Exploring the potential of functional polymer-lipid hybrid nanoparticles for enhanced oral delivery of paclitaxel

Most biopharmaceutics classification system(BCS)class IV drugs,with poor solubility and inferior permeability,are also substrates of P-glycoprotein(P-gp)and cytochrome P450(CYP450),leading to their low oral bioavailability.The objective of this study is to explore the potential of using functional polymer-lipid hybrid nanoparticles(PLHNs)to enhance the oral absorption of BCS IV drugs.In this paper,taking paclitaxel(PTX)as a drug model,PTX-loaded PLHNs were prepared by a self-assembly method.Chitosan was selected to modify the PLHN to enhance its mucoadhesion and stability.Three P-gp inhibitors(D-α-tocopherol polyethylene glycol 1000 succinate,pluronic P123 and Solutol RHS15)were incorporated into selected PLHNs,and a CYP450 inhibitor(the extract of VBRB,BC0)was utilized to jointly promote the drug absorption.Properties of all the PLHNs were characterized systemically,including particle size,zeta potential,encapsulation efficiency,morphology,stability,in vitro drug release,mucoadhesion,in situ intestinal permeability and in vivo systemic exposure.It was found mucoadhesion of the CS-modified PLHNs was the strongest among all the formulations tested,with absolute bioavailability 21.95%.P-gp and CYP450 inhibitors incorporation further improved the oral bioavailability of PTX to 42.60%,8-fold increase compared with that of PTX itself(4.75%).Taken together,our study might shed light on constructing multifunctional PLHNs based on drug delivery barriers for better oral absorption,especially for BCS IV drugs.

Rapid and simple analysis of amphetamine-type illegal drugs using excitation–emission matrix fluorescence coupled with parallel factor analysis

Nowadays,the abuse of illegal drugs has been an increasingly grim problem in the world.Excitation–emission matrix fluorescence combined with parallel factor analysis was used to make a quantitative analysis of the simulated amphetamine-type illegal drugs.Satisfactory results were achieved for simultaneous determination of methamphetamine(MAM)and 3,4-methylenedioxymethamphetamine(MDMA)in the presence of adulterants.The average recoveries were(99.8±0.6)%and(101.6±5.7)%for MAM and MDMA,respectively.Figures of merit including root-mean-square error of calibration and prediction,sensitivity and selectivity were investigated to evaluate the performance of the proposed method.The limits of detection were 0.054 and 0.0021 g/mL for MAM and MDMA,respectively.

Metabolomic Analysis of the Brain and Blood from Rats Exposed to High‑dose Chlorpyrifos

Chlorpyrifos is an organophosphate pesticide used to kill pests such as insects and worms.Wide use of chlorpyrifos has led to serious safety concerns worldwide.Research on the mechanism of action of chlorpyrifos poisoning is continuing.We investigated changes in the small‑molecular metabolites in the brain and blood of rats upon exposure to chlorpyrifos at an acute‑poisoning dose.Rats were given twice the lowest dose of chlorpyrifos that is lethal for 100%of exposed animals(2×LD_(100))and then killed after 2 h.After treatment,gas chromatography‑mass spectrometry was used to analyze the metabolomic changes in the brain and blood samples of rats.An increase in blood levels of creatinine and uric acid were noted,along with a decrease in levels of various amino acids.These changes suggested that chlorpyrifos exposure may damage kidney function and cause disorders in amino‑acid metabolism of rats.Decreased concentrations of gamma‑aminobutyric acid and niacinamide in the brain and increased concentrations of 3‑hydroxybutyric acid in rats with acute poisoning by chlorpyrifos were observed,which may suggest oxidative damage in the body.

The molecular mechanisms of plasticity in crystal forms of theophylline

Plastic and elastic behaviors of organic crystals have profound influence on the processability of pharmaceutical substances.Analogous to metals,the identifications of molecular slip planes in organic crystals are regarded as a strategy for harnessing plasticity.In this work,we experimentally characterized the form II anhydrous theophylline(THPa)and its monohydrate(THPm)for their distinct plastic and elastic behaviors.Extensive DFT calculations were performed to model the effects of increasing lattice strains on molecular packing.We discovered that the energy barrier associated with the strain-induced molecular rearrangement would link to the plasticity of THPa,and possibly other simple aromatic compounds.Meanwhile,water molecules in THPm disrupt the stacking architecture from THPm and effectively undermine the general mechanism for plasticity.Hydrate formation would therefore be an alternative strategy to engineer the mechanical property of organic crystalline materials.

Polymorphism study of nine SNPs associated with subjective response to alcohol in Chinese Han, Hui, Tibetan, Mongolian and Uygur populations

Heavy alcohol drinking is a major public health problem,causing a large disease,social and economic burden in societies.Subjective response (SR) to alcohol is an intermediate characteristic of heavy drinking.A variety of candidate genes have been reported to be associated with SR to alcohol.In this study,we investigated nine single nucleotide polymorphisms (SNPs) related to SR to alcohol in healthy individuals from five Chinese ethnic groups,the Han,Hui,Tibetan,Mongolian and Uygur populations,and a total of 584 bloodstain samples were collected.The nine SNPs included four SNPs in alcohol-metabolizing genes (ADH1B,ADH1C,ALDH2 and CYP2E1*5B) and five SNPs in genes of neurobiological pathways (GABRA2,OPRM1,CHRNA3,HYKK and SLC6A4).A SNaPshot analysis method was developed to type these SNPs simultaneously,and all samples were typed successfully.Statistical analyses of the allele frequencies indicated that the frequencies of all SNPs,except for ADH1C,showed varying degrees of difference in the five studied ethnic groups.Tibetans showed the highest frequencies of risk alleles for heavy drinking at most loci.The genetic polymorphic differences found in this study revealed the variation in genetic susceptibility to heavy drinking in the studied populations.

