Paediatric clinical study of 3D printed personalised medicines for rare metabolic disorders.

Rare diseases are infrequent, but together they affect up to 6-10 % of the world's population, mainly children. Patients require precise doses and strict adherence to avoid metabolic or cardiac failure in some cases, which cannot be addressed in a reliable way using pharmaceutical compounding. 3D printing (3DP) is a disruptive technology that allows the real-time personalization of the dose and the modulation of the dosage form to adapt the medicine to the therapeutic needs of each patient. 3D printed chewable medicines containing amino acids (citrulline, isoleucine, valine, and isoleucine and valine combinations) were prepared in a hospital setting, and the efficacy and acceptability were evaluated in comparison to conventional compounded medicines in six children. The inclusion of new flavours (lemon, vanilla and peach) to obtain more information on patient preferences and the implementation of a mobile app to obtain patient feedback in real-time was also used. The 3D printed medicines controlled amino acid levels within target levels as well as the conventional medicines. The deviation of citrulline levels was narrower and closer within the target concentration with the chewable formulations. According to participants' responses, the chewable formulations were well accepted and can improve adherence and quality of life. For the first time, 3DP enabled two actives to be combined in the same formulation, reducing the number of administrations. This study demonstrated the benefits of preparing 3D printed personalized treatments for children diagnosed with rare metabolic disorders using a novel technology in real clinical practice.

Principal Component Analysis Applied to Digital Pulse Shape Analysis for Isotope Discrimination.

Digital pulse shape analysis (DPSA) techniques are becoming increasingly important for the study of nuclear reactions since the development of fast digitizers. These techniques allow us to obtain the (A, Z) values of the reaction products impinging on the new generation solid-state detectors. In this paper, we present a computationally efficient method to discriminate isotopes with similar energy levels, with the aim of enabling the edge-computing paradigm in future field-programmable gate-array-based acquisition systems. The discrimination of isotope pairs with analogous energy levels has been a topic of interest in the literature, leading to various solutions based on statistical features or convolutional neural networks. Leveraging a valuable dataset obtained from experiments conducted by researchers in the FAZIA Collaboration at the CIME cyclotron in GANIL laboratories, we aim to establish a comparative analysis regarding selectivity and computational efficiency, as this dataset has been employed in several prior publications. Specifically, this work presents an approach to discriminate between pairs of isotopes with similar energies, namely, 12,13C, 36,40Ar, and 80,84Kr, using principal component analysis (PCA) for data preprocessing. Consequently, a linear and cubic machine learning (ML) support vector machine (SVM) classification model was trained and tested, achieving a high identification capability, especially in the cubic one. These results offer improved computational efficiency compared to the previously reported methodologies.

Advances in the discovery of heterocyclic-based drugs against Alzheimer's disease.

INTRODUCTION: Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by beta-amyloid accumulation and tau protein hyperphosphorylation. The disease involves interconnected mechanisms, which can be clustered into two target-packs based on the affected proteins. Pack-1 focuses on beta-amyloid accumulation, oxidative stress, and metal homeostasis dysfunction, and Pack-2 involves tau protein, calcium homeostasis, and neuroinflammation. Against this background heterocyclic system, there is a powerful source of pharmacophores to develop effective small drugs to treat multifactorial diseases like Alzheimer's. AREAS COVERED: This review highlights the most promising heterocyclic systems as potential hit candidates with multi-target capacity for the development of new drugs targeting Alzheimer's disease. The selection of these heterocyclic systems was based on two crucial factors: their synthetic versatility and their well-documented biological properties of therapeutic potential in neurodegenerative diseases. EXPERT OPINION: The synthesis of small drugs against Alzheimer's disease requires a multifactorial approach that targets the key pathological proteins. In this context, the utilization of heterocyclic systems, with well-established synthetic processes and facile functionalization, becomes a crucial element in the design phases. Furthermore, the selection of hit heterocyclic should be guided by a full understanding of their biological activities. Thus, the identification of promising heterocyclic scaffolds with known biological effects increases the potential to develop effective molecules against Alzheimer's disease.

