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Evaluation of the efficacy of topical ethyl vanillate in enhancing the effect of narrow band ultraviolet B against Vitiligo: a double blind randomized, placebo-controlled clinical trial.

Introduction

Vitiligo is defined as a chronic and progressive destruction of melanocytes in the epidermis that leads to symmetric depigmented macules or patches. Vitiligo is considered as an acquired and multifactorial disease with a prevalence of 0.5-2%. The most common type is the generalized form, which affects more than 20% of body surface area. It usually can have unpredictable course. (1) There is no sex predilection and at least 30% of cases have a positive family history of vitiligo. (2)

There are multiple pathogenic hypotheses for vitiligo, including the following hypotheses:

1. Melanocyte destruction due to antibodies against their proteins

2. A defect in melanocyte structure, adhesion or survival

3. Lack of proper defense against oxidative stress

Oxidative stress may be the triggering factor for the destruction of melanocytes in the epidermis.

Free radicals like hydrogen peroxide (H2O2), super oxide, or nitric oxide are produced during different processes, including melanogenesis. (3) These reactive oxygen species inhibit tyrosinase. They are scavenged by superoxide dismutase, catalase, and other antioxidant enzymes. If these free radicals are not scavenged by antioxidants like catalase, they cause cell damage by crossing cell membrane. Catalase, the key enzyme in scavenging free radicals, changes H2O2 to H2O and O2. (4) There is a low level of catalase and other antioxidants and high levels of H2O2 in the epidermis of vitiliginous lesions. (1,4)

There are high levels of superoxide dismutase enzyme, which converts pro-oxidant superoxide into H2O2 in vitiligo. Hence, there is accumulation of H2O2 in cytoplasm or mitochondrial parts of the cell, which causes damage to melanocytes. The activity of aforementioned enzyme is higher in active vitiligo compared with stable vitiligo. (5)

There are high oxidative stress index and low serum total oxidant status values, based on a study. (6)

High levels of H2O2 and reactive oxygen species inhibit tyrosinase activity (melanogenic) through oxidation of methionine residues. (7) Also, melanocytes in vitiligo patients are more susceptible to damage than normal ones. (8) High levels of H2O2 are cytotoxic to melanocytes and lead to their destruction in the skin.

In summary, imbalance between oxidative and antioxidative processes and excess reactive oxygen species in the active vitiligo skin are thought to be pathogenic events in vitiligo. (9,10) H2O2 leads to increase production of tetrahydrobiopterin. (11)

Vanillin is a flavoring component that is used in beverages, food, and drugs. It has been proved that vanillin has a superoxide anion scavenging ability via testing with 25 mg/ml orally in mice. Vanillic acid is a metabolite of vanillin. (12) Vanillic acid is the most effective H2O2 scavenger. If H2O2 is not scavenged efficiently, it leads to the production of hydroxyl free radicals by fenton-type reactions. (13) Ethyl vanillate is vanillic acid ethyl ester. It is a white powder and soluble in alcohol and slightly water. (14)

Since narrow band ultraviolet B (NB-UVB) is one of the best modalities in the treatment of generalized vitiligo, (1) vanillic acid scavenges H2O213 and there is a high level of H2O2 in vitiliginous epidermis. (4) Thus, we decided to evaluate the efficacy of topical ethyl vanillate 20% cream (vanillic acid ethyl ester) in enhancing the effect of NB-UVB therapy in the treatment of vitiligo in order to lessen total sessions of phototherapy, lessen side effects of it, also to hasten pigmentation of lesions and most importantly strong role for oxidative stress in vitiligo.

Materials and Methods

Patient Selection

This study was a single center, doubleblind, randomized, placebo-controlled clinical trial. Among the 44 patients who came to the phototherapy center, only 30 patients (23 females (76.6%) and 7 males (23.4%)) who met the study criteria were included. They served as both cases and controls since the drug was applied on one side while the placebo was applied on the other side of their bodies. The inclusion criteria were generalized (more than 20% of body surface area), and inactive disease (no progression, nor development of new lesions within the last 3 months). The patients were selected randomly by arbitrary selection of patients' phototherapy receipt number. The process of patient selection is shown in Figure 1. The exclusion criteria were pregnant women, children less than 6 years of age, patients with a history of cutaneous malignancy, those who were immunosuppressed, taking or applying any medications for vitiligo within the last 3 months, or those with photosensitive disorders.

