the use of botanically derived agents for hyperpigmentation: a … · develop disorders of...
TRANSCRIPT
REVIEW
The use of botanically derived agents forhyperpigmentation: A systematic review
Whitney A. Fisk, MS,a Oma Agbai, MD,b Hadar A. Lev-Tov, MD,b,c and Raja K. Sivamani, MD, MS, AHEb
Sacramento and Mather, California
See related articles on pages 281 and 369
From
U
fa
Fund
Conf
Acce
352
Background: Hyperpigmentation disorders are common among those seeking care from dermatologistsand primary care physicians. The cosmeceutical and natural product industries are rapidly growing andmany botanical agents are purported to improve hyperpigmentation disorders.
Objective: We sought to review clinical evidence for the use of botanical agents in the treatment ofhyperpigmentation.
Methods: We searched MEDLINE and Embase databases and a total of 26 articles met inclusion criteria.Study methodology was analyzed and the reproducibility of the studies was graded.
Results: Several botanical agents appear promising as treatment options but few studies were method-ologically rigorous. Several plant extract and phytochemicals effectively lighten signs of epidermalmelasma and hyperpigmentation induced by ultraviolet radiation exposure. Results were mixed fortreatment of solar lentigines or dermal hyperpigmentation.
Limitations: There were few rigorously designed studies; future research will be critical to furtherascertain the discussed results.
Conclusions: The subtype of hyperpigmentation is important for treatment prognosis, with dermalhyperpigmentation less responsive to treatment. Botanical extracts may play an integrative role in thetreatment of hyperpigmentation and further studies that integrate them with standard therapies are needed.Side effects, including worsened hyperpigmentation, need to be discussed when considering thesetherapies. ( J Am Acad Dermatol 2014;70:352-65.)
Key words: botanical; hyperpigmentation; lentigo; melasma; natural; phytochemical; plant.
Hyperpigmentation is a common symptomencountered by dermatologists and primarycare physicians. Pigmentation disorders
were the third most common diagnosis in a cohortof 2000 dark-complexioned dermatology patients,1
secondary only to acne and eczema. Common hyper-pigmentation disorders include melasma, solar len-tigines, postinflammatory hyperpigmentation (PIH),and chloasma, which refers to melasma precipitatedin the setting of hormonal stimulation such as preg-nancy or oral contraceptive use. Ultraviolet (UV)exposure can exacerbate all of these conditions.2
the School of Medicinea and Department of Dermatology,b
niversity of CaliforniaeDavis, Sacramento; and Veterans Af-
irs Northern California Health Care System, Mather.c
ing sources: None.
licts of interest: None declared.
pted for publication September 20, 2013.
Darker-complexioned individuals are more likely todevelop disorders of hyperpigmentation.3
Clinically, hyperpigmentation manifests as brownor blue skin discoloration depending on whethermelanin deposition occurs in the epidermis or thedermis, respectively.4 The location of pigmentdeposition can be evaluated with Wood’s lamp andmay impact treatment decisions.4 For example,epidermal melasma responds better to topical ther-apies,2 than does dermal or mixed-type melasma,both of which include a component of dermalpigment deposition. Dermal hypermelanosis is less
Reprint requests: Raja K. Sivamani, MD, MS, AHE, Department of
Dermatology, University of CaliforniaeDavis, 3301 C St, Suite
1400, Sacramento, CA 95816. E-mail: [email protected].
Published online November 25, 2013.
0190-9622/$36.00
� 2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.09.048
J AM ACAD DERMATOL
VOLUME 70, NUMBER 2Fisk et al 353
responsive to treatment partially because residentdermal macrophages phagocytose pigment andmany therapies do not target these cells5 (Fig 1).
‘‘Cosmeceuticals,’’ products containing biologi-cally active ingredients that purportedly improvethe appearance of skin, are increasingly popularalternatives to standard depigmenting agents (Table
CAPSULE SUMMARY
d Topical botanical therapies areincreasingly popular alternativetherapies.
d Clinical studies suggest botanicals mosteffectively treat superficial forms ofhyperpigmentation, including epidermalmelasma.
d Botanicals should be considered forintegration with standard therapies forhyperpigmentation and furtherintegrated clinical studies are needed.
I).6 Such products are attrac-tive to consumers becausethey are presumed safe, of-ten inexpensive, and avail-able over the counter.Evidence-based knowledgeof the beneficial effects, theside effects, and the indica-tions of these cosmeceuticalswill be increasingly helpfulfor dermatologists, who willundoubtedly encountermany patients using theseproducts. This review sys-tematically reviews clinicalstudies examining the effectsof plant extracts, herbal
preparations, and isolated plant-derived compoundsin the treatment of hyperpigmentation disorders.METHODSBetween April and August 2013 we searched
Embase and MEDLINE databases for published clin-ical studies examining the use of plant-derivedproducts for the treatment of hyperpigmentation.Embase database was searched using Emtree searchterms ‘‘phytotherapy,’’ ‘‘plant medicinal product,’’‘‘herbal medicine,’’ and ‘‘hyperpigmentation,’’ whichincluded subcategories ‘‘flavonoid,’’ ‘‘herbaceousagent,’’ ‘‘melanosis,’’ ‘‘post-inflammatory hyperpig-mentation,’’ ‘‘chloasma,’’ ‘‘lentigo,’’ and ‘‘melanocy-tosis.’’ MEDLINE database was searched using theMeSH terms ‘‘phytotherapy,’’ ‘‘plants, medicinal,’’‘‘plant extracts,’’ ‘‘complementary therapies,’’ and‘‘hyperpigmentation,’’ which included the subcate-gories ‘‘flavonoids,’’ ‘‘melanosis,’’ ‘‘post-inflamma-tory hyperpigmentation,’’ and ‘‘lentigo.’’ The term‘‘melasma’’ is not specifically included in eitherPubMed MeSH or Embase Emtree databases; it isincluded under the umbrella terms ‘‘melanosis’’ and‘‘chloasma,’’ respectively. Given this, we includedthe key word ‘‘melasma’’ in searching both data-bases, in addition to the MeSH and Emtree termslisted above. Studies involving plant-derived com-pounds and pigmentation as an outcome measurewere included. The searches were filtered to onlyinclude clinical studies and those written in English.
Bibliographies were searched for additional studiesthat met inclusion and exclusion criteria. Of 149articles found, 26 met inclusion criteria (Table II).
RESULTS/DISCUSSIONThe studies are summarized in Table II. Botanical
therapies were studied as topical, oral, adjunctive,
and preventative treatments.Oral therapies includedprocyanidin,7 Pycnogenol(standardized extract ofFrench maritime pine bark),8Polypodium leucotomos ex-tract,9 and Chinese herbs,10-12
all of which have strong anti-oxidant activities. Several stud-ies examined botanicals incombination with standardtreatments,7,13,14butonly1 iso-lated the complimentary effectof the botanical compound14
by studying a cosmetic formu-lation with and without theextract.
Therapeutic mechanisms of actionHyperpigmentation results from excessive mela-
nin deposition, which leads to areas of increasedpigment density or areas of unusual pigmentdispersion.4 Inhibition at any stage of melaninproduction or dispersion may affect clinicalpigmentation and botanicals inhibit pigmentationthrough a variety of mechanisms.
