CN115551495A - 管理损伤后面部挛缩的治疗策略 - Google Patents
管理损伤后面部挛缩的治疗策略 Download PDFInfo
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- CN115551495A CN115551495A CN202180026641.2A CN202180026641A CN115551495A CN 115551495 A CN115551495 A CN 115551495A CN 202180026641 A CN202180026641 A CN 202180026641A CN 115551495 A CN115551495 A CN 115551495A
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Abstract
提供了用于降低面部挛缩并减轻面部热损伤相关的缺陷的组合物和方法,这些缺陷包括睑外翻(上皮‑眼连接处)、唇外翻(上皮‑口腔连接处)和口腔闭合不全(流涎)。根据一个实施例,将这样的组合物与用于烧伤患者的已知治疗结合使用。
Description
相关申请的交叉引用
本申请要求于2020年4月8日提交的美国临时专利申请号63/007,101的优先权,其披露内容明确地并入本文。
背景技术
面部通常是对人类进行识别的部位,它可能是最强有力的非语言交流“通道”,并且生活在由于烧伤或其他外伤造成的面部外观变形中是具有挑战性的。在美国,每年约有125万人接受烧伤治疗,并且有40,000人因这些损伤进行住院治疗,这导致每年大约79亿美元的高额医疗成本。上颌面热损伤的一个来源是暴露于***冲击波的热量下,导致未受保护的面部的闪光灼伤。这些烧伤涉及皮肤、皮下肌肉,并且甚至经常涉及骨骼。由于***冲击波涉及的高热量,六度烧伤很常见。上颌面热损伤或其他损伤导致被视为严重瘢痕的大型挛缩,这些挛缩给受试者造成社会、情感、心理和功能负担。由这样的皮肤挛缩诱导的面部热损伤的严重且独特的功能缺陷包括睑外翻(上皮-眼连接处)、唇外翻(上皮-口腔连接处)和口腔闭合不全(oral incompetence)(流涎(drooling))。
与身体其他部位的皮肤不同,面部皮肤起源于神经嵴(与身体其他部位的中胚层起源相反)。鉴于这种差异,申请人研究并且发现面部瘢痕的发展遵循机制独特的路径,其中骨骼肌(大部分)和心肌(少数)的收缩元件在皮肤中表达。与身体其他部位的瘢痕应答相比,面部瘢痕挛缩要严重得多。现有的瘢痕疗法源自对中胚层起源的皮肤的研究,并且不利于面部挛缩情况下的应用。鉴于缺乏合适的面部烧伤模型来测试疗法,这种差异在以前无法区分。因此,本披露涉及用于治疗由烧伤或其它外伤引起的面部皮肤损伤的新方法。这些方法可能会扩展到管理身体其他部位的挛缩。
发明内容
根据本披露的一个实施例,提供了治疗经受上颌面损伤影响的患者的方法,这些上颌面损伤包括例如上颌面热损伤,该上颌面热损伤导致引起变形的重度面部挛缩。申请人发现,面部挛缩遵循与身体上其它皮肤组织中的瘢痕的发展不同的途径。与身体其他部位的瘢痕应答相比,这种替代性途径导致面部瘢痕挛缩更严重。在受损面部皮肤上,骨骼肌(大部分)和心肌(少数)的收缩元件在涉及修复受损组织的细胞中表达,导致所得瘢痕组织中的重度挛缩。因此,对于目前治疗瘢痕的策略来说,面部瘢痕更为难治。
