terbinafine, Lamisil
Multiple drug resistance and conservative amplification of the H region in Leishmania major.

Ellenberger TE, Beverley SM.

Department of Biological Chemistry and Molecular Pharmacolgy, Harvard Medical School, Boston, Masschusetts 02115.

Amplification of the H region has been previously observed in methotrexate (MTX)-resistant strains of Leishmania major and in unselected laboratory stocks of L. tarentolae. We now show that selection of L. major with the structurally unrelated drugs primaquine or terbinafine generated resistant lines exhibiting H region amplification and 23- and 12-fold cross-resistance to MTX, respectively. These and other drug-resistant lines bearing H region amplification also exhibited weak cross-resistance to primaquine and terbinafine, associating the amplified H region with pleiotropic resistance to MTX and other drugs. In contrast, lines selected for chloroquine or pentamidine resistance did not show H region amplification or this pattern of drug cross-resistance. The primaquine- and terbinafine-selected lines exhibited wild-type levels of dihydrofolate reductase-thymidylate synthase and normal uptake and accumulation of MTX, and the MTX resistance of these lines was not reversed by verapamil. These data suggest that the mechanism of MTX cross-resistance associated with H region amplification is novel and distinct from that mediated by overexpression of MDR genes in multidrug-resistant mammalian cells. Structural studies indicated that the amplified H region DNA in these L. major lines was largely (possibly exclusively) extra-chromosomal and consisted of circular inverted repeats joined at two DNA rearrangement junctions. Southern blot analyses showed that these rearrangement junctions were identical in four independent cell lines, suggesting that these sites are "hotspots" for DNA rearrangement. H region amplification in all of these lines was conservative, defined as retention of the chromosomal H region locus without structural alteration or reduction in copy number. This finding is consistent with an over-replication/recombination model for amplification of the H region.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2768255&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Comparative effects of two antimycotic agents, ketoconazole and terbinafine on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes in vitro.

Back DJ, Stevenson P, Tjia JF.

Department of Pharmacology and Therapeutics, University of Liverpool.

Two antimycotic agents, the azole ketoconazole and the allylamine terbinafine, have been examined for their effects on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes (n = 4) in vitro. Ketoconazole caused marked inhibition of all enzyme activities with mean IC50 values (concentration producing 50% inhibition) of 17.9 microM (tolbutamide hydroxylase), 1.9 microM (ethinyloestradiol 2-hydroxylase), 2.0 microM (cyclosporin N-demethylase), 2.1 microM (cyclosporin hydroxylase) and 25 microM (ethoxycoumarin O-deethylase). At 50 microM terbinafine concentration, inhibition was less than 5% for tolbutamide and ethoxycoumarin, approximately 12% for both cyclosporin pathways and 35% for ethinyloestradiol. Terbinafine does not have the same inhibitory potential for cytochrome P-450 isozymes as ketoconazole.

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terbinafine, Lamisil
Effects of bifonazole, fluconazole, itraconazole, and terbinafine on the chemiluminescence response of immune cells.

Abruzzo GK, Fromtling RA, Turnbull TA, Giltinan DM.

The luminol-enhanced chemiluminescence (CL) assay was used to examine the effects of antifungal agents tested at concentrations above and below therapeutically achievable levels on the CL response of mouse spleen cells. Reduction in the CL response of phagocytic cells may be indicative of an inhibition of the cellular immune response. Concomitantly, an increase in the CL response of phagocytic cells may indicate an enhancement of the immune capacity of these cells. The effects of four antifungal agents, bifonazole, fluconazole (UK-49,858), itraconazole, and terbinafine were studied. Changes in the CL response were assessed in terms of peak intensity, time to peak intensity, and area under the intensity-time curve compared with appropriate diluent controls for each drug. Both bifonazole and itraconazole caused significant reduction in peak CL intensity only at the highest level assayed (20 mg/l). Fluconazole had no significant effect on the CL response of mouse spleen cells at levels up to 20 mg/l, inclusive. Although terbinafine had no significant effect on peak CL intensity, it did cause a significant decrease in time to peak response at levels above 5 mg/l. This decrease in time to peak response may be indicative of an enhancement in the immune capacity of the mouse spleen cells; the clinical significance of this observation remains to be determined.

