CN111054226A - 用于治疗不宁腿综合征的膜和装置 - Google Patents
用于治疗不宁腿综合征的膜和装置 Download PDFInfo
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- CN111054226A CN111054226A CN201910967402.1A CN201910967402A CN111054226A CN 111054226 A CN111054226 A CN 111054226A CN 201910967402 A CN201910967402 A CN 201910967402A CN 111054226 A CN111054226 A CN 111054226A
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Abstract
本公开涉及一种用于尤其是在重度和极重度的情况下和/或在患有肾衰竭并且已经接受血液透析的患者中治疗不宁腿综合征(RLS)的血液透析膜。因此,本公开还涉及治疗不宁腿综合征的方法。所述治疗和方法包括使用血液透析膜,该血液透析膜的特征在于其包含至少一种疏水性聚合物和至少一种亲水性聚合物,并且其具有8.5至14.0kD的MWRO和55kD至130kD的MWCO。
Description
技术领域
本公开涉及一种用于尤其是在重度和极重度的情况下和/或在患有肾衰竭并且已经接受血液透析的患者中治疗不宁腿综合征(restless leg syndrome,RLS)的血液透析膜。因此,本公开还涉及治疗不宁腿综合征的方法。所述治疗和方法包括使用血液透析膜,该血液透析膜的特征在于其包含至少一种疏水性聚合物和至少一种亲水性聚合物,并且其具有8.5至14.0kD的MWRO和55kD至130kD的MWCO。
背景技术
不宁腿综合征(RLS),也称为Willis-Ekbom病,导致腿部不适或不舒服的感觉,并产生无法抗拒的移动腿的冲动。症状通常发生在午后或傍晚,常常在晚上人休息时最为严重。由于症状会在夜间增加并且变得更严重,因此相关人员可能难以入睡或难以醒来后再入睡。移动腿或行走通常缓解不适感,但是一旦运动停止,感觉常常会复发(Ohayon etal.:Epidemiology of Restless Legs Syndrome:A Synthesis of theLiterature.Sleep Med Rev.16(4),2012:283-95)。RLS被归类为睡眠障碍,因为症状是由休息和试图入睡触发的,以及被归类为运动障碍,因为人们被迫移动其双腿以缓解症状。然而,其最适合被表征为神经感觉运动疾病,但其病理生理学途径仍是未知的。症状在频率和严重程度方面变化很大,频率从一月或一年不足一次到每天一次,严重程度从轻度烦恼到致残。RLS是能够导致严重疲惫和白天嗜睡的几种病症之一。因此,它能强烈影响情绪、注意力、记忆力以及生活和健康的总体质量。患有RLS的患者通常不能集中注意力,记忆力受损或无法完成日常任务。未经治疗的中度至重度RLS能导致一般生产力降低约20%,并能严重导致抑郁和焦虑。超过80%的患有RLS的人还会经历睡眠周期性肢体运动(periodic limbmovement of sleep,PLMS)。PLMS的特征在于睡眠期间不自主的腿部(有时是手臂)抽搐或痉挛动作,通常每15到40秒发生一次,有时是整夜。尽管许多具有RLS的个体也发展了PLMS,但是大多数具有PLMS的人并没有经历RLS。
通过确定符合以下五个必备标准的症状模式,并在适当时加上临床分类(clinical specifiers),来诊断RLS/WED(Allen et al.:Restless legs syndrome/Willis–Ekbom disease diagnostic criteria:updated International Restless LegsSyndrome Study Group(IRLSSG)consensus criteria–history,rationale,description,and significance.Sleep Medicine 15(8),2014:860-873)。必备诊断标准(必须满足所有标准)是:
1.一种移动腿的冲动,通常但不是总是伴随腿部不舒服和不适的感觉或者感觉是由腿部不舒服和不适的感觉引起的。
2.在休息或不活动(如躺下或坐着)的过程中,移动腿的冲动或任何伴随的不适感觉开始或加重。
3.至少在活动持续期间,通过运动(如步行或伸展)部分地或完全地消除移动腿的冲动和任何伴随的不适感觉。
