Progress on New Therapeuties for Fungal
`Nail Infections
`Stephen J. Bakera, Xiaoying Huib and Howard I. Maibachb
`
`aAnacor Pharmaceuticals, 1060 East Meadow Circle, Palo Alto, CA 94303, USA
`bDepartment of Dermatology, Surge Building, Room 110, 90 Medical Center Way, University
`of California at San Francisco, San Francisco, CA, 94143, USA
`
`Contents
`1. Introduction
`2. Drug Therapy
`2.1. Systemic treatments
`2.2. Topical treatments
`2.3. Combination and booster treatments
`3. Drug Penetration Through the Nail
`3.1. Composition of the nail plate
`3.2. Nail penetration models
`4. Factors Affecting Drug Penetration
`4.1. Physicochemical properties of the drug
`4.2. External factors
`5. Infection Models
`5.1. In vitro infection models
`5.2. In vivo infection models
`6. Preclinical/Clinical Pipeline
`7. Conclusion
`References
`
`1. INTRODUCTION
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`Onychomycosis is a fungal infection of the toe and finger nails, with the majority of
`cases involving infection of the toe nails [1]. The disease is mostly caused by a class
`of fungi known as the dermatophytes, which are also responsible for skin fungal
`infections. Dermatophytes flourish on dead keratinized tissue and normally infect
`the stratum corneum layer of skin, scalp hair and nails [2]. Non-dermatophyte
`species including yeasts and molds can also be involved. The dermatophytes ac-
`count for around 90% of all cases of onychomycosis [1,3] and include Trichophyton,
`Microsporum and Epidermophyton species. However, Trichophyton rubrum and
`Trichophyton mentagrophytes are by far the major causative agents accounting for
`60–70% of the cases [1,3,4]. The fungi can infect the nail plate, nail bed and sur-
`rounding skin folds (proximal fold at the cuticle and lateral folds on either side of
`the nail plate). Onychomycosis damages the nail plate causing thickening and
`discoloration. In more advanced cases, the nail plate lifts away from the nail
`bed, termed onycholysis, which causes discomfort and sometimes can be painful.
`
`ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOLUME 40
`ISSN: 0065-7743 DOI 10.1016/S0065-7743(05)40021-4
`
`r 2005 Elsevier Inc.
`All rights reserved
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`Clinical presentations of onychomycosis have been divided into four categories:
`distal subungual (infection occurs at or near the tip of the nail plate and involves the
`underlying nail bed), proximal subungual (infection is at or near the cuticle and
`involves the underlying nail bed), superficial (infection is in the nail plate only with
`no nail bed involvement) and total dystrophic onychomycosis (whole nail involve-
`ment and considered a combination of the other types) [5]. Between 6.5 to 13.8% of
`the population in North America is reported to be infected with this disease and the
`prevalence increases with age [1,4,6,7]. One study reported 48% of 70 year olds are
`infected with onychomycosis [6].
`
`2. DRUG THERAPY
`
`Onychomycosis is difficult to permanently cure. Treatment failures and relapses are
`common, which exacerbate the problem [8–10].
`In order for an antifungal drug to be effective, it must presumably disseminate
`throughout the nail plate, nail bed and other locations occupied by the fungi, and
`reach concentrations that will eliminate the pathogen. This can be especially dif-
`ficult when the nail plate has lifted from the bed (onycholysis). Unlike damaged skin
`that can repair itself, the nail plate cannot, therefore results of therapeutic treatment
`are not evident until new nail growth occurs and is clear of infection. Toe nails
`typically take about 1 year to fully grow out.
`Because of the length of time required to observe new nail growth, clinical trials
`typically take around 9–12 months (either 3 months systemic treatment with 6–9
`months follow up or 6–9 months topical treatment with 3–6 months follow up).
