New therapeutic options for onychomycosis

Introduction: Onychomycosis is a fungal infection of the nail apparatus that affects 10 – 30% of the global population. Current therapeutic options for onychomycosis have a low to moderate efficacy and result in a 20 – 25% rate of relapse and reinfection. New therapeutic options are needed to broaden the spectrum of treatment options and improve the efficacy of treatment.

Areas covered: This review discusses the emerging pharmacotherapeutics; including topical reformulations of terbinafine, new azole molecules for systemic and topical administration, topical benzoxaboroles and topical polymer barriers. The paper also discusses device-based options, which may be designed to activate a drug or to improve drug delivery, such as photodynamic therapy and iontophoresis; laser device systems have also begun to receive regulatory approval for onychomycosis.

Expert opinion: Device-based therapeutic options for onychomycosis are expanding more rapidly than pharmacotherapy. Systemic azoles are the only class of pharmacotherapy that has shown a comparable efficacy to systemic terbinafine; however terbinafine remains the gold standard. The most notable new topical drugs are tavaborole, efinaconazole and luliconazole, which belong to the benzoxaborole and azole classes of drugs. Photodynamic therapy, iontophoresis and laser therapy have shown positive initial results, but randomized controlled trials are necessary to determine the long-term success of these devices.     

New pharmacotherapy for the treatment of onychomycosis: an update

Introduction: Onychomycosis is an infection of the nail plate that is an important priority area for the development of antifungal drugs. The high incidence of relapse and reinfection often makes onychomycosis a chronic condition. The current gold standard is oral therapy, but the development of effective topical agents remains a priority as they have fewer systemic interactions.

Areas covered: This review summarizes development of antifungals from early phase development through Phase III clinical trials for onychomycosis. The oral molecules in development are azole molecules. Topical drugs in development include azoles, allylamines, benzoxaboroles and nanoemulsions. Photosensitizers for photodynamic therapy and new laser systems are also emerging therapeutic options. There is a diverse array of antifungal drugs in the early phases of development.

Expert opinion: The goals of onychomycosis therapy are a mycological cure and a normal appearing nail. The recent development of topical antifungals has been successful at improving the nail permeation and efficacy. The diversification of molecular targets is the next primary goal of antifungal development. Incomplete treatment of onychomycosis provides an environment conducive to the development of antifungal resistance. New topical agents and device-based therapies expand the therapeutic options. Combination therapy using multiple drug classes may improve the overall efficacy of antifungal treatment in onychomycosis.     

Terbinafine. A pharmacoeconomic evaluation of its use in superficial fungal infections

Terbinafine is an orally and topically active allylamine antifungal drug which is an effective and well tolerated therapy for a wide range of superficial dermatophyte infections. In contrast to most other commonly prescribed antifungal agents, terbinafine is fungicidal in vitro and possesses improved pharmacokinetic properties with respect to drug penetration into nail tissue following oral administration. These properties enable terbinafine to achieve high success rates with shortened therapy regimens in the treatment of dermatophyte skin infections and onychomycosis. Pharmacoeconomic analyses have shown that oral terbinafine, with its higher rates of clinical efficacy and lower rates of relapse/reinfection, is less costly and more cost effective than oral griseofulvin, ketoconazole and itraconazole when used as initial therapy in the treatment of onychomycosis. However, some points regarding the clinical efficacy of itraconazole relative to terbinafine and the drug treatment regimens used in these studies need further clarification. In the management of tinea pedis, a cost analysis suggested that initial therapy with terbinafine 1% cream was more costly than initial therapy with miconazole, oxiconazole or clotrimazole. However, in cost-effectiveness studies, terbinafine had a lower cost per disease-free day than ciclopirox, clotrimazole, ketoconazole and miconazole in the treatment of dermatophyte skin infections. In conclusion, available clinical and pharmacoeconomic data support the use of topical terbinafine as first-line treatment of dermatophyte skin infections unless the acquisition cost of terbinafine is markedly greater than that of alternative topical antifungal agents. Oral terbinafine can be recommended as a cost-effective first-line treatment, preferable to oral griseofulvin, ketoconazole and itraconazole, in patients with dermatophyte onychomycosis.     