4.在休息或不活动期间移动腿的冲动以及任何伴随的不适感觉仅在晚上或夜间发生,或者比白天加重。
5.上述特征的出现不能单独解释为另一种医学或行为状况的主要症状(例如肌痛、静脉淤滞、腿水肿、关节炎、腿抽筋、体位不适、习惯性抖腿)。
RLS/WED临床病程的分类:
A.慢性持续性RLS/WED:最近一年内,如果未经治疗,症状出现的频率为平均每周至少两次。
B.间歇性RLS/WED:最近一年内,如果未经治疗,症状出现的频率为平均每周少于2次,并且具有至少五次终身事件(at least five lifetime event)。
根据国际不宁腿综合征研究组(International Restless Legs Syndrome StudyGroup,IRLS)评分量表,RLS的严重程度可分为轻度、中度、重度或极重度,尽管也可以使用其他方法,如RLS-6量表(Kohnen et al.:Rating of daytime and nighttime symptomsin RLS:validation of the RLS-6scale of restless legs syndrome/Willis–Ekbomdisease.Sleep Medicine 20,2016:116-122)。IRLS是使用最广泛的评定RLS/WED严重程度的量表。它已被充分验证,并且是大多数RLS/WED治疗性和非治疗性研究的主要终点。它基于心理测量特性。IRLS得分为11-20表示中度RLS,21-30表示重度RLS,31-40表示极重度RLS。透析患者的总体健康状况和生活质量也可以用KDQOLTM-36调查(由RAND和亚利桑那大学的Kidney Disease and Quality of LifeTM(KDQOLTM-36),2000)进行评估,该调查将要求患者回答有关总体健康、患者感觉如何和他们的背景等问题。KDQOLTM-36有助于评价患者对其护理的感觉如何,并进一步了解医疗护理对患者健康的作用。
例如,在白种人中,RLS的估计患病率为约7-10%(Ohayon et al.,Sleep MedRev.16(4),2012:283-95)。男性和女性都会发生RLS,但是女性比男性更容易患RLS。它可以在任何年龄开始。许多受到严重影响的个体是中年人或更老的人,症状通常随着年龄的增长而变得更加频繁并且持续更长时间。尽管有越来越多的证据指向多巴胺能和脑-铁失调以及遗传组分,但RLS的病理生理学仍不清楚。RLS的病因另外可分为原发性或继发性(Sinclair et al.:“Interventions for chronic kidney disease-associatedrestless legs syndrome”.International Journal of Evidence-Based Healthcare 16(3),2018:182–184)。原发性RLS是特发性的,原因未知,但似乎与遗传风险因素有关。继发性RLS与某些临床状况(如周围神经病变、铁缺乏症、2型糖尿病、帕金森氏病和多发性硬化症)相关。
约12%至25%的终末期肾病(ESRD)患者也受到RLS的影响(Araujo et al.:Restless legs syndrome in end-stage renal disease:Clinical characteristicsand associated comorbidities.Sleep Medicine 11(8),2010:785-790和Ricardo etal.:Association of Sleep Duration,Symptoms,and Disorders With Mortality inAdults With Chronic Kidney Disease.Kidney International Reports 2,2017,866-873)。
当前用于RLS的药物治疗方法大体上取决于个人和RLS的怀疑病因,但可能包括补充铁;α2激动剂,具体是在原发性RLS的情况下;布洛芬(ibuprofen),一种非甾体抗炎药(NSAID),在轻度症状的情况下;抗惊厥药,如纽诺汀或加巴喷丁(neurontin或gabapentin);苯二氮卓类药物,在持续性和轻度症状的情况下,包括例如替马西泮(Restoril或temazepam)、赞安诺或阿普唑仑(Xanax或alprazolam)以及氯硝安定(Klonopin或clonazepam);提高大脑中神经递质多巴胺的水平从而解决与RLS相关的腿部不适感觉的多巴胺能药物,例如左旋多巴(Levodopa)和卡比多巴(carbidopa);以及可以在其他药物不起作用时使用的阿片类药物,如可待因(codeine)和丙氧芬(propoxyphene)(低剂量阿片类药物),盐酸羟考酮(oxycodone hydrochloride)、盐酸美沙酮(methadonehydrochloride)和酒石酸左啡诺(levorphanol tartrate)(高剂量阿片类药物)。
