Article — Artikel

The effects of firocoxib (Previcox™) in geriatric dogs over a period of 90 days

K E Jouberta

0.5–7 %21. With age there is a loss of renal ABSTRACT mass and glomeruli and a decrease in The long-term use of non-steroidal anti-inflammatory agents in geriatric dogs with renal blood flow11. Creatinine clearance osteoarthritis has not been well studied in veterinary medicine. This study evaluated the decreases but serum creatinine remains effects of firocoxib administered to dogs over 7 years of age for 90 days. Pain and lameness normal due to a decrease in muscle mass scores were evaluated by the owner weekly for the 1st month and then biweekly through to and a decrease in urine SG11. NSAIDs are the end of the study, the veterinarian evaluated the dogs monthly. Serum chemistry, known to have a potential to influence including urea, creatinine, alanine transferase, aspartate transaminase, bile acids and 15 bilirubin, urine specific gravity and a urine dipstick, were performed at monthly intervals. renal function . Hepatic mass also de- 11 Forty-five dogs were enrolled into the treatment group and 9 into the control group. A total creases with age . There is a loss of func- of 33 dogs completed the trial in the treatment group and 8 in the control group. Lameness tional reserve within the liver and this 11 and pain scores were found to be significantly lower in the treated group from day 30 for may become problematic . The most most parameters evaluated. Bile acids (although not comparable to controls, with higher common conditions diagnosed in geriatric mean value and a high standard deviation in the control group; in addition the control patients undergoing routine screening group had increased bile acids at day 0) and urea (within normal reference range provided before anaesthesia were neoplasia, chronic (WNL)) were significantly different in the treatment group between days 0 and 90. Urea kidney disease and Cushing’s disease12. (WNL) on days 30 and 90 and creatinine (WNL) on day 90 were significantly different From the literature, it is evident that between the control group and the treatment group. The most common adverse events NSAIDs are well tolerated in general in reported were diarrhoea, vomition, dark faeces and anorexia. This study showed that animals. The long-term effect of NSAIDs firocoxib was effective in managing pain associated with osteoarthritis for 90 days. Despite in geriatric dogs has, however, not been the geriatric high-risk population used for this study, minimal biochemical changes were well studied. The age-related changes in seen and adverse drug events seen were in agreement with those previously reported. organ function may predispose these Keywords: adverse events, canine, lameness, firocoxib, geriatric, long term, non-steroidal patients to an increase in side-effects anti-inflammatory drugs, pain control. associated with NSAIDs. Osteoarthritis is Joubert K E The effects of firocoxib (Previcox™) in geriatric dogs over a period of 90 days. a common condition in geriatric dogs Journal of the South African Veterinary Association (2009) 80(3): 179–184 (En.). PO Box 1898, requiring pain relief and is generally Lonehill, 2062 South Africa. treated with NSAIDs. This study was undertaken to evaluate the effects of a 90-day administration of Previcox in INTRODUCTION and significantly better than the placebo geriatric dogs (dogs older than 7 years). Previcox™ (firocoxib) is a new generation and at the 7 hours post- The effects on pain and lameness as well non-steroidal anti-inflammatory drug treatment9. Improvement in lameness as renal and liver function were evaluated. (NSAID) that is highly COX-2 (cyclo-oxy- score was also significantly better in the genase 2 isoenzyme)-specific in dogs18.At dogs treated with firocoxib than placebo MATERIALS AND METHODS an 80 % inhibition of cyclo-oxygenase and carprofen at both 3 and 7 hours Forty-five dogs were enrolled in a treat- enzymes it has a 427:1 affinity for COX-218. post-treatment9. The use of the highly se- ment