JPH10204098A - Pharmacotherapeutic use of glutathione derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To normalize the damaged cell substance metabolism and the redox potential and enable the prevention or treatment of various diseases such as inflammatory disease, radiation damage, benign tumor, malignant tumor and infectious disease by using a glutathionethiol as an agent. SOLUTION: A glutathionethiol derivative of the formula (R is CH3 , CH2 -CH3 , etc.) is used as a pharmaceutical agent. Preferable examples of the compound of the formula are methyl (thio)ether of γ-glutamyl-cysteinyl-glycine and mono- phosphoric acid (thio)ester of γ-glutamyl-cysteinyl-glycine. It is administered preferably by intravenous injection or subcutaneous injection in the case of grave, acute or malignant diseases. The daily administration dose of the compound is principally 2-20mg per 1kg of body weight. The daily dose can be increased to >=20mg/kg only in the case of cancerous diseases accompanying Schnitzler metastasis and having a total tumor weight of >100g.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the therapeutic use of glutathione derivatives.

[0002] All highly organized multicellular biological systems, including humans, cover the energy demands of their cells and tissues by the principle of in vivo redox.

[0003] Carbohydrates, amino acids, fatty acids and nucleotides are dehydrogenated (dehydrogenation =
Oxidation) releases some of the chemical energy stored within the molecule and is then subjected to a common final decomposition in the citric acid cycle.

In the metabolic cycle of healthy cells or tissues, which constitutes a common final step for monosaccharides, fatty acids and amino acids, the C-6 compound (citric acid) produced in this cycle undergoes a two-step decarboxylation reaction. Decomposes into a C-4 compound (oxalacetic acid) during one cycle, and the carbon chain is reduced to two carbon atoms.

Further, in the citric acid cycle, eight H
Atoms are oxidized with the receipt of energy through the biooxidation chain to form four water molecules.

[0006] The water produced in the various decomposition modes during dehydrogenation is transported by the water-loaded coenzymes NAD and FAD to the inner membrane of mitochondria, an organelle that acts as a power station for cells. This water, together with the structurally-bound oxygen and cytochromes of the biological oxidation chain, can transport electrons in the last stage of the electron transfer chain, reacting with oxygen in a redox reaction to form water, which can function in the same way as all metabolism. Form a chain. The steady-state voltage E in this redox reaction is +0.810 volts at a pH value of 7, and is drawn in the electron transfer chain.

Oxygen is the final water or electron acceptor in the metabolic process, and its presence keeps the electron transfer in cellular metabolism straight.

[0008] The biological oxidation chain in mitochondria is
It proceeds in a kind of biochemical oxyhydrogen reaction, which dehydrogenates the respiratory substrate. Due to the stepwise reaction of water or electrons, the high enthalpy of reaction released in the formation of water from hydrogen and oxygen, via the intermediate carrier step, is gradually released, and a significant part of the cell reactions consumes energy. For,
It is stored in scientific energy form as adenosine phosphate (ATP).

[0009] Healthy cells having mitochondria are:
In this way, it meets its energy needs. Depending on the metabolic load, the number of mitochondria is 1 per cell
It varies between 0 ^{2 and 6} × 10 ³ , and its oxygen demand is correspondingly different.

[0010] Oxygen must be supplied to the mitochondria of all cells in sufficient amounts in the survival of oxidized biological systems. To do so, there is a continuous and smooth flow of oxygen from the inhaled air with sufficient oxygen partial pressure in the trachea, oxygen transfer at the lung-blood interface of the alveoli, diffusion through the erythrocyte membrane, hemoglobin formation and hemoglobin into tissue capillaries. Release of oxygen into the cell, diffusion of oxygen into the intercellular space, and flow through the cell membrane and mitochondrial membrane to the biooxidation chain are required.

