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TAK-456 (25) showed strong in vitro activity against clinical isolates of Candida spp., Aspergillus spp., and C. neoformans-, however, activity was less for C. glabrata. TAK-456 inhibited sterol synthesis of C. albicans and A. fumigatus by 50% at 3 to 11 ng/mL (59). Ravuconazole (BMS-207147/ER-30346, 26), is an orally available broad spectrum agent that recently completed a double-blind, randomized, placebo-controlled Phase l/ll clinical trial. At a dose of 200 mg once daily, it is a safe and effective treatment for toenail onychomycosis (60). The pharmacokinetics, safety and efficacy at doses of 200 mg once daily, 100 mg once weekly and 400 mg once weekly versus placebo for 12 weeks were performed with a 36-week follow-up showing mycological eradication of the causative pathogens Trichophyton rubrum and T. mentagrophytes.

In vitro experiments with SS750 (27), demonstrated that this compound had comparable activity to itraconazole and better potency versus fluconazole against Candida spp. and C. neoformans. Introduction of an ethanesulfonyl and a gem-difluoro moiety into SS750 enhanced its in vitro and in vivo activities by increasing its lipid solubility. SS750 per os to immune suppressed mice having systemic and pulmonary candidiasis caused by C. albicans showed dose dependent increases in survival. SS750 binds with strong affinity to C. kursi cytochrome P-450 (61). SS750 was suggested to be useful for the treatment of deep mycoses caused by Candida spp. and C. neoformans in immune compromised patients and is currently in development (62). Ro-098246 (28), was reported to have potent and broad-spectrum activity and was also potent against Aspergillus spp. and Mucor spp. (63). The enantiomer of SCH 42427 (29) was tested in animals to evaluate its chiral inversion after oral administration. The racemate, genaconazole, was also examined. (64). Posaconazole (SCH-56592), currently in Phase III clinical trials, with a structure is similar to itraconazole, was compared to other well-known agents showing good reported antifungal activity (65).

26 27 28 29

Echinocandins - The echinocandins are a new class of semi-synthetic cyclic lipopeptide fungicidal agents which act by preventing cell wall synthesis by noncompetitive inhibition of essential cell wall p-(1,3)-D-glucan synthase, an essential glucan synthase enzyme in fungal cell wall synthesis. Inhibition of glucan synthase leads to increased cell wall permeability and cell lysis (66,67).

Caspofungin (30) was the first echinocandin approved in the US and in Europe for treatment of candidiasis and invasive aspergillosis in adult patients who are refractory to amphotericin B and/or itraconazole (68,69). Due to low intestinal absorption, an oral formulation has not been developed. Micafungin (FK-463, 31) is a water-soluble lipopeptide semi-synthetic derivative in Phase III clinical trials against Candida spp. (70,71). Micafungin is structurally similar to the echinocandins and pneumocandins, showing good MIC activity in the presence of 10, 20, and 50% human serum and plasma against Candida spp. European approval is anticipated in 2004 for patients suffering from cancer and AIDS. Micafungin's drug interactions were reported and human plasma protein binding indicated micafungin to be >99% plasma protein bound (72). Anidulafungin (VER002/LY-303366, 32) a semi-synthetic agent structurally related to cllofungin was tested in vitro versus fluconazole and itraconazole against 460 clinical yeast isolates. The report indicates anidulafungin was superior to itraconazole and fluconazole against C. albicans, C. tropicaiis, C. giabrata and C. krusei (73).

Polyenes - Polyene antifungal agents form complexes with ergosterol and disrupt the fungal plasma membrane which results In increased membrane permeability, leakage of the cytoplasmic contents and death of the fungal cell (74). The agents have the broadest spectrum of antifungal activity including Candida, Aspergillus, and are effective in severe systemic fungal infections. They are fungicidal (75). Amphotericin B (33), is well-known in several formulations and is used to treat invasive fungal infections related to cancer, organ transplantation and other conditions. Because of the strong supporting data indicating reduced toxicity, an improved formulation of amphotericin B was approved by the FDA (76,77).

The pharmacokinetics and tissue distribution reported for SPA-S-753 (a derivative of partricin) was compared to amphotericin B in a single dose trial in mice at 1.25 mg/kg by intravenous route of administration in 5% glucose. The report showed a serum elimination half-life of 15.1 hours compared to amphotericin B of 19.8 hours and SPA-S-753 has been reported effective and nontoxic in vivo on murine candidiasis, aspergillosis, and cryptococcosis (78). An alternate salt form, SPK-843 was selected to undergo Phase I clinical trials in late 2001 (79,80).

Pvrimidines - Flucytosine (5-Fluorocytosine, 34) is currently the only FDA approved fluorinated pyrimidine agent. 5-Fluorocytosine is a water-soluble agent having at least two mechanisms of action. 5-Fluorocytosine is taken up by the fungal cell via a permease system that recognizes several purines like the natural analog cytosine. Once inside of the cell, fluctosine is rapidly deaminated by the enzyme cytosine deaminase to the antimetabolite 5-FC that incorporates into the fungal RNA instead of uridine, resulting in inhibition of protein synthesis. In mammalian cells, cytosine deaminase is either absent or has a minimal activity. The second mechanism of action is the conversion of flucytosine into 5-fluorodeoxyuridine monophosphate by the enzyme uridine monophosphate pyrophosphorylase (81). This results in the subsequent inhibition of thymidylate sythetase and interferes with DNA synthesis. Unfortunately, it has a narrow spectrum of activity against Candida spp. and C. neoformans. However, recent reports tested 5-FC against 8,803 clinical isolates of Candida spp. (18 species) indicating that lower doses can be used to reduce host toxicity while maintaining efficacy (82).

Summary - Undoubtedly, innovative research efforts will continue in the 21st century as we seek to minimize the incidence of opportunistic fungal infections worldwide, exploit available and emerging technologies such as genomics and proteomics, and develop new chemical entities (NCE) with improved efficacy and safety profiles. Finally, strategies for combining several antifungal drugs as an alternative approach for antifungal therapy is an evolving option (83).


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Chapter 18. Recent Advances in the Chemotherapy of HIV

Steven D. Young Merck Research Laboratories WP14-3, West Point, PA 19486

Introduction - The global pandemic of human immunodeficiency virus (HIV) infection/AIDS is showing no sign of abatement. In 2002 the number of people living with HIV infection grew by 5 million to 42 million individuals worldwide. Epidemiological projections point to that number increasing to 100 million by 2010, with most of the infected individuals living in developing countries (1). In the developed world, the number of new infections continues to grow, albeit at a much slower rate. For those patients with access to anti-retroviral medications, the emergence of viral strains resistant to the current therapeutic agents represents a significant threat (2). The challenge facing anti-retroviral drug research in 2002 and beyond is the discovery and development of new agents that address the issue of resistance, either through improvements in existing drug classes or by the discovery of agents targeting new mechanisms of action. This chapter will therefore be divided into two sections, first, new compounds for existing viral targets and second, compounds for novel viral targets.

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