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Thomas J. Walsh - One of the best experts on this subject based on the ideXlab platform.
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dosage dependent antifungal efficacy of v <B>EchinocandinB> ly303366 against experimental fluconazole resistant oropharyngeal and esophageal candidiasis
Antimicrobial Agents and Chemotherapy, 2001Co-Authors: Vidmantas Petraitis, Andreas H Groll, Ruta Petraitiene, Tin Sein, Robert L Schaufele, Caron A Lyman, Andrea Francesconi, John Bacher, Stephen C Piscitelli, Thomas J. WalshAbstract:Esophageal candidiasis is one of the most common opportunistic fungal infections in immunocompromised patients, including human immunodeficiency virus (HIV)-positive patients and those who are immunosuppressed as a result of underlying diseases or medications (2, 35). A numBer of agents have Been used to treat esophageal candidiasis, including nystatin, miconazole, ketoconazole, fluconazole, itraconazole, and amphotericin B. Fluconazole is frequently selected for systemic therapy Because it is well tolerated and has excellent oral BioavailaBility. During the past several years, however, there have Been increasing reports of fluconazole-resistant oropharyngeal and esophageal candidiasis (OPEC) (27). The emergence of fluconazole-resistant OPEC has heightened the need for development of new antifungal compounds with novel targets. The <B>EchinocandinB>s are semisynthetic lipopeptides with potent and Broad-spectrum antifungal activity which act By inhiBiting the synthesis of (1,3)-β-d-glucan, leading to cell wall damage and ultimately cell death (6, 7, 10, 16, 17). This novel mode of action and potent antifungal activity in vitro have led to the design of several new <B>EchinocandinB> compounds for potential clinical development. V-<B>EchinocandinB> (VER-002; LY303366) is a semisynthetic <B>EchinocandinB> B derivative (9; I. Rajman, K. Desante, B. Hatcher, J. Hemingway, R. Lachno, S. Brooks, and M. Turik, ABstr. 37th Intersci. Conf. AntimicroB. Agents Chemother, aBstr. F-74, p. 158, 1997) which demonstrates potent and non-cross-resistant antifungal activity against Candida alBicans, Candida tropicalis, Candida glaBrata, and other non-C. alBicans species (8, 13, 14, 15, 24, 26, 29). Little is known, however, aBout the activity of VER-002 is treatment for fluconazole-resistant OPEC. We therefore investigated the concentrations in the esophageus and saliva the safety, and the antifungal efficacy of VER-002 in an immunosuppressed raBBit model of fluconazole-resistant OPEC.
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antifungal activity of ly303366 a novel <B>EchinocandinB> B in experimental disseminated candidiasis in raBBits
Antimicrobial Agents and Chemotherapy, 1999Co-Authors: Ruta Petraitiene, Andreas H Groll, Vidmantas Petraitis, Tin Sein, Caron A Lyman, John Bacher, Aaron Bell, Carl L Mcmillian, Myrna Candelario, Thomas J. WalshAbstract:The safety and antifungal activity of LY303366 (LY), a new Broad-spectrum semisynthetic <B>EchinocandinB>, were studied against disseminated candidiasis in persistently neutropenic raBBits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic raBBits suggested a linear relationship Between dose and area under the curve (AUC). The times spent aBove the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of Body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected raBBits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 103 Candida alBicans Blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. RaBBits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. alBicans from the liver, spleen, kidney, lung, vena cava, and Brain in comparison to that for UCs. There was a dose-dependent clearance of C. alBicans from tissues in response to LY. Among raBBits treated with LY0.1 there was a significant reduction of C. alBicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues But the Brain. By comparison, LY0.5 and LY1 cleared all tissues, including the Brain, of C. alBicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was oBserved among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated raBBits than in UCs and LY- and FLU-treated raBBits. LY0.5 and LY1 were well tolerated, displayed predictaBle pharmacokinetics in plasma, and had activities comparaBle to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic raBBits.