Therapeutic potential of TDT 067 (terbinafine in Transfersome®): a carrier-based dosage form of terbinafine for onychomycosis

Introduction: Current topical treatments for onychomycosis are unsatisfactory. New topical agents that offer efficacy without the potential adverse effects of oral antifungal therapy would benefit patients with this condition and encourage a greater treatment rate. Areas covered: Currently available topical therapies are reviewed, and new approaches for enhancing delivery of the established antifungal terbinafine through the nail are summarized. We focus on the use of ultra-deformable lipid vesicles to facilitate delivery of terbinafine to the nail and surrounding tissue. TDT 067 (terbinafine in Transfersome?) is the only such therapy in development for onychomycosis, and we review published preclinical and clinical studies on this formulation. Expert opinion: TDT 067 offers the use of new technology to deliver an established antifungal, terbinafine. Preclinical data suggest that the Transfersome? accelerates entry of terbinafine released from TDT 067 into fungi and potentiates its antifungal effects, resulting in enhanced activity, compared with conventional terbinafine. This translated into high rates of mycological cure and evidence of clinical effect in a study of TDT 067 administered twice daily for 12 weeks in patients with onychomycosis. An ongoing Phase-III trial involving more than 700 patients treated for 48 weeks is investigating the efficacy and safety of TDT 067.     

Iontophoretic drug delivery across the nail

INTRODUCTION: Topical drug delivery to treat nail diseases such as onychomycosis and psoriasis is receiving increasing attention. Topical nail delivery is challenged by the complicated structure of the nail and the low permeability of most drugs across the nail plate. Considerable effort has been directed at developing methods to promote drug permeation across the nail plate. Iontophoresis efficiently enhances molecular transport across the skin and the eye and is now being tested for its potential in ungual delivery. AREAS COVERED: This review covers the basic mechanisms of transport (electro-osmosis and -migration) and their relative contribution to nail iontophoresis as well as the key factors governing nail permselectivity and ionic transport numbers. Methodological issues concerning research in this area are summarized. The data available in vivo on nail iontophoresis of terbinafine specifically are reviewed in separate sections. EXPERT OPINION: Our understanding of nail iontophoresis has improved considerably since 2007; most decisively, the feasibility of nail iontophoresis in vivo has been clearly demonstrated. Future work is required to establish the adequate implementation of the technique so that its clinical efficacy to treat onychomycosis and nail psoriasis can be unequivocally determined.     

Onychomycosis in the elderly : drug treatment options

The prevalence of onychomycosis is nearly 20% in patients aged >60 years. In North America, 90% of toenail onychomycosis is caused by dermatophytes (Trichophyton species). Distal-lateral subungual onychomycosis is the most common clinical presentation. The potassium hydroxide test is the most cost-effective diagnostic method. Although nail clipping for histology using periodic acid-Schiff stain is more sensitive, it is much more expensive.Elderly patients have specific risk factors for poor response to therapy for onychomycosis, including frequent nail dystrophy, slow growth of nails and increased prevalence of peripheral vascular disease and diabetes mellitus. Elderly people with diabetes should be treated for onychomycosis to prevent secondary bacterial infections and subsequent complications. Terbinafine is the drug of choice for dermatophyte onychomycosis, with greater mycological cure rates, less serious and fewer drug interactions, and a lower cost than continuous itraconazole therapy. Adjunct debridement may improve the clinical and complete cure rates compared with terbinafine alone. Common adverse effects of terbinafine in the elderly include nausea, sinusitis, arthralgia and hypercholesterolaemia. For onychomycosis caused by Candida or nondermatophyte moulds, there is no superior systemic therapy. In general, topical nail lacquers, amorolfine and ciclopirox are not practical for elderly patients because of the recommended frequency of application, periodic routine debridement of affected nails and long duration of therapy. However, nail lacquers may be a good option as monotherapy for patients with superficial white onychomycosis or in combination with systemic antifungal therapy for patients with predisposing factors for poor response or recurrence.     

