|Year : 2017 | Volume
| Issue : 3 | Page : 24-29
Topical antifungals: A review and their role in current management of dermatophytoses
Shital Amin Poojary
Member, IADVL Task-force Against Recalcitrant Tinea (ITART); Department of Dermatology, K. J. Somaiya Medical College, Mumbai, Maharashtra, India
|Date of Web Publication||10-Oct-2017|
Shital Amin Poojary
Department of Dermatology, K. J. Somaiya Medical College, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Topical antifungals are an important adjuvant in treatment of dermatophytosis. Also specific situations such as dermatophytoses in pregnancy and infants often warrant topical therapy. Several new topical antifungals and newer formulations hold out the promise of enhanced effectiveness of topical therapy in dermatophytosis. This article reviews the entire spectrum of topical antifungals and formulations and their role in management of dermatophytosis.
Keywords: Antifungals, dermatophytes, topical
|How to cite this article:|
Poojary SA. Topical antifungals: A review and their role in current management of dermatophytoses. Clin Dermatol Rev 2017;1, Suppl S1:24-9
| Introduction|| |
Dermatophytosis has become a raging epidemic in India in the recent past. In this scenario, though oral antifungals are the mainstay of therapy, the role of topical antifungals is also crucial. Earlier, localized dermatophytic infection was the main indication of topical antifungal therapy. Other important indications for use of topical antifungals include: (1) pregnancy, (2) pediatric dermatophytic infections, especially infants, (3) patients with systemic diseases such as liver, renal, or cardiovascular diseases, (4) patients on other drugs, which have potential interactions with oral antifungals, and (5) as an adjuvant to systemic therapy.
The advantages of topical antifungal therapy over oral antifungals include: (1) lack of systemic side effects and complications due to limited systemic absorption, (2) very low incidence of drug interactions, (3) ease of use, (4) comparatively low cost of therapy, and (5) additional benefit of anti-inflammatory activity of several topical antifungals including azoles and allylamines.
The disadvantages of topical antifungals include: (1) difficult to use in extensive dermatophytic infections, (2) application of inadequate amount results in poor response, (3) inability to apply in difficult-to-reach areas (e.g., natal cleft) may leave residual foci of infection, (4) low effectiveness in onychomycosis due to inadequate penetration, and (5) rarely contact dermatitis.
| Topical Antifungal Formulations|| |
Topical formulations of antifungals are listed in [Table 1]. Almost all groups of antifungals are available as topical formulations; the azole group including triazoles and allylamines, however, has been predominantly used in topical formulations. Commonly used topical formulations for onychomycosis include amorolfine and ciclopirox nail lacquers.
| Mechanism of Action of Antifungals|| |
The azoles inhibit lanosterol 14α-demethylase of the ergosterol synthesis pathway resulting in the inhibition of conversion of lanosterol to ergosterol. Decreased availability of ergosterol and accumulation of intracellular 14α methyl sterols result in increased membrane rigidity, membrane permeability changes, inhibition of growth, and ultimately death.
Certain azoles have additional modes of action which are useful in the ultimate outcome of treatment, for example, sertaconazole apart from inhibiting ergosterol synthesis pathway also binds directly to nonsterol lipids in the fungal cell wall, leading to increased permeability and subsequent lysis of the mycelium. Thus, at higher concentration, sertaconazole exhibits fungicidal action. The unique benzothiophene ring of sertaconazole enhances the lipophilic property, enabling dermal retention and attainment of fungicidal concentration in the stratum corneum.
Luliconazole has an imidazole moiety incorporated into the ketone dithioacetate structure, resulting in high potency against dermatophytes with very low minimum inhibitory concentration (MIC) levels for Trichophyton rubrum. It has also strong in vitro activity against Candida albicans and Aspergillus fumigatus.
Allylamines inhibit squalene epoxidase of the ergosterol synthesis pathway, thus blocking the conversion of squalene into squalene-2, 3-epoxide, a precursor of ergosterol. The resultant accumulation of squalene is toxic to the fungal cell membrane and is responsible for the fungicidal activity of allylamines.
Ciclopirox has a high affinity for trivalent metal cations, leading to inhibition of cytochrome oxidase and metal-dependent enzymes, which are responsible for the degradation of peroxide inside the fungal cell. Ciclopirox targets several proteins involved in cellular metabolism, including DNA replication, DNA repair, and cellular transport, thus targeting cell growth and metabolism.
