CN101219138A - 使用光动力疗法治疗巴瑞特氏食道症 - Google Patents
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Abstract
一种治疗巴瑞特氏食道症的方法,其包括如下步骤:向具有巴瑞特氏食道症组织的患者注射在生理相容介质中的HPPH,来提供3~5mg/m2体表面积的剂量水平;等待24~60小时以使HPPH优先吸收进入巴瑞特氏食道症组织中;以及将巴瑞特氏食道症组织暴露于波长为约670±5nm、能量为约75~约200Joules/cm的光。
Description
相关专利申请的交叉引用
本申请要求来自2007年1月9日提交的美国临时申请60/879,474的优先权。
关于联邦政府资助研究的声明
本发明是在国立卫生研究院(National Institute of Health)的资金号NIH(1R21 CA109914-01和CA55792)的资助下进行的。美国政府在本发明中具有某些权利。
发明背景
巴瑞特氏食道症(Barrett′s esophagus)的特征在于异常组织的发育,通常作为对由酸反流引起的食道腐蚀的一种保护性应答。虽然巴瑞特氏食道症不是一种常见的疾病,但由于其治疗药丸的广告,相关的酸反流已经被人们所熟知。然而,尽管这样的药丸实际上有助于预防酸反流,但它们对于治疗已经产生的巴瑞特氏食道症起很少的作用或不起作用。虽然巴瑞特氏食道症本身可能会引起不适或疼痛,也可能不会,但它的出现是引发使身体虚弱甚至能够威胁生命的食道癌的一个危险因素。祛除巴瑞特氏食道症还不能很容易地实现。试验方法包括通过RF能量或热进行的内窥镜祛除以及内窥镜粘膜切除,它们通常限于巴瑞特氏食道症的小段。
近年来,卟啉类化合物已经被应用于通过光动力疗法(PDT)对癌症进行治疗上。某些卟啉和相关的四吡咯***在恶性肿瘤中的浓度比在大多数正常组织中要高,这成为使用这些分子作为光敏剂的一个主要原因。一些四吡咯类化合物对于多种恶性肿瘤均是有效的,包括皮肤、肺、膀胱、脑和颈以及食道。但是,伴随它们的使用存在一些相关问题,包括皮肤光毒性、正常组织损伤、渗透深度不足以及高比例的食道狭窄。PDT精确的机理还不清楚,但是,体内的动物数据显示直接细胞杀伤和肿瘤血管功能的丧失二者都起着重要的作用。一种新的并得到充分试验的四吡咯化合物是焦脱镁叶绿酸-a的3-(1-己氧基)乙基-衍生物(HPPH)。此处所使用的HPPH表示为游离酸、酯和盐形式的焦脱镁叶绿酸-a的3-(1-己氧基)乙基-衍生物。这种化合物是亲肿瘤的,且已经在纽约Buffalo的罗兹韦尔公园癌症研究所(Roswell ParkCancer Institute)进行了I/II期人临床试验。
光动力疗法(PDT)据信是利用了通过光动力学过程引发的局部氧化损伤的生物学后果。最初的光动力学过程发生所需的三个关键要素是:光敏剂、在光敏剂特定吸收频率或波长处的光、以及氧。在所需波长处的光据信引发了单线态氧的产生从而破坏该单线态氧集中于其中的组织。
诸如以商标名PHOTOFRINTM出售的光敏剂卟吩姆钠,和HPPH的四吡咯光敏剂在大多数肿瘤组织中大量富集。
巴瑞特氏食道症与粘膜发育异常和食道癌发病率的增加有关(Overholt et al.,GastrointestinaI Endoscopy,volume 49:1-7,1999;volume62:488-498,2005;未被本发明人公开的资料)。已经发现使用卟吩姆钠的光动力疗法是一种非手术的治疗方法,其消除或减轻了巴瑞特氏粘膜的程度,从而减少了食道癌发生的危险。
然而,使用卟吩姆钠治疗巴瑞特氏食道症存在许多严重的副作用,其包括对光、特别是太阳光的长期敏感性,以及对周围正常组织的损伤,特别是食道狭窄的形成。
对并非限于本发明的现有技术的已公开文献(Overholt等,GastrointestinaI Endoscopy,volume 49:1-7,1999;volume 62:488-498,2005)以及未公开资料的回顾,显示卟吩姆钠按2mg/kg的最佳剂量水平使用、在630nm其优选光吸收波长处的活化、以及100至250J/cm的光暴露导致在所有接受治疗的患者(100名患者)中75~80%的巴瑞特氏粘膜被正常的食道粘膜取代。观察到43%的患者的巴瑞特氏粘膜被完全祛除。其中,只采用PDT治疗中8%的患者获得巴瑞特氏粘膜的完全祛除,而35%需要热祛除来破坏异常粘膜的少量残留岛。不幸的是,所有接受治疗的患者中,34%出现食道狭窄。
已经有报道使用HPPH治疗阻塞性食道癌。(Optical Methods fortumor Treatment and Detection:Mechanisms and Techniques inPhotodynamic Therapy IX,Thomas Dougherty,Editor,Proceedings ofSPIE Vol.3909(2000))。这份资料中没有描述对巴瑞特氏食道症的作用。
