Potentially Inappropriate Medication Prescribing in Older Adults According to EU(7)-Potentially Inappropriate Medication List: A Nationwide Study in Portugal.

Background: Portugal has among the highest rates of dependency among older adults in Europe. Older adults with aging-related comorbidities are prone to the use of potentially inappropriate medication (PIM). Objective: The aim of this study was to analyze PIM prescriptions in older Portuguese adults, as well as the change rate of PIM prescriptions over time, and assess the geographical variability between the different regions of mainland Portugal. Methods: Using a national database, PIM prescriptions were analyzed for older adults (aged 65 years and older) between 2019 and 2021 from 2 perspectives: PIM-defined daily dose (DDD) frequency (%) and DDD per 1000 inhabitants per day (DID). Results: Overall, mainland Portugal presented a PIM DDD frequency of 9.20%, which was relatively higher in Alentejo and Centro and lower in the North. Alprazolam, fluoxetine, and rivaroxaban were PIM with higher DDD frequency values. Over the years, the DID change rates for these three PIM were -3.80%, -14.86%, and +18.54%, respectively, depending on the geographic region. Alprazolam and fluoxetine were mostly prescribed to older women, whereas rivaroxaban was mostly prescribed to older men. Conclusions: These results emphasize the need to implement initiatives and interventions to decrease PIM prescriptions in older adults.

Perspectives on mitochondrial uncoupling proteins-mediated neuroprotection.

The integrity of mitochondrial function is essential to cell life. It follows that disturbances of mitochondrial function will lead to disruption of cell function, expressed as disease or even death. Considering that neuronal uncoupling proteins (UCPs) decrease reactive oxygen species (ROS) production at the expense of energy production, it is important to understand the underlying mechanisms by which UCPs control the balance between the production of adenosine triphosphate (ATP) and ROS in the context of normal physiological activity and in pathological conditions. Here we review the current understanding of neuronal UCPs-mediated respiratory uncoupling process by performing a survey in their physiology and regulation. The latest findings regarding neuronal UCPs physiological roles and their involvement and interest as potential targets for therapeutic intervention in brain diseases will also be exploited.

Potentially Inappropriate Medication at Admission and at Discharge: A Geriatric Study in an Internal Medicine Service in Portugal.

Aging is associated with an increase in the prevalence of chronic diseases and polypharmacy, and with the prescription of potentially inappropriate medications (PIMs). This study aimed to analyze the variation in PIMs from hospital admission to discharge. A retrospective cohort study was conducted on inpatients of an internal medicine service. According to the Beers criteria, 80.7% of the patients had been prescribed at least one PIM at admission and 87.2% at discharge; metoclopramide was the most-prescribed PIM from admission to discharge, and acetylsalicylic acid was the most-deprescribed one. According to the STOPP criteria, 49.4% of patients had been prescribed at least one PIM at admission and 62.2% at discharge; quetiapine was the most-prescribed PIM from admission to discharge, and captopril was the most-deprescribed one. According to the EU(7)-PIM list, 51.3% of patients had been prescribed at least one PIM at admission and 70.3% at discharge, and bisacodyl was the most-prescribed PIM from admission to discharge and propranolol the most-deprescribed one. It was found that the number of PIMs at discharge was higher than at admission, suggesting the need to develop a guide with adapted criteria to be applied in an internal medicine service.

The impairment of insulin signaling in Alzheimer's disease.

Alterations of the insulin signaling cascade underlie cognitive decline and the development of several neurodegenerative diseases. In recent years, a great interest has been put in studying the interaction between diabetes and Alzheimer's disease (AD). In fact, evidence shows that both diseases present several biochemical similarities including defects in the insulin signaling pathway. Here, we give an overview of the main functions of insulin in the central nervous system. The impact of insulin signaling impairment in brain aging and AD is also discussed. Finally, we present evidence supporting the notion that insulin is a link between diabetes and AD.

Early Real-World Data to Assess Benefits and Risks of COVID-19 Vaccines: A Systematic Review of Methods.

Since the authorization of the first COVID-19 vaccines in December 2020, multiple studies using real-world data (RWD) have been published to assess their effectiveness/safety profile. This systematic review aimed to characterize the methods and outcomes of studies using RWD for assessment of COVID-19 vaccines, four months after vaccine approval. MEDLINE and EMBASE were searched to identify published studies until 6 May 2021. Two independent researchers selected relevant publications and extracted data from included studies. The risk of bias was assessed using New-Castle Ottawa tools. After screening 1086 studies, 15 were included. Out of the 15 studies, 12 (80%) followed a cohort design, 8 (53%) were based on USA data, 7 (47%) assessed health care professionals, and 14 articles (93%) assessed the BNT162b2 vaccine. Data sources included institutional databases, electronic health records, and patient-generated data. The primary endpoint mainly described was SARS-CoV-2-infection. Hospitalization and mortality were assessed in 2 studies. For the comparability domain, six studies (40%) had a high risk of bias. A few months after the beginning of COVID-19 vaccination, Real-world Evidence (RWE) provided timely safety surveillance and comparative effectiveness with findings that showed similar findings to Randomized control trial (RCT). Most of the initiatives assessed BNT162b2 and were conducted in the USA and used healthcare workers' data.

Profile of Prescription Medication in an Internal Medicine Ward.

Aging-related loss of resilience associated with the lack of evidence regarding the therapeutic efficacy of medicines can prompt a lack of efficacy of treatments and multiple prescriptions. This work aims to characterize the medication profile of Portuguese older adult inpatients and explore the relationship between hospitalization days and the consumption of medicines. A retrospective data analysis study in older patients who were admitted to a medical internal medicine ward during 2019. The median age of the 616 patients included was 85 years. During the hospitalized period, patients took on average 18.08 medicines. The most prescribed drugs belong to the subgroup of (a) anti-thrombotic agents (6.7%), with enoxaparin being the most prescribed, (b) other analgesics and antipyretics (6.6%), paracetamol being the most frequent, and (c) the Angiotensin Conversion Enzyme Inhibitor (ACE) (6.5%), captopril being the most frequent. The high number of prescriptions in older adults during their hospitalization suggests the need of changing therapeutics to achieve a better efficacy of treatment, which corroborates the hypothesis that the lack of scientific evidence concerning the risk/benefits of many medical therapies in older adults can make it difficult to achieve good clinical outcomes and promote the wastage of health resources.

Effectiveness of Interventions to Reduce Potentially Inappropriate Medication in Older Patients: A Systematic Review.

Background: Age-related multiple comorbidities cause older adults to be prone to the use of potentially inappropriate medicines (PIM) resulting in an increased risk of adverse events. Several strategies have emerged to support PIM prescription, and a huge number of interventions to reduce PIM have been proposed. This work aims to analyze the effectiveness of PIM interventions directed to older adults. Methods: A systematic review was performed searching the literature in the MEDLINE PubMed, EMBASE, and Cochrane scientific databases for interventional studies that assessed the PIM interventions in older adults (≥65 years). Results: Forty-seven articles were included, involving 52 to 124,802 patients. Various types of interventions were analyzed such as medication review, educational strategies, clinical decision support system, and organizational and multifaceted approaches. In the hospital, the most successful intervention was medication review (75.0%), while in primary care, the analysis of all included studies revealed that educational strategies were the most effective. However, the analysis of interventions that have greater evidence by its design was inconclusive. Conclusion: The results obtained in this work suggested that PIM-setting-directed interventions should be developed to promote the wellbeing of the patients through PIM reduction. Although the data obtained suggested that medication review was the most assertive strategy to decrease the number of PIM in the hospital setting, more studies are necessary. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021233484], identifier [PROSPERO 2021 CRD42021233484].

Prescription of Potentially Inappropriate Medication in Older Inpatients of an Internal Medicine Ward: Concordance and Overlap Among the EU(7)-PIM List and Beers and STOPP Criteria.

Background: Age-related comorbidities prone older adults to polypharmacy and to an increased risk of potentially inappropriate medication (PIM) use. This work aims to analyze the concordance and overlap among the EU(7)-PIM list, 2019 Beers criteria, and Screening Tool of Older Person's Prescriptions (STOPP) version 2 criteria and also to analyze the prevalence of PIM. Methods: A retrospective cohort study was conducted on older inpatients of an internal medicine ward. Demographic, clinical, and pharmacological data were collected, during March 2020. After PIM identification by the EU(7)-PIM list, Beers criteria, and STOPP v2 criteria, the concordance and overlap between criteria were analyzed. A descriptive analysis was performed, and all the results with a p-value lower than 0.05 were considered statistically significant. Results: A total of 616 older patients were included in the study whose median age was 85 (Q1-Q3) (78-89) years. Most of the older patients were male (51.6%), and the median (Q1-Q3) number of days of hospitalization was 17 (13-22) days. According to the EU(7)-PIM list, Beers criteria, and STOPP criteria, 79.7, 92.0, and 76.5% of older adults, respectively, used at least one PIM. A poor concordance (<63.4%) among criteria was observed. An association between PIM and the number of prescribed medicines was found in all applied criteria. Moreover, an association between the number of PIMs and diagnoses of endocrine, nutritional, and metabolic diseases, mental, behavioral, and neurodevelopmental disorders, and circulatory system diseases and days of hospitalization was observed according to Beers criteria, and that with diseases of the circulatory system and musculoskeletal system and connective tissue was observed according to STOPP criteria. Conclusion: Despite the poor concordance between the EU(7)-PIM list, 2019 Beers, and STOPP v2 criteria, this work highlights the need for more studies in inpatients to develop strategies to facilitate the identification of PIM to decrease the high prevalence of PIM in hospitalized patients. The poor concordance among criteria also highlights the need to develop new tools adapting the existing criteria to medical ward inpatients.

