Discovery of Fluconazole, a Novel Antifungal Agent

Richardson, K.; Cooper, Keith; Marriott, M. S.; Tarbit, M. H.; Troke, Peter F.; Whittle, Peter J.

doi:10.1093/clinids/12.supplement_3.s267

Cited by 113 publications

(57 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since its introduction in the early 1990s, fluconazole (FLZ) has emerged as the primary treatment option for virtually all forms of susceptible Candida infections in both immunocompetent and immunocompromised hosts (27,28,34,35,37,38). FLZ inhibits 14␣-lanosterol demethylase in the ergosterol biosynthetic pathway, resulting in the accumulation of lanosterol and toxic 14␣-methylated sterols in the fungal membrane (5,(19)(20)(21).…”

mentioning

confidence: 99%

Fungicidal Activity of Fluconazole against Candida albicans in a Synthetic Vagina-Simulative Medium

Moosa¹,

Sobel²,

Elhalis

et al. 2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Fluconazole (FLZ) has emerged as a highly successful agent in the management of systemic infections of Candida. Cure rates for symptomatic candidiasis following single 150-mg FLZ dose therapy exceed 90%. In vitro, however, FLZ is fungistatic only in a narrow pH range and is not effective at vaginal pH, 4.2. This study evaluated the effect of FLZ on Candida albicans under in vitro conditions resembling the vaginal microenvironment, using vagina-simulative medium (VS). We found that FLZ was fungicidal for C. albicans in VS, but not in other media at the same pH, 4.2. In VS, FLZ was fungicidal at concentrations of >8 g/ml and reduced viability by greater than 99.9%. Analysis of the components of VS indicated that 17 mM acetic acid, a concentration achieved in the vagina, was responsible for the synergistic, fungicidal effect. This effect was not seen at neutral pH. Other substrates were not effective substitutes for acetic acid; however, short-chained carboxylic acids, glyoxylate and malonate, were effective. Most strains of C. albicans that were resistant to FLZ under standard conditions were killed by FLZ plus acetate. Other species of Candida were also killed, except C. krusei and C. glabrata. This study shows that FLZ has fungicidal activity for Candida species under in vitro conditions that mimic the vaginal microenvironment. This raises the possibility that FLZ may also have fungicidal effects during treatment of vaginal candidiasis. Elucidating the mechanism by which FLZ and acetate interact may disclose vulnerable pathways that could be exploited in drug development.

show abstract

mentioning

confidence: 99%

Fungicidal Activity of Fluconazole against Candida albicans in a Synthetic Vagina-Simulative Medium

Moosa¹,

Sobel²,

Elhalis

et al. 2004

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Fluconazole is the first of a new class of synthetic antifungal agents (22)(23)(24). The principal mechanism for its fungistatic action is inhibition of fungal cytochrome P-450 sterol C-14 alpha demethylation, which results in depletion of normal fungal sterols and accumulation of 14 alpha methyl sterols (30)(31)(32)34).…”

mentioning

confidence: 99%

Pharmacokinetics of 18F-labeled fluconazole in healthy human subjects by positron emission tomography

Fischman

Alpert

Livni

et al. 1993

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The distribution of fluconazole in tissue of human volunteers was determined by positron emission tomographic scanning over a 2-h period following the infusion of a tracer dose of 18F-fluconazole (5 to 7 mCi) plus 400 mg of unlabeled drug (the standard daily dose of fluconazole). Previous studies have validated this approach for animals. From serial positron emission tomographic imaging and blood sampling, pharmacokinetics of fluconazole in tissue were determined. There was significant distribution of the radiolabeled drug in all organs studied, with nearly constant levels achieved by 1 h. Since levels of fluconazole of >6 ,ug/g are needed to treat infection with most strains of Candida and levels of > 10 ,ug/g are needed for Cryptococcus neoformans, Coccidioides immitis, and Histoplasma capsulatum, the following predictions can be made. The current standard dose of 400 mg/day should be more than adequate in the treatment of urinary tract and hepatosplenic candidiasis but problematic in the treatment of candidal osteomyelitis, even with the higher levels that develop after multiple doses. Similarly, higher doses should be considered, particularly in immunocompromised patients, with infection with C. neoformans, H. capsulatum, and C. immitis that involves the central nervous and musculoskeletal systems.

