The potential role of the three-dimensional-bioprinting model in screening and developing drugs

Recently,we have read with great interest the original article used different spatial configuration models of colorectal cancer(CRC)for validating the antitumor efficacy with Diiminoquinone.We feel obliged to provide new insight into the drug screening models by integrating and analyzing the original method and result.These comments may provide comprehensive insights into threedimensional drug screening models and the difference between pathologic subtypes in CRC.

A Study on the Multi-Compartment Linear Circulation Pharmacokinetic Model for the Targeting Drug Delivery System

By analyzing the observed phenomena and the data collected in the study, a multi-compartment linear circulation model for targeting drug delivery system was developed and the function formulas of the drug concentration-time in blood and target organ by computing were figured out. The drug concentration-time curve for target organ can be plotted with reference to the data of drug concentration in blood according to the model. The pharmacokinetic parameters of the drug in target organ could also be obtained. The practicability of the model was further checked by the curves of drug concentration-time in blood and target organ(liver) of liver-targeting nanoparticles in animal tests. Based on the liver drug concentration-time curves calculated by the function formula of the drug in target organ, the pharmacokinetic behavior of the drug in target organ(liver) was analyzed by statistical moment, and its pharmacokinetic parameters in liver were obtained. It is suggested that the (relative targeting index( can be used for quantitative evaluation of the targeting drug delivery systems.

Non-human primate models in drug addiction deserve more attention

Dear Editor, The process of relapse involves firm or aberrant memories of environmental cues associated with drug craving or addiction. To date, it is not known where these memories are stored in the brain, what kinds of regulatory biological factors or molecules are involved, nor why it is so difficult to stop addiction psychologically. Currently, rodent animal models, such as the self-administration and conditioning place preference / aversion paradigm are still widely used in the studies of drug withdrawal syndromes or drug-associate memories. However, the differences between humans and rodents--particularly in terms of genetics, and pathology and pharmacology--have significantly limited the application of further studies on this topic. Essentially, rodents lack the longterm or life-time memories humans possess and lose their drug-associated memory only after a few weeks of withdrawal.

Bovine Serum Albumin Loaded Solid Lipid Nanoparticles Prepared by Double Emulsion Method

Solid lipid nanoparticles loaded with bovine serum albumin（BSA） were prepared by a double emulsion method. As the mass fraction of the model drug BSA increased from 0 to 15%, the particle size gradually increased. The physical stability of the nanoparticles was investigated by zeta potential measurement and they were shown to be quite stable. Fluorescence spectroscopy confirmed that the loaded position of BSA was on the interface between the inner aqueous phase and the solid lipid phase. Both Fourier-transform infrared spectroscopy and circular dichroism spectra indicate that BSA in the nanoparticles was not destroyed, but the secondary structure was disrupted slightly.

An on-chip intestine-liver model for multiple drugs absorption and metabolism behavior simulation

A double-layer microfluidic chip integrated with a hollow fiber(HF)was developed to reconstitute the intestine-liver functionality for studying the absorption and metabolism of combination drugs.Caco-2 cells were inoculated in the HF cavity at the top of the serpentine channel to simulate the intestinal tissue for drug absorption and transport studied,and Hep G2 cells,seeded in the bottom chamber,were used to mimic the liver for metabolism-related studies.Genistein and dacarbazine were selected for combination drug therapy and its effects on cell viability,hepatotoxicity,and cell cycle arrest under drug-conditioned culture were investigated.The results suggested that the combined concentration below-100μg/m L had no significant inhibitory effect on Hep G2 cell viability,and therefore Hep G2 cells maintained their drug metabolism ability.When the drug concentration was increased above 250μg/m L,Hep G2 cells underwent apoptosis.Detection of metabolites by mass spectrometry proved the effective metabolism in the microchip model.This dynamic,co-culture microchip successfully provided a podium for long-term observation of absorption,transport,and metabolism of combination drugs,and could be an effective in vitro simulation model for further clinical research.

pH-sensitive KHA/CMC-Fe^(3+)@CS hydrogel loading and the drug release properties of riboflavin

