PH26996A - Use of PAF-antagonists for treating autoimmune diseases - Google Patents
Use of PAF-antagonists for treating autoimmune diseases Download PDFInfo
- Publication number
- PH26996A PH26996A PH39147A PH39147A PH26996A PH 26996 A PH26996 A PH 26996A PH 39147 A PH39147 A PH 39147A PH 39147 A PH39147 A PH 39147A PH 26996 A PH26996 A PH 26996A
- Authority
- PH
- Philippines
- Prior art keywords
- triazolo
- diazepine
- chlorophenyl
- thieno
- paf
- Prior art date
Links
- 239000005557 antagonist Substances 0.000 title description 11
- 208000023275 Autoimmune disease Diseases 0.000 title description 6
- FGNAJWFZOBYZLR-UHFFFAOYSA-N 3h-[1,2,4]triazolo[4,3-a][1,4]diazepine Chemical compound N1=CC=CN2CN=NC2=C1 FGNAJWFZOBYZLR-UHFFFAOYSA-N 0.000 claims description 23
- FWYVRZOREBYLCY-UHFFFAOYSA-N bepafant Chemical compound C1C=2SC=3N4C(C)=NN=C4CN=C(C=4C(=CC=CC=4)Cl)C=3C=2CC1C(=O)N1CCOCC1 FWYVRZOREBYLCY-UHFFFAOYSA-N 0.000 claims description 12
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 9
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 8
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 8
- 239000003848 thrombocyte activating factor antagonist Substances 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 241000282414 Homo sapiens Species 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- 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 description 20
- 229930105110 Cyclosporin A Natural products 0.000 description 20
- 108010036949 Cyclosporine Proteins 0.000 description 20
- 229960001265 ciclosporin Drugs 0.000 description 20
- 229930182912 cyclosporin Natural products 0.000 description 19
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 10
- 210000001772 blood platelet Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 8
- HNDGEYCCZGRMTN-UHFFFAOYSA-N thieno[3,2-f:4,5-f]bis[1]benzothiophene Chemical compound S1C2=CC=3SC=CC=3C=C2C2=C1C=C(SC=C1)C1=C2 HNDGEYCCZGRMTN-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 206010029155 Nephropathy toxic Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 229940109239 creatinine Drugs 0.000 description 4
- 230000007694 nephrotoxicity Effects 0.000 description 4
- 231100000417 nephrotoxicity Toxicity 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- BVAYTJBBDODANA-UHFFFAOYSA-N Prednisolon Natural products O=C1C=CC2(C)C3CCC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 BVAYTJBBDODANA-UHFFFAOYSA-N 0.000 description 3
- SCSIRWUYQVAIRL-UHFFFAOYSA-N ac1miw90 Chemical compound C1=2CC(C(=O)N(CCC)CCC)CC=2SC(N2C(C)=NN=C2CN=2)=C1C=2C1=CC=CC=C1Cl SCSIRWUYQVAIRL-UHFFFAOYSA-N 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000003018 immunosuppressive agent Substances 0.000 description 3
- -1 prednisolon Chemical class 0.000 description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 2
- 108010003541 Platelet Activating Factor Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- OJVYTHBLIPSGII-UHFFFAOYSA-N 16-thia-2,4,5,8-tetrazatetracyclo[8.6.0.02,6.011,15]hexadeca-1(10),4,6,8,11(15),13-hexaene Chemical compound N12CN=NC2=CN=CC2=C1SC1=C2CC=C1 OJVYTHBLIPSGII-UHFFFAOYSA-N 0.000 description 1
- LGNWUMGEJQAWQD-UHFFFAOYSA-N 1h-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chemical compound N1=CC2=CC=CC=C2N2CN=NC2=C1 LGNWUMGEJQAWQD-UHFFFAOYSA-N 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 208000004300 Atrophic Gastritis Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 108010036941 Cyclosporins Proteins 0.000 description 1
- 208000036495 Gastritis atrophic Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010028665 Myxoedema Diseases 0.000 description 1
- HCVFCFINNNNWBK-UHFFFAOYSA-O O=C(CNC(C(C(NNC1)N1C1=C(C2)C(CC=C3)=C3[S+]1Br)N2C(C=CC=C1)=C1Cl)=O)N1CCOCC1 Chemical compound O=C(CNC(C(C(NNC1)N1C1=C(C2)C(CC=C3)=C3[S+]1Br)N2C(C=CC=C1)=C1Cl)=O)N1CCOCC1 HCVFCFINNNNWBK-UHFFFAOYSA-O 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- JANHWNKOVXOFLY-QPPIDDCLSA-N [(2r,5s)-2,5-dimethyl-5-(octadecylcarbamoyloxymethyl)oxolan-2-yl]methyl 2-quinolin-1-ium-1-ylethyl phosphate Chemical compound O1[C@@](COC(=O)NCCCCCCCCCCCCCCCCCC)(C)CC[C@]1(C)COP([O-])(=O)OCC[N+]1=CC=CC2=CC=CC=C12 JANHWNKOVXOFLY-QPPIDDCLSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000016644 chronic atrophic gastritis Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- BYLPZVAKOZYZPH-UHFFFAOYSA-N imidazo[2,1-a]isoquinoline Chemical class C1=CC=C2C3=NC=CN3C=CC2=C1 BYLPZVAKOZYZPH-UHFFFAOYSA-N 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- XUWVIABDWDTJRZ-UHFFFAOYSA-N propan-2-ylazanide Chemical compound CC(C)[NH-] XUWVIABDWDTJRZ-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
This invention relates to the use of PAF-antagonists for treating autoimmune diseases.
