Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis
Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis
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DOI：
10.1111/1523-1747.ep12297888
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发表时间：
1996-07-01
影响因子：
6.5
通讯作者：
Weiner, ES
中科院分区：
文献类型：
--
作者：
Hanifin, JM;Chan, SC;Weiner, ES
外周血白细胞中环腺苷酸磷酸二酯酶活性增加与特应性皮炎的免疫和炎症高反应性有关。特应性磷酸二酯酶对多种酶抑制剂具有高度敏感性，提示其具有更高的治疗优势。本研究的目的是使用体外试验来鉴定有效的磷酸二酯酶抑制剂，然后研究其治疗特应性皮炎的有效性。而前列腺素E（2）和白细胞介素10（IL-10）和4（IL-4）在单核白细胞的24小时培养上清液中通过免疫测定法测定。局部磷酸二酯酶抑制剂对特应性皮炎皮损皮肤的作用是通过双盲、配对比较活性药物和安慰剂软膏应用于对称受累部位超过28天来评估的。使用体外试验，我们证明了选择性高效磷酸二酯酶抑制剂减少特应性单核白细胞培养物中前列腺素E2、IL-10和IL-4产生的能力。我们选择了4型磷酸二酯酶抑制剂，CP 80，633，基于其抑制效力，在20名特应性皮炎患者中通过局部、双侧配对比较进行临床测试，并证明了所有炎症参数的显着降低。磷酸二酯酶抑制剂调节几种有助于夸大的免疫和炎症反应的途径，这是特应性皮炎的特征，这种在体内证明的类固醇疗效图提供了一个有用的替代过度依赖皮质类固醇治疗的特应性疾病。
Increased cyclic AMP-phosphodiesterase activity in peripheral blood leukocytes is associated with the immune and inflammatory hyperreactivity that characterizes atopic dermatitis. Atopic phosphodiesterase has high sensitivity to a variety of enzyme inhibitors, suggesting an increased therapeutic advantage, The objective of this study was to use in vitro assays to identify a potent phosphodiesterase inhibitor and then to investigate its effectiveness in treating atopic dermatitis.Leukocyte enzyme activity was measured by radioenzyme assay, whereas prostaglandin E(2) and interleukins 10 (IL-10) and 4 (IL-4) were measured in 24-h culture supernatants of mononuclear leukocytes by immunoassays. The effect of a topical phosphodiesterase inhibitor on atopic dermatitis lesional skin was assessed by double-blind, paired comparisons of active drug and placebo ointments applied to symmetrically involved sites over a 28-d period.Using in vitro assays, we demonstrated the ability of selective high-potency phosphodiesterase inhibitors to reduce prostaglandin E(2), IL-10, and IL-4 production in atopic mononuclear leukocyte cultures. We selected the Type 4 phosphodiesterase inhibitor, CP80,633, based on its inhibitory potency, for clinical testing by topical, bilateral paired comparisons in 20 patients with atopic dermatitis and demonstrated significant reductions of all inflammatory parameters.Phosphodiesterase inhibitors modulate several pathways contributing to the exaggerated immune and inflammatory responses, which characterize atopic dermatitis, This in vivo demonstration of antiinflammatory efficacy map provide a useful alternative to the over-reliance on corticosteroid therapy in atopic disease.