Therapeutic Drug Monitoring in Oncohematological Patients: A Fast and Accurate HPLC-UV Method for the Quantification of Nilotinib in Human Plasma and Its Clinical Application.

Nilotinib, a second-generation tyrosine kinase inhibitor, has demonstrated clinical activity in chronic myeloid leukemia. As an exposure-response relationship has been observed for nilotinib, its therapeutic drug monitoring could be a valuable tool in clinical practice. Therefore, the aim of this study was to develop and validate a selective and precise high performance liquid chromatography-ultraviolet method for the measurement of nilotinib in plasma from patients with cancer. After protein precipitation extraction with acetonitrile, nilotinib and rilpivirine were separated using isocratic elution on a Tracer Excel 120 ODS C18 column using a mobile phase consisting of a mixture of potassium dihydrogen phosphate-buffered solution (pH 5.5; 0.037 M)-methanol-acetonitrile (45:45:10, v/v/v), pumped at a flow rate of 1.7 mL·min-1. A wavelength of 254 nm was selected for the quantification of the analyte and the internal standard (IS). The technique was validated following the guidelines for the validation of analytical methods of regulatory agencies (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)). Linearity was established in a concentration range between 125 and 7000 ng/mL. The detection limit was 90 ng/mL, and the lower limit of quantification was 125 ng/mL. For all concentrations in the calibration curve, the intraday and interday coefficients of variation were less than 4.1%. Median recovery of nilotinib from plasma was ≥65.1% (±21.4%). The method described is sensitive, selective, reproducible, and rapid, and can be used for the accurate determination of nilotinib in human plasma for pharmacokinetics studies and for therapeutic drug monitoring (TDM) of nilotinib in routine clinical practice.

Six months multicentre pilot open label single-arm study to evaluate patient experience, acceptability and satisfaction of switching certolizumab pegol from a prefilled syringe or autoinjection pen to an AVA® e-Device in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis patients.

WHAT IS KNOWN AND OBJECTIVE: The study aimed to assess acceptability and patient experience of Certolizumab (CZP) self-injection with AVA® and clarify patient device preference after switching CZP from the syringe or auto-injection pen to AVA® in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) patients. METHOD: A multicentre open-label, cross-sectional and prospective study among four Spanish hospitals was performed. Adult RA, PsA, axSpA patients treated for at least 6 months with the CZP syringe or pen were recruited. At the first visit, patients completed Pre-AVA® questionnaire. Patients were instructed on proper administration of CZP by AVA®. After 2 and 6 months of CZP self-injections using the AVA®, patient experience, adherence, preference and safety of each administration was assessed using post-AVA® questionnaire. RESULTS AND DISCUSSION: Thirty four patients were included (28 women). All patients self-administered CZP AVA® the full dose of CZP was injected. Patients reported >90% adherence to CZP AVA® assessed with the injection log. Pain at the injection site was reduced after switching to AVA®. Twenty nine patients preferred CZP AVA® and five patients preferred the CZP pen. No safety-related findings related to AVA® CZP administration were identified. WHAT IS NEW AND CONCLUSION: The AVA® is an advantageous delivery option for CZP in patients with RA, PsA, axSpA.

Inflammatory bowel disease new-onset during secukinumab therapy: real-world data from a tertiary center.

Secukinumab is a monoclonal antibody that inhibits interleukin-17A. It is currently prescribed for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis, which are immune-mediated diseases that show significant co-heritability with inflammatory bowel disease (IBD). Although this treatment appears to be well tolerated by patients, several cases of new-onset IBD after secukinumab have been reported during the last years.

Midazolam and haloperidol for palliative sedation: physicochemical stability and compatibility of parenteral admixtures