As shown in Tables III and IV, several botanicalsinhibit tyrosinase, the enzyme that catalyzes severaloxidative reactions required for melanin synthesisfrom its precursor amino acid, tyrosine.15 Tyrosinaseis a glycoprotein located within the membrane ofvesicles that transport melanin polymers, termed‘‘melanosomes.’’15
Once formed in epidermal melanocytes, melano-somes are transferred to surrounding keratinocytes(Fig 1). Soy extract contains serine protease inhibi-tors, heat labile enzymes that suppress melanosometransfer through inhibition of the keratinocyteprotease-activated-receptor 2.16,17
Several botanicals inhibit hyperpigmentationthrough anti-inflammatory and antioxidant effects. Invitro studies have shown that inflammatory mediatorsenhance melanogenesis; leukotrienes C4 and D4 andprostaglandin E2 stimulate melanocyte cell growthand dendrite proliferation and several inflammatorymediators stimulate melanocyte pigment production,including interleukin-1, interleukin-6, and reactiveoxygen species.18-20 Also, inflammation-induced
Fig 1. Hyperpigmentation: pathogenic mechanisms. Epidermal hyperpigmentation may resultfrommelanocyte proliferation, melanocyte hyperactivity, or increased transfer of melanosomesto keratinocytes. Melanin extravasation into the dermis leads to the blue discoloration ofdermal hyperpigmentation. Dermal melanin can be phagocytosed by macrophages to formmelanophages. (1) Increased synthesis of melanin from its tyrosine precursor is a tyrosinase-dependent process and requires several oxidative reactions. (2) Increased transfer of melano-somes to keratinocytes is dependent on activation of the keratinocyte protease-activatedreceptor-2. (3) Melanophages are dermal macrophages that have phagocytosed melaningranules. The presence of these cells results in a blue hyperpigmentation, which is oftenresistant to topical therapies.
J AM ACAD DERMATOL
FEBRUARY 2014354 Fisk et al
melanocyte cell damage facilitates aberrant transfer ofmelanosomes into the dermis.2 UV radiation mayexacerbate dyspigmentation partially by up-regulating inflammatory mediators. For example,UV-induced lipid-membrane peroxidation increasesthe production of reactive oxygen species.21 UV radi-ation contributes to hypermelanosis through othermechanisms as well, including up-regulated keratino-cyte expression of melanogenic mediators22-24 andprotease-activated-receptor 2.17
Several extracts contain flavonoids, a class ofphytochemicals with potent antioxidant activities.Flavonoids in silymarin, Pycnogenol, and soyextract suppress melanogenesis by inhibiting reac-tive oxygen species formation. However, flavo-noids are not universally antimelanogenic. Forexample, the citrus flavonoid naringenin25 in-creased melanogenesis in vitro in melanoma cells,although this effect has not been investigatedclinically.
Role of subtype of hyperpigmentation inrelation to treatment response
Botanical therapies consistently improved epider-mal melasma,7,8,26-31 subclinical photoaging,32,33 andacute pigmentation induced by UV exposure.9,14,34
Results were mixed for solar lentigines33,35,36 anddermal melasma.37,38 This suggests botanical treat-ments are most effective for acute forms of hyper-pigmentation and hyperpigmentation confined tothe epidermis. These factors may be more predictiveof treatment success than the underlying cause ofhyperpigmentation.
This conclusion is reinforced by several studies.Licorice extract significantly lightened melasma, butwas less effective when melasma included a com-ponent of dermal pigmentation.38 Soy lightenedsubclinical hyperpigmentation but did not clinicallyimprove solar lentigines despite reducing pigmentload in the epidermis of these macules.33 Thissuggests soy reduces epidermal pigment but may
Table I. Standard treatments of hyperpigmentation
Treatment Mechanism of action Side effects Notes
Retinoids 1) Tyrosinase inhibition2) Increased keratinocyteturnover
3) Increased keratinocytepigment granule dispersal
Erythema, irritation, desquamation Slow onset if used asmonotherapy
Azelaic acid 1) Tyrosinase inhibition2) Melanocyte proliferationinhibition
3) ROS suppression
Irritation, pruritus, erythema
Chemical peels Removal of melanin throughthinning of stratumcorneum and epidermolysis
Erythema, atrophy, scarring,hypopigmentation, hyperpigmentation
Unpredictable results
Laser treatments Thermal damage to melanin Atrophy, scarring, hypopigmentation,hyperpigmentation
Unpredictable results,hyperpigmentation muchmore likely in phototypesIV-VI
Kojic acid 1) Tyrosinase inhibition2) ROS scavenger
Irritation, sensitization
Hydroquinone 1) Tyrosinase inhibition2) Melanocyte DNA and RNAsynthesis inhibition
Irritation, transient or permanentdepigmentation, allergic contactdermatitis, ochronosis
Carcinogenic in animalstudies, yet not proven inclinical studies
ROS, Reactive oxygen species.
J AM ACAD DERMATOL
VOLUME 70, NUMBER 2Fisk et al 355
not improve dermal hypermelanosis. Tadokoroet al35 found an inconsistent lightening effect of atopical botanical formulation on solar lentigines.35
Poor responders may have had a component ofdermal pigmentation, but this was not specificallyassessed.
PIH and drug-induced hyperpigmentation werenot specifically evaluated in any of the reviewedstudies. Because PIH may occur through a distinctmechanism involving aberrant dermal transfer ofmelanin,5 it is not clear if treatments for other formsof hyperpigmentation will be useful for PIH. Drug-induced hyperpigmentation is a special subset ofpigmentary disorders because the causes are pro-tean, including increased melanin, iron, lipofuscin,and drug-melanin complexes.39,40 In addition thepigmentation may be found in the epidermis, der-mis, or both.39,40 More clinical studies are needed toassess botanical therapies of dermal hyperpigmen-tation, PIH, and drug-induced hyperpigmentation.
Use as preventative agentsSeveral studies10,28,32,41 suggest that botanicals
may effectively prevent the development of hyper-pigmentation. One study reported that soy extractmay prevent the pigmentary changes that precedeclinically apparent hyperpigmentation,32 and an-other found that oral proanthrocyanidin preventedworsening of melasma during summer months.28
Glechomahederacea extract suppressedUV-induced
pigmentation but did not lighten pre-existingmelasma lesions.41 Ha et al41 suggest Glechomahederacea extract has an antipigmenting effect,rather than depigmenting effects, because of antiox-idant and anti-inflammatory effect. Thus, somebotanicals may be more appropriately used as pre-ventative, rather than therapeutic, agents. Individualswith risk factors such as chronic sun exposure or afamily history of dyspigmentation may benefit fromthese preventative measures.
LimitationsInterpretation of these results is limited by incon-
sistencies in study methodology and botanicalextractionmethod. Also, controlling for confoundingvariables, such as sun exposure and sunscreen use, isdifficult in clinical studies.
The reproducibility of botanical studies is depen-dent on equivalent methods of preparing botanicalingredients. The potency and composition of activephytochemicals varies significantly with differentextractionmethods.42 Only one third of the reviewedstudies provided a reasonably reproducible methodfor obtaining their active ingredient (Table V). Ofnote, extraction methodologies of ingredients ob-tained from companies may be proprietary andtherefore incompletely described.
