¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Pacific Derm, Vancouver, BC, Canada
³Department of Dermatology, New York University Medical Center, New York, NY, USA

Conflict of interest:
Jason Rivers has been an advisory board member, investigator, speaker, consultant, or received honoraria from Allergan, DermTech, Galderma, Janssen, Leo, MetaOptima, Regeneron, Sanofi, Valeant. Michael Copely has no conflicts to disclose. Ryan Svoboda participated in a fellowship program partly funded by Castle Biosciences and received and participated in an focus group for Castle Biosciences, for which he received an honorarium. Darrell Rigel is a consultant for DermTech.

Abstract
The Pigmented Lesion Assay (PLA) is a gene expression test that helps rule out melanoma and has the potential to reduce the need for surgical biopsies of atypical pigmented skin lesions. Utilizing a new technological platform for the non-invasive profiling of skin, the assay analyzes samples collected from adhesive patches for expression of two key genes (PRAME and LINC00518) known to be overexpressed in melanoma. The test result is binary (positive/negative) based on the detection of one or both genes. PLA positive cases are generally biopsied to establish the histopathologic diagosis, while PLA negative cases are considered for ongoing monitoring. The combination of visual inspection with histopathology, the current gold standard for melanoma diagnosis, has a relatively low negative predictive value (NPV) of approximately 83%, meaning that 17% of melanomas will be interpreted as benign lesions. In contrast, the PLA has a very high NPV (>99%). Further, with its high specificity (69-91%), use of the PLA can reduce the number of false positive samples subjected to histopathology review. By adding the PLA to the current care pathway, the number of surgical biopsies needed to find a melanoma (number needed to biopsy) is markedly reduced from 20-25 biopsies for dermatologists and 39 biopsies for physician assistants, to an average of 2.7. To date, unnecessary surgical procedures of benign lesions have been reduced by 88% based on a sample of more than 20,000 analyzed cases. This has resulted in fewer missed melanomas and significant cost savings to health care systems.

Key Words:
Pigmented Lesion Assay, non-invasive, melanoma, gene expression, test

Introduction and Current Care Pathway

Management of atypical pigmented lesions involves ruling out melanoma via visual and/or dermoscopic assessment followed by surgical biopsy and histopathologic examination (Figure 1A).^1,2 Ideally, when melanomas are identified, they are found at the earliest stages (melanoma in situ [MIS]/Stage 1a) when a high cure rate is possible by wide excision.^3,4 While the purpose of the visual assessment/surgical biopsy paradigm is to rule out melanoma, this approach has relatively poor performance metrics with an estimated 3-10% specificity for visual examination alone.⁵ This, coupled with the low sensitivity of 64-84% for histologic assessment^6,7 and the estimated in-office prevalence of around 5-10%, leads to a low NPV for early stage disease (83%, Figure 1). Thus, during histopathologic assessment, a small number of melanomas are identified from a large pool of biopsied pigmented lesions. Perhaps even more concerning is the risk of false negative histologic diagnoses resulting from a significant overlap in the histopathologic criteria between atypical nevi and early stage melanoma^6-8 Elmore et al. concluded the diagnosis of early stage melanoma was not accurate after finding 187 pathologists misinterpreted 35% of slide interpretations for MIS/Stage 1a melanomas.⁶ Given the prevalence of early stage melanoma in biopsied lesions is approximately 5-10%, the NPV can be approximated as between 75-89%.^5-7,9,10

The number of surgical biopsies needed to identify one melanoma (NNB, number needed to biopsy) averages around 20-25 and ranges from 8 to >30 depending on the clinical setting.^5,9,11-13 Further complicating the issue is that the histopathologic assessment of routinely biopsied lesions, without serial sectioning, is limited. With routine step sectioning of the tissue block providing less than 2% of the material for evaluation, there remains uncertainty as to what is present in the rest of the specimen. With the current diagnostic approach, it is estimated that, in the United States, 3 million pigmented lesion surgical biopsies were performed in the year 2017 alone, yielding <200,000 melanoma diagnoses.^14,15

Pigmented Lesion Assay Overview

The PLA is a gene expression test that helps clinicians rule out melanoma and avoid the need for a surgical biopsy of concerning pigmented lesions (Figure 1B).^16-22 The PLA is based on a new technology for non-invasive skin testing that permits gene expression analysis of skin samples collected with adhesive patches.¹⁹ In order to retrieve enough genetic material, the lesion is sampled consecutively four times, each time with a different patch. For each patch, the clinical margin of the lesion is delineated in pen and then the outlined tissue is dissected from the surrounding sample at the processing lab. Finally, the recovered RNA is extracted and analyzed for two indicator genes. The indicator genes used are PRAME (Preferentially Expressed Antigen in Melanoma) and LINC00518 (Long Intergenic Non- Coding RNA 518), both of which are overexpressed in melanoma. These genes were categorized as the key factors driving test performance in a microarray-based gene expression screen that identified a group of 312 genes differentially expressed in melanoma versus non-melanoma pigmented lesion samples.^16,21 Sampling of the most superficial skin layers contains information from deeper epidermal cells as a result of normal skin physiology in which basal cells migrate to the surface of the skin as they differentiate into squamous cells. During this process, keratinocytes acquire melanosomes from melanocytes through a phagocytic process of the melanocyte dendrite. In addition, some melanocytes migrate to the skin surface by a process known as pagetoid spread. Consequently, epidermal sampling with an adhesive patch yields molecular material from a variety of cells, including melanocytes, keratinocytes, and immune cells.¹⁹ In contrast to histopathologic sectioning, this method of genetic tissue sampling allows for the collection of material from the entire lesion. The PLA is intended for use in patients 18 years of age or older with pigmented lesions measuring 5 mm or larger and suspicious for, but without obvious clinical features of melanoma. It is not intended for use on non-melanocytic lesions (e.g., seborrheic keratoses), non-melanoma skin cancers (e.g., basal cell carcinomas) and bleeding or ulcerated lesions. Further, at present, the PLA cannot be used on palms, soles, nails, or mucous membranes.

Importantly, the PLA is intended to aid clinicians in surgical biopsy decisions but not to be used as a diagnostic test for melanoma. Positive PLA tests should be followed with a surgical biopsy, while patients with a negative test can have the lesion monitored per standard of care.

PLA Versus Current Standard of Care

Table 1 compares the key performance metrics of the PLA against the current standard of care (visual assessment and surgical biopsy/histopathology) for pigmented lesion management. In contrast to the current standard of care, the PLA has a very high NPV (>99%) coupled with a high sensitivity (91-95%), ensuring a very low probability of missing a melanoma.^16,17 The relatively high specificity of the PLA (69-91%) also helps to effectively reduce the number of lesions that would require subsequent histopathology review.¹⁶ Consequently, using the PLA, the number of lesions needed to be biopsied to find one melanoma is reduced from 20-25 to 2.7 (Table 1, Figure 2).^5,9,11-13,17

By utilizing the PLA, unnecessary surgical procedures may be reduced by as much as 88%.¹⁸ The findings of this internal data set is consistent with a recently published review of 18,715 biopsied pigmented lesions where 83% of those lesions were either benign or mildly atypical nevi and did not require additional treatment.¹⁰ Thus, about 90% of surgical biopsies performed on pigmented lesions in the general community may be avoidable.

Conclusion

In the current diagnostic pathway for pigmented lesions, the relatively low specificity of the clinical examination has resulted in a large number of biopsies to ensure the detection of melanoma. The addition of PLA to this diagnostic pathway, can lead to fewer surgical procedures and would provide signficiant benefits to patients such as reduced pain, infections and scarring. In addition, significant benefits accrue to the healthcare system because the PLA can reduce the costs associated with unnecessary surgical procedures.²² Most important, however, is the lower probability of missing a melanoma compared with the current standard of care. The PLA provides a unique and disruptive technology for the assessment of pigmented lesions that may soon transform the current diagnostic pathway to one that is less often invasive, highly reproducible, and a cost savings to the health care system.^16-20

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¹MD/MBA/MPH Candidate at Yale University, New Haven, CT, USA
²Baylor College of Medicine, Houston, TX, USA
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁴Pacific Dermaesthetics, Vancouver, BC, Canada

Conflict of interest:
Jason Rivers has been a consultant for Almirall; Harrison Nguyen has no conflicts to report.

Introduction

Actinic keratosis (AK), a common cutaneous lesion with the potential to transform into squamous cell carcinoma, has traditionally been treated with ablative and/or surgical procedures. Recently, a topical formulation combining 0.5% 5-fluorouracil with 10% salicylic acid (5-FU-SA) was introduced in Europe under the trade name Actikerall™ for the treatment of grade I/II AK. In a single randomized phase III trial, 5-FU-SA was shown to be superior to diclofenac 3% gel in hyaluronic acid, as measured by the histological clearance of one defined lesion (72% vs. 59.1%) and by complete clinical clearance (55.4% vs. 32.0%). 5-FU-SA should be applied once daily to a total area of up to 25 cm2, which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks. The most commonly reported side effects are local inflammation and pruritus at the application site, and no serious adverse effects have been reported to date. Now commercially available in Canada, 5-FU-SA represents a patient-applied therapeutic option for the treatment of both overt and subclinical AK.

Background

• Actinic keratosis (AK) is a lesion considered to be on a continuum with squamous cell carcinoma (SCC).^1-6
• Invasive disease occurs in up to 10% of cases over time, which highlights the need for early recognition and adequate treatment of all AK, including subclinical lesions.⁷
• Although many AK never progress to SCC, their treatment has been recommended to preempt this eventuality.
• Treatment options can generally be stratified based on whether only discrete lesions are treated, or whether subclinical lesions are also targeted, which is referred to as field-directed therapy.
• Lesion-directed therapy has historically consisted of ablative and/or surgical procedures. However, several topical agents have emerged as attractive alternatives in the treatment of AK.
• Examples of topical agents available in Canada include 5-fluorouracil (5-FU), imiquimod (2.5%, 3.75%, and 5% formulations), diclofenac 3%, methylaminolevulinate/aminolevulinic acid (for photodynamic therapy), and ingenol mebutate.⁸
• In one controlled clinical trial, topical 5-FU applied to AK resulted in a 96% clearance after 4 weeks of twice daily application.9 However, high rates of severe localized tissue reactions with 5-FU have led to reduced patient compliance, and this, in part, may explain why the long-term clearance of AK in clinical practice is around 50%.⁸
• This problem has resulted in a search for therapeutic agents less likely to induce skin irritation.¹⁰
• In 2011, a topical formulation combining 0.5% 5-FU with 10% salicylic acid (5-FU-SA) was introduced to the European market under the trade name Actikerall™ for the topical treatment of grade 1/2 AK (slightly palpable and/or moderately thick hyperkeratotic lesions) in immunocompetent adult patients.^11,12 This preparation is not novel as the same agent has been used in Europe for more than 30 years in the treatment of plantar warts (Verrumal®).

In this brief review, we present some of the clinical data to support the use of 5-FU-SA in patient-directed* management of AK and we summarize the salient information that the provider should be aware of when prescribing this product.

*Health Canada has elected to classify Actikerall™ as neither lesion-directed nor field-directed. This was done to support the individual needs of patients; the locational distribution of a patient’s lesions will dictate whether a lesion-directed versus a field-directed approach is preferred.

Evidence from Clinical Trials

• The primary evidence used to support the efficacy of 5-FU-SA in the treatment of AK comes from a single randomized, multi-center, phase 3 trial.¹³ The study included 470 patients with histologically diagnosed AK on the face, forehead, or bald scalp. Subjects were randomly assigned to 5-FU-SA, diclofenac 3% gel in hyaluronic acid (diclofenac HA), or placebo (5-FU-SA vehicle). Treatment was continued until either complete resolution of the lesions was evident, or for a maximum of 12 weeks.
• Subjects were instructed to apply their assigned intervention directly to their lesions – once daily for the 5-FU-SA and vehicle groups and twice daily for the diclofenac group.
• The primary outcome – histological clearance of one defined lesion within 8 weeks of treatment cessation – was achieved in 72.0%, 59.1%, and 44.8% of patients treated with low-dose 5-FU-SA, diclofenac and placebo, respectively.
• In addition to the histological data, the rate of complete clinical clearance was also highest in the study group (55.4% vs. 32.0% and 15.1% for 5-FU-SA, diclofenac HA, and vehicle groups, respectively).¹³ Similar to the temporary lesion increase associated with other topical therapies, an ephemeral increase in mean lesion area was observed only in patients treated with 5-FU-SA at week 2.
• However, by the end of the treatment period, reduction in mean lesion area was more evident in the study medication group compared to the comparator and placebo groups.
• In a more recent non-interventional study, a reduction in number and size of AK after 0.5% 5-FU-SA therapy was observed even after a short period of use: target results were achieved in approximately half of patients within 6 weeks of treatment commencement.¹⁵
• Another study assessed the efficacy of low-dose 5-FU-SA versus cryosurgery in patients with grade II/III hyperkeratotic AK.¹⁶ In this open labelled, randomized trial, patients with histologically confirmed AK received either a 6-week course of once daily topical 5-FU-SA applied directly to lesions or up to two cryosurgical treatments spaced 3 weeks apart.
• 5-FU-SA achieved greater histological clearance as measured by mean lesion area and lower recurrence of lesions compared to cryosurgery at the 6-month follow-up.

Adverse Effects

• In the phase 3 mentioned above¹³, about 95% of patients in the study medication group reported treatment-emergent adverse effects (TEAEs), with local inflammation and pruritus at the application site being the most common.
• Approximately 60% of patients in the vehicle group also reported application site burning, suggesting the etiology of this sensation was likely related to dimethyl sulfoxide, which facilitates tissue absorption and is a known irritant present in the 5-FU-SA excipients.
• For patients who have difficulty tolerating the side effects, dosing can be reduced from daily applications to treatment three times a week.
• In spite of the relatively high rate of TEAEs, patients have reported a high level of satisfaction with the use of low-dose 5-FU-SA.¹⁵
• No serious adverse effects directly related to 5-FU-SA treatment, including usage as Verrumal® for warts, have been reported in either clinical studies or post-marketing surveillance.

