Transforming Commercial Polymers into Tough yet Switchable Adhesives by Trident Photoswitch Molecule Doping: Break Adhesion-Switchability Paradox.

Here, a trident molecule doping strategy is introduced to overcome both cohesion-adhesion trade-off and adhesion-switchability conflict, transforming commercial polymers into tough yet photo-switchable adhesives. The strategy involves initial rational design of new trident photoswitch molecules namely TAzo-3 featuring azobenzene and hydroxy-terminated alkyl chains involved rigid-soft tri-branch structure, and subsequent doping into commercial polycaprolactone (PCL) via simple blending. Unique design enables TAzo-3 as a versatile dopant, not only regulating the internal and external supramolecular interaction to balance cohesion and interface adhesion for tough bonding, but also affording marked photothermal effect to facilitate rapid adhesive melting for great photo-switchability. Thus, the optimal TAzo-3-doped PCL (TAzo-3@P) displays markedly-improved bonding performance on diverse substrates compared to linear azobenzene-doped PCL and pure PCL. Impressively, TAzo-3@P on polymethyl methacrylate (PMMA) attains large room-temperature adhesion strength of 6.7 MPa - surpassing most reported adhesives and many commercial adhesives on PMMA, along with easy photo-induced detachment with remarkable switch ratio of 2.09 × 105. Besides, TAzo-3@P can also act as "permanent" adhesives for only adhesion, demonstrating excellent multi-reusability, anti-freezing and waterproof ability. Mechanism studies unveil that the switchable adhesion is closely linked with the dopant molecule structure while rigid-soft coupled trident structures and hydroxy-terminated alkyl chains are key factors.

Chemoselectivity Inversion of Responsive Metal-Organic Frameworks by Particle Size Tuning in the Micrometer Regime.

Gated adsorption is one of the unique physical properties of flexible metal-organic frameworks with high application potential in selective adsorption and sensing of molecules. Despite recent studies that have provided some guidelines in understanding and designing structural flexibility for controlling gate opening by chemical modification of the secondary building units, currently, there is no established strategy to design a flexible MOF showing selective gated adsorption for a specific guest molecule. In a present contribution it is demonstrated for the first time, that the selectivity in the gate opening of a particular compound can be tuned, changed, and even reversed using particle size engineering DUT-8(Zn) ([Zn2(2,6-ndc)2(dabco)]n, 2,6-ndc = 2,6-naphthalenedicarboxylate, dabco = 1,4-diazabicyclo-[2.2.2]-octane, DUT = Dresden University of Technology) experiences phase transition from open (op) to closed (cp) pore phase upon removal of solvent from the pores. Microcrystals show selective reopening in the presence of dichloromethane (DCM) over alcohols. Crystal downsizing to micron size unexpectedly reverses the gate opening selectivity, causing DUT-8(Zn) to open its nanosized pores for alcohols but suppressing the responsivity toward DCM.

pH-responsive polyzwitterion covered nanocarriers for DNA delivery.

The success of gene therapy relies on gene nanocarriers to achieve therapeutic effects in vivo. Surface shielding of poly(ethylene glycol) (PEG), known as PEGylation, onto gene delivery carriers is a predominant strategy for extending blood circulation and improving therapeutic outcomes in vivo. Nevertheless, PEGylation frequently compromises the transfection efficiency by decreasing the interactions with the cellular membrane of the targeted cells, thereby preventing the cellular uptake and the subsequent endosomal escape. Herein, we developed a stepwise pH-responsive polyplex micelle for the plasmid DNA delivery with the surface covered by ethylenediamine-based polycarboxybetaines. This polyplex micelle switched its surface charge from neutral at pH 7.4 to positive at tumorous and endo-/lysosomal pH (i.e., pH 6.5 and 5.5, respectively), thus enhancing the cellular uptake and facilitating the endosomal escape toward efficient gene transfection. Additionally, the polyplex micelle demonstrated prolonged blood circulation as well as enhanced tumor accumulation, leading to highly effective tumor growth suppression by delivering an antiangiogenic gene. These results suggest the usefulness of a pH-responsive charge-switchable shell polymer on the surface of the polyplex micelle for the efficient nucleic acid delivery.

