terbinafine, Lamisil
Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei.

Onyewu C, Blankenship JR, Del Poeta M, Heitman J.

Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Azoles target the ergosterol biosynthetic enzyme lanosterol 14alpha-demethylase and are a widely applied class of antifungal agents because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Unfortunately, azoles are generally fungistatic and resistance to fluconazole is emerging in several fungal pathogens. We recently established that the protein phosphatase calcineurin allows survival of Candida albicans during the membrane stress exerted by azoles. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) are dramatically synergistic with azoles, resulting in potent fungicidal activity, and mutant strains lacking calcineurin are markedly hypersensitive to azoles. Here we establish that drugs targeting other enzymes in the ergosterol biosynthetic pathway (terbinafine and fenpropimorph) also exhibit dramatic synergistic antifungal activity against wild-type C. albicans when used in conjunction with CsA and FK506. Similarly, C. albicans mutant strains lacking calcineurin B are markedly hypersensitive to terbinafine and fenpropimorph. The FK506 binding protein FKBP12 is required for FK506 synergism with ergosterol biosynthesis inhibitors, and a calcineurin mutation that confers FK506 resistance abolishes drug synergism. Additionally, we provide evidence of drug synergy between the nonimmunosuppressive FK506 analog L-685,818 and fenpropimorph or terbinafine against wild-type C. albicans. These drug combinations also exert synergistic effects against two other Candida species, C. glabrata and C. krusei, which are known for intrinsic or rapidly acquired resistance to azoles. These studies demonstrate that the activity of non-azole antifungal agents that target ergosterol biosynthesis can be enhanced by inhibition of the calcineurin signaling pathway, extending their spectrum of action and providing an alternative approach by which to overcome antifungal drug resistance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12604527&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Inappropriate use of oral terbinafine in family practice.

Wilcock M, Hartley J, Gould D.

Cornwall & Isles of Scilly Health Authority, John Keay House, St Austell, Cornwall, PL25 4NQ, UK. Mike.Wilcock ClosHA.Cornwall.nhs.uk

OBJECTIVE: To review whether oral terbinafine, used for fungal nail infections, is prescribed appropriately by general practitioners. METHOD: Cross-sectional survey of forty volunteer practices. Prescribing systems were searched to identify patients who had been prescribed a course of oral terbinafine during 1998. The clinical records of five such patients in each practice were examined for additional information regarding appropriate diagnostic tests. RESULTS: Five hundred sixty-nine patients (0.25% of the population aged 12 and over) were reported to have received a course of oral terbinafine. Sixty-four percent had been treated empirically without any recorded diagnostic test. CONCLUSION: Treatment of onychomycosis with terbinafine is commonly undertaken without diagnostic confirmation. This empirical treatment does not comply with locally recommended good practice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12661473&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Effect of itraconazole and terbinafine on Leishmania promastigotes.

Zakai HA, Zimmo SKh, Fouad MA.

Medical Technology Program, Faculty of Medicine and Allied Sciences, King Abdulaziz University, P.O. Box 80205, Jeddah 21589, Saudi Arabia. haythamzakai yahoo.com

The antiproliferative effect induced in vitro by two antifungal compounds, the azole itraconazole and the allylamine terbinafine on Leishmania major, L. donovani and L. mexicana promastigotes are reported. Treatment of promastigotes cultures with itraconazole or with terbinafine induced growth arrest with L. major but neither with L. donovani nor with L. mexicana. Concentrations of 0.75 microl/l or more of itraconazole induced cell lysis after 72 hours with L. major. However, even relatively large concentrations of terbinafine (2.0 microl/l) did not induce cell lysis. For L. major, the IC 50 for itraconazole and terbinafine were 0.31 microl/l and 3.3 microl/l respectively.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12739804&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
[A short-term treatment of tinea corporis and tinea cruris with oral terbinafine]

[Article in Japanese]

Shiraki Y, Hiruma M, Inoue A, Matsushita A, Ogawa H.

Department of Dermatology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan.

