Pharmacology of the allylamines Jay E. Birnbaum, PhD East Hanover, New Jersey The allylamines are a new class of antifungal drugs that inhibit ergosterol synthesis at the levelof squaleneepoxidase,These agents are highlyselective for the fungal enzymeand have a minimal effect on mammalian cholesterol synthesis. Naftifine,the originalmember of the allylamine series, possesses onlytopical activity, whereas the naftifine analog terbinafineis active both topically and orally. In vitro, terbinafine is exceptionally active against dermatophytes, molds,and dimorphic fungi in whichit exerts a fungicidal action. This in vitro profile is reflected by the clinical effectiveness of this allylamine in the treatment of dermatophyte infections. When given orally, terbinafine is well absorbed and rapidly and extensively distributed to the skin and sebum in concentrations that exceedthe minimum inhibitoryconcentrations of these organisms by several orders of magnitude. (J AM ACAD DERMATOL 1990;23:782-5.)
The allylamine class of antifungal agents was discovered by chance during a chemical research program for the synthesis of new central nervous system drugs. I An unexpected chemical reaction yielded a product with a novel chemical structure. When evaluated in vitro in routine biologic screening assays, this compound, later named naftifine, was observed to possess excellent antifungal activity.2 This property was confirmed both in experimental studies of animal models of infection and in clinical trials in humans.
STRUCTURAL FEATURES The name of this new chemical class of antifungal agents is based on the presence in their molecular structure of a tertiary allylamine function, that is, a nitrogen atom with a neighboring double bond. This structural feature is shared by all active members of the allylamine series. Two allylamines have been studied clinicallynaftifine, the original member of this class, and the analog terbinafine. N aftifine is active only topically. The synthesis of terbinafine resulted from research undertaken to optimize the antifungal efficacy profile of the allylamines by modifying their chemical structure. Terbinafine (Fig. 1) incorporates two important structural changes, a triple bond and branching of the alkyl side chain adjacent to it. Substitution of the phenyl ring in the naftifine molFrom the Sandoz Research Institute. Reprint requests; Jay Birnbaum, PhD, Director of Dermatology, Sandoz Research Institute, East Hanover, NJ 07936.
16jOj23519
782
ecule by the tert-butylacetylene group provides greater antifungal potency, oral efficacy, and a broader spectrum of activity that includes Aspergillus fumigatus and Candida albicans as well as dermatophytes.' In vitro data indicate that terbinafine is particularly active against dermatophytes, molds, and dimorphic fungi. The mean minimum inhibitory concentrations (MICs) of terbinafine for Trichophyton spp., Epidermophyton floccosum, and Microsporum canis range from 0.001 to 0.01 ~g/m1.4 Mean MIC values for Aspergillus spp. and Sporothrix schenckii are 0.63 and 0.2 ~g/ml, respectively. The activity of terbinafine against yeasts is weaker and varies among the different species and strains. For example, MIC values against C. parapsilosis are tenfold to 100-fold lower than against C. albicans? The in vitro activity of terbinafine against dermatophytic fingi is approximately 10 to 100 times greater than that of naftifine," 2 to 30 times greater than ketoconazole, and approximately 10 times greater than the triazole derivative, itraconazole." MECHANISM OF ACTION
The allylamines are potent inhibitors of the pathway for the biosynthesis of ergosterol, an essential component of the fungal cell membrane." The precise site of blockade of this reaction sequence can be localized by measuring (I) the extent of ergosterol synthesis that occurs in cell-free extracts when various intermediates along the pathway are used as substrates and (2) the intermediate products that accumulate when substrates involved in the early stages of ergosterol biosynthesis,such as acetate and
Volume 23 Number 4, Part 2 October 1990
Pharmacology of allylamines 783 CHa Jt.CHa
CH I
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Fig. 1. Chemical structure of terbinafine,
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Time (h) Fig. 2. Effect of 0.003 mg/L ofterbinafine on viable cell count (e), squalene content (4), and ergosterol content (.) in cells of Trichophyton mentagrophytes. (Reprinted with permission from Ryder NS. Clin Exp Dermatol1989;14:99.)
