cx-659s and Dermatitis--Contact

CX-659S ((S)-6-amino-5-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione), a newly discovered anti-inflammatory compound, exerts inhibitory effects against picryl chloride-, oxazolone-, and dinitrochlorobenzene-induced acute contact hypersensitivity responses (CHRs) characterized by Th1-type reactions. Furthermore, this compound suppressed chronic CHRs characterized by Th2-type reactions, which is well known to mimic many, if not all, events occurring within the lesional skin of patients with atopic dermatitis (AD). The present study was conducted to determine the combined effect of topical CX-659S with topical corticosteroid on immediate type (ITR), late type (LTR), and delayed type hypersensitivity (DTHR) allergic reactions that are involved in AD. An ineffective dose of CX-659S (0.03 mg/ear) combined with betamethasone valerate (BV) significantly potentiated inhibitory activity of BV alone (0.1 micro g/ear and 0.3Shizuokag/ear) on both the ITR and the LTR in mice with the ovalbumin (OVA)-induced biphasic cutaneous reaction. Furthermore, the combined effect of CX-659S with BV was also observed on dinitrochlorobenzene (DNCB)-induced DTHR in guinea pigs. These results indicate that CX-659S has a combined effect with corticosteroids on every ITR, LTR, and DTHR. Proper treatment with corticosteroids for a safe and effective treatment of AD is needed. Thus, the combination therapy of topical CX-659S with topical corticosteroid would be one of the potential approaches for devising a proper treatment with corticosteroids.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Betamethasone Valerate; Dermatitis, Contact; Dinitrochlorobenzene; Guinea Pigs; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Indicators and Reagents; Irritants; Mice; Mice, Inbred ICR; Ovalbumin; Skin; Uracil

CX-659S, a newly discovered anti-inflammatory compound, exerts inhibitory effects on chronic contact hypersensitivity responses (CHRs) induced by repeated application with picryl chloride (PC), which is known to mimic many, if not all, events occurring within lesional skin of patients with atopic dermatitis (AD). CX-659S suppresses the expression of mRNA for interleukin (IL)-4 and IL-10 but not that for IFN-gamma, and inhibits serum IgE production in a chronic CHR model. Although topical corticosteroids have been widely utilized in steroid-responsive dermatoses such as AD, their chronic use may be associated with significant side effects. In addition, a rebound phenomenon often occurs after discontinuation of prolonged use of topical corticosteroids, with enhanced production of IgE and Th2 cell cytokines. The purpose of this study was to assess whether CX- 659S inhibits the rebound phenomenon after discontinuation of chronic treatment with prednisolone in a chronic CHR model in mice.. The efficacy of CX-659S as a sequential therapeutic agent after discontinuation of chronic treatment with prednisolone was tested on PC-treated ears of BALB/c mice with chronic CHR. Effects were quantified by measurements of ear thickness, serum IgE and cytokine mRNA expression.. The rebound phenomenon was confirmed after discontinuation of chronic treatment with prednisolone in chronic CHR in mice, i.e. by evidence of flare thickening of the ear, enhanced expression of mRNA for IL-4 and IL-10 and increased serum IgE. Sequentially applied CX-659S suppressed these rebound phenomena with a good cosmetic result.. CX-659S is the first promising compound with inhibitory activity on the rebound phenomenon following withdrawal of corticosteroid therapy without immunosuppression.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Chronic Disease; Dermatitis, Atopic; Dermatitis, Contact; Glucocorticoids; Ibuprofen; Immunoglobulin E; Male; Mice; Mice, Inbred BALB C; Models, Animal; Ointments; Picryl Chloride; Prednisolone; Recurrence; Uracil

CX-659S (1) [(S)-6-amino-5-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)-3-methyl-1-phenyl-2,4-(1H,3H)-pyrimidinedione], has been developed as a new type anti-inflammatory agent for the treatment of dermatitis. The structure of a major metabolite of CX-659S was determined as (S)-6-amino-5-[2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadienyl)butanamide]-3-methyl-1-phenyl-2,4-(1H,3H)-pyrimidinedione (2) by direct comparison with the synthesized authentic compound. The anti-inflammatory activity of 2 was equipotent with that of 1 on the contact hypersensitivity reaction (CHR) induced by picryl chloride (PC) in mice, suggesting that compound 2 contributes, at least in part, to the anti-inflammatory activity of CX-659S.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Contact; Dogs; Male; Mice; Mice, Inbred ICR; Uracil

The T-cell-mediated contact hypersensitivity reaction (CHR) is thought to be involved in the pathogenesis of clinical cutaneous disorders including atopic dermatitis. A novel diaminouracil derivative, CX-659S, has been reported to have an inhibitory activity against picryl chloride (PC)-induced CHR when administered either orally or percutaneously. The inhibitory effect of topical CX-659S was assessed in three CHR models in the present study. In addition, to elucidate the mechanism of action of this compound, we examined the effect of CX-659S on the expression of messenger RNAs for proinflammatory cytokines after elicitation in PC models.. For the in vivo evaluation of the efficacy of CX-659S, we used PC- or oxazolone-induced CHR in mice and 2,4-dinitrochlorobenzene (DNCB)-induced CHR in guinea pigs. CX-659S was topically applied immediately after the hapten challenge in each model. To assess the effect on gene expression of cytokines, we used the reverse transcriptase-polymerase chain reaction (RT-PCR), a semiquantitative technique with specific primers.. Topical CX-659S dose-dependently inhibited ear swelling at 24 h after the challenge in the two mouse models. This inhibitory effect was histologically confirmed in the PC model. Topically applied CX-659S also inhibited erythema and edema formation 24 h after challenge in the guinea pig model. CX-659S inhibited the expression of mRNA for proinflammatory cytokines IL-1 beta and TNF-alpha in vivo.. Topically applied CX-659S showed significant inhibitory activities against CHR models both in mice and in guinea pigs. Inhibition profiles of CX-659S toward mRNA expression for proinflammatory cytokines corroborated these findings. CX-659S thus could be a useful therapeutic agent for allergic cutaneous disorders such as allergic contact dermatitis and atopic dermatitis.

Topics: Administration, Topical; Animals; Base Sequence; Dermatitis, Contact; Dinitrochlorobenzene; Disease Models, Animal; DNA Primers; Guinea Pigs; Humans; Immunosuppressive Agents; Interleukin-1; Male; Mice; Mice, Inbred ICR; Oxazolone; RNA, Messenger; Tumor Necrosis Factor-alpha; Uracil