I
MYCOSES,
ACCEPTED:NOVEMBER 30, 1990
34,93-95 ( 199 1)
Efficacy of ciclopiroxolamine 1% cream in onychomycosis and tinea pedis
Die Wirksamkeit von 1%-Ciclopiroxolamin-Creme bei Onychomykose und Tinea pedis Y.-C. Wu, M.-T. Chuan and Y.-C. Lu Key words. Onychomycosis, tinea pedis, antimycotic chemotherapy, ciclopiroxolamine. Schlusselwiirter. Onychomykose, Tinea pedis, antimykotische Chemotherapie, Ciclopiroxolarnin.
Summary. Ciclopiroxolamine is now under use as an antifungal agent for about a decade. Its activity is well-known in moderate climates, but there is a lack of knowledge on the activity in tropical and subtropical areas. 49 patients suffering from onychomycosis (42) and/or tinea pedis (33) were enrolled in a clinical trial in Taiwan. The patients received ciclopiroxolamine 1 yo cream 2-3 times a day for 3 to 24 month. I n addition, infected nails were filed to facilitate drug penetration. In onychomycosis, 14% of the patients were cured and another 36% improved. One patient relapsed after 10 months. Cure was achieved more easily, if there were only modest alterations of the nail plate. With respect to tinea pedis the results were more favourable, the cure rate was 42%, another 45% of the patients improved. Following this dosage regimen, side effects did not occur. The results show onychomycosis to be highly resistent to antifungal therapy, perhaps even more as compared to tinea pedis in temperate climates. The good tolerability favours topical ciclopiroxolamine for this recalcitrant disease. Zusammenfassung. Ciclopiroxolamin dient seit etwa 10 Jahren zur Behandlung von Pilzinfektionen. Wahrend seine Wirksamkeit in gemaljigten Klimazonen gut dokumentiert ist, bestehen noch
Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan, R.O.C. Correspondence: Professor Dr Ying-Chin Wu, National Taiwan University Hospital, 1, Chang T e Str., Taipei, Taiwan, R.O.C.
Unsicherheiten hinsichtlich seiner Wirksamkeit in den Tropen und Subtropen. 49 Patienten mit Onychomykose (42) und/oder Tinea pedis (33) nahmen an einer klinischen Prufung in Taiwan teil. l%ige Ciclopiroxolamin-Creme wurde zwei- bis dreimal taglich uber 3 bis 24 Monate appliziert. Zur Erleichterung der Wirkstoffpenetration wurden die infizierten Nagelplatten durch Feilen verdunnt. 14 % der Patienten mit Onychomykose konnten geheilt, bei weiteren 36 % die Krankheitserscheinungen gebessert werden. Bei einem Patienten trat nach 10 Monaten ein Rezidiv auf. Der Therapieerfolg war bei geringfugigen Nagelveranderungen besser als bei ausgedehntem Befall. Gunstigere Behandlungserfolge konnten bei der Tinea pedis erzielt werden. 42 % dieser Patienten wurden geheilt, weitere 45 yo gebessert. Nebenwirkungen traten bei diesem Dosisregime nicht auE Die Ergebnisse zeigen die hohe Therapieresistenz der Onychomykose, die moglichenveise in Taiwan noch starker ausgepragt ist als in gemaljigten Klimazonen. Angesichts der sehr guten Vertraglichkeit kann die topische Behandlung dieser Problemmykose mi t Ciclopiroxolamin-Creme empfohlen werden. Introduction Fungal infections are frequently observed in Taiwan. Warm temperature and extensive humidity may be predisposing factors. Whereas many tinea forms are no major therapeutic problem, this holds not true with respect to tinea unguium. Onychomycosis often fails to respond to topical as well as systemic treatment [I-31. One of the most promising agents in topical antifungal therapy is ciclopi-
94
Y.-c. W
U ET AL.
roxolamine which differs from most other antifungals by an improved penetration into horny material [4, 51. Ciclopiroxolamine is highly active in experimental dermatophytoses of animals [6, 71 as well as in patients suffering from tinea of glabrate skin [7]. Efficacy has been demonstrated in onychomycosis of patients living in Central Europe, too [8, 91. There is, however, a lack of data on ciclopiroxolamine activity in tropical and subtropical climates. This paper reports the results of a clinical study with ciclopiroxolamine 1yo cream performed in Taiwan.
