Category Ed50 Munoz Et Al

GW 471558

GW 471558

GR 135402



Figure 4.4 Chemical structures of Sordarin and its derivatives, azosordarin and R-135853

decreasing toxicity and increasing target specificity (Abuhammour and Habte-Gaber, 2004; Ng et al., 2003). Incorporating AMB into phospholipid vesicles (Liposomes) or cholesterol esters permit delivery of larger amounts of the drug with minimal nephrotoxicity. AMB lipid complex (AMBLC) was the first lipid-formulated AMB product to be approved by the FDA for clinical. The lipid-formulated AMB colloidal dispersion (AMBCD), which consists of disc-like structures of cholesteryl sulfate complexed with AMB in a 1:1 molar ratio received FDA approval in 1996. Addition of cholesterol to the phospholipid bilayer enhances liposome stability, decrease rate of clearance, and prolong halflife. The clinical response of patients with invasive aspergillosis (IA) was slightly better when treated by a lipid formulation compared with conventional AMBD (Bowden et al., 2002; Reichenberger et al., 2002; Wingard et al., 2000). Lipid formulations used empirically in neutropenic cancer patients resulted in decreased nephrotoxicity while maitaining clinical efficacy comparable to that of AMBD. Use of AMBLC in patients with aspergillosis, disseminated candidiasis, zygomycosis, and fusariosis, who were refractory/ intolerant to conventional antifungal therapy produced reasonable efficacy (Bowden et al., 1996, 2002).

NY binds ergosterol and causes alterations in membrane permeability that lead to cell death. NY is active against Candida, Aspergillus, Histoplasma spp., and Coccidioides immitis. Significant antifungal activity and reduced toxicity was reported following intravenous (IV) administration of NY (Arikan et al., 2002; Groll et al., 1999a, b). L-NY increases survival, reduces tissue injury, clears the infection and produces tolerable side effects in neutropenic rabbits with pulmonary aspergillosis (PA) (Groll et al., 1999a, b). At 1-7 mg/kg/day dose in humans, L-NY exhibits linear plasma pharmacokinetics with peak plasma levels above the MIC of most relevant fungi and a terminal halflife of 5-7 h (Groll et al., 1999a). Currently, clinical trials are targeting non-neutropenic patients with candidemia, neutropenia, persistent fever, and patients with invasive fungal infection refractory to standard therapy (Groll and Kolve, 2004; Ng et al., 2003).

SPA-S-753 (N-dimethylaminoacetyl-partricin A2-dimethyl-aminoethylamide diascorbate), a new water soluble partricin-A derivative semisynthetic polyene antifungal agent is active against strains of Candida, Cryptococcus, and Saccharomyces spp. SPA-S-753 is effective against murine candidiasis, aspergillosis and cryptococcosis (Rimaroli et al., 2002). Although its spectrum of activity is similar to that of AMB, it yields higher survival rates, longer survival times and comprehensive sterilization of kidneys, liver, and spleen (Rimaroli et al., 2002; Rimaroli & Bruzzese, 2000;1998).

Azoles: Fluconazole derivatives, voriconazole (UK-109-496) and ravuconazole (BMS-207147, ER-30346), and the hydroxylated analog of itraconazole, posacona-zole (SCH56592), are significant additions to the azole family (Figure 4.5). Voriconazole, active both orally and parenterally, has one triazole moiety replaced by a fluropyrimidine group and a methyl group added to the propanol backbone (Figure 4.5). Like other azoles, Voriconazole inhibits ergosterol synthesis by inhibiting the P450-dependent 14 a-demethylase demethylation step C. albicans and A. fumigatus lysates at 1.6 and 160 folds greater than the parent molecule. Voriconazole


