terbinafine, Lamisil
Activity of terbinafine against Pneumocystis carinii in vitro and its efficacy in the treatment of experimental pneumonia.

Contini C, Manganaro M, Romani R, Tzantzoglou S, Poggesi I, Vullo V, Delia S, De Simone C.

Institute of Infectious and Respiratory Diseases, University of Ferrara, Italy.

The antiprotozoan and antifungal agent, the terbinafine, was investigated for its potential activity against Pneumocystis carinii infection of the A549 cell line culture and on immunosuppressed Sprague Dawley rats in comparison with trimethoprim-sulphamethoxazole and pentamidine isethionate. Terbinafine suppressed P. carinii growth at doses up to 3 g/L within 24 h and it was able to inhibit cyst forms at 60 h post inoculation. With respect to trimethoprim-sulphamethoxazole and pentamidine isethionate P. carinii organisms decreased at the same time interval but cyst form elimination was less apparent than with terbinafine. The results of the in-vitro culture were consistent with the in-vivo observations. Of the 3 groups of rats tested, the occurrence of P. carinii pneumonia was documented in 18 (60%) of the control rats (group 3) which showed a high degree of P. carinii burden and a marked weight loss with respect to the beginning of the experiment. Among terbinafine treated rats (group 1), P. carinii pneumonia was present in one rat (3.3%), while no P. carinii infection occurred in the pentamidine isethionate and in trimethoprim-sulphamethoxazole treatment rat groups (group 2). All the agents investigated showed no particular signs of toxicity. These preliminary results suggest further explorations of the terbinafine in clinical trials for treatment and prophylaxis of P. carinii pneumonia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7706168&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Determination of terbinafine and its desmethyl metabolite in human plasma by high-performance liquid chromatography.

Denouel J, Keller HP, Schaub P, Delaborde C, Humbert H.

Department of Human Pharmacology, Laboratories Sandoz, Rueil-Malmaison, France.

A reliable reversed-phase high-performance liquid chromatographic method has been developed for the determination of terbinafine (Terb) and its desmethyl metabolite (DMT) in human plasma. The analytes and the internal standard (I.S.) are extracted by a liquid-liquid technique followed by an aqueous back-extraction, allowing injection of an aqueous solvent in the HPLC system. The mobile phase is acetonitrile + 0.012 M triethylamine -0.020 M orthophosphoric acid (50:50, v/v) and the UV detection is at 224 nm. The inter-assay precision over the concentration range 2-1000 ng/ml is between 2.9 and 9.8% for both compounds. The limit of quantification, 2 ng/ml for both compounds, is sufficient for investigating the pharmacokinetics of Lamisil in human studies. With an additional preparation step, this method can be used for assaying Terb in tissues such as nail, sebum and stratum corneum.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7735483&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Synthesis and structure-activity relationships of side-chain-substituted analogs of the allylamine antimycotic terbinafine lacking the central amino function.

Nussbaumer P, Leitner I, Mraz K, Stutz A.

Department of General Dermatology, SANDOZ Research Institute, Vienna, Austria.

Terbinafine is a therapeutically used inhibitor of fungal squalene epoxidase that has prompted extensive derivatization programs for structure-activity relationship studies. In the present study, derivatives of terbinafine were synthesized that lack the central tertiary amino group but have polar substitutents at the tert-butyl residue of the side chain. Evaluation of the antifungal potential revealed that representatives of this novel structural type can also exhibit broad antifungal activity, indicating that the central amino function of allylamine antimycotics is not essential for inhibition of fungal growth. Potency appears to correlate with the polarity of the introduced functional groups, while broad antifungal activity seems to be restricted to compounds with basic substituents. The dimethylamino-substituted "carba-analog" of terbinafine (8k) showed the best antimycotic profile within the whole series.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7752208&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Molecular cloning and expression of rat squalene epoxidase.

Sakakibara J, Watanabe R, Kanai Y, Ono T.

Department of Biochemistry, Niigata University School of Medicine, Japan.

Squalene epoxidase (SE) (EC 1.14.99.7) catalyzes the first oxygenation step in sterol biosynthesis and is suggested to be one of the rate-limiting enzymes in this pathway. Rat SE cDNA was isolated by selecting yeast transformants expressing rat cDNA in the presence of transformants expressing rat cDNA in the presence of terbinafine, an inhibitor specific for fungal SE. The expression of rat SE in the isolated terbinafine-resistant clone was confirmed by its survival in the presence of either terbinafine or an inhibitor specific for mammalian SE, NB-598, but not in the presence of both terbinafine and NB-598. Rat SE polypeptide deduced from the nucleotide sequence contains 573 amino acids, and its molecular weight is 63,950 Da. The amino acid sequence reveals one potential transmembrane domain, a hydrophobic segment (Leu27 to Tyr43) in the NH2-terminal region. This region also contains a beta 1-alpha A-beta 2 motif, which is the consensus sequence for an FAD binding domain, suggesting that SE is a flavoenzyme. This deduced rat SE sequence is 30.2% identical to the ERG 1 gene, which encodes SE from an allylamine-resistant Saccharomyces cerevisiae mutant. Expression of a full-length rat SE protein in Escherichia coli confirms this polypeptide as a functional SE. This is the first report of the molecular cloning of mammalian SE.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7814369&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Effects of naftifine and terbinafine, two allylamine antifungal drugs, on selected functions of human polymorphonuclear leukocytes.

