CN1400905A - 依诺肝素的新治疗应用 - Google Patents
依诺肝素的新治疗应用 Download PDFInfo
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- CN1400905A CN1400905A CN01803471A CN01803471A CN1400905A CN 1400905 A CN1400905 A CN 1400905A CN 01803471 A CN01803471 A CN 01803471A CN 01803471 A CN01803471 A CN 01803471A CN 1400905 A CN1400905 A CN 1400905A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
本发明涉及依诺肝素在治疗脑缺血中的应用。
Description
本发明涉及依诺肝素的新治疗应用。
依诺肝素(Lovenox,Clexane)是一种市场销售的低分子量肝素,它用于预防性治疗在外科手术有中等或高度危险的静脉血栓栓塞的疾病,预防在血液透析过程中体外循环回路的血凝固,治疗体质的深度静脉血栓形成,它还与阿司匹林配合用于治疗不稳定的心绞疼和急性期无Q波的心肌梗塞。依诺肝素同样适用于预防和/或治疗中枢神经系统创伤(WO 98/53833)和脑水肿(WO98/53834)。
在预防和/或治疗脑缺血患者体内的深度静脉血栓形成时曾试验低分子量肝素,但未证明对局部缺血产生任何效果(A.ELIAS及其同事,《内科学杂志》《La Revue de Médecine Interne》,1(XI),95-98(1990);MH.PRINS及其同事,《Haemostasis》,19,245-250(1989);AGG.TURPIE及其同事,《Lancet》,523-526(1987))。
现在发现依诺肝素能够减少脑缺血后遗症,因此可以用于治疗脑局部缺血。
根据下述方案在鼠体内确定了这种新的治疗应用:
随意地向雄性斯—道鼠(230-250克,Iffa Credo)喂食喂水并且对其保持12小时昼-夜循环。在氟烷(1.4%,在70%N2O/30%O2混合物中)下进行外科手术。在麻醉期间,将该鼠放在恒温毡下保持体温正常。剥离左颈总动脉,进行松弛捆扎。通过颞下开颅术暴露开左脑中动脉,用微型夹钳钳住该动脉端部,接着用颈动脉绷带扎住。两小时后,这些动物再次被麻醉,通过取下脑中动脉夹钳和颈动脉绷带,恢复脑循环。这时这些鼠被放回到26-28℃恒温间的笼中。
在外科手术48小时后,由不了解处理情况的研究人员对每只鼠进行神经学研究。在表1中列出使用的神经学评级。
表1
项目 | 正常 | 不足 | |
紧紧抓住不放的本能反应 | 右前爪 | 1 | 0 |
移位反应 | |||
失去支撑 | 右前爪 | 1 | 0 |
右后爪 | 1 | 0 | |
伸直本能反应 | |||
旋转 | 右侧 | 1 | 0 |
左侧 | 1 | 0 | |
非正常姿势 | 无 | 有 | |
右前爪弯曲 | 1 | 0 | |
身体扭曲 | 1 | 0 | |
神经学总分 | 7 | 0 |
在神经学研究后,使这些鼠无痛苦死亡,再取出它们的脑。制备厚度1.5毫米的系列切片,并用2%2,3,5-三苯基四唑氯(TTC)着色。在10%甲醛溶液中后固定24小时后,在皮层和纹状体处测量损伤(脑梗塞)区域;通过积分损伤表面积计算出体积。这些值用毫米3表示(平均值±E.S.M)。通过用于非参数偏差分析的Mann-Whitney检验或Kruskal-Wallis检验,接着通过组之间的比较(相对于对照组,*:p<0.05,**:p<0.01,***:p<0.001)的Dunn检验,进行统计分析。
在研究1中,在局部缺血开始后2小时和24小时,12只鼠以1.5毫克/千克的剂量静脉给药依诺肝素。按照同样的方案,对照组的10只鼠只被给予赋形剂(0.9%氯化钠生理盐水)。
在研究2中,研究依诺肝素治疗时机。在局部缺血后5小时开始治疗,接着在24小时第二次给药。该研究在于依诺肝素剂量对脑损伤所产生的功效。研究的剂量是静脉给药0.5,1和1.5毫克/千克(每组9-10只鼠)。对照组的11只鼠只被给予赋形剂(0.9%氯化钠生理盐水)。
在研究3中,在局部缺血开始后5和24小时,10只鼠按照1.5毫克/千克的剂量静脉给药依诺肝素。对照组的13只鼠只是给予赋形剂(0.9%氯化钠生理盐水)。
在研究4中,其方案与其他研究过程相同,不同之处在于永久性地烧灼左脑中动脉并且不闭塞左颈动脉。13只鼠在局部缺血开始后5和24小时按照1.5毫克/千克的剂量静脉给药依诺肝素。对照组的13只鼠只是给予赋形剂(0.9%氯化钠生理盐水)。
得到的结果汇集于下表2。
表2
研究 | 皮层损伤(毫米3) | 神经学分7分级 | |
研究1 | 对照组依诺肝素组2×1.5毫克/千克静脉内 | 186±18131±13* | 1.7±0.33.1±0.2** |
研究2 | 对照组依诺肝素组2×0.5毫克/千克静脉内2×1毫克/千克静脉内2×1.5毫克/千克静脉内 | 203±12164±15142±24*129±17* | |
研究3 | 对照组依诺肝素组2×1.5毫克/千克静脉内 | 195±12129±16** | 1.8±0.33.4±0.3*** |
研究4 | 对照组依诺肝素组2×1.5毫克/千克静脉内 | 137±2371±13* | 1.7±0.22.9±0.3** |
这些结果证明,
-在研究1中,依诺肝素显著地提高脑缺血后48小时的神经学分,另外显著降低皮层损伤达30%,
-在研究2中,依诺肝素降低皮层损伤达30%(2×1毫克/千克)和36%(2×1.5毫克/千克),
-在研究3中,依诺肝素显著地提高神经学分,降低皮层损伤达34%,
-在研究4中,依诺肝素显著地提高神经学分,降低皮层损伤达49%。
这些研究中没有遇到任何出血问题。
这些药物由呈组合物形式的依诺肝素组成,其中依诺肝素可与任何其他在药学上相容的产品组合,这些产品可以是惰性的或在生理学上是活性的。优选地可以通过静脉内和皮下途径给药本发明的药物。
用于静脉内和皮下给药的无菌组合物一般是水溶液。这些组合物还可以含有添加剂,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,例如通过灭菌过滤、混入灭菌剂组合物之中、辐照来进行。这些组合物还可以制备成无菌的固体组合物形式,在使用时可以将这些组合物溶于无菌的水中或任何其他可注射的无菌介质中。
作为一种组合物实例,可以将20毫克依诺肝素溶于其量足以制备0.2毫升溶液的蒸馏水中。
剂量取决于追求的效果,治疗时间和用药方式。皮下用药剂量一般是每天0.2-4毫克/千克,即每个成人每天14-280毫克,单位剂量是5-280毫克。
