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Transdermal iontophoresis can be used to noninvasively deliver vasoactive drugs into the skin by means of electric current pulses (1). A limitation of iontophoresis is that the delivered drug dose is unknown and the vascular response can only be measured in arbitrary units. Time-response modeling may give better insight in the physiology underlying the vascular drug responses (2). Acetylcholine (ACh) causes endothelium-dependent vasodilatation after iontophoretic delivery in the skin, and is therefore widely used for measuring endothelial function. ACh is rapidly hydrolyzed by acetylcholinesterase (AChE). Metacholine (MCh) has similar actions as ACh but is hydrolyzed by AChE at a considerably slower rate (3). In this study, we applied a mechanistic time-response model to the blood flow response to ACh and MCh delivered by iontophoresis in 21 healthy subjects. We measured skin blood flow using laser-Doppler flowmetry. We took into account the physical transport of drugs into the skin and the vascular response to these drugs. The kinetic part of the model consists of one-compartment, with a zero-order influx of drugs, a first order elimination and a lag time constant accounting for the delay between drug delivery and onset of response. The response dynamics are modeled using the Hill equation. Then, we compared the response to an identical dose (12 mC) of ACh given using a single 10-min current pulse and five 2-minute current pulses with 1-minute intervals. We found that ACh and MCh caused similar increases in blood flow, whereas the return to baseline perfusion after iontophoresis differed distinctly between drugs (Figure 1). Modeling revealed a mean (95% CI) elimination half-life of 9.0 min (8.0-10.3 min) for ACh and 71 min (41-247 min) for MCh. ACh delivered using a single current pulse resulted in stronger vasodilatation than with multiple shorter pulses (38.5 ± 31.7 vs. 30.7 ± 15.5 PU, p < 0.01, Figure 2). These findings can be explained by the differences in drug kinetics in the skin, as ACh is rapidly hydrolyzed by AChE while MCh is not actively degraded. The sustained vasodilatation after iontophoresis of MCh suggests that washout of these drugs by skin blood flow is slow and that the return to baseline is mainly caused by active degradation. In conclusion, modeling of drug kinetics and dynamics gives a better understanding for the physiological and pharmacological parameters during iontophoresis of vasoactive drugs and may improve iontophoresis as a non-invasive technique for assessment of vascular function. [ABSTRACT FROM AUTHOR]

Throughout history, herbal medicinal products have been commonly used in the world. Many medicinal plants have been able to clarify composition and biological activities by advancing the phytochemical and phytopharmaceutical sciences. The effectiveness of many plant species in medicines relies on the supply of active ingredients. Most natural components, such as flavonoids, tannins, and terpenoids, are soluble in water, but they can hardly pass through the cell membrane; therefore, their absorption is low. Because of these obstacles, some extracts are not used clinically. It is widely envisaged that the combination of sophisticated medicines with herbal products could be ready to enhance the action, reduce the specific dose and facet effects of plant extracts, and increase activity due to nanostructured systems. Nanosystems will deliver an active component required for all treatment volumes at a replacement concentration. Typical treatments do not meet these necessities. This is to investigate structures and herbal drugs dependent on nanotechnology. [ABSTRACT FROM AUTHOR]

Amiodarone (AMD) is an antiarrhythmic agent included in the 2nd class according to the biopharmaceutical classification of drug substances. The oral bioavailability of AMD in conventional pharmaceutical formulations exhibits large interindividual variations due to the rapid dealkylation of the molecule to desethylaminodarone (inactive metabolite) and due to low hydrosolubility. The complexation of the drug substance in the central cavity of various kinds of cyclodextrins is one of the most effective methods for optimizing the oral bioavailability of drug substances such as AMD, and it can be accomplished by complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD). The objective of the study was to evaluate the influence of complexation on the oral bioavailability of AMD. The HP-β-CD/AMD inclusion complex was prepared in a 1:1 molar ratio, using the lyophilization method. It was characterized in terms of physico-chemical proprieties, pharmacokinetics, release kinetics, and in vivo bioavailability. The study was conducted according to the legislation in force, using male, Wistar, white mice. The animals were grouped in 2 batches: Lot 1 (control batch) which received AMD·HCL and Lot 2 (positive control batch) which received HP-β- CD/AMD. The analysis of AMD peak plasma concentrations for AMD·HCl (Cmax = 165.67 ± 80.21 ng/mL) and HP-β-CD/AMD (Cmax = 249.67 ± 94.50ng / mL) proved that HP-β- CD/AMD generates 1.5-fold higher average plasma concentrations and therefore those concentration levels are released concurrently. The analysis of areas under the curve for the variation of AMD plasma concentration in time (AUC0-t), showed that the values were approximately 1.15-fold higher for HP-β-CD/AMD (AUC0-t = 0 ± 2.2h) than for AMD·HCl (AUC0-t = 5.5 ± 1.9h). In conclusion, the results obtained confirmed that HP- β-CD is a type of cyclodextrin that can function as the host molecule for AMD in order to optimize oral bioavailability through formulation in modified-release oral therapeutic systems. [ABSTRACT FROM AUTHOR]

The paper considers models of the IV-administration of a drug with differential equations describing the drug concentration in the body. An explanation is given of the fluctuating and irregular plasma concentration patterns of some drugs observed during intravenous infusion. A new mathematical model is offered of drug intravenous administration with respect to the existence of one or more peaks or undulations of the plasma concentration curve. An illustrative example is considered for certain values of the drug infusion rate and its elimination rate. [ABSTRACT FROM AUTHOR]

