KR20050059066A - Use of fermented wheat germ extract as anti-inflammatory agent - Google Patents

Abstract

The present invention relates to a new therapeutic use of a fermented wheat germ extract under the trade name Avemar(R) more specifically to use of Avemar(R) for the manufacture of a medicament useful as anti-inflammatory agent for preventing or treating or alleviating inflammatory conditions, particularly arthritis.

Description

USE OF FERMENTED WHEAT GERM EXTRACT AS ANTI-INFLAMMATORY AGENT}

The present invention is a product name (Avemar A novel therapeutic use of fermented wheat pear extract sold commercially), more specifically Abbe as a preparation for pharmaceutical compositions useful as anti-inflammatory agents for preventing, treating or alleviating inflammatory conditions, especially arthritis It relates to the use of.

Extract of fermented wheat pears (hereafter Abema Immunostimulatory and anti-metastatic effects as well as methods of preparation are described in WO99 / 08694. This material can be obtained by fermenting wheat pears with Saccharomyces cerevisiae in an aqueous medium and drying the filtered liquid fermentation. The material obtained is characterized by a 2,6-dimethoxy-p-benzoquinone component which represents about 0.4 mg / g dry material.

Surprisingly, Abema during our investigation It has been found that can be applied to treat or prevent inflammatory diseases, particularly rheumatoid arthritis occurring in mammals, including humans.

Arthritis is a generic name for many arthritis diseases such as rheumatoid arthritis, bacterial arthritis, reactive arthritis, and the like. Rheumatoid arthritis is a non-bacterial condition and includes a number of groups, the most important of which are inflammation and deformation of the joints. In most cases, traditional rheumatoid arthritis affects multiple joints (polyarthritis), but it can also be limited to a single joint (monoarthritis). Aging cartilage attack is just one of the factors that deform many joints and bones and destroy joint function. The disease also affects joint sheaths, ligaments and bone tissue. In most cases, the disease is characterized by varying course, including periods of exacerbation and improvement over its entire lifespan. However, joint deformation and systemic disorders continue to worsen. Only about 10% of patients are treated spontaneously.

Disseminated treatment methods are indicated to alleviate pain and reduce signs. There is currently no cure to fully recover from this disease. In most known methods of treatment, anti-inflammatory agents such as steroids (prednisolon, dexamethasone), nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-rheumatic drugs (DMARDs) that affect the disease are applied. do. NSAID groups include salicilate, ibuprofen, fenoprofen, naproxen, pyroxicam, tolmetine, indomethacin and other agents Such as cyclooxygenase enzyme inhibitors. These chemotherapy drugs have little effect and have high toxicity properties.

Groups of DMARDs or SAARs (anti-rheumatic drugs with extended effects) include D-penicillinamine, salts of gold, chloroquine, asatioprine, mesotrexate and Cyclophosphamide. In terms of their high toxicity, these drugs are usually selected by the specialist only in secondary cases when the patient's response to NSAIDs is poor. These agents are usually applied in combination with NSAIDs.

Recently, nonsteroidal anti-inflammatory agents have also been developed to treat rheumatoid arthritis, examples of which include gamma-interferon and interleukin-6 antagonists, cyclosporine, PAF-antagonists, and eicosapentaenoic acid. , EPA), somatostatine analogs, peptide derivatives and immune modulators.

Hungarian patent 203044 describes pharmaceutical preparations for ameliorating arthritis, wherein the active agent is an herbal extract.

Despite the large number of medications currently available, it is difficult or impossible to improve the condition of many patients by medical treatment. In addition, there is no preventive method for rheumatoid arthritis.

Accordingly, there is a continuing need for new classes of antirheumatic drugs that are toxic, produce little side effects and are suitable for eliminating, alleviating and preventing the signs of rheumatoid arthritis. The new formulations are required to inhibit or reduce inflammation, swelling and abnormal neovascularization, erosion of bones or joints, which will simultaneously suffer.

1 shows p.o. The effect of the treatment is shown (injected foot pads).

2 shows p.o. for 22 days for AA. Show the effect of the treatment (non-injected foot pads).