Figure 4.5 Chemical structures of new triazole antifungal agents posaconazole

Figure 4.5 Chemical structures of new triazole antifungal agents is active against Candida spp. (Marco et al., 1998; Pfaller et al., 1998a), Aspergillus spp. (Clancy & Nguyen, 1998; Murphy et al., 1997), C. neoformans (both flucona-zole-susceptible and -resistant strains) (Nguyen & Yu, 1998), and dimorphic fungi (Groll et al., 2003). Voriconazole is more active than AMB and flucytosine (5-FC) against all Candida spp. except for C. glabrata (Marco et al., 1998). It is more active than itraconazole against strains of A. fumigatus and A. niger but less active against strains of A. flavus (Murphy et al., 1997). Data from phases II & III clinical trails indicate that voriconazole is active against oropharyngeal candidiasis (OPC) and EC (Groll & Walsh, 2002; Ally et al., 2001), IC and IA (Denning et al., 2002; Walsh et al., 2002a).

The drug is superior to AMBD or LAMB evidence by improved survival, fewer breakthrough infections and decreased infusion-related toxicity and nephrotoxicity in patients receiving voriconazole (Groll & Walsh, 2002). Excellent CNS-penetration properties make voriconazole a good choice for treating cerebral mold infections (Denning et al., 2002; Walsh et al., 2002b). At 58% plasma protein binding rate, the concentration of voriconazole in saliva reaches 65% that of plasma (Groll & Klove, 2004; Chiou et al., 2000). The drug is extensively metabolized; while 78-88% of a single dose appears in urine, <5% appears as unchanged suggesting that elimination occurs by oxidative hepatic metabolism primarily by CYP2C19 (Pearson et al., 2003; Denning et al., 2002).

Posaconazole (SCH 56592) is a hydroxylated analog of itraconazole with a 1,3-dioxolone skeleton (Figure 4.5). The oral formula is currently used to prevent and treat invasive mycoses (Cuenca-Estrella et al., 2006; Vazquez et al., 2006; Courtney et al., 2004a). Posaconazole is active against Candida spp., C. neoformans, Aspergillus spp., filamentous fungi including zygomycetes, Fusarium spp., and some dematiaceous molds (Carrillo-Munoz et al., 2006; Cuenca-Estrella et al., 2006; Van Burik et al., 2006; Raad et al., 2006a; Torres et al., 2005; Barchiesi et al., 2004; Herbrecht, 2004; Pfaller et al., 2004). In a study that investigated 2000 bloodstream Candida isolates, most isolates gave low posaconazole MICs (0.030.13 |ig/mL) with higher MICs noted for C. glabrata and C. krusei (Ostrosky-Zeichner et al., 2003). For C. parapsilosis and C. krusei, MICs were in the range of 0.015-1 and 0.12-2 |ig/mL, respectively (Pfaller et al., 2004). Posaconazole can inhibit 100% of C. neoformans isolates including fluconazole-resistant ones at 1 | g/ mL dose (Cuenca-Estrella et al., 2006; Pfaller et al., 2004; Barchiesi et al., 2004). Posaconazole displays linear, dose-proportional pharmacokinetics at a single dose of 800mg/kg/day (Table 4.2) (Courtney et al., 2003; 2004a, b; Krieter et al., 2004). It is orally bioavailable with maximum concentration reached about 6-10 h post-dosing (Krieter et al., 2004; Courtney et al., 2003). Absorption is linear at 400 mg/12 h (Ezzet et al., 2005) and can be enhanced 2.6-4 folds if coadministered with food (Courtney et al., 2004b). The drug binds albumin at high proportions (97-99%) without affecting its penetration and distribution into CSF (Groll & Walsh, 2006; Al-Abdely et al., 2005). Posaconazole degrades in the liver by glucuronidation to produce inactive metabolites for excretion in feces and urine (Herbrecht, 2004; Krieter et al., 2004). Therefore, it could potentially represent an appropriate alternative to AMB in patients with impaired renal function (Torres et al., 2005).