`During this time, the infected nails can be monitored for growth of new clear nail
`and for presence of viable dermatophytes. Efficacy is usually recorded in one of
`three ways: mycological cure, clinical cure or complete cure. Standard definitions of
`these cures are not completely uniform; each report usually provides the criteria
`that were used in the study. A mycological cure is defined by the extent of erad-
`ication of the fungi. It is assessed by removing a section of nail and screening for the
`presence of dermatophytes by microscopy and by culturing the nail for growth of
`dermatophytes in vitro. A clinical cure is defined by the extent of new nail growth at
`the proximal fold which is visibly clear of infection. A complete cure is defined when
`a patient has a mycological cure and clinical cure. Obviously, a complete cure is
`most desirable but hindering this is the fact that in many cases more than one digit
`is infected and not every digit may be cleared of infection.
`Onychomycosis is treated both systemically and topically. Current systemic
`treatments include terbinafine (1), itraconazole (2) and griseofulvin (3). Current
`topical treatments include ciclopirox (4), amorolfine (5) and tioconazole (6).
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`
`2.1. Systemic treatments
`
`is the most effective method of curing ony-
`Currently, systemic treatment
`chomycosis. Even so, between 20–25% of patients fail to respond [11]. Terbina-
`fine (1) and itraconazole (2) are the two systemic treatments of choice with ter-
`binafine showing greater efficacy than itraconazole and lower rates of recurrence
`[11–15].
`Terbinafine (1), a representative of the allylamine class of antifungal agents,
`inhibits squalene epoxidase [16,17] and thereby prevents the biosynthesis of ergos-
`terol, a key ingredient in the fungal cell wall. Terbinafine is active against de-
`rmatophytes, M. furfur, Aspergillus species and some Candida species including
`C. parapsilosis; however, it is fungistatic against C. albicans [2]. A single oral dose of
`250 mg terbinafine given to humans produces peak plasma concentrations of 1 mg/
`mL within two hours [14]. It is 499% protein bound and has a half-life of about 36
`hours. It is administered at a dose of 250 mg once daily for 6 weeks for finger nails
`or 12 weeks for toe nails [14]. One study showed that terbinafine localizes in the
`stratum corneum via sebum [18]. Terbinafine has a cLogP of 6.5 and a molecular
`weigh of 292 Da.
`Itraconazole (2), which is from the azole class of antifungal agents, inhibits la-
`nosterol 14 a-demethylase and thus stops the biosynthesis of ergosterol. It has
`broad spectrum activity against species including dermatophytes, Candida species,
`Aspergillus species and M. furfur [2]. Blood levels of itraconazole after a single
`200 mg dose given to humans reached a peak level of 0.2–0.3 mg/mL after 4–5 hours
`[15]. It is 99.8% protein bound and has a half-life of 21 hours. It is administered
`either 200 mg once daily for 12 weeks or 200 mg twice daily for 7 days followed
`by 3 weeks with no treatment and repeated for three months. Like terbinafine,
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`itraconazole also localizes in the stratum corneum via sebum but at much lower
`levels [18,19]. Itraconazole has a cLogP of 3.3 and molecular weight of 706 Da.
`Griseofulvin (3), isolated from Penicillium griseofulvin in 1939 [20], has a limited
`spectrum of activity. It is fungistatic against dermatophytes only and works by
`binding to microtubular proteins thus inhibiting cell mitosis. It has a cLogP of 2.2
`and a molecular weight of 353 Da.
`The commonly used antifungal agent, fluconazole, has also been prescribed, off-
`label, for the treatment of onychomycosis.
`
`2.2. Topical treatments
`
`Treatment of onychomycosis by topical methods has been met with limited success
`and reasons for this will be explored in more detail in Section 3. As with treating
`skin fungal
`infections such as tinea pedis (athletes foot), topical application
`for onychomycosis would seem the obvious choice. However, unlike the stratum
`corneum, the nail plate is a more difficult barrier to penetrate, requiring the drug
`to have much different physicochemical properties than are required for skin
`penetration. The two main topical treatments used today are ciclopirox and am-
`orolfine, both of which are formulated in lacquers that are painted onto the infected
`nails. The lacquer dries to leave a water-insoluble film on top of the infected nail,
`which then acts like a drug depot releasing the drug into the nail plate [21,22].
`Tioconazole has also been used but has been largely replaced by ciclopirox and
`amorolfine.
