Objective—To determine pharmacodynamic and pharmacokinetic properties of clopidogrel and the metabolite SR 26334 in dogs.
Animals—9 mixed-breed dogs.
Procedures—8 dogs received clopidogrel (mean ± SD 1.13 ± 0.17 mg/kg, PO, q 24 h) for 3 days; 5 of these dogs subsequently received a lower dose of clopidogrel (0.5 ± 0.18 mg/kg, PO, q 24 h) for 3 days. Later, 5 dogs received clopidogrel (1.09 ± 0.12 mg/kg, PO, q 24 h) for 5 days. Blood samples were collected for optical platelet aggregometry, citrated native and platelet mapping thrombelastography (TEG), and measurement of plasma drug concentrations. Impedance aggregometry was performed on samples from 3 dogs in each 3-day treatment group.
Results—ADP-induced platelet aggregation decreased (mean ± SD 93 ± 6% and 80 ± 22% of baseline values, respectively) after 72 hours in dogs in both 3-day treatment groups; duration of effect ranged from > 3 to > 7 days. Platelet mapping TEG and impedance aggregometry yielded similar results. Citrated native TEG was not different among groups. Clopidogrel was not detected in any samples; in dogs given 1.13 ± 0.17 mg/kg, maximum concentration of SR 26334 (mean ± SD, 0.206 ± 0.2 μg/mL) was detected 1 hour after administration.
Conclusions and Clinical Relevance—Clopidogrel inhibited ADP-induced platelet aggregation in healthy dogs and may be a viable antiplatelet agent for use in dogs.
Impact for Human Medicine—Pharmacodynamic effects of clopidogrel in dogs were similar to effects reported in humans; clopidogrel may be useful in studies involving dogs used to investigate human disease.
To investigate the ability of a proprietary antagonist of E-type prostanoid receptor (EP) 4, grapiprant, and carprofen to attenuate lameness attributable to urate-induced synovitis in dogs.
5 purpose-bred hound-cross dogs.
A blinded, 3-way crossover study was performed. Dogs received each of 3 treatments (L-766, a proprietary antagonist of EP4; 4.0 mg/kg), grapiprant (an antagonist of EP4; 2.0 mg/kg), and carprofen (4.4 mg/kg); dogs received 4 doses of each treatment (14 and 2 hours before and 22 and 46 hours after urate injection). Synovitis was induced by intra-articular injection of sodium urate. Measurements (vertical ground reaction forces and clinical lameness scores) were obtained immediately before (0 hours; baseline) and 6, 12, 24, 36, and 48 hours after sodium urate injection. All data were analyzed with repeated-measures ANOVA.
Lameness scores at 6 hours were significantly higher than baseline lameness scores for all treatments. Lameness scores for the grapiprant treatment remained significantly higher at 12 and 24 hours, compared with baseline lameness scores. Lameness scores for the carprofen treatment were significantly lower than lameness scores for the grapiprant treatment at 6, 12, and 24 hours. Analysis of peak vertical force and vertical impulse data revealed a pattern similar to that for lameness scores. Treatment with L-766 resulted in a significantly higher vertical impulse at 48 hours than did treatment with carprofen or grapiprant.
CONCLUSIONS AND CLINICAL RELEVANCE
In these dogs, carprofen was the most effective treatment for attenuating lameness induced by injection of sodium urate, and grapiprant was the least effective treatment.
To compare the ability of acetaminophen-codeine (AC; 15.5 to 18.5 mg/kg and 1.6 to 2.0 mg/kg, respectively) or carprofen (4.2 to 4.5 mg/kg) administered PO to attenuate experimentally induced lameness in dogs.
7 purpose-bred dogs.
A blinded crossover study was performed. Dogs were randomly assigned to receive AC or carprofen treatment first and then the alternate treatment a minimum of 21 days later. Synovitis was induced in 1 stifle joint during each treatment by intra-articular injection of sodium urate (SU). Ground reaction forces were assessed, and clinical lameness was scored at baseline (before lameness induction) and 3, 6, 9, 12, 24, 36, and 48 hours after SU injection. Plasma concentrations of acetaminophen, carprofen, codeine, and morphine were measured at various points. Data were compared between and within treatments by repeated-measures ANOVA.
During AC treatment, dogs had significantly higher lameness scores than during carprofen treatment at 3, 6, and 9 hours after SU injection. Peak vertical force and vertical impulse during AC treatment were significantly lower than values during carprofen treatment at 3, 6, and 9 hours. Plasma concentrations of carprofen (R)- and (S)-enantiomers ranged from 2.5 to 19.2 μg/mL and 4.6 to 25.0 μg/mL, respectively, over a 24-hour period. Plasma acetaminophen concentrations ranged from 0.14 to 4.6 μg/mL and codeine concentrations from 7.0 to 26.8 ng/mL, whereas plasma morphine concentrations ranged from 4.0 to 58.6 ng/mL.
CONCLUSIONS AND CLINICAL RELEVANCE
Carprofen as administered was more effective than AC at attenuating SU-induced lameness in dogs.
ANIMALS 40 dogs with clinical osteoarthritis of the elbow or stifle joint.
PROCEDURES Dogs orally received 3 times/d (morning, midday, and night) for a 10-day period each of 3 identically appearing treatments (placebo; carprofen at 2.2 mg/kg [1 mg/lb], q 12 h [morning and night], with placebo at midday; or tramadol hydrochloride at 5 mg/kg [2.3 mg/lb], q 8 h) in random order, with treatment sessions separated by a minimum 7-day washout period. Vertical ground reaction forces (vertical impulse [VI] and peak vertical force [PVF]) were measured and Canine Brief Pain Inventory (CBPI) scores assigned prior to (baseline) and at the end of each treatment period. Repeated-measures ANOVA was performed to compare VI and PVF data among and within treatments, and the χ2 test was used to compare proportions of dogs with a CBPI-defined positive response to treatment.
RESULTS 35 dogs completed the study. No significant changes from baseline in VI and PVF were identified for placebo and tramadol treatments; however, these values increased significantly with carprofen treatment. Changes from baseline in VI and PVF values were significantly greater with carprofen versus placebo or tramadol treatment. A significant improvement from baseline in CBPI scores was identified with carprofen treatment but not placebo or tramadol treatment.
CONCLUSIONS AND CLINICAL RELEVANCE 10 days of treatment with tramadol as administered (5 mg/kg, PO, q 8 h) provided no clinical benefit for dogs with osteoarthritis of the elbow or stifle joint.
To evaluate and compare postoperative analgesic effects of grapiprant and carprofen in dogs undergoing ovariohysterectomy.
42 sexually intact female healthy dogs (< 35 kg and 0.5 to 7 years old) were enrolled.
In a masked, randomized, noninferiority clinical trial, dogs received either 2 mg/kg of grapiprant or 4.4 mg/kg of carprofen orally 2 hours prior to ovariohysterectomy. Postoperative pain was assessed using the Glasgow Composite Pain Scale–Short Form (GCPS-SF) at extubation and 2, 4, 6, 8, 18, and 24 hours postextubation and compared to baseline. After each pain scoring, mechanical nociceptive testing with von Frey monofilaments (vF) was performed to assess hyperalgesia. Hydromorphone (0.05 mg/kg, IM) was administered to any dog with a GCPS-SF of ≥ 5/24. The noninferiority limit (NI) for the GCPS-SF was Δ = 3. The NI for vF was Δ = –0.2. Following noninferiority, a mixed-effect ANOVA and post hoc comparisons were made with the Tukey correction method (P < .05).
3 dogs required rescue analgesia and were excluded from statistical analysis. Of the remaining 39 dogs, the upper CI for GCPS-SF was below the NI of 3 and the lower CI for vF was greater than the NI of –0.2, indicating noninferiority of grapiprant as compared to carprofen. There was no difference between treatment (P = .89) nor treatment by time (P = .62) for GCPS-SF. There was no difference between groups at any time point or over time when vF were used.
Our study results support the use of grapiprant as an analgesic alternative to carprofen in dogs undergoing ovariohysterectomy.
OBJECTIVE To determine the minimum alveolar concentration that blunts adrenergic responses (MACBAR) for isoflurane and evaluate effects of fentanyl on isoflurane MACBAR in sheep.
ANIMALS 13 healthy adult Dorset-cross adult ewes.
PROCEDURES In a crossover design, each ewe was anesthetized 2 times for determination of isoflurane MACBAR. Anesthesia was induced with propofol administered IV. Sheep initially received fentanyl (5 μg/kg, IV, followed by a constant rate infusion of 5 μg/kg/h) or an equivalent volume of saline (0.9% NaCl) solution (control treatment). After a washout period of at least 8 days, the other treatment was administered. For MACBAR determination, a mechanical nociceptive stimulus (ie, sponge forceps) was applied at the coronary band for 1 minute. The MACBAR values of the 2 treatments were compared by means of a paired t test. During MACBAR determination, blood samples were collected for measurement of plasma fentanyl concentration.
RESULTS Mean ± SD isoflurane MACBAR of the fentanyl and control treatments was 1.70 ± 0.28% and 1.79 ± 0.35%, respectively; no significant difference was found between the 2 treatments. Plasma concentration of fentanyl reached a median steady-state concentration of 1.69 ng/mL (interquartile range [25th to 75th percentile], 1.47 to 1.79 ng/mL), which was maintained throughout the study.
CONCLUSIONS AND CLINICAL RELEVANCE Administration of fentanyl at 5 μg/kg, IV, followed by a constant rate infusion of the drug at 5 μg/kg/h did not decrease isoflurane MACBAR. Further studies to determine the effect of higher doses of fentanyl on inhalation anesthetic agents and their potential adverse effects are warranted. (Am J Vet Res 2016;77:119–126)