To improve drug utilization,reduce the drug administration frequency,increase the release time,and reduce the drug side effects in the human body,we prepared(KHA/CMC-Fe^(3+))@CS hydrogel spheres using green and natural potassium humate(KHA),carboxymethyl cellulose(CMC),and chitosan(CS)as raw materials and Fe3+as a crosslinking agent,and loaded them with riboflavin for drug sustainedrelease study using the drop ball method.The tests with FTIR,SEM,TG,and X-ray diffractometer showed that the coordination among KHA,CMC,and Fe^(3+)formed a three-dimensional network structure,where cs was encapsulated on the surface of the hydrogel spheres via noncovalent bonding,resulting in good thermal stability.The stability,drug loading,swelling,and in vitro release of the(KHA/CMC-Fe^(3+))@CS hydrogel spheres were investigated.The results showed that the hydrogel spheres were significantly pH-sensitive,with 11.16 g/g higher swelling in an alkaline environment(pH=7.4)than that in an acidic environment(pH=1.2).The swelling and drug release process of the hydrogel spheres were analyzed using mathematical models,concluding that the hydrogel swelling follows Schott second-order swelling kinetics,and the drug release mechanism was Fickian delivery mode.

The analysis of a drug transmission model with family education and public health education

In this paper,we formulate a six dimensional drug transmission model to study the effect of family education and public health education.The dynamical behaviors of the model are discussed in terms of the basic reproduction number R0.By constructing Lyapunov functions,we obtain the drug-free equilibrium is globally asymptotically stable if R0≤1 and the drug addiction equilibrium is globally asymptotically stable if R0>1.Sensitivity analyses are performed to seek for effective control measures for drug spread.The analysis show that both the family and public health education can influence the spread of drug transmission.However,the combination of family and public health education is more effective to reduce the prevalence of drugs.Some numerical simulations are given to confirm the obtained theoretical results.

Investigating Genotype 1a HCV Drug Resistance in NS5A Region via Bayesian Inference

Hepatitis C virus（HCV） treatment is on the cutting edge of medicine. Due to the high rate of mutations and low fidelity of HCV replication, resistant strains quickly become dominant in a viral population under the selection pressure of a drug. In this paper, we examined the drug resistance mechanism in the NS5 A region of genotype1 a HCV virus by comparing the sequence data from interferon-ribavirin treated and untreated patients. To find the drug resistance difference, we used innovative Bayesian probability models to detect mutation combinations and inferred detailed interaction structures of these mutations. We aim to provide reference to drug design and mutation mechanism understanding through our work.

Simulation-based simplification of target-mediated drug disposition model of denosumab

Target-mediated drug disposition (TMDD)model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK)ofmonoclonal antibodies.However,there are too many parameters in full TMDD model to be estimated based on limited clinical data,leading to instability of the final model.In the present study,we analyzed the predictive ability and applicability of a simplified quasi-steady state (QSS)model with the assumption that the total target concentration was a constant parameter during treatment with monoelonal antibody in clinical data modeling.Based on the parameters of a published TMDD model of denosumab,simulations were performed at population and individual levels.Then,a simplified TMDD model,QSS model, was used to examine the effects of hypotheses,in which the total receptor concentration was constant or variable on model fit and stability of parameter estimation.Both simulations at the population level and model fit results of simulated individual data showed that at the therapeutic doses,the total receptor concentration had little influence on changes in drug concentration,and the model with constant total receptor concentration had the same predictive power.The validated hypothesis could be applied to clinical trial design and selection of the optimal PK model in the development of monoclonal antibodies.

Dynamic analysis based on the relapse rate of drug epidemic model

In this paper,we study a drug epidemic model based on epidemiology by dividing thehuman population into four classes at time t:susceptibles(S),drug users(1),drugusers who are treated in isolation and temporarily quit drugs(Q_(T))and drug users whoare treated in isolation and permanently quit drugs(Qp).We obtain the basic repro-duction number Ro of the model and perform its sensitivity analysis.We show that if R_(0)<β1A/μ(μ+δ1)<1,then the drug-free equilibrium is globally asymptotically stable,and if R_(0)>1,there exists an drug-abuse equilibrium and it is locally asymptoticallystable.The proposed model may possess forward and backward bifurcations.Moreover,three different control strategies and numerical results are presented.Through differentadjustments to obtain graphical results,we obtain the best strategy to control the drugepidemic.