Note: Descriptions are shown in the official language in which they were submitted.
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;
__-, ~08899~
~;,. . 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
O CH2 H
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 ~
O CH2 H
i
S- CH3
methylglutathionyl(thio)ether or monomethyl thioester
CCOH
CH CH N ~ CH2 ,
H z N / \ ~H 2 ~ z \ ~ ~ ~ ~ ~ ~' N ~ ~ CcoH
p CH2 H
S-CH2 CH3
ethylglutathionyl(thio)ether or monoethyl thioester
CCOH
CH H N O CH2
/ \ ~ 2\C~ \CH/ \N/ ~CCOH
H2N CHZ a CH H
O
l
S-C--CN3
II
O
mono-acetylglutathionyl(thio)ester or monoacetyl thioester
5
H
.. CCOH N o CH 2
/ CH \, / CH 2 ~ C ~ ~ CH / c~ N / ' CCOH
H2N CH2 O CH H
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~~
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. .
