Substances usable for treating psoriasis cases
SUBSTANCE: method involves administering diacerine influencing DNA synthesis for reducing keratinocytes proliferation without changing their vital activity, inhibiting interleukines IL-1,IL-6 and α-TNF (tumor necrosis factor).
EFFECT: enhanced effectiveness of treatment.
11 cl, 7 dwg, 2 tbl
The technical field to which the invention relates.
The invention relates to substances intended for the treatment of psoriasis and related diseases.
The level of technology
Psoriasis is a heterogeneous chronic inflammatory skin disease of unknown etiology.
The prevalence of psoriasis in the world human population is estimated at 2-3%, and psoriasis varies from a minimum of lesions on the elbows and knees to a large number of lesions scattered throughout the skin, with equal defeat men and women.
Psoriasis can appear on any part of skin on the elbows, knees, head and nails.
Most patients with psoriasis vulgaris is manifested in mild or moderate and affects less than 20% of the surface of the skin.
Classic psoriasis manifests itself in the form of papules (nodules and plaques with layers of scales, and these damage eritematosny, covered with a layer of silvery-white scales and clearly separated from the surrounding skin.
However, psoriasis may manifest in various forms and may be accompanied by various forms of inflammatory arthritis, including asymmetric oligoarthritis, symmetric arthritis, spondylitis and arthritis deformans.
For example, estimates psoriatic arthritis affects from 2.7 to 7% of the total population of patients with psoriasis and in most cases it appears the I in a few years after the onset of psoriasis.
Histologically, psoriasis is characterized by epidermal hyperproliferative/hyperplasia, resulting from infiltration of inflammatory keratinocytes in the skin, enhanced vascularization and release of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and α-TNF.
The etiopathogenesis of psoriasis related arthritis (PsA) is still not a complete explanation, but it is recognized that an important role in the development and manifestation of these diseases play genetic, immunological factors and environmental factors.
The role of genetic factors in the etiology and pathogenesis of psoriasis and related psoriatic arthritis is confirmed by the studies on twins, presents Espinoza LR in "Proceedings of the XIX ILAR Congress of Rheumatology 1997, Singapore, pp.262-263".
Research in this area also indicate a direct role of the immune system in the pathogenesis of psoriasis and associated psoriatic arthritis.
First of all, the presence of lymphocytes CD4+ and CD8+ in the skin and synovial membranes means that these cells are involved in these diseases.
In addition, the role of the immune system, particularly T cells, indicative action immunosuppressing drugs on the inflammatory process in psoriasis in the skin and synovial membrane, and some immunosuppressive drugs, including methotrexate and cyclosporine A, in which SIMA effective in the treatment of psoriasis and associated psoriatic arthritis.
In addition, Espinoza showed that psoriatic fibroblasts contribute to the inflammatory and proliferative changes seen in psoriasis and associated psoriatic arthritis.
Psoriatic skin fibroblasts and synovial membrane are changes in cell cycle and DNA in response to growth factors cause increased expression β-receptor for the growth factor from platelets (PDGF) and synthesis of interleukins IL-1β, IL-8, PDGF, and constitutively Express IL-6.
This means that when psoriasis and associated psoriatic arthritis former pressurewise IL-1β, IL-6 and IL-8, which are Pro-inflammatory cytokines.
Further, in the synovial fluid of patients with psoriasis related arthritis were found high levels of tumor necrosis factor (α-TNF), IL-1, IL-6 and IL-8.
The currently used methods of treatment of psoriasis can be divided into three main categories: topical treatment, phototherapy and systemic therapy (cyclosporine, methotrexate, oral retinoids).
Described a large number of pharmaceutical compositions used in the treatment of psoriasis with varying degrees of success, often accompanied by undesirable side effects.
Moreover, the currently used methods of treatment of psoriasis is not able to heal Zabol the sámi and their purpose is only to reduce the severity and distribution of lesions.
Until the present invention no effective therapeutic method for the treatment of psoriasis and related conditions, such as psoriatic arthritis.
Taking into account the severity of psoriasis and related diseases and the relatively high prevalence of them in the General human population, and given that psoriasis is described and explored from the beginning of the nineteenth century, there is a tangible long-awaited need for effective therapeutic method for the treatment of psoriasis and related diseases.
The purpose of the present invention is to obtain substances, applicable in the treatment of psoriasis and related diseases.
According to the present invention this objective was achieved as a result of unexpected discoveries in the treatment of psoriasis and related diseases has proven useful diacerein.
Diacerein, also known as diacetylene or 4,5-bis(atomic charges)-9,10-dihydro-9,10-dioxo-2-astratenkova acid (see The Merck Index, Twelfth Edition, 1996, Product No. 3003, pages 501-502), is an anthraquinone derivative and has the following structure:
It is known for its use in the treatment of rheumatoid arthritis and osteoarthritis, as described, for example, in US-A-4244968 (Prof. C.A. Friedman), EP-B-0520414 (Madaus AG) and EP-B-0636602 (Laboratoire Medidom S.A.).
