Strategies for Treatment of Onychomycosis

 

Shawinki Rai, Venkatesh Kamath B, V M Subrahmanyam*

Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104

 

ABSTRACT:

Dermatophytescan cause nail plate affections relating to Onychomycosis. Many cases are reported due to tineaunguium infection. Onychomycosis accounts for 13% of the nail disorders in western countries and India accounts for 45% of the cases worldwide. Treatment for this affection is through the use of topical agentscontaining Ketoconazole, Itraconazole, Griseofulvin, Terbinafine etc. But inadequate penetration, inability to apply for difficult-reach-areas, occasional contact dermatitis and poor response due to application of inadequate amounts of dosage form are the associated problems. The present review gives an insight into the available methods and strategies for treatment. Use of Keratinolytic enzymes along with other topical antifungal agents is advocated as a strategy for better therapy.Keratinase can effectively potentiate the antifungal therapy by acting in a synergistic mode.

 

 

 

1. INTRODUCTION:

Onychomycosis is an infection which occurs in nail plate caused by Dermatophytes.Many reported cases are due to moldtineaunguium. The hyphae of these hyaline septated mycelia molds penetrate the stratum corneum of the skin and nail causing infection. The term onychomycosis is derived from the terms onyx meaning nails and mykes meaning fungus. This infection can cause nail plate discoloration, thickening and onycholysis.Onycholysis is another term used for defining nail detachment.The infection spreads to other parts of the body if not controlled^1,2.

 

1.1 Keratin- the protective layer:

Keratin is an insoluble fibrous structural protein whichforms a major component of epidermis as a monomer. It is also found in appendages like hair, feathers, nails, horns, hooves and wool. This protein mainly consists of two major groups i.e. α Keratin and βKeratin. Both of them have a common structure consisting of a central coiled α helical rod domain with non-helical head and tail domains.

 

Keratin is chiefly made up of amino acids, glycine and alanine. In spite of poles apart in their structure and composition, they share a similar function which is mainly protective in a human body³.

 

Fifty four different kind of functional genes exist in human being for keratin. Cross linkage occurs in keratin structure. These cross-linkages help in epidermal differentiation. Keratin may be cross-linked itself or to stratum corneum forming both soluble and insoluble aggregates. The tight packing of alpha helix chain and beta sheets structure linked by disulfide bonds provides keratin the mechanical stability and resistance to its biochemical degradation. Keratin is grouped into hard and soft keratin on the basis of sulphur content. Hard keratin is tough, having high disulfide bond content and found in appendages like feather, hair, hooves and nails. Soft keratin has low disulfide content⁴. Abnormal Keratinization caused by keratin producing cells can lead to extremely rare lethal congenital disorder Harlequin ichthyosis⁵.

 

1.2 Onychomycosis epidemiology:

Nail disorders are frequently found in western countries of which onychomycosis accounts for nearly 13% of cases. In our country, this disease is quite rampant with an estimate of 45%. In a recent outpatient-based survey of 1,038 patients in Cleveland, Ohio, onychomycosis was seen in 8.7% of the total population waiting in a dermatology clinic. Out of which 6.5% was female and 13.3% was of malesubgroups,respectively. Several studies have shown that this fungal nail infection increaseswithage. An estimated 28.1% of old aged patients had suffered with this disorder in Ohio. The prevalence rate of onychomycosis occurrence was estimated on the basis of age due to poor peripheral circulation, diabetes and immunodeficiency. Lifestyle habits, climatic conditions leading to reduced growth of nail and poor nail maintenance could be the other cause.In comparison to adults, the prevalence rate of onychomycosis in children is less⁶.

 

2. Types of Onychomycosis–Classification:

Based upon type of nail invasion, onychomycosis can be classified as distal lateral subungualonychomycosis (DLSO), proximal white subungualonychomycosis (PSO), white superficial onychomycosis (WSO) and candidalonychomycosis. Treatment is based on oftype of fungal species and number of affected nails.Initially, infection is thought to be due to contaminants but later it was reported that yeast could also be a part of the infection.

 

In DLSO infection the nail bed is affected resulting in subungual hyperkeratosis (characterized by excessive growth of skin cells between nail and nail bed) and onycholysis. It doesn’t affect the nail plate. It affects either one side of the nail or it spreads all over the nailbed and progresses till it reaches the posterior nail folds. This progression makes the nail plate friable and leads to nail destruction. Nail destruction is caused by the invasion of dermatophytes which have keratolytic properties in the nail plate.PSO occurs in patients who are suffering from immunosuppressed conditions viz., HIV.

 

WSO affects the nail plate rather than the nail bed. In this condition the surface of nail plate appears flaky followed by white discoloration. Candidalonychomycosisis caused by Candida albicanswhich can manifest as-

a)    Chronic paronychia with secondary nail dystrophy

b)    Distal nail infection

c)     Chronic mucocutaneous candidiasis

d)    Secondary candidiasis

e)     Total dystrophic onychomycosis

 

a)    Chronic paronychia: Due to allergic reactions, swelling occurs in the posterior part of nail fold which is due to chronic immersion in water. The cuticle detaches from the nail plate thus facilitating yeasts and bacteria to enter the subcuticular space.

 

b)    Nail dystrophy Distal:This nail infectionleads to Reynaud’s phenomenon characterized by vascular insufficiency. The underlying mechanism of onycholysis is still not clear. Yeast infectionscan aggravate the condition. The infected patient loses his toenail or suffers from less subungual hyperkeratosis (which are the key diagnostic features).

c)     Chronic mucocutaneous Candidiasis: Theprognosis of this Candidial infection is by diminishing cell-mediated immunity. It causes thickening of the nails, leading to a Candida granuloma.

d)    Secondary Candidalonychomycosis:This occurs in different nail affections causing psoriasis.

e)     Total dystrophic onychomycosis: In this affection the nail plate is almost destroyed nail leading to total nail dystrophy.

