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`4) 2006 European Academy oi Dermatology and Vertereoloey
`
`CFAD v. Anacor, |PR201 5-01776
`ANACOR EX. 2073 - 2/‘IO
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`CFAD v. Anacor, IPR2015-01776
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`

`
`CONTENTS
`
`Volume 20, Issue 10, November 2006
`
`REVIEW ARTICLE
`
`1171
`
`1188
`
`1194
`
`1197
`
`1201
`
`1207
`
`1214
`
`1220
`
`1226
`
`1232
`
`1237
`
`1243
`
`1252
`
`1256
`
`Treatment of inflammatory dermatoses by tumour necrosis factor aiitagonists
`A. Jacobi", 1/. /l/f(I/’IfL’)‘, G. Sc/mler, M. Herzl
`
`ORIGINAL ARTICLES
`
`Pulse itracoiiazole vs. continuous terbiiiafine for the treatment of derinatopliyte toenail oiiyclioiiiycosis in
`patients with diabetes mellitus
`A.K. Gupta, M.D. G01/L’I', C.l/V. Lynda’
`Fifth toenail clinical response to systemic antifungal therapy is not a marker of successful therapy for other
`toenails with onyclioinycosis
`S. Amer, N. Nir, T. Henri
`
`Multiple neonatal staphylococcal cold abscesses of the large folds
`R Huber, C. Léazité-Labieze, G. Liim, J. Sm‘/(II’l_£]llC’, A. Taieb, F. Borcilcvi
`The prevalence of HFE C282Y gene imitation is increased in Spanish patients with porpliyria cutanea tarda
`without hepatitis C virus inlectioii
`A. Tall, R. Ce/is, M.D. Ozcil/ci, M. Biwgi/ei‘a, C. Herrera, M.G. Erci//ci
`Association of HLA liaplotype with alopecia areata in Chinese Hans
`F.-L. Xi'an, D.-Q. Ye, S. Yai1_q, F.-S. Z/ioz/, S.—M. Z/mi/,
`l’.—G. Z/ii./, Y.-H. Liaiig, Y.-Q. Rcii, X.-J. Zlmiig
`Algoritlimic reproduction of asyininetry and border cut—off parameters according to the ABCD rule for
`dernioscopy
`G. Pt.’//lI('fll'If, C. Grana, S. S€idL’l'I(1l‘/
`
`IinmLiiioliistoclieiiiical study of apoptosis niarl<ers and involvement of clieinokiiie CXCR4 in skin Merkel cell
`carcinoma
`
`M.G. T1/sci‘, G. LIlC[Il‘flIf, M. Gin/igizico/iii, A. Zizzi, P. Crimire, G. Ri'corti', G. Bf(Iyfl‘Ii
`Broad-band ultraviolet B pliototlierapy is associated with elevated serum tliiobarbitiiric acid reactive
`substance and nitrite-nitrate levels in psoriatic patients
`Yi'Idi'ri'm SOZl'I1L’l'I
`I. l<ili/1c KtlI‘£1t1l‘S/(II1, F. Gi'i;qi'/1 Stlyffl, I. Ermm, S. A/per, G. Ozmrk,
`Seroprevaleiice of herpes simplex virus type 1 and type 2 in Tui'l<ey
`N. [)0/til‘, S. Seidarog/i/, G. Y1’/mciz, S. Ergiii
`Derinatofibrosarcoina protul)erans: a population-based cancer registry descriptive study of 66 consecutive cases
`diagnosed between 1982 and 2002
`D. /Vl0I’Il’Il‘t’I‘, C. Vidal, L. lVlarti'ri, A. Dmizori, PI I’el/clier, E. I’iizemi!, M.P. Algros, I). Bf(Il'lC, R. L(IIH‘t’l'1l, P.I1. HI!/IIl7L’I'I,
`IE Aiibin
`
`Efficacy and safety of a new clobetasol propioiiate 0.05% foam in alopecia areata: a raiidoinized, doiible-bliiid
`placebo-controlled trial
`A. Tosii, M. Iorfzzo, G.L. Botta, M. Mi’/mu’
`
`Treatment of poil<iloderina of Civatte with the ptilsed dye laser: a series of patients with severe depiginentation