Amorolfine interferes with ergosterol biosynthesis at two steps: the delta 14 reduction and the delta 7-8 isomerization. As a consequence of this inhibition, the delta 14 sterol ignosterol is accumulated in the cell membrane and ergosterol is depleted. It has a broad antifungal activity against dermatophytes, yeasts, dimorphic fungi, and molds, and is fungicidal against most species.
| Additional Actions of Topical Antifungals|| |
Azoles such as clotrimazole, econazole, miconazole, ketoconazole, and sertaconazole have additional anti-inflammatory action which can be useful in reducing the symptoms. Sertaconazole nitrate inhibits the release of interleukin 2 (IL-2), tumor necrosis factor alpha, interferon alpha, IL-4, and granulocyte-macrophage-colony-stimulating factor from activated human lymphocytes. Clotrimazole, econazole, miconazole, and ketoconazole have been shown to inhibit chemotactic ability of polymorphonuclear leukocytes.
Allylamines have a dose-dependent inhibitory effect on chemotaxis of polymorphonuclear leukocytes and also reduces the production of reactive oxygen intermediates.
Azoles such as clotrimazole, econazole, miconazole, oxiconazole, and sertaconazole, and allylamines such as terbinafine and naftifine have anti-bacterial activity against Gram-positive bacteria and few Gram-negative bacteria. Ciclopirox has demonstrated clinically relevant MIC against Pseudomonas aeruginosa, Proteus mirabilis, and Escherichia More Details coli.
| Comparative Efficacy of Topical Antifungals|| |
A Cochrane systematic review did not find significant difference in effectiveness between azoles and benzylamines from pooled studies. Crawford and Hollis, however, have reported allylamines to be more effective than azoles due to faster mode of action and shorter treatment duration. Luliconazole has the advantage of effectiveness even on once-daily application, hence can improve compliance., Amorolfine has a different mechanism of action compared to azoles or allylamines, hence can be a useful topical adjuvant in the present scenario of recalcitrant dermatophytosis.
| Methods to Enhance Topical Drug Delivery|| |
Most of the advancements in topical formulations have been made for onychomycosis.
Challenges in topical therapy of onychomycosis: Current topical antifungal formulations for nails often do not achieve adequate therapeutic concentrations in the deeper layers of the nail.
Mechanical, physical, and chemical methods can be used to enhance topical drug delivery, especially in onychomycosis.
Mechanical methods to enhance drug delivery
- Nail abrasives such as sand paper can be used to remove nail debris and enhance the penetration of drugs
- In recalcitrant onychomycosis, partial or total nail avulsion can be done.
Chemical methods to enhance drug delivery
Use of keratolytics, for example, 40% urea and 10%–40% salicylic acid causes softening of nail plate and chemical avulsion of the nail, especially when applied under occlusion for 1–2 weeks and will enhance the absorption of topical antifungals.
One percent salicylic acid powder and Whitfield's ointment can also be used as adjuvants to topical therapy of tinea of glabrous skin as the keratolytic effect of salicylic acid can help in reducing the fungal burden. However, caution is to be exercised in view of potential skin irritation and salicylism, especially when used on widespread areas.
Addition of propylene glycol, hydroxypropyl-β-cyclodextrin or 2-n-nonyl-1, and 3-dioxolane to nail lacquers enhances penetration of the antifungals in the nails., Ethyl cellulose added to nail lacquers can give sustained and slow release of the drug.
Physical methods to enhance drug delivery
Iontophoresis has been used to enhance terbinafine delivery in onychomycosis. For nail iontophoresis, selected drugs should be cationic, should become ionized in an acceptable pH range, and should have a low molecular weight. An electrokinetic transungual system uses a low level of electric current to propel the topical drug into the nail, thus leading to improved availability of the drug in the nail.
Photodynamic therapy (PDT) combines a chromophore (photosensitizer), with light corresponding to the chromophore's specific absorption wavelength, thus inducing the production of oxidative radicals, such as reactive species of oxygen and reactive nitrogen species, which are capable of killing cells.
