Effect of Myristyl Nicotinate on Retinoic Acid Therapy for Facial Photodamage

By Myron K. Jacobson, PhD, Hyuntae Kim, PhD, W. Russell Coyle, Moonsun Kim, PhD, Donna L. Coyle, MS, Ronald L. Rizer, PhD, & Elaine L. Jacobson, PhD
Published Published in Exp Dermatol 2007, 16;11:927–935

Introduction

The study authors explored retinoids, which act on both the dermis and epidermis and are known to produce smoother, less wrinkled and less pigmented skin. Working in the epidermis, retinoids increase epidermal and granular layer thickness, stratum corneum compaction, decrease melanin content, and improved epidermal atypia.

The benefits of retinoids have been especially important for photodamaged skin. However, the use of retinoids was often associated with skin irritation, including dryness, peeling, erythema and sensation. These side effects decreased compliance with retinoid treatment. Additionally, the side-effects were not completely understood, but they have been known to impair barrier function when determined by the transepidermal water loss (TEWL) measurements.

Myristyl nicotinate (MN), a niacin derivative developed for optimal topical delivery of nicotinic acid to skin has been shown to enhance epidermal differentiation in photodamaged skin, which resulted in increased stratum corneum and epidermal thickness, and enhanced barrier protection. The authors proposed that simultaneous use of MN with retinoic acid would diminish loss of barrier function, improve tolerability, yet would not interfere with the efficacy of the retinoid therapy.

Methods

The authors conducted a 12-week random study. It was a double-blind, placebo controlled study to determine the effects of a 5% MN formulation on skin barrier function, clinical and sensory irritation, and clinical efficacy associated with the use of retinoic acid. The study’s participants were females age 30 to 60 with Fitzpatrick Skin Classifications of I-IV with mild to moderate photodamage, and dyschromia on the face.

The subjects were divided into 3 groups:Group 1 received a placebo for 1 month prior to initiation of retinoic acid therapy, then placebo and retinoic acid from baseline to 12 weeks; The second group received a placebo for 1 month prior to initiation of retinoic acid therapy, then MN and retinoic acid from baseline to 12 weeks.

Finally, group 3 received MN for 1 month prior to initiation of retinoic acid therapy, then MN and retinoic acid from baseline to 12 weeks.

The subjects were also given a gentle liquid cleanser and a sun protection product with SPF 30 for daily use. They were required to apply moisturizer (MN or placebo) twice daily to cleansed skin and the retinoid was applied once daily after the moisturizer during the application stage of the study.

Punch Biopsies

A 2-mm punch biopsy was collected from the right or left side of the face from 10 subjects from each group at baseline and after 12 weeks of treatment. Thirty slices from each array were cut, mounted onto glass slides and immunohistochemistry was performed.

TEWL Measurements

Subjects were required to maintain ambient conditions for at least 20 minutes and were maintained between 66 and 72 degrees Fahrenheit with humidity between 15% and 55%. Using a Dermalab instrument, the TEWL was assessed at 2 points above the skin surface and the rate of water loss. Each TEWL measurement was averaged over a 1 minute period.

Image Analyses

The authors of the study had histological images taken and analysis software was used to examine the images and perform measurements. Epidermal thickness and stratum corneum thickness were assessed. For each specimen, 5 different sites were measured and their average calculated.

Clinical Grading of Tolerability and Efficacy

Subjects were clinically graded on the right and/or left side of the face for efficacy/performance parameters and irritation/safety parameters at baseline at 2, 4, 8, and 12 weeks. For tolerability assessment; scaling, peeling, and degree of erythema were graded on a 3-point scoring system. Subjects were questioned during scheduled visits about side effects including dryness, stinging, burning, and tingling. To determine clinical efficacy subjects were assessed on a 5 point scale of 5 parameters commonly experience of retinoids for facial photodamage including dyschromia, fine lines, shallow wrinkles, tactile roughness and temple laxity.

Subject Self-Assessment of Efficacy

At the end of the study, subjects were asked to complete questionnaires regarding their perception of a decrease in signs of aging, disappearance of fine lines, increase in smoothness/softness, improvement in skin radiance and increase in healthy appearance of the skin. Subjects were to indicate if they strongly agree, agree, neither agree or disagree, disagree, or strongly disagree.

