Implementing Vancomycin Population Pharmacokinetic Models: An App for Individualized Antibiotic Therapy in Critically Ill Patients

13 páginasIn individualized therapy, the Bayesian approach integrated with population pharmacokinetic models (PopPK) for predictions together with therapeutic drug monitoring (TDM) to maintain adequate objectives is useful to maximize the efficacy and minimize the probability of toxicity of vancomycin in critically ill patients. Although there are limitations to implementation, model-informed precision dosing (MIPD) is an approach to integrate these elements, which has the potential to optimize the TDM process and maximize the success of antibacterial therapy. The objective of this work was to present an app for individualized therapy and perform a validation of the implemented vancomycin PopPK models. A pragmatic approach was used for selecting the models of Llopis, Goti and Revilla for developing a Shiny app with R. Through ordinary differential equation (ODE)-based mixed effects models from the mlxR package, the app simulates the concentrations’ behavior, estimates whether the model was simulated without variability and predicts whether the model was simulated with variability. Moreover, we evaluated the predictive performance with retrospective trough concentration data from patients admitted to the adult critical care unit. Although there were no significant differences in the performance of the estimates, the Llopis model showed better accuracy (mean 80.88%; SD 46.5%); however, it had greater bias (mean 34.47%, SD 63.38%) compared to the Revilla et al. (mean 10.61%, SD 66.37%) and Goti et al. (mean of 13.54%, SD 64.93%) models. With respect to the RMSE (root mean square error), the Llopis (mean of 10.69 mg/L, SD 12.23 mg/L) and Revilla models (mean of 10.65 mg/L, SD 12.81 mg/L) were comparable, and the lowest RMSE was found in the Goti model (mean 9.06 mg/L, SD 9 mg/L). Regarding the predictions, this behavior did not change, and the results varied relatively little. Although our results are satisfactory, the predictive performance in recent studies with vancomycin is heterogeneous, and although these three models have proven to be useful for clinical application, further research and adaptation of PopPK models is required, as well as implementation in the clinical practice of MIPD and TDM in real time.Especialización en Farmacología ClínicaEspecialista en Farmacología Clínic

A systematic review on cannabinoids for neuropathic pain administered by routes other than oral or inhalation

12 páginasThe use of cannabis and cannabinoid products for the treatment of neuropathic pain is a growing area of research. This type of pain has a high prevalence, limited response to available therapies and high social and economic costs. Systemic cannabinoid-based therapies have shown some unwanted side effects. Alternative routes of administration in the treatment of neuropathic pain may provide better acceptance for the treatment of multiple pathologies associated with neuropathic pain. To examine the efficacy, tolerability, and safety of cannabinoids (individualized formulations, phytocannabinoids, and synthetics) administered by routes other than oral or inhalation compared to placebo and/or conventional medications in the management of neuropathic pain. This systematic review of the literature reveals a lack of clinical research investigating cannabis by routes other than oral and inhalation as a potential treatment for neuropathic pain and highlights the need for further investigation with well-designed clinical trials. There is a significant lack of evidence indicating that cannabinoids administered by routes other than oral or inhaled may be an effective alternative, with better tolerance and safety in the treatment of neuropathic pain. Higher quality, long-term, randomized controlled trials are needed to examine whether cannabinoids administered by routes other than inhalation and oral routes may have a role in the treatment of neuropathic pain.Especialización en Farmacología ClínicaEspecialista en Farmacología Clínic

The short-term cost-effectiveness of once-weekly semaglutide versus once-weekly dulaglutide for the treatment of type 2 diabetes mellitus in Colombian adults [version 2; peer review: 2 approved]

