Posaconazole

N.º de catálogoS1257 Lote:S125708

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Datos técnicos

Fórmula

C₃₇H₄₂F₂N₈O₄

Peso molecular

700.78

Número CAS

171228-49-2

Solubilidad (25°C)*

In vitro

DMSO

100 mg/mL (142.69 mM)

Water

Insoluble

Ethanol

Insoluble

In vivo (Agregue los solventes al producto individualmente y en orden.)

Homogeneous suspension

CMC-NA

≥5mg/ml

Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

* <1 mg/ml significa ligeramente soluble o insoluble.
* Tenga en cuenta que Selleck prueba la solubilidad de todos los compuestos internamente, y la solubilidad real puede diferir ligeramente de los valores publicados. Esto es normal y se debe a ligeras variaciones entre lotes.
* Envío a temperatura ambiente (Las pruebas de estabilidad demuestran que este producto se puede enviar sin medidas de refrigeración.)

Preparación de soluciones madre

Actividad biológica

Descripción

Posaconazole es un inhibidor principalmente de CYP3A4, pero no inhibe la actividad de otras enzimas CYP; También es un inhibidor de la esterol C14ɑ desmetilasa con una IC50 de 0,25 μM. Este compuesto tiene una vida media de eliminación terminal mediana de 15 a 35 horas.

Objetivos

lanosterol 14α-demethylase

CYP3A4

In vitro

Posaconazole tiene una potente actividad tripanocida. La amiodarona actúa sinérgicamente con este compuesto. También afecta y altera la homeostasis de Ca²⁺ en T. cruzi. Este químico bloquea la biosíntesis de ergosterol, que es esencial para la supervivencia del parásito. Tiene un efecto claro y dosis-dependiente sobre la proliferación de las etapas epimastigotes (extracelulares), con una concentración inhibitoria mínima de 20 nM y una IC50 de 14 nM. Contra la forma amastigote intracelular clínicamente relevante del parásito, este compuesto es aún más potente. Tiene valores de concentración inhibitoria mínima e IC50 de 3 nM y 0,25 nM. Es activo contra aislados de Candida y Aspergillus spp. que exhiben resistencia a Fluconazole, Voriconazole y Anfotericina B y es mucho más activo que los otros triazoles contra los cigomicetos.

In vivo

El tratamiento de animales infectados solo con amiodarona reduce la parasitemia, aumenta la supervivencia 60 días post-infección (0% para los controles no tratados frente al 40% para los animales tratados con amiodarona) y, cuando se administra en combinación con Posaconazole, retrasa el desarrollo de la parasitemia. La coadministración de este compuesto y Boost Plus aumenta la exposición al fármaco en comparación con la administración de este compuesto solo en ayunas. Los alimentos, particularmente las comidas con alto contenido de grasas, aumentan significativamente la biodisponibilidad de este compuesto. La exposición sistémica a este compuesto aumenta 4 y 2,6 veces cuando se consume con una comida rica en grasas y una comida sin grasas, respectivamente. Este compuesto y la amiodarona pueden constituir una terapia anti-T. cruzi eficaz con pocos efectos secundarios. A dosis de dos veces al día de ≥15 mg/kg de peso corporal, este compuesto prolonga la supervivencia de los ratones y reduce la carga tisular.

Características

Actualmente, el candidato más avanzado para el tratamiento de la enfermedad de Chagas.

Protocolo (de referencia)

Ensayo celular:^{^[1]}	Líneas celulares Epimastigote form of T. cruzi amastigotes Concentraciones 0 nM -4 nM Tiempo de incubación 96 hours Método The epimastigote form of the parasite is cultivated in liver infusion tryptose medium, supplemented with 10% new born calf serum at 28 °C with strong (120 rpm) agitation. Cultures are initiated at a cell density of 2 × 10⁶ epimastigotes/mL, and Posaconazole is added at a cell density of 0.5−1.0 × 10⁷ epimastigotes/mL. Cell densities are measured by using an electronic particle counter as well as by direct counting with a hemocytometer. Cell viability is followed by Trypan blue exclusion, using light microscopy. Amastigotes are cultured in Vero cells maintained in minimal essential medium supplemented with 1% fetal calf serum in a humidified atmosphere (95% air−5% CO₂) at 37 °C. Cells are infected with 10 tissue culture-derived trypomastigotes per cell for 2 hours and then washed three times with phosphate-buffered saline (PBS) to remove nonadherent parasites. Fresh medium with and without this compound is added, and the cells are incubated for 96 hours with a medium change at 48 hours. The percent of infected cells and the numbers of parasites per cell are determined directly using light microscopy, and a statistical analysis of the results is carried out. IC50 values are calculated by nonlinear regression, using the program GraFit. Fractional inhibitory concentrations (FIC) are calculated. Cytoplasmic free Ca²⁺ concentrations in control and drug-treated extracellular epimastigotes are determined by fluorimetric methods using Fura-2. Subcellular Ca²⁺ levels and mitochondrial membrane potentials are monitored on individual Vero cells infected with T. cruzi amastigotes by using time-scan confocal microscopy. Briefly, Vero cells heavily infected (72 hours) with T. cruzi amastigotes are plated onto 22 × 40 mm glass coverslips (0.15 mm thickness) and incubated simultaneously with 10 μM cell-permeant Rhod-2 and 10 μg/mL Rhodamine-123 for 50 minutes at 37 °C in culture medium and then washed and incubated with Ringer's solution, with or without amiodarone. Under the conditions used fluorescence of Rhod-2 comes mainly from intracellular Ca²⁺-rich compartments, like mitochondria, since its low affinity for Ca²⁺ limits its fluorescence in the Ca²⁺-poor cytoplasm of the Vero cells or amastigotes. Rhodamine-123 is a mitochondrion-specific cationic dye, which distributes across the inner mitochondrial membranes strictly according to their membrane potential.
Estudio en animales:^{^[1]}	Modelos animales Female NMRI−IVIC mice with acute Chagas Dosificaciones 20 mg/kg/d Administración Oral

