@article{gilbertie_davis_davidson_mcdonald_schirmer_schnabel_2019, title={Oral reserpine administration in horses results in low plasma concentrations that alter platelet biology}, volume={51}, ISSN={["2042-3306"]}, DOI={10.1111/evj.13048}, abstractNote={SummaryBackgroundReserpine is a popular drug in the equine industry for long‐term tranquilisation. Clinical observations revealed that blood from horses receiving oral reserpine was hypercoagulable. No studies have documented the pharmacokinetics of orally administered reserpine nor the effects of reserpine on platelets in horses.ObjectivesTo evaluate the pharmacokinetics of oral reserpine in horses and the effects of clinically relevant concentrations of reserpine on platelet functionality in vitro.Study designExperimental controlled study.MethodsThe pharmacokinetics of oral reserpine (2.5 mg/horse, once) were determined in six healthy adult horses. Plasma samples were collected and concentrations of reserpine were determined by UPLC‐MS/MS. Using this data, the in vitro effects of reserpine on platelets were examined. Aggregation, adhesion and releasate assays for serotonin and thromboxane B2 were performed on platelets exposed to varying concentrations of reserpine (0.01–10 ng/mL), aspirin (negative control) and saline (unexposed control).ResultsOral reserpine administration demonstrated low plasma concentrations with a Cmax of 0.2 ± 0.06 ng/mL and a prolonged half‐life of 23.6 ± 6.24 h. Simulations over a dose range of 2–8 μg/kg predicted Cmax at steady state between 0.06–0.9 ng/mL. Platelets exposed to these reserpine concentrations in vitro displayed increased aggregation and adhesion compared to unexposed or aspirin‐exposed platelets as well as compared to higher concentrations of reserpine. These functional changes correlated with lower concentrations of serotonin and higher concentrations of thromboxane B2 in the platelet suspension supernatant.Main limitationsThis study used a small number of horses and only in vitro platelet experiments.ConclusionsOral reserpine demonstrates low plasma concentrations and a prolonged half‐life in horses. At these concentrations, reserpine causes significant changes in platelet function, most likely due to serotonin release and re‐uptake which primes platelets for activation and thromboxane B2 release. These findings suggest that clinicians should harvest blood for biological processing prior to the onset of reserpine administration.}, number={4}, journal={EQUINE VETERINARY JOURNAL}, author={Gilbertie, J. M. and Davis, J. L. and Davidson, G. S. and McDonald, A. M. and Schirmer, J. M. and Schnabel, L. V.}, year={2019}, month={Jul}, pages={537–543} }
 @article{martin_schirmer_jones_davis_2018, title={Pharmacokinetics and ex vivo anti‐inflammatory effects of oral misoprostol in horses}, volume={51}, ISSN={0425-1644 2042-3306}, url={http://dx.doi.org/10.1111/evj.13024}, DOI={10.1111/evj.13024}, abstractNote={SummaryBackgroundMisoprostol is an E prostanoid (EP) 2, 3 and 4 receptor agonist that is anecdotally used to treat and prevent NSAID‐induced GI injury in horses. Misoprostol elicits anti‐inflammatory effects in vivo in men and rodents, and inhibits TNFα production in equine leucocytes in vitro.ObjectiveDefine the pharmacokinetic parameters of oral misoprostol in horses, and determine the inhibitory effect of oral misoprostol administration on equine leucocyte TNFα production in an ex vivo inflammation model.Study designPharmacokinetic study, ex vivo experimental study.MethodsSix healthy adult horses of mixed breeds were used. In phase one, horses were given 5 μg/kg misoprostol orally, and blood was collected at predetermined times for determination of misoprostol free acid (MFA) by UHPLC‐MS/MS. Pharmacokinetic parameters were calculated. In phase two, horses were dosed as in phase one, and blood was collected at T0, 0.5, 1 and 4 h following misoprostol administration for leucocyte isolation. Leucocytes were stimulated with 100 ng/mL LPS, and TNFα mRNA concentrations were determined via quantitative real‐time PCR.ResultsAbout 5 μg/kg oral misoprostol produced a rapid time to maximum concentration (Tmax) of 23.4 ± 2.4 min, with a maximum concentration (Cmax) of 0.29 ± 0.07 ng/mL and area under the curve (AUC0−∞) of 0.4 ± 0.12 h ng/mL. LPS stimulation of equine leucocytes ex vivo significantly increased TNFα mRNA concentrations, and there was no significant effect of misoprostol even at the Tmax.Main limitationsOnly a single dose was used, and sample size was small.ConclusionsMisoprostol is rapidly absorbed following oral administration in horses, and a single 5 μg/kg dose had no significant inhibitory effect on ex vivo LPS‐stimulated TNFα mRNA production in leucocytes. Further studies analysing different dosing strategies, including repeat administration or combination with other anti‐inflammatory drugs, are warranted.}, number={3}, journal={Equine Veterinary Journal}, publisher={Wiley}, author={Martin, E. M. and Schirmer, J. M. and Jones, S. L. and Davis, J. L.}, year={2018}, month={Oct}, pages={415–421} }
