Lonapalene

Topical administration of lipoxygenase and cyclooxygenase inhibitors, antipsoriatic drugs and some immunomodulating drugs on adult mouse tail scales showed variable induction of of orthokeratosis. Dithranol and retinoic acid showed ED₅₀ concentrations of 0.5% and 0.23%, respectively. The lipoxygenase inhibitors catechol and octyl gallate showed ED₅₀ of 2.5 and 13.4%. 10% lonapalene showed 20% activity, curcumin, linoleic acid, primrose oil and AA673 10–15% activity, methyl and ethyl gallate 5% activity, nordihydroguaiaretic acid, diethylcarbamazine, ebselen, esculetin, quercetin, AA861, gallic acid, dodecyl gallate and 15-hydroxyeicosatetraenoic acid no activity. The cyclooxygenase inhibitors indomethacin, acetylsalicylic acid and bufexamac were inactive, benoxaprof-en showed 14% activity. The immunomodulating drugs fluo-rouracil and triamcinolone showed > 10% activity, cyclosporin A and thalidomide no activity. Fumaric acid showed 5% activity. The results show that this model could be proposed for screening antipsoriatic drugs.

The percutaneous absorption and metabolism of lonapalene (6-chloro-2,3-dimethoxynaphthalene-1,4-diol-diacetate; RS-43179), a topically effective 5-lipoxygenase inhibitor, has been measured in six subjects with stable plaque-type psoriasis of the lower extremities. Lonapalene readily penetrates psoriatic skin, is rapidly and completely metabolized, and is almost entirely excreted in the urine. Unexpectedly we observed a trend for thigh (T) plaque skin to be more permeable than lower leg (LL) plaque skin as measured by total absorption (T, 44.8 +/- 13.4%; LL, 24.9 +/- 12.6% applied dose excreted), peak plasma levels (T, 209 +/- 107; LL, 146 +/- 81 ng Eq/ml), and peak rate of urinary excretion (T, 591.7 +/- 112.2; LL, 318.4 +/- 143.9 micrograms Eq/hr). There were also differences in the metabolic profiles between the two sites as measured by the quantity and proportion of dealkylated and conjugated products excreted in the urine.