`Ciclopirox (4) is a hydroxypyridone antifungal agent and is believed to work by
`inhibiting metal dependant enzymes that degrade intracellular toxic peroxides. It
`does this by chelating the polyvalent cations (Fe3+ or Al3+) required by these
`enzymes [23–25]. Ciclopirox has antifungal, antibacterial and anti-inflammatory
`activities [25]. It is administered to the infected nails daily and due to the slow
`growth of nails, this treatment continues for at least 6 months. Ciclopirox has a
`cLogP of 2.5 and a molecular weight of 207.
`Amorolfine (5) is a morpholine antifungal agent and works by inhibiting ergos-
`terol biosynthesis. Amorolfine is administered once or twice weekly to the infected
`nails for 6 to 12 months. Amorolfine has a cLogP of 5.8 and molecular weight of
`317.
`The relative lack of clinical efficacy seen by topical antifungal treatments has led
`to a substantial research effort to understand the reasons for this failure. The most
`common belief
`is that
`treatment
`failure following topical
`therapy for on-
`ychomycosis results from the inability of the drug to penetrate and disseminate
`throughout the nail. This topic will be explored in more depth in Sections 3 and 4.
`Other factors that have been implicated include lack of microbiological activity in
`the presence of keratin [26,27], lack of microbiological activity against the dormant
`dermatophytes in the nail keratin [28] and poor penetration of drug into the de-
`rmatophytoma, a thick mass of fungi and nail debris, that builds up between the
`nail plate and nail bed [29].
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`2.3. Combination and booster treatments
`
`Since there are no current antifungal treatments available that will provide a com-
`plete cure, practitioners are attempting combination therapy and/or booster thera-
`py in an attempt to improve efficacy rates [30–32]. Combination therapy includes
`the use of oral plus oral therapy e.g. oral teribinafine plus oral itraconazole either in
`parallel or sequentially; oral plus topical therapy, e.g. oral terbinafine plus topical
`ciclopirox lacquer; or other dual, triple or quadruple combinations. However, these
`studies show only marginal improvement at best and further studies are warranted.
`Booster therapy involves giving a second course of systemic treatment, terbinafine
`or itraconazole, 6–9 months after systemic treatment began [30].
`
`3. DRUG PENETRATION THROUGH THE NAIL
`
`3.1. Composition of the nail plate
`
`The human nail anatomy consists of nail plate, nail bed and nail matrix. The nail
`plate consists of three layers: the dorsal and intermediate layers derived from the
`matrix, and the ventral layer derived from the nail bed [33,34]. The upper (dorsal)
`layer is a few cell layers thick and consists of hard keratin. It constitutes the main
`barrier to drug diffusion into and through the nail plate. The intermediate layer
`constitutes three quarters of the whole nail thickness, and consists of soft keratin.
`Below the intermediate layer is the ventral layer of soft keratin, a few cells thick,
`that connects to the underlying nail bed, in which many pathological changes can
`occur. Thus, in the treatment of nail diseases, achieving an effective drug concen-
`tration in the ventral nail plate is of great importance. The nail bed consists of non-
`cornified soft tissue under the nail plate, and is highly vascularized. Beneath the nail
`bed at the proximal fold is the nail matrix, which is a heavily vascularized thick
`layer of highly proliferative epithelial tissue that forms the nail plate.
`The human nail is approximately 100 times thicker than the stratum corneum of
`the skin, and both are rich in keratin. However, they exhibit some physical and
`chemical differences [35,36]. The nail possesses high sulphur content (cystine) in its
`hard keratin domain, whereas the stratum corneum does not. The total lipid con-
`tent of the nail ranges from 0.1% to 1%, as opposed to approximately 10% for the
`stratum corneum.
`Under average conditions, the nail contains 7% to 12% water, in comparison to
`25% in the stratum corneum. At 100% relative humidity, the maximum water
`content in the nail is approximately 25%, in sharp contrast to that in the stratum
`corneum, which can increase to 200–300%.
