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Naftifine: A topical allylamine antifungal agent
Naf tifine: A Topical Allylamine Antifungal Agent JOHANNES
MATTHIAS
MUHLBACHER,
MD
istorically, there have been only a limited number of effective antimycotic drugs, such as the dyes magenta paint, brilliant green, and gentian violet.’ The earliest of the topically applicable compounds was Whitfield’s ointment consisting of benzoic and salicylic acids. During the last 20 to 30 years a remarkable number of useful antifungals have been discovered. The most important antifungals in current use belong to five groups: (1) the polyenes, (2) the azoles, (3) the group of unrelated compounds, (4) the morpholines, and (5) the allylamines. (The allylamines, of which terbinafine and naftifine are the principal drugs, constitute a comparatively new class of antifungal agents.) Naftifine was discovered in 19742 at the Sandoz Research Institute in Vienna, Austria, and was found to be highly active against a considerable number of important fungi. Thus, the first derivative of the class of allylamines turned out to be a very reliable and safe agent against fungi pathogenic to humans.
H
Chemistry Chemically, naftifine belongs, as pointed out above, to the class of allylamines (Fig 1).3 Its empiric formula is C,rH,,ClN. It is a lightly yellowish, crystalline powder. Naftifine is not related chemically to any other antimycotic compound discovered so far.
Mechanism of Action Avltimycotic Action Naftifine is a synthetic agent that inhibits squalene epoxidase and thus inhibits the biosynthesis of ergosterol, an essential component of the cell membrane of fungi (Fig From the Department of Clinical Research, Biochemie Ges.m.b.H, Kundl, Austria. Address correspondence to: Iohannes Matthias Miihlbacher, MD, Medical Department PM/PP, Biochemie Ges.m.b.H., A-6250 Kundl Austria.
0
1992 by Elsevier
Science
Publishing
Co.,
2).4 The result of this kind of inhibition is ergosterol deficiency and accumulation of squalene epoxidase. A certain quantity of sterol is necessary for fungal cell growth; a lack of sterols leads to cessation of growth of fungal cells. Therefore, ergosterol deficiency may account for the fungistatic action of naftifine. On the other hand, the accumulation of squalene caused by the inhibition of squalene epoxidase leads to several intracellular degenerative processes such as the deposition of lipid droplets. This accumulation of squalene takes place not only in the cell membrane but also in other membranes, such as the endoplasmic reticulum. Finally, the alterations in membrane properties, as well as the impairment of all intracellular processes associated with lipid membranes, may lead to damage of the cell wall. This explains the fungicida1 action of naftifine.5 Various investigations were performed to distinguish the fungistatic and fungicidal effects of naftifine in vitro. By observation of the effects of naftifine on Candida parapsilosis and Trichophyton mentagrophytes it became evident that naftifine had a fungicidal effect. For Candida albicans and most other yeasts, however, it turned out to be fungistatic. Generally, naftifine acts fungicidally against dermatophytes and molds, but fungistatically against the majority of yeasts.
Antibacterial
Naftifine possesses local bactericidal properties against both gram-positive and gram-negative bacteria. The minimum bactericidal concentrations (MBCs) determined for various bacteria range between 0.04 and 1.25% of the active substance (Table 1).
Antibacterial
Properties
in Vivo
In a clinical trial, the antibacterial efficacy of naftifine was compared with that of gentamicin for the indication of pyoderma. Naftifine showed the same effect on clinical symptoms and growth of bacteria as did gentamicin (Figs 3 and 4).’
Inc. 0738-081x/92/$5.00 l
Activity
479
480
MiiHLBACHER
Clinics in Dermatology 1992:9:479-485 Table 1. Antibacterial
Gh, H
I
Test Strain Staphylococcus aureus Streptococcus pyogenes Coynebacterium xerosis Corynebacterium equi Pseudomonas aeruginosa Escherichia coli E. coli Proteus mirabilis Klebsiella pneumoniae
H
Figure
1.
Chemical structure of naftifine.
Anfi-inflammatory
Action
Dermatomycoses can be accompanied by a dermatitis in connection with the irritative, toxic nature of the disease. The inflammatory reaction of the skin has to be considered simply as a sign of the defense mechanism of the skin. Very rarely, an inflammatory reaction is caused by the antimycotic compound itself. Occasionally, dermatomycoses combined with inflammatory reactions of the skin are treated with a combination of an antifungal and a topical corticosteroid. Corticosteroids inhibit early, as well as late, inflammatory reactions, protect the integrity of the cell and plasma membranes, and stabilize the membranes of lysosomes, thus inhibiting the release of lysosomal enzymes. In the case of naftifine, it could be proved in several new investigations, both experimentally and experimentally/clinically, that there is an immediate vasoconstrictive and inflammatory effect: 1. The efficacy of natifine was compared with that of a combination of econazole and triamcinolone in paFigure
2.
