Conversion of the etiology of autoimmune hemolytic anemia / Conversión de etiología de anemia hemolítica autoinmune

Autoimmune hemolytic anemia (AIHA) is disorder that involves the destruction of erythrocytes, differentiating between warm AIHA (WAIHA) with extravascular hemolysis mediated by IgG, cold agglutinin disease (CAD) with intravascular hemolysis mediated by IgM/Cd3 or mixed AIHA. Treatment of WAIHA consists of corticosteroids, immunoglobulins, rituximab, immunosuppressants, cyclophosphamide and splenectomy, whereas in CAD the response to corticosteroids is low.The 46-year-old patient came to the emergency department with a drop of 4.5 hemoglobin points in 15 days, associated with tachycardia, muco-cutaneous pallor and dyspnea. After analytical parameters compatible with AIHA and Coombs test Cd3+/IgM-, a diagnosis of CAD was made and rituximab and warm transfusion support were started. When intravascular haemolysis intensified, intravenous immunoglobulin, plasmapheresis and darbepoetin alpha were associated with no clinical improvement, later receiving bortezomib as third line and eculizumab due to refractoriness. The Coombs’ test was repeated, with a result compatible with WAIHA and slight splenomegaly associated due to extravascular hemolysis, so a splenectomy was performed achieving stabilization of analytical parameters and allowing the patient to be discharged. This clinical case evidences a conversion in the etiology of AIHA, with initial diagnosis of CAD since Coombs’ test was Cd3+/IgG- and converted to WAIHA after 37 days of admission since Coombs’ test changed to Cd3-/IgG+. (AU)

La anemia hemolítica autoinmune (AIHA) es una patología que conlleva la destrucción de eritrocitos, diferenciando entre AIHA por anticuerpos calientes (WAIHA) con hemólisis extravascular por IgG, AIHA por crioaglutininas (CAD) con hemólisis intravascular por IgM/Cd3 o AIHA mixtas. El tratamiento de AIHA por anticuerpos calientes consiste en corticoides, inmunoglobulinas, rituximab, inmunosupresores, ciclofosfamida y esplenectomía, mientras que en AIHA por crioaglutininas la respuesta a corticoides es baja. La paciente de 46 años acudió a urgencias con caída de 4,5 puntos de hemoglobina en 15 días, asociando taquicardia, palidez y disnea. Tras parámetros analíticos compatibles con AIHA y test de Coombs Cd3+/IgM- se diagnosticó de CAD e inició rituximab y transfusiones con calentador. Ante una intensificación de la hemólisis intravascular se asoció inmunoglobulina intravenosa, plasmaféresis y darbepoetina alfa sin mejoría clínica, recibiendo posteriormente bortezomib como tercera línea y eculizumab ante refractariedad. Se repitió el test de Coombs evidenciando en ese momento un diagnóstico por WAIHA, con ligera esplenomegalia asociada a la hemólisis extravascular, por lo que se realizó una esplenectomía alcanzando una estabilización de los parámetros analíticos y permitiendo el alta de la paciente. Este caso clínico evidencia una conversión en la etiología de la AIHA, con diagnóstico inicial de CAD ante test de Coombs Cd3+/IgG- y cambio a WAIHA después de 37 días de ingreso ante Coombs Cd3-/IgG+. (AU)

[Parenteral administration medicines: recommendations of preparation, administration and stability]. / Medicamentos de administración parenteral: recomendaciones de preparación, administración y estabilidad.

OBJECTIVE: To develop recommendations for the preparation of parenteral drugs (MAP), to assess the transferability of their preparation, from nursing units in the hospital ward to the pharmacy service (SF). METHOD: A table of stabilities of parenteral drugs included in the pharmacotherapeutic guideline was developed using the american and spanish guidelines. Information about MAP was collected (method of preparation, support, maintenance, validity, administration specifications and packaging) by consulting product technical sheets, pharmaceutical industries, literature review and databases. RESULTS: After reviewing 209 drugs, a list of recommendations was developed. According to the data, MAP will be prepared as follows: 89 drugs will be prepared from SF, 62 drugs at nursing units because of its immediate administration requirement and 58 are already packed for its administration by the industry. Of these 62 drugs prepared a nursing units, 14 of them will be prepared in the following doses by the SF. Therefore, 48 drugs will be prepared at nursing units from the 209 parenteral drugs reviewed. CONCLUSIONS: A standardized method of preparation, storage, administration and validity of MAP was established by the SF. The preparation of MAP in the SF extends its shelf life, by considering physicochemical stability, level of risk and product vulnerability to microbiological contamination. The information provided will contribute to a reduction of errors associated with the preparation and administration of MAP.