PDT has shown effective fungicidal activity to T. rubrum in vitro: 25 μM toluidine blue O (TBO) followed by exposure to 630 nm light-emitting diode (LED) (energy density of 72 J/cm2).
Several in vivo studies have also demonstrated the efficacy of PDT. Calzavara-Pinton et al. demonstrated the effective treatment of tinea pedis with PDT, using 20% aminolevulinic acid (ALA) (duration of 4 h) followed by irradiation with red light (75 J/cm2).
Sotiriou et al. demonstrated cure at 18 months in 43.3% of patients with onychomycosis using ALA followed by irradiation with red light (570–670 nm) from a noncoherent light source in three sessions.
Another study by Baltazar Lde et al. concluded that the optimal conditions for photodynamic inhibition were 10 mg/L of TBO and 48 J/cm2 of LED which caused 98% reduction in T. rubrum viability. The viability of the conidia was shown to be destroyed 24 h after treatment. It was also found to be more effective than ciclopirox in promoting fungal cell death.
Ultraviolet-curable gel formulations
Ultraviolet (UV)-curable gel formulations have been used as topical antifungal formulations for onychomycosis. The gels are composed of diurethanedimethacrylate, ethyl methacrylate, and 2-hydroxy-2-methylpropiophenone, an organic liquid (ethanol or NMP) as drug solvent, in addition to the antifungal (amorolfine HCl or terbinafine HCl). A 2 min exposure to a UVA lamp polymerizes the gel resulting in the formation of a smooth, glossy, and amorphous film.
Long-pulse neodymium-yttrium aluminum garnet laser has a fungicidal effect due to accumulation of heat (43°C–51°C). Fractional CO2 laser is useful to create microscopic thermal wounds in the nail and thereby enhanced penetration of the antifungal.
The Food and Drug Administration approved handheld microcutting device that has been utilized to create an opening in the nail plate without pain.
General instructions to enhance the outcome of topical antifungal therapy
- Medication to be applied on the affected skin including 1–2 cm of peripheral apparently normal skin, starting from outside to inside
- Choice of formulation: Different formulations can be used according to the site involved
- Lotions: Intertriginous, hairy areas, on oozing lesions and extensive lesions
- Creams: Scaly lesions, glabrous skin
- Ointments: Hyperkeratotic lesions
- Gels can be used on the face for a better cosmetic effect
- Nail lacquers: Onychomycosis
- Shampoos can be used as an adjunct in tinea capitis
- It may be mentioned that the comparable efficacy and safety of different formulations of terbinafine and ciclopirox have been demonstrated in studies.
Frequency of application: Most topical antifungals should be applied twice daily except luliconazole and terbinafine which are effective on once-daily applicationsFor onychomycosis: Nail lacquers should also be applied to hyponychium and under surface of the nail plate when it is free of the nail bed. Similarly, antifungal nail solutions should cover toenail, toenail folds, toenail bed, hyponychium, and the undersurface of toenail plate.
| Newer Topical Antifungals|| |
It is a new triazole topical antifungal. A low surface tension 10% (wt/wt) topical efinaconazole solution has been used for the treatment of mild-to-moderate distal and lateral subungual onychomycosis.
The methylene-piperidine group at the C-4 position of the efinaconazole molecule may be responsible for its relatively low keratin binding. Efinaconazole possesses broad-spectrum antifungal activity against dermatophyte and nondermatophyte molds (Scopulariopsis brevicaulis and Fusarium species) and yeasts (Candida). Thus, efinaconazole maybe effective in treating nondermatophyte onychomycosis. Various studies have demonstrated 53%–56% mycological cure rates with efinaconazole.
Tavaborole, an oxaborole, is a low molecular weight (152 kDa) and highly specific fungal protein synthesis inhibitor that forms a boron-based bond at the enzyme-editing site to prevent catalytic turnover of leucyl-tRNA synthetase and block fungal protein synthesis resulting in the suppression of fungal cell activity. It has 1000-fold greater selectivity for the fungal leucyl-tRNA synthase compared to the mammalian leucyl-tRNA synthetase. It has low propensity to develop resistance as demonstrated by a study in which isolates of T. rubrum and Trichophyton mentagrophytes did not develop resistance even after repeated exposure to tavaborole. The low molecular weight of tavaborole enables its good penetrability through the thickness of the nail plate. An in vitro study showed 250 times more penetration of tavaborole than ciclopirox into the nail. Tavaborole nail concentrations were found to be twenty times higher than the minimum fungicidal concentration against the dermatophytes 3 months after the end of treatment.
