Background: Mosquito bite reaction is a common skin disease. Topical steroids and oral antihistamines are the conventional treatment. However, the side effects from prolonged use of topical steroids are the limitation of the treatment. Recently, herbal extracts are emerging interest for an alternative anti-inflammatory dermatoses therapy. Objective: To assess the effectiveness of herbal extracted gel containing, Perilla frutescens, Portulaca oleracea, Ipomoea pescaprae, Aloe vera, Centella asiatica and Broussonetia papyrifera in comparing with 1% hydrocortisone (HC) gel. Material and Methods: An experimental study was conducted on 50 mosquito bite hypersensitive volunteers (15 - 19 years old) with double-blinded split randomized control method. After the volunteers were exposed for one bite on their arms by a non-infectious mosquito, Aedes albopictus, the drugs were applied twice daily. The diameter of lesion, pruritus analog score, erythema and melanin index were measured at 2, 6, 24 hours and 2, 3, 4 weeks. The volunteers “self-satisfaction” and side effects were recorded. Results: The mean age was 17.42 ± 1.14 years old. The diameter of lesion, pruritus analog score, erythema and melanin index were decreased on both sides at each visit with significant difference (p < 0.05). There was no significant difference between two agents of all parameters and the satisfaction of the volunteers (p > 0.05). The post-inflammatory hyperpigmentation rate of 1% HC and herbal gel was 64% and 54% respectively without significant difference (p = 0.267). Conclusion: The herbal gel was as effective as 1% HC for the treatment of acute and late reaction of mosquito bite reaction in adolescent. It may be used as the alternative treatment for mosquito bite reaction.
Mosquito bite reaction is very common in children especially who live in tropical countries [1,2].The clinical manifestation is starting with an immediate type I hypersensitivity response which is presented as wheals and flares within 20 minutes. Then it is followed by the delayed type IV hypersensitivity reaction which is presented as itching, burning, erythematous, edematous papules, occured approximately 24 hours later and may last for several days. The common complications of mosquito bite reaction are secondary skin infection such as impetigo, ecthyma, post-inflammatory hyperpigmentation and scar.
There are many herbal extract medicaments for various treatments of indications such as anti-inflammation, scar and pigmentation. Recently, there is an immerging interest in topical non-steroidal anti-inflammatory agents including herbal extracts [4], for example, the study which showed that moisturizer containing licochalcone A was as effective as 1% hydrocortisone (HC) in the treatment of childhood atopic dermatitis [5]. This present study, a combination of herbal extracted gel was assessed on the effectiveness in comparing with 1% HC gel. The herbal extracts included Ipomoea pescaprae, Perilla frutescens, Portulaca oleracea, Centella asiatica, Aloe vera, Allium cepa for the anti-inflammatory effect and Brous- sonetia papyrifera for the depigmentatory effect. The hypothesis of this study is that the herbal extract is as effective as 1% HC in the treatment of mosquito bite reaction.
2. Patients and Methods
Fifty mosquito bite hypersensitive adolescences (aged 15 - 19 years old) who have history of popular urticaria (pruritic, edematous, erythematous papules with central punc- tum) with or without post-inflammatory hypo/hyperpig- mentation, scars on extremities from mosquito bites in the field, were recruited in this study. They must have at least Fitzpatrick’s photo-skintype III and normal skin on the tested areas. The volunteers who received topical corticosteroids, anti-inflammatory drugs, or oral antihistamines for 2 weeks and oral corticosteroids for 4 weeks before initiating the study were excluded. All eligible volunteers agree to participate by signing the informed consent form according to the Declaration of Helsinki (1964).
The descriptive analysis was used on the demographic data. Comparison of the lesion size, the intensity of pruritus, erythema, hyperpigmentation between both arms was done by using paired t-test and the outcomes from each visit were analysed by using repeated ANOVA. The global satisfactory were evaluated by using McNemar Test. The significance of all values is attained when p < 0.05. This study was approved by the clinical ethic committee of Faculty of Medicine, Srinakharinwirot University.
3. Results
Fifty volunteers completed the study protocol. The mean age of the volunteers was 17.42 ± 1.14 years old; 48 were female. Concerning the Fitzpatrick photo-skin type of the volunteers, 25/50(50%), 15/50(30%) and 10/50(20%) were types III, IV and V respectively.