This study was done to determine the time while the binary admixtures with midazolam and haloperidol drugs are administered by perfusion to the patients in the clinical routine. Samples with different concentrations of both drugs were prepared following the usual clinical practice. Solvents used were 0.9 % sodium chloride solution and 5% dextrose, and viaflo plastic bags were used as the containers of the admixtures. Samples were not protected from light and were stored at 20 ºC or at 4 ºC. Compatibility and physicochemical stability were studied by visual inspection, turbidity measurement, pH determination and ultraviolet detection high performance liquid chromatography (UV-HPLC) was used to determine midazolam and haloperidol concentrations. The assay was validated following the FDA and EMA guidelines. Darunavir was used as internal standard (IS). For the studied admixtures, turbidity measurements and pH determinations showed little changes in function of the time. Haloperidol and midazolam concentrations determined by HPLC are within the acceptable range of drug concentrations, which are considered stable for four days in case of admixtures stored at 20 ºC and for seven days for refrigerated admixtures. Taking into account the microbiological risk matrix, the compatibility and the chemical and microbiological stability of the midazolam and haloperidol in the co-administered admixtures in viaflo plastic bags with 0.9 % sodium chloride solution and 5% dextrose can be set as 48 hours when samples are stored at 20 ºC and one week if they are refrigerated.

Relationship between the rs1414334 C/G polymorphism in the HTR2C gene and smoking in patients treated with atypical antipsychotics. / Relación entre el polimorfismo rs1414334 C/G del gen HTR2C y tabaquismo en pacientes tratados con antipsicóticos atípicos.

An association has been found between the C allele of the rs1414334 polymorphism in the HTR2C gene and the metabolic syndrome in psychiatric patients. However, no study has yet evaluated whether this allele is associated with smoking. To assess this issue, therefore, we performed a cross-sectional study with a sample of 166 adult patients treated with atypical antipsychotics in 2012-2013 in a region of Spain. The primary variable was the presence of the C allele of the rs1414334 polymorphism in the HTR2C gene. Secondary variables were the number of pack-years (number of cigarettes per day x number of smoking years ÷ 20), age, gender, schizophrenia, years since diagnosis, metabolic syndrome criteria and SCORE. A stepwise binary logistic regression model was constructed to determine associations between primary and secondary variables and their area under the ROC curve (AUC) was calculated. Of the total sample, 33 patients (19.9%) had the C allele of the polymorphism analyzed. Mean cigarette consumption was 11.6 pack-years. The multivariate analysis showed the following factors as associated with the polymorphism: higher cigarette consumption, being a woman, and not having abdominal obesity. The AUC was 0.706. An association was found between increased cigarette consumption over the years and the presence of the C allele of the rs1414334 polymorphism in the HTR2C gene.

En pacientes psiquiátricos, otros autores han encontrado una asociación entre el alelo C del polimorfismo rs1414334 del gen HTR2C y el síndrome metabólico. Ninguno de ellos ha valorado si este alelo se asocia con el consumo de tabaco, por lo que se decidió realizar un estudio en una región española valorando esta cuestión. Estudio observacional transversal de una muestra de 166 pacientes adultos tratados con antipsicóticos atípicos en 2012-2013. Variable principal: presencia del alelo C del polimorfismo rs1414334 del gen HTR2C. Variables secundarias: número de años-paquete (número de cigarrillos al día x número de años fumando ÷ 20), edad, sexo, esquizofrenia, años diagnosticados del trastorno, criterios de síndrome metabólico y SCORE. Se construyó un modelo de regresión logística binaria por pasos para determinar asociaciones entre la variable principal y las variables secundarias del estudio y se calculó su área bajo la curva ROC (ABC). Del total de la muestra, 33 pacientes presentaron el alelo C del polimorfismo analizado (19,9%). El consumo de tabaco medio fue de 11.6 paquetes-año. El modelo multivariante arrojó los siguientes factores asociados al polimorfismo: mayor consumo tabáquico, ser mujer y no tener obesidad abdominal. El ABC fue de 0,706. Se ha encontrado asociación entre un mayor consumo de tabaco a lo largo de los años y la presencia del alelo C del polimorfismo rs1414334 del gen HTR2C. Se necesitan trabajos que corroboren nuestros resultados.

