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Pedunculagin
Pedunculagin is an ellagitannin, a group of polyphenolic hydrolyzable tannins, found in various plants, including Emblica officinalis, Pimenta dioica, and several others (Arch. Pharm. Res. 2014, Feb 7. [Epub ahead of print]; Curr. Drug Targets 2012;13:1900-06). The substance is reported to exhibit anti-inflammatory, anticancer, and antimicrobial activities, and it is considered a potent dietary antioxidant (Z. Naturforsch C. 2007;62:526-36; J. Org. Chem. 1996;61:2606-12; J. Nutr. 2014;144(4 Suppl):555S-60S). Purified from the Manchurian alder (Alnus hirsuta), pedunculagin is also a novel immunomodulating agent (Skin Res. Technol. 2010;16:371-7). Pedunculagin is also one of the hydrolyzable tannins found in Punica granatum (pomegranate), fruit extracts of which have been shown by Afaq et al. to exert photochemopreventive effects against the deleterious effects of ultraviolet B radiation (Photochem. Photobiol. 2005;81:38-45). Pedunculagin was first synthesized (in 2,3- and 4,6-coupled form) in 1996 (J. Org. Chem. 1996;61:2606-12).
Anticancer and antioxidant activity
In a study of 57 tannins and related compounds, Kashiwada et al. noted in a 1992 study that pedunculagin exhibited selective cytotoxicity against melanoma cells (J. Nat. Prod. 1992;55:1033-43).
According to a 2007 report by Marzouk et al., pedunculagin is among one of several tannins identified in the leaves of Pimenta dioica, and it is among the most potent free radical scavengers, as well as one of the most cytotoxic substances against solid tumor cancer cells. Pedunculagin also was found to significantly suppress nitric oxide production and spur the proliferation of T-lymphocytes and macrophages (Z. Naturforsch C. 2007;62:526-36).
In 2012, Kähkönen et al. observed that red raspberry and cloudberry ellagitannins, including pedunculagin, acted as effective radical scavengers, substantially contributing to the antioxidant activity of the berries in lipoprotein and lipid emulsion environments (J. Agric. Food Chem. 2012;60:1167-74).
A 2014 review by Hardman summarized several studies suggesting that potent anticancer properties, including antiproliferative and antiangiogenic activities, have been linked to walnuts. She noted that pedunculagin is one of the key constituents in walnuts to which such characteristics have been attributed (J. Nutr. 2014;144(4 Suppl):555S-60S).
Potential cutaneous applications
In 2010, Lee et al. assessed the effects of pedunculagin on 2,4,6-trinitrochlorobenzene (TNCB)-induced atopic dermatitis-like lesions in NC/Nga mice. Investigators applied a cream containing 0.1% or 0.5% pedunculagin to the positive treatment group; the negative treatment group received the base cream without pedunculagin, with no topical formulations administered to a control group. The investigators found, 4 weeks after treatment, that greater and more rapid improvement in the lesions was experienced by the group that received the higher concentration of pedunculagin (Skin Res. Technol. 2010;16:371-7).
Kim et al., in 2014, isolated pedunculagin and five other phenolic compounds from the leaves of Quercus mongolica (Mongolian oak). They found that pedunculagin exhibited strong in vitro inhibition against the expression of matrix metalloproteinase (MMP)-1 and increased type I procollagen in human fibroblasts exposed to UVB. The Q. mongolica constituent was also found to concentration-dependently exhibit potent scavenging activity against the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical. The investigators suggested that the ellagitannin shows promise for use in preventing and treating cutaneous aging (Arch. Pharm. Res. 2014 Feb. 7. [Epub ahead of print]).
Conclusion
Pedunculagin shows some promise as an agent that can yield dermatologic benefits. However, the body of research on this natural compound is relatively scant. More expansive follow-up work is needed to determine the extent to which pedunculagin can be reasonably incorporated into the dermatologic armamentarium.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy,Topix Pharmaceuticals, and Unilever.
Pedunculagin is an ellagitannin, a group of polyphenolic hydrolyzable tannins, found in various plants, including Emblica officinalis, Pimenta dioica, and several others (Arch. Pharm. Res. 2014, Feb 7. [Epub ahead of print]; Curr. Drug Targets 2012;13:1900-06). The substance is reported to exhibit anti-inflammatory, anticancer, and antimicrobial activities, and it is considered a potent dietary antioxidant (Z. Naturforsch C. 2007;62:526-36; J. Org. Chem. 1996;61:2606-12; J. Nutr. 2014;144(4 Suppl):555S-60S). Purified from the Manchurian alder (Alnus hirsuta), pedunculagin is also a novel immunomodulating agent (Skin Res. Technol. 2010;16:371-7). Pedunculagin is also one of the hydrolyzable tannins found in Punica granatum (pomegranate), fruit extracts of which have been shown by Afaq et al. to exert photochemopreventive effects against the deleterious effects of ultraviolet B radiation (Photochem. Photobiol. 2005;81:38-45). Pedunculagin was first synthesized (in 2,3- and 4,6-coupled form) in 1996 (J. Org. Chem. 1996;61:2606-12).
Anticancer and antioxidant activity
In a study of 57 tannins and related compounds, Kashiwada et al. noted in a 1992 study that pedunculagin exhibited selective cytotoxicity against melanoma cells (J. Nat. Prod. 1992;55:1033-43).
According to a 2007 report by Marzouk et al., pedunculagin is among one of several tannins identified in the leaves of Pimenta dioica, and it is among the most potent free radical scavengers, as well as one of the most cytotoxic substances against solid tumor cancer cells. Pedunculagin also was found to significantly suppress nitric oxide production and spur the proliferation of T-lymphocytes and macrophages (Z. Naturforsch C. 2007;62:526-36).
In 2012, Kähkönen et al. observed that red raspberry and cloudberry ellagitannins, including pedunculagin, acted as effective radical scavengers, substantially contributing to the antioxidant activity of the berries in lipoprotein and lipid emulsion environments (J. Agric. Food Chem. 2012;60:1167-74).
A 2014 review by Hardman summarized several studies suggesting that potent anticancer properties, including antiproliferative and antiangiogenic activities, have been linked to walnuts. She noted that pedunculagin is one of the key constituents in walnuts to which such characteristics have been attributed (J. Nutr. 2014;144(4 Suppl):555S-60S).
Potential cutaneous applications
In 2010, Lee et al. assessed the effects of pedunculagin on 2,4,6-trinitrochlorobenzene (TNCB)-induced atopic dermatitis-like lesions in NC/Nga mice. Investigators applied a cream containing 0.1% or 0.5% pedunculagin to the positive treatment group; the negative treatment group received the base cream without pedunculagin, with no topical formulations administered to a control group. The investigators found, 4 weeks after treatment, that greater and more rapid improvement in the lesions was experienced by the group that received the higher concentration of pedunculagin (Skin Res. Technol. 2010;16:371-7).
Kim et al., in 2014, isolated pedunculagin and five other phenolic compounds from the leaves of Quercus mongolica (Mongolian oak). They found that pedunculagin exhibited strong in vitro inhibition against the expression of matrix metalloproteinase (MMP)-1 and increased type I procollagen in human fibroblasts exposed to UVB. The Q. mongolica constituent was also found to concentration-dependently exhibit potent scavenging activity against the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical. The investigators suggested that the ellagitannin shows promise for use in preventing and treating cutaneous aging (Arch. Pharm. Res. 2014 Feb. 7. [Epub ahead of print]).
Conclusion
Pedunculagin shows some promise as an agent that can yield dermatologic benefits. However, the body of research on this natural compound is relatively scant. More expansive follow-up work is needed to determine the extent to which pedunculagin can be reasonably incorporated into the dermatologic armamentarium.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy,Topix Pharmaceuticals, and Unilever.
Pedunculagin is an ellagitannin, a group of polyphenolic hydrolyzable tannins, found in various plants, including Emblica officinalis, Pimenta dioica, and several others (Arch. Pharm. Res. 2014, Feb 7. [Epub ahead of print]; Curr. Drug Targets 2012;13:1900-06). The substance is reported to exhibit anti-inflammatory, anticancer, and antimicrobial activities, and it is considered a potent dietary antioxidant (Z. Naturforsch C. 2007;62:526-36; J. Org. Chem. 1996;61:2606-12; J. Nutr. 2014;144(4 Suppl):555S-60S). Purified from the Manchurian alder (Alnus hirsuta), pedunculagin is also a novel immunomodulating agent (Skin Res. Technol. 2010;16:371-7). Pedunculagin is also one of the hydrolyzable tannins found in Punica granatum (pomegranate), fruit extracts of which have been shown by Afaq et al. to exert photochemopreventive effects against the deleterious effects of ultraviolet B radiation (Photochem. Photobiol. 2005;81:38-45). Pedunculagin was first synthesized (in 2,3- and 4,6-coupled form) in 1996 (J. Org. Chem. 1996;61:2606-12).
Anticancer and antioxidant activity
In a study of 57 tannins and related compounds, Kashiwada et al. noted in a 1992 study that pedunculagin exhibited selective cytotoxicity against melanoma cells (J. Nat. Prod. 1992;55:1033-43).
According to a 2007 report by Marzouk et al., pedunculagin is among one of several tannins identified in the leaves of Pimenta dioica, and it is among the most potent free radical scavengers, as well as one of the most cytotoxic substances against solid tumor cancer cells. Pedunculagin also was found to significantly suppress nitric oxide production and spur the proliferation of T-lymphocytes and macrophages (Z. Naturforsch C. 2007;62:526-36).
In 2012, Kähkönen et al. observed that red raspberry and cloudberry ellagitannins, including pedunculagin, acted as effective radical scavengers, substantially contributing to the antioxidant activity of the berries in lipoprotein and lipid emulsion environments (J. Agric. Food Chem. 2012;60:1167-74).
A 2014 review by Hardman summarized several studies suggesting that potent anticancer properties, including antiproliferative and antiangiogenic activities, have been linked to walnuts. She noted that pedunculagin is one of the key constituents in walnuts to which such characteristics have been attributed (J. Nutr. 2014;144(4 Suppl):555S-60S).
Potential cutaneous applications
In 2010, Lee et al. assessed the effects of pedunculagin on 2,4,6-trinitrochlorobenzene (TNCB)-induced atopic dermatitis-like lesions in NC/Nga mice. Investigators applied a cream containing 0.1% or 0.5% pedunculagin to the positive treatment group; the negative treatment group received the base cream without pedunculagin, with no topical formulations administered to a control group. The investigators found, 4 weeks after treatment, that greater and more rapid improvement in the lesions was experienced by the group that received the higher concentration of pedunculagin (Skin Res. Technol. 2010;16:371-7).
Kim et al., in 2014, isolated pedunculagin and five other phenolic compounds from the leaves of Quercus mongolica (Mongolian oak). They found that pedunculagin exhibited strong in vitro inhibition against the expression of matrix metalloproteinase (MMP)-1 and increased type I procollagen in human fibroblasts exposed to UVB. The Q. mongolica constituent was also found to concentration-dependently exhibit potent scavenging activity against the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical. The investigators suggested that the ellagitannin shows promise for use in preventing and treating cutaneous aging (Arch. Pharm. Res. 2014 Feb. 7. [Epub ahead of print]).
Conclusion
Pedunculagin shows some promise as an agent that can yield dermatologic benefits. However, the body of research on this natural compound is relatively scant. More expansive follow-up work is needed to determine the extent to which pedunculagin can be reasonably incorporated into the dermatologic armamentarium.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy,Topix Pharmaceuticals, and Unilever.
Almonds
A tree species belonging to the Rosaceae family and native to the Middle East and South Asia, Prunus dulcis (also called Prunus amygdalus), popularly known as almond, is cultivated widely in warm, arid locations and used primarily for its edible seeds (J. Agric. Food Chem. 2007;55:8498-507; J. Agric. Food Chem. 2006;54:312-8). Almonds and almond skins are rich in polyphenols and are an important source of these phytonutrients, particularly flavan-3-ols and flavonols (J. Proteome Res. 2010;9:5859-67). Almonds also are known to contain an abundance of fiber (Anaerobe 2014;26:1-6). Almond extracts are used in cosmetic formulations because of their high concentration of polyphenols, particularly flavonoids and phenolic acids (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Key components
In 2006, Milbury et al. determined that the main flavonoids and phenolic acids in Prunus dulcis skins and kernels are isorhamnetin-3-O-rutinoside and isorhamnetin-3-O-glucoside (in combination), catechin, kaempferol-3-O-rutinoside, epicatechin, quercetin-3-O-galactoside, and isorhamnetin-3-O-galactoside (J. Agric. Food Chem. 2006;54:5027-33).
In a separate study that year, Wijeratne et al. identified quercetin, isorhamnetin, quercitrin, kaempferol 3-O-rutinoside, isorhamnetin 3-O-glucoside, and morin as the primary flavonoids in various whole-seed, brown, skin, and green-shell-cover almond extracts (J. Agric. Food Chem. 2006;54:312-8). Almond seed skin also has been shown to contain highly polymerized polyphenols that exhibit potent alpha-amylase inhibitory activity, thus slowing the absorption of carbohydrate (J. Agric. Food Chem. 2013;61:4570-6).
In 2010, Bartolomé et al. identified A- and B-type procyanidin, propelargonidin, and prodelphinidin polymers in almond skins. In human plasma and urine samples taken after consumption of almond skin polyphenols, the investigators detected O-methyl glucuronide sulfate and O-methyl sulfate derivatives of (epi)catechin; the glucuronide conjugates of naringenin and isorhamnetin; and sulfate conjugates of isorhamnetin, together with conjugates of hydroxyphenylvalerolactones. They also identified various microbial-derived metabolites, including hydroxyphenylpropionic, hydroxyphenylacetic, hydroxycinnamic, hydroxybenzoic, and hydroxyhippuric acids (Arch. Biochem. Biophys. 2010;501:124-33).
A functional food: Antioxidant constituents and activity
In a study of two human subjects conducted in 2009, Urpi-Sarda et al. profiled microbial-derived phenolic metabolites in plasma and urine samples before and after the consumption of almond skins. They detected glucuronide, O-methyl glucuronide sulfate, and O-methyl sulfate derivatives of epicatechin, the glucuronide conjugates of naringenin and glucuronide, and sulfate conjugates of isorhamnetin. The researchers also detected, in their glucuronide and sulfate forms, microbial-derived metabolites of flavanols, including 5-(dihydroxyphenyl)-gamma-valerolactone and 5-(hydroxymethoxyphenyl)-gamma-valerolactone (J. Agric. Food Chem. 2009;57:10134-42).
A 2010 study with 24 volunteers conducted by Llorach et al. investigated urinary metabolome changes during the 24-hour period following ingestion of a single dose of almond skin extract. The participants, who were following a polyphenol-free diet for 48 hours, were divided into two groups: the almond skin group or a placebo group. Thirty-four metabolites were linked to the consumption of the almond extract (J. Proteome Res. 2010;9:5859-67).
Monagas et al. previously led a comprehensive investigation of the phenolic composition of almond skins to elucidate its potential as a functional food. They identified 33 compounds, including flavanols, flavonols, dihydroflavonols, and flavanones, as well as nonflavonoid substances. The most abundant phenols were flavanols (38%-57%) and flavonol glycosides (14%-35%). Further, the researchers measured the oxygen radical absorbance capacity of almond skins at 0.398-0.500 mmol Trolox/g, a range that suggests its antioxidant potency (J. Agric. Food Chem. 2007;55:8498-507).
In 2008, Garrido et al. investigated the phenolic composition and antioxidant activity of almond skins (Prunus dulcis) obtained from three almond varieties and through various industrial processes, including blanching, blanching and drying, as well as roasting. Identified were 31 phenolic compounds, including flavan-3-ols, flavonol glycosides, hydroxybenzoic acids and aldehydes, flavonol aglycones, flavanone glycosides, flavanone aglycones, hydroxycinnamic acids, and dihydroflavonol aglycones. Phenolic content as well as antioxidant activity were significantly higher in the roasted samples (J. Food Sci. 2008;73:C106-15).
In 2014, Liu et al. conducted a study in healthy humans of the potential prebiotic effects of consuming almonds and almond skins. For 6 weeks, 48 adult volunteers ingested a daily dose of roasted almonds, almond skins, or a positive control (commercial fructo-oligosaccharides). The investigators collected fecal samples and analyzed them for microbiota composition. They observed significant increases in populations of Bifidobacterium spp. and Lactobacillus spp. in fecal samples after almond or almond skin supplementation; substantial inhibition of the growth of the pathogen Clostridium perfringens; and favorable changes in bacterial enzyme activities. They concluded that almonds and almond skins appear to exhibit potential prebiotic qualities (Anaerobe 2014;26:1-6).
Topical antiaging potential
In 2011, Sachdeva and Katyal assessed the antioxidant and antiwrinkle effects of almond skin extracts in UV-induced photoaging in mice. Twenty-five mice were used as an unirradiated control, receiving neither UV exposure nor almond skin treatment. A second group of 24 mice received only UV exposure of 5 minutes twice a day, and served as an irradiated control. Further groups of 24 mice received both UV radiation and treatment with prepared formulation. The treatment groups received various topical almond skin extract doses 2 hours prior to the same level of UV exposure. Significant decreases in malondialdehyde and increases in glutathione levels, respectively, suggested to the investigators that the almond skin extracts effectively scavenged free radicals while also enhancing moisturization. They concluded that almond skin extracts display potential as antiaging ingredients in topical cosmetic formulations (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Conclusion
Almonds are believed to be a healthy addition to the human diet, with their regular consumption thought to confer cardiovascular benefits. The healthful effects of dietary intake of almonds are often attributed to the presence of several polyphenolic constituents. While it is speculated that such ingredients also play a role in imparting cutaneous benefits, the body of evidence supporting such claims remains sparse to date. Nevertheless, P. dulcis is incorporated in various cosmetic formulations. More research is necessary to ascertain whether such inclusion is warranted.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
A tree species belonging to the Rosaceae family and native to the Middle East and South Asia, Prunus dulcis (also called Prunus amygdalus), popularly known as almond, is cultivated widely in warm, arid locations and used primarily for its edible seeds (J. Agric. Food Chem. 2007;55:8498-507; J. Agric. Food Chem. 2006;54:312-8). Almonds and almond skins are rich in polyphenols and are an important source of these phytonutrients, particularly flavan-3-ols and flavonols (J. Proteome Res. 2010;9:5859-67). Almonds also are known to contain an abundance of fiber (Anaerobe 2014;26:1-6). Almond extracts are used in cosmetic formulations because of their high concentration of polyphenols, particularly flavonoids and phenolic acids (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Key components
In 2006, Milbury et al. determined that the main flavonoids and phenolic acids in Prunus dulcis skins and kernels are isorhamnetin-3-O-rutinoside and isorhamnetin-3-O-glucoside (in combination), catechin, kaempferol-3-O-rutinoside, epicatechin, quercetin-3-O-galactoside, and isorhamnetin-3-O-galactoside (J. Agric. Food Chem. 2006;54:5027-33).
In a separate study that year, Wijeratne et al. identified quercetin, isorhamnetin, quercitrin, kaempferol 3-O-rutinoside, isorhamnetin 3-O-glucoside, and morin as the primary flavonoids in various whole-seed, brown, skin, and green-shell-cover almond extracts (J. Agric. Food Chem. 2006;54:312-8). Almond seed skin also has been shown to contain highly polymerized polyphenols that exhibit potent alpha-amylase inhibitory activity, thus slowing the absorption of carbohydrate (J. Agric. Food Chem. 2013;61:4570-6).
In 2010, Bartolomé et al. identified A- and B-type procyanidin, propelargonidin, and prodelphinidin polymers in almond skins. In human plasma and urine samples taken after consumption of almond skin polyphenols, the investigators detected O-methyl glucuronide sulfate and O-methyl sulfate derivatives of (epi)catechin; the glucuronide conjugates of naringenin and isorhamnetin; and sulfate conjugates of isorhamnetin, together with conjugates of hydroxyphenylvalerolactones. They also identified various microbial-derived metabolites, including hydroxyphenylpropionic, hydroxyphenylacetic, hydroxycinnamic, hydroxybenzoic, and hydroxyhippuric acids (Arch. Biochem. Biophys. 2010;501:124-33).
A functional food: Antioxidant constituents and activity
In a study of two human subjects conducted in 2009, Urpi-Sarda et al. profiled microbial-derived phenolic metabolites in plasma and urine samples before and after the consumption of almond skins. They detected glucuronide, O-methyl glucuronide sulfate, and O-methyl sulfate derivatives of epicatechin, the glucuronide conjugates of naringenin and glucuronide, and sulfate conjugates of isorhamnetin. The researchers also detected, in their glucuronide and sulfate forms, microbial-derived metabolites of flavanols, including 5-(dihydroxyphenyl)-gamma-valerolactone and 5-(hydroxymethoxyphenyl)-gamma-valerolactone (J. Agric. Food Chem. 2009;57:10134-42).
A 2010 study with 24 volunteers conducted by Llorach et al. investigated urinary metabolome changes during the 24-hour period following ingestion of a single dose of almond skin extract. The participants, who were following a polyphenol-free diet for 48 hours, were divided into two groups: the almond skin group or a placebo group. Thirty-four metabolites were linked to the consumption of the almond extract (J. Proteome Res. 2010;9:5859-67).
Monagas et al. previously led a comprehensive investigation of the phenolic composition of almond skins to elucidate its potential as a functional food. They identified 33 compounds, including flavanols, flavonols, dihydroflavonols, and flavanones, as well as nonflavonoid substances. The most abundant phenols were flavanols (38%-57%) and flavonol glycosides (14%-35%). Further, the researchers measured the oxygen radical absorbance capacity of almond skins at 0.398-0.500 mmol Trolox/g, a range that suggests its antioxidant potency (J. Agric. Food Chem. 2007;55:8498-507).
In 2008, Garrido et al. investigated the phenolic composition and antioxidant activity of almond skins (Prunus dulcis) obtained from three almond varieties and through various industrial processes, including blanching, blanching and drying, as well as roasting. Identified were 31 phenolic compounds, including flavan-3-ols, flavonol glycosides, hydroxybenzoic acids and aldehydes, flavonol aglycones, flavanone glycosides, flavanone aglycones, hydroxycinnamic acids, and dihydroflavonol aglycones. Phenolic content as well as antioxidant activity were significantly higher in the roasted samples (J. Food Sci. 2008;73:C106-15).
In 2014, Liu et al. conducted a study in healthy humans of the potential prebiotic effects of consuming almonds and almond skins. For 6 weeks, 48 adult volunteers ingested a daily dose of roasted almonds, almond skins, or a positive control (commercial fructo-oligosaccharides). The investigators collected fecal samples and analyzed them for microbiota composition. They observed significant increases in populations of Bifidobacterium spp. and Lactobacillus spp. in fecal samples after almond or almond skin supplementation; substantial inhibition of the growth of the pathogen Clostridium perfringens; and favorable changes in bacterial enzyme activities. They concluded that almonds and almond skins appear to exhibit potential prebiotic qualities (Anaerobe 2014;26:1-6).
Topical antiaging potential
In 2011, Sachdeva and Katyal assessed the antioxidant and antiwrinkle effects of almond skin extracts in UV-induced photoaging in mice. Twenty-five mice were used as an unirradiated control, receiving neither UV exposure nor almond skin treatment. A second group of 24 mice received only UV exposure of 5 minutes twice a day, and served as an irradiated control. Further groups of 24 mice received both UV radiation and treatment with prepared formulation. The treatment groups received various topical almond skin extract doses 2 hours prior to the same level of UV exposure. Significant decreases in malondialdehyde and increases in glutathione levels, respectively, suggested to the investigators that the almond skin extracts effectively scavenged free radicals while also enhancing moisturization. They concluded that almond skin extracts display potential as antiaging ingredients in topical cosmetic formulations (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Conclusion
Almonds are believed to be a healthy addition to the human diet, with their regular consumption thought to confer cardiovascular benefits. The healthful effects of dietary intake of almonds are often attributed to the presence of several polyphenolic constituents. While it is speculated that such ingredients also play a role in imparting cutaneous benefits, the body of evidence supporting such claims remains sparse to date. Nevertheless, P. dulcis is incorporated in various cosmetic formulations. More research is necessary to ascertain whether such inclusion is warranted.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
A tree species belonging to the Rosaceae family and native to the Middle East and South Asia, Prunus dulcis (also called Prunus amygdalus), popularly known as almond, is cultivated widely in warm, arid locations and used primarily for its edible seeds (J. Agric. Food Chem. 2007;55:8498-507; J. Agric. Food Chem. 2006;54:312-8). Almonds and almond skins are rich in polyphenols and are an important source of these phytonutrients, particularly flavan-3-ols and flavonols (J. Proteome Res. 2010;9:5859-67). Almonds also are known to contain an abundance of fiber (Anaerobe 2014;26:1-6). Almond extracts are used in cosmetic formulations because of their high concentration of polyphenols, particularly flavonoids and phenolic acids (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Key components
In 2006, Milbury et al. determined that the main flavonoids and phenolic acids in Prunus dulcis skins and kernels are isorhamnetin-3-O-rutinoside and isorhamnetin-3-O-glucoside (in combination), catechin, kaempferol-3-O-rutinoside, epicatechin, quercetin-3-O-galactoside, and isorhamnetin-3-O-galactoside (J. Agric. Food Chem. 2006;54:5027-33).
In a separate study that year, Wijeratne et al. identified quercetin, isorhamnetin, quercitrin, kaempferol 3-O-rutinoside, isorhamnetin 3-O-glucoside, and morin as the primary flavonoids in various whole-seed, brown, skin, and green-shell-cover almond extracts (J. Agric. Food Chem. 2006;54:312-8). Almond seed skin also has been shown to contain highly polymerized polyphenols that exhibit potent alpha-amylase inhibitory activity, thus slowing the absorption of carbohydrate (J. Agric. Food Chem. 2013;61:4570-6).
