Lamisil (Terbinafinum)

Lamisil is an antifungal medicine which acts as an antibiotic, but only on fungal infections and not on bacterial ones. The most common reason for prescribing it is to treat fungal nail infections. The drug works by traveling with the bloodstream to the site of the infection and attacking the fungus from the inside. Moreover, the substance is accumulated under the nails (or other infection site) and stays there for a long time after the treatment, assuring that the infection does not occur again and that the site heals naturally and quickly. Generally Lamisil does not cause side effects, or if it does they are mild and short lasting. Also, recent studies have shown that perhaps terbinafine, the active ingredient of Lamisil, has the ability to inhibit the proliferation of human cancer cells.

J Dermatol. 2005 Jan;32(1):22-5.
Efficacy of terbinafine 1% cream on seborrhoeic dermatitis.
Gunduz K, Inanir I, Sacar H.
Department of Dermatology, Medical Faculty, Celal Bayar University, Manisa, Turkey.

Seborrhoeic dermatitis (SD) is a common chronic inflammatory skin disease. Although the exact pathogenesis of SD is unknown, Malassezia yeasts as well as genetic and environmental factors have been implicated. The aim of this study was to evaluate the efficacy of terbinafine 1% cream on SD lesions with face localisation. Thirty-five patients with SD were included in the study. Patients applied terbinafine 1% cream twice daily for four weeks. The severity of the signs (erythema, scaling, infiltration) was assessed using a 4-point score (0=absent, 1=mild, 2=moderate, and 3=intense) at baseline and at the 2nd and 4th weeks of the therapy. Also, self-assessment was done by the patients on a 100 mm visual analogue score (VAS) at each visit. Complete remission was observed in 10 (32.3%) patients at the end of the therapy. Statistically significant reductions in the scores of all parameters were observed at both the 2nd and 4th weeks of the therapy. Patients' self assessments in the 2nd and 4th weeks were similarly better than at the baseline.

Childs Nerv Syst. 2005 Apr 30;
Successful treatment of multiple Pseudallescheria boydii brain abscesses and ventriculitis/ependymitis in a 2-year-old child after a near-drowning episode.
Mursch K, Trnovec S, Ratz H, Hammer D, Horre R, Klinghammer A, de Hoog S, Behnke-Mursch J.
Department of Neurosurgery, Zentralklinik, Robert-Koch Allee 9, 99438, Bad Berka, Germany, nec@zentralklinik-bad-berka.de.

RATIONALE: We report on a cerebral infection by Pseudallescheria boydii in a 21-month-old boy after a near-drowning episode. MRI revealed multiple (>60) intracerebral abscesses. METHODS: The surgical therapy included CSF drainage and microsurgical resection of one abscess for microbiological diagnosis. Antimycotic therapy included terbinafine and intraventricular caspofungin in addition to voriconazole. RESULTS: Systemic side effects of chemotherapy were not observed. After placement of a ventriculoperitoneal shunt, the boy was transferred to a rehabilitation clinic and improved neurologically. After 20 months, MRI documented a continuing remission of the disease. CONCLUSION: Our case proves that an aggressive treatment should be undertaken and can be successful in CNS pseudallescheriasis.

Mycopathologia. 2005 Apr;159(3):377-80.
In vitro susceptibility testing of Microsporum gypseum isolated from healthy cattle and soil samples against itraconazole, terbinafine, fluconazole and topical veterinarian drugs.
Krakhecke AG, Afonso E, Ferreira JC, Candido RC.
Faculdade de Ciencias Agrarias e Veterinarias of Universidade Estadual Paulista, Estopeira street 363 carande Bosque II, Campo Grande, 79032150, Mato Grosso do Sul, Brazil, agkrakhecke@hotmail.com.

The present study evaluated in vitro susceptibility testing of dermatophytes isolates from healthy cattle and soil samples against three antifungal agents and three topical veterinarian drugs. Itraconazole and terbinafine showed a higher in vitro fungicidal activity than fluconazole. The veterinarian drugs LEPECID((R)) and iodine 5% were more active in vitro than the UNGUENTO((R)) spray. All drugs showed fungicidal activity against Microsporum gypseum, and they may be considered as efficient agents for the topical treatment of dermatophytoses in cattle.

Eur J Clin Pharmacol. 2005 Feb 4;
Co-prescription of cytochrome(P450) 2D6/3A4 inhibitor-substrate pairs in clinical practice. A retrospective analysis of data from Norwegian primary pharmacies.
Molden E, Garcia BH, Braathen P, Eggen AE.
School of Pharmacy, University of Oslo, PO Box 1068, Blindern, 0316, Oslo, Norway, emolden@farmasi.uio.no.

OBJECTIVE: Inhibition of cytochrome P(P450) (CYP) enzymes, in particular CYP3A4 and CYP2D6, is an important drug-interacting mechanism. The objective of our study was to assess how frequently CYP3A4 and CYP2D6 inhibitors are co-prescribed with substrates of the respective enzymes.METHODS: Included inhibitors were clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole and nefazodone (CYP3A4 inhibitors) and bupropion, fluoxetine, paroxetine and terbinafine (CYP2D6 inhibitors). The inhibitors were combined with substrates shown to be pharmacokinetically sensitive towards inhibition (190 drug pairs in total). Lists of patients receiving inhibitors and substrates were drawn from prescription databases (~43,500 patients) of three Norwegian primary pharmacies during a 6-month period (July 2002 to January 2003). The lists were matched on name and date of birth to identify patients using drug pairs. Concurrent use was made probable from dates of purchase and drug profiles.RESULTS: Inhibitors were prescribed to 2,062 patients. Altogether, 369 events of substrate co-prescription were registered. The highest frequencies of co-prescribed substrates were found for paroxetine (101 events per 267 patients, 38%), fluoxetine (36 events per 110 patients, 33%) and clarithromycin (59 events per 242 patients, 24%). The drugs most often detected in combination with inhibitors were codeine (116 events) and metoprolol (38 events) for CYP2D6 and zopiclone (45 events) and simvastatin (26 events) for CYP3A4.CONCLUSION: Several commonly used CYP2D6 and CYP3A4 inhibitors are frequently co-prescribed with substrates in Norwegian clinical practice. Alertness when inhibitors are prescribed would aid physicians and pharmacists to detect many drug combinations with potential interaction risk.

