Treatment of chronic tinea pedis (athlete's foot type) with topical terbinafine Ronald C. Savin, MD New Haven, Connecticut Twenty-seven patients with chronic tinea pedis, athlete's foot type, were enrolled in a randomized, double-blind trial of topical treatmentwith terbinafine 1%creamversus its vehicle(placebo). Patients were examined weekly during 4 weeks oftwice-daily treatmentand at follow-up 2 weeks after the conclusion of therapy. No adverse events werereported in either treatment group. Drugefficacy wasevaluated in 22 patients, of whom nine(41%) were treated with terbinafine and 13 (59%) with placebo. Analysis of combined mycologic and clinical results showed that terbinafine was significantly moreeffective than placebo at the end oftherapy(78% vszero) and at the 2-week follow-up (89% vszero) (P :5 0.001 at both intervals. (J AM ACAD DERMATOL 1990;23:786-9.) Terbinafine (Lamisil) is a member of a new class of antifungal drugs, the allylamines, that possess primary fungicidal activity,' that is, the minimum inhibitory concentration isthe same as the minimum fungicidal concentration. In vitro studies have shown that terbinafine is the most potent antifungal allylamine to date with demonstrated efficacy against a wide range of pathogenic fungi.2,3 In vivo terbinafine is active topically and systemically.4 In patients with tinea corporis oral and topical forms of terbinafine are virtually equivalent in effectiveness.l Furthermore, the efficacy of topical terbinafine in interdigital tinea pedis is equivalent to that of oral terbinafine in plantar-type tinea pedis.5 In one study of oral terbinafine therapy (125 mg twice daily), more than 70% of patients treated for tinea corporis had test results negative for fungi and a marked clearing of signs and symptoms after 2 weeks of treatment, 5 In a randomized double-blind comparison, oral terbinafine was found to be safe and significantly more effective than griseofulvin in the treatment of moccasin (plantar)-type tinea pedis.'' We describe the results of a single-center, randomized, double-blind, placebo-controlled trial of topical terbinafine in the treatment of chronic tinea pedis, athlete's foot type. From the Department of Dermatology, Yale University School of Medicine. Sponsored in part by an educational grant from SandozPharmaceuticals Corp., East Hanover, N.J. Reprint requests: RonaldC.Savin,MD, 123YorkStreet, New Haven, CT 06511.
16/0/23518
786
PATIENTS AND METHODS
Twenty-seven patientswith clinicallydocumented tinea pedis of both interdigital and moccasin types were enrolled in the study. All patients werewhitemen, 19 to 61 yearsof age. Patientswereexcluded if theyhad received systemic antifungal drugs in the preceding 4 weeks or topical antifungal therapyduringthe preceding 2 weeks. Concomitant medication for diabetes, hypertension, or other chronic diseases was continued. Patients with abnormal microscopy findings couldberemoved fromthe study after treatment was started if the culture for dermatophytes, which requires 2 weeks of observation, proved to be negative (delayed exclusion). At entry, allpatientshad a positive KOH preparation, and a culturefor dermatophytes wasobtained. Patients were randomly assigned to 4 weeks of twice-daily treatment with either terbinafine 1% cream (13 patients) or placebo vehicle cream (14 patients). All patients were seen weekly during therapy and at a follow-up visit 2 weeks afterconclusion oftherapy. At eachvisit, signs and symptoms of erythema, pustules, desquamation, incrustation,vesiculation, andpruritus werescored ona scaleof oto 3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Skinscrapings weretakenfor KOH microscopy and culture each week, with the results recorded as positive or negative. Laboratory tests consisting of CBC and automatedchemistry panel(SMA23)were performed before therapyand at the completion of therapy. At the completion of therapy and at the follow-up examination, a combined evaluation of the mycologic response and the clinical response was usedto determine overall effectiveness of treatment. Treatmentfailurewas defined asnosignificant clinical response to therapyOr by persistent abnormal microscopy findings and/or positive culture for fungi. Therapy was rated as effective if patients showed a complete cure (normal microscopy findings and negative culturewith no residual signs and
Volume 23 Number 4, Part 2 October 1990
Topical terbinafine in tinea pedis 787
100 :>.