In 2010, Bartolomé et al. identified A- and B-type procyanidin, propelargonidin, and prodelphinidin polymers in almond skins. In human plasma and urine samples taken after consumption of almond skin polyphenols, the investigators detected O-methyl glucuronide sulfate and O-methyl sulfate derivatives of (epi)catechin; the glucuronide conjugates of naringenin and isorhamnetin; and sulfate conjugates of isorhamnetin, together with conjugates of hydroxyphenylvalerolactones. They also identified various microbial-derived metabolites, including hydroxyphenylpropionic, hydroxyphenylacetic, hydroxycinnamic, hydroxybenzoic, and hydroxyhippuric acids (Arch. Biochem. Biophys. 2010;501:124-33).
A functional food: Antioxidant constituents and activity
In a study of two human subjects conducted in 2009, Urpi-Sarda et al. profiled microbial-derived phenolic metabolites in plasma and urine samples before and after the consumption of almond skins. They detected glucuronide, O-methyl glucuronide sulfate, and O-methyl sulfate derivatives of epicatechin, the glucuronide conjugates of naringenin and glucuronide, and sulfate conjugates of isorhamnetin. The researchers also detected, in their glucuronide and sulfate forms, microbial-derived metabolites of flavanols, including 5-(dihydroxyphenyl)-gamma-valerolactone and 5-(hydroxymethoxyphenyl)-gamma-valerolactone (J. Agric. Food Chem. 2009;57:10134-42).
A 2010 study with 24 volunteers conducted by Llorach et al. investigated urinary metabolome changes during the 24-hour period following ingestion of a single dose of almond skin extract. The participants, who were following a polyphenol-free diet for 48 hours, were divided into two groups: the almond skin group or a placebo group. Thirty-four metabolites were linked to the consumption of the almond extract (J. Proteome Res. 2010;9:5859-67).
Monagas et al. previously led a comprehensive investigation of the phenolic composition of almond skins to elucidate its potential as a functional food. They identified 33 compounds, including flavanols, flavonols, dihydroflavonols, and flavanones, as well as nonflavonoid substances. The most abundant phenols were flavanols (38%-57%) and flavonol glycosides (14%-35%). Further, the researchers measured the oxygen radical absorbance capacity of almond skins at 0.398-0.500 mmol Trolox/g, a range that suggests its antioxidant potency (J. Agric. Food Chem. 2007;55:8498-507).
In 2008, Garrido et al. investigated the phenolic composition and antioxidant activity of almond skins (Prunus dulcis) obtained from three almond varieties and through various industrial processes, including blanching, blanching and drying, as well as roasting. Identified were 31 phenolic compounds, including flavan-3-ols, flavonol glycosides, hydroxybenzoic acids and aldehydes, flavonol aglycones, flavanone glycosides, flavanone aglycones, hydroxycinnamic acids, and dihydroflavonol aglycones. Phenolic content as well as antioxidant activity were significantly higher in the roasted samples (J. Food Sci. 2008;73:C106-15).
In 2014, Liu et al. conducted a study in healthy humans of the potential prebiotic effects of consuming almonds and almond skins. For 6 weeks, 48 adult volunteers ingested a daily dose of roasted almonds, almond skins, or a positive control (commercial fructo-oligosaccharides). The investigators collected fecal samples and analyzed them for microbiota composition. They observed significant increases in populations of Bifidobacterium spp. and Lactobacillus spp. in fecal samples after almond or almond skin supplementation; substantial inhibition of the growth of the pathogen Clostridium perfringens; and favorable changes in bacterial enzyme activities. They concluded that almonds and almond skins appear to exhibit potential prebiotic qualities (Anaerobe 2014;26:1-6).
Topical antiaging potential
In 2011, Sachdeva and Katyal assessed the antioxidant and antiwrinkle effects of almond skin extracts in UV-induced photoaging in mice. Twenty-five mice were used as an unirradiated control, receiving neither UV exposure nor almond skin treatment. A second group of 24 mice received only UV exposure of 5 minutes twice a day, and served as an irradiated control. Further groups of 24 mice received both UV radiation and treatment with prepared formulation. The treatment groups received various topical almond skin extract doses 2 hours prior to the same level of UV exposure. Significant decreases in malondialdehyde and increases in glutathione levels, respectively, suggested to the investigators that the almond skin extracts effectively scavenged free radicals while also enhancing moisturization. They concluded that almond skin extracts display potential as antiaging ingredients in topical cosmetic formulations (Int. J. Curr. Pharm. Res. 2011;3:57-9).
Conclusion
Almonds are believed to be a healthy addition to the human diet, with their regular consumption thought to confer cardiovascular benefits. The healthful effects of dietary intake of almonds are often attributed to the presence of several polyphenolic constituents. While it is speculated that such ingredients also play a role in imparting cutaneous benefits, the body of evidence supporting such claims remains sparse to date. Nevertheless, P. dulcis is incorporated in various cosmetic formulations. More research is necessary to ascertain whether such inclusion is warranted.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Steps to optimizing skin care retail in your practice
I have been writing Cosmeceutical Critique for more than a decade, and over the years I have received many calls and e-mails about the column. The most frequent question is, "I read your column every month and understand the ingredient science, but I still do not know what products to sell in my practice. Can you help?" For this reason, I will begin to add columns that discuss the process of skin care retail, and how to choose which products to sell. I admit that finding effective products and designing the right regimen for each patient are daunting tasks, but I have simplified the process out of necessity in my own Miami practice.
The goal is to achieve good patient outcomes with minimal side effects, which strengthens the physician-patient relationship. In order to achieve this goal, you need to find the most efficacious products and properly match them to your patient’s skin type. In addition, patients must be compliant with the prescribed regimen. If only it were that simple. The difficulty in separating fact (science) from fiction (marketing claims), time constraints with each patient, and the need for staff training can complicate this process.
In my practice, we use the Skin Type Solutions system that I developed to match skin care products for each skin type (
- <cf number="\"2\"">’</cf>
Fitzpatricks Dermatology in General Medicine, 8th Ed., 2012, Ch. 250, p. 1343).This system accurately determines a patient’s Baumann Skin Type (there are 16) and provides a preset regimen designed to address that particular skin type’s needs. The system has been tested in more than 100,000 people worldwide, of all ethnicities and ages, as well as both genders, and has demonstrated accuracy in assessing skin care needs (Dermatol. Clin. 2008;26:359-73; J. Cosmet. Dermatol. Sci. Appl. 2014;4:78-84).
The Baumann Skin Typing System saves my staff time by streamlining the process of designing skin care regimens. It works like this:
• The patient takes the skin type questionnaire and is assigned to one of the 16 Baumann Skin types.
• A staff member matches the skin type to the preset regimen.
• The doctor (or designee) reviews the regimen and makes any necessary changes or additions (including prescription medications).
• The patient is given a step-by-step skin care regimen.
• The patient purchases the correct products.
• The patient is given instruction sheets to increase compliance.
• The patient returns in 4 weeks for follow-up with the staff designee to ensure that the regimen is being properly followed.
Sounds easy, right? The hard part is choosing which products to use for each skin type. In order to ethically sell skin care products to patients, you must ensure that they are getting efficacious products to address their skin concerns (Clin. Dermatol. 2012;30:522-7).
Keep these steps in mind when selecting skin care products:
• Know your ingredient science.
There is so much interesting research on cosmetic ingredients, but there is also plenty of hype and misinformation. One key point is that no one ingredient is right for all skin types. It’s essential to know which ingredients work well together and which do not. The order in which ingredients are placed on the skin is crucial as well, because they can inactivate each other and affect absorption. All of my ingredient columns are available at edermatologynews.com and will be published in my new book, Cosmeceuticals and Cosmetic Ingredients (McGraw-Hill).
It is important to understand which ingredients are worthless (like stem cells and peptides) and which ones are crucial (such as retinoids and antioxidants) so that you can arm your patients with products that work. When products do not work, your patients will have poor outcomes, your physician-patient relationships will be damaged, and patients’ trust in you will decrease.
• Choose ingredients appropriate for the patient’s skin type.
It is important to understand the characteristics of various ingredients and match those to your patient’s skin type. The process of assessing the patient’s skin type can be long because you need to ask numerous historical questions (invariably including, "Do you get irritated from skin care products?" and "What happens if you do not use a moisturizer?"). Looking at a patient’s skin at one point in time is not as accurate as asking a series of questions about how their skin has behaved in the past under varying conditions. I use a validated questionnaire to streamline this process in my practice. The questionnaire takes 3 to 5 minutes, does not require a staff member, and is done on a tablet device in the waiting room or exam room.
• Properly identify the Baumann Skin Type using a validated questionnaire.
To determine a patient’s true skin type, a scientifically validated questionnaire is used to assess skin oiliness, dryness, sensitivity, uneven skin tone, and risk factors for wrinkles. When these parameters are combined, there are 16 possible Baumann Skin Types, which yield an accurate history of the patient’s skin characteristics.
• Choose products for each skin type.
There are many factors to consider in choosing what brands and SKUs (stock keeping units, in industry parlance, but particular products for our purposes) to use for each skin type. I use a brand-agnostic approach to choose the best technologies from various brands from around the world. I believe that brands often have a core competency, such as sunscreen technology, but that not all of the products in a particular line are superior. I select the best products (SKUs) from each brand, and combine and test them on various skin types to see which products and what combinations of products work best.
The following are the factors that I take into account when choosing SKUs for each Baumann Skin Type:
A. Importance of the ingredient recipe
Although the product label lists ingredients, it does not list the formulation’s recipe, which is proprietary and often patented. The "recipe" includes the order that ingredients are added in the process, the pH, the amount of each ingredient, the temperature at which the ingredient is added, and many other important factors that determine the final chemistry. Ingredients like vitamin C, green tea, and argan oil are expensive when formulated properly. Many copycat brands, such as the Walgreens and CVS knockoffs, use the same ingredients. However, they cannot use the patented recipe, and therefore their end product is different.
B. Manufacturing and packaging process
How a product is made and packaged is crucial. For example, retinol breaks down when exposed to light and air. I once visited a manufacturing plant that was stirring its "antiaging" retinol preparation in open vats. The retinol was losing its activity, which is why the product was "less irritating." The process of packaging the completed product is also important. In some cases the product is formulated in one place and shipped to another location for final packaging – and several ingredients can lose their potency during transit. Finally, the container that the product is packaged in is important. Air and light can get into tubes, affecting the efficacy of a product.
C. Ingredient interactions
The order of application and the combination of ingredients affect stability, efficacy, safety, and the chemical structure. Master formulators understand that every ingredient in the formulation matters, and there is really no such thing as an inactive ingredient. Ingredients can affect penetration and render other ingredients more or less effective depending on the order in which the ingredients are used on the skin. For example, olive oil actually increases penetration of other ingredients because it has a high content of oleic acid, while safflower oil can decrease penetration by strengthening the skin barrier.
• Design the regimen and order of application of products.
Once you have determined your patient’s skin type and matched the proper products to their skin type, you must tell them exactly how to apply them. The order in which products are applied makes a difference. Consider ingredient interactions, ingredient penetration times, and cross-reactions, plus skin type factors such as the condition of the skin barrier, sebum production, thickness of the stratum corneum, sun exposure, and bathing habits. I recommend providing a printed regimen with step-by-step instructions for morning and night.
• Educate patients.
Take the time to educate your patients on their skin issues. If you explain why you chose each product and why the particular ingredients are important, they are more likely to be compliant and get better results (and return to you for product recommendations and repurchases). Because we do not have the time to sit and explain all of these issues to each patient, we use educational newsletters that we send to patients based on their Baumann Skin Type. This helps keep them engaged and educates them about new technologies and products that are appropriate for their skin type.
• Encourage compliance.
Schedule a follow-up visit after 1 month to check on their progress and ensure compliance, and emphasize the importance of this visit. If you prescribed a retinoid, patients may experience irritation and stop using it. If you have an imaging system, baseline and follow-up photos help illustrate patients’ progress and keep them vigilant. Four weeks is a good time frame because patients tend to lose interest at that point.
• Sell skin care products in your practice.
I was against selling skin care products for ethical reasons for several years. However, in 2005, I surveyed my patients, and 100% of them wanted me to sell products so that they could feel sure that they were purchasing the right products for their needs. In fact, my patients appreciate expert medical advice on skin care. As a practitioner, you can make more educated choices about skin care products and help them avoid products that don’t work or cause harm.
• Contact me for more information.
In order to improve patient outcomes, you must ensure that you stay current on skin care science so your patients can benefit from your expertise. I recognize that not everyone has the time and inclination to stay current on the various skin care ingredients, products, and brands. Several of my dermatology friends have adopted my skin typing system in their practices and, in the process, observed better patient outcomes and increased profitability, while reducing the burden on their staff. These successes led to the development of an in-office store system utilizing my concept, which I am offering only to dermatologists. Feel free to email me at DrB@derm.net, or visit STSFranchise.com, if you want to learn more.
• Look for this column each month.
I will be sharing more advice on in-office skin care retail and will continue my review of new cosmeceutical ingredients. Let’s work together to put skin care back in the hands of dermatologists.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
I have been writing Cosmeceutical Critique for more than a decade, and over the years I have received many calls and e-mails about the column. The most frequent question is, "I read your column every month and understand the ingredient science, but I still do not know what products to sell in my practice. Can you help?" For this reason, I will begin to add columns that discuss the process of skin care retail, and how to choose which products to sell. I admit that finding effective products and designing the right regimen for each patient are daunting tasks, but I have simplified the process out of necessity in my own Miami practice.
The goal is to achieve good patient outcomes with minimal side effects, which strengthens the physician-patient relationship. In order to achieve this goal, you need to find the most efficacious products and properly match them to your patient’s skin type. In addition, patients must be compliant with the prescribed regimen. If only it were that simple. The difficulty in separating fact (science) from fiction (marketing claims), time constraints with each patient, and the need for staff training can complicate this process.
In my practice, we use the Skin Type Solutions system that I developed to match skin care products for each skin type (
- <cf number="\"2\"">’</cf>
Fitzpatricks Dermatology in General Medicine, 8th Ed., 2012, Ch. 250, p. 1343).This system accurately determines a patient’s Baumann Skin Type (there are 16) and provides a preset regimen designed to address that particular skin type’s needs. The system has been tested in more than 100,000 people worldwide, of all ethnicities and ages, as well as both genders, and has demonstrated accuracy in assessing skin care needs (Dermatol. Clin. 2008;26:359-73; J. Cosmet. Dermatol. Sci. Appl. 2014;4:78-84).
The Baumann Skin Typing System saves my staff time by streamlining the process of designing skin care regimens. It works like this:
• The patient takes the skin type questionnaire and is assigned to one of the 16 Baumann Skin types.
• A staff member matches the skin type to the preset regimen.
• The doctor (or designee) reviews the regimen and makes any necessary changes or additions (including prescription medications).
• The patient is given a step-by-step skin care regimen.
• The patient purchases the correct products.
• The patient is given instruction sheets to increase compliance.
• The patient returns in 4 weeks for follow-up with the staff designee to ensure that the regimen is being properly followed.
Sounds easy, right? The hard part is choosing which products to use for each skin type. In order to ethically sell skin care products to patients, you must ensure that they are getting efficacious products to address their skin concerns (Clin. Dermatol. 2012;30:522-7).
Keep these steps in mind when selecting skin care products:
• Know your ingredient science.
There is so much interesting research on cosmetic ingredients, but there is also plenty of hype and misinformation. One key point is that no one ingredient is right for all skin types. It’s essential to know which ingredients work well together and which do not. The order in which ingredients are placed on the skin is crucial as well, because they can inactivate each other and affect absorption. All of my ingredient columns are available at edermatologynews.com and will be published in my new book, Cosmeceuticals and Cosmetic Ingredients (McGraw-Hill).
It is important to understand which ingredients are worthless (like stem cells and peptides) and which ones are crucial (such as retinoids and antioxidants) so that you can arm your patients with products that work. When products do not work, your patients will have poor outcomes, your physician-patient relationships will be damaged, and patients’ trust in you will decrease.
• Choose ingredients appropriate for the patient’s skin type.
It is important to understand the characteristics of various ingredients and match those to your patient’s skin type. The process of assessing the patient’s skin type can be long because you need to ask numerous historical questions (invariably including, "Do you get irritated from skin care products?" and "What happens if you do not use a moisturizer?"). Looking at a patient’s skin at one point in time is not as accurate as asking a series of questions about how their skin has behaved in the past under varying conditions. I use a validated questionnaire to streamline this process in my practice. The questionnaire takes 3 to 5 minutes, does not require a staff member, and is done on a tablet device in the waiting room or exam room.
• Properly identify the Baumann Skin Type using a validated questionnaire.
To determine a patient’s true skin type, a scientifically validated questionnaire is used to assess skin oiliness, dryness, sensitivity, uneven skin tone, and risk factors for wrinkles. When these parameters are combined, there are 16 possible Baumann Skin Types, which yield an accurate history of the patient’s skin characteristics.
• Choose products for each skin type.
There are many factors to consider in choosing what brands and SKUs (stock keeping units, in industry parlance, but particular products for our purposes) to use for each skin type. I use a brand-agnostic approach to choose the best technologies from various brands from around the world. I believe that brands often have a core competency, such as sunscreen technology, but that not all of the products in a particular line are superior. I select the best products (SKUs) from each brand, and combine and test them on various skin types to see which products and what combinations of products work best.
The following are the factors that I take into account when choosing SKUs for each Baumann Skin Type:
A. Importance of the ingredient recipe
Although the product label lists ingredients, it does not list the formulation’s recipe, which is proprietary and often patented. The "recipe" includes the order that ingredients are added in the process, the pH, the amount of each ingredient, the temperature at which the ingredient is added, and many other important factors that determine the final chemistry. Ingredients like vitamin C, green tea, and argan oil are expensive when formulated properly. Many copycat brands, such as the Walgreens and CVS knockoffs, use the same ingredients. However, they cannot use the patented recipe, and therefore their end product is different.
B. Manufacturing and packaging process
How a product is made and packaged is crucial. For example, retinol breaks down when exposed to light and air. I once visited a manufacturing plant that was stirring its "antiaging" retinol preparation in open vats. The retinol was losing its activity, which is why the product was "less irritating." The process of packaging the completed product is also important. In some cases the product is formulated in one place and shipped to another location for final packaging – and several ingredients can lose their potency during transit. Finally, the container that the product is packaged in is important. Air and light can get into tubes, affecting the efficacy of a product.
C. Ingredient interactions
The order of application and the combination of ingredients affect stability, efficacy, safety, and the chemical structure. Master formulators understand that every ingredient in the formulation matters, and there is really no such thing as an inactive ingredient. Ingredients can affect penetration and render other ingredients more or less effective depending on the order in which the ingredients are used on the skin. For example, olive oil actually increases penetration of other ingredients because it has a high content of oleic acid, while safflower oil can decrease penetration by strengthening the skin barrier.
• Design the regimen and order of application of products.
Once you have determined your patient’s skin type and matched the proper products to their skin type, you must tell them exactly how to apply them. The order in which products are applied makes a difference. Consider ingredient interactions, ingredient penetration times, and cross-reactions, plus skin type factors such as the condition of the skin barrier, sebum production, thickness of the stratum corneum, sun exposure, and bathing habits. I recommend providing a printed regimen with step-by-step instructions for morning and night.
• Educate patients.
Take the time to educate your patients on their skin issues. If you explain why you chose each product and why the particular ingredients are important, they are more likely to be compliant and get better results (and return to you for product recommendations and repurchases). Because we do not have the time to sit and explain all of these issues to each patient, we use educational newsletters that we send to patients based on their Baumann Skin Type. This helps keep them engaged and educates them about new technologies and products that are appropriate for their skin type.
• Encourage compliance.
Schedule a follow-up visit after 1 month to check on their progress and ensure compliance, and emphasize the importance of this visit. If you prescribed a retinoid, patients may experience irritation and stop using it. If you have an imaging system, baseline and follow-up photos help illustrate patients’ progress and keep them vigilant. Four weeks is a good time frame because patients tend to lose interest at that point.
• Sell skin care products in your practice.
I was against selling skin care products for ethical reasons for several years. However, in 2005, I surveyed my patients, and 100% of them wanted me to sell products so that they could feel sure that they were purchasing the right products for their needs. In fact, my patients appreciate expert medical advice on skin care. As a practitioner, you can make more educated choices about skin care products and help them avoid products that don’t work or cause harm.
• Contact me for more information.
In order to improve patient outcomes, you must ensure that you stay current on skin care science so your patients can benefit from your expertise. I recognize that not everyone has the time and inclination to stay current on the various skin care ingredients, products, and brands. Several of my dermatology friends have adopted my skin typing system in their practices and, in the process, observed better patient outcomes and increased profitability, while reducing the burden on their staff. These successes led to the development of an in-office store system utilizing my concept, which I am offering only to dermatologists. Feel free to email me at DrB@derm.net, or visit STSFranchise.com, if you want to learn more.
• Look for this column each month.
I will be sharing more advice on in-office skin care retail and will continue my review of new cosmeceutical ingredients. Let’s work together to put skin care back in the hands of dermatologists.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
I have been writing Cosmeceutical Critique for more than a decade, and over the years I have received many calls and e-mails about the column. The most frequent question is, "I read your column every month and understand the ingredient science, but I still do not know what products to sell in my practice. Can you help?" For this reason, I will begin to add columns that discuss the process of skin care retail, and how to choose which products to sell. I admit that finding effective products and designing the right regimen for each patient are daunting tasks, but I have simplified the process out of necessity in my own Miami practice.
The goal is to achieve good patient outcomes with minimal side effects, which strengthens the physician-patient relationship. In order to achieve this goal, you need to find the most efficacious products and properly match them to your patient’s skin type. In addition, patients must be compliant with the prescribed regimen. If only it were that simple. The difficulty in separating fact (science) from fiction (marketing claims), time constraints with each patient, and the need for staff training can complicate this process.
In my practice, we use the Skin Type Solutions system that I developed to match skin care products for each skin type (
- <cf number="\"2\"">’</cf>
Fitzpatricks Dermatology in General Medicine, 8th Ed., 2012, Ch. 250, p. 1343).This system accurately determines a patient’s Baumann Skin Type (there are 16) and provides a preset regimen designed to address that particular skin type’s needs. The system has been tested in more than 100,000 people worldwide, of all ethnicities and ages, as well as both genders, and has demonstrated accuracy in assessing skin care needs (Dermatol. Clin. 2008;26:359-73; J. Cosmet. Dermatol. Sci. Appl. 2014;4:78-84).
The Baumann Skin Typing System saves my staff time by streamlining the process of designing skin care regimens. It works like this:
• The patient takes the skin type questionnaire and is assigned to one of the 16 Baumann Skin types.
• A staff member matches the skin type to the preset regimen.
• The doctor (or designee) reviews the regimen and makes any necessary changes or additions (including prescription medications).
• The patient is given a step-by-step skin care regimen.
• The patient purchases the correct products.
• The patient is given instruction sheets to increase compliance.
• The patient returns in 4 weeks for follow-up with the staff designee to ensure that the regimen is being properly followed.
Sounds easy, right? The hard part is choosing which products to use for each skin type. In order to ethically sell skin care products to patients, you must ensure that they are getting efficacious products to address their skin concerns (Clin. Dermatol. 2012;30:522-7).
Keep these steps in mind when selecting skin care products:
• Know your ingredient science.
There is so much interesting research on cosmetic ingredients, but there is also plenty of hype and misinformation. One key point is that no one ingredient is right for all skin types. It’s essential to know which ingredients work well together and which do not. The order in which ingredients are placed on the skin is crucial as well, because they can inactivate each other and affect absorption. All of my ingredient columns are available at edermatologynews.com and will be published in my new book, Cosmeceuticals and Cosmetic Ingredients (McGraw-Hill).
It is important to understand which ingredients are worthless (like stem cells and peptides) and which ones are crucial (such as retinoids and antioxidants) so that you can arm your patients with products that work. When products do not work, your patients will have poor outcomes, your physician-patient relationships will be damaged, and patients’ trust in you will decrease.
• Choose ingredients appropriate for the patient’s skin type.
It is important to understand the characteristics of various ingredients and match those to your patient’s skin type. The process of assessing the patient’s skin type can be long because you need to ask numerous historical questions (invariably including, "Do you get irritated from skin care products?" and "What happens if you do not use a moisturizer?"). Looking at a patient’s skin at one point in time is not as accurate as asking a series of questions about how their skin has behaved in the past under varying conditions. I use a validated questionnaire to streamline this process in my practice. The questionnaire takes 3 to 5 minutes, does not require a staff member, and is done on a tablet device in the waiting room or exam room.
• Properly identify the Baumann Skin Type using a validated questionnaire.
To determine a patient’s true skin type, a scientifically validated questionnaire is used to assess skin oiliness, dryness, sensitivity, uneven skin tone, and risk factors for wrinkles. When these parameters are combined, there are 16 possible Baumann Skin Types, which yield an accurate history of the patient’s skin characteristics.
• Choose products for each skin type.
There are many factors to consider in choosing what brands and SKUs (stock keeping units, in industry parlance, but particular products for our purposes) to use for each skin type. I use a brand-agnostic approach to choose the best technologies from various brands from around the world. I believe that brands often have a core competency, such as sunscreen technology, but that not all of the products in a particular line are superior. I select the best products (SKUs) from each brand, and combine and test them on various skin types to see which products and what combinations of products work best.
The following are the factors that I take into account when choosing SKUs for each Baumann Skin Type:
A. Importance of the ingredient recipe
Although the product label lists ingredients, it does not list the formulation’s recipe, which is proprietary and often patented. The "recipe" includes the order that ingredients are added in the process, the pH, the amount of each ingredient, the temperature at which the ingredient is added, and many other important factors that determine the final chemistry. Ingredients like vitamin C, green tea, and argan oil are expensive when formulated properly. Many copycat brands, such as the Walgreens and CVS knockoffs, use the same ingredients. However, they cannot use the patented recipe, and therefore their end product is different.