`M.M. Mefjs, F.A.A. Blo/<, M.A. de Ric
`
`Therapeutic effects of a 12-week course of alefacept on nail psoriasis
`J.E.M. I<b‘ri/er, A.M.G. Lci/'igcw0iitei‘s, P.C.M. Van De I<erk/mfl M.C. PCISC/'1
`The effectiveness of interinittent isotretinoin treatment in mild or moderate acne
`l/. Kaymci/<, N. iltcr
`
`This material was rnpied
`at the NLM anvd may be
`Subject Ufiflwpyright Laws
`
`CFAD V. Anacor, |PR2015-01776
`ANACOR EX. 2073 - 3/10
`
`CFAD v. Anacor, IPR2015-01776
`ANACOR EX. 2073 - 3/10
`
`

`
`
`
`1261
`
`1266
`
`1271
`
`1277
`
`1287
`
`1296
`
`1302
`
`1307
`
`1314
`
`1317
`
`1322
`
`1325
`
`1328
`
`1329
`
`1331
`
`1332
`
`1334
`
`1335
`
`1337
`
`1338
`
`1 340
`
`Skin capacitance mapping of psoriasis
`E. X/mi/f/aire-U/mdcz, C. Piérard-Fm/ic/rimorzt, G.E. I’ie'rarci
`Burow’s grafts in tlie facial region
`R. Cczbezcz-MarI1’neZ, V. Leis, M. Campos, 1’. de la CL/evn, R. Smirez, P. Lcizaro
`Outpatient dermatology major surgery: a 1-year experience in a Spanish tertiary hospital
`3. Ferrzcirzdez—.l02ye, C. Pe/in-I’e/mbac/, V. Vieirzz, S. Pziradela, J. Rodriguez-Loza/'10, A. Fermir1dez—Erztra/go, J. Gzircfa-S1"/Va,
`lj‘. F0/isecci
`
`Treatment of patients with atopic dermatitis using wet-wrap dressings with diluted steroids and/or emollients.
`An expert panel's opinion and review of the literature
`/11’. Omnje, /LC./l. Devillezs, B. Kurzz, S.L. .10/765', L. DeRaeve, D. Van Gysel, FIB. de Wzmrd-van der Spek, R. Grima/I,
`/1. Torre/0, .1. S/eve//zs, .1. Harper
`The prevalence of acne in the north of Portugal
`J.M. Amado, M.E. Mates, /1.M. /tbreu, 1.. Loureiro, J. 0/iveirn, A. Verde, /1. Mnsm
`
`Do systemic antibiotics increase the survival of a full thickness graft on the nose?
`D.I.M. Kuijpers, N.W.J. S/Heels, K. l.api€’re, M.R.T.M. T//z1'ss'en, G./l.M. Kre/<e/s, I-I./l.M. N€£NI1(Il’II'I
`A simple and practical method in treatment of ingrown nails: splinting by flexible tube
`S. Nzzzari
`
`Efficacy and safety of a new single-dose terbinafine 1% formulation in patients with tinea pedis (athlete's
`foot): a randomized, double-blind, placebo—controlled study
`J.P. Ortarme, H.C. I<0rI1'/73. C. V1'gzu'e'—Val/cmet, C. Larnfer. E. Szzvalimy
`
`CASE REPORTS
`
`Unilateral eruptive vellus hair cysts occurring on the lace
`B.-L. Lew, M.—H. Lee, C.-R. Haw
`
`Eosinophilic folliculitis in a Caucasian patient: association with toxocariasis?
`A. Gesieric/7, S. Herzoy, S.M. Grmiewala’, D. Tappe, E.-B. Br<')'cker, M.P. Sc/752'//1
`Cutaneous melioidosis
`
`L. Tea, Y.-K. Tay, K..1.F. Mzmeer
`Surgical management of extensive gnathophyma
`M.V. Sc’/11'r1!/er, E. /lrbab, W. /tberer. S. Sperzdel, E. Sc/tar/mg!
`
`LETTERS TO THE EDITOR
`
`Cutaneous sarcoidosis by interferon therapy in a patient with melanoma
`A. /1/onso—1’e'/'62, M. Ba//esrero-Dz’ez, J. Fraga, A. Gzzrcfa-D/’ez, J. Fermiudez-Herrera
`The first report of non-hereditary benign telangiectasia
`I. Na/<aji/mi, R. Okuyzmm, T. Terz/1', I-I.