Varied is oppozitsii for parenteral or oral administration of derivatives of diacerein.
Useful preparation for oral administration is described, for example, in EP-A-0264989.
At that time, as diacerein and its derivatives were considered as useful for the treatment of rheumatoid arthritis and osteoarthritis, which seriological to rheumatoid factor, to date they have not been examined in the treatment of psoriasis and related diseases type of psoriatic arthritis, which thereotically to rheumatoid factor.
The mechanism of action of diacerein and its derivatives in the treatment of psoriasis related arthritis (PsA) is not entirely clear, however, it was shown that diacerein and its active metabolite failure to comply inhibit the synthesis and activity of Pro-inflammatory catabolic cytokine family, IL-1, particularly IL-1βand antagonists of the receptor for IL-1 (IL-1 ha)and inhibit IL-6 and other cytokines - α-TNF and LIF.
Therefore, it is assumed that the above-mentioned effects of diacerein on cytokines are one of the possible explanations for its effectiveness in the treatment of psoriasis, as in the synovial fluid of patients with psoriasis and psoriatic arthritis have high levels α-TNF, IL-1, IL-6 and IL-8.
One aspect of the present invention concerns the application of diacerein or its pharmaceutically acceptable derivative to obtain a pharmaceutical composition for the treatment of psoriasis and tie is the R with them diseases.
Another aspect of the present invention concerns the application of diacerein or its pharmaceutically acceptable derivative to obtain a pharmaceutical composition for the treatment of psoriasis.
Another aspect of the present invention concerns the application of diacerein or its pharmaceutically acceptable derivative to obtain a pharmaceutical composition for the treatment of psoriasis and psoriatic arthritis.
Another aspect of the present invention concerns the application of diacerein to obtain a pharmaceutical composition for the treatment of psoriasis.
Another aspect of the present invention concerns the application of diacerein to obtain a pharmaceutical composition for the treatment of psoriasis and psoriatic arthritis.
Another aspect of the present invention relates to a method of treatment of psoriasis, which includes the introduction of a pharmaceutical composition containing an effective amount of diacerein or its pharmaceutically acceptable derivative.
Another aspect of the present invention relates to a method of treatment of psoriasis and psoriatic arthritis, which includes the introduction of a pharmaceutical composition containing an effective amount of diacerein or its pharmaceutically acceptable derivative.
The present invention satisfies a long-awaited need, providing persons the NGOs for effective treatment of psoriasis and related diseases through the application of diacerein or its pharmaceutically acceptable derivative.
The advantage of using diacerein is that it is well tolerated and does not show Carcinogenicity because diacerein is already widely used for the treatment of osteoarthritis and rheumatoid arthritis and was subjected to extensive Toxicological studies.
Another advantage of diacerein is that it does not affect the formation of prostaglandin PGE2 and therefore does not have gastrointestinal properties.
Other advantages of the present invention will become apparent from the subsequent detailed description.
In the present invention can use any diacerein with a sufficient degree of purity for use in pharmaceutical compositions.
According to the Merck Index, Twelfth Edition, diacerein can be synthesized in accordance with A. Tschirch, C. Heuberger, Arch. Pharm. 240, 596 (1902); V.K. Murty et al., Tetrahedron 23, 515 (1987).
Known compositions containing diacerein is, for example, Artrodar®, Art50®, Zondar50®, Fisiodar®, Artrofast®, Verboril®, Matrix®, Cartivix® and Artrolyt® distributed in France, Italy, Greece, Portugal, Israel, Brazil, Argentina and Peru company Laboratoire Medidom S.A. (Geneva) or the license of this company), and these compositions do on sale for the treatment of osteoarthritis.
Several ways of obtaining diacerein by extraction or synthesis are protected by patents or patent applications which, owned by or licensed to them is the company Laboratoire Medidom S.A. (Geneva) (see for example EP-B-0636602 and ER-IN-0520414).
In the present invention can be any pharmaceutically acceptable derivative of diacerein, in which the acid group of diacerein is in the form of a salt or ester.
Non-limiting examples of derivatives of diacerein that can be used in the present invention include the salts of alkali or alkaline earth metals, for example salts of sodium, potassium, magnesium, calcium, etc. and ethers alcohols C1-C6such as methanol, ethanol, etc.
However, preferably used diacerein.
In the present invention of diacerein preferably receive pharmaceutical compositions intended for oral administration.
Pharmaceutical compositions intended for oral administration, is the syrups, tablets, capsules, etc.
When the pharmaceutical composition is intended for oral administration, the dosage preferably are in the range of 30-200 mg / day, more preferably 100 mg per day.
The daily dose is preferably take at least two steps.
Especially effective dosage of diacerein when administered for the treatment of psoriasis 100 mg twice a day for at least 6 months.