A Preliminary Urinary Metabolomics Study of Sprague-Dawley Rats after Short‑term Ketamine Administration by Proton Nuclear Magnetic Resonance Spectroscopy

Drug abuse has become a global problem.The mass spectrometry‑based metabolic consequences of ketamine administration in anesthesia and therapy have been well studied,but to the best of our knowledge,metabolomic studies of ketamine abuse based on nuclear magnetic resonance(NMR)spectroscopy are still lacking.In this study,twenty Sprague–Dawley rats were randomly assigned into two groups:a control group(n=10)and a ketamine group(n=10).The animals in the ketamine group received intraperitoneal injections of ketamine twice daily at 12‑h intervals at progressively increasing doses over a period of 9 days,while the control group received an equal volume of saline.The urine samples were collected for 24 h at days 0,1,3,5,7,and 9 for the metabolomics study.The metabolic changes in urine after short‑term ketamine administration were analyzed by proton NMR coupled with multivariate statistical analysis.The results indicated that short‑term ketamine exposure led to significant alterations of the metabolites in the urine of the rats.Specifically,1,3,7‑trimethyluric acid,1,3‑dimethyluric acid,acetoacetic acid,acetylglycine,creatine,sarcosine,dimethylglycine,glycine,and theobromine were significantly increased in the urine.Significant changes were also found in metabolites related to antioxidant and energy metabolism,including acetoacetic acid,succinate,1,3,7‑trimethyluric acid,1,3‑dimethyluric acid,creatine,and taurine.Our findings indicated that short‑term ketamine administration leads to disorder of energy metabolism and oxidative stress.In addition,the modified metabolites identified could serve as the new biological markers and potential biological indices reflecting the underlying mechanism of ketamine abuse.

A Gas Chromatography-Mass Spectrometry‑Based Metabonomic Study on Estimation of Toxicant in Rats

The aim of this study was to develop a gas chromatography‑mass spectrometry(GC‑MS)‑based metabolomics method to distinguish different kinds of poisons in the blood.We examined the changes in blood metabolites using GC‑MS following administration of four different poisons(paraquat,dichlorvos,aconitine,and sodium nitrite).The data were analyzed with orthogonal partial least squares.Then,total and single differential metabolite profiles were evaluated with support vector machine(SVM)models.The results showed that various metabolites(5‑ketone proline,1,5‑anhydrohexitol,lactic acid,glycine 2,2‑furoic acid,and 3‑hydroxybutyric acid)were differential between the experimental groups and the control groups.The accuracy rates of the SVM models established using total and single differential metabolites were 80%and 100%,respectively.In conclusion,we successfully developed a poison screening method.The established SVM models can distinguish four kinds of poisons and could be used to establish a complete poison metabonomic information database.Furthermore,some of the metabolites could be biomarkers of these poisons.Finally,both the models and potential biomarkers may reduce the time required for poison detection and provide direction for solving cases and auxiliary diagnosis.

Determination of Periplocymarin in Human Blood and Urine by High-Performance Liquid Chromatography-Mass Spectrometry

A simple,rapid and sensitive liquid chromatography with tandem mass spectrometry method for the determination of periplocymarin in human blood and urine was developed.The digoxin‑d3 was used as an internal standard.Periplocymarin and digoxin‑d3(IS)were processed with ethyl acetate by liquid–liquid extraction.The chromatographic separation was performed on a Shim‑pack XR‑ODSIII C18 column with a 7 min gradient elution using methanol‑ammonium formate(5 mmol/L)as mobile phase at a flow rate of 0.3 mL/min(65:35,v/v).The detection was performed on a triple quadrupole tandem mass spectrometer using positive‑ion mode electrospray ionization in selected reaction monitoring mode.The periplocymarin was well separated from the internal standard.Two calibration curves were linear within the concentration range 0.01–1µg/mL.The limit of detection and quantification of blood and urine samples were both estimated at 0.005 and 0.01µg/mL.The interday and intraday precisions,accuracy,and recovery were assessed to verify this method.The results showed that the method was suitable for the determination of periplocymarin in forensic toxicological analysis and clinical diagnosis.

Determination of Chlorpyrifos in Human Blood by Gas Chromatography-Mass Spectrometry

Gas chromatography-mass spectrometry method was developed for the qualitative and quantitative analyses of chlorpyrifos in human blood samples.The chlorpyrifos and parathion(internal standard)in human blood were extracted with a mixed solvent of hexane and acetonitrile.Chlorpyrifos was well separated from the internal standard.The linear range of chlorpyrifos was 0.01-2 μg/ml in blood.The limit of detection and limit of quantification were estimated at 0.002 and 0.01μg/ml,respectively.The inter-and intra-day precisions,accuracy,and recovery were assessed to verify this method.The results showed that the developed method is rapid,sensitive,and reliable.It is suitable for the determination of chlorpyrifos in forensic toxicological analysis and clinical diagnosis.