多巴胺激动剂,如罗匹尼罗(ropinirole)和左旋多巴,也会提高脑部多巴胺水平并治疗腿部不适感觉,但可能引起不良反应,尤其是在老年患者中。此外,在慢性肾病患者中尚未确定这些治疗的有效性(Sinclair et al.,2018)。罗替戈汀(Rotigotine)用于与血液透析相关的不宁腿综合征,并取得了一些成功(Dauvilliers et al.:Rotigotine inHemodialysis-Associated Restless Legs Syndrome:A Randomized Controlled Trial:Am J Kidney Dis.68(3),2016:434-443)。
因此,非常需要对RLS起作用的新方法,特别是在重度或极重度的情况下。
尤其是但不仅是在已经接受血液透析治疗的终末期肾病患者中,适当地进行血液透析用于治疗或改善RLS,将具有有用且直接解决RLS的可能性。然而,这需要血液透析滤器或透析器,其可以显着改善RLS。当前尚无有记载的或已知的此类能改善相关患者的RLS的透析器。相比之下,接受血液透析的终末期肾病患者常常受到RLS的困扰。还不了解该疗法中使用的血液透析和各自的血液透析器如何影响RLS的出现或持续,或它们如何能有助于改善患者的RLS。但是,如果通过使用适当的透析器可以减少或避免RLS的发生,它将明显有助于改善尤其是血液透析患者的生活质量。尤其是在根据IRLS得分评定为RLS重度或极重度的情况下,其中药物治疗没有显示出任何明显的作用或伴有无法忍受的副作用,对于患有另一种继发性RLS(例如多发性硬化症或帕金森氏病)或者患有原发性RLS的非肾脏患者,也可以选择定期或间歇性血液透析。
通常,透析膜设计成实现从患有慢性肾衰竭的患者的血液中去除尿毒症毒素和过量的水,同时用透析液平衡血液中的电解质含量。膜的筛分性能,即其对溶质的渗透性,是由孔径决定的,并设置了可随流体流被拉动通过膜的溶质的最大尺寸。给定物质的筛分系数可以简单地描述为滤液中的物质浓度与其在进料(即血液或血浆)中的浓度之间的比值,因此为0至1之间的值。假设溶质的尺寸与其分子量成比例,则说明膜特性的常见方式是建立筛分曲线,该筛分曲线描绘为随分子量变化的筛分系数。截留分子量(molecular weightcut-off,MWCO)定义为筛分系数为0.1时的分子量(图1)。针对多分散右旋糖酐混合物确定的筛分曲线可被视为膜的标准表征技术。常规的透析膜根据其渗透性分为低通量或高通量。在某些市场上也可获得第三类,称为蛋白质泄漏膜。这三种膜类型记载在以下综述中:Ward(2005),J Am Soc Nephrol 16:2421-2430。不久前出现的第四种类型是上述高截留或HCO膜,其具有非常特殊的特性(Boschetti-de-Fierro et al.(2013):“Extendedcharacterization of a new class of membranes for blood purification:The highcut-off membranes”,Int J Artif Organs 36(7),455-463)。在Boschetti-de-Fierro等人中示出了所述膜的一般分类和性能的简要概述,在本文中根据Boschetti-de-Fierro等人(2013)中给出的定义使用此类膜和/或透析器的相应表述(“低通量”或“高通量”(HF)、“高截留(HCO)”和“蛋白质泄漏”)。最新的膜开发步骤是定位在高通量膜和高截留膜之间的空白的一种膜类型。所述膜也称为“中截留”膜(也参见表I)。这些膜及其制备方法详细记载在PCT/EP2015/052365中。基于此类膜的血液透析器详细记载在PCT/EP2015/052364中。(Baxter)是透析器的一个实例,其同时是可商购的,并且符合中截留透析器关于如本文中进一步定义的MWRO和MWCO的标准。
