Interacciones farmacológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos: revisión sistemática / Drug-drug interactions in patients undergoing hematopoietic stem cell transplantation: systematic review

Objetivo: El objetivo principal de este trabajo es identificar, medianterevisión bibliográfica sistemática, los estudios sobre interacciones farmacológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos.Los objetivos secundarios son describir la prevalencia de dichas interacciones y extraer información de interacciones fármaco-fármaco concretas.Método: Búsquedas en PubMed con los términos “drug-drug interaction”, “drug interaction”, “stem cell transplant”, “transplantation conditioning” y “conditioning regimen” y en Embase “drug interaction”, “stem celltransplantation” y “transplantation conditioning”, seleccionando aquellosresultados relacionados directamente con el objetivo de la revisión. Sepriorizaron estudios en humanos, en idiomas inglés y español, entre enerode 2000 y noviembre de 2020.Resultados: La revisión identificó dos grupos de estudios (epidemiológicosy de análisis de interacciones entre fármacos concretos). Los 10 estudiosepidemiológicos mostraron una prevalencia de interacciones entre el 60% yel 100%, la base de datos más utilizada fue Micromedex®, el mecanismofarmacocinético y los fármacos más implicados fueron los antifúngicos azólicos, con resultados muy heterogéneos. Los 52 estudios de interacciones entre fármacos fueron casi todos farmacocinéticos y se centraron fundamentalmente en las interacciones de antifúngicos azólicos e inhibidores de la calcineurina. Algunos estudios describieron la posible relación entre interaccionesy reacciones adversas concretas o muertes por efectos adversos. (AU)

Objective: The present paper provides a systematic review aimed atidentifying studies on pharmacological interactions in patients undergoinghematopoietic stem cell transplantation. Secondary objectives include acharacterization of the prevalence of such interactions and an investigation of their specific characteristics.Method: A search was performed of the terms “drug-drug interaction”,“drug interaction”, “stem cell transplant”, “transplantation conditioning”,and “conditioning regimen” in the PubMed database, and of the terms“drug interaction”, “stem cell transplantation”, and “transplantation conditioning” in the Embase database. Only results directly related to the objective of the review were selected. Studies in humans published betweenJanuary 2000 and November 2020, written in English or Spanish, wereprioritized.Results: The review identified two groups of studies: epidemiologicalstudies and studies analyzing interactions between specific drugs. The10 epidemiological studies selected, which showed a prevalence of interactions between 60 and 100%, mainly used the Micromedex® database, focused on pharmacokinetic interactions involving azole antifungals. Results were highly heterogeneous. Of the 52 drug interaction studiesreviewed, the majority were pharmacokinetic and focused primarily on theinteractions of azole antifungals with calcineurin inhibitors. Some studiesdescribed the possible relationship between the interactions and specificadverse reactions or deaths from adverse events. (AU)

Drug-drug interactions in patients undergoing hematopoietic stem cell transplantation: systematic review.

OBJECTIVE: The present paper provides a systematic review aimed at identifying studies on pharmacological interactions in patients  undergoing hematopoietic stem cell transplantation. Secondary objectives  include a characterization of the prevalence of such interactions and an  investigation of their specific characteristics. METHOD: A search was performed of the terms "drug-drug interaction", "drug interaction", "stem cell transplant", "transplantation  conditioning", and "conditioning regimen" in the PubMed database, and of  the terms "drug interaction", "stem cell transplantation", and  "transplantation conditioning" in the Embase database. Only results  directly related to the objective of the review were selected. Studies in  humans published between January 2000 and November 2020, written in  English or Spanish, were prioritized. RESULTS: The review identified two groups of studies: epidemiological studies and studies analyzing interactions between specific drugs. The 10 epidemiological studies selected, which showed a prevalence of interactions between 60 and 100%, mainly used the Micromedex®  database, focused on pharmacokinetic interactions involving azole  antifungals.Results were highly heterogeneous. Of the 52 drug interaction studies reviewed, the majority were pharmacokinetic and focused primarily on the interactions of azole antifungals with calcineurin inhibitors. Some  studies described the possible relationship between the interactions and  specific adverse reactions or deaths from adverse events. CONCLUSIONS: The prevalence of drug-drug interactions in patients  undergoing hematopoietic stem cell transplantation is high, with  heterogeneous results both in terms of prevalence and of the profile of the interactions resulting from the use of disparate study designs and  databases. The most common factor associated with drug-drug  interactions was the number of drugs administered. Studies evaluating  drug-drug interactions are mostly pharmacokinetic and focus mainly on  azole antifungals and calcineurin inhibitors. It would be important to unify  the criteria followed in epidemiological studies to obtain results that may  help establish risk reduction strategies and conduct a more in-depth  investigation into the pharmacodynamic mechanisms involved and into the interactions between other drugs frequently used in patients undergoing  transplantation, including those recently introduced in our therapeutic  arsenal.

