Deciphering resistancemechanisms and novel strategies to overcome drug resistance in ovarian cancer:a comprehensive review

Ovarian cancer is among the most lethal gynecological cancers,primarily due to the lack of specific symptoms leading to an advanced-stage diagnosis and resistance to chemotherapy.Drug resistance(DR)poses the most significant challenge in treating patients with existing drugs.The Food and Drug Administration(FDA)has recently approved three new therapeutic drugs,including two poly(ADP-ribose)polymerase(PARP)inhibitors(olaparib and niraparib)and one vascular endothelial growth factor(VEGF)inhibitor(bevacizumab)for maintenance therapy.However,resistance to these new drugs has emerged.Therefore,understanding the mechanisms of DR and exploring new approaches to overcome them is crucial for effective management.In this review,we summarize the major molecular mechanisms of DR and discuss novel strategies to combat DR.

Mechanism of imipenem-induced mental disorder: A meta-analysis

BACKGROUND Imipenem is a highly effective carbapenem antibiotic,which is widely used in the treatment of many serious bacterial infections.At the same time,it can also cause some adverse reactions,mental abnormalities are the most concerned central nervous system adverse reactions.Different patients respond differently to imipenem,and the effect of imipenem on psychiatric disorders is unclear.Therefore,meta-analysis summarizing the results of multiple previous studies can provide stronger evidence support for clinical guidelines to guide clinical rational use of imipenem to minimize risks.After reviewing the literature published between 2003 and 2017,seven controlled trials with a total of 550 patients were included,with 273 and 277 patients in the control and experimental groups,respectively.The sample size of the study ranged from a minimum of 30 cases to a maximum of 61 cases.Patients in the experimental group were treated with imipenem while the control group was treated with conventional drugs.Meta-analysis showed that the incidence of mental disorders in the experimental group was higher than that in the control group(odds ratio=3.66,95%confidence interval:1.11-12.11,P=0.030);however,there was no significant difference in the incidence of adverse reactions between the two groups(odds ratio=0.05,95%confidence interval:0.00 to 0.10,P=0.060).Funnel diagrams showed that the scattered points of each study were symmetrical and distributed in an inverted funnel shape;therefore,there was no publication bias.CONCLUSION Imipenem can cause mental disorders in patients.However,the low quality of the included literature may have affected the final results.Therefore,it is necessary to conduct a high-quality randomized controlled study with multiple samples to further confirm the mechanism of imipenem-induced mental disorders and provide effective guidance for clinical treatment.

Insights into the swelling process and drug release mechanisms from cross-linked pectin/high amylose starch matrices

Cross-linked pectin/high amylose mixtures were evaluated as a new excipient for matrix tablets formulations,since the mixing of polymers and cross-linking reaction represent rational tools to reach materials with modulated and specific properties that meet specific therapeutic needs.Objective:In this work the influence of polymer ratio and cross-linking process on the swelling and the mechanism driving the drug release from swellable matrix tablets prepared with this excipient was investigated.Methods:Cross-linked samples were characterized by their micromeritic properties(size and shape,density,angle of repose and flow rate)and liquid uptake ability.Matrix tablets were evaluated according their physical properties and the drug release rates and mechanisms were also investigated.Results:Cross-linked samples demonstrated size homogeneity and irregular shape,with liquid uptake ability insensible to pH.Cross-linking process of samples allowed the control of drug release rates and the drug release mechanism was influenced by both polymer ratio and cross-linking process.The drug release of samples with minor proportion of pectin was driven by an anomalous transport and the increase of the pectin proportion contributed to the erosion of the matrix.Conclusion:The cross-linked mixtures of high amylose and pectin showed a suitable excipient for slowing the drug release rates.

Analysis of spironolactone residues in industrial wastewater and in drug formulations by cathodic stripping voltammetry

The redox behavior of spironolactone（SP） drug in Britton-Robinson（BR） buffer of pH 2-11 was investigated by differential pulse cathodic stripping voltammetry（DPCSV） and cyclic voltammetry（CV） at hanging mercury dropping electrode（HMDE）.At pH 9-10.5,the DPCSV of SP drug showed two cathodic peaks at1.15 and1.38 V at the HMDE vs.Ag/AgCl reference electrode.In the CV,at pH 9-10,the dependence of the cathodic peak current,Ip,c and peak potential,Ep,c of the second peak（Ep,c2） on the scan rate（n） and on the depolizer（SP） concentrations was typical of an electrode coupled（EC） chemical reaction type mechanism.The plot of Ip,cat 1.380 V of the DPCSV vs.SP concentration at pH 9 was linear over the concentration range of 1.2×1010-9.6×107 M.The lower limit of detection（LLOD） and limit of quantification（LOQ） of the drug were 1.1×1011 and 4.14×1011 M,respectively.The method was successfully applied for the analysis of SP residues in industrial wastewater,in pure form（98.273.1%） and in drug formulations e.g.Aldactones tablet（98.3572.9%）.The method was validated by comparison with HPLC and the official data methods.

