Modulating epigenetic modifications for cancer therapy (Review)

Cancer is a global public health concern. Alterations in epigenetic processes are among the earliest genomic aber- rations occurring during cancer development and are closely related to progression. Unlike genetic mutations, aberrations in epigenetic processes are reversible, which opens the possi- bility for novel pharmacological treatments. Non-coding RNAs (ncRNAs) represent an essential epigenetic mechanism, and emerging evidence links ncRNAs to carcinogenesis. Epigenetic drugs (epidrugs) are a group of promising target therapies for cancer treatment acting as coadjuvants to reverse drug resis- tance in cancer. The present review describes central epigenetic aberrations during malignant transformation and explains how epidrugs target DNA methylation, histone modifications and ncRNAs. Furthermore, clinical trials focused on evaluating the effect of these epidrugs alone or in combination with other anticancer therapies and other ncRNA-based therapies are discussed. The use of epidrugs promises to be an effective tool for reversing drug resistance in some patients with cancer.</p

Effects of the Off-Label Drug Prescription in the Paediatric Population in Spain from the Adoption of the Latest European Regulation: A Pre-Post Study

The year 2021 marks the 15th anniversary of the Paediatric Regulation (1901/2006/EC) in Europe. The main aim of the study was to conduct a pre-post comparison on the annual off-label prescription rates in the under-18 population in Spain and assess the potential influence of the Paediatric Regulation adoption. An observational study in the paediatric population was performed. Four cross-sectional annual periods, one before and the three latest periods after the adoption of the Regulation, were compared. Prescriptions in the primary health care setting were sorted by age group and drug and off-label status were determined. The number of off-label prescriptions issued by paediatricians was over two million per year. Prior to the adoption of the Paediatric Regulation, the off-label prescription rate was estimated at 7% of total prescriptions. Although the increase in the off-label rate over the study periods was mild, it was statistically significant (OR: 1.045; 95% CI: 1.043-1.046; p < 0.05). One of the most vulnerable population groups was neonates and infants up to 1 year, in which the off-label prescription rates showed the highest increase during the post follow-up period, which was statistically significant (OR: 4.270; 95% CI: 4.253-4.287; p < 0.05). The findings can help raise awareness and advocate for the development and authorization of medicines for children in the primary health care setting. Keywords: off-label prescription, paediatrics, paediatric regulation, pharmaceutical products, prescription drugs, primary health car

Prevention strategies to identify LASA errors: building and sustaining a culture of patient safety

Background: Potential look-alike, sound-alike (LASA) errors in outpatient and inpatient prescriptions have been widely described worldwide. However, most strategies of reducing drug name confusion have been only focused on the processes of prescribing and dispensing, often following local rules. Main text: An illustrative recent example about this topic is given: the antidepressant Brintellix® (vortioxetine)(Takeda Pharmaceuticals USA, Inc.) and the antiplatelet medication Brilinta® (ticagrelor) (AstraZeneca LP). Revision of the initiatives that are currently applied to prevent potential LASA errors in different countries around the world and debate about the emerging strategies that could be implemented in short and mid-term. At present, a common policy worldwide on the authorization of unique names for innovative medicines does not exist. The implication of authorities in topdown strategies and the importance of developing an international health policy on the authorization of unique names for innovative medicines are highlighted in the following piece of opinion. Conclusions: Building and sustaining a culture of patient safety should be considered as a global top-down strategy which involved all the elements in the system (regulatory bodies, manufacturers and suppliers). The precedent established by the FDA in prevention strategies to identify and avoid LASA errors has been extremely important and should lead to international discussion. Coordinated international efforts are urgently needed in this area for the sake of patients' safety

Diarrhea associated with rotaviruses, enterotoxigenic Escherichia coli, Campylobacter, and other agents in costa rican children, 1976-1981

artículo -- Universidad de Costa Rica. Instituto de Investigaciones en Salud, 1983Rotaviruses, enterotoxigenic Escherichia coil, Salmonella, Shigella, and parasites were investigated in outpatient diarrheic children, and in hospitalized diarrheic and nondiarrheic children, between January 1976 and June 1979. In outpatient cases studied within 4 days of onset of symptoms, rotaviruses were the most common agents (45.3%); E. coil heatstable enterotoxin ranked second (13.4%); Shigella was third (8.1%); Salmonella was fourth (7.3%). In 63.2%, one or more enteric agents were detected. In hospitalized non-diarrheic children, asymptomatic shedding of pathogens was rarely observed. A later survey of outpatient diarrheic children revealed Campylobacter fetus jejuni in 8%. In 5.5 years of observation rotaviruses were endemic with excess frequency in the dry and cooler months of December and January. The excess occurrence of bacterial pathogens did not coincide with that of rotaviruses.Universidad de Costa Rica, Instituto de investigaciones en Salud.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

Experimental pathology of local tissue damage induced by Bothrops asper snake venom

Envenomations by Bothrops asper are often associated with complex and severe local pathological manifestations, including edema, blistering, dermonecrosis, myonecrosis and hemorrhage. The pathogenesis of these alterations has been investigated at the experimental level. These effects are mostly the consequence of the direct action of zinc-dependent metalloproteinases (SVMPs) and myotoxic phospholipases A2 (PLA2s). SVMPs induce hemorrhage, blistering, dermonecrosis and general extracellular matrix degradation, whereas PLA2s induce myonecrosis and also affect lymphatic vessels. In addition, the prominent vascular alterations leading to hemorrhage and edema may contribute to ischemia and further tissue necrosis. The mechanisms of action of SVMPs and PLA2s are discussed in detail in this review. Venom-induced tissue damage plays also a role in promoting bacterial infection. A prominent inflammatory reaction develops as a consequence of these local pathological alterations, with the synthesis and release of abundant mediators, resulting in edema and pain. However, whether inflammatory cells and mediators contribute to further tissue damage is not clear at present. Muscle tissue regeneration after venom-induced pathological effects is often impaired, thus resulting in permanent tissue loss and dysfunction. SVMP-induced microvessel damage is likely to be responsible of this poor regenerative outcome. Antivenoms are only partially effective in the neutralization of B. asper-induced local effects, and the search for novel toxin inhibitors represents a potential avenue for improving the treatment of this serious aspect of snakebite envenomation.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP

Reversible and bidirectional signaling of notch ligands

The Notch signaling pathway is a direct cell-cell communication system involved in a wide variety of biological processes, and its disruption is observed in several pathologies. The pathway is comprised of a ligand-expressing (sender) cell and a receptor-expressing (receiver) cell. The canonical ligands are members of the Delta/Serrate/Lag-1 (DSL) family of proteins. Their binding to a Notch receptor in a neighboring cell induces a conformational change in the receptor, which will undergo regulated intramembrane proteolysis (RIP), liberating the Notch intracellular domain (NICD). The NICD is translocated to the nucleus and promotes gene transcription. It has been demonstrated that the ligands can also undergo RIP and nuclear translocation, suggesting a function for the ligands in the sender cell and possible bidirectionality of the Notch pathway. Although the complete mechanism of ligand processing is not entirely understood, and its dependence on Notch receptors has not been ruled out. Also, ligands have autonomous functions beyond Notch activation. Here we review the concepts of reverse and bidirectional signalization of DSL proteins and discuss the characteristics that make them more than just ligands of the Notch pathway

Profile, cost and pattern of prescriptions for polymedicated patients in Catalonia, Spain

OBJECTIVES: Polypharmacy is one of the main management issues in public health policies because of its financial impact and the increasing number of people involved. The polymedicated population according to their demographic and therapeutic profile and the cost for the public healthcare system were characterised. DESIGN: Cross-sectional study. SETTING: Primary healthcare in Barcelona Health Region, Catalonia, Spain (5 105 551 inhabitants registered). PARTICIPANTS: All insured polymedicated patients. Polymedicated patients were those with a consumption of ≥16 drugs/month. MAIN OUTCOMES MEASURES: The study variables were related to age, gender and medication intake obtained from the 2008 census and records of prescriptions dispensed in pharmacies and charged to the public health system. RESULTS: There were 36 880 polymedicated patients (women: 64.2%; average age: 74.5±10.9 years). The total number of prescriptions billed in 2008 was 2 266 830 (2 272 920 total package units). The most polymedicated group (up to 40% of the total prescriptions) was patients between 75 and 84 years old. The average number of prescriptions billed monthly per patient was 32±2, with an average cost of 452.7±27.5. The total cost of those prescriptions corresponded to 2% of the drug expenditure in Catalonia. The groups N, C, A, R and M represented 71.4% of the total number of drug package units dispensed to polymedicated patients. Great variability was found between the medication profiles of men and women, and between age groups; greater discrepancies were found in paediatric patients (5-14 years) and the elderly (≥65 years). CONCLUSIONS: This study provides essential information to take steps towards rational drug use and a structured approach in the polymedicated population in primary healthcare

Efficacy comparison of oral rehydration solutions containing either 90 or 75 millimoles of sodium per liter

In a randomized trial, 62 infants 2 to 35 months of age with dehydration due to acute watery diarrhea were allocated to one of two groups: group A received solution A (World Health Organization-recommended oral rehydration solution), which contained (mmol/L): Na+ 90, K+ 20, Cl- 80, citrate3- 10, and glucose 110; group B received solution B (Pedialyte RS; Abbott Laboratories, North Chicago), which contained (in mmol/L): Na+ 75, K+ 20, Cl- 65, citrate3- 10, and glucose 139. Oral therapy was given until clinical signs of hydration status were normal. During the 48-hour trial, the following laboratory data were collected: blood gases, serum electrolytes, glucose, urea, and creatinine values and sodium and potassium concentrations in stool and urine; serial weights and clinical signs were also reported. Six of the 62 infants, three in each group, required intravenous fluids because of high stool output. Results of clinical outcome and normalization of altered serum electrolyte values were similar in both groups. During the 48-hour trial, eight patients in group A and four in group B had mild, asymptomatic hypernatremia. Pedialyte RS was found to be a safe glucose/electrolyte solution for oral rehydration therapy.Universidad de Costa Rica//UCR/Costa RicaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA