`f ’RCHIVES
`
`
`r
`
`-
`
`
`
`DERMATOLOGY
`
`JANUARY 1996
`
`
`
`Pmunmcoccal ceihdia‘s. See page 81.
`
`
`
`GROUP A STREPTOCOCCAL (GAS)
`INFECTIONS: AN OLD ADVERSARY
`REEMERGING WITH NEW TRICKS?
`
`ANTIFUNGAL PULSE THERAPY
`FOR ONYCHOMYCOSIS
`
`
`
`RECURRENT TOXIN-MED1ATED
`PERINEAL ERYTHEMA
`
`STAPHYLOCOCCAL ENTEROTOXIN B
`APPLIED 0N ATOPIC SKIN
`INDUCES DERMATITIS
`
`DETECTION OF MYCOBACTERIAL DNA
`IN THE SKIN
`
`INFRAORBITAL GREASE, ETHNIC GROUP.
`AND ATOPIC DERMATITIS
`
`‘
`[
`
`g
`"‘
`
`American Medical Association
`wahhmMiwmwthe mun ofAmerica
`
`SEAT TLE HA
`
`3 D I on 96 1
`-
`35L *IlIttinIHt
`ggiggaz359022#190004
`9512
`UNIVERSITY OF HASHINGION
`333% 5c 1 ENC E s L I an Ange 195
`
`Page 1 of 10
`
`KakaExhflfit2077
`
`Acrux V. Kaken
`
`IPR2017-00190
`
`

`

`H r ,.,.
`
`..
`
`1
`
`.j
`
`r
`
`v
`
`DERMATOLOGY
`
`VOL 132 NO. LIANUARY 1996
`
` Staphylococcal Enterotoxin B Applied
`
`
`Studies
`
`on Intact Normal and intact Atopic
`Skin Induces Dermatitis
`Poul Strange, MD; Lone Shov, MD;
`Steen Lisby, MD;
`Preben Lovgreen Nielsen, MD;
`Ole Baadsgaard, MD
`
`Antifungal Pulse Therapy for
`Onychonziycosis: A Pharmacokinetic and
`Pharmacodynamic Investigation of
`Monthly Cycles of l-Week Pulse
`Therapy With Itraconazole
`Pier De Doncker, PhD; Jacques Decroix, MD;
`Gerald E. Piérard, MD, PhD; Dirk Roelant;
`Robert Woestenborghs; Philippe Jacqmin, PhD;
`Frank Odds, PhD; Annie Heremans, MD, PhD;
`Pierre Dockx, MD, PhD; Diane Roseeiiw, MD, PhD
`
`Increased Sennn Concentration
`of the Soluble Interleukin-2 Receptor in
`Cutaneous T—Cell Lymphoma: Clinical
`and Prognostic Implications
`Mariusz A. Wasilz, MD; Eric C. Vonclerlieid, MD;
`Robert D. Bigler, MD,- Rosa Marti, MD;
`Stuart R. Lessin, MD; Marcia Polansky, ScD;
`Marshall E. Kadin, MD
`
`27
`
`34
`
`42
`
`Infraorbital Crease, Ethnic Group,
`and Atopic Dermatitis
`Hywel C. Williams, PhD,
`Andrew C. Pembroke, FRCP
`
`
`Observations
`
`Recurrent Toxin-Mediated
`Perineal Erythema
`Steven M. Manders, MD;
`Warren R. Heymann, MD;
`Ercem Atillasoy, MD; jeffrey Kleeman, DO;
`Patrick M. Schlievert, PhD
`
`Arcanobacterium haemolyticum
`Pharyngitis and Exanthem: Three Case
`Reports and Literature Review
`David A. Gaston, MD,
`Susan M. Zurowshi, MD
`
`
`Review
`
`Detection of Mycobacterial DNA
`in the Skin: Etiologic Insights
`and Diagnostic Perspectives
`Klaus Degitz, MD
`
`51
`
`57
`
`61
`
`71
`
`
`
`
`
`
`
`American Medical Association
`
`Physicians dedicated to the health of America
`
`Copyright 1996 by the American Medical Associalion. All rights reserved.
`Reproduction without permission is prohibited.
`
`All articles published, including editorials, letters, and book re-
`views, represent the opinions of the authors and do not reflect the
`policy of the American Medical Association, the Editorial Board,
`or the instiluLion with which the author is affiliated, unless this is
`clearly specified.
