公开(公告)号：US06184356B2

公开(公告)日：2001-02-06

申请号：US09058562

申请日：1998-04-13

申请人： David C. Anderson ,  Antony J. Mathews ,  Gary L. Stetler

发明人： David C. Anderson ,  Antony J. Mathews ,  Gary L. Stetler

IPC分类号： C07K14805

CPC分类号： C12N15/81 ,  A61K38/00 ,  A61K47/6445 ,  C07K14/805 ,  C07K2319/00 ,  C07K2319/50 ,  C07K2319/92 ,  Y10S530/829

摘要： DNA molecules which encode pseudodimeric globin-like polypeptides with an asymmetric cysteine mutation suitable for crosslinking two tetramers, or which encode pseudooligomeric globin-like polypeptides comprising four or more globin-like domains, are useful in the preparation of multimeric hemoglobin-like proteins.

摘要翻译： 编码具有适用于交联两个四聚体的不对称半胱氨酸突变的伪二聚球蛋白样多肽的DNA分子或编码包含四个或更多个珠蛋白样结构域的假寡聚寡核苷酸样多肽的DNA分子可用于制备多聚体血红蛋白样蛋白。

公开(公告)号：US06610654B2

公开(公告)日：2003-08-26

申请号：US10128581

申请日：2002-04-24

申请人： Irena Tsyrlova ,  Stephen D. Wolfe

发明人： Irena Tsyrlova ,  Stephen D. Wolfe

IPC分类号： C07K14805

CPC分类号： C07K14/805 ,  A61K38/42 ,  C07K14/4703 ,  C07K14/475 ,  C07K14/52 ,  A61K2300/00

摘要： Disclosed and claimed are methods for the isolation and use of stem cell inhibiting factors for regulating the abnormal stem cell cycle and for accelerating the post-chemotherapy peripheral blood cell recovery. Also disclosed and claimed are the inhibitors of stem cell proliferation.

公开(公告)号：US06610832B1

公开(公告)日：2003-08-26

申请号：US09349290

申请日：1999-07-07

申请人： Maria S. Gawryl ,  Robert A. Houtchens ,  William R. Light

发明人： Maria S. Gawryl ,  Robert A. Houtchens ,  William R. Light

IPC分类号： C07K14805

CPC分类号： A61J1/05 ,  A01N1/02 ,  A01N1/0263 ,  A61K35/00 ,  A61K38/42 ,  B32B7/02 ,  B32B15/08 ,  B32B27/08 ,  B32B27/18 ,  B32B27/304 ,  B32B27/32 ,  B32B27/36 ,  B32B2250/24 ,  B32B2264/102 ,  B32B2307/412 ,  B32B2307/7244 ,  B32B2439/80 ,  B32B2535/00 ,  C07K14/805

摘要： The invention relates to a method for preserving the stability of a hemoglobin blood substitute comprising maintaining the hemoglobin blood substitute in an atmosphere substantially free of oxygen. The invention also involves a method for producing a stable polymerized hemoglobin blood-substitute from blood. The method of this invention includes mixing blood with an anticoagulant to form a blood solution, washing the red blood cells in the blood solution and then separating the washed red blood cells from the white blood cells. This method also includes disrupting the red blood cells to release hemoglobin and form a hemoglobin solution, which is then treated by high performance liquid chromatography to form a hemoglobin eluate. The hemoglobin eluate is then deoxygenated, contacted with a first sulfhydryl compound to form an oxidation-stabilized deoxygenated hemoglobin solution, and mixed with a cross-linking agent to form a polymerization reaction mixture, which is then polymerized. The polymerized hemoglobin solution is then diafiltered with a physiologic solution and with a sulfhydryl compound, whereby the polymerized hemoglobin solution is made physiologically acceptable, and whereby the sulfhydryl compound scavenges oxygen, to form a stable polymerized hemoglobin blood-substitute, which is then packaged and stored in an atmosphere substantially free of oxygen.

摘要翻译： 本发明涉及一种保持血红蛋白血液替代品的稳定性的方法，包括将血红蛋白血液替代物维持在基本上不含氧的气氛中。 本发明还涉及从血液制备稳定的聚合血红蛋白血液代用品的方法。 本发明的方法包括将血液与抗凝血剂混合以形成血液溶液，洗涤血液中的红细胞，然后从白细胞中分离洗涤的红细胞。 该方法还包括破坏红细胞以释放血红蛋白并形成血红蛋白溶液，然后通过高效液相色谱法处理以形成血红蛋白洗脱液。 然后将血红蛋白洗脱液脱氧，与第一巯基化合物接触以形成氧化稳定的脱氧血红蛋白溶液，并与交联剂混合以形成聚合反应混合物，然后将其聚合。 然后将聚合的血红蛋白溶液与生理溶液和巯基化合物进行渗滤，由此将聚合的血红蛋白溶液制成生理学上可接受的，由此巯基化合物清除氧气，形成稳定的聚合血红蛋白血液替代物，然后将其包装， 储存在基本上不含氧的气氛中。