In idiopathic thrombocytopenic purpura (ITP), a disorder of the immune mechanism causes massive destruction of the body's own thrombocytes, which are finally eliminated in the spleen. The thrombocyte survival time, instead of being 10 days, is frequently only a few hours and the megacariocytes in the bone marrow which form the thrombocytes are multiplied in compensation.
Previously, this disease was fatal in 60-80% of cases.
Since therapy with steroids, particularly prednisolon, the prognosis for ITP has improved significantly.
With this syndrome it is essential in many cases for the therapy, i.e. the drug treatment, to be maintained throughout the patient's life. The disadvantages of long-term cortisone therapy are well known to those skilled in the art.
According to one aspect of the invention, we have found that surprisingly, PAF-antagonists (PAF-acether antagonists) may be used successfully in therapy for treating autoimmune diseases, particularly idiopathic thrombocytopenic purpura, without giving rise to the known side effects of steroid treatment.
Many of the compounds which are used as PAF-antagonists (PAF = platelet activating factor) which may be used according to the invention are known from the patent literature and the specialist literature, e.g. in Prostaglandins 35, 781 (1988).
Ili g,
Examples of known PAF-antagonists include the tetrahydrofuran derivatives SDZ 63-4471, SDZ 63-675, L 659.886. BN 52 111, thiazole derivatives of the type RP 59 227, imidazo[2,1-a]- isoquinolines of the type SDZ 64412 and SD7 63135, dihydro- pyridines, compounds of type SRI 63441, RO 19-3704, CV 6209 and hetrazepine compounds such as thienodiazepines and benzodiazepines. Preferably, PAF-antagonists according to
European Patent Applications 194 416 and 254 245, published
A on September 17, 1986 and January 27, 1988, respectively, may be used according to the invention. The compounds listed below are particularly preferred. [4-(2-chlorophenyl)-1-methy1-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-carboxylic acid morpholide [4-(2-chloropheny1)-9-methy1-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-carboxylic acid amide 2-[4-(2-chlorophenyl)-9-methy1-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-ethane-1-carboxylic acid diethyl- amide 2-[4-(2-chlorophenyl)-9-methy1-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-yl]-ethane-1-carboxylic acid N,N-di- (2-hydroxyethyl)amide 2-[4-(2-chloropheny1)-9-methy1-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-ethane-1-carboxylic acid methylamide 2-[4-(2-chloropheny1)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-ethane-1-carboxylic acid isopropylamide egy, 2-[4-(2-chloropheny1)-9-methy1-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-ethane-1-carboxylic acid dimethyl- amide 2-[4,(2-chloropheny1)-9-methy1-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-ethane-1-carboxylic acid N'-methyl- piperazide 2-[4-(2-chloropheny1)-9-methy1-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4])diazepin-2-y1]-ethane-1-carboxylic acid pyrrolidide 2-[4-(2-chlorophenyl)-9-methy1-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-ethane-1-carboxylic acid piperidide 2-[4-(2-chloropheny1)-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a]- [1,4]diazepin-2-y1]-ethane-1-carboxylic acid morpholide 2-[4-(2-chloropheny1)-9-bromo-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-ethane-1-carboxylic acid morpholide 2-[4-(2-chlorophenyl)-9-methoxy-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepin-2-y1]-ethane-1-carboxylic acid morpholide 4-(morpholin-4-yl-carbonyl)-6-(2-chlorophenyl)-11-methy1-2,3,4,5- tetrahydro-8H-[1]benzothieno(3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine 3-(morpholin-4-y1-carbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5- tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo[4,3-a] [1.4] diazepine