Steroid biosynthesis. Testosterone
COrtlSOl wj\e”e
cholesterol
Squalene epoxlde
lanosterol
Number of Patients
Naftifine (% active substance)
85 68 1077 51
1.25 0.04 0.16 0.31
1581 1086 1084 89 217
0.63 0.63 0.31 0.63 0.16
Reprinted, with permission, from Biochemie Ges.m.b.H.6
tients with inflammatory dermatomycoses. Naftifine was shown to have an anti-inflammatory effect equal to that of the imidazole/class I corticosteroid combination (Figs 5 and 6).* Another way that the anti-inflammatory effect of naftifine was evaluated was by means of the intracutaneous histamine test. Naftifine cream, cream base, and a 10% clemastine ointment (an antihistaminic drug) were compared in the intracutaneous histamine test. The results of the test showed that naftifine had an anti-inflammatory and antihistaminic effect equal to 70% of the action of clemastine. Eventually, the anti-inflammatory efficacy of naftifine was evaluated by the erythema response to ultraviolet light: In a double-blind “left-versus-right” comparison the anti-inflammatory effect of naftifine was investigated in 20 healthy subjects on the basis of the erythema response to ultraviolet light. Topically applied naftifine demonstrated an anti-inflammatory effect that was due mainly to a genuine effect on the mediators of the early phase of inflammation (prostaglandins). This indicates that naftifine works like antiinflammatories, which inhibit the formation, release, or effect of prostaglandins (Fig 7).9 The mechanism of the anti-inflammatory action of naftifine, however, remains unclear and is currently being investigated.
HOd’i:rflY-
squalene
Activity
14.demethyllanosterol
Pharmacology, Pharmacokinetics, and Metabolism NAFT~F~NE SF 86-327 other ALLYLAMINES
KETOCONAZOLE other AZOLES
1
In several pharmacologic experiments naftifine was tested (intradermally and intravenously) for possible vascular effects in cats and dogs. In mice and rats it was tested for possible side effects in the central nervous system (CNS).‘j As a result it could be shown that naftifine was very well tolerated and that no relevant side effects were
Clinics in Dermatology
MijHLBACHER
1992;9:479-485
481
NAFTIFINE
n 30naftifine 25-
... .::: .::: ... . . lIzI
gentamicin
20-
15-
IO-
Pathogens
naftifine
5-
o4
0
Figure 3.
7
Naftifine and gentamicin
12
Nuftifine in pyoderma (n = 30). Overall evaluation overall
gentamicin
days
in pyoderma (n = 30). Decrease in positive cultures.
detectabIe, in either the vascular system or the CNS. Naftifine is applied as a topically effective antimycotic agent against dermatophytes, molds, and yeasts. Therefore, a basic precondition is the permeability of the skin, to allow the antimycotic to penetrate sufficiently. The most favorite site of infection in the skin is the uppermost layer, the stratum comeum. Naftifine takes the so-called transderma1 route of penetration into the skin. Its penetration was proved in vitro with 14C-labeled naftifine.‘O The several concentrations in the different skin layers were 1300 pg/ mL in the stratum corneum, 38 pg/mL in the other layers of the epidermis, 13.5 pg/mL in the corium, and only 0.5 pg/mL in the subcutis. Penetration of naftifine into various layers of the nail was tested in vitro as well. Naf-
Figure 4. efficacy.
before start of therapy
of
tifine was found in all layers of the nail. Maximum concentrations were detected in the superficial layers. Naftifine is well absorbed. The extended percutaneous absorption was proved by use of 3H-labeled naftifine. Naftifine was applied to a large cutaneous area, and the percutaneous absorption rate in guinea pigs and rabbits was found to be several times higher than that in human beings (Table 2).4 Retention
Time in the Skin
The retention time in the skin, after a single application of 3H-labeled naftifine cream 1% to healthy forearm skin of several patients, was remarkable. This in vivo investigation proved that even 5 to 10 days after application, the naftifine concentrations detectable in the epidermis were three to five times higher than the minimum inhibitory concentration (MIC) for Trichophyfon menfagrophytes.
evaluation % rlO0 -
90
-
80
-
70
Figure 5. Ejfect of naftifine or econazole/friamcinolone acetonide on clinical symptoms in patients with inflammatory dermatomycoses (n = 57). itching
erythema
- 60 - 50 - 40 - 30 - 20 -slightly effective
Naftifine
Gentamicin
-
10
-
0
L*“.‘a
naftlflne day O-28 econazole/trlamcinolone econazole day 14-28
acetonlde
day O-l 4
482
Clinics in Dermatology
MtiHLBACHER
1992;9:479-485
Therapeutic Action Antifungal
-
Y”“*a
naftiflne day O-28 econazole/trlamclnolone econazole day 14-28
acetonlde
Activity
Profile
Naftifine, as a representative of the allylamines, is highly active against various fungi (Table 3). The MIC of naftifine was determined for various dermatophytes, molds, and yeasts in vitro. Naftifine is primarily fungicidal against dermatophytes and molds; against yeasts, naftifine is either fungistatic or fungicidal depending on the strain, but is mainly fungistatic. Furthermore it could be shown that naftifine is pH dependent; it exhibits the highest degree of activity in the neutral pH range.
day O-l 4
Figure 6. Effect of naftifine or econazole triamcinolone acetonide on clinical symptoms in patients with inflammatory dermatomycoses (n = 57).