B. Manufacturing and packaging process
How a product is made and packaged is crucial. For example, retinol breaks down when exposed to light and air. I once visited a manufacturing plant that was stirring its "antiaging" retinol preparation in open vats. The retinol was losing its activity, which is why the product was "less irritating." The process of packaging the completed product is also important. In some cases the product is formulated in one place and shipped to another location for final packaging – and several ingredients can lose their potency during transit. Finally, the container that the product is packaged in is important. Air and light can get into tubes, affecting the efficacy of a product.
C. Ingredient interactions
The order of application and the combination of ingredients affect stability, efficacy, safety, and the chemical structure. Master formulators understand that every ingredient in the formulation matters, and there is really no such thing as an inactive ingredient. Ingredients can affect penetration and render other ingredients more or less effective depending on the order in which the ingredients are used on the skin. For example, olive oil actually increases penetration of other ingredients because it has a high content of oleic acid, while safflower oil can decrease penetration by strengthening the skin barrier.
• Design the regimen and order of application of products.
Once you have determined your patient’s skin type and matched the proper products to their skin type, you must tell them exactly how to apply them. The order in which products are applied makes a difference. Consider ingredient interactions, ingredient penetration times, and cross-reactions, plus skin type factors such as the condition of the skin barrier, sebum production, thickness of the stratum corneum, sun exposure, and bathing habits. I recommend providing a printed regimen with step-by-step instructions for morning and night.
• Educate patients.
Take the time to educate your patients on their skin issues. If you explain why you chose each product and why the particular ingredients are important, they are more likely to be compliant and get better results (and return to you for product recommendations and repurchases). Because we do not have the time to sit and explain all of these issues to each patient, we use educational newsletters that we send to patients based on their Baumann Skin Type. This helps keep them engaged and educates them about new technologies and products that are appropriate for their skin type.
• Encourage compliance.
Schedule a follow-up visit after 1 month to check on their progress and ensure compliance, and emphasize the importance of this visit. If you prescribed a retinoid, patients may experience irritation and stop using it. If you have an imaging system, baseline and follow-up photos help illustrate patients’ progress and keep them vigilant. Four weeks is a good time frame because patients tend to lose interest at that point.
• Sell skin care products in your practice.
I was against selling skin care products for ethical reasons for several years. However, in 2005, I surveyed my patients, and 100% of them wanted me to sell products so that they could feel sure that they were purchasing the right products for their needs. In fact, my patients appreciate expert medical advice on skin care. As a practitioner, you can make more educated choices about skin care products and help them avoid products that don’t work or cause harm.
• Contact me for more information.
In order to improve patient outcomes, you must ensure that you stay current on skin care science so your patients can benefit from your expertise. I recognize that not everyone has the time and inclination to stay current on the various skin care ingredients, products, and brands. Several of my dermatology friends have adopted my skin typing system in their practices and, in the process, observed better patient outcomes and increased profitability, while reducing the burden on their staff. These successes led to the development of an in-office store system utilizing my concept, which I am offering only to dermatologists. Feel free to email me at DrB@derm.net, or visit STSFranchise.com, if you want to learn more.
• Look for this column each month.
I will be sharing more advice on in-office skin care retail and will continue my review of new cosmeceutical ingredients. Let’s work together to put skin care back in the hands of dermatologists.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Bellis perennis
Known also as the common daisy or English daisy, Bellis perennis is a perennial plant belonging to the Asteraceae or Compositae (aster, daisy, or sunflower) family. Native to Europe and North Africa, it has been used in traditional medicine in Europe since the Middle Ages to treat bruises, broken bones, muscle pain, cutaneous wounds, and rheumatism. Other skin applications include eczema, boils, inflammation, and purulent skin disease. In addition, B. perennis has been used in folk medicine to treat upper respiratory tract infections, gastritis, stomachache, diarrhea, bleeding, rheumatism, common colds, and headache (Pharm. Biol. 2014 March 12 [Epub ahead of print]; Pharm. Biol. 2012;50:1031-7; Chem. Pharm. Bull. [Tokyo] 2008;56:559-68; Chem. Pharm. Bull. [Tokyo] 2011;59:889-95; Lim, T.K. Edible Medicinal and Non-Medicinal Plants. Springer: Dordrecht, 2014, pp. 204-11).
Chemistry
B. perennis roots and flowers have been shown to contain several important bioactive constituents, including triterpene saponins, anthocyanins, flavonoids, polysaccharides, and polyacetylenes (Chem. Pharm. Bull. [Tokyo] 2008;56:559-68; SOFW J. 2005;131:40-9). In 2008, Morikawa et al. identified newly isolated triterpene saponins in B. perennis. These compounds, labeled as perennisosides I-VII, exhibited inhibitory activity on serum triglyceride elevation in olive oil–treated mice (J. Nat. Prod. 2008;71:828-35). That same year, Yoshikawa et al. isolated six new acylated oleanane-type triterpene oligoglycosides (perennisaponins A-F) from the flowers of B. perennis in addition to 14 saponins, 9 flavonoids, and 2 glycosides (Chem. Pharm. Bull. [Tokyo] 2008;56:559-68).
In 2011, Morikawa et al. isolated five new triterpene saponins (perennisosides VIII-XII) from the methanolic extract of B. perennis flowers. The extract was shown to suppress gastric emptying in olive oil–laded mice (Chem. Pharm. Bull. [Tokyo] 2011;59:889-95).
Early in 2014, Pehlivan et al. used bioassay-guided fractionation and isolation procedures to isolate an oleanane-type saponin from B. perennis that exhibited antitumor activity, the first such finding associated with B. perennis flowers. Tumor inhibition of 99% was achieved by the most active fraction at 3,000 mg/L (Pharm. Biol. 2014 March 12 [Epub ahead of print]).
Wound-healing capacity
In 2012, Karakas et al. studied the wound-healing activity displayed by the dried flowers of B. perennis in 12 male adult Wistar albino rats over a 30-day period. Six wounds were introduced onto each animal, with two treated topically once a day with a hydrophilic ointment containing an n-butanol fraction of B. perennis, two treated daily with the ointment minus the B. perennis fraction, and two untreated wounds used as control. Statistically significant differences were noted with 100% wound closure in the B. perennis group, 87% in the control group, and 85% in the other treatment group. The investigators concluded that their findings represented the first scientific confirmation supporting the traditional usage of B. perennis for wound healing. They noted that the topical administration of an ointment formulated with an n-butanol fraction of B. perennis flowers exhibits wound healing activity without inducing scars in a circular excision wound model in rats (Pharm. Biol. 2012;50:1031-7).
Antimicrobial activity against gram-positive and gram-negative bacteria, as well as anticancer activity against human leukemia cells in vitro, has also been associated with B. perennis (Lim, T.K. Edible Medicinal and Non-Medicinal Plants. Springer: Dordrecht, 2014, pp. 204-11).
Skin-lightening activity
Extracts of B. perennis are included in the product Belides that has been combined in a formulation with emblica and licorice for use as a skin-lightening agent. In 2010, Costa et al. conducted a monoblind clinical study to assess the clinical efficacy of the combination of Belides, emblica, and licorice 7%, compared with hydroquinone 2% for the treatment of epidermal or mixed melasma in 56 women aged 18-60 years. Subjects (ranging from Fitzpatrick skin type I to IV) exclusively used an SPF 35 sunscreen for 60 days before being selected for either the herbal combination cream treatment, applied twice daily, or the hydroquinone group, applied nightly.
Depigmentation was observed in 78.3% of the herbal combination group and 88.9% of the hydroquinone group, among the 23 volunteers in the herbal group and 27 in the hydroquinone group who completed the study. No statistically significant differences were found between the treatment regimens in ameliorating melasma, but fewer adverse cutaneous reactions were associated with the herbal treatment. The investigators found the combination of Belides, emblica, and licorice to be a safe and effective option for treating melasma (An. Bras. Dermatol. 2010;85:613-20). Previously, Belides was shown to be nearly twice as active as arbutin and an effective skin-lightening agent in a pilot study with human volunteers (SOFW J. 2005;131:40-9; Lim, T.K. Edible Medicinal and Non-Medicinal Plants. Springer: Dordrecht, 2014, pp. 204-11).
Conclusion
The roots and flowers of B. perennis have been used for many years in traditional medicine to treat various conditions, including skin disorders. While modern scientific interest has been piqued, the current body of evidence is meager. Much more research is necessary to determine the potential role of topical B. perennis in the dermatologic armamentarium. But recent data and the history of traditional use suggest that such research is warranted.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Known also as the common daisy or English daisy, Bellis perennis is a perennial plant belonging to the Asteraceae or Compositae (aster, daisy, or sunflower) family. Native to Europe and North Africa, it has been used in traditional medicine in Europe since the Middle Ages to treat bruises, broken bones, muscle pain, cutaneous wounds, and rheumatism. Other skin applications include eczema, boils, inflammation, and purulent skin disease. In addition, B. perennis has been used in folk medicine to treat upper respiratory tract infections, gastritis, stomachache, diarrhea, bleeding, rheumatism, common colds, and headache (Pharm. Biol. 2014 March 12 [Epub ahead of print]; Pharm. Biol. 2012;50:1031-7; Chem. Pharm. Bull. [Tokyo] 2008;56:559-68; Chem. Pharm. Bull. [Tokyo] 2011;59:889-95; Lim, T.K. Edible Medicinal and Non-Medicinal Plants. Springer: Dordrecht, 2014, pp. 204-11).
Chemistry
B. perennis roots and flowers have been shown to contain several important bioactive constituents, including triterpene saponins, anthocyanins, flavonoids, polysaccharides, and polyacetylenes (Chem. Pharm. Bull. [Tokyo] 2008;56:559-68; SOFW J. 2005;131:40-9). In 2008, Morikawa et al. identified newly isolated triterpene saponins in B. perennis. These compounds, labeled as perennisosides I-VII, exhibited inhibitory activity on serum triglyceride elevation in olive oil–treated mice (J. Nat. Prod. 2008;71:828-35). That same year, Yoshikawa et al. isolated six new acylated oleanane-type triterpene oligoglycosides (perennisaponins A-F) from the flowers of B. perennis in addition to 14 saponins, 9 flavonoids, and 2 glycosides (Chem. Pharm. Bull. [Tokyo] 2008;56:559-68).
In 2011, Morikawa et al. isolated five new triterpene saponins (perennisosides VIII-XII) from the methanolic extract of B. perennis flowers. The extract was shown to suppress gastric emptying in olive oil–laded mice (Chem. Pharm. Bull. [Tokyo] 2011;59:889-95).
Early in 2014, Pehlivan et al. used bioassay-guided fractionation and isolation procedures to isolate an oleanane-type saponin from B. perennis that exhibited antitumor activity, the first such finding associated with B. perennis flowers. Tumor inhibition of 99% was achieved by the most active fraction at 3,000 mg/L (Pharm. Biol. 2014 March 12 [Epub ahead of print]).
Wound-healing capacity
In 2012, Karakas et al. studied the wound-healing activity displayed by the dried flowers of B. perennis in 12 male adult Wistar albino rats over a 30-day period. Six wounds were introduced onto each animal, with two treated topically once a day with a hydrophilic ointment containing an n-butanol fraction of B. perennis, two treated daily with the ointment minus the B. perennis fraction, and two untreated wounds used as control. Statistically significant differences were noted with 100% wound closure in the B. perennis group, 87% in the control group, and 85% in the other treatment group. The investigators concluded that their findings represented the first scientific confirmation supporting the traditional usage of B. perennis for wound healing. They noted that the topical administration of an ointment formulated with an n-butanol fraction of B. perennis flowers exhibits wound healing activity without inducing scars in a circular excision wound model in rats (Pharm. Biol. 2012;50:1031-7).
Antimicrobial activity against gram-positive and gram-negative bacteria, as well as anticancer activity against human leukemia cells in vitro, has also been associated with B. perennis (Lim, T.K. Edible Medicinal and Non-Medicinal Plants. Springer: Dordrecht, 2014, pp. 204-11).
Skin-lightening activity
Extracts of B. perennis are included in the product Belides that has been combined in a formulation with emblica and licorice for use as a skin-lightening agent. In 2010, Costa et al. conducted a monoblind clinical study to assess the clinical efficacy of the combination of Belides, emblica, and licorice 7%, compared with hydroquinone 2% for the treatment of epidermal or mixed melasma in 56 women aged 18-60 years. Subjects (ranging from Fitzpatrick skin type I to IV) exclusively used an SPF 35 sunscreen for 60 days before being selected for either the herbal combination cream treatment, applied twice daily, or the hydroquinone group, applied nightly.
Depigmentation was observed in 78.3% of the herbal combination group and 88.9% of the hydroquinone group, among the 23 volunteers in the herbal group and 27 in the hydroquinone group who completed the study. No statistically significant differences were found between the treatment regimens in ameliorating melasma, but fewer adverse cutaneous reactions were associated with the herbal treatment. The investigators found the combination of Belides, emblica, and licorice to be a safe and effective option for treating melasma (An. Bras. Dermatol. 2010;85:613-20). Previously, Belides was shown to be nearly twice as active as arbutin and an effective skin-lightening agent in a pilot study with human volunteers (SOFW J. 2005;131:40-9; Lim, T.K. Edible Medicinal and Non-Medicinal Plants. Springer: Dordrecht, 2014, pp. 204-11).
Conclusion
The roots and flowers of B. perennis have been used for many years in traditional medicine to treat various conditions, including skin disorders. While modern scientific interest has been piqued, the current body of evidence is meager. Much more research is necessary to determine the potential role of topical B. perennis in the dermatologic armamentarium. But recent data and the history of traditional use suggest that such research is warranted.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Known also as the common daisy or English daisy, Bellis perennis is a perennial plant belonging to the Asteraceae or Compositae (aster, daisy, or sunflower) family. Native to Europe and North Africa, it has been used in traditional medicine in Europe since the Middle Ages to treat bruises, broken bones, muscle pain, cutaneous wounds, and rheumatism. Other skin applications include eczema, boils, inflammation, and purulent skin disease. In addition, B. perennis has been used in folk medicine to treat upper respiratory tract infections, gastritis, stomachache, diarrhea, bleeding, rheumatism, common colds, and headache (Pharm. Biol. 2014 March 12 [Epub ahead of print]; Pharm. Biol. 2012;50:1031-7; Chem. Pharm. Bull. [Tokyo] 2008;56:559-68; Chem. Pharm. Bull. [Tokyo] 2011;59:889-95; Lim, T.K. Edible Medicinal and Non-Medicinal Plants. Springer: Dordrecht, 2014, pp. 204-11).
Chemistry
B. perennis roots and flowers have been shown to contain several important bioactive constituents, including triterpene saponins, anthocyanins, flavonoids, polysaccharides, and polyacetylenes (Chem. Pharm. Bull. [Tokyo] 2008;56:559-68; SOFW J. 2005;131:40-9). In 2008, Morikawa et al. identified newly isolated triterpene saponins in B. perennis. These compounds, labeled as perennisosides I-VII, exhibited inhibitory activity on serum triglyceride elevation in olive oil–treated mice (J. Nat. Prod. 2008;71:828-35). That same year, Yoshikawa et al. isolated six new acylated oleanane-type triterpene oligoglycosides (perennisaponins A-F) from the flowers of B. perennis in addition to 14 saponins, 9 flavonoids, and 2 glycosides (Chem. Pharm. Bull. [Tokyo] 2008;56:559-68).
In 2011, Morikawa et al. isolated five new triterpene saponins (perennisosides VIII-XII) from the methanolic extract of B. perennis flowers. The extract was shown to suppress gastric emptying in olive oil–laded mice (Chem. Pharm. Bull. [Tokyo] 2011;59:889-95).
Early in 2014, Pehlivan et al. used bioassay-guided fractionation and isolation procedures to isolate an oleanane-type saponin from B. perennis that exhibited antitumor activity, the first such finding associated with B. perennis flowers. Tumor inhibition of 99% was achieved by the most active fraction at 3,000 mg/L (Pharm. Biol. 2014 March 12 [Epub ahead of print]).
Wound-healing capacity
In 2012, Karakas et al. studied the wound-healing activity displayed by the dried flowers of B. perennis in 12 male adult Wistar albino rats over a 30-day period. Six wounds were introduced onto each animal, with two treated topically once a day with a hydrophilic ointment containing an n-butanol fraction of B. perennis, two treated daily with the ointment minus the B. perennis fraction, and two untreated wounds used as control. Statistically significant differences were noted with 100% wound closure in the B. perennis group, 87% in the control group, and 85% in the other treatment group. The investigators concluded that their findings represented the first scientific confirmation supporting the traditional usage of B. perennis for wound healing. They noted that the topical administration of an ointment formulated with an n-butanol fraction of B. perennis flowers exhibits wound healing activity without inducing scars in a circular excision wound model in rats (Pharm. Biol. 2012;50:1031-7).
Antimicrobial activity against gram-positive and gram-negative bacteria, as well as anticancer activity against human leukemia cells in vitro, has also been associated with B. perennis (Lim, T.K. Edible Medicinal and Non-Medicinal Plants. Springer: Dordrecht, 2014, pp. 204-11).
Skin-lightening activity
Extracts of B. perennis are included in the product Belides that has been combined in a formulation with emblica and licorice for use as a skin-lightening agent. In 2010, Costa et al. conducted a monoblind clinical study to assess the clinical efficacy of the combination of Belides, emblica, and licorice 7%, compared with hydroquinone 2% for the treatment of epidermal or mixed melasma in 56 women aged 18-60 years. Subjects (ranging from Fitzpatrick skin type I to IV) exclusively used an SPF 35 sunscreen for 60 days before being selected for either the herbal combination cream treatment, applied twice daily, or the hydroquinone group, applied nightly.
Depigmentation was observed in 78.3% of the herbal combination group and 88.9% of the hydroquinone group, among the 23 volunteers in the herbal group and 27 in the hydroquinone group who completed the study. No statistically significant differences were found between the treatment regimens in ameliorating melasma, but fewer adverse cutaneous reactions were associated with the herbal treatment. The investigators found the combination of Belides, emblica, and licorice to be a safe and effective option for treating melasma (An. Bras. Dermatol. 2010;85:613-20). Previously, Belides was shown to be nearly twice as active as arbutin and an effective skin-lightening agent in a pilot study with human volunteers (SOFW J. 2005;131:40-9; Lim, T.K. Edible Medicinal and Non-Medicinal Plants. Springer: Dordrecht, 2014, pp. 204-11).
Conclusion
The roots and flowers of B. perennis have been used for many years in traditional medicine to treat various conditions, including skin disorders. While modern scientific interest has been piqued, the current body of evidence is meager. Much more research is necessary to determine the potential role of topical B. perennis in the dermatologic armamentarium. But recent data and the history of traditional use suggest that such research is warranted.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Cosmeceutical Critique: Benzoyl peroxide
Benzoyl peroxide (BPO) has been used for more than 45 years for the treatment of acne, and has recently been enjoying renewed popularity, thanks to its performance in recent studies of both prescription and over-the-counter formulations (J. Drugs Dermatol. 2013;12:180-5). In fact, BPO is one of the two most common ingredients in OTC acne products (Semin. Cutan. Med. Surg. 2008;27:170-6). The prescription form is used alone or in combination with tretinoin, adapalene, or clindamycin. BPO, originally sourced from the coal tar component chlorhydroxyquinoline, is now typically prepared by treating hydrogen peroxide with benzoyl chloride (Dermatol. Clin. 2009;27:17-24). Because it can generate reactive oxygen species and commonly leads to skin irritation, its use is somewhat limited.
Antibacterial uses
BPO imparts bactericidal activity by releasing highly reactive oxygen (free radicals) that can oxidize proteins in bacterial cell membranes. It also exhibits antibacterial action against Propionibacterium acnes and Corynebacterium acnes, the bacteria implicated in the pathophysiology of acne (Dermatol. Ther. 2012;25:6-11), as well as Staphylococcus capitis, S. epidermis, S. hominis, P. avidum, P. granulosum, and the yeast Pityrosporum ovale (J. Appl. Bacteriol. 1983;54:379-82).
Acne
Many studies over the years have shown that topically applied BPO effectively treats acne (Expert Opin. Pharmacother. 2009;10:2555-62). These ameliorative results, which include enhancing the benefits of other topical antimicrobials, are thought to arise because BPO, a highly lipophilic molecule, penetrates through the sebum and into the pilosebaceous unit, and exerts bactericidal, keratolytic, and anti-inflammatory activity (Skin Pharmacol. Physiol. 2006;19:283-9). BPO may contribute to the antiacne efficacy of other antimicrobials by preventing bacterial resistance and promoting penetration into the sebum, keratin, and polysaccharides to reach the target bacteria. Specifically, the oxidative activity of BPO helps eliminate the biofilm polysaccharides secreted by P. acnes, thus expediting the delivery of other agents to the bacteria (Int. J. Dermatol. 2006;45:872; Int. J. Dermatol. 2003;42:925-7).
Not surprisingly, several studies have shown that the antiacne efficacy of a combination of BPO with other antimicrobials, such as clindamycin, is greater than that of either agent used alone. Simpson et al. demonstrated that the use of clindamycin and BPO together led to a 61% decline in inflammatory lesions after 3 months, as compared with 39% and 35%, respectively, when the agents were used alone (J. Am. Acad. Dermatol. 1997;37:590-5). BPO is frequently paired with salicylic acid to treat acne (Clin. Exp. Dermatol. 2011;36:840-3).
Acne often improves more rapidly with BPO treatment than with retinoids and other acne therapies, and data suggest that the faster clearing of acne lesions and comedones is most likely because of its keratolytic activity (Dermatol. Clin. 2009;27:17-24; J. Dermatolog. Treat. 2003;14:166-71). However, the dryness and irritation associated with BPO usage may undermine patient compliance. Several studies have suggested that BPO is effective in cleanser formulations, which seem to reduce irritation (Clin. Exp. Dermatol. 2011;36:840-3).
Photocarcinogenicity
Reports that BPO predisposed mice to skin cancer, particularly when they were exposed to ultraviolet radiation, prompted the Food and Drug Administration to form an advisory committee in 1992 to review the safety of BPO. The committee called for additional photocarcinogenicity studies while suggesting that BPO products include animal safety data on the labels. BPO-containing acne products were kept on the market. In the ensuing two decades, newer safety studies have led the FDA to change the classification of BPO to category I, deeming the OTC topical treatment of acne to be generally recognized as safe and effective (GRASE) (Fed. Regist. 2010;75:9767-77).
Photoaging
When BPO breaks down into benzoic acid in the skin, benzoyloxy, a free radical, forms as an intermediate (Prog. Clin. Biol. Res. 1995;391:245). Benzoyloxy can decarboxylate into a phenyl radical. These free radicals produce oxidative stress, which may cause DNA strand breaks in keratinocytes or may harm proteins or lipids. In addition to becoming a free radical, BPO depletes membrane and cytosolic antioxidants (Toxicology 2001;165:225-34). No retrospective trials looking at the effects of long-term use of BP on photoaging have been performed, so the role of BPO in photoaging is not clear. One study in mice found that topical BP has some of the same effects on skin as UVB (J. Invest. Dermatol. 1999;112:933-38).
Other safety issues
Acne is not uncommon among pregnant women. Although safety studies of BPO use by pregnant women have not been performed, various authors suggest that only about 5% of topically applied BPO is absorbed systemically, implying that topical BPO can be safely used during pregnancy (Int. J. Dermatol. 2002;41:197-203; Can. Fam. Physician 2011;57:665-7; Drugs 2013;73:779-87; Dermatol. Ther. 2013;26:302-11).
In approximately 1% of patients, topical BPO causes contact or irritant dermatitis (Contact Dermatitis 1999;41:233; Contact Dermatitis 1996;34:68-9). The use of barrier repair moisturizers may reduce the incidence of irritation, though this has not been proven.
Usage considerations
BPO use for acne is linked to a reduction in antibiotic resistance (J. Drugs Dermatol. 2013;12:s73-6). Because BPO, a potent oxidizer, eliminates bacteria by generating reactive oxygen species in the sebaceous follicle, it is important to consider the chemical compatibility of BPO with other agents (J. Am. Acad. Dermatol. 1981;4:31-7). Martin et al. showed that BPO tends to degrade tretinoin to about 80% of initial content, an effect that is markedly enhanced by indoor light. However, even in the presence of light, adapalene is not degraded by BPO (Br. J. Dermatol. 1998;139 Suppl 52:8-11). But the order in which products are applied is important, given that BPO can inactivate other ingredients.
Studies have demonstrated that the use of BPO in body washes leads to greater efficacy when the product is left on for 5 minutes before rinsing (J. Drugs Dermatol. 2010;9:622-5; J. Clin. Aesthet. Dermatol. 2010;3:26-9). Notably, the efficacy of BPO in cleansing products is comparable to that observed in leave-on products, but BPO provokes less irritation than leave-on formulations (J. Drugs Dermatol. 2009;8:657-61; Skinmed. 2005;4:370).
Conclusion
BPO remains quite effective in acne therapy, and it is one of the few acne medications available both over the counter and by prescription in the United States. BPO helps prevent antibiotic resistance to erythromycin and clindamycin, which makes it an important ingredient in many acne skin care regimens. However, it is pro-oxidant, and clinicians and patients should take into account the risk of BPO contributing to skin aging because of the free radicals it produces.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Benzoyl peroxide (BPO) has been used for more than 45 years for the treatment of acne, and has recently been enjoying renewed popularity, thanks to its performance in recent studies of both prescription and over-the-counter formulations (J. Drugs Dermatol. 2013;12:180-5). In fact, BPO is one of the two most common ingredients in OTC acne products (Semin. Cutan. Med. Surg. 2008;27:170-6). The prescription form is used alone or in combination with tretinoin, adapalene, or clindamycin. BPO, originally sourced from the coal tar component chlorhydroxyquinoline, is now typically prepared by treating hydrogen peroxide with benzoyl chloride (Dermatol. Clin. 2009;27:17-24). Because it can generate reactive oxygen species and commonly leads to skin irritation, its use is somewhat limited.