`
`James S. Todd, MD
`Executive Vice President
`Kennaill E. Monroe
`Deputy Executive Vice President
`James F, flannel
`Group Vice President,
`Business and Management Services
`acorns D. Luminary, MD
`Editor in Chief, Scientific
`inlormaiion and Multimedia
`Bnhert L Kennett
`Vice President, Publishing,
`Michael D. Springer
`Publisher
`Mary C. Siaermann
`Director, Production and
`Distribution Division
`
`Cheryl lverson
`Director, Editorial Processing
`91mm"
`Polar L, Payerll
`Director, Advertising Sales
`Gunfire! A. Flick
`Manager, Marketing Services
`
`Advertisinn Office: Phillip B. Alia—
`inore, 119 Cherry Hill Rd, 3rd Flr,
`Parsippany, NJ 07054 (201) 263-
`9191. MA Physician Recruitment Ad-
`vertising Department Carri Lynch, Su-
`pervrsor, 80046172260.
`
`—_——
`ARCH DERMATOLNOL 132, JAN 1995
`7
`
`
`
`Page 2 of 10
`
`

`

`
`
`m—
`
`Antifungal Pulse Therapy for Onychomycosis
`
`A Pharmacokinetic and Pharmacodynamic Investigation of Monthly Cycles
`of l-Weelz Pulse Therapy With Itraconazole
`
`Piet De Doncker, PhD; jacques Decroix, MD; Gerald E, Piérard, MD, PhD; Dirk Roelant;
`Robert Woestenborghs; Philippe Jacqmin, PhD; Frank Odds, PhD; Annie Heremans, MD, PhD;
`Pierre Dockx, MD, PhD; Diane Roseeuw, MD, PhD
`
`Background and Design: In the treatment of onycho-
`mycosis, oral therapies have generally been given as a con-
`tinuous—dosing regimen. For example, the suggested dose
`of itraconazole for the treatment of onychomycosis has
`thus far been 200 mg/d for 3 months. Based on the ad-
`vances in our understanding of the pharmacokinetics of
`itraconazole, we investigated the efficacy and nail kinet-
`ics of intermittent pulse-dosing therapy with oral itra-
`conazole in patients who were suffering from onycho-
`mycosis. Fifty patients with confirmed onychomycosis
`of the toenails, predominantly Trichophyton rubrum, were
`recruited and randomly assigned to three (n=25) or
`four (n=25) pulses of 1-week itraconazole therapy
`(200 mg twice daily for each month). Clinical and
`mycological evaluation of the infected toenails, and
`determination of the drug levels in the distal nail ends
`of the fingernails and toenails, were performed at the
`end of each month up to month 6 and then every 2
`months up to 1 year.
`
`
`
`Insults: In the three-pulse treatment group, the mean
`concentration of itraconazole in the distal ends of the toe-
`
`respectively. In the four—pulse treatment group, the mean
`concentration of itraconazole in the distal ends of the toe-
`
`nails ranged from 32 (month 1) to 623 (month 8) ng/g,
`and in the distal ends of the fingernails, it ranged from
`42 (month 1) to 380 (month 6) ng/g. The highest indi-
`vidual concentrations of 1549 and 946 ng/g were reached
`at month 7 for toenails and at month 9 for fingernails,
`respectively. At month 12, the drug was still present in
`the distal ends of the toenails at an average concentra—
`tion of 196 ng/g. At end-point follow»up, toenails in 76%
`of the patients were clinically cured with a negative p0-
`tassium hydroxide preparation and culture in 72% and
`80% of the patients, respectively. There were no signifi—
`cant intergroup differences between the three- and four-
`pulse treatment groups for the primary efficacy param—
`eters. The drug was well tolerated with no significant side
`effects in either patieht group.
`
`conclusions: Following pulse therapy with itracona~
`zole (400 mg/d given for 1 week each month for 3 to 4
`months), the drug has been detected in the distal ends
`of nails after the first pulse, and it has reached therapeu-
`tic concentrations With further therapy. After stopping
`the last pulse, the drug remains in the nail plate at levels
`above 300 ng/g for several months. Clinical cure rates
`between 76% and 84% and negative mycological exami-
`nation findings between 72% and 80%, respectively, were
`observed in toenail onychomycosis. The data suggest that
`pulse therapy with itraconazole is an effective and safe
`treatment option for onychomycosis.