Am J Clin Dermatol. 2004;5(6):443-51.
Topical therapy for fungal infections.
Kyle AA, Dahl MV.
Department of Dermatology, Mayo Medical School, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259, USA.

Fungi often infect the skin surface and subsequently invade the stratum corneum to avoid being shed from the skin surface by desquamation. Pharmacologic agents applied to the surface of the skin in the form of creams, lotions, or sprays, readily penetrate into the stratum corneum to kill the fungi (fungicidal agents), or at least render them unable to grow or divide (fungistatic agents). Thus, topical therapies work well to rid the skin of topical fungi and yeasts. Azole drugs such as miconazole, clotrimazole, and ketoconazole are fungistatic, limiting fungal growth but depending on epidermal turnover to shed the still-living fungus from the skin surface. Allylamines and benzylamines such as terbinafine, naftifine, and butenafine are fungicidal, actually killing the fungal organisms. Fungicidal drugs are often preferred over fungistatic drugs for treatment of dermatophytic fungal infections, since treatment times as short as one application daily for 1 week are associated with high cure rates. Furthermore, patients often stop treatments when the skin appears healed, usually after about a week of treatment. If this short-term treatment is stopped, fungi recur more often when fungistatic, rather than fungicidal, drugs have been used. Yeast infections such as those caused by Candida albicans respond less well to allylamine drugs. The azole drugs are often preferred for these types of infections. Nail infections are difficult to cure with topical therapies because the infections usually occur under the nail instead of on top of it and products penetrate poorly, if at all, through the nail plate. Infections of hair follicles, nails, and widespread infections often require systemic treatments. Antifungal agents are compounded into many different types of vehicles. Patients often prefer to treat weeping infections with spray formulations. Most physicians prescribe branded products in cream or lotion bases. Cost is a factor dictating prescription choice, especially since most products work well regardless of mechanism of action. Cost becomes especially important when infections involve large areas of the body surface. This article reviews various treatments of cutaneous fungal infections, with special emphasis on cure rates and rationales for choosing particular products.

Antimicrob Agents Chemother. 2004 Sep;48(9):3530-5.
Terbinafine resistance mediated by salicylate 1-monooxygenase in Aspergillus nidulans.
Graminha MA, Rocha EM, Prade RA, Martinez-Rossi NM.
Departamento de Genetica, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, 14049-900 Ribeirao Preto, Sao Paulo, Brazil.
Resistance to antifungal agents is a recurring and growing problem among patients with systemic fungal infections. UV-induced Aspergillus nidulans mutants resistant to terbinafine have been identified, and we report here the characterization of one such gene. A sib-selected, 6.6-kb genomic DNA fragment encodes a salicylate 1-monooxygenase (salA), and a fatty acid synthase subunit (fasC) confers terbinafine resistance upon transformation of a sensitive strain. Subfragments carrying salA but not fasC confer terbinafine resistance. salA is present as a single-copy gene on chromosome VI and encodes a protein of 473 amino acids that is homologous to salicylate 1-monooxygenase, a well-characterized naphthalene-degrading enzyme in bacteria. salA transcript accumulation analysis showed terbinafine-dependent induction in the wild type and the UV-induced mutant Terb7, as well as overexpression in a strain containing the salA subgenomic DNA fragment, probably due to the multicopy effect caused by the transformation event. Additional naphthalene degradation enzyme-coding genes are present in fungal genomes, suggesting that resistance could follow degradation of the naphthalene ring contained in terbinafine.

Antimicrob Agents Chemother. 2004 Sep;48(9):3317-22.
In vitro activities of voriconazole in combination with three other antifungal agents against Candida glabrata.
Barchiesi F, Spreghini E, Maracci M, Fothergill AW, Baldassarri I, Rinaldi MG, Scalise G.
Istituo di Malattie Infettive e Medicina Pubblica, Universita Politecnica delle Marche, Azienda Ospedaliera Umberto I degrees, Via Conca, 60020 Torrette di Ancona, Ancona, Italy.
Candida glabrata has recently emerged as a significant pathogen involved in both superficial and deep-seated infections. In the present study, a checkerboard broth microdilution method was performed to investigate the in vitro activities of voriconazole (VOR) in combination with terbinafine (TRB), amphotericin B (AMB), and flucytosine (5FC) against 20 clinical isolates of C. glabrata. Synergy, defined as a fractional inhibitory concentration (FIC) index of < or = 0.50, was observed in 75% of VOR-TRB, 10% of VOR-AMB, and 5% of VOR-5FC interactions. None of these combinations yielded antagonistic interactions (FIC index > 4). When synergy was not achieved, there was still a decrease in the MIC of one or both drugs used in the combination. In particular, the MICs were reduced to < or = 1.0 microg/ml as a result of the combination for all isolates for which the AMB MIC at the baseline was > or = 2.0 microg/ml. By a disk diffusion assay, the halo diameters produced by antifungal agents in combination were greater that those produced by each drug alone. Finally, killing curves showed that VOR-AMB exhibited synergistic interactions, while VOR-5FC sustained fungicidal activities against C. glabrata. These studies demonstrate that the in vitro activity of VOR against this important yeast pathogen can be enhanced upon combination with other drugs that have different modes of action or that target a different step in the ergosterol pathway. Further studies are warranted to elucidate the potential beneficial effects of such combination regimens in vivo.

