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O R I G I NA L C O N T R I BU T I O N
The combination of 2% 4-hydroxyanisole (mequinol) and 0.01%
tretinoin effectively improves the appearance of solar lentigines in
ethnic groups
Zoe Diana Draelos, MD
While the efficacy and safety of topical 4-hydroxyanisole (mequinol) 2%/tretinoin 0.01%therapy has been established in Caucasian populations, those with skin types I–II, littleresearch has focused on individuals with darker skin types. The purpose of this open-labelstudy was to evaluate the efficacy and safety of mequinol 2%/tretinoin 0.01% solutionin the treatment of solar lentigines in Asian, Latin/Hispanic, and African Americanethnic groups with skin types II–V. Subjects were required to have ≥ 10 solar lentigineson the dorsal forearms/hands and ≥ 3 on the face. One lesion was designated the targetlesion, however, all lesions were treated. Patients were treated with topical mequinol 2%/tretinoin 0.01% and clinically evaluated at 4, 8, 12, 16, 20, and 24 weeks as well as4 weeks following treatment cessation. At each visit, lesions were evaluated using Targetand Overall Lesion Pigmentation Index scores ranging from 0 (lightest) to 8 (darkest),where 4 indicated equal pigment with surrounding skin. Efficacy was determined basedon pigmentation index scores, and safety was assessed using laboratory monitoringand adverse event (AE) reporting. Over 80% of the 259 subjects completing this studyresponded to mequinol 2%/tretinoin 0.01% therapy, with a majority of subjects main-taining clinical benefit at 4 weeks post-treatment. Most AEs reported were tolerable andoverall mequinol 2%/tretinoin 0.01% therapy had a favorable benefit-to-risk ratio. Thisstudy therefore supports the theory that topical mequinol 2%/tretinoin 0.01% is aneffective and safe treatment of solar lentigines in ethnic populations, and in those withdark skin types.
Keywords: ethnic groups, mequinol, solar lentigines, tretinoin exposure. Lesions occur most frequently in fair-skinned Introduction
individuals and in middle-aged and elderly populations.1–3 Solar lentigines are a common dermatologic condition This condition currently causes significant cosmetic that manifest as localized, hyperpigmented, macular concerns for more than 20 million Americans and is lesions usually found on sun-exposed areas of the skin.
becoming increasingly prevalent due to the increased rate The benign condition is caused by an increased number at which the US population is aging.4 Although new and of active melanocytes and increased melanin production effective therapies are available, the majority of therapeutic in response to chronic, accumulated ultraviolet radiation research has focused on Caucasian populations or thosewith skin types I or II (Table 1). This is not surprising given the Correspondence: Zoe Diana Draelos, MD, 2444 North Main Street, High epidemiological data on the disease. However, the condition Point, NC 27262. E-mail: [email protected] affects all skin types and requires research supporting its Accepted for publication May 16, 2006 treatment in ethnic groups and those with darker skin.5–7 2006 Blackwell Publishing • Journal of Cosmetic Dermatology, 5, 239– 244
Mequinol 2%/tretinoin 0.01% use with ethnic groups • Z D Draelos Table 1 Demographic information.
With the exception of these investigations, no studies have specifically addressed solar lentigines in non-Caucasian Given the limited exploration in these patient popula- tions, the present study was designed to assess the efficacy and safety of mequinol 2%/tretinoin 0.01% therapy in II – Usually burns, tans less than average The present study was an open-label, single-arm safety III – Sometimes burns (mildly), tans about average and efficacy study of mequinol 2%/tretinoin 0.01% IV – Rarely burns, tans more than average topical solution in the depigmentation of circumscribed macular solar lentigines in males and females ≥ 30 years of Asian, Latin/Hispanic, African American ethnicity andskin types II–V. Using the wand applicator to specifically target only the solar lentigines, subjects applied thequick-drying test solution twice daily to lesions on the Recent evidence supports the use of combination therapy face, forearms, and hands for up to 24 weeks.
with mequinol 2%/tretinoin 0.01% (Solagé®, Barrier After giving written informed consent, 45 (17.4%) Therapeutics, Princeton, NJ) as an effective and safe treat- males and 214 (82.6%) females (total n = 259) were ment for solar lentigines.1–4,8,9 Widely accepted treatments, enrolled into 17 study centers in the United States and 3 such as tretinoin and hydroquinone monotherapies, and in Canada. The mean age of the subjects was 55.8 years, ablative treatment strategies, such as cryo- and laser with a range of 31–82 years. Sixty-three (24.3%) of the removal, often produce variable depigmentation results.
subjects were Asian, 35 (13.5%) were African American, Additionally, such therapies often have negative side and 161 (62.2%) were Hispanic (Table 1). Eligible subjects effects and can result in significant patient discomfort.3 were demonstrably nongravid and had ≥ 10 solar lentigines Mequinol 2%/tretinoin 0.01% combines two effective on the dorsal forearms/hands and ≥ 3 on the face. A single depigmenting agents and has been proven more effective lesion in each area was designated as a target lesion, than either agent alone while offering a safety profile however, all lesions were treated. At baseline the overall similar to tretinoin monotherapy.2 Tretinoin (all-trans- lesion pigmentation index score was 6 on a 9-point scale retinoic) is a vitamin A analogue thought to inhibit ranging from 0 (lightest) to 8 (darkest), where 4 (equal) melanogenesis through growth factor modulation,3,10 The indicated equal pigmentation with the surrounding skin exact mechanism of action of mequinol’s depigmentation effects is unknown although it is speculated that it Subjects returned to the clinic for evaluations after 4, includes oxidation by tyrosinase to cytotoxic products in 8, 12, 16, 20 and 24 weeks of treatment and again melanocytes, a direct/selective toxic effect on melanocytes, 4 weeks later for follow-up assessment. In this open-label, or inhibition of melanin formation.11–15 single-arm study, all the assessments for a subject were Although multiple recent studies have shown mequinol performed by the same investigator; evaluations were 2%/tretinoin 0.01% combination therapy to provideclinically significant improvement in up to 80% of Table 2 Lesion pigmentation index.
patients, little work has been done to specifically evaluate its efficacy in ethnic populations or in those with 0 – Extremely lighter than pigment of surrounding skin darker skin tones.2,3 One study has suggested that 2% hydroquinone-cyclodextrin therapy significantly reduced 1 – Markedly lighter than pigment of surrounding skin pigmentation in Asian patients with solar lentigines, 2 – Moderately lighter than pigment of surrounding skin another study explored concomitant application of all-trans- 3 – Slightly lighter than pigment of surrounding skin retinoic acid aqueous gel with hydroquinone-lactic acid 4 – Equal with pigment of surrounding skin 5 – Slightly darker than pigment of surrounding skin ointment for bleaching of senile lentigines and post- 6 – Moderately darker than pigment of surrounding skin inflammatory hyperpigmentations, while other work has 7 – Markedly darker than pigment of surrounding skin looked at hyperpigmentation responses to topical whiten- 8 – Extremely darker than pigment of surrounding skin ing agents in women of South-east Asian descent.5–7 2006 Blackwell Publishing • Journal of Cosmetic Dermatology, 5, 239– 244
Mequinol 2%/tretinoin 0.01% use with ethnic groups • Z D Draelos based on the target lesions presented at baseline. Basedon investigator interest, experience and training, colorphotographs, for illustrative purposes only, were takenat three selected study sites at baseline, week 24, orupon successful depigmentation to grade 4 (Fig. 1a,b).
Figure 2a,b is representative before and after images ofsubjects with deeply pigmented skin who were treatedwith the test formulation. At each visit, a Target and anOverall Lesion Pigmentation Index Score were recordedbased on clinical assessment for each of the two treatmentareas, resulting in a total of four scores per visit. Preg-nancy status was monitored at each visit, and laboratorytests (blood chemistry, urinalysis, and hematology) wereperformed at baseline, 12 weeks, and 24 weeks (or at lastvisit) for safety monitoring. For each treated lesion, if ascore of 4 was reached, treatment was stopped for thatlesion. When all treated lesions were at grade 4, treatmentwas stopped altogether, regardless of study duration.
Efficacy was determined by clinical assessment using Target Lesion and Overall Lesion Pigmentation Index
scores and was quantified by dividing responders into
three categories:
• Complete responders – subjects who reached an Overall
• Partial responders – subjects who had significant
improvement in their pigmentation, defined as animprovement of at least 1 grade, compared to baseline; • Treatment failures – subjects who did not fulfill the
Figure 1 Facial pigmentation lightening occurred in the facial
above criteria or subjects achieving an Overall Lesion treatment sites after 24 weeks of therapy in an African American Pigmentation Index score of less than 4.
subject. (a) baseline and (b) 24 weeks.
Figure 2 Representative (a) before and (b)
after images of subjects with deeply
pigmented skin who were treated with the
test formulation.
2006 Blackwell Publishing • Journal of Cosmetic Dermatology, 5, 239– 244
Mequinol 2%/tretinoin 0.01% use with ethnic groups • Z D Draelos The time to reach a response in partial and complete Table 3 Summary of adverse events.
responders was defined as the time from first treatmentapplication to the first measurable response.
In addition to the aforementioned laboratory tests, safety was assessed by evaluating reported adverse events(AEs). Assessment of AEs, including abnormal pigmentation changes, was performed at each visit, and any events were recorded throughout the duration of the study. Subjects were instructed to avoid sun exposure as well as exposure to other sources of ultraviolet radiation (i.e., tanning beds) whenever possible for the duration of the study. They were also instructed to keep treatment areas covered with Over 80% of subjects responded to treatment as assessed by Overall Lesion Pigmentation Index scores. One hundred and seventy-six (68.0%) and 198 (76.4%) subjects had partial responses for the arm and face, respectively, while 35 (13.5%) and 21 (8.1%) subjects experienced complete responses for the same respective areas. Forty-eight (18.5%) and 40 (15.4%) subjects had treatment failures for the arm and face, respectively.
Over 85% of subjects responded to treatment based on Target Lesion Pigmentation Index scores. Once again the A subject was counted only once per AE regardless of the number of majority of subjects had a partial response to treatment with 176 (68.0%) and 185 (71.4%) showing a lesion *Defined as erythema plus at least two additional, prespecified improvement by at least 1 grade for the arm and face signs/symptoms (scaling, dryness, stinging/burning) starting at regions, respectively. Forty-nine (18.9%) and 45 (17.4%) subjects experienced complete responses, while 34 (13.1%)and 29 (11.2%) subjects had treatment failures for thearm and face, respectively.
AEs were reported by 121 (46.7%) subjects, all of whom The median time to response (partial and complete) for had dermatological AEs. Thirteen (5%) subjects discon- the Overall Lesion Pigmentation Index was 56 days tinued treatment due to an AE, nine (3.5%) of which were (range 21–173 days) for both the arm and face. Median dermatological in nature. Additionally, 15 (5.8%) subjects response times were 51 and 35 days for the Target Lesion stopped treatment due to dermatological AEs in one area Pigmentation Index for the same respective regions. At (either the face or arm) but remained in the study and 4-week follow-up, the majority of subjects maintained continued undergoing treatment in the nonaffected area.
the same pigmentation index scores as observed at the Serious AEs were reported by six (2.3%) subjects; all were nondermatological, including one subject who died of a Exposure to the study medication ranged from 1 to myocardial infarction considered unrelated to study 232 days (mean of 151.2 days) with most subjects treatment by the investigators. Laboratory AEs were (> 70% per area) receiving treatment for over 141 days.
infrequent; hematuria occurred in nine (3.5%) subjects Mequinol 2%/tretinoin 0.01% treatment showed an (seven of which were female). No laboratory AE resulted overall favorable safety profile consistent with previous in treatment discontinuation and none were considered clinical studies.1–3 Of 259 subjects, 160 (61.8%) reported related to treatment by the investigators.