`'I‘aga/7'11’, S. /liba
`Partial depigmentation arise in the naevus of [to
`C. Tan, W.-Y. Z/m, Z.—S. Ming
`A case of infantile psoriasis with pseudoainhurn successfully treated with topical pimecrolimus and low-dose
`narrowband UVB phototherapy
`S.-J. /1/m, S.-H. 0/1, S.-E. C/1arz_q,J.-H. C/101‘, .1.-K. K0//I
`Toxic shock syndrome with extensive epidermal necrosis in a 9-year-old girl
`K. Ni.s‘/riiyori, K. I;/mva, K. Sam/<i, Y. Sawada
`A case of Behcet’s disease: extensive venous involvement without clinical signs of peripheral occlusions
`’I‘. 1'1/<rzur, E. Fen], M.C. Soya/, E. Mert, S. Oz/mu, /LT. Giinea
`Dermograpltism secondary to trauma from a coral reef
`.l.J. Wu, D.B. Hlltmg,
`Mirrase, G.D. Wei‘/zslei//2
`Neutrophilic eccrine hidradenitis to acetaminophen
`IZEL. Sayed, A. Ammoizry, M. C/mlmbi, R. D/iczybi, ./. Bazex
`Papular mucinosis associated with subclinical hypothyroidism: improvement with thyroxine therapy
`G. Marli/1-E2111./emz, M. Sam‘/iez-leega/in, .1. Mnssmza-Gi/, P. Umbe/‘I-/\/Iil/er
`
`This material was mxpsied
`at the NLM and may be
`Subject U12 {is-pyright Laws
`
`CFAD v. Anacor, |PR20‘|5-01776
`ANACOR EX. 2073 - 4/10
`
`CFAD v. Anacor, IPR2015-01776
`ANACOR EX. 2073 - 4/10
`
`

`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`JEADV ISSN 1468-3083
`
`ORIGINAL ARTICLE
`
`Pulse itraconazole vs. continuous terbinafine for the treatment of
`dermatophyte toenail onychomycosis in patients with diabetes
`mellitus
`
`AK Gupta,*’r¢ MD Gover,qE CW Lynde§
`
`)Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Sciences Center (Sunnybrook site) and the University of
`Toronto, Toronto, Canada, tMediprobe Research lnc., London, Ontario, Canada, §Division of Dermatology, Department of Medicine, Toronto General
`Hospital and Toronto Western Hospital (Western site), and the University of Toronto, Toronto, Canada
`
`Keywords
`diabetes, itraconazole, onychomycosis,
`Wbinafine
`
`*Corresponding author, 645 Windermere
`Road, London, Ontario, Canada NSX 2P1,
`tel. +519 6574222 ext. 277; fax +519 6574233;
`E-
`"l:
`t @
`I’ k.
`mm agup a exewm Com
`Received: 25 May 2005,
`accepted 4 July 2005
`
`DOI:10.1l11/j.l468-3083.2006.01698.><
`
`Abstract
`
`V
`
`.
`the most
`itracona7.ole are two ()1
`terbinafine and oral
`Background Oral
`common agents used for the treatment of toenail dermatophyte onycho-
`mycosis. Despite the fact that diabetic patients are Inore likely to have onycho-
`mycosis than normal individuals are, there is little research into the efficacy
`of standard oral regimens of terbinafine and itraconazole for onychomycosis
`.
`.
`.
`.
`in the diabeticpopulation.
`Study design We present a prospective, randomi7.ed, single-blind, parallel
`group, comparator-controlled, multi-centre study designed to assess the
`efficacy of the pulse itraconazole (200 mg twice daily,
`1 week on, 3 weeks off,
`for 12 weeks) vs. Continuous terbinafine (250 mg once daily lor 12 weeks) oral
`therapies in the treatment of dermatophyte toenail distal and lateral subungual
`onychomycosis (DLSO) in the diabetic population.
`Efficacy parameters Primary efficacy measures included mycological cure
`rate (negative KOH and culture) and effective cure (mycological ctire plus nail
`plate involvement of 10% or less) at Week 48.
`Results At Week 48, mycological cure was attained by 88.2% (30 of 34) and
`79.3% (23 of 29) of patients in the itraconazole and terbinafine groups,
`respectively (P not significant). Effective cure (mycological cure with 3 10% of
`nail plate involvement) was attained by 52.9% (18 of 34) of the itraconazole
`group and 51.7% (15 of 29) ol the terbinafine group (P not significant). Three
`itraconazole patients experienced side effects in the lorm of gastrointestinal
`problems. There were no serious adverse events and no interactions with
`concomitant medications recorded.