Understanding MOF Flexibility: An Analysis Focused on Pillared Layer MOFs as a Model System.

Flexible porous frameworks are at the forefront of materials research. A unique feature is their ability to open and close their pores in an adaptive manner induced by chemical and physical stimuli. Such enzyme-like selective recognition offers a wide range of functions ranging from gas storage and separation to sensing, actuation, mechanical energy storage and catalysis. However, the factors affecting switchability are poorly understood. In particular, the role of building blocks, as well as secondary factors (crystal size, defects, cooperativity) and the role of host-guest interactions, profit from systematic investigations of an idealized model by advanced analytical techniques and simulations. The review describes an integrated approach targeting the deliberate design of pillared layer metal-organic frameworks as idealized model materials for the analysis of critical factors affecting framework dynamics and summarizes the resulting progress in their understanding and application.

Overcoming the adhesion paradox and switchability conflict on rough surfaces with shape-memory polymers.

Smart adhesives that can be applied and removed on demand play an important role in modern life and manufacturing. However, current smart adhesives made of elastomers suffer from the long-standing challenges of the adhesion paradox (rapid decrease in adhesion strength on rough surfaces despite adhesive molecular interactions) and the switchability conflict (trade-off between adhesion strength and easy detachment). Here, we report the use of shape-memory polymers (SMPs) to overcome the adhesion paradox and switchability conflict on rough surfaces. Utilizing the rubbery-glassy phase transition in SMPs, we demonstrate, through mechanical testing and mechanics modeling, that the conformal contact in the rubbery state followed by the shape-locking effect in the glassy state results in the so-called rubber-to-glass (R2G) adhesion (defined as making contact in the rubbery state to a certain indentation depth followed by detachment in the glassy state), with extraordinary adhesion strength (>1 MPa) proportional to the true surface area of a rough surface, overcoming the classic adhesion paradox. Furthermore, upon transitioning back to the rubbery state, the SMP adhesives can detach easily due to the shape-memory effect, leading to a simultaneous improvement in adhesion switchability (up to 103, defined as the ratio of the SMP R2G adhesion to its rubbery-state adhesion) as the surface roughness increases. The working principle and the mechanics model of R2G adhesion provide guidelines for developing stronger and more switchable adhesives adaptable to rough surfaces, thereby enhancing the capabilities of smart adhesives, and impacting various fields such as adhesive grippers and climbing robots.

Enzyme-Triggered Size-Switchable Nanosystem for Deep Tumor Penetration and Hydrogen Therapy.

The poor penetration of nanocarriers within tumor dense extracellular matrices (ECM) greatly restricts the access of anticancer drugs to the deep tumor cells, resulting in low therapeutic efficacy. Moreover, the high toxicity of the traditional chemotherapeutics inevitably causes undesirable side effects. Herein, taking the advantages of biosafe H2 and small-sized nanoparticles in diffusion within tumor ECM, we develop a matrix metalloprotease 2 (MMP-2) responsive size-switchable nanoparticle (UAMSN@Gel-PEG) that is composed of ultrasmall amino-modified mesoporous silica nanoparticles (UAMSN) wrapped within a PEG-conjugated gelatin to deliver H2 to the deep part of tumors for effective gas therapy. Ammonia borane (AB) is chosen as the H2 prodrug that can be effectively loaded into UAMSN by hydrogen-bonding adsorption. Gelatin is used as the substrate of MMP-2 to trigger size change and block AB inside UAMSN during blood circulation. PEG is introduced to further increase the particle size and endow the nanoparticle with long blood circulation to achieve effective tumor accumulation via the EPR effect. After accumulation into the tumor site, MMP-2 promptly digests gelatin to expose UAMSN loading AB for deep tumor penetration. Upon stimulation by the acidic tumor microenvironment, AB decomposes into H2 for further intratumor diffusion to achieve effective hydrogen therapy. Consequently, such a simultaneous deep tumor penetration of nanocarriers and H2 results in an evident suppression on tumor growth in a 4T1 tumor-bearing model without any obvious toxicity on normal tissues. Our synthetic nanosystem provides a promising strategy for the development of nanomedicines with enhanced tumor permeability and good biosafety for efficient tumor treatment.

