CN104490873A - 一种治疗儿童结节性硬化症的药物 - Google Patents
一种治疗儿童结节性硬化症的药物 Download PDFInfo
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Abstract
本发明涉及医药领域，具体公开了一种治疗儿童结节性硬化症的药物，所述药物包含雷帕霉素，所述儿童结节性硬化症包括儿童结节性硬化症合并难治性癫痫、儿童结节性硬化症合并心脏横纹肌瘤、儿童结节性硬化症合并色素脱失斑、儿童结节性硬化症合并面部皮脂腺瘤和儿童结节性硬化症合并肾脏血管平滑肌脂肪瘤。所述药物的使用方法，其中，雷帕霉素的起始剂量为1mg/(m2·d)，并维持血药浓度为5-10ng/mL。
Description
技术领域
本发明涉及医药领域，具体涉及一种治疗儿童结节性硬化症的药物。
背景技术
结节性硬化症(tuberous sclerosis complex，TSC)是一种常染色体显性遗传病，发病率约为1:6000,男女之比大约为1.44:1，多见于儿童，致病基因分别为TSC1和TSC2，国内外多项较大样本研究均显示在非选择性TSC入组病例中，致病突变检出率在69％-89％。患儿临床上常表现为多个器官受累(如皮肤,脑，眼，肾，肝和心脏等)，以面部血管纤维瘤、癫痫发作和智能减退为主要临床特征。
结节性硬化症神经系统合并症是患儿最常见的死亡和致残原因，44％的患儿精神运动发育障碍，30％的病例IQ低于21。其中癫痫发作是患儿就诊的主要原因。80％～90％的结节性硬化症的患者可以合并癫痫发作，多在儿童期早期或婴儿期发病。目前无特殊治疗，有惊厥者可用抗癫痫药物治疗，脑电图呈高度失律者可用促肾上腺皮质激素(ACTH)，手术切除有病变的大脑皮质及皮质下结节，可使癫痫停止，但仅适用于单个病灶且智力较好者。结节性硬化症患儿的癫痫，由于病灶不断进展，所以往往发展成为难治性癫痫。但是目前对于结节性硬化的皮肤病变、肾脏囊肿、血管肌脂瘤以及神经系统合并症(如难治性癫痫、皮质发育不良、室管膜下结节、室管膜下巨细胞型星形细胞瘤)，除了对症治疗、必要时手术切除外，并没有针对病因的治疗。
TSC1和TSC2基因分别编码错构瘤蛋白和马铃薯球蛋白，这两种蛋白抑制mTOR激活，TSC1和TSC2基因突变破坏这种抑制功能，导致mTOR过度激活。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是一种丝/苏氨酸蛋白激酶，在细胞生长、增殖、分化、细胞周期调控等多个方面起到重要作用。mTOR信号通路是调控细胞生长增殖和蛋白质合成的重要信号通路。mTOR激酶是该信号通路中的关键分子，受控于蛋白激酶P13K和Akt；如果解除TSC1/TSC2复合体活性对mTOR的抑制，就会激活mTOR以及下游的S6K激酶，使核糖体蛋白S6磷酸化，导致蛋白质合成和细胞增殖分化；这是TSC发生发展的主要致病机制。在神经系统，mTOR信号通路调节神经元发育和突触可塑性。
雷帕霉素(又称西罗莫司)为mTOR特异性抑制剂，是新型大环内酯的抗排斥药物，是目前世界上最新的强效免疫抑制剂，临床上用于器官移植的抗排斥反应和自身免疫性疾病的治疗，儿童用药安全可靠。
发明内容
针对现有技术中存在的问题，本发明的目的是提供一种治疗儿童结节性硬化症的药物。
为达到上述目的，本发明的技术方案是这样实现的。
(1)一种治疗儿童结节性硬化症的药物，其特征在于，所述药物包含雷帕霉素。
(2)雷帕霉素在治疗儿童结节性硬化症的药物中的用途，所述儿童结节性硬化症包括儿童结节性硬化症合并难治性癫痫、儿童结节性硬化症合并心脏横纹肌瘤、儿童结节性硬化症合并色素脱失斑、儿童结节性硬化症合并面部皮脂腺瘤和儿童结节性硬化症合并肾脏血管平滑肌脂肪瘤。
