Herramientas para un ajuste de dosis de tacrolimus más personalizado en el seguimiento de los pacientes con transplante renal. Fenotipo metabolizador según polimorfismos genéticos del CYP3A vs. el cociente concentración-dosis / Tools for a personalized tacrolimus dose adjustment in the follow-up of renal transplant recipients: Metabolizing phenotype according to CYP3A genetic polymorphisms versus concentration–dose ratio

Antecedentes y justificación: La estrategia de la aproximación concentración-dosis (C/D) y los distintos perfiles del tacrolimus (Tac), según los polimorfismos del citocromo P450 (CYPs) se centran en el metabolismo de Tac y se plantean como herramientas para el seguimiento de los pacientes trasplantados. El objetivo de este estudio es comparar la exposición al Tac analizado según ambas estrategias. Materiales y métodos: Se han incluido 425 pacientes trasplantados renales. El cálculo del cociente concentración Tac/dosis (C/D) permitió dividir la población en terciles y clasificar los pacientes según su tasa de metabolismo del Tac en tres grupos (rápida, intermedia y lenta). Con base en los polimorfismos del CYP3A4 y A5, los pacientes se agruparon en metabolizadores rápidos (portadores del CYP3A5*1 y CYP34A *1/*1), intermedios (CYP3A5*3/3 y CYP3A4*1/*1) y lentos (CYP3A5 *3/*3 y portadores del CYP3A4*22). Resultados: Al comparar los pacientes de cada grupo metabolizador según los dos criterios, coincidieron 47% (65/139) de los metabolizadores rápidos, 85% (125/146) de los intermedios y solo 12% (17/140) de los lentos. Se observaron concentraciones de Tac estadísticamente menores en los metabolizadores rápidos y concentraciones mayores en los lentos, comparándolos con el grupo intermedio según el cociente C/D o según polimorfismos. Los metabolizadores rápidos requirieron alrededor de 60% más de dosis de Tac que los intermedios a lo largo del seguimiento, mientras que los lentos aproximadamente 20% menos de dosis que los intermedios. Los metabolizadores rápidos clasificados por ambos criterios presentan un porcentaje mayor de veces con valores de concentración de Tac en sangre infraterapéuticos... (AU)

Background and justification: The strategy of the concentration–dose (C/D) approach and the different profiles of tacrolimus (Tac) according to the cytochrome P450 polymorphisms (CYPs) focus on the metabolism of Tac and are proposed as tools for the follow-up of transplant patients. The objective of this study is to analyse both strategies to confirm whether the stratification of patients according to the pharmacokinetic behaviour of C/D corresponds to the classification according to their CYP3A4/5 cluster metabolizer profile. Materials and methods: Four hundred and twenty-five kidney transplant patients who received Tac as immunosuppressive treatment have been included. The concentration/dose ratio (C/D) was used to divided patients in terciles and classify them according to their Tac metabolism rate (fast, intermediate, and slow). Based on CYP3A4 and A5 polymorphisms, patients were classified into three metabolizer groups: fast (CYP3A5*1 and CYP34A*1/*1 carriers), intermediate (CYP3A5*3/3 and CYP3A4*1/*1) and slow (CYP3A5*3/*3 and CYP3A4*22 carriers). Results: When comparing patients included in each metabolizer group according to C/D ratio, 47% (65/139) of the fast metabolizers, 85% (125/146) of the intermediate and only 12% (17/140) of the slow also fitted in the homonym genotype group. Statistically lower Tac concentrations were observed in the fast metabolizers group and higher Tac concentrations in the slow metabolizers when compared with the intermediate group both in C/D ratio and polymorphisms criteria. High metabolizers required approximately 60% more Tac doses than intermediates throughout follow-up, while poor metabolizers required approximately 20% fewer doses than intermediates. Fast metabolizers classified by both criteria presented a higher percentage of times with sub-therapeutic blood Tac concentration values... (AU)

Aplicación de un modelo farmacocinético poblacional para el seguimiento de pacientes en tratamiento con dolutegravir: estudio piloto

Introducción: a pesar de los avances en tratamiento antirretroviral, existe la posibilidad de que personas que viven con el virus de la inmunodeficiencia humana (VIH) experimenten falla terapéutica vinculada a múltiples factores que impactan en la respuesta al fármaco. Objetivos: evaluar la utilidad de aplicar un modelo farmacocinético en pacientes con diagnóstico de VIH en tratamiento con dolutegravir para el análisis de las concentraciones plasmáticas experimentales. Adicionalmente, se pretende identificar potenciales interacciones farmacológicas, evaluar adherencia y fallo terapéutico. Material y método: se realizó un estudio piloto transversal y observacional en pacientes VIH tratados con dolutegravir que incluyó la dosificación de la concentración plasmática, evaluación de adherencia mediante el cuestionario simplificado de adherencia a la medicación (SMAQ) y retiro de medicación. Se utilizó un modelo poblacional referenciado en la bibliografía para la predicción de concentraciones de dolutegravir en cada paciente y se compararon con las concentraciones experimentales. Resultados: fueron incluidos en el estudio 21 pacientes. Al cotejar las concentraciones plasmáticas experimentales con la simulación farmacocinética se encontraron diferencias para 12 pacientes, las cuales se explican por posibles interacciones farmacológicas, mala adherencia u otros factores que afectan la farmacocinética. Se detectó 38% de no adherencia de acuerdo con SMAQ y 23% de acuerdo con el retiro de medicación. Conclusiones: se expone el rol potencial de los modelos farmacocinéticos para la interpretación de concentraciones plasmáticas y se genera la necesidad de avanzar en este tipo de estudios para el establecimiento de rango terapéutico y aplicabilidad clínica.