Background Type 2 Diabetes Mellitus (T2DM) is a highly prevalent disease worldwide and in Colombia, representing one of the main causes of death and placing a considerable burden on healthcare systems. 13 classes of drugs are approved for the treatment of T2DM, with Glucagon-like Peptide-1 (GLP-1) receptor agonists being a first-line treatment option for patients with or at high risk of certain cardiovascular diseases and chronic kidney disease. The objective of this study is to conduct a short-term cost-effectiveness analysis of once-weekly semaglutide versus once-weekly dulaglutide in Colombian adults with T2DM, from a third-party payer perspective. Methods Numbers needed to treat were calculated for different single and composite endpoints of the SUSTAIN 7 trial, annual costs for once weekly semaglutide 1.0 mg and dulaglutide 1.5 mg were extracted from the public SISMED database. With these inputs a cost of control model was developed, to obtain the annual cost of bringing one T2DM patient to relevant clinical outcomes by using semaglutide or dulaglutide. Results Semaglutide was considered cost-effective compared to dulaglutide across all pre-specified endpoints, even in the different scenarios evaluated in the sensitivity analyses, and in a particularly pronounced manner for weight loss outcomes. Semaglutide at a dose of 1.0 mg once-weekly was cost-effective compared to dulaglutide 1.5 mg across all outcomes in the short-term, making it an appropriate first-line choice in the treatment of T2DM when deciding between these two GLP-1 receptor agonists. Conclusions This is the first short-term cost-effectiveness study of semaglutide and dulaglutide in T2DM Colombian patients. Our modeled results suggest that once-weekly semaglutide represents a cost-effective option for treating individuals with T2DM in Colombia who are not achieving glycaemia control with metformin, and it would be expected to improve HbA1C, promote greater weight loss and reduce costs from a third-payer perspective compared with treatment with dulaglutide

Effects of an exercise program on hepatic metabolism, hepatic fat, and cardiovascular health in overweight/obese adolescents from Bogotá, Colombia (the HEPAFIT study): study protocol for a randomized controlled trial

Background: A considerable proportion of contemporary youth have a high risk of obesity-related disorders such as cardiovascular disease, metabolic syndrome, or non-alcoholic fatty liver disease (NAFLD). Although there is consistent evidence for the positive effects of physical activity on several health aspects, most adolescents in Colombia are sedentary. It is, therefore, important to implement strategies that generate changes in lifestyle. The HEPAFIT study aims to examine whether a 6-month exercise program has benefits for hepatic fat content and cardiovascular health outcomes among overweight/obese adolescents from Bogotá, Colombia. Methods/design: Altogether, 100 hundred overweight/obese, sedentary adolescents (aged 11–17 years) attending two public schools in Bogotá, Colombia, will be included in a parallel-group randomized controlled trial. Adolescents will be randomly assigned to an intervention group following one of four curricula: (1) the standard physical education curriculum (60 min per week of physical activity, n = 25) at low-to-moderate intensity; (2) a high-intensity physical education curriculum (HIPE, n = 25), consisting of endurance and resistance games and non-competitive activities, such as running, gymkhanas, lifting, pushing, wrestling, or hauling, for 60-min sessions, three times per week, with an energy expenditure goal of 300 to 500 kcal/session at 75–85% maximum heart rate (HRmax); (3) a low-to-moderate intensity physical education curriculum (LIPE, n = 25) consisting of endurance and resistance games and non-competitive activities (e.g., chasing, sprinting, dribbling, or hopping) for 60-min sessions, three times per week with an energy expenditure goal of 300 kcal/session at 55–75% HRmax; and (4) a combined HIPE and LIPE curriculum (n = 25). The HIPE, LIPE, and combined interventions were performed in addition to the standard physical education curriculum. The primary outcome for effectiveness is liver fat content, as measured by the controlled attenuation parameter 1 week after the end of the intervention program. Discussion: The translational focus may be suitable for collecting new information in a school setting on the possible effects of physical activity interventions to reduce liver fat content and to improve metabolic profiles and the cardiometabolic health of overweight/obese adolescents. This may lead to the more efficient use of school physical education resources.The HEPAFIT study was carried out with the financial support of Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología “Francisco José de Caldas” COLCIENCIAS (code 59700 and no 122277757900). Katherine González-Ruíz receive a scholarship from Universidad del Rosario, Colombia, Escuela de Medicina y Ciencias de la Salud, to do a Doctorate. This article presents independent research commissioned by COLCIENCIAS under its Program Grants for Applied Research funding scheme (Convocatoria 777–2017)

