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5-Methoxy-3-(5-methoxyindolin-2-yl)-1H-indole (3), whose structure was unambiguously elucidated by X-ray analysis, was identified as a multi-target compound with potential application in neurodegenerative diseases. It is a low nanomolar inhibitor of QR2 (IC50 = 7.7 nM), with greater potency than melatonin and comparable efficacy to the most potent QR2 inhibitors described to date. Molecular docking studies revealed the potential binding mode of 3 to QR2, which explains its superior potency compared to melatonin. Furthermore, compound 3 inhibits hMAO-A, hMAO-B and hLOX-5 in the low micromolar range and is an excellent ROS scavenger. In phenotypic assays, compound 3 showed neuroprotective activity in a cellular model of oxidative stress damage, it was non-toxic, and was able to activate neurogenesis from neural stem-cell niches of adult mice. These excellent biological properties, together with its both good in silico and in vitro drug-like profile, highlight compound 3 as a promising drug candidate for neurodegenerative diseases.
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(1) Background: The rise of online health resources and AI has reshaped the diagnosis and treatment of disease, altering the relationship between patients and healthcare professionals and encouraging self-medication. However, questionnaires validated in the literature on self-medication seem to lack questions on the possible causes that induce such behaviors, including items that explore trust toward websites and artificial intelligence. The aim of this study is to design and validate the content of a questionnaire designed to assess self-medication in health professionals, delving into the underlying etiologies, the pharmacological categories involved and the degree of confidence placed in clinical assessments derived from AI tools. (2) Methods: Validation study of the content of an instrument consisting of two phases: 1. The content validation phase involved evaluation by a selected group of health experts, who, using a Likert-type scale, analyzed the clarity, coherence and relevance of the items. 2. Pilot study of health professionals who have indicated the practice of self-administration of medications. (3) Results: In the first phase of the study, the experts considered most of the questionnaire items to be clear, representative and consistent with the construct to be measured. In its second phase, the preliminary results of our pilot study suggest a significant trend toward self-medication among healthcare workers, along with a strong inclination to use online resources to search for health-related information. (4) Conclusions: The development of a validated instrument to measure the influence of the different causes that lead healthcare personnel to practice self-medication, guaranteeing validity and efficacy, allows us to establish strategies to reduce this growing problem.
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Cancer survival is becoming more common which means that there is now a growing population of cancer survivors, in whom pain may be common. However, its prevalence has hardly been addressed systematically. We aimed to assess the prevalence and explore the pathophysiology and impact of pain on health outcomes in cancer survivors. We conducted a retrospective-prospective cohort study in cancer-free patients diagnosed with cancer at least five years before the study start date. We used multivariable regression to establish the association of patients' cancer characteristics with pain, and then the association of patients' pain features with health outcomes and related symptoms. Between March and July 2021, 278 long-term cancer survivors were evaluated. Almost half of them (130/278, 46.8%) had pain, of whom 58.9% had a probable neuropathic component, but only 18 (13.8%) were taking specific drugs for neuropathic pain. A history of surgery-related pain syndrome in breast cancer patients was more than twice as frequent in the pain cohort. Post-chemotherapy and post-radiotherapy pain syndromes were uncommon. Pain was associated with lower QoL, emotional functioning, professional performance, and disability scores. Pain is a frequent health determinant in cancer survivors. Referral to specialised pain services may be a reasonable move in some cases.
