Abstract
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 (AUC 0−∞) 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.
Highlights
Tumour necrosis factor a (TNFa) is a potent pro-inflammatory cytokine that plays an important role in equine diseases such as mild to moderate equine asthma, systemic inflammatory response syndrome (SIRS) and laminitis [1,2,3]
Current anti-inflammatory regimens used in equine medicine rely heavily on nonsteroidal antiinflammatory drugs (NSAIDs), which are associated with gastrointestinal (GI) effects, most notably in critically ill horses [7]
This study was conducted in two phases: the first was a misoprostol free acid pharmacokinetic study, and the second was an ex vivo experimental study determining the effect of oral misoprostol on TNFa mRNA concentrations
Summary
Tumour necrosis factor a (TNFa) is a potent pro-inflammatory cytokine that plays an important role in equine diseases such as mild to moderate equine asthma, systemic inflammatory response syndrome (SIRS) and laminitis [1,2,3]. TNFa induces multiple leucocyte effector functions that elicit extensive tissue damage in disease states including sepsis, equine laminitis and equine asthma [4,5,6]. Current anti-inflammatory regimens used in equine medicine rely heavily on nonsteroidal antiinflammatory drugs (NSAIDs), which are associated with gastrointestinal (GI) effects, most notably in critically ill horses [7] These adverse effects are thought to be due to inhibition of gastroprotective prostaglandins [7,8]. While in vivo efficacy research is lacking, misoprostol is used clinically to treat and prevent NSAID-induced gastroenteropathies In addition to this role, misoprostol has been shown to elicit antiinflammatory effects on human leucocytes through an agonistic effect on the E-type prostaglandin receptor, EP2 [11,12]. Oral misoprostol at a dose of 5 lg/kg twice daily has been shown to aid in healing of equine gastric glandular disease (EGGD) lesions in vivo [18], the pathology of which is
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