Effects of Prolonged Intravenous of Flunixin Meglumine in Healthy Dogs

Erdogan H. M., V. Gunes, H. I . Gokce, M. Uzun, M. Cit i l , N. Yuksek: Effects of Prolonged Intravenous of Flunixin Meglumine in Healthy Dogs. Acta Vet. Brno 2003, 72: 71-78. This study was designed to evaluate possible side effects on liver and kidney functions and haematological indices, associated with long-term intravenous (IV) administration of flunixin meglumine in healthy dogs. For this purpose, 12 dogs were divided into 2 equal groups. Group I was intravenously given flunixin meglumine at the dose of 1.1 mg/kg/day for 5 days and group II received 2.2 mg/kg/day IV for 5 days. Blood samples were withdrawn before treatment (day 0), 2 h post injection on each day of treatment and one day after the last injection for biochemical (glucose, sodium-Na, potassium-K, chloride-Cl, creatinine, urea, alkaline phosphatase-AP, alanine amino transferase-ALT and total protein) and haematological (bleeding time, coagulation time, red blood cell, white blood cell, platelet count, differential leukocyte count, haematocrit and haemoglobin) analyses. Faecal and urine samples were collected on the same days as blood samples for the presence of any abnormalities. The results revealed a significant increase in bleeding (P < 0.001) and coagulation time (P < 0.001) and a decrease in platelet count (P < 0.001) in both groups. There was also a significant increase in the concentration of Na and Cl in group I and an elevation in AP (P < 0.001), ALT (P < 0.001) and glucose (P < 0.001) in group II. Blood in urine and faeces was also evident in both groups. The results may suggest that the dose of 1.1 mg/kg IV for 5 d does not cause any significant side effects provided that no bleeding disorder exists, and the dose of 2.2 mg/kg IV for 5 d should not exceed 3 d as liver enzymes began to increase significantly afterwards. Flunixin meglumine, liver, kidney, haematology, dog Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in veterinary and human medicine in the management of pain and inflammation associated with infectious or non-infectious conditions (McKellar et al. 1991a; Lees et al. 1991; Watson et al. 1996; Lees et al. 2000). Their therapeutic and side effects are due to the inhibition of cyclooxygenase enzyme (COX), resulting in the blockade of eicosanoids synthesis involved in central pyresis, pain perception, tissue inflammation and pre-aggregation (Lees et al. 1991; McKellar et al. 1991a; Lees et al. 2000). Although NSAIDs have beneficial effects as antipyretic, analgesic, antiinflammatory, antiendotoxaemic, antithrombic, anticancer and chondroprotective agents (Lees et al. 2000), their effect is offset by undesirable side effects on various organs especially the gastrointestinal tract (Rubin 1986; Dow et al. 1990; McKellar e t al. 1991a). Flunixin, an aminonicotinic acid derivative of carboxylic acid group of NSAIDs, reversibly inhibits COX and is thus a potent inhibitor of synthesis of prostaglandins and thromboxanes. It possesses, like other NSAIDs, similar beneficial and side effects (Rubin 1986; Dow et al. 1990; McKellar et al. 1991a; Lees et al. 1991; Lees et al. 2000). Flunixin has been found to reduce haemodynamic changes effectively in endotoxemic dogs (Stegelmeier et al. 1988; Bot toms et al. 1983) and to increase survival of dogs with ACTA VET. BRNO 2003, 72: 71–78 Address for correspondence: Dr. Hidayet Metin Erdogan Kafkas Universitesi, Veteriner Fakultesi, Ic Hastaliklari Bolumu 36300 Kars, Turkey Tel.: +90 474 242 68 00 Fax: +90 474 242 68 53 e-mail: [email protected] http://www.vfu.cz/acta-vet/actavet.htm septic peritonitis (Hardie et al. 1985a). It has also been used as an analgesic (Reid and Nolan 1991) and in the symptomatic and supportive treatment of musculoskeletal disorder and osteoarthritis (McKellar et al. 1991a; Jones and Budsberg 2000). Flunixin has been reported to induce gastrointestinal ulcerations and nephrotoxicity (Stegelmeier et al. 1988; Dow et al. 1990; McKellar et al. 1991a; Elwood et al. 1992; McNeil 1992; Vonderhaar and Sal isbury 1993). It is likely that the duration of exposure to the drug to induce a toxic effect is as important as the dose administered. Therefore, the recommended dose rate is 1.0 or 1.1 mg/kg body weight (bw) for 3 d followed by a four-day rest period (McKellar et al. 1989; McKellar et al. 1991a). However, severe conditions may require higher dosages and longer duration of treatment. This necessitates satisfactory knowledge on possible side effects associated with long-term administration of flunixin. Studies to date have mainly focused on pharmacokinetics and pharmacodynamics of flunixin meglumine (Hardie et al. 1985b; McKellar et al. 1989; McKellar et al. 1991b; Brideau et al. 2001). The toxic effect of the drug in dogs has been dealt with in a limited number of studies (Dow et al. 1990; Stegelmeier et al. 1988) and they usually come out of either clinical case reports (Elwood et al. 1992; McNeil l 1992; Vonderhaar and Sal isbury 1993) or studies in which endotoxemic dogs were used (Bottoms et al. 1983; Stegelmeier et al. 1988). This study was therefore designed to determine the side effects, especially on liver and kidney functions and haematological parameters, associated with long term intravenous injection of two different dosages of flunixin meglumine, 1.1 mg/kg and 2.2 mg/kg bw, IV, for 5 d, in healthy dogs. Materials and Methods The study involved 12 healthy dogs of different breed, age, sex, and body weight (between 10 and 30 kg). Prior to the experiment, all dogs were subjected to thorough clinical and laboratory examinations, dewormed and then observed for up to 2 weeks for any clinical signs. The dogs were housed in individual cages, and water and food were provided ad libitum both during the observational and the experimental period. Experimental design Animals were divided into 2 equal groups. In group I (n = 6), animals were intravenously (IV) given flunixin meglumine (Finadyne®, Sanofi-DIF, Turkey) at the dose of 1.1 mg/kg/day, for 5 d, and group II (n = 6) received 2.2 mg/kg/day IV, for 5 d. Blood samples were withdrawn from the left lateral saphenous vein into the plain and EDTA-treated test tubes on each day 2 h post injection and one day after the last injection for haematological and biochemical analyses. Faecal and urine samples were also collected on the same days as blood samples. Faecal samples were collected from the rectum. Urine samples were taken using a sterile bladder catheter. Blood, urine and faecal samples were also collected before the administration of flunixin meglumine (day 0) to serve as control or baseline values. Cl inical examinat ions All animals were clinically examined for any disorder on each day of the experiment. Daily rectal temperature (T), respiratory rate (RR) and heart rate (HR, beats/min) were measured. Biochemical analyses Blood samples collected for biochemical analyses were centrifuged at 3000 g for 5 minutes, and serum was separated and stored at -20 0C until analyses. Biochemical analyses included the measurement of glucose, sodium (Na), potassium (K), chloride (Cl), creatinine, urea, alkaline phosphatase (AP), alanine amino transferase (ALT) and total protein. Analyses of glucose, total protein, urea, ALP and ALT were carried out on Boehringer PHOTOMETER 5010 autoanalyser (Mannheim, Germany), using commercial kits (Diasis Diagnostic Systems, Istanbul, Turkey). Na, K, Cl and creatinine measurements were determined by Moduler-900 (Roche Diagnostics, Mannheim, Germany) using commercial kits (Roche Diagnostics, Mannheim, Germany) Haematological analyses Haematological analyses were performed immediately after blood sampling. Two mililitre of EDTA-treated blood was used for determination of total Red Blood Cell (RBC), White Blood Cell (WBC), Differential leukocyte, Platelet count, Haematocrit (Ht) and Haemoglobin (Hb). RBC, WBC and thrombocytes were counted by 72