Dosing and Administration

• Actikerall™ is a transparent, colorless to slightly orange-white solution that is packaged in 25 mL glass bottles, accompanied by a nylon brush that allows for easy application. It is recommended for application once daily to a total area of up to 25 cm2, which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks (Table 1).

• If the lesions are located in areas with thin epidermis, the solution may be applied less frequently (e.g., 3 times per week).
• The solution should be allowed to dry on the skin but prior to re-application on subsequent days, the existing film should be peeled off, which can be facilitated by using warm water.
• A significant reduction in lesions is usually seen within 6 weeks of starting treatment, and patients most likely to benefit from the full 12-week course are those who have failed previous treatments with other modalities.¹⁵
• Patients should be advised that lesions may continue to regress for up to 8 weeks after cessation of therapy.
• 5-FU-SA is contraindicated for use during lactation or pregnancy. Other contraindications include renal insufficiency and concurrent usage of brivudine, sorivudine, or similar analogues. Of note, although these agents are structurally similar to acyclovir, which does not inhibit dihydropyrimidine dehydrogenase to any significant extent and is therefore safe to administer concurrently with 5-FU-SA.
• Additionally, instances of phenytoin toxicity related to the concurrent use of topical 5-FU-SA have been reported, so these patients should be tested at monthly intervals for plasma levels of phenytoin when this combination of therapies exists.¹¹
• 5-FU-SA should not be applied on bleeding lesions and has not been evaluated for the treatment of recurrent lesions.
• Patients should be educated on FU-SA’s flammability, propensity to desiccate quickly (the bottle needs to be closed tightly after use and it should be discarded if crystallization occurs), and ability to cause permanent stains on textiles and acrylics.

Conclusion

5-FU-SA represents a new addition to our treatment of AK, especially
for individuals who want to avoid the pain or potential consequences
associated with destructive therapy for isolated lesions. An emerging
role for 5-FU-SA may be in combination therapy with other agents
that have been unsuccessful in clearing hyperkeratotic lesions in the
treatment zone.

References

1. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988 Apr 9;1(8589):795-7.
2. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma (“actinic keratosis”). J Am Acad Dermatol. 2000 Jan;42(1 Pt 2):11-7.
3. Ehrig T, Cockerell C, Piacquadio D, et al. Actinic keratoses and the incidence of occult squamous cell carcinoma: a clinical-histopathologic correlation. Dermatol Surg. 2006 Oct;32(10):1261-5.
4. Quaedvlieg PJ, Tirsi E, Thissen MR, et al. Actinic keratosis: how to differentiate the good from the bad ones? Eur J Dermatol. 2006 Jul-Aug;16(4):335-9.
5. Fuchs A, Marmur E. The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma. Dermatol Surg. 2007 Sep;33(9):1099-101.
6. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009 Jun 1;115(11):2523-30.
7. Stockfleth E, Ortonne JP, Alomar A. Actinic Keratosis and field cancerisation. Eur J Dermatol. 2011 Feb; 21(Suppl 1):3-12.
8. Samrao A, Cockerell CJ. Pharmacotherapeutic management of actinic keratosis: focus on newer topical agents. Am J Clin Dermatol. 2013 Aug;14(4):273-7.
9. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007 Dec;157 Suppl 2:34-40.
10. Perl M, Goldenberg G. Field therapy in the treatment of actinic keratosis. Cutis. 2014 Apr;93(4):172-3.
11. The electronic Medicines Compendium (eMC). Actikerall 5mg/g and 100mg/g cutaneous solution. Summary of product characteristics. Almirall Limited, Uxbridge, Middlesex, UK. Last updated June 4, 2014.
12. Olsen EA, Abernethy ML, Kulp-Shorten C, et al. A double-blind, vehicle-controlled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck. J Am Acad Dermatol. 1991 May;24(5 Pt 1):738-43.
13. Stockfleth E, Kerl H, Zwingers T, et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011 Nov;165(5):1101-8.
14. Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a Queensland community. J Invest Dermatol. 2000 Aug;115(2):273-7.
15. Szeimies RM, Dirschka T, Prechtl A, et al. Efficacy of low-dose 5-fluorouracil/salicylic acid in actinic keratoses in relation to treatment duration. J Dtsch Dermatol Ges. 2015 May;13(5):430-8.
16. Simon JC, Dominicus R, Karl L, et al. A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis. J Eur Acad Dermatol Venereol. 2015 May;29(5):881-9.

¹MD/MBA/MPH Candidate at Yale University, New Haven, CT, USA;
²Baylor College of Medicine, Houston, TX, USA
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁴Pacific Dermaesthetics, Vancouver, BC, Canada

Conflict of interest:
Jason Rivers has been a consultant for Almirall; Harrison Nguyen has no conflicts to report.

ABSTRACT
Actinic keratosis (AK), a common cutaneous lesion with the potential to transform into squamous cell carcinoma, has traditionally been treated with ablative and/or surgical procedures. Recently, a topical formulation combining 0.5% 5-fluorouracil with 10% salicylic acid (5-FU-SA) was introduced in Europe under the trade name Actikerall™ for the treatment of grade I/II AKs. In a single randomized phase III trial, 5-FU-SA was shown to be superior to diclofenac 3% gel in hyaluronic acid, as measured by the histological clearance of one defined lesion (72% vs. 59.1%) and by complete clinical clearance (55.4% vs. 32.0%). 5-FU-SA should be applied once daily to a total area of up to 25 cm², which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks. The most common side effects are local inflammation and pruritus at the application site, and no serious adverse effects have been reported to date. Now commercially available in Canada, 5-FU-SA represents a patient applied therapeutic option for the treatment of both overt and subclinical AKs.

Key Words:
Actikerall, actinic keratosis, antineoplastic antimetabolite, drug combinations, immunosuppressive agents, keratolytic agents, salicylic acid, skin neoplasms, topical therapy

Introduction

Actinic keratosis (AK) is a lesion considered to be on a continuum with squamous cell carcinoma (SCC).^1-6 Invasive disease occurs in up to 10% of cases over time, which highlights the need for early recognition and adequate treatment of all AKs, including subclinical lesions.⁷ Although many AKs never progress to SCC, their treatment has been recommended to preempt this eventuality.

Treatment options can generally be stratified based on whether only discrete lesions are treated, or whether subclinical lesions are also targeted, which is referred to as eld-directed therapy. Lesion-directed therapy has historically consisted of ablative and/or surgical procedures. However, several topical agents have emerged as attractive alternatives in the treatment of AKs. Examples of topical agents available in Canada and/or the United States include 5- fluorouracil (5-FU), imiquimod (2.5%, 3.75%, and 5% formulations), diclofenac 3%, methylaminolevulinate/ aminolevulinic acid (for photodynamic therapy), and ingenol mebutate.⁸

In one controlled clinical trial, topical 5-FU applied to AKs resulted in 96% clearance after 4 weeks of twice daily application.⁹ However, high rates of severe localized tissue reactions with 5-FU have led to reduced patient compliance, and this, in part, may explain why the long-term clearance of AKs in clinical practice is around 50%.⁸ This problem has resulted in a search for therapeutic agents less likely to induce skin irritation.¹⁰ In 2011, a topical formulation combining 0.5% 5-FU with 10% salicylic acid (5-FU-SA) was introduced to the European market under the trade name Actikerall™ for the topical treatment of grade I/II AKs (slightly palpable and/or moderately thick hyperkeratotic lesions) in immunocompetent adult patients.^11,12 This preparation is not novel as the same agent has been used in Europe for more than 30 years in the treatment of plantar warts (Verrumal®).

Functionally, 5-FU is a pyrimidine analogue that inhibits nucleic acid synthesis and its efficacy is thought to be enhanced by the addition of salicylic acid, a keratolytic agent that facilitates penetration of 5-FU into AKs.¹³ In this brief review, we present some of the clinical data to support the use of 5-FU-SA in patient-directed* management of AKs and we summarize the salient information that the provider should be aware of when prescribing this product.

^{*Health Canada has elected to classify Actikerall™ as neither lesion-directed nor field-directed. This was done to support the individual needs of patients; the locational distribution of a patient’s lesions will dictate whether a lesion-directed versus a field-directed approach is preferred.}

Evidence from Clinical Trials

The primary evidence used to support the efficacy of 5-FU-SA in the treatment of AKs comes from a single randomized, multi- center, phase III trial.¹⁴ The study included 470 patients with histologically diagnosed AK on the face, forehead, or bald scalp. Subjects were randomly assigned to 5-FU-SA, diclofenac 3% gel in hyaluronic acid (diclofenac HA), or placebo (5-FU-SA vehicle) and treatment was continued until complete resolution of the lesions, or for a maximum of 12 weeks. Subjects were instructed to apply their assigned intervention directly to the lesions – once daily for the 5-FU-SA and vehicle groups, and twice daily for the diclofenac group. The primary outcome – histological clearance of one defined lesion within 8 weeks of treatment cessation – was achieved in 72.0%, 59.1%, and 44.8% of patients treated with low- dose 5-FU-SA, diclofenac and placebo, respectively. Of note, up to 25% of untreated AKs may regress spontaneously over a 1 year period,¹⁵ and therefore, this phenomenon does not fully explain the high rate of clearance noted in the aforementioned study’s placebo group.

In addition to the histological data, the rate of complete clinical clearance was also highest in the study group (55.4% vs. 32.0% and 15.1% for 5-FU-SA, diclofenac HA, and vehicle groups, respectively).¹⁴ Similar to the temporary lesion increase associated with other topical therapies, an ephemeral increase in mean lesion area was observed only in patients treated with 5-FU-SA at week 2. However, by the end of the treatment period, reduction in mean lesion area was more evident in the study medication group compared to the comparator and placebo groups (355.9 mm², 345.7 mm², and 341.4 mm², respectively). In a more recent non- interventional study, the reduction in number and size of AKs after 0.5% 5-FU-SA therapy was observed even after a short period of use: target results were achieved in approximately half of patients within 6 weeks of treatment commencement.¹⁶

Another study assessed the efficacy of low-dose 5-FU-SA versus cryosurgery in patients with grade II/III hyperkeratotic AKs.¹⁷ In this open labelled, randomized trial, patients with histologically con rmed AK received either a 6-week course of once daily topical 5-FU-SA applied directly to lesions or up to two cryosurgical treatments spaced 3 weeks apart. Although the sample size (33 per treatment arm) was not powered to draw statistically significant conclusions, 5-FU-SA achieved greater histological clearance as measured by mean lesion area and lower recurrence of lesions compared to cryosurgery at the 6-month follow-up.

Non-invasive assessment using reflectance confocal microscopy and high-definition optical coherence tomography has provided insight into the in vivo pharmacodynamic changes induced by 5-FU-SA. In one study, AKs were assessed 2 weeks after the last treatment with 5-FU-SA, and the measurement of stratum corneum and epidermis thickness showed significant reduction in both clinical and subclinical lesions.¹⁸ Moreover, histological characteristics of AK – including scaling, detached corneocytes, atypical honeycombing, round nucleated cells in the spinosum granulosum, round vessels, and inflammatory cells were all markedly reduced in lesions treated with 5-FU-SA.¹⁸

Unlike 5-FU alone, there have been no studies to assess 5-FU- SA’s ability to treat superficial basal cell carcinoma or Bowen’s disease.¹⁹

Adverse Effects

In the first trial mentioned above,¹⁴ 7.4% (35/470) of patients withdrew from the study prematurely: 14 patients from the 5-FU-SA group, 16 patients from the diclofenac group, and 5 patients from the vehicle group. About 95% of patients in the study medication group reported treatment-emergent adverse effects (TEAEs), with local inflammation and pruritus at the application site being the most common. Approximately 60% of patients in the vehicle group also reported application site burning, suggesting the etiology of this sensation was likely related to dimethyl sulfoxide, which facilitates tissue absorption and is a known irritant present in the 5-FU-SA excipients. For patients who have difficulty tolerating the side effects, dosing can be reduced from daily application to treatment 3 times a week. In spite of the relatively high rate of TEAEs, patients have reported a high level of satisfaction with the use of low-dose 5-FU-SA.¹⁶ No serious adverse effects directly related to 5-FU-SA treatment, including usage as Verrumal® for warts, have been reported in either clinical studies or post-marketing surveillance.

Dosing and Administration

Actikerall™ is a transparent, colorless to slightly orange-white solution packaged in 25 mL glass bottles, accompanied by a nylon brush that allows for easy application. 5-FU-SA is recommended for application once daily to a total area of up to 25 cm², which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks (Table 1). However, if the patient has lesions in areas with thin epidermis, the solution may be applied less frequently (e.g., 3 times per week). To avoid excess application, the brush can be wiped on the neck of the bottle. The solution should be allowed to dry on the skin but prior to re-application on subsequent days, the existing film should be peeled off, which can be facilitated by using warm water.

As noted, significant reduction in the lesion count is usually
observed within 6 weeks of starting treatment, and patients most
likely to benefit from the full 12-week course are those who have
failed previous therapy with other modalities.¹⁶ Patients should be advised that lesions may continue to regress for up to 8 weeks after cessation of therapy.

The use of 5-FU-SA in areas other than the face and scalp has
only been reported in the setting of small case series. In one
publication,²¹ two patients with multiple AKs on the dorsal aspect of the hands achieved complete clearance after sequential treatment with diclofenac 3% gel and 5-FU-SA. A notable observation has been a lower therapeutic response of AKs located on the upper extremities compared to lesions on the face and scalp.¹⁶ This finding has also been observed with photodynamic therapy, ingenol mebutate and other topical agents used to treat AKs. Although the reason for this observation remains poorly understood, one hypothesis is that increased skin thickness in the upper extremities restricts drug absorption, thus limiting its therapeutic efficacy.²²

5-FU-SA is contraindicated for use during lactation or pregnancy.
Other contraindications include renal insufficiency and
concurrent usage of brivudine, sorivudine, or similar analogues.
The latter consideration is related to the ability of these agents to inhibit the enzyme dihydropyrimidine dehydrogenase, which plays a critical role in breakdown of fluorouracil.²³ Of note, although these agents are structurally similar to acyclovir, the latter drug does not inhibit dihydropyrimidine dehydrogenase to any significant extent and is therefore safe to administer concurrently with 5-FU-SA. Additionally, instances of phenytoin toxicity related to the concurrent use of topical 5-FU-SA have been reported, so these patients should be tested at monthly intervals for plasma levels of phenytoin when this combination of therapies exists.¹¹ 5-FU-SA should not be applied on bleeding lesions and has not been evaluated for the treatment of recurrent lesions. With regards to user experience and safety, the patient should be educated on the solution’s flammability, propensity to desiccate quickly (the bottle needs to be closed tightly after use and it should be discarded if crystallization occurs), and ability to cause permanent stains on textiles and acrylics

Cipher Pharmaceuticals, which owns the rights to Actikerall™ in Canada, has indicated that each bottle will be sold for a
wholesale price of $36.25.²⁴ Commercial availability commenced in February 2016.