如本文所披露的,申请人发现收缩元件在受损面部皮肤中被诱导,因此申请人提出了治疗现有成熟瘢痕(晚期)并最小化损伤后面部挛缩形成(早期)的新策略。本文披露的方法可以降低或预防与现有面部瘢痕相关的挛缩并减轻与面部热损伤相关的缺陷,包括降低睑外翻(上皮-眼连接处)、唇外翻(上皮-口腔连接处)和口腔闭合不全(流涎)。
如本文所披露的,预计靶向肌肉松弛的药物有助于治疗成熟面部挛缩。在早期,损伤后不久(两周至2个月),抑制肌生成的药物将有所帮助。晚期可被改变用途的FDA批准的肌肉松弛药物的实例包括:巴氯芬、丹曲林以及替扎尼定。适用于在本发明中使用的另外的肌肉松弛药物包括卡立普多、氯唑沙宗、环苯扎林、美他沙酮、美索巴莫以及奥芬那君。早期改变用途的肌生成抑制剂药物的实例包括尼罗替尼(诺华股份有限公司(Novartis))。此外,肌生成的其他抑制剂(如但不限于,基质相互作用分子(STIM)抑制剂和***相关受体α抑制剂)也适用于本发明。
具体实施方式
定义
在描述和要求保护本发明时,将依据以下列出的定义使用以下术语。
如本文所用,“约”意指比所述的值或值的范围大或小10%,但并不旨在将任何值或值的范围仅限于此更广泛的定义。以术语“约”开头的每个值或值范围也旨在包括所述绝对值或值范围的实施例。
如本文所用,术语“纯化的”和类似术语涉及在天然或自然环境中以基本上不含通常与分子或化合物相关的污染物的形式分离分子或化合物。如本文所用,术语“纯化的”不需要绝对纯度;相反,这旨在作为相对的定义。本文中使用术语“纯化的多肽”来描述从其他化合物中分离的多肽,这些化合物包括但不限于核酸分子、脂质以及碳水化合物。
术语“分离的”要求将参考材料从其原始环境(例如,自然环境(如果它是天然存在的))中移除。例如,存在于活的动物中的天然存在的多核苷酸不是分离的,但是从天然***中的一些或全部共存材料分离的相同多核苷酸是分离的。
如本文所用,术语“药学上可接受的载体”包括任何标准的药用载体,如磷酸盐缓冲盐水、水、乳液(如油/水或水/油乳液)、以及多种类型的润湿剂。该术语还包括由美国联邦政府的监管机构批准的或在美国药典中列出的用于动物(包括人)的任何药剂。
如本文所用,术语“磷酸盐缓冲盐水”或“PBS”是指包含氯化钠和磷酸钠的水溶液。PBS的不同配制品是本领域技术人员已知的,但出于本发明的目的,短语“标准PBS”是指最终浓度为137mM NaCl、10mM磷酸盐、2.7mM KCl,并且pH为7.2-7.4的溶液。
如本文所用,术语“治疗”包括减轻与特定障碍或病症相关的症状和/或预防或消除所述症状。
如本文所用,药物的“有效量”或“治疗有效量”是指无毒性但足以提供所需作用的药物。“有效”的量将因受试者而变化,或甚至在受试者内随时间变化,这取决于个体的年龄和一般状况、施用模式等。因此,不总是能够指定精确的“有效量”。然而,在任何个体情况下适当的“有效”量可由本领域普通技术人员使用常规实验来确定。
如本文所用,未进一步指定的术语“患者”旨在涵盖任何温血的脊椎家养动物(包括例如但不限于家畜、马、猫、狗以及其他宠物)和人,并且包括不在医生直接护理下的个体。
术语“载体”意指一种化合物、组合物、物质或结构,当与化合物或组合物组合时,其有助于或促进化合物或组合物(用于其预期用途或目的)的制备、储存、施用、递送、有效性、选择性或任何其它特征。例如,可以选择载体以最小化活性成分的任何降解,并最小化受试者中的任何不良副作用。
