Aesthetic Dermatology

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.¹ Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.¹ The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.²

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.¹ Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.^3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.⁶ Shin et al¹ reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.² The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.⁷ Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.^2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.^8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.^10-12 CO₂ lasers also have demonstrated promising results.¹³

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.¹ Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.¹ The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.²

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.¹ Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.^3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.⁶ Shin et al¹ reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.² The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.⁷ Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.^2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.^8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.^10-12 CO₂ lasers also have demonstrated promising results.¹³

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.¹ Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.¹ The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.²

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.¹ Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.^3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.⁶ Shin et al¹ reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.² The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.⁷ Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.^2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.^8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.^10-12 CO₂ lasers also have demonstrated promising results.¹³

Actinic keratosis (AK), also referred to as solar keratosis or senile keratosis, is an intraepidermal proliferation of dysplastic keratinocytes that develops in response to chronic exposure to UV radiation. Actinic keratoses are among the most commonly encountered lesions seen by dermatologists, and it has been estimated that 60% of predisposed individuals older than 40 years have at least one AK.^1,2 Prevalence is notably higher in light-skinned individuals and increases with age, presumably from higher cumulative sun exposure and decreased effectiveness of the immune system.^1,3 It remains a point of contention as to whether or not AKs actually represent squamous cell carcinoma (SCC) in situ, but the potential for progression to invasive disease has been well demonstrated, as the majority of SCCs develop from preexisting AKs.^4-6 The risk for progression to invasive disease for an individual AK has been estimated to range from 0.025% to 16% per year, with an average of approximately 8% in immunocompetent patients.⁷

The clinical morphology of AK can vary widely, but the most common presentation is an erythematous scaly macule, papule, or plaque on sun-exposed skin. The skin surrounding AKs typically shows evidence of solar damage with deep wrinkling, mottled pigmentation, scattered telangiectases, purpura, or xerosis (Figure). A variety of clinical variants with unique presentations exist, including atrophic, hypertrophic, acantholytic, lichenoid, bowenoid, and pigmented subtypes. Because more than 80% of AKs occur on highly visible areas such as the head, neck, back of the hands, and forearms, AKs can have an obvious detrimental effect on cosmetic appearance. Studies also have shown a strong association between AKs and decreased overall quality of life (QOL).^3,8,9

Patient with numerous actinic keratoses, scattered plaques suspicious for squamous cell carcinoma, and numerous scars from prior squamous cell carcinoma treatments.

Topical Treatments

5-Fluorouracil

5-Fluorouracil (5-FU) is a US Food and Drug Administration (FDA)–approved, topically applied pyrimidine analogue that inhibits thymidylate synthase. The resulting suppression of DNA and RNA synthesis induces cell death with a preference for mitotically active cells.¹⁰ 5-Fluorouracil has been used for more than 
50 years as a treatment of AK and its efficacy is well established. A systematic review of 5 randomized controlled studies of topical 5-FU reported an average of 49% of 423 patients achieving complete lesion clearance with 5-FU cream 5% applied once or twice daily for up to 7 weeks.¹¹ Some notable drawbacks of 5-FU, however, are application-site erythema, blistering, pruritus, necrosis, erosion, and pain. These effects often lead to premature cessation of therapy, but newer formulations of 5-FU cream 0.5% have shown good efficacy with better tolerability.¹² A randomized, double-blind, multicenter, parallel-group study of 177 patients using 5-FU cream 0.5% once daily for either 1, 2, or 4 weeks demonstrated significant (P<.001) efficacy over vehicle gel in all treatment arms.¹³ The most effective therapy was 
4 weeks of treatment, which achieved a mean 91.7% reduction in lesion count as assessed 1 month after cessation of therapy. The primary adverse effect (AE) reported in this trial was mild to moderate facial irritation, which generally resolved within 
18 to 21 days after treatment cessation.¹³ Overall, 5-FU is a highly effective therapy for treating AKs that also can improve signs of photoaging, but patients should be aware of cosmetically unappealing effects that generally occur throughout therapy and during the immediate posttreatment period.¹⁴

Chemical Peels

Chemical peels traditionally employ acidic compounds to strip away outer layers of skin to variable depths depending on the concentration of the agent being applied. For treatment of AK, trichloroacetic acid (TCA) is a commonly employed cauterant that has shown efficacy comparable to topical 5-FU as well as ablative CO₂ laser resurfacing.¹⁵ Trichloroacetic acid peels also are a convenient therapy, as good results can be achieved after a single treatment session. A split-face study of 15 patients treated with either a single application of 35% TCA and Jessner solution or twice-daily application of 5-FU cream 5% for 3 weeks demonstrated a reduction in 75% of visible AKs in both treatment arms over a 1-year follow-up period.¹⁶ Although 80% of patients self-reported considerable cosmetic improvement with both therapies, patient preference was reported to be in favor of the TCA peel, given its quick results and relatively mild side effects as compared to 5-FU. Treatment with chemical peels will result in temporary erythema and mild desquamation that usually resolves within 2 weeks; however, there are cases in which erythema has been reported to persist for several months.¹⁶ Adverse effects such as permanent scarring or pigmentation changes rarely are seen with TCA concentrations less than 45%.¹⁷ Caution should be used in patients with a history of herpes simplex virus, keloids, postinflammatory hyperpigmentation, radiation exposure, immunosuppression, and those unable or unwilling to use sunscreen and avoid sun exposure in the immediate posttreatment period.

Diclofenac Sodium

Diclofenac sodium (DFS) is an FDA-approved topical, nonsteroidal, 
anti-inflammatory drug whose mechanism of action in the treatment of AK is thought to involve inhibition of the cyclooxygenase 2 enzyme.¹⁸ The resulting reduction of prostaglandins is believed to inhibit tumor angiogenesis, induce apoptosis, and inhibit cell differentiation.^19-22 In a multicenter, double-blind, placebo-controlled study of 195 patients, application of DFS 3% in hyaluronan gel 2.5% twice daily for 60 days showed significant (P<.05) efficacy over placebo in achieving complete resolution of target lesions during a 30-day follow-up period (31% vs 10%). Furthermore, qualitative patient assessment of complete global improvement also was significantly (P<.05) higher in the active treatment group as compared to placebo (31% vs 10%).²³ Additional studies of DFS 3% in hyaluronan gel 2.5% applied twice daily for 90 days have shown even higher rates of success, with complete resolution of target lesions in 40% to 58% of cases.^24,25 This therapy also has been reported to substantially improve QOL following treatment completion.²⁶ The most frequently cited AEs include pruritus, rash, dry skin, erythema, and application-site reactions. Overall, DFS is a 
well-tolerated therapy with efficacy comparable to that of 5-FU but with a lower incidence of AEs 
and higher patient satisfaction as determined in 
2 head-to-head studies.^27,28
ImiquimodImiquimod (IMQ) is an FDA-approved topical agent that functions as an immune response modifier via agonism of toll-like receptor 7.¹⁸ The resulting cytokine production and release enhances the innate and acquired immune responses leading to anticancer activity.²⁹ The efficacy of IMQ for treatment of AK has been demonstrated in numerous well-designed clinical trials. A 
meta-analysis of 5 randomized, double-blind trials including 1293 patients treated with IMQ cream 5% 
2 to 3 times per week for 12 to 16 weeks reported complete clearance of AKs in 50% of patients treated with IMQ as compared to 5% of patients treated with vehicle.³⁰ The most frequently reported AEs with this therapy include erythema, scabbing, flaking, and erosion. These effects generally resolve following cessation of treatment, and therapy is considered to be well tolerated; however, there are case reports of IMQ triggering or exacerbating existing inflammatory conditions.³¹ Imiquimod cream also is approved at 2.5% and 3.75% concentrations, which have demonstrated significant (P<.001) efficacy over placebo and a reduced incidence of AEs; complete clearance rates have been reported as 30.6% and 35.6%, respectively.³² Notably, a study comparing 75 patients randomized to either IMQ cream 5% 
3 times per week for 4 weeks, 1 or 2 courses of cryosurgery, or 5-FU ointment 5% twice daily for 4 weeks reported that IMQ achieved significantly (P<.01) superior sustained clearance rates during a 12-month follow-up period over cryosurgery and 5-FU 
(73% vs 4% vs 33%).³³ Additionally, cosmetic outcomes as determined by both participants and investigators were reported as excellent at 12 months posttreatment in more than 80% of participants treated with IMQ. These excellent, long-lasting cosmetic outcomes also were determined to be significantly (P<.0001) superior to the cosmetic outcomes of 5-FU and cryotherapy, which both reported excellent outcomes in less than 10% of cases.³³
Ingenol MebutateIngenol mebutate (IM) is a macrocyclic diterpene ester derived from the Euphorbia peplus plant that is FDA approved for the treatment of AK.¹ Ingenol mebutate’s mechanism of action is thought to involve induction of cell death via disruption of the plasma membrane and mitochondria in addition to production of an inflammatory response, which produces tumor-specific antibodies and a large influx of neutrophils.^34,35 The overall evidence for the efficacy of IM is strong. A combined analysis of 4 multicenter, randomized, double-blind studies of 1005 participants reported that IM gel 0.015% applied once daily for 3 days to the face or scalp was significantly superior (P<.001) to placebo in achieving complete clearance as assessed 54 days after completion of therapy (42.2% vs 3.7%) and that IM gel 0.05% applied once daily for 2 days to the trunk or extremities also was significantly superior (P<.001) to placebo in achieving complete clearance as determined 55 days after completion of therapy (34.1% vs 4.7%).³⁶ A follow-up report to this study indicated that IM also appears to achieve long-lasting effects with an overall 87% decrease in total AKs at 12 months follow-up in both trial groups.³⁷ Additionally, it has been recently reported that treatment with IM in these trials was associated with significantly higher overall treatment satisfaction (P<.001) and improved QOL (P<.001) as compared to vehicle.³⁸ Cosmetic outcomes of IM therapy have been assessed in a trial analyzing the efficacy of IM gel 0.025% for 3 days or IM gel 0.05% for 2 or 3 days on nonfacial AKs. This study reported significantly (P<.0001) higher patient satisfaction with the cosmetic outcome at 8 weeks after therapy as compared to vehicle.³⁴ Studies performed in mice have demonstrated that IM is able to promote collagen matrix turnover and impose dermal elasticity, which may contribute to these good cosmetic outcomes.³⁹ The most common AEs of IM therapy are erythema, crusting, and flaking; these effects generally occur 3 to 8 days after starting treatment. These effects, however, generally are short lived and resolve within 2 weeks of treatment cessation when IM is applied to the face or scalp or 4 weeks when applied to the trunk or extremities.⁴⁰ Overall, IM is a useful therapeutic option given its relatively short treatment course as compared to other topically applied agents, as well as its lasting efficacy, mild AEs, and good cosmetic outcomes.

Procedural Modalities

Surgical Procedures

Surgical approaches for the treatment of AK include excision, curettage with or without electrodesiccation, and dermabrasion. In the past, these modalities were used with greater frequency, but the advent of effective topical medications with lower risks of AEs has largely reduced their use.⁴¹ Excision may still be indicated in cases where SCC is suspected, and curettage can be used for treatment of thicker hypertrophic AKs.⁴² Although these approaches have not been evaluated in clinical trials, they are generally effective but require the use of local anesthetics and come with substantial risk for infection, permanent scarring, and hypopigmentation. Dermabrasion employs the use of a motorized device equipped with an abrasive material to physically remove superficial layers of the skin. Studies are limited, but this method has been reported as an effective treatment in a retrospective review of 23 participants in which 96% remained free of AKs at 1 year, 83% at 2 years, 64% at 4 years, and 54% at 5 years posttherapy.⁴³ Notably, one split-face study of 40 participants treated with dermabrasion followed by 25% TCA on one side and either Jessner solution and 35% TCA or dermabrasion alone on the other side reported that the combination of dermabrasion with 25% TCA consistently produced excellent cosmetic results with nearly complete eradication of AKs.⁴⁴ In general, however, cosmetic outcomes with dermabrasion are variable, as the technique is highly operator dependent and treatment is associated with notable discomfort as well as risk for scarring and permanent pigmentation alteration.

Cryotherapy

Cryotherapy remains one of the most commonly utilized treatments of AK and involves the delivery of liquid nitrogen via a spray device or a cotton tip applicator to rapidly freeze cells, thus causing cellular destruction via ice crystal formation and protein denaturation.⁴⁵ Efficacy with this technique has been reported to be as high as 98.8% at 12 months follow-up, but more recent studies cite lower rates of success.⁴⁶ A prospective multicenter study of 90 participants with 421 AKs on the face or scalp treated with a single freeze-thaw cycle of liquid nitrogen reported an overall complete response rate of 67.2% at 3 months posttherapy. Additionally, higher complete response rates were associated with longer freeze times, and cosmetic outcomes were reported as good to excellent in 94% of complete response lesions.⁴⁷ Similar results were reported in an open-label, prospective, randomized, controlled clinical trial of 200 participants with 
543 AKs, which compared a single freeze-thaw cycle with liquid nitrogen to a single session of CO₂ laser ablation in the treatment of isolated AKs of the face and scalp.⁴⁸ At 3 months posttherapy, complete clearance was observed in 71.6% of participants treated with cryotherapy and in 65.3% of participants treated with laser ablation (P=.532). At 
12 months posttherapy, participants who originally showed complete response at 3 months were assessed for relapse. Complete clearance was preserved in 72.6% of participants treated with cryotherapy versus 21.9% of participants treated with laser ablation (P<.0001), and cosmetic outcomes were reported by participants as good or excellent at 3 months follow-up in more than 93% of participants for both treatment arms.⁴⁸ Possible AEs of cryotherapy include pain during treatment, blister formation with possible hemorrhage, infection, scarring, and permanent pigmentary changes.^47,48 Notably, the risk for hypopigmentation increases with longer freezing times, thus requiring clinicians to consider the balance between improved efficacy and reduced cosmetic outcomes.⁴⁷

Light-Based Therapies

Laser Therapy

Ablative laser resurfacing with either the CO₂ or erbium-doped:YAG (Er:YAG) laser utilizes light of specific wavelengths to selectively induce thermolysis and destruction of the epidermal layer. Both lasers have been studied as treatments of AK, but there is a lack of large, well-designed studies. In one small study of 14 participants treated with 
1 to 2 passes of the CO₂ laser, complete clearance was reported in all cases without any recurrences during a follow-up period of 6 to 24 months. Additionally, all participants in this study reported satisfaction with the cosmetic outcome.⁴⁹ The CO₂ laser also has demonstrated efficacy comparable to that of the TCA peel and 5-FU therapy in a prospective randomized trial of 34 patients with facial or scalp AKs who received either CO₂ laser with 2 passes, 30% TCA peel, or 5-FU cream 5% twice daily for 
3 weeks.¹⁵ Reduction in mean AK counts at 3 months posttherapy was significantly (P<.03) higher in all treatment arms as compared to the control group (92% for CO₂ laser, 89% for TCA peel, and 83% for 5-FU cream). No significant (P=.31) difference in outcomes was noted among the different treatment arms.¹⁵ Similar results were reported for the Er:YAG laser in a small prospective study of 5 participants treated with 2 to 3 passes with the Er:YAG laser in which reduction in mean AK counts was reported as ranging from 86% to 96% at 3 months posttherapy.⁵⁰ The Er:YAG laser in combination with the CO₂ laser has shown notable long-term efficacy in achieving higher lesion clearance rates and sustained complete clearance rates over treatment with topical 5-FU.⁵¹ In a prospective randomized study of 55 par-ticipants with multiple AKs on the face or scalp, participants were assigned to receive either combination laser ablation with the Er:YAG and CO₂ lasers down to the level of the papillary dermis or 
5-FU cream 5% applied twice daily for 2 to 7 weeks until an appropriate clinical inflammatory response was achieved. At 12 months follow-up, the laser treatment group achieved significantly (P=.048) higher mean lesion clearance rates (91.1%) as compared to the 5-FU arm (76.6%) and significantly (P=.003) higher sustained complete clearance rates (59.3%) as compared to 5-FU (29.2%). The proportion of participants with an improvement in photoaging score at 12 months follow-up approached statistical significance (P=.07), with 74% of the laser-treated group showing improvement as compared to 43% of the 5-FU–treated group. Long-term, cosmetically unappealing side effects such as erythema and hypopigmentation occurred notably more often in the laser-treated group as compared to the 5-FU group.⁵¹ In summary, ablative lasers appear to be a highly effective therapy for AK but at the cost of increased risk for AEs such as permanent pigmentary changes, prolonged erythema lasting up to several months, and scarring.^50,52-55

Fractional photothermolysis is a relatively new advancement in the field of laser therapy that has received FDA approval for the treatment of AK.⁵⁶ This treatment works by creating multiple noncontiguous microscopic columns of thermal injury while sparing adjacent zones of viable tissue.⁵⁷ Although there are limited studies involving the use of such lasers in the treatment of AK, initial findings suggest that 1927-nm thulium lasers may be more effective than 1550-nm erbium lasers in achieving lesion clearance. A trial of 14 participants who received 5 laser treatments with a 1550-nm fractionated erbium-doped fiber laser reported an average reduction in AK counts of 66.2% at 3 months follow-up and a 55.6% reduction at 6 months follow-up. A participant-determined marked or very significant improvement of lesions was reported in 83% of participants at 1 month posttreatment but only in 44% of participants at 6 months posttreatment.⁵⁸ A similar trial of 24 participants treated with up to 4 treatment sessions of the fractionated 1927-nm thulium laser reported an 87.3% reduction in number of AKs at 3 months follow-up and an 86.6% reduction at 
6 months follow-up.⁵⁶ The primary advantage of fractional laser therapy is a faster recovery period generally lasting only 2 or 3 days as compared to 
2 weeks or more with traditional ablative lasers, thus limiting the amount of time a patient must tolerate cosmetically unappealing erythema.^59,60 The quick recovery time has been attributed to the fractional laser’s ability to preserve the stratum corneum and skin barrier, which also helps reduce the risk for other AEs such as scarring and infection.^56,59-61 Additional studies are needed to better assess the true efficacy of fractional laser therapy, but treatment with the fractional 1927-nm thulium laser appears to be a promising and well-tolerated therapeutic option for treatment of AK with similar efficacy to traditional ablative lasers but with a lower risk of AEs.