Lack of association between generic brittleness and neuropsychiatric measures in patients with epilepsy.

PURPOSE: In a prior bioequivalence study, generic brittle (GB) patients with epilepsy who were considered at risk of worsened seizures or drug side effects from switching antiepileptic drug (AED) formulations demonstrated no significant difference in their drug levels when switched between a brand and generic AED. An alternative basis for being GB may relate to having a personality or mindset that predisposes to poor outcomes from a formulation switch. The objective of this study was to explore whether GB patients with epilepsy could be differentiated from not GB patients based on standardized measures of personality, mood, outlook, and beliefs. METHODS: This was an exploratory, observational, case-control, non-therapeutic study in patients with epilepsy. Patient interviews were conducted, and histories were collected, yielding each patient (n = 148) to be determined as GB or not GB. Eight neuropsychiatry tests were administered to n = 127 of these patients. Tests included Neuroticism Extraversion Openness Personality Inventory 3 (NEO-PI 3), Life Orientation Test-Revised (LOT-R), Quality of Life in Epilepsy Inventory-89 (QOLIE-89), Adverse Childhood Experiences Score (ACE), Physical Symptoms Questionnaire or Patient Health Questionnaire-15 (PHQ-15), Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory (BAI), and the Beliefs About Medicines Questionnaire Epilepsy (BMQ-Epilepsy). A total of 23 Chi squared analyses, along with logistical regression, were performed to assess which tests and sub-elements associated with GB status. RESULTS: None of the neuropsychiatry tests or their sub-elements differentiated GB patients from not GB patients. Results implicate that standardized measures of personality, mood, outlook, and beliefs about their healthcare do not differ between GB and not GB patients with epilepsy, possibly because generic brittleness is caused by factors that neuropsychiatry tests do not measure. CONCLUSIONS: We hypothesized that being GB may relate to having a personality or mindset that predisposes patients to attributing poor outcomes to a formulation switch. However, findings here in patients with epilepsy did not uncover neuropsychiatric factors that predict which patients were GB and which were not GB.

Bioequivalence and switchability of generic antiseizure medications (ASMs): A re-appraisal based on analysis of generic ASM products approved in Europe.

The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%-111%) applied to NTI drugs. Intra-subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra-subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non-bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.

[Biosimilar medicines: Regulatory issues and medico-economic impacts]. / Médicaments biosimilaires : enjeux réglementaires et impacts médicoéconomiques.

The concept of biosimilar medicine was launched by 2001 and 2004 European Directives. First European marketing authorizations were delivered in 2006. They are "copies" of biologically manufactured medicines, mostly proteins. Taking into account the intrinsic variability related to the biological manufacture process, some variation of the chemical structure of the finished compound may be observed. They impact especially the glycosylation residues but not the amino-acid sequence (for proteins). For this reason, the marketing authorization application dossier has to involve, as opposed to the generic medicine procedure, the demonstration of the therapeutic equivalence in at least one clinical indication of the princeps medicine. Introduction of biosimilar medicines of monoclonal antibodies has represented a remarkable event in the domain of rheumatology, gastroenterology and dermatology with infliximab, etanercept and adalimumab biosimilars and in cancerology domains with rituximab, trastuzumab and bevacizumab biosimilars. Biosimilar medicines availability reduces the risk of drug supply rupture of princeps but their main impact is the economic one allowing cost reduction of costly princeps biological medicines. With the acquired clinical experience, the initial fears concerning switch form princeps to a biosimilar for a given patient has progressively disappeared.

Photoresponsive Photoacid-Macroion Nano-Assemblies.