Results

Myristyl nicotinate prevents retinoic acid-associated stratum corneum thinning. The authors compared their baseline biopsy and the 12 week biopsy to determine the thickness of the stratum corneum. At baseline, they found the mean thickness of group 3, (which had been treated with MN 1 month prior and during the course of retinoic acid) was approximately 11% higher than the other two groups. This was consistent with the findings of previous studies which showed MN to increase the thickness of the stratum corneum. At 12 weeks, Group 1 saw a decrease in stratum corneum thickness of approximately 24%. Group 2 saw no thinning of the stratum corneum, while Group 3 saw an insignificant decrease in thickness. However, because there was a highly statistically significant difference in the thickness of group 3 as opposed to that of group 1, the study results indicated the use of MN mitigates stratum corneum thinning associated with retinoic acid therapy.

Myristyl Nicotinate Reduces Retinoic Acid Associated Barrier Impairment

TEWL provided a non-invasive assessment of relative barrier function and these measurements were used to mark barrier function when comparing placebo and MN-treated groups. In this study, the rate of TEWL increased in group 1 by approximately 45%. In groups 2 and 3 there was TEWL but it was not statistically significant. During the study, the rates of TEWL for group 3, was consistently lower than the other two groups indicating that concurrent use of MN mitigates barrier impairment, and that prior plus concurrent use provides greater barrier protection than concurrent use alone.

Myristyl Nicontinate Improves the Tolerability of Retinoic Acid Therapy

Clinical grading was used to assess the tolerability of retinoic acid therapy using scaling, peeling, and degree of erythema as parameters. They determined that concurrent use of MN with retinoic acid decreased the frequency of tightness/dryness, stinging and burning, while prior and concurrent MN use further reduced the frequency these side effects.

The subject’s self-assessment reflected the same results as the clinicals. Subjects also reported less frequency of comedones. In total, the results show that use of the MN improved the tolerability of retinoic acid therapy.

Myristyl nicotinate does not interfere with the and in some cases improves the efficacy of retinoic acid therapy as assessed by clinical grading and patient self-assessment

The authors used both clinical grading and patient self-assessment to assess the effect of MN on the efficacy of retinoic acid therapy on visible clinical parameters. The clinical grading involved evaluation of dyschromia, fine lines, shallow wrinkles, tactile roughness, and temple laxity. Similar rates of improvement for all three groups were observed for each of the parameters evaluated, however; group 3 showed the most improvement. With self-assessment, the subjects in group 3 rated efficacy higher than those in group 1. The results indicated that concurrent or prior or concurrent use of MN does not interfere with retinoic acid efficacy and that MN use can result in improved efficacy in some cases.

Myristyl Nicotinate Does Not Interfere with the Efficacy of Retinoic Acid Therapy as Assessed by Analysis of Skin Biopsies

Retinoids typically decrease epidermal thickness initially then after approximately 6 months epidermal thickness increases. In the study, the mean epidermal thickness of the group receiving retinoic acid and placebo cream decreased by nearly 5% over the 12-week study. Group 2 increased by 3% and group 3 saw the greatest increase at nearly 10%. These results support the possibility that MN use does accelerate efficacy of retinoic acid therapy.

Discussion

The relationship between stratum corneum thinning and increased rates of TEWL support the hypothesis that stratum corneum compaction is a factor in barrier impairment associated with retinoic acid therapy. Using paraffin-embedded samples, the study reported changes in stratum corneum thickness. Earlier studies indicated that MN stimulates increased in both epidermal and stratum corneum thickness and resulted in increased barrier function as evidenced by decreased rates of TEWL. The authors’ results demonstrated that concurrent and prior plus concurrent use of MN reduces stratum corneum thinning and reduced the increase in rates of TEWL in subjects on retinoic acid therapy. Additionally, the results presented in this study, supported the link between barrier impairment and the irritation/inflammation potential of retinoic acid. However, the use of MN to reduce stratum corneum thinning and reduce barrier impairment was coincident with reduced frequency to tightness/dryness, stinging, burning, and tingling side effects. Furthermore, the use of 1 month pretreatment with MN showed a pattern of less side-effects than did use initiated concurrent with initiation of retinoic acid therapy and that the improved tolerability was coincident with positive effects of pretreatment on barrier impairment as assessed by TEWL measurements.

The authors questioned whether MN would negatively affect the efficacy of retinoic cid therapy. The results of clinical grading of subject self-assessments argued that is not the case but that it statistically significantly increased efficacy. Additionally, the study demonstrated that MN does not interfere with retinoic acid’s efficacy while possibly accelerating the efficacy. The study results indicated that MN has no negative effect on retinoic acid therapy. The possibility that oral retinoid reduce the risk of skin cancer has been reported. This study resulted in the suggestion that use of MN in conjunction with retinoic acid to limit the progression of early stage actinic skin damage to actinic keratoses and non-melanoma skin cancer is worthy of further investigation.

Reprint requests to: Myron K. Jacobson, PhD, Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724.