Evaluation of selective inhibition of canine cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs.

OBJECTIVE: To evaluate the activity of carprofen and other nonsteroidal anti-inflammatory drugs (NSAID) against isozymes of canine cyclooxygenases (COX1 and COX2). PROCEDURE: Constitutive COX1 was obtained from washed canine platelets, and COX2 was obtained from a canine macrophage-like cell line that was induced with endotoxin. Activity of carprofen and other NSAID against COX1 and COX2 was compared. Dose-response curves were plotted, and calculations were performed to identify concentrations that caused 50% inhibition (IC50 [microM]) for each isozyme. Ratio of the COX1-to-COX2 IC50 was used as a measure of isozyme selectivity. RESULTS: Of the compounds evaluated, carprofen had the greatest selectivity for COX2. Potency of carprofen for canine COX2 was more than 100-fold greater than for canine COX1. Inhibition of canine COX2 (IC50, 0.102 microM) for the racemic mixture of carprofen (S and R stereoisomers) was primarily attributable to the S enantiomer (IC50, 0.0371 microM), which was approximately 200-fold more potent than the R enantiomer (IC50, 5.97 microM). Nimesulide had the next highest selectivity for COX2 (38-fold), and tolfenamic acid and meclofenamic acid had 15-fold selectivity for COX2. The other compounds tested did not have substantial selectivity for canine COX2 or were more selective for canine COX1. CONCLUSIONS: Carprofen was found to be a potent inhibitor of canine COX2. Of the compounds tested, carprofen had the highest selectivity for canine COX2. CLINICAL RELEVANCE: The selectivity of carprofen for canine COX2 may be an important factor for its use in dogs.

Quantitative structure-activity relationships among macrolide antibacterial agents: in vitro and in vivo potency against Pasteurella multocida.

Quantitative structure-activity relationships have been found among macrolide antibacterial agents in their potencies against the bacterial pathogen Pasteurella multocida both in vitro and in mouse infections. To obtain these relationships we measured, among other things, the pK(a)'s and log P's of 15 known macrolides of diverse structures. Among these compounds, in vitro potency [log(1/MIC)] is a function of log P, log D, and CMR (R = 0.86). In vivo potency is a function of the higher pK(a), the HPLC chromatographic capacity factor log k', log(1/MIC) and pNF (R = 0.93). pNF is defined as the negative logarithm of the fraction of neutral drug molecules present in aqueous solution at pH 7.4. The same physical properties were determined for 14 macrolides not used in developing the original QSAR models. Using the in vivo model, we calculated the mouse protection potency ranges for these new compounds. Ten estimates agreed with those observed, three were lower by a half-order of magnitude, and one was calculated to be active in the range of 15-50 mg/kg, but in fact was not active at 50 mg/kg, the highest level tested. When these new compounds were combined with the original 15, and the QSAR's updated, the new equations for the in vitro and in vivo potencies were essentially the same as those originally found. Hence, the physical properties indicated above are major determinants of macrolide antibacterial potencies.

Repromicin derivatives with potent antibacterial activity against Pasteurella multocida.

Reductive amination of repromicin with polyfunctional amines has led to new macrolide antibacterial agents, some of which are highly potent against the Gram-negative pathogen Pasteurella multocida both in vitro and in a mouse infection model. A key element in this discovery was the recognition that among certain known macrolides increasing lipophilicity results in diminished in vivo activity. One repromicin derivative, 20-[N-[3-(dimethylamino)-propyl]-N-L-alanylamino]-20-deoxorepro micin (35), was selected for advanced evaluation. At 5 mg/kg, a single subcutaneous dose was found to control induced pasteurellosis in swine and induced respiratory disease in cattle.