Veg, 3-(N,N-diethylaminocarbony1)-6-(2-chlorophenyl)-11-methyl- 2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine 4-(N,N-diethylaminocarbonyl)-6-(2-chlorophenyl)-11-methyl-
2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine 4-(4-methylpiperazinylcarbonyl)-6-(2-chlorophenyl)-11-methyl- 2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine
4-(N-methy1-N-2-hydroxyethylaminocarbony1)-6-(2-chlorophenyl)- 11-methy1-2,3,4,5-tetrahydro-8H-[1]benzothieno(3,2-f] [1,2,4]- triazolo[4,3-a] [1,4]diazepine 4-(N,N-dimethylaminocarbony1)-5-(2-chloropheny1)-10-methy1- 3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo-
[4,3-a] [1,4]diazepine 3-(N,N-diethylaminocarbonyl)-5-(2-chlorophenyl)-10-methyl- 3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine 3-(N,N-diethylaminocarbonyl-5-(2-chlorophenyl)-10-bromo-3,4-
dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine 4-(morpholin-4-yl-carbonylmethylaminocarbonyl)-5-(2-chlorophenyl)- 10-bromo-3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]- triazolo[4,3-a] [1,4]diazepine
“gg 4-(morpholin-4-yl-cartonyl)-6-(2-chlorophenyl)-11-methy1- 2,3,4,5-tetrahydro-8H-[1]benzothieno[ 3,2-f]imidazo[1,2-a] [1,4]- diazepine 4-(N,N-diethylamino)-6-(2-chlorophenyl)-11-methyl1-2,3,4,5-
tetrahydro-8H-[1]benzothieno[3,2-f]Jimidazo[1,2-a] [1,4]diazepine 3-(N-morpholinomethyl)-5-(2-chlorophenyl)-10-methyl-3,4-dihydro- 2H,7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine 3-(acetoxymethyl)-5-(2-chlorophenyl)-10-methy1-3,4-dihydro-2H,
7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4] diazepine 3-(1,2,4-triazolyl-1-y1-methyl)-5-(2-chlorophenyl)-10-methy1- 3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine
3-(N-2,6-dimethylmorpholino-methyl)-5-(2-chlorophenyl)-10-methyl- 3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine 3-acetoxymethy1-5-(2-chlorophenyl)-3,4-dihydro-2H,7H-cyclopenta- [4,5]thieno[3,2-f] [1,2,4]triazol0[4,3-a] [1,4]diazepine
4-acetoxymethyl-6-(2-chlorophenyl)-11-methy1-2,3,4,5-tetra- hydro-8H~[1]benzothieno[3,2-f)imidazo[1,2-a] [1,4]diazepine 3-acetoxymethyl-5-(2-chlorophenyl)-10-methyl-3,4-dihydro-2H, 7H-cyclopenta[4,5]thieno[3,2-f}imidazo[1,2-a] [1,4]diazepine
2 “qi 3-diethylaminomethy1-5-(2-chlorophenyl)-10-methy1-3,4-dihydro- 2H,7H-cyclopental4,5]thienoc[3,2-f] [ 1,2,4]triazolo[4,3-a] [1,4]diazepine 4-hydroxymethyl-6-(2-chlorophenyl)-11-methyl1-2,3,4,5-tetrahydro-
8H-[1]benzothieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine 4-(N-morpholinomethyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5- tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine 4-(pyrazolyl-1-yl-methyl)-6-(2-chlorophenyl1)-2,3,4,5-tetra-
hydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine 4-[4,4-dimethyl-2-oxazolin-2-y1]-6-(2-chlorophenyl)-11-methyl- 2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine
4-[4,4-dimethyl-2-imidazolin-2-y1}-6-(2-chlorophenyl)-11-methyl- 2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine 4-[1,4,4-trimethyl-2-imidazolin-2-y1]-6-(2-chloropheny1)-11- methyl-2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]-
triazolo[4,3-a] [1,4]diazepine 4-aminocarbonyl-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetra- hydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo[4,3-a]- [1,4]diazepine ee e———————————
Qs 4-[morpholin-4-y1-carbony1]-6-(2-chlorophenyl)-2,3,4,5-tetra- hydro-8H-[1]benzothieno[3,2-f]imidazo[1,5-a] [1,4]diazepine 4-[4,4-dimethy1-2-thiazolin-2- y1]-6-(2-chlorophenyl)-11-methyl- 2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine 4-amino-6-(2-chlorophenyl)-11-methy1-2,3,4,5-tetrahydro-8H- [1Jbenzothieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine 3-(N-morpholiny1-methy1)-5-(2-chlorophenyl)-10-methyl-3,4- dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f Jimidazo[1,2-a] ~ [1,4]diazepine 4-(1,2,4-triazol-1-y1-methy1)-6-(2-chloropheny1)-11-methy1- 2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-f] [1,2,4]triazol- [4,3-a] [1,4]diazepine 4-(1,2,4-triazol-1-yl-methy1)-6-(2-chloropheny1)-11-methyl- 2,3,4,5-tetrahydro-8H-[1]benzothieno[3,2-fJimidazo[1,2-a] [1,4]diazepine
