terbinafine, Lamisil
Antifungal susceptibility testing of dermatophytes: establishing a medium for inducing conidial growth and evaluation of susceptibility of clinical isolates.

Jessup CJ, Warner J, Isham N, Hasan I, Ghannoum MA.

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

A standardized reference method for dermatophyte in vitro susceptibility testing is lacking. In a previous study, Norris et al. (H. A. Norris, B. E. Elewski, and M. A. Ghannoum, J. Am. Acad. Dermatol. 40(6, part 2):S9-S13) established the optimal medium and other growth variables. However, the earlier study did not address two issues: (i) selection of an optimal medium for conidial formation by dermatophytes and (ii) validation of the method with a large number of dermatophytes. The present study addresses these two points. To select which agar medium best supported conidial growth, representative isolates of dermatophytes were grown on different agars. Preliminary experiments showed that only oatmeal cereal agar supported the production of conidia by Trichophyton rubrum. We tested the abilities of 251 T. rubrum isolates to form conidia using three different cereal agars and potato dextrose agar. Overall, oatmeal cereal and rice agar media were comparable in their abilities to support T. rubrum conidial growth. Next, we used the oatmeal cereal agar for conidial formation along with the optimal conditions for dermatophyte susceptibility testing proposed by Norris et al. and determined the antifungal susceptibilities of 217 dermatophytes to fluconazole, griseofulvin, itraconazole, and terbinafine. Relative to the other agents tested, terbinafine possessed the highest antifungal activity against all of the dermatophytes. The mean +/- standard error of the mean MICs of fluconazole, itraconazole, terbinafine, and griseofulvin were 2.07 +/- 0.29, 0.13 +/- 0.01, 0.002 +/- 0.0003, and 0.71 +/- 0.05 microgram/ml, respectively. This study is the first step in the identification of optimal conditions that could be used for the standardization of the antifungal susceptibility testing method for dermatophytes. Inter- and intralaboratory agreement as well as clinical correlations need to be established.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10618112&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Quantitative analysis of terbinafine (Lamisil) in human and minipig plasma by liquid chromatography tandem mass spectrometry.

Brignol N, Bakhtiar R, Dou L, Majumdar T, Tse FL.

Department of Drug Metabolism & Pharmacokinetics, Novartis Institute for Biomedical Research, East Hanover, NJ 07936, USA.

A method using liquid chromatography/tandem mass spectrometry (LC/MS/MS) for the determination of terbinafine in human and minipig plasma has been developed and validated. The method used positive-ion mode for monitoring terbinafine, and used a stable isotope labelled terbinafine as the internal standard. Subsequent to acetonitrile protein precipitation, the supernatant was directly (unfiltered) injected onto the LC column (retention time approximately 4.3 min) for analysis. Interday and intraday accuracy and precision were assessed from the relative recoveries (observed concentration in percent of the nominal value) of spiked samples analyzed on three different days. The lower limit of quantitation (LLOQ) was 0.0679 ng/mL in human and minipig using a plasma sample volume of 0.08 mL. The method was fast, specific, and exhibited ruggedness. Furthermore, the use of turbulent flow chromatography (TurboFlow LC/MS/MS) coupled to mass spectrometry for direct analysis of terbinafine in plasma is discussed. The technique allowed direct introduction of plasma with satisfactory chromatographic peak shape and increased throughput.Copyright 2000 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10637419&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
In vitro interaction of terbinafine with itraconazole against clinical isolates of Scedosporium prolificans.

Meletiadis J, Mouton JW, Rodriguez-Tudela JL, Meis JF, Verweij PE.

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

In order to develop new approaches for the chemotherapy of invasive infections caused by Scedosporium prolificans, the in vitro interaction between itraconazole and terbinafine against 20 clinical isolates was studied using a checkerboard microdilution method. Itraconazole and terbinafine alone were inactive against most isolates, but the combination was synergistic against 95 and 85% of isolates after 48 and 72 h of incubation, respectively. Antagonism was not observed. The MICs obtained with the terbinafine-itraconazole combination were within levels that can be achieved in plasma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10639389&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Terbinafine: tolerability in general medical practice.

O'Sullivan DP.

Novartis Pharmaceuticals UK Ltd, Frimley, Surrey. des.osullivan pharma.Novartis.com

