A intervenção de enfermagem de reabilitação na pessoa submetida a implantação de dispositivos cardíacos / A rehabilitation nursing intervention in a person undergoing cardiac device implantation

As doenças cardiovasculares representam a primeira causa de morte no mundo, sendo a utilização de dispositivos implantáveis uma intervenção que tem permitido o aumento da sobrevida e da qualidade de vida. No entanto, quanto maior o défice de conhecimento, maior será a dificuldade no retorno às atividades de vida diárias, o que condiciona negativamente a qualidade de vida. Para isso, é fundamental a intervenção de um enfermeiro especialista em enfermagem de reabilitação na componente educacional de um programa de reabilitação. Objetivo ­ Obter ganhos em conhecimento resultantes de um programa educacional implementado por enfermeira de reabilitação em utentes submetidos a implantação de dispositivos cardíacos; Avaliar se os ganhos em conhecimento têm impacto na capacidade de autogestão do autocuidado na doença cardíaca. Métodos ­ Um estudo exploratório que compara os conhecimentos, antes e após uma intervenção de enfermagem de reabilitação na pessoa submetida a implantação de dispositivos cardíacos. Para isso, foi elaborado um programa de enfermagem de reabilitação estruturado tendo por base a componente educativa. De modo a verificar a eficácia do mesmo foi aplicado um questionário pré e pós intervenção. Além disso, foi utilizada a Escala Europeia de Autocuidado na Insuficiência Cardíaca, de forma a avaliar se os ganhos em conhecimento têm impacto na capacidade de autogestão. Resultados ­ Foram incluídos 18 utentes, maioritariamente do sexo masculino (61%) e que apresentavam uma média de idade 73,17±9,02. A maioria da amostra não necessitou de internamento (61%). Antes da intervenção, os doentes apresentaram respostas corretas em 68% das questões realizadas, enquanto no final em 98%. Verificou-se, ainda, que 89% da amostra apresenta conhecimentos sobre o autocuidado na insuficiência cardíaca, sendo o autocuidado moderadamente satisfatório. Conclusões ­ A reabilitação é crucial para a recuperação dos portadores de dispositivos cardíacos, uma vez que um programa de enfermagem de reabilitação na componente educativa conduz a ganhos de conhecimento e à melhoria do autocuidado terapêutico. No entanto, considera-se necessário a realização de estudos futuros semelhantes com amostras de maiores dimensões de forma a ser analisadas outras variáveis significativas.

Cardiovascular diseases represent the first cause of death in the world, and the use of implantable devices is an intervention that has allowed an increase in survival and quality of life. However, the greater the lack of knowledge, the greater the difficulty in returning to daily life activities, which negatively affects the quality of life. Thus, the intervention of a nurse specializing in rehabilitation nursing in the educational component of a rehabilitation program is essential. Objective ­ Obtain gains in knowledge resulting from an educational program implemented by a rehabilitation nurse in users undergoing implantation of cardiac devices; To assess whether gains in knowledge have an impact on self-management capacity for self-care in heart disease. Methods ­ An exploratory study that compares the knowledge, before and after a rehabilitation nursing intervention in the person submitted to the implantation of cardiac devices. For this, a structured rehabilitation nursing program was developed based on an educational component. In order to verify its effectiveness, a pre and post intervention questionnaire was applied. In addition, the European Heart Failure Self-Care Scale was used to assess whether gains in knowledge have an impact on self-management capacity. Results ­ Eighteen users were included, mostly male (61%) with an average age of 73.17±9.02. Most of the sample did not require hospitalization (61%). Before the intervention, the patients presented correct answers in 68% of the questions asked, while at the end in 98%. It was also found that 89% of the sample had knowledge about self-care in cardiac insufficiency, with self-care being moderately satisfactory. Conclusions ­ Rehabilitation is crucial for the recovery of patients with cardiac devices, since a rehabilitation nursing program with an educational component leads to gains in knowledge and improvement in therapeutic self-care. However, it is considered necessary to carry out similar future studies with larger samples in order to analyze other significant variables.

Mixed Edge Activators in Ibuprofen-Loaded Transfersomes: An Innovative Optimization Strategy Using Box-Behnken Factorial Design.

