Adam Friedman, MD

As a chronic inflammatory skin disease well known for its poor cosmesis including scarring, residual macular erythema, and postinflammatory pigment alteration, acne vulgaris may, according to recent research, confer some antiaging benefits to affected patients. In a research letter published online on September 27 in the Journal of Investigative Dermatology, Ribero et al analyzed white blood cells and found that women who said they had acne had longer telomeres (the "caps" at the end of chromosomes that protect them from deteriorating following repeated cell replication). Telomere length, or rather shortening, has been correlated with age-related degenerative change, according to Saum et al (Exp Gerontol. 2014;58:250-255), and therefore the thinking is that in women with acne, something is going on that maintains the length of the cellular guardians. Let's clarify a couple things to help us all understand the why and what.

The impetus of this study, according to Ribero et al, was the observation that women with acne show signs of aging later than those who have never had acne. I personally have not witnessed this finding in my patients, and given that acne in its essence is a disease of chronic inflammation resulting from, for example, persistent activation of toll-like receptor 2 (TLR2) and NOD-like receptor family pyrin domain containing 3 (NLRP3) pattern recognition receptors, one would think the skin damage accrued would make these individuals look older, right? Last I checked, pitted scarring does not make one immediately think of the fountain of youth.

The results from the study show that there is a link between acne and longer telomeres, but the study did not show that telomere length is a cause of acne, that women with longer telomeres had fewer signs of skin aging, or that women with acne lived longer.

Given these points, Ribero et al concluded that "delayed skin aging may be due to reduced senescence," which means that skin aging may be delayed because the longer telomeres in the cells protect them from deterioration. They did find that the expression of one gene in particular was reduced in women with acne--the regulatory gene zinc finger protein 420, ZNF420--suggesting that those without acne may produce more of a particular protein linked to that gene, though the significance is unclear.

What's the issue?

This study is interesting, but it is important not to make any broad conclusions, such as those who get acne will live longer or look younger longer regardless of other factors such as acne treatment, comorbidities, or even environmental factors. This study may give more support for the genetic contribution of acne, but much more work is needed to determine the clinical relevance. For starters, what about men?

Would you assure your acne patients that their disease may be for their own cosmetic good?

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

As a chronic inflammatory skin disease well known for its poor cosmesis including scarring, residual macular erythema, and postinflammatory pigment alteration, acne vulgaris may, according to recent research, confer some antiaging benefits to affected patients. In a research letter published online on September 27 in the Journal of Investigative Dermatology, Ribero et al analyzed white blood cells and found that women who said they had acne had longer telomeres (the "caps" at the end of chromosomes that protect them from deteriorating following repeated cell replication). Telomere length, or rather shortening, has been correlated with age-related degenerative change, according to Saum et al (Exp Gerontol. 2014;58:250-255), and therefore the thinking is that in women with acne, something is going on that maintains the length of the cellular guardians. Let's clarify a couple things to help us all understand the why and what.

The impetus of this study, according to Ribero et al, was the observation that women with acne show signs of aging later than those who have never had acne. I personally have not witnessed this finding in my patients, and given that acne in its essence is a disease of chronic inflammation resulting from, for example, persistent activation of toll-like receptor 2 (TLR2) and NOD-like receptor family pyrin domain containing 3 (NLRP3) pattern recognition receptors, one would think the skin damage accrued would make these individuals look older, right? Last I checked, pitted scarring does not make one immediately think of the fountain of youth.

The results from the study show that there is a link between acne and longer telomeres, but the study did not show that telomere length is a cause of acne, that women with longer telomeres had fewer signs of skin aging, or that women with acne lived longer.

Given these points, Ribero et al concluded that "delayed skin aging may be due to reduced senescence," which means that skin aging may be delayed because the longer telomeres in the cells protect them from deterioration. They did find that the expression of one gene in particular was reduced in women with acne--the regulatory gene zinc finger protein 420, ZNF420--suggesting that those without acne may produce more of a particular protein linked to that gene, though the significance is unclear.

What's the issue?

This study is interesting, but it is important not to make any broad conclusions, such as those who get acne will live longer or look younger longer regardless of other factors such as acne treatment, comorbidities, or even environmental factors. This study may give more support for the genetic contribution of acne, but much more work is needed to determine the clinical relevance. For starters, what about men?

Would you assure your acne patients that their disease may be for their own cosmetic good?

