SUPPORTED BY AN EDUCATIONAL GRANT FROM PFIZER INC
`
`Onychomycosis" therapeutic update
`
`Richard K. Scher, MD New York, New York
`
`Onychomycosis is a common disease of the nail unit caused by dermatophytes, yeasts, and
`molds. In more than 80% of cases, onychomycosis is caused by the dermatophytes
`Trichophyton rubrum and Trichophyton mentagrophytes. The prevalence of onychomyco-
`sis in the world’s population is 2% to 18% or higher and accounts for approximately 50%
`of all nail disorders. Until recently, available therapies were inadequate because of low
`cure rates, high relapse rates, and often dangerous side effects. An increased understand-
`ing of nail pharmacokinetics has led to the development of safer, more effective systemic
`therapies for onychomycosis, such as itraconazole, fluconazole, and terbinafine. These
`new oral antifungal agents allow shorter periods of treatment, provide rapid efficacy, and
`may improve patient compliance and attitudes regarding therapy. Treatment selection will
`depend on several factors, including appropriate spectrum of activity, adverse effects, and
`potential drug interactions plus patient preferences for specific dosing regimens. (J Am
`Acad Dermatol 1999;40:$21-6.)
`
`Onychomycosis is a common fungal infection
`of 1 or more components of the nail unit.1
`Although the exact prevalence is unknown, ony-
`chomycosis accounts for up to 50% of all nail dis-
`ease and affects 2% to 18% or more of the world’s
`population.2-4 The incidence of onychomycosis
`increases with age, and some studies suggest that
`up to 48% of the population may be affected by
`age 70 years.1 Toenail infection is several times
`more common than fingernail infection and is gen-
`erally more difficult to treat because of the slow
`rate of toenail growth.1
`In the United States and other developed coun-
`tries, the incidence of onychomycosis may have
`increased dramatically in recent years. This is like-
`ly the result of such factors as the aging of the pop-
`ulation, possible higher incidence of diabetes mel-
`litus, greater use ofimmunosuppressive and antibi-
`otic agents, increased exposure to infecting
`organisms, and the acquired immunodeficiency
`syndrome epidemic),2
`
`From the Department of Dermatology, Columbia-Presbyterian
`Medical Center, New York, New York.
`This work was supported by a research grant from Pfizer Inc. The
`author has also served as an investigator, consultant, and a speak-
`er for Novartis, Pfizer, and Janssen. CMD, Inc. assisted in the writ-
`ing of this article.
`Reprint requests: Richard K. Scher, MD, Department of Dermatology,
`Columbia-Presbyterian Medical Center, 161 Fort Washington Ave,
`Room 750, NewYork, NY 10032.
`Copyright © 1999 by the American Academy of Dermatology, Inc.
`0190-9622/99/$8.00 + 0 16/0/98108
`
`Table I. Principal causes of onychomycosis
`
`Dermatophytes
`T rubrum
`T mentagrophytes
`Epidermophyton floccosum
`Nondermatophytes
`Acremonium
`Aspergillus
`Onychocola canadensis
`S brevicauHs
`Scytalidium dimidiatum
`S hyalinum
`Yeasts
`C albicans
`
`From Elewsld BE, Charif MA, Daniel CR III. Onychomycosis. In:
`Scher RK, Daniel CR III, editors. Nails: diagnosis, treatment,
`surgery. 2nd ed. Philadelphia: WB Saunders, 1997. p. 151-62. By
`permission.
`
`In more than 80% of cases, onychomycosis is
`caused by the dermatophytes Trichophyton
`rubrum and T mentagrophytes and is then referred
`to as tinea unguium.2 Yeasts are responsible for
`between 5% and 17% of cases of onychomycosis,
`and in over 70% of these cases Candida albicans
`is the infecting organism. The nondermatophyte
`molds Scopulariopsis, Scytalidium, Acremonium,
`Aspergillus, and Fusarium cause approximately
`3% to 5% of fungal nail disease (Table I))-3
`Far from being merely a cosmetic issue, ony-
`chomycosis may have serious emotional and phys-
`ical consequences for the patient.2,5 The condition
`
`$21
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`ACRUX DDS PTY LTD. et al.