Tavaborole is also active against the far less common nondermatophytic molds, such as A. fumigatus, Fusarium solani, and yeasts (C. albicans). Its mycologic cure rate is 30%–36%, though is lower than oral antifungal agents (50%–76%). Yet it is a good substitute for oral antifungals in patients with associated comorbidities. However, more studies are required to assess recurrence rates with topical tavaborole.
ME1111 (2-(3, 5-Dimethyl-1H-pyrazol-1-yl)-5-methylphenol) is a novel antifungal which selectively inhibits fungal succinate dehydrogenase (complex II), an important enzyme involved in mitochondrial respiratory electron transfer leading to the blockade of ATP production and demonstrates fungicidal activity. The small molecular size of ME1111 enhances its ability to penetrate the nail plate.
A study by Ghannoum et al. demonstrated potent activity of ME1111 even against dermatophyte strains with elevated MICs to terbinafine or itraconazole. Similar to tavaborole, ME1111 also has a low propensity to the development of resistance in dermatophytes; there was no increase in MICs even after repeated exposure to ME1111. This is probably an indication of extensive structural damage to the hyphae due to the fungicidal activity of ME1111.
| Newer Topical Antifungal Drug Formulations|| |
Anhydrous gel formulations
An anhydrous vehicle may be preferred as a topical vehicle for azole antifungals. The higher solubility of the drug in the vehicle may result in higher thermodynamic activity and, thus, greater partitioning into the skin and increased bioavailability of antifungal in the skin, for example, sertaconazole anhydrous gel.
Transfersomes are flexible and ultra-deformable drug carriers composed of complex lipid vesicles, which can be used for noninvasive drug delivery through the skin/nail. The nail acts as a hydrophilic gel network through which the transfersome carrier can easily traverse, increasing drug concentration in the nail bed. TDT-067 (terbinafine 15 mg/mL in transfersome) is a novel preparation that can deliver high concentrations of terbinafine to the site of infection in the nail bed.
Microemulsions are clear, stable, isotropic mixtures of oil, water, and surfactant, frequently in combination with a cosurfactant. Microemulsions have the advantages of enhanced drug solubility, good thermodynamic stability, and higher transdermal permeability over conventional formulations such as itraconazole, fluconazole, and clotrimazole. Clotrimazole microemulsion formulations achieved significantly higher skin retention as against clotrimazole creams.
Ethosomes are soft malleable vesicles constituting phospholipids, ethanol (relatively high concentration), and water. They act as noninvasive delivery carriers for targeting antifungal drugs to deep skin layers for an extended period of time, for example, terbinafine HCL ethosomes.
Poloxamer 407-based formulations
Ciclopirox: Permeation coefficient from P407-based formulations was higher in comparison to the nail lacquer.
Nail penetration enhancer containing nanovesicles
Sertaconazole: Higher hydration and enhanced drug uptake were observed compared to creams.
Terbinafine, a film-forming solution, forms a thin film following topical application. The fungicidal effect can be maintained for about 13 days following single application.
Luliconazole, 10% nail solution, has also shown high penetration in the nails at 7 days after 29-day application for onychomycosis and is now under phase 2/3 randomized controlled trial.
Solid lipid nanoparticles and nanostructured lipid carriers
Solid lipid nanoparticles have the drug entrapped within a solid lipid core matrix. Nanostructured lipid carriers have a matrix composed of a mixture of solid and liquid lipids. Solid lipid nanoparticles of clotrimazole and miconazole have shown sustained and 10-fold better retention than hydrogels.
| Caution in the Use of Antifungal Topical Formulations|| |
Although antifungal powders and soaps are available, it would be advisable not to use them as the concentrations achieved on the body surface are extremely low, thus increasing the chances of development of resistance. This is especially true of critical antifungals, for example, amphotericin B. In fact, all important antifungals available orally should not be used in powder formulations.