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This study investigated the effects of occupational enrichment, specifically underwater currents, on the stress status of rainbow trout (Oncorhynchus mykiss). A total of 540 fish were divided into three groups: control tanks without artificial currents (CO), tanks with randomly fired underwater currents (RFC), and tanks with continuous current throughout the day (CT). After 30 days, half of the fish in each group underwent a 5-day pre-slaughter fasting (5D), while the others were fed until the day before slaughter (0D). Fish in the RFC group exhibited lower levels of plasma cortisol and acetylcholinesterase enzyme activity in hypothalamus and optic tract than other groups, suggesting an improved stress status. RFC group also showed higher levels of non-esterified fatty acids (NEFA) in 5D fish and higher liver glycogen stores, suggesting improved energy reserves. In comparison, the CT group had higher LDH levels, possibly due to their increased swimming activity. The CO group had significantly lower NEFA levels at 5D compared to the RFC group, suggesting lower energy reserves. The RFC fish had darker and yellow-reddish skin and liver color, suggesting an improved stress status and lower lipid reserves, respectively. Overall, although a significant stress response was not observed in fasted individuals, possibly due to the relatively short fasting period, the study suggests that providing occupational enrichment using randomly fired underwater currents for 1 month helped to improve stress status in rainbow trout, indicating that occupational enrichment during the grow-out phase can positively impact the welfare of rainbow trout during routine handling procedures.
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Oncorhynchus mykiss , Animales , Oncorhynchus mykiss/fisiología , Ácidos Grasos no Esterificados/farmacología , Acetilcolinesterasa , Hígado , Ayuno/fisiologíaRESUMEN
BACKGROUND: Some environmental enrichment methods, such as occupational enrichment (OE), can improve fish growth, but little is known about its effects on fillet quality. In this study, we evaluated the effects of OE using underwater currents on different aspects of fillet quality and muscle metabolism in rainbow trout (Oncorhynchus mykiss), before and after a handling procedure (fasting). The trout were placed in groups of 30 in separate tanks in three treatments for 30 days: no artificial currents (CON), randomly fired underwater currents (RFC), and continuous underwater currents (CUC). Additionally, half of the individuals in each treatment were fasted (5 days, 45.2 °C days). RESULTS: Slaughter weight, condition factor, and relative growth were lower in CON fish, indicating a positive effect of OE on growth. Rigor mortis, muscle pH, and muscle glycogen levels were similar among treatments, indicating no effect of OE on classical measures of fillet quality. However, significant differences were found regarding fillet colour and muscle enzymes. The fillets of RFC fish were more salmon-pink in colour, which is favoured by consumers. Also, activity levels of pyruvate kinase and glycogen phosphorylase in muscle were significantly higher in CUC fish, probably due to increased energy demands, as pumps were on continually in that treatment. CONCLUSION: Overall, RFC fish seemed to have received enough stimulation to improve growth while not being excessive in terms of exhausting the animals (avoiding negative effects on muscle metabolism), whereas OE may have provided a hormetic effect, allowing fish to better adjust to fasting. © 2023 Society of Chemical Industry.
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Oncorhynchus mykiss , Animales , Oncorhynchus mykiss/metabolismo , Alimentos Marinos/análisis , Rigor MortisRESUMEN
BACKGROUND: During the COVID-19 pandemic, public confrontations between people who had agreed to be vaccinated and those who had not, highlighted the relevance of the deepening dissemination of violent and discriminatory expressions and determined a level of perception of hate discourses. METHOD: A cross-sectional observational study was carried out, based on an innovative methodology: simulations of WhatsApp conversations. In addition, the following variables were considered among others: level of empathy, personality traits and conflict resolution. RESULTS: The participants were 567 nursing students (413 females, 153 males and 1 person who did not identify with any gender). The results showed that, for the most part, the participants correctly identified hate speech, but were unable to discern the frame of reference. CONCLUSIONS: It is necessary to implement intervention strategies to minimize the impact of hate speech, which continues to be used on many levels to harass others, justify violence or undermine rights, generating an environment of prejudice and intolerance that encourages discrimination and violent attacks against certain individuals or collectives.
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Stress and stressors related to clinical practice are some of the main reasons for the discomfort reported by nursing students. It is important to identify the causes of stress and seek strategies to reduce the stress levels in nursing students. Clinical training seminars have proven to be a useful tool to reduce stress levels. This study aims to evaluate the effects of a series of clinical training seminars on the levels of stress and perception of stress factors before the start of clinical practice among undergraduate Spanish nursing students. A two-phase, sequential mixed-methods design was used. For the quantitative phase, data were collected using Cohen's Perceived Stress Scale and the KEZKAK questionnaire before and after the clinical training seminars. Qualitative data were collected through a focus group session held after the clinical training period. The results show a significant reduction (p = 0.002) in perceived stress levels after the clinical training seminars, and also a change in students' perception of stressors in the clinical placement. This study provides valuable information for the development of content for clinical training seminars. Universities should develop strategies to reduce stress in their students caused by the clinical placement.
