Dose range finding study for the efficacy of meloxicam administered prior to sodium urate-induced synovitis in cats

ObjectiveTo determine the lowest efficacious dose of oral meloxicam for relieving pain in cats with a sodium urate (SU)-induced acute inflammatory synovitis.Study designRandomized, blinded, controlled, and four-way crossover study.AnimalsEight surgically neutered cats (four males, four females) paired according to sex.MethodsEach pair of cats was treated with 0 (placebo), 0.025, 0.05, or 0.075 mg kg^?1 oral meloxicam once daily for 4 days prior to injection, into alternating stifles, of 1 mL of 20 mg mL^?1 SU crystals, beginning with the right stifle. Each cat received each of the four treatments, separated by at least 21 days. Analgesic efficacy was evaluated based on objective (e.g., pressure mat data total force, contact pressure, and contact area) and subjective (e.g., scores for Analgesia Scale [AS], Lameness Scale [LS], and Visual Analog Scale [VAS]) outcome measures for pain assessment. All outcome measures were recorded before and during 30 hours after SU injection. The pre-defined primary outcome measure was the area under the response–time curve (AUC_0–30 hours) of the total force of the injected limb. Data were analyzed by analysis of variance. A sequential test procedure was applied and the test sequence stopped in case of a nonsignificant result.ResultsMeloxicam at doses of 0.05 and 0.075 mg kg^?1 day^?1 PO was significantly different from placebo for the pre-defined primary outcome measure (i.e., AUC_0–30 hours of total force). All tested meloxicam doses were lower than placebo for the subjective outcome measures (i.e., AUC_0–30 hours of AS, LS, and VAS).Conclusions and clinical relevanceThe lowest efficacious dose of meloxicam for relieving pain in cats with an SU-induced synovitis was 0.05 mg kg^?1 day^?1 PO according to the pre-defined primary outcome measure. However, lower doses may also be effective as seen in the subjective outcome measures.     

Efficacy of tolfenamic acid and meloxicam in the control of postoperative pain following ovariohysterectomy in the cat

Objective The hypothesis was that Visual Analog Scale (VAS) scores would be lower, and mechanical wound thresholds (MWT) higher, in cats receiving tolfenamic acid compared to those receiving placebo in the postoperative period following elective ovariohysterectomy. Animals Sixty‐nine client‐owned cats. Methods A prospective, randomized, blinded and placebo‐controlled study was performed in cats which underwent ovariohysterectomy following preoperative tolfenamic acid, meloxicam, or placebo. A second dose of the same analgesic was administered 24 hours postoperatively. Assessments were made 1‐hour before induction and 1, 2, 4, 6, 22, and 25 hours postoperatively. Pain was assessed by a blinded observer using Numerical Rating (NRS) and VAS scales. The MWT were measured using a force‐measuring device. Group comparison was performed by using one‐way anova and chi‐squared test for qualitative and quantitative data, respectively, and a mixed model for repeated measurements (p < 0.05). Results Sixty‐five cats were included in the study. There were no differences between groups at baseline. There was a treatment effect on the NRS scores at 6, 22 and 25 hours. The meloxicam group was less painful than controls at 6 and 22 hours; both treatment groups were less painful than controls at 25 hours. There were no differences between groups in VAS for pain or sedation. The number of animals receiving rescue analgesia did not differ between groups. There was a treatment effect on MWT; thresholds in both treatment groups were significantly higher than that observed in controls at all time points. Conclusions Preoperative tolfenamic acid or meloxicam reduced wound sensitivity following ovariohysterectomy in the cat. Clinical relevance Tolfenamic acid and meloxicam administered preoperatively provided a similar analgesic effect in the postoperative period lasting 24 hours. Mechanical thresholds may be a better way of evaluating postoperative analgesia provided by nonsteroidal anti‐inflammatory drugs in cats.     