Hyperpigmentation severity can be assessed sub-jectively, semiquantitatively, or objectively. UV lightphotography and MASI scores are examples
Table II. Summary of clinical studies
Intervention
Pigmentation
disorder
Study
design Subjects Comparison
Major outcome
measures Major results Study limitations
Level of
evidence*
Melasma7% Alpha-arbutin
combined withlaser treatment
Polnikorn,37 2010
Melasma(dermaland mixed)
Singlegroup efficacytrial
N = 35 None Visual inspection forfading of lesion on5-point scale
67% Of participants with[50%reduction of melasma after6-mo treatment
1) Arbutin not studied independentof laser treatment
2) Criteria for 5-point scaleevaluation of not described
IIB
Chinese herbs (oral)combined withHe-Ne lasertreatment
Wu et al,10 2009
Chloasma RCT N = 90 Oral vitaminsC and E withtopical 20%azelaic acidcream
1) Serum LPO and SOD2) Visual inspection for
change in size andcolor
1) Treatment significantlymore effective thancontrol based on totaleffectiveness rate
2) Significant decrease inserum LPO and increasein serum SOD levels aftertreatment
1) Color evaluated subjectively2) Area calculation not described3) Macule size and color data
not reported4) Herbs not studied independently
IB
Chinese herbs (oral)combined withacupuncture
Feng et al,12 2010
Chloasma RCT N = 60 Oral vitaminsC and E
Visual inspection forchange in size andcolor
Chinese herbs significantlymore effective thancontrol based on totaleffectiveness rate
1) 3 Different herb combinationsused in treatment group
2) Macule size and color datanot reported
3) Chinese herbs not studiedindependently
IB
Chinese herbs (oral)combined withacupuncture
Shi and Xu,11 2007
Melasma RCT N = 61 Both groupsreceived oralvitamins C andE with topicalChinese herbalpreparation
1) Scored size and color ofskin lesions
2) Re-evaluated lesions1-2 y after study
1) Significantly greater totaleffectiveness rate andimproved area and colorscores in treatment group
2) Continued improvementsat long-term follow-up
1) Semiquantitative analysis2) Chinese herbs not studied
independently
IB
Ellagic acid, plantderived
Ertam et al,26 2008
Melasma(epidermaland mixed)
RCT,open-labeldesign
N = 30PhototypeII-IV
1) Arbutin2) Synthetic
ellagic acid
Mexameter (Chourage-Khazaka Electronic,Cologne, Germany)measurementfor pigment density
Significant improvement inpigment density in allgroups, with no statisticaldifference between them
Plant-derived ellagic acid not studiedindependently (treatment groupreceived combination of syntheticand plant-derived ellagic acid)
IB
Emblica, licorice, andbelides extracts
Costa et al,46 2010
Melasma(epidermaland mixed)
RCT N = 56PhototypeI-IV
HQ 2% 1) UV image analysis (Visia,Canfield Scientific Inc,Fairfield, NJ)for number, size, andtone of macules
2) Subjective medicaland self-evaluations
Statistically significantimprovement in subjectiveevaluations and number,size, and tone of lesions inboth groups, comparedwith baseline; no statisticallysignificant differencebetween groups
1) Participants not blinded to treatment2) Burning and erythema more common
in HQ group (no statistical analysisfor significance of this difference)
IB
Grape seedextract rich inproanthrocyanidin (oral)
Yamakoshi et al,28
2004
Chloasma Single groupefficacy study
N = 12 None 1) Colorimetry(spectrophotometerfor L*, a*, and b* values)
2) Melanin index (from L*,a*, and b* values)
3) Focal macule size
1) Significant lightening(decrease in melanin index)effect with maximum benefitat 6 mo
2) Decreased size of lesions3) Unclear distinction from
melasma
1) Authors did not comment onstatistical analysis of change in focalmacule size
2) No comparative control group
IIB
LiquiritinZubair and Mujtaba,29
2009
Melasma(epidermal)
RCT N = 90 HQ 4% 1) Color compared withnormal-appearing skin
2) Focal macule size3) Change in photographic
appearance
4% Liquiritin significantlymore effective than HQand 2% liquitirin basedon change in maculecolor, macule size, andimprovement inphotographic appearance
1) Subjective assessments2) Macule size data not reported3) Authors suggest that liquiritin
depigments skin more evenly thanHQ, but do not provide evidence
4) No report on potential confoundingbecause of sunscreen noncompliancerate between groups
IB JAM
ACADD
ERM
ATOL
FEBRUARY20
14356
Fisk
etal
LiquiritinAmer and Metwalli,30
2000
Melasma(epidermal)
Split-facecontrolledclinical trial
N = 20 Vehicle cream(ingredientsnot described)
1) Color compared withnormal-appearing skin
2) Focal macule size
1) 60% With reduction inlesion size[75%
2) 70% With reduction inpigmentintensity by 3 levels
3) Control with only verymild improvement in2 patients
1) No statistical analysis performed2) Size measurements not described
IIA
Mulberry extractAlvin et al,31 2011
Melasma(epidermaland mixed)
RCT N = 50PhototypeIII-V
Vehicle(coconutoil base)
1) MASI score2) Mexameter
measurement formelanin andhemoglobin content
3) Melasma QOL score
1) Significant improvementin MASI score, averageMexametermeasurements, andQOL scores intreatment group
2) No significantimprovements inthe placebo group
1) Methods to ensure consistency ofareas chosen for Mexameterreadings were not discussed
2) Investigators not blinded
IB
ProcyanidinHandog et al,7 2009
Melasma(epidermal)
RCT N = 60PhototypeIII-V
Placebo tabletscontainingstarch
1) Mexametermeasurement formelanin andhemoglobin indices
2) MASI score
Treatment group withsignificantly improvedMexameter measurementsand MASI scorescompared with placebo
Procyanidin combinedwith vitamins A, C, and E and notstudied independently of these
IB
Pycnogenol:standardized barkextract of Frenchmaritime pine (oral)
Ni et al,8 2002
Melasma Single groupefficacytrial
N = 30 None 1) Focal macule size2) Pigment intensity
based on nationalstandard color chart
1) Significant decrease indiameter, averagedecrease of 25.8 mm2
2) Significant decrease inpigment intensity,average of 0.47 U
3) Overall effective rateof 80%
1) Effectiveness defined as any reductionin the size of macule or reduction inpigment intensity by $ 1 point
2) Semiquantitative analysis of color3) No comparative control group
IIB
Rumex occidentalisextract
Sabancilar et al,13
2011
Melasma(epidermal,dermal, andmixed)
Single groupefficacytrial
N = 30PhototypeII-IV
None 1) Colorimetry for L, H, andC values
2) Clinical evaluation byphysician for overallimprovement
1) Significant skinlightening after twicedaily application
2) Milder significant skinlightening after twiceweekly application
3) Good or moderateimprovement in 55% ofparticipants by clinicalassessment
1) Contribution of Rumex occidentalisunclear as there was no vehiclecontrol
2) Vehicle contained glycolic acid,salicylic acid, and sunscreen, whichmay contributed to lightening
IIB
SilymarinAltaei,53 2012
Melasma RCT N = 96 Vehicle cream 1) Focal macule size2) MASI3) Physician Global
Assessment4) Subject survey for
satisfaction
1) Treatment group withsignificant improvementsin macule size, MASI scores,and physician assessments;no significant improvementsin control group
2) 100% Satisfaction reportedby subjects in treatmentgroup
Melasma type not specified IB
Plant extracts includingorchid extract
Tadokoro et al,35 2010
Melasma(type notspecified)and lentigosenilis
Split-facecontrolledclinicaltrial
N = 48 Formulationcontainingvitamin-Cderivative
1) Mexametermeasurement formelanin index
2) Skin tone color scale3) Focal macule diameter4) Clinical assessment for
lesion color intensity,number, skin clarity,global appearance,and complexionhomogeneity
5) Subject survey
1) Significant improvementsin macule size, macule color,and subjective surveys in bothgroups
2) Lentigo color improvedsignificantly only in olderparticipants
3) Melanin indices unchangedin both groups
4) Global assessment improvedonly with orchid extract
1) Melanin indices unchanged despiteclinical lightening effect
