Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active...
Reexamination Certificate
2002-12-19
2004-02-17
Dodson, Shelley A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
C424S078100, C424S078120, C424S078130, C424S078140, C424S078310, C424S078330
Reexamination Certificate
active
06692732
ABSTRACT:
BACKGROUND OF THE INVENTION
Many pathogens produce toxins which are detrimental, and in some cases, lethal, to the host organism. Toxins produced by pathogens can be secreted, or excreted from pathogenic organisms (e.g., “exotoxins”) or toxic structural elements of pathogenic organisms (e.g., “endotoxins,” or toxin structural proteins).
Exotoxins are generally proteins or polypeptides. These toxins, which are secreted by the pathogen, can travel within the host and cause damage in regions of the host far removed from the infection site. Symptoms associated with exotoxins vary greatly and include hemolysis, systemic shock, destruction of leukocytes, vomiting, paralysis and diarrhea.
Enterotoxins are exotoxins which act on the small intestine and cause massive secretion of fluid into the intestinal lumen, leading to diarrhea. Enterotoxins are produced by a variety of bacteria and viruses, including the food-poisoning organisms
Staphylococcus aureus, Clostridium perfringens
, and
Bacillus cereus
, and the intestinal pathogens
Vibrio cholerae, Escherichia coli
, and
Salmonella enteritidis.
Endotoxins are lipopolysaccharides/lipoproteins found in the outer layer of the cell walls of gram-negative bacteria. These lipopolysaccharides are bound to the cell membrane and are released upon cytolysis. Symptoms associated with the release of endotoxins include fever, diarrhea and vomiting. Specifically, endotoxins stimulate host cells to release proteins, endogenous pyrogens, which affect the area of the brain which regulates body temperature. In addition to fever, diarrhea and vomiting, the host animal may experience a rapid decrease in lymphocyte, leukocyte, and platelet numbers, and enter into a general inflammatory state.
Although endotoxins are less toxic than exotoxins, large doses of endotoxins can cause death, generally through hemorrhagic shock and tissue necrosis. Examples of bacteria which produce endotoxins include the genera Escherichia, Shigella, and especially Salmonella.
In some cases, the active disease caused by an exotoxin can be treated by administering an antitoxin to the patient. An antitoxin comprises antibodies to the toxin derived from the serum of an animal, typically a horse, which has been immunized by injection of a toxoid, a nontoxic derivative of the toxin. However, the effectiveness of antitoxins is limited because toxins are rapidly taken up by cells and become unavailable to the antibodies. Furthermore, the patient's immune system can respond to foreign proteins present in the antitoxin, creating a condition known as serum sickness.
Therefore, a need exists for an improved method of treating toxins which significantly reduces or eliminates the above-mentioned problems.
SUMMARY OF THE INVENTION
One aspect of the present invention is a method for inhibiting a pathogenic toxin in a mammal, comprising administering to the mammal a therapeutically effective amount of a polymer having a cationic group, such as an amino group, an ammonium group or a phosphonium group, which is connected to the polymer backbone.
The polymer to be administered can be a homopolymer or a copolymer. In one embodiment, the polymer further includes a monomer comprising a hydrophobic group, such as an aryl group or a normal or branched C
2
-C
24
-alkyl group.
The polymer to be administered can, optionally, further include a monomer comprising a neutral hydrophilic group, such as a hydroxyl group or an amide group.
Another aspect of the invention is a method for inhibiting a pathogenic toxin in a mammal, such as a human, comprising administering to the mammal a therapeutically effective amount of a polymer comprising a polymethylene backbone which is interrupted at one or more points by a cationic group, such as an amino group, an ammonium group or a phosphonium group.
The present method has several advantages. For example, the polymers employed are easily prepared using standard techniques of polymer synthesis and inexpensive starting materials. The polymers will not be substantially degraded in the digestive tract and, therefore, can be administered orally. Polymer compositions can also be readily varied, to optimize properties such as solubility or water swellability and antitoxin activity.
DETAILED DESCRIPTION OF THE INVENTION
A description of preferred embodiments of the invention follows.
The present invention relates to a method for inhibiting a pathogenic toxin in a mammal, such as a human, by administering to the mammal a therapeutically effective amount of a polymer comprising a plurality of amino or ammonium groups.
As used herein, the inhibition of a pathogenic toxin refers to the reduction in activity of a toxin produced by a pathogenic microbe. The activity of the toxin can be reduced, for example, by interfering with the production or secretion of the toxin or by binding the toxin to form an inactive complex. Without being bound by theory, one mechanism by which the polymers disclosed herein may inhibit a pathogenic toxin is by binding the toxin.
A “therapeutically effective amount” is an amount sufficient to inhibit, partially or totally, the activity of a pathogenic toxin. The term “polymer” refers to a macromolecule comprising a plurality of repeat units or monomers. The term includes homopolymers, which are formed from a single type of monomer, and copolymers, which are formed of two or more different monomers. A “terpolymer” is a copolymer formed from three different monomers. The term polymer, as used herein, is intended to exclude proteins, peptides, polypeptides and proteinaceous materials.
As used herein, the term “polymer backbone” or “backbone” refers to that portion of the polymer which is a continuous chain, comprising the bonds which are formed between monomers upon polymerization. The composition of the polymer backbone can be described in terms of the identity of the monomers from which it is formed, without regard to the composition of branches, or side chains, off of the polymer backbone. Thus, poly(acrylamide) is said to have a poly(ethylene) backbone substituted with carboxamide (—C(O)NH
2
) groups as side chains.
The term “polymer side chain” or “side chain” refers to the portion of a monomer which, following polymerization, forms a branch off of the polymer backbone. In a homopolymer, all of the polymer side chains are identical. A copolymer can comprise two or more distinct side chains. When a side chain comprises an ionic unit, for example, the ionic unit depends from, or is a substituent of, the polymer backbone, and is referred to as a “pendant ionic unit”. The term “spacer group”, as used herein, refers to a polyvalent molecular fragment which is a component of a polymer side chain and connects a pendant moiety to the polymer backbone. The term “aliphatic spacer group” refers to a spacer group which does not include an aromatic unit, such as a phenylene unit.
The term “addition polymer”, as used herein, is a polymer formed by the addition of monomers without the consequent release of a small molecule. A common type of addition polymer is formed by polymerizing olefinic monomers, wherein monomers are joined by the formation of a carbon-carbon bonds between monomers, without the loss of any atoms which compose the unreacted monomers.
The term “monomer”, as used herein, refers to both (a) a single molecule comprising one or more polymerizable functional groups prior to or following polymerization, and (b) a repeat unit of a polymer. An unpolymerized monomer capable of addition polymerization, can, for example, comprise an olefinic bond which is lost upon polymerization.
The term “cationic group”, as used herein, refers to a functional group which bears a net positive charge or a basic group which gains a net positive charge upon protonation at physiological pH. Suitable cationic groups include ammonium groups, such as primary, secondary, tertiary and quaternary ammonium groups; amino groups, such as primary, secondary and tertiary amino groups; sulfonium groups; and phosphonium groups.
The quantity of a given polymer to be administered wil
Bacon Kurtz Caroline Isabelle
Fitzpatrick Richard
Huval Chad Cori
Mandeville, III W. Harry
Neenan Thomas X.
Dodson Shelley A.
Genzyme Corporation
Hamilton Brook Smith & Reynolds P.C.
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