ABSTRACT
OBJECTIVES: To determine the pharmacodynamics and pharmacokinetics of rivaroxaban (RVX), in healthy cats and to evaluate the clinicopathologic effects of various plasma RVX concentrations within target therapeutic ranges established for people. DESIGN: Prospective randomized cross-over study performed between July 2013 and November 2014. SETTING: Veterinary university teaching hospital. ANIMALS: Six healthy adult domestic shorthair cats (3 males, 3 females). INTERVENTIONS: Cats were treated with oral RVX at single, fixed doses (1.25, 2.5, 5 mg PO), q 12 h for 3 days (1.25 mg); q 24 h for 7 days (2.5 mg); and q 24 h for 28 days (1.25 mg). Blood samples were collected for complete blood count, blood chemistry, and RVX anticoagulant activity based on prolongation of dilute prothrombin time, activated partial thromboplastin time (aPTT), activated Factor X (FXa) inhibition (anti-Xa activity [aXa]) and high-pressure liquid chromatography tandem mass spectrometry determination of drug concentration. MEASUREMENTS AND MAIN RESULTS: Treated cats had no signs of hemorrhage or clinicopathologic off-target adverse effects. There were dose-dependent prolongations of coagulation times and increase in aXa, with peak effect at 3 hours postadministration. There was a direct correlation between plasma RVX concentration and dilute prothrombin time and aXa. Coagulation parameters returned to baseline by 24 hours after the last dose. CONCLUSIONS: Oral RVX was well tolerated by healthy cats with predictable pharmacokinetics and anticoagulant effects. Clinical studies of RVX are warranted in cats with heart disease.
Subject(s)
Cats/metabolism , Factor Xa Inhibitors/pharmacology , Factor Xa Inhibitors/pharmacokinetics , Rivaroxaban/pharmacology , Rivaroxaban/pharmacokinetics , Administration, Oral , Animals , Blood Coagulation/drug effects , Blood Coagulation Tests/veterinary , Cross-Over Studies , Dose-Response Relationship, Drug , Factor Xa Inhibitors/administration & dosage , Female , Male , Partial Thromboplastin Time , Prospective Studies , Prothrombin Time , Rivaroxaban/administration & dosageABSTRACT
Snake fungal disease (SFD) is a clinical syndrome associated with dermatitis, myositis, osteomyelitis, and pneumonia in several species of free-ranging snakes in the US. The causative agent has been suggested as Ophidiomyces ophiodiicola, but other agents may contribute to the syndrome and the pathogenesis is not understood. To understand the role of O. ophiodiicola in SFD, a cottonmouth snake model of SFD was designed. Five cottonmouths (Agkistrodon piscivorous) were experimentally challenged by nasolabial pit inoculation with a pure culture of O. ophiodiicola. Development of skin lesions or facial swelling at the site of inoculation was observed in all snakes. Twice weekly swabs of the inoculation site revealed variable presence of O. ophiodiicola DNA by qPCR in all five inoculated snakes for 3 to 58 days post-inoculation; nasolabial flushes were not a useful sampling method for detection. Inoculated snakes had a 40% mortality rate. All inoculated snakes had microscopic lesions unilaterally on the side of the swabbed nasolabial pit, including erosions to ulcerations and heterophilic dermatitis. All signs were consistent with SFD; however, the severity of lesions varied in individual snakes, and fungal hyphae were only observed in 3 of 5 inoculated snakes. These three snakes correlated with post-mortem tissue qPCR evidence of O. ophiodiicola. The findings of this study conclude that O. ophiodiicola inoculation in a cottonmouth snake model leads to disease similar to SFD, although lesion severity and the fungal load are quite variable within the model. Future studies may utilize this model to further understand the pathogenesis of this disease and develop management strategies that mitigate disease effects, but investigation of other models with less variability may be warranted.
