Different physicochemical properties of antimycotic agents are relevant for penetration into and through human nails

This article reports the characterization of the physicochemical properties of two important antifungal topical drugs, amorolfine and ciclopirox. Furthermore, the release of the drugs from commercial lacquer formulations for treatment of onychomycosis was studied using the online FTIR-ATR technique. Based on the physicochemical background of these two drugs and their release from commercial lacquer formulations for treatment of onychomycosis, the suitability of these drugs for optimized local antifungal therapy to human nails is discussed. Amorolfine appears to be more suitable for drug delivery to human nails because it penetrates into the nails via the hydrophilic pathway. Furthermore amorolfine penetrates very well into fungal cells, due to the pH value of the nail, as well as the pKa value of this antimycotic agent and the lipophilic properties of its base form.     

Development of ciclopirox nail lacquer with enhanced permeation and retention

Onychomycosis is a prevailing disease caused by fungal infection of nails that mostly affects athletes and the elderly. Ciclopirox is approved by the US Food and Drug Administration for the topical treatment of onychomycosis. However, the desired penetration of ciclopirox into the nail bed has not been achieved via topical application for efficient treatment. Therefore, the main aim of this study was to enhance ciclopirox permeation and retention in nail by the development of a new nail lacquer formulation. We screened the effects of different solvents, alkalizing agents, and permeation enhancers on the permeation of bovine hooves by ciclopirox and its retention in human nail clippings. The results suggest that isopropyl alcohol, potassium hydroxide, and urea as the solvent, alkalizing agent, and permeation enhancer, respectively, improved the permeation of the ciclopirox nail lacquer formulation the most with high flux rates. Comparison of the final formulation and marketed product revealed enhanced retention of ciclopirox from our developed formulation in human nail clippings. Therefore, our newly developed nail lacquer may be a potentially effective formulation for the treatment of onychomycosis in humans.     

Ciclopirox olamine 1% cream. A preliminary review of its antimicrobial activity and therapeutic use

Ciclopirox olamine is a substituted pyridone antimycotic, unrelated to the imidazole derivatives, with activity against a broad spectrum of dermatophytes, yeasts, actinomycetes, molds, other fungi, and a variety of Gram-positive and Gram-negative bacteria. The efficacy of ciclopirox olamine cream has been demonstrated in open and placebo-controlled studies in patients with superficial dermatophyte or yeast infections, and in double-blind comparative trials in patients with dermatomycoses, topical ciclopirox olamine was comparable to or better than clotrimazole in efficacy and caused a similar number of side effects. Ciclopirox olamine penetrates through fingernails and in preliminary studies has been successfully used in onychomycoses. However, further studies are needed to establish the role of ciclopirox in the treatment of onychomycoses and dermatomycoses relative to that of the more recently introduced antigungal agents.     

The safety and efficacy of ciclopirox olamine for the treatment of seborrheic dermatitis

Ciclopirox olamine is a synthetic hydroxypiridone derived, broad spectrum, antifungal agent which has been used effectively to treat seborrheic dermatitis. Seborrheic dermatitis is a chronic dermatosis, more common in men than women, which usually occurs in sites dense with sebaceous glands in the form of mild inflammatory desquamate erythema. Treatment modalities for seborrheic dermatitis include keratolytic agents, corticosteroids and antifungal agents. Due to its antimycotic and anti-inflammatory activities, ciclopirox olamine is established as an effective treatment for this condition.     

In vitro evaluation of three topical antimycotics against ring-worm fungi singly and in combination.

Three antimycotic drugs, viz., Miconazole nitrate, Econazole nitrate and ciclopirox olamine were tested singly and in combination of miconazole nitrate and Econazole nitrate, Miconazole nitrate and Ciclopirox olamine, and Econazole nitrate and Ciclopirox olamine to evaluate in vitro efficacy against Trichophyton mentagrophytes and Macrosporum nanum. The best efficacy was shown by Ciclopirox olamine (MIC 0.78 microgram/ml) and a combination of Miconazole nitrate and Econazole nitrate (MIC 0.78 microgram/ml).     

