Efficacy of beta-carotene topical application in melasma: An open clinical trial

Introduction

Melasma is a common acquired hypermelanosis that occurs exclusively in sun-exposed area. It is exacerbated by sun exposure, pregnancy, oral contraceptives and certain anti epileptic drugs. It is associated with epidermal melanisation without melanocyte proliferation, rather appears to be due to more efficient production of melanin granules by the melanocytes.

Beta-carotene, a structural analogous of vitamin A, works as an agonist of this vitamin, by reversibly sticking the chemical mechanism of melanogenesis, by saturating the nuclear receptors of melanocytes, and/or the binding proteins, and thus reducing the production of melanin.

Materials and Methods

For this study topical formulation containing b-carotene encapsulated in nanothalosphere, UVA/UVB sunscreens (Octyl methoxy cinnamate 4%, and Butyl-methoxy dibenzoyl methane 3%) along with barrage oil and wheat germ oil 3% manufactured by ISIS Cosmetics R&D Staff and supplied by brown & Burks Pharmaceutical for this trial.

Thirty-one patients (26 females and 05 males) clinically diagnosed to be having melasma were included in this open trial. Exclusion criteria were pregnancy, lactation, patient with less than 12 years of age, patients who have been on oral contraceptives, and patients with outdoor occupation. The selected patients underwent a complete physical examination after obtaining a detailed medical history. They were made to entertrial after obtaining a written consent. Patients who have been treated with other medications earlier were given a wash out period of two weeks. Patients were advised to refrain from using any cosmetics and to avoid sun exposure through out the trial. Patients were asked to apply the above topical formulation twice daily avoiding vigorous rubbing for eight weeks. Nine of them continued applying for 16 weeks more.

Two clinical parameters were used to assess these patients. They were melasma pigment intensity (MPI) scale and size of the lesion. MPI was rated as a 3- grade scale in relation to the patient′s normal facial skin-Grade I: slightly more pigmented, Grade II: moderately more pigmented, Grade III: markedly more pigmented. Size of the lesion is measured in terms of the percentage involvement of the face.

All the patients were followed up at an interval of two weeks for a period of eight weeks and those who continued treatment beyond eight weeks were assessed for a further period of 16 weeks at interval of four weeks. The two clinical parameters were determined prior to treatment and at each follow up visit. Clinical photograph was taken in all cases just before treatment and at the end of treatment period. The overall response to treatment was rated by the physician and the patient at end of the study as excellent (75-100% improvement), good (50-74% improvement), fair (20-49% improvement), and poor (0-19% improvement). Adverse effects were noted during each visit.

Results

Thirty-one patients, 26 females and 05 males, age ranging from 21 to 53 years with duration of pigmentation varying from 6 months to 13 years were included in the study. The intensity of pigmentation was directly proportional to the duration. Out of 31 cases 26 completed 08 weeks and 9 completed 24 weeks treatment period. Adverse effects were observed in 04 patients, two had mild erythema and two had local irritation. All these four patients were advised to discontinue treatment. One case was a defaulter from the very beginning. Among the remaining 26 patients who continued treatment regularly, not a single case showed any deterioration of the lesion. The [Table - 1] depicts the improvement of the patients as per the MPI grading. The single-I case showed complete recovery of the lesion at the end of eight weeks. Out of 13 grade II cases only one showed complete recovery, 10 showed lightening of the lesion to grade-I and rest two did not show any improvement. Out of 12 grade-III cases 10 showed lightening to grade-II, one patient to grade-I and to other one did not show any change.

From Grade-II category, those two cases who did not show any improvement during first eight weeks period, did show regression of pigmentation to grade-I on continuation of same therapy at end of 24 weeks. Similarly in grade-III category, one who did not show any improvement at eight weeks and six who had improvement from grade-III to grade-II, continued treatment till the end of 24 weeks. All of them improved to next one grade below.

[Table - 2] depicts the evaluation of the lesion as per the size of the lesion at the end of eight weeks. Five out of 26 did not show any decrease in size of the lesion, although there was definite lightening of the pigmentation. Among the nine cases who continued treatment till the end of 24 weeks, although there was improvement of severity of pigmentation, none showed complete clearing of the lesion.

[Table - 3] shows the overall patient/ physician rating of the therapeutic efficacy and clinical response at the end of 8/24 weeks. There was 100% concurrence between the patient and the physician, as regards to the overall efficacy.

Discussion

Successful treatment of melasma involves the triad of sunscreen, bleach, and time. [1] Conventional bleaching preparations include 2 to 5% hydroquinone containing lotions, gels or creams frequently is associated with leukoderma, ochronosis, and colloid milia. Similarly local corticosteroid on long them use is associated with various side effects like epidermal and dermal atrophy, stretch marks, vascular fragility, and cutaneous infection. Topical tretinoin cream (0. 025 to 0. 05%) is also helpful. The main drawback of retinoic acid is the risk of inflammation with resultant post-inflammatory hyperpigmentation.

The present formulation, beta-carotene in nanothalospheres which are special vectors to deliver the Beta-carotene into the intracellular area of melanocytes without being changed into vitamin A, i. e. thus avoid membranal enzymes. Then, beta-carotene could work as an agonist of vitamin A towards the cellular receptors of the melanocytes.

In this study, all the patients were either of grade III or grade II except one case of grade I. Since Wood′s lamp examination did not help much for Indian skin type particularly skin photo types V and VI to classify melasma to epidermal, dermal and mixed type of melasma without skin biopsy, MPI grading was used for graduation as well as evaluation purpose. By the end of 8 weeks application, except three cases, all showed gradual improvement, although excellent improvement was noticed in 19% cases [Table - 3], where as similar improvement was noticed in 44. 4% cases by the end of 24 weeks. This might be due to a big quantity of melanin, already systhesised before starting therapy, is stored at level of keratinocytes and corneocytes, therefore a certain time is necessary for the elimination of this residual melanin. However, except two cases (One grade I and one grade II) none showed complete recovery of pigmentation even at end of 24 weeks. This might be due to persistent dermal melanin component in dermal mixed type of melasma. However, broad spectrum sunscreens were added to the formulation to reduce risk of exacerbation by UV light. The tolerability of the cream appears to be good. All of the patients showed progressive improvement when they continued treatment beyond 8 weeks showing from fair to excellent result [Table - 3].

To conclude, beta-carotene in nanothalospheres appears to be an effective drug added to armamentorium of fight against melasma with minimal side effects. Long duration of treatment is associated with better result. However, a further longitudinal prospective double blind trial is required to establish its efficacy and a long term follow up to look out for recurrence with a larger number of patients.