3 shows p.o. for 22 days for AA at day 14. The effect of the treatment is shown (injected foot pads).

4 shows p.o. for 22 days for AA at day 18. FIG. The effect of the treatment is shown (injected foot pads).

5 shows p.o. for 22 days for AA at day 22. FIG. The effect of the treatment is shown (injected foot pads).

FIG. 6 shows p.o. for 22 days for AA at day 14. FIG. Show the effect of the treatment (non-injected foot pads).

FIG. 7 shows p.o. for 22 days for AA on day 18. FIG. Show the effect of the treatment (non-injected foot pads).

8 shows p.o. for 22 days for AA at day 22. FIG. Show the effect of the treatment (non-injected foot pads).

9 shows p.o. 22 days for body weight of rats as a function of time. It shows the effect of the treatment.

10 is p.o. of 22 days for body weight of rats at day 22. FIG. It shows the effect of the treatment.

11 shows p.o. for 35 days for AA. The effect of the treatment is shown (injected foot pads).

12 shows p.o. for 35 days for AA. Show the effect of the treatment (non-injected foot pads).

FIG. 13 shows p.o. for 35 days for AA on day 28. FIG. The effect of the treatment is shown (injected foot pads).

14 shows p.o. for 35 days for AA at day 32. FIG. The effect of the treatment is shown (injected foot pads).

FIG. 15 shows p.o. for 35 days for AA at day 35. FIG. The effect of the treatment is shown (injected foot pads).

FIG. 16 shows p.o. for 35 days for AA on day 28. FIG. Show the effect of the treatment (non-injected foot pads).

17 shows p.o. for 35 days for AA at day 32. FIG. Show the effect of the treatment (non-injected foot pads).

18 shows p.o. for 35 days for AA at day 35. FIG. Show the effect of the treatment (non-injected foot pads).

FIG. 19 is a 35-day p.o. of body weight of rats as a function of time. It shows the effect of the treatment.

20 shows p.o. for 35 days for body weight of rats on day 35. FIG. It shows the effect of the treatment.

21 shows severe chronic inflammatory penetration in synoviium and adjacent tissues of untreated rats showing AA.

FIG. 22 shows severe infiltration containing giant cells in the synovial membrane of untreated rats showing AA.

FIG. 23 shows microscopic boils in inflammatory penetration in periarticular tissue of untreated rats showing AA.

24 shows CD4 positive lymphocytes in inflammatory infiltration found in the synovial membrane of untreated rats showing AA.

25 shows the lack of infection penetration in the synovial membrane and surrounding synovial tissue of rats previously showing AA and treated with Abema.

Thus, Abema The effect of was investigated in the adjuvant arthritis (AA) in rats most often used as an experimental model of human rheumatoid arthritis (RA). The development of adjuvant arthritis corresponds in some properties with human rheumatoid arthritis, and thus it has been found that it can be used appropriately to select compounds. Most often this chronic inflammation model is used by pharmacologists to test the anti-inflammatory and immunosuppressive effects of pharmacones.

The time and extent of AA development in rats depends on several factors, such as the triggering agent and its dosage, location of infusion, species of the experimental rat, and the like. An acute inflammatory response (first response) occurs within 24 hours after administration on the infused foot pad, and the volume of the foot gradually increases for 4 or 5 days. Depending on the species of rat used, the degree of inflammation is constant on days 6-11 (static effect), and then the intensity of the response is further increased. Inflammatory responses also occur in non-injected foot pads 10 to 12 days post-infusion (second or immune mediated response). The inflammatory response, ie, an increase in foot volume, reaches a maximum on both treated and untreated foot pads on days 18-21.