`
`Discussion Both continuous terbinaiine and itraconazole pulse therapy are
`effective and sale in the management of dermatophyte toenail onychomycosis
`in people with diabetes.
`
`Introduction
`
`Onychomycosis can cause thickened and mycotic nails,
`which results in pressure necrosis of the nail bed. Toenails
`may also become brittle and sharp, often resulting in
`injury to the surrounding skin. Diabetics, who often
`possess peripheral neuropathy,
`tend to have impaired
`sensation, which can lead to unnoticed trauma or
`
`There was no conflict of interest. The study was sell‘-luntled.
`
`ulcerations, and poor wound healing due to compromised
`circulation and reduced tissue oxygenation. These ulcera-
`tions, if lelt untreated, can lead to infections that maybe
`serious and possibly life-tlireatening.”
`In a multi-centre survey of 550 diabetic patients by
`Gupta etal.‘ it was determined that diabetic patients are
`more likely to have onychomycosis than normal individ-
`uals do and it was projected to affect approximatelyone-
`third of subjects with diabetes.‘ In the year 2000 there was
`an estimated 171 million cases of diabetes in adults aged
`
`1188
`
`JEADV 2006, 20, 1188-1193(5) 2006 European Academy of Dermatology and Venereology
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`atthe NLM and may be
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`
`Gupta et a/.
`
`ftraconazole or terbinafine for the treatment of onychomycosis in diabetic patients
`
`is estimated that
`2 20 years worldwide. Furthermore, it
`by the year 2030 the prevalence worldwide will have
`increased to approximately 366 million cases.“ A MEDLINE
`search (1966-2005) revealed only one study‘ that
`evaluated the efficacy of onychomycosis treatment
`in
`individuals with diabetes. We present a study designed to
`assess the efficacy of the pulse itraconazole and continu-
`ous terbinafine oral therapies for dermatophyte toenail
`onychomycosis in the diabetic population.
`
`Patients and methods
`
`randomized, evaluator-blind,
`This was a prospective,
`parallel group, comparator-controlled, non-industry spon-
`sored, multi-centre study designed to assess the efficacy
`and safety of itraconazole (itra) or terbinafine (terb) in the
`treatment of distal and lateral subungual onychomycosis
`(DLSO) in people with diabetes mellitus.
`
`Inclusion and exclusion criteria
`
`To be eligible for enrolment, patients were required to
`have either type I or II diabetes mellitus and a clinical and
`mycological
`(positive potassium hydroxide (KOH) and
`culture) diagnosis of a dermatophyte infection of at least
`one great toenail with 2 10% involvement. Patients had
`to be 18 years old or older. Female patients were required
`to have a negative urine pregnancy test and women of
`childbearing potential had to be on an effective means of
`contraception during the trial.
`Patients were excluded from the trial for the following
`reasons: baseline liver function tests (alanine amino-
`transferase (ALT), aspartate transaminase (AST), alkaline
`phosphatase and total bilirubin) elevated to more than
`twice the upper limit of normal; history of uncontrolled
`renal or hepatic disease; treatment with innnunosuppres-
`sant drugs within 6 months; treatment with systemic or
`topical anti-fungal therapy within 12 months or 4 weeks,
`respectively, prior to screening; history of untreated malig-
`nancy other than basal or squamous cell carcinoma. Women
`who were pregnant, trying to get pregnant, or were breast-
`feeding were also excluded from the trial.
`Patients were discontinued from the study if they expe-
`rienced significant side effects or developed laboratory test
`abnormalities, which in the opinion of the investigator
`merited withdrawal from the trial. All patients provided
`written informed consent. This study protocol was approved
`by an Institutional Review Board.
`
`Study design
`
`Patients
`
`meeting
`dermatophyte onychomycosis of the target great toenails
`
`inclusion/exclusion
`
`criteria with
`
`Continuous terbinafine
`
`Pulse itraconazole
`
`
`
`
`
`
`8
`Weeks of treatment
`Terbinatine: 250 mg qd; Itraconazole: 200 mg bid
`
`12
`
`fig. 1 Pulse itraconazole (200 mg twice daily) and continuous terbinafine
`(250 mg once daily) regimens for 12 weeks of treatment of dermatophyte
`onychomycosis in diabetic patients.
