scholarly journals Efficacy of FK463, a New Lipopeptide Antifungal Agent, in Mouse Models of Pulmonary Aspergillosis

2000 ◽  
Vol 44 (3) ◽  
pp. 619-621 ◽  
Author(s):  
Satoru Matsumoto ◽  
Yoshimi Wakai ◽  
Toru Nakai ◽  
Kazuo Hatano ◽  
Tomoe Ushitani ◽  
...  
Keyword(s):  
Animal Model ◽  
Body Weight ◽  
Mouse Models ◽  
Antifungal Agent ◽  
Target Organ ◽  
Water Soluble ◽  
Pulmonary Aspergillosis ◽  
Intranasal Inoculation ◽  
Effective Doses ◽  
Immunosuppressed Mice

ABSTRACT The efficacy of FK463, a novel water-soluble lipopeptide, was evaluated in mouse models of pulmonary aspergillosis and was compared with that of amphotericin B (AMPH-B). In the pulmonary aspergillosis models induced by intranasal inoculation, FK463 exhibited good efficacy, with 50% effective doses in the range of 0.26 to 0.51 mg/kg of body weight; these values were comparable to those of AMPH-B. In anAspergillus target organ assay with immunosuppressed mice, under conditions of constant plasma levels of FK463, using a subcutaneously implanted osmotic pressure pump, a significant reduction in viable fungal cells was observed at plasma FK463 levels of 0.55 to 0.80 μg/ml or higher. We conclude that FK463 is highly effective in the treatment of pulmonary aspergillosis in this animal model. These results indicate that FK463 may be a potent parenterally administered antifungal agent for pulmonary aspergillosis.

scholarly journals Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive pulmonary aspergillosis.

1997 ◽  
Vol 41 (3) ◽  
pp. 696-698 ◽  
Author(s):  
M Murphy ◽  
E M Bernard ◽  
T Ishimaru ◽  
D Armstrong
Keyword(s):  
Body Weight ◽  
Experimental Model ◽  
Antifungal Agent ◽  
Invasive Pulmonary Aspergillosis ◽  
Clinical Isolates ◽  
Aspergillus Species ◽  
Pulmonary Aspergillosis

Voriconazole, a new azole antifungal agent, showed potent activity against clinical isolates of Aspergillus spp. in vitro. For A. fumigatus, the MIC range was < 0.03 to 0.5 microgram/ml and the MIC at which 90% of isolates are inhibited was 0.25 microgram/ml. In an experimental model of invasive pulmonary aspergillosis which mimics infection in humans, oral voriconazole at dosages of 30 mg/kg of body weight per day significantly delayed or prevented mortality.

scholarly journals In Vitro and In Vivo Activities of CS-758 (R-120758), a New Triazole Antifungal Agent

2002 ◽  
Vol 46 (2) ◽  
pp. 367-370 ◽  
Author(s):  
Yasuki Kamai ◽  
Tamako Harasaki ◽  
Takashi Fukuoka ◽  
Satoshi Ohya ◽  
Katsuhisa Uchida ◽  
...  
Keyword(s):  
Body Weight ◽  
Amphotericin B ◽  
Antifungal Agent ◽  
The Other ◽  
In Vitro Activity ◽  
Effective Doses ◽  
Low Levels ◽  
Systemic Infections

ABSTRACT The activity of CS-758 (R-120758), a new triazole antifungal agent, was evaluated and compared with those of fluconazole, itraconazole, and amphotericin B in vitro and with those of fluconazole and itraconazole in vivo. CS-758 exhibited potent in vitro activity against clinically important fungi. The activity of CS-758 against Candida spp. was superior to that of fluconazole and comparable or superior to those of itraconazole and amphotericin B. CS-758 retained potent activity against Candida albicans strains with low levels of susceptibility to fluconazole (fluconazole MIC, 4 to 32 μg/ml). Against Aspergillus spp. and Cryptococcus neoformans, the activity of CS-758 was at least fourfold superior to those of the other drugs tested. CS-758 also exhibited potent in vivo activity against murine systemic infections caused by C. albicans, C. neoformans, Aspergillus fumigatus, and Aspergillus flavus. The 50% effective doses against these infections were 0.41 to 5.0 mg/kg of body weight. These results suggest that CS-758 may be useful in the treatment of candidiasis, cryptococcosis, and aspergillosis.

