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70 MINERVA OFTALMOLOGICA December 2016
rier function, loss of elasticity, modication of
rhytides, changes in pigmentation, loss of pap-
illary organization of the subcutaneous vascu-
lature, slower turnover of epidermal cells, and
atrophy.1, 2 The prominent cellular and molec-
ular features of skin aging are: general atrophy
of the extracellular matrix, decreased number
of broblasts and reduced levels of collagen
The periorbital facial region plays an impor-
tant role in overall physical appearance but
it is the rst areas to reveal signs of aging. The
aging process is inuenced by several factors
including genetics, environmental exposure,
hormonal changes and metabolic processes;
the physiological changes associated with
aging include xerosis, alteration of skin bar-
ORIGINAL ARTICLE
Under-eye bags in healthy subjects:
evaluation of the effects of a new escin-based
cosmetic cream in an eight-week study
Gianni BELCARO 1, Mark DUGALL 1, Giada MARAMALDI 2,
Stefano TOGNI 2, Luca GIACOMELLI 3*
1Department of SMO Biotech, Irvine3 Labs, Circulation Sciences, University of Chieti-Pescara, Chieti, Italy;
2Indena SpA, Milan, Italy; 3Department of Surgical Sciences and Integrated Diagnostics, School of Medicine,
Genova University, Genoa, Italy
*Corresponding author: Luca Giacomelli, Department of Surgical Sciences and Integrated Diagnostics, School of Medicine, Genova
University, Genoa, Italy. E-mail: lu.giacomelli6@gmail.com
Anno: 2016
Mese: December
Volume: 58
No: 4
Rivista: Minerva Oftalmologica
Cod Rivista: Minerva Oftalmol
Lavoro: 1766-MOFTAL
titolo breve: UNDER-EYE BAGS IN HEALTHY SUBJECTS
primo autore: BELCARO
pagine: 70-4
citazione: Minerva Oftalmol 2016;58:70-4
ABSTRACT
BACKGROUND: In order to nd effective natural products to reduce under-eye bags, a multi-component formulation,
containing escin as the main active ingredient has been tested in healthy subjects with lower eyelid bags.
METHODS: In this randomized, vehicle-controlled study, 57 healthy subjects with lower eyelid bags were advised to
apply in the periorbital region and surrounding area, 1 g of the assigned formulation twice a day for 8 weeks. The three
topical products used in this study were: vehicle (no active ingredients); escin 0.2% cream; a multi-component cream
composed by escin β-sitosterol Phytosome® 1%, Zanthalene® 0.5%, Ximilene® 0.5%, Ruscogenins 0.1%. Esthetics and
cosmetic parameters were evaluated at inclusion and after 4 and 8 weeks. Moreover, each subject gave a subjective evalu-
ation of their lower eyelid appearance and their global facial appearance.
RESULTS: The 57 individuals recruited in this study were randomly assigned to either vehicle group (N.=18), escin 0.2%
cream group (N.=19) or multicomponent cream group (N.=20). Signicant improvements in the cosmetic and esthetic
skin parameters of the lower eyelid area (infra-orbital hollow; skin moisture; skin content of water, oily substances and
dead cells) were observed for the multicomponent cream-treated group. In addition, globally favorable were also the
results of the subjective evaluations of the lower eyelid and global facial appearance in the group treated with the mul-
ticomponent cream.
CONCLUSIONS: Our study showed that the escin-based, multicomponent, topical cream is effective in reducing the
lower eyelid bags appearance.
(Cite this article as: Belcaro G, Dugall M, Maramaldi G, Togni S, Giacomelli L. Under-eye bags in healthy subjects: evalua-
tion of the effects of a new escin-based cosmetic cream in an eight-week study. Minerva Oftalmol 2016;58:70-4)
Key words: Eyelids - Eyelid diseases - Escin.
Minerva Oftalmol 2016 December;58(4):70-4
© 2016 EDIZIONI MINERVA MEDICA
Online version at http://www.minervamedica.it
COPYRIGHT© 2016 EDIZIONI MINERVA MEDICA
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
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not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or ter ms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
or other proprietary information of the Publisher.