group (Group P) and 9 dogs in a It has been suggested that for an NSAID lective COX-2 inhibitor firocoxib reduced control group (Group C). Group P dogs to exert its clinical effect an 80 % inhibi- acute pain due to synovitis and provided had to be older than 7 years of age and tion of the cyclo-oxygenase enzyme is significant improvement in weight bear- have a diagnosis of osteoarthritis in one or required13,14. This makes Previcox a COX-2 ing at a dose of ≥5 mg/kg body weight9. more joints, having not received any specific drug in clinical practice and the These effects were better than those ob- treatment in the last 3 months for this con- 1st to be introduced onto the South Afri- served with carprofen and similar to dition, free of systemic disease (cardiovas- can market for dogs. those with vedaprofen9. At a therapeutic cular, respiratory, renal, hepatic, gastro- Previcox has a half life of 7.59 hours and dose of 5 mg/kg almost no inhibition of intestinal) and not currently receiving an oral bioavailability of 36.9 %5.Ina COX-1 takes place. any for any specific disease. randomised, placebo-controlled 4-period The target population used in this study Group P dogs received a 90-day treat- cross-over laboratory study involving 8 was a geriatric, high-risk population ment with Previcox at the recommended dogs conducted to confirm the effective which inherently involves certain physio- dose according to weight. Group C con- analgesic dose of firocoxib in a synovitis logical changes associated with senior sisted of a similar group of dogs except model of arthritis, the firocoxib treatment pets. The prevalence of chronic kidney that no diagnosis of osteoarthritis was group performed significantly better disease in dogs increases with age, with made and no treatment was required. than placebo at 3 hours post-treatment 20 % of dogs between 7 and 10 years of Group C dogs received no treatment. No a age and 45 % more than 10 years of age complementary medicines were allowed PO Box 1898, Lonehill, 2062 South Africa. 21 E-mail: [email protected] having renal disease . The actual inci- during the trial period. Received: September 2008. Accepted: August 2009. dence in a canine population is between On admission to the trial, the owner’s

0038-2809 Jl S.Afr.vet.Ass. (2009) 80(3): 179–184 179 informed consent was obtained. The Table 1: Veterinarians’ evaluation of lameness, pain and range of motion. owners were informed that they could withdraw their animal at any point Scoring system during the study without giving a reason. Lameness The age, sex, breed and weight were 0 – No lameness recorded for each patient enrolled. No 1 – Mild lameness (Occasional gait abnormality) distinction was made on sterilisation 2 – Moderate lameness (obvious gait abnormality with/without occasional non-weight bearing) 3 – Severe lameness (consistently non-weight bearing) status as very few of the animals were not sterilised. The veterinarian examined the Pain on manipulation/palpation dog to determine the overall health and 0 – No pain well-being of the dog before entering the 1 – Slight pain (scarcely withdraws limb) 2 – Moderately painful (definitely withdraws limb) trial. Attention was given to the cardio- 3 – Severely painful (prominently withdraws limb) vascular, respiratory, gastrointestinal and renal systems. Dogs with heart disease, Range of motion respiratory disease, gastric ulceration and 0 – Normal 1 – Slightly reduced renal failure were excluded from the 2 – Moderately reduced study. Acute infectious arthritis was 3 – Severely reduced excluded from admission to the study. The veterinarian was required to accu- rately make the diagnosis of osteoarthritis using confirmatory tests as required. The Table 2: Owners’ evaluation of pain in dogs. joint or joints affected were recorded as well as the method of diagnosis. Parameter Definition Score The veterinarian evaluated the dog’s Reluctance to climb stair or hop into a car? Cannot 0 clinical signs associated with osteoarthritis Can but very reluctantly 1 using