CN1209057A - 一氧化氮(no)合酶抑制剂用于治疗或预防ii型糖尿病 - Google Patents
一氧化氮(no)合酶抑制剂用于治疗或预防ii型糖尿病 Download PDFInfo
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Abstract
一种治疗和/或预防Ⅱ型糖尿病的方法,该方法包括给予人或非人哺乳动物有效无毒的可药用量的NO合酶抑制剂如氨基胍,或其药学上可接受的衍生物。
Description
本发明涉及新的治疗和/或预防非胰岛素依赖性(NIDDM或II型)糖尿病的方法，特别是涉及NO合酶抑制剂，如氨基胍，用于所述治疗和/或预防。
Hydrazinecarboximidamide(下文称作氨基胍)是已知的化合物(Journal of American Chemical Society，57，2730，1935)。
已知氨基胍是一种蛋白糖化(glycation)抑制剂并正在用动物模型评价它对糖尿病并发症的治疗作用(Diabetes 42，221-232 1993；Diabetologia 35，946-950)。
已知氨基胍是一种NO合酶抑制剂(Eur.J.Pharmacol.，233，119-125)并用于治疗以过量产生NO为特征的疾病(Eur.J.Pharmacol.，233，1993，119-125)。对一氧化氮形成的抑制作用特别被认为与氨基胍治疗糖尿病并发症的已知活性有关(欧洲专利申请公开号)。氨基胍正在用动物模型评价对糖尿病并发症的治疗作用(Diabetes 42，221-232 1993；Diabetologia 35，946-950)。
目前，还没有证据表明氨基胍或任何其它一氧化氮合酶抑制剂会对II型糖尿病本身具有有益的作用。如上所述，已将注意力集中在糖尿病并发症上。我们现已惊奇地发现氨基胍显示用于治疗和/或预防II型糖尿病本身的潜力。特别是，氨基胍显示延缓或防止非胰岛素依赖性糖尿病由血胰岛素过多向明显的糖尿病的发展。这种新的和出人意料的作用被认为是由于氨基胍对II型糖尿病的胰腺的NO合酶的抑制活性。
因此，本发明提供一种治疗和/或预防II型糖尿病的方法，该方法包括给予人或非人哺乳动物有效和无毒的可药用量的NO合酶抑制剂或其可药用衍生物。
优选地，本发明提供一种预防性治疗II型糖尿病，特别是延迟或防止血胰岛素过多向血糖过多发展的方法。
合适的NO合酶抑制剂包括蛋白质和非蛋白质化合物，如氨基胍、n-单甲基精氨酸或其它类似的l-精氨酸。
一种特定的NO合酶抑制剂是氨基胍。
本文所使用的术语“NO合酶抑制剂”指抑制由l-精氨酸形成NO的试剂。
在常规试验中评价化合物的NO合酶抑制活性，例如在体外抑制〔3H〕l-精氨酸到〔3H〕-瓜氨酸，或者抑制通过细胞或组织提取物产生一氧化氮或通过重组一氧化氮合酶同功酶产生一氧化氮(FASEB.J.1993；7：349-360)。
一种合适的药学上可接受的衍生物是其可药用盐或可药用的溶剂化物。
合适的可药用盐包括与酸加成的盐。
合适的酸加成盐包括与可药用的无机酸如硫酸、硝酸、磷酸、硼酸、盐酸和氢溴酸以及可药用有机酸如乙酸、酒石酸、马来酸、柠檬酸、琥珀酸、苯甲酸、抗坏血酸、甲磺酸、α-酮戊二酸和α-甘油磷酸，特别是马来酸，加成的盐。
合适的可药用溶剂化物包括水合物。
本发明方法中使用的NO合酶抑制剂可按常规方法来制备，如上文所述出版物中所描述的方法，例如可按J.Amer.Chem.Soc.57，2730，(1935)公开的方法制备氨基胍。
可按常规方法制备和分离盐和/或溶剂化物。
本发明另一方面也提供NO合酶抑制剂，如氨基胍，或其可药用衍生物用于治疗和/或预防II型糖尿病。
还提供了NO合酶抑制剂，如氨基胍，或其可药用衍生物作为制备治疗和/或预防II型糖尿病药物的应用。
在上述治疗和/或预防中，可给予NO合酶抑制剂，如氨基胍，或其药学上可接受的衍生物本身，或优选以还含有可药用载体的药物组合物的形式来给药。
因此，本发明还提供一种治疗和/或预防II型糖尿病的药物组合物，该组合物含有NO合酶抑制剂如氨基胍或其药学可接受的衍生物和可药用载体。
实施例
dbdb小鼠模型法
过度肥胖的db/db小鼠是胰岛素抗性的和血糖过多的II型非胰岛素依赖性糖尿病的遗传模型。获得6周龄的雄性小鼠。经尾末端剪下取出血样用于测量治疗前的血糖。将动物分成治疗组和对照组以使得每组禁食血糖浓度的平均值和标准偏差类似。
在研究的当天，将一组过度肥胖的动物及其瘦的同窝动物杀死用于测量生化和组织学基线。另外，以标准饲料喂养一组动物(对照；n＝14)并以相同饲料喂养另一组接受氨基胍的动物(500mg/kg；n＝14)。允许动物自由接近食物和水并每日测量其摄入量。每周还测量24小时排尿量。在开始处理后的30天和85天杀死动物(n＝7)。取出血用于测量糖和胰岛素浓度并取出胰腺进行组织学分析和测量胰腺胰岛素。由dbdb小鼠模型获得的数据
在整个试验期中，对照组和治疗组动物的食物摄入和体重增加均是类似的。
在给药之前，过度肥胖动物的血糖是正常的(血中的葡萄糖为10.4±0.97mM)但血胰岛素比其瘦的同窝动物高(血清胰岛素肥胖动物为127±37ng/ml，瘦的动物为3.05±1.03ng/ml)。给药后30天时，肥胖对照组的血糖是高的(血中葡萄糖为24.9±1.0mM)而血清胰岛素浓度比治疗前的值明显较低(30.75±4.3mM)。治疗后85天时，禁食的血糖升高到28.1±2mM并且血清胰岛素浓度继续下降，到11.7±1.8ng/ml。氨基胍减弱禁食胰岛素浓度的下降(30天时为58.3±13ng/ml，85天时为23.3±4.1ng/ml)并且在85天时明显降低占优势的禁食高血糖(21±1.7mM)。氨基胍治疗组肥胖动物的胰腺胰岛素含量为未治疗动物的两倍(分别为64.3±17.8ng/mg与30.0±2.6ng/mg)。从试验的63天开始，肥胖对照动物明显比第7天烦渴和多尿。这种水摄入和尿排出的增加是糖尿病(血糖过高)的特征并且通过用氨基胍治疗来预防(图1)。类似地，在试验期内，未治疗动物和治疗动物的尿糖排泄持续增加，但从35天开始，氨基胍治疗组的较低(图1)。糖尿病(血糖过高)的发展与胰岛形态学的变化有关，并且未治疗组对照动物的胰岛明显肥大，结构破坏并且具有无规律的边界。胰岛中的胰岛素含量明显减少。治疗后30天时，氨基胍治疗组动物保持正常的胰岛形态，并且胰岛中胰岛素含量较高。
