Research Article

Treatment of warts by Topical retinoids: An

Exploration and meticulosity
Ruchi Tiwari1, Gaurav Tiwari2, Pranay Wal3, Ankita Wal4
Abstract
Warts are clinically skin infections caused by Human Papilloma Virus (HPV). Some warts are painful while
others cause frustration in patients. Warts are contagious and need to be diagnosed clinically from the
outgrowth of skin. Topical retinoids have clinical use for treatment of chronic skin conditions. Topical
retinoids for treatment of skin cancer are tretinoin, the acid form of vitamin A, also known as all-trans
retinoic acid, which is the active vitamin A metabolite in several tissues, isotretinoin (13-cis-retinoic acid),
and two third-generation retinoids, adapalene and tazarotene. Vitamin A is necessary for the growth and
differentiation of epithelial tissues. Retinoids influence the process of vitamin A by interacting with specific
cellular and nuclear receptors of skin. In that way retinoids control cell proliferation and differentiation and
potentially interfere with the tumor promotion phase of carcinogenesis by inducing apoptosis. Review of
medical literatures from past few years revealed monotherapies and combination therapies to eradicate
viral infections caused by HPV. Purpose of this review article is to provide general information about warts,
its mechanism and treatment by topical retinoids.

Keywords: Antiquity of warts, Diagnosis, Topical retinoids and its mechanism of action, Exploration
of tretinoin

Introduction
Warts are skin growths that are caused by the human papillomavirus (HPV). But seborrhoeic keratoses or seborrhoeic
warts are wart like lesions which are not caused by HPV infection. In this article term warts deals with infection caused
by HPV. There are more than 60 kinds of HPV, some of which tend to cause warts on the skin. HPV stimulates quick
growth of cells on the skin’s outer layer [1]. Cutaneous warts are benign papillomas of the skin of which common warts
(verrucae vulgaris) and plantar warts (verrucae plantaris) are the most common types. Up to one third of primary school
children have cutaneous warts. Although cutaneous warts have a benign natural history, they cause significant physical
and psychological inconvenience. Therefore, patients with warts frequently consult physicians, mostly in primary care
[2]. Cutaneous squamous cell carcinoma (SCC) is the second most common non-melanoma skin cancer after basal
cell carcinoma (BCC), and its incidence has increased in recent years. Compared to BCC, it carries a substantial risk
of metastasis and has a higher rate of mortality. Some of the known risk factors of cutaneous SCC are UV radiation,
fair complexion, older age, male gender, longstanding skin ulcers, scars, ionizing radiation, chemical carcinogens and
immunosuppression [3]. Human papilloma viruses (HPV) are members of the Papillomaviridae family of DNA viruses [4].
The preferential association of types of warts with various HPVs is shown in Table 1. In our very large series of cutaneous
warts, studied for over 20 years, HPV type was determined by Southern blot analysis of the DNA extracted from single
warts or pooled lesions of the same type of the same patients, or by blot hybridization. Thus we were able to show
that a characteristic clinical and histologic morphology is related to HPV type [5]. HPV associated warts are subdivided

Pranveer Singh Institute of Technology, Kanpur - Agra - Delhi National Highway - 2, Bhauti, Kanpur, India.
1,2,3,4

Correspondence: Dr. Ruchi Tiwari, Pranveer Singh Institute of Technology, Kanpur - Agra - Delhi National Highway - 2, Bhauti,
Kanpur, India.

E-mail Id: dr.ruchitiwari@psit.in

How to cite this article: Tiwari R, Tiwari G, Wal P et al. Treatment of warts by Topical retinoids: An Exploration and meticulosity. J
Durg Dis Dev 2017; 1(1): 48-53.

© ADR Journals 2017. All Rights Reserved.

