mykosen 19 (7) 251--256
`~) Grosse Verlag 1976
`
`Eingegangen am 29. September 1975
`
`Miconazole alcoholic solution in the treatment
`of mycotic nail infections
`
`J. VANDERDONCKT, W. LAUWERS and J. BOCKAERT
`
`Summary
`
`Nineteen men, suffering from dlronic onychomycosis of their toe nails, were treated for
`32 weeks with a 2 ~o miconazole alcoholic solution. Of 20 nails positive by culture before
`treatment, all were cured clinically and 15 showed no growth of pathogenic fungi six
`months after treatment. The medication was excellently tolerated.
`
`Zusammenfassung
`
`Neunzehn m~nnliche Patienten, die mit daronischer Onychomykose der Zehenn~igel
`befallen waren, wurden wiihrend 32 Wochen mit einer 2 ~o Miconazole enthaltenden
`AlkohollSsung behandelt. Von den 20 mykologisch positiv gesicherten N~igeln haben sich
`alle nach Behandlung als klinisch geheilt erwiesen, und bei 15 yon ihnen wurden 6 Monate
`nach Behandlung keine pathogenen Pilze nachgewiesen. Die Miconazol-Lfsung wurde aus-
`gezdchnet vertragen.
`
`In recent years, several new drugs have been introduced for the treatment of onycho-
`mycosis, by either local or systemic routes. Results have often been disappointing.
`In 1971, however, BOTTER (1) reported extremely good results in the treatment of
`onychomycosis with miconazole 2 ~o cream. The drug was applied under occlusive ban-
`dages and, in some instances, combined with griseofulvin therapy. HEmKE confirmed
`these findings (2).
`Miconazole is a synthetic compound, produced in the laboratories of Janssen Pharma-
`ceutica. It has proved to be active against most fungi, including dermatophytes and yeasts,
`and against gram-positive bacteria, both in vitro (3) and in vivo (1, 4, 5, 6).
`When the drug became available as a film forming alcoholic solution,* the advantages
`of th.is formulation over the cream for the treatment of onychomycosis were obvious, i. e.
`easy application of the drug and inconspicuousness of the treatment.
`In the present paper we report on the first clinical evaluation of 2 % miconazole alco-
`holic solution.
`
`* Formula: miconazole base
`carbosept No. 525
`carbosept No. 515
`propylene glycol U. S.P.
`ethanol U. S. P. ad
`
`0.2 gram
`0,475 gram
`0.025 gram
`gram
`2
`ml
`10
`
`Key words: Miconazole a!coholic solution, onychomycosis, dermatophytes, yeasts.
`
`ACRUX DDS PTY LTD. et al.
`EXHIBIT 1035
`IPR Petition for
`U.S. Patent No. 7,214,506
`
`1 of 6
`
`

`
`252
`
`J. VANDERDONCKT, W. LAUW~RS and J. BOCKAERT
`
`Table 1: Individual case data; causative fungi and severity of lesions before treatment
`
`Patient
`No.
`
`Age
`
`Left food
`
`Fungus
`
`Fungal etiology
`
`Right food
`
`Severity
`of lesion
`
`Fungus
`
`Severity
`of lesion
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`
`67
`68
`78
`36
`69
`42
`69
`65
`65
`53
`67
`43
`44
`37
`49
`37
`43
`47
`30
`
`Trichophyton mentagrophytes + + +
`+ + +
`T. mentagrophytes
`+ + +
`T. rubrum
`+ + +
`T. mentagrophytes
`+ +
`T. mentagrophytes
`negative
`+ + +
`+ +
`T. mentagrophytes
`+ + +
`T. rubrum
`+ + +
`negative
`positive
`+ + +
`+ +
`positive
`+ + +
`T. mentagrophytes
`negative
`+ + +
`Candida troplcalis
`+ +
`+ + +
`negative
`--::"
`+ +
`Scopulariopsis brevicz~ulis
`+ +
`+ +
`negative
`+ +
`negative
`
`negative
`+ + +
`0
`--**
`+ + +
`negative
`Trichosporon cutanet~m + + +
`T. mentagrophytes
`+ +
`T. mentagrophytes
`+ + +
`T. mentagrophytes
`+ +
`+ +
`T. rubrum
`T. rubrum
`+ + +
`T. mentagrophytcs
`+ +
`+
`T. mentagrophytcs
`T. mentagrophytcs
`+ + +
`negative
`+ + +
`negative
`+ +
`negative
`+ +
`--*
`+ +
`+ +
`S. brevicaulis
`--**
`0
`--**
`0
`
`*: no mycological examination
`"*: normal nail
`
`O: not affected
`+ : light
`+ + : moderate
`+++: severe
`
`Material and methods
`
`Patient selection: Nineteen male long-term in-patients, were selected for the trial
`(median age: 49 years; range: 30--78 years) (Table 1). All of them presented with clinical
`signs of onychomycosis of at least the big-toe nails. These included subungual keratosis,
`discoloration, onycholysis, brittleness of the nails and, in some, paronychial inflammation.