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

As a chronic inflammatory skin disease well known for its poor cosmesis including scarring, residual macular erythema, and postinflammatory pigment alteration, acne vulgaris may, according to recent research, confer some antiaging benefits to affected patients. In a research letter published online on September 27 in the Journal of Investigative Dermatology, Ribero et al analyzed white blood cells and found that women who said they had acne had longer telomeres (the "caps" at the end of chromosomes that protect them from deteriorating following repeated cell replication). Telomere length, or rather shortening, has been correlated with age-related degenerative change, according to Saum et al (Exp Gerontol. 2014;58:250-255), and therefore the thinking is that in women with acne, something is going on that maintains the length of the cellular guardians. Let's clarify a couple things to help us all understand the why and what.

The impetus of this study, according to Ribero et al, was the observation that women with acne show signs of aging later than those who have never had acne. I personally have not witnessed this finding in my patients, and given that acne in its essence is a disease of chronic inflammation resulting from, for example, persistent activation of toll-like receptor 2 (TLR2) and NOD-like receptor family pyrin domain containing 3 (NLRP3) pattern recognition receptors, one would think the skin damage accrued would make these individuals look older, right? Last I checked, pitted scarring does not make one immediately think of the fountain of youth.

The results from the study show that there is a link between acne and longer telomeres, but the study did not show that telomere length is a cause of acne, that women with longer telomeres had fewer signs of skin aging, or that women with acne lived longer.

Given these points, Ribero et al concluded that "delayed skin aging may be due to reduced senescence," which means that skin aging may be delayed because the longer telomeres in the cells protect them from deterioration. They did find that the expression of one gene in particular was reduced in women with acne--the regulatory gene zinc finger protein 420, ZNF420--suggesting that those without acne may produce more of a particular protein linked to that gene, though the significance is unclear.

What's the issue?

This study is interesting, but it is important not to make any broad conclusions, such as those who get acne will live longer or look younger longer regardless of other factors such as acne treatment, comorbidities, or even environmental factors. This study may give more support for the genetic contribution of acne, but much more work is needed to determine the clinical relevance. For starters, what about men?

Would you assure your acne patients that their disease may be for their own cosmetic good?

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

Over the past few years there have been studies published that support a relationship between acne and nutritional factors. Most suggest that high-glycemic-load diets and milk/dairy consumption might promote the development or exacerbation of acne vulgaris. So, what’s the mechanism? Some investigators believe that a high-glycemic-index diet induces hyperinsulinemia, which in turn elicits endocrine responses such as increasing androgen synthesis, ultimately inducing acne through mediators such as androgens, insulinlike growth factor (IGF) 1, and IGF binding protein 3. Insulinlike growth factor 1 itself can induce keratinocyte proliferation, sebocyte proliferation, and sebum production. We know that acne can be related to some endocrine diseases, such as polycystic ovary syndrome, which is characterized by peripheral insulin resistance and hyperinsulinemia, as well as acne, hirsutism, and androgenic alopecia.

In a study published by Çerman et al (J Am Acad Dermatol. 2016;75:155-162), investigators aimed to support the relationship between acne and diet and proposed that adiponectin levels, an adipocyte-derived hormone with established anti-inflammatory, antioxidant, and antidiabetic effects, are inversely associated with glycemic intake. Adiponectin inhibits proinflammatory cytokines, downregulates adhesion molecule expression, suppresses toll-like receptors and their ligands, and increases insulin sensitivity. In this small study of 50 patients with acne matched to 36 healthy controls, mean (SD) serum adiponectin concentrations were significantly lower in the patients with acne vulgaris than in the healthy controls (9.93 [2.29] ng/mL^_1 vs 11.28 [2.74] ng/mL^_1; P=.015), though milk and dairy product consumption, serum glucose, insulin, IGF-1, IGF binding protein 3, and homeostasis model assessment of insulin resistance values of the acne vulgaris and control groups did not differ significantly. The authors argued that this finding supports low-glycemic-load diets given the inverse correlation with adiponectin concentrations.

For every promising study comes one that may refute it. A study published online in February 2016 in Human & Experimental Toxicology aimed to evaluate several adipokines (adipocyte-derived cytokines) such as leptin, adiponectin, ghrelin and adiponectin levels, and adiponectin and leptin rates that indicate insulin resistance in nonobese patients with severe acne vulgaris. Although this study was smaller (30 acne patients and 15 controls), investigators found no difference between the 2 groups for any of these adipokines. It is important to note that patients studied were nonobese, nondiabetic, and glycemic load was not taken into account, so it is possible that this correlation is more significant for patients with factors such as insulin resistance and obesity.

What’s the issue?

Regardless of these findings, we have enough evidence to support that eating poorly can worsen acne and have other effects on the body. Are we all in agreement with this conclusion? Eating poorly is bad for more than just acne. High glycemic load leads to a proinflammatory state. Think psoriasis here. Chronic inflammation is detrimental for every organ system. Therefore, in addition to focusing on the pathways and elucidating the biology, let’s also design curricula to train current and future dermatologists how to counsel patients on diet or at the very least create resources to enable us to guide our patients. I published a survey study (J Am Acad Dermatol. 2014;71:1028-1029) showing that dermatologists are not comfortable counseling patients, specifically psoriasis patients, on diet, smoking, and drinking alcohol. It is time to create these tools. Do you want these types of resources?

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

Over the past few years there have been studies published that support a relationship between acne and nutritional factors. Most suggest that high-glycemic-load diets and milk/dairy consumption might promote the development or exacerbation of acne vulgaris. So, what’s the mechanism? Some investigators believe that a high-glycemic-index diet induces hyperinsulinemia, which in turn elicits endocrine responses such as increasing androgen synthesis, ultimately inducing acne through mediators such as androgens, insulinlike growth factor (IGF) 1, and IGF binding protein 3. Insulinlike growth factor 1 itself can induce keratinocyte proliferation, sebocyte proliferation, and sebum production. We know that acne can be related to some endocrine diseases, such as polycystic ovary syndrome, which is characterized by peripheral insulin resistance and hyperinsulinemia, as well as acne, hirsutism, and androgenic alopecia.

In a study published by Çerman et al (J Am Acad Dermatol. 2016;75:155-162), investigators aimed to support the relationship between acne and diet and proposed that adiponectin levels, an adipocyte-derived hormone with established anti-inflammatory, antioxidant, and antidiabetic effects, are inversely associated with glycemic intake. Adiponectin inhibits proinflammatory cytokines, downregulates adhesion molecule expression, suppresses toll-like receptors and their ligands, and increases insulin sensitivity. In this small study of 50 patients with acne matched to 36 healthy controls, mean (SD) serum adiponectin concentrations were significantly lower in the patients with acne vulgaris than in the healthy controls (9.93 [2.29] ng/mL^_1 vs 11.28 [2.74] ng/mL^_1; P=.015), though milk and dairy product consumption, serum glucose, insulin, IGF-1, IGF binding protein 3, and homeostasis model assessment of insulin resistance values of the acne vulgaris and control groups did not differ significantly. The authors argued that this finding supports low-glycemic-load diets given the inverse correlation with adiponectin concentrations.

For every promising study comes one that may refute it. A study published online in February 2016 in Human & Experimental Toxicology aimed to evaluate several adipokines (adipocyte-derived cytokines) such as leptin, adiponectin, ghrelin and adiponectin levels, and adiponectin and leptin rates that indicate insulin resistance in nonobese patients with severe acne vulgaris. Although this study was smaller (30 acne patients and 15 controls), investigators found no difference between the 2 groups for any of these adipokines. It is important to note that patients studied were nonobese, nondiabetic, and glycemic load was not taken into account, so it is possible that this correlation is more significant for patients with factors such as insulin resistance and obesity.

What’s the issue?

Regardless of these findings, we have enough evidence to support that eating poorly can worsen acne and have other effects on the body. Are we all in agreement with this conclusion? Eating poorly is bad for more than just acne. High glycemic load leads to a proinflammatory state. Think psoriasis here. Chronic inflammation is detrimental for every organ system. Therefore, in addition to focusing on the pathways and elucidating the biology, let’s also design curricula to train current and future dermatologists how to counsel patients on diet or at the very least create resources to enable us to guide our patients. I published a survey study (J Am Acad Dermatol. 2014;71:1028-1029) showing that dermatologists are not comfortable counseling patients, specifically psoriasis patients, on diet, smoking, and drinking alcohol. It is time to create these tools. Do you want these types of resources?

