AU654152B2 - Immunosuppressant composition - Google Patents
Immunosuppressant compositionInfo
- Publication number
- AU654152B2 AU654152B2 AU85042/91A AU8504291A AU654152B2 AU 654152 B2 AU654152 B2 AU 654152B2 AU 85042/91 A AU85042/91 A AU 85042/91A AU 8504291 A AU8504291 A AU 8504291A AU 654152 B2 AU654152 B2 AU 654152B2
- Authority
- AU
- Australia
- Prior art keywords
- composition
- castanospermine
- immunosuppressant
- analogues
- propoxy
- 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.)
- Ceased
Links
- 239000003018 immunosuppressive agent Substances 0.000 title claims description 25
- 239000000203 mixture Substances 0.000 title claims description 21
- 229960003444 immunosuppressant agent Drugs 0.000 title claims description 13
- 230000001861 immunosuppressant effect Effects 0.000 title claims description 13
- -1 methoxy, ethoxy, propoxy, iso- propoxy, butoxy, sec-butoxy, isobutoxy, phenoxy, benzyloxy, hydroxy Chemical group 0.000 claims description 38
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 28
- JDVVGAQPNNXQDW-TVNFTVLESA-N Castinospermine Chemical compound C1[C@H](O)[C@@H](O)[C@H](O)[C@H]2[C@@H](O)CCN21 JDVVGAQPNNXQDW-TVNFTVLESA-N 0.000 claims description 27
- 108010036949 Cyclosporine Proteins 0.000 claims description 26
- 229960001265 ciclosporin Drugs 0.000 claims description 26
- 229930105110 Cyclosporin A Natural products 0.000 claims description 23
- JDVVGAQPNNXQDW-WCMLQCRESA-N Castanospermine Natural products O[C@H]1[C@@H](O)[C@H]2[C@@H](O)CCN2C[C@H]1O JDVVGAQPNNXQDW-WCMLQCRESA-N 0.000 claims description 19
- 229930182912 cyclosporin Natural products 0.000 claims description 16
- 102000003886 Glycoproteins Human genes 0.000 claims description 11
- 108090000288 Glycoproteins Proteins 0.000 claims description 11
- 239000003112 inhibitor Substances 0.000 claims description 11
- 102000006395 Globulins Human genes 0.000 claims description 10
- 108010044091 Globulins Proteins 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 230000001506 immunosuppresive effect Effects 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- LXBIFEVIBLOUGU-JGWLITMVSA-N duvoglustat Chemical compound OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O LXBIFEVIBLOUGU-JGWLITMVSA-N 0.000 claims description 7
- LXBIFEVIBLOUGU-UHFFFAOYSA-N Deoxymannojirimycin Natural products OCC1NCC(O)C(O)C1O LXBIFEVIBLOUGU-UHFFFAOYSA-N 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- JDVVGAQPNNXQDW-SLBCVNJHSA-N 6-epicastanospermine Natural products C1[C@@H](O)[C@@H](O)[C@H](O)[C@H]2[C@@H](O)CCN21 JDVVGAQPNNXQDW-SLBCVNJHSA-N 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- BGMYHTUCJVZIRP-UHFFFAOYSA-N Nojirimycin Natural products OCC1NC(O)C(O)C(O)C1O BGMYHTUCJVZIRP-UHFFFAOYSA-N 0.000 claims description 5
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 5
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- BGMYHTUCJVZIRP-GASJEMHNSA-N nojirimycin Chemical compound OC[C@H]1NC(O)[C@H](O)[C@@H](O)[C@@H]1O BGMYHTUCJVZIRP-GASJEMHNSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000003092 anti-cytokine Effects 0.000 claims description 3
- 229960002170 azathioprine Drugs 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 230000001494 anti-thymocyte effect Effects 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 241000700159 Rattus Species 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 229940124589 immunosuppressive drug Drugs 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 230000000747 cardiac effect Effects 0.000 description 5
- 229940125721 immunosuppressive agent Drugs 0.000 description 5
- 238000002054 transplantation Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 238000011694 lewis rat Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- KLXQAXYSOJNJRI-JGWLITMVSA-N (2r,3s,4r,5r)-5-amino-2,3,4,6-tetrahydroxyhexanal Chemical compound OC[C@@H](N)[C@@H](O)[C@H](O)[C@@H](O)C=O KLXQAXYSOJNJRI-JGWLITMVSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101001023866 Arabidopsis thaliana Mannosyl-oligosaccharide glucosidase GCS1 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241001107116 Castanospermum australe Species 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 101000609219 Homo sapiens Polyadenylate-binding protein 4 Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101000577106 Mus musculus Mannosyl-oligosaccharide glucosidase Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102100039424 Polyadenylate-binding protein 4 Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- NKLCHDQGUHMCGL-UHFFFAOYSA-N cyclohexylidenemethanone Chemical group O=C=C1CCCCC1 NKLCHDQGUHMCGL-UHFFFAOYSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- HAJKHJOABGFIGP-UHFFFAOYSA-N indolizidine Chemical class C1CCCN2CCCC21 HAJKHJOABGFIGP-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 235000021374 legumes Nutrition 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003589 nefrotoxic effect Effects 0.000 description 1