Hair cells are exquisitely sensitive to auditory stimuli, but also to damage from a variety of sources including noise trauma and ototoxic drugs. Mammals cannot regenerate cochlear hair cells, while non-mammalian vertebrates exhibit robust regenerative capacity. Our research group uses the lateral line system of larval zebrafish to explore the mechanisms underlying hair cell damage, identify protective therapies, and determine molecular drivers of innate regeneration. The lateral line system contains externally located sensory organs called neuromasts, each composed of ~8-20 hair cells. Lateral line hair cells are homologous to vertebrate inner ear hair cells and share similar susceptibility to ototoxic damage. In the last decade, the lateral line has emerged as a powerful model system for understanding hair cell death mechanisms and for identifying novel protective compounds. Here we demonstrate that the lateral line is a tractable model for noise-induced hair cell death. We have developed a novel noise damage system capable of inducing over 50% loss of lateral line hair cells, with hair cell death occurring in a dose- and time-dependent manner. Cell death is greatest 72 hours post-exposure. However, early signs of hair cell damage, including changes in membrane integrity and reduced mechanotransduction, are apparent within hours of noise exposure. These features, early signs of damage followed by delayed hair cell death, are consistent with mammalian data, suggesting that noise acts similarly on zebrafish and mammalian hair cells. In our future work we will use our new model system to investigate noise damage events in real time, and to develop protective therapies for future translational research. [ABSTRACT FROM AUTHOR]

The administration of amoxicillin trihydrate in Helicobacter pylori infection is not effective enough because the conventional preparations used have a short retention time in the stomach. To overcome this problem, amoxicillin trihydrate was encapsulated into the floating drug delivery matrix-matrix. In this study, the full-ipn acetaldehyde crosslinked hydrogel (N-vinyl caprolactam) was synthesized with a 10% CaCO3 pore forming agent and then encapsulated on amoxicillin trihydrate and studied the mechanism of drug dissolution with its kinetic kinetics approach. The K-PNVCL Hydrogel produces optimal properties which are then loaded with amoxicillin trihydrate in situ and post loading. In this research, we have got the percentage of swelling, floating time, the efficiency of in situ and post loading 873%; 3.15 minutes; 99.8% and 99.4%. The dissolution test was performed on amoxicillin trihydrate which had been encapsulated K-PNVCL hydrogel in vitro at pH 1.2 resulting in 94.5% for in situ loading and 98.5% for post loading. Results of the kinetics of drug release for post loading and in situ loading methods tend to follow the Higuchi model kinetics. The drug release mechanism occurs by Fickian diffusion. Proof of drug release mechanism from K-PNVCL hydrogel matrix is further done by Scanning Electron Microscope (SEM) instrument. [ABSTRACT FROM AUTHOR]

Background and aims: Gestational diabetes mellitus (GDM) is characterised by maternal hyperglycaemia that is first recognised during pregnancy. GDM results in chronic foetal hyperglycaemia and hyperinsulinaemia, with consequent changes in foetal endothelial gene expression and endothelial cell (EC) function. We aim to determine whether exposure to a diabetic intrauterine environment alters human umbilical vein EC (HUVEC) function, with further investigation into microRNA (miR) expression and epigenetic pathways. Methods: HUVECs were extracted from expecting mothers with and without GDM. We performed functional assays and focused miR and target gene analyses on extracted cell line-ages. Finally, we also studied 'healthy' HUVECs that were grown in high glucose conditions. Results: We observed a reduced capacity of closure on scratch assay, diminished capillary-like tube formation on Matrigel and decreased proliferation in response to foetal bovine serum (FBS), after a period of FBS-starvation, in the GDM-extracted lineages compared with the controls. On microRNA screening we found a tendency towards increased levels of miRs belonging to the miR-15 family. Specifically, miR-101 was significantly upregulated in the GDM-extracted lineages; hence we focused on this miR's molecular mechanisms in our target cell lineages. There was a strong positive correlation between miR-101 levels and apoptosis (Pearson r = 0.9, p value < 0.001). There was a decreased expression of Enhancer of Zester Homolog 2 (EZH2) in the GDM-extracted lineages. Confirming previous reports which have validated EZH2 as a target-gene of miR-101 in HUVECs, we found their expression levels were negatively correlated. EZH2 mRNA levels correlated positively with KDM2B and VEGF-A; conversely miR-101 levels correlated negatively with KDM2B. These data are in line with the described KDM2B/EZH2/miR-101/EZH2 axis. Anti-miR-101 treatment in GDM cells resulted in upregulation of EZH2, decreased apoptosis and an improved angiogenic phenotype, restoring the endothelial tube formation to the level seen in control lineages. As expected, in vitro exposure of "healthy" HUVECs to high glucose significantly impaired cellular function. Moreover, we found a concomitant upregulation of miR-101, which is in agreement with high miR-101 levels in GDM HUVECs.. Conclusion: These data identify a signalling pathway that links hyperglycaemia to miR-101 and its target gene EZH2, suggesting new targets in the fields of gestational diabetes and EC dysfunction induced by hyperglycaemia in utero. We characterise a novel mechanism regulating hyperglycaemia-impaired angiogenesis, with the possibility of restoring the angiogenic capacity of GDM cells in vitro by blocking miR-101 and subsequently upregulating its target EZH2. [ABSTRACT FROM AUTHOR]

Two blastemal nephroblastoma cases have been successfully clinically adapted under two simulation scenarios of a clinically-oriented multiscale computational model, providing insight into the tumor characteristics. [ABSTRACT FROM PUBLISHER]