Photodynamic TherapyPhotodynamic therapy (PDT) is an FDA-approved treatment that involves the use of a topical photosensitizing agent such as 5-aminolevulinic acid (ALA) or methyl aminovulinate (MAL) before exposure to an activating light source to generate reactive oxygen species that lead to cell death.^62-65 Multiple PDT regimens with varying combinations of photosensitizers, incubation time, and light sources have been studied, but a 
2012 Cochrane review determined that treatment with conventional formulations of MAL and ALA with either blue- or red-light PDT were similarly efficacious for treatment of individual AKs as compared to vehicle with blue- or red-light PDT. One exception was that longer incubation time (ie, 4 hours) with ALA resulted in better results than shorter incubation times (ie, 0.5, 1, 2 hours) with ALA.⁶⁶

Standard PDT treatment with MAL also has consistently demonstrated superior efficacy in achieving complete clearance rates in addition to superior cosmetic outcomes over treatment with either cryotherapy, DFS, or 5-FU.^67-73 Three studies in particular noted an excellent or good investigator-determined cosmetic outcome in 96% to 98% of participants treated with MAL-PDT.^69,71,74 Photodynamic therapy with ALA also has been reported as superior over CO2 laser ablation for AK reduction as well as both patient and investigator overall satisfaction.⁷⁵

More recently, several methods of improving photosensitizer delivery have been studied, which have demonstrated remarkable efficacy at achieving lesion clearance over standard cream formulations or application routines. One such method involves the use of gentle heating to increase photosensitizer uptake. In a split-extremity study of 20 participants who were treated with 20% ALA under occlusion for 1 hour with one side heated to 38.8°C, the heated side demonstrated significant (P<.0001) efficacy at achieving higher median clearance rates over control when evaluated at 2 and 6 months posttherapy.⁷⁶ Notably, occlusion of ALA in itself during the incubation period also has been demonstrated to significantly (P<.0001) improve clearance rates.⁷⁷ Another method involves the use of a new nanoemulsion-based formulation of 
ALA gel, known as BF-200 ALA, which has demonstrated remarkable efficacy over standard 
MAL cream and placebo in a long-term follow-up 
analysis of 2 prospective, randomized, controlled trials.⁷⁸ In a similar vein, 3 prospective randomized trials with a minimum follow-up time of 3 months demonstrated that MAL-PDT in combination with fractional ablative laser pretreatment has significant (P<.02 in all trials) efficacy over MAL-PDT without pretreatment in achieving complete AK clearance. Although the cosmetic outcomes were good or excellent in 87% to 100% of patients, they were not significantly different from stand-alone 
MAL-PDT treatment in any of the trials.^79-81 However, pretreatment with microneedling in MAL-PDT has been shown to achieve superior cosmetic outcomes over 
MAL-PDT without microneedling, according to one small split-face study of 10 participants.⁸²

Overall, PDT is an excellent therapeutic option that is able to provide efficacious clearance of AKs as well as superior cosmetic outcomes. Common AEs of PDT include burning, itching, and stinging during therapy, but pain intensity decreases dramatically upon termination of illumination, with cessation of most symptoms by 12 hours posttherapy.⁷³ Permanent pigmentation changes have been reported to occasionally occur following PDT therapy.⁸¹

Conclusion

When determining which therapy to use in a patient, clinicians must take into account a variety of factors such as patient preference, cost of treatment, availability, tolerance for AEs, and the need for field therapy. Although all therapies discussed within this article are effective and reasonable treatment choices, patients who are particularly concerned about cosmetic outcomes would most likely benefit from either IMQ or PDT, as the data for cosmetic outcomes with these therapies are the strongest. Combination or sequential treatments may be required in some cases and all patients should be monitored for lesion recurrence regardless of treatment choice. A summary of the therapies and key studies discussed here is available in the PDF.

Actinic keratosis (AK), also referred to as solar keratosis or senile keratosis, is an intraepidermal proliferation of dysplastic keratinocytes that develops in response to chronic exposure to UV radiation. Actinic keratoses are among the most commonly encountered lesions seen by dermatologists, and it has been estimated that 60% of predisposed individuals older than 40 years have at least one AK.^1,2 Prevalence is notably higher in light-skinned individuals and increases with age, presumably from higher cumulative sun exposure and decreased effectiveness of the immune system.^1,3 It remains a point of contention as to whether or not AKs actually represent squamous cell carcinoma (SCC) in situ, but the potential for progression to invasive disease has been well demonstrated, as the majority of SCCs develop from preexisting AKs.^4-6 The risk for progression to invasive disease for an individual AK has been estimated to range from 0.025% to 16% per year, with an average of approximately 8% in immunocompetent patients.⁷

The clinical morphology of AK can vary widely, but the most common presentation is an erythematous scaly macule, papule, or plaque on sun-exposed skin. The skin surrounding AKs typically shows evidence of solar damage with deep wrinkling, mottled pigmentation, scattered telangiectases, purpura, or xerosis (Figure). A variety of clinical variants with unique presentations exist, including atrophic, hypertrophic, acantholytic, lichenoid, bowenoid, and pigmented subtypes. Because more than 80% of AKs occur on highly visible areas such as the head, neck, back of the hands, and forearms, AKs can have an obvious detrimental effect on cosmetic appearance. Studies also have shown a strong association between AKs and decreased overall quality of life (QOL).^3,8,9

Patient with numerous actinic keratoses, scattered plaques suspicious for squamous cell carcinoma, and numerous scars from prior squamous cell carcinoma treatments.

Topical Treatments

5-Fluorouracil

5-Fluorouracil (5-FU) is a US Food and Drug Administration (FDA)–approved, topically applied pyrimidine analogue that inhibits thymidylate synthase. The resulting suppression of DNA and RNA synthesis induces cell death with a preference for mitotically active cells.¹⁰ 5-Fluorouracil has been used for more than 
50 years as a treatment of AK and its efficacy is well established. A systematic review of 5 randomized controlled studies of topical 5-FU reported an average of 49% of 423 patients achieving complete lesion clearance with 5-FU cream 5% applied once or twice daily for up to 7 weeks.¹¹ Some notable drawbacks of 5-FU, however, are application-site erythema, blistering, pruritus, necrosis, erosion, and pain. These effects often lead to premature cessation of therapy, but newer formulations of 5-FU cream 0.5% have shown good efficacy with better tolerability.¹² A randomized, double-blind, multicenter, parallel-group study of 177 patients using 5-FU cream 0.5% once daily for either 1, 2, or 4 weeks demonstrated significant (P<.001) efficacy over vehicle gel in all treatment arms.¹³ The most effective therapy was 
4 weeks of treatment, which achieved a mean 91.7% reduction in lesion count as assessed 1 month after cessation of therapy. The primary adverse effect (AE) reported in this trial was mild to moderate facial irritation, which generally resolved within 
18 to 21 days after treatment cessation.¹³ Overall, 5-FU is a highly effective therapy for treating AKs that also can improve signs of photoaging, but patients should be aware of cosmetically unappealing effects that generally occur throughout therapy and during the immediate posttreatment period.¹⁴

Chemical Peels

Chemical peels traditionally employ acidic compounds to strip away outer layers of skin to variable depths depending on the concentration of the agent being applied. For treatment of AK, trichloroacetic acid (TCA) is a commonly employed cauterant that has shown efficacy comparable to topical 5-FU as well as ablative CO₂ laser resurfacing.¹⁵ Trichloroacetic acid peels also are a convenient therapy, as good results can be achieved after a single treatment session. A split-face study of 15 patients treated with either a single application of 35% TCA and Jessner solution or twice-daily application of 5-FU cream 5% for 3 weeks demonstrated a reduction in 75% of visible AKs in both treatment arms over a 1-year follow-up period.¹⁶ Although 80% of patients self-reported considerable cosmetic improvement with both therapies, patient preference was reported to be in favor of the TCA peel, given its quick results and relatively mild side effects as compared to 5-FU. Treatment with chemical peels will result in temporary erythema and mild desquamation that usually resolves within 2 weeks; however, there are cases in which erythema has been reported to persist for several months.¹⁶ Adverse effects such as permanent scarring or pigmentation changes rarely are seen with TCA concentrations less than 45%.¹⁷ Caution should be used in patients with a history of herpes simplex virus, keloids, postinflammatory hyperpigmentation, radiation exposure, immunosuppression, and those unable or unwilling to use sunscreen and avoid sun exposure in the immediate posttreatment period.

Diclofenac Sodium

Diclofenac sodium (DFS) is an FDA-approved topical, nonsteroidal, 
anti-inflammatory drug whose mechanism of action in the treatment of AK is thought to involve inhibition of the cyclooxygenase 2 enzyme.¹⁸ The resulting reduction of prostaglandins is believed to inhibit tumor angiogenesis, induce apoptosis, and inhibit cell differentiation.^19-22 In a multicenter, double-blind, placebo-controlled study of 195 patients, application of DFS 3% in hyaluronan gel 2.5% twice daily for 60 days showed significant (P<.05) efficacy over placebo in achieving complete resolution of target lesions during a 30-day follow-up period (31% vs 10%). Furthermore, qualitative patient assessment of complete global improvement also was significantly (P<.05) higher in the active treatment group as compared to placebo (31% vs 10%).²³ Additional studies of DFS 3% in hyaluronan gel 2.5% applied twice daily for 90 days have shown even higher rates of success, with complete resolution of target lesions in 40% to 58% of cases.^24,25 This therapy also has been reported to substantially improve QOL following treatment completion.²⁶ The most frequently cited AEs include pruritus, rash, dry skin, erythema, and application-site reactions. Overall, DFS is a 
well-tolerated therapy with efficacy comparable to that of 5-FU but with a lower incidence of AEs 
and higher patient satisfaction as determined in 
2 head-to-head studies.^27,28
ImiquimodImiquimod (IMQ) is an FDA-approved topical agent that functions as an immune response modifier via agonism of toll-like receptor 7.¹⁸ The resulting cytokine production and release enhances the innate and acquired immune responses leading to anticancer activity.²⁹ The efficacy of IMQ for treatment of AK has been demonstrated in numerous well-designed clinical trials. A 
meta-analysis of 5 randomized, double-blind trials including 1293 patients treated with IMQ cream 5% 
2 to 3 times per week for 12 to 16 weeks reported complete clearance of AKs in 50% of patients treated with IMQ as compared to 5% of patients treated with vehicle.³⁰ The most frequently reported AEs with this therapy include erythema, scabbing, flaking, and erosion. These effects generally resolve following cessation of treatment, and therapy is considered to be well tolerated; however, there are case reports of IMQ triggering or exacerbating existing inflammatory conditions.³¹ Imiquimod cream also is approved at 2.5% and 3.75% concentrations, which have demonstrated significant (P<.001) efficacy over placebo and a reduced incidence of AEs; complete clearance rates have been reported as 30.6% and 35.6%, respectively.³² Notably, a study comparing 75 patients randomized to either IMQ cream 5% 
3 times per week for 4 weeks, 1 or 2 courses of cryosurgery, or 5-FU ointment 5% twice daily for 4 weeks reported that IMQ achieved significantly (P<.01) superior sustained clearance rates during a 12-month follow-up period over cryosurgery and 5-FU 
(73% vs 4% vs 33%).³³ Additionally, cosmetic outcomes as determined by both participants and investigators were reported as excellent at 12 months posttreatment in more than 80% of participants treated with IMQ. These excellent, long-lasting cosmetic outcomes also were determined to be significantly (P<.0001) superior to the cosmetic outcomes of 5-FU and cryotherapy, which both reported excellent outcomes in less than 10% of cases.³³
Ingenol MebutateIngenol mebutate (IM) is a macrocyclic diterpene ester derived from the Euphorbia peplus plant that is FDA approved for the treatment of AK.¹ Ingenol mebutate’s mechanism of action is thought to involve induction of cell death via disruption of the plasma membrane and mitochondria in addition to production of an inflammatory response, which produces tumor-specific antibodies and a large influx of neutrophils.^34,35 The overall evidence for the efficacy of IM is strong. A combined analysis of 4 multicenter, randomized, double-blind studies of 1005 participants reported that IM gel 0.015% applied once daily for 3 days to the face or scalp was significantly superior (P<.001) to placebo in achieving complete clearance as assessed 54 days after completion of therapy (42.2% vs 3.7%) and that IM gel 0.05% applied once daily for 2 days to the trunk or extremities also was significantly superior (P<.001) to placebo in achieving complete clearance as determined 55 days after completion of therapy (34.1% vs 4.7%).³⁶ A follow-up report to this study indicated that IM also appears to achieve long-lasting effects with an overall 87% decrease in total AKs at 12 months follow-up in both trial groups.³⁷ Additionally, it has been recently reported that treatment with IM in these trials was associated with significantly higher overall treatment satisfaction (P<.001) and improved QOL (P<.001) as compared to vehicle.³⁸ Cosmetic outcomes of IM therapy have been assessed in a trial analyzing the efficacy of IM gel 0.025% for 3 days or IM gel 0.05% for 2 or 3 days on nonfacial AKs. This study reported significantly (P<.0001) higher patient satisfaction with the cosmetic outcome at 8 weeks after therapy as compared to vehicle.³⁴ Studies performed in mice have demonstrated that IM is able to promote collagen matrix turnover and impose dermal elasticity, which may contribute to these good cosmetic outcomes.³⁹ The most common AEs of IM therapy are erythema, crusting, and flaking; these effects generally occur 3 to 8 days after starting treatment. These effects, however, generally are short lived and resolve within 2 weeks of treatment cessation when IM is applied to the face or scalp or 4 weeks when applied to the trunk or extremities.⁴⁰ Overall, IM is a useful therapeutic option given its relatively short treatment course as compared to other topically applied agents, as well as its lasting efficacy, mild AEs, and good cosmetic outcomes.

Procedural Modalities

Surgical Procedures

Surgical approaches for the treatment of AK include excision, curettage with or without electrodesiccation, and dermabrasion. In the past, these modalities were used with greater frequency, but the advent of effective topical medications with lower risks of AEs has largely reduced their use.⁴¹ Excision may still be indicated in cases where SCC is suspected, and curettage can be used for treatment of thicker hypertrophic AKs.⁴² Although these approaches have not been evaluated in clinical trials, they are generally effective but require the use of local anesthetics and come with substantial risk for infection, permanent scarring, and hypopigmentation. Dermabrasion employs the use of a motorized device equipped with an abrasive material to physically remove superficial layers of the skin. Studies are limited, but this method has been reported as an effective treatment in a retrospective review of 23 participants in which 96% remained free of AKs at 1 year, 83% at 2 years, 64% at 4 years, and 54% at 5 years posttherapy.⁴³ Notably, one split-face study of 40 participants treated with dermabrasion followed by 25% TCA on one side and either Jessner solution and 35% TCA or dermabrasion alone on the other side reported that the combination of dermabrasion with 25% TCA consistently produced excellent cosmetic results with nearly complete eradication of AKs.⁴⁴ In general, however, cosmetic outcomes with dermabrasion are variable, as the technique is highly operator dependent and treatment is associated with notable discomfort as well as risk for scarring and permanent pigmentation alteration.