Pharmaceutical compositions containing Dieter the Institute or its pharmaceutically acceptable derivatives, can also be written in the form of a cream or ointment for topical application to areas of skin affected by psoriasis, for example hyperkeratosis areas.
When the pharmaceutical composition is intended for topical application, the dosage of the composition and frequency of application is chosen based on considerations of efficiency.
Pharmaceutical compositions containing diacerein or its pharmaceutically acceptable derivatives, can be obtained simply by mixing diacerein or its pharmaceutically acceptable derivative with the corresponding standard fillers and bringing the song to the appropriate pharmaceutical form or by any suitable conventional method.
Disclosure of the nature of the present invention will turn now to the detailed description of examples, including the experiments in vitro, clinical trials and shapes.
Brief description of drawings
On figa presents a graph showing the viability of keratinocytes after 24 hours after making diacerein in vitro, which was measured by the method of exclusion dye tripan blue.
On FIGU presents a graph showing the viability of keratinocytes through 96 hours after making diacerein in vitro, which was measured by the method of exclusion dye tripan blue.
On figa presented on agrama, showing the number of keratinocytes after 24 hours after making diacerein in vitro.
On FIGU presents a graph showing the number of keratinocytes through 96 hours after making diacerein in vitro.
On figa presents a graph showing DNA synthesis (incorporation3H-thymidine) within 24 hours after making diacerein in vitro.
On FIGU presents a graph showing DNA synthesis after 46 hours after making diacerein in vitro (enable3H-thymidine).
On figs presents a graph showing DNA synthesis at 72 hours after making diacerein in vitro (enable3H-thymidine).
On fig.3D presents a graph showing DNA synthesis through 96 hours after making diacerein in vitro (enable3H-thymidine).
On figa presents a graph showing the levels of IL-1 using ELISA method.
On FIGU presents a graph showing the levels of IL-1 using ELISA after 24 hours exposure to ultraviolet light UV-B.
On figa presents a graph showing the levels of IL-6 using ELISA method.
On FIGU presents a graph showing the levels of IL-6 using ELISA method after 24 hours exposure to ultraviolet light UV-B.
On figa presents a graph showing the levels of IL-8 by ELISA method.
On FIGU presents a graph showing the contents of the EL-8 using ELISA method 24 hours after irradiation ultra is the violet UV-B.
On figs presents a graph showing the levels of IL-8 by ELISA method after 24 hours of application α-TNF.
Figure 7 presents a graph showing the contents of α-TNF ELISA method after 24 hours exposure to ultraviolet UVB.
Evaluation of in vitro effects of diacerein on the proliferation of keratinocytes and analysis highlight the most important cytokines from keratinocytes after treatment with diacerein
Materials and methods
In these experiments used pure diacerein.
Culture of keratinocytes
The keratinocytes of the human epidermis was obtained from foreskin by separating strips of epidermis handling dispute II (5 mg/ml, for 60 min at 37°, Boehringer Mannheim, Germany).
The epidermis was incubated in 0.25% trypsin/0.02% EDTA for 20 minutes at 37°and were separated mechanically.
Suspension of epidermal cells were sown (2,5×104/cm2) treated with mitomycin C cells 3T3-J2 (2,4×104/cm2ADS, Rockville, MD, USA) and were grown in humidified atmosphere with 5% CO2in the medium for cultivation of keratinocytes, consisting of a modified Dulbecco eagle medium and medium F12 ham (a mixture of 3:1, Biochrom KG, Berlin, Germany) containing calf serum (10%, ICN Biomedicals, Aurora, Ohio), insulin (5 mg/ml, Sigma, St. Louis, MO, USA), transferrin (5 mg/ml, Sigma), adenine (0.18 mm, Sigma), hydrocortisone (0.4 mg/ml, Sigma), triiodothyronin (20 p is, Sigma), cholera toxin (0.1 nm, Sigma), the growth factor of the epidermis (10 ng/ml, Sigma), glutamine (4 mm, Sigma) and penicillin/streptomycin (50 U/ml, Biochrom).
In primary cultures, after the formation of a nearly continuous layer, the residual cells 3T3-J2 separated using 0.02% EDTA, and keratinocytes were trypsinization 0.05% trypsin/0.02% EDTA and re-sown at a density of 5×103cells/cm2treated with mitomycin C cells 3T3-J2 (2,4×104/cm2).
Secondary culture that formed a nearly continuous layer that has trypsinization as described above and were sown for experiments in serum-free environment of a particular composition (KGM, Clonetics Corp., San Diego, CA, USA).
Cell viability was determined by exclusion of the dye tripan blue.
Ultraviolet radiation UV-B
Ultraviolet radiation UV-B was performed using sets of lamps (TL 20W/12 RS UV-B Philips Medical) before and after treatment with diacerein. In other experiments the irradiation with ultraviolet light UV-B was performed only after the addition of diacerein. Before irradiation the cells were washed once with PBS and irradiated in the presence of PBS.
