EP0841915A1 - Use of ipriflavone to reduce the number of cd8+ cells - Google Patents
Use of ipriflavone to reduce the number of cd8+ cellsInfo
- Publication number
- EP0841915A1 EP0841915A1 EP96923004A EP96923004A EP0841915A1 EP 0841915 A1 EP0841915 A1 EP 0841915A1 EP 96923004 A EP96923004 A EP 96923004A EP 96923004 A EP96923004 A EP 96923004A EP 0841915 A1 EP0841915 A1 EP 0841915A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cells
- lymphocytes
- decrease
- ipriflavone
- isopropoxyisoflavone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Definitions
- the invention relates to pharmaceutical compositions suitable to decrease the number of CD8+ cells containing 7-isopropoxyisoflavone (IPRIFLAVONE) as active ingredient.
- IPRIFLAVONE 7-isopropoxyisoflavone
- IPRIFLAVONE is a known antiosteoporotic agent. Its preparation is described in Hungarian patent specifications Nr. 162377 and 196981. It is known that the organism has two basic protective functions, the humoral and the cell-mediated immune responses. The so-called cell-mediated immune response is primarily directed against endogen antigens on cells infected with a virus or with an intracellular parasite, tumor cells, chemically modified cells and foreign tissues.
- T lymphocytes thymus dependent lymphocytes
- the CD4+ cells the so-called helper cells are activated upon the presentation of exogen antigens and help the immune response by increasing their cytokine production.
- the CD8+ cells the so-called cytotoxic cells are activated upon recognition of the endogen antigen then they destroy the cells recognized as foreign by cytolysis.
- peripheral lymphocytes Approximately 2/3 of the peripheral lymphocytes are CD4+ and 1/3 CD8+.
- the cytotoxic immune response is a basic protective mechanism in case of intracellular infections because by the destruction of the infected cell it eliminates the possibility for the pathogenic agent to reproduce. Similarly it has an important role in the destruction of tumor cells. In these cases the cytotoxic immune response serves to protect the integrity of the organism.
- cytotoxic immune response is undesired or even harmful.
- cytotoxic reaction is directed towards own cells of the organism causing severe functional disturbances as a result.
- Characteristic example of T cell mediated immune disease is rheumatoid arthritis.
- Pathologic cytotoxic reaction can be seen in case of certain aplastic anemias and chronic active hepatitis.
- Rejection reaction following tissue or organ transplantations is also based on the cytotoxic immune response.
- the so-called dawngraft versus host is also based on the cytotoxic reaction.
- CD4+/CD8+ ratio decreases, in certain cases reverses which is mainly the result ofthe increase of CD8+ cells and less the result ofthe decrease ofthe CD4+ cells.
- autoimmune diseases and rejection reactions following tissue/organ transplantations it is a usual treatment procedure to moderate the immune response, in certain cases even to drastically reduce it (immunosuppressive treatment).
- Immunosuppressive treatment causes not only a decrease in the number of T lymphocytes but it also has an effect toward normalization of the CD4+/CD8+ cell ratio.
- an allogen bone marrow transplant which does not contain CD8+ cell drapegraft versus host" reaction can be observed in significantly less numbers. Therefore, in the mentioned diseases a therapy that decreases specifically the number of CD8+ cells could be advantageous.
- CD8+ count was 10.43xl0 9 /l (range 0.28-0.64). Although this value is within the normal range, it falls in its lower quartilis, which finding supports the selectivite nature ofthe effect.
- CD4+ helper and CD8+ cytotoxic subgroups the average decrease was significantly different.
- the 50% CD4+ helper cell decrease, the decrease of CD8+ cytotoxic cells was 77%.
- Subject of the invention is a pharmaceutical composition suitable to decrease the number of CD8+cells comprising as active ingredient 7-isopropoxyisoflavone in admixture with suitable inert, solid or liquid carriers and optionally with usual therapeutic additives and auxiliary agents.
- suitable inert, solid or liquid carriers and optionally with usual therapeutic additives and auxiliary agents.
- the above composition can be used for the treatment of a human or animal subject
- compositions according to the invention may be prepared in the form of injection, infusion, capsule, tablet, solution, syrup, transdermal preparation, etc. by methods known per se.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The present invention relates to pharmaceutical composition suitable to decrease the number of CD8+ cells comprising as active ingredient 7-isopropoxyisoflavone in admixture with suitable inert, solid or liquid carriers and optionally with usual therapeutic additives and auxiliary agents. The pharmaceutical compositions according to the invention are prepared by known methods and are suitable for the treatment of human or animal subjects being in a condition where selective suppression of CD8+ lymphocytes is desirable.
Description
USE OF IPRIFLAVONE TO REDUCE THE NUMBER OF CD8 + CELLS
The invention relates to pharmaceutical compositions suitable to decrease the number of CD8+ cells containing 7-isopropoxyisoflavone (IPRIFLAVONE) as active ingredient.
IPRIFLAVONE is a known antiosteoporotic agent. Its preparation is described in Hungarian patent specifications Nr. 162377 and 196981. It is known that the organism has two basic protective functions, the humoral and the cell-mediated immune responses. The so-called cell-mediated immune response is primarily directed against endogen antigens on cells infected with a virus or with an intracellular parasite, tumor cells, chemically modified cells and foreign tissues.
Cell-mediated immune response is attached to the so-called thymus dependent (cells maturing in the thymus) lymphocytes (T lymphocytes). At the end ofthe maturation process two types of T lymphocytes -based on their surface markers clearly differentiable subgroups- will be released to the periphery. The CD4+ cells, the so- called helper cells are activated upon the presentation of exogen antigens and help the immune response by increasing their cytokine production. The CD8+ cells, the so-called cytotoxic cells are activated upon recognition of the endogen antigen then they destroy the cells recognized as foreign by cytolysis.
Approximately 2/3 of the peripheral lymphocytes are CD4+ and 1/3 CD8+.
Corresponding to this the normal CD4+/CD8+ ratio is 2: 1.
(Andras Falus; Immunology pages 111-138 TEMPUS ITC Bp./1993)
The cytotoxic immune response is a basic protective mechanism in case of intracellular infections because by the destruction of the infected cell it eliminates the possibility for the pathogenic agent to reproduce. Similarly it has an important role in the destruction of tumor cells. In these cases the cytotoxic immune response serves to protect the integrity of the organism.
Cases are also known where with respect to the organism cytotoxic immune response is undesired or even harmful. In case of certain autoimmune diseases cytotoxic reaction is directed towards own cells of the organism causing severe functional disturbances as a result. Characteristic example of T cell mediated immune disease is rheumatoid arthritis.
Pathologic cytotoxic reaction can be seen in case of certain aplastic anemias and chronic active hepatitis. Rejection reaction following tissue or organ transplantations is also based on the cytotoxic immune response. In case of special organ transplantation -bone marrow- the so-called „graft versus host" is also based on the cytotoxic reaction. In these cases CD4+/CD8+ ratio decreases, in certain cases reverses which is mainly the result ofthe increase of CD8+ cells and less the result ofthe decrease ofthe CD4+ cells. In cases of autoimmune diseases and rejection reactions following tissue/organ transplantations it is a usual treatment procedure to moderate the immune response, in certain cases even to drastically reduce it (immunosuppressive treatment). Immunosuppressive treatment causes not only a decrease in the number of T lymphocytes but it also has an effect toward normalization of the CD4+/CD8+ cell ratio. In case of an allogen bone marrow transplant which does not contain CD8+ cell „graft versus host" reaction can be observed in significantly less numbers. Therefore, in the mentioned diseases a therapy that decreases specifically the number of CD8+ cells could be advantageous.
Based on the above theoretical considerations and practical experiences we examined the kind of effect ipriflavone treatment has on T lymphocytes responsible for the cell- mediated immune response and on the number of CD4+ helper and CD8+ cytotoxic cells. To separate certain types of lymphocytes and subgroups we used flow cytometry. In a clinical trial the absolute lymphocyte count and the change in certain lymphocyte subpopulations were studied in 60 patients taking a daily dose of 400 mg ipriflavone. In 51 patients a mild or moderate decrease of absolute lymphocyte count was observed. The mean absolute lymphocyte count of patients was 0.85x10 /I (range 0.25-0.89) following the treatment. (Normal range: 0.9-3.22x109/l) In 9 patients the mean absolute lymphocyte count was found within the normal range, 1.84xl09/l. In the 51 patients with lymphopenia the decrease was characteristic only for the so called T lymphocytes and among them primarily and pronounced for the CD8+ subpopulation. The mean CD8+ count was 0.08x109/l (range 0.02-0.23), which represents a rather significant cell count reduction taking into account the normal range of 0.3- 1.44x 10 /1.
