CURRENT MANAGEMENT OF ONYCHOMYCOSIS

~ ~~~~ ~ ~ ~ ~

ADVANCES IN CLINICAL RESEARCH 0733-8635/97 $0.00 + .20

CURRENT MANAGEMENT OF ONYCHOMYCOSIS

An Overview

Aditya K. Gupta, MD, FRCP(C), Richard K. Scher, MD, FACP, and Piet De Doncker, PhD

Until recently, the only oral therapies available for the treatment of onychomycosis were griseofulvin and ketoconazole. Relatively lit- tle is known about the pharmacokinetics of these drugs in nails; the plasma levels of these drugs may not be an accurate reflection of the concentration of the antifungal agent within the nail plate. There are several factors that need to be considered in the management of onychomycosis: (1) drugs (efficacy, adverse-effects profile, dosage schedule, duration of therapy, relapse rates, monitoring schedule, and cost-effectiveness), (2) patient and disease profile (the location and extent of onychomycosis, etiologic agent[s], any concomitant health problems, and concurrent medications), and (3) physician and country characteristics (the drugs approved for use in onychomycosis in the particular country, physician experience and preferences, and variations in epidemiologic patterns of etiologic fungi).

The growing nail receives a contribution from both the matrix and the nail bed?*, 83 For the rational use of the newer oral antifungal agents, itraconazole, terbinafine, and fluconazole, it is important to know the route of drug delivery to the nails, the speed with

which the antifungal agent reaches the nail, and the rate at which the drug disappears from the nail plate. Topical antifungal agents have sometimes been considered for the treatment of early onychomycosis, in the absence of nail matrix involvement, with the nail var- nishes or creams being more popular in Eu- rope than in North America. In some instances surgical therapy or chemical avulsion may be an useful adjunct to medical management.

TOPICAL ANTIFUNGAL AGENTS IN ONYCHOMYCOSIS

Numerous topical antifungal agents have been tried for the treatment of onychomycosis. The results are generally disappoint- ing, particularly when there is moderate-to- extensive infection of the nail plate with matrix involvement. For a topical agent to be effective, a sufficient amount of drug has to penetrate through the nail plate and reach concentrations that exceed the minimum in- hibitory concentration (MIC) for the infecting organism(s).

The structure of nail differs from that of

From the Division of Dermatology, Department of Medicine, Sunnybrook Health Science Center and the University of Toronto, Toronto, Ontario, Canada (AKG); the Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, New York (RKS); and the Departments of International Clinical Research, Dermatol- ogy, Infectious Diseases, and Allergy, Janssen Research Foundation, Beerse, Belgium (PDD)

DEWTOLOGIC CLINICS

VOLUME 15 * NUMBER 1 - JANUARY 1997 121

122 GUPTA et a1

skin in several important respects. The nail plate has a compact structure with tight binding of the cells that is facilitated by numerous intercellular links with disulfide bridges.2y Nail proteins can be divided into three cate- gories: low sulfur keratins (40-60 kilodal- tons), high sulphur proteins (10-25 kilodal- tons) and high glycine/tyrosine proteins (6-9 kilodalt~ns).~~ Compared with the stratum corneum of the epidermis, the proteins of the nail plate are composed of distinct keratins, with the presence of a high sulfur matrix component that is absent in the stratum c~rneum.~, 94 In nails the fat content is 0.1% to 1% compared with 10% in the stratum ~orneum.~O The water content in nail is 7% to 12%, which is less than the corresponding value of 15% to 25% for the stratum cor- ne~m.~O In view of the absence of sebaceous and sweat glands in nails, the pathways in the stratum corneum that rely on the delivery of drug to the epidermis via the sebaceous or eccrine sweat routes are not relevant in the nail.31

The more commonly used topical agents for the treatment of onychomycosis are 5% amorolfine lacquer, 8% ciclopirox nail lacquer, 28% tioconazole, and bifonazole with 40% urea paste.

Amorolfine

Amorolfine is a morpholine derivative that is not structurally related to the polyenes, imidazoles, or allylamines.l’, 5y Morpholine derivatives are active against fungi that are pathogenic to humans, animals, and plants.’l’ Amorolfine (4-[3p-[p-(l,l-dimethylpropyl)- phenyl]-2-methyl-propylJ-2,6-cis-dimethylmor- pholine hydrochloride) is more active against human fungi compared to the structurally similar fenpropimorph, which demonstrates greatest activity against plant pathogens.

Antifungal Activity

Amorolfine is active in vitro against dermatophytes and dimorphic fungi, with the activity against yeasts and molds being more variable.68 Of the organisms tested (Trichophy- ton mentagrophytes, Candida albicans, Histo- plasma capsulatum, and Cryptococcus neofor- mans), amorolfine demonstrates the greatest fungicidal activity against T. mentagrophytes.

In animal studies amorolfine does not ap-

pear to be effective when given systemically for life-threatening myc~ses.”~ This is in contrast to its in vitro activity against these fungi. Thus, the effectiveness of amorolfine appears to be confined to superficial cutaneous fungal infections and vaginal candidiasis. The lack of systemic activity may be due to several causes: rapid metabolism, extensive protein binding of the drug, or the lowered susceptibility exhibited by some drugs to amorolfine at 37°C.

Mechanism of Action

Most antifungal agents interfere with one or more of the enzymatic steps involved in ergosterol synthesis, an essential component of the fungal cell membrane. Amorolfine interferes with two, or perhaps even three, steps in the sterol biosynthesis pathway. These include the enzymes A,,-reductase and A74-isomerase.111 Amorolfine may also have secondary effects. An alteration in the sterol content of the fungal membrane may result in hyperfluidity and permeability changes, with the fungus eventually becoming nonviable.

Pharmacokinetics

The percutaneous absorption of amorolfine has been measured through both skin and nail using an in vitro technique. Human nails obtained at autopsy were mounted in special glass diffusion chambers and percutaneous absorption was measured using a modifica- tion of the method described by F r a n ~ . ~ ~ Nail uptake of 5% amorolfine was higher when it was in the methylene chloride formulation compared with the ethanol lacquer. Further- more, pretreatment of the nail with the penetration enhancer dimethyl sulfoxide (DMSO) resulted in a large increase in the amorolfine penetration.

In another study, Polak112 found that the kinetics of penetration into nail typically followed an exponential law, with the concentration of amorolfine in the upper layer being about 100 times higher compared with the lowest layer. In this study there was no significant difference between the methylene chloride and ethanol formulations. Both the degree and the kinetics of penetration were influenced by the condition of the nail. Soft and ”floury” nails retained amorolfine to a lesser extent than hard nails. In vitro studies suggest that the levels of amorolfine in nail

CURRENT MANAGEMENT OF ONYCHOMYCOSIS 123

are well in excess of the MIC for most fungi causing nail infections.112

In an open-label, parallel group, randomized studyI4 C-labeled amorolfine was used to determine percutaneous absorption of the 0.25% cream formulation in healthy male volunteers (n = 12).Iz1 A single dose of 0.5 g was applied over a 100 cm2 area, corresponding roughly to the size of a lesion of moderate dermatomycoses. In six volunteers the drug was applied to intact skin and in the other six to stripped skin, in each instance under an occlusive dressing for 24 hours. The average percutaneous absorption following a single application of the 0.25% cream did not exceed 8% to 10% of the applied dose.

Efficacy in Onychomycosis The 5% amorolfine nail lacquer is more

effective than the 2% formulation.120 Using 5% amorolfine nail lacquer, the once- and twice-weekly regimens were found to be equivalent for the treatment of toenail onychomycosis; however, fingernails exhibited a better response when treated twice weekly.115 Zaug and Berg~traesser'~~ have reviewed several studies (n = 727) in which mild-to-moderate onychomycosis (affected nail area <SO% total nail area and not involving the matrix) was treated with 2% or 5% amorolfine lacquer once or twice weekly for an average of 6 months (range, 1-14 months). In pedal onychomycosis, 3 months after the end of treatment, the clinical response (cure plus marked improvement) was 70%, and the clinical cure at follow-up was 44%. In general, the response was better when the duration of onychomycosis was less than or equal to 5 years.

In patients with onychomycosis the recommended treatment regimen is the application of 5% amorolfine nail lacquer once or twice weekly until clinical cure, usually 6 months for fingernails and 12 months for toenails. The patient is encouraged to file the affected nail(s) while applying amorolfine lacquer. More recently, the use of combination therapies of amorolfine nail lacquer with griseoful- vin92 and oral terbinafh~e*~ has been reported. A combination of topical and oral therapies may help increase overall efficacy, reduce the duration of oral therapy, and decrease side effects associated with the oral agent.

