Publications by authors named "Joana Moreira"

41 Publications

Chalcones as Promising Antitumor Agents by Targeting the p53 Pathway: An Overview and New Insights in Drug-Likeness.

Molecules 2021 Jun 19;26(12). Epub 2021 Jun 19.

Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.

The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine double minute (MDM)2. Therefore, the reestablishment of p53 activity has received great attention concerning the discovery of new cancer therapeutics. Chalcones are naturally occurring compounds widely described as potential antitumor agents through several mechanisms, including those involving the p53 pathway. The inhibitory effect of these compounds in the interaction between p53 and MDM2 has also been recognized, with this effect associated with binding to a subsite of the p53 binding cleft of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of chalcones recognized as p53-MDM2 interaction inhibitors were accomplished considering molecular descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with those from p53-MDM2 in clinical trials. With this review, we expect to guide the design of new and more effective chalcones targeting the p53 pathway.
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http://dx.doi.org/10.3390/molecules26123737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233907PMC
June 2021

A New Chalcone Derivative with Promising Antiproliferative and Anti-Invasion Activities in Glioblastoma Cells.

Molecules 2021 Jun 3;26(11). Epub 2021 Jun 3.

3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco, 4805-017 Guimarães, Portugal.

Glioblastoma (GBM) is the most common and most deadly primary malignant brain tumor. Current therapies are not effective, the average survival of GBM patients after diagnosis being limited to few months. Therefore, the discovery of new treatments for this highly aggressive brain cancer is urgently needed. Chalcones are synthetic and naturally occurring compounds that have been widely investigated as anticancer agents. In this work, three chalcone derivatives were tested regarding their inhibitory activity and selectivity towards GBM cell lines (human and mouse) and a non-cancerous mouse brain cell line. The chalcone 1 showed the most potent and selective cytotoxic effects in the GBM cell lines, being further investigated regarding its ability to reduce critical hallmark features of GBM and to induce apoptosis and cell cycle arrest. This derivative showed to successfully reduce the invasion and proliferation capacity of tumor cells, both key targets for cancer treatment. Moreover, to overcome potential systemic side effects and its poor water solubility, this compound was encapsulated into liposomes. Therapeutic concentrations were incorporated retaining the potent in vitro growth inhibitory effect of the selected compound. In conclusion, our results demonstrated that this new formulation can be a promising starting point for the discovery of new and more effective drug treatments for GBM.
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http://dx.doi.org/10.3390/molecules26113383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199914PMC
June 2021

The Role of Anthocyanins, Deoxyanthocyanins and Pyranoanthocyanins on the Modulation of Tyrosinase Activity: An In Vitro and In Silico Approach.

Int J Mol Sci 2021 Jun 8;22(12). Epub 2021 Jun 8.

LAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.

Tyrosinase is the central enzyme involved in the highly complex process of melanin formation, catalyzing the rate-limiting steps of this biosynthetic pathway. Due to such a preponderant role, it has become a major target in the treatment of undesired skin pigmentation conditions and also in the prevention of enzymatic food browning. Numerous phenolic-based structures from natural sources have been pointed out as potential tyrosinase inhibitors, including anthocyanins. The aim of the present study was to individually assess the tyrosinase inhibitory activity of eight purified compounds with a variable degree of structural complexity: native anthocyanins, deoxyanthocyanins, and pyranoanthocyanins. The latter two, the groups of anthocyanin-related compounds with enhanced stability, were tested for the first time. Compounds to (luteolinidin, deoxymalvidin, cyanidin-, and malvidin-3--glucoside) revealed to be the most effective inhibitors, and further kinetic studies suggested their inhibition mechanism to be of a competitive nature. Structure-activity relationships were proposed based on molecular docking studies conducted with mushroom tyrosinase (mTYR) and human tyrosinase-related protein 1 (hTYRP1) crystal structures, providing information about the binding affinity and the different types of interactions established with the enzyme's active center which corroborated the findings of the inhibition and kinetic studies. Overall, these results support the applicability of these compounds as pigmentation modulators.
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http://dx.doi.org/10.3390/ijms22126192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230073PMC
June 2021

A Diarylpentanoid with Potential Activation of the p53 Pathway: Combination of in silico Screening Studies, Synthesis, and Biological Activity Evaluation.

ChemMedChem 2021 Jun 25. Epub 2021 Jun 25.

Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.

In silico studies of a library of diarylpentanoids led us to the identification of potential new MDM2/X ligands. The diarylpentanoids with the best docking scores obeying the druglikeness and ADMET prediction properties were subsequently synthesized and evaluated for their antiproliferative activity on colon cancer HCT116 and fibroblasts HFF-1 cells. The effect on p53-MDM2/X interactions was evaluated through yeast-based assays for compounds showing potent antiproliferative activity in HCT116 cells and low toxicity in normal cells, resulting in the identification of a potential dual inhibitor. Moreover, its antiproliferative effect was significantly reduced in the absence of p53 and in MDA-MB-231 cells expressing a mutant p53 form. The antiproliferative effect of this compound was associated with induction of cell cycle arrest, apoptosis, PARP cleavage and increased p53 and its transcriptional targets, p21 and PUMA, in HCT116 cells. Docking poses and residues involved in the inhibition of p53-MDM2/X interactions were predicted by docking studies.
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http://dx.doi.org/10.1002/cmdc.202100337DOI Listing
June 2021

Spin-coated freestanding films for biomedical applications.

