Fungal squalene epoxidase (squalene epoxidation inhibition). [1]
Fungal squalene epoxidase. [3]

Butenafine hydrochloride, a benzylamine derivative, is an antifungal medication that treats fungal skin infections like athlete's foot and ringworm. Butenafine Hydrochronide is a squalene epoxidase inhibitor that prevents the production of ergosterol, which is necessary for fungal cell membranes. The medication exhibits great epidermal permeability, a lengthy retention duration after topical administration, and residual therapeutic action after treatment discontinuation. Butenafine also has anti-inflammatory properties. 1% butenafine hydrochloride cream is both safe and efficient for treating tinea cruris and tinea pedis.

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The minimum concentration that completely inhibited the growth of dermatophytes (MIC) and minimum fungicidal concentration (MFC) of butenafine against T. mentagrophytes and M. canis were almost similar (0.012 to 0.025 μg/ml), which was 4 to 130 times lower than that of naftifine, tolnaftate, clotrimazole, and bifonazole. [1]
In an in vitro study, both butenafine and terbinafine demonstrated more potent antifungal activity against Trichophyton spp. compared to neticonazole and ketoconazole. [1]
Against clinical isolates of T. rubrum, the geometric mean MIC for butenafine was 0.007 mg/L at 48 hours and 0.015 mg/L at 72 hours after inoculation. The MIC and MFC findings for butenafine against T. mentagrophytes were the same (0.012 mg/L), suggesting fungicidal action. [3]
Butenafine demonstrated activity against all tested dermatophytes (Trichophyton mentagrophytes, Trichophyton tonsurans, Trichophyton rubrum, Microsporum canis, Microsporum gypseum, Epidermophyton floccosum) with a MIC range of 0.03 - 0.25 μg/ml. [2]
Butenafine showed limited activity against Candida albicans (MIC > 32 μg/ml for most isolates, one isolate MIC = 16 μg/ml) and no activity against Malassezia furfur (MIC > 32 μg/ml for all isolates). [2]
For Gram-positive bacteria, butenafine showed activity against β-hemolytic Streptococcus Group A (MIC range 4 - 0.25 μg/ml? Note: Table 3 shows MIC values of 16, 0.25, 4, 0.25, 0.25? Let me re-check: Table 3 shows for β-Hemolytic Strep. Group A: isolate 735: 16; 736: 0.25; 737: 4; 738: 0.25; 739: 0.25. The range is 0.25-16 μg/ml) and Corynebacterium species (MIC < 0.001 μg/ml for some isolates). Butenafine did not inhibit Staphylococcus aureus (MIC > 128 μg/ml) or any Gram-negative bacteria tested (Pseudomonas aeruginosa, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae; MIC > 128 μg/ml). [2]
In vitro MIC findings against clinical isolates of T. rubrum ranged from mean 0.007 to 0.015 mg/l 48 h after initial inoculation, and reached a mean of 0.015 mg/l at 72 h after inoculation. The MIC and MFC findings for butenafine against T. mentagrophytes were the same (0.012 mg/l). [3]
Butenafine is active against C. albicans, presumably due to its direct action on the organism's membrane structure. [3]
The results of in vitro findings have shown that antifungal agents can be ranked in order of potency as butenafine > terbinafine > naftifine > azoles. [3]

In experimental dermatophytosis on guinea-pig dorsal skin induced by T. mentagrophytes or M. canis, topical butenafine exhibited excellent and superior therapeutic efficacy compared to naftifine, tolnaftate, clotrimazole, and bifonazole. [1]
In a guinea-pig model of plantar tinea pedis induced by T. mentagrophytes, 1% butenafine achieved greater mycological eradication (88.5%) compared to bifonazole (31.3%) and clotrimazole (27.1%, p < 0.001). [1]
In a guinea-pig model of interdigital tinea pedis, after 20 days of application of butenafine 1% cream, 8.3% of skin sections had positive cultures, compared to 44.2% for bifonazole and 97.5% for no treatment. Butenafine prevented relapse in 75% of samples compared to bifonazole (8.3%) or no treatment (0%). [1]
Butenafine exhibits excellent prophylactic efficacy. A 1% solution applied once 24 or 48 hours before fungal inoculation with T. mentagrophytes in guinea-pig dorsal skin completely prevented mycological infection for up to 17 days. [1]
In a guinea-pig model of interdigital tinea pedis, treatment with 1% butenafine cream for 20 days resulted in 8.3% positive cultures, versus 44.2% for bifonazole and 97.5% for no treatment. Post-treatment evaluation 30 days after drug cessation showed that butenafine was superior in preventing relapse (75% negative cultures). [3]
Butenafine has been shown to possess inherent anti-inflammatory properties in vivo, as demonstrated by reduced cutaneous erythema response after UVB irradiation in a randomized single-blinded control investigation in humans. [1]