The following are more particularly preferred: 6-(2-chloropheny1)-8,9-dihydro-1-methy1-8-[(4-morpholiny1)- carbony1]-4H,7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine (Web 2170) 4-(2-chloropheny1)-9-methy1-2-[3- (4-morpholiny1)-3-propanon- 1-y1]-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (Web 2086)
ER —————— re 6-(2-chloropheny1)-8,9-dihydro-1-methy1-8-[dipropylamino- carbony1]-4H,7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine (Web 2347).
Any reference herein to PAF antagonists includes within its scope all pharmaceutically acceptable acid addition salts thereof, and any and all isomers and tautomers thereof having similar activity.
According to another aspect of the invention we provide a method of treating autoimmune diseases especially idiopathic thromocytopenic purpura in a human or animal subject which comprises administering to the said subject an effective amount of a PAF-antagonist as hereinbefore described.
By way of Example of the application of the invention, a 52 year old male patient with ITP was treated with the PAF- antagonist Web 2086 {4-(2-chlorophenyl)-9-methyl-2-[3-(4- morpholinyl)-3-propanon-1-y1]-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine} in a dosage of 4 x 20 mg a day, by oral route, instead of prednisolon. There was a rapid increase in the thrombocytes which had previously not been observed in the patient in question in the 3 years he had had the disease, reliably diagnosed, during his treatment with steroids. The treatment with Web 2086 was discontinued after 10 days, and there was a corresponding fall in the thrombocyte count, as expected. This is illustrated graphically in Fig. 1, as described below.
The advantage of treatment with PAF-antagonists according to the invention consists in the total absence of side effects, : ry
Ke Gc as far as is currently known in humans, compared with the thera- peutic agents hitherto used for this treatment, which have been shown to have considerable side effects, and the rapid increase in the thrombocytes. For a single dose, a dosage range of between 5 and 50 mg for oral administration appears to be acceptable whilst for intravenous administration single doses of between 2.5 and 30 mg are advisable.
In another embodiment according to the invention, the
PAF-antagonist may be used in conjunction with a cofactor in a low-dose form. Examples of possible cofactors include substances with an immune suppressant effect as well as steroids in low concentrations.
It is known from prior art that immunosuppressive substances, for example cyclosporin, are recommended for the treatment of idiopathic thrombocytopenic purpura. As is known, cyclosporins give rise to strong side effects. The use of a compound according to the invention has been found to lead to a considerable reduction of these side effects. In this connection, special note has to be taken of the pharmaceutical compositions consisting of a PAF-antagonist, selected from European Patent Applications 176 928, 268 242, 230 942, 240 899, 194 416, 254 245, and 255 028, and a cyclosporin, in particular cyclosporin A, azathioprin or prednisolon. The European Patent Applications listed above contain, as their central structural element, a thieno[3,2-f]- [1,2,4]triazolo-[4,3-a] [1,4]diazepine or a [1,2,4]triazolo- [4,3-a] [1,4]-benzodiazepine. Agents containing the PAF- antagonists Web 2086, Web 2170 or Web 2347 and a cyclosporin, particularly cyclosporin A, are of special significance.
