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A Promising Strategy for the Treatment of Onychomycosis with Curcumin and Photodynamic Therapy

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Onychomycosis is a disease of high incidence in the nail plate and responsible for approximately half of the cases of nail infections. Conventionally, dermatologists prescribe antibiotics and antifungals for long periods for its treatment. The high incidence of this type of infection and the increase of microbial strains resistant to the available drugs have justified the importance of the development of new technologies and treatments. This paper presents the photodynamic therapy as an alternative treatment of onychomycosis. New strategies for the use of curcumin as a photosensitizer and its therapeutic response were investigated in different formulations (gel and emulsion). Photodynamic therapy is a promising technique by which microorganisms are eliminated by a photosensitizing compound , light and oxygen. It was evaluated in two patients who had developed lesions in the fingernails caused by onychomycosis for approximately 10 years. The lesions were treated by photodynamic therapy with curcumin. The therapeutic efficacy was observed after a maximum of six photodynamic therapy sessions without any other adjuvant therapy. Curcumin has become more promising than the therapeutic standard as it is a natural and versatible drug for incorporation in different formulations, at low cost and low probability of side effects.
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Journal of Pharmacy and Pharmacology 3 (2015) 434-437
doi: 10.17265/2328-2150/2015.09.005
A Promising Strategy for the Treatment of
Onychomycosis with Curcumin and Photodynamic
Therapy
Ana Paula da Silva, Fernanda M. Carbinatto, Vanderlei S. Bagnato and Natalia M. Inada
University of Sao Paulo, Physics Institute of Sao Carlos, 13566-590 Sao Carlos, SP, Brazil
Abstract: Onychomycosis is a disease of high incidence in the nail plate and responsible for approximately half of the cases of nail
infections. Conventionally, dermatologists prescribe antibiotics and antifungals for long periods for its treatment. The high incidence
of this type of infection and the increase of microbial strains resistant to the available drugs have justified the importance of the
development of new technologies and treatments. This paper presents the photodynamic therapy as an alternative treatment of
onychomycosis. New strategies for the use of curcumin as a photosensitizer and its therapeutic response were investigated in
different formulations (gel and emulsion). Photodynamic therapy is a promising technique by which microorganisms are eliminated
by a photosensitizing compound , light and oxygen. It was evaluated in two patients who had developed lesions in the fingernails
caused by onychomycosis for approximately 10 years. The lesions were treated by photodynamic therapy with curcumin. The
therapeutic efficacy was observed after a maximum of six photodynamic therapy sessions without any other adjuvant therapy.
Curcumin has become more promising than the therapeutic standard as it is a natural and versatible drug for incorporation in different
formulations, at low cost and low probability of side effects.
Key words: Onychomycosis, photodynamic therapy, curcumin, formulations.
1. Introduction
Onychomycosis is a nail fungal infection caused by
dermatophytes, yeasts or nondermatophytes. Systemic
and topical antifungal agents can be used in its
conventional treatment [1, 2]. However, oral
antifungals may cause adverse effects. The topical
formulation with antifungal agents may have low
therapeutic efficacy because of their limited ability to
penetrate the nail plate and reach the affected area
[3].These factors and the high incidence of this
infection are important parameters for the analyses of
Corresponding author: Natalia M. Inada, Ph.D., doctor of
medical pathophysiology, post-doctorate by the physics
institute of USP in São Carlos (IFSC), researcher, research
fields: biology, medicine, pharmacy, chemistry and physics,
with a background in biochemistry (metabolism and
bioenergetics), operates mainly in: mitochondrial bioenergetics,
tumor cells, reactive oxygen species, cell death mechanisms,
basic photodynamic therapy (in vitro and in vivo) and applied
(clinical research), optical devices applied in health. E-mail:
nataliainada@gmail.com.
new formulations associated with other techniques to
ensure the success of the therapy.
PDT (photodynamic therapy) is a noninvasive
simple technique, therefore it is an interesting therapy
for the treatment of onychomycosis. It is characterized
by the association of a photosensitizing agent and a
light source of suitable wavelength. When this
photosensitizer is activated by light in the presence of
oxygen, it produces reactive oxygen species that
inactivate the fungi and cause onychomycosis [4].