Butenafine exerts its antifungal action by inhibiting the conversion of squalene to 2,3-oxydosqualene, a reaction catalyzed by the enzyme squalene epoxidase, thereby suppressing the biosynthesis of ergosterol. This was demonstrated in studies using cell-free extracts of fungi. [1]
The antifungal mechanism of butenafine was studied by measuring its inhibition of squalene epoxidation in Sporothrix schenckii cells. The drug inhibited the conversion of squalene to squalene epoxide, leading to accumulation of squalene and decreased ergosterol synthesis. [3]

For determination of antifungal susceptibility, a microdilution method adapted from NCCLS was used. Dermatophytes and C. albicans were grown on potato dextrose agar at 35°C for 24-48 hours. Five colonies ≥1 mm were selected and placed in sterile saline. The suspension was vortexed and counted using a hemacytometer. The final working concentration was adjusted to 2-5 × 10^3 conidia per ml in RPMI-1640 medium. For M. furfur, cells were grown at 35°C for 10 days on Sabouraud dextrose broth containing Tween 80, and the inoculum was adjusted to 2-5 × 10^3 cells per ml. Butenafine was dissolved in ethanol, and serial two-fold dilutions were prepared (concentration range 0.06 - 32 μg/ml). 100 μl of 2X antifungal concentrations were dispensed into microtiter plate wells, followed by 100 μl of fungal suspension. Plates were incubated at 35°C for 4-5 days for dermatophytes, 24-48 h for C. albicans, and 5 days for M. furfur. The MIC end point was defined as the minimum concentration causing 80% inhibition compared to the growth control. [2]

In the guinea-pig dorsal skin trichophytosis model, butenafine (as a 1% solution) was applied topically at a volume of 0.2 ml. The animals were inoculated with T. mentagrophytes arthroconidia, and treatment was applied once daily for several days. The fungicidal and fungistatic activities were compared to clotrimazole. [1]
In a guinea-pig model of plantar tinea pedis induced by T. mentagrophytes, butenafine 1% cream was applied once daily. The dosage was not explicitly stated, but the cream was applied topically to the infected area. Treatment efficacy was compared to bifonazole and clotrimazole. [1]
For the interdigital tinea pedis model in guinea-pigs, butenafine 1% cream was applied topically once daily for 20 days. After treatment cessation, animals were followed for an additional 30 days to assess relapse rates. [1]
For the prophylactic efficacy study, a 1% solution of butenafine was applied once to the dorsal skin of guinea-pigs at either 24 or 48 hours before fungal inoculation with T. mentagrophytes. The volume applied was 0.2 ml. [1]
In a guinea-pig model, 0.2 ml of a 1% solution of butenafine was applied topically to the dorsal skin. Skin permeation was assessed at various time points (24, 48, 72 hours, up to 7 days) by measuring radioactivity of 14C-labelled drug in different skin layers (epidermis, dermis, sebaceous glands, hair follicles). [3]

After topical application of 0.2 ml of 1% 14C-labelled butenafine solution on guinea-pig skin, the highest radioactivity per gram of skin was observed in the epidermis including the horny layer (depth 0 to 50 μm). Low concentrations were located at the level of sebaceous glands (100 to 300 μm) and hair follicles (1300-1600 μm), suggesting penetration to deeper dermis through these structures. [1]
The concentration of butenafine achieved in guinea-pig skin at 24 h after a single application was 31.5 μg/g of tissue, and it gradually decreased to 8.8 μg/g of tissue at 72 h. These concentrations were several hundred times higher than the MFCs against T. mentagrophytes and M. canis (0.012 and 0.05 mg/l). [1]
Butenafine has poor systemic distribution after topical application. [1]
In patients with tinea cruris who applied butenafine 1% cream once daily for 14 days, the mean plasma concentration of the drug was 0.91 μg/L. Five weeks after treatment termination, mean butenafine plasma concentrations were between 0.15 and 0.28 μg/L in 5 of 17 patients. [3]

