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Prevention of cardiovascular events and regression of atherosclerotic changes are the primary aims of preventive cardiovascular medicine. Arterial thrombosis is caused by endothelial dysfunction, which disrupts vascular haemostasis. Glucagon-like peptide 1 (GLP-1) receptor agonists have been initially used as glucose lowering agents, but over time have been used for other indications due to their cardiorenal benefit, as well as their benefit in the regression of atherosclerosis process. The aim of this paper is to present the benefits of GLP-1 receptor agonists in the prevention of atherosclerotic changes, in the preservation of brain vascular function, and to show the possible role in the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The genus Crataegus (hawthorn), a member of the Rosaceae family, encompasses several species with broad geographical distribution across the Northern Hemisphere, including Asia, Europe, and the Americas. Hawthorn is recognized as an edible medicinal plant with applications related to strengthening the digestive system, promoting blood circulation, and resolving blood stasis. This study critically summarized the traditional uses, phytochemistry, and pharmacological properties to provide a theoretical basis for further studies on hawthorn and its applications in medicine and food. The available information on hawthorn was gathered from scientific databases (including Google Scholar, Web of Science, PubMed, ScienceDirect, Baidu Scholar, CNKI, online ethnobotanical databases, and ethnobotanical monographs, and considered data from 1952 to 2023). Information about traditional uses, phytochemistry, pharmacology, and safety concerns of the collected data is comprehensively summarized in this paper. The literature review revealed that hawthorn includes more than 1000 species primarily distributed in the northern temperate zone. Traditional uses of hawthorn have lasted for millennia in Asia, Europe, and the Americas. Within the past decade, 337 chemical compounds, including flavonoids, lignans, fatty acids and organic acids, monoterpenoids and sesquiterpenoids, terpenoids and steroids, have been identified from hawthorn. Modern pharmacological studies have confirmed numerous bioactivities, such as cardiovascular system influence, antitumor activity, hepatoprotective activity, antimicrobial properties, immunomodulatory functions, and anti-inflammatory activities. Additionally, evaluations have indicated that hawthorn lacks toxicity. Based on its traditional uses, chemical composition, and pharmacological studies, hawthorn has significant potential as a medicinal and edible plant with a diverse range of pharmacological activities. Traditional uses of the hawthorn include the treatment of indigestion, dysmenorrhea, and osteoporosis. However, modern pharmacological research primarily focuses on its cardiovascular and cerebrovascular system effects, antitumor effects, and liver protection properties. Currently, there is a lack of correlative research involving its traditional uses and pharmacological activities. Moreover, phytochemical and pharmacological research has yet to focus on many types of hawthorn with traditional applications. Therefore, it is imperative to research the genus Crataegus extensively. [Display omitted] • Traditional uses, phytochemistry, pharmacology, and safety concerns of hawthorn. • The medicinal uses and edible value of hawthorn. • The application and medicinal value of hawthorn in ethnopharmacology. • The challenges and opportunities of hawthorn were envisioned. [ABSTRACT FROM AUTHOR]

• Mechanisms of cardiovascular disease are complex and multifactorial, driven by genetic variants. • Attractive drug targets require a substantial body of mechanistic and clinical evidence. • Drug target discovery in CVD is only possible through multidisciplinary collaboration. • To maximise impact, collaboration between independent research consortia is advised. Research consortia in Europe often compete with each other for skills, human and technical resources and, eventually, recognition of the scientific impact of their work. In response to the same EU Horizon2020 call, we received funding for our research project proposals to identify and validate novel drug targets for cardiovascular disease treatment. Each consortium followed a unique and independent research strategy. However, as coordinators of these consortia we envisioned we could increase impact, outcomes and efficiency by intensifying our interaction. At an agreed stage during our projects we chose to share our knowledge, vision and ideas. In this paper we present what we learned, in the hope that future consortia will see the benefits of this approach. [ABSTRACT FROM AUTHOR]

Abstract Stainless steel (SS) has been widely used as a material for fabricating cardiovascular stents/valves, orthopedic prosthesis, and other devices and implants used in biomedicine due to its malleability and resistance to corrosion and fatigue. Despite its good mechanical properties, SS (as other metals) lacks biofunctionality. To be successfully used as a biomaterial, SS must be made resistant to the biological environment by increasing its anti-fouling properties, preventing biofilm formation (passive surface modification), and imparting functionality for eluting a specific drug or capturing selected cells (active surface modification); these features depend on the final application. Various physico-chemical techniques, including plasma vapor deposition, electrochemical treatment, and attachment of different linkers that add functional groups, are used to obtain SS with increased corrosion resistance, improved osseointegration capabilities, added hemocompatibility, and enhanced antibacterial properties. Existing literature on this topic is extensive and has not been covered in an integrated way in previous reviews. This review aims to fill this gap, by surveying the literature on SS surface modification methods, as well as modification routes tailored for specific biomedical applications. Statement of significance Stainless steel (SS) is widely used in many biomedical applications including bone implants and cardiovascular stents due to its good mechanical properties, biocompatibility and low price. Surface modification allows improving its characteristics without compromising its important bulk properties. SS with improved blood compatibility (blood contacting implants), enhanced ability to resist bacterial infection (long-term devices), better integration with a tissue (bone implants) are examples of successful SS surface modifications. Existing literature on this topic is extensive and has not been covered in an integrated way in previous reviews. This review paper aims to fill this gap, by surveying the literature on SS surface modification methods, as well as to provide guidance for selecting appropriate modification routes tailored for specific biomedical applications. Graphical abstract Unlabelled Image Highlights • Ongoing research aim to overcome inherent flaws of stainless steel and meet new application needs in biomedicine; • Metal properties are determined by the intended biomedical application; • Stainless steel has been modified with various functional groups through different linkers or physico-chemical techniques; • Surface modification is used to improve blood compatibility, osseointegration and anti-fouling properties. [ABSTRACT FROM AUTHOR]

Cardiovascular reactivity to stress is an established marker of lifetime disease risk, with both elevated and blunted reactions empirically identified as being predictive of ill-health. However, in the relevant studies, traditional laboratory protocols do not account for patterns of response adaptation across time, patterns that may be particularly important in the prediction of future health outcomes. We outline the evidence suggesting that habituation to repeated or prolonged stress represents an informative and health-relevant aspect of the cardiovascular stress response. In this position paper, we outline what studies of cardiovascular adaptation have elucidated to date. Cardiovascular response habituation occurs for various types of stressor, is most pronounced after initial stress responses have subsided (making initial stress responses potentially misleading if scrutinized in isolation), emerges in both women and men, and is subject to individual differences. Such moderating factors fit within the biopsychosocial model, suggesting that CVR adaptation is etiologically relevant and potentially modifiable through intervention. However, as yet, there is no prospective evidence to confirm that patterns of adaptation predict adverse health, despite there being strong reasonable and logical grounds to suspect so. We suggest how existing studies may offer a means to fill this gap in prospective evidence, and outline four potential typologies in cardiovascular reactivity patterns that fit within and extend the classic reactivity hypothesis. [ABSTRACT FROM AUTHOR]

