Reecehampton2897

The physiologically based pharmacokinetic (PBPK) approach can be used to develop mathematical models for predicting the absorption, distribution, metabolism, and elimination (ADME) of administered drugs in virtual human populations. Haloperidol is a typical antipsychotic drug with a narrow therapeutic index and is commonly used in the management of several medical conditions, including psychotic disorders. Due to the large interindividual variability among patients taking haloperidol, it is very likely for them to experience either toxic or subtherapeutic effects. We intend to develop a haloperidol PBPK model for identifying the potential sources of pharmacokinetic (PK) variability after intravenous and oral administration by using the population-based simulator, PK-Sim. The model was initially developed and evaluated to predict the PK of haloperidol and its reduced metabolite in adult healthy population after intravenous and oral administration. After evaluating the developed PBPK model in healthy adults, it was used to predict haloperidol-rifampicin drug-drug interaction and was extended to tuberculosis patients. The model evaluation was performed using visual assessments, prediction error, and mean fold error of the ratio of the observed-to-predicted values of the PK parameters. The predicted PK values were in good agreement with the corresponding reported values. The effects of the pathophysiological changes and enzyme induction associated with tuberculosis and its treatment, respectively, on haloperidol PK, have been predicted precisely. For all clinical scenarios that were evaluated, the predicted values were within the acceptable two-fold error range.The mechanism of cellular uptake and intracellular fate of nanodiamond/nucleic acid complexes (diamoplexes) are major determinants of its performance as a gene carrier. Our group designed lysine-nanodiamonds (K-NDs) as vectors for nucleic acid delivery. In this work, we modified the surface of K-NDs with histidine to overcome endo-lysosomal entrapment diamoplexes, the major rate limiting step in gene transfer. Histidine is conjugated onto the NDs in two configurations lysyl-histidine-NDs (HK-NDs) where histidine is loaded on 100% of the lysine moieties and lysine/lysyl-histidine-NDs (H50K50-NDs) where histidine is loaded on 50% of the lysine moieties. Both HK-NDs and H50K50-NDs maintained the optimum size distribution (i.e., <200 nm) and a cationic surface (zeta potential > 20 mV), similar to K-NDs. HK-NDs binds plasmid deoxyribonucleic acid (pDNA) and small interfering ribonucleic acid (siRNA) forming diamoplexes at mass ratios of 101 and 601, respectively. H50K50-NDs significantly improved nucleic acing entity in the functionalization design at an optimized ratio, renders high efficiency to the diamoplexes. Further studies will elucidate the uptake mechanism and intracellular fate to build the relationship between physicochemical characteristics and biological efficacy and create a platform for solid-core nanoparticle-based gene delivery.Nowadays, pancreatic cancer is still a formidable disease to diagnose. The CXC chemokine receptor 4 (CXCR4) and integrin αvβ3 play important roles in tumor development, progression, invasion, and metastasis, which are overexpressed in many types of human cancers. In this study, we developed a heterodimeric tracer 68Ga-yG5-RGD targeting both CXCR4 and integrin αvβ3, and evaluated its feasibility and utility in PET imaging of pancreatic cancer. The 68Ga-yG5-RGD could accumulate in CXCR4/integrin αvβ3 positive BxPC3 tumors in a high concentration and was much higher than that of 68Ga-yG5 (p < 0.001) and 68Ga-RGD (p < 0.001). No increased uptake of 68Ga-yG5-RGD was found in MX-1 tumors (CXCR4/integrin αvβ3, negative). In addition, the uptake of 68Ga-yG5-RGD in BxPC3 was significantly blocked by excess amounts of AMD3100 (an FDA-approved CXCR4 antagonist) and/or unlabeled RGD (p < 0.001), confirming its dual-receptor targeting properties. The ex vivo biodistribution and immunohistochemical results were consistent with the in vivo imaging results. The dual-receptor targeting strategy achieved improved tumor-targeting efficiency and prolonged tumor retention in BxPC3 tumors, suggesting 68Ga-yG5-RGD is a promising tracer for the noninvasive detection of tumors that express either CXCR4 or integrin αvβ3 or both, and therefore may have good prospects for clinical translation.The aim of this work was to study the healing activity of amitriptyline (Amitrip) in rat diabetic wounds. A nanoformula of the drug was prepared as Amitrip-based biodegradable PEG-PLGA self-assembled nanoparticles (Amitrip-NPs) with a mean particle size of 67.4 nm. An in vivo investigation was conducted to evaluate the wound-healing process of Amitrip-NPs in streptozotocin-induced diabetic rats. Wound contraction was accelerated in rats treated with Amitrip-NPs. Histological examinations confirmed these findings, with expedited remodeling and collagen deposition in the NPs-treated animals. The formula showed anti-inflammatory activities as demonstrated by inhibition of interleukin-6 (IL-6) expression and tumor necrosis factor-α (TNF-α) expression, as well as enhanced expression of interleukin-10 (IL-10). In addition, Amitrip-NPs protected against malondialdehyde (MDA) buildup and superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic exhaustion. The pro-collagen activity of Amitrip-NPs was confirmed by the observed enhancement of hydroxyproline wounded skin content, upregulation of Col 1A1 mRNA expression and immune expression of collagen type IV expression. Further, Amitrip-NPs significantly increased expression transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor-A (VEGF-A), platelet-derived growth factor-B (PDGF-B) and cluster of differentiation 31 (CD31). In conclusion, the developed Amitrip-NPs expedited wound healing in diabetic rats. This involves anti-inflammatory, antioxidant, pro-collagen and angiogenic activities of the prepared NPs. This opens the gate for evaluating the usefulness of other structurally related tricyclic antidepressants in diabetic wounds.Flavonoids are types of natural substances with phenolic structures isolated from a variety of plants. Flavonoids have antioxidant, anti-inflammatory, anticancer, and antiviral activities. Although most of the research or applications of flavonoids are focused on human diseases, flavonoids also show potential applicability against porcine virus infection. This review focuses on the recent progress in antiviral mechanisms of potential flavonoids against the most common porcine viruses. The mechanism discussed in this paper may provide a theoretical basis for drug screening and application of natural flavonoid compounds and flavonoid-containing herbs to control porcine virus infection and guide the research and development of pig feed additives.The effective dermal penetration of active ingredients (AI) is a major task in the formulation of topical products. Besides the vehicle, the mechanical skin treatments are also considered to impact the penetration efficacy of AI. In particular, professional skin treatments, i.e., professional cosmetic skin treatments, are considered to be optimal for the dermal delivery of AI. However, a systematic study that proves these theories is not yet available and was therefore performed in this study while utilizing an ex vivo porcine ear model with subsequent digital image analysis. Hydrophilic and lipophilic fluorescent dyes were used as AI surrogates and were applied onto the skin without and with professional skin treatments. The skin hydration and the penetration efficacy were determined, respectively. Results showed that professional skin treatments with massage were able to increase the skin hydration, whereas a professional skin treatment without massage could not increase the skin hydration when compared to skin without professional skin treatment. Regarding the penetration efficacy, it was found that all parameters tested, i.e., type of professional skin treatment, lipophilicity of the AI, and the time point at which the AI are applied onto the skin, can have a tremendous impact on the penetration efficacy of the AI. The most effective penetration and the most effective skin hydration is achieved with a professional skin treatment that includes a professional skin massage. This kind of skin treatment can therefore be used to improve dermal drug delivery.The stratum corneum (SC) forms a strong barrier against topical drug delivery. Therefore, understanding the penetration depth and pathways into the SC is important for the efficiency of drug delivery and cosmetic safety. In this study, TPT-FLIM (two-photon tomography combined with fluorescence lifetime imaging) was applied as a non-invasive optical method for the visualization of skin structure and components to study penetration depths of exemplary substances, like hydrophilic propylene glycol (PG), sodium fluorescein (NaFl) and lipophilic Nile red (NR) into porcine ear skin ex vivo. selleck chemicals llc Non-fluorescent PG was detected indirectly based on the pH-dependent increase in the fluorescence lifetime of SC components. The pH similarity between PG and viable epidermis limited the detection of PG. NaFl reached the viable epidermis, which was also proved by laser scanning microscopy. Tape stripping and confocal Raman micro-spectroscopy were performed additionally to study NaFl, which revealed penetration depths of ≈5 and ≈8 μm, respectively. Lastly, NR did not permeate the SC. We concluded that the amplitude-weighted mean fluorescence lifetime is the most appropriate FLIM parameter to build up penetration profiles. This work is anticipated to provide a non-invasive TPT-FLIM method for studying the penetration of topically applied drugs and cosmetics into the skin.This work investigated the influence of liquid vehicles on the release, mucosal permeation and deposition of cannabidiol (CBD) from liquisolid systems. Various vehicles, including EtOH, nonvolatile low- and semi-polar solvents, and liquid surfactants, were investigated. The CBD solution was converted into free-flowing powder using carrier (microcrystalline cellulose) and coating materials (colloidal silica). A physical mixture of the CBD and carrier-coating materials was prepared as a control. The non-crystalline state of CBD in the liquisolid systems was confirmed using XRD, FTIR and SEM studies. The CBD liquisolid powder prepared with volatile and nonvolatile solvents had a better CBD release performance than the CBD formed as the surfactant-based and control powders. The liquisolid systems provided the CBD permeation flux through porcine esophageal mucosa ranging from 0.68 ± 0.11 to 13.68 ± 0.74 µg·cm-2·h-1, with the CBD deposition levels of 0.74 ± 0.04 to 2.62 ± 0.30 μg/mg for the dry mucosa. Diethylene glycol monoethyl ether showed significant CBD permeation enhancement (2.1 folds) without an increase in mucosal deposition, while the surfactants retarded the permeation (6.7-9.0 folds) and deposition (1.5-3.2 folds) significantly. In conclusion, besides the drug release, liquid vehicles significantly influence mucosal permeation and deposition, either enhanced or suppressed, in liquisolid systems. Special attention must be paid to the selection and screening of suitable liquid vehicles for liquisolid systems designed for transmucosal applications.