Int J Cancer. 2004 Aug 10;111(1):51-9.
Inhibition of human vascular endothelial cells proliferation by terbinafine.
Ho PY, Liang YC, Ho YS, Chen CT, Lee WS.
Graduate Institute of Cellular and Molecular Biology, Taipei Medical University, Taipei, Taiwan.
We have demonstrated previously that terbinafine (TB), an oral antifungal agent used in the treatment of superficial mycosis, suppresses proliferation of various cultured human cancer cells in vitro and in vivo by inhibiting DNA synthesis and activating apoptosis. In our study, we further demonstrated that TB at a range of concentrations (0-120 microM) dose-dependently decreased cell number in cultured human umbilical vascular endothelial cells (HUVEC). Terbinafine was not cytotoxic at a concentration of 120 microM, indicating that it may have an inhibitory effect on the cell proliferation in HUVEC. The TB-induced inhibition of cell growth rate is reversible. [(3)H]thymidine incorporation revealed that TB reduced the [(3)H]thymidine incorporation into HUVEC during the S-phase of the cell-cycle. Western blot analysis demonstrated that the protein levels of cyclin A, but not cyclins B, D1, D3, E, CDK2 and CDK4, decreased after TB treatment. The TB-induced cell-cycle arrest in HUVEC occurred when the cyclin-dependent kinase 2 (CDK2) activity was inhibited just as the protein level of p21 was increased and cyclin A was decreased. Pretreatment of HUVEC with a p21 specific antisense oligonucleotide reversed the TB-induced inhibition of [(3)H]thymidine incorporation. Taken together, these results suggest an involvement of the p21-associated signaling pathway in the TB-induced antiproliferation in HUVEC. Capillary-like tube formation and chick embryo chorioallantoic membrane (CAM) assays further demonstrated the anti-angiogenic effect of TB. These findings demonstrate for the first time that TB can inhibit the angiogenesis. Copyright 2004 Wiley-Liss, Inc.

J Biol Chem. 2004 Jul 23;279(30):31190-6. Epub 2004 May 21.
A yeast strain lacking lipid particles bears a defect in ergosterol formation.
Sorger D, Athenstaedt K, Hrastnik C, Daum G.
Institut fur Biochemie, Technische Universitat Graz, Petersgasse12/2, A-8010 Graz, Austria.
Lipid particles of the yeast Saccharomyces cerevisiae are storage compartments for triacylglycerols (TAG) and steryl esters (STE). Four gene products, namely the TAG synthases Dga1p and Lro1p, and the STE synthases Are1p and Are2p contribute to storage lipid synthesis. A yeast strain lacking the four respective genes is devoid of lipid particles thus providing a valuable tool to study the physiological role of storage lipids and lipid particles. Using a dga1lro1are1are2 quadruple mutant transformed with plasmids bearing inducible DGA1, LRO1, or ARE2 we demonstrate that TAG synthesis contributes more efficiently to lipid particle proliferation than synthesis of STE. Moreover, we show that proteins typically located to lipid particles in wild type such as Erg1p, Erg6p, Erg7p, and Ayr1p are refined to microsomal fractions of the dga1lro1are1are2 quadruple mutant. This result confirms the close relationship between lipid particles and endoplasmic reticulum. Most interestingly, the amount of the squalene epoxidase Erg1p, which is dually located in lipid particles and endoplasmic reticulum of wild type, is decreased in the quadruple mutant, whereas amounts of other lipid particle proteins tested were not reduced. This decrease is not caused by down-regulation of ERG1 transcription but by the low stability of Erg1p in the quadruple mutant. Because a similar effect was also observed in are1are2 mutants this finding can be mainly attributed to the lack of STE. The quadruple mutant, however, was more sensitive to terbinafine, an inhibitor of Erg1p, than the are1are2 strain suggesting that the presence of TAG and/or intact lipid particles has an additional protective effect. In a strain lacking the two STE synthases, Are1p and Are2p, incorporation of ergosterol into the plasma membrane was reduced, although the total cellular amount of free ergosterol was higher in the mutant than in wild type. Thus, an esterification/deacylation mechanism appears to contribute to the supply of ergosterol to the plasma membrane.

Antimicrob Agents Chemother. 2004 Jul;48(7):2727-9.
In vitro interactions of approved and novel drugs against Paecilomyces spp.
Ortoneda M, Capilla J, Pastor FJ, Pujol I, Yustes C, Serena C, Guarro J.
Unitat de Microbiologia, Facultat de Medicina i Ciencies de la Salut, Universitat Rovira i Virgili, Carrer Sant Llorenc, 21.43201 Reus, Spain.
We have evaluated the in vitro activity of 15 combinations of antifungal drugs (amphotericin B, itraconazole, voriconazole, albaconazole, ravuconazole, terbinafine, and micafungin) against four isolates of Paecilomyces variotii and three of P. lilacinus. The interaction of terbinafine with the four azoles was synergistic for 53% of the combinations, while the interactions of both amphotericin B and micafungin with the rest of antifungal agents were mainly indifferent.

Antimicrob Agents Chemother. 2004 Jul;48(7):2490-6.
Extra copies of the Aspergillus fumigatus squalene epoxidase gene confer resistance to terbinafine: genetic approach to studying gene dose-dependent resistance to antifungals in A. fumigatus.
Liu W, May GS, Lionakis MS, Lewis RE, Kontoyiannis DP.
Department of Infectious Diseases, Infection Control and Employee Health, Unit 402, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
With the increasing use of antifungals such as amphotericin B, itraconazole, voriconazole, caspofungin, and terbinafine (TRB) in patients at high risk for invasive aspergillosis, resistance of Aspergillus fumigatus to these agents will ultimately emerge. Due to the limited availability of molecular genetics for A. fumigatus, few studies have addressed its mechanisms of resistance to antifungals. We transformed A. fumigatus protoplasts with a pyrG-based A. fumigatus genomic DNA library (constructed in the multicopy nonintegrating vector pRG3-AMA1-NotI, which also has the pyr-4 gene for selection). We obtained one pyrG(+) transformant that grew in medium containing a fungicidal concentration (0.625 microg/ml) of TRB. To determine whether TRB resistance in that transformant was plasmid dependent, we evicted the plasmid and found concomitant loss of uracil prototrophy and TRB resistance. DNA sequence analysis identified the gene responsible for TRB resistance as the A. fumigatus squalene epoxidase gene (ERG1), which encodes the target enzyme of TRB. Authentic A. fumigatus ERG1, amplified from the genome and cloned into pRG3-AMA1-NotI, also conferred TRB-specific resistance. This molecular approach has the potential to enhance our knowledge of the mechanisms of A. fumigatus resistance to modern antifungals.