Novel investigational therapies for onychomycosis: an update

Introduction: Onychomycosis is an infection of the nail plate that is prevalent among the ageing population. Onychomycosis is difficult to treat with low initial cure rates, high rates of relapse, and reinfection. Present treatment options include oral and topical therapies, with oral therapies yielding better results. However, there has been a greater emphasis on the development of topical antifungal therapies as they have fewer side effects and drug interactions.

Areas Covered: This review summarizes new and reformulated drugs. Results from in vitro studies to Phase III clinical trials are discussed. Novel drugs include: the oral azole VT-1161, the topical azole efinaconazole, the benzoxaborole tavaborole, reformulations of terbinafine P-3058 and LI-P, novel inhibitor of succinate dehydrogenase ME1111, and off-label use of tazarotene. Enhanced permeation of the morpholine amorolfine through the nail plate is also discussed using ultraviolet (UV) curable gels, and a fractional CO₂ laser.

Expert opinion: Novel topical antifungals and the reformulation of current antifungals have demonstrated marked improvement in nail penetration. Current research has an emphasis on topical therapies due to their minimized risk for adverse effects and higher patient demand. Nevertheless, few topical agents have surfaced in the past few years and the investigation of efficacious combination therapies may become more important.     

Terbinafine. An update of its use in superficial mycoses.

Terbinafine is an allylamine antifungal agent which has fungicidal activity against a wide variety of dermatophytes, moulds and certain dimorphic fungi, and fungistatic activity against Candida albicans. Oral terbinafine 250 mg/day is effective in the treatment of superficial dermatophyte infections such as onychomycosis, tinea pedis and tinea corporis/cruris, generally achieving mycological cure in > 80% of patients. The drug is also effective in children with tinea capitis when administered orally in the dosage range 62.5 to 250 mg/day for 4 weeks. Comparative data indicate that oral terbinafine is more effective than continuous or intermittent intraconazole in dermatophyte onychomycosis, and is as effective as itraconazole 400 mg/day in tinea pedis. The drug has shown greater efficacy than griseofulvin in dermatophyte onychomycosis, tinea pedis and tinea corporis/cruris, and comparable efficacy in children with tinea capitis. Additionally, oral terbinafine is more effective than ketoconazole 200 mg/day in tinea corporis/cruris. Topical terbinafine 1% formulations are effective when applied once or twice daily for up to 2 weeks, achieving mycological cure in > 80% of patients with tinea pedis, tinea corporis/cruris, cutaneous candidiasis and pityriasis versicolor. Its formulations are at least as effective as miconazole 2% cream and naftifine 1% gel in tinea pedis, and more effective than clotrimazole 1% cream, bifonazole 1% cream and oxiconazole 1% lotion. Mycological cure rates achieved with terbinafine generally improve after treatment cessation, reflecting the drug's fungicidal mechanism of action and its residual effect in tissue. Terbinafine is well tolerated after oral or topical administration and has a relatively low potential for drug interactions. Pharmacoeconomic data support the use of terbinafine in dermatophyte infections of the skin or nails. CONCLUSIONS: Evidence suggests that oral terbinafine is the treatment of choice for dermatophyte onychomycosis, as it achieves high rates of mycological and clinical cure, is generally well tolerated and has a relatively low potential for drug interactions. It must also be considered a first-line treatment option, along with itraconazole, in cutaneous mycoses which warrant systemic treatment; topical terbinafine is a treatment of choice in less extensive mycoses. The use of terbinafine in non-dermatophyte or mixed infections has not been fully defined.     