Table 4.2 Comparison of pharmacokinetic characteristics of Voriconazole, Posaconazole, and Ravuconazole










Oral and intravenous

Oral and topical

Oral and intravenous

Bioavailability (%)

Bioavailability decreases



to about 80% with fatty

increases with

increases with


food or nutrition




Hepatic, primarily via N-

Hepatic. Inhibits


oxidation. Metabolized

hepatic CYP3A4

via several hepatic CYP

but no other

isoenzymes, including


CYP2C19, CYP2C9,

and CYP3A4

Plasma Cmax (mg/L)


More than 1


Plasma protein




binding (%)

Terminal elimination




halflife (h)

Current status




Posaconazole can successfully treat refractory fungal infections including fusariosis, zygomycosis, pseudallescheriasis, endemic mycosis, chromoblastomycosis, and mycetoma (Raad et al., 2006b). In a randomized trial (Vazques et al., 2006) conducted to evaluate the capacity of posaconazole to treat OPC in HIV subjects, clinical success occurred in 91.7% of posaconazole recipients versus 92.5% of flu-conazole recipients; sustained clinical success following treatment cessation was noted. In patients with invasive fusariosis treated with oral posaconazole (800 mg/ day), successful outcome was >45% (Herbrecht, 2004). Leukemic patients who received posaconazole for <3 days, an overall success rate of 50% for those who recovered from myelo-suppression and 20% for those with persistent neutropenia was noted (Raad et al., 2006a). A 70% clinical response rate was reported in posaconazole-treated patients with zygomycosis intolerant or refractory to standard therapy (Greenberg et al., 2006). The drug may be useful in treating mycetoma coccidioidomycosis, chromoblastomycosis, hyalohyphomycosis, and phaeohypho-mycosis (Keating, 2006; Torres et al., 2005).

Ravuconazole is an oral derivative of fluconazole (Figure 4.5) with expanded spectrum of in vitro activity. Its inhibitory potency and binding affinity to yeast P-450 dependent 14a-demethylase is similar to that of itraconazole. Ravuconazole is active against Candida spp., A. fumigatus, C. neoformans, most hyaline hyphomycetes (except Fusarium spp. and P. boydii), dermatophytes, and dematiaceous fungi (Cuenca-Estrella et al., 2006; Espinel-Ingroff, 2003; Yamazumi et al., 2000; Pfaller et al., 1998a). After 8 h of oral administration of 10 mg/kg body weight, maximum plasma concentration reaches 1.68 |ig/mL (Mikamo et al., 2002; Andes et al., 2003b). In neutropenic mice with candidiasis, area under the concentration-time curve (AUCs)/MIC ratio for ravuconazole was similar to that of fluconazole (Andes et al., 2003b). Serum elimination halflife is 3.9-4.8 h, protein binding is 95.8%. Except for minor headaches, the drug is well tolerated at 800 mg single dose or 400 mg/day dose for up to 14 days (Ernst, 2001).

Other azoles: Systematic modifications of the piperazine moiety resulted in the discovery of several novel triazoles like SYN-2869 (Figure 4.6). SY-2869 is orally active against isolates of Candida spp., Aspergillus spp., C. neoformans, and several dematiaceous molds (Johnson et al., 1999). SYN-2869 derivatives, SYN-2836 (has a P-trifluoromethyl moiety at the benzyl group) and 3'-fluoro-substituted analogs of SYN-2836 (SYN-2903) and SYN-2869 (SYN-2921) have activities comparable to those of other azoles (Figure 4.6). SYN azoles (SYN-2836, SYN-2869, SYN-2903, and SYN-2921) are rapidly absorbed into the circulation reaching maximum concentration in mice following a 50 mg/kg body weight oral dose with >45% bioavailability and 4.5-6 h halflife of (Khan et al., 2000). Higher lung concentration of SYN-2869 enhances its capacity to manage respiratory tract infections (Khan et al., 2000). R-126638 (Figure 4.6) is activite against dermatophytes, Candida spp. and Malassezia spp. (Odds et al., 2004). R-126638 is superior to itraconazole in treating dermatophytic infections (ED50 being three- to eightfold lower) and cutaneous model of Trichophyton mentagrophytes dermatophytosis (ED50 bieng fivefold lower) (Odds et al., 2004). The in vitro activity of BAL4815 (the active component of BAL8557) was compared with that of itraconazole, voriconazole, caspofungin, and AMB against isolates of Aspergillus spp. fumigatus, terreus, flavus, and niger (Warn et al., 2006).