Antibacterial
Activity Profile
See Antibacterial Activity under Mechanism of Action. This supports the preference for a treatment schedule of a once-daily application. When naftifine was administered intravenously to cats and dogs in the form of tritiated or 14C-labeled naftifine, 70% of the dose (in rats) and 57% (in dogs) were eliminated in the bile. Naftifine is almost completely metabolized. In the process, a multitude of metabolites are formed. The metabolites are antimycotically ineffective and are excreted in the urine and the bile.
Figure
7.
Inhibition
of ultraviolet
Anti-inflammatory
Activity Profile
See Anti-inflammatory tion.
Action under Mechanism
Clinical Efficacy As the results of in vitro investigations of naftifine were very promising, a large number of clinical investigations
light eythema
by naftifine: summation curve.
Probands without etythema
n
n
Nait.
0
2
4
of Ac-
Plac.
8
16 sec. Duration of
irradiation
MiiHLBACHER
Clinics in Dermatology
483
NAFTIFINE
7992;9:479-485
Table 2. Absorvtion Human
Absorption % of dose &cm* Wkg Dose (mg) Dose/unit area @g/cm’)
Gel
Gel
Cream
Guinea Pig (cream?
Rabbit (gel)
2.5 9.32 6.8 22 367
3.4 2.8 2.0 5 81
3.3 2.7 2.1 5 83
79 148 11,820 4 187
67 139 10,060 50 207
Reprinted, with permission, from Czok.’ l Similnr uafues were found for npplication with gel and/or for infected animals.
studies to determine the clinical and mycologic efficacy and tolerance of naftifine for various indications were carried out. Naftifine is a topically active antimycotic agent with an additional antibacterial and anti-inflammatory effect and is indicated in several dermatomycoses caused by Trichophyton species, Microsporum species, and Epidermophyton floccosum and in superficial candidiasis, onychomycosis, and pityriasis versicolor. In many comparative clinical trials naftifine was examined for both its clinical and its mycologic cure rates. Naftifine was compared with placebo, with imidazole derivatives, and with imidazoles combined with corticosteroids (Table 4). Generally, the clinical cure rates in dermatomycoses treated with naftifine ranged between 70 and 92% when compared with imidazole derivatives3 Naftifine cream 1% was compared with respect to safety and efficacy with a combination of clotrimazole 1% and betamethasone dipropionate 0.05%, for treatment of tinea pedis. In this study, naftifine had a significantly higher cure rate than clotrimazole/betamethasone dipropionate in terms of mycologic cure, treatment success, and global improvement. With respect to mycologic cure rates, treatment success, and global improvement, naftifine cream 1% was finally shown to be significantly more effective than clotrimazole l%/betamethasone dipropionate 0.05% cream in this study (Tables 5 and 6).‘* and
Table 3. MIC Ranges of Naftifine Species
Tested
Trichophyton spp Epidermophyton floccosum Microsporum spp Aspergillus spp Sporothrix schenckii Candida spp Cryptococcus spp Reprinted, with permission, from Petranyi et al.”
Untoward Effects and Safety of Naftifine Dermatotoxicologic
Evaluation
A series of toxicologic studies were performed to investigate the safety of naftifine. Various preclinical evaluations were carried out to determine the acute toxicity of the active compound; the dermal tolerance of naftifine formulations (cream, gel and solution); the systemic safety of naftifine in rats, dogs, and monkeys; the reproductive toxicology; the mutagenicity; and the cell transformation capacity. When the results of all preclinical studies concerning dermal and systemic tolerance are reviewed, it is concluded that 1% formulations of naftifine may be safely used for topical application in human beings. Thus, naftifine can be considered to be very well tolerated both dermally and systemically.13
Adverse Reactions In cliff erent preclinical and clinical trials topical naftifine was investigated for possible dermatotoxicologic and other adverse effects. Naftifine is very well tolerated and shows no evidence of irritancy, phototoxicity, sensitation, or photosensitation. Moreover, it is assumed that naftifine is rarely a cause of contact dermatitis.** Side effects were mild or moderate, for example, mild erythema, rash, and moderate burning on application. The relationship of these mild side effects to the drug was not verified.‘*
Monitoring and Guidelines for Use Naftifine 018/mL) 0.1-0.2 0.1-0.2 0.1-0.2 0.8-12.5 0.8-1.5 1.5-100 12.5-25
Naftifine is used in the treatment of infections of the skin and its appendages (hair and nail) such as dermatophytoTable 4. Comparison of Naftifine with Placebo Clinical Cure (%)
Tinea auris Tinea pedis
Mycologic Cure (%)
Naftifine
Placebo
Naftifine
Placebo
78 80
23 31
83 90
45 25
484
Clinics in Dermatology
MijHLBACHER
1992;9:479-485 Table 5. Comparison of Naffifine with Clofrimazole Clinical Cure (%) Naffifine
Clofrimazole
Naffifine
61 39 73 71 74 78 70
70 69 86 82 90 72 91
Tinea pedis Tinea pedis Tinea cruris Tinea corporis Dermatophytoses Yeast infections of skin Dermatophytoses
Mycologic Cure (O/O) Clofrimazole
87 72 86 82 92 89 86
80 42 76 74 78 87 74
Reprinted, with permission, from Rbder.3
cent area of skin should be smeared with zinc paste. Then an occlusive bandage is applied for 3 to 4 days. Subsequently, the affected nail is removed with a curet as thoroughly as possible. Then, naftifine treatment can be started. The aforementioned pretreatment markedly facilitates the penetration of naftifine and optimizes therapeutic efficacy.