Curcumin is a component obtained from the rizoma
of Curcuma Longa Linn and investigated as a
potential PS (photosensitizing compound) in PDT for
the inactivation of microorganisms. Besides its use as
a PS, it can act on localized superficial infections.
Initially, curcumin was used mainly in the food
industry, but its application is not limited to the food
area. It has shown several biological effects, such as
suppression of carcinogenesis by avoiding the
D
DAVID PUBLISHING
A Promising Strategy for the Treatment of Onychomycosis with Curcumin and Photodynamic Therapy
435
proliferation of a wide variety of tumor cells (skin,
lung, stomach, colon and breast), anti-inflammatory,
antioxidant and bactericidal activitivies.
Pharmacological actions can be intensified when
curcumin is irradiated with blue light [5-7].
Silva, A. P. et al reported some promising results
regarding the use of curcumin solutions for
onychomycosis treatments in patients that had showed
unsatisfactory results in conventional therapies and
had been affected by the disease for more than 5 years.
The patients nail plates were applied a curcumin
solution and then illuminated with LED (light emitting
diode) 450 nm [8]. However, curcumin in solution
does not remain long in contact with the lesion due to
the limitation of its standard formulation. As the nail
plate is composed mainly of keratin, a low content of
lipids and water, it works as a hydrophilic barrier.
Lipids may represent an important route of
transportation mainly for hydrophobic substances [9].
As the nail plate hampers the permeation of the PS,
we have studied new formulations to improve the
success of the therapy with curcumin.
Due to the structural characteristics of the nail plate,
curcumin was used in different formulations
(hydrophilic gel and water/oil emulsion) for the
analysis of the success of the therapy.
2. Material and Methods
2.1 Patient Selection
The patients with onychomycosis were selected
with a clinical diagnosis confirmed by podiatrist.
The experiments were approved by the Ethics
Committee of Anhembi Morumbi University (79th
Ethics Committee Meeting on November 16, 2010)
and patients signed an informed consent.
2.2 Formulation with PS
Curcumin was solubilize with 1% alcohol and 0,1%
dimethyl sulfoxide after Curcumin was incorporated
in the 1.5% concentration in two different formulation,
in carbopol gel and emulsion W/O.
2.3 PDT for Treatment Onycomycosis
Patients with Onychomycosis were treated for 20
min by an LED (450 nm, 100 mW/cm²) system
developed in the Laboratory of Technological Support
and anatomically designed for fingernails and
Toenails (total fluence of 120 J/cm²) (Fig. 1).
Patients had their nail plate prepared with a solution
of 40% urea emollient two hours before the treatment.
Urea was in contact with the nail for one hour and
after this period its excess was removed and PS was
applied for one hour before illumination.
Curcumin in the 1.5% concentration was topically
applied in gel or emulsion and subjected to
illumination. After a seven-day treatment, a new
evaluation was conducted for the analysis of the
clinical response to the treatment. The follow-up
treatment was performed by a clinical evaluation and
documented by photographic images weekly.
For a comparative analysis of different formulations,
the treatment was performed in two patients (case 1:
male, aged 27 and case 2: female, 65 years old) with
Fig. 1 Design of the device registered in the National Institute of Industrial Property (INPI Protocol No. 18110047225,
December 5th, 2011).
A Promising Strategy for the Treatment of Onychomycosis with Curcumin and Photodynamic Therapy
436
fingernail diseases caused by fungi. Both patients had
had the lesions for approximately 10 years. The results
were positive for the laboratory cultures, which
indicated the presence of fungi.
3. Results
3.1 Patient 1: Treatment of Onychomycosis with Gel
Curcumin
Gel curcumin (1.5%) was topically applied to the
fingernail (Fig. 2) in case 1. The nail was then
protected from light for 1h. Only 6 PDT sessions were
applied and a complete healing was achieved (Fig. 2b)
and evidenced by the negative culture of
microorganisms for fungi that cause onychomycosis.
3.2 Patient 2: Treatment of Onychomycosis with
Emulsion Curcumin
Curcumin incorporated in emulsion (1.5%) was
topically applied to the fingernail (Fig. 3) in case 2.
The nail was then protected from light for 1h. Only 5
PDT sessions were necessary and a complete healing
was achieved (Fig. 3b) and evidenced by the negative
culture of microorganisms for fungi that cause
onychomycosis.
Fig. 2 Male patient, 10 years of lesion, (a) before treatment and (b) after 6 sessions of PDT with curcumin (PDT pharma gel
1.5%).
