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Get to Know NO: Deconstructing the Data on Nitric Oxide–Releasing Technologies for Acne

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In addition to the standard fare at the 74th Annual Meeting of the American Academy of Dermatology (AAD) in Washington, DC (March 4–8, 2016), this year there were several lectures addressing the use of nitric oxide (NO) for the treatment of acne. Therefore, I would like to review how NO gets delivered and the therapeutic implications as well as provide some context and understanding of the varying NO delivery systems being investigated.

Let’s start with some basics: Why should we even consider NO, a diatomic lipophilic gaseous molecule, for acne? It may be a surprise, but you already use NO for this purpose.

  • NO is produced on the surface of the skin by action of commensal bacteria and plays a physiologic role in inhibition of infection by pathogenic organisms including bacteria, fungi, and viruses, and a microbicidal role against Propionibacterium acnes.
  • NO minimizes inflammation by inhibiting neutrophil chemotaxis; production of lipases by P acnes (minimizes production of immunogenic free fatty acids); production of multiple cytokines such as tumor necrosis factor α, IL-8, and IL-6; antigen-presenting cell recognition of P acnes; and multiple elements of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome, the specific inflammasome reported to be impressively activated when monocytes, and even sebocytes, are exposed to P acnes, thereby inhibiting the conversion of pro–IL-1β to IL-1β.

However, NO’s direct biological action is not enough to explain these effects. It is S-nitrosylation, the covalent modification of a protein cysteine thiol by a NO group to generate an S-nitrosothiol such as nitrosoglutathione, that explains NO’s potent modulation of gene expression and enzymatic functions.

Nitric oxide was first featured in the late-breaking research session presented by Lawrence F. Eichenfield, MD, at the AAD (Efficacy and Safety of SB204 Gel in the Treatment of Acne Vulgaris)(F053). Results were presented from a phase 2b, multicenter, randomized, double-blind study comparing the efficacy, safety, and tolerability of SB204 NO-releasing gel 4% to vehicle in participants with acne vulgaris. The investigators concluded that SB204 once daily was safe and effective for the treatment of acne vulgaris, though they did not present data on the technology itself.

The NO-releasing technology being used in SB204 is an NO donor that falls under a class of NO donors called the diazeniumdiolates, or NONOates, which have been used experimentally for more than 50 years. These compounds consist of a diolate group (N[O-]N=O) bound to a nucleophile adduct (a primary or secondary amine or polyamine) by means of a nitrogen atom. Thus, you have NO bound to a donor that under appropriate environmental conditions will release its NO following first-order kinetics. It simply releases NO, rather then generate or create it.

Two issues are to be raised in relation to Dr. Eichenfield’s presentation:

  1. The anti-inflammatory mechanism data cited in the study by Qin et al and discussed was not generated using the NONOate SB204.

    Here is the most important point to be made: Not all NO-releasing platforms are created equal. The technology used to demonstrate the anti-inflammatory impact of NO, specifically inhibition of IL-1β through the NLRP3 inflammasome, was a different platform than SB204, and one I developed at the Albert Einstein College of Medicine (Bronx, New York) and is currently under development. This NO generator, as opposed to donor, has been shown to uniquely facilitate the formation of NO from nitrite salt through a stable and potent NO intermediate N2O3 (designated NO-np).

    N2O3 can effectively facilitate trans-nitrosylation under both aerobic and anaerobic conditions, a feat my research group has found that NONOates cannot accomplish. It is both NO and its effect when placed on cellular thiols that together generate its biological impact. Therefore, it cannot be assumed that efficacy data produced from the use of NO-np would result from using any NONOate.

  2. A highlight of this presentation was safety. First, a reality check: When do we ever use a topical agent for only 12 weeks, as in the study discussed by Dr. Eichenfield? In fact, given the mechanism by which NO exerts its anti-inflammatory activity, the efficacy will be short-lived and require continued use.

Accumulation of amines and their metabolites released from NONOates have been shown to induce cytotoxicity in a study by Saavedra et al (J Med Chem. 1997;40:1947-1954). In the study by Blecher et al (Nanomedicine. 2012;8:1364-1371), topical application of DETA (diethylenetriamine) NONOate, another type of NONOate, actually delayed wound closure in NOD-SCID (nonobese diabetic severe combined immunodeficiency) mice as compared to untreated controls in a study by Blecher et al. Systemic infusion at concentrations required to reduce blood pressure resulted in methemoglobinemia and diminished oxygen-carrying capacity in a study by Cabrales et al (Free Radic Biol Med. 2010;49:530-538). The NONOate utilized in SB204 is encapsulated in a hydrogel particle to prevent permeation of said metabolites and donor compounds through the skin; however, a 12-week safety evaluation is certainly not long enough to determine whether local or systemic absorption has occurred. Of note, the NO-np has undergone extensive safety testing from cell culture of embryonic zebra fish to Syrian hamsters and even pigs showing no significant toxicity at any of the effective concentrations in animal studies.

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