scholarly journals Pretreatment with Empty Liposomes Attenuates the Immunopathology of Invasive Pulmonary Aspergillosis in Corticosteroid-Immunosuppressed Mice

2006 ◽  
Vol 51 (3) ◽  
pp. 1078-1081 ◽  
Author(s):  
Russell E. Lewis ◽  
Georgios Chamilos ◽  
Randall A. Prince ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Body Weight ◽  
Antifungal Activity ◽  
Amphotericin B ◽  
Murine Model ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis ◽  
Amphotericin B Deoxycholate ◽  
Immunomodulatory Properties ◽  
Immunosuppressed Mice

ABSTRACT In a nonneutropenic murine model of invasive pulmonary aspergillosis, pretreatment with empty liposomes (E-lipo) was nearly as effective as 10 mg/kg of body weight liposomal amphotericin B and superior to 1 mg/kg amphotericin B deoxycholate. The beneficial immunomodulatory properties of E-lipo appear to compensate for their lack of direct antifungal activity.

scholarly journals Efficacy of FK463, a New Lipopeptide Antifungal Agent, in Mouse Models of Disseminated Candidiasis and Aspergillosis

2000 ◽  
Vol 44 (3) ◽  
pp. 614-618 ◽  
Author(s):  
Fumiaki Ikeda ◽  
Yoshimi Wakai ◽  
Satoru Matsumoto ◽  
Katsuyuki Maki ◽  
Etsuko Watabe ◽  
...  
Keyword(s):  
Mouse Models ◽  
Suppressive Effect ◽  
Inoculum Size ◽  
Water Soluble ◽  
Yeast Cells ◽  
Control Group ◽  
Disseminated Candidiasis ◽  
Group A ◽  
Effective Doses ◽  
Disseminated Aspergillosis

ABSTRACT The efficacy of intravenous injection of FK463, a novel water-soluble lipopeptide, was evaluated in mouse models of disseminated candidiasis and aspergillosis and was compared with those of fluconazole (FLCZ) and amphotericin B (AMPH-B). In the candidiasis model, FK463 significantly prolonged the survival of intravenously infected mice at doses of 0.125 mg/kg of body weight or higher. In disseminated candidiasis caused by Candida species, including FLCZ-resistant Candida albicans, FK463 exhibited an efficacy 1.4 to 18 times inferior to that of AMPH-B, with 50% effective doses (ED50s) ranging from 0.21 to 1.00 mg/kg and 0.06 to 0.26 mg/kg, respectively, and was much more active than FLCZ. The protective effect of FK463 was not obviously influenced by the fungal inoculum size, the starting time of the treatment, or the immunosuppressed status of the host. The reduction in efficacy was less than that observed with FLCZ or AMPH-B. The efficacy of FK463 was also evaluated in the disseminated candidiasis target organ assay and was compared with those of FLCZ and AMPH-B. Efficacies were evaluated on the basis of a comparison between the mean log10 CFU in kidneys in the groups treated with antifungal agents and that in control group. A single dose of FK463 at 0.5 mg/kg or higher significantly reduced the viable counts in kidneys compared with the numbers of yeast cells before treatment, and its efficacy was comparable to that of AMPH-B, while FLCZ at 4 mg/kg showed only a suppressive effect on the growth of C. albicans in the kidneys. In the disseminated aspergillosis model, FK463 given at doses of 0.5 mg/kg or higher significantly prolonged the survival of mice infected intravenously with Aspergillus fumigatus conidia. The efficacy of FK463 was about 2 times inferior to that of AMPH-B, with ED50s ranging from 0.25 to 0.50 mg/kg and 0.11 to 0.29 mg/kg, respectively. These results indicate that FK463 may be a potent parenterally administered therapeutic agent for disseminated candidiasis and aspergillosis.

scholarly journals EDTA as an Adjunct Antifungal Agent for Invasive Pulmonary Aspergillosis in a Rodent Model

