CN1170535C - 外消旋α-硫辛酸在制备用于治疗偏头痛的药物中的应用 - Google Patents
外消旋α-硫辛酸在制备用于治疗偏头痛的药物中的应用 Download PDFInfo
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Abstract
本发明涉及使用外消旋α-硫辛酸、或其对映体、或其药用盐、酰胺类、酯类、或硫代酸酯,以氧化或还原的形式,作为预防性的、或者紧急、长期治疗偏头痛的活性组分。
Description
技术领域
本发明涉及使用外消旋α-硫辛酸、或其对映体,或其药用盐、酰胺类、酯类、或硫代酸酯,以氧化或还原的形式,作为预防性的、或者紧急、长期治疗偏头痛的活性组分。
背景技术
偏头痛是一种常见病症。国际头痛学会(IHS)定义偏头痛是一种以周期性发作、伴随自发(autonomic)症状,疼痛发作具有偶发性和突发性,但是该病症是一种慢性病症。有些病人没有所谓先兆,疼痛持续4-72小时,通常是单侧的,并伴有恶心和呕吐,以及畏光症和恐响症。具有所谓先兆的患者,发病前持续几分钟有可恢复的神经性症状如失语、轻瘫、共济失调、以及晕眩。流行病学研究表明,大约8-15%的人偶然或经常有轻微至严重的短暂的偏头痛发作。女性发病率高于男性。偏头痛通常第一次发作于20-35岁,成人发病率高于儿童。医生的诊断通常基于病历或发病史。没有技术或生化方法提供可靠的诊断。
偏头痛的病理生理学和病理生化学还未形成。在过去,曾认为偏头痛是一种没有生物学原因的身心失调,并且不清楚其是身体方面还是心理方面的失调。然而,绝大多数专家不再对此存有疑问。但是通常认为要考虑心理方面的变化可能诱发偏头痛,并且其他多种因素也会对患偏头痛产生影响,例如激素(月经影响)、营养(酒精以及营养不良)、药物(药剂)、环境(噪音),以及心理因素(压力)。患者仍在寻求半职业的帮助,例如顺式疗法或细胞疗法(zelltherapie)。
对于有些患者,减少局部脑部血流与偏头痛发作有关(Lauritzen& Hansen,1988)。血管周围的变化刺激相关中枢疼痛传导神经纤维,至少对部分病人来说与偏头痛发作有关(Moskowitz A.M.等,《神经医学研究》(Rev Neurol)145:181-195;1989),如各类神经传导变化(去甲肾上腺素、5-羟色胺、速激肽(tachykinine)等)(Edvinsson L.等在:Olesen J.Edvinsson L(ed.),《头痛的基本机理》(Basic mechanisms of headache)Elsevier Science Publishers,Amsterdam 129-144;1988)。最近有关于偏头痛患者线粒体磷酸化势能减少的讨论,但目前还不能确定此为偏头痛原发的缺陷还是伴随的病理表现(Schoenen等,《神经学》(Neurology)50:466-470;1998)。
至今对偏头痛依然采用症状性治疗。一些药物疗法用来调节(β阻断子),所谓的偏头痛发作诱发因素。其他化合物对血管有作用(5-羟色胺拮抗剂如舒马坦(sumatriptan),非类固醇抗感染药如乙酰水杨酸,抗惊厥药如丙戊酸)。麦角胺(ergotamine)的血管作用临床效果不明显。维生素B2是一种在线粒体呼吸链中的重要的共作用因子,据报道,对68%患者可减少偏头痛发作(Schoenen J.等.,aao)。但是未见偏头痛患者伴有维生素B2缺乏,也没有关于维生素B2缺乏患者与偏头痛患者临床症状比较性描述。
所有这些可能的干涉都是治标的方法,用以缓解至少部分患者的急性偏头痛发作的症状。各种药物和其他疗法的结合用于单独的病例以获得临床疗效。所用的药物既不能明显缓解偏头痛发作,也不能长时间内减少该病的发作频率。避免药物或环境诱发因素,也是另一种类似的重要的,希望有助于患者的方法。然而,这仍然不能治疗偏头痛病症本身,这些可以归因于缺乏对偏头痛病症病理的理解。实效疗法对许多患者是有价值的,但是无法治愈他们的疾病。
α-硫辛酸是一种自然界存在的抗氧化剂,以及一种葡萄糖代谢丙酮酸脱氢酶的辅因子(Packer L.等《生物与药物中的自由基》“Free Radicals in Biology & medicine 19(2):227-250:1995”),并广泛用于治疗糖尿病多发性神经病(Ziegler D.等《糖尿病学》(Diabetologia)38:1425-1422;1995)。另外,α-硫辛酸几十年来用于治疗肝脏疾病(Bode J.Ch.等,DMW 112(9),349-352;1987),以及霉菌真菌中毒(Brunn J.等Internist.Prax.19:475-478,1979)。最近有关于糖尿病类抗氧化剂分子级活性的描述(Nagamatsu M.等,《糖尿病治疗》(Diabees Care)18(8):1160-1167;1995)。