Relación entre el polimorfismo rs1414334 C/G del gen HTR2C y tabaquismo en pacientes tratados con antipsicóticos atípicos / Relationship between the rs1414334 C/G polymorphism in the HTR2C gene and smoking in patients treated with atypical antipsychotics

En pacientes psiquiátricos, otros autores han encontrado una asociación entre el alelo C del polimorfismo rs1414334 del gen HTR2C y el síndrome metabólico. Ninguno de ellos ha valorado si este alelo se asocia con el consumo de tabaco, por lo que se decidió realizar un estudio en una región española valorando esta cuestión. Estudio observacional transversal de una muestra de 166 pacientes adultos tratados con antipsicóticos atípicos en 2012-2013. Variable principal: presencia del alelo C del polimorfismo rs1414334 del gen HTR2C. Variables secundarias: número de años-paquete (número de cigarrillos al día x número de años fumando ÷ 20), edad, sexo, esquizofrenia, años diagnosticados del trastorno, criterios de síndrome metabólico y SCORE. Se construyó un modelo de regresión logística binaria por pasos para determinar asociaciones entre la variable principal y las variables secundarias del estudio y se calculó su área bajo la curva ROC (ABC). Del total de la muestra, 33 pacientes presentaron el alelo C del polimorfismo analizado (19,9%). El consumo de tabaco medio fue de 11.6 paquetes-año. El modelo multivariante arrojó los siguientes factores asociados al polimorfismo: mayor consumo tabáquico, ser mujer y no tener obesidad abdominal. El ABC fue de 0,706. Se ha encontrado asociación entre un mayor consumo de tabaco a lo largo de los años y la presencia del alelo C del polimorfismo rs1414334 del gen HTR2C. Se necesitan trabajos que corroboren nuestros resultados

An association has been found between the C allele of the rs1414334 polymorphism in the HTR2C gene and the metabolic syndrome in psychiatric patients. However, no study has yet evaluated whether this allele is associated with smoking. To assess this issue, therefore, we performed a cross-sectional study with a sample of 166 adult patients treated with atypical antipsychotics in 2012-2013 in a region of Spain. The primary variable was the presence of the C allele of the rs1414334 polymorphism in the HTR2C gene. Secondary variables were the number of pack-years (number of cigarettes per day x number of smoking years ÷ 20), age, gender, schizophrenia, years since diagnosis, metabolic syndrome criteria and SCORE. A stepwise binary logistic regression model was constructed to determine associations between primary and secondary variables and their area under the ROC curve (AUC) was calculated. Of the total sample, 33 patients (19.9%) had the C allele of the polymorphism analyzed. Mean cigarette consumption was 11.6 pack-years. The multivariate analysis showed the following factors as associated with the polymorphism: higher cigarette consumption, being a woman, and not having abdominal obesity. The AUC was 0.706. An association was found between increased cigarette consumption over the years and the presence of the C allele of the rs1414334 polymorphism in the HTR2C gene

Pharmacokinetic monitoring of chronic treatment with digoxin from Primary Health Care / Seguimiento farmacocinético del tratamiento crónico con digoxina desde Atención Primaria

Objective: To assess the pharmacokinetic monitoring of SDC performed from primary healthcare (PH) in patients with chronic treatment. Methods: Cross-sectional retrospective study of patients with chronic treatment with digoxin belonging to the department of a General University Hospital. Data were analized: age, sex, diagnosis, number of serum digoxin concentration determinations, date and origin of the request for monitoring, analytical result and pharmacokinetic assessment are collected. Results: 624 patients are undergoing chronic treatment with digoxin, 68% women, mean age 78.4 (39-98) years. 308 (49.4%) patients haven’t analytical determination of SDC (Group 1), 183 (29.3%) patients have a SDC occasionally performed with a request from specialist care (Group 2) and 133 (21,3%) patients have CSD performed with a request from primary healthcare doctors, with an average of 2.42 monitoring per patient and year (Group 3). These are those patients who have pharmacokinetic monitoring of chronic treatment with digoxin. Of the group 2.25 (13.6%) patientes were hospital admission from emergency department for presenting digitalis intoxication with CSD>2 ng/ml, and 39 (21.3%) patients for low dosing with CSD (AU)