In control experiments conducted to simulate exposure of the same duration with the help of light radiometer International Light Research Radiometer (Newburyport, MA).
Determination of cell proliferation
Normal human keratinocytes (9000 cells/well) were grown in 96 tablets holes in the rede KGM and were treated by diacerein one or solvent.
Counting of cells was performed after 24, 48 and 96 hours. In addition, for 12 hours before harvesting the cells was the inclusion of3H-thymidine (1 µci/well, Amersham-Pharmacia Biotech, Rainham, UK) and collected cells after 24, 48, 72 and 96 hours.
Incorporation of radioactivity was measured on β-the counter.
Determine by the method of ELISA
Quantitative determination of the level of cytokines was performed quantitative dvuhsostavnogo enzyme immunoassay according to the manufacturer's instructions, using the ELISA kits for IL-1, IL-6, IL-8 and α-TNF.
The concentration of the samples was determined by absorption at 450 nm with correction at 540 nm.
Results and discussion
1. The viability of keratinocytes exclusion of tripan blue
In order to learn how diacerein effect on human keratinocytes, investigated possible changes in the viability of the exclusion of tripan blue. As can be seen from tiga and FIGU, increasing doses of diacerein did not cause significant changes in the viability of keratinocytes, in addition to the doses of 100 and 200 μm at 96 hours.
Thus, it is shown that diacerein does not affect the viability of keratinocytes.
2. Analysis of cell proliferation
To assess therapeutic effect of diacerein psoriasis in culture keratinocytes were made a number of doses of the drug and count the number of keratinocytes.
As can be seen from tiga, 24 chesapake processing the number of cells decreased significantly only when used doses ranging from 10 to 200 μm (p<0,05).
On the other hand, as can be seen from FIGU through 96 hours after treatment showed a clear dose-dependent decrease in the number of keratinocytes from 5 up to 100 μm of diacerein (p<0,05) (figa and 2B).
This result confirms the strong influence of diacerein on DNA synthesis. In particular, adding diacerein the inclusion of3H-thymidine was significantly decreased in a dose-dependent manner after 24 hours (10-200 μm), 48 (1-200 μm), 72 and 96 of 0.1-200 μm) hours after treatment (figa, 3B, 3C and 3D).
Collectively, these data indicate that diacerein is a strong inhibitor of proliferation of keratinocytes.
3. Analysis of the allocation of IL-1 using ELISA
IL-1 is expressed constitutively in human keratinocytes. The secretion of IL-1 was measured after adding the number of doses of diacerein.
As can be seen from tiga, in normal conditions diacerein had no effect on constitutive levels of IL-1 in keratinocytes.
Since it is known that ultraviolet light is the most powerful stimulator selection of cytokines, keratinocytes were irradiated with ultraviolet light UV-B before or after treatment with diacerein.
As can be seen from FIGU, UV-B caused a sharp increase in the excretion of IL-1, whereas diacerein prevented this effect 24 hours after irradiation. In particular, as can be seen from FIGU, diacerein had a greater effect when made and its exposure to UV-B.
It should be noted that the drug was able to inhibit the secretion of IL-1 almost to the initial level already at 0.1 ám.
4. Analysis of the allocation of IL-6 using ELISA method
In normal IL-6 is not detected in the keratinocytes at the constitutive level. Therefore, the excretion of IL-6 stimulated by irradiation with ultraviolet light UV-C.
Diacerein did not affect the level of IL-6 in the initial conditions (figa), however, he caused a reduction induced by UV-B allocation of IL-6 after 24 hours of exposure.
Diacerein was significantly more effective when it was added before and after exposure to UV-B. In fact, in this case, a significant reduction in the excretion of IL-6 was observed at a dose of 1 μm, then as required 5 μm of diacerein to reduce IL-6, when the drug was introduced only exposure to UV-B (pigv).
5. Analysis of the allocation of IL-8 by ELISA method
As in the case of IL-6 diacerein did not affect the level of IL-8 in normal conditions (figa). However, when the secretion of IL-8 stimulated by irradiation with UV-B, diacerein (5-100 μm) caused a significant reduction in the level of this cytokine in 24 hours. Again diacerein was more effective when it was made before and after exposure to UV-B (pigv).
Because α-TNF is a potent inducer of IL-8 in keratinocytes and plays an important role in the pathogenesis of psoriasis, investigated the impact of diacerein on IL-8 after stimulation of keratinocytes α -TNF. Only high doses of diacerein (50-200 μm) reduced induced α-TNF allocation of IL-8 in keratinocytes (figs).
6. Analysis of discharge α-TNF ELISA method
As indicated above, α-TNF is of great importance in the pathogenesis of psoriasis. Therefore, we decided to investigate the influence of diacerein allocation of this cytokine from human keratinocytes.
Diacerein was reduced induced by UV-B selection α-TNF only at high doses (50-200 μm) (Fig.7).