Ciclopirox delivery into the human nail plate

The human nail penetration of the antifungal ciclopirox was determined for marketed gel containing 0.77% of ciclopirox, an experimental gel containing 2% of ciclopirox, and a marketed lacquer containing 8% of ciclopirox. After 14 days dosing, unabsorbed drug remaining on the surface, drug within the infection-prone area, and the amount that had penetrated through the nail were determined. Ciclopirox delivery into and through the nail was significantly greater from the marketed gel, than from either the experimental gel or the nail lacquer (p < 0.05). In addition, the surface nail contained more unabsorbed drug from the lacquer. Further, the drug penetrating into and through the nail was also greater from the marketed gel, leading to a higher Calculated Efficacy Coefficient for the marketed gel, than from the marketed lacquer or the experimental gel. The formulation plays an important role in the enhancement of ciclopirox permeation into and through the human nail plate, and the concentration of ciclopirox in the formulation was not a factor in determining penetration.     

Common fungal infections of the feet in patients with diabetes mellitus

Superficial fungal infections of the foot (tinea pedis and onychomycosis) are common among elderly patients. Although most authorities believe that patients with diabetes mellitus have an increased predisposition to dermatophytic infections, some controversies still remain. Because these infections disrupt the skin integrity and provide an avenue for bacterial superinfection, elderly diabetic patients with dermatophytic infection should be promptly treated with an antifungal agent. For most dermatophytic infections of the foot, topical agents are usually effective and less expensive than oral agents. Laboratory diagnosis of fungal infection prior to institution of therapy is recommended. Proper technique for obtaining the specimen is important to ensure a higher chance of isolating the infecting fungus. Commonly used anti-dermatophytic agents that are also active against the yeasts include the imidazoles, the allylamines-benzylamines and the hydroxypyridones, which are also effective against most of the moulds. Oral therapy for tinea pedis, although not well studied, should be limited to patients with more extensive infections, such as vesicobullous and moccasin type, resistant infections or chronic infections. In addition, oral agents should also be considered in diabetic and immunosuppressed patients. On the other hand, treatment of onychomycosis of the foot usually requires systemic therapy. Griseofulvin is the least effective agent when compared with the newer agents. Terbinafine, itraconazole and fluconazole have been shown to have acceptable cure rates. More recently, topical treatment of the nail with 8% ciclopirox nail lacquer, bifonazole with urea and amorolfine have been reported to be successful. Over the past decade, fungal foot infections of the skin and nail are more effectively treated with the introduction of numerous topical and oral agents.     

Double-blind clinical trial for evaluating the effectiveness and tolerability of Ageratina pichinchensis extract on patients with mild to moderate onychomycosis. A comparative study with ciclopirox

Aerial parts of AGERATINA PICHINCHENSIS have been used, in Mexican traditional medicine, as a remedy for the treatment of skin mycosis. Onychomycosis, also known as tinea of the nails or tinea unguium, constitutes an infection of the nails produced by dermatophytes. Clinically, onychomycosis is manifested by changes on the color, texture and thickness of the nail. The agent most frequently found in this disease is TRICOPHYTON RUBRUM. The present study evaluated the therapeutic effectiveness and tolerability of topical administration of A. PICHINCHENSIS extract on the nails of patients with the clinical and mycological diagnosis of onychomycosis. A phytopharmaceutical formulation was developed in a lacquer solution containing the standardized (encecalin) extract of A. PICHINCHENSIS. A similar lacquer solution containing 8 % ciclopirox was used as control. Treatments were assigned randomly and administered topically for 6 months. Ninety six patients concluded the study (49 in the experimental group and 47 in the control); 71.1 % of patients from the experimental and 80.9 % from the control group showed therapeutic effectiveness, while 59.1 % and 63.8 % from the experimental and control group, respectively, achieved mycological effectiveness. Therapeutic success was observed in 55.1 and 63.8 %, respectively. No patient exhibited intense side effects. Statistical analysis demonstrated no differences between treatments.     

Effects of subinhibitory concentrations of ciclopirox on the adherence of Candida albicans to human buccal and vaginal epithelial cells.

At present, only a limited number of studies of the effects of sub-inhibitory antifungal agents on the adherence of Candida to epithelial (buccal and vaginal) host cells are available. The adherence of Candida albicans to the epithelial cell surface is accepted as an important first step in persistent colonization and in the following symptomatic or asymptomatic infection of mucosal surface. Ciclopirox (ciclopiroxolamine, CAS 29342-05-0) is a substituted pyridone antimycotic drug, unrelated to the imidazole derivatives and its topical application ensures maximum local bioavailability. The present study was done to investigate the effects of sub-inhibitory concentrations of ciclopirox on the adherence of Candida albicans to human buccal and vaginal epithelial cells. The findings on the adherence of different strains of Candida indicate that the drug caused a significant reduction in the mean number of Candida adhering to both buccal and vaginal cells. This reduction was maximal at concentration of 1/2 MIC and still significant at 1/4, 1/8, 1/16 MIC, but with progressive return to mean control values at 1/32 MIC. Ciclopirox acts on fungi by inhibiting the intracellular uptake of essential substrates and ions and this probably acts on the Candida ability to express its adherence mechanisms.     