- 231100000381 nephrotoxic Toxicity 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
"IMMUNOSUPPRESSANT COMPOSITION"
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 R1, R2, R3 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. This phenomenon allows these immunosuppressive drugs or agents to be used in such a manner that toxic or other undesirable sequelae, such as those described below for drugs such as cyclosporin, azathioprine and glucocorticosteroids, are less likely to be encountered in use.
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.
According to the present invention there is provided 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-CD3 or anti-CD4 globulins), or various anti-cytokine globulins (such as anti-interleukin 1 and anti-interleukin 2, anti-tumour necrosis factor and anti-α-, β- or γ-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.
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 R1, R2, R3 and R4 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,. hydroxy, fluoro, chloro, or bromo; 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, isό-propoxy, butoxy, sec-butoxy, isobutoxy,phenoxy, benzyloxy, hydroxy, fluoro, chloro, or bromo; thiophenecarbonyl; pyridinecarbonyl; pyrimidine- carbonyl; and furancarbonyl.
Where R1, R2, R3 and R4 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.
Where R1, R2, R3 and R4 in structural formula I are cycloalkanoyl (C3-C7), these substituents are exemplified by cyclopropanecarbonyl; cyclobutanecarbonyl; cyclopentanecarbonyl; cyclohexanecarbonyl; and cycloheptanecarbonyl.
Various quaternary ammonium derivatives of castanospermine (or 6-epicastanospermine) may also be used such as those of structural formula II where R1, R2, R3 and R4 are as described above and R5 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:
Other inhibitors of glycoprotein processing which behave in a similar manner to castanospermine in inhibiting the enzyme glucosidase 1 include deoxynojirimycin and nojirimycin and their derivatives. 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. nojirienslε ) . Deoxynojirimycin has the structural formula III where R1, R2, R3, R4 and R5 are hydrogen.
rπ
Suitable derivatives of deoxynojirimycin and nojirimycin include compounds of structural formula III wherein R1, R2, R3 and R4 are the same or different and are selected from the groups described above with reference to structural formula I, and R5 is hydrogen or methyl.
Experiments in animals have shown that doses of castanospermine or cyclosporin which, when administered individually, were too low to prevent host rejection of cardiac allografts proved to be effective at prolonging graft survival when given in combination. Furthermore, this combined therapy has allowed the survival of fully allogeneic cardiac grafts even when the therapy was terminated af er seven days.
The present invention is further exemplified in the following Example which demonstrates the immunosuppressive effects of castanospermine in combination with cyclosporin.
EXAMPLE 1
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.
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:
TABLE 1 Survival of PVG cardiac allografts in DA hosts treated with cyclosporin A, castanospermine or both drugs.
These results indicate the potential for the use of lower doses of cyclosporin clinically. This is especially important for kidney transplant recipients, since one of the dose- limiting serious side effects of cyclosporin therapy is nephrotoxicity - the issue of side effects associated with cyclosporin therapy has been well reviewed by Kahan (1989).
EXAMPLE 2
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.
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.
The results are set out in Table 2:
TABLE 2: Survival of Brown Norwegian cardiac allografts in Lewis hosts treated with cyclosporin A, cas anospermine or both drugs.
