In vivo effects of nonsteroidal anti-inflammatory drugs on cyclooxygenase activity in dogs.

MONTOYA, L.; ABA, M. A.; CAVILLA, V.; BIANCHI, C.; HALLÚ, R.; SORACI, A. L.

JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS

Blackwell Publishing Ltd.

Lugar: Oxford, UK; Año: 2006 vol. 29 p. 89 - 108

0140-7783

INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAID) are well known to induce bleeding and gastric mucosal damage related with the inhibition of the enzyme cyclooxygenase (COX) which is the established mechanism of action for these drugs [1]. Two isoforms of COX, the key enzyme in prostaglandins (PGE2) and thromboxane (TXB2) biosynthesis, known as COX-1 and COX-2 have been identified [1,4]. The objective of this study was to determine in an in vivo assay the differential suppressive activity on COX-1 of NSAID, meloxicam (MLX) and ketoprofen (KTF), testing the PGE2 and TXB2 concentrations in gastric mucosa and whole blood from dogs. MATERIALS AND METHODS The protocol was approved by the Institutional Animal Care and Use Committee (CICUAL) School of Veterinary, UBA. Eleven cross-breed dogs, aged 2–6 years and weighing between 17 and 24 kg, were used in this study. The dogs were found to be healthy by physical examination, complete blood count and serum biochemistry. They were randomly assigned to three experimental groups and treated orally with gelatin capsules (control group n = 3), 1 mg kg)1 of racemic KTF (Ketofen tablets, Merial; n = 4) and 0.1 mg kg)1 MLX (Metacam suspension, Boehringer Ingelheim). All the treatments were made once daily for 40 days. Gastric mucosal biopsies obtained by endoscopy examination and venous blood analyses, were performed 2 days prior to treatment, and were repeated after 7, 15, and 39 days of treatment. The tissue and whole blood samples were conditioned and extracted by conventional techniques [2, 3]. PGE2 and TXB2 content were determined by a competitive enzyme immunoassay kit PGE2 and TXB2 (Cayman) and the results were used to describe the% activity of COX- 1 [3].The One-way ANOVA followed by Tukey post hoc test were used to determine effects of treatment at each time period and effects within a treatment group at different time periods. For all statistical tests, P £ 0.05 was considered significant. RESULTS In control samples, TXB2 and PGE2 maintained constant values, indicating that COX-1 activity was present and measurable. The synthesis of TXB2 was significantly reduced at 7, 15 and 39 days of KTF treatment compared with the control group. No differences were found between the MLX and the control group. The synthesis of PGE2 was significantly reduced at 7, 15 and 39 days of KTF treatment and the MLX only produced a significantly inhibition of prostaglandin production at 7 days compared with the control group. The COX-1 inhibition was significantly higher with KTF than MLX at 7 and 39 days. No differences were found in COX-1 activity during the MLX treatment and there was a decreased COX-1 activity at 7 days which was maintained throughout the whole KTF treatment period. DISCUSSION When the synthesis of TXB2 was measured, the MLX was the drug which caused a smaller inhibition of COX-1 when compared to KTF. Although the two drugs both reduced gastric PGE2 levels in a marked way, KTF produced the most pronounced inhibition in all the determinations. Considering the present results, it would be expected that administration of preferential COX-2 inhibitors (eg MLX) to dogs would cause fewer adverse effects than the nonselective inhibitor KTF.