AmBisome: liposomal formulation, structure, mechanism of action and pre-clinical experience

2002 ◽  
Vol 49 (suppl_1) ◽  
pp. 21-30 ◽  
Author(s):  
Jill Adler-Moore ◽  
Richard T. Proffitt
Keyword(s):  
Animal Models ◽  
Amphotericin B ◽  
Mechanism Of Action ◽  
Mammalian Cells ◽  
Fungal Infections ◽  
Liposomal Formulation ◽  
Fungal Cell ◽  
High Transition ◽  
High Doses

Abstract Amphotericin B is the treatment of choice for life-threatening systemic fungal infections such as candidosis and aspergillosis. To improve this drug's efficacy and reduce its acute and chronic toxicities, several lipid formulations of the drug have been developed, including AmBisome, a liposomal formulation of amphotericin B. The liposome is composed of high transition temperature phospholipids and cholesterol, designed to incorporate amphotericin B securely into the liposomal bilayer. AmBisome can bind to fungal cell walls, where the liposome is disrupted. The amphotericin B, after being released from the liposomes, is thought to transfer through the cell wall and bind to ergosterol in the fungal cell membrane. This mechanism of action of AmBisome results in its potent in vitro fungicidal activity while the integrity of the liposome is maintained in the presence of mammalian cells, for which it has minimal toxicity. In animal models, AmBisome is effective in treating both intracellular (leishmaniasis and histoplasmosis) and extracellular (candidosis and aspergillosis) systemic infections. Because of its low toxicity at the organ level, intravenous AmBisome can be safely delivered at markedly high doses of amphotericin B (1–30 mg/kg) for the treatment of systemic fungal infections. AmBisome has a circulating half-life of 5–24 h in animals, and in animal models appears to localize at sites of infection in the brain (cryptococcosis, aspergillosis, coccidioidomycosis), lungs (blastomycosis, paracoccidioidomycosis, aspergillosis) and kidneys (candidosis), delivering amphotericin B that remains bioavailable in tissues for several weeks following treatment.

scholarly journals Carrier effects on biological activity of amphotericin B.

1996 ◽  
Vol 9 (4) ◽  
pp. 512-531 ◽  
Author(s):  
J Brajtburg ◽  
J Bolard
Keyword(s):  
Amphotericin B ◽  
Mammalian Cells ◽  
Fungal Infections ◽  
Therapeutic Index ◽  
Fungal Cell ◽  
Drug Of Choice ◽  
Higher Doses ◽  
Lipid Formulations

Amphotericin B (AmB), the drug of choice for the treatment of most systemic fungal infections, is marketed under the trademark Fungizone, as an AmB-deoxycholate complex suitable for intravenous administration. The association between AmB and deoxycholate is relatively weak; therefore, dissociation occurs in the blood. The drug itself interacts with both mammalian and fungal cell membranes to damage cells, but the greater susceptibility of fungal cells to its effects forms the basis for its clinical usefulness. The ability of the drug to form stable complexes with lipids has allowed the development of new formulations of AmB based on this property. Several lipid-based formulations of the drug which are more selective in damaging fungal or parasitic cells than mammalian cells and some of which also have a better therapeutic index than Fungizone have been developed. In vitro investigations have led to the conclusion that the increase in selectivity observed is due to the selective transfer of AmB from lipid complexes to fungal cells or to the higher thermodynamic stability of lipid formulations. Association with lipids modulates AmB binding to lipoproteins in vivo, thus influencing tissue distribution and toxicity. For example, lipid complexes of AmB can be internalized by macrophages, and the macrophages then serve as a reservoir for the drug. Furthermore, stable AmB-lipid complexes are much less toxic to the host than Fungizone and can therefore be administered in higher doses. Experimentally, the efficacy of AmB-lipid formulations compared with Fungizone depends on the animal model used. Improved therapeutic indices for AmB-lipid formations have been demonstrated in clinical trials, but the definitive trials leading to the selection of an optimal formulation and therapeutic regimen have not been done.

scholarly journals Monoclonal antibodies against cell wall chitooligomers as accessory tools for the control of cryptococcosis

