Pharmacokinetics and safety of repeated oral dosing of acetaminophen in adult horses.

BACKGROUND: There are no published studies on the pharmacokinetics of acetaminophen at the dosage used clinically (20 mg/kg), nor has the safety of multiple doses in horses been investigated. OBJECTIVE: Define the pharmacokinetic parameters of oral acetaminophen at 20 mg/kg in adult horses as a single dose, and twice daily for 14 days to assess the safety of multiple dosing. STUDY DESIGN: Pharmacokinetic study, multiple dose safety study. METHODS: Eight healthy Thoroughbred geldings were given acetaminophen (20 mg/kg; 500 mg tablets) orally as a single dose followed by doses every 12 h for 14 days. Serial blood samples were collected for determination of plasma acetaminophen concentrations using high performance liquid chromatography with ultraviolet detection. Serum biochemical analysis, gastroscopy and liver biopsy were examined during the safety study. RESULTS: Following a single dose, mean maximum concentration (Cmax ) was 16.61 µg/mL at 1.35 h (Tmax ), and drug concentration was below the lower limit of detection in most horses by 24 h. Elimination half-life (T1/2 ) was 2.78 h. No significant accumulation was noted following multiple doses. Average Cmax of acetaminophen following multiple oral dosing was 15.85 µg/mL, with a Tmax of 0.99 h and T1/2 of 4 h. Serum activities of sorbitol dehydrogenase were significantly decreased and total bilirubin concentrations were significantly increased following the last dose. No statistically significant changes were noted in gastroscopy scores. MAIN LIMITATIONS: Only one dose level (20 mg/kg) was studied, sample size was small and only a single breed and sex was used, with no pretreatment liver biopsies. CONCLUSION: This study described the pharmacokinetics of acetaminophen following single and multiple 20 mg/kg oral doses in adult horses and demonstrated the safety of acetaminophen with multiple oral dosing over 14 days. The summary is available in Portuguese - see Supporting information.

Fall panicum (Panicum dichotomiflorum) hepatotoxicosis in horses and sheep.

BACKGROUND: Fourteen horses at a boarding stable in Virginia were diagnosed with hepatic disease and locally grown hay was implicated as the cause. HYPOTHESIS: Panicum dichotomiflorum, the predominant grass species in the hay, is hepatotoxic to horses. ANIMALS: Naturally occurring cases were adult horses of various breeds. Two healthy adult horses and 2 healthy adult sheep were used in feeding trials. METHODS: Blood and liver specimens collected from affected animals during the outbreak were analyzed. Some of the affected animals were treated supportively; the main intervention was hay withdrawal. Feeding trials were not blinded and no treatments were provided. Blood and liver specimens were collected and analyzed throughout the trials. RESULTS: Five affected animals were euthanized, whereas the others recovered. One research horse was euthanized for postmortem examination, and the other research animals recovered after hay withdrawal. All affected animals had evidence of hepatic disease with abnormally high aspartate aminotransferase (AST), sorbitol dehydrogenase (SDH), gamma glutamyl transferase (GGT), and alkaline phosphatase (ALP) activity. Evaluation of liver biopsy specimens disclosed mild lymphocytic and histiocytic inflammation, mild vacuolar change (hydropic degeneration), prominently clumped chromatin, and necrosis of individual hepatocytes. CONCLUSIONS AND CLINICAL IMPORTANCE: Severe hepatotoxicosis developed rapidly after Panicum hay exposure. Patchy hepatocyte necrosis was observed, implicating apoptosis as the mechanism of hepatotoxicosis. Absence of fibrosis in the research animals indicates that immediate withdrawal of Panicum hay should allow all but severely affected animals to recover from acute exposure.