Clinical and Experimental Dermatology (1985) to, t l I-I 15.
`
`Tioconazole nail solution
`efficacy in onychomycosis
`
`an open study of its
`
`R.J. HAY, R.M. MACKIE* AND Y.M. CLAYTON
`St. John’s Hospital for Diseases of the Skin, Lisle Street, Leicester Square, London WC2H 7BI and
`*Department of Dermatology, University of Glasgow, Anderson College Building, Dumbarton
`Road, Glasgow GI I 6NU
`
`Accepted for publication 8 August 1984
`
`Summary
`
`In view of the problems encountered in the treatment of onychomycosis with orally
`administered antifungal drugs, alternative forms of therapy are needed. Tioconazole (28’,,.) nail
`solution is a new topical preparation for use on infected nails. In this study 27 patients received
`treatment with tioconazole (28°,0) for up to i2 months. Six patients (22%) achieved complete
`clinical remission and were free of infection at follow-up, 3 months after therapy. They included
`infections caused by Trichophyton rubrum (4), Hendersonula toruloidea (I) and Acremonium (i).
`Apart from the latter, all infections responding to treatment were in the finger nails, even though
`three patients had active infection in the toe nails as well which did not respond to therapy.
`Significant improvements were recorded in a further I I patients. They did not, however,
`achieve complete clinical and mycological recovery. The results indicate that cures of
`onychomycosis are possible after topical therapy, and further methods of using this form of
`treatment such as combined surgical and topical therapy are discussed.
`
`Tioconazole is an imidazole antifungal agent of established value in the topical treatment o:f
`superficial mycoses (Kuokkanen, 1981; Clayton et al., 1982; Grigoriu & Grigoriu, 198 3)- It has a
`broad spectrum of anti-fungal activity with a minimum inhibitory concentration (MIC) range
`of o-2-25"0 og ml-’ for common dermatophytes and o’2-I2-5 pg ml ’ for Candida atbicans
`(Jevons et al., t979). MIC values against mould fungi which less commonly cause onychomy-
`cosis (e.g. Scopulariopsis brevicaulis and Hendersonula toruloidea) usually exceed 25 l~g ml-~.
`Tioconazole has been shown to be effective in dermatophytosis and superficial Candida
`infections including vaginal candidosis as well as pityriasis versicolor (Rieth, 1983). Normally,
`the drug is prescribed in i "~. or 2",, cream formulations, although an ointment containing 6".o
`tioconazole is under investigation for single dose treatment of vaginal candidosis (Artner, I983).
`
`Ill
`
`ARGENTUM EX1014
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`R.J. Hay, R.M. Mackie and Y.M. Clayton
`
`Treatment of nail infections caused by fungi is both difficult and lengthy. It has been
`estimated that less than 4°0 o of onychomycoses of the toe nails caused by dermatophytes can be
`cured by griseofulvin (Davies, T967) or ketoconazole (Hay & Clayton, I982). The results are
`better in finger nail infections. Onchomycosis caused by mould fungi other than dermatophytes
`does not usually respond to chemotherapy. The only therapeutic alternatives at present are
`surgical avulsion or chemical removal using 4o% topical urea (White & Clayton, I982), but in
`both cases the relapse rate is high.
`We have evaluated a new formulation of tioconazole nail solution--tioconazole (28 %) as the
`sole treatment for onychomycosis in an open study. The compound is presented as a solution
`which can be applied to infected nails as a daily treatment.
`
`Patients and methods
`
`All patients entering the study had onychomycosis confirmed by culture and/or direct
`microscopy. None had received specific antifungal treatment for a period of 2 months preceding
`the study. Informed consent was obtained from all patients who were also instructed not to
`apply varnish or other nail preparations to nails under treatment.
`The following laboratory tests were carried out before treatment and at monthly intervals
`thereafter: full blood picture, liver function tests, urea, creatinine, glucose. The urine was tested
`for blood, sugar and protein at each visit.
`All patients were instructed to paint the solution onto infected nails twice daily. The initial
`period of therapy was 3 months, but this was extended up to a maximum of t2 months at the
`discretion of the investigators. In view of the length of the proposed study only the active
`compound was assessed. A clinical assessment of the extent of infection and clinical
`improvement, as well as direct microscopy and cultural examination were carried out monthly
`for the first 3 months and every 2 months thereafter. The percentage of the surface area of
`involved nails was estimated at each visit. Note was made of infection in adjacent sites and, if
`present, this was treated by application of I",, tioconazole cream twice daily until the site was
`clinically and mycologically free of infection. At the end of therapy patients with completely
`normal nails and negative direct microscopy were rated as cured. Improvements were scored as
`’ + + ’ or ’ + ’ depending on whether less than 5o",, or more than 5o°,, of the affected nail
`remained clinically and microscopically infected. Patients were seen at follow-up 6 weeks and 3
`months after conclusion of therapy.
`The studies were carried out at St. John’s Hospital for Diseases of the Skin, London, and the
`Western Infirmary, Glasgow.
`
`Results
`
`A total of 27 patients (I 5 males and I2 females) completed at least 3 months of treatment. The
`duration of treatment ranged from 2 to ~2 months, and x 4 patients received more than 3 months
`of therapy. Ten patients had infections confined to the finger nails, 13 the toe nails, and in four
`both sites were involved. Eighteen patients had received previous systemic treatment with
`either griseofulvin or ketoconazole which had been unsuccessful.
`
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`

