Thalidomide remains one of the world’s most notorious drugs due to the severe birth defects it induced in children between 1957 and 1962. Yet, to some this drug is a lifesaver, as it now enjoys renaissance in the treatment for a wide range of conditions including leprosy, multiple myeloma, Behcet’s disease, and some cancers. However, thalidomide has also been linked to causing a new generation of thalidomide survivors in Brazil, where the drug is used to treat leprosy. Surprisingly how thalidomide causes birth defects and how it acts in the treatment of clinical conditions are still far from clear. In the past decade great strides in our understanding of the actions of the drug, as well as molecular targets, have been made. The purpose of this review is to look at the recent work carried out into understanding how thalidomide causes birth defects, it’s molecular targets and the challenges that remain to be elucidated. These challenges include identifying clinically relevant but nonteratogenic forms of the drug, and the mechanisms underlying phocomelia and species specificity. 1. Introduction 1.1. History Thalidomide was produced and released as a nonaddictive, nonbarbiturate sedative in 1957 by Chemie-Grunenthal. Thalidomide was marketed as very safe with no untoward side effects [1] and quickly became something of a wonder drug between 1957 and 1961 in the treatment of a range of conditions, in particular morning sickness. Thalidomide was marketed in 46 countries, under different names (e.g. Distaval in the UK and Australia, Isomin in Japan, Contergan in Germany, and Softenon in Europe) [1–4]. However soon after the drug’s release in Europe reports linked thalidomide to causing peripheral neuropathy in adult patients (which prevented its licensing and general release in the USA) as well as being behind the occurrence of a high and sudden increase of rare birth defects [3, 5–8]. The range and type of birth defects seen were unprecedented with the most striking and stereotypic feature being phocomelia, where the handplate remains but the proximal elements are missing or very short. Children also exhibited amelia in some cases (no limb) forelimb anomalies, handplate anomalies, and other damage to ears, eyes, internal organs, genitalia, and the heart [7, 9–20]. The damage caused by thalidomide was not mutually exclusive, with the majority of children exhibiting damage to multiple organs and tissues [3, 7]. It took until 1961, when reports and concerns from two independent clinicians, Lenz in Germany and McBride in Australia, confirmed that ingestion of
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