RESUMEN
The pharmacokinetics, excretion, and tissue distribution of [(14)C]-labeled polyethylene glycol-alanine (PEG-Ala) were determined after slow bolus administration into the femoral vein of male CD-1 mice. The pharmacokinetics of PEG-Ala in blood and plasma revealed a biphasic elimination with a terminal half-life of 20 h. Eighty-five percent of the excreted material was voided in the urine and the remaining amount was detected in the feces. PEG-Ala-derived radioactivity was widely distributed with detectable levels of radioactivity observed in all tissues examined. The highest concentration was observed in the kidneys followed by lungs, heart, and liver. Six hours after administration, PEG-Ala levels were significantly reduced in all tissues. Despite a slow prolonged decrease, radioactivity was still detectable after 28 days.
Asunto(s)
Polietilenglicoles/farmacocinética , Administración Intravenosa , Alanina/química , Alanina/farmacocinética , Animales , Isótopos de Carbono/farmacocinética , Heces/química , Masculino , Ratones , Polietilenglicoles/química , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Mannose-binding lectin (MBL) targets diverse microorganisms for phagocytosis and complement-mediated lysis by binding specific surface glycans. Although recombinant human MBL (rhMBL) trials have focused on reconstitution therapy, safety studies have identified no barriers to its use at higher levels. Ebola viruses cause fatal hemorrhagic fevers for which no treatment exists and that are feared as potential biothreat agents. We found that mice whose rhMBL serum concentrations were increased ≥7-fold above average human levels survived otherwise fatal Ebola virus infections and became immune to virus rechallenge. Because Ebola glycoproteins potentially model other glycosylated viruses, rhMBL may offer a novel broad-spectrum antiviral approach.
Asunto(s)
Ebolavirus/inmunología , Ebolavirus/patogenicidad , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Fiebre Hemorrágica Ebola/patología , Factores Inmunológicos/administración & dosificación , Lectina de Unión a Manosa/administración & dosificación , Animales , Antivirales/administración & dosificación , Humanos , Ratones , Ratones Noqueados , Proteínas Recombinantes/administración & dosificación , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PEG-amide vancomycin derivatives (V(3) position) have been synthesized and found to behave as prodrugs in vivo, demonstrating anti-microbial activity in mice when challenged with Staphylococcus aureus. The corresponding PEG-carbamate derivatives do not manifest this in vivo activity, although both classes of compounds have similar in vitro rat plasma stability. Thus, it appears that extra vascular cleavage of the amide bond can occur if the condition of extended circulation of the conjugate is met, resulting in the release of vancomycin.
Asunto(s)
Amidas/metabolismo , Antibacterianos/química , Antibacterianos/farmacología , Polietilenglicoles/química , Vancomicina/análogos & derivados , Vancomicina/farmacología , Amidas/química , Animales , Antibacterianos/metabolismo , Biotransformación , Carbamatos/química , Ratones , Pruebas de Sensibilidad Microbiana , Polietilenglicoles/metabolismo , Profármacos/química , Profármacos/farmacología , Ratas , Staphylococcus aureus/efectos de los fármacos , Vancomicina/químicaRESUMEN
6-Mercaptopurine (6-MP) is an orally administered, water-insoluble purine analog that is effective against acute lymphatic leukemia. Oral absorption of 6-MP, however, is quite erratic, with only 16-50% of the administered dose reaching the blood. In this report, water-soluble parenterally administered poly(ethylene glycol) (PEG) prodrugs of 6-MP were synthesized using several chemical approaches that enabled the protection of the thiol group through a modification of the benzyl elimination (BE) system. In our earlier work on antimetabolites, it was found that branching of the PEG allowed greater loading of the active drug. This approach was also utilized within this work to give multiloaded systems. The resulting conjugates were stable in pH 7.4 PBS buffer as well as in rat plasma for extended periods. However, these conjugates did act as prodrugs in vivo and a number of PEG-6-MP constructs had significant (P < 0.05) activity in murine leukemia, as well as certain solid tumors, compared with unconjugated 6-MP in a solubilizing vehicle. The fact that some PEG-6-MP conjugates were stable during in vitro plasma dissociation assays, but demonstrated in vivo anticancer activity, suggests extravascular cleavage of the linking group. This work demonstrates that PEG conjugation is an effective means of solubilizing 6-MP for parenteral administration.
