terbinafine, Lamisil
Determination of terbinafine in nail samples during systemic treatment for onychomycoses.

Dykes PJ, Thomas R, Finlay AY.

Department of Medicine (Dermatology), University of Wales College of Medicine, Cardiff, U.K.

A combination of alkali treatment and proteinase K digestion was used to solubilize nail samples from patients with onychomycosis treated orally with terbinafine. The samples were extracted and the levels of terbinafine and its metabolite measured by high-pressure liquid chromatography. The results showed a relatively rapid penetration of terbinafine into normal nail plate, suggesting that diffusion via the nail plate is the primary route of entry into this tissue. The levels of terbinafine achieved in nail samples exceeded the range of MICs for dermatophytes at the earliest time point (4 weeks) tested in 50% of patients and remained stable, without accumulation, during periods of treatment of up to 3 months.

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terbinafine, Lamisil
The successful treatment of finger Trichophyton rubrum onychomycosis with oral terbinafine.

Zaias N, Serrano L.

Eleven patients with distal subungal onychomycosis of the fingers by Trichophyton rubrum infection were treated with daily doses of oral terbinafine, a new allylamine derivative. A 125-mg capsule was given twice daily. Each patient's nailplate was marked appropriately following the Zaias and Drachman method for the determination of antifungal efficacy in onychomycosis. Patients were monitored monthly for the antifungal effect of the drug, as well as side-effects, including laboratory values for liver and kidney function tests and a full blood count. At the end of 6 months, all 11 patients were clinically and mycologically normal. It can be concluded that 250 mg (125 mg b.i.d.) oral terbinafine is the most appropriate drug for the treatment of finger onychomycosis. No side-effects of any kind were noted in this 6-month period. Onychomycosis is a common disease of the toenails. No topical treatments have yet been found to be satisfactory. In a very motivated patient-doctor relationship, the use of topically applied thiabendazole has proved effective, particularly after nailplate avulsion. Systemic antifungal treatment is possible with griseofulvin and ketoconazole. Griseofulvin may cause enzyme induction in the liver, which requires a higher dose intake to achieve results. This has been demonstrated using the Zaias and Drachman method of judging successful antifungal clinical effects in onychomycosis. Ketoconazole is a very effective drug which must be carefully monitored. Its difficulties are with liver function, anti-androgenic dysfunction in males, and adrenal dysfunction. There is a great need for an effective and safe oral systemic drug. Terbinafine is an allylamine derivative which is highly antifungal.(ABSTRACT TRUNCATED AT 250 WORDS)

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terbinafine, Lamisil
Terbinafine inhibits the mitogenic response to platelet-derived growth factor in vitro and neointimal proliferation in vivo.

Nemecek GM, St Denny IH, Van Valen RG, McCarthy LA, Handley DA, Stutz A.

Sandoz Research Institute, East Hanover, New Jersey.

Terbinafine [(E)-N(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthale nemethanamine], an antimycotic agent that inhibits fungal squalene epoxidase activity, was examined for its effects on platelet-derived growth factor (PDGF)-stimulated aortic smooth muscle cell DNA synthesis in vitro and neointimal proliferation in vivo. Exposure of bovine aortic smooth muscle cells to 0.25 to 25 microM terbinafine resulted in a concentration-dependent inhibition of PDGF-induced mitogenesis as determined by [3H]thymidine incorporation into DNA or cell number. The IC50 for inhibition of PDGF-stimulated smooth muscle cell DNA synthesis was approximately 5 microM. Micromolar concentrations of terbinafine also suppressed the mitogenic response to PDGF in fibroblasts. Neither the binding of [125I]PDGF to its plasma membrane receptors nor the uptake of [3H]thymidine or [3H]uridine was affected significantly by terbinafine. Oral administration of terbinafine (200 mg/kg/day) to rats for 2 days before and 14 days after balloon catheter injury to the carotid artery was associated with a 40% decrease in the area of the neointimal lesion. These observations indicate that terbinafine is both a potent in vitro antagonist of the smooth muscle cell mitogenic response to PDGF and an effective, well-tolerated p.o. active inhibitor of neointimal proliferation in vivo.

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terbinafine, Lamisil
Influence of plasma protein binding on the brain uptake of an antifungal agent, terbinafine, in rats.

Machard B, Misslin P, Lemaire M.

Biopharmaceutical Department, Sandoz Ltd., Basle, Switzerland.

