PHARMACOLOGY AND THERAPEUTICS
TERBINAEINE: EFFICACY AND SAFETY IN THE TREATMENT OF DERMATOPHYTOSIS YALgiN TUZUN, M.D., AGOP KOTOGYAN, M.D., AND OYA OGUZ, M.D.
Abstract A double-blind study with terbinafine was performed in 39 patients with dermatophyte infection, between 1987 and 1989, to compare the safety and efficacy of two dosage schedules of 125 mg twice daily versus 250 mg once daily, Mycologic assessments were negative by microscopic examination and Sabouraud's culture in 59% and 100% of patients in the first and the fourth weeks of treatment, respectively. There was no statistically significant difference between the two groups of patients receiving 125 mg b,i,d, and 260 mg q,d, with respect to the safety and efficacy of the treatment; bowever, the differences between the sums of clinical scores before and after the treatment were statistically significant. There were no adverse effects, and the drug was well tolerated, IntJ Dermatol 1992,31:720-721 The development of new systemic antifungal agents has special importance since 10 to 20% of the world population encounters fungus infection at least once.' Terbinafine is a new allylamine, which performs an inhibiting effect on the cell membrane of fungi.^ It has already been found to be effective on dermatophytes, yeasts, and moulds;^"'' there are many clinical experiences with terbinafine in dermatophyte infections.''"^
agar, and incubated at 30°C for 2 weeks. Positive results obtained by these examinations were considered the main inclusion criteria, Hematologic and biochemical tests on blood samples and urinalysis were done before treatment and were repeated in tbe 2nd, 4th, and 6th weeks of treatment, and also at the follow-up examination along with the mycologic assessments. Clinical signs and symptoms including erythema, scaling vesiculation, pustules, crusting, and pruritus were assessed at the initial and subsequent examinations. They were rated on the scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe. Six weeks after the initiation of therapy the response of each patient was noted as follows. Complete cure: microscopy and culture negative, no residual clinical signs and symptoms, Mycologic cure: microscopy and culture negative, residual erythema and/or scaling and/or pruritus. Improvement: (A) Mycologic cure, clinical signs and symptoms diminished to < 50% sum of scores, (B) Mycologic cure, clinical signs and symptoms diminished to > 50% sum of scores, (C) Pathogen still detectable, but signs and symptoms diminisbed significantly. Failure: No significant response to therapy or exacerbation.
RESULTS
Materials and Methods Tbirty-nine cases, 6 women and 33 men, suffering from a suspected superficial fungus disease were entered into the study, which was performed in the Dermatology Department of Cerrahpasa Faculty of Medicine between 1987 and 1989. Patients were given terbinafine either 250 mg once daily or 125 mg twice daily for 6 weeks and were followed up for 4 to 8 weeks. Women of childbearing potential were only included if reliable contraceptive measures were maintained throughout the study. Only the patients suffering from body dermatophytosis (tinea corporis) were included, with preference to cases with follicular involvement on either pilose skin of the trunk, inguinal region, or head and neck. Infections ofthe soles or palms were not included. For mycologic diagnosis, each specimen was examined on KOH wet mount, inoculated on Sabouraud's 2% glucose
The mean duration of the present disease of patients entered in the study was 54 + 61.9 (±SD) weeks; 34% of cases had been treated previously. The fungi identified by culture methods were Trichophyton species in 34 cases and Epidermophyton in five cases. Clinical diagnosis was tinea corporis in 10 patients, tinea inguinalis and cruris in 16 patients (Table 1). Complete mycologic cure was recorded in 23 cases (59%) after 1 week, in 35 cases (90%) after 3 weeks, and in all cases after 4 weeks of treatment (Table 2). The mean of the sums of scores for clinical signs was recorded as 7.7 + 2.3 and decreased to 0.33 ± 0.7 in the 21 cases given 250 mg q.d. These recordings re-
Table 1. Glinical Types of Dermatophytosis in This Study Clinical Diagnosis
Erom the Department of Dermatology, Gerrahpasa Faculty of Medicine, Istanbul, Turkey.
