CN1177587C - 利鲁唑和α-生育酚联合制剂 - Google Patents
利鲁唑和α-生育酚联合制剂 Download PDFInfo
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Abstract
α-生育酚和利鲁唑或该化合物在药学上可接受的盐的联合制剂以及这种联合制剂在治疗肌萎缩性侧索硬化方面的用途。
Description
本发明涉及利鲁唑(RILUZOLE)或在药学上可接受的这种化合物的盐和α-生育酚的联合制剂以及这种联合制剂在治疗肌萎缩性侧索硬化(SLA)方面的用途。
CHARCOT在1865年第一次描述也被称作CHARCOT病和LOU GEHRIG病的肌萎缩性侧索硬化。SLA是一种由运动神经元退化造成的致死疾病。这种疾病伴随逐渐麻痹，因此导致丧失运动和呼吸功能，而后在出现第一个症兆后2-8年内死亡。
直到今天，仅存在以RILUTEK商品名销售的利鲁唑(2-氨基-6-三氟甲氧基苯并噻唑)用于治疗肌萎缩性侧索硬化。利鲁唑原则上能够延缓疾病的发展。
现在发现，利鲁唑或其药学上可接受的盐与α-生育酚(α-生育酚)的联合制剂比仅用利鲁唑能够更显著地延缓这种疾病发展，还能够缓解患者的疲劳和降低血浆中丙二醛的浓度。
对总数为289位年龄在18岁以上的患者进行研究，这些患者患有SLA不到5年，其肿活量/理论肺活量之比高于或等于60％(肺活量是通常的呼吸功能的常规度量，也称作呼吸功能试验)。
这些患者分成两组：
第一组：145位患者通过口服100毫克/天利鲁唑和口服1000毫克/天α-生育酚进行治疗，
第二组：144位患者通过口服100毫克/天利鲁唑和安慰剂进行治疗。
这2组患者中在第二次评价中不再符合给药标准或未正确地进行合理治疗的某些患者未被考虑进行结果确定。
这些患者被跟踪一年。这些结果根据功能等级(Munsat功能阶段(RIVIERE等人，Arch.Neurol.，55，526(1998))，类比的易疲劳性目视等级(EVA)(LACOMBLEZ及其同事，Lancet，347，1425(1996)；Bensimon及其同事，新英格兰医学杂志(New England Journal of Medicine)，330，585(1994))和血浆中丙二醛浓度，氧化性应激的生物化学标记物(FAVIER，生物系统中自由基分析(Analysis of free radical inbiological system)，Birk Hauser，Basel/Switzerland，1995，第100-117页)度量。
Munsat功能阶段A涉及一般或中等阶段的患者：
-一般阶段：在3个方面(语言、手臂和下肢)一般地出现功能缺陷，在语言能力、日常生活和步行中上肢活动方面出现功能自主性，
-中等阶段：在3个方面一般地出现功能缺陷，或在一个方面中等至严重地出现功能缺陷，而另外两个方面是正常的或稍微产生不利影响。
Munsat功能阶段B涉及严重级或最后阶段患者：
-严重阶段：需要在2或3个方面得到帮助，构音障碍和/或行走需要帮助和/或日常生活中上肢活动需要帮助的患者，
-最后阶段：至少2个方面非功能使用和第3方面中等使用或非功能使用。
在给药时刻(M0)和治疗12个月后(M12)测定了功能阶段A和B的变化。得到如下结果：
| 利鲁唑和安慰剂(患者数) | 利鲁唑和α-生育酚(患者数) | |
| 给药时刻(M0)A级B级 | 10910 | 11210 |
| 治疗后状态(M12)A级B级 | 5663 | 7349 |
这些结果表明，在用利鲁唑和安慰剂治疗12个月之后，53位患者(44.5％)病情恶化，66位患者(55.3％)没有变化，而在经过利鲁唑和α-生育酚联合制剂治疗的患者中只有39位患者(32％)病情恶化，83位患者(68％)没有变化。
因此，给药利鲁唑和α-生育酚联合制剂比只用利鲁唑可以进一步减缓病情发展。
根据类比的目视等级(EVA)，测定给药时刻(M0)和3个月(M3)后的易疲劳性。
在这个试验中，得到如下平均值：
| M0时刻的EVA(毫米) | M3时刻的EVA(毫米) | M0与M3之差(毫米) | |
| 利鲁唑和安慰剂(115位患者) | 48.4 | 65.7 | 17.3 |
| 利鲁唑和α-生育酚联合制剂(118位患者) | 46.4 | 58.6 | 12.2 |
这些值清楚地表明，通过利鲁唑和α-生育酚联合制剂治疗的患者与通过利鲁唑和安慰剂治疗的患者相比，疲劳程度更低。
在给药时刻(M0)和3个月(M3)时测定作为SLA变化预示性因素的血浆中丙二醛浓度。
得到的浓度平均值如下：
| M0时刻的浓度(微摩尔) | M3时刻的浓度(微摩尔) | M3与M0之差(微摩尔) | |
| 利鲁唑和安慰剂(65位患者) | 2.94±0.40 | 2.72±0.40 | 0.22±0.40 |
| 利鲁唑和α-生育酚(58位患者) | 2.86±0.40 | 2.36±0.30 | 0.50±0.50 |