2) The vehicle cream containedcomponents such as licorice root,which is a known to modulatemelanin production and confoundsanalysis of orchid extract
3) Melasma type not specified
IIA
Chronic UV-induced hyperpigmentation
Continued
JAM
ACADD
ERM
ATOL
VOLU
ME70
,NUM
BER2
Fisk
etal
357
Table II. Cont’d
Intervention
Pigmentation
disorder
Study
design Subjects Comparison
Major outcome
measures Major results Study limitations
Level of
evidence*
Coffea arabica, fruit andvegetable extracts
Palmer and Kitchin,54
2010
Photoaging(Glogauscale IIor III)
RCT N = 40CaucasianphototypeI-IV
Control facewash andmoisturizer(ingredientsnot described)
1) Clinical evaluationby dermatologist forhyperpigmentationrated on 0-9 scale
2) Subject self-assessment3) UV imaging
Statistically significantimprovement inhyperpigmentation,compared with control,assessed by clinical gradingand confirmed by self-assessment questionnairesand UV imaging
1) Did not describe criteria for clinicalgrading scales
2) Did not report between-groupsstatistical analysis
3) Did not describe other vegetableand fruit extracts in formulation
IB
Plant HQ glucosidesClarys and Barel,36
1998
Solar lentigo Single groupefficacytrial
N = 14Caucasian
None Colorimetry (chromometermeasurements for L, a,and b values)
1) Significant lightening effectbased on increase in L value
2) Trend toward shift away fromred and yellow pigmentation,based on a and b values
Authors claim treated lesions werevisibly lighter than untreated lesionsat conclusion of study but did notconfirm this with colorimetricevaluation
IIB
Soybean extractWallo et al,55 2007
Photoaging RCT N = 68PhototypeI-III
Moisturizervehicle
1) Clinical evaluationby dermatologist forhyperpigmentation,lentigines, blotchiness,dullness on 0-9 scale
2) Chroma Meter, KonicaMinolta, Ramsey, NJ(Colorimetry for L, a,and b values)
3) Subject self-assessment
1) Soy moisturizer significantlymore effective than vehiclefor improving mottledpigmentation, blotchiness,dullness, and overall skin tone
2) Self-assessment withsignificant improvementsafter 1 wk with soy and after12 wk with vehicle
Results of colorimetry not consistentwith clinical assessment; authorssuggest this may be becausecolorimetry evaluates a small areawhereas clinician assessedaverage appearance
IB
Soybean extractHermanns et al,32
2000
Subclinicalfacialhyperpig-mentation
Controlledclinicaltrial
N = 15PhototypeII
1) 15% Azelaicacid
2) 12% Glycolicacid
UV light image analysisusing highmagnification tomeasure total area ofhyperpigmentation
Significant decrease in totalarea of hyperpigmentationin azelaic acid and soygroups but not in glycolicacid group
1) Selection of participants for treatmentgroups not described
2) No between-groups comparisonsdone
3) Outcome measure only evaluatedarea, not density, of macules
IIA
Soybean extractHermanns et al,33 2002
Solar lentigoandsubclinicalhyperpigmen-tation onarms
Controlledclinicaltrial
N = 30 Asian Untreatedskin
1) Spectrophotometermeasurement formelanin index
2) Corneomelametry3) UV light image
recording ofperilesional skin toassess subclinicalhyperpigmentation
1) No decrease in melaninindex of solar lentigines
2) Soy significantly reducedmelanin load in stratumcorneum of solar lentigo
3) Soy showed significantdepigmenting effect onsubclinical hyperpigmentation
No vehicle control was used IIA
Acute UV-induced hyperpigmentation
Alpha-bisabololLee et al,34 2010
UVA and UVBtanned skin(with solarsimulator)
Controlledclinicaltrial
N = 28PhototypeIII-IV
Vehiclecream
1) Spectrophotometermeasurement for L, a,and b values
2) Clinical evaluation
1) Significantly more effectivelightening as measured byspectrophotometer thanvehicle control
2) No difference between groupsdetected by clinical evaluation
1) Lightening effect measured withspectrophotometer not detected inclinical evaluation
2) Did not describe criteriaused for clinical evaluation
IB
DPMammone et al,14
2010
UVB tannedskin (withsolarsimulator)
Controlledclinicaltrial
N = 10Per panelphototypeIII
1) 4% HQ2) Kojic acid3) Vehicle for
DP (cosmeticblend)
4) Cream offluocinoloneacetonide 0.01%,HQ 4%, tretinoin0.05% cream
5) Untreated skin
Colorimetrymeasurements forchange in L valuesplotted against timeto evaluate rate offade of induced tan
1) Addition of DP to cosmeticformulation increased rate offade of tan
2) Authors concluded effect ofDP was similar to that of HQand kojic acid
1) No between-groups analysis of data tocompare effects of DP with standardtreatments
2) No discussion of randomization orblinding
IIA JAM
ACADD
ERM
ATOL
FEBRUARY20
14358
Fisk
etal
Glechoma hederaceaextract
Ha et al,41 2011
UVA and UVBtanned skinon forearm(with solarsimulator)and facialhyperpig-mentation
Split-faceRCT
N = 23 AsianphototypeII-IV
1) Vehicle lotion2) Untreated skin
1) Spectrophotometermeasurement for L, a,and b values
2) Clinical assessmentof skin color on a9-point scale
3) Clinical assessmentof facialhyperpigmentationtreated with Glechomahederacea
1) Significantly weakerinflammatory reaction(lower a value), weakerpigmentation, and fasterfading of pigmentation afterUV radiation, compared withplacebo and untreated skin
2) Significantly faster fadingof pigmentation by clinicalexamination
3) No difference betweenGlechoma hederaceaetreatedand placebo-treated facialhyperpigmentation
Characteristics of facialhyperpigmentation not described;unclear whether macules werea result of melasma, lentigines, orsome other cause
IB
Polypodiumleucotomosextract (oral)
Middelkamp-Hupet al,9 2004
Psoralen-UVA-inducedpigmentationand skindamage
Singlegroupefficacytrial
N = 10PhototypeII-III
All outcomemeasurescomparedbetweenlesions inducedbefore and afterPolypodiumleucotomosingestion
1) Clinical evaluationusing erythema andedema scoring system
2) Histology for sunburncells
3) Immunohistochemistryfor Langerhans cells,proliferatingkeratinocytes, dermalmast cells, andendothelial cells
1) Significantly lower erythemaand edema scores in maculesinduced after Polypodiumleucotomos treatment
2) Pigmentation reduced 4mo later in lesions inducedafter Polypodium leucotomostreatment
3) Significantly fewer sunburncells and dermal mast cells,less depletion of Langerhanscells and less vasodilation inlesions induced afterPolypodium leucotomostreatment
1) Follow-up evaluation donequalitatively and only in 6 patients
2) No objective measurement ofdifference in color
IIB
AbstractsGreen tea extract
(EGCG analogue)Syed et al,56 2009
Melasma RCT N = 60 Placebo Investigator GlobalAssessment,clearing of lesions
Significant results in bothgroups, treatment creamsignificantly more effective
Awaiting final manuscript for completemethods and results
IB
Oral hesperidinGueniche et al,57 2012
Solar lentigo RCT N = 66 Maltodextrinsupplement
Brightness and agespots measured
Significant improvement inbrightness compared withplacebo
Awaiting final manuscript for completemethods and results
IB
Glycyrrhiza glabraextract
Tsilika et al,38 2011
Melasma Singlegroupefficacytrial
N = 10PhototypeII-IV
None 1) Clinicalexamination
2) MASI score3) Standard and
UV-lightphotographs
4) RCM examination
1) Significant reduction inMASI score confirmedby UV photography
2) Significant decrease inhyperpigmentedkeratinocytes detectedby RCM
3) Patients with dermalmelanophages onmicroscopy had limitedresponse and melanophagespersisted after treatment
Awaiting final manuscript for completemethods and results
IIB
DP, 1-(2,4-Dihydrophenyl)-3-(2,4-dimethoxy-3-methylphenyl) propane; EGCG, epigallocatechin-3-gallate; HQ, hydroquinone; LPO, lipoperoxide; MASI, Melasma Area and Severity Index; QOL, quality
of life; RCM, reflectance confocal microscopy; RCT, randomized controlled trial; SOD, superoxide dismutase; UV, ultraviolet Color spaces: L, C, H; L,a,b; and L*,a*,b* color spaces are similar in that
L represents lightness (black/white), C/a/a* represent the red/green color space, and H/b/b* represent the blue/yellow color space.