`
`(Arch Dermatol. 1996;132:3441)
`
`nails ranged from 67 (month 1) to 471 (month 6) ng/g,
`and in the distal ends of the fingernails, it ranged from
`103 (month 1) to 424 (month 6) ngg, At month 11, the
`drug was still present in the distal ends of the toenails at
`an average concentration of 186 ng/g. The highest indi-
`vidual concentrations of 1064 and 1166 ngfg were reached
`at month 6 for toenails and fingernails, respectively. At
`end-point follow-up, toenails in 84% of the patients were
`clinically cured with a negative potassium hydroxide
`preparation and culture in 72% and 80% of the patients,
`
`NYCHOMYCOSIS IS one of
`
`cal characteristics of slow growth, mak-
`ing it an ideal substrate for fungi but a poor
`biophase for drugs.10 This may partly ex-
`plain the chronic course of onychomy-
`costs with the lack of spontaneous heal-
`ing, the lengthy and often incomplete
`
`See Patients, Materials,
`
`and Methods on next page
`
`the major causes of the
`onychopathies,” and it
`may affect a patient’s
`quality of life.3 The nail
`changes can cause varying degrees of
`physical impairment, pain, loss of dexter-
`ity, and social and psychological stress. In
`addition, onychomycosis may be the
`source ofdiSSemination of infection to the
`skin.” Finally, the nail contains densely
`packed onychocytes and has physiologi-
`__—_.___.._..——
`ARCH DERMATOLNOL 132, JAN 1996
`34
`
`Afliliations of the authors are
`given in the acknowledgement
`section at the end of the
`article.
`
`Page 3 of 10
`
`

`

`‘l
`
`Fifty patients with microscopically and culture—proved ony-
`chomycosis of the toenails were entered into this open triai.
`Twenty-five patients (12 men and 13 women) were ran-
`domly assigned to the three-pulse dosage group, and 25 pa-
`tients (12 men and 13 women) were randomly assigned to
`the four-pulse dosage group. Previous systemic and topical
`antifungal treatment was discontinued in patients at 3 months
`and 2 weeks, respectively, before the study. All patients gave
`informed consent and met the requirements of the Decla-
`ration of Helsinki (Finland). The trial was monitored and
`carried out according to Good Clinical (Research) Practice,
`the official guidelines of the European Community for per
`forming clinical trials. The following patients were ex-
`cluded from this trial: pregnant patients or women of child—
`bearing age who were not using reliable contraceptive
`methods; patients with psoriasis; patients who Were receiv-
`ing concurrent therapy with rifampin, phenytoin, digoxin,
`oral anticoagulants, and cyclosporine; and patients who
`showed a previous hypersensitivity to azole antifungal drugs.
`No patients in either dosage groups had taken itra-
`conazole before the start of the study. One patient, belong-
`ing to the three-pulse dosage group, was treated subcuta-
`neously with insulin (rapid-acting) throughout the trial.
`
`improved, unchanged, and deteriorated. Clinical cure
`was defined as patients who were cured without or with
`nail malformation. Clinical response was defined as
`patients who were cured or markedly improved. Myco-
`logical examination (direct microscopical examination
`and culture) was performed at each visit. Mycological
`cure was obtained when a potassium hydroxide prepara-
`tion and culture were negative. Adverse experiences
`were recorded during the entire study period.
`For both groups, the tolerabilitiy of the medication was
`assessed after 3 months of therapy by using a five-point scale
`(l=very good, 2=good, 3=moderate, 4=poor, and 5=not tol-
`erated).
`
`Drug Kinetics in the Nail
`
`Distal nail ends were collected from each patient at the end
`of each month and pooled into separate samples of finger-
`nails and toenails for each patient. ltraconazole concen-
`trations were determined separately for the toenail and fin-
`gernail sampies in each patient on a monthly basis by using
`high-pressure liquid chromatography after extraction as de-
`scribed below.5E3
`
`STANDARDS AND REAGENTS
`
`PATIENTS, MATERIALS,
`AND METHODS
`
`
`
`
`
`
`
`
`
`TREATMENT PHASE
`
`Patients received either the three— or four-pulse regimen: three
`pulses of itraconazole (200 mg twice daily) given with the
`meal during the first week of each month (ie, the drug was
`administered to this group during weeks 1, 5, and 9), or four
`pulses of itraconazole (200 mg twice daily) given with a meal
`during the first week of each month (ie, the drug was ad—
`ministered to this group during weeks 1, 5, 9, and 13).