这些结果表明，患有肌萎缩性侧索硬化的患者体内血浆丙二醛浓度(M0时刻浓度)增加，治疗期间降低，但使用利鲁唑和α-生育酚联合制剂与只使用利鲁唑和安慰剂的情况相比，降低程度更明显。
作为药学上可接受的利鲁唑盐，特别可以列举与无机酸的加合盐，例如盐酸盐、硫酸盐、硝酸盐、磷酸盐，或与有机酸的加合盐，例如乙酸盐、丙酸盐、琥珀酸盐、草酸盐、苯甲酸盐、富马酸盐、马来酸盐、甲磺酸盐、羟乙磺酸盐、茶叶碱-乙酸盐、水杨酸盐、酚酞酸盐、亚甲基-双-β-萘酚酸盐或这些衍生物的取代衍生物。
该联合制剂可以通过口服、肠胃道外或直肠同时、分别地或在时间上错开地分期用药。
本发明还涉及含有纯的或为与一种或多种相容的和药学上可接受的稀释剂和/或添加剂组合的形式和/或任选地与另外一种药学上相容的和生理学活性化合物结合的利鲁唑和α-生育酚联合制剂的药物组合物。
作为口服的固体组合物，可以使用片、丸、粉剂(胶囊、凝胶、片)或颗粒剂。在这些组合物中，在氩气流下，让这些活性组分与一种或多种惰性稀释剂如淀粉、纤维素、蔗糖、乳糖或二氧化硅混合。这些组合物还可以含有除稀释剂之外的物质，例如一种或多种润滑剂如硬脂酸镁或滑石、着色剂、包裹剂(糖衣)或漆。
作为口服液体组合物，可以使用含有惰性稀释剂如水、乙醇、甘油、植物油或石蜡油的药学上可接受的溶液、悬混液、乳液、糖浆和酏剂。这些组合物可以含有除稀释剂之外的物质，例如润湿剂、甜味剂、增稠剂、芳香剂或稳定剂。
灭菌的肠胃道外用药组合物优选地可以是含水或非水溶液、悬混液或乳液。作为溶剂或载体，可以使用水、丙二醇、聚乙二醇、植物油，特别是橄榄油、可注射有机酯，例如油酸乙酯或其它合适的有机溶剂。这些组合物还可以含有助剂，特别是润湿剂、等渗剂、乳化剂、分散剂和稳定剂。灭菌可以多种方式如采用通过在组合物中加入灭菌剂进行灭菌过滤、辐照或加热的方式进行。它们还可以制成灭菌固体组合物，在使用时将这些组合物溶于无菌水或任何其它可注射无菌介质中。
直肠给药组合物是除了活性产品以外还含有载体如椰子油、半合成甘油酯或聚乙二醇的栓剂或直肠用胶囊。
本发明还涉及对患有肌萎缩性侧索硬化的患者进行治疗的方法，其中包括同时、分别地或在时间上错开地分期向患者给药利鲁唑或它在药学上可接受的盐和α-生育酚的联合制剂。
使用的剂量取决于要求达到的效果、治疗时间和给药方式；其剂量一般是成人每天口服10-400毫克、单位剂量为10-200毫克的利鲁唑，成人每天口服250-4000毫克、单位剂量为100-1000毫克的α-生育酚。
一般地，医生将依据待治疗者的年龄、体重和其它固有因素确定合适的剂量。
Claims (6)
1、α-生育酚或其在药学上可接受的盐和利鲁唑或其在药学上可接受的盐的联合制剂，其中每250-4000重量份α-生育酚使用10-400重量份利鲁唑。
2、根据权利要求1的联合制剂，其中该联合制剂是用于同时、分别地或在时间上错开地分期使用的形式。
3、α-生育酚或其在药学上可接受的盐和利鲁唑或其在药学上可接受的盐在制备用于治疗肌萎缩性侧索硬化的药物中的用途。
4、利鲁唑在制备权利要求1的联合制剂方面的用途。
5、基本上由α-生育酚或其在药学上可接受的盐和利鲁唑或其在药学上可接受的盐组成的药物组合物，其中每250-4000重量份α-生育酚使用10-400重量份利鲁唑。
6、基本上由α-生育酚或其在药学上可接受的盐和利鲁唑或其在药学上可接受的盐以及任何相容的和药学上可接受的稀释剂或添加剂组成的药物组合物，其中每250-4000重量份α-生育酚使用10-400重量份利鲁唑。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR98/14250 | 1998-11-13 | ||
| FR9814250A FR2785808B1 (fr) | 1998-11-13 | 1998-11-13 | Association riluzole et alpha-tocopherol |
Publications (2)
| Publication Number | Publication Date |
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| CN1326348A CN1326348A (zh) | 2001-12-12 |
| CN1177587C true CN1177587C (zh) | 2004-12-01 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB998131903A Expired - Fee Related CN1177587C (zh) | 1998-11-13 | 1999-11-09 | 利鲁唑和α-生育酚联合制剂 |
Country Status (23)
| Country | Link |
|---|---|
| US (2) | US6642262B2 (zh) |
| EP (1) | EP1128829B1 (zh) |
| JP (1) | JP4693241B2 (zh) |
| KR (1) | KR100641472B1 (zh) |