J Mater Chem B 2021 05;9(18):3778-3799

3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal. and ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.

Spin-coating is a widely employed technique for the fabrication of thin-film coatings over large areas with smooth and homogeneous surfaces. In recent years, research has extended the scope of spin-coating by developing methods involving the interface of the substrate and the deposited solution to obtain self-supported films, also called freestanding films. Thereby, such structures have been developed for a wide range of areas. Biomedical applications of spin-coated freestanding films include wound dressings, drug delivery, and biosensing. This review will discuss the fundamental physical and chemical processes governing the conventional spin-coating as well as the techniques to obtain freestanding films. Furthermore, developments within this field with a primary focus on tissue engineering applications will be reviewed.
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http://dx.doi.org/10.1039/d1tb00233cDOI Listing
May 2021

Long-term safety and tolerability of adjunctive eslicarbazepine acetate in children with focal seizures.

Epilepsy Behav 2020 11 24;112:107458. Epub 2020 Sep 24.

Sunovion Pharmaceuticals Inc., Marlborough, MA, USA. Electronic address:

Objective: The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive eslicarbazepine acetate (ESL) in children with focal seizures.

Methods: Safety data from patients aged 4-17 years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1-2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5 years total duration). The OLEs evaluated the safety and tolerability of ESL (10-30 mg/kg/day; maximum 1200 mg/day).

Results: The 1-year OLE and post-1-year OLE safety populations comprised 337 and 177 ESL-treated patients, respectively. The overall incidence of treatment-emergent adverse events (TEAEs) with ESL was 64.1% during the 1-year OLE and 52.5% during the post-1-year OLE. Nasopharyngitis, partial seizures, vomiting, pyrexia, headache, somnolence, and respiratory tract infection were the most frequently reported TEAEs during the 1-year OLE. The overall incidence of serious adverse events (AEs) was 8.9% during the 1-year OLE and 10.2% during the post-1-year OLE. Partial seizures (1.2%) and pneumonia (1.2%) were the most frequently reported serious AEs during the 1-year OLE. The overall incidence of TEAEs leading to discontinuation was 4.2% during the 1-year OLE and 0.6% during the post-1-year OLE. Partial seizures (1.5%) was the most frequently reported TEAE leading to discontinuation during the 1-year OLE.

Conclusions: Overall, long-term treatment with ESL was generally well tolerated in pediatric patients aged 4-17 years with focal seizures. TEAEs were comparable to those observed in adults with no new events of concern.
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http://dx.doi.org/10.1016/j.yebeh.2020.107458DOI Listing
November 2020

Long-term efficacy and safety of eslicarbazepine acetate monotherapy for adults with newly diagnosed focal epilepsy: An open-label extension study.

Epilepsia 2020 10 17;61(10):2129-2141. Epub 2020 Sep 17.

Bial-Portela & Cª, S.A., Coronado, Portugal.

Objective: To assess the efficacy, safety, and tolerability of eslicarbazepine acetate (ESL) monotherapy during long-term treatment.

Methods: An open-label extension (OLE) study was conducted in adults completing a phase 3, randomized, double-blind, noninferiority trial, during which they had received monotherapy with either once-daily ESL or twice-daily controlled-release carbamazepine (CBZ-CR) for newly diagnosed focal epilepsy. In the OLE study, all patients received ESL (800-1600 mg/d) for 2 years. Primary efficacy outcome was retention time (from baseline of the OLE study). Secondary efficacy assessments included seizure freedom rate (no seizures during the OLE study) and responder rate (≥50% seizure frequency reduction from baseline of double-blind trial). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs).

Results: Of 206 randomized patients, 96 who received ESL in the double-blind trial (ESL/ESL) and 88 who received CBZ-CR in the double-blind trial (CBZ-CR/ESL) were treated with ESL monotherapy (89.3% overall). Treatment retention time was similar between groups, with low probability of ESL withdrawal overall (<0.07 at any time). After 24 months, the probability of ESL withdrawal was 0.0638 (95% confidence interval [CI] = 0.0292-0.1366) in the ESL/ESL group and 0.0472 (95% CI = 0.0180-0.1210) in the CBZ-CR/ESL group. Seizure freedom rates were 90.6% (ESL/ESL) and 80.7% (CBZ-CR/ESL; P = .0531). Responder rates remained >80% in both groups throughout the study. Incidence of serious TEAEs was similar between groups (7.3% vs 5.7%; 0% vs 1.1% possibly related), as were the incidences of TEAEs considered at least possibly related to treatment (17.7% vs 18.2%) and TEAEs leading to discontinuation (3.1% vs 4.5%). The types of TEAEs were generally consistent with the known safety profile of ESL.

Significance: ESL monotherapy was efficacious and generally well tolerated over the long term, including in patients who transitioned from CBZ-CR monotherapy. No new safety concerns emerged.
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http://dx.doi.org/10.1111/epi.16666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693183PMC
October 2020

Analysing the Initial Bacterial Adhesion to Evaluate the Performance of Antifouling Surfaces.

Antibiotics (Basel) 2020 Jul 17;9(7). Epub 2020 Jul 17.

LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal.