mevalonate, are used. Such studies have identified the transformation of squalene to squalene epoxide by the action of squalene epoxidase as the site of action of the allylamines. In contrast, the azoles act at a more distal point in the pathway of ergosterol synthesis, namely, the 14a-demethylation of lanesterol. It is not known whether the higher sensitivity of dermatophytes to terbinafine, as compared with other fungal species, is attributable to a greater sensitivity of the squalene epoxidase enzyme, to a greater sensitivity of the dermatophytes to such inhibition, or to greater accumulation of the drug within these cells. Exposureofdermatophytes such as Trichophyton
mentagrophytes to the MIC of terbinafine results in a time-dependent decrease in the viable cell count (Fig. 2) and indicates that the drug is fungicidal to the dermatophyte." that is, the MIC is identical to the minimal fungicidal concentration. The inhibition of squalene epoxidase by terbinafine results in the accumulation of squalene within the cell and a modest decline in the ergosterol content by approximately 20%. However, despite only partial inhibition of sterol synthesis by this concentration of terbinafine, cell growth is fully inhibited. This finding suggests that death of susceptible fungi may be related to the accumulation of squalene, which at high concentrations may be toxic to the fungus.
Journal of the American Academy of Dermatology
784 Birnbaum ~
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Terbinafine concentration (mg/L) Fig. 3. Effect ofvarious concentrations ofterbinafine on viable cell count (-), squalene content (.), and ergosterol content (_) in cells of the yeast form of Candida albicans after 24 hours of drug treatment. (Reprinted with permission from Ryder NS. Clin Exp Dermatol
1989;14:100.)
A somewhat different pattern is seen when the yeast form of C. albicans is exposed to terbinafine." Terbinafine concentrations required for the inhibition of this yeast species are 100-fold greater than those effective against dermatophytes. Even at very high concentrations of the allylamine, however, squalene accumulation in C. albicans is only a fraction ofthat observed in dermatophytes (Fig. 3). The incomplete inhibition of cell growth, which reaches only about 80%, parallels the reduction in ergosterol content. Thus ergosterol deficiency appears to be the mechanism of action causing the fungistatic effect of terbinafine against C. albicans. The activity of terbinafine against Candida organisms observed in clinical studies is actually somewhat better than predicted by these in vitro findings." This relatively high level of clinical efficacy is most likely attributable to inhibition by terbinafine of the pseudohyphal growth of Candida, which is thought to be associated with pathogenesis. This form of the organism is known to be suppressed at terbinafine concentrations considerably lower than those required for inhibition of the yeast form. 11
SELECTIVE ACTIVITY FOR FUNGI Squalene epoxidation and lanosterol demethylation are important steps not only in the biosynthesis of ergosterol in fungi but also in the formation of cholesterol in mammals. Comparative studies of the effect of terbinafine on squalene epoxidase from mammalian cell systems and from fungi have shown
that the allylamine is three to four orders of magnitude more selective for the fungal enzyme.F The ratio of the relative terbinafine concentration required for inhibition of mammalian cholesterol synthesis versus the concentration needed for inhibition of fungal ergosterol synthesis is 4000: 1. In contrast, the ratio of these concentrations for ketoconazole is 160:1, which indicates much less fungal selectivity. The 14 o-demethylase enzyme is one of many cytochrome P-450-dependent mammalian enzymes that are inhibited by most azoles. Others include the 11,B-hydroxylasein the mitochondria of the adrenal cortex and the 17 a, 20-lyase in the microsomes of Leydig cells. Enzyme inhibition at these sites has been implicated as the cause of azole-induced effects on cortisol and testosterone. In contrast to the azoles, the allylamines do not interact with cytochrome P-450 in steroidogenic tissues' ' and, consequently, do not reduce cortisol or testosterone levels, even with high doses.
