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  • Author or Editor: Michael L. Keowen x
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Abstract

Objective—To characterize the bioavailability and pharmacokinetics of oral and injectable formulations of methadone after IV, oral, and intragastric administration in horses.

Animals—6 healthy adult horses.

Procedures—Horses received single doses (each 0.15 mg/kg) of an oral formulation of methadone hydrochloride orally or intragastrically or an injectable formulation of the drug orally, intragastrically, or IV (5 experimental treatments/horse; 2-week washout period between each experimental treatment). A blood sample was collected from each horse before and at predetermined time points over a 360-minute period after each administration of the drug to determine serum drug concentration by use of gas chromatography–mass spectrometry analysis and to estimate pharmacokinetic parameters by use of a noncompartmental model. Horses were monitored for adverse effects.

Results—In treated horses, serum methadone concentrations were equivalent to or higher than the effective concentration range reported for humans, without induction of adverse effects. Oral pharmacokinetics in horses included a short half-life (approx 1 hour), high total body clearance corrected for bioavailability (5 to 8 mL/min/kg), and small apparent volume of distribution corrected for bioavailability (0.6 to 0.9 L/kg). The bioavailability of methadone administered orally was approximately 3 times that associated with intragastric administration.

Conclusions and Clinical Relevance—Absorption of methadone in the small intestine in horses appeared to be limited owing to the low bioavailability after intragastric administration. Better understanding of drug disposition, including absorption, could lead to a more appropriate choice of administration route that would enhance analgesia and minimize adverse effects in horses.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To evaluate systemic effects of IV infusion of ATP-MgCl2 subsequent to infusion of a low dose of endotoxin in horses.

Animals—12 adult horses.

Procedure—Horses were administered endotoxin (lipopolysaccharide [LPS]) or saline (0.9% NaCl) solution, IV, during a 30-minute period. Immediately thereafter, horses in each group were infused IV with ATP-MgCl2 or saline solution. Two weeks later, horses were administered the opposite solution (LPS or saline solution), but it was followed by the same infusion as 2 weeks previously (ie, ATP-MgCl2 or saline solution). Cardiopulmonary and clinicopathologic variables, cytokine activity, and endothelin (ET) concentrations were recorded.

Results—IV infusion of ATP-MgCl2 after administration of a low dose of endotoxin failed to attenuate the cardiopulmonary, clinicopathologic, and cytokine alterations that develop secondary to endotoxin exposure. The combination of LPS and ATP-MgCl2 potentiated pulmonary hypertension, leukopenia, and neutropenia when compared with the combination of LPS and saline solution. The combination of LPS and ATP-MgCl2 resulted in thrombocytopenia. Endothelin concentration was increased in jugular venous and pulmonary arterial plasma in horses receiving LPS and ATP-MgCl2. Similar increases were not observed with LPS and saline solution.

Conclusions and Clinical Relevance—Administration of ATP-MgCl2 did not protect horses from systemic effects of experimentally induced endotoxemia. Furthermore, the use of ATP-MgCl2 during endotoxemia may worsen the cardiopulmonary and clinicopathologic status of affected horses. Because ATP and other adenine nucleotides are released from cells during shock, their potential role in the development of hemodynamic derangements, leukocyte adherence, and coagulopathies during endotoxemic episodes warrants further investigation. (Am J Vet Res 2004;65: 225–237)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To establish an in vivo method for matrix metalloproteinase (MMP)-2 and MMP-9 induction in horses via IV administration of lipopolysaccharide (LPS) and to evaluate the ability of doxycycline, oxytetracycline, flunixin meglumine, and pentoxifylline to inhibit equine MMP-2 and MMP-9 production.

Animals—29 adult horses of various ages and breeds and either sex.

Procedures—In part 1, horses received an IV administration of LPS (n = 5) or saline (0.9% NaCl) solution (5). Venous blood samples were collected before and at specified times for 24 hours after infusion. Plasma was harvested and analyzed for MMP-2 and MMP-9 activities via zymography. In part 2, horses received doxycycline (n = 5), oxytetracycline (5), flunixin meglumine (5), or pentoxifylline (4) before and for up to 12 hours after administration of LPS. Plasma was obtained and analyzed, and results were compared with results from the LPS-infused horses of part 1.

Results—Administration of LPS significantly increased MMP-2 and MMP-9 activities in the venous circulation of horses. All MMP inhibitors significantly decreased LPS-induced increases in MMP activities but to differing degrees. Pentoxifylline and oxytetracycline appeared to be the most effective MMP-2 and MMP-9 inhibitors, whereas doxycycline and flunixin meglumine were more effective at inhibiting MMP-2 activity than MMP-9 activity.

Conclusions and Clinical Relevance—IV administration of LPS to horses caused increased venous plasma activities of MMP-2 and MMP-9. These MMP activities were reduced by pentoxifylline and oxytetracycline, suggesting that further evaluation of these medications for treatment and prevention of MMP-associated diseases in horses is indicated.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine the feasibility of performing serial laminar and skin biopsies on sedated horses and whether sampling affected adjacent tissues.

Animals—6 horses.

Procedures—Laminar tissues were harvested via biopsy through the hoof wall from healthy conscious horses via sedation and regional anesthesia. Eight specimens were collected at 4 time points during 24 hours from a single foot. Laminar biopsy specimens were harvested with a 6-mm-diameter biopsy punch after burring through the horny corium to the stratum medium. Skin biopsy specimens were collected from an area proximal to the coronary band. All tissues were examined via light microscopy. Total RNA was extracted and quantified, and gene expression analysis was completed for 2 housekeeping genes and the inflammatory mediator cyclooxygenase-2.

Results—Laminar and skin biopsies yielded adequate specimens for histologic and gene expression evaluation. There was no extension of inflammation or detectable damage to adjacent tissues during the 24-hour period in either laminar or skin specimens as judged via histologic findings and cyclooxygenase-2 expression. Lameness and discomfort induced by the procedure were minimal.

Conclusions and Clinical Relevance—Laminar biopsy provided a satisfactory method of collecting laminar specimens and allowed serial sampling of individual horses.

Full access
in American Journal of Veterinary Research