show abstract

“…A descoberta do fluconazol foi resultado de um programa de pesquisa dirigido ao desenvolvimento de um agente antifúngico de amplo espectro de ação, ativo pelas vias oral e intravenosa, para tratamento de infecções superficiais e sistêmicas 18 . Os derivados imidazólicos foram escolhidos como materiais de partida porque eram geralmente bem tolerados e, também, porque ofereciam a vantagem de um modo de ação seletivo -a inibição de uma enzima crucial na biossíntese do ergosterol da membrana de fungos: a C-14 desmetilase 20 .…”

Section: A Descoberta Do Antifúngico Fluconazolunclassified

Importância do metabolismo no planejamento de fármacos

Pereira¹

2007

Quím. Nova

View full text Add to dashboard Cite

Recebido em 11/7/05; aceito em 10/2/06; publicado na web em 30/8/06 THE IMPORTANCE OF METABOLISM IN DRUG DESIGN. It is widely recognized that pharmacokinetic optimization needs to be addressed early in drug discovery to reduce the high failure rate in bringing drugs to market. Poor absorption, too short duration of action due to high elimination rate, or the presence of active metabolites are examples of properties that can potentially lead to unsuccessful clinical programmes. Here I describe a brief overview of advantages and molecular strategies for improving metabolic and pharmacokinetic properties applied to the discovery of fluconazol, β-blockers, ritonavir and ezetimibe and to the development of the prodrugs enalapril and bambuterol.Keywords: drug metabolism; drug design; structure-metabolism relationship. INTRODUÇÃOA ação de um fármaco, quando administrado a humanos ou animais, pode ser dividida em três fases: fase farmacêutica, fase farmacocinética e fase farmacodinâmica 1 (Esquema 1). Na fase farmacêutica, ocorre a desintegração da forma de dosagem, seguida da dissolução da substância ativa. A fase farmacocinética abrange os processos de absorção, distribuição, metabolismo e excreção (ADME), ou seja, "o que o organismo faz com o fármaco". A fase farmacodinâmica está relacionada com a interação do fármaco com seu alvo (receptor, enzimas etc.) e a conseqüente produção do efeito terapêutico, e pode ser entendida como "o que o fármaco faz no organismo".Nota-se que a fase farmacocinética pode ter profundo impacto sobre o efeito farmacológico, uma vez que os processos de ADME determinam a concentração e o tempo despendido das moléculas do fármaco no seu local de ação 2 . Tradicionalmente, a pesquisa de fármacos concentra seus esforços iniciais na fase farmacodinâmica. Triagens preliminares usam modelos in vitro, tais como enzimas, receptores ou tecidos, para obter a relação entre os novos compostos e sua potência agonista ou antagonista. A partir destes estudos, triagens secundárias e terciárias freqüentemente são dirigidas à administração do composto a animais, por via oral ou intravenosa, com observação do efeito farmacológico 3 . Entretanto, muitos dos compostos que se mostram promissores nos testes in vitro não apresentam boa atividade em animais 4 . Esta falha de correlação, muitas vezes associada a problemas farmacocinéticos dos compostos, como baixa biodisponibilidade, duração de ação (muito curta ou muito longa), ou a presença de metabólitos ativos, pode levar a programas clíni-cos mal-sucedidos. Para ilustrar, Prentis e colaboradores 5 relata- No processo de descoberta de novos medicamentos, a previsão dos processos de ADME logo nos estágios iniciais da pesquisa é de extrema importância 6 . A otimização destas propriedades, através de modificações moleculares de compostos promissores, é essencial na seleção de compostos candidatos com maiores probabilidades de não serem abandonados, mais adiante, na fase clínica. O fracasso na fase clínica representa grandes perdas de tempo e dinheiro 7 . Dentre as e...

show abstract

Discovery of Fluconazole, a Novel Antifungal Agent

Cited by 113 publications

References 6 publications

Fungicidal Activity of Fluconazole against Candida albicans in a Synthetic Vagina-Simulative Medium

Fungicidal Activity of Fluconazole against Candida albicans in a Synthetic Vagina-Simulative Medium

Pharmacokinetics of 18F-labeled fluconazole in healthy human subjects by positron emission tomography

Importância do metabolismo no planejamento de fármacos

Contact Info

Product

Resources

About