`The nail’s unique properties, particularly its thickness and relatively compact
`construction, make it a formidable barrier to the entry of topically applied agents
`[37]. In one study, the concentration of an applied drug across the nail dropped
`about 1000-fold from the outer surface to the inner surface [38]. As a result, the
`drug concentration presumably had not reached a therapeutically effective level in
`the inner ventral layer.
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`The existing clinical evidence suggests that a key to successful treatment of ony-
`chomycosis by a topical antifungal product lies in effectively overcoming the nail
`barrier.
`
`3.2. Nail penetration models
`
`To achieve an effective drug concentration into and through the human nail plate,
`development of an appropriate in vitro method to explore the physicochemical
`characteristics and permeability of the nail is of importance.
`Walters and his colleagues pioneered the study of the permeability characteristics
`of the human nail plate in the early 1980’s. They designed an in vitro method
`utilizing a stainless steel diffusion cell that permitted the exposure of nail plate to a
`bathing medium that was stirred by small motors mounted above the cell. Their
`most important research finding is that, as a permeable membrane, the hydrated
`human nail plate behaves more like a hydrophilic gel membrane in its barrier
`properties than as a lipophilic membrane such as stratum corneum [37]. This finding
`also explains the behavior of some solvents that promote diffusion through the skin
`horny layer but have little promise as accelerants of nail plate permeability [39].
`Mertin and Lippold [35,36,40] modified Franz diffusion cells to measure nail per-
`meability characteristics and drug uptake into nails. For onychomycosis treatment,
`they indicated, not only the flux of an antifungal drug through the nail plate is of
`importance, but also the antifungal potency, which is expressed as minimum inhib-
`itory concentration (MIC). An efficacy coefficient, E, was therefore introduced, which
`should be maximized for high therapeutic effectiveness. Thus, for maximum efficacy,
`a high flux of drug through the nail and a low MIC are desired characteristics.
`E ¼ Flux=MIC
`Kobayashi and his coworkers [34] investigated the permeation characteristics of
`drugs with different lipophilicity through three layers of the human nail plate (the
`dorsal, intermediate, and ventral nail layers), using a modified side-by-side diffusion
`cell. The data suggested that the upper (dorsal) layer functions as the main nail barrier
`to drug permeation, exhibiting low drug diffusivity.
`However, most published in vitro nail study methods required the human nail
`sample to be in contact with an aqueous solution on either or both sides during
`incubation. Consequently, the human nail plate is artificially hydrated beyond
`normal levels. Methods of nail sample preparation have also used scalpel or sand
`paper to remove nail samples, which is not only time consuming, but also may not
`be accurate [34,41]. Recently Hui et al. [42–44] developed a novel experimental
`system that simulates the in vivo conditions of therapeutic, non-occluded applica-
`tion of drug to a human nail. In this device, the human nail (top center) surface was
`open to air, while the inner (ventral) surface made contact with a small saline-
`wetted cotton ball, which acted as both a nail supporting bed and a moisture
`supplier. The average of hydration of the wetted cotton balls, 11879.4 AU, re-
`sembles the average hydration of a human nail bed, 99.978.9 AU, as measured in
`fresh human cadavers. After completion of the dosing and incubation phase, the
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`nail plate was transferred to a micrometer-controlled nail sampling instrument that
`enables accurate and reproducible sampling of the inside of the nail with high mass
`balance efficiency (Fig. 1).
`Data shows that the average depth of nail sampling from the inner center surface
`was well controlled at 0.2670.05 mm (corresponding with the ventral/intermediate
`layer), which was close to the expected depth of 0.24 mm. With this in vitro nail study
`system, Hui et al. examined antifungal drugs delivered into the dorsal/intermediate
`and ventral/intermediate nail layers, and into the support bed (cotton ball) to de-
`termine the flux and the efficacy coefficient (E) of drugs in nail (Table 1). This study
`shows both ciclopirox and econazole penetrate to the deep layer of the nail plate in
`
`Dorsal layer
`
` Topical dose
`
`Dorsal/intermediate center
`
`Intermediate layer
`
`Remainder nail
`
`Ventral layer
`
`Ventral/intermediate center
`
`Cutting tip
`for nail sampling
`
`Fig. 1. Nail and nail drilling tip.