上述膜类型之间最明显的区别是它们在分子量轴上的位置(图2)。高通量膜的筛分曲线反映了它们去除小分子量毒素(如尿素)的能力。它们还允许去除相对较大的毒素,如β2-微球蛋白和肌红蛋白。高截留膜的筛分曲线位于比肾小球膜的筛分曲线更高的分子量处。尽管高截留筛分特性直到20kDa时类似于肾小球膜,但高截留膜对大于20kDa的分子量开放。这意味着高截留膜允许某些蛋白质通过,这些蛋白质会被肾小球膜保留。WO 2004/056460已经公开了某些早期的高截留膜。当前在市场上销售的采用高截留膜的先进透析器是例如(Baxter)。高截留膜的已知用途包括治疗慢性炎症(EP 2 161 072A1)、淀粉样变性和横纹肌溶解以及治疗贫血(US 2012/0305487 A1),迄今为止探索最多的治疗是骨髓瘤肾的治疗(US 7,875,183 B2)。在这种情况下,在接受化学疗法的多发性骨髓瘤患者中去除游离的轻链已使大量患者的肾功能得以恢复。如表I中所示,这种高截留膜的特征在于在膜与血液或血液制品接触之前,通过右旋糖酐筛分曲线测定,起始分子量保留(molecular retention onset,MWRO)介于15.0kDa至20.0kDa之间,且截留分子量(MWCO)介于170kDa至320kDa之间。由于采用上述透析器每次疗程损失高达40g白蛋白,因此高截留膜将主要用于急性应用,但是一些医生已经预期将其用于慢性应用的益处,可能与白蛋白替代联合。
前面提到的中截留膜和透析器的发展填补了高通量和高截留透析器之间的空白。此类半渗透膜的特征在于,在膜与血液或血液制品接触之前,通过右旋糖酐筛分曲线测定,起始分子量保留(MWRO)介于9.0kDa至14.0kDa之间,且截留分子量(MWCO)介于55kDa至130kDa之间。由于这种非常独特的筛分特性,该膜极大地扩展了当前高通量膜和透析器的性能,因为它们允许去除中等和大的尿毒症溶质,而所述中等和大的尿毒症溶质是当前高通量膜无法解决的。因此,它们也被称为“具有增大的渗透性的膜”,而采用的血液透析被称为扩展血液透析疗法(expanded hemodialysis therapy,HDx)。同时,此类膜能够去除较高分子量的化合物,而在处理过程中不必面对不可接受的白蛋白损失。因此,这些类型的膜可用于急性和慢性环境。为了避免疑义,如本文所用的表述“具有增大的(或“扩展的”)渗透性的膜”等同于表述“中截留膜”。
如本文所用的表述“截留分子量”或“MWCO”或“标称截留分子量”是用于描述膜的保留能力的值,并且是指当膜具有90%的截留率(参见上文和图1),相当于0.1的筛分系数时溶质的分子质量。MWCO可以可替代地描述为当膜允许10%的分子通过时的溶质(例如右旋糖酐或蛋白质)的分子质量。曲线的形状在很大程度上取决于孔径分布,并因此与膜的物理外观有关。如前所述,筛分曲线提供两个维度上的相关信息:曲线的形状描述孔径分布,而其在分子量轴上的位置则指示孔的尺寸。截留分子量(MWCO)将筛分曲线的分析仅局限于一个维度,即筛分系数为0.1时孔的尺寸。为了增强膜的表征,已引入起始分子量保留(MWRO)来表征膜,如高截留膜和中截留膜(Boschetti-de-Fierro et al.)。MWRO定义为筛分系数为0.9时的分子量,如图1示意性示出的。它类似于MWCO,并且描述了筛分系数何时开始从1下降到0,即膜何时开始截留一定尺寸的化合物。在筛分曲线上定义两个点可以更好地表征S型曲线,从而显示出孔径以及孔径分布。因此,如本文所用的表述“起始分子量截留”或“MWRO”或“标称起始分子量截留”是指膜的截留率为10%或者换句话说允许90%的溶质通过(相当于筛分系数为0.9)时的溶质的溶质分子质量。
表I:基于右旋糖酐筛分的血液透析膜的一般分类
申请人已经发现,如上文和表I中所定义的中截留膜可用于有效地解决患者的RLS。中截留膜的渗透性扩展还对血液透析患者的RLS具有惊人的影响。更具体地,本申请发明人能够表明通过采用具有增大的渗透性的膜处理来减轻RLS,从而证明包含中截留膜的透析器是治疗或改善RLS症状的有效方法。
发明概述
本发明的目的是提供一种治疗或改善诊断患有RLS的患者的不宁腿综合征(RLS)的方法,该方法包括以连续流的方式抽取患者的血液并使其走旁路与膜的一面接触,同时在膜的相反面上以连续流的方式使透析液通过,以及使血液返回到患者体内,其中血液透析膜的特征在于,其包含至少一种疏水性聚合物和至少一种亲水性聚合物,以及在于其MWRO为8.5kD至14.0kD,且MWCO为55kD至130kD。给定膜的MWRO和MWCO值是如Boschetti-de-Fierro等人(2013)和PCT/EP2015/052364中描述的在膜与血液接触之前基于右旋糖酐筛分实验得出的。因此,本公开涉及用于治疗患有不宁腿综合征(RLS)的患者的中截留膜。采用中截留膜的血液透析治疗优选应用于以下情况中:RLS被分类为重度或极重度,药物治疗被禁忌或不能改善状况以及患者已经接受血液透析治疗。相关患者的基于中截留膜的血液透析治疗可以优选与包含多巴胺激动剂的药物治疗联合使用。