ses, candidiases, onychomycoses, and pityriasis versicolor. It was shown in several clinical studies that naftifine can be applied once daily. Naftifine, having a high affinity for the hornified epithelium of the skin, showed concentrations several times higher than the MICs for dermatophytes, even 5 days after a single application. There was no significant difference with respect to both mycologic and clinical cure rates between applying naftifine once daily and twice daily.15 Before naftifine is used, the affected area of skin or nail should be thoroughly cleaned with a cotton swab and warm water and dried. Subsequently, naftifine should be thinly applied once daily to the affected area and gently rubbed in (the best time is before going to bed). The entire visibly affected area of skin or nail and an approximately 1-in.-wide margin of clinically healthy skin around the lesion must be treated. In onychomycosis the affected nail should be cut as short as possible. Initially, some urea ointment (40%) should be applied to the affected area of nail. The adja-
Availability (Formulation and Status in Various Countries) Naftifine is commercially available in various countries in three different forms: cream, gel, and solution. Exoderil 1% cream in 15- and 30-g tubes; Exoderil 1% gel (15 and 30 g); Exoderil 1% dermatologic solution (10 and 20 mL). Naftin (1% naftifine cream) is available in the United States.
Table 6. Cure Rates (O/o) Follow-up
Treatment Week 4 Naffifine Mycologic cure Treatment success Global improvement Overall cure Clinical cure
68t 51t 90t 11 11
Week 6
c/bmdp*
Naffifine
50 35 77 16 17
74t 54t 89t 16 16
Week 8
c/bmdp*
Naffifine
45 35 76 16 20
73t 62t 93t 21 25
c/bmdp* 45 39 71 27 31
Mycologic cure = negative KOH and negative culture Treatment success = negative KOH, negative culture, and improvement to mild or none from baseline in clinical evidence of disease Global improvement = response to treatment which is good, excellent, or completely cleared Overall cure = negative KOH, negative culture, and no evidence of disease on clinical evaluation Clinical cure = no evidence of disease on clinical evaluation l Clotrimazole l%/betamethasone dipropionate 0.05% cream. t Significant difference compared with clotrimazole/betnmethasone
dipropionnte cream, P < 0.05.
Clinics in Dermatology
MijHLBACHER NAFTIFINE
7992;9:479-485
References introduction. J Dermatol 1. Hay RJ. Antifungal drugs-An Treat 199O;l(suppl 2):1-3. 2. Berney D, Schuh K. Heterocyclic spironaphthalenones. Part I. Synthesis and reactions of some Spiro (14-naphthalenone)-1,3_pipertidines. Helv Chim Acta 1978;61:126273. Platform 1. Data 3. Roder C. ExoderilB (Naftifine)-Product on file, Biochemie Kundl, Austria. 4. Czok R. Preclinical evaluation of ExoderilB (naftifme). II. Mechanism of action, absorption, metabolism and excretion. Mykosen 1987;3O(suppl 1):28-31. 5. Schaude M, Ackerbauer H, Mieth H. Inhibitory effect of antifungal agents on germ tube formation in Candida albicans. Mykosen 1987;30:281-7. 6. Summary ExoderilB (Cream, Gel, Solution). Biochemie Ges. m.b.H., Vienna, Austria. 7. Nolting S. Investigation of the antibacterial effect of the antifungal agent naftifine-“Left versus right” clinical comparative study between naftifine and gentamycin in pyoderma. Mykosen 1987;3O(suppl 1):124-8. dermatomycoses-Compara8. Tronnier H. Inflammatory tive study of naftifine and a combination of a corticosteroid
and an imidazole derivative. 78-87.
Mykosen
485
1987;3O(suppl 1):
9. Jung EG. The anti-inflammatory efficacy of naftifine as evaluated from the erythema response to ultraviolet light. Mykosen 1987;3O(suppl 1):88-91. 10. Stiittgen G. Biopharmaceutical aspects of topically applied antifungal treatment. Mykosen 1987;3O(suppl 1):7-14. 11. Petranyi G, et al. In vivo antimycotic activity of naftifine. Antimicrob Agents Chemother 1981;19:390-2. 12. Millikan LE, et al. Safety and efficacy of naftifine cream 1% versus clotrimazole l%/betamethasone dipropionate 0.05% (LotrisoneB) cream in the twice-daily treatment of tinea pedis. Final Report NAFT-216-7170 (data on file, Herbert Laboratories). 13. Obenaus H, Schbn H. Preclinical evaluation of ExoderilB (naftifine). III. Summary of results of toxicological studies. Mykosen 1987;3O(suppl 1):32 - 7. 14. Maibach HI. Naftifme: Dermatotoxicology cacy. Mykosen 1987;3O(suppl 1):57-62.
and clinical effi-
15. Meinicke K, Striegel C, Weidinger G. Treatment of dermatomycoses with naftifine. Therapeutic efficacy on application once daily and twice daily. Mykosen 1987;3O(suppl 1):98-103.
