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

Article Type

Changed

Tue, 05/07/2019 - 15:16

Display Headline

Author(s)

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:

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.
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.

Data published on the NO-np’s preclinical efficacy for the treatment of acne, infected excisions, and burn wounds were presented in 2 of my lectures at the AAD (Nanotechnology and Immunomodulators [F085] and Antimicrobial Dressings: Silver and Beyond [S056])(Chouake et al [J Drugs Dermatol. 2012;11:1471-1477]; Friedman et al [Virulence. 2011;2:217-221]; Han et al [PLoS One. 2009;4:e7804]; Marcherla et al [Front Microbiol. 2012;3:193]; Martinez et al [J Invest Dermatol. 2009;129:2463-2469]; Qin et al [J Invest Dermatol. 2015;135:2723-2731]; Blecher et al [Nanomedicine. 2012;8:1364-1371]). These data can be found within the suggested reading below.

What’s the issue?

Know the awesome biological power of NO. Know the differences between delivery systems, including donors and generators. Know the differences in therapeutic relevance, including efficacy and safety.

Do you know NO?

We want to know your views! Tell us what you think.

Suggested Readings

Multidrug-Resistant Bacterial and Fungal Skin and Soft Tissue Infections

Ahmadi M, Lee H, Sanchez D, et al. Sustained nitric oxide releasing nanoparticles induce cell death in Candida albicans yeast and hyphal cells preventing biofilm formation in vitro and in a rodent central venous catheter model. Antimicrob Agents Chemother. 2016;60:2185-2194.
Chouake J, Schairer D, Kutner A, et al. Nitrosoglutathione generating nitric oxide nanoparticles as an improved strategy for combating Pseudomonas aeruginosa–infected wounds. J Drugs Dermatol. 2012;11:1471-1477.
Friedman A, Blecher K, Sanchez D, et al. Susceptibility of gram positive and negative bacteria to novel nitric oxide-releasing nanoparticle technology. Virulence. 2011;2:217-221.
Friedman A, Blecher K, Schairer D, et al. Improved antimicrobial efficacy with nitric oxide releasing nanoparticle generated S-nitrosoglutathione. Nitric Oxide. 2011;25:381-386.
Han G, Martinez LM, Mihu MR, et al. Nitric oxide releasing nanoparticles are therapeutic for Staphylococcus aureus abscesses in murine model of infection. PLoS One. 2009;4:e7804.
Landriscina A, Rosen J, Blecher-Paz K, et al. Nitric oxide-releasing nanoparticles as a treatment for cutaneous dermatophyte infections. Sci Lett. 2015,4:193.
Marcherla C, Sanchez DA, Ahmadi M, et al. Nitric oxide releasing nanoparticles for the treatment of Candida albicans burn infections [published online June 8, 2012]. Front Microbiol. 2012;3:193.
Martinez L, Han G, Chacko M, et al. Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infections. J Invest Dermatol. 2009;129:2463-2469.
Mihu MR, Sandkovsky U, Han G, et al. The use of nitric oxide releasing nanoparticles as a treatment against Acinetobacter baumannii in wound infections. Virulence. 2010;1:62-67.
Mordorski B, Pelgrift R, Adler B, et al. S-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology. Nanomedicine. 2015;11:283-291.
Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles prevent Propionibacterium acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. 2015;135:2723-2731.
Schairer D, Martinez L, Blecher K, et al. Nitric oxide nanoparticles: pre-clinical utility as a therapeutic for intramuscular abscesses. Virulence. 2012;3:1-6.

Wound Healing

Blecher K, Martinez LR, Tuckman-Vernon C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing in NOD-SCID mice. Nanomedicine. 2012;8:1364-1371.
Han G, Nguyen LN, Macherla C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing by promoting fibroblast migration and collagen deposition. Am J Pathol. 2012;180:1465-1473.

Erectile Dysfunction

Han G, Tar M, Kuppam DS, et al. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction [published online September 18, 2009. J Sex Med. 2010;7(1 pt 1):224-333.
Tar M, CabralesP, Navati M, et al. Topically applied NO-releasing nanoparticles can increase intracorporal pressure and elicit spontaneous erections in a rat model of radical prostatectomy. J Sex Med. 2014;11:2903-2914.

