Antimalarials and macrolides: a review of off-label pharmacotherapies during the first wave of the SARS-CoV-2 pandemic

We critically analyzed clinical trials performed with chloroquine (CQ) and hydroxychloroquine (HCQ) with or without macrolides during the first wave of COVID-19 and discussed the design and limitations of peer-reviewed studies from January to July 2020. Seventeen studies were eligible for the discussion. CQ and HCQ did not demonstrate clinical advantages that justified their inclusion in therapeutic regimens of free prescription for treatment or prophylactic purposes, as suggested by health authorities, including in Brazil, during the first wave. Around August 2020, robust data had already indicated that pharmacological effects of CQ, HCQ and macrolides as anti-SARS-CoV-2 molecules were limited to in vitro conditions and largely based on retrospective trials with low quality and weak internal validity, which made evidence superficial for decision-making. Up to that point, most randomized and nonrandomized clinical trials did not reveal beneficial effects of CQ or HCQ with or without macrolides to reduce lethality, rate of intubation, days of hospitalization, respiratory support/mechanical ventilation requirements, duration, type and number of symptoms, and death and were unsuccessful in increasing virus elimination and/or days alive in hospitalized or ambulatory patients with COVID-19. In addition, many studies have demonstrated that side effects are more common in CQ-or HCQ-treated patients

Procjena akutne toksičnosti umjetnih aroma grožđa, šljive i naranče pomoću testova in vivo

The present study evaluates the acute toxicity of synthetic grape, plum and orange flavourings in root meristem cells of Allium cepa at the doses of 3.5, 7.0 and 14.0 mL/kg and exposure times of 24 and 48 h, and in bone marrow erythrocytes of mice treated orally for seven days with 0.5, 1.0, 2.0, 5.0 and 10.0 mL/kg of flavouring. The results of the plant test showed that grape, plum and orange flavourings, at both exposure times, inhibited cell division and promoted the formation of a significant number of micronuclei and mitotic spindle changes. These alterations were observed in at least one exposure time analysed, demonstrating a significant cytotoxic, genotoxic and mutagenic activity. In mouse bioassay, animals treated with 2.0, 5.0 and 10.0 mL/kg of flavouring died before the seventh day of treatment. The amounts of 0.5 and 1.0 mL/kg of the three additives were cytotoxic to erythrocytes, and treatment with the grape flavouring significantly induced the formation of micronucleated cells in the bone marrow of animals. Therefore, under the study conditions, the grape, plum and orange flavouring additives promoted significant toxicity to cells of the test systems used.U radu je ispitan akutni toksični učinak umjetnih aroma grožđa, šljive i naranče u dozama od 3,5; 7 i 14 mL/kg tijekom 24 i 48 sati na meristemske stanice korijena luka (Allium cepa) te u peroralnim dozama od 0,5; 1; 2; 5 i 10 mL/kg tijekom 7 dana na eritrocite iz koštane srži miševa. Rezultati pokazuju da je izlaganje meristemskih stanica korijena luka umjetnim aromama grožđa, šljive i naranče tijekom 24 i 48 sata inhibiralo diobu stanica te potaklo tvorbu većeg broja mikronukleusa i promjenu strukture diobenog vretena. Promjene su uočene već nakon 24 sata, što potvrđuje znatnu citotoksičnost, genotoksičnost i mutagenost umjetnih aroma. Miševi hranjeni s 2, 5 i 10 mL/kg umjetnih aroma uginuli su prije sedmog dana tretmana. Dodatak umjetnih aroma u dozama od 0,5 i 1 mL/kg smanjio je broj eritrocita u koštanoj srži miševa, a dodatak arome grožđa znatno je potaknuo tvorbu mikronukleusa. Stoga je zaključeno da arome grožđa, šljive i naranče pri navedenim uvjetima imaju izraženi toksični učinak na meristemske stanice korijena luka i eritrocite iz koštane srži miševa

Proteomics profiling of vitreous humor reveals complement and coagulation components, adhesion factors, and neurodegeneration markers as discriminatory biomarkers of vitreoretinal eye diseases