`
`Table 1. Two antifungal drugs, econazole and ciclopirox, concentration and rela-
`tive antifungal efficacy
`
`Parameter
`
`Nail Lacquera
`
`Control
`Formulation
`
`p Value (t Test)
`
`Econazole in the deeper
`layer (mg/cm3)b
`Efficacy coefficient E
`(MIC ¼ 1 mg/mL)
`Ciclopirox in the deeper
`layer (mg/cm3)b
`Efficacy coefficient E
`(MIC ¼ 0.04 mg/mL)
`
`14,830 (341)
`
`2,371 (426)
`
`0.008
`
`14,830
`
`2,371
`
`0.008
`
`407 (106)
`
`10,175
`
`—
`
`—
`
`—
`
`—
`
`Sources: econazole data is from reference [43]; ciclopirox data is from reference [44].
`aThe data represent the mean (SD) of each group (n ¼ 5). The nail lacquer group of econ-
`azole contains 18% 2-n-nonyl-1,3-dioxolane and the control formulation contains no
`2-n-nonyl-1,3-dioxolane.
`bThe deeper layer is the center of the ventral/intermediate layer of the nail plate. The data
`represent the amount drug in the sample after a 14-day dosing period.
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`concentrations above the MIC and that econazole penetration is significantly im-
`proved when formulated with a lacquer containing a penetration enhancer.
`
`4. FACTORS AFFECTING DRUG PENETRATION
`
`Using in vitro nail penetration models, studies have been performed to help un-
`derstand the physicochemical properties that allow a molecule to penetrate into and
`through the human nail plate. External factors also have a major influence upon
`nail penetration and they are: nail thickness, the vehicle within which the drug is
`formulated, pH of the vehicle and addition of permeation enhancing agents to the
`vehicle. These factors have been recently reviewed [21,45].
`
`4.1. Physicochemical properties of the drug
`
`A recent study [46] investigated the relationship of molecular weight and lipophili-
`city of benzoic acid derivatives upon nail penetration. Using p-hydroxybenzoic
`esters ranging from methyl to hexyl, they found that permeation through the nail
`was mostly influenced by molecular weight and little, if any, by lipophilicity, which
`is in agreement with earlier studies [35,36]. This finding can be understood after
`consideration nail plate morphology. Because the nail plate is composed of many
`strands of keratin held together through disulfide bonds, the space between the
`strands must have a finite size causing the nail plate to act like a molecular sieve or
`size exclusion medium. Small molecules can weave through these spaces while larger
`molecules are unable to pass [21].
`The molecular weight of most antifungal agents is4300 Da. Accordingly, these
`drugs will have difficulty penetrating the nail plate, a likely reason for the low
`clinical efficacy observed [47].
`
`4.2. External factors
`
`4.2.1. Nail plate effect
`
`Nails infected with onychomycosis are thicker than healthy nails due to the pres-
`ence of the dermatophyte and the damage they have caused. The effect of nail
`thickness on penetration has been investigated and found to have an inverse re-
`lationship; as the nail increases in thickness drug penetration is reduced [46]. In the
`same study, the authors compared penetration of 5-fluorouracil though healthy
`nails versus fungal infected nails. They concluded that there was no significant
`difference between healthy and infect nails. However, they did not investigate
`heavily infected nail plates because the thickness of the uneven plate could not be
`accurately measured and that the uneven nail plate would collapse in water. They
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`speculated that penetration through this type of nail plate should increase due to the
`destruction of the plate caused by the fungi.
`
`4.2.2. Excipients
`
`The nail plate acts like a hydrogel and swells in the presence of water resulting in
`increased pore size [34]. This has the overall effect of increasing permeation [21]. A
`study into the penetration of ciclopirox (4) in three formulations concluded that
`when ciclopirox was formulated in an aqueous gel, its penetration was far superior
`than when formulated in a lacquer [44]. The effect of lipophilic vehicles on drug
`penetration through the nail plate has been investigated [40]. The authors concluded
`that providing the formulation does not affect the hydration level of the nail plate
`and the lipophilic vehicle does not penetrate the nail plate, then penetration of the
`drug is independent of the vehicle medium.