(3)包含有雷帕霉素的所述治疗儿童结节性硬化症的药物的使用方法，其中，所述雷帕霉素的起始剂量为1mg/(m2·d)，并维持血药浓度为5-10ng/mL。
雷帕霉素(又称西罗莫司)为mTOR特异性抑制剂，是新型大环内酯的抗排斥药物，是目前世界上最新的强效免疫抑制剂，临床上用于器官移植的抗排斥反应和自身免疫性疾病的治疗。但是，研究发现在结节性硬化病、局灶性皮质发育异常、胶质细胞瘤和大脑半球增大症等几种疾病中mTOR信号通路均被异常激活，而这几种疾病均与癫痫高度相关，提示mTOR信号通路参与了癫痫的发生，并证明mTOR信号通路是连接TSC1/TSC2基因突变与结节性硬化症表型的主要桥梁。
本发明通过大量临床实验发现：患有结节性硬化症的儿童服用雷帕霉素，所有的临床症状均改善，且监护人对患者的总体改善和耐受性评价良好。
具体实施方式
下面结合具体实施例对本发明做进一步详细说明，但本发明不限于这些实施例。
实施例：利用雷帕霉素治疗儿童结节性硬化症的临床研究
本项临床研究是开放性、前瞻性、自身对照的研究。
具体研究方法及观察结果如下：
(1)病例选择
在解放军总医院门诊及病房选择具有完整资料的TSC合并难治性癫痫患儿，纳入标准：年龄14岁以下，男女不限；TSC诊断标准按照美国国立TSC协会诊断标准委员会1998年修订的结节性硬化症诊断标准；入组前每月癫痫发作次数≥4次，使用抗癫痫药物治疗无效的患儿；已经阅读受试者须知，监护人同意并签署书面知情同意书；最少完成24周的治疗和随访。
排除标准：目前正参加其他临床研究或在近1个月内参加过其他临床研究的患者；除TSC以外患有严重的肝肾疾病、血液系统疾病、自身免疫性疾病或其他慢性严重感染性疾病等。
根据纳入标准和排除标准共入组52例结节性硬化症合并难治性癫痫患儿，完成至少24周随访。其中男34例，女18例，患儿发病年龄中位数为4.8个月(4天-49月)，就诊年龄中位数24个月(4-170月)。
本项研究中，52例患儿中有10例有TSC家族史，2例有癫痫家族史。入组前10例患儿服用5种抗癫痫药物，7例患儿服用4种抗癫痫药物，14例患儿服用3种抗癫痫药物，15例患儿服用2种抗癫痫药物，6例患儿服用1种抗癫痫药物。入组患儿最常服用的3种抗癫痫药物依次为：托吡酯(29％)、丙戊酸钠(24％)和氨己烯酸(9％)。24例患儿进行了TSC基因检测，4例为TSC1突变，20例为TSC2突变。TSC的其他表型特征情况为，皮肤表现：色素脱失斑(48/52例)、面部血管纤维瘤(7/52)、鲨鱼皮样斑(2/52)；神经系统表现：皮质结节(50/52)、室管膜下结节(51/52)、SEGA(1/52)；肾脏表现：肾血管平滑肌脂肪瘤(1/40)、肾囊肿/多囊肾(5/40)；心脏表现：心脏横纹肌瘤(14/40)。本项研究52例患儿中，其中31例病程中曾诊断或目前被诊断为婴儿痉挛症(59.6％)。入组患者发作类型依次表现为痉挛发作23例(诊断婴儿痉挛症)，部分性发作22例(其中部分性发作泛化2例，复杂部分性发作5例)，痉挛发作3例，强直发作3例，1例表现为痉挛、强直和不典型失神发作(诊断Lennox-Gastaut综合征)。
(2)治疗方法
入组患者在使用原抗癫痫药物的基础上加用雷帕霉素(商品名：赛莫司，规格50mg/50mL，上市批准文号：国药准字H20051081，杭州中美华东制药有限公司)，口服，每日一次。患者连续服药24-96周。起始剂量1mg/(m2·d)，逐渐滴定到血药浓度达到5-10ng/mL，体表面积计算方法如下：
体重≤30kg体重(kg)×0.0375+0.1
体重＞30kg[体重(kg)-30]×0.02+1.05
(3)观察指标
