查看更多>>摘要：Alzheimer's disease (AD) is the most common type of dementia, the exact etiology of the disease has not been known yet. The use of single-target drugs limits the efficacy of drugs and has certain side effects. In this study, the 'hidden' multi-target strategy was used in combination with chrysin's metal chelating site and rivastigmine's anti-cholinesterase pharmacophore to form an ester, which improves the hydrophobicity and protects the phenolic hydroxyl group at the same time. Four derivatives (1-4) were synthesized as the hidden multifunctional agents for AD therapy. Most of the compounds displayed good activities of anti-cholinesterase, antioxidant, appropriate blood brain barrier (BBB) penetration and certain inhibitory activity of beta-amyloid (A beta) aggregation. Compound 3 was demonstrated as the highest selective butyrylcholinesterase (BuChE) inhibitor and targeted both the catalytic active site (CAS) and the peripheral anion site (PAS). And it could be hydrolyzed by BuChE to release chrysin with good ability to chelate Cu2+ and Fe2+. At the same time, phenol fragment can exert its good antioxidant effect. Overall, these findings demonstrated that compound 3 might be considered as a potential hidden multifunctional candidate in the therapy of AD.
查看更多>>摘要：The current research article focused on formulating an easily applied, water-based buccal film loaded with the antiepileptic drug, lamotrigine (LTG). The designed film can be comfortably administered by epileptic patients to ensure a controllable therapeutic efficacy against seizures. The solubility of LTG in water was significantly improved by micellar solubilization. Upon testing several surfactants, three of them (Synperonic PE/P84, Brij L23, and Brij 78) achieved maximum possible solubility for LTG and were characterized for their micellar size, cloud point, and % transmittance. Selected micellar systems were incorporated within a buccal film prepared using solvent casting method based on either gelatin or polyvinylpyrrolidone (3%w/v) with 1.5%w/v propylene glycol as a plasticizer. Different micellar films were characterized for their physicochemical characteristics, swelling index, folding endurance, drug content uniformity, and in vitro LTG release. From the tested formu-lations, one formulation; LTG-BF1 (in which Brij 78 was used for the micellar solubilization and gelatin as the matrix former), was selected as the optimum and extensively studied for mucoadhesion, ex vivo permeation studies by Franz diffusion cells and confocal laser scanning microscopy. Results showed superior enhanced permeation of micellar film. LTG-BF1 was evaluated for the in vivo performance using rats. Status epilepticus was induced in rats by injecting Pentylenetetrazol (PTZ) i.p. at an initial dose of 30 mg/kg, followed by 10 mg/kg every10 min till 60 min. A group of rats receiving the designed buccal formulation (20 mg/kg) was compared with a group receiving the same dose of the oral market product and the normal control and PTZ groups. Rats receiving LTG-BF1 recorded reduced seizure scores at all stages, longer latency time, and higher threshold PTZ dose compared to PTZ and market product groups. In addition, LTG-BF1 reduced brain concentrations of TNF-alpha and TGF-beta with an elevation of EAAT2 and GABA brain contents compared to PTZ and market product groups and ameliorated neuronal damage. In conclusion, LTG-loaded buccal micellar film proved a superior antiepi-leptic effect in PTZ induced acute epileptic model.
查看更多>>摘要：Chemotherapy has several adverse effects to patients, some of which are life-threatening. We hypothesized that Doxorubicin induced microbiome imbalance and intestinal damage may contribute to Doxorubicin induced cardiac dysfunction. Male adult (2-3 months) C57BL/6 mice were administered 3 mg/kg, 5 mg/kg, 7.5 mg/ kg,15 mg/kg, 20 mg/kg doses of Doxorubicin. Echocardiography was performed at 7 and 14 days after Doxo-rubicin administration. 16S rRNA amplicon sequencing was used to characterize microbiome changes. Fecal microbiota transplantation (FMT) was performed to evaluate the role of the microbiota on Doxorubicin induced cardiac dysfunction.