2021 ◽  
Author(s):  
Alexandre Figueiredo ◽  
Fernanda Fonseca ◽  
Fernando Conte ◽  
Marcia Arissawa ◽  
Marcio L. Rodrigues
Keyword(s):  
Cell Wall ◽  
Monoclonal Antibodies ◽  
Amphotericin B ◽  
Fungal Infections ◽  
In Vitro Tests ◽  
Fungal Cell ◽  
Promising Therapeutic Target ◽  
Significant Toxicity ◽  
Essential Properties

Therapeutic strategies against systemic mycoses can involve antifungal resistance and significant toxicity. Thus, novel therapeutic approaches to fight fungal infections are urgent. Monoclonal antibodies (mAbs) are promising tools to fight systemic mycoses. In this study, mAbs of the IgM isotype were developed against chitin oligomers. Chitooligomers derive from chitin, an essential component of the fungal cell wall and a promising therapeutic target, as it is not synthesized by humans or animals. Surface plasmon resonance (SPR) assays and cell-binding tests showed that the mAbs recognizing chitooligomers have high affinity and specificity for the chitin derivatives. In vitro tests showed that the chitooligomer mAbs increased the fungicidal capacity of amphotericin B against Cryptococcus neoformans. The chitooligomer-binding mAbs interfered with two essential properties related to cryptococcal pathogenesis: biofilm formation and melanin production. In a murine model of C. neoformans infection, the combined administration of the chitooligomer-binding mAb and subinhibitory doses of amphotericin B promoted disease control. The data obtained in this study support the hypothesis that chitooligomer antibodies are of great potential as accessory tools in the control of cryptococcosis.

scholarly journals Monoclonal antibodies against cell wall chitooligomers as accessory tools for the control of cryptococcosis

2021 ◽  
Author(s):  
Alexandre Bezerra Conde Figueiredo ◽  
Fernanda L. Fonseca ◽  
Diogo Kuczera ◽  
Fernando de Paiva Conte ◽  
Marcia Arissawa ◽  
...  
Keyword(s):  
Cell Wall ◽  
Monoclonal Antibodies ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Fungal Cell ◽  
Promising Therapeutic Target ◽  
Significant Toxicity ◽  
Essential Properties ◽  
Study Support

Therapeutic strategies against systemic mycoses can involve antifungal resistance and significant toxicity. Thus, novel therapeutic approaches to fight fungal infections are urgent. Monoclonal antibodies (mAbs) are promising tools to fight systemic mycoses. In this study, mAbs of the IgM isotype were developed against chitin oligomers. Chitooligomers derive from chitin, an essential component of the fungal cell wall and a promising therapeutic target, as it is not synthesized by humans or animals. Surface plasmon resonance (SPR) assays and cell-binding tests showed that the mAbs recognizing chitooligomers have high affinity and specificity for the chitin derivatives. In vitro tests showed that the chitooligomer mAbs increased the fungicidal capacity of amphotericin B against Cryptococcus neoformans . The chitooligomer-binding mAbs interfered with two essential properties related to cryptococcal pathogenesis: biofilm formation and melanin production. In a murine model of C. neoformans infection, the combined administration of the chitooligomer-binding mAb and subinhibitory doses of amphotericin B promoted disease control. The data obtained in this study support the hypothesis that chitooligomer antibodies are of great potential as accessory tools in the control of cryptococcosis.

scholarly journals A Glucan Synthase FKS1 Homolog inCryptococcus neoformans Is Single Copy and Encodes an Essential Function

1999 ◽  
Vol 181 (2) ◽  
pp. 444-453 ◽  
Author(s):  
John R. Thompson ◽  
Cameron M. Douglas ◽  
Weili Li ◽  
Chong K. Jue ◽  
Barnali Pramanik ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mammalian Cells ◽  
Fungal Infections ◽  
Single Copy ◽  
Fungal Species ◽  
Term Treatment ◽  
Fungal Cell ◽  
Glucan Synthase ◽  
Long Term Treatment