公开(公告)号：US06500930B2

公开(公告)日：2002-12-31

申请号：US09276686

申请日：1999-03-26

申请人： Gordon J. Adamson

发明人： Gordon J. Adamson

IPC分类号： C07K14805

CPC分类号： A61K47/61 ,  A61K9/0026

摘要： Hemoglobin conjugates useful as a hemoglobin-based oxygen carriers are prepared by reacting hemoglobin with oxidatively ring-opened polysaccharides such as hydroxyethyl starch or dextran, and storing the resultant conjugate under conditions which allow it to transform to a lower molecular weight product, after conjugation. The conjugate is then reductively stabilized to form secondary amino bonds between the hemoglobin and the polysaccharide, and formulated as an BOC.

摘要翻译： 通过使血红蛋白与氧化开环的多糖如羟乙基淀粉或葡聚糖反应，并将所得的缀合物在共轭后将其转化为较低分子量的产物的条件下制备用作基于血红蛋白的氧载体的血红蛋白缀合物。 然后将缀合物还原稳定，在血红蛋白和多糖之间形成仲氨基键，并配制成BOC。

公开(公告)号：US06271351B1

公开(公告)日：2001-08-07

申请号：US09173189

申请日：1998-10-14

申请人： Maria S. Gawryl ,  Robert A. Houtchens ,  William R. Light

发明人： Maria S. Gawryl ,  Robert A. Houtchens ,  William R. Light

IPC分类号： C07K14805

CPC分类号： A01N1/02 ,  A01N1/0263 ,  A61J1/05 ,  A61J1/10 ,  A61K38/00 ,  B32B15/08 ,  B32B27/08 ,  C07K14/805 ,  Y02A50/395

摘要： The invention relates to a method for preserving the stability of a hemoglobin blood substitute comprising maintaining the hemoglobin blood substitute in an atmosphere substantially free of oxygen. The invention also involves a method for producing a stable polymerized hemoglobin blood-substitute from blood. The method of this invention includes mixing blood with an anticoagulent to form a blood solution, washing the red blood cells in the blood solution and then separating the washed red blood cells from the white blood cells. This method also includes disrupting the red blood cells to release hemoglobin and form a hemoglobin solution, which is then treated by high performance liquid chromatography to form a hemoglobin eluate. The hemoglobin eluate is then deoxygenated, contacted with a first sulfhydryl compound to form an oxidation-stabilized deoxygenated hemoglobin solution, and mixed with with a cross-linking agent to form a polymerization reaction mixture, which is then polymerized. The polymerized hemoglobin solution is then diafiltered with a physiologic solution and with a sulfhydryl compound, whereby the polymerized hemoglobin solution is made physiologically acceptable, and whereby the sulfhydryl compound scavanges oxygen, to form a stable polymerized hemoglobin blood-substitute, which is then packaged and stored in an atmosphere substantially free of oxygen.

摘要翻译： 本发明涉及一种保持血红蛋白血液替代品的稳定性的方法，包括将血红蛋白血液替代物维持在基本上不含氧的气氛中。 本发明还涉及从血液制备稳定的聚合血红蛋白血液代用品的方法。 本发明的方法包括将血液与抗凝血剂混合以形成血液溶液，洗涤血液中的红细胞，然后从白细胞中分离洗涤的红细胞。 该方法还包括破坏红细胞以释放血红蛋白并形成血红蛋白溶液，然后通过高效液相色谱法处理以形成血红蛋白洗脱液。 然后将血红蛋白洗脱物脱氧，与第一巯基化合物接触以形成氧化稳定的脱氧血红蛋白溶液，并与交联剂混合以形成聚合反应混合物，然后将其聚合。 然后将聚合的血红蛋白溶液用生理溶液和巯基化合物进行渗滤，由此将聚合的血红蛋白溶液制成生理学上可接受的，并且由此巯基化合物将氧气清除以形成稳定的聚合血红蛋白血液替代品，然后将其包装， 储存在基本上不含氧的气氛中。

公开(公告)号：US06455676B1

公开(公告)日：2002-09-24

申请号：US09403208

申请日：2000-04-25

申请人： Michael J. Weickert ,  Christopher B. Glascock ,  Antony J. Mathews ,  Douglas D. Lemon ,  Daniel H. Doherty ,  John S. Olson

发明人： Michael J. Weickert ,  Christopher B. Glascock ,  Antony J. Mathews ,  Douglas D. Lemon ,  Daniel H. Doherty ,  John S. Olson

IPC分类号： C07K14805

CPC分类号： C07K14/805 ,  A61K38/00

摘要： The invention relates to novel recombinant hemoglobins having reduced nitric oxide scavenging and/or increased high soluble expression. The invention further relates to methods of increasing the soluble expression of recombinant hemoglobin by adding exogenous hemin in molar excess of the heme binding sites of recombinant hemoglobin.