Transfersomes have been highlighted as an interesting nanotechnology-based approach to facilitate the skin delivery of bioactive compounds. Nevertheless, the properties of these nanosystems still need to be improved to enable knowledge transfer to the pharmaceutical industry and the development of more efficacious topical medicines. Quality-by-design strategies, such as Box-Behnken factorial design (BBD), are in line with the current need to use sustainable processes to develop new formulations. Thus, this work aimed at optimizing the physicochemical properties of transfersomes for cutaneous applications, by applying a BBD strategy to incorporate mixed edge activators with opposing hydrophilic-lipophilic balance (HLB). Tween® 80 and Span® 80 were used as edge activators and ibuprofen sodium salt (IBU) was selected as the model drug. After the initial screening of the IBU solubility in aqueous media, a BBD protocol was implemented, and the optimized formulation displayed appropriate physicochemical properties for skin delivery. By comparing the optimized transfersomes to equivalent liposomes, the incorporation of mixed edge activators was found to be beneficial to upgrade the storage stability of the nanosystems. Furthermore, their cytocompatibility was shown by cell viability studies using 3D HaCaT cultures. Altogether, the data herein bode well for future advances in the use of mixed edge activators in transfersomes for the management of skin conditions.

Rational design of magnetoliposomes for enhanced interaction with bacterial membrane models.

There is a growing need for alternatives to target and treat bacterial infection. Thus, the present work aims to develop and optimize the production of PEGylated magnetoliposomes (MLPs@PEG), by encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) within fusogenic liposomes. A Box-Behnken design was applied to modulate size distribution variables, using lipid concentration, SPIONs amount and ultrasonication time as independent variables. As a result of the optimization, it was possible to obtain MLPs@PEG with a mean size of 182 nm, with polydispersity index (PDI) of 0.19, and SPIONs encapsulation efficiency (%EE) around 76%. Cytocompatibility assays showed that no toxicity was observed in fibroblasts, for iron concentrations up to 400µg/ml. Also, for safe lipid and iron concentrations, no hemolytic effect was detected. The fusogenicity of the nanosystems was first evaluated through lipid mixing assays, based on Förster resonance energy transfer (FRET), using liposomal membrane models, mimicking bacterial cytoplasmic membrane and eukaryotic plasma membrane. It was shown that the hybrid nanosystems preferentially interact with the bacterial membrane model. Confocal microscopy and fluorescence lifetime measurements, using giant unilamellar vesicles (GUVs), validated these results. Overall, the developed hybrid nanosystem may represent an efficient drug delivery system with improved targetability for bacterial membrane.

The Golgi Apparatus as an Anticancer Therapeutic Target.

Although the discovery of the Golgi apparatus (GA) was made over 125 years ago, only a very limited number of therapeutic approaches have been developed to target this complex organelle. The GA serves as a modification and transport center for proteins and lipids and also has more recently emerged as an important store for some ions. The dysregulation of GA functions is implicated in many cellular processes associated with cancer and some GA proteins are indeed described as cancer biomarkers. This dysregulation can affect protein modification, localization, and secretion, but also cellular metabolism, redox status, extracellular pH, and the extracellular matrix structure. Consequently, it can directly or indirectly affect cancer progression. For these reasons, the GA is an appealing anticancer pharmacological target. Despite this, no anticancer drug specifically targeting the GA has reached the clinic and few have entered the clinical trial stage. Advances in nanodelivery approaches may help change this scenario by specifically targeting tumor cells and/or the GA through passive, active, or physical strategies. This article aims to examine the currently available anticancer GA-targeted drugs and the nanodelivery strategies explored for their administration. The potential benefits and challenges of modulating and specifically targeting the GA function in the context of cancer therapy are discussed.

Delivery Systems Based on Innovative Nanomaterials.

There has been an increasing interest in using nanomaterials to develop innovative delivery systems [...].

Long-term SARS-CoV-2-specific and cross-reactive cellular immune responses correlate with humoral responses, disease severity, and symptomatology.

