Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1999-02-24
2000-05-30
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 31, 514394, 514395, A61K 3800, A61K 3170, A61K 31415
Patent
active
060691263
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to antifungal combination therapy comprising the use of known antifungal agents such as the azoles or polyenes in combination with a pneumocandin derivative antifungal agent. More particularly, the invention relates to antifungal combination therapy comprising the use of azoles such as fluconazole (hereinafter referred to as FCZ), voriconazole, itraconazole, ketoconazole, miconazole, ER 30346, SCH 56592; polyenes such as amphotericin B (hereinafter referred to as AmB), nystatin or liposomal and lipid forms thereof such as Abelcet, AmBisome and Amphocil; purine or pyrimidine nucleotide inhibitors such as flucytosine; or polyoxins such as nikkomycins, in particular nikkomycin Z or other chitin inhibitors, elongation factor inhibitors such as sordarin and analogs thereof, mannan inhibitors such as predamycin, bactericidal/permeability-inducing (BPI) protein products such as XMP.97 or XMP.127 or complex carbohydrate antifungal agents such as CAN-296 in combination with a pneumocandin derivative of the structure ##STR1## or a pharmaceutically acceptable salt or other pharmaceutically acceptable formulation thereof.
These combination therapies have been shown to be useful against such opportunistic pathogens as Cryptococcus spp., Candida spp., Aspergillus spp., Histoplasma spp., Coccidioides spp., Paracoccidioides spp. Blastomyces spp., Fusarium spp., Sporothrix spp., Trichosporon spp., Rhizopus spp., Pseudallescheria spp., dermatophytes, Paeciliomyces spp., Alternaria spp., Curvularia spp., Exophiala spp., Wangiella spp., Penicillium spp., Saccharomyces spp., Dematiaceous fungi and Pneumocystis carinii.
BACKGROUND OF THE INVENTION
There is an increasing need for agents which are effective against opportunistic mycotic infections by such agents as Cryptococcus spp., Candida spp., Aspergillus spp., Histoplasma spp., Coccidioides spp., Paracoccidioides spp. Blastomyces spp., Fusarium spp., Sporothrix spp., Trichosporon spp., Rhizopus spp., Pseudallescheria spp., dermatophytes, Paeciliomyces spp., Alternaria spp., Curvularia spp., Exophiala spp., Wangiella spp., Penicillium spp., Saccharomyces spp., Dematiaceous fungi and Pneumocystis carinii. The present treatments, i.e., polyenes, such as amphotericin B, cause severe side effects and azoles, such as fluconazole, are only fungistatic. The pneumocandins, which are related to the echinocandins, are cyclic hexapeptides which inhibit cell wall 1,3.beta.-D-glucan synthesis. The pneumocandins have shown potent in vivo activity against Candida spp., Pneumocystis carinii, Aspergillus spp., as well as the other fungal pathogens listed above. However, the pneumocandins, by themselves, have weak activity against Cryptococcus spp.
Combination therapy with antifungal drugs may provide additional options for treating Cryptococcus and other fungal pathogens.
Previous studies have evaluated the efficacy of other pneumocandin derivatives against Cryptococcus neoformans in combination with amphotericin B and fluconazole (Abruzzo et al., Antimicrob. Agents Chemo. 1995, 39:1077-1081 and Bartizal et al., Antimicrob. Agents Chemo. 1995, 39:1070-1076). However, none of these studies have demonstrated the results found using Compound I as the pneumocandin derivative.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to antifungal combination therapy comprising the use of known antifungal agents such as the azoles or polyenes in combination with a pneumocandin derivative antifungal agent. More particularly, the invention relates to antifungal combination therapy comprising the use of azoles such as fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, ER 30346, SCH 56592; polyenes such as amphotericin B, nystatin or liposomal and lipid forms thereof such as Abelcet, AmBisome and Amphocil; purine or pyrimidine nucleotide inhibitors such as flucytosine; or polyoxins such as nikkomycins, in particular nikkomycin Z or other chitin inhibitors, elongation factor inhibitors such as sordarin and analogs the
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Abruzzo George K.
Bartizal Kenneth F.
Flattery Amy M.
Daniel Mark R.
Korsen Elliott
Merck & Co. , Inc.
Weddington Kevin E.
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