Ciclopirox Olamine

Ciclopirox olamine is a hydroxypyridone topical antifungal that is structurally unre-

lated to the imidazole derivatives or to other antifungal agents.'

Antifungal Activity

Ciclopirox olamine is fungicidal in vitro against Trichophyton rubrum, T. mentagrophytes, Epidermophyta jloccosum, Microsporsum canis, and Candida albicans. For most dermatophytes and yeasts the MIC falls in the range of 0.9 to 3.9 pg/mL when the organisms are cultured in Sabouraud dextrose medium containing beef peptone and free of certain met- als.' In humans, both dermatophytes and the molds Scopulariopsis brevicaulis, Aspergillus niger, Aspergillusfumigatus, and Scytalidium dim- idiatum (Hendersonula toruloidea) may exhibit a response to ciclopirox olamine nail 1acq~er . l~~

Mechanism of Action

The primary site of action of ciclopirox olamine is the cell membrane. The antifungal agent may inhibit transport of certain essential substrates into fungal cells and interfere with the synthesis of DNA, RNA, and proteins in growing cells. At higher concentrations of ciclopirox olamine the integrity of the cell membrane of sensitive organisms may be altered.

Pharmacokinetics

Ciclopirox 8% in a lacquer base can penetrate human fingernail^.^^ When ciclopirox was applied twice daily to fingernails for 45 days, the concentration of drug in nails grad- ually increased through day 30, beyond which it remained at a plateau until day 45. Sectioning of the nail into four layers revealed that by day 30 the drug was distributed relatively evenly throughout the nail. In the in- nermost quarter (ventral aspect) of nail, 19% of the drug was present compared with 35% in the outermost quarter (dorsal aspect) of the nail. Ciclopirox olamine drug levels measured l week after discontinuation of therapy demonstrated a substantial decrease, and a week later (i.e., 2 weeks after stopping therapy), drug levels in nail were almost negligi- ble.

Animal studies have demonstrated that ciclopirox olamine 1% cream or 1% lotion may be able to penetrate skin and inhibit or kill T. mentagrophyte~.~~ In vivo pharmacokinetic studies have also been performed to determine penetration of ciclopirox olamine

124 GUPTAetal

cream 1%. The cream was applied to the fore- arms in ten healthy volunteers for 2, 6, and 24 hours and the stratum corneum then removed by 20 tape strippings. The strips were divided into four groups each containing five strips. Six hours after application, the concentration of drug in the four descending layers of skin was 5,3,2, and 3 pg/mL, respectively. This was in the range of the MIC for the susceptible organisms.” Twenty-four hours after application of cream, drug levels in the four layers were 4.1, 2.6, 1.6, and 2.0 pg/mL, respectively.

Efficacy in Onychomycosis

Wu et all5* treated 42 patients who had onychomycosis with ciclopirox olamine 1% cream two to three times daily for 3 to 24 months. Diseased nails were filed down to improve penetration of drug into the nail plate. The cure rate was 14%, with improvement in another 36%. In an open, multicenter trial a combination of 1% ciclopirox olamine solution and cream was applied for a mean duration of 12.7 _+ 5.6 weeks followed by a 6-week follow-up period. A very strict ”nail toilet” was adhered to. An improvement was reported in 96% of the patients, with 57% being free from signs of infection.l14 Topical ciclopirox olamine has been reported to be beneficial in treating onychomycosis in acquired immunodeficiency syndrome pa- t i e n t ~ . ~ ~

Tioconazole Nail Solution

Tioconazole is an imidazole with a broad spectrum of antifungal activity. The MIC Val- ues are dermatophytes, 0.2 to 25 pg/mL; C. ulbicans, 0.2 to 12.5 pg/mL; and for nondermatophyte molds such as Scopuluriopsis brevi- cuulis and Scytalidium dimidiutum (Hender- sonulu toruloidea), the values are generally greater than 25 pg/mL?l Hay et al” treated 27 patients with tioconazole 28% solution for up to 12 months. In six (22%) patients clinical and mycologic cure was observed at follow- up 3 months after stopping therapy. The organisms that responded included Trichophy- ton rubrum, Scytalidium dimidiutum (Hender- sonulu toruloidea), and Acremonium species. A further 11 patients exhibited marked improvement. Subsequently, Hay et aP9 demonstrated that combination therapy of oral griseofulvin, 500 mg twice daily with tiocona-

zole 28% nail solution (n = 70 nails), resulted in clinical and mycologic cure in 69% of nails compared with 41% of nails in the group (n = 70 nails) receiving oral drug plus placebo solution.

1% Bifonazole and 40% Urea Combination

Several studies have examined the use of a paste formulation of 1% bifonazole and 40% urea for the treatment of onychomycosis.75~ 135

Hay et a175 observed that daily application of the paste for 1 week produced a mycologic cure rate of 62.5% at 12 weeks, with 46% of the patients still being in remission at 24 weeks.

Other Topical Agents

There have been reports of other topical therapies being used to treat onychomycosis: clotrimazole cream and solution*46; miconazole tincturel6; glutaraldehyde 10% aqueous solutionz8, lN; 1% fluorouracil in propylene glycol8; a tincture containing triacetin, sodium propionate, benzalkonium chloride, cetylpyri- dinium chloride, and chloroxyleno197~ 9B; 100% Meluleucu ulternifaliu (tea tree) oilz1; vitamin E55; naftifine hydrochloride 1% gelB7, 96; and topical ketoconazole under occlusion following nail avulsion.n

THE PLACE OF TOPICAL AND SURGICAL THERAPIES IN ONYCHOMYCOSIS

Myriad topical therapies have been reported for the treatment of onychomycosis. Topical therapies should not be expected to be beneficial when there is moderate-to- severe onychomycosis, including matrix involvement. Some response may be observed in instances in which there is minimal nail disease limited to only a few nails. In such a situation the probability of cure will be enhanced if adjunctive surgical or nonsurgical measures are undertaken. In general, topical therapies such as amorolfine, ciclopirox olamine, tioconazole, and bifonazole urea paste are used more commonly in Europe than in North America. Furthermore, surgery of the nail including chemical and nonchemi-


cal avulsion tends to be performed more commonly by podiatrists, and mostly in Europe.

Removal of diseased nail and reduction of the ”fungal load” may serve as useful adjuncts to oral or topical agents. The presence of hyperkeratotic subungual debris and “yellow streaks,” where the nail plate is thickened, making penetration of drug diffi- cult, may reduce the concentration of the orally administered antifungal agent that reaches the site of fungus in the affected nail.12 Some measures, such as filing and trim- ming the nails back, can be undertaken by the patient at home. In other instances, the physician may be able to remove part or whole of the diseased nail by curetting, dril- ling, or surgical removal of the nail. Nail avulsion may be partial or complete in na- ture, sometimes with a matrixectomy, and can be followed by the application of topical antifungals.6, 14, 119, lZo In certain instances the carbon dioxide laser has been used to avulse the involved portion of the nail plate and to remove underlying hyperkeratotic tissue containing fungus?, lZ3

Chemical avulsion of the nail is an altema- tive method by which infected nail can be removed. This may be accomplished using ointments containing 30% salicylic acid, 50% potassium iodide, or 40% urea.1o3 Application of urea under occlusion improves hydration and increases penetration of drug. Further- more, high urea concentrations may have an antiproliferative effect. Farber and 132

reported the use of 22% or 40% urea ointment as a nonsurgical and atraumatic method for avulsing dystrophic nails. Subsequently, Bu- selmeierZ described the combined application of urea and salicylic acid for nail removal. Other investigators have used mixtures containing 40% urea,147 propylene glycol-urea- lactic acid,@ and 20% urea with 2% tolnaftate ointment.80

It is our personal experience and that of othersN* 65* that infection including the nails and soles of the feet by T. rubrum, and possibly other dermatophytes, may be present more commonly in families and in communal areas such as public swimming pools. In some cases T. rubrum infection may be familial, possibly displaying an autosomal domi- nant pattern, and typically presenting as distal subungual onychomycosis with concomitant tinea pedis.’% An understanding of the familial and communal factors might prompt the patient to take measures to reduce reinfection once cure of the onychomycosis has been achieved. These might include hy-

gienic issues, keeping feet dry, the use of 100% cotton socks, appropriate footwear that enables the feet to ”breathe,” judicious use of foot powders and topical antifungals in cream or shampoo form, and possibly treating other affected family members and friends.

