Assessment of the Efficacy of Firocoxib and Robenacoxib
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Assessment of the Efficacy of Firocoxib and Robenacoxib in an Induced Synovitis Model of Acute Arthritis in Dogs Christelle Dauteloupa Corinne Pichoub Frederic Beugneta,* aMerial SAS, 2 Av Pasteur, 69007, Lyon, France b Amatsigroup, Site AmatsiAvogadro, Parc de Génibrat, 31470 Fontenilles, France * Corresponding author: E-mail address: [email protected] KEY WORDS: Firocoxib, Robenacoxib, and the increased PVF values compared to Arthritis, Lameness score, Peak Vertical the control group at 3 and 5 hours post- force injection. Firocoxib performed significantly better than robenacoxib at 3, 5, and 10 hours ABSTRACT post-UC injection. In this model, robena- The objective of this study was to compare coxib was not different from control for both the analgesic activity of a single oral dose the VLS and the PVF values. Pre-treatment of two COX-2 selective inhibitors, firo- with firocoxib reduced the induced pain as- coxib (Previcox®, Merial) and robenacoxib sociated with intra-articular administration (Onsior®, Elanco), in an acute pain model of urate crystals. in dogs. Sixteen healthy Beagle dogs were randomly allocated to three groups. Two INTRODUCTION successive experiments were conducted, in Chronic osteoarthritis is common in dogs which eight dogs served as control. Eight and is estimated to affect 20% of dogs dogs received firocoxib or robenacoxib in a over 1 year of age (Johnston, 1997). Since cross-over design at the recommended dos- no drug has been shown to reverse the age 13 hours before intra-articular injection pathological changes of osteoarthritis, the of a urate crystal suspension (UC) for induc- objective of treatment is to reduce pain and tion of synovitis. Ground reaction forces inflammation, and thus maintain the dog’s (Peak Vertical Force, PVF) and clinical mobility and quality of life (Kukanich et al., Visual Lameness Scores (VLS) were mea- 2012). sured before induction of synovitis, at 1.5, Non-steroidal anti-inflammatory drugs 3, 5, 7, 10, and 24 hours after UC injection (NSAIDs) are the most widely used anal- (except PVF which was not measured after gesics in veterinary medicine. They are com- 10 hours). In this study, pretreatment with monly used in the treatment of acute pain firocoxib significantly reduced the acute following surgical and dental procedures and pain and lameness induced by UC injection, are the cornerstone in the treatment of os- as shown by the decreased combined visual teoarthritis and other painful conditions. The score of lameness at 3 hours post-injection, main mechanism of action of NSAIDs is in 10 Vol. 15, No.1, 2017 • Intern J Appl Res Vet Med. the inhibition of cyclooxygenase (COX), 2004; Drag et al, 2007; Steagall et al, 2007; an enzyme in the arachidonic acid cascade, Hazewinkel et al, 2008; Schmid et al, 2010; which generates inflammatory mediators of King et al, 2011) and in field studies (Han- the prostaglandin (PG) group (Vane, 1971; son et al, 2006; Pollmeier et al, 2006; Ryan Lees et al., 2004). et al, 2006; Joubert, 2009; Ryan et al, 2010; Two isoforms of COX have been identi- Autefage et al, 2011; Reymond et al; 2012; fied. Cyclooxygenase-1 (COX-1) is pres- and Edamura et al, 2012). ent constitutively in almost all cell types The specific objective of the present (excluding erythrocytes) and is mainly in- study was to evaluate the daily analgesic ac- volved in maintaining physiologic functions, tivity (potency and persistence of analgesia including gastroprotection and maintenance over 24 hours) of a single oral dose of firo- of renal homeostasis, and is implicated in coxib and robenacoxib in an acute synovitis blood clotting (Jones et al., 2000; Lees et model. To assess the ability of each NSAID al., 2004). Cyclooxygenase-2 (COX-2) is in- to control pain over 24 hours, each was duced in inflammatory responses producing administered 13 hours prior to the induction pro-inflammatory PGs, such as PGE2 (Jones of acute inflammation by the intra-articular et al., 2000; Lees et al., 2004). It is generally injection of urate crystals accepted that inhibition of COX-1 is likely to account for most of the side-effects of MATERIALS AND METHODS NSAIDs (gastric irritation, renal damage, Animals and prolonged bleeding time) and that their Animal housing and care complied with efficacy is mainly dependent on the inhibi- the recommendations of Directive 86/609/ tion of COX-2 (Warner et al., 1999; Lees et EEC. The animal care and use program was al., 2004). AAALAC accredited. The study plan was Intensive efforts have been made to approved by the AmatsiAvogadro Animal develop specific inhibitors of the COX- Ethic Committee. 