terbinafine, Lamisil
The efficacy of orally applied terbinafine, itraconazole and fluconazole in models of experimental trichophytoses.

Mieth H, Leitner I, Meingassner JG.

Dermatology Department, Sandoz Research Institute, Vienna, Austria.

The antimycotic efficacy of terbinafine, itraconazole and fluconazole was evaluated in guinea-pig trichophytoses (Trichophyton mentagrophytes, Trichophyton rubrum) by use of the hair root invasion test (HIT) and the auricular skin temperature test (STT). In the prophylactic HIT model using T. mentagrophytes as the infective agent, statistical evaluation of the ratios of protected/inoculated animals revealed ED50 values of 2.8 mg kg-1 for terbinafine, 10.7 mg kg-1 for itraconazole and 11.6 mg kg-1 for fluconazole. When T. rubrum was used in the same model the ED50 value of terbinafine was 7.3 mg kg-1 whereas only two of eight animals became protected by itraconazole and fluconazole at the highest dose of 16 mg kg-1. In the therapeutic HIT model carried out with T. mentagrophytes, the curative doses were increased for all test compounds, revealing an ED50 of 12.3 mg kg-1 for terbinafine and > 40 mg kg-1 for itraconazole and fluconazole. In the STT model, decline of temperature was quicker and more pronounced during therapy with terbinafine than during treatment with the triazole derivatives. Skin temperature was back to normal on day 8 (after seven treatments) with 20 mg kg-1 terbinafine, whereas a decline to, or almost to, physiological skin temperature was not observed until day 24 (5 days after the last treatment) in animals treated with 40 mg kg-1 itraconazole or fluconazole.

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terbinafine, Lamisil
[Oral treatment of onychomycosis of the toe nails; comparison of cost-effectiveness of griseofulvin, itraconazole, ketoconazole and terbinafine]

[Article in Dutch]

Bergman W, Rutten FF.

Academisch Ziekenhuis, afd. Dermatologie, Leiden.

OBJECTIVE. Determination of the most cost-effective oral drug treatment of onychomycosis of the toenails in the Dutch situation, by comparing griseofulvin, itraconazole, ketoconazole and terbinafine. DESIGN. Calculation of cost prices using a published meta-analysis. SETTING. The Netherlands. METHOD. Published efficacy and adverse reactions of treatment with griseofulvin, itraconazole, ketoconazole or terbinafine were related to 1993 Dutch cost prices of treatment. RESULTS. Itraconazole and terbinafine offered similar chances of success, but itroconazole treatment had to be repeated more often. On average, the costs of the treatment with itraconazole were 1.5 times as high as those of treatment with terbinafine. Griseofulvin treatment was cheapest but required the longest treatment course. CONCLUSION. A treatment with terbinafine is the most cost-effective, provided that onychomycosis has actually been established mycologically and all possible measures have been taken to prevent recurrence. It remains to be seen whether this drug treatment should be offered to all people affected by this essentially cosmetic problem.

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terbinafine, Lamisil
Disk diffusion susceptibility testing of dermatophytes with allylamines.

Venugopal PV, Venugopal TV.

Institute of Microbiology, Madurai, Medical College, India.

BACKGROUND. Allylamines are a newly developed group of drugs possessing a broad spectrum of activity against a wide range of fungi. With the advent of new antifungal drugs, susceptibility testing of fungi is receiving increased attention as important laboratory procedures for aiding in the selection of appropriate drug therapy. METHODS. In vitro susceptibility testing of 43 clinical isolates of dermatophytes which included Microsporum sp., (18) Trichophyton sp., (23) and Epidermophyton floccosum (2) were carried out against the two allylamine derivatives, naftifine and terbinafine, by agar dilution and disk diffusion methods. RESULTS. Terbinafine was found to be more active minimal inhibitory concentration (MIC range < or = 0.0001-0.1 micrograms/mL), inhibiting 50% (MIC 50) and 90% (MIC 90) of the isolates at 0.01 and 0.1 micrograms/mL, respectively. The MIC 50s and MIC 90s of naftifine were 0.1 micrograms/mL (MIC range 0.001-0.5 micrograms/mL). Both the drugs showed good correlation between the MIC and sizes of zones of inhibition around the disks. Regression analysis was used to measure the degree of correlation between the MIC values and matched averaged zones of inhibition; the correlation coefficients for both terbinafine and naftifine were -0.6841 (P < 0.001) and -0.5455 (P < 0.001), respectively. CONCLUSIONS. The allylamines, naftifine and terbinafine, could be used successfully for susceptibility testing of dermatophytes by the disk diffusion method. With proper standardization of the test conditions, in vitro susceptibility testing of filamentous fungi by disk diffusion would become a useful laboratory procedure in the near future for determining the best drug therapy.