Antibacterial uses
BPO imparts bactericidal activity by releasing highly reactive oxygen (free radicals) that can oxidize proteins in bacterial cell membranes. It also exhibits antibacterial action against Propionibacterium acnes and Corynebacterium acnes, the bacteria implicated in the pathophysiology of acne (Dermatol. Ther. 2012;25:6-11), as well as Staphylococcus capitis, S. epidermis, S. hominis, P. avidum, P. granulosum, and the yeast Pityrosporum ovale (J. Appl. Bacteriol. 1983;54:379-82).
Acne
Many studies over the years have shown that topically applied BPO effectively treats acne (Expert Opin. Pharmacother. 2009;10:2555-62). These ameliorative results, which include enhancing the benefits of other topical antimicrobials, are thought to arise because BPO, a highly lipophilic molecule, penetrates through the sebum and into the pilosebaceous unit, and exerts bactericidal, keratolytic, and anti-inflammatory activity (Skin Pharmacol. Physiol. 2006;19:283-9). BPO may contribute to the antiacne efficacy of other antimicrobials by preventing bacterial resistance and promoting penetration into the sebum, keratin, and polysaccharides to reach the target bacteria. Specifically, the oxidative activity of BPO helps eliminate the biofilm polysaccharides secreted by P. acnes, thus expediting the delivery of other agents to the bacteria (Int. J. Dermatol. 2006;45:872; Int. J. Dermatol. 2003;42:925-7).
Not surprisingly, several studies have shown that the antiacne efficacy of a combination of BPO with other antimicrobials, such as clindamycin, is greater than that of either agent used alone. Simpson et al. demonstrated that the use of clindamycin and BPO together led to a 61% decline in inflammatory lesions after 3 months, as compared with 39% and 35%, respectively, when the agents were used alone (J. Am. Acad. Dermatol. 1997;37:590-5). BPO is frequently paired with salicylic acid to treat acne (Clin. Exp. Dermatol. 2011;36:840-3).
Acne often improves more rapidly with BPO treatment than with retinoids and other acne therapies, and data suggest that the faster clearing of acne lesions and comedones is most likely because of its keratolytic activity (Dermatol. Clin. 2009;27:17-24; J. Dermatolog. Treat. 2003;14:166-71). However, the dryness and irritation associated with BPO usage may undermine patient compliance. Several studies have suggested that BPO is effective in cleanser formulations, which seem to reduce irritation (Clin. Exp. Dermatol. 2011;36:840-3).
Photocarcinogenicity
Reports that BPO predisposed mice to skin cancer, particularly when they were exposed to ultraviolet radiation, prompted the Food and Drug Administration to form an advisory committee in 1992 to review the safety of BPO. The committee called for additional photocarcinogenicity studies while suggesting that BPO products include animal safety data on the labels. BPO-containing acne products were kept on the market. In the ensuing two decades, newer safety studies have led the FDA to change the classification of BPO to category I, deeming the OTC topical treatment of acne to be generally recognized as safe and effective (GRASE) (Fed. Regist. 2010;75:9767-77).
Photoaging
When BPO breaks down into benzoic acid in the skin, benzoyloxy, a free radical, forms as an intermediate (Prog. Clin. Biol. Res. 1995;391:245). Benzoyloxy can decarboxylate into a phenyl radical. These free radicals produce oxidative stress, which may cause DNA strand breaks in keratinocytes or may harm proteins or lipids. In addition to becoming a free radical, BPO depletes membrane and cytosolic antioxidants (Toxicology 2001;165:225-34). No retrospective trials looking at the effects of long-term use of BP on photoaging have been performed, so the role of BPO in photoaging is not clear. One study in mice found that topical BP has some of the same effects on skin as UVB (J. Invest. Dermatol. 1999;112:933-38).
Other safety issues
Acne is not uncommon among pregnant women. Although safety studies of BPO use by pregnant women have not been performed, various authors suggest that only about 5% of topically applied BPO is absorbed systemically, implying that topical BPO can be safely used during pregnancy (Int. J. Dermatol. 2002;41:197-203; Can. Fam. Physician 2011;57:665-7; Drugs 2013;73:779-87; Dermatol. Ther. 2013;26:302-11).
In approximately 1% of patients, topical BPO causes contact or irritant dermatitis (Contact Dermatitis 1999;41:233; Contact Dermatitis 1996;34:68-9). The use of barrier repair moisturizers may reduce the incidence of irritation, though this has not been proven.
Usage considerations
BPO use for acne is linked to a reduction in antibiotic resistance (J. Drugs Dermatol. 2013;12:s73-6). Because BPO, a potent oxidizer, eliminates bacteria by generating reactive oxygen species in the sebaceous follicle, it is important to consider the chemical compatibility of BPO with other agents (J. Am. Acad. Dermatol. 1981;4:31-7). Martin et al. showed that BPO tends to degrade tretinoin to about 80% of initial content, an effect that is markedly enhanced by indoor light. However, even in the presence of light, adapalene is not degraded by BPO (Br. J. Dermatol. 1998;139 Suppl 52:8-11). But the order in which products are applied is important, given that BPO can inactivate other ingredients.
Studies have demonstrated that the use of BPO in body washes leads to greater efficacy when the product is left on for 5 minutes before rinsing (J. Drugs Dermatol. 2010;9:622-5; J. Clin. Aesthet. Dermatol. 2010;3:26-9). Notably, the efficacy of BPO in cleansing products is comparable to that observed in leave-on products, but BPO provokes less irritation than leave-on formulations (J. Drugs Dermatol. 2009;8:657-61; Skinmed. 2005;4:370).
Conclusion
BPO remains quite effective in acne therapy, and it is one of the few acne medications available both over the counter and by prescription in the United States. BPO helps prevent antibiotic resistance to erythromycin and clindamycin, which makes it an important ingredient in many acne skin care regimens. However, it is pro-oxidant, and clinicians and patients should take into account the risk of BPO contributing to skin aging because of the free radicals it produces.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Benzoyl peroxide (BPO) has been used for more than 45 years for the treatment of acne, and has recently been enjoying renewed popularity, thanks to its performance in recent studies of both prescription and over-the-counter formulations (J. Drugs Dermatol. 2013;12:180-5). In fact, BPO is one of the two most common ingredients in OTC acne products (Semin. Cutan. Med. Surg. 2008;27:170-6). The prescription form is used alone or in combination with tretinoin, adapalene, or clindamycin. BPO, originally sourced from the coal tar component chlorhydroxyquinoline, is now typically prepared by treating hydrogen peroxide with benzoyl chloride (Dermatol. Clin. 2009;27:17-24). Because it can generate reactive oxygen species and commonly leads to skin irritation, its use is somewhat limited.
Antibacterial uses
BPO imparts bactericidal activity by releasing highly reactive oxygen (free radicals) that can oxidize proteins in bacterial cell membranes. It also exhibits antibacterial action against Propionibacterium acnes and Corynebacterium acnes, the bacteria implicated in the pathophysiology of acne (Dermatol. Ther. 2012;25:6-11), as well as Staphylococcus capitis, S. epidermis, S. hominis, P. avidum, P. granulosum, and the yeast Pityrosporum ovale (J. Appl. Bacteriol. 1983;54:379-82).
Acne
Many studies over the years have shown that topically applied BPO effectively treats acne (Expert Opin. Pharmacother. 2009;10:2555-62). These ameliorative results, which include enhancing the benefits of other topical antimicrobials, are thought to arise because BPO, a highly lipophilic molecule, penetrates through the sebum and into the pilosebaceous unit, and exerts bactericidal, keratolytic, and anti-inflammatory activity (Skin Pharmacol. Physiol. 2006;19:283-9). BPO may contribute to the antiacne efficacy of other antimicrobials by preventing bacterial resistance and promoting penetration into the sebum, keratin, and polysaccharides to reach the target bacteria. Specifically, the oxidative activity of BPO helps eliminate the biofilm polysaccharides secreted by P. acnes, thus expediting the delivery of other agents to the bacteria (Int. J. Dermatol. 2006;45:872; Int. J. Dermatol. 2003;42:925-7).
Not surprisingly, several studies have shown that the antiacne efficacy of a combination of BPO with other antimicrobials, such as clindamycin, is greater than that of either agent used alone. Simpson et al. demonstrated that the use of clindamycin and BPO together led to a 61% decline in inflammatory lesions after 3 months, as compared with 39% and 35%, respectively, when the agents were used alone (J. Am. Acad. Dermatol. 1997;37:590-5). BPO is frequently paired with salicylic acid to treat acne (Clin. Exp. Dermatol. 2011;36:840-3).
Acne often improves more rapidly with BPO treatment than with retinoids and other acne therapies, and data suggest that the faster clearing of acne lesions and comedones is most likely because of its keratolytic activity (Dermatol. Clin. 2009;27:17-24; J. Dermatolog. Treat. 2003;14:166-71). However, the dryness and irritation associated with BPO usage may undermine patient compliance. Several studies have suggested that BPO is effective in cleanser formulations, which seem to reduce irritation (Clin. Exp. Dermatol. 2011;36:840-3).
Photocarcinogenicity
Reports that BPO predisposed mice to skin cancer, particularly when they were exposed to ultraviolet radiation, prompted the Food and Drug Administration to form an advisory committee in 1992 to review the safety of BPO. The committee called for additional photocarcinogenicity studies while suggesting that BPO products include animal safety data on the labels. BPO-containing acne products were kept on the market. In the ensuing two decades, newer safety studies have led the FDA to change the classification of BPO to category I, deeming the OTC topical treatment of acne to be generally recognized as safe and effective (GRASE) (Fed. Regist. 2010;75:9767-77).
Photoaging
When BPO breaks down into benzoic acid in the skin, benzoyloxy, a free radical, forms as an intermediate (Prog. Clin. Biol. Res. 1995;391:245). Benzoyloxy can decarboxylate into a phenyl radical. These free radicals produce oxidative stress, which may cause DNA strand breaks in keratinocytes or may harm proteins or lipids. In addition to becoming a free radical, BPO depletes membrane and cytosolic antioxidants (Toxicology 2001;165:225-34). No retrospective trials looking at the effects of long-term use of BP on photoaging have been performed, so the role of BPO in photoaging is not clear. One study in mice found that topical BP has some of the same effects on skin as UVB (J. Invest. Dermatol. 1999;112:933-38).
Other safety issues
Acne is not uncommon among pregnant women. Although safety studies of BPO use by pregnant women have not been performed, various authors suggest that only about 5% of topically applied BPO is absorbed systemically, implying that topical BPO can be safely used during pregnancy (Int. J. Dermatol. 2002;41:197-203; Can. Fam. Physician 2011;57:665-7; Drugs 2013;73:779-87; Dermatol. Ther. 2013;26:302-11).
In approximately 1% of patients, topical BPO causes contact or irritant dermatitis (Contact Dermatitis 1999;41:233; Contact Dermatitis 1996;34:68-9). The use of barrier repair moisturizers may reduce the incidence of irritation, though this has not been proven.
Usage considerations
BPO use for acne is linked to a reduction in antibiotic resistance (J. Drugs Dermatol. 2013;12:s73-6). Because BPO, a potent oxidizer, eliminates bacteria by generating reactive oxygen species in the sebaceous follicle, it is important to consider the chemical compatibility of BPO with other agents (J. Am. Acad. Dermatol. 1981;4:31-7). Martin et al. showed that BPO tends to degrade tretinoin to about 80% of initial content, an effect that is markedly enhanced by indoor light. However, even in the presence of light, adapalene is not degraded by BPO (Br. J. Dermatol. 1998;139 Suppl 52:8-11). But the order in which products are applied is important, given that BPO can inactivate other ingredients.
Studies have demonstrated that the use of BPO in body washes leads to greater efficacy when the product is left on for 5 minutes before rinsing (J. Drugs Dermatol. 2010;9:622-5; J. Clin. Aesthet. Dermatol. 2010;3:26-9). Notably, the efficacy of BPO in cleansing products is comparable to that observed in leave-on products, but BPO provokes less irritation than leave-on formulations (J. Drugs Dermatol. 2009;8:657-61; Skinmed. 2005;4:370).
Conclusion
BPO remains quite effective in acne therapy, and it is one of the few acne medications available both over the counter and by prescription in the United States. BPO helps prevent antibiotic resistance to erythromycin and clindamycin, which makes it an important ingredient in many acne skin care regimens. However, it is pro-oxidant, and clinicians and patients should take into account the risk of BPO contributing to skin aging because of the free radicals it produces.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Titanium dioxide
Titanium dioxide (TiO2) and zinc oxide (ZnO) in large-particle form have long been used in various sunscreens to protect the skin by reflecting or physically blocking ultraviolet (UV) radiation. In recent years, TiO2 as well as ZnO nanoparticles have been incorporated into sunscreens and cosmetics to act as a UV shield. They have been shown to be effective barriers against UV-induced damage, and yield stronger protection against UV insult, while leaving less white residue, than previous generations of the physical sunblocks.
However, some data suggest that in nanoparticle form, TiO2 and ZnO absorb UV radiation, leading to photocatalysis and the release of reactive oxygen species (Australas. J. Dermatol. 2011;52:1-6). This column will focus primarily on the safety of TiO2 in nanoparticle form.
While numerous studies examine both TiO2 and ZnO, the primary inorganic sunscreens, the sheer number of separate investigations warrants individual articles, and ZnO was addressed in previous columns. Briefly, though, TiO2 is more photoactive and exhibits a higher refractive index in visible light than ZnO (J. Am. Acad. Dermatol. 1999;40:85-90); therefore, TiO2 appears whiter and is more difficult to incorporate into transparent products.
A 2011 study by Kang et al. showed that TiO2 nanoparticles, but not normal-sized TiO2, and UVA synergistically foster rapid production of reactive oxygen species and breakdown of mitochondrial membrane potential, leading to apoptosis, and that TiO2 nanoparticles are more phototoxic than larger ones (Drug Chem. Toxicol. 2011;34:277-84).
However, also in 2011, Tyner et al. investigated the effects of nanoscale TiO2 use on UV attenuation in simple to complex sunscreen products. They found that barrier function was diminished by none of the formulations, and that optimal UV attenuation resulted when TiO2 particles were stabilized with a coating and evenly dispersed. The researchers concluded that nanoscale TiO2 is nontoxic and may impart greater efficacy (Int. J. Cosmet. Sci. 2011;33:234-44).
In vitro and in vivo studies
In 2010, Tiano et al. evaluated five modified TiO2 particles, developed and marketed for sunscreens. They used different in vitro models, including cultured human skin fibroblasts, to determine potential photocatalytic effects after UVA exposure. The investigators found that the kind of modification to and crystal form of the TiO2 nanoparticle influences its ability to augment or reduce DNA damage, increase or decrease intracellular reactive oxygen species, diminish cell viability, and promote other effects of photocatalysis. In particular, they noted that the anatase crystal form of TiO2 retained photocatalytic activity. The authors suggested that while the debate continues over the penetration of nanosized TiO2 into the viable epidermis, their results help elucidate the potential effects of TiO2 particles at the cellular level (Free Radic. Biol. Med. 2010;49:408-15).
A 2010 study by Senzui et al. using in vitro intact, stripped, and hair-removed skin of Yucatan micropigs to test the skin penetration of four different types of rutile (the most natural form of) TiO2 (two coated, two uncoated) revealed no penetration of TiO2 type in intact and stripped skin. The concentration of titanium in skin was significantly higher when one of the coated forms was applied on hair-removed skin, with titanium penetrating into vacant hair follicles (greater than 1 mm below the skin surface), but not into dermis or viable epidermis (J. Toxicol. Sci. 2010;35:107-13).
Animal studies
In 2009, the Food and Drug Administration Center for Drug Evaluation and Research worked with the National Center for Toxicology Research using minipigs and four sunscreen formulations to determine whether nanoscale TiO2 can penetrate intact skin. Their use of scanning electron microscopy and x-ray diffraction revealed that TiO2 particles were the same size as that observed for the raw materials, implying that the formulation process influenced neither the size nor the shape of TiO2 particles (Drug Dev. Ind. Pharm. 2009;35:1180-9).
In 2010, Sadrieh et al. performed a study of the dermal penetration of three TiO2 particles: uncoated submicrometer-sized, uncoated nano-sized, and dimethicone/methicone copolymer-coated nanosized. The investigators applied 5% by weight of each of the types of particles in a sunscreen on minipigs and found no significant penetration into intact normal epidermis (Toxicol. Sci. 2010;115(1):156-66).
In 2011, Furukawa et al. studied the postinitiation carcinogenic potential of coated and uncoated TiO2 nanoparticles in a two-stage skin carcinogenesis model using 7-week-old CD1 (ICR) female mice. They found that application of coated and uncoated nanoparticles after initiation and promotion with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol 13-acetate at doses of up to 20 mg/mouse failed to augment nodule development. The investigators concluded that TiO2 nanoparticles do not exhibit postinitiation potential for mouse skin carcinogenesis (Food Chem. Toxicol. 2011;49(4):744-9).
Human data
Given the persistent concerns about possible side effects of coated TiO2 and ZnO nanoparticles used in physical sun blockers, Filipe et al., in 2009, assessed the localization and potential skin penetration of TiO2 and ZnO nanoparticles dispersed in three sunscreen formulations, under realistic in vivo conditions in normal and altered skin. The investigators examined a test hydrophobic formulation containing coated 20-nm TiO2 nanoparticles and two commercially available sunscreen formulations containing TiO2 alone or in combination with ZnO, with respect to how consumers actually used sunscreens compared with the recommended standard condition for the sun protection factor test. They found that traces of the physical blockers could be detected only at the skin surface and uppermost area of the stratum corneum in normal human skin after a 2-hour exposure. After 48 hours of exposure, layers deeper than the stratum corneum contained no detectable TiO2 or ZnO nanoparticles. While preferential deposition of the nanoparticles in the openings of pilosebaceous follicles was noted, no penetration into viable skin tissue was observed. The investigators concluded that significant penetration of TiO2 or ZnO nanoparticles into keratinocytes is improbable (Skin Pharmacol. Physiol. 2009;22:266-75).
The weight of evidence
Current evidence suggests minimal risks to human health from the use of TiO2 or ZnO nanoparticles at concentrations up to 25% in cosmetic preparations or sunscreens, according to Schilling et al., regardless of coatings or crystalline structure. In a safety review of these ingredients, they noted that these nanoparticles formulated in topical products occur as aggregates of primary particles 30-150 nm in size, and bond in such a way that renders them impervious to the force of product application. Thus their structure remains unaffected, and no primary particles are released. The authors also noted that nanoparticles exhibit equivalence with larger particles in terms of distribution and duration and, therefore, recognition and elimination from the body (Photochem. Photobiol. Sci. 2010;9:495-509).
But in 2011, Tran and Salmon, in light of findings that nanoparticles may penetrate the stratum corneum under certain conditions, considered the possible photocarcinogenic results of nanoparticle sunscreens. They noted, though, that most such results were obtained through the use of animal skin models, not investigations with human skin (Australas. J. Dermatol. 2011;52:1-6). To this point, the weight of evidence appears to show that such TiO2 nanoparticles are safe when applied to intact human skin (Semin. Cutan. Med. Surg. 2011;30:210-13).
In response to the increased scrutiny and concern exhibited by the general public and government agencies regarding the safety of TiO2 and ZnO nanoparticles, Newman et al. reviewed the literature and position statements from 1980 to 2008 to ascertain and describe the use, safety, and regulatory state of such ingredients in sunscreens. They found no evidence of significant penetration deeper than the stratum corneum of TiO2 and ZnO nanoparticles, but caution that additional studies simulating real-world conditions (i.e., sunburned skin and under UV exposure) are necessary (J. Am. Acad. Dermatol. 2009;61:685-92).
Conclusion
Titanium dioxide is a well-established, safe, and effective physical sunblock. Nanotechnology has introduced some cause for concern regarding its use in physical sunblocks. In particular, evidence suggesting that photoexcitation of TiO2 nanoparticles leads to the generation of reactive oxygen species that damage DNA, potentially launching a cascade of adverse events, has prompted investigations into the safety of TiO2 in nanoparticle form. However, to date, multiple studies suggest that TiO2 nanoparticles do not penetrate or are highly unlikely to penetrate beyond the stratum corneum.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Titanium dioxide (TiO2) and zinc oxide (ZnO) in large-particle form have long been used in various sunscreens to protect the skin by reflecting or physically blocking ultraviolet (UV) radiation. In recent years, TiO2 as well as ZnO nanoparticles have been incorporated into sunscreens and cosmetics to act as a UV shield. They have been shown to be effective barriers against UV-induced damage, and yield stronger protection against UV insult, while leaving less white residue, than previous generations of the physical sunblocks.
However, some data suggest that in nanoparticle form, TiO2 and ZnO absorb UV radiation, leading to photocatalysis and the release of reactive oxygen species (Australas. J. Dermatol. 2011;52:1-6). This column will focus primarily on the safety of TiO2 in nanoparticle form.
While numerous studies examine both TiO2 and ZnO, the primary inorganic sunscreens, the sheer number of separate investigations warrants individual articles, and ZnO was addressed in previous columns. Briefly, though, TiO2 is more photoactive and exhibits a higher refractive index in visible light than ZnO (J. Am. Acad. Dermatol. 1999;40:85-90); therefore, TiO2 appears whiter and is more difficult to incorporate into transparent products.
A 2011 study by Kang et al. showed that TiO2 nanoparticles, but not normal-sized TiO2, and UVA synergistically foster rapid production of reactive oxygen species and breakdown of mitochondrial membrane potential, leading to apoptosis, and that TiO2 nanoparticles are more phototoxic than larger ones (Drug Chem. Toxicol. 2011;34:277-84).
However, also in 2011, Tyner et al. investigated the effects of nanoscale TiO2 use on UV attenuation in simple to complex sunscreen products. They found that barrier function was diminished by none of the formulations, and that optimal UV attenuation resulted when TiO2 particles were stabilized with a coating and evenly dispersed. The researchers concluded that nanoscale TiO2 is nontoxic and may impart greater efficacy (Int. J. Cosmet. Sci. 2011;33:234-44).
In vitro and in vivo studies
In 2010, Tiano et al. evaluated five modified TiO2 particles, developed and marketed for sunscreens. They used different in vitro models, including cultured human skin fibroblasts, to determine potential photocatalytic effects after UVA exposure. The investigators found that the kind of modification to and crystal form of the TiO2 nanoparticle influences its ability to augment or reduce DNA damage, increase or decrease intracellular reactive oxygen species, diminish cell viability, and promote other effects of photocatalysis. In particular, they noted that the anatase crystal form of TiO2 retained photocatalytic activity. The authors suggested that while the debate continues over the penetration of nanosized TiO2 into the viable epidermis, their results help elucidate the potential effects of TiO2 particles at the cellular level (Free Radic. Biol. Med. 2010;49:408-15).
A 2010 study by Senzui et al. using in vitro intact, stripped, and hair-removed skin of Yucatan micropigs to test the skin penetration of four different types of rutile (the most natural form of) TiO2 (two coated, two uncoated) revealed no penetration of TiO2 type in intact and stripped skin. The concentration of titanium in skin was significantly higher when one of the coated forms was applied on hair-removed skin, with titanium penetrating into vacant hair follicles (greater than 1 mm below the skin surface), but not into dermis or viable epidermis (J. Toxicol. Sci. 2010;35:107-13).
Animal studies
In 2009, the Food and Drug Administration Center for Drug Evaluation and Research worked with the National Center for Toxicology Research using minipigs and four sunscreen formulations to determine whether nanoscale TiO2 can penetrate intact skin. Their use of scanning electron microscopy and x-ray diffraction revealed that TiO2 particles were the same size as that observed for the raw materials, implying that the formulation process influenced neither the size nor the shape of TiO2 particles (Drug Dev. Ind. Pharm. 2009;35:1180-9).
In 2010, Sadrieh et al. performed a study of the dermal penetration of three TiO2 particles: uncoated submicrometer-sized, uncoated nano-sized, and dimethicone/methicone copolymer-coated nanosized. The investigators applied 5% by weight of each of the types of particles in a sunscreen on minipigs and found no significant penetration into intact normal epidermis (Toxicol. Sci. 2010;115(1):156-66).
In 2011, Furukawa et al. studied the postinitiation carcinogenic potential of coated and uncoated TiO2 nanoparticles in a two-stage skin carcinogenesis model using 7-week-old CD1 (ICR) female mice. They found that application of coated and uncoated nanoparticles after initiation and promotion with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol 13-acetate at doses of up to 20 mg/mouse failed to augment nodule development. The investigators concluded that TiO2 nanoparticles do not exhibit postinitiation potential for mouse skin carcinogenesis (Food Chem. Toxicol. 2011;49(4):744-9).
Human data
Given the persistent concerns about possible side effects of coated TiO2 and ZnO nanoparticles used in physical sun blockers, Filipe et al., in 2009, assessed the localization and potential skin penetration of TiO2 and ZnO nanoparticles dispersed in three sunscreen formulations, under realistic in vivo conditions in normal and altered skin. The investigators examined a test hydrophobic formulation containing coated 20-nm TiO2 nanoparticles and two commercially available sunscreen formulations containing TiO2 alone or in combination with ZnO, with respect to how consumers actually used sunscreens compared with the recommended standard condition for the sun protection factor test. They found that traces of the physical blockers could be detected only at the skin surface and uppermost area of the stratum corneum in normal human skin after a 2-hour exposure. After 48 hours of exposure, layers deeper than the stratum corneum contained no detectable TiO2 or ZnO nanoparticles. While preferential deposition of the nanoparticles in the openings of pilosebaceous follicles was noted, no penetration into viable skin tissue was observed. The investigators concluded that significant penetration of TiO2 or ZnO nanoparticles into keratinocytes is improbable (Skin Pharmacol. Physiol. 2009;22:266-75).
The weight of evidence
Current evidence suggests minimal risks to human health from the use of TiO2 or ZnO nanoparticles at concentrations up to 25% in cosmetic preparations or sunscreens, according to Schilling et al., regardless of coatings or crystalline structure. In a safety review of these ingredients, they noted that these nanoparticles formulated in topical products occur as aggregates of primary particles 30-150 nm in size, and bond in such a way that renders them impervious to the force of product application. Thus their structure remains unaffected, and no primary particles are released. The authors also noted that nanoparticles exhibit equivalence with larger particles in terms of distribution and duration and, therefore, recognition and elimination from the body (Photochem. Photobiol. Sci. 2010;9:495-509).