In this study, light-responsive nano-assemblies with light-switchable size based on photoacids are presented. Anionic disulfonated napthol derivates and cationic dendrimer macroions are used as building blocks for electrostatic self-assembly. Nanoparticles are already formed under the exclusion of light as a result of electrostatic interactions. Upon photoexcitation, an excited-state dissociation of the photoacidic hydroxyl group takes place, which leads to a more highly charged linker molecule and, subsequently, to a change in size and structure of the nano-assemblies. The effects of the charge ratio and the concentration on the stability have been examined with absorption spectroscopy and ζ-potential measurements. The influence of the chemical structure of three isomeric photoacids on the size and shape of the nanoscale aggregates has been studied by dynamic light scattering and atomic force microscopy, revealing a direct correlation of the strength of the photoacid with the changes of the assemblies upon irradiation.

Has the Time Come to Employ Population and Individual Bioequivalence for the Evaluation of Generics?

BACKGROUND: Bioequivalence studies are a vital part of drug development. The average bioequivalence approach is the standard method of assessment to conclude whether the generic product is bioequivalent to the innovator product. Of late, debates are on whether the average bioequivalence approach adequately addresses drug interchangeability as it considers only population mean for the evaluation especially when highly variable drug products and narrow therapeutic index drugs are dealt with. Hence, the alternative approaches like population bioequivalence and individual bioequivalence assessment approaches emerge as they consider inter/intra-subject variance and subject- by-formulation variance along with population mean. OBJECTIVES: The objective of the study was to apply different bioequivalence assessment approaches in a replicate bioequivalence study to evaluate the drug interchangeability. METHODS: This was an open-label, single-dose, randomized, balanced, two-treatment, three-period, three-sequence, partial replicate crossover bioequivalence study of omeprazole enteric-coated tablet 20 mg conducted on 48 normal healthy subjects under fed conditions. The plasma concentration of omeprazole was analyzed by a validated bioanalytical method to determine the pharmacokinetic and statistical parameters to assess average bioequivalence, population bioequivalence, and individual bioequivalence. RESULTS: In this study, test formulation was shown to be bio-inequivalent to the reference formulation by average bioequivalence, population bioequivalence, and individual bioequivalence approaches. CONCLUSION: The outcome of the evaluation clearly states that the bioequivalence outcome of all these approaches are the same. Obviously, it does not mean that these three approaches provide the same outcome though the consideration of variances varies. Certainly, population bioequivalence and individual bioequivalence approach will be more accurate for the assessment of drug interchangeability.

Detection of biological switches using the method of Gröebner bases.

BACKGROUND: Bistability and ability to switch between two stable states is the hallmark of cellular responses. Cellular signaling pathways often contain bistable switches that regulate the transmission of the extracellular information to the nucleus where important biological functions are executed. RESULTS: In this work we show how the method of Gröebner bases can be used to detect bistability and output switchability. The method of Gröebner bases can be seen as a multivariate, non-linear generalization of the Gaussian elimination for linear systems which conveniently seperates the variables and drastically simplifies the simultaneous solution of polynomial equations. A necessary condition for fixed-point state bistability is for the Gröbner basis to have three distinct solutions for the state. A sufficient condition is provided by the eigenvalues of the local Jacobians. We also introduce the concept of output switchability which is defined as the ability of an output of a bistable system to switch between two different stable steady-state values. It is shown that bistability does not necessarily guarantee switchability of every state variable of the system. We further show that, for a bistable system, the necessary conditions for output switchability can be derived using the Gröebner basis. The theoretical results are incorporated into an analysis procedure and applied to several systems including the AKT (Protein kinase B), RAS (Rat Sarcoma) and MAPK (Mitogen-activated protein kinase) signal transduction pathways. Results demonstrate that the Gröebner bases can be conveniently used to analyze biological switches by simultaneously detecting bistability and output switchability. CONCLUSION: The Gröebner bases provides a novel methodology to analyze bistability. Results clarify the distinction between bistability and output switchability which is lacking in the literature. We have shown that theoretically, it is possible to have an output subspace of an n-dimensional bistable system where certain variables cannot switch. It is possible to construct such systems as we have done with two reaction networks.

