Long-Acting Injectable Second-Generation Antipsychotics in Seriously Ill Patients with Schizophrenia: Doses, Plasma Levels, and Treatment Outcomes.

This research studies the dose-plasma level (PL) relationship of second-generation antipsychotics, together with the treatment outcomes achieved, in seriously ill people with schizophrenia. An observational, prospective, one-year follow-up study was carried out with patients (N = 68) with severe schizophrenia treated with paliperidone three-month (PP3M) or aripiprazole one-month (ARIM). Participants were divided into standard-dose or high-dose groups. PLs were divided into "standard PL" and "high PL" (above the therapeutic reference range, TRR) groups. The dose/PL relationship, and severity, hospitalizations, tolerability, compliance, and their relationship with doses and PLs were evaluated. There was no clear linear relationship between ARIM or PP3M doses and the PLs achieved. In half of the subjects, standard doses reached PLs above the TRR. The improvements in clinical outcomes (decrease in clinical severity and relapses) were related to high PLs, without worse treatment tolerability or adherence. All participants remained in the study, regardless of dose or PL. Clinical severity and hospitalizations decreased significantly more in those patients with high PLs. Considering the non-linear dose-PL relationship of ARIM and PP3M in people with severe schizophrenia, PLs above the TRR are linked to better treatment outcomes, without worse tolerability. The need in a notable number of cases for high doses to reach those effective PLs is highlighted.

From the breakdown of psychiatry during nazism and the Nuremberg Code, to the materialist neuropsychological model in contemporary science and society: A bioethical analysis / De la quiebra de la psiquiatría durante el nazismo y el Código de Nüremberg al modelo neuropsicológico materialista en la ciencia y la sociedad contemporáneas: Un análisis en clave bioética

Abstract The breakdown of German psychiatry with the coming to power of the National Socialist regime in 1933 resulted in a revival after the war of bioethical issues, the immediate effect of which was the enactment of the Nuremberg Code. In many ways, this breakdown was the result of the historical evolution of psychomedical knowledge and the mass dissemination of reductionist discourses and ideas that created a breeding ground for tragedy. The cyclical discourse of psychic materialism, which has been repeated for centuries in the history of science in different formulations, can, if not properly interpreted, lead to far-reaching appropriations and risks, to which due attention must be paid. The latest manifestation of this issue, the view of mental life as basically cerebral, neurological, biochemical, and determinist, a view that has not been managed or presented adequately to the public, could become the basis for perverse new perspectives and applications in the current context of research and academic activity.

Resumen La llamada "quiebra" de la psiquiatría alemana en 1933, tras la llegada al poder del régimen nacionalsocialista, tuvo como resultado una reactivación de la cuestión bioética, cuyo efecto inmediato fue la promulgación del famoso Código de Nuremberg. En más de un sentido, tal ruptura fue el resultado del devenir histórico del conocimiento psicomédico, así como de la difusión masiva de discursos e ideas reduccionistas que terminaron por generar un caldo de cultivo propicio para la tragedia. El discurso cíclico del materialismo psíquico, que se reedita en la historia de la ciencia, en diferentes formatos y formulaciones, desde hace siglos, no bien interpretado, puede inducir apropiaciones y riesgos de largo alcance a los que se debe prestar la debida atención. Así, el último episodio de este asunto, la visión de la vida mental como vida básicamente cerebral, neurológica, bioquímica y determinista, no bien gestionado y presentado a la opinión pública, aunado a las condiciones actuales de la actividad investigadora y académica, podría convertirse en piedra angular de nuevas perspectivas y aplicaciones perversas de este asunto.

Redox Regulation of Microglial Inflammatory Response: Fine Control of NLRP3 Inflammasome through Nrf2 and NOX4.

