THALIDOMIDE (Synovir by Celegene)---An immunosuppresive agent.

Pharmacology: Thalidomide is being investigated for several conditions. It has received orphan drug status for the treatment of aphthous ulcers, clinical manifestations of mycobacterial infections and primary brain malignancies. It is also available under an open-label, expanded access protocol for cachexia. It is being investigated for soy-oral immune and inflammatory conditions including erythema nodosum leprosum (ENL),. prurigo nodularis. actinic prurigo, discoid lupus erythematosus, aphthous stomatitis, Bechet's syndrome, graft-versus-host disease, HI V/AIDS progression. rheumatoid arthritis, Type 2 diabetes mellitus and multiple sclerosis.

Thalidomide is a derivative of glutamic acid and glutethimide but has a different activity profile. It has sedative-hypnotic, anti-inflammatory and immunosuppressive effects. Its imrnunosuppressant effects appear to be related to selective inhibition of tumor necrosis factor-alpha (TNF-() synthesis. Thalidomide may also stimulate supressor T cell proliferation. It has been shown to change surface receptors on CD4+ cells, CD8+ cells and leukocytes and increase numbers of B-cells. Its sedative-hypnotic effects may involve the activation of a forebrain sleep center, but even at high doses, it does not result in respiratory depression. Thalidomide has also been reported to inhibit basic fibroblast growth factor-induced angiogenesis.

 Pharmacokinetics: Oral absorption is highly variable. Mean peak levels of 0.47 and 1.5 rncg/ml are evident at 4 and 6 hours following 100 and 200 mg doses; doses of 800 mg/day yield peaks of 5 mcg/ml The mean volume of distribution is 120 L with high levels found in the GI tract. liver and kidney and lower levels detected in muscle, brain and adipose tissue. Thalidomide appears to be highly protein bound. Degradation appears to be mainly by non-enzymatic hydrolytic cleavage with only the parent compound possibly being modified by the P4W system. Thalidomide has been detected in plasma for  (24 hours following a single 200 my dose. Total body clearance is "10.5 L/hr with an elimination half-life of "8.7 hours. Urinary excretion accounts for 0.6% of the total dose indicating predominantly a non-renal route of elimination.

 Clinical studies: In 73 patients with severe, recurrent aphthous stomatitis (including Bechet's  disease), complete remission was achieved in 32 thalidomide patients (100 mg/day) versus 6 placebo patients. Improvement has been observed in 90% of 4500 patients with serious  erythema nodosom leprosum or Type 2 reaction in lepromatous leprosy (200 to 500 mg/day). A complete response was observed in 14/44 patients with refractory or "high-risk" chronic graft-versus-hosts disease and a partial response was seen in 12 patients (800 to 1600 mg/day). Thalidomide inhibited viral activation in the peripheral blood mononuclear calls In 16/17 patients with advanced HIV infection In 23 patients with systemic lupus erythematosus and cutaneous lesions unresponsive to standard therapies, 90% had complete remission and a significant reduction in average prednisone dose (from 40.5 to 17.4 mg/day) while receiving thalidomide 300 mg/day. In 29 hemodialysis patients with refractory uremic pruritis 55% of patients experienced a 78% mean reduction in pruritis when given 100mg/day of thalidomide compared with no response in the control group.

 Side effects: Drowsiness is the most frequent adverse effect and, depending on the treatment population, has occurred in 11% to 100% of patients; it can be minimized with bedtime administration. Constipation (3% to 30%) is mild and easily controlled with stool softeners or mild laxatives. An erythematous rash (<1%) can occur 2 to 10 days after initiation of therapy, which resolves upon discontinuation and if necessary, with antihistamines. Thalidomide-induced peripheral neuropathy has occurred in 15% to 50% of non-lepromatous patients but is rare (<1%) in ENI patients; it is reversible with drug discontinuation. Other reported adverse reactions include increased appetite, weight gain, headache, loss of libido, edema of the face and extremities, nausea, pruritis, alopecia, eosinophilia, leukopenia, menstrual abnormalities, dry skin and galactorrhea.

 Summary: Thalidomide is currently being investigated for several different conditions. Despite serious safety Issues (eg, teratogenecity and peripheral neuropathy) it may be very useful in select patients. Optimal dosing of thalidomide has not been established because sedation and constipation often limit dose escalation.

The FDA issued an approvable letter on September 19, 1997 to Celegene for thalidomide as treatment for ENL, a serious complication Of leprosy indicating the benefits are viewed to outweigh the risks in this patient population. Details of a restricted distribution control system must be submitted before a final approval can be made.