发明内容
根据本发明,我们已经发现HPPH,与卟吩姆钠类似,当与将巴瑞特氏食道症组织暴露于HPPH的优先吸收波长(670±5nm)处的光进行联合处理时,其也能祛除巴瑞特氏食道症。但是,令人惊讶地发现,HPPH以较低的剂量非常成功地实现了期望的结果,并且非常重要的是仅有很少的食道狭窄。HPPH在仅为0.08~0.13mg/kg体重(3~5mg/m2体表面积)的给药剂量下就有效,相比之下卟吩姆钠的最小有效剂量为2mg/kg体重。
HPPH,即焦脱镁叶绿酸-a的3-(1-己氧基)乙基-衍生物,具有下述通式:
且包括其盐和烷基酯,并且可以如美国专利5,198,460和5,314,905,分别再公告为RE39094和RE38994中所述方法制备,所有上述文件在此引为参考。
本发明的方法包括如下步骤:
向具有巴瑞特氏食道症组织的患者注射在生理相容介质中的HPPH来提供3~5mg/m2体表面积的剂量水平,优选为3~4mg/m2体表面积的剂量水平;
等待24~60小时以使HPPH的优先吸收进入巴瑞特氏食道症组织中;以及
将巴瑞特氏食道症组织暴露于波长约为670±5nm、能量为75~200Joules/cm、优选75~200Joules/cm的光。
发明详述
HPPH注射优选经静脉内途径在生理相容介质中通常超过0.75~3小时的时间完成。这段时间在函数上取决于期望的输注速度以及剂量水平。在介质中的浓度优选为0.5~1.5mg/mL,介质优选为0.1%聚山梨醇酯80、2%乙醇和5%葡萄糖的生理盐水溶液。
利用携带由激光器发射的激光的光纤,完成照射。所述激光器可以是任一种在所需波长和能量处发射光的激光器,例如染料激光器或二极管激光器。可以通过调整暴露的时间长短和/或调整光强度调整暴露。
使用上述参数,使用HPPH进行I/II期试验,以及使用PHOTOFRINTM进行III期试验,后者由美国食品药品管理局批准,得到巴瑞特氏食道症的下列反应结果。如本上下文中使用的“CR”是指在治疗后没有巴瑞特氏食道症组织残留,并且未指出没有之后的复发。
PHOTOFRIN100名患者 | HPPH30名患者 | ||
治疗反应 | |||
仅PDT(汇集1~3 PDT治疗) | 8%CR | 仅PDT(仅1 PDT治疗) | 4%CR |
PDT+NdYAG(汇集1~3 PDT治疗+热祛除) | 35%CR | 仅PDT(仅1 PDT治疗;不包括NdYAG热祛除) | 47%(>90到<100%祛除) |
并发症 | |||
食道狭窄(汇集1~3 PDT治疗) | 34% | 食道狭窄(仅1 PDT治疗) | 12% |
日晒 | 25~30% | 日晒 | <7% |
鉴于上述,与单独用PHOTOFRINTM和用PHOTOFRINTM反复治疗的联合治疗相比,甚至当用HPPH进行单独治疗时,可以明确以较低剂量HPPH治疗巴瑞特氏食道症比PHOTOFRINTM同样有效或者更有效,甚至不用随后用HPPH进行热祛除。使用HPPH同时伴随反复治疗和/或热祛除可以期望获得更好的结果。
Claims (4)
1.一种治疗巴瑞特氏食道症的方法,其包括如下步骤:
向具有巴瑞特氏食道症组织的患者注射在生理相容介质中的HPPH来提供3~5mg/m2体表面积的剂量水平;
等待24~60小时以使HPPH优先吸收进入巴瑞特氏食道症组织中;以及
将巴瑞特氏食道症组织暴露于波长为约670±5nm处、能量为约75~约200Joules/cm的光。
2.如权利要求1所述方法,其中,HPPH的剂量水平为3.0~4.0mg/m2。
3.如权利要求1所述方法,其中,能量为约75~约150Joules。
4.如权利要求1所述方法,其中,等待时间为约24~约60小时。
Applications Claiming Priority (3)
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US87947407P | 2007-01-09 | 2007-01-09 | |
US60/879,474 | 2007-01-09 | ||
USPCT/US2007/020817 | 2007-09-27 |
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CNA2007101600008A Pending CN101219138A (zh) | 2007-01-09 | 2007-12-18 | 使用光动力疗法治疗巴瑞特氏食道症 |
CNA200710159998XA Pending CN101254193A (zh) | 2007-01-09 | 2007-12-18 | 用于pdt的治疗性hpph剂量 |