`EXHIBIT 1033
`IPR Petition for
`U.S. Patent No. 7,214,506
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`Table II. Treatment selection criteria in
`onychomycosis
`
`Causative pathogen
`Potential adverse effects
`Potential drug interactions
`Dosage schedule
`Patient compliance
`Age and health of patient
`Allergic history
`Prior antifungal therapy
`Cost
`
`From Elewsld BE, Charif MA, Daniel CR III. Onychomycosis. In:
`Scher RK, Daniel CR III, editors. Nails: diagnosis, treatment,
`surgery. 2nd ed. Philadelphia: WB Saunders, 1997. p. 151-62.
`
`may be associated with significant pain and dis-
`comfort; in severe cases, onychomycosis could lead
`to disfigurement and loss of dexterity and mobility.
`As a recent quality-of-life study by Lubeck et al6
`has demonstrated, onychomycosis can impose sig-
`nificant psychologic and social limitations.7 In this
`study, supported by Sandoz Research Institute,
`patients with fungal nail disease reported avoiding
`intimate and social situations for fear of exposing
`their disfigured nails and experienced difficulties
`with work-related activities requiring them to use
`their fingers or to be on their feet for long periods
`of time.
`Treatment of onychomycosis has traditionally
`been difficult, in part because of the unique
`absorption properties of the nail unit. To be effec-
`tive, antifungal drugs must penetrate the affected
`nail tissue and remain in high concentrations until
`the pathogen is eradicated.8 Topical antifungal
`drugs, which poorly penetrate the nail plate, have
`only limited use in onychomycosis treatment.4
`The early systemic treatments, griseofulvin and
`ketoconazole, have also proved unsatisfactory.4,8
`Griseofulvin has a narrow spectrum of activity and
`requires prolonged courses of treatment; low cure
`rates and high relapse rates further limit its useful-
`ness in onychomycosis.4,8 Although ketoconazole
`has demonstrated higher cure rates than griseofulvin,
`prolonged therapy (12 to 18 months for toenails) is
`required, and relapse rates have been high. In addi-
`tion, ketoconazole carries a risk of drug interactions
`and serious adverse effects, such as hepatotoxicity.8
`
`NEW TREATMENT OPTIONS
`
`The newer agents itraconazole, fluconazole, and
`terbinafine show great promise in the treatment of
`
`fungal nail disease. Pharmacokinetic studies indi-
`cate that these drugs reach the distal end of the nail
`shortly after therapy begins.2 When selecting
`among these agents, however, several factors need
`to be considered, including efficacy against the
`causative pathogen, potential adverse effects and
`drug interactions, dosage regimens, cost, and com-
`pliance issues (Table II).l
`
`Itraconazole
`
`Itraconazole, like fluconazole, is a triazole anti-
`fungal agent. The 3 nitrogen atoms in the 5-mem-
`ber triazole ring may be responsible for itracona-
`zole’s broad spectrum of activity, which includes
`dermatophytes, yeasts, and nondermatophyte
`molds; improved tissue penetration; and lower tox-
`icity compared with ketoconazole. Unlike keto-
`conazole, an imidazole derivative, the triazoles
`have increased specificity for fungal rather than
`mammalian cytochrome P-450 enzymes at thera-
`peutic levels, which significantly decreases the
`risk of drug interactions.9
`Mechanism of action. Itraconazole is fungista-
`tic in vitro; it impairs ergosterol synthesis in fun-
`gal cells by blocking the cytochrome P-450-
`dependent enzyme lanosterol cl4-~z-demethylase.