MATTHIAS
MUHLBACHER,
MD
istorically, there have been only a limited number of effective antimycotic drugs, such as the dyes magenta paint, brilliant green, and gentian violet.’ The earliest of the topically applicable compounds was Whitfield’s ointment consisting of benzoic and salicylic acids. During the last 20 to 30 years a remarkable number of useful antifungals have been discovered. The most important antifungals in current use belong to five groups: (1) the polyenes, (2) the azoles, (3) the group of unrelated compounds, (4) the morpholines, and (5) the allylamines. (The allylamines, of which terbinafine and naftifine are the principal drugs, constitute a comparatively new class of antifungal agents.) Naftifine was discovered in 19742 at the Sandoz Research Institute in Vienna, Austria, and was found to be highly active against a considerable number of important fungi. Thus, the first derivative of the class of allylamines turned out to be a very reliable and safe agent against fungi pathogenic to humans.
H
Chemistry Chemically, naftifine belongs, as pointed out above, to the class of allylamines (Fig 1).3 Its empiric formula is C,rH,,ClN. It is a lightly yellowish, crystalline powder. Naftifine is not related chemically to any other antimycotic compound discovered so far.
Mechanism of Action Avltimycotic Action Naftifine is a synthetic agent that inhibits squalene epoxidase and thus inhibits the biosynthesis of ergosterol, an essential component of the cell membrane of fungi (Fig From the Department of Clinical Research, Biochemie Ges.m.b.H, Kundl, Austria. Address correspondence to: Iohannes Matthias Miihlbacher, MD, Medical Department PM/PP, Biochemie Ges.m.b.H., A-6250 Kundl Austria.
0
1992 by Elsevier
Science
Publishing
Co.,
2).4 The result of this kind of inhibition is ergosterol deficiency and accumulation of squalene epoxidase. A certain quantity of sterol is necessary for fungal cell growth; a lack of sterols leads to cessation of growth of fungal cells. Therefore, ergosterol deficiency may account for the fungistatic action of naftifine. On the other hand, the accumulation of squalene caused by the inhibition of squalene epoxidase leads to several intracellular degenerative processes such as the deposition of lipid droplets. This accumulation of squalene takes place not only in the cell membrane but also in other membranes, such as the endoplasmic reticulum. Finally, the alterations in membrane properties, as well as the impairment of all intracellular processes associated with lipid membranes, may lead to damage of the cell wall. This explains the fungicida1 action of naftifine.5 Various investigations were performed to distinguish the fungistatic and fungicidal effects of naftifine in vitro. By observation of the effects of naftifine on Candida parapsilosis and Trichophyton mentagrophytes it became evident that naftifine had a fungicidal effect. For Candida albicans and most other yeasts, however, it turned out to be fungistatic. Generally, naftifine acts fungicidally against dermatophytes and molds, but fungistatically against the majority of yeasts.
Antibacterial
Naftifine possesses local bactericidal properties against both gram-positive and gram-negative bacteria. The minimum bactericidal concentrations (MBCs) determined for various bacteria range between 0.04 and 1.25% of the active substance (Table 1).
Antibacterial
Properties
in Vivo
In a clinical trial, the antibacterial efficacy of naftifine was compared with that of gentamicin for the indication of pyoderma. Naftifine showed the same effect on clinical symptoms and growth of bacteria as did gentamicin (Figs 3 and 4).’
Inc. 0738-081x/92/$5.00 l
Activity
479
480
MiiHLBACHER
Clinics in Dermatology 1992:9:479-485 Table 1. Antibacterial
Gh, H
I
Test Strain Staphylococcus aureus Streptococcus pyogenes Coynebacterium xerosis Corynebacterium equi Pseudomonas aeruginosa Escherichia coli E. coli Proteus mirabilis Klebsiella pneumoniae
H
Figure
1.
Chemical structure of naftifine.
Anfi-inflammatory
Action
Dermatomycoses can be accompanied by a dermatitis in connection with the irritative, toxic nature of the disease. The inflammatory reaction of the skin has to be considered simply as a sign of the defense mechanism of the skin. Very rarely, an inflammatory reaction is caused by the antimycotic compound itself. Occasionally, dermatomycoses combined with inflammatory reactions of the skin are treated with a combination of an antifungal and a topical corticosteroid. Corticosteroids inhibit early, as well as late, inflammatory reactions, protect the integrity of the cell and plasma membranes, and stabilize the membranes of lysosomes, thus inhibiting the release of lysosomal enzymes. In the case of naftifine, it could be proved in several new investigations, both experimentally and experimentally/clinically, that there is an immediate vasoconstrictive and inflammatory effect: 1. The efficacy of natifine was compared with that of a combination of econazole and triamcinolone in paFigure
2.