Topical antifungals thus have a critical role to play in the management of dermatophytoses. Newer topical antifungals and specialized formulations do hold a lot of promise in the future in the management of dermatophytic infections.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sahoo AK, Mahajan R. Management of tinea corporis, tinea cruris, and tinea pedis: A comprehensive review. Indian Dermatol Online J 2016;7:77-86.
] [Full text]
Croxtall JD, Plosker GL. Sertaconazole: A review of its use in the management of superficial mycoses in dermatology and gynaecology. Drugs 2009;69:339-59.
Liebel F, Lyte P, Garay M, Babad J, Southall MD. Anti-inflammatory and anti-itch activity of sertaconazole nitrate. Arch Dermatol Res 2006;298:191-9.
van Zuuren EJ, Fedorowicz Z, El-Gohary M. Evidence-based topical treatments for tinea cruris and tinea corporis: A summary of a Cochrane systematic review. Br J Dermatol 2015;172:616-41.
Crawford F, Hollis S. Topical treatments for fungal infections of the skin and nails of the foot. Cochrane Database Syst Rev. 2007;3:CD001434.
Scher RK, Nakamura N, Tavakkol A. Luliconazole: A review of a new antifungal agent for the topical treatment of onychomycosis. Mycoses 2014;57:389-93.
Gupta AK, Daigle D. A critical appraisal of once-daily topical luliconazole for the treatment of superficial fungal infections. Infect Drug Resist 2016;9:1-6.
Zane LT, Chanda S, Coronado D, Del Rosso J. Antifungal agents for onychomycosis: new treatment strategies to improve safety. Dermatol Online J 2016;22(3). pii: 13030/qt8dg124gs.
Akhtar N, Sharma H, Pathak K. Onychomycosis: Potential of nail lacquers in transungual delivery of antifungals. Scientifica (Cairo) 2016;2016:1387936.
Chouhan P, Saini TR. Hydroxypropyl-β-cyclodextrin: A novel transungual permeation enhancer for development of topical drug delivery system for onychomycosis. J Drug Deliv 2014;2014:950358.
Hui X, Chan TC, Barbadillo S, Lee C, Maibach HI, Wester RC, et al.
Enhanced econazole penetration into human nail by 2-n-nonyl-1,3-dioxolane. J Pharm Sci 2003;92:142-8.
Nair AB, Kim HD, Chakraborty B, Singh J, Zaman M, Gupta A, et al.
Ungual and trans-ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis. J Pharm Sci 2009;98:4130-40.
Amorim JC, Soares BM, Alves OA, Ferreira MV, Sousa GR, Silveira Lde B, et al.
Phototoxic action of light emitting diode in the in vitro
viability of Trichophyton rubrum
. An Bras Dermatol 2012;87:250-5.
Calzavara-Pinton PG, Venturini M, Capezzera R, Sala R, Zane C. Photodynamic therapy of interdigital mycoses of the feet with topical application of 5-aminolevulinic acid. Photodermatol Photoimmunol Photomed 2004;20:144-7.
Sotiriou E, Koussidou-Eremonti T, Chaidemenos G, Apalla Z, Ioannides D. Photodynamic therapy for distal and lateral subungual toenail onychomycosis caused by Trichophyton rubrum
: Preliminary results of a single-centre open trial. Acta Derm Venereol 2010;90:216-7.
Baltazar Lde M, Soares BM, Carneiro HC, Avila TV, Gouveia LF, Souza DG, et al.
Photodynamic inhibition of Trichophyton rubrum
: In vitro
activity and the role of oxidative and nitrosative bursts in fungal death. J Antimicrob Chemother 2013;68:354-61.
Kerai LV, Hilton S, Murdan S. UV-curable gel formulations: Potential drug carriers for the topical treatment of nail diseases. Int J Pharm 2015;492:177-90.
Wanitphakdeedecha R, Thanomkitti K, Bunyaratavej S, Manuskiatti W. Efficacy and safety of 1064-nm Nd:YAG laser in treatment of onychomycosis. J Dermatolog Treat 2016;27:75-9.
Bhatta AK, Keyal U, Huang X, Zhao JJ. Fractional carbon-dioxide (CO2) laser-assisted topical therapy for the treatment of onychomycosis. J Am Acad Dermatol 2016;74:916-23.
Tatsumi Y, Nagashima M, Shibanushi T, Iwata A, Kangawa Y, Inui F, et al.