The above in vitro experiments show that diacerein can act on two of the most important pathogenetic factors leading to the appearance of psoriatic lesions, the proliferation of keratinocytes and changes in the system of cytokines.
These experiments showed that in therapeutic doses diacerein strongly inhibits proliferation of keratinocytes dose-dependent manner, and that already at 0.1 μm diacerein inhibits the release of IL-1 almost to the initial level.
In addition, these experiments showed that diacerein decreases significantly induced by UV-B secretion of IL-6, IL-8 and α-TNF, which play a role in the pathogenesis of psoriasis.
Clinical trials showing the efficacy and safety of pharmaceutical compositions containing diacerein in the treatment of psoriasis and psoriatic arthritis
The aim of this study was to evaluate the efficacy and safety of diaze Eina in the treatment of psoriasis with light or moderate psoriatic arthritis.
The pharmaceutical composition
Study drug - Artrodar® (Laboratoire Medidom S.A., Geneva) is a hard gelatin capsule 1-th size.
Each capsule contains:
|lactose, monohydrate||214,5 mg|
|crosscarmellose sodium||11,5 mg|
|polyvidone C||11,5 mg|
|colloidal silicon dioxide||11,5 mg|
|magnesium stearate||1,2 mg|
Capsule shell has the following composition:
base: white, opaque (002)
|titanium dioxide||0,5434 mg|
finish: dark green, opaque
|FD&C blue No. 2||0,4106 mg|
|yellow iron oxide||0,0272|
|dioxide titanium||2,3041 mg|
Tests were conducted on 10 patients that met the inclusion criteria and exceptions.
male or female, under the age of 18 years who have:
- psoriasis affected certain areas of the skin with a specific severity index (PASI<15);
- the mouth of icily negative result on rheumatoid factor by latex test or ELISA;
- diagnosed with psoriatic arthritis mild or moderate severity for at least 3 months with signs of oligoarthritis (affected<4 joints) and/or spondylitis;
normal results normal and clinical blood analysis (ROE 1 hour<30 mm, the number of leukocytes in groups, erythrocytes, hemoglobin>11 mg/DL, platelets, creatinine, transaminases, alkaline phosphatase, bilirubin);
- blood pressure is normal or under drug control;
- resistance to local (including softeners and resin) and phototherapy;
confirmation permitted in medicine methods of preventing pregnancy in women of childbearing age;
- written informed consent of each patient.
- if the patient has not reached 18 years of age;
- tested positive for rheumatoid factor (RF) or anti-nuclear antibodies (ANA)>1:80;
inflammatory bowel disease in the past or signs of other rheumatic diseases;
- set individual sensitivity to diacerein or any other component of the capsules;
chronic disease, which, in the opinion of the investigator, may interfere with participation in the trial;
- reception of the slow acting drugs and/or corticosteroids within one month before the test;
if the patient according to the researcher, will perform the test procedure.
The treatment was to receive 2×50 mg capsules Artrodar® (capsules contain 50 mg of diacerein) a day for 6 months. One capsule was taken after lunch and another after dinner.
Taking other medicines
Were not permitted the admission of the slow acting drugs for psoriatic arthritis or corticosteroids within one month before the test and during the test. Taking other medicines such as NSAIDs and analgesics, and never ceased during the test, and their doses were recorded every week.
Evaluated the following parameters in the initial state and at regular intervals during the test:
the PASI index (Fredriksson and Peterson, 1978) to assess the extent of damage to the skin;
- pain at movement (in this joint) by the method of VAS;
- articular index Ritchie.
The patient believed respond positively to treatment, if he or she was a decrease in the severity of psoriasis on a scale PASI.
It was noted all adverse cases reported by researchers or doctors.
Results the final data table. 1 and the individual data table. 2
The test involved 10 patients with mild or moderate psoriatic arthritis.
- Three patients who underwent only the initial examination, therefore, performance data were missing at the time of this report.
- One patient took the drug only 1 month.
Six patients took the drug for more than 1 month.
Thus, in table. 1 presents data for 7 patients who took the drug for at least 1 month (summary). The source data for each patient are given in the table. 2 (individual data).
All 7 patients treated diacerein not less than 1 month, respond positively to treatment, with regard to psoriasis (decrease of PASI index):
- 4 patients showed improvement after 1 month
- 2 patients showed improvement after 2 months
- 1 patient showed improvement after 3 months.
One of these patients dropped out of the test after 1 month of treatment due to diarrhea. However, the symptoms of psoriasis and arthritis he has greatly improved within 1 month of treatment, so it can be considered positively reacting.
Of the remaining 3 patients showed no improvement in the condition of psoriasis, because it was only 1 month of treatment, and the remaining 2 patients underwent only the initial examination.
Of the 7 patients (including retired patient)who diacerein for one month or more, all (100%) respond positively to treatment.
The only known adverse effect is diarrhea in one patient, which forced him to retire from the test.
With this in mind, diacerein was surprisingly effective in the treatment of psoriasis and related diseases.