`
`POSTTREATMENT PHASE
`
`The following reference compounds were obtained
`commercially (lanssen Life Sciences Products Division,
`Beerse, Belgium): itraconazole (R 51211), and the internal
`standard (R 51012), cis-4- [4- [4-[4— [ [2-(2,4-dichlorophenyl)
`—2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan—4wyll-
`methoxy1phenyl]-1-piperazinyl]phenyll-2,4-dihydro-5—
`methyl-2-(3-methylbutyl)-3H-1,2,3-triazol-3vl .
`Spectrophotometric-grade acetronitrile, n-heptane, and
`methanol were used. The other solvent was of an analytical
`grade and included isoamyl alcohol. The anorganic
`reagents (sulfuric acid, sodium hydroxide, ammonium ac-
`etate, and ammonia) were prepared in double-distilled wa—
`ter. Stock solutions that corresponded to methanol (0.1
`mg/mL) were prepared for itraconazole and the internal stan-
`After the last pulse (weeks 9 and 13 for groups 1 and 2., re-
`dard. Standard solutions were obtained by dilution of the
`spectively), drug therapy was discontinued, and patients were
`itracottazole stock solution to concentrations down to 0.020
`followed up to 1 year from the start of treatment.
`mg/L. The internal standard stock solution was diluted to
`EVALUATION
`final concentrations of 2 and 10 mg/L.
`
`EXTRACTION PROCEDURE
`Clinical Assessment
`
`Patients were examined clinically on a monthly basis
`until month 6, then bimonthly up to 1 year. The most
`severely affected toenail was chosen as the target nail at
`the start. For this nail dystrophy, onycholysis and sub-
`ungual hyperkeratosis were assessed on each visit
`according to a four-grade scale (0:3b5ettl, 1=rnild,
`2=moderate, and 3=severe). The altered part of the target
`nail plate was recorded as the percentage-affected area1
`including any destroyed and missing portion of the nail
`plate. Progress or regression of infection was monitored
`by recording the percentage of nail that was affected by
`the infection. A global assessment was carried out from
`month 3 onward, using the following categories: cured
`without residual nail malformation, cured with residual
`nail malformation, markedly improved, moderately
`
`Nail samples were first saponified in a vial with 2.5N so-
`dium hydroxide (1 mL). These vials were spiked with the
`internal standard (R 51012, 0.2 mg/L) and incubated for 30
`minutes at 80“C. The remaining acidic phase was made al—
`kaline with concentrated ammonia (1 mL; pH 9 to 10) and
`reextracted twice with 2-mL aliquots of the same n—heptarte—
`isoamyl alcohol mixture. The combined organic layers were
`then evaporated until dry under a gentle stream of nitrogen
`in a water bath at 55°C and submitted to high-pressure liq-
`uid chromatographic analysis. Chromatograms from nail ex-
`tracts are very similar to chromatogratrts of plasma or other
`tissue extracts. The detection limit is about 2 to 5 ng per
`sample, and the lower limit of quantitation, expressed as a
`
`Continued on next page
`
`
`
`
`
`
`
`
`
` __.———
`
`
`ARCH DERMATDWOL 132, JAN 1996
`
`Page 4 of 10
`
`

`

`
`
`concentration, thus strongly depends on the amount
`provided. The weight of the nail material was the criti-
`cal factor in the assay with a detection limit of 2 rig
`per nail sample. Ideally, a weight of a 50-mg nail is
`recommended for having an accurate determination
`of the drug in the nail.
`All chromatographic analyseswere performedon
`a high-pressure liquid chromatograph (model 1050,
`Hewlett-Packard, Brussels, Belgium) with a variable-
`volume injector (model 79841 A), an automatic-
`sampling system (model 79842 A) , and a variable wave-
`length detector (model 1050 DAD) that operated at
`263 nm. The separations were carried out by means of
`a reverse-phase 10-cmX4.6-mm internal diameter col-
`umn. with 3-th basic deactivated silica-carbon 18 par-
`ticles (Alltech, laarne, Belgium). The samples were eluted
`with a water-acetonitrile solution (40:60) at a constant
`flow rate of 0.5 mL/min. To suppress the ionization of
`the basic functions ofthe investigated compounds, 0.05%
`diethylamine was added to the solvent system. Arm
`integrations, calculations, and plotting of the chroma!
`tograms were carried out by an integrated chromatog-
`raphy data processing system (Perkin-Elmer Nelson
`Systems Inc, Zaventern, Belgium).58 In this assay, the
`hydroxyitraconazole in the nail samples was not cal—
`culated because of its short retention time and the in—
`terference of the solvent peak.