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OBJECTIVES: The use of off-label pharmacotherapies for neuropathic pain (NP) is growing relating to the many unmet needs of patients. However, clinical guidelines fail to address it, and the available evidence is sparse and fragmented. We arranged a formal expert consensus to address this controversial issue and provide some guidance on judicious use. METHODS: A two-round standard Delphi survey that involved pain clinic specialists with experience in the research and management of NP was done over an ad hoc 40-item questionnaire prepared by the authors. Consensus on each statement was defined as at least either 80% endorsement or rejection after the second round. RESULTS: Forty-three and thirty-seven panelists participated in the first and second round, respectively. Consensus was reached in 34 out of 40 statements. Endorsed alternatives for unresponsive patients include non-gabapentinoid antiepileptics (oxcarbazepine and eslicarbazepine), venlafaxine, intravenous lidocaine (when doses can be optimized), and some vaporized cannabinoids (under appropriate surveillance). In addition, lacosamide, low-dose naltrexone, propofol, or ketamine could prove beneficial if subjected to more research. Other options were rejected, and there was controversy about the usefulness of topical preparations. DISCUSSION: For patients who do not respond to standard NP treatments, some other viable pharmacological options can be attempted before advancing to other therapeutic stages. This may help patients who are reluctant to or have some contraindication for interventional therapies.
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Ketamina , Neuralgia , Humanos , Técnica Delphi , Uso Fuera de lo Indicado , Neuralgia/tratamiento farmacológico , Anticonvulsivantes , Ketamina/uso terapéuticoRESUMEN
Los fármacos multidiana son entidades moleculares diseñadas para presentar más de una actividad biológica. Debido a esta propiedad, estos compuestos son considerados herramientas privilegiadas para el tratamiento de enfermedades complejas como las infecciones bacterianas, el cáncer o las enfermedades neurodegenerativas. Las estrategias de diseño para crear fármacos multidiana han sido típicamente unión, fusión e incorporación. En este trabajo presentamos la creación de compuestos multidiana combinando fragmentos activos de tal manera que puedan inhibir una tercera diana adicional una vez unidos, con el objetivo de crear fármacos prometedores para el tratamiento de enfermedades neurodegenerativas. Este tipo de fármacos multidiana resultan muy apropiados para el tratamiento de estas patologías multifactoriales, de las que a día de hoy se desconoce su etiología y que carecen de tratamientos efectivos. Para conseguir este objetivo hemos combinado fragmentos de moléculas que inhiben quinasas involucradas en los mecanismos patomoleculares principales de la enfermedad de Alzheimer como la agregación de tau, la neuroinflamación y la disminución de la neurogénesis. Además se ha buscado una tercera actividad en la enzima BACE1, responsable patología del β-amiloide en la enfermedad de Alzheimer. Finalmente, y tras los resultados prometedores obtenidos con los fármacos multidiana, hemos comenzado a implementar la técnica de química click in situ para optimizar la selección de inhibidores utilizando la enzima BACE1 como molde de reacción. (AU)
Multitarget drugs are molecular entities that are designed to present more than one biological activity. They are arising as powerful tools to tackle complex diseases including bacterial resistances, cancer or neurodegenerative diseases. Typically, the rational strategies to design multitarget drugs are linkage, fusion and incorporation or merge. Here we present the creation of a multitarget drug combining active fragments in a way that could inhibit an additional third target with the objective to create powerful modulating agents for neurodegenerative diseases. Multitarget compounds are ideally suited for the treatment of these pathologies due to their unknown etiology, multifactorial pathology and lack of efficient treatments. To achieve this aim we have combined fragments that inhibit kinases involved in the main pathomolecular pathways of Alzheimers disease such as tau aggregation, neuroinflammation and decreased neurogenesis, looking for a third action in BACE1, responsible of β-amyloid production. Finally, and after the successful results obtained using this methodology, we have started to implement the in situ click chemistry technique to better select the multitarget compounds using BACE1 as a template. (AU)
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Humanos , Enfermedad de Alzheimer , Fosfotransferasas , Infecciones Bacterianas , Enfermedades NeurodegenerativasRESUMEN
The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.