Clinical pharmacists´ interventions in the management of type 2 diabetes mellitus: a systematic review.

BACKGROUND: Type 2 diabetes mellitus is a chronic disease that is reaching epidemic proportions worldwide. It is imperative to adopt an integrated strategy, which involves a close collaboration between the patient and a multidisciplinary team of which pharmacists should be integral elements. OBJECTIVE: This work aims to identify and summarize the main effects of interventions carried out by clinical pharmacists in the management of patients with type 2 diabetes, considering clinical, humanistic and economic outcomes. METHODS: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials assessing the effectiveness of such interventions compared with usual care that took place in hospitals or outpatient facilities. RESULTS: This review included 39 studies, involving a total of 5,474 participants. Beneficial effects were observed on various clinical outcomes such as glycemia, blood pressure, lipid profile, body mass index and coronary heart disease risk. For the following parameters, the range for the difference in change from baseline to final follow-up between the intervention and control groups was: HbA1c, -0.05% to -2.1%; systolic blood pressure, +3.45 mmHg to -10.6 mmHg; total cholesterol, +10.06 mg/dL to -32.48 mg/dL; body mass index, +0.6 kg/m2 to -1.94 kg/m2; and coronary heart disease risk, -3.0% and -12.0% (among the studies that used Framinghan prediction method). The effect on medication adherence and health-related quality of life was also positive. In the studies that performed an economic evaluation, the interventions proved to be economically viable. CONCLUSIONS: These findings support and encourage the integration of clinical pharmacists into multidisciplinary teams, underlining their role in improving the management of type 2 diabetes.

Drug-related Problems in Home-dwelling Older Adults: A Systematic Review.

PURPOSE: The complex combination of medicines associated with age-related physiological alterations leads older adults to experience drug-related problems (DRPs). The goal of this study was to review the frequency and type of DRPs and DRP risk factors in home-dwelling older adults. METHODS: A MEDLINE PubMed and EMBASE scientific databases search was performed. Articles published from January 2000 through December 2018 reporting DRPs in home-dwelling older adults were included. FINDINGS: From 668 articles screened, 13 met the inclusion criteria and were included in this study. Overall, the studies included 8935 home-dwelling patients. The mean number of DRPs per patient observed was 4.16 (1.37-10). The main causes of DRPs were "drug selection" (51.41%), "dose selection" (11.62%), and "patient related" (10.70%) problems. The drug classes more frequently associated with DRPs were "cardiovascular system," "alimentary tract and metabolism," and "nervous system," and they represented 32.1%, 29.4%, and 16.5% of all drug selection problems, respectively. Respiratory system medicines accounted for 6.65% of all DRPs, of which "patient related" problems accounted for 97.28%. IMPLICATIONS: Despite the heterogeneity of methodology of the included studies and the heterogeneity of tools used to identify DRPs, this analysis clearly shows the high prevalence of DRPs in home-dwelling older adults and highlights the need for interventions to improve medicine use in this population. This work also provides useful information for the development of strategies to improve medication use in home-dwelling older adults.

Arbutus unedo L.: From traditional medicine to potential uses in modern pharmacotherapy.

