Search results for "ENHANCERS"

Contribution of allelic imbalance to colorectal cancer

2018

Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point muta…

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

2020

Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In …

Influence of Chemical Enhancers and Iontophoresis on the In Vitro Transdermal Permeation of Propranolol: Evaluation by Dermatopharmacokinetics

2018

[EN] The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum corneum, using propranolol as a model compound. Four chemical enhancers (decenoic and oleic acid, laurocapram, and R-(+)-limonene) and iontophoresis at two current densities, 0.25 and 0.5 mA/cm(2) were tested. R-(+)-limonene, and iontophoresis at 0.5 mA/cm(2) were proven to be the most efficient in increasing propranolol transdermal flux, both doubled the original propranolol transdermal flux. Iontophoresis was demonstrated to be superior than the chemical…

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

2014

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regressionmodels adjusting for stud…

Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA

2017

There is a renewed interest from the pharmaceutical field to develop oral formulations of compounds, such as peptides, oligonucleotides, and polar drugs. However, these often suffer from insufficient absorption across the intestinal mucosal barrier. One approach to circumvent this problem is the use of absorption modifying excipient(s) (AME). This study determined the absorption enhancing effect of four AMEs (sodium dodecyl sulfate, caprate, chitosan, N-acetylcysteine) on five model compounds in a rat jejunal perfusion model. The aim was to correlate the model compound absorption to the blood-to-lumen clearance of the mucosal marker for barrier integrity, 51Cr-EDTA. Sodium dodecyl sulfate a…

Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability

2022

The X-linked gene encoding aristaless-related homeobox (ARX) is a bi-functional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders (NDDs); these include cortical malformations, paediatric epilepsy, intellectual disability (ID) and autism. In addition to point mutations, duplications of the ARX locus have been detected in male patients with ID. These rearrangements include telencephalon ultraconserved enhancers, whose structural alterations can interfere with the control of ARX expression in the developing brain. Here, we review the structural features of 15 gain copy-number variants …

Diffusion of naltrexone across reconstituted human oral epithelium and histomorphological features

2006

Abstract In transbuccal absorption a major limitation could be the low permeability of the mucosa which implies low drug bioavailability. The ability of naltrexone hydrochloride (NLX) to penetrate a resembling histologically human buccal mucosa was assessed and the occurrence of any histomorphological changes observed. We used reconstituted human oral (RHO) non-keratinised epithelium as mucosal section and a Transwell diffusion cells system as bicompartmental model. Buccal permeation was expressed in terms of drug flux ( J s ) and permeability coefficients ( K p ). Data were collected using both artificial and natural human saliva. The main finding was that RHO does not restrain NLX permeat…

MICELLE POLIMERICHE A BASE DI NUOVI DERIVATI ANFIFILICI DELL’INULINA PER LA SOMMINISTRAZIONE OCULARE TOPICA DI CORTICOSTEROIDI NEL TRATTAMENTO DELLE …

2016

Al giorno d’oggi, la via di somministrazione oftalmica costituisce ancora una sfida per i tecnologi farmaceutici. Si tratta, inoltre, probabilmente di uno degli ambiti che più di ogni altro potrebbe beneficiare dello sviluppo di nuovi Drug Delivery Systems basati sull’utilizzo di nanovettori. Infatti, più del 50% delle patologie oculari maggiormente debilitanti (es. degenerazione maculare legata all’età, retinopatia diabetica ed edema maculare diabetico) ha origine a livello del segmento oculare posteriore. Ad oggi, la terapia intravitreale costituisce il gold standard per garantire il raggiungimento del sito target, ovvero la retina. Tuttavia, la necessità di ricorrere a frequenti somminis…

Ocular Drug Delivery Systems per la veicolazione di molecole bioattive al segmento posteriore dell'occhio

Transdermal and Skin-Targeted Drug Delivery

1997

Background: The application of therapeutic agents to the skin addresses three general objectives: (a) the treatment of a variety of dermatologic diseases; (b) the “targeted” delivery of drugs to deeper subcutaneous tissues, with a concomitant reduction in systemic exposure; and (c) socalled transdermal administration to elicit a systemic pharmacologic effect. Objective: Recently, significant progress towards all three goals has been recorded and the level of research and development activity remains high. We aim to discuss these advances from mechanistic and clinical standpoints. Results: For the topical treatment of skin disease, novel vehicles (e.g., stabilized, supersaturated systems and…