Four open, prospective, postmarketing studies with consistent protocols were undertaken, involving over 25,000 patients and nearly 3600 physicians in four European countries (UK, Netherlands, Germany and Austria). The purpose was to determine the tolerability of terbinafine when prescribed to a large, unselected patient population in general medical practice. Patients were recruited from dermatology departments and from general and family practitioners. All received at least one dose of terbinafine. No specific exclusion criteria were applied. The only treatment instructions provided were those contained in the manufacturer's product information. Patients were monitored for adverse events at baseline, during treatment, and at the end of treatment. Of the 25,884 patients entering the study, 38.6% (9991) had concomitant disease, 42.8% (11,078) were taking other medications, and 22.7% (5876) were older than 60 years. The predominant indication for prescribing terbinafine was onychomycosis. Mean duration of treatment was 13.2 weeks. No adverse events were reported in 89.5% (23,167) of patients. The remaining 10.5% (2717) reported one or more adverse events, primarily gastrointestinal (4.9%) or dermatological (2.3%). A total of 115 serious adverse events were recorded, but of these only four were probably and eight possibly related to terbinafine. There were no reported drug-drug interactions, even in patients receiving concomitant medications metabolized by cytochrome P-450 enzymes. There were also no clinically significant drug-disease interactions. In conclusion, terbinafine is well tolerated in an unselected general practice population. This confirms its good tolerability previously established during controlled clinical trials.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10730910&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
In vitro susceptibility to itraconazole, clotrimazole, ketoconazole and terbinafine of 100 isolates of Trichophyton rubrum.

Fernandez-Torres B, Vazquez-Veiga H, Llovo X, Pereiro M Jr, Guarro J.

Unitat de Microbiologia, Facultat de Medicina i Institut d'Estudis Avancats, Universitat Rovira i Virgili, Reus, Espana.

BACKGROUND: A reference method for dermatophyte in vitro susceptibility testing is lacking. With the advent of new antimycotics, susceptibility testing has received increasing attention as an important laboratory tool for aiding the selection of appropriate drug therapy. METHODS: One hundred strains of Trichophyton rubrum were tested against four antifungal agents, itraconazole, clotrimazole, ketoconazole and terbinafine, by using a modification of the proposed standard M38-P of the National Committee for Clinical Laboratory Standards and two types of standardized inocula, 1.4 x 10(4) and 5 x 10(3) CFU/ml. RESULTS: Terbinafine was revealed to be the most effective antifungal drug. Of the three azole derivatives tested, clotrimazole showed the highest antifungal activity, while the minimum inhibitory concentrations (MICs) of itraconazole and ketoconazole were similar. Inoculum size did not affect the MIC of any of the antifungal agents tested. CONCLUSION: Our preliminary data provide promising results for the development of a reference method for dermatophyte susceptibility testing based on the microdilution technique, although more dermatophytes should be tested and the method evaluated in different laboratories. Copyright 2000 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11053904&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Inhibitory effect of terbinafine on the invasion of nails by Trichophyton mentagrophytes.

Rashid A, Scott EM, Richardson MD.

Department of Dermatology, University of Glasgow, UK.

BACKGROUND: Terbinafine has a broad spectrum of action in vitro and primary fungicidal action against many pathogenic fungi. Its mode of action against dermatophyte fungi in nail keratin is little understood. OBJECTIVE: Our purpose was to determine the bioavailability of terbinafine in a nail fragment model. METHODS: The effect of terbinafine on adherence and germination of arthroconidia of Trichophyton mentagrophytes on nail fragments was assessed by gross examination and light and electron microscopy. RESULTS: Preexposure of nail fragments to terbinafine concentrations (0.001 to 10 mg/L) inhibited fungal growth and acted as a barrier to dermatophyte invasion. Damaged arthroconidia and distorted hyphae on the surface of nail fragments were observed. CONCLUSION: This in vitro model provides an alternative system for studying the activity of antifungal agents in nail and demonstrates the morphologic changes in dermatophyte fungi after exposure to terbinafine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7593768&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Alterations induced by the antifungal compounds ketoconazole and terbinafine in Leishmania.

Vannier-Santos MA, Urbina JA, Martiny A, Neves A, de Souza W.

Programa de Parasitologia e Biologia Celular, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brasil.

The antiproliferative effects and ultrastructural alterations induced in vitro by two antifungal compounds, the azole ketoconazole and the allylamine terbinafine on Leishmania amazonensis are reported. Promastigotes treatment with ketoconazole and terbinafine induced growth arrest and cell lysis in 72 hours. Combination of the two agents produced additive effects on promastigote axenic growth and synergistic effects on intracellular amastigote proliferation. The amastigotes, either axenically grown or infecting murine macrophages, were about 100-fold more sensitive to the drugs. These compounds induced the appearance of large multivesicular bodies, especially after ketoconazole treatment, increased amount of lipid inclusions as well as numerous, polymorphic volutin granules, particularly in terbinafine-treated cells. Multivesicular bodies were observed in close apposition with organelles such as mitochondria, which also showed alterations in the distribution and appearance of cristae, and the formation of paracrystalline arrays within the matrix. Some cells presented large portions of cytoplasm wrapped by endoplasmic reticulum and many parasites also presented myelin-like endoplasmic reticulum profiles. Such alterations together with the strong acid phosphatase activity observed in the multivesicular bodies and volutin granules may indicate the existence of an unusual autophagic process in cells treated with ergosterol biosynthesis inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7620457&dopt=Abstract terbinafine Lamisil