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

Over the past few years there have been studies published that support a relationship between acne and nutritional factors. Most suggest that high-glycemic-load diets and milk/dairy consumption might promote the development or exacerbation of acne vulgaris. So, what’s the mechanism? Some investigators believe that a high-glycemic-index diet induces hyperinsulinemia, which in turn elicits endocrine responses such as increasing androgen synthesis, ultimately inducing acne through mediators such as androgens, insulinlike growth factor (IGF) 1, and IGF binding protein 3. Insulinlike growth factor 1 itself can induce keratinocyte proliferation, sebocyte proliferation, and sebum production. We know that acne can be related to some endocrine diseases, such as polycystic ovary syndrome, which is characterized by peripheral insulin resistance and hyperinsulinemia, as well as acne, hirsutism, and androgenic alopecia.

In a study published by Çerman et al (J Am Acad Dermatol. 2016;75:155-162), investigators aimed to support the relationship between acne and diet and proposed that adiponectin levels, an adipocyte-derived hormone with established anti-inflammatory, antioxidant, and antidiabetic effects, are inversely associated with glycemic intake. Adiponectin inhibits proinflammatory cytokines, downregulates adhesion molecule expression, suppresses toll-like receptors and their ligands, and increases insulin sensitivity. In this small study of 50 patients with acne matched to 36 healthy controls, mean (SD) serum adiponectin concentrations were significantly lower in the patients with acne vulgaris than in the healthy controls (9.93 [2.29] ng/mL^_1 vs 11.28 [2.74] ng/mL^_1; P=.015), though milk and dairy product consumption, serum glucose, insulin, IGF-1, IGF binding protein 3, and homeostasis model assessment of insulin resistance values of the acne vulgaris and control groups did not differ significantly. The authors argued that this finding supports low-glycemic-load diets given the inverse correlation with adiponectin concentrations.

For every promising study comes one that may refute it. A study published online in February 2016 in Human & Experimental Toxicology aimed to evaluate several adipokines (adipocyte-derived cytokines) such as leptin, adiponectin, ghrelin and adiponectin levels, and adiponectin and leptin rates that indicate insulin resistance in nonobese patients with severe acne vulgaris. Although this study was smaller (30 acne patients and 15 controls), investigators found no difference between the 2 groups for any of these adipokines. It is important to note that patients studied were nonobese, nondiabetic, and glycemic load was not taken into account, so it is possible that this correlation is more significant for patients with factors such as insulin resistance and obesity.

What’s the issue?

Regardless of these findings, we have enough evidence to support that eating poorly can worsen acne and have other effects on the body. Are we all in agreement with this conclusion? Eating poorly is bad for more than just acne. High glycemic load leads to a proinflammatory state. Think psoriasis here. Chronic inflammation is detrimental for every organ system. Therefore, in addition to focusing on the pathways and elucidating the biology, let’s also design curricula to train current and future dermatologists how to counsel patients on diet or at the very least create resources to enable us to guide our patients. I published a survey study (J Am Acad Dermatol. 2014;71:1028-1029) showing that dermatologists are not comfortable counseling patients, specifically psoriasis patients, on diet, smoking, and drinking alcohol. It is time to create these tools. Do you want these types of resources?

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

The Food and Drug Administration issued a health warning on May 16th, 2016, regarding the use of oral ketoconazole for the treatment of skin and nail dermatophyte and candidal infections – wait what? Why is this even an active discussion? Let’s take a step back: In July 2013, the FDA strengthened its warnings and withdrew FDA indications for ketoconazole, specifically stating that its use for Candida and dermatophyte infections is no longer indicated and that it should only be considered in fungal infections, such as blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis, when other antifungals are not available.

The reality is that for, most clinicians, it has been well accepted for years that this drug has significant toxicities, probably the most among the azole class, especially in terms of liver issues and drug interactions being one of the most potent inhibitors of the hepatic CYP (cytochrome P450) system.

Endocrinologists have been preaching that the drug can impair adrenal function, causing insufficiency. So this warning begs the question … who is still actively prescribing this medication? Sadly, this advisory was in response to data showing that this drug was still being prescribed for skin and nail fungal infections in 2015, as well as one documented death associated with its use for this indication. Seriously? Terbinafine (250 mg daily for 6 weeks for fingernails, 12 weeks for toenails) and fluconazole (300 mg weekly for 6 months for fingernails and 9 months for toenails) are both safe and cheap means to treat onychomycosis. If you can get it covered, we even have effective topical treatments for onychomycosis, not to mention we have ALWAYS had topical options for superficial cutaneous mycoses. This is a no brainer. Just say NO to oral ketoconazole.

