Design and synthesis of orally active inhibitors of TNF synthesis as anti-rheumatoid arthritis drugs.

A novel series of TNF inhibitors was identified based on the screening of existing MMP inhibitor libraries. Further SAR optimization led to the discovery of a novel lead compound. Its synthesis, efficacy in experimental animal models, and pharmacokinetic data are discussed.

Mycophenolic acid increases apoptosis, lysosomes and lipid droplets in human lymphoid and monocytic cell lines.

Background: Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase, is the active agent of the immunosuppressive drug, mycophenolate mofetil (MMF). Previous studies have shown that MPA inhibits DNA synthesis in T and B lymphocytes by blocking de novo guanosine synthesis, and that MPA induces monocyte differentiation. MMF is being used for prevention of organ graft rejection and has also shown efficacy in rheumatoid arthritis trials.

Lymphocyte-selective antiproliferative and immunosuppressive effects of mycophenolic acid in mice.

Mycophenolic acid (MPA), administered orally to mice, inhibits the formation of antibodies to sheep erythrocytes. MPA also suppresses, in a dose-related manner, the generation of cytotoxic T-lymphocytes against allogeneic cells in mice and prevents the elimination of allogeneic cells. However, short-term of T lymphocytes with therapeutically attainable doses of MPA does not inhibit the effector phase of cytotoxicity.

The effects of histamine and serotonin on polymorphonuclear leukocyte accumulation in the rat.

Histamine and serotonin were evaluated for their effects on rat polymorphonuclear leukocyte (PMN) accumulation in vivo and PMN migration in vitro. Both of the mediators inhibited the accumulation of PMNs when injected into the pleural cavity in a saline vehicle, and reduced the PMN content of the peripheral blood. Histamine also reduced the cellular influx when administered in combination with an intrapleural injection of carrageenan.

Increased myelopoiesis during Leishmania major infection in mice: generation of 'safe targets', a possible way to evade the effector immune mechanism.

BALB/c mice are highly susceptible to Leishmania major infection and develop a disseminated lethal disease. Previous experiments indicate that during infection the spleen is heavily populated with large mononuclear cells containing amastigotes. Morphologically these cells resemble undifferentiated monocytes and granulocytes.

In vivo and in vitro effects of dexamethasone on leukocyte migration in the rat adjuvant arthritis model.

When polymorphonuclear leukocytes (PMNs) and mononuclear cells were isolated from the blood of dexamethasone-treated normal rats, in vitro mononuclear cell migration was inhibited and PMN migration was stimulated in comparison to controls. Inflammogen-induced PMNs showed inhibited cell migration due to dexamethasone treatment. Gamma camera imaging was then used to detect cells in vivo after labeling with indium-111.

Relationship between adherence, chemotaxis and the accumulation of rat polymorphonuclear leukocytes at an inflammatory site.

The effects of a nonsteroidal anti-inflammatory agent, indomethacin, a steroidal anti-inflammatory drug, dexamethasone and an antirheumatic agent, levamisole, on rat polymorphonuclear leukocyte (PMN) adherence and migration were examined. Adherence was evaluated using nylon fiber columns and migration was studied in vitro using Boyden chambers In addition, the effects of these drugs on PMN accumulation in he carrageenan-injected pleural cavity was evaluated. PMNs removed from animals treated with indomethacin, 1 mg/kg p.

Lymphocytotoxicity in mycosis fungoides.

The phenomenon of lymphocytotoxicity was demonstrated in 29 patients with mycosis fungoides, using a newly described epithelial cell culture system and an isotope marker, 125Iododeoxyuridine (125IUdR). Lymphocytotoxicity was demonstrated in patients in the generalized plaque and the erythroderma phases of the disease (P is less than or equal to 0.05).