Objetivo: El objetivo principal de este trabajo es identificar, mediante revisión bibliográfica sistemática, los estudios sobre  interacciones farmacológicas en pacientes sometidos a trasplante de  progenitores hematopoyéticos. Los objetivos secundarios son describir la  prevalencia de dichas interacciones y extraer información de interacciones  fármaco-fármaco concretas.Método: Búsquedas en PubMed con los términos "drug-drug interaction", "drug interaction", "stem cell transplant", "transplantation  conditioning" y "conditioning regimen" y en Embase "drug interaction",  "stem cell transplantation" y "transplantation conditioning", seleccionando  aquellos resultados relacionados directamente con el objetivo de la  revisión. Se priorizaron estudios en humanos, en idiomas inglés y español, entre enero de 2000 y noviembre de 2020.Resultados: La revisión identificó dos grupos de estudios  epidemiológicos y de análisis de interacciones entre fármacos concretos).  Los 10 estudios epidemiológicos mostraron una prevalencia de  interacciones entre el 60% y el 100%, la base de datos más utilizada fue  Micromedex®, el mecanismo farmacocinético y los fármacos más  implicados fueron los antifúngicos azólicos, con resultados muy  heterogéneos. Los 52 estudios de interacciones entre fármacos fueron casi todos farmacocinéticos y se centraron fundamentalmente en las  interacciones de antifúngicos azólicos e inhibidores de la calcineurina. Algunos estudios describieron la posible relación entre interacciones y  reacciones adversas concretas o muertes por efectos adversos.Conclusiones: La prevalencia de interacciones en pacientes sometidos a  trasplante de progenitores hematopoyéticos es elevada, siendo los  esultados heterogéneos, tanto en prevalencia como en el perfil de las  interacciones. En ello repercuten las diferencias en los diseños de los  estudios y en las bases de datos utilizadas. Entre los factores relacionados  con el riesgo de que se produzcan interacciones farmacológicas destaca el  elevado número de fármacos administrados. Los estudios que evalúan las  interacciones fármaco-fármaco son casi todos farmacocinéticos y se  centran mayoritariamente en antifúngicos azólicos e inhibidores de la  calcineurina. Sería importante unificar los criterios de los estudios  epidemiológicos para obtener resultados que ayuden a establecer  estrategias de reducción de riesgo, investigar en mayor profundidad las  interacciones de mecanismo farmacodinámico, las interacciones entre  otros fármacos de uso frecuente en el trasplante y en aquellos de  introducción reciente en el arsenal terapéutico.

Biomarcadores predictivos de respuesta a los inhibidores de los puntos de control inmunitario / Predictive biomarkers of response to immune checkpoint inhibitors

OBJETIVO: El objetivo del presente trabajo es identificar mediante revisión bibliográfica los factores dependientes del tumor que condicionan la respuesta a los inhibidores de los puntos de control inmunitario, incidiendo especialmente en aquellos que se postulan como posibles biomarcadores predictivos. MÉTODO: Búsquedas en Pubmed con los términos biomarkers, PD-1, PD-L1, CTLA-4, checkpoint inhibitors, en el título o el abstract, seleccionando aquellos que incluyeran información relevante sobre factores tumorales que condicionan la respuesta a los inhibidores de los puntos de control inmunitario. Se priorizaron estudios en humanos (ensayos clínicos y revisiones) publica-dos entre enero de 2015 y junio de 2019, en idiomas inglés y español. RESULTADOS: La revisión pone de manifiesto las complejas relaciones entre sistema inmunitario y tumor, con factores que influyen en la respuesta a los inhibidores de los puntos de control inmunitario variados, y aun poco conocidos, lo cual dificulta la obtención de biomarcadores predictivos sencillos y/o universales. CONCLUSIONES: Actualmente los únicos biomarcadores utilizados en práctica clínica, en algunos escenarios, son la expresión del ligando del receptor de muerte celular programada-1 y la inestabilidad de microsatélites/deficiencias en las enzimas de reparación de los apareamientos erróneos durante la replicación del ácido desoxirribonucleico, aunque su utilidad es limitada. La carga mutacional y las firmas génicas asociadas a interferón gamma se postulan como biomarcadores útiles, una vez sistematizadas las técnicas de determinación y los puntos de corte

OBJECTIVE: The present paper provides a literature review aimed at identifying the tumor-dependent factors capable of influencing a subject's response to immune checkpoint inhibitors, with a special emphasis on those that may act as predictive biomarkers. METHOD: A search was performed of the terms biomarkers, PD -1, P D - L1, CTLA-4, and checkpoint inhibitors in the title and the abstract of the re-cords in the PubMed database. Articles including relevant information on the tumor-dependent factors capable of influencing a subject's response of immune checkpoint inhibitors were selected. Priority was given to studies in humans (clinical trials and reviews) published between January 2015 and June 2019, in English and Spanish. RESULTS: The literature review exposed the complex relationship that exists between the immune system and tumors. It also revealed that the factors capable of influencing a subject's response to immune checkpoint inhibitors are multiple, heterogeneous and ill understood, which makes it difficult to obtain simple and/or universal predictive biomarkers. CONCLUSIONS: The only biomarkers currently used in clinical practice include the expression of the programmed cell death ligand-1 and micro-satellite instability/ deficient DNA mismatch repair, but their usefulness is limited. Tumor mutational burden and gene signatures associated to IFN-γ could become useful biomarkers once determination techniques and cutoff points are systematized

Predictive biomarkers of response to immune checkpoint inhibitors.

OBJECTIVE: The present paper provides a literature review aimed at  identifying the tumor-dependent factors capable of influencing a  subject's response to immune checkpoint inhibitors, with a special  emphasis on those that may act as predictive biomarkers. METHOD: A search was performed of the terms biomarkers, PD-1, PD- L1, CTLA-4, and checkpoint inhibitors in the title and the abstract of the  records in the PubMed database. Articles including relevant information  on the tumor-dependent factors capable of influencing a subject's  response of immune checkpoint inhibitors were selected. Priority was  given to studies in humans (clinical trials and reviews) published  between January 2015 and June 2019, in English and Spanish. Results: The literature review exposed the complex relationship that xists between the immune system and tumors. It also revealed that the factors capable of influencing a subject's response to immune  checkpoint inhibitors are multiple, heterogeneous and ill understood,  which makes it difficult to obtain simple and/or universal predictive  biomarkers. CONCLUSIONS: The only biomarkers currently used in clinical practice include the expression of the programmed cell death ligand-1  and microsatellite instability/ deficient DNA mismatch repair, but their  usefulness is limited. Tumor mutational burden and gene signatures  associated to IFN-γ could become useful biomarkers once determination techniques and cutoff points are systematized.

