Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1999-05-25
2000-10-31
Lee, Howard C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536115, 536118, 536119, 53612312, A61K 3172, C08B 3700
Patent
active
06140313&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to new partial or total butyric esters of polysaccharides, with high antiproliferative activity; these esters are therapeutically effective in the treatment and prevention of diseases characterized by abnormal cell proliferation like neoplasms and synovial diseases.
STATE OF THE ART
The biological activity of many classes of polysaccharides was thoroughly studied in relation to their use as drugs for the treatment of different pathologies. Among the polysaccharides used in therapy, heparins with either a low or an high molecular weight, are known as anticlotting agents, while dextrans are notoriously used as plasma expanders.
Recently new biological activities of polysaccharidic compounds have been identified, allowing to foresee a wider use of these polysaccharides in medicine.
Among the polysaccharides that constitute the active compounds of drugs presently in use, it is worth mentioning hyaluronic acid, which is used in the treatment of osteoarthrosis and other pathologies, since it can inhibit the lymphocyte proliferation (G. F. Peluso et al., Current Therapeutic Research, 47(3): 437-443, March 1990), and scleroglucan (commercialized as the active compound of a formulation called Sizofiran.RTM.) that is used as an immunostimulant in the treatment of some tumors (Eric J. Lien, Prog. Drug. Disc., 34: 395-420, 1990).
Moreover, some drugs of polysaccharidic nature are known in an advanced stage of clinical development, such as, for example, pentosan polysulphate which is used in the treatment of some tumors, and several derivatives of hyaluronic acid which are used as adjuvants in the healing processes and in the prevention of post-surgical adhesions. Results of particular relevance have recently emerged from the search for new pharmacological uses of polysaccharides.
Among the many pharmacological activities exerted by some families of polysaccharides, the antiproliferative activity leads to the possibility to use them as antitumour drugs, since they can inhibit the development of some lines of tumor cells. (A. Misaki et al., Carbohydrate Research, 92 (1981): 115-192).
The butyric acid is a compound of natural origin, non toxic, normally present in food and in the gastrointestinal tract as a product of the bacterial fermentation of complex carbohydrates. From a pharmacological viewpoint, this compound exerts an antiproliferative activity, by inhibiting the cell growth and by inducing the differentiation of a large variety of neoplastic cells, as widely shown by experimental tests carried out both in vitro and in vivo on different cell lines. The cell and molecular mechanisms which underlie the differentiating activity of butyric acid have not been fully elucidated so far. In particular, the sodium salt of the butyric acid is a known inducer of cytodifferentiation (A. Leder e P. Leder, Cell, 5:319, 1975). However, even though it is endowed with a good antiproliferative potential, the sodium salt of butyric acid exhibits the disadvantage of having a very short half-life, which has, so far, limited its use in vivo and that excludes the possibility of using it as a drug, since it is difficult to obtain sufficient plasma concentrations to exert a therapeutical effect.
As a matter of fact, once it is administered by the intravenous route, the active compound circulates for just 5-6 minutes before being metabolized.
Several attempts to overcome this drawback have been performed; esterification, so as to delay its degradation and to prolong its biological activity. Some simple esters of butyric acid are in fact known; among these, the phenyl butyrate, which can exert an antineoplastic activity in prostate cancer models (Proceedings of the American Association for Cancer Research, vol. 37, March 1996, 498) and in other tumors. In this case, the esterification is simply aimed at increasing the plasma half-life of the active compound by converting the active compound into a pro-drug which, by hydrolysis, slowly releases the butyric acid in the target organ. Ho
REFERENCES:
patent: 4024334 (1977-05-01), Chandler et al.
patent: 4959466 (1990-09-01), White
patent: 4981959 (1991-01-01), Diamantoglou
patent: 5093486 (1992-03-01), Diamantoglou
patent: 5597912 (1997-01-01), Edgar et al.
patent: 5717087 (1998-02-01), Kalbe et al.
patent: 5733750 (1998-03-01), Lund et al.
patent: 5830872 (1998-11-01), Baldwin et al.
patent: 5877144 (1999-03-01), Ehrhardt et al.
patent: 5916883 (1999-06-01), Shalaby et al.
Eliasson, Ann-Charlotte. Carbohydrates in Food, published by Marcel Dekker, Inc., pp. 366-368, 1996.
Nikitin, N.I. The Chemistry of Cellulose and Wood, pp. 63-66, 1966.
G.F. Feluso et al., The Effect of High and Low Molecular Weight Hyaluronic Acid on Mitogen-Induced Lymphocyte Proliferation, Current Therapeutic Research, vol. 47, No. 3, Mar. 1990.
Studies on Interralation of Structure and Antitumor Effects of Polysaccharides: Antitumor Action of Periodatemodified, Branched (1.fwdarw.3)-.beta.-D-Glucan of Auricularia auricula-judae, and other Polysaccharides Containing (1.fwdarw.3)-Glycosidic Linkages., Carbohydrates Research, 92 (1981) 115-129.
Proceedings of the American Association for Cancer Research, vol. 37, Mar. 1996, Monday, Apr. 22, 1996, 1:00-5:00, Poster Section 1.
Julie Dechanet et al., IL-4 Inhibits Growth Factor-Stimulated Rheumatoid Synoviocyte Proliferation by Blocking the Early Phases of the Cell Cycle, The Journal of Immunology, vol. 151, 4908-4917, No. 9, Nov. 1, 1993.
Bernard Levin, Ulcerative Colitis and Colon Cancer: Biology and Surveilance, Journal of Cellular Biochemistry, Supplement of Cellular Biochemistry, Supplement 16G: 47-50 (1992).
C.A. Rubio, MD et al., Crohn's Disease and Adenocarcinoma of the Intestinal Tract, Disease of the Colon & Rectum, vol. 14, No. 2, 174-180.
Gert Storm et al, Liposomes and Biotherapeutiics, Biotherapy 3, 25-42, 1991.
Aya Leder and Philip Leder, Butyric Acid, a Potent Inducer of Erythoid Differation in Cultured Erythroid Differentation in Cultured Erythroleukemic Cells, Cell, vol. 5, 319-322, Jul. 1975.
Coradini Danila
Perbellini Alberto
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