Enhancing the nail permeability of topically applied drugs

The topical therapy of nail diseases, especially of onychomycosis, and to a smaller extent, of nail psoriasis, is desirable to avoid the side effects associated with their systemic therapy, to increase patient compliance and reduce the cost of treatment. Systemic therapy is however the mainstay of treatment due to the poor permeability of the nail plate to topically applied drugs. For effective topical therapy, ungual drug permeation must be enhanced. This can be achieved by disrupting the nail plate using physical techniques or chemical agents. Alternatively, drug permeation into the intact nail plate may be encouraged, for example, by iontophoresis or by formulating the drug within a vehicle which enables high drug partition out of the vehicle and into the nail plate. The physical techniques (manual and electrical nail abrasion, acid etching, ablation by lasers, microporation, application of low-frequency ultrasound and electric currents) and chemicals (thiols, sulphites, hydrogen peroxide, urea, water, enzymes) that have shown ungual enhancer activity are discussed in this review. Optimal drug formulation, while crucial to ungual drug delivery, is only briefly reviewed due to the limited literature.     

Enhancing the nail permeability of topically applied drugs

The topical therapy of nail diseases, especially of onychomycosis, and to a smaller extent, of nail psoriasis, is desirable to avoid the side effects associated with their systemic therapy, to increase patient compliance and reduce the cost of treatment. Systemic therapy is however the mainstay of treatment due to the poor permeability of the nail plate to topically applied drugs. For effective topical therapy, ungual drug permeation must be enhanced. This can be achieved by disrupting the nail plate using physical techniques or chemical agents. Alternatively, drug permeation into the intact nail plate may be encouraged, for example, by iontophoresis or by formulating the drug within a vehicle which enables high drug partition out of the vehicle and into the nail plate. The physical techniques (manual and electrical nail abrasion, acid etching, ablation by lasers, microporation, application of low-frequency ultrasound and electric currents) and chemicals (thiols, sulphites, hydrogen peroxide, urea, water, enzymes) that have shown ungual enhancer activity are discussed in this review. Optimal drug formulation, while crucial to ungual drug delivery, is only briefly reviewed due to the limited literature.     

Fungicidal activity plus reservoir effect allow short treatment courses with terbinafine in tinea pedis

Terbinafine, a synthetic allylamine, exerts fungicidal activity against dermatophytes, the causative pathogens of tinea pedis. As proven in numerous clinical trials, tinea pedis can be effectively and safely treated by topical terbinafine. In fact, a 1-week application of terbinafine 1% cream eradicated fungal pathogens at least as effectively as 4-week treatment courses with topical azole derivative antifungals and showed lower relapse rates. A new innovative single-application formulation of terbinafine 1% in a film-forming solution produces a high concentration gradient on the skin surface and enables a prolonged (up to 13 days) exposure of the skin to terbinafine. High drug penetration into the skin results in an otherwise not obtained drug reservoir in the horny layer, the location of dermatophytes in tinea pedis. Although azole antimycotics can also effectively penetrate into the horny layer of the skin, short-term therapy might not be feasible due to its primarily fungistatic activity against dermatophytes. Thus, we conclude that the high efficacy of short-term treatment with terbinafine in patients with tinea pedis is possible due to its fungicidal activity coupled with a distinct reservoir formation in the upper layers of the epidermis.     

Trans-ungual iontophoretic delivery of terbinafine

Successful treatment of deep-seated nail infections remains elusive as the delivery of efficacious levels of antifungal drug to the site of action is very difficult. The aim of the present study was to attain rapid trans-ungual delivery of an antifungal agent, terbinafine, via the topical route using iontophoresis. Initial studies revealed that application of current (0.5 mA/cm(2)) could significantly enhance the trans-ungual delivery of terbinafine. An increase in the applied current or duration of current application enhanced the trans-ungual delivery of terbinafine. Permeation of terbinafine through the nail and drug load in the nail correlated well with the applied electrical dose. Release of drug from nails loaded using iontophoresis followed a two-phase release profile. Light microscopy studies substantiated the capability of iontophoresis to drive a charged molecule across the nail plate. The results of these studies indicate that iontophoresis could be developed as a potential technique for onychomycosis therapy.     