Tinea corporis Tinea inguinalis Tinea cruris Multiple lesions
Supported by Sandoz Ltd., Basel. Address for correspondence: Yalgin Tiizlin, M.D., Millet Gad. No. 111/11, Capa, Istanbul, Turkey. 720
Number of Cases 10 8 8 13
Terbinafine Tiizijn, Kotogyan, and Oguz
Table 2. Assessment of Mycologic Gulture between Weeks 1 and 4
Table 4. Assessment of Safety and Efficacy Tolerability
Investigators' Opinion of Efficacy
Patient's Opinion of Efficacy
31 7 1
27 8 3 0
11 14 3
Number of Cases witb (-) Culture Week 1 Week 2 Week 3 Week 4
125 mg b.i.d. 13 17 17 19
250 mg q.d.
Total
10 15 18 20
23 32 35 39
Very good Good Moderate Failure
Table 3. Assessment of Glinical Response in Two Groups of Patients 125 mg b.i.d. Group Day 7 Failure Improvement
A
B G Mycologic cure Gomplete cure Total Day 21 Failure Improvement A B G Mycologic cure Gomplete cure Total Day 42 Failure Improvement A B G Mycologic cure Gomplete cure Total
A 7 1 S 0 0 18 1 1 1 2 6 ¥ 18 0 0 0 1 0 17 18
0
ment of tinea corporis; this is in agreement with previous reports.' Ninety percent of patients showed significant improvement in 3 weeks of treatment. Although gastrointestinal side effects were reported to be frequent with terbinafine, we did not observe any adverse effects.'"-" It has already been proven in more than 30 clinical trials that terbinafine has no hepatotoxicity.' This study shows that oral terbinafine is effective and well tolerated in the treatment of tinea corporis; however, larger studies are needed for detailed investigations about its safety and efficacy.
250 mg q.d. Group 3 8 5 5 0 0 21
4 1 1
REFERENCES
2 7
1.
6 21
2.
0 0 1 0 2
3.
4.
18 21
mained the same during the follow-up period. In the 18 cases receiving 125 mg b.i.d., the mean of the sums of scores was recorded as 8.6 ± 2.3 before treatment, 0.8 ± 1 . 3 after treatment, and 0.6 ± 1 . 7 during the follow-up period. There was no significant difference in the change in clinical scores between the two treatment regimens (Kolmogorov-Simirnov, P = 0.9). The difference between the means of sums of scores in each group was statistically significant before and after treatment (Wilcoxon, P < 0.0001). The data for the assessment of the clinical response were given in Table 3. No adverse effects or abnormal laboratory values, which may have caused withdrawal from the study, were observed (Table 4).
5.
Shadomy S, et al. In vitro studies with SF 86-327, a new orally active allylamine derivative. Sabouraudia 1985; 23:125-132.
6.
Petranyi GG, Meingasser JG, Mieth H. Activity of terbinafine in experimental fungal infections of laboratory animals. Antimicrob Agents Ghemotber 1987; 31: 1558-1561.
7.
Zaias N, Serrano L. Effectiveness and safety of SF 86-327 in treatment of T. rubrum onchomycosis. 17th World Gongress of Dermatology, Berlin, 1987:550.(Abstr) Savin R. Successful treatment of chronic tinea pedis (moccasin type) with terbinafine (Lamisil). Glin Exp Dermatol 1989:14.
8.
9.
Villars V. Present status of the efficacy and tolerability of terbinafine (Lamisil) used systemically in tbe treatment of dermatomycoses of skin and nails. J Dermatol Treat 1990; l(2):33-38.
10.
Goodfield, Rowell NR, Forster RA, et al. Treatment of dermatophyte infection of the finger and toe nails with terbinafine (SF 86-327, Lamisil), an orally active fungicidal agent. Br J Dermatol 1989; 121:753-757. Gole WG, Stricklin G. A comparison of a new oral antifungal Terbinafine with griseofulvin as therapy for tinea corporis. Arch Dermatol 1989; 125:1537-1539.
DISCUSSION
The clinical and laboratory results of this study confirmed that oral administration of terbinafine 125 mg b.i.d. or 250 mg. q.d. have equal efficiency in the treat-
11.
721
Salzman RS, et al. Tropical and geographic medicine. New York: McGrawHill, 1984:949. Petranyi GG, Ryder NS, Stutz A. Allylamine derivates: new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 1984; 224:1239-1241. Petranyi GG, et al. Antifungal activity of the allylamine derivative terbinafine in vitro. Antimicrob Agents Ghemotber 1987; 31:1365-1368, Glayton YM. The in vitro activity of terbinafine. Glin Exp Dermatol 1989; 14:101-103.