The role of inflammation and immunity in the pathomechanism of neurodegenerative diseases has become increasingly relevant within the past few years. In this context, the NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in the activation of inflammatory responses by promoting the maturation and secretion of pro-inflammatory cytokines such as interleukin-1ß and interleukin-18. We hypothesized that the interplay between nuclear factor erythroid 2-related factor 2 (Nrf2) and NADPH oxidase 4 (NOX4) may play a critical role in the activation of the NLRP3 inflammasome and subsequent inflammatory responses. After priming mixed glial cultures with lipopolysaccharide (LPS), cells were stimulated with ATP, showing a significant reduction of IL1-ß release in NOX4 and Nrf2 KO mice. Importantly, NOX4 inhibition using GKT136901 also reduced IL-1ß release, as in NOX4 KO mixed glial cultures. Moreover, we measured NOX4 and NLRP3 expression in wild-type mixed glial cultures following LPS treatment, observing that both increased after TLR4 activation, while 24 h treatment with tert-butylhydroquinone, a potent Nrf2 inducer, significantly reduced NLRP3 expression. LPS administration resulted in significant cognitive impairment compared to the control group. Indeed, LPS also modified the expression of NLRP3 and NOX4 in mouse hippocampus. However, mice treated with GKT136901 after LPS impairment showed a significantly improved discrimination index and recovered the expression of inflammatory genes to normal levels compared with wild-type animals. Hence, we here validate NOX4 as a key player in NLRP3 inflammasome activation, suggesting NOX4 pharmacological inhibition as a potent therapeutic approach in neurodegenerative diseases.

Neuroprotective and Antioxidant Properties of CholesteroNitrone ChN2 and QuinolylNitrone QN23 in an Experimental Model of Cerebral Ischemia: Involvement of Necrotic and Apoptotic Cell Death.

Ischemic stroke is the leading cause of disability and the second leading cause of death worldwide. However, current therapeutic strategies are scarce and of limited efficacy. The abundance of information available on the molecular pathophysiology of ischemic stroke has sparked considerable interest in developing new neuroprotective agents that can target different events of the ischemic cascade and may be used in combination with existing treatments. In this regard, nitrones represent a very promising alternative due to their renowned antioxidant and anti-inflammatory effects. In this study, we aimed to further investigate the neuroprotective effects of two nitrones, cholesteronitrone 2 (ChN2) and quinolylnitrone 23 (QN23), which have previously shown great potential for the treatment of stroke. Using an experimental in vitro model of cerebral ischemia, we compared their anti-necrotic, anti-apoptotic, and antioxidant properties with those of three reference compounds. Both ChN2 and QN23 demonstrated significant neuroprotective effects (EC50 = 0.66 ± 0.23 µM and EC50 = 2.13 ± 0.47 µM, respectively) comparable to those of homo-bis-nitrone 6 (HBN6) and N-acetylcysteine (NAC) and superior to those of α-phenyl-N-tert-butylnitrone (PBN). While primarily derived from the nitrones' anti-necrotic capacities, their anti-apoptotic effects at high concentrations and antioxidant powers-especially in the case of QN23-also contribute to their neuroprotective effects.

Therapeutic Potential of Melatonin Counteracting Chemotherapy-Induced Toxicity in Breast Cancer Patients: A Systematic Review.

The purpose of this systematic review is to provide an overview of the existing knowledge on the therapeutic potential of melatonin to counteract the undesirable effects of chemotherapy in breast cancer patients. To this aim, we summarized and critically reviewed preclinical- and clinical-related evidence according to the PRISMA guidelines. Additionally, we developed an extrapolation of melatonin doses in animal studies to the human equivalent doses (HEDs) for randomized clinical trials (RCTs) with breast cancer patients. For the revision, 341 primary records were screened, which were reduced to 8 selected RCTs that met the inclusion criteria. We assembled the evidence drawn from these studies by analyzing the remaining gaps and treatment efficacy and suggested future translational research and clinical trials. Overall, the selected RCTs allow us to conclude that melatonin combined with standard chemotherapy lines would derive, at least, a better quality of life for breast cancer patients. Moreover, regular doses of 20 mg/day seemed to increase partial response and 1-year survival rates. Accordingly, this systematic review leads us to draw attention to the need for more RCTs to provide a comprehensive view of the promising actions of melatonin in breast cancer and, given the safety profile of this molecule, adequate translational doses should be established in further RCTs.