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.
REFERENCES:
Grochowicz, P.K., Hibberd, A.D., Clark, D.A. , Bowen, K.M. ,m Cowden, W.B. and Willenborg, D.O. (1990). Castanospermine, an α-glucosidase inhibitor, prolongs renal allograft survival in the rat. Transplant. Proc. 22: 2117- 2118.
Hohenschutz, L.D., Bell, E.A., Jewess, P.J., Leworthy, D.P., Pyrce, R.J., Arnold, E. and Clardy, J. (1981). Castanospermine, a1,6,7,8-tetrahydroxy-octahydroindolizine alkaloid, from seeds of Castanospermixm Australe. Phytochemistry. 20: 811-814.
Kahan, B.D. (1989). Cyclosporine. N.Engl. J. Med. 321: 1725-1738.
Claims (12)
1. 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.
2. A composition of claim 1, wherein said immunosuppressant is selected from the group consisting of cyclosporin and analogues of cyclosporin, FK506 and analogues of FK506, azathioprine and analogues of azathioprine, and glucocorticosteroids.
3. A composition of claim 1, wherein said immunosuppressant is selected from the group consisting of anti-thymocyte (T-cell) globulins, anti-T-cell receptor globulins, anti-cytokine globulins, and anti-cytokine receptor globulins.
4. A composition of claim 1, wherein said immunosuppressant is cyclosporin.
5. A composition of claim 1, wherein said inhibitor of glycoprotein processing is selected from the group consisting of castanospermine or an analogue or derivative of castanospermine, nojirimycin or its analogues or derivatives, deoxynojirimycin or its analogues or derivatives, or 6-epicastanospermine or its analogues or derivatives.
6. A composition of claim 1, wherein said inhibitor of glycoprotein processing is selected from (i) castanospermine or derivatives thereof having the structural formula I:
wherein R1, R2, R3 and R4 are the same or different and each represents 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, hydroxy, fluoro, chloro, or bromo; 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, iso-propoxy, butoxy, sec-butoxy, isobutoxy,phenoxy, benzyloxy, hydroxy, fluoro, chloro, or bromo; thiophenecarbonyl; pyridinecarbonyl; pyrimidine- carbonyl; and furancarbonyl;
or the structural formula II:
OR .'3
where R1, R2, R3 and R4 are as defined above, and R5 is alkyl (C1-C10) or branched alkyl (C3-C10), and X is a pharmaceutically acceptable anion;
and (ii) 6-epimers thereof.
7. A composition of claim 1, wherein said inhibitor of glycoprotein processing is selected from deoxynojirimycin or derivatives thereof having the structural formula III:
wherein R1, R2, R3 and R4 are as defined in claim 6, and R5 is hydrogen or methyl.
8. A composition of claim 1, wherein said inhibitor of glycoprotein processing is castanospermine.
9. An immunosuppressant composition of claim 1, comprising cyclosporin and castanospermine, together with a pharmaceutically acceptable carrier or diluent.
10. A method of immunosuppressive treatment of an animal or human patient which comprises administration of an immunosuppressive effective amount of a composition of any of claims 1 to 9.
11. Use of a composition of any of claims 1 to 9 for immunosuppressive treatment of an animal or human patient.
12. Use of a composition of any of claims 1 to 9 for manufacture of a medicament for immunosuppressive treatment of an animal or human patient.