摘要翻译： 本发明涉及具有减少的一氧化氮清除和/或增加的高可溶性表达的新型重组血红蛋白。 本发明还涉及通过在重组血红蛋白的血红素结合位点的摩尔过量中加入外源血红素来增加重组血红蛋白的可溶性表达的方法。

公开(公告)号：US06323175B1

公开(公告)日：2001-11-27

申请号：US09545661

申请日：2000-04-10

申请人： Jen-Chang Hsia

发明人： Jen-Chang Hsia

IPC分类号： C07K14805

CPC分类号： B82Y5/00 ,  A61K9/127 ,  A61K38/42 ,  A61K45/06 ,  A61K47/52 ,  A61K47/6445 ,  A61K47/6895 ,  A61K47/69 ,  A61K49/0002 ,  A61K49/20 ,  C07K14/76 ,  C07K14/805 ,  C07K16/00 ,  Y10S514/832 ,  Y10S530/829 ,  A61K2300/00

摘要： Compositions and processes to alleviate oxygen toxicity are disclosed based on the addition of nitroxides to physio-logically compatible macromolecules. In particular, hemoglobin-based red cell substitutes are described featuring stable nitroxide free radicals for use in cell-free hemoglobin solutions, encapsulated hemoglobin solutions, stabilized hemoglobin solutions, polymerized hemoglobin solutions, conjugated hemoglobin solutions, nitroxide-labelled albumin, and nitroxide-labelled immunoglobulin. The formulations described herein interact with free radicals, act as antioxidant enzyme-mimics, and alleviate oxidative stress and oxygen-related toxicity.

摘要翻译： 基于向生理学上相容的大分子中加入硝基氧而公开减轻氧气毒性的组合物和方法。 特别地，描述了基于血红蛋白的红细胞替代物，其特征在于稳定的氮氧自由基用于无细胞血红蛋白溶液，包封的血红蛋白溶液，稳定的血红蛋白溶液，聚合血红蛋白溶液，共轭血红蛋白溶液，氮氧自由基标记的白蛋白和氮氧化物标记 免疫球蛋白。 本文描述的制剂与自由基相互作用，起抗氧化酶 - 模拟物质的作用，并减轻氧化应激和氧相关毒性。

公开(公告)号：US06288027B1

公开(公告)日：2001-09-11

申请号：US09348881

申请日：1999-07-07

申请人： Maria S. Gawryl ,  Robert A. Houtchens ,  William R. Light

发明人： Maria S. Gawryl ,  Robert A. Houtchens ,  William R. Light

IPC分类号： C07K14805

CPC分类号： B32B1/02 ,  A01N1/02 ,  A01N1/0263 ,  A61J1/05 ,  A61J1/10 ,  A61K38/42 ,  A61M1/0272 ,  B32B15/08 ,  B32B15/082 ,  B32B27/08 ,  B32B27/306 ,  B32B27/32 ,  B32B37/153 ,  B32B2307/412 ,  B32B2307/7244 ,  B32B2439/80 ,  C07K14/805

摘要： The invention relates to a method for preserving the stability of a hemoglobin blood substitute comprising maintaining the hemoglobin blood substitute in an atmosphere substantially free of oxygen. The invention also involves a method for producing a stable polymerized hemoglobin blood-substitute from blood. The method of this invention includes mixing blood with an anticoagulent to form a blood solution, washing the red blood cells in the blood solution and then separating the washed red blood cells from the white blood cells. This method also includes disrupting the red blood cells to release hemoglobin and form a hemoglobin solution, which is then treated by high performance liquid chromatography to form a hemoglobin eluate. The hemoglobin eluate is then deoxygenated, contacted with a first sulfhydryl compound to form an oxidation-stabilized deoxygenated hemoglobin solution, and mixed with a cross-linking agent to form a polymerization reaction mixture, which is then polymerized. The polymerized hemoglobin solution is then diafiltered with a physiologic solution and with a sulfhydryl compound, whereby the polymerized hemoglobin solution is made physiologically acceptable, and whereby the sulfhydryl compound scavenges oxygen, to form a stable polymerized hemoglobin blood-substitute, which is then packaged and stored in an atmosphere substantially free of oxygen.