Measurement of platelet aggregation in ovine blood using a new impedance aggregometer

Background: Whole blood platelet aggregometry (impedance) is an important method to investigate platelet function disorders. Examination of hemostatic function in sheep is important with respect to their role as an animal model of human disease. Objective: The aim of this study was to evaluate and optimize selected methodological aspects (anticoagulant, agonist concentration) of impedance aggregometry in ovine blood using the new Multiplate 5.0 analyzer. Methods: Blood samples were collected in hirudin anticoagulant from 40 clinically healthy sheep. Samples from selected sheep were collected in citrate, with or without the addition of calcium chloride. The agonists adenosine diphosphate (ADP), collagen, ristocetin, arachidonic acid, and thrombin receptor‐activating peptide (TRAP) were added in several concentrations to induce aggregation. Results: Based on maximum aggregation values and internal precision, no significant difference was found between ADP concentrations of 3–10 μmol/L and collagen concentrations of 3–5 μg/mL (P>.05). The lowest interindividual variation of approximately 3–4‐fold was seen with 4 and 5 μmol/L ADP and 4 and 5 μg/mL collagen. Ristocetin, arachidonic acid, and TRAP did not induce significant aggregation at any concentration. Aggregation results were significantly lower when measured in citrate‐ vs hirudin‐anticoagulated blood, regardless of the presence of calcium chloride. Conclusions: Our results indicate that the multiplate impedance aggregometer is suitable for the measurement of platelet aggregation in sheep using optimal agonist concentrations of 4–5 μmol/L ADP and 4–5 μg/mL collagen. Hirudin‐anticoagulated blood is the preferred sample material.     

Effects of tramadol alone,in combination with meloxicam or dipyrone,on postoperative pain and the analgesic requirement in dogs undergoing unilateral mastectomy with or without ovariohysterectomy

ObjectiveTo compare the effects of tramadol alone, or in combination with dipyrone or meloxicam, on postoperative pain and analgesia requirement after unilateral mastectomy with or without ovariohysterectomy in dogs.Study designProspective, randomized, clinical study.AnimalsTwenty seven bitches undergoing unilateral mastectomy with or without ovariohysterectomy.MethodsAnesthesia was induced with propofol and maintained with isoflurane and a constant rate infusion of morphine. Before the end of surgery, dogs were randomly assigned to receive intravenous tramadol alone (3 mg kg^?1, group T), combined with dipyrone (30 mg kg^?1, group TD) or meloxicam (0.2 mg kg^?1, group TM). Dogs received additional doses of tramadol (groups T and TM) or tramadol with dipyrone (group TD) at 8 and 16 hours after extubation. Postoperative pain was assessed by a blinded observer before anesthesia (baseline) and at 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours after extubation using a visual analog scale (VAS) and a modified Glasgow scale. Rescue analgesia (morphine, 0.5 mg kg^?1) was administered if the Glasgow pain score was >3.5.ResultsThere were no significant differences among groups in pain scores evaluated by the VAS or the Glasgow scale. In groups T, TD and TM, pain scores were significantly higher than at baseline for 6, 8 and 2 hours, respectively. Rescue analgesia was administered to 3/9, 2/9 and 1/9 dogs in groups T, TD and TM, respectively (p > 0.05) [Correction added on 15 August 2013, after first online publication: ‘T, TM and TD’ was changed to ‘T, TD and TM’.].Conclusions and clinical relevanceUnder the conditions of this study, tramadol alone or in combination with dypyrone or meloxicam provided effective analgesia for 24 hours in most dogs after unilateral mastectomy with or without ovariohysterectomy. Further evaluation of combination therapies is needed in larger groups of dogs.     

