5 reduced cytotoxicity of TAC on the Neuro-2a cell line. Moreover, in vivo co-administration of both DG4.0-TAC and DG4.5-TAC reduced the morphological and hepatotoxic effects of TAC in zebrafish larvae. The reduction of TAC toxicity was not accompanied by a reduction in its activity since the anti-acetylcholinesterase activity remains when it is co-administrated with dendrimers. In conclusion, the co-administration of TAC with both DG4.0 and DG4.5 is a novel therapy since it was less-toxic, was more biocompatible, and has the same effectiveness than the free drug. Graphical abstract.PURPOSE To examine the theoretical/practical utility of the liver-to-blood partition coefficient (Kpuu) for predicting drug-drug interactions (DDIs), and compare the Kpuu-approach to the extended clearance concept AUCR-approach. METHODS The Kpuu relationship was derived from first principles. Theoretical simulations investigated the impact of changes in a single hepatic-disposition process on unbound systemic (AUCB,u) and hepatic exposure (AUCH,u) versus Kpuu. Practical aspects regarding Kpuu utilization were examined by predicting the magnitude of DDI between ketoconazole and midazolam employing published ketoconazole Kpuu values. RESULTS The Kpuu hepatic-disposition relationship is based on the well-stirred model. Simulations emphasize that changes in influx/efflux intrinsic clearances result in Kpuu changes, however AUCH,u remains unchanged. Although incorporation of Kpuu is believed to improve DDI-predictions, utilizing published ketoconazole Kpuu values resulted in prediction errors for a midazolam DDI. CONCLUSIONS There is limited benefit in using Kpuu for DDI-predictions as the AUCR-based approach can reasonably predict DDIs without measurement of intracellular drug concentrations, a difficult task hindered by experimental variability. Further, Kpuu changes can mislead as they may not correlate with changes in AUCB,u or AUCH,u. The well-stirred model basis of Kpuu when applied to hepatic-disposition implies that nuances of intracellular drug distribution are not considered by the Kpuu model.PURPOSE Zonisamide clinical indications are expanding beyond the classic treatment of epileptic seizures to Parkinson’s disease and other neurodegenerative diseases. However, the systemic safety profile of zonisamide may compromise its use as a first-line drug in any clinical condition. Since zonisamide is marketed as oral formulations, the present study aimed at exploring the potential of the intranasal route to centrally administer zonisamide, evaluating the systemic bioavailability of zonisamide and comparing its brain, lung and kidney pharmacokinetics after intranasal, oral and intravenous administrations. METHODS In vitro cell studies demonstrated that zonisamide and proposed thermoreversible gels did not affect the viability of RPMI 2650 or Calu-3 cells. Thereafter, male CD-1 mice were randomly administered with zonisamide by oral (80 mg/kg), intranasal or intravenous (16.7 mg/kg) route. At predefined time points, animals were sacrificed and plasma and tissues were collected to quantify zonisamide and describe its pharmacokinetics. RESULTS Intranasal route revealed a low absolute bioavailability (54.95%) but the highest value of the ratio between the area under the curve (AUC) between brain and plasma, suggesting lower systemic adverse events and non-inferior effects in central nervous system comparatively to intravenous and oral routes. Furthermore, drug targeting efficiency and direct transport percentage into the brain were 149.54% and 33.13%, respectively, corroborating that a significant fraction of zonisamide suffers direct nose-to-brain transport. Lung and kidney exposures obtained after intranasal administration were lower than those observed after intravenous injection. CONCLUSIONS This pre-clinical investigation demonstrates a direct nose-to-brain delivery of zonisamide, which may be a promising strategy for the treatment of central diseases.PURPOSE Combination of PCI and chemotherapy represents a promising strategy for combating drug resistance of cancer. However, poor solubility of photosensitizers and unselectively released drugs at unwanted sites significantly impaired the treatment efficacy. Therefore, in the present study, we aimed to develop a nano-platform which could efficiently co-entrapping photosensitizers and chemotherapeutics for active targeting therapy of drug resistant cancers. METHODS Two pro-drugs were respectively developed by covalently linking the Ce6 with each other via the GSH-sensitive linkage and the PTX with mPEG-PLA-COOH through the ROS sensitive-linker. The dual-responsive nanoparticles (PNP-Ce6) was developed by emulsion/solvent evaporation method and further modified with tLyp-1 peptides. Physicochemical properties of nanoparticles were determined by the TEM and DLC. Cellular uptake assay was investigated with the Ce6 acting as the fluorescent probe and cell growth was studied by the MTT experiment. In vivo tumor tapresents the blood vessels stained with CD31, blue signal represents the cell nuclei stained with DAPI and red shows fluorescence of Ce6 as the indicator of the nanoparticles.BACKGROUND Urinary dysfunction (UD) remains a significant complication of rectal cancer surgery. see more In modern surgical treatment for rectal cancer, multiple operative approaches are used. Such approaches include open, laparoscopic, and robotic-assisted surgery; and multiple procedures, including anterior, intersphincteric, and abdominoperineal resection. Thus, modern surgical treatments for rectal cancer have diversified. This study aimed to identify risk factors for early UD (EUD) after total mesorectal excision (TME) and to explore the methods for decreasing postoperative EUD in diverse surgical treatments for rectal cancer. METHODS In our retrospective cohort study, we enrolled patients with lower rectal cancer who underwent TME alone at a single high-volume cancer center between 2010 and 2017. EUD was defined as the presence of ≥ 50 mL residual urine volume. Multivariate analysis was performed to determine clinicopathological factors significantly associated with postoperative EUD. RESULTS Of a total of 337 eligible patients, 32 patients (10%) had postoperative EUD.