Claims (8)
1、一种治疗和/或预防II型糖尿病的方法，该方法包括给予人或非人哺乳动物有效和无毒的可药用量的一氧化氮合酶抑制剂或其药学上可接受的衍生物。
2、权利要求1的方法，用于预防性治疗II型糖尿病。
3、权利要求1或2的方法，用于延迟或防止由血胰岛素过多向血糖过多发展。
4、权利要求1-3的任一方法，其中NO合酶抑制剂选自氨基胍、n-单甲基精氨酸或其它l-精氨酸的类似物。
5、权利要求1-4的任一方法，其中NO合酶抑制剂是氨基胍。
6、NO合酶抑制剂或其药学上可接受的衍生物用于治疗和/或预防II型糖尿病。
7、NO合酶抑制剂或其药学上可接受的衍生物作为制备治疗和/或预防II型糖尿病药物的应用。
8、一种治疗和/或预防II型糖尿病的药物组合物，该组合物含有NO合酶抑制剂或其药学上可接受的衍生物和可药用载体。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9526331.5A GB9526331D0 (en) | 1995-12-22 | 1995-12-22 | Novel method |
| GB9526331.5 | 1995-12-22 |
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| CN1209057A true CN1209057A (zh) | 1999-02-24 |
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| CN96199955A Pending CN1209057A (zh) | 1995-12-22 | 1996-12-18 | 一氧化氮(no)合酶抑制剂用于治疗或预防ii型糖尿病 |
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| Country | Link |
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| EP (1) | EP0868175B1 (zh) |
| JP (1) | JP2000502668A (zh) |
| KR (1) | KR19990076595A (zh) |
| CN (1) | CN1209057A (zh) |
| AT (1) | ATE232724T1 (zh) |
| AU (1) | AU1379497A (zh) |
| BR (1) | BR9612245A (zh) |
| CA (1) | CA2240396A1 (zh) |
| CZ (1) | CZ198698A3 (zh) |
| DE (1) | DE69626307T2 (zh) |
| ES (1) | ES2193285T3 (zh) |
| GB (1) | GB9526331D0 (zh) |
| HU (1) | HUP9903979A3 (zh) |
| IL (1) | IL124870A0 (zh) |
| MX (1) | MX9805098A (zh) |
| NO (1) | NO982854L (zh) |
| NZ (1) | NZ325307A (zh) |
| PL (1) | PL327472A1 (zh) |
| TR (1) | TR199801133T2 (zh) |
| WO (1) | WO1997023204A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1660428B (zh) * | 2005-01-10 | 2011-09-07 | 王振军 | 一氧化氮合酶（nos）抑制剂用于治疗痔的新用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1999044598A2 (en) * | 1998-03-03 | 1999-09-10 | Board Of Regents, The University Of Texas System | Methods for inhibiting βcell apoptosis |
| ES2386831B1 (es) * | 2011-02-04 | 2013-07-08 | Servicio Andaluz De Salud | Uso de inhibidores de la actividad de las NO sintasas (NOS) y sus composiciones, en la elaboración de un medicamento para el tratamiento y la prevención de la prediabetes y la diabetes mellitus tipo 1 (DM1) |
