LT3355B - Pharmaceutical and its use for the treatment of states of agitation and nerve dysfunctions - Google Patents

Abstract

This invention belongs to the field of medicine and its use for curing irritation conditions and nervous dysfunctions. The medicine differs in that it consists of active indissoluble substances obtained by extracting, with alcohol corydalis and eschscholtzia, where necessary, usual additives. The indissoluble eschscholtzia and corydalis proportion (according to the weight) makes from 20:1 to 1:1.

Description

The invention relates to medicaments and their use in the alleviation of irritation and nervous dysfunctions.

Intermediate and final metabolites of pyrocatechinamine are known to have a major influence on the human irritation state. Thus, for example, the end product adrenaline acts as a neurotransmitter of the adrenergic nervous system, as well as alpha receptors. As a sympathomimetic agent, adrenaline increases cardiac contractility. In addition, because adrenaline increases the oxidative metabolism of cells, it increases the mobilization capacity of the body. As a result, stress situations monitor the increase in adrenaline ejected. Extremely high levels of adrenaline, as well as norepinephrine in its pre-stages, can cause extreme irritation, nervousness, and at the same time lack of functional ability of the body, with only slightly elevated levels of these amines acting quite positively: pulse and blood pressure barely elevated; increased sensitivity.

In addition, it is known that subsequent violations of pre-adrenaline dopamine levels can lead to irritation and nerve dysfunction. In part, depopulation can lead to depopulation. Special dopamine deficiency syndrome is Parkinson's disease with partial symptoms including akinesis, stiffness and fibrillation

Recent clinical dopa efficacy in treating dormancy demonstrates results in the state of therapeutic action of Parkinsonism. This is evident by monitoring the decrease in dopamine in the major nerve

There are known drugs based on active substances and additives (see CS A.L. No. 262751, A 61 K 35/78).

However, due to their composition, they do not have the potential to increase a patient's dopamine levels, while undergoing natural metabolism, and at the same time alleviate or eliminate irritation and nerve dysfunctions based on amino balance.

Also known are drugs based on active substances and additives (see U.S. Patent No. 4,810,498, A 61 K 35/78).

However, due to their composition, they do not have the ability to increase the patient's dopamine levels during the natural metabolism and at the same time to alleviate or eliminate the irritation and nervous dysfunctions that are based on the amino balance.

In this way, it is desirable to increase the concentration of this pyrocatechinemin naturally in the absence of dopamine. This can be achieved, first, by increasing dopa / dopamine synthesis, and second, by preventing dopamine from breaking down.

The object of the present invention is to provide a medicament which increases the dopamine concentration of the patient during natural metabolism.

The object of the invention is achieved by the use of medicaments according to claim 1, characterized in that they contain, as active substances, extracts of corydalis eschscholtzia (2.5: 10) and, where appropriate, conventional additives containing corydalis to eschscholtzia in extracts. weight) is 20: 1 to 1: 1.

Suitable embodiments of the invention are set forth in claims 2 to 9 of the formula. Further, the present invention includes the use of a medicament according to claim 10 for the alleviation or elimination of irritation and nerve dysfunction resulting from impaired amine balance, particularly dopa / dopamine concentrations. Further, the invention includes the use of an extract obtained by alcohol extraction (2.5: 10) for the treatment of irritation and neural dysfunctions caused by an impaired amino balance according to claims 11 and 12. Application forms are given in 1313.

The medicaments of the present invention may contain lyophilized extracts of alcohol extracts in powder form or in aqueous and / or alcoholic solution. The lyophilized powder is obtained, as a rule, by lyophilization of the extract (extract from vegetable raw material) obtained by alcohol extraction, by conventional lyophilization techniques.

Dried lyophilized extracts of corydalis and eschscholtzia may be stored separately or mixed and, if necessary, reconstituted with pharmaceutically acceptable carriers / diluents. Water and / or alcohol are suitable for the preparation of tinctures. Medicinal products include, in particular, extracts of the active ingredients obtained by the alcoholic extraction (2.5: 10) of the vegetable raw material and include such extract from the vegetable raw material.

The ratio of Eschscholtzia to corydalis (in terms of dry extract weight) is preferably from 10: 1 to 2: 1, and in particular 4: 1.