Patients and methods In total 49 out-patients (18 male, 31 female, aged 20-60 years) were enrolled in the trial. Fourty-two of them suffered from onychomycosis. Above that 22 of these patients presented tinea pedis, three tinea pedis plus tinea manuum, two tinea manuum and one more patient tinea pedis plus tinea cruris. In 14 patients fungal infections were restricted to the nails. In total 69 fingernails and 200 toenails were infected. In addition to the patients with onychomycosis 7 patients suffering from tinea pedis were included in the trial. Fungal infections were confirmed by direct microscopic examination and/or culture. The patients were instructed to grind affected nails with a file as thin as possible to remove horny material. Filing was performed prior to the first drug application and repeated in the evenings during the treatment period. Ciclopiroxolamine 1 yo cream (Batrafen, Hoechst Taiwan) was applied to the infected areas 2-3 times a day (in the evening after filing the nail). After application of the cream washing of the handslfeet was not allowed. Despite the study medication, the patients received neither topical nor systemic antifungal treatment. Clinical and mycological examinations were repeated once a month in the patients suffering from onychomycosis. Patients with tinea pedis returned to the hospital every 7 to 14 days for follow-up visits.
Results Trichophyton rubrum was isolated from the material of 6 patients, T. mentagrophytes from 3, Epidermophyton floccosum'from one and T. spec. from 10 patients. Onychomycosis was treated for at least 3 months. After 6 to 24 month, 6 patients were cured and another 15 showed considerable improvement (Table 1). I n the latter group not all but several nails were free from signs of fungal disease. Favourable results were obtained in nails with modest surface
Table 1. Treatment results
Cured Improved No changelworse
Onychomycosis (n = 42)
Tinea pedis (n = 33)
6 (14%) 15 (36%) 21 (50%)
14 (42%) 15 (45%) 4 (13%)
alterations. I n a patient who received ciclopiroxolamine treatment for one year two out of three infected nails were cured. One nail, however, relapsed 10 month after stopping treatment. Tinea pedis was cured in 42% and improved in 45% of the patients (Table 1). A minor side effect, paronychia, was seen in one patient only who applied the cream more frequently. Redness and swelling disappeared after the patient started to conform to the protocol.
Discussion Although onychomycosis is a frequent fungal disease [lo] its treatment is rather neglected. This results from a prolonged treatment period, poor cure rates and frequent relapses after the end of treatment [3]. Treatment periods for 6 month and even more, which are necessary in onychomycosis [9], often lead to poor patient compliance [l 13. Although possibly more active [2], systemic treatment of onychomycosis is hampered by the induction of unwanted side effects. This holds true for griseofulvin [ l , 2, 121, itraconazole [I21 and even more with respect to ketoconazole which cannot be used for long-term treatment. Hepatotoxicity occurred especially in those patients receiving long-term therapy for onychomycosis [l, 21. On the other hand, topical therapy often is regarded as rather ineficient [ 131. Due to the higher tolerability an active topical treatment is highly desirable. Onychomycosis can result from infections with dermatophytes, yeasts and even molds [ l , 101. Thus a broad-spectrum of antifungal activity may be preferred. Since the horny layer of the nail impedes drug penetration in general and even more if there is a increased thickness due to a fungal infection, the topical antifungal drug should exhibit a very good ability to penetrate the nail plate which characterises ciclopiroxolamine [4,6]. Favourable treatment responses have been described with this agent used in temperate climates [8, 91. With respect to Taiwan, satisfying treatment responses are seen with tinea pedis. Nearly half of the patients were cured, whereas improvement was not obtained in 13% only (Table 1). O n the other hand, cure rates were much lower in onychomycosis. This holds true despite of facilitated drug penetration due mycoses 34, 93-95 (1991)