In both treatment groups, the pruritus score reduced significantly after 2 hours (p < 0.05) and continued to decrease after 1 week. After 2 weeks, there was no pruritic symptom (Figure 2). There was no significance in size difference between the treatments with 1% hydrocortisone gel and herbal extracted gel (p = 0.849).
Initially, on both sides, the erythema of the lesions increased within 24 hours and then decreased significantly at each visit (p < 0.05) (Figure 3). There was no significant difference between the treatments with both agents (p = 0.860).
Less post-inflammatory hyperpigmentation was observed on the treatment group with herbal extracted gel
The comparison of diameter of the lesions between 1% hydrocortisone and herbal extracted gel
The comparison of pruritus (VAS) between 1% hydrocortisone and herbal extracted gel
The comparison of erythema index between 1% hydrocortisone and herbal extracted gel
compared to 1% hydrocortisone gel (54% VS 64%). However, there was no significant group difference (p = 0.267) (Table 1). By using Mexameter MX16, melanin index, both groups increased in pigment intensities by week 1 - 2 and then started to decrease in the week 3 and 4 (Figure 4). There was also no significant difference between the treatments with 1% hydrocortisone gel and herbal extracted gel (p = 0.562).
Regarding the volunteers’ self satisfaction to the treat- ments, the volunteers evaluated the excellent outcomes in majority of the cases on both agents (58%―for 1% hydrocortisone gel; 66%―for herbal extracted gel) (Figure 5). There was no significant difference between the two agents (p = 0.481).
4. Discussion
The results of this experimental study showed that the combination of herbal extracts could improve the mosquito bite reaction both subjective measurements (diameter of lesions, pruritus score), objective assessments (erythema index, melanin index), and volunteer’s self satisfactions evaluation with statistically significant difference from the base line. When the effectiveness was compared with 1% HC, it was demonstrated that there was no significant difference. Though the prevalence of post inflammation was lower in the herbal extracted gel treated group (54% for herbal extracted gel group VS 64% for 1% HC), there was no statistically signifi-
Post Inflammatory Hyperpigmentation (PIH) between two agents
Total Value
PIH
% with PIH
p value
1% Hydrocortisone gel
50
32
64%
p = 0.267
Herbal extracted gel
50
27
54%
The comparison of melanin index between 1% hydrocortisone and herbal extracted gel
The comparison of volunteer’s satisfaction between 1% hydrocortisone and herbal extracted gel
cant group difference, as well as the melanin index reduction score.
The herbal extracted gel used in this study containing a combination of Ipomoea pescaprae, Centella asiatica, Perilla frutescens, Portulaca oleracea, and Aloe vera for the anti-inflammatory properties. There were studies demonstrated that these herbal extracts had anti-inflam- matory actions. In vitro study, beta-damascenone, an active ingredient extracted from Ipomoea pescaprae [6,7], and asiaticoside from Centella asiatica [8] exhibit anti- inflammatory effect through prostaglandins formation inhibition. Oral intake of Perilla frutescens Britton leaves which contain high amount of rosmarinic acid, apolyphenolic phytochemical, demonstrated the inhibitory effect on mice ear passive cutaneous anaphylaxis reaction [9]. It can inhibit house dust mite induced asthma in mouse model by inhibiting the enhanced protein expression of Interleukin (IL)-4, IL-5, eotaxin and specific IgG [10,11]. In addition, rosmarinic acid in Perilla frutescens also protects against UV-induced of murine skin [12].
Linolenic acid from Portulaca oleracea shows anti-in- flammatory action via prostaglandins formation inhibition both in vitro and in vivo studies [13,14]. In vitro study of aloins and 1, 8 dihydroxyanthraquinone, the major active ingredients of Aloe vera demonstrated the inhibitory action on the prostaglandin E production [15], IL-8 [15-18], tumor necrotic factor-alpha, IL-6 [17], and leukocyte adhesion inhibition as well [17,19]. Concerning clinical trial, the systematic review of Aloe vera effectiveness shows that topical application of this agent might be effective for genital herpes [20] and psoriasis [16,20]. Moreover there was clinical trial demonstrated its effectiveness on a partial thickness burn wound [21].
Finally, regarding the treatment of post-inflammatory hyperpigmentation after the recovering from skin inflammation, Kazinol F extracted from Broussonetia papyrifera plays the major role. The mechanism of action is through the inhibition of tyrosinase [22], and L-dihy- droxyphenylalanine (DOPA) auto-oxidation [23].