Extracts of corydalidis cavae rhizoma and eschscholtzia californicae are particularly suitable as active ingredients in the invention.

The medicaments of the invention may be formulated for conventional oral administration, in particular tablets, dragees, capsules, and especially tinctures. These administration forms may be formulated, where appropriate, in the form of administration forms and / or carriers, using conventional or suitable pharmaceutical diluents commonly used for individual administration, encapsulating the lyophilized extract or an alcoholic and / or aqueous solution thereof. To obtain liquid delivery forms, such as tinctures, use the alcoholic extracts obtained from the plant raw material obtained by alcohol extraction. In addition to these lyophilized spirit extracts from the vegetable stock, dry residues may also be obtained by dry evaporation of the spirit extracts from the vegetable stock itself, preferably under vacuum and / or inert gas to a dry residue, and the resulting residue may be given the desired administration form.

The concentration of active substances in the medicaments according to the invention can be varied within wide limits. As a rule, the concentration ranges from 0.5 to 20% by weight, based on the final formulation, especially from 1 to 10% by weight, and most preferably from 1 to 4% by weight. If the alcoholic extract (2.5: 10) obtained from the extraction of the vegetable raw material is used, it is most appropriate to use it directly from the concentration obtained after extraction; the extract of the vegetable raw material from corydalidis and eschscholtzia is usually used in such a ratio that the ratio corydalis and eschscholtzia corresponds to those mentioned above as the most suitable.

To get eschscholtzia, eschscholtziae meet the DAB

individual extracts corydalis and especially the corydalis in itself rhizoma and californicae coat of arms, medications has 9 (German Pharmacopoeia) description. That's it

achieved through quality control in the drug manufacturing process.

The individual extracts are obtained by conventional and standard extraction techniques such as maceration or percolation using ethanol or ethanol / water. The 2.5: 10 ratio of medicinal herb extract to medicinal plant is preserved, i.e. from 2.5 g of medicinal herbs obtains 10 ml of medicinal herb extract of medicinal plants. The most commonly used extraction agent is 30% ethanol. The receipt can be controlled by controlling the process.

Uses standard quality criteria to evaluate and guarantee consistent extraction quality. This is partly served by the full spectrum of the extracted materials and, on the other hand, by the analysis of the basic alkaloids of both medicinal plants (e.g., cf.) known in the literature.

After quality control, the extracts are further processed as a liquid extract or lyophilized extract, depending on the form of administration desired and the concentration desired.

The type and amount of medication prescribed depends in part on the severity of the illness, on the general well-being and on the patient's age. As a rule, the amount of the drug is prescribed in the form of a tincture, which is considered to be the most suitable according to the invention, and is from 2 drops / kg body weight, once or several times a day. Where other forms of oral administration are used, the appropriate amount, usually 2 to 5 mg / kg total dry extract / kg body weight, should be administered once or several times daily.

The attached shapes represent:

FIG. 1 shows a metabolic scheme for the synthesis of pyrocatechinamine.

FIG. 2 shows an overview of the tyrosine reaction through dopa, dopachinone to dopachrome, or melanin.

FIG. 3 shows the hydroxylation of the tyrosine at 303 nm in the presence of 1: 10,000 corydalis extract, 1: 10,000 eschscholtzia extract, or 20 units of phenolysis.

FIG. 4 shows a graph of the reaction of Lineweaver-Burk phenolysis with corydalis extract (Figs. 4a and 4b) and for comparison without corydalis extract (fig. 4a).

4c-4f).

FIG. 5 shows the phenolysis reaction in the presence of 3,4-dihydroxybenzene.

FIG. 6 shows the effect of D, L-dopa on the reaction of phenolysis at different concentrations of dopa (K-control).

FIG. 7 shows the stop of dopamine-p-hydroxylase in the extract of eschscholtzia (curve A) and also in a 1% aqueous solution of corydalis and eschscholtzia extracts subjected to sublimation drying (curve B).

FIG. Fig. 8 shows the stop of the conversion of benzylamine to benzaldehyde by corydalis extract at 241 nm, catalysed by amino oxidase.

FIG. 9 shows the inhibition of the formation of catalyzed MAO (monoamine oxidase) benzaldehyde at 241 nm, depending on the concentration of the eschscholtzia extract.