Advanced measurement methods are critical for quantifying spatial systole and diastole of cardiomyocytes in heart disease research. However, restricted by traditional microscopic observation and measurement methods, current research on the kinetics of a single cardiomyocyte mainly focuses on the focal plane of the utilized microscope. This paper proposes a novel, non-invasive, multi-point, and high-resolution three dimensional (3D) measuring method based on microsphere tracking, which can be used to analyze the mechanical beating of cardiomyocytes at a single-cell level. An expansion rotation method was proposed to analyze off-focus imaging informatics for characterizing the contractile motion of a single cardiomyocyte, obviating the need for costly and complex equipment to monitor cardiomyocytes' mechanical beating activity. Furthermore, to the best of our knowledge, a 3D beating curve of a single cardiomyocyte was drawn for the first time, and the actual spatial movement states of cardiomyocytes in different scenarios were recorded. The applicability of the motion characterization method was tested to determine the pharmacological effects of a typical cardiovascular drug, isoprenaline (1 μM and 5 μM). Within 18 days, the 3D beating curves indicated that the motion of cardiomyocytes tends to be smooth and regular during maturation. The findings offer insights into the contractile motion of single cardiomyocytes and a deep understanding of their kinetics at a single-cell level for multiple scenarios. • Brightfield motility cell mechanoresponse measurements for the first time using SiO 2 microsphere sensors. • Simultaneous measurement of the single cardiomyocyte and cardiomyocyte clusters within the same field of view. • Three-dimensional spatial nanoscale beating measurement of cardiomyocytes. • Long-term monitoring of multiple types of cardiomyocytes. • A new generation of potential in vitro cardiomyocyte drug screening platform. [ABSTRACT FROM AUTHOR]

Introduction: In view of the popularity of Internet usage in Hong Kong, an interactive web-based drug information platform entitled "Ask My Pharmacist - Online University Led drug Enquiry Platform" (AMPOULE) was launched in 2009 to better serve the needs of drug information in Hong Kong. This paper aimed to evaluate the utility of AMPOULE in improving drug-related knowledge among the public and to reassess the needs of the general public in Hong Kong.Methods: All enquiries sent via AMPOULE were reviewed. Demographic data, nature of questions and types of drug class covered were analyzed. The workload of pharmacists was examined with respect to the preparation time needed for the enquiry, the lag days to reply and also the timing of enquiry recipient.Results: 2122 enquiries were received from 2009 to 2017. Most enquirers were from Hong Kong (56.6%) and female gender (49.2%). 13% of the concerned subjects were aged over 61-year-old. The most frequent types of questions and medications covered were "Drug Ingredients and Indications" (28.0%) and Adverse Drug Reactions (26.8%) and "Cardiovascular Medication" (21.9%) respectively but these varied in different age groups or enquirer groups. The median time for preparation was 40.0 min (IQR: 25-65 min) while the median time lag was found to be 2.5 days (IQR: 1.0-5.0 days). The number of enquiries received was evenly distributed throughout the day except during 1:00 am to 9:00 am and 7:00 pm to 8:00 pm.Conclusion: AMPOULE has demonstrated that an online platform providing patient-oriented drug information service through the Internet is promising and further promotion is warranted. Current data suggested that the need of different age groups and enquirer groups are different and should therefore be individualized. [ABSTRACT FROM AUTHOR]

Regulators and payers have contrasting priorities that can lead to divergent decisions and delays in patient access to new treatments. Those involved in coverage decisions have not routinely been integrated in the drug development process. Theoretically, inclusion of payer representatives early in development could help discern discordance among stakeholder priorities; facilitate cooperation to align objectives; foster agreement on the evidence required for approval and reimbursement; improve transparency, accountability, and consistency of payer decision making; and ideally, minimize delays in patient access to new therapies. However, early participation by payers may not provide these expected benefits if payers' decision-making processes are not evidence based or cannot be reliably predicted. This paper describes current interactions among regulatory agencies, payers, sponsors, and investigators and proposes collaboration among all stakeholders earlier in the development process. The premise that a priori discussions might facilitate the delivery of advances in cardiovascular care is a hypothesis worth testing. [ABSTRACT FROM AUTHOR]

With the increasing incidence and mortality of cardiovascular diseases, high consumption of the cardiovascular drug salbutamol (SAL) has made this compound an emerging pollutant in natural water and a challenge for traditional wastewater treatment. In this paper, an efficient advanced oxidation process was used to degrade SAL by electron beam (EB) irradiation. The results revealed that 100 mg L−1 of SAL could be nearly completely removed (95.1%) at 10 kGy and the degradation kinetic well followed pseudo first-order kinetic model. Different factors, including pH, inorganic ions and water matrix, had varying effects on the degradation of SAL owing to their important influence on the formation of reactive species in the aqueous solution. And it was found that e a q − played a major role in the degradation of SAL parent. Moreover, the addition of K 2 S 2 O 8 (20 mM) increased the SAL mineralization rate from 2.9% to 64.2%, suggesting that oxidation free radicals could greatly improve the mineralization rate of SAL. Combining with the theoretical calculations and determined degradation by-products, four possible degradation pathways of SAL by EB irradiation were proposed, including H • , • O H and e a q − all participated in the degradation of SAL. Finally, toxicity evaluation suggested that the toxicity of SAL aqueous solution reduced after EB irradiation, indicating that it is an effective method to degrade SAL. [Display omitted] • Electron beam irradiation was effective in degrading salbutamol. • e a q − played a major role in the degradation of salbutamol. • The addition of persulfate could promote the mineralization of salbutamol. • The possible degradation pathways of salbutamol were proposed. • The toxicity of salbutamol solution decreased after EB irradiation. [ABSTRACT FROM AUTHOR]