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antifungal efficacy safety and single dose pharmacokinetics of ly303366 a novel <B>EchinocandinB> B in experimental pulmonary aspergillosis in persistently neutropenic raBBits
Antimicrobial Agents and Chemotherapy, 1998Co-Authors: Vidmantas Petraitis, Andreas H Groll, Ruta Petraitiene, Tin Sein, Robert L Schaufele, John Bacher, Aaron Bell, D P Callender, Carl L Mcmillian, Thomas J. WalshAbstract:LY303366 is a novel semisynthetic derivative of <B>EchinocandinB> B and a potent inhiBitor of fungal (1,3)-β-d-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic raBBits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of Body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In raBBits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured By the numBer of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. RaBBits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparaBle therapeutic efficacies By all parameters with the exception of reduction in tissue Burden of A. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels aBove the MIC for 18 h, and dosages of ≥5 mg/kg maintained plasma drug levels aBove the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated raBBits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic raBBits.
Yu-guo Zheng - One of the best experts on this subject based on the ideXlab platform.
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functional expression of an <B>EchinocandinB> B deacylase from actinoplanes utahensis in escherichia coli
International Journal of Biological Macromolecules, 2021Co-Authors: Shu-ping Zou, Zhi-qiang Liu, Xin Han, Hanyue Zhu, Qi Sheng, Heng Tang, Yu-guo ZhengAbstract:ABstract <B>EchinocandinB> B deacylase (ECBD) from Actinoplanes utahensis can Be applied to produce <B>EchinocandinB> B nucleus (ECBN), an essential intermediate of the <B>EchinocandinB>s antifungal drugs such as anidulafungin. To date, the expression of ECBD has Been limited to Streptomyces. To achieve the active expression of ECBD in Escherichia coli (E. coli), we constructed a plasmid carrying two suBunits of ECBD for T7 RNA polymerase driven transcription of dicistron messenger after codon optimization. SuBsequently, the introduction of peptide tags in the recomBinant ECBD was adopted to reduce the formation of inclusion Bodies and enhance the ECBD soluBility. The peptide tags with the opposite electrostatic charge, hexa-lysine (6K) and GEGEG (GE), exhiBited the Best positive effect, which was verified By activity assay and structural simulation. After that, optimization of culture conditions and characterization of ECBD were conducted, the optimal pH and temperature were 7.0 and 60 °C. It is the first report concerning the functional expression of ECBD in the host E. coli. Our results reported here can provide a reference for the high-level expression of other deacylases with respect to a possiBle industrial application.
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effects of lipids and surfactants on the fermentation production of <B>EchinocandinB> B By aspergillus nidulans
Journal of Applied Microbiology, 2021Co-Authors: Kun Niu, Shu-ping Zou, Zhi-qiang Liu, Kepeng Lang, Yu-guo ZhengAbstract:Aims <B>EchinocandinB> B (ECB) is a kind of lipopeptide antifungal antiBiotic, as well as the key precursor of antifungal drug Anidulafungin. Its efficient Bioproduction plays an important role in promoting the industrial production of Anidulafungin. Methods and results In this study, methyl oleate and Tween 80 were firstly used to enhance the ECB fermentation By Aspergillus nidulans, the results showed that the ECB titre was significantly enhanced with the addition of methyl oleate and Tween 80. Among the lipids, methyl oleate was found to play a pivotal role in increasing the ECB titre to 2123 mg l-1 , which was more than five times higher than that of the control. The addition of Tween 80 in the medium resulted in ECB titre increased to 2584 mg l-1 . The scanning electron microscope (SEM) and N-phenyl-1-naphthylamine (NPN) assay indicated that Tween 80 could influence the cell memBrane permeaBility of A. nidulans, and enhance the intracellular and extracellular suBstance exchange, therefore lead to the increasing of ECB titre. Conclusions Methyl oleate and Tween 80 are optimal carBon sources and surfactants for efficient ECB Biosynthesis respectively. Significance and impact of the study Surfactant was used in ECB fermentation for the first time, which provided feasiBle ideas for optimizing the fermentation process of other fungi.
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Effects of methyl oleate and microparticle-enhanced cultivation on <B>EchinocandinB> B fermentation titer.