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.

We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 µmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.

N-palmitoylethanolamide synergizes the antinociception of morphine and gabapentin in the formalin test in mice.

OBJECTIVE: The antinociceptive pharmacological interaction between N-palmitoylethanolamide (PEA) and morphine (MOR), as well as gabapentin (GBP), was investigated to obtain synergistic antinociception at doses where side effects were minimal. In addition, the possible antinociceptive mechanism of PEA + MOR or PEA + GBP combinations was explored. METHODS: Individual dose-response curves (DRCs) of PEA, MOR and GBP were evaluated in female mice in which intraplantar nociception was induced with 2% formalin. Isobolographic method was used to detect the pharmacological interaction in the combination of PEA + MOR or PEA + GBP. KEY FINDINGS: The ED50 was calculated from the DRC; the order of potency was MOR > PEA > GBP. The isobolographic analysis was obtained at a 1:1 ratio to determine the pharmacological interaction. The experimental values of flinching (PEA + MOR, Zexp = 2.72 ± 0.2 µg/paw and PEA + GBP Zexp = 2.77 ± 0.19 µg/paw) were significantly lower than those calculated theoretically (PEA + MOR Zadd = 7.78 ± 1.07 and PEA + GBP Zadd = 24.05 ± 1.91 µg/paw), resulting in synergistic antinociception. Pretreatment with GW6471 and naloxone demonstrated that peroxisome proliferator-activated receptor alpha (PPARα) and opioid receptors are involved in both interactions. CONCLUSIONS: These results suggest that MOR and GBP synergistically enhance PEA-induced antinociception through PPARα and opioid receptor mechanisms. Furthermore, the results suggest that combinations containing PEA with MOR or GBP could be of interest in aiding the treatment of inflammatory pain.

Determinants of Public Health Personnel Spending in Spain.

Public health is funded with government funds gathered from tax revenues, whether national, provincial or municipal. The health system therefore suffers during economic crisis periods, whether due to disinvestment, loss of purchasing power among health care personnel or the decrease in the number of professionals. This worsens the situation, as it is necessary to cover the needs of an increasingly elderly population and with a longer life expectancy at birth. The present study intends to show a model which explains the determination of the "Public Health Personnel Expenditure" in Spain for a determined period. A multiple linear regression model was applied to the period including the years 1980-2021. Macroeconomic and demographic variables were analyzed to explain the dependent variable. Variation in health personnel expenditure: "We included those variables which presented a high or very high correlation above r > 0.6. The variables which explain the behavior of Variation in health personnel expenditure". It was a determining factor in the present study to consider that the variables with the greatest repercussions on health policy were mainly macroeconomic variables rather than demographic variables, with the only significant demographic variable that had a specific weight lower than macroeconomic variables being "Birth Rate". In this sense, the contribution made to the scientific literature is to establish an explanatory model so that public policy managers and states in particular can consider it in their public spending policies, bearing in mind that health expenditures in a Beveridge-style health system, as Spain has, are paid with funds drawn from tax revenues.

Direct and Indirect Management Models in Public Health in the Framework of Mental Health.

This article analyzes the relationship between per capita expenditure and financial and macroeconomic variables in the framework of mental health, in regions where the prevailing system is public healthcare governed by the state and in regions where the prevailing system is that of public ownership. The period 2006-2017 was analyzed. A simple linear regression analysis was carried out to determine the relationship between the expenditure per inhabitant and a series of relevant variables such as asset turnover, cash flow, and expenditure as a percentage of gross domestic product (GDP), applying statistical tests to validate the study. In regions where public-private co-financing prevails in the health system, two crucial variables to measure per capita expenditure on mental health were GDP per capita and cash flow of mental health providers. In the regions where management is direct, the crucial variables were asset turnover of mental health providers and expenditure on mental health as a percentage of GDP per capita. These elements are key to determining how to develop public investment policies in hospital systems in the different regions of Europe and the world.