Management of toenail onychomycosis.

The treatment of toenail onychomycosis is reviewed. Onychomycosis contributes to 40% of all nail disorders and appears to be increasing in frequency. Mycotic nail infections are usually caused by dermatophytes, yeasts, and nondermatophyte molds. Most cases of toenail onychomycosis are caused by dermatophytes. Mycotic nail infections do not always resolve spontaneously and may have a substantial impact on the patient's quality of life. Current treatment modalities for onychomycosis include surgery, topical antifungals, and oral antifungals. Surgery is generally not recommended as first-line therapy. Broad-spectrum topical and oral antifungal agents are the most frequently used treatments. Topical treatment is well tolerated but is usually not effective because of poor patient compliance and inadequate penetration of the nail. Oral antifungals are more successful but carry greater risks. Griseofulvin and ketoconazole have been oral antifungals traditionally used for onychomycosis, but these agents are associated with relatively low cure rates. Itraconazole and terbinafine are both safe and effective first-line agents, with reported overall cure rates of 50-90% for dermatophyte-related onychomycosis. Intermittent oral antifungal therapy may reduce the risk of systemic adverse effects and the cost of therapy; more study of this approach is needed. Oral antifungal agents offer patients with toenail onychomycosis greater likelihood of a cure than topical antifungals, but oral therapy carries greater risks and requires closer monitoring.     

伊曲康唑和特比萘芬序贯疗法治疗甲真菌病的成本-效果分析

目的:探讨不同药物治疗方案对甲真菌病的经济效果.方法:根据文献数据,对75例甲真菌病患者分别采用伊曲康唑和特比萘芬序贯治疗、伊曲康唑冲击治疗和特比萘芬连续治疗,运用药物经济学的成本-效果分析方法进行评价.结果:3组具有相似的临床疗效,但序贯疗法与其他治疗方案相比,明显降低了医疗费用,具有药物经济学意义.结论:伊曲康唑和特比萘芬序贯疗法是治疗甲真菌病的最佳治疗方案.     

Emerging Topical Onychomycosis Therapies – Quo Vadis?

Introduction: Onychomycosis, a common chronic fungal infection affecting fingernails and toenails, globally may affect 10 – 30% of the population. This chronic disease is difficult to eradicate. The goal of developing a highly effective and safe topical treatment has not yet been reached as it depends on the type of onychomycosis and the variety of invaders.

Areas covered: Topical drug delivery to the nail is highly desirable in treating nail disorders. However, efficacy of topical therapies is low due to their limited permeability across the nail plate. Advances have especially been made by the development of new therapeutic options including new drug entities, new formulations and reformulations. This overview updates emerging topical treatments for onychomycosis, research progress and future perspectives.

Expert opinion: Development of novel effective noninvasive topical therapy for treating onychomycosis and other nail diseases such as psoriasis is long overdue. Previously there was a lack of basic knowledge about nail and its barrier properties, but with the recent increased interest in this field both from industry and academia, we hope extensive research will continue in this field to bring about successful and safe treatments for such chronic diseases.     

Pentapeptide modified ethosomes for enhanced skin retention and topical efficacy activity of indomethacin

Challenges associated with topical analgesics and anti-inflammatory drugs include poor drug penetration and retention at the desired lesion site. Therefore, improving these challenges would help to reduce the toxic and side effects caused by drug absorption into the systemic circulation and improve the therapeutic efficacy of topical therapeutic drugs. Pentapeptide (KTTKS) is a signal peptide in skin tissue, it can be recognized and bound by signal recognition particles. In the current study, we successfully prepared novel indomethacin (IMC) loaded KTTKS-modified ethosomes (IMC-KTTKS-Es), and the physicochemical properties and topical efficacy were investigated. Results showed that the prepared IMC-KTTKS-Es displayed a particle size of about 244 nm, a negative charge, good deformability, and encapsulation efficiency (EE) exceeding 80% for IMC, with a sustained release pattern. In vitro percutaneous permeation studies revealed that the skin retention was increased after the drug was loaded in the IMC-KTTKS-Es. Confocal laser scanning microscopy also showed improved skin retention of IMC-KTTKS-Es. In addition, IMC-KTTKS-Es showed improved topical analgesic and anti-inflammatory activity with no potentially hazardous skin irritation. This study suggested that the IMC-KTTKS-Es might be an effective drug carrier for topical skin therapy with a good safety profile.     