 

3. Treatment of Onychomycosis:

Current treatment of onychomycosis includes usage of both oral and topical antifungal agents.The other physical modalities like mechanical, chemical debridement and nail avulsion are used in conjunction. The drugs which are mainly used in therapy include griseofulvin, ketoconazole, terbinafine and itraconazole. These belong to azole class of antifungals. Out of these, US FDA approved terbinafine and itraconazole over griseofulvin because of their ability to penetrate nail (superior efficacy). Ketoconazole was not used frequently because of safety concerns (drug showing hepatotoxicity). The significant drug interactions shown by itraconazole drug reduces its acceptance for nail infection treatment. Recurrence rates of onychomycosisreported for itraconazole and terbinafine drugs were 33.7 and 11.9% respectively. This is the main cause for their reduced usability against this infection^7,8.

 

Approved topical agents for onychomycosis are- ciclopirox 8% nail laquer, efinaconazole 10% solution and tavaborole 5% solution. Ciclopirox is usually used for mildest cases. Prolonged and repeated therapy is required to decrease the rate of its re-occurrence⁹.

 

Topical antifungal therapy is advocated as the agents are easy to apply without drug interactions and systemic side effects due to limited systemic absorption. Also anti inflammatory action of several topic antifungals belonging to azoles and allylamines is pronounced. However these advantages are offset by limitations of therapy which include–inadequate penetration, inability to apply for difficult-reach-areas, occasional contact dermatitis and poor response due to application of inadequate amounts of dosage form⁶.

 

 

3.2 Keratinase as a model enzyme:

Keratinase is an extracellular enzyme belonging to serine hydrolase, capable of degrading protein keratin. It cleaves the peptide bond between linkages and produced by dermatophytic fungi. Among thegram positive organisms keratin degradation is mostly limited in the cases of B. licheniformis, B. subtilis, B.pseudofirmusand micro bacterium species. Among the gram negative onesXanthomonas andChryseobacteriumare reported to have keratinolytic activity. In the group ofactinomycetes, the organisms belonging to streptomyces viz.,S. fradiae, S. thermoviolaceus are the commonly known keratin degraders⁴. Beside these, fungal keratinolytics includeChrysosporium, Aspergillus, Alternaria, Fusarium, Paecilomyces and Doratomyces¹⁰. This enzyme has promising applications which include-dehairing in leather industry, detergent industry and food industry, development of biodegradable films, waste treatment and to process keratin waste feather^11,12. Potential therapeutic antimicrobial and anticancer applications of the enzyme were also reported¹³. Insecticidal activity was reported for a bacterial keratinolytic enzyme. This study is based on production of mosquitocidal toxins by the enzyme¹⁴.

 

Purification of keratinase is essential to hasten its efficiency and increasing its industrial application. Purification of enzyme is done by precipitation followed by a series of column chromatography operations which include size exclusion chromatography, ion exchange chromatography and ultrafiltration chromatography^15,16.

 

3.3Mechanism of action of keratinases and treatment strategies:

Keratinasesbreak down the barrier properties of nail plate and actas ungual enhancers. These enzymes shows hydrolytic action of keratin filament and tissues of nail plate. Keratin degradation includes proteolysis, sulfitolysis followed by deamination. Keratinase cleaves peptide bond of B-pleated sheet of protein resulting in deamination. This reduction of disulfide bridges could be responsible for rigidity causing conformational changes in protein structure,exposing hydrolytic sites for Keratinase attack⁴.Formulation development with transungual drug delivery of drugs like terbinafine for treatment of oychomycosis are becoming increasingly popular in the recent times^17,18. However, the problems regarding poorpenetration andabsorption of drugs from topical and transdermal formulations still persist^19,20,21 .Development of therapeutic strategies by potentiation of antibiotics with chemical moieties such as EDTA, caffeine, citric acid etc., are reported^22,23. To improve the penetration of antifungal agents it would be worthwhile to use keratinase in combination with antifungal agents. This enzyme can effectively potentiate the antifungal therapy by acting in a synergistic mode.

Development of newer topical formulations by using new chemical entities discovered through combinatorial approaches can usher in effective treatment of onychomycosis.

 

4. CONCLUSION:

Onychomycosis is a nail fungal infection caused by dermatophytes. It is reported to be increased with age and is more prevalent in patients suffering from diabetes and HIV. Both systemic and topical antifungal agents are available for the treatment of this disease. However due to their poor efficacy and safety concerns, newer treatment strategies are being reported. Along with topical antifungals, physical, mechanical and chemical debridement nail avulsions are used to overcome the problem of penetration of drug through nail bed. Keratin protein present in nail bed causes obstruction of antifungal effect by the drugs. It would be possible to hydrolyse keratin protein by using keratinasethereby facilitating treatment of onychomycosis.A combination of this enzyme and antifungal drugs is advocated as a strategy for treatment.

 

5. ACKNOWLEDGEMENT:

The authors are thankful to authorities of Manipal academy of higher education for making available the literature for compilation of the article. The authors would also like to acknowledge Dept. of Biotechnology, Govt. of India for sanctioning a research project I.D. BT/PR 10827/AAQ/3/661/2014 in the above area.

 

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Accepted on 14.10.2018           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(11): 5135-5138.