FIG. 10 shows the suspension of catalyzed formation of MAO benzaldehyde at 241 nm in the 20:80 mixture of eschscholtzia (A), corydalis (B), and extracts of corydalis and eschscholtzia.

From FIG. 1 shows the metabolic diagram of pyrocatechinamine. The concentrations of dopa and dopamine compounds that occur at that time depend, firstly, on the rate at which tyrosine is converted to dopa and secondly on the rate at which dopamine reacts further to norepinephrine and adrenaline. In addition, dopamine is also broken down by monoamine oxidase (MAO), so that it can significantly affect its metabolic concentration. As can be seen from FIG. 1, increased dopamine (if increased by phenol oxidase tyrosinase), hydroxylase and monoamine oxidase decrease. Experiments have been carried out to show the degree to which the active drug components of the invention effect three enzymatic reactions.

concentration is obtained, reaction (phenolysis, and dopamine-β-pathway possible

Subsequent studies, in the absence of anything else, were conducted with commercial enzymes and with the coat of arms of corydalidis cavae rhizoma and eschscholtziae californicae.

1. Tyrosinase reaction studies:

During metabolism, tyrosine is hydroxylated in an oxygen-consuming reaction to L-dopa. This first step in the synthesis of pyrocatechinamine is catalyzed by tyrosinase or phenolase or a phenol oxidase containing copper, a low specific enzyme. Phenolases are known to be widespread in nature, found in plants, fungi and various animal tissues. They play an important role wherever they oxidize mono- or diphenols, and in many cases oxidation polymerization reactions, such as the formation of lignin or melanin, start.

Phenolases catalyze two successive oxidation steps, which can be described as follows:

1. The activity of the enzyme cresolase induces hydroxylation of monophenol in the ortho position with the formation of diphenol.

2. The activity of pyrocatechinolase catalyzes the further oxidation of the formed o-diol to the corresponding quinone.

Both reactions are directly dependent on each other. Elastic krezolazės pirokatechinolazės reaction and the reaction is based on the connection of copper atom oxidation state in the active center, which according to D. Kertesz and R. Zito, Hayaishi (publisher) Oxygenases, Academic Press, London (1962), Chapter 8: Fenoliazė shown as follows: (Cu ^{+ +} ) _2- enzyme + o-dihydroxyphenol - »(Cu ⁺ ) _2- enzyme + o-quinone + 2H *.

(Cu *) _2- enzyme + 0.5 O ₂ + 2H * -> (Cu **) _2- enzyme + H ₂ O.

In the copper balance shown above, the cresolase reaction is not accepted in the domain. Factins, it remains unclear whether the catalysis of monophenol hydroxylation is catalyzed by a direct enzymatic reaction or whether this reaction is chemically parallel to the oxidation of pyrocatechinamine by the following scheme:

o-Quinone + Monophenol + H ₂ O -> 20-Diphenol.

The non-enzymatic reaction is first and foremost confirmed by the fact that monophenols with phenolases can be monitored for an induction phase that can last up to one hour to animal tyrosinases.

The continuous fermentation reaction can only start if the diols or quinones are present as impurities or are formed by autoxidation.

Investigation of the reaction of tyrosinase with plant extracts from corydalis and eschscholtzia.

FIG. 2 schematically shows an overview of the reaction from tyrosine to dopachrome and its conversion to quinonimine or melanin.

Experimental observations were made after tyrosine oxidation to dopachrome (Fig. 2), the first dihydroxylenylalanine product (dopa). Dopachrome itself is a substrate of dopachrome tatumerase and is a precursor to melanin formation.

Like the formation of dopachrome, the synthesis of melanin leads to the degradation of dopa and hence to the reduction of dopamine synthesis.

The concentration of dopachrome can be monitored in the ultraviolet spectrum at 303-318 nm. Its formation from tyrosine is equated with the activity of the phenolase under investigation which can be considered as determining the rate of the reaction.

The following substrate mixtures were investigated:

mM tyrosine;

100 mM phosphate buffer pH 6.5;

units of tyrosinase or eschscholtzia or corydalis of spirit extracts, diluted 1: 10000 (prepared from the basic extract according to the following example).

io

FIG. 3 shows the tyrosine hydroxylline detected at 303 nm in the presence of phenol oxidase or corydalis and eschscholtzia extracts. In addition, monolayer monitors approximately 15 minutes of dormancy.