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. METHODS: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. FINDINGS: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. INTERPRETATION: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. FUNDING: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

The Genetic Diagnosis of Neurodegenerative Diseases and Therapeutic Perspectives

Genetics has led to a new focus regarding approaches to the most prevalent diseases today. Ascertaining the molecular secrets of neurodegenerative diseases will lead to developing drugs that will change natural history, thereby affecting the quality of life and mortality of patients. The sequencing of candidate genes in patients suffering neurodegenerative pathologies is faster, more accurate, and has a lower cost, thereby enabling algorithms to be proposed regarding the risk of neurodegeneration onset in healthy persons including the year of onset and neurodegeneration severity. Next generation sequencing has resulted in an explosion of articles regarding the diagnosis of neurodegenerative diseases involving exome sequencing or sequencing a whole gene for correlating phenotypical expression with genetic mutations in proteins having key functions. Many of them occur in neuronal glia, which can trigger a proinflammatory effect leading to defective proteins causing sporadic or familial mutations. This article reviews the genetic diagnosis techniques and the importance of bioinformatics in interpreting results from neurodegenerative diseases. Risk scores must be established in the near future regarding diseases with a high incidence in healthy people for defining prevention strategies or an early start for giving drugs in the absence of symptoms

Personalized Medicine for Antibiotics: The Role of Nanobiosensors in Therapeutic Drug Monitoring

Due to the high bacterial resistance to antibiotics (AB), it has become necessary to adjust the dose aimed at personalized medicine by means of therapeutic drug monitoring (TDM). TDM is a fundamental tool for measuring the concentration of drugs that have a limited or highly toxic dose in different body fluids, such as blood, plasma, serum, and urine, among others. Using different techniques that allow for the pharmacokinetic (PK) and pharmacodynamic (PD) analysis of the drug, TDM can reduce the risks inherent in treatment. Among these techniques, nanotechnology focused on biosensors, which are relevant due to their versatility, sensitivity, specificity, and low cost. They provide results in real time, using an element for biological recognition coupled to a signal transducer. This review describes recent advances in the quantification of AB using biosensors with a focus on TDM as a fundamental aspect of personalized medicine

Implementing Vancomycin Population Pharmacokinetic Models: An App for Individualized Antibiotic Therapy in Critically Ill Patients

In individualized therapy, the Bayesian approach integrated with population pharmacokinetic models (PopPK) for predictions together with therapeutic drug monitoring (TDM) to maintain adequate objectives is useful to maximize the efficacy and minimize the probability of toxicity of vancomycin in critically ill patients. Although there are limitations to implementation, model-informed precision dosing (MIPD) is an approach to integrate these elements, which has the potential to optimize the TDM process and maximize the success of antibacterial therapy. The objective of this work was to present an app for individualized therapy and perform a validation of the implemented vancomycin PopPK models. A pragmatic approach was used for selecting the models of Llopis, Goti and Revilla for developing a Shiny app with R. Through ordinary differential equation (ODE)-based mixed effects models from the mlxR package, the app simulates the concentrations&rsquo; behavior, estimates whether the model was simulated without variability and predicts whether the model was simulated with variability. Moreover, we evaluated the predictive performance with retrospective trough concentration data from patients admitted to the adult critical care unit. Although there were no significant differences in the performance of the estimates, the Llopis model showed better accuracy (mean 80.88%; SD 46.5%); however, it had greater bias (mean &minus;34.47%, SD 63.38%) compared to the Revilla et al. (mean 10.61%, SD 66.37%) and Goti et al. (mean of 13.54%, SD 64.93%) models. With respect to the RMSE (root mean square error), the Llopis (mean of 10.69 mg/L, SD 12.23 mg/L) and Revilla models (mean of 10.65 mg/L, SD 12.81 mg/L) were comparable, and the lowest RMSE was found in the Goti model (mean 9.06 mg/L, SD 9 mg/L). Regarding the predictions, this behavior did not change, and the results varied relatively little. Although our results are satisfactory, the predictive performance in recent studies with vancomycin is heterogeneous, and although these three models have proven to be useful for clinical application, further research and adaptation of PopPK models is required, as well as implementation in the clinical practice of MIPD and TDM in real time