UNDER-EYE BAGS IN HEALTHY SUBJECTS BELCARO
Vol. 58 - No. 4 MINERVA OFTALMOLOGICA 71
Materials and methods
Subjects and procedures
Healthy subjects with lower eyelid bags
were recruited in this randomized, vehicle-
controlled study. Participants had to be free
from any pathological condition. Each sub-
ject was advised to apply, in the periorbital
region and surrounding area (Figure 1), 1 g
of the assigned formulation twice a day for
eight weeks, by gently rubbing for 3 minutes
with ngertips. During the study, enrolled
subjects could not use any other systemic or
topical products. All participants gave written
informed consent before enrollment in this
study. All procedures received local ethics
committee approval, in accordance with the
latest version of the Declaration of Helsinki.
Treatment formulations
Three formulations were applied in this
study: vehicle (no active ingredients); escin
0.2% cream; a multicomponent cream com-
posed by lecithin/escin/b-sitosterol (escin
β-sitosterol Phytosome® from Indena, Milan,
Italy) 1%, oleyl alcohol/Zanthoxylum Bungea-
num fruit extract (Zanthalene® from Indena,
and elastin, leading to their impaired organiza-
tion.3
Eyelid bags, namely mild swelling or puf-
ness under the eyes, are considered a sign of
ageing, although they often appear prema-
turely, due to a variety of causes that can favor
them.4 Based on patients’ perception, Gold-
berg et al.5 showed that lower eyelid bags are
complex esthetic problems involving several
anatomic changes, such as orbital fat prolapse,
lower eyelid skin elasticity, tear trough defor-
mity and eyelid uid accumulation.
Nowadays, there are many invasive or
minimally-invasive treatment options to ad-
dress these complaints, including surgical in-
tervention and nonsurgical approaches (laser
resurfacing, soft tissue llers, neurotoxins, and
energy-based skin tightening).6 However, in-
vasive or minimally-invasive eyelid bags treat-
ment approaches present high costs and poten-
tial side effects.7 Eyelid skin is the thinnest
skin in the body, measuring 0.2 mm in thick-
ness in some individuals.6 Taking into account
the vulnerability (due to its thin nature) and
the close proximity of the eye, caution must
be taken to treat this area. Therefore, consider-
ing eyelid bags as mainly a non-clinical con-
dition, treatment of the eyelid bags should be
oriented to the reduction of predisposing fac-
tors (getting adequate sleep, minimizing salt
and alcohol consumption, avoiding allergens)
and the evaluation of alternative management
methods, such as naturally-derived topical
treatment.8, 9 To this purpose, a multi-compo-
nent formulation was developed, containing
escin 10 as the main active compound and other
functional natural ingredients with recognized
cosmetic, anti-inammatory and skin micro-
circulation-stimulatory activities.
In this study, we aimed at evaluating the
synergistic effect of different active ingredi-
ents in attenuating the appearance of eyelid
bags in healthy subjects. To this purpose, we
compared the well-known cosmetics and anti-
edema activities 11-14 of the active compound
escin in two product typologies: formulation
with 0.2% escin only and multicomponent for-
mulation containing escin as the main active
ingredient.
Figure 1.—Cream application area.
COPYRIGHT© 2016 EDIZIONI MINERVA MEDICA
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or ter ms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
or other proprietary information of the Publisher.
BELCARO UNDER-EYE BAGS IN HEALTHY SUBJECTS
72 MINERVA OFTALMOLOGICA December 2016
the quantity of dead skin cells were assessed
by EP-HYDR8 (CA, US). The evaluation were
expressed by an arbitrary scale ranging from
0 (very dehydrated/dry) to 5 (very hydrated/
oily) for water and oil content; from 0 (soft
skin) to 5 (exfoliating skin) for dead skin cells.
Each subject gave a subjective evaluation of
their lower eyelid appearance at the inclusion,
during and at the end of the study (arbitrary
scale: 0 = absent; 1 = very mild, 2 = mild; 3
= moderate, 4 = severe, 5 = very severe) and
their global facial appearance at 4 and 8 weeks
by awarding a score, according to the follow-
ing scale: 0 = very dissatised; 1 = dissatised;
2 = neither satised or dissatised; 3 = satis-
ed; 4 = very satised.
Statistical analysis
Intra- and inter-group comparisons of non-
parametric, numerical data were performed by
ANOVA test. A P value <0.05 was considered
statistically signicant.
