Tissue
inflammation is a major component of the
acne process.
Leukotriene B(4) (LTB(4)) is considered to be a major player in the development of tissue
inflammation. Synthesis of LTB(4) is controlled by the
enzyme 5-lipoxygenase. Since
Zileuton blocks the activity of
5-lipoxygenase, experimental and clinical studies have been conducted to test mode of function, as well as efficacy and safety of this compound in the treatment of
acne vulgaris. Human SZ95 sebocytes and inflammatory cells in vitro express the
enzymes of the
leukotriene pathway at
mRNA and
protein levels and
enzymes involved in the biosynthesis of LTB(4) are activated in sebaceous glands of
acne lesions. Pre-treatment of SZ95 sebocytes with
Zileuton partially prevented short-term
arachidonic acid-induced effects, such as induction of LTB(4), increase of neutral
lipid content and stimulation of interlekin-6 release. Long-term treatment with
Zileuton directly reduced the content of neutral
lipids and
interleukin-6 release from SZ95 seb ocytes.
PPAR mRNA levels were not regulated by
Zileuton. In a first pilot clinical study with 10 patients with papulopustular
acne Zileuton 4 x 600 mg/d p.o. for 3 months decreased the
acne severity index in a time-dependent manner being 41% of the initial score at week 12 (p < 0.05). This was mostly due to a decrease of the number of inflammatory lesions of 29% (p < 0.01). In addition, total sebum
lipids significantly decreased (35%, p < 0.05) and the pro-inflammatory
free fatty acids (22%) and
lipoperoxides (26%) were markedly diminished in patients' sebum under treatment. The magnitude of clinical improvement strongly correlated with the reduction of total sebum
lipids (p = 0.0009, r(2) = 0.81) and
free fatty acids (p = 0.0003, r(2) = 0.82). In a further study, a 40-year-old female with mild disseminated sebaceous gland
hyperplasia and
seborrhea, responded with normalization of the casual skin surface
lipids and similar reduction of facial sebum synthesis under treatment with
Zileuton over 2weeks and-after a wash-out phase-low-dose
isotretinoin (10 mg/2nd d) over 5 weeks. These data are in agreement with a phase II multicenter, clinical study in 101 patients with mild to moderate inflammatory facial
acne conducted in the US, which showed a significant efficacy of
Zileuton in a subset of patients with moderate
acne, whereas those patients treated with
Zileuton showed a significant mean decrease in inflammatory lesions compared to the placebo group. In all clinical studies,
Zileuton was found to be safe and well tolerated.