2006 ◽  
Vol 50 (5) ◽  
pp. 1823-1827 ◽  
Author(s):  
Ray Hachem ◽  
Paul Bahna ◽  
Hend Hanna ◽  
L. Clifton Stephens ◽  
Issam Raad
Keyword(s):  
Body Weight ◽  
Antifungal Agent ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Optimal Dosing ◽  
Amphotericin B Lipid Complex ◽  
Severe Lung

ABSTRACT Rats immunosuppressed by the administration of cyclophosphamide and cortisone acetate and then infected with Aspergillus fumigatus were treated with an antifungal drug, EDTA, or a combination of one of the antifungal agents, amphotericin B lipid complex (ABLC; 5 mg/kg of body weight/day for 7 days), and EDTA (30 mg/kg/day for 7 days). The mortality rate was reduced, the duration of survival was increased, fewer A. fumigatus organisms were recovered from the lungs, and less-severe lung lesions were seen histopathologically in the rats receiving the combination treatment than in the rats receiving either an antifungal agent or EDTA alone. Further studies regarding the mechanisms of EDTA and its interactions with ABLC are warranted, and further studies are needed to more fully examine the safety, tolerance, and optimal dosing of EDTA in the treatment of this and other fungal infections.

scholarly journals T-8581, a new orally and parenterally active triazole antifungal agent: in vitro and in vivo evaluations.

1997 ◽  
Vol 41 (1) ◽  
pp. 30-34 ◽  
Author(s):  
A Yotsuji ◽  
K Shimizu ◽  
H Araki ◽  
K Fujimaki ◽  
N Nishida ◽  
...  
Keyword(s):  
Optical Density ◽  
Antifungal Agent ◽  
Geometric Mean ◽  
Water Soluble ◽  
Concentration Time ◽  
Effective Doses ◽  
High Concentrations ◽  
Drug Free

T-8581 is a new water-soluble triazole antifungal agent. The geometric mean IC80s (GM-IC80S; where the IC80 is the lowest drug concentration which reduced the optical density at 630 nm by 80% compared with the optical density at 630 nm of the drug-free control) for Candida albicans were as follows: T-8581, 0.218 microgram/ml; fluconazole; 0.148 microgram/ml; and itraconazole, 0.0170 microgram/ml. For Cryptococcus neoformans the GM-IC80s were as follows: T-8581, 9.28 micrograms/ml; fluconazole, 4.00 micrograms/ml; and itraconazole, 0.119 microgram/ml. For Aspergillus fumigatus the GM-IC80s were as follows: T-8581, 71.0 micrograms/ml; fluconazole, 239 micrograms/ml; and itraconazole, 0.379 microgram/ml. Against systemic candidiasis in mice, the 50% effective doses (ED50s) of T-8581, fluconazole, and itraconazole (given orally) were 0.412, 0.392, and > 320 mg/kg of body weight, respectively. Against systemic aspergillosis in mice, the ED50s of T-8581, fluconazole, and itraconazole (given orally) were 50.5, 138, > 320 mg/kg, respectively. T-8581 was also efficacious when it was given parenterally (ED50, 59.2 mg/kg), while the ED50 of fluconazole given parenterally was > 20 mg/kg. Against systemic aspergillosis in rabbits, T-8581 was more effective than fluconazole and itraconazole in prolonging the life span. The high concentrations of T-8581 were observed in the sera of mice, rats, rabbits and dogs. Species differences in half-lives and areas under the concentration-time curves were observed, with the values for mice, rats, rabbits, and dogs increasing in that order. These results suggest that T-8581 would be a potentially effective antifungal drug for oral and parenteral use.

Effect of direct infusion of antifungal agent on invasive pulmonary aspergillosis in a patient with acute leukemia

2002 ◽  
Vol 8 (1) ◽  
pp. 106-108 ◽  
Author(s):  
Kazunori Nakase ◽  
Akira Yazaki ◽  
Hiroshi Shiku ◽  
Sigehisa Tamaki ◽  
Motoaki Tanigawa ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Antifungal Agent ◽  
Invasive Pulmonary Aspergillosis ◽  
Direct Infusion ◽  
Pulmonary Aspergillosis