[0011] This continuous and smooth oxidation of all cells is an important prerequisite for maintaining a healthy body. The working characteristics of healthy cells can be described in general terms with electrical or electronic devices and their circuits. There is an ideal point of action, but this can deviate slightly from the operating characteristics. However,
If this point of action deviates significantly from its ideal point, this is a sign that there is considerable impairment of cellular metabolism. This type of disorder is caused, for example, by a superoxidation phenomenon also called oxidative stress. This oxidative stress
It is caused by an oversupply of the active oxygen stage (oxygen radicals) and / or by a reduction in molecules, called scavenger molecules, which normally allow this radical energy to be removed. Failure of the cell to eliminate this disorder leads to the destruction of biomolecules and cellular structures such as lipid peroxidation of cell membranes, various cell dysfunctions, cancerous changes in cells, and finally cell death.

In biological systems, it is designed to protect from its molecular stages, in its cellular structure, from exogenous toxins and against destructive oxygen radicals which are constantly produced in the metabolism of cellular substances, which radicals can It forms protective molecules and protective enzymes as scavengers that can be quickly arrested and captured.

However, if the damaged cells cannot block and capture active oxygen, as a result, cancer of each gene, acute lesion of blood cells, liver lesion, fatty liver, fatty cirrhosis, cirrhosis, natural killer cell Immune dysfunction in the area of T, lymphatic complex disorder in T helper cells, myocardial lesions, inflammatory, allergic or degenerative neurological lesions, blood cell lesions, ocular disorders, proliferation disorders of epithelial-endothelial and mucosal tissues, differentiation It causes various lesions such as disorders. What lesions result depends essentially on which cells and tissue have been most significantly attacked.

Therefore, the oxidation which is indispensable in the living system must not lead to the super oxidation.

From a scientific point of view, oxidation is: Donation of electrons 2. 2. Donation of hydrogen Reduction refers to the acceptance of oxygen. 1. Accepting electrons 2. Acceptance of hydrogen It means donation of oxygen.

[0016] All reductions are thermodynamically considered endothermic and all oxidations are considered exothermic. This means that the oxidation process is "poor energy"
It means that the reduction step is "energy rich". The reduction step can always donate "energy" or electrons, while the oxidation step is reduced by "energy acceptance" and acceptance of electrons.

Underlying all reducing power in the blood of humans and mammals and in most cells is the reduced form of the three amino acids glutamic acid, cysteine and glycine, having the following structure: (G-
SH) tripeptide glutathione.

[0018]

Embedded image Glutathione (gamma-glutamyl-cystinyl-glycine = G-SH) The function of biological systems based on biological oxidation can only be fulfilled by the sustained reductive protection of this important molecule, G-SH.

By dehydrogenation or oxidation, two molecules of reduced glutathione (G-SH) form a disulfide to form 1
The molecule becomes oxidized glutathione (GSSG).

[0020]

Embedded image

As a result of many studies, cells that fulfill their inherent functions satisfactorily have a reduced glutathione (G-SH) to oxidized glutathione (GSSG) ratio of about 400: 1.
Has been confirmed. That is, whole living cells have a high reducing potential in the form of reduced glutathione content. 400-to-1 G-SH vs. G-S-
The SG amount ratio can be evaluated as an index of ideal function and reliable structure maintenance.

In order to maintain many or all cellular metabolic enzyme functions, to prevent oxidative alteration of its catalytic and allosteric centers, and to provide an optimal response,
The reducing potential of reduced glutathione, ie, its optimal high intracellular fraction, is of great importance.

Traditional medical practice so far has involved the oxidative phenomena of the biological system, ie the oxidative aspects, or the metabolism of metabolism by the drugs necessary to degrade as a heterogeneous organism and to form metabolites of oxidation. In “oxidized potatoes”, capture the cytochrome-p-450 system and drug degradation.

[0024] In contrast, the present invention seeks to enhance or monopolize redox potential in cells damaged in metabolism instead of conventional medical treatment.

This problem is solved as a glutathione derivative,

[0026]

Embedded image By using a thiol derivative of glutathione.

[0027] Due to the important molecular biological significance of the intracellular proportion of physiologically quantified reduced glutathione, the following physiological, biochemical and vital cellular functions are dependent on the intracellular glutathione status (G- SH> mixed disulfide> GSSG) alone.

* Redox potential * Optimal potency of all enzyme reactions (active and allosteric centers of enzyme molecules) * Protection of the integrity of all biological membranes (cell membranes and organelle membranes) * This is also a structure-binding enzyme To optimize the function of the membrane
It is very important for the carrier mechanism, for the function of all cell receptors and for the allosteric specification.