CIcr.OPIROXOLAMINE IN
to repeated filing of the nail surface. Only 14% of our patients were cured and another 36% improved. Therapeutic success was superior, if the infected area was not extended. This was observed in other studies, too [9, 141. The higher cure rate reported previously [8, 91 was not obtained in our study. Besides from the climate, this may result from the location and extension of the disease as well as from patient compliance. The low incidence of side effects, however, stresses that ciclopiroxolamine is a good choice for the treatment of onychomycosis. If used as considered, no side effects occur. Thus tolerability is superior to systemic treatment and also better than topical application of bifonazole/urea which induced local inflammatory reactions in three out of 39 patients [15]. To keep the local area sanitated after the end of treatment, however, it is important to avoid reinfection after recovery. References 1 Roberts D. T. & Tuyp, E. (1985) Onychomycosis. Sem. Derrnatol. 4, 222-226. 2 Korting, H. C. (1989) Orale Therapie von Onychomykosen. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin: Springer Verlag, pp. 32-40. 3 Meisel, C. W. (1989) Die Onychomykose-Therapie in der Praxis. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin: Springer Verlag, pp. 9-20. 4 Dittmar, W. (1981) Zur Penetration und antimykotischen Wirksamkeit von Ciclopiroxolamin in verhorn tem Korpergewebe. Anneimittel-Forsch. 31, 1353-1 359.
mycoses 34, 93-95 (1991)
ONYCHOMYCOSIS AND TINEA PEDIS
95
5 Dittmar, W. & Jovic, N. (1987) Laboratory techniques alternative to in vivo experiments for studying the liberation, penetration and fungicidal action of topical antimycotic agents in the skin, including ciclopiroxolamine. mycoses 30, 326-342. 6 Hanel, H., Braun, B. & Loschhorn, K. (1990) Experimental dermatophytosis in nude guinea pigs compared with infections in Pirbright white animals. mycoses 33, 17S189. 7 Hanel, H., Abrams, B., Dittmar, W. & Ehlers, G. (1988) A comparison of bifonazole and ciclopiroxolarnine: in vitro, animal, and clinical studies. rnycoses 31, 632-640. 8 Qadripur, S.-A., Horn, G. & Hoehler, T. (1981) Zur Lokalwirksamkeit von Ciclopiroxolamin bei Nagelmykosen. A n neimittel-Forsch. 31, 1369-1372. 9 Effendy, I. & Kolczak, H. (1989) Alternatives Behandlungskonzept der Nagelmykosen. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin, Springer Verlag, pp. 2131. 10 Haneke, E. (1989) Epidemiologie und Pathologie der Onychomykosen. In: Nolting, S. & Korting, H. C. (eds) Onychornykosen. Berlin: Springer Verlag, pp. 2-8. 11 Meinhof, W., Girardi, R. M. & Stracke, A. (1984) Patient noncompliance in dermatomycosis. Results of a survey among dermatologists and general practitioners and patients. Dennatologica 169(Suppl. l), 5766. 12 Van Hecke, E. & Van Cutsem, J. (1988) Double-blind comparison of itraconazole with griseofulvin in the treatment of tinea pedis and tinea manuum. mycoses 31,641-649. 13 Meinhof, W. (1989) Probleme der Compliance bei Patienten mit Onychomykose. In: Nolting, S. & Korting, H. C. (eds)Onychomykosen. Berlin: Springer Verlag, pp. 54-57. 14 Nolting, K. S. (1989) Erfahrungen mit Bifonazol/HarnstoffFormulierungen in Deutschland. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin: Springer Verlag, pp. 58-62. 15 Worret, W.-I. (1989) Erfahrung mit Bifonazol/Harnstoff in der Klinik. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin: Springer Verlag, pp. 6347.