`

`Tioconazole and onychomycosis
`
`I 13
`
`Table x, Tioconazole (28",,)--results of treatment
`
`Numbers of
`patients
`
`Clinical
`improvement
`
`Clinical and
`No clinical mycological
`improvement remission
`
`Dermatophyte Infections
`Candidosis
`Hendersonuta toruloidea
`Acremonium sp
`Unclassified (culture negative)
`
`x 8
`x
`3
`1
`4
`
`* Finger nail infections
`
`++ +
`8
`o
`
`4
`o
`
`0
`
`3
`
`I
`
`o
`
`o
`2
`I
`
`I
`
`0
`I
`
`4*
`o
`
`I’~
`
`I
`--
`
`The organisms isolated before treatment are shown in Table z. Most patients showed a
`pattern distal and lateral subungual onychomycosis, DLSO (Zaias, 1972). One patient had
`superficial white onychomycosis (SWO) of the toe nails caused by Acremonium sp.
`The results of treatment are shown in Table z. Six patients were found to be clinically and
`mycologically free from infection after 2-7 months (mean 5"2) of treatment (Figs. t a, I b). They
`included the one patient with SWO caused by Acremonium spp. as well as four patients with
`infections caused by T. rubrum and one individual with onychomycosis caused by H. toruloidea.
`Eleven patients showed marked improvement (+ + ) on subjective assessment whereas there
`was little ( + ) or no improvement in five and five individuals respectively. Of those patients who
`were cured, all remained free of infection at 6 weeks and 3 months after completion of treatment.
`The patient with SWO relapsed 6 months after the end of therapy. A total of I45 nails were
`assessed. At the beginning of treatment the mean area of nail involvement in these patients was
`66°,, (-+ 35). The mean improvement recorded at the end of treatment in the area of nail
`involved was 29(! ~ ( ± 30) for all treated nails; but in I 14 nails showing any clinical improvement
`the mean area of new nail growth was 37’)~ (_+ 3I).
`
`Table 2. Fungi isolated before therapy
`
`Fungus isolated
`
`Finger nails Toe nails Both sites
`
`Candida albicans
`Dermatophyte*
`Acremonium species
`Hendersonula toruloidea
`Unclassified (culture negative)
`
`I
`5
`o
`z
`z
`
`o
`io
`
`I
`o
`2
`
`o
`
`3
`o
`
`~t
`
`* Includes Trichophyton rubrum (17), T. soudanense (I).
`t includes H. toruloidea in toe nails, unclassified finger nails.
`
`Page 3
`
`