A 1: 10000 dilution of Corydalis extracts shortens this quiescent phase or initial phase as seen in FIG. 3. At higher concentrations of corydalis, monitors the rapid onset of peak rate without the dormant phase.

The extract from eschscholtzia also led to a truncated initial phase, but the efficiency of the extract from eschscholtzia was significantly lower than that of corydalis.

Control tests showed that the presence of an appropriate amount of ethanol had no effect on the reaction. In addition, experiments with pyrroloquinolinquinone (PQQ) have shown that the addition of this physiologically very interesting quinone has no effect on the initial phase of the phenolysis reaction. And hypericin, which like parachinone could affect the resting phase, does not affect the reaction either.

Interesting in this series of tests is the fact that the extract from corydalis, although it pushes forward the moment of maximum tyrosine conversion rate, does not affect the maximum rate of conversion. Assays with different concentrations of substrate in the graph LineweaverBurk do not show any magnitude of the K _m -phenolysis reaction (see Fig. 4a-4f).

To further explain the mechanism of the tyrosinase reaction, by partially evaluating the resting phase shortening, other substances are added to the test starting mixture:

(a) the addition of copper salts had no effect on the enzymatic reaction;

b) Ascorbic acid as a reducing agent - As is known in the literature, it can affect the quiescent stage in various reaction types. However, this cannot be observed within this test series: ascorbic acid, although it cannot initiate the conversion of tyrosine to L-dopa, does not interfere with its further oxidation to dopachrome. The phenolysis reaction could not be observed in the presence of ascorbic acid at 303 nm for 30 min, and the resting phase was greatly prolonged;

c) Combination of PQQ with ascorbic acid additionally results in the reconstituted form of PQQH ₂ , which was able to act as a diol as well as prolonging the quiescent stage;

d) Addition of real diols such as 3,4-dihydroxybenzene and D, L-dopa (dopa; 3,4-dioxyphenylalanine), shortens the quiescent stage of the reaction (with the addition of 3,4-dioxyphenylalanine) and increases the rate of dopachrome formation .

FIG. 5 depicts the phenolysis reaction in the presence of 3,4-dihydroxybezole. FIG. 6 shows the effect of D, L-dopa on the phenolysis reaction in a dopa-dependent manner. As from FIG. 5, so also from FIG. The influence of named diols on the dormancy stage can be clearly seen.

Autoxidation of 3,4-dioxyphenylalanine to alkaline pHs can be overlooked, or only slightly to pH 6.5.

The above tests show that the shortening of the initial phase of the phenolase reaction can only be induced by the addition of diols. Quinoline and ascorbic acid have no effect. For this reason, extracts of corydalis and eschscholtzia should be considered to contain ortho diols, which trigger the rapid conversion of tyrosine to 3,4-dioxifelalanine. Further, it can be seen that the extracts of corydalis and eschscholtzia in the living organism cause a faster conversion of tyrosine and thus a higher concentration of dopa (3,4-dioxyphenylalanine).

2. Dopamine-p-hydroxylase reaction assay

The enzyme dopamine-p-hydroxylase catalyzes the conversion of dopamine to norepinephrine. Dopamine-p-hydroxylase is also a copper-containing enzyme. Hydroxylation occurs through the decomposition of oxygen and ascorbic acid and fumarate are needed as restoring agents to restore the oxidation status of the copper atom.

Enzyme activity is determined by potentiometer based on molecular oxygen yield. The appropriate test accessory shall contain the following components:

100 μΐ of tyramine, fumarate, ascorbate (5 mmol each);

ml of phosphate buffer, pH 5 (100 mmol);

ml of water;

100 μΐ of enzyme (0.1 units, respectively).

Oxygen yield rates were calculated on the basis of a solution containing O ₂ at 37 ° C at the appropriate volume.

When an extract of eschscholtzia is added, a significant concentration-dependent inhibition of the enzymatic reaction occurs, i. y. significantly inhibits side chain hydroxylation. It was observed that the enzymatic activity is also stopped by ethanol. Still, braking with the extract is much greater, so that a clear difference can be seen.

