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MalPEG-Hb conjugate- containing compositions for delivering carbon monoxide (CO) to cells

a technology of conjugate-containing compositions and carbon monoxide, which is applied in the direction of drug compositions, peptide/protein ingredients, peptide sources, etc., can solve the problems of increased blood capacity through the blood vessel, increased resistance and increased flow through the vessel, and harmful free hemoglobin in the bloodstream

Inactive Publication Date: 2009-03-26
SANGART INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Interestingly, free hemoglobin in the bloodstream is actually harmful, because of its vasoactivity.
Vasodilation is a physical change in a blood vessel, which results in an increased blood capacity through the blood vessel; and leads to decreased resistance and increased flow through the vessel.
Although these drugs may be successful in lowering the pulmonary blood pressure, they typically also decrease systemic blood pressure, which may result in dangerous pooling of the blood in the venous circulation.
This can lead to hypotension, ischemia and consequent heart failure.
However, in both studies, it was concluded that the dangers of CO inhalation outweighed the benefits.

Method used

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  • MalPEG-Hb conjugate- containing compositions for delivering carbon monoxide (CO) to cells
  • MalPEG-Hb conjugate- containing compositions for delivering carbon monoxide (CO) to cells
  • MalPEG-Hb conjugate- containing compositions for delivering carbon monoxide (CO) to cells

Examples

Experimental program
Comparison scheme
Effect test

experiment 1

In Vitro Mixtures of COMP4 and Red Blood Cells

[0081]In this experiment, MP4 (human hemoglobin modified with maleimide-PEG 5000 prepared according to U.S. Pat. No. 6,844,317) was equilibrated with 100% CO and mixed in various proportions with fresh human blood (see Table 1). After 30 minutes at room temperature, the cells and plasma were separated by centrifugation and the percent CO hemoglobin in each was determined using a Co-Oximeter. In each case, the saturation of CO in red blood cells increased and the CO saturation in MP4 decreased, indicating a net transfer of CO from MP4 to red blood cells

TABLE 1Before MixingAfter MixingRBCMP4RBCMP4Coservation of COHbCOHbvolHbCOHbvolCOHbCOHb(mL × conc × % CO)Expt(g / dL)(%)(mL)(g / dL)(%)(mL)(%)(%)startend117.41.744.592.616.92.8rbc CO118.3480.2MP4 CO416.712.6Total CO535.0492.8217.41.744.592.6212.46.7rbc CO118.3863.0MP4 CO833.460.3Total CO951.7923.3317.41.744.592.6422.415.6rbc CO118.31559.0MP4 CO1666.8280.8Total CO1785.11839.8

[0082]In a variant o...

experiment 2

20% Topload Infusion of COMP4 in the Rat

[0084]To test the overall toxity of COMP4 in the rat, a topload infusion of 20% of estimated blood volume was carried out at 2 mL / minute. Given the size of the animals in this study, the infusion was complete in approximately 7 minutes. FIG. 1 shows a fall in hematocrit that is predicted by the expansion of the blood volume and dilution of the red cell mass. After infusion, however, there is no further change in hematocrit, indicating that the blood volume is stable. The hemodynamic changes (FIG. 2) include an initial increase in the force of cardiac contraction (dP / dt), probably because of the expanded blood volume. Very little change in mean arterial pressure (MAP) or heart rate (HR) are seen. The percent COHb, in both the red blood cells and MP4 compartments (FIG. 3) are nearly identical, indicating that the redistribution of CO between the 2 compartments is almost instantaneous after the infusion, or that it is complete by the end of the t...

experiment 3

50% Blood Volume Exchange Transfusion (ET) with COMP4 Followed by 60% Blood Volume Controlled Hemorrhage

[0087]In this experiment, rats are exchanged transfused at 0.5 mL / min with fully saturated COMP4. After a short rest period, a controlled hemorrhage of 60% of estimated blood volume is performed over one hour. Animals are observed for an additional hour, then euthanized if they survive. The control in this case is CO-saturated stroma free hemoglobin (CO-SFH). In addition to survival, the outcomes to be measured include the location of the CO, hemodynamics and acid-base balance.

[0088]The hemodynamic response to the COMP4 is similar to that seen with O2-MP4 (FIG. 5). That is, a very small fall in mean arterial pressure during the initial stages of the hemorrhage, followed by a stabilization and eventual survival of the animal. In contrast, the animals infused with CO-SFH did not survive the hemorrhage period. The heart rate initially falls and then returns to baseline in the COMP4 a...

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Abstract

The present invention relates to compositions for delivering carbon monoxide (CO) to cells using heme proteins as carriers. In one embodiment, the present invention relates to the use of MalPEG surface modified hemoglobin to deliver CO to cells.

Description

RELATED APPLICATIONS[0001]This application is a continuation application of U.S. Utility application Ser. No. 11 / 370,502, which was filed on Mar. 7, 2006, which claims the benefit of U.S. Provisional Application Ser. No. 60 / 659,137, which was filed on Mar. 7, 2005, each of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to compositions for delivering carbon monoxide (CO) to cells using heme proteins as carriers. In one embodiment, the present invention relates to the use of MalPEG surface modified hemoglobin to deliver CO to cells.BACKGROUND OF THE INVENTION[0003]The delivery of oxygen in higher organisms is carried out by the protein hemoglobin. In mammals, hemoglobin has a molecular weight of approximately 64,000 Da and is composed of about 6% heme and 94% globin. Heme is a type of porphyrin molecule that coordinates to Fe(II) using its four nitrogen atoms as electron-pair donors. In coordination with globin (i.e. the globular p...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/42C07K14/435
CPCA61K33/00A61K47/48307A61K47/48215A61K38/42A61K47/60A61K47/6445A61P9/00A61P9/12
Inventor WINSLOW, ROBERT M.
Owner SANGART INC
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