CLINICAL EFFICACY The clinical efficacy of terbinafine corresponds with both its in vitro profile and data obtained in experimental infections in animals. Mycologic cure rates according to the infecting organism have been calculated for almost 1000 patients enrolled in clinical trials with oral terbinafine.!" Mycologic cure is defined as the elimination of the causative organisms, a reduction in signs and symptoms, and no signs of recurrence at the follow-up evaluation. The mycologic cure rates for patients with various
Volume 23 Number 4, Part 2 October 1990
dermatophyte infections ranged from 86% to 100%. The 606 study subjects in whom infection was attributable to T. rubrum had a mycologiccure rate of 93%. The clinical diagnoses in this subgroup of patients consisted of tinea corporis in 60%, tinea pedisin 20%, and onychomycosisin 20%. Mycologic cure rates for patients with Candida infections ranged from 66% to 75%. TERBINAFINE PHARMACOKINETICS
Terbinafine is well absorbed after oral administration. Maximal plasma concentrations of approximately 0.8 p.gjml are achieved within 2 hours after dosing. The drug is extensively metabolized in the liver and widely distributed to the tissues." This pattern of metabolism and distribution isa reflection of the lipophilicity of terbinafine. Three metabolic pathways have been identified: (1) N-demethylation of the nitrogen atom, (2) alkyl side chain oxidation of any of the three methyl groups, and (3) oxidation on the naphthalene ring. These reactions involve a small fract ion, approximately 5% or less, of the total cytochrome P-450 capacity of the liver.P Consequently, terbinafine does not alter the disposition of other drugs whose metabolism involvesthese enzyme systems.In contrast, metabolism of ketoconazole involves greater than 60% of the total cytochrome P-450 enzyme capacity of the liver. The high lipophilicity and keratophilicity of terbinafine results in its distribution and accumulation in the adipose tissue and skin, from which it is slowly released, metabolized, and eliminated. Levelsof terbinafine in the hair, skin, and nails of monkeys treated with the drug for 6 months were found to be at least 10 times higher than trough plasma levels (Sandoz Research Institute, unpublished data). Terbinafineconcentrations were particularly high in the nails in which levels 55 times greater than trough plasma levels were detected . Concentrations of terbinafine have also been determined from the skin of humans after oral treatment (J. Faergemann and H. Maibach, unpublished data). The results indicate rapid accumulation of terbinafine in the stratum corneum. Within 2 days stratum corneum levels of drug approximated peak plasma levels and after 12 days of treatment exceeded trough plasma levels by a factor of 75, well above the MICs for dermatophytes. Even higher levelswere achieved in the sebum, where terbinafine concentrations exceeded trough plasma levels by
Pharmacology of allylamines 785 more than 300-fold. Consistent with this finding, levels of drug in the stratum corneum were 25 times those in the underlying epidermis and dermis. Terbinafine could not be detected in eccrine sweat after 12 days of oral treatment. Thus it appears that two routes are available for terbinafine distributiondiffusion through the dermis and epidermis and transport via the sebum, which results in high drug levels in the hair follicle, the hair, and sebum-rich areas of the skin. REFERENCES I. Berney D, Schuh K. Heterocyclic spiro-naphthalenones. Part I: Synthesis and reactions of some Spiro [(IH-naphthal enone)]-1,3 ' ,-piperidines. Helv Chim Acta 1978;61: 1262-73. 2. Georgopoulos A, Petranyi G, Mieth H , et aI. In vitro activity of naftifine,a new ant ifungal agent. Antimicrob Agents Chemother 1981;19:386-9. 