The aim of this work was to study the initial events of adhesion to polydimethylsiloxane, which is critical for the development of antifouling surfaces. A parallel plate flow cell was used to perform the initial adhesion experiments under controlled hydrodynamic conditions (shear rates ranging between 8 and 100/s), mimicking biomedical scenarios. Initial adhesion studies capture more accurately the cell-surface interactions as in later stages, incoming cells may interact with the surface but also with already adhered cells. Adhesion rates were calculated and results shown that after some time (between 5 and 9 min), these rates decreased (by 55% on average), from the initial values for all tested conditions. The common explanation for this decrease is the occurrence of hydrodynamic blocking, where the area behind each adhered cell is screened from incoming cells. This was investigated using a pair correlation map from which two-dimensional histograms showing the density probability function were constructed. The results highlighted a lower density probability (below 4.0 × 10) of the presence of cells around a given cell under different shear rates irrespectively of the radial direction. A shadowing area behind the already adhered cells was not observed, indicating that hydrodynamic blocking was not occurring and therefore it could not be the cause for the decreases in cell adhesion rates. Afterward, cell transport rates from the bulk solution to the surface were estimated using the Smoluchowski-Levich approximation and values in the range of 80-170 cells/cm.s were obtained. The drag forces that adhered cells have to withstand were also estimated and values in the range of 3-50 × 10 N were determined. Although mass transport increases with the flow rate, drag forces also increase and the relative importance of these factors may change in different conditions. This work demonstrates that adjustment of operational parameters in initial adhesion experiments may be required to avoid hydrodynamic blocking, in order to obtain reliable data about cell-surface interactions that can be used in the development of more efficient antifouling surfaces.
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http://dx.doi.org/10.3390/antibiotics9070421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400106PMC
July 2020

Carbon Nanotube/Poly(dimethylsiloxane) Composite Materials to Reduce Bacterial Adhesion.

Antibiotics (Basel) 2020 Jul 22;9(8). Epub 2020 Jul 22.

LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Roberto Frias, 4200-465 Porto, Portugal.

Different studies have shown that the incorporation of carbon nanotubes (CNTs) into poly(dimethylsiloxane) (PDMS) enables the production of composite materials with enhanced properties, which can find important applications in the biomedical field. In the present work, CNT/PDMS composite materials have been prepared to evaluate the effects of pristine and chemically functionalized CNT incorporation into PDMS on the composite's thermal, electrical, and surface properties on bacterial adhesion in dynamic conditions. Initial bacterial adhesion was studied using a parallel-plate flow chamber assay performed in conditions prevailing in urinary tract devices (catheters and stents) using as a model organism and PDMS as a control due to its relevance in these applications. The results indicated that the introduction of the CNTs in the PDMS matrix yielded, in general, less bacterial adhesion than the PDMS alone and that the reduction could be dependent on the surface chemistry of CNTs, with less adhesion obtained on the composites with pristine rather than functionalized CNTs. It was also shown CNT pre-treatment and incorporation by different methods affected the electrical properties of the composites when compared to PDMS. Composites enabling a 60% reduction in cell adhesion were obtained by CNT treatment by ball-milling, whereas an increase in electrical conductivity of seven orders of magnitude was obtained after solvent-mediated incorporation. The results suggest even at low CNT loading values (1%), these treatments may be beneficial for the production of CNT composites with application in biomedical devices for the urinary tract and for other applications where electrical conductance is required.
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http://dx.doi.org/10.3390/antibiotics9080434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459730PMC
July 2020

Aortic Anastomotic Aneurysm After Infra Renal Grafting.

Rev Port Cir Cardiotorac Vasc 2020 Apr-Jun;27(2):145

Angiology and Vascular Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

An 87 year-old male presented with a 71mm proximal anastomotic aneurysm causing left renal artery displacement (Figures 1 and 2), 19 years after infra-renal aorto-aortic grafting for an infra-renal abdominal aortic aneurysm. Dilatation of visceral aorta was also observed. Management would be challenging but patient denied further intervention.
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October 2020

Erratum: Moreira, J., et al., Spin-Coated Polysaccharide-Based Multilayered Freestanding Films with Adhesive and Bioactive Moieties. 2020, , 840.

Molecules 2020 Jun 12;25(12). Epub 2020 Jun 12.

3Bs Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Barco, 4805-017 Guimarães, Portugal.

The authors wish to make changes to the published paper [...].
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http://dx.doi.org/10.3390/molecules25122727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355543PMC
June 2020

Synthesis of a Small Library of Nature-Inspired Xanthones and Study of Their Antimicrobial Activity.

Molecules 2020 May 21;25(10). Epub 2020 May 21.

CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal.

A series of thirteen xanthones - was prepared based on substitutional (appendage) diversity reactions. The series was structurally characterized based on their spectral data and HRMS, and the structures of xanthone derivatives , , and were determined by single-crystal X-ray diffraction. This series, along with an in-house series of aminated xanthones - was tested for in-vitro antimicrobial activity against seven bacterial (including two multidrug-resistant) strains and five fungal strains. 1-(Dibromomethyl)-3,4-dimethoxy-9-xanthen-9-one () and 1-(dibromomethyl)-3,4,6-trimethoxy-9-xanthen-9-one () exhibited antibacterial activity against all tested strains. In addition, 3,4-dihydroxy-1-methyl-9-xanthen-9-one () revealed a potent inhibitory effect on the growth of dermatophyte clinical strains ( FF5, FF1 and FF9), with a MIC of 16 µg/mL for all the tested strains. Compounds and showed a potent inhibitory effect on two virulence factors: germ tube and biofilm formation.
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http://dx.doi.org/10.3390/molecules25102405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287773PMC
May 2020

Norhierridin B, a New Hierridin B-Based Hydroquinone with Improved Antiproliferative Activity.