Avema for Assisted Arthritis in Rats Effect

In our experiments, in female Wistar rats by injecting 0.1 ml of 0.5% Mycobacterium butyricum (Difco) suspended and homogenized in liquid paraffin under the bottom skin of the right hind paw of the female Wistar rats. Secondary arthritis was induced. The average initial body weight of the experimental animals was 138 ± 5 g in the 22-day treated group and 118 ± 5 g in the 35-day treated group. The body weight of the animals, together with the volume of the injected right leg and the non-injected left leg (follows the change in the first and second reactions), By plethysmography during treatment with 0, 1, 4, 7, 12, 14, 18 and 22 for 22 days of experiment, 0, 3, 7, 11, 15, for 35 days of experiment Measurements were taken at 18, 21, 25, 28, 32 and 35 days. Inflammatory Response Avema It was induced on day 1 (22 day test) and day 14 (35 day test), respectively, after the start of treatment. The following experimental groups and methods were applied to both experiments: 1. Control 2 × 1.0 ml / 150 g (distilled water); 2. Abema 2 x 2.5 g / kg / day; 3. Abema 2 x 1.0 g / kg / day; 4. Abema 2 x 0.25 g / kg / day; 5. Abema 2 x 0.05 g / kg / day; 6. Indomethacin 2 × 0.5 mg / kg / day; 7. Dexamethasone 2 x 0.05 mg / kg / day. Each experimental group consists of 10 to 16 rats.

Abema Suspension (manufactured by Hungary Budapest Viromedisina Pcl.) And dexamethasone solution were always prepared and / or diluted immediately prior to administration. Indomethacin (manufactured by Hungary Budapest and Chinoin Pharmaceutical and Chemical Works) applied as a positive control was suspended and administered in 0.5% carboxymethylcellulose. Indomethacin and dexamethasone (manufactured by Organon) as well as Abema A variety of doses of twice daily, i.e. between the first half of the daily dose between 8.00 am and 10.00 pm, and the other half between 4.00 pm and 6.00 pm, were placed in the gastrointestinal tube at 1.0 ml / 150 g body weight. By administration. The control group received 1 ml / 150 g of distilled water.

Single-way analysis of variable conditions (ANOVA) was performed for statistical evaluation of the results.

result

The results of the 22-day treatment are shown in FIGS. 1-10, and the results of the 35-day treatment are shown in FIGS. 11-22. The figures show group mean values with standard deviation (± SEM) (n = 14-15 in 22-day experiments and n = 10-12 in 35-day experiments). Compared to the control group, the importance level is indicated by * on the bar graph (* = p <0.05; ** = p <0.01; *** = p <0.001).

The result is Abema Indicates that depending on the dosage, it can significantly prevent the development of both the first and second inflammatory responses in rats, which is Abema Support the anti-inflammatory effects of. Similar to indomethacin and dexamethasone, Abema Minimized adjuvant arthritis in rats treated in a dose dependent manner. (Its effect did not reach that of indomethacin and dexamethasone applied as a positive control, but it can still significantly prevent co-arthritis.) During the 14 days of pretreatment, there was no effect on leg volume, which it generalized. Means that it does not cause an inflammatory response. Depending on the pretreatment period, it prevents the development of arthritis. Abema Pretreatment by may or may not only slightly increase the body weight of rats with arthritis during 22 or 35 days of treatment.

Histological studies

The affected joints of the right hind paw, along with the epiphysis and surrounding fibrous and muscular tissue of the bone, were fixed in buffered neutral 4% formalin. Calcium depletion was performed using EDTA and the sample was embedded in paraffin. A thin longitudinal section of 8 μm was cut and the sections were colored with hemotoxiline (H) and eosine (E). For selected positive controls, and in treated cases, immunoperoxidase reactions were performed to show CD4 and CD8 positive T-lymphocytes. The antibody used was a product of Santa Cruz (Santa Cruz, CA, USA) diluted 1: 100.

Histological examination of the joints of untreated control rats with AA showed severe inflammatory changes in the synovial membrane and surrounding (peripheral synovial) tissue (stained by Figures 21, H and E, 300-fold magnification). Cell infiltration consisted of lymphocytes, plasma cells, histocytes, multinucleated giant cells and fibroplas (stained by FIG. 22, H and E, magnified 300 times). Within inflammatory infiltration, microspecies formed by neutrophil granulocytes was also observed (stained by Figure 23, H and E, magnified 300 times). Most lymphocytes were found to be CD4 positive in inflammatory penetration of AA rats (FIG. 24, CD4 immunoperoxidase).

