Indomethacin effect

El Maghraby, G.M. Self-microemulsifying and microemulsion systems for transdermal delivery of indomethacin Effect of phase transition. Colloids Surf. B Biointerfaces 2010, 75 (2), 595-600. 

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]. 

Indomethacin treatment is associated with a high incidence (30%) of side effects typical for those seen with other NSAIDs (see above). Gastrointestinal side effects, in particular, are more frequently observed after indomethacin than after administration of other NSAIDs. The market share of indomethacin ( 5%) is therefore low compared to that for other non-steroidal anti-rheumatic agents. 

In the search for new anti-inflammatory drugs structurally derived from indomethacine [147], Pravadoline showed psychotropic side effects in clinical trials. It became apparent that these effects are mediated through the cannabinoid receptor. Optimization of the structure Anally led to WIN-55,212-2 (8.6), which has a higher affinity to the CBl receptor than THC [148]... 

Gastric mucosal injury induced by non-steroidal antiinflammatory drugs such as aspirin and indomethacin has also been extensively studied, again with somewhat conflicting results. Several studies have shown a protective effect of SOD, catalase, hydroxyurea and desferrioxamine (Takeuchi et al., 1991a Vaananen et al., 1991 Naito et al., 1992). Del Soldato etal. (1985) also found aminopy-rine, thiourea and its derivative, MK 447, and SAZ to be protective. Allopurinol has been shown to be both protective (Takeuchi etal., 1991a) and ineffective (Vaananen etal., 1991). 

It has been proposed that the capacity of antiinflammatory drugs to scavenge and inhibit ROM production is pertinent to their therapeutic effect (Hal-hwell et al., 1988). NSAIDs, namely indomethacin, inhibit superoxide generation by stimulated guinea-pig macrophages (Oyanagui, 1976) and the scavenging effects of PMN-derived ROMs by the sulphasalazine... 

In the early clinical trials of Pravadoline (248), the Sterling-Winthrop Research group observed CNS side effects. In an effort to circumvent these issues, indenes were explored as an alternative core [197]. The rationale behind this approach came from the observation that sulindac (308), an indene analogue of indomethacin (309), had anti-inflammatory properties comparable to (309) but without the CNS-associated side effects. 

Indomethacin was used traditionally, but its relative cyclooxygenase-1 (COX-1) selectivity theoretically increases its gastropathy risk. Thus other generic NSAIDs may be preferred. Adverse effects of NSAIDs include gastropathy (primarily peptic ulcers), renal dysfunction, and fluid retention. NSAIDs generally should be avoided in patients at risk for peptic ulcers, those taking warfarin, and those with renal insufficiency or uncontrolled hypertension or heart failure. 

N Ammoury, H Fessi, JP Devissaguet, M Allix, M Plotkine, RG Boulu. Effect on cerebral blood flow of orally administered indomethacin-loaded poly (isobutylcyanoacrylate) and poly(d,l-lactide) nanocapsules. J Pharm Pharmacol 42 558-561, 1990. 

Davies GR, Wilkie ME, Rampton DS Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability. Dig Dis Sci 1993 38 417-425. 

Del Soldato P, Foschi D, Varin L, Daniotti S Indomethacin-induced intestinal ulcers in rats Effects of salicylazosulfapyridine and dexamethasone. Agents Actions 1985,16 393-396. 

The interaction between drug compounds and excipients, as these influence drug dissolution, can be successfully studied by means of reflectance spectroscopy. In one study concerning probucol and indomethacin, it was deduced that hydrogen bonding and van der Waals forces determined the physisorption between the active and the excipients in several model formulations [36]. Chemisorption forces were found to play only minor roles in these interactions. These studies indicated that surface catalytic effects could be important during the selection of formulation excipients. 

Ramtoola Z, Corrigan 01. Effect of agitation intensity on the dissolution rate of indomethacin and indomethacin-citric acid compressed discs. Drug Dev Ind Pharm 1988 14(15-17) 2241-2253. 

Smart et al. discovered that indomethacin also blocks caveolae uptake and suggest arachidonate accumulation as a potential inhibitor (66). Indomethacin is described as inhibiting both the internalization of caveolae and the return of plasmalemma vesicles after an incubation time of 30 minutes in the presence of 400 pM in MA104 cells (rhesus monkey kidney cells). The effects are rapidly reversible after removing the drug (66). 

Furthermore, our own studies showed that not all inhibitors seem to be useful for their suggested application in all cell types. Some inhibitors (amiloride and indomethacin) did not show an effect (not even on the uptake of the corresponding marker substances) in COS-7 and HUVEC. Consequently, not only one but a series of inhibiting agents with preferably different modes of inhibition should be applied and combined with colocalization studies. 

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