Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from filicinae
Reexamination Certificate
2002-06-10
2004-03-16
Lankford, Jr., Leon B. (Department: 1654)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from filicinae
C424S773000
Reexamination Certificate
active
06706293
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel pharmacological use of Anapsos. Anapsos is a neutral extract of Polypodium comprising 118 milligrams of a water soluble extracts and 2 milligrams of a lipid soluble fraction.
The present invention describes the involvement of the Anapsos in the regulation of the expression of the adhesion molecules. Anapsos reduces the expression of the alpha chain of integrins &bgr;-2 (CD11a and CD11b), the beta chain of integrins &bgr;-2 (CD18), and the differentiation antigen CD54 of the immunoglobulins superfamily. It is also capable of normalizing alterations of the immunological phenotype.
Further, is described the use of Anapsos in any diseases where an excess of inflammation, derived from cellular and tissue lesions, is responsible for pathologically symptoms and indications.
BACKGROUND OF THE INVENTION
The cells of the immune system are in contact with other cells and the extra-cellular matrix in order to efficiently perform their required functions. This is due to that they must be able to recognize the situation of their surroundings. Accordingly, the leukocytes not only have specific surface receptors capable of being specifically activated in response to determined stimuli, but also comprises a number of molecules which globally are called adhesion molecules. The adhesion molecules act as receptors for ligands which are situated on other cells and as receptors capable of binding amino acid sequences present in different extracellular matrix proteins, such as collagen, fibronectin, lamina, and others. The adhesion molecules, beside being involved in the cell—cell and cell—extracellular matrix adhesion, collaborate in the cellular activation by sending co-activator signals into the interior of the cell.
The migration of leukocytes to the tissue, essential for the immunological response, is mediated by a number of molecular interactions where the adhesion molecules play a fundamental role. The adhesion molecules are classified into 3 structural based categories:
the selectins
the family of integrins
the superfamily of immunoglobulins
In the first step of inflammation, the leukocytes acumulate around the endothelial wall causing the endothelial cells to remove themselves from each other. This initial process is mediated by the interaction of specific endothelial selecting (selectin E and P) and their corresponding leukocyte receptor (sLex) and between leukocyte selectin L and specific adhesion molecules of the endothelium. Simultaneously, with the expression of the adhesion molecules, are also released pro-inflammatory cytokines. Following, an activation signal induces a conformational change in the extra-cellular domains of the leukocyte integrins which gives a stronger adhesion. This is mediated by interactions between specific integrins and their ligands (LFA-1/ICAM-1, VLA-4/VCAM-1). As a consequence of the leukocyte/endothilium adhesion the accumulation of leukocytes is reduced and there are produced extravasation and migration of the leukocytes, from the blood circulation to the focus of inflammation, by chemotaxis. Consequently, the adhesion molecules are responsible for different processes of adhesion, mediating the final adhesion to the endothelium, the extravasation, and the migration towards the focus of inflammation.
The alpha and beta Chains of the integrins &bgr;-2 (CD11a, CD11b, CD18) are extended throughout all tissues. Consequently, a decrease in their expression gives an anti-inflammatory effect in the tissues. The adhesion molecule CD54 belongs to the immunoglobulin superfamily and is also highly distributed in various tissues, such as endothelium, leukocytes, etc.
In patients with multiple sclerosis there has been observed an increase in the lymphocyte population CD4+CD29+CD45RA. Further, recent data from the literature of virgin and memory cells indicates that revertant CD4+CD29+CD45RA+ cells are of fundamental importance as these are the authentic memory cells. They have a longer half-life as compared to CD45RO+ and once activated capable of being maintained years in the organism.
Inflammation, which might well be a normal physiological process, is when it is taken to its extreme converted into a pathological issue. For example, this happens in the major part of the auto-immune processes (systematic or organ specific), chronic inflammatory diseases, or infections which symptoms are characterized by an exaggerated inflammation giving rise to the corresponding damage of organs or tissues. Consequently, any medicament capable of decreasing the expression of the adhesion molecules, which under inflammation processes normally have an increased expression, may be suitable for the treatment of these diseases, independently if the aetiological cause of the specific disease. Such disease might be neuro-degenerative disorders (multiple sclerosis, Alzheimer), and connective tissue diseases (systematic lupus eritematose, Sjögren syndrome, reumatoide arthritis, Behcet disease, etc).
The anti-inflammatory action, due to reduction of the expression of the adhesion molecules, is performed independently of the inhibition-stimulation of the inflammatory cytokines and the stimulatory effect of the cellular immunity (increase of TH1-like cytokines and increase of T CD8+ lymphocytes and NK cells).
The extracts of the genus of the Polypodiaceae family have traditionally been used in Central America in the popular medicine attributing to it different activities such as: anti-inflammatory activity, Boletin de la Sociedad Quimica del Perú pag 91 (1988); prevention of tumor malignant,
Nature
214: 1256-1258 (1967). There have been described clinical effects in diseases related to immunological deficits, such as atopic dermatitis; Dermatológica 173: 154-156 (1986); atopic dermatitis, Allergology et Inmunopathology 15: 185-189 (1987); International Journal of Dermatology 13: 276-282 (1974); Planta Médica 58: 306-310 (1992) and vitiligo, International journal of Dermatology 28: 479 (1989). In these publications it has been identified that the extracts of
Polypodium leucotomos
have activity in relation to hyperqueratosis, paraquerotosis, epidermal mitosis, and lesions of the epidermis.
The extracts of these ferns have been described to have immuno-modulatory capacity in patients with atopic dermatitis, giving a normalization of the CD4+/CD8+ relation after treatment with extract of
Polypodium leucotomos
(Anapsos®), Dermatólogica 173:154-56 (1986); Annals Inmulogie 134:393-400 (1983). Annals of Psychiatry 3: 329-341 (1992) describes that the Anapsos® improve the memorizing, Decrease the levels of cytokines IL-1&bgr;-2 and IL-2 in the frontparietal cortex and decrease IL-1&bgr; in hypo-campus, Br. J. Clin. Pharmacol 43: 85-89 (1997) describes the immuno-modulatory effect in vitro of the polar extract of
Polypodium leucotomos
(Anapsos®) in relation to the cytokines IL-1&bgr;, IL-2, IL-10, INF-(which could give a pleiotropic effect in the different populations of the immune system.
Concerning the patent literature following documents of relevance have been identified.
The European patent application EP-503.208 describes a process for obtaining a water-soluble extract by extraction of the leaves and/or rhizomes of different ferns. This document specifies that these extracts have immunological activity and consequently useable in diseases involving a depression of the immune system, generally with a deficit of T suppressor lymphocytes, and with beneficial affects in the auto-immuno diseases and viral infections. Examples of pathological utilities are: reumatoide arthritis, lupus eritematose, syndrome of Sjögren, multiple sclerosis, hepatitis B, syndrome of Di George, auto-haemolytic anaemia, atopic dermatitis, psoriasis, Basedow disease, Chron disease, mistenia, vitiigo, herpes zoster, etc. The extract increases the level of T-suppressor lymphocytes.
The Spanish patent ES-2.088.770 teaches a pharmaceutical composition based on a water-soluble and a lipid soluble fraction of the leaves
Diaz Alperi Joaquín
Quintanilla Almagro Eliseo
Coe Susan D
Especialidades Farmaceuticas Centrum, S.A.
Lankford , Jr. Leon B.
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