Study Protocol

Informed consent was obtained from each patient. The study was approved by the Ethical Committee of Shiraz Medical University and the proposal was accepted by three faculties of dermatology department. A questionnaire was filled out for each patient regarding associated autoimmune diseases like thyroid problems or diabetes, family history of vitiligo, number of phototherapy sessions prior to study, consumption of any medication, site and pattern of lesions, stability or progression of lesions, and some demographic information.

The patients were selected randomly based on their phototherapy receipt number. A third person assigned number 1 and 2 to both creams. Medication was ethyl vanillate 20% cream and placebo was Eucerin (same color as the medication). The selected patients were randomly (by tossing coins) assigned to apply cream 1 on the right side and cream 2 on the left side of the lesion. The next patient applied cream 1 on the left side and cream 2 on the right side twice daily. Two symmetric lesions (nearly the same size and location) were chosen in each patient. Meanwhile, each patient received NB-UVB, 2-3 times a week and patients were assessed in terms of any discomfort or side effect of phototherapy by a physician and the dose was adjusted when necessary. The patients were asked to report any side effect or problem with the medication or phototherapy at will. Our study for each patient lasted 12 weeks. Each patient was visited at the end of the 4th, 8th, and 12th week and evaluated in terms of response to the therapy or any significant side effects. Both the patient and physician were blinded to the treatment and placebo.

Assessments

We determined the degree of pigmentation of specified lesions on both sides prior to the study by the Vitiligo Area Severity Index (VASI) score. Photos of the lesions were taken from both sides at the end of the 4th, 8th, and 12th week in addition to pre-study photos. Then, we compared the photos at the end of the study with baseline, according to VASI score.

VASI score 100%: Depigmentation, 90%: Specks of pigment, 75%: Depigmented areas more than the pigmented areas, 50%: Equal pigmented and depigmented areas, 25%: Pigmented areas more than depigmented area and 10%: Specks of depigmentation. The patients were asked about any adverse effects of medications in each visit. There is no special unit for numbers in VASI score.

Statistical Methods

Paired t-test and Wilcoxon signed ranks test were used for statistical analysis (with SPSS 15.0 software). All results were significant if P values were 0.05 or less.

Results

Patient Population

Thirty cases of generalized vitiligo, aged from 22 to 60 years were enrolled in this study.

They were randomly instructed to apply topical ethyl vanillate 20% cream and placebo (Eucerin) twice daily on the right or left sided specified symmetrical lesions along with 2-3 times a week NB-UVB phototherapy. We chose the sample size of 30 similar to other studies as mentioned in the discussion section of this article and in consultation with a statistician (alpha=0.05, power=80 %). All patients completed the 12-week study. Test sites are mentioned in Table 1.

Treatment Efficacy

Of the 30 patients, there were 76.6% (23) female and 23.4% (7) male. 16.6% of cases had positive family history of vitiligo, 3.3% were hypothyroid, and 6.6% had diabetes. Pigmentation of lesions based on VASI (before and at the end of the trial), mean scores of pigmentation on both sides based on VASI, and the difference between both sides are shown Tables 2-4, respectively. The final results at the end of the 12th week are shown to demonstrate the maximum effect. Lower pigmentation numbers indicate more repigmentation and higher numbers show more depigmentation.

In summary, 36.6% of lesions which were treated with ethyl vanillate showed a change in pigmentation (mostly mild clinically) compared with 13.3% in placebo side. There were no changes in other cases on both sides compared with baseline. Figures 2 and 3 shows both sides of a patient (medication and placebo) before (a) and after (b) the trial.

Safety and Tolerability

Both ethyl vanillate and placebo were tolerated with a few transient burning and stinging as reported by some patients. No serious problem was observed with NB-UVB phototherapy.

Discussion

We sought to evaluate whether topical ethyl vanillate would enhance NB-UVB efficacy in the treatment of vitiligo.

This double-blinded randomized clinical trial indicated that ethyl vanillate, as an antioxidant agent, can improve repigmentation and enhance the efficacy of NB-UVB in vitiligo patients. However, such increase in pigmentation is not marked or excellent clinically. Ethyl vanillate was not tested in higher concentrations as we were not sure if patients could tolerate the medication or what the side effects would have been.