Introduction: Despite advances in antiretroviral treatment, there is a possibility that people living with HIV may experience treatment failure linked to multiple factors that impact drug response. Objective: To evaluate the usefulness of applying a pharmacokinetic model in patients diagnosed with HIV undergoing treatment with dolutegravir for the analysis of experimental plasma concentrations. Additionally, the aim is to identify potential drug interactions, assess adherence, and therapeutic failure. Method: A cross-sectional, observational pilot study was conducted in HIV patients treated with dolutegravir, which included plasma concentration dosing, assessment of adherence using the Simplified Medication Adherence Questionnaire (SMAQ), and medication withdrawal. A population-based model referenced in the literature was used to predict dolutegravir concentrations in each patient and these were compared with experimental concentrations. Results: Twenty-one patients were included in the study. When comparing experimental plasma concentrations with pharmacokinetic simulation, differences were found for 12 patients, which can be explained by possible drug interactions, poor adherence, or other factors affecting pharmacokinetics. Non-adherence was detected in 38% according to the SMAQ and 23% according to medication withdrawal. Conclusions: The potential role of pharmacokinetic models in the interpretation of plasma concentrations is highlighted, emphasizing the need to advance in this type of studies to establish therapeutic ranges and clinical applicability.

Introdução: Apesar dos avanços no tratamento antirretroviral, existe a possibilidade de que pessoas que vivem com HIV experimentem falha terapêutica ligada a múltiplos fatores que impactam na resposta ao medicamento. Objetivos: Avaliar a utilidade da aplicação de um modelo farmacocinético em pacientes com diagnóstico de HIV em tratamento com dolutegravir para análise de concentrações plasmáticas experimentais. Além disso, pretende-se identificar potenciais interações medicamentosas, avaliar a adesão e a falha terapêutica. Método: Um estudo piloto observacional transversal foi conduzido em pacientes HIV tratados com dolutegravir que incluiu dosagem de concentração plasmática, avaliação de adesão usando o questionário simplificado de adesão à medicação (SMAQ) e retirada da medicação. Um modelo populacional referenciado na literatura foi utilizado para prever as concentrações de dolutegravir em cada paciente e compará-las com as concentrações experimentais. Resultados: 21 pacientes foram incluídos no estudo. Ao comparar as concentrações plasmáticas experimentais com a simulação farmacocinética, foram encontradas diferenças em 12 pacientes, que são explicadas por possíveis interações medicamentosas, má adesão ou outros fatores que afetam a farmacocinética. Foram detectadas 38% de não adesão segundo o SMAQ e 23% segundo retirada da medicação. Conclusões: Fica exposto o papel potencial dos modelos farmacocinéticos para a interpretação das concentrações plasmáticas e gera-se a necessidade de avançar neste tipo de estudos para estabelecer a faixa terapêutica e a aplicabilidade clínica.

Eficacia y seguridad de la profilaxis con emicizumab en la hemofilia A: estudio de 13 pacientes / Efficacy and safety of prophylaxis with emicizumab in hemophilia A: A study of 13 patients

Introducción: Emicizumab es el primer tratamiento no sustitutivo para profilaxis en hemofilia A grave. Objetivos: Describir los resultados de nuestros pacientes en profilaxis con emicizumab, según la práctica clínica habitual. Material y métodos: Seguimiento de 13 pacientes desde el inicio de la profilaxis, registro de hemorragias, cirugías, reacciones adversas y necesidad o no de tratamiento factorial. Se midieron los niveles plasmáticos en las visitas de seguimiento; la técnica ha sido coagulativa en una etapa, modificada mediante dilución 1:20. Resultados: La mediana de niveles plasmáticos fue de 52,2mg [30,7-71,9]. La profilaxis resultó segura y eficaz; solamente se contabilizó una hemorragia espontánea a lo largo del tiempo y no precisó tratamiento. No hubo episodios tromboembólicos ni reacciones graves de hipersensibilidad, anafilaxia o anafilactoides. La incidencia de reacciones en el lugar de la inyección fue del 8%. El abordaje perioperatorio en las intervenciones menores se llevó a cabo sin tratamiento factorial coadyuvante, en 2 cirugías mayores se precisó una dosis de concentrado de FVIII plasmático en el paciente con hemofilia A sin inhibidor y FVII en el paciente con inhibidor, y fue suficiente para parar la hemorragia. Conclusión: Este estudio demostró que la farmacocinética de emicizumab y su vida media aseguran niveles óptimos con tratamiento profiláctico a las dosis establecidas en la ficha técnica.(AU)

Introduction: Emicizumab is the first non-replacement therapy for prophylaxis in severe hemophilia A. Aims: The principal aim of this study is to describe the results of our patients in prophylaxis with emicizumab, according to the usual clinical practice. Material and methods: Follow-up of 13 patients from the start of prophylaxis, recording of bleeding, surgeries, adverse reactions and the need or not for factor therapy. Plasma levels were measured at follow-up visits, the technique was coagulative in one stage, modified by 1:20 dilution. Results: Median plasma levels were 52.2mg [30.7–71.9]. Prophylaxis was safe and effective; only one spontaneous haemorrhage was recorded over time and no treatment was required. There were no thromboembolic events or serious hypersensitivity, anaphylaxis or anaphylactoid reactions. The incidence of injection site reactions was 8%. Perioperative management in minor interventions was carried out without adjuvant factorial therapy, in 2 major surgeries a dose of plasmatic FVIII concentrate was required in the patient with hemophilia A without inhibitor and FVII in the patient with inhibitor, and it was sufficient to stop the bleeding. Conclusion: This study demonstrated emicizumab pharmacokinetics and its half life ensure optimal levels with prophylaxis treatment at doses established in the technical data sheet.(AU)

Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3 / Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy

Objetivo analizar y describir las concentraciones de eculizumab y el bloqueo del complemento en los pacientes con síndrome hemolítico urémico atípico (SHUa) y glomerulopatía C3, y definir un margen terapéutico donde se alcance una alta probabilidad de conseguir eficacia terapéutica. Métodos estudio observacional, ambispectivo y multicéntrico que incluyó pacientes adultos y pediátricos diagnosticados de SHUa y glomerulopatía C3 desde septiembre de 2020 hasta octubre de 2022 en 5 hospitales de España. Eculizumab se administró a las dosis recomendadas por la ficha técnica. Se determinaron las concentraciones pre y posdosis de eculizumab, así como del bloqueo de la vía clásica del complemento (CH50). Se recogieron variables sociodemográficas, analíticas y clínicas, y se calcularon los parámetros farmacocinéticos. Para establecer el punto de corte de las concentraciones de eculizumab que predecían el bloqueo del complemento se realizó un análisis de curvas ROC (Receiver Operating Characteristic). Se utilizó el test de Kruskal-Wallis para contrastar las diferencias en distintos parámetros según las concentraciones de eculizumab. Resultados se incluyeron 25 pacientes, 19 adultos (76,0%) y 6 pediátricos (24,0%), con edades medianas de 43,4 (RIC 35,7-48,8) y 10,1 (RIC 9,6-11,3) años, respectivamente. De ellos, 22 (88,0%) pacientes fueron diagnosticados con SHUa y 3 (12,0%) con glomerulopatía C3. Se determinaron un total de 111 concentraciones de eculizumab. Las concentraciones predosis y posdosis medias detectadas durante la fase de mantenimiento fueron 243,8 (SD 240,6) μg/ml y 747,4 (SD 444,3) μg/ml, respectivamente (AU)

Objective The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. Methods Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. Results Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined (AU)

Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis. / Monitorización terapéutica de los fármacos biológicos en la enfermedad inflamatoria intestinal. Documento de Posicionamiento del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU).

