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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.
