Graphical representations (box-plot) of the EPHX1 c.377T>C genotypes with CDR_CBZ CBZ: Carbamazepine; CDR: Concentration/dose ratio.

<p>Data are mean ± standard deviations. Statistical significance for difference of means is shown (P values, one way ANOVA analysis followed by Student’s T-test).</p

Graphical representations (box-plot) of the EPHX1 c.416A>G genotypes associations with (A) CBZD:CBZ, (B) CBZD:CBZE and (C) CDR_CBZD,.

<p>CBZ: Carbamazepine; CBZD: Carbamazepine-10,11-trans dihydrodiol; CBZE: Carbamazepine-10,11-epoxide; CDR: Concentration/dose ratio. Data are mean ± standard deviations. Statistical significance for difference of means is shown (P values, one way ANOVA analysis followed by Student’s T-test).</p

Graphical representations (box-plot) of the sodium channels (SCN1A IVS5-91 G>A) SNPs genotypes associations with (A) CBZ daily dosage (mg/day), (B) CBZ maintenance dose (mg/kg per day), (C) CDR_CBZ and (D) CBZD:CBZ.

<p>Statistical significance for difference of means is shown (P values, one way ANOVA analysis followed by Student’s T-test).</p

Distribution of SCN1A, ABCB1, EPHX1 genes polymorphism in drug-resistant and drug-responsive epileptic patients.

<p>Distribution of SCN1A, ABCB1, EPHX1 genes polymorphism in drug-resistant and drug-responsive epileptic patients.</p

Correlation between CBZ and CBZE plasma concentrations (Pearson’s correlation coefficient R).

<p>Correlation between CBZ and CBZE plasma concentrations (Pearson’s correlation coefficient R).</p

CBZ daily dose, maintenance dose, concentration/dose adjusted ratios of CBZ, CBZE, CBZD and their concentration ratios stratified by individual SNPs genotypes.

<p>^a,b Values sharing same letter are not significantly different.</p><p>*P<0.05</p><p>**P<0.01. (one way ANOVA analysis followed by Student’s T-test). CBZE: carbamazepine-10,11-epoxide; CBZD: 10,11-dihydroxy-carbazepine.</p><p>Data are mean ± standard deviations.</p

Probing milk extracellular vesicles for intestinal delivery of RNA therapies

Background Oral delivery remains unattainable for nucleic acid therapies. Many nanoparticle-based drug delivery systems have been investigated for this, but most suffer from poor gut stability, poor mucus diffusion and/or inefficient epithelial uptake. Extracellular vesicles from bovine milk (mEVs) possess desirable characteristics for oral delivery of nucleic acid therapies since they both survive digestion and traverse the intestinal mucosa. Results Using novel tools, we comprehensively examine the intestinal delivery of mEVs, probing whether they could be used as, or inform the design of, nanoparticles for oral nucleic acid therapies. We show that mEVs efficiently translocate across the Caco-2 intestinal model, which is not compromised by treatment with simulated intestinal fluids. For the first time, we also demonstrate transport of mEVs in novel 3D ‘apical-out’ and monolayer-based human intestinal epithelial organoids (IEOs). Importantly, mEVs loaded with small interfering RNA (siRNA) induced (glyceraldehyde 3-phosphate dehydrogenase, GAPDH) gene silencing in macrophages. Using inflammatory bowel disease (IBD) as an example application, we show that administration of anti-tumour necrosis factor alpha (TNFα) siRNA-loaded mEVs reduced inflammation in a IBD rat model. Conclusions Together, this work demonstrates that mEVs could either act as natural and safe systems for oral delivery or nucleic acid therapies, or inform the design of synthetic systems for such application. Graphical Abstract</p