附图简要说明
图1是右旋糖酐筛分曲线的图示,其中示出了起始分子量保留值(MWRO,在SC=0.9时获得)和截留分子量值(MWCO,在SC=0.1时获得)。
图2显示了不同类型的透析膜的特征性右旋糖酐筛分曲线:低通量、高通量和高截留。已加入肾小球膜的数据(如Axelsson et al.(2009):Loss of size selectivity ofthe glomerular filtration barrier in rats following laparotomy and muscletrauma.American Journal of Physiology-Renal Physiology,297,F577-F582所报告的)用于说明。
图3示出了基于来自右旋糖酐筛分曲线的起始分子量保留和截留分子量的不同类型的血膜的图。虚线正方形大致代表界定透析器家族的边界。字母和数字表示如US 2017/165616 A1中进一步定义的各种膜。
发明详述
不宁腿综合征(RLS),也称为Willis-Ekbom病(WED),是众所周知的神经感觉运动障碍,通常以几乎无法抗拒的移动腿的冲动为特征。不宁腿综合征可以分为轻度、重度或极重度,取决于症状的发生频率和严重程度、四处走动可缓解症状的程度以及其所造成的干扰程度。
本文所用的表述“不宁腿综合征”或“RLS”是指满足国际不宁腿综合征研究组(IRLSSG)为更新的不宁腿综合征/Willis–Ekbom病(RLS/WED)诊断标准而制定的诊断标准的状况,参见Allen et al.:Restless legs syndrome/Willis–Ekbom diseasediagnostic criteria:updated International Restless Legs Syndrome Study Group(IRLSSG)consensus criteria–history,rationale,description,andsignificance.Sleep Medicine 15(8),2014,860-873。
以下编号的实施方案是预期的并且是非限制性的:
1.一种中空纤维膜,在所述膜与血液接触之前通过右旋糖酐筛分测定,所述中空纤维膜的MWRO为约8.5kD至约14.0kD,且MWCO为约55kD至约130kD,
其中所述中空纤维膜包含选自聚砜、聚醚砜和聚芳醚砜的至少一种聚合物,并且
其中所述中空纤维膜还包含聚乙烯吡咯烷酮,所述中空纤维膜用于治疗或改善诊断患有RLS的患者的不宁腿综合征(RLS)的方法中,所述方法包括以连续流的方式抽出患者的血液并使其走旁路与所述膜的一面接触,同时在膜的相反面上以连续流的方式使透析液通过,以及使血液返回到患者体内。
2.根据条款1所述的中空纤维膜的用途,其中在所述膜与血液接触之前通过右旋糖酐筛分测定,所述膜的MWRO为约9.0kD至约14.0kD,且MWCO为约55kD至约110kD。
3.根据条款1或条款2所述的中空纤维膜的用途,其中所述患者符合国际不宁腿综合征研究组(IRLSSG)的共识标准。
4.根据条款1至3中任一项所述的中空纤维膜的用途,其中所述患者的IRLS得分为11-20(中度)、21-30(重度)或31-40(极重度)。
5.根据条款1至4中任一项所述的中空纤维膜的用途,其中所述患者接受多巴胺激动剂(例如罗替戈汀)伴随药物治疗。
6.根据条款1至5中的任一项所述的中空纤维膜的用途,其中所述患者是血液透析患者。
7.根据条款1至6中任一项所述的中空纤维膜的用途,其中,从基于右旋糖酐筛分的MWCO得到的膜的选择层上的平均有效孔径(半径)大于约5.0nm且小于约7.0nm。
8.根据条款1至7中任一项所述的中空纤维膜的用途,其中,所述膜的内径小于约200μm,并且壁厚度小于约40μm。
9.一种治疗患者的不宁腿综合征(RLS)的方法,包括以连续流的方式抽出患者的血液并使其走旁路与膜的一面接触,同时在所述膜的相反面上以连续流的方式使透析液通过,以及使血液返回到患者体内,其中在所述膜与血液接触之前通过右旋糖酐筛分测定,所述膜的MWRO为约8.5kD至约14.0kD,且MWCO为约55kD至约130kD,并且其中所述膜包含选自聚砜、聚醚砜和聚芳醚砜的至少一种聚合物,并且还包含聚乙烯吡咯烷酮。
10.根据条款9所述的治疗不宁腿综合征(RLS)的方法,其中所述中空纤维膜的特征在于,在所述膜与血液接触之前通过右旋糖酐筛分测定,所述膜的MWRO为约9.0kD至约14.0kD,且MWCO为约55kD至约110kD。