lJ)
.2
§,
;::!;
~
'flJ)a
--.-
80
TERBINAFINE
--0- Placebo 60
Q)
2: s:
40
~4l
20
l
e #. :;::>
0
0
2
4
3
6
5
Treatment Week
(Follow-up)
Fig. 1. Percentage of patients withnormal microscopy findings andnegative culture after treatmentwith topical terbinafine 1%or placebo fortinea pedis, athlete's foot type. Fordropouts and patients not appearing at eachweekly visit, results at lastexamination were carried forward; percentages are based on n == 9 forterbinafine, n = 13forplacebo; actual observations at week 6 were n = 9 for terbinafine and n = 10for placebo. Table I. Combined clinical and mycologic evaluation of athlete's foot-type tinea pedis after treatment with terbinafine or placebo End of therapy Response
Complete cure Mycotic Cure with or without minimal signs Effective Rx* Mycotic cure with or without clinical improvement Mycotic failure with or without clinical improvement Failure Ineffective Rx
Terbinafine
I
Placebo
Follow-up Terbinafine
I
Placebo
0(0%)
6 2
8" (89%)
0 0 0(0%)
2
1
1
1
0
4
0
2
8
0 1(11%)
6 1
0 0
"7 (78%)
0
2 (22%)
TI (100%)
10 13 (100%)
Data expressed as number of patients. *Terbinafine was statisticallysignificantly superior to placebo (p < 0.001, one-tailed Fisherexact test) in overall efficacy.
symptoms) or mycologic cure (normal microscopy findings and negative culturewith mildresidual erythema). Therapy was rated as ineffective in all othercases, even if signs and symptoms had shown improvement. Sign tests were used descriptively to assess changes from baseline separately for microscopy, culture, and signs and symptoms. At each weekly visit, comparison between terbinafine and placebo wasperformed bymeans of Wilcoxon-Mann-Whitney U testsonthe totalscore as well as on its changefrom baseline. The one-tailed Fisher exact test was used for confir-
matory testing of the null hypothesis ofterbinafine having the same effect as placebo. RESULTS Twenty-seven patients were enrolledin the study and all 27 were included in the analysisof drug tolerability. However, four patients were classified as delayed exclusions (three in the terbinafine group, one in the placebogroup) becauseof negativeinitial culture for dermatophytes. One additionalpatient in
Journal of the American Academy of Dermatology
788 Savin
100.--------------------------, 80 .5
~ Q)
~l!!
60
E~
e1V
-:= ~
oCl)ffi
.2
ia; ::i: '#.
40
20
___
1ERBINAFINE
--0-
Placebo
o
o
2
3
4
5
Treatment Week
6 (FolloW-Up)
Fig. 2. Percentage of reduction from baseline in meantotal signs and symptoms score in patients treated with topical terbinafine or placebo. Signs andsymptoms include erythema, desquamation, pruritus, incrustation, vesiculation, andpustules. Fordropouts andpatients not appearing at each weekly visit, results at last examination were carried forward; percentages are based on n = 9 for terbinafine, n = 13 for placebo; actual observations at week 6 were n = 9 for terbinafine and n = 10 for placebo. the terbinafine group was dropped from the study becauseoffailureto take medication as instructed. Thustherewere22evaluable patients, 9treated with terbinafine and 13 treated with placebo. The causative organism was Trichophyton rubrum in 21 patients (nine in the terbinafine group, 12 inthe placebo group)and Epidermophytonjloccosum in onepatient(placebo group). Nineteen patients (eightin the terbinafine group, 11 in the placebo group) had received previous therapy for the present dermatophyte infection. The mean age of patientswas 36years in the terbinafinegroup and 37 years in the placebo group. Demographic data showed that patients in the two treatment groups were comparable withregard to age, race, previous therapy, size and location of lesions, organism, and predisposing factors. However, the meanduration of disease before entrance into the study waslonger in the terbinafine group (13 years)than inthe placebo group (8 years). Mycologic efficacy The time to permanently negative microscopy and culture in the twotreatment groups is plotted in Fig. 1. After the first weekof treatment, the terbinafine-treated patients showed mycologic clearing of 44% followed by 100% clearing at week4 (end of treatment) and at 6 weeks (2-week follow-up). The
comparable clearing rate at these intervals in the placebo group was zero and 8%, respectively. Clinical efficacy Before treatment, the most common signs and symptoms were erythema (100%), desquamation (100%), and pruritus (95%). Signs and symptoms, measured by the sum of scores for these three factors and incrustation,vesiculation, and pustuleswere reduced faster and more completely in the terbinafine-treatedgroup than in the placebogroup (Fig. 2). This marked reduction in mean total scores occurred throughouttreatment and continuedthrough follow-up in the terbinafine-treated group. In contrast, a moderate reduction in signs and symptoms occurreduntil week 3 in the placebogroup, at which time they began to increase. The U test showeda significant differencefor the sum of signs and symptoms scores between the terbinafinegroup(mean ± standard error ofthe mean, 7.08 ± 0.26) and the placebo group (5.56 ± OAl) before therapy. Thus, despite randomization, the terbinafinegrouphad significantly more severesigns and symptoms than the placebogroup. However, at week 3 of treatment the total signs and symptoms scores for both groups were similar. At week 4, a significant difference in favorofterbinafinewas seen (p = 0.006) and again at week 6 (p = O.COl). Be-
Volume 23 Number 4, Part 2 October 1990
causeof the significantdifference in the baseline sum of scores, analysis of covariance was performedfor each week's measures (sum of score at week0 as covariate). The results are consistentwith the U tests on changes from baseline. Both analyses show results at the "border" of significance (covariance p = 0.06, change from baselinep = 0.07),therefore consistent with the difference between the two groups in mean sum of scores at follow-up.