ABSTRACT Cryptococcal meningitis is a fungal infection, caused byCryptococcus neoformans, which is prevalent in immunocompromised patient populations. Treatment failures of this disease are emerging in the clinic, usually associated with long-term treatment with existing antifungal agents. The fungal cell wall is an attractive target for drug therapy because the syntheses of cell wall glucan and chitin are processes that are absent in mammalian cells. Echinocandins comprise a class of lipopeptide compounds known to inhibit 1,3-β-glucan synthesis, and at least two compounds belonging to this class are currently in clinical trials as therapy for life-threatening fungal infections. Studies ofSaccharomyces cerevisiae and Candida albicansmutants identify the membrane-spanning subunit of glucan synthase, encoded by the FKS genes, as the molecular target of echinocandins. In vitro, the echinocandins show potent antifungal activity against Candida and Aspergillusspecies but are much less potent against C. neoformans. In order to examine why C. neoformans cells are less susceptible to echinocandin treatment, we have cloned a homolog of S. cerevisiae FKS1 from C. neoformans. We have developed a generalized method to evaluate the essentiality of genes inCryptococcus and applied it to the FKS1 gene. The method relies on homologous integrative transformation with a plasmid that can integrate in two orientations, only one of which will disrupt the target gene function. The results of this analysis suggest that the C. neoformans FKS1 gene is essential for viability. The C. neoformans FKS1 sequence is closely related to the FKS1 sequences from other fungal species and appears to be single copy in C. neoformans. Furthermore, amino acid residues known to be critical for echinocandin susceptibility in Saccharomyces are conserved in theC. neoformans FKS1 sequence.

scholarly journals Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations

2021 ◽  
Vol 7 (2) ◽  
pp. 113
Author(s):  
Anne-Laure Bidaud ◽  
Patrick Schwarz ◽  
Guillaume Herbreteau ◽  
Eric Dannaoui
Keyword(s):  
Animal Models ◽  
Fungal Infections ◽  
Acquired Resistance ◽  
Adequate Treatment ◽  
Combination Treatments ◽  
Target Organs ◽  
Fungal Load ◽  
Time Kill

Systemic fungal infections are associated with high mortality rates despite adequate treatment. Moreover, acquired resistance to antifungals is increasing, which further complicates the therapeutic management. One strategy to overcome antifungal resistance is to use antifungal combinations. In vitro, several techniques are used to assess drug interactions, such as the broth microdilution checkerboard, agar-diffusion methods, and time-kill curves. Currently, the most widely used technique is the checkerboard method. The aim of all these techniques is to determine if the interaction between antifungal agents is synergistic, indifferent, or antagonistic. However, the interpretation of the results remains difficult. Several methods of analysis can be used, based on different theories. The most commonly used method is the calculation of the fractional inhibitory concentration index. Determination of the usefulness of combination treatments in patients needs well-conducted clinical trials, which are difficult. It is therefore important to study antifungal combinations in vivo, in experimental animal models of fungal infections. Although mammalian models have mostly been used, new alternative animal models in invertebrates look promising. To evaluate the antifungal efficacy, the most commonly used criteria are the mortality rate and the fungal load in the target organs.

scholarly journals Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential

2021 ◽  
Vol 7 (2) ◽  
pp. 130
Author(s):  
Nathan P. Wiederhold
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Candida Species ◽  
Mammalian Cells ◽  
Mitochondrial Membrane ◽  
Fungal Infections ◽  
Published Data ◽  
Candida Auris

Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non-albicans Candida species have been documented in multiple countries on several continents. This situation has been further exacerbated over the last several years by Candida auris, as isolates of this emerging pathogen that are often resistant to multiple antifungals. T-2307 is an aromatic diamidine currently in development for the treatment of invasive fungal infections. This agent has been shown to selectively cause the collapse of the mitochondrial membrane potential in yeasts when compared to mammalian cells. In vitro activity has been demonstrated against Candida species, including C. albicans, C. glabrata, and C. auris strains, which are resistant to azole and echinocandin antifungals. Activity has also been reported against Cryptococcus species, and this has translated into in vivo efficacy in experimental models of invasive candidiasis and cryptococcosis. However, little is known regarding the clinical efficacy and safety of this agent, as published data from studies involving humans are not currently available.

scholarly journals Synthesis and Activity of New Schiff Bases of Furocoumarin

2020 ◽  
Vol 26 (1) ◽  
pp. 176-184
Author(s):  
Huijun Xie ◽  
Chao Niu ◽  
Zeyang Chao ◽  
Nuramina Mamat ◽  
Haji Akber Aisa
Keyword(s):  
Animal Models ◽  
Amphotericin B ◽  
Molecular Mechanism ◽  
Schiff Bases ◽  
Positive Control ◽  
Excellent Performance ◽  
Activation Rate ◽  
Antibacterial Spectrum ◽  
Better Than

