terbinafine, Lamisil
Scavenging effects of terbinafine on free radicals in vitro.

Camera E, Cannistraci C, Briganti S, Colombo D, Picardo M.

Laboratory of Cutaneous Physiopathology, San Gallicano Dermatological Institute, Via San Gallicano 25/A, I-00153 Rome Italy.

One of the goals of antifungal therapy is to combine an anti-inflammatory activity with antimycotic properties, and therefore it is interesting to evaluate the capacity of active antifungal drugs to interfere with different phases of the inflammatory reaction. In order to identify a possible scavenger property of free radical species of the antifungal agent terbinafine, we studied its activity on the reduction of nitrotetrazolium blue chloride (NTB), induced by superoxide anions with the ultraviolet (UV)- and chemical-induced peroxidation of unsaturated lipid targets. NTB reduction was followed by spectrophotometer and the decomposition of squalene or methyl arachidonate by gas chromatography-mass spectrometry. Terbinafine (20 microgram and over) was capable of significantly inhibiting NTB reduction, indicating that the drug scavenges superoxide anion radicals. In these conditions no modifications of the concentration of the drug, as evaluated by high performance liquid chromatography, were observed. The UV- or chemically induced peroxidation of squalene and arachidonic acid was significantly reduced in the presence of 50 microgram of terbinafine, suggesting that the substance interferes with the chemical properties of peroxyl radicals. In all the tests used the degree of inhibition was proportional to the amount of free radicals generated. In conclusion our results indicate that terbinafine, at therapeutic concentrations, can be considered to be a free radical interceptor in vitro and could exert a mild anti-inflammatory activity in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10233313&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
[Etiopathogenesis and therapy of dermatophytosis of the nails]

[Article in Slovak]

Buchvald J.

Dermatovenerologicka klinika LF UK a FN, Bratislava.

The importance of mycotic infections of the skin and its adnexa has a rising trend. The causal agents are not only dermatophytes and candidae but to an increasing extent opportune fungal microorganisms. Most frequently these diseases develop during intense immunosuppressive treatment, e.g. in oncological, oncohaematological diseases and in developed AIDS syndrome. In addition to the reduced defence capacities of the organism favourable conditions are created e.g. by antibiotic treatment, treatment with female hormones, unsuitable clothing, obesity, a certain part is played also by occupational predisposition. Treatment of onychomycoses is complicated and difficult. Before griseofulvin was available there was only surgical ablation and treatment with keratolytics. At present a number of substances with marked fungistatic effects is available. The author mentions: griseofulvin, ketoconazole, fluconazole, itraconazole (azole derivatives), allylamines (terbinafine-Lamisil). He discusses the mode of administration, dosage and undesirable effects. The recent antimycotics are ciclopiroxolamines (Batrafen) and amorolfin (Loceryl) in the form of lac.

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terbinafine, Lamisil
Potent inhibition of cytochrome P-450 2D6-mediated dextromethorphan O-demethylation by terbinafine.

Abdel-Rahman SM, Marcucci K, Boge T, Gotschall RR, Kearns GL, Leeder JS.

Section of Pediatric Clinical Pharmacology and Experimental Therapeutics, The Children's Mercy Hospital, Kansas City, Missouri 64108, USA. srahman cmh.edu

Cytochrome P-450 (CYP) 2D6 is responsible for the biotransformation of over 35 pharmacologic agents. In the process of studying CYP2D6 we identified phenotype-genotype discordance in two individuals receiving terbinafine. This prompted evaluation of the potential for terbinafine to inhibit CYP2D6 in vitro. Human hepatic microsomes and heterologously expressed CYP2D6 were incubated with terbinafine or quinidine and the formation of dextrorphan from dextromethorphan was determined by HPLC. Additionally, preliminary conformational analyses were conducted to determine the fit of terbinafine into a previously described pharmacophore model for CYP2D6 inhibitors. The apparent Km and Vmax of dextrorphan formation from four human hepatic microsome samples ranged from 5.8 to 6.8 microM and from 172 to 300 pmol/min/mg protein, respectively. Values of Km and Vmax in the heterologously expressed CYP2D6 system averaged 6.5 +/- 2.1 microM and 1342 +/- 147 pmol/min/mg protein, respectively. Terbinafine inhibited dextromethorphan O-demethylation with an apparent Ki ranging from 28 to 44 nM in human hepatic microsomes and averaging 22.4 +/- 0.6 nM for the heterologously expressed enzymes. Results of quinidine in these systems produced values for Ki ranging from 18 to 43 nM. Such strong inhibition of CYP2D6 by terbinafine would not have been predicted by the previously proposed pharmacophore model of CYP2D6 inhibitors based on molecular structure. Terbinafine is a potent inhibitor of CYP2D6 with apparent Ki values well below plasma and tissue concentrations typically achieved during a therapeutic course. This agent needs to be evaluated in vivo to determine the impact of CYP2D6 inhibition by terbinafine on the metabolism of concomitantly administered CYP2D6 substrates.

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terbinafine, Lamisil
Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions.

Vickers AE, Sinclair JR, Zollinger M, Heitz F, Glanzel U, Johanson L, Fischer V.

Drug Metabolism and Pharmacokinetics, Novartis Institute for Biomedical Research, East Hanover, New Jersey 07936, USA.