Easy and Versatile Technique for the Preparation of Stable and Active Lipase-Based CLEA-like Copolymers by Using Two Homofunctional Cross-Linking Agents: Application to the Preparation of Enantiopure Ibuprofen.

An easy and versatile method was designed and applied successfully to obtain access to lipase-based cross-linked-enzyme aggregate-like copolymers (CLEA-LCs) using one-pot, consecutive cross-linking steps using two types of homobifunctional cross-linkers (glutaraldehyde and putrescine), mediated with amine activation through pH alteration (pH jump) as a key step in the process. Six lipases were utilised in order to assess the effectiveness of the technique, in terms of immobilization yields, hydrolytic activities, thermal stability and application in kinetic resolution. A good retention of catalytic properties was found for all cases, together with an important thermal and storage stability improvement. Particularly, the CLEA-LCs derived from Candida rugosa lipase showed an outstanding behaviour in terms of thermostability and capability for catalysing the enantioselective hydrolysis of racemic ibuprofen ethyl ester, furnishing the eutomer (S)-ibuprofen with very high conversion and enantioselectivity.

Advanced System-on-Chip Field-Programmable-Gate-Array-Powered Data Acquisition System for Pixel Detectors.

Particle detector systems require data acquisition systems (DAQs) as their back-end. This paper presents a new edge-computing DAQ that is capable of handling multiple pixel detectors simultaneously and was designed for particle-tracking experiments. The system was designed for the ROC4SENS readout chip, but its control logic can be adapted for other pixel detectors. The DAQ was based on a system-on-chip FPGA (SoC FPGA), which includes an embedded microprocessor running a fully functional Linux system. An application using a client-server architecture was developed to facilitate remote control and data visualization. The comprehensive DAQ is very compact, thus reducing the typical hardware load in particle tracking experiments, especially during the obligatory characterization of particle telescopes.

Regional well-being inequalities arising from healthcare expenditure public policies in Spain.

Well-being inequalities arising from different healthcare expenditure public policies is currently a hot topic at a national scale, but especially so at a sub-national level because the inequalities in question are among citizens of the same country. Spain is an optimal study area to carry out research on this topic because it is considered to have one of the best health systems in the world, it is one of the top-ranking countries in terms of life expectancy rates (the indicators we use for well-being), and it has a decentralized public health system with significantly different regional healthcare expenditure public policies. Given that the factors involved in the complex direct, indirect, and second-order relationships between well-being and health spending are latent in nature, and that there are more hypotheses than certainties regarding these relationships, we propose a partial least squares structural equation modeling specification to test the research hypotheses and to estimate the corresponding impacts. These constructs are proxied by a set of 26 indicators, for which annual values at a regional scale were used for the period 2005-2018. From the estimation of this model, it can be concluded that mortality, expenditure and resources are the factors that have the greatest impact on well-being. In addition, a cluster analysis of the indicators for the constructs included in this research reveals the existence of three clearly differentiated groups of autonomous communities: the northern part of the country plus Extremadura (characterized by the lowest well-being and the highest mortality rates), Madrid (with the best results in well-being and mortality, the lowest public health expenditure per inhabitant and percentage of pharmaceutical spending, and the highest percentage in specialty care services and medical staff spending), and the rest of the country (south-eastern regions, with similar well-being values to those of the first group but with less health expenditure). Finally, a principal component analysis reveals that "healthiness" and "basic spending" are the optimal factors for mapping well-being and health spending in Spain.

Biocatalysis for the asymmetric synthesis of Active Pharmaceutical Ingredients (APIs): this time is for real.