ORAL ANTIFUNGAL AGENTS

There are three antifungal agents that are being increasingly considered for the treatment of onychomycosis. There are several good reviews on this t0pic.3~. 6w, 70, 74, 93

Itraconazole is approved in the United States for the treatment of dermatophyte onychomycosis and terbinafine in Canada for this indication. The third agent, flucorazole, has not been approved as yet for the treatment of onychomycosis.

Terbinafine

The allylamine class of antifungal agents was discovered in the 197Os.l7, 129, 142, 143 Naf- tifine was the first compound in this ~ 1 a s s . l ~ ~ Subsequently, terbinafine was developed. It is the second significant allylamine to come to the market and the first agent in this class that has oral activity. These compounds have a common tertiary allylamine fun~ti0n. l~~ The chemical name of terbinafine is (E)-N-(6,6- dimethyl-2-hepten-4-inyl) - N-methyl-l-naph- thaline-methenamine-hydrochloride.

Antifungal Activity

In vitro terbinafine is primarily fungicidal against dermatophytes, Aspergillus species, Scopulariopsis brevicaulis, and the dimorphic fungi Blastomyces dermatitidis and Histoplasma capsulatum.106 The MIC values for dermatophytes range from 0.001 to 0.01 mg/L.’O The activity against yeasts is more variable, with terbinafine being more active against C. parapsilosis compared with C. afbicans.’06 It should be kept in mind that MIC values may be influenced by several factors including the type of medium used, pH, the inoculum size, and the duration of the incubation.’O, 53 Fur- thermore, there may be variable correlation between in vitro susceptibility and clinical efficacy.1°

In vivo studies have shown that oral and topical terbinafine are effective against experimentally induced T. mentagrophytes, M . canis, and C. albicans in laboratory animals.lo7 Oral

126 GUPTA et a1

terbinafine has been ineffective in some mu- rine models of infection involving organisms that exhibit in vitro sensitivity.128

Pharmacokinetics in Nail and Plasma

Orally administered terbinafine reaches the nail plate by diffusion from both the nail matrix and the nail bed.loo Application of 1% terbinafine cream to the outer surface of the nail plate in 53 involved nails did not alter the mean severity of clinical improvement of the nails.lo1 This excluded the possibility of significant diffusion of drug through the nail plate. Finlay et al" found that the kinetics profile of terbinafine in unaffected nails was not significantly different from that of affected nails. Furthermore, the kinetics of dimethyl terbinafine in the nail plate, the major metabolite of terbinafine, closely paralleled that of terbinafine. When terbinafine, 250 mg/ d, was administered to human male volm- teers, the drug was detected in peripheral nail clippings after 7 days of medi~ation.4~ The concentration of terbinafine in nails 90 days following a 7-day course of medication was 0.2 Lg/g (MIC of common dermatophytes such as Trickupkyton species ranges from 0.0015-0.01 ~ g / m L ) . ~ ~ , 45 Fifteen metabolites of terbinafine have been identified, none of them active.156 The main metabolites in plasma are N-dimethyl terbinafine and the 2-carboxy metabolites. Following daily oral administration of terbinafine, 250 mg over 4 weeks, there is initially rapid elimination from plasma followed by a terminal elimination phase reached around day 41, with a mean terminal half-life of 22 days.

Mechanism of Action

Ergosterol is required for the integrity of fungal cell membranes and is essential for the viability of virtually all fungal cells.125 The primary target of terbinafine in fungi is the membrane-bound enzyme, squalene epoxidase. This produces ergosterol deficiency, which interferes with membrane function cell growth, causing growth arrest and resulting in fungistatic action in vitro. On the other hand, accumulation of squalene results in its deposition in lipid vesicles with disruption of cellular membranes. This may be responsible for the fungicidal action in ~ i t r o . ' ~ ~ The mammalian epoxidase is much less sensitive than the fungal enzyme to inhibition by terbinafine.lZ6 There is no significant effect on mam-

malian cholesterol biosynthesis and no inhibition of the cytochrome P450 class of enzymes.lZ6


The dosage regimen of terbinafine is 250 mg/d for 6 and 12 weeks in fingernail and toenail onychomycosis, respectively. In a duration-finding study for pedal onychomycosis, the efficacy of oral terbinafine, 250 mg/d given for 6, 12, and 24 weeks, was assessed at 48 weeks after starting therapy. At this follow-up time the cure rates were 40%, 71%, and 79%, respe~tively.'~~ These results demonstrate that a 12-week therapy period for pedal onychomycosis may be sufficient. Review of published studies for pedal onychomycosis in which patients were treated with terbinafine, 250 mg/d for 12 weeks, gives (meta-analytic average k standard error, 95% confidence interval) complete cure in 62 2 6% (50%-74%), marked improvement in 91 ? 10% (71%-100%), and mycologic cure in 82 -+ 3% (76%-88%) pa- t ient~.~, 20, 56, 141 For fingernail onychomycosis cure, marked improvement and mycologic cure each occurred in 88% of patients.56, 141 Studies in which the length of treatment was longer than the recommended duration of 12 weeks for toenail onychomycosis and 6 weeks for fingernail onychomycosis have been excluded from the ana1y~is.l~. 27, 42, 67, 79, 153

Terbinafine is highly effective in the treatment of dermatophyte nail disease; however, it may not be as effective in nondermatophyte onychomycosis such as that caused by Can- dida species and molds.104, 118 Roberts et allla treated Candida onychomycosis and chronic paronychia with terbinafine, 250 mg/d for 12 weeks, in a placebo-controlled, randomized, double-blind study. At the end of 12 weeks there was no statistical difference in efficacy between terbinafine and placebo in the treatment of these conditions. Patients with C. parapsilosis alone responded better to therapy. Nolting et allo4 treated onychomycosis involving the yeasts C. albicans or C. parapsilosis (n = 65) and the mold S. brevicaulis (n = 7) with terbinafine, 250 mg/d for 48 weeks. At the end of therapy mycologic and clinical cure rates were 70% and 54%, respectively for C. albicans, with 85% and 63%, respectively for C. parapsilosis. The cure rate for S. brevi- cadis was 43%. Within 6 months of discontinuing therapy, relapses occurred in 46% of


cured patients with C. albicuns and 13% of cured patients with C. purupsilosis.

The pharmacokinetics of terbinafine therapy for onychomycosis may enable the treatment period to be shortened even further, perhaps with a higher daily dosage. Shuster and M ~ n r o ' ~ ~ treated patients with T. rubrum or T. interdigitale onychomycosis with terbinafine, 1000 mg, given once (five patients), twice (two patients), or three times (four patients) with 2 weeks between doses. No patient given a single dose responded. One of two patients given two doses and three of four patients administered three doses showed a clear response. In another study, Munro et alloo treated eight patients who had T. rubrum onychomycosis with terbinafine, 125 mg twice daily for 14 days. Seven of the eight patients showed marked improvement, with 80% of fingernails and 37% of toenails being clinically cured after 6 months. These studies suggest that provided no significant adverse effects occur, short courses of terbinafine therapy, 500 to 1000 mg daily, or even higher, may be possible.

Wong and ChoI5l determined the effectiveness of terbinafine therapy, 250 mg/d for 2 weeks, in 20 patients with fingernail onychomycosis. At the follow-up in 4 weeks' time, if the color and shape of the target nail were unchanged, a further 2 weeks of therapy was administered. A second course of therapy was given in 5 of the 20 patients. When seen in follow-up, 6 months after starting therapy, 13 (65%) of the 20 patients exhibited complete cure and 2 (10%) had only a mycologic cure. Patients with dermatophyte infections showed a better response (80%) compared with Cundidu onychomycosis (40%), suggesting that the pre- viously mentioned regimen may be an altema- tive treatment schedule for fingernail dermatophyte onychomycosis that merits further consideration.

Itraconazole

Itraconazole is a triazole with three nitrogen atoms in the five-membered azole ring. It was synthesized in 1980 and entered clinical trials in the early 1 9 8 0 ~ . ~ ~ Itraconazole (R- 51211) ( k )-cis-4-[4-[4-[4-[2-(2,4-dichlorophe- nyl)-2,(1H-1,2,4-triazol-l-ylmethyl) - 1,3-dioxo- lan-4-yl]methoxy]phenyl]-l-piperazinyl]phenyl]-2,4-dihydro-2-( l-methylpropyl)-3H-l,2,4- triazol-3-one has a molecular weight of 705.65. It is a weak base (pKa 3.7) and is

practically nonionized at physiologic pH. In contrast to the imidazoles such as miconazole and ketoconazole that contain two nitrogen atoms in the five-membered azole ring, the triazole ring may result in improved tissue penetration, prolonged serum half-life, and an increased specificity for fungal rather than mammalian enzymes.'57 Thus, compared with the azoles, the triazoles have increased efficacy with less toxicity.