Onychomycosis in the elderly

Onychomycosis is found more frequently in the elderly, and in more males than females. Onychomycosis of the toes is usually caused by dermatophytes, most commonly Trichophyton rubrum and T. mentagrophytes. The most common clinical presentations are distal and lateral subungual onychomycosis (which usually affects the great/first toe) and white superficial onychomycosis (which generally involves the third/fourth toes). Only about 50% of all abnormal-appearing nails are due to onychomycosis. In the remainder, trauma to the nail, psoriasis and conditions such as lichen planus should be considered in the differential diagnosis. Therefore, the clinical impression of onychomycosis should be confirmed by mycological examination, whenever possible. The management of onychomycosis may include no therapy, palliative treatment with mechanical or chemical debridement, topical antifungal therapy, oral antifungal agents or a combination of treatment modalities. In the US, the only new oral agents approved for treatment of onychomycosis are terbinafine and itraconazole. Fluconazole is approved for onychomycosis in some other countries. Ciclopirox nail lacquer has recently been approved in the US for the treatment of onychomycosis. In some other countries topical agents such as amorolfine are also used. Griseofulvin and ketoconazole are no longer preferred for the treatment of onychomycosis. The new oral antifungal agents are effective and well tolerated in the elderly. Patient selection should be based on the history (including systems review and medication record), examination and baseline monitoring, if indicated. Laboratory monitoring during therapy for onychomycosis varies among physicians. A combination of removal of the diseased nail plate or local measures and oral antifungal therapy may be optimal in certain instances, e.g. when lateral onychomycosis or dermatophytoma are present. For dermatophyte toe onychomycosis the recommended duration of therapy with terbinafine is 250 mg/day for 12 weeks. For itraconazole (pulse) the regimen is 200 mg twice daily for 1 week on, 3 weeks off, repeated for 3 consecutive pulses and with fluconazole the regimen is 150 to 300 mg once weekly given for a usual range of 6 to 12 months or until the nail plate has grown out. In some instances, if extra therapy is required, one suggestion is that 4 weeks of terbinafine or an extra pulse of itraconazole are given between months 6 and 9 from the start of therapy. Once cure has been achieved, it is important to counsel patients on the strategies of reducing recurrence of disease.     

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.     

Onychomycosis in children: an overview

Onychomycosis in children is relatively uncommon, with a prevalence of approximately 0.3% worldwide. The most common etiologic organism in Trichophyton rubrum. The oral antifungal agents terbinafine, itraconazole, and fluconazole, and the topical nail lacquers ciclopirox and amorolfine, are not approved for use in treating onychomycosis in children. However, these agents appear to be effective and safe in this indication.     

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.     

In Vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate

Onychomycosis is a challenging fungal infection to treat topically, likely due to the unique properties of the nail plate. This seemingly impenetrable barrier has high resistance to the passage of antifungal drugs in sufficient concentrations to kill the causative fungi deep in the nail bed. Recently, a new class of antifungal agent was described, termed oxaboroles, which have broad-spectrum activity. These oxaboroles were designed with properties believed to be required to allow for easier transit through the nail plate. Herein, we report (i) the nail penetration results of four oxaboroles that led to the selection of AN2690, (ii) the results of the nail penetration of AN2690 from four vehicles, and (iii) the nail penetration of AN2690 in its chosen vehicle compared to a commercial control, ciclopirox. AN2690 has superior penetration compared to ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosis.     