We studied the effectiveness of short-term treatment of tinea corporis and tinea cruris with oral terbinafine at 250 mg/day for 2-3 days. The treatment on an open study basis consisted of two groups: the first group (n=17) was given 250 mg/day for two consecutive days, and the second group (n=24) was given the same dose for three consecutive days. No patient was treated topically. Effectiveness was evaluated at the end of the second week both clinically and mycologically (KOH examination and culture). In the two-day group, five cases showed an excellent response, three had a good response and nine had a fairly good response. Patients with good response or better comprised 47.1% of the total, while those with excellent response stood at 29.4%. The negative mycological examination ratio was 47.1%. In the three-day group, 12 cases showed an excellent response, four a good response while eight had a fairly good response. Patients with a good response or better comprised 66.7% of the group, while cases with an excellent response comprised 50.0%. The negative mycological examination ratio stood at 66.7%. The overall effectiveness evaluation showed no statistically significant difference between the two treatment groups in the Wilcoxon's rank sum test. No side effect was observed in either group. These findings showed that terbinafine therapy of tinea cruris is effective even with a short-term treatment of 2-3 days at a small dose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12748594&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Characterization of the precursor of tetraether lipid biosynthesis in the thermoacidophilic archaeon Thermoplasma acidophilum.

Nemoto N, Shida Y, Shimada H, Oshima T, Yamagishi A.

Department of Molecular Biology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.

Polar lipid biosynthesis in the thermoacidophilic archaeon Thermoplasma acidophilum was analyzed using terbinafine, an inhibitor of tetraether lipid biosynthesis. Cells of T. acidophilum were labeled with [(14)C]mevalonic acid, and their lipids were extracted and analyzed by two-dimensional thin-layer chromatography. Lipids labeled with [(14)C]mevalonic acid, [(14)C]glycerol, and [(32)P]orthophosphoric acid were extracted and hydrolyzed under different conditions to determine the structure of polar lipids. The polar lipids were estimated to be archaetidylglycerol, glycerophosphatidylcaldarchaetidylglycerol, caldarchaetidylglycerol, and beta- l-gulopyranosylcaldarchaetidylglycerol, the main polar lipid of T. acidophilum. Pulse and chase experiments with terbinafine revealed that one tetraether lipid molecule is synthesized by head-to-head condensation of two molecules of archaetidylglycerol and that a sugar group of tetraether phosphoglycolipid is expected to attach to the tetraether lipid core after head-to-head condensation in T. acidophilum. A precursor accumulated in the presence of terbinafine with a fast-atom-bombardment mass spectrometry peak m/z 806 was compatible with archaetidylglycerol. The relative height of the peak m/z 806 decreased after removal of the inhibitor. The results suggest that most of the precursor, archaetidylglycerol, is in fully saturated form.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12768455&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
In vitro and in vivo studies of the anticancer action of terbinafine in human cancer cell lines: G0/G1 p53-associated cell cycle arrest.

Lee WS, Chen RJ, Wang YJ, Tseng H, Jeng JH, Lin SY, Liang YC, Chen CH, Lin CH, Lin JK, Ho PY, Chu JS, Ho WL, Chen LC, Ho YS.

Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.

Terbinafine (TB) (Lamisil), a promising oral antifungal agent used worldwide, has been used in the treatment of superficial mycosis. In our study, we demonstrated that TB dose-dependently decreased cell number in various cultured human malignant cells. Flow cytometry analysis revealed that TB interrupts the cell cycle at the G0/G1 transition. The TB-induced cell cycle arrest in colon cancer cell line (COLO 205) occurred when the cyclin-dependent kinase (cdk) system was inhibited just as the levels of p53, p21/Cip1 and p27/Kip1 proteins were augmented. In the TB-treated COLO 205, the binding between p53 protein and p53 consensus binding site in p21/Cip1 promoter DNA probe was increased. Pretreatment of COLO 205 with p53-specific antisense oligodeoxynucleotide decreased the TB-induced elevations of p53 and p21/Cip1 proteins, which in turn led to arrest in the cell cycle at the G0/G1 phase. Moreover, in the p53 null cells, HL60, TB treatment did not induce cell cycle arrest. Taken together, these results suggest an involvement of the p53-associated signaling pathway in the TB-induced antiproliferation in COLO 205. We further examined whether administration of TB could affect the growth of tumors derived from human colon cancer cells in an in vivo setting. COLO 205 cells implanted subcutaneously in nude mice formed solid tumor; subsequent intraperitoneal injections of TB (50 mg/kg) led to obvious decline in tumor size, up to 50-60%. In these tumors, increases in the p21/Cip1, p27/Kip1 and p53 proteins and the occurrence of apoptosis were observed. Combined treatment with TB and nocodazole (ND), a clinically used anticancer agent, potentiated the apoptotic effect in COLO 205. These findings demonstrate for the first time that TB can inhibit the proliferation of tumor cells in vitro and in vivo. Copyright 2003 Wiley-Liss, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12794767&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity.

