terbinafine, Lamisil
Activity of terbinafine against serious fungal pathogens.

Ryder NS.

Novartis Research Institute, Vienna, Austria.

Although primarily indicated for dermatophyte infections, the allylamine terbinafine is active in vitro against a broad spectrum of filamentous and dimorphic fungi, in most cases with a primary fungicidal action. Using the standard NCCLS M27-A assay, recent studies confirmed the high activity of terbinafine against dematiaceous fungi and other medically important moulds such as Aspergillus and Penicillium marneffei. Terbinafine displayed a geometric mean MIC of 1.4 micrograms/ml against Candida albicans (n = 259) and has significant in vitro activity against other species of Candida, Cryptococcus, Trichosporon and Blastoschizomyces. As an approach to treatment of refractory infections, interactions of terbinafine with azoles and other agents are being investigated. Terbinafine was synergistic with azoles (and in some cases amphotericin B) against Candida species, Trichosporon beigelii, Aspergillus species, Pseudallescheria boydii and Scopulariopsis brevicaulis, some of which were unresponsive to any drug used singly. Terbinafine combined with fluconazole showed potent synergy against fluconazole- and multidrug-resistant C. albicans isolates. In conclusion, recent in vitro data suggest that terbinafine, either alone or in combination with other antifungal drugs, has potential in the therapy of a range of more severe fungal infections, in addition to its current widespread use against dermatomycoses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10865917&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
In vitro comparison of activities of terbinafine and itraconazole against Paracoccidioides brasiliensis.

Hahn RC, Fontes CJ, Batista RD, Hamdan JS.

Department of Microbiology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.

In vitro, terbinafine is highly active against a broad spectrum of pathogenic fungi. We evaluated the activities of terbinafine and itraconazole against 31 isolates of Paracoccidioides brasiliensis. The tests were conducted by using a broth macrodilution procedure. MICs, in micrograms per milliliter, were as follows: terbinafine, 0.015 to 1.0 (geometric mean, 0.1188); itraconazole, 0.007 to 0.5 (geometric mean, 0.03165). The usual therapy for paracoccidioidomycosis is sulfonamides, amphotericin B, and azole derivatives (ketoconazole, itraconazole, and fluconazole). In comparison to amphotericin B, azole derivatives allow shorter treatment courses, can be administered orally, and are equally effective. Itraconazole has as high efficacy as ketoconazole, but with superior tolerance. It is the current drug of choice for treatment of paracoccidioidomycosis. The data obtained in this study indicate that terbinafine is active against P. brasiliensis in vitro and suggest that this allylamine can be considered a new option as drug therapy for paracoccidioidomycosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12149337&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
In vitro interaction of terbinafine with itraconazole, fluconazole, amphotericin B and 5-flucytosine against Aspergillus spp.

Mosquera J, Sharp A, Moore CB, Warn PA, Denning DW.

School of Medicine, University of Manchester, Hope Hospital, Salford, Manchester M6 8HD, UK.

We investigated the in vitro interaction of terbinafine with itraconazole, fluconazole, amphotericin B and 5-flucytosine, against Aspergillus spp. We tested three isolates of Aspergillus fumigatus (one resistant to itraconazole), and two each of Aspergillus flavus, Aspergillus niger and Aspergillus terreus. We employed a broth microdilution-based method derived from an in vivo validated method capable of detecting itraconazole resistance in A. fumigatus. We studied the effect on the MICs by calculation of the fractional inhibitory concentration (FIC) and fractional fungicidal concentration (FFC) (99.99% kill). Itraconazole and terbinafine were synergic or additive in all strains (FIC = 0.15-1.0). Fluconazole and terbinafine were synergic with A. fumigatus, A. terreus and A. flavus (FIC = 0.3-0.5) and indifferent with A. niger (FIC = 2) isolates. Amphotericin B and terbinafine were mostly indifferent or antagonistic (FIC = 1.0-4.02). Flucytosine and terbinafine were usually indifferent or antagonistic (FIC = 0.63-8.5). FFCs were generally in accord with FICs. The use of terbinafine in combination therapy for Aspergillus infections with azoles seems promising, whereas terbinafine and amphotericin B or flucytosine in combination were less effective.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12161398&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Identification of genes involved in terbinafine resistance in Aspergillus nidulans.

Rocha EM, Almeida CB, Martinez-Rossi NM.

Departamento de Genetica e Bioquimica, Universidade Federal de Uberlandia, Uberlandia, MG, Brazil.

AIMS: To determine the pattern and the genetic basis of resistance to terbinafine, a drug extensively used for the treatment of fungal infections in humans. METHODS AND RESULTS: Four resistant mutants from Aspergillus nidulans isolated after irradiation with ultraviolet light were crossed with the master strain F (MSF). Genetic analysis revealed that a single gene, located on chromosome IV, is responsible for resistance to terbinafine and that the alleles responsible for this resistance in these mutants are of a codominant or dominant nature at high terbinafine concentrations. Furthermore, the interaction of this mutation with another one identified on chromosome II causes the double mutant to be highly resistant. CONCLUSIONS: Periodic surveillance of antimycotic susceptibility would be an important measure in detecting the emergence and spread of resistance. Mutation in a single gene could be responsible for resistance to terbinafine and a genic interaction may be responsible for a higher level of antimycotic resistance. SIGNIFICANCE AND IMPACT OF THE STUDY: The understanding of the mechanisms that lead to changes in the sensitivity of a fungus to a given antifungal agent is important both in order to define strategies for the use of such agent and to guide the development of new antifungal agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12180946&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Antifungal activity in Saccharomyces cerevisiae is modulated by calcium signalling.

Edlind T, Smith L, Henry K, Katiyar S, Nickels J.

