A synthetic glutamic acid derivative.
And oral agent that is not soluble in water.
Mean proteins binding 55-66%, metabolized by non-enzymatic hydrolysis to varying metabolites eliminated in the urine.
Mechanisms of action include: inhibition of synthesis of monocyte derived tumor necrosis factor, inhibition of angiogenesis, and stimulates T-cell that have been partially activated by the T cell receptor, facilitating T cell activation and generation of antigen specific effector response.
A small molecule with anti-tumor necrosis factor alpha, immunomodulatory, and antiangiogenic properties.
Side effects include constipation, weakness, fatigue, sleepiness, and peripheral neuropathy, rash, hypothyroidism and thromboembolic phenomenon.
Stevens-Johnson syndrome and toxic epidermal necrolysis can rarely occur.
Can cause hepatic dysfunction.
Toxicity results in discontinuation of therapy in about 20% of patients.
The increase in risk of thromboembolism does not occur when the drug is administered in myeloma as a single agent but exists when combines with high dose corticosteroids or certain chemotherapeutic agents.
Effective in the treatment of erythema nodosum leprosum, AIDS related cachexia, aphthous ulcers in Behcets disease, chronic graft host disease, multiple myeloma, Kaposi’s sarcoma, prostate cancer, mouth and esophageal ulcers in HIV, mucocutaneous graft versus host disease, and cutaneous manifestations of systemic lupus erythematosus. myelofibrosis with myeloid metaplasia and myelodysplastic syndromes.
Reported response rates with Crohn’s disease associated with the remission rates ranging from 40-70%.
In children and adolescents with refractory Crohn’s disease thalidomide compare with placebo results in improved clinical remission at eight weeks.
Response rate 32% in multiple myeloma and with dexamethasone response rates are as high as 72%.
Increases complete response rate and event-free survival when combined with stem cell transplant and high-dose melphalan but does increase overall survival.
Relapses when thalidomide and high-dose melphalan and stem cell transplant are utilized appear to be more drug resistant than relapses in a controlled group not treated with thalidomide.
When utilized with high-dose melphalan and stem cell transplant the relapsed patients have a higher failure rate and shorter survival after salvage treatment.
30% durable responses even in patients with refractory or relapsed myeloma.
Targets myeloma cells in the bone marrow milieu.
Powerful teratogen with nearly 10,000 infants affected worldwide.
Fetal malformations occur when the drug is ingested by a pregnant woman between days 35 and 49 after the last menstrual period.
A single pill can cause teratogenic effects.
Approximately 40% of affected children die within the first year.
Malformations include absence of ears, arms, deafness, facial deformities, phocomelia, and gastrointestinal malformations.
Inhibits angiogenesis.
Teratogenicity results from inhibition of angiogenesis and neovascularization.
Peripheral neuropathy is the major dose limiting factor.
Neuropathy seen at doses varying from 25-16000 mg/day.
Neuropathy predominantly sensory, axonal, length dependent and nonreversible pattern that may affect the dorsal root ganglia.
Thalidomide neuropathy causes a small and large fire sensory peripheral neuropathy with symmetrical loss of all modalities, in the lower extremities were affected most.
Typical neurologic complaints from thalidomide include tingling or painful paresthesias and numbness in the feet and sometimes the hands.
Motor neuropathy recurs very infrequently with this agent and if present is usually mild.
Autonomic manifestations are common and include constipation, anorexia nausea hypotension, and bradycardia.
Peripheral neuropathy symptoms are usually reversible with dose reduction or stoppage of treatment, occasionally some side effects may be permanent.
Incidence of thalidomide induced peripheral neuropathy ranges from 37-83%, with most patients experiencing mild to moderate grade 1-2 toxicity.
Peripheral neuropthy typically is associated with symmetric paresthesias, with loss of tactile and pain response along with numbness and muscle cramps.
Rates of peripheral neuropathy after thalidomide treatment varies from 15-70%, with the risk related to cumulative dose and duration of therapy.
Factors influencing risk of neurotoxicity include prior neuropathy, advancing age, exposure to previous neurotoxic chemotherapy, vitamin B12 and/or folate deficiencies.
The risk and severity of thalidomide peripheral neuropathy increases with Coumadin dose and treatment duration, particularly if greater than 6 months.
Neurotoxicity may occur even with short term exposure.
Reduction or withdrawal of drug treatment can lead to symptom resolution in up to 16 weeks, although in some cases the neuropathy is irreversible.
Suppresses tumor necrosis-alpha factor production from monocytes and macrophages by accelerating TNF-alpha mRNA degradation and inhibiting activation of the transcription factor NF-kB.
Inhibits other cytokines including TGF-ß and IL-1ß.
Decreases the helper to suppressor T cell ratio in the peripheral blood of healthy men.
Maybe useful in patients with renal insufficiency and or cytopenias.
Has activity in Behcet’s syndrome.
In a randomized study of 722 patients given placebo or Thalidomide with gemcitabine or carboplatin chemotherapy in advanced non-small cell lung cancer: Resulted in no improvement in overall survival, and increased risk of thrombotic events, and an unexpected impaired survival in patients with non-squamous histology (Siow Ming Lee).
Wide dosing range with daily doses of 50-800 mg.