Biotransformation pathways and the potential for drug-drug interactions of the orally active antifungal terbinafine were characterized using human liver microsomes and recombinant human cytochrome P-450s (CYPs). The terbinafine metabolites represented four major pathways: 1) N-demethylation, 2) deamination, 3) alkyl side chain oxidation, and 4) dihydrodiol formation. Michaelis-Menten kinetics for the pathways revealed mean K(m) values ranging from 4.4 to 27.8 microM, and V(max) values of 9.8 to 82 nmol/h/mg protein. At least seven CYP enzymes are involved in terbinafine metabolism. Recombinant human CYPs predict that CYP2C9, CYP1A2, and CYP3A4 are the most important for total metabolism. N-demethylation is primarily mediated by CYP2C9, CYP2C8, and CYP1A2; dihydrodiol formation by CYP2C9 and CYP1A2; deamination by CYP3A4; and side chain oxidation equally by CYP1A2, CYP2C8, CYP2C9, and CYP2C19. Additionally, characteristic CYP substrates inhibited pathways of terbinafine metabolite formation, confirming the involvement of multiple enzymes. The deamination pathway was mainly inhibited by CYP3A inhibitors, including troleandomycin and azole antifungals. Dihydrodiol formation was inhibited by the CYP1A2 inhibitor furafylline. Terbinafine had little or no effect on the metabolism of many characteristic CYP substrates. Terbinafine, however, is a competitive inhibitor of the CYP2D6 reaction, dextromethorphan O-demethylation (K(i) = 0.03 microM). In summary, terbinafine is metabolized by at least seven CYPs. The potential for terbinafine interaction with other drugs is predicted to be insignificant with the exception that it may inhibit the metabolism of CYP2D6 substrates. Clinical trials are needed to assess the relevance of these findings.

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terbinafine, Lamisil
Safety of itraconazole pulse therapy for onychomycosis. An update.

De Doncker P, Gupta AK, Cel Rosso JQ, Daniel CR 3rd, Rosen T, Verspeelt J, Marynissen G, Meuleneers L, Moskovitz B, Jacko M, Shear N, Odom RB, Aly R, Scher RK, Elewski BE.

Department of Clinical Research, Janssen Research Foundation, Beerse, Belgium.

After experience with more than 34 million patients over 10 years, the safety of itraconazole and its potential drug-drug interactions are well known. In clinical trials, the average incidence of adverse events with a 1-week pulse regimen was 18% in pooled safety data (n = 2,867); only 2.2% of patients dropped out. In direct comparative trials, the incidence of mild and reversible adverse effects was comparable for itraconazole and terbinafine (31% and 28%, respectively) during treatment. The rate of permanent withdrawal because of adverse events was 3.6% for itraconazole and 7.5% for terbinafine (P < .05). Itraconazole was significantly better tolerated as evaluated by the investigator and patients. The analysis of the elderly subpopulation showed that patients 65 and older tolerated itraconazole pulse well, with only 20% experiencing mild and reversible side effects (total group). In direct comparative trials, itraconazole also produced fewer adverse effects than terbinafine (13% vs 32%, respectively). As newer oral antifungal agents gain widespread use, clinicians need to be aware of their potential drug-drug interactions and their possibly serious adverse events. However, pooled data from the 1-week itraconazole pulse regimen indicated a favorable safety profile, and a dose increase to 400 mg had no impact on safety.

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terbinafine, Lamisil
Effectiveness of treatment of severe tinea pedis with 1% terbinafine cream in members of the Japanese self-defense forces.

Noguchi H, Hiruma M, Kawada A.

Department of Dermatology, Kumamoto University School of Medicine, Tokyo.

A clinical study was conducted to determine the efficacy of terbinafine cream in severe cases of tinea pedis. The subjects were 21 men, members of the Japanese Self-Defense Forces who were judged to have severe symptoms of tinea pedis. The description 'severe' was defined as 'considered to require the concurrent internal administration of antifungals for complete cure', or as meeting criterion 5 or 6 for the severity of tinea pedis. A simple surface application of terbinafine cream was given once daily, the subjects' clinical manifestations, mycological cure rates and safety-related changes were observed, and a final assessment was made in the 12th week. In the final assessment, the improvement rate of the cutaneous symptoms was 95.2%, and the fungal eradication and efficacy rates were 81.0%. As for side-effects, one patient complained of local irritation. These results suggested that terbinafine cream is a beneficial topical antifungal cream for severe tinea pedis.

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terbinafine, Lamisil
A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs.

Garcia Rodriguez LA, Duque A, Castellsague J, Perez-Gutthann S, Stricker BH.

Centro Espanol de Investigacion Farmacoepidemiologica (CEIFE), Madrid, Spain.

AIMS: The aim of this cohort study was to estimate the risk of clinical acute liver injury among users of oral antifungals identified in the general population of the General Practice Research Database in UK. METHODS: The cohort included 69 830 patients, 20-79 years old, free of liver and systemic disease, who had received at least one prescription for either oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine between 1991 and 1996. RESULTS: Sixteen cases of acute liver injury were identified and validated. Ten cases occurred during nonuse of oral antifungals with a background rate of 0.6 per 100,000 person-months (95% confidence interval 0.3,1.1). Five cases occurred during current use of oral antifungals. Two were using ketoconazole, another two itraconazole, and one terbinafine. Incidence rates of acute liver injury were 134.1 per 100 000 person-months (36.8,488.0) for ketoconazole, 10.4 (2.9-38.1) for itraconazole, and 2.5 (0.4,13. 9) for terbinafine. The remaining case was associated with past use of fluconazole. Ketoconazole was the antifungal associated with the highest relative risk, 228.0 (95% confidence interval 33.9,933.0), when compared with the risk among nonusers, followed by itraconazole and terbinafine with relative risks of 17.7 (2.6,72.6) and 4.2 (0.2, 24.9), respectively. CONCLUSIONS: Ketoconazole and itraconazole were the two oral antifungal associated with a marked increase of clinical acute liver injury. The risk associated with ketoconazole should be taken into account when prescribing it as initial treatment for uncomplicated fungal infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10594489&dopt=Abstract terbinafine Lamisil