`The duration of the infections ranged from 2 to 20 years. None of the patients had
`received antifungal treatment during the last two years.
`Assessments and identification of the etiologic fungi: Several patients had more than
`one infected nail. The nails were clinically scored with regard to the severity of the lesions
`(Table 2). Samples of the affected nails were taken and examined microcopically after
`potassium hydroxide clearing. Cultures were grown on Sabouraud P.S. and Sabouraud
`P. S. A. media. Identification of fungi was possible for 20 n~ils from 14 of the patients.
`Twelve infections were by Tricbopbyton mentagropbytes, 4 by T. rubrum, 2 by Scopu-
`lariopsis brevicaulis, 1 by Candida tropicalis and 1 by Tricbosporon cutaneum. Two nails
`positive on microscopical examanation, did not yield pathogenic fungi when cultured.
`Thirteen other nails presented a clinical picture of onychomycosis, but microscopic and
`cultural investigations were negative. One patient was not present at the time when
`samples for mycological procedures were taken.
`
`mykosen 19, Heft 7 (1976)
`
`2 of 6
`
`

`
`Miconazole alcoholic solution in the treatment of mycotic nail infections
`
`253
`
`Table z: Clinical evaluation of healing process during treatment period
`
`Pat. Nail
`No.
`
`4 w
`
`8w
`
`12 w 16 w 20 w Z8 w 32 w
`
`0
`0
`/ ,
`
`0
`0
`
`/
`
`I
`II
`II M
`I1
`I/
`
`II lit
`II III
`It
`lit
`
`o
`o
`
`I
`I
`I
`I
`
`o
`!
`
`e~
`
`ee
`
`/
`0
`
`o
`/
`
`!
`!
`o
`o
`/
`/
`o
`f
`0
`o
`
`0
`
`o
`e
`
`II
`M
`l/
`/
`II
`M
`I
`I
`/I
`I1
`o
`I
`
`M
`M
`
`M
`M
`o
`o
`
`o
`M
`0
`0
`
`f,
`
`/
`
`6
`
`M
`
`e
`
`o(cid:128)
`
`¢o
`
`MI MI
`MI
`let
`Ill
`tl1
`M/
`///
`
`ItM/
`/;1
`M/ MI
`III
`M/
`
`II/
`MI
`III
`IM
`II/
`//!
`M/ M/
`/M
`IM
`//t
`I//
`I1
`IM
`t
`M
`I//
`IM
`IM
`lit
`o
`I
`M M
`/
`M
`/
`M
`
`M
`
`o
`
`M!
`/ M
`
`I/ M
`
`# @
`
`3 7
`
`M IM
`M M/
`o
`M
`II M/
`
`II/
`MI
`I// MI
`f, , ’I’,,
`M/
`/1
`II
`IM
`MY IM
`MY MI
`7,
`’A
`II/ III
`M? IM
`"*
`II
`III ""
`" M/
`//// MY
`M/
`M IM
`Ill tit
`o
`
`!
`
`2
`
`3
`
`4
`
`s
`
`6
`
`7
`
`8
`
`9
`
`10
`
`II
`
`IZ
`
`13
`
`14
`
`15
`
`16
`
`L
`R
`
`L
`R
`L
`R
`
`L
`R
`L
`R
`L
`R
`
`h
`R
`
`L,
`R
`
`L
`R
`
`L
`R
`
`L
`R
`
`L
`R
`
`L
`R
`
`L
`
`K
`
`L
`R
`L
`g
`
`17 L
`R
`L
`R
`
`18
`
`0
`0
`
`0
`.P
`/
`0
`
`0
`0
`!
`!