MYCOSES,
ACCEPTED:NOVEMBER 30, 1990
34,93-95 ( 199 1)
Efficacy of ciclopiroxolamine 1% cream in onychomycosis and tinea pedis
Die Wirksamkeit von 1%-Ciclopiroxolamin-Creme bei Onychomykose und Tinea pedis Y.-C. Wu, M.-T. Chuan and Y.-C. Lu Key words. Onychomycosis, tinea pedis, antimycotic chemotherapy, ciclopiroxolamine. Schlusselwiirter. Onychomykose, Tinea pedis, antimykotische Chemotherapie, Ciclopiroxolarnin.
Summary. Ciclopiroxolamine is now under use as an antifungal agent for about a decade. Its activity is well-known in moderate climates, but there is a lack of knowledge on the activity in tropical and subtropical areas. 49 patients suffering from onychomycosis (42) and/or tinea pedis (33) were enrolled in a clinical trial in Taiwan. The patients received ciclopiroxolamine 1 yo cream 2-3 times a day for 3 to 24 month. I n addition, infected nails were filed to facilitate drug penetration. In onychomycosis, 14% of the patients were cured and another 36% improved. One patient relapsed after 10 months. Cure was achieved more easily, if there were only modest alterations of the nail plate. With respect to tinea pedis the results were more favourable, the cure rate was 42%, another 45% of the patients improved. Following this dosage regimen, side effects did not occur. The results show onychomycosis to be highly resistent to antifungal therapy, perhaps even more as compared to tinea pedis in temperate climates. The good tolerability favours topical ciclopiroxolamine for this recalcitrant disease. Zusammenfassung. Ciclopiroxolamin dient seit etwa 10 Jahren zur Behandlung von Pilzinfektionen. Wahrend seine Wirksamkeit in gemaljigten Klimazonen gut dokumentiert ist, bestehen noch
Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan, R.O.C. Correspondence: Professor Dr Ying-Chin Wu, National Taiwan University Hospital, 1, Chang T e Str., Taipei, Taiwan, R.O.C.
Unsicherheiten hinsichtlich seiner Wirksamkeit in den Tropen und Subtropen. 49 Patienten mit Onychomykose (42) und/oder Tinea pedis (33) nahmen an einer klinischen Prufung in Taiwan teil. l%ige Ciclopiroxolamin-Creme wurde zwei- bis dreimal taglich uber 3 bis 24 Monate appliziert. Zur Erleichterung der Wirkstoffpenetration wurden die infizierten Nagelplatten durch Feilen verdunnt. 14 % der Patienten mit Onychomykose konnten geheilt, bei weiteren 36 % die Krankheitserscheinungen gebessert werden. Bei einem Patienten trat nach 10 Monaten ein Rezidiv auf. Der Therapieerfolg war bei geringfugigen Nagelveranderungen besser als bei ausgedehntem Befall. Gunstigere Behandlungserfolge konnten bei der Tinea pedis erzielt werden. 42 % dieser Patienten wurden geheilt, weitere 45 yo gebessert. Nebenwirkungen traten bei diesem Dosisregime nicht auE Die Ergebnisse zeigen die hohe Therapieresistenz der Onychomykose, die moglichenveise in Taiwan noch starker ausgepragt ist als in gemaljigten Klimazonen. Angesichts der sehr guten Vertraglichkeit kann die topische Behandlung dieser Problemmykose mi t Ciclopiroxolamin-Creme empfohlen werden. Introduction Fungal infections are frequently observed in Taiwan. Warm temperature and extensive humidity may be predisposing factors. Whereas many tinea forms are no major therapeutic problem, this holds not true with respect to tinea unguium. Onychomycosis often fails to respond to topical as well as systemic treatment [I-31. One of the most promising agents in topical antifungal therapy is ciclopi-
94
Y.-c. W
U ET AL.
roxolamine which differs from most other antifungals by an improved penetration into horny material [4, 51. Ciclopiroxolamine is highly active in experimental dermatophytoses of animals [6, 71 as well as in patients suffering from tinea of glabrate skin [7]. Efficacy has been demonstrated in onychomycosis of patients living in Central Europe, too [8, 91. There is, however, a lack of data on ciclopiroxolamine activity in tropical and subtropical climates. This paper reports the results of a clinical study with ciclopiroxolamine 1yo cream performed in Taiwan.
