Fluconazole and Other Azoles: Translation of in Vitro Activity to in Vivo and Clinical Efficacy

Troke, Peter F.; Andrews, R. J.; Pye, G.; Richardson, K.

doi:10.1093/clinids/12.supplement_3.s276

Cited by 53 publications

(31 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Selectivity, rather than potency or affinity, is the most relevant feature that impacts on drug efficacy in vivo (Mattie et al, 1989;Troke et al, 1990;Brook, 1991;Vella and Floridia, 1998;Waldman, 2002). For example, despite its high TrkA binding affinity (K d , 10-100 pM), NGF has a narrow therapeutic window partly because of poor selectivity (e.g., it binds p75 receptors), partly because of pleiotropic activation, and partly because of a short half-life.…”

Section: Efficacy and Selectivitymentioning

confidence: 99%

Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

Bruno¹,

Clarke²,

Seltzer³

et al. 2004

J. Neurosci.

View full text Add to dashboard Cite

Previously, we developed a proteolytically stable small molecule peptidomimetic termed D3 as a selective ligand of the extracellular domain of the TrkA receptor for the NGF. Ex vivo D3 was defined as a selective, partial TrkA agonist. Here, the in vivo efficacy of D3 as a potential therapeutic for cholinergic neurons was tested in cognitively impaired aged rats, and we compared the consequence of partial TrkA activation (D3) versus full TrkA/p75 activation (NGF). We show that in vivo D3 binds to TrkA receptors and affords a significant and long-lived phenotypic rescue of the cholinergic phenotype both in the cortex and in the nucleus basalis. The cholinergic rescue was selective and correlates with a significant improvement of memory/learning in cognitively impaired aged rats. The effects of the synthetic ligand D3 and the natural ligand NGF were comparable. Small, proteolytically stable ligands with selective agonistic activity at a growth factor receptor may have therapeutic potential for neurodegenerative disorders.

show abstract

Section: Efficacy and Selectivitymentioning

confidence: 99%

Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

Bruno¹,

Clarke²,

Seltzer³

et al. 2004

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Unfortunately, standardized in vitro methods for assessment of the intrinsic activity of antifungal agents are not available. In addition, most of the in vitro methods that are used are criticized because of the poor correlation with in vivo antifungal activity (5,6,11,12,18,27,28,36).…”

mentioning

confidence: 99%

Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans

Etten

Rhee

Kampen

et al. 1991

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans were studied. With respect to the extracellular growth of C. albicans, antifungal activity was measured in terms of MICs and minimal fungicidal concentrations as well as by determination of the concentration that effectively killed (>99.9%) C. albicans in the absence or presence (amphotericin B only) of serum. Amphotericin B was highly active in terms of killing, even at an increased inoculum size. In the presence of serum, amphotericin B activity was substantially reduced. For fluconazole, activity was restricted to inhibition of fungal growth, even after the inoculum size was reduced. With respect to the intracellular growth of C. albicans, antifungal activity was measured by using monolayers of murine peritoneal macrophages infected with C. albicans and was measured in terms of inhibition of germ tube formation as well'as effective killing (>99%) of C. albicans. Amphotericin B was highly active against C. albicans. At an increased ratio of infection, amphotericin B activity was slightly reduced. Fluconazole had no antifungal activity. Neither a reduction in the ratio of infection nor exposure of C. albicans to fluconaz'ole prior to macrophage ingestion resulted in activity against intracellular C. albicans by fluconazole. Previous exposure of C. albicans to amphotericin B resulted in increased intracellular activity of amphotericin B. The. intracellular antifungal activity of the combination of fluconazole with amphotericin B was les than that of amphotericin B alone. Amphotericin B showed fungicidal activity against C. albicans growing both extracellularly and intracellularly, whereas fluconazole inhibited growth only of extracellular C. albicans. A slight antagonistic effect between fluconazole and aiflphotericin B was found with respect to intracellular as well as extracellular C. albicans.Deep-seated candidal infections are an important cause of morbidity and mortality in immunocompromised patients (15,21,22). The current drug of choice for most systemic mycoses is still amphotericin B (AmB), but its use is restricted by a variety of toxic side effects (6,13,15,21,22). Consequently, there is a need for effective and less toxic drugs for the treatment of patients with these infections. One of these antifungal agents is the triazole fluconazole (Flu) (4,10,14,33,34,41). In vivo experimental studies suggested that Flu is active against disseminated candidiasis (8,9,29,31,32,35,37). Recently, the antifungal efficacy of Flu was demonstrated in persistently granulocytopenic rabbits when it was used for prevention or early treatment (39,40). Little is still known, however, on the role of Flu in the treatment of systemic candidiasis in immunocompromised patients. Since the host defense mechanisms in these patients are severely impaired, the intrinsic antifungal activity of the antifungal agent is of great importance for effective treatment. Unfortunately, standardized in vitro methods for assessment of ...