Molecules 2020 Mar 30;25(7). Epub 2020 Mar 30.

Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.

Hierridin B (), a methylated hydroquinone isolated from the marine picocyanobacterium sp. LEGE 06113, moderately inhibited the growth of colon adenocarcinoma HT-29 cells. Aiming to improve the potential antitumor activity of this natural product, the demethylated analogue, norhierridin B (), as well as its structurally-related quinone (), were synthesized and evaluated for their growth inhibitory effect on a panel of human tumor cell lines, including the triple-negative breast cancer (TNBC) cells MDA-MB-231, SKBR3, and MDA-MB-468. Norhierridin B () showed a potent growth inhibitory effect on all cancer cell lines. Moreover, the growth inhibitory effect of compound on MDA-MB-231 cells was associated with cell cycle arrest and apoptosis. Norhierridin B () interfered with several p53 transcriptional targets, increasing p21, Bax, and MDM2, while decreasing Bcl-2 protein levels, which suggested the potential activation of a p53 pathway. Altogether, these results evidenced a great improvement of the antitumor activity of hydroquinone when compared to and its structurally-related quinone (). Notably, hydroquinone displayed a prominent growth inhibitory activity against TNBC cells, which are characterized by high therapeutic resistance.
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http://dx.doi.org/10.3390/molecules25071578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181126PMC
March 2020

Diarylpentanoids with antitumor activity: A critical review of structure-activity relationship studies.

Eur J Med Chem 2020 Apr 27;192:112177. Epub 2020 Feb 27.

Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira nº 228, 4050-313, Porto, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208, Matosinhos, Portugal. Electronic address:

Diarypentanoids are commonly considered as monocarbonyl analogues of curcumin. Since the discovery of this compound in 1962, twenty one diarylpentanoids have been isolated and almost 600 synthetic analogues with antitumor activity have been synthesized. This review reports the exploitation of diarylpentanoids to develop curcumin analogues with improved antitumor activity over the last two decades. The mechanism of action and structure-activity relationship (SAR) studies are also highlighted. More importantly, structural features for the antitumor activity that may guide the design of new and more effective diarylpentanoids are also proposed.
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http://dx.doi.org/10.1016/j.ejmech.2020.112177DOI Listing
April 2020

Efficacy and safety of eslicarbazepine acetate as adjunctive therapy for refractory focal-onset seizures in children: A double-blind, randomized, placebo-controlled, parallel-group, multicenter, phase-III clinical trial.

Epilepsy Behav 2020 04 6;105:106962. Epub 2020 Mar 6.

BIAL - Portela & Cª. S.A., S. Mamede do Coronado, Portugal; Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University Porto, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University Porto, Porto, Portugal. Electronic address:

Purpose: This was a phase-III, randomized, double-blind, placebo-controlled study aimed to evaluate efficacy and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in pediatric patients with refractory focal-onset seizures (FOS).

Methods: Children (2-18 years old) with FOS, receiving 1-2 antiepileptic drugs, were randomized to ESL or placebo. Treatment was started at 10 mg/kg/day, up-titrated up to 20-30 mg/kg/day, and maintained for 12 weeks, followed by one-year open-label follow-up. Primary efficacy endpoints were relative reduction in standardized seizure frequency (SSF) and proportion of responders (≥50% SSF reduction) from baseline. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs).

Results: The intention-to-treat (ITT) set included 134 patients randomized to ESL and 129 to placebo; 89.6% and 91.5%, respectively, completed the trial. An unbalanced number of seizures at baseline were observed between groups. Least square (LS) mean relative change in SSF from baseline was higher in the ESL group (-18.1%) than in placebo (-8.6%). Proportion of responders between ESL and placebo groups was not statistically different. A post hoc analysis showed greater relative reduction in SSF in patients above 6 years old treated with ESL 20 or 30 mg/kg/day compared with placebo; this was significant in patients above 6 years old treated with ESL 30 mg/kg/day (LS mean difference: 31.9%; p = 0.0478). The observed safety profile in children was consistent with that established in adult studies.

Conclusions: Adjunctive ESL treatment was well-tolerated, but this trial failed to demonstrate that ESL was more effective than placebo in the predefined efficacy endpoints; factors that may have contributed to this outcome, affecting particularly the young age group, include etiological heterogeneity, difficulty in recognizing simple partial seizures, high seizure frequency with risk of imbalance, and underestimation of the efficacious dose range.
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http://dx.doi.org/10.1016/j.yebeh.2020.106962DOI Listing
April 2020

Spin-Coated Polysaccharide-Based Multilayered Freestanding Films with Adhesive and Bioactive Moieties.

Molecules 2020 Feb 14;25(4). Epub 2020 Feb 14.

3Bs Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark, Barco, 4805-017 Guimarães, Portugal.

