Maybe thalidomide is one of the most controversial drug in the medicinal history. It was initially withdrew from the market 'cause of its teratogenecity tragedy. Then it raised a lot of interest since it was found to have anti TNF-a and anti-angiogenesis properties. It is now on the market again for the treatment of multiple myeloma, and other therapeutic potentials are also under investigation. Another controversial issue is its pharmacological mechanisms. I don't think thalidomide works as a real TNF-a inhibitor in vivo, because we could see the inhibition effect in vitro only under a rather high concentration, about 100~200 uM, which is nearly impossible to achieve in vivo.
See the derivative of thalidomide in this publication. Most of what you said is true. http://www.urologiconcology.org/article/S1078-1439(12)00169-X/abstract
You are right, in vivo and in vitro studies have yielded variable results, however, according to these papers, it inhibits TNF-a in vivo:
Thalidomide reduces tumour necrosis factor alpha and interleukin 12 production in patients with chronic active Crohn's disease" PMID:11788559
The minimum dose of thalidomide used (1 µM) inhibited TNF-α production by peripheral blood mononuclear cells from HTLV-1-infected individuals PMID:22011961
It is concluded that compared with conventional chemotherapy, thalidomide is a effective drug for treating MM patients. Thalidomide in combination with chemotherapy (T-VAD, T-MP) may be one better therapeutic regimen with high efficiency and milder adverse reactions. Serum level of TNF-alpha is an indicator for finding effects of thalidomide, and plays a role in the pathogenesis of MM.
PMID:19099634
Thalidomide analogues had a greater inhibitory effect on TNF production than did thalidomide. In patients with advanced HF, thalidomide was safe and potentially effective when used at lower doses. However, dose-limiting toxicity was observed in two patients. PMID:12411981
In rabbits: "We previously reported that rabbits with experimental tuberculous meningitis were protected from death by a combination of antibiotics and thalidomide therapy. Survival was associated with inhibition of tumor necrosis factor alpha (TNF-alpha) production by thalidomide" PMID:10318940
Best Regards
Thank you Rolando, your informations are of great help!
I have noticed that in vivo thalidomide does inhibit the production of TNF-a. I think the situations are more complicated when the drug goes into the body. The drug are undergoing the metabolism (maybe the metabolites have pharmacological activities, and indeed it has been shown that they contributed to the anti-angiogenesis effect of thalidomide), the biol-pathways are crossover, and the effect of TNF-a inhibition may be indirect.
In the article you provided (PMID:11788559), the authors showed that in vitro 1~5ug/ml of thalidomide significantly reduced the production of TNF-a from lamina propria mononuclear cells (LPMC) derived from Crohn’s disease patients. This concentration (equal to 3~16 uM) are lower than 100~200 uM I mentioned previously and could be much easier to achieve in this disease treatment. I think the pharmacology activities of thalidomide are quite depend on the models it used, since the 100~200 uM potency are seen in the LPS stimulated PBMC model, which should be quite different from the LPMC model.
You are welcome!, for more information on the interaction of thalidomide with genes, etc, pls take a look at this record of the pharmacogenomics knowledgebase http://www.pharmgkb.org/drug/PA451644#tabview=tab4&subtab=33
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