1. Pharmaceutical composition for the treatment of psoriasis in its various forms and psoriatic arthritis, containing an effective amount of diacerein or its pharmaceutically acceptable salt or a complex ester.
2. The pharmaceutical composition according to claim 1 for the treatment of psoriasis in its various forms and psoriatic arthritis, containing an effective amount of diacerein.
3. The pharmaceutical composition according to claim 1, intended for the treatment of psoriasis.
4. The pharmaceutical composition according to claim 1, intended for the treatment of psoriatic arthritis.
5. The pharmaceutical composition according to claim 1, which is in a form suitable for oral administration.
6. The pharmaceutical composition according to claim 1, which is in the form of a cream or ointment for local application on the part of the skin, the affected psora is atom.
7. A method of treating psoriasis, comprising the introduction of a pharmaceutical composition containing an effective amount of diacerein or its pharmaceutically acceptable salt or a complex ester.
8. A method of treatment of psoriasis and psoriatic arthritis, including the introduction of a pharmaceutical composition containing an effective amount of diacerein or its pharmaceutically acceptable salt or a complex ester.
9. The method according to claim 7 or 8, in which the pharmaceutical composition is in a form suitable for oral administration.
10. The method according to any of claims 7 to 9, in which the pharmaceutical composition comprises a dose corresponding to a daily intake of 30-200 mg of diacerein.
11. The method according to any of claims 7 to 9, in which the dosage is 100 mg per day in at least two installments.
FIELD: medicine, chemistry of peptides, amino acids.
SUBSTANCE: invention relates to novel biologically active substances. Invention proposes the novel composition comprising peptides of the formula: H-Arg-Gly-Asp-OH and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys. The composition shows ability to inhibit proliferative activity of mononuclear cells, to induce suppressive activity and their ability for secretion of cytokines TNF-1β (tumor necrosis factor-1β) and IL-10 (interleukin-10 ).
EFFECT: simplified method for preparing composition, valuable medicinal properties of composition.
4 cl, 16 tbl, 9 ex
FIELD: medicine, phthisiology, pharmacy.
SUBSTANCE: invention proposes the inhalation preparation in treatment of tuberculosis comprising an antibacterial medicinal agent an aqueous solution. The preparation comprises also a medicinal preparation with the immunomodulating effect as 5-amino-2,3-dihydro-1,4-phthalazinedione potassium salt or 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, or 5-amino-2,3-dihydro-1,4-phthalazinedione potassium and sodium salts taken in the equal ratio in the following ratio of components, wt.-%: antibacterial medicinal agent, 1.0-10.0; 5-amino-2,3-dihydro-1,4-phthalazinedione potassium salt or 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, or 5-amino-2,3-dihydro-1,4-phthalazinedione potassium and sodium salts taken in the equal ratio, 1.0-10.0; water, the balance. The preparation inhibits activity of macrophages reducing the level of tumor necrosis factor (TNF) and acute-phase proteins that results to weakening intoxication symptoms, activates superoxide-forming function and phagocyte activity of neutrophile granulocytes, enhances the microbiocide system of cells that, in turn, results to arresting the inflammation process. Invention can be used as the inhalation agent in treatment of tuberculosis.
EFFECT: valuable medicinal properties of preparation.
2 cl, 2 ex
FIELD: medicine, rheumatology, pharmacy.
SUBSTANCE: invention proposes ointment as a curative agent that comprises the following components: 5-amino-2,3-dihydro-1,4-phthalazinedione alkaline salt of mixture of alkaline salts, medicinal vaseline, vaseline oil as an ointment base and distilled water taken in the following ratio of components, wt.-%: 5-amino-2,3-dihydro-1,4-phthalazinedione alkaline salt or 5-amino-2,3-dihydro-1,4-phthalazinedione mixture of alkaline salts, 1.0-50.0; medicinal vaseline, 10.0-20.0; vaseline oil, 5.0-10.0, and water, the balance, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione sodium or potassium salt is used as an alkaline salt, and 5-amino-2,3-dihydro-1,4-phthalazinedione sodium and potassium salts mixture is used as mixture of alkaline salts composed of the equal ratio of components, i. e. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium and potassium salts mixture. Indicated ointment normalizes membrane cell to the normal state damaged as result of disease, regulated intra- and intercellular metabolic processes that, in turn, promotes to normalization of metabolism and arresting inflammation for the shortest times. Invention can be used in treatment of autoimmune disease.
EFFECT: improved and valuable medicinal properties of ointment.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new 6-alkyl-5-(2-isonicotinoylsulfohydrazoyl)uracil hydrochlorides of the general formula (I) wherein R means alkyl comprising 1-4 carbon atom. Compounds possess an anti-mycobacterial and an immunotropic activity and can be used as an immunomodulating agent and an anti-mycobacterial agents. Also, invention relates to a pharmaceutical composition based on thereof.
EFFECT: valuable medicinal properties of compounds.