Freestanding films based on catechol functionalized chitosan (CHI), hyaluronic acid (HA), and bioglass nanoparticles (BGNPs) were developed by spin-coating layer-by-layer assembly (SA-LbL). The catechol groups of 3,4-dihydroxy-l-phenylalanine (DOPA) present in the marine mussels adhesive proteins (MAPs) are the main factors responsible for their characteristic strong wet adhesion. Then, the produced films were cross-linked with genipin to improve their stability in wet state. Overall, the incorporation of BGNPs resulted in thicker and bioactive films, hydrophilic and rougher surfaces, reduced swelling, higher weight loss, and lower stiffness. The incorporation of catechol groups onto the films showed a significant increase in the films' adhesion and stiffness, lower swelling, and weight loss. Interestingly, a synergetic effect on the stiffness increase was observed upon the combined incorporation of BGNPs with catechol-modified polymers, given that such films were the stiffest. Regarding the biological assays, the films exhibited no negative effects on cellular viability, adhesion, and proliferation, and the BGNPs seemed to promote higher cellular metabolic activity. These bioactive LbL freestanding films combine enhanced adhesion with improved mechanical properties and could find applications in the biomedical field, such as guided hard tissue regeneration membranes.
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http://dx.doi.org/10.3390/molecules25040840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070374PMC
February 2020

Combined Endovascular Exclusion with Percutaneous Sac Aspiration and Thrombin Injection in the Management of Popliteal Artery Aneurysm.

Ann Vasc Surg 2020 Jul 1;66:662-664. Epub 2020 Feb 1.

Angiology and Vascular Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Background: Symptomatic popliteal artery aneurysms (PAAs) can be managed by open surgery or endovascular exclusion.

Methods: The authors describe a case of a 68-mm PAA causing compressive symptoms and managed by endovascular exclusion combined with percutaneous sac decompression.

Results: Endovascular exclusion allows sac pressure reduction. Additional percutaneous sac aspiration and thrombin injection promote sac shrinking and avoid persistent collateral flow.

Conclusions: In challenging cases, matching different techniques can be helpful.
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http://dx.doi.org/10.1016/j.avsg.2020.01.084DOI Listing
July 2020

Safety and Tolerability of Adjunctive Eslicarbazepine Acetate in Pediatric Patients (Aged 4-17 Years) With Focal Seizures.

J Child Neurol 2020 03 26;35(4):265-273. Epub 2019 Dec 26.

Sunovion Pharmaceuticals Inc, Marlborough, MA, USA.

Objective: To evaluate the safety and tolerability of adjunctive eslicarbazepine acetate (ESL) in pediatric patients (aged 4-17 years) with refractory focal seizures.

Methods: Pooled safety data from patients aged 4-17 years in Study 208 (NCT01527513) and Study 305 (NCT00988156) were analyzed. Both were randomized, double-blind, placebo-controlled studies of ESL as adjunctive treatment in pediatric patients with refractory focal seizures receiving 1 or 2 antiepileptic drugs. Incidences of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs of special interest were evaluated.

Results: The safety population comprised 362 patients (placebo, n = 160; ESL, n = 202). The overall incidence of TEAEs was similar between the ESL (67.8%) and placebo groups (65.6%), with no clear dose-response relationship. The most frequently reported TEAEs with ESL were headache, somnolence, vomiting, and diplopia. Overall incidences of SAEs and TEAEs leading to discontinuation were higher with ESL versus placebo (9.9% vs 5.0% and 5.9% vs 2.5%, respectively). The majority of SAEs with ESL occurred in Study 305. Two deaths were reported, 1 with ESL (0.5%) due to cluster seizures (resulting in herniation of the cerebellar tonsils) and 1 with placebo (0.6%) due to asphyxia. TEAEs related to allergic reaction, hyponatremia, hypothyroidism, cytopenia, seizure exacerbation, cognitive dysfunction, psychiatric disorders, or suicide occurred infrequently (<9%).

Conclusion: Adjunctive ESL was generally well tolerated in children aged 4-17 years with focal seizures. The safety profile of ESL in children was comparable to that observed in adults.
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http://dx.doi.org/10.1177/0883073819890997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005936PMC
March 2020

Chalcone derivatives targeting mitosis: synthesis, evaluation of antitumor activity and lipophilicity.

Eur J Med Chem 2019 Dec 3;184:111752. Epub 2019 Oct 3.

Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos S/n, 4450-208, Matosinhos, Portugal. Electronic address:

This study describes the synthesis of a series of chalcones, including pyrazole and α,β-epoxide derivatives, and evaluation of their cell growth inhibitory activity in three human tumor cell lines, as well as their lipophilicity using liposomes as a biomimetic membrane model. Structure-activity and structure-lipophilicity relationships were established for the synthetized chalcones. From this work, nine chalcones (3, 5, 9, 11, 15-19) showing suitable drug-like lipophilicity with potent growth inhibitory activity were identified, being the growth inhibitory effect of compounds 15-17 associated with a pronounced antimitotic effect. Compounds 15-17 affected spindle assembly and, as a consequence, arrested cells at metaphase in NCI-H460 cells, culminating in cell death. Amongst the compounds tested, compound 15 exhibited the highest antimitotic activity as revealed by mitotic index calculation. Moreover, 15 was able to enhance chemosensitivity of tumor cells to low doses of paclitaxel in NCI-H460 cells. The results indicate that 15 exerts its antiproliferative activity by affecting microtubules and causing cell death subsequently to a mitotic arrest, and thus has the potential for antitumor activity.
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http://dx.doi.org/10.1016/j.ejmech.2019.111752DOI Listing
December 2019

Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy.

Epilepsia 2019 07 1;60(7):1341-1352. Epub 2019 Jul 1.

BIAL - Portela & Cª., S.A., Coronado (S. Romão e S. Mamede), Portugal.

Objective: To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal- (partial-) onset seizures.

Methods: This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400-1200 mg once daily), two phase 3 trials of ESL monotherapy (1200-1600 mg once daily), and their open-label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na ]), incidences of hyponatremia-related treatment-emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia.