Mechanism of action of efinaconazole, a novel triazole antifungal agent. Antimicrob Agents Chemother 2013;57:2405-9.
Jinna S, Finch J. Spotlight on tavaborole for the treatment of onychomycosis. Drug Des Devel Ther 2015;9:6185-90.
Elewski BE, Aly R, Baldwin SL, González Soto RF, Rich P, Weisfeld M, et al.
Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: Results from 2 randomized phase-III studies. J Am Acad Dermatol 2015;73:62-9.
Tabata Y, Takei-Masuda N, Kubota N, Takahata S, Ohyama M, Kaneda K, et al.
Characterization of antifungal activity and nail penetration of ME1111, a new antifungal agent for topical treatment of onychomycosis. Antimicrob Agents Chemother 2016;60:1035-9.
Ghannoum M, Isham N, Long L.In vitro
antifungal activity of ME1111, a new topical agent for onychomycosis, against clinical isolates of dermatophytes. Antimicrob Agents Chemother 2015;59:5154-8.
Manian M, Madrasi K, Chaturvedula A, Banga AK. Investigation of the Dermal Absorption and Irritation Potential of Sertaconazole Nitrate Anhydrous Gel. Pharmaceutics 2016;8:21.
Hashem FM, Shaker DS, Ghorab MK, Nasr M, Ismail A. Formulation, characterization, and clinical evaluation of microemulsion containing clotrimazole for topical delivery. AAPS PharmSciTech 2011;12:879-86.
Iizhar SA, Syed IA, Satar R, Ansari SA.In vitro
assessment of pharmaceutical potential of ethosomes entrapped with terbinafine hydrochloride. J Adv Res 2016;7:453-61.
Li RY, Wang AP, Xu JH, Xi LY, Fu MH, Zhu M, et al.
Efficacy and safety of 1% terbinafine film-forming solution in Chinese patients with tinea pedis: A randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Clin Drug Investig 2014;34:223-30.
|This article has been cited by|
||A novel method for predicting the efficacy of topical drugs on onychomycosis: a comparison of efinaconazole and luliconazole
| ||Akane Masumoto, Masashi Takagi, Keita Sugiura, Yoshiki Matsuda, Saki Nakamura, Yoshiyuki Tatsumi |
| ||Journal of Medical Mycology. 2022; : 101259 |
|[Pubmed] | [DOI]|
||Emerging Trends in the Use of Topical Antifungal-Corticosteroid Combinations
| ||Dalibor Mijaljica, Fabrizio Spada, Ian P. Harrison |
| ||Journal of Fungi. 2022; 8(8): 812 |
|[Pubmed] | [DOI]|
||Lipid Based Nanocarriers: Promising Drug Delivery System for Topical Application
| ||Darshana Patel,Brijesh Patel,Hetal Thakkar |
| ||European Journal of Lipid Science and Technology. 2021; : 2000264 |
|[Pubmed] | [DOI]|
||In Vitro Combination Effect of Topical and Oral Anti-Onychomycosis Drugs on Trichophyton rubrum and Trichophyton interdigitale
| ||Keita Sugiura,Akane Masumoto,Haruki Tachibana,Yoshiyuki Tatsumi |
| ||Journal of Fungi. 2021; 7(3): 208 |
|[Pubmed] | [DOI]|
||Major challenges and perspectives in the diagnostics and treatment of dermatophyte infections
| ||S. Gnat,D. Lagowski,A. Nowakiewicz |
| ||Journal of Applied Microbiology. 2020; |
|[Pubmed] | [DOI]|
||Indian association of dermatologists, venereologists and leprologists (IADVL) task force against recalcitrant tinea (ITART) consensus on the management of glabrous tinea (INTACT)
| ||Madhu Rengasamy, ManjunathM Shenoy, Sunil Dogra, Neelakandhan Asokan, Ananta Khurana, Shital Poojary, Jyothi Jayaraman, AmeetR Valia, Kabir Sardana, Seetharam Kolalapudi, Yogesh Marfatia, PNarasimha Rao, RameshM Bhat, Mahendra Kura, Deepika Pandhi, Shyamanta Barua, Vibhor Kaushal |
| ||Indian Dermatology Online Journal. 2020; 11(4): 502 |
|[Pubmed] | [DOI]|