CA2088994C - Therapeutically active mixture of glutathion and anthocyan compounds - Google Patents

Abstract

A mixture of substances for therapeutically treating the human or animal body contains reduced glutathion and at least an anthocyan compound from the group composed of pelargonidine, peonidine, cyanidine, melvidine, petunidine and delphinidine.
The reduced glutathion can be entirely of partially substituted by at least a thiol-derivate of glutathion from the group composed of methyl-glutathionyl-(thio)-ether, ethylglutathionyl-(thio)-ether, mono-acetyl-glutathionyl-(thio)-ester, and mono-phosphoric ac-id glutationyl-(thio)-ester.

Description

E;.::.,:, Specification A therapeutically active mixture of glutathione and anthocyanin compounds.
Scientific findings of the past few years show that destruc-tive physical chemical processes by "free" radicals, radical chain reactions, and/or activated oxygen states become ever more important aspects in the pathogenesis of many acute diseases and especially of chronic diseases, among others of arterial and venous angiopathies, allergies, autoaggressive diseases, and tumors. Reactions of "free" radicals and ac-tivated oxygen states.(ASS) and also of radicals formed by ionizing radiation in water radiolysis always lead to changes and destructions of the biomolecules (DNA, RNA, enzyme and structural proteins, unsaturated fatty acids, etc.) and also to membrane damage and membrane destruction in all cells and cell organellae by way of radical reaction phenomena of the lipoperoxidation. Radical processes are included in the eti-ology of all diseases; often they even are the cause of these diseases, or they sustain them by radical chain reactions.
For this reason man and animals are protected by certain en-zymes having anti-oxidative action, such as superoxide dis-mutases, catalases, and peroxidases which "defuse" the activated oxygen states.
It is known (WO 89/00427) that the reduction potential of re-duced glutathione, i.e. its optimum high intracellular concen-tration, is extremely important to maintain the functioning of many, perhaps all the enzymes of cell metabolism, to prevent oxidative alterations o~ their catalytic and allosteric cen-ters, and to uphold optimum conformation, and that it can be increased by doses of reduced glutathione or at least be reestablished -- where the metabolism dysfunctions.' It is likewise known (WO 89/00427) that it may be more favor-able to supply a thiol derivative of glutathione to the body S f ~ i ~ n . 2 ~~
from outside, instead of the reduced glutathione itself. Thiol derivatives are characterized by a particularly good bio-availability. Their capability of permeation through bio-logical membranes is high. The SH group of glutathione which is important for the therapeutic effect is protected on the way through biological compartments up to 'the desired site of action, and they cause no inhibition of the enzymes which take part in the endogenous glutathione biosynthesis.
Likewise known (DE-OS 27 40 346) are medicines which contain an anthocyanidin, such as cyanidin, peonidin, delphinidin, pe-tunidin, pelargonidin, and/or malvidin as the active compo-nent. These medicines are intended for use in the treatment of wounds, ulcers, inflammatory symptoms, and pathogenic condi-tions of the vascular system or of disturbances caused by a deterioration of the lipoid or glycide metabolisms.
Although, as a coenzyme (selenium dependent glutathione per-oxidases) and as a cofactor (glutathione S transferases), but also as a non-enzymatic scavenger and nucleophilic substance, reduced glutathione can detoxify electrophilic xenobioties directly as primary or secondary radicals and can detoxify radicals which are formed in the cell metabolism by exposition to energy-rich radiation, insufficiencies may result if re-duced glutathione is the only therapy applied, even if applied sufficiently. Such insufficiencies are explained by:
- poor genetic equipment with anti-oxidative, i.e. scavenge enzymes (enzymopathies) - deficient biosynthesis of anti-oxidative enzymes in dif-ferent compartments and in dependence on certain unfavor-able phases in life (enzymopenias);
- "oxidative wear" of reduced glutathione under certain circumstances, such as intoxications, inflammations, in-fections, shortages of non-enzymatic or enzymatic scaven-gers, with the extremely unfavorable possibility of the formation of thyil radicals, glutathione disulfide an-ionic radicals, or glutathione peroxisulphenyl radicals;

