Polyenes

Polyene antibiotics and their semi-synthetic derivatives are macrocycle compounds characterized by the presence of a series of conjugated double bonds that are essential for antifungal activity. The chemical characteristics of these derivatives determine their mechanism of action. In fact, they bind primarily to ergosterol, resulting in alterations in membrane permeability, leakage of cellular components and cell death (fungicidal action). Amphotericin B (10) has been used since 1950, and is considered to be the gold standard of therapy for numerous serious, invasive fungal infections, due to its broad spectrum of activity, fungicidal properties and existing efficacy data [52]. Amphotericin B is used in clinical practice as deoxycho-late (Fungizone®), lipid complex (Abelcet®), colloidal dispersion (Amphotec®) and (since 1997) as liposomal formulation [53]. Amphotericin B lipid complex was successful in the treatment of cryptococcosis. Its efficacy and renal safety were proven in 106 patients with cryptococcal infection (66% of clinical response) [54]. Amphotericin B lipid complex also gave positive response in 65% of 398 treated patients with invasive aspergillosis [55]. SPK-843 (11) is a water-soluble polyene that entered the phase II clinical trials for systemic mycosis in November 2004. It demonstrated activity against fungi in pre-clinical studies both in vitro and in vivo. 11 possesses broad-spectrum antifungal activity against yeast, dimorphic and filamentous fungi, and its eradicative efficacies in candidiasis were superior compared with amphotericin B [56]. SPK-843 was well tolerated in intravenous infusion in rabbits. The result of the test in this animal model indicate that doses up to 0.5 mg/ kg can be administered for long periods of time [57].

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