the following parameters: overall Will do it 2 lameness, pain on palpation/manipula- Expedient 3 tion (most severely affected limb) and Rising from a resting position Cannot 0 range of motion (most severely affected Can but very reluctantly 1 limb). This was scored according to Table 1 Will do it 2 by the veterinarian on days 0, 30, 60 and 90. Expedient 3 The owner evaluated the lameness and Stiffness after playing Cannot play 0 activity of the dog using a visual analogue Can play but very reluctantly 1 scale. A simple 4-point scoring system Plays but tires 2 was used to evaluate the dog’s ability to Expedient 3 climb stairs, rise from a resting position, Degree of limping or lameness All the time 0 stiffness after playing, limping, amount of Often signs 1 time spent sleeping or lying and overall Occasional signs 2 functionality. The 4-point scoring system No signs 3 is described in Table 2 The owner evalu- Amount of time spent sleeping or lying around Sleeps all the time 0 ated the dog on days 0, 7, 14, 21, 30, 45, 60, Inactive 1 75 and 90. These data were only collected Moderate activity 2 for dogs in Group P. Normal activity 3 A urine sample was obtained by the Over activity and functionality Inactive 0 veterinarian. Urine specific gravity was Reluctant to be active 1 recorded. A dipstick was used to record Functionally active 2 the presence of proteins, red blood cells, Active and lively 3 glucose and pH and the results recorded. All trace readings were scored as 1. A blood sample was taken and submitted to water intake (polydypsia), bloody or dark (Excel, Microsoft Corporation, Red- a veterinary pathology laboratory (Idexx tarry faeces. The owner was requested to mond). Statistical analysis was performed Golden Vet, Sunninghill) for routine record the number of times any of these using SigmaStat for Windows, (Jandel analysis. Urea, creatinine, alanine trans- side effects occurred or any other abnor- Corporation). Statistical significance was ferase (ALT), aspartate transaminase mality they detected during the course of set at P < 0.05. Descriptive statistics were (AST), bile acids and bilirubin were deter- the trial. If the owner suspected any of the used to describe the populations in mined for each sample submitted. Urine adverse events (as listed in the monitor- and serum chemistry was done on days 0, ing sheet) to be due to the drug being Table 3: Normal values for serum chemistry. 30, 60 and 90 for dogs in group P and administered they were instructed to on days 0 and 90 for dogs in group C. discontinue the therapy and contact the Parameter Units Normal range Normal values for serum chemistry are veterinarian or study coordinator. When given in Table 3. the owner felt that the pain was not being Urea mmol/ 3.6–8.9 A list of common clinical adverse events controlled by the trial drug at any time, Creatinine µmol/ 100–130 ALT U/ 60–10 of non-steroidal anti-inflammatory drugs codeine at 1–4 mg/kg administered 2–4 AST U/ 60–20 was provided to the owner. The list times daily was allowed, and recorded by Bilirubin µmol/ 0–12 included: anorexia, depression, lethargy, the owners. Bile Acids µmol/ 0–15 increased urination (polyuria), increased Data were entered into a spreadsheet

180 0038-2809 Tydskr.S.Afr.vet.Ver. (2009) 80(3): 179–184 Groups P and C. The t-test was used to Table 4: Demographics of Group C. Table 5: Demographics of Group P. determine differences between groups P and C for age and weight. A Mann- n n Whitney rank sum test was used to deter- Breed Breed mine the difference in group C between 0 Great Dane 1 German shepherd dog 4 and 90 days for rank data and the t-test for Staffordshire bull terrier 1 Staffordshire bull terrier 4 nominal data in the clinical pathology Belgium shepherd 1 Cross breed 4 data. A 1-way analysis of variance was Spaniel 1 Boxer 3 used to detect statistical differences in Labrador 1 Great Dane 3 group P for clinical pathology data be- Schnauzer 1 Spaniel 2 tween the different days. When statistical Dalmatian 1 Bearded collie 1 difference was found, Dunn’s