Allylamines and thiocarbamates: The allylamines terbinafine and naftifine and the thiocarbamate tolnaftate are synthetic fungicidals that act as reversible, noncom-petitive inhibitors of squalene epoxidase, the enzyme responsible for the cyclization of squalene to lanosterol (Figure 4.7) (Andriole, 1999; 1998). Terbinafine is effective against dermatophytes, Aspegillus spp., Fusarium spp. Penicillium marneffei and other filamentous fungi (Garcia- Effron et al., 2004). Mean MIC of terbinafine against C. albicans is 1.2 |ig/mL (Perea et al., 2002a; McGinnis et al., 2000). Terbinafine shows strong in vitro activity against Penicillium spp., Paecilomyces spp., Trichoderma spp. Acremonoim spp., and Arthrographis spp. with a mean MIC of <1 mg/L. Scedosporium spp., Fusarium spp., Scopulariopsis brevicaulis, and most of Mucorales exhibit high MICs of the allylamine with a mean MIC of >4 mg/ L (Garcia-Effron et al., 2004). Although terbinafine is relatively active against murine aspergillosis especially when combined with AMB, pharmacokinetic properties confine the clinical efficacy of allylamines and thiocarbamates to dermatophytes (Gupta et al., 2006;2005; 2003).

Antimitotic antifungal agents: 5-fluorocytosine (5-FC) is active against Candida and Cryptococcus spp., dematiaceous fungi causing chromomycosis like Phialophora and Cladosporium spp. and Aspergillus spp. (Vermes et al., 2000). MICs of 5-FC is 0.1-25 mg/L for these fungal species; MIC values for 5-FC >25 mg/L signifies resistance. 5-FC inhibits pyrimidine metabolism by interfering with RNA and ch, n-n





no o


Figure 4.6 Structures of novel triazole antifungal agents SYN-2836, SYN-2869, SYN-2903, SYN-2921, and R-126638



epoxidase cyclase


C-14 demethylase


A14 reductase


A8^A7 isomerase Ergosterol

Figure 4.7 Ergosterol biosynthesis pathway, showing sites of inhibition of different antifungal agents protein synthesis. Flucytosine is readily absorbed from the GI tract, 76-89% is bioavailable after oral administration (Groll & Kolve, 2004; Vermes et al., 2000). Small molecular size and increased hydrosolubility enables 5-FC to penetrate into CSF, vitreous and peritoneal fluids and inflamed joints. The drug is used to treat chromoblastomycosis, uncomplicated lower urinary tract candidiasis and VC (Groll & Kolve, 2004). Successful treatment of candidiasis, cryptococcosis and chromoblastomycosis using combinations of 5-FC and AMB, fluconazole or itraconazole has been reported (Schwarz et al., 2006; Johnson et al., 2004; Kontoyiannis & Lewis, 2004). The combination of 5-FC with LAMB has proven useful in clearing the CSF in non-HIV infected patients with cryptococcal meningitis (Brouwer et al., 2004; Brandt et al., 2001). 5-FC-AMB combination is recommended for treating CNS cryptococcosis and candidiasis, Candida endophthalmitis, renal and hepatosplenic candidiasis, Candida thrombophlebitis of the great veins, aspergillosis and CNS phaeohyphomycosis (Johnson et al., 2004).

Acknowledgments We thank Eman Mahmoud, Aula Abu-Halaweh, and Khawla Salem for help with figure drawing and manuscript typing. This work was supported by research grant KHA/MH-2006, Hashemite University, Jordan.

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