Results: The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open-label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na ] measurement ≤125 mEq/L, <9% had a >10 mEq/L decrease in [Na ] from baseline, <6% had a hyponatremia-related TEAE, and <2% discontinued the controlled trials due to a hyponatremia-related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator-reported TEAE of "hyponatremia" or "blood sodium decreased" did not have a corresponding laboratory [Na ] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na ] measurement ≤125 mEq/L.

Significance: Reductions in serum sodium concentrations and hyponatremia-related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na ] measurements.
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http://dx.doi.org/10.1111/epi.16069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852335PMC
July 2019

Bilateral assessment of body core temperature through axillar, tympanic and inner canthi thermometers in a young population.

Physiol Meas 2019 09 30;40(9):094001. Epub 2019 Sep 30.

LABIOMEP, INEGI-LAETA, Faculdade de Engenharia, Universidade do Porto, Porto, Portugal. Faculty of Computing, Engineering and Science, University of South Wales, Pontypridd, United Kingdom. Author to whom any correspondence should be addressed.

There are several sites in which the human body core temperature can be estimated and used to identify febrile states in a threat of pandemic situations at high-populational-traffic places (e.g. airports, ports, universities, schools, public buildings). In these locations, a fast method is required for temperature screening of masses. The most common methods are axillar and tympanic thermometers. However, in addition, measurement of the inner canthi (IC) of the eye with infrared thermal (IRT) imaging has been suggested as a fast mass measurement screening tool.

Objective: It is the aim of this research to identify the bilateral difference of the available body temperature screening methods with potential use for large-scale fever screening and to verify if such a difference is acceptable.

Approach: A total of 206 young participants (104 females and 102 males) were recruited, having their temperatures taken with the different methods bilaterally under neutral environmental conditions. The obtained results were statistically processed.

Main Results: Results established absent reference data for site and method in west European populations. The bilateral differences were minor using the IC of the eye monitored with infrared imaging, which was also proved with the Bland-Altmann limits of agreement.

Significance: Based on the findings of this research, despite all methods being able to estimate body core temperature, it is suggested to use IRT images of the IC of the eye, due to its fast, reliable and reproducible procedure for mass screening. Further research is required to understand the higher bilateral variability in using the traditional thermometer axilla and tympanic membrane assessments, since these are the methods currently used within a clinical setup. The same procedure must be applied to fever cases to establish a decision threshold per method.
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http://dx.doi.org/10.1088/1361-6579/ab2af6DOI Listing
September 2019

Unusual Presentation of Ruptured Abdominal Aortic Aneurysm.

Rev Port Cir Cardiotorac Vasc 2019 Jan-Mar;26(1):71-73

Angiology and Vascular Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Abdominal aortic aneurysm affects 5-9% of the population over the age of 65 years; is more common in male smokers and in patients with a positive family history of aortic aneurysms. Most patients are asymptomatic; rupture is the most common and dreaded complication. The classical triad of back pain, hypotension and pulsatile mass is the most common presentation but is present in only 25-50% of patients. Clinical presentation seems dependent on rupture site. Our report illustrate a rare clinical presentation for a serious clinical condition. Knowledge of different presentations can lead to timely diagnosis and management and decrease in rupture related morbidity and mortality.
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September 2019

New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma.

Cancer Lett 2019 04 19;446:90-102. Epub 2019 Jan 19.

LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n.° 228, 4050-313, Porto, Portugal. Electronic address:

TAp73 is a key tumor suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumors with impaired p53 signaling, like neuroblastoma, TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumor growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumor activity. Notably, LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53, enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumor cells. Importantly, LEM2 displayed potent antitumor activity against patient-derived neuroblastoma cells, consistent with an activation of the TAp73 pathway. Additionally, potent synergistic effects were obtained for the combination of LEM2 with doxorubicin and cisplatin in patient-derived neuroblastoma cells. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against neuroblastoma.
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http://dx.doi.org/10.1016/j.canlet.2019.01.014DOI Listing
April 2019

New Alkoxy Flavone Derivatives Targeting Caspases: Synthesis and Antitumor Activity Evaluation.

Molecules 2018 Dec 31;24(1). Epub 2018 Dec 31.

Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.

The antitumor activity of natural flavonoids has been exhaustively reported. Previously it has been demonstrated that prenylation of flavonoids allows the discovery of new compounds with improved antitumor activity through the activation of caspase-7 activity. The synthesis of twenty-five flavonoids (⁻) with one or more alkyl side chains was carried out. The synthetic approach was based on the reaction with alkyl halide in alkaline medium by microwave (MW) irradiation. The in vitro cell growth inhibitory activity of synthesized compounds was investigated in three human tumor cell lines. Among the tested compounds, derivatives , , , , , , and revealed potent growth inhibitory activity (GI < 10 μM), being the growth inhibitory effect of compound related with a pronounced caspase-7 activation on MCF-7 breast cancer cells and yeasts expressing human caspase-7. A quantitative structure-activity relationship (QSAR) model predicted that hydrophilicity, pattern of ring substitution/shape, and presence of partial negative charged atoms were the descriptors implied in the growth inhibitory effect of synthesized compounds. Docking studies on procaspase-7 allowed predicting the binding of compound to the allosteric site of procaspase-7.
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http://dx.doi.org/10.3390/molecules24010129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337158PMC
December 2018

Targeting the MDM2-p53 protein-protein interaction with prenylchalcones: Synthesis of a small library and evaluation of potential antitumor activity.

