CA2227421A1 - Use of ipriflavone to reduce the number of cd8+ cells - Google Patents
Use of ipriflavone to reduce the number of cd8+ cells Download PDFInfo
- Publication number
- CA2227421A1 CA2227421A1 CA002227421A CA2227421A CA2227421A1 CA 2227421 A1 CA2227421 A1 CA 2227421A1 CA 002227421 A CA002227421 A CA 002227421A CA 2227421 A CA2227421 A CA 2227421A CA 2227421 A1 CA2227421 A1 CA 2227421A1
- Authority
- CA
- Canada
- Prior art keywords
- cells
- decrease
- isopropoxyisoflavone
- ipriflavone
- treatment
- 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.)
- Abandoned
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
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- 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)
- Medicines Containing Plant Substances (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (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 liq uid carriers and optionally with usual therapeutic additives and auxiliary agents. The pharmaceutical composition 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 suppr ession of CD8+ lymphocytes is desirable.
Description
W O 97/03664 PCTnHU96/00038 USE OF IPRIFLAVONE TO REDUCE THE NUMBER OF CD8 ~ CELLS
The invention relates to pharmaceutical compositions suitable to decrease the number of CD8+ cells cont~inin~ 7-isopropoxyisoflavone (IPRIFLAVONE) as active ingredient.
IPRIFLAVONE is a known antiosteoporotic agent. Its p,ep~udLion 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-m~ tefi immune 10 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-mef~i~ted immune response is ~tt~-~ht-d to the so-called thymus dependent (cells maturing in the thymus) Iymphocytes (T lymphocytes).At the end of the maturation15 process two types of T Iymphocytes -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 bv increasing their cvtokine production. The CD8+ cells. the so-called cytotoxic cells are activated upon recognition of the endogen antigen then they destro-20 the cells recognized as foreign by cytolysis.
Approximately , /3 of the peripheral Iymphocytes 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 cvtotoxic immune response is a basic protective mechanism in case of intracellular 25 infections because by the destruction of the infected cell it elimin~tt-s the possibilitv for the pathogenic agent to reproduce. Similarly it has an important role in the destruction of tumor cells. In these cases the cytotoxic immun~ response serves to protect the integritv of the organism.
30 Cases are also known where with respect to the organism cytotoxic immune response is undesired or even harmful. In case of certain autoimmun~ e~c~ cytotoxic reaction is directed towards own cells of the organism causing severe functional disturbances as a result. Characteristic example of T cell mP~ tec~ immune disease is rheumatoid arthritis.
W O 97/03664 PCTAHU9~ B
Pathologic cytotoxic reaction can be seen in case of certain aplastic ~nerni~c and chronic active hepatitis. Rejection reaction following tissue or organ transplantations is also based on the cytotoxic immllne ~ Jollse. In case of special organ transplantation -bone marrow- the so-called "graft versus host" is also based on the cytotoxic reaction.
5 In these cases CD4+/CD8+ ratio decreases, in certain cases reverses which is mainly the result of the increase of CD8+ cells and less the result of the decrease of the CD4+ cells.
In cases of autoimml-nP ~lice~es and rejection reactions following tissue/organ transplantations it is a usual IlG~ procedure to moderate the immunP re~ollse, in certain cases even to drastically reduce it (immunosuppressive trç~tment).
10 Immunosu~plt:s~ e treatment causes not only a decrease in the number of T
Iymphocytes but it also has an effect toward norm~li7~tion 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 signific~ntly less numbers. Therefore, in the mentioned ~lice~Pc a therapy that decreases specifically the number of CD8+ cells could 15 be advantageous.
Based on the above theoretical considerations and practical experiences we e~minPd the kind of effect ipriflavone treatment has on T Iymphocytes responsible for the cell-me~ ted immune response and on the number of CD4+ helper and CD8+ cytotoxic 20 cells. To separate certain types of Iymphocytes and subgroups we used flow cytometry.
In a clinical trial the absolute Iymphocyte couni and the change in certain Iymphocyte subpopulations were studied in 60 patients taking a daily dose of 400 mg ipriflavone.
In 51 patients a mild or moderate decrease of absolute Iymphocyte count was observed.
The mean absolute Iymphocyte count of patients was 0.85xl O9/l (range 0.75-0.89)25 following the treatment. (Normal range: 0.9-3.22xlO9/l) In 9 patients the mean absolute Iymphocyte count was found within the normal range, 1.84xlO9/l. In the 51 patients with Iymphopenia the decrease was rh~ractPristic only for the so called T Iymphocytes and among them primarily and pronounced for the CD8+ subpopulation. The mean CD8+ count was 0.08xlO9/l (range 0.02-0.23), which represents a rather significant cell 30 count reduction taking into account the normal range of 0.3-1.44xlO9/l.