But in 2011, Tran and Salmon, in light of findings that nanoparticles may penetrate the stratum corneum under certain conditions, considered the possible photocarcinogenic results of nanoparticle sunscreens. They noted, though, that most such results were obtained through the use of animal skin models, not investigations with human skin (Australas. J. Dermatol. 2011;52:1-6). To this point, the weight of evidence appears to show that such TiO2 nanoparticles are safe when applied to intact human skin (Semin. Cutan. Med. Surg. 2011;30:210-13).
In response to the increased scrutiny and concern exhibited by the general public and government agencies regarding the safety of TiO2 and ZnO nanoparticles, Newman et al. reviewed the literature and position statements from 1980 to 2008 to ascertain and describe the use, safety, and regulatory state of such ingredients in sunscreens. They found no evidence of significant penetration deeper than the stratum corneum of TiO2 and ZnO nanoparticles, but caution that additional studies simulating real-world conditions (i.e., sunburned skin and under UV exposure) are necessary (J. Am. Acad. Dermatol. 2009;61:685-92).
Conclusion
Titanium dioxide is a well-established, safe, and effective physical sunblock. Nanotechnology has introduced some cause for concern regarding its use in physical sunblocks. In particular, evidence suggesting that photoexcitation of TiO2 nanoparticles leads to the generation of reactive oxygen species that damage DNA, potentially launching a cascade of adverse events, has prompted investigations into the safety of TiO2 in nanoparticle form. However, to date, multiple studies suggest that TiO2 nanoparticles do not penetrate or are highly unlikely to penetrate beyond the stratum corneum.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Titanium dioxide (TiO2) and zinc oxide (ZnO) in large-particle form have long been used in various sunscreens to protect the skin by reflecting or physically blocking ultraviolet (UV) radiation. In recent years, TiO2 as well as ZnO nanoparticles have been incorporated into sunscreens and cosmetics to act as a UV shield. They have been shown to be effective barriers against UV-induced damage, and yield stronger protection against UV insult, while leaving less white residue, than previous generations of the physical sunblocks.
However, some data suggest that in nanoparticle form, TiO2 and ZnO absorb UV radiation, leading to photocatalysis and the release of reactive oxygen species (Australas. J. Dermatol. 2011;52:1-6). This column will focus primarily on the safety of TiO2 in nanoparticle form.
While numerous studies examine both TiO2 and ZnO, the primary inorganic sunscreens, the sheer number of separate investigations warrants individual articles, and ZnO was addressed in previous columns. Briefly, though, TiO2 is more photoactive and exhibits a higher refractive index in visible light than ZnO (J. Am. Acad. Dermatol. 1999;40:85-90); therefore, TiO2 appears whiter and is more difficult to incorporate into transparent products.
A 2011 study by Kang et al. showed that TiO2 nanoparticles, but not normal-sized TiO2, and UVA synergistically foster rapid production of reactive oxygen species and breakdown of mitochondrial membrane potential, leading to apoptosis, and that TiO2 nanoparticles are more phototoxic than larger ones (Drug Chem. Toxicol. 2011;34:277-84).
However, also in 2011, Tyner et al. investigated the effects of nanoscale TiO2 use on UV attenuation in simple to complex sunscreen products. They found that barrier function was diminished by none of the formulations, and that optimal UV attenuation resulted when TiO2 particles were stabilized with a coating and evenly dispersed. The researchers concluded that nanoscale TiO2 is nontoxic and may impart greater efficacy (Int. J. Cosmet. Sci. 2011;33:234-44).
In vitro and in vivo studies
In 2010, Tiano et al. evaluated five modified TiO2 particles, developed and marketed for sunscreens. They used different in vitro models, including cultured human skin fibroblasts, to determine potential photocatalytic effects after UVA exposure. The investigators found that the kind of modification to and crystal form of the TiO2 nanoparticle influences its ability to augment or reduce DNA damage, increase or decrease intracellular reactive oxygen species, diminish cell viability, and promote other effects of photocatalysis. In particular, they noted that the anatase crystal form of TiO2 retained photocatalytic activity. The authors suggested that while the debate continues over the penetration of nanosized TiO2 into the viable epidermis, their results help elucidate the potential effects of TiO2 particles at the cellular level (Free Radic. Biol. Med. 2010;49:408-15).
A 2010 study by Senzui et al. using in vitro intact, stripped, and hair-removed skin of Yucatan micropigs to test the skin penetration of four different types of rutile (the most natural form of) TiO2 (two coated, two uncoated) revealed no penetration of TiO2 type in intact and stripped skin. The concentration of titanium in skin was significantly higher when one of the coated forms was applied on hair-removed skin, with titanium penetrating into vacant hair follicles (greater than 1 mm below the skin surface), but not into dermis or viable epidermis (J. Toxicol. Sci. 2010;35:107-13).
Animal studies
In 2009, the Food and Drug Administration Center for Drug Evaluation and Research worked with the National Center for Toxicology Research using minipigs and four sunscreen formulations to determine whether nanoscale TiO2 can penetrate intact skin. Their use of scanning electron microscopy and x-ray diffraction revealed that TiO2 particles were the same size as that observed for the raw materials, implying that the formulation process influenced neither the size nor the shape of TiO2 particles (Drug Dev. Ind. Pharm. 2009;35:1180-9).
In 2010, Sadrieh et al. performed a study of the dermal penetration of three TiO2 particles: uncoated submicrometer-sized, uncoated nano-sized, and dimethicone/methicone copolymer-coated nanosized. The investigators applied 5% by weight of each of the types of particles in a sunscreen on minipigs and found no significant penetration into intact normal epidermis (Toxicol. Sci. 2010;115(1):156-66).
In 2011, Furukawa et al. studied the postinitiation carcinogenic potential of coated and uncoated TiO2 nanoparticles in a two-stage skin carcinogenesis model using 7-week-old CD1 (ICR) female mice. They found that application of coated and uncoated nanoparticles after initiation and promotion with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol 13-acetate at doses of up to 20 mg/mouse failed to augment nodule development. The investigators concluded that TiO2 nanoparticles do not exhibit postinitiation potential for mouse skin carcinogenesis (Food Chem. Toxicol. 2011;49(4):744-9).
Human data
Given the persistent concerns about possible side effects of coated TiO2 and ZnO nanoparticles used in physical sun blockers, Filipe et al., in 2009, assessed the localization and potential skin penetration of TiO2 and ZnO nanoparticles dispersed in three sunscreen formulations, under realistic in vivo conditions in normal and altered skin. The investigators examined a test hydrophobic formulation containing coated 20-nm TiO2 nanoparticles and two commercially available sunscreen formulations containing TiO2 alone or in combination with ZnO, with respect to how consumers actually used sunscreens compared with the recommended standard condition for the sun protection factor test. They found that traces of the physical blockers could be detected only at the skin surface and uppermost area of the stratum corneum in normal human skin after a 2-hour exposure. After 48 hours of exposure, layers deeper than the stratum corneum contained no detectable TiO2 or ZnO nanoparticles. While preferential deposition of the nanoparticles in the openings of pilosebaceous follicles was noted, no penetration into viable skin tissue was observed. The investigators concluded that significant penetration of TiO2 or ZnO nanoparticles into keratinocytes is improbable (Skin Pharmacol. Physiol. 2009;22:266-75).
The weight of evidence
Current evidence suggests minimal risks to human health from the use of TiO2 or ZnO nanoparticles at concentrations up to 25% in cosmetic preparations or sunscreens, according to Schilling et al., regardless of coatings or crystalline structure. In a safety review of these ingredients, they noted that these nanoparticles formulated in topical products occur as aggregates of primary particles 30-150 nm in size, and bond in such a way that renders them impervious to the force of product application. Thus their structure remains unaffected, and no primary particles are released. The authors also noted that nanoparticles exhibit equivalence with larger particles in terms of distribution and duration and, therefore, recognition and elimination from the body (Photochem. Photobiol. Sci. 2010;9:495-509).
But in 2011, Tran and Salmon, in light of findings that nanoparticles may penetrate the stratum corneum under certain conditions, considered the possible photocarcinogenic results of nanoparticle sunscreens. They noted, though, that most such results were obtained through the use of animal skin models, not investigations with human skin (Australas. J. Dermatol. 2011;52:1-6). To this point, the weight of evidence appears to show that such TiO2 nanoparticles are safe when applied to intact human skin (Semin. Cutan. Med. Surg. 2011;30:210-13).
In response to the increased scrutiny and concern exhibited by the general public and government agencies regarding the safety of TiO2 and ZnO nanoparticles, Newman et al. reviewed the literature and position statements from 1980 to 2008 to ascertain and describe the use, safety, and regulatory state of such ingredients in sunscreens. They found no evidence of significant penetration deeper than the stratum corneum of TiO2 and ZnO nanoparticles, but caution that additional studies simulating real-world conditions (i.e., sunburned skin and under UV exposure) are necessary (J. Am. Acad. Dermatol. 2009;61:685-92).
Conclusion
Titanium dioxide is a well-established, safe, and effective physical sunblock. Nanotechnology has introduced some cause for concern regarding its use in physical sunblocks. In particular, evidence suggesting that photoexcitation of TiO2 nanoparticles leads to the generation of reactive oxygen species that damage DNA, potentially launching a cascade of adverse events, has prompted investigations into the safety of TiO2 in nanoparticle form. However, to date, multiple studies suggest that TiO2 nanoparticles do not penetrate or are highly unlikely to penetrate beyond the stratum corneum.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Peptides
Peptides have recently generated interest as biologically active compounds incorporated into cosmeceutical products intended to treat aging skin. Peptides are composed of chains of amino acids, which are derived from DNA transcription. In typical cellular settings, peptides communicate or signal between DNA and the cellular network. Consequently, they are thought to be capable of being used or exploited to direct cells to maintain youthful behavior, yielding a stable, nonaging manifestation. In addition, peptides can be rendered by protein degradation, thus forming an essential feedback inhibition and upregulation loop (Facial Plast. Surg. 2009;25:285-9). Downregulation of metalloproteinases (MMPs), notably collagenase, by peptides is a good example, as well as a window into why peptides have sparked interest within antiaging research (Dermatol. Surg. 2005;31[7 Pt 2]:832-6, discussion 836).
Researchers at the University of Tennessee, Memphis, performed some of the seminal work that has paved the way for understanding how to harness the activity of natural peptides by showing that the production of the extracellular matrix in fibroblasts is fostered by a pentapeptide subfragment of propeptide of type I collagen (J. Biol. Chem. 1993;268:9941-4).
But the foundational work setting the stage for development of cosmeceutical peptides has been in the research for ameliorating wounds, which dates back several decades and can be traced to the use of yeast extracts for wound care in the 1930s, later leading to the extraction of a usable protein fraction (Dermatol. Ther. 2007;20:343-9; Clin. Ther. 1991;13:430-4). Signal peptides, enzyme-inhibitor peptides, neurotransmitter-inhibitor peptides (or neuropeptides), and carrier peptides are the four primary classes of topical or cosmeceutical peptides. This column will offer a brief summary of each and acknowledge additional recent research. Future columns may address each of these peptide categories pertinent to antiaging cosmeceuticals.
Signal peptides
Specific bioactive amino acid chains have been discovered in recent years that promote human skin dermal fibroblast growth in vitro and in vivo, and reduce the length and depth of wrinkles (Dermatol. Ther. 2007;20:343-9). The most popular signal peptide is the lysine-threonine-threonine-lysine-serine (KTTKS) located on type 1 procollagen. To enhance epidermal delivery, it has been linked to palmitic acid, thus the marketed version (Matrixyl) is a palmitoyl pentapeptide, which has been shown to augment the synthesis of collagen by fibroblasts and yield reductions in fine lines and wrinkles, according to quantitative analysis and self-reports (J. Biol. Chem. 1993;268:9941-4; Int. J. Cosmet. Sci. 2005;27:155-60).
New signal peptides are expected to be stronger and better targeted than those presently marketed (Facial Plast. Surg. 2009;25:285-9). Signal peptides promote the synthesis of matrix proteins, collagen in particular, which leads to firmer, younger looking skin, and also augments levels of elastin, proteoglycans, glycosaminoglycans, and fibronectin (Int. J. Cosmet. Sci. 2009;31:327-45).
Enzyme-inhibitor peptides
These peptides suppress enzymatic activity either directly or indirectly. Enzyme-inhibiting peptides extracted from soybeans have been incorporated into antiaging, moisturizing, and cleansing products as well as hair care formulations (Int. J. Cosmet. Sci. 2009;31:327-45). In a small study in 10 white females, a 2% soya biopeptide performed better than did placebo in collagen and glycosaminoglycan promotion (Int. J. Cosmet. Sci. 1999;21:299-311).
More recently, a rice peptide derived from germinated black rice, which has been used in traditional Asian medicines, was found to block MMP activity and dose-dependently stimulate hyaluronan synthase 2 gene expression (a twofold increase) in human keratinocytes (J. Microbiol. Biotechnol. 2007;17:271-9). Such peptides are found in antiaging and hair products.
In addition, antioxidant activity, a high affinity to chelate with copper, and the capacity to suppress tyrosinase activity and keratinocyte apoptosis have been displayed by the enzyme-inhibiting peptide sericin, derived from the silkworm Bombyx mori (Int. J. Cosmet. Sci. 2009;31:327-45). Sericin also has been shown to facilitate the intrinsic moisturization of skin by restoring amino acids and imparting an occlusive effect (J. Cosmet. Dermatol. 2005;4:250-7).
Neuropeptides
Neuropeptides are known to mediate skin inflammation and, thus, contribute as an underlying aspect of reactive skin conditions (Eur. J. Dermatol. 2010;20:731-7). Also known as neurotransmitter-affecting peptides, these compounds are included in cosmeceuticals to mimic the action of botulinum toxin A. Essentially, they inhibit acetylcholine release at the neuromuscular junction.
The best known of these is acetyl hexapeptide-3, marketed as Argireline. Attached to acetic acid residue, this synthetic peptide, based on the N-terminal end of the synaptosomal-associated protein (SNAP)–25 that blocks soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex development and catecholamine release (Int. J. Cosmet. Sci. 2009;31:327-45), is thought to suppress the release of neurotransmitters, easing facial tension, and thus reducing wrinkles. Evidence of its effectiveness has appeared largely in proprietary studies. Much more research is necessary to establish the suitability of this form of peptide for topical antiaging applications.
Carrier peptides
Carrier peptides stabilize and transport trace elements essential for healing wounds and enzymatic processes (Dermatol. Ther. 2007;20:343-9). Although it also confers signal peptide effects, glycyl-L-histidyl-L-lysine (GHK), a naturally occurring tripeptide initially isolated from human plasma (Nat. New Biol. 1973;243:85-7), is known mainly as a carrier peptide. It is typically linked with copper, given its high affinity for it, and several studies have shown that copper peptide molecules using GHK (glycyl-L-histidyl-L-lysine-Cu2+ or GHK-Cu) deliver varied restorative effects, including the improvement in the appearance of fine lines and wrinkles (Dermatol. Ther. 2007;20:343-9). This tripeptide complex has been used for many years to accelerate wound healing and is found in several moisturizers. Significantly, the GHK-Cu complex also has been shown to stimulate collagen synthesis (FEBS Lett. 1988;238:343-6) and to augment sulfated proteoglycans levels in fibroblast cultures as well as experimental animal wound models (J. Clin. Invest. 1993;92:2368-76). GHK-Cu also influences tissue remodeling by raising the levels of MMP-2 and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) (Life Sci. 2000;67:2257-65). More research is necessary to ascertain the efficacy of copper peptide as an antiaging agent.
Recent general research findings
A double-blind clinical study in 2004 of 20 healthy women volunteers between 40 and 62 years of age revealed that a gel formula containing 3% of a collagen-like hexapeptide significantly reduced the total surface of wrinkles as well as the number and average depth of wrinkles (Int. J. Tissue React. 2004;26:105-11).
In 2005, a literature review of studies published on the effects and practical applications of peptides as topical agents for skin improvement showed that peptide cosmeceuticals seem to exhibit the potential to blunt the visual effects of aging on the skin, and that formulations must be stable, absorbed into the skin, and biologically active (Dermatol. Surg. 2005;31[7 Pt 2]:832-6, discussion 836).
In 2007, investigators reported on the development of a new hand care formulation derived from wool peptides. The keratin fraction from wool was shown through long-term in vivo studies to enhance cutaneous hydration, water-holding capacity, and elasticity in volunteers with dry skin. In addition, the researchers found that the keratin peptide preparation blunted some of the adverse effects due to surfactant exposure (J. Cosmet. Sci. 2007;58:99-107).
That same year, researchers reported that they prepared two stable cosmetic formulations, an emulsion with an external aqueous phase for normal-to-dry skin and a gel for oily skin, with acetyl hexapeptide-8 (Argireline) as the active ingredient (J. Cosmet. Sci. 2007;58:157-71).
Previously, Argireline was shown in healthy women volunteers, in a skin topography analysis of an oil/water (O/W) emulsion containing 10% of the hexapeptide, to have decreased wrinkle depth up to 30% after 30 days of treatment. Researchers determined that the synthetic hexapeptide significantly suppresses neurotransmitter release comparably to botulinum toxin A, with fewer side effects but lower efficacy. They also noted that Argireline displayed no in vivo oral toxicity and evoked no irritation at high doses, suggesting that the peptide is a topical nontoxic antiwrinkle alternative to botulinum toxins (Int. J. Cosmet. Sci. 2002;24:303-10).
In 2008, investigators tested a hydrolyzed keratin peptide derived from wool on skin in two different formulations. Long-term in vivo studies yielded significant differences between the control and treated sites, with the treated areas exhibiting an increase in hydration and elasticity because of keratin peptide application. The investigators also noted measurements showing that the keratin formulations supported skin barrier integrity, enhancing its water-holding capacity. In particular, the formulation combining keratin peptide with internal wool lipids in a liposome suspension showed promising effects that they deemed appropriate for new cosmetic products (Skin Res. Technol. 2008;14:243-8).
Conclusion
Peptide cosmeceuticals represent a new and popular choice for consumers shopping for antiaging products. Are they worthy options? As always, the capacity of topical products to penetrate the skin and exert a biologic impact is of great significance. Some products appear to exert antiaging effects, but most evidence of effectiveness has emerged from in vitro studies or small in vivo investigations. More research, in the form of large randomized controlled trials, is necessary to establish the effectiveness of these intriguing products. As it is, though, numerous products are on the market and this area of research and product development shows promise.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Peptides have recently generated interest as biologically active compounds incorporated into cosmeceutical products intended to treat aging skin. Peptides are composed of chains of amino acids, which are derived from DNA transcription. In typical cellular settings, peptides communicate or signal between DNA and the cellular network. Consequently, they are thought to be capable of being used or exploited to direct cells to maintain youthful behavior, yielding a stable, nonaging manifestation. In addition, peptides can be rendered by protein degradation, thus forming an essential feedback inhibition and upregulation loop (Facial Plast. Surg. 2009;25:285-9). Downregulation of metalloproteinases (MMPs), notably collagenase, by peptides is a good example, as well as a window into why peptides have sparked interest within antiaging research (Dermatol. Surg. 2005;31[7 Pt 2]:832-6, discussion 836).
Researchers at the University of Tennessee, Memphis, performed some of the seminal work that has paved the way for understanding how to harness the activity of natural peptides by showing that the production of the extracellular matrix in fibroblasts is fostered by a pentapeptide subfragment of propeptide of type I collagen (J. Biol. Chem. 1993;268:9941-4).
But the foundational work setting the stage for development of cosmeceutical peptides has been in the research for ameliorating wounds, which dates back several decades and can be traced to the use of yeast extracts for wound care in the 1930s, later leading to the extraction of a usable protein fraction (Dermatol. Ther. 2007;20:343-9; Clin. Ther. 1991;13:430-4). Signal peptides, enzyme-inhibitor peptides, neurotransmitter-inhibitor peptides (or neuropeptides), and carrier peptides are the four primary classes of topical or cosmeceutical peptides. This column will offer a brief summary of each and acknowledge additional recent research. Future columns may address each of these peptide categories pertinent to antiaging cosmeceuticals.
Signal peptides
Specific bioactive amino acid chains have been discovered in recent years that promote human skin dermal fibroblast growth in vitro and in vivo, and reduce the length and depth of wrinkles (Dermatol. Ther. 2007;20:343-9). The most popular signal peptide is the lysine-threonine-threonine-lysine-serine (KTTKS) located on type 1 procollagen. To enhance epidermal delivery, it has been linked to palmitic acid, thus the marketed version (Matrixyl) is a palmitoyl pentapeptide, which has been shown to augment the synthesis of collagen by fibroblasts and yield reductions in fine lines and wrinkles, according to quantitative analysis and self-reports (J. Biol. Chem. 1993;268:9941-4; Int. J. Cosmet. Sci. 2005;27:155-60).
New signal peptides are expected to be stronger and better targeted than those presently marketed (Facial Plast. Surg. 2009;25:285-9). Signal peptides promote the synthesis of matrix proteins, collagen in particular, which leads to firmer, younger looking skin, and also augments levels of elastin, proteoglycans, glycosaminoglycans, and fibronectin (Int. J. Cosmet. Sci. 2009;31:327-45).
Enzyme-inhibitor peptides
These peptides suppress enzymatic activity either directly or indirectly. Enzyme-inhibiting peptides extracted from soybeans have been incorporated into antiaging, moisturizing, and cleansing products as well as hair care formulations (Int. J. Cosmet. Sci. 2009;31:327-45). In a small study in 10 white females, a 2% soya biopeptide performed better than did placebo in collagen and glycosaminoglycan promotion (Int. J. Cosmet. Sci. 1999;21:299-311).
More recently, a rice peptide derived from germinated black rice, which has been used in traditional Asian medicines, was found to block MMP activity and dose-dependently stimulate hyaluronan synthase 2 gene expression (a twofold increase) in human keratinocytes (J. Microbiol. Biotechnol. 2007;17:271-9). Such peptides are found in antiaging and hair products.
In addition, antioxidant activity, a high affinity to chelate with copper, and the capacity to suppress tyrosinase activity and keratinocyte apoptosis have been displayed by the enzyme-inhibiting peptide sericin, derived from the silkworm Bombyx mori (Int. J. Cosmet. Sci. 2009;31:327-45). Sericin also has been shown to facilitate the intrinsic moisturization of skin by restoring amino acids and imparting an occlusive effect (J. Cosmet. Dermatol. 2005;4:250-7).
Neuropeptides
Neuropeptides are known to mediate skin inflammation and, thus, contribute as an underlying aspect of reactive skin conditions (Eur. J. Dermatol. 2010;20:731-7). Also known as neurotransmitter-affecting peptides, these compounds are included in cosmeceuticals to mimic the action of botulinum toxin A. Essentially, they inhibit acetylcholine release at the neuromuscular junction.
The best known of these is acetyl hexapeptide-3, marketed as Argireline. Attached to acetic acid residue, this synthetic peptide, based on the N-terminal end of the synaptosomal-associated protein (SNAP)–25 that blocks soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex development and catecholamine release (Int. J. Cosmet. Sci. 2009;31:327-45), is thought to suppress the release of neurotransmitters, easing facial tension, and thus reducing wrinkles. Evidence of its effectiveness has appeared largely in proprietary studies. Much more research is necessary to establish the suitability of this form of peptide for topical antiaging applications.
Carrier peptides
Carrier peptides stabilize and transport trace elements essential for healing wounds and enzymatic processes (Dermatol. Ther. 2007;20:343-9). Although it also confers signal peptide effects, glycyl-L-histidyl-L-lysine (GHK), a naturally occurring tripeptide initially isolated from human plasma (Nat. New Biol. 1973;243:85-7), is known mainly as a carrier peptide. It is typically linked with copper, given its high affinity for it, and several studies have shown that copper peptide molecules using GHK (glycyl-L-histidyl-L-lysine-Cu2+ or GHK-Cu) deliver varied restorative effects, including the improvement in the appearance of fine lines and wrinkles (Dermatol. Ther. 2007;20:343-9). This tripeptide complex has been used for many years to accelerate wound healing and is found in several moisturizers. Significantly, the GHK-Cu complex also has been shown to stimulate collagen synthesis (FEBS Lett. 1988;238:343-6) and to augment sulfated proteoglycans levels in fibroblast cultures as well as experimental animal wound models (J. Clin. Invest. 1993;92:2368-76). GHK-Cu also influences tissue remodeling by raising the levels of MMP-2 and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) (Life Sci. 2000;67:2257-65). More research is necessary to ascertain the efficacy of copper peptide as an antiaging agent.
Recent general research findings
A double-blind clinical study in 2004 of 20 healthy women volunteers between 40 and 62 years of age revealed that a gel formula containing 3% of a collagen-like hexapeptide significantly reduced the total surface of wrinkles as well as the number and average depth of wrinkles (Int. J. Tissue React. 2004;26:105-11).
In 2005, a literature review of studies published on the effects and practical applications of peptides as topical agents for skin improvement showed that peptide cosmeceuticals seem to exhibit the potential to blunt the visual effects of aging on the skin, and that formulations must be stable, absorbed into the skin, and biologically active (Dermatol. Surg. 2005;31[7 Pt 2]:832-6, discussion 836).
In 2007, investigators reported on the development of a new hand care formulation derived from wool peptides. The keratin fraction from wool was shown through long-term in vivo studies to enhance cutaneous hydration, water-holding capacity, and elasticity in volunteers with dry skin. In addition, the researchers found that the keratin peptide preparation blunted some of the adverse effects due to surfactant exposure (J. Cosmet. Sci. 2007;58:99-107).
That same year, researchers reported that they prepared two stable cosmetic formulations, an emulsion with an external aqueous phase for normal-to-dry skin and a gel for oily skin, with acetyl hexapeptide-8 (Argireline) as the active ingredient (J. Cosmet. Sci. 2007;58:157-71).