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 (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPK216590 | 1990-09-06 | ||
AUPK2165 | 1990-09-06 | ||
PCT/AU1991/000414 WO1992004055A1 (en) | 1990-09-06 | 1991-09-05 | Immunosuppressant composition |
AU85042/91A AU654152B2 (en) | 1990-09-06 | 1991-09-05 | Immunosuppressant composition |
Publications (2)
Publication Number | Publication Date |
---|---|
AU8504291A AU8504291A (en) | 1992-03-30 |
AU654152B2 true AU654152B2 (en) | 1994-10-27 |
Family
ID=25640427
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU85042/91A Ceased AU654152B2 (en) | 1990-09-06 | 1991-09-05 | Immunosuppressant composition |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU654152B2 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0401194A1 (en) * | 1989-06-02 | 1990-12-05 | G.D. SEARLE & COMPANY | Pharmaceutical composition for use in a method of inhibiting virus |
AU618838B2 (en) * | 1988-08-10 | 1992-01-09 | Praxis Pharmaceuticals, Inc. | Use of castanospermine as an anti-inflammatory and immunosuppressant agent |
AU623910B2 (en) * | 1988-05-16 | 1992-05-28 | United States of America, as represented by the Secretary, U.S. Department of Commerce, The | Chemotherapeutic composition for aids |
-
1991
- 1991-09-05 AU AU85042/91A patent/AU654152B2/en not_active Ceased
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU623910B2 (en) * | 1988-05-16 | 1992-05-28 | United States of America, as represented by the Secretary, U.S. Department of Commerce, The | Chemotherapeutic composition for aids |
AU618838B2 (en) * | 1988-08-10 | 1992-01-09 | Praxis Pharmaceuticals, Inc. | Use of castanospermine as an anti-inflammatory and immunosuppressant agent |
EP0401194A1 (en) * | 1989-06-02 | 1990-12-05 | G.D. SEARLE & COMPANY | Pharmaceutical composition for use in a method of inhibiting virus |
Also Published As
Publication number | Publication date |
---|---|
AU8504291A (en) | 1992-03-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4149905B2 (en) | Pharmaceutical composition for the treatment of transplant rejection, autoimmune disease or inflammatory condition comprising cyclosporin A and 40-O- (2-hydroxyethyl) -rapamycin | |
KR0160957B1 (en) | Rapamycin composition inhibiting transplant rejection in mammals | |
Benhaim et al. | Use of combination of low-dose cyclosporine and RS-61443 in a rat hindlimb model of composite tissue allotransplantation | |
KR101297302B1 (en) | Therapeutic agent for liver disease containing 2-amino-1,3-propanediol derivative as active ingredient and therapeutic method for liver disease | |
JP4004070B2 (en) | New uses of 1,3-propanediol derivatives | |
US8435520B2 (en) | Combinations of immunosuppressive agents for the treatment or prevention of graft rejections | |
AU630159B2 (en) | S-adenosyl-methionine in the treatment of pancreatitis and of the immuno rejection in the pancreas transplant | |
KR100515196B1 (en) | A pharmaceutical composition for preventing nephrotoxicity or renal dysfunction involving fibrotic lesions or scarring in the kidney interstitium induced by administration of a cyclosporin or tacrolimus | |
JP3179235B2 (en) | Methods for inducing immunosuppression | |
AU654152B2 (en) | Immunosuppressant composition | |
EP0081882B1 (en) | Medicine having transplant rejection and/or immunological inflammation inhibiting activities, as well as a method for inhibiting transplant rejection and/or immunological inflammation | |
WO1992004055A1 (en) | Immunosuppressant composition | |
US6355639B1 (en) | Reverse prenyl compounds as immunosuppressants | |
JP2000501118A (en) | Synergistic immunosuppressant composition containing 2,2'-bi-1H-pyrrole compound | |
US5837709A (en) | Use of castanospermine as an anti-inflammatory and immunosupressant agent | |
JP4846151B2 (en) | Use of treosulphan for conditioning patients prior to bone marrow or blood stem cell transplantation | |
EP1558240B1 (en) | Hypoestoxides, derivatives and agonists thereof for use in the treatment and prophylaxis of hyperlipidemia | |
JP2548491B2 (en) | Agent for the prevention and treatment of intimal thickening | |
US7368423B1 (en) | Composition and method for treating chronic allograft rejection | |
MACRIS et al. | Improved immunosuppression for heart transplant patients using intravenous doses of cyclosporine | |
Galmarini et al. | Cyclosporin Toxicity and Liver Transplantation in High Risk Patients | |
Sobh et al. | Cyclosporine in the treatment of steroid resistant rejection episodes in living donor kidney transplants | |
GaImarini et al. | CYCLOSPORIN TOXICITY AND LIVER TRANSPLANTATION IN mGH RISK PATIENTS | |
JPH08157364A (en) | Immunorejection suppressing agent |