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| PT793646E (pt) * | 1994-11-23 | 2002-03-28 | Biovitrum Ab | Carboxilatos de aminoguanidina destinados ao tratamento de diabetes mellitus nao-insulinodependente |
-
1995
- 1995-12-22 GB GBGB9526331.5A patent/GB9526331D0/en active Pending
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1996
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- 1996-12-18 BR BR9612245A patent/BR9612245A/pt not_active Application Discontinuation
- 1996-12-18 EP EP96944077A patent/EP0868175B1/en not_active Expired - Lifetime
- 1996-12-18 CN CN96199955A patent/CN1209057A/zh active Pending
- 1996-12-18 KR KR1019980704676A patent/KR19990076595A/ko not_active Application Discontinuation
- 1996-12-18 IL IL12487096A patent/IL124870A0/xx unknown
- 1996-12-18 WO PCT/EP1996/005871 patent/WO1997023204A1/en active IP Right Grant
- 1996-12-18 AU AU13794/97A patent/AU1379497A/en not_active Abandoned
- 1996-12-18 TR TR1998/01133T patent/TR199801133T2/xx unknown
- 1996-12-18 JP JP9523337A patent/JP2000502668A/ja not_active Ceased
- 1996-12-18 AT AT96944077T patent/ATE232724T1/de not_active IP Right Cessation
- 1996-12-18 CA CA002240396A patent/CA2240396A1/en not_active Abandoned
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- 1996-12-18 CZ CZ981986A patent/CZ198698A3/cs unknown
- 1996-12-18 HU HU9903979A patent/HUP9903979A3/hu unknown
- 1996-12-18 DE DE69626307T patent/DE69626307T2/de not_active Expired - Fee Related
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1998
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660428B (zh) * | 2005-01-10 | 2011-09-07 | 王振军 | 一氧化氮合酶（nos）抑制剂用于治疗痔的新用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2193285T3 (es) | 2003-11-01 |
| ATE232724T1 (de) | 2003-03-15 |
| NO982854D0 (no) | 1998-06-19 |
| NZ325307A (en) | 1999-11-29 |
| HUP9903979A2 (hu) | 2000-03-28 |
| CA2240396A1 (en) | 1997-07-03 |
| PL327472A1 (en) | 1998-12-07 |
| KR19990076595A (ko) | 1999-10-15 |
| JP2000502668A (ja) | 2000-03-07 |
| NO982854L (no) | 1998-06-19 |
| CZ198698A3 (cs) | 1999-06-16 |
| TR199801133T2 (xx) | 1998-09-21 |
| MX9805098A (es) | 1998-10-31 |
| GB9526331D0 (en) | 1996-02-21 |
| WO1997023204A1 (en) | 1997-07-03 |
| HUP9903979A3 (en) | 2000-05-29 |
| DE69626307T2 (de) | 2003-10-16 |
| IL124870A0 (en) | 1999-01-26 |
| EP0868175B1 (en) | 2003-02-19 |
| EP0868175A1 (en) | 1998-10-07 |
| BR9612245A (pt) | 1999-07-13 |
| DE69626307D1 (de) | 2003-03-27 |
| AU1379497A (en) | 1997-07-17 |
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