ETHNOPHARMACOLOGICAL RELEVANCE: Arbutus unedo L., the strawberry tree (Ericaceae family) is of increasing interest because of its common traditional, industrial, chemical and pharmaceutical uses. The plant is a typical evergreen plant of the Mediterranean basin, as well as of other regions with hot summers and mild rainy winters. This review covers the studies relevant to Arbutus unedo L. utilization in the current pharmacological therapy. MATERIALS AND METHODS: The available information on traditional uses, phytochemistry and biological activities of Arbutus unedo L. was collected from scientific databases through a search using the keywords 'Arbutus unedo L.' and/or 'strawberry tree' in 'Google Scholar', 'Pubmed', 'Sciencedirect', 'SpringerLink', 'Web of Science - Clarivate Analytics' and 'Wiley'. Unpublished Ph.D. and M.Sc. dissertations were also consulted for chemical composition, biological activities and traditional uses of Arbutus unedo L. and for manual search of additional references. RESULTS: The fruits of the plant have been traditionally used as antiseptics, diuretics and laxatives in folk medicine, while the leaves have been used due to their diuretic, urinary antiseptic, antidiarrheal, astringent, depurative and antihypertensive properties. According to the scientific literature survey, different extracts obtained from Arbutus unedo L. have demonstrated a high pharmacological potential due to their in vitro and preclinical antibiotic, antifungal, antiparasitic, antiaggregant, antidiabetic, antihypertensive, anti-inflammatory, antitumoral, antioxidant, and spasmolytic properties. CONCLUSION: This review suggests that A. unedo is a promising source of phytopharmaceutical products. The potential advantages of Arbutus unedo are related with the presence of polyphenolic compounds in its composition. However, further studies are needed to ascertain some profitable effects in humans. The beneficial effects associated with this shrub suggest that Arbutus unedo can be used for the development of new drugs to treat diseases such diabetes, hypertension, among others. Nonetheless, the safety of the Arbutus unedo compounds should also be examined.

Phosphatase 2A Inhibition Affects Endoplasmic Reticulum and Mitochondria Homeostasis Via Cytoskeletal Alterations in Brain Endothelial Cells.

The loss of endothelial cells (ECs) homeostasis is a trigger for cerebrovascular dysfunction that is a common event in several neurodegenerative disorders such as Alzheimer's disease (AD). The present work addressed the role of phosphatase 2A (PP2A) in cytoskeleton rearrangement, endoplasmic reticulum (ER) homeostasis, ER-mitochondria communication and mitochondrial dynamics in brain ECs. For this purpose, rat brain endothelial (RBE4) cells were exposed to okadaic acid, a well-known inhibitor of PP2A activity. An increase in the levels of tau phosphorylated on Ser396 and Thr181 residues was observed upon PP2A inhibition, concomitantly with the rearrangement of microtubules and actin cytoskeleton. Under these conditions, an increase in the levels of ER stress markers, namely GRP78, XBP1, p-eIF2αSer51, and ERO1α, was observed. Moreover, PP2A inhibition upregulated the Sigma-1 receptor, an ER chaperone located at the ER-mitochondria interface, and enhanced inter-organelle Ca2+ transfer, culminating in mitochondrial Ca2+ overload and activation of mitochondria-dependent apoptosis. The inhibition of PP2A activity also promoted an alteration of the structural and spatial mitochondria network due to upregulation of mitochondrial fission (Drp1 and Fis1) and fusion (Mfn1, Mfn2 and OPA1) proteins, suggesting detrimental changes in mitochondrial dynamics. In accordance with our in vitro observations, brain vessels from 3xTg-AD mice showed a significant decrease in PP2A protein levels accompanied by an increase in tau phosphorylated on Ser396 and GRP78 protein levels. Collectively, these results suggest that the loss of cerebrovascular homeostasis that occurs in AD might be a downstream event of the compromised activity and/or expression of PP2A, which is observed in the brain of individuals affected with this devastating neurodegenerative disorder.

Enhanced amyloidogenic processing of amyloid precursor protein and cell death under prolonged endoplasmic reticulum stress in brain endothelial cells.

Cerebral amyloid angiopathy resulting from the deposition of misfolded amyloid beta (Aß) peptide in the walls of brain's blood vessels is exhibited by the majority of Alzheimer's disease (AD) patients, suggesting that alterations in protein quality control contribute to AD-associated vascular dysfunction. The present work addressed the role of ER stress in the amyloidogenic amyloid precursor protein (APP) processing and subsequent Aß generation in brain endothelial cells (ECs). For that purpose, the RBE4 cell line was exposed to the classical ER stressors thapsigargin or brefeldin A to mimic the altered ER homeostasis observed in AD. In treated cells, an increase in the levels of markers of ER stress (XBP1 and GRP78) and of the ER stress-induced apoptotic pathway (caspase-12, JNK, and CHOP) was observed concomitantly with the accumulation of reactive oxygen species. Under these conditions, a significant ER-to-mitochondria Ca(2+) transfer was also found, which culminated in mitochondrial Ca(2+) overload and activation of mitochondria-dependent apoptosis. Moreover, it was showed that prolonged ER stress induces intracellular APP accumulation, which colocalizes with the ER chaperone GRP78, and activation of ß-secretase, leading to increased intracellular Aß levels, together with a decrease in secreted Aß. Finally, it was demonstrated that ER stress-induced changes in Aß levels and apoptotic cell death can be ameliorated by a blocker of the mitochondrial Bax channel. These observations suggest that chronic ER stress triggers APP accumulation in early comportments along the secretory pathway in brain ECs and increases its amyloidogenic processing and Aß generation leading to apoptotic cell death.