`0
`0
`
`0
`0
`
`0
`0
`
`0
`0
`
`0
`0
`
`0
`0
`
`O
`0
`
`0
`0
`
`~e
`
`e*
`
`0
`0
`0
`0
`0
`0
`~o
`1o ~
`
`R ~
`
`o: not affected
`O@: absent
`
`Scoring of newly rown, clinically healthy nail
`O: no growth
`
`ifi growth up to 50~
`
`growth up to 75%
`practically complete or complege cure
`
`Treatment: Twice daily, 2 ~o miconazole alcoholic solution was applied to the affected
`toe nails using the drip-nozzle fitted to the bottles. The solution was allowed sufficient
`time to dry. Each time the previously applied miconazole film was removed. Special
`attention was paid to the application under the front edge of the nails along the lateral
`edges and the cuticles. The treatment lasted 32 weeks, during which time no other anti-
`fungal therapy was prescribed. Each patient was treated with his own bottle of micona-
`zole.
`The nursing staff of the hospital took special care of the hygienic measures taken during
`the trial. Feet were washed and socks were changed daily. Except for keeping the nails
`short, no special surgical treatment was applied.
`
`mykosen 19, Hef~ 7 (1976)
`
`3 of 6
`
`

`
`254
`
`J. VANDERDONCKT, W. LAUWERS and J. BOCKAERT
`
`Table 3: Individual results of mycological examination, 6 months after cessation of treatment
`
`Patient No.
`
`Left
`
`Fungal isolations
`
`1
`2
`3*
`4
`5
`6
`7
`8
`9
`10
`11
`12
`14
`16**
`17***
`
`negative
`negative
`--
`negative
`negative
`negative
`T. mentagrophytes
`T. mentagrophytes
`negative
`negative
`negative
`negative
`negative
`negative
`i
`
`Right
`
`negative
`negative
`
`negative
`negative
`negative
`T. mentagrophytes
`negative
`negative
`negative
`T. mentagrophytes
`negative
`negative
`T. rubrum
`I
`
`’:" Patient died before the control examination.
`** Not present at first examination.
`*** Not present at control examination.
`Patients 13, 15, 18 and 19 were negative before and after treatment.
`
`The aspect of the treated nails was evaluated monthly and the healing process was
`scored clinically. Six months after cessation of treatment a second mycological examina-
`tion (microscopic examination and culture) was performed to assess whether a permanent
`mycological cure had been obtained.
`
`Results
`
`Table 2 presents the individual clinical evaluation of the healing process and Figure 1
`the cumulative evaluation of all treated nails.
`After 16 weeks of treatment, more than 80 g of the treated nails showed a positive
`response to treatment. At the end of the 32-week treatment period, 80 g of the treated
`nails were virtually cured and in these cases a new and clinically healthy nail had devel-
`oped.
`During the entire treatment period the mlconazole alcoholic solution was well tolerated.
`No adverse local reactions occurred.
`Table 3 shows the results of the mycological examination six months after cessation
`of the treatment in 13 patients. Only 4 of the 17 nails that had been mycologically posi-
`tive before treatment yielded a pathogenic fungus. In three nails T. rnentagrophytes was
`still present. In one nail this fungus was also isolated; although before treatment T. ru-
`bruin had been recovered. Control samples could not be obtained from two patients
`(No. 3; No. 17). One patient had not been examined before treatment (No. 16). However
`after treatment T. rubrum was isolated from one nail while in another the microscopic
`examination was positive but no fungus could be cultured. Clinically, these 4 infected
`nails showed a picture of developing onychomycosis.
`
`mykosen 19, Heft 7 (1976)
`
`4 of 6
`
`

`
`Miconazole alcoholic solution in the treatment of mycotic nail infections
`
`255
`
`~0-
`
`30-
`
`20-
`
`Fig. 1: Cumulative evaluation of
`nail treatment: all treated nails
`
`I/~: SrOWt~ up to 75’7.
`/~i(cid:128)~: practically complete or complete cure
`
`O: no change
`
`Glinical evaluation
`
`Comments
`
`Clinical experience with miconazole in the treatment of onychomycosis is still limited.
`Our present study with a 2 g miconazole alcoholic solution appears to substantiate the
`results obtained with 2 g miconazole cream by BOTTER and HEmKE (1, 2).
`
`The main advantages of the miconazole solution are its broad spectrum of efficacy
`against fungi, including yeasts; ease of applicability and the absence of local irritation or
`allergic manifestations.
`It seems that, in long-standing and rooted onychomycoses, such as the cases treated here,
`miconazole solution is a convenient alternative to treatment with griseofulvin. The
`duration of treatment appears to be equal but, clearly, a topical application is to be
`preferred for the treatment of a localized disease such as onychomycosis.
`
`Acknowledgements -- We wish to thank the medical staff and nursing personnel of the Sint-
`Kamillus Instituut, Bierbeek, Belgium, for their constant and efficient collaboration during this
`clinical study. The technical help that was provided by the research staff of Janssen Pharmaceutica,
`Beerse, Belgium, was deeply appreciated.
