Diflunisal toxicity

Clark and colleagues (27) found evidence of maternal toxicity influencing fetal findings in studies with diflunisal in rabbits, in which fetal axial skeletal defects were observed. Diflunisal was found to produce severe maternal hemolytic anemia and greatly decreased erythrocyte ATP levels. The authors were able to demonstrate that the skeletal malformations resulted from maternal hypoxia secondary to anemia, rather than from a direct effect of the drug on the embryo or fetus. In addition, it was demonstrated that diflunisal had no effects on rat erythrocyte ATP levels, and the compound was categorized as not teratogenic in rats or mice. 

Unfortunately, high-dosage chronic toxicity tests in rats and dogs resulted in gastrointestinal lesions and papillary necrosis. Clinical tests ceased. Reexamination of close analogs of flufenisal led to the selection of the 5-(2,4-difluorophenyl) derivative of salicylic acid—diflunisal. The additional fluorine atom may have compensated for loss of potency attributable to the lack of the O-acetyl group, which in turn probably accounts for... 

B. Diflunisal overdose produces toxicity resembling salicylate poisoning (see... 

The gastrointestinal toxicity of the NSAIDs is well documented, and it appears that combined use increases this risk. The CSM in the UK state that not more than one NSAID should be used concurrently. " The marked rise in plasma levels of indometacin with diflunisal gives an additional reason why this combination in particular should not be used. Some NSAIDs cause more gastrointestinal toxicity than others, a suggested broad rank order of seven NSAIDs is as follows. Highest risk (azapro-pazone) intermediate risk (diclofenac, indometacin, ketoprofen and naproxen, with piroxicam more risky) lowest risk (ibuprofen), which has been home out in another analysis. The ranking was based on epidemiological studies and the yellow card database. Ketorolac may also be... 

Probenecid reduces the clearance of dexketoprofen, diflunisal, in-dometacin (toxicity seen), ketoprofen, ketorolac, naproxen, sodium meclofenamate, tenoxicam and tiaprofenic acid and raises their levels. Ketorolac and probenecid are specifically contraindicated. The uricosuric effects of probenecid are not affected by in-dometacin but may be slightly reduced by sulindac. 

Valproate toxicity developed in three patients given large and repeated doses of aspirin. Increased levels of free valproate were found in S children within hours of them taking aspirin. Con-versefy, a slightly reduced valproate level was reported in one patient who took ibuprofen. Modestly altered protein binding has been shown when sodium valproate was given with diflunisal or naproxen, but this appears unlikely to be clinically important... 

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