Cornea. 2004 Jul;23(5):516-21.
Fungal keratitis caused by Paecilomyces lilacinus associated with a retained intracorneal hair.
Anderson KL, Mitra S, Salouti R, Pham TA, Taylor HR.
Department of Ophthalmology and Centre for Eye Research Australia, The University of Melbourne, The Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia. ka_anderson@msn.com
OBJECTIVE: To report a case of fungal keratitis caused by Paecilomyces lilacinus (P. lilacinus) associated with a retained intracorneal hair. METHODS: A 61-year-old man developed pain, decreased vision, hyperemia, and corneal infiltrates in his right eye without any predisposing factor. An intracorneal hair had migrated superiorly in the corneal stroma, giving rise to 3 separate stromal infiltrates. The patient demonstrated a waxing and waning course over several months despite antimicrobial and steroid therapy. RESULTS: Histopathologic examination of a corneal biopsy specimen disclosed the presence of fungal elements, and intensive antifungal therapy was initiated. Verticillium sp. was initially identified as the causative organism, but after failure to improve on topical natamycin, subsequent investigations demonstrated the pathogen to be P. lilacinus that was resistant to routine antifungal agents. The patient was then initiated on systemic voriconazole and terbinafine. He responded well to treatment and ultimately recovered a best-corrected visual acuity of 6/15 in the affected eye. CONCLUSION: This is the first case of P. lilacinus keratitis associated with a retained intracorneal hair. Hair in the cornea could be a predisposing factor for this infection. Early corneal biopsy should be considered to properly diagnose and manage atypical keratitis and to prevent further complications.

Ann Hematol. 2004 Jun;83(6):394-7. Epub 2003 Nov 27.
Combination therapy of disseminated Fusarium oxysporum infection with terbinafine and amphotericin B.
Rothe A, Seibold M, Hoppe T, Seifert H, Engert A, Caspar C, Karthaus M, Fatkenheuer G, Bethe U, Tintelnot K, Cornely OA.
Klinik I fur Innere Medizin, Universitat zu Koln, Joseph-Stelzmann-Str. 9, 50931 Cologne, Germany.
A case of disseminated infection with Fusarium oxysporum following chemotherapy of acute myelogenous leukemia is reported. Antifungal treatment was successful with a 13-day course of oral terbinafine 250 mg t.i.d. in combination with amphotericin B deoxycholate 1.0-1.5 mg/kg qd and subsequently intravenous liposomal amphotericin B 5 mg/kg qd. Preceding monotherapy with amphotericin B deoxycholate 1.0-1.5 mg/kg qd had not stopped the progression of infection. The combination therapy described here represents a novel approach to the treatment of Fusarium spp. in the immunocompromised host in whom Fusarium spp. are known to cause disseminated infection with high mortality.

Arch Dermatol. 2004 Jun;140(6):691-5.
The successful treatment of Trichophyton rubrum nail bed (distal subungual) onychomycosis with intermittent pulse-dosed terbinafine.
Zaias N, Rebell G.
Greater Miami Skin and Laser Center and Mount Sinai Medical Center, Miami Beach, FL 33140, USA. nardozaias@aol.com
BACKGROUND: The standard treatment of Trichophyton rubrum nail bed onychomycosis (or distal subungual onychomycosis [DSO]) with daily terbinafine for 12 weeks involves treating for a fixed period shorter than the time required for complete replacement of the nail bed and overlying nail plate by normal growth. The same total amount of terbinafine pulse-dosed for approximately 12 months would treat the patient until normal replacement of the mycotic nail bed has occurred.OBJECTIVES: To determine the effectiveness of intermittent administration of oral terbinafine (250 mg/d for 7 consecutive days every 2-4 months) to cure DSO and to determine the maximum effective treatment interval. DESIGN: A prospective, nonrandomized, open study of sequential groups of office patients. SETTING: A private dermatology practice. METHODS: A sequence of 4 groups of office patients with DSO (n = 10-20 each) were treated with pulse-dosed terbinafine for 7 consecutive days at intervals of 2, 3, and 4 months, respectively. In each group, treatment was continued until the distally advancing new nail bed and nail had completely removed the mycotic defect or failure of fungistasis was detected. MAIN OUTCOME MEASUREMENT: Results were determined by monthly evaluation. Cure was noted as complete replacement of the mycotic nail bed and overlying nail plate (ascertained by monthly metric measurements of the mycosis-free nail bed and overlying nail place distal to the proximal nail fold). Treatment failure was noted when the mycosis-free proximal portion of the nail bed failed to increase in correspondence with the distally directed movement of the nail bed and overlying nail. RESULTS: Thirty-nine (93%) of the 42 patients in the first 3 groups were cured (95% binomial confidence interval, 67%-100%) with no evidence of decrease in efficacy. However, the group of patients who received the 7-day pulse treatment every 4 months experienced significantly more failures (P<.01), and cures dropped to 10 of 17 cases. CONCLUSION: Terbinafine is an effective treatment for DSO when pulse-dosed for 7 days every 3 months but not every 4 months.

Clin Infect Dis. 2004 Jun 1;38(11):e112-5. Epub 2004 May 11.
Exophiala jeanselmei infection in a heart transplant recipient successfully treated with oral terbinafine.
Agger WA, Andes D, Burgess JW.
Gundersen Lutheran Medical Center, La Crosse, WI, USA.
An immunosuppressed heart transplant recipient developed Exophiala jeanselmei infection on the second toe. After unsuccessful treatment with different antifungal drugs, the infection responded to a high-dose regimen of oral terbinafine (an antifungal agent not yet approved in the United States for use against the dematiaceous fungi) and warm packs. This is, to our knowledge, the only known case of successful terbinafine treatment of E. jeanselmei infection.