2 isoform while sparing the activity of Sixteen male Beagle dogs, aged from 16 COX-1. Firocoxib (Previcox®, Merial) and to 28 months and weighing from 8.5 to 11 robenacoxib (Onsior®, Elanco) are highly kg, were included. The animals were select- selective inhibitors of COX-2 developed ed based on a full clinical examination and specifically for veterinary use (McCann et blood (haematology and blood chemistry) al., 2004; King et al., 2009). Both products analyses. Particular attention was paid to the are registered for once daily administration locomotory system of the enrolled animals (24 hourly). In whole blood canine as- to ensure the absence of lameness before says (the gold standard for assessing COX inclusion. Animals were housed individually activity), the COX-2 selectivity, determined throughout the study and fed with a com- on the basis of the COX-1: COX-2 ratio of mercially available dog food with unlimited the IC50 values (inhibition of 50% of COX access to water. Animals were identified activity) was 384 for firocoxib (McCann et using a microchip. al., 2004) and 128.8 for robenacoxib (King During the acclimatization period (3 et al., 2010). In vivo, firocoxib and robena- weeks) before the first experiment, dogs coxib induce marked inhibition of COX-2, were trained to walk on a lead during the while sparing COX-1, when administered at first week and to walk on the force plate in clinically recommended dosages (McCann the two following weeks. et al., 2004; King et al., 2010; Schmid et al., Study design and treatments 2010; King et al., 2011). The efficacy and The study was divided into two experiments safety of firocoxib and robenacoxib in the (Exp1 and Exp2) separated by a 2 month dog have been extensively demonstrated in wash out period in order to reduce the num- experimental clinical studies (McCann et al, ber of dogs included in the study for ethical Intern J Appl Res Vet Med • Vol. 15, No. 1, 2017. 11 Table 1. Allocation of the 16 dogs in the different groups. Experiments Untreated Firocoxib Robenacoxib control dogs treated dogs treated dogs Exp.1 1, 2, 3, 4 5, 6, 7, 8 13, 14, 15, 16 Washout period (2 months) Exp.2 9, 10, 11, 12 13, 14, 15, 16 5, 6, 7, 8 reasons. Each experiment included three present study). groups of four dogs: four untreated control Experimental Model dogs, four treated with firocoxib, and four Lameness was induced 13 hours after test with robenacoxib. During the second experi- drug administration using an established ment, four new control dogs were included, reversible urate crystal (UC) arthritis model whereas the four dogs treated with firocoxib (Toutain et al, 2001). corresponded to the four previously treated The sodium UC suspension (Sigma with robenacoxib, and vice versa (Table 1). Aldrich, USA) was prepared to a final The washout period and cross over design concentration of 10 mg/mL according to the allowed the inclusion of fewer dogs but published method (Toutain et al, 2001). One also to consider that the variances would be mL of suspension was used for each intra- similar between the treated groups. articular injection. Dogs were anesthetized Sixteen dogs were ranked by weight and with propofol intravenously at a dose of 6.5 then randomized into three groups of four mg/kg, before the intra-articular injection of dogs in Exp 1 and Exp 2. For analysis, the UC. data from the two experiments were pooled. All UC injections were administered Treatments were administered orally 13 into the right stifle (femoro-tibial) joint un- hours before UC injection in each experi- der aseptic conditions using 19-gauge sterile ment. Animals were fasted 7 hours before needles (30 mm long) and 2.5-mL syringes. firocoxib or robenacoxib administration, and overnight before each UC injection. The Using this model, the duration of the dogs were fed approximately 1 hour after induced inflammatory and painful process each UC injection on day 1. Firocoxib and is approximately 16-24 hours, with a pain robenacoxib were administered at the ap- intensity peak within 2 to 3 hours after proved label dosages for the control of pain induction in untreated animals (Toutain et and inflammation associated with osteoar- al., 2001). thritis. Firocoxib (Previcox®, Merial) was Efficacy Assessment given at a dose of 1 tablet of 57 mg for dogs The anti-inflammatory and analgesic ef- with a bodyweight ranging from 5.6 to 10.0 ficacy of the test items was assessed through kg and 1 + 1/2 tablet of 57 mg for dogs with two parameters: the Visual Lameness Score a bodyweight ranging from 10.1 to 15.0 kg (VLS) and the Peak Vertical Force (PVF). (targeted therapeutic dose of 5mg/kg, with The VLS was assessed for each period on a range of 5-10 mg/kg, ie, ranging 6.4-8.3 the day before induction (Day 0 before UC mg/kg in the present study). Robenacoxib injection), and 1.5h, 3h, 5h, 7h, 10h, and 24h (Onsior®, Elanco) was administered at a post-UC injection (corresponding to 14.5h, dose of one tablet of 10 mg for dogs with a 16h, 18h, 20h, 23h, and 37h after test drug bodyweight ranging from 5.0 to 10.0 kg and administration).