New mechanisms of multidrug resistance: an introduction to the Cancer Drug Resistance special collection

Cancer Drug Resistance publishes contributions to understanding the biology and consequences of mechanisms that interfere with successful treatment of cancer. Since virtually all patients who die of metastatic cancer have multidrug-resistant tumors, improved treatment will require an understanding of the mechanisms of resistance to design therapies that circumvent these mechanisms, exploit these mechanisms, or inactivate these multidrug resistance mechanisms. One example of a resistance mechanism is the expression of ATP-binding cassette efflux pumps, but unfortunately, inhibition of these transporters has not proved to be the solution to overcome multidrug resistance in cancer. Other mechanisms that confer multidrug resistance, and the confluence of multiple different mechanisms (multifactorial multidrug resistance) have been identified, and it is the goal of this Special Collection to expand this catalog of potential multidrug resistance mechanisms, to explore novel ways to overcome resistance, and to present thoughtful reviews on the problem of multidrug resistance in cancer.

Preparation and evaluation of tamsulosin hydrochloride sustained-release pellets modified by two-layered membrane techniques

The aim of the present study was to develop tamsulosin hydrochloride sustained-release pellets using two-layered membrane techniques.Centrifugal granulator and fluidizedbed coater were employed to prepare drug-loaded pellets and to employ two-layered membrane coating respectively.The prepared pellets were evaluated for physicochemical characterization,subjected to differential scanning calorimetry(DSC)and in vitro release of different pH.Different release models and scanning electron microscopy(SEM)were utilized to analyze the release mechanism of Harnual■ and home-made pellets.By comparing the dissolution profiles,the ratio and coating weight gain of Eudragit■ NE30D and Eudragit■ L30D55 which constitute the inside membrane were identified as 18:1 and 10%-11%.The coating amount of outside membrane containing Eudragit■ L30D55 was determined to be 0.8%.The similarity factors(f_(2))of home-made capsule and commercially available product(Harnual■)were above 50 in different dissolution media.DSC studies confirmed that drug and excipients had good compatibility and SEM photographs showed the similarities and differences of coating surface between Harnual■ and self-made pellets before and after dissolution.According to Ritger-Peppas model,the two dosage form had different release mechanism.

Silicone matrices for controlled dexamethasone release:toward a better understanding of the underlying mass transport mechanisms

Dexamethasone-loaded silicone matrices offer an interesting potential as innovative drug delivery systems,e.g.for the treatment of inner ear diseases or for pacemakers.Generally,very long drug release periods are targeted:several years/decades.This renders the development and optimization of novel drug products cumbersome:experimental feedback on the impact of the device design is obtained very slowly.A better understanding of the underlying mass transport mechanisms can help facilitating research in this field.A variety of silicone films were prepared in this study,loaded with amorphous or crystalline dexamethasone.Different polymorphic drug forms were investigated,the film thickness was altered and the drug optionally partially/completely exchanged by much more water-soluble dexamethasone‘phosphate’.Drug release studies in artificial perilymph,scanning electron microscopy,optical microscopy,differential scanning calorimetry,X-ray diffraction and Raman imaging were used to elucidate the physical states of the drugs and polymer,and of the systems’structure as well as dynamic changes thereof upon exposure to the release medium.Dexamethasone particles were initially homogeneously distributed throughout the systems.The hydrophobicity of the matrix former very much limits the amounts of water penetrating into the system,resulting in only partial drug dissolution.The mobile drug molecules diffuse out into the surrounding environment,due to concentration gradients.Interestingly,Raman imaging revealed that even very thin silicone layers(<20µm)can effectively trap the drug for prolonged periods of time.The physical state of the drug(amorphous,crystalline)did not affect the resulting drug release kinetics to a noteworthy extent.

Effects of antibiotic antitumor drugs on nucleotide levels in cultured tumor cells:an exploratory method to distinguish the mechanisms of antitumor drug action based on targeted metabolomics

Nucleotide pools in mammalian cells change due to the influence of antitumor drugs,which may help in evaluating the drug effect and understanding the mechanism of drug action.In this study,an ion-pair RP-HPLC method was used for a simple,sensitive and simultaneous determination of the levels of 12 nucleotides in mammalian cells treated with antibiotic antitumor drugs(daunorubicin,epirubicin and dactinomycin D).Through the use of this targeted metabolomics approach to find potential biomarkers,UTP and ATP were verified to be the most appropriate biomarkers.Moreover,a holistic statistical approach was put forward to develop a model which could distinguish 4 categories of drugs with different mechanisms of action.This model can be further validated by evaluating drugs with different mechanismsof action.This targeted metabolomics study may provide a novel approach to predict the mechanism of action of antitumor drugs.