 @article{davis_schirmer_medlin_2018, title={Pharmacokinetics, pharmacodynamics and clinical use of trazodone and its active metabolite m-chlorophenylpiperazine in the horse}, volume={41}, ISSN={["1365-2885"]}, DOI={10.1111/jvp.12477}, abstractNote={Trazodone is a serotonin receptor antagonist and reuptake inhibitor used extensively as an anxiolytic in human and small animal veterinary medicine. The aims of this study were to determine the pharmacokinetics of oral trazodone in experimental horses and to evaluate the effect of oral trazodone in clinical horses. Six experimental horses were administered trazodone at 7.5 or 10 mg/kg. Plasma concentrations of trazodone and its metabolite (m‐CPP) were determined via UPLC‐MS/MS. Noncompartmental pharmacokinetic analysis, sedation and ataxia scores were determined. Trazodone was rapidly absorbed after oral administration with a maximum concentration of 2.5–4.1 μg/ml and half‐life of the terminal phase of approximately 7 hr. The metabolite was present at low levels in all horses, representing only 2.5% of the total area under the curve. In experimental horses, concentration‐dependent sedation and ataxia were noted, lasting up to 12 hr. For clinical cases, medical records of horses treated with trazodone for various abnormal behaviours were reviewed and data were summarized. Trazodone was successful in modifying behavioural problems to some degree in 17 of 18 clinical cases. Tolerance and subsequent lack of drug effect occurred in two of 18 clinical cases following 14 or 21 days of use. In both populations of horses, adverse effects attributed to trazodone include oversedation, muscle fasciculations and transient arrhythmias.}, number={3}, journal={JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS}, author={Davis, J. L. and Schirmer, J. and Medlin, E.}, year={2018}, month={Jun}, pages={393–401} }
 @article{holland_fogle_blikslager_curling_barlow_schirmer_davis_2014, title={Pharmacokinetics and pharmacodynamics of three formulations of firocoxib in healthy horses}, volume={38}, ISSN={0140-7783}, url={http://dx.doi.org/10.1111/jvp.12177}, DOI={10.1111/jvp.12177}, abstractNote={The objectives of this study were to compare the pharmacokinetics and COX selectivity of three commercially available formulations of firocoxib in the horse. Six healthy adult horses were administered a single dose of 57 mg intravenous, oral paste or oral tablet firocoxib in a three‐way, randomized, crossover design. Blood was collected at predetermined times for PGE2 and TXB2 concentrations, as well as plasma drug concentrations. Similar to other reports, firocoxib exhibited a long elimination half‐life (31.07 ± 10.64 h), a large volume of distribution (1.81 ± 0.59L/kg), and a slow clearance (42.61 ± 11.28 mL/h/kg). Comparison of the oral formulations revealed a higher Cmax, shorter Tmax, and greater AUC for the paste compared to the tablet. Bioavailability was 112% and 88% for the paste and tablet, respectively. Maximum inhibition of PGE2 was 83.76% for the I.V. formulation, 52.95% for the oral paste formulation, and 46.22% for the oral tablet formulation. Pharmacodynamic modeling suggests an IC50 of approximately 27 ng/mL and an IC80 of 108 ng/ mL for COX2 inhibition. Inhibition of TXB2 production was not detected. This study indicates a lack of bioequivalence between the oral formulations of firocoxib when administered as a single dose to healthy horses.}, number={3}, journal={Journal of Veterinary Pharmacology and Therapeutics}, publisher={Wiley}, author={Holland, B. and Fogle, C. and Blikslager, A. T. and Curling, A. and Barlow, B. M. and Schirmer, J. and Davis, J. L.}, year={2014}, month={Nov}, pages={249–256} }
 @article{davis_kruger_lafevers_barlow_schirmer_breuhaus_2014, title={Effects of quinapril on angiotensin converting enzyme and plasma renin activity as well as pharmacokinetic parameters of quinapril and its active metabolite, quinaprilat, after intravenous and oral administration to mature horses}, volume={46}, ISSN={["2042-3306"]}, DOI={10.1111/evj.12206}, abstractNote={SummaryReasons for performing studyAngiotensin converting enzyme (ACE) inhibitors improve survival and quality of life in human patients and small animals with cardiovascular and renal disease. There is limited information regarding their effects in horses.ObjectivesThe purpose of this study was to determine the pharmacokinetics of quinapril and its effects on ACE and renin in horses.Study designExperimental study using healthy mature horses.MethodsSix healthy horses were administered quinapril at 120 mg i.v., 120 mg per os and 240 mg per os in a 3‐way crossover design. Blood was collected for measurement of quinapril and quinaprilat concentrations using ultra‐high pressure liquid chromatography with mass spectrometry. Angiotensin converting enzyme activity and renin activity were measured using a radioenzymatic assay. Noncompartmental pharmacokinetic modelling and statistical analyses were performed.ResultsNo adverse effects were observed during the study period. Intravenous and oral administration significantly inhibited ACE activity. Renin concentrations increased in all groups, but this increase was not statistically significant. Following i.v. administration of quinapril, mean terminal half‐life was 0.694 h and 1.734 h for quinapril and quinaprilat, respectively. The mean volume of distribution and clearance for quinapril were 0.242 l/kg bwt and 11.93 ml/kg bwt/min, respectively. Maximum concentration for quinaprilat was 145 ng/ml at 0.167 h. Bioavailability of quinapril following oral administration was <5%. Quinaprilat was detected in all horses following oral administration of quinapril; however, it was below the limit of quantification of the assay (2.5 ng/ml) for most horses in the 120 mg dosing group.ConclusionsThese results suggest that, despite low plasma concentrations, quinapril has sufficient oral absorption to produce inhibition of ACE in healthy horses. Controlled studies in clinically affected horses are indicated. Quinapril provides a potential treatment alternative for horses with cardiovascular and renal disease.}, number={6}, journal={EQUINE VETERINARY JOURNAL}, author={Davis, J. L. and Kruger, K. and LaFevers, D. H. and Barlow, B. M. and Schirmer, J. M. and Breuhaus, B. A.}, year={2014}, month={Nov}, pages={729–733} }