DE19518156C2 - Use of deproteinized hemodialysate - Google Patents

Description

The invention relates to the use of deproteinized hemodialysate according to the preamble of the claim 1.

Osteoarthritis is one of the most common illnesses apparatus, with about half of all men from the age of 35 arthrotic changes in the Has joints. Accordingly, one strives, Thera pien to develop with which osteoarthritis curable or at least least to slow the change in the articular apparatus is.

As a general measure, adequate immobilization can be used of the affected joints. Above all, it is important an avoidance of traumatization of the joint or of Overloading of affected joints, this also affects Ge weight reduction, especially when the joints of the un upper limb or spine. Wich The avoidance of static incorrect loads also appears to be important stungen, d. that is, posture needs to be checked Posture in the workplace, or corresponding compulsory postures Getting corrected.

Orthopedic aids are e.g. B. Deposits on incorrect deposits available to choose from, there are also elastic knee caps or rail sleeve devices, corsets, crutches, etc. to disposal. Any existing circulatory disorders, mainly on the lower extremities, of course also treated.

The so-called physical therapy measures the physiotherapy exercise treatment in the foreground, d. i.e., the stretching of contracting muscles near the joint continues strengthening these muscle groups. The important thing is  Expansion of joint capsules so that there is no stiffening gene and arthrosis development.

Massages can also be used, this elegantly Lich to improve the lo kalen blood circulation. Packs and have also proven themselves Wrap, e.g. B. mud, paraffin or bog packs.

In the case of acute inflammation and acute irritation with Joint swelling is an ice therapy of the infested ne joint indicated. Furthermore, thermal exercise machines or electrotherapy, e.g. B. ultra-short wave treatment, Ultrasound or diadynamic currents can be applied.

Surgical therapy is generally for the Swiss Reserved in other cases, with part of the surgical therapy to correct the malposition of the ex tremors is used. A common surgical The Therapy is the so-called removal of the synovia, i.e. i.e. the Joint skin that is crucial for inflammation and Swelling of the joints is responsible. However, this will only used in more severe cases. Position corrections by changing the axes of the bones should just if performed if the deformity the Ursa progressive osteoarthritis. For those already in End-stage osteoarthritis stands for a lot today number of joints a partial or total joint replacement to disposal.

In the following, we will focus on drug therapy be gone.

By using so-called non-steroidal anti-rheumatism On the one hand, tika can be used as an anal have a toxic effect, the pain is considerably reduced can continue due to the anti-inflammatory effects These medications eliminate the joint effusion.  

These drugs can be taken both in oral and in pa renteral form. You will only be in one late stage osteoarthritis used, d. i.e. if already Changes in the area of the synovia are present their cause is the breakdown of the articular cartilage in arthrosis to have. That is, here you can essentially only symptomatic become active, causal therapy is no longer an option handle of these drugs. The general adjunct of these so-called non-steroidal anti-inflammatory drugs are known. They cannot be used for gastric Intestinal complaints, if you are predisposed to an allergic reaction such as B. asthma bronchial, hay fever, etc. Furthermore caution is advised in children, with high blood pressure, elderly ren patients and renal insufficiency.

Side effects can include severe hypersensitivity disorders Skin disorders occur, central nervous disorders stanchions, visual disturbances, hearing disturbances, gastrointestinal disturbances stances, liver dysfunction, sodium and water disorders genes, as well as hyperkalaemia. There are also About sensitivity reactions in the area of the immune system. Egg a variety of interactions with other medications is known.

Part of these so-called non-steroidal anti-inflammatory drugs can also be used in ointment form, this leads to egg a certain swelling of the joints, but here too a causal therapy is not possible. The above already be Written side effects can be found here, however in redu graced form, also occur.

Another form of therapy is the application of Corticosteroids. The intra-articular steroid treatment should only be used in certain suitable cases activated arthrosis. Essentially the inflammation on the joint is reduced  capsule. Of course, this is associated with a reduction in unwanted joint effusion. Problematic with the cor tisontherapy is an activation in case of overdose the inflammation can be caused, it continues the cortisones themselves break down the cartilage matrix comes and thereby overall in a deterioration of in the arthrosis already unfavorable situation of the Cartilage metabolism results. To general ancillary cortisone therapy changes in the area to hold on to the stomach and intestines, a för change in osteoporosis, muscle weakness or aseptic Bone necrosis. Skin is also often clearly visible changes with bleeding, acne, or delayed wounds lung. With a higher dosage, a full moon face or fat add sodium is retained and the potassium ver reduces excretion. Hypertension can occur the risk of thrombosis is also increased.