查看更多>>摘要：The present work focuses on modifying a local anaesthetic drug procaine into an ionic liquid and evaluating the resulting thermal behaviour and structural changes. Counter ions, salicylate, ibuprofenate, and docusate, were chosen due to different hydrogen-bonding abilities, molecular size, charge distribution, and functional groups. After synthesis of procaine salicylate, procaine ibuprofenate, and procaine docusate, spectroscopic investigations were performed using infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy to confirm proton transfer. Differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis were used to determine the obtained ionic liquids' thermal behaviour. Experimental measurements of density, viscosity, and electrical conductivity were performed to get insight into the interactions occurring in the obtained ionic liquids. The viscosity and electrical conductivity data were analysed using the Vogel-Fulcher-Tammann (VFT) equation, while thermal expansion coefficients were calculated from measured density data. The obtained results found that the synthesised procaine salicylate and procaine docusate an ionic liquid's behaviours, including weak intermolecular forces, while procaine ibuprofenate showed more liquid co-crystal behaviour due to the absence of proton transfer for ibuprofen. In a theoretical phase of the investigation, the density functional theory (DFT) and molecular dynamics (MD) calculations were conducted. The obtained descriptors and radial distribution functions were used to analyse the interactions between ions of synthesised ionic liquids. In addition, solubility determination results proved that procaine transformation into procaine salicylate and procaine ibuprofenate ionic liquids enhanced its solubility in water, while procaine docusate reduces procaine solubility.
查看更多>>摘要：Superficial infections in chronic wounds can prevent the wound healing process by the development of persistent infections and drug-resistant biofilms. Topically applied antimicrobial formulations with stabilized and controlled release offer significant benefits for the effective treatment of wound infections. Bacteriocins are the antimicrobial peptides (AMPs) produced by bacteria that are viable alternatives to antibiotics owing to their natural origin and low propensity for resistance development. Herein, we developed a hybrid hydrogel composed of Pluronic F127 (PF127), ethylenediaminetetraacetic acid (EDTA) loaded liposomes, glutathione (GSH), and the bacteriocin Garvicin KS (GarKS) referred to as "GarKS gel". The GarKS gel exhibited suitable viscosity and rheological properties along with controlled release behavior (up to 9 days) for effective peptide delivery following topical application. Potent in vitro antibacterial and anti-biofilm effects of GarKS gel were evident against the Gram-positive bacterium Staphylococcus aureus. The in vivo treatment of methicillin resistant S. aureus (MRSA) infected mouse wounds suggested potent antibacterial effects of the GarKS gel following multiple applications of once-a-day application for three consecutive days. Altogether, these results provide proof-of-concept for the successful development of AMP loaded topical formulation for effective treatment of wound infections.
查看更多>>摘要：Our study aimed to formulate a novel dexamethasone (DXM)-loaded, mixed polymeric micelle-based drug delivery system, focusing on the auspicious nose-to-brain pathway, as a key delivery route to treat central nervous system (CNS) associated diseases. Polymeric micelles might be a solution to deliver drugs to the place of action compared to conventional formulations. Due to low Z-average (89.92 +/- 2.7 nm), a polydispersity index of 0.216 +/- 0.014 and high surface polarity (52.23%), a significant increase in water solubility (14-fold) was experienced. This increase resulted in favourable dissolution profile at nasal and axonal conditions with high in vitro permeability value (14.6x10- 6 cm/s) on polar brain (porcine) lipid extract. Modified Side-bi-side (R) type diffusion study confirmed rapid and efficient passive diffusion through the nasal mucosa contributed by strong mucoadhesive properties. The final formulation met all the requirements of a nasal drug delivery system with rapid onset of action, meaning DXM can reach the CNS and there it can exert its beneficial effects in pathological conditions.
查看更多>>摘要：Oral transmucosal drug delivery is a non-invasive administration route for rapid therapeutic onset and greater bioavailability avoiding the first-pass metabolism. Mucoadhesive formulations are advantageous as they may retain the drug at the administration site. Proper equipment to assess mucoadhesive properties and corresponding drug absorption is fundamental for the development of novel drug delivery systems. Here we developed a new flow-through donor chamber for well-established diffusion cells, and we tested the effects on drug and formulation retention in situ of adding mucoadhesive polymers or mesoporous silica particles to a reference formulation. Mesoporous silica particles are of particular interest as they may be used to encapsulate and retain drug molecules. Compared to other ex-vivo methods described in literature for assessing mucoadhesive performance and transmucosal drug delivery, this new donor chamber provides several advantages: i) it reflects physiological conditions better as a realistic saliva flow can be provided over the administration site, ii) it is versatile since it can be mounted on any kind of vertical diffusion cell allowing simultaneous detection of drug retention at the administration site and drug permeation through the tissue, and iii) it enables optical quantification of formulations residence time aided by image processing. This new flow-through donor diffusion cell set-up proved sensitive to differentiate a reference formulation from one where 20 %(w/w) Carbomer was added (to further improve the mucoadhesive properties), with respect to both drug and formulation residence times. We also found that mesoporous silica particles, investigated as particles only and mixed together with the reference formulation, gave very similar drug and formulation retention to what we observed with the mucoadhesive Carbomer. However, after some time (>30 min) it became obvious that the tablet excipients in the reference formulation promote particle retention on the mucosa. This work provides a new simple and versatile biorelevant test for the evaluation of oral mucoadhesive formulations and paves the way for further studies on mesoporous silica particles as valuable excipients for enhancing oral mucoadhesion.
