terbinafine, Lamisil
Mevinolin (lovastatin) potentiates the antiproliferative effects of ketoconazole and terbinafine against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies.

Urbina JA, Lazardi K, Marchan E, Visbal G, Aguirre T, Piras MM, Piras R, Maldonado RA, Payares G, de Souza W.

Laboratorio de Quimica Biologica, Instituto Venezolano de Investigaciones Cientificas, Caracas.

We have studied the antiproliferative effects of mevinolin (lovastatin), an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, on the protozoan parasite Trypanosoma (Schizotrypanum) cruzi and its ability to potentiate the action of specific ergosterol biosynthesis inhibitors, such as ketoconazole and terbinafine, both in vitro and in vivo. Against the epimastigote form in vitro, mevinolin produced a dose-dependent reduction of the growth rate up to 25 microM, but at 50 and 75 microM, complete growth arrest and cell lysis took place after 144 and 96 h, respectively. A systematic study of the effects of mevinolin combined with ketoconazole and terbinafine, which act at different points in the ergosterol biosynthesis pathway, on the proliferation of epimastigotes indicated a synergic action, as shown by concave isobolograms and fractional inhibitory concentration indexes ranging from 0.17 to 0.54. Analysis of the sterol composition and de novo sterol synthesis in control and treated cells by thin-layer and gas-liquid chromatographies showed that the antiproliferative effects of the drug alone and in combination were correlated with the depletion of the endogenous ergosterol pool and particularly with a critical (exogenous) cholesterol/endogenous 4-desmethyl sterol ratio in the cells. When we studied the effects of mevinolin on the amastigote form proliferating inside Vero cells in vitro, only very modest effects on the parasites were observed up to 0.75 microM; above this concentration, significant deleterious effects on the host cells were found. However, when the same concentration of the drug was combined with ketoconazole, it was able to reduce by a factor of 10 the concentration of the azole required to eradicate the parasite (from 10 to 1 nM), again indicating a synergic action. On the other hand, a combination of mevinolin and terbinafine had only additive effects on amastigotes, but a ternary combination of mevinolin, ketoconazole, and terbinafine was again clearly synergistic. In vivo studies with a murine model of Chagas' disease showed that mevinolin can also potentiate the therapeutic effects of ketoconazole in this system; combined treatment with the two drugs at doses that alone offered only limited protection against the parasite was able to essentially eliminate circulating parasites and produce complete protection against death. These results confirm the synergic action against the proliferative stages of T. cruzi both in vitro and in vivo and in vivo of combined ergosterol biosynthesis inhibitors that act at different points in the pathway and suggest that mevinolin combined with azoles, such as ketoconazole, can be used in the treatment of human Chagas' disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8460926&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Activity of terbinafine on Trichophyton mentagrophytes in a human living skin equivalent model.

Rashid A, Edward M, Richardson MD.

Department of Dermatology, University of Glasgow, UK.

Germination of arthroconidia of Trichophyton mentagrophytes in the presence of the allylamine antifungal terbinafine was assessed utilizing a human living skin equivalent model. Arthroconidia were inoculated onto the skin-equivalent previously exposed to low concentrations of terbinafine (0.01-1.0 mg l-1) and then incubated at 28 degrees C for 7 days. An assessment of fungal growth inhibition was made by light and scanning electron microscopy. In the absence of terbinafine, adherence, germination and hyphal extension were observed. Penetration of the model was seen, with hyphae present in the dermal component. In the presence of terbinafine, inhibition of fungal growth was apparent and the drug was seen to act as a barrier against fungal invasion of the dermis. The data indicate that the living skin equivalent model is a promising in vitro system for evaluating new antifungal agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8531020&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Influence of serum protein binding on the in vitro activity of anti-fungal agents.

Schafer-Korting M, Korting HC, Rittler W, Obermuller W.

Fachbereich Pharmazie der Freien Universitat Berlin, Germany.