Abema Joints of rats treated with 2 × 1.0 or 2 × 2.5 g / kg / day showed no or minimal inflammatory penetration. Abema Infiltration of CD4 lymphocytes in synovial fluid and surrounding synovial cells as a result of treatment with almost no appearance and fibrosis was minimized (staining, magnified 300 times by FIG. 25, H and E). Similar results were found in animals treated with indomethacin and dexamethasone used as positive controls. A semi-quantitative assessment of the extent of inflammatory penetration in the different groups is shown in Table 1. There was no significant difference between the groups that received pretreatment for 24 hours and 14 days respectively.

Semi-quantitative histological evaluation of inflammatory penetration in AA rats treated and untreated by Abema process Histological grade (average 1-3) 24-hour pretreatment 14 days pretreatment contrast 2.8 2.2 2 x 2.5 g / kg / day 1.6 1.4 2 x 1.0 g / kg / day 1.0 1.2 2 × 0.25 g / kg / day avema 2.4 2.6 2 x 0.05 g / kg / day 2.6 2.6 2 x 0.5 mg / kg / day indomethacin 1.0 1.2 2 × 0.05 mg / kg / day dexamethasone 1.4 1.2

As a result, histological studies are certainly Abema Support the anti-inflammatory effects of.

Based on these results, the development of rheumatoid arthritis is Abema It can be expected that it can be prevented by proper administration of.

Acute and subacute toxicity tests performed under GLP (Good Laboratory Practice) conditions, unlike steroidal and nonsteroidal anti-inflammatory compounds, Showed no toxic effects, including purulent gastritis and acute gastric ulcer (Report. Acute oral toxicity study of Avemar) in mice. Code: 9901. Univ. Vet. Sci., Dept. Pharmacol. Toxicol., Budapest, 1999; Acute oral toxicity study of Avemar in rats. Code: 9902. Univ. Vet. Sci., Dept. Pharmacol. Toxicol., Budapest, 1999; Subacute oral toxicity study of avemar . Code: 0001. Univ. Vet. Sci., Dept. Pharmacol. Toxicol., Budapest, 2000). In addition, the formulation was not genotoxic in the micronucleus test of rat bone marrow.

Based on the above experimental results, Abbe Has been proposed to be a suitable therapeutic tool for the treatment of rheumatoid arthritis in humans. Other immunopathological diseases can also be considered in this regard.

Avema for Human Rheumatoid Arthritis Effect

Treatment-resistant patients who have been proven to have rheumatoid arthritis are treated by Abbema in Part IV of Rheumatology of the National Institute of Rheumatology and Physiotherapy (Budapest, Hungary). Treated by. This self-administered open clinical test is Abema The purpose was to assess the effectiveness, resistance and side effects of the drug. The following is an evaluation of the experimental results obtained during the 1 year treatment of 15 patients.

A. Patient Choice

Fifteen outpatients, classified as Steinbrocker's anatomical stages II to III, have been shown to suffer from RA based on their ACR classification criteria in the study. Their RA is Abema It was stagnant and worsened under the treatment set for 3 months before starting treatment by. Patients agreed to participate in the study.

B. Criteria for Exclusion

Ages under 18 and over 80;

Serious diseases of the liver, heart, kidneys and hematopoietic organs;

Active gastric ulcer;

Psychiatric illness, mental degeneration;

-Lack of cooperation;

-Pregnancy or lactation.

If the formulation is ineffective, that is, the expected improvement does not appear after about three months, administration will be discontinued.

C. Research Process

In addition to the original medical treatment (baseline treatment, steroids and NSAIDs), 15 patients with RA received a daily dose of 2 × 9 g of water-soluble granules Avema Was administered (9 g in the morning and 9 g in the evening). Patients were checked at the start of treatment and monthly, and their statistical evaluation was performed in June and December, respectively.

D. Test Parameters

The clinical parameters of this study are as follows;

Ritchie index;

-HAQ (Health Assessment Questionnaire);

-Time of morning joint stiffness period;

-Deposition;

CRP;

Hematocrit values.

