Liquid purification or separation – Processes – Ion exchange or selective sorption
Reexamination Certificate
2000-08-15
2002-10-08
Simmons, David A. (Department: 1724)
Liquid purification or separation
Processes
Ion exchange or selective sorption
C210S198100, C604S005040, C604S006090
Reexamination Certificate
active
06461517
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a material having selective affinity for compounds produced by prokaryotic micro-organisms, namely gram-negative bacteria and gram-positive bacteria. From among the compounds produced by bacteria, it relates to a material which removes or results in a loss of toxic activity (detoxification) of lipoteichoic acid (hereinafter abbreviated to LTA), protein A (hereinafter abbreviated to PrA), &agr;-hemolysin (abbreviated to aHL) or proteinase. In particular, since it binds to the LTA and/or PrA and/or aHL and/or proteinase occurring in blood and other such solutions of high protein concentration, it is ideally used either as a medicinal agent which brings about a loss of the toxic activity (detoxification) of LTA and/or PrA and/or aHL and/or proteinase, or as a purification column or dressing which removes LTA and/or PrA and/or aHL and/or proteinase.
TECHNICAL BACKGROUND
In recent years, as a result of a variety of studies, LTA has come to be regarded as one of the causal substances of gram-positive bacterial sepsis. For example, it has been reported that it induces expression of nitric oxide synthase in cultured vascular smooth muscle cells (J. Cardiovasc. Pharmacol., 20, S145-S147 (1992)), that as a result of intravenous infusion in rats there occurs a reduction in blood pressure and a reduction in the pressor reaction due to noradrenaline (Br. J. Pharmacol, 144, 1317-1323 (1995)), that as a result of intrathoracic administration to animals, neutrophil infiltration into the thoracic cavity is observed and pleurisy occurs (JP-A-9-163896) and, furthermore, that if LTA and peptidoglycan are jointly administered to rats, shock and internal organ disturbances occur (J. Exp Med., 188 (2), 305-315 (1998)). By way of contrast, it has been reported that nitric oxide production is inhibited by anti-mouse CD14 antibodies (Biochem Biophys Res Commun, 233 (2), 375-379 (1997)) or by N(omega)-nitro-L-arginine methyl ester (Infect Immun, 65 (6), 2074-2079 (1997)), and that platelet activating factor antagonist inhibits shock deaths resulting from LTA administration to mice (JP-A-9-208493). Furthermore, the effects of aminoguanidine and dexamethasone (Br J Pharmacol. 119 (7), 1411-1421 (1996)) have also been investigated. However, these all target substances produced in the latter part of the inflammatory response initiated by LTA and there are no reports of drugs which target the LTA itself. Now, regarding materials for medical use, there is a report (ASAIO J, 44 (1), 48-53 (1998) that fibre-immobilized polymyxin-B brings about a 20% reduction in the TNF-&agr; production due to a Staphylococcus aureus culture supernatant (diluted with 10% human plasma-containing medium). However, various toxins are contained in the culture supernatant and LTA removal has not been confirmed. Moreover, the percentage removal was also low, at 20%. Thus, there have not been known hitherto materials which have a high affinity for LTA in high protein solutions such as plasma.
In addition, it is known that, as a result of the agglomeration brought about by PrA binding to immunoglobulin G (hereinafter abbreviated to IgG), which is the main protein of the human immune system, deactivation of the activity thereof is brought about. As a result of the IgG deactivation and a lowering of the immune capability, bacteria readily invade the body and sepsis is aggravated. In the same way, aHL is a protein which harms cells by bringing about the formation of pores in the cell membranes of human cells (particularly blood corpuscles) and, by destroying cells, there is created a situation where infection readily occurs and sepsis is aggravated. No materials are known which have a characteristic affinity for such toxins, PrA and aHL.
OBJECTIVE OF THE INVENTION
The present invention relates to a material which resolves these prior-art problems and also has further novel functions, and its objective is to provide a material which can rapidly bring about a loss of toxic activity (detoxification) of, or can remove, the LTA and/or PrA and/or aHL and/or proteinase in blood or other such solutions of high protein concentration.
Specifically, the material of the present invention has a high affinity for bacterially-derived components and binds LTA and/or PrA and/or aHL and/or proteinase present in blood, plasma and other such body fluids, or in pharmaceutical preparations and, it this way, it is possible to detoxify the activities of these toxins and to treat and prevent sepsis and infectious diseases. Moreover, where this material is water-insoluble, there can then be provided a material which adsorbs LTA and/or PrA and/or aHL and/or proteinase present in blood, plasma and other such body fluids, or in drugs, by binding such toxins, and by employing such a material there can be provided a blood purification column or a wound dressing for the treatment or prevention of sepsis or infectious disease.
DISCLOSURE OF THE INVENTION
The present invention has the following constitution for resolving the problems described above.
(1) A bacterially-derived component detoxification or removal material which is characterized in that it has at least one functional group capable of hydrogen bond formation and detoxifies or removes at least one of the bacterially-derived components selected from lipoteichoic acid, protein A, &agr; hemolysin proteinase and endotoxin.
(2) A bacterially-derived component detoxification or removal material which is characterized in that it has a functional group capable of hydrogen bond formation and a hydrophobic group and/or ether bond, and it detoxifies or removes at least one of the bacterially-derived components selected from lipoteichoic acid, protein A, &agr; hemolysin, proteinase and endotoxin.
(3) A material for sepsis treatment where a material according to (1) and (2) is employed.
(4) A wound dressing employing a material according to (1) and (2).
(5) A method for the removal or detoxification of lipoteichoic acid and/or protein A and/or a hemolysin and/or proteinase in liquids, using a material according to (1) and (2).
OPTIMUM FORM FOR PRACTICING THE INVENTION
In the present invention, LTA refers to a substance from which the cell membrane and cell wall of gram-positive bacteria such as bacteria of the genera Streptococcus, Micrococcus, Lactobacillus, Staphylococcus, Bacillus and Enterococcus are composed (“Ika Saikingaku [Medical Bacteriology]”, Ed. by Masanosuke Yoshikawa, Published by Nankodo). Furthermore, PrA and aHL are proteins produced by Staphylococcus aureus. Again, in the present invention, proteinase refers to bacterially-derived proteinase which cleaves partial sequences from protein precursors, producing active proteins. These bacterially-derived components are toxins which are highly likely to be involved in the aggravation of infectious diseases, in particular sepsis.
In addition, it is suspected that there is a relationship between streptolysin, coagulase, enterohemorrhagic toxin, pseudomonas exotoxin A, cholera toxin, botulinus toxin, verotoxin, leukocidin, superantigen, endotoxin and the like, and the aggravation of infectious diseases, in particular, sepsis. Of these, superantigen and endotoxin are highly toxic and the detoxification or removal of these toxins is desirable at the same time as that of LTA, PrA and aHL.
In the present invention, there are no particular restrictions on the functional groups capable of hydrogen bond formation, and examples are the urea bond, thiourea bond, urethane bond, amide group, amino group, hydroxyl group, carboxyl group, aldehyde group, mercapto group and guanidino group, but possession of at least one urea bond, thiourea bond, amide bond, amino group or hydroxyl group is preferred. There are no particular restrictions on the structure adjoining the group capable of forming a hydrogen bond, and there can be employed aliphatic compounds such as propane, hexane, octane and dodecane, or alicyclic compounds such as cyclohexane and cyclopentane but, taking into consideration their high affinity, aromatic
Fukuyama Mayumi
Ishii Rumiko
Miwa Keishi
Nixon & Vanderhye P.C.
Prince Fred
Simmons David A.
Toray Industries Inc.
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