`This results in decreased ergosterol and increased
`lanosterol in the fungal cell membrane, which
`alters its function and permeability. This mecha-
`nism of action is common to all azoles.9
`Pharmacokinetics. Itraconazole is well absorbed
`when administered orally with food but is erratically
`absorbed with changing gastric pH. However, it
`achieves excellent tissue distribution. The pharma-
`cokinetic properties of itraconazole are related to its
`pronounced lipophilicity.3 The plasma half-life
`varies between 15 and 25 hours; the peak plasma
`concentration is reached within 2 to 4 hours after a
`single 100-mg dose. Itraconazole also binds firmly
`to protein and has a marked affinity for lipids) The
`slow elimination of itraconazole from tissues may
`explain its continued therapeutic efficacy after treat-
`ment is discontinued.3 Itraconazole also has a strong
`affinity for keratinized tissue, which results in high
`drug concentrations in the nails and explains the
`drug’s efficacy in onychomycosis) The concentra-
`tion of itraconazole in nails, 90 days after a 7-day
`course of medication, greatly exceeds the minimum
`inhibitory concentration (MIC) of common der-
`matophytes.1°
`Dosing. Two dosing schedules have been inves-
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`tigated: continuous and intermittent (pulse) thera-
`py. The fixed dosage of itraconazole is 200 mg
`daily for 12 weeks in onychomycosis of the toenail
`and for 8 weeks in fingernail disease. Studies
`demonstrate that although the nail is not yet nor-
`mal when therapy ends, the new nail will grow free
`of fungus because of the continued presence of
`itraconazole in the nail.1 Pulse or intermittent ther-
`apy is based on the rationale that the drug reaches
`the nail within 7 days of therapy and remains there
`for 6 to 9 months, although serum levels of the
`drug are no longer detectable 1 week after discon-
`tinuation of therapy.1 The Food and Drug Admin-
`istration recently approved 2 pulse doses of itra-
`conazole for onychomycosis of the fingernails, but
`no pulse therapy has been approved for toenails at
`present. Intermittent cycles of 400 mg daily for 1
`week per month can be continued for 2 months for
`fingernail infection and 3 months for toenail infec-
`tion.1 Cure rates approaching 80% have been
`reported in European studies with these regi-
`mens,11 although cure rates have been lower in
`other studies. 12
`Efficacy. Results of US studies of itraconazole
`effectiveness in the toenail have shown a mycolog-
`ic cure rate of 54%, a clinical success rate of 65%,
`and an overall success rate (clinical success and
`mycologic cure) of 35%.1 Investigators using itra-
`conazole in toenail infections at doses of 200
`mg/day for 3 months have reported mycologic
`cure rates of 86% at 9 months and 79% at 12
`months.2 At 18-month follow-up, mycologic cure
`rates decreased to 67%. Relapse rates in toenail
`infections at 9 and 12 months after treatment with
`this regimen have been reported to be 9% to 11%.2
`Safety. The principal safety concern regarding
`itraconazole relates to its potential for serious drug
`interactions. Elevated liver function tests have been
`reported in 0.3% to 5% of patients receiving itra-
`conazole therapy, but symptomatic hepatic injury
`has rarely been reported. In general, liver function
`tests return to normal 4 to 10 weeks after therapy is
`discontinued. Itraconazole should be avoided dur-
`ing pregnancy (Food and Drug Administration
`Pregnancy Category C), and women of childbear-
`ing age should be advised to take adequate contra-
`ceptive precautions during therapy.2
`Adverse effects. The adverse effects reported
`for itraconazole by more than 1% of patients in
`clinical trials for the treatment of onychomycosis
`of the fingernail are as follows: headache (5%),
`
`pruritus (5%), nausea (5%), rhinitis (5%), rash
`(3%), and dyspepsia (3%).13 Other side effects
`reported include dizziness, fatigue, fever, somno-
`lence, impotence, decreased libido, and malaise.2
`Drug interactions and contraindications.
`Itraconazole and its major metabolite are potent
`inhibitors of the cytochrome P-450 3A4 enzyme
`system. Concomitant use of itraconazole with
`drugs metabolized by this enzyme system may
`result in increased plasma concentrations of these
`drugs, leading to potentially serious or life-threat-
`ening events. Coadministration ofitraconazole and
`drugs such as terfenadine, astemizole, simvastatin,
`lovastatin, midazolam, triazolam, and cisapride are
`specifically contraindicated. Coadministration of
`itraconazole with drugs such as digoxin, cyclo-
`sporine, and phenytoin requires close monitoring.
`When oral warfarin or hypoglycemic agents are
`coadministered with itraconazole, prothrombin time
`and blood glucose levels may also require monitor-
`ing.2,3,13 Food increases the gastrointestinal absorp-
`tion of itraconazole, whereas antacids and gastric
`acid secretion suppressors that lower gastric acidity
`decrease absorption of itraconazole.2
`
`Fluconazole
`
`Fluconazole is an oral antifungal agent with
`activity against dermatophytes, Candida, and
`some nondermatophyte molds. It has only recently
`been studied as a potential therapy for onychomy-
`cosis. Fluconazole has a distinct chemical struc-
`ture and unique pharmacologic and pharmacoki-
`netic properties.
`Fluconazole is a bis-triazole, having 2 triazole
`groups with each containing 3 nitrogen atoms.