Current Regulatory Standpoint on Evaluating the Bioequivalence of Different Classes of Generic Drugs - Is the Evaluation in the Right Direction?

BACKGROUND: The concept of evaluating bioequivalence has changed over a period of time. Currently, the Average Bioequivalence approach (ABE) is the gold standard tool for the evaluation of generics. Of late, many debates had arisen about employing ABE approach for the appraisal of all drug categories. This review aims to examine the limitations of ABE approach and the significances of Population Bioequivalence (PBE) and Individual Bioequivalence (IBE) approach, current regulatory thinking for assessing different categories of the drug, whether they are adequately assessed, and the evaluation is in the right direction. METHODS: We carried out an organized search of bibliographic databases for peer-reviewed research literatures, regulatory recommendations, guidance documents using a focused review question and eligibility criteria. The standard tools were used to appraise the quality of retrieved documents and to make sure the authenticity of the data. RESULTS: In total 73 references were used in the review, the majority of the references (guidance documents) were from the different regulatory agencies and product-specific guidance. There were 29 product-specific guidance from USFDA and EMA. The limitations of the ABE approach were discussed in detail along with the significances of Population Bioequivalence (PBE) approach and Individual Bioequivalence (IBE) approaches. CONCLUSION: It is apparent from the review that IBE approach is a precise method for evaluating the drugs as it answers drug interchangeability (prescribability and switchability). IBE approach is followed by PBE approach and ABE approach for the evaluation of different categories of drugs in terms of precision.

Adjusted indirect comparisons to assess bioequivalence between generic clopidogrel products in Serbia.

AIMS: Generic products can be regarded as therapeutically equivalent and switchable with the reference product. However, switchability between generics is unknown, as direct comparisons between generics are not performed. The aim of this study was to investigate the bioequivalence between generic clopidogrel products by means of adjusted indirect comparisons (AICs). METHODS: AICs were conducted to assess bioequivalence between 4 generic clopidogrel products that are authorised in Serbia. Generics are considered equivalent to the reference if the 90% confidence intervals (CIs) for the ratios test/reference of the maximum concentration (Cmax ) and area under the curve up to the last measurable concentration (AUC0-t ) fall within the acceptance range 80.00-125.00%. However, for AICs between generics, the Canadian acceptance criterion for Cmax was employed, where only the point estimate of Cmax needs to be within 80.00-125.00%. RESULTS: The 90% CIs of the AICs demonstrated bioequivalence within 80.00-125.00% for all AUC0-t comparisons. The point estimates of Cmax in all AICs were also within this range. CONCLUSION: This study demonstrates that the bioavailability of these 4 generic clopidogrel products authorised in Serbia is very similar. Despite the limited power of AICs, bioequivalence was demonstrated for all 90% CIs of AUC0-t and all 90% CIs of Cmax comparisons were within or very close to the acceptance range, being able to comply with the acceptance criterion employed in Canada for Cmax . Therefore, these 4 generic clopidogrel products authorised in Serbia can be considered switchable with each other in clinical practice based on the adjusted indirect comparisons.

Exploring generic brittleness and the demographic factors for its susceptibility in patients with epilepsy.