Previously, Argireline was shown in healthy women volunteers, in a skin topography analysis of an oil/water (O/W) emulsion containing 10% of the hexapeptide, to have decreased wrinkle depth up to 30% after 30 days of treatment. Researchers determined that the synthetic hexapeptide significantly suppresses neurotransmitter release comparably to botulinum toxin A, with fewer side effects but lower efficacy. They also noted that Argireline displayed no in vivo oral toxicity and evoked no irritation at high doses, suggesting that the peptide is a topical nontoxic antiwrinkle alternative to botulinum toxins (Int. J. Cosmet. Sci. 2002;24:303-10).
In 2008, investigators tested a hydrolyzed keratin peptide derived from wool on skin in two different formulations. Long-term in vivo studies yielded significant differences between the control and treated sites, with the treated areas exhibiting an increase in hydration and elasticity because of keratin peptide application. The investigators also noted measurements showing that the keratin formulations supported skin barrier integrity, enhancing its water-holding capacity. In particular, the formulation combining keratin peptide with internal wool lipids in a liposome suspension showed promising effects that they deemed appropriate for new cosmetic products (Skin Res. Technol. 2008;14:243-8).
Conclusion
Peptide cosmeceuticals represent a new and popular choice for consumers shopping for antiaging products. Are they worthy options? As always, the capacity of topical products to penetrate the skin and exert a biologic impact is of great significance. Some products appear to exert antiaging effects, but most evidence of effectiveness has emerged from in vitro studies or small in vivo investigations. More research, in the form of large randomized controlled trials, is necessary to establish the effectiveness of these intriguing products. As it is, though, numerous products are on the market and this area of research and product development shows promise.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Peptides have recently generated interest as biologically active compounds incorporated into cosmeceutical products intended to treat aging skin. Peptides are composed of chains of amino acids, which are derived from DNA transcription. In typical cellular settings, peptides communicate or signal between DNA and the cellular network. Consequently, they are thought to be capable of being used or exploited to direct cells to maintain youthful behavior, yielding a stable, nonaging manifestation. In addition, peptides can be rendered by protein degradation, thus forming an essential feedback inhibition and upregulation loop (Facial Plast. Surg. 2009;25:285-9). Downregulation of metalloproteinases (MMPs), notably collagenase, by peptides is a good example, as well as a window into why peptides have sparked interest within antiaging research (Dermatol. Surg. 2005;31[7 Pt 2]:832-6, discussion 836).
Researchers at the University of Tennessee, Memphis, performed some of the seminal work that has paved the way for understanding how to harness the activity of natural peptides by showing that the production of the extracellular matrix in fibroblasts is fostered by a pentapeptide subfragment of propeptide of type I collagen (J. Biol. Chem. 1993;268:9941-4).
But the foundational work setting the stage for development of cosmeceutical peptides has been in the research for ameliorating wounds, which dates back several decades and can be traced to the use of yeast extracts for wound care in the 1930s, later leading to the extraction of a usable protein fraction (Dermatol. Ther. 2007;20:343-9; Clin. Ther. 1991;13:430-4). Signal peptides, enzyme-inhibitor peptides, neurotransmitter-inhibitor peptides (or neuropeptides), and carrier peptides are the four primary classes of topical or cosmeceutical peptides. This column will offer a brief summary of each and acknowledge additional recent research. Future columns may address each of these peptide categories pertinent to antiaging cosmeceuticals.
Signal peptides
Specific bioactive amino acid chains have been discovered in recent years that promote human skin dermal fibroblast growth in vitro and in vivo, and reduce the length and depth of wrinkles (Dermatol. Ther. 2007;20:343-9). The most popular signal peptide is the lysine-threonine-threonine-lysine-serine (KTTKS) located on type 1 procollagen. To enhance epidermal delivery, it has been linked to palmitic acid, thus the marketed version (Matrixyl) is a palmitoyl pentapeptide, which has been shown to augment the synthesis of collagen by fibroblasts and yield reductions in fine lines and wrinkles, according to quantitative analysis and self-reports (J. Biol. Chem. 1993;268:9941-4; Int. J. Cosmet. Sci. 2005;27:155-60).
New signal peptides are expected to be stronger and better targeted than those presently marketed (Facial Plast. Surg. 2009;25:285-9). Signal peptides promote the synthesis of matrix proteins, collagen in particular, which leads to firmer, younger looking skin, and also augments levels of elastin, proteoglycans, glycosaminoglycans, and fibronectin (Int. J. Cosmet. Sci. 2009;31:327-45).
Enzyme-inhibitor peptides
These peptides suppress enzymatic activity either directly or indirectly. Enzyme-inhibiting peptides extracted from soybeans have been incorporated into antiaging, moisturizing, and cleansing products as well as hair care formulations (Int. J. Cosmet. Sci. 2009;31:327-45). In a small study in 10 white females, a 2% soya biopeptide performed better than did placebo in collagen and glycosaminoglycan promotion (Int. J. Cosmet. Sci. 1999;21:299-311).
More recently, a rice peptide derived from germinated black rice, which has been used in traditional Asian medicines, was found to block MMP activity and dose-dependently stimulate hyaluronan synthase 2 gene expression (a twofold increase) in human keratinocytes (J. Microbiol. Biotechnol. 2007;17:271-9). Such peptides are found in antiaging and hair products.
In addition, antioxidant activity, a high affinity to chelate with copper, and the capacity to suppress tyrosinase activity and keratinocyte apoptosis have been displayed by the enzyme-inhibiting peptide sericin, derived from the silkworm Bombyx mori (Int. J. Cosmet. Sci. 2009;31:327-45). Sericin also has been shown to facilitate the intrinsic moisturization of skin by restoring amino acids and imparting an occlusive effect (J. Cosmet. Dermatol. 2005;4:250-7).
Neuropeptides
Neuropeptides are known to mediate skin inflammation and, thus, contribute as an underlying aspect of reactive skin conditions (Eur. J. Dermatol. 2010;20:731-7). Also known as neurotransmitter-affecting peptides, these compounds are included in cosmeceuticals to mimic the action of botulinum toxin A. Essentially, they inhibit acetylcholine release at the neuromuscular junction.
The best known of these is acetyl hexapeptide-3, marketed as Argireline. Attached to acetic acid residue, this synthetic peptide, based on the N-terminal end of the synaptosomal-associated protein (SNAP)–25 that blocks soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex development and catecholamine release (Int. J. Cosmet. Sci. 2009;31:327-45), is thought to suppress the release of neurotransmitters, easing facial tension, and thus reducing wrinkles. Evidence of its effectiveness has appeared largely in proprietary studies. Much more research is necessary to establish the suitability of this form of peptide for topical antiaging applications.
Carrier peptides
Carrier peptides stabilize and transport trace elements essential for healing wounds and enzymatic processes (Dermatol. Ther. 2007;20:343-9). Although it also confers signal peptide effects, glycyl-L-histidyl-L-lysine (GHK), a naturally occurring tripeptide initially isolated from human plasma (Nat. New Biol. 1973;243:85-7), is known mainly as a carrier peptide. It is typically linked with copper, given its high affinity for it, and several studies have shown that copper peptide molecules using GHK (glycyl-L-histidyl-L-lysine-Cu2+ or GHK-Cu) deliver varied restorative effects, including the improvement in the appearance of fine lines and wrinkles (Dermatol. Ther. 2007;20:343-9). This tripeptide complex has been used for many years to accelerate wound healing and is found in several moisturizers. Significantly, the GHK-Cu complex also has been shown to stimulate collagen synthesis (FEBS Lett. 1988;238:343-6) and to augment sulfated proteoglycans levels in fibroblast cultures as well as experimental animal wound models (J. Clin. Invest. 1993;92:2368-76). GHK-Cu also influences tissue remodeling by raising the levels of MMP-2 and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) (Life Sci. 2000;67:2257-65). More research is necessary to ascertain the efficacy of copper peptide as an antiaging agent.
Recent general research findings
A double-blind clinical study in 2004 of 20 healthy women volunteers between 40 and 62 years of age revealed that a gel formula containing 3% of a collagen-like hexapeptide significantly reduced the total surface of wrinkles as well as the number and average depth of wrinkles (Int. J. Tissue React. 2004;26:105-11).
In 2005, a literature review of studies published on the effects and practical applications of peptides as topical agents for skin improvement showed that peptide cosmeceuticals seem to exhibit the potential to blunt the visual effects of aging on the skin, and that formulations must be stable, absorbed into the skin, and biologically active (Dermatol. Surg. 2005;31[7 Pt 2]:832-6, discussion 836).
In 2007, investigators reported on the development of a new hand care formulation derived from wool peptides. The keratin fraction from wool was shown through long-term in vivo studies to enhance cutaneous hydration, water-holding capacity, and elasticity in volunteers with dry skin. In addition, the researchers found that the keratin peptide preparation blunted some of the adverse effects due to surfactant exposure (J. Cosmet. Sci. 2007;58:99-107).
That same year, researchers reported that they prepared two stable cosmetic formulations, an emulsion with an external aqueous phase for normal-to-dry skin and a gel for oily skin, with acetyl hexapeptide-8 (Argireline) as the active ingredient (J. Cosmet. Sci. 2007;58:157-71).
Previously, Argireline was shown in healthy women volunteers, in a skin topography analysis of an oil/water (O/W) emulsion containing 10% of the hexapeptide, to have decreased wrinkle depth up to 30% after 30 days of treatment. Researchers determined that the synthetic hexapeptide significantly suppresses neurotransmitter release comparably to botulinum toxin A, with fewer side effects but lower efficacy. They also noted that Argireline displayed no in vivo oral toxicity and evoked no irritation at high doses, suggesting that the peptide is a topical nontoxic antiwrinkle alternative to botulinum toxins (Int. J. Cosmet. Sci. 2002;24:303-10).
In 2008, investigators tested a hydrolyzed keratin peptide derived from wool on skin in two different formulations. Long-term in vivo studies yielded significant differences between the control and treated sites, with the treated areas exhibiting an increase in hydration and elasticity because of keratin peptide application. The investigators also noted measurements showing that the keratin formulations supported skin barrier integrity, enhancing its water-holding capacity. In particular, the formulation combining keratin peptide with internal wool lipids in a liposome suspension showed promising effects that they deemed appropriate for new cosmetic products (Skin Res. Technol. 2008;14:243-8).
Conclusion
Peptide cosmeceuticals represent a new and popular choice for consumers shopping for antiaging products. Are they worthy options? As always, the capacity of topical products to penetrate the skin and exert a biologic impact is of great significance. Some products appear to exert antiaging effects, but most evidence of effectiveness has emerged from in vitro studies or small in vivo investigations. More research, in the form of large randomized controlled trials, is necessary to establish the effectiveness of these intriguing products. As it is, though, numerous products are on the market and this area of research and product development shows promise.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Zinc oxide, part 2
Nanotechnology, which applies gathered knowledge on the characteristics of matter to design new products on the nanoscale (<1,000 nm), emerged in the 1980s and has made great strides since then. Dermatology is a prime area of interest for nanotech applications, as numerous products using nanotechnology have been marketed. In fact, the sixth-largest U.S. patent holder in nanotechnology is a cosmetics company (Skin Therapy Lett. 2010;15:1-4). The newest generation of skin products is characterized by improved skin penetration (Arch. Dermatol. Res. 2011;303:533-50), and these products may have a role in enhancing the treatment of several skin disorders; however, toxicological studies must establish the safety of formulations increasingly likely to penetrate multiple skin layers.
Zinc oxide (ZnO) and titanium dioxide (TiO2) are two of the most prominent ingredients in the dermatologic armamentarium that are used in micro- and nanoparticle forms. Efficacy has been well established for these ingredients as inorganic sunscreens, but their relative safety has been debated and remains somewhat controversial. This column discusses findings regarding the safety of ZnO nanoparticles.
Elevated risk
Absorption and effects of zinc ions. In a small study (n = 20) in humans conducted in 2010, Gulson et al. found that small amounts of zinc from ZnO in sunscreens applied for five consecutive days outdoors were absorbed in the skin, with levels of the stable isotope tracer (68)Zn in blood and urine from females receiving the nano sunscreen higher than in males receiving the same sunscreen and higher than in all participants who received the bulk sunscreen (Toxicol. Sci. 2010;118:140-9).
In 2010, Martorano et al. examined the separation of zinc ions from ZnO in commercial sunscreens under UVB exposure and studied the effects of zinc ion accumulation in human epidermal keratinocytes. They noted that UVB light exposure led to a significant concentration-dependent and radiation intensity–dependent rise in zinc ion levels. In turn, a late- or delayed-type cytotoxicity in human epidermal keratinocytes was observed, as was the induction of reactive oxygen species (ROS) in the keratinocytes. The investigators concluded that UVB exposure leads to an elevation in zinc ion dissociation in ZnO sunscreen, yielding cytotoxic effects and oxidative stress (J. Cosmet. Dermatol. 2010;9:276-86).
Genotoxic potential. As Wang and Tooley aptly noted, the concerns regarding the safety of nanoparticles in sunscreens pertain to potential toxicity and capacity to penetrate the skin (Sem. Cutan. Med. Surg. 2011;30:210-13).
In a 2010 in vitro study of the toxicity of ZnO and TiO2 on keratinocytes over short- and long-term application periods, Kocbek et al. found that ZnO nanoparticles conferred more adverse effects than TiO2, with ZnO inhibiting cell viability above 15 mcg/mL after brief exposure while TiO2 exerted no effect up to 100 mcg/mL. Prolonged exposure to ZnO nanoparticles at 10 mcg/mL yielded diminished mitochondrial activity as well as changes in cell morphology and cell-cycle distribution; no such changes were associated with TiO2 nanoparticles. The researchers also reported more nanotubular intercellular structures in keratinocytes exposed to either nanoparticle type as compared to unexposed cells and nanoparticles present in vesicles within the cell cytoplasm. Finally, they observed that partially soluble ZnO spurred the synthesis of ROS, as opposed to insoluble TiO2. They concluded that their findings of an adverse effect on human keratinocytes suggest that long-term exposure to ZnO and TiO2 nanoparticles poses a possible health risk (Small 2010;6:1908-17).
In early 2011, Sharma et al. studied the cytotoxic and genotoxic potential of ZnO nanoparticles in the human liver carcinoma cell line HepG2, given what they argued was the pervasiveness of ZnO in consumer products and industrial applications and the concomitant likelihood of transmission to the liver. Their various assays revealed a significant concentration- and time-dependent toxicity after 12 and 24 hours at 14 and 20 mcg/mL, as well as a significant surge in DNA damage in cells exposed to ZnO nanoparticles for 6 hours (J. Biomed. Nanotechnol. 2011;7:98-9).
Previously, in 2009, Sharma et al. had investigated the potential genotoxicity of ZnO nanoparticles in the human epidermal cell line A431. They found concentration- and time-dependent decreases in cell viability as well as DNA damage potential, as revealed by Comet assay results. In addition, oxidative stress was provoked by ZnO nanoparticles, as evidenced by significant reductions in glutathione, catalase, and superoxide dismutase. The investigators urged caution related to dermatologic formulations containing ZnO nanoparticles, suggesting that their findings indicate a genotoxic potential in human epidermal cells, possibly mediated via lipid peroxidation and oxidative stress (Toxicol. Lett. 2009;185:211-8).
In May 2011, Sharma et al. investigated the biological interactions of ZnO nanoparticles in human epidermal keratinocytes, where electron microscopy showed the internalization of the nanoparticles after 6 hours of exposure at a concentration of 14 mcg/mL. Various assays revealed a time- and concentration-dependent suppression of mitochondrial activity as well as DNA damage in cells, compared with controls. The investigators concluded that ZnO nanoparticles are internalized by human epidermal keratinocytes and provoke a cytotoxic and genotoxic response, providing reason for caution when using consumer products containing nanoparticles. Specifically, they warned that any disruptions in the stratum corneum (SC) could allow the exposure of internal cells to nanoparticles (J. Nanosci. Nanotechnol. 2011;11:3782-8).
Also, in a recent study of the interactions of ZnO nanoparticles with the tumor suppressor p53, Ng et al. found that the p53 pathway was activated in BJ cells (skin fibroblasts) upon treatment with ZnO nanoparticles, leading to a reduction in cell numbers. One implication of this response, the researchers concluded, was that in cells lacking robust p53, the protective response can be turned toward carcinogenesis due to exposure to DNA damage–inducing agents like ZnO nanoparticles (Biomaterials 2011;32:8218-25).
Weight of evidence
However, several researchers contend that current data strongly suggest that nanosized ZnO and TiO2 do not, in fact, pose such risks (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Int. J. Dermatol. 2011;50:247-54; Sem. Cutan. Med. Surg. 2011;30:210-13).
In 2009, in response to increasing concerns about the potential adverse effects of ZnO- and TiO2-coated nanoparticles used in physical sunblocks, Filipe et al. evaluated the localization and possible skin penetration of these nanoparticles in three sunscreen formulations under realistic in vivo conditions in normal and altered skin. They tested a hydrophobic formulation containing coated 20-nm TiO2 nanoparticles and two commercially available formulations containing TiO2 alone or in combination with ZnO. The goal was to assess how consumers actually use sunscreens in comparison to the recommended standard condition for the sun protection factor test. Traces of the physical blockers could only be detected at the skin surface and uppermost area of the SC in normal human skin after a 2-hour exposure. No ZnO or TiO2 nanoparticles could be detected in layers deeper than the SC after 48 hours of exposure. The investigators concluded that significant penetration by ZnO or TiO2 nanoparticles into keratinocytes is unlikely (Skin Pharmacol. Physiol. 2009;22:266-75).
According to a safety review by Schilling et al., the current evidence implies that there are minimal risks to human health posed from the use of ZnO or TiO2 nanoparticles at concentrations of up to 25% in cosmetic preparations or sunscreens, regardless of coatings or crystalline structure. The researchers observed that these nanoparticles incorporated in topical products occur as aggregates of primary particles 30-150 nm in size that bond in a way that leaves them impervious to the force of product application. Consequently, their structure is unaffected, and no primary particles are released (Photochem. Photobiol. Sci. 2010;9:495-509).
Newman et al. reviewed studies and position statements from 1980 to 2008 in order to characterize the safety, use, and regulatory conditions related to nanosized ZnO and TiO2 in sunscreens. They reported that, while no data suggested significant penetration of the particles beyond the SC, there is a need for additional studies simulating real-world conditions, especially related to UV exposure and sunburned skin (J. Am. Acad. Dermatol. 2009;61:685-92).
In 2011, Monteiro-Riviere et al. performed in vitro and in vivo studies in which pigs received moderate sunburn from UVB exposure. The researchers found that UVB-damaged skin slightly mediated ZnO or TiO2 nanoparticle penetration in multiple tested sunscreen formulations, but they observed no transdermal absorption (Toxicol. Sci. 2011;123:264-80).
Conclusion
Zinc oxide has long been used as one of the two primary inorganic physical sunscreens. Its use in nanoparticle form has appeared effective, but the different physicochemical qualities of the metal oxide in nanosized form have prompted questions regarding safety. Current data suggest minimal risk to intact skin, but additional studies are needed.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Nanotechnology, which applies gathered knowledge on the characteristics of matter to design new products on the nanoscale (<1,000 nm), emerged in the 1980s and has made great strides since then. Dermatology is a prime area of interest for nanotech applications, as numerous products using nanotechnology have been marketed. In fact, the sixth-largest U.S. patent holder in nanotechnology is a cosmetics company (Skin Therapy Lett. 2010;15:1-4). The newest generation of skin products is characterized by improved skin penetration (Arch. Dermatol. Res. 2011;303:533-50), and these products may have a role in enhancing the treatment of several skin disorders; however, toxicological studies must establish the safety of formulations increasingly likely to penetrate multiple skin layers.
Zinc oxide (ZnO) and titanium dioxide (TiO2) are two of the most prominent ingredients in the dermatologic armamentarium that are used in micro- and nanoparticle forms. Efficacy has been well established for these ingredients as inorganic sunscreens, but their relative safety has been debated and remains somewhat controversial. This column discusses findings regarding the safety of ZnO nanoparticles.
Elevated risk
Absorption and effects of zinc ions. In a small study (n = 20) in humans conducted in 2010, Gulson et al. found that small amounts of zinc from ZnO in sunscreens applied for five consecutive days outdoors were absorbed in the skin, with levels of the stable isotope tracer (68)Zn in blood and urine from females receiving the nano sunscreen higher than in males receiving the same sunscreen and higher than in all participants who received the bulk sunscreen (Toxicol. Sci. 2010;118:140-9).
In 2010, Martorano et al. examined the separation of zinc ions from ZnO in commercial sunscreens under UVB exposure and studied the effects of zinc ion accumulation in human epidermal keratinocytes. They noted that UVB light exposure led to a significant concentration-dependent and radiation intensity–dependent rise in zinc ion levels. In turn, a late- or delayed-type cytotoxicity in human epidermal keratinocytes was observed, as was the induction of reactive oxygen species (ROS) in the keratinocytes. The investigators concluded that UVB exposure leads to an elevation in zinc ion dissociation in ZnO sunscreen, yielding cytotoxic effects and oxidative stress (J. Cosmet. Dermatol. 2010;9:276-86).
Genotoxic potential. As Wang and Tooley aptly noted, the concerns regarding the safety of nanoparticles in sunscreens pertain to potential toxicity and capacity to penetrate the skin (Sem. Cutan. Med. Surg. 2011;30:210-13).
In a 2010 in vitro study of the toxicity of ZnO and TiO2 on keratinocytes over short- and long-term application periods, Kocbek et al. found that ZnO nanoparticles conferred more adverse effects than TiO2, with ZnO inhibiting cell viability above 15 mcg/mL after brief exposure while TiO2 exerted no effect up to 100 mcg/mL. Prolonged exposure to ZnO nanoparticles at 10 mcg/mL yielded diminished mitochondrial activity as well as changes in cell morphology and cell-cycle distribution; no such changes were associated with TiO2 nanoparticles. The researchers also reported more nanotubular intercellular structures in keratinocytes exposed to either nanoparticle type as compared to unexposed cells and nanoparticles present in vesicles within the cell cytoplasm. Finally, they observed that partially soluble ZnO spurred the synthesis of ROS, as opposed to insoluble TiO2. They concluded that their findings of an adverse effect on human keratinocytes suggest that long-term exposure to ZnO and TiO2 nanoparticles poses a possible health risk (Small 2010;6:1908-17).
In early 2011, Sharma et al. studied the cytotoxic and genotoxic potential of ZnO nanoparticles in the human liver carcinoma cell line HepG2, given what they argued was the pervasiveness of ZnO in consumer products and industrial applications and the concomitant likelihood of transmission to the liver. Their various assays revealed a significant concentration- and time-dependent toxicity after 12 and 24 hours at 14 and 20 mcg/mL, as well as a significant surge in DNA damage in cells exposed to ZnO nanoparticles for 6 hours (J. Biomed. Nanotechnol. 2011;7:98-9).
Previously, in 2009, Sharma et al. had investigated the potential genotoxicity of ZnO nanoparticles in the human epidermal cell line A431. They found concentration- and time-dependent decreases in cell viability as well as DNA damage potential, as revealed by Comet assay results. In addition, oxidative stress was provoked by ZnO nanoparticles, as evidenced by significant reductions in glutathione, catalase, and superoxide dismutase. The investigators urged caution related to dermatologic formulations containing ZnO nanoparticles, suggesting that their findings indicate a genotoxic potential in human epidermal cells, possibly mediated via lipid peroxidation and oxidative stress (Toxicol. Lett. 2009;185:211-8).
In May 2011, Sharma et al. investigated the biological interactions of ZnO nanoparticles in human epidermal keratinocytes, where electron microscopy showed the internalization of the nanoparticles after 6 hours of exposure at a concentration of 14 mcg/mL. Various assays revealed a time- and concentration-dependent suppression of mitochondrial activity as well as DNA damage in cells, compared with controls. The investigators concluded that ZnO nanoparticles are internalized by human epidermal keratinocytes and provoke a cytotoxic and genotoxic response, providing reason for caution when using consumer products containing nanoparticles. Specifically, they warned that any disruptions in the stratum corneum (SC) could allow the exposure of internal cells to nanoparticles (J. Nanosci. Nanotechnol. 2011;11:3782-8).
Also, in a recent study of the interactions of ZnO nanoparticles with the tumor suppressor p53, Ng et al. found that the p53 pathway was activated in BJ cells (skin fibroblasts) upon treatment with ZnO nanoparticles, leading to a reduction in cell numbers. One implication of this response, the researchers concluded, was that in cells lacking robust p53, the protective response can be turned toward carcinogenesis due to exposure to DNA damage–inducing agents like ZnO nanoparticles (Biomaterials 2011;32:8218-25).
Weight of evidence
However, several researchers contend that current data strongly suggest that nanosized ZnO and TiO2 do not, in fact, pose such risks (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Int. J. Dermatol. 2011;50:247-54; Sem. Cutan. Med. Surg. 2011;30:210-13).
In 2009, in response to increasing concerns about the potential adverse effects of ZnO- and TiO2-coated nanoparticles used in physical sunblocks, Filipe et al. evaluated the localization and possible skin penetration of these nanoparticles in three sunscreen formulations under realistic in vivo conditions in normal and altered skin. They tested a hydrophobic formulation containing coated 20-nm TiO2 nanoparticles and two commercially available formulations containing TiO2 alone or in combination with ZnO. The goal was to assess how consumers actually use sunscreens in comparison to the recommended standard condition for the sun protection factor test. Traces of the physical blockers could only be detected at the skin surface and uppermost area of the SC in normal human skin after a 2-hour exposure. No ZnO or TiO2 nanoparticles could be detected in layers deeper than the SC after 48 hours of exposure. The investigators concluded that significant penetration by ZnO or TiO2 nanoparticles into keratinocytes is unlikely (Skin Pharmacol. Physiol. 2009;22:266-75).
