Master of Science / Clinical Sciences - Veterinary Medicine / Laurie A. Beard / Objective: To determine the pharmacokinetic properties of oral pergolide in normal mares. Animals: 6 horses, 3-17 years of age, 355-582 kg Procedures: In a randomized, cross over design six healthy adult female horses received pergolide (PO) 0.01mg/kg or placebo after 8 hours of fasting. Samples were taken over a period of 6 day for each portion of the study (treatment or placebo) with a two week minimum wash out period between study periods. Quantification of pergolide concentration was determined by UPLC-MS. Quantification of α-MSH was determined by radioimmunoassay validated for horses. Quantification of ACTH concentration was determined by chemiluminescent enzyme immunoassay. Results: Pergolide was detected in all treated horses. The relatively short time to peak concentration (0.5 hours) indicates a rapid absorption. Mean maximum concentration measured was 4.05 ng/ml + 2.02 with a median time to maximum concentration being 0.415 hours (range:0.33-1.0). The mean half life of pergolide was determined to be 5.86 hours + 3.42. Lower limits of quantitation for the UPLC-MS assay was 0.5 ng/ml. α-MSH results were evaluated using a multiple analysis of variance assay for repeated measures comparing treatment, time, and period. There was a significant treatment to period effect with p=0.02. The effect of period appears to be more significant (p=0.06) compared to the effect of treatment (p=0.77). No effect from pergolide was noted on ACTH concentrations. Conclusions and Clinical Relevance: Horses appear to absorb and eliminate pergolide more rapidly than previously expected. Based on this pharmacokinetic data the dosing strategies of pergolide may need to be altered. However, assay sensitivity does need to be improved prior to recommendations being made.

Pituitary pars intermedia dysfunction (PPID) is one of the most common endocrine diseases affecting senior horses. PPID causes abnormally high concentrations of adrenocorticotropic hormone (ACTH) in the plasma and a very distinct, long, shaggy haircoat (hypertrichosis). At present, the recommended treatment for PPID is daily oral administration of pergolide mesylate. Due to the increased ACTH levels associated with PPID, it is commonly thought that these horses are immunosuppressed and at increased risk of opportunistic infections, although current research in this area is sparse. Additionally, it is not well-understood how treatment with Prascend® (pergolide tablets) affects endocrine measures other than ACTH and if it also impacts the immune response. To better understand how PPID influences endocrine and immune function in the horse, Non-PPID horses (n=10), untreated PPID horses (n=9), and PRASCEND-treated PPID horses (n=9) were followed over 15 months. Endocrine measures assessed included basal ACTH, ACTH responses to thyrotropin-releasing hormone (TRH) stimulation tests, basal insulin, insulin responses to oral sugar tests (OST), total cortisol, and free cortisol. Systemic immune function measures included basal and stimulated whole blood and peripheral blood mononuclear cell (PBMCs) cytokine and receptor expression, plasma myeloperoxidase levels, and complete blood counts. Localized immune function measures within the lung included cytokine and receptor expression after stimulation of cells obtained via bronchoalveolar lavage (BAL), myeloperoxidase levels in BAL fluid, and BAL fluid cytology. We hypothesized that PPID would affect immune function, but that any alterations would be corrected by treatment with PRASCEND. Results for the endocrine analyses showed that basal ACTH was reduced in the PRASCEND-treated horses to the levels of the Non-PPID horses, but ACTH in response to TRH stimulation was only reduced in the PRASCEND-treated horses at non-fall timepoints. PPID did not affect basal insulin, insulin responses to OSTs, total cortisol, or free cortisol, and PRASCEND treatment did not appear to have an impact on these measures either. These results suggest that PPID and hyperinsulinemia/insulin dysregulation are distinct endocrine conditions, and that the excess ACTH in horses with PPID is inactive, as it is unable to stimulate a normal cortisol response. In the immune function analyses, PPID horses had decreased expression of interferon gamma (IFNγ) from PBMCs stimulated with Rhodococcus equi and Escherichia coli and increased transforming growth factor beta (TGFβ) expression from the E. coli-stimulated PBMCs. TGFβ was also increased in PPID horses in the unstimulated whole blood samples. These results suggest that PPID horses are unable to mount an appropriate Th1 response, and that the regulatory subset of T-lymphocytes may be contributing to this decreased Th1 response. Results for the localized immune function analyses may indicate altered Th2 responses within the lung of PPID horses, although these results were severely limited by the sample size available for analyses. PRASCEND did not appear to affect immune function as measured in this study. In summary, PRASCEND successfully reduces basal ACTH in PPID horses and remains the best choice for veterinarians in monitoring dosage and response to PRASCEND treatment. Insulin, total cortisol, and free cortisol were not affected by PPID status or PRASCEND treatment in this study. Immune function was altered in horses with PPID, and it is likely that these horses are indeed at increased risk of opportunistic infection. PRASCEND treatment did not correct the differences in immune function in this study. Additional research is needed to further understand which mechanisms are driving the alterations in immune function for horses with PPID.

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