一般地,医生将根据待治疗患者的年龄、体重和所有其他自身因素确定适当的剂量。
本发明还涉及治疗人的脑缺血方法,该方法包括给药有效量的依诺肝素。
本发明还涉及依诺肝素在制备适用于治疗脑缺血药物中的应用。
Claims (2)
1、依诺肝素在制备适用于治疗脑缺血药物中的用途。
2、权利要求1的用途,其中所述药物含有5-280毫克依诺肝素。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR00/00137 | 2000-01-06 | ||
FR0000137A FR2803522B1 (fr) | 2000-01-06 | 2000-01-06 | Nouvelle application therapeutique de l'enoxaparine |
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CN1400905A true CN1400905A (zh) | 2003-03-05 |
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CN01803471A Pending CN1400905A (zh) | 2000-01-06 | 2001-01-03 | 依诺肝素的新治疗应用 |
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EP (1) | EP1248638B1 (zh) |
JP (1) | JP2003519185A (zh) |
KR (1) | KR20020069240A (zh) |
CN (1) | CN1400905A (zh) |
AR (1) | AR026804A1 (zh) |
AT (1) | ATE344671T1 (zh) |
AU (1) | AU784656B2 (zh) |
BR (1) | BR0107442A (zh) |
CA (1) | CA2396178A1 (zh) |
CZ (1) | CZ20022303A3 (zh) |
DE (1) | DE60124373T2 (zh) |
DK (1) | DK1248638T3 (zh) |
EA (1) | EA006035B1 (zh) |
EE (1) | EE200200374A (zh) |
ES (1) | ES2275648T3 (zh) |
FR (1) | FR2803522B1 (zh) |
HK (1) | HK1052649A1 (zh) |
HR (1) | HRP20020573A2 (zh) |
HU (1) | HUP0204040A3 (zh) |
IL (1) | IL150477A0 (zh) |
MX (1) | MXPA02006672A (zh) |
NO (1) | NO20023243L (zh) |
NZ (1) | NZ520283A (zh) |
PL (1) | PL357192A1 (zh) |
PT (1) | PT1248638E (zh) |
SK (1) | SK9612002A3 (zh) |
UA (1) | UA75587C2 (zh) |
WO (1) | WO2001049298A2 (zh) |
YU (1) | YU51802A (zh) |
ZA (1) | ZA200205415B (zh) |
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AR063530A1 (es) * | 2006-10-30 | 2009-01-28 | Aventis Pharma Sa | Procedimiento de utilizacion de enoxaparina sodica para la preparacion de un medicamento |
ITMI20091445A1 (it) * | 2009-08-07 | 2011-02-08 | Inalco S P A A Socio Unico | Derivati semi-sintetici del polisaccaride k5 per la prevenzione ed il trattamento del danno tissutale associato a ischemia e/o riperfusione |
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AU5442594A (en) * | 1992-10-13 | 1994-05-09 | Virginia Commonwealth University | Use of non-anticoagulant heparin for treating ischemia/reperfusion injury |
US5767269A (en) * | 1996-10-01 | 1998-06-16 | Hamilton Civic Hospitals Research Development Inc. | Processes for the preparation of low-affinity, low molecular weight heparins useful as antithrombotics |
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- 2001-01-03 PT PT01903859T patent/PT1248638E/pt unknown
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- 2001-01-03 CZ CZ20022303A patent/CZ20022303A3/cs unknown
- 2001-01-03 EP EP01903859A patent/EP1248638B1/fr not_active Expired - Lifetime
- 2001-01-03 ES ES01903859T patent/ES2275648T3/es not_active Expired - Lifetime
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- 2002-07-04 NO NO20023243A patent/NO20023243L/no not_active Application Discontinuation
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