terbinafine, Lamisil
Risk of serious skin disorders among users of oral antifungals: a population-based study.

Castellsague J, Garcia-Rodriguez LA, Duque A, Perez S.

Novartis Global Epidemiology, Barcelona, Spain.

BACKGROUND: Serious skin disorders have been associated with the use of oral antifungals in a number of case reports and series of cases. However the incidence of these disorders remains unknown. METHODS: We estimated the risk of serious skin disorders in a cohort of users of oral antifungals identified in the general population of the General Practice Research Database in the UK. The cohort included 61,858 patients, 20 to 79 years old, who had received at least one prescription for either oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine. RESULTS: The background rate of serious cutaneous adverse reactions (the one corresponding to non use of oral antifungals) was 3.9 per 10,000 person-years (95% CI 2.9-5.2). Incidence rates for current use were 15.4 per 10,000 person-years (1.9-55.7) for itraconazole, 11.1 (3.0-28.5) for terbinafine, 10.4 (1.3-37.5) for fluconazole, and 4.6 (0.1-25.8) for griseofulvin. Itraconazole was the antifungal associated with the highest relative risk, 3.9 (0.5-15.0), when compared to the risk among non users, followed by terbinafine and fluconazole, with relative risks of 2.8 (0.7-7.8) and 2.6 (0.3-10.1), respectively. CONCLUSIONS: We conclude that cutaneous disorders associated with the use of oral antifungals in this study were all of mild severity and that the risk associated with the use of oral antifungals was slightly higher than the risk in non-users. The safety profile of terbinafine regarding cutaneous disorders is similar to other antifungals and in the very low range of risks associated with other drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12456265&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
In vitro susceptibilities of zygomycetes to conventional and new antifungals.

Dannaoui E, Meletiadis J, Mouton JW, Meis JF, Verweij PE; Eurofung Network.

Department of Medical Microbiology, University Medical Center, St Radboud, PO Box 9101, 6500 HB Nijmegen.

In vitro susceptibilities of 36 zygomycete isolates, belonging to six genera, to itraconazole, posaconazole, voriconazole, terbinafine, amphotericin B and 5-fluorocytosine were determined by using a broth microdilution adaptation of the National Committee for Clinical Laboratory Standards M-38P reference method. The influence of incubation time on MIC values, and the performance of a spectrophotometric method for MIC determination in comparison with the visual reference method, were also evaluated. Amphotericin B was active against most of the isolates. All the isolates were highly resistant to 5-fluorocytosine (MICs > 256 mg/L). Voriconazole was significantly less active than the other drugs with an overall MIC(90) (MIC at which 90% of the isolates were inhibited) of 32 mg/L. In contrast, posaconazole showed good activity (MIC(90) 1 mg/L). A wide range of MICs, from 0.03 to > or =32 mg/L, was obtained for itraconazole and terbinafine. Differences in susceptibility between and within genera were noted. Rhizopus spp. were significantly less susceptible to itraconazole, posaconazole, terbinafine and amphotericin B than Absidia spp., and less susceptible than Mucor spp. to amphotericin B. Terbinafine appeared to be more active against Rhizopus microsporus than against Rhizopus oryzae (geometric mean MIC of 0.15 and 64 mg/L, respectively). The activity of the drugs was dependent on the incubation period. A significant increase in MICs was noted between 24 and 48 h of incubation. On the other hand, the two methods used for MIC determination (visual and spectrophotometric readings) showed good agreement. These results suggest that the zygomycetes are a heterogeneous group for antifungal susceptibility. Some of the conventional and new antifungals are effective in vitro; their efficacies in vivo remain to be determined. The spectrophotometric method appears to be a valuable alternative to the visual method for MIC determination for zygomycetes.

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terbinafine, Lamisil
Clinical Trichophyton rubrum strain exhibiting primary resistance to terbinafine.

Mukherjee PK, Leidich SD, Isham N, Leitner I, Ryder NS, Ghannoum MA.

Center for Medical Mycology, Department of Dermatology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.

The in vitro antifungal susceptibilities of six clinical Trichophyton rubrum isolates obtained sequentially from a single onychomycosis patient who failed oral terbinafine therapy (250 mg/day for 24 weeks) were determined by broth microdilution and macrodilution methodologies. Strain relatedness was examined by random amplified polymorphic DNA (RAPD) analyses. Data obtained from both broth micro- and macrodilution assays were in agreement and revealed that the six clinical isolates had greatly reduced susceptibilities to terbinafine. The MICs of terbinafine for these strains were >4 microg/ml, whereas they were <0.0002 microg/ml for the susceptible reference strains. Consistent with these findings, the minimum fungicidal concentrations (MFCs) of terbinafine for all six strains were >128 microg/ml, whereas they were 0.0002 microg/ml for the reference strain. The MIC of terbinafine for the baseline strain (cultured at the initial screening visit and before therapy was started) was already 4,000-fold higher than normal, suggesting that this is a case of primary resistance to terbinafine. The results obtained by the broth macrodilution procedure revealed that the terbinafine MICs and MFCs for sequential isolates apparently increased during the course of therapy. RAPD analyses did not reveal any differences between the isolates. The terbinafine-resistant isolates exhibited normal susceptibilities to clinically available antimycotics including itraconazole, fluconazole, and griseofulvin. However, these isolates were fully cross resistant to several other known squalene epoxidase inhibitors, including naftifine, butenafine, tolnaftate, and tolciclate, suggesting a target-specific mechanism of resistance. This is the first confirmed report of terbinafine resistance in dermatophytes.