4 cl, 10 tbl, 2 ex
FIELD: veterinary science.
SUBSTANCE: the present innovation deals with cooling selected fertilized uninfected eggs at 2-4 C up to 7 d followed by homogenization, diluting with physiological solution of egg mass, bactericidal treatment, conservation with phenol solution up to its concentration being 0.3% at subsequent filtration of target product. Moreover, egg mass should be diluted with physiological solution at the ratio of 1:5, then comes thermal treatment upon water bath at 70-80 C for 1 h and before conservation one should cool the target product in bactericidal chamber under the lamp with ultraviolet irradiation for 30-40 min. The method provides increased total and specific body resistance, it enables to obtain cheaper and more acceptable biostimulant and simplified way for preparing.
EFFECT: higher efficiency.
4 ex, 3 tbl
FIELD: medicine, biopharmacology, immunology.
SUBSTANCE: invention relates to manufacturing curative-prophylactic preparations based on leukocyte interferon and natural cytokines. The preparation based on complex of natural cytokines is prepared by induction of human leukocytes with Newcastle disease virus of strain "H". Indicated complex of natural cytokines is prepared by at least two treatments of leukocytes before induction stage with virus with the same natural complex of cytokines prepared in previous stage of induction. Complex is purified from foreign proteins of inductor and comprises 104 IU of antiviral activity of human interferon-alpha in one ampoule, not less, and cellular cytokines, phosphate buffer for maintaining pH 6.9-7.5, sodium chloride and mannitol. The end product is lyophilized for preparing the injection preparation. Invention provides increasing activity of the preparation and to retain the natural complex of cytokines.
EFFECT: improved preparing method, valuable medicinal properties of preparation.
3 cl, 2 ex
FIELD: medicine, gastroenterology, pharmacy.
SUBSTANCE: invention relates to agents used in treatment of ulcerous-erosion injures in gastroduodenal region. Method involves diluting 100 mcg of dry lyophilized powder of immunomodulating agent "Superlimf" in 3-5 ml of 0.9% isotonic solution and irrigation of ulcer or erosion with this solution 1 time per a day by the endoscopy method. The treatment course is 3-4 procedures with break for 4-5 days. Method provides alteration of cytokine pattern of tissues, induction of influx of mononuclear phagocytes to the injure focus that results to localization of inflammation and the complete epithelization of ulcers and erosions.
EFFECT: improved and effective method for treatment.
FIELD: medicine, pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to a method for preparing an anti-inflammatory, wound-healing, capillary-strengthening, immunomodulating agent. Method for preparing an anti-inflammatory, wound-healing, capillary-strengthening, immunomodulating agent is carried out for four stages. At the first stage violet tricolor and/or field milled herb is extracted with fluidized carbon dioxide under the definite condition followed by separation of grist from lipophilic fraction of extract; at the second stage defatted grist is subjected for three-fold extraction by remaceration method under the definite condition followed by treatment and purification of combined extract, treatment, condensation and preparing liquid alcoholic extract; at the third stage liquid alcoholic extract is used for preparing polysaccharide and flavonoid complexes by precipitation of polysaccharide with three-fold volume of 96% ethyl alcohol and the following drying at the definite temperature; at the forth stage grist after isolation of polysaccharide and flavonoid complexes is used for preparing pectins by treatment with three-fold volume of ammonium oxalate solution at the definite temperature, evaporation and drying. Liquid alcoholic is evaporated to 1/5 of the parent volume, dried by spraying drying or lyophilic drying at definite temperatures. Each end product prepared at each stage can be used as both independent medicinal formulation and can be used for preparing other medicinal formulations (tablets, capsules, suppositories, films). Also, invention relates to a method for preparing an anti-inflammatory, wound-healing, capillary-strengthening, immunomodulating agent that involves extraction of violet tricolor and/or field milled herb with 70% ethyl alcohol by infusion for a definite time followed by purification of the end product, settling at the definite temperature and filtration. Method provides preparing agent with broad pharmacological pattern of action and provides the maximal using the medicinal vegetable raw.
EFFECT: improved preparing method, valuable medicinal properties of agent.
5 cl, 5 tbl, 17 ex
SUBSTANCE: means has lipid fraction obtained from Berryteuthis Magister Comandor squid liver containing 10% of polyunsaturated fatty acids and 50% of alkyl-diacylglycerides showing marked lipid-correcting and immunomodulating properties.
EFFECT: enhanced effectiveness in treating lipid metabolism disorders and immunity system disorders.
SUBSTANCE: method involves administering inmmunotherapy with recombinant interferon-α2b in daily dose of 3x106 MU. It is incubated in thermostat during 1 h at 37°C with 100 ml of autoblood and then it is intravenously introduced to a patient during 1-1.5h daily under blood formula control to reach leukocyte content of>4*109 /l, granulocytes >2*109 /l.