TERBINAEINE: EFFICACY AND SAFETY IN THE TREATMENT OF DERMATOPHYTOSIS YALgiN TUZUN, M.D., AGOP KOTOGYAN, M.D., AND OYA OGUZ, M.D.
Abstract A double-blind study with terbinafine was performed in 39 patients with dermatophyte infection, between 1987 and 1989, to compare the safety and efficacy of two dosage schedules of 125 mg twice daily versus 250 mg once daily, Mycologic assessments were negative by microscopic examination and Sabouraud's culture in 59% and 100% of patients in the first and the fourth weeks of treatment, respectively. There was no statistically significant difference between the two groups of patients receiving 125 mg b,i,d, and 260 mg q,d, with respect to the safety and efficacy of the treatment; bowever, the differences between the sums of clinical scores before and after the treatment were statistically significant. There were no adverse effects, and the drug was well tolerated, IntJ Dermatol 1992,31:720-721 The development of new systemic antifungal agents has special importance since 10 to 20% of the world population encounters fungus infection at least once.' Terbinafine is a new allylamine, which performs an inhibiting effect on the cell membrane of fungi.^ It has already been found to be effective on dermatophytes, yeasts, and moulds;^"'' there are many clinical experiences with terbinafine in dermatophyte infections.''"^
agar, and incubated at 30°C for 2 weeks. Positive results obtained by these examinations were considered the main inclusion criteria, Hematologic and biochemical tests on blood samples and urinalysis were done before treatment and were repeated in tbe 2nd, 4th, and 6th weeks of treatment, and also at the follow-up examination along with the mycologic assessments. Clinical signs and symptoms including erythema, scaling vesiculation, pustules, crusting, and pruritus were assessed at the initial and subsequent examinations. They were rated on the scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe. Six weeks after the initiation of therapy the response of each patient was noted as follows. Complete cure: microscopy and culture negative, no residual clinical signs and symptoms, Mycologic cure: microscopy and culture negative, residual erythema and/or scaling and/or pruritus. Improvement: (A) Mycologic cure, clinical signs and symptoms diminished to < 50% sum of scores, (B) Mycologic cure, clinical signs and symptoms diminished to > 50% sum of scores, (C) Pathogen still detectable, but signs and symptoms diminisbed significantly. Failure: No significant response to therapy or exacerbation.
RESULTS
Materials and Methods Tbirty-nine cases, 6 women and 33 men, suffering from a suspected superficial fungus disease were entered into the study, which was performed in the Dermatology Department of Cerrahpasa Faculty of Medicine between 1987 and 1989. Patients were given terbinafine either 250 mg once daily or 125 mg twice daily for 6 weeks and were followed up for 4 to 8 weeks. Women of childbearing potential were only included if reliable contraceptive measures were maintained throughout the study. Only the patients suffering from body dermatophytosis (tinea corporis) were included, with preference to cases with follicular involvement on either pilose skin of the trunk, inguinal region, or head and neck. Infections ofthe soles or palms were not included. For mycologic diagnosis, each specimen was examined on KOH wet mount, inoculated on Sabouraud's 2% glucose
The mean duration of the present disease of patients entered in the study was 54 + 61.9 (±SD) weeks; 34% of cases had been treated previously. The fungi identified by culture methods were Trichophyton species in 34 cases and Epidermophyton in five cases. Clinical diagnosis was tinea corporis in 10 patients, tinea inguinalis and cruris in 16 patients (Table 1). Complete mycologic cure was recorded in 23 cases (59%) after 1 week, in 35 cases (90%) after 3 weeks, and in all cases after 4 weeks of treatment (Table 2). The mean of the sums of scores for clinical signs was recorded as 7.7 + 2.3 and decreased to 0.33 ± 0.7 in the 21 cases given 250 mg q.d. These recordings re-
Table 1. Glinical Types of Dermatophytosis in This Study Clinical Diagnosis
Erom the Department of Dermatology, Gerrahpasa Faculty of Medicine, Istanbul, Turkey.