J Antimicrob Chemother. 2004 Jun;53(6):1086-9. Epub 2004 Apr 21.
In vitro activity of terbinafine against medically important non-dermatophyte species of filamentous fungi.
Garcia-Effron G, Gomez-Lopez A, Mellado E, Monzon A, Rodriguez-Tudela JL, Cuenca-Estrella M.
Servicio de Micologia, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Ctra Majadahonda-Pozuelo Km 2, 28220 Majadahonda, Madrid, Spain.
OBJECTIVES: The activity in vitro of terbinafine against 442 clinical isolates of several species of filamentous fungi was analysed. METHODS: A broth microdilution test was carried out following the National Committee for Clinical Laboratory Standards reference method, with modifications described previously. RESULTS: The geometric mean (GM) of MICs of terbinafine for non-Aspergillus fumigatus species was 0.24 mg/L whereas the GM for A. fumigatus rose as far as 2.92 mg/L. Terbinafine showed a very strong activity in vitro against Penicillium spp., Paecilomyces spp., Trichoderma spp., Acremonium spp. and Arthrographis spp. with GMs <1 mg/L. However, some species such as Scedosporium spp., Fusarium spp., Scopulariopsis brevicaulis, and most of Mucorales exhibited high MICs of the allylamine with GMs >/= 4 mg/L. CONCLUSIONS: Overall, the GM of MICs of terbinafine was 1.57 mg/L, but significant differences in susceptibilities were seen between genera and species.

Mycoses. 2004 Jun;47(5-6):238-41.
Disseminated dermatophytosis caused by Microsporum gypseum in an AIDS patient: response to terbinafine and amorolfine.
Galhardo MC, Wanke B, Reis RS, Oliveira LA, Valle AC.
Evandro Chagas Clinical Research Institute--Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil. mclara@ipec.fiocruz.br
A 51-year-old white male, native of Rio de Janeiro, Brazil, with advanced AIDS and in chronic use of imidazoles for oral candidosis, presented erythematous, desquamative, pruriginous plaques of 1 month evolution on the trunk, inguinal/crural region, and lower limbs. The diagnosis of dermatophytosis was based on the isolation of Microsporum gypseum from scales scraped from the skin lesions. The lesions regressed after 30 days treatment with itraconazole, 100 mg day(-1). After interruption of this antifungal, the mycosis recurred 2 months later, along with a toe onychomycosis also caused by M. gypseum. Attempted reintroduction of itraconazole at higher dose was unsuccessful. Patient responded well to treatment with terbinafine 250 mg day(-1) for 45 days. However, the medication had to be interrupted as a result of the emergence of a disseminated erythematous/papulous rash. Topical treatment with amorolfine cream was then performed, with a good clinical and mycological response.

Mycoses. 2004 Jun;47(5-6):216-21.
Susceptibility of sequential Fonsecaea pedrosoi isolates from chromoblastomycosis patients to antifungal agents.
Andrade TS, Castro LG, Nunes RS, Gimenes VM, Cury AE.
Departamento de Analises Clinicas, Laboratorio de Micologia Clinica, Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Sao Paulo, Brazil. tsandrad@zaz.com.br
Fourteen Fonsecaea pedrosoi isolates from six chromoblastomycosis patients were submitted to susceptibility testing. Some patients were undergoing treatment with itraconazole (ITZ) and/or cryosurgery with liquid nitrogen. The antifungal agents amphotericin B (AMB), ITZ, fluconazole (FCZ), ketoconazole (KCZ), 5-fluorocytosine (5-FC), and terbinafine (TBF) were tested. AMB and FCZ showed less activity for all isolates. The most active agents were KCZ and TBF. Sequentially isolates from four patients presented ITZ minimal inhibitory concentration (MIC) higher than the previous ones; for two of these patients, response to therapy with this agent was not observed. These results suggest development of microbiologic resistance to ITZ in four instances, two of them coinciding with lack of clinical response to this drug.

Arerugi. 2004 May;53(5):515-21.
Analysis of facial lesions on adult type atopic dermatitis with anti-fungus drug (terbinafine hydrochloride) -- analysis of serum anti-Malassezia IgE antibody titers and histamine release test
Maejima H, Tokunaga C, Kaneko S, Mukai H, Abe A.
Division of Dermatology, Yokohama rosai Hospital. hm4765@yahoo.ac.jp
Malassezia furfur has been described as an aggravating factor in facial lesions of atopic dermatitis, and oral antifungal agents have been reported to be effective against these lesions. We used terbinafine hydrochloride to treat 15 patients with adult-type atopic dermatitis and evaluated its efficacy by measuring the improvement in facial skin manifestations, serum IgE values, and serum anti-Malassezia IgE antibody titers. A histamine release test (HRT) for Malassezia. was also performed in 6 of the 15 patients. The facial skin manifestations improved in 8 (53.3%) of the 15 patients, and there were significant simultaneous decreases in their serum IgE values. The serum anti-Malassezia IgE antibody titer decreased significantly in all 15 patients. However, no significant correlation was observed between the HRT and the facial skin manifestations. We concluded that oral terbinafine hydrochloride is effective against the facial lesions of atopic dermatitis patients and this is possibly caused by decrease of Malassezia antigen in the facial lesions.

Clin Exp Dermatol. 2004 May;29(3):300-3.
Treatment of Microsporum spp. tinea capitis with pulsed oral terbinafine.
Ungpakorn R, Ayutyanont T, Reangchainam S, Supanya S.
Institute of Dermatology, Bangkok, Thailand. rataporn@health.moph.go.th
Oral terbinafine is widely used in the treatment of superficial dermatomycoses as well as subcutaneous and systemic mycoses. It is also useful in treating tinea capitis, although for Microsporum canis and some ectothrix organisms, the effectiveness of the drug may be less than for some endothrix infections. In this study, we undertook a double-blind randomized trial comparing standard and double doses of terbinafine given in a pulsed protocol (1 week on, 3 weeks off) in treating Microsporum spp. tinea capitis in 42 individuals. We found that pulsed terbinafine at a higher dose did not improve treatment efficacy. However, our data clearly demonstrated that the duration of treatment is an important factor in determining clinical outcome and cure. Two pulses of standard dose terbinafine were found to be sufficient for treating most cases of Microsporum spp. tinea capitis, although additional treatment (a third pulse) may be needed if clinical improvement is not evident at 8 weeks after initiating therapy.

