Ademetionine in Different Combination Regimens to Treat Rosacea: Results from a Randomized, Prospective Clinical Trial

Introduction: Rosacea is characterized by transient or persistent facial erythema, telangiectasia, papules and pustules and is classified into 4 subtypes: erythematoteleangiectatic (stage I), papulopustular (stage II), phymatous (stage III), and ocular rosacea. Objective: The study assessed the efficacy of different combinations of oral and topical medications, combined or not with ademetionine, in rosacea. Methods: This randomized, open label, prospective and exploratory study was conducted in 110 healthy male subjects of at least 18 years of age with stage I, stage II or stage III rosacea. Efficacy and safety of different basic (BCR) and complex (basic regimen + ademetionine, CCR) combinations of oral and topical rosacea medications were assessed throughout histopathological, immunohistochemical and clinical methods. Results: Multiple combination regimens using topical and oral medications significantly improved stage I and stage II/III rosacea. Improvement on a histological, immunohistochemical and clinical level was significantly superior (p < 0.05) when ademetionine was added. Recurrence of stage I or stage II/III rosacea was significantly less frequent (p < 0.05) in patients who received the CCR treatment regimens. No systemic adverse event was observed. Irritation was reported in 9 patients in the stage I group during the first 3 to 7 days of application of azelaic acid 15% gel: 5 patients (16.7%) in the CCR group, and 4 patients (20%) in the BCR group. No local adverse events were reported in the stage II/III patient group. Conclusion: Ademetionine may be a sparring partner in the treatment of rosacea using combination treatments. *Corresponding author: Tetiana Sviatenko, Dnepropetrovsk Medical Academy, 1a 49000 Dniepropetrovsk, Ukraine, Tel: 056 735-20-35; E-mail: tsvyat@rambler.ru Citation: Sviatenko Т. V. , et al. Ademetionine in Different Combination Regimens to Treat Rosacea: Results from a Randomized, Prospective Clinical Trial. (2016) Invest Dermatol Venereol Res 2(2): 16. Ademetionine in Different Combination Regimens to Treat Rosacea: Results from a Randomized, Prospective Clinical Trial Sviatenko Т. V1*, Kharitonova О. G2, Starostina О. А3 Received date: January 21, 2016 Accepted date: February 9, 2016 Published date: February 13, 2016 DOI: 10.15436/2381-0858.16.758 Invest Dermatol Venereol Res | Volume 2: Issue 2 Sviatenko Т. V. , et al. 2 to favor the colonization and multiplication of Demodex folliculorum which has been cited to cause inflammation in papules and pustules as well asgranulomas[9]. But, dysregulation of the microbiome and over-colonization by D. folliculorum may also influence the balanced presence of other microbes present on the skin. In this perspective, the role of Bacillus oleronius and Helibiobacterium pylori has been extensively reviewed by Yamasaki and Gallo in 2009[8]. In their review, the authors reported that B.oleronius was isolated from D. folliculorum and that the antigens reacting to sera from rosacea individuals but not from control individuals could be identified[10]. The extracts of the B.oleronius stimulated proliferation of mononuclear cells from patients with rosacea suggesting that rosacea individuals are exposed to the B.oleronius molecules and that B.oleronius from D. folliculorum induces inflammatory in rosacea. Conversely, the correlation of H. pylori infection and rosacea is controversial and inconsistent among clinical observation[11-14]. Several reports showed seropositivity to H. pylori in rosacea individuals. Eradication therapy for gastric H. pylori infection showed preferable outcome for rosacea symptoms though it is not clear if the improve of rosacea is due to H. pylori eradication[15-17]. The authors further raised the hypothesis that innate immunity and stimulation of toll-like receptors (TLR) may be caused by D. folliculorum leading to inflammation of the skin tissues[8,18]. The development of rhinophyma, observed in stage III rosacea, remains poorly explained. The vascular abnormalities induce local production of transforming growth factor β1 (TGF-β1) capable of creating fibrosis and therefore cetaceous thickening[19]. Dissection of major players for disease progression is severely hindered by the complex activation of the innate and adaptive immune systems, enhanced neuroimmune communication, profound blood vessel and possibly lymphatic vessel changes, and activation of almost every resident cell in the skin[7,20]. Furthermore, elevated expression of vascular endothelial growth factor (VEGF) has been observed in the skin of patients with rosacea[21]. VEGF proliferates vascular endothelial cells as well as increase permeability of vessels. Rosacea is not an isolated skin disease. It has been reported to be associated with allergies (airborne, food), respiratory diseases, gastroesophageal reflux disease, other gastrointestinal diseases, hypertension, metabolic and urogenital diseases, and female hormone imbalance. Compared with mild rosacea (stage I), moderate to severe rosacea (stage II to III) was significantly associated with hyperlipidemia, hypertension, metabolic diseases, cardiovascular diseases, and gastroesophageal reflux disease[22]. Each subtype requires a different therapeutic approach[3-5]. Today, the management of rosacea is largely based on long-established treatments empirically tailored to the specific presenting symptoms and no real breakthrough has occurred to date[23]. Topical treatments that are widely accepted are metronidazole and azelaic acid; agents under investigation that show promise include permethrin, calcineurin inhibitors and sulfur compounds. For systemic therapy, antibiotics (tetracyclines, macrolides) and recently doxycycline in anti-inflammatory rather than antimicrobial dosages are used, as well as isotretinoin in severe cases[24-26]. Furthermore, effective protection from UV light is recommended[26]. The present study was conducted to assess the efficacy of different combinations of oral and topical medications in rosacea using histopathological, immunohistochemical and clinical methods. Regimens were adapted to patients with stage I or stage II/III rosacea; patients with ocular rosacea were not considered for this study. Basic combination regimens (BCR) included diosmine, a venotonic, sulpiride, a neuroleptic and pimecrolimus, and a calcineurin inhibitor to treat stage I rosacea; doxycycline, considered as an anti-inflammatory drug at beyond the recommended doses, sulpiride, adapalene, a retinoid, clindamycin, an oral antibiotic and pimecrolimus were used for patients with stage II/III rosacea. Both groups were compared after 16 weeks to patients receiving a complex combination regimen (CCR) consisting of the BCR treatment to which ademetionine, shown to regulate the vascular endothelial growth factor (VEGF) in cancer, was added[27,28].