Pharmacologic manipulation of graft versus host induced splenomegaly.
A murine graft versus host (GVH) model was developed as a tool for drug discovery. A pharmacological survey revealed that as a class the anti-rheumatics (e.g., auranofin, azathioprine, and methotrexate) were the most potent inhibitors of GVH induced splenomegaly. The immunosuppressants, cyclophosphamide and cyclosporine A, and the glucocorticoids (e.g., dexamethasone, hydrocortisone, and corticosterone) were all able to suppress the GVH response. Anti-inflammatory agents (e.g., indomethacin and piroxicam), and a series of central nervous system affecting drugs, including serotonin agonists (e.g., trifluromethylphenylpiperazine (tfMPP), 1-(3-chlorophenyl)piperazine (mCPP), and quipazine), and tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, and nortriptyline) typically were ineffective at doses up to 10 mg/kg. However, at high dose levels (30 mg/kg) piroxicam enhanced while amitriptyline and cyproheptadine (a mixed serotonin and histamine antagonist) suppressed GVH induced splenomegaly. These data provide a pharmacological profile for a series of immunomodulator, anti-inflammatory, and central nervous system active compounds in a classic immunologic model.
Roudebush
R E
RE
Department of Skeletal Disease Research, Eli Lilly and Company, Indianapolis, IN 46285.
Bryant
H U
HU
D000818:Animals; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002491:Central Nervous System Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006087:Graft vs Host Reaction / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D013163:Splenomegaly / Q000209:etiology / Q000517:prevention & control*
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002491:Central Nervous System Agents; D007166:Immunosuppressive Agents