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terbinafine, Lamisil
A new bioassay for terbinafine.

Hauser M, Schmitt HJ, Bernard EM, Armstrong D.

Infectious Diseases Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.

A simple, sensitive and specific agar diffusion bioassay for the antifungal agent terbinafine is described. Using a strain of Aspergillus flavus as the test organism, terbinafine at concentrations ranging from 0.2 microgram/ml to 6.4 micrograms/ml could be measured in serum.

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terbinafine, Lamisil
[In vitro sensitivity of Aspergillus to terbinafine: comparative study on amphotericin B, 5-fluorocytosine and ketoconazole]

[Article in French]

Goudard M, Regli P, Buffard Y, Gabriel B.

Laboratoire de Botanique et Cryptogamie, Faculte de Pharmacie, Marseille, France.

Terbinafine, a new antifungal agent derived from allylamine, effective by oral route, was tested against 32 different strains of Aspergilli to determine its in vitro efficiency compared with amphotericin B, 5-fluorocytosine and ketoconazole. Antifungal sensitivity was determine by the MIC method in liquid and solid mediums (Sabouraud, Casitone, YMA, YMB, YNB): with MIC between 0.005 and 5 micrograms/ml, whatever the species and the techniques, terbinafine is more efficient than amphotericin B, ketoconazole (0.5 to 100 micrograms/ml) and 5-FC (1-greater than 100 micrograms/ml).

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terbinafine, Lamisil
Activity of terbinafine in experimental fungal infections of laboratory animals.

Petranyi G, Meingassner JG, Mieth H.

Sandoz Forschungsinstitut, Vienna, Austria.

The allylamine derivative terbinafine is the first antifungal agent with primary fungicidal properties against dermatophytes which acts systemically after oral application as well as locally after topical application. Comparative oral studies carried out with griseofulvin and ketoconazole in model infections such as guinea pig trichophytosis and microsporosis revealed terbinafine to be superior to the reference compounds both clinically and mycologically. An excellent antimycotic activity of terbinafine was also demonstrable after topical treatment of guinea pig dermatophytoses caused by Trichophyton mentagrophytes or Microsporum canis. Results of comparative chemotherapeutic studies carried out with econazole and tolnaftate demonstrated superior efficacy of terbinafine in the treatment of both trichophytosis and microsporosis. Skin infections of guinea pigs caused by Candida albicans and vaginal candidiasis in rats proved to be responsive to a topical application of terbinafine also. However, the reference compounds, clotrimazole and miconazole, exhibited activity superior to that of terbinafine in both models.

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terbinafine, Lamisil
[In vitro spectrum of action of a new antifungal derivative of naftifin: terbinafin (SF 86-327)]

[Article in French]

Goudard M, Buffard Y, Ferrari H, Regli P.

Terbinafine (SF 86-327) is a new antifungal agent derived from naftifine and effective by the oral route. We studied the in vitro antifungal activity of terbinafine (SF 86-327) against several pathogenic fungi responsible for human disease. Tested pathogens included yeasts (Candida), dermatophytes (Microsporum, Trichophyton, Epidermophyton), molds (Aspergillus, Scopulariopsis) and dimorphic fungi (Sporothrix schenkii). Broth dilution (Sabouraud) or agar dilution (Sabouraud, Kimmig) were used. 322 strains of pathogenic fungi belonging to 23 different species were tested. The yeasts showed varying degrees of susceptibility (MICs ranging from 10 to 100 micrograms/ml) except for Candida parapsilosis (MICs 1 to 2 micrograms/ml). Strong susceptibility was found for molds (MICs 0.1 to 2 micrograms/ml), especially Scopulariopsis brevicaulis and Sporothrix schenkii (MICs 0.2 microgram/ml). Dermatophytes were also highly susceptible to terbinafine (MICs 0.001 to 0.02 microgram/ml).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3534767&dopt=Abstract terbinafine Lamisil