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~;,. . 3 - de novo biosynthesis dysfunctions of endogenous reduced glutathione;
- high-performance sports, cachexies, consumptive diseases, age.
All these insufficiencies of various origin lead to altera-tions of the negative redox potential which exists in all bio-logical spaces of living systems and to enzyme disorders by way of "derailing" in the "redox shifting system"
reduced glutathione ~, mixed disulfides ~-, oxidized glutathione, especially so in anti-oxidative enzymes and repair enzymes, further to metabolic dysfunction, mutations, malignant trans-formation, or even cellular necrosis.
Now it has been found that the therapeutic failures which re-sult from the pathogenic disorders mentioned upon exclusive use of reduced glutathione can be prevented by a combination of reduced glutathione with anthocyanins, with the possibility of advantageously using thiol derivatives of glutathione instead of the reduced glutathione or in addition to the same.
The invention thus provides a mixture of substances for thera-peutic treatment of the human or animal body, which mixture contains reduced glutathione and at least one anthocyanin com-pound of the group consisting of pelargonidin, peonidin, cyanidin, melvidin, petunidin, delphinidin, with the reduced glutathione .possibly being substituted altogether or in part by at least one thiol derivative of glutathione of the group consisting of methylglutathionyl(thio)ether, ethylglutathio-nyl(thio)ether, mono-acetylglutathionyl(thio)ester, mono- .
phosphoric glutathionyl(thio)ester.
Reduced glutathione is a tripeptide present, in its-reduced form (G-SH), in most human and mammal cells; it consists of the three amino acids glutamic acid, cysteine, and glycine and has the structural formula below:

_ _,,~ , CCOH H O
I 1 n CH ~ / CH N C CH
H2N~ CHZ 2\C~ \CH/ \N / Z~CCOH
a ~ I

i SH
reduced glutathione (gamma-glutamyl-cysteinyl-glycine)e The thiol derivatives of glutathione used according to 'the in-vention have the following structural formula COOH H O
H N~ CH~CH / CHZ\ C/N\CH/C\N/~2\ CCOH
z z n I ~

i methylglutathionyl(thio)ether or monomethyl thioester CCOH
CH CH N ~ CH2 , H z N / \ ~H 2 ~ z \ ~ ~ ~ ~ ~ ~' N ~ ~ CcoH
p CH2 H

ethylglutathionyl(thio)ether or monoethyl thioester CCOH

/ \ ~ 2\C~ \CH/ \N/ ~CCOH
H2N CHZ a CH H
O
l II
O
mono-acetylglutathionyl(thio)ester or monoacetyl thioester H
.. CCOH N o CH 2 / CH \, / CH 2 ~ C ~ ~ CH / c~ N / ' CCOH

