5 research outputs found
Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles
There are very few drug delivery
systems that target key organs
via the oral route, as oral delivery advances normally address gastrointestinal
drug dissolution, permeation, and stability. Here we introduce a nanomedicine
in which nanoparticles, while also protecting the drug from gastric
degradation, are taken up by the gastrointestinal epithelia and transported
to the lung, liver, and spleen, thus selectively enhancing drug bioavailability
in these target organs and diminishing kidney exposure (relevant to
nephrotoxic drugs). Our work demonstrates, for the first time, that
oral particle uptake and translocation to specific organs may be used
to achieve a beneficial therapeutic response. We have illustrated
this using amphotericin B, a nephrotoxic drug encapsulated within <i>N</i>-palmitoyl-<i>N</i>-methyl-<i>N</i>,<i>N</i>-dimethyl-<i>N</i>,<i>N</i>,<i>N</i>-trimethyl-6-<i>O</i>-glycol chitosan
(GCPQ) nanoparticles, and have evidenced our approach in three separate
disease states (visceral leishmaniasis, candidiasis, and aspergillosis)
using industry standard models of the disease in small animals. The
oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease
models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral
liposomal AmB (AmBisome). Our work thus paves the way for others to
use nanoparticles to achieve a specific targeted delivery of drug
to key organs via the oral route. This is especially important for
drugs with a narrow therapeutic index
Synthetic Oxoisoaporphine Alkaloids: In Vitro, In Vivo and In Silico Assessment of Antileishmanial Activities
Oral Particle Uptake and Organ Targeting Drives the Activity of Amphotericin B Nanoparticles
There are very few drug delivery
systems that target key organs
via the oral route, as oral delivery advances normally address gastrointestinal
drug dissolution, permeation, and stability. Here we introduce a nanomedicine
in which nanoparticles, while also protecting the drug from gastric
degradation, are taken up by the gastrointestinal epithelia and transported
to the lung, liver, and spleen, thus selectively enhancing drug bioavailability
in these target organs and diminishing kidney exposure (relevant to
nephrotoxic drugs). Our work demonstrates, for the first time, that
oral particle uptake and translocation to specific organs may be used
to achieve a beneficial therapeutic response. We have illustrated
this using amphotericin B, a nephrotoxic drug encapsulated within <i>N</i>-palmitoyl-<i>N</i>-methyl-<i>N</i>,<i>N</i>-dimethyl-<i>N</i>,<i>N</i>,<i>N</i>-trimethyl-6-<i>O</i>-glycol chitosan
(GCPQ) nanoparticles, and have evidenced our approach in three separate
disease states (visceral leishmaniasis, candidiasis, and aspergillosis)
using industry standard models of the disease in small animals. The
oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease
models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral
liposomal AmB (AmBisome). Our work thus paves the way for others to
use nanoparticles to achieve a specific targeted delivery of drug
to key organs via the oral route. This is especially important for
drugs with a narrow therapeutic index
Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy.
The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels