Lidocaine continuous-rate infusions (CRI) are the most commonly used prokinetic in equine practice for the treatment of post-operative ileus and are also increasingly being used in pain management, such as in cases of severe laminitis, and are often used for prolonged durations. To date only limited time/concentration relationships of lidocaine administered as a short term (24hours) CRI to horses are reported. This study examined the time/concentration profile of lidocaine and its active metabolites (GX, MEGX) during a 96 hour lidocaine infusion in eight mature healthy horses. Serum lidocaine concentrations reached steady state by three hours and did not accumulate thereafter. The serum concentration of lidocaine was above the target therapeutic concentration (980ng/ml) only at 6 and 48 hours. The serum lidocaine concentration did not reach the range described as potentially causing toxicity (>1850ng/ml). The MEGX metabolite did not accumulate over time, while the GX metabolite accumulated significantly up to 48 hours and then remained constant. The serum concentrations of lidocaine, MEGX and GX were below the limit of detection within 24 hours of discontinuation of the infusion. None of the horses developed any signs of lidocaine toxicity during the study. It was concluded that the metabolism of lidocaine was not significantly impaired by prolonged infusion, contrasting with studies in dogs and humans. No adverse effects were observed in this study, which with the lack of lidocaine accumulation suggests that prolonged infusions are safe. However the accumulation of GX, a potentially toxic active metabolite, is cause for concern. / Master of Science

No / The neuromedin U (NMU) receptors, NMU1 and NMU2, are expressed in the gut but their functions are unclear. This study explores the role of NMU in gastrointestinal motility. Experimental approach: The effects of NMU were examined in the forestomach and colon isolated from NMU2R wild-type and NMU2R-/- (knockout) mice, looking for changes in muscle tension and in nerve-mediated responses evoked by electrical field stimulation (EFS), and in models of peristalsis in mouse colon and faecal pellet transit in guinea-pig colon. Key results: In the mouse forestomach, NMU (1 nM-10 ¿M) concentration-dependently induced muscle contraction, in the presence of tetrodotoxin and atropine, in preparations from both wild-type and NMU2R-/- mice (pEC50: 7.9, 7.6, Emax: 0.26, 0.20g tension, respectively, n=8 each concentration). The same concentrations of NMU had no consistent effects on the responses to EFS (n=8). In the mouse colon, NMU (0.1 nM-1 ¿M) had no significant effect on baseline muscle tension (n=8), but concentration-dependently potentiated EFS-evoked contractions in preparations from both wild-type and NMU2R-/- mice, pEC50: 8.1, 7.8, Emax: 24%, 21%, respectively, n=6-11. NMU (0.01 nM-0.1 ¿M, n=5-7) concentration-dependently decreased the interval between waves of peristalsis in the mouse colon (pEC50: 8.8) and increased the rate at which a faecal pellet moved along the guinea-pig colon. Conclusions and implications: These results demonstrate that NMU exerts colon-specific, nerve-mediated, prokinetic activity, via a pathway involving activation of NMU1 receptors. This suggests that this receptor may represent a molecular target for the treatment of intestinal motility disorders.

Small intestinal ileus affects up to half of all horses undergoing small intestinal surgery, leading to prolonged gastrointestinal (GI) transit time which can be life-threatening. Various prokinetic medications have been associated with varying side effects, questionable efficacy, and increased cost. Gum chewing as a form of sham feeding is used as a safe, effective, well-tolerated, and inexpensive way to ameliorate ileus following GI surgery in humans. Bit chewing for horses, an analogous activity, has been shown to significantly decrease GI total transit time (TTT); however, a direct effect of bit chewing on gastric emptying time (GET), small intestinal transit time (SITT), and total orocecal transit time (OCTT) has not been investigated. Our objective was to determine whether bit chewing increased small intestinal motility and decreased GE, SITT, and OCTT in clinically normal horses. Gastrointestinal motility was compared in horses that were bit chewing compared to control conditions (no bit chewing) in a prospective crossover design study using acetaminophen as a marker for GET and video endoscopy (ALICAM) capsules to determine GET, SITT, and OCTT. Bit chewing was well tolerated by all horses with no side effects noted. Bit chewing led to a shorter GET, SITT, and significantly shorter OCTT when compared to the control group (P = 0.015). Median times for bit chewing conditions were as follows: GE 2.86 hr, SITT 3.65 hr, and OCTT 6.15 hr whereas the median times for control conditions were as follows: GE: 5 hr, SITT 4.4 hr, and OCTT 9.92 hr. In summary, bit chewing proves to be a potential tool to hasten the motility of the oral GIT. It is safe, inexpensive, and potentially effective prokinetic treatment to horses suffering from postoperative ileus and further investigation is warranted. / Master of Science / Ileus, or a temporary lack of intestinal motility, is a common life-threatening problem in horses, especially following abdominal surgery. Current treatments have questionable efficacy and high cost. In human patients suffering from ileus, sham feeding with gum chewing that mimics normal food consumption with no food ingested has shown promising results in improving clinical signs and restarting gastrointestinal motility. Bit chewing, an analogous activity in horses, also decreases gastrointestinal (GI) total transit time (TTT). However, ileus in horses typically affects the small intestine, which is a part of the GI tract that has not been investigated in regards to bit chewing. Our objective was to determine whether bit chewing shortens gastric emptying time (GET), small intestinal transit time (SITT), and total orocecal transit time (OCTT) in clinically normal horses. Gastrointestinal motility was compared in horses that were bit chewing compared to control (no bit chewing) conditions in a prospective crossover design study using acetaminophen serum samples as a marker for GET and video endoscopy (ALICAM) capsules to determine GET, SITT, and OCTT. There were no adverse effects to bit chewing and OCTT was significantly shortened in horses when bit chewing compared to the control group. In summary, bit chewing is a tool to hasten gastrointestinal motility, specifically small intestinal motility, and it may be a safe, inexpensive, and effective treatment to improve small intestinal motility in horses suffering from ileus and further investigation is warranted.