BACKGROUND: Cellular immune memory responses post coronavirus disease 2019 (COVID-19) have been difficult to assess due to the risks of contaminating the immune response readout with memory responses stemming from previous exposure to endemic coronaviruses. The work herein presents a large-scale long-term follow-up study investigating the correlation between symptomology and cellular immune responses four to five months post seroconversion based on a unique severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific peptide pool that contains no overlapping peptides with endemic human coronaviruses. METHODS: Peptide stimulated memory T cell responses were assessed with dual interferon-gamma (IFNγ) and interleukin (IL)-2 Fluorospot. Serological analyses were performed using a multiplex antigen bead array. RESULTS: Our work demonstrates that long-term SARS-CoV-2-specific memory T cell responses feature dual IFNγ and IL-2 responses, whereas cross-reactive memory T cell responses primarily generate IFNγ in response to SARS-CoV-2 peptide stimulation. T cell responses correlated to long-term humoral immune responses. Disease severity as well as specific COVID-19 symptoms correlated with the magnitude of the SARS-CoV-2-specific memory T cell response four to five months post seroconversion. CONCLUSION: Using a large cohort and a SARS-CoV-2-specific peptide pool we were able to substantiate that initial disease severity and symptoms correlate with the magnitude of the SARS-CoV-2-specific memory T cell responses.

Randomized feasibility trial of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program.

BACKGROUND: The Scleroderma Patient-centered Intervention Network (SPIN) developed an online self-management program (SPIN-SELF) designed to improve disease-management self-efficacy in people with systemic sclerosis (SSc, or scleroderma). The aim of this study was to evaluate feasibility aspects for conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF Program. METHODS: This feasibility trial was embedded in the SPIN Cohort and utilized the cohort multiple RCT design. In this design, at the time of cohort enrollment, cohort participants consent to be assessed for trial eligibility and randomized prior to being informed about the trial. Participants in the intervention arm are informed and provide consent, but not the control group. Forty English-speaking SPIN Cohort participants from Canada, the USA, or the UK with low disease-management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale [SEMCD] score ≤ 7) who were interested in using an online self-management program were randomized (3:2 ratio) to be offered the SPIN-SELF Program or usual care for 3 months. Program usage was examined via automated usage logs. User satisfaction was assessed with semi-structured interviews. Trial personnel time requirements and implementation challenges were logged. RESULTS: Of 40 SPIN Cohort participants randomized, 26 were allocated to SPIN-SELF and 14 to usual care. Automated eligibility and randomization procedures via the SPIN Cohort platform functioned properly, except that two participants with SEMCD scores > 7 (scores of 7.2 and 7.3, respectively) were included, which was caused by a system programming error that rounded SEMCD scores. Of 26 SPIN Cohort participants offered the SPIN-SELF Program, only 9 (35%) consented to use the program. Usage logs showed that use of the SPIN-SELF Program was low: 2 of 9 users (22%) logged into the program only once (median = 3), and 4 of 9 (44%) accessed none or only 1 of the 9 program's modules (median = 2). CONCLUSIONS: The results of this study will lead to substantial changes for the planned full-scale RCT of the SPIN-SELF Program that we will incorporate into a planned additional feasibility trial with progression to a full-scale trial. These changes include transitioning to a conventional RCT design with pre-randomization consent and supplementing the online self-help with peer-facilitated videoconference-based groups to enhance engagement. TRIAL REGISTRATION: clinicaltrials.gov , NCT03914781 . Registered 16 April 2019.

Nanodelivery Strategies for Skin Diseases with Barrier Impairment: Focusing on Ceramides and Glucocorticoids.

The human epidermis has a characteristic lipidic composition in the stratum corneum, where ceramides play a crucial role in the skin barrier homeostasis and in water-holding capacity. Several skin diseases, such as atopic dermatitis and psoriasis, exhibit a dysfunction in the lipid barrier with altered ceramide levels and increased loss of transepidermal water. Glucocorticoids are normally employed in the therapeutical management of these pathologies. However, they have shown a poor safety profile and reduced treatment efficiency. The main objective of this review is to, within the framework of the limitations of the currently available therapeutical approaches, establish the relevance of nanocarriers as a safe and efficient delivery strategy for glucocorticoids and ceramides in the topical treatment of skin disorders with barrier impairment.

The Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program: protocol for a two-arm parallel partially nested randomized controlled feasibility trial with progression to full-scale trial.