`
`STATISTICS
`
`An intent-to-treat analysis was performed on all ran-
`domized patients regardless of their compliance with
`the protocol, and these patients were included in the
`analysis. All statistical tests were interpreted at the
`5% significance level (two-tailed). The comparabil-
`ity of the two treatment groups was evaluated for de-
`mographical and baseline variables. For discrete vari-
`ables, the analysis was performed by using Fisher‘s
`exact probability test. The Mann—Whitney U test was
`used for intergroup comparison of the ordered vari»
`ables. and the x1 test was used for the nominal cat—
`egorical variables. To evaluate the degree of improve
`ment or deterioration, the mycological cure, and the
`clinical global evaluation, the Mann—Whitney U test
`was used. The primary efficacy parameters were the
`clinical response and mycological cure rate.
`The following tests were used in the efficacy
`analysis: for categorical parameters, the Cochran-
`Mantel-Haensze] statistic controlling for the type of
`infection; for time variables, the stratified Gehan-
`Wilcoxon statistic for censored data; and for the other
`continuous parameters, an analysis of variance was
`applied with factors for the type of infection and
`treatment.
`
`
`
`
`
`
`
`trix with slow incorporation into the newly formed
`nail.l°'l"’lfi Such systemic therapy permitted a suppos—
`edly fungal-free nail to grow15 but required lengthy treat-
`ment.”17
`
`For any drug therapy, the risk-benefit consider-
`ation is important. This is determined by the intrinsic tox-
`icity of the drug, its clinical efficacy and tolerance, and
`the length of therapy needed to provide a cure.” Be-
`cause of the shortcomings associated with the use of ke-
`toconazole and griseofulvin, oral antifungal agents (eg,
`itraconazole, fluconazole, and terbinafine) with im-
`proved pharmacokinetic and pharmacodynamic prop-
`erties, have been developed. These agents enable a shorter
`treatment period and provide an improved safety and ef-
`ficacy profile.‘8'3]
`Itraconazole is a broad—spectrum triazole deriva-
`tive that is highly lipophilic and keratophilic, with good
`oral absorption when it is taken with meals, and it has
`an extensive tissue distribution.19"”-33 The main active me-
`tabolite of itraconazole is hydmxyitraconazole and its
`plasma levels exceed those of the parent drug.”32 At the
`steady state of twice-daily administrations of itracona-
`zole (200 mg), the peak plasma level of hydroxyitracona-
`zole is, on average, 50% higher compared with that of
`itraconazole; the area under the curve is 70% higher, but
`the metabolite has a shorter half-life (14 hours) com-
`pared with that of the parent drug (half—life, 17 to 25
`hours) .3“ The in vitro antifungal activity ofa hydroxyme-
`tabolite is similar to that of itraconazole.” Itraconazole
`
`demonstrates a broad spectrum of activity of itraconazole
`against yeasts and a number of nondermatophytic fungi,
`and it is particularly useful for the treatment of onycho-
`mycosis.2°-”"‘° The required minimum inhibitory con—
`centrations for 90% of the group is 100 ng/ml. for derma-
`tophytes and most Candida species?5
`Several studies have been performed on the phar-
`macokinetics of itraconazole in nails, and these have given
`us an improved insight into the mechanism by which the
`drug reaches the site of infection, the time that is re-
`quired to reach adequate therapeutic concentrations, and
`the retention time at the infection site.”"” These nail ki—
`
`netic studies have demonstrated that itraconazole readily
`penetrates into the nail via the matrix and bed.”-“-*2 In the
`initial studies, the dose of itraconazole for the treatment
`of onychomycosis was 100 mg/d, and this was given until
`a cure was achieved.“-“ The levels, obtained within 1 week
`of starting therapy with 100 mg/d, were below the level
`of the minimum inhibitory concentration for 90% of the
`group for dermatophytes and yeasts (100 ng/mL), and they
`continued to increase during the subsequent weeks of
`therapy.“-“2 The clinical efficacy of long-term itracona-
`zole in the treatment of onychomycosis has been demon-
`strated with daily doses of 100 mg given for an average of
`9 months.4348
`
`response to oral treatments, and the failure of topical
`Following therapy with itraconazole (100 mg/d) for
`3 months, only borderline therapeutic concentrations were
`agentss-nmz
`obtained in the keratin of the distal ends of the rtail.“‘3 These
`Until recently, the drugs available for the oral treat-
`ment of dermatomycoses have been limited; such treat-
`concentrations persisted in fingernails for 3 months and
`in toenails for up to 6 months after stopping treatment.
