The following is an article about a drug that many of us thought would never be on the market again.
(Synovir by Celegene)---An immunosuppresive agent.
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
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.
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.
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.
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.
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.