BACKGROUND: Systemic sclerosis (scleroderma; SSc) is a rare autoimmune connective tissue disease. We completed an initial feasibility trial of an online self-administered version of the Scleroderma Patient-centered Intervention Network Self-Management (SPIN-SELF) Program using the cohort multiple randomized controlled trial (RCT) design. Due to low intervention offer uptake, we will conduct a new feasibility trial with progression to full-scale trial, using a two-arm parallel, partially nested RCT design. The SPIN-SELF Program has also been revised to include facilitator-led videoconference group sessions in addition to online material. We will test the group-based intervention delivery format, then evaluate the effect of the SPIN-SELF Program on disease management self-efficacy (primary) and patient activation, social appearance anxiety, and functional health outcomes (secondary). METHODS: This study is a feasibility trial with progression to full-scale RCT, pending meeting pre-defined criteria, of the SPIN-SELF Program. Participants will be recruited from the ongoing SPIN Cohort ( http://www.spinsclero.com/en/cohort ) and via social media and partner patient organizations. Eligible participants must have SSc and low to moderate disease management self-efficacy (Self-Efficacy for Managing Chronic Disease (SEMCD) Scale score ≤ 7.0). Participants will be randomized (1:1 allocation) to the group-based SPIN-SELF Program or usual care for 3 months. The primary outcome in the full-scale trial will be disease management self-efficacy based on SEMCD Scale scores at 3 months post-randomization. Secondary outcomes include SEMCD scores 6 months post-randomization plus patient activation, social appearance anxiety, and functional health outcomes at 3 and 6 months post-randomization. We will include 40 participants to assess feasibility. At the end of the feasibility portion, stoppage criteria will be used to determine if the trial procedures or SPIN-SELF Program need important modifications, thereby requiring a re-set for the full-scale trial. Otherwise, the full-scale RCT will proceed, and outcome data from the feasibility portion will be utilized in the full-scale trial. In the full-scale RCT, 524 participants will be recruited. DISCUSSION: The SPIN-SELF Program may improve disease management self-efficacy, patient activation, social appearance anxiety, and functional health outcomes in people with SSc. SPIN works with partner patient organizations around the world to disseminate its programs free-of-charge. TRIAL REGISTRATION: ClinicalTrials.gov NCT04246528 . Registered on 27 January 2020.

Characterization of Kefir Produced in Household Conditions: Physicochemical and Nutritional Profile, and Storage Stability.

Kefir, a traditional fermented food, has numerous health benefits due to its unique chemical composition, which is reflected in its excellent nutritional value. Physicochemical and microbial composition of kefir obtained from fermented milk are influenced by the type of the milk, grain to milk ratio, time and temperature of fermentation, and storage conditions. It is crucial that kefir characteristics are maintained during storage since continuous metabolic activities of residual kefir microbiota may occur. This study aimed to examine the nutritional profile of kefir produced in traditional in use conditions by fermentation of ultra-high temperature pasteurized (UHT) semi-skimmed cow milk using argentinean kefir grains and compare the stability and nutritional compliance of freshly made and refrigerated kefir. Results indicate that kefir produced under home use conditions maintains the expected characteristics with respect to the physicochemical parameters and composition, both after fermentation and after refrigerated storage. This work further contributes to the characterization of this food product that is so widely consumed around the world by focusing on kefir that was produced in a typical household setting.

Perivascular Macrophages Regulate Blood Flow Following Tissue Damage.

[Figure: see text].

Interface-Mediated Mechanism of Action-The Root of the Cytoprotective Effect of Immediate-Release Omeprazole.

Omeprazole is usually administered under an enteric coating. However, there is a Food and Drug Administration-approved strategy that enables its release in the stomach. When locally absorbed, omeprazole shows a higher efficacy and a cytoprotective effect, whose mechanism was still unknown. Therefore, we aimed to assess the effect of the absorption route on the gastric mucosa. 2D and 3D models of dipalmitoylphosphatidylcholine (DPPC) at different pH values (5.0 and 7.4) were used to mimic different absorption conditions. Several experimental techniques, namely, fluorescence studies, X-ray scattering methodologies, and Langmuir monolayers coupled with microscopy, X-ray diffraction, and infrared spectroscopy techniques, were combined with molecular dynamics simulations. The results showed that electrostatic and hydrophobic interactions between omeprazole and DPPC rearranged the conformational state of DPPC. Omeprazole intercalates among DPPC molecules, promoting domain formation with untilted phospholipids. Hence, the local release of omeprazole enables its action as a phospholipid-like drug, which can reinforce and protect the gastric mucosa.