Conclusion

5-FU-SA represents a new addition to our treatment of AK,
especially for individuals who want to avoid the pain or potential consequences associated with destructive therapy for isolated lesions. An emerging role for 5-FU-SA may be in combination therapy with other agents that have been unsuccessful in clearing hyperkeratotic lesions in the treatment zone.

References

1. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet. 1988 Apr 9;1(8589):795-7.
2. Cockerell CJ. Histopathology of incipient intraepidermal squamous cell carcinoma (“actinic keratosis”). J Am Acad Dermatol. 2000 Jan;42(1 Pt 2):11-7.
3. Ehrig T, Cockerell C, Piacquadio D, et al. Actinic keratoses and the incidence of occult squamous cell carcinoma: a clinical-histopathologic correlation. Dermatol Surg. 2006 Oct;32(10):1261-5.
4. Quaedvlieg PJ, Tirsi E, Thissen MR, et al. Actinic keratosis: how to differentiate the good from the bad ones? Eur J Dermatol. 2006 Jul-Aug;16(4):335-9.
5. Fuchs A, Marmur E. The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma. Dermatol Surg. 2007 Sep;33(9):1099-101.
6. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009 Jun 1;115(11):2523-30.
7. Stockfleth E, Ortonne JP, Alomar A. Actinic Keratosis and field cancerisation. Eur J Dermatol. 2011 Feb; 21(Suppl 1):3-12.
8. Samrao A, Cockerell CJ. Pharmacotherapeutic management of actinic keratosis: focus on newer topical agents. Am J Clin Dermatol. 2013 Aug;14(4):273-7.
9. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007 Dec;157 Suppl 2: 34-40.
10. Perl M, Goldenberg G. Field therapy in the treatment of actinic keratosis. Cutis. 2014 Apr;93(4):172-3.
11. The electronic Medicines Compendium (eMC). Actikerall 5mg/g and 100mg/g cutaneous solution. Summary of product characteristics. Almirall Limited, Uxbridge, Middlesex, UK. Last updated June 4, 2014. Available at: https://www. medicines.org.uk/emc/medicine/24614. Accessed April 3, 2016.
12. Olsen EA, Abernethy ML, Kulp-Shorten C, et al. A double-blind, vehiclecontrolled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck. J Am Acad Dermatol. 1991 May;24(5 Pt 1): 738-43.
13. Ceilley RI. Mechanisms of action of topical 5-fluorouracil: review and implications for the treatment of dermatological disorders. J Dermatolog Treat. 2012 Apr;23(2):83-9.
14. Stockfleth E, Kerl H, Zwingers T, et al. Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results. Br J Dermatol. 2011 Nov;165(5):1101-8.
15. Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a queensland community. J Invest Dermatol. 2000 Aug;115(2):273-7.
16. Szeimies RM, Dirschka T, Prechtl A, et al. Efficacy of low-dose 5-fluorouracil/salicylic acid in actinic keratoses in relation to treatment duration. J Dtsch Dermatol Ges. 2015 May;13(5):430-8.
17. Simon JC, Dominicus R, Karl L, et al. A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis. J Eur Acad Dermatol Venereol. 2015 May;29(5):881-9.
18. Malvehy J, Alarcon I, Montoya J, et al. Treatment monitoring of 0.5% 5-fluorouracil and 10% salicylic acid in clinical and subclinical actinic keratoses with the combination of optical coherence tomography and reflectance confocal microscopy. J Eur Acad Dermatol Venereol. 2016 Feb;30(2):258-65.
19. Metterle L, Nelson C, Patel N. Intralesional 5-fluorouracil (FU) as a treatment for nonmelanoma skin cancer (NMSC): A review. J Am Acad Dermatol. 2016 Mar;74(3):552-7.
20. Actikerall™: fluorouracil and salicylic acid solution (0.5%/10%) topical antineoplastic agent [Product monograph]; August 7, 2015. Cipher Pharmaceuticals Inc., Mississauga, ON.
21. Dirschka T, Lear JT. Sequential treatment of multiple actinic keratoses with solaraze and actikerall. Case Rep Dermatol. 2014 May;6(2):164-8.
22. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012 Mar 15;366(11):1010-9.
23. De Clercq E. Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster. Biochem Pharmacol. 2004 Dec 15;68(12):2301-15.
24. Markowitz L. Personal communication. January 18, 2016.

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC
Pacific Dermaesthetics, Vancouver, BC

ABSTRACT

As baby boomers get older, they have shown an increasing interest in maintaining a youthful appearance. As a result, there has been a corresponding increase in topical antiaging formulations, which are commonly referred to as cosmeceuticals. These products come with a seemingly limitless number of key active ingredients and claims of reducing the signs of aging and/or maintaining a youthful appearance. This paper reviews the more common cosmeceutical ingredients.

Key Words:
Cosmeceuticals; alpha hydroxy acids; antioxidants; botanicals; exfoliants; depigmenting agents; moisturizers; retinoids; sunscreens

As baby boomers begin to reach retirement age, there has been an increased interest in antiaging preparations, or cosmeceuticals, and their purported ability to enhance a person’s more youthful appearance. Antiaging topicals, with their multiple claims, seemingly limitless key active ingredients, and complex formulations are leading the way in this huge growth industry of cosmeceuticals, especially as this segment of the population opts for less invasive, non-surgical alternatives to slow the effects of aging on the skin. Market trends in the US for cosmeceuticals and antiaging products project sales of more than $16 billion by 2010.¹

The term cosmeceutical was introduced by Albert Kligman in 1984 to refer to substances that exerted both cosmetic and therapeutic benefits.² Many contain biologically active ingredients, and in general, cosmeceuticals undergo tests to determine safety, but claims of efficacy are largely unsubstantiated.³ Efforts have only recently been initiated to address the issues surrounding quality control and to establish industry standards and regulations. Demonstrating the skin effect of a cosmeceutical can be difficult; there are no placebos because anything that is applied to the skin will have an effect.

This term is not applied to the same products universally (e.g., sunscreen is considered to be an over-the-counter drug in North America, but a cosmeceutical in Europe), and the term “cosmeceutical” is not recognized by the US FDA. Categorization and regulation will depend upon how product claims are presented to the public.

Vehicles

One of the most important parts of any cosmeceutical is the vehicle that carries the active ingredient into the skin.4 Vehicle delivery systems can:

• • augment the efficacy of the active ingredient
• • inactivate the active ingredient
• • improve the skin barrier
• • provoke allergic contact dermatitis.4

In some skin conditions, the vehicle may be as good as the active preparation, and it may take 3 months or more to see a difference.

Cosmeceutical Research

There is limited research being done on cosmeceuticals in academic dermatology, and there have been no NIH grants available for cosmeceutical research to date. As a result, the best research comes from industry sponsored studies.

Some Common Types of Cosmeceutical Ingredients

Alpha Hydroxy Acids (AHAs)

Also referred to as fruit acids, they are a common ingredient found in cosmeceutical products. Examples include:

AHAs improve skin texture and reduce the signs of aging by promoting cell shedding in the outer layers of the epidermis and by restoring hydration. The mechanism of action is not completely understood. One hypothesis suggests that AHAs reduce the calcium ion concentration in the epidermis and, through chelation, remove the ions from the cell adhesions, which are thereby disrupted, resulting in desquamation. This is enhanced by cleavage of the endogenous stratum corneum chymotryptic enzyme on the cadherins, which are otherwise protected from proteolysis by conjugation with calcium ions. The resulting reduction of the calcium ion levels tends to promote cell growth and slow cell differentiation, thus giving rise to younger looking skin.⁵

Antioxidants

Antioxidants reduce free-radical damage, thereby preventing impairment at the cellular level. They inhibit inflammation, which leads to collagen depletion, and they offer protection against photodamage and skin cancer.

However, there is no completely satisfactory agent available for humans. Explanations for this could include the fact that:

• Reactive oxygen species (ROS) affect different pathways in different situations and an antioxidant focused on 1 such pathway may be ineffective in a redundant pathway.
• ROS pharmacokinetics in the target tissue may not relate to that of the antioxidant.
• Bioavailability and target organ concentration of the antioxidant may be a limiting issue.⁶

Common antioxidants include alpha-lipoic acid (ALA), L-ascorbic acid (vitamin C), niacinamide (vitamin B3), N-acetyl-glucosamine (NAG), á-tocopherol, and ubiquinone (CoQ10).

Alpha-lipoic Acid (ALA)

Alpha-lipoic acid has anti-inflammatory properties and acts as an exfoliant. In a split face study, topical 5% ALA applied b.i.d. for 12 weeks reduced skin roughness, lentigines and fine wrinkles.⁷ This agent does not protect against UV-induced erythema or reduce the number of sunburn cells.

L-Ascorbic Acid (Vitamin C)

There is clinical data to support the use of topical vitamin C to improve fine lines and reduce both pigmentation and inflammation,⁸ and many cosmeceutical formulations contain this antioxidant. However, many of these formulations are not effective on the skin because:

• the concentration of L-ascorbic acid is too low.
• exposure of the product to air and light compromises the stability of the product.
• the L-ascorbic acid molecule (in the form of an ester or a mixture of isomers) cannot be absorbed or metabolized effectively by the skin.

In high enough concentrations (i.e., at least 10%) of the nonesterified, optimal isomer, this antioxidant does inhibit UV damage.9 It is important to note that stabilizing ascorbic acid presents many formulary challenges; however, a formulation that has an acid pH of approximately 3.⁵ may optimize vitamin C absorption.⁹ Newer formulations of stabilized ascorbic acid derivatives may prove to be more efficacious.

Niacinamide (Vitamin B3)

Niacinamide is a potent antioxidant that is generally well tolerated. It improves the lipid barrier component of the epidermis, thus reducing transepidermal water loss, and acts as an inhibitor of melanosome transfer, resulting in reduced hyperpigmentation. Studies have revealed significant reduction in fine lines and wrinkles, hyperpigmented spots, red blotchiness, and skin sallowness, as well as improved skin elasticity.^10,11

N-Acetyl-Glucosamine (NAG)
NAG is a more stable form of glucosamine, and may prevent new signs of photodamage from occurring, and fade existing imperfections by interrupting the chemical signals that promote melanin production. A placebo-controlled study comparing 3.5% NAG with the combination of 3.5% NAG plus 3.5% niacinamide on hyperpigmented spots showed a superior reduction in pigmentation in the combination treatment group vs. both the placebo and NAG only groups. When combined they produced synergistic effects.¹²

á-Tocopherol (Vitamin E)
When taken orally, á-tocopherol protects membrane lipids from peroxidation. It has been shown to reduce sunburn cells after UV exposure, neutralize free radicals, and act as a humectant.13 Its activity can be renewed by combining it with a vitamin C preparation. As a component in topical formulations, it, like unmodified L-ascorbic acid, has shown some limited efficacy; however, when a stable formulation delivers a high concentration of the nonesterified, optimal isomer of this antioxidant, vitamin E does inhibit the acute UV damage of erythema, sunburn, and tanning, as well as chronic UV photoaging and skin cancer.9 Because vitamin C regenerates oxidized vitamin E, the combination in a cosmeceutical formulation is synergistic – particularly with regard to UV protection.⁹

Ubiquinone (CoQ10)
Ubiquinone is a naturally occurring, fat-soluble antioxidant and there is good in vitro evidence that it can suppress fibroblast production of UVA-induced collagenase, thereby reducing collagen breakdown.14 It has been shown to be effective against UVA mediated oxidative stress in human keratinocytes. Ubiquinone was also able to significantly suppress the expression of collagenase in human dermal fibroblasts following UVA irradiation.15 Another study showed that ubiquinone can strongly inhibit oxidative stress in the skin induced by UVB.¹⁶ It is an effective antioxidant protecting the dermal matrix from both intrinsic and extrinsic aging.¹⁴

Botanicals

Botanicals comprise the largest category of cosmeceutical additives found in the marketplace today. Their use is unregulated and often unsupported by science and their purported therapeutic properties remain largely unexplored.
Some botanicals that may benefit the skin include: green tea extract, ferulic acid, and grape seed extract.

Green Tea Extract
Research has shown that green tea (Cammelia sinensis) polyphenols are potent suppressors of carcinogenic activity from UV radiation and can exert broad protection against other UV-mediated responses, such as sunburn, immunosuppression, and photoaging.¹⁷

Ferulic Acid
This compound, which is derived from plants, is considered to be a potent antioxidant, and has been shown to provide photoprotection to skin.^17,18 Furthermore, when ferulic acid is combined with vitamins C and E, the product has been shown to provide substantial UV protection for human skin.19,20 Moreover, Murray et al. report that because its mechanism of action is different from sunscreens, ferulic acid could be expected to supplement the sun protection provided by sunscreens.²⁰

Grape Seed Extract
This botanical has been established as a potent antioxidant and has been shown to speed wound contraction and closure.21 Topical application of grape seed extract has also been shown to enhance the sun protection factor in humans.²²

Depigmenting Agents

Skin-lightening agents added to product formulations have become increasingly popular. Common depigmenting ingredients include hydroquinone, ascorbic acid (vitamin C), kojic acid, and licorice extract (glabridin).

Hydroquinone
Hydroquinone has been the agent of choice for skin lightening. However, there are concerns over exogenous ochronosis and permanent depigmentation, as well as possible carcinogenicity,²³ and it has been banned as an over-the-counter depigmenting agent in Europe, Australia and Japan.²⁴ The US FDA has proposed concentrations between 1.5% and 2% in skin lighteners.²⁵ A recent report suggested that this concern has been based mainly on studies with animal models utilizing long-term exposure at high dosages. Routine topical application may pose no greater risk than that from levels present in common foods.²⁶

Ascorbic acid (Vitamin C)
Ascorbic acid is a naturally occurring antioxidant found in citrus fruits and leafy green vegetables. It is hydrophilic, so skin penetration is low.

