Treatment of Experimental Invasive Aspergillosis with Novel Amphotericin B/Cholesterol-Sulfate Complexes

Patterson, Thomas F.; Miniter, Peggy; Dijkstra, J.W.; Szoka, Francis C.; Ryan, John L.; Andriole, Vincent T.

doi:10.1093/infdis/159.4.717

Cited by 92 publications

(55 citation statements)

References 19 publications

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“…It is interesting that current antifungal therapeutic research involves noncovalently bonded AmB preparations such as lipid complexes (liposomes) and colloidal preparations (29,33,41). These preparations generally exhibit reduced in vitro antifungal activity (35) and inferior in vivo chemotherapeutic activity (4,5) in experimental animals.…”

Section: Discussionmentioning

confidence: 99%

Comparative neurotoxicities of amphotericin B and its mono-methyl ester derivative in rats

Reuhl

Vapiwala

Ryzlak

et al. 1993

Antimicrob Agents Chemother

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The intracisternal administration of amphotericin B (AmB) and its mono-methyl ester derivative (AME), via direct intraventricular injection (0.01 to 5 mg/ml, 6 IlI) in adult female Wistar rats, revealed that AmB was significantly more toxic than AME, as measured by weight loss, lethargy, death, and central nervous system histopathology. Light and electron microscopy confirmed a greater neurotoxicity for AmB, manifested as edema and modest gliosis extending along and beyond the injection tract. Neuronal degeneration and myelin damage were present in AmB-treated (1 mg/ml) animals but were present only modestly in animals treated with AME at a fivefold greater concentration. Intravenous administration ofAmB to adult female Wistar rats as five daily doses of 5 mg/kg of body weight resulted in significant weight loss and some deaths. Histopathologic examination of the brains, spinal cords, and sural nerves of surviving animals revealed neurotoxicity manifested by neuronal degeneration, gliosis, and myelin edema. In sharp contrast, similar treatment with AME at a 10-fold greater dose resulted in neither death nor significant neurotoxicity. The administration of five daily doses of a mixture of AME-AmB (9:1; wt/wt) at 50 mg/kg of body weight resulted in neurotoxicity. These results indicate that AmB exhibits significantly greater in vivo neurotoxicity than AME.Parenteral amphotericin B (AmB) has been the most effective antibiotic for the treatment of serious systemic mycotic infections, conditions that result in high morbidities and mortalities. Its use, however, has been associated with serious toxic side effects, most notably, nephrotoxicity. Numerous attempts have been made to modify the molecule chemically in the hope of producing a less toxic and equally effective derivative (38). The AmB mono-methyl ester (AME) is a derivative that is reportedly highly soluble in water (31,39) and that has excellent in vitro and in vivo antifungal activity (1,2,21,22,26).With apparent reduced parenteral toxicity in experimental animals (24, 25), in particular, significantly reduced nephrotoxicity, clinical evaluation of AME for the treatment of deep-seated systemic fungal infections was initiated (15). During this initial trial nephrotoxicity was rare, even at doses five times greater than those usually used with AmB. Clinical efficacy was also encouraging, since several patients who were thought to be terminal survived their mycotic infections. As the trial progressed, several patients developed a progressive neurologic disorder (20). There was a clinical association between the administration of AME in some of the patients and the appearance of neuropsychiatric aberrations. Analysis of the clinical AME preparations by high-pressure liquid chromatography (HPLC) (20) revealed, in addition to AME and residual AmB, numerous components later described as overmethylated AmB derivatives (36). The many components in AME preparations were initially detected and separated by HPLC (20) and analyzed by fast atom bombardment (36). Autopsy s...

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Section: Discussionmentioning

confidence: 99%

Comparative neurotoxicities of amphotericin B and its mono-methyl ester derivative in rats

Reuhl

Vapiwala

Ryzlak

et al. 1993

Antimicrob Agents Chemother

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“…or when semiquantitative cultures of tissue homogenates contained more than 20 CFU/g of tissue (12). The burdens of Aspergillus in tissues were evaluated with semiquantitative cultures that could detect from 20 to 20,000 CFU/g of tissue (23). Samples of each organ were finely chopped (manually), weighed, diluted 1:10 (wt/vol) with sterile saline, and homogenized for 25 s with an electric tissue homogenizer (IKA-Works, Inc., Cincinnati, Ohio).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Caspofungin Alone and in Combination with Voriconazole in a Guinea Pig Model of Invasive Aspergillosis

Kirkpatrick

Perea

Coco

et al. 2002

Antimicrob Agents Chemother

264

170

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The antifungal activity of caspofungin acetate (CAS) alone and in combination with voriconazole (VRC) was evaluated in an immunosuppressed transiently neutropenic guinea pig model of invasive aspergillosis. Guinea pigs were immunosuppressed with triamcinolone at 20 mg/kg of body weight/day subcutaneously beginning 4 days prior to lethal intravenous challenge with Aspergillus fumigatus and were made temporarily neutropenic with cyclophosphamide administered at 150 mg/kg intraperitoneally (i.p.) 1 day prior to challenge. Therapy with i.p. CAS at 1 and 2.5 mg/kg/day (with and without oral VRC at 5 mg/kg/day), oral VRC at 5 mg/kg/day, or i.p. amphotericin B (AMB) at 1.25 mg/kg/day was begun 24 h after challenge and was continued for 5 days. Mortality occurred in 12 of 12 untreated controls, whereas mortality occurred in 4 of 12 and 6 of 12 guinea pigs treated with CAS at 1 and 2.5 mg/kg/day, respectively, and in 3 of 12 guinea pigs treated with AMB. No mortality occurred among animals treated with CAS at 1 mg/kg/day plus VRC at 5 mg/kg/day, CAS at 2.5 mg/kg/day plus VRC at 5 mg/kg/day, or VRC at 5 mg/kg/day alone. Both CAS regimens increased the survival times and reduced the colony counts in tissue compared with those for the controls. Treatment with VRC and AMB significantly reduced the colony counts in the tissues of selected animals compared with those in the tissues of the controls. Treatment with VRC and AMB also resulted in reductions in colony counts in tissues compared with those in the tissues of animals treated with CAS (the difference was not statistically significant) and improved the survival times but did not sterilize tissues. Combination therapies with CAS plus VRC at either dose reduced colony counts in tissues 1,000-fold over those for the controls and were the only regimens that significantly reduced the numbers of positive cultures. The combinations of CAS plus VRC were highly effective in this model and should be further evaluated for use against invasive aspergillosis.

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“…ABCD manteve sua ação antifúngica no tratamento de aspergilose em coelhos (Patterson et al, 1989) e sua administração em camundongos com candidíase levou à redução do número de unidades formadoras de colônia (UFC) nos rins, sugerindo ação do antifúngico mesmo com as baixas concentrações atingidas nesse órgão (Fielding et al, 1991).…”

Section: Estudos Em Animaisunclassified

Eficiência terapêutica das formulações lipídicas de anfotericina B

Filippin

Souza

2006

Rev. Bras. Cienc. Farm.

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Treatment of Experimental Invasive Aspergillosis with Novel Amphotericin B/Cholesterol-Sulfate Complexes

Cited by 92 publications

References 19 publications

Comparative neurotoxicities of amphotericin B and its mono-methyl ester derivative in rats

Comparative neurotoxicities of amphotericin B and its mono-methyl ester derivative in rats

Efficacy of Caspofungin Alone and in Combination with Voriconazole in a Guinea Pig Model of Invasive Aspergillosis

Eficiência terapêutica das formulações lipídicas de anfotericina B

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