Anti-inflammatory drugs pyrazolones

As anti-inflammatory drugs, pyrazolone preparations have been used topically for superficial phlebitis and similar inflammatory conditions. Krook (1975) described three cases of contact allergy, one sensitive to oxyphenbutazone, the two others sensitive to phenylbutazone. Phenylbutazone did not cause cross-sensitivity to oxyphenbutazone, while cross-sensitivity the opposite way was found. Vooys and Van Ketel (1977) added one more case of phenylbutazone allergy, and Thormann and Kaaber (1978) recorded four, emphasizing the increased risk of developing hypersensitivity in patients with preexisting skin disorders. 

Little information is available regarding tissue distribution or metabolic products of nonsteroidal anti-inflammatory drugs in cattle. The early synthetic compounds were simple derivatives either of salicylic acid such as acetylsalicylic acid and methylsalicylic acid, or of pyrazolone such as metamizole, oxyphenbuta-zone, phenylbutazone, propylphenazone, and suxibuzone. Modern nonsteroidal anti-inflammatory drugs are derivatives either of anthranilic acid such as dido-... 

The eight groups of nonsteroidal anti-inflammatory drugs are salicylates, parachlorobenzoic acid derivatives, pyrazolone derivatives, propionic acid derivatives, fenamates, oxicams, phenylacetic acid, and selective COX-2 inhibitors. 

The exact mechanism for intolerance to azo dyes and benzoates is still unknown. Since cross-reactions to various analgesics and anti-inflammatory drugs such as aspirin, indomethacin, dextropropoxyphene, phenylbutazone, menfenamate, ibu-profen, and sodium salicylate also occur, a nonallergic mechanism seems probable for most patients. A chemical resemblance can clearly be seen only between benzoates and salicylates (Fig. 1). When azo dyes are taken orally there will be an azo-reductive cleavage in the intestinal tract into sulfanilic acid and a pyrazolone derivative which can be further hydrolyzed to sulfophenylhydrazine (Ryan et al. 1969). Some azo dyes can form aniline compounds, which could explain their cross-reactions with preservatives (Walker 1970). 

However, a patient sensitized to another prodrug, pyrazinobutazone, a piperazine salt of phenylbutazone, reacted with a flare-up to oral provocation (Dorado Bris et al. 1992). Benzydamine, a topical and systemic nonsteroidal anti-inflammatory drug has caused two cases of occupational sensitization (Foti et al. 1992). An unusual case of a multilocular fixed drug eruption upon inhalation of pyrazolones with positive oral provocation has also been described (Vanuytrecht-Henderickx et al. 1986). 

Fig. 9.4 Some important pyrazolone nonsteroidal anti-inflammatory drugs showing the 1-phenyl-2,3-dimethyl-3-pyrazoline-5-one common core structure in bold...

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