Bioprocess and biosystems engineering, 2020Co-Authors: Kun Niu, Shu-ping Zou, Zhi-qiang Liu, Yu-guo ZhengAbstract:<B>EchinocandinB> B (ECB) is a key precursor of antifungal agent Anidulafungin, which has demonstrated clinical efficacy in patients with invasive candidiasis. In this study, the effects of microparticle-enhanced cultivation and methyl oleate on <B>EchinocandinB> B fermentation titer were investigated. The results showed that the titer was significantly influenced By the morphological type of mycelium, and mycelium pellet was Beneficial to improve the titer of this secondary metaBolism. First, different carBon sources were chosen for the fermentation, and methyl oleate achieved the highest <B>EchinocandinB> B titer of 2133 ± 50 mg/L, which was two times higher than that of the mannitol. The study further investigated the metaBolic process of the fermentation, and the results showed that L-threonine concentration inside the cell could reach 275 mg/L at 168 h with methyl oleate, aBout 2.5 times higher than that of the mannitol. Therefore, L-threonine may Be a key precursor of <B>EchinocandinB> B. In the end, a new method of adding microparticles for improving the mycelial morphology was used, and the addition of talcum powder (20 g/L, diameter of 45 µm) could make the maximum titer of <B>EchinocandinB> B reach 3148 ± 100 mg/L.
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enhancing catalytic efficiency of an actinoplanes utahensis <B>EchinocandinB> B deacylase through random mutagenesis and site directed mutagenesis
Applied Biochemistry and Biotechnology, 2020Co-Authors: Yingnan Cheng, Shuai Qiu, Feng Cheng, Chunyue Weng, Yajun Wang, Yu-guo ZhengAbstract:<B>EchinocandinB> B deacylase (EBDA), from Actinoplanes utahensis ZJB-08196, is capaBle of cleaving the linoleoyl group from <B>EchinocandinB> B (ECB), forming the <B>EchinocandinB> B nucleus (ECBN), which is a key precursor of semisynthetic antifungal antiBiotics. In the present study, molecular evolution of AuEBDA By random mutagenesis comBined with site-directed mutagenesis (SDM) and screening was performed. Random mutagenesis on the wild-type (WT) AuEBDA generated two Beneficial suBstitutions of G287Q, R527V. The "Best" variant AuEBDA-G287Q/R527V was oBtained By comBining G287Q with R527V through SDM, which was most active at 35 °C, pH 7.5, with Km and vmax values of 0.68 mM and 395.26 U/mg, respectively. Mutation of G287Q/R527V markedly increased the catalytic efficiency kcat/Km By 290% compared with the WT-AuEBDA.
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mutagenesis of <B>EchinocandinB> B overproducing aspergillus nidulans capaBle of using starch as main carBon source
Preparative Biochemistry & Biotechnology, 2020Co-Authors: Shu-ping Zou, Kun Niu, Yu-guo ZhengAbstract:<B>EchinocandinB> B, a kind of antimycotic with cyclic lipo-hexapeptides, was produced By fermentation with Aspergillus nidulans using fructose as main carBon source. The oBjective of this study was to ...
Vidmantas Petraitis - One of the best experts on this subject based on the ideXlab platform.
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dosage dependent antifungal efficacy of v <B>EchinocandinB> ly303366 against experimental fluconazole resistant oropharyngeal and esophageal candidiasis
Antimicrobial Agents and Chemotherapy, 2001Co-Authors: Vidmantas Petraitis, Andreas H Groll, Ruta Petraitiene, Tin Sein, Robert L Schaufele, Caron A Lyman, Andrea Francesconi, John Bacher, Stephen C Piscitelli, Thomas J. WalshAbstract:Esophageal candidiasis is one of the most common opportunistic fungal infections in immunocompromised patients, including human immunodeficiency virus (HIV)-positive patients and those who are immunosuppressed as a result of underlying diseases or medications (2, 35). A numBer of agents have Been used to treat esophageal candidiasis, including nystatin, miconazole, ketoconazole, fluconazole, itraconazole, and amphotericin B. Fluconazole is frequently selected for systemic therapy Because it is well tolerated and has excellent oral BioavailaBility. During the past several years, however, there have Been increasing reports of fluconazole-resistant oropharyngeal and esophageal candidiasis (OPEC) (27). The emergence of fluconazole-resistant OPEC has heightened the need for development of new antifungal compounds with novel targets. The <B>EchinocandinB>s are semisynthetic lipopeptides with potent and Broad-spectrum antifungal activity which act By inhiBiting the synthesis of (1,3)-β-d-glucan, leading to cell wall damage and ultimately cell death (6, 7, 10, 16, 17). This novel mode of action and potent antifungal activity in vitro have led to the design of several new <B>EchinocandinB> compounds for potential clinical development. V-<B>EchinocandinB> (VER-002; LY303366) is a semisynthetic <B>EchinocandinB> B derivative (9; I. Rajman, K. Desante, B. Hatcher, J. Hemingway, R. Lachno, S. Brooks, and M. Turik, ABstr. 37th Intersci. Conf. AntimicroB. Agents Chemother, aBstr. F-74, p. 158, 1997) which demonstrates potent and non-cross-resistant antifungal activity against Candida alBicans, Candida tropicalis, Candida glaBrata, and other non-C. alBicans species (8, 13, 14, 15, 24, 26, 29). Little is known, however, aBout the activity of VER-002 is treatment for fluconazole-resistant OPEC. We therefore investigated the concentrations in the esophageus and saliva the safety, and the antifungal efficacy of VER-002 in an immunosuppressed raBBit model of fluconazole-resistant OPEC.
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antifungal activity of ly303366 a novel <B>EchinocandinB> B in experimental disseminated candidiasis in raBBits
Antimicrobial Agents and Chemotherapy, 1999Co-Authors: Ruta Petraitiene, Andreas H Groll, Vidmantas Petraitis, Tin Sein, Caron A Lyman, John Bacher, Aaron Bell, Carl L Mcmillian, Myrna Candelario, Thomas J. WalshAbstract:The safety and antifungal activity of LY303366 (LY), a new Broad-spectrum semisynthetic <B>EchinocandinB>, were studied against disseminated candidiasis in persistently neutropenic raBBits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic raBBits suggested a linear relationship Between dose and area under the curve (AUC). The times spent aBove the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of Body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected raBBits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 103 Candida alBicans Blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. RaBBits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. alBicans from the liver, spleen, kidney, lung, vena cava, and Brain in comparison to that for UCs. There was a dose-dependent clearance of C. alBicans from tissues in response to LY. Among raBBits treated with LY0.1 there was a significant reduction of C. alBicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues But the Brain. By comparison, LY0.5 and LY1 cleared all tissues, including the Brain, of C. alBicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was oBserved among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated raBBits than in UCs and LY- and FLU-treated raBBits. LY0.5 and LY1 were well tolerated, displayed predictaBle pharmacokinetics in plasma, and had activities comparaBle to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic raBBits.
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antifungal efficacy safety and single dose pharmacokinetics of ly303366 a novel <B>EchinocandinB> B in experimental pulmonary aspergillosis in persistently neutropenic raBBits
Antimicrobial Agents and Chemotherapy, 1998Co-Authors: Vidmantas Petraitis, Andreas H Groll, Ruta Petraitiene, Tin Sein, Robert L Schaufele, John Bacher, Aaron Bell, D P Callender, Carl L Mcmillian, Thomas J. WalshAbstract:LY303366 is a novel semisynthetic derivative of <B>EchinocandinB> B and a potent inhiBitor of fungal (1,3)-β-d-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic raBBits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of Body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In raBBits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured By the numBer of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. RaBBits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparaBle therapeutic efficacies By all parameters with the exception of reduction in tissue Burden of A. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels aBove the MIC for 18 h, and dosages of ≥5 mg/kg maintained plasma drug levels aBove the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated raBBits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic raBBits.
Ruta Petraitiene - One of the best experts on this subject based on the ideXlab platform.
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dosage dependent antifungal efficacy of v <B>EchinocandinB> ly303366 against experimental fluconazole resistant oropharyngeal and esophageal candidiasis
Antimicrobial Agents and Chemotherapy, 2001Co-Authors: Vidmantas Petraitis, Andreas H Groll, Ruta Petraitiene, Tin Sein, Robert L Schaufele, Caron A Lyman, Andrea Francesconi, John Bacher, Stephen C Piscitelli, Thomas J. WalshAbstract:Esophageal candidiasis is one of the most common opportunistic fungal infections in immunocompromised patients, including human immunodeficiency virus (HIV)-positive patients and those who are immunosuppressed as a result of underlying diseases or medications (2, 35). A numBer of agents have Been used to treat esophageal candidiasis, including nystatin, miconazole, ketoconazole, fluconazole, itraconazole, and amphotericin B. Fluconazole is frequently selected for systemic therapy Because it is well tolerated and has excellent oral BioavailaBility. During the past several years, however, there have Been increasing reports of fluconazole-resistant oropharyngeal and esophageal candidiasis (OPEC) (27). The emergence of fluconazole-resistant OPEC has heightened the need for development of new antifungal compounds with novel targets. The <B>EchinocandinB>s are semisynthetic lipopeptides with potent and Broad-spectrum antifungal activity which act By inhiBiting the synthesis of (1,3)-β-d-glucan, leading to cell wall damage and ultimately cell death (6, 7, 10, 16, 17). This novel mode of action and potent antifungal activity in vitro have led to the design of several new <B>EchinocandinB> compounds for potential clinical development. V-<B>EchinocandinB> (VER-002; LY303366) is a semisynthetic <B>EchinocandinB> B derivative (9; I. Rajman, K. Desante, B. Hatcher, J. Hemingway, R. Lachno, S. Brooks, and M. Turik, ABstr. 37th Intersci. Conf. AntimicroB. Agents Chemother, aBstr. F-74, p. 158, 1997) which demonstrates potent and non-cross-resistant antifungal activity against Candida alBicans, Candida tropicalis, Candida glaBrata, and other non-C. alBicans species (8, 13, 14, 15, 24, 26, 29). Little is known, however, aBout the activity of VER-002 is treatment for fluconazole-resistant OPEC. We therefore investigated the concentrations in the esophageus and saliva the safety, and the antifungal efficacy of VER-002 in an immunosuppressed raBBit model of fluconazole-resistant OPEC.
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antifungal activity of ly303366 a novel <B>EchinocandinB> B in experimental disseminated candidiasis in raBBits
Antimicrobial Agents and Chemotherapy, 1999Co-Authors: Ruta Petraitiene, Andreas H Groll, Vidmantas Petraitis, Tin Sein, Caron A Lyman, John Bacher, Aaron Bell, Carl L Mcmillian, Myrna Candelario, Thomas J. WalshAbstract:The safety and antifungal activity of LY303366 (LY), a new Broad-spectrum semisynthetic <B>EchinocandinB>, were studied against disseminated candidiasis in persistently neutropenic raBBits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic raBBits suggested a linear relationship Between dose and area under the curve (AUC). The times spent aBove the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of Body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected raBBits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 103 Candida alBicans Blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. RaBBits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. alBicans from the liver, spleen, kidney, lung, vena cava, and Brain in comparison to that for UCs. There was a dose-dependent clearance of C. alBicans from tissues in response to LY. Among raBBits treated with LY0.1 there was a significant reduction of C. alBicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues But the Brain. By comparison, LY0.5 and LY1 cleared all tissues, including the Brain, of C. alBicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was oBserved among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated raBBits than in UCs and LY- and FLU-treated raBBits. LY0.5 and LY1 were well tolerated, displayed predictaBle pharmacokinetics in plasma, and had activities comparaBle to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic raBBits.
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antifungal efficacy safety and single dose pharmacokinetics of ly303366 a novel <B>EchinocandinB> B in experimental pulmonary aspergillosis in persistently neutropenic raBBits
Antimicrobial Agents and Chemotherapy, 1998Co-Authors: Vidmantas Petraitis, Andreas H Groll, Ruta Petraitiene, Tin Sein, Robert L Schaufele, John Bacher, Aaron Bell, D P Callender, Carl L Mcmillian, Thomas J. WalshAbstract:LY303366 is a novel semisynthetic derivative of <B>EchinocandinB> B and a potent inhiBitor of fungal (1,3)-β-d-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic raBBits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of Body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In raBBits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured By the numBer of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. RaBBits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparaBle therapeutic efficacies By all parameters with the exception of reduction in tissue Burden of A. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels aBove the MIC for 18 h, and dosages of ≥5 mg/kg maintained plasma drug levels aBove the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated raBBits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic raBBits.
Andreas H Groll - One of the best experts on this subject based on the ideXlab platform.