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terbinafine, Lamisil
Levels of terbinafine in plasma, stratum corneum, dermis-epidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once daily for 7 and 14 days.

Faergemann J, Zehender H, Millerioux L.

Department of Dermatology, University of Gothenburg, Sahlgren's Hospital, Sweden.

In earlier skin pharmacokinetic studies we have shown that terbinafine is rapidly delivered to the stratum corneum, nails and hair both through sebum and by direct diffusion through dermis-epidermis. In the present study the skin pharmacokinetic profile of terbinafine was studied in two groups of eight human male volunteers during and after 250 mg orally once daily for 7 and 14 days. In the 7-day study high terbinafine levels were found in sebum (19.0 micrograms/g) and stratum corneum (2.5 micrograms/g), and a concentration in stratum corneum above the minimal inhibitory concentration for most dermatophytes was still found 48 days after the last day of medication. Terbinafine was found in peripheral nail clippings after 7 days of medication and the concentration was, in the 7-day study, 0.5 microgram/g 1 day after stopping medication; it was still 0.2 microgram/g 90 days after stopping treatment. The results in the 14-day study were in parallel with, but higher than, in the 7-day study. The elimination of terbinafine from several compartments is biphasic, with a faster initial elimination followed by a slower secondary elimination. For nails, the elimination is slower compared with the other compartments. The results indicate that terbinafine may be effective in short-term treatment of several dermatophytoses. The concentration of 0.2 microgram/g of terbinafine found in nails 90 days after stopping medication, following 7 days of treatment, indicates that the duration of therapy, even in tinea ungium, may be shorter than is currently the case.

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terbinafine, Lamisil
[Efficacy and tolerance of terbinafine (Lamisil) in a series of 50 cases of dermatophyte onychomycoses]

[Article in French]

Cribier B, Grosshans E.

Clinique Dermatologique des Hopitaux Universitaires, Strasbourg.

Terbinafine is an antifungal agent of the allylamine class, which is fungicidal when administered per os. Because of its pharmacokinetic properties, terbinafine proved successful in onychomycoses. The purpose of this study was the evaluation of terbinafine efficacy and tolerance in dermatophyte onychomycoses, in a monocenter open study. Fifty patients have been treated with 250 mg terbinafine daily. Feet were involved in 43 cases, hands and feet in 6 cas, and hand alone in 1 case. Trichophyton rubrum has been isolated in 46 malades, and Trichophyton mentagrophytes in 4 patients. The severity of onychomycoses has been evaluated as follows: involvement of the first toenail (44 cases), total involvement of the nail plate (38 cases), ineffective or non tolerated previous antifungal treatments (37 cases), chronic evolution (mean duration 6.5 years), multiple nails involved (average 6). The mean duration of treatment was 22.2 weeks (range 4 to 8 months). Mycological cure rate was 92 p. 100, and complete cure rate was 86 p. 100. The mean time to mycological cure was 22.4 weeks and the mean time to complete cure was 31.5 weeks. Tolerance was good: minor side effects were noted in 3 patients, and 1 developed reversible agueusia; a moderate elevation of ALAT and ASAT occurred in 1 case. Other drugs were simultaneously administered in 15 patients: no side effects due to drug interactions have been observed. Terbinafine proved highly successful and well tolerated even in those onychomycoses which were difficult to treat. High cure rates were obtained with an average of 5 month-treatment.

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terbinafine, Lamisil
Current Management of Onychomycosis and Dermatomycoses.

Del Rosso JQ.

Department of Dermatology, University of Nevada School of Medicine, Las Vegas Skin and Cancer Clinic, 4488 South Pecos Road, Las Vegas, NV 89121, USA.

