CN1882331A - 作为心血管风险升高指示剂的肾小管性蛋白尿 - Google Patents

作为心血管风险升高指示剂的肾小管性蛋白尿 Download PDF

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CN1882331A
CN1882331A CNA2004800344206A CN200480034420A CN1882331A CN 1882331 A CN1882331 A CN 1882331A CN A2004800344206 A CNA2004800344206 A CN A2004800344206A CN 200480034420 A CN200480034420 A CN 200480034420A CN 1882331 A CN1882331 A CN 1882331A
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microglobulin
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cardiovascular event
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J·施拉德尔
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Sanofi Aventis Deutschland GmbH
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • 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

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Abstract

本发明涉及ACE抑制剂或血管紧张素受体拮抗剂在制备药物组合物中的用途，所述药物组合物用于在非糖尿病人类个体中减少肾小管性蛋白尿和/或α1－微球蛋白，从而降低心血管事件的风险。

Description

作为心血管风险升高指示剂的肾小管性蛋白尿
在美国，冠心病仍然是发病率和死亡率的主要原因。心血管疾病的危险因素可能是直接原因、可能是更基本的潜在代谢异常的继发表现或可能代表疾病的早期症状。若干危险因素与心血管疾病的发病率增加有关，包括吸烟、高血压、血脂异常、糖尿病、微量蛋白尿、肥胖症、久坐的生活方式(sedentary lifestyle)、性和营养不良。在成人中危险因素的效应是累加性的，高危因素的数量越多，心血管疾病的风险就越大。
一些可逆的、直接成为原因的危险因素的干预已经有效地被用于降低形成心血管疾病的风险以及心血管事件如中风或心肌梗死的发生率。
已知肾小球蛋白尿的一种形式——微量蛋白尿是心血管危险因素和心血管发病的指示剂。
现已出乎意料地发现：肾小管性蛋白尿(tubular proteinuria)和尿α1-微球蛋白水平升高独立地指示了形成心血管疾病和心血管死亡率的风险增加。
此外，已发现，通过降低肾小管性蛋白尿和/或尿α1-微球蛋白，可降低心血管事件的发生率。
因此已经显示：血管紧张素/肾素-系统的调制剂，如血管紧张素转换酶(ACE)抑制剂或血管紧张素受体拮抗剂可以有效地被用于降低肾小管蛋白尿和α1-微球蛋白。
此外，在大规模的干预试验中已经确定：在呈现肾小管性蛋白尿或尿α1-微球蛋白升高的个体中，这类治疗性干预可有效地降低心血管事件的风险。
根据以上发现，本发明提供了用于评价个体心血管风险的新筛选方法。
此外，根据本发明的用于评价心血管风险的筛选方法比使用微量蛋白尿作为心血管事件预测剂的筛选方法更容易、更快速并且更可靠，因为肾小管性蛋白尿和α1-微球蛋白的测定可通过标准方法测定。
在进一方面，本发明还提供了药物组合物，其包含血管紧张素/肾素-系统调制剂，如血管紧张素转换酶(ACE)抑制剂或血管紧张素受体拮抗剂，用于在非糖尿病患者中降低肾小管性蛋白尿和/或尿α1-微球蛋白，以降低心血管事件的风险。
用本发明的诊断筛选方法诊断后的治疗性干预可在无症状健康个体以及在高血压或明显心血管疾病患者中进行。
根据本发明优选的ACE-抑制剂为雷米普利、培哚普利、群多普利、赖诺普利、依那普利或卡托普利以及它们的可药用盐和衍生物。
根据本发明使用的血管紧张素拮抗剂优选氯沙坦、坎地沙坦、缬沙坦、依贝沙坦、奥美沙坦(olmesartan)、依普沙坦或替米沙坦、它们的可药用盐和衍生物。
尿分析可通过任何标准的实验室试验进行。尿白蛋白的测定优选通过定量蛋白质测定(散射测浊法)和SDS-电泳进行。
可以利用市售试剂盒，如Roche Diagnostics的浊度试验、Tinaquant α-微球蛋白试剂盒。
在肾小管性蛋白尿中，可发现小分子量蛋白质包括视黄醇结合蛋白、α1-微球蛋白、β2-微球蛋白溶菌酶、轻链、血红蛋白和肌红蛋白。

Claims (5)

1.ACE抑制剂或血管紧张素受体拮抗剂在制备药物组合物中的用途，所述药物组合物用于在非糖尿病人类个体中减少肾小管性蛋白尿和/或α1-微球蛋白，从而降低心血管事件的风险。
2.根据权利要求1的用途，其中的ACE抑制剂选自雷米普利、培哚普利、群多普利、赖诺普利、依那普利或卡托普利。
3.根据权利要求1的用途，其中的血管紧张素拮抗剂为氯沙坦、坎地沙坦、缬沙坦、依贝沙坦、奥美沙坦、依普沙坦和替米沙坦。
4.根据权利要求1的用途，其中的心血管事件选自中风或心肌梗死。
5.用于评价人类个体遭受心血管疾病或心血管事件风险的体外诊断方法，包括测定尿β-微球蛋白或其他的肾小管蛋白质和α1-微球蛋白的水平。
CNA2004800344206A 2003-11-26 2004-11-26 作为心血管风险升高指示剂的肾小管性蛋白尿 Pending CN1882331A (zh)

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US (2) US20060264488A1 (zh)
EP (1) EP1689386A1 (zh)
JP (1) JP2007513884A (zh)
KR (1) KR20060110306A (zh)
CN (1) CN1882331A (zh)
AU (1) AU2004292775A1 (zh)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104661673A (zh) * 2012-09-05 2015-05-27 A1M制药公司 用于治疗线粒体相关的疾病的α1-微球蛋白

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE031613T2 (en) * 2007-02-12 2017-09-28 A1M Pharma Ab Diagnosis and treatment of preeclampsia
CN101869710A (zh) * 2009-04-24 2010-10-27 北京奥萨医药研究中心有限公司 降压药物组合物
CN103903553A (zh) * 2014-03-14 2014-07-02 四川虹欧显示器件有限公司 一种解决高Xe含量下画面切换后低放电的方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104661673A (zh) * 2012-09-05 2015-05-27 A1M制药公司 用于治疗线粒体相关的疾病的α1-微球蛋白

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WO2005051379A1 (en) 2005-06-09
IL175792A0 (en) 2008-04-13
BRPI0416906A (pt) 2007-01-16
CA2547124A1 (en) 2005-06-09
AU2004292775A1 (en) 2005-06-09
US20070191446A1 (en) 2007-08-16
US20060264488A1 (en) 2006-11-23
JP2007513884A (ja) 2007-05-31
EP1689386A1 (en) 2006-08-16

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