INTRODUCTION: Biocatalysis has emerged as a powerful and useful strategy for the synthesis of active pharmaceutical ingredients (APIs). The outstanding developments in molecular biology techniques allow nowadays the screening, large-scale production, and designing of biocatalysts, adapting them to desired reactions. Many enzymes can perform reactions both in aqueous and non-aqueous media, broadening even further the opportunities to integrate them in complex pharmaceutical multi-step syntheses. AREAS COVERED: This paper showcases several examples of biocatalysis in the pharmaceutical industry, covering examples of different enzymes, such as lipases, oxidoreductases, and transaminases, to deliver active drugs through complex synthetic routes. Examples are critically discussed in terms of reaction conditions, motivation for using an enzyme, and how biocatalysts can be integrated in multi-step syntheses. When possible, biocatalytic routes are benchmarked with chemical reactions. EXPERT OPINION: The reported enzymatic examples are performed with high substrate loadings (>100 g L-1) and with excellent selectivity, making them inspiring strategies for present and future industrial applications. The combination of powerful molecular biology techniques with the needs of the pharmaceutical industry can be aligned, creating promising platforms for synthesis under more sustainable conditions.

Analogues of cannabinoids as multitarget drugs in the treatment of Alzheimer's disease.

Given that neuronal degeneration in Alzheimer's disease (AD) is caused by the combination of multiple neurotoxic insults, current directions in the research of novel therapies to treat this disease attempts to design multitarget strategies that could be more effective than the simply use of acetylcholinesterase inhibitors; currently, the most used therapy for AD. One option, explored recently, is the synthesis of new analogues of cannabinoids that could competitively inhibit the acetylcholinesterase (AChE) enzyme and showing the classic neuroprotective profile of cannabinoid compounds. In this work, molecular docking has been used to design some cannabinoid analogues with such multitarget properties, based on the similarities of donepezil and Δ9-tetrahydrocannabinol. The analogues synthesized, compounds 1 and 2, demonstrated to have two interesting characteristics in different in vitro assays: competitive inhibition of AChE and competitive antagonism at the CB1/CB2 receptors. They are highly lipophilic, highlighting that they could easily reach the CNS, and apparently presented a low toxicity. These results open the door to the synthesis of new compounds for a more effective treatment of AD.

Therapeutic drug monitoring of anti-tumour necrosis factor-α agents in inflammatory bowel disease: Limits and improvements.

AIMS: Since the publication of the American Gastroenterological Association's recommendations in 2017, there have been no significant changes in the biological monitoring recommendations in inflammatory bowel disease. Possible limitations are the lack of evidence to recommend proactive therapeutic drug monitoring (pTDM) over reactive TDM (rTDM), and the limited information about individualized dosing methods. This article aims to review the TDM strategy updates and the use of individualized dosing methods. METHODS: For the analysis of the TDM strategies and individualized dosing method, a search was carried out in PubMed and Cochrane Central. In the TDM case, since August 2017. RESULTS: A total of 263 publications were found, but only 7 related to proactive TDM. Five of these publications directly compared pTDM vs rTDM and 2 were randomized clinical trials. Six studies found benefits of pTDM and 1 found no differences. Regarding the individualized dosing method, 229 distinct results were found. Population pharmacokinetics was the most widely used method to develop individual dosage models and to analyse the influence of factors on drug concentrations (albumin concentration, weight, presence of anti-drug antibodies etc). CONCLUSION: We have found no major changes in TDM strategies. There is a growing trend towards the use of pTDM because it has shown a longer duration of treatment response, lower rates of discontinuation and relapses. However, the available evidence is limited and of low quality. Despite the common use of population pharmacokinetic methods to analyse pharmacokinetic factors, they are not commonly used for personalized dosing.

Utilización rápida y segura de los autoinyectores de adrenalina. ¡Tenemos un problema / Rapid and safe use of adrenaline auto-injectors: We have a problem

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Automated therapy preparation of isoleucine formulations using 3D printing for the treatment of MSUD: First single-centre, prospective, crossover study in patients.