Cryotherapy

Cryotherapy remains one of the most commonly utilized treatments of AK and involves the delivery of liquid nitrogen via a spray device or a cotton tip applicator to rapidly freeze cells, thus causing cellular destruction via ice crystal formation and protein denaturation.⁴⁵ Efficacy with this technique has been reported to be as high as 98.8% at 12 months follow-up, but more recent studies cite lower rates of success.⁴⁶ A prospective multicenter study of 90 participants with 421 AKs on the face or scalp treated with a single freeze-thaw cycle of liquid nitrogen reported an overall complete response rate of 67.2% at 3 months posttherapy. Additionally, higher complete response rates were associated with longer freeze times, and cosmetic outcomes were reported as good to excellent in 94% of complete response lesions.⁴⁷ Similar results were reported in an open-label, prospective, randomized, controlled clinical trial of 200 participants with 
543 AKs, which compared a single freeze-thaw cycle with liquid nitrogen to a single session of CO₂ laser ablation in the treatment of isolated AKs of the face and scalp.⁴⁸ At 3 months posttherapy, complete clearance was observed in 71.6% of participants treated with cryotherapy and in 65.3% of participants treated with laser ablation (P=.532). At 
12 months posttherapy, participants who originally showed complete response at 3 months were assessed for relapse. Complete clearance was preserved in 72.6% of participants treated with cryotherapy versus 21.9% of participants treated with laser ablation (P<.0001), and cosmetic outcomes were reported by participants as good or excellent at 3 months follow-up in more than 93% of participants for both treatment arms.⁴⁸ Possible AEs of cryotherapy include pain during treatment, blister formation with possible hemorrhage, infection, scarring, and permanent pigmentary changes.^47,48 Notably, the risk for hypopigmentation increases with longer freezing times, thus requiring clinicians to consider the balance between improved efficacy and reduced cosmetic outcomes.⁴⁷

Light-Based Therapies

Laser Therapy

Ablative laser resurfacing with either the CO₂ or erbium-doped:YAG (Er:YAG) laser utilizes light of specific wavelengths to selectively induce thermolysis and destruction of the epidermal layer. Both lasers have been studied as treatments of AK, but there is a lack of large, well-designed studies. In one small study of 14 participants treated with 
1 to 2 passes of the CO₂ laser, complete clearance was reported in all cases without any recurrences during a follow-up period of 6 to 24 months. Additionally, all participants in this study reported satisfaction with the cosmetic outcome.⁴⁹ The CO₂ laser also has demonstrated efficacy comparable to that of the TCA peel and 5-FU therapy in a prospective randomized trial of 34 patients with facial or scalp AKs who received either CO₂ laser with 2 passes, 30% TCA peel, or 5-FU cream 5% twice daily for 
3 weeks.¹⁵ Reduction in mean AK counts at 3 months posttherapy was significantly (P<.03) higher in all treatment arms as compared to the control group (92% for CO₂ laser, 89% for TCA peel, and 83% for 5-FU cream). No significant (P=.31) difference in outcomes was noted among the different treatment arms.¹⁵ Similar results were reported for the Er:YAG laser in a small prospective study of 5 participants treated with 2 to 3 passes with the Er:YAG laser in which reduction in mean AK counts was reported as ranging from 86% to 96% at 3 months posttherapy.⁵⁰ The Er:YAG laser in combination with the CO₂ laser has shown notable long-term efficacy in achieving higher lesion clearance rates and sustained complete clearance rates over treatment with topical 5-FU.⁵¹ In a prospective randomized study of 55 par-ticipants with multiple AKs on the face or scalp, participants were assigned to receive either combination laser ablation with the Er:YAG and CO₂ lasers down to the level of the papillary dermis or 
5-FU cream 5% applied twice daily for 2 to 7 weeks until an appropriate clinical inflammatory response was achieved. At 12 months follow-up, the laser treatment group achieved significantly (P=.048) higher mean lesion clearance rates (91.1%) as compared to the 5-FU arm (76.6%) and significantly (P=.003) higher sustained complete clearance rates (59.3%) as compared to 5-FU (29.2%). The proportion of participants with an improvement in photoaging score at 12 months follow-up approached statistical significance (P=.07), with 74% of the laser-treated group showing improvement as compared to 43% of the 5-FU–treated group. Long-term, cosmetically unappealing side effects such as erythema and hypopigmentation occurred notably more often in the laser-treated group as compared to the 5-FU group.⁵¹ In summary, ablative lasers appear to be a highly effective therapy for AK but at the cost of increased risk for AEs such as permanent pigmentary changes, prolonged erythema lasting up to several months, and scarring.^50,52-55

Fractional photothermolysis is a relatively new advancement in the field of laser therapy that has received FDA approval for the treatment of AK.⁵⁶ This treatment works by creating multiple noncontiguous microscopic columns of thermal injury while sparing adjacent zones of viable tissue.⁵⁷ Although there are limited studies involving the use of such lasers in the treatment of AK, initial findings suggest that 1927-nm thulium lasers may be more effective than 1550-nm erbium lasers in achieving lesion clearance. A trial of 14 participants who received 5 laser treatments with a 1550-nm fractionated erbium-doped fiber laser reported an average reduction in AK counts of 66.2% at 3 months follow-up and a 55.6% reduction at 6 months follow-up. A participant-determined marked or very significant improvement of lesions was reported in 83% of participants at 1 month posttreatment but only in 44% of participants at 6 months posttreatment.⁵⁸ A similar trial of 24 participants treated with up to 4 treatment sessions of the fractionated 1927-nm thulium laser reported an 87.3% reduction in number of AKs at 3 months follow-up and an 86.6% reduction at 
6 months follow-up.⁵⁶ The primary advantage of fractional laser therapy is a faster recovery period generally lasting only 2 or 3 days as compared to 
2 weeks or more with traditional ablative lasers, thus limiting the amount of time a patient must tolerate cosmetically unappealing erythema.^59,60 The quick recovery time has been attributed to the fractional laser’s ability to preserve the stratum corneum and skin barrier, which also helps reduce the risk for other AEs such as scarring and infection.^56,59-61 Additional studies are needed to better assess the true efficacy of fractional laser therapy, but treatment with the fractional 1927-nm thulium laser appears to be a promising and well-tolerated therapeutic option for treatment of AK with similar efficacy to traditional ablative lasers but with a lower risk of AEs.

Photodynamic TherapyPhotodynamic therapy (PDT) is an FDA-approved treatment that involves the use of a topical photosensitizing agent such as 5-aminolevulinic acid (ALA) or methyl aminovulinate (MAL) before exposure to an activating light source to generate reactive oxygen species that lead to cell death.^62-65 Multiple PDT regimens with varying combinations of photosensitizers, incubation time, and light sources have been studied, but a 
2012 Cochrane review determined that treatment with conventional formulations of MAL and ALA with either blue- or red-light PDT were similarly efficacious for treatment of individual AKs as compared to vehicle with blue- or red-light PDT. One exception was that longer incubation time (ie, 4 hours) with ALA resulted in better results than shorter incubation times (ie, 0.5, 1, 2 hours) with ALA.⁶⁶

Standard PDT treatment with MAL also has consistently demonstrated superior efficacy in achieving complete clearance rates in addition to superior cosmetic outcomes over treatment with either cryotherapy, DFS, or 5-FU.^67-73 Three studies in particular noted an excellent or good investigator-determined cosmetic outcome in 96% to 98% of participants treated with MAL-PDT.^69,71,74 Photodynamic therapy with ALA also has been reported as superior over CO2 laser ablation for AK reduction as well as both patient and investigator overall satisfaction.⁷⁵

More recently, several methods of improving photosensitizer delivery have been studied, which have demonstrated remarkable efficacy at achieving lesion clearance over standard cream formulations or application routines. One such method involves the use of gentle heating to increase photosensitizer uptake. In a split-extremity study of 20 participants who were treated with 20% ALA under occlusion for 1 hour with one side heated to 38.8°C, the heated side demonstrated significant (P<.0001) efficacy at achieving higher median clearance rates over control when evaluated at 2 and 6 months posttherapy.⁷⁶ Notably, occlusion of ALA in itself during the incubation period also has been demonstrated to significantly (P<.0001) improve clearance rates.⁷⁷ Another method involves the use of a new nanoemulsion-based formulation of 
ALA gel, known as BF-200 ALA, which has demonstrated remarkable efficacy over standard 
MAL cream and placebo in a long-term follow-up 
analysis of 2 prospective, randomized, controlled trials.⁷⁸ In a similar vein, 3 prospective randomized trials with a minimum follow-up time of 3 months demonstrated that MAL-PDT in combination with fractional ablative laser pretreatment has significant (P<.02 in all trials) efficacy over MAL-PDT without pretreatment in achieving complete AK clearance. Although the cosmetic outcomes were good or excellent in 87% to 100% of patients, they were not significantly different from stand-alone 
MAL-PDT treatment in any of the trials.^79-81 However, pretreatment with microneedling in MAL-PDT has been shown to achieve superior cosmetic outcomes over 
MAL-PDT without microneedling, according to one small split-face study of 10 participants.⁸²

Overall, PDT is an excellent therapeutic option that is able to provide efficacious clearance of AKs as well as superior cosmetic outcomes. Common AEs of PDT include burning, itching, and stinging during therapy, but pain intensity decreases dramatically upon termination of illumination, with cessation of most symptoms by 12 hours posttherapy.⁷³ Permanent pigmentation changes have been reported to occasionally occur following PDT therapy.⁸¹

Conclusion

When determining which therapy to use in a patient, clinicians must take into account a variety of factors such as patient preference, cost of treatment, availability, tolerance for AEs, and the need for field therapy. Although all therapies discussed within this article are effective and reasonable treatment choices, patients who are particularly concerned about cosmetic outcomes would most likely benefit from either IMQ or PDT, as the data for cosmetic outcomes with these therapies are the strongest. Combination or sequential treatments may be required in some cases and all patients should be monitored for lesion recurrence regardless of treatment choice. A summary of the therapies and key studies discussed here is available in the PDF.

Actinic keratosis (AK), also referred to as solar keratosis or senile keratosis, is an intraepidermal proliferation of dysplastic keratinocytes that develops in response to chronic exposure to UV radiation. Actinic keratoses are among the most commonly encountered lesions seen by dermatologists, and it has been estimated that 60% of predisposed individuals older than 40 years have at least one AK.^1,2 Prevalence is notably higher in light-skinned individuals and increases with age, presumably from higher cumulative sun exposure and decreased effectiveness of the immune system.^1,3 It remains a point of contention as to whether or not AKs actually represent squamous cell carcinoma (SCC) in situ, but the potential for progression to invasive disease has been well demonstrated, as the majority of SCCs develop from preexisting AKs.^4-6 The risk for progression to invasive disease for an individual AK has been estimated to range from 0.025% to 16% per year, with an average of approximately 8% in immunocompetent patients.⁷

The clinical morphology of AK can vary widely, but the most common presentation is an erythematous scaly macule, papule, or plaque on sun-exposed skin. The skin surrounding AKs typically shows evidence of solar damage with deep wrinkling, mottled pigmentation, scattered telangiectases, purpura, or xerosis (Figure). A variety of clinical variants with unique presentations exist, including atrophic, hypertrophic, acantholytic, lichenoid, bowenoid, and pigmented subtypes. Because more than 80% of AKs occur on highly visible areas such as the head, neck, back of the hands, and forearms, AKs can have an obvious detrimental effect on cosmetic appearance. Studies also have shown a strong association between AKs and decreased overall quality of life (QOL).^3,8,9

Patient with numerous actinic keratoses, scattered plaques suspicious for squamous cell carcinoma, and numerous scars from prior squamous cell carcinoma treatments.

Topical Treatments

5-Fluorouracil

5-Fluorouracil (5-FU) is a US Food and Drug Administration (FDA)–approved, topically applied pyrimidine analogue that inhibits thymidylate synthase. The resulting suppression of DNA and RNA synthesis induces cell death with a preference for mitotically active cells.¹⁰ 5-Fluorouracil has been used for more than 
50 years as a treatment of AK and its efficacy is well established. A systematic review of 5 randomized controlled studies of topical 5-FU reported an average of 49% of 423 patients achieving complete lesion clearance with 5-FU cream 5% applied once or twice daily for up to 7 weeks.¹¹ Some notable drawbacks of 5-FU, however, are application-site erythema, blistering, pruritus, necrosis, erosion, and pain. These effects often lead to premature cessation of therapy, but newer formulations of 5-FU cream 0.5% have shown good efficacy with better tolerability.¹² A randomized, double-blind, multicenter, parallel-group study of 177 patients using 5-FU cream 0.5% once daily for either 1, 2, or 4 weeks demonstrated significant (P<.001) efficacy over vehicle gel in all treatment arms.¹³ The most effective therapy was 
4 weeks of treatment, which achieved a mean 91.7% reduction in lesion count as assessed 1 month after cessation of therapy. The primary adverse effect (AE) reported in this trial was mild to moderate facial irritation, which generally resolved within 
18 to 21 days after treatment cessation.¹³ Overall, 5-FU is a highly effective therapy for treating AKs that also can improve signs of photoaging, but patients should be aware of cosmetically unappealing effects that generally occur throughout therapy and during the immediate posttreatment period.¹⁴

Chemical Peels

Chemical peels traditionally employ acidic compounds to strip away outer layers of skin to variable depths depending on the concentration of the agent being applied. For treatment of AK, trichloroacetic acid (TCA) is a commonly employed cauterant that has shown efficacy comparable to topical 5-FU as well as ablative CO₂ laser resurfacing.¹⁵ Trichloroacetic acid peels also are a convenient therapy, as good results can be achieved after a single treatment session. A split-face study of 15 patients treated with either a single application of 35% TCA and Jessner solution or twice-daily application of 5-FU cream 5% for 3 weeks demonstrated a reduction in 75% of visible AKs in both treatment arms over a 1-year follow-up period.¹⁶ Although 80% of patients self-reported considerable cosmetic improvement with both therapies, patient preference was reported to be in favor of the TCA peel, given its quick results and relatively mild side effects as compared to 5-FU. Treatment with chemical peels will result in temporary erythema and mild desquamation that usually resolves within 2 weeks; however, there are cases in which erythema has been reported to persist for several months.¹⁶ Adverse effects such as permanent scarring or pigmentation changes rarely are seen with TCA concentrations less than 45%.¹⁷ Caution should be used in patients with a history of herpes simplex virus, keloids, postinflammatory hyperpigmentation, radiation exposure, immunosuppression, and those unable or unwilling to use sunscreen and avoid sun exposure in the immediate posttreatment period.

Diclofenac Sodium

Diclofenac sodium (DFS) is an FDA-approved topical, nonsteroidal, 
anti-inflammatory drug whose mechanism of action in the treatment of AK is thought to involve inhibition of the cyclooxygenase 2 enzyme.¹⁸ The resulting reduction of prostaglandins is believed to inhibit tumor angiogenesis, induce apoptosis, and inhibit cell differentiation.^19-22 In a multicenter, double-blind, placebo-controlled study of 195 patients, application of DFS 3% in hyaluronan gel 2.5% twice daily for 60 days showed significant (P<.05) efficacy over placebo in achieving complete resolution of target lesions during a 30-day follow-up period (31% vs 10%). Furthermore, qualitative patient assessment of complete global improvement also was significantly (P<.05) higher in the active treatment group as compared to placebo (31% vs 10%).²³ Additional studies of DFS 3% in hyaluronan gel 2.5% applied twice daily for 90 days have shown even higher rates of success, with complete resolution of target lesions in 40% to 58% of cases.^24,25 This therapy also has been reported to substantially improve QOL following treatment completion.²⁶ The most frequently cited AEs include pruritus, rash, dry skin, erythema, and application-site reactions. Overall, DFS is a 
well-tolerated therapy with efficacy comparable to that of 5-FU but with a lower incidence of AEs 
and higher patient satisfaction as determined in 
2 head-to-head studies.^27,28
ImiquimodImiquimod (IMQ) is an FDA-approved topical agent that functions as an immune response modifier via agonism of toll-like receptor 7.¹⁸ The resulting cytokine production and release enhances the innate and acquired immune responses leading to anticancer activity.²⁹ The efficacy of IMQ for treatment of AK has been demonstrated in numerous well-designed clinical trials. A 
meta-analysis of 5 randomized, double-blind trials including 1293 patients treated with IMQ cream 5% 
2 to 3 times per week for 12 to 16 weeks reported complete clearance of AKs in 50% of patients treated with IMQ as compared to 5% of patients treated with vehicle.³⁰ The most frequently reported AEs with this therapy include erythema, scabbing, flaking, and erosion. These effects generally resolve following cessation of treatment, and therapy is considered to be well tolerated; however, there are case reports of IMQ triggering or exacerbating existing inflammatory conditions.³¹ Imiquimod cream also is approved at 2.5% and 3.75% concentrations, which have demonstrated significant (P<.001) efficacy over placebo and a reduced incidence of AEs; complete clearance rates have been reported as 30.6% and 35.6%, respectively.³² Notably, a study comparing 75 patients randomized to either IMQ cream 5% 
3 times per week for 4 weeks, 1 or 2 courses of cryosurgery, or 5-FU ointment 5% twice daily for 4 weeks reported that IMQ achieved significantly (P<.01) superior sustained clearance rates during a 12-month follow-up period over cryosurgery and 5-FU 
(73% vs 4% vs 33%).³³ Additionally, cosmetic outcomes as determined by both participants and investigators were reported as excellent at 12 months posttreatment in more than 80% of participants treated with IMQ. These excellent, long-lasting cosmetic outcomes also were determined to be significantly (P<.0001) superior to the cosmetic outcomes of 5-FU and cryotherapy, which both reported excellent outcomes in less than 10% of cases.³³
Ingenol MebutateIngenol mebutate (IM) is a macrocyclic diterpene ester derived from the Euphorbia peplus plant that is FDA approved for the treatment of AK.¹ Ingenol mebutate’s mechanism of action is thought to involve induction of cell death via disruption of the plasma membrane and mitochondria in addition to production of an inflammatory response, which produces tumor-specific antibodies and a large influx of neutrophils.^34,35 The overall evidence for the efficacy of IM is strong. A combined analysis of 4 multicenter, randomized, double-blind studies of 1005 participants reported that IM gel 0.015% applied once daily for 3 days to the face or scalp was significantly superior (P<.001) to placebo in achieving complete clearance as assessed 54 days after completion of therapy (42.2% vs 3.7%) and that IM gel 0.05% applied once daily for 2 days to the trunk or extremities also was significantly superior (P<.001) to placebo in achieving complete clearance as determined 55 days after completion of therapy (34.1% vs 4.7%).³⁶ A follow-up report to this study indicated that IM also appears to achieve long-lasting effects with an overall 87% decrease in total AKs at 12 months follow-up in both trial groups.³⁷ Additionally, it has been recently reported that treatment with IM in these trials was associated with significantly higher overall treatment satisfaction (P<.001) and improved QOL (P<.001) as compared to vehicle.³⁸ Cosmetic outcomes of IM therapy have been assessed in a trial analyzing the efficacy of IM gel 0.025% for 3 days or IM gel 0.05% for 2 or 3 days on nonfacial AKs. This study reported significantly (P<.0001) higher patient satisfaction with the cosmetic outcome at 8 weeks after therapy as compared to vehicle.³⁴ Studies performed in mice have demonstrated that IM is able to promote collagen matrix turnover and impose dermal elasticity, which may contribute to these good cosmetic outcomes.³⁹ The most common AEs of IM therapy are erythema, crusting, and flaking; these effects generally occur 3 to 8 days after starting treatment. These effects, however, generally are short lived and resolve within 2 weeks of treatment cessation when IM is applied to the face or scalp or 4 weeks when applied to the trunk or extremities.⁴⁰ Overall, IM is a useful therapeutic option given its relatively short treatment course as compared to other topically applied agents, as well as its lasting efficacy, mild AEs, and good cosmetic outcomes.

Procedural Modalities

Surgical Procedures

Surgical approaches for the treatment of AK include excision, curettage with or without electrodesiccation, and dermabrasion. In the past, these modalities were used with greater frequency, but the advent of effective topical medications with lower risks of AEs has largely reduced their use.⁴¹ Excision may still be indicated in cases where SCC is suspected, and curettage can be used for treatment of thicker hypertrophic AKs.⁴² Although these approaches have not been evaluated in clinical trials, they are generally effective but require the use of local anesthetics and come with substantial risk for infection, permanent scarring, and hypopigmentation. Dermabrasion employs the use of a motorized device equipped with an abrasive material to physically remove superficial layers of the skin. Studies are limited, but this method has been reported as an effective treatment in a retrospective review of 23 participants in which 96% remained free of AKs at 1 year, 83% at 2 years, 64% at 4 years, and 54% at 5 years posttherapy.⁴³ Notably, one split-face study of 40 participants treated with dermabrasion followed by 25% TCA on one side and either Jessner solution and 35% TCA or dermabrasion alone on the other side reported that the combination of dermabrasion with 25% TCA consistently produced excellent cosmetic results with nearly complete eradication of AKs.⁴⁴ In general, however, cosmetic outcomes with dermabrasion are variable, as the technique is highly operator dependent and treatment is associated with notable discomfort as well as risk for scarring and permanent pigmentation alteration.

Cryotherapy

Cryotherapy remains one of the most commonly utilized treatments of AK and involves the delivery of liquid nitrogen via a spray device or a cotton tip applicator to rapidly freeze cells, thus causing cellular destruction via ice crystal formation and protein denaturation.⁴⁵ Efficacy with this technique has been reported to be as high as 98.8% at 12 months follow-up, but more recent studies cite lower rates of success.⁴⁶ A prospective multicenter study of 90 participants with 421 AKs on the face or scalp treated with a single freeze-thaw cycle of liquid nitrogen reported an overall complete response rate of 67.2% at 3 months posttherapy. Additionally, higher complete response rates were associated with longer freeze times, and cosmetic outcomes were reported as good to excellent in 94% of complete response lesions.⁴⁷ Similar results were reported in an open-label, prospective, randomized, controlled clinical trial of 200 participants with 
543 AKs, which compared a single freeze-thaw cycle with liquid nitrogen to a single session of CO₂ laser ablation in the treatment of isolated AKs of the face and scalp.⁴⁸ At 3 months posttherapy, complete clearance was observed in 71.6% of participants treated with cryotherapy and in 65.3% of participants treated with laser ablation (P=.532). At 
12 months posttherapy, participants who originally showed complete response at 3 months were assessed for relapse. Complete clearance was preserved in 72.6% of participants treated with cryotherapy versus 21.9% of participants treated with laser ablation (P<.0001), and cosmetic outcomes were reported by participants as good or excellent at 3 months follow-up in more than 93% of participants for both treatment arms.⁴⁸ Possible AEs of cryotherapy include pain during treatment, blister formation with possible hemorrhage, infection, scarring, and permanent pigmentary changes.^47,48 Notably, the risk for hypopigmentation increases with longer freezing times, thus requiring clinicians to consider the balance between improved efficacy and reduced cosmetic outcomes.⁴⁷

Light-Based Therapies

Laser Therapy

Ablative laser resurfacing with either the CO₂ or erbium-doped:YAG (Er:YAG) laser utilizes light of specific wavelengths to selectively induce thermolysis and destruction of the epidermal layer. Both lasers have been studied as treatments of AK, but there is a lack of large, well-designed studies. In one small study of 14 participants treated with 
1 to 2 passes of the CO₂ laser, complete clearance was reported in all cases without any recurrences during a follow-up period of 6 to 24 months. Additionally, all participants in this study reported satisfaction with the cosmetic outcome.⁴⁹ The CO₂ laser also has demonstrated efficacy comparable to that of the TCA peel and 5-FU therapy in a prospective randomized trial of 34 patients with facial or scalp AKs who received either CO₂ laser with 2 passes, 30% TCA peel, or 5-FU cream 5% twice daily for 
3 weeks.¹⁵ Reduction in mean AK counts at 3 months posttherapy was significantly (P<.03) higher in all treatment arms as compared to the control group (92% for CO₂ laser, 89% for TCA peel, and 83% for 5-FU cream). No significant (P=.31) difference in outcomes was noted among the different treatment arms.¹⁵ Similar results were reported for the Er:YAG laser in a small prospective study of 5 participants treated with 2 to 3 passes with the Er:YAG laser in which reduction in mean AK counts was reported as ranging from 86% to 96% at 3 months posttherapy.⁵⁰ The Er:YAG laser in combination with the CO₂ laser has shown notable long-term efficacy in achieving higher lesion clearance rates and sustained complete clearance rates over treatment with topical 5-FU.⁵¹ In a prospective randomized study of 55 par-ticipants with multiple AKs on the face or scalp, participants were assigned to receive either combination laser ablation with the Er:YAG and CO₂ lasers down to the level of the papillary dermis or 
5-FU cream 5% applied twice daily for 2 to 7 weeks until an appropriate clinical inflammatory response was achieved. At 12 months follow-up, the laser treatment group achieved significantly (P=.048) higher mean lesion clearance rates (91.1%) as compared to the 5-FU arm (76.6%) and significantly (P=.003) higher sustained complete clearance rates (59.3%) as compared to 5-FU (29.2%). The proportion of participants with an improvement in photoaging score at 12 months follow-up approached statistical significance (P=.07), with 74% of the laser-treated group showing improvement as compared to 43% of the 5-FU–treated group. Long-term, cosmetically unappealing side effects such as erythema and hypopigmentation occurred notably more often in the laser-treated group as compared to the 5-FU group.⁵¹ In summary, ablative lasers appear to be a highly effective therapy for AK but at the cost of increased risk for AEs such as permanent pigmentary changes, prolonged erythema lasting up to several months, and scarring.^50,52-55

Fractional photothermolysis is a relatively new advancement in the field of laser therapy that has received FDA approval for the treatment of AK.⁵⁶ This treatment works by creating multiple noncontiguous microscopic columns of thermal injury while sparing adjacent zones of viable tissue.⁵⁷ Although there are limited studies involving the use of such lasers in the treatment of AK, initial findings suggest that 1927-nm thulium lasers may be more effective than 1550-nm erbium lasers in achieving lesion clearance. A trial of 14 participants who received 5 laser treatments with a 1550-nm fractionated erbium-doped fiber laser reported an average reduction in AK counts of 66.2% at 3 months follow-up and a 55.6% reduction at 6 months follow-up. A participant-determined marked or very significant improvement of lesions was reported in 83% of participants at 1 month posttreatment but only in 44% of participants at 6 months posttreatment.⁵⁸ A similar trial of 24 participants treated with up to 4 treatment sessions of the fractionated 1927-nm thulium laser reported an 87.3% reduction in number of AKs at 3 months follow-up and an 86.6% reduction at 
6 months follow-up.⁵⁶ The primary advantage of fractional laser therapy is a faster recovery period generally lasting only 2 or 3 days as compared to 
2 weeks or more with traditional ablative lasers, thus limiting the amount of time a patient must tolerate cosmetically unappealing erythema.^59,60 The quick recovery time has been attributed to the fractional laser’s ability to preserve the stratum corneum and skin barrier, which also helps reduce the risk for other AEs such as scarring and infection.^56,59-61 Additional studies are needed to better assess the true efficacy of fractional laser therapy, but treatment with the fractional 1927-nm thulium laser appears to be a promising and well-tolerated therapeutic option for treatment of AK with similar efficacy to traditional ablative lasers but with a lower risk of AEs.

Photodynamic TherapyPhotodynamic therapy (PDT) is an FDA-approved treatment that involves the use of a topical photosensitizing agent such as 5-aminolevulinic acid (ALA) or methyl aminovulinate (MAL) before exposure to an activating light source to generate reactive oxygen species that lead to cell death.^62-65 Multiple PDT regimens with varying combinations of photosensitizers, incubation time, and light sources have been studied, but a 
2012 Cochrane review determined that treatment with conventional formulations of MAL and ALA with either blue- or red-light PDT were similarly efficacious for treatment of individual AKs as compared to vehicle with blue- or red-light PDT. One exception was that longer incubation time (ie, 4 hours) with ALA resulted in better results than shorter incubation times (ie, 0.5, 1, 2 hours) with ALA.⁶⁶

Standard PDT treatment with MAL also has consistently demonstrated superior efficacy in achieving complete clearance rates in addition to superior cosmetic outcomes over treatment with either cryotherapy, DFS, or 5-FU.^67-73 Three studies in particular noted an excellent or good investigator-determined cosmetic outcome in 96% to 98% of participants treated with MAL-PDT.^69,71,74 Photodynamic therapy with ALA also has been reported as superior over CO2 laser ablation for AK reduction as well as both patient and investigator overall satisfaction.⁷⁵

More recently, several methods of improving photosensitizer delivery have been studied, which have demonstrated remarkable efficacy at achieving lesion clearance over standard cream formulations or application routines. One such method involves the use of gentle heating to increase photosensitizer uptake. In a split-extremity study of 20 participants who were treated with 20% ALA under occlusion for 1 hour with one side heated to 38.8°C, the heated side demonstrated significant (P<.0001) efficacy at achieving higher median clearance rates over control when evaluated at 2 and 6 months posttherapy.⁷⁶ Notably, occlusion of ALA in itself during the incubation period also has been demonstrated to significantly (P<.0001) improve clearance rates.⁷⁷ Another method involves the use of a new nanoemulsion-based formulation of 
ALA gel, known as BF-200 ALA, which has demonstrated remarkable efficacy over standard 
MAL cream and placebo in a long-term follow-up 
analysis of 2 prospective, randomized, controlled trials.⁷⁸ In a similar vein, 3 prospective randomized trials with a minimum follow-up time of 3 months demonstrated that MAL-PDT in combination with fractional ablative laser pretreatment has significant (P<.02 in all trials) efficacy over MAL-PDT without pretreatment in achieving complete AK clearance. Although the cosmetic outcomes were good or excellent in 87% to 100% of patients, they were not significantly different from stand-alone 
MAL-PDT treatment in any of the trials.^79-81 However, pretreatment with microneedling in MAL-PDT has been shown to achieve superior cosmetic outcomes over 
MAL-PDT without microneedling, according to one small split-face study of 10 participants.⁸²

Overall, PDT is an excellent therapeutic option that is able to provide efficacious clearance of AKs as well as superior cosmetic outcomes. Common AEs of PDT include burning, itching, and stinging during therapy, but pain intensity decreases dramatically upon termination of illumination, with cessation of most symptoms by 12 hours posttherapy.⁷³ Permanent pigmentation changes have been reported to occasionally occur following PDT therapy.⁸¹

Conclusion

When determining which therapy to use in a patient, clinicians must take into account a variety of factors such as patient preference, cost of treatment, availability, tolerance for AEs, and the need for field therapy. Although all therapies discussed within this article are effective and reasonable treatment choices, patients who are particularly concerned about cosmetic outcomes would most likely benefit from either IMQ or PDT, as the data for cosmetic outcomes with these therapies are the strongest. Combination or sequential treatments may be required in some cases and all patients should be monitored for lesion recurrence regardless of treatment choice. A summary of the therapies and key studies discussed here is available in the PDF.

Topical synthetic epidermal growth factor serum moderately improved the appearance of atrophic acne scars in a small pilot study.

At the end of 12 weeks of twice-daily application, scar appearance improved from 2.875 to 2.38 points on a 5-point investigator global assessment scale. Mean Goodman and Baron acne scar grade fell from 3.00 to 2.75, with 3 representing moderate disease and 2 mild disease. Of eight pairs of before and after photographs given to a blinded investigator, posttreatment images were correctly identified in five. Two were assessed as 76%-100% improved, and three were assessed as 50%-75% improved (J Drugs Dermatol. 2015;14[9]:1005-1010).

The patients were an average of 38 years old, split about equally between the sexes, and racially diverse. They used a basic facial cleanser during the study, but were banned from using tretinoin and other topicals.

Previously studied topicals don’t do much for acne scars, so the usual go-to treatments are chemical peels, dermabrasion, resurfacing lasers, and percutaneous collagen needling. They all work in part by promoting collagen synthesis, but at the cost of pain and side effects. Epidermal growth factor (EGF) also promotes collagen synthesis, so the investigators thought it might help. The EGF used in the study – DNA Regeneration Serum, derived from barley – was supplied by its maker, DNA EGF Renewal in Los Angeles.

“The findings suggest EGF serum has the potential to be a modern, noninvasive treatment for an otherwise highly refractory condition. Whereas resurfacing procedures rely on skin injury to trigger [EGF] release, direct topical application offers the effects of EGF without the associated discomfort and recovery time,” said Dr. Ronald L. Moy of the University of Southern California, Los Angeles, and Rachel Seidel, a medical student at Georgetown University in Washington, D.C.

“All subjects in this study [also] noted improvements in skin texture, fine lines, and wrinkles, while the vast majority also saw a reduction in brown and age spots,” they said.

The investigators said they are interested next in seeing if topical EGF prevents scars in active acne. “We believe that, by counteracting collagen degradation during the course of the inflammatory response, significant tissue atrophy capable of causing visible scarring may be prevented,” they said.

Dr. Moy owns stock in DNA EGF Renewal and is the company’s scientific adviser.

aotto@frontlinemedcom.com

Topical synthetic epidermal growth factor serum moderately improved the appearance of atrophic acne scars in a small pilot study.

At the end of 12 weeks of twice-daily application, scar appearance improved from 2.875 to 2.38 points on a 5-point investigator global assessment scale. Mean Goodman and Baron acne scar grade fell from 3.00 to 2.75, with 3 representing moderate disease and 2 mild disease. Of eight pairs of before and after photographs given to a blinded investigator, posttreatment images were correctly identified in five. Two were assessed as 76%-100% improved, and three were assessed as 50%-75% improved (J Drugs Dermatol. 2015;14[9]:1005-1010).

The patients were an average of 38 years old, split about equally between the sexes, and racially diverse. They used a basic facial cleanser during the study, but were banned from using tretinoin and other topicals.

Previously studied topicals don’t do much for acne scars, so the usual go-to treatments are chemical peels, dermabrasion, resurfacing lasers, and percutaneous collagen needling. They all work in part by promoting collagen synthesis, but at the cost of pain and side effects. Epidermal growth factor (EGF) also promotes collagen synthesis, so the investigators thought it might help. The EGF used in the study – DNA Regeneration Serum, derived from barley – was supplied by its maker, DNA EGF Renewal in Los Angeles.

“The findings suggest EGF serum has the potential to be a modern, noninvasive treatment for an otherwise highly refractory condition. Whereas resurfacing procedures rely on skin injury to trigger [EGF] release, direct topical application offers the effects of EGF without the associated discomfort and recovery time,” said Dr. Ronald L. Moy of the University of Southern California, Los Angeles, and Rachel Seidel, a medical student at Georgetown University in Washington, D.C.

“All subjects in this study [also] noted improvements in skin texture, fine lines, and wrinkles, while the vast majority also saw a reduction in brown and age spots,” they said.

The investigators said they are interested next in seeing if topical EGF prevents scars in active acne. “We believe that, by counteracting collagen degradation during the course of the inflammatory response, significant tissue atrophy capable of causing visible scarring may be prevented,” they said.

Dr. Moy owns stock in DNA EGF Renewal and is the company’s scientific adviser.

aotto@frontlinemedcom.com

Topical synthetic epidermal growth factor serum moderately improved the appearance of atrophic acne scars in a small pilot study.

At the end of 12 weeks of twice-daily application, scar appearance improved from 2.875 to 2.38 points on a 5-point investigator global assessment scale. Mean Goodman and Baron acne scar grade fell from 3.00 to 2.75, with 3 representing moderate disease and 2 mild disease. Of eight pairs of before and after photographs given to a blinded investigator, posttreatment images were correctly identified in five. Two were assessed as 76%-100% improved, and three were assessed as 50%-75% improved (J Drugs Dermatol. 2015;14[9]:1005-1010).

The patients were an average of 38 years old, split about equally between the sexes, and racially diverse. They used a basic facial cleanser during the study, but were banned from using tretinoin and other topicals.

Previously studied topicals don’t do much for acne scars, so the usual go-to treatments are chemical peels, dermabrasion, resurfacing lasers, and percutaneous collagen needling. They all work in part by promoting collagen synthesis, but at the cost of pain and side effects. Epidermal growth factor (EGF) also promotes collagen synthesis, so the investigators thought it might help. The EGF used in the study – DNA Regeneration Serum, derived from barley – was supplied by its maker, DNA EGF Renewal in Los Angeles.

“The findings suggest EGF serum has the potential to be a modern, noninvasive treatment for an otherwise highly refractory condition. Whereas resurfacing procedures rely on skin injury to trigger [EGF] release, direct topical application offers the effects of EGF without the associated discomfort and recovery time,” said Dr. Ronald L. Moy of the University of Southern California, Los Angeles, and Rachel Seidel, a medical student at Georgetown University in Washington, D.C.

“All subjects in this study [also] noted improvements in skin texture, fine lines, and wrinkles, while the vast majority also saw a reduction in brown and age spots,” they said.

The investigators said they are interested next in seeing if topical EGF prevents scars in active acne. “We believe that, by counteracting collagen degradation during the course of the inflammatory response, significant tissue atrophy capable of causing visible scarring may be prevented,” they said.

Dr. Moy owns stock in DNA EGF Renewal and is the company’s scientific adviser.

aotto@frontlinemedcom.com

A powerful endogenous antioxidant found most abundantly in mammalian tissues, especially brain and skeletal muscle tissue, carnosine is a dipeptide of alanine and histidine.^1,2,3,4,5.

Carnosine was first isolated in 1900 by the Russian scientist Gulewitsch as a substance extracted from muscle tissue.^6,4. L-carnosine (beta-alanyl-L-histidine) is the synthetic version identical to the natural form alpha-alanyl-L-histidine.⁷ Carnosine has long been reputed to confer immunomodulating, wound healing, antiglycating, and antineoplastic effects.² Several reports have shown that carnosine can accelerate the healing of surface skin wounds and burns.^4,8

Wound healing

An early study by Nagai et al. in 1986 on carnosine in wound healing showed that rats treated locally with carnosine exhibited greater tensile skin strength at an incision site after hydrocortisone had been administered to hinder healing. The investigators concluded that carnosine bolsters wound healing by stimulating early effusion by histamine and of collagen biosynthesis by beta-alanine. They also found that the compound significantly augmented granulation inhibited by cortisone, mitomycin C, 5-fluorouracil, and bleomycin.⁹

Studies by Fitzpatrick and Fisher in the early 1980s revealed that carnosine acts as a histidine reserve in relation to histamine production during trauma, suggesting a role for carnosine in wound healing.^10,11

In 2012, Ansurudeen et al. examined the effects of carnosine in wound healing in a diabetic mouse model. Carnosine was applied locally and injected daily, yielding significant amelioration in wound healing, with analysis revealing elevated expression of growth factors and cytokines implicated in wound healing. The investigators also observed that carnosine supported cell viability in the presence of high glucose in human dermal fibroblasts and microvascular endothelial cells in vitro.²

Other findings with implications for cutaneous therapy

In 2006, Babizhayev reported that the L-carnosine-related peptidomimetic N-acetylcarnosine (N-acetyl-beta-alanyl-L-histidine) can act as a timed-release (carrier) stable version of L-carnosine in cosmetic preparations, including lubricants.⁶ Babizhayev et al. have since claimed that they have developed a technology using imidazole-containing dipeptide-based compounds (including L-carnosine and derivatives) that enhances protein hydration in photoaged skin.^12,13,14

A double-blind comparative study conducted by Dieamant et al. in 2008 in 124 volunteers with sensitive skin aimed to evaluate the therapeutic potential of the combination of the antioxidant L-carnosine and neuromodulatory Rhodiola rosea. For 28 days, the groups of 62 received twice-daily applications of the 1% combination formulation or placebo. Skin barrier function (reduction of transepidermal water loss) improved in the treatment group, and favorable subjective responses regarding skin dryness were reported. Discomfort after the stinging test was also reduced. In vitro results showed that the release of proopiomelanocortin peptides was spurred by treatment, with the elevated levels of neuropeptides and cytokines produced by keratinocytes exposed to UV radiation returning to normal.¹⁵

Two years later, Renner et al. showed that carnosine hindered tumor growth in vivo in an NIH3T3-HER2/neu mouse model. They contended that this naturally occurring dipeptide warrants increased consideration and study for its potential as an anticancer agent.¹⁶

In 2012, Federici et al. conducted a randomized, evaluator-blinded, controlled comparative trial over 1month to assess the efficacy of twice-daily topical urea 5% with arginine and carnosine (Ureadin Rx) as compared with twice-daily application of a glycerol-based emollient topical product (Dexeryl) in treating xerosis in 40 type 2 diabetes patients (40-75 years of age). Use of the carnosine-containing formulation yielded significantly greater hydration and an 89% decline in Dryness Areas Severity Index (DASI) scores, compared with baseline. The DASI score after 4 weeks of treatment was much lower in the treatment group than the control group. The Visual Analog Scale (VAS) score was also significantly higher in the Ureadin group than the Dexeryl group. The investigators concluded that the topical application of a urea 5%, arginine, and carnosine cream enhances skin hydration and relieves dryness in type 2 diabetic patients in comparison with a control glycerol-based emollient formulation.¹⁷

Antiaging potential

In 1993, Reeve et al. showed that dietary or topically applied carnosine potentiated the contact hypersensitivity reaction in hairless mice and prevented the systemic inhibition of this reaction after dorsal skin exposure to UVB. Carnosine was found to also prevent the systemic suppression provoked by the topical application of a lotion containing cis-urocanic acid.³

Carnosine was a key active ingredient in antiaging products evaluated by Kaczvinsky et al. in 2009 in two double-blind, randomized, controlled, split-face studies. The researchers used the Fast Optical in vivo Topometry of Human Skin (FOITS) technique to measure changes in periorbital wrinkles in the two studies in women between the ages of 30 and 70 years old (study 1, n = 42; study 2, n = 35). They reported that 4 weeks of treatment with the test products, which contained niacinamide, the peptides Pal-KT and Pal-KTTKS, and carnosine, ameliorated periorbital skin, enhancing smoothness and diminishing larger wrinkle depth.¹⁸

In 2012, Babizhayev et al. conducted a 4-month randomized, double-blind, controlled study with 42 subjects to evaluate the effects on skin aging of oral nonhydrolyzed carnosine (Can-C Plus formulation). Skin parameters exhibited a consistent and significant improvement during 3 months of supplementation in the treatment group, compared with the placebo group, with overall skin appearance enhanced and fine lines diminished based on visual inspection. There were no reports of adverse effects. The investigators concluded that supplementation with nonhydrolyzed carnosine or carcinine in patented oral formulations has potential as an agent for antiaging purposes.¹⁹

Two years later, Emanuele et al. conducted an experimental double-blind irradiation study to compare a complex novel topical product (TPF50) consisting of three active ingredients (traditional physical sunscreens, SPF 50; a liposome-encapsulated DNA repair enzymes complex – photolyase, endonuclease, and 8-oxoguanine glycosylase [OGG1]; and a robust antioxidant complex containing carnosine, arazine, and ergothionine) to available DNA repair and antioxidant and growth factor topical products. They found that the new topical agent was the most effective product in reducing three molecular markers (cyclobutane pyrimidine dimers, protein carbonylation, and 8-oxo-7,8-dihydro-2’-deoxyguanosine) in human skin biopsies. The researchers concluded that the carnosine-containing formulation enhances the genomic and proteomic integrity of skin cells after continual UV exposure, suggesting its potential efficacy in lowering the risk of UV-induced cutaneous aging and nonmelanoma skin cancer.²⁰

Conclusion

Carnosine is an intriguing compound with well-documented antioxidant and wound healing activity. While more research is necessary to determine its wider applications in dermatology, recent work in formulating topical products to impart antiaging effects appears to show promise.

References

1. Nutr. Res. Pract. 2011;5:421-8.

2. Amino Acids 2012;43:127-34.

3. Immunology 1993;78:99-104.

4. Mol. Aspects Med. 1992;13:379-444.

5. Am. J. Ther. 2012;19:e69-89.

6. Life Sci. 2006;78:2343-57.

7. J. Cosmet. Dermatol. 2004;3:26-34.

8. Nihon Yakurigaku Zasshi. 1992;100:165-72.

9. Surgery 1986;100:815-21.

10. Surgery 1982;91:430-4.

11. Surgery 1982;91:56-60.

12. Int. J. Cosmet. Sci. 2011;33:1-16.

13. Crit. Rev. Ther. Drug Carrier Syst. 2011;28:203-53.

14. Crit. Rev. Ther. Drug Carrier Syst. 2010;27:85-154.

15. J. Cosmet. Dermatol. 2008;7:112-9.

16. Mol. Cancer 2010;9:2.

17. BMC Dermatol. 2012;12:16.

18. J. Cosmet. Dermatol. 2009;8:228-33.

19. J. Dermatolog. Treat. 2012;23:345-84.

20. J. Drugs Dermatol. 2014;13:309-14.

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 Dermatology 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 Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

A powerful endogenous antioxidant found most abundantly in mammalian tissues, especially brain and skeletal muscle tissue, carnosine is a dipeptide of alanine and histidine.^1,2,3,4,5.

Carnosine was first isolated in 1900 by the Russian scientist Gulewitsch as a substance extracted from muscle tissue.^6,4. L-carnosine (beta-alanyl-L-histidine) is the synthetic version identical to the natural form alpha-alanyl-L-histidine.⁷ Carnosine has long been reputed to confer immunomodulating, wound healing, antiglycating, and antineoplastic effects.² Several reports have shown that carnosine can accelerate the healing of surface skin wounds and burns.^4,8

Wound healing

An early study by Nagai et al. in 1986 on carnosine in wound healing showed that rats treated locally with carnosine exhibited greater tensile skin strength at an incision site after hydrocortisone had been administered to hinder healing. The investigators concluded that carnosine bolsters wound healing by stimulating early effusion by histamine and of collagen biosynthesis by beta-alanine. They also found that the compound significantly augmented granulation inhibited by cortisone, mitomycin C, 5-fluorouracil, and bleomycin.⁹

Studies by Fitzpatrick and Fisher in the early 1980s revealed that carnosine acts as a histidine reserve in relation to histamine production during trauma, suggesting a role for carnosine in wound healing.^10,11

In 2012, Ansurudeen et al. examined the effects of carnosine in wound healing in a diabetic mouse model. Carnosine was applied locally and injected daily, yielding significant amelioration in wound healing, with analysis revealing elevated expression of growth factors and cytokines implicated in wound healing. The investigators also observed that carnosine supported cell viability in the presence of high glucose in human dermal fibroblasts and microvascular endothelial cells in vitro.²

Other findings with implications for cutaneous therapy

In 2006, Babizhayev reported that the L-carnosine-related peptidomimetic N-acetylcarnosine (N-acetyl-beta-alanyl-L-histidine) can act as a timed-release (carrier) stable version of L-carnosine in cosmetic preparations, including lubricants.⁶ Babizhayev et al. have since claimed that they have developed a technology using imidazole-containing dipeptide-based compounds (including L-carnosine and derivatives) that enhances protein hydration in photoaged skin.^12,13,14

A double-blind comparative study conducted by Dieamant et al. in 2008 in 124 volunteers with sensitive skin aimed to evaluate the therapeutic potential of the combination of the antioxidant L-carnosine and neuromodulatory Rhodiola rosea. For 28 days, the groups of 62 received twice-daily applications of the 1% combination formulation or placebo. Skin barrier function (reduction of transepidermal water loss) improved in the treatment group, and favorable subjective responses regarding skin dryness were reported. Discomfort after the stinging test was also reduced. In vitro results showed that the release of proopiomelanocortin peptides was spurred by treatment, with the elevated levels of neuropeptides and cytokines produced by keratinocytes exposed to UV radiation returning to normal.¹⁵

Two years later, Renner et al. showed that carnosine hindered tumor growth in vivo in an NIH3T3-HER2/neu mouse model. They contended that this naturally occurring dipeptide warrants increased consideration and study for its potential as an anticancer agent.¹⁶

In 2012, Federici et al. conducted a randomized, evaluator-blinded, controlled comparative trial over 1month to assess the efficacy of twice-daily topical urea 5% with arginine and carnosine (Ureadin Rx) as compared with twice-daily application of a glycerol-based emollient topical product (Dexeryl) in treating xerosis in 40 type 2 diabetes patients (40-75 years of age). Use of the carnosine-containing formulation yielded significantly greater hydration and an 89% decline in Dryness Areas Severity Index (DASI) scores, compared with baseline. The DASI score after 4 weeks of treatment was much lower in the treatment group than the control group. The Visual Analog Scale (VAS) score was also significantly higher in the Ureadin group than the Dexeryl group. The investigators concluded that the topical application of a urea 5%, arginine, and carnosine cream enhances skin hydration and relieves dryness in type 2 diabetic patients in comparison with a control glycerol-based emollient formulation.¹⁷

Antiaging potential

In 1993, Reeve et al. showed that dietary or topically applied carnosine potentiated the contact hypersensitivity reaction in hairless mice and prevented the systemic inhibition of this reaction after dorsal skin exposure to UVB. Carnosine was found to also prevent the systemic suppression provoked by the topical application of a lotion containing cis-urocanic acid.³

Carnosine was a key active ingredient in antiaging products evaluated by Kaczvinsky et al. in 2009 in two double-blind, randomized, controlled, split-face studies. The researchers used the Fast Optical in vivo Topometry of Human Skin (FOITS) technique to measure changes in periorbital wrinkles in the two studies in women between the ages of 30 and 70 years old (study 1, n = 42; study 2, n = 35). They reported that 4 weeks of treatment with the test products, which contained niacinamide, the peptides Pal-KT and Pal-KTTKS, and carnosine, ameliorated periorbital skin, enhancing smoothness and diminishing larger wrinkle depth.¹⁸

In 2012, Babizhayev et al. conducted a 4-month randomized, double-blind, controlled study with 42 subjects to evaluate the effects on skin aging of oral nonhydrolyzed carnosine (Can-C Plus formulation). Skin parameters exhibited a consistent and significant improvement during 3 months of supplementation in the treatment group, compared with the placebo group, with overall skin appearance enhanced and fine lines diminished based on visual inspection. There were no reports of adverse effects. The investigators concluded that supplementation with nonhydrolyzed carnosine or carcinine in patented oral formulations has potential as an agent for antiaging purposes.¹⁹

Two years later, Emanuele et al. conducted an experimental double-blind irradiation study to compare a complex novel topical product (TPF50) consisting of three active ingredients (traditional physical sunscreens, SPF 50; a liposome-encapsulated DNA repair enzymes complex – photolyase, endonuclease, and 8-oxoguanine glycosylase [OGG1]; and a robust antioxidant complex containing carnosine, arazine, and ergothionine) to available DNA repair and antioxidant and growth factor topical products. They found that the new topical agent was the most effective product in reducing three molecular markers (cyclobutane pyrimidine dimers, protein carbonylation, and 8-oxo-7,8-dihydro-2’-deoxyguanosine) in human skin biopsies. The researchers concluded that the carnosine-containing formulation enhances the genomic and proteomic integrity of skin cells after continual UV exposure, suggesting its potential efficacy in lowering the risk of UV-induced cutaneous aging and nonmelanoma skin cancer.²⁰

Conclusion

Carnosine is an intriguing compound with well-documented antioxidant and wound healing activity. While more research is necessary to determine its wider applications in dermatology, recent work in formulating topical products to impart antiaging effects appears to show promise.

References

1. Nutr. Res. Pract. 2011;5:421-8.

2. Amino Acids 2012;43:127-34.

3. Immunology 1993;78:99-104.

4. Mol. Aspects Med. 1992;13:379-444.

5. Am. J. Ther. 2012;19:e69-89.

6. Life Sci. 2006;78:2343-57.

7. J. Cosmet. Dermatol. 2004;3:26-34.

8. Nihon Yakurigaku Zasshi. 1992;100:165-72.

9. Surgery 1986;100:815-21.

10. Surgery 1982;91:430-4.

11. Surgery 1982;91:56-60.

12. Int. J. Cosmet. Sci. 2011;33:1-16.

13. Crit. Rev. Ther. Drug Carrier Syst. 2011;28:203-53.

14. Crit. Rev. Ther. Drug Carrier Syst. 2010;27:85-154.

15. J. Cosmet. Dermatol. 2008;7:112-9.

16. Mol. Cancer 2010;9:2.

17. BMC Dermatol. 2012;12:16.

18. J. Cosmet. Dermatol. 2009;8:228-33.

19. J. Dermatolog. Treat. 2012;23:345-84.

20. J. Drugs Dermatol. 2014;13:309-14.

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 Dermatology 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 Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

A powerful endogenous antioxidant found most abundantly in mammalian tissues, especially brain and skeletal muscle tissue, carnosine is a dipeptide of alanine and histidine.^1,2,3,4,5.