`
`were allocated through contputer-generated block random-
`ization in blocks of 10 in a ratio of 1
`:
`1
`to one of two
`
`treatment groups (fig. 1). Patients in the itracona7.ole pulse
`therapy group were instructed to take three pulses of oral
`itraconazole over 12 weeks. Each pulse consisted of 2()() mg
`of itraconazole twice daily for one week on medication
`(1 pulse), followed by 3 weeks off. Those assigned to the
`continuous terbinafine regimen were instructed to take
`250 mg of oral terbinafine once daily for 12 weeks. Random-
`ization was concealed and performed by someone other
`than the investigators assessing the outcome measures.
`During the treatment period, the designated evaluators
`remained blinded. For consistency,
`the same evaluator
`carried out all visit assessments. The samples were pro-
`cessed by the mycology laboratory with the laboratory
`staff blinded to the treatment arm and time-point.
`Patients were assessed at Weeks 1 (baseline), 6, 12, 24-,
`36, 48, 60 and 72. The primary end-point was 48 weeks;
`however, some patients were followed up to Week 72 (follow-
`up population). At each visit, a sample of the affected
`target toenail was taken for microscopy and mycology
`culture and the area of affected target toenail was evaluated.
`Liver function tests were conducted at baseline, after
`
`6 weeks of terbinafine therapy or two pulses of i1racona-
`zole, and at the end of drug therapy.
`
`Compliance
`
`Patients were questioned about missed doses of drug at
`each visit and medication packages were inspected to
`confirm product use. Adverse events (AE5) reported by
`the patients were recorded at each visit, and the potential
`relationship of the AEs to the study drug was assessed.
`
`Efficacy parameters
`
`The primary efficacy measures were mycological cure rate
`(negative K011 and culture) and effective cure at Week
`48. Effective cure was defined as mycological cure plus
`either clinical cure or nail plate involvement (affected
`area) of 10% or less.
`
`JEADV 2006, 20, 1 t88~i 193 ts) 2006 European Academy of Dermatology and Venereology
`This material was copied
`atthe NLM and may be
`Subject U.‘:1rCLa-pyright Laws
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`

`
`Itraconazole or terbinafine for the treatment of onychomycosis in diabetic patients
`
`Gupta et al.
`
`Statistical analysis
`
`Response rates were analysed using 95 "/0 confidence intervals.
`A significance level of 0.05 was used for all statistical tests.
`The primary time-point of interest was 48 weeks and the
`secondary was 72 weeks. The baseline characteristics such
`as gender, diabetes medications, concomitant diseases and
`the aetiological organisms were compared using the Pearson
`chi—square test. The mean ages as well as mean affected
`areas at baseline, Week 48 and Week 72 were compared
`between groups using an independent samples r-test. The
`change in mean affected area from baseline to Week 48
`and Week 72 within each treatment group were analysed
`using the paired t-test. The mycological and effective cure
`rates were analysed using the Pearson chi-square test.
`Missing data was entered with the last observation carried
`forward method. Statistical analysis was performed on the
`evaluable patients (patients who completed the study per
`protocol). All subjects who received at least one dose of the
`treatment medication were included in the analysis. All
`statistical analysis was performed using SPSS 9.0 for
`Windows (SPSS Inc., Chicago, IL, USA).
`
`Results
`
`itraconazole group withdrew because of gastric side
`effects. The remaining five patients withdrew for reasons
`unrelated to study medication. In total, there were 64
`evaluable patients (per protocol population) (rim = 34,
`1'Im1_ = 30) at Week 48. At follow-up Week 72, 19 addi-
`tional patients were lost
`to follow-up, due to reasons
`unrelated to study medication; data was available for
`analysis from 45 patients (Ilim = 1‘), limb = 26).
`Patient demographics and baseline characteristics are
`sunn'nari'/.ed in Table 1. A total of 34 males and 36 females
`
`participated in the study. There was no significant differ-
`ence in gender, mean age, causative organism, or type of
`diabetes control between the treatment groups at base-
`line. The types of oral hypoglycaemics taken by patients
`are listed in Table 2. There was no significant difference
`between comorbid diseases, except high blood pressure,
`which was significantly higher in the itracona'/.ole group
`(1) < 0.05).
`All patients had dermatophyte onychomycosis (Table 1),
`including Tric//zap/iylorz rubrum (80.0%), T. me/2m_q/‘op/zyIc*s
`(15.7%) and IE‘picier111op/1yIa11flocossum (4.3%); there was no
`significant difference in dermatophyte infection between
`the treatment groups at baseline.