查看更多>>摘要：Anti-cutaneous melanoma activity of the skin-delivered gambogic acid (GA) has been reported in our previous study. However, it is difficult for GA to diffuse passively through intact skin without any enhancement means. In this study, a combination of chemical enhancers (EN: azone and propylene glycol) and physical ultrasound (US) was used to improve the percutaneous permeation of GA and enhance the anti-melanoma activity. The enhancement effect of the combination of EN and US (EN-US) on GA in vitro and in vivo was studied, and the enhancement mechanism and skin irritation were also evaluated. We showed that the parameters of US application at a constant frequency (30 kHz) with a duty cycle of 100% and intensity of 1.75 W/cm2 for 20 min were optimal. In vitro, EN-US showed a considerable enhancement of the permeation of GA, and the enhancement effect was stronger than that with the use of EN or US alone. In vivo antitumor study showed that the tumor growth was significantly inhibited after percutaneous administration of GA by EN-US, more than in the intravenous injection group. The penetration enhancement mechanism revealed that EN-US not only altered the structure of lipid bilayers and keratins to reduce the barrier effect of the stratum corneum but also produced diffusion channels in the skin under the cavitation effect of US, thereby promoting the skin penetration of GA. In addition, there was no observable skin irritation in mice after treatment with EN-US. Our study demonstrated that the combination of EN and US improved the skin permeation and retention of GA to enhance the antimelanoma activity. This method also provides technical guidance for the future development of topical and transdermal therapeutic system of GA.
查看更多>>摘要：Nifurtimox is approved in Chagas disease and has been used in endemic countries since the 1960s. Nifurtimox, available as a 120 mg tablet, is administered with food typically three times daily, and dose is adjusted for age and bodyweight. Accurately or reproducibly fragmenting the 120 mg tablet for dose adjustment in young children and those with low bodyweight is problematic. Based on the existing tablet formulation, new nifurtimox 30 mg and 120 mg tablets have been developed in a format that can be divided accurately into 15 mg and 60 mg fragments. In adults with chronic Chagas disease, we investigated whether nifurtimox bioavailability is affected by tablet dissolution rate, and whether different diets affect nifurtimox bioavailability. In an open-label, three period cross-over study (n=36; ClinicalTrials.gov, NCT03350295), patients randomly received three 30 mg tablet formulations (slow, medium, or fast dissolution; a 4 x 30 mg dose of one formulation per period). In an open label, four-period cross-over study (n=24; ClinicalTrials.gov, NCT03334838) patients randomly fasted or received one of three meal types (high-fat/high-calorie, low-fat, dairy-based) before ingesting nifurtimox (a 4 x 30 mg dose per period). Acceptance criteria for no difference between groups were 90% confidence intervals (CIs) of exposure ratios in the range 0.8-1.25. Nifurtimox bioavailability was unaffected by tablet dissolution kinetics. Ratios of area under the curve at final assessment (AUC((0-tlast)) [90% CI]) were: fast/medium dissolution, 1.061 (0.990-1.137); slow/medium dissolution, 0.964 (0.900-1.033); fast/slow dissolution, 1.100 (1.027-1.179). Compared with a fasting state, nifurtimox bioavailability increased by 73% after a high-fat/highcalorie meal (AUC((0-tlast)) ratio [90% CI], 1.732 [1.581-1.898]); smaller increases were seen with the other meal types (low-fat: 1.602 [1.462-1.755]; dairy-based: 1.340 [1.222-1.468]). Although type of diet can affect bioavailability, taking nifurtimox with food is most important.
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Elsevier