J. Durg. Dis. Dev. 2017; 1(1)
on anatomical or morphological grounds into (i) common
wart (Verruca vulgaris); (ii) wart on the sole of the foot,
plantar wart (Verruca plantaris); (iii) flat wart or plane
wart (Verruca plana) and (iv) genital wart (Condyloma
accuminatum) [6]. The main source of infection with
cutaneous HPVs is patients with warts or contaminated
individuals. Plantar warts are frequently contracted in public
baths and swimming pools. Schoolchildren in general are
a high risk population for all types of cutaneous warts [5].
Antiquity of Cutaneous Warts
Even prior to their demonstration, the infectious nature of
these lesions was shown in auto- and heteroinoculation
experiments, where cell-free extracts resulted in the
induction of flat warts [7]. Non-genital warts in healthy
people are quite harmless and usually resolve spontaneously
due to natural immunity within months or years. The rate
of resolution probably depends on a number of factors
including host immunity, HPV type and the site of infection.
One well known study in an institutional population showed
that two thirds resolved within a two year period but the
rates of cure in placebo and no treatment groups of some
of the trials reviewed here clearly show a more rapid
rate of resolution. In view of this, and because there are
probably no universally effective treatments for warts,
many clinicians and health planners suggest, if possible,
avoiding the treatment of viral warts. On the other hand
some viral warts persist for many years and untreated warts
represent a pool of HPV infection within the community.
Retinoids
Topical retinoids have been in clinical use for more than
3 decades for the treatment of chronic skin conditions,
including acne, photodamage, and psoriasis. Tretinoin
was the first topical retinoid available for clinical use. Since
its approval by the US Food and Drug Administration in
1971, clinical experience has corroborated the efficacy
and safety profile of topical tretinoin. Its low systemic
absorption reduces the potential for the development of
systemic adverse effects. Percutaneous absorption of topical
tretinoin 0.05% after more than 1 year of daily application
ranges from 1% to 2%. No significant changes in mean
plasma retinoid concentrations have been reported after
long-term applications of topical tretinoin [9]. Tretinoin
(all-trans-retinoic acid) is the active form of a metabolic
product of Vitamin A, also called retinoic acid. It belongs
to the first generation of retinoids along with isotretinoin,
which is a cis-isomer of retinoic acid. This drug is effective
in the topical treatment of different skin diseases such
as acne vulgaris, ichtiosys, psoriasis, and neoplasias [10].
Topical retinoids used in the treatment of skin cancer
include tretinoin, the acid form of vitamin A, also known
as all-trans retinoic acid, which is the active vitamin A
metabolite in several tissues, isotretinoin (13-cis-retinoic
49
Tiwari R et al.
acid), and two third-generation retinoids, adapalene
and tazarotene. Tretinoin, as an essential substance for
physiological processes, has wide physiological activity
and bioactivity. However, tretinoin is also among the most
potent known animal teratogens [11]. However, despite
these interesting features, its utility is strongly limited by
several disadvantages, such as skin irritation, very low water
solubility, and high instability in the presence of air, light
and heat. The low solubility may limit its incorporation in
a suitable vehicle, while its poor photostability may render
the topically applied drug ineffective [18]. Unfortunately,
this drug is very unstable in the presence of air, light and
heat and tretinoin degradation was reported to occur within
1–2 h after application[19]. It is rapidly isomerized, forming
13-cis and 9-cis retinoic acids [20]. Retinoic acids with potent
biological activity include the all-trans isomer (tretinoin),
the 13-cis isomer (isotretinoin) and the 9-cis isomer
(alitretinoin) [12]. However, as all topical retinoids, TRA
may cause xerosis, irritation, erythema, and desquamation
due to hyperproliferative effect and increased cell turnover
of the epidermal keratinocytes. In order to overcome all
these drawbacks, nanoparticulate drugdelivery systems,
which include liposomes, niosomes, nanocap-sules, solid
lipid nanoparticles, and nanoemulsions, have been used
widely [20]. In addition, the tretinoin teratogenicity is
the most serious side effect. This teratogenic effect is
caused by the interference of the exogenous retinoic acid
with endogenous retinoic acid signaling, which plays a
role in patterning the developing embryo. However, the
transdermal penetration and systemic bioavailability of
topical retinoids are not yet completely clarified. Thus, there
is not a consensual opinion about the use of topical retinoids
during the pregnancy [13]. Excessive Vitamin A intake during
gestation produces embryo- fetal developmental toxicity
in several animal species including humans. Moreover,
during last years the benefits of trans-retinoic acid (TRA)
incorporation in liposomes and niosomes on its dermal
delivery have also been extensively studied. Trans-retinoic
acid or tretinoin (TRA) is a natural retinoid widely used
in proliferative and inflammatory skin diseases, such as
psoriasis, acne, and epithelial skin cancer. Unfortunately,
this drug is very unstable in the presence of air, light and
heat and, in addition, its topical application may cause
irritation and peeling of the treated area [14].
Mechanism of action