Ensayo celular:^{^[1]}

Líneas celulares
Epimastigote form of T. cruzi amastigotes
Concentraciones
0 nM -4 nM
Tiempo de incubación
96 hours
Método
The epimastigote form of the parasite is cultivated in liver infusion tryptose medium, supplemented with 10% new born calf serum at 28 °C with strong (120 rpm) agitation. Cultures are initiated at a cell density of 2 × 10⁶ epimastigotes/mL, and Posaconazole is added at a cell density of 0.5−1.0 × 10⁷ epimastigotes/mL. Cell densities are measured by using an electronic particle counter as well as by direct counting with a hemocytometer. Cell viability is followed by Trypan blue exclusion, using light microscopy. Amastigotes are cultured in Vero cells maintained in minimal essential medium supplemented with 1% fetal calf serum in a humidified atmosphere (95% air−5% CO₂) at 37 °C. Cells are infected with 10 tissue culture-derived trypomastigotes per cell for 2 hours and then washed three times with phosphate-buffered saline (PBS) to remove nonadherent parasites. Fresh medium with and without this compound is added, and the cells are incubated for 96 hours with a medium change at 48 hours. The percent of infected cells and the numbers of parasites per cell are determined directly using light microscopy, and a statistical analysis of the results is carried out. IC50 values are calculated by nonlinear regression, using the program GraFit. Fractional inhibitory concentrations (FIC) are calculated. Cytoplasmic free Ca²⁺ concentrations in control and drug-treated extracellular epimastigotes are determined by fluorimetric methods using Fura-2. Subcellular Ca²⁺ levels and mitochondrial membrane potentials are monitored on individual Vero cells infected with T. cruzi amastigotes by using time-scan confocal microscopy. Briefly, Vero cells heavily infected (72 hours) with T. cruzi amastigotes are plated onto 22 × 40 mm glass coverslips (0.15 mm thickness) and incubated simultaneously with 10 μM cell-permeant Rhod-2 and 10 μg/mL Rhodamine-123 for 50 minutes at 37 °C in culture medium and then washed and incubated with Ringer's solution, with or without amiodarone. Under the conditions used fluorescence of Rhod-2 comes mainly from intracellular Ca²⁺-rich compartments, like mitochondria, since its low affinity for Ca²⁺ limits its fluorescence in the Ca²⁺-poor cytoplasm of the Vero cells or amastigotes. Rhodamine-123 is a mitochondrion-specific cationic dye, which distributes across the inner mitochondrial membranes strictly according to their membrane potential.

Estudio en animales:^{^[1]}

Modelos animales
Female NMRI−IVIC mice with acute Chagas
Dosificaciones
20 mg/kg/d
Administración
Oral

Referencias

https://pubmed.ncbi.nlm.nih.gov/16451055/
https://pubmed.ncbi.nlm.nih.gov/16723559/
https://pubmed.ncbi.nlm.nih.gov/16641468/

https://pubmed.ncbi.nlm.nih.gov/22591838/
https://pubmed.ncbi.nlm.nih.gov/12069997/
https://pubmed.ncbi.nlm.nih.gov/15311563/

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Validación de productos por parte del cliente

: Datos de [ , , Eur J Pharm Sci, 2016, 91:190-195. ]

Sellecks Posaconazole Ha sido citado por 28 Publicaciones

Pyrvinium Pamoate Synergizes with Azoles in vitro and in vivo to Exert Antifungal Efficacy Against Candida auris and Other Candida Species [ Infect Drug Resist, 2025, 18:783-789]	PubMed: 39958982
Interactions between antifungals and everolimus against Cryptococcus neoformans [ Front Cell Infect Microbiol, 2023, 13:1131641]	PubMed: 37026056
The Synergistic Effect of Tacrolimus (FK506) or Everolimus and Azoles Against Scedosporium and Lomentospora Species In Vivo and In Vitro [ Front Cell Infect Microbiol, 2022, 12:864912]	PubMed: 35493742
Synergistic effect of pyrvinium pamoate and posaconazole against Cryptococcus neoformans in vitro and in vivo [ Front Cell Infect Microbiol, 2022, 12:1074903]	PubMed: 36569209
Terconazole, an Azole Antifungal Drug, Increases Cytotoxicity in Antimitotic Drug-Treated Resistant Cancer Cells with Substrate-Specific P-gp Inhibitory Activity [ Int J Mol Sci, 2022, 23(22)13809]	PubMed: 36430288
A Preliminary in vitro and in vivo Evaluation of the Effect and Action Mechanism of 17-AAG Combined With Azoles Against Azole-Resistant Candida spp [ Front Microbiol, 2022, 13:825745]	PubMed: 35875545
The synergistic effect of minocycline and azole antifungal drugs against Scedosporium and Lomentospora species [ BMC Microbiol, 2022, 22(1):21]	PubMed: 35016611
The Role of Isavuconazonium Sulphate for the Treatment of Blastomycosis: A Case Series and Antifungal Susceptibility [ Open Forum Infect Dis, 2022, 9(7):ofac220]	PubMed: 35821730
In Vitro and In Vivo Interactions of TOR Inhibitor AZD8055 and Azoles against Pathogenic Fungi [ Microbiol Spectr, 2022, 10(1):e0200721]	PubMed: 35019705
Antifungal Activity of Minocycline and Azoles Against Fluconazole-Resistant Candida Species [ Front Microbiol, 2021, 12:649026]	PubMed: 34054751

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