Pharmacokinetics of thiamine (vitamin B1) in adult horses after administration of three single intravenous doses.

Thiamine is a vital co-factor for several anti-inflammatory and antioxidant processes that are critical for mitigation of sepsis-associated inflammation, but pharmacokinetic (PK) analysis has not been reported in horses. We hypothesized that IV thiamine hydrochloride (TH) at increasing dosages would result in corresponding increases in plasma thiamine concentrations without causing adverse effects. A randomized cross-over study was performed in 9 healthy horses that each received TH at 5, 10, and 20 mg/kg IV. Blood was collected immediately prior to drug administration and at several time points thereafter. High-performance liquid chromatography with mass spectrometry was used to quantify thiamine concentrations at each time point. Non-compartmental PK methods showed that IV TH resulted in supraphysiologic plasma concentrations with a short half-life (0.77-1.12 h) and no adverse clinical signs were observed. The terminal rate constant decreased as the dosage increased (p < .0001) and clearance significantly decreased at the 20 mg/kg dosage (p = .0011). The area under the curve (AUC) increased in a non-linear fashion. These findings suggest that thiamine follows non-linear elimination kinetics in horses, which is likely due to saturation of renal elimination. Future studies are needed to identify therapeutic plasma concentrations and develop thiamine dosing recommendations for horses.

Effects of administration of ascorbic acid and low-dose hydrocortisone after infusion of sublethal doses of lipopolysaccharide to horses.

BACKGROUND: Sepsis is associated with ascorbic acid (AA) depletion and critical illness-related corticosteroid insufficiency (CIRCI) in humans. HYPOTHESES: Intravenous infusion of lipopolysaccharide (LPS) would (a) decrease endogneous AA concentrations, (b) induce CIRCI and (c) administration of a combination of AA and hydrocortisone (HC) would have decreased indices of inflammation compared to either drug alone. ANIMALS: Thirty-two healthy horses. METHODS: Randomized placebo-controlled experimental trial. Horses were assigned to 1 of 4 groups (saline, AA and HC, AA only, or HC only). Treatments were administered 1 hour after completion of LPS infusion. Clinical signs, clinicopathological variables, pro-inflammatory cytokine gene expression and production, and plasma AA concentrations were assessed at various time points. Serum cortisol concentrations and ACTH stimulation tests were used to detect CIRCI. RESULTS: There was no effect of drug on clinical signs or pro-inflammatory cytokine gene expression or production compared to controls at any time point. Administration of AA was associated with higher blood neutrophil counts 6 hours after LPS infusion (11.01 ± 1.02 K/µl) compared to other groups (8.99 ± 0.94 K/µL; P < .009). Adminstration of HC was associated with higher blood neutrophil counts 12 hours after LPS infusion (10.40 ± 0.75 K/µl) compared to other groups (6.88 ± 0.68 K/µl; P < .001). Serum cortisol increased from 5.11 ± 1.48 µg/dL before LPS administration to 9.59 ± 1.83 µg/dL 1 h after completion of LPS infusion (T1) without an effect of treatment (P = 0.59). CONCLUSIONS AND CLINICAL IMPORTANCE: Ascorbic acid and HC appeared to protect against LPS-induced neutrophil depletion and could be considered as adjunctive therapy in horses with endotoxemia.