3. Stutz A.Synthesis an d structure-activitycorrelations within allylamine antimycotics. Ann NY Acad Sci 1988;544:4662. 4. Petranyi G , Ryder NS, Stiitz A . Allylamine derivatives: new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 1984;224:1239-41. 5. Petranyi G, Meingassner JG, M ieth H. Antifungal activity of the allylamine derivative terbinafine in vitro. Antimicrob Agents Chemother 1987;31:1365-8. 6. Petranyi G, Stiitz A, R yder NS, et aI. Experimental antimycotic activity of naftifine terbinafine. In: Fromtling RA , ed. Recent trends in the discovery, development , and evaluation of antifungal agents . Barcelona: JR Prous, 1987:441-50. 7. Shadomy S, Espinel-Ingroff A, Gebhart RJ. In vitro studies with SF 86-327, a new orally active allylamine derivative. J Med Vet Mycol 1985;23:125-32. 8. Ryder NS. Specific inhibition of fungal sterol biosynthesis by SF 86-327, a new allylamine antimycotic agent. Antimicrob Agents Chemother 1985:27:252-6. 9. Ryder NS. The mechan ism of action of terb inafine. Clin Exp DermatoI1989;1 4:98-100. 10. Stephen A, Czok R , Male O. Terbinafine: initial clinical results. Recent trends in the discovery, development and evaluation of antifungal agen ts. In: Fromtling RA, ed. Recent trends in the discovery, development, and evaluation of antifungal agents. Barcelona: JR Prous, 1987:511-20. II. Schaude M, Ackerbauer H , Mieth H. Inhibitory effect of antifungal agents on germ tube formation in Candidaalbicans. Mykosen 1987;30:281-7. 12. Ryder NS, Dupont MC. Inhibition of squalene epoxidase by allylamine antimycotic compounds: a comparative study of the fungal and mammalian enzymes. Biochem J 1985; 230:765-70. 13. Schuster I. The interaction of representat ivemembers from two classes of antimycotics-the azoles and the allylamines-with cytochrome P-450 in steroidogenic tissues and liver. Xenobiotica 1985;15:529-46. 14. Villars V, Jones TC. Present status of the efficacy and tolerability of terbinafine (Lamisil) used systemically in the treatment of dermatomycoses of skin and nails. J Dermatol Treat 1990;1(suppl 2):33-8 . 15. Jensen JC. The clinical pharmacokinetics of terbinafine (Lamisil). Clin Exp Dermatol 1989;14:110-3.
The allylamine class of antifungal agents was discovered by chance during a chemical research program for the synthesis of new central nervous system drugs. I An unexpected chemical reaction yielded a product with a novel chemical structure. When evaluated in vitro in routine biologic screening assays, this compound, later named naftifine, was observed to possess excellent antifungal activity.2 This property was confirmed both in experimental studies of animal models of infection and in clinical trials in humans.
STRUCTURAL FEATURES The name of this new chemical class of antifungal agents is based on the presence in their molecular structure of a tertiary allylamine function, that is, a nitrogen atom with a neighboring double bond. This structural feature is shared by all active members of the allylamine series. Two allylamines have been studied clinicallynaftifine, the original member of this class, and the analog terbinafine. N aftifine is active only topically. The synthesis of terbinafine resulted from research undertaken to optimize the antifungal efficacy profile of the allylamines by modifying their chemical structure. Terbinafine (Fig. 1) incorporates two important structural changes, a triple bond and branching of the alkyl side chain adjacent to it. Substitution of the phenyl ring in the naftifine molFrom the Sandoz Research Institute. Reprint requests; Jay Birnbaum, PhD, Director of Dermatology, Sandoz Research Institute, East Hanover, NJ 07936.