During the study, changes in the steroid dose administered were also recorded. The average age of the 15 female RA patients in this study was 54.5 years (44-68 years), and the mean disease duration was 8 years (3-25 years). At the start of the study, 10 of the patients received baseline treatment: one patient received salzopyrin, five patients methotrexate (Lachema), and three patients cyclosporin (Sandimmun, Neoral). One patient was treated with chloroquine (Delagil). Five patients did not receive baseline treatment. Baseline therapeutic drugs applied sooner have not been proven to be effective and / or have side effects. At the start of the study, 11 patients received steroids, with the highest oral steroid dose being 7.5-10 mg of prednisolone or an equivalent amount of methylprednisolone or dexamethasone. Patient characteristics are shown in Table 2.

steroid

Dexamethasone: D

Methylprednisolone: M

Triamcinolone: T

Prednisolone: P

Baseline Therapeutic Agents

Chloroquine: Ch

Methotrexate: MTX

Cyclosporin: C

Sulfasalazine: S

ESR: red blood cell deposition rate

HAQ: Health Assessment Questionnaire

result

Statistical calculations were performed using the Wilcoxon test.

The results are shown in Tables 3-9.

Change in Ritchie Index compared to initial value at 6 and 12 months time Z value importance 0-6 months 2.574 p <0.010 0-12 months 2.953 p <0.003 6-12 months 0.534 p <0.594 N.S.

Changes in HAQ values compared to baseline at 6 and 12 months time Z value importance 0-6 months 3.020 p <0.003 0-12 months 2.448 p <0.014 6-12 months 1.433 p <0.152 N.S.

Changes in the duration of morning joint stiffness compared to baseline at 6 and 12 months Treatment period stoppage Improving immutability reinforce Importance p 0-6 months 2 9 2 0 0.009 0-12 months 2 9 One One 0.002

Deposition change compared to initial value at 6 and 12 months time Z value importance 0-6 months 2.131 p <0.033 0-12 months 1.250 p <0.211 N.S. 6-12 months 0.559 p <0.576 N.S.

Changes in CRP Levels time Z value importance 0-6 months 1.318 p <0.187 N.S. 0-12 months 0.426 p <0.670 N.S. 6-12 months 0.565 p <0.572 N.S.

The comparison was made with a T-test of a single sample.

Changes in hematocrit values time Z value importance 0-6 months 1.494 p <0.157 N.S. 0-12 months 3.011 p <0.009 6-12 months 0.722 p <0.482 N.S.

The comparison was made with a T-test of a single sample.

Changes in steroid dosage at 6 and 12 months Treatment period Constant dosing Reduced dosing Increased dosing Importance, p 0-6 months 5 6 0 0.031 0-12 months 5 5 One 0.116 N.S.

Four patients did not receive steroids.

Five of the eleven patients on steroids consumed the unchanged initial dose of medication, two patients adjusted to halved the initial dose, and two patients adjusted from 7.5 mg to 5 mg. The dose of baseline treatment drug varied in four patients during the 12-month test period: in one of them the MTX increased from 12.5 mg to 15 mg, and in the other three, the dose of cyclosporin from 175 to 125 mg, Decreased from 225 to 100 mg and from 200 to 100 mg. This dose did not change in five patients.

No significant changes were detected in the laboratory parameters of hemoglobin, liver and kidney function.

The data obtained is Abema Treatment of patients with treatment resistant RA by surprisingly surprisingly improved outcomes within the first 6 months. Regarding the clinical parameters of the patients, a significant improvement appeared without exception, and moreover this could also reduce the patient's steroid dose. Significant improvements in clinical parameters were still made by the end of the second half of treatment compared to the initial state.

Based on the above, an object of the present invention is to provide a fermented wheat pear extract (Abema) for preparing a pharmaceutical composition for treating, preventing or alleviating an inflammatory condition. ).

Preferably, Abema Can be applied to prepare pharmaceutical compositions useful for treating, preventing or alleviating arthritis, more preferably rheumatoid arthritis.

Another object of the present invention is a method of preparing a pharmaceutical composition containing fermented wheat pear extract as an active ingredient, together with pharmaceutical additives generally used in pharmaceutical compositions useful for treating, preventing or alleviating inflammatory diseases. It is a method comprising the step of preparing by adding the active ingredient.