* Cofactors and reduction potentials of many enzymes, particularly those involved in detoxification * For regulation and normalization of complex space-time patterns of cell growth and differentiation processes * Radical reactions and Because of the inhibition, mitigation and termination of the radical chain reaction, the physiological intracellular proportion of reduced glutathione is the first prerequisite for all basic cellular functions.

Normalize the concentration or amount of G-SH in cells for the treatment and prevention of most lesions due to many lesions, various etiologies and various pathologically different pathological and biochemical pathogens. This has causal therapeutic significance.

A reliable basic treatment for the normalization of cellular metabolism impaired by various pathogens is only possible with physiologically usable and effective glutathione derivatives as follows:

2) methyl- (thio) -ether of gamma-glutamyl-cysteinyl-glycine; 3) ethyl- (thio) -ether of gamma-glutamyl-cysteinyl-glycine; 4) mono-acetyl of gamma-glutamyl-cysteinyl-glycine. (Thio) -esters, 5) monophosphate- (thio) -esters of gamma glutamyl-cysteinyl-glycine, all the studies performed on cells, animals and humans for the signs indicated in paragraphs 0066 to 0085, Glutathione derivatives according to claims 1 and 2, and claims 3 to 5
Could be demonstrated with the combination of

The essential advantages of the reduced glutathione (G-SH) derivatives described again in claims 1 and 2, and thus also of the present invention, in the pharmacotherapy of human and animal lesions are as follows.

A) Good biomembrane permeability of these derivatives (claims 1 and 2). This enables an effective intracellular treatment with glutamine only with a certain physiological mechanism.

B) Protection of the glutathione SH group, which is crucial for the drug effect, on the way through the biological compartment to the desired site of action.

C) Non-inhibitory to enzymes involved in endogenous glutathione-biosynthesis (gamma-glutamylcysteine synthetase, glutathione-controlled enzyme in the sense of passive feedback, glutathione synthase).

Thus, in a competitive and / or allosteric inhibition manner, glutathione (G) for intracellular space can be produced without inhibiting or preventing endogenous glutathione biosynthesis, which is still possible depending on the degree of cytotoxicity.
-SH) offers the possibility of substitution.

D) The pharmacotherapeutic use of the glutathione derivatives of claims 1 and 2 above results in a slight suppression of endogenous glutathione biosynthesis in healthy cells.

Glutathione therapy, which can be used for therapy, can be administered in various ways (oral, nasal, buccal, sublingual, inhalant, transluminal, etc.) to provide effective and appropriate intracellular concentrations. Rectal, transdermal, subcutaneous, intramuscular, intravenous,
(Injectable, transarterial), it must be able to act completely SH-based molecules intracellularly and show good membrane permeability.

Thus, the requirements for the possibility of relatively wide therapeutic administration of glutathione (G-SH) can be met by the derivatives described and discussed in claims 1 and 2 above.

In order to cause G-SH to act at an appropriate intracellular concentration so as to normalize the basic mechanism of cellular metabolism, the above-mentioned derivatives of claims 1 and 2 alone and / or claims 3 to 4 are used. It is used as a mixture according to claim 5 or in the form of a preparation.

Any inflammatory (including allergic and self-aggressive), chemical , physical (including radiation damage from electromagnetic and / or particle radiation), infectious toxins
Sex cells, tissues and organs disorders; histological pathological tissue and on the inner
Deposition, wetness ; atrophy, hypertrophy, degeneration, dysplasia , ie benign tumor
In the case of 瘍 and malignant tumors not associated with or without metastasis.

Changes in biomolecules, normotrophic and congested vegetative tissues
In case of quality In case of immune injury of each gene .

For cancer prevention and adjuvant cancer treatment in the range of other cancer therapies and in the range of chemotherapy or radiation therapy. The possibility of use as a medicament regulated by claims 1 to 5 for each of the above therapeutic purposes is clarified.

In addition, oxygen radicals which increase due to lack of reduced glutathione, damage molecular structure and cell structure, and cause pathological deterioration or cell death can be effectively prevented.

