HRP20050114A2 - Use of fermented wheat germ extract as anti-inflammatory agent - Google Patents

Description

This invention relates to a new therapeutic application of fermented wheat germ extract, which has the trade name Avemar®, and for the preparation of pharmaceutical preparations useful as an anti-inflammatory agent for the prevention and treatment or improvement of inflammatory conditions, especially arthritis.

Preparation methods as well as immunostimulating and anti-metastatic effects of fermented wheat germ (hereafter referred to as Avemar®) are described in WO 99/08694. This substance can be obtained by fermentation of wheat germ with Saccharomyces cerevisiae in an aqueous medium, and by drying and filtering the fermentation liquid. The obtained substance is characterized by the content of 2,6-dimethoxy-p-benzoquinone, which is present at approximately 0.4 mg/g of dry substance.

It was surprisingly found during our research that Avemar® can be used for the treatment or prevention of inflammatory diseases, especially rheumatoid arthritis that occurs in mammals including humans.

Arthritis is a general term for numerous arthritic diseases such as rheumatoid arthritis, bacterial arthritis, reactive arthritis, etc. Rheumatoid arthritis includes a large group of non-bacterial conditions, the most important of which are inflammation and joint deformation. In most cases, classic rheumatoid arthritis affects many joints (polyarthritis), but it can also be limited to one joint (monoarthritis). An attack on arthritic cartilage is only one factor in the deformation of numerous cartilages and bones that destroys joint function. This disease affects the lining of the joint, ligaments and bone tissue. In the majority of cases, the disease is characterized by different courses including exacerbations and periods of improvement throughout life, however, joint deformity and systemic disability increase over time. Only about 10% of patients recover spontaneously.

The main methods of treatment are aimed at reducing pain and improving symptoms, and there is no treatment that leads to a complete recovery from this disease. In most known treatment methods, anti-inflammatory agents such as steroids (prednisolone, dexamethasone), non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) are used. The NSAID group includes salicylates, ibuprofen, fenoprofen, naproxen, piroxicam, tolmetin, indomethacin and others, eg cyclooxidase enzyme inhibitors. These chemotherapeutics are characterized by low efficacy and high toxicity.

The DMARD or SAAR (long-acting antirheumatic drugs) groups include D-penicillinamide, gold salts, chlorquine, azathioprine, methotrexate, and cyclophosphamide. Due to their toxicity, these drugs are usually chosen by a professional only as a second option, and when the patient's response to NSAIDs is insufficient. These agents are usually used in combination with NSAIDs.

Recently, NSAIDs have also been developed for the treatment of rheumatoid arthritis including gamma-interferon and interleukin-6 agonists, cyclosporine, PAF-antagonists, eicosapentanoic acid (EPA), somastatin analogs, peptide derivatives, and immunomodulators.

Hungarian patent no. 203044 describes a pharmaceutical composition that improves arthritis when the active ingredient is a plant extract.

Despite the large number of drugs now available, it is difficult or impossible to improve the status of many patients with medical treatment. Furthermore, there is no method of prevention for rheumatoid arthritis.

Therefore, there is a constant need for new types of antirheumatic drugs that are less toxic, have fewer side effects, and are suitable for eliminating, improving, and preventing the symptoms of rheumatoid arthritis (RA). The development of adjuvant arthritis was found to correspond to human rheumatoid arthritis in several characteristics and therefore can be properly used for compound screening. Mainly the anti-inflammatory model is used by the pharmacologist to test the anti-inflammatory and immunosuppressive effect of the pharmacon.

The time and degree of development of AA in rats depends on several factors, such as the agent that initiates the process and its doses, the injection site, the type of experimental rat, etc. An acute inflammatory reaction (primary response) occurs on the paw where it was injected, and within 24 hours after administration, the volume of the paw slowly increases for 4 to 5 days. Depending on the type of rat used, the degree of inflammation becomes constant (saturation effect) between days 6 and 11, and then the intensity of the reaction increases further. An inflammatory reaction was generated also on the paw that was not injected (secondary immune response) on the 10th to 12th day after the injection. The inflammatory reaction, which is an increase in the volume of the paw, reaches its maximum on the untreated paw between the 18th and 21st days.

