Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-04-22
2001-03-27
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C514S008100, C514S012200, C514S059000, C514S921000, C514S950000, C424S085100, C424S085200, C536S102000, C536S112000
Reexamination Certificate
active
06207654
ABSTRACT:
The present invention relates to a method for treating human subjects to prevent leakage of macromolecules from capillary endothelial junctions as a consequence of extremely severe and life threatening side effects due to cancer biological therapy for cancer, infectious diseases, septic shock, and in viral infections implicated in human cancers. More particularly this invention relates to a method for preventing leakage of macromolecules from capillary endothelial junctions during a period of increased capillary permeability secondary to cytotoxicity of biological agents used to treat cancer, infectious diseases, (bacterial and viral) and to provide antiviral therapy in viral infections implicated in human cancers, as an approach to improving the immune response of cancer patients as well as preventing the inflammatory processes set into play during treatment with other anticancer drugs, radiation and as a consequence of the numerous infections that cancer patients acquire as a result of being immunologically compromised.
The invention comprises the use of compositions containing a single polysaccharide or a combination of two polysaccharides for the prevention of leakage from capillary endothelial junctions of macromolecules. The compositions comprise in addition to one or two polysaccharides, a biological agent preferably interleukin-2 or interferon.
The polysaccharide(s) for inclusion in the compositions of the invention include hydroxyethyl starch (HES,hetastarch, Hespan®) and dextran. The protective action of these polysaccharides has been found by the inventor to be brought about by a biophysical/biochemical process resulting in membrane stabilization of the capillary endothelial cell by virtue of the “sealing” effects as well as capillary membrane stabilization brought about by these molecules.
Current scientific literature reveals that inflammatory mediators initiate a biochemical chain of events that increase capillary permeability and deteriorate capillary membrane stability. These mediators include pharmacologically active amines such as histamine and 5-hydroxytryptamine, polypeptides such as bradykinin, kallikrein and leukotoxine, the prostaglandins, and various complements including derivatives thereof. These mediators act specifically on the junction of the endothelial cells of capillaries so that the junctions cannot contain colloids such as serum albumin within the vessel. The serum albumin escapes into the interstitium creating a nonfunctional “third space”, the volume of which increases proportionally to albumin leakage and the presence of cytokines as well as proteolytic enzyme activity within the matrix. This leakage further widens capillary membrane-transport between the circulatory system and the functional cells resulting in cellular anoxia, cellular energy deficit, acidosis and possibly leads to sequential organ failure.
In the past, the problem of albumin leakage and the concurrent creation of a third space has been approached through pharmacological means. The present invention approaches the problem as a biophysical phenomenon by utilization of natural or synthetic polysaccharides (macromolecules) as sealants and capillary membrane stabilizers to prevent or substantially reduce the escape of albumin and other molecules through the junction of the endothelial cells of the capillaries as well as stabilize the colloidal oncotic pressure. This is accomplished by virtue of the configuration and biophysical/biochemical properties (adhesiveness) of the utilized polysaccharides.
Hydroxyethyl starch (Hespan U.S. Pat. No. 3,523,938) is an artificial colloid derived from a waxy starch, composed almost entirely of amylopectin. The branched amylopectin polymer has a degree of polymerization on the order of several hundred glucose residues. The segments between the branched points average about 25 glucose residues linked by alpha-D-(1-4) glucosidic bonds, while the branched points are linked by alpha-D-(1-6) bonds. Hydroxyethyl ether groups are introduced into the glucose units of the starch and the resultant material is hydrolyzed. Clinical hetastarch is characterized by its molecular weight and its degree of substitution. The average molecular weight is approximately 480,000 daltons with a range of 400,000 to 500,000 and with 80% of its polymer units falling within the range of 30,000 to 2,400,000 daltons. The molar substitution is 0.7 which means hetastarch has 7 hydroxyethyl groups for every 10 glucose units. The polymerized glucose units in hetastarch are joined primarily by 1-4 linkage with hydroxethyl groups being attached primarily at the number 2 position. The polymer closely resembles glycogen. The degree of branching is approximately 1:20 which means that there is one 1-6 branch for every 20 glucose units. The chemical name for hetastarch is hydroxyethyl starch. The structural formula is as follows:
Amylopectin derivative in which R
2
, R
3
, and R
6
are H or CH
2
CH
2
OH, or R
6
is a branching point in the starch polymer connected through a 1-6 linkage to additional &agr;-D-glucopyranosyl units.
The colloidal properties of 6% hetastarch approximate those of human albumin. Intravenous infusion of HES results in expansion of the plasma volume slightly in excess of the volume infused but which decreases over the succeeding 24-36 hours. This expansion of plasma volume improves the hemodynamic status of the subject for 24 hours or longer. Hydroxyethyl starch molecules below 50,000 daltons are rapidly eliminated by renal excretion with approximately 40% of a given total dose appearing in the urine in 24 hours. The hydroxethyl group is not cleaved by the body, but remains intact and attached to the glucose units when excreted. Significant quantities of glucose are not produced (metabolism) as hydroxyethylation prevents complete metabolism. Despite its extensive clinical use hetastarch has not been observed to act in a way more than merely exerting a colloidal oncotic pressure when compared to albumin.
Hydroxyethyl starch is administered by intravenous infusion only. In adults the amount usually administered is 500 to 1500 mls. Doses of 1500 mls per day of 6% hydroxyethyl starch per 70 kg man have been used in postoperative open heart operations and trauma patients. Hydroxyethyl starch can be delivered in 0.9% saline, 5% dextrose or Ringer's lactate.
The inventors have utilized other polysaccharides in addition to hetastarch and have produced promising results. These polysaccharide macromolecules include glycogen and dextran.
Glycogen is a readily mobilized storage form of glucose. It is a very large polymer of glucose residues. Most of the glucose residues are linked by alpha-1-4 glycosidic bonds of which there is one in about 10 residues. Glycogen granules are 100 to 400 Angstrom and have a molecular weight range of about 270,000 to 350,000 daltons. The molecules of glycogen do not have a unique size. The average molecular weight is several hundred kilodaltons.
Dextran, another polysaccharide is made up of glucose residues only, mainly in alpha-1-6 linkage. Occasional branches are formed by alpha-1-2, alpha-1-3 or alpha-1-4 linkages. The nature of the linkages are dependent on the source of the dextran. Certain bacteria secrete dextran as a by-product of their growth and commercial dextran is manufactured by bacterial culture procedures. By varying the growth conditions of the bacteria, the molecular weight of the dextran can be controlled to bring about the desired size. Useful molecular weights for plasma substitution range from 100,000 to 500,000. Dextran of appropriate molecular size does not pass through the capillary pores and therefore, can replace plasma proteins as colloid osmotic agents.
Few toxic reactions have been observed when using either dextran or hetastarch for fluid replacement therapy.
The capillary wall is composed of a unicellular layer of endothelial cells and is surrounded by a basement membrane. The thickness of the wall is about 0.5 micron. The diameter of the capillary is 4 to 9 microns. The endothelial cells of the capill
Zikria Bashir
Zikria Jemal D.
Mertz Prema
Sommer Evelyn M.
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