An experiment using glutathione and / or a thiol derivative thereof as a medicament in humans and mammals for the first time in a laboratory was carried out using a thoughtful method capable of coping with the symptoms and diseases shown in the following examples. And, in fact, a completely new treatment.

Inhibiting "superoxidation" by the physiological modulation of redox potential in cells and tissues using reduced glutathione and / or its thiol derivatives as therapeutic agents involves the prevention and treatment of malignant tumors It is an entirely new method for treating various diseases.

Glutathione reductase, a flavin protein that performs the electron transfer function, has a ratio of (G-SH) to (GSSG) of about 400 in all human cells.
Adjust one to one. This value reflects the vitality or physiological functionality of the cell.

The biosynthesis of glutathione from three amino acids, glutamate, cysteine and glycine, involves two enzymes, gamma glutamyl-
In the presence of cysteine synthetase and glutathione synthase, this is done consuming 2 moles of adenosine-triphosphate (ATP) independently of intracellular DNA.

[0050]

Embedded image

The relatively unusual peptide bond to the gamma carboxyl group of glutamic acid prevents the uncontrolled destruction of the glutathione molecule by peptidase.

Reduced glutathione is a white crystalline substance that dissolves at 192-195 ° C. while decomposing. It has a molecular weight of 307.33. Reduced glutathione is readily soluble in water and saline, and is soluble in ethanol.

The “extended” molecule G-SH has a length of 15 °. Despite slight differences in the absorption properties of some of the functional groups of the glutathione molecule, stable absorption properties with an absorption maximum at 230 nm are observed.

The pK value is 9.66 for SH and 8.8 for NH ₃ ⁺ .
66, 3.53 for COOH ₍₁₎ and 2.53 for COOH ₍₂₎ .
12

The SH group is a reduced glutathione (G-SH)
Is an extremely active radical scavenger, including its SH group, which donates its hydrogen atoms to carbon, oxygen and nitrogen radicals. G as a basic redox system of biological systems
The very interesting hydrogen transfer function of the active SH group, together with the -SH / GSSG-based system function, has special significance for the overall biological function of G-SH.

One electron transfer process can be described as follows.

[0057]

[Table 1]

Two electron transfer is also possible, so
G-SH shifts to 1GSSG.

Different tissues of humans have different glutathione biological half-lives. About 10 for erythrocytes
0 hours, about 70 hours in the brain, about 30 hours in the eye lens, and only about 4 hours in the liver.

Glutathione can carry out mixed disulfide formation and thiol / disulfide exchange reaction in addition to one- and two-electron transfer.

Glutathione is a component of many important enzymes, such as glutathione peroxidase and glutathione reductase.

Glutathione peroxidase, which depends on selenium, decomposes into H ₂ O ₂ and organic peroxide (ROOH). The second selenium-dependent glutathione peroxidase degrades exclusively to organic peroxides.

Glutathione reductase is used in the aforementioned 6-SH
Intracellular adjustments are made for the physiological amount ratio of GSSG to GSSG. The intracellular concentration of G-SH is 1-50 × 10 ⁻⁴ M, and the G-SSG concentration is only 6-200 × 10 ⁴ M.
^-6 M.

About 30% of G-SH is present in the form of mixed disulfide (Prot-SSG).

The function of glutathione in human mediator metabolism is as follows.

1) Redox system 2) Thiol / disulfide exchange reaction with enzymes and tissue proteins 3) Detoxification of alkylated drugs and chemicals 4) Transport of amino acids across cell membrane 5) Chelate formation and chelate binding 6) "Free" radical Protection, energy absorption of "free" radicals 7) Enzyme reactions regulated by reaction partners Glutathione peroxidase; Glutathione reductase; Glutathione-S-aryltransferase, Glutathione-S-alkyltransferase, Glutathione-S-epoxide transfer Glutathione-S-transferases such as enzymes, glutathione-S-dihydroascorbate-reductase In view of the above functions, the following features of treatment with reduced glutathione are mentioned.