Kojic acid
Kojic acid is a less commonly used bleaching agent. When combined with dipalmitate, there is improved skin penetration and greater stability, but there is little research to support its efficacy.²⁷

Licorice Extract (Glabridin)
Several studies on melasma have shown good efficacy with only mild irritation that disappeared with discontinuation.²⁵

Moisturizers

Moisturizers restore water content to the epidermis, and provide a soothing protective film. They improve the appearance and tactile properties of dry and aging skin, restore the normal barrier function of the skin, and reduce the release of inflammatory cytokines. Moisturizers comprise an important therapeutic component in the management of various skin conditions (e.g., eczema, psoriasis, pruritus, and aged skin)²⁹

Topical Peptides

Topical peptides are regarded as cellular messengers that are formed from amino acids and are designed to mimic peptide fragments with endogenous biologic activity. These pentapeptides (e.g., KTTKS) are comprised of a subfragment of type I collagen propeptide, and play a role in signalling fibroblasts to produce collagen in the skin,³⁰ which can improve the appearance of wrinkles.
One variation, the palmitoyl pentapeptide known as Pal-KKTKS (Matrixyl™, Sederma) was tested in a controlled, double-blind, left-right randomized, split-face study of 93 women between 35 and 55 years of age who had Fitzpatrick I-III type skin. Pal-KTTKS concentration was 3ppm; both groups were treated twice daily for 12 weeks. Improvements in wrinkle appearance and length were observed.³¹

Retinoids

Retinoids are among the most common ingredients found in cosmeceuticals. In fact, they are the most studied and have the most data behind them. They consist of natural and synthetic derivatives of vitamin A that reduce hyperpigmentation and inhibit enzymes from breaking down collagen. Many of their cosmeceutical claims are based on data derived from studies on tretinoin and other classes of retinoid drugs. Some key retinoids include retinoic acid (tretinoin), retinol, retinaldehyde.

Retinoic Acid (Tretinoin)
There is extensive literature on the use of tretinoin, which is considered to be one of the most potent compounds for treating the signs of aging and/or photodamaged skin, including fine lines, hyperpigmented spots, and wrinkles.^32-34 However, side-effects such as burning and scaling have limited its acceptance. In order to minimize these side-effects, various novel drug delivery systems are being developed.³⁴

Retinol (Vitamin A)
Retinol is oxidized into retinaldehyde and then into retinoic acid, the biologically active form of vitamin A. In vivo studies showed that topical retinol had only a modest retinoid-like biologic activity compared with topical retinaldehyde and retinoic acid.³² Two randomized, controlled trials reported significant improvement in fine wrinkles after 12 and 24 weeks of treatment, respectively.^35,36

Retinaldehyde
Retinaldehyde is viewed in a large part as an intermediate form during the conversion of retinol to retinoic acid. Studies have shown that it does have activity in human skin.³³ Moreover, some studies have reported that this retinoid can produce significant clinical improvement in the appearance of fine and deep wrinkles.^32,37

Sunscreens

Sunscreens are the single most important cosmeceutical, because they protect skin against solar radiation, which is the most important damaging environmental agent. As a result, they help to prevent the signs of aging. To be effective, sunscreens should provide broad spectrum coverage that includes both UVA and UVB blocking agents to inhibit photoaging and be part of a daily skin care regimen. Sunscreens contain active ingredients that act as ultraviolet filters. The recommended application is 2mg/cm2, though this is rarely achieved in real-life practice.³⁸ Labeling changes proposed by the US FDA on sunscreen products are forthcoming.³⁹

Formulation Considerations and Conclusions

Although some product claims for the active ingredients used in cosmeceutical formulations are evidence-based, consumers often place their confidence in the claims made by the manufacturer. Without testing to assess the efficacy of key active ingredients in relation to overall product content, it is possible that at inadequate concentrations, any beneficial effect will become inapparent. Ensuring consistency of formulations is also an area that has been neglected and necessitates regulation.

References

1. Market trends: the US cosmeceuticals and antiaging products market. Packaged Facts (2005 Jan 1). At: http://www.packagedfacts.com/prod-toc/Trends-Cosmeceuticals-Anti-1037623/. Last accessed: Sept 24, 2008.
2. Kligman A. The future of cosmeceuticals: an interview with Albert Kligman, MD PhD. Interview by Zoe Diana Draelos. Dermatol Surg 31(7 Pt 2):890-1 (2005 Jul).
3. US FDA. Office of Cosmetics and Colors Fact Sheet, Feb 3, 1995; rev Feb 24, 2000.
4. Klein K. Cosmeceutical formulation considerations. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders pp 19-22 (2005).
5. Wang X. A theory for the mechanism of action of the alpha hydroxy acids applied to the skin. Med Hypotheses 53(5):380-2 (1999 Nov).
6. Bickers DR, Athar M. Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol 126:2565-75 (2006).
7. Beitner H. Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoageing of facial skin. Br J Dermatol 149(4):841-9 (2003 Oct)
8. Gaspar LR, Campos PM. Photostability and efficacy studies of topical formulations containing UV filters combination and vitamins A, C, and E. Int J Pharm 343(1-2):181-9 (2007 Oct).
9. Burke KE. Interaction of vitamins C and E as better cosmeceuticals. Dermatol Ther 20(5):314-21 (2007 Sep-Oct).
10. Bissett DL, Miyamoto K, Sun P, et al. Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin. Int J Cosmet Sci 26(5):231-8 (2004 Oct).
11. Bissett DL, Oblong JE, Berge CA. Niacinamide: A B vitamin that improves aging facial skin appearance. Dermatol Surg 31(7 Pt 2):860-5 (2005 Jul).
12. Katayama K, Armendariz-Borunda J, Raghow R, et al. A pentapeptide from type I procollagen promotes extracellular matrix production. J Biol Chem 268(14):9941-4 (1993 May)
13. Robinson LR, Fitzgerald NC, Doughty DG, et al. Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin. Int J Cosmet Sci 27(3):155-60 (2005 Jun).
14. Bissett D, Kimball AB, Robinson L, et al. Topical formulation containing N-acetyl glucosamine and niacinamide reduces the appearance of hyperpigmented spots on human facial skin. Presented at: the 64th Annual Meeting of the American Academy of Dermatology; San Francisco, CA; March 3-7, 2006. Poster #P235.
15. Choi CM, Berson DS. Cosmeceuticals. Semin Cutan Med Surg 25(3):163-8 (2006 Sep).
16. Burke KE. Nutritional Antioxidants. In: Draelos ZD (ed). Cosmeceuticals. Philadelphia: Elsevier Saunders pp 125-32 (2005).
17. Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors 9(204):371-8 (1999).
18. Kim DW, Hwang IK, Kim DW, et al. Coenzyme Q10 effects on manganese superoxide dismutase and glutathione peroxidase in the hairless mouse skin induced by ultraviolet B irradiation. Biofactors 30(3):139-47 (2007).
19. Bauman L. Botanical ingredients in cosmeceuticals. J Drugs Dermatol 6(11):1084-8 (2007 Nov).
20. Saija A, Tomaino A, Trombetta D, et al. In vitro and in vivo evaluation of caffeic and ferulic acids as topical photoprotective agents. Int J Pharm 199:39-47 (2000 Apr 10).
21. Tournas JA, Lin FH, Burch JA, et al. Ubiquinone, idebenone, and kinetin provide ineffective Photoprotection to the skin when compared to a topical antioxidant combination of vitamins C and E with ferulic acid. J Invest Dermatol 126:1185-7 (2006 May).
22. Murray JC, Burch JA, Streilein RD, et al. A topical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation. J Am Acad Dermatol 59(3):481-25 (2008 Sep).
23. Khanna S, Venojarvi M, Roy S, et al. Dermal wound healing properties of redox-active grape seed proanthocianidins. Free Radic Biol Med 33(8):1089-96 (2002 Oct 15).
24. Bagchi D, Bagchi M, Stohs SJ, et al. Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. Toxicology 148(2-3):187-97 (2000 Aug).
25. Badreshia-Bansal S, Draelos ZD. Insight into skin lightening cosmeceuticals for women of color. J Drugs Dermatol 6(1):32-9 (2007 Jan).
26. Rendon MI, Gaviria JI. Skin lightening agents. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders pp 103-9 (2005).
27. Dermal Safety. In: Gillner M, Moore GS, Cederberg H, et al. Environmental Health Criteria 157. Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. Available at: http://www.inchem.org/documents/ehc/ehc/ehc157.htm#SubSectionNumber:8.2.1. Last accessed September 16, 2008.
28. Levitt J. The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register. J Am Acad Dermatol 57(5):854-72 (2007 Nov).
29. Gupta AK, Gover MD, Nouri K, et al. The treatment of melasma: a review of clinical trials. J Am Acad Dermatol 55(6):1048-65 (2006 Dec)
30. Cosmetic Ingredient Review Expert Panel.Safety assessment of salixylic acid, butyloctyl salicylates, calcium salicylates, C12-15 Alkyl salicylates, capryloyl salicylic acid, hesyldodecyl salicylates, isocetyl salicylates, isodecyl salicylates, magnesium salicylates, MEA salicylates, ethylhexyl salicylates, potassium salicylates, methyl salicylate, sodium salicylates, TEA-salicylate, and tridecyl salicylate. Int J Toxicol 22(Suppl 3):1-108 (2003)
31. Buraczewska I, Berne B, Lindberg M, et al. Changes in skin barrier function following long-term treatment with moisturizers, a randomized controlled trial. Br J Dermatol 156(3):492-8 (2007 Mar).
32. Sorg O, Antille C, Kaya G, et al. Retinoids in cosmeceuticals. Dermatol Ther 19(5):289-96 (2006 Sep-Oct)
33. Oblong JE, Bissett DL. Retinoids. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders pp 36-42 (2005).
34. Mukherjee S, Date A, Patravale V, et al. Retinoides in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging 1(4):327-48 (2006).
35. Piérard-Franchimont C, Castelli D, Van Cromphaut IV, et al. Tensile properties and contours of aging facial skin. A controlled double blind comparative study of the effects of retinol, melibiose-lactose and their association. Skin Res Technol 4:237-43 (1998).
36. Kafi R, Kwak HS, Schumacher WE, et al. Improvement of naturally aged skin with vitamin A (retinol). Arch Dermatol 143(5):606-12 (2007 May).
37. Creidi P, Vienne MP, Onchonisky S, et al. Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol 39(6):960-5 (1998 Dec).
38. Rivers JK. Sunscreens. Skin Ther Lett Pharm Ed 2(1):6-7 (2007 Mar).
39. US FDA. FDA proposes new rule for sunscreen products. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01687.html. Last accessed September 15, 2008

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC
Pacific Dermaesthetics, Vancouver, BC

ABSTRACT

As baby boomers get older, they have shown an increasing interest in maintaining a youthful appearance. As a result, there has been a corresponding increase in topical antiaging formulations, which are commonly referred to as cosmeceuticals. These products come with a seemingly limitless number of key active ingredients and claims of reducing the signs of aging and/or maintaining a youthful appearance. This paper reviews the more common cosmeceutical ingredients.

Key Words:
Cosmeceuticals; alpha hydroxy acids; antioxidants; botanicals; exfoliants; depigmenting agents; moisturizers; retinoids; sunscreens

As baby boomers begin to reach retirement age, there has been an increased interest in antiaging preparations, or cosmeceuticals, and their purported ability to enhance a person’s more youthful appearance. Antiaging topicals, with their multiple claims, seemingly limitless key active ingredients, and complex formulations are leading the way in this huge growth industry of cosmeceuticals, especially as this segment of the population opts for less invasive, non-surgical alternatives to slow the effects of aging on the skin. Market trends in the US for cosmeceuticals and antiaging products project sales of more than $16 billion by 2010.¹

The term cosmeceutical was introduced by Albert Kligman in 1984 to refer to substances that exerted both cosmetic and therapeutic benefits.² Many contain biologically active ingredients, and in general, cosmeceuticals undergo tests to determine safety, but claims of efficacy are largely unsubstantiated.³ Efforts have only recently been initiated to address the issues surrounding quality control and to establish industry standards and regulations. Demonstrating the skin effect of a cosmeceutical can be difficult; there are no placebos because anything that is applied to the skin will have an effect.

This term is not applied to the same products universally (e.g., sunscreen is considered to be an over-the-counter drug in North America, but a cosmeceutical in Europe), and the term “cosmeceutical” is not recognized by the US FDA. Categorization and regulation will depend upon how product claims are presented to the public.

Vehicles

One of the most important parts of any cosmeceutical is the vehicle that carries the active ingredient into the skin.4 Vehicle delivery systems can:

• • augment the efficacy of the active ingredient
• • inactivate the active ingredient
• • improve the skin barrier
• • provoke allergic contact dermatitis.4

In some skin conditions, the vehicle may be as good as the active preparation, and it may take 3 months or more to see a difference.

Cosmeceutical Research

There is limited research being done on cosmeceuticals in academic dermatology, and there have been no NIH grants available for cosmeceutical research to date. As a result, the best research comes from industry sponsored studies.

Some Common Types of Cosmeceutical Ingredients

Alpha Hydroxy Acids (AHAs)

Also referred to as fruit acids, they are a common ingredient found in cosmeceutical products. Examples include:

AHAs improve skin texture and reduce the signs of aging by promoting cell shedding in the outer layers of the epidermis and by restoring hydration. The mechanism of action is not completely understood. One hypothesis suggests that AHAs reduce the calcium ion concentration in the epidermis and, through chelation, remove the ions from the cell adhesions, which are thereby disrupted, resulting in desquamation. This is enhanced by cleavage of the endogenous stratum corneum chymotryptic enzyme on the cadherins, which are otherwise protected from proteolysis by conjugation with calcium ions. The resulting reduction of the calcium ion levels tends to promote cell growth and slow cell differentiation, thus giving rise to younger looking skin.⁵

Antioxidants

Antioxidants reduce free-radical damage, thereby preventing impairment at the cellular level. They inhibit inflammation, which leads to collagen depletion, and they offer protection against photodamage and skin cancer.