The use of pure pain relievers without so-called anti-inflammatory Effect is only indicated for severe pain, especially in the case of osteoarthritis, which is otherwise no longer treatable. she are in this context, d. that is, at the idea of an in traarticular antiarthrosis agent not interesting.

Another group of drugs has a so-called regene effect on cartilage metabolism. It stays to note that the arthrosis begins at the articular cartilage. So if causal therapy should be done then in the area of the articular cartilage, d. that is, at the beginning arthrosis. All previously described therapy shapes are more likely to be activated or later Apply osteoarthritis in the early stages of osteoarthritis are the drugs that we use on cartilage metabolism ken, indexed.

One is in the knowledge of the cause of osteoarthritis still not clear, but one thing remains  to note that by genetic factors or by Irritation factors lead to inactivation of performance of the chondrocyte, i.e. the active cartilage cell. Of there is obviously a change in the type of collagen, so that the initially intact cartilage suddenly breaks open and becomes vulnerable. So-called superficial then arise Cartilage erosions, there is a breakdown of cartilage-specific Substances and thus irritation of the synovia, d. that is the joint capsule. In this area, if the cartilage erosion begins, cartilage protection therapy would be indicated. The currently most widely used preparation is the so-called Hyaluronic acid, a polysaccharide that comes from cockscombs is won. This cartilage-specific substance is said to exist can be built into the cartilage and thus the Proteo Increase glycan binding. When the hyaluronic acid in the knor pelmatrix is installed, there would be a normalization the water content and elasticity of the cartilage. Next there is an influence on the synovial membrane and the syno vial fluid described, the viscosity is said to be increased, inflammatory cells blocked and thus the pain reduction can be initiated.

Side effects are known here that pain on the Puncture site and in the joint area can occur. It are a large number of patients who do not use the product tolerated and react with a significant feeling of heat, white It is not uncommon for there to be an increase in fluid in the joints speed with considerable overheating and swelling of the Ge steer. This drug still exists no long-term experience.

This is another form of cartilage protection therapy Glucosamine sulfate. In the meantime, however only available as an oral form and as an intramuscular form ten, the intra-articular form has been withdrawn from the market because of too many side effects. A clear stimulation of hyaluronic acid is also intended here  resynthesis take place. With increasing hyaluronic acid comes it to the positive effects in the joint described above.

Another preparation, which, however, in the meantime from Is glycosaminoglycan polysulfate (Arteparon®). Here too there would be an increase in Hyaluron concentration has been observed, however it did joint bleeding in many patients, so this Preparation no longer exists on the market. The same applies to the superoxide dismutase (Peroxinom®), this preparation is in the meantime also withdrawn from the market, since it means To cases have been observed.

There are still a variety of homeopathic substances the parenteral form partially injected into the joint be decorated (e.g. Zeel®, Traumeel®), of which Me medication not scientifically stable clinical study services exist, respectively the biomechanical / biochemical Effectiveness is not known.

Are on therapy with an antiarthrotic substance to make the following requirements:

The drug should control the structure and metabolism of the Hyaluronate, proteoglycans and collagen in syno normalize and stabilize the vial system. It should have the ability to break down the hyaluronate, the proteo glycans, collagen and other matrix building blocks in syno inhibit vial system and continue inflammatory response that occur during the activated phase of osteoarthritis can stop.

These requirements are not being met by anyone at the moment antiarthrotic substances on the market fills.

In contrast, the invention is based, ei to find an active ingredient that is used to treat arthrosis is suitable and the above-described side effects does not have or at least to a reduced extent.

This object is achieved by the features of patent claim 1 solved.

By using a deproteinized according to the invention ten hemodialysates, preferably from calf blood, for loading osteoarthritis becomes a highly effective joint protector droprotektivum provided, the active ingredient be has long been for completely different areas of application is available on the market and that according to the ge experiences made practically no side effects points. In DE-PS 10 76 888 a method for Preparation of a hemodialysate from the blood of slaughter animals described.

Particularly good effect in antiarthrotic therapy could with a preparation based on deproteinized hemodialysate from calf blood with low molecular weight pep tides and nucleic acid derivatives can be achieved. A derar active ingredient is sold under trade names such as Actovegin®, Actihaemyl® or Solcoseryl® or Heractyl® sold. The hemodialysate is obtained by ultrafiltration where through a protein, pyrogen and antigen free product will hold. After ultrafiltration they contain the above mentioned preparations according to the manufacturer in addition to inorganic connections such as electrolytes and essential spu 30% organic elements, including Ami noacids, intermediate products of carbohydrate and fat metabolism, oligopeptides, nucleosides and glycolipids.

Due to the ultrafiltration, the molecular weight of the organic compounds below 10,000 daltons.

