Comparison of the in Vitro Antifungal Activities of Miconazole and a New Imidazole, R41,400

Dixon, Dennis R.; Shadomy, Smith; Shadomy, H. Jean; Espinel-Ingroff, Ana; Kerkering, Thomas M.

doi:10.1093/infdis/138.2.245

Cited by 136 publications

(45 citation statements)

References 5 publications

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“…The in vitro activity of ketoconazole was first reported by Dixon et al (73) in 1978. These investigators studied 175 isolates of pathogenic yeasts and filamentous fungi and observed that ketoconazole was comparable to miconazole in all cases and was more active than miconazole against isolates of Coccidioides immitis.…”

Section: Ketoconazolementioning

confidence: 97%

Overview of medically important antifungal azole derivatives

1988

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Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739).

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Section: Ketoconazolementioning

confidence: 97%

Overview of medically important antifungal azole derivatives

1988

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“…The high activity of KTZ in vivo against candidosis is in striking contrast to its low activity against C. albicans in vitro in conventional culture media (4).…”

mentioning

confidence: 88%

Entry of ketoconazole into Candida albicans

Boiron¹,

Drouhet²,

Dupont³

et al. 1987

Antimicrob Agents Chemother

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To define characteristics that determine the entry of ketoconazole (KTZ) into Candida albicans cells, we studied the uptake of [3H]KTZ. The cells rapidly and markedly concentrated the drug: 30% of the final 80-fold intracellular concentration was attained in less than 1 min, and >60% was attained in 10 min. Penetration of [3H]KTZ at an extracellular concentration higher than 0.1875 FM (0.1 ,ug/ml) occurred by a simple diffusion mechanism. At lower concentrations, accumulation of the drug was an active, energy-requiring process, dependent at least in part on glycolysis, and pH dependent (optimal pH, 6.6). The active transport system had a high binding affinity (Km = 50 nM) and a high maximum velocity of uptake (V..x = 1.4 ,umol min -10-7 cells). It was not possible to displace intracellular [3H]KTZ with high concentrations of unlabeled KTZ or other antifungal agents. These findings suggest that KTZ is rapidly taken up, highly concentrated, and tightly bound to cellular components of C. albicans.Ketoconazole (KTZ) (12) is a broad-spectrum antifungal agent which is active against a variety of pathogenic fungi, including Candida albicans and dermatophytes (5). Several investigators (13, 16) have shown that low concentrations of KTZ inhibit ergosterol synthesis by blocking C-14 demethylation. This fungistatic action can be related to the accumulation of a-methylated intermediates, such as lanosterol, in the fungal membrane. It can also be related to the depletion of ergosterol, which is specifically required for membrane integrity. A recent study (1) showed that high concentrations of KTZ can have a rapid fungicidal action by direct membrane-damaging effect on C. albicans cells.The high activity of KTZ in vivo against candidosis is in striking contrast to its low activity against C. albicans in vitro in conventional culture media (4).The ability of antifungal agents to enter yeast cells may be an important factor affecting pathogen susceptibility and the outcome of therapy.Because little is known about the factors which mediate the entry of KTZ into C. albicans cells and about the permeation process, we examined the in vitro uptake of this antifungal agent. MATERIALS AND METHODSOrganism and growth conditions. C. albicans IP 740, supplied by the Collection of the Institut Pasteur, Paris, France, was maintained on Casitone (Difco Laboratories, Detroit, Mich.) liquid medium at 37°C (5).Materials and drugs. Unlabeled KTZ and [3H]KTZ were gifts from Janssen Pharmaceutica, Beerse, Belgium. The labeled material has a specific activity of 445.8 mCi/mmol. Radioactivity was measured in a liquid scintillation counter (LKB 1211 Rackbeta liquid scintillation system).Determination of KTZ uptake by C. albicans. Cells grown in the absence of drug for 16 h were harvested, washed three times, and incubated in 0.1 M phosphate buffer (pH 7.4) at 370C.For most experiments, [3H]KTZ was added to a suspension of yeast cells at a final concentration of 0.1875 ,uM (0.1 ,ug/ml; containing 83.9 nCi of radioactivity per ml), which is the MIC for...

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“…First time imidazole was prepared in 1858. Now-a-days several methods of sythesis of imidazoles are available some of these are given below in Schemes 1-9 [20][21][22][23][24][25][26][27][28][29]. From alkene, carbon monoxide and ammonia [25].…”

Section: Synthesis Of Imidazole and Their Derivativesmentioning

confidence: 99%

Studies on Imidazole and Its Derivatives with Particular Emphasis on Their Chemical/biological Applications as Bioactive Molecules/Intermediated to Bioactive Molecule

kumar¹,

Kumar²,

Raj³

2017

Curr Synthetic Sys Biol

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Imidazoles are heterocycles with five-member ring structure heterocyclic compounds have gained very remarkable place in recent years because of their exceptional pharmacological activities. The imidazole nucleus is a main synthetic strategy in drug discovery. Imidazole is a planar five-member ring system having N atom at 1 and 3 positions. The systemic name for the compound is 1, 3 diazoles, one of the N bear an H atom and other to be termed as a pyrrole type N. Imidazole was first named as glyoxaline. It is amphoteric in nature, and it has susceptibility to be attacked by electrophile and nucleophile. It is a constituent of the purine nucleus and histidine amino acid, 4-amino imidazole-5-carboxamide found naturally as a riboside. This interesting group of heterocyclic compounds has wide range biological activities such as, analgesic, anti-inflammatory anticancer, antiviral, anthelmintic, anticonvulsant, antiulcer, antimicrobial, anti-allergic activity etc. Various methods employed for the synthesis of imidazole's and their chemical structure reactions offer enormous scope in the field of medicinal chemistry.

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Comparison of the in Vitro Antifungal Activities of Miconazole and a New Imidazole, R41,400

Cited by 136 publications

References 5 publications

Overview of medically important antifungal azole derivatives

Overview of medically important antifungal azole derivatives

Entry of ketoconazole into Candida albicans

Studies on Imidazole and Its Derivatives with Particular Emphasis on Their Chemical/biological Applications as Bioactive Molecules/Intermediated to Bioactive Molecule

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