Maple syrup urine disease (MSUD) is a rare metabolic disorder with a worldwide prevalence of 1 in every 185,000 live births. However, certain populations display a significant overexpression of the disorder where incidence is reported to be 1 in every 52,541 new-borns. The first-line therapy for MSUD involves a strict dietary leucine restriction and oral supplementation of isoleucine and valine. The dose administered to patients requires strict tailoring according to age, weight and blood levels. In current clinical practice, however, practitioners still have to prepare extemporaneous formulations due to the lack of suitable oral treatments for MSUD. Herein, we evaluate the first time use of 3D printing in a hospital setting for the preparation of personalised therapies with the aim of improving safety and acceptability to isoleucine supplementation in paediatric patients suffering from MSUD. This investigation was a single-centre, prospective crossover experimental study. Four paediatric patients with MSUD (aged 3-16 years) were treated at the Clinic University Hospital in Santiago de Compostela, Spain which is a MSUD reference hospital in Europe. The primary objective was to evaluate isoleucine blood levels after six months of treatment with two types of formulations; conventional capsules prepared by manual compounding and personalised chewable formulations prepared by automated 3D printing. A secondary investigation was to evaluate patient acceptability of 3D printed formulations prepared with different flavours and colours. Isoleucine blood levels in patients were well controlled using both types of formulations, however, the 3D printed therapy showed mean levels closer to the target value and with less variability (200-400 µM). The 3D printed formulations were well accepted by patients regarding flavour and colour. The study demonstrates for the first time that 3D printing offers a feasible, rapid and automated approach to prepare oral tailored-dose therapies in a hospital setting. 3D printing has shown to be an effective manufacturing technology in producing chewable isoleucine printlets as a treatment of MSUD with good acceptability.

Developments with multi-target drugs for Alzheimer's disease: an overview of the current discovery approaches.

Introduction: Alzheimer's disease (AD), the most common type of dementia among older adults, is a chronic neurodegenerative pathology that causes a progressive loss of cognitive functioning with a decline of rational skills. It is well known that AD is multifactorial, so there are many different pharmacological targets that can be pursued. Areas covered: The authors highlight the strategic value of privileged scaffolds in a multi-target lead compound generation against AD, exploring the concept of multi-target design, with a special emphasis on hybrid compounds. Hence, the most promising building blocks for designing and synthesizing hybrid anti-AD drugs are shown, while also presenting the more advanced hybrid compounds. Expert opinion: The available therapeutic arsenal for AD, designed under the traditional paradigm of 'one-drug/one target/one-disease', is based on the inhibition of brain acetylcholinesterase (AChE) to increase acetylcholine (ACh) levels. However, this classical approach has not been sufficiently effective when used to treat any multifactor-depending pathology (cancer, diabetes or AD). The multi-target drug concept has been quickly adopted by medicinal chemists. The basic research developments reported in recent years are a solid foundation that will pave the way for the construction of future AD therapeutics.

Synthesis and Characterization of Elongated-Shaped Silver Nanoparticles as a Biocompatible Anisotropic SERS Probe for Intracellular Imaging: Theoretical Modeling and Experimental Verification.

Progress in the field of biocompatible SERS nanoparticles has promising prospects for biomedical applications. In this work, we have developed a biocompatible Raman probe by combining anisotropic silver nanoparticles with the dye rhodamine 6G followed by subsequent coating with bovine serum albumin. This nanosystem presents strong SERS capabilities in the near infrared (NIR) with a very high (2.7 × 107) analytical enhancement factor. Theoretical calculations reveal the effects of the electromagnetic and chemical mechanisms in the observed SERS effect for this nanosystem. Finite element method (FEM) calculations showed a considerable near field enhancement in NIR. Using density functional quantum chemical calculations, the chemical enhancement mechanism of rhodamine 6G by interaction with the nanoparticles was probed, allowing us to calculate spectra that closely reproduce the experimental results. The nanosystem was tested in cell culture experiments, showing cell internalization and also proving to be completely biocompatible, as no cell death was observed. Using a NIR laser, SERS signals could be detected even from inside cells, proving the applicability of this nanosystem as a biocompatible SERS probe.