Also, Abema Has been found to be preferably applied in combination with other nonsteroidal (NSAID) types of anti-inflammatory agents such as diclophenac, ibuprofen, pyroxhamm, tolmetin and the like. As a result of the combined administration, the dosage of NSAID class drugs can be significantly reduced, which is a great advantage with regard to the toxicity of these drugs. For example, co-administration with Diclofenac can reduce the amount of these two agents by 50% while at the same time achieving similar enhancements.

Based on the above, another object of the present invention is to provide a fermented wheat pear extract (abbema) for the manufacture of a medicament for treating, preventing or alleviating arthritis. ) And another active ingredient, in particular anti-inflammatory. According to the invention, nonsteroidal anti-inflammatory agents are preferably used as another anti-inflammatory agent.

Moreover, the present invention also provides an effective amount of fermented wheat pear extract (Abema) with another active ingredient, in particular an anti-inflammatory agent and a pharmaceutically acceptable carrier. To a mixed pharmaceutical composition containing).

Preferred anti-inflammatory pharmaceutical compositions of the present invention comprise an effective amount of fermented wheat pear extract (Abema ) And diclofenac.

The active ingredients used in the present invention can be formulated into a variety of oral and parenteral dosage forms and administered to treat and prevent rheumatoid arthritis. Generally, the active ingredient is present in the composition at about 5% to 95%.

Pharmaceutically acceptable additives used to prepare the pharmaceutical compositions may be solid or liquid. Examples of solid pharmaceutical compositions include powders, tablets, pills, capsules, cachets, rhombic pharmaceutical formulations, suppositories, and dispersible granules. The solid composition may comprise various additives such as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or capsules.

In the context of powders, additives are finely powdered solid materials which constitute a mixture with the finely dispersed active ingredient.

With regard to tablets, the carrier with the necessary binding properties is mixed with the active ingredient in suitable proportions and compacted in the shape and size required.

Preferably the powders and tablets contain 5% to 70% of the formulation. Examples of suitable additives are magnesium carbonate, magnesium stearate, talcum, sugar, lactose, pectin, dextrin, cyclodextrin, maltodextrin, starch, gelatin, tragacanta, methylcellulose, sodium carboxymethylcellulose Low melting point waxes, cocoa butter and the like. The preparation includes the formulation of the active ingredient with the encapsulating material as an additive, whereby a capsule is obtained in which the active ingredient with or without other carriers is surrounded by the additive, thus connecting the additive with the active ingredient. Caching and rhombus drug formulations are similarly prepared. Tablets, powders, capsules, pills, cachets and rhombic drug formulations may be applied for oral administration.

To prepare suppositories, waxes with low melting points such as fatty acid glycerides or cocoa butter are first melted and homogeneously dispersed therein by mixing the active ingredients. The molten homogeneous mixture is then poured into suppository molds of suitable size, cooled and solidified.

Liquid pharmaceutical formulations include solutions, suspensions, emulsions, syrups and elixirs, such as aqueous or water soluble propylene glycol solutions. For parenteral injection, the liquid pharmaceutical composition may be formulated with a water soluble polyethylene glycol solution.

Solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding the appropriate colorants, flavors, stabilizers, and flocculants.

Suspensions suitable for oral administration can be prepared by dispersing the finely divided active ingredient in water together with viscous materials such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents.

Solid pharmaceutical compositions also include those intended to be rapidly converted to liquid formulations prior to use for oral administration. Examples of these liquid pharmaceutical formulations include solutions, suspensions, and emulsions. In addition to the active ingredients, these pharmaceutical preparations may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, flocculants, solubilizers and similar materials.

Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol of the same kind, vegetable oils such as olive oil, injectable organic esters such as ethyl oleate can be applied as solvent. These compositions may also contain other adjuvants, in particular glidants, istonizing, emulgeating agents, dispersants and stabilizers. Sterilization can be performed in a variety of ways, including aseptic filtration, incorporation of the sterilant into the composition, spinning or heat treatment. Sterile solid compositions can also be prepared so that they can be dissolved in sterile water or any other injectable medium immediately following use.