Cardiovascular Disease

Cabrales P, Han G, Nacharaju P, et al. Reversal of hemoglobin-induced vasoconstriction with sustained release of nitric oxide [published online November 5, 2010]. Am J Physiol Heart Circ Physiol. 2011;300:H49-H56.
Cabrales P, Han G, Roche C, et al. Sustained release nitric oxide from long-lived circulation nanoparticles. Free Radic Biol Med. 2010;49:530-538.
Nacharaju P, Friedman AJ, Friedman JM, et al. Exogenous nitric oxide prevents collapse during hemorrhagic shock. Resuscitation. 2011;82:607-613.

Safety of NO Donors

Friedman A, Friedman JM. Novel biomaterials for the sustained release of nitric oxide: past, present, and future. Expert Opin Drug Deliv. 2009;6:1113-1122.
Liang H, Nacharaju P, Friedman A, et al. Nitric oxide generating/releasing materials. Future Sci OA. 2015;1. doi:10.4155/fso.15.54.
Saavedra JE, Billiar TR, Williams DL, et al. Targeting nitric oxide (NO) delivery in vivo. design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. J Med Chem. 1997;40:1947-1954.

Author and Disclosure Information

Dr. Friedman is Associate Professor of Dermatology, Residency Program Director, and Director of Translational Research at the George Washington School of Medicine and Health Sciences, Washington, DC.

Dr. Friedman is coinventor of the NO-np technology described in this post, which is being developed by Nano Biomed, Inc.

Publications

Topics

Legacy Keywords

acne vulgaris, nitric oxide, NO, acne, AAD, American Academy of Dermatology

Sections

Author(s)

Author(s)

Author and Disclosure Information

Dr. Friedman is Associate Professor of Dermatology, Residency Program Director, and Director of Translational Research at the George Washington School of Medicine and Health Sciences, Washington, DC.

Dr. Friedman is coinventor of the NO-np technology described in this post, which is being developed by Nano Biomed, Inc.

Author and Disclosure Information

Dr. Friedman is Associate Professor of Dermatology, Residency Program Director, and Director of Translational Research at the George Washington School of Medicine and Health Sciences, Washington, DC.

Dr. Friedman is coinventor of the NO-np technology described in this post, which is being developed by Nano Biomed, Inc.

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:

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.
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.

Data published on the NO-np’s preclinical efficacy for the treatment of acne, infected excisions, and burn wounds were presented in 2 of my lectures at the AAD (Nanotechnology and Immunomodulators [F085] and Antimicrobial Dressings: Silver and Beyond [S056])(Chouake et al [J Drugs Dermatol. 2012;11:1471-1477]; Friedman et al [Virulence. 2011;2:217-221]; Han et al [PLoS One. 2009;4:e7804]; Marcherla et al [Front Microbiol. 2012;3:193]; Martinez et al [J Invest Dermatol. 2009;129:2463-2469]; Qin et al [J Invest Dermatol. 2015;135:2723-2731]; Blecher et al [Nanomedicine. 2012;8:1364-1371]). These data can be found within the suggested reading below.

What’s the issue?

Know the awesome biological power of NO. Know the differences between delivery systems, including donors and generators. Know the differences in therapeutic relevance, including efficacy and safety.

Do you know NO?

We want to know your views! Tell us what you think.