α-硫辛酸在氧化和还原形式所发现的各种衍生物,在生物学和治疗效果方面,有些是减弱的,有些是增强的(例如,3-酮硫辛酸、1,2-二硒醇烷-3-戊酸、硫锌酰胺、奥托硫胺、2-(N,N-二甲胺)乙基酰胺基硫辛酸-盐酸、生育硫辛酸酯(Tocopheryl-lipoat)和生育三烯基硫辛酸酯(Tocotrienyl-lipoat)、γ-羟基丁酸基硫辛酸酯、维生素E硫辛酸酯(liponsure-Vitamine E-Ester)、硫辛酸的N-乙酰基-对-氨基酚衍生物,及其他)(Tirosh O.Sen CK,Roy S,Kobayashi S,Packer L.《α-硫辛酸及其带正电荷氨基化类似物的神经保护作用》(Neuroprotective effects of α-lipoic acid and ist positively chargedamide analogue),《自由基药物》(Free Rad Med)26(11/12),1418-1426,1999;EP 0 855 396 A1,EP 0 869 126 A1,PCT/GB98/02155,WO 99/06040,DE 43 27 462 A1)。
这些衍生物被认为可以改善体内代谢和分布,也可用来分布进入中枢神经系统。有些衍生物也可改善在生物靶(生物氧化还原作用系统,例如α-酮酸脱氢酶、H-蛋白、硫氧还蛋白、谷胱甘肽还原酶、或细胞氧化还原系统,例如谷胱甘肽、辅酶Q、呼吸链复合物I,或者氧化还原和SH-敏感蛋白及酶、NO系统、过氧化氢酶、细胞的胱氨酸/半胱氨酸穿梭、同种半胱氨酸、酪氨酸激酶、MAP激酶、金属离子(用于复合作用)、α-1-抗蛋白酶、或氧化还原敏感转录因子,如NF-KB或AP1)的效果(例如,亲和性以及置换速率),或结合其他活性分子与α-硫辛酸以起增效剂作用,或者增强药物作用。
名词“α-硫辛酸”在本文中用于通用的形式,除了对映体、外消旋化合物及对映体混合物,只要α-硫辛酸的活性双硫醇烷烃基团继续部分地进行生物响应以及衍生物的药物作用,也包括衍生物(酯、硫酯、醚、盐、酰胺、代谢产物,等等)。
含α-硫辛酸的药品已出现几十年,耐受性良好。有过很多可能用途的实验,但是,从未有关于偏头痛治疗的报导。
发明内容
本发明的目的是改善偏头痛患者的健康状态。
本发明的目的是通过应用外消旋α-硫辛酸、或其对映体、或其药用盐、酰胺类、酯类、或硫酯类,以氧化或还原形式,作为活性成分预防或紧急或长期治疗偏头痛。
减轻发作症状,以及更重要的是,减少发作频率。最好的情况下,长期使用α-硫辛酸或以上所提到的衍生物,可以完全治愈偏头痛,使其不发作。
本发明另一优点是所用活性成分具有很好的耐受性(Vertrglichkeit)。
该活性成分可配置成用于口服、肠胃给药的药剂,或者作为食物补充剂、或肠胃外营养药用食物。
合适的制备方式可参考一些专利文献,或举例说,见以下公开出版文件:
EP 0858 802 A2
EP 0318 891 A1
EP 0 560 092 B1
US 5,650,429 A
US 5,334,612 A
US 5,569,670 A
用这些方法生产的产品可投放市场,标签说明用法,有必要按照一定的国内法规写明由专业人士指示患者使用。在这种情况下,该产品可能有必要提交一定的药品管理法律机构,必要时,也要提交食品管理法律机构。
活性成分的剂量通常是外消旋α-硫辛酸(α-liponsure)每日100-1800mg,较好200-1200mg,优选200-600mg,基于双硫醇烷烃残基,相当剂量一种或其他活性成分,该总剂量一天一次给药,或者分成每天二至三次给药。
α-硫辛酸的衍生物以氧化或还原形式(例如盐、酯、硫酯、醚、酰胺、代谢物),只要其给药用量在靶组织上具相当浓度或生物作用,可以类似地使用。
优选是右旋α-硫辛酸(R(+)-α-硫辛酸、或R(-)-二氢硫辛酸)、或衍生物。
本发明进一步的优选实施例包括将该活性组分随意或固定结合其他治疗偏头痛的一种或多种物质给药。
结合组分的优选实施例是舒马坦(sumatriptan),或另一种化合物选自2,2,3-三甲基丁烷类(Triptangruppe)、麦角胺、或其衍生物、一种β阻断子、抗惊厥药、镇痛药、一种抗呕吐药、或一种钙离子阻滞剂,本发明对此没有限定。类似有利的给药方式包括将活性成分与维生素、抗氧化剂、和/或和生物功能辅因子固定或随意结合给药。特别优选与维生素B2结合给药。
具体实施方式
以下以实施例方式对本发明进行解释,这些实施例不对本发明构成限制。
药剂实施例
实施例1:含600mg外消旋α-硫辛酸的片剂
1200g外消旋α-硫辛酸,颗粒尺寸60%>100μm,与120g低级取代羟基丙基纤维素(L-HPC-LH 22/Shin Etsu),混合物与600g纯净水湿润捏合。
通过筛目宽度2mm的筛子,对颗粒进行干燥,再通过筛目宽度1mm的筛子,与加入的48g硬脂酸镁混合,压制成椭圆形片剂,重684g,长18mm,宽8mm,以及曲率6毫米。一粒片剂含有外消旋α-硫辛酸600mg。
接着,可以用常规标准方法对该片剂外涂敷一层可溶于胃液的、或可以在胃液中渗透的膜。
实施例2:200mg外消旋α-硫辛酸制成氨基丁三醇盐10ml溶液
250g的外消旋α-硫辛酸,352.3g氨基丁三醇(2-氨基-2-(羟基甲基)-1,3-丙二醇),于9升注射用水和200g 1,2-丙二醇的混合物中溶解,并进行搅拌。该溶液用注射用水配置成12.5升,然后通过孔径0.2μm并带有玻璃纤维预过滤器的隔膜过滤器进行过滤。滤出液按照10ml一份无菌条件下分装在10ml安瓿中。一安瓿含有200mg外消旋α-硫辛酸的氨基丁三醇盐10ml注射溶液。
临床实施例
外消旋α-硫辛酸以口服方式给药偏头痛患者日剂量200-600mg,以商业可获得不同强度的剂量形式紧急或长期使用。以单一药剂的活性成分给药,在早上给药,或按照要求全天给药。偏头痛发作频度与严重程度与治疗前比较。给药未经治疗患者,或者用其他抗偏头痛活性组分治疗但未见成效的患者。
所治疗患者 | 临床效果 | |