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Epóxido Hidrolasas , Dolor Visceral , Ratones , Humanos , Animales , Urea/química , Modelos Animales de Enfermedad , Dolor Visceral/inducido químicamente , Dolor Visceral/tratamiento farmacológico , Capsaicina , Inhibidores Enzimáticos/farmacología , Analgésicos/farmacología , Analgésicos/uso terapéutico , CiclofosfamidaRESUMEN
Multitarget drugs are a promising therapeutic approach against Alzheimer's disease. In this work, a new family of 5-substituted indazole derivatives with a multitarget profile including cholinesterase and BACE1 inhibition is described. Thus, the synthesis and evaluation of a new class of 5-substituted indazoles has been performed. Pharmacological evaluation includes in vitro inhibitory assays on AChE/BuChE and BACE1 enzymes. Also, the corresponding competition studies on BuChE were carried out. Additionally, antioxidant properties have been calculated from ORAC assays. Furthermore, studies of anti-inflammatory properties on Raw 264.7 cells and neuroprotective effects in human neuroblastoma SH-SY5Y cells have been performed. The results of pharmacological tests have shown that some of these 5-substituted indazole derivatives 1-4 and 6 behave as AChE/BuChE and BACE1 inhibitors, simultaneously. In addition, some indazole derivatives showed anti-inflammatory (3, 6) and neuroprotective (1-4 and 6) effects against Aß-induced cell death in human neuroblastoma SH-SY5Y cells with antioxidant properties.
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Enfermedad de Alzheimer , Neuroblastoma , Fármacos Neuroprotectores , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Ácido Aspártico Endopeptidasas/metabolismo , Inhibidores de la Colinesterasa , Humanos , Indazoles/farmacología , Neuroblastoma/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
More than 1 billion people live in areas endemic for leishmaniasis, which is a relevant threat for public health worldwide. Due to the inadequate treatments, there is an urgent need to develop novel alternative drugs and to validate new targets to fight this disease. One appealing approach is the selective inhibition of protein kinases (PKs), enzymes involved in a wide range of processes along the life cycle of Leishmania. Several PKs, including glycogen synthase kinase 3 (GSK-3), have been validated as essential for this parasite by genetic or pharmacological methods. Recently, novel chemical scaffolds have been uncovered as Leishmania GSK-3 inhibitors with antiparasitic activity. In order to find new inhibitors of this enzyme, a virtual screening of our in-house chemical library was carried out on the structure of the Leishmania GSK-3. The virtual hits identified were experimentally assayed both for leishmanicidal activity and for in vitro inhibition of the enzyme. The best hits have a quinone scaffold. Their optimization through a medicinal chemistry approach led to a set of new compounds, provided a frame to establish biochemical and antiparasitic structure-activity relationships, and delivered molecules with an improved selectivity index. Altogether, this study paves the way for a systemic search of this class of inhibitors for further development as potential leishmanicidal drugs.
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By replacing a phenolic ring of (E)-resveratrol with an 1,3,4-oxadiazol-2(3H)-one heterocycle, new resveratrol-based multitarget-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection vs okadaic acid). 5-[(E)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3H)-one (4e) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 µM), selective inhibition of both hMAO-B and QR2 (IC50s = 8.05 and 0.57 µM), and the best ability to promote hippocampal neurogenesis. It showed a good drug-like profile (positive in vitro central nervous system permeability, good physiological solubility, no glutathione conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective and antioxidant actions in both acute and chronic Alzheimer models using hippocampal tissues. Thus, 4e is an interesting MTDL that could stimulate defensive and regenerative pathways and block early events in neurodegenerative cascades.