Steroid biosynthesis. Testosterone
COrtlSOl wj\e”e
cholesterol
Squalene epoxlde
lanosterol
Number of Patients
Naftifine (% active substance)
85 68 1077 51
1.25 0.04 0.16 0.31
1581 1086 1084 89 217
0.63 0.63 0.31 0.63 0.16
Reprinted, with permission, from Biochemie Ges.m.b.H.6
tients with inflammatory dermatomycoses. Naftifine was shown to have an anti-inflammatory effect equal to that of the imidazole/class I corticosteroid combination (Figs 5 and 6).* Another way that the anti-inflammatory effect of naftifine was evaluated was by means of the intracutaneous histamine test. Naftifine cream, cream base, and a 10% clemastine ointment (an antihistaminic drug) were compared in the intracutaneous histamine test. The results of the test showed that naftifine had an anti-inflammatory and antihistaminic effect equal to 70% of the action of clemastine. Eventually, the anti-inflammatory efficacy of naftifine was evaluated by the erythema response to ultraviolet light: In a double-blind “left-versus-right” comparison the anti-inflammatory effect of naftifine was investigated in 20 healthy subjects on the basis of the erythema response to ultraviolet light. Topically applied naftifine demonstrated an anti-inflammatory effect that was due mainly to a genuine effect on the mediators of the early phase of inflammation (prostaglandins). This indicates that naftifine works like antiinflammatories, which inhibit the formation, release, or effect of prostaglandins (Fig 7).9 The mechanism of the anti-inflammatory action of naftifine, however, remains unclear and is currently being investigated.
HOd’i:rflY-
squalene
Activity
14.demethyllanosterol
Pharmacology, Pharmacokinetics, and Metabolism NAFT~F~NE SF 86-327 other ALLYLAMINES
KETOCONAZOLE other AZOLES
1
In several pharmacologic experiments naftifine was tested (intradermally and intravenously) for possible vascular effects in cats and dogs. In mice and rats it was tested for possible side effects in the central nervous system (CNS).‘j As a result it could be shown that naftifine was very well tolerated and that no relevant side effects were
Clinics in Dermatology
MijHLBACHER
1992;9:479-485
481
NAFTIFINE
n 30naftifine 25-
... .::: .::: ... . . lIzI
gentamicin
20-
15-
IO-
Pathogens
naftifine
5-
o4
0
Figure 3.
7
Naftifine and gentamicin
12
Nuftifine in pyoderma (n = 30). Overall evaluation overall
gentamicin
days
in pyoderma (n = 30). Decrease in positive cultures.
detectabIe, in either the vascular system or the CNS. Naftifine is applied as a topically effective antimycotic agent against dermatophytes, molds, and yeasts. Therefore, a basic precondition is the permeability of the skin, to allow the antimycotic to penetrate sufficiently. The most favorite site of infection in the skin is the uppermost layer, the stratum comeum. Naftifine takes the so-called transderma1 route of penetration into the skin. Its penetration was proved in vitro with 14C-labeled naftifine.‘O The several concentrations in the different skin layers were 1300 pg/ mL in the stratum corneum, 38 pg/mL in the other layers of the epidermis, 13.5 pg/mL in the corium, and only 0.5 pg/mL in the subcutis. Penetration of naftifine into various layers of the nail was tested in vitro as well. Naf-
Figure 4. efficacy.
before start of therapy
of
tifine was found in all layers of the nail. Maximum concentrations were detected in the superficial layers. Naftifine is well absorbed. The extended percutaneous absorption was proved by use of 3H-labeled naftifine. Naftifine was applied to a large cutaneous area, and the percutaneous absorption rate in guinea pigs and rabbits was found to be several times higher than that in human beings (Table 2).4 Retention
Time in the Skin
The retention time in the skin, after a single application of 3H-labeled naftifine cream 1% to healthy forearm skin of several patients, was remarkable. This in vivo investigation proved that even 5 to 10 days after application, the naftifine concentrations detectable in the epidermis were three to five times higher than the minimum inhibitory concentration (MIC) for Trichophyfon menfagrophytes.
evaluation % rlO0 -
90
-
80
-
70
Figure 5. Ejfect of naftifine or econazole/friamcinolone acetonide on clinical symptoms in patients with inflammatory dermatomycoses (n = 57). itching
erythema
- 60 - 50 - 40 - 30 - 20 -slightly effective
Naftifine
Gentamicin
-
10
-
0
L*“.‘a
naftlflne day O-28 econazole/trlamcinolone econazole day 14-28
acetonlde
day O-l 4
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Therapeutic Action Antifungal
-
Y”“*a
naftiflne day O-28 econazole/trlamclnolone econazole day 14-28
acetonlde
Activity
Profile
Naftifine, as a representative of the allylamines, is highly active against various fungi (Table 3). The MIC of naftifine was determined for various dermatophytes, molds, and yeasts in vitro. Naftifine is primarily fungicidal against dermatophytes and molds; against yeasts, naftifine is either fungistatic or fungicidal depending on the strain, but is mainly fungistatic. Furthermore it could be shown that naftifine is pH dependent; it exhibits the highest degree of activity in the neutral pH range.
day O-l 4
Figure 6. Effect of naftifine or econazole triamcinolone acetonide on clinical symptoms in patients with inflammatory dermatomycoses (n = 57).
