Pharmacological effects of a specific leukotriene B-4 receptor antagonist (VML 295) on blood leukocytes, cutaneous inflammation and epidermal proliferation

VML 295 (LY 293111) is a potent and specific leukotriene(4) receptor antago nist. It has previously been shown in human volunteers that VML 295 at a do sage of 48 mg twice daily inhibits the ex vivo leukotriene B-4 (LTB4)-induc ed upregulation of CD11b on peripheral blood neutrophils. A clear dose-resp onse relatinship was shown. In addition, VML 295 inhibits various inflammat ory aspects resulting from LTB4 challenge of the skin, again showing a dose -response relationship. in view of the large variation in the elimination h alf-life of VML 295 (25-88.5 h) in individual human subjects, the present p harmacological study was designed to provide information on the pharmacodyn amics of the drug by the assessment of VML 295 plasma concentrations, ex vi vo LTB4-induced CD11b upregulation of neutrophils, neutrophil accumulation in the skin following epicutaneous application of LTB4 and epidermal regene ration following standardized surface trauma. A group of 36 healthy volunte ers 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 pl asma concentrations and CD11b upregulation of blood neutrophils were assess ed. In 18 subjects, the effects of the three treatments on LTB4-induced inf lammatory were assessed before and at the end of treatment, and in the rema ining 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 LTB4-induced CD11b upregulation of blood neutrophils, LTB4-induced neutrophil accumulation in the skin, trauma -induced hyperproliferation of the epidermis and regenerative keratinizatio n. 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. T he twice daily schedule tended to be more efficient in skin biopsies, altho ugh this difference was not statistically significant in the number of subj ects investigated. A plasma concentration of 100 ng/ml proved to be the thr eshold for these effects. The profound biological effects, both systemicall y and cutaneously, as well as the safety profile, make VML 295 a promising drug for skin disorders characterized by epidermal proliferation and neutro phil accumulation. Copyright (C) 2000 S. Karaer AG. Basel.