Historically it has been assumed that the pharmacological effect is related to the free drug concentration. In exposing Candida albicans to itraconazole and ketoconazole serum concentration-time profiles, however, antifungal activity was not diminished despite intense albumin binding. The relevance of serum protein binding was further investigated, by in vitro susceptibility testing of C. albicans (40 clinical isolates) and Trichophyton rubrum (ten strains) against antifungal agents using microdilution tests allowing the determination of IC30- and MIC-values. The range of serum protein binding ranges from 11% with fluconazole to > 99% with itraconazole and terbinafine. The ratios of IC30- and MIC-values with and without serum protein (albumin, alpha- and gamma-globulin, human plasma) were related to the loss of susceptibility expected according to the free-drug hypothesis. A difference in the albumin effect with the test strains was not observed. With most antifungals including terbinafine, the activity declined as expected. IC30- and MIC-ratios for miconazole were 7 and 13 (observed) vs. 12-20 (expected), for fluconazole 1.5 and 3.5 vs. 1.1, for amphotericin B 10 vs. 11-20, for griseofulvin 3.6 vs. 4, and for terbinafine 61 vs. 100. Itraconazole activity, however, was not diminished by albumin (expected ratio 286), and ketoconazole effects decreased less than expected (ratio 5-15, expected about 100). alpha-globulin, but not gamma-globulin induced a major loss in anti-Candida activity of itraconazole and ketoconazole, which is paralleled by a decline in ketoconazole (but not itraconazole) activity due to plasma. With the other antifungals (except for ciclopiroxolamine) IC30-values for C. albicans increased, too. Due to the complete inhibition of T. rubrum growth by gamma-globulin, this species proved unsuitable for studying the gamma-globulin effects. The present study demonstrates that the effects of intense protein binding on drug activity are only partly predictable from binding studies in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8557388&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Pharmacokinetics and pharmacodynamics of multiple-dose terbinafine.

Nedelman JR, Gibiansky E, Robbins BA, Cramer JA, Riefler JF, Lin T, Meligeni JA.

Department of Drug Metabolism and Pharmacokinetics, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA.

Data from clinical trials of terbinafine for the treatment of onychomycosis were analyzed with the following two objectives: 1) to identify demographic predictors of the duration and extent of systemic drug exposure; and 2) to explore whether increased systemic exposure or demographic predictors of increased exposure were associated with altered safety or efficacy. Demographic predictors of exposure were identified by a model-free, nonparametric approach applied to the sparse pharmacokinetic data from the onychomycosis studies. Those covariates were then incorporated into a multicompartmental nonlinear mixed effects model. Post hoc parameter estimates from the nonlinear mixed effects model provided individual measures of exposure. Safety scores were derived for adverse events that were frequently attributed to drug exposure and for liver function tests. Terbinafine was found to have an average terminal half-life (t1/2) of approximately 3 weeks. That terminal elimination phase contributed so little to the total exposure, however, that average concentrations accumulated only approximately two-fold at steady state with once daily dosing. Age and concomitant hypertension were predictors of higher plasma concentrations of terbinafine; smokers had lower levels than nonsmokers. Although some statistically significant associations between adverse events and systemic exposure were found, in all cases the actual frequency of the adverse events and systemic exposure were found, in all cases the actual frequency of the adverse events was low, and there were no trends in severity with respect to exposure. Above-normal levels of gamma-glutamyl transferase were associated with exposure, but there was no trend in severity with respect to exposure. No other liver function test abnormalities were associated with exposure, nor were there any significant associations between adverse events or liver function abnormalities and demographic subgroups that differed with respect to exposure. Among patients taking the active drug there were no significant associations between exposure levels and efficacy, nor were there differences in efficacy between demographic subgroups that differed with respect to exposure.

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terbinafine, Lamisil
New mechanisms of action with fungicidal antifungals.

Rashid A.

Department of Dermatology, Khyber Medical College, Peshawar, Pakistan.