Antibacterial
Activity Profile
See Antibacterial Activity under Mechanism of Action. This supports the preference for a treatment schedule of a once-daily application. When naftifine was administered intravenously to cats and dogs in the form of tritiated or 14C-labeled naftifine, 70% of the dose (in rats) and 57% (in dogs) were eliminated in the bile. Naftifine is almost completely metabolized. In the process, a multitude of metabolites are formed. The metabolites are antimycotically ineffective and are excreted in the urine and the bile.
Figure
7.
Inhibition
of ultraviolet
Anti-inflammatory
Activity Profile
See Anti-inflammatory tion.
Action under Mechanism
Clinical Efficacy As the results of in vitro investigations of naftifine were very promising, a large number of clinical investigations
light eythema
by naftifine: summation curve.
Probands without etythema
n
n
Nait.
0
2
4
of Ac-
Plac.
8
16 sec. Duration of
irradiation
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Table 2. Absorvtion Human
Absorption % of dose &cm* Wkg Dose (mg) Dose/unit area @g/cm’)
Gel
Gel
Cream
Guinea Pig (cream?
Rabbit (gel)
2.5 9.32 6.8 22 367
3.4 2.8 2.0 5 81
3.3 2.7 2.1 5 83
79 148 11,820 4 187
67 139 10,060 50 207
Reprinted, with permission, from Czok.’ l Similnr uafues were found for npplication with gel and/or for infected animals.
studies to determine the clinical and mycologic efficacy and tolerance of naftifine for various indications were carried out. Naftifine is a topically active antimycotic agent with an additional antibacterial and anti-inflammatory effect and is indicated in several dermatomycoses caused by Trichophyton species, Microsporum species, and Epidermophyton floccosum and in superficial candidiasis, onychomycosis, and pityriasis versicolor. In many comparative clinical trials naftifine was examined for both its clinical and its mycologic cure rates. Naftifine was compared with placebo, with imidazole derivatives, and with imidazoles combined with corticosteroids (Table 4). Generally, the clinical cure rates in dermatomycoses treated with naftifine ranged between 70 and 92% when compared with imidazole derivatives3 Naftifine cream 1% was compared with respect to safety and efficacy with a combination of clotrimazole 1% and betamethasone dipropionate 0.05%, for treatment of tinea pedis. In this study, naftifine had a significantly higher cure rate than clotrimazole/betamethasone dipropionate in terms of mycologic cure, treatment success, and global improvement. With respect to mycologic cure rates, treatment success, and global improvement, naftifine cream 1% was finally shown to be significantly more effective than clotrimazole l%/betamethasone dipropionate 0.05% cream in this study (Tables 5 and 6).‘* and
Table 3. MIC Ranges of Naftifine Species
Tested
Trichophyton spp Epidermophyton floccosum Microsporum spp Aspergillus spp Sporothrix schenckii Candida spp Cryptococcus spp Reprinted, with permission, from Petranyi et al.”
Untoward Effects and Safety of Naftifine Dermatotoxicologic
Evaluation
A series of toxicologic studies were performed to investigate the safety of naftifine. Various preclinical evaluations were carried out to determine the acute toxicity of the active compound; the dermal tolerance of naftifine formulations (cream, gel and solution); the systemic safety of naftifine in rats, dogs, and monkeys; the reproductive toxicology; the mutagenicity; and the cell transformation capacity. When the results of all preclinical studies concerning dermal and systemic tolerance are reviewed, it is concluded that 1% formulations of naftifine may be safely used for topical application in human beings. Thus, naftifine can be considered to be very well tolerated both dermally and systemically.13
Adverse Reactions In cliff erent preclinical and clinical trials topical naftifine was investigated for possible dermatotoxicologic and other adverse effects. Naftifine is very well tolerated and shows no evidence of irritancy, phototoxicity, sensitation, or photosensitation. Moreover, it is assumed that naftifine is rarely a cause of contact dermatitis.** Side effects were mild or moderate, for example, mild erythema, rash, and moderate burning on application. The relationship of these mild side effects to the drug was not verified.‘*
Monitoring and Guidelines for Use Naftifine 018/mL) 0.1-0.2 0.1-0.2 0.1-0.2 0.8-12.5 0.8-1.5 1.5-100 12.5-25
Naftifine is used in the treatment of infections of the skin and its appendages (hair and nail) such as dermatophytoTable 4. Comparison of Naftifine with Placebo Clinical Cure (%)
Tinea auris Tinea pedis
Mycologic Cure (%)
Naftifine
Placebo
Naftifine
Placebo
78 80
23 31
83 90
45 25
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1992;9:479-485 Table 5. Comparison of Naffifine with Clofrimazole Clinical Cure (%) Naffifine
Clofrimazole
Naffifine
61 39 73 71 74 78 70
70 69 86 82 90 72 91
Tinea pedis Tinea pedis Tinea cruris Tinea corporis Dermatophytoses Yeast infections of skin Dermatophytoses
Mycologic Cure (O/O) Clofrimazole
87 72 86 82 92 89 86
80 42 76 74 78 87 74
Reprinted, with permission, from Rbder.3
cent area of skin should be smeared with zinc paste. Then an occlusive bandage is applied for 3 to 4 days. Subsequently, the affected nail is removed with a curet as thoroughly as possible. Then, naftifine treatment can be started. The aforementioned pretreatment markedly facilitates the penetration of naftifine and optimizes therapeutic efficacy.
