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Pemoline, a central nervous system stimulant reportedly occurring naturally in equine samples in Europe and elsewhere – a review and analysis

Retrospektive Studie der Pferde mit chronisch rekurrierender Blinddarmobstipation nach chirurgischer Versorgung mittels Erweiterungsplastik des Ostium caecocolicum

Kimberly Brewer, Abelardo Morales Briceño, Robert Holland, George Maylin, Clara Fenger, Levent Dirikolu, Andreas . Lehner and Thomas Tobin

Abstract

Pemoline, (RS)-2-amino-5-phenyl-1,3-oxazol-4(5H)-one, is a member of the 4-oxazolidinone group of substances and a central nervous system stimulant closely related structurally and pharmacologically to aminorex. With the increased sensitivity of equine drug testing, low concentration identifications of pemoline have increasingly been identified in horse racing. In 2009 two pemoline and one tetramisole identification in English racing were reported in horses administered levamisole, leading to suggestions that levamisole, known to metabolize to aminorex, could also metabolize to pemoline. In April 2016 the French, German, and South African horseracing laboratories reported frequent identifications of pemoline in equine urine samples, such that these laboratories had “in-house” reporting limits below which urinary pemoline identifications were not reported. In 2016 and again in 2018 the matter of potential pemoline identifications in Indiana horse rac ing was communicated by the Indiana Horse Racing Commission to Indiana horsemen, with requests that horsemen avoid use of levamisole. Soon thereafter, in late 2018, we became aware that plant barbarin was a potential source of equine urinary aminorex identifications. In Spring 2019 we therefore harvested flowering “Yellow Rocket” (Barbarea vulgaris), a barbarin-containing invasive plant widely distributed in North America and administered it orally to horses. Urine samples collected from these horses were found to contain aminorex. Aminorex, closely related chemically and pharmacologically to pemoline, is therefore a naturally occurring alkaloid that may be identified in equine urine, suggesting possible similar botanical origins for pemoline, now not infrequently being identified at low ng/mL concentrations in equine urine samples in Europe and elsewhere. Addressing the regulatory implications of these findings, we have therefore reviewed the pharmacological literature on pemoline in the horse and using the Toutain & Lassourd safety factor of 500 we now propose 2 ng/mL of pemoline as an Irrelevant Plasma Concentration (IPC) of pemoline in horses.

Keywords: Pemoline, race horse, doping, drug testing, urine sample

Pengliang Li, Xuyan Wu, Wei Wang, Cheng Zhang, Xiaochen Yang, Jixiang Li

Abstract

Impaction is one of the most common disease of the cecum in horses. It is important to distinguish between acute and chronic recurrent cases. Acute impaction occurs suddenly and resolves within a few days with medical and/or surgical treatment whereas in chronic cases the impaction within the base or the whole cecum occurs repeatedly at irregular intervals. The chronic recurrent cecal impaction (CRCI) is characterized by hypertrophy of muscle in the cecal base or entire cecum. The pathogenesis is not fully understood: hypothesis is that the cecal impaction induces a distension during the contraction of the circular muscle layer which is a stimulus of a hypertrophy of the circular and longitudinal muscle layer in the cecum. Furthermore, neuronal density in the plexus myentericus was found to be decreased significantly in the cecal wall of CRCI. Initially, in cases of CRCI the cecocolic orifice is not entirely blocked allowing partial transit of ingesta. Hypertrophy of the muscle layer (longitudinal and circular muscle) begins at the cecal base and as the disease progresses, the cecocolic opening becomes completely obstructed due to the automatic closure mechanism. The rectal and ultrasound exam are the most useful diagnostic steps while different degrees of cecal impaction and/or tympany, a marked thickening and cecal wall contractility due to palpation are found. The hypertrophy can be regarded as a pathognomonic sign. Treatment in our study was done by surgical enlargement of the cecocolic orifice (created by Huskamp 1990). Tissue samples of defined cecal regions were taken during surgery or necropsy: the circular and longitudinal muscle layer were significantly thicker, linear neuron densities were significantly lower each compared to clinically healthy horses. Based on smooth muscle thickening and neuron deficit, rectally palpable and ultrasound visible cecal wall thickening, horses suffering from CRI have a poor prognosis. Surgery by enlargement of the cecocolic orifice in horses with CRCI have a better prognosis if only the cecal base has a thickening and a normal cecal body wall.

Keywords: horses, chronic recurrent cecal impaction, surgical treatment enlargement cecocolic orifice, long-term survival

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