In the 9 patients showing normal lymphocyte count the mean CD8+ count was 10.43xl09/l (range 0.28-0.64). Although this value is within the normal range, it falls in its lower quartilis, which finding supports the selectivite nature ofthe effect.
We found that under ipriflavone treatment the namber of T lymphocytes decreased on the average by 66.6%. Considering CD4+ helper and CD8+ cytotoxic subgroups the average decrease was significantly different. Next to the 50% CD4+ helper cell ( decrease, the decrease of CD8+ cytotoxic cells was 77%. CD4+/CD8+ ratio
5 characterizes the differing number of Cd4+ and CD8+ cells, the ratio of which changed i to 5:1 upon ipriflavone treatment.
The decrease in the number of T lymphocytes, CD4+ helper and CD8+ cytotoxic cells and the basic change in their ratios are considerable in two aspects. In the course of customary immunosuppressive treatments the observed decrease in cell number was as a 10 rule smaller than experienced in case of ipriflavone. Further significant difference is the more pronounced decrease in the number of CD8+ cytotoxic cells than in the number of CD4+ helper cells. Based on the results it can be assumed that ipriflavone is capable to decrease or to inhibit specifically the cytotoxic reaction.
15 Subject of the invention is a pharmaceutical composition suitable to decrease the number of CD8+cells comprising as active ingredient 7-isopropoxyisoflavone in admixture with suitable inert, solid or liquid carriers and optionally with usual therapeutic additives and auxiliary agents. The above composition can be used for the treatment of a human or animal subject
20 being in a condition where selective suppression of CD8+lymphocytes is desirable.
The compositions according to the invention may be prepared in the form of injection, infusion, capsule, tablet, solution, syrup, transdermal preparation, etc. by methods known per se.
25
In diseases or states of condition where inhibition of the cytotoxic reaction has a therapeutic value are rather different in their nature, appearance and course of disease. Therefore the dose has to be determined in knowledge of the diagnosis, initial number of lymphocytes and the ratio of Cd4+/CD8+ cells.
Claims
1. Pharmaceutical composition suitable to decrease the number of CD8+ cells comprising a therapautically active amount of 7-isopropoxyisoflavone as active ingredient in admixture with suitable inert, solid or liquid carriers and optionally with usual therapeutic additives and auxiliary agents.
2. Composition according to claim 1 prepared as injection, infusion, capsule, tablet, solution, syrup or transdermal preparation.
3. Use ofthe composition according to claims 1 and 2 in clinical conditions where selective suppression of CD8+lymphocytes is desirable.
4. Method of treatment of a human or animal subject being in a condition where selective suppression of CD8+ lymphocytes is desirable which comprises the step of administering in an effective amount 7-isopropoxyisoflavone in admixture with suitable inert, solid or liquid carriers and optionally with usual therapeutic additives and auxiliary agents.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9502198 | 1995-07-21 | ||
| HU9502198A HU9502198D0 (en) | 1995-07-21 | 1995-07-21 | Novel indication |
| PCT/HU1996/000038 WO1997003664A1 (en) | 1995-07-21 | 1996-07-16 | Use of ipriflavone to reduce the number of cd8+ cells |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0841915A1 true EP0841915A1 (en) | 1998-05-20 |
Family
ID=10987063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP96923004A Withdrawn EP0841915A1 (en) | 1995-07-21 | 1996-07-16 | Use of ipriflavone to reduce the number of cd8+ cells |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0841915A1 (en) |