Objetivo: Elaborar unas recomendaciones de preparacion de medicamentos de administracion parenteral (MAP) para valorar la posibilidad de transferir su preparacion, desde las unidades de enfermeria en planta de hospitalizacion al servicio de farmacia (SF). Método: Se procede a elaborar una tabla de estabilidades de los medicamentos incluidos en la guia farmacoterapeutica del Hospital, aplicando la Guia USP (Pharmaceutical compounding Sterile Preparations) y la Guia de de buenas practicas de preparacion de medicamentos en los servicios de farmacia hospitalaria. Se recopilo informacion sobre las MAP: metodo de preparacion, compatibilidad, conservacion, periodo de validez, modo de administracion y tipo de envase. Los datos se obtuvieron mediante consulta de las fichas tecnicas, laboratorios, revision bibliografica y otras bases de datos. Resultados: Tras revisar 209 farmacos se elaboro un listado de recomendaciones. Segun los datos obtenidos, las MAP se prepararan de la siguiente forma: 89 seran preparadas desde el SF, 62 en unidad de enfermeria en planta de hospitalizacion pues son medicamentos que requieren administracion inmediata y 58 ya van acondicionados para su administracion por la industria. De los 62 farmacos que se prepararan por enfermeria, en 14 de ellos las dosis siguientes se prepararan desde el SF. Por lo tanto de los 209 farmacos solo 48 se prepararan exclusivamente en la unidad de enfermeria. Conclusiones: Desde el SF se ha establecido un metodo normalizado de preparacion, conservacion, administracion y periodo de validez de MAP. La preparacion de MAP en SF ampliaria su tiempo de conservacion, al tener en cuenta la estabilidad fisicoquimica, el nivel de riesgo y la vulnerabilidad del preparado a la contaminacion microbiologica. La informacion aportada contribuira a una disminucion de errores asociados al proceso de preparacion y administracion de MAP.

Medicamentos de Administración Parenteral: Recomendaciones de preparación, administración y estabilidad / Parenteral administration medicines: Recommendations of preparation, administration and stability

Objetivo: Elaborar unas recomendaciones de preparación de medicamentos de administración parenteral (MAP) para valorarla posibilidad de transferir su preparación, desde las unidades de enfermería en planta de hospitalización al servicio de farmacia (SF).Método: Se procede a elaborar una tabla de estabilidades delos medicamentos incluidos en la guía farmacoterapéutica del Hospital, aplicando la Guía USP (Pharmaceutical compounding Sterile Preparations) y la Guía de buenas prácticas de preparación de medicamentos en los servicios de farmacia hospitalaria. Se recopiló información sobre las MAP: método de preparación, compatibilidad, conservación, período de validez, modo de administración y tipo de envase. Los datos se obtuvieron mediante consulta de las fichas técnicas, laboratorios, revisión bibliográfica y otras bases de datos. Resultados: Tras revisar 209 fármacos se elaboró un listado de recomendaciones. Según los datos obtenidos, las MAP se prepararán de la siguiente forma: 89 serán preparadas desde el SF,62 en unidad de enfermería en planta de hospitalización pues son medicamentos que requieren administración inmediata y 58 ya van acondicionados para su administración por la industria. De los 62 fármacos que se prepararán por enfermería, en 14 de ellos las dosis siguientes se prepararán desde el SF. Por lo tanto de los 209 fármacos sólo 48 se prepararán exclusivamente en la unidad de enfermería. Conclusiones: Desde el SF se ha establecido un método normalizado de preparación, conservación, administración y período de validez de MAP. La preparación de MAP en SF ampliaría su tiempo de conservación, al tener en cuenta la estabilidad fisicoquímica, el nivel de riesgo y la vulnerabilidad del preparado a la contaminación microbiológica. La información aportada contribuirá a una disminución de errores asociados al proceso de preparación y administración de MAP

