公开(公告)号：WO2006135621A2

公开(公告)日：2006-12-21

申请号：PCT/US2006/022028

申请日：2006-06-07

Applicant: TEXAS TECH UNIVERSITY ,  SIMONI, Jan S. ,  SIMONI, Grace ,  MOELLER, John F.

Inventor： SIMONI, Jan S. ,  SIMONI, Grace ,  MOELLER, John F.

IPC: A61K31/00 ,  A61K35/14 ,  A61K45/06 ,  A61P7/08

CPC classification number: A61K45/06 ,  A61K31/401 ,  A61K31/41 ,  A61K31/4184 ,  A61K31/585 ,  A61K35/14 ,  A61K38/42 ,  A61K38/556 ,  A61K2300/00

Abstract: An improved blood substitute composition comprising a blood substitute and a renin-angiotensin-aldosterone An improved blood substitute composition comprising a blood substitute and a renin-angiotensin-aldosterone system inhibitor. A method of treating a patient having a disorder requiring a blood transfusion comprising administering a free hemoglobin based blood substitute and a renin-angiotensin-aldosterone system inhibitor. A renin-angiotensin-aldosterone system activator comprising hemoglobin or hemoglobin and a peroxide. A method of increasing the activity of angiotensin converting enzyme comprising incubation with hemoglobin or hemoglobin and peroxide. A method according of activating the renin-angiotensin-aldosterone system comprising contacting in vivo a free hemoglobin based blood substitute with a peroxide wherein the product induces the production of angiotensin I metabolites which comprise metabolites capable of affecting the vascular tone and/or stimulating aldosterone production.

Abstract translation: 包含血液替代物和肾素 - 血管紧张素 - 醛固酮的改进的血液替代物组合物包含血液代用品和肾素 - 血管紧张素 - 醛固酮系统抑制剂的改进的血液替代物组合物。 一种治疗患有需要输血的病症的方法，包括施用游离血红蛋白基血液替代物和肾素 - 血管紧张素 - 醛固酮系统抑制剂。 包含血红蛋白或血红蛋白和过氧化物的肾素 - 血管紧张素 - 醛固酮系统激活剂。 包括增加血管紧张素转换酶的活性的方法，包括与血红蛋白或血红蛋白和过氧化物孵育。 一种激活肾素 - 血管紧张素 - 醛固酮系统的方法，其包括使体内游离血红蛋白基血液替代物与过氧化物接触，其中所述产物诱导产生能够影响血管紧张度和/或刺激醛固酮生成的代谢物的血管紧张素I代谢物 。

公开(公告)号：WO2006135621A3

公开(公告)日：2008-01-10

申请号：PCT/US2006022028

申请日：2006-06-07

Applicant: UNIV TEXAS TECH ,  SIMONI JAN S ,  SIMONI GRACE ,  MOELLER JOHN F

Inventor： SIMONI JAN S ,  SIMONI GRACE ,  MOELLER JOHN F

IPC: A61K31/00 ,  A61K35/14 ,  A61K38/42 ,  A61K45/06 ,  A61P7/08

CPC classification number: A61K45/06 ,  A61K31/401 ,  A61K31/41 ,  A61K31/4184 ,  A61K31/585 ,  A61K35/14 ,  A61K38/42 ,  A61K38/556 ,  A61K2300/00

Abstract: An improved blood substitute composition comprising a blood substitute and a renin-angiotensin-aldosterone system inhibitor. A method of treating a patient having a disorder requiring a blood transfusion comprising administering a free hemoglobin based blood substitute and a renin-angiotensin-aldosterone system inhibitor. A renin-angiotensin-aldosterone system activator comprising hemoglobin or hemoglobin and a peroxide. A method of increasing the activity of angiotensin converting enzyme comprising incubation with hemoglobin or hemoglobin and peroxide. A method according of activating the renin-angiotensin-aldosterone system comprising contacting in vivo a free hemoglobin based blood substitute with a peroxide wherein the product induces the production of angiotensin I metabolites which comprise metabolites capable of affecting the vascular tone and/or stimulating aldosterone production.

