Research Article: Plasma pharmacokinetic profile and efficacy of meloxicam administered subcutaneously and intramuscularly to sheep

Date Published: April 24, 2019

Publisher: Public Library of Science

Author(s): Alyssa N. Woodland, Dominique Van der Saag, Benjamin Kimble, Peter J. White, Merran Govendir, Sabrina Lomax, Francesco Staffieri.

http://doi.org/10.1371/journal.pone.0215842

Abstract

Plasma pharmacokinetic profiles and the anti-inflammatory efficacy of meloxicam were determined when administered subcutaneously (SC) or intramuscularly (IM) to sheep. Merino ewes were initially injected with 0.1 mL of oil of turpentine into a forelimb to induce inflammation, followed by either 1.0 mg/kg or 2.0 mg/kg of meloxicam administered either SC or IM (n = 6 per treatment group) or followed by no meloxicam administration (control) (n = 4). Ewes were examined to determine skin temperature, limb circumference, limb sensitivity and signs of lameness at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24 and 48 h following treatment, with blood collected at these time-points to quantify meloxicam plasma concentrations. Skin temperature of ewes dosed with meloxicam at 1.0 mg/kg SC and 2.0 mg/kg IM at 12 h and 1.0 mg/kg SC at 24 were significantly different to the controls (P < 0.05). Limb circumferences of ewes dosed with 1.0 mg/kg IM were significantly different to controls at 10 h and 12 h (P < 0.05). All meloxicam treatment groups resulted in reduced limb sensitivity compared to controls at 6 h, with the 1.0 and 2.0 mg/kg IM treatments significantly different at 12 h (P < 0.05) and 1.0 and 2.0 mg/kg SC groups, significantly different to controls at 48 h (P < 0.05). No significant difference in lameness scores were detected over 48 h. The 1.0 mg/kg IM treatment had a significantly greater plasma meloxicam concentration than the 1.0 mg/kg SC treatment over 0.5 to 4 h (P < 0.001). Both 1.0 mg/kg SC and IM treatments demonstrated elimination half-lives (mean ± SD) of 10.82 ± 2.46 and 12.63 ± 2.37 h, respectively. Meloxicam at all doses provided some anti-inflammatory and analgesic effects from 6 to 48 h; however no route could be distinguished as more efficacious than the others.

Partial Text

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) registered for a number of species including humans, cats, dogs, cattle, pigs and most recently sheep [1]. Mechanistically, meloxicam inhibits the enzyme cyclo-oxygenase (COX) that converts arachidonic acid to prostaglandins [2]. Therefore NSAIDs, such as meloxicam, reduce formation of those prostaglandins (PG), such as PGE2, that induce inflammation, pain and fever [3]. Meloxicam is considered to selectively inhibit the COX-2 isoenzyme in humans [4], resulting in low ulcerogenic potential of the gastric mucosa, however this may not be the case for all species [2]. Aspects of meloxicam’s pharmacokinetic profile has been documented for numerous species including dogs [3], goats [5], horses [6], cattle [7] and other domesticated and non-domesticated species [8]. Consequently, meloxicam has demonstrated favourable characteristics in many species, such as an extended elimination half-life of 24 h in dogs [3], 20 h in humans [3] and 8.5 h in horses [9], and a high oral availability such as 106% in dogs [3], 89% in humans [10] and 85% in horses [9].

This is the first study to quantify plasma meloxicam concentrations and provide some observations of efficacy when meloxicam is administered SC and IM to sheep. No treatment group appeared consistently superior to any other. This current study demonstrates that when meloxicam is administered by both SC and IM routes, it provides some anti-inflammatory action and pain relief, but not surprisingly, this occurs later than that observed from 2 to 4 h when meloxicam was injected at 1.0 mg/kg IV [13]. In the current study, statistically significant differences between treatment versus control groups were evident 6 to 48 h after meloxicam administration, and summarised in Table 3. The observations of the current study are similar to another that administered 0.5, 1.0 and 1.5 mg/kg meloxicam SC, 90 minutes prior to the 0.1 mL oil of turpentine injection into the pastern in Merino ewes [23]. Meloxicam, when administered at 1.5 mg/kg SC pre-emptively, did not provide any additional analgesic benefits compared to a 1.0 mg/kg dose and the strongest effects of meloxicam were observed 6 to 9 h after administration [23].

This study demonstrates that meloxicam when administered at 1.0 or 2.0 mg/kg SC or IM is effective at providing some analgesia after injection of turpentine into the front limbs of sheep. Whilst some observations of anti-inflammatory and analgesic efficacy according to dose and administration route over time were obtained, this study could not significantly distinguish therapeutic efficacy of meloxicam between treatments in sheep. Although the IM route reaches the Tmax faster than the SC route, and the higher dose resulted in greater maximal plasma concentration, there is no clear evidence that the IM route or 2.0 mg/kg SC provided significantly superior analgesia than 1.0 mg/kg SC in Merino sheep. The recommended dosage of 1.0 mg/kg SC or 1.0 mg/kg IM appears to provide significant anti-inflammatory action and analgesia for Merino ewes with some significant differences to untreated controls observed from 6 to 48 h.

 

Source:

http://doi.org/10.1371/journal.pone.0215842

 

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