Short description of the pictures

Figure 1 shows the effect of a 22-day p.o. treatment AA (injected paw)

Figure 2 shows the effect of a 22-day p.o. of treatment AA (non-injected paw)

Figure 3 shows the effect of a 22-day p.o. of AA treatment on day 14 (injected paw)

Figure 4 shows the effect of a 22-day p.o. of AA treatment on day 18 (injected paw)

Figure 4 shows the effect of a 22-day p.o. of AA treatment on day 22 (injected paw)

Figure 6 shows the effect of a 22-day p.o. of AA treatment on day 14 (non-injected paw)

Figure 7 shows the effect of a 22-day p.o. of AA treatment on day 18 (non-injected paw)

Figure 8 shows the effect of a 22-day p.o. of AA treatment on day 22 (non-injected paw)

Figure 9 shows the effect of a 22-day p.o. treatment on body weight of rats depending on time

Figure 10 shows the effect of a 22-day p.o. treatment on the body weight of rats on the 22nd day

Figure 11 shows the performance of the 35-day p.o. treatment AA (injected paw)

Figure 12 shows the performance of the 35-day p.o. of treatment AA (non-injected paw)

Figure 13 shows the performance of the 35-day p.o. of AA treatment on day 28 (injected paw)

Figure 14 shows the performance of the 35-day p.o. of AA treatment on day 32 (injected paw)

Figure 15 shows the performance of the 35-day p.o. of AA treatment on day 35 (injected paw)

Figure 16 shows the performance of the 35-day p.o. of AA treatment on day 28 (non-injected paw)

Figure 17 shows the performance of the 35-day p.o. of AA treatment on day 32 (non-injected paw)

Figure 18 shows the performance of the 35-day p.o. of AA treatment on day 35 (non-injected paw)

Figure 19 shows the performance of the 35-day p.o. treatment on body weight of rats depending on time

Figure 20 shows the performance of the 35-day p.o. treatment on the body weight of rats on the 35th day

Figure 21 shows severe chronic inflammatory infiltration in the synovium and adjacent tissues in etretized rats representing AA

Figure 22 shows severe chronic inflammatory infiltration in the synovium containing large cells in untreated rats representing AA

Figure 23 shows the micropapces within the inflammatory infiltration in the periarticular tissue of treated rats representing AA

Figure 24 shows CD4 positive lymphocytes in the inflammatory infiltration in the synovium of untreated rats representing AA

Figure 25 shows the absence of inflammatory infiltration in the synovial and perisynovial tissue in rats previously exposed to AA and treated with Avemar.

Effect of Avemar® on adjuvant arthritis in rats

In our experiments, adjuvant arthritis was induced in female Wistar rats by injecting under the skin of the foot of the animal's right paw 0.1 mL of 0.5% killed Mycobacterium butyricum (Difco) suspended in homogenized liquid paraffin. The average initial body weight of the experimental animals was 138±5 g in the groups treated for 22 days, and 118±5 g in the groups treated for 35 days. Body weight of the animals was measured plethysmographically during treatment with Avemar®, together with the volume of the injected left paw and the uninjected left paw (to monitor changes in primary and secondary reactions) on days 0, 11, 4, 7, 12, 14, 18 and 22 in to the 22-day experiment and days 0, 3, 7, 11, 15, 18, 21, 25, 28, 32 and 35 in the 35-day experiment. The inflammatory reaction was induced on day 1 (22-day test) and day 14 (35-day test), after the start of treatment with Avemar®. The following experimental groups and methods were applied in both experiments: 1. control 2x1.0 mL/150 g (distilled water); 2. Avemar® 2x2.5 g/kg/day; 3. Avemar® 2.1.0 g/kg/day; 4. Avemar® 2x0.25 g/kg/day; 5. Avemar® 2x0. 5 g/kg/day; 6. indomethacin 2x05 mg/kg/day; 7. dexamethasone 2x0.05 mg/kg/day. Each experimental group consisted of 10-16 rats.