Mechanism of Action

The azoles have a similar mode of action with the free azole nitrogen competing for oxygen at the catalytic heme iron atom of cytochrome P450 sites?, I4O The synthesis of ergosterol in the fungal cell membranes is impaired because of the inhibition of the enzyme 14-a-demethylase, which is cytochrome P450 dependent. The resultant decrease in ergosterol and accumulation of 14-a-methyl ste- rols manifests as a defective cell membrane with altered permeability and function. At higher concentrations, azoles may increase the saturation of fatty acids in the phospho- lipid bilayer, resulting in membrane-bound enzyme dysfunction.lY In contrast to ketoconazole, the triazoles have a higher affinity for fungal cytochrome P450 enzymes and bind only weakly to the mammalian cytochrome P450 enzyme system.57

Spectrum of Activity

Itraconazole has a broad spectrum of in vitro activity. When the brain-heart infusion broth is used, the majority of dermatophytes (Trichophyton spp., Microsporum spp., and Epidermophyton spp.) are sensitive to itraconazole less than or equal to 0.1 ~ . g / m L . ' ~ ~ With yeasts the range of MICs is wider, with the majority of isolates being sensitive to itraconazole, 0.001 to 10 kg/mL. Itraconazole also demonstrates in vitro activity against As- pergillus species (except Aspergillus niger) with a MIC less than or equal to 1 ~ g / m L . ~ ' , 13y

Using diagnostic sensitivity test agar medium, itraconazole is active against Mulussezia (pityrosporum) ovule with MICs 0.1 to 0.2 pg/ mL.&

It must be stressed that in vitro susceptibility testing of antifungal agents may lack in universally accepted guidelines and standard meth~dology.~~ Therefore, the MIC values for azoles may vary depending on the protocol used, and the results can vary widely.88, lo5

128 GUPTA et a1

In animal models, oral and topical itraconazole are effective against experimental infections induced by Trichophyton, Microsporurn, and Pityrosporurn 139 Itraconazole is also effective in animal models of vaginal candidiasis. Itraconazole may also be effective in some experimentally induced systemic mycoses: aspergillosis, cryptococcosis, sporotri- chosis, histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis.57

Pierard et alllo have compared the antifungal activity of itraconazole, 200 mg daily and twice daily, and terbinafine, 250 mg daily, using human stratum corneum ex vivo. Cya- noacrylate skin surface strippings (CSSS) were taken from the back and superficial der- matome skin samples (SDSS) were obtained from plantar skin. Spores or yeasts of selected fungi (7'. rubrum, 7'. rnentugrophytes, M . canis, and C. albicans) were deposited and cultured on the CSSS and SDSS. The 1-week fungal growth on CSSS and SDSS was assessed over time. Fungitoxic activity was also evaluated using 2-day cultures on CSSS followed by transfer to Sabouraud medium. Comparable antifungal activity against dermatophytes was observed for all three regimens. Itracona- zole, at both dosages, was significantly more active than terbinafine against C. ulbicans on CSSS and SDSS. Overall, itraconazole, 200 mg twice daily, appeared to be more fungitoxic than itraconazole, 200 mg/d, and terbinafine, 250 mg/d.

Pharmacokinetics in Nail and Plasma

In volunteers given itraconazole 100 mg/d, the drug could be measured at the distal end of the fingernail after 1 week of therapy.u This would suggest that itraconazole gets incorporated into the nail both via the nail matrix and the nail When itraconazole therapy is discontinued the drug remains at relatively unchanged concentrations in toenails for at least 6 months during the follow- up period, i.e., 9 months from the initiation of therapy.149 At this time, in patients receiving itraconazole (continuous) dosing, 200 mg/d, the mean level in toenails exceeded 600 ng/ g. In nails the MIC for dermatophytes and yeasts is approximately 100 ng/g and better therapeutic results are associated with itraconazole levels in nail exceeding 250 ng/g.32 Thus, the pharmacokinetic profile of itraconazole results in drug levels in the therapeutic range for several months following discontinuation of therapy. In fingernails, itraconazole

levels decline faster because of their more rapid growth rate.*49 Once itraconazole has become incorporated into the nail, the drug remains bound to the nail and does not repar- tition into the plasma. In contrast to nails, plasma levels decrease to an almost undetect- able value within 7 days.

When itraconazole is administered as pulse therapy, 200 mg twice daily for 1 week a month for 3 consecutive the itraconazole concentration in toenails exceeds the MIC,, value (100 ng/g) for dermatophytes and yeasts for approximately 9 months after completing three pulses of therapy. Itracona- zole therapy has also been associated with faster nail g r o ~ t h . 3 ~ For comparison, the normal nail growth for toenails is about 1.1 mm/m.13


Although onychomycosis may be treated with itraconazole using either pulse therapy", 35 or continuous regimen, the 1-week pulse concept is likely to become the pre- ferred treatment strategy not only for the treatment of onychomycosis but also for other dermatomycosis. Itraconazole pulse therapy (200 mg twice daily for 1 wk/mo for 3 consecutive months) is generally effective in the treatment of pedal onychomycosis with complete cure, marked improvement, and mycologic cure in 64%, 8870, and 64% patients, respectively, at follow-up 12 months after start of therapy.32 With itraconazole, 200 mg/ d (continuous), therapy given for 3 months for pedal onychomycosis the results from published studies are (meta-analytic average f standard error, 95% confidence interval): complete cure in 50 k 9% (319'0-68%), marked improvement in 85 +- 6% (73"/0-98"/.), and mycologic cure in 80 f 6% (69%-92%).3* 20, 66, lZ2, 149 Early studies with continuous dosing for 3 months were sometimes conducted using a subtherapeutic dosage of less than 200 mg/d4, 72, 89, *09, la5; these results may not be representative efficacy rates.

With itraconazole (continuous) dosing, 200 mg/d given for 6 weeks, to treat fingernail onychomycosis, the rates of complete cure, clinical response, and mycologic cure are 8l%, 969'0, and 90%, respectively, at follow- up 12 weeks after starting therapy.66*86 With fingernail onychomycosis, two pulses of itraconazole therapy are generally effective.

Ttraconazole is effective for the treatment of Candida onychomycosis.36, 72, 84 In six patients


(20 affected nails) with C. albicans fingemail infection in the absence of paronychia, itraconazole, 100 mg/d, given for a mean period of 5.9 months resulted in complete remission.” One patient relapsed at 5 months but responded to a further course of 3 months of therapy.

Onychomycosis associated with nondermatophyte molds may also respond well to itraconazole. De Doncker et a P used itraconazole (continuous) or pulse therapy to treat the molds Aspergillus spp., Fusarium spp., Scopulariopsis brevicaulis, and Alternaria spp., present either as a single mold or mixed etiology infection with a dermatophyte. With molds the clinical and mycologic cures were 88% in each case. In cases of mixed etiology the clinical and mycologic cure rates were 84% and 68%, respectively. In another instance Scher and BamettIZ7 successfully treated Aspergillus flavus onychomycosis with itraconazole, 100 mg/d, given for 5 months.

Fluconazole

Fluconazole (UK-49858) is a synthetic, orally active, broad-spectrum antifungal agent that became available for use in the United States early in 1990. The currently approved indications are vaginal candidiasis, oropharyngeal and esophageal candidiasis, and cryptococcal meningitis. The use of fluconazole for the treatment of dermatomycosis is currently an off-label indication in both the United States and Canada. Fluconazole is a bis-triazole with two triazole groups each containing three nitrogen atoms. Further- more, the two chlorine atoms in the 2 and 4 positions of the phenyl ring in ketoconazole are replaced in fluconazole by fluorine atoms. These changes have contributed to its lower lipophilicity and protein binding, decreased vulnerability to metabolism, increased specificity, and higher potency. Fluconazole has a hydroxyl group and a low molecular weight of 306.27 that makes it more water soluble than the other azoles. The formula is [2-(2,4,- difluorophenyl)l,3 - bis( lH-l,2,4-triazol-l-y1)- 2-propanol]).

