terbinafine, Lamisil
[In vivo Terbinafine inefficacy on cutaneous leishmaniasis caused by Leishmania (Leishmania) amazonensis in C57BL/6 mice]

[Article in Portuguese]

Sampaio RN, Takano GH, Malacarne AC, Pereira TR, de Magalhaes AV.

Laboratorio de Dermatomicologia, Faculdade de Medicina, Universidade de Brasilia, Brasilia, DF, Brasil. mrsampaio hotmail.com

The efficiency of terbinafine was tested in C57BL/6 mice inoculated with the Leishmania (Leishmania) amazonensis strain MHOM/BR/PH8. The mice were administered: terbinafine at a dose of 100mg/kg/d by via oral; 0.9% saline solution orally as the control; and subcutaneous sodium stibogluconate 400mg SbV/kg/d as gold standard, for 20 days. Terbinafine was demonstrated to be ineffective when compared to the controls, using clinical and parasitological parameters and the limiting dilution assay.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12937735&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Terbinafine resistance in a pleiotropic yeast mutant is caused by a single point mutation in the ERG1 gene.

Klobucnikova V, Kohut P, Leber R, Fuchsbichler S, Schweighofer N, Turnowsky F, Hapala I.

Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences, Ivanka pri Dunaji, Slovak Republic.

A terbinafine-resistant mutant of the yeast Saccharomyces cerevisiae with a complex pleiotropic phenotype (resistance to terbinafine and itraconazole, sensitivity to several antifungal compounds, respiration deficiency, and temperature sensitivity) has been isolated after chemical mutagenesis. Detailed analysis revealed that some of its traits (thermosensitive growth, sensitivity to the polyene antimycotic nystatin and to calcofluor white) are linked to alterations in the cell wall. A single C1288G base change in the ERG1 gene resulting in the substitution of proline by alanine at position 430 in the enzyme squalene epoxidase (Erg1p) was identified as the sole cause of terbinafine resistance. This novel mutation in the ERG1 gene confers only partial resistance of Erg1p to terbinafine, however, even the low level of resistance enables terbinafine-treated mutant cells to maintain adequate ergosterol levels over longer cultivation periods. Lack of interference of squalene accumulation with growth of terbinafine-treated mutant cells indicates that the antimycotic effect of terbinafine in S. cerevisiae may be linked primarily to ergosterol depletion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12963042&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
In vitro analysis of the ability of Trichophyton rubrum to become resistant to terbinafine.

Osborne CS, Hofbauer B, Favre B, Ryder NS.

Novartis Research Institute, 1235 Vienna, Austria. colin.osborne pharma.novartis.com

In this study, we have investigated in vitro the resistance frequency and development of resistance to terbinafine of Trichophyton rubrum. Results demonstrated that naturally occurring mutants are rare and that T. rubrum appears to have little capacity to develop resistance to terbinafine even after prolonged exposure.

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terbinafine, Lamisil
Use of terbinafine for tinea in Australian Aboriginal communities in the Top End.

Koh KJ, Parker CJ, Ellis DH, Pruim B, Leysley L, Currie BJ.

Royal Darwin Hospital and Northern Territory Clinical School, Darwin, South Australia, Australia.

Tinea of the skin and nails is a common problem in remote Aboriginal communities of the Top End of Australia. A retrospective study was performed on data collected from 104 patients from several indigenous communities. Worksheets were filled in by district medical officers and rural general practitioners, detailing the extent of the tinea. Patients were prescribed between 4 and 12 weeks of 250 mg daily oral terbinafine. Fifty-two patients were followed up, with 45 having a good response to treatment (87%) and with 22 of these patients having full clearance of tinea (42%). A prospective study with 44 subjects was performed. The extent of the tinea was documented and fungal scrapings/clippings were taken. Forty subjects were recruited and given oral terbinafine (2-12 weeks depending on skin/nail involvement) or topical terbinafine if oral treatment was contraindicated. Twenty-five of the 40 (63%) subjects were reviewed. Twenty-three (92%) subjects that were followed up improved clinically, with 8/25 (32%) clearing completely. Twenty (80%) of followed-up patients complied fully with treatment. Terbinafine was found to be a well-tolerated and effective treatment of tinea of the skin and nails.

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terbinafine, Lamisil
Molecular mechanism of terbinafine resistance in Saccharomyces cerevisiae.

Leber R, Fuchsbichler S, Klobucnikova V, Schweighofer N, Pitters E, Wohlfarter K, Lederer M, Landl K, Ruckenstuhl C, Hapala I, Turnowsky F.

Institute of Molecular Biology, Biochemistry and Microbiology, Karl-Franzens-Universitat Graz, Graz, Austria.