16jOj23519
782
ecule by the tert-butylacetylene group provides greater antifungal potency, oral efficacy, and a broader spectrum of activity that includes Aspergillus fumigatus and Candida albicans as well as dermatophytes.' In vitro data indicate that terbinafine is particularly active against dermatophytes, molds, and dimorphic fungi. The mean minimum inhibitory concentrations (MICs) of terbinafine for Trichophyton spp., Epidermophyton floccosum, and Microsporum canis range from 0.001 to 0.01 ~g/m1.4 Mean MIC values for Aspergillus spp. and Sporothrix schenckii are 0.63 and 0.2 ~g/ml, respectively. The activity of terbinafine against yeasts is weaker and varies among the different species and strains. For example, MIC values against C. parapsilosis are tenfold to 100-fold lower than against C. albicans? The in vitro activity of terbinafine against dermatophytic fingi is approximately 10 to 100 times greater than that of naftifine," 2 to 30 times greater than ketoconazole, and approximately 10 times greater than the triazole derivative, itraconazole." MECHANISM OF ACTION
The allylamines are potent inhibitors of the pathway for the biosynthesis of ergosterol, an essential component of the fungal cell membrane." The precise site of blockade of this reaction sequence can be localized by measuring (I) the extent of ergosterol synthesis that occurs in cell-free extracts when various intermediates along the pathway are used as substrates and (2) the intermediate products that accumulate when substrates involved in the early stages of ergosterol biosynthesis,such as acetate and
Volume 23 Number 4, Part 2 October 1990
Pharmacology of allylamines 783 CHa Jt.CHa
CH I
/~
3
~;;N~"""""""""'~,;',*,
..
a
..
.......................... :
...................
CH
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Common structural element of the allylamines
Fig. 1. Chemical structure of terbinafine,
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2T 40 Q)
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Time (h) Fig. 2. Effect of 0.003 mg/L ofterbinafine on viable cell count (e), squalene content (4), and ergosterol content (.) in cells of Trichophyton mentagrophytes. (Reprinted with permission from Ryder NS. Clin Exp Dermatol1989;14:99.)
mevalonate, are used. Such studies have identified the transformation of squalene to squalene epoxide by the action of squalene epoxidase as the site of action of the allylamines. In contrast, the azoles act at a more distal point in the pathway of ergosterol synthesis, namely, the 14a-demethylation of lanesterol. It is not known whether the higher sensitivity of dermatophytes to terbinafine, as compared with other fungal species, is attributable to a greater sensitivity of the squalene epoxidase enzyme, to a greater sensitivity of the dermatophytes to such inhibition, or to greater accumulation of the drug within these cells. Exposureofdermatophytes such as Trichophyton
mentagrophytes to the MIC of terbinafine results in a time-dependent decrease in the viable cell count (Fig. 2) and indicates that the drug is fungicidal to the dermatophyte." that is, the MIC is identical to the minimal fungicidal concentration. The inhibition of squalene epoxidase by terbinafine results in the accumulation of squalene within the cell and a modest decline in the ergosterol content by approximately 20%. However, despite only partial inhibition of sterol synthesis by this concentration of terbinafine, cell growth is fully inhibited. This finding suggests that death of susceptible fungi may be related to the accumulation of squalene, which at high concentrations may be toxic to the fungus.
Journal of the American Academy of Dermatology
784 Birnbaum ~
a;- 8 Ci5 7 0 ~ 6 0) 5
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Terbinafine concentration (mg/L) Fig. 3. Effect ofvarious concentrations ofterbinafine on viable cell count (-), squalene content (.), and ergosterol content (_) in cells of the yeast form of Candida albicans after 24 hours of drug treatment. (Reprinted with permission from Ryder NS. Clin Exp Dermatol
1989;14:100.)