Mechanism of Action

Fluconazole has a mechanism of action similar to the other azoles (see section on itraconazole). As with itraconazole, fluconazole is fungistatic in vitro. The triazoles have a

high affinity for the fungal cytochrome P450 enzymes but only a weak affinity for the mammalian P450 enzymes. In C. albicans the azoles inhibit transformation of blastospores into the invasive mycelium form.137

Spectrum of Action

In vitro testing may not be a reliable indicator of clinical response because the test results can vary depending on the methodology used. Use of the broth macrodilution and mi- crodilution assay systems may produce results that more accurately predict the in vivo response.%, lo8 Fluconazole has demonstrated activity against C. albicans, C. tropicalis, and C. pavapsilosis (MIC,, 5 5 p,g/mL). Flucona- zole was noted to have variable activity against C. glabvata ~ t o ~ ~ l o p ~ i ~ ) ~ ~ ~ and resistance to C. k r ~ s e i . ~ ~ In a defined medium the geo- metric mean MIC of fluconazole for most Candida species lies between 0.5 and 1.5 pg/ mL.50 For the Trichophyton species commonly encountered in dermatology-T. rubrum, T. mentagrophytes, and T. tonsurans-the MIC range is 12.5 to 100 pg/mL.SO With Aspergillus species the MIC is greater than 100 pg/rnL.%

In vivo studies in both immunocompetent and immunodeficient animal models suggest that fluconazole is able to reduce fungal bur- den in tissues and improve survival in infections caused by Candida (primarily C. albicans), Crypfococcus, and Histoplasma species, but not C. krusei and A. f l a z ~ u s . ~ ~ , 144 In a guinea pig model of dermatophytosis, fluconazole produced a dose-dependent decrease of T. mentagrophytes with complete cure in 10 days using a dose of 10 mg/kg/d.*17 T. rubrum and M . canis were also sensitive to fluconazole in this model. The issue of resistance of Candida species to fluconazole has been reviewed by Rex et a1.116

Pharmacokinetics in Nails and Plasma

The plasma half-life of fluconazole is approximately 30 hours. The drug reaches a steady state in about a week at plasma concentrations that are approximately 2.5 times that following a single dose. Seven hours following the administration of a single capsule of fluconazole, 200 mg, the levels in plasma and stratum comeum were 3 p.g/mL and 98 pg/g, After receiving fluconazole, 200 mg/d for 5 days, the levels in the plasma and stratum comeum were 10 kg/mL and 127 pg/g, respectively. The elim-

130 GUPTA et a1

ination of fluconazole from the stratum corneum occurs with a half-life of approximately 60 to 90 hours, which is two to three times slower than the elimination from plasma. Flu- conazole lies in a borderline hydrophobic/ hydrophillic region in contrast to the highly lipophilic itraconazole. In another study, patients received fluconazole, 50 mg/d for 14 days.71 On day 1 the levels in nails, skin, and plasma were 1.31 pg/g, 11.7 pg/g, and 0.76 pg/mL, respectively. By day 14 the levels in these three tissues were 1.80 pg/g, 24.16 pg/ g, and 2.12 pg/mL, respectively. This suggests that fluconazole reaches the nail plate via both the nail bed and nail matrix. In the study by Wildfeuer et al,14* fluconazole, 0.3 to 0.5 pg/mL, was detected in the toenail 4 to 5 months following a regimen of 200 mg/d for 5 days. For comparison, the in vitro MIC of fluconazole for T. rubrum and T. mentagrophytes is 7 and 28 pg/mL, respectively. When fluconazole, 150 mg once weekly, is given for approximately 6 months, the drug has been detected in nail 6 months after discontinuing the medication.43, 51 The peak levels in nail and at 3 and 6 months follow-up off therapy were 8.5 pg/g, 1.7 pg/g, and 1.4 pg/g, respectively. This suggests that shorter dura- tions of therapy may be possible.


Compared with itraconazole and terbinafine, currently there are fewer published studies that have investigated the efficacy of fluconazole in the management of onychomycosis.5, 26, 43, 51, 78, 90, 99, 102, 131 K uokkanen and Alava90 treated 20 patients (46 affected nails) who had T. rubrum infection with fluconazole, 150 mg once weekly. At the beginning of therapy patients had chemical nail removal using 40% urea ointment and the nails were filed on approximately four occasions at approximately 2-month intervals. Furthermore, patients were instructed to use sandpaper files at home. The mean duration of fluconazole therapy was 9.3 months, with all fingernails and 92% of toenails being clinically and mycologically free of infection at the end of treatment. At follow-up 6 months later, the cure rate in the fingernails and toenails was 100% and 83%, respectively.

Fraki et al5I treated onychomycosis with fluconazole, 150 mg once weekly, for 5 to 12 (mean, 9.3) months. At the last follow-up visit, 6 months following discontinuation of therapy, cure was observed in 54% patients,

marked improvement in 77%, and mycologic cure in 76% patients. Clinical cure rates were enhanced by urea nail pedicure, used by approximately half the patients. This adjunctive therapy, however, did not result in a significant difference in the total clinical response and relapse rates.

Montero-Gei et a199 treated onychomycosis with fluconazole, 150 mg/wk, for 3 to 12 months. At the end of follow-up, 6 months after stopping therapy, the clinical cure, clinical response (cure plus marked improvement), and mycologic cure were 72%, 87%, and 79%, respectively, with a relapse rate of 11%.

Fluconazole has also been shown to be effective in Candida onychomycosis5~ 131 and some molds (Bipolaris species and ~ ~ o ~ o ~ o r u 2 ~ ru bra). 131

COMPARATIVE STUDIES IN THE TREATMENT OF ONYCHOMYCOSIS

There are two published studies comparing the efficacy of itraconazole (continuous) therapy, 200 mg/d, with terbinafine, 250 mg/d, each given for 3 months in the treatment of pedal onychomycosis.3~ 2o In one reportz0 terbinafine was the more effective agent, whereas in the other3 the two antifungal agents had similar efficacies.

In comparative studies, terbinafine has been more effective than griseofulvin in the treatment of pedal onychomycosis42~ 79 and fingernail onychomycosis.67

The newer antifungal agents appear to be much more effective than griseofulvin in the treatment of onychomycosis. For terbinafine and itraconazole it is interesting to observe the wide and overlapping range of cure rates and clinical responses reported in the various studies. It is therefore possible that the choice of drug for the treatment of onychomycosis in a given patient may also depend on several other factors such as dosage schedule, adverse-effects profile, sensitivity of drug to organism(s) isolated, concomitant medical conditions, concurrent drugs, cost-effectiveness and availability of comparative treatments, and physician and patient preferences.

SUMMARY

Until recently pedal onychomycosis, particularly when it affected several nails or in-


volved a large nail plate area, was often re- garded as untreatable. The advent of new therapies such as itraconazole, terbinafine, and fluconazole has been a significant and welcome addition to the armamentarium of therapies at the disposal of the physician. These drugs appear in the nail plate within days of starting oral therapy, being taken up by both the nail matrix and the nail bed. The duration required for effective therapy has been reduced, while the efficacy rates and cost-effectiveness have increased compared with the older treatments, such as griseofulvin. Some of the newer agents appear to have a wider spectrum of activity. Thus far, the newer agents have exhibited a low risk to benefit ratio. It may be possible to combine oral therapies with topical and surgical treatments, thereby further increasing efficacy rates and the cost-effectiveness while decreas- ing adverse effects and duration of oral therapy.

References

1. Abrams BB, Hanel H, Hoehler T: Ciclopirox olamine: A hydroxypyridone antifungal agent. Clin Dermatol9:471-477, 1991

2. Apfelberg DB, Rothermel E, Widtfeldt A Prelimi- nary report on use of carbon dioxide laser in podia- try. J Am Podiatr Med Assoc 74:509-513, 1984

3. Arenas R, Dominguez-Cherit J, Femhdez LM: Open randomized comparison of itraconazole versus terbinafine in onychomycosis. Int J Dermatol

4. Arenas R, Femandez G, Dominguez L Onycho- mycosis treated with itraconazole or griseofulvin alone with and without a topical antimycotic or keratolytic agent. Int J Dermatol30:586-589, 1991

5. Assaf RR. Elewski BE: Intermittent fluconazole dos-

34138-143,1993

6.

7.

8.

9.

10.

11.