Suspensions with Avemar® (supplied by Biromedicina Pcl, Budapest, Hungary) and dexamethasone solutions were always prepared and/or diluted immediately before administration. Indomethacin (manufactured by Chinoin Pharmaceutical and Chemical Works, Budapest, Hungary) applied as a positive control was suspended in 0.5% carboxymethylcellulose and given. Different doses of Avemar® as well as indomethacin and dexamethasone (prepared by Organon) were given via tube at a dose of 1.0 mL/150 g body weight twice a day, i.e. the first half of the daily dose is between 8.0 and 10.00 a.m. and the other half is between 4.00 and 6.00 p.m. The control group received 1 mL/150 g of distilled water.

One-way analysis of variance (ANOVA) was performed for statistical evaluation of the results.

the results

The results of the 22-day treatment are shown in Figures 1 to 10, and the results of the 35-day treatment are shown in Figures 11 to 20. The figure shows the average values with standard deviation (±SEM) (for the 22-day experiment n=14-15 and for the 35- daily experiment n=10-12). The level of significance compared with the control group is marked as * in the graphic representation (*=p<0.05; **=p<0.01; ***=p<0.001).

The results show that Avemar® can, depending on the dose, significantly inhibit the development of primary and secondary inflammatory reactions in rats, which indicates their anti-inflammatory effect. Similar to indomycin and dexamethasone, Avemar® reduces adjuvant arthritis in a dose-dependent manner in treated rats. (Although the efficacy does not reach that of indomethacin and dexamethasone used in the positive control, it can still significantly inhibit adjuvant arthritis.) The 14-day pretreatment does not affect the leg volume, which means it does not cause a general inflammatory response. Depending on the duration of the previous treatment, it inhibits the development of arthritis. Pretreatment with Avemar® failed to increase or only slightly increased body weight in arthritic rats during the 22-day and 35-day treatment.

Histological examinations

The affected joints of the right paw together with the epiphysis from the bone and the surrounding connective and muscle tissues were fixed in buffered neutral 4% formalin. Decalcification was performed using EDTA and samples were embedded in paraffin. Thin longitudinal sections of 8 μm were cut and stained with hematoxylin (H) and eosin (E). In selected positive control and treated cases, immunoperoxidase reaction was performed to demonstrate CD4 and CD8 positive T-lymphocytes. Antibodies used were obtained from Santa Cruz (Santa Cruz, Ca, USA) and applied at a 1:100 dilution.

Histological examination of the joints of untreated control rats with AA showed severe inflammatory changes in the synovium and surrounding (persinovinal) tissues (Figure 21, stained with H and E, magnified 300 times). Cellular infiltration consisting of lymphocytes, plasma cells, histocytes, large multinucleated cells, and fibroblasts (Figure 22, stained with H and E, magnified 300 times). As part of the inflammatory infiltration, microabscesses formed by neutrophil granulocytes were also observed (Figure 23, CD4 immunoperoxidase).

The joints of rats treated with Avemar® 2x1.0 or 2x2.5 g/kg/day showed no or minimal inflammatory infiltration. Infiltration of CD4 positive lymphocytes in synovinal and perisynovinal cells almost gradually disappeared and fibrosis was minimized, as a result of treatment with Avemar® (Figure 25, stained with H and E, magnified 300 times). Similar results were obtained in animals treated with indomethane and dexamethasone, which were used as positive controls. Semi-quantitative assessment of the degree of inflammatory infiltration in different groups is shown in Table 1. There was no significant difference between the groups pretreated for 24 hours or 14 days.

Table 1

Semiquantitative histological results of inflammatory infiltrates in AA rats untreated and treated with Avemar, indomethacin or dexamethasone

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Therefore, histological studies clearly indicate that Avemar® has anti-inflammatory activity.

Based on these results, it can be assumed that the development of rheumatoid arthritis can be inhibited by an appropriate dose of Avemar®.

Acute or subacute toxicity tests performed according to GLP (Good Laboratory Practice) show that, in contrast to steroidal and nonsteroidal anti-inflammatory compounds, Avemar® does not have any toxic effect, including erosive gastritis and acute gastric ulceration (Exhibit: Acute oral toxicity test of Avemar® in mice, code: 9901. Univ. Vet. Sci., Dept. Pharamcol. Toxical., Budapest, 1999; Acute oral toxicity test of Avemar® in mice, code: 9902. Univ. Vet. Sci., Dept. Pharamcol. Toxical., Budapest, 1999 , 1999; Avemar® subacute toxicity test, code: 0001. Univ. Vet. Sci., Dept. Pharamcol. Toxical., Budapest, 2000). Furthermore, the preparation was not genotoxic in the mouse bone marrow mucronuclear test.