Ten mutants of the yeast Saccharomyces cerevisiae resistant to the antimycotic terbinafine were isolated after chemical or UV mutagenesis. Molecular analysis of these mutants revealed single base pair exchanges in the ERG1 gene coding for squalene epoxidase, the target of terbinafine. The mutants did not show cross-resistance to any of the substrates of various pleiotropic drug resistance efflux pumps tested. The ERG1 mRNA levels in the mutants did not differ from those in the wild-type parent strains. Terbinafine resistance was transmitted with the mutated alleles in gene replacement experiments, proving that single amino acid substitutions in the Erg1 protein were sufficient to confer the resistance phenotype. The amino acid changes caused by the point mutations were clustered in two regions of the Erg1 protein. Seven mutants carried the amino acid substitutions F402L (one mutant), F420L (one mutant), and P430S (five mutants) in the C-terminal part of the protein; and three mutants carried an L251F exchange in the central part of the protein. Interestingly, all exchanges identified involved amino acids which are conserved in the squalene epoxidases of yeasts and mammals. Two mutations that were generated by PCR mutagenesis of the ERG1 gene and that conferred terbinafine resistance mapped in the same regions of the Erg1 protein, with one resulting in an L251F exchange and the other resulting in an F433S exchange. The results strongly indicate that these regions are responsible for the interaction of yeast squalene epoxidase with terbinafine.

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terbinafine, Lamisil
Action mechanisms of modern antifungal agents and resulting problems in the management of onychomycosis.

Seebacher C.

Dermatological Clinic of Dresden Friedrichstadt Municipal Hospital, Dresden, Germany. Claus.Seebacher gmx.de

Successful treatment of onychomycosis in the infection site depends not only on achieving the minimal inhibitory concentration (MIC) of the antifungal agent, usually determined on fresh, proliferating fungal strains, but also on the effectivity against fungal spores dormant in nail keratin. Ciclopiroxolamine and terbinafine were investigated for their fungicidal properties against proliferating and dormant dermatophyte strains. While ciclopiroxolamine was 100% effective against Trichophyton mentagrophytes (50 microg ml(-1)) and Microsporum canis (5 microg ml(-1)) both in the proliferative and dormant phase after 5 days of incubation, the same result was achieved under identical test conditions with 0.002 microg ml(-1) terbinafine using T. mentagrophytes as test organism in the proliferative and 2.0 microg ml-1 in the dormant phase. The terbinafine concentrations of 0.52 microg g(-1) measured in the nail are well below 2.0. This explains the high treatment failure and relapse rates observed under monotherapy of toenail onychomycosis even with modern antifungals. Consequently, combined therapy is recommended, beginning with atraumatic removal of the affected toenails and continuing with an antifungal nail lacquer combined with a systemic antifungal.

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terbinafine, Lamisil
An independent comparison of terbinafine and itraconazole in the treatment of toenail onychomycosis.

Cohen AD, Medvesovsky E, Shalev R, Biton A, Chetov T, Naimer S, Shai A, Vardy DA.

Dermatology Centre, Clalit Health Services (Southern District), Beer-Sheva, Israel. arnonco clalit.org.il

BACKGROUND: Previously, sponsored publications have shown that either terbinafine or itraconazole (pulse regimen) are effective for patients with toenail onychomycosis. However, independent comparative studies are lacking. OBJECTIVES: To objectively compare treatment with terbinafine and itraconazole in patients with toenail onychomycosis. METHODS: The effectiveness of terbinafine (250 mg/day 3 months) versus itraconazole pulse regimen (400 mg/day for the first week of each month, for three cycles) was retrospectively evaluated in patients with toenail onychomycosis using mycological tests and subjective outcome measures. Statistical analyses were performed using one-way analyses of variance (ANOVA) for continuous variables and Fisher exact tests for categorical variables. RESULTS: Included in the study were 117 patients (74 patients treated by terbinafine and 43 patients treated with itraconazole). Patients were examined at an average period of 20 months after the end of therapy. Mycological cure was observed in 70.6% and 62.8% of the patients who were treated by terbinafine or itraconazole, respectively (not statistically significant). Mean visual analogue scale assessment of treatment outcome was 79.9 mm (SD 24.7 mm) and 65.2 mm (SD 34.6 mm) for patients treated by terbinafine or itraconazole, respectively (p=0.008). When the results were stratified according to age and gender, it was observed that the advantage of terbinafine versus itraconazole retained statistical significance only for patients who were 55 years old and above, or females. CONCLUSIONS: Mycological cure proportions were not statistically significant between patients treated by terbinafine or itraconazole for toenail onychomycosis. However, better subjective outcome measures indicated an advantage for terbinafine over itraconazole, noticeable in females and patients 55 years old and above.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14660272&dopt=Abstract terbinafine Lamisil