1234567891011 | 未进行在先治疗在先用丙戊酸盐(valproate)治疗,接着用α-硫辛酸替换在先用维生素B2治疗在先用维生素B2治疗在先用丙戊酸盐治疗在先用丙戊酸盐、维生素B2、乙酰水杨酸治疗在先用丙戊酸盐治疗在先用丙戊酸盐治疗未进行在先治疗在先用环丙桃酯治疗未进行在先治疗 | 偏头痛发病频度50%减少替换后维持用丙戊酸盐的治疗效果偏头痛发病频度100%减少偏头痛发病频度100%减少偏头痛发病频度50%减少偏头痛发病频度80%减少偏头痛发病频度50%减少偏头痛发病程度50%减轻偏头痛发病频度75%减少偏头痛发病频度40%减少给药200-600mgα-硫辛酸之日起,30-100%病情减轻 |
对偏头痛患者进行药物治疗观察的评估,一定要考虑发现的额外的效果,与根据其他疗法的经验测定比较是很突出的。特别是对于抗治疗患者的效果是很有价值并且令人吃惊的。这些突出了本发明对于今后治疗偏头痛的价值。
Claims (11)
1.外消旋α-硫辛酸、或其对映体、或其药用盐、酰胺、酯、或硫酯在制备用于预防、或紧急、或长期治疗偏头痛的药物中的应用。
2.根据权利要求1所述的应用,其中所述偏头痛发作症状的严重性和频度得以减少。
3.根据权利要求1或2所述的应用,其中所述药物的活性组分是以药剂形式应用。
4.根据权利要求1或2所述的应用,其中所述药物的活性组分是以食物、或肠胃营养食物补充剂形式应用。
5.根据权利要求1或2所述的应用,其中所述药物的活性组分是用外消旋α-硫辛酸每日100-1800mg,或者,基于双硫醇烷烃残基,一种或其他活性成分的相当剂量。
6.根据权利要求1或2所述的应用,其中所述药物的活性组分是用外消旋α-硫辛酸每日200-1200mg,或者,基于双硫醇烷烃残基,一种或其他活性成分的相当剂量。
7.根据权利要求1或2所述的应用,其中所述药物的活性组分是用外消旋α-硫辛酸每日200-600mg,或者,基于双硫醇烷烃残基,一种或其他活性成分的相当剂量。
8.根据权利要求5所述的应用,其中所述剂量是一天一次给药,或者分成每天二至三次给药。
9. 根据权利要求1所述的应用,其中所述药物的活性组分是通过固定或随意结合另一种、或多种物质给药,用于治疗偏头痛。
10.根据权利要求9所述的应用,其中所述其他物质是舒马坦、或另一种化合物,选自2,2,3-三甲基丁烷类、麦角胺或其衍生物、一种β阻断子、抗惊厥药、镇痛药、一种抗呕吐药、或一种钙离子阻滞剂。
11.根据权利要求10所述的应用,其中所述的活性组分与维生素、抗氧化剂、和/或和生物功能辅因子固定或随意结合给药。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19941217A DE19941217A1 (de) | 1999-08-30 | 1999-08-30 | Behandlung der Migräne durch Verabreichung von alpha-Liponsäure oder Derivaten derselben |
DE19941217.0 | 1999-08-30 |
Publications (2)
Publication Number | Publication Date |
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CN1371280A CN1371280A (zh) | 2002-09-25 |
CN1170535C true CN1170535C (zh) | 2004-10-13 |
Family
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Application Number | Title | Priority Date | Filing Date |
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CNB008122032A Expired - Fee Related CN1170535C (zh) | 1999-08-30 | 2000-08-26 | 外消旋α-硫辛酸在制备用于治疗偏头痛的药物中的应用 |
Country Status (32)
Country | Link |
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US (1) | US6251935B1 (zh) |
EP (1) | EP1207878B1 (zh) |
JP (1) | JP4773015B2 (zh) |
KR (1) | KR100624215B1 (zh) |
CN (1) | CN1170535C (zh) |
AT (1) | ATE232725T1 (zh) |
AU (1) | AU781505B2 (zh) |
BG (1) | BG65735B1 (zh) |
BR (1) | BR0013651A (zh) |
CA (1) | CA2382548C (zh) |
CZ (1) | CZ301789B6 (zh) |
DE (2) | DE19941217A1 (zh) |
DK (1) | DK1207878T3 (zh) |
EE (1) | EE04869B1 (zh) |
ES (1) | ES2190985T3 (zh) |
HK (1) | HK1046637A1 (zh) |