*Levels of evidence: IA: evidence from meta-analysis of randomized controlled trials. IB: evidence from at least 1 randomized controlled trial. IIA: evidence from at least 1 controlled study without
randomization. IIB: evidence from at least 1 other type of experimental study.
JAM
ACADD
ERM
ATOL
VOLU
ME70
,NUM
BER2
Fisk
etal
359
Table III. Mechanism of action of botanicals and extracts
Scientific name Common name Mechanism of action Active constituents
Bellis perennis flowers46 Belides 1) Anti-inflammatory46
2) ROS suppression46
3) Suppresses melanosometransfer46
Polyphenols
Brassocattleya marcella35 Orchid ROS suppression58
Camellia sinensis56 Green tea 1) ROS suppression59
2) Anti-inflammatory59
3) Tyrosinase inhibitor60
Polyphenols including EGCG
Coffea arabica fruit54 Coffee fruit(coffeeberry)
ROS suppression61 Polyphenols includingproanthrocyanidins
Glechoma hederacea41 Ground ivy 1) Anti-inflammatory62
2) ROS suppression63
Glycine max32,33,55 Soy bean 1) Suppresses melanosometransfer (serine proteaseinhibitors)17
2) ROS suppression64
(isoflavones)
Serine protease inhibitorsFlavonoidsIsoflavones including genistein
Glycyrrhiza glabra46 Licorice 1) ROS suppression65
2) Tyrosinase inhibition66Flavonoids including liquiritin andglabridin
Morus alba31 Mulberry plant 1) Tyrosinase inhibition67
2) ROS suppression67Flavonoids including mulberroside F(moracin M-6, 3’-di-O-beta-D-glucopyranoside)
Phyllanthus emblica fruit46 Emblica 1) ROS suppression68
2) Tyrosinase inhibitionPolyphenols
Pinus pinaster8 French maritimepine (Pycnogenol)
1) ROS suppression69
2) Regenerates active formsof vitamins C and E70
3) Tyrosinase inhibition
Flavonoids including procyanidin
Polypodium leucotomosextract9
Cabbage palm fern ROS suppression71 Caffeic acid and ferulic acid(non-flavonoid catacholicantioxidants)72
Rumex occidentalis13 Western dock Tyrosinase inhibition73
Silybum marianum53 Milk thistle extract(silymarin)
1) ROS scavenger2) Tyrosinase inhibition74
Flavonoids
Vitis vinifera28 Grape seed extract ROS suppression75 Polyphenols including procyanidin
EGCG, Epigallocatechin-3-gallate; ROS, reactive oxygen species.
Table IV. Mechanism of action of isolated compounds
Compound Structure Example sources Mechanism of action
Alpha-arbutin37 Beta-D-glucopyranoside(derivative of hydroquinone)
Pear, blueberry, cranberry, wheat Tyrosinase inhibition74,75
Alpha-bisabolol34 Sesquiterpene alcohol German chamomile Inhibits a-MSH-inducedmelanogenesis76
DP14 DP Dianella ensifolia 1) ROS suppression2) Tyrosinase inhibition77
Ellagic acid26 Polyphenol Strawberry, geranium, grapes,cherries, walnuts, green tea
Tyrosinase inhibition throughcopper chelation78
Hesperidin57 Flavonoid Citrus fruits 1) Tyrosinase inhibition79
2) Suppression of UVA-inducedoxidative damage80
Liquiritin29,30 Flavonoid Licorice Melanin dispersion81,82
a-MSH, Alpha-melanocyte stimulating hormone; DP, 1-(2,4-dihydrophenyl)-3-(2,4-dimethoxy-3-methylphenyl) propane; ROS, reactive oxygen
species; UV, ultraviolet.
J AM ACAD DERMATOL
FEBRUARY 2014360 Fisk et al
Table V. Reproducibility of studies
Active ingredient Study Extraction method Method of obtaining materials
Reproducibility
of active
ingredientz
Isolated compoundsAlpha-bisabolol Lee et al,34 2010 N/A Purchased from Sigma
Chemical Co, St Louis, MO1
Alpha-arbutin Polnikorn,37 2010 N/A Obtained from Skin AdvanceLaboratory, Tokyo, Japan
1
Dianella ensifolia Mammone et al,14 2010 Not described Not described 3Liquiritin Amer and Metwalli,30
2000Not described Not described 3
Liquiritin Zubair and Mujtaba,29
2009N/A Obtained from a licensed
pharmacy in Multan, Pakistan2
Procyanidin Handog et al,7 2009 N/A Obtained procyanidin tabletscontaining defined amountof active ingredients;supplier not identified
2
Silymarin Altaei,53 2012 Not described Obtained from App-Chem-Bio,China
2
Herbal preparationsChinese herbs Wu et al,10 2009 Not described Not described 3Chinese herbs Feng et al,12 2010 Not described Not described 3Chinese herbs Shi and Xu,11 2007 Not described Not described 3
Plant extractsEllagic acid Ertam et al,26 2008 Methanol
extractionCastanea sativa stem barks andJuglans regia leaves collectedfrom Sultanhisar, Turkey(Malgecemir village) in Aydin
Eucalyptus camaldulensis leavescollected from EgeUniversity, Izmir, Turkey, inSeptember 2002
2
Glechoma hederacea Ha et al,41 2011 Ethanol extraction Not described 2Grape seed Yamakoshi et al,28 2004 Aqueous ethanol
extract*Product provided: grape seedextract; (Gravinol, KikkomanCo, Chiba, Japan)
2
Mulberry extract Alvin et al,31 2011 Not described Not described 3Polypodiumleucotomos
Middelkamp-Hup et al,9
2004N/A Capsules containing 180 mg
Polypodium leucotomossupplied by IF Cantabria SA,Madrid, Spain
1
Soy bean Hermanns et al,32 2000 N/A Formulation provided by theJohnson & Johnson SkinResearch Center
2
Soy bean Hermanns et al,33 2002 Not described Not described 3Commercial formulationsCoffea arabica Palmer and Kitchin,54
2010Not described Not describedy 3
Emblica, licorice, andbelides
Costa et al,46 2010 N/A Product obtained, identified as:Clariderm Clear, StiefelLaboratories Inc, Guarulhos,Brazil
1
Hydroquinoneglucosides(plant derived)
Clarys and Barel,36 1998 N/A Product obtained: QuniodermEemedis, Brussels, Belgium
1
Continued
J AM ACAD DERMATOL
VOLUME 70, NUMBER 2Fisk et al 361
Table V. Cont’d
Active ingredient Study Extraction method Method of obtaining materials
Reproducibility
of active
ingredientz
Orchid extracts(combination withother plant extracts)
Tadokoro et al,35 2010 N/A Formulation developed byLVMH Recherche, Saint Jeande Braye, France
2
Pycnogenol Ni et al,8 2002 N/A Patented commercial product,provider not identified
2
Rumex occidentalis Sabancilar et al,13 2011 N/A Babe Depigmentation Cream,Spain
1
Soy bean Wallo et al,55 2007 N/A Aveeno Positively Radiant soymoisturizer, Johnson andJohnson CCI, Skillman, NJ
1
Poster abstractsOral hesperidin Gueniche et al,57 2012 Not described in
abstractNot described 3
Green tea extract Syed et al,56 2009 Not described inabstract
Not described 3
Glycyrrhiza glabraextract
Tsilika et al,38 2011 N/A (commercialproduct)
Product identified asDermamelan (Mesoestetic,Barcelona, Spain)
1
N/A, Not available.