Objetivo: El objetivo del presente trabajo es identificar mediante  revisión bibliográfica los factores dependientes del tumor que  condicionan la respuesta a los inhibidores de los puntos de control  inmunitario, incidiendo especialmente en aquellos que se postulan como posibles biomarcadores predictivos.Método: Búsquedas en Pubmed con los términos biomarkers, PD-1,  PD­L1, CTLA-4, checkpoint inhibitors, en el título o el abstract,  seleccionando aquellos que incluyeran información relevante sobre  factores tumorales que condicionan la respuesta a los inhibidores de los  puntos de control inmunitario. Se priorizaron estudios en humanos  (ensayos clínicos y revisiones) publicados entre enero de 2015 y junio  de 2019, en idiomas inglés y español.Resultados: La revisión pone de manifiesto las complejas relaciones entre sistema inmunitario y tumor, con factores que influyen  en la respuesta a los inhibidores de los puntos de control inmunitario  variados, y aun poco conocidos, lo cual dificulta la obtención de  biomarcadores predictivos sencillos y/o universales.Conclusiones: Actualmente los únicos biomarcadores utilizados en práctica clínica, en algunos escenarios, son la expresión del ligando  del receptor de muerte celular programada-1 y la inestabilidad de  microsatélites/deficiencias en las enzimas de reparación de los  apareamientos erróneos durante la replicación del ácido  desoxirribonucleico, aunque su utilidad es limitada. La carga mutacional  y las firmas génicas asociadas a interferón gamma se postulan como  biomarcadores útiles, una vez sistematizadas las técnicas de  determinación y los puntos de corte.

Evaluation of standardized triple intrathecal therapy toxicity in oncohematological adult patients / Evaluación de la toxicidad tras la administración de quimioterapia triple intratecal estandarizada en pacientes onco-hematológicos adultos

Objective: To assess the toxicity of a standardized triple intrathecal chemotherapy in onco- hematological adult patients and to establish risk factors of toxicity. Method: Observational and prospective study of standardized triple intrathecal chemotherapy administrations in onco-hematologic adult patients for 18 months. Results: There were some adverse events in 39.3% of the 56 administrations registered. 96.7% of the events were grade 1-2 and only 1 event was grade 3. The lower age of the patient and the greater difference between the administered drug volume and cerebrospinal fluid removed volume were shown as risk factors for toxicity. Conclusions: The administration of standardized triple intrathecal chemotherapy was related to a low frequency of toxicity and most of adverse events were mild-moderate. The detection of adverse effects was significantly greater in young adults and in those administrations where the difference between cerebrospinal fluid remove volume and the administered drug was greater (AU)

Objetivo: Evaluar la toxicidad asociada a la administración de quimioterapia triple intratecal estandarizada en pacientes onco-hematológicos adultos e identificar los factores de riesgo asociados. Método: Estudio observacional y prospectivo de las administraciones de quimioterapia triple intratecal estandarizada administradas a pacientes onco-hematológicos adultos durante 18 meses. Resultados: Se registró algún evento adverso en el 39,3% de las 56 administraciones registradas. El 96,7% de los eventos fueron grado 1-2 y solo 1 evento fue grado 3. La menor edad del paciente y la mayor diferencia entre el volumen administrado y el líquido cefalorraquídeo extraído se mostraron como factores de riesgo de toxicidad. Conclusiones: La administración de quimioterapia triple intratecal estandarizada estuvo relacionada con una baja frecuencia de toxicidad y la mayoría de los eventos adversos fueron de gravedad leve-moderada. La detección de efectos adversos fue significativamente mayor en adultos jóvenes y en aquellas administraciones en las que la diferencia entre el volumen de líquido cefalorraquídeo extraído y de fármaco administrado fue mayor (AU)

Evaluation of standardized triple intrathecal therapy toxicity in oncohematological adult patients.

