Effect of orally administered KF66490, a phosphodiesterase 4 inhibitor, on dermatitis in mouse models.

Abstract

Due to the broad anti-inflammatory and immunomodulatory actions of phosphodiesterase (PDE) 4 inhibitors, it has been proposed that PDE4 inhibitors might be efficacious for skin disorders such as atopic dermatitis. KF66490 is a newly developed PDE4 inhibitor that inhibits PDE4B (IC(50)=220 nM) and the production of tumor necrosis factor (TNF)-alpha by mouse peritoneal exudated cells stimulated with lipopolysaccharide (IC(50)=855 nM). To evaluate efficacy of KF66490 in atopic dermatitis (AD) models, on skin inflammation induced by repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) on ear in BALB/c mice and on spontaneously AD-like skin diseases in NC/Nga mice. BALB/c mice were sensitized with 0.3% w/v TNCB applied to the ear on day-7, followed by application three times a week from days 0 to 21. NC/Nga mice spontaneously developed dermatitis symptoms under conventional conditions. Test compounds were administered orally once daily during experiments. In the TNCB-induced dermatitis model, KF66490 significantly inhibited the increase in ear thickness and interleukin (IL)-4 and IL-1beta levels in the ear. Histopathological and immunohistochemical analysis revealed that KF66490 significantly inhibited the proliferation of fibroblasts and CD3-positive T cells infiltration into the ear. In addition, KF66490 significantly suppressed the development of dermatitis in NC/Nga mice on all observation days, except for 5 and 6 weeks after the first dose. Furthermore, KF66490 produced less potent emetic effects than the first generation PDE4 inhibitor, rolipram. The present results suggest that KF66490 has excellent potential as an oral medicine for the treatment of atopic dermatitis.

• Authors: Daisuke Harada, Chie Takada, Yukino Nosaka, Yuko Takashima, Katsuya Kobayashi, Katsumi Takaba, Haruhiko Manabe
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 9 Issue 1 Pg. 55-62 (Jan 2009) ISSN: 1567-5769 [Print] Netherlands
• PMID: 18854230 (Publication Type: Journal Article)

Chemical References

• 4-cyano-4-(2,3-dihydro-8-methoxy-1,4-benzodioxin-5-yl)cyclohexanecarboxylic acid
• Anti-Inflammatory Agents
• Cyclohexanecarboxylic Acids
• Cytokines
• Dioxanes
• Interleukin-1beta
• Phosphodiesterase 4 Inhibitors
• Phosphodiesterase Inhibitors
• Interleukin-4
• Immunoglobulin E
• Prednisolone
• Picryl Chloride

Topics

• Administration, Oral
• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Body Weight (drug effects)
• Cyclohexanecarboxylic Acids (adverse effects, pharmacology, therapeutic use)
• Cytokines (metabolism)
• Dermatitis, Contact (drug therapy, metabolism, pathology)
• Dioxanes (adverse effects, pharmacology, therapeutic use)
• Ear, External (metabolism, pathology)
• Immunoglobulin E (biosynthesis, metabolism)
• Immunohistochemistry
• Interleukin-1beta (biosynthesis)
• Interleukin-4 (biosynthesis)
• Male
• Mice
• Mice, Inbred BALB C
• Phosphodiesterase 4 Inhibitors
• Phosphodiesterase Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Picryl Chloride
• Prednisolone (therapeutic use)
• Vomiting (chemically induced)