Neuroprotective and antioxidant properties of new quinolylnitrones in in vitro and in vivo cerebral ischemia models.

Cerebral ischemia is a condition affecting an increasing number of people worldwide, and the main cause of disability. Current research focuses on the search for neuroprotective drugs for its treatment, based on the molecular targets involved in the ischemic cascade. Nitrones are potent antioxidant molecules that can reduce oxidative stress. Here we report the neuroprotective properties and the antioxidant power of the six new quinolylnitrones (QNs) 1-6 for their potential application in stroke therapy. QNs 1-4 are 2-chloro-8-hydroxy-substituted QNs bearing N-t-butyl or N-benzyl substituents at the nitrone motif located at C3, whereas QN5 and QN6 are 8-hydroxy QNs bearing N-t-butyl or N-benzyl substituents at the nitrone motif located at C2, respectively. In vitro neuroprotection studies using QNs 1-6 in an oxygen-glucose-deprivation model of cerebral ischemia, in human neuroblastoma cell cultures, indicate that all QNs have promising neuroprotective, anti-necrotic, anti-apoptotic, and anti-oxidant properties against experimental ischemia-reperfusion in neuronal cultures. QN6 stands out as the most balanced nitrone out of all tested QNs, as it strongly prevents decreased neuronal metabolic activity (EC50 = 3.97 ± 0.78 µM), as well as necrotic (EC50 = 3.79 ± 0.83 µM) and apoptotic cell death (EC50 = 3.99 ± 0.21 µM). QN6 showed high capacity to decrease superoxide production (EC50 = 3.94 ± 0.76 µM), similar to its parent molecule α-phenyl-tert-butyl nitrone (PBN) and the well-known anti-oxidant molecule N-acetyl-L-cysteine (NAC). Thus, QN6 demonstrated the highest antioxidant power out of the other tested QNs. Finally, in vivo treatment with QN6 in an experimental permanent stroke model elicited a significant reduction (75.21 ± 5.31%) of the volume size of brain lesion. Overall, QN6 is a potential agent for the therapy of cerebral ischemia that should be further investigated.

Melatonin as Modulator for Sulfur and Nitrogen Mustard-Induced Inflammation, Oxidative Stress and DNA Damage: Molecular Therapeutics.

Sulfur and nitrogen mustards, bis(2-chloroethyl)sulfide and tertiary bis(2-chloroethyl) amines, respectively, are vesicant warfare agents with alkylating activity. Moreover, oxidative/nitrosative stress, inflammatory response induction, metalloproteinases activation, DNA damage or calcium disruption are some of the toxicological mechanisms of sulfur and nitrogen mustard-induced injury that affects the cell integrity and function. In this review, we not only propose melatonin as a therapeutic option in order to counteract and modulate several pathways involved in physiopathological mechanisms activated after exposure to mustards, but also for the first time, we predict whether metabolites of melatonin, cyclic-3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and N1-acetyl-5-methoxykynuramine could be capable of exerting a scavenger action and neutralize the toxic damage induced by these blister agents. NLRP3 inflammasome is activated in response to a wide variety of infectious stimuli or cellular stressors, however, although the precise mechanisms leading to activation are not known, mustards are postulated as activators. In this regard, melatonin, through its anti-inflammatory action and NLRP3 inflammasome modulation could exert a protective effect in the pathophysiology and management of sulfur and nitrogen mustard-induced injury. The ability of melatonin to attenuate sulfur and nitrogen mustard-induced toxicity and its high safety profile make melatonin a suitable molecule to be a part of medical countermeasures against blister agents poisoning in the near future.

