It may interact with sedatives due to its sedative action and bradycardic agents, like beta-blockers, due to its bradycardia-inducing effects. The risk of peripheral neuropathy may be increased by concomitant treatment with other agents known to cause peripheral neuropathy.[17] The risk of venous thromboembolisms with thalidomide seems to be increased when patients are treated with oral contraceptives or other cytotoxic agents (including doxorubicin and melphalan) concurrently. Thalidomide may interfere with various contraceptives, and hence it is advised that women of reproductive age use at least two different means of contraception to ensure that no child will be conceived while they are taking thalidomide.[17][10][9]As of 2013, eighteen cases of overdoses had been reported with doses of up to 14.4 grams, none of them fatal.[17] No specific antidote for overdose exists and treatment is purely supportive.[17]The precise mechanism of action for thalidomide is not known, although efforts to identify thalidomide's teratogenic action generated 2,000 research papers and the proposal of 15 or 16 plausible mechanisms by the year 2000.[18] As of 2015, the main theories were inhibition of the process of angiogenesis, its inhibition of cereblon, a ubiquitin ligase, and its ability to generate reactive oxygen species which in turn kills cells.[19][20] In 2018, results were first published which suggested that thalidomide's teratogenic effects are mediated through degradation of the transcription factor, SALL4, an as yet unverified finding.[21]Thalidomide also binds to and acts as an antagonist of the androgen receptor (AR) and hence is a nonsteroidal antiandrogen (NSAA) of some capacity.[22] In accordance, it can produce gynecomastia and sexual dysfunction as side effects in men.[23]Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood.[16]Thalidomide is racemic; while R-thalidomide is the bioactive form of the molecule, the individual enantiomers can racemize to each other due to the acidic hydrogen at the chiral centre, which is the carbon of the glutarimide ring bonded to the phthalimide substituent. The racemization process can occur in vivo.[2][24][25][26]Celgene Corporation originally synthesized thalidomide using a three-step sequence starting with L-glutamic acid treatment, but this has since been reformed by the use of L-glutamine.[27] As shown in the image below, N-carbethoxyphthalimide (1) can react with L-glutamine to yield N-phthaloyl-L-glutamine (2). Cyclization of N-phthaloyl-L-glutamine occurs using carbonyldiimidazole, which then yields thalidomide (3).[27] Celgene Corporation's original method resulted in a 31% yield of S-thalidomide, whereas the two-step synthesis yields 85–93% product that is 99% pure.In 1952, thalidomide was synthesised by Chemical Industry Basel (CIBA), but was found "to have no effect on animals and was discarded" on that basis.[28] In 1957, it was acquired by Chemie-Grunenthal in Germany.[28] The German company had been established as a soap maker after World War II ended, to address the urgent market need for antibiotics.[citation needed] Heinrich Mueckter[29] was appointed to head the discovery program based on his experience working with the German army's antiviral research. While preparing reagents for the work, Mueckter's assistant Wilhelm Kunz isolated a by-product that was recognized by pharmacologist Herbert Keller as an analog of glutethimide, a sedative. The medicinal chemistry work turned to improving the lead compound into a suitable drug: the result was thalidomide. The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative, but it was never tested on pregnant women.[30]Researchers at Chemie Grünenthal found that thalidomide was a particularly effective antiemetic that had an inhibitory effect on morning sickness