method Rottweiler 1 Belgium shepherd 1 with day 0 as the control was applied to Sex Border collie 1 identify the days that were different. Male 4 Bouvier 1 Bull mastiff 1 Group C combined data were compared Female 4 Doberman 1 to group P data using 1-way analysis of Weight (kg) 32.64 ± 20.82 Fox terrier 1 variance. When statistical difference was Age (years) 9.63 ± 2.07 Labrador 1 found, Dunn’s method with group C data Maltese 1 as the control was applied to identify Miniature Schnauzer 1 the days that were different. The veteri- ment group due to conditions unrelated Old English sheep dog 1 narian’s evaluation of lameness and the to the treatment. One dog died 17 days Rough collie 1 owner’s evaluation of pain and activity after starting treatment – the cause is Whippet 1 were compared using 1-way analysis of unknown and the owner declined a post Sex variance on ranks. If statistical signifi- mortem. A 2nd dog died 14 days after start- Male 11 cance was found, Dunn’s method was ing treatment due to babesiosis. A 3rd dog Female 20 applied to identify days that were differ- was euthanased on humane grounds Not Stated 2 ent using a pair-wise comparison. after 30 days of treatment and a 4th dog Weight (kg) 31.64 ± 17.26 after 45 days of treatment. A total of Age (years) 9.83 ± 1.84 RESULTS 33 dogs in the treatment group and 8 dogs A total of 45 forms were collected in the in the control group were analysed. treatment group and 9 in the control The demographics of the group C dogs Table 6: Sites of osteoarthritis in Group P. group. In the treatment group, 3 owners are are given in Table 4 and of group P in provided incomplete data sheets. One Table 5. The control and treatment groups Osteoarthritis n owner did not provide the information were not statistically different with re- on whether the animal preferred to sleep spect to age and weight. The sites of osteo- Hip dysplasia 10 all day. One owner did not collect informa- arthritis in group P is given in Table 6. Stifle 9 tion on stair climbing beyond day 21. One The veterinarians’ evaluation of lame- Stifle and hips 6 owner only collected information to ness score was statistically significantly Elbows 2 day 45, one to day 21 and one to day 60. different between days 0 and 60, 0 and 90 Hips and elbows 2 Elbows and lumbar spine 1 One form was rejected because data were and 30 and 90, palpation score on days 0 Lumbar spine 1 only collected at 0 and 30 days. One dog and 30, 0 and 60 and 0 and 90, range of Shoulders and lumbar spine 1 missed the day-30 check-up, but the motion on days 0 and 60 and 0 and 90 and Stifle and elbow 1 remaining data were included. No urine the overall score on days 0 and 30, 0 was obtained from 1 dog on a single occa- and 60 and 0 and 90. The owner evalua- sion (3rd sample) in the treatment group. tion of pain was statistically different and 60, 0 and 75 and 0 and 90. This is No urine was obtained on 2 occasions between days 0 and 45, 0 and 60, 0 and 75, graphically represented in Fig. 1. The from a control dog but the serum chemistry 0 and 90, 7 and 60, 7 and 75 and 7 and 90 dogs’ ability to climb stairs, pain on rising, results were included. No urine was ob- and the activity score on days 0 and 45, 0 limping, sleeping and activity was signifi- tained on the 2nd occasion from a control dog. A single AST value from the baseline reading was not analysed for 1 treatment dog and the 1 control dog. One control dog (2 years of age) and 3 treatment dogs (1 – 4 years; 2 – 5 years) were excluded as they were too young for inclusion. Two dogs were withdrawn from the study after the 1st blood sample due to grossly abnormal blood results (AST) in the treatment group. One dog was withdrawn from the trial by the owner on day 60 in the treatment group owing to poor appetite and weight loss. Two owners withdrew their dogs volun- tarily owing to gastrointestinal side effects (diarrhoea) after 7 days and 60 days of treatment. Four dogs died in the treat- Fig. 1: Owners’ evaluation of activity and pain using a visual analogue scale.

0038-2809 Jl S.Afr.vet.Ass. (2009) 80(3): 179–184 181 cantly different on days 0 and 30, 0 and 45, Table 7: Urine results for Groups P and C. Urine RBC = urine red blood cells. 0 and 60, 0 and 75 and 0 and 90. Stiff after playing was significantly different on days Group P Group C 0 and 45, 0 and 60 and 0 and 75. Parameter Day Mean SD Mean SD The clinical pathology results for groups P and C are contained in Tables 7 Urine specific gravity 0 1028.61 12.32 1027.86 4.95 30 1035.03 12.91 & 8. No statistical difference was found 60 1032.73 11.39 between day 0 and day 90 in group C. 90 1035.50 13.44 1020.17 12.04 Group C data for days 0 and 90 were Urine pH 0 6.58 0.91 6.50 1.12 combined for comparison to group P 30 6.25 0.92 data. In group P,bile acids and urea were 60 6.47 1.11 statistically different between days 0 and 90 6.12 0.86 6.50 1.22 90. A statistically significant difference Urine protein 0 0.58 0.71 0.86 0.69 was found between the combined data of 30 0.67 0.76 group C and group P for creatinine at 60 0.60 0.62 90 0.57 0.57 1.17 0.98 day 90 and urea at days 30 and 90. Side effects were noted in 13 dogs with Urine glucose 0 0.00 0.00 0.00 0.00 27 adverse events recorded. Four dogs 30 0.00 0.00 60 0.00 0.00 had a single event while the remaining 90 0.00 0.00 0.00 0.00 dogs had more than 1 adverse event. One Urine RBC 0 0.24 0.56 0.57 1.13 dog had 4 adverse events. This study cov- 30 0.37 0.76 ered a total of 2970 treatment days and 60 0.33 0.84 this represents an adverse event rate of 90 0.23 0.63 0.17 0.41 0.009 % per day of treatment. The most common adverse events reported were diarrhoea, vomition, dark faeces and Table 8: Serum chemistry results for Groups P and C. anorexia. The number and type of side effects recorded by owners during the Group P Group C study is reported in Table 9. No dogs Parameter Day Mean SD Mean SD received any codeine for uncontrolled pain. ALT 0 51.91 35.25 68.75 48.06 30 58.69 47.92 60 85.41 98.37 DISCUSSION 90 72.23 61.06 99.63 76.87 This study should be interpreted in the AST 0 53.63 22.08 54.00 18.98 light of the fact that it was conducted in 30 51.27 17.09 patients older than 7 years of age. Geriatric 60 67.19 58.20 patients are known to develop changes in 90 54.17 19.66 52.57 15.53 hepatic and renal function that are age Bilirubin 0 14.61 14.20 24.00 20.97 related. NSAIDs are commonly prescribed 30 10.03 8.02 for osteoarthritis, which is common in 60 11.06 10.79 geriatric patients, and these drugs are 90 10.40 9.32 9.00 5.68 known to have effects on hepatic and Bile acids 0 11.35 8.94 77.25 165.34 renal function. The effects of NSAIDs 30 14.10 9.44 have not been well studied in this group 60 11.03 9.99 90 25.32 33.05 18.48 11.41 of patients, rendering the data collected here difficult to interpret. Urea 0 5.40 1.43 5.10 1.44 30 6.76 2.12 Firocoxib has been evaluated in 6 60 6.38 1.97 healthy experimental dogs when admin- 90 7.00 2.21 5.11 1.03 25 istered for 28 days . Complete blood Creatinine 0 99.76 23.06 97.75 19.00 count, urea, creatinine, alanine trans- 30 107.13 23.23 aminase (ALT), alkaline phosphatise 60 111.38 25.20 (ALP), gamma-glutamyltransferase (GGT), 90 111.90 23.50 91.25 16.10 occult faecal blood, platelet function and mucosal bleeding time were measured on days 0, 7, 14, 21 and 2925. Urine analysis Table 9: Adverse events reported during the study. and gastroscopy were preformed on days 0 and 2925. No significant difference Adverse events Number of incidences Number of dogs with a particular condition between measured values was shown over the 28 days25. The long-term effects Diarrhoea 9 5 of carprofen, , , ketopro- Vomition 6 3 fen and have been studied in Dark stool 4 2 dogs16,22. This was performed in medium- Anorexia 3 2 sized dogs aged between 1 and 5 years of Constipation 2 1 16 Weight loss 1 1 age . A complete blood count, urea, Urination 1 1 creatinine, ALT, ALP, GGT, protein, albu- Increased water consumption 1 1 min, globulin, bleeding time, clotting