HR (1) | HRP20020168A2 (zh) |
HU (1) | HU229603B1 (zh) |
IL (2) | IL148068A0 (zh) |
IS (1) | IS2214B (zh) |
MX (1) | MXPA02002246A (zh) |
NO (1) | NO328692B1 (zh) |
NZ (1) | NZ517276A (zh) |
PL (1) | PL200928B1 (zh) |
PT (1) | PT1207878E (zh) |
RS (1) | RS50139B (zh) |
RU (1) | RU2232577C2 (zh) |
SK (1) | SK286260B6 (zh) |
TR (1) | TR200200461T2 (zh) |
UA (1) | UA71031C2 (zh) |
WO (1) | WO2001015693A2 (zh) |
ZA (1) | ZA200201637B (zh) |
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CA2352144A1 (en) * | 1998-11-25 | 2000-06-02 | Yissum Research Development Company Of The Hebrew University In Jerusale M | Scavenger compounds |
US7030154B2 (en) | 2002-06-07 | 2006-04-18 | Juvenon, Inc. | Stability of lipoic acid |
US20050065094A1 (en) | 2003-09-05 | 2005-03-24 | Boehringer Ingelheim International Gmbh | Use of telmisartan for the prevention and treatment of vascular headache |
US20050282879A1 (en) * | 2004-06-17 | 2005-12-22 | Foad Salehani | Methods and composition for treatment of migraine and symptoms thereof |
US7943163B2 (en) * | 2007-08-22 | 2011-05-17 | Response Scientific, Inc. | Medical food or nutritional supplement, method of manufacturing same, and method of managing diabetes |
US20090054513A1 (en) * | 2007-08-22 | 2009-02-26 | Response Scientific, Inc. | Method of managing blood glucose levels, insulin levels and/or insulin receptor functionality in individuals with diabetes, polycystic ovarian syndrome and/or alzheimer's disease |
KR101493125B1 (ko) | 2008-11-24 | 2015-02-12 | 세다르스-신나이 메디칼 센터 | 항산화성 캠토테신 유도체 및 이들의 항산화성 항종양성 나노구체 |
AU2010247141A1 (en) | 2009-05-15 | 2011-12-15 | Redx Pharma Plc | Redox drug derivatives |
KR100935554B1 (ko) | 2009-06-24 | 2010-01-07 | 주식회사 셀트리온제약 | 피페라진 다이티옥트산염 및 이를 포함하는 약제학적 조성물 |
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SU620265A1 (ru) * | 1977-02-21 | 1978-08-25 | Центральный Ордена Трудового Красного Знамени Научно-Исследовательский Институт Курортологии И Физиотерапии | Способ лечени атеросклероза сосудов головного мозга и гипертонической болезни |
ES2043897T3 (es) * | 1988-01-28 | 1994-01-01 | Koeltringer Peter | Preparado de combinacion, en especial para el tratamiento de enfermedades de las celulas nerviosas. |
IE904034A1 (en) * | 1989-11-09 | 1991-05-22 | Asta Medica Ag | A medicament containing r-ó-lipoic acid or s-ó-lipoic acid¹as active substance |