Funding Information: This project was supported by the University of Beira Interior— Health Sciences Research Centre (CICS-UBI) supported by FEDER funds through the POCI—COMPETE 2020—Operational Programme Competitiveness and Internationalisation in Axis I—Strengthening research, technological development, and innovation Project (POCI-01- 0145-FEDER-007491). CNB-CSIC proteomics lab is a member of Proteored, PRB2-ISCIII and is supported by grant PT13/0001, of the PE I +D+i 2013–2016, funded by ISCIII and FEDER. Publisher Copyright: Copyright © 2023 Santos, Ciordia, Mesquita, Cruz, Sousa, Passarinha, Tomaz and Paradela.Introduction: Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are leading causes of visual impairment and blindness in people aged 50 years or older in middle-income and industrialized countries. Anti-VEGF therapies have improved the management of neovascular AMD (nAMD) and proliferative DR (PDR), no treatment options exist for the highly prevalent dry form of AMD.  Methods: To unravel the biological processes underlying these pathologies and to find new potential biomarkers, a label-free quantitative (LFQ) method was applied to analyze the vitreous proteome in PDR (n=4), AMD (n=4) compared to idiopathic epiretinal membranes (ERM) (n=4).  Results and discussion: Post-hoc tests revealed 96 proteins capable of differentiating among the different groups, whereas 118 proteins were found differentially regulated in PDR compared to ERM and 95 proteins in PDR compared to dry AMD. Pathway analysis indicates that mediators of complement, coagulation cascades and acute phase responses are enriched in PDR vitreous, whilst proteins highly correlated to the extracellular matrix (ECM) organization, platelet degranulation, lysosomal degradation, cell adhesion, and central nervous system development were found underexpressed. According to these results, 35 proteins were selected and monitored by MRM (multiple reaction monitoring) in a larger cohort of patients with ERM (n=21), DR/PDR (n=20), AMD (n=11), and retinal detachment (n=13). Of these, 26 proteins could differentiate between these vitreoretinal diseases. Based on Partial least squares discriminant and multivariate exploratory receiver operating characteristic (ROC) analyses, a panel of 15 discriminatory biomarkers was defined, which includes complement and coagulation components (complement C2 and prothrombin), acute-phase mediators (alpha-1-antichymotrypsin), adhesion molecules (e.g., myocilin, galectin-3-binding protein), ECM components (opticin), and neurodegeneration biomarkers (beta-amyloid, amyloid-like protein 2).publishersversionpublishe

Cost-effectiveness of the endovascular repair of Abdominal Aortic Aneurysm in Portugal

AbstractEndovascular Aneurysm Repair (EVAR) for the treatment of aortic abdominal aneurism has been shown to improve short-term survival and quality of life as compared to Open Repair (OR), while reducing the rate of serious complications and allowing for the treatment of more patients.ObjectivesTo examine the cost-effectiveness of EVAR compared to OR in the treatment of aortic abdominal aneurism in the Portuguese context using a model previously developed in the UK.MethodologyWe adapted an international economic evaluation model to the Portuguese situation, assuming that the health benefits of EVAR observed in clinical trials would also apply to Portuguese patients. We carried out an expert panel survey to calculate the resource use associated with the intervention and its short and long-term consequences, valued with Portuguese prices.ResultsThe major cost difference in the primary intervention (difference of 3,064 € in favor of OR) is related to the cost of the endograft/graft. No major differences are observed in the total cost of complications and re-interventions between the two procedures. EVAR represents a cost of 16,709 € over lifetime compared to 12,130 € for OR. Using data from the literature we show that EVAR allows for 0.17 additional undiscounted years of life and 0.091 additional undiscounted quality-adjusted life years. The incremental cost-effectiveness ratio (ICER) of EVAR is of 65,605 €/QALY.ConclusionEndovascular repair of aortic abdominal aneurysm represents an effective alternative and has been used increasingly in Portugal and elsewhere. Our study shows that its cost-effectiveness is currently above the commonly accepted threshold in Portugal, but that the economic value of EVAR would greatly improve if benefits were confirmed in the long run after the intervention. Under these circumstances, EVAR would become an economically valuable intervention that could be adopted on a large scale in Portugal

Potencial citotóxico, genotóxico e citoprotetor de extratos aquosos de Caesalpinia pyramidalis Tul., Caesalpinia ferrea Mart. e Caesalpinia pulcherrima Sw.