| JP (1) | JP2001503371A (en) |
| KR (1) | KR19990028933A (en) |
| CN (1) | CN1191483A (en) |
| AR (1) | AR002905A1 (en) |
| AU (1) | AU6367096A (en) |
| BG (1) | BG102182A (en) |
| BR (1) | BR9610187A (en) |
| CA (1) | CA2227421A1 (en) |
| CZ (1) | CZ2798A3 (en) |
| EA (1) | EA199800146A1 (en) |
| EE (1) | EE9800020A (en) |
| HR (1) | HRP960345A2 (en) |
| HU (1) | HU9502198D0 (en) |
| IL (1) | IL122751A0 (en) |
| MX (1) | MX9800603A (en) |
| NO (1) | NO980127D0 (en) |
| PL (1) | PL324460A1 (en) |
| SK (1) | SK3298A3 (en) |
| WO (1) | WO1997003664A1 (en) |
| YU (1) | YU42796A (en) |
| ZA (1) | ZA966079B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1241079B (en) * | 1990-03-23 | 1993-12-29 | Chiesi Farma Spa | PHARMACEUTICAL COMPOSITIONS CONTAINING IPRIFLAVONE, PROCEDURE FOR THEIR PREPARATION AND RELATED THERAPEUTIC USE |
| HU212932B (en) * | 1993-08-02 | 1996-12-30 | Chinoin Gyogyszer Es Vegyeszet | Parmaceutical composition containing ipriflavone, hydroxyapatit and tricalciumphosphate for treating lack of bones and process for producing the composition |
-
1995
- 1995-07-21 HU HU9502198A patent/HU9502198D0/en unknown
-
1996
- 1996-07-16 EA EA199800146A patent/EA199800146A1/en unknown
- 1996-07-16 CN CN96195722A patent/CN1191483A/en active Pending
- 1996-07-16 IL IL12275196A patent/IL122751A0/en unknown
- 1996-07-16 CZ CZ9827A patent/CZ2798A3/en unknown
- 1996-07-16 KR KR1019980700235A patent/KR19990028933A/en not_active Application Discontinuation
- 1996-07-16 CA CA002227421A patent/CA2227421A1/en not_active Abandoned
- 1996-07-16 MX MX9800603A patent/MX9800603A/en unknown
- 1996-07-16 JP JP50646497A patent/JP2001503371A/en active Pending
- 1996-07-16 PL PL96324460A patent/PL324460A1/en unknown
- 1996-07-16 EE EE9800020A patent/EE9800020A/en unknown
- 1996-07-16 AU AU63670/96A patent/AU6367096A/en not_active Abandoned
- 1996-07-16 BR BR9610187A patent/BR9610187A/en not_active Application Discontinuation
- 1996-07-16 EP EP96923004A patent/EP0841915A1/en not_active Withdrawn
- 1996-07-16 WO PCT/HU1996/000038 patent/WO1997003664A1/en not_active Application Discontinuation
- 1996-07-16 SK SK32-98A patent/SK3298A3/en unknown
- 1996-07-17 ZA ZA9606079A patent/ZA966079B/en unknown
- 1996-07-18 HR HRP9502198A patent/HRP960345A2/en not_active Application Discontinuation
- 1996-07-19 YU YU42796A patent/YU42796A/en unknown
- 1996-07-22 AR ARP960103677A patent/AR002905A1/en unknown
-
1998
- 1998-01-12 NO NO980127A patent/NO980127D0/en unknown
- 1998-01-14 BG BG102182A patent/BG102182A/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9703664A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AR002905A1 (en) | 1998-04-29 |
| EE9800020A (en) | 1998-08-17 |
| SK3298A3 (en) | 1998-07-08 |
| KR19990028933A (en) | 1999-04-15 |
| AU6367096A (en) | 1997-02-18 |
| CZ2798A3 (en) | 1998-06-17 |
| CA2227421A1 (en) | 1997-02-06 |
| MX9800603A (en) | 1998-04-30 |
| BG102182A (en) | 1998-08-31 |
| IL122751A0 (en) | 1998-08-16 |
| NO980127L (en) | 1998-01-12 |
| JP2001503371A (en) | 2001-03-13 |
| HU9502198D0 (en) | 1995-09-28 |
| PL324460A1 (en) | 1998-05-25 |
| ZA966079B (en) | 1998-01-19 |
| EA199800146A1 (en) | 1998-08-27 |
| BR9610187A (en) | 1998-07-28 |
| YU42796A (en) | 1999-03-04 |
| WO1997003664A1 (en) | 1997-02-06 |
| NO980127D0 (en) | 1998-01-12 |
| HRP960345A2 (en) | 1998-02-28 |
| CN1191483A (en) | 1998-08-26 |
| WO1997003664A8 (en) | 1999-08-05 |
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| STAA | Information on the status of an ep patent application or granted ep patent |
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| 18D | Application deemed to be withdrawn |
Effective date: 20000201 |