Actividad sexual en pacientes con desfibrilador automático implantable incluidos en rehabilitación cardiaca / Sexual activity in implantable cardioverter defibrillator patients included in cardiac rehabilitation

Resumen Objetivos: Analizar los efectos de un programa de rehabilitación cardiaca (PRC) en pacientes portadores de desfibrilador automático implantable (DAI), a nivel de calidad de vida y de actividad sexual. Método: Se incluyeron 25 pacientes (22 hombres y 3 mujeres). Se estudiaron la existencia de descargas del desfibrilador y su repercusión sobre la pareja, así como los efectos del PRC a nivel físico, psicológico y en la esfera sexual. Resultados: La edad media de los enfermos fue de 55 años (22 a 79). Al inicio, el miedo a las descargas del dispositivo estaba presente en todos los enfermos. A su llegada, 14 pacientes (56%) no habían tenido actividad sexual: 2 con edades de 69 y 79 años; una mujer por ansiedad severa, un hombre alcohólico, y 10 por haber transcurrido menos de un mes desde el implante. Nueve hombres y dos mujeres la habían reiniciado: 5 a los 5-52 meses del implante y 6 a los 30 días de hacerse implantado el DAI, mientras realizaban el PRC. Al finalizar, 21 pacientes habían reiniciado la actividad sexual. Dos hombres presentaron signos clínicos de depresión y ansiedad, uno de ellos precisó tratamiento especializado. La capacidad funcional mejoró de forma significativa: 6,5 ± 3,0 MET al inicio del programa y 9,2 ± 3,3 MET al final, con p < 0,005. Hubo una sola descarga inapropiada. Conclusiones: Las descargas con los nuevos dispositivos han descendido significativamente. Por este motivo, y con las acciones de los PRC a nivel físico, psicológico e informativo, se consigue controlar las disfunciones en calidad de vida y sexualidad. © 2017 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. Este es un artículo Open Access bajo la licencia CC BY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract Objectives: To analyse the effects of a Cardiac Rehabilitation Program (CRP) on quality of life and sexual activity levels in patients with implantable cardioverter defibrillators (ICD). Method: A total of 25 patients (22 men and 3 women) were included in a study that consisted of the analysis of any defibrillator discharges, their repercussion on the couple, and the effects of CRP on physical and psychological aspects, and on sexual activity (SA). Results: The mean age of the patients was 55 years (22 to 79). Initially, fear for device discharges was present in all patients. On arrival, 14 patients (56%) did not have any SA: 2 with ages of 69 and 79 years; one woman due to severe anxiety; an alcoholic man, and 10 because the ICD had been implanted less than 1 month before. Nine men and two women had restarted SA: 5 of them 5-52 months after the implantation, and the other 6, 30 days after implantation of the ICD while attending the CRP. At the end of the study, 21 patients had regained SA. Two men had clinical signs of depression and anxiety, with one requiring specialised treatment. Functional capacity improved significantly, 6.5 ± 3.0 METs at the beginning of the program and 9.2 ± 3.3 METs at the end, with a P < .005. There was only one inappropriate discharge. Conclusions: Discharges caused by newest devices have dropped significantly. This fact, together with the action of CRP at physical, psychological, and informative levels, makes it possible to control the dysfunctions in the quality of life and sexuality in patients. © 2017 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

[Sexual activity in implantable cardioverter defibrillator patients included in cardiac rehabilitation]. / Actividad sexual en pacientes con desfibrilador automático implantable incluidos en rehabilitación cardiaca.

OBJECTIVES: To analyse the effects of a Cardiac Rehabilitation Program (CRP) on quality of life and sexual activity levels in patients with implantable cardioverter defibrillators (ICD). METHOD: A total of 25 patients (22 men and 3 women) were included in a study that consisted of the analysis of any defibrillator discharges, their repercussion on the couple, and the effects of CRP on physical and psychological aspects, and on sexual activity (SA). RESULTS: The mean age of the patients was 55years (22 to 79). Initially, fear for device discharges was present in all patients. On arrival, 14 patients (56%) did not have any SA: 2 with ages of 69 and 79years; one woman due to severe anxiety; an alcoholic man, and 10 because the ICD had been implanted less than 1 month before. Nine men and two women had restarted SA: 5 of them 5-52months after the implantation, and the other 6, 30days after implantation of the ICD while attending the CRP. At the end of the study, 21 patients had regained SA. Two men had clinical signs of depression and anxiety, with one requiring specialised treatment. Functional capacity improved significantly, 6.5±3.0METs at the beginning of the program and 9.2±3.3METs at the end, with a P<.005. There was only one inappropriate discharge. CONCLUSIONS: Discharges caused by newest devices have dropped significantly. This fact, together with the action of CRP at physical, psychological, and informative levels, makes it possible to control the dysfunctions in the quality of life and sexuality in patients.

