👤 Carlos Escobar

The primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD). Naloxone is used to reverse OIRD, but this drug is a competitive antagonist of µ-opioid receptor (MOR) and reverses analgesia, which limits its therapeutic use. Alternative non-opioid receptor antagonist-based approaches to OIRD treatment and prevention are needed. The aim of this study was to evaluate if setmelanotide (SET) is capable of reversing OIRD in a mouse model. C57BL/6J male and female mice and Sprague-Dawley rats were given IP morphine or fentanyl and then treated 15 min later with either SET or vehicle VEH (IP) in a random order. Breathing was recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. In mice with OIRD, SET induced a 3-fold reduction of the apnea index, and decreased apnea duration as compared to the VEH treatment. SET increased respiratory rate and did not affect opioid-induced analgesia. Photostimulation of MC4R+ ChR2-expressing fibers in the parafacial region of MC4R-Cre mice elicited short-latency excitatory postsynaptic current in rostral ventral respiratory group (rVRG) pre-motoneurons projecting to the phrenic nucleus in the C3-C4 ventral horns of the spinal cord. Fentanyl inhibited the activity of rVRG neurons and SET reversed this effect. SET effectively treated OIRD by increasing respiratory rate and inducing a significant decrease in the number of apneas without decreasing analgesia. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by extreme hypertriglyceridemia (>1000 mg/dL), recurrent pancreatitis, and lipoprotein lipase (LPL) deficiency. FCS is caused by biallelic loss-of-function variants in LPL or in 4 other genes encoding its cofactors and regulators, including LMF1 (lipase maturation factor 1). Variants in LMF1 are rare and present only in 1% to 2% of the FCS cases. To assess in 3 patients with severe hypertriglyceridemia and recurrent pancreatitis and in whom a homozygous LMF1 duplication, initially classified as a variant of uncertain significance (VUS) was identified, post-heparin LPL activity. We collected demographics, fasting lipid profiles, and body mass index, and performed next-generation sequencing using a targeted panel that included canonical FCS genes. A homozygous in-frame duplication in LMF1 (c.914₉₂₈dup; p.Ser309_Phe310dup) was identified. Variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines and cross-referenced with public archive of reports of the relationships among human variations and phenotypes (ClinVar), The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff (HGMD), Leiden Open Variation Database (LOVD), The Single Nucleotide Polymorphism database (dbSNP), The Genome Aggregation Database (gnomAD), and in-house databases. LPL activity was assessed in post-heparin plasma using a radiometric assay. All 3 patients were homozygous for c.914₉₂₈dup (this variant was classified as a VUS) and exhibited markedly reduced LPL activity (<20% of normal). Clinical manifestations were consistent with FCS, including extreme triglyceride elevations and recurrent pancreatitis. One patient died from fulminant pancreatitis. The combined clinical, biochemical, and genetic evidence supports the reclassification of LMF1 c.914₉₂₈dup (p.Ser309_Phe310dup) as likely pathogenic according to ACMG/AMP guidelines and indicates its association with severe pancreatitis. Show less

In recent years we have been experiencing an advance in lipid-lowering therapies, with the appearance of new drugs that act on the different metabolic pathways, reducing both the levels of cholesterol associated with low-density lipoproteins (LDL-C) containing apoproteinB (ApoB), and vascular risk. However, the results in achieving goals are still scarce, as well as the use of the different therapies that help us to achieve them. Among the reasons that justify this situation are: the inadequate identification of vascular risk, the underuse of therapies, poor adherence to the recommended treatment, the lack of organization in terms of the assignment of roles and algorithms of action in the follow-up of patients and the need for improved education and psychosocial interventions that influence both adherence and consolidation of Healthy lifestyle habits. This consensus document aims to improve the approach and follow-up of dyslipidemia in a comprehensive way, defining the planning of lipid-lowering therapies as a control strategy (SEC/SEA/SEEN/SEMFYC/SEMERGEN/SEMG/SEN/SEACV/S.E.N.). Show less

The knowledge about the role of MC3 receptors (MC3r) in the regulation of feeding behavior is limited. The present study was conducted to determine whether MC3r mediates the hypophagic effects of the melanocortins under conditions of positive energy balance. Male Wistar rats were fed with a high-fat diet (HFD) for 15 days and on day 16 the animals received an intracerebroventricular injection of the following treatments: Vehicle, D-Trp8-γ-melanocyte-stimulating hormone (MSH; MC3r agonist), SHU9119 (MC3r/MC4r antagonist), or D-Trp8-γ-MSH+SHU9119. Food intake was measured and the behavioral satiety sequence (BSS) analysis was carried out during the first hour of the dark phase. The c-Fos and α-MSH immunoreactivity in the arcuate nucleus (ARC) was evaluated 60 min later the onset of food intake. The results indicated that D-Trp8-γ-MSH decreased the ingestion of the HFD and this effect is associated with the early development of the satiation process Moreover, the D-Trp8-γ-MSH increased the accumulation of the α-MSH in the ARC and the c-Fos activity in the PVN. The antagonist SHU9119 partially prevented the D-Trp8-γ-MSH-induced hypophagia. Moreover, behavioral analysis suggests that central activation of MC3r accelerated the cessation of feeding in conditions of positive energy balance; the possible role of MC4r is discussed. Present data indicate that central stimulation of MC3r prevented the overconsumption of the HFD without affecting the natural satiation process, suggesting a potential use of MC3r for the treatment of eating disorders that are stimulated by hypercaloric diets. (PsycInfo Database Record (c) 2021 APA, all rights reserved). Show less

Among many causes of hypertriglyceridemia (HTG), familial chylomicronemia syndrome (FCS) is a rare monogenic disorder that manifests as severe HTG and acute pancreatitis. Among the known causal genes for FCS, mutations in We present the challenging care of a 43-year-old man with FCS with apoC-II deficiency and the results of two types of TPE and of investigational TG-lowering biologic therapies. The patient's lipid profile was consistent with FCS. A novel homozygous variant was identified in Our case demonstrates the importance of delineating and defining the underlying etiology of a rare disorder to optimize therapy and to minimize unfavorable outcomes. Show less