182 0038-2809 Tydskr.S.Afr.vet.Ver. (2009) 80(3): 179–184 time, occult blood in faeces and gastric ul- and this may have resulted in the erratic 1.9 %, diarrhoea 0.6 % and vomition and ceration through gastroscopy were moni- high values seen in the study. It is impor- diarrhoea 0.4 %24. In 128 dogs that tored16. The dogs were treated for 90 days tant to realise that most of the results were received firocoxib for 30 days the most and samples were taken on day 0, 7 30, 60 not beyond the normal clinical range common adverse events were diarrhoea and 9016. GGT was increased in the con- supplied by the laboratory. The changes 0.8 %, vomition 3.9 %, anorexia 2.3 % and trol, etodolac and meloxicam and bleed- seen may represent normal variation. lethargy 0.8 %8. In total, 9.4 % of the dogs ing time increased in the meloxicam, Hepatoxicity has not yet been observed had an adverse event8. The most common and flunixin groups16. with firocoxib8,24,25. The control group had adverse events seen in the present study Clotting time was increased in the a higher mean value and a high standard were related to the gastrointestinal tract. carprofen, flunixin, ketoprofen and deviation and had increased bile acids at The incidence seen in this study may meloxicam groups16.Gastric ulceration was day 0. represent the geriatric patient group that seen in the etodolac, ketoprofen and In veterinary medicine, carprofen has was targeted as opposed to the original flunixin groups16. Carprofen and meloxi- been documented to induce liver failure17. and pre-marketing studies that sampled cam induced the lowest frequency of A number of NSAIDs have been with- dogs between the ages of 7 months and gastrointestinal effects16. drawn from the human market due to liver 19 years, with the vast majority being The long-term effects of carprofen were failure1. Most initial studies are under- middle-aged and relatively healthy indi- studied compared to placebo in a small powered to detect rare adverse events1.It viduals. These patients are potentially group of medium to large dogs with a has been suggested that a sample of 30 000 more likely to develop adverse events mean age of 5.7 ± 2.5 years over a period is required to detect these rare adverse based on age-related deterioration in liver of 2 months22. Protein, albumin, urea, events with a certainty of 95 %1. , and renal function. creatinine, ALP,AST and urinary protein and cause cholestatic The result of this study may have been creatinine ratio were studied at day 0, 30 liver injury1. NSAIDs have been shown to influenced by sample size. The sample and 6022. Serum albumin was lower in induce changes in bile salts that alter their size is relatively small; however, the treated dogs22. No difference was found conformation that makes them toxic to results are still useful. This study shows in serum and urine chemistry results22. the gastrointestinal tract20. This change in that firocoxib is effective for managing In this study, pain scores as recorded by conformation may affect bile flow and pain associated with osteoarthritis and both veterinarians and owners showed induce cholestatic liver damage. Does the the improvement is seen up to day 90. The statistical improvement from day 30 rise in bile acids indicate cholestasis? The effect of NSAIDs in geriatric dogs has not onwards. For the owner, some variables rise in bile acids and urea should be inves- been well researched and subtle changes only became statistically significant after tigated further to exclude a possible rare reported here may represent part of day 45. Statistical difference was also seen underlying liver effect. normal aging. This should be borne in for the owners’ pain evaluation between A rise in urea from the control group mind when interpreting these data. The day 7 and days 60, 75 and 90. The veteri- to the treatment group was detected on drug is safe with minimal biochemical narians’ evaluation of pain was also days 30 and 90. After 28 days treated with changes. The adverse events seen are in significantly different between days 30 firocoxib in 6 dogs, a single dog devel- line with what has been reported and 90. These data suggest that a prolonged oped a raised urea level but this also previously. This is one of the 1st reports in course of firocoxib may show continued occurred during placebo treatment25.No geriatric veterinary patients and further improvement. This concept is supported gastric ulcers were detected in healthy follow-up and studies of other NSAIDs by a dose-reduction study with meloxicam dogs treated for 28 days with firocoxib25.A are required in this target population. where differences where found to day raised urea value in 12 of a 1000 dogs 6,10 120 , and in a study using tolfenamic withdrawn from a firocoxib study has ACKNOWLEDGEMENTS 24 acid in dogs following a femoral head been reported . An increase in urea (17.6 Without the funding and support of excision, improved functionality was to 23.7 mg/d ) although not statistically Merial South Africa (Pty) Ltd this study found in dogs treated for 4 months com- significant, was shown in 128 client- would not have been possible. Anthony 8 pared with normal post-operative treat- owned dogs that received firocoxib . Crossley, Dr Hein Hesse and Dr Arthur 4 ment for 5 days . This certainly poses the These results did not exceed normal refer- Wellington are thanked for their support question as to what is an appropriate ence ranges. and motivation. The following clinics are length of treatment for dogs with osteo- A rise in urea can be related to renal thanked for their support: Kragga Kamma arthritis. The data presented above would dysfunction, a high protein diet or gastro- Veterinary Hospital (Drs T Reed, D indicate that a longer course is better. intestinal bleeding. No increase in Evezard), Blue Cross Veterinary Hospital More research is required to establish the creatinine was observed in the treatment (Dr L De Klerk), Tygerberg Animal Hospi- optimum duration for dosing NSAIDs in group over time and the urine analysis tal (Dr C Levitan), Westville Veterinary dogs with osteoarthritis and the long- remained normal. This makes it unlikely Hospital (Dr R Smith), Olivedale Veteri- 2,3,7,19,23 term effect on cartilage . Does the that a decline in renal function increased nary Clinic (Dr S Arp) and Bedfordview increased production of proteoglycans the urea value. Gastric ulceration or Veterinary Hospital (Drs C Killian, K translate into an improvement in the gastrointestinal disease as a cause for the Schmidt). Idexx Golden Vet is thanked for joints or does the disease process of increase in urea can not be excluded. undertaking the clinical pathology. osteoarthritis continue in spite of this Gastrointestinal adverse events were benefit? seen and no specific tests were conducted REFERENCES Bile acids were significantly raised in to exclude gastrointestinal disease. Starv- 1. Aithal G P,Day C P 2007 Nonsteroidal anti- the treatment group between days 0 and ing was not required for samples taken inflammatory drug-induced hepatotoxic- 90, but the liver enzymes did not change and this may have affected the results. ity. Clinics in Liver Disease 11: 563–575 during this study and correlated with the In 1000 dogs followed for 40 days that 2. Armstrong S, Lees P 1999 Effects of R and S 25 enantiomers and a racemic mixture of study in healthy dogs . Bile acids are received firocoxib the most common carprofen on the production and release of known to rise after food intake. Dogs adverse events associated with with- proteoglycan and E2 from were not controlled with regard to fasting drawal from the study were: vomition equine chondrocytes and cartilage explants.

0038-2809 Jl S.Afr.vet.Ass. (2009) 80(3): 179–184 183 American Journal of Veterinary Research 60: meloxicam therapy in osteoarthritic dogs. American Journal of Veterinary Research 65: 98–104 Proceedings of the 32nd Annual World Small 503–512 3. Blot L, Marcelis A, Devogelaer J-P, Animal Veterinary Congress 2007, Sydney, 19. Pelletier J-P, Lajeunesse D, Jovanovic D V, Manicourt D-H 2000 Effects of diclofenac, 19–23 August 2007: 1–2 Lascau-Coman V, Jolicoeur F-C, Hilal G, and meloxicam on the metabo- 11. John A D, Sieber F E 2004 Age associated Fernandes J C, Martel-Pelletier J 2000 Car- lism of proteoglycans and hyaluronan in issues: geriatrics. Anesthesiology Clinics of profen simultaneously reduces progression osteoarthritic human cartilage. British North America 22: 45–58 of morphological changes in cartilage and Journal of Pharmacology 131: 1413–1421 12. Joubert K E 2007 Pre-anaesthetic