`ment has traditionally relied on griseofulvin and keto-
`The difference in drug elimination is explained by the
`(:onazole.""-7-'2'H For the treatment of onychomycosis, it
`has been assumed these orally administered antifungal
`different speed of nail growth between fingernails and
`toenails.” In contrast, itraconazole (200 mg/d given for
`agents were delivered into the nail through the nail ma-
`
`ARCH DERMATOUVOL 132, jAN 1996
`
`Page 5 of 10
`
`

`

`""lw -
`
`-_
`
`‘rrv- v
`
`Posttreatmem Follow-up
`
`Time, m0
`
`Pusttreatmant Follow-up
`
`
`
`s's‘
`
`.4a
`
`1000
`
`100
`
`a
`
`ng/a
`ltraconazoteConcentration,
`
`
`nglg 01234567891011
`
`ItraconazoleConcentration.
`
`Time,rno
`
`
`Flgure 1. Top, itraconazole concentrations (mean: SEM values in
`nanograms per gram) in the distal ends of hails from 20 patients who
`were receiving three pulses of itraconazaie {400 night for 1 week each
`month). Bottom, ltraconazoie concentrations (mean:SEM values in
`nanograms per gram) in the distal ends of hails from 17 patients who
`were receiving four pulses of ilraconazole (400 mg/d for 1 week each
`month). Rx indicates treatment; Mics”, minimum inhibitory concentration
`for 90% of the group; squares, toenails; and circles, fingernails.
`
`3 months) resulted in drug concentrations between 250
`and 1000 ng/g in the distal ends of the nail; these con-
`centrations were well within the Lherapeu tic range for the
`most common fungal nail pathogens. Based on these phar—
`macokinetic and pharmacodynamic studies, the stan-
`dard duration of treatment of onychomycosis with first—
`conazole was established at 12 weeks for toenails and 6
`
`weeks for fingernails at a daily dose of 200 mg.“"“" Cure
`rates in multicenter studies with this treatment regimen
`have varied between 70% and 80% for onychomycosis
`of the toenail and between 80% and 90% for fingernail
`diseaseflifl‘54
`Most of the data pertaining to the safetyprofile of itra-
`conazole have been obtained from patients who were treated
`for onychomycosis with doses of 100 to 200 mg daily for
`3 to 12 months. In general, the drug is well tolerated with
`an adverse experience incidence of 28% in patients who
`receive itraconazole (100 mg/d up to 12 months).4“752'5*
`In patients who receive itraconazole (200 mg/d for 3
`months) for treatment of onychomycosis, the incidence of
`side effects is 19% compared with 15% with placebo
`t11erapy.5"5“ The most common side effects are gastroin—
`testinal complaints and headache. At therapeutic concen-
`trations, itraconazole has a significantly less inhibitory or
`inducing effect on microsomal enzymes compared with that
`of ketoconazole.32 Nevertheless, drug interactions may re-
`sult (eg, with rifampin, phenytoin, astemizole, terfena-
`dine, cisapride, midazolam, and triazolam).32'55'5°
`Treatment of onychomycosis using the pulse therapy
`regimen exploits the favorable pharmacokinetic profile
`of the drug with persistence of the drug in keratin for
`prolonged periods with a rapid plasma elimina-
`tion.“’-‘“'57 The dosage and duration of therapy are based
`on the distribution ofitraconazole in the nail. In this study,
`we have quantified the uptake and elimination of oral itra-
`conazole in toenails and fingernails after monthly pulses
`of itraconazole (400 mg given for 1 week of each month
`for 3 or 4 months). In addition, we attempted to corre-
`late the kinetic findings in toenails with the clinical
`response.
`
`
`
`—W
`
`Fifty patients with confirmed onychomycosis of the toe-
`nails were entered into the trial. There were no drop-
`outs. Protocol deviations were noted in three patients:
`one patient in the three-pulse treatment group and one
`in the four-pulse treatment group were older than 70 years.
`One patient of the former group had onychomycosis of
`the fingernails without affected toenails. All patients were
`included in the analysis of the clinical data. Baseline pa-
`tient characteristics were comparable for the two treat—
`ment groups (no statistically significant difference). Over-
`all, 48% of the patients were male, and the mean ages in
`the three— and four-pulse treatment groups were 44 and
`50 years, respectively. Onychomycosis had been pres—
`ent for a median of 7 months. Distal and lateral subun-
`
`(46%) patients (10 patients in the three-pulse treatment
`group and 13 patients in the four-pulse treatment group).
