Thalidomide mechanism

DRUGS THAT INTEREFERE WITH ANGIOGENESIS: THALIDOMIDE

reintroduced in 1998 (in the US) for use in erythema nodosum leprosum (ENL), a complication of Hansen's disease
- ENL is characterized by painful skin nodules and nerve damage

in Hansen's disease, THALIDOMIDE works by suppressing immune and inflammatory reactions, i.e., it doesn't function as an antibiotic - as soon as treatment is stopped, symptoms reappear

unknown, complex mechanism of action as antineoplastic - no cytotoxic effects on immune system cells, but does alter the ratios of various types of immune cells and changes the expression of molecular markers on their surfaces

specifically:

is antiangiogenic (decreases FGF) - also causes decreased cell movement (anti-metastatic?)

causes a shift in the pattern of T cell responses, favouring a Th2 response over Th1 ("more interleukins, less interferon and TNF") - perhaps the most effective anti-TNF agent known (which is why it's under investigation for use in inflammatory bowel disease)

is sedating and improves well being - restores appetite and decreases wasting

originally developed in the 1950's as an antihistamine (explaining the sedation), and marketed as a "wonder drug for prevention of morning sickness" because of its ability to relieve "the anxiety and stress of pregnancy"
- compare this 1960's promotional wording to the text of a warning letter issued by the FDA shortly after the reintroduction of THALIDOMIDE as an approved treatment for Hansen's disease (see esp. the bottom of page 3)
identified as a developmental toxin because of the dramatic increase in birth defects following its prescrption to pregnant women in Canada and Europe in the late 1950's and early 1960's
the table identifies the rapid increase of cases of phocomelia in one town (Hamburg Germany) following approval for use of THALIDOMIDE in early 1959