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Monoaminooxidasa , Fármacos Neuroprotectores , Antioxidantes/metabolismo , Antioxidantes/farmacología , Ligandos , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo , Resveratrol/farmacologíaRESUMEN
Endothelial adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of vascular tone through stimulating nitric oxide (NO) release in endothelial cells. Since obesity leads to endothelial dysfunction and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. Here, we report the identification of a novel AMPK modulator, the indolic derivative IND6, which shows affinity for AMPKα1ß1γ1, the primary AMPK isoform in human EA.Hy926 endothelial cells. IND6 shows inhibitory action of the enzymatic activity in vitro, but increases the levels of p-Thr174AMPK, p-Ser1177eNOS and p-Ser79ACC in EA.Hy926. This paradoxical finding might be explained by the ability of IND6 to act as a mixed-type inhibitor, but also to promote the enzyme activation by adopting two distinct binding modes at the ADaM site. Moreover, functional assays reveal that IND6 increased the eNOS-dependent production of NO and elicited a concentration-dependent vasodilation of endothelium-intact rat aorta due to AMPK and eNOS activation, demonstrating a functional activation of the AMPK-eNOS-NO endothelial pathway. This kinase inhibition profile, combined with the paradoxical AMPK activation in cells and arteries, suggests that these new chemical entities may constitute a valuable starting point for the development of new AMPK modulators with therapeutic potential for the treatment of vascular complications associated with obesity.
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Proteínas Quinasas Activadas por AMP , Vasodilatación , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Obesidad/metabolismo , Fosforilación , Ratas , Transducción de Señal , Vasodilatación/efectos de los fármacosRESUMEN
Aggregation of mutant huntingtin, because of an expanded polyglutamine track, underlies the cause of neurodegeneration in Huntington disease (HD). However, it remains unclear how some alterations at the cellular level lead to specific structural changes in HD brains. In this context, the neuroprotective effect of the activation of AMP-activated protein kinase (AMPK) appears to be a determinant factor in several neurodegenerative diseases, including HD. In the present work, we describe a series of indole-derived compounds able to activate AMPK at the cellular level. By using animal models of HD (both worms and mice), we demonstrate the in vivo efficacy of one of these compounds (IND1316), confirming that it can reduce the neuropathological symptoms of this disease. Taken together, in vivo results and in silico studies of druggability, allow us to suggest that IND1316 could be considered as a promising new lead compound for the treatment of HD and other central nervous system diseases in which the activation of AMPK results in neuroprotection.
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Enfermedad de Huntington , Fármacos Neuroprotectores , Proteínas Quinasas Activadas por AMP , Animales , Modelos Animales de Enfermedad , Proteína Huntingtina/genética , Enfermedad de Huntington/tratamiento farmacológico , Indoles/farmacología , Ratones , Fármacos Neuroprotectores/farmacologíaRESUMEN
BACKGROUND: Failed Back Surgery Syndrome (FBSS) causes disability and lowers health-related quality of life (HRQoL) for patients. Many patients become refractory to Conventional Medical Management (CMM) and Spinal Cord Stimulation (SCS) is advised. However, comparative effectiveness research of both clinical approaches still lacks further evidence. OBJECTIVES: This study describes Comparative Effectiveness Research of CMM versus SCS to provide real world evidence regarding the appropriate means for FBSS management, in terms of Patient-Reported Outcomes Measures. STUDY DESIGN: Naturalistic, pragmatic, prospective observational multicenter SEFUDOCE-study. SETTING: FBSS patients attending clinical programmed visits in Pain Unit at Hospital Universitario de La Princesa and at Hospital General Universitario de Alicante (Spain). METHODS: Study evaluates the impact on pain, functional limitation, and HRQoL of CMM versus SCS in the