Similar to other studies, we chose to evaluate patients for 12 weeks. This was in-line with studies on tacrolimus ointment or vitamin D ointment with NB-UVB for 3 months in vitiligo patients.15 Notably, the selection of such duration was based on a textbook; where at least 2-3 months were required to evaluate the effectiveness of vitiligo treatment. (1)

Based on a review of non-surgical treatments for vitiligo, oral antioxidants were useful in the management of vitiligo, but there were no longterm follow up in most studies and the sample size was limited. (16)

Some researches were done on the role of antioxidants in the treatment of vitiligo. For instance, Elgoweini et al. (17) evaluated vitamin E along with NB-UVB against vitiligo on 24 patients. This study showed that vitamin E, as an antioxidant, could increase the efficacy of NB-UVB and induces good repigmentation (72.7% in the treatment group vs. 55.6% in the placebo group).

In another double-blind placebo controlled clinical trial on 35 patients by Dell Anna et al.,18 antioxidants such as alpha-lipoic acid, vitamins C and E were given to a treatment group before and during NB-UVB therapy. Results showed greater repigmentation of 47% in the treatment group versus 18% in the placebo group.

Contrary to the above researches, in a study by Jayanth et al. (9) on 30 stable vitiligo patients (not on any treatment for 1 month), the treatment group received oral antioxidants with photochemotherapy while the placebo group received only photochemotherapy for 3 months. There were no significant differences betweenthe groups.

Other studies compared betamethasone ointment with topical catalase/superoxide dismutase (which are deficient in vitiligo) on 25 vitiligo patients. Photos were taken and compared for both sides. No statistical difference (P=0.758) on the percentage of pigmentation was observed between the two sides (similar lesions) at 4 months. In this study, the authors suggested a stronger role for oxidative stress. (19) Topical catalase/superoxide dismutase combined with NB-UVB were evaluated on 15 vitiligo patients versus 15 patients only on NB-UVB as the control group. The patients applied the cream for 6 months. No significant changes between the groups (P > 0.05) were observed. The authors recommended larger studies to be carried out. (20)

Another study compared pseudocatalase cream with NB-UVB versus placebo and NB-UVB on 32 vitiligo patients for 24 weeks. No statistically significant difference between the groups was reported, but significant improvement was seen in each group by week 12 and was stable until the end of the study. It was concluded that pseudocatalase cream does not enhance the efficacy of phototherapy. (21)

In conclusion, some studies are in favor of antioxidants, but others are inconclusive.

Recently, a topical gel including phenylalanine, cucumis melo extract and acetyl cysteine was tested on vitiligo patients who were on phototherapy. Topical gel was applied for 12 weeks. This study showed that the gel was effective and improved repigmentation. (22)

The limitations of our study were possibly a low concentration of ethyl vanillate, the selection of some resistant to therapy sites (e.g. the hands) and poor compliance of some patients.

This study showed that ethyl vanillate could be used as an adjunct modality to NB-UVB or possibly other modalities in the treatment of vitiligo. Therefore, it can reduce the need for phototherapy by improving repigmentation. However, most patients may not notice small changes in pigmentation of lesions.

Since this study, using ethyl vanillate, was done for the first time (based on the important role of H2O2 in damaging melanocytes and efficient scavenging ability of vanillic acid), lower concentrations of ethyl vanillate was used. However, it is recommended that higher concentrations in larger studies be used in the future in order to achieve better repigmentation. Since patients cannot receive long-term phototherapy or other therapies like steroids due to adverse side effects, and stronger role for oxidative stress in the pathogenesis of vitiligo according to many studies, adjunct therapies like newer antioxidant modalities, might help accelerating repigmentation and be used as maintenance therapy.

Acknowledgment

The present article was extracted from the thesis by Amir Kalafi Shotorbani and was financially supported by Shiraz University of Medical Sciences, grant NO.90-01-01-3321. IRCT registration number IRCT201107317160N1.

Conflict of interest: None declared.

References

(1.) Ortonne J, Passeron TH. Vitiligo and other disorders of hypopigmentation. In: Bolognia J, Jorrizo JL, Rapini R, editors. Dermatology. China: Elsevier; 2012. p. 1023-9.