The preparations mentioned above were previously on different areas of application, for example at zere  bralen metabolic and circulatory disorders (cerebral Deficiency Syndrome, Ischemic Insult, Skull-Brain Injury), peripheral circulatory disorders (arterial angiopathy, Ulcus cruris (arterial, venous)), wound healing (ulcers and different origins, trophic lesions (pressure ulcers), Secondary healing, corneal and conjunctival lesions), Burns, scalds, burns and radiation craze skin, mucous membrane, nerve tissue with success turns.

Furthermore, the preparation is also used successfully in the Sports medicine applied to the hei in case of an injury shortening the process. In particular, he was successful aims at Achillodynia and in the treatment of mus torn fiber.

With regard to further details on the previous application of the The above-mentioned preparations are based on the existing specialist information cations of the manufacturers of the above-mentioned preparations sen.

However, the specialist literature contains no evidence that that the above-described hemoderivate also in therapy can be used by osteoarthritis.

The investigations of the inventor made it possible for the first time demonstrated that the use of the hemoderivative surprisingly shows an antiarthrotic effect. As will be explained in more detail below, showed the investigations continue that through the intra-articular Injection of an Actovegin® / glucose solution not to he waiting effect on pain reduction and swelling inclination of the joints was observed. This could be due to of the existing indications are not expected, so that here there is obviously a mechanism of action that was unpredictable and cannot be fully explained can. It was also surprising that the patients had a clear  aching subjective relief regarding her night ache or their movement pain.

The use of deproteinized hemo according to the invention dialysates therefore represents a completely new approach antiarthrotic therapy.

Of course, the invention is not hemodialy sate from calf blood limited, it is also the use blood of other species possible.

Depending on the type of application, the hemoderivative can be used as an additive to isotonic sodium chloride solution, glucose solution or usual infusion solution can be used.

Particularly good results were achieved when the Hä moderate as an intra-articular injection into the affected Joint was administered, with the In ejection solution advantageously from a volume fraction Hemodialysate, for example 1.5 ml and 2 parts by volume 5% glucose solution, i.e. 3 ml.

A treatment interval spans approximately 55 to 60 Days, with an In. Advantageously every 3 to 4 days jection should take place.

Advantageous developments of the invention are the subject of other subclaims.

The following is the antiarthrotic effect of hemodia lysates explained using some schematic diagrams. It demonstrate

. Figure 1 shows the development of spontaneous pain within a Be treatment interval;

Figure 2 shows the development of night pain within the treatment interval.

Fig. 3, the resting pain development within the treatmen averaging interval;

. Figure 4 shows the Gelenkergußentwicklung within the treatmen averaging interval;

Fig. 5, the morning stiffness development within the treatment interval, and Be

Fig. 6 is a diagram from which the overall assessment of the treatment success by doctor and patient can be seen.

A clinical study was carried out to demonstrate the antiarthrotic effect of the deproteinized hemodialysate. Patients aged 24 to 70 years with inflammatory, non-inflammatory and post-traumatic knee joint arthrosis were enrolled in this study, who were not radiologically more pronounced than stage 111 according to Kellgren. The overall clinical picture of osteoarthritis was rated on a 3-point scale with light, medium and severe analogous to the ARA criteria.

Pregnant women and style were not included in the study loin, patients with allergic diathesis (especially against the investigational medicinal product), patients with an uncertain con protection against reception, patients with acute infectious disease, Diabetics, hemophiliacs and patients within three An intra-articular injection months before enrollment have received. The study was monocentric, open, and not randomized.

All patients received eight intra-articular injections to the knee joint. The injection consisted of a Mi  1.5 ml hemodialysate solution for injection plus 3 ml 5% glucose solution, i.e. in a mixing ratio of 1: 2 Dilute the hemodialysate ampoule solution with 5% gluco The reason for this was that the hemodialysate solution hy is pertonic and can lead to synovial irritation in the joint. Deproteinized hemodialy was used in the clinical test sat from Nycomed Arzneimittel GmbH, which in Germany sold under the trade name "Actovegin" ® becomes.

The injections were made three or four days apart An additional therapy to influence the patient picture was not allowed. The effectiveness of loading action was due to clinical parameters at three times ten (7th to 8th day, 28th to 29th day, final examination 56th to 57th day) by comparison with the initial situation (Beginning of treatment) checked.

The main clinical parameter for assessing the The effectiveness of the treatment was spontaneous pain (in space day), measured with a visual analog scale (so-called Dolo meters: scale from 0 = no pain to 10 = very strong Pain). Other parameters were night pain and pain at rest (graduation: absent, easy, medium, strong). Furthermore, the amount of joint effusion (measured in ml), morning stiffness (expressed in minutes), exercise extent (measured in degrees of active flexion and extension). At the The overall assessment by doctor and patient ended (very good, good, sufficient, bad). At all times the compatibility was checked.