术语“抑制”是指活性、应答、病症、疾病或其他生物学参数的降低。这可以包括但不限于活性、应答、病症、或疾病的完全消融。这还可以包括例如,与天然或对照水平相比,活性、应答、病症、或疾病降低10%。因此,与天然或对照水平相比,降低可以为10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或之间的任何降低量。
如本文所用,对“面部”的提及包括头部的前部,其在人类中从前额延伸到下颏并且横向延伸到头部的侧面,并且包括耳朵、嘴、鼻子、颊和眼睛。
如本文所用,“面部外伤”,也称为上颌面外伤,是对面部和颈部的任何物理外伤。面部外伤可能涉及软组织损伤(如烧伤、撕裂和挫伤),并且可能包括面部骨骼骨折和损坏,如鼻骨骨折和颌骨骨折。
如本文所定义,“伤口愈合”定义了一种过程,其中活生物体用新产生的组织代替被破坏或受损的组织。
实施例
当真皮受损时,瘢痕作为自然愈合过程的一部分形成。为应答这样的损坏,身体会形成新的胶原纤维来修复损坏,从而形成瘢痕组织。如果治疗得当,瘢痕组织典型地可以重塑为类似于正常、健康的组织。然而,根据初始损伤和愈合应答的程度,一些瘢痕很严重并且可能毁容。
例如,***冲击波的热量导致没有盔甲保护的面部的闪光灼伤。这些烧伤涉及皮肤、皮下肌肉,并且甚至经常涉及骨骼。由于涉及的高热量,四度至六度烧伤很常见。这样的上颌面热损伤导致严重的面部挛缩,这些挛缩给受试者造成社会、情感、心理和功能负担。面部热损伤的严重且独特的功能缺陷包括睑外翻(上皮-眼连接处)、唇外翻(上皮-口腔连接处)和口腔闭合不全(流涎)。与身体其他部位的瘢痕应答相比,面部挛缩要严重得多。
为了开发管理面部挛缩的新策略,在配对的临床前猪环境中比较了烧伤后面部挛缩与背部皮肤瘢痕形成的分子机制。与身体其他部位的皮肤不同,面部皮肤起源于神经嵴。对重度面部烧伤模型的测序研究发现,肌源性基因在面部皮肤组织的挛缩形成中起着独特的作用。更特别地,申请人发现在重度烧伤之后,面部中的皮肤和相关伤口细胞经历肌源性转化,导致明显的挛缩,这是造成上述面部热损伤的独特特征的原因。面部皮肤组织的修复遵循机制独特的路径,其中骨骼肌(大部分)和心肌(少数)的收缩元件在皮肤中表达。目前使用的常规抗瘢痕形成策略不能轻易治疗面部瘢痕形成。根据本披露,可以使用基于面部伤口修复阶段的两种方法来管理面部挛缩的治疗。一种治疗策略涉及现有的成熟瘢痕(晚期),其中治疗现有的瘢痕以减轻与瘢痕相关的疼痛和变形。另一种治疗方法涉及损伤后挛缩形成(早期)和施用治疗剂以减少瘢痕组织形成,包括减少形成的瘢痕组织中存在的胶原的量和/或减少瘢痕组织的表面积。
根据一个实施例,刺激肌肉松弛的药物将用于治疗成熟的面部挛缩。在一个实施例中,受试者是人,并且待治疗的成熟面部挛缩是由面部皮肤的外伤性损坏导致的严重瘢痕。在一个实施例中,瘢痕在烧伤愈合后形成,该烧伤由热、化学、电、阳光或核辐射引起的组织损伤导致。在一个实施例中,本披露的方法涉及治疗人面部皮肤热损伤后形成的成熟挛缩,包括二度、三度、四度、五度或六度烧伤愈合后形成的瘢痕。
一种治疗位于哺乳动物受试者的面部或颈部的成熟挛缩的方法包括向需要这样的治疗的受试者施用包含骨骼肌松弛剂和药学上可接受的载体的组合物的步骤。根据一个实施例,制备药物配制品,该药物配制品包含选自由以下组成的组的化合物:巴氯芬、丹曲林、替扎尼定、卡立普多、氯唑沙宗、环苯扎林、美他沙酮、美索巴莫以及奥芬那君。在一个实施例中,将药物组合物配制用于通过任何可接受的途径施用,包括作为口服、注射或局部配制品。在一个实施例中,将组合物配制用于口服施用。在一个实施例中,将组合物配制为与瘢痕外表面接触的局部乳膏或软膏。在一个实施例中,局部乳膏或软膏可以直接应用于瘢痕组织,或可以将瘢痕用纱布、绷带或其它基质覆盖,这些基质以时间释放的方式将配制品释放到患者的受影响的皮肤上。