Relevancia y prevalencia de los parámetros histopatológicos y subtipos moleculares del cáncer de mama en mujeres del área costera de Ecuador atendidas en una institución de Salud Pública / Prevalence and significance of breast cancer pathologycal subtypes in Ecuador

BACKGROUND: The success of breast cancer (BC) treatment depends largely on the clinical-histological characteristics of the patient. Immunohistochemical (IHC) Breast Cancer Subtypes are crucial for therapeutic purposes. AIM: To determine the relevance and prevalence of the histopathological parameters and molecular subtypes of BC among women attending public health services. MATERIAL AND METHODS: A retrospective cross-sectional study was carried out in 199 female patients with histopathological diagnosis of breast cancer, treated at a Guayaquil city hospital in Ecuador, from January 2014 to December 2017. RESULTS: Luminal A carcinoma was the most prevalent tumor in the studied women (54%). Thirty seven percent of patients did not have nodal involvement, 40% had one to three lymph nodes involved and 2% had 10 or more nodes involved. Most patients had a tumor size > 2 and ≤ 5 cm (72%) and moderately differentiated specifications (57%). CONCLUSIONS: The study allowed the characterization of breast cancer according to the prevalence of molecular subtypes and clinical and histological characteristics. These factors determine therapeutic behaviors that optimize the use of the limited resources of the Public Health System.

Bibliometría y mapeo de redes de la producción científica internacional de Cuba sobre ataxias (1993-2020) / Bibliometrics and network mapping of Cuban international scientific production on ataxias (1993-2020)

El objetivo del estudio fue caracterizar el potencial investigador cubano en el ámbito de las ataxias y su evolución temporal. Se realizó una búsqueda en la base de datos Web of Science y se obtuvieron todos los documentos publicados entre 1993 y 2020. Se aplicaron indicadores bibliométricos para explorar la producción, dispersión, distribución y crecimiento anual de los documentos (ley de Price, ley de Lotka, índice de transitoriedad y modelo de Bradford). Se calculó el índice de participación y colaboración de países e instituciones y, por cartografía bibliométrica, se exploraron las redes de coocurrencia de los términos más utilizados. La producción científica de Cuba sobre ataxias hereditarias es alta (219 documentos) y se ajusta a un crecimiento lineal (r= 0,7580). El período estudiado concentra el 47,95 por ciento de los registros con un ritmo anual de publicaciones del 6,6 por ciento y tiempo de duplicidad de 10,8 años. El total de citas fue de 3807 (índice medio: 131,27; índice -h: 31). Se concluye que el crecimiento de la literatura científica cubana sobre ataxias fue lineal para el período estudiado, lo que confirma el incumplimiento de la ley de Price de crecimiento de la literatura científica. El estudio también corrobora la importante red de integración y cooperación internacional entre los diferentes autores y la interdisciplinariedad de los trabajos, evidencia del éxito del Centro para la Investigación y Rehabilitación de las Ataxias Hereditarias (CIRAH), al planificar una estrategia de colaboración científica con objetivos definidos(AU)

The objective of this study was to characterize the Cuban research potential in the field of ataxias and its temporal evolution. A search was carried out in the Web of Science database and all the documents published from 1993 to 2020 were retrieved. Bibliometric indicators were applied to explore the production, dispersion, distribution and annual growth of the documents (Price's law, Lotka's law, transience index and Bradford model). The participation and collaboration index of countries and institutions was calculated and, through bibliometric cartography, the co-occurrence networks of the most used terms were explored. The Cuban scientific production on hereditary ataxias is high (219 documents) and it adjusts to a linear growth (r = 0.7580). The period studied concentrates 47.95percent of the records with an annual publication rate of 6.6percent and 10.8 years' duplication time. The total number of citations was 3807 (mean index: 131.27; h-index: 31). Growth of the Cuban scientific literature on ataxias was concluded to be linear for the period studied, which confirms the non-compliance with Price's law of growth of scientific literature. The study also corroborates the important network of integration and international cooperation among the different authors and the interdisciplinarity of the papers, marking the success of the Center for Research and Rehabilitation of Hereditary Ataxias (CIRAH), when planning a strategy of scientific collaboration with objectives defined(AU)

Potential of melatonin to reverse epigenetic aberrations in oral cancer: new findings.