Carnosine was first isolated in 1900 by the Russian scientist Gulewitsch as a substance extracted from muscle tissue.^6,4. L-carnosine (beta-alanyl-L-histidine) is the synthetic version identical to the natural form alpha-alanyl-L-histidine.⁷ Carnosine has long been reputed to confer immunomodulating, wound healing, antiglycating, and antineoplastic effects.² Several reports have shown that carnosine can accelerate the healing of surface skin wounds and burns.^4,8

Wound healing

An early study by Nagai et al. in 1986 on carnosine in wound healing showed that rats treated locally with carnosine exhibited greater tensile skin strength at an incision site after hydrocortisone had been administered to hinder healing. The investigators concluded that carnosine bolsters wound healing by stimulating early effusion by histamine and of collagen biosynthesis by beta-alanine. They also found that the compound significantly augmented granulation inhibited by cortisone, mitomycin C, 5-fluorouracil, and bleomycin.⁹

Studies by Fitzpatrick and Fisher in the early 1980s revealed that carnosine acts as a histidine reserve in relation to histamine production during trauma, suggesting a role for carnosine in wound healing.^10,11

In 2012, Ansurudeen et al. examined the effects of carnosine in wound healing in a diabetic mouse model. Carnosine was applied locally and injected daily, yielding significant amelioration in wound healing, with analysis revealing elevated expression of growth factors and cytokines implicated in wound healing. The investigators also observed that carnosine supported cell viability in the presence of high glucose in human dermal fibroblasts and microvascular endothelial cells in vitro.²

Other findings with implications for cutaneous therapy

In 2006, Babizhayev reported that the L-carnosine-related peptidomimetic N-acetylcarnosine (N-acetyl-beta-alanyl-L-histidine) can act as a timed-release (carrier) stable version of L-carnosine in cosmetic preparations, including lubricants.⁶ Babizhayev et al. have since claimed that they have developed a technology using imidazole-containing dipeptide-based compounds (including L-carnosine and derivatives) that enhances protein hydration in photoaged skin.^12,13,14

A double-blind comparative study conducted by Dieamant et al. in 2008 in 124 volunteers with sensitive skin aimed to evaluate the therapeutic potential of the combination of the antioxidant L-carnosine and neuromodulatory Rhodiola rosea. For 28 days, the groups of 62 received twice-daily applications of the 1% combination formulation or placebo. Skin barrier function (reduction of transepidermal water loss) improved in the treatment group, and favorable subjective responses regarding skin dryness were reported. Discomfort after the stinging test was also reduced. In vitro results showed that the release of proopiomelanocortin peptides was spurred by treatment, with the elevated levels of neuropeptides and cytokines produced by keratinocytes exposed to UV radiation returning to normal.¹⁵

Two years later, Renner et al. showed that carnosine hindered tumor growth in vivo in an NIH3T3-HER2/neu mouse model. They contended that this naturally occurring dipeptide warrants increased consideration and study for its potential as an anticancer agent.¹⁶

In 2012, Federici et al. conducted a randomized, evaluator-blinded, controlled comparative trial over 1month to assess the efficacy of twice-daily topical urea 5% with arginine and carnosine (Ureadin Rx) as compared with twice-daily application of a glycerol-based emollient topical product (Dexeryl) in treating xerosis in 40 type 2 diabetes patients (40-75 years of age). Use of the carnosine-containing formulation yielded significantly greater hydration and an 89% decline in Dryness Areas Severity Index (DASI) scores, compared with baseline. The DASI score after 4 weeks of treatment was much lower in the treatment group than the control group. The Visual Analog Scale (VAS) score was also significantly higher in the Ureadin group than the Dexeryl group. The investigators concluded that the topical application of a urea 5%, arginine, and carnosine cream enhances skin hydration and relieves dryness in type 2 diabetic patients in comparison with a control glycerol-based emollient formulation.¹⁷

Antiaging potential

In 1993, Reeve et al. showed that dietary or topically applied carnosine potentiated the contact hypersensitivity reaction in hairless mice and prevented the systemic inhibition of this reaction after dorsal skin exposure to UVB. Carnosine was found to also prevent the systemic suppression provoked by the topical application of a lotion containing cis-urocanic acid.³

Carnosine was a key active ingredient in antiaging products evaluated by Kaczvinsky et al. in 2009 in two double-blind, randomized, controlled, split-face studies. The researchers used the Fast Optical in vivo Topometry of Human Skin (FOITS) technique to measure changes in periorbital wrinkles in the two studies in women between the ages of 30 and 70 years old (study 1, n = 42; study 2, n = 35). They reported that 4 weeks of treatment with the test products, which contained niacinamide, the peptides Pal-KT and Pal-KTTKS, and carnosine, ameliorated periorbital skin, enhancing smoothness and diminishing larger wrinkle depth.¹⁸

In 2012, Babizhayev et al. conducted a 4-month randomized, double-blind, controlled study with 42 subjects to evaluate the effects on skin aging of oral nonhydrolyzed carnosine (Can-C Plus formulation). Skin parameters exhibited a consistent and significant improvement during 3 months of supplementation in the treatment group, compared with the placebo group, with overall skin appearance enhanced and fine lines diminished based on visual inspection. There were no reports of adverse effects. The investigators concluded that supplementation with nonhydrolyzed carnosine or carcinine in patented oral formulations has potential as an agent for antiaging purposes.¹⁹

Two years later, Emanuele et al. conducted an experimental double-blind irradiation study to compare a complex novel topical product (TPF50) consisting of three active ingredients (traditional physical sunscreens, SPF 50; a liposome-encapsulated DNA repair enzymes complex – photolyase, endonuclease, and 8-oxoguanine glycosylase [OGG1]; and a robust antioxidant complex containing carnosine, arazine, and ergothionine) to available DNA repair and antioxidant and growth factor topical products. They found that the new topical agent was the most effective product in reducing three molecular markers (cyclobutane pyrimidine dimers, protein carbonylation, and 8-oxo-7,8-dihydro-2’-deoxyguanosine) in human skin biopsies. The researchers concluded that the carnosine-containing formulation enhances the genomic and proteomic integrity of skin cells after continual UV exposure, suggesting its potential efficacy in lowering the risk of UV-induced cutaneous aging and nonmelanoma skin cancer.²⁰

Conclusion

Carnosine is an intriguing compound with well-documented antioxidant and wound healing activity. While more research is necessary to determine its wider applications in dermatology, recent work in formulating topical products to impart antiaging effects appears to show promise.

References

1. Nutr. Res. Pract. 2011;5:421-8.

2. Amino Acids 2012;43:127-34.

3. Immunology 1993;78:99-104.

4. Mol. Aspects Med. 1992;13:379-444.

5. Am. J. Ther. 2012;19:e69-89.

6. Life Sci. 2006;78:2343-57.

7. J. Cosmet. Dermatol. 2004;3:26-34.

8. Nihon Yakurigaku Zasshi. 1992;100:165-72.

9. Surgery 1986;100:815-21.

10. Surgery 1982;91:430-4.

11. Surgery 1982;91:56-60.

12. Int. J. Cosmet. Sci. 2011;33:1-16.

13. Crit. Rev. Ther. Drug Carrier Syst. 2011;28:203-53.

14. Crit. Rev. Ther. Drug Carrier Syst. 2010;27:85-154.

15. J. Cosmet. Dermatol. 2008;7:112-9.

16. Mol. Cancer 2010;9:2.

17. BMC Dermatol. 2012;12:16.

18. J. Cosmet. Dermatol. 2009;8:228-33.

19. J. Dermatolog. Treat. 2012;23:345-84.

20. J. Drugs Dermatol. 2014;13:309-14.

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 Dermatology 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 Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Pogostemon cablin, known in the West as patchouli or guang huo-xiang in China, is a long-time staple in traditional Chinese medicine for various indications, particularly gastrointestinal and skin disorders¹.

Patchouli oil, which contains several mono- and sesquiterpenoids, alkaloids, and flavonoids, is thought to possess significant anti-inflammatory and antioxidant qualities².In fact, it is reputed to impart antiviral, antioxidant, anti-inflammatory, and analgesic effects, and is also known to protect intestinal barrier function³. Peng et al. have found that patchouli oil exerts significant antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)^4.

After a comprehensive 2013 review, Chen et al. deemed P. cablin to have potential clinical benefits as an effective adaptogenic herbal treatment³. It is thought to have some antiacne properties as well¹. Further, P. cablin is among the Top 10 most-often-used traditional Chinese medicine prescriptions for skin care and appearance¹.

In Brazil, China, Indonesia, and Malaysia, P. cablin is cultivated for its essential oil, which plays an important role in the perfume industry. Patchouli essential oil, featured in perfumes, soaps, cosmetics, and as incense, is used by aromatherapists for its calming and reviving effects. The essential oil has also been shown to impart antioxidant activity⁵.

In 2014, Lin et al. studied the protective effects of P. cablin essential oil against ultraviolet (UV)-induced skin photoaging in mice. The researchers applied patchouli oil for 2 hours before UV exposure to the dorsal depilated skin of mice. They found that patchouli oil doses of 6 mg/mouse and 9 mg/mouse significantly suppressed skin wrinkle formation, mitigated skin elasticity impairment, and augmented collagen content (21.9% and 26.3%, respectively). The same doses also yielded significant reductions in epidermal thickness and malondialdehyde content, and blocked the disruption of collagen and elastic fibers. Patchouli oil treatment also resulted in the up-regulation of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. The investigators concluded that patchouli oil, perhaps due to its antioxidant characteristics, and sesquiterpene constituents in particular, was effective in preventing photoaging in mice, and warrants attention as a potential agent to hinder photoaging in humans¹.

Feng et al. also investigated the effects of topically applied patchouli alcohol on UV-induced photoaging in mice that year. For 9 weeks, investigators applied patchouli oil solution or a vehicle to the depilated dorsal skin of 6-week-old mice. They found that patchouli oil significantly hastened the recovery of UV-induced skin lesions, which they ascribed to the antioxidant and anti-inflammatory activity of the agent and its down-regulation of the expression of matrix metalloproteinase (MMP)-1 and MMP-3².

Antimicrobial and mosquito repellent activity

In a 2005 study by Trongtokit et al. of the mosquito-repellent activity of 38 essential oils at three concentrations (10%, 50%, or undiluted) against the mosquito Aedes aegypti under laboratory conditions using human volunteers, undiluted P. cablin oil was one of four [along with Cymbopogon nardus (citronella), Syzygium aromaticum (clove), and Zanthoxylum limonella (Thai name: makaen)] undiluted oils to yield an effect, 2 hours of full repellency. The investigators then tested the same concentrations of these oils for repellency against Culex quinquefasciatus (the Southern house mosquito) and Anopheles dirus (the mosquito considered to be a vector of malaria in Asian forested zones. The undiluted oils provided the greatest protection, with clove oil rendering the most durable repellency⁶.

Photoaging

Forest &amp; Kim Starr/Wikimedia Commons/CC BY 3.0

Wu et al. determined the acaricidal activity of compounds extracted from patchouli oil against the house dust mite (Dermatophagoides farinae) in 2012. They isolated 2-(1,3-dihydroxy-but-2-enylidene)-6-methyl-3-oxo-heptanoic acid (DHEMH), the hydrolysate of pogostone, and 15 other constituents in patchouli oil, ultimately ascertaining that DHEMH and patchouli oil itself were the most toxic substances to D. farinae. The investigators concluded that patchouli oil and DHEMH warrant consideration and more study for their acaricidal potential as environmentally friendly, effective, and simple fumigant alternatives to chemical agents⁷.

In 2013, Yang et al. used molecular docking technology to evaluate the antibacterial activity of patchouli oil in vitro. They identified 26 compounds in patchouli oil displaying antibacterial activity, with pogostone and (-)-patchouli alcohol exhibiting the strongest activity⁸. Later that year, Yang et al. used the same technology to establish that Herba pogostemonis oil exhibited potent antibacterial effects, especially the constituents pogostone and (-)-Herba pogostemonis alcohol⁹. Raharjo and Fatchiyah also used molecular docking tools and Chimera 1.7s viewer software in a virtual screening of compounds from patchouli oil, concluding that alpha-patchouli alcohol is a potential inhibitor of the cyclo-oxygenase (COX)-1 enzyme. This is notable given the pivotal role of COX-1 in the inflammatory response¹⁰.

The next year, Peng et al. isolated one of the primary constituents of patchouli oil, pogostone, and assessed its antibacterial activity in vitro and in vivo. They found that pogostone suppressed both gram-negative and gram-positive bacteria in vitro. The researchers noted that pogostone was active against some drug-resistant bacteria (such as MRSA). Via intraperitoneal injection, pogostone displayed antibacterial activity in male and female Kunming mice against Escherichia coli and MRSA. At concentrations of 50 and 100 mg/kg, 90% of the mice infected with E. coli were protected; 60% of the mice at 25 mg/kg were protected. For mice with MRSA, 60% were protected at a dose of 100 mg/kg and 50% at a dose of 50 mg/kg. The investigators concluded that pogostone is a viable antibacterial agent for clinical use⁴.

Transdermal delivery

A 2008 study by Luo et al. showed that patchouli oil was among three volatile oils that improved the skin penetration of the flavonoids baicalin¹¹. It was less effective than several compounds, including clove oil, camphor, menthol, and oleic acid, as a transdermal enhancer in a subsequent study by Zheng et al.¹².

Conclusion

Patchouli oil continues to be used today in traditional Chinese medicine. In the West, the established literature on Pogostemon cablin is thin, but what has emerged recently, particularly studies on the protection against photoaging in mice, supports the continued investigation of this ancient herb to determine its potential role in dermatologic practice. As it is, much more research is necessary.

References

1. J Ethnopharmacol. 2014;154(2):408-18.

2. Eur J Pharm Sci. 2014;63:113-23.

3. Expert Opin Investig Drugs. 2013;22(2):245-57.

4. Chin Med J. (Engl) 2014;127(23):4001-5.

5. J Agric Food Chem. 2007;55(5):1737-42

6. Phytother Res. 2005;19(4):303-9.

7. Chem Pharm Bull (Tokyo). 2012;60(2):178-82.

8. Iran J Pharm Res. 2013 Summer;12(3):307-16.

9. Pak J Pharm Sci. 2013;26(6):1173-9.

10. Bioinformation 2013;9(6):321-4.

11. Zhong Yao Cai. 2008;31(11):1721-4

12. Zhongguo Zhong Yao Za Zhi. 2009;34(20):2599-603.

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 Dermatology 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 Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Pogostemon cablin, known in the West as patchouli or guang huo-xiang in China, is a long-time staple in traditional Chinese medicine for various indications, particularly gastrointestinal and skin disorders¹.

Patchouli oil, which contains several mono- and sesquiterpenoids, alkaloids, and flavonoids, is thought to possess significant anti-inflammatory and antioxidant qualities².In fact, it is reputed to impart antiviral, antioxidant, anti-inflammatory, and analgesic effects, and is also known to protect intestinal barrier function³. Peng et al. have found that patchouli oil exerts significant antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)^4.

After a comprehensive 2013 review, Chen et al. deemed P. cablin to have potential clinical benefits as an effective adaptogenic herbal treatment³. It is thought to have some antiacne properties as well¹. Further, P. cablin is among the Top 10 most-often-used traditional Chinese medicine prescriptions for skin care and appearance¹.

In Brazil, China, Indonesia, and Malaysia, P. cablin is cultivated for its essential oil, which plays an important role in the perfume industry. Patchouli essential oil, featured in perfumes, soaps, cosmetics, and as incense, is used by aromatherapists for its calming and reviving effects. The essential oil has also been shown to impart antioxidant activity⁵.

In 2014, Lin et al. studied the protective effects of P. cablin essential oil against ultraviolet (UV)-induced skin photoaging in mice. The researchers applied patchouli oil for 2 hours before UV exposure to the dorsal depilated skin of mice. They found that patchouli oil doses of 6 mg/mouse and 9 mg/mouse significantly suppressed skin wrinkle formation, mitigated skin elasticity impairment, and augmented collagen content (21.9% and 26.3%, respectively). The same doses also yielded significant reductions in epidermal thickness and malondialdehyde content, and blocked the disruption of collagen and elastic fibers. Patchouli oil treatment also resulted in the up-regulation of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. The investigators concluded that patchouli oil, perhaps due to its antioxidant characteristics, and sesquiterpene constituents in particular, was effective in preventing photoaging in mice, and warrants attention as a potential agent to hinder photoaging in humans¹.

Feng et al. also investigated the effects of topically applied patchouli alcohol on UV-induced photoaging in mice that year. For 9 weeks, investigators applied patchouli oil solution or a vehicle to the depilated dorsal skin of 6-week-old mice. They found that patchouli oil significantly hastened the recovery of UV-induced skin lesions, which they ascribed to the antioxidant and anti-inflammatory activity of the agent and its down-regulation of the expression of matrix metalloproteinase (MMP)-1 and MMP-3².

