Disease relevance of PLD 118

• All except two in vitro-resistant mutants were pathogenic in a murine candidiasis model, and BAY 10-8888 failed to cure the infection [1].
• This was demonstrated in a lethal model of C. albicans infection in mice and rats in which icofungipen showed dose-dependent protection at oral doses of 10 to 20 mg/kg of body weight per day in mice and 2 to 10 mg/kg/day in rats [2].

High impact information on PLD 118

• Icofungipen shows nearly complete oral bioavailability in a variety of species, and its in vivo efficacy indicates its potential for the oral treatment of yeast infections [2].
• The efficacy of icofungipen in mice and rats was not influenced by concomitant administration of equimolar amounts of L-isoleucine, which was shown to antagonize its antifungal activity in vitro [2].
• Pharmacokinetics of icofungipen in plasma approximated a dose-dependent relationship of the maximum concentration of drug in serum and the area under the concentration-time curve [3].
• We investigated the efficacy, plasma pharmacokinetics, and safety of icofungipen in escalating dosages for the treatment of experimental subacute disseminated candidiasis in persistently neutropenic rabbits [3].
• PLD-118- and DAMB-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, and esophagus in comparison to untreated controls (P </= 0.05, P </= 0.01, P </= 0.001, respectively), while FLC had no significant activity [4].

Chemical compound and disease context of PLD 118

• Study groups consisted of untreated controls; animals receiving PLD-118 at 4, 10, 25, or 50 mg/kg of body weight/day via intravenous (i.v.) twice daily (BID) injections; animals receiving FLC at 2 mg/kg/day via i.v. BID injections; and animals receiving desoxycholate amphotericin B (DAMB) i.v. at 0.5 mg/kg/day [4].

Biological context of PLD 118

• BAY 10-8888 inhibited isoleucyl-tRNA synthetase with the same concentration dependency as protein biosynthesis in intact cells assuming 200-fold accumulation [5].
• Inside the cell BAY 10-8888 inhibited specifically isoleucyl-tRNA synthetase, resulting in inhibition of protein synthesis and cell growth [5].

Anatomical context of PLD 118

• Icofungipen followed dose-dependent pharmacokinetics and was effective in the treatment of experimental disseminated candidiasis, including central nervous system infection, in persistently neutropenic rabbits [3].
• A small (8%) decrease in PLD-118 at 100 microM (not detected at 10 microM) with human microsomes was considered to be biologically irrelevant [6].
• The novel antifungal agent PLD-118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro [6].

Associations of PLD 118 with other chemical compounds

• PLD-118 (10 and 100 microM) incubated for 0-60 min with S9 fractions and NADPH was determined by HPLC, using the Waters AccQ.Tag method after derivatization of amino acids to stable, fluorescent derivatives [6].

Analytical, diagnostic and therapeutic context of PLD 118

• Levels of icofungipen in plasma were derivatized by phthaldialdehyde and quantified by high-performance liquid chromatography with fluorescence detection [3].

References