British Journal of Dermatology

RYDER, N.S.

doi: 10.1111/j.1365-2133.1992.tb00001.xpmid: 1543672

SummaryTerbinafine (Lamisil®) has primary fungicidal action against many fungi as a result of its specific mechanism of squalene epoxidase inhibition. Treated fungi accumulate squalene while becoming deficient in ergosterol, an essential component of fungal cell membranes. The cidal action is closely associated with the development of high intracellular squalene concentrations, which are believed to interfere with fungal membrane function and cell wall synthesis. In the case of Candida albicans, growth inhibition with terbinafine appears to result from the ergosterol deficiency. The filamentous form of this fungus is more susceptible than the yeast form. Measurement of ergosterol biosynthesis by incorporation of radiolabelled precursors indicates a correlation between inhibition of growth and ergosterol biosynthesis in a range of pathogenic fungi. Terbinafine is a potent non‐competitive inhibitor of squalene epoxidase from Candida (Ki=30nm). In constrast, inhibition of rat liver squalene epoxidase only occurs at higher drug concentrations (Ki=77 μm), and is competitive with squalene. Thus, terbinafine has no effect on cholesterol biosynthesis in vivo. Squalene epoxidase is not an enzyme of the cytochrome P‐450 type, thereby avoiding potential inhibition of this class of enzymes.

KOVARIK, J.M.; KIRKESSELI, S.; HUMBERT, H.; GRASS, P.; KUTZ, K.

doi: 10.1111/j.1365-2133.1992.tb00002.xpmid: 1543677

SummaryThe dose‐dependency of the pharmacokinetic parameters of terbinafine and its N‐demethyl derivative was investigated in a randomized four‐way crossover study in healthy volunteers following single oral administrations of 125, 250, 500 and 750 mg of terbinafine. Plasma concentrations of terbinafine and its metabolite were measured by a validated high‐performance liquid chromatography (HPLC) method using ultraviolet detection. Concentration data were fitted to a two‐compartment model. The relationship between Cmax or the area under the concentration curve (AUC) and the terbinafine dose was analysed by classical linear regression. Terbinafine disposition parameters were dose‐independent, with the exception of Tmax and t1/2x, which were prolonged with the 500‐ and 750‐mg doses. The terbinafine Cmax and AUC, however, were linear and dose‐proportional over the entire dose range. The N‐demethylated metabolite appeared in plasma at the same time as terbinafine and showed similar prolongations in Tmax and t1/2x with the 500‐ and 750‐mg doses. In addition, the Cmax deviated from proportionality at these doses, giving values 22% lower than projected, while the AUC was linear and dose‐proportional over the whole range of doses. The slight disproportionality in the dispositions of terbinafine and its N‐demethyl metabolite at 500 and 750 mg are not expected to be clinically significant.

BACK, D.J.; TJIA, J.F.; ABEL, S.M.

doi: 10.1111/j.1365-2133.1992.tb00003.xpmid: 1311943

SummaryFour antifungal drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine, were studied for their effects on the metabolism of cyclosporine 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 μm, respectively. On the basis of the IC50, itraconazole was 10 times less potent (IC50 of 2.2±0.2μm), and fluconazole and terbinafine were each above 100 μm. No kinetic parameters were calculated for terbinafine because of the lack of inhibitory effects. Ketoconazole was the most potent inhibitor of cortisol metabolism (to 6β‐hydroxycortisol, IC50=0.6 μm). Itraconazole produced marked inhibition of cortisol metabolism (IC50=2.4 μm), 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 intraconazole have been reported; in contrast to these azoles, terbinafine does not have the same interaction potential.

BRECKENDRIDGE, A.

doi: 10.1111/j.1365-2133.1992.tb00004.xpmid: 1311944

SummaryAntifungal drugs act by a variety of mechanisms. Agents such as substituent imidazoles and triazoles, which act by inhibiting the fungal cytochrome P‐450‐dependent enzyme lanosterol N‐demethylase, have the potential to inhibit host cytochrome pP‐450‐dependent drug metabolism. This is discussed with respect to ketoconazole, fluconazole and itraconazole. In contrast, allylamines, which have a different mode of action and a weaker ability to bind to cytochrome pP‐450, are not expected to inhibit clinical drug oxidation. Inducers of drug metabolism, especially rifampicin, phenobarbitone and phenytoin, may lower plasma (and tissue) concentrations of those antifungals metabolized by mixed function oxidases, with therapeutic consequences.

ROBERTS, D.T.

doi: 10.1111/j.1365-2133.1992.tb00005.xpmid: 1531924

SummaryA computer omnibus survey to determine the prevalence of onychomycosis in the United Kingdom was carried out in the early part of 1990. A total population of 9322 adults, aged 16 years and over, was interviewed face‐to‐face, and a questionnaire completed, which consisted of questions and photographs of various nail dystrophies, including onychomycosis. The results in the population surveyed revealed a prevalence of dermatophyte nail infection of 2.8% in men and 2.6% in women. In the group aged 16–34 years, the prevalence rate was 1.3%; this increased to 2.4% in the group aged 35–50 years, and to 4.7% in those aged 55 years or over. Of those found to have onychomycosis, 27% had sought advice from a chiropodist and less than 12% had consulted a specialist. These results suggest that nearly 1.2 million people in the UK have a fungal nail infection and the majority had not sought medical advice, although over 80% stated that they would do so if they were aware that their nail disorder was of fungal origin. A similar proportion would wish to be treated if an effective treatment was available.