The average age of the patients examined was 50.4 years, 13 women and 7 men participated in the study part. The average duration of illness was 9.7 months with a range between 2 and 24 months. The clinic overall picture was four times with easy, twelve times with tel and rated four times as difficult. The radiological loading  The knee osteoarthritis was rated ten times grade 1, six times Grade 2 and four times grade 3.

The main confirmatory goal of the study was spontaneous pain, as measured by the patient using a visual analogue scale. Referring to FIG. 1, the pain index was reduced from an initial average value of 7.75 to 2.25 at the end of the study (day 56-57), the drop between the 2nd and 3rd, and 3rd and 4th day of examination was most .

The night and rest pain was indexed in the evaluation as follows: missing = 0, slight = 1, medium = 2, strong = 3. As can be seen from FIGS. 2 and 3, there was a pain reduction of a mean value of for both parameters 1.5 to 0.4 (night pain Fig. 2) and 0.35 (rest pain Fig. 3). The decrease was roughly linear.

The joint effusion shown in Fig. 4 is an important parameter for assessing an inflammatory component in the joint. At baseline, the mean was 10.15 ml, with a range between 0 and 40 ml. At the end of the study (56/57 days) there was a mean of 1.2 ml, with the drop being almost 50% in the first week of treatment wore.

As can further be seen from FIG. 5, the duration of morning stiffness (measured in minutes of restricted joint mobility until free mobility) was initially 2.4 minutes on average and 1.0 minutes at the end of the treatment. Towards the end of therapy, the improvement in mobility was most pronounced (see graphic).

Regarding the improvement of the range of motion of the Ge steer (degree measurement in diffraction and extension to the respective towards the time of the examination) there was a tendency to increase the ability to bend and stretch,  However, this could not be evaluated statistically will.

At the end of the study there was an evaluation of the therapy by the doctor and the patient. The doctor then judged the success of the treatment to be very good eight times and the patients fourteen times. The doctor rated nine times as good and the patients five times. The doctor saw only three successes, only one patient once. Thus, the doctor saw a good or very good success in 17 patients, whereas 19 patients considered the therapy assessment good or very good (see Fig. 6).

Side effects of the medication administered could not are found, d. that is, the tolerance was gone draws.

In summary, it can be stated that the intra-articular Injection therapy with Actovegin® in combination with 5% glucose solution in this study made a significant reduction the measured pain parameter still showed the Ge Steering inflammation (joint effusion) can be significantly reduced could. Thus, the drug Actovegin® can be effective Joint chondroprotective are considered.

In view of these results and knowing the previous clinical application areas of deproteinized Hemodialysate from calf blood can be suspected that in Early stage of joint arthrosis, which with death of the Cartilage cells go hand in hand with the nutrition of the chondrocytes Glucose has a significantly disease-delaying effect. The chondrocyte is one of the most glycogen-rich cells in the human body, synthesized from simple sugars, Fatty acids and amino acids the proteoglycans and gly coproteins, which are the important basic sub-cells in the extracellular space represent punch of the cartilage.  

The apparently proven activation of glucose transportes into the cell through ingredients from deprotei Accordingly, the applied hemodialysate appears through the appliqué tion of the drug in the interior of the joint as cartilage protective therapy to be meaningful. The simultaneous In Injection of glucose increases the articular availability of this important cellular building block and energy suppliers.

The main side effects of the preparation are so far not known. In the case of glucose and actove Twenty patients could also be treated no side effects were determined during intra-articular therapy be put.

In summary, it should be noted that the intraar ticular injection of the deproteinized hemodialysate Calf blood is an unexpected, surprisingly antiarthrotic effect occurred.

Although intra-articular In injections are used, the invention is not based this application is limited, but basically other types of application (infusion, ointment, etc.) applicable.

Claims (6)

1. Use of deproteinized hemodialysate, for loading treatment and / or prophylaxis of joint arthrosis. 2. Use according to claim 1, characterized by the treatment of inflammatory and / or not ent inflammatory joint arthrosis. 3. Use according to claim 1 or 2, characterized ge indicates that the hemodialysate low molecular weight An parts with a molecular weight below 10,000 daltons contains. 4. Use according to one of the preceding claims che, characterized in that the hemodialysate ver is thin. 5. Use according to claim 4, characterized by a composition of a volume fraction of hemodialy sat and 2 parts by volume solution. 6. Use according to one of the preceding claims che, characterized in that a hemodialysate Calf blood is used.