AbstractFurocoumarins, such as 8-MOP, are the most common medications used to relieve the symptoms of vitiligo clinically. Some furocoumarins also showed excellent performance in an anti-bacterial assay. This paper describes the synthesis of a series of novel Schiff bases (6a-6k), and their promotion in melanogenesis and anti-bacterial properties were studied in vitro.The pigment production of B16 cells and bacterial inhibition ring assay were applied for the bioactivity of 6a-6k. According to the results, a stronger promotion on pigment content was observed, when six compounds co-cultured with cells, compared with positive control (8-MOP). Significantly, compound 6k (237%) as the most active was found to increase the amount of melanin more than 1.7 times compared with 8-MOP activation rate (136%). All the compounds could moderately retard C. albicans growth. Interestingly, aldehyde 5, which possessed a broader antibacterial spectrum, showed the highest inhibition against C. albicans as well and much better than the positive control (Amphotericin B).Studies of 6k in animal models of vitiligo and related molecular mechanism are presently under way, with the aim of discovering an anti-vitiligo leading compound.

scholarly journals Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
Robert Rieger ◽  
Hari Krishna Ananthula ◽  
Pankaj B. Desai ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Content Type ◽  
Highly Active ◽  
Pharmacokinetic Properties ◽  
Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

scholarly journals Fluconazole plus Cyclosporine: a Fungicidal Combination Effective against Experimental Endocarditis Due to Candida albicans

2000 ◽  
Vol 44 (11) ◽  
pp. 2932-2938 ◽  
Author(s):  
O. Marchetti ◽  
J. M. Entenza ◽  
D. Sanglard ◽  
J. Bille ◽  
M. P. Glauser ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Cyclosporine A ◽  
Test Organism ◽  
The Other ◽  
High Dose ◽  
Therapeutic Results ◽  
Fluconazole Therapy ◽  
High Doses

ABSTRACT Recent observations demonstrated that fluconazole plus cyclosporine (Cy) synergistically killed Candida albicans in vitro. This combination was tested in rats with C. albicansexperimental endocarditis. The MICs of fluconazole and Cy for the test organism were 0.25 and >10 mg/liter, respectively. Rats were treated for 5 days with either Cy, amphotericin B, fluconazole, or fluconazole-Cy. Although used at high doses, the peak concentrations of fluconazole in the serum of rats (up to 4.5 mg/liter) were compatible with high-dose fluconazole therapy in humans. On the other hand, Cy concentrations in serum (up to 4.5 mg/liter) were greater than recommended therapeutic levels. Untreated rats demonstrated massive pseudohyphal growth in both the vegetations and the kidneys. However, only the kidneys displayed concomitant polymorphonuclear infiltration. The therapeutic results reflected this dissociation. In the vegetations, only the fungicidal fluconazole-Cy combination significantly decreased fungal densities compared to all groups, including amphotericin B (P < 0.0001). In the kidneys, all regimens except the Cy regimen were effective, but fluconazole-Cy remained superior to amphotericin B and fluconazole alone in sterilizing the organs (P < 0.0001). While the mechanism responsible for the fluconazole-Cy interaction is hypothetical, this observation opens new perspectives for fungicidal combinations between azoles and other drugs.

scholarly journals Fenbendazole Controls In Vitro Growth, Virulence Potential, and Animal Infection in the Cryptococcus Model

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Haroldo C. de Oliveira ◽  
Luna S. Joffe ◽  
Karina S. Simon ◽  
Rafael F. Castelli ◽  
Flavia C. G. Reis ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Mammalian Cells ◽  
Fungal Pathogens ◽  
Therapeutic Potential ◽  
Low Cost ◽  
Macrophage Infection ◽  
Content Type ◽  
Virulence Potential ◽  
Cryptococcal Disease

ABSTRACT The human diseases caused by the fungal pathogens Cryptococcus neoformans and Cryptococcus gattii are associated with high indices of mortality and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anticryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anticryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anticryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anticryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mouse model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.

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