`Before therapy, the average extent of target nail alter-
`ation was lower in the three-pulse treatment group
`(56.6%) compared with that in the four-pulse treatment
`group (61.9%).
`Trichophyton rubrum was present in 19 patients
`(76%) in the three-pulse treatment group and in 17
`(68%) in the four-pulse treatment group. Other patho-
`gens, including Candida pampsilosis, Scopulariopsis
`brevicaulis, Trichophyton mentagrophytes, and Aspergil-
`lus species, were found in four or fewer patients per
`treatment group.
`Nail material was collected from 37 of the patients,
`of whom 20 (nine men and 11 women) were assigned to
`the three-pulse dosage group and 17 (13 men and 14
`women) were assigned to the four-pulse dosage group.
`The kinetics of itraconazole in the nails of patients who
`were receiving itraconazole pulse therapy is shown in
`Figure ‘I.
`In the group of patients who were receiving three
`consecutive monthly pulses (Figure 1, top), the mean itra-
`conazole concentrations in the tOenails ranged from 67
`ng/g (month 1) to a peak concentration of 4-71 ng/g
`(month 6) and persisted to month 1 1, with drug cone
`gual onychomycosis was present in 27 (54%) patients (15
`centrations being 186 ng/g at that time point. In finger-
`patients in the three-pulse treatment group and 12 pa-
`nails, itraconazole concentrations were 103 ng/g
`tients in the four-pulse treatment group). The total dys-
`trophic type of onychomycosis (>75% nail involve-
`(month 1), with an increase to 424 ng/g at month 6. The
`drug concentration dropped to 131 ng/g at month 8, and
`ment, including the proximal region) was found in 23
`
`ARCH DERMATOLNOL 132, JAN 1996
`37
`
`Page 6 of 10
`
`

`

`Cllntcal null analogical Results In Toenail
`Dnycimmymis II End-Point Fellow-up Visit‘
`
`
`
`Ell-Palm Evaluation
`. Clinical cure
`Clinical response
`Mycolauical outcome
`Potassium hydroxide preparation
`Cutture. negative
`Mycological cure
`
`a. tileJ'l'ohI No.)
`of him
`
`3 Must
`(n-ZS)
`84 (21.95)
`88 (22125)
`
`12 (18125)
`80 (20/25)
`64 (15/25)
`
`4 Pulse:
`lit-:25)
`76 (19/25)
`84 (21:25)
`
`72 (1825)
`30 (20/25)
`72 (18425)
`
`
`
`be associated with an increase in nail growth. Clinical
`improvement was accompanied by the development of
`nail surface beading in several patients who were receiv-
`ing itraconazole (400 mg/d) (Figure 2, right). Histologi-
`cal examination demonstrated hyperplasia of the dorsal
`portion of the nail plate without parakeratosis or nail pit-
`ting (Flglll'o 4), The latter finding suggests a focal and
`temporary increase in the number of proliferating cells
`(in clusters) in the dorsal matrix. This beading has been
`found to be absent in patients who have been seen dur-
`ing further follow-up, suggesting that itraconazole may
`directly influence nail growth.
`The area of an altered nail plate decreased compa-
`rably in the two treatment groups with residual values
`of 2% vs 9% at end point (llglll'. 5). The length of un—
`affected nail in the target toenail increased steadily in both
`groups, with the appearance of an almost healthy toe-
`nail at month 6. There were no significant differences be-
`tween the groups.
`At end-point analysis of the follow-up, cultures were
`negative in 80% of the patients in both treatment groups.
`Mycolog'ical cure, as defined by cultures and negative po—
`tassium hydroxide preparations, was 64% and 72% for
`the three- and four—pulse regimens, respectively.
`None of the patients reported any significant side
`effects. The dosage of 400 mg that was given for 1 week
`each month was well tolerated; all patients evaluated the
`tolerability of itraconazole as being “very good.”
`
`@—
`
`*Resulrs found after itracanazala pulse therapy {400 mg/d for
`1 wit/each month tar three or tour pulses).
`Tana patient had fingernail onychomycasfs.
`
`itraconazole became undetectable from month 9 on-
`ward. The highest individual concentrations of 1064 and
`1166 ng/g were reached at month 6 for toenails and fin-
`gernails. respectively.