1) Normalization of redox potential,
Improve all specific cell functions by protecting important biomolecules and cell structures by superoxidation before injury and by optimizing protection before lipid oxidation 2) Adjustment of optimal redox potential and partially mixed disulfide for cells 3) Normalization of cell division by adjusting redox potential, thereby effecting tumor protection and tumor therapy 4) Enzyme reaction that should occur only when sufficient glutathione is present (Glutathione is a component of many specific enzymes, such as glutathione peroxidase, glutathione-S-transferase, glutathione-dihydroascorbate reductase). 5) All physiology enabled by the action of glutathione The positive effect is simply due to reduced glutathione It does not result from reduced glutathione derivatives, especially reduced glutathione monomethyl ester, reduced glutathione monoethyl ester, reduced glutathione monoacetyl ester and reduced glutathione monophosphate.

[0068]

Embedded image

1.1) Methyl-glutathionyl- (H
O) - ether R-CH ₃ 1.2) of ethyl - glutathionyl - (thio) - ether
R-CH ₂ -CH ₃ 1.3) mono - acetyl - glutathionyl - (thio) -
Ester R-COCH ₃ 1.4) mono - phosphate - glutathionyl - (thio) - Es
Tell R-PO ₃ H ₂

Excellent affinity and high efficacy are provided by combined preparations containing reduced glutathione and the above-mentioned derivatives in combination with an organically bound semiconductor element such as silicon, selenium or germanium. The same applies to combination preparations with vitamins such as vitamin A and vitamin E or provitamin beta-carotene and combination preparations with amino acids such as L-cysteine and L-methionine. Such a combination preparation can contain reduced glutathione itself, its derivatives, and the above-mentioned substances. This type of formulation is suitable for treating a number of diseases that exhibit a wide range of symptoms.

Symptoms Cancer disease of each gene, malignant disease of blood cells, and treatment at the preceding stage.

Alternatives and metabolic control in providing other cancer treatments, chemotherapy, radiation therapy and / or naturopathic treatments.

Prevention and treatment of metastases in a range of malignant diseases.

Liver diseases, especially acute and chronic hepatitis, such as scientific toxicity, infectious hepatitis, viral, rickettsial, bacterial or protozoan hepatitis, and chronic progressive hepatitis, fatty liver, fatty cirrhosis and Cirrhosis.

Impaired immune defense function of natural killer cells, single cells, macrophages, granule cells, T and B lymphocytes, plasma cells and impaired complement factors and antibody synthesis.

Impaired lymphokin synthesis in helper T cells, macrophages and other cells.

Prevention of coronary artery disease, angina pectoris, myocardial infarction in all aspects and emergency treatment of cardiac lesions in combination with other fast-acting medications.

Acquired and congenital skeletal muscle disorders.

Neurological lesions of inflammatory, allergic or regressive genes.

All forms of blood cell pathology, anemia, leukopenia, lymphopenia and thrombocytopenia.

Prevention of eye disorders, retinal and lens disorders and cataract prevention.

For example, oxygen therapy, superoxidation or acid stress in all aspects in the case of treatment using active oxygen (oxygen radicals), and protective measures in hyperoxia treatment, multistage oxygen therapy, ozone therapy and HOT therapy .

Intoxication that leads to damage of the main molecule and tissue in human tissues by radical chain reaction.

Radiation treatment, cell static treatment and accompanying treatment, and reduction or suppression of nausea and nausea.

Anesthesia, especially after anterior anesthesia in the case of heart and liver disease.

Poisoning by foreign organisms, especially toxic rare elements and heavy metals.

Disordered proliferation and differentiation of epithelial, subcutaneous and mucosal tissues.

The treatment of arteriosclerosis of pathophysiological and various other properties.

Basic and adjunct treatment of allergies.

Treatment of impotence and fertility, as well as impaired fertility and impaired potency of each gene. In addition, treatment of premature aging and decay of any tissue and precautionary measures in the process leading to premature aging or organ decay.

Application Aspects Reduced glutathione or its thiol derivative can be applied for treatment in the following manner.

1) Intravenous, subcutaneous injection, 2) intramuscular, 3) subcutaneous and subcutaneous, 4) oral, 5) nasal, buccal and sublingual, 6) inhalation, 7) vaginal, 8) Transrectal.