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CNA200710159998XA Pending CN101254193A (zh) | 2007-01-09 | 2007-12-18 | 用于pdt的治疗性hpph剂量 |
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US (1) | US20100130909A1 (zh) |
KR (1) | KR20090108069A (zh) |
CN (2) | CN101219138A (zh) |
WO (1) | WO2008085215A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102470239A (zh) * | 2009-08-06 | 2012-05-23 | 健康研究有限公司 | 使用光动力法治疗癌症 |
CN110922451A (zh) * | 2019-12-09 | 2020-03-27 | 福州大学 | 一种卟啉修饰的穿膜肽及其制备和应用 |
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US3069219A (en) * | 1955-07-08 | 1962-12-18 | British Celanese | Colouring cellulose triacetate textile materials |
MXPA01001336A (es) * | 1998-08-06 | 2002-04-24 | Photogen Inc | Metodo mejorado para tratamiento topico selectivo de enfermedad. |
WO2003011286A1 (en) * | 2001-07-30 | 2003-02-13 | The Research Foundation Of State University Of New York | Core modified porphyrins |
US20050154277A1 (en) * | 2002-12-31 | 2005-07-14 | Jing Tang | Apparatus and methods of using built-in micro-spectroscopy micro-biosensors and specimen collection system for a wireless capsule in a biological body in vivo |
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- 2007-09-27 US US12/448,662 patent/US20100130909A1/en not_active Abandoned
- 2007-09-27 KR KR1020097016432A patent/KR20090108069A/ko not_active Application Discontinuation
- 2007-09-27 WO PCT/US2007/020817 patent/WO2008085215A1/en active Application Filing
- 2007-12-18 CN CNA2007101600008A patent/CN101219138A/zh active Pending
- 2007-12-18 CN CNA200710159998XA patent/CN101254193A/zh active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102470239A (zh) * | 2009-08-06 | 2012-05-23 | 健康研究有限公司 | 使用光动力法治疗癌症 |
CN110922451A (zh) * | 2019-12-09 | 2020-03-27 | 福州大学 | 一种卟啉修饰的穿膜肽及其制备和应用 |
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KR20090108069A (ko) | 2009-10-14 |
WO2008085215A1 (en) | 2008-07-17 |
CN101254193A (zh) | 2008-09-03 |
US20100130909A1 (en) | 2010-05-27 |
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