Evaluation of cardiovascular effects of intravenous robenacoxib in dogs

The objective of the study was to assess the cardiovascular effects of intravenous (IV) dosing with robenacoxib (Onsior^®) in conscious adult healthy beagle dogs. The study employed a randomized, open, placebo‐controlled, four‐phase Latin square design. A total of eight dogs received a single dose of 2 mg/kg and 4 mg/kg IV robenacoxib (test groups), 2 mg/kg subcutaneous (SC) robenacoxib (reference dose and route), and IV isotonic saline (control). There were no significant differences between groups for clinical observations, buccal mucosal bleeding time or blood hematology, coagulation, and clinical chemistry variables in all eight dogs. In a subset of four dogs, no significant differences between groups were detected using telemetric assessment for arterial blood pressure, heart rate, electrocardiogram, or body temperature over 8 hr postdose. In conclusion, no significant cardiovascular effects were detected after a single IV dose of 2 or 4 mg/kg robenacoxib in conscious healthy dogs.     

Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in meat goats

The aim of this study was to determine the pharmacokinetics and prostaglandin E₂ (PGE₂) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight adult female Boer goats. A dose of 2.2 mg/kg was administered intravenously (IV) and 3.3 mg/kg administered TD using a cross‐over design. Plasma flunixin concentrations were measured by LC‐MS/MS. Prostaglandin E₂ concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE₂ concentrations decreased after flunixin meglumine for both routes of administration. Mean λ_z‐HL after IV administration was 6.032 hr (range 4.735–9.244 hr) resulting from a mean V_z of 584.1 ml/kg (range, 357.1–1,092 ml/kg) and plasma clearance of 67.11 ml kg^?1 hr^?1 (range, 45.57–82.35 ml kg^?1 hr^?1). The mean C_max, T_max, and λ_z‐HL for flunixin following TD administration was 0.134 μg/ml (range, 0.050–0.188 μg/ml), 11.41 hr (range, 6.00–36.00 hr), and 43.12 hr (15.98–62.49 hr), respectively. The mean bioavailability for TD flunixin was calculated as 24.76%. The mean 80% inhibitory concentration (IC₈₀) of PGE₂ by flunixin meglumine was 0.28 μg/ml (range, 0.08–0.69 μg/ml) and was only achieved with IV formulation of flunixin in this study. The PK results support clinical studies to examine the efficacy of TD flunixin in goats. Determining the systemic effects of flunixin‐mediated PGE₂ suppression in goats is also warranted.     

Pharmacokinetics of multiple doses of transdermal flunixin meglumine in adult Holstein dairy cows

A transdermal formulation of the nonsteroidal anti‐inflammatory drug, flunixin meglumine, has been approved in the United States and Canada for single‐dose administration. Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33 mg/kg every 24 hr for three total treatments. Plasma flunixin concentrations were determined using high‐pressure liquid chromatography with mass spectroscopy (HPLC ‐MS ). Pharmacokinetic analysis was completed on each individual animal with noncompartmental methods using computer software. The time to maximum drug concentration (T max) was 2.81 hr, and the maximum drug concentration was 1.08 μg/ml. The mean terminal half‐life (T½) was determined to be 5.20 hr. Clearance per fraction absorbed (Cl/F) was calculated to be 0.294 L/hr kg^?1, and volume of distribution of fraction (V z/F ) absorbed was 2.20 L/kg. The mean accumulation factor was 1.10 after three doses. This indicates changes in dosing may not be required when giving multiple doses of flunixin transdermal. Further work is required to investigate the clinical efficacy of transdermal flunixin after multiple daily doses.     

Platelet function in dogs: breed differences and effect of acetylsalicylic acid administration