Suggested Readings

Multidrug-Resistant Bacterial and Fungal Skin and Soft Tissue Infections

Ahmadi M, Lee H, Sanchez D, et al. Sustained nitric oxide releasing nanoparticles induce cell death in Candida albicans yeast and hyphal cells preventing biofilm formation in vitro and in a rodent central venous catheter model. Antimicrob Agents Chemother. 2016;60:2185-2194.
Chouake J, Schairer D, Kutner A, et al. Nitrosoglutathione generating nitric oxide nanoparticles as an improved strategy for combating Pseudomonas aeruginosa–infected wounds. J Drugs Dermatol. 2012;11:1471-1477.
Friedman A, Blecher K, Sanchez D, et al. Susceptibility of gram positive and negative bacteria to novel nitric oxide-releasing nanoparticle technology. Virulence. 2011;2:217-221.
Friedman A, Blecher K, Schairer D, et al. Improved antimicrobial efficacy with nitric oxide releasing nanoparticle generated S-nitrosoglutathione. Nitric Oxide. 2011;25:381-386.
Han G, Martinez LM, Mihu MR, et al. Nitric oxide releasing nanoparticles are therapeutic for Staphylococcus aureus abscesses in murine model of infection. PLoS One. 2009;4:e7804.
Landriscina A, Rosen J, Blecher-Paz K, et al. Nitric oxide-releasing nanoparticles as a treatment for cutaneous dermatophyte infections. Sci Lett. 2015,4:193.
Marcherla C, Sanchez DA, Ahmadi M, et al. Nitric oxide releasing nanoparticles for the treatment of Candida albicans burn infections [published online June 8, 2012]. Front Microbiol. 2012;3:193.
Martinez L, Han G, Chacko M, et al. Antimicrobial and healing efficacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infections. J Invest Dermatol. 2009;129:2463-2469.
Mihu MR, Sandkovsky U, Han G, et al. The use of nitric oxide releasing nanoparticles as a treatment against Acinetobacter baumannii in wound infections. Virulence. 2010;1:62-67.
Mordorski B, Pelgrift R, Adler B, et al. S-nitrosocaptopril nanoparticles as nitric oxide-liberating and transnitrosylating anti-infective technology. Nanomedicine. 2015;11:283-291.
Qin M, Landriscina A, Rosen JM, et al. Nitric oxide-releasing nanoparticles prevent Propionibacterium acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response. J Invest Dermatol. 2015;135:2723-2731.
Schairer D, Martinez L, Blecher K, et al. Nitric oxide nanoparticles: pre-clinical utility as a therapeutic for intramuscular abscesses. Virulence. 2012;3:1-6.

Wound Healing

Blecher K, Martinez LR, Tuckman-Vernon C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing in NOD-SCID mice. Nanomedicine. 2012;8:1364-1371.
Han G, Nguyen LN, Macherla C, et al. Nitric oxide-releasing nanoparticles accelerate wound healing by promoting fibroblast migration and collagen deposition. Am J Pathol. 2012;180:1465-1473.

Erectile Dysfunction

Han G, Tar M, Kuppam DS, et al. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction [published online September 18, 2009. J Sex Med. 2010;7(1 pt 1):224-333.
Tar M, CabralesP, Navati M, et al. Topically applied NO-releasing nanoparticles can increase intracorporal pressure and elicit spontaneous erections in a rat model of radical prostatectomy. J Sex Med. 2014;11:2903-2914.

Cardiovascular Disease

Cabrales P, Han G, Nacharaju P, et al. Reversal of hemoglobin-induced vasoconstriction with sustained release of nitric oxide [published online November 5, 2010]. Am J Physiol Heart Circ Physiol. 2011;300:H49-H56.
Cabrales P, Han G, Roche C, et al. Sustained release nitric oxide from long-lived circulation nanoparticles. Free Radic Biol Med. 2010;49:530-538.
Nacharaju P, Friedman AJ, Friedman JM, et al. Exogenous nitric oxide prevents collapse during hemorrhagic shock. Resuscitation. 2011;82:607-613.

Safety of NO Donors

Friedman A, Friedman JM. Novel biomaterials for the sustained release of nitric oxide: past, present, and future. Expert Opin Drug Deliv. 2009;6:1113-1122.
Liang H, Nacharaju P, Friedman A, et al. Nitric oxide generating/releasing materials. Future Sci OA. 2015;1. doi:10.4155/fso.15.54.
Saavedra JE, Billiar TR, Williams DL, et al. Targeting nitric oxide (NO) delivery in vivo. design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. J Med Chem. 1997;40:1947-1954.

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:

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.
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.

Data published on the NO-np’s preclinical efficacy for the treatment of acne, infected excisions, and burn wounds were presented in 2 of my lectures at the AAD (Nanotechnology and Immunomodulators [F085] and Antimicrobial Dressings: Silver and Beyond [S056])(Chouake et al [J Drugs Dermatol. 2012;11:1471-1477]; Friedman et al [Virulence. 2011;2:217-221]; Han et al [PLoS One. 2009;4:e7804]; Marcherla et al [Front Microbiol. 2012;3:193]; Martinez et al [J Invest Dermatol. 2009;129:2463-2469]; Qin et al [J Invest Dermatol. 2015;135:2723-2731]; Blecher et al [Nanomedicine. 2012;8:1364-1371]). These data can be found within the suggested reading below.

What’s the issue?

Know the awesome biological power of NO. Know the differences between delivery systems, including donors and generators. Know the differences in therapeutic relevance, including efficacy and safety.

Do you know NO?

We want to know your views! Tell us what you think.

User login