ABSTRACT
Acanthamoeba sp. are the causative agents of severe illnesses in humans such as Acanthamoeba keratitis (AK) and granulomatous amoebic encephalitis (GAE). Medical therapy is not yet well established. Treatments of AK last for several months and generate toxicity, resistances appear due to the cysts stage and recurrences can occur. In this study has been demonstrated that the combination of chlorhexidine digluconate (CLX) and carbosilane dendrimers containing ammonium or guanidine moieties has in vitro synergistic effect against Acanthamoeba polyphaga. This synergy provokes an important reduction in the minimal trophozoite amoebicidal concentration (MTAC) of CLX, which means a reduction of their toxic effects on human cells. Moreover, some CLX/dendrimer combinations show important activity against the cyst resistance stage.
Subject(s)
Acanthamoeba/drug effects , Cations/pharmacology , Chlorhexidine/analogs & derivatives , Cysts/drug therapy , Dendrimers/pharmacology , Silanes/pharmacology , Trophozoites/drug effects , Acanthamoeba Keratitis/drug therapy , Anti-Infective Agents, Local/pharmacology , Cell Line, Tumor , Chlorhexidine/pharmacology , Drug Synergism , HeLa Cells , HumansABSTRACT
The purpose of this research was to determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (generations 1-3) as mucoadhesive polymers in eyedrop formulations. Cationic carbosilane dendrimers decorated with ammonium -NH3(+) groups were prepared by hydrosylilation of Boc-protected allylamine and followed by deprotection with HCl. Anionic carbosilane dendrimers with terminal carboxylate groups were also employed in this study. In vitro and in vivo tolerance studies were performed in human ocular epithelial cell lines and rabbit eyes respectively. The interaction of dendrimers with transmembrane ocular mucins was evaluated with a surface biosensor. As proof of concept, the hypotensive effect of a carbosilane dendrimer eyedrop formulation containing acetazolamide (ACZ), a poorly water-soluble drug with limited ocular penetration, was tested after instillation in normotensive rabbits. The methodology used to synthesize cationic dendrimers avoids the difficulty of obtaining neutral -NH2 dendrimers that require harsher reaction conditions and also present high aggregation tendency. Tolerance studies demonstrated that both prototypes of water-soluble anionic and cationic carbosilane dendrimers were well tolerated in a range of concentrations between 5 and 10 µM. Permanent interactions between cationic carbosilane dendrimers and ocular mucins were observed using biosensor assays, predominantly for the generation-three (G3) dendrimer. An eyedrop formulation containing G3 cationic carbosilane dendrimers (5 µM) and ACZ (0.07%) (289.4 mOsm; 5.6 pH; 41.7 mN/m) induced a rapid (onset time 1 h) and extended (up to 7 h) hypotensive effect, and led to a significant increment in the efficacy determined by AUC0(8h) and maximal intraocular pressure reduction. This work takes advantage of the high-affinity interaction between cationic carbosilane dendrimers and ocular transmembrane mucins, as well as the tensioactive behavior observed for these polymers. Our results indicate that low amounts of cationic carbosilane dendrimers are well tolerated and able to improve the hypotensive effect of an acetazolamide solution. Our results suggest that carbosilane dendrimers can be used in a safe range of concentrations to enhance the bioavailability of drugs topically administered in the eye.
Subject(s)
Dendrimers/chemistry , Dendrimers/pharmacokinetics , Silanes/chemistry , Silanes/pharmacokinetics , Acetazolamide/chemistry , Administration, Ophthalmic , Animals , Cell Line , Cell Survival/drug effects , Dendrimers/administration & dosage , Dendrimers/pharmacology , Humans , Male , Rabbits , Silanes/administration & dosage , Silanes/pharmacology , Surface Plasmon ResonanceABSTRACT
This paper examines the formation and stability of nano-complexes that could provide a new therapeutic approach against HIV-1 infection. Poly(propylene imine) glycodendrimers decorated with 2(nd) generation cationic carbosilane dendrons were generated and their use in polyplex formation checked. Owing to their positively-charged terminal amino groups the hybrid glycodendrimers can bind anionic peptides. It was shown that they form nano-complexes with the HIV-derived peptides P24, Gp160 and Nef. Complexes 130-190 nm in size were formed in molar ratios (dendrimer/ peptide) of (3-4):1. These were sufficiently stable over time and at different pHs. The results obtained suggest that the hybrid dendrimers studied can be considered as alternative carriers for delivering HIV peptides to dendritic cells.
Subject(s)
Dendrimers/chemistry , Drug Carriers/chemistry , HIV-1 , Nanoparticles/chemistry , Peptides/chemistry , HIV Core Protein p24/chemistry , HIV Envelope Protein gp160/chemistry , Polypropylenes/chemistry , Silanes/chemistry , nef Gene Products, Human Immunodeficiency Virus/chemistryABSTRACT
Como parte de la búsqueda de sustancias activas antimicrobianasnovedosas se analizó la actividad in vitro de losextractos orgánicos crudos de 15 especies de esponjas marinasde la costa noreste de Colombia contra microorganismosde importancia clínica en humanos (una cepa de cada especiede Streptococcus faecalis, Staphylococcus aureus, Escherichiacoli, Pseudomonas aeruginosa y Candida albicans).Los extractos de las esponjas Halichondria sp., Petromicaciocalyptoides y Xestospongia proxima exhibieron actividadcontra las bacterias grampositivas y contra el hongo, mientrasque la esponja Dragmacidon reticulata sólo mostró actividadcontra esta levadura. La bioactividad de los extractosfue contrastada con un antibiótico (cefoperazona) y un antimicótico(nistatina) comerciales y se encontró que los valoresde inhibición in vitro del extracto de X. proxima son mayores,en algunos casos, a los observados para la cefoperazona yla nistatina. Los extractos de las esponjas Myrmekiodermagyroderma, Myrmekioderma rea, Biemna cribaria, Cinachyrellakuekenthali, Iotrochota imminuta, Oceanapia peltata,Polymastia tenax, Desmapsamma anchorata, Spirastrellacoccinea, Cribrochalina infundibulum y Oceanapia bartschino presentaron actividad antimicrobiana (AU)
As part of the search for new natural sources of antibioticcompounds, in this study, carried out in the northeasterncoast of Colombia, 15 sponge species were collected.A crude organic extract was obtained from each one and evaluated regarding their antimicrobial propertiesin vitro against microorganisms with clinical importancefor humans (one strain for each specie of Streptococcusfaecalis, Staphylococcus aureus, Escherichia coli, Pseudomonasaeruginosa and Candida albicans). Sponge extractsfrom Halichondria spp., Petromica ciocalyptoides and Xestospongiaproxima exhibited antibacterial activity againstgram-positive bacteria and antifungal activity against thefungi, while the sponge Dragmacidon reticulata showedactivity only for the same yeast specie. Bioactivity of theextracts was compared with that of both a antibiotic (cefoperazone)and an antimicotic (nistatine). It was found thatinhibition values of X. proxima extracts in vitro are, in somecases, higher than those observed for cefoperazone andnistatine. Crude extracts from the sponges Myrmekiodermagyroderma, Myrmekioderma rea, Biemna cribaria, Cinachyrellakuekenthali, Iotrochota imminuta, Oceanapiapeltata, Polymastia tenax, Desmapsamma anchorata, Spirastrellacoccinea, Cribrochalina infundibulum and Oceanapiabartschi did not show any antimicrobial activitywhatsoever (AU)