DOSAGE OF DRUGS IN INFANTS AND CHILDREN: III. NEOSTIGMINE

PEDIATRICS ◽  
1956 ◽  
Vol 18 (1) ◽  
pp. 31-38
Author(s):  
Paul R. Patterson ◽  
Earle L. Lipton ◽  
Klaus R. Unna ◽  
Kurt Glaser
Keyword(s):  
Body Weight ◽  
Gastrointestinal Motility ◽  
Age Groups ◽  
Sweat Glands ◽  
Healthy Children ◽  
Controlled Experiments ◽  
Hypodermic Injection ◽  
Effective Doses ◽  
In Infants And Children ◽  
Stimulation Of

The susceptibility of healthy children to neostigmine by hypodermic injection was studied in controlled experiments on 45 children ranging in age from 1 month to 12 years. Minimum effective doses (MED) of neostigmine were determined by their effect in stimulating salivary and sweat glands, and in increasing gastrointestinal motility. The MED of neostigmine for stimulation of salivation is in all age groups smaller (by 6 to 38 per cent) than the MED increasing gastrointestinal motility. The average MED either for glandular (.025 to .036 mg./kg.) or gastrointestinal (.036 to .045 mg./kg.) activity fails to show significant differences among the various age groups when expressed in terms of body weight. Exceptions were found exclusively in children weighing more than 30 kg. The findings do not support the view that a physiologic vagotonia is present in infants.

Abstract 064: 20-HETE Contributes to Vasoconstriction of Renal Microvessels and Sodium Retention in Cyp4a14-/- Mice, a Model of 20-HETE Dependent Hypertension

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Ankit Gilani ◽  
Varunkumar Pandey ◽  
Joseph Zullo ◽  
Priyanka Mishra ◽  
John R Falck ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Isotonic Saline ◽  
Urinary Sodium Excretion ◽  
Water Soluble ◽  
Arachidonic Acid Metabolite ◽  
Male Mice ◽  
Kidney Weight ◽  
Doppler Flowmetry ◽  
In The Wild

20-HETE (20-Hydroxyeicosatetraenoic acid), is a cytochrome P450 (CYP) 4A-derived arachidonic acid metabolite. 20-HETE has been linked to both pro-hypertensive (via increased vasoconstriction, vascular remodeling and vascular injury of renal microvessels) and anti-hypertensive (inhibiting ion transport in the distal nephron) functions. In this study we examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water soluble antagonist of the actions of 20-HETE on renal hemodynamics and sodium (Na) excretion in Cyp4a14 knockout (CYP4a14-/-) male mice. The CYP4a14-/- male mice display hypertension accompanied by increased vascular 20-HETE levels. Administration of 20-SOLA (10mg/kg/day in drinking water) normalized blood pressure (BP) in male Cyp4a14-/- mice at day 10 of treatment (124±1 vs. 153±2 mmHg in untreated male Cyp4a14-/- mice; p<0.05). The normalization of blood pressure was accompanied by transient increase in the urinary sodium excretion in the Cyp4a14-/- male mice (8.3±0.7 vs. 5.8±0.5 μmol/g body weight/day; p<0.05). Importantly, 20-SOLA increased glomerular filtration rate (GFR) of Cyp4a14-/- mice (2.38±0.05 vs. 1.88±0.18 μL/min/mg kidney weight, p<0.05) as opposed to no changes observed in the wild type (WT: (2.26±0.18 vs. 2.33±0.20μL/min/mg kidney weight). Evaluation of the renal blood flow (RBF) by laser Doppler flowmetry showed that treatment with 20-SOLA increased the RBF in Cyp4a14-/- mice by 12.3±4%, which remained unaltered in the WT. Additionally, the pressure-induced myogenic tone of isolated preglomerular microvessels was significantly elevated in Cyp4a14-/- mice; 20-SOLA treatment prevented the increase in myogenic responses. The natriuretic response to an isotonic saline loading challenge (10% of body weight, IP) was significantly attenuated in the Cyp4a14-/- mice as compared to the WT (35.5±2.8 vs. 57.4±8.3 percentage of Na load, p<0.05); this was corrected by 20-SOLA (61.7±5.7 percentage of Na load, p<0.05). These results confirm that 20-SOLA normalizes blood pressure of Cyp4a14-/- male mice and demonstrates that this is associated with increases in GFR, RBF and natriuresis.

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