Anti-inflammatory Toxicity Research Articles

Cytotoxicity of Topical Medications Used for Infection and Inflammation Control after Cataract Surgery in Cultured Corneal Endothelial Cells

Postoperative vision-threatening corneal edema sometimes occurs after eye surgery, and corneal endothelial damage may be caused or exacerbated by drug toxicity. A range of commercially available antibiotic and anti-inflammatory ophthalmic solutions used postoperatively, namely levofloxacin, moxifloxacin, gatifloxacin, cefmenoxime, diclofenac, bromfenac, pranoprofen, betamethasone, and fluoromethorone, were assessed by using human corneal endothelial cells (HCECs). Propylparaoxybenzoate and methylparaoxybenzoate were also examined. Cell survival after 48 h exposure to the drugs was evaluated using the WST assay. Cefmenoxime and betamethasone were the least toxic antibiotic and anti-inflammatory drug, respectively. Cell survival was concentration dependent and increased markedly to ≥ 80% with dilutions of 100-fold or more. Two preservatives seemed to cause minimal cytotoxicity among those tested. Antibiotic cytotoxicity to HCEC was ranked as cefmenoxime < levofloxacin = gatifloxacin < moxifloxacin, while the toxicity of anti-inflammatory drugs was dependent on benzalkonium chloride and polysorbate. These drugs are unlikely to cause HCEC damage at the concentrations used under the usual conditions. Preservatives are essential ingredients in ophthalmic solutions to control postoperative infection and inflammation and we should be aware of their toxicity as well as efficacy.

NO-Aspirin: A Safer Form of Aspirin?

The gastrointestinal toxicity of aspirin and other traditional nonsteroidal anti-inflammatory drugs (NSAIDs) led to the development of cyclooxygenase

Comparison of the Intestinal Toxicity of Celecoxib, a Selective COX-2 Inhibitor, and Indomethacin in the Experimental Rat

Background: It is suggested that the gastrointestinal toxicity of conventional non-steroid anti-inflammatory drugs (NSAIDs) is due to a 'topical' effect in addition to inhibition of the mucosal constitutive cyclo-oxygenase-1 (COX-1) enzyme. COX-2 selective inhibitors have been shown to have excellent gastrointestinal tolerability, but it is not known whether this is due to their selectivity and/or a lack of a 'topical' effect. We assessed the effects of celecoxib (a highly selective COX-2 inhibitor) on key pathophysiologic events in NSAID enteropathy. Methods: The 'topical' effects of indomethacin and celecoxib were assessed in vitro (coupled mitochondrial respiration) and in vivo (mitochondrial electron microscopy) and the consequences by study of intestinal permeability (51-Cr-labelled ethylenediaminetetraacetic acid urinary excretion) and inflammation. We also assessed intestinal prostanoid levels (prostaglandin E, PGE) and the propensity of the drugs to induce intestinal ulcers. Results: Indomethacin uncoupled mitochondrial oxidative phosphorylation in vitro and in vivo, caused a significant (P < 0.0001) increase in intestinal permeability, caused mucosal inflammation and a 90% decline in intestinal PGE levels, and was associated with multiple small intestinal ulcers. Celecoxib caused no significant increase in any of these parameters, did not decrease intestinal PGE levels, and caused no intestinal ulcers. Conclusions: The intestinal tolerability of celecoxib appears to be due to a combination of the absence of a `topical' damaging effect and selective COX inhibition.

Inhibition of Nicotinate Phosphoribosyl Transferase by Nonsteroidal Anti-Inflammatory Drugs: A Possible Mechanism of Action

When incubated with 14C-nicotinic acid and phosphorylribose-1-pyrophosphate, human platelet lysate incorporates radioactivity into nicotinic acid mononucleotide. Under these conditions, the apparent Km of nicotinic acid for nicotinate phosphoribosyl transferase is 2.4 × 10−5M. Along with 2-hydroxynicotinic acid (Ki = 2.3 × 10−4M), the following nonsteroidal anti-inflammatory compounds competed reversibly with nicotinic acid for the enzyme: flufenamic acid (Ki = 4.6 × 10−5M), mefenamic acid (Ki = 7.6 × 10−5M), salicylic acid (Ki = 1.6 × 10−4M), phenylbutazone (Ki = 1.6 × 10−4M), and indomethacin (Ki = 4.2 × 10−4M). Such inhibition may explain the decreases in nicotinamide adenine dinucleotide phosphate content of rat liver after administration of salicylate. Furthermore, suppression of nicotinamide adenine dinucleotide biosynthesis by anti-inflammatory drugs may restrain mucopolysaccharide biosynthesis and, thereby, reduce inflammatory responsiveness. Hence, this antagonism of niacin may be involved in the pharmacologic activity and, particularly, the toxicity of anti-inflammatory drugs.