• Dried urine spot as an alternative to urine sampling in extreme conditions particularly during spaceflight missions. • A method was developed to detect 5 antihypertensive drugs in urine. • The DUS method coupled to LC-MS/MS detects these drugs in a single analysis with a simple and fast preparation. • This analytical assay was tested in different temperatures conditions. • The urine transfer was successful on paper card during microgravity. Cardiovascular pharmacological countermeasures will be required as a preventive measure of cardiovascular deconditioning and early vascular ageing for long term space travelers. Physiological changes during spaceflight could have severe implications on drug pharmacokinetics and pharmacodynamics (PK/PD). However, limitations exist for the implementation of drug studies due to the requirements and constraints of this extreme environment. Therefore, we developed an easy sampling method on dried urine spot (DUS), for the simultaneous quantification of 5 antihypertensive drugs in human urine: irbesartan, valsartan, olmesartan, metoprolol and furosemide analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), considering spaceflight parameters. This assay was validated in terms of linearity, accuracy, and precision with satisfactory results. There were no relevant carry-over, matrix interferences. The targeted drugs were stable in urine collected by DUS until 6 months at +21 °C, +4°C, −20 °C (with or without desiccants) and at 30 °C during 48 h. Irbesartan, valsartan and olmesartan were not stable at 50 °C during 48 h. This method was found to be eligible for space pharmacology studies in terms of practicality, safety, robustness and energy costs. It has been successfully implemented in space tests programs led in 2022. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) is a field of computer science that aims to mimic human thought processes, learning capacity, and knowledge storage. AI techniques have been applied in cardiovascular medicine to explore novel genotypes and phenotypes in existing diseases, improve the quality of patient care, enable cost-effectiveness, and reduce readmission and mortality rates. Over the past decade, several machine-learning techniques have been used for cardiovascular disease diagnosis and prediction. Each problem requires some degree of understanding of the problem, in terms of cardiovascular medicine and statistics, to apply the optimal machine-learning algorithm. In the near future, AI will result in a paradigm shift toward precision cardiovascular medicine. The potential of AI in cardiovascular medicine is tremendous; however, ignorance of the challenges may overshadow its potential clinical impact. This paper gives a glimpse of AI's application in cardiovascular clinical care and discusses its potential role in facilitating precision cardiovascular medicine. [ABSTRACT FROM AUTHOR]

We review the current analytical methods for analyzing type 2 diabetes (T2D) medication in human and animal samples. We discuss the advantages and limitations during sample preparation, separation, and detection of these drugs. Finally, we highlight the parameters to be considered for multi-targeted analytical methods and for assessing T2D medication adherence. By reviewing over 140 original papers, we can conclude that current analytical methods for T2D drug analysis involve: (1) extraction using protein precipitation with acetonitrile or methanol, (2) reversed-phase liquid chromatography separation using octadecyl (C18)-based columns with analysis time <20 min, and (3) electrospray ionization in positive ion mode with a triple quadrupole or quadrupole/linear ion trap mass analyzer. Methods for screening antidiabetics were limited to 1–5 analytes, far less than in other areas, such as analysis of cardiovascular agents, anticancer drugs, or drug screening for forensic services. [Display omitted] • State of the art in the analysis of type 2 diabetes medication in human samples. • Advantages and limitations during sample preparation, separation, and detection. • Challenges in multi-targeted analysis of T2D medication. • Monitoring and assessment of T2D medication adherence. [ABSTRACT FROM AUTHOR]

This paper, based on the 2015 CSANZ Cardiovascular Nursing Lecture, takes its title from the invitation to give this lecture in Melbourne being received when the author was visiting Florence, after whom Florence Nightingale, the founder of modern nursing, is named. Her work has indirectly shaped and influenced cardiovascular nursing, which has developed over the past 50 years. Despite its relatively short history, cardiovascular nursing has made a major contribution to improving the cardiovascular health and well-being of patients and families through health promotion, risk reduction and disease prevention. Examples include cardiac rehabilitation and secondary prevention and chronic heart failure disease management. Challenges, however, remain, including nurses practising to the full extent of their education and training, working as full partners with physicians and other health professionals in redesigning healthcare, ensuring better data collection and being more active in advocacy and policy initiatives. Cardiovascular nursing has a strong record of innovation but should always remember that it is there to serve the public and, bearing in mind the risk of potential harm versus benefit, be mindful of Florence Nightingale's wise counsel, "First, do no harm". [ABSTRACT FROM AUTHOR]

Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits, using clinically-evident cardiovascular endpoints. To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, regulatory bodies, and government agencies convened for a think tank meeting in July 2014 in Washington, DC. This paper summarizes the proceedings of the meeting and aims to delineate the current adverse trends in cardiovascular drug development, understand the key issues that underlie these trends within the context of a recognized need for a rigorous regulatory review process, and provide potential solutions to the problems identified. [ABSTRACT FROM AUTHOR]

Pharmaceuticals consumption in Poland is high. One of the most frequently prescribed is cardiovascular drugs. Due to their relatively high hydrophilic properties, they are not completely eliminated during wastewater treatment processes. In contrast to parent compounds, the presence of cardiovascular metabolites is rarely investigated in surface waters. The goal of this paper was to develop the methodology for detection of metabolites of selected beta-blockers: metoprolol, bisoprolol and propranolol. These metabolites were obtained by the incubation of parent compounds with S9 rat's liver fraction and used for the development and optimization of the low resolution LC–MS/MS method. Accurate mass spectrometry measurements were applied for validation of this method. The incubation of the parent compound with S9 fraction resulted only in propranolol's metabolites generation. However, on the basis of hydroxypropranolol, theoretically transitions for mono- and dihydroxy-metoprolol and bisoprolol derivatives were generated for MRM mode and applied for surface water analysis. The analysis revealed the presence of some of the target metabolites in the Vistula river. This work is the first one proposing the application of biotrasformation in the methodology of low resolution LC–MS–MS analysis of metabolites of cardiovascular drugs in surface water. [ABSTRACT FROM AUTHOR]

In this paper, a new methodology to reconstruct missing segments of multidimensional data is introduced. Using the signals׳ history we identify the interconnections between the signals in the form of composite infinite impulse response (IIR) transfer functions. Assuming that the connections do not vary in time, we managed to reconstruct the missing signals using the yet available parallel measured signals and the transfer functions. The filter coefficients are fitted to the data using particle swarm optimization (PSO). The method was successfully applied to intensive care unit (ICU) data. Besides simplicity, short running time and good results on available datasets, further advantages of the proposed method are trivial parallelization and the possibility of application in an online setting. [ABSTRACT FROM AUTHOR]

