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Methods to enhance hemodynamic stability using oxygen carrying compositions

a technology of hemodynamic stability and oxygen carrying composition, which is applied in the direction of drug compositions, peptide/protein ingredients, extracellular fluid disorder, etc., can solve the problems of widespread use of whole blood nor hbocs for prophylactic indications, unsuitable prophylactic use of human blood, and somewhat questionable practice, so as to enhance hemodynamic stability, monitor the hemodynamic stability of the patient, and enhance hemodynamic stability

Inactive Publication Date: 2006-08-03
SANGART INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] The present invention relates to the use of a composition in the treatment of a normovolemic subject undergoing surgery to enhance hemodynamic stability. In one embodiment, the invention relates to a method for enhancing hemodynamic stability of a normovolemic subject undergoing surgery comprising: a) administering a composition containing a hemoglobin-based oxygen carrier (HBOC) with an oxygen affinity higher than whole blood to the subject in connection with the surgery; and b) monitoring the hemodynamic stability of the patient. Such administration may occur prior to, during or after surgery, or any combination thereof. In addition, the hemodynamic stability may be measured before, during or after surgery, or any combination thereof. In addition, monitoring the hemodynamic stability of the patient may take many forms, such as monitoring the blood pressure of a patient. In one embodiment, hemodynamic stability is characterized by systolic pressure remaining above 90 mm Hg.

Problems solved by technology

This usually means that human blood is not appropriate for prophylactic use, such as “blood doping” (i.e. administering whole blood for the purpose of enhancing performance by increasing the oxygen carrying capacity of the blood).
Accordingly, neither the use of whole blood nor HBOCs for prophylactic indications are widespread, and in most cases are considered to be a somewhat questionable practice.
However, this procedure does not address the need for prophylactic measures to avoid the detrimental primary effects of surgical procedures such as hemodynamic stability, and only addresses the secondary effects of blood loss associated with surgery.
First, hemodynamic instability caused by blood loss or other factors can lead to tissue damage and even death.
Second and most importantly, hemodynamic instability, even minor and transient, may affect a patient's post-surgical recovery.
These events can cause cognitive damage and other complications that exacerbate recovery following surgery.
In addition, such patients are often not suitable candidates for ANH, and enhancing their hemodynamic stability would be expected to lessen their need for transfusions using donor blood.
However, these non-oxygen carrying solutions only dilute the oxygen capacity of the blood, even without concomitant ANH, and may actually cause hemodynamic instability in some instances.
However, the administration of these solutions may result in excessive water retention and edema, which can also cause fluctuations in hemodynamic properties.

Method used

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  • Methods to enhance hemodynamic stability using oxygen carrying compositions
  • Methods to enhance hemodynamic stability using oxygen carrying compositions
  • Methods to enhance hemodynamic stability using oxygen carrying compositions

Examples

Experimental program
Comparison scheme
Effect test

example 1

Production of Stroma-Free Hemoglobin

Step 1: Procurement of Outdated Red Blood Cells

[0084] Outdated packed red blood cells are procured from a commercial source, such as the San Diego Blood Bank or the American Red Cross. Preferably, outdated material is received not more than 45 days from the time of collection. Packed RBCs (pRBCs) are stored at 4±2° C. until further processed (1-7 days). All units are screened for viral infection and subjected to nucleic acid testing prior to use.

Step 2: Pooling of Outdated Blood

[0085] Packed red blood cells are pooled into a sterile vessel in a clean facility. Packed red blood cell volume is noted, and hemoglobin concentration is determined using a commercially available co-oximeter or other art-recognized method.

Step 3: Leukodepletion

[0086] Leukodepletion (i.e. removal of white blood cells) is carried out using membrane filtration. Initial and final leukocyte counts are made to monitor the efficiency of this process.

Step 4: Cell Separa...

example 2

Modification of Stroma Free Hemoglobin

Step 1: Thiolation

[0093] Thiolation is carried out using 10-fold molar excess iminothiolane over hemoglobin for 4 hours at 4±2° C. with continuous stirring.

[0094] Reaction conditions:

[0095] 1 mM hemoglobin (tetramer) in RL (pH 7.0-7.5) or PBS (pH 7.4)

[0096] 10 mM iminothiolane in RL (pH 7.0-7.5) or PBS (pH 7.4)

[0097] The ratio of 1:10 SFH:iminothiolane and reaction timing were optimized to maximize the number of PEGylated thiol groups and to minimize product heterogeneity.

Step 2: PEGylation of Thiolated Hemoglobin

[0098] Thiolated hemoglobin is PEGylated using a 20-fold molar excess of Mal PEG (with an alkyl or phenyl linker) based on starting tetrameric hemoglobin concentration. The hemoglobin is first allowed to equilibrate with the atmosphere to oxygenate the hemoglobin. The reaction takes place for 2 hours at 4±2° C. with continuous stirring.

[0099] Reaction conditions:

[0100] 1 m thiolated hemoglobin in RL or PBS (pH 7.4)

[0101] 20...

example 3

Physiochemical Analysis of MalPEG-Hb

Methodology for Physicochemical Analysis

[0106] Homogeneity and molecular size of the MalPEG-Hb blood substitute are characterized by Liquid Chromatography (LC). Analytical LC is used to evaluate homogeneity of the PEGylated hemoglobin and extent of removal of unreacted Mal-PEG. Absorbance at 540 urn is used to evaluate hemoglobin and resolves PEGylated hemoglobin from unreacted hemoglobin by peak position. Absorbance at 280 nm is used to resolve PEGylated hemoglobin from free Mal-PEG, which absorbs in the ultraviolet (UV) spectrum due to the ring structures in MalPEG.

[0107] Optical spectra are collected using a rapid scanning diode array spectrophotometer (Milton Roy 2000 or Hewlett Packard Model 8453) in the Soret and visible regions for analysis of hemoglobin concentration and percent methemoglobin by multicomponent analysis (Vandegriff K. D., and R. E., Shrager. Evaluation of oxygen equilibrium binding to hemoglobin by rapid-scanning spcetr...

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Abstract

The present invention relates to methods for enhancing the hemodynamic stability of an individual undergoing surgery by administering a composition comprising a hemoglobin-based oxygen carrier. In one embodiment, the present invention relates to the use of polyalkylene oxide modified hemoglobins with reduced cooperativity and a high oxygen affinity to enhance oxygen offloading as a preventative measure to avoid hemodynamic stability-related complications during surgery.

Description

TECHNICAL FIELD [0001] The present invention relates to methods for enhancing the hemodynamic stability of an individual undergoing surgery by administering a composition comprising a hemoglobin-based oxygen carrier. In one embodiment, the present invention relates to the use of polyalkylene oxide modified hemoglobins with reduced Cooperativity and a high oxygen affinity to enhance oxygen offloading as a preventative measure to avoid hemodynamic stability-related complications during surgery. BACKGROUND OF THE INVENTION [0002] The blood is the means for delivering oxygen and nutrients and removing waste products from the tissues. The blood is composed of plasma in which red blood cells (RBCs or erythrocytes), white blood cells (WBCs), and platelets are suspended. Red blood cells comprise approximately 99% of the cells in blood, and their principal function is the transport of oxygen to the tissues and the removal of carbon dioxide therefrom. [0003] The left ventricle of the heart pu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/42
CPCA61K38/42A61P41/00A61P7/00A61P7/08A61P9/00C07K1/00
Inventor WINSLOW, ROBERT M.VANDEGRIFF, KIM D.
Owner SANGART INC
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