Evidence of d-phenylglycine as delivering tool for improving l-dopa absorption

<p>Abstract</p> <p>Background</p> <p><it>l</it>-Dopa has been used for Parkinson's disease management for a long time. However, its wide variety in the rate and the extent of absorption remained challenge in designing suitable therapeutic regime. We report here a design of using <it>d</it>-phenylglycine to guard <it>l</it>-dopa for better absorption in the intestine via intestinal peptide transporter I (PepT1).</p> <p>Methods</p> <p><it>d</it>-Phenylglycine was chemically attached on <it>l</it>-dopa to form <it>d</it>-phenylglycine-<it>l</it>-dopa as a dipeptide prodrug of <it>l</it>-dopa. The cross-membrane transport of this dipeptide and <it>l</it>-dopa via PepT1 was compared in brush-boarder membrane vesicle (BBMV) prepared from rat intestine. The intestinal absorption was compared by <it>in situ </it>jejunal perfusion in rats. The pharmacokinetics after i.v. and p.o. administration of both compounds were also compared in Wistar rats. The striatal dopamine released after i.v. administration of <it>d</it>-phenylglycine-<it>l</it>-dopa was collected by brain microdialysis and monitored by HPLC. Anti-Parkinsonism effect was determined by counting the rotation of 6-OHDA-treated unilateral striatal lesioned rats elicited rotation with (+)-methamphetamine (MA).</p> <p>Results</p> <p>The BBMV uptake of <it>d</it>-phenylglycine-<it>l</it>-dopa was inhibited by Gly-Pro, Gly-Phe and cephradine, the typical PepT1 substrates, but not by amino acids Phe or <it>l</it>-dopa. The cross-membrane permeability (Pm*) determined in rat jejunal perfusion of <it>d</it>-phenylglycine-<it>l</it>-dopa was higher than that of <it>l</it>-dopa (2.58 ± 0.14 vs. 0.94 ± 0.10). The oral bioavailability of <it>d</it>-phenylglycine-<it>l</it>-dopa was 31.7 times higher than that of <it>l-</it>dopa in rats. A sustained releasing profile of striatal dopamine was demonstrated after i. v. injection of <it>d</it>-phenylglycine-<it>l</it>-dopa (50 mg/kg), indicated that <it>d</it>-phenylglycine-<it>l</it>-dopa might be a prodrug of dopamine. <it>d</it>-Phenylglycine-<it>l</it>-dopa was more efficient than <it>l-</it>dopa in lowering the rotation of unilateral striatal lesioned rats (19.1 ± 1.7% vs. 9.9 ± 1.4%).</p> <p>Conclusion</p> <p>The BBMV uptake studies indicated that <it>d</it>-phenylglycine facilitated the transport of <it>l</it>-dopa through the intestinal PepT1 transporter. The higher jejunal permeability and the improved systemic bioavailability of <it>d-</it>phenylglycine-<it>l</it>-dopa in comparison to that of <it>l</it>-dopa suggested that <it>d-</it>phenylglycine is an effective delivery tool for improving the oral absorption of drugs like <it>l</it>-dopa with unsatisfactory pharmacokinetics. The gradual release of dopamine in brain striatum rendered this dipeptide as a potential dopamine sustained-releasing prodrug.</p

Вихретоковый анизотропный термоэлектрический первичный преобразователь лучистого потока

Представлена оригинальная конструкция первичного преобразователя лучистого потока, который может служить основой для создания приемника неселективного излучения с повышенной чувствительностью

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

The influence of water transport on drug absorption in the small intestine.

The effects of food and fluid volume on the variability in rate and extent to which oral drug dosage forms are absorbed have recently generated significant interest in pharmaceutics. One fed-state effect which may enhance drug absorption is provided by the intestinal water absorption generated by mucosal sodium/D-glucose co-transporters. In situ jejunal perfusions (which isolate membrane transport phenomena) were performed in rats to determine the extent of water transport as a function of perfusion buffers, flow rates, perfusate osmolalities, pH and D-glucose concentrations. Jejunal perfusion (pH 6.5) of iso-osmolar 112 mM D-glucose/MES buffer, at a flow rate of 191 $\mu$L/min can generate a significant amount of water absorption (2.4 to 2.9 $\mu$L/min-cm). This result permitted studies of nutrient-induced water absorption on drug uptake as a function of drug properties. Under the same perfusion conditions,the jejunal dimensionless membrane permeabilities of the neutral compounds acetaminophen and prednisolone were incrementally increased by 0.6 to 0.8 units. For the weakly basic cimetidine (pKa = 7.1), the glucose effect on drug permeability was observed to be pH dependent and followed the pH-partition hypothesis at pH 6.5 and 7.5. It is noteworthy that the increase in permeability was the same as for acetaminophen and prednisolone. The permeability of zidovudine increased 2.3 units with glucose-induced water transport. The magnitude of the increase in zidovudine was exceptional and suggests that the mechanism of intestinal uptake of this nucleoside derivative may be more directly coupled to glucose uptake. The effect of glucose-induced water absorption on drug uptake was also studied in the in vivo chronic loop system and in vitro flux chamber system. The in situ and in vivo experimental systems were comparable with respect to both water and solute transport while the in vitro system proved inadequate for generating sufficient transepithelial water transport. The increase in permeability can be argued to be less important in vivo for more hydrophobic drugs since their baseline permeabilities are already quite high and the drugs are well absorbed from solution. The effect is likely more important in vivo for more hydrophilic drugs with low baseline permeabilities where such increases constitute a significant enhancement of drug uptake.Ph.D.PharmaceuticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105566/1/9135640.pdfDescription of 9135640.pdf : Restricted to UM users only