OBJECTIVE: To assess the toxicity of a standardized triple intrathecal chemotherapy in onco- hematological adult patients and to establish risk factors of toxicity. METHOD: Observational and prospective study of standardized triple intrathecal chemotherapy administrations in onco-hematologic adult patients for 18 months. RESULTS: There were some adverse events in 39.3% of the 56 administrations registered. 96.7% of the events were grade 1-2 and only 1 event was grade 3. The lower age of the patient and the greater difference between the administered drug volume and cerebrospinal fluid removed volume were shown as risk factors for toxicity. CONCLUSIONS: The administration of standardized triple intrathecal chemotherapy was related to a low frequency of toxicity and most of adverse events were mild-moderate. The detection of adverse effects was significantly greater in young adults and in those administrations where the difference between cerebrospinal fluid remove volume and the administered drug was greater.

Objetivo: Evaluar la toxicidad asociada a la administración de quimioterapia triple intratecal estandarizada en pacientes onco-hematológicos adultos e identificar los factores de riesgo asociados.Método: Estudio observacional y prospectivo de las administraciones de quimioterapia triple intratecal estandarizada administradas a pacientes onco-hematológicos adultos durante 18 meses.Resultados: Se registró algún evento adverso en el 39,3% de las 56 administraciones registradas. El 96,7% de los eventos fueron grado 1-2 y solo 1 evento fue grado 3. La menor edad del paciente y la mayor diferencia entre el volumen administrado y el líquido cefalorraquídeo extraído se mostraron como factores de riesgo de toxicidad.Conclusiones: La administración de quimioterapia triple intratecal estandarizada estuvo relacionada con una baja frecuencia de toxicidad y la mayoría de los eventos adversos fueron de gravedad leve-moderada. La detección de efectos adversos fue significativamente mayor en adultos jóvenes y en aquellas administraciones en las que la diferencia entre el volumen de líquido cefalorraquídeo extraído y de fármaco administrado fue mayor.

Practical aspects of the use of intrathecal chemotherapy / Aspectos prácticos de la utilización de quimioterapia intratecal

Introduction: Intrathecal chemotherapy is frequently used in clinical practice for treatment and prevention of neoplastic meningitis. Despite its widespread use, there is little information about practical aspects such as the volume of drug to be administered or its preparation and administration. Objective: To conduct a literature review about practical aspects of the use of intrathecal chemotherapy. Materials: Search in PubMed/ Medline using the terms ‘chemotherapy AND intrathecal’, analysis of secondary and tertiary information sources. Results: The most widely used drugs in intrathecal therapy are methotrexate and cytarabine, at variable doses. One of the aspects with higher variability among different studies is their potential combination with a glucocorticoid, the specific corticoid selected and its dose. The efficacy and toxicity of the different combinations have not been compared. Regarding preparation, it is worth highlighting the recommendation to adjust pH and osmolarity to the physiological range, with the aim of improving tolerability. The volume of administration can influence distribution, and recommendated range is between 5 and 12 mL. Overall, it is recommended to extract a similar volume of cerebrospinal fluid before administration. The position of the patient during and after administration can have an impact on distribution and toxicity; lateral decubitus or sitting position is recommended in the first case, and prone and/ or supine position in the second one. Most publications don’t explain how the treatment has been prepared or administered, and the lack of standardization could affect results. Conclusions: There is a great variability in practice when using intrathecal chemotherapy, despite being an effective therapy, accepted by all international groups. This uncertainty is not limited to the drugs and doses administered, but it also includes the manner of preparation and the administration technique. The heterogeneity in clinical practice can influence the efficacy and toxicity of this therapy (AU)