Eur J Med Chem 2018 Aug 17;156:711-721. Epub 2018 Jul 17.

Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal; Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/nm, 4450-208, Matosinhos, Portugal. Electronic address:

Prenylation of several bioactive scaffolds is a very interesting strategy used in Medicinal Chemistry in order to improve biological/pharmacological effects. A small library of prenylchalcones was synthesized and evaluated for the ability to inhibit the MDM2-p53 interaction using a yeast-based assay. The capacity of all synthesized prenylchalcones and their non-prenylated precursors to inhibit the growth of human colon tumor HCT116 cells was also evaluated. The obtained results led to the identification of a hit compound, prenylchalcone 2e, which behaved as potential inhibitor of the MDM2-p53 interaction in yeast, and showed improved cytotoxicity against human tumor cells expressing wild-type p53, including liver hepatocellular carcinoma HepG2, breast adenocarcinoma MCF-7, and malignant melanoma A375 cells. In colon cancer cells, it was also shown that the growth inhibitory effect of prenylchalcone 2e was associated with the induction of cell cycle arrest, apoptosis, and increased protein expression levels of p53 transcriptional targets. Moreover, computational docking studies were performed in order to predict docking poses and residues involved in the MDM2-p53 potential interaction.
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http://dx.doi.org/10.1016/j.ejmech.2018.07.037DOI Listing
August 2018

Eslicarbazepine acetate exposure in pregnant women with epilepsy.

Seizure 2018 May 10;58:72-74. Epub 2018 Apr 10.

Dept. Research & Development, BIAL - Portela & C(a),, S.A., 4745-457 Coronado (S. Romão e S. Mamede), Portugal(1); Dept. of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University Porto, Porto, Portugal; MedInUP, Center for Drug Discovery and Innovative Medicines, University Porto, Porto, Portugal.

Purpose: Epilepsy is a common neurologic disorder requiring continued treatment during pregnancy. Treatment with antiepileptic drugs (AEDs) is needed for seizure control, but the risk of adverse events has to be minimized for both mother and foetus. Available data on pregnancy and foetal/postnatal outcomes following eslicarbazepine acetate (ESL) exposure via parent is herein presented for the first time.

Methods: ESL's global safety database was reviewed to identify pregnancy cases with exposure to ESL reported up to October 21st, 2017. The EMBASE™ and MEDLINE databases were searched to identify literature reports of such cases published between May 1st, 2009 and October 21st, 2017.

Results: Overall, 91 notifications of pregnancy were identified, of which 79 involved ESL exposure: 28 during clinical trials and 51 from 8-years of post-marketing surveillance. Thirty pregnancies resulted in live birth without congenital anomalies; in 25 pregnancies the outcome was ongoing and 3 was unknown; 18 cases resulted in abortion (10 spontaneous and 8 induced) and congenital anomalies were identified in 5 cases (no clear relationship with ESL was established). ESL was used concomitantly to other AEDs in 11 of the 15 pregnancies for which the outcome was spontaneous abortion and congenital anomaly. Literature review did not yield additional information.

Conclusions: Available data are insufficient to draw conclusions regarding ESL use during pregnancy. Although no particular safety problem was identified, ESL exposure during pregnancy will continue to be monitored and evaluated.
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http://dx.doi.org/10.1016/j.seizure.2018.04.007DOI Listing
May 2018

Effects of adjunctive eslicarbazepine acetate on serum lipids in patients with partial-onset seizures: Impact of concomitant statins and enzyme-inducing antiepileptic drugs.

Epilepsy Res 2018 03 9;141:83-89. Epub 2018 Feb 9.

Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, USA. Electronic address:

Purpose: To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences.

Subjects And Methods: We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200 mg once daily) in patients with treatment-refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period.

Key Findings: In total, 426 and 1021 placebo- and ESL-treated patients, respectively, were included in the analysis. With regard to the changes from baseline in serum concentrations, there were statistically significant differences between the placebo and ESL 1200 mg QD groups, for both total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), but the effect sizes were small (+4.1 mg/dL and +1.8 mg/dL, respectively). A small but significant difference in low-density lipoprotein cholesterol (LDL-C; -5.0 mg/dL) was observed between the ESL 400 mg QD group and the placebo group. In patients not taking a concomitant EIAED, there were no changes with ESL 400 mg QD, but modest and statistically significant increases in cholesterol fractions (TC, LDL-C and HDL-C) with ESL 800 mg QD (<6 mg/dL) and ESL 1200 mg QD (<10 mg/dL). ESL had no consistent effect on lipids in patients taking a concomitant EIAED. In patients taking statins during baseline, there were no clinically relevant changes in serum lipids during use of ESL, although the subgroups were small.

Significance: These results suggest that ESL does not appear to have clinically significant effects on serum lipids, nor does the pharmacokinetic interaction between ESL and statins have an impact on serum lipid concentrations.
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http://dx.doi.org/10.1016/j.eplepsyres.2018.02.001DOI Listing
March 2018

Pooled efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: Data from four double-blind placebo-controlled pivotal phase III clinical studies.

CNS Neurosci Ther 2017 Dec 13;23(12):961-972. Epub 2017 Oct 13.

Department of Research and Development, BIAL - Portela & Cª, S.A., S. Mamede do Coronado, Portugal.