Butenafine is generally well tolerated and shows no carcinogenicity, mutagenicity, or impaired fertility when used topically as directed. The most common complaint is local, transient mild burning and/or stinging at the time of application, observed in 0.5 to 2.2% of patients. No withdrawal was reported due to this adverse event. [1]
In a skin patch test on 36 healthy volunteers, butenafine 0.5% cream and 0.1% solutions did not result in any positive skin patch test (0% irritation potential). In comparison, positive patch tests were observed in 8.3% for econazole solution, 5.6% for econazole cream, and 2.8% for tolciclate cream. [1]
Butenafine appears to be generally safe and well tolerated with few non-objective drug interactions. No patients withdrew from clinical trials because of drug-related adverse symptoms. Compared to terbinafine (which showed mild pruritus, erythema, scaling, pustules), butenafine has shown only a mild localized burning sensation as a drug-related adverse event. [3]

[1]. Singal A. Butenafine and superficial mycoses: current status. Expert Opin Drug Metab Toxicol. 2008 Jul;4(7):999-1005.

[2]. Kokjohn K, Bradley M, Griffiths B, Ghannoum M. Evaluation of in vitro activity of ciclopirox olamine, butenafine HCl and econazole nitrate against dermatophytes, yeasts and bacteria. Int J Dermatol. 2003 Sep;42 Suppl 1:11-7.

[3]. Syed TA, Maibach HI. Butenafine hydrochloride: for the treatment of interdigital tinea pedis. Expert Opin Pharmacother. 2000 Mar;1(3):467-73.

[4]. McNeely W, Spencer CM. Butenafine. Drugs. 1998 Mar;55(3):405-12; discussion 413.

[5]. Butenafine.

Butenafine hydrochloride is the hydrochloride salt of butenafine. It is a squalene epoxidase inhibitor, and squalene epoxidase is responsible for synthesizing sterols required for fungal cell membranes; therefore, butenafine hydrochloride is used to treat fungal skin infections. It is an EC 1.14.13.132 (squalene monooxygenase) inhibitor and antifungal drug. It is a hydrochloride and ammonium salt. It contains butenafine. Butenafine hydrochloride is the hydrochloride form of butenafine, a synthetic benzylamine derivative with antifungal properties. Butenafine hydrochloride interferes with the biosynthesis of ergosterol, an important component of fungal cell membranes, by inhibiting the epoxidation of squalene. This alters the permeability of the fungal cell membrane, thereby inhibiting fungal growth. Butenafine hydrochloride is effective against a variety of dermatophytes, including Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, and Sporothrix schenckii, as well as yeasts, including Candida albicans and Candida parapsilosis. See also: butenafine (which has an active ingredient).

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Butenafine hydrochloride 1% cream was first approved in Japan in 1992 for the treatment of tinea pedis, tinea cruris, tinea corporis, tinea versicolor, and cutaneous candidal infections. It was approved for use in the US in 1997. [1]
In randomized double-blind trials, butenafine has been shown to be significantly superior to placebo/vehicle in the treatment of tinea pedis, tinea corporis, and tinea cruris. High cure rates have been achieved with once-a-day application for 2-4 weeks. Cure rates continue to improve after application has stopped due to its reservoir effect. [1]
Butenafine has been found effective for toe-nail onychomycosis when used in a cream formulation with 2% butenafine and 20% urea (cured 88% of patients vs 0% placebo) or with 2% butenafine and 5% tea tree oil (cured 80% vs 0% placebo). [1]
The recommended dosage for butenafine cream 1%: for tinea pedis, twice daily for 7 days or once daily for 4 weeks; for tinea cruris and tinea corporis, once daily for 2 weeks. [1]
Butenafine is a fungal squalene epoxidase inhibitor that has been launched in some countries including Japan and the US for use in tinea infections. [3]
In a cost analysis, the total approximate cost for treating tinea pedis with butenafine (once daily) was $94, compared to $152 for azoles (twice daily) and $152 for terbinafine (twice daily), indicating better cost effectiveness for butenafine. [3]

C23H28CLN

353.9281

353.191

101827-46-7

Butenafine;101828-21-1;Butenafine-13C,d3 hydrochloride

443867

White to off-white solid powder

1.0±0.1 g/cm3

426.1±14.0 °C at 760 mmHg

210-214°C

187.7±17.0 °C

0.0±1.0 mmHg at 25°C

1.598

6.77

1

1

5

25

374

0

LJBSAUIFGPSHCN-UHFFFAOYSA-N

InChI=1S/C23H27N.ClH/c1-23(2,3)21-14-12-18(13-15-21)16-24(4)17-20-10-7-9-19-8-5-6-11-22(19)20;/h5-15H,16-17H2,1-4H3;1H

1-(4-tert-butylphenyl)-N-methyl-N-(naphthalen-1-ylmethyl)methanamine;hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~70.64 mM)
H2O : ~1 mg/mL (~2.83 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)