Implementing Vancomycin Population Pharmacokinetic Models: An App for Individualized Antibiotic Therapy in Critically Ill Patients

In individualized therapy, the Bayesian approach integrated with population pharmacokinetic models (PopPK) for predictions together with therapeutic drug monitoring (TDM) to maintain adequate objectives is useful to maximize the efficacy and minimize the probability of toxicity of vancomycin in critically ill patients. Although there are limitations to implementation, model-informed precision dosing (MIPD) is an approach to integrate these elements, which has the potential to optimize the TDM process and maximize the success of antibacterial therapy. The objective of this work was to present an app for individualized therapy and perform a validation of the implemented vancomycin PopPK models. A pragmatic approach was used for selecting the models of Llopis, Goti and Revilla for developing a Shiny app with R. Through ordinary differential equation (ODE)-based mixed effects models from the mlxR package, the app simulates the concentrations’ behavior, estimates whether the model was simulated without variability and predicts whether the model was simulated with variability. Moreover, we evaluated the predictive performance with retrospective trough concentration data from patients admitted to the adult critical care unit. Although there were no significant differences in the performance of the estimates, the Llopis model showed better accuracy (mean 80.88%; SD 46.5%); however, it had greater bias (mean −34.47%, SD 63.38%) compared to the Revilla et al. (mean 10.61%, SD 66.37%) and Goti et al. (mean of 13.54%, SD 64.93%) models. With respect to the RMSE (root mean square error), the Llopis (mean of 10.69 mg/L, SD 12.23 mg/L) and Revilla models (mean of 10.65 mg/L, SD 12.81 mg/L) were comparable, and the lowest RMSE was found in the Goti model (mean 9.06 mg/L, SD 9 mg/L). Regarding the predictions, this behavior did not change, and the results varied relatively little. Although our results are satisfactory, the predictive performance in recent studies with vancomycin is heterogeneous, and although these three models have proven to be useful for clinical application, further research and adaptation of PopPK models is required, as well as implementation in the clinical practice of MIPD and TDM in real time

Construcción de un currículo pertinente para la Institución Educativa Municipal Nuestra Señora de Guadalupe corregimiento de Catambuco (Pasto)

La investigación se presenta en la Ciudad de Pasto en el corregimiento de Catambuco, localidad de Botanilla, en la Institución Educativa Municipal “Nuestra Señora de Guadalupe” donde se desarrolla un currículo pertinente, un currículo genuino, socialmente legítimo y culturalmente coherente. “Con sentido e identidad propia y que a su vez se identifica armónicamente con la comunidad y con su entorno, con sus historias, necesidades, potencialidades y sueños” La propuesta “UN CURRICULO PERTINENTE… PARA UNA OPCION DE FUTURO”, parte de una investigación del análisis entornal como de un proceso prospectivo en el cual intervienen los actores sociales del currículo para determinar en una red de significaciones, los ejes de pertinencia alrededor de los cuales se origina la movilidad de los campos de pertinencia. Como resultado del ejercicio prospectivo participativo y comunitario, se obtienen los cinco ejes de pertinencia: articulación y educación superior a través de círculos propedéuticos; bilingüismo; uso de medios y nuevas tecnologías para la información y comunicación; formación artística a través de la danza y la música; y la formación ambiental. La acción prospectiva parte de la definición de currículo pertinente, pertinencia educativa y enfoque curricular, estos constructos teóricos son la base para prospectar el horizonte institucional y se construyó colectivamente una estructura curricular pertinente para la Institución la cual se desglosa en estructura básica o diseño curricular, la específica o diseño subsidiario y la estructura unitaria. Los ejes de pertinencia que originan la actual movilidad de la Institución Educativa se están ejecutando y dieron origen a una URDIMBRE DE PERTINENCIA que genera la estructura curricular la cual se desagrega en los pentágonos de pertinencia bases que originan un entramado y que conforman una red de pertinencia signálica y simbólica ante la realidad de la comunidad de Catambuco. En el momento histórico actual, la propuesta se encuentra en ejecución