WO1992004055A1 - Composition immunosuppressive - Google Patents
Composition immunosuppressive Download PDFInfo
- Publication number
- WO1992004055A1 WO1992004055A1 PCT/AU1991/000414 AU9100414W WO9204055A1 WO 1992004055 A1 WO1992004055 A1 WO 1992004055A1 AU 9100414 W AU9100414 W AU 9100414W WO 9204055 A1 WO9204055 A1 WO 9204055A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- castanospermine
- immunosuppressant
- analogues
- propoxy
- Prior art date
Links
- 0 C[C@](C1)[C@]([C@@](CC*)O*)N(*)C[C@]1O Chemical compound C[C@](C1)[C@]([C@@](CC*)O*)N(*)C[C@]1O 0.000 description 1
Classifications
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
Definitions
- This invention relates to an immunosuppressant composition, and in particular it relates to an immunosuppressant composition comprising an inhibitor of glycoprotein processing such as castanospermine or derivatives of castanospermine as one active component thereof.
- Castanospermine is an alkaloid of the indolizidine class which was first extracted from the Australian native legume Castanospermum australe (Hohenschutze et. al . , 1981). It has the structural formula I depicted below where R 1 , R 2 , R 3 and R* are hydrogen atoms:
- the related compound 6-epicastanospermine, has a similar structure except that the stereochemistry at position 6 of the molecule is opposite to that depicted in structural formula I.
- Castanospermine has recently been shown to have anti-inflammatory and immunomodulatory effects (disclosed in International Patent Application No. PCT/AU89/00341) and is useful in preventing organ transplant (tissue allograft) rejection (Grochowicz et. al . , 1990). It has now been discovered that previously unsuspected benefits can be obtained from the use of castanospermine (or other inhibitors of glycoprotein processing) in conjunction with other clinically useful immunosuppressive drugs or agents, whereby both castanospermine and the additional immunosuppressive drugs or agents may be used at doses lower than those found to be effective when these agents are used individually.
- Immunosuppressive drugs such as cyclosporin (also called ciclosporin or cyclosporine) are used at present to improve the initial and probably long term survival of renal allografts, and to mitigate the impact of immunologic risk factors such as H A mismatching and the absence of pre-transplantation blood transfusion. These drugs have also reduced the rate and severity of episodes of rejection on cardiac, hepatic, heart-lung, single-lung and multiple organ and composite organ transplantation in which the risk of lethal immune reactions restricts clinical implementation. They are also used for graft versus host disease associated with bone marrow transplants. The use of cyclosporin and other immunosuppressive drugs, however, is not without problems.
- the toxic effects include severe neurological, gastrointestinal, hormonal, hepatotoxic, osteoporitic, vascular and, most notably, nephrotoxic symptoms. At present it is necessary for treatment of patients to follow a narrow course between effective immunosuppression and drug toxicity. Such treatment is difficult to achieve when long term immunosuppressive therapy is necessary.
- an immunosuppressant composition comprising: (a) at least one immunosuppressant; and (b) an inhibitor of glycoprotein processing; together with a pharmaceutically acceptable carrier or diluent therefor.
- the present invention also extends to a method of immunosuppressive treatment of an animal or human patient which comprises administration to the patient of an immunosuppressive-effective amount of a composition as broadly described above.
- the immunosuppressant (a) may be any compound or material known in the art as a clinically useful immunosuppressive drug or agent.
- Such drugs include, for example, cyclosporin or analogues of cyclosporin, FK506 or analogues of FK506, azathioprine or analogues of azathioprine, or glucocorticosteroids.
- FK506 is described, for example, on page APP-1 of The Merck Index, 11th Edition, 1989.
- Other immunosuppressive agents may include various anti-thymocyte (T-cell) globulins, anti T-cell receptor globulins (such as anti-CD 3 or anti-CD 4 globulins), or various anti-cytokine globulins (such as anti-interleukin 1 and anti-interleukin 2, anti-tumour necrosis factor and anti- ⁇ -, ⁇ - or ⁇ -interferon globulins) or globulin directed against cell surface receptors for these cytokines, which have both demonstrated and potential utility in suppressing organ graft rejections. These agents, like the immunosuppressive drugs mentioned earlier, have demonstrated or potential deleterious dose-limiting side effects.
- T-cell anti-thymocyte
- anti T-cell receptor globulins such as anti-CD 3 or anti-CD 4 globulins
- anti-cytokine globulins such as anti-interleukin 1 and anti-interleukin 2, anti-tumour necrosis factor and
- the inhibitors of glycoprotein processing may be selected from the group consisting of castanospermine or an analogue or derivative of castanospermine, or other similar inhibitors of glycoprotein processing such as, nojirimycin or its analogues or derivatives, deoxynojirimycin or its analogues or derivatives, or 6-epicastanospermine or its analogues or derivatives.
- Suitable derivatives of castanospermine and 6- epicastanospermine for use in the composition of this invention include esters where R 1 , R 2 , R 3 and R 4 in structural formula I are the same or different and are selected from: hydrogen; alkanoyl (straight or branched chain C1-C8); cycloalkanoyl (C3-C7); benzoyl, optionally substituted by methyl, methoxy, ethoxy, propoxy, iso- propoxy, butoxy, sec-butoxy, isobutoxy, phenoxy, benzyloxy,.
- phenylacetyl optionally substituted by methyl, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, sec-butoxy, isobutoxy, phenoxy, benzyloxy, hydroxy, fluoro, chloro, or bromo; 1- and 2- phenylpropanoyl, optionally substituted by methyl, methoxy, ethoxy, propoxy, is ⁇ -propoxy, butoxy, sec-butoxy, isobutoxy,phenoxy, benzyloxy, hydroxy, fluoro, chloro, or bromo; thiophenecarbonyl; pyridinecarbonyl; pyrimidine- carbonyl; and furancarbonyl.
- R 1 , R 2 , R 3 and R 4 in structural formula I are alkanoyl (C1-C8), these substituents are exemplified by formyl; acetyl; propanoyl; isopropanoyl; butanoyl; isobutanoyl; pentanoyl; 2-methylbutanoyl; isopentanoyl; trimethylacetyl; hexanoyl; 2-methylpentanoyl; 3- methylpentanoyl; 2,2-dimethylbutanoyl; heptanoyl; 2- methylhexanoyl; 3-methylhexanoyl; 4-methylhexanoyl; 2,2- dimethylpentanoyl; octanoyl; 2-methylheptanoyl; and 2,2- dimethylhexanoyl.
- R 1 , R 2 , R 3 and R 4 in structural formula I are cycloalkanoyl (C3-C7), these substituents are exemplified by cyclopropanecarbonyl; cyclobutanecarbonyl; cyclopentanecarbonyl; cyclohexanecarbonyl; and cycloheptanecarbonyl.
- quaternary ammonium derivatives of castanospermine may also be used such as those of structural formula II where R 1 , R 2 , R 3 and R 4 are as described above and R 5 is alkyl (C1-C10) or branched alkyl (C3-C10), and the counter ion, X, is selected from chloride, bromide, iodide, sulfate, phosphate, nitrate, methanesulfonate, acetate, tartrate, citrate, lactate or any other pharmaceutically acceptable anion:
- Deoxynojirimycin is the reduction product of the antibiotic nojirimycin (5-amino-5- deoxy-D-glucose) which is produced by several strains of Streptomyces (e.g. Str. roseoclirogenes , Str. lavendulae and Str. nojiriensl ⁇ ) .
- Deoxynojirimycin has the structural formula III where R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen.
- Suitable derivatives of deoxynojirimycin and nojirimycin include compounds of structural formula III wherein R 1 , R 2 , R 3 and R 4 are the same or different and are selected from the groups described above with reference to structural formula I, and R 5 is hydrogen or methyl.
- the present invention is further exemplified in the following Example which demonstrates the immunosuppressive effects of castanospermine in combination with cyclosporin.
- This Example demonstrates graft survival of DA rats receiving PVG rat cardiac-allografts where the recipient rats were treated with cyclosporin A (CsA); castanospermine (Cast) or a CsA/Cast composition.