| CN (1) | CN1177587C (zh) |
| AT (1) | ATE295168T1 (zh) |
| AU (1) | AU776242B2 (zh) |
| BR (1) | BR9915292A (zh) |
| CA (1) | CA2350671C (zh) |
| CZ (1) | CZ298808B6 (zh) |
| DE (1) | DE69925301T2 (zh) |
| DK (1) | DK1128829T3 (zh) |
| EA (1) | EA003671B1 (zh) |
| ES (1) | ES2239858T3 (zh) |
| FR (1) | FR2785808B1 (zh) |
| HK (1) | HK1041220B (zh) |
| HU (1) | HU226067B1 (zh) |
| IL (1) | IL142708A0 (zh) |
| NO (1) | NO328349B1 (zh) |
| PT (1) | PT1128829E (zh) |
| TR (1) | TR200101346T2 (zh) |
| WO (1) | WO2000028992A1 (zh) |
| ZA (1) | ZA200103810B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2786101B1 (fr) * | 1998-11-24 | 2002-07-05 | Aventis Laboratoire | Utilisation de la nicergoline dans le traitement de la spasticite |
| KR20080066014A (ko) * | 2005-10-18 | 2008-07-15 | 오노 야꾸힝 고교 가부시키가이샤 | 근위축성측삭경화증 환자의 운동 신경 보호용 의약 |
| US20070099156A1 (en) * | 2005-10-28 | 2007-05-03 | Jeff Wagner | Self-etching dental primer compositions and methods and systems utilizing such compositions |
| FR2957077B1 (fr) * | 2010-03-02 | 2012-04-13 | Univ Dauvergne Clermont I | Utilisation du riluzole pour traiter ou prevenir les effets indesirables d'agents anti-cancereux |
| WO2014145776A2 (en) * | 2013-03-15 | 2014-09-18 | Baylor College Of Medicine | Msp and its receptors in the therapy of amyotrophic lateral sclerosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2688138B1 (fr) * | 1992-03-06 | 1995-05-05 | Rhone Poulenc Rorer Sa | Application de l'amino-2 trifluoromethoxy-6 benzothiazole pour obtenir un medicament destine au traitement de la sclerose laterale amyotrophique. |
| US5843641A (en) * | 1993-02-26 | 1998-12-01 | Massachusetts Institute Of Technology | Methods for the daignosis, of familial amyotrophic lateral sclerosis |
| US6380252B1 (en) * | 1996-07-05 | 2002-04-30 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Use of L-acetylcarnitine, L-isovalerylcarnitine, L-propionylcarnitine for increasing the levels of IGF-1 |
| US5780489A (en) * | 1996-08-21 | 1998-07-14 | Brooks; Benjamin Rix | Method for treating amyotrophic lateral sclerosis |
| JP3889844B2 (ja) * | 1997-02-10 | 2007-03-07 | 龍兒 梶 | 筋萎縮性側索硬化症治療剤 |