Some species of mosquito, for example, Aedes albopictus that was used in this study, can survive even in the cold weather. Although, mosquitoes bite reaction is the common problem of the people especially the children in tropical countries. Because of the global warming problem, this skin reaction might be the major problem of the people living in the temperate countries in the future. Taken together with the limitation of long term topical corticosteroid application as we described previously, this herbal extract medications which have anti-inflam- matory properties may be an alternative treatment.
5. Conclusion
The herbal extracted gel with anti-inflammation and depigmentation properties used in this study is as effective as 1% hydrocortisone gel in treatment of both immediate and delayed mosquito bite reactions in adolescents. The herbal extracted gel might be used as the alternative treatment.
Acknowledgements
We would like to acknowledge Department of Medical Entomology, Faculty of Topical Medicine, Mahidol University, Bangkok, Thailand for supplying the mosquitoes for this experimental study, Dr Suchada Boonit for the English grammars correction, Bangkok botanica Ltd., for herbal extracted gel.
REFERENCES
[1] K. Oka and N. Ohtaki, “Clinical Observations of Mos- quito Bite Reactions in Man: A Survey of the Relation- ship between Age and Bite Reaction,” The Journal of Dermatology, Vol. 16, 1989, pp. 212-219.
[2] K. Kulthanan, S. Wongkamchai and D. Triwongwaranat, “Mosquito Allergy: Clinical Features and Natural Course,” Journal of Dermatology, Vol. 37, No. 12, 2010, pp. 1025- 1031. http://dx.doi.org/10.1111/j.1346-8138.2010.00958.x
[3] T. Reunala, H. Brummer-Korvenkontio, A. Karppinen, P. Coulie and T. Palosuo, “Treatment of Mosquito Bites with Cetirizine,” Clinical and Experimental Allergy, Vol. 23, No. 1, 1993, pp. 72-75. http://dx.doi.org/10.1111/j.1365-2222.1993.tb02487.x
[4] J. H. Klotz, S. A. Klotz and J. L. Pinnas, “Animal Bites and Stings with Anaphylactic Potential,” The Journal of Emergency Medicine, Vol. 36, No. 2, 2009, pp. 148-156. http://dx.doi.org/10.1016/j.jemermed.2007.06.018
[5] M. Udompataikul and W. Srisatwaja, “Comparative Trial of Moisturizer Containing Licochalcone A vs Hydrocor- tisone Lotion in the Treatment of Childhood Atopic Der- matitis: A Pilot Study,” Journal of the European Academy of Dermatology and Venerology, Vol. 25, No. 6, 2010, pp. 660-665. http://dx.doi.org/10.1111/j.1468-3083.2010.03845.x
[6] U. Pongprayoon, L. Bohlin, P. Baeckstrom, U. Jacobsson, M. Linstrom, P. Soonthornsaratune and S. Wasuwat, “Anti-Inflammatory Activity of Ipomoea Pes-Caprae,” Planta Medica, 1990, pp. 656-661.
[7] U. Pongprayoon, P. Baeckstrom, U. Jacobsson, M. Lind- strom and L. Bohlin, “Compounds Inhibiting Prostaglan- din Synthesis Isolated from Ipomoea Pes-Caprae,” Planta Medica, Vol. 57, No. 6, 1991, pp. 515-518. http://dx.doi.org/10.1055/s-2006-960196
[8] C. A. Dunstan, Y. Noreen, G. Serrano, P. A. Cox, P. Pe- rera and L. Bohlin, “Evaluation of Some Samoan and Pe- ruvian Medicinal Plants by Prostaglandin Biosynthesis and Rat Ear Oedema Assays,” Journal of Ethnopharma- cology, Vol. 57, No. 1, pp. 35-56. http://dx.doi.org/10.1016/S0378-8741(97)00043-3
[9] T. Makino, Y. Furuta, H. Wakushima, H. Fuji, K. Saito and Y. Kano, “Anti-Allergic Effect of Perillafrutescens and Its Active Constituents,” Phytotherapy Research, Vol. 17, No. 3, 2003, pp. 240-243. http://dx.doi.org/10.1002/ptr.1115
[10] C. Sanbongi, H. Takano, N. Osakabe, N. Sasa, M. Nat- sume, R. Yanagisawa, et al., “Rosmarinic Acid in Perilla Extract Inhibits Allergic Inflammation Induced by Mite Allergen, in a Mouse Model,” Clinical & Experimental Allergy, Vol. 34, No. 6, 2004, pp. 971-977. http://dx.doi.org/10.1111/j.1365-2222.2004.01979.x
[11] K. Inoue, H. Takano, A. Shiga, Y. Fujita, H. Makino, R. Yanagisawa, et al., “Effects of Volatile Constituents of a Rosemary Extract on Allergic Airway Inflammation Re- lated to House Dust Mite Allergen in Mice,” Internation- al Journal of Molecular Medicine, Vol. 16, No. 2, 2005, pp. 315-319.
[12] M. Sanchez-Compillo, J. A. Gabaldon, J. Castillo, O. Be- navente-Garcia, M. J. Del Bano, M. Alcaraz, et al., “Ros- marinic Acid, a Photo-Protective Agent against UV and Other Ionizing Radiations,” Food and Chemical Toxicol- ogy, Vol. 47, No. 2, 2009, pp. 386-392. http://dx.doi.org/10.1016/j.fct.2008.11.026
[13] K. Chan, M. W. Islam, M. Kamil, R. Radhakrishnan, M. N. M. Zakaria, M. Habibullah, et al., “The Analgesic and Anti-Inflammatory Effects of Portulaca oleracea L. Subsp. sativa (Haw.) Celak,” Journal of Ethnopharmacology, Vol. 73, No. 3, 2000, pp. 445-451. http://dx.doi.org/10.1016/S0378-8741(00)00318-4
[14] Y. Y. Lim, H. M. Kim, W. S. Park, J. H. Kim, H. J. Shin, M. N. Kim, et al., “Anti-Inflammatory and Anti-Pruritic Effects of Portulaca oleracea L. Extract Using in Vitro and in Vivo Inflammation Model: LPS-Treated Raw264.7 Cells, Keratinocytes, NC/Nga Mice and Hairless SKH-1 Mice,” Korean Journal of Asthma, Allergy and Clinical Immunology, Vol. 31, No. 3, 2011, pp. 199-206.
[15] B. Vazquez, G. Avila, D. Segura and B. Escalante, “An- ti-Inflammatory Activity of Extracts from Aloe Verage,” Journal of Ethnopharmacology, Vol. 55, No. 1, 1996, pp. 69-75. http://dx.doi.org/10.1016/S0378-8741(96)01476-6
[16] T. A. Syed, S. A. Ahmad, A. H. Holt, S. H. Ahmad and M. Afzal, “Management of Psoriasis with Aloe Vera Ex- tract in a Hydrophilic Cream: A Placebo-Controlled, Double-Blind Study,” Tropical Medicine & International Health, Vol. 1, No. 4, 1996, pp. 505-509. http://dx.doi.org/10.1046/j.1365-3156.1996.d01-91.x
[17] D. Duansak, J. Somboonwonng and S. Patumraj, “Effects of Aloe Vera on Leukocyte Adhesion and TNF-Alpha and IL-6 Levels in Burn Wounded Rats,” Clinical Hemorhe- ology and Microcirculation, Vol. 29, No. 3-4, 2003, pp. 239-246.
[18] L. Langmead, R. J. Makins and D. S. Rampton, “Anti- Inflammatory Effects of Aloe Vera Gel in Human Colo- rectal Mucosa in Vitro,” Alimentary Pharmacology & The- rapeutics, Vol. 19, No. 5, 2004, pp. 521-527. http://dx.doi.org/10.1111/j.1365-2036.2004.01874.x
[19] J. Somboonwond, S. Thanamittramanee, A. Jariyapongs- kul and S. Patumraj, “Therapeutic Effects of Aloe Vera on Cutaneous Microcirculation and Wound Healing in Second Degree Burn Model in Rats,” Journal of the Medical Association of Thailand, Vol. 83, No. 4, 2000, pp. 417-425.
[20] B. K. Vogler and E. Ernst, “Aloe Vera: A Systematic Re- view of Its Clinical Effectiveness,” British Journal of General Practice, Vol. 49, 1999, pp. 823-828.
[21] V. Visuthikosol, B. Chowchuen, Y. Sukwanarat, S. Sri- urairatana and V. Boonpucknavig, “Effect of Aloe Vera Gel to Healing of Burn Wound a Clinical and Histologic Study,” Journal of the Medical Association of Thailand, Vol. 78, No. 8, 1995, pp. 403-409.