Gupta AK, Kohli Y.

Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Science Center, Sunnybrook site, and the University of Toronto, Toronto, ON, Canada. agupta execulonk.com

BACKGROUND: With the development of newer antifungal agents with activity against both yeasts and filamentous fungi, there is an increased need to develop and standardize in vitro assays that will evaluate the activity of antimycotics against filamentous fungi. In vitro analysis of antifungal activity of these agents would also allow for the comparison between different antimycotics, which in turn may clarify the reasons for lack of clinical response or serve as an effective therapy for patients with chronic infection. OBJECTIVES: To determine the in vitro susceptibility of fungal organisms to ciclopirox, terbinafine, ketoconazole and itraconazole and to evaluate the in vitro activity and mode of interaction of ciclopirox in combination with either terbinafine or itraconazole. MATERIALS AND METHODS: In the minimum inhibitory concentration (MIC) study 133 strains were evaluated, including dermatophytes (110 strains; 98 from Trichophyton spp.), Candida spp. (14 strains) and nondermatophyte moulds (nine strains). In vitro susceptibility testing was conducted in microbroth dilutions based on the National Committee for Clinical Laboratory Standards (NCCLS) M27-A proposed standard. The testing MIC ranges were 0.003-2 microg mL-1 for ciclopirox and terbinafine, and 0.06-32 microg mL-1 for itraconazole and ketoconazole. For inoculum preparation, dermatophytes were grown on Heinz oatmeal cereal agar slants. Inoculum suspensions of dermatophytes were diluted in RPMI 1640 (Sigma-Aldrich) with the desired final concentration being 2-5 x 103 c.f.u. mL-1. Once inoculated, the microdilution plates were set up according to the NCCLS M27-A method, incubated at 35 degrees C, and read visually following 7 days of incubation. For azole agents, the MIC was the lowest concentration showing 80% growth inhibition; for terbinafine and ciclopirox, the MIC was the lowest concentration showing 100% growth inhibition. In the synergy studies, 29 strains from nondermatophyte species were evaluated using a checkerboard microdilution method. The concentrations tested were: 0 and 0.06-32 microg mL-1 for itraconazole, and 0 and 0.003-4 microg mL-1 for both terbinafine and ciclopirox. Modes of interaction between drugs were classified as synergism, additivism, antagonism or indifference based on fractional inhibitory concentration index values (FIC index). Synergism was defined as an FIC index of < or = 0.50, additivity as an FIC index of < or = 1.0, and antagonism as an FIC index of > or = 2.0. The drug combination was interpreted as indifferent if neither of the drugs had any visible effect on the presence of the other drug. RESULTS: In the MIC study, the dermatophyte MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (0.04 +/- 0.02), terbinafine (0.04 +/- 0.23), itraconazole (2.28 +/- 7.42) and ketoconazole (0.83 +/- 1.99). The yeast MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (0.05 +/- 0.02), terbinafine (1.77 +/- 0.58), itraconazole (0.18 +/- 0.27) and ketoconazole (0.56 +/- 0.60). The non-dermatophyte fungi MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (1.04 +/- 2.62), terbinafine (1.04 +/- 0.95), itraconazole (17.87 +/- 16.75) and ketoconazole (10.69 +/- 13.09). In the synergy study, with ciclopirox in combination with terbinafine, mainly a synergistic or additive reaction was observed; there were no cases of antagonism. For ciclopirox in combination with itraconazole, there were some instances of additivism or synergism, with indifference in the majority of instances; there were no cases of antagonism. CONCLUSIONS: In vitro susceptibility testing indicates that ciclopirox may have a broad antimicrobial profile including dermatophytes, yeasts and other nondermatophytes. Terbinafine is extremely potent against dermatophytes. In vitro evaluation of activity of ciclopirox and terbinafine suggests many instances of synergy or additivism; for ciclopirox and itraconazole there may be indifference, synergy or additivism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12932235&dopt=Abstract terbinafine Lamisil