Disease relevance of Sch 56592

• On the basis of compassionate treatment data, posaconazole appears to be effective for treatment of zygomycosis [1].
• Overall, posaconazole shows potential for treating CNS aspergillosis [2].
• Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis [3].
• This study shows posaconazole activity for the treatment of histoplasmosis in immunosuppressed animals [4].
• Posaconazole also demonstrated potential in febrile neutropenia in an open-label phase II study (success rate of 81% 7 days after the end of treatment) [5].

High impact information on Sch 56592

• The MICs and fractional inhibitory concentrations of posaconazole (POS) and voriconazole (VRZ), alone and in combination with amphotericin B (AMB), for the conidia and hyphae of 100 Aspergillus isolates were evaluated [6].
• Posaconazole Enhances the Activity of Amphotericin B against Aspergillus Hyphae In Vitro [6].
• Effects of age, gender, and race/ethnicity on the pharmacokinetics of posaconazole in healthy volunteers [7].
• Posaconazole is a triazole antifungal for prophylaxis of invasive fungal infection and treatment of oropharyngeal candidiasis [7].
• Additionally, we explored the effect of P-glycoprotein expression and MDR1 genotype on posaconazole pharmacokinetics in black and white subjects [7].

Chemical compound and disease context of Sch 56592

• On days -2 and -1 and at 2 h prior to infection, the mice received either posaconazole (POS) at doses ranging from 20 to 80 mg/kg of body weight/day or amphotericin B (AMB) at 1 mg/kg/day [8].
• Effect of granulocyte colony-stimulating factor combination therapy on efficacy of posaconazole (SCH56592) in an inhalation model of murine pulmonary aspergillosis [9].
• The Anti-Trypanosoma cruzi Activity of Posaconazole in a Murine Model of Acute Chagas' Disease Is Less Dependent on Gamma Interferon than That of Benznidazole [10].
• Antifungal activity of posaconazole compared with fluconazole and amphotericin B against yeasts from oropharyngeal candidiasis and other infections [11].
• A total of two agents are currently available: voriconazole (which is becoming a primary treatment for the management of invasive aspergillosis) and posaconazole (which demonstrates a broad antifungal spectrum) [12].

Biological context of Sch 56592

• Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations [13].
• The posaconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (6.12 to 26.7, mean +/- SD = 16.9 +/- 7.8, P value, 0.42) [3].
• These observations suggest that oxidative (phase 1) metabolism by cytochrome P450 isoforms represents only a minor route of elimination for posaconazole, and therefore cytochrome P450-mediated drug interactions should have a limited potential to impact posaconazole pharmacokinetics [14].
• Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice [3].
• No association was observed between any MDR1 single-nucleotide polymorphism and the area under the concentration-time curve for posaconazole [7].

Anatomical context of Sch 56592

• Pharmacokinetics and safety of oral posaconazole in neutropenic stem cell transplant recipients [15].
• Efficacy of posaconazole in a murine model of central nervous system aspergillosis [2].
• Posaconazole at 0.1 mg/kg/day reduced fungal colony counts and antigen levels in spleens but not in lungs [4].
• The current report demonstrates successful treatment, even in the setting of subsequent bone marrow transplantation and immunosuppression, using a combination of surgical resection and posaconazole therapy [16].
• Posaconazole is not metabolized to a significant extent through the cytochrome P450 enzyme system and is primarily excreted in an unchanged form in the feces [17].

Associations of Sch 56592 with other chemical compounds

• Multiresistant filamentous fungi, such as Scedosporium prolificans, Scopulariopsis brevicaulis, and Fusarium solani, were also resistant to voriconazole, caspofungin, and posaconazole [18].
• In immunosuppressed ICR mice infected intravenously, posaconazole, itraconazole, and amphotericin B prolonged survival [19].
• There existed a clear rank order of in vitro activity of the five azoles examined in this study when they were tested versus C. glabrata: voriconazole > BMS-207147 = Sch 56592 = itraconazole > fluconazole (MIC90s, 2.0, 4.0, 4.0, 4.0, and 64 microgram/ml, respectively) [20].
• Amphotericin B and posaconazole were found to be active against most of the Mucorales strains tested [18].
• We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole, posaconazole [3].

Gene context of Sch 56592

• However, the midazolam AUC((tf)) was higher in the posaconazole than no-treatment group (93.4 n gh/ml versus 51.4 ng h/ml, P<0.01), indicating inhibition of hepatic CYP3A4 [21].
• Based on insignificant differences in mean probe ratios, posaconazole did not inhibit CYP1A2, 2C8/9, 2D6, or 2E1 [21].
• Despite both the increases in pump expression and the ERG11 mutations, only one of the patient isolates exhibited a large decrease in posaconazole susceptibility [22].
• Screening of 10 cDNA-expressed recombinant human UDP-glucuronosyltransferase (UGT) enzymes showed that only UGT1A4 exhibited catalytic activity with respect to the formation of the glucuronide of posaconazole [23].
• Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study [21].

Analytical, diagnostic and therapeutic context of Sch 56592

• Posaconazole as salvage therapy for zygomycosis [24].
• Pulmonary mucormycosis (zygomycosis) in a lung transplant recipient: recovery after posaconazole therapy [25].
• The long elimination-phase half-life of posaconazole supports once- or twice-daily dosing in clinical trials; however, additional studies are required to determine if further division of the dose will enhance exposure [26].
• We conducted a randomized, crossover study in healthy adults to examine the effects of a nutritional supplement (Boost Plus) on posaconazole pharmacokinetics [27].
• Disposition of posaconazole following single-dose oral administration in healthy subjects [14].

References