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dosage dependent antifungal efficacy of v <B>EchinocandinB> ly303366 against experimental fluconazole resistant oropharyngeal and esophageal candidiasis
Antimicrobial Agents and Chemotherapy, 2001Co-Authors: Vidmantas Petraitis, Andreas H Groll, Ruta Petraitiene, Tin Sein, Robert L Schaufele, Caron A Lyman, Andrea Francesconi, John Bacher, Stephen C Piscitelli, Thomas J. WalshAbstract:Esophageal candidiasis is one of the most common opportunistic fungal infections in immunocompromised patients, including human immunodeficiency virus (HIV)-positive patients and those who are immunosuppressed as a result of underlying diseases or medications (2, 35). A numBer of agents have Been used to treat esophageal candidiasis, including nystatin, miconazole, ketoconazole, fluconazole, itraconazole, and amphotericin B. Fluconazole is frequently selected for systemic therapy Because it is well tolerated and has excellent oral BioavailaBility. During the past several years, however, there have Been increasing reports of fluconazole-resistant oropharyngeal and esophageal candidiasis (OPEC) (27). The emergence of fluconazole-resistant OPEC has heightened the need for development of new antifungal compounds with novel targets. The <B>EchinocandinB>s are semisynthetic lipopeptides with potent and Broad-spectrum antifungal activity which act By inhiBiting the synthesis of (1,3)-β-d-glucan, leading to cell wall damage and ultimately cell death (6, 7, 10, 16, 17). This novel mode of action and potent antifungal activity in vitro have led to the design of several new <B>EchinocandinB> compounds for potential clinical development. V-<B>EchinocandinB> (VER-002; LY303366) is a semisynthetic <B>EchinocandinB> B derivative (9; I. Rajman, K. Desante, B. Hatcher, J. Hemingway, R. Lachno, S. Brooks, and M. Turik, ABstr. 37th Intersci. Conf. AntimicroB. Agents Chemother, aBstr. F-74, p. 158, 1997) which demonstrates potent and non-cross-resistant antifungal activity against Candida alBicans, Candida tropicalis, Candida glaBrata, and other non-C. alBicans species (8, 13, 14, 15, 24, 26, 29). Little is known, however, aBout the activity of VER-002 is treatment for fluconazole-resistant OPEC. We therefore investigated the concentrations in the esophageus and saliva the safety, and the antifungal efficacy of VER-002 in an immunosuppressed raBBit model of fluconazole-resistant OPEC.
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antifungal activity of ly303366 a novel <B>EchinocandinB> B in experimental disseminated candidiasis in raBBits
Antimicrobial Agents and Chemotherapy, 1999Co-Authors: Ruta Petraitiene, Andreas H Groll, Vidmantas Petraitis, Tin Sein, Caron A Lyman, John Bacher, Aaron Bell, Carl L Mcmillian, Myrna Candelario, Thomas J. WalshAbstract:The safety and antifungal activity of LY303366 (LY), a new Broad-spectrum semisynthetic <B>EchinocandinB>, were studied against disseminated candidiasis in persistently neutropenic raBBits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic raBBits suggested a linear relationship Between dose and area under the curve (AUC). The times spent aBove the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of Body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected raBBits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 103 Candida alBicans Blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. RaBBits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. alBicans from the liver, spleen, kidney, lung, vena cava, and Brain in comparison to that for UCs. There was a dose-dependent clearance of C. alBicans from tissues in response to LY. Among raBBits treated with LY0.1 there was a significant reduction of C. alBicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues But the Brain. By comparison, LY0.5 and LY1 cleared all tissues, including the Brain, of C. alBicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was oBserved among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated raBBits than in UCs and LY- and FLU-treated raBBits. LY0.5 and LY1 were well tolerated, displayed predictaBle pharmacokinetics in plasma, and had activities comparaBle to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic raBBits.
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antifungal efficacy safety and single dose pharmacokinetics of ly303366 a novel <B>EchinocandinB> B in experimental pulmonary aspergillosis in persistently neutropenic raBBits
Antimicrobial Agents and Chemotherapy, 1998Co-Authors: Vidmantas Petraitis, Andreas H Groll, Ruta Petraitiene, Tin Sein, Robert L Schaufele, John Bacher, Aaron Bell, D P Callender, Carl L Mcmillian, Thomas J. WalshAbstract:LY303366 is a novel semisynthetic derivative of <B>EchinocandinB> B and a potent inhiBitor of fungal (1,3)-β-d-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic raBBits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of Body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In raBBits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured By the numBer of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. RaBBits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparaBle therapeutic efficacies By all parameters with the exception of reduction in tissue Burden of A. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels aBove the MIC for 18 h, and dosages of ≥5 mg/kg maintained plasma drug levels aBove the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated raBBits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic raBBits.