Introducción: La quimioterapia intratecal es utilizada frecuentemente, en la práctica clínica, para el tratamiento y prevención de la meningitis neoplásica. A pesar de su uso extendido, existe poca información acerca de aspectos prácticos tales como el volumen de fármaco a administrar o la forma de preparación y administración. Objetivo: Realizar una revisión de la literatura acerca de aspectos prácticos de la utilización de la quimioterapia intratecal. Material: Búsqueda en PubMed/Medline utilizando los términos ‘chemotherapy AND intrathecal’, análisis de fuentes de información secundarias y terciarias. Resultados: Los fármacos más utilizados en terapia intratecal son metotrexato y citarabina, con dosis variables. La asociación o no con un glucocorticoide, el corticoide concreto seleccionado y su dosis es uno de los aspectos con mayor variabilidad entre distintos estudios. No se han comparado la eficacia y toxicidad de las distintas combinaciones. En la preparación destaca la recomendación de ajustar pH y osmolaridad al rango fisiológico, con el objetivo de mejorar la tolerancia. El volumen de administración puede influir en la distribución, oscilando las recomendaciones entre 5-12 mL. En general, se aconseja extraer previamente un volumen de líquido cefalorraquídeo similar. La posición del paciente durante y tras la administración puede influir en la distribución y la toxicidad; se recomienda el decúbito lateral o la sedestación, en el primer caso, y el decúbito prono y/o supino, en el segundo. La mayoría de las publicaciones no indican cómo se ha preparado o administrado el tratamiento, y la falta de estandarización podría afectar a los resultados. Conclusiones: Existe gran variabilidad en la práctica a la hora de utilizar la quimioterapia intratecal, a pesar de ser una terapia efectiva asumida por todos los grupos internacionales. La incertidumbre no se limita a los fármacos y dosis administradas, sino que se extiende a la forma de preparación de las mezclas y la técnica de administración. La heterogeneidad en la práctica clínica puede influir en la efectividad y toxicidad de esta terapia (AU)

Practical aspects of the use of intrathecal chemotherapy.

INTRODUCTION: Intrathecal chemotherapy is frequently used in clinical practice for treatment and prevention of neoplastic meningitis. Despite its widespread use, there is little information about practical aspects such as the volume of drug to be administered or its preparation and administration. OBJECTIVE: To conduct a literature review about practical aspects of the use of intrathecal chemotherapy. MATERIALS: Search in PubMed/ Medline using the terms "chemotherapy AND intrathecal", analysis of secondary and tertiary information sources. RESULTS: The most widely used drugs in intrathecal therapy are methotrexate and cytarabine, at variable doses. One of the aspects with higher variability among different studies is their potential combination with a glucocorticoid, the specific corticoid selected and its dose. The efficacy and toxicity of the different combinations have not been compared. Regarding preparation, it is worth highlighting the recommendation to adjust pH and osmolarity to the physiological range, with the aim of improving tolerability. The volume of administration can influence distribution, and recommendated range is between 5 and 12 mL. Overall, it is recommended to extract a similar volume of cerebrospinal fluid before administration. The position of the patient during and after administration can have an impact on distribution and toxicity; lateral decubitus or sitting position is recommended in the first case, and prone and/ or supine position in the second one. Most publications don't explain how the treatment has been prepared or administered, and the lack of standardization could affect results. CONCLUSIONS: There is a great variability in practice when using intrathecal chemotherapy, despite being an effective therapy, accepted by all international groups. This uncertainty is not li mited to the drugs and doses administered, but it also includes the manner of preparation and the administration technique. The heterogeneity in clinical practice can influence the efficacy and toxicity of this therapy.