DE4218572A1 (de) * | 1992-06-05 | 1993-12-09 | Asta Medica Ag | Synergistische Kombination von Arzneimitteln enthaltend als Wirkstoff alpha-Liponsäure, Dihydroliponsäure, deren Metaboliten sowie die oxidierten und reduzierten Enantiomere der alpha-Liponsäure wie die R-alpha-Liponsäure oder S-alpha-Liponsäure sowie Metaboliten der alpha-Liponsäure mit den Vitaminen A, B1-6, B12, C und E |
US5569670A (en) * | 1992-06-05 | 1996-10-29 | Asta Medica Aktiengesellschaft | Combination medications containing alpha-lipoic acid and related |
EP0604641B1 (en) * | 1992-06-30 | 2002-03-20 | SHAPIRO, Howard, K. | Use of a combination containing an amine or amine-related derivative of benzoic acid and an amino-polysaccharide in the manufacture of a medicament for the treatment of inflammatory diseases |
DE4327426A1 (de) * | 1993-08-14 | 1995-02-16 | F H Erdaussiebung Gmbh | Anbaugerät zum Sieben und Verfüllen von Erdmaterialien |
DE4327462A1 (de) * | 1993-08-16 | 1995-02-23 | Carl Heinrich Dr Weischer | Neue N-Acetyl-p-Aminophenol-Derivate zur Bekämpfung von Schmerzzuständen |
DE4331168A1 (de) * | 1993-09-14 | 1995-03-16 | Carl Heinrich Dr Weischer | Kombination von N-Acetyl-p-Aminophenol mit schwefelenthaltenden Carbonsäuren, wie z. B. alpha-Liponsäure und deren Derivate, zur Bekämpfung von Schmerzzuständen |
EP0855396A1 (en) * | 1997-01-22 | 1998-07-29 | ASTA Medica Aktiengesellschaft | Thioctic acid metabolites and methods of use thereof |
CZ96798A3 (cs) * | 1997-04-02 | 1998-10-14 | Sankyo Company Limited | Deriváty dithiolanu, jejich příprava a jejich terapeutické účinky |
AU8768098A (en) * | 1997-08-04 | 1999-02-22 | Christopher J. Berry | Method of treating disease using a tocotrienol and alpha-lipoic acid r derivatives or an ester thereof |
GB2333757B (en) * | 1998-02-03 | 2001-06-27 | Cheung Kwok Chung | Sliding platform |
JP2002510604A (ja) * | 1998-04-02 | 2002-04-09 | アビセナ グループ, インク. | クレアチン化合物及び第二物質の組み合わせを含む組成 |
AR042572A1 (es) * | 1999-04-02 | 2005-06-29 | Sod Conseils Rech Applic | Derivados de acido lipoico, procedimiento para su preparacion, medicamentos y composiciones farmaceuticas que los contienen y utilizacion de dichos derivados para la preparacion de los referidos medicamentos |
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