Preliminary study on in vitro activity and cytotoxicity on cell cultures of a new polyene antifungal molecule (SPA-S-843)

Pessina, Augusto; Rossoni, Lorena; Piccirillo, Michela; Sala, Giuliana; Neri, Maria Grazia

doi:10.1016/s0939-6411(98)00065-4

Cited by 3 publications

(2 citation statements)

References 6 publications

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“…The cytotoxicity on cell cultures revealed that SPK-843 was less toxic than AMB (6). With intravenous administration of AMB in conventional strains of mice, such as ICR or DBA2/N, the antifungal efficacy of 2.0 mg/kg is less than that of 1.0 mg/kg due to acute toxicities (data not shown).…”

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confidence: 96%

Efficacy of SPK-843, a Novel Polyene Antifungal, in a Murine Model of Systemic Cryptococcosis

Kakeya

Miyazaki

Senda

et al. 2008

Antimicrob Agents Chemother

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SPK-843, a new polyene antifungal, possessed efficacy in a murine model of systemic infection caused byCryptococcus neoformans. The administration of 4.0 mg/kg SPK-843 led to better survival prolongation and fungal reduction than those observed with the administration of 0.7 mg/kg amphotericin B and 80 mg/kg fluconazole (P < 0.001), without histopathological renal changes.Cryptococcus neoformans is fungus that is an important cause of morbidity and mortality in immunocompromised patients. Central nervous system infection by C. neoformans is a major clinical concern for those patients. Amphotericin B (AMB), lipid-associated formulations of AMB, and fluconazole (FLC) are current standard antifungals used against cryptococcal central nervous system infection; however, the toxicity of AMB and the fungistatic characteristics of FLC sometimes limit their usage and clinical efficacy. Consequently, effective antifungal agents with fungicidal activity and low toxicity are required.SPK-843 is a new polyene antifungal which is a water-soluble diascorbate salt from SPA-S-752, an amide derivative of partricin A produced by a mutant strain of Streptomyces aureofaciens. SPK-843 is reported to have in vitro inhibitory activity equal to or better than that of AMB against Candida spp., C. neoformans, and Aspergillus spp. (4,7,8), and the pharmacokinetics of SPK-843 was well determined to possess a profile suitable for its therapeutic effect (1, 2). In this work, we evaluated in a murine model of systemic cryptococcosis the treatment efficacy of SPK-843 compared to AMB and FLC.AMB (Fungizone; Bristol-Myers Squibb K.K., Tokyo, Japan) and FLC (Pfizer Inc., New York) were dissolved in a 5% glucose solution, and SPK-843 (Kaken Pharmaceutical Co., Tokyo, Japan) was dissolved in a 10% lipid emulsion (Terumo, Tokyo, Japan). The MICs of antifungals were determined by the microdilution method, according to standard M27-A of the Clinical Laboratory Standards Institute. In the cryptococcosis model, 8-week-old female BALB/c mice (Charles River Inc., Yokohama, Japan) were inoculated via the tail vein with a lethal dose of 6 ϫ 10 5 to 8 ϫ 10 5 cells of C. neoformans (YC-11) (3). The mice were treated once daily intravenously with the drugs or the vehicles (n ϭ 10) daily for 5 days after the fungal inoculation. Each experiment was repeated two times to confirm the reproducibility of results. The maximum tolerated dose of each drug was included as the highest dose for the mouse strain. For the analysis of fungal burden in the brain and histopathological changes in brain, kidneys, and liver, the animals were sacrificed 7 days after inoculation. The guidelines of the Nagasaki University Laboratory Animal Center for Biomedical Research for animal experimentation were followed. Tests for differences in survival distributions were based on a generalized log rank test from survival rates calculated by the Kaplan-Meier method. The mean numbers of CFU per brain from the mycological study were compared by Scheffe's multiple-comparison test. A P value of l...

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confidence: 96%

Efficacy of SPK-843, a Novel Polyene Antifungal, in a Murine Model of Systemic Cryptococcosis

Kakeya

Miyazaki

Senda

et al. 2008

Antimicrob Agents Chemother

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“…This implies that nystatin, another commonly used fungicide that is a structural analog of amphotericin B, is probably also toxic to sponge cells (Hahn et al, 1996). However, other fungicides, such as SPA-S-843 (Pessina et al, 1999) and hexachlorobenzene (Salmon et al, 2002), have been found to be toxic to eukaryotic cell cultures and may affect spongecell viability. Therefore, one should carefully assess the effects of fungicides on cell viability before application in sponge-cell culture media.…”

Section: Amphotericin Bmentioning

confidence: 99%

The life and death of sponge cells

Sipkema

Snijders

Schroën

et al. 2003

Biotech & Bioengineering

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Cell viability is an essential touchstone in the study of the effect of medium components on cell physiology. We developed a flow-cytometric assay to determine sponge-cell viability, based on the combined use of fluorescein diacetate (FDA) and propidium iodide (PI). Cell fluorescence measurements based on incubation of cells with FDA or PI resulted in a useful and reproducible estimate of the viability of primary sponge-cell cultures. We studied the effects of temperature, ammonium, and the fungicide amphotericin B on the viability of a primary-cell culture from the marine sponge Suberites domuncula using the aforementioned flow-cytometric assay. S. domuncula cells die rapidly at a temperature of >or=22 degrees C, but they are insensitive to ammonium concentrations of up to 25 mM. Amphotericin B, which is frequently used in sponge-cell culture media, was found to be toxic to S. domuncula cells.

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Methods for the Recovery and Purification of Polyene Antifungals

Worthen

Jay

Bummer

2001

Drug Development and Industrial Pharmacy

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Despite the development of newer antifungal drugs, the polyene antifungals continue to be the most potent broad-spectrum fungicides available for clinical use. The incidence and severity of fungal infections are on the rise, underscoring the need for new and more effective antifungal drugs. Thus, the search for new polyene antifungals is ongoing. The limited solubility, polymorphic character, and inherent chemical instability of these compounds make their economical recovery and purification from mass culture challenging problems in biotechnology. This article provides a comprehensive review of the methods that have been developed for the recovery and purification of amphotericin B and nystatin, the two most important polyenes currently in clinical use.

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Preliminary study on in vitro activity and cytotoxicity on cell cultures of a new polyene antifungal molecule (SPA-S-843)

Cited by 3 publications

References 6 publications

Efficacy of SPK-843, a Novel Polyene Antifungal, in a Murine Model of Systemic Cryptococcosis

Efficacy of SPK-843, a Novel Polyene Antifungal, in a Murine Model of Systemic Cryptococcosis

The life and death of sponge cells

Methods for the Recovery and Purification of Polyene Antifungals

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