However, there is no completely satisfactory agent available for humans. Explanations for this could include the fact that:

• Reactive oxygen species (ROS) affect different pathways in different situations and an antioxidant focused on 1 such pathway may be ineffective in a redundant pathway.
• ROS pharmacokinetics in the target tissue may not relate to that of the antioxidant.
• Bioavailability and target organ concentration of the antioxidant may be a limiting issue.⁶

Common antioxidants include alpha-lipoic acid (ALA), L-ascorbic acid (vitamin C), niacinamide (vitamin B3), N-acetyl-glucosamine (NAG), á-tocopherol, and ubiquinone (CoQ10).

Alpha-lipoic Acid (ALA)

Alpha-lipoic acid has anti-inflammatory properties and acts as an exfoliant. In a split face study, topical 5% ALA applied b.i.d. for 12 weeks reduced skin roughness, lentigines and fine wrinkles.⁷ This agent does not protect against UV-induced erythema or reduce the number of sunburn cells.

L-Ascorbic Acid (Vitamin C)

There is clinical data to support the use of topical vitamin C to improve fine lines and reduce both pigmentation and inflammation,⁸ and many cosmeceutical formulations contain this antioxidant. However, many of these formulations are not effective on the skin because:

• the concentration of L-ascorbic acid is too low.
• exposure of the product to air and light compromises the stability of the product.
• the L-ascorbic acid molecule (in the form of an ester or a mixture of isomers) cannot be absorbed or metabolized effectively by the skin.

In high enough concentrations (i.e., at least 10%) of the nonesterified, optimal isomer, this antioxidant does inhibit UV damage.9 It is important to note that stabilizing ascorbic acid presents many formulary challenges; however, a formulation that has an acid pH of approximately 3.⁵ may optimize vitamin C absorption.⁹ Newer formulations of stabilized ascorbic acid derivatives may prove to be more efficacious.

Niacinamide (Vitamin B3)

Niacinamide is a potent antioxidant that is generally well tolerated. It improves the lipid barrier component of the epidermis, thus reducing transepidermal water loss, and acts as an inhibitor of melanosome transfer, resulting in reduced hyperpigmentation. Studies have revealed significant reduction in fine lines and wrinkles, hyperpigmented spots, red blotchiness, and skin sallowness, as well as improved skin elasticity.^10,11

N-Acetyl-Glucosamine (NAG)
NAG is a more stable form of glucosamine, and may prevent new signs of photodamage from occurring, and fade existing imperfections by interrupting the chemical signals that promote melanin production. A placebo-controlled study comparing 3.5% NAG with the combination of 3.5% NAG plus 3.5% niacinamide on hyperpigmented spots showed a superior reduction in pigmentation in the combination treatment group vs. both the placebo and NAG only groups. When combined they produced synergistic effects.¹²

á-Tocopherol (Vitamin E)
When taken orally, á-tocopherol protects membrane lipids from peroxidation. It has been shown to reduce sunburn cells after UV exposure, neutralize free radicals, and act as a humectant.13 Its activity can be renewed by combining it with a vitamin C preparation. As a component in topical formulations, it, like unmodified L-ascorbic acid, has shown some limited efficacy; however, when a stable formulation delivers a high concentration of the nonesterified, optimal isomer of this antioxidant, vitamin E does inhibit the acute UV damage of erythema, sunburn, and tanning, as well as chronic UV photoaging and skin cancer.9 Because vitamin C regenerates oxidized vitamin E, the combination in a cosmeceutical formulation is synergistic – particularly with regard to UV protection.⁹

Ubiquinone (CoQ10)
Ubiquinone is a naturally occurring, fat-soluble antioxidant and there is good in vitro evidence that it can suppress fibroblast production of UVA-induced collagenase, thereby reducing collagen breakdown.14 It has been shown to be effective against UVA mediated oxidative stress in human keratinocytes. Ubiquinone was also able to significantly suppress the expression of collagenase in human dermal fibroblasts following UVA irradiation.15 Another study showed that ubiquinone can strongly inhibit oxidative stress in the skin induced by UVB.¹⁶ It is an effective antioxidant protecting the dermal matrix from both intrinsic and extrinsic aging.¹⁴

Botanicals

Botanicals comprise the largest category of cosmeceutical additives found in the marketplace today. Their use is unregulated and often unsupported by science and their purported therapeutic properties remain largely unexplored.
Some botanicals that may benefit the skin include: green tea extract, ferulic acid, and grape seed extract.

Green Tea Extract
Research has shown that green tea (Cammelia sinensis) polyphenols are potent suppressors of carcinogenic activity from UV radiation and can exert broad protection against other UV-mediated responses, such as sunburn, immunosuppression, and photoaging.¹⁷

Ferulic Acid
This compound, which is derived from plants, is considered to be a potent antioxidant, and has been shown to provide photoprotection to skin.^17,18 Furthermore, when ferulic acid is combined with vitamins C and E, the product has been shown to provide substantial UV protection for human skin.19,20 Moreover, Murray et al. report that because its mechanism of action is different from sunscreens, ferulic acid could be expected to supplement the sun protection provided by sunscreens.²⁰

Grape Seed Extract
This botanical has been established as a potent antioxidant and has been shown to speed wound contraction and closure.21 Topical application of grape seed extract has also been shown to enhance the sun protection factor in humans.²²

Depigmenting Agents

Skin-lightening agents added to product formulations have become increasingly popular. Common depigmenting ingredients include hydroquinone, ascorbic acid (vitamin C), kojic acid, and licorice extract (glabridin).

Hydroquinone
Hydroquinone has been the agent of choice for skin lightening. However, there are concerns over exogenous ochronosis and permanent depigmentation, as well as possible carcinogenicity,²³ and it has been banned as an over-the-counter depigmenting agent in Europe, Australia and Japan.²⁴ The US FDA has proposed concentrations between 1.5% and 2% in skin lighteners.²⁵ A recent report suggested that this concern has been based mainly on studies with animal models utilizing long-term exposure at high dosages. Routine topical application may pose no greater risk than that from levels present in common foods.²⁶

Ascorbic acid (Vitamin C)
Ascorbic acid is a naturally occurring antioxidant found in citrus fruits and leafy green vegetables. It is hydrophilic, so skin penetration is low.

Kojic acid
Kojic acid is a less commonly used bleaching agent. When combined with dipalmitate, there is improved skin penetration and greater stability, but there is little research to support its efficacy.²⁷

Licorice Extract (Glabridin)
Several studies on melasma have shown good efficacy with only mild irritation that disappeared with discontinuation.²⁵

Moisturizers

Moisturizers restore water content to the epidermis, and provide a soothing protective film. They improve the appearance and tactile properties of dry and aging skin, restore the normal barrier function of the skin, and reduce the release of inflammatory cytokines. Moisturizers comprise an important therapeutic component in the management of various skin conditions (e.g., eczema, psoriasis, pruritus, and aged skin)²⁹

Topical Peptides

Topical peptides are regarded as cellular messengers that are formed from amino acids and are designed to mimic peptide fragments with endogenous biologic activity. These pentapeptides (e.g., KTTKS) are comprised of a subfragment of type I collagen propeptide, and play a role in signalling fibroblasts to produce collagen in the skin,³⁰ which can improve the appearance of wrinkles.
One variation, the palmitoyl pentapeptide known as Pal-KKTKS (Matrixyl™, Sederma) was tested in a controlled, double-blind, left-right randomized, split-face study of 93 women between 35 and 55 years of age who had Fitzpatrick I-III type skin. Pal-KTTKS concentration was 3ppm; both groups were treated twice daily for 12 weeks. Improvements in wrinkle appearance and length were observed.³¹

Retinoids

Retinoids are among the most common ingredients found in cosmeceuticals. In fact, they are the most studied and have the most data behind them. They consist of natural and synthetic derivatives of vitamin A that reduce hyperpigmentation and inhibit enzymes from breaking down collagen. Many of their cosmeceutical claims are based on data derived from studies on tretinoin and other classes of retinoid drugs. Some key retinoids include retinoic acid (tretinoin), retinol, retinaldehyde.

Retinoic Acid (Tretinoin)
There is extensive literature on the use of tretinoin, which is considered to be one of the most potent compounds for treating the signs of aging and/or photodamaged skin, including fine lines, hyperpigmented spots, and wrinkles.^32-34 However, side-effects such as burning and scaling have limited its acceptance. In order to minimize these side-effects, various novel drug delivery systems are being developed.³⁴

Retinol (Vitamin A)
Retinol is oxidized into retinaldehyde and then into retinoic acid, the biologically active form of vitamin A. In vivo studies showed that topical retinol had only a modest retinoid-like biologic activity compared with topical retinaldehyde and retinoic acid.³² Two randomized, controlled trials reported significant improvement in fine wrinkles after 12 and 24 weeks of treatment, respectively.^35,36

Retinaldehyde
Retinaldehyde is viewed in a large part as an intermediate form during the conversion of retinol to retinoic acid. Studies have shown that it does have activity in human skin.³³ Moreover, some studies have reported that this retinoid can produce significant clinical improvement in the appearance of fine and deep wrinkles.^32,37

Sunscreens

Sunscreens are the single most important cosmeceutical, because they protect skin against solar radiation, which is the most important damaging environmental agent. As a result, they help to prevent the signs of aging. To be effective, sunscreens should provide broad spectrum coverage that includes both UVA and UVB blocking agents to inhibit photoaging and be part of a daily skin care regimen. Sunscreens contain active ingredients that act as ultraviolet filters. The recommended application is 2mg/cm2, though this is rarely achieved in real-life practice.³⁸ Labeling changes proposed by the US FDA on sunscreen products are forthcoming.³⁹

Formulation Considerations and Conclusions

Although some product claims for the active ingredients used in cosmeceutical formulations are evidence-based, consumers often place their confidence in the claims made by the manufacturer. Without testing to assess the efficacy of key active ingredients in relation to overall product content, it is possible that at inadequate concentrations, any beneficial effect will become inapparent. Ensuring consistency of formulations is also an area that has been neglected and necessitates regulation.

References

1. Market trends: the US cosmeceuticals and antiaging products market. Packaged Facts (2005 Jan 1). At: http://www.packagedfacts.com/prod-toc/Trends-Cosmeceuticals-Anti-1037623/. Last accessed: Sept 24, 2008.
2. Kligman A. The future of cosmeceuticals: an interview with Albert Kligman, MD PhD. Interview by Zoe Diana Draelos. Dermatol Surg 31(7 Pt 2):890-1 (2005 Jul).
3. US FDA. Office of Cosmetics and Colors Fact Sheet, Feb 3, 1995; rev Feb 24, 2000.
4. Klein K. Cosmeceutical formulation considerations. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders pp 19-22 (2005).
5. Wang X. A theory for the mechanism of action of the alpha hydroxy acids applied to the skin. Med Hypotheses 53(5):380-2 (1999 Nov).
6. Bickers DR, Athar M. Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol 126:2565-75 (2006).
7. Beitner H. Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoageing of facial skin. Br J Dermatol 149(4):841-9 (2003 Oct)
8. Gaspar LR, Campos PM. Photostability and efficacy studies of topical formulations containing UV filters combination and vitamins A, C, and E. Int J Pharm 343(1-2):181-9 (2007 Oct).
9. Burke KE. Interaction of vitamins C and E as better cosmeceuticals. Dermatol Ther 20(5):314-21 (2007 Sep-Oct).
10. Bissett DL, Miyamoto K, Sun P, et al. Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin. Int J Cosmet Sci 26(5):231-8 (2004 Oct).
11. Bissett DL, Oblong JE, Berge CA. Niacinamide: A B vitamin that improves aging facial skin appearance. Dermatol Surg 31(7 Pt 2):860-5 (2005 Jul).
12. Katayama K, Armendariz-Borunda J, Raghow R, et al. A pentapeptide from type I procollagen promotes extracellular matrix production. J Biol Chem 268(14):9941-4 (1993 May)
13. Robinson LR, Fitzgerald NC, Doughty DG, et al. Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin. Int J Cosmet Sci 27(3):155-60 (2005 Jun).
14. Bissett D, Kimball AB, Robinson L, et al. Topical formulation containing N-acetyl glucosamine and niacinamide reduces the appearance of hyperpigmented spots on human facial skin. Presented at: the 64th Annual Meeting of the American Academy of Dermatology; San Francisco, CA; March 3-7, 2006. Poster #P235.
15. Choi CM, Berson DS. Cosmeceuticals. Semin Cutan Med Surg 25(3):163-8 (2006 Sep).
16. Burke KE. Nutritional Antioxidants. In: Draelos ZD (ed). Cosmeceuticals. Philadelphia: Elsevier Saunders pp 125-32 (2005).
17. Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors 9(204):371-8 (1999).
18. Kim DW, Hwang IK, Kim DW, et al. Coenzyme Q10 effects on manganese superoxide dismutase and glutathione peroxidase in the hairless mouse skin induced by ultraviolet B irradiation. Biofactors 30(3):139-47 (2007).
19. Bauman L. Botanical ingredients in cosmeceuticals. J Drugs Dermatol 6(11):1084-8 (2007 Nov).
20. Saija A, Tomaino A, Trombetta D, et al. In vitro and in vivo evaluation of caffeic and ferulic acids as topical photoprotective agents. Int J Pharm 199:39-47 (2000 Apr 10).
21. Tournas JA, Lin FH, Burch JA, et al. Ubiquinone, idebenone, and kinetin provide ineffective Photoprotection to the skin when compared to a topical antioxidant combination of vitamins C and E with ferulic acid. J Invest Dermatol 126:1185-7 (2006 May).
22. Murray JC, Burch JA, Streilein RD, et al. A topical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation. J Am Acad Dermatol 59(3):481-25 (2008 Sep).
23. Khanna S, Venojarvi M, Roy S, et al. Dermal wound healing properties of redox-active grape seed proanthocianidins. Free Radic Biol Med 33(8):1089-96 (2002 Oct 15).
24. Bagchi D, Bagchi M, Stohs SJ, et al. Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. Toxicology 148(2-3):187-97 (2000 Aug).
25. Badreshia-Bansal S, Draelos ZD. Insight into skin lightening cosmeceuticals for women of color. J Drugs Dermatol 6(1):32-9 (2007 Jan).
26. Rendon MI, Gaviria JI. Skin lightening agents. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders pp 103-9 (2005).
27. Dermal Safety. In: Gillner M, Moore GS, Cederberg H, et al. Environmental Health Criteria 157. Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. Available at: http://www.inchem.org/documents/ehc/ehc/ehc157.htm#SubSectionNumber:8.2.1. Last accessed September 16, 2008.
28. Levitt J. The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register. J Am Acad Dermatol 57(5):854-72 (2007 Nov).
29. Gupta AK, Gover MD, Nouri K, et al. The treatment of melasma: a review of clinical trials. J Am Acad Dermatol 55(6):1048-65 (2006 Dec)
30. Cosmetic Ingredient Review Expert Panel.Safety assessment of salixylic acid, butyloctyl salicylates, calcium salicylates, C12-15 Alkyl salicylates, capryloyl salicylic acid, hesyldodecyl salicylates, isocetyl salicylates, isodecyl salicylates, magnesium salicylates, MEA salicylates, ethylhexyl salicylates, potassium salicylates, methyl salicylate, sodium salicylates, TEA-salicylate, and tridecyl salicylate. Int J Toxicol 22(Suppl 3):1-108 (2003)
31. Buraczewska I, Berne B, Lindberg M, et al. Changes in skin barrier function following long-term treatment with moisturizers, a randomized controlled trial. Br J Dermatol 156(3):492-8 (2007 Mar).
32. Sorg O, Antille C, Kaya G, et al. Retinoids in cosmeceuticals. Dermatol Ther 19(5):289-96 (2006 Sep-Oct)
33. Oblong JE, Bissett DL. Retinoids. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders pp 36-42 (2005).
34. Mukherjee S, Date A, Patravale V, et al. Retinoides in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging 1(4):327-48 (2006).
35. Piérard-Franchimont C, Castelli D, Van Cromphaut IV, et al. Tensile properties and contours of aging facial skin. A controlled double blind comparative study of the effects of retinol, melibiose-lactose and their association. Skin Res Technol 4:237-43 (1998).
36. Kafi R, Kwak HS, Schumacher WE, et al. Improvement of naturally aged skin with vitamin A (retinol). Arch Dermatol 143(5):606-12 (2007 May).
37. Creidi P, Vienne MP, Onchonisky S, et al. Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol 39(6):960-5 (1998 Dec).
38. Rivers JK. Sunscreens. Skin Ther Lett Pharm Ed 2(1):6-7 (2007 Mar).
39. US FDA. FDA proposes new rule for sunscreen products. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01687.html. Last accessed September 15, 2008

