Page - (000334) - in Biomedical Chemistry: Current Trends and Developments

parenterally, broadly distributed throughout the body, and has proven highly effective for the treatment of uncomplicated or severe malaria (Achan, 2011). In the age of resistance, quinine has made a resurgence in usage. Although quinine resistance has been reported, it is generally low-grade, and is largely found in Asia and South America (Noedl, 2006; Parola, 2001). Perhaps a larger issue still in play for quinine is tolerance. Quinine has several notable and potential severe adverse events associated with usage. Most common side-effects include tinnitus and hearing impairment, but more severe effects can include vertigo, vomiting, abdominal pain, or hypotension (Achan, 2011). The most severe and potentially least understood is a syndrome called blackwater fever characterized by hemolysis and hemoglobinuria (George, 2009). Recent studies suggest a potential link between CYP mediated oxidative metabolites of quinine and this potentially fatal reaction (Marcsisin, 2013). It should also be noted that while clinically different from the hemolytic events observed with the 8-aminoquinolines (which we will discuss in a later section), as with the 8-aminoquinolines a link may exist between glucose-6-phosphate (G6PD) deficiency and hemolysis (Hue, 2009). This is significant as it suggests common metabolic pathways for some quinoline drugs that should be avoided or at least considered when developing new drugs in these classes. For quinine, the formation of redox active quinones may lead to increased oxidative stress under conditions of high parasitemia or in G6PD deficient individuals that ultimately results in the destruction of red-cells through mechanisms which are not fully understood (Fig. 3.4.2) (Marcsisin, 2013). Arguably one of the most successful classes of drugs to arise from WWII efforts is the 4-aminoquinolines. Fig. 3.4.3 illustrates two members of the class, chloroquine and amodiaquine, and can serve as a generic paradigm for its structure. Chloroquine was originally discovered by Hans Andersag in 1934 while working for Bayer, however, the drug was discarded for perceived toxicity. After its re-discovery by British and American chemists, it quickly won favor as a safe and effective anti-malarial (CDC, August 18, 2014). In fact, chloroquine was used extensively in post-war eradication efforts. While the mechanism of