`

`1 I4
`
`R.J. Hay, R.M. Mackie and Y.M. Clayton
`
`Figure i. T. rubrum infection of the fingernail (a) before treatment, (b) after 7 months oftioconazole (28",:,)
`nail solution.
`
`The blood tests were compared with pre-treatment values using Wilcoxon’s signed rank test
`and Student’s t-test. No significant change in laboratory values was recorded.
`
`Discussion
`
`This study has shown that six (22’:!o) of 27 patients receiving tioconazole (28°,) nail solution for
`onychomyeosis caused by Acremonium spp. Three of the responding group had infections of the
`of infection 6 months after the end of treatment. The infections responding to treatment were
`onychomycosis of the finger nails in all cases apart from the one patient with superficial white
`onychomycosis caused by ,4 cremonium spp. Three of the responding group had infections of the
`toe nails as well which did not clear completely on treatment. A further I I patients showed
`marked improvement as judged by the investigators whereas io showed minimal improvement
`or failed to respond. It was found that mycological assessment by cultural isolation was not
`possible during treatment because no growth was obtained from any nail, presumably reflecting
`the inhibitory effect of tioconazole remaining in the nail matrix. The treatment appeared to be
`safe and patients found the solution easy to apply. Some glazing of nail plates occurred but this
`disappeared after cessation of treatment.
`Spontaneous remission of dermatophyte or Hendersonuta infections of the nail plates are
`exceptionally rare, and therefore some form of therapeutic intervention offers the only real
`chance of recovery. Most of the patients receiving treatment in this study had already failed to
`respond to systemic therapy. This included three of those who achieved complete remission on
`tioconazole alone. There are therefore a number of conclusions which can be drawn from this
`
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`

`

`Tioconazole and onychornycosis
`
`t 15
`
`investigation. In some patients it is possible to obtain clinical and mycological cures in
`onychomycosis using topical therapy alone. This is of potential value to patients because the use
`of prolonged administration of systemically active drugs is thus avoided. Five of the six
`responders had full thickness involvement of the nail plate, including the superior aspect, and it
`is possible that abrasion of this surface using a dental burr or an emery board might enhance the
`penetration of drug into the nail. These five patients all had finger nail involvement. In view of
`the encouraging response recorded here it may be possible to obtain better results by using
`tioconazole (28".’,,) solution either in combination with griseofulvin or ketoconazole, or
`(following removal of the nail plate) with urea. Further studies along these lines are in progress.
`
`Acknowledgments
`
`Tioconazole (28%) nail solution was supplied by Pfizer Pharmaceuticals Limited, Sandwich,
`U.K. We would like to acknowledge the assistance of Glenda Nelson in analysing the data.
`
`References
`
`ARTNER J. (x983) Open study of the efficacy toleration, systemic absorption, and vaginal persistence of
`tioconazole following a single application of tioconazole ointment in the treatment of patients with
`vaginal candidosis. Gynakologische Rundschau, 23 (suppl. 1), 12-I9.
`CLAYTON, Y.M., HAY, R.J., McGmBoN, D.H. & PYE, R.J. (t982) Double-blind comparison of the efficacy
`of tioconazole and miconazole for the treatment of fungal infections of the skin or erythrasma. Clinical
`and Experimental Dermatology, 7, 543-55 I.
`DAVIES, R.R., EVERALL, J.D. & HAMILTON, E. (I967) Mycological and clinical evaluation of griseofulvin
`for chronic onychomycosis. British Medical Journal, iii~ 464-469
`GRIGORIU, D. & GRIGORIU, A. (I983) Double-blind comparison of the efficacy, toleration and safety of
`tioconazole base ~",, and econazole nitrate x"~, cream in the treatment of patients with fungal
`infections of the skin or erythrasma. Dermatologica, x66 (suppl. i), 8-13.
`HAY, R.J. & CLAYTON, Y.M. (I982) Treatment of chronic dermatophyte infections. The use of
`ketoconazole in griseofulvin treatment failures. Clinical and Experimental Dermatology, 7, 6t 1-617.
`JEVONS, S., GYMER, G.E., BRAMMER, K.W., Cox, D.A. & LEEMING, M.R.G. (1979) Antifungal activity of
`tioconazole (UKm2o349), a new imidazole derivative. Antimicrobial Agents and Chemotherapy, 15,
`597-602.
`KUOKKANEN, K. (I98 I)Topical tioconazole in dermatomycosis. Mykosen, 25, 279-280.
`RIETrI, H. ed (I983)A comprehensive guide to the therapeutic use of tioconazole, p.I-64. Pharmalibri,
`Chicago,
`WHITE, M.I. & CLAYTON, Y.M. (I982) The treatment of fungus and yeast infections of the nails by the
`method of ’chemical removal’. Clinical and Experimental Dermatology, 7, 273-276.
`gAlAS, N. (I972) Onychomycosis. Archives of Dermatology, Io5, 263-266.
`
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