ses, candidiases, onychomycoses, and pityriasis versicolor. It was shown in several clinical studies that naftifine can be applied once daily. Naftifine, having a high affinity for the hornified epithelium of the skin, showed concentrations several times higher than the MICs for dermatophytes, even 5 days after a single application. There was no significant difference with respect to both mycologic and clinical cure rates between applying naftifine once daily and twice daily.15 Before naftifine is used, the affected area of skin or nail should be thoroughly cleaned with a cotton swab and warm water and dried. Subsequently, naftifine should be thinly applied once daily to the affected area and gently rubbed in (the best time is before going to bed). The entire visibly affected area of skin or nail and an approximately 1-in.-wide margin of clinically healthy skin around the lesion must be treated. In onychomycosis the affected nail should be cut as short as possible. Initially, some urea ointment (40%) should be applied to the affected area of nail. The adja-
Availability (Formulation and Status in Various Countries) Naftifine is commercially available in various countries in three different forms: cream, gel, and solution. Exoderil 1% cream in 15- and 30-g tubes; Exoderil 1% gel (15 and 30 g); Exoderil 1% dermatologic solution (10 and 20 mL). Naftin (1% naftifine cream) is available in the United States.
Table 6. Cure Rates (O/o) Follow-up
Treatment Week 4 Naffifine Mycologic cure Treatment success Global improvement Overall cure Clinical cure
68t 51t 90t 11 11
Week 6
c/bmdp*
Naffifine
50 35 77 16 17
74t 54t 89t 16 16
Week 8
c/bmdp*
Naffifine
45 35 76 16 20
73t 62t 93t 21 25
c/bmdp* 45 39 71 27 31
Mycologic cure = negative KOH and negative culture Treatment success = negative KOH, negative culture, and improvement to mild or none from baseline in clinical evidence of disease Global improvement = response to treatment which is good, excellent, or completely cleared Overall cure = negative KOH, negative culture, and no evidence of disease on clinical evaluation Clinical cure = no evidence of disease on clinical evaluation l Clotrimazole l%/betamethasone dipropionate 0.05% cream. t Significant difference compared with clotrimazole/betnmethasone
dipropionnte cream, P < 0.05.
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References introduction. J Dermatol 1. Hay RJ. Antifungal drugs-An Treat 199O;l(suppl 2):1-3. 2. Berney D, Schuh K. Heterocyclic spironaphthalenones. Part I. Synthesis and reactions of some Spiro (14-naphthalenone)-1,3_pipertidines. Helv Chim Acta 1978;61:126273. Platform 1. Data 3. Roder C. ExoderilB (Naftifine)-Product on file, Biochemie Kundl, Austria. 4. Czok R. Preclinical evaluation of ExoderilB (naftifme). II. Mechanism of action, absorption, metabolism and excretion. Mykosen 1987;3O(suppl 1):28-31. 5. Schaude M, Ackerbauer H, Mieth H. Inhibitory effect of antifungal agents on germ tube formation in Candida albicans. Mykosen 1987;30:281-7. 6. Summary ExoderilB (Cream, Gel, Solution). Biochemie Ges. m.b.H., Vienna, Austria. 7. Nolting S. Investigation of the antibacterial effect of the antifungal agent naftifine-“Left versus right” clinical comparative study between naftifine and gentamycin in pyoderma. Mykosen 1987;3O(suppl 1):124-8. dermatomycoses-Compara8. Tronnier H. Inflammatory tive study of naftifine and a combination of a corticosteroid
and an imidazole derivative. 78-87.
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9. Jung EG. The anti-inflammatory efficacy of naftifine as evaluated from the erythema response to ultraviolet light. Mykosen 1987;3O(suppl 1):88-91. 10. Stiittgen G. Biopharmaceutical aspects of topically applied antifungal treatment. Mykosen 1987;3O(suppl 1):7-14. 11. Petranyi G, et al. In vivo antimycotic activity of naftifine. Antimicrob Agents Chemother 1981;19:390-2. 12. Millikan LE, et al. Safety and efficacy of naftifine cream 1% versus clotrimazole l%/betamethasone dipropionate 0.05% (LotrisoneB) cream in the twice-daily treatment of tinea pedis. Final Report NAFT-216-7170 (data on file, Herbert Laboratories). 13. Obenaus H, Schbn H. Preclinical evaluation of ExoderilB (naftifine). III. Summary of results of toxicological studies. Mykosen 1987;3O(suppl 1):32 - 7. 14. Maibach HI. Naftifme: Dermatotoxicology cacy. Mykosen 1987;3O(suppl 1):57-62.
and clinical effi-
15. Meinicke K, Striegel C, Weidinger G. Treatment of dermatomycoses with naftifine. Therapeutic efficacy on application once daily and twice daily. Mykosen 1987;3O(suppl 1):98-103.