Antimicrobial and mosquito repellent activity

In a 2005 study by Trongtokit et al. of the mosquito-repellent activity of 38 essential oils at three concentrations (10%, 50%, or undiluted) against the mosquito Aedes aegypti under laboratory conditions using human volunteers, undiluted P. cablin oil was one of four [along with Cymbopogon nardus (citronella), Syzygium aromaticum (clove), and Zanthoxylum limonella (Thai name: makaen)] undiluted oils to yield an effect, 2 hours of full repellency. The investigators then tested the same concentrations of these oils for repellency against Culex quinquefasciatus (the Southern house mosquito) and Anopheles dirus (the mosquito considered to be a vector of malaria in Asian forested zones. The undiluted oils provided the greatest protection, with clove oil rendering the most durable repellency⁶.

Photoaging

Forest &amp; Kim Starr/Wikimedia Commons/CC BY 3.0

Wu et al. determined the acaricidal activity of compounds extracted from patchouli oil against the house dust mite (Dermatophagoides farinae) in 2012. They isolated 2-(1,3-dihydroxy-but-2-enylidene)-6-methyl-3-oxo-heptanoic acid (DHEMH), the hydrolysate of pogostone, and 15 other constituents in patchouli oil, ultimately ascertaining that DHEMH and patchouli oil itself were the most toxic substances to D. farinae. The investigators concluded that patchouli oil and DHEMH warrant consideration and more study for their acaricidal potential as environmentally friendly, effective, and simple fumigant alternatives to chemical agents⁷.

In 2013, Yang et al. used molecular docking technology to evaluate the antibacterial activity of patchouli oil in vitro. They identified 26 compounds in patchouli oil displaying antibacterial activity, with pogostone and (-)-patchouli alcohol exhibiting the strongest activity⁸. Later that year, Yang et al. used the same technology to establish that Herba pogostemonis oil exhibited potent antibacterial effects, especially the constituents pogostone and (-)-Herba pogostemonis alcohol⁹. Raharjo and Fatchiyah also used molecular docking tools and Chimera 1.7s viewer software in a virtual screening of compounds from patchouli oil, concluding that alpha-patchouli alcohol is a potential inhibitor of the cyclo-oxygenase (COX)-1 enzyme. This is notable given the pivotal role of COX-1 in the inflammatory response¹⁰.

The next year, Peng et al. isolated one of the primary constituents of patchouli oil, pogostone, and assessed its antibacterial activity in vitro and in vivo. They found that pogostone suppressed both gram-negative and gram-positive bacteria in vitro. The researchers noted that pogostone was active against some drug-resistant bacteria (such as MRSA). Via intraperitoneal injection, pogostone displayed antibacterial activity in male and female Kunming mice against Escherichia coli and MRSA. At concentrations of 50 and 100 mg/kg, 90% of the mice infected with E. coli were protected; 60% of the mice at 25 mg/kg were protected. For mice with MRSA, 60% were protected at a dose of 100 mg/kg and 50% at a dose of 50 mg/kg. The investigators concluded that pogostone is a viable antibacterial agent for clinical use⁴.

Transdermal delivery

A 2008 study by Luo et al. showed that patchouli oil was among three volatile oils that improved the skin penetration of the flavonoids baicalin¹¹. It was less effective than several compounds, including clove oil, camphor, menthol, and oleic acid, as a transdermal enhancer in a subsequent study by Zheng et al.¹².

Conclusion

Patchouli oil continues to be used today in traditional Chinese medicine. In the West, the established literature on Pogostemon cablin is thin, but what has emerged recently, particularly studies on the protection against photoaging in mice, supports the continued investigation of this ancient herb to determine its potential role in dermatologic practice. As it is, much more research is necessary.

References

1. J Ethnopharmacol. 2014;154(2):408-18.

2. Eur J Pharm Sci. 2014;63:113-23.

3. Expert Opin Investig Drugs. 2013;22(2):245-57.

4. Chin Med J. (Engl) 2014;127(23):4001-5.

5. J Agric Food Chem. 2007;55(5):1737-42

6. Phytother Res. 2005;19(4):303-9.

7. Chem Pharm Bull (Tokyo). 2012;60(2):178-82.

8. Iran J Pharm Res. 2013 Summer;12(3):307-16.

9. Pak J Pharm Sci. 2013;26(6):1173-9.

10. Bioinformation 2013;9(6):321-4.

11. Zhong Yao Cai. 2008;31(11):1721-4

12. Zhongguo Zhong Yao Za Zhi. 2009;34(20):2599-603.

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 Dermatology 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 Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Pogostemon cablin, known in the West as patchouli or guang huo-xiang in China, is a long-time staple in traditional Chinese medicine for various indications, particularly gastrointestinal and skin disorders¹.

Patchouli oil, which contains several mono- and sesquiterpenoids, alkaloids, and flavonoids, is thought to possess significant anti-inflammatory and antioxidant qualities².In fact, it is reputed to impart antiviral, antioxidant, anti-inflammatory, and analgesic effects, and is also known to protect intestinal barrier function³. Peng et al. have found that patchouli oil exerts significant antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)^4.

After a comprehensive 2013 review, Chen et al. deemed P. cablin to have potential clinical benefits as an effective adaptogenic herbal treatment³. It is thought to have some antiacne properties as well¹. Further, P. cablin is among the Top 10 most-often-used traditional Chinese medicine prescriptions for skin care and appearance¹.

In Brazil, China, Indonesia, and Malaysia, P. cablin is cultivated for its essential oil, which plays an important role in the perfume industry. Patchouli essential oil, featured in perfumes, soaps, cosmetics, and as incense, is used by aromatherapists for its calming and reviving effects. The essential oil has also been shown to impart antioxidant activity⁵.

In 2014, Lin et al. studied the protective effects of P. cablin essential oil against ultraviolet (UV)-induced skin photoaging in mice. The researchers applied patchouli oil for 2 hours before UV exposure to the dorsal depilated skin of mice. They found that patchouli oil doses of 6 mg/mouse and 9 mg/mouse significantly suppressed skin wrinkle formation, mitigated skin elasticity impairment, and augmented collagen content (21.9% and 26.3%, respectively). The same doses also yielded significant reductions in epidermal thickness and malondialdehyde content, and blocked the disruption of collagen and elastic fibers. Patchouli oil treatment also resulted in the up-regulation of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. The investigators concluded that patchouli oil, perhaps due to its antioxidant characteristics, and sesquiterpene constituents in particular, was effective in preventing photoaging in mice, and warrants attention as a potential agent to hinder photoaging in humans¹.

Feng et al. also investigated the effects of topically applied patchouli alcohol on UV-induced photoaging in mice that year. For 9 weeks, investigators applied patchouli oil solution or a vehicle to the depilated dorsal skin of 6-week-old mice. They found that patchouli oil significantly hastened the recovery of UV-induced skin lesions, which they ascribed to the antioxidant and anti-inflammatory activity of the agent and its down-regulation of the expression of matrix metalloproteinase (MMP)-1 and MMP-3².

Antimicrobial and mosquito repellent activity

In a 2005 study by Trongtokit et al. of the mosquito-repellent activity of 38 essential oils at three concentrations (10%, 50%, or undiluted) against the mosquito Aedes aegypti under laboratory conditions using human volunteers, undiluted P. cablin oil was one of four [along with Cymbopogon nardus (citronella), Syzygium aromaticum (clove), and Zanthoxylum limonella (Thai name: makaen)] undiluted oils to yield an effect, 2 hours of full repellency. The investigators then tested the same concentrations of these oils for repellency against Culex quinquefasciatus (the Southern house mosquito) and Anopheles dirus (the mosquito considered to be a vector of malaria in Asian forested zones. The undiluted oils provided the greatest protection, with clove oil rendering the most durable repellency⁶.

Photoaging

Forest &amp; Kim Starr/Wikimedia Commons/CC BY 3.0

Wu et al. determined the acaricidal activity of compounds extracted from patchouli oil against the house dust mite (Dermatophagoides farinae) in 2012. They isolated 2-(1,3-dihydroxy-but-2-enylidene)-6-methyl-3-oxo-heptanoic acid (DHEMH), the hydrolysate of pogostone, and 15 other constituents in patchouli oil, ultimately ascertaining that DHEMH and patchouli oil itself were the most toxic substances to D. farinae. The investigators concluded that patchouli oil and DHEMH warrant consideration and more study for their acaricidal potential as environmentally friendly, effective, and simple fumigant alternatives to chemical agents⁷.

In 2013, Yang et al. used molecular docking technology to evaluate the antibacterial activity of patchouli oil in vitro. They identified 26 compounds in patchouli oil displaying antibacterial activity, with pogostone and (-)-patchouli alcohol exhibiting the strongest activity⁸. Later that year, Yang et al. used the same technology to establish that Herba pogostemonis oil exhibited potent antibacterial effects, especially the constituents pogostone and (-)-Herba pogostemonis alcohol⁹. Raharjo and Fatchiyah also used molecular docking tools and Chimera 1.7s viewer software in a virtual screening of compounds from patchouli oil, concluding that alpha-patchouli alcohol is a potential inhibitor of the cyclo-oxygenase (COX)-1 enzyme. This is notable given the pivotal role of COX-1 in the inflammatory response¹⁰.

The next year, Peng et al. isolated one of the primary constituents of patchouli oil, pogostone, and assessed its antibacterial activity in vitro and in vivo. They found that pogostone suppressed both gram-negative and gram-positive bacteria in vitro. The researchers noted that pogostone was active against some drug-resistant bacteria (such as MRSA). Via intraperitoneal injection, pogostone displayed antibacterial activity in male and female Kunming mice against Escherichia coli and MRSA. At concentrations of 50 and 100 mg/kg, 90% of the mice infected with E. coli were protected; 60% of the mice at 25 mg/kg were protected. For mice with MRSA, 60% were protected at a dose of 100 mg/kg and 50% at a dose of 50 mg/kg. The investigators concluded that pogostone is a viable antibacterial agent for clinical use⁴.

Transdermal delivery

A 2008 study by Luo et al. showed that patchouli oil was among three volatile oils that improved the skin penetration of the flavonoids baicalin¹¹. It was less effective than several compounds, including clove oil, camphor, menthol, and oleic acid, as a transdermal enhancer in a subsequent study by Zheng et al.¹².

Conclusion

Patchouli oil continues to be used today in traditional Chinese medicine. In the West, the established literature on Pogostemon cablin is thin, but what has emerged recently, particularly studies on the protection against photoaging in mice, supports the continued investigation of this ancient herb to determine its potential role in dermatologic practice. As it is, much more research is necessary.

References

1. J Ethnopharmacol. 2014;154(2):408-18.

2. Eur J Pharm Sci. 2014;63:113-23.

3. Expert Opin Investig Drugs. 2013;22(2):245-57.

4. Chin Med J. (Engl) 2014;127(23):4001-5.

5. J Agric Food Chem. 2007;55(5):1737-42

6. Phytother Res. 2005;19(4):303-9.

7. Chem Pharm Bull (Tokyo). 2012;60(2):178-82.

8. Iran J Pharm Res. 2013 Summer;12(3):307-16.

9. Pak J Pharm Sci. 2013;26(6):1173-9.

10. Bioinformation 2013;9(6):321-4.

11. Zhong Yao Cai. 2008;31(11):1721-4

12. Zhongguo Zhong Yao Za Zhi. 2009;34(20):2599-603.

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 Dermatology 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 Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

The way Dr. Adam Friedman sees it, dermatologists deserve a prominent place at the table when it comes to the treatment of acute and chronic wounds.

“As masters of the integument, we should be central to wound care, whether it be for research, in terms of developing better technologies, medications, approaches, diagnostics, but also in terms of managing these wounds, given the rich breadth of pathophysiology and biology we learn during our residency and maintain during our continuing education as practicing dermatologists,” said Dr. Friedman of the department of dermatology at George Washington University, Washington.

When the Journal of Drugs in Dermatology invited Dr. Friedman to serve as guest editor for a special feature section on wound care for its July 2015 issue, he jumped at the chance “to give the dermatology community a small taste of what’s going on in the wound healing world.”

Currently, he said, there is wide variability in the types of clinicians leading wound care centers in the United States, with dermatologists often sitting on the sidelines. “At one institution, it may be the vascular surgery service, at others it may be the family medicine service or even the emergency medicine department,” said Dr. Friedman, who is an editorial advisor to Dermatology News.

“That’s a big problem, in that there’s no uniformity from one center to the next in terms of who is expected to and should be taking responsibility for the wound healing service at their institutions. The reality is, it should be an interdisciplinary team, which not only involves dermatology but vascular surgery, nutrition, internal medicine, subspecialties of medicine like rheumatology, and rehab medicine. However, what is happening more often than not is that you’re getting just one or two of these elements, which cannot be as effective because you miss out on a broader, holistic view.”

There are two chief reasons why dermatologists aren’t more involved in wound care management, he continued. One stems from a lack of training on the topic. In one of the abstracts from the special JDD wound care section, researchers led by Dr. Emily Stamell Ruiz conducted an online survey of dermatology residents in the United States, to ask them about their preparedness to care for wounds and to assess the amount and type of training devoted to wound care during residency. Of the 175 respondents, 78% and 85% did not feel prepared to manage acute and chronic wounds, respectively, while 77% felt that more education is needed during their residency (J Drugs Dermatol. 2015;14[7]:716-20). “Residents felt that there was a clinical as well as a didactical gap, so they felt that they needed more training both through lectures as well as in clinics,” said Dr. Ruiz of the department of dermatology at Brigham and Women’s Hospital, Boston. “It’s not just a focal problem, it really is a universal curriculum problem. Future reforms to the current dermatology curriculum to include wound care training could help close the gap in wound care training.”

Another reason why dermatologists aren’t more involved in wound care management is the time commitment, said Dr. Friedman, who is also director of translational research at George Washington. The treatment of chronic wounds is “physically and financially burdensome,” he said. “It takes not only yourself being comfortable with managing the whole patient which includes the wound[s] with a side order of comorbidities, but your support staff as well – having nurses who know how to use the different wound dressings and how to help you with debridement. You need the right infrastructure. It also costs a lot on the provider side to manage wounds. You need a setup where you can get these patients in, have support staff to help with the wound dressings once you’ve identified what’s necessary, and be able to move on to the next patient.”

In another manuscript contained in the JDD special section, Dr. Friedman and his associates retrospectively reviewed the characteristics of 51 patients with burn injuries who were seen by seven different dermatologists at the Einstein-Montefiore division of dermatology from April 2010 to July 2014 (J Drugs Dermatol. 2015;14[7]:721-4). It found that the main mechanism of injury was burn from hot metal (22%), followed by contact with hot liquids (18%). It also found that silver sulfadiazine was the most commonly prescribed treatment, “even though there are considerable data illustrating that its use will delay wound closure and healing (J Invest Dermatol. 2015 May;135[5]:1459-62),” Dr. Friedman said. He went on to note that for patients who suffer an acute burn, “the ability to access a dermatologist is somewhat limited because their schedules are heavily booked well in advance, and the format doesn’t allow for these types of emergencies. More often than not they go to the ED or to primary care. That might not necessarily be the right decision because these are physicians who may not have the necessary training in terms of not only proper burn care, but skin care overall.”

Another manuscript in the special section describes a method in which partial thickness wounds were induced by cryosurgery to create wounds that could facilitate wound healing research and development. For the study, researchers led by Dr. Robert Kirsner, interim chairman of the department of dermatology and cutaneous surgery at the University of Miami, used liquid nitrogen spray to induce freeze injuries on the forearms of eight healthy adult volunteers (J. Drugs Dermatol. 2015;14[7]: 734-8). They delivered the spray onto a target area of a 1-cm circular opening at a distance from the cryodevice to the skin of 0.5-1 cm and implemented several freeze-thaw time cycles by administering pulses that ranged from 3-12 seconds.

After a 24-hour follow-up, Dr. Kirsner and his associates observed that freeze times exceeding 5 seconds caused a majority of study participants to develop blisters, while freeze times exceeding 8 seconds caused uniform blister formation. Time to healing among subjects in the 8-second freeze time group was 12-13 days, while time to healing among those in the 12-second time freeze group was 21 days.

“Cryo-induced wound healing is a little bit slower than you’d expect with a scalpel, but that wasn’t really surprising,” Dr. Kirsner said. “The fact that it healed a little bit slower was a pretty good thing because if everything healed too fast then it couldn’t serve as a model to speed or slow epithelialization. We were quite pleased.” He noted that the model “could be used as a safety test for chronic wound treatment and as an efficacy test for acute wound treatment. It’s relatively inexpensive and a relatively simple technique. If you’re developing a product for widespread use, it’s probably a minor cost in the whole development process.”

Other manuscripts in the JDD special section include a preclinical study using a murine multithermal burn model which found that N-acetylcysteine S-nitrosothiol nanoparticles prevent wound expansion and accelerate burn closure, and a practical, systematic approach to using wound dressings for the wound care novice. Dr. Friedman hopes that the special section not only stimulates further interest in wound care, but that it serves as “a call for action. We really need to be more involved in wound care from the acute and chronic perspective,” he said. “Wound centers around the country should be involving dermatologists. We have so much to offer from bench to bedside because the skin is our thing. I hope this is a reminder that we should be part of this picture.”