Preferably, the pharmaceutical composition may be packaged in unit doses. In the above drug form wherein the agent is divided into unit doses, each contains a specific amount of active ingredient. The unit dosage form can be a packaged preparation, such as tablets, capsules and powders, which are packaged in a package containing an individual amount of the preparation, such as a bottle or ampoule. Unit dosage forms may also include capsules, tablets, cachets, rhombic drugs, or a specific number thereof contained in a package.

The amount of active ingredient can vary and can be adjusted to 1 to 1000 mg, preferably 10 to 100 mg in unit dosage formulations depending on the use and potential of the active ingredient. The pharmaceutical composition may also contain other compatible therapeutic agents if necessary.

The effective dosage of the composition applied according to the invention and the dosage ratio for preventing, inhibiting or preventing arthritis depend on a number of factors. Appropriate dosages are mandatory and must be determined by a specialist. In general, it is the physician in charge who specifies the appropriate dosage depending on the age, weight and other individual factors of the person to be treated. Daily dosage levels vary from about 0.1 to 1000 mg / kg body weight, preferably from about 1 to 500 mg / kg / day, more preferably from about 50 to 250 mg / kg day. For safety reasons, the entire daily dose may be divided into several portions throughout the day, if necessary.

Pharmaceutical Composition Abema When other active ingredients are included, the other agents may be selected from corticosteroids, anti-inflammatory agents, antirheumatic agents, immunosuppressants, anti-metabolic agents and immunomodulators. A list of compounds that fall under these categories can be found in Comprehensive Medical Chemistry, Pergamon Press, Oxford, 970-986 (1990). This group includes, for example, sulfasalazine and aminosalicylates (anti-inflammatory); Cyclosporin, FK-506 and rapamicin (immune inhibitor); Cyclophosphamide and methotrexate (antimetabolites); Dexamethasone, methylprednisolone, triamcinolone, prednisolone (steroid); And interferon (immune modulators). Abema When is used in combination with one or more agents, they may be packaged together or they may be co-administered. Abema Combination administration with and one or more agents can be carried out substantially simultaneously or sequentially. The expert can determine the most appropriate method of administration depending on the agent being released, the desired result, the patient and the condition to be treated.

Through the foregoing embodiments of the present invention, those skilled in the art will recognize that the above description is merely exemplary and that various alternatives, modifications and variations are within the scope of the present invention and are intended by the applicant. Accordingly, the invention is not limited to the particular embodiments illustrated above, but only by the claims set forth below.

The invention is trade name Avemar A novel therapeutic use of fermented wheat pear extract sold commercially), more specifically Abbe as a preparation for pharmaceutical compositions useful as anti-inflammatory agents for preventing, treating or alleviating inflammatory conditions, especially arthritis It relates to the use of.

Claims (10)

Fermented wheat pear extract for the manufacture of a medicament for treating, preventing or alleviating an inflammatory condition (Abema ) Use. Use according to claim 1, wherein the inflammatory condition is arthritis. Use according to claim 2, wherein the arthritis is rheumatoid arthritis. Fermented wheat pear extract (Abema) for the manufacture of a medicament for treating, preventing or alleviating arthritis ) And other active ingredients, in particular anti-inflammatory agents. 5. Use according to claim 4, wherein the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. 6. The use of claim 5, wherein the nonsteroidal anti-inflammatory agent is diclophenac. Effective amount of fermented wheat pear extract (Abema ) With another active ingredient and a pharmaceutically acceptable carrier. 8. An extract of fermented wheat pear extract (Abema) ) A pharmaceutical composition having anti-inflammatory activity comprising a) together with a nonsteroidal anti-inflammatory agent. Effective amounts of fermented wheat pear extracts desirable for the treatment, prevention or alleviation of inflammatory conditions (Abema A method of treating, preventing or alleviating an inflammatory condition in a mammal, including human, comprising administering to a mammal, including human. 10. The method of claim 9, further comprising administering an anti-inflammatory agent.