screening subchondral bone in experimental dog osteo- 4. Charrette B, Dupuis J, Moreau M, Daminet of geriatric dogs. Journal of the South African arthritis. Journal of Rheumatology 27: 2893–2902 S, Hebert P,Grisneaux E 2003 Assessing the Veterinary Association 78: 31–35 20. Petruzzelli M, VaccaM, Moschetta A, Cinzia efficacy of long-term administration of tolfe- 13. Lees P 2003 Pharmacology of drugs used to Sasso R C, Palasciano G, van Erpecum K J, namic acid in dogs undergoing femoral head treat osteoarthritis in veterinary practice. Portincasa P 2007 Intestinal mucosal dam- and neck excision. Veterinary Comparative Inflammopharmacology 11: 385–399 age caused by non-steroidal anti-inflam- Orthopaedics and Traumatology 16: 232–237 14. Lees P,Landoni M F,Giraudel J, Toutain P L matory drugs: role of bile salts. Clinical 5. EMEA Scientific Discussion Document, 2004 Pharmacodynamics and pharma- Biochemistry 40: 503–510 Merial South Africa, Midrand cokinetics of nonsteroidal anti-inflammatory 21. Polzin D J, Osborne C A, Ross S 2005 6. Doig P A 1999 The long-term tolerance and drugs in species of veterinary interest. Chronic kidney disease. In Ettinger S J, efficacy of meloxicam in the treatment of Journal of Veterinary Pharmacology and Thera- Feldman E C (eds) Textbook of veterinary chronic osteoarthritis in dogs. In Bennett, D peutics 27: 479–490 internal medicine (6th edn). Elsevier (ed.) Recent advances in non-steroidal anti- 15. Lobetti R G, Joubert K E 2000 Effects of Saunders, St Louis, Missouri: 1756–1785 inflammatory therapy in small animals. administration of nonsteroidal anti-inflam- 22. Raekallio M R, Hielm-Björkman A K, Boehringer-Ingelheim, Paris: 61 matory drugs before surgery on renal func- Kejonen J, Salonen H M, Sankari S M 2006 7. Frean S P,Abraham L A, Lees P 1999 In vitro tion in clinically normal dogs. American Evaluation of adverse effects of long-term stimulation of equine cartilage proteogly- Journal of Veterinary Research 61: 1501–1506 orally administered carprofen in dogs. Jour- can synthesis by hyaluronan and carpro- 16. Luna S P L, Basílio A C, Steagall P V M, nal of the American Veterinary Medical Associa- fen. Research in Veterinary Science 67: 183–190 Machado L P,Moutinho F Q, Takahira R K, tion 228: 876–880 8. Hanson P D, Brooks K C, Case J, Conzemius BrandáoCVS2007 Evaluation of adverse 23. Rainsford K D, Skerry T M, Chindemi P, M, Gordon W, Schuessler J, Shelley B, effects of long-term oral administration of Delaney K 1999 Effects of the NSAIDs Sifferman R, Drag M, Alva R, Bell L, carprofen, etodolac, flunixin meglumine, meloxicam and indomethacin on cartilage Romano D, Fleishman C 2006 Efficacy and ketoprofen, and meloxicam in dogs. Ameri- proteoglycan synthesis and joint responses safety of firocoxib in the management of ca- can Journal of Veterinary Research 68: 258–264 to calcium pyrophosphate crystals in dogs. nine osteoarthritis under field conditions. 17. MacPhail C M, Lappin M R, Meyer D J, Veterinary Research Communications 23: 101– Veterinary Therapeutics 7: 127–140 Smith S G, WebsterCRL,Armstrong P J 113 9. HazewinkelHAW,vandenBrom W E, 1998 Hepatocellular toxicosis associated 24. Ryan W G, Moldave K, Carithers D 2006 TheyseLFH,Pollmeier M, Hanson P D with administration of carprofen in 21 Clinical effectiveness and safety of a new 2008 Comparison of the effects of firocoxib, dogs. Journal of the American Veterinary NSAID, firocoxib: a 1000 dog study. Veteri- carprofen and in a sodium Medical Association 212: 1895–1901 nary Therapeutics 7: 119–126 urate crystal induced synovitis model of 18. McCann M E, Andersen D R, Zhang D, 25. SteagallPVM,Mantovani F B, Ferreira T H, arthritis in dogs. Research in Veterinary Brideau C, Black W C, Hanson P D, Hickey Salcedo E S, Moutinho F Q, LunaSPL2007 Science 84: 74–79 G J 2004 In vitro effects and in vivo efficacy of Evaluation of the adverse effects of oral firo- 10. Huneault L, Moreau M, Troncy E 2007 A a novel -2 inhibitor in dogs coxib in healthy dogs. Journal of Veterinary pilot study of long-term, lower dose with experimentally induced synovitis. Pharmacology and Therapeutics 30: 218–223

184 0038-2809 Tydskr.S.Afr.vet.Ver. (2009) 80(3): 179–184