FIG. Fig. 7 shows inhibition by dopamine-p-hydroxylase eschscholtzia extract (curve A) and aqueous 1% eschscholtzia and corydalis extracts subjected to sublimation drying at a ratio of 20: 1 (curve B) according to the invention.

FIG. 7 both curves show marked inhibition of enzymatic activity. The differences between these curves depend on the presence or absence of ethanol and corydalis extract (curve B). The reduced effect of enzymatic inhibition in the presence of the eschscholtzia extract can partly be explained by the oxygen yield of the different substrates of the extract. While the corydalis and eschscholtzia extracts have undergone sublimation drying, the aqueous solution also shows oxygen yield with thyramine, ascorbate, and fumarate; however, the inhibitory effect on the enzyme is not reduced, which makes interpretation of the effect very difficult.

The above tests clearly show that dopamine β-hydroxylase enzyme is inhibited by alcoholic extract of eschscholtzia (curve A) as well as by corydalis and eschschlotzia extracts subjected to sublimation drying in aqueous solution (curve B) leading to pyrocatechinamine metabolism and decrease in adrenaline formation. This inhibitory effect explains the calming effect of the medicaments of the invention. Braking maintains high levels of dopamine

14th concentration causes and positive influence to Parkinsonism syndrome, where broken up dopaminergic nerve cells and large dopamine quantity heads

the brain has to be supported by artificial means.

3. Investigation of mono-amino-oxidase reaction

As can be seen from FIG. The concentration of dopa (3,4-dioxyphenylalanine) or dopamine is also regulated by their cleavage by monoamine oxidases. Monoamine oxidases convert primary amines with oxygen in the aqueous environment to the corresponding aldehyde, ammonia and hydrogen peroxide in a stoichiometric ratio. The aminooxidase used herein was purchased from Sigma Chemicals. This amino oxidase is very similar to the substrate benzylamine. Therefore, the following substrate-based benzylamine assays were performed and the effects of corydalis and eschscholtzia on the activity of this monoamine oxidase were tested.

The conversion of benzylamine to benzylaldehyde by monoamine oxidase was determined by photometry and potentiometer:

(a) Using a photometer, find the benzaldehyde forming agent, which has a high molecular absorption index (l, 2x10 ⁴ ) at 241 nm. This high sensitivity allows the use of very small amounts of the enzyme, which can be contained in 0.01 and 0.02 units of monoamine oxidase per 2 ml reaction volume.

An appropriate test supplement with a total volume of 2000 μΐ includes:

μΐ 100 m mol hydrogen benzylamine-HCl solution (2,5 m mol respectively);

100mM phosphate buffer pH 7.4;

0.01 or 0.02 units of (U) MAO added in portions of 100 μΐ to the respective stock solution;

reference cell with buffer, water and benzylamine.

In the assays with the above assay additive, after 10 minutes of reaction time, dilute eschscholtzia and corydalis were added to the measuring cuvette and the reference cuvette and detected altered activity. FIG. 8 shows the inhibition of benzaldehyde formation depending on the concentration of corydalis (20 or 40 μΐ in a 1:10 dilute stock solution).

FIG. 9 shows the inhibition of MAO activity by the extract from eshscholtzia at different amounts of extract. Significant inhibition of MAO activity is observed.

FIG. Fig. 10 shows the inhibitory activity of MAO activity by adding various mixtures of eschscholtzia extract (curve A), corydalis extract (curve B), and 20:80 (curve C) mixture of corydalis and eschscholtzia extracts. For better comparison of the test results in FIG. 10 is a blocking diagram in%.

MAO activity in each was assumed to be 100% (viscous ammonium sulfate - enzyme based, it was difficult to express constant quantities of the enzyme commercially available).

Evaluation of the tests indicates that corydalis in the extract causes moderate inhibition of MAO activity. Greater influence can be observed in the presence of eschscholtzia extract. Significant inhibition of MAO occurs with a mixture of both extracts consisting of 80% eschscholtzia extract and 20% corydalis extract.

(b) The reaction of benzylamine + O ₂ + H ₂ O -> benzaldehyde + NH ₃ + H ₂ O ₂ with the aid of a platinum oxygen electrode may be determined by means of a potentiometer. Demonstration of oxygen conversion requires higher amounts of substrate and enzyme. The relevant test accessory contained:

200 μΐ of 100 m mol benzylamine solution (10 m mol respectively);

1.000 μΐ of 20 m mol phosphate buffer pH 7.5 (100 m mol, respectively);

1.000 μΐ distilled water, 0.054 MAO.