在入组(0周)及12周、24周、36周和48周随访时，记录两次随访之间癫痫发作次数和发作时间(对成串痉挛以痉挛的次数为准)，并观察毒副作用，记录出现的不良事件以及监护人对患者总体改善和耐受性的评价。用药前及用药后每3个月查血常规、肝肾功能、雷帕霉素血药浓度、脑电图(视频或动态)及头颅MRI，随访至少24周。
(4)疗效评估：
主要指标：儿童结节性硬化症中难治性癫痫的改善
①抗癫痫疗效判断：
计算患者治疗前后的癫痫发作下降百分率：
根据癫痫发作下降百分率值按5级疗效划分对总体疗效进行评价。完全控制：100％，显效：≥75％且＜100％，有效：≥50％且＜75％，无效：≥0且＜50％，加重＜0。前三者为有效，总有效率＝完全控制率+显效率+有效率。
②脑电图评定：根据治疗后脑电图的表现分为：A.正常：痫样放电完全消失；B.明显好转：减少50％以上；C.好转：减少25-49％；D.无变化；E.痫样放电增加。
次要指标：结节性硬化症伴随的其他症状的改善
①色素脱失斑和/或面部皮脂腺瘤的改善程度
疗效判断标准：明显好转，为面积减少50％以上；好转，为面积减少25-49％；无变化，为面积减少0-25％。
②心脏横纹肌瘤改善程度
疗效判断标准:明显好转，为体积减少50％以上；好转，为体积减少25-49％；无变化，为体积减少0-25％。
③肾脏血管平滑肌脂肪瘤
疗效判断标准:明显好转，为体积减少50％以上；好转，为体积减少25-49％；无变化，为体积减少0-25％。
④对总体改善和耐受性的评价：通过患者监护人对患者总体改善和耐受性的观察结果，分为非常满意、比较满意、一般、不太满意、很不满意五个等级。
所有数据分析采用SPSS18.0统计软件包对数据进行分析，符合正态分布的计量资料以(x±s)表示。Kolmogorov-Smirnov检验数据的正态性，等级资料间的相关应用Spearman相关(性别、发病年龄、病程不服从正态分布)，不同随访时间点有效率的比较采用Friedman检验，P＜0.05为差异有统计学意义。
(5)研究结果
主要指标：儿童结节性硬化症中难治性癫痫的控制情况
①抗癫痫疗效：抗癫痫疗效评估数据见表1。至治疗后24周，48周、72周和96周随访，总有效率分别为73％、74％、76％和74％。24周，48周、72周和96周随访时，总有效率与治疗前均有显著性差异(P<0.01)。
利用雷帕霉素治疗前，患儿平均发作次数70.27次/d,平均使用抗癫痫药物种类1.30种；治疗半年、1年、2年时，患儿平均发作次数1.94-2.8次/d，平均使用抗癫痫药物种类0.83-0.97种；随着病人发作次数的减少，病人使用的抗癫痫药物种类也同时减少。
表1抗癫痫疗效评估
对52例入组患者中的23例结节性硬化症合并婴儿痉挛的患者进行亚组分析。23例结节性硬化症合并婴儿痉挛患者的基本情况见表2。
表2儿童结节性硬化症合并婴儿痉挛患儿服用雷帕霉素前一般发病特点
对23例结节性硬化症合并婴儿痉挛患者全部完成24周随访，其中13例完成48周随访，7例完成72周随访，5例完成96周随访。统计23例患儿服用雷帕霉素治疗前以及治疗后12周、24周癫痫发作频率以及抗癫痫药物(AEDs)种类。结果显示，治疗后发作频率以及AEDs种类较用药前明显减少(p<0.01)。治疗后发作频率结果见表3，AEDs种类见表4，疗效评估见表5。
表3结节性硬化症合并婴儿痉挛的患儿服用雷帕霉素治疗前后癫痫发作控制的比较
表4结节性硬化症合并婴儿痉挛的患儿服用雷帕霉素后服用抗癫痫药物(AEDs)种类的比较
表5结节性硬化症合并婴儿痉挛的患儿雷帕霉素治疗前后不同随访时间疗效评估
结果显示，雷帕霉素对于儿童结节性硬化症合并婴儿痉挛的患者有积极的治疗作用。在服用雷帕霉素后，儿童结节性硬化症合并婴儿痉挛的患者的难治性癫痫发作频率显著降低，且使用的抗癫痫药物种类也显著减少。
