Transcriptomic signature, bioactivity and safety of a non-hepatotoxic analgesic generating AM404 in the midbrain PAG region.

Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca2+ channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.

Real-World Safety and Efficacy Clinical Data of an Improved Allergen-Specific Immunotherapy Product for the Treatment of Bee Venom Allergy.

The aim of this study is to explore the safety and efficacy of bee venom immunotherapy without HSA, in real-life patients. Methods: This is an observational retrospective study developed in seven hospitals in Spain, where patients treated with this immunotherapy were included. They gathered the protocol used to initiate the immunotherapy, adverse reactions, field re-stings, and the patient clinical data (clinical history, biomarkers, and skin prick test). Results: A total of 108 patients were included. In total, 4 protocols were used (5 weeks reaching 200 µg, and 4, 3, and 2 weeks reaching 100 µg). An incidence of systemic adverse reactions for each 100 injections of 1.5, 1.7, 0, and 0.58, respectively, was found. The demographic data showed not to directly affect the appearance of adverse reactions, except for those having a grade 2 systemic reaction with immunotherapy previously had a grade 4 systemic reaction; the IgE to Apis mellifera was 3 times higher in patients with systemic reactions of grade 1 than in the general group, and other specific IgEs were lower in those with systemic reactions. Most of the patients recognized Api m 1 followed by Api m 10. In the sample, 32% experienced spontaneous re-stings, without presenting systemic reactions, after a year of treatment.

The emerging role of mixed lineage kinase 3 (MLK3) and its potential as a target for neurodegenerative diseases therapies.

Selective and brain-permeable protein kinase inhibitors are in preclinical development for treating neurodegenerative diseases. Among them, MLK3 inhibitors, with a potent neuroprotective biological action have emerged as valuable agents for the treatment of pathologies such as Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis. In fact, one MLK3 inhibitor, CEP-1347, reached clinical trials for Parkinson's disease. Additionally, another compound called prostetin/12k, a potent and rather selective MLK3 inhibitor has started clinical development for ALS based on its motor neuron protection in both in vitro and in vivo models. In this review, we will focus on the role of MLK3 in neuron-related cell death processes, neurodegenerative diseases, and the potential advantages of targeting this kinase through pharmacological modulation for neuroprotective treatment.

Two-photon activated precision molecular photosensitizer targeting mitochondria.

Mitochondria metabolism is an emergent target for the development of novel anticancer agents. It is amply recognized that strategies that allow for modulation of mitochondrial function in specific cell populations need to be developed for the therapeutic potential of mitochondria-targeting agents to become a reality in the clinic. In this work, we report dipolar and quadrupolar quinolizinium and benzimidazolium cations that show mitochondria targeting ability and localized light-induced mitochondria damage in live animal cells. Some of the dyes induce a very efficient disruption of mitochondrial potential and subsequent cell death under two-photon excitation in the Near-infrared (NIR) opening up possible applications of azonia/azolium aromatic heterocycles as precision photosensitizers. The dipolar compounds could be excited in the NIR due to a high two-photon brightness while exhibiting emission in the red part of the visible spectra (600-700 nm). Interaction with the mitochondria leads to an unexpected blue-shift of the emission of the far-red emitting compounds, which we assign to emission from the locally excited state. Interaction and possibly aggregation at the mitochondria prevents access to the intramolecular charge transfer state responsible for far-red emission.

Factors that Influence Treatment Delay for Patients with Breast Cancer.

INTRODUCTION: The diagnosis or treatment of breast cancer is sometimes delayed. A lengthy delay may have a negative psychological impact on patients. The aim of our study was to evaluate the sociodemographic, clinical and pathological factors associated with delay in the provision of surgical treatment for localised breast cancer, in a prospective cohort of patients. METHODS: This observational, prospective, multicentre study was conducted in ten hospitals belonging to the Spanish national public health system, located in four Autonomous Communities (regions). The study included 1236 patients, diagnosed through a screening programme or found to be symptomatic, between April 2013 and May 2015. The study variables analysed included each patient's personal history, care situation, tumour history and data on the surgical intervention, pathological anatomy, hospital admission and follow-up. Treatment delay was defined as more than 30 days elapsed between biopsy and surgery. RESULTS: Over half of the study population experienced surgical treatment delay. This delay was greater for patients with no formal education and among widows, persons not requiring assistance for usual activities, those experiencing anxiety or depression, those who had a high BMI or an above-average number of comorbidities, those who were symptomatic, who did not receive NMR spectroscopy, who presented a histology other than infiltrating ductal carcinoma or who had poorly differentiated carcinomas. CONCLUSIONS: Certain sociodemographic and clinical variables are associated with surgical treatment delay. This study identifies factors that influence surgical delays, highlighting the importance of preventing these factors and of raising awareness among the population at risk and among health personnel.

The Genomics and Metagenomics of Asthma Severity (GEMAS) Study: Rationale and Design.

Asthma exacerbations are a major contributor to the global disease burden, but no significant predictive biomarkers are known. The Genomics and Metagenomics of Asthma Severity (GEMAS) study aims to assess the role of genomics and the microbiome in severe asthma exacerbations. Here, we present the design of GEMAS and the characteristics of patients recruited from March 2018 to March 2020. Different biological samples and demographic and clinical variables were collected from asthma patients recruited by allergy and pulmonary medicine units in several hospitals from Spain. Cases and controls were defined by the presence/absence of severe asthma exacerbations in the past year (oral corticosteroid use, emergency room visits, and/or asthma-related hospitalizations). A total of 137 cases and 120 controls were recruited. After stratifying by recruitment location (i.e., Canary Islands and Basque Country), cases and controls did not differ for most demographic and clinical variables (p > 0.05). However, cases showed a higher proportion of characteristics inherent to asthma exacerbations (impaired lung function, severe disease, uncontrolled asthma, gastroesophageal reflux, and use of asthma medications) compared to controls (p < 0.05). Similar results were found after stratification by recruitment unit. Thereby, asthma patients enrolled in GEMAS are balanced for potential confounders and have clinical characteristics that support the phenotype definition. GEMAS will improve the knowledge of potential biomarkers of asthma exacerbations.

Corrigendum: Bradykinin-Mediated Angioedema: An Update of the Genetic Causes and the Impact of Genomics.

[This corrects the article DOI: 10.3389/fgene.2019.00900.].

A novel pipeline of 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analgesics that lack hepatotoxicity and retain antipyresis.

Although acetaminophen (ApAP) is one of the most commonly used medicines worldwide, hepatotoxicity is a risk with overdose or in patients with compromised liver function. ApAP overdose is the most common cause of acute fulminant hepatic failure. Oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI) is the mechanism for hepatotoxicity. 1 is a non-hepatotoxic, metabolically unstable lipophilic ApAP analog that is not antipyretic. The newly synthesized 3 is a non-hepatotoxic ApAP analog that is stable, lipophilic, and retains analgesia and antipyresis. Intraperitoneal or po administration of the new chemical entities (NCEs), 3b and 3r, in concentrations equal to a toxic dose of ApAP did not result in the formation of NAPQI. Unlike livers from NCE-treated mice, the livers from ApAP-treated mice demonstrated large amounts of nitrotyrosine, a marker of mitochondrial free radical formation, and loss of hepatic tight junction integrity. Given the widespread use of ApAP, hepatotoxicity risk with overuse, and the ongoing opioid epidemic, these NCEs represent a novel, non-narcotic therapeutic pipeline.

Metástasis de carcinoma pulmonar pleomórfico como causa de abdomen agudo / Small Bowel Perforation Due to Metastatic Pleomorphic Lung Cancer

No disponible

Studies on the preparation of aminobipyridines and bipyridine sultams via an intramolecular free radical pathway.

A variety of aminated bipyridines and bipyridine sultams are prepared by intramolecular radical [1,5]-ipso and [1,6]-ortho substitutions, using a sulfonamide as a linker to connect the pyridyl radical to the pyridine under attack. For the cases studied, different regiochemistries are observed depending on the initial position of the sulfonamide linker.

Bradykinin-Mediated Angioedema: An Update of the Genetic Causes and the Impact of Genomics.

Recurrent episodes of bradykinin-mediated angioedema (Bk-AE) can associate with acquired or hereditary conditions, the former most commonly developing secondarily to a pharmacological treatment. Despite successful genomic advances that have led to the identification of a large number of disease genes irrespective of disease prevalence, their application to Bk-AE has barely occurred. As a consequence, the genetic causes of Bk-AE remain poorly understood, obstructing the identification of patient subtypes and the development of precision medicine strategies. This review provides an update of the genetic studies completed to date on the acquired forms, which have almost exclusively focused on Bk-AE secondarily to the angiotensin-converting enzyme inhibitor treatment, and the blooming subdivision of the hereditary forms established by the identification of novel causal genes with next-generation sequencing (NGS) technology-based exome studies in genetically undiagnosed patients. Finally, based on the diverse benefits that are offered by the technology, we present arguments favoring the use of holistic NGS approaches as first-tier genetic tests as a promise to reduce the diagnostic odyssey of patients with suspected hereditary forms of Bk-AE.

Immunodeficiency associated with tumour pathology: Good's syndrome.

The Good's syndrome (GS) is a low prevalence entity where thymoma often is associated with immunodeficiency. Patients may start presenting recurrent rhinosinusal infections, bronchopulmonary infections, haematological alterations and diarrhoea, secondary to immunodeficiency. They can also present respiratory symptoms and parathymic syndromes derived from the existence of thymoma, a slow-growing neoplasm located in the anterior mediastinum. We present the case of a 76-year-old man diagnosed with thymoma by image analysis, which had presented multiple episodes of pneumonia and two admissions to the hospital for diarrhoea of weeks of evolution. After finishing the study, the patient is diagnosed of GS. In this case, thymectomy prevented the appearance of parathymic syndrome, but without any effect on immunodeficiency symptoms. To decrease repeat infections, substitution therapy with immunoglobulins was started. The prognosis will depend mainly on the recurrent infectious and to a lesser extent on the thymic neoplasm.

Bone marrow transplantation improves motor activity in a mouse model of ataxia.

Ataxias are locomotor disorders that can have an origin both neural and muscular, although both impairments are related. Unfortunately, ataxia has no cure, and the current therapies are aimed at motor re-education or muscular reinforcement. Nevertheless, cell therapy is becoming a promising approach to deal with incurable neural diseases, including neuromuscular ataxias. Here, we have used a model of ataxia, the Purkinje Cell Degeneration (PCD) mutant mouse, to study the effect of healthy (wild-type) bone marrow transplantation on the restoration of defective mobility. Bone marrow transplants (from both mutant and healthy donors) were performed in wild-type and PCD mice. Then, a wide battery of behavioural tests was employed to determine possible motor amelioration in mutants. Finally, cerebellum, spinal cord, and muscle were analysed to study the integration of the transplant-derived cells and the origin of the behavioural changes. Our results demonstrated that the transplant of wild-type bone marrow restores the mobility of PCD mice, increasing their capabilities of movement (52-100% of recovery), exploration (20-71% of recovery), speed (35% of recovery), and motor coordination (25% of recovery). Surprisingly, our results showed that bone marrow transplant notably improves the skeletal muscle structure, which is severely damaged in the mutants, rather than ameliorating the central nervous system. Although a multimodal effect of the transplant is not discarded, muscular improvements appear to be the basis of this motor recovery. Furthermore, the results from our study indicate that bone marrow stem cell therapy can be a safe and effective alternative for dealing with movement disorders such as ataxias.

Prodrug approach: An overview of recent cases.

In this review we highlight the most modern trends in the prodrug strategy. In drug research and development, the prodrug concept has found a number of useful applications. Selected examples of this approach are provided in this paper and they are classified according to the aim of their design.

Causa inusual d'obstrucció gàstrica en el lactant: membrana antropilòrica / Causa inusual de obstrucción gástrica en el lactante: membrane antropilórica / Unusual cause of gastric outlet obstruction in infants; antral web

Introducció: la membrana antropilòrica (MA) és una alteració congènita de baixa incidència i difícil diagnòstic per la seva semblança clinicoradiològica amb l'estenosi hipertròfica de pílor (EHP). La MA completa o parcial causa una obstrucció del buidament gàstric que provoca vòmits de repetició no biliosos, deshidratació, pèrdua de pes i alcalosi metabòlica hipoclorèmica. La radiografia d'abdomen mostra una dilatació gàstrica greu, i l'ecografia abdominal ens descarta l'EHP. Aleshores cal plantejar altres causes d'obstrucció a la sortida gàstrica en el lactant, com la MA. Cas clínic: es presenta el cas d'un lactant d'1 mes i 5 dies, sense antecedents obstètrics d'interès, que consulta per vòmits no biliosos, estancament ponderal i hipotonia de 24 hores d'evolució. Les exploracions complementàries fetes van ser normals, tret d'un lleu reflux gastroesofàgic, i es va descartar l'EHP per ecografia abdominal. Davant la sospita d'intolerància a proteïnes de llet de vaca es va fer un canvi de fórmula d'inici a fórmula elemental amb persistència de la clínica i instauració progressiva d'alcalosi metabòlica. Amb la sospita de MA, es va fer un segon estudi ecogràfic dirigit que mostrava un petit ressort antropilòric que es va confirmar en la fibrogastroscòpia, i es va diagnosticar una MA parcial. La resecció quirúrgica de la membrana va re-soldre la clínica. Comentaris: davant d'un lactant amb obstrucció gàstrica, i un cop descartada la causa més comú (EHP), cal pensar en la membrana antral com a possible etiologia, ja que si aquesta es confirma, el seu maneig quirúrgic és definitiu amb resolució clínica posterio

Introducción. La membrana antropilórica (MA) es una alteración de baja incidencia y difícil diagnóstico por el parecido clínico-radiológico con la estenosis hipertrófica de píloro (EHP). La MA completa o parcial causa una obstrucción en la salida gástrica produciendo vómitos de repetición no biliosos, deshidratación, pérdida de peso y alcalosis metabólica hipoclorémica. La radiografía de abdomen muestra una dilatación gástrica severa y la ecografía abdominal descarta la EHP. Es entonces cuando hemos de plantear otras causas de obstrucción de la salida gástrica en el lactante, como la MA. Caso clínico. Se presenta el caso de un lactante de 1 mes y 5 días, sin antecedentes obstétricos de interés, que consulta por vómitos no biliosos, estancamiento ponderal e hipotonía de 24 horas de evolución. Las exploraciones complementarias realizadas fueron normales, excepto un leve reflujo gastroesofágico, y se descartó la EHP por ecografía abdominal. Ante la sospecha de intolerancia a proteínas de leche de vaca se realizó un cambio de fórmula de inicio a fórmula elemental, con persistencia de la clínica e instauración progresiva de alcalosis metabólica. Con la sospecha de MA, se realizó un segundo estudio ecográfico dirigido que mostraba un pequeño resorte antropilórico que se confirmaba en la fibrogastroscopia, y se diagnosticó una MA parcial. Con la resección quirúrgica de la membrana se resolvió la clínica. Comentarios. Ante un lactante con obstrucción gástrica, y una vez descartada la causa más común (EHP), se ha de pensar en la membrana antral como posible etiología, ya que si esta se confirma, su manejo quirúrgico es definitivo con la resolución clínica posterior (AU)

Introduction. The antral web (AW) is a disorder of low incidence and difficult diagnosis despite its similar clinical and radiological findings to hypertrophic pyloric stenosis (HPS). Complete or partial AW cause gastric outlet obstruction with persistent non-bilious vomiting, dehydration, weight loss, and hypochloremic metabolic alkalosis. Abdominal radiograph shows severe gastric dilatation; however, the normal abdominal ultrasound ruling out HPS should raise the suspicion of other causes of gastric outlet obstruction, such as AW. Case report. We report a case of a one-month and five days-old infant with no relevant obstetric history, who presented with a 24- hour history of non-bilious vomiting, lack of weight gain and hypotonia. Diagnostic studies suggested mild gastroesophageal reflux, and an abdominal ultrasound ruled out HPS. The diagnosis of intolerance to cow’s milk protein was first considered, and elemental formula was started without improvement. Suspecting AW, a repeat abdominal ultrasound showed a small prepyloric spring. Gastroscopy confirmed the diagnosis of partial AW, and surgical resection of the membrane resulted in resolution of the symptoms. Comments. In the presence of an infant with gastric outlet obstruction syndrome, and after the most common cause (HPS) has been ruled out, the diagnosis of AW should be considered. Surgery is curative (AU)