The addition of 100 μΐ of corydalis and eschscholtzia extracts after a reaction time of 3 minutes can be used to calculate the various oxygen conversion rates.

Oxygen electrode results show a decrease in monoamine oxidase activity due to separate extracts from corydalis and eschscholtzia. The potent activity of eschscholtzia extract on MAO activity was confirmed.

The examples above show that significant inhibition of MAO can be achieved with corydalis and eschscholtzia extracts and a mixture of the two extracts. From this it can be concluded that amines, like dopamine, have a prolonged blood residence time and thus remain active for a longer period in the plasma. Hence the beneficial effect of the medicaments according to the invention in the alleviation of irritation and nerve dysfunction and the resulting depression, particularly in the case of dopamine deficiency syndrome such as parkinsonism.

EXAMPLES

EXAMPLE I

Preparation of extract

Separate extracts of corydalis cavae rhizoma and eschscholtzia extracts were obtained by percolation,

50 ° C coat of arms. Separate way using 16 hours. The colifornicae was maintained at the extraction temperature by the ratio of medicinal herbs to extract 2.5: 10, i.e. received 10 ml of the medicinal plant extract from 2.5 g of the medicinal herb in question. Extracting agent: 30% ethanol.

The extracts thus obtained can be used directly in the formulation of the medicaments or can be converted into a dry extract by lyophilization.

EXAMPLE

Effect of D, L-dihydroxyphenylalanine on the phenolysis reaction

Reaction conditions: phosphate buffer, pH = 6.5 100 m M, tyrosine 2 m M, phenolase 20 V, D, L-dihydroxyphenylalanine, variable amount

phenolysis ₊ DOPA 500 nM ₊ DOPA 5 μΜ ₊ DOPA 50 μΜ t (min. ) mU +/- mU +/- mU +/- mU +/- 0 0 0 0 0 0 0 0 0 2 4 0 23rd 2.2 70 4.5 4 13th 1.5 69 2.9 157 8.1 6th 5 0.53 28th 3.2 117 5.2 236 11th 8th 6th 1.2 50 2.9 170 4.7 321 15th 10th 12th 1.5 75 5.1 228 7.2 402 15th 12th 23rd 2.2 14th 39 3.1 16th 60 4.7 18th 84 7.3 20th 139 18th 291 14th 554 16th 775 29th 30th 404 32 562 28th 883 21st 1090 37 How shows FIG. 6, DL -dopa can significantly to shorten

phenolysis at rest, and 5 μΜ dopa induces 5 rapid dopachrome formation. With 50 μΜ dopa, the onset of the reaction induced by the enzyme is already occurring at maximum boiling point.

Dopa autoxidation, i.e. formation of dopachrome without the involvement of 10 enzymes at pH = 6 was not observed for the 5 observed time intervals.

However, DL-dopa is not just any diol but a substrate for phenylase, the product of which again yields dopachrome. Therefore, comparative studies with 3,4-dihydroxybenzene were performed below (in Example 3).

EXAMPLE

The action of 3,4-dihydroxybenzene (as a starter) on the 5 phenolase reaction.

Reaction conditions: phosphate buffer, pH = 6.5, 100 m M, tyrosine 2 m M, phenolase 20 U, 3,4-dihydroxy15

benzene, variable quantity phenolysis + 3,4-DHB ₊ 3,4- • DHB 5µΜ 50 μΜ t (min. ) mE +/- mE +/- mE +/- 0 0 0 0 0 0 0 2 6th 1.7 27th 2.7 4 15th 1.3 63 4.8 6th 8th 0.91 33 4.1 102 8.9 8th 16th 1.3 58 6, 2 143 13th 10th 38 2.7 97 11th 180 18th 20th 312 14th 355 42 446 42 30th 678 29th 638 64 712 69 That's it shows, that ortho- i dihydroxybenzene to concentrations 5 and 50 μ mol can to shorten or eliminate phenolysis reaction os at rest (fig ·

5).