According to a safety review by Schilling et al., the current evidence implies that there are minimal risks to human health posed from the use of ZnO or TiO2 nanoparticles at concentrations of up to 25% in cosmetic preparations or sunscreens, regardless of coatings or crystalline structure. The researchers observed that these nanoparticles incorporated in topical products occur as aggregates of primary particles 30-150 nm in size that bond in a way that leaves them impervious to the force of product application. Consequently, their structure is unaffected, and no primary particles are released (Photochem. Photobiol. Sci. 2010;9:495-509).
Newman et al. reviewed studies and position statements from 1980 to 2008 in order to characterize the safety, use, and regulatory conditions related to nanosized ZnO and TiO2 in sunscreens. They reported that, while no data suggested significant penetration of the particles beyond the SC, there is a need for additional studies simulating real-world conditions, especially related to UV exposure and sunburned skin (J. Am. Acad. Dermatol. 2009;61:685-92).
In 2011, Monteiro-Riviere et al. performed in vitro and in vivo studies in which pigs received moderate sunburn from UVB exposure. The researchers found that UVB-damaged skin slightly mediated ZnO or TiO2 nanoparticle penetration in multiple tested sunscreen formulations, but they observed no transdermal absorption (Toxicol. Sci. 2011;123:264-80).
Conclusion
Zinc oxide has long been used as one of the two primary inorganic physical sunscreens. Its use in nanoparticle form has appeared effective, but the different physicochemical qualities of the metal oxide in nanosized form have prompted questions regarding safety. Current data suggest minimal risk to intact skin, but additional studies are needed.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Nanotechnology, which applies gathered knowledge on the characteristics of matter to design new products on the nanoscale (<1,000 nm), emerged in the 1980s and has made great strides since then. Dermatology is a prime area of interest for nanotech applications, as numerous products using nanotechnology have been marketed. In fact, the sixth-largest U.S. patent holder in nanotechnology is a cosmetics company (Skin Therapy Lett. 2010;15:1-4). The newest generation of skin products is characterized by improved skin penetration (Arch. Dermatol. Res. 2011;303:533-50), and these products may have a role in enhancing the treatment of several skin disorders; however, toxicological studies must establish the safety of formulations increasingly likely to penetrate multiple skin layers.
Zinc oxide (ZnO) and titanium dioxide (TiO2) are two of the most prominent ingredients in the dermatologic armamentarium that are used in micro- and nanoparticle forms. Efficacy has been well established for these ingredients as inorganic sunscreens, but their relative safety has been debated and remains somewhat controversial. This column discusses findings regarding the safety of ZnO nanoparticles.
Elevated risk
Absorption and effects of zinc ions. In a small study (n = 20) in humans conducted in 2010, Gulson et al. found that small amounts of zinc from ZnO in sunscreens applied for five consecutive days outdoors were absorbed in the skin, with levels of the stable isotope tracer (68)Zn in blood and urine from females receiving the nano sunscreen higher than in males receiving the same sunscreen and higher than in all participants who received the bulk sunscreen (Toxicol. Sci. 2010;118:140-9).
In 2010, Martorano et al. examined the separation of zinc ions from ZnO in commercial sunscreens under UVB exposure and studied the effects of zinc ion accumulation in human epidermal keratinocytes. They noted that UVB light exposure led to a significant concentration-dependent and radiation intensity–dependent rise in zinc ion levels. In turn, a late- or delayed-type cytotoxicity in human epidermal keratinocytes was observed, as was the induction of reactive oxygen species (ROS) in the keratinocytes. The investigators concluded that UVB exposure leads to an elevation in zinc ion dissociation in ZnO sunscreen, yielding cytotoxic effects and oxidative stress (J. Cosmet. Dermatol. 2010;9:276-86).
Genotoxic potential. As Wang and Tooley aptly noted, the concerns regarding the safety of nanoparticles in sunscreens pertain to potential toxicity and capacity to penetrate the skin (Sem. Cutan. Med. Surg. 2011;30:210-13).
In a 2010 in vitro study of the toxicity of ZnO and TiO2 on keratinocytes over short- and long-term application periods, Kocbek et al. found that ZnO nanoparticles conferred more adverse effects than TiO2, with ZnO inhibiting cell viability above 15 mcg/mL after brief exposure while TiO2 exerted no effect up to 100 mcg/mL. Prolonged exposure to ZnO nanoparticles at 10 mcg/mL yielded diminished mitochondrial activity as well as changes in cell morphology and cell-cycle distribution; no such changes were associated with TiO2 nanoparticles. The researchers also reported more nanotubular intercellular structures in keratinocytes exposed to either nanoparticle type as compared to unexposed cells and nanoparticles present in vesicles within the cell cytoplasm. Finally, they observed that partially soluble ZnO spurred the synthesis of ROS, as opposed to insoluble TiO2. They concluded that their findings of an adverse effect on human keratinocytes suggest that long-term exposure to ZnO and TiO2 nanoparticles poses a possible health risk (Small 2010;6:1908-17).
In early 2011, Sharma et al. studied the cytotoxic and genotoxic potential of ZnO nanoparticles in the human liver carcinoma cell line HepG2, given what they argued was the pervasiveness of ZnO in consumer products and industrial applications and the concomitant likelihood of transmission to the liver. Their various assays revealed a significant concentration- and time-dependent toxicity after 12 and 24 hours at 14 and 20 mcg/mL, as well as a significant surge in DNA damage in cells exposed to ZnO nanoparticles for 6 hours (J. Biomed. Nanotechnol. 2011;7:98-9).
Previously, in 2009, Sharma et al. had investigated the potential genotoxicity of ZnO nanoparticles in the human epidermal cell line A431. They found concentration- and time-dependent decreases in cell viability as well as DNA damage potential, as revealed by Comet assay results. In addition, oxidative stress was provoked by ZnO nanoparticles, as evidenced by significant reductions in glutathione, catalase, and superoxide dismutase. The investigators urged caution related to dermatologic formulations containing ZnO nanoparticles, suggesting that their findings indicate a genotoxic potential in human epidermal cells, possibly mediated via lipid peroxidation and oxidative stress (Toxicol. Lett. 2009;185:211-8).
In May 2011, Sharma et al. investigated the biological interactions of ZnO nanoparticles in human epidermal keratinocytes, where electron microscopy showed the internalization of the nanoparticles after 6 hours of exposure at a concentration of 14 mcg/mL. Various assays revealed a time- and concentration-dependent suppression of mitochondrial activity as well as DNA damage in cells, compared with controls. The investigators concluded that ZnO nanoparticles are internalized by human epidermal keratinocytes and provoke a cytotoxic and genotoxic response, providing reason for caution when using consumer products containing nanoparticles. Specifically, they warned that any disruptions in the stratum corneum (SC) could allow the exposure of internal cells to nanoparticles (J. Nanosci. Nanotechnol. 2011;11:3782-8).
Also, in a recent study of the interactions of ZnO nanoparticles with the tumor suppressor p53, Ng et al. found that the p53 pathway was activated in BJ cells (skin fibroblasts) upon treatment with ZnO nanoparticles, leading to a reduction in cell numbers. One implication of this response, the researchers concluded, was that in cells lacking robust p53, the protective response can be turned toward carcinogenesis due to exposure to DNA damage–inducing agents like ZnO nanoparticles (Biomaterials 2011;32:8218-25).
Weight of evidence
However, several researchers contend that current data strongly suggest that nanosized ZnO and TiO2 do not, in fact, pose such risks (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Int. J. Dermatol. 2011;50:247-54; Sem. Cutan. Med. Surg. 2011;30:210-13).
In 2009, in response to increasing concerns about the potential adverse effects of ZnO- and TiO2-coated nanoparticles used in physical sunblocks, Filipe et al. evaluated the localization and possible skin penetration of these nanoparticles in three sunscreen formulations under realistic in vivo conditions in normal and altered skin. They tested a hydrophobic formulation containing coated 20-nm TiO2 nanoparticles and two commercially available formulations containing TiO2 alone or in combination with ZnO. The goal was to assess how consumers actually use sunscreens in comparison to the recommended standard condition for the sun protection factor test. Traces of the physical blockers could only be detected at the skin surface and uppermost area of the SC in normal human skin after a 2-hour exposure. No ZnO or TiO2 nanoparticles could be detected in layers deeper than the SC after 48 hours of exposure. The investigators concluded that significant penetration by ZnO or TiO2 nanoparticles into keratinocytes is unlikely (Skin Pharmacol. Physiol. 2009;22:266-75).
According to a safety review by Schilling et al., the current evidence implies that there are minimal risks to human health posed from the use of ZnO or TiO2 nanoparticles at concentrations of up to 25% in cosmetic preparations or sunscreens, regardless of coatings or crystalline structure. The researchers observed that these nanoparticles incorporated in topical products occur as aggregates of primary particles 30-150 nm in size that bond in a way that leaves them impervious to the force of product application. Consequently, their structure is unaffected, and no primary particles are released (Photochem. Photobiol. Sci. 2010;9:495-509).
Newman et al. reviewed studies and position statements from 1980 to 2008 in order to characterize the safety, use, and regulatory conditions related to nanosized ZnO and TiO2 in sunscreens. They reported that, while no data suggested significant penetration of the particles beyond the SC, there is a need for additional studies simulating real-world conditions, especially related to UV exposure and sunburned skin (J. Am. Acad. Dermatol. 2009;61:685-92).
In 2011, Monteiro-Riviere et al. performed in vitro and in vivo studies in which pigs received moderate sunburn from UVB exposure. The researchers found that UVB-damaged skin slightly mediated ZnO or TiO2 nanoparticle penetration in multiple tested sunscreen formulations, but they observed no transdermal absorption (Toxicol. Sci. 2011;123:264-80).
Conclusion
Zinc oxide has long been used as one of the two primary inorganic physical sunscreens. Its use in nanoparticle form has appeared effective, but the different physicochemical qualities of the metal oxide in nanosized form have prompted questions regarding safety. Current data suggest minimal risk to intact skin, but additional studies are needed.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Zinc oxide
Zinc is a trace element, and it is not synthesized by the human body. The element was identified in the 1960s as being essential for human health and development. Zinc is a cofactor in more than 300 enzymes necessary for cell function. In the dermatologic realm, zinc deficiency has been associated with skin alterations, delayed wound healing, and hair loss.
Zinc oxide (ZnO) is a metal oxide that also has a broad profile in dermatology. It is perhaps best known as a physical sunscreen ingredient. ZnO and titanium dioxide (TiO2) have long been used in this manner. Both ZnO and TiO2 also have been increasingly used to replace large-particle compounds in numerous cosmetics and sunscreens. These two compounds have demonstrated effective protection against UV-induced damage, providing stronger protection against UV radiation while leaving less white residue than previous generations of physical sunscreens.
Particles of ZnO in earlier sunscreens were found to be too large to penetrate the stratum corneum and, thus, were deemed biologically inactive (J. Am. Acad. Dermatol. 1999;40:85-90). However, in novel nanoparticle form, such metal oxides absorb UV radiation, leading to photocatalysis and the release of reactive oxygen species (Australas. J. Dermatol. 2011;52:1-6). Indeed, nanoparticles exhibit new physiochemical properties as a result of increased surface area as compared to large-form products, and the potential adverse effects of the novel nanoparticle formulations in sunscreens cannot be adequately extrapolated from the effects of older-generation larger-particle skin care products (J. Drugs Dermatol. 2010;9:475-81; Int. J. Dermatol. 2011;50:247-54. The relative safety of ZnO nanoparticles will be discussed in a future column. The focus in this column will be a brief comparison with TiO2 and other indications for ZnO.
ZnO and TiO2
While numerous studies explore both TiO2 and ZnO, the latter is noted for greater versatility within the dermatologic armamentarium. In addition, ZnO is less photoactive and is associated with a lower refractive index in visible light than TiO2 (1.9 vs. 2.6, respectively) (J. Am. Acad. Dermatol. 1999;40:85-90); therefore, TiO2 appears whiter and is more difficult to incorporate into transparent products.
Another important difference is the spectrum of action. That is, only avobenzone (butyl methoxydibenzoylmethane) and ZnO are approved in the United States for broad-spectrum protection against UVA wavelengths greater than 360 nm, because TiO2 has been shown to be effective only against UV wavelengths less than 360 nm (UVA is 320-400 nm). In a study by Beasley and Meyer, TiO2 delivered neither the same level of UVA attenuation nor protection from UVA to human skin as did photostabilized formulations of avobenzone or ZnO. Therefore, TiO2 is not a suitable substitute for avobenzone and ZnO for strong UVA protection (Am. J. Clin. Dermatol. 2010;11:413-21).
Indications beyond photoprotection
More than 20 years ago, Hughes and McLean showed that a ZnO tape was effective in dressing fingertip and soft tissue injuries that were resistant to healing (Arch. Emerg. Med. 1988;5:223-7). More recently, Parboteeah and Brown demonstrated the efficacy of treating recalcitrant venous leg ulcers with ZnO paste bandages (Br. J. Nurs. 2008;17:S30, S32, S34-6). In addition, Treadwell has shown that the weekly application of ZnO compression dressings to surgical wounds of the lower leg promotes healing (Dermatol. Surg. 2011;37:166-7).
Micronized zinc oxide is included in a 4% hydroquinone/10% L-ascorbic acid treatment system recently found (in a small study of 34 females) to be effective in alleviating early signs of photodamage in normal to oily skin. Thirty patients, with minimal or mild facial photodamage and hyperpigmentation, completed the 12-week treatment regimen. All the participants were satisfied with the appearance of their skin after the study, with median scores for all assessment parameters significantly improved compared with baseline (J. Drugs Dermatol. 2011;10:1455-61). ZnO also is an active ingredient in formulations intended to support the healing of perianal eczema (Hautarzt. 2010;61:33-8).
A 2001 report on a series of blinded, randomized clinical trials conducted by Baldwin et al. showed that clinical benefits were derived from the continuous topical administration of a ZnO/petrolatum formulation in a diaper introduced at that time. The first study was undertaken to verify that the ZnO/petrolatum formulation was indeed transferred from the diaper to the child’s skin. Stratum corneum (SC) samples were analyzed from each child after the wearing of a single diaper for 3 hours or multiple diapers for 24 hours. The results indicated effective transfer, with ZnO increasing in the SC from 4.2 mcg/cm2 at 3 hours to more than 8 mcg/cm2 at 24 hours.
The second study of the formulation, in an adult arm model, assessed the prevention of irritation and SC damage induced by sodium laureth sulfate. The investigators found that the ZnO/petrolatum combination yielded significant reductions in SC damage and erythema. The third study, a 4-week trial in which 268 infants were assessed, considered the effects of the formulation on erythema and diaper rash. Half of the infants wore the test diaper and half used a control diaper lacking the ZnO/petrolatum product. Significant reductions in erythema and diaper rash were indeed observed in the test group (J. Eur. Acad. Dermatol. Venereol. 2001;15 Suppl 1:5-11).
A 2009 study showed that an unmedicated ZnO/petrolatum paste was effective in restoring the properties of the skin, allowing for balanced transepidermal water loss and water retention by SC previously compromised by diaper dermatitis. This skin condition affects approximately 50% of infants and a small percentage of the bedridden elderly (Int. J. Cosmet. Sci. 2009;31:369-74).
In 2010, a study that assessed the effectiveness of topical ZnO ointment using the rabbit ear hypertrophic scar model showed that the application of 40% ZnO significantly reduced clinical scar hypertrophy scores at 6 weeks compared with placebo. The researchers concluded that these results may suggest clinical applications for ZnO in the treatment of hypertrophic scars in humans (Burns 2010;36:1027-35). In addition, ZnO has demonstrated antibacterial properties, with nanoparticles exhibiting more potent antibacterial activity than bulk ZnO (Sci. Technol. Adv. Mater. 2008;9:1-7).
Products
ZnO is a key ingredient in calamine lotion, an antipruritic compound used to treat various mild conditions such as bites and stings from insects, eczema, poison ivy, rashes, and sunburn. It is also available over the counter in ointment or suppository form for healing hemorrhoids and fissures. In addition, ZnO is used widely in baby powders, barrier creams, moisturizers, antiseptic ointments, antidandruff shampoos, athletic bandage tape, and, of course, sunscreens.
Conclusion
ZnO is a versatile inorganic metal oxide with multiple indications in dermatology. Consequently, it is included in a wide array of skin care products, including shampoos, moisturizers, and sunscreens. Its use in nanoparticle form, along with the similar use of its physical sunscreen counterpart TiO2, represents one of the many subjects debated within the larger context of sunscreen use. The next edition of this column will focus on the relative safety of zinc oxide nanoparticles.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
This column, "Cosmeceutical Critique," appears regularly in Skin & Allergy News, a publication of Frontline Medical News.
Zinc is a trace element, and it is not synthesized by the human body. The element was identified in the 1960s as being essential for human health and development. Zinc is a cofactor in more than 300 enzymes necessary for cell function. In the dermatologic realm, zinc deficiency has been associated with skin alterations, delayed wound healing, and hair loss.
Zinc oxide (ZnO) is a metal oxide that also has a broad profile in dermatology. It is perhaps best known as a physical sunscreen ingredient. ZnO and titanium dioxide (TiO2) have long been used in this manner. Both ZnO and TiO2 also have been increasingly used to replace large-particle compounds in numerous cosmetics and sunscreens. These two compounds have demonstrated effective protection against UV-induced damage, providing stronger protection against UV radiation while leaving less white residue than previous generations of physical sunscreens.
Particles of ZnO in earlier sunscreens were found to be too large to penetrate the stratum corneum and, thus, were deemed biologically inactive (J. Am. Acad. Dermatol. 1999;40:85-90). However, in novel nanoparticle form, such metal oxides absorb UV radiation, leading to photocatalysis and the release of reactive oxygen species (Australas. J. Dermatol. 2011;52:1-6). Indeed, nanoparticles exhibit new physiochemical properties as a result of increased surface area as compared to large-form products, and the potential adverse effects of the novel nanoparticle formulations in sunscreens cannot be adequately extrapolated from the effects of older-generation larger-particle skin care products (J. Drugs Dermatol. 2010;9:475-81; Int. J. Dermatol. 2011;50:247-54. The relative safety of ZnO nanoparticles will be discussed in a future column. The focus in this column will be a brief comparison with TiO2 and other indications for ZnO.
ZnO and TiO2
While numerous studies explore both TiO2 and ZnO, the latter is noted for greater versatility within the dermatologic armamentarium. In addition, ZnO is less photoactive and is associated with a lower refractive index in visible light than TiO2 (1.9 vs. 2.6, respectively) (J. Am. Acad. Dermatol. 1999;40:85-90); therefore, TiO2 appears whiter and is more difficult to incorporate into transparent products.
Another important difference is the spectrum of action. That is, only avobenzone (butyl methoxydibenzoylmethane) and ZnO are approved in the United States for broad-spectrum protection against UVA wavelengths greater than 360 nm, because TiO2 has been shown to be effective only against UV wavelengths less than 360 nm (UVA is 320-400 nm). In a study by Beasley and Meyer, TiO2 delivered neither the same level of UVA attenuation nor protection from UVA to human skin as did photostabilized formulations of avobenzone or ZnO. Therefore, TiO2 is not a suitable substitute for avobenzone and ZnO for strong UVA protection (Am. J. Clin. Dermatol. 2010;11:413-21).
Indications beyond photoprotection
More than 20 years ago, Hughes and McLean showed that a ZnO tape was effective in dressing fingertip and soft tissue injuries that were resistant to healing (Arch. Emerg. Med. 1988;5:223-7). More recently, Parboteeah and Brown demonstrated the efficacy of treating recalcitrant venous leg ulcers with ZnO paste bandages (Br. J. Nurs. 2008;17:S30, S32, S34-6). In addition, Treadwell has shown that the weekly application of ZnO compression dressings to surgical wounds of the lower leg promotes healing (Dermatol. Surg. 2011;37:166-7).
Micronized zinc oxide is included in a 4% hydroquinone/10% L-ascorbic acid treatment system recently found (in a small study of 34 females) to be effective in alleviating early signs of photodamage in normal to oily skin. Thirty patients, with minimal or mild facial photodamage and hyperpigmentation, completed the 12-week treatment regimen. All the participants were satisfied with the appearance of their skin after the study, with median scores for all assessment parameters significantly improved compared with baseline (J. Drugs Dermatol. 2011;10:1455-61). ZnO also is an active ingredient in formulations intended to support the healing of perianal eczema (Hautarzt. 2010;61:33-8).
A 2001 report on a series of blinded, randomized clinical trials conducted by Baldwin et al. showed that clinical benefits were derived from the continuous topical administration of a ZnO/petrolatum formulation in a diaper introduced at that time. The first study was undertaken to verify that the ZnO/petrolatum formulation was indeed transferred from the diaper to the child’s skin. Stratum corneum (SC) samples were analyzed from each child after the wearing of a single diaper for 3 hours or multiple diapers for 24 hours. The results indicated effective transfer, with ZnO increasing in the SC from 4.2 mcg/cm2 at 3 hours to more than 8 mcg/cm2 at 24 hours.
The second study of the formulation, in an adult arm model, assessed the prevention of irritation and SC damage induced by sodium laureth sulfate. The investigators found that the ZnO/petrolatum combination yielded significant reductions in SC damage and erythema. The third study, a 4-week trial in which 268 infants were assessed, considered the effects of the formulation on erythema and diaper rash. Half of the infants wore the test diaper and half used a control diaper lacking the ZnO/petrolatum product. Significant reductions in erythema and diaper rash were indeed observed in the test group (J. Eur. Acad. Dermatol. Venereol. 2001;15 Suppl 1:5-11).
A 2009 study showed that an unmedicated ZnO/petrolatum paste was effective in restoring the properties of the skin, allowing for balanced transepidermal water loss and water retention by SC previously compromised by diaper dermatitis. This skin condition affects approximately 50% of infants and a small percentage of the bedridden elderly (Int. J. Cosmet. Sci. 2009;31:369-74).
In 2010, a study that assessed the effectiveness of topical ZnO ointment using the rabbit ear hypertrophic scar model showed that the application of 40% ZnO significantly reduced clinical scar hypertrophy scores at 6 weeks compared with placebo. The researchers concluded that these results may suggest clinical applications for ZnO in the treatment of hypertrophic scars in humans (Burns 2010;36:1027-35). In addition, ZnO has demonstrated antibacterial properties, with nanoparticles exhibiting more potent antibacterial activity than bulk ZnO (Sci. Technol. Adv. Mater. 2008;9:1-7).
Products
ZnO is a key ingredient in calamine lotion, an antipruritic compound used to treat various mild conditions such as bites and stings from insects, eczema, poison ivy, rashes, and sunburn. It is also available over the counter in ointment or suppository form for healing hemorrhoids and fissures. In addition, ZnO is used widely in baby powders, barrier creams, moisturizers, antiseptic ointments, antidandruff shampoos, athletic bandage tape, and, of course, sunscreens.
Conclusion
ZnO is a versatile inorganic metal oxide with multiple indications in dermatology. Consequently, it is included in a wide array of skin care products, including shampoos, moisturizers, and sunscreens. Its use in nanoparticle form, along with the similar use of its physical sunscreen counterpart TiO2, represents one of the many subjects debated within the larger context of sunscreen use. The next edition of this column will focus on the relative safety of zinc oxide nanoparticles.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
This column, "Cosmeceutical Critique," appears regularly in Skin & Allergy News, a publication of Frontline Medical News.
Zinc is a trace element, and it is not synthesized by the human body. The element was identified in the 1960s as being essential for human health and development. Zinc is a cofactor in more than 300 enzymes necessary for cell function. In the dermatologic realm, zinc deficiency has been associated with skin alterations, delayed wound healing, and hair loss.
Zinc oxide (ZnO) is a metal oxide that also has a broad profile in dermatology. It is perhaps best known as a physical sunscreen ingredient. ZnO and titanium dioxide (TiO2) have long been used in this manner. Both ZnO and TiO2 also have been increasingly used to replace large-particle compounds in numerous cosmetics and sunscreens. These two compounds have demonstrated effective protection against UV-induced damage, providing stronger protection against UV radiation while leaving less white residue than previous generations of physical sunscreens.
Particles of ZnO in earlier sunscreens were found to be too large to penetrate the stratum corneum and, thus, were deemed biologically inactive (J. Am. Acad. Dermatol. 1999;40:85-90). However, in novel nanoparticle form, such metal oxides absorb UV radiation, leading to photocatalysis and the release of reactive oxygen species (Australas. J. Dermatol. 2011;52:1-6). Indeed, nanoparticles exhibit new physiochemical properties as a result of increased surface area as compared to large-form products, and the potential adverse effects of the novel nanoparticle formulations in sunscreens cannot be adequately extrapolated from the effects of older-generation larger-particle skin care products (J. Drugs Dermatol. 2010;9:475-81; Int. J. Dermatol. 2011;50:247-54. The relative safety of ZnO nanoparticles will be discussed in a future column. The focus in this column will be a brief comparison with TiO2 and other indications for ZnO.
ZnO and TiO2
While numerous studies explore both TiO2 and ZnO, the latter is noted for greater versatility within the dermatologic armamentarium. In addition, ZnO is less photoactive and is associated with a lower refractive index in visible light than TiO2 (1.9 vs. 2.6, respectively) (J. Am. Acad. Dermatol. 1999;40:85-90); therefore, TiO2 appears whiter and is more difficult to incorporate into transparent products.
Another important difference is the spectrum of action. That is, only avobenzone (butyl methoxydibenzoylmethane) and ZnO are approved in the United States for broad-spectrum protection against UVA wavelengths greater than 360 nm, because TiO2 has been shown to be effective only against UV wavelengths less than 360 nm (UVA is 320-400 nm). In a study by Beasley and Meyer, TiO2 delivered neither the same level of UVA attenuation nor protection from UVA to human skin as did photostabilized formulations of avobenzone or ZnO. Therefore, TiO2 is not a suitable substitute for avobenzone and ZnO for strong UVA protection (Am. J. Clin. Dermatol. 2010;11:413-21).