*Paper does not described method, instead references process described by Yamaguchi et al, 1999.75
yFootnotes mention www.replere.com, a World Wide Web site advertising cosmetic skin care products but article does not specify which
product used.z1 = Reasonably reproducible; 2 = some information missing to be reasonably reproducible; 3 = no information is provided to be reasonably
reproducible.
J AM ACAD DERMATOL
FEBRUARY 2014362 Fisk et al
of subjective and semiquantitative assessmentmethods, respectively.4 Colorimetry is the mostcommonly used objective measurement andanalyzes pigment based on wavelength of reflectedlight.43 Skin color is analyzed with the L*a*b* systemin which L* represents the black/white scale, a*represents the red/green scale, and b* represents theyellow/blue scale.44 Corneomelametry, anotherobjective method, assesses melanin content ofthe stratum corneum by histochemical analysis ofskin-surface scrapings.45
Fourteen of the reviewed studies incorporatedobjective assessments of hyperpigmentation. Ofnote, 2 studies35,45 reported conflicting resultswhen comparing objective and subjective measure-ments. For example, orchid extract clinically light-ened melasma without altering colorimetricanalysis.35 The authors suggest colorimetry detectschanges in pigment density but may not accuratelymeasure changes in melanin distribution. Given this,future clinical studies should include both objectiveand subjective measurements. Objective measure-ment techniques need to be refined to allow forassessment of melanin density, depth, and distribu-tion so that they can integrate better with subjectiveassessments.
Adverse effectsBotanical agents are commonly assumed to be
safer than pharmaceuticals. Among the reviewedstudies, botanicals were shown to be lessirritating than conventional therapies.29,46 However,plant-based therapies are known to cause allergicreactions47 and phototoxic reactions.48 Infrequently,serious adverse events are possible,49 especially withoral and high-concentration formulations. Of note,the Food and Drug Administration does not requirerigorous efficacy and safety testing of botanicalsbefore marketing.50 Also, botanical creams adulter-ated with potent corticosteroids have been reported,which would put consumers at risk for steroid sideeffects including atrophy, acneiform eruptions, anddyspigmentation.51,52
CONCLUSIONSDermatologists should be aware of the evidence
to support or avoid the use of botanically derivedproducts in the treatment of hyperpigmentation. Theuse of botanical therapies for the treatment ofhyperpigmentation is promising, although morerigorous clinical studies are needed. Assessment ofthe subtype and the depth of hyperpigmentation arecritical in determining the success of treatment,
J AM ACAD DERMATOL
VOLUME 70, NUMBER 2Fisk et al 363
regardless of whether this includes standard orbotanical therapies. As research continues to expandin this exciting field, we continue to refine ourunderstanding of how botanical therapies may beintegrated into the therapy of hyperpigmentation.Finally, all patients should be counseled on theimportance of sun hygiene and sun-protectivehabits, as this is the cornerstone to any effectivetreatment regimen against hyperpigmentation.
We are grateful to McKenzie Fisk for her artistic exper-tise in creation of the figure used in this article. We alsothank Bruce Abbot for his valuable guidance in searchingthe scientific literature.
REFERENCES
1. Halder RM, Grimes PE, McLaurin CI, Kress MA, Kenney JA Jr.
Incidence of common dermatoses in a predominantly black
dermatologic practice. Cutis 1983;32:388, 390.
2. Lynde CB, Kraft JN, Lynde CW. Topical treatments for
melasma and postinflammatory hyperpigmentation. Skin
Therapy Lett 2006;11:1-6.
3. Rendon M, Berneburg M, Arellano I, Picardo M. Treatment of
melasma. J Am Acad Dermatol 2006;54(Suppl):S272-81.
4. Ortonne JP, Passeron T. Melanin pigmentary disorders:
treatment update. Dermatol Clin 2005;23:209-26.
5. Davis EC, Callender VD. Postinflammatory hyperpigmenta-
tion: a review of the epidemiology, clinical features, and
treatment options in skin of color. J Clin Aesthet Dermatol
2010;3:20-31.
6. Levin J, Momin SB. How much do we really know about our
favorite cosmeceutical ingredients? J Clin Aesthet Dermatol
2010;3:22-41.
7. Handog EB, Galang DAVF, De Leon-Godinez MA, Chan GP. A
randomized, double-blind, placebo-controlled trial of oral
procyanidin with vitamins A, C, E for melasma among Filipino
women. Int J Dermatol 2009;48:896-901.
8. Ni Z, Mu Y, Gulati O. Treatment of melasma with Pycnogenol.
Phytother Res 2002;16:567-71.
9. Middelkamp-HupMA, PathakMA, ParradoC,Garcia-Caballero T,
Rius-Diaz F, Fitzpatrick TB, et al. Orally administered Polypodium
leucotomos extract decreases psoralen-UVA-induced photo-
toxicity, pigmentation, and damage of human skin. J Am Acad
Dermatol 2004;50:41-9.
10. Wu YH, Li QL, Yang XW. Effects of Chinese herbal medicine
combined with He-Ne laser on lipoperoxide and superoxide
dismutase in chloasma patients. J Tradit Chin Med 2009;29:
163-6.
11. Shi HF, Xu B. Clinical observation on the treatment of
chloasma by Chinese herbs combined with acupuncture.
Chin J Integr Med 2007;13:219-23.
12. Feng XJ, Fu JY, Liu F. Clinical observation on the combined
use of acupuncture and herbal medicine for treatment of
chloasma. J Tradit Chin Med 2010;30:15-7.
13. Sabancilar E, Aydin F, Bek Y, Ozden MG, Ozcan M, Senturk N,
et al. Treatment of melasma with a depigmentation cream
determined with colorimetry. J Cosmet Laser Ther 2011;13:
255-9.
14. Mammone T, Muizzuddin N, Declercq L, Clio D, Corstjens
H, Sente I, et al. Modification of skin discoloration by a
topical treatment containing an extract of Dianella ensi-
folia: a potent antioxidant. J Cosmet Dermatol 2010;9:
89-95.
15. Gillbro JM, Olsson MJ. The melanogenesis and mechanisms
of skin-lightening agentseexisting and new approaches. Int J
Cosmet Sci 2011;33:210-21.
