Chemistry: molecular biology and microbiology – Maintaining blood or sperm in a physiologically active state...
Reexamination Certificate
2001-03-09
2003-10-28
Weber, Jon P. (Department: 1651)
Chemistry: molecular biology and microbiology
Maintaining blood or sperm in a physiologically active state...
C210S198100, C210S198200, C210S502100, C210S656000, C210S679000, C210S691000, C210S692000, C210S905000
Reexamination Certificate
active
06638710
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an adsorbent for the purpose of reducing the concentration of fibrinogen and/or fibrin in blood or blood plasma, comprising a matrix and synthetic lateral chains covalently bonded to the matrix having at least two amino groups whose nitrogen atoms, in the chain, are removed at least 2.6 Angstroms (0.26 nm) from one another, such that the synthetic lateral chains are peptide-free and exhibit no aromatic groups. Furthermore, the invention relates to a method of producing an adsorber from the adsorbent for the purpose of reducing the concentration of fibrinogen and/or fibrin in blood or blood plasma, as well as the adsorber itself.
BACKGROUND OF THE INVENTION
Adsorbents are widespread in medical technology. Adsorbers with adsorbents that remove lipoproteins of low density (LDL) from blood, or rather, reduce their concentration, such as those known from German Patent No. 39 32 971, are frequently described. German Patent No. 39 32 971 describes the adsorber material as an organic carrier having a fixed particle size and exclusionary threshold, which bears a ligand on its surface, to which the LDL molecule bonds.
In German Patent No. 197 29 591, the use of a ligand for fibrinogen and/or fibrin is claimed in order to cure the diseases engendered on the basis of an excessively elevated proportion of fibrinogen in the blood, or to at least prevent such diseases. In the process described in German Patent No. 197 29 591, the ligand is defined as a substance that binds, specifically, to fibrinogen and/or fibrin, and is, preferably, a peptide with three to ten amino acids.
The reduction of concentrations of plasma fibrinogen, immunoglobulin G (IgG) and immunoglobulin M ‘(IgM)’ by means of immunoadsorption therapy with tryptophan or phenylalanine adsorbents is known from
Artificial Organs,
volume 20, No. 9 (1996), pp. 986-990. In immunoadsorption therapy, adsorption columns are used which exhibit spherical polyvinyl alcohol (PVA) gel particles as carriers. On their surfaces, the PVA gel particles carry either tryptophan or phenylalanine as an amino acid ligand, which is covalently bonded to the PVA by way of spacers. The plasma, which is separated from blood cells, is conducted via the adsorption column and thereafter, before being led back to the patient, reunited with the blood cells again. With this immunoadsorption therapy, simultaneously, the concentrations of fibrinogen, IgG and IgM are significantly reduced.
Even if adsorption has, in the meantime, made its way into the clinical routine as a means of ameliorating illnesses, increasing demands are being made regarding the selectivity of adsorption. In other words, although the adsorbers are not permitted to adsorb any proteins that are necessary for human beings, or rather, as few of them as possible, it is also desirable that the reduction of the concentration of harmful proteins be so great that the extra-corporal treatment, which is a burden to the patient, is as effective as possible.
It has been known for some time that a number of diseases are based upon a lack of micro-circulation of the blood. The diseases enumerated in Table 1, which follows below, could be mentioned by way of example.