Modulation of endoplasmic reticulum stress: an opportunity to prevent neurodegeneration?

Neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-related diseases) have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected. In these pathologies, accumulating evidence supports a close correlation between neurodegeneration and endoplasmic reticulum (ER) stress, a condition that arises from ER lumen overload with misfolded proteins. Under these conditions, ER stress sensors initiate the unfolded protein response to restore normal ER function. If stress is too prolonged, or adaptive responses fail, apoptotic cell death ensues. Therefore, it was recently suggested that the manipulation of the ER unfolded protein response could be an effective strategy to avoid neuronal loss in neurodegenerative disorders. We will review the mechanisms underlying ER stress-associated neurodegeneration and discuss the possibility of ER as a therapeutic target.

The role of mitochondrial disturbances in Alzheimer, Parkinson and Huntington diseases.

Mitochondria are highly dynamic organelles involved in a multitude of cellular events. Disturbances of mitochondrial function and dynamics are associated with cells degeneration and death. Neurons, perhaps more than any other cell, depend on mitochondria for their survival. In fact, accumulating evidence reveals that mitochondria take center stage in several neurodegenerative diseases. Here we will give an overview of the mechanisms involved in the maintenance of a healthy mitochondrial pool in neuronal cells and how disturbances in these processes underlie the pathophysiology of three common neurodegenerative disorders, Alzheimer, Parkinson and Huntington diseases. Additionally, we will discuss the role of sirtuins in neurodegeneration and how mitohormesis and vitagenes activation may counteract neurodegenerative events.

Defective HIF signaling pathway and brain response to hypoxia in neurodegenerative diseases: not an "iffy" question!

Brain structural and functional integrity exquisitely relies on a regular supply of oxygen. In order to circumvent the potential deleterious consequences of deficient oxygen availability, brain triggers endogenous adaptive and pro-survival mechanisms - a phenomenon known as brain hypoxic tolerance. The highly conserved hypoxia-inducible family (HIF) of transcription factors is the "headquarter" of the homeostatic response of the brain to hypoxia. HIF acts as a cellular oxygen sensor and regulates the expression of proteins involved in a broad range of biological processes, including neurogenesis, angiogenesis, erythropoiesis, and glucose metabolism, and thus, enables brain cells to survive in low-oxygen conditions. Hypoxia, as well as hypoxia-reoxygenation, is intimately implicated in the clinical and pathological course of several neurodegenerative diseases. Thus, two major questions can arise: Is HIF signaling and brain response to hypoxia compromised in neurodegenerative diseases? If so, are HIF stabilizers a possible therapeutic strategy to halt or prevent the progression of neurodegenerative diseases? This review highlights the current knowledge pertaining the role of HIF on brain response to hypoxia and its close association with the development of Alzheimer's, and Parkinson's disease and amyotrophic lateral sclerosis. Finally, the potential therapeutic effects of HIF stabilizers (deferoxamine, clioquinol, M30, HLA20, DHB, FG0041, and VK-28) against the symptomatic and neuropathological features of the abovementioned neurodegenerative diseases will be discussed.

Alzheimer disease as a vascular disorder: where do mitochondria fit?

Although the precise culprit in the etiopathogenesis of Alzheimer disease (AD) is still obscure, defective mitochondria functioning has been proposed to be an upstream event in AD. Mitochondria fulfill a number of essential cellular functions, and it is recognized that the strict regulation of the structure, function and turnover of these organelles is an immutable control node for the maintenance of neuronal and vascular homeostasis. Extensive research in postmortem brain tissue from AD subjects, and AD animal and cellular models revealed that mitochondria undergo multiple malfunctions during the course of this disease. The present review summarizes the current views on how mitochondria are implicated in both AD-related neuronal and cerebrovascular degeneration. The understanding of the mitochondrial mechanisms underlying AD pathology is critical to design more effective strategies to halt or delay disease progression.