Pharmacological Effects of a Specific Leukotriene B₄ Receptor Antagonist (VML 295) on Blood Leukocytes, Cutaneous Inflammation and Epidermal Proliferation

Abstract

VML 295 (LY 293111) is a potent and specific leukotriene₄ 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 B₄ (LTB₄)-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 LTB₄ 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 LTB₄-induced CD11b upregulation of neutrophils, neutrophil accumulation in the skin following epicutaneous application of LTB₄ 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 LTB₄-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 LTB₄-induced CD11b upregulation of blood neutrophils, LTB₄-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.

Time- and dose-dependent analysis of gene expression using microarrays in sulfur mustard-exposed mice

“…High-affinity LTB 4 receptors are on peripheral blood leukocytes as well as in the spleen and thymus, while low-affinity LTB 4 receptors are present on granulocytes and in the spleen [36]. The potent role of LTB 4 receptors in many different inflammatory diseases has led to the development of LTB 4 receptor antagonists as potential anti-inflammatory therapeutic treatments for pulmonary [37] and cutaneous [38][39][40] inflammatory states as well as immunosuppressive agents [41]. Such studies demonstrate that the LTB 4 receptor could be a potential target for therapeutic treatments for SMinduced skin injury.…”

Leukotriene receptor expression in esophageal squamous cell cancer and non-transformed esophageal epithelium: a matched case control study

“…LTB4R expression was observed to be increased in the proliferative zone of gastric epithelium [ 25 ]. Moreover, in a placebo controlled trial on human volunteers, the oral LTB4-receptor antagonist VML295 diminished the proliferative epidermal activity after traumatically induced skin lesions [ 26 ]. LTB4R showed an up-regulation in proliferative areas of esophageal mucosa as well, suggesting a role of this receptor for the proliferation of esophageal squamous epithelium.…”

VML 295 (LY-293111), a novel LTB4 antagonist, is not effective in the prevention of relapse in psoriasis

“… 30 Moreover, it has been shown that VML 295 is able to block the ex vivo LTB 4 ‐induced CD11b upregulation on peripheral blood PMNs of healthy volunteers treated orally for 10 days, 28 , 30 and that there is a strong dose‐relationship with respect to these effects, with a maximum effect seen on a 200‐mg twice a day regimen. 31 Because of these very marked effects, a double‐blind randomized study in psoriatic patients was performed. 32 This study, in which patients with psoriasis were treated with VML 295 or placebo for 4 weeks, showed that VML 295 is a safe and well tolerated drug, with no evident side‐effects.…”