management of FBSS. Patients completed Pain Detect Questionnaire, Oswestry Disability Index, EQ-5D-3L, Medical Outcomes Study Sleep Scale, and Hospital Anxiety and Depression Scale at baseline and at 3, 6, 12, 18 and 24 months. Longitudinal data were analysed with repeated-measures one-way analysis of variance adjusting by confounders. RESULTS: Eighty-five adults patients with FBSS receiving treatment according to current clinical practice were assessed. After 24 months, the PainDETECT Questionnnaire showed that CMM patients maintained similar scores, while SCS patients reduced their overall score (current pain: 6 CMM versus 4.21 SCS, P = 0.0091; intensity strongest pain: 7.77 CMM versus 6.07 SCS, P = 0.0103; average pain: 6.46 CMM versus 4.75 SCS, P = 0.0012). For the Oswestry Disability Index, the Medical Outcomes Study Sleep Scale, and the Hospital Anxiety and Depression Scale no significant inter-group differences were found. EQ-5D utility improved in SCS patients from baseline (baseline: 0.32 CMM versus 0.22 SCS; 24-month: 0.37 CMM versus 0.63 SCS, P = 0.026). Twenty-four month follow-up showed unlikely presence of neuropathic pain and moderate disability in SCS patients, whereas the CMM patients maintained baseline health state. LIMITATIONS: Given the nature of the intervention, conducting a blinded study was not considered practically feasible. A larger sample could also overcome having younger patients in the SCS arm. CONCLUSIONS: SCS may improve the HRQoL and functionality of FBSS patients with refractory pain in the long-term compared to CMM alone.
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Síndrome de Fracaso de la Cirugía Espinal Lumbar , Neuralgia , Dolor Intratable , Estimulación de la Médula Espinal , Adulto , Síndrome de Fracaso de la Cirugía Espinal Lumbar/terapia , Humanos , Calidad de Vida , Médula Espinal , Resultado del TratamientoRESUMEN
RESUMEN Fundamento: El linfedema congénito primario es una condición rara con un componente genético importante que se caracteriza por edema crónico de la zona afectada. Objetivo: Presentar un linfedema congénito primario bilateral y discutir su origen. Presentación de caso: Se presentó un caso de linfedema congénito primario bilateral en un niño de 2 años de edad, sin antecedentes patológicos familiares de la enfermedad. Se discutieron sus posibles causas genéticas ya que existen varias mutaciones que explican su origen. Aunque no se pudieron realizar estudios genéticos para conocer la etiología exacta, existen evidencias clínicas de que no se trata de una enfermedad de Milroy, a menos que se presente como una mutación de novo. Se le realizó al paciente un seguimiento desde su diagnóstico hasta la actualidad. Conclusiones: Existen múltiples mutaciones genéticas que explican el origen de un linfedema congénito primario, por lo que no necesariamente debe tratarse de enfermedad de Milroy cuando este se presente. Se destacó como elemento importante que en este caso no se evidenciaron antecedentes familiares. Se empleó el tratamiento conservador como conducta fundamental a seguir, se evidenció en el paciente una notable mejoría clínica.
ABSTRACT Background: Primary congenital lymphedema is a rare condition with an important genetic component characterized by chronic edema of the affected area. Objective: To present a bilateral primary congenital lymphedema and discuss its origin. Case report: A case of bilateral primary congenital lymphedema was presented in a 2-year-old boy with no any family background of the disease. Its possible genetic causes were discussed since there are several mutations that explain its origin. Although genetic studies could not be performed to know the exact etiology, there is clinical evidence that it is not a Milroy's disease, unless it presents as a de novo mutation. The patient was followed up from diagnosis to the present. Conclusions: There are multiple genetic mutations that explain the origin of a primary congenital lymphedema, so it should not necessarily be Milroy's disease when present. A highlighted and important element was that in this case no any family background was evidenced. Conservative treatment was used as the essential conduct to follow up, a remarkable clinical progress was evidenced in the patient.