Dr. Friedman disclosed that he serves as a consultant for Galderma, Biogen, Aveeno, Intraderm, Puracore, La Roche-Posay, Amgen, Pfizer, PHD Skin Care. He also serves as an advisory board member for Nerium International, Valeant, Nano BioMed, MicroCures, and Novartis, and has received research grants from Valeant. Dr. Ruiz and Dr. Kirsner reported no financial disclosures.

dbrunk@frontlinemedcom.com

The way Dr. Adam Friedman sees it, dermatologists deserve a prominent place at the table when it comes to the treatment of acute and chronic wounds.

“As masters of the integument, we should be central to wound care, whether it be for research, in terms of developing better technologies, medications, approaches, diagnostics, but also in terms of managing these wounds, given the rich breadth of pathophysiology and biology we learn during our residency and maintain during our continuing education as practicing dermatologists,” said Dr. Friedman of the department of dermatology at George Washington University, Washington.

When the Journal of Drugs in Dermatology invited Dr. Friedman to serve as guest editor for a special feature section on wound care for its July 2015 issue, he jumped at the chance “to give the dermatology community a small taste of what’s going on in the wound healing world.”

Currently, he said, there is wide variability in the types of clinicians leading wound care centers in the United States, with dermatologists often sitting on the sidelines. “At one institution, it may be the vascular surgery service, at others it may be the family medicine service or even the emergency medicine department,” said Dr. Friedman, who is an editorial advisor to Dermatology News.

“That’s a big problem, in that there’s no uniformity from one center to the next in terms of who is expected to and should be taking responsibility for the wound healing service at their institutions. The reality is, it should be an interdisciplinary team, which not only involves dermatology but vascular surgery, nutrition, internal medicine, subspecialties of medicine like rheumatology, and rehab medicine. However, what is happening more often than not is that you’re getting just one or two of these elements, which cannot be as effective because you miss out on a broader, holistic view.”

There are two chief reasons why dermatologists aren’t more involved in wound care management, he continued. One stems from a lack of training on the topic. In one of the abstracts from the special JDD wound care section, researchers led by Dr. Emily Stamell Ruiz conducted an online survey of dermatology residents in the United States, to ask them about their preparedness to care for wounds and to assess the amount and type of training devoted to wound care during residency. Of the 175 respondents, 78% and 85% did not feel prepared to manage acute and chronic wounds, respectively, while 77% felt that more education is needed during their residency (J Drugs Dermatol. 2015;14[7]:716-20). “Residents felt that there was a clinical as well as a didactical gap, so they felt that they needed more training both through lectures as well as in clinics,” said Dr. Ruiz of the department of dermatology at Brigham and Women’s Hospital, Boston. “It’s not just a focal problem, it really is a universal curriculum problem. Future reforms to the current dermatology curriculum to include wound care training could help close the gap in wound care training.”

Another reason why dermatologists aren’t more involved in wound care management is the time commitment, said Dr. Friedman, who is also director of translational research at George Washington. The treatment of chronic wounds is “physically and financially burdensome,” he said. “It takes not only yourself being comfortable with managing the whole patient which includes the wound[s] with a side order of comorbidities, but your support staff as well – having nurses who know how to use the different wound dressings and how to help you with debridement. You need the right infrastructure. It also costs a lot on the provider side to manage wounds. You need a setup where you can get these patients in, have support staff to help with the wound dressings once you’ve identified what’s necessary, and be able to move on to the next patient.”

In another manuscript contained in the JDD special section, Dr. Friedman and his associates retrospectively reviewed the characteristics of 51 patients with burn injuries who were seen by seven different dermatologists at the Einstein-Montefiore division of dermatology from April 2010 to July 2014 (J Drugs Dermatol. 2015;14[7]:721-4). It found that the main mechanism of injury was burn from hot metal (22%), followed by contact with hot liquids (18%). It also found that silver sulfadiazine was the most commonly prescribed treatment, “even though there are considerable data illustrating that its use will delay wound closure and healing (J Invest Dermatol. 2015 May;135[5]:1459-62),” Dr. Friedman said. He went on to note that for patients who suffer an acute burn, “the ability to access a dermatologist is somewhat limited because their schedules are heavily booked well in advance, and the format doesn’t allow for these types of emergencies. More often than not they go to the ED or to primary care. That might not necessarily be the right decision because these are physicians who may not have the necessary training in terms of not only proper burn care, but skin care overall.”

Another manuscript in the special section describes a method in which partial thickness wounds were induced by cryosurgery to create wounds that could facilitate wound healing research and development. For the study, researchers led by Dr. Robert Kirsner, interim chairman of the department of dermatology and cutaneous surgery at the University of Miami, used liquid nitrogen spray to induce freeze injuries on the forearms of eight healthy adult volunteers (J. Drugs Dermatol. 2015;14[7]: 734-8). They delivered the spray onto a target area of a 1-cm circular opening at a distance from the cryodevice to the skin of 0.5-1 cm and implemented several freeze-thaw time cycles by administering pulses that ranged from 3-12 seconds.

After a 24-hour follow-up, Dr. Kirsner and his associates observed that freeze times exceeding 5 seconds caused a majority of study participants to develop blisters, while freeze times exceeding 8 seconds caused uniform blister formation. Time to healing among subjects in the 8-second freeze time group was 12-13 days, while time to healing among those in the 12-second time freeze group was 21 days.

“Cryo-induced wound healing is a little bit slower than you’d expect with a scalpel, but that wasn’t really surprising,” Dr. Kirsner said. “The fact that it healed a little bit slower was a pretty good thing because if everything healed too fast then it couldn’t serve as a model to speed or slow epithelialization. We were quite pleased.” He noted that the model “could be used as a safety test for chronic wound treatment and as an efficacy test for acute wound treatment. It’s relatively inexpensive and a relatively simple technique. If you’re developing a product for widespread use, it’s probably a minor cost in the whole development process.”

Other manuscripts in the JDD special section include a preclinical study using a murine multithermal burn model which found that N-acetylcysteine S-nitrosothiol nanoparticles prevent wound expansion and accelerate burn closure, and a practical, systematic approach to using wound dressings for the wound care novice. Dr. Friedman hopes that the special section not only stimulates further interest in wound care, but that it serves as “a call for action. We really need to be more involved in wound care from the acute and chronic perspective,” he said. “Wound centers around the country should be involving dermatologists. We have so much to offer from bench to bedside because the skin is our thing. I hope this is a reminder that we should be part of this picture.”

Dr. Friedman disclosed that he serves as a consultant for Galderma, Biogen, Aveeno, Intraderm, Puracore, La Roche-Posay, Amgen, Pfizer, PHD Skin Care. He also serves as an advisory board member for Nerium International, Valeant, Nano BioMed, MicroCures, and Novartis, and has received research grants from Valeant. Dr. Ruiz and Dr. Kirsner reported no financial disclosures.

dbrunk@frontlinemedcom.com

The way Dr. Adam Friedman sees it, dermatologists deserve a prominent place at the table when it comes to the treatment of acute and chronic wounds.

“As masters of the integument, we should be central to wound care, whether it be for research, in terms of developing better technologies, medications, approaches, diagnostics, but also in terms of managing these wounds, given the rich breadth of pathophysiology and biology we learn during our residency and maintain during our continuing education as practicing dermatologists,” said Dr. Friedman of the department of dermatology at George Washington University, Washington.

When the Journal of Drugs in Dermatology invited Dr. Friedman to serve as guest editor for a special feature section on wound care for its July 2015 issue, he jumped at the chance “to give the dermatology community a small taste of what’s going on in the wound healing world.”

Currently, he said, there is wide variability in the types of clinicians leading wound care centers in the United States, with dermatologists often sitting on the sidelines. “At one institution, it may be the vascular surgery service, at others it may be the family medicine service or even the emergency medicine department,” said Dr. Friedman, who is an editorial advisor to Dermatology News.

“That’s a big problem, in that there’s no uniformity from one center to the next in terms of who is expected to and should be taking responsibility for the wound healing service at their institutions. The reality is, it should be an interdisciplinary team, which not only involves dermatology but vascular surgery, nutrition, internal medicine, subspecialties of medicine like rheumatology, and rehab medicine. However, what is happening more often than not is that you’re getting just one or two of these elements, which cannot be as effective because you miss out on a broader, holistic view.”

There are two chief reasons why dermatologists aren’t more involved in wound care management, he continued. One stems from a lack of training on the topic. In one of the abstracts from the special JDD wound care section, researchers led by Dr. Emily Stamell Ruiz conducted an online survey of dermatology residents in the United States, to ask them about their preparedness to care for wounds and to assess the amount and type of training devoted to wound care during residency. Of the 175 respondents, 78% and 85% did not feel prepared to manage acute and chronic wounds, respectively, while 77% felt that more education is needed during their residency (J Drugs Dermatol. 2015;14[7]:716-20). “Residents felt that there was a clinical as well as a didactical gap, so they felt that they needed more training both through lectures as well as in clinics,” said Dr. Ruiz of the department of dermatology at Brigham and Women’s Hospital, Boston. “It’s not just a focal problem, it really is a universal curriculum problem. Future reforms to the current dermatology curriculum to include wound care training could help close the gap in wound care training.”

Another reason why dermatologists aren’t more involved in wound care management is the time commitment, said Dr. Friedman, who is also director of translational research at George Washington. The treatment of chronic wounds is “physically and financially burdensome,” he said. “It takes not only yourself being comfortable with managing the whole patient which includes the wound[s] with a side order of comorbidities, but your support staff as well – having nurses who know how to use the different wound dressings and how to help you with debridement. You need the right infrastructure. It also costs a lot on the provider side to manage wounds. You need a setup where you can get these patients in, have support staff to help with the wound dressings once you’ve identified what’s necessary, and be able to move on to the next patient.”

In another manuscript contained in the JDD special section, Dr. Friedman and his associates retrospectively reviewed the characteristics of 51 patients with burn injuries who were seen by seven different dermatologists at the Einstein-Montefiore division of dermatology from April 2010 to July 2014 (J Drugs Dermatol. 2015;14[7]:721-4). It found that the main mechanism of injury was burn from hot metal (22%), followed by contact with hot liquids (18%). It also found that silver sulfadiazine was the most commonly prescribed treatment, “even though there are considerable data illustrating that its use will delay wound closure and healing (J Invest Dermatol. 2015 May;135[5]:1459-62),” Dr. Friedman said. He went on to note that for patients who suffer an acute burn, “the ability to access a dermatologist is somewhat limited because their schedules are heavily booked well in advance, and the format doesn’t allow for these types of emergencies. More often than not they go to the ED or to primary care. That might not necessarily be the right decision because these are physicians who may not have the necessary training in terms of not only proper burn care, but skin care overall.”

Another manuscript in the special section describes a method in which partial thickness wounds were induced by cryosurgery to create wounds that could facilitate wound healing research and development. For the study, researchers led by Dr. Robert Kirsner, interim chairman of the department of dermatology and cutaneous surgery at the University of Miami, used liquid nitrogen spray to induce freeze injuries on the forearms of eight healthy adult volunteers (J. Drugs Dermatol. 2015;14[7]: 734-8). They delivered the spray onto a target area of a 1-cm circular opening at a distance from the cryodevice to the skin of 0.5-1 cm and implemented several freeze-thaw time cycles by administering pulses that ranged from 3-12 seconds.

After a 24-hour follow-up, Dr. Kirsner and his associates observed that freeze times exceeding 5 seconds caused a majority of study participants to develop blisters, while freeze times exceeding 8 seconds caused uniform blister formation. Time to healing among subjects in the 8-second freeze time group was 12-13 days, while time to healing among those in the 12-second time freeze group was 21 days.

“Cryo-induced wound healing is a little bit slower than you’d expect with a scalpel, but that wasn’t really surprising,” Dr. Kirsner said. “The fact that it healed a little bit slower was a pretty good thing because if everything healed too fast then it couldn’t serve as a model to speed or slow epithelialization. We were quite pleased.” He noted that the model “could be used as a safety test for chronic wound treatment and as an efficacy test for acute wound treatment. It’s relatively inexpensive and a relatively simple technique. If you’re developing a product for widespread use, it’s probably a minor cost in the whole development process.”

Other manuscripts in the JDD special section include a preclinical study using a murine multithermal burn model which found that N-acetylcysteine S-nitrosothiol nanoparticles prevent wound expansion and accelerate burn closure, and a practical, systematic approach to using wound dressings for the wound care novice. Dr. Friedman hopes that the special section not only stimulates further interest in wound care, but that it serves as “a call for action. We really need to be more involved in wound care from the acute and chronic perspective,” he said. “Wound centers around the country should be involving dermatologists. We have so much to offer from bench to bedside because the skin is our thing. I hope this is a reminder that we should be part of this picture.”

Dr. Friedman disclosed that he serves as a consultant for Galderma, Biogen, Aveeno, Intraderm, Puracore, La Roche-Posay, Amgen, Pfizer, PHD Skin Care. He also serves as an advisory board member for Nerium International, Valeant, Nano BioMed, MicroCures, and Novartis, and has received research grants from Valeant. Dr. Ruiz and Dr. Kirsner reported no financial disclosures.

dbrunk@frontlinemedcom.com

To improve patient care and outcomes, leading dermatologists offered their recommendations on the top OTC dandruff treatments. Consideration must be given to:

• Head & Shoulders Shampoo
  Procter & Gamble
  “OTC dandruff products are more for maintenance rather than active treatment, which is why many consumers and patients become frustrated with their use. I recommend to soak [this product] on the scalp skin (not hair) for 5 minutes 2 to 3 times per week.”—Adam Friedman, MD, Washington, DC

• Moroccanoil Treatment
  Moroccanoil
  “I think it’s great to actually put [this product] directly onto the scalp after shampooing to get any remaining scales off.”—Anthony M. Rossi, MD, New York, New York

• Neutrogena T/Gel Therapeutic Hair Care
  Johnson & Johnson Consumer Inc
  Recommended by Gary Goldenberg, MD, New York, New York

• Neutrogena T/Sal Therapeutic Shampoo
  Johnson & Johnson Consumer Inc
  Recommended by Gary Goldenberg, MD, New York, New York

• Nizoral A-D Ketoconazole Shampoo 1%
  McNeil-PPC, Inc
  “I recommend to soak [this product] on the scalp skin (not hair) for 5 minutes 2 to 3 times per week.”—Adam Friedman, MD, Washington, DC

Cutis invites readers to send us their recommendations. Eye creams, men’s shaving products, and products for babies will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to cutis@frontlinemedcom.com.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on the top OTC dandruff treatments. Consideration must be given to:

• Head & Shoulders Shampoo
  Procter & Gamble
  “OTC dandruff products are more for maintenance rather than active treatment, which is why many consumers and patients become frustrated with their use. I recommend to soak [this product] on the scalp skin (not hair) for 5 minutes 2 to 3 times per week.”—Adam Friedman, MD, Washington, DC

• Moroccanoil Treatment
  Moroccanoil
  “I think it’s great to actually put [this product] directly onto the scalp after shampooing to get any remaining scales off.”—Anthony M. Rossi, MD, New York, New York

• Neutrogena T/Gel Therapeutic Hair Care
  Johnson & Johnson Consumer Inc
  Recommended by Gary Goldenberg, MD, New York, New York

• Neutrogena T/Sal Therapeutic Shampoo
  Johnson & Johnson Consumer Inc
  Recommended by Gary Goldenberg, MD, New York, New York

• Nizoral A-D Ketoconazole Shampoo 1%
  McNeil-PPC, Inc
  “I recommend to soak [this product] on the scalp skin (not hair) for 5 minutes 2 to 3 times per week.”—Adam Friedman, MD, Washington, DC

Cutis invites readers to send us their recommendations. Eye creams, men’s shaving products, and products for babies will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to cutis@frontlinemedcom.com.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on the top OTC dandruff treatments. Consideration must be given to:

• Head & Shoulders Shampoo
  Procter & Gamble
  “OTC dandruff products are more for maintenance rather than active treatment, which is why many consumers and patients become frustrated with their use. I recommend to soak [this product] on the scalp skin (not hair) for 5 minutes 2 to 3 times per week.”—Adam Friedman, MD, Washington, DC

• Moroccanoil Treatment
  Moroccanoil
  “I think it’s great to actually put [this product] directly onto the scalp after shampooing to get any remaining scales off.”—Anthony M. Rossi, MD, New York, New York

• Neutrogena T/Gel Therapeutic Hair Care
  Johnson & Johnson Consumer Inc
  Recommended by Gary Goldenberg, MD, New York, New York

• Neutrogena T/Sal Therapeutic Shampoo
  Johnson & Johnson Consumer Inc
  Recommended by Gary Goldenberg, MD, New York, New York

• Nizoral A-D Ketoconazole Shampoo 1%
  McNeil-PPC, Inc
  “I recommend to soak [this product] on the scalp skin (not hair) for 5 minutes 2 to 3 times per week.”—Adam Friedman, MD, Washington, DC

Cutis invites readers to send us their recommendations. Eye creams, men’s shaving products, and products for babies will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to cutis@frontlinemedcom.com.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.