The discovery of the thiopurine derivative, thioguanine, dates back more than 65 years when it was originally developed to treat leukaemia in children, see Figure 1.

Figure 1: Thioguanine timeline from discovery to rediscovery and re‑registration

AZA: azathioprine; IBD: inflammatory bowel disease; MP: mercaptopurine; TG: thioguanine.

Early trials conducted to evaluate the efficacy of thioguanine in inflammatory bowel disease (IBD) treatment described that up to 80% of these patients were able to tolerate this drug and experienced clinical benefit from its use. However, a clinically alarming association of high dosages of thioguanine with the development of nodular regenerative hyper-plasia of the liver overshadowed these findings.

Later trials, however, demonstrated that thioguanine did not increase the risk of liver abnormalities when given in low but therapeutically adequate dosages (0.2−0.3 mg/kg, not exceeding 25 mg per day). In light of these more positive results, a re‑registration of thioguanine was proposed to the Dutch Medicines Evaluation Board (MEB).

This proposal, say the authors, ‘created awareness about drug rediscovery, and the importance of safe and efficient use of existing drugs was recognized by health institutes in The Netherlands’. However, they also point out that ‘there is a need for a structured protocol for further development of old drugs to optimize licensing and avoid long-lasting procedures, as was the case in the repositioning of thioguanine for IBD in The Netherlands’.

Related articles
Challenges in the rediscovery of old generics

Repurposing and re-registering old generics

Reference
1. Simsek M, Meijer B, van Bodegraven AA, de Boer NKH, Mulder CJJ. Finding hidden treasures in old drugs: the challenges and importance of licensing generics. Drug Discov Today. 2017 Sep 1. doi:10.1016/j.drudis.2017.08.008. [Epub ahead of print]

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