Abstract translation: 一种改良的血液替代物组合物，其包含血液代用品和肾素 - 血管紧张素 - 醛固酮系统抑制剂。 一种治疗患有需要输血的病症的方法，包括施用游离血红蛋白基血液替代物和肾素 - 血管紧张素 - 醛固酮系统抑制剂。 包含血红蛋白或血红蛋白和过氧化物的肾素 - 血管紧张素 - 醛固酮系统激活剂。 包括增加血管紧张素转换酶的活性的方法，包括与血红蛋白或血红蛋白和过氧化物孵育。 一种激活肾素 - 血管紧张素 - 醛固酮系统的方法，其包括使体内游离血红蛋白基血液替代物与过氧化物接触，其中所述产物诱导产生能够影响血管紧张度和/或刺激醛固酮生成的代谢物的血管紧张素I代谢物 。

公开(公告)号：WO2007136641A2

公开(公告)日：2007-11-29

申请号：PCT/US2007011697

申请日：2007-05-15

Applicant: UNIV TEXAS TECH ,  SIMONI JAN S ,  SIMONI GRACE ,  FEOLA MARIA J

Inventor： SIMONI JAN S ,  SIMONI GRACE ,  FEOLA MARIA J

IPC: A61K38/42 ,  A61P7/00

CPC classification number: A61K38/42

Abstract: The present invention relates to novel methods of using blood substitutes to treat acute blood loss and novel pharmaceutical compositions comprising blood substitutes. Blood substitutes useful for the methods of the present invention can (1) induce expression of erythropoietin as tested in a cell culture under normoxic conditions, and/or (2) induce erythropoiesis under normoxic conditions as measured by (a) a decrease in the doubling time of the subject's hematocrit or hemoglobin, and/or (b) an increase in the subject's circulating erythropoietin level. Blood substitutes useful for the pharmaceutical compositions of the present invention can (1) stabilize HIF-I alpha expression, and/or (2) down regulate NF-kappa B. Preferably, the blood substitutes are cross-linked hemoglobin blood substitutes, or more preferably, cross-linked hemoglobins that comprise a hemoglobin that is cross-linked intramolecularly with periodate-oxidized ATP5 cross-linked intermolecularly with periodate-oxidized adenosine, and conugated with reduced glutathione.

Abstract translation: 本发明涉及使用血液代用品治疗急性失血的新方法和包含血液代用品的新型药物组合物。 可用于本发明方法的血液替代物可以（1）在常氧条件下，在细胞培养物中测试促进促红细胞生成素的表达，和/或（2）在常氧条件下诱导红细胞生成，如（a）倍增的减少 受试者的血细胞比容或血红蛋白的时间，和/或（b）受试者的循环促红细胞生成素水平的增加。 可用于本发明的药物组合物的血液代用品可以（1）稳定HIF-1α表达，和/或（2）下调NF-κB。优选地，血液代用品是交联血红蛋白血液代用品或更多 优选地，包含血红蛋白的交联血红蛋白，其通过分子内与高碘酸盐氧化的腺苷分子间交联的高碘酸盐氧化的ATP5交联并与还原型谷胱甘肽结合的血红蛋白。

公开(公告)号：WO2008083236A1

公开(公告)日：2008-07-10

申请号：PCT/US2007/088976

申请日：2007-12-27

Applicant: TEXAS TECH UNIVERSITY ,  SIMONI, Jan S. ,  SIMONI, Grace ,  MOELLER, John, F.

Inventor： SIMONI, Jan S. ,  SIMONI, Grace ,  MOELLER, John, F.