Curr Opin Infect Dis. 2004 Apr;17(2):97-103.
New treatments for tinea capitis.
Chan YC, Friedlander SF.
National Skin Centre, 1 Mandalay Road, Singapore 308205.
PURPOSE OF REVIEW: Tinea capitis, a dermatophyte infection involving the hair shaft on the scalp, is primarily a disease of preadolescent children. The predominant pathogen varies according to the geographical location. Trichophyton tonsurans and Microsporum canis account for the majority of infections in north America and certain parts of Europe. The current standard of care for the treatment of tinea capitis in the USA is oral griseofulvin, but evidence is accumulating that some of the newer antifungal agents may also be useful. RECENT FINDINGS: The newer oral antifungal agents such as terbinafine, itraconazole and fluconazole seem to be effective, safe, and have the advantage of a shorter treatment duration. Although a significant number of clinical studies and reports have documented experience with terbinafine and itraconazole for the treatment of tinea capitis, it should be noted that only a few trials have been conducted utilizing fluconazole. Both 2% ketoconazole and 1% selenium sulfide shampoos are often recommended as adjuvant topical therapy. SUMMARY: Currently, many experts consider griseofulvin to be the drug of choice for tinea capitis. Short-term terbinafine, itraconazole and fluconazole therapy have been shown to be comparable in efficacy and safety with griseofulvin. Regular epidemiological surveillance of causative fungal organisms in the community and their antifungal susceptibility is an essential component in the management of this condition.

J Chemother. 2004 Apr;16(2):139-44.
Evaluation of antifungal efficacy in an optimized animal model of Trichophyton mentagrophytes-dermatophytosis.
Ghannoum MA, Hossain MA, Long L, Mohamed S, Reyes G, Mukherjee PK.
Center for Medical Mycology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106-5028, USA. mag3@cwru.edu
Dermatophytoses are known to cause considerable discomfort, cosmetic problems and financial loss that have been recognized as a significant health concern worldwide. Since currently available antifungal agents have limitations in their efficacy, new agents are being developed. This study was undertaken to optimize an in vivo model of experimental dermatophytosis for evaluation of the efficacy of antifungal compounds. Guinea pigs were infected with different inocula of T. mentagrophytes to establish dermatophytosis. The optimal conditions for dermatophytosis in guinea pigs were found to be an inoculum size of 1 x 10(7) fungal cells applied on abraded skin. After optimization, animals were treated with oral or topical formulations of terbinafine. The optimized guinea pig model was found to be highly reproducible, and useful in the primary screening and evaluation of the anti-dermatophytic efficacy of topical and oral formulations of antifungal agents.

Med Mycol. 2004 Apr;42(2):159-63.
Antifungal drug response in an in vitro model of dermatophyte nail infection.
Osborne CS, Leitner I, Favre B, Ryder NS.
Infectious Diseases Department, Novartis Research Institute, Vienna, Austria. colin.osborne@pharma.novartis.com
Despite terbinafine being fungicidal against Trichophyton rubrum in standard NCCLS assays and rapidly accumulating in nails in vivo, onychomycosis patients require prolonged terbinafine treatment to be cured. To investigate this, we developed a more clinically relevant onychomycosis in vitro test model. Human nail powder inoculated with T. rubrum and incubated in liquid RPMI 1640 salt medium, which did not support growth alone, developed extensive and invasive mycelial growth. Antifungal drugs were added at different concentrations and cultures incubated for 1 to 4 weeks. Fungal survival was determined by spreading cultures on PDA plates without drug and measuring CFU after 1 to 4 weeks incubation. Drug activity was expressed as the nail minimum fungicidal concentration (Nail-MFC) required for 99.9% elimination of viable fungus. Terbinafine Nail-MFC was 4 microg/ml after 1 week exposure, decreasing to 1 microg/ml after 4 weeks exposure, much higher than MFCs < or = 0.03 microg/ml determined in standard NCCLS MIC assays. In contrast, other clinically used drugs were unable to kill T. rubrum after 4 weeks incubation in this model. Invasive mycelial growth on nail appears to protect T. rubrum from the cidal action of systemic drugs, thus providing a rationale for the long treatment periods in onychomycosis.

Vet Dermatol. 2004 Apr;15(2):99-107.
Treatment of dermatophytosis in dogs and cats: review of published studies.
Moriello KA.
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA. moriellk@svm.vetmed.wisc.edu
The recent literature on the treatment of dermatophytosis in dogs and cats was reviewed. Based upon in vitro studies using isolated infected hairs and controlled or field in vivo studies, the following topical treatments were consistently found to be antifungal (i.e. antidermatophyte): lime sulfur (1:16), 0.2% enilconazole rinses, and a combined 2% miconazole/chlorhexidine shampoo. Animals or hairs were either bathed or rinsed once or twice weekly. Itraconazole, griseofulvin and terbinafine were evaluated in controlled or field studies, most commonly involving cats. Griseofulvin (50 mg kg(-1)) was reported to cure infected animals in 41-70 days. Itraconazole (10 mg kg(-1) once daily or in a combined daily/pulse therapy 10 mg kg(-1) once daily for 28 days and then week on/week off) was reported to cure infected animals in 56-70 days. Low-dose itraconazole (1.5-3.0 mg kg(-1)) in 15-day cycles required 1-3 cycles (15-45 days). Various doses of terbinafine (5-40 mg kg(-1)) were reportedly used to treat dogs or cats. The higher doses of terbinafine (> 20 mg kg(-1)) were required to achieve a mycological cure; the number of treatment days to cure varied from 21 to > 126 days. Lufenuron was reported anecdotally to be an effective cure, however, this was not substantiated in controlled studies. Finally, fungal vaccines were not found to be effective against challenge exposure, however, there is evidence that they may be useful in treatment protocols.