A somewhat different pattern is seen when the yeast form of C. albicans is exposed to terbinafine." Terbinafine concentrations required for the inhibition of this yeast species are 100-fold greater than those effective against dermatophytes. Even at very high concentrations of the allylamine, however, squalene accumulation in C. albicans is only a fraction ofthat observed in dermatophytes (Fig. 3). The incomplete inhibition of cell growth, which reaches only about 80%, parallels the reduction in ergosterol content. Thus ergosterol deficiency appears to be the mechanism of action causing the fungistatic effect of terbinafine against C. albicans. The activity of terbinafine against Candida organisms observed in clinical studies is actually somewhat better than predicted by these in vitro findings." This relatively high level of clinical efficacy is most likely attributable to inhibition by terbinafine of the pseudohyphal growth of Candida, which is thought to be associated with pathogenesis. This form of the organism is known to be suppressed at terbinafine concentrations considerably lower than those required for inhibition of the yeast form. 11
SELECTIVE ACTIVITY FOR FUNGI Squalene epoxidation and lanosterol demethylation are important steps not only in the biosynthesis of ergosterol in fungi but also in the formation of cholesterol in mammals. Comparative studies of the effect of terbinafine on squalene epoxidase from mammalian cell systems and from fungi have shown
that the allylamine is three to four orders of magnitude more selective for the fungal enzyme.F The ratio of the relative terbinafine concentration required for inhibition of mammalian cholesterol synthesis versus the concentration needed for inhibition of fungal ergosterol synthesis is 4000: 1. In contrast, the ratio of these concentrations for ketoconazole is 160:1, which indicates much less fungal selectivity. The 14 o-demethylase enzyme is one of many cytochrome P-450-dependent mammalian enzymes that are inhibited by most azoles. Others include the 11,B-hydroxylasein the mitochondria of the adrenal cortex and the 17 a, 20-lyase in the microsomes of Leydig cells. Enzyme inhibition at these sites has been implicated as the cause of azole-induced effects on cortisol and testosterone. In contrast to the azoles, the allylamines do not interact with cytochrome P-450 in steroidogenic tissues' ' and, consequently, do not reduce cortisol or testosterone levels, even with high doses.
CLINICAL EFFICACY The clinical efficacy of terbinafine corresponds with both its in vitro profile and data obtained in experimental infections in animals. Mycologic cure rates according to the infecting organism have been calculated for almost 1000 patients enrolled in clinical trials with oral terbinafine.!" Mycologic cure is defined as the elimination of the causative organisms, a reduction in signs and symptoms, and no signs of recurrence at the follow-up evaluation. The mycologic cure rates for patients with various
Volume 23 Number 4, Part 2 October 1990
dermatophyte infections ranged from 86% to 100%. The 606 study subjects in whom infection was attributable to T. rubrum had a mycologiccure rate of 93%. The clinical diagnoses in this subgroup of patients consisted of tinea corporis in 60%, tinea pedisin 20%, and onychomycosisin 20%. Mycologic cure rates for patients with Candida infections ranged from 66% to 75%. TERBINAFINE PHARMACOKINETICS
Terbinafine is well absorbed after oral administration. Maximal plasma concentrations of approximately 0.8 p.gjml are achieved within 2 hours after dosing. The drug is extensively metabolized in the liver and widely distributed to the tissues." This pattern of metabolism and distribution isa reflection of the lipophilicity of terbinafine. Three metabolic pathways have been identified: (1) N-demethylation of the nitrogen atom, (2) alkyl side chain oxidation of any of the three methyl groups, and (3) oxidation on the naphthalene ring. These reactions involve a small fract ion, approximately 5% or less, of the total cytochrome P-450 capacity of the liver.P Consequently, terbinafine does not alter the disposition of other drugs whose metabolism involvesthese enzyme systems.In