Influence of plasma protein on the potencies of inhibitors of cyclooxygenase-1 and -2.

It is widely believed that the potencies of nonsteroid anti-inflammatory drugs (NSAIDs) as inhibitors of cyclooxygenase (COX) are influenced by protein binding in the extracellular fluid, since NSAIDs are bound to circulating albumin by well over 95%. This is an important point because the protein concentrations in synovial fluid and the central nervous system, which are sites of NSAID action, are markedly different from those in plasma. Here we have used a modified whole-blood assay to compare the potencies of aspirin, celecoxib, diclofenac, indomethacin, lumiracoxib, meloxicam, naproxen, rofecoxib, sodium salicylate, and SC560 as inhibitors of COX-1 and COX-2 in the presence of differing concentrations of protein. The potencies of diclofenac, naproxen, rofecoxib, and salicylate, but not aspirin, celecoxib, indomethacin, lumiracoxib, meloxicam, or SC560, against COX-1 (human platelets) increased as protein concentrations were reduced. Varying protein concentrations did not affect the potencies of any of the drugs against COX-2, with the exception of sodium salicylate (A549 cells). Clearly, our findings show that the selectivity of inhibitors for COX-1 and COX-2, which are taken to be linked to their efficacy and side effects, may change in different extracellular fluid conditions. In particular, selectivity in one body compartment does not demonstrate selectivity in another. Thus, whole-body safety or toxicity cannot be linked to one definitive measure of COX selectivity.

Respiratory and acid-base parameters during salicylic intoxication in dogs.

This paper examines the mechanism responsible for hyperventilation and accompanying respiratory alkalosis during acute salicylism. Sodium salicylate (250 mg/kg) was administered to 8 spontaneously breathing anesthetized dogs (alpha-chloralose, 50 mg/kg, and urethane, 500 mg/kg, iv). The trachea was sectioned and connected to a pneumotachograph. A catheter was placed in the cisterna magna for sampling cerebrospinal fluid (CSF) and a femoral artery was cannulated for blood sampling and pressure determinations. Once the cardiorespiratory steady-state was obtained, air flow, tidal volume, arterial pressure, ECG and rectal temperature were measured for baseline control. The measurements were repeated 8 times during 100 min after salicylate infusion. Simultaneous determinations of CSF and plasma salicylate showed that plasmatic levels were maximal just after infusion, diminishing with time. CSF concentration increased gradually as the salicylate diffused through the blood-brain barrier. Minute ventilation increased to more than 600% of control values and was maximal between 60-100 min after salicylate infusion. Respiratory alkalosis and hyperthermia (up to 40.3 degrees C) followed the time-course of hyperventilation. Only a small part of hyperventilation can be attributed to the temperature increase. A high correlation coefficient (r = 0.974) was obtained by regression analysis of the values for ventilation and CSF salicylate. We conclude that the central action of salicylate is much more important for increasing ventilation than effects related to oxidative phosphorylation uncoupling.