Asunto(s)
Compuestos de Bencilo/administración & dosificación , Mercaptopurina/administración & dosificación , Polietilenglicoles/administración & dosificación , Profármacos/administración & dosificación , Compuestos de Sulfhidrilo/administración & dosificación , Animales , Compuestos de Bencilo/farmacocinética , Línea Celular Tumoral , Femenino , Infusiones Intravenosas , Mercaptopurina/farmacocinética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Polietilenglicoles/farmacocinética , Profármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Compuestos de Sulfhidrilo/farmacocinéticaRESUMEN
This paper reports on the synthesis, safety, and efficacy of a series of water-soluble derivatives of poly(ethylene glycol) (PEG)-conjugated amphotericin B (AmB). PEG 40 000 attached to the sugar amino group of AmB via labile carbamate and carbonate linkages was examined. The synthetic program conducted for this investigation provided a series of disubstituted PEG-AmB derivatives which had in vitro PEG half-life of hydrolyses rates in rat plasma varying between 1 and 3 h. Importantly, all conjugates demonstrated less than 6% hydrolysis following 24 h incubation in pH 7.4 phosphate buffer at 25 degrees C and showed solubilities greater than 46 mg/mL in aqueous solutions. The solubility of AmB in the conjugates increased up to approximately 200 times compared to unmodified AmB in saline. As a major finding, this investigation demonstrated that conjugation of PEG to AmB could produce conjugates that were significantly (6x) less toxic than AmB-deoxycholate and maintained, or even had enhanced, in vivo antifungal activity.
Asunto(s)
Anfotericina B/metabolismo , Polietilenglicoles/metabolismo , Profármacos/metabolismo , Anfotericina B/administración & dosificación , Anfotericina B/síntesis química , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , Polietilenglicoles/administración & dosificación , Polietilenglicoles/síntesis química , Profármacos/administración & dosificación , Profármacos/síntesis química , Conejos , Ratas , Ratas Sprague-DawleyRESUMEN
Des-(N-methyl-D-leucyl)eremomycin was obtained by Edman degradation of eremomycin. Derivatives with a hydrophobic substituent at the exterior of the molecule were then synthesized, and their antibacterial activities were compared with similar derivatives of eremomycin. Comparison of derivatives of eremomycin containing the n-decyl or p-(p-chlorophenyl)benzyl substituent in the eremosamine moiety (N') and n-decyl or p-(p-chlorophenyl)benzylamides with similar derivatives of eremomycin possessing the damaged peptide core (a defective binding pocket) showed that compounds of both types are almost equally active against glycopeptide-resistant strains of enterococci (GRE), whereas eremomycin derivatives are more active against staphylococci. Hydrophobic 7d-alkylaminomethylated derivatives of eremomycin (9, 10) demonstrated similar antibacterial properties. Since the basic mode of action of glycopeptide antibiotics involves binding to cell wall intermediates terminating in -D-Ala-D-Ala and this interaction is seriously decreased in the hexapeptide derivatives (lacking the critical N-methyl-D-leucine), we suggest that these hydrophobic derivatives may inhibit peptidoglycan synthesis in the absence of dipeptide binding. NMR binding experiments using Ac-D-Ala-D-Ala show that binding constants of these hexapeptide derivativies are decreased in comparison with the corresponding heptapeptides with intact binding pocket. This is in agreement with the decreased biological activity of the hexapeptide derivatives against vancomycin-sensitive strains in comparison with the activity of parent compounds. Binding to the lactate cell wall analogue Ac-D-Ala-D-Lac with decylamide of eremomycin 8 was not observed, demonstrating that the interaction with this target in GRE does not occur. While hydrophobic glycopeptide derivatives retain the ability to inhibit the synthesis of peptidoglycan in manner of natural glycopeptides, biochemical investigation supports the hypothesis that they inhibit the transglycosylase stage of bacterial peptidoglycan biosynthesis even in the absence of dipeptide or depsipeptide binding.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Glicopéptidos/síntesis química , Glicopéptidos/farmacología , Antibacterianos/química , Enterococcus/efectos de los fármacos , Humanos , Ligandos , Pruebas de Sensibilidad Microbiana , Resonancia Magnética Nuclear Biomolecular , Peptidoglicano/biosíntesis , Staphylococcus aureus/efectos de los fármacos , Propiedades de SuperficieRESUMEN
Moenomycin is a natural product glycolipid that inhibits the growth of a broad spectrum of Gram-positive bacteria. In Escherichia coli, moenomycin inhibits peptidoglycan synthesis at the transglycosylation stage, causes accumulation of cell-wall intermediates, and leads to lysis and cell death. However, unlike Esc. coli, where 5-6 log units of killing are observed, 0-2 log units of killing occurred when Gram-positive bacteria were treated with similar multiples of the MIC. In addition, bulk peptidoglycan synthesis in intact Gram-positive cells was resistant to the effects of moenomycin. In contrast, synthetic disaccharides based on the moenomycin disaccharide core structure were identified that were bactericidal to Gram-positive bacteria, inhibited cell-wall synthesis in intact cells, and were active on both sensitive and vancomycin-resistant enterococci. These disaccharide analogues do not inhibit the formation of N:-acetylglucosamine-ss-1, 4-MurNAc-pentapeptide-pyrophosphoryl-undecaprenol (lipid II), but do inhibit the polymerization of lipid II into peptidoglycan in Esc. coli. In addition, cell growth was required for bactericidal activity. The data indicate that synthetic disaccharide analogues of moenomycin inhibit cell-wall synthesis at the transglycosylation stage, and that their activity on Gram-positive bacteria differs from moenomycin due to differential targeting of the transglycosylation process. Inhibition of the transglycosylation process represents a promising approach to the design of new antibacterial agents active on drug-resistant bacteria.