BACKGROUND: Clinical studies investigating platelet function in dogs have had conflicting results that may be caused by normal physiologic variation in platelet response to agonists. OBJECTIVES: The objective of this study was to investigate platelet function in clinically healthy dogs of 4 different breeds by whole-blood aggregometry and with a point-of-care platelet function analyzer (PFA-100), and to evaluate the effect of acetylsalicylic acid (ASA) administration on the results from both methods. METHODS: Forty-five clinically healthy dogs (12 Cavalier King Charles Spaniels [CKCS], 12 Cairn Terriers, 10 Boxers, and 11 Labrador Retrievers) were included in the study. Platelet function was assessed by whole-blood aggregation with ADP (1, 5, 10, and 20 microM) as agonist and by PFA-100 using collagen and epinephrine (Col + Epi) and Col + ADP as agonists. Plasma thromboxane B(2) concentration was determined by an enzyme immunoassay. To investigate the effect of ASA, 10 dogs were dosed daily (75 or 250 mg ASA orally) for 4 consecutive days. RESULTS: A higher platelet aggregation response was found in CKCS compared to the other breeds. Longer PFA-100 closure time (Col + Epi) was found in Cairn Terriers compared to Boxers. Plasma thromboxane B(2) concentration was not statistically different between groups. Administration of ASA prolonged the PFA-100 closure times, using Col + Epi (but not Col + ADP) as agonists. Furthermore, ASA resulted in a decrease in whole-blood platelet aggregation. CONCLUSIONS: Platelet function is influenced by breed, depending upon the methodology applied. However, the importance of these breed differences remains to be investigated. The PFA-100 method with Col + Epi as agonists, and ADP-induced platelet aggregation appear to be sensitive to ASA in dogs.     

The effect of oral phenylbutazone on whole blood platelet aggregation in the dog.

Platelet aggregation to collagen, arachidonic acid and adenosine diphosphate was evaluated in six dogs using a whole blood electronic aggregometer. The six dogs were then given phenylbutazone orally according to four different dosage levels and durations of treatment. Aggregation responses were measured at established intervals of time following phenylbutazone administration. Data on untreated dogs indicated that arachidonic acid, at a final concentration of 50 micrograms/mL and collagen, at a final concentration of 5 micrograms/mL, were useful agents for studying whole blood platelet aggregation in the dog, but adenosine diphosphate, at a final concentration of 30 microM was not. The high single dose (900 mg) of phenylbutazone significantly inhibited platelet aggregation to arachidonic acid at 1.5,4,7 and 12 hours following administration. The results indicated that the whole blood electronic aggregometer was of limited value in detecting subtle changes in platelet aggregation. It was concluded, however, that the instrument is potentially useful as a rapid screening aid for detecting canine patients at high risk of platelet-related bleeding problems.     

Effect of tepoxalin on renal function and hepatic enzymes in dogs exposed to hypotension with isoflurane

ObjectiveTo evaluate the possible renal and hepatic toxicity of tepoxalin in dogs exposed to hypotension during isoflurane anesthesia.Study designProspective, randomized experimental study.AnimalsTwenty adult mixed-breed dogs, weighing 18.8 ± 2.8 kg.MethodsThe animals received 10 mg kg^?1 tepoxalin orally 2 hours before the anesthetic procedure (PRE; n = 6), or 30 minutes after anesthesia (POST; n = 6), along with a control group (CON; n = 8), which were only anesthetized. The PRE and POST groups also received the same dose of tepoxalin for 5 days post-procedure. All dogs were anesthetized with propofol and maintained with isoflurane and the end-tidal isoflurane (Fe’Iso) was increased until mean arterial pressure decreased to 50–60 mmHg. These pressures were maintained for 60 minutes. Heart rate, arterial pressures and Fe’Iso were recorded at 0, 10 and every 10 minutes up to 60 minutes of hypotension. Blood gases, pH, electrolytes and bleeding time were analyzed before and at 30 and 60 minutes of hypotension. Renal and hepatic changes were quantified by serum and urinary biochemistry and creatinine clearance.ResultsSerum concentrations of alanine amino transferase (ALT), alkaline phosphatase (ALP) and σ-glutamyl transferase (GGT), blood urea nitrogen (BUN) and creatinine (Cr), and urinary output, urinary Cr, Cr clearance, and GGT:Cr ratio remained stable throughout the evaluations. During the anesthetic procedure there were no important variations in the physiological parameters. No side effects were observed in any of the groups.Conclusions and clinical relevanceTepoxalin did not cause significant effects on renal function or cause hepatic injury in healthy dogs exposed to hypotension with isoflurane, when administered pre- or postanesthetic and continued for five consecutive days.     