摘要翻译： 本发明涉及一种保持血红蛋白血液替代品的稳定性的方法，包括将血红蛋白血液替代物维持在基本上不含氧的气氛中。 本发明还涉及从血液制备稳定的聚合血红蛋白血液代用品的方法。 本发明的方法包括将血液与抗凝血剂混合以形成血液溶液，洗涤血液中的红细胞，然后从白细胞中分离洗涤的红细胞。 该方法还包括破坏红细胞以释放血红蛋白并形成血红蛋白溶液，然后通过高效液相色谱法处理以形成血红蛋白洗脱液。 然后将血红蛋白洗脱液脱氧，与第一巯基化合物接触以形成氧化稳定的脱氧血红蛋白溶液，并与交联剂混合以形成聚合反应混合物，然后将其聚合。 然后将聚合的血红蛋白溶液与生理溶液和巯基化合物进行渗滤，由此将聚合的血红蛋白溶液制成生理学上可接受的，由此巯基化合物清除氧气，形成稳定的聚合血红蛋白血液替代物，然后将其包装， 储存在基本上不含氧的气氛中。

公开(公告)号：US06670323B1

公开(公告)日：2003-12-30

申请号：US09709914

申请日：2000-11-10

申请人： Douglas L. Looker ,  Izydor Z. Apostol ,  Eric A. Brucker ,  Michael P. Doyle ,  David L. Foster ,  Christopher B. Glascock ,  James C. Hartman ,  Geoffrey F. Lee ,  Douglas D. Lemon ,  Edwin G. Moore ,  Jane P. Richards ,  Michael R. Schick ,  Stephen P. Trimble ,  David Pereira ,  Ton-That Hai ,  Kenneth E. Burhop

发明人： Douglas L. Looker ,  Izydor Z. Apostol ,  Eric A. Brucker ,  Michael P. Doyle ,  David L. Foster ,  Christopher B. Glascock ,  James C. Hartman ,  Geoffrey F. Lee ,  Douglas D. Lemon ,  Edwin G. Moore ,  Jane P. Richards ,  Michael R. Schick ,  Stephen P. Trimble ,  David Pereira ,  Ton-That Hai ,  Kenneth E. Burhop

IPC分类号： C07K14805

CPC分类号： C07K14/805 ,  A61K38/00

摘要： The invention relates to novel hemoglobin compositions, particularly novel recombinant mutant hemoglobin compositions, which eliminate or substantially reduce 1) the creation of heart lesions, 2) gastrointestinal discomfort, 3) pressor effects, and 4) endotoxin hypersensitivity associated with the administration of extracellular hemoglobin compositions in various therapeutic applications. Applications described include treatments for anemia, head injury, hemorrhage or hypovolemia, ischemia, cachexia, sickle cell crisis and stroke; enhancing cancer treatments; stimulating hematopoiesis; improving repair of physically damaged tissues; alleviating cardiogenic shock; and shock resuscitation.

摘要翻译： 本发明涉及新型血红蛋白组合物，特别是新型重组突变体血红蛋白组合物，其消除或显着减少1）心脏病变的产生，2）胃肠道不适，3）加压作用，和4）与施用细胞外血红蛋白相关的内毒素超敏反应 各种治疗应用中的组合物。 描述的应用包括贫血，头部损伤，出血或血容量不足，局部缺血，恶病质，镰状细胞危象和中风的治疗。 加强癌症治疗; 刺激造血; 改善身体损伤组织的修复; 减轻心源性休克; 和休克复苏。

公开(公告)号：US06627738B2

公开(公告)日：2003-09-30

申请号：US09369966

申请日：1999-08-06

申请人： Jonathan S. Stamler ,  Andrew J. Gow

发明人： Jonathan S. Stamler ,  Andrew J. Gow

IPC分类号： C07K14805

CPC分类号： A61K31/00 ,  A61K31/04 ,  A61K31/095 ,  A61K31/195 ,  A61K35/18 ,  A61K38/00 ,  A61K38/44 ,  A61K47/6445 ,  A61K47/6901 ,  C07K14/00 ,  C07K14/805 ,  G01N21/631 ,  G01N21/76 ,  G01N33/721 ,  Y10T436/105831

摘要： Nitrosylhemoglobin can be produced by introducing gaseous NO into an aqueous solution of hemoglobin. It has been demonstrated that nitrosylhemoglobin in aqueous solution can be converted to SNO-hemoglobin upon introduction of oxygen to the solution, as is postulated to occur in the lungs. Nitrosylhemoglobin can be used in methods to produce the physiological effects of NO, for example, to reduce vasoconstriction and to inhibit platelet aggregation.