Overall efficacy Table I shows the overalleffectiveness of therapy based on the combined clinical and mycologic evaluations performed at the end of the therapy and at follow-up 2 weeks later. Terbinafine was significantly superior to placebo in overall efficacy (p = 0.001, one-tailed Fisher exact test).
J\dverse effects No adverse effects were reported in either treatment group. CBCs, blood urea nitrogen level, and liver function tests performed before and after treatment revealed no abnormalities, with one exception. One terbinafine-treated patient had elevated AST (SOOT) (140 U jL), ALT (SGPT) (260 U jL), and lipemic serum at the end of treatment, which was not believed to be related to the drug treatment. Bilirubin and lactate dehydrogenase levels remained normal. No follow-up tests were done and no clinical signswere observed in this patient. DISCUSSION
Previous reports have shown veryfew adverse reactions to terbinafine- 7 However, wedid observe an unexplained elevationof liverfunctiontest results in one terbinafine-treated patient with lipemic serum. However, this was not considered related to drug treatment. The development of new,clinically effective antifungal agents is important because at anyone time, approximately 10% to 20%ofthe world'spopulation is infected with fungus." Most of these chronic superficial fungal infections are not life-threatening but may be debilitating. Furthermore, the increase in opportunistic fungal infections that occur in immunodeficiency disorders and from aggressive chemotherapeutic regimens underscores the need for more effective antifungal agents. Early data suggestthat topical terbinafine cream is superior to clotrimazolefor the treatment oftinea pedis and tinea cruris? (R. C. Savin, unpublished
Topical terbinafine in tinea pedis 789
data, multicenter study). In a recent study of 629 patients, terbinafine 1% cream was foundto be safe and effective in the treatment ofcutaneous yeast infections and dermatophytoses, including tinea pedis," On thebasis of earlierdata,the authorofthat study suggested that terbinafinecream may also be superior to naftifine-another allylamine derivative-in the treatment of tinea pedis, with respect to the overall clinical and mycologic evaluaticn.l? Other studies have shown promising results with systemic terbinafine in the treatment oftinea pedis." Another advantage of terbinafine isits fungicidal property,which bringsabout morerapid and persistent clearing. In patients with tinea pedis, therapy with fungistatic drugs,such as most azoles, is often prolonged and may be associated with high recurrence rates. As the current studyshows, the fungicidal activityof terbinafinemay permit a relatively brief course of drug therapy, with long-lasting effects, evenin patientswith chronic infections that have not been responsive to other agents. We concludethat topicalterbinafine represents a significant advance in the topical treatment of chronic tinea pedis. REFERENCES
1. Ryder NS, Dupont M-C. Inhibition ofsqualene epoxidase byallylamine antimycotic compounds: a comparative study of the antifungal and mammalian enzymes. Biochem J 1985;230:765-70. 2. PetranyiG, Stutz A, Ryder N, et al.Experimental antimycoticactivity ofnaftifine and terbinafine. In:Fromtling RA, ed. Recent trends in the discovery, development, and evaluationofantifungal agents.Barcelona: JR Prous, 1987:44150. 3. Mieth H, Petranyi G. Preclinical evaluation of terbinafine in vivo. Clin Exp DermatoI1989;14:104-7. 4. Petranyi G, Meingassner JG, Mieth H. Activity of terbinafine in experimental fungal infections of laboratory animals. Antimicrob Agents Chemother 1987;31:1558-61. 5. Villars V, Jones TC. Clinical efficacy and tolerability of terbinafine (Lamisil)-a new topical and systemic fungicidal drug for treatment of dermatomycoses. Clin Exp DermatoI1989;14:124-7. 6. Savin R. Successful treatment ofchronic tineapedis (moccasin type) with terbinafine (Larnisil). ClinExpDermatol 1989;14:116-9. 7. Kagawa S. Clinical efficacy ofterbinafine in 629Japanese patients with dermatomycosis. Clin Exp Dermatol 1989; 14:114-5. 8. Salzman RS, Jones HE, Ringworm. In: WarrenKS,Mahmoud AAF, eds, Tropical and geographic medicine. New York: McGraw-Hili, 1984:949-65. 9. Stephen A, Czok R, Male O. Terbinafine: initial clinical results.In: Fromtling RA, ed, Recent trends in the discovery, development, and evaluation of antifungal agents. Barcelona; JR Prous, 1987:511-20. 10. Kagawa S. Comparative clinical trial ofnaftifineand clotrimazole in tinea pedis, tinea cruris and tinea corporis. Mykosen 1985;28(suppl 1):82-8.
16/0/23518
786
PATIENTS AND METHODS
Twenty-seven patientswith clinicallydocumented tinea pedis of both interdigital and moccasin types were enrolled in the study. All patients werewhitemen, 19 to 61 yearsof age. Patientswereexcluded if theyhad received systemic antifungal drugs in the preceding 4 weeks or topical antifungal therapyduringthe preceding 2 weeks. Concomitant medication for diabetes, hypertension, or other chronic diseases was continued. Patients with abnormal microscopy findings couldberemoved fromthe study after treatment was started if the culture for dermatophytes, which requires 2 weeks of observation, proved to be negative (delayed exclusion). At entry, allpatientshad a positive KOH preparation, and a culturefor dermatophytes wasobtained. Patients were randomly assigned to 4 weeks of twice-daily treatment with either terbinafine 1% cream (13 patients) or placebo vehicle cream (14 patients). All patients were seen weekly during therapy and at a follow-up visit 2 weeks afterconclusion oftherapy. At eachvisit, signs and symptoms of erythema, pustules, desquamation, incrustation,vesiculation, andpruritus werescored ona scaleof oto 3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Skinscrapings weretakenfor KOH microscopy and culture each week, with the results recorded as positive or negative. Laboratory tests consisting of CBC and automatedchemistry panel(SMA23)were performed before therapyand at the completion of therapy. At the completion of therapy and at the follow-up examination, a combined evaluation of the mycologic response and the clinical response was usedto determine overall effectiveness of treatment. Treatmentfailurewas defined asnosignificant clinical response to therapyOr by persistent abnormal microscopy findings and/or positive culture for fungi. Therapy was rated as effective if patients showed a complete cure (normal microscopy findings and negative culturewith no residual signs and
Volume 23 Number 4, Part 2 October 1990
Topical terbinafine in tinea pedis 787
100 :>.
lJ)
.2
§,
;::!;
~
'flJ)a
--.-
80
TERBINAFINE
--0- Placebo 60
Q)
2: s:
40
~4l
20
l
e #. :;::>
0
0
2
4
3
6
5
Treatment Week
(Follow-up)
Fig. 1. Percentage of patients withnormal microscopy findings andnegative culture after treatmentwith topical terbinafine 1%or placebo fortinea pedis, athlete's foot type. Fordropouts and patients not appearing at eachweekly visit, results at lastexamination were carried forward; percentages are based on n == 9 forterbinafine, n = 13forplacebo; actual observations at week 6 were n = 9 for terbinafine and n = 10for placebo. Table I. Combined clinical and mycologic evaluation of athlete's foot-type tinea pedis after treatment with terbinafine or placebo End of therapy Response
Complete cure Mycotic Cure with or without minimal signs Effective Rx* Mycotic cure with or without clinical improvement Mycotic failure with or without clinical improvement Failure Ineffective Rx
Terbinafine
I
Placebo
Follow-up Terbinafine
I
Placebo
0(0%)
6 2
8" (89%)
0 0 0(0%)
2
1
1
1
0
4
0
2
8
0 1(11%)
6 1
0 0
"7 (78%)
0
2 (22%)
TI (100%)
10 13 (100%)
Data expressed as number of patients. *Terbinafine was statisticallysignificantly superior to placebo (p < 0.001, one-tailed Fisherexact test) in overall efficacy.