Based on the experimental results, it is suggested that Avemar® may be a suitable therapeutic tool in the treatment of rheumatoid arthritis in humans. According to this, the treatment of other immunopathological diseases can also be considered.

Effect of Avemar® on rheumatoid arthritis in humans

Refractory patients suffering from rheumatoid arthritis were treated with Avemar® at the Department IV of Rheumatology and the National Institute of Rheumatology and Physiotherapy (Budapest, Hungary). The aim of these open clinical trials with self-monitoring is to evaluate the efficacy, tolerability and side effects of Avemar®. The following experimental results were obtained during the one-year treatment of 15 patients.

A. Patient selection

15 outpatients classified as Steinbrocker anatomic grade II to III were shown to have RA based on their ACR criteria classification participating in the trial. Their RA had stagnated or worsened with therapy that was administered 3 months prior to starting Avemar® treatment. The patients agreed to participate in the trial.

B. Exclusion criteria

- age below 18 and above 80 years,

- serious liver, heart, kidney disease of hemopathic organs,

- active stomach ulcer,

- mental illnesses, mental retardation,

- lack of cooperation,

- pregnancy or lactation.

If the preparation is inactive, meaning that there is no expected improvement after 3 months, the administration will be stopped.

C. Test course

In addition to the original medical treatment (basic therapy, steroid and NSAID), 15 patients with RA received a daily dose of 2x9 g of Avemar® dissolved in water (9 g in the morning and 9 g in the evening). Patients were checked at the beginning of treatment and every month, their statistical evaluation was carried out after one month, and after 6 and 12 months.

D. Tested parameters:

The clinical parameters of the test are as follows:

- Ritchie index,

- HAQ (Health Assessment Questionnaire),

- duration of morning ankylosis expressed in hours,

- sedimentation,

- CPR,

- hematocrit value.

During the study, changes in the dose of steroids given were also recorded. The average age of the 15 women with RA who participated in the trial was 54.5 years (44-68 years) with an average disease duration of 8 years (3-25 years), and all but one patient was seropositive. At the beginning of the study, 10 patients received basic therapy, 1 patient was treated with sulfasalazine (Salazopyrin), 5 patients with methotrexate (Methotrexate, Lachema), 3 patients with cyclosporine (Sandimmun, Neoral), and 1 patient with chlorquinine (Delagil). 5 patients did not receive basic therapy: the previously applied basic therapy did not prove to be effective and/or caused side effects. At the beginning of the trial, 11 patients were given steroids, and the highest oral dose of steroids was 7.5-10 mg of prednisolone or an equivalent dose of methylprednisolone or dexamethasone. The characteristics of the patients are shown in Table 2.

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the results

Statistical calculations were performed using the Wilcoxon test. The results are shown in Tables 3 to 9.

Table 3

Change in the Ritchie index compared to the initial value

after 6 and 12 months

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Table 4

Change in HAQ compared to baseline at 6 and 12 months

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Table 5

Change in duration of morning ankylosis compared to baseline after 6 and 12 months

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Table 6

Change in sedimentation compared to the initial value after 6 and 12 months

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Table 7

Change in CRP levels

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Table 8

Change in hematocrit value

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Table 9

Change in steroid dose after 6 and 12 months

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4 patients did not receive steroid

In 5 out of 11 patients who took steroids, the initial dose of the drug was not changed; 2 patients reduced the initial dose by half and 2 patients from 7.5 to 5 mg. The dose of basic drug therapy in 4 patients in the 12-month tested period was changed: in one of the patients, MTX was increased from 12.5 mg to 15 mg, and in the other three, the cyclosporine dose was reduced from 175 to 125 mg, from 225 to 100 mg, from 200 to 100 mg. The dose was not changed in 5 patients.

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

The data show that treatment of therapy-resistant patients with RA with Avemar® produced surprisingly favorable results in the first six months. In the first six months, there was a significant improvement in all clinical parameters in patients, without exception; moreover, it was also possible to reduce the steroid dose in patients. At the end of the second half of the treatment, there was still a significant improvement in clinical parameters compared to the initial status.