`Fluorine atoms in the 2 and 4 positions of the
`phenyl ring contribute to fluconazole’s decreased
`lipophilicity and protein binding (approximately
`12%), resistance to metabolism, increased speci-
`ficity, and higher potency compared with other
`azole antifungal agents.9 A hydroxyl group and
`low molecular weight also make fluconazole more
`water-soluble than the other azoles, which results
`in rapid absorption, high bioavailability (>90%),
`and wide tissue distribution. Fluconazole has a
`volume of distribution similar to that of water in
`the body, a long half-life (30 hours), and dose-pro-
`portional serum concentrations.9
`Mechanism of action. The mechanism of
`action is similar to the other azoles. As with itra-
`conazole, fluconazole is fungistatic in vitro. The
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`triazoles have a high affinity for fungal cyto-
`chrome P-450 enzymes but a very weak affinity
`for mammalian P-450 enzymes. In C albicans, the
`azoles inhibit transformation of blastospores into
`the invasive mycelium form.9
`Pharmacokinetics. Studies have demonstrated
`that fluconazole penetrates nails rapidly. In a small
`pilot study, Hay14 found that fluconazole was
`detectable in nails within 2 hours after a single 50-
`mg oral dose. Fluconazole accumulates well in or
`on the stratum comeum of nails, reaching levels up
`to 50 times those found in plasma, and remains
`there even after the drug is no longer detectable in
`plasma. This factor is believed to contribute to the
`continued improvement observed in some patients
`even after the end of active treatment.4 Recent
`studies have demonstrated that concentrations of
`fluconazole are found 2 weeks after the onset of
`treatment and throughout the treatment and post-
`treatment period were well above the MIC for der-
`matophytes and nondermatophytes,s Unlike keto-
`conazole and itraconazole, food intake and gastric
`pH do not affect fluconazole absorption or bio-
`availability.4
`Dosing. The most common dosage regimen of
`fluconazole prescribed for skin and nail infections
`world-wide is 150 to 300 mg once weekly.15
`However, depending on the clinical situation,
`dosages may vary. The duration of treatment is
`usually 2 weeks for tinea corporis, 4 to 6 weeks for
`tinea pedis, and 6 to 12 months for toenails until
`regrown.16 Different doses of fluconazole have
`been investigated in the treatment of onychomyco-
`sis but none have yet been FDA approved. Doses
`of 50 to 100 mg daily or on alternate days until the
`normal nail has grown out have been shown to be
`effective.2 In a study of 11 patients with ony-
`chomycosis of the toenail and fingernail, 8 patients
`received fluconazole 300 mg once weekly, 1
`patient received 200 mg once weekly, and 2
`patients received alternate-day therapy with 100
`mg or 200 mg of fluconazole. Eight of the patients
`also received a topical antimycotic treatment. All 6
`patients with toenail involvement were clinically
`cured after a mean duration of 6 months. All 5
`patients with fingernail involvement were cured
`after 3.7 months. No adverse laboratory or clinical
`adverse events were recorded.17
`The use of chemical urea nail avulsion with flu-
`conazole therapy has also been demonstrated to
`improve cure rates.1 In patients who do not
`
`respond to treatment, the dose of fluconazole can
`be increased to 300 or 450 mg once weekly.1 This
`once-weekly regimen may be especially useful for
`patients who are receiving multiple medications
`and for whom compliance may be an issue.1
`Efficacy. The efficacy of fluconazole in ony-
`chomycosis is well studied. Montero-Gei et alis
`demonstrated that fluconazole 150 mg once week-
`ly for 3 to 12 months for dermatophyte infections
`of the fingernails and toenails produced a favor-
`able clinical response in 97% of patients at the end
`of treatment and in 87% at follow-up. A multicen-
`ter trial by Frfiki et a119 in Finland reported similar
`results. Treatment with 150 mg of fluconazole
`once weekly for 5 to 12 months was effective and
`well tolerated and produced a favorable clinical
`response in 77% of patients at follow-up.
`In a recent study by Scher et al,15 treatment of
`onychomycosis of the toenail with dosages of flu-
`conazole ranging between 150 and 450 mg once
`weekly for a mean period of 6 to 7 months result-
`ed in a clinical success rate greater than 86% with
`a low relapse rate.
`Safety. More than 50 million adult and pediatric
`patients worldwide have taken fluconazole for fun-
`gal infections (including vaginal candidiasis,
`oropharyngeal and esophageal candidiasis), skin
`and nail infections, systemic candidiasis, and cryp-
`tococcal meningitis. The use of doses of 400 mg/
`day in severely ill, immunocompromised patients
`confirms the safety and tolerability of flucona-
`zole.4 Fluconazole is well tolerated, and hepato-
`toxicity is rare. Daily doses as high as 1600 to
`2000 mg have been shown to be effective and well
`tolerated in severely ill patients, although these
`higher doses are not yet approved for use in most
`countries. Thus doses used in skin and nail infec-
`tions are well below the maximum doses in this
`wide dosage-safety margin.