Noe TG
Because of the aetiology of ITP (Werlhof disease) as an autoimmune disease, treatment with PAF-antagonists, particularly 4-(2-chloropheny1)-9-methy1-2-[3-(4-morpholiny1)-3-propanon-1- y1]-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (Web 2086), may also be advisable in the following autoimmune diseases: autoimmune haemolytic anaemia, autoimmunologically ~ caused glomerulonephritis, thyreoidis Hashimoto, primary 0 myxoedema, pernicious anaemia, autoimmune atrophic gastritis,
Addison's disease, juvenile diabetes, Goodpasture syndrome, idiopathic leucopenia, primary biliary cirrhosis, active or chronically aggressive hepatitis (HBsAg-neg.), ulcerative colitis, chronic polyarthritis and systemic lupus erythematodes (SLE).
The synthesis of 4-(2-chlorophenyl)-9-methyl-2-[3-(4- morpholinyl)-3-propanon-1-y1]-6H-thieno[3,2-f] [1,2,4]triazolo- [4,3-a] [1,4]diazepine (Web 2086) and the production of galenic preparations is known from German Offenlegungsschrift DE Al 35 02 392 (Example 1). The synthesis of Web 2170 and Web 2347 is known from European Patent Application 254 245. The active substances may be used in the form of conventional galenic preparations such as tablets, suppositories or injectable solutions. Details of the preparation thereof are disclosed in
European Patent Applications 194 416 and 254 245, to which reference is hereby made.
According to a further aspect of this invention, we provide pharmaceutical preparations containing a PAF-antagonist and a substance having an immune suppressant effect, generally containing up to 40% by weight of the immunosuppressive substance relative to the total amount of the active substance. Such oo “¢q9¢ a preparation may be in association with a pharmaceutically acceptable carrier, diluent or excipient. A proportion of between 10 and 20% by weight is preferred. The amount of the
PAF-antagonist in a preparation per single dose amounts to between 5 and 50 mg, when administered orally, and between 2 and 30 mg, when administered intravenously.
The effective compositions according to the invention may be used in the form of the conventional galenic preparations, for instance 1. Tablets 5 parts by weight of effective component according to the invention 1 part by weight of stearic acid 194 parts by weight of glucose
The components are compressed to form tablets of 200 mg. 2. Ampoule solutions 5 mg of effective component 45 mg of sodium chloride ad 5 ml Aqua pro inj | In Figure I, the number of thrombocytes is shown in thousands against the time in days. The treatment starts on day 0 and as expected, because of a certain latency, the number of thrombocytes drops again on the next day, to rise very rapidly to approximately normal levels of about 150,000 in the course of the treatment. After the treatment ends on the eleventh day, the number of thrombocytes also falls again, as expected.
“gq
The thrombocytes were counted by known methods using a
Coultex Counter® Model S-Plus II.
Figure I 150,00 » 140,00 130,00 120,000" 110,00 wn $100,000 stort > . . 0 90,000 finish
G 80,000 1 91 £ £70,000" 60,000 o o 50,000 40,000 i
TTT TTT CYT rT TT TT Tr TTY TY TTT TTT rT a TTT —TiTT “v0 YY 2 0% 4 5 6 7 B 9 0111213141516 17 days
—— - = ——————
N ej) (
An important side-effect of cyclosporin in man is nephro- toxicity (Mihatsch MJ, Thiel G. Spichtin HP, Oberholzer M,
Brunner FP, Harder F et al. Transplant Proc (1983) 15:2821-2835),
The treatment of male spontaneously hypertensive (SH) rats with cyclosporin causes damage to the kidneys which has been used as a model for cyclosporin nephrotoxicity (Reference:Ryttel
B, Siegel H, Mueller AM, Hauser R, Mihatsch MJ, Transplant Proc (1985) 17:1430-1431).