The intracarotid injection technique has been used to determine the unidirectional brain uptake of an antifungal, lipophilic agent, terbinafine (Lamisil, Sandoz Basle), in the rat. Ultrafiltration showed it to be highly bound to human plasma, human serum albumin (HSA), alpha 1-acid glycoprotein (AAG) and lipoproteins (VLDL, LDL, HDL). The effect of plasma protein binding of the drug on brain uptake was also examined with the technique. The lowest brain uptake was observed in the presence of plasma (6%); it varied from 23 to 30% with physiological concentrations of VLDL, LDL and HSA and was significantly higher (43-45%) in the presence of physiological concentrations of AAG and HDL. The free fraction as determined in-vitro and the brain uptake of the drug varied inversely with the plasma protein concentrations; however, the brain uptake was higher than expected from in-vitro measurements. These data indicate that the amount of circulating Lamisil available for brain penetration exceeds its free fraction; they also show that plasma proteins differently reduce the brain transport of the drug.

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terbinafine, Lamisil
Antipyrine metabolism is not affected by terbinafine, a new antifungal agent.

Seyffer R, Eichelbaum M, Jensen JC, Klotz U.

Dr. Margarete-Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Federal Republic of Germany.

The potential to inhibit drug metabolism of the new antifungal agent terbinafine has been studied using antipyrine (single oral dose of 10 mg/kg) as a probe drug. In a cross-over study in 8 healthy volunteers, antipyrine was administered prior to, during and after 8 days of oral terbinafine 125 mg b.d. Antipyrine, its major metabolites 4-hydroxyantipyrine (4-OH-AP), 3-hydroxymethylantipyrine (3-OH-CH3-AP) and norantipyrine (Nor-AP) were analyzed by specific HPLC assays in multiple plasma and urine samples. During all three parts of the study, the pharmacokinetics of antipyrine viz. t1/2 (11.7 h), total plasma (38.5 ml.h-1.kg-1) and renal clearance (1.6 ml.h-1.kg-1), and its clearance rates to metabolites (CLM), eg. CLM for 4-OH-AP (12.3 ml.h-1.kg-1), CLM for 3-OH-CH3-AP (4.2 ml.h-1.kg-1) and CLM for Nor-AP (6.7 ml.h-1.kg-1) did not differ from the control values. Thus, all the cytochrome P-450-dependent isozymes involved in the metabolism of antipyrine and many other drugs should not be affected by therapeutic doses of terbinafine.

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terbinafine, Lamisil
Effect of ketoconazole and terbinafine on the pharmacokinetics of caffeine in healthy volunteers.

Wahllander A, Paumgartner G.

Department of Medicine II, University of Munich, Federal Republic of Germany.

The effects of single oral doses of ketoconazole 400 mg and terbinafine 500 mg on the hepatic microsomal system have been investigated in 8 healthy male volunteers. Microsomal activity caffeine was assessed by following the metabolism of 3 mg/kg bodyweight i.v. administered 1 h after the drug. The inhibitory effect of terbinafine was more pronounced than that of ketoconazole: clearance was decreased from 1.34 ml.kg-1.min-1 in controls to 1.06 and 1.21 ml.kg-1.min-1, respectively, and the corresponding half-life was increased from 5.8 h in controls to 7.6 and 6.7 h, respectively. The apparent volume of distribution remained unchanged. The serum levels of the antimycotics were within the therapeutic range in each subject. Although all three substances are metabolised by microsomes, the kinetic parameters (Cmax, half-life, elimination constant) of the antimycotics were poorly if at all correlated with the elimination of caffeine.

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terbinafine, Lamisil
Analytical methods for the determination of terbinafine and its metabolites in human plasma, milk and urine.

Schatz F, Haberl H.

Sandoz Forschungsinstitut, Vienna, Austria.

Analytical procedures have been developed for the determination of the allylamine antimycotic terbinafine (1) and its demethylderivate (2) in plasma, milk and urine, and the metabolite carboxy-terbinafine (3) in plasma and urine, as well as the further metabolites demethyl-carboxy-terbinafine (4) and naphthoic acid (5) in urine. HPLC-methods for plasma analysis employed either electrochemical detection (for 1 and 2) or UV-detection (for 3) following a protein precipitation step with methanol or sample extraction with hexane as appropriate. For quantitative urine analysis of substances 1-4 native urine samples were deconjugated, mixed with internal standard and injected by an autosampler into a microprocessor controlled HPLC-system. The substances were monitored by UV-absorption. The metabolite 5 was determined in urine after deconjugation, sample preparation with commercially available cartridges and silylation by automatized GC with fused silica capillary column and FID-detection. The standard calibration curves for the parent compound (1) and metabolites (2-5) are linear within the required analytical ranges. The detection limit for 1 and 2 is 50 ng/ml in plasma and 150 ng/ml in milk and for 3 in plasma 100 ng/ml. The detection limit in urine is 300 ng/ml for all substances (1-4) analyzed by HPLC and 50 ng/ml for 5 analyzed by GC.

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