`Adverse effects. Most researchers acknowl-
`edge that analyzing the adverse reactions associat-
`ed with fluconazole is difficult because the drug
`has been used primarily in patients with severe
`underlying disease.2 In studies involving 4000
`patients receiving fluconazole therapy for 7 days
`or more for various indications, the incidence of
`side effects was 16%.2,4 Treatment was discontin-
`ued in 1.3% of patients because of laboratory test
`abnormalities and in 1.5% of patients because of
`adverse clinical effects. These were mainly gas-
`trointestinal disturbances. Other reported side
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`effects included headaches, rash (such as urticaria
`or papulomacular or morbilliform eruptions),
`exfoliative skin eruptions, abnormal liver function
`tests, and, in some instances, hepatotoxicity)6
`Drug interactions and eontraindieations.
`Rifampin enhances fluconazole metabolism,
`whereas fluconazole increases the prothrombin
`time of coumarin-type anticoagulants and increas-
`es the plasma concentrations of phenytoin and
`cyclosporine)6 In addition, fluconazole increases
`serum theophylline concentrations and may
`increase the bioavailability of oral hypoglycemic
`agents. As with other azole antifungal drugs, coad-
`ministration of fluconazole with terfenadine,
`astemizole, or cisapride is contraindicated.2,3,16
`Unlike itraconazole, absorption of fluconazole is
`not affected by antacids or by drugs that increase
`gastric pH)6
`
`Terbinaflne
`
`Terbinafine is a member of the allylamine class
`of antifungal agents. It exerts its antifungal effects
`at an earlier phase in fungal-cell membrane devel-
`opment than do the azoles)4
`Mechanism of action. Terbinafine’s mecha-
`nism of action is different than the azoles. It blocks
`ergosterol synthesis by inhibiting squalene epoxi-
`dase. This inhibition results in an increase in squa-
`lene, which is toxic to fungal cells. In vitro,
`terbinafine is primarily fungicidal against der-
`matophytes, Aspergillus species, Scopulariopsis
`brevicaulis, Sporothrix schenckii, and the dimor-
`phic fungi Blastomyces dermatitidis and Histo-
`plasma capsulatum. Activity against yeasts is vari-
`able. Terbinafine is more active against C parap-
`silosis than C albicans.2
`Pharmaeokineties. Oral terbinafine reaches the
`nail plate by diffusion from both the nail bed and
`nail matrix.9 When 250 rag/day of terbinafine was
`administered to healthy volunteers, the drug was
`detected in peripheral nail clippings after 7 days.9
`The concentration of terbinafine in nails 90 days
`after a 7-day course of medication greatly exceed-
`ed the MIC of common dermatophytes.9
`Dosing. A 6-week course of 250 rag/day of
`terbinafine is effective in fingernail disease; a 12-
`week course at the same dose is generally effective
`in toenail disease),9
`Efficacy. In standard long-term treatment (6
`months for fingernails, 12 months for toenails),
`250 rag/day of terbinafine demonstrated mycolog-
`
`ic cure rates of 95% for fingernail and 80% for toe-
`nail infections. At 250 mg/day for 3 months, 82% of
`patients achieved mycologic cure at 1 year after
`treatment. When treatment regimens of 250 mg/day
`for 6, 12, and 24 weeks were compared, it was
`shown that for onychomycosis of the toenail, a 12-
`week course of treatment was comparable to 24
`weeks of therapy. A regimen of 250 mg/day for 6
`weeks in fingernail infection and 12 weeks in toenail
`infections achieved 90% and 80% cure rates, respec-
`tively. At 12 months, relapse rates were between 6%
`and 12% for fingernails and toenails, respectively?
`Safety. Terbinafine is generally safe and well
`tolerated, and there are few significant drug inter-
`actions. Although hepatotoxic reactions are rare,
`many experts believe that periodic monitoring of
`liver function and hematopoietic parameters is rea-
`sonable, as for itraconazole and fluconazole)
`Adverse effects. The most common adverse
`effect reported with terbinafine in 3 US/Canadian
`clinical trials was headache, occurring in 12.9% of
`patients. Gastrointestinal disturbances and skin
`reactions accounted for most other adverse effects:
`diarrhea (5.8%), dyspepsia (4.3%), and nausea
`(2.6%); and rash, including urticaria (6.7%), and
`pruritus (2.8%).20 Less common side effects re-
`ported included fatigue, inability to concentrate,
`pain (back, leg, and flank), taste disturbances,
`erectile dysfunction, transient hypoglycemia, and
`elevated liver function tests. No specific muta-
`genic effects have been reported with terbinafine,
`and animal studies reveal no evidence of embry-
`onic or fetal toxicity or teratogenicity.2
`Drug interactions and eontraindieations.
