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Attenuation of vasoactive oxygen carrier-induced vasoconstriction

An oxygen-carrying carrier and vasoconstriction technology, applied in the fields of inorganic active ingredients, cardiovascular system diseases, blood diseases, etc.

Inactive Publication Date: 2009-11-04
THE GENERAL HOSPITAL CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the above advantages, administration of heme-based oxygen carriers usually triggers vasoconstriction in the recipient

Method used

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  • Attenuation of vasoactive oxygen carrier-induced vasoconstriction
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  • Attenuation of vasoactive oxygen carrier-induced vasoconstriction

Examples

Experimental program
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Effect test

preparation example Construction

[0079] For a detailed review of the preparation and use of heme-based oxygen carriers see, for example, Spahn et al., (2005) Curr Pharm Des. 11(31):4099, Greenburg et al., (2004) Crit Care.8 Suppl 2:S61, and Artificial Oxygen Carrier: Its Front Line (Koichi Kobayashi et al., eds., 2005).

[0080] Nitric oxide gas administration

[0081] Administration of a vasoactive oxygen carrier (eg, a heme-based oxygen carrier such as a hemoglobin-based oxygen carrier) can induce systemic and pulmonary vasoconstriction in the recipient. As described in detail herein, inhalation of nitric oxide gas before and optionally after administration of the vasoactive oxygen carrier can prevent or reduce the occurrence of vasoconstriction that would otherwise occur after administration of the artificial oxygen carrier.

[0082] Safe and effective methods of administering nitric oxide are described, for example, in Zapol, US Patent 5,570,683; Zapol et al, US Patent 5,904,938; Bach et al, US Patent Ap...

Embodiment 1

[0111] Example 1: Nitric oxide-dependent increase in blood pressure following infusion of a hemoglobin tetramer solution

[0112] Nitric oxide synthase 3 (NOS3) is expressed in pulmonary vascular endothelial cells and participates in the control of pulmonary vascular tone by synthesizing nitric oxide, which stimulates vascular smooth muscle cGMP synthesis and causes vasodilation. NOS3-deficient mice (NOS3- / -) exhibit systemic and pulmonary hypertension under normoxic conditions (Huang et al., (1995) Nature 377:239; and Steudel et al., (1997) Circ. Res. 81:34).

[0113] animal preparation

[0114] 8- to 10-week-old male C57BL / 6 wild-type mice and male NOS3-deficient mice (B6129P2-NOS3 tml / Unc ;NOS3 - / - )research. All mice were obtained from the Jackson Laboratory (Bar Harbor, ME) and maintained in the Animal Resources Facility of the Massachusetts General Hospital.

[0115] Preparation of Mouse Hemoglobin Tetramer Solution

[0116] Murine whole blood was collected from wi...

Embodiment 2

[0133] Example 2: Continuous Nitric Oxide Inhalation Prevents Increase in Systolic Blood Pressure and Converts Plasma Hemoglobin to Methemoglobin Before and After Infusion of Hemoglobin Tetramer Solution

[0134] Tail systolic pressure was measured in conscious wild-type mice (n=4) after intravenous injection of 0.012 ml / gram body weight of a solution of murine tetrameric hemoglobin. The "NO inhalation" group inhaled 80 ppm nitric oxide in air and the "control" group inhaled air. Continuous breathing of 80 ppm nitric oxide before and after infusion of mouse hemoglobin tetramer solution prevented hemoglobin-induced systolic blood pressure increase ( image 3 ).

[0135] Intravenous injection of 0.012 mL / g body weight while breathing air (n=4), breathing 80 ppm nitric oxide in air (n=4), or breathing 8 ppm nitric oxide in air (n=7) Methemoglobin concentrations in plasma were measured after mouse hemoglobin tetramer solution was administered to wild-type mice. Administration o...

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Abstract

Compositions and methods for preventing or reducing vasoconstriction in a mammal following administration of a vasoactive oxygen carrier (e.g., a heme-based oxygen carrier such as a hemoglobin-based oxygen carrier) are disclosed. The methods include administering to a mammal a composition containing a vasoactive oxygen carrier in combination with one or more of a nitric oxide-releasing compound, atherapeutic gas containing gaseous nitric oxide, a phosphodiesterase inhibitor, and / or a soluble guanylate cyclase sensitizer.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application 60 / 864,734, filed November 7, 2006, which priority application is incorporated herein by reference in its entirety. [0003] Statement of Federally Funded Research [0004] This invention was made with government support under Grant No. 5R01HL042397-17 awarded by the National Institutes of Health / National Heart, Lung and Blood Institute. The government has certain rights in this invention. technical field [0005] The present invention relates to compositions and methods for preventing or reducing vasoconstriction in a mammal following administration of a vasoactive oxygen carrier. Background technique [0006] Red blood cells reversibly bind oxygen under physiological conditions and mediate the continuous delivery to tissues of oxygen required for cellular respiration. Blood transfusion is a routine treatment option for patients presenting with red bloo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K33/00A61K38/16A61K38/42
CPCA61M16/12A61K38/42A61M2016/1035A61K33/00A61M2202/0275A61M16/208A61M2016/003A61M2016/0039A61K45/06A61M16/1015A61P7/06A61P7/08A61P9/00A61P9/08A61P9/10A61P11/00A61P43/00A61K2300/00
Inventor 沃伦·M·扎波尔俞秉兰一濑史人
Owner THE GENERAL HOSPITAL CORP
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