Three newer oral antifungal agents, itraconazole, terbinafine and fluconazole, have revolutionized treatment of superficial mycoses. The tissue pharmacokinetics of itraconazole and terbinafine allow much shorter courses of therapy- with higher efficacy-in the treatment of onychomycosis, compared to other oral agents. Itraconazole pulse dosing and terbinafine daily dosing have shown comparable efficacy against dermatophyte onychomycosis; similar itraconazole regimens have been effective against nondermatophyte infections. Refractory clinical patterns of nail disease appear to be more responsive to oral antifungal therapy when combined with adjunctive therapy, such as debridement. These agents are effective against cutaneous dermatophytosis, with shorter treatment regimens. Tinea versicolor may be treated with a single-dose, intermittent, or daily regimen of an oral azole agent, depending on the drug selected. These newer oral antifungal agents have been proven effective against tinea capitis; effective regimens are shorter than those for griseofulvin. The safety profile of these newer agents has been very favorable.

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terbinafine, Lamisil
Experimental chemotherapy with combinations of ergosterol biosynthesis inhibitors in murine models of Chagas' disease.

Maldonado RA, Molina J, Payares G, Urbina JA.

Departamento de Parasitologia, Facultad de Ciencias, Universidad Central de Venezuela, Caracas.

We report the effects of ketoconazole and the bistriazole ICI 195,739 acting alone or in combination with the allylamine terbinafine (Lamisil) on murine models of Chagas' disease. Mice infected with 10(5) Trypanosoma (Schizotrypanum) cruzi blood trypomastigotes and treated orally with 30 mg of ketoconazole per kg of body weight per day for 7 days, starting at 24 h postinoculation, had 100% survival after 35 days, while controls (untreated) or animals that received 15 mg of ketoconazole or 100 mg of terbinafine per kg/day by the same route had 0% survival after the same period of time. However, all mice receiving the combination of 15 mg of ketoconazole plus 100 mg of terbinafine per kg/day survived for 35 days after infection; it was shown that the survival of the animals treated with this combination was statistically greater than that obtained with either drug acting alone and was indistinguishable from that observed with the high doses of ketoconazole, indicating a synergistic action of the drugs in vivo. However, most animals that survived after the 7-day treatments were not cured, as indicated by a delayed but persistent parasitemia. When the treatment was extended to 14 days, 100% survival was obtained 10 weeks after inoculation for mice treated with 30 mg of ketoconazole per kg/day and the combination of 15 mg of ketoconazole per kg/day plus 100 mg of terbinafine per kg/day, while two-thirds of the mice treated with 15 mg of ketoconazole per kg/day alone were alive after the 14-day treatment; controls or animals that received 100 mg of terbinafine per kg/day did not survive after 25 days. Parasitemia in all surviving mice was negative after 55 days but parasitological cure, as assessed by subinoculation of organs in naive animals, was predominant only in animals that received the combined drug treatment. We also investigated the bistriazole ICI 195,739 and found, as reported previously, that just 1 mg of the compound per kg/day administered orally for 5 days was enough to protect most mice from death 30 days after inoculation, but no parasitological cures were observed. However, in the protocol used in the present study, the protective activity of ICI 195,739 at suboptimal doses (0.5 mg/kg/day) could be enhanced when it was used in combination with terbinafine at doses of the allylamine that by themselves induced no significant protection. Survival of the mice was inversely correlated with the levels of parasitemia in all cases. Extension of the treatment period with the triazole to 15 days at 1 mg/kg/day afforded definitive protection against death, with parasitological cure being achieved in 50% of mice at 10 weeks postinoculation, but no enhancement of its activity at suboptimal doses was observed when it was used in combination with terbinafine during this extended observation period. Taken together, these results supports the proposition that ketoconazole used in combination with terbinafine could be useful in the treatment of humans with Chagas' disease because it can promote parasitological cure without the need to resort to the use of high levels of the azole, which is known to interfere with hepatic function and steroid synthesis in the host. They also support the conclusions of previous in vitro studies which suggested that the triazole ICI 195,739 blocks the proliferation of T. cruzi by a mechanism which differs from those of classical ergosterol biosynthesis inhibitors.

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