TABLE 1
CNS:
Stroke
TIA (Transient Ischemic Attack)
PRIND (Prolonged Reversible Ischemic Neurological Deficit)
Chronic vascular diseases of the CNS
Chronic intracranial perfusion disorders
Chronic extracranial perfusion disorders
Cerebro-vascular perfusion disorders
Dementia
Alzheimer's disease
Severe central vertigo
Eye:
Chronic perfusion disorder
Acute vascular occlusion
Ear:
Sudden deafness
Vertigo emanating from inner ear
Ménière's disease
Lung:
Primary pulmonary hypertension
Veno-occlusive lung diseases
Thrombotic primary pulmonary hypertension
Thromboembolitic diseases of the major vessels
Heart:
Transplant vasculopathies
Acute myocardial infarction
Unstable angina pectoris
Small vessel disease of the heart
Inoperable severe coronary heart disease
Cardiomyopathies
Abdomen:
Angina abdominalis
Kidneys:
Renal vasculopathies
Glomerulonephritides
Chronic renal insufficiency
Peripheral arterial occlusion diseases
Acute vascular occlusions
Vasculitides
Septic shock
Disseminated intravascular coagulation (DIC) of different
origin, e.g. in tumors
Type I + II diabetes
Diabetic retinopathy
Diabetic neuropathy
Diabetic nephropathy
Thus far, these diseases have been treated with medications, for the most part, and in the process, nothing more than an elimination of the symptoms has occurred. The measures that have been known thus far for treating and influencing the micro-circulation and the rheology of the blood consist of plasma exchange, heparin-induced extra-corporal LDL cholesterol precipitation (HELP) and the adsorption of fibrinogen with the aid of a ligand, to which fibrin and/or fibrinogen specifically binds. The use of a ligand of that type is described in German Patent No. 197 29 591. Peptides that exhibit, preferably, three to ten amino acids, such that the particularly preferred sequence is said to be glycine-proline-arginine-proline-X, are cited as ligands.
The synthetic production of peptides, however, is a complex and costly process, so that the use of a specific adsorber as a ligand is very costly.
Beyond that, peptides longer than a certain length trigger antibody reactions so that after repeated use, pronounced immune reactions can result in the long term. Indeed, in order to reduce the immune defense, peptide oligomers that are as short as possible are used, but immunogenicity can never be fully precluded. In addition, leakage, an unnoticed release of pieces of peptide, is particularly dangerous, because as components of the body's inherent structures, peptides represent bioactive molecules.
In addition, as described in
Artificial Organs,
volume 20, No. 9 (1996), pp. 986-990, immunoadsorption therapy employs the amino acids tryptophan or phenylalanine for bonding onto the PVA gel particles, and therefore, it too is complicated and costly. Furthermore, with this therapy, even substances that should not be removed from the plasma, such as IgG and IgM, are removed from the plasma in amounts that are comparable to those of the fibrinogen.
SUMMARY OF THE INVENTION
The object of the present invention is to create an adsorbent for the purpose of reducing the concentration of fibrinogen and/or fibrin in blood or blood plasma that exhibits better elimination ratios and can be produced more cost-effectively than those adsorbents known in the art, while at the same time being bio-compatible, possessing selectivity for fibrinogen and/or fibrin, and causing no immune defense.
It has been surprisingly discovered herein that an adsorbent that exhibits a matrix and synthetic lateral chains that are covalently bonded to the matrix, such that the lateral chains contain at least two amino groups that are spatially separated from one another, causes such a distinct reduction of the fibrinogen level that following treatment, micro-circulation is improved.
DETAILED DESCRIPTION
According to the present invention, the spatial distance of the amino groups is important for the capacity to bind, as it must be at least 2.6 Angstroms (0.26 nm). If the amino groups are farther than ten atoms removed from one another, the atoms being selected from the group of carbon, oxygen, sulfur, and/or phosphorous, such that the atoms are, preferably, carbon atoms, the binding effect is reduced once more. In the process, the atoms can consist of just one type of atom, however, any combination of the aforementioned types of atoms is possible. If the amino groups are less than four atoms removed from one another, then the lateral chain becomes more unstable chemically. For this reason, a chain length of four to six atoms, preferably carbon atoms, is preferred between the amino groups.
The possibility of being sterilized, especially the possibility of being sterilized by means of heat, is important for the use of such an adsorbent, due to the fact that the treated blood is to be returned to the
Hepper Martin
Leinenbach Hans-Peter
Otto Veit
Fresenius Hemocare GmbH
Srivastava Kailash C.
Weber Jon P.
LandOfFree
Adsorbent for reducing the concentration of fibrinogen... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Adsorbent for reducing the concentration of fibrinogen..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Adsorbent for reducing the concentration of fibrinogen... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3171938