Indications beyond photoprotection
More than 20 years ago, Hughes and McLean showed that a ZnO tape was effective in dressing fingertip and soft tissue injuries that were resistant to healing (Arch. Emerg. Med. 1988;5:223-7). More recently, Parboteeah and Brown demonstrated the efficacy of treating recalcitrant venous leg ulcers with ZnO paste bandages (Br. J. Nurs. 2008;17:S30, S32, S34-6). In addition, Treadwell has shown that the weekly application of ZnO compression dressings to surgical wounds of the lower leg promotes healing (Dermatol. Surg. 2011;37:166-7).
Micronized zinc oxide is included in a 4% hydroquinone/10% L-ascorbic acid treatment system recently found (in a small study of 34 females) to be effective in alleviating early signs of photodamage in normal to oily skin. Thirty patients, with minimal or mild facial photodamage and hyperpigmentation, completed the 12-week treatment regimen. All the participants were satisfied with the appearance of their skin after the study, with median scores for all assessment parameters significantly improved compared with baseline (J. Drugs Dermatol. 2011;10:1455-61). ZnO also is an active ingredient in formulations intended to support the healing of perianal eczema (Hautarzt. 2010;61:33-8).
A 2001 report on a series of blinded, randomized clinical trials conducted by Baldwin et al. showed that clinical benefits were derived from the continuous topical administration of a ZnO/petrolatum formulation in a diaper introduced at that time. The first study was undertaken to verify that the ZnO/petrolatum formulation was indeed transferred from the diaper to the child’s skin. Stratum corneum (SC) samples were analyzed from each child after the wearing of a single diaper for 3 hours or multiple diapers for 24 hours. The results indicated effective transfer, with ZnO increasing in the SC from 4.2 mcg/cm2 at 3 hours to more than 8 mcg/cm2 at 24 hours.
The second study of the formulation, in an adult arm model, assessed the prevention of irritation and SC damage induced by sodium laureth sulfate. The investigators found that the ZnO/petrolatum combination yielded significant reductions in SC damage and erythema. The third study, a 4-week trial in which 268 infants were assessed, considered the effects of the formulation on erythema and diaper rash. Half of the infants wore the test diaper and half used a control diaper lacking the ZnO/petrolatum product. Significant reductions in erythema and diaper rash were indeed observed in the test group (J. Eur. Acad. Dermatol. Venereol. 2001;15 Suppl 1:5-11).
A 2009 study showed that an unmedicated ZnO/petrolatum paste was effective in restoring the properties of the skin, allowing for balanced transepidermal water loss and water retention by SC previously compromised by diaper dermatitis. This skin condition affects approximately 50% of infants and a small percentage of the bedridden elderly (Int. J. Cosmet. Sci. 2009;31:369-74).
In 2010, a study that assessed the effectiveness of topical ZnO ointment using the rabbit ear hypertrophic scar model showed that the application of 40% ZnO significantly reduced clinical scar hypertrophy scores at 6 weeks compared with placebo. The researchers concluded that these results may suggest clinical applications for ZnO in the treatment of hypertrophic scars in humans (Burns 2010;36:1027-35). In addition, ZnO has demonstrated antibacterial properties, with nanoparticles exhibiting more potent antibacterial activity than bulk ZnO (Sci. Technol. Adv. Mater. 2008;9:1-7).
Products
ZnO is a key ingredient in calamine lotion, an antipruritic compound used to treat various mild conditions such as bites and stings from insects, eczema, poison ivy, rashes, and sunburn. It is also available over the counter in ointment or suppository form for healing hemorrhoids and fissures. In addition, ZnO is used widely in baby powders, barrier creams, moisturizers, antiseptic ointments, antidandruff shampoos, athletic bandage tape, and, of course, sunscreens.
Conclusion
ZnO is a versatile inorganic metal oxide with multiple indications in dermatology. Consequently, it is included in a wide array of skin care products, including shampoos, moisturizers, and sunscreens. Its use in nanoparticle form, along with the similar use of its physical sunscreen counterpart TiO2, represents one of the many subjects debated within the larger context of sunscreen use. The next edition of this column will focus on the relative safety of zinc oxide nanoparticles.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
This column, "Cosmeceutical Critique," appears regularly in Skin & Allergy News, a publication of Frontline Medical News.
Peppermint and menthol
Mentha piperita, better known as peppermint, is used worldwide in many ways. Its use for culinary and medical purposes dates back to the ancient Greek and Roman civilizations. Peppermint is used in numerous forms (i.e., oil, leaf, leaf extract, and leaf water), with the oil as the most versatile (Dermatitis 2010;21:327-9). Peppermint has long been known for its beneficial gastrointestinal effects, and it has a well-established record of antimicrobial, antifungal, and analgesic activity (Mills S., Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine. [London: Churchill Livingstone, 2000, pp 507-13]; J. Environ. Biol. 2011;32:23-9).
Menthol (C10H20O) is a naturally occurring monocyclic terpene alcohol derived from Mentha piperita as well as other mint oils (Skin Therapy Lett. 2010;15:5-9), and has been associated with several health benefits. Recently, anticancer properties have been ascribed to menthol (Biochim. Biophys. Acta 2009;1792:33-8). This column will discuss recent findings regarding the actual or potential cutaneous benefits of peppermint and menthol.
Various Mentha species, including M. piperita, have exhibited significant antioxidant activity (Toxicol. Ind. Health. 2012;28:83-9; Nat. Prod. Commun. 2009;4:1107-12; Nat. Prod. Commun. 2009;4:535-42). In a 2010 study of the antioxidant activity of the essential oils of six popular herbs, including lavender (Lavendular angustifolia), peppermint (M. piperita), rosemary (Rosmarius officinalis), lemon (Citrus limon), grapefruit (C. paradise), and frankincense (Boswellia carteri), investigators found, in testing free radical-scavenging capacity and lipid peroxidation in the linoleic acid system, that peppermint essential oil exhibited the greatest radical-scavenging activity against the 2,2\'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) ABTS radical (Nat. Prod. Res. 2010;24:140-51).
In 2010, Baliga and Rao showed that M. piperita and M. arvensis (wild mint) protected mice against gamma-radiation–induced morbidity and mortality. Specifically, M. piperita protected murine testes as well as gastrointestinal and hemopoietic systems (J. Cancer Res. Ther. 2010;6:255-62).
Anticancer activity
Investigations by Jain et al. into the molecular mechanisms supporting the anticarcinogenic potential of M. piperita leaf extracts on six human cancer cell lines (HeLa, MCF-7, Jurkat, T24, HT-29, MIAPaCa-2) in 2011 revealed that chloroform and ethyl acetate extracts dose- and time-dependently displayed anticarcinogenic activity leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis among the cascade of effects. The investigators identified their findings as the first evidence of direct anticarcinogenic activity of Mentha leaf extracts and suggested that future work might focus on isolating active constituents as a foundation for mechanistic and translational studies leading to new anticancer drugs, alone or in combination, to prevent and treat human cancers (Int. J. Toxicol. 2011;30:225-36).
Topical benefits of menthol
In a recent examination of the antibacterial and antifungal properties, as well as speculated anti-inflammatory activity of menthol as a topical treatment for diaper dermatitis, investigators conducted a pilot clinical trial in a hospital setting. The study involved 84 neonates with diagnosed candidal diaper dermatitis who required no critical care or systemic antifungal and anti-inflammatory medications. The menthol group (n = 42) received topical clotrimazole and topically applied menthol drops and the control group (n = 42) received topical clotrimazole and a placebo. Thirty-five infants in each group completed the study. The researchers found that complete healing was shorter in the menthol group, with significant relief of erythema and pustules observed in this group. They concluded that topically-applied menthol may be an effective agent in the treatment of candidal diaper dermatitis (World J. Pediatr. 2011;7:167-70).
In 2011, Qiu et al. showed, through various assays, that menthol, in low concentrations, could significantly suppress the expression of alpha-hemolysin, enterotoxins A and B, and toxic shock syndrome toxin 1 in Staphylococcus aureus. The investigators concluded that menthol may warrant inclusion in the armamentarium against S. aureus when combined with beta-lactam antibiotics, which, at subinhibitory concentrations, can actually augment S. aureus toxin secretion. They added that menthol may also have possible uses in novel anti-virulence drugs (Appl. Microbiol. Biotechnol. 2011;90:705-12). It should be noted that menthol is considered safe and effective, with concentrations up to 16% approved in OTC external products by the Food and Drug Administration (J. Am. Acad. Dermatol. 2007;57:873-8).
Pruritus, TRPM8, and melanoma
Topically applied menthol, in concentrations of 1%-3%, is often used to treat pruritus, particularly in the elderly (Skin Therapy Lett. 2010;15:5-9). In addition, recent evidence suggests that the presence of menthol can facilitate penetration of other agents in topical products (Int. J. Toxicol. 2001;20 Suppl 3:61-73; J. Am. Acad. Dermatol. 2007;57:873-8). Patel and Yosipovitch suggest that elderly patients who report diminished pruritus with cooling may stand to benefit from menthol-containing topical therapies (J. Am. Acad. Dermatol. 2007;57:873-8; Skin Therapy Lett. 2010;15:5-9). Interestingly, menthol, via the transient receptor potential melastatin subfamily 8 (TRPM8) receptor, a member of a family of excitatory ion channels, engenders the same cooling sensation as low temperature, though menthol is not linked to a reduction in skin temperature (J. Am. Acad. Dermatol. 2007;57:873-8; Skin Therapy Lett. 2010;15:5-9).
Although the exact mechanism by which menthol exerts its antipruritic and analgesic effects has yet to be determined, the discovery that the TRPM8 is its underlying receptor is proving to be significant, particularly in understanding the cooling effect of the botanical (J. Am. Acad. Dermatol. 2007;57:873-8). There are also indications that menthol has therapeutic potential for melanoma. Specifically, melanoma expresses TRPM8 receptors, the activation of which inhibits melanoma viability. Menthol appears to mediate this response through an influx of extracellular calcium ions (Am. J. Physiol. Cell Physiol. 2008;295:C296-301; Am. J. Physiol. Cell Physiol. 2008;295:C293-5).
Peppermint oil
In 2003, Schuhmacher et al. investigated the virucidal effect of peppermint oil and found that it had a direct effect against herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) as well as an acyclovir-resistant HSV-1 strain. The investigators concluded, noting the lipophilic nature of peppermint oil, that it might be an appropriate topical treatment for recurrent herpes outbreaks (Phytomedicine 2003;10:504-10).
Because of its flavor, aroma, and cooling qualities, peppermint oil is used in a wide range of products, including cosmeceuticals, personal hygiene products (e.g., bath preparations, mouthwashes, toothpastes, and topical formulations), foods, pharmaceutical products, and aromatherapy. Topical indications include pruritus, irritation, and inflammation. Peppermint oil can act as a skin sensitizer, though, particularly in impaired and sensitive skin (Dermatitis 2010;21:327-9). Although peppermint oil has been reported to be a sensitizer in isolated cases, peppermint oil 8% was not found to be a sensitizer in a recent test using a maximization protocol and the various forms of peppermint (i.e., oil, extract, leaves, and water) are considered to be safe in cosmetic formulations. In rinse-off products, peppermint oil is used in concentrations up to 3% and up to 0.2% in leave-on formulations (Int. J. Toxicol. 2001;20 Suppl 3:61-73).
Conclusion
Peppermint and menthol, its naturally occurring monocyclic terpene alcohol derivative, have long been used for medical purposes. Contemporary practice and continuing research continue to support various uses of M. piperita in the medical armamentarium, with specific and additional uses continually being found in the dermatologic realm.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Mentha piperita, better known as peppermint, is used worldwide in many ways. Its use for culinary and medical purposes dates back to the ancient Greek and Roman civilizations. Peppermint is used in numerous forms (i.e., oil, leaf, leaf extract, and leaf water), with the oil as the most versatile (Dermatitis 2010;21:327-9). Peppermint has long been known for its beneficial gastrointestinal effects, and it has a well-established record of antimicrobial, antifungal, and analgesic activity (Mills S., Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine. [London: Churchill Livingstone, 2000, pp 507-13]; J. Environ. Biol. 2011;32:23-9).
Menthol (C10H20O) is a naturally occurring monocyclic terpene alcohol derived from Mentha piperita as well as other mint oils (Skin Therapy Lett. 2010;15:5-9), and has been associated with several health benefits. Recently, anticancer properties have been ascribed to menthol (Biochim. Biophys. Acta 2009;1792:33-8). This column will discuss recent findings regarding the actual or potential cutaneous benefits of peppermint and menthol.
Various Mentha species, including M. piperita, have exhibited significant antioxidant activity (Toxicol. Ind. Health. 2012;28:83-9; Nat. Prod. Commun. 2009;4:1107-12; Nat. Prod. Commun. 2009;4:535-42). In a 2010 study of the antioxidant activity of the essential oils of six popular herbs, including lavender (Lavendular angustifolia), peppermint (M. piperita), rosemary (Rosmarius officinalis), lemon (Citrus limon), grapefruit (C. paradise), and frankincense (Boswellia carteri), investigators found, in testing free radical-scavenging capacity and lipid peroxidation in the linoleic acid system, that peppermint essential oil exhibited the greatest radical-scavenging activity against the 2,2\'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) ABTS radical (Nat. Prod. Res. 2010;24:140-51).
In 2010, Baliga and Rao showed that M. piperita and M. arvensis (wild mint) protected mice against gamma-radiation–induced morbidity and mortality. Specifically, M. piperita protected murine testes as well as gastrointestinal and hemopoietic systems (J. Cancer Res. Ther. 2010;6:255-62).
Anticancer activity
Investigations by Jain et al. into the molecular mechanisms supporting the anticarcinogenic potential of M. piperita leaf extracts on six human cancer cell lines (HeLa, MCF-7, Jurkat, T24, HT-29, MIAPaCa-2) in 2011 revealed that chloroform and ethyl acetate extracts dose- and time-dependently displayed anticarcinogenic activity leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis among the cascade of effects. The investigators identified their findings as the first evidence of direct anticarcinogenic activity of Mentha leaf extracts and suggested that future work might focus on isolating active constituents as a foundation for mechanistic and translational studies leading to new anticancer drugs, alone or in combination, to prevent and treat human cancers (Int. J. Toxicol. 2011;30:225-36).
Topical benefits of menthol
In a recent examination of the antibacterial and antifungal properties, as well as speculated anti-inflammatory activity of menthol as a topical treatment for diaper dermatitis, investigators conducted a pilot clinical trial in a hospital setting. The study involved 84 neonates with diagnosed candidal diaper dermatitis who required no critical care or systemic antifungal and anti-inflammatory medications. The menthol group (n = 42) received topical clotrimazole and topically applied menthol drops and the control group (n = 42) received topical clotrimazole and a placebo. Thirty-five infants in each group completed the study. The researchers found that complete healing was shorter in the menthol group, with significant relief of erythema and pustules observed in this group. They concluded that topically-applied menthol may be an effective agent in the treatment of candidal diaper dermatitis (World J. Pediatr. 2011;7:167-70).
In 2011, Qiu et al. showed, through various assays, that menthol, in low concentrations, could significantly suppress the expression of alpha-hemolysin, enterotoxins A and B, and toxic shock syndrome toxin 1 in Staphylococcus aureus. The investigators concluded that menthol may warrant inclusion in the armamentarium against S. aureus when combined with beta-lactam antibiotics, which, at subinhibitory concentrations, can actually augment S. aureus toxin secretion. They added that menthol may also have possible uses in novel anti-virulence drugs (Appl. Microbiol. Biotechnol. 2011;90:705-12). It should be noted that menthol is considered safe and effective, with concentrations up to 16% approved in OTC external products by the Food and Drug Administration (J. Am. Acad. Dermatol. 2007;57:873-8).
Pruritus, TRPM8, and melanoma
Topically applied menthol, in concentrations of 1%-3%, is often used to treat pruritus, particularly in the elderly (Skin Therapy Lett. 2010;15:5-9). In addition, recent evidence suggests that the presence of menthol can facilitate penetration of other agents in topical products (Int. J. Toxicol. 2001;20 Suppl 3:61-73; J. Am. Acad. Dermatol. 2007;57:873-8). Patel and Yosipovitch suggest that elderly patients who report diminished pruritus with cooling may stand to benefit from menthol-containing topical therapies (J. Am. Acad. Dermatol. 2007;57:873-8; Skin Therapy Lett. 2010;15:5-9). Interestingly, menthol, via the transient receptor potential melastatin subfamily 8 (TRPM8) receptor, a member of a family of excitatory ion channels, engenders the same cooling sensation as low temperature, though menthol is not linked to a reduction in skin temperature (J. Am. Acad. Dermatol. 2007;57:873-8; Skin Therapy Lett. 2010;15:5-9).
Although the exact mechanism by which menthol exerts its antipruritic and analgesic effects has yet to be determined, the discovery that the TRPM8 is its underlying receptor is proving to be significant, particularly in understanding the cooling effect of the botanical (J. Am. Acad. Dermatol. 2007;57:873-8). There are also indications that menthol has therapeutic potential for melanoma. Specifically, melanoma expresses TRPM8 receptors, the activation of which inhibits melanoma viability. Menthol appears to mediate this response through an influx of extracellular calcium ions (Am. J. Physiol. Cell Physiol. 2008;295:C296-301; Am. J. Physiol. Cell Physiol. 2008;295:C293-5).
Peppermint oil
In 2003, Schuhmacher et al. investigated the virucidal effect of peppermint oil and found that it had a direct effect against herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) as well as an acyclovir-resistant HSV-1 strain. The investigators concluded, noting the lipophilic nature of peppermint oil, that it might be an appropriate topical treatment for recurrent herpes outbreaks (Phytomedicine 2003;10:504-10).
Because of its flavor, aroma, and cooling qualities, peppermint oil is used in a wide range of products, including cosmeceuticals, personal hygiene products (e.g., bath preparations, mouthwashes, toothpastes, and topical formulations), foods, pharmaceutical products, and aromatherapy. Topical indications include pruritus, irritation, and inflammation. Peppermint oil can act as a skin sensitizer, though, particularly in impaired and sensitive skin (Dermatitis 2010;21:327-9). Although peppermint oil has been reported to be a sensitizer in isolated cases, peppermint oil 8% was not found to be a sensitizer in a recent test using a maximization protocol and the various forms of peppermint (i.e., oil, extract, leaves, and water) are considered to be safe in cosmetic formulations. In rinse-off products, peppermint oil is used in concentrations up to 3% and up to 0.2% in leave-on formulations (Int. J. Toxicol. 2001;20 Suppl 3:61-73).
Conclusion
Peppermint and menthol, its naturally occurring monocyclic terpene alcohol derivative, have long been used for medical purposes. Contemporary practice and continuing research continue to support various uses of M. piperita in the medical armamentarium, with specific and additional uses continually being found in the dermatologic realm.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
Mentha piperita, better known as peppermint, is used worldwide in many ways. Its use for culinary and medical purposes dates back to the ancient Greek and Roman civilizations. Peppermint is used in numerous forms (i.e., oil, leaf, leaf extract, and leaf water), with the oil as the most versatile (Dermatitis 2010;21:327-9). Peppermint has long been known for its beneficial gastrointestinal effects, and it has a well-established record of antimicrobial, antifungal, and analgesic activity (Mills S., Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine. [London: Churchill Livingstone, 2000, pp 507-13]; J. Environ. Biol. 2011;32:23-9).
Menthol (C10H20O) is a naturally occurring monocyclic terpene alcohol derived from Mentha piperita as well as other mint oils (Skin Therapy Lett. 2010;15:5-9), and has been associated with several health benefits. Recently, anticancer properties have been ascribed to menthol (Biochim. Biophys. Acta 2009;1792:33-8). This column will discuss recent findings regarding the actual or potential cutaneous benefits of peppermint and menthol.
Various Mentha species, including M. piperita, have exhibited significant antioxidant activity (Toxicol. Ind. Health. 2012;28:83-9; Nat. Prod. Commun. 2009;4:1107-12; Nat. Prod. Commun. 2009;4:535-42). In a 2010 study of the antioxidant activity of the essential oils of six popular herbs, including lavender (Lavendular angustifolia), peppermint (M. piperita), rosemary (Rosmarius officinalis), lemon (Citrus limon), grapefruit (C. paradise), and frankincense (Boswellia carteri), investigators found, in testing free radical-scavenging capacity and lipid peroxidation in the linoleic acid system, that peppermint essential oil exhibited the greatest radical-scavenging activity against the 2,2\'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) ABTS radical (Nat. Prod. Res. 2010;24:140-51).
In 2010, Baliga and Rao showed that M. piperita and M. arvensis (wild mint) protected mice against gamma-radiation–induced morbidity and mortality. Specifically, M. piperita protected murine testes as well as gastrointestinal and hemopoietic systems (J. Cancer Res. Ther. 2010;6:255-62).
Anticancer activity
Investigations by Jain et al. into the molecular mechanisms supporting the anticarcinogenic potential of M. piperita leaf extracts on six human cancer cell lines (HeLa, MCF-7, Jurkat, T24, HT-29, MIAPaCa-2) in 2011 revealed that chloroform and ethyl acetate extracts dose- and time-dependently displayed anticarcinogenic activity leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis among the cascade of effects. The investigators identified their findings as the first evidence of direct anticarcinogenic activity of Mentha leaf extracts and suggested that future work might focus on isolating active constituents as a foundation for mechanistic and translational studies leading to new anticancer drugs, alone or in combination, to prevent and treat human cancers (Int. J. Toxicol. 2011;30:225-36).
Topical benefits of menthol
In a recent examination of the antibacterial and antifungal properties, as well as speculated anti-inflammatory activity of menthol as a topical treatment for diaper dermatitis, investigators conducted a pilot clinical trial in a hospital setting. The study involved 84 neonates with diagnosed candidal diaper dermatitis who required no critical care or systemic antifungal and anti-inflammatory medications. The menthol group (n = 42) received topical clotrimazole and topically applied menthol drops and the control group (n = 42) received topical clotrimazole and a placebo. Thirty-five infants in each group completed the study. The researchers found that complete healing was shorter in the menthol group, with significant relief of erythema and pustules observed in this group. They concluded that topically-applied menthol may be an effective agent in the treatment of candidal diaper dermatitis (World J. Pediatr. 2011;7:167-70).
In 2011, Qiu et al. showed, through various assays, that menthol, in low concentrations, could significantly suppress the expression of alpha-hemolysin, enterotoxins A and B, and toxic shock syndrome toxin 1 in Staphylococcus aureus. The investigators concluded that menthol may warrant inclusion in the armamentarium against S. aureus when combined with beta-lactam antibiotics, which, at subinhibitory concentrations, can actually augment S. aureus toxin secretion. They added that menthol may also have possible uses in novel anti-virulence drugs (Appl. Microbiol. Biotechnol. 2011;90:705-12). It should be noted that menthol is considered safe and effective, with concentrations up to 16% approved in OTC external products by the Food and Drug Administration (J. Am. Acad. Dermatol. 2007;57:873-8).
Pruritus, TRPM8, and melanoma
Topically applied menthol, in concentrations of 1%-3%, is often used to treat pruritus, particularly in the elderly (Skin Therapy Lett. 2010;15:5-9). In addition, recent evidence suggests that the presence of menthol can facilitate penetration of other agents in topical products (Int. J. Toxicol. 2001;20 Suppl 3:61-73; J. Am. Acad. Dermatol. 2007;57:873-8). Patel and Yosipovitch suggest that elderly patients who report diminished pruritus with cooling may stand to benefit from menthol-containing topical therapies (J. Am. Acad. Dermatol. 2007;57:873-8; Skin Therapy Lett. 2010;15:5-9). Interestingly, menthol, via the transient receptor potential melastatin subfamily 8 (TRPM8) receptor, a member of a family of excitatory ion channels, engenders the same cooling sensation as low temperature, though menthol is not linked to a reduction in skin temperature (J. Am. Acad. Dermatol. 2007;57:873-8; Skin Therapy Lett. 2010;15:5-9).
Although the exact mechanism by which menthol exerts its antipruritic and analgesic effects has yet to be determined, the discovery that the TRPM8 is its underlying receptor is proving to be significant, particularly in understanding the cooling effect of the botanical (J. Am. Acad. Dermatol. 2007;57:873-8). There are also indications that menthol has therapeutic potential for melanoma. Specifically, melanoma expresses TRPM8 receptors, the activation of which inhibits melanoma viability. Menthol appears to mediate this response through an influx of extracellular calcium ions (Am. J. Physiol. Cell Physiol. 2008;295:C296-301; Am. J. Physiol. Cell Physiol. 2008;295:C293-5).
Peppermint oil
In 2003, Schuhmacher et al. investigated the virucidal effect of peppermint oil and found that it had a direct effect against herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) as well as an acyclovir-resistant HSV-1 strain. The investigators concluded, noting the lipophilic nature of peppermint oil, that it might be an appropriate topical treatment for recurrent herpes outbreaks (Phytomedicine 2003;10:504-10).
Because of its flavor, aroma, and cooling qualities, peppermint oil is used in a wide range of products, including cosmeceuticals, personal hygiene products (e.g., bath preparations, mouthwashes, toothpastes, and topical formulations), foods, pharmaceutical products, and aromatherapy. Topical indications include pruritus, irritation, and inflammation. Peppermint oil can act as a skin sensitizer, though, particularly in impaired and sensitive skin (Dermatitis 2010;21:327-9). Although peppermint oil has been reported to be a sensitizer in isolated cases, peppermint oil 8% was not found to be a sensitizer in a recent test using a maximization protocol and the various forms of peppermint (i.e., oil, extract, leaves, and water) are considered to be safe in cosmetic formulations. In rinse-off products, peppermint oil is used in concentrations up to 3% and up to 0.2% in leave-on formulations (Int. J. Toxicol. 2001;20 Suppl 3:61-73).
Conclusion
Peppermint and menthol, its naturally occurring monocyclic terpene alcohol derivative, have long been used for medical purposes. Contemporary practice and continuing research continue to support various uses of M. piperita in the medical armamentarium, with specific and additional uses continually being found in the dermatologic realm.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.