EXAMPLE

(a) Determination of the Michael constant during tyrosine conversion by phenol oxidase.

Reaction conditions: phosphate buffer, pH = 6.5, 100 m M, tyrosine 20 μ M to 2 m M, phenolysis 20 U / prim. mixture

Substrate concentration Reverses concentration 1 / (M) Reverses rollover rate 1 / (mE / min) Range from 2 μΜ up to 1 m M 20 μ mol 0.05 0, 27th 40 μ mol 0.025 oh, 173 60 μ mol 0.0167 0, 0116 80 μ mol 0.0125 0, 098 100 μ mol 0.01 0, 076 500 μ mol 0, 002 0, 044 1 m mol 0.001 0, 040

K _M = 141 μ mol

Area from 20 to 70 μ mol 20th μ mole 0.05 0, 163 30th μ mole 0.033 0.125 40 μ mole 0.025 0, 100 50 μ mol 0.020 0, 081 70 μ mole 0.014 0, 061

K _M = 145 μ mol Range 100 to 20 μ mol 100 μ mol 0.01 0.0555 120 μ mol 0.0083 0.0525 140 μ mol 0.0071 0.0475 160 μ mol 0.0063 0.0435 180 μ mol 0.0056 0.0415 200 μ mol 0, 005 0, 40 Km = 142 μ mol Area from 1 to 2 μ mol 1000 μ mol 0, 001 0.03352 1400 μ mol 0.00071 0.0340 1800 μ mol 0.00055 0.0334 2000 μ mol 0.0005 0.0330 K _H = 137 μ mol

The results are shown in Figures 4c - 4f.

b) Michael constant in the reaction in the presence of corydalis 5 extract

Cooking rate studies with corydalis extract are carried out by diluting the extract to 1: 200. This amount of extract immediately induced full fermentation activity in the previous experiments, the initial phase being 0 minutes.

Determination of size K _M shows a slight increase in scattering in the presence of corydalis extract but is within the same range of concentrations.

Michael constants in the presence of corydalis extract.

Reaction conditions: phosphate buffer, pH = 6.5, 100 m M, tyrosine 20 μ M to 2 m M, phenolysis 20 U / prim.

mixture, corydalis extract 1: 2000

Substrate Reverses Reverses concentration concentration rollover rate 1 / (M) 1 / (mE / min) Area from 20th up to 100 μ mol 20 μ mol 0, 05 0.0083 0.262 30 μ mol 0, 033 0.057 40 μ mol 0, 025 0, 045 50 μ mol 0, 020 0, 040 60 μ mol 0, 017 0.033 0, 10 70 μ mol 0, 014 0.030 100 μ mol 0.080 K '= 164 μ mol 137 μ M Range from 100 up to 200 μ mol 100 μ mol 0.01 0.0500 120 μ mol 0.0083 0.0435 140 μ mol 0.0071 0.0414 160 μ mol 0.0063 0.0383 180 μ mol 0.0056 0.0370 200 μ mol 0, 005 0.0344 II s 151 μ mol

The results are shown in Figures 4a and 4b.

EXAMPLE

a) Influence of Corydalis extract

As can be seen from the table below and FIG. 8, extract from corydalis cava inhibits MAO activity. Uses 20 or 40 μΐ of 1:10 diluted extract solution (2 or 4 μΐ of starting material). These amounts correspond to a dilution of 1: 1000 or 1: 500, converted to a total reaction volume of 2 ml. The absorption of the extract itself at 241 nm, due to the presence of many aromatic compounds, hinders the study of larger volumes of the extract, since in this case it is not possible to further balance the reaction in the reference cell.

MAO activity (mE / min) in corydalis

Reaction Conditions: Phosphate Buffer, pH = 7.4, 100mM, Benzylamine 2.5mM, Monoamine Oxidase 0.01, 0.02 Units / Stock Mixture, Corydalis Extract, 1:10, Variable Amount

benzaldehyde (mE / min) 0.01 U MAO 0.02 U MAO

8.35 ± 0.50 (100%) 18.4 + 1.00 (100%) + 2 μΐ COR 6, 30 ± 0.02 (75%) 12, 6 ± 1% (68.5%) + 4 μΐ COR 5.50 ± 0.00 (65.9%) 12.2 ± 0.45 (66.3%)

The results are shown in FIG. 8th

(b) Influence of Eschscholtzia extract.