Morphological modifications of growth forms of dermatophyte fungi, arthroconidia and germ tubes exposed to terbinafine incorporated in the stratum corneum were studied by scanning and transmission electron microscopy. Changes observed in arthroconidial morphology included pores and erosions present in the cell wall, with layers peeling off. The cell membrane was destroyed. Dilated vacuoles and small electron-dense areas were evident in the arthroconidial cytosol. Although germination was partially arrested, inhibition of hyphal extension was seen on all body sites examined. Germ tubes were susceptible to terbinafine, with pores appearing along their length and collapsed hyphae seen following exposure to the drug. This study suggests that the outer and inner layers of the arthroconidial cell wall are the initial targets of terbinafine action, followed by alterations to the cytosol and intracellular organelles.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8763459&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Use of terbinafine in HIV-positive subjects: pilot studies in onychomycosis and oral candidiasis.

Nandwani R, Parnell A, Youle M, Lacey CJ, Evans EG, Midgley J, Cartledge J, Hawkins DA.

St Stephen's Centre, Chelsea & Westminster Hospital, London, U.K.

Study 1. Eighteen HIV-positive Caucasian homosexual men with initial positive fungal microscopy were recruited into this prospective, dual-centre, open-label study. They received a once-daily oral dose of 250 mg terbinafine for 12 weeks. Eight were subsequently excluded after screening cultures proved negative. The mean CD4 count of the 10 evaluable subjects was 302/mm3. All 10 positive fungal cultures were confirmed as Trichophyton rubrum. Using an intention-to-treat analysis, healthy unaffected nail growth increased from a mean of 1.6 mm at baseline to 5.2 mm after 12 weeks' treatment. Clinical response after treatment was 6.4 mm at 36 weeks and 8.0 mm at 48 weeks. Three of the 10 toenail infections were cured mycologically. This 30% cure rate was maintained over 48 weeks' follow-up, despite three patients discontinuing the study. One withdrew following a terbinafine-induced drug rash. Two others stopped treatment during HIV-related illnesses, but without terbinafine side-effects. Study 2. Ten HIV-positive subjects, nine culture-positive for Candida albicans and one for Candida albicans and Candida glabrata, were recruited into this pilot study. They received 250 mg oral terbinafine daily for 14 days. Their average CD4 count was 131/mm3. All patients remained culture-positive throughout the study. Slight improvements in signs and symptoms were seen in one or two patients but this might well have been attributable to improved oral hygiene. Oral terbinafine at this dosage was therefore not thought an effective treatment for this indication in HIV-positive patients. The drug was well tolerated and no serious treatment-related adverse events were reported.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8763464&dopt=Abstract terbinafine Lamisil



terbinafine, Lamisil
Employment of terbinafine against Pneumocystis carinii infection in rat models.

Contini C, Colombo D, Cultrera R, Prini E, Sechi T, Angelici E, Canipari R.

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

The anti-Pneumocystis carinii response of terbinafine together with that of three other compounds, trimethoprim sulphamethoxazole (TMP-SMX), atovaquone (ATQ) and albendazole (ALB), has been investigated in immunosuppressed Sprague-Dawley rats with established pneumocystosis. Drugs were administered orally (terbinafine in dosages of 40 and 80 mg/kg per day, TMP 12.5 mg/kg per day plus SMX 62.5 mg/kg per day, ATQ 100 mg/kg per day and ALB 600 mg/kg per day) to six rat groups except one which served as a control. P. carinii pneumonia (PCP) was identified post-mortem in nine (90%) of the control rats which exhibited a marked P. carinii burden, and mean lung weights were higher with respect to the other treatment groups. During treatment, five rats in the control group died, whereas between 11 and 13 rats in all treatment groups survived. In the terbinafine groups (40 mg and 80 mg/kg per day), a mild P. carinii infection developed in three and two rats (27.2 and 18%), respectively, and almost the same infectivity score was obtained for those treated with 40 mg and 80 mg/kg per day. Histological changes in the lungs in animals receiving terbinafine treatment were minimal. Among the remaining compounds the rate of infection was seven (58.3%) for the ALB treatment group and five (45.4%) for the ATQ group (mean score 19.4 +/- 7.1 and 23 +/- 2.1, respectively). In the TMP-SMX treatment group, there were 13 surviving rats and P. carinii organisms were found in two (15.3%, mean infection score 8 +/- 1.1).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8763466&dopt=Abstract terbinafine Lamisil