It is now an accepted principle that epigenetic alterations cause cellular dyshomeostasis and functional changes, both of which are essential for the initiation and completion of the tumor cycle. Oral carcinogenesis is no exception in this regard, as most of the tumors in the different subsites of the oral cavity arise from the cross-reaction between (epi)genetic inheritance and the huge challenge of environmental stressors. Currently, the biochemical machinery is put at the service of the tumor program, halting the cell cycle, triggering uncontrolled proliferation, driving angiogenesis and resistance to apoptosis, until the archetypes of the tumor phenotype are reached. Melatonin has the ability to dynamically affect the epigenetic code. It has become accepted that melatonin can reverse (epi)genetic aberrations present in oral and other cancers, suggesting the possibility of enhancing the oncostatic capacity of standard multimodal treatments by incorporating this indolamine as an adjuvant. First steps in this direction confirm the potential of melatonin as a countermeasure to mitigate the detrimental side effects of conventional first-line radiochemotherapy. This single effect could produce synergies of extraordinary clinical importance, allowing doses to be increased and treatments not to be interrupted, ultimately improving patients' quality of life and prognosis. Motivated by the urgency of improving the medical management of oral cancer, many authors advocate moving from in vitro and preclinical research, where the bulk of melatonin cancer research is concentrated, to systematic randomized clinical trials on large cohorts. Recognizing the challenge to improve the clinical management of cancer, our motivation is to encourage comprehensive and robust research to reveal the clinical potential of melatonin in oral cancer control. To improve the outcome and quality of life of patients with oral cancer, here we provide the latest evidence of the oncolytic activity that melatonin can achieve by manipulating epigenetic patterns in oronasopharyngeal tissue.

[Relevancia y prevalencia histopatológica y molecular del cáncer de mamaPrevalence and significance of breast cancer pathologycal subtypes in Ecuador]. / Relevancia y prevalencia de los parámetros histopatológicos y subtipos moleculares del cáncer de mama en mujeres del área costera de Ecuador atendidas en una institución de Salud Pública.

BACKGROUND: The success of breast cancer (BC) treatment depends largely on the clinical-histological characteristics of the patient. Immunohistochemical (IHC) Breast Cancer Subtypes are crucial for therapeutic purposes. AIM: To determine the relevance and prevalence of the histopathological parameters and molecular subtypes of BC among women attending public health services. MATERIAL AND METHODS: A retrospective cross-sectional study was carried out in 199 female patients with histopathological diagnosis of breast cancer, treated at a Guayaquil city hospital in Ecuador, from January 2014 to December 2017. RESULTS: Luminal A carcinoma was the most prevalent tumor in the studied women (54%). Thirty seven percent of patients did not have nodal involvement, 40% had one to three lymph nodes involved and 2% had 10 or more nodes involved. Most patients had a tumor size > 2 and ≤ 5 cm (72%) and moderately differentiated specifications (57%). CONCLUSIONS: The study allowed the characterization of breast cancer according to the prevalence of molecular subtypes and clinical and histological characteristics. These factors determine therapeutic behaviors that optimize the use of the limited resources of the Public Health System.

The Chemotype of Chromanones as a Privileged Scaffold for Multineurotarget Anti-Alzheimer Agents.

The multifactorial nature of Alzheimer's disease necessitates the development of agents able to interfere with different relevant targets. A series of 22 tailored chromanones was conceptualized, synthesized, and subjected to biological evaluation. We identified one representative bearing a linker-connected azepane moiety (compound 19) with balanced pharmacological properties. Compound 19 exhibited inhibitory activities against human acetyl-, butyrylcholinesterase and monoamine oxidase-B, as well as high affinity to both the σ1 and σ2 receptors. Our study provides a framework for the development of further chromanone-based multineurotarget agents.

