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

Introduction

Melasma is a relatively common acquired symmetric hypermelanosis characterised by irregular light to grey brown macules involving sun-exposed areas. It is exacerbated by sun exposure, pregnancy, oral contraceptives, 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 melonocytes.

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

Materials and Methods

For this study topical formulation containing Beta-carotene encapsulated in nanothalospere, UVA/UVB screens (Octyl methoxy cinnamata 4%, and Butyl-methoxy dibenzoyl methane 3% ) along with barrage oil 1 % and germ oil 3% as bases in the trial group. The second topical formulation containing same sunscreens and bases, but without Beta-carotene was used for the control group.

Thirty one patients (26 females and 05 males) in trial group and well matched 12 patients (10 females and 02 males) in control group, clinically diagnosed to be having melasma, were included in this study. 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 enter trial after obtaining a written consent. Patients who had been treated with other medications 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. The trial group cases 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. The control group cases used the second topical formulation twice daily for eight weeks.

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 three 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 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 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

The trial group patients (age ranging from 21 to 53 years) were having melasma of various grades [Table - 1] with duration varying from - 6 months to 13 years. The intensity of pigmentation was directly proportional to the duration. Out of 31 trial cases 26 and 09 completed 8 weeks and 24 weeks treatment period respectively. Adverse effects were observed in four cases, two with mild erythema and two with local irritation. They were advised to discontinue treatment as per the protocol. One case was a defaulter from the very beginning, Among the remaining 26 patients who continued treatment regularly, no case showed any deteriortion of the lesion. The [Table - 1] depicts the improvement as at the end of eight weeks, out of 13 grade- II cases only one showed complete recovery. 10 showed lightening of lesion to grade-l, one patient to grade-II and 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. Only two cases showed complete recovery of lesion.

[Table - 3] showed 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.

All 12 cases in control group (age ranging from 20 to 51 year and duration of pigmentation varying from 6 months to 12 years) have completed eight weeks treatment period. Out of these 12 patients (two with grade - I, six in grade - II, and four grade - III) after eight weeks treatment, none showed any reduction of pigmentation or size except one case of grade-I I, who showed reduction of pigmentation of grade--I. However, none showed any exacerbation of lesion. One case had local irritation to topical sunscreens. The overall patient/physician rating of the therapeutic efficacy at the end of eight weeks in control groups showed 100% concurrence.

Discussion

Melasma is often a therapeutically challenging disease, and current treatments include hypopigmenting agents, chemical peels, and laser.[1] Conventional bleaching preparations include 2 to 5% hydroquione containing lotions, gels or creams which is frequently associated with leukoderma, ochronosis, and colloid milia. Similarly local corticosteroid on long term 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.[2] The main drawback of retinoic acid is the risk of inflammation with resultant post-inflammatory hyperpigmentation.

In the present formulation, Beta-carotene is encapsulated in nanthalasphers, which are special vectors to deliver the Beta-carotene into the intracellular area of melanocytes without being changed into vitamin A thus avoiding membrane 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 three cases of grade I. Since Wood′s lamp examination did not help much for Indian skin type particularly skin photo types V & VI to classify melasma to epidermal, dermal and mixed type of melasma without skin biopsy, MPI grading was used for gradation as well as for 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 persistent demal melanin component in dermal and mixed type of melasma. However, broad spectrum sunscreens were added to the formulation to reduce risk of exacerbation by U V 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]. In the control group, topical application of sunsreens for a period of eight weeks, did not show any decrease in size or improvement of pigmentation except one case.

To conclude, Beta-carotene in nanothalospheres appears to be an effective drug added to armamentorium to fight against melasma with minimal side effects. Long duration of treatment is associated with better result. However, a long term follow up is necessary to look out for recurrence with a larger number of patients.