Results
The 57 individuals recruited in this study
were randomly assigned to either vehicle
group (N.=18), escin 0.2% cream group
(N.=19) or multi-component cream group
(N.=20). The groups had similar demograph-
ics characteristics at inclusion (Table I). Over-
all, the topical formulations containing active
ingredients (escin 0.2% and multicomponent
creams) and the placebo (vehicle) were very
well tolerated by all subjects. No skin pig-
mentation alterations, skin allergy or any local
problems were observed during the study and
in the follow up period (up to 8 weeks). Table
Milan, Italy) 0.5%, ethyl ximenynate (Ximi-
lene® from Indena, Milan, Italy) 0.5%, neor-
uscogenin/ruscogenin (Ruscogenins C from
Indena, Milan, Italy) 0.1%.
Clinical assessment and instrumental exami-
nations
Each individual was subjected to several
non-invasive clinical and instrumental exami-
nations at the following time period: at inclu-
sion, to evaluate the basal conditions of the
subject prior to the beginning of the study, af-
ter 4 weeks to evaluate the efcacy of the for-
mulation tested, and after 8 weeks to evaluate
the efcacy and the safety of the formulation
tested.
The following tests were performed:
—Merz Esthetics Scales: infraorbital hol-
low was evaluated by an arbitrary scale: 0 =
no hollowness, 1 = mild hollowness, 2 = mod-
erate hollowness, 3 = severe hollowness, 4 =
very severe hollowness.
—Skin moisture test: surface skin mois-
ture condition was evaluated and expressed
as a percentage (moisture range: 0-99.9%) by
Digital Skin Moisture Meter Facial tester SK-
III (YongSun Beauty & Healthcare Equipment
Co., Guangzhou, China).
—Bio-Impedance Analysis (BIA): the con-
tent of water and oily substances in the skin and
Table II.—Estethic and cosmetic parameters of the lower eyelid skin.
Vehicle Escin 0.2% cream Multicomponent cream
Inclusion 4 weeks 8 weeks Inclusion 4 weeks 8 weeks Inclusion 4 weeks 8 weeks
Skin moisture (range 0-99.9%) 26.5±4.3 29.2±2* 29.1±1* 27±2.8 32±2.4* 33.9±1* 26.4±5.5 34.7±8.3* 35.4±1.1*†
HYDR8 water (range 0-5) 2.2±0.4 1.9±0.6 2.0±0.2 2.3±0.7 1.1±0.4* 1.2±0.4* 2.2±0.9 3.4±1.0* 3.6±0.7*†
HYDR8 oil (range 0-5) 3.3±1.0 3.4±0.6 3.4±0.2 3.1±0.6 3.0±1.1 2.7±0.3* 3.3±0.8 2.8±1.0* 2.6±0.3*†
HYDR8 dead cells (range 0-5) 3.2±0.4 3.3±0.7 3.3±0.3 3.0±1.1 2.6±0.4* 2.4±0.3* 3.2±1.0 2.1±0.6* 1.7±0.4*†
All data are expressed as mean ± standard deviation.
*P<0.05 vs. inclusion. †P<0.05 vs. other groups.
Table I.—Details of the subjects enrolled in the study.
Vehicle Escin 0.2%
cream
Multicom-
ponent
cream
Subjects 18 19 20
Age, years (mean±SD) 51.3±2.2 50±0.8 61.2±1.4
SD: standard deviation.
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or ter ms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
or other proprietary information of the Publisher.
UNDER-EYE BAGS IN HEALTHY SUBJECTS BELCARO
Vol. 58 - No. 4 MINERVA OFTALMOLOGICA 73
of the escin-based multi-component cream
has been shown at 8 weeks, compared to the
other groups (Figure 2).
Globally favorable were also the results of
the subjective evaluations of the lower eyelid
and global facial appearance in the group treat-
ed with the multicomponent cream (Table III).