The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial.

[Translated article] Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy.

OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective, and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in 5 hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre- and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (interquartile range (IQR) 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre- and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (standard deviation (SD) 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (P = .002) and decreased serum creatinine at both higher pre- and post-dose concentrations (P = .001 and P = .017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 µg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% variation coefficient (CV)) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Efficacy and safety of prophylaxis with emicizumab in hemophilia A: A study of 13 patients. / Eficacia y seguridad de la profilaxis con emicizumab en la hemofilia A: estudio de 13 pacientes.

INTRODUCTION: Emicizumab is the first non-replacement therapy for prophylaxis in severe hemophilia A. AIMS: The principal aim of this study is to describe the results of our patients in prophylaxis with emicizumab, according to the usual clinical practice. MATERIAL AND METHODS: Follow-up of 13 patients from the start of prophylaxis, recording of bleeding, surgeries, adverse reactions and the need or not for factor therapy. Plasma levels were measured at follow-up visits, the technique was coagulative in one stage, modified by 1:20 dilution. RESULTS: Median plasma levels were 52.2mg [30.7-71.9]. Prophylaxis was safe and effective; only one spontaneous haemorrhage was recorded over time and no treatment was required. There were no thromboembolic events or serious hypersensitivity, anaphylaxis or anaphylactoid reactions. The incidence of injection site reactions was 8%. Perioperative management in minor interventions was carried out without adjuvant factorial therapy, in 2 major surgeries a dose of plasmatic FVIII concentrate was required in the patient with hemophilia A without inhibitor and FVII in the patient with inhibitor, and it was sufficient to stop the bleeding. CONCLUSION: This study demonstrated emicizumab pharmacokinetics and its half life ensure optimal levels with prophylaxis treatment at doses established in the technical data sheet.

Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy. / Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3.

OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre-dose and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (SD 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (p=0.002) and decreased serum creatinine at both higher pre- and post-dose concentrations (p=0.001 and p=0.017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 µg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% CV) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Cardiac output and the pharmacology of general anesthetics: a narrative review

The relationship between cardiac output and anesthetic drugs is important to anesthesiologists, since cardiac output determines the speed with which a drug infused into the bloodstream reaches its target and the intensity of the drug's effect. But rather than focus on how anesthetic drugs affect cardiac output, this narrative review focuses on how changes in cardiac output affect the pharmacokinetics and pharmacodynamics of general anesthetics during the three phases of anesthesia. At induction, an increase in cardiac output shortens both the onset time of propofol for hypnosis and the neuromuscular blocking effect of rapid-acting neuromuscular blockers, favoring the conditions for rapid sequence intubation. During maintenance, changes in cardiac output are followed by opposite changes in the drug plasma concentration of anesthetic drugs. Thus, an increase in cardiac output followed by a decrease in the plasma concentration of the anesthetic could expose the patient to a real risk of intraoperative awakening, which can be avoided by increasing the dose of hypnotic drugs. At emergence, an increase in cardiac output secondary to an increase in pC02 allows for a more rapid recovery from anesthesia. The pC02 can be increased by adding CO2 to the respiratory circuit, lowering the ventilatory rate, or placing the patient on partial rebreathing. Finally, the reversal action of sugammadex for rocuronium-induced neuromuscular block can be shortened by increasing the cardiac output.

La relación entre el gasto cardíaco y los fármacos anestésicos es importante para los anestesiólogos puesto que el gasto cardíaco determina la velocidad con la cual un medicamento que se infunde al torrente sanguíneo llega a su diana y la intensidad del efecto del agente. Pero en lugar de concentrarnos en cómo los fármacos anestésicos afectan el gasto cardíaco, esta revisión narrativa se enfoca en cómo los cambios en el gasto cardíaco afectan la farmacocinética y la farmacodinámica de los agentes anestésicos generales durante las tres fases de la anestesia. En el momento de la inducción, un incremento en el gasto cardíaco acorta tanto el tiempo de inicio del efecto del propofol para la hipnosis como el efecto del bloqueo neuromuscular causado por los bloqueadores neuromusculares de acción rápida, favoreciendo las condiciones para la intubación de secuencia rápida. Durante la fase de mantenimiento, los cambios en el gasto cardíaco vienen seguidos de cambios opuestos en la concentración plasmática del medicamento de los agentes anestésicos. Por lo tanto, un aumento del gasto cardíaco, seguido de una reducción en la concentración plasmática del anestésico, podría exponer al paciente a un riesgo real de despertar intraoperatorio, lo cual puede evitarse aumentando la dosis de los fármacos hipnóticos. En la educción, un aumento en el gasto cardíaco secundario al incremento en el pCO2 permite una recuperación más rápida de la anestesia. El pCO2 puede aumentar agregando CO2 al circuito de la respiración, reduciendo la tasa ventilatoria, o colocando al paciente en re-inhalación parcial. Finalmente, la acción de reversión de sugammadex en caso de bloqueo neuromuscular inducido por rocuronio, puede acortarse aumentando el gasto cardíaco.