`
`Demographics and baseline characteristics
`il 1'-I
`
`= 35, /1,,.,.,, = 35): this
`Seventy patients were enrolled (17
`was the intention-to—treat population (fig. 2). Six patients
`withdrew consent, one from the itraconazole and five
`
`from the terbinafine treatment arms. The patient from the
`
`Mycological cure at Week 48 was 88.2% (3() of 34) in the
`itraconazole group vs. 76.7% (23 of 30) in the terbina-
`fine group (fig. 3). The mycological cure rates in the
`itraconazole and terbinafine groups at Week 72 were
`84.2% (16 of 19) and 76.0% (19 of 2'3), respectively.
`
`Mycological cure
`
`Total (ITT)
`I7 = 70
`(n = 34 males;
`n = 36 females)
`
`
`
`
`Baseline ITT
`Terbinafine
`n = 35
`
`
`
`Baseline ITT
`ltraconazole
`n = 35
`
`
`
`
`
`PP Week 48
`n = 84
`
`Withdrew
`n = 1
`
`PP Week 48
`n = 30
`
`Withdrew
`n = 5
`
`
`
`;
`
`LTF
`n=4
`
`Follow-up
`Week 72
`n = 26
`
`ITT — Intent-to-Treat
`
`PP — Per Protocol
`
`LTF - Lost to Follow-up
`
`fig. 2 Patienttreatment group allocation and the
`number of patients enrolled, withdrawn and lost
`to iolloweup.
`
`1190
`
`JEADV 2006, 20, 1 188-1 193 (E) 2006 European Academy of Dermatology and Venereology
`This material was copied
`at the NLM and may me
`Su bjeezt Ufitlepsyright: Laws
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`CFAD v. Anacor, |PR201 5-01776
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`

`
`Gupta et al.
`
`ltraconazole orterbinafine for the treatment of onychomycosis in diabetic patients
`
`Table 1 Demographics and baseline characteristics of diabetic patients
`with toenail onychomycosis
`
`88.2
`
`Characteristic
`
`ltraconazole Terbinafine
`(n = 35)
`(n = 35)
`
`Total
`(n = 70)
`
`5777 i: 2.303 63.65 i1.879 60.67 i 1.522
`16
`18
`34
`19
`17
`36
`
`Mean age (years) : SE
`Male
`Female
`Diabetes control
`Diet
`Insulin
`Oral hypoglycaemics
`Concomitant diseases
`Peripheral vascular
`disease
`Coronary artery disease
`High cholesterol
`High blood pressure
`Dermatophytes
`Trichophyton rubrum
`Trichophyton
`mentogrophytes
`3
`O
`3
`Epidermophyton
`fiocossum
`
`6
`5
`24
`
`1
`
`1
`9
`13
`
`25
`7
`
`5
`6
`25
`
`2
`
`5
`12
`4
`
`31
`4
`
`11
`11*
`49*
`
`3
`
`6
`21
`17
`
`56
`1 1
`
`
`
`
`
`Curerates($8)
`
`20-
`
`Effective
`
`Mycological
`
`I ltra I: Terb
`
`fig. 3 ‘he mycological and effective cure rates at Week /18 for patients with
`diabetes meliitus and dermatophyte onychomycosis were not significantly
`different between the itraconazole and terbinafine treatment groups.
`
`Affected area
`
`The mean affected area significantly decreased from
`baseline by 54.7% and 57.4% at Week 48 and Week 72,
`respectively, within the itraconazole group (P < 0.05).
`Similarly, in the terbinafine group there was a significant
`decrease in mean affected area from baseline by 45.5%
`and 54.9%, at Week 48 and Week 72 (P< 0.05), respec-
`tively. There was no significant difference in mean affected
`area between the treatment groups at baseline, Week 48
`or Week 72.
`
`Safety and tolerability
`
`reported were gastrointestinal
`The only side effects
`problems,
`including diarrhoea or gastric pain (/1: 3).
`These were considered related to or possibly related to
`itraconazole use. One patient in the itracona7.ole group
`dropped out title to gastric pain. There were no serious
`adverse events or interactions with concomitant medica-
`
`tions recorded from either treatment group. There were no
`laboratory abnormalities reported.