Objetivo: Evaluar el seguimiento farmacocinético de las CSD que se realiza desde Atención Primaria (AP) en pacientes con tratamiento crónico. Métodos: Estudio trasversal observacional retrospectivo de pacientes en tratamiento crónico con digoxina que pertenecen al departamento de un Hospital General Universitario. Se recogen datos de edad, sexo, diagnóstico, número de determinaciones séricas de digoxina realizadas, fecha y origen de la solicitud de monitorización, resultado analítico y valoración farmacocinética. (Infradosificación, normodosificación o supradosificación). Resultados: 624 pacientes están en tratamiento crónico con digoxina: 68% mujeres, edad media 78,4 (39-98) años. 308 (49,4%) pacientes no tienen realizada ninguna determinación analítica de CSD (Grupo 1), 183 (29,3%) pacientes tienen CSD realizadas de manera esporádica con solicitud tramitada desde Atención Especializada (Grupo 2) y 133 (21,3%) pacientes tienen CSD realizadas de manera periódica con solicitud cursada por médicos de AP, con un promedio de 2,42 monitorizaciones por paciente y año (Grupo 3). Estos son los que tienen un seguimiento farmacocinético del tratamiento crónico con digoxina. Del Grupo 2,25(13,6%) entran por el Servicio de Urgencias por presentar intoxicación digitálica con CSD>2 ng/ml, y 39 (21,3%) pacientes por baja dosificación con CSD (AU)

Pharmacokinetic monitoring of chronic treatment with digoxin from Primary Health Care.

INTRODUCTION: The serum digoxin concentration (SDC) should be between 0.8 and 2 ng/ml. The objective is to assess the pharmacokinetic monitoring of SDC performed from primary healthcare (PH) in patients with chronic treatment. METHODS: Cross-sectional retrospective study of patients with chronic treatment with digoxin belonging to the department of a General University Hospital.Data were analized: age, sex, diagnosis, number of serum digoxin concentration determinations, date and origin of the request for monitoring, analytical result and pharmacokinetic assessment are collected. RESULTS: 624 patients are undergoing chronic treatment with digoxin, 68% women, mean age 78.4 (39-98) years. 308 (49.4%) patients haven't analytical determination of SDC (Group 1), 183 (29.3%) patients have a SDC occasionally performed with a request from specialist care (Group 2) and 133 (21,3%) patients have CSD performed with a request from primary healthcare doctors, with an average of 2.42 monitoring per patient and year (Group 3). These are those patients who have pharmacokinetic monitoring of chronic treatment with digoxin. Of the group 2.25 (13.6%) patientes were hospital admission from emergency department for presenting digitalis intoxication with CSD>2 ng/ml, and 39 (21.3%) patients for low dosing with CSD<0.5 ng/ml. Group 3.4 (3%) patients presented digitalis intoxication and 5 (3.8%) for insufficient dosing. CONCLUSIONS: A small proportion of patients undergoing chronic treatment with digoxin are under pharmacokinetic monitoring and a reduction in complications derived from inappropriate CSD compared to those not under pharmacokinetic follow-up is observed.

Introducción: La concentración sérica de digoxina (CSD) debe situarse entre 0,8 y 2 ng/ml. El objetivo es valuar el seguimiento farmacocinético de las CSD que se realiza desde Atención Primaria (AP) en pacientes con tratamiento crónico.Métodos: Estudio trasversal observacional retrospectivo de pacientes en tratamiento crónico con digoxina que pertenecen al departamento de un Hospital General Universitario. Se recogen datos de edad, sexo, diagnóstico, número de determinaciones séricas de digoxina realizadas, fecha y origen de la solicitud de monitorización, resultado analítico y valoración farmacocinética. (Infradosificación, normodosificación o supradosificación).Resultados: 624 pacientes están en tratamiento crónico con digoxina: 68% mujeres, edad media 78,4 (39-98) años. 308 (49,4%) pacientes no tienen realizada ninguna determinación analítica de CSD (Grupo 1), 183 (29,3%) pacientes tienen CSD realizadas de manera esporádica con solicitud tramitada desde Atención Especializada (Grupo 2) y 133 (21,3%) pacientes tienen CSD realizadas de manera periódica con solicitud cursada por médicos de AP, con un promedio de 2,42 monitorizaciones por paciente y año (Grupo 3). Estos son los que tienen un seguimiento farmacocinético del tratamiento crónico con digoxina.Del Grupo 2,2(13,6%) entran por el Servicio de Urgencias por presentar intoxicación digitálica con CSD>2 ng/ml, y 39 (21,3%) pacientes por baja dosificación con CSD<0,5ng/ml. Del Grupo 3,4 (3%) presentan intoxicación digitálica y 5 (3,8%) infradosificación.Conclusiones: Una pequeña parte de los pacientes que se encuentran en tratamiento crónico con digoxina están en seguimiento farmacocinético. Se observa una reducción de las complicaciones derivadas de CSD inapropiadas con respecto a los que no están en seguimiento farmacocinético.

