Witold Mechlinski

Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers.

The influence of food on itraconazole pharmacokinetics was evaluated for 27 healthy male volunteers in a single-dose (200 mg) crossover study with capsules containing itraconazole-coated sugar spheres. This study was followed by a study of the steady-state pharmacokinetics for the same subjects with 15 days of administration of itraconazole at 200 mg every 12 h. Concentrations of itraconazole and hydroxyitraconazole, the active main metabolite, were measured in plasma by high-performance liquid chromatography. The results of the food interaction segment showed that a meal significantly enhances the amount of itraconazole absorbed. The mean maximum concentration in plasma of unmetabolized itraconazole after fasting (140 ng/ml) was about 59% that after the standard meal (239 ng/ml). The rate of elimination was not affected (terminal half-life, approximately 21 h). The mean maximum concentration in plasma of hydroxyitraconazole after fasting was about 72% the postmeal concentration (287 and 397 ng/ml, respectively). The terminal half-life of hydroxyitraconazole was approximately 12 h. Steady-state concentrations of itraconazole and hydroxyitraconazole were reached after 14 or 15 days of daily dosing. The average steady-state concentrations were approximately 1,900 ng/ml for itraconazole and 3,200 ng/ml for hydroxyitraconazole. The shape of the elimination curve for itraconazole after the last dose was indicative of saturable elimination. This conclusion was confirmed by the sevenfold increase in the area under the curve from 0 to 12 h at steady state compared with the area under the curve from 0 h to infinity after a single dose. It was furthermore confirmed by the larger-than-expected number of half-lives required to achieve steady-state plasma drug levels.

Separation of polyene antifungal antibiotics by high-speed liquid chromatography

Abstract High-speed liquid chromatography was applied to separate the components of different classes of polyene macrolides. The instrument contained at UV detector and VYDAC RP packing and a solvent mixture of water methanol tetrahydrofuran (420:90:45-90, v/v) was employed. Optimum conditions for the separation of different antibiotics were achieved by changing the amount of tetrahydrofuran in the solvent mixture. Eurdocidin separated completely in 5 min into two components, which were quantitated from peak height measurements. In less than 20 min. candicidin separated into five components with better resolution than that obtained after 600 transfer with counter-current distribution separation. The reproducibility of retention times was very good. It was observed that antibiotics with longer retention times, as measured under identical conditions, were also more active as antifungal agents. The heptaenes appeared to form three distinct groups with characteristic similar ranges of retention time and levels of antifungal activity.

In vitro antiherpetic activity of water-soluble amphotericin B methyl ester

SummaryAntiherpetic activity of AME was demonstrated inin vitro inactivation tests and in cell culture systems against herpes zoster and five strains of herpes simplex virus.

Comparative Chemotherapeutic Activity of Amphotericin B and Amphotericin B Methyl Ester

The comparative efficacy of amphotericin B and amphotericin B methyl ester (AME) against experimental histoplasmosis, blastomycosis, cryptococcosis, and candidosis in mice was assessed by determining the effect of daily intraperitoneal therapy on 21-day survival and persistence of organisms in internal organs. AME, like amphotericin B, was effective against each of the experimental infections, but the efficacy was lower than the parent compound. For Histoplasma and Blastomyces infections the mean effective dose (ED50) of amphotericin B was 0.3 mg/kg, whereas the corresponding values for AME, respectively, were 2.4 and 2.8 mg/kg. For Cryptococcus infection the ED50 for amphotericin B was 0.2 mg/kg compared with 2.0 mg/kg for AME. The ED50 of amphotericin B for Candida infection was lower than 0.05 mg/kg and the value of AME was between 0.5 to 0.05 mg/kg. The colony counts from internal organs of the surviving animals after the therapeutic regimens were compatible with the data on survival.

The effect of fetal bovine serum on polyene macrolide antibiotic cytotoxicity and antifungal activity.

SummaryThe relationships between fetal bovine serum (FBS) concentration and polyene macrolide antibiotic cytotoxicity to animal cells and to fungi were evaluated. The toxicity of amphotericin B (AB) and its derivative, amphotericin B methyl ester (AME), toward KB cells was found to be directly related to fetal bovine serum concentration. At higher FBS levels, increased concentrations of AB and AME were required to reduce 72-hr KB viable cell numbers to 50% of control values. Similarly, polyene macrolide antibiotic levels required to inhibit the growth ofSaccharomyces cerevisiae to 50% of controls, and for obtaining minimum fungicidal concentrations (MFC), were greater when higher levels of FBS were used. In addition, AME was less toxic than AB toward KB cells grown in media containing 2, 5, 10, 15 or 20% FBS, whereas the antifungal activities of AB and AME were similar. AME was also capable of eliminatingCandida albicans, Saccharomyces cerevisiae, Aspergillus niger orFusarium moniliforme from KB cultures at antibiotic levels which exhibited less cell toxicity than did the concentrations of AB required for a similar response. These findings indicate that AME may be a potentially useful antifungal antibiotic for tissue culture systems.

Altered Amphibian Cell Morphology Following Treatment with Polyene Antibiotic and a Mammalian RNA Virus

Summary Polyene antibiotics are agents known to damage cell membranes. The hexaene antibiotic, mediocidin, was used in an attempt to introduce a mammalian virus (Mengo) into normally nonpermissive ICR 2A haploid frog cells. Although no infectious virus could be recovered from mediocidin treated cells exposed to Mengo virus, a change in VSV susceptibility, temperature sensitivity and an apparently permanent change in morphology took place—from fibroblastic to epithelial—in the cells cultured at 23°. Neither the polyene antibiotic nor the virus used alone was capable of inducing these alterations in ICR 2A cells.