在一个实施例中,提供了在哺乳动物受试者面部的外伤性损伤后的愈合过程期间,降低瘢痕组织形成的严重程度的方法。在一个实施例中,该方法包括向需要这样的治疗的受试者施用包含肌生成抑制剂的组合物的步骤。在一个实施例中,该方法包括治疗从面部烧伤恢复的人以降低或预防愈合过程期间瘢痕组织形成的量,其中向患者施用包含肌生成抑制剂和药学上可接受的载体的药物组合物。降低瘢痕组织形成的量包括降低形成的瘢痕组织中挛缩的量、降低形成的瘢痕组织中胶原的量、降低瘢痕的大小中的任一种。在一个实施例中,肌生成抑制剂是尼罗替尼。在一个实施例中,药物组合物包含肌生成抑制剂以及骨骼肌松弛剂,该骨骼肌松弛剂包括选自由以下组成的组的肌肉松弛剂:巴氯芬、丹曲林、替扎尼定、卡立普多、氯唑沙宗、环苯扎林、美他沙酮、美索巴莫以及奥芬那君。在一个实施例中,在面部初始外伤后的2、3、4、5、6周,施用本发明的药物组合物。
在一个实施例中,将用于在面部外伤性损伤后的愈合过程期间,降低瘢痕组织形成的严重程度的药物组合物配制成通过任何可接受的途径施用,包括作为口服、注射或局部配制品。在一个实施例中,将组合物配制用于口服施用。在一个实施例中,将组合物配制为与瘢痕外表面接触的局部乳膏或软膏。在一个实施例中,局部乳膏或软膏可以直接应用于瘢痕组织,或瘢痕可以用纱布、绷带或其它基质覆盖,这些基质以时间释放的方式将配制品释放到患者的受影响的皮肤上。在一个实施例中,将包含肌生成抑制剂和骨骼肌松弛剂的组合物配制为乳膏、软膏或时间释放基质,以在面部皮肤热外伤后直接应用于形成的或形成过程中的面部挛缩组织。
根据本披露,包含肌生成抑制剂和/或骨骼肌松弛剂的组合物可以用于治疗患有上颌面热损伤的患者。本文披露的方法降低或预防了面部挛缩形成以减轻面部热损伤相关的缺陷,这些缺陷包括睑外翻(上皮-眼连接处)、唇外翻(上皮-口腔连接处)和口腔闭合不全(流涎)。根据一个实施例,将这样的组合物与用于烧伤患者的已知治疗结合使用,这些治疗包括皮肤磨削术、化学换肤术和激光换肤术,并且它不是任何指定的所需外科重建的替代物。
在一个实施例中,提供了用于治疗面部烧伤的组合物,其中该组合物包含肌生成抑制剂、骨骼肌松弛剂和药学上可接受的载体。在一个实施例中,将组合物配制为用于局部应用,包括例如作为凝胶、软膏、洗剂或乳膏。局部配制品可以包括与防腐剂、乳化剂或吸收促进剂混合的水、油、醇或丙二醇。在一个实施例中,将组合物制备为以时间释放方式释放活性剂的凝胶或其他基质。在一个实施例中,将组合物制备为应用于瘢痕的透皮贴剂或绷带。
实例1
猪上颌面热外伤模型中的伤口愈合
材料与方法
使白猪在面部区域(约50%的面部)或背部6(2”x 2”)烧伤伤口处遭受重度烧伤外伤。使用非侵入性成像跟踪烧伤伤口愈合的进展,直至第84天,该非侵入性成像为:a)激光散斑微灌注成像(LSI);b)用于组织僵硬和血液供应的多普勒谐波超声成像(HUSD);以及c)用于面部软组织和骨骼的3D重建的计算机断层扫描(CT)。此外,使用标准免疫组织化学检查伤口炎症、血管生成和重塑。在烧伤后第84天进行上皮激光捕获显微切割(LCM),然后进行全基因组RNA测序。
CT和超声成像确定六度烧伤与骨累及,其显示包括睑外翻、口腔外翻和挛缩、过度瘢痕形成以及进食时流涎的重度缺陷。所有这些特征与面部烧伤的人中常见的表现一致。严重的面部挛缩在烧伤后第84天时很明显。使用LSI、HUSD和CT成像可视化血管和骨骼缺陷(n=7)。