Discussion
Facial beauty, specically the periorbital
region, is an important component of physical
attractiveness and non-verbal communication,
and reects the chronological age.15 Changes
in the periorbital area, such as under-eye bags
and wrinkles, signicantly impact the per-
ceived age of an individual. However, lower
eyelid bags often appear prematurely, as a
consequence of lifestyle habits and in certain
clinical conditions. Therefore, eyelid bags can
cause emotional stress affecting self-con-
dence and, consequently, quality of life espe-
cially for those subjects who suffer from pre-
mature periorbital swelling. Nowadays, there
are several invasive and minimally-invasive
approaches to ameliorate eyelid bags, howev-
er, benets should be compared with potential
risks and social and economical costs. Recent
clinical data support the use of growth factors
and cytokines in alleviating the appearance of
under-eye bags.16, 17 In fact, growth factors and
cytokines regulate the proliferation of dermal
broblasts and extracellular matrix produc-
tion, playing an integral role in repairing and
remodeling dermal structure.7 However, a the-
oretical complication associated with the use
of human growth factors could be the develop-
ment of skin cancers or the progression of pre-
cancerous lesions to skin cancer, in susceptible
or predisposed individuals.6
II summarizes the cosmetic and aesthetic skin
parameters of the lower eyelid area assessed
before, during and at the end of the study peri-
od. Interestingly, the escin-based formulations
seem to ameliorate all the parameters evalu-
ated (skin moisture; skin content of water, oily
substances and dead cells) at 4 and 8 weeks.
However, at 8 weeks, the multicomponent
cream resulted superior compared to the other
products. Importantly, uid retention leading
to eyelid swelling is not associated with the
skin content of water. Dehydrated skin is char-
acterized by the lack of moisture in the stra-
tum corneum of the skin and can cause dermal
depletion which results in deeper wrinkles, as
well as elastosis and sagging skin. Signicant
variations associated with the escin-based
formulations were observed in the under-eye
hollowness parameter, measured through the
Merz Scale (Figure 2). Noteworthy, a superior
effect in reducing the infra-orbital hollowness
Table III.—Subjective evaluation of the lower eyelid and global facial appearance.
Vehicle Escin 0.2% cream Multicomponent cream
Inclusion 4 weeks 8 weeks Inclusion 4 weeks 8 weeks Inclusion 4 weeks 8 weeks
Lower eyelid appearance (range 0-5) 3.3±1.0 3.2±1 3.2±0.1 3.2±0.9 3.0±0.5 2.9±0.2* 3.2±0.7 2.7±0.4* 2.3±0.4*
Facial appearance (0-4) - 2.0±0.5 2.1±0.3 - 2.4±0.5 2.5±0.2 - 3.3±0.3* 3.5±0.3*
Data are reported as mean±standard deviation.
*P<0.05 vs. other groups.
Figure 2.—Infraorbital hollow measurements (range 0-4).
Data are shown as mean±standard deviation.
*P<0.05; +P<0.04 versus other groups at the same timepoint.
Vehicle Escin 0.2% cream Multi-component cream
+
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or ter ms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
or other proprietary information of the Publisher.
BELCARO UNDER-EYE BAGS IN HEALTHY SUBJECTS
74 MINERVA OFTALMOLOGICA December 2016
What causes eyelid bags? Analysis of 114 consecutive
patients. Plast Reconstr Surg 2005;115:1395-402.
6. Bucay VW, Day D. Adjunctive skin care of the brow and
periorbital region. Clin Plast Surg 2013;40:225-36.
7. Pilkington SJ, Belden S, Miller RA. The tricky tear trough:
a review of topical cosmeceuticals for periorbital skin reju-
venation. J Clin Aesthet Dermatol 2015;8:39-47.
8. Sparavigna A, Tenconi B, De Ponti I, Guglielmini G.
Evaluation of the activity and tolerability of a cosmetic
treatment for the periocular area on the aging face: con-
trolled clinical and instrumental evaluation vs. placebo.
Cosmetics 2014;1:105-16.
9. Amnuaikit T, Maneenuan D, Boonme P. Evaluation of
caffeine gels on physicochemical characteristics and in
vivo efcacy in reducing puffy eyes. J Appl Pharmaceut
Sci 2011;1:56-9.
10. Sirtori CR. Escin: pharmacology, pharmacokinetics and
therapeutic prole. Pharmacol Res 2001;44:183-93.
11. Cesarone MR, Belcaro G, Ippolito E, Ricci A, Rufni M,
Dugall M. Microcirculatory efcacy of topical treatment
with escin + essential phospholipids gel on transcutaneous
PO2 in venous insufciency. Angiology 2004;55:S7-10.
12. Belcaro G, Cesarone MR, Dugall M. Microcirculatory
efcacy of topical treatment with escin + essential phos-
pholipids gel in venous insufciency and hypertension:
new clinical observations. Angiology 2004;55:S1-5.