12.

ing in patients with onychomycosis: Results of a pilot study. J Am Acad Dermatol35:216-219, 1996 Baden HI': Treatment of distal onychomycosis with avulsion and topical antifungal agents under occlusion. Arch Dermatol 130558-559, 1994 Baden HP, Kubiius J: A comparative study of the immunologic properties of hoof and nail fibrous proteins. J Invest Dermatol 83:327, 1984 Bagatell F K Topical therapy for onychomycosis. Arch Dermatol 113:378, 1977 Bailey EM, Krakovsky DJ, Rybak MJ: The triazole antifungal agents: A review of itraconazole and fluconazole. Pharmacotherapy 10:146-153, 1990 Balfour JA, Faulds D: Terbinafine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drugs 43:259-284, 1992 Baran R: Amorolfine nail lacquer: A new transun- gual delivery system for nail mycoses. JAMA South- east Asia Supplement 9:5-6, 1993 Baran R, DeDoncker P: Lateral edge nail involvement indicates poor prognosis for treating onycho-

mycosis with the new systemic antifungals. Acta Derm Venereol, 76:82-93, 1996

13. Baran R, Dawber RPR Investigations and some physiochemical properties of nails. In Baran R, Dawber RPR (eds): Diseases of the Nails and Their Management. Oxford, Blackwell, 1984, pp 81-104

14. Baran R, Hay RJ: Partial surgical avulsion of the nail in onychomycosis. Clin Exp Dermatol 10:413- 418, 1985

15. Baudraz-Rosselet F, Rakosi T, Wili PB, et al: Treat-

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

ment of onychomycosis with terbinafine. Br J Der- matol 126:40-46, 1992 Bentley-Phillips B: The treatment of onychomycosis with miconazole tincture. South Afr Med J 62:57- 58, 1981 Bemey D, Schuh K: 125. Heterocyclic spiro-naph- thalenones Part 1: Synthesis and reactions of some spiro [(l H-naphthalenome)I-l,3,-piperidines. Helv Chir Acta 61:1262-1273, 1978 Birnbaum JE: Pharmacology of the allylamines. J Am Acad Dermatol 23:782-785, 1990 Borgers M, Van den Bossche H: The mode of action of antifungal drugs. In Levine HB (ed): Ketocona- zole in the management of fungal disease. New York, Adis Press, 1982, pp 2547 Brautigam M, Nolting S, Schopf RE, et al: Ran- domised double blind comparison of terbinafine and itraconazole for treatment of toenail tinea infection. BMJ 311:919-922, 1995 Buck D, Nidorf D, Addino J: Comparison of two topical preparations for the treatment of onychomycosis: Meluleucu ulternifoliu (tea tree) oil and clotrimazole. J Fam Pract 38:601405, 1994 Buselmeier TJ: Combination urea and salicylic acid ointment nail avulsion in nondystrophic nails: A follow-up observation. Cutis 25:397, 405, 1980 Cauwenbergh G, Degreef H, Heykants J, et a1 Phar- macokinetic profile of orally administered itraconazole in human skin. J Am Acad Dermatol 18:263- 268, 1988 Ceschin-Roques CG, Hanel H, Pruja-Bougaret SM, et a1 Ciclopiroxolamine cream 1%: In vitro and in vivo penetration into the stratum corneum. Skin Pharmacol495-99, 1991 Clayton YM: In vitro activity of terbinafine. Clin Exp Dermatol 14101-103, 1989 Coldiron B Recalcitrant onychomycosis of the toenails successfully treated with fluconazole. Arch Dermatol 128:909-910, 1992 Cribier B, Grosshans E: Efficacite et tolQance de la terbinafine (Lamisil) dans une skrie de 50 onychomycoses a dermatophytes. Ann Dermatol Venereol 121:15-20, 1994 Dabrowa N, Landau JW, Newcomer VD: Antifungal activity of glutaraldehyde in vitro. Arch Dermatol 1053555557, 1972 Dawber RPR The ultrastructure and growth of human nails. Arch Dermatol Res 269:197-204, 1980 Dawber RPR, DeBerker DAR, Baran R Science of the nail apparatus. In Baran R (ed): Diseases of the nails and their management. Osney Mead, Oxford, Blackwell, 1994, pp 1-34 De Doncker P: Pharmacokinetics of onychomycosis. In Jacobs PH, Nall L (eds): Fungal Disease: Biology, [mmunology & Diagnosis. New York, Marcel Dek- ker, 1996 De Doncker P, Decroix J, Pierard GE, et al: Antifun- gal pulse therapy for onychomycosis. Arch Derma- to1 132:3441, 1996

132 GUPTA et a1

33. De Doncker P, Pierard GE: Acquired nail beading in patients receiving itraconazole-An indicator of faster nail growth? A study using optical profi- lometry. Clin Exp Dermatol 19:404-406,1994

34. De Doncker P, Scher R, Baran R, et a1 Efficacy of itraconazole in the treatment of nondermatophyte onychomycosis of the toenail. J Am Acad Dermatol, in press

35. De Doncker P, Van Lint J, Dockx P, et a1 Pulse therapy with one-week itraconazole monthly for three or four months in the treatment of onychomycosis. Cutis 56180-183, 1995

36. De Padova-Elder SM, Ditre CM, Kantor GR, et al: Candidiasis endocrinopathy syndrome. Arch Der- matol 130:19-22, 1994

37. Dermoumi H In vitro susceptibility of fungal isolates of clinically important specimens to itraconazole, fluconazole, and amphotericin 8. Chemother- apy (Basel) 40:92-98, 1994

38. Dompmartin D, Dompmartin A, Deluol AM, et al: Onychomycosis and AIDS Treatment with topical ciclopirox olamine. Int J Dermatol 29233, 1990

39. Elewski BE: Onychomycosis. Fitzpatrick’s Journal of Clinical Dermatology 1:48-54, 1994

40. English MD. Trichophyton rubrum infection in families. BMJ 1:744-746, 1957

41. Espinel-Ingroff A, Shadomy S, Gebhart RJ: In vitro studies with R 51,211 (Itraconazole). Antimicrob Agents Chemother 2659,1984

42. Faergemann J, Anderson C, Hersle K, et al: Double- blind, parallel-group comparison of terbinafine and griseofulvin in the treatment of toenail onychomycosis. J Am Acad Dermatol32750-753, 1995

43. Faergemann J, Laufen H: Levels of fluconazole in normal and diseased nails during and after treatment of onychomycoses in toenails with fluconazole 150 mg once weekly. In press, 1996

44. Faergemann J, Swanbeck G: Treatment of onychomycosis with a propylene glycol-urea-lactic acid solution. Mycoses 32536-539, 1989

45. Faergemann J, Zehender H, Millerioux L Levels of terbinafine in plasma, stratum corneum, dermis- epidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once daily for 7 and 14 days. Clin Exp Dermatol

46. Faergemann J: Activity of triazole derivatives against Pityrosporum orbiculare in vitro and in vivo. Ann New York Acad Sci 544:348-353, 1988

47. Farber EM, South DA: Urea ointment in the nonsurgical avulsion of nail dystrophies. Cutis 22689- 692, 1978

48. Feuilhade M, Baran R, Goettmann S, et a1 Interest of the combination of 5% amorolfine nail lacquer plus terbinafine tablet in the treatment of foot dermatophyte onychomycosis with involved matrix. J Eur Acad Dermatol Venereol 5:S93, 1995

49. Finlay AY, Lever L, Thomas R, et al: Nail matrix kinetics of oral terbinafine in onychomycosis and normal nails. J Dermatol Treat 1:51-53, 1990

50. Fluconazole product monograph. Pfizer Canada, Inc., September 1995

51. Fraki J, Heikkila H, Kero M, et a1 A noncomparative study of the efficacy and safety of fluconazole in the treatment of onychomycosis. J Am Acad Derma- tol, in press, 1996

52. Franz TJ: Percutaneous absorption: On the relevance of in-vitro data. J Invest Dermatol 64:190-195, 1975

53. Galgioni J N Antifungal susceptibility tests. Antimi- crob Agents Chemother 31:1867-1870, 1987

19~121-126, 1994

54. Goa KL, Barradell LB Fluconazole: An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs 50658-690, 1995

55. Goldsmith S: Vitamin E and onychomycosis. J Am Acad Dermatol8:910-911, 1983

56. Goodfield MJD Short-duration therapy with terbinafine for dermatophyte onychomycosis: A multi- centre trial. Br J Dermatol 126:33-35, 1992

57. Grant SM, Clissold SP: Itraconazole: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 37310-344,1989

58. Graybill JR Future directions of antifungal chemotherapy. Clin Infect Dis 145170-181, 1992

59. Gupta AK Amorolfine: An overview. Drugs of To- day 31:145-153, 1995

60. Gupta AK, Sauder DN, Shear NH: Antifungal agents: An overview. Part I. J Am Acad Dermatol 30677498, 1994

61. Gupta AK, Sauder DN, Shear N H Antifungal agents: An overview. Part 11. J Am Acad Dermatol

62. Gupta AK, Shear N H Terbinafine in the treatment of superficial dermatomycoses. Can J Derm 6:561- 565, 1994

63. Gupta AK, Shear NH: Onychomycosis-going for cure. Can Fam Physician, in press, 1996

64. Gupta AK, Shear NH, Sauder DN: New antifungal agents. Curr @in Dermatol2200-206, 1993

65. Gupta AK, Sibbald RG, Lynde CW, et al: A survey and treatment of onychomycosis in children. J Am Acad Dermatol, in press