Patients and methods In total 49 out-patients (18 male, 31 female, aged 20-60 years) were enrolled in the trial. Fourty-two of them suffered from onychomycosis. Above that 22 of these patients presented tinea pedis, three tinea pedis plus tinea manuum, two tinea manuum and one more patient tinea pedis plus tinea cruris. In 14 patients fungal infections were restricted to the nails. In total 69 fingernails and 200 toenails were infected. In addition to the patients with onychomycosis 7 patients suffering from tinea pedis were included in the trial. Fungal infections were confirmed by direct microscopic examination and/or culture. The patients were instructed to grind affected nails with a file as thin as possible to remove horny material. Filing was performed prior to the first drug application and repeated in the evenings during the treatment period. Ciclopiroxolamine 1 yo cream (Batrafen, Hoechst Taiwan) was applied to the infected areas 2-3 times a day (in the evening after filing the nail). After application of the cream washing of the handslfeet was not allowed. Despite the study medication, the patients received neither topical nor systemic antifungal treatment. Clinical and mycological examinations were repeated once a month in the patients suffering from onychomycosis. Patients with tinea pedis returned to the hospital every 7 to 14 days for follow-up visits.
Results Trichophyton rubrum was isolated from the material of 6 patients, T. mentagrophytes from 3, Epidermophyton floccosum'from one and T. spec. from 10 patients. Onychomycosis was treated for at least 3 months. After 6 to 24 month, 6 patients were cured and another 15 showed considerable improvement (Table 1). I n the latter group not all but several nails were free from signs of fungal disease. Favourable results were obtained in nails with modest surface
Table 1. Treatment results
Cured Improved No changelworse
Onychomycosis (n = 42)
Tinea pedis (n = 33)
6 (14%) 15 (36%) 21 (50%)
14 (42%) 15 (45%) 4 (13%)
alterations. I n a patient who received ciclopiroxolamine treatment for one year two out of three infected nails were cured. One nail, however, relapsed 10 month after stopping treatment. Tinea pedis was cured in 42% and improved in 45% of the patients (Table 1). A minor side effect, paronychia, was seen in one patient only who applied the cream more frequently. Redness and swelling disappeared after the patient started to conform to the protocol.
Discussion Although onychomycosis is a frequent fungal disease [lo] its treatment is rather neglected. This results from a prolonged treatment period, poor cure rates and frequent relapses after the end of treatment [3]. Treatment periods for 6 month and even more, which are necessary in onychomycosis [9], often lead to poor patient compliance [l 13. Although possibly more active [2], systemic treatment of onychomycosis is hampered by the induction of unwanted side effects. This holds true for griseofulvin [ l , 2, 121, itraconazole [I21 and even more with respect to ketoconazole which cannot be used for long-term treatment. Hepatotoxicity occurred especially in those patients receiving long-term therapy for onychomycosis [l, 21. On the other hand, topical therapy often is regarded as rather ineficient [ 131. Due to the higher tolerability an active topical treatment is highly desirable. Onychomycosis can result from infections with dermatophytes, yeasts and even molds [ l , 101. Thus a broad-spectrum of antifungal activity may be preferred. Since the horny layer of the nail impedes drug penetration in general and even more if there is a increased thickness due to a fungal infection, the topical antifungal drug should exhibit a very good ability to penetrate the nail plate which characterises ciclopiroxolamine [4,6]. Favourable treatment responses have been described with this agent used in temperate climates [8, 91. With respect to Taiwan, satisfying treatment responses are seen with tinea pedis. Nearly half of the patients were cured, whereas improvement was not obtained in 13% only (Table 1). O n the other hand, cure rates were much lower in onychomycosis. This holds true despite of facilitated drug penetration due mycoses 34, 93-95 (1991)
