History of the development of azole derivatives

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History of the development of azole derivatives
J. A. Maertens Department of Haematology, University Hospital Gasthuisberg, Leuven, Belgium

ABSTRACT Until the 1940s, relatively few agents were available for the treatment of systemic fungal infections. The development of the polyene antifungals represented a major advance in medical mycology. Although amphotericin B quickly became the mainstayof therapy for serious infections, its use was associated with infusion-related side-effects and dose-limiting nephrotoxicity. The continued search for new and less toxic antifungals led to the discovery of the azoles several decades later. Ketoconazole, the first available compound for the oral treatment of systemic fungal infections, was released in the early 1980s. For almost a decade,ketoconazole was regarded as the drug of choice in nonlife-threatening endemic mycoses. The introduction of the first-generation triazoles represented a second major advance in the treatment of fungal infections. Both fluconazole and itraconazole displayed a broader spectrum of antifungal activity than the imidazoles and had a markedly improved safety profile compared with amphotericin B and ketoconazole.Despite widespread use, however, these agents became subject to a number of clinically important limitations related to their suboptimal spectrum of activity, the development of resistance, the induction of hazardous drug–drug interactions, their less than optimal pharmacokinetic profile (itraconazole capsules), and toxicity. In order to overcome these limitations, several analogues have beendeveloped. These so-called ‘second-generation’ triazoles, including voriconazole, posaconazole and ravuconazole, have greater potency and possess increased activity against resistant and emerging pathogens, in particular against Aspergillus spp. If the toxicity profile of these agents is comparable to or better than that of the first-generation triazoles and drug interactions remain manageable, then thesecompounds represent a true expansion of our antifungal arsenal.

Antifungal, azole, overview

Clin Microbiol Infect 2004; 10 (Suppl. 1): 1–10 death due to bacterial sepsis, thereby setting the stage for fungal colonisation and putting patients at risk for subsequent mycotic infections. Medical procedures have become more invasive and aggressive; the accompanying disruption ofprotective anatomical barriers as a result of indwelling catheters, therapy-induced mucositis, viral infections, and graft-versus-host disease, or following major abdominal surgery or associated with extensive burns, allows fungi to reach normally sterile body sites [5]. In addition, the community of vulnerable patients is continuously expanding as a result of the spread of human immunodeficiency virus(HIV) infections, the increased use of (novel) immunosuppressive drugs in autoimmune disorders and to prevent or treat rejection in the expanding area of transplant medicine, the popularity of dose-escalated, often myelo-ablative cytotoxic therapy, the

INTRODUCTION Despite the implementation of several preventive measures and the use of antifungal chemoprophylaxis, physicians have witnessed anincreased incidence of both mucosal and invasive fungal infections during the past two decades [1–4]. This increase is linked with progress in medical technology and novel therapeutic options and appears to be multifactorial. The widespread use of quinolone prophylaxis in neutropenic cancer patients and the availability of broad-spectrum antibacterial agents has virtually eliminated earlyCorresponding author and reprint requests: J. A. Maertens, MD, Department of Haematology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium Tel: + 32 16 34 68 80 Fax: + 32 16 34 68 81 E-mail: johan.maertens@uz.kuleuven.ac.be

Ó 2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 Clinical Microbiology and Infection, Volume 10 Supplement 1,...
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