Pemoline and tetramisole 'positives' in English racehorses following levamisole administration

Pemoline, [(RS)-2-amino-5-phenyl-1,3-oxazol-4(5H)-one] is a central nervous system stimulant used to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy in humans (Molina and others 1981). In horse racing, pemoline is classified as an Association of Racing Commissioners International (ARCI) ‘Class 1’ foreign substance, i.e., an agent with high potential to influence performance (Tobin 1981 and ARCI website). Pemoline is unusually identified in a post-race sample, and its identification would usually be interpreted as an attempt to improperly influence performance. However, an entirely innocent explanation is possible for such pemoline identifications, as we will now set forth. The explanation is based on the fact that in the horse, and possibly other species, pemoline is a metabolite of levamisole, an anthelmintic and immune stimulant not uncommonly administered to horses (Mohri and others 2005). The recommended dose in the horse is 2/mg/ kg orally, once a day for three-to-five days, as an immune modulator (Britt and Byars, 1997). Furthermore, in the horse levamisole, metabolism has recently been shown to produce a closely related substance, aminorex (Barker 2008, Ho and others 2009, Pellegrini, 2010). Aminorex, which is structurally related to levamisole and pemoline (Figure 1), is a central nervous system stimulant which was marketed as a prescription anorectic in Europe, but withdrawn when it became associated with pulmonary hypertension (Gurtner 1985). In the United States, Aminorex is a DEA Schedule 1 substance and an ARCI ‘Class 1’ substance, like pemoline. In the United States, the link between levamisole administration and aminorex identifications has been associated with a series of no fewer than 82 aminorex ‘positives’ in post-race urines. These aminorex ‘positives’ star ted with a single identification in Belgium, then, in the United States, first in October 2004 in Ohio, and later in both Pennsylvania and Ontario (Weber 2010) as set for th in Table 1. In Pennsylvania, beginning aBstraCt Pemoline is a central nervous system stimulant that has been used to treat attention-deficit hyperactivity disorder and narcolepsy in humans; its identification in horses could be considered evidence of attempts to influence performance. Two recent pemoline ‘positives’ in English racehorses led us to review the chemical relationships between tetramisole, levamisole, aminorex and pemoline. Pemoline is a simple oxidation product of aminorex, which has been shown in the United States and elsewhere to be an equine metabolite of levamisole. Based on the clear structural relationships between aminorex and pemoline, we conclude that levamisole can metabolise to pemoline in horses and that pemoline identifications in horses post levamisole administration are likely to be associated with levamisole administration. Levamisole should not be administered to horses about to compete because of its ability to metabolise to two central nervous system stimulants, aminorex and pemoline.