16. Seiberg M, Paine C, Sharlow E, Andrade-Gordon P, Costanzo
M, Eisinger M, et al. The protease-activated receptor 2
regulates pigmentation via keratinocyte-melanocyte interac-
tions. Exp Cell Res 2000;254:25-32.
17. Paine C, Sharlow E, Liebel F, Eisinger M, Shapiro S, Seiberg M.
An alternative approach to depigmentation by soybean
extracts via inhibition of the PAR-2 pathway. J Invest
Dermatol 2001;116:587-95.
18. Morelli JG, Norris DA. Influence of inflammatory mediators
and cytokines on human melanocyte function. J Invest
Dermatol 1993;100:191S-5S.
19. Tomita Y, Maeda K, Tagami H. Melanocyte-stimulating prop-
erties of arachidonic acid metabolites: possible role in
postinflammatory pigmentation. Pigment Cell Res 1992;5:
357-61.
20. Taylor S, Grimes P, Lim J, Im S, Lui H. Postinflammatory
hyperpigmentation. J Cutan Med Surg 2009;13:183-91.
21. Costin GE, Hearing VJ. Human skin pigmentation: melano-
cytes modulate skin color in response to stress. FASEB J 2007;
21:976-94.
22. Sivamani RK, Porter SM, Isseroff RR. An epinephrine-depend-
ent mechanism for the control of UV-induced pigmentation.
J Invest Dermatol 2009;129:784-7.
23. Yamaguchi Y, Hearing VJ. Physiological factors that regulate
skin pigmentation. Biofactors 2009;35:193-9.
24. Imokawa G. Autocrine and paracrine regulation of melano-
cytes in human skin and in pigmentary disorders. Pigment
Cell Res 2004;17:96-110.
25. Ohguchi K, Akao Y, Nozawa Y. Stimulation of melanogenesis
by the citrus flavonoid naringenin in mouse B16 melanoma
cells. Biosci Biotechnol Biochem 2006;70:1499-501.
26. Ertam I, Mutlu B, Unal I, Alper S, Kivcak B, Ozer O. Efficiency of
ellagic acid and arbutin in melasma: a randomized, prospec-
tive, open-label study. J Dermatol 2008;35:570-4.
27. Michaelsson G, Gerden B, Hagforsen E, Nilsson B, Pihl-Lundin
I, Kraaz W, et al. Psoriasis patients with antibodies to gliadin
can be improved by a gluten-free diet. Br J Dermatol 2000;
142:44-51.
28. Yamakoshi J, Sano A, Tokutake S, Saito M, Kikuchi M, Kubota
Y, et al. Oral intake of proanthocyanidin-rich extract from
grape seeds improves chloasma. Phytother Res 2004;18:
895-9.
29. Zubair S, Mujtaba G. Comparison of efficacy of topical 2%
liquiritin, topical 4% liquiritin and topical 4% hydroquinone
in the management of melasma. J Pak Assoc Dermatol 2009;
19:158-63.
30. Amer M, Metwalli M. Topical liquiritin improves melasma. Int
J Dermatol 2000;39:299-301.
31. Alvin G, Catambay N, Vergara A, Jamora MJ. A comparative
study of the safety and efficacy of 75% mulberry (Morus alba)
extract oil versus placebo as a topical treatment for melasma:
a randomized, single-blind, placebo-controlled trial. J Drugs
Dermatol 2011;10:1025-31.
32. Hermanns JF, Petit L, Martalo O, Pierard-Franchimont C,
Cauwenbergh G, Pierard GE. Unraveling the patterns of
subclinical pheomelanin-enriched facial hyperpigmentation:
effect of depigmenting agents. Dermatology 2000;201:
118-22.
33. Hermanns JF, Petit L, Pierard-Franchimont C, Paquet P,
Pierard GE. Assessment of topical hypopigmenting agents
on solar lentigines of Asian women. Dermatology 2002;204:
281-6.
J AM ACAD DERMATOL
FEBRUARY 2014364 Fisk et al
34. Lee J, Jun H, Jung E, Ha J, Park D. Whitening effect of
(alpha)-bisabolol in Asian women subjects. Int J Cosmet Sci
2010;32:299-303.
35. Tadokoro T, Bonte F, Archambault JC, Cauchard JH, Neveu M,
Ozawa K, et al. Whitening efficacy of plant extracts including
orchid extracts on Japanese female skin with melasma and
lentigo senilis. J Dermatol 2010;37:522-30.
36. Clarys P, Barel A. Efficacy of topical treatment of pigmenta-
tion skin disorders with plant hydroquinone glucosides as
assessed by quantitative color analysis. J Dermatol 1998;25:
412-4.
37. Polnikorn N. Treatment of refractory melasma with the
MedLite C6 Q-switched Nd:YAG laser and alpha arbutin: a
prospective study. J Cosmet Laser Ther 2010;12:126-31.
38. Tsilika K, Levy JL, Kang HY, Duteil L, Khemis A, Passeron T,
et al. Efficacy of a novel non-hydroquinone formulation in
the treatment of melasma: a reflectance confocal microscope
study. Lasers Surg Med 2011;43:985.
39. Geria AN, Tajirian AL, Kihiczak G, Schwartz RA. Minocycline-
induced skin pigmentation: an update. Acta Dermatovenerol
Croat 2009;17:123-6.
40. D’Agostino ML, Risser J, Robinson-Bostom L. Imipramine-
induced hyperpigmentation: a case report and review of the
literature. J Cutan Pathol 2009;36:799-803.
41. Ha JH, Kang WH, Ok Lee J, Cho YK, Park SK, Lee SK, et al.
Clinical evaluation of the depigmenting effect of Glechoma
hederacea extract by topical treatment for 8 weeks on
UV-induced pigmentation in Asian skin. Eur J Dermatol
2011;21:218-22.
42. C’De Baca J, Lapham SC, Paine S, Skipper BJ. Victim impact
panels: who is sentenced to attend? Does attendance affect
recidivism of first-time DWI offenders? Alcohol Clin Exp Res
2000;24:1420-6.
43. Nystrom J, Svensk AC, Lindholm-Sethson B, Geladi P, Larson
J, Franzen L. Comparison of three instrumental methods for
the objective evaluation of radiotherapy induced erythema
in breast cancer patients and a study of the effect of skin
lotions. Acta Oncol 2007;46:893-9.
44. Clarys P, Alewaeters K, Lambrecht R, Barel AO. Skin color
measurements: comparison between three instruments: the
Chromameter(R), the DermaSpectrometer(R) and the Mex-
ameter(R). Skin Res Technol 2000;6:230-8.
45. Uhlenhuth EH, Matuzas W, Warner TD, Paine S, Lydiard RB,
Pollack MH. Do antidepressants selectively suppress sponta-
neous (unexpected) panic attacks? A replication. J Clin
Psychopharmacol 2000;20:622-7.
46. Costa A, Moises TA, Cordero T, Alves CRT, Marmirori J.
Association of emblica, licorice and belides as an alternative
to hydroquinone in the clinical treatment of melasma. An
Bras Dermatol 2010;85:613-20.
47. Reuter J,Merfort I, SchemppCM. Botanicals in dermatology: an
evidence-based review. Am J Clin Dermatol 2010;11:247-67.
48. Sasseville D. Clinical patterns of phytodermatitis. Dermatol
Clin 2009;27:299-308, vi.
49. Kokcam I. Toxic epidermal necrolysis probably due to
cosmetic cream: a case report. Acta Dermatovenerol Alp
Panonica Adriat 2009;18:39-42.