Br J Dermatol. 2004 Mar;150(3):537-44.
Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis.
Gupta AK, Ryder JE, Johnson AM.
Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Science Center (Sunnybrook Site) and the University of Toronto, Toronto, Ontario, Canada. agupta@execulink.com
BACKGROUND: Onychomycosis is a common nail disease that is often chronic, difficult to eradicate, and has a tendency to recur. The most common oral therapies for dermatophyte toenail onychomycosis include terbinafine, itraconazole and fluconazole. OBJECTIVES: A cumulative meta-analysis of the randomized controlled trials (RCTs) for antimycotic agents was performed to determine whether the pooled estimate of the cure rates has remained consistent over the years. Furthermore, for each agent we compared the overall meta-analytical average of both mycological and clinical response rates of RCTs vs. open studies. METHODS: We searched MEDLINE (1966 to November 2002) for relevant studies evaluating the efficacy of the oral antifungal agents terbinafine, itraconazole (pulse or continuous), fluconazole and griseofulvin for treating dermatophyte toenail onychomycosis. Studies included in this meta-analysis required a standard accepted dosage regimen, treatment duration and follow-up period. To determine the cumulative meta-analytical average, studies were sequentially pooled by adding one study at a time according to the date of publication (i.e. earliest to the most recent). RESULTS: There were 36 studies included in the analyses. For RCTs the change in efficacy of mycological cure rates from the first trial to the overall cumulative meta-average for each drug comparator is as follows (with 95% confidence interval): terbinafine, 78 +/- 6% (n = 2 studies, 79 patients) to 76 +/- 3% (n = 18 studies, 993 patients) (P = 0.68); itraconazole pulse, 75 +/- 10% (n = 1 study, 20 patients) to 63 +/- 7% (n = 6 studies, 318 patients) (P = 0.25); itraconazole continuous, 63 +/- 5% (n = 1 study, 84 patients) to 59 +/- 5% (n = 7 studies, 1131 patients) (P = 0.47); fluconazole, 53 +/- 6% (n = 1 study, 72 patients) to 48 +/- 5% (n = 3 studies, 131 patients) (P = 0.50); and griseofulvin, 55 +/- 8% (n = 2 studies, 109 patients) to 60 +/- 6% (n = 3 studies, 167 patients) (P = 0.41). The cumulative meta-analytical average of mycological cure rates when comparing RCTs vs. open studies was: terbinafine, 76 +/- 3% (n = 18 studies, 993 patients) vs. 83 +/- 12% (n = 2 studies, 391 patients) (P = 0.0028); itraconazole pulse, 63 +/- 7% (n = 6 studies, 318 patients) vs. 84 +/- 9% (n = 3 studies, 194 patients) (P = 0.0001); and fluconazole, 48 +/- 5% (n = 3 studies, 131 patients) vs. 79 +/- 3% (n = 3 studies, 208 patients) (P = 0.0001). CONCLUSIONS: The cumulative meta-analysis of cure rates for RCTs suggests that over time, as new RCTs have been conducted, the efficacy rates have remained consistent. The efficacy rates of open studies are substantially higher compared with RCTs and may therefore overestimate cure rates.

Br J Dermatol. 2004 Mar;150(3):414-20.
Terbinafine in the treatment of onychomycosis: a review of its efficacy in high-risk populations and in patients with nondermatophyte infections.
Cribier BJ, Bakshi R.
Clinique Dermatologique des Hopitaux Universitaires de Strasbourg, 1 Place de l'Hopital, 67091 Strasbourg, France. bernard.cribier@chru-strasbourg.fr
BACKGROUND: The prevalence of onychomycosis is higher in certain high-risk populations, such as the immunocompromised, diabetics and human immunodeficiency virus (HIV)-positive patients. These patients can also develop onychomycosis due to nondermatophyte fungi. Although the efficacy of terbinafine is well demonstrated in the treatment of conventional dermatophyte nail infection, there are few data on the efficacy of terbinafine in high-risk patient groups or in nondermatophyte fungi, which can be difficult to treat. OBJECTIVES: To review previously published data regarding the safety and efficacy of terbinafine in special patient populations, such as those with diabetes mellitus or HIV infection, those receiving immunosuppressive therapy, and patients with onychomycosis due to nondermatophyte fungi. METHODS: A Medline literature search up to October 2002 was performed in order to identify relevant studies. Pertinent abstracts presented at international meetings were also included. Cure rates (per-protocol and intention-to-treat) were extracted or calculated. All available safety data were also collated. RESULTS: Terbinafine was highly effective and well tolerated in patients with diabetes mellitus. Mycological cure rates of 62-78% were achieved in three studies, which is comparable with the efficacy in nondiabetic populations. Mycological cure rates of 64-91% were achieved in subsets of diabetic patients with Candida-positive nail cultures. The efficacy of terbinafine in patients receiving immunosuppressive therapy was also similar to that reported in immunocompetent patients. Levels of ciclosporin in the blood clearly decreased, with little clinical consequence; however, consideration should be given to the monitoring of ciclosporin levels in patients concomitantly receiving immunosuppressive therapy and terbinafine. Two small studies reported that terbinafine was also effective in treating onychomycosis in HIV-positive patients. Terbinafine was also effective and well tolerated in the treatment of nondermatophyte onychomycosis. CONCLUSIONS: This review suggests that terbinafine is a safe and effective treatment for onychomycosis in high-risk populations. However, the majority of these studies only included small numbers of patients and larger clinical trials are needed, especially in patients with HIV infection.

J Eur Acad Dermatol Venereol. 2004 Mar;18(2):201-3.
Erythema multiforme during cytomegalovirus infection and oral therapy with terbinafine: a virus-drug interaction.
Carducci M, Latini A, Acierno F, Amantea A, Capitanio B, Santucci B.
Department of Inflammatory, Istituto San Gallicano, Via Elio Chianesi, 53, 00144 Rome, Italy. macard@ifo.it
The authors report a case of erythema multiforme in a 32-year-old woman who was also taking oral terbinafine for an onychomycosis. The patient data analysis showed serological positivity for cytomegalovirus (IgM and IgG) and hepatitis C virus and serological titre of antinuclear antibody was elevated. After a brief review of the literature the authors propose the possibility of virus-drug interaction as a model of adverse drug reactions.