Based on the above results, the subject of this invention is the use of fermented wheat germ (Avemar®) for the preparation of pharmaceutical compositions for the treatment or prevention or improvement of inflammatory conditions.

Preferably, Avemar® can be used to prepare pharmaceutical compositions useful for the treatment or prevention or amelioration of arthritis, more preferably rheumatoid arthritis.

A further subject of this invention is the process of preparing pharmaceutical preparations containing fermented wheat germ extract as an active ingredient which contains the preparation of said active ingredient with usual pharmaceutical additives for a pharmaceutical preparation for the treatment or prevention or improvement of inflammatory diseases.

Furthermore, it has been found that Avemar® can be preferentially administered together with other nonsteroidal (NSAID) type anti-inflammatory agents, such as diclofenac, ibuprofen, piroxicam, tolmetin, etc. As a result of simultaneous administration, the dose of NSAID type drugs can be significantly reduced, which is very suitable because of the toxicity of these drugs. For example, the simultaneous administration of diclofenac allows a 50% reduction of both agents, while at the same time obtaining a similar improvement effect.

Based on the above results, a further object of this invention is the use of fermented wheat germ extract (Avemar®) and another active agent, especially an anti-inflammatory agent for the preparation of a drug for the treatment or prevention or improvement of arthritis. According to the invention, a non-steroidal anti-inflammatory agent is preferably used as a second anti-inflammatory agent.

Furthermore, this invention also relates to a combined pharmaceutical preparation containing an effective amount of fermented wheat germ extract (Avemar®) in combination with another active ingredient, in particular an anti-inflammatory agent and a pharmaceutically acceptable carrier.

Preferred anti-inflammatory pharmaceutical compositions of the invention contain an effective dose of fermented wheat germ extract (Avemar®) and diclofenac.

The active ingredient used in the present invention can be formulated in several oral and parenteral dosage forms and administered for the treatment or prevention of rheumatoid arthritis. Generally, the active ingredient in this invention is from 5% to 95% by weight in the composition.

Pharmaceutically acceptable excipients used to obtain pharmaceutical preparations can be in solid or liquid phase. Examples of solid pharmaceutical preparations are as follows: powders, tablets, pills, capsules, sachets, rhomboidal medicinal formulations, suppositories and dispersible granules. Solid preparations include several additives such as thickeners, flavoring agents, solubilizing agents, glidants, suspending agents, binders, preservatives, tablet disintegrators or encapsulating agents.

As far as powders are concerned, the excipient is a fine powdered solid that forms a mixture with a finely dispersed active substance.

As for tablets, a carrier that has the required binding characteristics is mixed in the right proportion with the active substance and pressed into the required shape and size.

Preferably, powders and tablets contain 5% to 70% of the active agent. Examples of suitable excipients are: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, cyclodextrin, maltodextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low-melting waxes, butters, etc. The preparation includes the formulation of the active ingredient with an encapsulating substance as an excipient, resulting in a capsule in which the active ingredient with or without another carrier is surrounded by the excipient, which is later bound to the active ingredient. Sachets and rhomboid formulations of the drug are prepared in a similar way. Tablets, powders, capsules, pills, sachets and rhomboid formulations of the drug can be used for oral administration.

To obtain suppositories, low-melting waxes, for example, a mixture of glycerides of fatty acids or cocoa butter, are first melted and the active ingredient is homogeneously dispersed by mixing. Then the homogeneous mixture is poured into suppository molds of the appropriate size, they are left to cool and harden.

Liquid pharmaceutical preparations include solutions, suspensions, emulsions, syrups and elixirs, such as aqueous or aqueous and propylene glycol solutions. For parenteral injections, liquid pharmaceutical preparations can be formulated in an aqueous propylene glycol solution.

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

Suspensions suitable for oral administration can be prepared by dispersing the finely ground active ingredient in water together with a viscous material such as natural or synthetic gums, resin, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

Solid pharmaceutical preparations also include those intended to be converted into liquid preparations shortly before use for oral administration. Examples of such liquid pharmaceutical formulations also include solutions, suspensions and emulsions. In addition to the active ingredient, these pharmaceutical preparations may contain dyes, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, coagulators, soluble agents and similar substances.