PURPOSE: The purpose of this study was to provide an algorithm for generic brittleness and to elucidate the demographic factors that anticipate generic brittleness for patients with epilepsy. METHODS: This exploratory, observational, and nontherapeutic study was conducted in patients with epilepsy who were routinely followed at the University of Maryland epilepsy outpatient clinic in Baltimore, Maryland. Patients were taking at least one antiepileptic drug (AED) for treatment of epilepsy. Based on patient interview and medical history, 12 demographic factors were collected. Each patient was assessed to be either generic brittle (GB) or not GB. Demographic factors were subjected to binary logistical regression and other statistical tests, to elucidate determinants of GB status. RESULTS: N = 148 patients completed the study. An algorithm to define whether a patient was GB or not GB was devised. The two elements that defined GB status are as follows: patient opinion about generics and (if needed) whether patients were currently taking brand or generic of their most problematic AED. About 40% of patients were GB. From binary logistical regression, two demographic factors that contributed to patients being GB were whether a patient was currently taking a problem AED and total number of current medications for a patient, with odds ratios of 4.06 (95% confidence interval [CI] from 1.53 to 10.81) and 1.10 (95% CI from 1.003 to 1.21), respectively. Of the patients on a problem AED, 46.9% were GB, while only 18.2% of patients not currently on a problem AED were GB. The total number of current medications ranged from 1 to 22, with mode of four medications. From regression, for each additional medication that a patient took, the odds of being GB increased 1.10-fold. Although patient seizure and adverse event history was not employed to define GB status, being GB was associated with less seizure control and greater adverse events. CONCLUSIONS: An algorithm for generic brittleness was derived, and about 40% of patients were GB, usually due to prior history of a switch problem. Two demographic factors favored patients being GB: whether the patient was currently taking a problem AED and the total number of current medications.

Polarity-Switchable Symmetric Graphite Batteries with High Energy and High Power Densities.

Multifunctional batteries with enhanced safety performance have received considerable attention for their applications at extreme conditions. However, few batteries can endure a mix-up of battery polarity during charging, a common wrong operation of rechargeable batteries. Herein, a polarity-switchable battery based on the switchable intercalation feature of graphite is demonstrated. The unique redox-amphoteric intercalation behavior of graphite allows a reversible switching of graphite between anode and cathode, thus enabling polarity-switchable symmetric graphite batteries. The large potential gap between anion and cation intercalation delivers a high midpoint device voltage (≈average voltage) of ≈4.5 V. Further, both the graphite anode and cathode are kinetically activated during the polarity switching. Consequently, polarity-switchable symmetric graphite batteries exhibit a remarkable cycling stability (96% capacity retention after 500 cycles), a high power density of 8.66 kW kg-1 , and a high energy density of 227 Wh kg-1 (calculated based on the total weight of active materials in both anode and cathode), which are superior to other symmetric batteries and recently reported dual-graphite or dual-carbon batteries. This work will inspire the development of new multifunctional energy-storage devices based on novel materials and electrolyte systems.

High-Sensitivity Detection of Iron(III) by Dopamine-Modified Funnel-Shaped Nanochannels.

Iron as an essential trace element in the human body participates in various biological processes. The demand for efficient and sensitive detection of FeIII has drawn wide attentions. Inspired by biological nanochannels, a high-sensitivity, economic, and recyclable FeIII detection method is proposed by using dopamine (DOPA)-modified funnel-shaped nanochannels. Along with the FeIII concentration changing, different FeIII-DOPA chelates are generated in the channel, which affect the wettability and charge distribution of the pore surface, resulting in a change of ionic current through the nanochannels. Meanwhile, the funnel-shaped nanochannel applied in this work with a narrow cylindrical segment (a diameter close to 10 nm) as the critical section can enhance the sensing ability to the ultra-trace level (down to 10-12 M). We expound the mechanism and feasibility of this method and anticipate that the system can be a good example to design highly sensitive and stable ion detection devices.

Studies on drug switchability showed heterogeneity in methodological approaches: a scoping review.