Dr. Adam Friedman is the residency program director and director of translational research in the department of dermatology, George Washington University, Washington. He is on the editorial advisory board of Dermatology News. He has no related disclosures.

The Food and Drug Administration issued a health warning on May 16th, 2016, regarding the use of oral ketoconazole for the treatment of skin and nail dermatophyte and candidal infections – wait what? Why is this even an active discussion? Let’s take a step back: In July 2013, the FDA strengthened its warnings and withdrew FDA indications for ketoconazole, specifically stating that its use for Candida and dermatophyte infections is no longer indicated and that it should only be considered in fungal infections, such as blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis, when other antifungals are not available.

The reality is that for, most clinicians, it has been well accepted for years that this drug has significant toxicities, probably the most among the azole class, especially in terms of liver issues and drug interactions being one of the most potent inhibitors of the hepatic CYP (cytochrome P450) system.

Endocrinologists have been preaching that the drug can impair adrenal function, causing insufficiency. So this warning begs the question … who is still actively prescribing this medication? Sadly, this advisory was in response to data showing that this drug was still being prescribed for skin and nail fungal infections in 2015, as well as one documented death associated with its use for this indication. Seriously? Terbinafine (250 mg daily for 6 weeks for fingernails, 12 weeks for toenails) and fluconazole (300 mg weekly for 6 months for fingernails and 9 months for toenails) are both safe and cheap means to treat onychomycosis. If you can get it covered, we even have effective topical treatments for onychomycosis, not to mention we have ALWAYS had topical options for superficial cutaneous mycoses. This is a no brainer. Just say NO to oral ketoconazole.

Dr. Adam Friedman is the residency program director and director of translational research in the department of dermatology, George Washington University, Washington. He is on the editorial advisory board of Dermatology News. He has no related disclosures.

The Food and Drug Administration issued a health warning on May 16th, 2016, regarding the use of oral ketoconazole for the treatment of skin and nail dermatophyte and candidal infections – wait what? Why is this even an active discussion? Let’s take a step back: In July 2013, the FDA strengthened its warnings and withdrew FDA indications for ketoconazole, specifically stating that its use for Candida and dermatophyte infections is no longer indicated and that it should only be considered in fungal infections, such as blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis, when other antifungals are not available.

The reality is that for, most clinicians, it has been well accepted for years that this drug has significant toxicities, probably the most among the azole class, especially in terms of liver issues and drug interactions being one of the most potent inhibitors of the hepatic CYP (cytochrome P450) system.

Endocrinologists have been preaching that the drug can impair adrenal function, causing insufficiency. So this warning begs the question … who is still actively prescribing this medication? Sadly, this advisory was in response to data showing that this drug was still being prescribed for skin and nail fungal infections in 2015, as well as one documented death associated with its use for this indication. Seriously? Terbinafine (250 mg daily for 6 weeks for fingernails, 12 weeks for toenails) and fluconazole (300 mg weekly for 6 months for fingernails and 9 months for toenails) are both safe and cheap means to treat onychomycosis. If you can get it covered, we even have effective topical treatments for onychomycosis, not to mention we have ALWAYS had topical options for superficial cutaneous mycoses. This is a no brainer. Just say NO to oral ketoconazole.

Dr. Adam Friedman is the residency program director and director of translational research in the department of dermatology, George Washington University, Washington. He is on the editorial advisory board of Dermatology News. He has no related disclosures.

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:

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

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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

1. 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.
2. 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

1. 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.
2. 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

1. 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.
2. 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.
3. 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

1. 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.
2. Liang H, Nacharaju P, Friedman A, et al. Nitric oxide generating/releasing materials. Future Sci OA. 2015;1. doi:10.4155/fso.15.54.
3. 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:

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

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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

1. 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.
2. 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

1. 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.
2. 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

1. 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.
2. 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.
3. 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

1. 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.
2. Liang H, Nacharaju P, Friedman A, et al. Nitric oxide generating/releasing materials. Future Sci OA. 2015;1. doi:10.4155/fso.15.54.
3. 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:

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

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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

1. 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.
2. 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

1. 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.
2. 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

1. 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.
2. 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.
3. 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

1. 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.
2. Liang H, Nacharaju P, Friedman A, et al. Nitric oxide generating/releasing materials. Future Sci OA. 2015;1. doi:10.4155/fso.15.54.
3. 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.