Impact of proactive of infliximab monitoring using the Bayesian approach in the maintenance phase in patients with inflammatory bowel disease / Impacto de la monitorización proactiva de infliximab en fase de mantenimiento mediante estimación bayesiana en pacientes con enfermedad inflamatoria intestinal

Background and objectives: There is increasing evidence that proactive monitoring is useful in improving the control of inflammatory bowel disease, although it remains controversial. The aim of this study was to evaluate the efficacy of proactive TDM based on the Bayesian approach to optimise the IFX dose compared with the standard of care dosing in patients with IBD. Methods: Retrospective observational cohort of inflammatory bowel disease patients>18 years. Patients were classified into two groups according to the strategy used to optimise the dose of IFX: a standard therapy group (ST-group) with clinically based dose adjustment and therapeutic drug monitoring group (TDM-group), with estimation of pharmacokinetic parameters calculated by Bayesian prediction. Results: A total of 153 patients were included. Of these, 75 were in the TDM-group. Clinical response at week 52 was evaluated in 114 patients. The proportion of patients who achieved clinical remission was higher in the TDM than in the ST-group (80.7% vs 61.4%, respectively, p=0.023). A total of 28 patients (24.6%) met the parameters for the composite variable ‘poor clinical outcome’ at week 52. The proportion of patients who reached this outcome was lower in the TDM-group than in the ST-group (12.3% vs 36.8%, respectively, p=0.002). Conclusions: Proactive therapeutic drug monitoring using Bayesian approach is associated with higher secondary response and fewer long-term complications.(AU)

Antecedentes y objetivos: Cada vez hay más evidencia de que la monitorización proactiva es útil para mejorar el control de la enfermedad inflamatoria intestinal (EII), aunque sigue siendo controvertida. El objetivo de este estudio fue evaluar la eficacia de la monitorización de fármacos terapéuticos (TDM) proactiva basada en el enfoque bayesiano en comparación con el manejo estándar en pacientes con EII. Métodos: Cohorte observacional retrospectiva de pacientes con EEI > 18 años. Los pacientes se clasificaron en dos grupos de acuerdo con la estrategia utilizada para optimizar la dosis de infliximab (IFX): un grupo de terapia estándar (grupo-ST) con ajuste de dosis basado en la clínica y un grupo de monitorización terapéutica del fármaco (grupo-TDM), con estimación de parámetros farmacocinéticos calculados mediante estimación bayesiana. Resultados: Se incluyeron un total de 153 pacientes. De estos, 75 estaban en el grupo-TDM. La respuesta clínica en la semana 52 se evaluó en 114 pacientes. La proporción de pacientes que alcanzaron la remisión clínica fue mayor en el grupo-TDM que en el grupo-ST (80,7 vs. 61,4%, respectivamente, p = 0,023). Un total de 28 pacientes (24,6%) cumplieron los parámetros de la variable compuesta «resultado clínico deficiente» en la semana 52. La proporción de pacientes que alcanzaron este resultado fue menor en el grupo-TDM que en el grupo-ST (12,3 vs. 36,8%, respectivamente, p = 0,002). Conclusiones: La TDM proactiva mediante el enfoque bayesiano se asocia con una mayor respuesta secundaria y menos complicaciones a largo plazo.(AU)

Comparative effectiveness and drug survival of biosimilar infliximab CPT-13 vs. reference infliximab in inflammatory bowel disease: A retrospective cohort study.

BACKGROUND: Studies have investigated the efficacy and safety of switching to the biosimilar infliximab (CT-P13) in patients with inflammatory bowel disease (IBD). However, there is limited research directly comparing the effectiveness, drug survival, and pharmacokinetic profiles of the reference infliximab (IFX) and CT-P13 in real clinical settings. OBJECTIVE: To compare the effectiveness and drug survival of CPT-13 and reference IFX at weeks 26 and 52, and to determine the pharmacokinetic profiles and safety profile in real-world settings. METHODS: A retrospective observational cohort analysis was conducted at a single center. The study compared the proportion of patients achieving clinical remission and experiencing poor clinical outcomes at weeks 26 and 52. The drug survival rate of CT-P13 and reference infliximab was also assessed during the follow-up period. RESULTS: A total of 153 patients were included in the study, 39.2% receiving CPT-13 and 60.8% reference IFX. At week 26, clinical remission rates were 66.7% (CPT-13: 74.4% vs. reference IFX: 62.3%, p=0.178), and at week 52, they were 64% (CPT-13: 85.4% vs. reference IFX: 63.0%, p=0.012). Subgroup analysis with therapeutic drug monitoring (TDM) found no significant differences at week 26 (CPT-13: 74.4% vs. reference IFX: 58.8%, p=0.235) or at week 52 (CPT-13: 85.4% vs. reference IFX: 68.8%, p=0.153). CONCLUSION: Our study demonstrates comparable efficacy, drug survival, pharmacokinetic profiles, and incidence of immunogenicity between both drugs in a real clinical setting. Further studies with greater statistical power are needed to validate these findings.

Tratamiento con sirolimus oral o tópico en anomalías vasculares complejas en pediatría. Experiencia en un hospital terciario / Treatment with oral or topical sirolimus in complex vascular anomalies in pediatrics. Experience in a third-level hospital

Objetivo:El uso de sirolimus en anomalías vasculares es una in-dicación especial no autorizada en ficha técnica. El objetivo de esteestudio es incrementar la evidencia del empleo por vía oral o tópica desirolimus en esta indicación en población pediátrica. Método. Estudio observacional retrospectivo de pacientes meno-res de 18 años tratados con sirolimus oral o tópico para anomalíasvasculares recogiendo: diagnóstico y ubicación de lesiones, forma deadministración y dosificación de sirolimus, niveles sanguíneos de fár-maco en los pacientes con tratamiento oral, duración del tratamiento,respuesta y toxicidad. Resultados: Se incluyeron 18 pacientes (7 con tratamiento oral y11 tópico). Con sirolimus oral, la tasa de respuesta global fue 85,7%.Se interrumpió sirolimus en 2 casos: por resolución completa y porprogresión. El 57,1% experimentó algún efecto adverso, en su mayoríaleves; siendo la dislipemia el efecto adverso más frecuente. La moni-torización de niveles sanguíneos fue empleada en todos los pacientespara el ajuste de dosis. Con el tratamiento tópico, la tasa de respuestaglobal fue 72,7%. Se interrumpió sirolimus en 3 casos: progresión en2 casos y estabilidad en 1. El 27,3% experimentó algún efecto adverso,siendo el prurito el más frecuente. Conclusiones: Los resultados favorables del tratamiento con siroli-mus en nuestros pacientes parecen confirmar la efectividad y seguridaddel fármaco en anomalías vasculares y lo posicionan como una opciónterapéutica en pacientes pediátricos. Aun así, parece necesaria mayorinvestigación que trate de aclarar, entre otros, el régimen óptimo deltratamiento, la duración del mismo y los potenciales efectos adversosa largo plazo.(AU)

