In-vitro studies with SF 86–327, a new orally active allylamine derivative

The allylamine derivative terbinafine is the first antifungal agent with primary fungicidal properties against dermatophytes which acts systemically after oral application as well as locally after topical application. Comparative oral studies carried out with griseofulvin and ketoconazole in model infections such as guinea pig trichophytosis and microsporosis revealed terbinafine to be superior to the reference compounds both clinically and mycologically. An excellent antimycotic activity of terbinafine was also demonstrable after topical treatment of guinea pig dermatophytoses caused by Trichophyton mentagrophytes or Microsporum canis. Results of comparative chemotherapeutic studies carried out with econazole and tolnaftate demonstrated superior efficacy of terbinafine in the treatment of both trichophytosis and microsporosis. Skin infections of guinea pigs caused by Candida albicans and vaginal candidiasis in rats proved to be responsive to a topical application of terbinafine also. However, the reference compounds, clotrimazole and miconazole, exhibited activity superior to that of terbinafine in both models.

mentioning

confidence: 99%

Activity of terbinafine in experimental fungal infections of laboratory animals

Petrányi

Meingassner

Mieth

1987

“…In one in vitro study, the MIC90s for A. fumigatus (11 strains) and A. flavus (9 strains) were 0.5 and 0.06 ,ug/ml, respectively (6). This study used Kimmig agar and an agar dilution method for in vitro testing.…”

mentioning

confidence: 99%

MIC and fungicidal activity of terbinafine against clinical isolates of Aspergillus spp

Schmitt

Bernard

Andrade

et al. 1988

Terbinafine and amphotericin B MICs for 90% of strains tested were 1.6 and 0.4 ,ug/ml against Aspergillus fumigatus (16 strains), 0.8 and 3.2 ,ug/mI against Aspergillusflavus (10 strains), and 0.4 and 1.6 jig/ml against Aspergillus niger (10 strains), respectively. For all species tested, the minimal inhibitory and fungicidal concentrations for 90% of strains of both drugs were identical and the inoculum size did not have a major effect on the results.Aspergillus species can cause life-threatening opportunistic infections among immunocompromised patients. Invasive aspergillosis is difficult to diagnose and often responds poorly to treatment. Amphotericin B remains the drug of choice despite its considerable toxicity.Terbinafine belongs to a new class of antifungal agents (8). It is a synthetic naphthalenemethanamine that inhibits squalene epoxidase, a key enzyme in ergosterol biosynthesis of fungi (3,5). Its mode of action is highly selective, i.e., it is much more inhibitory to fungal than to mammalian sterol biosynthesis (4). Terbinafine can be administered orally, and preliminary studies in humans indicate that it is well tolerated (7).To evaluate the potential use of terbinafine in human aspergillosis, we compared its in vitro inhibitory and lethal activities against 36 clinical isolates of Aspergillus species with the activities of amphotericin B and ketoconazole.(These data were presented in part at the 27th Source and preparation of antifungal agents. Amphotericin B (Fungizone) was obtained from E. R. Squibb & Sons, Princeton, N. J., and terbinafine was obtained from Sandoz Ltd., Basel, Switzerland. Amphotericin B was initially diluted in distilled water, and terbinafine was initially diluted in dimethyl sulfoxide. Ketoconazole was initially diluted in absolute ethanol. Further drug dilutions were made in distilled water at log 2 concentrations ranging from 0.025 to 51.2 ,ug/ml. Finally, 0.1-ml portions of each concentration were added to wells of microdilution plates.Source and preparation of fungal species. The Aspergillus strains tested were isolated from patients treated at Memorial Sloan-Kettering Cancer Center from January 1985 to April 1987. The control organisms for amphotericin B were Candida albicans B311 and C. tropicalis CT4. The organisms (16 strains of Aspergillus fumigatus, 10 strains of A. flavus, and 10 strains of A. niger) were subcultured on Sabouraud dextrose agar and incubated at 35°C for 4 days. Spores were harvested with 0.02% Tween 80, centrifuged (10 min, 1,500 x g), suspended in distilled water, and counted in * Corresponding author. a hemacytometer. The spores were diluted in 2 x yeast nitrogen glucose broth (Difco Laboratories; 5% glucose) to produce the high (105 spores per ml) and low (2 x 103 spores per ml) inocula.Susceptibility testing. Portions of 0.1 ml of each spore suspension at either the high or low inoculum were added to microdilution tray wells that contained no drug (control wells), terbinafine, amphotericin B, or ketoconazole. Plates were incubated at 35°C for 4...

“…Terbinafine has a broad spectrum of activity in vitro and in vivo against pathogenic fungi responsible for superficial fungal infections (such as dermatophytosis and onychomycosis) and systemic fungal infections (such as histoplasmosis, aspergillosis, and Pneumocystis carinii infection) (1,8,39,40). The data presented in this study clearly show that terbinafine achieves high and sustained concentrations in skin, which is the target tissue for this drug.…”

Section: Discussionmentioning

confidence: 64%

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

Hosseini-Yeganeh

McLachlan

2002

The aim of this study was to develop a physiologically based pharmacokinetic (PB-PK) model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. A PB-PK model consisting of 12 tissue and 2 blood compartments was developed using concentration-time data for tissues from rats (n ‫؍‬ 33) after intravenous bolus administration of terbinafine (6 mg/kg of body weight). It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations. The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation. The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans. The estimated volume of distribution at steady state (V ss ) obtained from the PB-PK model agreed with the reported value of 11 liters/kg. The apparent volume of distribution of terbinafine in skin and adipose tissues accounted for 41 and 52%, respectively, of the V ss for humans, indicating that uptake into and redistribution from these tissues dominate the pharmacokinetic profile of terbinafine. The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition.Terbinafine is an antifungal agent from the allylamine class that inhibits the fungal squalene epoxidase enzyme, leading to the intracellular accumulation of squalene, which causes the rapid death of fungi (36,37). It has demonstrated activity against most superficial fungal infections, including onychomycosis and dermatomycosis (11,17), and systemic fungal infections, such as histoplasmosis (1), Pneumocystis carinii infection, (8), and aspergillosis (39). Terbinafine is highly lipophilic and keratophilic, so it is extensively distributed throughout adipose tissue, dermis, epidermis, and nails in humans (12,19). The apparent volume of distribution in humans is relatively large and has been reported to be in the range of 780 to 2,000 liters (22,25,27,28,33). The large volume of distribution of terbinafine and its accumulation in peripheral tissue as well as the slow redistribution of the drug into blood are likely to significantly influence the half-life of terbinafine. Previous studies have variously reported the elimination half-life of terbinafine in humans to be 15 h (33), 26 h (27), 290 h (35), and 22 days (33,35,43). Terbinafine is extensively metabolize...