Tretinoin acts by modulating the proliferation and
differentiation of epidermal cells within the stratum
corneum and restores normal desquamation of follicular
cells, thereby facilitating comedolysis [15]. Vitamin A is
necessary for the growth and differentiation of epithelial
tissues. Retinoids are known to influence these processes
through their interaction with specific cellular and nuclear
receptors [16]. Retinoic acids either enter the cell directly
from the circulation or are synthesized from retinol and
Tiwari R et al.
retinal in the target cell. Like steroids and thyroid hormones,
they bind to two small cytoplasmic proteins. The cellular
or cytoplasm receptors include the cellular retinoic acid
binding protein (CRABP) types I and II and the cellular retinol
binding protein. The nuclear retinoic acid receptor (RARs)
are related to a super family of nuclear DNA transcription
factors, which include steroid, thyroid hormone, and
Figure 1.Mechanism of action of Tretinoin
receptors can also interact with other pathways
independently of interaction with RAREs. (Encapsulation
in lipid-core nanocapsules overcomes). As a consequence,
retinoids control cell proliferation and differentiation and
might potentially interfere with the tumor promotion phase
of carcinogenesis by inducing apoptosis.
Attainable Topical Retinoids
Topical tretinoin (all-trans-retinoic acid), a first-line
therapy for acne vulgaris treatment, is recommended as
maintenance therapy for acne, primarily due to its ability
to reduce comedone formation without inducing bacterial
resistance. Tretinoin also produces anti-inflammatory
effects and normalizes keratinization. However, like
all topical retinoids, it can cause cutaneous irritation,
particularly during the first 3-4 weeks of treatment.  Factors
that influence cutaneous irritation include individual
differences in skin sensitivity, tretinoin concentration, and
vehicle formulation. Thus, improvements in cutaneous
irritation may be achieved both by optimizing the drug
concentration and by changing the delivery vehicle.
Tretinoin products, including generic formulations, were
originally formulated with a high concentration of tretinoin
solubilized in solutions containing isopropyl myristate or
alcohol. In these formulations, tretinoin is rapidly released
when applied to the epidermis, which can cause cutaneous
irritation (ie, skin drying, peeling, erythema, scaling).
J. Durg. Dis. Dev. 2017; 1(1)
vitamin D receptors, and comprise 3 forms: RAR-a, RAR-b,
and RAR-g. Tretinoin and isotretinoin represent nonspecific
RARs agonists, while adapalene and tazarotene selectively
bind to the RAR subtypes b and g (Figure 1) [16]. Tretinoin
binds to the RAR subunit of heterodimer RAR–RXR and
induces transcription. These
These formulations may therefore be more irritating
than newer branded formulations, which are designed
with novel delivery vehicles and dispensers. These newer
formulations may not only reduce irritation, but also
provide dosing flexibility and enhanced patient satisfaction
and compliance. With the current availability of multiple
concentrations of tretinoin and the development of newer
vehicles, physicians may be able to provide customized
treatment that provides proven efficacy while minimizing
irritation. The aim of this article is to evaluate different
formulations and combinations of topical tretinoin in
the treatment of acne vulgaris [17]. The first formulation
of tretinoin consisted of a high concentration of active
ingredient in a penetrating hydroalcoholic solution, and
excessive skin irritation was common. Subsequently,
tretinoin became available in cream and gel vehicles in a
variety of concentrations, but irritation was still an issue
in some patients [1].
Use of Tretinoin: An Exploration
Ragno et al. studied photostability of tretinoin and
isotretinoin in liposome formulations. Results revealed
that inclusion of tretinoin and isotretinoin in liposome
matrix was proved to show an improved stability to light.
The inclusion of tretinoin in liposome showed a worse
performance probably due to low inclusion due to the
non-linear molecular structure.
50
J. Durg. Dis. Dev. 2017; 1(1)
Jacobson et al. reported a methodology that allows rapid,
precise and accurate determination of tretinoin and
isotretinoin in gel and cream dermatological formulation.
Duran et al. 2012 prepared solid lipid nanoparticle containing
tretinoin with and without addition of chitosan to access
their in vitro cytotoxicity in keratinocytes and evaluated
their antibacterial activity against bacteria involved in
acne development process. Result suggested that solid
lipid nanoparticle with chitosan have great potential for
topical delivery of tretinoin due to their high encapsulation
efficiency, high physical stability and absence of cytotoxicity
in keratinocytes.
The combination of chitosan with solid lipid nanoparicle
can improve the solid lipid nanoparticle properties as
carrier for tretinoin because the solid lipid nanoparticle
chitosan-tretinoin exhibited an important antibacterial
activity against bacteria involved in acne.
Fadda et al. generated innovative niosomes composed
of diolein alone or in association with the hydrophilic
penetration enhancer abrasol ® as carrier for cutaneous
delivery of tretenoin. It was notified that diolein is able
to form vesicle that are similar to liposome in structure,
size and stability. Fadda et al. reported that labrasol can
be used in association with non ionic surfactant to obtain
vesicle with high potentiality in cutaneous drug delivery.