Department of Microbiology and Immunology, MCP Hahnemann School of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA. edlind drexel.edu

The most important group of antifungals is the azoles (e.g. miconazole), which act by inhibiting lanosterol demethylase in the sterol biosynthesis pathway. Azole activity can be modulated through structural changes in lanosterol demethylase, altered expression of its gene ERG11, alterations in other sterol biosynthesis enzymes or altered expression of multidrug transporters. We present evidence that azole activity versus Saccharomyces cerevisiae is also modulated by Ca2+-regulated signalling. (i) Azole activity was reduced by the addition of Ca2+. Conversely, azole activity was enhanced by the addition of Ca2+ chelator EGTA. (ii) Three structurally distinct inhibitors (fluphenazine, calmidazolium and a W-7 analogue) of the Ca2+-binding regulatory protein calmodulin enhanced azole activity. (iii) Two structurally distinct inhibitors (cyclosporin and FK506) of the Ca2+-calmodulin-regulated phosphatase calcineurin enhanced azole activity. (iv) Strains in which the Ca2+ binding sites of calmodulin were eliminated and strains in which the calcineurin subunit genes were disrupted demonstrated enhanced azole sensitivity; conversely, a mutant with constitutively activated calcineurin phosphatase demonstrated decreased azole sensitivity. (v) CRZ1/TCN1 encodes a transcription factor regulated by calcineurin phosphatase; its disruption enhanced azole sensitivity, whereas its overexpression decreased azole sensitivity. All the above treatments had comparable effects on the activity of terbinafine, an inhibitor of squalene epoxidase within the sterol biosynthesis pathway, but had little or no effect on the activity of drugs with unrelated targets. (vi) Treatment of S. cerevisiae with azole or terbinafine resulted in transcriptional upregulation of genes FKS2 and PMR1 known to be Ca2+ regulated. A model to explain the role of Ca2+-regulated signalling in azole/terbinafine tolerance is proposed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12366848&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Histone deacetylase inhibitors enhance Candida albicans sensitivity to azoles and related antifungals: correlation with reduction in CDR and ERG upregulation.

Smith WL, Edlind TD.

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA.

Histone acetylation and deacetylation play important roles in eukaryotic gene regulation. Several histone deacetylase (HDA) inhibitors have been characterized, including trichostatin A (TSA), apicidin, and sodium butyrate. We tested their effects on Candida albicans in vitro growth, heat sensitivity, and germ tube formation; minimal effects were observed. However, there was a dramatic effect of TSA on C. albicans sensitivity to the azoles fluconazole, itraconazole, and miconazole. Similar effects were observed with other HDA inhibitors and with the antifungals terbinafine and fenpropimorph, which target, as do azoles, enzymes in the ergosterol biosynthetic pathway. In contrast, HDA inhibitors had minimal effect on the activities of amphotericin B, flucytosine, and echinocandin, which have unrelated targets. Specifically, addition of 3 micro g of TSA/ml lowered the itraconazole MIC for five susceptible C. albicans isolates an average of 2.7-fold at 24 h, but this increased to >200-fold at 48 h. Thus, the primary effect of TSA was a reduction in azole trailing. TSA also enhanced itraconazole activity against Candida parapsilosis and Candida tropicalis but had no effect with four less related yeast species. To examine the molecular basis for these effects, we studied expression of ERG genes (encoding azole and terbinafine targets) and CDR/MDR1 genes (encoding multidrug transporters) in C. albicans cells treated with fluconazole or terbinafine with or without TSA. Both antifungals induced to various levels the expression of ERG1, ERG11, CDR1, and CDR2; addition of TSA reduced this upregulation 50 to 100%. This most likely explains the inhibition of azole and terbinafine trailing by TSA and, more generally, provides evidence that trailing is mediated by upregulation of target enzymes and multidrug transporters.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12384361&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Therapeutic efficacy of topically applied KP-103 against experimental tinea unguium in guinea pigs in comparison with amorolfine and terbinafine.

Tatsumi Y, Yokoo M, Senda H, Kakehi K.

Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Shinomiya, Yamashina-ku, Kyoto-city, Kyoto 607-8042, Japan. tatsumi_yoshiyuki kaken.co.jp

The therapeutic efficacy of KP-103, a novel topical triazole, in a guinea pig tinea unguium model was investigated. Experimental tinea unguium and tinea pedis were produced by inoculation of Trichophyton mentagrophytes SM-110 between the toes of the hind paw of guinea pigs. One percent solution (0.1 ml) of KP-103, amorolfine, or terbinafine was topically applied to the nails and whole sole of an infected foot once daily for 30 consecutive days, and terbinafine was also orally administered at a daily dose of 40 mg/kg of body weight for 30 consecutive days, starting on day 60 postinfection. The fungal burdens of nails and plantar skin were assessed using a new method, which makes it possible to recover infecting fungi by removing a carryover of the drug remaining in the treated tissues into the culture medium. Topically applied KP-103 inhibited the development of nail collapse, significantly reduced the fungal burden of the nails, and sterilized the infected plantar skin. On the other hand, topical amorolfine and topical or oral terbinafine were ineffective for tinea unguium, although these drugs eradicated or reduced the fungal burden of plantar skin. The in vitro activities of amorolfine and terbinafine against T. mentagrophytes SM-110 were 8- and 32-fold, respectively, decreased by the addition of 5% keratin to Sabouraud dextrose broth medium. In contrast, the activity of KP-103 was not affected by keratin because its keratin affinity is lower than those of the reference drugs, suggesting that KP-103 largely exists in the nails as an active form that was not bound to keratin and diffuses in the nail without being trapped by keratin. The effectiveness of KP-103 against tinea unguium is probably due to its favorable pharmacokinetic properties in the nails together with its potent antifungal activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12435679&dopt=Abstract terbinafine Lamisil