This nephrotoxicity can be monitored by measurements of serum creatinine. Elevation of serum creatinine provides evidence of renal damage. Groups of 8 SH rats were dosed orally for 28 days either with 2, 25 or 50 mg/kg cyclosporin; 2, 25 or 50 mg/kg cyclosporin plus 13 mg/kg WEB 2170; 13 mg/kg
WEB 2170 alone or vehicles (olive oil and water alone). Blood was removed before and 4, 13, 22 and 29 days after commencement of treatment. The mean level of serum creatinine in rats treated with cyclosporin plus WEB 2170 was lower than that for rats treated with cyclosporin alone. The effect was statistically significant (0.05>p). As an example, at 20 days mean creatinine levels in micromoles per litre serum were:
Vehicle 56 : 13 mg/kg WEB 2170 alone 55 2 ma/kg cyclosporin alone 59 25/mg/kg cyclosporin alone 93 50 mg/kg cyclosporin along n 13 mg/kg WEB 2170 plus 2 mg/kg cyclosporin 53
-— ee — ee
NTE
13 mg/kg WEB 2170 plus 25 mg/kg cyclosporin 65 13 mg/kg WEB 2170 plus 50 mg/kg cyclosporin 67
Based on these results it appears that the combination cyclosporin/WEB 2170 may be associated with reduced nephrotoxicity in comparison with cyclosporin alone.
Claims (1)
1. A method of treating autoinmume diseases, including idiopathic thrombocytopenic purpura, in a human or animal subject which comprises administering to the said subject an effective amount of a PAF-antagonist selected from 4- (2-chlorophenyl)-9-methyl-2-{3- (4-morpholinyl)- 3-propanon-1-y1]-6H-thieno[3,2-f] [1,2,4] triazolo- [4,3-a][1,4]diazepine (Web 2086) and 6- (2-chlorophenyl)-8, 9-dihydro- 1-methyl-8- [ (4-morpholinyl)carbonyl] -4H, 7H-cvclopenta[4,5] -thieno- [3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine (Web 2170). HFTMUT LOHMANN Inventor
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3828678 | 1988-08-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PH26996A true PH26996A (en) | 1993-02-01 |
Family
ID=6361480
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PH39147A PH26996A (en) | 1988-08-24 | 1989-08-24 | Use of PAF-antagonists for treating autoimmune diseases |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0361077A3 (en) |
| JP (1) | JPH03500898A (en) |
| KR (1) | KR900701276A (en) |
| AU (1) | AU627763B2 (en) |
| DK (1) | DK95890D0 (en) |
| HU (1) | HUT59604A (en) |
| IL (1) | IL91386A0 (en) |
| NZ (1) | NZ230406A (en) |
| PH (1) | PH26996A (en) |
| WO (1) | WO1990001927A2 (en) |
| ZA (1) | ZA896422B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE170559T1 (en) * | 1991-05-31 | 1998-09-15 | Genentech Inc | TREATMENT OF HIV-ASSOCIATED IMMUNE THROMBOPENIA PURPURA |
| US5250732A (en) * | 1991-07-18 | 1993-10-05 | Genentech, Inc. | Ketamine analogues for treatment of thrombocytopenia |
| JP3060287B2 (en) * | 1995-10-09 | 2000-07-10 | 参天製薬株式会社 | Aqueous eye drops containing apaphant as the main drug |
| WO1998043638A1 (en) * | 1997-03-27 | 1998-10-08 | Kyowa Hakko Kogyo Co., Ltd. | Therapeutic agent for autoimmune diseases |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2591596B1 (en) * | 1985-12-13 | 1988-09-09 | Roussel Uclaf | NOVEL 4H-TRIAZOLO (4,3-A) (1,4) BENZODIAZEPINES, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS CONTAINING THEM |
| ES2037013T3 (en) * | 1986-01-21 | 1993-06-16 | Boehringer Ingelheim Kg | PROCEDURE FOR PREPARING TIENO-1,4-DIAZEPINES. |
| DE3610848A1 (en) * | 1986-04-01 | 1987-10-15 | Boehringer Ingelheim Kg | NEW 1,4-DIAZEPINE |
| PH30676A (en) * | 1986-07-22 | 1997-09-16 | Boehringer Ingelhein Kg | Hetrazepine compounds which have useful pharmaceutical utility |
| YU136287A (en) * | 1986-07-25 | 1990-06-30 | Boehringer Kg | Process for preparing new 1,4 benzodiazepines |
| DE3710921C2 (en) * | 1986-10-21 | 1996-09-26 | Korth Ruth | Use of Gingkolide BN 52020, BN 52021 and BN 52063 for the treatment of arteriosclerosis |
| EP0268242B1 (en) * | 1986-11-17 | 1992-03-18 | Yoshitomi Pharmaceutical Industries, Ltd. | Paf-antagonistic thienotriazolodiazepine compounds and pharmaceutical uses thereof |
-
1989
- 1989-08-22 IL IL91386A patent/IL91386A0/en unknown
- 1989-08-23 WO PCT/EP1989/000992 patent/WO1990001927A2/en unknown
- 1989-08-23 HU HU896004A patent/HUT59604A/en unknown
- 1989-08-23 EP EP89115506A patent/EP0361077A3/en not_active Withdrawn
- 1989-08-23 NZ NZ230406A patent/NZ230406A/en unknown
- 1989-08-23 ZA ZA896422A patent/ZA896422B/en unknown
- 1989-08-23 JP JP1509180A patent/JPH03500898A/en active Pending
- 1989-08-24 PH PH39147A patent/PH26996A/en unknown
- 1989-08-24 AU AU40173/89A patent/AU627763B2/en not_active Ceased
-
1990
- 1990-04-18 DK DK095890A patent/DK95890D0/en not_active Application Discontinuation
- 1990-04-20 KR KR1019900700805A patent/KR900701276A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1990001927A3 (en) | 1990-05-17 |
| IL91386A0 (en) | 1990-04-29 |
| DK95890A (en) | 1990-04-18 |
| WO1990001927A2 (en) | 1990-03-08 |
| HUT59604A (en) | 1992-06-29 |
| ZA896422B (en) | 1991-04-24 |
| AU4017389A (en) | 1990-03-01 |
| KR900701276A (en) | 1990-12-01 |
| HU896004D0 (en) | 1990-11-28 |
| EP0361077A2 (en) | 1990-04-04 |
| JPH03500898A (en) | 1991-02-28 |
| AU627763B2 (en) | 1992-09-03 |
| NZ230406A (en) | 1992-03-26 |
| EP0361077A3 (en) | 1990-07-11 |
| DK95890D0 (en) | 1990-04-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2002523370A5 (en) | ||
| KR20150016597A (en) | Drug for preventing and/or treating polycystic kidney disease | |
| WO2003100009A2 (en) | Enhancing the efficacy of reverse transcriptase and dna polymerase inhibitors (nucleoside analogs) using pnp inhibitors and/or 2'-deoxyguanosine and/or prodrug thereof | |
| AU2001238124B2 (en) | Adenosine a2a receptor antagonists for treating and preventing hepatic fibrosis,cirrhosis and fatty liver | |
| CA1091155A (en) | Method of pharmacologically treating drug addiction with alpha-methyl-para-tyrosine | |
| PH26996A (en) | Use of PAF-antagonists for treating autoimmune diseases | |
| US5958928A (en) | Pharmaceutical agents containing methotrexate derivative | |
| PL339774A1 (en) | Method of preventing nephrotoxicity caused by cephalosporins and tacrolimus | |
| HUT72496A (en) | Xanthine derivatives for use as diuretics | |
| HUGULEY et al. | Acute leukemia treated with divided doses of methotrexate | |
| BR0008054A (en) | Crystalline form of eplerenone | |
| US6660719B2 (en) | Inhibiting T-Cell proliferation | |
| EP0510837B1 (en) | Synergistic combinations in the treatment of anxiety | |
| Kahan | The evolution of therapeutic immunosuppression and the potential impact of drug concentration monitoring | |
| Bashey | Immunosuppression with limited toxicity: the characteristics of nucleoside analogs and anti-lymphocyte antibodies used in nonmyeloablative hematopoietic cell transplantation | |
| US5478815A (en) | Liver protectant tocophery-ascorbyl-phosphate | |
| CA1336825C (en) | Use and agent for reducing the side effects of tnf | |
| Haylor et al. | Endothelin antagonism and contrast nephropathy | |
| DE3927804A1 (en) | Treating auto-immune disease with platelet activating factor - opt. formulated with immunosuppressant, esp. for idiopathic thrombocytopaenic purpura | |
| Silberman | Dosage of corticosteroids in renal allograft rejection | |
| Vik et al. | An overdose of vincristine in an eleven-year-old boy | |
| Warzocha et al. | Fulminant 2-chlorodeoxyadenosine-related peripheral neuropathy in a patient with paraneoplastic neurological syndrome associated with lymphoma | |
| Ritschel | Cimetidine dosage regimen for patients with renal failure and for geriatric patients | |
| Ryan | Two Decades of Experience in the Treatment of Paget’s Disease of Bone with Plicamycin (Mithramycin) | |
| US20090270401A1 (en) | Use of a dihydroimidazopyrazoine derivative for treating or preventing pain |