Seegers B A, Andriessen M P, van Hooijdonk C A, de Bakker E S, van Vlijmen-Willems I M, Parker G L, van Erp P E, van de Kerkhof P C
Department of Dermatology, University Hospital, Nijmegen, The Netherlands.
Skin Pharmacol Appl Skin Physiol. 2000 Mar-Apr;13(2):75-85. doi: 10.1159/000029911.
VML 295 (LY 293111) is a potent and specific leukotriene(4) receptor antagonist. It has previously been shown in human volunteers that VML 295 at a dosage of 48 mg twice daily inhibits the ex vivo leukotriene B(4) (LTB(4))-induced upregulation of CD11b on peripheral blood neutrophils. A clear dose-response relatinship was shown. In addition, VML 295 inhibits various inflammatory aspects resulting from LTB(4) challenge of the skin, again showing a dose-response relationship. In view of the large variation in the elimination half-life of VML 295 (25-88.5 h) in individual human subjects, the present pharmacological study was designed to provide information on the pharmacodynamics of the drug by the assessment of VML 295 plasma concentrations, ex vivo LTB(4)-induced CD11b upregulation of neutrophils, neutrophil accumulation in the skin following epicutaneous application of LTB(4) and epidermal regeneration following standardized surface trauma. A group of 36 healthy volunteers were treated in a double-blind study with VML 295 at 200 mg twice daily, VML 295 at 200 mg once daily or placebo for 7 days. Before treatment, at the end of treatment and following discontinuation of treatment, VML 295 plasma concentrations and CD11b upregulation of blood neutrophils were assessed. In 18 subjects, the effects of the three treatments on LTB(4)-induced inflammatory were assessed before and at the end of treatment, and in the remaining 18 subjects the effects of these treatments on epidermal regeneration were assessed similarly. VML 295 at 200 mg either twice or once daily has a profound inhibitory effect on ex vivo LTB(4)-induced CD11b upregulation of blood neutrophils, LTB(4)-induced neutrophil accumulation in the skin, trauma-induced hyperproliferation of the epidermis and regenerative keratinization. The twice daily dose schedule was significantly more effective than the once daily regimen in reducing ex vivo CD11b stimulation of neutrophils, in blood samples collected 24 h after discontinuation of VML 295 treatment. The twice daily schedule tended to be more efficient in skin biopsies, although this difference was not statistically significant in the number of subjects investigated. A plasma concentration of 100 ng/ml proved to be the threshold for these effects. The profound biological effects, both systemically and cutaneously, as well as the safety profile, make VML 295 a promising drug for skin disorders characterized by epidermal proliferation and neutrophil accumulation.
VML 295（LY 293111）是一种强效且特异性的白三烯（4）受体拮抗剂。此前在人类志愿者中已表明，VML 295每日两次、每次48毫克的剂量可抑制体外白三烯B（4）（LTB（4））诱导的外周血中性粒细胞上CD11b的上调。呈现出明确的剂量 - 反应关系。此外，VML 295可抑制LTB（4）刺激皮肤所引发的各种炎症反应，同样呈现出剂量 - 反应关系。鉴于VML 295在个体人类受试者中的消除半衰期差异较大（25 - 88.5小时），本药理学研究旨在通过评估VML 295的血浆浓度、体外LTB（4）诱导的中性粒细胞CD11b上调、经皮应用LTB（4）后皮肤中的中性粒细胞积聚以及标准化表面创伤后的表皮再生，来提供该药物的药效学信息。一组36名健康志愿者在一项双盲研究中接受治疗，分别给予每日两次200毫克的VML 295、每日一次200毫克的VML 295或安慰剂，持续7天。在治疗前、治疗结束时以及治疗中断后，评估VML 295的血浆浓度和血液中性粒细胞的CD11b上调情况。在18名受试者中，在治疗前和治疗结束时评估这三种治疗对LTB（4）诱导的炎症的影响，在其余18名受试者中，同样评估这些治疗对表皮再生的影响。每日两次或每日一次200毫克的VML 295对体外LTB（4）诱导的血液中性粒细胞CD11b上调、LTB（4）诱导的皮肤中性粒细胞积聚、创伤诱导的表皮过度增殖和再生性角化均有显著抑制作用。在停止VML 295治疗24小时后采集的血样中，每日两次给药方案在降低体外中性粒细胞CD11b刺激方面显著比每日一次给药方案更有效。每日两次给药方案在皮肤活检中往往更有效，尽管在所研究的受试者数量上这种差异无统计学意义。血浆浓度达到100纳克/毫升被证明是产生这些效应的阈值。VML 295在全身和皮肤方面均具有显著的生物学效应以及安全性，使其成为一种有前景的药物，可用于治疗以表皮增殖和中性粒细胞积聚为特征的皮肤疾病。