50. Thornfeldt C. Cosmeceuticals containing herbs: fact, fiction,
and future. Dermatol Surg 2005;31:873-80.
51. Huang WF, Wen KC, Hsiao ML. Adulteration by synthetic
therapeutic substances of traditional Chinese medicines in
Taiwan. J Clin Pharmacol 1997;37:344-50.
52. Keane FM, Munn SE, du Vivier AW, Taylor NF, Higgins EM.
Analysis of Chinese herbal creams prescribed for dermato-
logical conditions. BMJ 1999;318:563-4.
53. Altaei T. The treatment of melasma by silymarin cream. BMC
Dermatol 2012;12:18.
54. Palmer DM, Kitchin JS. A double-blind, randomized, con-
trolled clinical trial evaluating the efficacy and tolerance of a
novel phenolic antioxidant skin care system containing
Coffea arabica and concentrated fruit and vegetable extracts.
J Drugs Dermatol 2010;9:1480-7.
55. Wallo W, Nebus J, Leyden JJ. Efficacy of a soy moisturizer in
photoaging: a double-blind, vehicle-controlled, 12-week
study. J Drugs Dermatol 2007;6:917-22.
56. Syed T, Aly R, Ahmad SA, Andersson T, Wong W. Manage-
ment of melasma with 2% analogue of green tea extract in a
hydrophilic cream: a placebo-controlled, double-blind study.
J Am Acad Dermatol 2009;60:AB160.
57. Gueniche AG, Philippe D, Bastien P, Sextius P, Barron D,
Buyukpamukcu E, et al. Hesperidin, a natural flavonoid,
reduces hyperpigmentation in vitro and aging spots
in vivo following oral intake. J Invest Dermatol 2012;132:
S131.
58. Johnson MK, Alexander KE, Lindquist N, Loo G. A phenolic
antioxidant from the freshwater orchid, Habenaria repens.
Comp Biochem Physiol C Toxicol Pharmacol 1999;122:
211-4.
59. Hsu S. Green tea and the skin. J Am Acad Dermatol 2005;52:
1049-59.
60. No JK, Soung DY, Kim YJ, Shim KH, Jun YS, Rhee SH, et al.
Inhibition of tyrosinase by green tea components. Life Sci
1999;65:PL241-6.
61. Charurin P, Ames JM, del Castillo MD. Antioxidant activity of
coffee model systems. J Agric Food Chem 2002;50:3751-6.
62. An HJ, Jeong HJ, Um JY, Kim HM, Hong SH. Glechoma
hederacea inhibits inflammatory mediator release in
IFN-gamma and LPS-stimulated mouse peritoneal macro-
phages. J Ethnopharmacol 2006;106:418-24.
63. Kim J, Song S, Lee I, Kim Y, Yoo I, Ryoo I, et al. Anti-inflam-
matory activity of constituents from Glechoma hederacea var
longituba. Bioorg Med Chem Lett 2011;21:3483-7.
64. Wei H, Cai Q, Rahn RO. Inhibition of UV light- and Fenton
reaction-induced oxidative DNA damage by the soybean
isoflavone genistein. Carcinogenesis 1996;17:73-7.
65. Vaya J, Belinky PA, Aviram M. Antioxidant constituents from
licorice roots: isolation, structure elucidation and antioxida-
tive capacity toward LDL oxidation. Free Radic Biol Med 1997;
23:302-13.
66. Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory
effect of glabridin from licorice extracts on melanogenesis
and inflammation. Pigment Cell Res 1998;11:355-61.
67. Chang LW, Juang LJ, Wang BS, Wang MY, Tai HM, Hung WJ,
et al. Antioxidant and antityrosinase activity of mulberry
(Morus alba L.) twigs and root bark. Food Chem Toxicol 2011;
49:785-90.
68. Golechha M, Bhatia J, Arya DS. Studies on effects of Emblica
officinalis (Amla) on oxidative stress and cholinergic function
in scopolamine induced amnesia in mice. J Environ Biol 2012;
33:95-100.
69. Packer L, Rimbach G, Virgili F. Antioxidant activity and
biologic properties of a procyanidin-rich extract from pine
(Pinus maritima) bark. Pycnogenol. Free Radic Biol Med 1999;
27:704-24.
70. Cossins E, Lee R, Packer L. ESR studies of vitamin C regen-
eration, order of reactivity of natural source phytochemical
preparations. Biochem Mol Biol Int 1998;45:583-97.
71. Gonzalez S, Pathak MA. Inhibition of ultraviolet-induced
formation of reactive oxygen species, lipid peroxidation,
erythema and skin photosensitization by Polypodium
J AM ACAD DERMATOL
VOLUME 70, NUMBER 2Fisk et al 365
leucotomos. Photodermatol Photoimmunol Photomed 1996;
12:45-56.
72. Gonzalez S, Gilaberte Y, Philips N. Mechanistic insights in the use
of a Polypodium leucotomos extract as an oral and topical
photoprotective agent. PhotochemPhotobiol Sci 2010;9:559-63.
73. Merinville E, Byrne AJ, Visdal-Johnsen L, Bouvry G, Gillbro JM,
Rawlings AV, et al. Clinical evaluation of a dioic acid-based
formulation on facial skin in an Indian population. Int J
Cosmet Sci 2012;34:575-81.
74. Choo SJ, Ryoo IJ, Kim YH, Xu GH, Kim WG, Kim KH, et al.
Silymarin inhibits melanin synthesis in melanocyte cells.
J Pharm Pharmacol 2009;61:663-7.
75. Yamaguchi F, Yoshimura Y, Nakazawa H, Ariga T. Free radical
scavenging activity of grape seed extract and antioxidants
by electron spin resonance spectrometry in an H(2)
O(2)/NaOH/DMSO system. J Agric Food Chem 1999;47:2544-8.
76. Kim S, Lee J, Jung E, Huh S, Park JO, Lee JW, et al. Mechanisms
of depigmentation by alpha-bisabolol. J Dermatol Sci 2008;52:
219-22.
77. NesterovA,Zhao J,MinterD,Hertel C,MaW,AbeysingheP, et al.
1-(2,4-Dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)-
propane, a novel tyrosinase inhibitor with strong depigment-
ing effects. Chem Pharm Bull 2008;56:1292-6.
78. Yoshimura M, Watanabe Y, Kasai K, Yamakoshi J, Koga T.
Inhibitory effect of an ellagic acid-rich pomegranate extract
on tyrosinase activity and ultraviolet-induced pigmentation.
Biosci Biotechnol Biochem 2005;69:2368-73.
79. Zhang C, Lu Y, Tao L, Tao X, Su X, Wei D. Tyrosinase inhibitory
effects and inhibition mechanisms of nobiletin and hesper-
idin from citrus peel crude extracts. J Enzyme Inhib Med
Chem 2007;22:91-8.
80. Proteggente AR, Basu-Modak S, Kuhnle G, Gordon MJ,
Youdim K, Tyrrell R, et al. Hesperetin glucuronide, a
photoprotective agent arising from flavonoid metabolism
in human skin fibroblasts. Photochem Photobiol 2003;78:
256-61.
81. Asl MN, Hosseinzadeh H. Review of pharmacological effects
of Glycyrrhiza sp and its bioactive compounds. Phytother Res
2008;22:709-24.
82. Briganti S, Camera E, Picardo M. Chemical and instrumental
approaches to treat hyperpigmentation. Pigment Cell Res
2003;16:101-10.