Effects of dietary flaxseed oil supplementation on equine plasma fatty acid concentrations and whole blood platelet aggregation

An 18-week feeding trial was performed to investigate the effects of an omega-3 (n-3) fatty acid-enriched ration on plasma fatty acid concentrations and platelet aggregation in healthy horses. Flaxseed oil served as the source of the n-3 fatty acid alpha-linolenic acid (ALA). Twelve horses were fed dietary maintenance requirements using a complete pelleted ration (80%) and timothy grass hay (20%) for a 2-week acclimation period before being randomly assigned either to a treatment (group 1) or control (group 2) group. Group 2 horses (n = 6) were fed the diet described in the acclimation period, whereas group I horses (n = 6) were fed a 10% flaxseed oil-enriched complete pellet (80%) and grass hay (20%). Biological samples and physical measurements were collected at one point during the acclimation period (week 0) and every 4 weeks thereafter (weeks 4, 8, 12, and 16). Body weight, CBC (including platelet count), plasma fibrinogen. electrolyte (Na, K, and Cl) concentrations, and biochemical profile enzyme activities (aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, and creatine kinase) did not change markedly with diet. Platelet aggregation was not altered by the supplementation of flaxseed oil in these healthy horses, although increases in plasma cis-polyunsaturated 18-carbon fatty acids C18:3; n-3 (ALA) and C18:2; n-6 (linoleic acid), biologically active C20:5; n-3 (eicosapentaenoic acid [EPA]), and malondialdehyde (MDA) were evident. There were no marked decreases in C20:4; n-6 (arachidonic acid [AA]) or increases in C22:6; n-3 (docosahexaenoic acid [DHA]), signifying that flaxseed oil may have had a high percentage of omega-6 (n-6) fatty acids as well as n-3 fatty acids, and this relatively high n-6: n-3 fatty acid ratio may have affected the biochemical effect of n-3 fatty acids. In healthy horses supplemented with flaxseed oil, platelet aggregation was not altered, which may have been due to the limited biologic effect in healthy subjects or the inability of flaxseed oil to induce the necessary biochemical effect of replacing n-6 fatty acids with n-3 types.     

Automated analysis of feline platelets in whole blood,including platelet count,mean platelet volume,and activation state

A new whole-blood flow cytometric method has been developed for counting and sizing platelets in samples from cats, a species in which platelet and red blood cell sizes overlap significantly. The method is a modified version of the two-angle laser light scattering technology used by Bayer H*System hematology analyzers. The new method provided accurate platelet counts and mean platelet volumes (MPV, fl) for cats. The method also measured mean platelet component concentration (MPC, g/dl), a parameter which was shown to be sensitive to platelet activation state, and which decreased in value as activation progressed.     

Effects of preoperative administration of meloxicam on whole blood platelet aggregation, buccal mucosal bleeding time, and haematological indices in dogs undergoing elective ovariohysterectomy

The purpose of the study was to evaluate the effect of preoperative administration of meloxicam, a non-steroidal anti-inflammatory drug used for pain control, on primary haemostasis in dogs. Twenty healthy female dogs undergoing elective ovariohysterectomy were enrolled in the study. Sixty minutes before pre-anaesthesia, a single dose of meloxicam (0.2 mg/kg) was randomly administered intravenously (IV) to 10 dogs (treatment group) while control dogs received an equivalent volume of saline solution IV. Platelet aggregation, buccal mucosa bleeding time, platelet count and haematological indices were measured at 0, 1, 6 and 24 h after administration of meloxicam. Since significant differences between groups were not observed for any of the measured parameters, preoperative administration of meloxicam may be used for pain control before elective ovariohysterectomy in healthy dogs, without compromising primary haemostasis.