涉及皮肤黏膜连接的面部特定区域与以不同方式愈合的瘢痕相反。LCM捕获上皮的RNA seq(每组n=6;p<0.001)和生物信息学分析表明面部烧伤外伤后一组独特基因的差异表达,其在愈合上皮背部损伤后表达的挛缩相关基因中不存在。与背部相比,面部上皮中独特上调的与挛缩、形态发生和细胞骨架相关的通路高度显著变化。
相对于背部皮肤瘢痕组织的面部瘢痕组织的免疫组织化学分析表明,相对于来自猪背部的愈合真皮,与收缩组织相关的两种蛋白(桩蛋白7(Pax7)和肌间线蛋白)在面部的愈合真皮中高度表达。桩蛋白是细胞骨架蛋白,其参与在细胞粘附至细胞外基质位点处的肌动蛋白-膜附着(局灶性粘附),并且肌间线蛋白是肌原纤维蛋白,是骨骼肌和心肌的主要中间丝。相对于猪背部的愈合上皮,在面部的愈合上皮中还检测到平滑肌肌动蛋白的表达水平升高。
这些数据表明了涉及皮肤黏膜连接的人面部烧伤的独特特征。组织病理学分析进一步表明解剖部位的不同炎症、血管化和瘢痕形成应答。这项工作强调了面部烧伤挛缩应答中独特的分子特征和途径,这将有助于设计充分的面部瘢痕挛缩治疗策略。
Claims (16)
1.一种治疗位于哺乳动物受试者的面部的挛缩组织的方法,所述方法包括向需要这样的治疗的受试者施用包含骨骼肌松弛剂的组合物的步骤。
2.如权利要求1所述的方法,其中该哺乳动物受试者是人。
3.如权利要求1或2所述的方法,其中该肌肉松弛剂是选自由以下组成的组的化合物:巴氯芬、丹曲林、替扎尼定、卡立普多、氯唑沙宗、环苯扎林、美他沙酮、美索巴莫以及奥芬那君。
4.如权利要求1-3中任一项所述的方法,其中所述挛缩是热烧伤的结果。
5.如权利要求1-4中任一项所述的方法,其中口服施用所述组合物。
6.如权利要求1-4中任一项所述的方法,其中将所述组合物配制为直接应用至该挛缩的外表面的局部乳膏或软膏。
7.一种在哺乳动物受试者面部损伤后的愈合期期间,降低该面部上的挛缩的严重程度的方法,所述方法包括向需要这样的治疗的受试者施用包含肌生成抑制剂的第一组合物的步骤。
8.如权利要求7所述的方法,其中该哺乳动物受试者是人。
9.如权利要求7或8所述的方法,该方法进一步包括施用包含骨骼肌松弛剂的补充组合物的步骤。
10.如权利要求7或8所述的方法,其中所述第一组合物进一步包含骨骼肌松弛剂。
11.如权利要求7或8所述的方法,其中所述肌生成抑制剂是尼罗替尼。
12.如权利要求9或10所述的方法,其中该肌肉松弛剂是选自由以下组成的组的化合物:巴氯芬、丹曲林、替扎尼定、卡立普多、氯唑沙宗、环苯扎林、美他沙酮、美索巴莫以及奥芬那君。
13.如权利要求7-12中任一项所述的方法,其中所述面部损伤是面部热烧伤。
14.如权利要求13所述的方法,其中该面部热烧伤是三度烧伤或更严重的烧伤。
15.如权利要求7-14中任一项所述的方法,其中口服施用所述组合物。
16.如权利要求7-14中任一项所述的方法,其中将所述组合物配制为直接应用至受损面部组织的愈合组织的外表面的局部乳膏或软膏。
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US20130030025A1 (en) * | 2011-01-28 | 2013-01-31 | Wessel Thomas C | Use of potassium channel blockers to treat cerebral palsy |
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