- CsA cyclosporin A
- Cast castanospermine
- the castanospermine was administered to the DA rats on the day of transplantation (day 0) in an Alzet 2 MLI mini-osmotic pump in a 2 ml volume of normal saline. These pumps deliver the drug for 7 days and are then removed, and no further treatment was given.
- the cyclosporin was administered orally by gavage at one dose/day starting at day 0 and stopping at day 7. The results are set out in Table 1:
- This Example demonstrates graft survival in Lewis rats receiving Brown Norwegian rat cardiac-allografts where the recipient rats were treated with cyclosporin A (CsA); castanospermine (Cast) or a CsA/Cast composition.
- CsA cyclosporin A
- Cast castanospermine
- the castanospermine was administered to the Lewis rats on the day of transplantation (day 0) in an Alzet 2 MLI mini- osmotic pump in a voluome of 2 ml. These pumps deliver the drug for 7 days and are then removed, and no further treatment was given.
- the cyclosporin was administered orally by gavage at one dose/day starting at day 0 and stopping at day 7.
- Table 2 shows the findings from experiments similar to those of Example 1 only in this case the strain combination of rats, Brown Norwegian grafts into Lewis recipients, was much more rigorous. Brown Norwegian into Lewis is one of the most difficult of the rat transplantation combinations; this is reflected in the lower success rate in the CsA 2 + Cast 100 group in this experiment when compared with the PVG into DA experiment shown in Table 1 above.
- Castanospermine a1,6,7,8-tetrahydroxy-octahydroindolizine alkaloid, from seeds of Castanospermixm Australe. Phytochemistry. 20: 811-814.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU85042/91A AU654152B2 (en) | 1990-09-06 | 1991-09-05 | Immunosuppressant composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPK2165 | 1990-09-06 | ||
AUPK216590 | 1990-09-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992004055A1 true WO1992004055A1 (fr) | 1992-03-19 |
Family
ID=3774939
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/AU1991/000414 WO1992004055A1 (fr) | 1990-09-06 | 1991-09-05 | Composition immunosuppressive |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP0547140A4 (fr) |
WO (1) | WO1992004055A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9765119B2 (en) | 2001-10-19 | 2017-09-19 | Aurinia Pharmaceuticals Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU3731989A (en) * | 1988-05-16 | 1989-12-12 | United States of America, as represented by the Secretary, U.S. Department of Commerce, The | Chemotherapeutic composition for aids |
AU4054189A (en) * | 1988-08-10 | 1990-03-05 | Praxis Pharmaceuticals, Inc. | Use of castanospermine as an anti-inflammatory and immunosuppressant agent |
EP0401194A1 (fr) * | 1989-06-02 | 1990-12-05 | G.D. SEARLE & COMPANY | Composition pharmaceutique pour utilisation dans un procédé d'inhibition de virus |
-
1991
- 1991-09-05 EP EP19910916526 patent/EP0547140A4/en not_active Withdrawn
- 1991-09-05 WO PCT/AU1991/000414 patent/WO1992004055A1/fr not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU3731989A (en) * | 1988-05-16 | 1989-12-12 | United States of America, as represented by the Secretary, U.S. Department of Commerce, The | Chemotherapeutic composition for aids |
AU4054189A (en) * | 1988-08-10 | 1990-03-05 | Praxis Pharmaceuticals, Inc. | Use of castanospermine as an anti-inflammatory and immunosuppressant agent |
EP0401194A1 (fr) * | 1989-06-02 | 1990-12-05 | G.D. SEARLE & COMPANY | Composition pharmaceutique pour utilisation dans un procédé d'inhibition de virus |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9765119B2 (en) | 2001-10-19 | 2017-09-19 | Aurinia Pharmaceuticals Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
US10472394B2 (en) | 2001-10-19 | 2019-11-12 | Aurinia Pharmaceuticals Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
USRE48226E1 (en) | 2001-10-19 | 2020-09-29 | Aurinia Pharmaceuticals Inc. | Cyclosporine analogue mixtures and their use as immunomodulating agents |
Also Published As
Publication number | Publication date |
---|---|
EP0547140A4 (en) | 1993-10-13 |
EP0547140A1 (fr) | 1993-06-23 |
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