Page - (000337) - in Biomedical Chemistry: Current Trends and Developments

pneumocystic pneumonia, and trypanosomiasis (Vale, 2009). However, as with other classes that we have reviewed here tolerability is a substantial problem for the 8-aminoquinolines. From this class, currently only primaquine is clinically available for these uses. Administration of 8-aminoquinolines is known to cause methemoglobinemia and hemolysis in G6PD deficient individuals. Both of these effects are linked to oxidative metabolites rather than the parent drug itself (Ganesan, 2009; Ganesan, 2012). Interestingly, these same metabolites were recently shown to play a crucial role in activity (Bennett, 2013; Marcsisin, 2014; Pybus, 2013). For both primaquine and tafenoquine (8-aminoquinoline, currently in clinical development), activity is mediated by CYP 2D6 (Fig. 3.4.2). The mechanism of activity for the 8-aminoquinolines is not fully understood, however, contemporary thought is that redox active metabolites produce peroxides and superoxides (oxidative stress), which ultimately interferes with electron transport in the parasite. Not surprisingly, what is also unknown at present is whether the toxicity can be mitigated while preserving efficacy. Work in this area is of paramount importance, as new 8-aminoquinolines with similar profiles to primaquine are of little clinical utility. The WHO currently calls for a 30 mg dose of primaquine as a chemoprophylaxis in areas where P. vivax is the predominant risk, however significant fractions of the population (10% in Europeans and as much as 50% in some Asians) possess 2D6 alleles with reduced function (Deye & Magill, 2014). It is therefore likely that primaquine prophylaxis and even anti-relapse therapy will fail in many of these individuals. All things considered, the importance of this class cannot be overemphasized and it cannot be abandoned without more study. As stated previously, primaquine is currently the only clinically available drug for the treatment of relapsing malaria. As such, the challenges posed for future 8-aminoquinoline development include re-routing metabolism through a non-CYP 2D6 pathway, circumventing hemolytic toxicity, or both. The primaquine enamine bulaquine showed some promise in recent animal studies at improving the therapeutic index (Lal, 2003; Mehrotra, 2007). This appears to be due to differential pharmacokinetic exposure patterns as compared to parent primaquine.