Ciclopirox topical solution, 8% combined with oral terbinafine to treat onychomycosis: a randomized, evaluator-blinded study

This randomized, evaluator-blind, 3-arm parallel, comparator controlled, multicenter pilot study evaluated the safety and efficacy of ciclopirox nail lacquer topical solution, 8% in combination with oral terbinafine for the treatment of moderate to severe toenail onychomycosis (> or =60% disease involvement of target nail and/or lunula/matrix involvement) (N = 73). Patients were randomized to 1 of 3 treatment arms: ciclopirox nail lacquer once daily for 48 weeks plus 4 weeks of terbinafine 250 mg/day, followed by 4 weeks of rest (no terbinafine), then another 4 weeks of terbinafine 250 mg/day (PLs); ciclopirox nail lacquer once daily for 48 weeks plus terbinafine 250 mg/day for 12 weeks (PL12); or terbinafine 250 mg/day for 12 weeks (L12). At week 48, mycological cure (negative microscopy and culture) occurred in 66.7% (14/21) (PL8), 70.4% (19/27) (PL12), and 56.0% (14/25) (L12) of patients confirmed dermatophyte positive, respectively (P: not significant). At this time point, effective cure (simultaneous mycological cure and > or =90% reduction in the disease area) was observed in 40.0% (8/20), 33.3% (8/24), and 34.8% (8/23) of patients, respectively (P: not significant). The PLs regimen was well-tolerated and had high compliance. The data suggest that combination therapy (PL8) may be an alternative regimen to continuous terbinafine (L12) in the treatment of moderate to severe dermatophyte toenail onychomycosis.     

Transungual delivery of ketoconazole using novel lacquer formulation

Onychomycosis, a common fungal infection of the nail, can have a substantial impact on quality of life. The success of topical therapy for onychomycosis depends on effective penetration, which can be enhanced using an appropriate delivery method. This study evaluated the effectiveness of a novel topical lacquer on enhancing [¹⁴C]-ketoconazole penetration by comparing nail absorption, nail distribution, and nail penetration of [¹⁴C]-ketoconazole dissolved in the novel lacquer versus a commercial ketoconazole cream. Using the in vitro finite dose model, the formulations were applied daily to human nail plates for 7 days. Drug absorption was measured by monitoring rate of appearance in each nail layer and the supporting bed. After the multiple day treatment, cumulative concentrations of ketoconazole formulated in novel lacquer in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of commercial ketoconazole (p < 0.05), as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of causative dermatophytic and yeast species. These results suggest that this novel ketoconazole lacquer has the potential to be an effective topical treatment for 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.     

Management of onychomycoses.

Onychomycoses, infections of the nail caused by fungi, are amongst the most common illnesses. Because of the high incidence of these infections and problems involved in their therapy, they have received much attention, particularly as concerns a better characterisation of the causative micro-organisms. Onychomycosis caused by dermatophytes (tinea unguium) is most common and is found more frequently on the feet than on the hands. The clinical presentation of onychomycosis is at best indicative of fungal infection, and the growth of a credible pathogen is an indispensable prerequisite for definite diagnosis. The clinical appearance is variable. Four major types of manifestation have been characterised, depending on localisation and spread. New antifungal agents for systemic or topical application based on novel active substances or vehicles are available, and cure is feasible for the majority of cases. Therapy can and should be individualised, depending on the characteristics of the particular case. Currently, continuous or intermittent oral treatment with itraconazole or terbinafine exhibit a particularly favourable risk : benefit ratio. Fluconazole might become an alternative in the near future. With respect to topical treatment, ciclopirox or amorolfine lacquer and the bifonazole/urea combination deserve particular interest. However, cure cannot be expected for every case.     

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.     

Thermogelling hydrogels of cyclodextrin/poloxamer polypseudorotaxanes as aqueous-based nail lacquers: Application to the delivery of triamcinolone acetonide and ciclopirox olamine

This work investigated the use of in situ gelling hydrogels based on polypseudorotaxanes of Pluronic F-127 and partially methylated β-cyclodextrin as aqueous nail lacquers. N-acetylcysteine and urea were incorporated as penetration enhancers. The formulations were tested for their ability to deliver ciclopirox and triamcinolone across human nail plate and bovine hoof. Simple aqueous solutions of the drugs with N-acetylcysteine provided measurable fluxes across hoof membranes but became quickly depleted of drug. Further, these solutions would have a short residence time upon nail application. Addition of Pluronic F-127 facilitated drug solubilization and provided the formulations with in situ gelling properties but drug entrapment into the micelles slowed down the delivery process. This was solved by addition of methylated β-cyclodextrin; the formulations retained the thermogelling properties, drug solubilization was further increased, and drug delivery was accelerated. The polymer chains compete with the drugs for the cyclodextrin cavity forming polypseudorotaxanes, which facilitated drug release. The permeability of both drugs was higher across bovine hoof than human nail. The new polypseudorotaxanes formulation delivered more ciclopirox across human nail than a marketed organic lacquer which supports the growing hypothesis that aqueous-based nail lacquers represent a superior formulation strategy in nail topical delivery.