If intravenous or subcutaneous injection is severe and acute,
It is suitable in the case of malignant diseases, and subcutaneous injection is preferred especially when a large amount should be applied over a long period of time.

As a base for preparing an injection, physiological saline (NaCl 0.9% in water), Ringer's solution or monosaccharide solution (glycose 5%, fructose 5%) may be used alone or as a mixture. It is appropriate to do. To protect the free SH group of reduced glutathione, the pH of the solution is 6.8 to 7.4.
Range.

Light shielding is required to preserve the reduced glutathione and its derivatives, and dark glass should be used as the ampoule.

In the case of intravenous injection, a large amount of reduced glutathione can be directly injected into an intravenous duct, but an application method in which the partially absorbed form of glutathione is absorbed is also considered.

However, for long-term treatment, subcutaneous injection, intramuscular injection, arterial injection and even oral administration in dry form are advantageous. Oral administration is in the form of tablets, granules, capsules, powders, and drops. In the case of oral absorption, the effect of oxidation is inevitably reduced due to the oxidation reaction, depending on the case.

[0098] Intratumoral and intraperitoneal applications are possible provided that the pharmaceutical premise is satisfied.

In the same manner, suppository form of reduced glutathione or a derivative thereof can be applied, and when relatively light and has good local applicability, rectal or transluminal application is also possible. is there.

In the case of a minor injury such as a burn, a frostbite or a fly, a good therapeutic effect can be obtained even when applied with an ointment, spray or other liquid.

The dose and galenic in each mode of administration are determined according to the bioavailability, bioadaptability, treatment certainty and administration safety which differ depending on each use.

[0102] dosage gray mice, Wistar rats, therapeutic dose that does not result in toxicity were observed to small animals such as rabbits, of 2~5mg in slow intravenous injection 1 dose per body weight 1kg for humans 5 ml of the injection solution contains 150 mg of reduced glutathione.

For intravenous injection, a daily dosage of up to 20 mg / kg body weight in a 250 ml carrier, and in special cases even larger doses. 20mg / kg body weight
For administration, the minimum infusion time should not be less than 30 minutes.

The injections and infusions containing reduced glutathione must not be contaminated with other drugs. Infusion solutions should be prepared immediately before administration and are regulated for immediate use.

A daily dosage of basically 2 to 20 mg / kg of body weight is recommended, but the exact dosage depends on the individual conditions in the range of the disease. Only in cases of cancer with Schnitzler metastasis,
If it exceeds 00 g, the daily dose per 1 kg of body weight can be 20 mg or more.

The duration of treatment depends on the underlying disease to be treated. If the treatment is performed for more than 4 weeks, it is adjusted with a trace plasmascope. For quantitative analysis, measurement of plasma zinc content is recommended as a parameter of the screening test.

The potassium and magnesium contents of the plasma electrolytes serve as therapeutic parameters.

The injection and infusion solution of galenic reduced glutathione and / or its thiol derivative must be a heavy metal-free solution in sterile, pyrogen-free water, having a conductivity of less than 5 μS , which is in dark glass ampoules. Storage is recommended.

The infusion solution is always used immediately after the ampoule formulation is prepared in a carrier infusion solution.

In all other preparations, the auxiliaries and fillers can be prepared, stored and used without the undesired reaction of the free SH groups of the reduced glutathione and the transformation of the active substance in the respective preparation. Care must be taken to be able to

Test Results 1.1) (Human erythrocyte test tube test for improvement and normalization of redox behavior) [0111] Venous blood of 20 patients with various diseases was collected in 10 ml portions, and the coagulability was measured by adding heparin. Tested.
As a parameter for optimal erythrocyte function, 3 mg before and after the incubation period using 0.5 mg of reduced glutathione at 37 ° C.
The erythrocyte content at 0 minutes was measured.

N = 20 (mean value and standard deviation value) Non-load value: 1.50 ± 0.47 mU After incubation period: 1.99 ± 0.15 mU 1.2) (test tube in human erythrocyte cell tissue) Tests The enzymes glucose-phosphate-dehydrogenase and glutathione-reductase from erythrocytes of 22 patients were subjected to the test under the conditions in the test described above.