| FR2782008B1 (fr) * | 1998-08-07 | 2003-04-25 | Sod Conseils Rech Applic | Utilisation d'extraits de ginkgo biloba pour preparer un medicament destine a traiter la sclerose laterale amyotrophique |
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1998
- 1998-11-13 FR FR9814250A patent/FR2785808B1/fr not_active Expired - Fee Related
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1999
- 1999-11-09 EP EP99972101A patent/EP1128829B1/fr not_active Expired - Lifetime
- 1999-11-09 BR BR9915292-4A patent/BR9915292A/pt not_active Application Discontinuation
- 1999-11-09 AT AT99972101T patent/ATE295168T1/de active
- 1999-11-09 IL IL14270899A patent/IL142708A0/xx not_active IP Right Cessation
- 1999-11-09 KR KR1020017005912A patent/KR100641472B1/ko not_active Expired - Fee Related
- 1999-11-09 DE DE69925301T patent/DE69925301T2/de not_active Expired - Lifetime
- 1999-11-09 HK HK02102998.6A patent/HK1041220B/zh not_active IP Right Cessation
- 1999-11-09 CN CNB998131903A patent/CN1177587C/zh not_active Expired - Fee Related
- 1999-11-09 HU HU0105301A patent/HU226067B1/hu not_active IP Right Cessation
- 1999-11-09 EA EA200100530A patent/EA003671B1/ru not_active IP Right Cessation
- 1999-11-09 TR TR2001/01346T patent/TR200101346T2/xx unknown
- 1999-11-09 CA CA2350671A patent/CA2350671C/fr not_active Expired - Fee Related
- 1999-11-09 CZ CZ20011561A patent/CZ298808B6/cs not_active IP Right Cessation
- 1999-11-09 DK DK99972101T patent/DK1128829T3/da active
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- 1999-11-09 JP JP2000582039A patent/JP4693241B2/ja not_active Expired - Fee Related
- 1999-11-09 ES ES99972101T patent/ES2239858T3/es not_active Expired - Lifetime
- 1999-11-09 WO PCT/FR1999/002753 patent/WO2000028992A1/fr active IP Right Grant
- 1999-11-09 AU AU11655/00A patent/AU776242B2/en not_active Ceased
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- 2001-05-10 ZA ZA200103810A patent/ZA200103810B/en unknown
- 2001-05-10 NO NO20012308A patent/NO328349B1/no not_active IP Right Cessation
- 2001-05-11 US US09/854,318 patent/US6642262B2/en not_active Expired - Lifetime
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