The legumenous Caesalpinia pyramidalys, Caesalpinia ferrea and Caesalpinia pulcherrima are widely used in folk medicine in many countries. Thus, this study aimed to cytogenetically evaluate, through the use of meristematic roots cells of Allium cepa, after the exposure times 24 and 48 hours, the cytotoxic potential of aqueous extracts, at concentrations 1 g/500 mL and 1 g/1000 mL, obtained from the inner bark of Caesalpinia pyramidalis, the pod of Caesalpinia ferrea and the leaves of Caesalpinia pulcherrima, and also verify the modulatory potential of these extracts on cellular alterations induced by Paracetamol. The treatment groups used were: negative control – distilled water; positive control – 0.008 mg/mL Paracetamol solution; plant aqueous extract control – water fraction from the plants at concentrations 1 g/500 mL and 1 g/1000 mL; and simultaneous treatment – water fraction from the plants at concentrations 1 g/500 mL and 1g/1000 mL associated with 0.008 mg/mL Paracetamol solution. The Chi-square statistical test was used at 5% probability for data analysis. The results showed that C. pyramidalis and C. ferrea had a significant antiproliferative effect on the cells of the test organism, at both concentrations (1 g/500 mL and 1 g/1000 mL) and at both times of exposure, thus being cytotoxic. All three plants promoted significant cytoprotective effect on the Paracetamol-treated meristematic root cells of A. cepa, thus showing, under the studied conditions, antimutagenic potential. Further studies using these plants should be carried out in order to properly define the cytotoxic and cytoprotective potential of pau-ferro’s pod, catingueira’s inner bark and flamboyazinho’s leaves.Os objetivos do presente trabalho foram avaliar, por meio das células meristemáticas de raízes de Allium cepa, nos tempos de exposição 24 e 48 horas, o potencial citotóxico de extratos aquosos, nas concentrações de 1g/500ml e 1g/1000ml, provenientes da entrecasca de Caesalpinia pyramidalis, da vagem de Caesalpinia ferrea e das folhas de Caesalpinia pulcherrima, e verificar o potencial modulador destes extratos frente as aberrações celulares induzidas por Paracetamol a partir dos seguintes grupos tratamentos:  controle negativo – água destilada; controle positivo – solução de Paracetamol a 0,008mg/ml, controle extrato aquoso da planta – fração aquosa de uma das plantas na concentração de 1g/500ml ou 1g/1000ml,  tratamento simultâneo - fração aquosa de uma das plantas na concentração de 1g/500ml ou 1g/1000ml associada a solução de Paracetamol a 0,008mg/ml. As raízes de A. cepa após os tratamentos foram fixadas em solução de Carnoy, hidrolisadas em ácido e coradas com orceína acética a 2%. Em seguida fez-se o esmagamento dos meristemas e montagem das lâminas. Analisou-se 5.000 células para cada grupo tratamento em microscopia de campo claro (40x), e utilizou-se o teste estatístico Qui-quadrado a 5% para análise dos dados. A partir dos resultados obtidos verificou-se que C. pyramidalis e C. ferrea nas duas concentrações e nos dois tempos de exposição avaliados tiveram efeito antiproliferativo significativo as células do organismo de prova utilizado, mostrando-se citotóxicas. Também foi observado que os respectivos tratamentos simultâneos de cada planta, nas duas concentrações e nos dois tempos de exposição avaliados, não diferiram do índice de divisão celular do seu respectivo controle extrato aquoso da planta. As três plantas promoveram efeito citoprotetor significativo as células meristemáticas de raízes de A. cepa tratadas com Paracetamol, demonstrando, nas condições analisadas, potencial antimutagênico. Os resultados obtidos aqui com A. cepa sugerem a realização de mais estudos, com outros sistemas testes e diferentes esquemas de tratamento, para assim se definir, com propriedade, o real potencial citotóxico e antimutagênico destas plantas

Prevention of hypertension in patients with pre-hypertension: protocol for the PREVER-prevention trial

<p>Abstract</p> <p>Background</p> <p>Blood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage.</p> <p>Methods</p> <p>This is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution.</p> <p>Discussion</p> <p>The early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.</p> <p>Trial Registration</p> <p>Clinical Trials <a href="http://www.clinicaltrials.gov/ct2/show/NCT00970931">NCT00970931</a>.</p

MAMMALS IN PORTUGAL : A data set of terrestrial, volant, and marine mammal occurrences in P ortugal

Mammals are threatened worldwide, with 26% of all species being includedin the IUCN threatened categories. This overall pattern is primarily associatedwith habitat loss or degradation, and human persecution for terrestrial mam-mals, and pollution, open net fishing, climate change, and prey depletion formarine mammals. Mammals play a key role in maintaining ecosystems func-tionality and resilience, and therefore information on their distribution is cru-cial to delineate and support conservation actions. MAMMALS INPORTUGAL is a publicly available data set compiling unpublishedgeoreferenced occurrence records of 92 terrestrial, volant, and marine mam-mals in mainland Portugal and archipelagos of the Azores and Madeira thatincludes 105,026 data entries between 1873 and 2021 (72% of the data occur-ring in 2000 and 2021). The methods used to collect the data were: live obser-vations/captures (43%), sign surveys (35%), camera trapping (16%),bioacoustics surveys (4%) and radiotracking, and inquiries that represent lessthan 1% of the records. The data set includes 13 types of records: (1) burrowsjsoil moundsjtunnel, (2) capture, (3) colony, (4) dead animaljhairjskullsjjaws, (5) genetic confirmation, (6) inquiries, (7) observation of live animal (8),observation in shelters, (9) photo trappingjvideo, (10) predators dietjpelletsjpine cones/nuts, (11) scatjtrackjditch, (12) telemetry and (13) vocalizationjecholocation. The spatial uncertainty of most records ranges between 0 and100 m (76%). Rodentia (n=31,573) has the highest number of records followedby Chiroptera (n=18,857), Carnivora (n=18,594), Lagomorpha (n=17,496),Cetartiodactyla (n=11,568) and Eulipotyphla (n=7008). The data setincludes records of species classified by the IUCN as threatened(e.g.,Oryctolagus cuniculus[n=12,159],Monachus monachus[n=1,512],andLynx pardinus[n=197]). We believe that this data set may stimulate thepublication of other European countries data sets that would certainly contrib-ute to ecology and conservation-related research, and therefore assisting onthe development of more accurate and tailored conservation managementstrategies for each species. There are no copyright restrictions; please cite thisdata paper when the data are used in publications.info:eu-repo/semantics/publishedVersio