(2.) Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 5th ed. China: Mosby; 2010.

(3.) Kamel N, Sobhy N, Kamal H, Ismail M. A comparative study of oxidant- antioxidant status in blood and tissue in vitiligo patients. Egyptian Dermatology Online Journal. 2010; 6:1-10.

(4.) Sravani PV, Babu NK, Gopal KV, Rao GR, Rao AR, Moorthy B, et al. Determination of oxidative stress in vitiligo by measuring superoxide dismutase and catalase levels in vitiliginous and non-vitiliginous skin. Indian J Dermatol Venereol Leprol. 2009; 75:268-71. PubMed PMID: 19439879.

(5.) Laddha NC, Dwivedi M, Gani AR, Shajil EM, Begum R. Involvement of superoxide dismutase isoenzymes and their genetic variants in progression of and higher susceptibility to vitiligo. Free Radic Biol Med. 2013; 65:1110-25. doi: 10.1016/j. freeradbiomed.2013.08.189. PubMed PMID: 24036105.

(6.) Akoglu G, Emre S, Metin A, Akbas A, Yorulmaz A, Isikoglu S, et al. Evaluation of total oxidant and antioxidant status in localized and generalized vitiligo. Clin Exp Dermatol. 2013; 38:701-6. doi: 10.1111/ ced.12054. PubMed PMID: 23601201.

(7.) Glassman SJ. Vitiligo, reactive oxygen species and T-cells. Clin Sci (Lond). 2011; 120:99-120. doi: 10.1042/CS20090603. PubMed PMID: 20958268.

(8.) Guerra L, Dellambra E, Brescia S, Raskovic D. Vitiligo: pathogenetic hypotheses and targets for current therapies. Curr Drug Metab. 2010; 11:451-67. doi: 10.2174/138920010791526105. PubMed PMID: 20540698.

(9.) Jayanth DP, Pai BS, Shenoi SD, Balachandran C. Efficacy of antioxidants as an adjunct to photochemotherapy in vitiligo: a case study of 30 patients. Indian J Dermatol Venereol Leprol. 2002; 68:202-5. PubMed PMID: 17656936.

(10.) Jalel A, Hamdaoui MH. Study of total antioxidant status and glutathione peroxidase activity in Tunisian vitiligo patients. Indian J Dermatol. 2009; 54:13-6. doi: 10.4103/00195154.48978. PubMed PMID: 20049261; PubMed Central PMCID: PMC2800862.

(11.) Chavan B, Beazley W, Wood JM, Rokos H, Ichinose H, Schallreuter KU. H(2)O(2) increases de novo synthesis of (6R)-Lerythro-5,6,7,8-tetrahydrobiopterin via GTP cyclohydrolase I and its feedback regulatory protein in vitiligo. J Inherit Metab Dis. 2009; 32:86-94. doi: 10.1007/s10545-0080971-1. PubMed PMID: 19101819.

(12.) Tai A, Sawano T, Yazama F, Ito H. Evaluation of antioxidant activity of vanillin by using multiple antioxidant assays. Biochim Biophys Acta. 2011; 1810:170-7. doi: 10.1016/j.bbagen.2010.11.004. PubMed PMID: 21095222.

(13.) Mansouri A, Makris DP, Kefalas P. Determination of hydrogen peroxide scavenging activity of cinnamic and benzoic acids employing a highly sensitive peroxyoxalate chemiluminescence-based assay: structure-activity relationships. J Pharm Biomed Anal. 2005; 39:22-6. doi: 10.1016/j.jpba.2005.03.044. PubMed PMID: 15953704.

(14.) Ethyl Vanillate [Internet]. Wisconsin: Goodscents,Inc.[cited2010 Feb 20].Available from: http://www.thegoodscentscompany. com/data/rw1043971.html

(15.) Sprang NV, Kersten S. Combination therapy enhances effect of NB-UVB for treatment of vitiligo. A systematic review. Erasmus Journal of Medicine. 2011; 1:43-6.

(16.) Bacigalupi RM, Postolova A, Davis RS. Evidence-based, non-surgical treatments for vitiligo: a review. Am J Clin Dermatol. 2012; 13:217-37. doi: 10.2165/11630540000000000-00000. PubMed PMID: 22423621.