Fig. 3 Female patient, 10 years of lesion, (a) before treatment and (b) after 5 sessions of PDT with curcumin (PDT Pharma
Emulsion 1.5%).
A Promising Strategy for the Treatment of Onychomycosis with Curcumin and Photodynamic Therapy
437
4. Discussions
This study has demonstrated the efficacy of PDT
with curcumin as a photosensitizer agent in the
treatment of onychomycosis. The possibility of using
vehicular curcumin in different formulations (gel and
emulsion) can be a positive aspect for this approach.
The new formulation combined with the
pre-treatment of the nail bed, can favor the penetration
of curcumin in the lesion. The patients reported no
pain during and after the treatment and the sessions
were repeated weekly.
The satisfactory results achieved with few treatment
sessions have proven the differential of this new
approach to treat onychomycosis in comparison to
conventional treatments, which require a higher
number of sessions and may cause discontinuity of the
treatment.
5. Conclusion
Photodynamic therapy has shown increased
potential to aid in microbial and fungal reductions . It
was possible to reach a favorable setting for
commercial viability of the formulations developed
for clinical research, which should help to expedite the
availability of this technique to the national and
international clinical reality. PDT using different
formulation with curcumin is a technique with great
potential and low-cost treatment of onychomycosis.
Acknowledgements
This research has been supported by grants from
Fundacão de Amparo à Pesquisa do Estado de São
Paulo (FAPESP; CEPOF Grant No. 98/14270-8) and
Financiadora de Estudos e Projeto FINEP-Gnatus
(Grant No. 554339/2010-2). APS was supported by
Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq FINEP-Gnatus; GrantNo.
381132/2010-2).
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The absorption of drugs into the nail unit, following topical application to the nail plate, is highly desirable to treat nail disorders, such as onychomycosis (fungal infections of the nail). Nail permeability is however quite low and limits topical therapy to early/mild disease states. In this paper, the recent research into ungual drug delivery is reviewed. The nail unit and the two most common diseases affecting the nail--onychomycosis and nail psoriasis--are briefly described to set the scene and to give an overview of the nature and scope of the problem. The factors, which affect drug uptake and permeation through the nail plate such as solute molecular size, hydrophilicity/hydrophobicity, charge, and the nature of the vehicle, are then discussed, followed by ways of enhancing drug transport into and through the nail plate. Finally, drug-containing nail lacquers which, like cosmetic varnish, are brushed onto the nail plates to form a film, and from which drug is released and penetrates into the nail, are reviewed.
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Natural curcumin was evaluated as a potential photosensitizer for oral applications. The photocytotoxicity of curcumin on salivary gland acinar cells (SM 10-12) was investigated in five aqueous preparations consisting of 5% DMSO, non-ionic micelles, cyclodextrin, liposomes, or a hydrophilic polymer. The difference in phototoxic effects between natural curcumin and synthetic curcumin was examined. Cytotoxicity in SM 10-12 cells exposed to curcumin in the concentration range 0.4-13.5 microM was investigated by MTT test, a fluorescence-staining microscopic test, and by Western immunoblotting techniques. The potential formation of a photoreaction product, hydrogen peroxide, was evaluated by a fluorescence assay. The light source was a halogen lamp used in the dental clinic, emitting mainly in the blue part of the spectrum. The phototoxic effect on SM 10-12 cells was dependent on curcumin concentration, the light dose and the type of preparation. Natural and synthetic curcumin induced phototoxicity to the same extent. Significant effects on the cells were obtained at low curcumin concentrations (< or =0.5 microM) and at a low light dose (< or =6 J cm(-2)), after 3 h incubation. Neither the activation of caspases-3, -7, -8 or -9, nor the formation of hydrogen peroxide could be detected in cells exposed to curcumin and light. The liposome preparation was the most efficient vehicle for curcumin to induce cell death. The phototoxic effect induced by curcumin is highly dependent on the type of preparation. Curcumin might be a potential photosensitizer in the treatment of oral lesions and cancers provided careful selection of the vehicle.
  • E M Bruzell
  • E Morisbak
  • H H Tønnesenet
Bruzell, E. M., Morisbak, E., and Tønnesenet, H. H. 2005. " Studies on Curcumin and Curcuminoids. XXIX.