Department of Dermatology and Skin Science, University of British Columbia,
Vancouver, BC, Canada

Background

Each part of the body requires specific care, and without exception, hair has its
own unique needs that demand special attention. The most noticeable and densest
hair on the human body is on the head, where, on average, there are approximately
100,000 hairs that typically grow at a rate of 12mm/month. The self-perceived
state of an individual’s hair, especially in women, can contribute to heightened
social distress, self-consciousness, and lower self-esteem. Consequently, for many
people, the management of head hair can cause ongoing frustration and the drive
to achieve the perfect head of hair often becomes an elusive pursuit; for some this
can evolve into a disruptive preoccupation. A simple common sense approach is
recommended for promoting and maintaining healthy hair. Apart from getting
a cut or re-style, basic modifications in hair care can be easily implemented to
achieve desirable effects.

Hair Structure

Hair is mostly made up of keratin, which is also found in the skin and nails. Each
strand of hair is comprised of three distinct layers:

• Cuticle – the outermost protective layer of the hair shaft.
• Cortex – mainly composed of keratin, this layer gives the hair its strength, color, shape, elasticity, and texture.
• Medulla – the innermost or core layer is usually only present in coarse hair, and absent in fine strands.

Ethnic Hair

Although there are no biochemical differences in the hair of people from different
backgrounds, there are structural variations. For example:

• Asians tend to have straight hair with the largest mean cross-sectional areas and hair follicles that are round.
• Caucasians have intermediate mean cross-sectional areas and oval shaped hair follicles.
• People of African descent have hair that is spiraled with the smallest crosssectional areas and follicles that are elliptical.
  Hair tends to be kinky and usually does not need to be shampooed as often as straight hair.
  • The removal of natural oils can leave the hair dull and difficult to style.
  • In general, their hair is more fragile; its spiral structure makes it more difficult for the sebum to easily coat the hair shaft, producing drier and less manageable hair.

Hair Growth Cycle

Hair follicles grow in repetitive cycles, which include three phases:

• Anagen – growth phase, which typically continues for 150 weeks on the scalp.
• Catagen – transitional phase, during which time, the bulbar portion of the follicle is almost completely degraded through apoptosis. Catagen lasts for 1 week.
• Telogen – resting phase, lasts for 12 weeks on the scalp. Approximately 50-100 telogen hairs are shed daily, mostly because of normal washing and combing.

Shampooing

• Shampooing regularly is the first step in maintaining healthy hair and scalp.
• Sebum lubricates and protects hair, but particles of dirt become embedded in the oil.
  • Shampooing too frequently can cause extensive sebum removal, which results in dull looking, static-prone hair that is difficult to comb.
• Shampoos consist primarily of:
  • surfactants
    • contain both hydrophobic ingredients, those attracted to oil, and hydrophilic ingredients, those attracted to water.
    • allow shampoo to bind to and emulsify dirt, sebum and styling products in the hair, and then remove them when rinsing.
  • silicones
    • responsible for lubricating the hair, allowing for easier brushing and a smoother look and feel to the hair when dried.
• • cationic polymers
    • provide unique wet-conditioning and delivery benefits.
    • allow many consumers to forego a separate conditioner if their hair is already in good condition.
• • contains preservatives, perfumes, and sometimes dyes and anti-dandruff ingredients.
• Added ingredients such as vitamins B and E, jojoba and aloe vera claim to strengthen hair, but there is no scientific validation.
• An endless array of formulations are available, and selecting an appropriate product can be confusing. A good place to start is to determine suitability by hair type, e.g., normal or dry.
• Other types of shampoo include:
  • products designed for chemically treated or damaged air.
  • mild infant formulations that do not irritate the eyes and exclude perfumes
  • those with added medical ingredients
  • conditioning shampoos that contain hydrolyzed proteins designed to penetrate the hair shaft
  • professional-grade cationic acidic shampoos that neutralize the residual alkalinity of chemical treatments.

Hair Condtioners

• Conditioners efficiently restore moisture that has been removed through washing.
• They contain many of the same ingredients that are found in shampoos, but in different concentrations.
• They effectively flatten the cuticle on the hair shaft and detangle the hair, which:
  • makes brushing easier.
  • creates smoother texture.
  • improves overall manageability.
  • reduces static electricity by
    • adding positively-charged ions on the hair shafts.
    • neutralizing the negative electric charges on the shaft that are generated following brushing.
• They are particularly useful for dry or damaged hair.
• Overuse of conditioners can result in a flattened, limp or oily appearance.
• Apply only to the hair and not the scalp.
• The cationic polymers found in conditioners are attracted to the damaged cuticle in the hair shaft, which results in the protection and repair of these areas by filling in the defects.

Damage to the hair shaft can be caused by:

• overdrying
• vigorous towel-drying
• washing long hair too frequently (e.g., more than once per day)
• excessive combing and brushing
• chemical treatments (e.g., permanent waving, bleaching, dyeing, straightening)
• over-exposure to sun and chlorine.

Anyone using heat generating devices or chemicalbased products for hair curling or straightening should be encouraged to carry out a regular conditioning regimen.
Applications that provide lubrication can somewhat reduce the damage and brittle texture that is associated with some of the chemicals that are used.

Drying Hair

Hair frequently sustains damage from the intense heat generated by hairdryers in combination with the pulling and tugging of styling.

• Air-dry or gently towel-dry whenever possible.
• Set hairdryer at a lower temperature.
• Chemically-damaged hair is more susceptible to further damage to the hair shaft.

Brushing

• Wet hair can be more easily damaged.
• Use a wide-tooth comb to gently untangle damp hair.
• When dry, particularly if the hair is fine or brittle, use of a natural bristle brush or comb will assist in spreading the oil (sebum) along the hair shaft.
• Makes the hair easier to style.
• Gives it a glossy appearance.

Treating Dandruff

• Dandruff is influenced by the presence of 3 factors: sebum, Malassezia yeasts, and one’s individual susceptibility to irritation caused by the yeasts metabolic byproducts (free fatty acids).
• Primary ingredients in anti-dandruff shampoos include:
  • Pyrithione zinc, ketoconazole, selenium sulfide, and cyclopyroxolamine
    • believed to address the fungal cause of dandruff
  • Salicylic acid and coal tar
    • treat the symptoms of flakes and skin hyperproliferation.
  • Pyrithione zinc-containing anti-dandruff formulations are safe for daily use.
  • Patient compliance is improved with the use of a cosmetically appealing and effective product.
• Use of a shampoo and conditioner containing the same active ingredient can improve efficacy.
  • In Canada, an anti-dandruff conditioner will become available in early 2008.
  • Using a regular conditioner can reduce the dandruff shampoo’s efficacy.
  • For conditioners containing anti-dandruff active ingredients, massage product into the scalp, then distribute evenly from hair root to tip.
• Avoid scratching the scalp, as this will loosen more flakes and cause further irritation.

Other Factors Influencing the Condition of Hair

• Excessive or incorrect use of chemical hair treatment processes such as dyeing, straightening, bleaching or perming can result in damage, accelerated hair loss and allergic reactions, more specifically, contact dermatitis.
• Exposure to the sun, chlorine in swimming pools, and seawater can inflict additional damage to hair and alter its color. Wearing a hat or applying special sunscreens formulated for the hair can provide some protection.
• Longer hair is particularly susceptible to additional damage due to the cumulative effects of various treatments and environmental elements.
• Drastic dietary changes can cause hair loss and retard growth through protein depletion.
• Tension on the hair shaft from styling can cause frontal shedding; heavy/tight ponytails can promote hair loss.
• During pregnancy, hair is particularly full and vibrant in appearance; however, postpartum hair loss (telogen effluvium) is commonly experienced by women for several months before returning to normal.
• Avoid shampooing prior to applying chemical hair treatments, as this will prevent removal of the natural oils or sebum, which will, to some degree, reduce the harsh effects of the agents used.
• Backcombing or teasing the hair by combing in the reverse direction can create damage to the hair shaft cuticle.

Allergic Contact Dermatitis

Symptoms of cosmetic, allergic, and contact dermatitis include swelling and inflammation on the scalp, face, neck, ears, and
hands. Some common examples of chemical allergens in hair products include:

• permanent hair waving agents such as glycerol monothioglycolate
• many additives in shampoos can be irritating to those with eczema
• metallic salts in permanent dyes; semipermanent and temporary variations tend to be less irritating to the scalp and cause less damage to the hair
• paraphenylenediamine, an ingredient in most hair dyes, commonly causes allergic contact dermatitis; owing to the high frequency of these reactions, manufacturers of at-home hair-coloring products encourage patch testing before use.

Conclusion

Implementing basic proper hair care is essential to maintaining healthy hair. Furthermore, minimizing exposure to chemical
agents, inadvisable grooming techniques, and prolonged exposure to environmental elements, will promote healthier hair
and avoid unnecessary hair loss.

Actinic keratoses (AKs) are premalignant inflammatory skin lesions with the potential to transform into squamous cell carcinoma (SCC). There are several treatment options available for patients presenting with multiple AKs. Imiquimod is believed to stimulate and enhance host immune responses locally against skin tumors and viral infections. Five clinical studies to date have demonstrated its safety and efficacy in the treatment of actinic keratoses. Long-term follow-up studies examining recurrence rates are limited.

Key Words:
actinic keratosis, squamous cell carcinoma, immune response modifier

Imiquimod (Aldara™, 3M) is an immune response modifier that acts via stimulation of toll-like receptor 7 (TLR-7) on plasmacytoid and myeloid dendritic cells.1 TLR-7 is part of a family of 11 TLRs that are important in the innate immune system’s recognition of various microbial antigens. Stimulation of TLR-7 most notably results in dissociation of nuclear factor kB (NFkB) away from its inhibitor, thereby freeing it to diffuse into the nucleus and transcribe genes for various cytokines including tumor necrosis factor a (TNFa), interferon g (IFNg), interferon a (IFNa), and interleukin-12 (IL-12), among others (see Figure 1). These cytokines upregulate cell mediated Th1 responses that have antitumor and antiviral effects and downregulate Th2 (humoral) responses. Imiquimod may also directly affect cell death through various pathways including via IFNg modulation of the p53 apoptotic pathway.
Although initially licensed for the treatment of genital warts, imiquimod 5% cream has demonstrated therapeutic efficacy in a variety of dermatologic conditions and has recently been given approval by both the US FDA and Health Canada for the treatment of multiple AKs.
Actinic Keratoses

AKs are relatively common premalignant inflammatory skin lesions. The risk of malignant transformation of an average AK into a SCC in 1 year is 0.0075%.2 However, over a 10-year period, a person with an average of 8 AKs has a
6%-10% chance of developing an SCC.3 Treatment modalities employed include cryotherapy, topical fluorouracil (5-FU), photodynamic therapy (PDT), topical 3% diclofenac in 2.5% hyaluronic acid, retinoids, curettage, surgical excision, laser, and chemical peels/resurfacing procedures.

Figure 1: Imiquimod stimulation of TLR-7 results in
activation of IKK, which phosphorylates IêB. Unphosphorylated IkB keeps NFkB inactive. Phosphorylated IkB is ubiquitinated and degraded, freeing NFkB to move into the nucleus. NFkB acts as a transcription factor for genes encoding various cytokines.

IKK = inhibitor IkB kinase; IkB = inhibitor of NFkB;
NFkB = nuclear factor kB
Reprinted with permission from A-K Somani, MD, PhD.