Objective: The use of sirolimus in vascular anomalies is a specialindication not authorized in its data sheet. The objective of this studywas to increase the evidence of oral or topical use of sirolimus for thisindication in the pediatric population. Materials and methods: An observational, retrospective study ofpatients under 18 years of age treated with oral or topical sirolimus forvascular anomalies was carried out. Diagnosis and location of lesions,administration route and dosage of sirolimus, blood levels of sirolimusin patients who received oral treatment, treatment duration, response,and toxicity were collected. Results: 18 patients –7 with oral treatment and 11 with topicaltreatment– were included. With oral sirolimus, the overall responserate was 85.7%. Sirolimus was discontinued in 2 cases –as a result offull resolution and progression. 57.1% of patients had adverse effects,most of which were mild. Dyslipidemia was the most frequent adverseeffect. Blood levels were monitored in all patients for dose adjustmentpurposes. With topical treatment, the overall response rate was 72.7%.Sirolimus was discontinued in 3 cases –due to progression in 2 casesand to stability in 1. 27.3% of patients had adverse effects, with itchingstanding out as the most frequent one. Conclusions: The favorable results of sirolimus treatment in ourpatients seem to confirm its effectiveness and safety in vascular anom-alies, which make it stand as a therapeutic option in pediatric patients.However, further research is required to establish the optimal treatmentregimen, treatment duration, and potential long-term adverse effects.(AU)

Bioequivalence of 2 formulations of montelukast (5 mg chewable tablet) in the fasting state: an open-label randomized, single-dose, 2-period, crossover study / Estudo de bioequivalência entre duas formulações de comprimidos mastigáveis de Montelucaste de 5 mg em condições de jejum: um estudo randomizado, de dose única, aberto, dois períodos, cruzado

Introduction: Montelukast, a selective and active leukotriene receptor antagonist, is one of the most common agents in asthma treatment for both adults and children. Objective: To assess whether the pharmacokinetic profiles of two formulations of montelukast were similar after a single 5 mg dose (chewable tablets), administered orally under fasting conditions, sampling blood before and 36 hours after administration. Methods: This was a randomized, 2-sequence, 2-period, crossover study of 2 chewable tablet formulations of the drug: Singulair®, provided by Merck Sharp and Dohme Farmacêutica Ltda. (reference), and generic montelukast, manufactured by Eurofarma Laboratórios S.A. (test). Plasma samples obtained from 35 participants were analyzed for montelukast through high-performance liquid chromatography coupled to tandem mass spectrometry, with montelukast-d6 as the internal standard. Peak montelukast concentrations were 299.313 (SD, 11.039) ng/mL for the reference formulation and 279.803 (SD, 10.085) ng/mL for test formulation. Results: Statistical analysis showed no significant differences between AUC0-36h, AUC0-inf, or Cmax between formulations, with the following test/reference ratios: 102.458 for AUC0-36h, 102.522 for AUC0-inf, and 93.490 for Cmax. No serious adverse events were reported during the trial. Our results demonstrated the bioequivalence of Singulair® and Eurofarma's generic montelukast. Conclusions: Our results revealed that the new generic tablets are clinically safe and can be used interchangeably with the brand name product. Eurofarma's montelukast offers a safe, effective, and cheaper treatment option for people with asthma or allergic rhinitis.

Introdução: O montelucaste, um antagonista seletivo e ativo dos receptores de leucotrienos, é um dos agentes mais comumente usados na prática clínica no tratamento da asma, tanto em adultos quanto em crianças. Objetivo: Avaliar se os perfis farmacocinéticos de duas formulações de montelucaste eram semelhantes após uma dose única de comprimidos mastigáveis de 5 mg, administrados por via oral em jejum, coletando amostras de sangue desde antes da administração até 36 horas depois disso. Métodos: Estudo comparativo randomizado, 2 sequências e 2 períodos, cruzado, de dois medicamentos em comprimidos mastigáveis: Singulair®, fornecido pela Merck Sharp e Dohme Farmacêutica Ltda. (referência) e Montelucaste 5 mg, fabricado pela Eurofarma Laboratórios S.A. (teste). Amostras de plasma obtidas de 35 indivíduos elegíveis foram analisadas para montelucaste por cromatografia líquida de alta eficiência acoplada a espectrometria de massa em tandem, tendo Montelucaste-d6 como padrão interno. As concentrações máximas de montelucaste foram 299,313±11,039 ng/mL para referência e 279,803±10,085 ng/mL para formulação de teste. Resultados: A análise estatística não mostrou diferenças significativas para AUC0-36h, AUC0-inf e nem para Cmax entre as formulações, apresentando as razões Teste/Referência: 102,458 para AUC0-36h, 102,522 para AUC0-inf e 93,490 para Cmax. Nenhum evento adverso grave foi relatado durante o estudo. De acordo com a regulamentação brasileira, o atual estudo farmacocinético demonstrou bioequivalência entre os agentes individuais e forneceu evidências de bioequivalência entre Singulair® e Montelukast fabricado pela Eurofarma. Resultado: Os resultados mostraram que os novos comprimidos genéricos são clinicamente seguros e podem ser trocados pela marca original. O montelucaste da Eurofarma oferece uma opção de tratamento mais barata, segura e eficaz para indivíduos com asma ou rinite alérgica.