J Eur Acad Dermatol Venereol. 2004 Mar;18(2):160-3.
Effect of infection with Trichophyton mentagrophytes varietas interdigitale on phagocytosis in humans.
Gregurek-Novak T.
Department of Dermatology, Clinical Hospital 'Sestre milosrdnice', Vinogradska 29, 10000 Zagreb, Croatia.
BACKGROUND AND AIM: Phagocytosis by polymorphonuclear leucocytes (PMNLs) and macrophages is important in the defence of human organisms, especially in mycotic infections of the skin. The aim of this study was to examine the relationship between phagocytosis and a chronic type of infection with Trichophyton mentagrophytes varietas interdigitale (T. m. var. interdig.). MATERIALS AND METHODS: A group of 256 patients was investigated from 1990 to 2000. They were all treated with terbinafine. The parameters for phagocytosis were analysed by the Hersy method. RESULTS: The immunological status of all of the patients was altered. Ingestion, digestion and random mobility decreased significantly (P < 0.001). Out of 256 patients treated with terbinafine, 196 (76%) were cured completely and the values for phagocytosis became normal. CONCLUSION: This investigation confirms the defect in the function of phagocytes of patients chronically infected by T. m. var. interdig. Terbinafine was shown to be an effective antimycotic drug, both fungicidal and immunostimulative.

Ann Dermatol Venereol. 2003 Jun-Jul;130(6-7):612-8.
Drugs associated with acute generalized exanthematic pustulosis
Saissi EH, Beau-Salinas F, Jonville-Bera AP, Lorette G, Autret-Leca E; Centres Regionaux de Pharmacovigilance.
Service de Pharmacologie,CHRU de Tours.
INTRODUCTION: Acute generalized exanthematous pustulosis is a severe eruption which is usually drug related. If the causative drug is discontinued, acute generalized exanthematous pustulosis resolves spontaneously in ten days. The aim of this study was to compare drugs suspected of causing acute generalized exanthematous pustulosis reported to French Pharmacovigilance centres and those reported in the literature. MATERIALS AND METHODS: All cases of "pustular eruption" qualified as "serious" reported to the French Pharmacovigilance Centers between January 1985 and December 2001 were analyzed. Cases for which the diagnosis of acute generalized exanthematous pustulosis was not clearly identified were reviewed by a dermatologist. The relationship between acute generalized exanthematous pustulosis and drug exposure was re-examined by one of us. An exhaustive review of the literature was also performed. RESULTS: Review of the data base revealed 207 cases of serious acute generalized exanthematous pustulosis leading to death in 4 cases (2%). Of these cases of acute generalized exanthematous pustulosis, only one drug was suspected in 107 cases (51.6%). The main drugs involved were: pristinamycin (18 cases), amoxicillin (+/- clavulanic acid) (16 cases), hydroxychloroquine (8 cases) and a combination of spiramycin + metronidazole (5 cases). DISCUSSION: The most frequent causal drugs in our study and in the literature are: amoxicillin +/- clavulanic acid, pristinamycin, hydroxychloroquine, ampicillin, diltiazem, co-trimoxazole, terbinafine, carbamazepine and spiramycin +/- metronidazole. Only pristinamycin and diltiazem have information in their summary of product characteristics regarding the risk of acute generalized exanthematous pustulosis. Because it is essential to discontinue the causative drug as soon as possible if a pustular eruption occurs, physicians must be informed of the risk, which should be added to the "adverse events", and "warnings" sections of the summary of product characteristics of the drugs concerned. CONCLUSION: Our results show the relevance of notification of side effects by physicians to pharmacovigilance centres, leading to the identification of a signal and public health dissemination of warnings.

Dermatol Clin. 2003 Jul;21(3):511-20.
The efficacy and safety of terbinafine in children.
Gupta AK, Cooper EA, Lynde CW.
Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Science Center (Sunnybrook Site), University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
In summary, terbinafine is a broad-spectrum allylamine, which has been used to treat superficial fungal infections including onychomycosis, and some systemic mycoses in adults. With a fungicidal activity, low minimum inhibitory concentration value, and high selectivity for fungal squalene epoxidase, terbinafine has demonstrated good efficacy in superficial fungal infections. Its lipophilic nature provides excellent, widespread absorption into hair, skin, and nails where it can eradicate fungal infection. Terbinafine has been shown to be effective and safe in several studies of the treatment of tinea capitis and onychomycosis in children. When treating Trichophyton tinea capitis the length of therapy may be 2 or 4 weeks. Microsporum tinea capitis may require somewhat higher or longer doses of terbinafine for adequate efficacy. These regimens still tend to be shorter than treatment with griseofulvin, and terbinafine may provide a higher compliance and a more cost-effective means of managing tinea capitis. It is possible that even higher cure rates and a shorter duration of therapy may be achieved following further optimization of treatment regimens that use a higher daily dosage of terbinafine than is currently recommended. The evidence is strongly in favor of using terbinafine to treat superficial fungal infections in children.

Vet Clin North Am Small Anim Pract. 2003 Jul;33(4):749-58, vi.
Update on antifungal therapy.
Grooters AM, Taboada J.
Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Skip Bertman Drive, Louisiana State University, Baton Rouge, LA 70803, USA.
Fungal pathogens are becoming increasingly important for human and small animal medicine. This article highlights many standards-of-care and new agents for treatment of these pathogens for small animals and people.

Br J Dermatol. 2003 Aug;149(2):296-305.
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
In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity.
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. 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. 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.

Int J Cancer. 2003 Aug 10;106(1):125-37.
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.
In vitro and in vivo studies of the anticancer action of terbinafine in human cancer cell lines: G0/G1 p53-associated cell cycle arrest.
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.