Clinical Trials
In a randomized, double-blind, vehicle-controlled study, imiquimod 5% cream or vehicle was applied to AKs three times weekly for a maximum of 12 weeks.4 Three to 10 lesions from the scalp, forehead, dorsal forearm, neck, or dorsal hand, in an area not exceeding 20cm2, could be selected. At 2 weeks post-treatment, 21/25 (84%) patients were clinically cleared and 2/25 (8%) were partially cleared. No response was seen in the 11 subjects in the vehicle treated group (p< 0.001). Within the treatment group, clearance was 100% (15/15) in patients who required reduction to once or twice weekly therapy because of a brisk response to imiquimod. In those who were able to continue therapy at a frequency of three times weekly for 12 weeks, the clearance rate was 60% (6/10). All patients experienced local adverse effects ranging from mild to severe erythema, edema, erosions, vesicles, flaking and scabbing. One patient in the treatment group required a rest period of 10 days. All patients completed the 12-week treatment course. At the 1-year follow-up there was a 10% (2/25) recurrence rate in the treatment group.

In another clinical trial, 22 patients received imiquimod 5% cream three times weekly for 8 weeks (or until clearance) to one affected side of the body (either face, arms, or legs) and vehicle to the other side.5 Application sites were randomized. Seventy-eight percent of patients (17/22) completed the study (8 weeks of treatment and 8 weeks of post-treatment observation). Among these 17 patients, the mean number of lesions decreased from 10.1 to 6.2 versus 8.1 to 7.6 for the vehicle-treated group at 8 weeks post-treatment. This reached statistical significance (p< 0.005). Nine patients (53%) required one to two rest periods of 2 weeks’ duration for local cutaneous reactions. Local side-effects were experienced by 14 patients (82%).
A third study examined the efficacy of cyclical imiquimod therapy.6 This was an open-label trial of 25 patients with 5-20 discrete AKs within one cosmetic unit: the scalp, the forehead and temples, or the cheeks. This contrasts with other studies, which have included the neck, arms, hands, and legs. Imiquimod was applied to the entire treatment area (“field treatment”) three times weekly for 4 weeks followed by a 4-week rest period. The cycle was repeated a maximum of three times if needed. Of the 25 patients with 33 total cosmetic units, 20 patients with 30 cosmetic units completed treatment. In the intention-to-treat analysis (ITT) 82% total clearance was achieved after three treatment cycles. Four patients had severe reactions that required early rest periods at 2-3 weeks of treatment. Of note, subclinical AKs exposed to imiquimod became evident in the treatment field. Furthermore, AK clearance continued during the rest period when no imiquimod was administered.

There have recently been large phase III, randomized, multicenter, double-blind, vehicle-controlled studies examining the use of imiquimod 5% cream for the treatment of AKs. The first of these published reports is a combination of two studies in which imiquimod 5% cream was applied once daily, 2 days per week for 16 weeks in 436 patients with 4-8 clinically diagnosed AKs on the face and scalp.7 Complete clearance, based on clinical assessment at 8 weeks post-treatment, was 45.1% (97/215) and 3.2% (7/221) for treatment and vehicle groups respectively (p< 0.001). Dosing days were a minimum of 3 days apart. Local skin reactions were common in both treatment and vehicle groups. However, these were more severe in the imiquimod treated group and resulted in 2 patients (1%) discontinuing treatment.

The second published study examined three times weekly imiquimod 5% cream applied to the face or balding scalp for 16 weeks in 286 patients with 5 to 9 clinically diagnosed and histologically confirmed AKs.8 Dosing days were the same nonconsecutive days every week. At 8 weeks post-treatment, the complete clinical clearance rate was 57.1% (84/147) with imiquimod versus 2.2% (3/139) in the vehicle treated group (p< 0.001). Adverse site reactions were reported by 46.3% (68/147) in the imiquimod group versus 11.5% (16/139) of patients using vehicle. Two patients using imiquimod (1%) discontinued therapy because of local side-effects.

Additional Treatment Options for AKs and Their Efficacy

There are no head-to-head trials comparing the efficacy of the various therapies used for the treatment of multiple actinic keratoses with that of imiquimod. Table 2 summarizes the response rates of various therapies that have been reported in the literature.

Cryotherapy is considered a standard treatment when patients present with a limited number of AKs (less than 15)9 or when there are multiple scattered lesions.10 The commonly used cryogen is liquid nitrogen (-195.8oC), which may be applied with techniques ranging from cotton-tip application to cryospray or cryoblast.11 The open-spray technique, with a freeze time of 5 to 10 seconds is effective.12 Prospective randomized controlled trials examining the efficacy of cryotherapy are lacking. Based on an observational study in which a 20 to 45 second total thaw time was used, a cure rate of 98.8% was achieved based on a recurrence rate of 12 out of 1,018 treated lesions in 70 patients followed for 1-8.5 years.10 Local side-effects such as blisters, scarring, and textural and pigmentary changes can rarely occur with cryotherapy.9
In patients with multiple AKs, the therapies listed below may be employed.

5-Fluorouracil (5-FU) is a structural analog of thymine that competes for enzymes with normal metabolites, such as uracil. Its cytotoxic effects are mediated by integration into RNA and inhibition of DNA synthesis by blockade of thymidylate synthetase.13 Typically the medication is applied twice daily for 3-4 weeks for facial lesions and 4-6 weeks on arms and hands until the lesions inflame and erode. In an effort to reduce the often intolerable side-effects of continuous therapy, the efficacy of pulse 5% 5-FU therapy has been examined in two studies. The earlier of these showed efficacy with once or twice weekly 5-FU applied for an average 6.7 weeks,14 while the other demonstrated little efficacy with intermittent therapy.15 Recently, a single-arm open-label study examined intermittent 5% 5-FU for up to 16 weeks in 53 patients with a total of 83 AKs on the face or scalp.16 All patients were initially treated 4 times per week (q.i.w.-twice daily on two consecutive days). After the first week, patients could switch to twice weekly application (b.i.w.-twice on a single day) if they experienced intolerable discomfort. Fifty patients (98%) with 79 lesions (95.1%) completed therapy. A total of 74.6% of lesions (59/79) were treated q.i.w., while 25.3% of lesions (20/70) were treated b.i.w. Complete healing was seen in 88.6% of lesions. Efficacy was not reduced as a result of less frequent application (complete clearance rates of 88.1% [52/59] and 90% [18/20] with q.i.w. and b.i.w. treatment respectively). Mean time to healing, however, did increase with decreased frequency of 5-FU application (7.4 weeks versus 10.2 weeks in the q.i.w. versus b.i.w. groups respectively).

One-half percent, 1%, and 2% concentrations of 5-FU have been developed. The one-half percent 5-FU cream was shown in two pooled, phase III studies of 384 patients to result in total AK clearance in 52.9% (45/85) of patients versus 1.6% (2/127) in the placebo group after 4 weeks of treatment (p< 0.001).17
In terms of comparative studies, chemical peel with Jessner’s solution (resorcinol, lactic acid, and salicylic acid) combined with trichloroacetic acid and 5% 5-FU twice daily for 3 weeks were equal in efficacy.18 Photodynamic therapy has also been found to be equivalent in efficacy to 3 weeks of 5-FU treatment.19

Diclofenac is a nonsteroidal, anti-inflammatory drug that inhibits cyclo-oxygenase-2 resulting in reduced prostaglandin synthesis.20 Raised prostaglandins have been linked with sun damage and AKs.21 In a randomized, double-blind placebo-controlled study of 96 patients treated twice daily with 0.5 grams of topical 3% diclofenac in 2.5% hyaluronic acid for 90 days, 50% of patients showed complete resolution of all target lesions compared with 20% in the placebo group (p< 0.001).22 Another multicenter, double-blind, placebo-controlled study of 195 patients treated twice daily for 30 or 60 days with the same formulation of diclofenac achieved total lesion clearance of approximately 30% (in both 30- and 60-day treatment groups) versus approximately 10% in the placebo group.23 Adverse events included mild-to-moderate local pruritus, erythema and rash. The medication was well tolerated overall.24

Photodynamic therapy (PDT) employs aminolevulinic acid (ALA), a prodrug that is intracellularly metabolized to protoporphyrin IX, a photosensitizing molecule.25 When this is activated by exposure to light, free radicals and reactive oxygen species are generated.25 These are cytotoxic. A recent phase III, multicenter, investigator-blinded, randomized controlled trial examined the efficacy of ALA topical solution versus vehicle followed by blue light in the treatment of multiple AKs on the face and scalp in 243 patients.26 Following initial treatment, remaining target lesions were retreated at 8 weeks. Complete response rates achieved at 8 and 12 weeks were 66% (109/166) and 73% (109/149) respectively (p< 0.001). In the vehicle treated groups, complete responses were achieved in 11% (6/55) and 8% (4/52) at 8 and 12 weeks.

Moderate-to-severe stinging and burning were reported in 90% of patients during treatment, but this decreased after 24 hours. Additional side-effects of PDT include erythema and edema, which improve over 1-4 weeks. Pruritus, crusting, scaling, hyperpigmentation, and hypopigmentation may also be seen. This therapy is indicated for non-hyperkeratotic AKs.

Dosage and Adverse Effects

Imiquimod 5% cream is supplied in single-use sachets containing 250mg of the cream (12.5mg imiquimod).27 Each sachet can cover an area between 150 and 200cm2.28 Patients are instructed to apply imiquimod nightly, leave on for 6-10hrs, and then wash off. Hands should be washed after imiquimod application.

In general, imiquimod is well tolerated. Local cutaneous adverse effects are common, however, and include pruritus, burning, pain, erythema, erosions, edema, scabbing, induration, and ulceration.27
Erythema is the most common adverse reaction. In many of the above studies, dosing adjustments were required due to local reactions. Pretreatment counseling along with adequate follow-up will facilitate patient compliance with therapy. Serious systemic effects have not been reported.27
There are no known contraindications to treatment and no known drug interactions.27

Conclusions

Imiquimod is a reasonable treatment option in patients with multiple AKs. Health Canada has approved the treatment course at twice weekly for 16 weeks. Other treatment regimens can also be considered after the above treatment schedule.

A key component in the management of AKs remains the adoption of sun protective behaviors and sunscreens as a preventative strategy.29

References

1. Hurwitz DJ, Pincus L, Kupper TS. Imiquimod: a topically applied link between innate and acquired immunity. Arch Dermatol 139(10):1347-50 (2003 Oct).
2. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1(8589):795-7 (1988 Apr).
3. Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic keratoses and the controversy over treatment. A patient-oriented perspective. Arch Dermatol 127(7):1029-31 (1991 Jul).
4. Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 138(11):1498-502 (2002 Nov).
5. 5Persaud AN, Shamuelova E, Sherer D, et al. Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis. J Am Acad Dermatol 47(4):553-6 (2002 Oct).
6. Salasche SJ, Levine N, Morrison L. Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: an open-label trial. J Am Acad Dermatol 47(4):571-7 (2002 Oct).
7. Lebwohl M, Dinehart S, Whiting D, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 50(5):714-21 (2004 May).
8. Szeimies R-M, Gerritsen MP, Gupta G, et al. Imiquimod 5% cream for the treatment of actinic keratosis: Results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 51(4):547-55 (2004 Oct).
9. Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol 42(1 Pt 2):25-8 (2000 Jan).
10. Lubritz RR, Smolewski SA. Cryosurgery cure rate of actinic keratoses. J Am Acad Dermatol 7(5):631-219 (1982 Nov).
11. Callaway SR, Ratz JL. Surgical pearl: cryoblast, a modified cryosurgical technique for thick lesions. J Am Acad Dermatol 51(3):458-9 (2004 Sep).
12. Kuflik EG. Cryosurgery updated. J Am Acad Dermatol 31(6):925-44 (1994 Dec).
13. Eaglstein WH, Weinstein GD, Frost P. Fluorouracil: mechanism of action in human skin and actinic keratoses. I. Effect on DNA synthesis in vivo. Arch Dermatol 101(2):132-9 (1970 Feb).
14. Pearlman DL Weekly pulse dosing: effective and comfortable topical 5-fluorouracil treatment of multiple facial actinic keratoses. J Am Acad Dermatol 25(4):665-7 (1991 Oct).
15. Epstein, E. Does intermittent “pulse” topical 5-fluorouracil therapy allow destruction of actinic keratoses without significant inflammation? J Am Acad Dermatol 38(1):77-80 (1998 Jan).
16. Labandeira J, Pereiro M Jr, Valdes F, Toribio J. Intermittent topical 5-fluorouracil is effective without significant irritation in the treatment of actinic keratoses but prolongs treatment duration. Dermatol Surg 30(4 Pt 1):517-20 (2004 Apr).
17. Gupta AK, Weiss JS, Jorizzo JL. 5-fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face and anterior scalp. Skin Therapy Lett 6(9):1-4. Review (2001 Jun).
18. Lawrence N, Cox SE, Cockerell CJ, Freeman RG, Cruz PD Jr. A comparison of the efficacy and safety of Jessner’s solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Arch Dermatol 131(2):176-81 (1995 Feb).
19. Kurwa HA, Yong-Gee SA, Seed PT, Markey AC, Barlow RJ. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 41(3 Pt 1):414-8 (1999 Sep).
20. Peters DC, Foster RH. Diclofenac/hyaluronic acid. Drugs Aging. 14(4):313-9 (1999 Apr).
21. An KP, Athar M, Tang X, et al. Cyclooxygenase-2 expression in murine and human nonmelanoma skin cancers: implications for therapeutic approaches. Photochem Photobiol 76(1):73-80 (2002 Jul).
22. Wolf JE Jr, Taylor JR, Tschen E, Kang S. Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 40(11):709-13 (2001 Nov).
23. Rivers JK, Arlette J, Shear N, Guenther L, Carey W, Poulin Y. Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 146(1):94-100 (2002 Jan).
24. Rivers JK. Topical 3% diclofenac in 2.5% hyaluronan gel for the treatment of actinic keratoses. Skin Therapy Lett 9(1):1-3 (2004 Jan).
25. Gupta AK, Ryder JE. Photodynamic therapy and topical aminolevulinic acid: an overview. Am J Clin Dermatol 4(10):699-708 (2003).
26. Piacquadio DJ, Chen DM, Farber HF, et al. Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3, multicenter trials. Arch Dermatol 140(1):41-6 (2004 Jan).
27. ALDARATM (imiquimod) CREAM, 5% Product Monograph 3M Pharmaceuticals (1997 May).
28. Berman B, Ricotti CA Jr, Cazzaniga A, Davis SC. Determination of the area of skin capable of being covered by the application of 250 mg of 5% imiquimod cream. Dermatol Surg 30(5):784-6 (2004 May).
29. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 329(16):1147-51 (1993 Oct).

