The ability of NO to inhibit IL-1β production and modulate Th-17 activity appear to be the most strongly supported anti-in ammatory modes of action in acne treatment based on available literature. Figure 1 summarizes acne pathophysiology and the modes of action of NO that are likely to be operative in acne treatment. Evidence supporting the therapeutic bene t of topically applied NO has been confirmed in a Phase 2 ef cacy and safety, dose-ranging, vehicle-controlled, randomized, 12-week study in subjects greater than 12 years of age with mild, moderate, or severe acne. This study utilized a 1% (n=51) or a 4% (n=50) topical gel formulation (SB204), applied twice daily, of a NO- releasing macromolecule comprised of N-diazeniumdiolate NO donors covalently bound to a polysiloxane backbone.14 This topical formulation is designed to release NO in a high- flux burst, similar to what occurs with iNOS activity. A prior pharmacokinetic (PK) study of systemic exposure to a higher concentration of the same topically applied formulation (SB204 8%) applied twice daily over 17% body surface area for 5 days showed no detectable parent compound nor increase in plasma nitrate concentrations and no alterations in hema- tologic indices, methemoglobin levels, or chemistry panels as compared to vehicle gel.38 The details of the Phase 2 study efficacy and safety study are published elsewhere, and utilized recognized study methodologies including inclusion criteria, exclusion criteria, washout periods, and assessment param- eters of ef cacy, tolerability, and safety. Figures 2 shows that both concentrations were effective and safe, with the 4% topical NO-releasing gel signi cantly reducing both inflammatory and non-in ammatory (comedonal) acne lesions as compared to vehicle; tolerability and safety were also favorable with both active concentrations.14 What Concluding Statements Can Be Made About Nitric Oxide and Its Potential for Therapeutic Applications in Dermatology Based on the Information Discussed and Literature Review? NO is an endogenously produced compound that exhib- its several biologic properties including antimicrobial and immunolmodulatory effects that may have application for management of skin disorders, including cutaneous infections, in ammatory disorders, and wound healing. The physiologic characteristics of NO, a diatomic gas, provide challenges related to stability and delivery that require creative and novel formulation approaches. NO application continues to be evaluated using a variety of delivery platforms, mostly topical approaches. A recent Phase 2 randomized, vehicle-controlled study of patients with acne has demonstrated ef cacy and safety with twice daily application over 12 weeks of a topical NO-releasing gel that incorporates NO donors into a macromolecule formulation stabilized both or container storage and activation when released for topical application. The major modes of action of topical NO that have been shown to inhibit acne pathophysiology are both antimicrobial (reduction in P acnes) and anti-inflammatory (decreased expression of IL-1β through in ammasome inhibition). Other immunoregulatory effects are also suggested as reviewed above. NO may provide a unique approach to acne treatment through inhibi- tion of IL-1β andTh17 activation. Microbial resistance to NO has not been demonstrated with high delivery concentrations provided with exogenous application. The antimicrobial modes of action of NO and its derivatives are diverse and cytotoxic with capability to inhibit many microbial pathogens, including several that are related to skin disorders (ie, P acnes, staphylococci, streptococci, dermatophytes, C albi- cans). This is very relevant clinically as avoidance of antibiotic resistance is a major issue, especially in dermatology where common skin disorders (ie, acne, rosacea) are often treated with prolonged antibiotic therapy.
Dr. Del Rosso: Anacor (consultant, speaker); Amgen (research); Aqua/Almirall (consultant, speaker); Bayer Dermatology (con- sultant, speaker, research); BioPharmX (consultant, research); Celgene (consultant, speaker, research); Cutanea (research); Dermira (consultant, research); Foamix (consultant, research); Ferndale (consultant, speaker); Galderma (consultant, speaker, research); Genentech (speaker); LeoPharma (consultant, speaker, research); Novan Inc (consultant, research); Novartis (consul- tant, speaker); Pharmaderm (consultant, speaker); Promius (consultant, speaker, research); Sebacia (consultant, research); SunPharma (consultant, speaker, research); Taro (speaker); Vale- ant (consultant, speaker, research), Viamet (consultant). Dr. Kircik: Allergan (consultant, investigator, speaker); Allmirall (consultant); Bayer (consultant, investigator, speaker); Gal- derma (consultant, investigator, speaker); Dermira (consultant, investigator); Novan (consultant, investigator); Foamix (con- sultant); Valeant (consultant, investigator, speaker); Promius (consultant, investigator, speaker); Sun Pharma (consultant, investigator).