contrast, metabolism of ketoconazole involves greater than 60% of the total cytochrome P-450 enzyme capacity of the liver. The high lipophilicity and keratophilicity of terbinafine results in its distribution and accumulation in the adipose tissue and skin, from which it is slowly released, metabolized, and eliminated. Levelsof terbinafine in the hair, skin, and nails of monkeys treated with the drug for 6 months were found to be at least 10 times higher than trough plasma levels (Sandoz Research Institute, unpublished data). Terbinafineconcentrations were particularly high in the nails in which levels 55 times greater than trough plasma levels were detected . Concentrations of terbinafine have also been determined from the skin of humans after oral treatment (J. Faergemann and H. Maibach, unpublished data). The results indicate rapid accumulation of terbinafine in the stratum corneum. Within 2 days stratum corneum levels of drug approximated peak plasma levels and after 12 days of treatment exceeded trough plasma levels by a factor of 75, well above the MICs for dermatophytes. Even higher levelswere achieved in the sebum, where terbinafine concentrations exceeded trough plasma levels by
Pharmacology of allylamines 785 more than 300-fold. Consistent with this finding, levels of drug in the stratum corneum were 25 times those in the underlying epidermis and dermis. Terbinafine could not be detected in eccrine sweat after 12 days of oral treatment. Thus it appears that two routes are available for terbinafine distributiondiffusion through the dermis and epidermis and transport via the sebum, which results in high drug levels in the hair follicle, the hair, and sebum-rich areas of the skin. REFERENCES I. Berney D, Schuh K. Heterocyclic spiro-naphthalenones. Part I: Synthesis and reactions of some Spiro [(IH-naphthal enone)]-1,3 ' ,-piperidines. Helv Chim Acta 1978;61: 1262-73. 2. Georgopoulos A, Petranyi G, Mieth H , et aI. In vitro activity of naftifine,a new ant ifungal agent. Antimicrob Agents Chemother 1981;19:386-9. 3. Stutz A.Synthesis an d structure-activitycorrelations within allylamine antimycotics. Ann NY Acad Sci 1988;544:4662. 4. Petranyi G , Ryder NS, Stiitz A . Allylamine derivatives: new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 1984;224:1239-41. 5. Petranyi G, Meingassner JG, M ieth H. Antifungal activity of the allylamine derivative terbinafine in vitro. Antimicrob Agents Chemother 1987;31:1365-8. 6. Petranyi G, Stiitz A, R yder NS, et aI. Experimental antimycotic activity of naftifine terbinafine. In: Fromtling RA , ed. Recent trends in the discovery, development , and evaluation of antifungal agents . Barcelona: JR Prous, 1987:441-50. 7. Shadomy S, Espinel-Ingroff A, Gebhart RJ. In vitro studies with SF 86-327, a new orally active allylamine derivative. J Med Vet Mycol 1985;23:125-32. 8. Ryder NS. Specific inhibition of fungal sterol biosynthesis by SF 86-327, a new allylamine antimycotic agent. Antimicrob Agents Chemother 1985:27:252-6. 9. Ryder NS. The mechan ism of action of terb inafine. Clin Exp DermatoI1989;1 4:98-100. 10. Stephen A, Czok R , Male O. Terbinafine: initial clinical results. Recent trends in the discovery, development and evaluation of antifungal agen ts. In: Fromtling RA, ed. Recent trends in the discovery, development, and evaluation of antifungal agents. Barcelona: JR Prous, 1987:511-20. II. Schaude M, Ackerbauer H , Mieth H. Inhibitory effect of antifungal agents on germ tube formation in Candidaalbicans. Mykosen 1987;30:281-7. 12. Ryder NS, Dupont MC. Inhibition of squalene epoxidase by allylamine antimycotic compounds: a comparative study of the fungal and mammalian enzymes. Biochem J 1985; 230:765-70. 13. Schuster I. The interaction of representat ivemembers from two classes of antimycotics-the azoles and the allylamines-with cytochrome P-450 in steroidogenic tissues and liver. Xenobiotica 1985;15:529-46. 14. Villars V, Jones TC. Present status of the efficacy and tolerability of terbinafine (Lamisil) used systemically in the treatment of dermatomycoses of skin and nails. J Dermatol Treat 1990;1(suppl 2):33-8 . 15. Jensen JC. The clinical pharmacokinetics of terbinafine (Lamisil). Clin Exp Dermatol 1989;14:110-3.