[22] Z.-P. Zheng, K.-W. Cheng, J. F. Chao, J. J. Wu and M. F. Wang, “Tyrosinase Inhibitors from Paper Mulberry (Br- oussonetia papyrifera),” Food Chemistry, Vol. 106, No. 2, 2008, pp. 529-535. http://dx.doi.org/10.1016/j.foodchem.2007.06.037
[23] J.-H. Hwang and B. M. Lee, “Inhibitory Effects of Plant Extracts on Tyrosinase, L-DOPA Oxidation, and Melanin Synthesis,” Journal of Toxicology and Environmental Health, Part A, Vol. 70, No. 5, 2007, pp. 393-407. http://dx.doi.org/10.1080/10937400600882871
*Corresponding author.
ReferencesK. Oka and N. Ohtaki, “Clinical Observations of Mosquito Bite Reactions in Man: A Survey of the Relationship between Age and Bite Reaction,” The Journal of Dermatology, Vol. 16, 1989, pp. 212-219.K. Kulthanan, S. Wongkamchai and D. Triwongwaranat, “Mosquito Allergy: Clinical Features and Natural Course,” Journal of Dermatology, Vol. 37, No. 12, 2010, pp. 1025-1031. http://dx.doi.org/10.1111/j.1346-8138.2010.00958.xT. Reunala, H. Brummer-Korvenkontio, A. Karppinen, P. Coulie and T. Palosuo, “Treatment of Mosquito Bites with Cetirizine,” Clinical and Experimental Allergy, Vol. 23, No. 1, 1993, pp. 72-75.
http://dx.doi.org/10.1111/j.1365-2222.1993.tb02487.xJ. H. Klotz, S. A. Klotz and J. L. Pinnas, “Animal Bites and Stings with Anaphylactic Potential,” The Journal of Emergency Medicine, Vol. 36, No. 2, 2009, pp. 148-156.
http://dx.doi.org/10.1016/j.jemermed.2007.06.018M. Udompataikul and W. Srisatwaja, “Comparative Trial of Moisturizer Containing Licochalcone A vs Hydrocortisone Lotion in the Treatment of Childhood Atopic Dermatitis: A Pilot Study,” Journal of the European Academy of Dermatology and Venerology, Vol. 25, No. 6, 2010, pp. 660-665.
http://dx.doi.org/10.1111/j.1468-3083.2010.03845.xU. Pongprayoon, L. Bohlin, P. Baeckstrom, U. Jacobsson, M. Linstrom, P. Soonthornsaratune and S. Wasuwat, “Anti-Inflammatory Activity of Ipomoea Pes-Caprae,” Planta Medica, 1990, pp. 656-661.U. Pongprayoon, P. Baeckstrom, U. Jacobsson, M. Lindstrom and L. Bohlin, “Compounds Inhibiting Prostaglandin Synthesis Isolated from Ipomoea Pes-Caprae,” Planta Medica, Vol. 57, No. 6, 1991, pp. 515-518.
http://dx.doi.org/10.1055/s-2006-960196C. A. Dunstan, Y. Noreen, G. Serrano, P. A. Cox, P. Perera and L. Bohlin, “Evaluation of Some Samoan and Peruvian Medicinal Plants by Prostaglandin Biosynthesis and Rat Ear Oedema Assays,” Journal of Ethnopharmacology, Vol. 57, No. 1, pp. 35-56.
http://dx.doi.org/10.1016/S0378-8741(97)00043-3T. Makino, Y. Furuta, H. Wakushima, H. Fuji, K. Saito and Y. Kano, “Anti-Allergic Effect of Perillafrutescens and Its Active Constituents,” Phytotherapy Research, Vol. 17, No. 3, 2003, pp. 240-243.
http://dx.doi.org/10.1002/ptr.1115C. Sanbongi, H. Takano, N. Osakabe, N. Sasa, M. Natsume, R. Yanagisawa, et al., “Rosmarinic Acid in Perilla Extract Inhibits Allergic Inflammation Induced by Mite Allergen, in a Mouse Model,” Clinical & Experimental Allergy, Vol. 34, No. 6, 2004, pp. 971-977.