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terbinafine, Lamisil
In vitro drug interaction modeling of combinations of azoles with terbinafine against clinical Scedosporium prolificans isolates.

Meletiadis J, Mouton JW, Meis JF, Verweij PE.

Department of Medical Microbiology, University Medical Center Nijmegen, Nijmegen, The Netherlands.

The in vitro interaction between terbinafine and the azoles voriconazole, miconazole, and itraconazole against five clinical Scedosporium prolificans isolates after 48 and 72 h of incubation was tested by a microdilution checkerboard (eight-by-twelve) technique. The antifungal effects of the drugs alone and in combination on the fungal biomass as well as on the metabolic activity of fungi were measured using a spectrophotometric method and two colorimetric methods, based on the lowest drug concentrations showed 75 and 50% growth inhibition (MIC-1 and MIC-2, respectively). The nature and the intensity of the interactions were assessed using a nonparametric approach (fractional inhibitory concentration [FIC] index model) and a fully parametric response surface approach (Greco model) of the Loewe additivity (LA) no-interaction theory as well as a nonparametric (Prichard model) and a semiparametric response surface approaches of the Bliss independence (BI) no-interaction theory. Statistically significant synergy was found between each of the three azoles and terbinafine in all cases, although with different intensities. A 27- to 64-fold and 16- to 90-fold reduction of the geometric mean of the azole and terbinafine MICs, respectively, was observed when they were combined, resulting in FIC indices of <1 to 0.02. Using the MIC-1 higher levels of synergy were obtained, which were more consistent between the two incubation periods than using the MIC-2. The strongest synergy among the azoles was found with miconazole using the BI-based models and with voriconazole using the LA-based models. The synergistic effects both on fungal growth and metabolic activity were more potent after 72 h of incubation. Fully parametric approaches in combination with the modified colorimetric method might prove useful for testing the in vitro interaction of antifungal drugs against filamentous fungi.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12499177&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
In-vitro activities of terbinafine, itraconazole and amphotericin B against Aspergillus and Cladosporium species.

Kantarcioglu AS, Yucel A.

Department of Microbiology and Clinical Microbiology, Cerrahpasa Medical Faculty, Istanbul University, 34303 Cerrahpasa, Istanbul, Turkey. s.kantarcioglu superonline.com

The in vitro fungicidal and fungistatic activities of terbinafine were compared with those of itraconazole and amphotericin B against Aspergillus (n=63) and Cladosporium (n=21) isolates. The broth macrodilution modification of NCCLS reference method for filamentous fungi (M38-P) was used to assess the minimum inhibitory concentrations (MICs). Our data show that the in vitro activities of terbinafine were comparable to those of itraconazole and amphotericin B against the Aspergillus spp and Cladosporium strains tested. Despite strain-dependent variabilities, in general, itraconazole's activity was similar to that of amphotericin B against strains of Aspergillus and Cladosporium. Our data suggest that terbinafine may be useful in the treatment of Aspergillus and Cladosporium infections.

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terbinafine, Lamisil
In vitro comparison of terbinafine and itraconazole against Penicillium marneffei.

McGinnis MR, Nordoff NG, Ryder NS, Nunn GB.

Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0609, USA. michael.mcginnis utmb.edu

We evaluated terbinafine and itraconazole against 30 isolates of Penicillium marneffei using a modification of the National Committee for Clinical Laboratory Standards broth macrodilution MIC testing protocol for yeasts. The minimal fungicidal concentration (MFC) was determined by plating 100 microl from each MIC drug dilution having no growth onto Sabouraud glucose agar incubated at 30 degrees C. The MFC was the dilution at which growth was absent at 72 h of incubation. The MICs, in micrograms per milliliter, were as follows: terbinafine, 0.03 to 1.0 (geometric mean titer, 0.09); itraconazole, 0.03 to 0.5 (geometric mean titer, 0.04). The MFCs, in micrograms per milliliter, were as follows: terbinafine, 0.03 to 8 (geometric mean titer, 2.60); itraconazole, 0.03 to 8 (geometric mean titer, 2. 45). Primary fungicidal activity (MFC within 2 dilutions of MIC) was observed with terbinafine in eight isolates and with itraconazole in four isolates. The data indicate that terbinafine is active against P. marneffei in vitro and may have a previously unrealized role in the management of infections caused by this fungus.

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terbinafine, Lamisil
Determination of terbinafine (Lamisil) in human hair by microbore liquid chromatography/tandem mass spectrometry.

Majumdar TK, Bakhtiar R, Melamed D, Tse FL.

Department of Drug Metabolism & Pharmacokinetics, Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA. tapan.majumdar pharma.novartis.com

An analytical method for the determination of terbinafine (Lamisil(R)) in human hair was developed and validated. Human hair (10 mg) was hydrolyzed in 0.50 mL of 5.0 N sodium hydroxide for 1.5 h. The aqueous layer was extracted with 1.5 mL of n-hexane. The organic layer was separated and re-extracted with 0.20 mL of formic acid (12.5%)/2-propanol (85:15, v/v). The aqueous layer was separated and 0.010 mL of the aqueous extract was injected onto a reversed-phase microbore (50 x 1.0 mm i.d.) column for analysis by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The instrument was equipped with an electrospray ionization (ESI) interface and operated in the positive ion mode of detection. Interday and intraday accuracy and precision were assessed from the relative recoveries of spiked samples analyzed on three different days. The method showed excellent specificity and ruggedness with a lower limit of quantitation of 10 ng/g (i.e., 10 ppb) using 10 mg of human hair. Copyright 2000 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10918370&dopt=Abstract terbinafine Lamisil