Passive Diffusion of Ciprofloxacin and its Metalloantibiotic: A Computational and Experimental study.

Fluoroquinolones (FQ) are antibiotics widely used in clinical practise, but the development of bacterial resistance to these drugs is currently a critical public health problem. In this context, ternary copper complexes of FQ (CuFQPhen) have been studied as a potential alternative. In this study, we compared the passive diffusion across the lipid bilayer of one of the most used FQ, ciprofloxacin (Cpx), and its ternary copper complex, CuCpxPhen, that has shown previous promising results regarding antibacterial activity and membrane partition. A combination of spectroscopic studies and molecular dynamics simulations were used and two different model membranes tested: one composed of anionic phospholipids, and the other composed of zwitterionic phospholipids. The obtained results showed a significantly higher membrane permeabilization activity, larger partition, and a more favourable free energy landscape for the permeation of CuCpxPhen across the membrane, when compared to Cpx. Furthermore, the computational results indicated a more favourable translocation of CuCpxPhen across the anionic membrane, when compared to the zwitterionic one, suggesting a higher specificity towards the former. These findings are important to decipher the influx mechanism of CuFQPhen in bacterial cells, which is crucial for the ultimate use of CuFQPhen complexes as an alternative to FQ to tackle multidrug-resistant bacteria.

TransfersomILs: From Ionic Liquids to a New Class of Nanovesicular Systems.

Ionic liquids (ILs) have increasingly been studied as key materials to upgrade the performance of many pharmaceutical formulations. In controlled delivery systems, ILs have improved multiple physicochemical properties, showing the relevance of continuing to study their incorporation into these formulations. Transfersomes are biocompatible nanovesicular systems, quite useful in controlled delivery. They have promising characteristics, such as elasticity and deformability, making them suitable for cutaneous delivery. Nonetheless, their overall properties and performance may still be improved. Herein, new TransfersomILs systems to load rutin were developed and the physicochemical properties of the formulations were assessed. These systems were prepared based on an optimized formulation obtained from a Box-Behnken factorial design (BBD). The impact of imidazole-based ILs, cholinium-based ILs, and their combinations on the cell viability of HaCaT cells and on the solubility of rutin was initially assessed. The newly developed TransfersomILs containing rutin presented a smaller size and, in general, a higher association efficiency, loading capacity, and total amount of drug release compared to the formulation without IL. The ILs also promoted the colloidal stability of the vesicles, upgrading storage stability. Thus, ILs were a bridge to develop new TransfersomILs systems with an overall improved performance.

Collaboration between patient organisations and a clinical research sponsor in a rare disease condition: learnings from a community advisory board and best practice for future collaborations.

Introduction Transparent collaborations between patient organisations (POs) and clinical research sponsors (CRS) can identify and address the unmet needs of patients and caregivers. These insights can improve clinical trial participant experience and delivery of medical innovations necessary to advance health outcomes and standards of care. We share our experiences from such a collaboration undertaken surrounding the SENSCIS® clinical trial (NCT02597933), and discuss its impact during, and legacy beyond, the trial.Summary We describe the establishment of a community advisory board (CAB): a transparent, multiyear collaboration between the scleroderma patient community and a CRS. We present shared learnings from the collaboration, which is split into three main areas: (1) the implementation and conduct of the clinical trial; (2) analysis and dissemination of the results; and (3) aspects of the collaboration not related to the trial.1. The scleroderma CAB reviewed and provided advice on trial conduct and reporting. This led to the improvement and optimisation of trial procedures; meaningful, patient-focused adaptations were made to address challenges relevant to scleroderma-associated interstitial lung disease patients.2. To ensure that results of the trial were accessible to lay audiences and patients, written lay summaries were developed by the trial sponsor with valuable input from the CAB to ensure that language and figures were understandable.3. The CAB and the CRS also collaborated to co-develop opening tools for medication blister packs and bottles. In addition, to raise disease awareness among physicians, patients and caregivers, educational materials to improve diagnosis and management of scleroderma were co-created and delivered by the CAB and CRS.Conclusions This collaboration between POs and a CRS, in a rare disease condition, led to meaningful improvements in patient safety, comfort and self-management and addressed information needs. This collaboration may serve as a template of best practice for future collaborations between POs, research sponsors and other healthcare stakeholders.

Assessing differential item functioning for the Social Appearance Anxiety Scale: a Scleroderma atient-centred Intervention Network (SPIN) Cohort Study.

OBJECTIVES: The Social Appearance Anxiety Scale (SAAS) is a 16-item questionnaire developed to evaluate fear of appearance-based evaluation by others. The primary objective of this research was to investigate the existence of differential item functioning (DIF) for the 16 SAAS items, comparing patients who completed the SAAS in English and French, either to confirm that scores are comparable or provide guidance on calculating comparable scores. A secondary research objective was to investigate the existence of DIF based on sex and disease status. A tertiary research objective was to assess DIF related to language, sex, and disease status on the recently developed SAAS-5. DESIGN: This was a cross-sectional analysis using baseline data from patients enrolled in the Scleroderma Patient-centred Intervention Network (SPIN). SETTING: SPIN patients included in the present study were enrolled at 43 centres in Canada, USA, UK, France and Australia, with questionnaires completed in April 2014 to July 2019. PARTICIPANTS: 1640 SPIN patients completed the SAAS in French (n=600) or English (n=1040). PRIMARY AND SECONDARY MEASURES: The SAAS was collected along with demographic and disease characteristics. RESULTS: Six items were identified with statistically significant language-based DIF, four with sex-based DIF and one with disease type-based DIF. However, factor scores before and after accounting for DIF were similar (Pearson correlation >0.99), and individual score differences were small. This was true for both the full and shortened versions of the SAAS. CONCLUSION: SAAS and SAAS-5 scores are comparable across language, sex, and disease-type, despite small differences in how patients respond to some items.

The Scleroderma Patient-Centered Intervention Network Self-Management Program: Protocol for a Randomized Feasibility Trial.

BACKGROUND: Systemic sclerosis (SSc), or scleroderma, is a rare disease that often results in significant disruptions to activities of daily living and can negatively affect physical and psychological well-being. Because there is no known cure, SSc treatment focuses on reducing symptoms and disability and improving health-related quality of life (HRQoL). Self-management programs are known to increase self-efficacy for disease management in many chronic diseases. The Scleroderma Patient-centered Intervention Network (SPIN) developed a Web-based self-management program (SPIN self-management; SPIN-SELF) to increase self-efficacy for disease management and to improve HRQoL for patients with SSc. OBJECTIVE: The proposed study aims to assess the feasibility of conducting a full-scale randomized controlled trial (RCT) of the SPIN-SELF program by evaluating the trial implementation processes, required resources and management, scientific aspects, and participant acceptability and usage of the SPIN-SELF program. METHODS: The SPIN-SELF feasibility trial will be conducted via the SPIN Cohort. The SPIN Cohort was developed as a framework for embedded pragmatic trials using the cohort multiple RCT design. In total, 40 English-speaking SPIN Cohort participants with low disease management self-efficacy (Self-Efficacy for Managing Chronic Disease Scale score ≤7), who have indicated interest in using a Web-based self-management program, will be randomized with a 3:2 ratio into the SPIN-SELF program or usual care for 3 months. Feasibility outcomes include trial implementation processes, required resources and management, scientific aspects, and patient acceptability and usage of the SPIN-SELF program. RESULTS: Enrollment of the 40 participants occurred between July 5, 2019, and July 27, 2019. By November 25, 2019, data collection of trial outcomes was completed. Data analysis is underway, and results are expected to be published in 2020. CONCLUSIONS: The SPIN-SELF program is a self-help tool that may improve disease-management self-efficacy and improve HRQoL in patients with SSc. The SPIN-SELF feasibility trial will ensure that trial methodology is robust, feasible, and consistent with trial participant expectations. The results will guide adjustments that need to be implemented before undertaking a full-scale RCT of the SPIN-SELF program. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16799.