1 or more AEs; 125 (48.3%) subjects reported 1 or moredermatological AEs. Thirty-two (12.4%) subjects reported Conclusions
hypopigmentation or halo-hypopigmentation (12 [4.6%]and 20 [7.7%], respectively) (Table 3). The majority of Overall, mequinol 2%/tretinoin 0.01% combination these events (84%) resolved during the study. Drug-related therapy demonstrated a favorable risk-to-benefit ratio in 2006 Blackwell Publishing • Journal of Cosmetic Dermatology, 5, 239– 244
Mequinol 2%/tretinoin 0.01% use with ethnic groups • Z D Draelos the treatment of solar lentigines in Asian, Latin/Hispanic, and irritation response—as they may have affected efficacy and African American subjects with skin types II–V.
This study has demonstrated that over 80% of treated The barrier properties of skin can produce variations in subjects achieved a significant response to the therapy skin permeability and thus absorption. When skin types for both arm and facial lesions, the majority of which V and VI was compared to types II and III, researchers maintained clinical benefit 4 weeks post-treatment. These concluded that darker skin was more compact than results mirror efficacy findings previously reported for lighter skin probably due to more cornified cell layers, light-skinned individuals and provide new evidence and that darker skin showed greater epidermal barrier.21 supporting the use of mequinol 2%/tretinoin 0.01% These results support the findings of an earlier study that specifically in ethnic and dark-skinned populations.2 It found that lighter skin was more permeable to certain is important to note that mequinol 2%/tretinoin 0.01% was found to have favorable treatment response times In the 1980s and early 1990s, researchers studied (both partial and complete) comparable, if not better, racial and ethnic differences in irritant reaction to topically than those seen with other therapies.16,17 The median applied chemicals by using biologic parameters. Based on response time for the Overall Lesion Pigmentation Index findings from several studies, Berardesca et al.23–27 con- was 56 days (range 21–173 days) for both the arm and face; median response times were 51 and 35 days for the • black subjects’ skin displays a stronger skin irritant
Target Lesion Pigmentation Index for the same respective regions. Noting the realistic amount of time it may take • the skin of black subjects is more sensitive to irritants
for a noticeable difference when treating solar lentigines may help in the management of patient expectations for • black subjects display less erythema, less blood vessel
therapy and ultimately support compliance.
reactivity, and less cutaneous blood flow to irritants There are no racial differences in the number of melanocytes,18,19 but the actual number of melanocytes • Hispanic subjects show a stronger irritant reaction
differ from one person to another or from one area of the compared with white subjects; their irritant reaction is body to another,20 which may account for the differences in treatment response of the test drug. All treatment • Hispanic subjects have stronger irritant reactions when
modalities have nonresponders. The small proportion of subjects in this trial with no improvement is not surprising • Hispanic and white subjects have similar erythematous
and was probably due to the individual’s unique biologic makeup. The approximately 3% difference in response Many current treatment strategies for solar lentigines with treated facial and arm lesions is consistent with the are associated with either inadequate depigmentation results found in studies of light-skinned subjects and responses or unfavorable side effects resulting in severe most likely not linked to racial differences2,3 but rather to patient discomfort.3 It has been widely reported that the difference in size and distribution of melanosomes in formulations containing hydroquinone and/or glucocor- ticoids are associated with an increased risk of ochronosis, Although AEs were reported by a significant number of a paradoxical hyperpigmentation response.28 Such patients, the treatment was overall tolerable, especially adverse reactions can be alarming to patients who initially when considering the overwhelming treatment response sought treatment in order to resolve hyperpigmentation rate. The most commonly reported AEs were erythema, abnormalities. Through avoidance of undesirable skin discomfort, and halo-hypopigmentation, occurring side effects such as ochronosis, mequinol 2%/tretinoin in 24.7%, 20.1%, and 7.7% of subjects, respectively.
0.01% offers patients an attractive alternative to other These results are significantly more favorable than AE therapies being used to treat solar lentigo. Therefore, the results previously reported in light skin populations present study supports the use of mequinol 2%/tretinoin further supporting the use of mequinol 2%/tretinoin 0.01% combination therapy as an effective, tolerable treatment option for ethnic and dark-skinned subjects.
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