IPC: A61L2/00

CPC classification number: A61L2/0017

Abstract: A method comprising contacting a biological fluid comprising hemoglobin and at least one pathogenic agent with a first filter and generating a first filtrate; contacting the first filtrate with a nanofiltration device and generating a second filtrate; contacting the second filtrate with a chromatographic material and isolating an eluted fraction; contacting the eluted fraction with a hydrophobic solvent and generating a hydrophobic and a hydrophilic phase; and isolating the hydrophilic phase wherein the biological fluids comprise components of interest of equal to or less than about 65 kDa. A method comprising contacting a biological fluid comprising high molecular weight components and at least one pathogenic agent with a first filter and generating a first filtrate; contacting the first filtrate with a hydrophilic membrane and generating a second filtrate; contacting the second filtrate with a chromatographic material and isolating an eluted fraction; contacting the eluted fraction with a hydrophobic solvent and generating a hydrophobic and a hydrophilic phase; and isolating the hydrophilic phase, wherein the high molecular weight components have molecular weights greater than about 65 kDa. A method comprising subjecting a biological fluid comprising hemoglobin and at least one pathogenic agent to at least two filtration steps and thereby reducing the amount of pathogenic agent associated with the biological fluid. A method comprising removing transmissible spongiform encephalopathy agents in a hemoglobin solution of human and/or animal origin by subjecting the hemoglobin solution to an orthogonal separation methodology comprising a plurality of filtration steps.

Abstract translation: 一种方法，包括使包含血红蛋白和至少一种病原体的生物流体与第一过滤器接触并产生第一滤液; 使第一滤液与纳滤装置接触并产生第二滤液; 使第二滤液与色谱材料接触并分离出洗脱级分; 将洗脱的级分与疏水性溶剂接触并产生疏水和亲水相; 并分离亲水相，其中生物流体包含等于或小于约65kDa的感兴趣组分。 一种方法，包括使包含高分子量组分的生物流体和至少一种病原体与第一过滤器接触并产生第一滤液; 使第一滤液与亲水膜接触并产生第二滤液; 使第二滤液与色谱材料接触并分离出洗脱级分; 将洗脱的级分与疏水性溶剂接触并产生疏水和亲水相; 并分离亲水相，其中高分子量组分具有大于约65kDa的分子量。 一种方法，包括使包含血红蛋白和至少一种病原体的生物流体经历至少两个过滤步骤，从而减少与生物流体相关的病原体的量。 一种方法，其包括通过使血红蛋白溶液进行包括多个过滤步骤的正交分离方法，从而在人和/或动物来源的血红蛋白溶液中除去可传播的海绵状脑病。

公开(公告)号：WO2007136641A3

公开(公告)日：2007-11-29

申请号：PCT/US2007/011697

申请日：2007-05-15

Applicant: TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER ,  SIMONI, Jan, S. ,  SIMONI, Grace ,  FEOLA, Maria, J.

Inventor： SIMONI, Jan, S. ,  SIMONI, Grace ,  FEOLA, Maria, J.

IPC: A61K38/42 ,  A61P7/00

Abstract: The present invention relates to novel methods of using blood substitutes to treat acute blood loss and novel pharmaceutical compositions comprising blood substitutes. Blood substitutes useful for the methods of the present invention can (1) induce expression of erythropoietin as tested in a cell culture under normoxic conditions, and/or (2) induce erythropoiesis under normoxic conditions as measured by (a) a decrease in the doubling time of the subject's hematocrit or hemoglobin, and/or (b) an increase in the subject's circulating erythropoietin level. Blood substitutes useful for the pharmaceutical compositions of the present invention can (1) stabilize HIF-I alpha expression, and/or (2) down regulate NF-kappa B. Preferably, the blood substitutes are cross-linked hemoglobin blood substitutes, or more preferably, cross-linked hemoglobins that comprise a hemoglobin that is cross-linked intramolecularly with periodate-oxidized ATP5 cross-linked intermolecularly with periodate-oxidized adenosine, and conugated with reduced glutathione.