Purpose: Pooled evaluation of the key efficacy and safety profile of eslicarbazepine acetate (ESL) added-on to stable antiepileptic therapy in adults with focal-onset seizures.

Methods: Data from 1703 patients enrolled in four phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2 week titration period, ESL was administered at 400 mg, 800 mg, and 1200 mg once-daily doses for 12 weeks (maintenance period). Pooled efficacy variable was standardized (/4 weeks) seizure frequency (SSF) analyzed over the maintenance period as reduction in absolute and relative SSF and proportion of responders (≥50% reduction in SSF). Pooled safety was analyzed by means of adverse events and clinical laboratory assessments.

Results: SSF was significantly reduced with ESL 800 mg (P < 0.0001) and 1200 mg (P < 0.0001) compared to placebo. Median relative reduction in SSF was 33.4% for ESL 800 mg and 37.8% for 1200 mg (placebo: 17.6%), and responder rate was 33.8% and 43.1% (placebo: 22.2%). ESL was more efficacious than placebo regardless of gender, geographical region, epilepsy duration, age at time of diagnosis, seizure type, and type of concomitant antiepileptic drugs (AED). Incidence of adverse events (AEs) and AEs leading to discontinuation was dose dependent. Most common AEs (>10% patients) were dizziness, somnolence, and nausea. The incidence of treatment-emergent AEs (dizziness, somnolence, ataxia, vomiting, and nausea) was lower in patients who began taking ESL 400 mg (followed by 400 mg increments to 800 or 1200 mg) than in those who began taking ESL 600 mg or 800 mg.

Conclusions: Once-daily ESL 800 mg and 1200 mg showed consistent results across all efficacy and safety endpoints, independent of study population characteristics and type of concomitant AEDs. Treatment initiated with ESL 400 mg followed by 400 mg increments to 800 or 1200 mg provides optimal balance of efficacy and tolerability.
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http://dx.doi.org/10.1111/cns.12765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813188PMC
December 2017

Surface conditioning with cell wall components can reduce biofilm formation by decreasing initial adhesion.

AIMS Microbiol 2017 18;3(3):613-628. Epub 2017 Jul 18.

LEPABE-Department of Chemical Engineering, Faculty of Engineering, University of Porto, Porto, Portugal.

Bacterial adhesion and biofilm formation on food processing surfaces pose major risks to human health. Non-efficient cleaning of equipment surfaces and piping can act as a conditioning layer that affects the development of a new biofilm post-disinfection. We have previously shown that surface conditioning with cell extracts could reduce biofilm formation. In the present work, we hypothesized that cell wall components could be implicated in this phenomena and therefore mannose, myristic acid and palmitic acid were tested as conditioning agents. To evaluate the effect of surface conditioning and flow topology on biofilm formation, assays were performed in agitated 96-well microtiter plates and in a parallel plate flow chamber (PPFC), both operated at the same average wall shear stress (0.07 Pa) as determined by computational fluid dynamics (CFD). It was observed that when the 96-well microtiter plate and the PPFC were used to form biofilms at the same shear stress, similar results were obtained. This shows that the referred hydrodynamic feature may be a good scale-up parameter from high-throughput platforms to larger scale flow cell systems as the PPFC used in this study. Mannose did not have any effect on biofilm formation, but myristic and palmitic acid inhibited biofilm development by decreasing cell adhesion (in about 50%). These results support the idea that in food processing equipment where biofilm formation is not critical below a certain threshold, bacterial lysis and adsorption of cell components to the surface may reduce biofilm buildup and extend the operational time.
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http://dx.doi.org/10.3934/microbiol.2017.3.613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604997PMC
July 2017

Adjunctive eslicarbazepine acetate: A pooled analysis of three phase III trials.

Epilepsy Behav 2017 07 7;72:127-134. Epub 2017 Jun 7.

Sunovion Pharmaceuticals Inc., Marlborough, MA, USA. Electronic address:

Objective: To assess the safety and efficacy of once-daily (QD) adjunctive eslicarbazepine acetate (ESL).

Methods: This post-hoc pooled analysis of three randomized, placebo-controlled trials (2093-301, -302, -304) involved adults with refractory partial-onset seizures (POS) receiving 1-3 antiepileptic drugs (AEDs). All studies included 8-week baseline, 2-week titration, and 12-week maintenance periods. Patients were randomized equally to placebo, ESL 400mg (studies 301, 302), 800mg, or 1200mg QD. The primary endpoint was standardized seizure frequency (SSF; per 4weeks); secondary endpoints included responder rates (maintenance period), and incidence of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, serious AEs (SAEs), and deaths.

Results: The safety and efficacy analysis populations totaled 1447 and 1410 patients, respectively. SSF was significantly reduced versus placebo with ESL 800mg (p=0.0001) and 1200mg (p<0.0001) but not 400mg (p=0.81). There were no significant interactions between treatment effect and age, gender, race/ethnicity, geographic region, epilepsy duration, or concomitant AED use. Incidences of TEAEs and TEAEs leading to discontinuation increased with ESL dose. Incidences of the most frequent TEAEs were lower for patients who initiated dosing at 400 versus 800mg QD, regardless of titration regimen and maintenance dose. SAE incidence was <10%; there were 3 deaths (placebo, n=2; ESL 800mg, n=1).

Conclusions: ESL (800 and 1200mg QD) was effective and well tolerated as adjunctive therapy for adults with refractory POS.
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http://dx.doi.org/10.1016/j.yebeh.2017.04.019DOI Listing
July 2017
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