show abstract

“…The excellent efficacies of TAK-456 in mycoses in neutropenic mice suggest a potent clinical efficacy of TAK-456, since deep-seated mycoses occur frequently in the immunocompromised patients with severe underlying diseases. Although we have not yet tested the in vivo activity of TAK-456 against the non-albicans Candida strains, it is expected that TAK-456 is active against systemic infections with these species, since TAK-456 showed Itraconazole possesses potent in vitro activity against fluconazole-resistant C. albicans and A. fumigatus (23). Although in vitro activities of TAK-456 against these strains were comparable to those of itraconazole, TAK-456 showed in vivo activity superior to that of itraconazole against some infections with fluconazole-resistant C. albicans and A. fumigatus at a dose of 10 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

“…The major opportunistic pathogens are Candida albicans and Aspergillus fumigatus (6,18,22). Although triazole antifungal agents such as fluconazole and itraconazole are used to treat mycoses (5,8), their clinical efficacies are still limited, especially against A. fumigatus (10,13,23). Moreover, an increase of azole-resistant C. albicans (1,7,20) and non-C. albicans Candida species (19,27), which are refractory to the repeated treatment with fluconazole, is also a big problem.…”

mentioning

confidence: 99%

In Vitro and In Vivo Antifungal Activities of TAK-456, a Novel Oral Triazole with a Broad Antifungal Spectrum

Tsuchimori

Hayashi

Kitamoto

et al. 2002

Antimicrob Agents Chemother

View full text Add to dashboard Cite

TAK-456 is a novel oral triazole compound with potent and broad-spectrum in vitro antifungal activity and strong in vivo efficacy against Candida albicans and Aspergillus fumigatus. TAK-456 inhibited sterol synthesis of C. albicans and A. fumigatus by 50% at 3 to 11 ng/ml. TAK-456 showed strong in vitro activity against clinical isolates of Candida spp., Aspergillus spp., and Cryptococcus neoformans, except for Candida glabrata. The MICs at which 90% of the isolates tested were inhibited byTAK-456, fluconazole, itraconazole, voriconazole, and amphotericin B were 0.25, 4, 0.5, 0.13, and 0.5 g/ml, respectively, for clinical isolates of C. albicans and 1, >64, 0.5, 0.5, and 0.5 g/ml, respectively, for clinical isolates of A. fumigatus. Therapeutic activities of TAK-456 and reference triazoles against systemic lethal infections caused by C. albicans and A. fumigatus in mice were investigated by orally administering drugs once daily for 5 days, and efficacies of the compounds were evaluated by the prolongation of survival. In normal mice, TAK-456 and fluconazole were effective against infection caused by fluconazole-susceptible C. albicans at a dose of 1 mg/kg. In transiently neutropenic mice, therapeutic activity of TAK-456 at 1 mg/kg of body weight against infection with the same strain was stronger than those at 1 mg/kg of fluconazole. TAK-456 was effective against infections with two strains of fluconazole-resistant C. albicans at a dose of 10 mg/kg. TAK-456 also expressed activities similar to or higher than those of itraconazole against the infections caused by two strains of A. fumigatus in neutropenic mice at a dose of 10 mg/kg. These results suggest that TAK-456 is a promising candidate for development for the treatment of candidiasis and aspergillosis in humans.

show abstract

Fluconazole and Other Azoles: Translation of in Vitro Activity to in Vivo and Clinical Efficacy

Cited by 53 publications

References 6 publications

Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans

In Vitro and In Vivo Antifungal Activities of TAK-456, a Novel Oral Triazole with a Broad Antifungal Spectrum

Contact Info

Product

Resources

About