`Terbinafine does not significantly induce or inhib-
`it the clearance of drugs metabolized by the
`cytochrome P-450 enzyme system; therefore at
`therapeutic levels, the potential for drug interac-
`tions is much lower for terbinafine than for the
`azoles. However, drugs that induce these enzymes,
`such as rifampin or phenobarbital, will increase
`plasma clearance of terbinafine, whereas drugs
`that inhibit these enzymes, such as cimetidine, will
`reduce terbinafine clearance. Bioavailability of
`terbinafine is not affected by the presence of
`food.2,20 The only contraindication is hypersensi-
`tivity to terbinafine.2°
`
`CONCLUSIONS
`Systemic treatment of onychomycosis has
`improved dramatically with the availability of the
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`newer antifungal agents itraconazole, fluconazole,
`and terbinafine. These drugs are generally safe and
`well tolerated and may allow shorter treatment
`periods. Selection of agents will depend on sever-
`al factors including spectrum of activity, potential
`for drug interactions, adverse effects, and patient
`preferences for specific dosage regimens. Treat-
`ment regimens range from continuous treatment
`with terbinafine for brief periods to pulse dosing
`with itraconazole 1 week each month or once-
`weekly dosing with fluconazole.
`
`REFERENCES
`
`1. Elewski BE, CharifMA, Daniel CR III. Onychomycosis.
`In: Scher RK, Daniel CR III, editors. Nails: diagnosis,
`treatment, surgery. 2nd ed. Philadelphia: WB Saunders,
`1997. p. 151-62.
`2. Chiritescu MM, Chiritescu M-E, Scher RK. Newer sys-
`temic antifungal drugs for the treatment of onychomyco-
`sis. Clin Podiatr Med Surg 1996; 13:741-58.
`3. Elewski BE, Hay RJ. Update on the management ofony-
`chomycosis: highlights on the Third Annual Inter-
`national Summit in Cutaneous Antifungal Therapy. Clin
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`4. Elewski BE. Once-weekly fluconazole in the treatment
`of onychomycosis. J Am Acad Dermatol 1998;38:$73-6.
`5. Scher RK. Onychomycosis is more than a cosmetic prob-
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`6. Lubeck DP, Patrick DL, McNulty R Fifer SK, Birnbaum
`J. Quality of life of persons with onychomycosis. Qual
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`7. Drake LA, Scher RK, Smith EB, et al. Effect of ony-
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`8. Rich R Scher RK, Brenemax~ D, et ah Pharmacokinetics
`of three doses of once-weekly fluconazole (150, 300, and
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`
`cosis of the toenail. J AmAcad Dermatol 1998;38:S103-
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`9. Gupta AK, Scher RK, De Doncker R Current manage-
`ment of onychomycosis: an overview. Dermatol Clin
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`10. Meinhof W. Kinetics and spectrum of activity of oral
`antifungals: the therapeutic implications. J Am Acad
`Dermatol 1993;29:$37-41.
`11. DeDoncker P, Decroix J, Pi~raJ:d GE, et al. Antifungal
`pulse therapy for onychomycosis: a pharmacokinetic and
`phaJ:macodynamic investigation of monthly cycles of 1-
`week pulse therapy with itraconazole. Arch Dermatol
`1996;132:34-41.
`12. Epstein E. How often does oral treatment of toenail ony-
`chomycosis produce a disease-free nail? An analysis of
`published data. Arch Dermatol 1998; 134:1551-4.
`13. Sporanox® (itraconazole) 100 mg capsules: package
`insert. Titusville (NJ): Janssen Pharmaceutica Inc.
`14. Hay RJ. Onychomycosis: agents of choice. Dermatol
`Clin 1993;11:161-9.
`15. Scher RK, Breneman D, Rich P, et al. A placebo-con-
`trolled, randomized, double-blind trial of once-weekly
`fluconazole (150, 300, or 450 rag) in the treatment of
`distal subungual onychomycosis of the toenail. J Am
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