Introducción: La quimioterapia intratecal es utilizada frecuentemente, en la practica clinica, para el tratamiento y prevencion de la meningitis neoplasica. A pesar de su uso extendido, existe poca informacion acerca de aspectos practicos tales como el volumen de farmaco a administrar o la forma de preparacion y administracion. Objetivo: Realizar una revision de la literatura acerca de aspectos practicos de la utilizacion de la quimioterapia intratecal. MATERIAL: Busqueda en PubMed/Medline utilizando los terminos "chemotherapy AND intrathecal", analisis de fuentes de informacion secundarias y terciarias. Resultados: Los farmacos mas utilizados en terapia intratecal son metotrexato y citarabina, con dosis variables. La asociacion o no con un glucocorticoide, el corticoide concreto seleccionado y su dosis es uno de los aspectos con mayor variabilidad entre distintos estudios. No se han comparado la eficacia y toxicidad de las distintas combinaciones. En la preparacion destaca la recomendacion de ajustar pH y osmolaridad al rango fisiologico, con el objetivo de mejorar la tolerancia. El volumen de administracion puede influir en la distribucion, oscilando las recomendaciones entre 5-12 mL. En general, se aconseja extraer previamente un volumen de liquido cefalorraquideo similar. La posicion del paciente durante y tras la administracion puede influir en la distribucion y la toxicidad; se recomienda el decubito lateral o la sedestacion, en el primer caso, y el decubito prono y/o supino, en el segundo. La mayoria de las publicaciones no indican como se ha preparado o administrado el tratamiento, y la falta de estandarizacion podria afectar a los resultados. Conclusiones: Existe gran variabilidad en la practica a la hora de utilizar la quimioterapia intratecal, a pesar de ser una terapia efectiva asumida por todos los grupos internacionales. La incertidumbre no se limita a los farmacos y dosis administradas, sino que se extiende a la forma de preparacion de las mezclas y la tecnica de administracion. La heterogeneidad en la practica clinica puede influir en la efectividad y toxicidad de esta terapia.

Evaluation of standardized triple intrathecal therapy toxicity in oncohematological pediatric patients.

Background The administration of triple intrathecal therapy with methotrexate, cytarabine and a corticosteroid for the prophylaxis and treatment of neoplastic cell infiltration in the central nervous system in hematological malignancies is a widespread practice. There is limited information available about its toxicity profile. Several factors related to intrathecal preparation can affect toxicity. Thus, it was decided to standardize intrathecal chemotherapy, trying to obtain the best toxicity profile. Objective To assess the toxicity of a standardized triple intrathecal chemotherapy in oncohematological pediatric patients and to establish risk factors of toxicity. Setting Oncohematological pediatric unit from a tertiary hospital in Spain. Methods Prospective, descriptive and observational study in which all the administrations of standardized triple intrathecal chemotherapy in pediatric patients were registered. Main outcome measure Toxicity of the intrathecal therapy was recorded and possible risk factors were assessed. Results A total of 269 administrations of triple intrathecal chemotherapy were registered in 41 patients (mean age = 6.6 ± 3.9 years). In 16.7% of the procedures, an adverse event was reported (total number of adverse events = 61). 47.5% were grade 1, 47.5% grade 2 and 4.9% grade 3. The administration of intrathecal chemotherapy inpatient and patient age ≥3 years were risk factors of toxicity in the multivariate analysis. Conclusions The administration of standardized triple intrathecal chemotherapy is related to a low frequency of toxicity and most of the adverse events registered were mild/moderate. The detection of adverse effects was significantly greater in children with age greater than or equal to three years and in hospitalized patients.

Púrpura trombótica trombocitopénica inducida por ciclosporina. Estudio de 3 casos / Cyclosporin-induced thrombotic thrombocytopenic purpura. Report of three cases

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Stability of four standardized preparations of methotrexate, cytarabine, and hydrocortisone for intrathecal use.

INTRODUCTION: Intrathecal administration of methotrexate, cytarabine, and hydrocortisone is commonly used to treat and prevent central nervous system involvement in leukemias and lymphomas. The use of intrathecal solutions with pH and osmolarity values close to physiologic range of CSF (pH 7.31-7.37, osmolarity 281-306 mOsm/kg) and standardization of the methotrexate, cytarabine, and hydrocortisone doses in children and adults based on age is highly recommended. Stability studies of standardized intrathecal mixtures under these conditions have not yet been published. OBJECTIVE: The purpose of this study was to evaluate the physical and chemical stabilities of four standardized mixtures of methotrexate, cytarabine, and hydrocortisone stored at 2-8℃ and 25℃ up to 7 days after preparation. METHODS: Four different standardized intrathecal mixtures were prepared and stored at 2-8℃ and 25℃ and protected from light. Triplicate samples were taken at different times and precipitation, appearance, color, pH, and osmolarity were analyzed. Methotrexate, cytarabine, and hydrocortisone concentrations were measured using a modified high-performance liquid chromatography method. RESULTS: No variation greater than 10% of the initial concentration of methotrexate, cytarabine, and hydrocortisone was observed in any of the four standardized mixtures for the 7 days of study when stored at 2-8℃ and 25℃ and protected from light. The osmolarity of the four preparations was within the physiologic range of CSF for 7 days at both 2-8℃ and 25℃. The pH values close to the physiologic range of CSF were stable for 48 h at 25℃ and for 120 h at 2-8℃. CONCLUSIONS: Triple intrathecal standardized preparations of methotrexate, cytarabine, and hydrocortisone sodium phosphate are physically and chemically stable at 25℃ for 48 h and at 2-8℃ for 5 days.

Potential drug-drug interactions in oncological adult inpatients at a Spanish hospital: epidemiology and risk factors.

BACKGROUND: Oncological patients are at high risk for drug-drug interactions (DDIs), which may contribute to therapeutic failure or lead to serious adverse events. OBJECTIVE: To determine the prevalence of potential DDIs in medication lists, to describe the most frequent DDIs and to investigate the possible risk factors associated with them. A prospective cohort study was performed at the Oncology Department of a tertiary hospital over a 12-week period. Twice a week, every inpatient's treatment sheet was collected and screened through two databases: Micromedex™ and Drug Interaction Facts™. All identified potential DDIs with a moderate or higher severity rating were recorded. Multivariate analysis was used to identify risk factors associated with DDIs. RESULT: A total of 1956 DDIs were detected in 699 treatment sheets. The prevalence of treatment sheets with DDIs was 81.0 % and 32.6 % by Micromedex™ and Drug Interaction Facts™, respectively. Central nervous depressant agents and antiemetics were the most commonly involved groups in DDIs. A higher number of non-antineoplastic drugs was related with potential DDIs [adjusted-OR 1.398 and 1.613 by Micromedex™ and Drug Interaction Facts™, respectively]. CONCLUSION The prevalence of potential DDIs was widely variable among databases. The main risk factor associated with DDIs was a higher number of non-antineoplastic medicines.

Pharmacoepidemiological study of drug-drug interactions in onco-hematological pediatric patients.

BACKGROUND: Onco-hematological patients are particularly susceptible to drug-drug interactions (DDIs) because they often undergo multiple combined treatments. Some studies have analyzed the frequency of DDIs in adult patients with cancer; however, the prevalence of DDIs in children, and especially among pediatric cancer patients, remains unknown. OBJECTIVE: To determine the prevalence of DDIs in treatment sheets comparing two commonly used drug interaction databases, to describe the most common clinically relevant DDIs (CR-DDIs) and to investigate the risk factors associated with them. SETTING: An onco-hematological pediatric unit from a tertiary hospital in Spain. METHOD: A prospective, observational and descriptive study was carried out from November 2012 to February 2013. Twice a week, every patient's treatment sheet was collected. Each medication list was screened through two databases: Thomson Micromedex™ and Drug Interaction Facts™. All identified DDIs were graded by their level of severity. Summary statistics were used to describe patient and disease characteristics, most often prescribed drugs, and frequency, types and classification of CR-DDIs. Multivariate analysis was used to identify risk factors associated with CRDDIs. MAIN OUTCOME MEASURE: Prevalence of CR-DDIs was measured as percentage. RESULTS: A total of 506 potential DDIs were detected in 150 treatment sheets. The prevalence of CR-DDIs by Micromedex database and Drug Interaction Facts database were 44.7 and 51.3% respectively. Amikacin, azole antifungals, antiemetics and cyclosporine were the most frequent drugs involved in CR-DDIs. In multivariate analysis, the main risk factor associated with increased odds for CR-DDIs was a higher number of drugs. CONCLUSION: The frequency of potential DDIs was related to a higher number of drugs, being immunosuppressant and azole antifungal agents the most commonly involved drugs. The lack of agreement between different databases enhances the complexity to detect drug interactions in clinical practice.