`In the group of patients who were receiving four con—
`secutive monthly pulses (Figure 1, bottom), the mean
`itraconazole concentrations in the toenails ranged from
`32 ng/g (month 1) to 623 ng/g (month 8) and persisted
`to month 13. At that time point, the itraconazole con-
`centration was 165 ng/g. ln fingernails, the concentra—
`tions were 42 rig/g (month 1), which increased to 380
`ng/g at month 6 and dropped to 8 ng/g at month ll. The
`highest individual concentrations of 1549 and 946 ng/g
`were reached at month 7 for toenails and at month 9 for
`
`fingernails, respectively. In each pulse-dose group, the
`mean itraconazole concentrations in fingernails de-
`clined faster than those in toenails.
`For toenails, after 2 months of treatment, clinical
`improvement was observed in most of the patients. At
`month 3, clinical responses of 67% and 65% were ob—
`tained for the three- and four-pulse dosage groups, re-
`spectively, with a mycological cure of 24% in the three-
`pulse dosage group and 16% in the four—pulse dosage
`group at that time point. The response exceeded 80% in
`nearly all patients from month 6 onward. At the end-
`point analysis of the follow«up period, 88% of patients
`who were receiving three pulses and 84% of patients who
`were receiving four pulses were classified as being cured
`or markedly improved ('I'Illllo). There were no signifi-
`cant differences belween the two treatment groups. In
`the global assessment at end point, nails were classified
`as being clinically cured, with or without nail malfor-
`mation, in 84% and 76% of patients in the three- and four-
`pulse dosage group, respectively (P=.68). In the two pa-
`tients of each pulse treatment group who were considered
`as clinically cured before the end point of the follow—up
`between months 6 and 12, the clinical condition of the
`nail became worse or a relapse occurred in 8.6% (323)
`for the three-pulse dosage group and in 9.5% (2/21) for
`the four-pulse dosage group. llgm 2 and Figure 3
`illustrate representative clinical results in the two pa-
`tients who were treated with the three- and four-pulse
`therapy regimen, respectively.
`in some patients, itraconazole therapy appeared to
`
`ARCH DERMATOUVDL I32, JAN 1996
`38
`
`The features that determine the effectiveness of an anti-
`
`fungal agent include its direct antifungal effect and the
`availability of the drug at the site of infections.59 There-
`fore, many recent investigations with antifungal agents
`have focused on nail pharmacokinetics in an attempt to
`optimize the treatment of onychomycosisFa-f'viz-““’-““"'5‘“'2
`This has resulted in a more rational dosing strategy with
`a shift in the duration of itraconazole therapy for toenail
`onychomycosis from long—term use that lasts several
`months to treatment for 3 months and, most recently,
`to the concept of intermittent pulse therapy. Studies of
`itraconazole kinetics have been essential in the devel-
`
`opment of the drug for the treatment of onychomycov
`sis but have also underlined the differences in pharma—
`‘ cokinetics and pharmacodynamics compared with
`those of terbinafine and fluconazole. leading to differ-
`ent approaches for treating onychomycosis.
`These other oral antifungal agents have recently
`become available to treat onychomycosis.555" Terbin—
`afine, an allylamine aniifungal agent, is a lipophilic and
`keratophilic compot.tnd”‘-‘”“’5 that is effective against
`derrnatophytes. but less active against Candida species.
`Terbinafine also penetrates the nail by diffusion through
`the nail matrix and nail bed.cum The efficacy of terbirt-
`afine has been extensively evaluated in onychomycosis
`for toenail infections—first with long— term therapy (250
`mg/d for 12 months of continuous therapy).2““ A treat-
`ment period of at least 6 weeks is currently recom-
`mended for fingernail infections, and a treatment pe—
`riod of 12 weeks is recommended for toenail disease. It
`
`
`
`Page 7 of 10
`
`

`

`
`
`
`Flame 2. Tn'chophyton tubrum onychomyoosis of the hip toenaii (as wet! as at the fourth and fitth digits) in a 34-yearpid woman who received a tour—poise
`regimen of itraconazoie (400 mg/d for 1 week each month} beiore therapy (iatt) and at faffaw-up performed 12 months after starting therapy (ie, a months
`not receiving therapy) (right). A clinical and mycaiogicai cure was obtained at month 5. The patient remained cured as of the 12-month follow-up visit (right).
`
`Figure 3. Trichophyton ruhrurn onychomycosis of the toenail (third and fourth digits) in a 37-year-old woman who received a three-pulse regimen of
`itraconazote (400 mp/d for 1 week mch month) before therapy (iett) and at toiiaw-up performed 12 months after starting therapy (to. 9 mo