`
`Discussion
`
`Our study evaluated the efficacy of itracona’/.ole and
`terbinafine in the treatment of dermatophyte toenail
`onychomycosis in diabetics; however, we have not
`addressed efficacy for onychomycosis caused by Cmididn
`spp. or non—dern1atopl1yte moulds, as dermatophytes are
`the causal organisms in approximately 90% of toenail
`infections.“
`
`Ottr efficacy rates for terbinafine or itraconaxole are
`comparable to those of previous sttitlies.“7”‘ In the present
`study, the clinically affected area decreased significantly
`from baseline in both the terbinafine and itraconazole
`groups; however, the mean affected area was not different
`
`*One patient in theterbiriafine group received concomitant metformin and
`insulin.
`
`Table 2 Types of oral hypoglycaemics taken by diabetic patients with
`dermatophyte toenail onychomycosis
`
`oral
`hypoglycaemics
`
`Itraconazole
`(n = 35)
`
`Terbinafine
`(n = 35)
`
`Total
`(n = 70)
`
`10
`1
`9
`Chlorpropamide
`4
`O
`4
`Glimepiride
`19
`19
`0
`Glyburide
`24
`6
`18
`Metformin
`
`
`
`31 * 261Total 57
`
`*5 patients received concomitant chiorpropamide and metformin;
`2 patients received concomitant glimepiride and metformin.
`ll patient received concomitant metformin and glyburide; 1 patient
`received concomitant metformin and insulin.
`
`Mycological cure rates were not significantly different
`between the treatment grottps at Week 48 or Week 72.
`
`Effective cure
`
`At Week 48, effective cure rates were 52.9% (18 of 34-)
`in the itraconazole group and 50.0% (15 of 30) in the
`terbinafine group (fig. 3). At Week 72, the effective cure
`rates were 68.4% (13 of 19) and 69.2% (18 of 26),
`respectively. The cure rates were not significantly different
`between the two groups at Week 48 and Week 72.
`
`/EADV 2006, 20, 1188419319 2006 European Academy of Dermatology and Venereology
`This mate rial was stapled
`acme NLM and may be
`Subject US flspyright Laws
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`CFAD V. Anacor, |PR20‘l5-01776
`ANACOR EX. 2073 - 8/‘IO
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`

`
`Itraconazole or terbinafine for the treatment of onychomycosis in diabetic patients
`
`Gupta et al.
`
`Table 3 Oral anti-diabetic and antifungal agents and the cytochrome
`P450 enzymes associated with their metabolism
`
`Agent
`
`Cytochrome P450 subfamily
`
`Anti-diabetics
`
`Sulphonylurea
`sulphonylurea
`Sulphonylurea
`Sulphonylurea
`Sulphonylurea
`Sulphonylurea
`Biguanide
`Meglitinide
`Meglitinide
`Thiazolidinedione
`Thiazolidlnedione
`
`CY3 2C9
`CY? 2C9
`CY3 2C9
`CY’ 2C9
`CY” 2C9
`CY’ 2C9
`—
`CY3 2C9; CYP 3A4
`CY? 2C8; CYP 3A4
`CY3 2C8; CYP 3A4
`CY” 2C8; CYP 2C9
`
`Chlorpropamide
`Gliclazide
`Glimepiride
`Glipizide
`Glyburide
`Tolbutamide
`Metformin
`Nateglinide
`Repaglinide
`Pioglitazone
`Rosiglitazone
`Anti-fungals
`CY’ 3A4
`Azole
`ltraconazole
`CY3 3A4
`Azole
`Ketoconazole
`
`
`AzoleFluconazole CY3 2C9; CYP 3A4
`
`between the two treatment groups at study-end. Further-
`more, both mycological and effective cure rates were sim-
`ilar in both treatment groups. Neither drug was deemed
`significantly more efficacious than the other in the treat-
`ment of dermatopliyte toenail onychomycosis within the
`diabetic population.
`There is a paucity of studies evaluating the efficacy of
`the oral anti-fungal agents for the treatment of dermato-
`phyte toenail onychomycosis in the diabetic popula-
`tion. Farkas etal." treated 104 enrolled diabetic patients
`having onychomycosis with terbinafine 250 mg/day for
`12 weeks. Efficacy was evaluated on the per protocol
`population (11: 89). At Week 48, the mycological cure was
`73% vs. our finding of 76.7%. After 12 weeks of treat-
`ment, 83% of patients had the sa