66. Haneke E, Delescluse J, Plinck EPB, et al: The use of itraconazole in onychomycosis. Eur J Dermatol

67. Haneke E, Tausch I, Brautigam M, et a1 Short- duration treatment of fingernail dermatophytosis: A randomized, double-blind study with terbinafine and griseofulvin. J Am Acad Dermatol 3272-77, 1995

68. Haria M, Bryson H M Amorolfine: A review of its pharmacological properties and therapeutic potential in the treatment of onychomycosis and other superficial fungal infections. Drugs 49:103-120, 1995

69. Hay RJ, Clayton YM, Moore MK A comparison of tioconazole 28% nail solution versus base as an adjunct to oral griseofulvin in patients with onychomycosis. Clin Exp Dermatol 1217.5177, 1986

70. Hay RJ: Onychomycosis: Agents of choice. Dermatol

71. Hay RJ: Pharmacokinetic evaluation of fluconazole in skin and nails. Int J Dermatol31:6-7, 1992

72. Hay RJ, Clayton YM, Moore MK, et al: An evaluation of itraconazole in the management of onychomycosis. Br J Dermatol 119:359-366, 1988

73. Hay RJ, Mackie RM, Clayton YM Tioconazole nail solution-an open study of its efficacy in onychomycosis. Clin Exp Dermatol 1O:lll-115, 1985

74. Hay RJ: Treatment of dermatomycoses and onychomycoses-state of the art. Clin Exp Dermatol

75. Hay RJ, Roberts DT, Doherty VR, et al: The topical treatment of onychomycosis using a new combined urea/imidazole preparation. Clin Exp Dermatol 13:164-167, 1988

76. Heeres J, Backx LJJ, Van Custem J: Antimycotic azoles. 7. Synthesis and antifungal properties of a

30:911-933, 1994

6:7-10, 1996

Clin 11:161-169, 1993

17(S~ppl 1):2-5, 1992


series of novel triazol-3-ones. J Med Chem 27894- 900, 1984

77. Hettinger D, Valinsky M: Treatment of onychomycosis with nail avulsion and topical ketoconazole. J Am Podiatr Med Assoc 81:28-32, 1991

78. Hochman LG, Scher RK, Meyerson MS, et al: The safety and efficacy of oral fluconazole in the treatment of onychomycosis. J Geriatr Dermatol 1:169- 172, 1993

79. Hofmann H, Brautigam M, Weidinger G, et al: Treatment of toenail onychomycosis: A randomized, double-blind study with terbinafine and griseofulvin. Arch Dermatol 131:919-922, 1995

80. Ishii M, Hamada T, Asai Y: Treatment of onychomycosis by ODT therapy with 20% urea ointment and 2% tolnaftate ointment. Dermatologica 167:273- 279, 1983

81. Jevons S, Gymer GE, Brammer KW, et al: Antifungal activity of tioconazole (UK-20349), a new imidazole derivative. Antimicrob Agents Chemother 15:597- 602, 1979

82. Johnson M, Comaish JS, Shuster S Nail is produced by the normal nail bed: A controversy resolved. Br J Dermatol 12527-29, 1991

83. Johnson M, Shuster S: Determinants of nail thick- ness and length. Br J Dermatol 130195-198, 1994

84. Kagawa S: A clinical evaluation of itraconazole, a new oral antifungal agent, in the treatment of tinea unguium, candida onychomycosis and candida onychia/paronychia. The Clinical Report 25433- 448, 1991

85. Karyotakis NC, Anaissie EJ, Hachem R, et al: Com- parison of the efficacy of polyenes and triazoles against hematogenous Candida krusei infection in neutropenic mice. J Infect Dis 168:1311-1313, 1993

86. Kim JA, Ahn KJ, Kjm JM, et al: Efficacy and tolerability of itraconazole in patients with fingemail onychomycosis: A 6-week pilot study. Curr Ther Res 56:1066-1075, 1995

87. Klaschka F: Treatment of onychomycosis with naftifine gel. Mycosen 3O(Suppl 1):119-123, 1987

88. Kobayashi GS, Spitzer E D Testing of organisms for susceptibility to triazoles: Is it justified. Eur J Clin Microbiol Infect Dis 8:387-389, 1989

89. Korting HC, Schafer-Korting M, Zienicke H, et al: Treatment of tinea unguium with medium and high doses of ultramicrosize griseofulvin compared with that with itraconazole. Antimicrob Agents Chemo- ther 372064-2068, 1993

90. Kuokkanen K, Alava S Fluconazole in the treatment of onychomycosis caused by dermatophytes. J Der- matol Treat 3:115-117, 1992

91. Lauharanta J: Comparative efficacy and safety of amorolfine nail lacquer 2% versus 5% once weekly. Clin Exp Dermatol 17(Suppl 1): 41-43, 1992

92. Lauharanta J, Zaug M, Polak A, et al: Combination of amorolfine with griseofulvin: In vitro activity and clinical results in onychomycosis. JAMA Southeast Asia Supplement 9:2%27, 1993

93. Lesher J L New antifungal agents. Dermatol Clin 10:799-805, 1992

94. Lynch MH, OGuin WM, Hardy C, et al: Acidic and basic hair/nail ("hard") keratins: Their colocaliza- tion in upper cortical and cuticle cells of the human hair follicle and their relationship to "soft" keratins. J Cell Biol 103:2593, 1986

95. Matthieu L, De Doncker P, Cauwenbergh G, et al: Itraconazole penetrates the nail via the nail matrix and the nail bed-An investigation in onychomycosis. Clin Exp Dermatol 16:37&376, 1991

96. Meyerson MS, Scher RK, Hochman LG, et al: Open- label study of the safety and efficacy of naftifine hydrochloride 1 percent gel in patients with distal subungual onychomycosis of the fingers. Cutis 51:205-207, 1993

97. Meyerson MS, Scher RK, Hochman LG, et al: Open- label study of the safety and efficacy of fungoid tincture in patients with distal subungual onychomycosis of the toes. Cutis 49:359-362,1992

98. Montana JB, Scher RK: A double-blind, vehicle-controlled study of the safety and efficacy of fungoid tincture in patients with distal subungual onychomycosis of the toes. Cutis 53:313-316, 1994

99. Montero-Gei F, Robles-Soto M, Schlager H: Flucora- zole in the treatment of severe onychomycosis. Int J Dermatol 35:587-588, 1996

100. Munro CS, Rees JL, Shuster S The unexpectedly rapid response of fungal nail infection to short duration therapy. Acta Derm Venereol 72131-133, 1992

101. Munro CS, Shuster S: The route of rapid access of drugs to the distal nail plate. Acta Derm Venereol

102. Nahass GT, Sisto M. Onychomycosis: successful treatment with once-weekly fluconazole. Dermatol- ogy 18659-61,1993

103. Nolting S: Non-traumatic removal of the nail and simultaneous treatment of onychomycosis. Derma- tologica 169:117-120, 1984

104. Nolting S, Brautigam M, Weidinger G: Terbinafine in onychomycosis with involvement by non-derma- tophytic fungi. Br J Dermatol 130:16-21, 1994

105. Odds FC: Antifungal susceptibility testing of Can- dida spp. by relative growth measurement at single concentrations of antifungal agents. Antimicrob Agents Chemother 36:1727-1737, 1992

106. Petranyi G, Meingassner JG, Mieth H. Antifungal activity of the allylamine derivative terbinafine in vitro. Antimicrob Agents Chemother 31:1365-1368, 1987

107. Petranyi G, Meingassner JG, Mieth H Activity of terbinafine in experimental fungal infections of laboratory animals. Antimicrob Agents Chemother 31:1558-1561, 1987

108. Pfaller MA, Grant C, Morthland V, et al: Compara- tive evaluation of alternative methods for broth di- lution susceptibility testing of fluconazole against Candida albicans. J Clin Microbiol 32:506-509, 1994

109. Piepponen T, et al: Efficacy and safety of itraconazole in the long-term treatment of onychomycosis. J Antimicrob Chemother 29:195-205, 1992