Neutral Diclofenac Causes Remarkable Changes in Phosphatidylcholine Bilayers: Relevance for Gastric Toxicity Mechanisms.

The main objective of this study was to clarify the topical mechanisms underlying diclofenac-induced gastric toxicity by considering for the first time both ionization states of this nonsteroidal anti-inflammatory drug. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes were the model system chosen to mimic the protective phospholipid layers of the gastric mucosa and to describe the interactions with diclofenac, considering the pH gradient found in the gastric mucosa (3 < pH < 7.4). Complementary experimental techniques were combined to evaluate the drug's affinity for DMPC bilayers, as well as to assess the drug's effects on the structural properties of the phospholipid bilayer. The diclofenac-DMPC interactions were clearly dependent on the drug's ionization state. Neutral diclofenac displayed greater affinity for DMPC bilayers than anionic diclofenac. Moreover, the protonated/neutral form of the drug induced more pronounced and/or distinct alterations in the structure of the DMPC bilayer than the deprotonated/ionized form, considering similar membrane concentrations. Therefore, neutral diclofenac-induced changes in the structural properties of the external phospholipid layers of the gastric mucosa may constitute an additional toxicity mechanism of this worldwide-used drug, which shall be considered for the development of safer therapeutic strategies. SIGNIFICANCE STATEMENT: Neutral or anionic diclofenac exerted distinct alterations in phosphatidylcholine bilayers, which are used in this work as models for the protective phospholipid layers of the gastric mucosa. Remarkable changes were induced by neutral diclofenac in the structural properties of the phospholipid bilayer, suggesting that both ionized and neutral states of nonsteroidal anti-inflammatory drugs must be considered to clarify their mechanisms of toxicity and to ultimately develop safer anti-inflammatory drugs.

Unraveling the Role of Drug-Lipid Interactions in NSAIDs-Induced Cardiotoxicity.

Cardiovascular (CV) toxicity is nowadays recognized as a class effect of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs). However, their mechanisms of cardiotoxicity are not yet well understood, since different compounds with similar action mechanisms exhibit distinct cardiotoxicity. For instance, diclofenac (DIC) is among the most cardiotoxic compounds, while naproxen (NAP) is associated with low CV risk. In this sense, this study aimed to unravel the role of drug-lipid interactions in NSAIDs-induced cardiotoxicity. For that, DIC and NAP interactions with lipid bilayers as model systems of cell and mitochondrial membranes were characterized by derivative spectrophotometry, fluorometric leakage assays, and synchrotron X-ray scattering. Both DIC and NAP were found to have the ability to permeabilize the membrane models, as well as to alter the bilayers' structure. The NSAIDs-induced modifications were dependent on the lipid composition of the membrane model, the three-dimensional structure of the drug, as well as the drug:lipid molar ratio tested. Altogether, this work supports the hypothesis that NSAIDs-lipid interactions, in particular at the mitochondrial level, may be another key step among the mechanisms underlying NSAIDs-induced cardiotoxicity.

Licofelone-DPPC Interactions: Putting Membrane Lipids on the Radar of Drug Development.

(1) Background: Membrane lipids have been disregarded in drug development throughout the years. Recently, they gained attention in drug design as targets, but they are still disregarded in the latter stages. Thus, this study aims to highlight the relevance of considering membrane lipids in the preclinical phase of drug development. (2) Methods: The interactions of a drug candidate for clinical use (licofelone) with a membrane model system made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were evaluated by combining Langmuir isotherms, Brewster angle microscopy (BAM), polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS), and grazing-incidence X-ray diffraction (GIXD) measurements. (3) Results: Licofelone caused the expansion of the DPPC isotherm without changing the lipid phase transition profile. Moreover, licofelone induced the reduction of DPPC packing density, while increasing the local order of the DPPC acyl chains. (4) Conclusions: The licofelone-induced alterations in the structural organization of phosphatidylcholine monolayers may be related to its pharmacological actions. Thus, the combination of studying drug-membrane interactions with the pharmacological characterization that occurs in the preclinical stage may gather additional information about the mechanisms of action and toxicity of drug candidates. Ultimately, the addition of this innovative step shall improve the success rate of drug development.