Abstract: Background: The photodegradation of drugs obeying unimolecular mechanisms such as that of nifedipine (NIF) were usually characterised in the literature by zero-, first- and second-order kinetics. This approach has been met with varying success. This paper addresses this issue and proposes a novel approach for unimolecular photodegradation kinetics. The photodegradation of the cardiovascular drug nifedipine is investigated within this framework. Methods: Experimental kinetic data of nifedipine photodegradation were obtained by continuous monochromatic irradiation and DAD analysis. Fourth-order Runge–Kutta calculated kinetic data served for the validation of the new semi-empirical integrated rate-law model proposed in this study. Results: A new model equation has been developed and proposed which faithfully describes the kinetic behaviour of NIF in solution for non-isosbestic irradiations at wavelengths where both NIF and its photoproduct absorb. NIF absolute quantum yield values were determined and found to increase with irradiation wavelength according to a defined sigmoid relationship. The effects of increasing NIF or excipients’ concentrations on NIF kinetics were successfully modelled and found to improve NIF photostability. The potential of NIF for actinometry has been explored and evaluated. A new reaction order (the so-called Φ-order) has been identified and specifically proposed for unimolecular photodegradation reactions. Conclusion: The semi-empirical and integrated rate-law models facilitated reliable kinetic studies of NIF photodegradation as an example of AB(1Φ) unimolecular reactions. It allowed filling a gap in kinetic studies of drugs since, thus far, thermal first-order or a combination of first- and zero- order kinetic equations were generally applied for drug photoreactions in the literature. Also, a new reaction order, the “Φ-order”, has been evidenced and proposed as a specific alternative for photodegradation kinetics. [Copyright &y& Elsevier]

Abstract: Biodegradability is a big advantage of magnesium-based materials in biomedical applications such as bone fixation, cardiovascular stents, and even stomach trauma repair. Different from other metals such as stainless steels and Ti alloys, the interface between the Mg-based implants and biological environment is dynamic. In order to improve the surface properties to allow better and more expeditious adaptation to the physiological surroundings, it is imperative to design and construct a surface to satisfy multiple clinical requirements such as mechanical strength, biocompatibility, and degradation rate. This paper reviews recent work pertaining to surface modification of Mg-based biomaterials with emphasis on surface coatings and ion implantation. The biodegradation behavior and related mechanism in the physiological environment after surface modification are also described. Surface modification is a promising means to elevate the performance of Mg-based biomaterials and expected to be extensively applied to surface design of biomaterials. [Copyright &y& Elsevier]

This paper proposes a new non-invasive, low-cost, and fully automated platform to quantitatively analyze dynamics of human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) at the single-cell level by holographic image-based tracking for cardiotoxicity screening. A dense Farneback optical flow method and holographic imaging informatics were combined to characterize the contractile motion of a single CM, which obviates the need for costly equipment to monitor a CM's mechanical beat activity. The reliability of the proposed platform was tested by single-cell motion characterization, synchronization analysis, motion speed measurement of fixed CMs versus live CMs, and noise sensitivity. The applicability of the motion characterization method was tested to determine the pharmacological effects of two cardiovascular drugs, isoprenaline (166 nM) and E−4031 (500 μM). The experiments were done using single CMs and multiple cells, and the results were compared to control conditions. Cardiomyocytes responded to isoprenaline by increasing the action potential (AP) speed and shortening the resting period, thus increasing the beat frequency. In the presence of E−4031, the AP speed was decreased, and the resting period was prolonged, thus decreasing the beat frequency. The findings offer insights into single hiPS-CMs' contractile motion and a deep understanding of their kinetics at the single-cell level for cardiotoxicity screening. • Single cardiomyocytes (CM) motion waveform was generated using holographic image-based tracking method. • Multiple dynamics parameters such as contraction/relaxation speed, contraction/relaxation/resting period were measured. • Verification was carried out with the motion speed measurement of live CMs versus fixed CMs and noise sensitivity analysis. • The beating synchronization between single CMs was tested using the motion waveform generated by the optical flow method. • The CM motion characteristics were compared in control versus drug-treated conditions, other properties were investigated. [ABSTRACT FROM AUTHOR]

Abstract: One of the major challenges facing the medicine today is developing new therapies that enhance human health. To help address these challenges the utilization of analytical technologies and high-throughput automated platforms has been employed; in order to perform more experiments in a shorter time frame with increased data quality. In the last decade various analytical strategies have been established to enhance separation speed and efficiency in liquid chromatography applications. Liquid chromatography is an increasingly important tool for monitoring drugs and their metabolites. Furthermore, liquid chromatography has played an important role in pharmacokinetics and metabolism studies at these drug development stages since its introduction. This paper provides an overview of current trends in fast chromatography for the analysis of cardiovascular drugs and their metabolites in clinical applications. Current trends in fast liquid chromatographic separations involve monolith technologies, fused-core columns, high-temperature liquid chromatography (HTLC) and ultra-high performance liquid chromatography (UHPLC). The high specificity in combination with high sensitivity makes it an attractive complementary method to traditional methodology used for routine applications. The practical aspects of, recent developments in and the present status of fast chromatography for the analysis of biological fluids for therapeutic drug and metabolite monitoring, pharmacokinetic studies and bioequivalence studies are presented. [Copyright &y& Elsevier]

Abstract: Cardiovascular studies investigating therapeutic intervention with clinical endpoints are costly due to the need for considerable duration and large number of patients, or both. Therefore, for evaluation of novel cardiovascular drug efficacy, surrogate endpoints are used. Cardiovascular imaging endpoints have proven their worth. Sometimes the relevance of imaging is questioned and other methods are suggested instead. There is also some confusion about the strengths of imaging endpoints. The aim of the present paper is to review ultrasound and radiology imaging techniques as surrogate endpoints in pharmacological trials. [Copyright &y& Elsevier]

Abstract: Structural identifiability should be considered when developing mathematical models. A globally or at least locally identifiable model has to be obtained in order to have some chance of obtaining unique parameter estimates when real data are available. An indicator of structural unidentifiability may be that some unknown parameter estimates are found to be not well determined from parameter estimation of a model. An example is discussed in this paper to illustrate the procedures involved when such situations arise. Problems with parameter estimation were observed for a PKPD model for an α 1 A /1 L -adrenoceptor partial agonist developed for the treatment of stress urinary incontinence The regulation of the side effects of the increased peripheral resistance, induced by the constriction of the blood vessels, was modelled by adapting a previous cardiovascular nonlinear PKPD model proposed by Franchetau and co-workers. Structural identifiability analysis confirmed that the model was unidentifiable. The model was then reparameterised (parameter list reduction) to obtain a globally identifiable model. Simulation studies confirm the superiority of the reduced parameterisation with respect to parameter estimation. The simulation study also confirms the models behave indistinguishably with respect to the input–output behaviour. The example demonstrates the importance of recognising an unidentifiable model and illustrates step by step identifiability analysis, reparameterisation and validation of reparameterised model against the original model. [Copyright &y& Elsevier]

Abstract: Pharmaceutical regulatory bodies require minimal presence of solvent in an active pharmaceutical ingredient (API) after crystallization. From a processing point of view bigger crystals with minimal agglomeration and uniform size distribution are preferred to avoid solvent inclusion and for improved downstream processing. The current work addresses these issues encountered during the production of the potential anti-arrhythmic cardiovascular drug, AZD7009. This paper demonstrates that by applying the automated direct nucleation control (ADNC) approach problems with agglomeration and solvent inclusion were resolved. This model free approach automatically induces temperature cycles in the system, with the number of cycles, temperature range and adaptive heating and cooling rates determined to maintain the number of particles in the system, as measured by a focused beam reflectance measurement (FBRM) probe, within a constant range during the crystallization. The ADNC approach was able to produce larger and more uniform crystals and also removed the residual solvent trapped between the crystals compared to the typical crystallization operation using linear cooling profile. The results illustrate the application of process analytical technologies, such as FBRM and ATR-UV–vis spectroscopy, for the design of optimal crystallization operating conditions for the production of pharmaceuticals, and demonstrate that the ADNC approach can be used for rapid crystallization development for APIs exhibiting problems with agglomeration and solvent inclusion. [Copyright &y& Elsevier]

Abstract: This paper reports an LC–MS/MS method with positive electrospray ionization for the screening of commonly prescribed cardiovascular drugs in human plasma, including compounds with antihypertensive (57), antidiabetic (12), hypolipemiant (5), anticoagulant (2) and platelet anti-aggregation (2) effects. Sample treatment consisted of a simple protein precipitation with MeOH/0.1M ZnSO4 (4:1, v/v) solution after the addition of internal standard, followed by evaporation and reconstitution. Analytes separation was performed on a Polar-RP column (150mm×2mm, 4μm) using a gradient elution of 15min. The MS system was operated in MRM mode, monitoring one quantitation and one confirmation transition for each analyte. The recovery of the protein precipitation step ranged from 50 to 70% for most of the compounds, while some were considerably affected by matrix effects. Since several analytes fulfilled the linearity, accuracy and precision values required by the ICH guidelines, the method proved to be suitable for their quantitative analysis. The limits of quantitation varied from 0.38 to 9.1μg/L and the limits of detection from 0.12 to 5.34μg/L. The method showed to be suitable for the detection of plasma samples of patients under cardiovascular treatment with the studied drugs, and for 55 compounds reliable quantitative results could be obtained. [ABSTRACT FROM AUTHOR]

Abstract: This American Society of Hypertension position paper focuses on the importance of out-of-office blood pressure (BP) measurement for the clinical management of patients with hypertension and its complications. Studies have supported direct and independent associations of cardiovascular risk with ambulatory BP and inverse associations with the degree of BP reduction from day to night. Self-monitoring of the BP (or home BP monitoring) also has advantages in evaluating patients with hypertension, especially those already on drug treatment, but less is known about its relation to future cardiovascular events. Data derived from ambulatory BP monitoring (ABPM) allow the identification of high-risk patients, independent from the BP obtained in the clinic or office setting. While neither ABPM nor self-BP monitoring are mandatory for the routine diagnosis of hypertension, these modalities can enhance the ability for identification of white-coat and masked hypertension and evaluate the extent of BP control in patients on drug therapy. [Copyright &y& Elsevier]

Thrombosis is the most important underlying mechanism of coronary artery disease and embolic stroke. Hence, antithrombotic therapy is widely used in these scenarios. However, not all patients achieve the same degree of benefit from antithrombotic agents, and a considerable number of treated patients will continue to experience a new thrombotic event. Such lack of clinical benefit may be related to a wide variability of responses to antithrombotic treatment among individuals (i.e., interindividual heterogeneity). Several factors have been identified in this interindividual heterogeneity in response to antithrombotic treatment. Pharmacogenetics has emerged as a field that identifies specific gene variants able to explain the variability in patient response to a given drug. Polymorphisms affecting the disposition, metabolism, transporters, or targets of a drug all can be implicated in the modification of an individual''s antithrombotic drug response and therefore the safety and efficacy of the aforementioned drug. The present paper reviews the modulating role of different polymorphisms on individuals'' responses to antithrombotic drugs commonly used in clinical practice. [Copyright &y& Elsevier]

Abstract: This paper describes a rapid and sensitive analytical method for the quantitation of iptakalim, a novel antihypertensive drug, in human plasma. The method is based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) using sildenafil as internal standard. Sample preparation involved liquid–liquid extraction with dichloromethane–diethyl ether (2:3, v/v) in a basic environment. Chromatography was carried out on an amino column with a mobile phase consisting of acetonitrile–water (55:45, v/v, water containing 0.5% formic acid). Detection employed electrospray ionization (ESI) tandem mass spectrometry in the multiple-reaction-monitoring (MRM) mode. The assay was linear in the concentration range of 0.5–100ng/ml with a lower limit of quantitation (LLOQ) of 0.5ng/ml. Intra- and inter-day precision (R.S.D.) were <4.5% and <12.0%, respectively and the accuracy (R.E.) was in the range ±5%. The method was successfully applied to a single oral dose pharmacokinetic study in human volunteers. [Copyright &y& Elsevier]

Abstract: Outcome after aSAH depends on several factors, including the severity of the initial event, perioperative medical management, surgical variables, and the incidence of complications. Cerebral vasospasm (CV) is ure to consistently respond to treatment, emphasizing the need for further research into the underlying mechanisms of SAH-induced cerebrovascular dysfunction. To this end, our paper reviews the relevant literature on the main therapies employed for CV after aSAH and discusses possible avenues for future investigations. Current management of this condition consists of maximal medical therapy, including triple H regimen and oral administration of calcium antagonists, followed by endovascular balloon angioplasty and/or injection of vasodilatory agents for refractory cases. As the precise pathophysiology of CV is further elucidated, the development of promising investigational therapies will follow. [Copyright &y& Elsevier]

