Therapeutical treatments

Details Therapeutical treatments Therapeutical treatments

2001-11-30

2003-12-09

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S123120, C536S123100, C536S124000, C536S122000

Reexamination Certificate

active

06660722

ABSTRACT:

The invention relates to therapeutical treatments.
More particularly it relates to therapeutical treatments based on the immunostimulant antitumoral and cytokine synthesis-inducing and -accelerating activities of laminarin, especially of soluble laminarin, a well known glucan, which activities were surprisingly and unexpectedly discovered by the Applicants in the course of extensive and thorough studies and searches and on which are founded the hereafter disclosed and claimed applications and uses.
The therapeutical treatments in question are intended to treat cancers, viral, bacterial and fungal diseases as well as diseases related to immunostimulant deficiencies of human beings and warm-blood animals.
The Applicant's discovery is all the more important and unexpected
as comparative test, which are hereafter disclosed, show the superiority from the point of view of efficiency of especially the soluble form of laminarin with respect to another glucan, i.e. lentinan, which is extracted from a mushroom and which is used in Japan since 25 years as an adjunctive in antitumor therapy, and
as glucans of the laminarin and pachyman type (single helical form) were considered as “antitumor negative” i.e. as not having antitumor properties in comparison with glucans of the family comprising lentinan, curdlan, schizophyllan and pachymaran (triple helical form) which were considered as “antitumor positive” i.e. as acting against tumors. (see G. CHIHARA, National Cancer Center Research Institute, Tokyo, Japan, article under the title “Immunopharmacology of lentinan and glucans”, published in EOS-Riv.Immunol.Immunopharmacol., 5:85, 1983).
Another important aspect of the invention comes from the fact that it makes available therapeutical treatments which permit to fight again the increasing occurrence of antibiotic-resistant, nosocomial infections which are often untreatable by classical procedure, the treatments of these diseases by immunomodulators such as cytokines, while efficient, being associated with the inherent toxicity of these materials.
Laminarin is extracted from brown algae and its molecular weight is from about 2500 to about 6000.
Laminarin is consisting of a main linear chain of 15 to 35 glucopyranose units joined by acetalic &bgr;-(1,3) linkages and to which a low proportion of branches, in essentially primary position of principally &bgr;-D-glucopyranose units are joined by &bgr;-(1,6) linkages, some of these &bgr;-D-glucopyranose units being joined to the main chain.
The average degree of polymerisation is close to 25.
The terminal unit of the main chain is consisting of glucose or of mannitol, thus providing two types of molecules respectively called G or M.
Complete hydrolysis provides glucose and manitol.
Two forms of laminarin have been identified; one of these forms is the here preferably used soluble form, while the other one is insoluble in water, the latter being probably characterized by few or even no branches.
Both the soluble and the insoluble form may be obtained by extraction from e.g. laminaria species; two of these species are laminaria digitata and laminaria hyperborea.
Soluble laminarin occurs under the form of a white to beige powder which is odourless and tasteless; the soluble form is very hygroscopical and water-soluble (up to 60 g/l), while being substantially insoluble in ethanol, 2-propanol and acetone.
The identification of soluble laminarin may be carried out by way of liquid chromatography using, for example, a device comprising an amperometric detector.
Procedure may be as follows, using
an anion-exchange column, fitted with a non-porous, polymeric resin whose particle size is about 5 &mgr;m, the length of the column being 250 mm and the internal diameter 4 mm,
a pulsed amperometric detector equipped with a gold electrode,
a mobile phase consisting of the mixture of a solution A with a solution B, the solution A initially representing 30% and the solution B 70%, the latter becoming isocratic of A after 4 minutes, which means that the mobile phase is only consisting of A.
Solution A is obtained by dissolving 41 g of sodium acetate in 950 ml of water, free of particles, and by introducing 8.2 ml of NaOH of 46-48%.
Solution B is 150 mM solution of NaOH obtained by mixing 8.2 ml of NaOH of 47% with 990 ml of water, free of particles.
A quantity of 50 ml of the solution to be examined is injected and eluted at a rate of 1 ml/min during 15 minutes.
The thus obtained chromatogramm comprises a Gauss pic of retention comprised between 5.8 and 12 minutes, of maximum amplitude located at about 8 minutes.
The pH of a solution of 1 g of soluble laminarin in water, free of carbon dioxyde, completed to 10 ml, is from 6.5 to 7.5.
The combustion residue of 1 g of soluble laminarin is not higher than 5%.
The fucan content of soluble laminarin obtained by liquid chromatography dosing of the fucose content of the product obtained by total hydrolysis of the said soluble laminarin appears to be lower than 5%.
As mentioned hereabove, laminarin is extracted from brown macrophytic marine algae of the Pheophyceae type, in particular from fucales or laminariales.
Various extraction methods can be used.
Reference may be made for example to the method described by Black et al., Appl. Chem. 1951, 1, pages 505 to 517.
More generally, laminarin can be obtained from brown algae by any extraction process provided it enables the constituents other than laminarin (wall polysaccharides, salts, etc.) to be successively removed.
In particular, these processes use steps involving grinding, precipitation in an acid or basic medium, ultrafiltration and dialysis.
The thus obtained product is consisting of a mixture of the soluble and the insoluble forms of laminarin, the respective proportions of which vary according to the selected algae.
For example, laminaria digitata or laminaria saccharina provide a mixture comprising about 90% by weight of the soluble form, while laminaria hyperborea provides a mixture comprising about 80% by weight of the insoluble form.
The latter is separated by precipitation.
The following non-limiting example illustrates the extraction process of soluble laminarin.


REFERENCES:
Marcuccio et al. Accad.Pugliese Sci., Atti Relaz., Parte 2 (1967), 25 (Pt. 2), 327-35.*
Arinaga, Shinya et al., “Enhanced production of Interleukin 1 and tumor necrosis factor by peripheral monocytes after lentinan administration in patients with gastric carcinoma”, Int. J. Immunopharmacol., 1992, pp. 43-47, vol. 14, No. 1.
Chihara, G., “Immunopharmacology of Lentinan and Glucans”, Immunol. Immunopharmacol., 1983, pp. 85-96, vol. 5.
Chihara, G. et al., “Antitumor and Metastasis-Inhibitory Activities of Lentinan as an Immunomodulator”, Cancer Detection and Prevention Supplement, 1987, pp. 423-443, vol. 1.
Dennert, Gunther and Derek Tucker, “Antitumor Polysaccharide Lentinan—A T Cell Adjuvant”, Journal of the National Cancer Institute, Nov. 1973, pp. 1727-1729, vol. 51, No. 5.
Fachet, Jozsef et al., “Effect of lentinan on different types of immune responses including anaphylactic shock”. (Publication information to follow).
Tazawa, K. et al., “Inhibitory effect of lentinan entrapped in liposomes on pulmonary metastasis in rats. Distribution of liposomes and enhancement of NK cell activity”, J. Exp. Clin. Cancer Res., 1992, pp. 21-27, vol. 11, No. 1.
Vervicka, Vaclav, “&bgr;-Glucans as Immunomodulators”, JANA, Winter 2001, pp. 13-16, vol. 3, No. 4.

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