(17.) Elgoweini M, Nour El, Din N. Response of vitiligo to narrowband ultraviolet B and oral antioxidants.J ClinPharmacol.2009; 49:852-5. doi: 10.1177/0091270009335769. PubMed PMID: 19553407.

(18.) Dell'Anna ML, Mastrofrancesco A, Sala R, Venturini M, Ottaviani M, Vidolin AP, et al. Antioxidants and narrow band-UVB in the treatment of vitiligo: a double-blind placebo controlled trial. Clin Exp Dermatol. 2007; 32:631-6. doi: 10.1111/j.1365 2230.2007.02514.x. PubMed PMID: 17953631.

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Mohammad Reza Namazi [1,2], MD; Amir Kalafi Shotorbani [1,3], MD

[1] Molecular Dermatology Research Center, Department of Dermatology, Shiraz University of Medical Sciences, Shiraz, Iran;

[2] Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran;

[3] Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran

Correspondence:

Amir Kalafi Shotorbani, MD; Department of Dermatology, Faghihi Hospital, Zand Street, Shiraz, Iran

Tel/Fax: +98 71 32319049

Email: amirkalafi@yahoo.com

Received: 11 November 2013

Revised: 14 January 2014

Accepted: 08 February 2014

Table 1: Sites (symmetrical) selected for test

Elbow 5     Ankle 1   Wrist 6   Arm 1    Hand 4
Forearm 6   Chest 1   Leg 3     Knee 2   Finger 1

Table 2: Pigmentation of lesions based on VASI
(baseline, end of trial)

Patient   Pig (VASI)   Pig (VASI)       VASI       VASI 12th
no        before med   before placebo   12th Med   placebo

1         100          100              100        100
2         90           75               75         75
3         90           100              90         100
4         50           50               50         50
5         100          100              100        100
6         90           90               90         90
7         100          75               50         50
8         75           90               50         75
9         100          100              90         100
10        75           100              75         100
11        100          100              90         100
12        100          100              90         100
13        100          100              90         100
14        100          100              90         100
15        75           75               50         50
16        100          90               90         90
17        90           90               90         90
18        75           75               75         75
19        100          100              100        100
20        100          100              100        100
21        100          100              100        100
22        100          75               90         75
23        90           90               90         90
24        75           75               75         75
25        100          100              100        100
26        100          100              100        100
27        100          100              100        100
28        50           50               50         50
29        100          100              100        90
30        90           100              75         100

Patient   Phototherapy sessions   Site of
no        before study            lesion

1         30                      Wrist
2         16                      Elbow
3         64                      Wrist
4         42                      Forearm
5         38                      Forearm
6         15                      Leg
7         24                      Leg
8         17                      Arm
9         60                      Wrist
10        20                      Forearm
11        38                      Knee
12        58                      Chest
13        21                      Wrist
14        37                      Hand
15        150                     Forearm
16        20                      Forearm
17        119                     Ankle
18        23                      Elbow
19        65                      Wrist
20        10                      Finger
21        10                      Elbow
22        104                     Hand
23        100                     Wrist
24        82                      Hand
25        10                      Hand
26        8                       Elbow
27        1                       Elbow
28        170                     Elbow
29        24                      Leg
30        18                      Forearm

Table 3: Mean scores of pigmentation based on
VASI (medication and placebo sides)

Indices             Mean [+ or -] SD
                    pigmentation             N

Before med          90.50 [+ or -] 14.40     30
After med           83.83 [+ or -] 17.50     30
Before placebo      90.00 [+ or -] 14.68     30
After placebo       87.50 [+ or -] 17.55     30

There was a significant change after applying ethyl
vanillate compared with baseline (P=0.002) on medication
side, but no significant change in placebo side (before and
after placebo) (P=0.066)

Table 4: Difference in mean pigmentation between
medication and placebo sides

Indices             Diff mean [+ or -] SD
                    pigmentation             P value

Med side            6.66 [+ or -] 11.09      0.002
Placebo side        2.50 [+ or -] 6.91       0.066

There was a significant difference between medication and
placebo sides (P=0.005)
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Title Annotation:Original Article
Author:Namazi, Mohammad Reza; Shotorbani, Amir Kalafi
Publication:Iranian Journal of Medical Sciences
Article Type:Report
Date:Nov 1, 2015
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