Ketamina en el manejo del dolor oncológico / Ketamine in cancer pain management

RESUMEN Fundamento la creciente demanda de nuevos analgésicos y sustancias neuromoduladoras en general para el tratamiento del dolor, hace necesario estandarizar el uso de estos. En el caso de la ketamina, la mayoría de las investigaciones giran en torno a su uso en el abordaje de los dolores agudos en situaciones de emergencias médicas. Objetivo realizar una revisión de la literatura científica actual sobre las potencialidades de la ketamina en el tratamiento del dolor oncológico. Métodos se realizó un estudio descriptivo, con diseño no experimental, longitudinal, el cual mediante la revisión documental en torno al tema de la ketamina en el manejo del dolor oncológico, permitió desarrollar una revisión sistemática de artículos científicos publicados en el período 2010-2019. Para ello fue aplicada la metodología Preferred Reporting Items for Systematic reviews and Meta-Analyses, según la cual fue desarrollado el proceso de extracción, búsqueda y elegibilidad de los artículos. Resultados: de un total de 250 artículos encontrados en la búsqueda inicial, fueron seleccionados 6, al considerar los criterios de selección muestral. Los que más se relacionaron con la salida de artículos, fueron el efecto de solapamiento y el temporal. Se obtuvieron respuestas positivas por cualquier vía de administración de la ketamina, excepto la tópica, variante aplicada precisamente en el estudio de mayor alcance. Conclusión conforme a la evidencia analizada en el presente trabajo, en tres de los seis estudios evaluados no se confirma la efectividad de la ketamina. No obstante, en dosis subanestésica aún podría considerarse su uso para el manejo del dolor oncológico.

ABSTRACT Background The growing demand for new analgesics and neuromodulatory substances in general for the treatment of pain, makes it necessary to standardize their use. In the case of ketamine, most research revolves around its use in treating acute pain in medical emergencies. Objective to carry out a review of the current scientific literature on the potentialities of ketamine in the treatment of cancer pain. Methods a descriptive study was carried out, with a non-experimental, longitudinal design, which, through a documentary review on the subject of ketamine in the management of cancer pain, allowed the development of a systematic review of scientific articles published from 2010 to 2019. The Preferred Reporting Items for Systematic reviews and Meta-Analyses methodology was applied, according to which the extraction, search and eligibility process of the articles was developed. Results of a total of 250 articles found in the initial search, 6 were selected, considering the sample selection criteria. The ones that were most related to the output of articles were the overlap effect and the temporal effect. Positive responses were obtained by any route of administration of ketamine, except topical, a variant applied precisely in the largest study. Conclusion according to the evidence analyzed in this study, the effectiveness of ketamine is not confirmed in three of the six studies evaluated. However, in subanesthetic doses, its use could still be considered for the management of cancer pain.

Polyfunctionalized α-Phenyl-tert-butyl(benzyl)nitrones: Multifunctional Antioxidants for Stroke Treatment.

Nowadays, most stroke patients are treated exclusively with recombinant tissue plasminogen activator, a drug with serious side effects and limited therapeutic window. For this reason, and because of the known effects of oxidative stress on stroke, a more tolerable and efficient therapy for stroke is being sought that focuses on the control and scavenging of highly toxic reactive oxygen species by appropriate small molecules, such as nitrones with antioxidant properties. In this context, herein we report here the synthesis, antioxidant, and neuroprotective properties of twelve novel polyfunctionalized α-phenyl-tert-butyl(benzyl)nitrones. The antioxidant capacity of these nitrones was investigated by various assays, including the inhibition of lipid peroxidation induced by AAPH, hydroxyl radical scavenging assay, ABTS+-decoloration assay, DPPH scavenging assay, and inhibition of soybean lipoxygenase. The inhibitory effect on monoamine oxidases and cholinesterases and inhibition of ß-amyloid aggregation were also investigated. As a result, (Z)-N-benzyl-1-(2-(3-(piperidin-1-yl)propoxy)phenyl)methanimine oxide (5) was found to be one of the most potent antioxidants, with high ABTS+ scavenging activity (19%), and potent lipoxygenase inhibitory capacity (IC50 = 10 µM), selectively inhibiting butyrylcholinesterase (IC50 = 3.46 ± 0.27 µM), and exhibited neuroprotective profile against the neurotoxicant okadaic acid in a neuronal damage model. Overall, these results pave the way for the further in-depth analysis of the neuroprotection of nitrone 5 in in vitro and in vivo models of stroke and possibly other neurodegenerative diseases in which oxidative stress is identified as a critical player.

Synthesis and Antioxidant Properties of HeteroBisNitrones Derived from Benzene Dicarbaldehydes.

We report herein the synthesis and antioxidant profile of nine novel heterobisnitrones (hBNs) as new α-phenyl-tert-butylnitrone (PBN) analogues. The synthesized hBNs 1-9 were evaluated for their antioxidant activity using different in vitro techniques, while they were also tested as inhibitors of soybean LOX, as an indication of their anti-inflammatory effect. Nitrone hBN9 is the most potent antioxidant presenting higher anti-lipid peroxidation and hydroxyl radicals scavenging activities as well as higher lipoxygenase inhibition. In silico calculations reveal that hBN9 follows Lipinski's rule of five and that the molecule is able to penetrate theoretically the brain. All these results led us to propose hBN9 as a new potent antioxidant nitrone.

Propuesta de una escala predictiva de deterioro cognitivo en pacientes adultos con neurocisticercosis / Proposal for a predictive scale of cognitive impairment in adult patients with neurocysticercosis

RESUMEN Fundamento La afectación cognitiva en pacientes con neurocisticercosis es frecuente, por lo tanto, resulta de gran utilidad contar con instrumentos pronósticos para establecer un mejor manejo de esta. Objetivo proponer una escala predictiva de deterioro cognitivo en pacientes adultos con neurocisticercosis. Métodos estudio con diseño correlacional, prospectivo y transversal, que incluyó 93 pacientes con neurocisticercosis. A través de datos aportados por investigaciones previas, se seleccionaron las variables, las cuales se relacionaron con la aparición de deterioro cognitivo en el análisis bivariado (p<0,05). Como técnica de análisis multivariado, se realizó un escalamiento multidimensional (PROXSCAL) (s-stress < 0,001 y coeficiente de congruencia de Tucker > 0,999). Se determinó el rendimiento pronóstico de cada uno de las variables, mediante la sensibilidad, especificidad y valores predictivos positivo y negativo, con sus respectivos intervalos de confianza al 95 %. Resultados se elaboró una escala con formato dicotómico, que incluyó 7 factores (4 clínicos y 3 tomográficos), con los que se obtuvo una puntuación de 0 a 7 puntos para la predicción de deterioro cognitivo en pacientes adultos con neurocisticercosis, con una probabilidad de: 0-1 punto: 75,3 %; 2-3 puntos: 95 %; ≥ 4 puntos: 96 %. Conclusión El instrumento propuesto presenta una precisión pronóstica aceptable; es sencillo, reproducible y necesita poco tiempo para su aplicación. A pesar de sus limitaciones, pudiera mejorar la calidad de la atención de los pacientes con neurocisticercosis, pues permite orientar el manejo de esta condición.

ABSTRACT Background Cognitive impairment in patients with neurocysticercosis is frequent, therefore, it is very useful to have prognostic instruments to establish a better management of it. Objective to propose a predictive scale of cognitive impairment in adult patients with neurocysticercosis. Methods study with a correlational, prospective and cross-sectional design, which included 93 patients with neurocysticercosis. Through data provided by previous research, the variables were selected, which were related to the appearance of cognitive impairment in the bivariate analysis (p<0.05). As a multivariate analysis technique, a multidimensional scaling (PROXSCAL) was performed (s-stress < 0.001 and Tucker's congruence coefficient > 0.999). The prognostic performance of each of the variables was determined by means of sensitivity, specificity, and positive and negative predictive values, with their respective 9 5% confidence intervals. Results a scale with a dichotomous format was developed, which included 7 factors (4 clinical and 3 tomographic), with which a score of 0 to 7 points was obtained for the prediction of cognitive impairment in adult patients with neurocysticercosis, with a probability of: 0-1 point: 75.3 %; 2-3 points: 95 %; ≥ 4 points: 96 %. Conclusion The proposed instrument has an acceptable prognostic accuracy; it is simple, reproducible and requires little time for its application. Despite its limitations, it could improve the quality of care for patients with neurocysticercosis, since it allows guiding the management of this condition.