And Grapiprant (Galliprant®) in an Induced Model of Acute Arthritis in Dogs Andrea García De Salazar Alcalá1, Lucile Gioda1, Alia Dehman2 and Frederic Beugnet3*
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Salazar Alcalá et al. BMC Veterinary Research (2019) 15:309 https://doi.org/10.1186/s12917-019-2052-0 RESEARCH ARTICLE Open Access Assessment of the efficacy of firocoxib (Previcox®) and grapiprant (Galliprant®) in an induced model of acute arthritis in dogs Andrea García de Salazar Alcalá1, Lucile Gioda1, Alia Dehman2 and Frederic Beugnet3* Abstract Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are an important tool in the management of canine osteoarthritis, with the most recent introduction into the category being grapiprant, a piprant that selectively targets the EP4 prostaglandin receptor. To date there have been no efficacy studies comparing grapiprant with other NSAIDs. A randomized, two-sequence, assessor-blinded study involving two separate experiments was undertaken to measure the potency and persistence of acute pain control over 24 h resulting from a single oral dose of either firocoxib (Previcox®) or grapiprant (Galliprant®) in an acute arthritis model. Results: Force-plate derived lameness ratios (0, no force recorded on the plate; 1, normal force) for the untreated group remained at 0 for most post-arthritis induction (PAI) assessments in both experiments. Throughout Experiment 1, mean PAI lameness ratios of the firocoxib-treated group remained at or above 0.80. In the grapiprant-treated group, ratios were 0 at 5 and 7 h PAI (7 and 9 h post-treatment), and 0.16 at 10 h PAI (12 h post-treatment). For lameness ratios, relative to the firocoxib group, the control and grapiprant group ratios were significantly lower at each PAI assessment (p ≤ 0.026 and p < 0.001, respectively), except at 1.5 h PAI at which acute pain was still not installed in untreated control dogs. In Experiment 2 the mean lameness ratios for the control group were 0 at 3, 5 and 7 h PAI, and in the grapiprant group at 5, 7 and 10 h PAI (i.e., 19, 21, and 24 h post-treatment). In the firocoxib group the lowest mean lameness ratio of 0.36 occurred at 3 h PAI (i.e. 17 h post-treatment). Except at 1.5 and 3 h PAI (i.e. 15.5 and 17 h post-treatment), due to the needed time for pain to install in the untreated control dogs, the lameness ratio differences between the firocoxib and both the control and grapiprant groups were significant at all assessments (p ≤ 0.033 for both groups). No significant differences were detected between the grapiprant and control groups in either experiment. Conclusions: Firocoxib treatment prior to induction of arthritis in dogs resulted in a high level of analgesia from the first post-treatment assessment at 1.5 h through 24 h post-treatment. The reduction in lameness provided by firocoxib was consistently superior to that provided by grapiprant, which was not significantly different from untreated controls. Keywords: Dog, Firocoxib, Grapiprant, Lameness ratio, Force-plate, Osteoarthritis Background importance in maintaining homeostasis through normal The use of non-steroidal anti-inflammatory drugs (NSAIDs) prostaglandin-related physiologic functions. The belief is an important tool in the management of canine osteoarth- that the inducible COX-2 was primarily responsible for ritis. The beneficial anti-inflammatory effects of NSAIDs pathologic processes led to the development of NSAIDs, arise from inhibition of the cyclooxygenase enzymes collectively coxibs, that would selectively target COX-2 (COX-1 and COX-2) that are produced by the break- while sparing COX-1 [2]. Members of the coxib class that down of arachidonic acid resulting from cell-wall dam- are now available for the treatment of canine osteoarthritis age [1]. COX-1 is recognized as constitutive with include cimicoxib, deracoxib, firocoxib, mavacoxib and robenacoxib. Thus, through sparing of COX-1, the object- * Correspondence: [email protected] ive of these coxibs is to reduce the risk of adverse effects 3Boehringer Ingelheim Animal Health, 29, avenue Tony Garnier, 69007 Lyon, France while maintaining the full benefit of anti-inflammatory and Full list of author information is available at the end of the article analgesic actions that would alleviate the inflammation and © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Salazar Alcalá et al. BMC Veterinary Research (2019) 15:309 Page 2 of 9 pain due to osteoarthritis. Recently, recognition that COX- control dogs, 6 fipronil treated and 6 grapiprant treated 2 also has constitutive activity led to a search