With the increased transparency of the extract of eschscholtzia, a 1:10 dilution of the solution can be used in this assay, the reaction mixture may be used at 20.40 or 60 μΐ.

1: 330 diluted eschscholtzia extract solution. The table below and FIG. 9 explains the high stopping ability of this extract: after dilution

1: 500 monoamine oxidase activity is maintained at exactly below 50%, and dilution of 1: 300 decreases enzyme activity to one third of its original size.

MAO activity in eschscholtzia

Reaction conditions: phosphate buffer pH 7.4, 100 m M, benzylamine 2.5 m M, monoamine oxidase 0.01, 0.02 U / primer. mixture, eschscholtzia extract, 1:10 changing

benzaldehyde (mE / min) MAO 0, 01 U 0.02 U 10.3 +/- 1.50 (100%) 20.0 +/- 0.30 (100%) 2 μΐ ESCH 6.75 / 0.25 (55.5%) 11.8 / 0.55 (59%) 4 μΐ 4.50 / 0.00 (43.7%) 8.50 / 0.30 (43.5%) 6th μΐ 3.50 / 0.00 (33.9%) 7.50 / 0.30 (37.5%)

The results are shown in FIG. 9th

EXAMPLE

Obtaining a pharmaceutical preparation

a) Obtaining tincture

To obtain the tincture, 20 ml of medicinal herb extract and 80 were mixed with the spirit extracts obtained according to Example 1 using the herb extract of corydalis cavae rhizoma ml of medicinal herb extract of eschscholtzia californicae. 100 ml of ready-to-use tincture were obtained.

b) Taking tablets 5

The extracts of corydalis cavae rhizoma and eschscholtzia californicae obtained according to Example 1 were dried (for example, by lyophilization) and the dry extracts were mixed in a weight ratio of eschscholtzia / corydalis = 4/1 together with powdered starch (as a pharmaceutical carrier). (0.5 g, 0.6 cm diameter). The content of the active ingredient extracts in the tablets was 2% by weight.

DEFINITION OF INVENTION

Claims (15)

DEFINITION OF INVENTION Medicaments, characterized in that they consist of active ingredient extracts obtained from spirit extract of corydalis and eschscholtzia (2.5: 10), optionally in combination with conventional additives, wherein the weight ratio of extracts of eschscholtzia and corydalis is from 20: 1 to 1. : 1. Medicaments according to claim 1, characterized in that they are in the form of powder of extracts of aqueous and / or alcoholic solution. Medicaments according to claim 1 or 2, characterized in that they are in the form of a spirit extract of the medicament. Medicaments according to claim 3, characterized in that they are presented in the form of an alcoholic extract. Medicaments according to any one of claims 1 to 4, characterized in that the ratio of eschscholtzia and corydalis spirit extracts is from 10: 1 to 2: 1. Medicaments according to any one of Claims 1 to 4, characterized in that the ratio of eschscholtzia to corydalis, translated into medicinal plant extracts, is 4: 1. Medicaments according to any one of claims 1 to 6, characterized in that they contain, as active substances, extracts of corydalidis cavae rhizoma and eschscholtzia californicae h <: - ba. Medicaments according to any one of claims 1 to 7, characterized in that they have an oral dosage form. Medicaments according to claim 8, characterized in that they are in the form of tablets, dragees, capsules or tinctures. Medicaments according to claims 1-9 for use in the alleviation or elimination of irritation states and nerve dysfunctions based on amine imbalance. 11. Corydalis and Eschscholtzia Extract obtained by alcoholic extraction (2.5: 10) for the treatment of irritable states and nervous dysfunctions based on amino balance disorder. Use of an extract obtained by extraction of corydalis and eschscholtzia spirits (2.5: 10) for the manufacture of a medicament for the alleviation or elimination of irritation states and nerve dysfunctions based on amino balance disorder. 13. Use according to claim 12 for the manufacture of a medicament for the treatment of irritable states and nervous dysfunctions based on reduced dopa / dopamine metabolism in a patient. Use according to claim 12, characterized in that it produces medicaments for the alleviation or elimination of depression. 15. Use according to claim 12 for the manufacture of a medicament for ameliorating Parkinson's disease.