A rapid validated UV-HPLC method for the simultaneous determination of the antiretroviral compounds darunavir and raltegravir in their dosage form / Determinación simultánea de los compuestos antirretrovirales darunavir y raltegravir en su forma farmacéutica mediante un método rápido y validado de UV-HPLC

Introduction. A rapid, simple and sensitive high-performance liquid chromatography (HPLC) method with ultraviolet detection has been developed for quantification of darunavir and raltegravir in their pharmaceutical dosage form. Material and methods. The assay enables the measurement of both drugs with a linear calibration curve (R2= 0.999) over the concentration range 5-100 mg/L. The determination was performed on an analytical Tracer Excel 120 ODSB (15x0.4.6 cm) column at 35ºC. The selected wavelength was 254 nm. The mobile phase was a mixture of 0.037 M sodium dihydrogen phosphate buffer, acetonitrile and methanol (40:50:10, v/v/v) at a flow rate of 2.0 mL/min Nevirapine (50 mg/L) was used as internal standard. Results. Accuracy, intraday repeatability (n = 5), and inter-day precision (n = 3) were found to be satisfactory, being the accuracy from -4.33 to 3.88% and precisions were intra-day and interday, 0.25% and 4.42% respectively in case of darunavir. Raltegravir intraday and interday precisions lower of 1.01 and 2.36%, respectively and accuracy values bet from -4.02 to 1.06%. Conclusions. Determination of the darunavir and raltegravir in their dosage form was done with a maximum deviation of 4%. This analytical method is rapid, easily implantable and offers good results (AU)

Introducción. Un método rápido, sencillo y sensible de cromatografía líquida de alto rendimiento (HPLC) con detección ultravioleta ha sido desarrollado para la cuantificación simultánea de darunavir y raltegravir en su forma farmacéutica. Material y métodos. La determinación se llevó a cabo empleando una columna Tracer Excel 120 ODSB (15x0.4.6 cm) C18 a 35 ºC. La longitud de onda empleada fue de 254 nm. La fase móvil fue una mezcla de una disolución tampón dihidrógeno fosfato de sodio 0,037 M, acetonitrilo y metanol (40:50:10, v/v/v) con un flujo de 2,0 mL/min. El fármaco nevirapina (50 mg/L) fue usado como patrón interno. Resultados. El ensayo realiza la medida de ambos fármacos con una curva de calibración lineal (R2= 0,999) en un rango de concentración de 5 a 100 mg/L. Los valores de exactitud, repetibilidad intradía (n = 5) e interdía (n = 3) han resultado satisfactorios, encontrándose los valores de exactitud entre -4.33 y 3.88%, y las precisiones intradía e interdía, 0,25% y 4,42%, respectivamente en caso de darunavir. En el caso del raltegravir, las precisiones intradía e interdía fueron de 1,01 y 2,36%, respectivamente y para la exactitud se obtuvieron valores entre -4,02 y 1,06%. Conclusiones. La determinación de darunavir y raltegravir en su forma farmacéutica fue llevada a cabo observándose una desviación máxima del 4%. El método es rápido, fácilmente implantable y ofrece buenos resultados (AU)

Association between the HTR2C rs1414334 C/G gene polymorphism and the development of the metabolic syndrome in patients treated with atypical antipsychotics.

Few studies have assessed the association between the rs1414334 C/G polymorphism in the HTR2C gene and the development of the metabolic syndrome in patients treated with atypical antipsychotics. To provide further evidence, a cross-sectional study was conducted in Spain between 2012 and 2013 in 166 patients with these characteristics. In these patients, the association between the polymorphism and the presence of the metabolic syndrome was determined by implementing binary logistic regression models adjusted for variables associated with the metabolic syndrome. We did not confirm previous claims that the C allele of the polymorphism was linked to the metabolic syndrome: the association was in the opposite direction and non-significant. This conclusion held after taking gender and lifestyle variables into account.