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions. Clopidogrel, in combination with aspirin, is currently the antiplatelet treatment of choice for prevention of stent thrombosis, and clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major cardiovascular events. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. Numerous in vitro studies have shown that individual responsiveness to clopidogrel is not uniform in all patients and is subject to inter- and intraindividual variability. Notably, there is a growing degree of evidence that recurrence of ischemic complications may be attributed to poor response to clopidogrel. The mechanisms leading to poor clopidogrel effects are not fully elucidated and are likely multifactorial. Although the gold standard definition to assess antiplatelet drug response has not been fully established, there is sufficient evidence to support that persistence of enhanced platelet reactivity despite the use of clopidogrel is a clinically relevant entity. This paper reviews the impact of individual response variability to clopidogrel on clinical outcomes and current and future directions for its management. [Copyright &y& Elsevier]

Abstract: In this paper, a simple, rapid and sensitive flow-injection chemiluminescence method has been developed for the determination of metoprolol tartrate, which acts as a kind of sensitizer in the chemiluminescence emission from the redox of SO3 2− with Ce(IV) in acidic medium. Under the optimized conditions, the proposed method allows the measurement of metoprolol tartrate over the range of 1.5×10−8 to 7.3×10−6 mol/L with a detection limit of 4.7×10−9 mol/L (3σ), and the relative standard deviation for 7.3×10−7 mol/L metoprolol tartrate (n =11) is 2.20%. The utility of this method was demonstrated by determining metoprolol tartrate in tablets and human urine sample. [Copyright &y& Elsevier]

Abstract: The goal of this symposium paper was to identify and quantify developmental plasticity in the onset of cardiovascular responses in the zebrafish. Developmental plasticity was induced by altering the developmental environment in one of three ways: (1) by developing zebrafish in a constant current of 5 body lengths per second, (2) by developing zebrafish at a colder temperature (20 °C), and (3) by developing zebrafish in severe hypoxia (DO=0.8 mg/L). Early morphological development was significantly affected by each of the treatment environments with hypoxia slowing development the most and producing the highest variation in measurements. Development in constant water current did not significantly affect the timing onset of cardiovascular responses to the pharmacological agents applied. Development at 20 °C significantly delayed the onset of all cardiovascular responses measured by 2–3 days. Development in hypoxia, however, not only delayed onset of all cardiovascular responses, but also shifted the onset relative to the developmental program. Hypoxia clearly has a profound affect on the onset of cardiovascular regulation and it will take many more studies to elucidate the mechanisms by which hypoxia is having its effect. Furthermore, long term studies are also needed to assess whether the plasticity measured in this study is adaptive in the evolutionary sense. [Copyright &y& Elsevier]

Abstract: The main purpose of this study was to investigate whether dipsogenic stimuli influences the sodium appetite of rats with ibotenic acid lesion of the dorsal raphe nucleus (IBO-DRN). Compared to control, rats microinjected with phosphate buffer (PB-DRN), the ingestion of 0.3M NaCl was enhanced in IBO-DRN at 21 and 35 days after DRN lesion under a protocol of fluids and food deprivation. Despite of similar dipsogenic response observed both in IBO-DRN and PB-DRN treated with isoproterenol (ISO, 300μg/kg, sc), the 0.3M NaCl intake was again significantly enhanced in IBO-DRN at 21 and 35 days post-lesion. Finally, treatment with polyethylene glycol (PEG, MW=20,000, 20%, w/v, 16.7ml/kg, sc) induced higher dipsogenic response in IBO-DRN than PB-DRN at 21 day after lesion. In addition, IBO-DRN also expressed higher sodium appetite than PB-DRN, concomitantly with a drinking response. These results suggest that ibotenic lesion of DRN promote an increase of the brain angiotensinergic response, possibly settled within the subfornical organ, through paradigms which increase circulating ANG II levels. The current paper supports the hypothesis that the ibotenic lesion of DRN suppresses a serotonergic component implicated on the modulation of the sodium appetite and, therefore, furthering homeostatic restoration of extracellular fluid volume. [Copyright &y& Elsevier]

This paper explores the influence of initial molecular weight and porosity on the release of the drug, theophylline, from polyglycolide (PGA). PGA was made by a variety of processes to vary the molecular weight and was blended with NaCl with different crystal sizes and in different proportions to vary the pore size and volume. Overall, results showed that decreasing the molecular weight and increasing the pore size and volume increased the rate of drug release. The exact variation of these trends agreed well with the previously established four-stage degradation mechanism for PGA, but was more complex than a simple linear behaviour. Because both the molecular weight and the porosity of PGA have a substantial influence on the polymer degradation, and can be varied in a controlled manner, these parameters can play an important role in developing PGA as a controlled drug delivery material with tailored drug release. [Copyright &y& Elsevier]

Introduction: Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. This paper describes a new strategy for treating conscious labrador dogs with drugs by inhalation using a specially designed mask and a novel inhaler device. Methods: Labrador dogs (male or female) were used that had transducers implanted for the measurement of left ventricular and descending aortic blood pressures and an ECG for use together with a telemetry system. Administration by inhalation was achieved using a novel delivery device. The Respimat device is a propellant-free inhaler to deliver aerosols from solutions. The new system was evaluated using Formoterol with four dogs using a 4×4 Latin square design. Three doses of Formoterol (0.6, 1.2, and 2.4 μg/kg, dissolved in 60% ethanol) were administered by inhalation together with a vehicle (60% ethanol) treatment by applying three inhalations, each consisting of 10 μl solution. Results: Formoterol increased HR, QRS-interval, QT-interval, and LVPdP/dtmax and dose-dependently decreased systolic and diastolic BP. This effect lasted up to 14 h. Discussion: Drug administration by inhalation in the conscious labrador dog using the Respimat is a useful new model for safety pharmacology studies of new drug candidates that are intended to be given by inhalation in the clinic. [Copyright &y& Elsevier]