`
`4.2.3. Vehicle pH
`
`Antifungal agents have a range of pKa values and so studies have been reported that
`compare the penetration of the ionic and non-ionic forms of the parent. These studies
`investigated the penetration of miconazole [48] (pK a ¼ 6:7), benzoic acid [35]
`(pK a ¼ 4:2), pyridine [35] (pK a ¼ 5:3) and 5-fluorouracil [49] (pK a ¼ 7:9) in vehicles
`over a pH range from 2 to 8.5. In the case of miconazole, it was reported that
`penetration was independent of the pH of the vehicle. However, in all the other cases,
`the ionic forms of the parent did not penetrate as well as the non-ionic forms. A recent
`study [46] investigating the penetration of ionic and non-ionic compounds and the
`relationship with molecular weight also found non-ionic compounds penetrate better.
`These authors speculated that the decrease in penetration of ionic drugs may be due to
`an apparent increase in molecular weight of around 100 Da from ion hydration.
`
`4.2.4. Penetration enhancers
`
`Efficacy rates of onychomycosis agents are widely believed to improve if penetra-
`tion of antifungal agents through the nail plate is increased. Initial research has
`focused upon modifying environmental conditions, using penetration enhancers, to
`allow larger molecules to penetrate more easily through the nail plate. The most
`common method is to add a chemical enhancer to the vehicle. This enhancer can be
`a keratolytic agent [50], such as urea or salicylic acid, which break down the nail
`keratin; mercaptans [50], which break disulfide bonds in the nail keratin; solvent
`carrier, such as DMSO [42]; or 2-n-nonyl-1,3-dioxolane [43], which has been shown
`to fluidize stratum corneum lipids [51] (although its effect on nails is unknown). In
`most cases reported, an increase in penetration of the nail plate was observed.
`Mechanical methods to increase penetration have also been attempted. Lacquer
`formulations are the most common method to enhance penetration and are used in
`commercial preparations of ciclopirox and amorofine. After the lacquer dries, the
`drug impregnated film remaining creates a large drug gradient across the nail plate,
`which may force the drug through the nail plate. The lacquer also increases
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`in the nail plate, which will assist dissemination of the drug
`hydration level
`throughout the nail plate [21]. Another report described the use of pressure sensitive
`adhesives to enhance ciclopirox penetration [52].
`
`5. INFECTION MODELS
`
`Since a complete cure is highly improbable without good nail penetration, in vitro nail
`penetration studies are becoming one of the first screening tools used in the selection
`of compounds for treatment of onychomycosis. Once a compound has been identified
`that exhibits good penetration properties, the next step in lead optimization is to
`assess efficacy in a model of onychomycosis. This is a relatively new area of research
`and few models of onychomycosis exist. Several of these are summarized below.
`
`5.1. In vitro infection models
`
`One recent model of infection tested the minimum fungicidal activity (MFC) of
`antifungal agents against T. rubrum in a medium containing human nail powder,
`which the authors termed nail-MFC [53]. The medium by itself would not support
`the growth of T. rubrum but addition of the pulverized keratin allowed the der-
`matophytes to grow. The antifungal agents were incubated with T. rubrum in this
`nail medium for four weeks, after which the viability of T. rubrum was assessed.
`Terbinafine had a nail-MFC of 1 mg/mL, but other antifungal agents did not show
`efficacy at the highest concentrations tested (amorolfine 1 mg/mL, ciclopiroxolamine
`128 mg/mL, clotrimazole 64 mg/mL, fluconazole 128 mg/mL, griseofulvin 64 mg/mL,
`itraconazole 4 mg/mL and naftifine 8 mg/mL).
`Two groups have reported models of dermatophyte infection in human nail
`plates. In one study, nail clipping were applied to the top of an agar plate cultured
`with T. mentagrophytes and after a few days the infection spread onto the nail plate.