`
`mykosen 19, Heft 7 (1976)
`
`5 of 6
`
`

`
`256
`
`j. VANDERDON’CKT, W. LAUWERS and J. BOCKAERT
`
`Literature
`
`1. BOTTEB, A. A., 1971: Topical treatment of
`nail and skin infections with miconazole, a
`new broad spectrum antimycotic. Mykosen
`14, 187--191.
`
`2. HE~NKE, E., 1972: Klinlsche Erfahrungen mit
`Miconazol unter besonderer Ber[icksichtigung
`einer konservativen Behandlung der Onycho-
`mycosen und Peronychien. Mykosen 15, 405
`--407.
`
`3. VAN CUTSEM, J. & D. THIENPONT, 1972:
`Miconazole, a broad-spectrum antimycotic
`agent with antibacterial activity. Chemo-
`therapy 17, 392--404.
`
`4. MULS, M., 1972: A new antifungal agent,
`miconazole nitrate, in the treatment of su-
`perficial mycosis of the glabrous skin. Pro-
`ceedings of the 14th International Congress
`on Dermatology, Padua-Venlce, May 1972.
`5. MANDY, S. H. & T. C. GARRO’rT, 1974: Mi-
`conazole treatment for severe dermatophy-
`toffs. JAMA 230, 72--75.
`6. GAT’tI, F., C. ROSETTI, S. MazlgBO & M.
`LOUTIE, 1973: Traitement des mycoses su-
`perficlelles par le miconazole en milieu tro-
`pical. Presented at the International Sym-
`posium of Medical Mycology, Bucharest, Sep-
`tember 1973.
`
`Author’s address: Dr. J. VANDERDONCKT ~ Medische Dienst -- Psychiatrisch Centrum St. Kamil-
`lus -- 3043 Bierbeek, Belgium.
`
`{ Re~erate
`
`BUTTERFIELD, W. S., S. C. JONG und M. T. ALEXANDER:
`(American Type Culture Collection, Rockville, Md. 20852, USA)
`Aufbewahrung human- und zoopathogener Pilze
`Preservation of living fungi pathogenic for man and animals
`Canadian Journal of Microbiology 20, 1665--1673 (1974)
`Die Arbeit beschreibt die Methoden der ATCC for die Langzeltaufbewahrung patho-
`gener Pilze. Im Vorder~rund stehen die Gefriertro&nung sowie Gefrieren mit nachfol-
`gender Lagerung unter fl0ssigem Stickstoff.
`
`K. LOHRS
`
`LAND, G. A)), W. C. McDONALD2)) R. L. STJERNHOLM und L. FRIEDMAN:
`(Dept. Microbiol. and Immunol., Biol., Biochem., Tulane Univ. Sch, Med., New Orleans,
`Louisiana 70112, USA
`1)Pres. address: Dept. Microbiol., Wadley Inst. Molec Med.,Dallas, Tx. 75235, USA
`2)Pres. address: Dept. Biol., Univ. Texas, Arlington, Texas, 76090, USA)
`Die Filamentation yon Candida alblcans beeinflussenden Faktoren: L)ber Beziehungen
`zwisd~en Aufnahme und Verteilung von Prolin zur Morphogenese
`Factors affecting filamentation in Candida albicans: Relationship of the uptake and
`distribution of proline to morphogenesls
`Infect. Immun. 11, 1014--1023 (1975)
`In Gegenwart verschiedener biologischer Fliissigkeiten (z. B. Serum) in vitro oder in
`Gewebe in vivo konvertiert die Hefe(H)form yon C. aibicans in die filamentiSse Myzei-
`-(M)form. Gewif~ spielen diverse Wirts- und Milieufaktoren eine grofle Rolle dabei sowie
`fi3r die Pathogenese (Lit.Ubers.). W. I. NICKERSON postulierte, dag eine Disulfhydryl-
`reductase diese Moroho~enese konrrolliert durch den enzymatls~en Transfer ,,reduzie-
`render Kratt" von den Mitochondrien zu den Zellw~inden. I’Deshalb Cystein-reiche Me-
`++
`dien). Sp~iter folgten Hinweise auf die Bedeutung yon PhosDhaten, Mg , yore CO2-O:~-
`VerMiltnls, yore S-Adenosylmethionin, yore Biotin usw. Verfasser fanden, daft C. albl-
`cans in phosphatgepuffertem Medium (0,008 M) + Biotin (250 mikrogramm/1) bei hoher
`
`mykosen 19, Hef~ 7 (1976)
`
`6 of 6