Patravale et al. prepared solid lipid nanoparticles using
highly purified, natural solid lipids (stearine fractions)
by microemulsion technique. Developed solid lipid
nanoparticles were utilised for topical delivery of lipophilic,
anti-acne drug tretinoin.
Yang et al. developed a new gel formulation as that show
sustained release for a period of time. Release of tretinoin
from carbopol gel was affected by the pH of the gels,
showing the best release of pH 8. Reports suggested that
by increasing in concentration of drug and temperature
drug release was increased. The 0.025% tretinoin carbopol
gels containing polyoxyethylene 2-oleyl ether could be
developed for inhanced transdermal drug delivery.
Beck et al. prepared hydrogels containing tretinoin loaded
lipid-core nano capsules without using alchoholic cosolvent,
showed adequate drug content and pH, pseudoplastic
behaviour and better spreadability compared to currently
marketed formulations. Reports suggested that after
incorporation of nanocapsules into hydrogels polymeric
nanocapsules are able to protect nanocapsulated tretinoin
against uva radiation.
Vercammen et al. investigated tretinoin photostability in
various oils and reports suggested that castor oil was best
against photodegredation.
51
Tiwari R et al.
Ascenso et al. proposed that tretinoin ultradeformable
vesicle formulation has a suitable dermal delivery tretinoin-
UDV was considerd as a promising delivery system for
tretinoin dermal delivery without promoting skin irritation.
Wang et al. has developed FeNi carbon microsphere with
large pore sizes, results suggested a low crystalline nature
of carbon microspheres.
Fadda et al. 2005 suggested that tretinoin dermal delivery
was found to be affected by several factors including vesicle
composition, morphology and size. Results supported that
negatively charged liposomes strongly improved new born
pig skin hydration and tretinoic acid retention though no
evidence of intact vesicle penetration was found.
Fadda et al. in 2013 studies cutaneous targeting and
photostability of tretinoin by using nanosuspension
formulation. Results revealed that nanosuspension was
able to localize the drug into skin. Nanosuspensions in
topical tretinoin delivery showed increase photostability
of drug as compared to nanoemulsions.
Fadda et al. in 2006 reported that composition of niosomes
is very important for improving cutaneous or transdermal
delivery of a lipophilic drug such as tretinoin. Very
hydrophilic surfactants may improve diffusion of tretinoin
through pig skin.
Fadda et al. in 2011 developed new penetration enhancer
containing vesicle (PEV) used as suitable carriers for
tretinoin in skin disease treatment.
Patravale et al. 2007 developed solid lipid nanoparticle of
tretinoin with the help of facile and simple emulsification
solvent diffusion (ESD) technique. Solid lipid nanoparticle
of tretinoin showed good photostability as compared to
tretinoin in methanol.
Richard et al. in 2009 developed tretinoin gel microspheres
(TGM) to minimize side effect of topical retinoids TGM in
concentration 0.04% & 0.01% were well tolerated.
Collares et al. in 2015 studied that in vitro oocyte
maturation (IVM) protocol can be improved by adding
chemical supplements in culture media. Collares suggested
an association of tretinoin with lipid-core nanocapsules
(LCN) in order to improve its solubility, chemical stability
and reduction in toxicity. Tretinoin-lipid core nanocapsule
when used at lower dose in in vitro oocyte maturation
(IVM) medium, improves the rates of in vitro produced
embryos and reduced ROS production.
Beck et al in 2008 prepared tretinoin loaded nano capsules
(0.5mg/ml) y interphasial deposition of preformed polymer
using two different oily phases: capric/caprylic tri glycerides
and sunflowers seed oil. These nanocapsules showed
Tiwari R et al.
improved tretinoin photostability, independently on the
type of oily phase used.
Conclusion
Meticulousness for refrainment of topical viral skin
infections must be needed. Treating warts by tretinoin
has been successfully done clinically. In more recent times,
tretinoin has been combined with antibacterials, such as
erythromycin, benzoyl peroxide, and clindamycin, to form
topical combination treatments for acne. Topical retinoids in
combination of antibiotics has proven to be a very effective
therapy for treating the various stages of acne. A number of
formulations have been developed for delivery of tretinoin
due to its effective anti-inflammatory properties.
Conflict of Interest: None
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Date of Submission: 2017-11-29
Date of Acceptance: 2017-12-30
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Table 1.Preferential Association of Wart types with distinct HPVs[5]

Types of warts HPV types
Myrmecia HPV 1
Plantar or palmar
Localization (rarely fingers)
Common warts HPV 2, 4, 7, 57
Plane warts HPV 3, 10, 41
Intermediate warts HPV 26, 27, 28, 29
(frequently in immunosuppressed patients)
Cystic or punctate,
Mainly plantar warts HPV 60, 63, 65

Table 2.Topical Retinoids for Acne Available in the United States

Retinoid
Tretinoin (Retin-A and generics)
Tretinoin in novel vehicles
Third-generation topical retinoids
Formulation
Cream: 0.025%, 0.05%, 0.1%
Gel: 0.01%, 0.025%
Solution: 0.05%
Microsphere vehicle (Retin-A Micro): 0.04% gel, 0.1% gel
Polyolprepolymer vehicle (Avita): 0.025% gel, 0.025% cream
Adapalene (Differin): 0.1% gel, 0.1% solution, 0.1% pledgets, 0.1% cream
Tazarotene (Tazorac): 0.1% cream, 0.1% gel

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