13. Cesarone MR, Ricci A, Di Renzo A, Belcaro G, Dugall
M. Efcacy of topical treatment with escin + essen-
tial phospholipids gel on capillary fragility. Angiology
2004;55:S23-5.
14. Curri SB, Bombardelli E, Della Loggia R, Del Negro P,
Tubaro A. Topical anti-inammatory activity of complex-
es of escin and sterols with phospholipids. Part II. Anti-
oedema properties in the treatment of panniculophaties of
the thigs and breast. Fitoterapia 1989;60:45-53.
15. Glaser DA, Patel U. Enhancing the eyes: use of mini-
mally invasive techniques for periorbital rejuvenation. J
Drugs Dermatol 2010;9:s118-28.
16. Lupo ML, Cohen JL, Rendon MI. Novel eye cream con-Novel eye cream con-
taining a mixture of human growth factors and cytokines
for periorbital skin rejuvenation. J Drugs Dermatol
2007;6:725-9.
17. Seidel R, Moy RL. Reduced appearance of under-eye
bags with twice-daily application of epidermal growth
factor (EGF) serum: a pilot study. J Drugs Dermatol
2015;14:405-10.
18. Artaria C, Maramaldi G, Bongli A, Rigano L, Appen-
dino G. Lifting properties of the alkamide fraction from
the fruit husks of Zanthoxylum bungeanum. Int J Cosmet
Sci 2011;33:328-33.
19. Bombardelli E, Guglielmini G, Morazzoni P, Curri SB,
Polinelli W. Microvasculokinetic activity of ximenynic
acid and ethyl ester. Fitoterapia 1994;65:195-201.
20. Facino RM, Carini M, Stefani R, Aldini G, Saibene L.
Anti-elastase and anti-hyaluronidase activities of sapo-
nins and sapogenins from Hedera helix, Aesculus hip-
pocastanum, and Ruscus aculeatus: factors contributing
to their efcacy in the treatment of venous insufciency.
Arch Pharm (Weinheim) 1995;328:720-4.
A novel escin-based, multicomponent for-
mulation has been developed as a natural, safe
and tolerable approach to reduce the appear-
ance of the under-eye bags. The widely-ac-
cepted action of escin in stimulating microcir-
culation and reducing edema, was associated
with the cosmetic, microvasculokinetic and
venotonic properties of Zanthalene®,18 Xi-
milene® 19 and Ruscogenins C,20 respectively.
The multicomponent cream showed bene-
cial effects in all the cosmetic and aesthetic
parameters evaluated at 4 and 8 weeks, with
respect to the baseline values. Moreover, com-
pared to the escin 0.2% only, the escin-based,
multicomponent cream resulted in statistically
signicant improvements in cosmetic and es-
thetic parameters, suggesting that the efcacy
of single natural medicines could increases in
the synergy with other active compounds.
Conclusions
Although our pilot study presents a number
of limitations (e.g., limited sample size and
short study period), it provides scientic evi-
dence of the efcacy of a escin-based, multi-
component cream in reducing the lower eyelid
bag appearance.
References
1. Balin A, Pratt L. Physiological consequences of human
skin aging. Cutis 1989;43:431-6.
2. Wulc AE, Sharma P, Czyz CN. The anatomic basis of
midfacial aging. In: Wulc AE, Sharma P, Czyzet CN,
editors. Midfacial rejuvenation. New York, NY, USA:
Springer Science Business Media; 2012. p. 15-28.
3. Callaghan TM, Wilhelm KP. A review of ageing and an
examination of clinical methods in the assessment of age-
ing skin. Part I: Cellular and molecular perspectives of
skin ageing. Int J Cosmet Sci 2008;30:313-22.
4. Inchingolo F, Tatullo M, Abenavoli FM, Marrelli M,
Inchingolo AD, Corelli R, et al. Eyelid bags. Head Face
Med 2010;6:9.
5. Goldberg RA, McCann JD, Fiaschetti D, Ben Simon GJ.
Conicts of interest.—Stefano Togni and Giada Maramaldi are employees of Indena S.p.A. Luca Giacomelli is a consultant for Indena
S.p.A. The other authors declare no conicts of interest.
Acknowledgements.—We thank Dr. Sara Parodi, PhD, who provided medical writing services, supported by internal funds.
Manuscript accepted: September 16, 2016. - Manuscript received: September 16, 2016.
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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or ter ms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
or other proprietary information of the Publisher.