Vago T, Baldi G, Colombo D, Barbareschi M, Norbiato G, Dallegri F, Bevilacqua M.

Servizio di Endocrinologia, Ospedale L. Sacco (Vialba), Milan, Italy.

Many antimycotic agents negatively affect the natural immune response. Typically, these drugs impair polymorphonuclear leukocyte (PMN) production of superoxide anion, chemotaxis, or the killing of pathogens. Allylamines are a new class of antimycotic compounds with a new mechanism of antifungal action, i.e., inhibition of the fungal squalene epoxidase. The trial that we describe aimed to evaluate the effects of two allylamines, terbinafine and naftifine, on selected functions of PMNs, i.e., superoxide anion production, chemotaxis, and killing of Candida albicans blastospores. Terbinafine and naftifine on their own did not affect superoxide anion production when they were added to PMNs. When PMNs were preincubated with allylamines and were then stimulated by N-formyl-Met-Leu-Phe or phorbol 12-myristate 13-acetate, superoxide anion production was increased (priming effect). Since intracellular free calcium (Ca2+i) is involved in the control of superoxide anion production, we evaluated the effects of the allylamines on the Ca2+i concentration ([Ca2+]i). In the presence of terbinafine or naftifine, the [Ca2+]i increased in a dose-dependent manner; the source of Ca2+i was not extracellular since it was not affected by extracellular calcium chelation with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. In the presence of terbinafine or naftifine, chemotaxis of PMNs was not impaired. Terbinafine and naftifine slightly but significantly increased the killing of C. albicans blastospores (P < 0.05 at 10 and 100 microM). In conclusion, in contrast to imidazole-like drugs, the allylamine antimycotic compounds terbinafine and naftifine enhance selected functions of PMNs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7872755&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Levels of terbinafine in plasma, stratum corneum, dermis-epidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once per day for four weeks.

Faergemann J, Zehender H, Denouel J, Millerioux L.

Department of Dermatology, University of Gothenburg, Sahlgren's Hospital, Sweden.

The distribution of terbinafine in stratum corneum dermis-epidermis (without stratum corneum), sebum, hair, nails and plasma was studied in human male volunteers during and after 250 mg orally once daily for 28 days. The highest concentration was seen in sebum, 56.07 micrograms/g, after 14 days of therapy. The concentration was still 1.0 microgram/g 44 days after stop of medication. In stratum corneum the highest concentration, 14.4 micrograms/g, was seen 1 day after the last day of therapy, and it was 2.1 micrograms/g 44 days after stop of medication. The concentrations in hair and nails were lower with a maximum of 2.36 and 0.39 micrograms/g respectively, 1 day after stop of therapy, and still 0.21 microgram/g in hair and 0.09 microgram/g in nails 55 days after the last day of medication. With the exception of nails, all other tissue levels were at all times above the plasma concentrations. For nails, tissue levels exceeded that of plasma as early as 1 day after stop of medication, and this difference continued to increase until the last day of tissue sampling, 55 days after the last tablet. These results indicate that terbinafine is delivered to the stratum corneum through sebum and to a minor extent by direct diffusion through dermis-epidermis. Probably short-term therapy with terbinafine may be effective in the treatment of several dermatomycoses, due to the strong binding of terbinafine to stratum corneum for a long time after stop of medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7904107&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Terbinafine induces the PMNL priming effect and enhances in vitro PMNL fungicidal activity against Candida albicans blastospores.

Barbareschi M, Vago T, Colombo D, Bevilacqua M.

First Department of Dermatology, University of Milan, Italy.

Terbinafine, a new antifungal drug of the allylamine category, has been shown not to interfere with some polymorphonuclear leucocyte (PMNL) functions such as chemotaxis and chemiluminescence. The aim of the present study was to elucidate the effects of terbinafine on PMNL respiratory burst activation and killing of Candida albicans blastospores by PMNLs at the biochemical and ultrastructural level by means of scanning electron microscopy (SEM). Terbinafine is shown to enhance the respiratory burst and superoxide anion release in human PMNLs stimulated by phorbol esters or chemotactic peptides, and to have a priming effect on PMNL functions. Moreover, in our experiments we found that terbinafine does not interfere with PMNL killing of C. albicans blastospores but, in fact, at the concentration found in tissues after oral administration, slightly increases it. As PMNLs play a key role in the early stages of fungal infections we suggest that in vivo terbinafine induces priming of PMNLs, and that this effect is related to enhanced candidacidal activity independent of direct drug damage to fungal particles.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7935572&dopt=Abstract terbinafine Lamisil