symptoms) or mycologic cure (normal microscopy findings and negative culturewith mildresidual erythema). Therapy was rated as ineffective in all othercases, even if signs and symptoms had shown improvement. Sign tests were used descriptively to assess changes from baseline separately for microscopy, culture, and signs and symptoms. At each weekly visit, comparison between terbinafine and placebo wasperformed bymeans of Wilcoxon-Mann-Whitney U testsonthe totalscore as well as on its changefrom baseline. The one-tailed Fisher exact test was used for confir-
matory testing of the null hypothesis ofterbinafine having the same effect as placebo. RESULTS Twenty-seven patients were enrolledin the study and all 27 were included in the analysisof drug tolerability. However, four patients were classified as delayed exclusions (three in the terbinafine group, one in the placebogroup) becauseof negativeinitial culture for dermatophytes. One additionalpatient in
Journal of the American Academy of Dermatology
788 Savin
100.--------------------------, 80 .5
~ Q)
~l!!
60
E~
e1V
-:= ~
oCl)ffi
.2
ia; ::i: '#.
40
20
___
1ERBINAFINE
--0-
Placebo
o
o
2
3
4
5
Treatment Week
6 (FolloW-Up)
Fig. 2. Percentage of reduction from baseline in meantotal signs and symptoms score in patients treated with topical terbinafine or placebo. Signs andsymptoms include erythema, desquamation, pruritus, incrustation, vesiculation, andpustules. Fordropouts andpatients not appearing at each weekly visit, results at last examination were carried forward; percentages are based on n = 9 for terbinafine, n = 13 for placebo; actual observations at week 6 were n = 9 for terbinafine and n = 10 for placebo. the terbinafine group was dropped from the study becauseoffailureto take medication as instructed. Thustherewere22evaluable patients, 9treated with terbinafine and 13 treated with placebo. The causative organism was Trichophyton rubrum in 21 patients (nine in the terbinafine group, 12 inthe placebo group)and Epidermophytonjloccosum in onepatient(placebo group). Nineteen patients (eightin the terbinafine group, 11 in the placebo group) had received previous therapy for the present dermatophyte infection. The mean age of patientswas 36years in the terbinafinegroup and 37 years in the placebo group. Demographic data showed that patients in the two treatment groups were comparable withregard to age, race, previous therapy, size and location of lesions, organism, and predisposing factors. However, the meanduration of disease before entrance into the study waslonger in the terbinafine group (13 years)than inthe placebo group (8 years). Mycologic efficacy The time to permanently negative microscopy and culture in the twotreatment groups is plotted in Fig. 1. After the first weekof treatment, the terbinafine-treated patients showed mycologic clearing of 44% followed by 100% clearing at week4 (end of treatment) and at 6 weeks (2-week follow-up). The
comparable clearing rate at these intervals in the placebo group was zero and 8%, respectively. Clinical efficacy Before treatment, the most common signs and symptoms were erythema (100%), desquamation (100%), and pruritus (95%). Signs and symptoms, measured by the sum of scores for these three factors and incrustation,vesiculation, and pustuleswere reduced faster and more completely in the terbinafine-treatedgroup than in the placebogroup (Fig. 2). This marked reduction in mean total scores occurred throughouttreatment and continuedthrough follow-up in the terbinafine-treated group. In contrast, a moderate reduction in signs and symptoms occurreduntil week 3 in the placebogroup, at which time they began to increase. The U test showeda significant differencefor the sum of signs and symptoms scores between the terbinafinegroup(mean ± standard error ofthe mean, 7.08 ± 0.26) and the placebo group (5.56 ± OAl) before therapy. Thus, despite randomization, the terbinafinegrouphad significantly more severesigns and symptoms than the placebogroup. However, at week 3 of treatment the total signs and symptoms scores for both groups were similar. At week 4, a significant difference in favorofterbinafinewas seen (p = 0.006) and again at week 6 (p = O.COl). Be-
Volume 23 Number 4, Part 2 October 1990
causeof the significantdifference in the baseline sum of scores, analysis of covariance was performedfor each week's measures (sum of score at week0 as covariate). The results are consistentwith the U tests on changes from baseline. Both analyses show results at the "border" of significance (covariance p = 0.06, change from baselinep = 0.07),therefore consistent with the difference between the two groups in mean sum of scores at follow-up.