`Drugs were assessed by applying the formulation to the top of the nail and com-
`paring the extent of dermatophyte infection that had spread to the nail plate with an
`untreated control [54]. In the second model, T. mentagrophytes was applied to the
`nail plate directly without a supporting medium and invasion occurred without
`addition of nutrients [55].
`
`5.2. In vivo infection models
`
`Two in vivo efficacy models in guinea pigs have been reported. In the first study, the
`authors infected the nails and toes of guinea pigs creating both onychomycosis and
`tinea pedis (fungal infection of the surrounding skin). They then used this model to
`show the efficacy of a topically applied triazole in comparison with amorolfine and
`terbinafine. All three were effective in clearing the tinea pedis, but only the exper-
`imental triazole showed efficacy against onychomycosis [27]. The second model was
`developed as an optimized in vivo model for dermatophytosis. The authors shaved
`and abraded the skin on the back of guinea pigs and infected the site with T.
`mentagrophytes. After the infection was established, the animals were treated with
`
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`

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`Fungal Nail Infections
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`343
`
`oral and topical formulations of terbinafine and observed for improvement of the
`infection [56]. In this study, 1% topical terbinafine treatment had 100% clinical and
`mycological efficacy. Although this is a model for dermatophytosis, this model was
`used to determine the efficacy of a topical lacquer formulation of terbinafine.HCl,
`currently in clinical development for onychomycosis [57].
`
`6. PRECLINICAL/CLINICAL PIPELINE
`
`New treatments in development for onychomycosis are listed in Table 2. Currently,
`most treatments that are in clinical trials represent re-formulations of known an-
`tifungal agents combined with penetration enhancers in an effort to increase pen-
`etration through the nail plate. There are two treatments in clinical trials that
`contain novel antifungal agents. The first, in Phase 2, is a topical treatment that
`generates nitric oxide. The second, in Phase 3, is a topical treatment containing
`abafungin (7), a membrane integrity antagonist that has antibacterial and antifun-
`gal activity. In addition to the treatments listed, azoline and ravuconazole, two oral
`triazole antifungal agents are in clinical trials for fungal infections and include
`onychomycosis as a potential indication.
`
`N
`
`H N
`
`H N
`
`N
`
`S
`
`O
`
`Me
`
`7
`
`Me
`
`Table 2. Onychomycosis treatments in preclinical and clinical development
`
`Status
`
`Discovery
`
`Phase 1
`
`Phase 2
`
`Phase 3
`
`Drug
`
`Further information
`
`Ciclopirox (4)
`Ketoconazole
`Econazole
`
`Formulated in a metered dose transdermal spray
`Formulation contains a topical carrier
`Formulation contains the penetration enhancer
`2-n-nonyl-1,3-dioxolane
`Formulation contains an absorption enhancer
`Clotrimazole
`Topical NO donor Novel topical treatment that generates nitric
`oxide
`Formulation contains a penetration enhancer
`Oral treatment, once daily regime
`A membrane integrity antagonist formulated as
`a topical treatment for bacterial and fungal
`skin infections
`
`Terbinafine
`Itraconazole
`Abafungin (7)
`
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`7. CONCLUSION
`
`S.J. Baker et al.
`
`Onychomycosis is a common disease, especially in the older generation, that is
`difficult to treat using current medicines. In efforts to understand why current
`topical treatments work so poorly, research studies have focused on the nail plate
`and factors affecting movement of organic molecules through this barrier. The
`major problem that must be overcome is penetration and dissemination of the drug
`throughout the nail plate. Several models of nail penetration have been developed
`in order to assess this parameter. Data from these models suggest the optimal
`properties for effective penetration are: low molecular weight, low polarity, activity
`in the presence of keratin and optimal vehicle formulation (favorable excipients, pH
`and/or penetration enhancers). Infection models have also been developed that
`provide additional screening tools during lead optimization studies. These studies
`represent a major advancement in the search for new and effective treatments.
`However, as this remains a young field, it is unknown how success in these pre-
`clinical models will translate into clinical efficacy.
`
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