Division of Dermatology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Actinic Keratoses (AKs) are epidermal skin lesions that have the potential to develop into squamous cell carcinoma. Many of the treatment options available can cause discomfort, pain or skin irritation. Topical 3% diclofenac in 2.5% hyaluronan gel (Solaraze™, Bioglan Pharma) is a relatively new treatment that has been shown to be effective and well tolerated for the treatment of AKs.
Key Words: actinic keratoses, diclofenac, hyaluronic acid

Actinic Keratoses (AKs) are a relatively common premalignant inflammatory skin lesion, which affect a large proportion of individuals with light skin that has been exposed to sun and/or artificial UV radiation. Over a period of 10 years, a person with 8 AKs has a 6.1-10.2% chance of developing a squamous cell carcinoma.¹ Risk factors for AKs include being:

• fair skinned
• male
• >50 years of age
• sensitive to the sun with poor ability to tan and frequent sunburns
• on a high fat diet
• immunosuppressed.^2-6

AKs have a wide range of clinical presentations and there is no single therapy that treats the complete spectrum of pathologies and individuals. Current treatment options include cryosurgery, curettage, surgical excision, laser, chemical peels, photodynamic therapy (PDT), topical fluorouracil, and retinoids. Topical imiquimod has also been used experimentally.⁷ However, all these options have been associated with local discomfort and pain in some cases.^8,9 Topical 3% diclofenac in 2.5% hyaluronic acid (Solaraze®, Bioglan Pharma) is a new treatment for AKs that has been approved in the US, Canada and several countries in the European Union.

Mechanism of Action

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that is a potent inhibitor of inducible cyclo-oxygenase (COX-2), resulting in a reduction of prostaglandin synthesis.8 Sun damage and AKs have been linked with raised prostaglandins in exposed skin.¹⁰ Oral administration of this drug can result in adverse effects. However, when this gel is applied topically, diclofenac is absorbed into the epidermis, and studies indicate that systemic absorption is much lower than that occurring after oral daily dosing of this drug.¹⁰

Clinical Trials

In an open-label study of 29 patients with mild to severe AKs, 1.0gm of the gel was applied twice daily for up to 180 days (the median was 62 days). At the end of the treatment, lesions were scored using visual and photographic assessment. There was a highly significant (p<0.001) improvement in lesions with 48% showing a complete response. Thirty days post treatment, 27 of the patients were reassessed and those who had a complete response rose to 81% with another four (15%) showing marked clinical improvement.⁹

In a randomized double-blind, placebo controlled trial involving individuals with >5 AK lesions, adult patients received either 3% diclofenac gel in 2.5% hyaluronan gel or the gel vehicle as a placebo. They received 0.5gm b.i.d for 90 days. Assessments were made at each visit and 1 month posttreatment, and included Target Lesion Number Score (TLNS), Cumulative Lesion Number Score (CLNS) and Global Improvement Indices (GII). At the follow-up visit, 50% of the patients using diclofenac showed complete resolution of all target lesions using TLNS compared to 20% in the placebo group (p<0.001). With regard to CLNS, 47% of patients applying diclofenac showed complete resolution compared to 19% in the placebo group (p<0.001) and the GII showed a 79% improvement in the diclofenac group vs. 45% in the placebo group (p<0.001).¹¹

Another multicenter, double-blind, placebo-controlled study of 195 patients received the same formulation of diclofenac, 0.5g or vehicle, twice daily for either 30 days or 60 days. While there was no statistical difference in complete responders in the 30 day treatment groups, significantly more patients given active treatment for 60 days had TLNS=0 (33% vs. 10%, p<0.05). With regard to CLNS, 31% of patients in the active group showed complete clearance vs. 8% for the placebo group (p<0.05). GII scores were also significantly better in the 60 day active treatment group (p<0.05).¹²

In a randomized, double-blind, controlled trial, 150 patients were asked to apply diclofenac 3% gel twice daily as well as a sunscreen once daily for 24 weeks. The complete response rates were 29% for the active gel and 17% for the control gel. The difference was not statistically significant (p=0.14).

Table 1: Clinical trials results for diclofenac 3% in 2.5% hyaluronan gel
*Measured 30 days post-treatment

Furthermore, a high percentage of patients in both groups experienced a partial response to the treatment (38%) for the diclofenac group and 45% for the control group, but there was no significant difference in the spectrum of response between the two treatments (p=0.18).¹³ It should be noted that the patients used sunscreens and there was no follow-up assessment 30 days post-treatment.

Adverse Events

Generally, adverse events have been mild-to-moderate in severity. The most commonly reported adverse events include: pruritus, application site reactions, dry skin, rash and erythema.

Conclusion

The primary cause of AKs is exposure to UV light. Wearing sun protective clothing, sunscreen and avoiding direct sunlight can help prevent them. However, for those patients who already have AKs, this new topical preparation provides an alternate therapeutic option. It has been shown to be effective, well-tolerated, and easy to administer.

References

1. Dobson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of actinic keratoses and the controversy over treatment. Arch Dermatol 127:1029-33 (1991 Jul).
2. Gloster HM Jr., Brodland DG. The epidemiology of skin cancer. Dermatol Surg 22(3):217-26 (1996 Mar).
3. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 2):4-7 (2000 Jan).
4. Black HS, Herd JA, Goldberg LH, et al. Effect of a low-fat diet on the incidence of actinic keratosis. N Eng J Med 330:1272-5 (1994 May).
5. Boyle J, MacKie RM, Briggs JD, Junor BJ Aitchison TC. Cancer, warts, and sunshine in renal transplant patients. A case-control study. Lancet 1:702-5 (1984).
6. McGregor JM, Barker JN, MacDonald DM. The development of excess numbers of melanocyte naevi in an immunosuppressed identical twin. Clin Exp Dermatol 16(2):131-2 (1991 Mar).
7. Persaud AN, Shamuelova E, Sherer D, et al. Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis. J Am Acad Dermatol 47(4):553-6 (2002 Oct).
8. Peters DC, Foster RH. Diclofenac/Hyaluronic Acid. Drugs & Aging 57(2) (1999 Feb).
9. Rivers JK, McLean DI. An open study to assess the efficacy and safety of topical 3% diclofenac in a 2.5% hyaluronic acid gel for the treatment of actinic keratoses. Arch Dermatol 133:1239-42 (1997 Oct).
10. Solaraze™ (diclofenac sodium) Gel, 3% package insert. Bioglan Pharma, Inc (2001 Oct).
11. Wolf JE, Taylor JR, Tschen E, Kang S. Topical 3.5% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 40:709-13 (2001).
12. Rivers JK, Arlette J, Shear N, Guenther L, Carey W, Poulin Y. Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 146:94-100 (2002).
13. McEwan LE, Smith JG. Topical diclofenac/hyaluronic acid gel in the treatment of solar keratoses. Australas J Dermatol 38:187-9 (1997).

ABSTRACT

Cyanoacrylates are surgical adhesives that provide another option for wound closure. When compared to sutures, cyanoacrylates were found to be as effective as sutures in low tension lacerations and for the attachment of some full-thickness skin grafts. In addition, clinical practitioners have found cyanoacrylates easier to apply, time saving, and more economical. There are a number of surgical adhesives either currently available or under development. The presently available butylcyanoacrylates and octylcyanoacrylates are reviewed.

Key Words:
N-2-butylcyanoacrylate, Sutures, Octylcyanoacrylate, Butylcyanoacrylate

PHARMACOLOGY

N-2-butylcyanoacrylate is a liquid compound that polymerizes rapidly in the presence of hydroxyl ions and is used for the closure of uncomplicated skin lacerations. It is useful in emergency rooms, for pediatric physicians, and in first-aid situations where wound closure is necessary and sutures are not warranted¹. Since its discovery in 1949, several different forms of cyanoacrylates have been developed. Tissue adhesives constitute one part of an ever-expanding range of surgical adhesives. These products have been used successfully for hair transplantation⁴, splitthickness skin grafting⁵, punctal occlusion⁶, cerebrospinal fluid leak closure⁷, facial plastic surgery⁸, and corneal perforations⁹.

CLINICAL TRIALS

N-2-butylcyanoacrylate vs Sutures

When dealing with low-tension lacerations, physicians have compared skin closure using cyanoacrylates to skin closure using sutures, and found the tissue adhesive to offer some advantages with few of the disadvantages of conventional suture techniques^8,13,14,15, especially in the pediatric setting^{2,11,12,13,14}. It is less traumatic, eliminating the pain associated with the injection of local anesthetic, which may frighten an already traumatized child¹.

Overall, the application of cyanoacrylate is a painless alternative to suturing for wound repair^3,11,12, and has comparable cosmetic results¹⁴. It can be applied rapidly and is cost effective^1,14. Further, n-2-butylcyanoacrylate has been shown to reduce the risk of wound infection when compared to sutures^15,16.

Wound strength on the day after closure using cyanoacrylates is only 10–15% of sutured wounds. However, careful technique may improve the outcome³, and routine tapestrip reinforcement of the wound is recommended by the manufacturer. Ointments must be avoided, because they will weaken the glue/skin bond.

Octylcyanoacrylate vs Sutures

Another form of cyanoacrylate (i.e., octylcyanoacrylate) has also been compared with sutures. In a randomized, controlled study, physicians at the University of Michigan concluded that octylcyanoacrylate effectively closes selected lacerations, and is a relatively painless and fast method of wound repair. They estimate that this product can replace the need for suturing several million lacerations each year³.

Butylcyanoacrylate vs Octylcyanoacrylate

One recent study compared two forms of cyanoacrylate: butylcyanoacrylate and octylcyanoacrylate. Pediatric patients with facial lacerations were treated, and the investigators examined issues of cosmesis, time of application, pain perceived by the patient, and wound healing. They concluded that there was little or no difference between these two forms of cyanoacrylate². Cost difference may dictate choice.

Full-Thickness Skin Grafts

N-2-butylcyanoacrylate has been investigated as an alternative to the meticulous and time-consuming suturing required to position full-thickness skin grafts. It has been found to be useful particularly for relatively immobile areas such as the temple, forehead, and distal nose¹⁰.

Conclusion

Cyanoacrylates are becoming increasingly popular for use in wound closure in low tension lacerations and for the attachment of some full-thickness skin grafts. Of the many minor procedures carried out in ambulatory offices (e.g., excisions and biopsies in low tension areas), a method of wound closure such as this is easier, more time saving, and more economical than traditional methods.

References

1. Product monograph, GluStitch Inc. www.glustitch.com.
2. Osmond MH, Quinn JV, Sutcliffe T, Jarmuske M, Klassen TP. A randomized, clinical trial comparing butylcyanoacrylate with octylcyanoacrylate in the management of selected pediatric facial lacerations. Acad Emerg Med 6(3):171-7 (1999 March).
3. Quinn J, Wells G, Sutcliffe T, Jarmuske M, Maw J, Stiell I, Johns P. A randomized trial comparing octylcyanoacrylate tissue adhesive and sutures in the management of lacerations. JAMA 277(19):1527-30 (1997 May 21).
4. Elliott RM, Thomas RA, True RH. Advanced use of tissue adhesive in hair transplantation. J Dermatol Surg Oncol 19(9):853-8 (1993 Sep).
5. Zaki I, Scerri L, Millard L. Split skin grafting on severely damaged skin. A technique using absorbable tissue adhesive. J Dermatol Surg Oncol 20(12):827-9 (1994 Dec).
6. Patten JT. Punctal occlusion with n-butyl cyanoacrylate tissue adhesive. Ophthalmic Surg 7(2):24-6(1976 Summer).
7. Maxwell JA, Goldware SI. Use of tissue adhesive in the surgical treatment of cerebrospinal fluid leak. Experience with isobutyl 2-cyanoacrylate in 12 cases. J Neurosurg 39(3):332-6 (1973 Sep).
8. Kamer FM, Joseph JH. Histoacryl. Its use in anesthetic facial plastic surgery. Arch Otolalaryngol Head Neck Surg 115(2):193-7 (1989 Feb).
9. Kinyoun JL, Hyndiuk RA, Hull DS. Treatment of corneal perforations with cyanoacrylate. Wis Med J 73(9):S117-8 (1974 Sep).
10. Craven NM, Telfer NR. An open study of tissue adhesive in full-thickness skin grafting. J Am Acad Dermatol 40(4):607-11 (1999 Apr).
11. Barnett P, Jarman FC, Goodge J, Silk G, Aickin R. Randomised trial of histoacryl blue tissue adhesive glue versus suturing in the repair of paediatric lacerations. J Paediatr Child Health 34(6):548-50 (1998 Dec).
12. Bruns TB, Robinson BS, Smith RJ, Kile DL, Davis TP, Sullivan KM, Quinn JV. A new tissue adhesive for laceration repair in children. J Pediatr 132(6):1067-70 (1998 Jun).
13. Simon HK, McLario DJ, Bruns TB, Zempsky WT, Wood RJ, Sullivan KM. Long-term appearance of lacerations repaired using a tissue adhesive. Pediatrics 99(2):193-5 (1997 Feb).
14. Bruns TB, Simon HK, McLario DJ, Sullivan KM, Wood RJ, Anand KJ. Laceration repair using a tissue adhesive in a children’s emergency department. Pediatrics 98(4 Pt 1):673-5 (1996 Oct).
15. Giray CB, Sungur A, Atasever A, Araz K. Comparison of silk sutures and n-butyl-2-cyanoacrylate on the healing of skin wounds. A pilot study. Aust Dent J 40(1):43-5 (1995 Feb).
16. Noordzij JP, Foresman PA, Rodeheaver GT, Quinn JV, Edlich RF. Tissue adhesive wound repair revisited. J Emerg Med 12(5):645-9 (1994 Sep-Oct).
17. Blacklock D, GluStitch Inc. Personal Communication. June, 1999.

SOME SURGICAL ADHESIVES CURRENTLY AVAILABLE¹⁷