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Linfedema/genéticaRESUMEN
Multitarget directed ligands (MTDLs) are arising as promising tools to tackle complex diseases. The main goal of this work is to create powerful modulating agents for neurodegenerative disorders. To achieve this aim, we have combined fragments that inhibit key protein kinases involved in the main pathomolecular pathways of Alzheimer's disease (AD) such as tau aggregation, neuroinflammation and decreased neurogenesis, whilst looking for a third action in beta-secretase (BACE1), responsible of ß-amyloid production. We obtained well-balanced MTDLs with in vitro activity in three different relevant targets and efficacy in two cellular models of AD. Furthermore, computational studies confirmed how these compounds accommodate adequately into the long and rather narrow BACE1 catalytic site. Finally, we employed in situ click chemistry using BACE1 as protein template as a versatile synthetic tool that allowed us to obtain further MTDLs.
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Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Fármacos Neuroprotectores/farmacología , Triazoles/farmacología , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Ligandos , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Triazoles/síntesis química , Triazoles/químicaRESUMEN
INTRODUCTION: Patients with moderate or severe pain due to osteoarthritis (OAP) usually undergo pharmacological treatment with NSAIDs and/or opioids. Many of them do not get adequate pain relief because of intolerances, contraindications and the ineffectiveness of these treatments. The main objective of the present study was to quantify the group of OAP patients who are inadequately treated for their pain in routine clinical practice in Spain and to describe the prescription flow of these patients. METHODS: This was a non-interventional, retrospective cohort study conducted using the IQVIA's electronic medical records database in Spain. Patients with osteoarthritis (OA), aged ≥ 15 years and receiving any pain treatment during 12 out of 24 months between 1 October 2017 and 30 September 2019 were studied. Assumptions were made to identify patients with contraindication or intolerance to NSAIDs or opioids and those who failed NSAID or opioid therapy. RESULTS: Out of 136,556 patients with OA, 29,886 had moderate-to-severe pain, which extrapolated to the general population in Spain represents 1,541,286 OAP patients. Mean age (SD) of OAP patients was 75 (12.8) years, and 73.8% were female; 52.8% were treated with NSAIDs and/or weak opioids. There were were 16,748 OAP patients (56.08%) (extrapolated figure 838,620) with one or more conditions associated with being inadequately treated (contraindication, intolerance or failed NSAID and/or opioid therapy). In most OAP patients (91%) pain treatment was initiated by the general practitioner (GP) alone. Considering overall successive therapy lines, after the first prescription, pain drugs were prescribed by a GP in 61% of the cases, by a specialist in 20% and by both in 18%. CONCLUSION: More than half of the patients with OA in Spain have unsatisfactory pain control. Pain drugs are mainly prescribed by GPs, and specialists (traumatologists, rheumatologists, physiatrists and pain management specialists) are not very involved in the management of OAP patients.
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RESUMEN:Introducción: En Cuba, 20 porciento de la población tiene 60 años y más, y la probabilidad de adquirir cáncer colorrectal es del cuatro al seis por ciento a lo largo de la vida,lo que constituye un problema social.Objetivo: Determinar la relación entre el cáncer colorrectal en el adulto mayor en la comunidad con ciencia, tecnología y sociedad.Métodos: Se realizó un estudio de intervención y desarrollo con la estrategia de autocuidado en adultos mayores con cáncer colorrectal en la comunidad en el Policlínico Dr. Rudesindo Antonio García del Rijoˮ del municipio y provincia de Sancti Spíritus, en el periodo 2007-2017. Variables: nivel de información de los médicos, estado de salud, autocuidado y el alivio del dolor en los adultos mayores con cáncer colorrectal. Se trabajó con la totalidad de la población, 116 adultos mayores con cáncer colorrectal y 37 médicos. Se utilizó estadística descriptiva de cada variable mediante tablas, con frecuencias absoluta y relativa como medida de resumen.Resultados: Se instruyó a los pacientes y se logró el alivio del dolor en un 76,72porciento, mejoró el autocuidado en un 50 porciento y el estado de salud fue aceptable en un44,82 porciento. La sobrevida se comportó en los pacientes que estuvieron desde su diagnóstico en la estrategia de autocuidado de cinco a siete años.Conclusiones: El cáncer colorrectal en la población adulta mayor constituye un problema de ciencia, tecnología y sociedad.[AU]