Tinea corporis Tinea inguinalis Tinea cruris Multiple lesions
Supported by Sandoz Ltd., Basel. Address for correspondence: Yalgin Tiizlin, M.D., Millet Gad. No. 111/11, Capa, Istanbul, Turkey. 720
Number of Cases 10 8 8 13
Terbinafine Tiizijn, Kotogyan, and Oguz
Table 2. Assessment of Mycologic Gulture between Weeks 1 and 4
Table 4. Assessment of Safety and Efficacy Tolerability
Investigators' Opinion of Efficacy
Patient's Opinion of Efficacy
31 7 1
27 8 3 0
11 14 3
Number of Cases witb (-) Culture Week 1 Week 2 Week 3 Week 4
125 mg b.i.d. 13 17 17 19
250 mg q.d.
Total
10 15 18 20
23 32 35 39
Very good Good Moderate Failure
Table 3. Assessment of Glinical Response in Two Groups of Patients 125 mg b.i.d. Group Day 7 Failure Improvement
A
B G Mycologic cure Gomplete cure Total Day 21 Failure Improvement A B G Mycologic cure Gomplete cure Total Day 42 Failure Improvement A B G Mycologic cure Gomplete cure Total
A 7 1 S 0 0 18 1 1 1 2 6 ¥ 18 0 0 0 1 0 17 18
0
ment of tinea corporis; this is in agreement with previous reports.' Ninety percent of patients showed significant improvement in 3 weeks of treatment. Although gastrointestinal side effects were reported to be frequent with terbinafine, we did not observe any adverse effects.'"-" It has already been proven in more than 30 clinical trials that terbinafine has no hepatotoxicity.' This study shows that oral terbinafine is effective and well tolerated in the treatment of tinea corporis; however, larger studies are needed for detailed investigations about its safety and efficacy.
250 mg q.d. Group 3 8 5 5 0 0 21
4 1 1
REFERENCES
2 7
1.
6 21
2.
0 0 1 0 2
3.
4.
18 21
mained the same during the follow-up period. In the 18 cases receiving 125 mg b.i.d., the mean of the sums of scores was recorded as 8.6 ± 2.3 before treatment, 0.8 ± 1 . 3 after treatment, and 0.6 ± 1 . 7 during the follow-up period. There was no significant difference in the change in clinical scores between the two treatment regimens (Kolmogorov-Simirnov, P = 0.9). The difference between the means of sums of scores in each group was statistically significant before and after treatment (Wilcoxon, P < 0.0001). The data for the assessment of the clinical response were given in Table 3. No adverse effects or abnormal laboratory values, which may have caused withdrawal from the study, were observed (Table 4).
5.
Shadomy S, et al. In vitro studies with SF 86-327, a new orally active allylamine derivative. Sabouraudia 1985; 23:125-132.
6.
Petranyi GG, Meingasser JG, Mieth H. Activity of terbinafine in experimental fungal infections of laboratory animals. Antimicrob Agents Ghemotber 1987; 31: 1558-1561.
7.
Zaias N, Serrano L. Effectiveness and safety of SF 86-327 in treatment of T. rubrum onchomycosis. 17th World Gongress of Dermatology, Berlin, 1987:550.(Abstr) Savin R. Successful treatment of chronic tinea pedis (moccasin type) with terbinafine (Lamisil). Glin Exp Dermatol 1989:14.
8.
9.
Villars V. Present status of the efficacy and tolerability of terbinafine (Lamisil) used systemically in tbe treatment of dermatomycoses of skin and nails. J Dermatol Treat 1990; l(2):33-38.
10.
Goodfield, Rowell NR, Forster RA, et al. Treatment of dermatophyte infection of the finger and toe nails with terbinafine (SF 86-327, Lamisil), an orally active fungicidal agent. Br J Dermatol 1989; 121:753-757. Gole WG, Stricklin G. A comparison of a new oral antifungal Terbinafine with griseofulvin as therapy for tinea corporis. Arch Dermatol 1989; 125:1537-1539.
DISCUSSION
The clinical and laboratory results of this study confirmed that oral administration of terbinafine 125 mg b.i.d. or 250 mg. q.d. have equal efficiency in the treat-
11.
721
Salzman RS, et al. Tropical and geographic medicine. New York: McGrawHill, 1984:949. Petranyi GG, Ryder NS, Stutz A. Allylamine derivates: new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 1984; 224:1239-1241. Petranyi GG, et al. Antifungal activity of the allylamine derivative terbinafine in vitro. Antimicrob Agents Ghemotber 1987; 31:1365-1368, Glayton YM. The in vitro activity of terbinafine. Glin Exp Dermatol 1989; 14:101-103.
