠道稳态、维护阴道健康、预防过敏反应、抑制幽门螺旋杆菌感染、减轻病毒感染引起的症状(Kurt Selle,Todd R.Klaenhamme，Genomic andphenotypic evidence for probiotic influences of Lactobacillus gasseri onhuman health.FEMS Microbiology Reviews,Volume 37,Issue 6,November 2013,Pages915–935)。格氏乳杆菌TTys-839是我公司从健康人体肠道菌群中筛选、分离出一株格氏乳杆菌(Lactobacillus garvieae)菌株，保藏于中国微生物菌种保藏管理委员会普通微生物中心，保藏编号为CGMCC No.20178。分类命名为TTys-839，经研究具有增强细胞免疫和体液免疫功能，保护胃黏膜、降低溃疡面积与溃疡体积的作用(专利申请号：202110288581.3；202110315930.6)。
地龙蛋白是从蚯蚓中提取的新资源食品，含有胶原酶、纤溶酶、蚓激酶、核酸、微量元素等多种成分。它对体内的凝血系统和纤溶系统具有广泛的影响，既可明显降低大鼠血小板黏附率，延长体内血栓形成和溶解体内血栓，又能增加大鼠脑血流量，减少脑血管阻力。地龙提取物还能提高小鼠红细胞变形能力，改善血液流变性和微循环障碍[王春玲.中药地龙的活性成分及药理作用研究[J].亚太传统医药，2015，11(7):53－54]。服用地龙蛋白一个月前后对比，在显微镜下观察，会发现被观察者指端微循环有明显变化，微循环弯曲度得到良好改善，微循环淤堵状况消失[吕中明，胡启之，李贵山，等.蚯蚓提取物对微循环障碍形成的保护作用.中国生化药物杂志，2003，24(2):61－64]。地龙蛋白作为一种优质蛋白，可以为人们所食用。卫生部于2009年12月22日，根据《中华人民共和国食品安全法》和《新资源食品管理办法》的规定，批准了地龙蛋白为新资源食品。目前现在市场的溶栓防栓保健品，也多有应用地龙蛋白作为主原料。因此，它是安全、可靠的。
该合剂不仅对帕金森病有明显的疗效，还可长期安全使用，较药物治疗有明显的优势。
益生菌“脆弱拟杆菌BF839、乳酸乳球菌乳亚种AD-839、格氏乳杆菌TTys-839和地龙蛋白”合剂治疗帕金森病的临床试验结果。
(一)入组标准
年龄：年满≥6周岁，≤80周岁；
根据临床症状和帕金森统一量表评分量表符合帕金森病诊断的患者；
患者进食未明显受疾病影响，可自主进食。
(二)排除标准：
在一月内接受了其它临床试验；
无法自主进食的情况；
患有严重的心、肝、肾功能不全、病情危重的患者；
肿瘤患者；
怀孕或哺乳。
(三)试验方案
试验用品为“脆弱拟杆菌BF839、乳酸乳球菌乳亚种AD-839、格氏乳杆菌TTys-839和地龙蛋白”的合剂，每天2次，每次一包(一包为12g,，含106CFU的脆弱拟杆菌BF839活菌量，106CFU的乳酸乳球菌乳亚种AD-839活菌量、106CFU的格氏乳杆菌TTys-839活菌量和0.3g的地龙蛋白)用温开水冲服。该合剂中的脆弱拟杆菌Bf839(图腾益生液)、格氏乳杆菌TTys-839和乳酸乳球菌乳亚种AD-839的菌液经冷冻干燥技术处理成冻干粉剂；地龙蛋白是以蚯蚓洗净，胶体磨粉碎，匀浆，离心，上清液，冷冻干燥成冻干粉剂。将它们混合成合剂。
实验组：常规治疗+试验用品10例；
对照组：常规治疗10例；
观察周期：3个月；
比较两组临床症状、帕金森量表UPDRS评分的改变，MMSE，汉密顿抑郁量表、焦虑量表评分)，以及安全性。
结果：
(一)疗效：与对照组相比，试验组降低了MDS-UPDRS(-6.5±3.81vs.-0.75±3.43,P＝0.009)。此外，对精神和情绪方面也有较大的改善。与对照组相比，实验组降低了HAMD汉密尔顿抑郁量表评分(-4.4±4.08vs.2.83±4.79,P＝0.013)；与对照组相比，实验组降低了SAS焦虑自评量表评分(-8.8±6.42vs.-1.83±2.78,P＝0.01)这一疗效，明显高于上述研究报道的结果。该疗法可以全面改善帕金森的运动及非运动症状。
(二)不良反应：
随访3月，仅有一例患者出现轻度荨麻疹，经停用后自行消失后缓解。
本发明是世界第一次采用脆弱拟杆菌BF839、乳酸乳球菌乳亚种AD-839、格氏乳杆菌TTys-839、地龙蛋白的合剂治疗帕金森取得成功的范例，具有高效、安全的特点。
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 (7)
1.一种治疗帕金森的药物组合物，其特征在于，所述药物组合物包括脆弱拟杆菌BF839、乳酸乳球菌乳亚种AD-839、格氏乳杆菌TTys-839和地龙蛋白；
每12g药物组合物含106CFU的脆弱拟杆菌BF839活菌量、106CFU的乳酸乳球菌乳亚种AD-839活菌量、106CFU的格氏乳杆菌TTys-839活菌量和0.3g的地龙蛋白。
2.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物为口服制剂。
3.如权利要求1-2任一所述的药物组合物在制备治疗帕金森的药物中的用途。
4.一种保健品，其特征在于，所述保健品包括脆弱拟杆菌BF839、乳酸乳球菌乳亚种AD-839、格氏乳杆菌TTys-839和地龙蛋白；
每12g保健品含106CFU的脆弱拟杆菌BF839活菌量、106CFU的乳酸乳球菌乳亚种AD-839活菌量、106CFU的格氏乳杆菌TTys-839活菌量和0.3g的地龙蛋白。
5.一种食品，其特征在于，所述食品包括脆弱拟杆菌BF839、乳酸乳球菌乳亚种AD-839、格氏乳杆菌TTys-839和地龙蛋白；
每12g食品含106CFU的脆弱拟杆菌BF839活菌量、106CFU的乳酸乳球菌乳亚种AD-839活菌量、106CFU的格氏乳杆菌TTys-839活菌量和0.3g的地龙蛋白。
6.根据权利要求4所述的保健品，其特征在于，所述保健品为口服制剂。
7.根据权利要求5所述的食品，其特征在于，所述食品为口服制剂。
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