Because most of myocardial perfusion takes place during diastole, reducing the heart rate is likely to have anti-ischaemic effects. The present paper reviews the role of heart rate in relation to coronary artery disease outcome, as well as ways to reduce heart rate in the clinical setting. Nonpharmacological intervention, and particularly exercise training, has a definite effect on both heart rate reduction and the prevention of myocardial ischaemia. The protective role of β-blockers after acute myocardial infarction is amply documented; their anti-ischaemic efficacy appears to be attributable to their effect on heart rate, but also to their role in cardiac inotropism. Recently, the If (funny) current inhibitor ivabradine, which has a potent heart rate reduction effect without any haemodynamic effect has demonstrated anti-ischaemic efficacy in a randomised trial versus placebo, as well as in trials where it showed an effect similar to that of the conventional anti-ischaemic agents amlodipine and atenolol. In addition, such an agent, which does not influence myocardial contractility, might be particularly valuable in the setting of myocardial stunning or acute left ventricular failure at the acute stage of myocardial infarction. However, only future studies will determine whether isolated heart rate reduction will have the same protective efficacy as that of β-blocking agents in secondary prevention after myocardial infarction. Keywords: heart rate, myocardial ischaemia, β-blockers, If current, ivabradine Résumé La perfusion myocardique a lieu principalement pendant la période diastolique. Dans cette revue, les liens entre fréquence cardiaque et maladie coronaire sont rappelés et les traitements utilisables pour abaisser la fréquence cardiaque en clinique humaine sont passés en revue. Parmi ceux-ci, certains sont de nature non médicamenteuse, comme l’entraînement à l’effort, et ont démontré un effet à la fois sur le ralentissement de la fréquence cardiaque, tant au repos qu’à l’effort, et sur l’ischémie myocardique. Parmi les traitements médicamenteux anti-ischémiques, les β-bloquants représentent le chef de file incontesté. Outre leur impact sur la fréquence cardiaque, ils ont une action de prévention secondaire établie dans le post-infarctus. Leur action anti-ischémique est cependant vraisemblablement à la fois la résultante de la bradycardie qu’ils induisent, mais aussi de la baisse de contractilité. Les résultats récemment obtenus avec l’ivabradine, inhibiteur sélectif des canaux If (dits de pacemaker), sont à cet égard particulièrement intéressants car ils démontrent qu’un médicament agissant uniquement en réduisant la fréquence cardiaque et n’ayant aucun effet hémodynamique a une action anti-ischémique vérifiée contre placebo chez le coronarien stable, et comparable à l’effet anti-ischémique de l’amlodipine ou de l’aténolol. Par ailleurs, un tel médicament pourrait avoir un intérêt tout particulier dans les situations aiguës telles que la sidération myocardique ou les décompensations ventriculaires gauches aiguës au stade aigu de l’infarctus. Il faudra cependant attendre avant de savoir si la simple réduction de fréquence cardiaque permet d’obtenir la même efficacité de prévention secondaire que les β-bloquants. Mots clés : fréquence cardiaque, ischémie myocardique, β-bloquants, courant If, ivabradine [ABSTRACT FROM AUTHOR]

Indication of cardiovascular risk is based on laboratory analysis of cardiovascular markers in blood. Assessment of diagnostic performance of traditionally used as well as new cardiovascular markers is the main goal of this paper. Performance of studied laboratory tests was evaluated by using the area below the corresponding receiver operating characteristic (ROC) curve. Application of an objective procedure for the determination of critical values of laboratory tests was based on maximum of efficiency. It was demonstrated that the patient''s diagnosis can be verified or predicted not only by using the results of a chosen individual laboratory test but also by a multivariate statistical approach, which jointly utilizes all performed tests in the form of their optimal linear combination. An effective combination of original variables (laboratory tests) is provided either by principal component or discriminant function or logit—in case of logistic regression. [Copyright &y& Elsevier]

This paper describes the design, syntheses, and biological evaluations of novel ATP-sensitive potassium channel (KATP) openers, benzopyranyl indoline and indole derivatives. Among those, two enantiomers of indoline-2-carboxylic ethyl esters (14, 18) showed the best cardioprotective activities both in vitro and in vivo, while their vasorelaxation potencies were very low (concentration for 50% inhibition of vasorelaxation >30 μM). The cardioprotective effect of 14 was completely reversed by 5-hydroxydecanoate, a selective mitochondrial KATP blocker, indicating its provable protective mechanism through the mitochondrial KATP opening. In addition, we performed conformational analyses using 2D-NMR, X-ray crystallography and molecular modeling to study the structure–activity relationships in this series of compounds. [Copyright &y& Elsevier]

Targeted drug delivery is a promising technique to direct the drug to the specific diseased region. Nanoparticles have provided an attractive approach for this purpose. In practice, the major focus of targeted delivery has been on targeting cell receptors. However, the complex fluid mechanics in diseased biomedical flows questions if a sufficient number of nanoparticles can reach the desired region. In this paper, we propose that hidden topological structures in cardiovascular flows identified with Lagrangian coherent structures (LCS) control drug transport and provide valuable information for optimizing targeted drug delivery efficiency. We couple image-based computational fluid dynamics (CFD) with continuum transport models to study nanoparticle transport in coronary artery disease. We simulate nanoparticle transport as well as the recently proposed shear targeted drug delivery system that couples micro-carriers with nanoparticle drugs. The role of the LCS formed near the stenosed artery in controlling drug transport is discussed. Our results motivate the design of smart micro-needles guided by flow topology, which could achieve optimal drug delivery efficiency. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases constitute a number of conditions which are the leading cause of death globally. To combat these diseases and improve the quality and duration of life, several cardiac implants have been developed, including stents, vascular grafts and valvular prostheses. The implantation of these vascular prosthesis has associated risks such as infection or blood clot formation. In order to overcome these limitations medicated vascular prosthesis have been previously used. The present paper describes a 3D printing method to develop medicated vascular prosthesis using fused deposition modelling (FDM) technology. For this purpose, rifampicin (RIF) was selected as a model molecule as it can be used to prevent vascular graft prosthesis infection. Thermoplastic polyurethane (TPU) and RIF were combined using hot melt extrusion (HME) to obtain filaments containing RIF concentrations ranging between 0 and 1% (w/w). These materials are capable of providing RIF release for periods ranging between 30 and 80 days. Moreover, TPU-based materials containing RIF were capable of inhibiting the growth of Staphylococcus aureus. This behaviour was observed even for TPU-based materials containing RIF concentrations of 0.1% (w/w). TPU containing 1% (w/w) of RIF showed antimicrobial properties even after 30 days of RIF release. Alternatively, these methods were used to prepare dipyridamole containing TPU filaments. Finally, using a dual extrusion 3D printer vascular grafts containing both drugs were prepared. [ABSTRACT FROM AUTHOR]

