Thalidomide toxicity

Toxicity. Thalidomide has a low acute toxicity in 2 cases of reported overdose there was no evidence of respiratory or cardiac depression. Thalidomide has teratogenic effects when administered to women early in pregnancy. 

One enantiomer of penicillamine (D-) exhibits antiarthritic properties but foe other is highly toxic (Figure 8.3). The teratogenic effects of thalidomide were induced by one enantiomer, foe other exhibited foe beneficial effects against morning sickness. 

The ideal solubility equation has significant value in chiral systems, where a single enantiomer is desired as the product [20]. The behaviour of chiral compounds is very important in biological systems and in drug development, where it is typical for just one enantiomer of an API to be biologically active. The undesired enantiomer may be inert, or possess more serious toxicity effects, as in the case of Thalidomide. Many enantiomeric systems form three discrete solid phases, depending on the solution concentration. Pure crystals of each enantiomer will form at high concentrations of their respective enantiomer. At... 

A number of subcommittees were also established to assist the main Committee. These were the Subcommittee on Toxicity and the Subcommittee on Clinical Trials and Therapeutic Efficacy. Against the background of the thalidomide tragedy, an important subcommittee established was the Subcommittee on Adverse Reactions. The memberships of the main... 

Lenalidomide, a derivative of thalidomide, was introduced in 2004. Patients with multiple myeloma stage II/III, who have undergone at least one previous treatment can be treated with bortezomib or with lenalidomide in combination with dexamethasone. There is good oral absorptin with peak plasma levels at 0.5-4 hours. Lenalidomide is maily eliminated by the kidneys with a half-life of circa 3-9 hours. Teratogenicity cannot be excluded. Side effects include thrombosis, pulmonary embolus, and hepato-toxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopenia. 

Neubert R, Neubert D (1997) Peculiarities and possible mode of actions of thalidomide. Chapter 22. Drug toxicity in embryonic development II. In Kavlock RJ, Daston GP (eds) Springer Verlag. The handbook of experimental Pharmacology 124/11, pp 41-119... 

Evaluation of the developmental toxicity of thalidomide using frog embryo teratogenesis -Xenopus (EETAX) ... 

Thalidomide was initially selected as Candidate K17. It was discovered from peptide research but promoted as being structurally related to barbiturate with hypnotic properties, beyond those of the classic barbiturate Luminal, but without toxicity. 

The adverse effect profile of thalidomide is extensive. The most important toxicity is teratogenesis. Because of this effect, thalidomide prescription and use is closely regulated by the manufacturer. Other adverse effects of thalidomide include peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, and increased risk of deep vein thrombosis. Thrombosis is sufficiently frequent, particularly in the hematologic malignancy population, that most patients are placed on some type of anticoagulant when thalidomide treatment is initiated. 

Pharmacopeial compendia establish a couple of tests that should be carried out with raw material batches to determine their level of impurities. Concomitants usually detected are heavy metals, chloride, or sulfated ash. The presence of byproducts varies from raw material to raw material. Examples can be both innocuous substances such as monohydrogen phosphate, which is an impurity in dihydrogen phosphate salts and glycine, which is an impurity in alanine, and toxic substances, such as the classical enantiomer S of thalidomide. 

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