N = 22 (mean and standard deviation) Unloaded value: Glycose-6-phosphate-dehydrogenase 148 ± 22 mU / 10 ⁹ Erys. Glutathione-reductase 9.5 ± 0.8 mU / 10 ¹¹ Erys. Value after incubation period: Glucose-6-phosphate-dehydrogenase 179 ± 16 mU / 10 ⁹ Erys. Glutathione-reductase 11.3 ± 1.2 mU / 10 ¹¹ Erys. 2.1) (Rabbit animal test for improvement and / or normalization of blood redox status) The following parameters were measured in 30 tests on venous blood by the method and apparatus of Vincent for 5 rabbits did.

Ohmic Resistance: r Redox Podential E _{H to} Electron Potential rH ₂ pH Value: The pH value was measured on venous blood of the ear due to a constant oxygen deprivation load.

N = 30 (mean and standard deviation) r = 199 ± 12 Ohm / cm ³ after loading without administration of reduced glutathione pH = 7.38 ± 0.21 rH ₂ = 24.9 ± 2. 3 The test animals were then injected intravenously with 10 mg reduced glutathione per kg body weight.

The numerical values of 5 to 10 minutes after administration of reduced glutathione were as follows.

R = 202 ± 14 Ohm / cm ³ Reduced glutathione and the value after applying the load pH = 7.15 ± 0.16 rH ₂ = 21.8 ± 0.95 Atmospheric temperature 20 ° C., pressure 767 mmHg 2. 2) (Self test on human for improvement and / or normalization of blood redox condition) For human venous blood, the same parameters as in the above test were measured under a constant oxygen-deficient load. Fifty tests were performed on different days.

N = 50 (mean and deviation) r = 197 ± 14.5 Ohm / cm ³ after loading without administration of reduced glutathione pH = 7.41 ± 0.18 rH ₂ = 26.3 ± 2 .1 Then, 600 mg of reduced glutathione was slowly intravenously administered.

The following values were measured 10 minutes after the administration of reduced glutathione.

R = 204 ± 12.3 Ohm / cm ³
Reduced glutathione and numerical values after loading pH = 7.23 ± 0.11 rH ₂ = 23.1 ± 1.4 Atmospheric temperature 20 ° C., Pressure 758 to 770 mmHg 2.3) (Human malignant melanoma (melanome) ) Test on 8 healthy gray mice by implantation) Fig. 1 illustrates the growth of the tumor over time.

When 10 ⁶ cells of human malignant melanoma were inoculated into n = 8 healthy gray mice,
Four animals not treated with reduced glutathione (control group) died in 8-14 days. Tumor growth in four animals (test group) treated with 250 mg reduced glutathione three times each week was significantly slower and survived to 7 weeks.

2.4) (Test on 40 healthy gray mice by inoculation of human malignant chromocytoma (melanoma)) 40 healthy gray mice were inoculated with 10 ⁶ cells of human malignant chromocytoma, respectively. Ten untreated control animals died between days 8 and 12.

30 mg three times a week from the start of the test, 300 mg each
Treated with reduced glutathione. Three of them died in 15 days, another 5 died in 20 days, and another 7 died in 30 days.

50% of animals treated with reduced glutathione
The 15 animals with the regression tumor cells after inoculation prolonged the life of 30 continuous observation days.

[Brief description of the drawings]

FIG. 1 shows the results of tests on gray mice inoculated with human malignant melanoma.

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Claims (5)

[Claims] 1. A compound of the formula for use as a medicament Glutathione thiol derivative. 2. A compound of the formula for use as a medicament. In the formula, R is CH ₃ , CH ₂ —CH ₃ , COCH ₃ or PO
Glutathione thiol derivative of ₃ H ₂ . 3. Glutathione thiol derivative according to claim 1 or 2 in combination with at least one vitamin. 4. A glutathione thiol derivative according to claim 1, which is combined with at least one substance containing a semiconductor element which is bound inorganically or organically. 5. The glutathione thiol derivative according to claim 1, which is combined with at least one kind of amino acid.