EFFECT: eliminated leukopenia and dose-limiting toxicity risk; accelerated treatment course; reduced risk of infectious complications.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):
wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).
EFFECT: improved control method, valuable medicinal properties of compounds.
9 cl, 5 sch, 36 tbl, 70 ex
FIELD: organic chemistry, pharmacy, biochemistry.
SUBSTANCE: invention relates to new substituted 2H-pyrano[2,3-c] of the general formula (1) eliciting ability to inhibit activity of protein kinase. In the general formula (1) X represents oxygen atom or group NR3; R1 represents group -C(O)R4, optionally substituted and optionally condensed azaheterocycle; R2 represents optionally substituted hydroxyl group or optionally substituted amino-group; R3 represents hydrogen atom or inert substitute meaning optionally substituted low- or non-reactive radical including such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, (C2-C12)-alkoxyalkyl, (C2-C10)-alkylsulfinyl, (C2-C10)-alkylsulfonyl, -(CH2)-O-(C1-C7-alkyl), -(CH2)m-N(C1-C7-alkyl)n, aryloxyalkyl, heterocyclyl wherein m and n have value from 1 to 7; R4 represents optionally substituted amino-group or hydrogenated optionally substituted azaheterocycle. Also, invention relates to combinatory and focused libraries consisting of compounds of the present invention and designated for the search of compound-hits and compound-leaders prepared by screening of these libraries for using in preparing medicinal agents.
EFFECT: valuable medicinal properties of compounds.
8 cl, 2 tbl, 6 ex
FIELD: organic chemistry, vitamins, medicine, pharmacy.
SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.
EFFECT: valuable medicinal properties of compounds.
13 cl, 3 sch, 3 tbl, 6 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new aminobenzophenones of the formula (I):
or their pharmaceutically acceptable salts. These compounds elicit properties of inhibitors of cytokines secretion, in particular, 1β-interleukin (IL-1β) and tumor necrosis α-factor (TNF-α) and to secretion of polymorphonuclear superoxide that are useful for treatment of inflammatory diseases, for example, skin diseases, such as psoriasis, atopic dermatitis. In the formula (I) R1 is taken among the group consisting of halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, cyano-group, carbamoyl, phenyl or nitro-group under condition that when R1 means a single substitute then it at ortho-position, and when R1 means more one substitute then at least one substitute of R1 is at ortho-position; R2 means one substitute at ortho-position being indicated substitute is taken among the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy-group; R3 means hydrogen, halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, phenyl, cyano-, carboxy-group or carbamoyl; R4 means hydrogen atom or (C1-C3)-alkyl; Q means a bond or -SO2-; Y means (C1-C15)-alkyl, (C3-C10)-carbocyclic group or phenyl being each of them can be substituted optionally with one or some similar or different substitutes designated by the formula R5; R5 means halogen atom, (C1-C4)-alkyl, amino-, (C1-C3)-alkoxy-group, (C1-C3)-alkoxycarbonyl or -COOH; X means oxygen or sulfur atom. Also, invention relates to a pharmaceutical composition and to a method for treatment and/or prophylaxis of inflammatory diseases.
EFFECT: valuable medicinal properties of compounds and composition.
9 cl, 2 sch, 2 tbl, 29 ex
or its pharmaceutically acceptable salts, which have the properties of inhibitors of the enzyme Lp-PLA2and can be used to treat or prevent a painful condition associated with the activity of the specified enzyme
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention concerns to applying RARγ agonist for preparing a medicinal agent comprising one or some such agonists and designated for treatment of emphysema wherein RARγ agonist is taken among compounds of the formula (I):
wherein R1 means residue of the formula:
or , or , or ; R2 means (C2-C8)-alkanoyl, (C2-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or group -OCH2R3 wherein R3 means hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl; each among R4-R9 means independently of one another hydrogen atom or (C1-C6)-alkyl; or R8 and R9 mean in common (CRaRb)n wherein Ra and Rb mean independently of one another hydrogen atom or (C1-C6)-alkyl; n = 1, 2 or 3; R4-R7 have above given values; R10 means carboxyl, (C1-C6)-alkoxycarbonyl or mono- or di-(C1-C6)-alkylcarbamoyl; and their pharmaceutically acceptable salts; or among compounds of the formula (VI):
wherein R1 means C(O)R6 or CH2OH (wherein R6 means hydroxy-group or (C1-C6)-alkoxy-group); R2 means hydrogen atom, (C1-C15)-alkyl, (C1-C6)-alkoxy-group or cycloaliphatic group; R3 means hydrogen atom, hydroxy-group, (C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, (C1-C10)-alkoxy-group or cycloaliphatic group; R4 and R5 mean independently of one another hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; or among compound of the formula (VIII):
. Invention provides applying agonists eliciting the selective effect with respect to RARγ, for preparing a medicinal agent comprising one or some such agonists designated for emphysema treatment.
EFFECT: valuable medicinal properties of compounds.
4 cl, 5 tbl, 3 ex