CIcr.OPIROXOLAMINE IN
to repeated filing of the nail surface. Only 14% of our patients were cured and another 36% improved. Therapeutic success was superior, if the infected area was not extended. This was observed in other studies, too [9, 141. The higher cure rate reported previously [8, 91 was not obtained in our study. Besides from the climate, this may result from the location and extension of the disease as well as from patient compliance. The low incidence of side effects, however, stresses that ciclopiroxolamine is a good choice for the treatment of onychomycosis. If used as considered, no side effects occur. Thus tolerability is superior to systemic treatment and also better than topical application of bifonazole/urea which induced local inflammatory reactions in three out of 39 patients [15]. To keep the local area sanitated after the end of treatment, however, it is important to avoid reinfection after recovery. References 1 Roberts D. T. & Tuyp, E. (1985) Onychomycosis. Sem. Derrnatol. 4, 222-226. 2 Korting, H. C. (1989) Orale Therapie von Onychomykosen. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin: Springer Verlag, pp. 32-40. 3 Meisel, C. W. (1989) Die Onychomykose-Therapie in der Praxis. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin: Springer Verlag, pp. 9-20. 4 Dittmar, W. (1981) Zur Penetration und antimykotischen Wirksamkeit von Ciclopiroxolamin in verhorn tem Korpergewebe. Anneimittel-Forsch. 31, 1353-1 359.
mycoses 34, 93-95 (1991)
ONYCHOMYCOSIS AND TINEA PEDIS
95
5 Dittmar, W. & Jovic, N. (1987) Laboratory techniques alternative to in vivo experiments for studying the liberation, penetration and fungicidal action of topical antimycotic agents in the skin, including ciclopiroxolamine. mycoses 30, 326-342. 6 Hanel, H., Braun, B. & Loschhorn, K. (1990) Experimental dermatophytosis in nude guinea pigs compared with infections in Pirbright white animals. mycoses 33, 17S189. 7 Hanel, H., Abrams, B., Dittmar, W. & Ehlers, G. (1988) A comparison of bifonazole and ciclopiroxolarnine: in vitro, animal, and clinical studies. rnycoses 31, 632-640. 8 Qadripur, S.-A., Horn, G. & Hoehler, T. (1981) Zur Lokalwirksamkeit von Ciclopiroxolamin bei Nagelmykosen. A n neimittel-Forsch. 31, 1369-1372. 9 Effendy, I. & Kolczak, H. (1989) Alternatives Behandlungskonzept der Nagelmykosen. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin, Springer Verlag, pp. 2131. 10 Haneke, E. (1989) Epidemiologie und Pathologie der Onychomykosen. In: Nolting, S. & Korting, H. C. (eds) Onychornykosen. Berlin: Springer Verlag, pp. 2-8. 11 Meinhof, W., Girardi, R. M. & Stracke, A. (1984) Patient noncompliance in dermatomycosis. Results of a survey among dermatologists and general practitioners and patients. Dennatologica 169(Suppl. l), 5766. 12 Van Hecke, E. & Van Cutsem, J. (1988) Double-blind comparison of itraconazole with griseofulvin in the treatment of tinea pedis and tinea manuum. mycoses 31,641-649. 13 Meinhof, W. (1989) Probleme der Compliance bei Patienten mit Onychomykose. In: Nolting, S. & Korting, H. C. (eds)Onychomykosen. Berlin: Springer Verlag, pp. 54-57. 14 Nolting, K. S. (1989) Erfahrungen mit Bifonazol/HarnstoffFormulierungen in Deutschland. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin: Springer Verlag, pp. 58-62. 15 Worret, W.-I. (1989) Erfahrung mit Bifonazol/Harnstoff in der Klinik. In: Nolting, S. & Korting, H. C. (eds) Onychomykosen. Berlin: Springer Verlag, pp. 6347.