http://dx.doi.org/10.1111/j.1365-2222.2004. 01979.xK. Inoue, H. Takano, A. Shiga, Y. Fujita, H. Makino, R. Yanagisawa, et al., “Effects of Volatile Constituents of a Rosemary Extract on Allergic Airway Inflammation Related to House Dust Mite Allergen in Mice,” International Journal of Molecular Medicine, Vol. 16, No. 2, 2005, pp. 315-319.M. Sanchez-Compillo, J. A. Gabaldon, J. Castillo, O. Benavente-Garcia, M. J. Del Bano, M. Alcaraz, et al., “Rosmarinic Acid, a Photo-Protective Agent against UV and Other Ionizing Radiations,” Food and Chemical Toxicology, Vol. 47, No. 2, 2009, pp. 386-392.
http://dx.doi.org/10.1016/j.fct.2008.11.026K. Chan, M. W. Islam, M. Kamil, R. Radhakrishnan, M. N. M. Zakaria, M. Habibullah, et al., “The Analgesic and Anti-Inflammatory Effects of Portulaca oleracea L. Subsp. sativa (Haw.) Celak,” Journal of Ethnopharmacology, Vol. 73, No. 3, 2000, pp. 445-451.
http://dx.doi.org/10.1016/S0378-8741(00) 00318-4Y. Y. Lim, H. M. Kim, W. S. Park, J. H. Kim, H. J. Shin, M. N. Kim, et al., “Anti-Inflammatory and Anti-Pruritic Effects of Portulaca oleracea L. Extract Using in Vitro and in Vivo Inflammation Model: LPS-Treated Raw264.7 Cells, Keratinocytes, NC/Nga Mice and Hairless SKH-1 Mice,” Korean Journal of Asthma, Allergy and Clinical Immunology, Vol. 31, No. 3, 2011, pp. 199-206.B. Vazquez, G. Avila, D. Segura and B. Escalante, “Anti-Inflammatory Activity of Extracts from Aloe Verage,” Journal of Ethnopharmacology, Vol. 55, No. 1, 1996, pp. 69-75. http://dx.doi.org/10.1016/ S0378-8741(96)01476-6T. A. Syed, S. A. Ahmad, A. H. Holt, S. H. Ahmad and M. Afzal, “Management of Psoriasis with Aloe Vera Extract in a Hydrophilic Cream: A Placebo-Controlled, Double-Blind Study,” Tropical Medicine & International Health, Vol. 1, No. 4, 1996, pp. 505-509.
http://dx.doi.org/10.1046/j.1365-3156.1996. d01-91.xD. Duansak, J. Somboonwonng and S. Patumraj, “Effects of Aloe Vera on Leukocyte Adhesion and TNF-Alpha and IL-6 Levels in Burn Wounded Rats,” Clinical Hemorheology and Microcirculation, Vol. 29, No. 3-4, 2003, pp. 239-246.L. Langmead, R. J. Makins and D. S. Rampton, “AntiInflammatory Effects of Aloe Vera Gel in Human Colorectal Mucosa in Vitro,” Alimentary Pharmacology & Therapeutics, Vol. 19, No. 5, 2004, pp. 521-527.
http://dx.doi.org/10.1111/j.1365-2036.2004.01874.xJ. Somboonwond, S. Thanamittramanee, A. Jariyapongskul and S. Patumraj, “Therapeutic Effects of Aloe Vera on Cutaneous Microcirculation and Wound Healing in Second Degree Burn Model in Rats,” Journal of the Medical Association of Thailand, Vol. 83, No. 4, 2000, pp. 417-425.B. K. Vogler and E. Ernst, “Aloe Vera: A Systematic Review of Its Clinical Effectiveness,” British Journal of General Practice, Vol. 49, 1999, pp. 823-828.V. Visuthikosol, B. Chowchuen, Y. Sukwanarat, S. Sriurairatana and V. Boonpucknavig, “Effect of Aloe Vera Gel to Healing of Burn Wound a Clinical and Histologic Study,” Journal of the Medical Association of Thailand, Vol. 78, No. 8, 1995, pp. 403-409.Z.-P. Zheng, K.-W. Cheng, J. F. Chao, J. J. Wu and M. F. Wang, “Tyrosinase Inhibitors from Paper Mulberry (Broussonetia papyrifera),” Food Chemistry, Vol. 106, No. 2, 2008, pp. 529-535.
http://dx.doi.org/10.1016/j.foodchem.2007.06.037J.-H. Hwang and B. M. Lee, “Inhibitory Effects of Plant Extracts on Tyrosinase, L-DOPA Oxidation, and Melanin Synthesis,” Journal of Toxicology and Environmental Health, Part A, Vol. 70, No. 5, 2007, pp. 393-407.
http://dx.doi.org/10.1080/10937400600882871