Definition of a therapeutic range for predicting long-term infliximab response in patients with inflammatory bowel disease / Definición de un rango terapéutico para predecir la respuesta al infliximab a largo plazo en pacientes con enfermedad inflamatoria intestinal

Introduction: Monitoring plasma levels of Infliximab plays an important role in optimising treatment in patients with inflammatory bowel disease (IBD). The aim of the following study has been to determine the predictive potential of monitoring infliximab plasma levels for sustained clinical response and evaluate its usefulness to improve treatment efficacy and symptom control, in patients with IBD.MethodsThis single-centre retrospective study (2017–2019) included patients diagnosed with IBD treated with infliximab. Serum levels and the occurrence of drug-associated immunogenicity were analysed at Week 8 post-induction and 6, 12 and 24 months. Clinical parameters and inflammatory markers were recorded such as subjective global assessment (SGA), C-reactive protein (CRP) and faecal calprotectin (FC). Factors associated with early discontinuation and dose intensification of infliximab were determined.ResultsMultivariate analysis determined that IFX concentrations>7μg/mL at week 8, and at 6 months, are associated with inflammatory remission (p=0.046, 0.045). IFX>7μg/mL at 12 months predicted remission at 18 months of treatment (p=0.006). IFX values>3μg/mL at 12 months are associated with stable SGA at 18 months (p=0.001). Such values at 18 months are associated with stable SGA at 24 months (p=0.044).Conclusions and relevanceThe predictive potential of monitoring IFX plasma levels as a strategy to evaluate sustained long-term clinical response was confirmed. Our results highlight the importance of its introduction into routine clinical practice to enable early identification of non-responders, treatment optimisation, relapse prevention and improve long-term therapy maintenance. (AU)

Introducción: La monitorización de infliximab (IFX) juega un papel importante en la optimización del tratamiento en pacientes con enfermedad inflamatoria intestinal (EII). El objetivo del estudio fue determinar el potencial predictivo de la monitorización de IFX para la respuesta clínica sostenida, y evaluar su utilidad en la eficacia del tratamiento y del control de los síntomas.MétodosEstudio retrospectivo unicéntrico (2017-2019) que incluyó pacientes con EII tratados con IFX. Se analizaron los niveles séricos y la inmunogenicidad asociada al fármaco en la semana 8 postinducción, y a los 6, 12 y 24 meses. Se registraron los parámetros clínicos y los marcadores inflamatorios correspondientes a la evaluación global subjetiva (SGA), proteína C reactiva (PCR) y calprotectina fecal (CF). Se determinaron los factores asociados a la interrupción precoz y a la intensificación de la dosis de IFX.ResultadosEl análisis multivariante determinó que las concentraciones de IFX>7μg/ml en la semana 8, y a los 6 meses, se asocian a la remisión inflamatoria (p=0,046-0,045). El IFX>7μg/ml a los 12 meses predijo la remisión a los 18 meses de tratamiento (p=0,006). Los valores de IFX>3μg/ml a los 12 meses se asocian a una SGA estable a los 18 meses (p=0,001). Dichos valores a los 18 meses se asocian a SGA estable a los 24 meses (p=0,044).Conclusiones y relevanciaSe confirma el potencial predictivo de la monitorización de los niveles plasmáticos de IFX como estrategia para evaluar la respuesta clínica sostenida a largo plazo. Nuestros resultados destacan la importancia de su introducción en la práctica clínica habitual para permitir la identificación temprana de los no respondedores, la optimización del tratamiento, la prevención de recaídas y mejorar el mantenimiento de la terapia a largo plazo. (AU)

Effectiveness of resveratrol as a hepatoprotector in a rat model of paracetamol-induced liver injury / Eficácia do resveratrol como hepatoprotetor em modelo de rato com lesão hepática induzida por paracetamol

Objective: Evaluate the effectiveness of resveratrol as a hepatoprotector in a rat model of paracetamol-induced liver injury and its biodistribution to understand its pharmacokinetics. Methodology: As an experimental approach, animals were divided into the test group with 4 subgroups and the control group with 4 subgroups. Animals of the "treated" group were subjected to resveratrol pre-treatment for eight days, followed by intoxication with a high dose of paracetamol on the 8th day. Animals were euthanized to collect the blood and liver tissue samples 24 and 72 h after the last administration. Hepatoprotective activity was evaluated through serum levels of glycogen and hepatic enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), histological and morphometric analysis of the liver tissue. For biodistribution analysis, different organs (organs, kidneys, heart and lungs) were collected and macerated, and resveratrol was quantified using high-performance liquid chromatography. Statistical analyses of morphometry, transaminases and alkaline phosphatase measurements, and biodistribution results were performed using GraphPad Prism® 3.0. Differences between groups were compared using ANOVA, followed by the Bonferroni test. Statistical significance was set at p < 0.05. Results: Resveratrol has a hepatoprotective action against acute intoxication by paracetamol, as evidenced by the histological decrease in necrosis and inflammatory foci, preservation of glycogen and other 1,2-glycols in zone 3, and reduction of serum ALT and AST levels. An increased presence of collagen was observed in acinar zones 1 and 3 with picrosirius red staining; therefore, quantification was performed in these regions showing smaller collagen areas in the R and RP groups than in the PC and NC groups Paracetamol caused a significant reduction in the resveratrol concentration in serum and the organs studied, indicating that the antioxidant activity of resveratrol is related to its hepatoprotective action. Conclusion: Resveratrol has hepatoprotective properties and can mitigate some of the liver damage caused by high doses of paracetamol, as indicated by changes in tissue characteristics and liver enzyme levels.

Objetivo: Avaliar a eficácia do resveratrol como hepatoprotetor em modelo de rato com lesão hepática induzida por paracetamol e sua biodistribuição para compreender sua farmacocinética. Metodologia: Como abordagem experimental, os animais foram divididos em grupo teste com 4 subgrupos e grupo controle com 4 subgrupos. Os animais do grupo "tratado" foram submetidos ao pré-tratamento com resveratrol durante oito dias, seguido de intoxicação com alta dose de paracetamol no oitavo dia. Os animais foram eutanasiados para coleta de amostras de sangue e tecido hepático 24 e 72 horas após a última administração. A atividade hepatoprotetora foi avaliada através dos níveis séricos de glicogênio e de enzimas hepáticas, como aspartato aminotransferase (AST), alanina aminotransferase (ALT) e fosfatase alcalina (ALP), análise histológica e morfométrica do tecido hepático. Para análise de biodistribuição, diferentes órgãos (órgãos, rins, coração e pulmões) foram coletados e macerados, e o resveratrol foi quantificado por cromatografia líquida de alta eficiência. Análises estatísticas de morfometria, medidas de transaminases e fosfatase alcalina e resultados de biodistribuição foram realizadas utilizando GraphPad Prism® 3.0. As diferenças entre os grupos foram comparadas por meio de ANOVA, seguida do teste de Bonferroni. A significância estatística foi estabelecida em p < 0,05. Resultados: O resveratrol tem ação hepatoprotetora contra a intoxicação aguda por paracetamol, evidenciada pela diminuição histológica da necrose e dos focos inflamatórios, preservação do glicogênio e outros 1,2-glicóis na zona 3 e redução dos níveis séricos de ALT e AST. Foi observada presença aumentada de colágeno nas zonas acinares 1 e 3 com coloração picrosirius red; portanto, foi realizada quantificação nessas regiões mostrando menores áreas de colágeno nos grupos tratados com resveratrol e resveratrol associado com paracetamol do que nos grupos controles positivo e negativo. O paracetamol causou redução significativa na concentração de resveratrol no soro e nos órgãos estudados, indicando que a atividade antioxidante do resveratrol está relacionada à sua ação hepatoprotetora. Conclusão: O resveratrol possui propriedades hepatoprotetoras e pode mitigar alguns dos danos hepáticos causados por altas doses de paracetamol, conforme indicado por alterações nas características dos tecidos e nos níveis de enzimas hepáticas.

