terbinafine, Lamisil
A retrospective cost-effectiveness analysis of the treatment of onychomycosis in general practice.

Humphrey KM, Cork MJ, Haycox A.

Abacus International, 3-4 Market Square, Bicester, Oxon OX6 7AA, U.K.

Analysis of the computer records of 100 general practices from the CompuFile Doctors Independent Network revealed 1492 patients receiving treatment for onychomycosis in the first 6 months of 1994 with terbinafine, tioconazole, amorolfine or griseofulvin. These records indicated the average treatment time for each agent, number of general practitioner consultations and incidence of hospital referrals and minor surgery. Applying standard costs to this resource consumption gave the direct costs for each of these four agents. Published clinical and mycological cure rates allowed a cost per success to be calculated. These were as follows: terbinafine (n = 511) pound258, amorolfine (n = 315) pound312, griseofulvin (n = 196) pound356 and tioconazole (n = 470) pound520. Sensitivity analysis showed that terbinafine remained the most cost-effective option despite variations in resource costs. The cost impact on a typical practice for switching from a less to a more cost-effective treatment is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9892910&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Immunohistochemical study of type I collagen turn-over and of matrix metalloproteinases in chromoblastomycosis before and after treatment by terbinafine.

Esterre P, Risteli L, Ricard-Blum S.

Parasitology Unit, Institut Pasteur de Madagascar, Antananarivo, Madagascar.

The distribution of type I collagen, the major component of human dermis, was characterized by immunohistochemistry in skin lesions of chromoblastomycosis, a chronic cutaneous mycosis, before and after a specific antifungal treatment with terbinafine to study the changes induced in the lesions by the treatment. Newly synthesized type I collagen was studied with an antibody directed against the aminoterminal propeptide of the molecule (PINP), whereas mature, cross-linked type I collagen was detected with an antibody against the carboxyterminal telopeptide of type I collagen (ICTP). The isopeptide N epsilon gamma-glutamyl lysine (N epsilon gamma GL), synthesized by transglutaminase and able to cross-link several components of the extracellular matrix, has also been investigated with two monoclonal antibodies to determine if it is involved in the stabilisation of the fibrotic cutaneous lesions. The degradative process involved in the remodelling has also been assessed by immunohistochemistry with anti-metalloproteinase (MMP-1 and MMP-9) and anti-tissue inhibitor (TIMP-1) antibodies. All tissue macrophages stained for CD68 and MMP-9, but not for MMP-1, while the polymorphonuclear neutrophils had an elastase and a weak MMP-9 phenotype. The fibroblasts of fibrotic areas stained constantly for N epsilon gamma GL and PINP. The immunostaining of extracellular matrix for ICTP and N epsilon gamma GL, and the number of PINP-positive fibroblasts, decreased significantly after one year of antifungal treatment. Terbinafine treatment decreases the synthesis of type I collagen and leads to a partial reversal of the cutaneous fibrotic lesions, independently of the cure of the fungal infection.

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terbinafine, Lamisil
Interaction of terbinafine with human serum and serum proteins.

Ryder NS, Frank I.

Dermatology Department, Sandoz Research Institute, Vienna, Austria.

The allylamine antimycotic terbinafine acts by inhibition of ergosterol biosynthesis at the level of squalene epoxidase. Using this mechanism in Candida parapsilosis cells, a functional assay was developed to investigate the effects of serum and serum proteins on the antifungal action of terbinafine and related drugs in vitro. Inhibition of ergosterol biosynthesis by terbinafine was antagonized by human serum in a dose-dependent non-saturable manner. The results were not affected by varying the period of pre-incubation of serum with the drug or with the fungal cells, or by performing the test in other species of Candida, Aspergillus and Trichophyton. Qualitatively similar effects were observed with the related allylamine compounds naftifine and SDZ 87-469, the extent of antagonism correlating with their lipophilicity. The effect appeared to be caused by non-specific binding of the drug to major serum components, including albumin and the lipoproteins (both LDL and HDL). Reduced bioavailability resulting from binding by serum may at least partly account for the low efficacy of terbinafine in experimental models of systemic infection, in contrast to its high efficacy in infections of the skin, nails and hair.

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terbinafine, Lamisil
Azoles, allylamines and drug metabolism.

Back DJ, Tjia JF, Abel SM.

Department of Pharmacology and Therapeutics, University of Liverpool, UK.

