Disease relevance of DRG-0078

• Treatment of experimental cryptococcal meningitis and disseminated candidiasis with SCH39304 [1].
• Efficacy of SCH39304 in murine cryptococcosis [2].
• Treatment of murine coccidioidal meningitis with SCH39304 [3].
• The 50% effective dose for SM-8668 was assessed at 10 days after infection and was 0.18, 3.7, and 5.9 mg/kg (body weight), respectively, for the above-mentioned fungal diseases [4].
• The prophylactic effect of SM-8668 was excellent against systemic candidiasis, aspergillosis, and cryptococcosis in mice [4].

High impact information on DRG-0078

• Stereoselective interaction of the azole antifungal agent SCH39304 with the cytochrome P-450 monooxygenase system isolated from Cryptococcus neoformans [5].
• Pharmacokinetics and metabolism of genaconazole, a potent antifungal drug, in men [6].
• The data demonstrate that genaconazole (racemate) is well absorbed, undergoes negligible biotransformation, and is slowly excreted, primarily in the urine [6].
• Both SCH51048 and SCH39304 at higher doses (30 and 50 mg/kg) reduced the number of viable Aspergillus fumigatus organisms in lung tissue (P < 0.05) [7].
• The 100% absolute bioavailability of genaconazole regardless of the route of administration provides greater dosing flexibility in various clinical settings than currently exists [8].

Chemical compound and disease context of DRG-0078

• The efficacies of SCH39304 (SCH) and fluconazole (FLU) were tested in a murine model of coccidioidomycosis [9].
• The triazole SCH39304 was compared with itraconazole and fluconazole for treatment of murine coccidioidal meningitis [3].
• These studies confirm clinical observations that itraconazole is effective in chromoblastomycosis and suggest that SCH39304 should be considered for clinical evaluation [10].

Biological context of DRG-0078

• The pharmacokinetics of genaconazole, a potent new difluorophenyl-triazole antifungal agent, was studied in 12 healthy male volunteers following a single oral or intravenous administration of the drug [8].
• Interaction of the azole antifungal aromatic group with Phe-233 or -235 may cause the higher activity for (R)-tetraconazole while inactivity of the (SS)-enantiomer of SCH39304 was predicted to result from incompatibility of the hydrophilic sulfonyl moiety when located into the hydrophobic pocket of the active site [11].

Anatomical context of DRG-0078

• In the treatment of experimental cryptococcal meningitis, SCH39304 was as effective as fluconazole in reducing yeast counts in the subarachnoid space [1].
• Electron microscopy showed damage to the fungal cell walls in mice treated with itraconazole or SCH39304, characterized by gaps, fragmentation, and delamination [10].

Associations of DRG-0078 with other chemical compounds

• Pharmacokinetics of the triazole antifungal agent genaconazole in healthy men after oral and intravenous administration [8].
• In addition, topical SM-8668 was as effective as topical miconazole or tioconazole against skin mycosis in guinea pigs [4].
• In a randomized two-way crossover design, each volunteer received either two 50-mg genaconazole tablets orally or a parenteral preparation containing 100 mg of genaconazole given as a 30-min intravenous infusion [8].
• The in vitro activity of saperconazole against eight candidal species (81 strains) was determined and compared with fluconazole, Sch 39304 and amphotericin B [12].
• Additionally, stereoselective inhibition of CYP3A4 and CYP51 was observed with enantiomers of the azole antifungal compounds diclobutrazol and SCH39304 [13].

Gene context of DRG-0078

• Interestingly, the SS(-) enantiomeric form of SCH39304 was inactive and failed to bind CYP3A4, as demonstrable by Type II binding spectra [13].

Analytical, diagnostic and therapeutic context of DRG-0078

• Concentrations of genaconazole in plasma and urine were determined by a specific high-performance liquid chromatography assay with a limit of quantitation of 0.1 microgram/ml [8].
• Both GC and HPLC methods were used for the determination of serum concentration-time curves of genaconazole in man following oral administration of a 50-mg dose [14].
• Gas chromatographic (GC) and high-performance liquid chromatographic (HPLC) methods were developed for the determination of genaconazole in biological fluids [14].
• Following topical administration, Sch 39304 (0.125%, twice daily, 10 days), was 5-8-fold more effective than FLZ, based on culture and lesion score results [15].

References