Combination of a dual 5-lipoxygenase/cyclooxygenase inhibitor with a glucocorticoid results in synergistic topical antiinflammatory activity without inducing skin atrophy.
Synthetic glucocorticosteroids are widely used in clinical dermatology in the treatment of a number of inflammatory skin disorders. However, cutaneous side effects such as induction of skin atrophy are among the factors that limit the chronic use of this class of agents. We have found that a combination of a dual 5-lipoxygenase/cyclooxygenase inhibitor (9-phenylnonanohydroxamic acid, BMY 30094) and a glucocorticosteroid (hydrocortisone valerate) has synergistic antiinflammatory activity. Topical application of a 0.2% solution of hydrocortisone valerate alone inhibited phorbol ester-induced mouse skin inflammation by 92%. A 1% solution of BMY 30094 alone or a low dose of hydrocortisone valerate (0.005%) had no significant effect on the inflammatory reaction. A combination of 1% BMY 30094 and 0.005% hydrocortisone valerate inhibited the inflammation by 76%. This latter combination produced no signs of skin atrophy in rats after 28 days of application. In contrast, a 0.1% dose of hydrocortisone valerate produced significant skin atrophy. These findings suggest that it is possible to reduce the skin atrophy potential of glucocorticoids while maintaining the antiinflammatory activity using a novel drug combination.
Tramposch
K M
KM
Dermatology Discovery Research, Bristol-Myers Squibb Pharmaceutical Research Institute, Buffalo, New York 14213.
D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001284:Atrophy / Q000517:prevention & control; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D003875:Drug Eruptions / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006854:Hydrocortisone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; C065338:9-phenylnonanohydroxamic acid; C038363:hydrocortisone valerate; D013755:Tetradecanoylphorbol Acetate; D006854:Hydrocortisone