In the 9 patients showing normal Iymphocyte count the mean CD8+ count was 10.43xlO9/l (range 0.28-0.64). Although this value is within the normal range, it falls in its lower quartilis, which finding ~u~olL~ the selectivite nature of the effect.
-W O 97/03664 PCTAHU~5/G~8 We found that under ipriflavone ll~at.l.cnt the n.lmber of T Iymphocytes decreased on the average by 66.6%. Considering CD4+ helper and CD8+ cytotoxic subgroups the average decrease was signific~ntly dirr~ lt. 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 to 5:1 upon ipriflavone tre~tment The decrease in the number of T Iymphocytes, CD4+ helper and CD8+ cytotoxic cells and the basic change in their ratios are considerable in two aspects. In the course of cu~,~oln~im mllnn~u~eSsi~e 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 ph~rm~-~elltical 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 tre~tmcnt of a human or animal subject20 being in a condition where selective suppression of CD8+1ymphocytes is desirable.
The compositions acco..lhlg to the invention may be prepared in the form of injection, infusion, capsule, tablet, solution, syrup, tr~n~ l p,el~dLion, etc. by methods known per se.
In riiee~ee, or states of condition where inhibition of the cytotoxic reaction has a therapeutic value are rather different in their nature, a~e~ ce and course of disease.
Therefore the dose has to be determinPd in knowledge of the diagnosis, initial number of Iymphocytes and the ratio of Cd4+/CD8+ cells.
The invention relates to pharmaceutical compositions suitable to decrease the number of CD8+ cells cont~inin~ 7-isopropoxyisoflavone (IPRIFLAVONE) as active ingredient.
IPRIFLAVONE is a known antiosteoporotic agent. Its p,ep~udLion 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-m~ tefi immune 10 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-mef~i~ted immune response is ~tt~-~ht-d to the so-called thymus dependent (cells maturing in the thymus) Iymphocytes (T lymphocytes).At the end of the maturation15 process two types of T Iymphocytes -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 bv increasing their cvtokine production. The CD8+ cells. the so-called cytotoxic cells are activated upon recognition of the endogen antigen then they destro-20 the cells recognized as foreign by cytolysis.
Approximately , /3 of the peripheral Iymphocytes 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 cvtotoxic immune response is a basic protective mechanism in case of intracellular 25 infections because by the destruction of the infected cell it elimin~tt-s the possibilitv for the pathogenic agent to reproduce. Similarly it has an important role in the destruction of tumor cells. In these cases the cytotoxic immun~ response serves to protect the integritv of the organism.
30 Cases are also known where with respect to the organism cytotoxic immune response is undesired or even harmful. In case of certain autoimmun~ e~c~ cytotoxic reaction is directed towards own cells of the organism causing severe functional disturbances as a result. Characteristic example of T cell mP~ tec~ immune disease is rheumatoid arthritis.
W O 97/03664 PCTAHU9~ B
Pathologic cytotoxic reaction can be seen in case of certain aplastic ~nerni~c and chronic active hepatitis. Rejection reaction following tissue or organ transplantations is also based on the cytotoxic immllne ~ Jollse. In case of special organ transplantation -bone marrow- the so-called "graft versus host" is also based on the cytotoxic reaction.
5 In these cases CD4+/CD8+ ratio decreases, in certain cases reverses which is mainly the result of the increase of CD8+ cells and less the result of the decrease of the CD4+ cells.
In cases of autoimml-nP ~lice~es and rejection reactions following tissue/organ transplantations it is a usual IlG~ procedure to moderate the immunP re~ollse, in certain cases even to drastically reduce it (immunosuppressive trç~tment).
10 Immunosu~plt:s~ e treatment causes not only a decrease in the number of T
Iymphocytes but it also has an effect toward norm~li7~tion 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 signific~ntly less numbers. Therefore, in the mentioned ~lice~Pc a therapy that decreases specifically the number of CD8+ cells could 15 be advantageous.
Based on the above theoretical considerations and practical experiences we e~minPd the kind of effect ipriflavone treatment has on T Iymphocytes responsible for the cell-me~ ted immune response and on the number of CD4+ helper and CD8+ cytotoxic 20 cells. To separate certain types of Iymphocytes and subgroups we used flow cytometry.
In a clinical trial the absolute Iymphocyte couni and the change in certain Iymphocyte subpopulations were studied in 60 patients taking a daily dose of 400 mg ipriflavone.
In 51 patients a mild or moderate decrease of absolute Iymphocyte count was observed.
The mean absolute Iymphocyte count of patients was 0.85xl O9/l (range 0.75-0.89)25 following the treatment. (Normal range: 0.9-3.22xlO9/l) In 9 patients the mean absolute Iymphocyte count was found within the normal range, 1.84xlO9/l. In the 51 patients with Iymphopenia the decrease was rh~ractPristic only for the so called T Iymphocytes and among them primarily and pronounced for the CD8+ subpopulation. The mean CD8+ count was 0.08xlO9/l (range 0.02-0.23), which represents a rather significant cell 30 count reduction taking into account the normal range of 0.3-1.44xlO9/l.