for drugs with dogs included in Experiment 1). Arthritis induction was modes of action, other than cyclooxygenase inhibition, to successful in this control dog during the Experiment 2. reduce inflammatory pathways [3]. In experiment 1, for one firocoxib treated dog, the A recent outcome of that research has been the release values were missing at 7 h post arthritis induction (PAI) of the piprant molecule, grapiprant, which selectively because of a computer error; therefore the statistical targets the EP4 prostaglandin receptor without inhibiting analysis included 5 fipronil treated dogs at 7 h PAI, and COX [3]. It is believed that this mechanism of action 6 at the other time-points. would not interfere with the production of many of the In Experiment 2 a computer error in the force plate prostanoids that cascade from the COX pathways af- and video recordings for one dog in the firocoxib group fected by traditional NSAIDs. Nevertheless, to date there at the final time point assessment (10 h PAI, i.e. 24 h is no clinical evidence of any safety advantages over post-treatment) prevented inclusion of data from that other NSAIDs and there have been no reports of efficacy dog at that particular time-point. comparisons of grapiprant with other NSAIDs. Other than for the induced lameness, no abnormal clin- To investigate the comparative efficacy of grapiprant, a ical signs were recorded during the study in any group. randomized, two-sequence, assessor-blinded study was designed to measure the potency and persistence of pain Lameness (vertical force) ratios control over 24 h resulting from a single oral dose of ei- In Experiment 1, prior to arthritis induction all dogs in ther firocoxib (Previcox®) or grapiprant (Galliprant®) in the study had mean vertical force measurements (the mean an acute arthritis model [4–8]. The acute arthritis of three crossings of the force plate) of at least 3.5 kg, with model, based on the intra-articular injection of urate means in the control, firocoxib and grapiprant groups of crystals, induces pain in one joint for duration of around 5.2, 4.7 and 4.5 kg, respectively, with no significant differ- 10 h, with a peak of pain between 3 to 7 h post-injection ence between groups (Fig. 1). These vertical force measure- [5, 7, 8]. The exact same methodology was already used ments before the induction of arthritis provided baseline in 2017 to compare the pain control of firocoxib and data for calculation of individual lameness ratios for each robenacoxib [5]. The study consisted of two experiments dog at each time-point PAI (i.e. 1.5, 3, 5, 7 and 10 h PAI). performed over two different periods following adminis- The assessment times were based on available published tration of the drugs. In the first experiment, arthritis was data regarding the model, from appearance to peak and induced approximately two hours post treatment, allow- decrease of pain within 10 h [5, 7, 8]. A lameness ratio ing assessing pain control from 3.5 h to 12 h post-treat- of 0 indicates that, due to acute pain, no pressure was ment (assessment times at 1.5, 3, 5, 7, and 10 h post applied from the affected limb onto the force plate, induction). In the second experiment, acute arthritis was while a ratio of 1 indicates that the force applied to the induced 14 h post-treatment, allowing to assess pain platewasthesameasthatappliedpriortoarthritisin- control until 24 h post-treatment. As these drugs are duction. The mean lameness ratios for all groups had intended to be administered daily (i.e., every 24 h), such values > 0 at 1.5 h PAI indicating that pain was still not design including two experiments allowed to assess the installed in the untreated control dogs. Lameness ratios maintenance of pain control over an entire day. for the control group remained at 0 for all subsequent assessments, indicating that acute pain was assessed at Results first 3 h PAI in control dogs (Table 1,Fig.2). In the The results present the pain control in dogs after induc- firocoxib-treated group the mean lameness ratio tion of a transient joint arthritis (see Methods). The remained at or above 0.80 throughout the experiment acute pain was obtained after intra-articular injection of (Table 1,Fig.3). In the grapiprant treated group, ratios 1 mL of a sodium urate crystal suspension into the were 0 at 5 h and 7 h PAI (i.e., at 7 and 9 h post-treat- femorotibial joint using a 30 mm by 1 mm sterile needle ment), and were 0.16 at 10 h PAI (i.e. 12 h post treat- (Experiment 1 – right joint; Experiment 2 – left) in ment). One of the firocoxib-treated dogs was non- anaesthetized dogs [5].