11.根据条款9或10所述的治疗不宁腿综合征(RLS)的方法,其中所述患者符合国际不宁腿综合征研究组(IRLSSG)的共识标准。
12.根据条款6至11中任一项所述的治疗不宁腿综合征(RLS)的方法,其中所述患者的IRLS得分为11-20(中度)、21-30(重度)或31-40(极重度)。
13.根据条款9至12中任一项所述的治疗不宁腿综合征(RLS)的方法,其中所述患者接受多巴胺激动剂伴随药物治疗。
14.根据条款9至13中任一项所述的治疗不宁腿综合征(RLS)的方法,其中所述患者是血液透析患者。
15.根据条款9至14中任一项所述的治疗不宁腿综合征(RLS)的方法,其中从基于右旋糖酐筛分的MWCO得到的膜的选择层上的平均有效孔径(半径)大于约5.0nm且小于约7.0nm。
16.根据条款9至条款15中任一项所述的治疗不宁腿综合征(RLS)的方法,其中所述膜的内径小于约200μm,并且壁厚度小于约40μm。
17.根据条款9至16中任一项所述的治疗不宁腿综合征(RLS)的方法,其中所述膜被包含在填充密度为约53%至约60%的纤维束中,并且其中所述纤维束包含至少80%的卷曲纤维。
18.根据条款9至16中任一项所述的治疗不宁腿综合征(RLS)的方法,其中所述膜被包含在填充密度为约53%至约60%的纤维束中,并且其中所述纤维束由至少80%的卷曲纤维组成。
本公开涉及用于治疗患有不宁腿综合征(RLS)的患者的扩展血液透析的中截留膜。血液透析治疗优选应用于RLS被分类为重度或极重度的情况下,无论是在原发性还是继发性RLS中。如果药物治疗被禁忌或者不能改善病情,则进一步建议该治疗。它也特别适合患者已经接受血液透析治疗的情况。尤其是在血液透析患者患有重度或极重度RLS并且其中药物治疗不会改善RLS症状的情况下需要治疗。然而,还建议该治疗与多巴胺激动剂,例如罗匹尼罗或左旋多巴,尤其是与罗替戈汀的施用联合。
治疗患有RLS的患者的方法包括以连续流的形式抽出患者血液并使其走旁路以与血液透析膜的一面接触,同时使透析液以连续流的形式在血液透析膜的相反面上通过到达血液透析膜与血液接触的一侧,透析液的流动与血液的流动方向成逆流,以及使血液返回到患者体内,其中血液透析膜的特征在于其MWRO介于8.5kDa至14kDa之间,且MWCO介于55kDa至130kDa之间。
根据本发明的一个具体实施方案,用于治疗RLS的血液透析膜的特征在于它是由聚砜或聚醚砜与聚乙烯吡咯烷酮的聚合物共混物制备的,并且其MWRO介于9kDa至12.0kDa,且MWCO介于55kDa至110kDa之间。根据本发明的另一个实施方案,其是由聚砜或聚醚砜与聚乙烯吡咯烷酮的聚合物共混物制备的,并且其MWRO介于9kDa至12.0kDa之间,且MWCO介于55kDa至90kDa之间。如本文用于给定膜的MWRO和MWCO值是基于如Boschetti-de-Fierro等人(2013)所述的右旋糖酐筛分实验。参见该参考文献的“材料和方法”部分,并且指的是在膜与血液接触前获得的值。
根据本发明的一个具体实施方案,治疗是(预期的)中度至重度溶血的连续治疗,患者的RLS可以用根据本发明的血液透析膜以连续性肾脏替代疗法(CRRT)的形式或者在施用于患有终末期肾病患者的标准(慢性)血液透析治疗期间来治疗。在本发明的上下文中,这样的膜被称为“中截留膜”,或者可替代地,被称为“具有扩展的渗透性的膜”。如前所述,这些膜被详细记载在PCT/EP2015/052365中。与现有技术中已知的膜和透析器相比,所述膜和包含所述膜的透析器的特征在于其有效减轻RLS症状的能力,如COREXH研究所证明的,参见本申请的实施例部分。除了上述药物治疗之一之外,根据本发明它们还可以在延长的治疗时间内安全地使用。
根据本发明的一个具体实施方案,上述具有扩展的渗透性的膜和基于其的滤血器也可以作为独立运行的过滤器用于血液透析治疗。除了根据本发明对患有肾病并显示RLS症状的患者进行正常的血液透析治疗,并且其中RLS被伴随治疗之外,所述膜和过滤器还可以用于治疗患有RLS的患者,尤其是重度或极重度RLS患者,例如用于每周一次、两次或三次定期治疗,最多四个小时,或者在重度或极重度RLS的急性发作期间,在有或没有伴随药物治疗的情况下,例如在与多巴胺拮抗剂的伴随治疗下,间歇性地治疗。这样的间歇性治疗可以例如作为标准血液透析治疗进行2至5小时,或者以CRRT的形式进行较长时间。
