Indomethacin COX inhibitor

B. Indomethacin s action as a potent nonselective COX inhibitor appears to be important in speeding up ductus closure. The other drugs do not have such an action, and prostaglandin Ej given by infusion would cause the ductus to remain open. 

The NSAIDs (eg, indomethacin, ibuprofen see Chapter 36) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. Selective COX-2 inhibitors, which were developed more recently, vary—as do the older drugs—in their degree of selectivity. Indeed, there is considerable variability between (and within) individuals in the selectivity attained by the same dose of the same NSAID. Aspirin is an irreversible COX inhibitor. In platelets, which are anuclear, COX-1 (the only isoform expressed in mature platelets) cannot be restored via protein biosynthesis, resulting in extended inhibition ofTXA2 biosynthesis. 

In delayed closure of the ductus arteriosus, COX inhibitors are often used to inhibit synthesis of PGE2 and so close the ductus. Premature infants in whom respiratory distress develops due to failure of ductus closure can be treated with a high degree of success with indomethacin. This treatment often precludes the need for surgical closure of the ductus. 

Indomethacin, introduced in 1963, is an indole derivative (Figure 36-1). It is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T-cell and -cell proliferation. 

Nonselective COX inhibitors (e.g. high dose aspirin, indomethacin)... 

It has been shown that arachidonic acid metabolism could contribute to the pathogenesis of cerebral edema. Treatment with indomethacin, a COX inhibitor, nordihydroguaiaretic acid, a LOX inhibitor, or their combination significantly reduced vasogenic edema induced by freezing lesions (Yen and Lee, 1987). 

Frenkian M, Segond N, Pidoux E, Cohen R, Jullienne A (2001) Indomethacin, a COX inhibitor, enhances 15-PGDH and decreases human tumoral C cells proliferation. Prostaglandins 65 11-20... 

Indomethacin was the product of a laboratory search for drugs with antiinflammatory properties. It was introduced in 1963 for the treatment of rheumatoid arthritis and related disorders. It is a nonselective COX inhibitor. Although indomethacin still is used clinically and is effective, toxicity and the availability of safer alternatives have limited its use. Sulindac was developed in an attempt to find a less toxic, but effective, congener of indomethacin and also is a nonselective COX inhibitor. 

Effects of Inhibitors of Eicosanoid Synthesis Enzymes on TNF-a Production. To further investigate how different eicosanoids affect TNF-a production, THP-1 cells were preincubated with COX inhibitors, and then stimulated with EPS. Indomethacin (5 [iM), which is a nonselective COX inhibitor, did not affect EPS-stimulated TNF-a production of THP-1 cells (Fig. 6). In addition, niflumic acid (2 iM), which is a selective inhibitor of COX-2, and aspirin (2 mM),... 

Flurbiprofen and indomethacin, which comprise the third class of inhibitors, cause a slow, time-dependent inhibition of COX-1 and COX-2, apparently via formation of a salt bridge between a carboxylate on the drug and Arg , which lies in the tunnel. 

The possibility still exists that selective COX-2 inhibitors may be used to treat cancer if the beneficial effect outweighs the side effects. They may also have a therapeutic role in treating premature labour, since labour is induced partly through the uterotonic effect of PGs synthesised by COX-2. Non-selective NSABDs such as indomethacin will also delay premature labour but they are contraindicated for this condition since they also cause early closure of the ductus arteriosus through inhibition of COX-1, which synthesises PGs maintaining patency of the ductus [5]. 

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. 

Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but many selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing using human whole blood, aspirin, ibuprofen, indomethacin, piroxicam, and sulindac are somewhat more effective in inhibiting COX-1. The efficacy of -2-selective drugs equals that of the older NSAIDs, while gastrointestinal safety may be improved. On the other hand, selective COX-2 inhibitors may increase the incidence of edema and hypertension. As of December 2008, celecoxib and the less selective meloxicam are the only COX-2 inhibitors marketed in the USA. Rofecoxib and valdecoxib, two previously marketed, selective COX-2 inhibitors, have been withdrawn from the market due to their association with increased cardiovascular thrombotic events. Celecoxib has an FDA-initiated "black box" warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to include cardiovascular risks. 

Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the gastrointestinal and renal side effects of ketorolac limit its use. Some surveys suggest that indomethacin or tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. The selective COX-2 inhibitors were not included in these analyses. 

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