Study on PEG-(NH_4)_2SO_4 Aqueous Two-Phase System and Distribution Behavior of Drugs

The distribution behavior of chlorpromazine hydrochloride (CPZ), procaine hydrochloride (PCN) and procaine amide hydrochloride (PCNA) in polyethylene glycol (PEG800 or PEG1500)-(NH4)2SO4 aqueous two-phase sys-tems has been investigated. The result shows that the PEG-(NH4)2SO4 aqueous two-phase system has potential ex-traction capability in small molecular drug separation. In PEG800-(NH4)2SO4 system, the extraction efficiencies (E) of CPZ, PCN and PCNA amount to 92.8%, 74.5% and 74.4%, respectively, with the distribution coefficients (KD) being 25.7, 5.9 and 5.8, correspondingly. In PEG1500-(NH4)2SO4 system, the extraction efficiencies (E) of CPZ, PCN and PCNA are 93.7%, 71.3% and 63.2%, respectively, with distribution coefficients (KD) of 39.6, 6.6 and 5.0, correspondingly. Based on the study on ultraviolet and fluorescence spectra and also distribution behavior of the drugs in PEG-(NH4)2SO4 aqueous two-phase system, extraction mechanism was further proposed that both hydro-gen bond and hydrophobic interaction are involved in extraction.

A perspective on general direction and challenges facing antimicrobial peptides

The emergence of drug resistant bacterium threatens the global public healthcare systems.The urgent need to obtain new antimicrobials has driven antimicrobial peptides（AMPs） research into spotlight.Here we give a brief introduction of the recent progress of AMPs regarding their structures,properties,production and modification,and antimicrobial mechanism.Thereby,this review will give an insight into the trends and challenges facing on this particular kind of antimicrobial materials.

Flow behavior and deposition study of pollen-shape carrier particles in an idealized inhalation path model

Pollen-shape （spiked sphere） hydroxyapatite （HA） particles for drug carrier application are studied. The particle shape and size effect on flow characteristics and deposition are assessed. The pollen-shape HA particles are synthesized to have comparable size as typical carrier particles with mean diameter of 30-50 μm and effective density less than 0.3 g/cm^3. The flow behaviors of HA and commonly used lactose （LA） carrier particles are characterized by the Carr＇s compressibility index （CI）. The HA particles have lower CI than the LA particles for the same size range. The flow fields of HA and LA carrier particles are measured in an idealized inhalation path model using particle image velocimetry （PLY） technique. The particle streamlines indicate that a large portion of particles may deposit at the bending section due to inertial impaction and gravitational deposition. The flow field result shows that HA particles give smaller separation regions than the LA particles for the same size range. The pollen-shape HA particles are found to be able to follow the gas flow in the model and minimize undesired deposition. Deposition result confirms the bending section to have the most deposition. Deposition is found to be a function of particle properties. An empirical correlation is derived for the deposition efficiency of the pollen-shape particles as a function of particles Stokes number.

Are the release characteristics of Erzhi pills in line with traditional Chinese medicine theory?A quantitative study

Objective:Traditional Chinese medicine(TCM)has been widely used throughout China to prevent and cure diseases for thousands of years,and now it is a part of the integrative medicine field that is available in Western societies.To ensure the safety and quality of the herbal medicines that are a major part of the TCM tradition,they must be held to modern pharmaceutical standards.Erzhi pill(EZP)is a Chinese Pharmacopeia-listed herbal preparation that is used in the long-term clinical management of postmenopausal symptoms,osteoporosis and menstrual disorders.Until now,whether the drug release mechanism of EZP is in line with its intended TCM usage has not been studied.Methods:The release of specnuezhenide from three EZPs(self-made,Leiyunshang and Renhe)in simulated gastric fluid(SGF),acetate buffer(p H 4.5 buffer)and simulated intestinal fluid(SIF)was investigated in a dissolution test.The water uptake capacity and erosion extent of the three EZPs were investigated using swelling and erosion studies.The drug release mechanism was further assessed through statistical model fitting,using DDSolver software.Results:The release of specnuezhenide from all three EZPs in SGF was less than 50%within a 4 h period.However,over 70%of the specnuezhenide was released from each EZP in both p H 4.5 buffer and SIF in the same time.Analysis of the swelling and erosion behaviors and the drug release mechanism of the three EZPs confirmed that the release rate from EZP followed a sustained release profile,which was an interactive combination of swelling and erosion.Conclusion:This study showed that the release pattern from the pills was in line with the intended TCM use of EZP.TCM had not only theoretically considered sustained release from the pills,but also formulated them to achieve this release pattern.When establishing quality control standards for pills,the theoretical TCM usage and the actual release patterns need to be considered.