Docking studies for melatonin receptors.

INTRODUCTION: Melatonin is a neurohormone that controls many relevant physiological processes beyond the control of circadian rhythms. Melatonin's actions are carried out by two main types of melatonin receptors; MT1 and MT2. These receptors are important, and not just because of the biological actions of its natural agonist; but also, because melatonin analogues can improve or antagonize their biological effect. Area covered: The following article describes the importance of melatonin as a biologically relevant molecule. It also defines the receptors for this substance, as well as the second messengers coupled to these receptors. Lastly, the article describes the amino acid residues involved in the docking process in both MT1 and MT2 melatonin receptors. Expert opinion: The biological actions of melatonin and their interpretations are becoming more relevant and therefore require the development of new pharmacological tools. Understanding the second messenger mechanisms involved in melatonin actions, as well as the characteristics of the docking of this molecule to MT1 and MT2 melatonin receptors, will permit the development of more selective agonists and antagonists which will help us to better understand this molecule as well to develop new therapeutic compounds.

61.º Congreso de la SEFH. Nutrición parenteral libre de aminoácidos ramificados para el manejo urgente de una descompensación grave de la enfermedad del jarabe de arce / No disponible

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Metodologías de modelado molecular en el diseño, sintesis y explicación racional de resultados / Molecular modeling methodologies in the design, synthesis and rational explanation of results

La Química computacional integra los conceptos básicos especializados de la Química, para la solución de problemas por medio de representaciones graficas que tratan de explicar los sucesos estudiados. El Modelado Molecular es una herramienta de gran utilidad, pues permite interpretar de manera racional por ejemplo el proceso de interacción entre una molécula y su diana, y proporciona datos fiables que permiten predecir el comportamiento del sistema. Por otra parte el auge experimentado por la Biología estructural así como la Resonancia Magnética Nuclear ha permitido incrementar en los últimos años el número de estructuras en 3D para su utilización en modelado. Sin duda, los grandes avances en el campo de la Bioinformática, asociados al empleo de medios computacionales cada vez más sofisticados, auguran la capacidad de extraer conclusiones racionales de los procesos químicos, por lo que esta área de investigación ha experimentado un considerable aumento reconocido en el año 2013 por la Real Academia Sueca de las Ciencias con la concesión del Premio Nobel de Química. En el presente trabajo revisamos algunos de los logros obtenidos en el campo de la modelización molecular realizados por nuestro grupo en el pasado, aplicados fundamentalmente a la Biocatálisis, así como los resultados obtenidos en el presente en el campo de liberación controlada de fármacos y postulamos modelos de predicción que pueden utilizarse en un futuro próximo en este campo de gran interés en Medicina

Computational Chemistry integrates basic concepts of chemistry to solve problems through graphical representations that attempt to explain the events studied. Molecular modeling is a useful tool because it allows rationally interpret for example the process of interaction between a molecule and its target, and provides reliable data that can predict system behavior. Moreover, the boom experienced by Structural Biology and Nuclear Magnetic Resonance has allowed in recent years to increase the number of 3D structures for use in modeling. Undoubtedly, the great advances in the field of bioinformatics, associated with the use of increasingly sophisticated computational means, portend the ability to draw sound conclusions from chemical processes, so this research area has experienced considerable recognized increase in 2013 by the Royal Swedish Academy of Sciences awarding the Nobel Prize in Chemistry. In this paper we review some of the achievements in the field of molecular modeling by our group in the past, mainly applied to Biocatalysis, and the results obtained in the present in the field of controlled drug release and posit models prediction that can be used in the near future in the field of great interest in medicine