Four antifungal drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine, were studied for their effects on the metabolism of cyclosporin A (CyA) and cortisol by human liver microsomes in vitro (n = 3). Ketoconazole produced marked inhibition of CyA hydroxylase (to metabolites M17 and M1) with IC50 and Ki values of 0.24 +/- 0.01 and 0.022 +/- 0.004 microM, respectively. On the basis of the IC50, itraconazole was 10 times less potent (IC50 of 2.2 +/- 0.2 microM), and fluconazole and terbinafine were each above 100 microM. No kinetic parameters were calculated for terbinafine because of the lack of inhibitory effects. Ketoconazole was the most potent inhibitor of cortisol metabolism (to 6 beta-hydroxycortisol, IC50 = 0.6 microM). Itraconazole produced marked inhibition of cortisol metabolism (IC50 = 2.4 microM), but fluconazole and terbinafine had little effect. These data confirm that ketoconazole is a potent inhibitor of cytochrome P-450-IIIA4, and this has clinical relevance. Although the inhibition with fluconazole was much less than with itraconazole at equimolar concentrations, it should be noted that in-vivo plasma concentrations of fluconazole are much greater than that of itraconazole. Clinical interactions of CyA with both fluconazole and itraconazole have been reported; in contrast to these azoles, terbinafine does not have the same interaction potential.

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terbinafine, Lamisil
Identification of a reactive metabolite of terbinafine: insights into terbinafine-induced hepatotoxicity.

Iverson SL, Uetrecht JP.

Faculties of Pharmacy, University of Toronto, Toronto, Ontario, Canada.

Oral terbinafine treatment for superficial fungal infections of toe and fingernails is associated with a low incidence (1:45000) of hepatobiliary dysfunction. Due to the rare and unpredictable nature of this adverse drug reaction, the mechanism of toxicity has been hypothesized to be either an uncommon immunological or metabolically mediated effect. However, there is little evidence to support either mechanism, and toxic metabolites of terbinafine have not been identified. We incubated terbinafine with both rat and human liver microsomal protein in the presence of GSH and were able to trap an allylic aldehyde, 7,7-dimethylhept-2-ene-4-ynal (TBF-A), which corresponds to the N-dealkylation product of terbinafine. TBF-A was also prepared synthetically and reacted with excess GSH to yield conjugates with HPLC retention times and mass spectra identical to those generated in the microsomal incubations. The major GSH conjugate, characterized by (1)H NMR, corresponds to addition of GSH in a 1,6-Michael fashion. There remains a second electrophilic site on this metabolite, which can bind either to a second molecule of GSH or to cellular proteins via a 1,4-Michael addition mechanism. Moreover, we demonstrated that the formation of the GSH conjugates was reversible. We speculate that this allylic aldehyde metabolite, formed by liver enzymes and conjugated with GSH, would be transported across the canalicular membrane of hepatocytes and concentrated in the bile. The mono-GSH conjugate, which is still reactive, could bind to hepatobiliary proteins and lead to direct toxicity. Alternatively, it could modify canalicular proteins and lead to an immune-mediated reaction causing cholestatic dysfunction.

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terbinafine, Lamisil
Effects of squalene epoxidase inhibitors on Candida albicans.

Georgopapadakou NH, Bertasso A.

Roche Research Center, Nutley, New Jersey 07110.

The relationship between sterol biosynthesis inhibition, membrane integrity, and cell growth inhibition in Candida albicans was examined for five squalene epoxidase inhibitors. The compounds were the thiocarbamates tolnaftate and tolciclate and the allylamines naftifine, terbinafine, and SDZ 87-469. All compounds inhibited sterol biosynthesis, with the concentrations that caused a 50% decrease in the total sterol-to-squalene ratio ranging from less than or equal to 0.01 microM for terbinafine and SDZ 87-469 to 500 microM for tolnaftate. At 100 microM, the compounds also caused up to a 30% release of intracellular [14C]aminoisobutyric acid. With terbinafine and SD2 87-469, aminoisobutyric acid release further increased in cells grown at concentrations that inhibited ergosterol biosynthesis. It is suggested that inhibition of ergosterol synthesis may render the C. albicans membrane susceptible to further damage, including direct damage from squalene epoxidase inhibitors.

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terbinafine, Lamisil
An open clinical pilot study of the efficacy and safety of oral terbinafine in dry non-inflammatory tinea capitis.

Haroon TS, Hussain I, Mahmood A, Nagi AH, Ahmad I, Zahid M.

Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore, Pakistan.

Ten patients with dry non-inflammatory tinea capitis were evaluated in a pilot study which ran from September 1989 to February 1990. Each patient was given oral terbinafine for 6 weeks; each was followed up 2 weeks later. Eight (80%) were completely cured, one (10%) was mycologically cured and showed minimal signs and symptoms, and another (10%) showed improvement (negative mycology, but persistent clinical signs and symptoms). No topical or systemic side-effects were noted. Terbinafine appears to be an effective and safe antifungal agent in the treatment of non-inflammatory tinea capitis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1543673&dopt=Abstract terbinafine Lamisil