In the 9 patients showing normal Iymphocyte count the mean CD8+ count was 10.43xlO9/l (range 0.28-0.64). Although this value is within the normal range, it falls in its lower quartilis, which finding ~u~olL~ the selectivite nature of the effect.
-W O 97/03664 PCTAHU~5/G~8 We found that under ipriflavone ll~at.l.cnt the n.lmber of T Iymphocytes decreased on the average by 66.6%. Considering CD4+ helper and CD8+ cytotoxic subgroups the average decrease was signific~ntly dirr~ lt. 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 to 5:1 upon ipriflavone tre~tment The decrease in the number of T Iymphocytes, CD4+ helper and CD8+ cytotoxic cells and the basic change in their ratios are considerable in two aspects. In the course of cu~,~oln~im mllnn~u~eSsi~e 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 ph~rm~-~elltical 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 tre~tmcnt of a human or animal subject20 being in a condition where selective suppression of CD8+1ymphocytes is desirable.
The compositions acco..lhlg to the invention may be prepared in the form of injection, infusion, capsule, tablet, solution, syrup, tr~n~ l p,el~dLion, etc. by methods known per se.
In riiee~ee, or states of condition where inhibition of the cytotoxic reaction has a therapeutic value are rather different in their nature, a~e~ ce and course of disease.
Therefore the dose has to be determinPd in knowledge of the diagnosis, initial number of Iymphocytes and the ratio of Cd4+/CD8+ cells.
Claims (4)
1. Pharmaceutical composition suitable to decrease the number of CD8+ cells comprising a therapeutically 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 of 7-isopropoxyisoflavone for the manufacture of a medicament for the treatment of 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 (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP9502198 | 1995-07-21 | ||
| HU9502198A HU9502198D0 (en) | 1995-07-21 | 1995-07-21 | Novel indication |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2227421A1 true CA2227421A1 (en) | 1997-02-06 |
Family
ID=10987063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002227421A Abandoned CA2227421A1 (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) | NO980127L (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 EE EE9800020A patent/EE9800020A/en unknown
- 1996-07-16 EA EA199800146A patent/EA199800146A1/en unknown
- 1996-07-16 CZ CZ9827A patent/CZ2798A3/en unknown
- 1996-07-16 CN CN96195722A patent/CN1191483A/en active Pending
- 1996-07-16 MX MX9800603A patent/MX9800603A/en unknown
- 1996-07-16 CA CA002227421A patent/CA2227421A1/en not_active Abandoned
- 1996-07-16 IL IL12275196A patent/IL122751A0/en unknown
- 1996-07-16 BR BR9610187A patent/BR9610187A/en not_active Application Discontinuation
- 1996-07-16 WO PCT/HU1996/000038 patent/WO1997003664A1/en not_active Application Discontinuation
- 1996-07-16 KR KR1019980700235A patent/KR19990028933A/en not_active Application Discontinuation
- 1996-07-16 PL PL96324460A patent/PL324460A1/en unknown
- 1996-07-16 JP JP50646497A patent/JP2001503371A/en active Pending
- 1996-07-16 AU AU63670/96A patent/AU6367096A/en not_active Abandoned
- 1996-07-16 SK SK32-98A patent/SK3298A3/en unknown
- 1996-07-16 EP EP96923004A patent/EP0841915A1/en not_active Withdrawn
- 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/NO980127L/en unknown
- 1998-01-14 BG BG102182A patent/BG102182A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HRP960345A2 (en) | 1998-02-28 |
| IL122751A0 (en) | 1998-08-16 |
| EE9800020A (en) | 1998-08-17 |
| BG102182A (en) | 1998-08-31 |
| NO980127D0 (en) | 1998-01-12 |
| EP0841915A1 (en) | 1998-05-20 |
| HU9502198D0 (en) | 1995-09-28 |
| PL324460A1 (en) | 1998-05-25 |
| CZ2798A3 (en) | 1998-06-17 |
| MX9800603A (en) | 1998-04-30 |
| KR19990028933A (en) | 1999-04-15 |
| AR002905A1 (en) | 1998-04-29 |
| SK3298A3 (en) | 1998-07-08 |
| JP2001503371A (en) | 2001-03-13 |
| NO980127L (en) | 1998-01-12 |
| EA199800146A1 (en) | 1998-08-27 |
| CN1191483A (en) | 1998-08-26 |
| YU42796A (en) | 1999-03-04 |
| WO1997003664A8 (en) | 1999-08-05 |
| WO1997003664A1 (en) | 1997-02-06 |
| AU6367096A (en) | 1997-02-18 |
| ZA966079B (en) | 1998-01-19 |
| BR9610187A (en) | 1998-07-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |