Note: Descriptions are shown in the official language in which they were submitted.
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Description
Therapeutic preparations containing oxygen anion radicals
and/or their secondary and decomposition products and
their use for the treatment of Morbus Parkinson
The invention relates to therapeutic preparations
containing oxygen anion radicals (superoxide radicals,
hereinafter abbreviated as "OAR" or "superoxides," ~2-)
and/or their secondary and decomposition products (e.g.
H2O2, O2H or their hydrate clusters) and their use for
the treatment of Morbus Parkinson.
The therapeutic use of negative air ions is well-known.
Until now, experience has been available on therapeutic
use of negative air ions mainly for bronchial asthma and
in cases of chronic obstructive lung diseases (Boulatov
P. K., (1975), Traitement de l'asthma bronchique par
l'aéro-ionisation negative. In Rager, ed., Problèmes
d'ionisation et d'aéro, Paris, Maloine, 178-85). But
their successful use in burns, shock syndrome, rheumatic
arthritis, chronic pain syndromes, especially migraine,
essential hypertonia, depressive states and stomach
ulcers has also been reported (Tschijevsky A. L., (1960),
[Aeroionization in National Economy], 758 ff., Moscow
Publishing House of the State Planning Commissioning of
the USSR).
In the German patent DE-19 514 522.4 therapeutic agents
containing oxygen anion radicals and their use in the
treatment of pain have been described. However there is
no description there of any effect on oxygen anion
radicals on Morbus Parkinson.
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Morbus Parkinson ("shaking palsy") is characterised by an
extrapyramidal motoric syndrome composed of akinesia
(inadequate or missing facial play), rigor (rigidity) and
tremor (muscle trembling). Parkinson's syndrome is the
most common neural disease in advanced age; however there
are cases in very young patients. The causes of the
disease are many, they extend from damage due, for
instance, to arteriosclerosis or tumours or toxication
from, for instance, CO or manganese up to pharmaceuticals
such as Reserpine. Even a genetic defect has been
discussed as causal.
A decisive factor for the genesis of motor disturbances
is the lack of dopamine in neurones of the brain stem's
substantia nigra. Such neurones have an inhibiting effect
on cholinergic neurones in the striatum. Together with
other nerves, the latter form the so-called
nigrostriatial feedback system which controls spinal
motoricity. A reduction in the dopamine concentration
entails rigor and the other Morbus Parkinson symptoms
mentioned above.
Therapy of Morbus Parkinson includes, besides gymnastics,
massages and psychotherapeutic treatment, individually
adjusted medicinal combination therapy of the underlying
ailment. Substances with effects on the motoric symptoms
of Morbus Parkinson belong to different categories of
substances. They are frequently derived from atropine or
antihistamines and possess cholinolytic properties, or
they achieve their effects via dopamine or dopamine
receptors. Rigor and akinesia are treated with L-3,4-
dihydroxy-phenyl-alanine (L-DOPA), amantadine and
memantine while metixene is primarily suitable for
therapy of the tremor symptoms which are often quite
persistent.
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In addition, Morbus Parkinson is treated in its early
stages with selegine, a mono-aminoxidase B (MAO-B)
inhibitor. MAO-B is responsible for the decomposition of
dopamine in the nigrostriatial system. The polypeptide
GDNF (glia cell-derived neurotrophic factor [NF]) is
currently undergoing clinical testing as a therapeutic
agent.
All agents previously used in therapy of Morbus Parkinson
have extreme side effects which frequently obstruct the
permanent therapy required and are very unpleasant for
the patient. Thus benzatropine, biperiden and metixene
can entail, inter alia, double vision, pupil dilation,
states of confusion and psychosis, L-DOPA can lead to
nausea, vomiting, disturbances in cardiac rhythm,
euphoria, anxiety states and psychoses, amantadine
results in tremor, ataxia, erythrema and gastrointestinal
complaints and selegiline in nausea, confusion and
dyskinesia.
The previously known literature sources and experience in
therapeutic use of negative air ions evidence
contradictions and lack of clarity which have heretofore
to a substantial extent obstructed practical use of air
ion therapy. One of the main reasons for the
contradictory findings has been in the construction and
use of unselective and unsuitable ionisers for
therapeutical use. In using such inhalers, an additional
loss on physiologically important oxygen anion radicals
(OAR) occurs on their way to the point of impact. For
this reason, a non-specific mixture of negative gas ions
with invariably negligible content in oxygen anion
radicals is administered.
The concept of "oxygen anion radicals and their secondary
and decomposition products" on which the present
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invention is based, refers in particular to the radicals
or radical-formers ~2-l H2O2, O2H or their hydrate
clusters which possess a similar physiological effect in
the terms of the invention.
By means of a device described by way of example in the
published application DE 41 12 459 A1, oxygen anion
radicals are generated. As an alternative to physical
generation of oxygen anion radicals (DE 41 12 459 A1)
their chemical or enzymatic generation is also possible
(Fridovich, I., (1970), "Quantitative Aspects of the
Production of Superoxide Anion Radicals by Milk Xanthine
Oxidase", J. Biol. Chem. 245, 4053).
It is an object of the present invention to provide a
suitable preparation for treating the symptoms of Morbus
Parkinson or other ailments connected with tremor which
does not show the disadvantages and side effects of the
anti-Parkinson's agents mentioned above and, in
particular, is suitable for therapy of the persistent
symptoms of tremor.
This object is solved according to the present invention
by creating a preparation containing oxygen anion
radicals and/or their decomposition and secondary
products. In doing so, the oxygen anion radicals are
selectively generated in an appropriate apparatus on the
basis of their metastable state (cf. e.g. DE 41 12 459
A1) or are generated with the aid of a suitable chemical
formula to be applied. For example, the application of
liposomes could be imagined which would serve as carriers
for the enzyme systems (e.g. xanthine / xanthinoxidase)
and in this way generate oxygen anion radicals. The
application of oxygen anion radicals should preferably be
done with low losses due to inhalation or intranasal
application, in which case the oxygen anion radicals are
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provided with a formation speed from 100 pmol l-ls-1 to 1
f l l-1 -1
Oxygen anion radicals and/or their secondary or
decomposition products means, for example, perhydroxyl
radicals, hydrogen peroxide, other species of activated
oxygen or their hydrate clusters.
Surprisingly, it was now found that the use of the
preparation according to the present invention has a
clear effect on tremor of the type occurring in
particular in Morbus Parkinson. However, the tremor can
be the result of another pathological syndrome as well.
In its preferred version, the preparation according to
the present invention is a highly diluted 10-1~ to 10-3
mol/l aqueous solution containing H2O2.
The innovative effect on which the present invention is
based consists of a positive effect of oxygen anion
radicals and/or their secondary or decomposition products
on the tremor which is hard to therapy as typically found
in Morbus Parkinson.
The advantages of a treatment of Morbus Parkinson with
OAR lie particularly in its easy tolerability for the
patient and in substantially reduced costs when compared
with the expensive medication previously used.
Experiments carried out thus far on rats show that
superoxide enhances the effect of the body's own
dopamine. This effect is presumably caused by the effect
of OAR on the enzyme mono-aminoxidase B (MAO-B) which
decomposes dopamine.
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The following examples shall illustrate the innovative
effect of OAR on Morbus Parkinson symptoms and, in
particular, on the tremor which is hard to therapy.
Exam~le 1:
Studies involving animal studies
Rats (n=6) were subjected to gaseous superoxide by means
of the superoxide inhaler described in DE-19 514 522.4.
After 30 days of being subjected to superoxide, a
significant lowering of mono-aminoxidase activity ensued
in the basal ganglions and in the hypothalamus of the
test animals. In addition, MAO A activity and the content
in conjugated dienes was reduced. The test results are
shown in Table 1.
.. .... . . . .... . .
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Table 1: Determination of the activity of various mono-
aminoxidase types and of the content of malondialdehyde
and conjugated dienes in the basal ganglions,
hypothalamus and brain stem of rats.
Animal group Basal Hypothalamus Brain stem
(n=6) ganglions
Enzyme Enzyme activity (nmol/mg of protein/min)
MAO A Control 0.28 + 0.02 0.99 + 0.05 0.16 + 0.02
group
Superoxide 0.34 + 0.02 lowered raised
effect *(pc0.001) * (p<0.05)
MAO B Control 0.65 + 0.05 0.93 + 0.05 0.34 + 0.06
group
Superoxide lowered lowered raised
effect *(p<0.05) *(p<0.001) (n.s.)
Substance Content (OD/m~ of tissue)
Malondial- Control 0.175 + 0.06 0.105 + 0.05 0.19 + 0.006
dehyde group
Superoxide raised raised raised
effect (n.s.) (n.s.) (n.s.)
Conjugated Control 0.100 + 0.02 0.014+ 0.008 0.109 +
dienes group 0.006
Superoxide lowered lowered 0.105 +
effect *(p<0.005) *(p<0.05) 0.006
* = level of significance vs. corresponding control group
n.s. = not significant
F.~rr~l e 2:
Effect of OAR on patients with Parkinson's syndrome
Four patients with Parkinson's syndrome (three females,
one male) with ages ranging from 74 to 82 years of age
were treated with superoxide inhalation. With all four
~, . ~ , . . .
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patients, the clinical focus was on tremor in both hands.
Two of the patients were additionally treated with
medication but the other two were not. After two
inhalations, each lasting about 15 minutes in duration,
the tremor was corrected in all four cases. The effect of
the treatment with OAR was followed for three weeks and
was stable during that period.
