Safety and tolerability of 3-week and 6-month dosing of Deramaxx (deracoxib) chewable tablets in dogs.

Although non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing pain and inflammation, these agents have adverse effects. Selective inhibitors of COX-2 are an alternative to traditional NSAIDs. Deramaxx [Novartis Animal Health US, Inc. (NAH), Greensboro, NC, USA] contains the selective COX-2 inhibitor, deracoxib, and is approved for the relief of pain and inflammation associated with orthopedic surgery and osteoarthritis in dogs. The safety of Deramaxx was evaluated in two target animal safety studies: 40 dogs (four dogs/sex/group) received 0, 4, 6, 8, or 10 mg/kg/day deracoxib once daily for 21 days; and 60 dogs (five dogs/sex/group) received 0, 2, 4, 6, 8, or 10 mg/kg/day deracoxib once daily for 6 months. There was a dose-dependent trend towards increased blood urea nitrogen (BUN) in treated dogs, however mean BUN values remained within the reference range at the labeled doses. In both trials, histopathology revealed focal renal tubular degeneration/regeneration in some dogs receiving >or=6 mg/kg/day deracoxib. Focal renal papillary necrosis was seen in one dog treated with 8 mg/kg/day and in three dogs receiving 10 mg/kg/day deracoxib on the 6-month study. No other parameters of renal function were adversely affected for either study. Results show that Deramaxx is safe and well-tolerated in dogs when administered as directed.

Kinetic evidence for different mechanisms of acetylcholinesterase inhibition by (1R)- and (1S)-stereoisomers of isomalathion.

Inhibition of acetylcholinesterase (AChE) by isomalathion has been assumed to proceed by expulsion of diethyl thiosuccinyl to produce O, S-dimethyl phosphorylated AChE. If this assumption is correct, AChE inhibited by (1R)- or (1S)-isomalathions should reactivate at the same rate as AChE inhibited by configurationally equivalent (S)- or (R)-isoparathion methyl, respectively, which are expected to inhibit AChE by loss of 4-nitrophenoxyl to yield O,S-dimethyl phosphorylated AChEs. Previous work has shown that rat brain AChE inhibited by (1R)-isomalathions reactivates at the same rate as the enzyme inhibited by (S)-isoparathion methyl. However, although rat brain AChE inhibited by (R)-isoparathion methyl reactivates at a measurable rate, the enzyme inhibited by (1S)-isomalathions is intractable to reactivation. This surprising finding suggests the hypothesis that (1R)- and (1S)-stereoisomers of isomalathion inhibit AChE by different mechanisms, yielding enzymatic species distinguishable by their postinhibitory kinetics. The present study was carried out to test this hypothesis by comparing kinetic constants of reactivation (k+3) and aging (k+4) of hen brain AChE and bovine erythrocyte AChE inhibited by the four stereoisomers of isomalathion and the two stereoisomers of isoparathion methyl. Both AChEs inhibited by either (1R,3R)- or (1R,3S)-isomalathion had comparable corresponding k+3 values (spontaneous and oxime-mediated) to those of AChEs inhibited with (S)-isoparathion methyl. However, spontaneous and oxime-mediated k+3 values comparable to those of (R)-isoparathion methyl could not be obtained for AChEs inhibited by (1S,3R)- and (1S,3S)-isomalathion. Comparison of k+4 values for hen brain AChE inhibited by each stereoisomer of isomalathion and isoparathion methyl corroborated that only the (1S)-isomalathions failed to produce the expected O,S-dimethyl phosphoryl-conjugated enzymes. The results for (1R)-isomalathions suggest that the mechanism of inhibition of AChE by these isomers is the expected one involving diethyl thiosuccinyl as the primary leaving group. In contrast, the results for (1S)-isomalathions are consistent with an alternative mechanism of inhibition by these isomers implicating loss of thiomethyl as the primary leaving group.