Overall efficacy Table I shows the overalleffectiveness of therapy based on the combined clinical and mycologic evaluations performed at the end of the therapy and at follow-up 2 weeks later. Terbinafine was significantly superior to placebo in overall efficacy (p = 0.001, one-tailed Fisher exact test).
J\dverse effects No adverse effects were reported in either treatment group. CBCs, blood urea nitrogen level, and liver function tests performed before and after treatment revealed no abnormalities, with one exception. One terbinafine-treated patient had elevated AST (SOOT) (140 U jL), ALT (SGPT) (260 U jL), and lipemic serum at the end of treatment, which was not believed to be related to the drug treatment. Bilirubin and lactate dehydrogenase levels remained normal. No follow-up tests were done and no clinical signswere observed in this patient. DISCUSSION
Previous reports have shown veryfew adverse reactions to terbinafine- 7 However, wedid observe an unexplained elevationof liverfunctiontest results in one terbinafine-treated patient with lipemic serum. However, this was not considered related to drug treatment. The development of new,clinically effective antifungal agents is important because at anyone time, approximately 10% to 20%ofthe world'spopulation is infected with fungus." Most of these chronic superficial fungal infections are not life-threatening but may be debilitating. Furthermore, the increase in opportunistic fungal infections that occur in immunodeficiency disorders and from aggressive chemotherapeutic regimens underscores the need for more effective antifungal agents. Early data suggestthat topical terbinafine cream is superior to clotrimazolefor the treatment oftinea pedis and tinea cruris? (R. C. Savin, unpublished
Topical terbinafine in tinea pedis 789
data, multicenter study). In a recent study of 629 patients, terbinafine 1% cream was foundto be safe and effective in the treatment ofcutaneous yeast infections and dermatophytoses, including tinea pedis," On thebasis of earlierdata,the authorofthat study suggested that terbinafinecream may also be superior to naftifine-another allylamine derivative-in the treatment of tinea pedis, with respect to the overall clinical and mycologic evaluaticn.l? Other studies have shown promising results with systemic terbinafine in the treatment oftinea pedis." Another advantage of terbinafine isits fungicidal property,which bringsabout morerapid and persistent clearing. In patients with tinea pedis, therapy with fungistatic drugs,such as most azoles, is often prolonged and may be associated with high recurrence rates. As the current studyshows, the fungicidal activityof terbinafinemay permit a relatively brief course of drug therapy, with long-lasting effects, evenin patientswith chronic infections that have not been responsive to other agents. We concludethat topicalterbinafine represents a significant advance in the topical treatment of chronic tinea pedis. REFERENCES
1. Ryder NS, Dupont M-C. Inhibition ofsqualene epoxidase byallylamine antimycotic compounds: a comparative study of the antifungal and mammalian enzymes. Biochem J 1985;230:765-70. 2. PetranyiG, Stutz A, Ryder N, et al.Experimental antimycoticactivity ofnaftifine and terbinafine. In:Fromtling RA, ed. Recent trends in the discovery, development, and evaluationofantifungal agents.Barcelona: JR Prous, 1987:44150. 3. Mieth H, Petranyi G. Preclinical evaluation of terbinafine in vivo. Clin Exp DermatoI1989;14:104-7. 4. Petranyi G, Meingassner JG, Mieth H. Activity of terbinafine in experimental fungal infections of laboratory animals. Antimicrob Agents Chemother 1987;31:1558-61. 5. Villars V, Jones TC. Clinical efficacy and tolerability of terbinafine (Lamisil)-a new topical and systemic fungicidal drug for treatment of dermatomycoses. Clin Exp DermatoI1989;14:124-7. 6. Savin R. Successful treatment ofchronic tineapedis (moccasin type) with terbinafine (Larnisil). ClinExpDermatol 1989;14:116-9. 7. Kagawa S. Clinical efficacy ofterbinafine in 629Japanese patients with dermatomycosis. Clin Exp Dermatol 1989; 14:114-5. 8. Salzman RS, Jones HE, Ringworm. In: WarrenKS,Mahmoud AAF, eds, Tropical and geographic medicine. New York: McGraw-Hili, 1984:949-65. 9. Stephen A, Czok R, Male O. Terbinafine: initial clinical results.In: Fromtling RA, ed, Recent trends in the discovery, development, and evaluation of antifungal agents. Barcelona; JR Prous, 1987:511-20. 10. Kagawa S. Comparative clinical trial ofnaftifineand clotrimazole in tinea pedis, tinea cruris and tinea corporis. Mykosen 1985;28(suppl 1):82-8.