S- P0.2H2 mono-phosphoric glutathionyl(thio)ester or monophosphoric thioester.
Anthocyanins are present in many plants of higher order where they are responsible for the red, violet, blue or bluish black colors of flowers and fruits. They are heterocyclic 2-phenyl--chromenol multiring systems of varying hydroxylating patterns and varying absorption spectra in,the visible light range. The sugar-free aglycon components of anthocyanins are referred ~t.o as anthocyanidins. They are obtained easily by hydrolysis of the glycosides contained in common fruits (cf. DE-OS 27 40 346) and their structural formula is as follows:
. R~ a OH ~ OH
i HO ~ 0~ ~ I z HO ~ 0 ~ ~ Ri Cl' ~~R
~ OH ~ ~ ~ OH
OH OH
R1 R2 popular name Amax (nm) (color) H pelargonidin 520 (red orange) , H OCH3 peonidin 532 (red violet) H Og cyanidin 535 (red violet) OCH3 OCH3 malvidin 542 (violet red) OH OCH3 petunidin 543 (violet red) OH OH delphinidin 544 (blue violet) Anthocyanins can act as good scavengers for the superoxide anion radical (02), for hydrogen peroxide (H2o2), f'or the hydroxyl radical (oH'), for alkoxyl radicals (LO'), peroxyl radicals (L O 0'), for singulett oxygen (o2(log), and many other radicals. Anthocyanins also can act a's photobiological ~., , °...
inhibitors, intervening as regulators and detoxifiers in sen-sitized photoreactions which 'take place through oxygen, thereby preventing the radical and radical chain reactions which damage cells and molecules, regardless of haw they came to be.
Anthocyanins protect against cell toxic and cancerogenic aldehydes (4-hydroxy-hexenal, 4-hydroxy-octenal, 4-hydroxy-nonenal, propanal, butanal, pentanal, hexanal, 2,4-hepta-dienal, malonic dialdehyde, and others). They even prevent the formation thereof within the framework of lipoperoxidative chain reactions. Furthermore, they detoxify the acetaldehyde resulting from ethanol decomposition and the formaldehyde re~-sulting from methanol decomposition or incorporated in other manners.
When used therapeutically, the anthocyanin compounds and re-duced glutathione and/or it's thiol derivatives supplement each other in optimum fashion, in response to the doses, with many cell disorders and many cell and enzyme dysfunctions. Apart from the qualitative therapeutic aspect, the combined use of reduced glutathione and/or its thiol derivatives together with anthocyanin compounds above all provides a much more effective quantum yield as regards the scavenge function. Thyil radicals (GS'), glutathione disulfide anion radicals (G-S-S-G'), and also glutathione peroxysulphenyl radicals (G-S 0 0') either axe prevented from forming or are detoxicated.
Moreover, not only reduction of oxidized glutathione (G-S-S-G) takes place and glutathion radicals are prevented and/or de-toxified but also a sustained regeneration of the radical- de-~toxi,fying functions occurs in an oscillating reaction cycle batween the two substances or groups of substances (glutathione and anthocyanins). The mutual complementation of the two groups of substances in the mixture of substances ac- a cording to the invention is of such optimum nature that the reduced glutathione once again can fulfill its vital control ~::-,.. ~ 7 functions to the full extent both on the genet is level and on the enzyme level and, finally, on all levels.
Reduced glutathione (G-SH) among others reacts with quinones, forming glutathionyl hydroquinone conjugates which can auto-oxidize to form the corresponding hydroquinones. The G-SH con-jugate reduces the radical electrophilic character of quinones, while improving their hydrophylic nature. Such for-mations of conjugates which are of great toxicologic interest are limited intracellularly both by the quinone concentration and that of G-SH. That presents another therapeutic approach for many diseases appearing so differently in phenomenology.
Apart from the readjustment of a physiological control be-havior on all biological levels and in all compartments of l~.ving systems, the combination of reduced glutathione or its thiol derivatives wittu anthocyanin compounds also displays therapeutic effect, above all, with radical and radical chain reactions initiated in different manner (thermally, che-mically, mechanically, infectious-toxically, due to radiation, and otherwise) and with the pathobiochemically important phe-nomenon of lipid peroxidation.
The mixture of substances according to the invention largely prevents the cross linking of biomolecules (connective tissue, proteins, DNA, and others) with diabetes mellitus and especi-ally also with the diabetic late syndrom (prevention of Ama-dori bodies). It further prevents polyneuropathic degenera-tions of the peripheral and central nervous systems, of lipo-peroxidative origin or pathogenetic cause, in the sense of preventing the formation of lipofuscin or lipofuscin foci.
Moreover, the very combination of glutathione and anthocyanin compounds makes sure that protein denaturing at bradytrophic tissues does not take place, such as at the cornea, crystal-lzne lens, and vitreous body of the eye.
A further increase in effectiveness results from the addition of vitamin E (alpha tocopherol acetate) and/or vitamin A

and/or 13-carotene and/or selenium and/or L-cystein to the mix-ture of substances according to the invention.
Especially well suited is an oral form of administration of the mixture of substances according to the invention, the therapeutic dose ranging from 50 mg to 2400 mg per day.
The mixture of substances according to the invention thus has a corresponding wide field of pharmacological and therapeutic application. Its use is indicated, among others, - for the treatment of cancerous diseases of any genesis, including malignant diseases of blood cells and their precursors, - for substitution and regulation of metabolic processes when other 'tumor therapies are applied, such as radiation therapy and/or naturopathic therapies, - for preventive treatment and therapy of metastases within the framework of malignant cancerous diseases, - for treatment of hepatopathies, especially acute and chronic illness from hepatitis, such as chemical-toxic and infectious-toxic hepatitis, viral hepatitis, hepati-tides caused by Rickettsiae, bacteria, or protozoa, as well as chronic aggressive hepatitis, fatty degeneration of the liver, fatty cirrhosis, and liver cirrhoses of any genesis, - f or the treatment of any dysfunction in the immunologic defense in the field of natural killer cells, monocytes, macrophages, granulocytes, T- and B-lymphocytes, plasma cells, and disorders of the complement factors and anti-body synthesis, -. for the treatment of complex dysfunctions of the lympho- ' con biosynthesis in T-helper cells, macrophages, and other cells, - for the treatment of cardiomyopathies of any genesis, also in combination with other therapies, any form of coronary ailment, angina pectoris, prophylaxis of myo-cardial infarction and emergency treatment of cardiac in-farction together with other emergency medicines, 20~~~9~~

y - for the treatment of acquired or congenital forms of skeletal muscle disorders, - for the treatment of neurologic diseases of inflammatory, allergic, or degenerative genesis, - for the treatment of all kinds of blood cell diseases, anemias, leukopenias, lymphopenias, and thrombocyto-penias, - for preventive treatment of crystalline lens damage, toxic disorders of the retina and vitreous body, as well as for cataract prophylaxis, - for the treatment of all kinds of over-oxidation or of the oxidative stress, for example within the framework of applying oxygen therapies or therapies with activated oxygen states (oxygen radicals), and for protection in the application of hyperbaric oxygen therapy, oxygen mul-tistep therapy, ozon therapies, and HOT therapies - for intoxication leading to biomolecule and tissue damage in the human organism by radical chain reactions, , - as an accompanying therapy in radiation treatment, treat-ment with cytostatics, and for attenuating or preventing sickness, nausea, and others , - following anesthesias, especially general anesthesias with patients suffering from lesions of the heart and liver, - for intoxications with xenobiotics, especially with 'toxic trace elements and with heavy metals, - for the treatment of proliferation disorders and dif-ferentiation disorders of epithelium, endothelium and mucosa tissues, - for the treatment of pathophysiological arteriosclerosis and arteriosclerosis of different genesis, -. f or basic treatment and adjuvant therapy of allergies, - for the treatment of impotentia coeundi and impotentia generandi, as well as fertility disorders and disturbance of the copulative power of any genesis, - upon premature aging, wear due to age of all tissues, including skin and skin connective tissues, and for pre-ventive treatment in case of activities and habits in 2O~U~~4 life that lead to premature aging or premature wear of organs and tissue. .

Claims (8)

WE CLAIM:

1. A composition containing reduced glutathione and at least one anthocyanin compound of the group consisting of pelargonidin peonidin cyanidin malvidin petunidin delphinidin for therapeutic treatment of the human or animal body.

2. A composition containing at least one thiol derivative of glutathione of the group consisting of methylglutathionyl (thio) ether ethylglutathionyl (thio) ether mono-acetylglutathionyl (thio) ester mono-phosphoric glutathionyl (thio) ester and at least one anthocyanin compound of the group consisting of pelargonidin peonidin cyanidin malvidin petunidin delphinidin for therapeutic treatment of the human or animal body.

3. A composition containing reduced glutathione and at least one thiol derivative of glutathione of the group consisting of methylglutathionyl (thio) ether ethylglutathionyl (thio) ether mono-acetylglutathionyl (thio) ester mono-phosphoric glutathionyl (thio) ester~

and at least one anthocyanin compound of the group consisting of pelargonidin peonidin cyanidin malvidin petunidin delphinidin for therapeutic treatment of the human or animal body.

4. The composition as claimed in claim 1, 2, or 3 containing, in addition, vitamin E
and/or vitamin A.

5. The composition as claimed in claim 1, 2, 3 or 4 containing, in addition, .beta.-carotene.

6. The composition as claimed in claim 1, 2, 3, 4 or 5 containing, in addition, selenium.

7. The composition as claimed in claim 1, 2, 3, 4, 5 or 6 containing, in addition, L-cysteine.

8. The composition as claimed in any one of claims 1 to 7 as a catcher of radicals (non-enzymatic scavenger) and radical chain terminator for the treatment of diseases accompanied by hyperradicalia, the "oxidative stress" phenomenon (hyperoxidation), and/or enzymopenias and enzymopathies of anti-oxidative enzymes.