110. PiCrard GE, Arrese JE, De Doncker P: Antifungal activity of itraconazole and terbinafine in human stratum comeum: A comparative study. J Am Acad Dermatol 32:429-435, 1995

111. Polak AM: Preclinical data and mode of action of amorolfine. Clin Exp Dermatol 17(Suppl 1):&12, 1992

112. Polak A: Kinetics of amorolfine in human nails. Mycoses 36:lOl-103, 1993

113. Polak A, Dixon DM: Antifungal activity of amorolfine (Ro14-4767/002) in vitro and in vivo. In Fromt- ling RA (ed): Recent Trends ~ I I the Discovery, Devel- opment and Evaluation of Antifungal Agents. Barcelona, J.R. Prous Science Publishers, 1987, pp 555-573

114. Qadripur VSA, Horn G, Hohler T Zur lokalwirk- samkeit von ciclopiroxolamin bei nagelmykosen. Drug Res 31:1369-1372,1981

72:387-388, 1992

134 GUPTA et a1

115. Reinel D, Clarke C: Comparative efficacy and safety of amorolfine nail lacquer 5% in onychomycosis, once-weekly versus twice-weekly. Clin Exp Derma- to1 17(Suppl 1):44-49, 1992

116. Rex JH, Rinaldi MG, Pfaller M A Resistance of candida species to fluconazole. Antimicrob Agents Che- mother 39A-8, 1995

117. Richardson K, Brammer KW, Marriott MS, et al: Activity of UK-49, 858, a bis-triazole derivative, against experimental infections with Candida albicans and Trichophyton mentagrophytes. Antimicrob Agents Chemother 27832435, 1985

118. Roberts DT, Richardson MD, Dwyer PK, et a1 Terbinafine in chronic paronychia and Candida onychomycosis. J Dermatol Treat 3:39-42, 1992

119. Rollman 0: Treatment of onychomycosis by partial nail avulsion and topical miconazole. Dermatologica 165:5441, 1982

120. Rollman 0, Johansson S Hendersonula toruloidea infection: Successful response of onychomycosis to nail avulsion and topical ciclopiroxolamine. Acta Derm Venereol67506-510,1987

121. Roncari G, Ponelle C, Zumbrunnen R Percutaneous absorption of amorolfine following a single topical application of an amorolfine cream formulation. Clin Exp Dermatol 1733-36, 1992

122. Roseeuw D, De Doncker P: New approaches to the treatment of onychomycosis. J Am Acad Dermatol

123. Rothermel E, Apfelberg DB Carbon dioxide laser use for certain diseases of the toenails. Clin Podiatr Med Surg 4:809-821, 1987

124. Ryder NS: Specific inhibition of fungal sterol biosynthesis by SF 86-327, a new allylamine antimycotic agent. Antimicrob Agents Chemother 27297- 300, 1985

125. Ryder N S Terbinafine: Mode of action and properties of the squalene epoxidase inhibition. Br J Der- matol 126(Suppl 39):Z-7, 1992

126. Ryder NS, Dupont M-C: Inhibition of squalene epoxidase by allylamine antimycotic compounds. Biochem J 230765-770,1985

127. Scher RK, Barnett JM: Successful treatment of Asper- gillus f l a w s onychomycosis with oral itraconazole. J Am Acad Dermatol 23:749-750, 1990

128. Schmitt HJ, Andrade J, Edwards F, et al: Inactivity of terbinafme in a rat model of pulmonary aspergillosis. Eur J Clin Microbiol Infect Dis 993324335, 1990

129. Shear NH, Gupta AK Terbinafine for the treatment of pedal onychomycosis: A foot closer to the prom- ised land of cured nails. Arch Dermatol 131:937- 942, 1995

130. Shuster S, Munro C: Single dose treatment of fungal nail disease. Lancet 339:1066, 1992

131. Smith SW, Sealy DP, Schneider E, et al: An evaluation of the safety and efficacy of fluconazole in the treatment of onychomycosis. South Med J 88:1217- 1220, 1995

132. South DA, Farber EM: Urea ointment in the nonsurgical avulsion of nail dystrophies-A reappraisal. Cutis 25:609-612, 1980

133. Stutz A: Synthesis and structure-activity correla- tions within allylamine antimycotics. Ann NY Acad Sci 544:4&62, 1988

134. Suringa DWR Treatment of superficial onychomycosis with topically applied glutaraldehyde. Arch Dermatol 102163-167, 1970

135. Torres-Rodriguez JM, Madrenys N, Nicolas MC: Non-traumatic topical treatment of onychomycosis

29:S45-550, 1993

with urea associated with bifonazole. Mycoses

136. Ulbricht H, Worz K Therapy of onychomycosis due to moulds with ciclopirox nail lacquer. Mycoses 3797-100, 1994

137. Drug information for the health care professional. Taunton, MA, Rand McNally, 1996, p 300

138. Van Cutsem J: Oral, topical and parenteral antifungal treatment with itraconazole in normal and in immunocompromised animals. Mycoses 32(Suppl 1):14-34, 1989

139. Van Cutsem J, Van Gerven F, Janssen PAJ: Activity of orally, topically, and parenterally administered itraconazole in the treatment of superficial and deep mycoses: Animal models. Rev Infect Dis 9:515-S32, 1987

140. Vanden Bossche H, Marichal P, Gorrens J, et a1 Biochemical approaches to selective antifungal activity. Focus on azole antifungals. Mycoses 3235- 52, 1989

141. Van Der Schroeff JG, Cirkel PKS, Crijns MB, et al: A randomized treatment duration-finding study of terbinafine in onychomycosis. Br J Dermatol 126:36- 39, 1992

142. Villars V, Jones TC: Clinical efficacy and tolerability of terbinafine (Lamisi1)-A new topical and systemic fungicidal drug for treatment of dermatomycoses. Clin Exp Dermatol 14124-127, 1989

143. Villars W, Jones TC: Special features of the clinical use of oral terbinafine in the treatment of fungal diseases. Br J Dermatol 126:6149, 1992

144. Walsh TJ, Aoki S, Mechinaud F, et al: Effects of preventive early and late antifungal chemotherapy with fluconazole in different granulocytopenic models of experimental disseminated candidiasis. J In- fect Dis 161:755-760, 1990

145. Walsoe I, Stangerup M, Svejgaard E: Itraconazole in onychomycosis: Open and double-blind studies. Acta Derm Venereol 70:137-140, 1990

146. Weuta V H Clotrimazol-creme und -1osung-klin- ische priifung im offenen versuch. Drug Res 221295-1299, 1972

147. White MI, Clayton YM: The treatment of fungus and yeast infections of nails by the method of chemical removal. Clin Exp Dermatol 7273-276, 1982

148. Wildfeuer A, Faergemann J, Laufen H, et al: Bio- availability of fluconazole in the skin after oral medication. Mycoses 37127-130, 1994

149. Willemsen M, De Doncker P, Willems J, et al: Post treatment itraconazole levels in the nail. J Am Acad Dermatol26:731-735, 1992

150. Wingard JR, Merz WG, Rinaldi MG, et al: Associa- tion of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients. Antimicrob Agents Chemother 371847- 1849, 1993

151. Wong CK, Cho YL Very short duration therapy with oral terbinafine for fingernail onychomycosis. Br J Dermatol 133:329-347, 1995

152. Wu YC, Chuan MT, Lii YC: Efficacy of ciclopiroxolamine 1% cream in onychomycosis and tinea pedis. Mycoses 34:93-95, 1991

153. Zaias N: Management of onychomycosis with oral terbinafine. J Am Acad Dermatol 23:810-812, 1990

154. Zaias N, Tosti A, Rebel1 G, et al: Autosomal domi- nant pattern of distal subungual onychomycosis caused by Trichophyton rubrum. J Am Acad Derma-

155. Zaug M, Bergstraesser M. Amorolfine in the treat-

34:499-504, 1991

to1 34302-304, 1996


ment of onychomycoses and dermatomycoses (an overview). Clin Exp Dermatol 1761-70, 1992

156. Zehender H, Denouel J, Faergemann J, et al: Elimi- nation kinetics of terbinafme from human plasma and tissues following multiple-dose administration,

and comparison with 3 main metabolites. Drug In- vest 8:203-210, 1994

157. Zuckerman JM, Tunkel AR Itraconazole: A new triazole antifungal agent. Infect Control 15:397410, 1994

Address reprint requests to Aditya K. Gupta, MD, FRCP(C)

490 Wonderland Road South Suite 6

London, Ontario N6K 1L6

CANADA

Documents

CURRENT MANAGEMENT OF ONYCHOMYCOSIS