FNLAY, A.Y.

doi: 10.1111/j.1365-2133.1992.tb00006.xpmid: 1531925

SummaryOral terbinafine is an effective therapy for dermatophyte onychomycosis, presumably because it reaches the infected areas of the nail rapidly and in fungicidal concentrations. For planning optimal clinical dosage regimes, it is necessary to know the rate of terbinafine movement through the nail plate, the concentrations achieved, and the persistence in the nail plate after stopping treatment. In a study of 12 patients receiving terbinafine at 250 mg/day for up to 48 weeks, measurement of terbinafine in distal nail clippings demonstrated that the drug was first detectable 3–18 weeks after starting therapy. A level of 0.25–0.55 ng/mg was quickly achieved and remained stable. Concentrations of terbinafine in distal clippings of unaffected nails were similar to those in affected nails. Although the average nail concentrations are within the fungicidal range for dermatophytes, the anatomy of an infected nail may result in relatively protected areas of infection. This results in the occasional persistence or recurrence of dermatophytic infection observed in some cases. However, the results of this study justify further trials of ‘short‐term’ oral terbinafine therapy for onychomycosis. A current study is addressing the relationship of oral dosage to nail drug concentration and its later persistence in the nail plate.

GOODFIELD, M.J.D.

doi: 10.1111/j.1365-2133.1992.tb00007.xpmid: 1531926

SummaryTerbinafine, an orally active antifungal agent, is effective in the treatment of dermatophyte onychomycosis when given for 12 months in the case of toenail infection (TN) and 6 months for fingernail infection (FN). The rapid response and short mycological cure time indicate a potential for a reduced treatment duration. In this multicentre double‐blind placebo‐controlled trial, 112 patients with mycologically proven dermatophyte onychomycosis were given 250 mg/day of terbinafine for 3 months. Twenty‐seven patients were excluded, leaving 85 fully evaluable [average age 44 (range 19–78) years; 55 men; 75 TN, 10 FN]. Forty‐nine of the TN patients and seven of the FN patients received terbinafine. At the end of the follow‐up period, the TN mycological cure rate with active treatment was 82% (37/45), but no patient taking placebo maintained mycological cure (P<0.001). Of the FN patients treated with active drug, 71% (5/7) achieved mycological cure at the end of follow‐up. Minor side‐effects occurred in 41% of the placebo‐treated group compared with 33% of those taking terbinafine. These adverse events were mainly gastrointestinal. Two patients taking terbinafine discontinued treatment—one with tonsillitis and another with diarrhoea. In conclusion, 3‐month treatment with terbinafine is effective, well tolerated and safe in dermatophyte onychomycosis. Shortduration therapy for this indication represents a major therapeutic advance.

SCHROEFF, J.G.VAN DER; CIRKEL, P.K.S.; CRIJNS, M.B.; DIJK, T.J.A.VAN; GOVAERT, F.J.; GROENEWEG, D.A.; TAZELAAR, D.J.; WIT, R.F.E.DE; WUITE, J.

doi: 10.1111/j.1365-2133.1992.tb00008.xpmid: 1531927

SummaryTerbinafine is an allylamine antifungal compound shown to be effective in the oral treatment of onychomycosis. Because of the fungicidal acivity of the drug, a shorter duration of treatment, compared with the currently used oral treatment modalities, can be expected in onychomycosis of the toenail. In the present randomized study, the efficacy of oral terbinaifne treatment (250mg/day) was assessed for periods of 6.12, and 24 weeks. All patients were followed for up to 48 weeks after starting treatment. Of the 120 patients with toenail onychomycosis who entered the study, 98 were evaluable for efficacy. The involvement of the toenails was assessed both clinically and mycologically throughout the study. Evaluation at 24 weeks showed that complete cure of toenail onychomycosis was achieved in 67% of patients treated for 6 weeks, 82% treated for 12 weeks, and 85% treated for 24 weeks. At the end of a further 24 weeks of follow‐up, cure rates were 40%, 71% and 79%, respectively. The adverse effects of terbinafine were mostly mild‐to‐moderate gastrointestinal symptoms. Three patients discontinued treatment because of side‐effects. In conclusion, oral treatment with terbinafine is effective and generally well tolerated in patients with onychomycosis. Our results demonstrate that, for toenail onychomycosis, a treatment period of 12 weeks is sufficient.

BAUDRAZ‐ROSSELET, F.; RAKOSI, T.; WILI, P.B.; KENZELMANN, R.

doi: 10.1111/j.1365-2133.1992.tb00009.xpmid: 1531928

SummaryAn open multicentre trial was conducted by 40 dermatologists in Switzerland involving 188 patients with onychomycosis of either the toenails or fingernails. Of these patients, 145 who had positive microscopy and culture of dermatophyte infection were evaluable: of the dermatophytes identified at the initial visit, 80% were Trichophyton rubrum and 12.4% were T. mentagrophytes. Only the most affected nail was evaluated during the obsevration period. Daily dosage was 250 mg of terbinafine (Lamisil®) orally for up to 6 months. The cure rate (negative microscopy and culture) at the end of treatment was 77% for toenails and 100% for fingernails. A follow‐up investigation was made 6 months after the end of treatment: of the 88 patients examined with onychomycosis of the toenail and the 14 with fingernail onychomycosis, 90.9% and 85.7%, respectively, remained free of recurrence. Of the 26 patients who had shown improvement, but not cure, by the end of the treatment period, 15 were clinically and mycologically cured at the time of the follow‐up investigation. Terbinafine was generally well tolerated: the most frequent drug‐related adverse events were mild‐to‐moderate gastrointestinal disturbances. Changes in liver or renal biochemical tests were not considered clinically relevant.

HAROON, T.S.; HUSSAIN, I.; MAHMOOD, A.; NAGI, A.H.; AHMAD, I.; ZAHID, M.

doi: 10.1111/j.1365-2133.1992.tb00010.xpmid: 1543673

SummaryTen 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.