序贯疗法治疗甲真菌病的临床研究

目的:探讨不同治疗方案对甲真菌病的作用及不良反应。方法:对125例甲真菌病患者分别采用伊曲康唑和特比萘芬序贯疗法、伊曲康唑冲击治疗和特比萘芬连续治疗,对其临床效果及不良反应进行评价。结果:三组具有相似的临床疗效,但序贯疗法更安全、经济。结论:序贯疗法是治疗甲真菌病的最佳治疗方案。     

A risk-benefit assessment of the newer oral antifungal agents used to treat onychomycosis.

The newer antifungal agents itraconazole, terbinafine and fluconazole have become available to treat onychomycosis over the last 10 years. During this time period these agents have superseded griseofulvin as the agent of choice for onychomycosis. Unlike griseofulvin, the new agents have a broad spectrum of action that includes dermatophytes, Candida species and nondermatophyte moulds. Each of the 3 oral antifungal agents, terbinafine, itraconazole and fluconazole, is effective against dermatophytes with relatively fewer data being available for the treatment of Candida species and nondermatophyte moulds. Itraconazole is effective against Candida onychomycosis. Terbinafine may be more effective against C. parapsilosis compared with C. albicans; furthermore with Candida species a higher dose of terbinafine or a longer duration of therapy may be required compared with the regimen for dermatophytes. The least amount of experience in treating onychomycosis is with fluconazole. Griseofulvin is not effective against Candida species or the nondermatophyte moulds. The main use of griseo-fulvin currently is to treat tinea capitis. Ketoconazole may be used by some to treat tinea versicolor with the dosage regimens being short and requiring the use of only a few doses. The preferred regimens for the 3 oral antimycotic agents are as follows: itraconazole - pulse therapy with the drug being administered for 1 week with 3 weeks off treatment between successive pulses; terbinafine - continuous once daily therapy; and fluconazole - once weekly treatment. The regimen for the treatment of dermatophyte onychomycosis is: itraconazole - 200mg twice daily for I week per month x 3 pulses; terbinafine - 250 mg/day for 12 weeks; or, fluconazole - 150 mg/wk until the abnormal-appearing nail plate has grown out, typically over a period of 9 to 18 months. For the 3 oral antifungal agents the more common adverse reactions pertain to the following systems, gastrointestinal (for example, nausea, gastrointestinal distress, diarrhoea, abdominal pain), cutaneous eruption, and CNS (for example, headache and malaise). Each of the new antifungal agents is more cost-effective than griseofulvin for the treatment of onychomycosis and is associated with high compliance, in part because of the shorter duration of therapy. The newer antifungal agents are generally well tolerated with drug interactions that are usually predictable.     

三种治疗甲真菌病药物的成本——效果分析

目的：探讨3种抗真菌药（伊曲康唑、特比奈芬、氟康唑）治疗甲真菌病的经济效果,找出既经济又有效的治疗方案。方法：根据文献选择3种不同的治疗方案（伊曲康唑组、特比奈芬组、氟康唑组）,应用药物经济学成本-效果分析法。结果：治疗指甲真菌病所需药品成本分别是666.68,634.42,459.96元;治疗趾甲真菌病所需的药品成本分别是1000.02,911.98,689.94元。远期治愈率指甲真菌病分别是94.4%,100.0%和77.8%;趾甲真菌病分别是86.4%,95.2%和68.2%。结论：根据药物经济学成本-效果分析,特比奈芬是治疗甲真菌病的最佳药物。