因此,根据本发明的用于治疗RLS的膜由聚砜、聚醚砜或聚芳醚砜与聚乙烯吡咯烷酮的聚合物共混物制备,并且具有介于8.5kDa至14.0kDa之间的MWRO和介于55kDa至130kDa之间的MWCO。根据本发明的一个具体实施方案,该膜用于治疗终末期肾病患者的RLS。根据本发明的另一个实施方案,具有扩展的渗透性的膜具有在9.0kDa至12.5kDa范围内的MWRO和在55kDa至110kDa范围内的MWCO。根据本发明的另一方面,所述膜具有在9.0kDa至12.5kDa范围内的MWRO和在68kDa至110kDa范围内的MWCO。根据本发明的又一方面,所述膜具有在9kDa至12.5kDa范围内的MWRO和在55kDa至90kDa范围内的MWCO。根据本发明的又一方面,所述膜具有大于8.5kDa且小于12.5kDa的MWRO和大于55.0kDa且小于90.0kDa的MWCO。根据本发明的又一方面,使用以商标名商购的膜和透析器来治疗根据本发明的RLS。
在关于使用中截留膜和包含该中截留膜的透析器的作用的临床研究中发现,根据本发明的血液透析治疗导致RLS症状的显著减轻。
可以通过本领域中通常已知的方法将中截留膜加工到血液透析滤器中,例如,将其加工成在外壳、面积、纤维和束的几何形状、填充密度和流动特性方面的设计类似于在市场上已经可以获得的产品(例如)或与其相同的血液透析滤器中,或者如PCT/EP2015/052364中对中截留膜所述的那样进行加工,该文献通过引用的方式以其全部内容并入本文。因此,在本发明的上下文中,表述“中截留膜”的使用包括在适合在体外透析机中/上使用的适当的滤器装置内使用膜。
根据本发明的一个方面,采用根据本发明的所述中截留膜的血液透析治疗每周分别进行2至4次,持续2至6小时的时间,并因此与标准血液透析治疗没有区别。根据本发明的另一方面,治疗可以持续直到RLS症状降低到可接受的值或完全消失。根据患者的具体状况,可以单独或定期地应用如上所述的这样的治疗方案或过程。
根据本发明的一个实施方案,根据本发明的血液透析治疗可以用现有技术的药物治疗来补充,该药物治疗本来被开处方给患有与RLS有因果关联的疾病的患者。
可以用于执行根据本发明的治疗的透析机是标准透析机。这种设备的实例是AK96、AK 200S和AK 200ULTRAS、PrismafleX eXeed或Baxter的Artis透析机。但是,也可以使用任何其他透析机来进行该治疗。
可以将用于执行根据本发明的治疗的参数调整为标准透析治疗或中截留参数以及中截留膜的规格。用于本治疗的典型流速可以改变。使用QB(血流)为100-500、优选250-400ml/min和QD(透析液流速)为100-1000、优选300-500ml/min的流速是有利的。
可以例如通过借助IRLS量表确定RLS的严重程度来评估患者状况的改善。
根据本发明的一个方面,根据本发明的透析膜包含至少一种亲水性聚合物和至少一种疏水性聚合物。在一个实施方案中,至少一种亲水性聚合物和至少一种疏水性聚合物作为透析膜表面上的区域存在于透析膜中。疏水性聚合物可以选自聚芳醚砜(PAES)、聚丙烯(PP)、聚砜(PSU)、聚甲基丙烯酸甲酯(PMMA)、聚碳酸酯(PC)、聚丙烯腈(PAN)、聚酰胺(PA)、聚四氟乙烯(PTFE)或其组合。在本发明的一个实施方案中,疏水性聚合物选自聚芳醚砜(PAES)、聚丙烯(PP)、聚砜(PSU)、聚碳酸酯(PC)、聚丙烯腈(PAN)、聚酰胺(PA)、聚四氟乙烯(PTFE)或其组合。在本发明的另一个实施方案中,疏水性聚合物选自聚芳醚砜(PAES)、聚醚砜(PES)和聚砜(PSU)。亲水性聚合物可以选自聚乙烯吡咯烷酮(PVP)、聚乙二醇(PEG)、聚乙烯醇(PVA)以及聚环氧丙烷和聚环氧乙烷的共聚物(PPO-PEO)。在本发明的一个实施方案中,亲水性聚合物可以选自聚乙烯吡咯烷酮(PVP)、聚乙二醇(PEG)和聚乙烯醇(PVA)。在本发明的一个实施方案中,亲水性聚合物是聚乙烯吡咯烷酮(PVP)。
公开了具有扩展的渗透性的膜(或中截留膜),并且可以如PCT/EP2015/052364中所述制备,该文献通过引用的方式以其整体并入本文。在EP 2 253 367A1中描述了也可根据本发明有效使用的类似膜及其制备方法,该文献通过引用的方式以其整体并入本文。
总之,在这种情况下,发明人的发现证明了通过使用基于根据本发明的中截留透析器的体外血液净化技术来治疗根据本发明的RLS的可能性。例如,在ESRD患者中,滤器与AK96透析机的组合联合标准血液透析治疗用于治疗RLS展示了在该研究中的显著临床益处,并且可能代表在急性环境中有效治疗RLS以及治疗重度RLS发作的合适选择。
对于本领域技术人员而言显而易见的是,在不脱离本发明的范围和精神的情况下,可以对本文公开的发明进行各种替换和修改。为了进一步促进对本发明的理解,在实施例部分中通过非限制性实施例说明本发明。
实施例
实施例1
基于哥伦比亚常规临床实践注册信息(TH-PO296,J Am Soc Nephrol 29,2018:190),对接受扩展血液透析(HDx)治疗的患者的RLS的临床结果
1.1研究设计
这项研究的目的是基于哥伦比亚RTS肾病诊所(RTS renal clinics)网络中一组长期接受血液透析治疗的患者的实际数据,评价采用中截留透析器进行的扩展血液透析对例如RLS的有效性。该研究是一项前瞻性队列、多中心、观察性研究。将在注册研究并签署知情同意书后,从第一个血液透析疗程获取研究数据。每个受试者将参加研究1年。除其他方面外,这项研究的目的是评价透析疗法从高通量HD变更为HDx后最初六个月的生活质量和不宁腿患病率的变化。
1.2研究人群
多达1,000名受试者接受采用透析器(中截留透析器)的扩展透析治疗,每周至少3次,每次疗程至少4个小时。每个受试者必须符合以下入选标准,才能注册本研究。患者必须≥18岁且已被诊断为CKD,并接受长期血液透析超过90天,血液透析方案为每周至少3次,每次疗程至少持续4个小时。每位入选患者的血液透析治疗持续时间将根据其治疗医师确定的当前扩展HD治疗处方而变化。
1.3透析器
1.4结果
患者报告的结果指标如下所示:
(1)DSI和KDQOLTM-36的单项分数和总分数以及根据IRLS的不宁腿诊断的频率。
(2)磷螯合剂的使用数量和血浆磷水平。
(3)红细胞生成素的剂量和血红蛋白水平。
(4)降压药的数量以及收缩压和舒张压。
(5)每天服用片剂/丸剂和KDQOLTM-36分数。
(6)营养补充剂的使用和营养状况。
1.5伴随用药评估
获取在受试者注册研究之前30天间隔内以及随访当年期间给予的预先确定的相关伴随药物的详细信息,所述相关伴随药物是例如红细胞生成刺激剂(ESA)、HD抗凝剂、磷酸盐结合剂、多巴胺激动剂、铁补充剂和降压药。
1.6结果
评估了666名患者,其中61.4%(n=409)为男性,平均年龄为59.8岁(SD=15.3),60.3%接受血液透析超过3年。发现,大部分的生活质量维度得到了显著改善(参见表II),而对不宁腿的诊断则显著减少(表III)。
表II:KDQOLTM-36生活质量
表III:诊断标准RLS(IRLS分数)
*Anova
**McNemar检验。
Claims (11)
1.一种治疗患者的不宁腿综合征(RLS)的方法,所述方法包括以下步骤:以连续流的方式抽取患者的血液并使其走旁路与膜的一面接触,同时在膜的相反面上以连续流的方式使透析液通过,以及使血液返回到患者体内,
其中在所述膜与血液接触之前通过右旋糖酐筛分测定,所述膜具有介于约8.5kD至约14.0kD之间的MWRO和介于约55kD至约130kD之间的MWCO,并且
其中所述膜包含选自聚砜、聚醚砜和聚芳醚砜的至少一种聚合物,并且还包含聚乙烯吡咯烷酮。
2.根据权利要求1所述的治疗不宁腿综合征(RLS)的方法,其中所述中空纤维膜的特征在于,在所述膜与血液接触之前通过右旋糖酐筛分测定,所述膜具有介于约9.0kD至约14.0kD之间的MWRO和介于约55kD至约110kD之间的MWCO。
3.根据权利要求1所述的治疗不宁腿综合征(RLS)的方法,其中所述患者满足国际不宁腿综合征研究组(IRLSSG)的共识标准。
4.根据权利要求1所述的治疗不宁腿综合征(RLS)的方法,其中所述患者的IRLS得分为11-20(中度)、21-30(重度)或31-40(极重度)。
5.根据权利要求1所述的治疗不宁腿综合征(RLS)的方法,其中所述患者接受多巴胺激动剂伴随用药。
6.根据权利要求5所述的治疗不宁腿综合征(RLS)的方法,其中所述多巴胺激动剂为罗替戈汀、罗匹尼罗或左旋多巴。
7.根据权利要求1所述的治疗不宁腿综合征(RLS)的方法,其中所述患者为血液透析患者。
8.根据权利要求1或2所述的治疗不宁腿综合征(RLS)的方法,其中从基于右旋糖酐筛分的MWCO得到的膜的选择性层上的平均有效孔径(半径)为高于约5.0nm且低于约7.0nm。
9.根据权利要求1或2所述的治疗不宁腿综合征(RLS)的方法,其中所述膜的内径小于约200μm,并且壁厚度小于约40μm。
10.根据权利要求1或2所述的治疗不宁腿综合征(RLS)的方法,其中所述膜包含在填充密度为约53%至约60%的纤维束中,并且其中所述纤维束包含至少80%的卷曲纤维。
11.根据权利要求1或2所述的治疗不宁腿综合征(RLS)的方法,其中所述膜包含在填充密度为约53%至约60%的纤维束中,并且其中所述纤维束由至少80%的卷曲纤维组成。
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