Definition of a therapeutic range for predicting long-term infliximab response in patients with inflammatory bowel disease.

INTRODUCTION: Monitoring plasma levels of Infliximab plays an important role in optimising treatment in patients with inflammatory bowel disease (IBD). The aim of the following study has been to determine the predictive potential of monitoring infliximab plasma levels for sustained clinical response and evaluate its usefulness to improve treatment efficacy and symptom control, in patients with IBD. METHODS: This single-centre retrospective study (2017-2019) included patients diagnosed with IBD treated with infliximab. Serum levels and the occurrence of drug-associated immunogenicity were analysed at Week 8 post-induction and 6, 12 and 24 months. Clinical parameters and inflammatory markers were recorded such as subjective global assessment (SGA), C-reactive protein (CRP) and faecal calprotectin (FC). Factors associated with early discontinuation and dose intensification of infliximab were determined. RESULTS: Multivariate analysis determined that IFX concentrations>7µg/mL at week 8, and at 6 months, are associated with inflammatory remission (p=0.046, 0.045). IFX>7µg/mL at 12 months predicted remission at 18 months of treatment (p=0.006). IFX values>3µg/mL at 12 months are associated with stable SGA at 18 months (p=0.001). Such values at 18 months are associated with stable SGA at 24 months (p=0.044). CONCLUSIONS AND RELEVANCE: The predictive potential of monitoring IFX plasma levels as a strategy to evaluate sustained long-term clinical response was confirmed. Our results highlight the importance of its introduction into routine clinical practice to enable early identification of non-responders, treatment optimisation, relapse prevention and improve long-term therapy maintenance.

Impact of proactive of infliximab monitoring using the Bayesian approach in the maintenance phase in patients with inflammatory bowel disease.

BACKGROUND AND OBJECTIVES: There is increasing evidence that proactive monitoring is useful in improving the control of inflammatory bowel disease, although it remains controversial. The aim of this study was to evaluate the efficacy of proactive TDM based on the Bayesian approach to optimise the IFX dose compared with the standard of care dosing in patients with IBD. METHODS: Retrospective observational cohort of inflammatory bowel disease patients>18 years. Patients were classified into two groups according to the strategy used to optimise the dose of IFX: a standard therapy group (ST-group) with clinically based dose adjustment and therapeutic drug monitoring group (TDM-group), with estimation of pharmacokinetic parameters calculated by Bayesian prediction. RESULTS: A total of 153 patients were included. Of these, 75 were in the TDM-group. Clinical response at week 52 was evaluated in 114 patients. The proportion of patients who achieved clinical remission was higher in the TDM than in the ST-group (80.7% vs 61.4%, respectively, p=0.023). A total of 28 patients (24.6%) met the parameters for the composite variable 'poor clinical outcome' at week 52. The proportion of patients who reached this outcome was lower in the TDM-group than in the ST-group (12.3% vs 36.8%, respectively, p=0.002). CONCLUSIONS: Proactive therapeutic drug monitoring using Bayesian approach is associated with higher secondary response and fewer long-term complications.

Meningitis por Listeria: administración de gentamicina intraventricular y monitorización de concentraciones en líquido cefalorraquídeo / Listeria meningitis: administration of intraventricular gentamicin and monitoring of concentrations in cerebrospinal fluid

La Listeria continúa siendo una posible etiología de meningitis bacteriana en nuestro medio, siendo causa más frecuente en neonatos, ancianos o pacientes inmunodeprimidos. Debido a la gravedad y la mortalidad asociada, resulta de gran interés disponer de nuevas herramientas que permitan un manejo clínico y farmacológico más eficaz.Presentamos un caso de meningitis por Listeria que ingresa en la Unidad de Cuidados Intensivos. Dada la escasa penetración de la gentamicina en el sistema nervioso central y siendo ésta uno de los tratamientos de elección en las guías clínicas de referencia, se decide la administración de gentamicina intraventricular llevando a cabo una monitorización de concentraciones de gentamicina en líquido cefalorraquídeo (LCR).Debido a la alta variabilidad farmacocinética del paciente crítico, la monitorización de concentraciones en LCR de gentamicina tras su administración intraventricular puede resultar de gran utilidad para asegurar el alcance de concentraciones de fármaco que permitan una mayor eficacia del tratamiento. (AU)

Listeria is currently a possible etiology of bacterial meningitis in our society, being one more frequent cause in neonates, elderly or immunosuppressed patients. Due to the severity and mortality associated, it is therefore very useful to have new tools that allow a more effective clinical and pharmacological management.We present a case of Listeria meningitis admitted to the Intensive Care Unit. Given the low penetration of gentamicin into the central nervous system and being one of the treatments of choice in the clinical reference guidelines, the administration of intraventricular gentamicin was decided by monitoring the concentrations of gentamicin in cerebrospinal fluid (CSF).Due to the high pharmacokinetic variability of the critically ill patient, monitoring CSF concentrations of gentamicin after intraventricular administration can be very useful to ensure the achievement of drug concentrations that allow greater treatment efficacy. (AU)

Dosificación de ceftriaxona en el paciente crítico hipoproteinémico: un factor más a tener en cuenta / Dosage of ceftriaxone in the critical hypoproteinemic patient: another factor to take into account

Introducción: El objetivo principal del estudio fue evaluar la necesidad de ajuste posológico de ceftriaxona en pacientes críticos hipoproteinémicos. Pacientes y métodos: Estudio observacional y retrospectivo, llevado a cabo en la unidad de cuidados intensivos (UCI) del Hospital General Universitario de Ciudad Real (médico-quirúrgica de 21 camas), en el que se incluyeron pacientes tratados con ceftriaxona en la UCI desde enero de 2014 a diciembre de 2019 y se clasificaron en dos grupos al inicio del tratamiento: pacientes normoproteinémicos (proteínas totales >5,5g/dl) e hipoproteinémicos (proteínas totales ≤5,5g/dl).Variables principales: Edad, sexo, APACHE II, diagnóstico-localización del foco infeccioso, estancia en UCI, dosis de ceftriaxona, pauta posológica, tratamiento antibiótico concomitante, empírico o dirigido, necesidad de cambio de tratamiento, días de antibioterapia y mortalidad. Resultados: Se incluyeron 98 pacientes (44 normoproteinémicos y 54 hipoproteinémicos). No se obtuvieron diferencias estadísticamente significativas entre las características basales de ambos grupos, exceptuando la localización del foco, siendo respiratorio con mayor frecuencia en el grupo de pacientes normoproteinémicos (p=0,044). Se obtuvieron diferencias estadísticamente significativas a favor del grupo de pacientes normoproteinémicos para: estancia en UCI (p=0,001), necesidad de cambio de tratamiento antibiótico (p=0,004), días de antibioterapia (p=0,007) y mortalidad (p=0,046). Conclusión: Los resultados terapéuticos obtenidos en el grupo de pacientes críticos hipoproteinémicos tratados con ceftriaxona ponen en evidencia la necesidad de considerar la hipoproteinemia como un factor que podría condicionar dicho resultado si se emplean las pautas posológicas de tratamiento habituales. (AU)

Introduction: The main objective of the study was to evaluate the need for posologic adjustment of ceftriaxone in critical hypoproteinemic patients. Patients and methods: Observational and retrospective study, carried out in the intensive care unit (ICU) of the General University Hospital of Ciudad Real (21-bed medical-surgical), which included patients treated with ceftriaxone in the ICU from January 2014 to December 2019 and classified into two groups at the beginning of treatment: normoproteinemic (total proteins >5.5 g/dl) and hypoproteinemic (total proteins ≤5.5g/dl) patients.Main variables: Age, sex, APACHE II, diagnosis-location of the infectious site, ICU stay, ceftriaxone dose, dosage regimen, concomitant antibiotic treatment, empirical or targeted antibiotic treatment, need to change treatment, days of antibiotic therapy and mortality. Results: 98 patients were included (44 normoproteinemics and 54 hypoproteinemics).No statistically significant differences were obtained between the basal characteristics of both groups, except for the location of the infectious site, being respiratory more frequently in the group of normoproteinemic patients (p=0.044).Statistically significant differences were obtained in favour of the group of normoproteinemic patients for: stay in ICU (p=0.001), need for change of antibiotic treatment (p=0.004), days of antibiotherapy (p=0.007) and mortality (p=0.046). Conclusion: The therapeutic results obtained in the group of critical hypoproteinemic patients treated with ceftriaxone show the need to consider hypoproteinemia as a factor that could condition such result if the usual treatment dosage guidelines are used.

Interacciones entre antineoplásicos orales y alimentos / Interactions between oral antineoplastic drugs and foods

Actualmente, la administración de antineoplásicos se realiza mayoritariamente por vía parenteral, sin embargo, la vía oral está cada vez más extendida en oncología por presentar beneficios importantes, como mayor comodidad o seguridad para el paciente. Sin embargo, la vía oral supone nuevos retos son las interacciones fármaco-alimentos (iAM), que puede dar lugar a importantes variaciones en la biodisponibilidad del fármaco. Esta mini-revisión se inicia comentando en una breve introducción algunos aspectos centrales sobre los inhibidores de tirosin-kinasa (TKI) y su mecanismo de acción y los planteamientos que han ido llevando a la aparición de TKI de segunda y tercera generación. Posteriormente y centrado en el tema interacción fármaco-alimentos se comentan algunos resultados y conclusiones de 47 artículos seleccionados de un total de 55 donde se describen distintos tipos de iAM que atañen a los TKI y otros antineoplásicos orales y que afectan a la biodisponibilidad de los mismos y los factores determinantes de dichas interacciones (p. ej. tipo de alimento, las reacciones físico-químicas entre fármaco y alimento, la fisiología postprandial). También resume algunos ejemplos bien definidos de dichas iAM, así como de las posibles consecuencias positivas de la coadministración de medicamentos y alimentos. La revisión termina con pautas futuras a considerar en este tipo de interacciones (estatus nutricional del paciente, farmacogenética relacionada con las isoformas del citocromo P450, cronoterapia y cronofarmacia relacionada con los genes CLOCK, efectos del consumo de compuestos bioactivos y perfiles dietéticos) y con unas conclusiones. Por todo ello, el conocimiento profesional de estos aspectos juega un papel fundamental a la hora de garantizar el éxito terapéutico. (AU)

Nowadays, the intravenous administration of antineoplastic drugs is more common than oral administration. However, oral chemotherapy on oncology is increasing due to some advantages, such as the comfort and safety of the patient. Nevertheless, oral administration implies new challenges as the food and drugs interactions that can change the drug’s bioavalability. Present mini-review stars with a short introduction in main aspects of the tyrosine kinase inhibitors (TKI), their action mechanism as well as the stages that have giving rise to the second and third generations of TKI are reviewed. Dealing with drugfood interaction the review discusses some results and conclusions derived from 47 articles selected from a total of 55 ones in which some food-drug interaction affecting bioavailability of TKI and other oral antineoplastics are described, as well as some determinant factors of such interactions (e.g. type of food, food and drug physicochemical reactions, postprandial physiology). Some well-defined and known examples of those interactions are commented as well the possible positive consequences of food and drug coadministration. The review ends with future remarks (e.g nutritional status, farmacogenetics related to the Cytochrome P450, chronotherapy and chronopharmacy related to CLOCK genes, the effects of bioactive compounds and dietary profiles) and with some conclusions. For all this, the professional knowledge and background seem fundamental in order to warrantee therapeutic success. (AU)