Sterile preparations for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. The following substances can be used as solvents: water, propylene glycol, some types of propylene glycol, vegetable oils such as olive oil, injectable organic esters such as ethyl oleate. These preparations may also contain other additives, especially sliding agents, isotonic agents, emulsifiers, dispersing agents and stabilizers. Sterilization can be accomplished in several ways, including aseptic filtration, incorporation of sterilizing agents into the preparation, irradiation, or heat treatment. Sterile solid preparations can also be prepared, which are then dissolved in sterile water or any other medium for injection immediately before use.

Pharmaceutical preparations are preferably packaged in dosage units. In this form of medicine, the preparation is divided into dosage units, each of which contains a specific amount of the active ingredient. The dosage unit form may be a packaged preparation in which the package contains discrete amounts of the preparation such as packaged tablets, capsules, powders in vials or ampoules. The dosage unit form may also include capsules, tablets, sachets, lozenges, or a number thereof in a package.

The amount of active ingredient can be changed or can be adjusted between 1 and 1000 mg, preferably between 10 and 100 mg per unit dose of the preparation, and in accordance with the use and activity of the ingredient. Pharmaceutical preparations may, if necessary, also contain other compatible therapeutic agents.

The effectiveness of the dose of the composition administered in this invention and the dosage to prevent, reduce or suppress arthritis depends on a number of factors. Suitable doses should be determined by a professional. In general, the doctor determines the appropriate dose depending on the age, body weight and other individual factors of the person being treated. The daily dose level will be between about 0.1 and 1000 mg/kg body weight, preferably about 1 to 500 mg/kg/day, and more preferably about 50 to 250 mg/kg/day. For safety reasons, the entire daily dose can be divided and given in portions during the day, and if necessary.

When the pharmaceutical preparation contains an active ingredient other than Avemar®, another agent can be selected from the following groups: corticosteroids, anti-inflammatory agents, antirheumatic agents, immunosuppressants, antimetabolites and immunomodulators. A list of compounds falling into these categories can be found in the following publication: "Comprehensive Medicinal Chemistry", Pergamin Press, Oxford, 970-986 (1990). This group includes, for example, sulfasalizine and aminosalicylates (anti-inflammatory agents), cyclophosphamide and methotrexate (antimetabolites), dexamethasone, methylprednisolone, triamcinolone, prednisolone (steroids) and interferons (immunomodulators). When Avemar® is administered in combination with one or more agents, they may be packaged together or may be given in combination. Administration of one or more agents in combination with Avemar® is carried out together or one after the other. An expert can determine the most suitable method of administration, depending on the release of funds, the desired result and the condition of the patient being treated.

In view of the entirety presented herein, those skilled in the art will recognize that this representation is only exemplary, so that various alternatives, adaptations and modifications are within the scope of the invention, and are contemplated, rather than defined in the following claims.

Claims (10)

1. The use of fermented wheat germ extract (Avemar®), indicated that it is for the preparation of a medicine for the treatment or prevention or improvement of arthritis. 2. Use according to claim 1, characterized in that the arthritis is rheumatoid arthritis. 3. Use of fermented wheat germ extract (Avemar®) and an anti-inflammatory agent, indicated to be for the preparation of a drug for the treatment or prevention or improvement of arthritis. 4. Use according to patent claim 3, characterized in that the anti-inflammatory agent is a non-steroidal anti-inflammatory agent. 5. Use according to claim 4, characterized in that the non-steroidal anti-inflammatory agent is dilcofenac. 6. A pharmaceutical composition, characterized in that it contains an effective amount of fermented wheat germ extract (Avemar®) in combination with an anti-inflammatory agent and a pharmaceutically acceptable carrier. 7. Pharmaceutical preparation according to patent claim 6, characterized in that the anti-inflammatory agent is a non-steroidal anti-inflammatory agent. 8. Pharmaceutical preparation according to patent claim 7, characterized in that the non-steroidal anti-inflammatory agent is dilcofenac. 9. A method of treating or preventing or ameliorating arthritis in a mammal, including humans, comprising administering to said mammal in whom such treatment or prevention or amelioration is desired, an effective amount of fermented wheat germ (Avemar®). 10. The method of claim 9, characterized in that it further comprises the administration of an anti-inflammatory agent.