Silybum marianum (L.) Gaertn. or Milk thistle is a medicinal plant native to Northern Africa, Southern Europe, Southern Russia and Anatolia. It also grows in South Australia, North and South America. In traditional knowledge, people have used S. marianum for liver disorders such as hepatitis, liver cirrhosis and gallbladder diseases. The main active compound of the plant seeds is silymarin, which is the most commonly used herbal supplement in the United States for liver problems. Nowadays, S. marianum products are available as capsules, powders, and extracts. The aim of our study is to draw a more comprehensive overview of the traditional heritage, pharmacological benefits and chemical fingerprint of S. marianum extracts and metabolites; as well as their metabolism and bioavailability. An extensive literature search has been conducted using relavant keywords and papers with rationale methodology and robust data were selected and discussed. Studies involving S. marianum or its main active ingredients with regards to hepatoprotective, antidiabetic, cardiovascular protection, anticancer and antimicrobial activities as well as the clinical trials performed on the plant, were discussed here. S. marianum was subjected to thousands of ethnopharmacological, experimental and clinical investigations. Although, the plant is available for use as a dietary supplement, the FDA did not yet approve its use for cancer therapy. Nowadays, clinical investigations are in progress where a global evidence of its real efficiency is needed. S. marianum is a worldwide used herb with unlimited number of investigations focusing on its benefits and properties, however, little is known about its clinical efficiency. Moreover, few studies have discussed its metabolism, pharmacokinetics and bioavailability, so that all future studies on S. marianum should focus on such areas. Image 1 [ABSTRACT FROM AUTHOR]

The fruit of Tetradium ruticarpum (FTR) known as Tetradii fructus or Evodiae fructus (Wu-Zhu-Yu in Chinese) is a versatile herbal medicine which has been prescribed in Chinese herbal formulas and recognized in Japanese Kampo. FTR has been clinically used to treat various diseases such as headache, vomit, diarrhea, abdominal pain, dysmenorrhea and pelvic inflammation for thousands of years. The present paper aimed to provide comprehensive information on the ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics, drug interaction and toxicology of FTR in order to build up a foundation on the mechanism of ethnopharmacological uses as well as to explore the trends and perspectives for further studies. This review collected the literatures published prior to July 2020 on the phytochemistry, pharmacology, pharmacokinetics and toxicity of FTR. All relevant information on FTR was gathered from worldwide accepted scientific search engines and databases, including Web of Science, PubMed, Elsevier, ACS, ResearchGate, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI). Information was also obtained from local books, PhD. and MSc. Dissertations as well as from Pharmacopeias. FTR has been used as an herbal medicine for centuries in East Asia. A total of 165 chemical compounds have been isolated so far and the main chemical compounds of FTR include alkaloids, terpenoids, flavonoids, phenolic acids, steroids, and phenylpropanoids. Crude extracts, processed products (medicinal slices) and pure components of FTR exhibit a wide range of pharmacological activities such as antitumor, anti-inflammatory, antibacterial, anti-obesity, antioxidant, insecticide, regulating central nervous system (CNS) homeostasis, cardiovascular protection. Furthermore, bioactive components isolated from FTR can induce drug interaction and hepatic injury. Therapeutic potential of FTR has been demonstrated with the pharmacological effects on cancer, inflammation, cardiovascular diseases, CNS, bacterial infection and obesity. Pharmacological and pharmacokinetic studies of FTR mostly focus on its main active alkaloids. Further in-depth studies on combined medication and processing approaches mechanisms, pharmacological and toxic effects not limited to the alkaloids, and toxic components of FTR should be designed. Image 1 [ABSTRACT FROM AUTHOR]

Summary: A recent analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration revealed that any commonly-used blood pressure (BP)-lowering regimen reduced the risk of total major cardiovascular events, and larger reductions in BP produced larger reductions in the risk. These observations suggest that most of the differences among treatment regimens in their effects on cardiovascular outcomes could be explained by the differences in achieved BP level. However, it may also be true that some treatment regimen is superior or inferior to others with regard to the risk reduction of cardiovascular events. Indeed, the data from dihydropyridine-based calcium antagonist (DHP) trails are consistent in that they could not protect against new-onset heart failure or progression of renal disease in patients with left-ventricular systolic dysfunction or overt proteinuria, respectively. However, a multicenter, randomized, placebo-controlled, double-blind ACTION trial, which compared the effect of long-acting nifedipine or placebo on mortality and cardiovascular morbidity in patients with stable angina, revealed that nifedipine reduced the risk for new-onset overt heart failure by 29%. Further, an open-label, randomized prospective J-MIND trial, which compared the effect of long-acting nifedipine or enalapril, an angiotensin-converting enzyme inhibitor on onset and progression of nephropathy in hypertensive patients with type 2 diabetes, showed that long-acting nifedipine had an equipotent reoprotective effect on diabetic nephropathy. In this paper, we would like to propose our hypothesis that nifedipine may be unique and superior in its effects on heart failure and proteinuria compared with various DHPs. For ensuring our hypothesis, the following clinical issues would be addressed. Does nifedipine treatment alone decrease the progression of renal disease with overt proteinuria? If these answers are yes, are these beneficial effects of nifedipine superior to that of other DHPs with equihypotensive properties? Does nifedipine treatment also reduce oxidative stress markers? Are these unique effects of nifedipine correlated with its anti-oxidative properties? These prospective studies will provide further valuable information whether nifedipine may be a preferred DHP to achieve BP goals in hypertensive patients with systolic dysfunction or overt proteinuria. [Copyright &y& Elsevier]

[Display omitted] • These hybrid hydrogels are synthesized via a "one-step" method without a toxic crosslinking agent. • These hybrid hydrogels have notable mechanical properties due to the interactions between multiple covalent bonds. • These hybrid hydrogels achieved excellent self-healing performance. • These hybrid hydrogels have pH responsiveness, good biocompatibility, high drug loading capacity, and sustained release behavior. Therapeutic drugs for human cardiovascular disease require specific carriers. Hydrogels have a porous structure, plasticity, and biocompatibility, and are ideal carriers for cardiovascular drugs. Moreover, for their intended functions, hydrogels also need to have high mechanical properties, self-healing properties, good pH-responsive performance, and other properties. Here, based on the interactions between multiple dynamic covalent bonds, we effectively synthesized hybrid hydrogels of carboxymethyl chitosan (C-CS), aldehyde-modified hyaluronic acid (OHA), polyvinyl alcohol (PVA), and boric acid (BA). The multiple covalent bonds reinforce each other, endowing the hydrogels with high mechanical properties, self-healing properties and pH responsiveness. In addition, the whole preparation process does not require crosslinking agents and the operation process is simple. The results show that the 5% PVA + C-CS + OHA + BA hydrogel has high mechanical properties (tensile stress 40.07 KPa; compressive stress 553.38 KPa), good self-healing performance (up to 92%) and excellent pH responsive performance. In addition, the hydrogel has high drug-loading capacity (117.54 mg/g) and sustained-release performance. In conclusion, this hybrid hydrogel can potentially be used as a drug carrier for clinical treatment. [ABSTRACT FROM AUTHOR]