BACKGROUND AND OBJECTIVE: Several drugs share the same therapeutic indication, including those undergoing patent expiration. Concerns on the interchangeability are frequent in clinical practice, challenging the evaluation of switchability through observational research. The objective of this study was to conduct a scoping review of observational studies on drug switchability to identify methodological strategies adopted to deal with bias and confounding. METHODS: We searched PubMed, EMBASE, and Web of Science (updated January 31, 2017) to identify studies evaluating switchability in terms of effectiveness/safety outcomes or compliance. Three reviewers independently screened studies extracting all characteristics. Strategies to address confounding, particularly previous drug use and switching reasons, were considered. All findings were summarized in descriptive analyses. RESULTS: Thirty-two studies, published in the last 10 years, met the inclusion criteria. Epilepsy, cardiovascular, and rheumatology were the most frequently represented clinical areas. Seventy-five percent of the studies reported data on effectiveness/safety outcomes. The most frequent study design was cohort (65.6%) followed by case-control (21.9%) and self-controlled (12.5%). Case-control and case-crossover studies showed homogeneous methodological strategies to deal with bias and confounding. Among cohort studies, the confounding associated with previous drug use was addressed introducing variables in multivariate model (47.3%) or selecting only adherent patients (14.3%). Around 30% of cohort studies did not report reasons for switching. In the remaining 70%, clinical parameters or previous occurrence of outcomes was measured to identify switching connected with lack of effectiveness or adverse events. CONCLUSION: This study represents a starting point for researchers and administrators who are approaching the investigation and assessment of issues related to interchangeability of drugs.

CO2 switchable hollow nanospheres.

HYPOTHESIS: Hollow nanospheres, characterized by a cavity inside a solid shell, have potential applications due to their unique structure, but the unchangeable morphology and permeability of the shell restrain their further practical utilization. While several smart hollow nanospheres that can respond to pH, ion strength, and temperature have been developed, they are inclined to suffer from problems associated with high energy consumption or the difficult removal of residual stimulants. Thus, it is desirable to develop a novel and free-of-residual trigger stimulating mode. EXPERIMENTS: In this work, CO2 is used to fabricate smart hollow nanospheres composed of crosslinked poly(diethylamino-ethyl methacrylate) (PDEAEMA) network from polystyrene (PS)/PDEAEMA core-shell nanospheres by a template-removal technique. The morphology evolution of the resultant nanospheres during the fabrication process was characterized by X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), thermogravimetry analysis (TGA) and dynamic light scattering (DLS) and was visualized by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). FINDINGS: Hollow nanospheres can be generated by experiencing a morphology change from a core nanosphere, core-shell, yolk-shell to a final hollow structure. The increase in shell-stiffness can restrain the collapse of hollow spheres. It is demonstrated that CO2 is easy to introduce and remove (via N2 input) without stimulation residues in this system. In addition, mild CO2/N2 purging can only reversibly change the swelling/collapse of hollow particles; violent CO2/N2 bubbling can reversibly regulate both the size and aggregation/re-dispersion state of the hollow nanospheres, which can be intuitively observed by atomic force microscopy (AFM).

pH-Driven Wetting Switchability of Electrodeposited Superhydrophobic Copolymers of Pyrene Bearing Acid Functions and Fluorinated Chains.

A smart stimuli-responsive surface was fabricated by the electro-copolymerization of pyrene monomers followed by base and acid treatment. Copolymers of pyrenes bearing fluorinated chains (Py-nF6 ) and acid functions (Py-COOH) were produced with different molar concentrations of each monomer (0, 25, 50, 75, and 100 % of Py-nF6 vs. Py-COOH) by an electrochemical process. Two different perfluorinated pyrenes containing ester and amide groups were used to reach superhydrophobic properties. The relation of those bonds with the final properties of the surface was explored. The pH-sensitive group of Py-COOH allowed the surfaces to be reversibly switched from superhydrophobic (water contact angle>θw >150° and very low hysteresis) to hydrophilic (θw <90°). The amide and ester bonds influenced the recovery of the original wettability after both base and acid treatment. Although the fluorinated homopolymer with ester bonds was insensitive to base and acid treatment due to its superhydrophobic properties with ultralow water adhesion, the recovery of the original wettability for the copolymers was much more important with amide bonds due to the amide functional groups be more resistant to the hydrolysis reaction. This strategy offered the opportunity to access superhydrophobic films with switchable wettability by simple pH treatment. The films proved to be a good tool for use in biological applications, for example, as a bacterial-resistant film if superhydrophobic and as a bacterial-adherent film if hydrophilic.