②脑电图评估：以治疗24周为时间点，8例痫样放电完全消失，22例脑电图明显好转，8例好转，14例脑电图无变化。
高峰失律是婴儿痉挛的特征性脑电图表现。入组时发作类型为婴儿痉挛的23例患儿均表现为高峰失律。到治疗24周时，14例患儿脑电图高峰失律消失，其中3例患儿脑电图未见异常。
次要指标：儿童结节性硬化症伴随的其他症状的改善
本研究中，16例伴有心脏横纹肌肉瘤的病人，12例好转，其中1例肿物完全消失，11例肿物缩小。10例患者伴有肾脏血管平滑肌脂肪瘤，8例均好转(3例肿物消失，5例肿物缩小)，2例肿物进展。1例患者有眼底错构瘤，1例患者有鼻咽部肿物，经治疗后均有好转。结果见表6。
表6结节性硬化症伴其他症状的改善情况
③对总体改善和耐受性的评价：对完成雷帕霉素治疗48周以上的31例患儿监护人进行电话随访，总结雷帕霉素对患儿的总体改善情况及耐受性的评价，得到反馈如下：12例(38.7％)患儿监护人对雷帕霉素治疗非常满意，17例(54.84％)患儿监护人对雷帕霉素治疗比较满意，2例(6.45％)患儿监护人认为雷帕霉素治疗一般。
(6)不良反应
入组患儿在服用雷帕霉素前完成了血常规、肝肾功能和血脂检测，并于服药后定期复查，患儿血常规、肝肾功能无明显异常。雷帕霉素血浓度维持在10ng/mL以下(平均6.5ng/mL)。
服用雷帕霉素的患儿，23％(12/52例)出现一过性口腔溃疡，口腔溃疡持续2-3天自行消失。17.2％(9/52例)出现上呼吸道感染。1例患儿服雷帕霉素3个月时出现双下肢水肿，停药后水肿消退，但发作增多，且认知倒退，家长再次给患儿服用雷帕霉素，服药4个月后患儿双下肢再次出现水肿，停药后消退。
(7)研究结论
患有结节性硬化症的儿童口服雷帕霉素，每日一次，起始剂量1mg/(m2·d)，维持血药浓度为5-10ng/mL，有效，安全。接受52例雷帕霉素治疗的患儿所有的临床症状均改善。特别是结节性硬化症合并难治性癫痫病人，其发作较入组前明显改善；特别是16例伴有心脏横纹肌肉瘤的病人，12例好转(其中1例肿物完全消失，11例肿物缩小)。10例患者伴有肾脏血管平滑肌脂肪瘤，其中8人好转(3例肿物消失，5例肿物缩小)，2例肿物进展。1例有眼底错构瘤，1例有鼻咽部肿物，经治疗后均有好转。
治疗效果稳定，在研究设定的剂量范围内患儿对于雷帕霉素治疗的耐受性好。
本发明的治疗儿童结节性硬化症合的药物包含有雷帕霉素，该药物由雷帕霉素与药学上可接受的载体和赋形剂一起可以制成本领域公知的常见药物剂型，如口服液、胶囊、片剂、颗粒剂或丸剂。
尽管以上对本发明的实施方案进行了描述，但本发明并不局限于上述的具体实施方案，上述的具体实施方案仅仅是示意性的、指导性的，而不是限制性的。本领域的普通技术人员在本说明书的启示下，在不脱离本发明权利要求所保护的范围的情况下，还可以做出很多种的形式，这些均属于本发明保护之列。
Claims (4)
1.一种治疗儿童结节性硬化症的药物，其特征在于，所述药物包含雷帕霉素。
2.根据权利要求1所述的治疗儿童结节性硬化症的药物，其特征在于，所述儿童结节性硬化症包括儿童结节性硬化症合并难治性癫痫、儿童结节性硬化症合并心脏横纹肌瘤、儿童结节性硬化症合并色素脱失斑、儿童结节性硬化症合并面部皮脂腺瘤和儿童结节性硬化症合并肾脏血管平滑肌脂肪瘤。
3.根据权利要求1所述的治疗儿童结节性硬化症的药物的使用方法，其特征在于，所述雷帕霉素的起始剂量为1mg/(m2·d)，并维持血药浓度为5-10ng/mL。
4.雷帕霉素在治疗儿童结节性硬化症的药物中的用途。
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