Objective: To develop recommendations for the preparation of parenteral drugs (MAP), to assess the transferability of their preparation, from nursing units in the hospital ward to the pharmacy service (SF).Method: A table of stabilities of parenteral drugs included in the pharmacotherapeutic guideline was developed using the american and spanish guidelines. Information about MAP was collected (method of preparation, support, maintenance, validity, administration specifications and packaging) by consulting product technical sheets, pharmaceutical industries, literature review and databases. Results: After reviewing 209 drugs, a list of recommendations was developed. According to the data, MAP will be prepared as follows: 89 drugs will be prepared from SF, 62 drugs at nursing units because of its immediate administration requirement and 58 are already packed for its administration by the industry. Of these 62 drugs prepared a nursing units, 14 of them will be prepared in the following doses by the SF. Therefore, 48 drugs will be prepared at nursing units from the 209 parenteral drugs reviewed. Conclusions: A standardized method of preparation, storage, administration and validity of MAP was established by the SF. The preparation of MAP in the SF extends its shelf life, by considering physicochemical stability, level of risk and product vulnerability to microbiological contamination. The information provided will contribute to a reduction of errors associated with the preparation and administration of MAP

Exposición a fármacos citotóxicos en el personal sanitario / Exposure to cytotoxic drugs among health care professionals

Objetivo: Cuantificar los niveles de exposición del personal sanitario a fármacos citotóxicos con el fin de establecer el nivel umbral de exposición e implantar medidas para incrementar la protección y seguridad. Material y método La cuantificación de la contaminación de 5-fluorouracilo, gemcitabina y ciclofosfamida se llevó a cabo en las superficies de las siguientes áreas: cabina de seguridad biológica clase II tipo B3 (S1), mesa de preparación de tratamientos en antecámara (S2) y mesa de la sala de administración en hospital de día (S3). Se tomaron muestras de las superficies con un paño absorbente a tiempo t0, previo inicio de la sesión de trabajo, y t1, tras 3 h de trabajo mediante arrastre. En cada superficie se calculó el valor de la masa mediana respecto al valor basal y los percentiles 90, 75, 50 y 25 para cada citotóxico en μg/m2.Se comprobó la normalidad de la distribución con la prueba Shapiro-Wilk. El análisis estadístico incluyó las pruebas U de Mann-Whitney, Kruskal-Wallis y Wilcoxon. Se fijó el nivel de significación estadística para valores de p < 0,05.ResultadosSe recogieron un total de 90 muestras en total, 30 muestras por cada superficie de estudio. La masa media registrada de cualquier compuesto citotóxico fue superior en S1 y t1, con un valor de p = 0,017 y p = 0,004, respectivamente. Para cada fármaco citotóxico se fijó como valor objetivo el percentil 25 donde se obtuvieron valores de contaminación indetectables. Conclusiones La introducción de un programa de monitorización continua de superficies de diversos compuestos citotóxicos es esencial para fijar unos niveles aceptables de contaminación residual y reducir la exposición ocupacional (AU)

Objective: To quantify levels of exposure to cytotoxic drugs among health professionals in order to establish an exposure threshold and implement measures to increase protection and safety Material and method: Contamination with 5-fluorouracil, gemcitabine and cyclophosphamide was measured on work surfaces in the following areas: a class II type B3 biological safety cabinet(S1), a treatment prep table in an antechamber (S2) and a desk from the administrative room in the Outpatient Unit (S3). We took samples from the work surfaces by wiping them with an absorbent cloth at time t0, prior to the work session, and at t1 after three hours of work. For each surface, we calculated the median mass value with respect to the baseline value and the90th, 75th, 50th and 25th percentiles for each cytotoxin in g/m2.Distribution normality was assessed using the Shapiro-Wilk test. Statistical analysis included the Kruskal-Wallis and Mann-Whitney-Wilcoxon tests. Statistical significance was established for values of P<.05.Results: We gathered a total of 90 samples, 30 from each of the studied work surfaces. The mean recorded mass of any of the cytotoxic compounds was higher for S1 and t1, with values of P=.017 and P=.004 respectively. The target value for each cytotoxic drug was established at the 25th percentile, where undetectable contamination values were obtained. Conclusions: Introducing a continuous programme to monitor work surfaces for an array of cytotoxic compounds is fundamental in order to establish acceptable levels of residual contamination and reduce exposure in the workplace (AU)

[Exposure to cytotoxic drugs among health care professionals]. / Exposición a fármacos citotóxicos en el personal sanitario.

OBJECTIVE: To quantify levels of exposure to cytotoxic drugs among health professionals in order to establish an exposure threshold and implement measures to increase protection and safety. MATERIAL AND METHOD: Contamination with 5-fluorouracil, gemcitabine and cyclophosphamide was measured on work surfaces in the following areas: a class II type B3 biological safety cabinet (S(1)), a treatment prep table in an antechamber (S(2)) and a desk from the administrative room in the Outpatient Unit (S(3)). We took samples from the work surfaces by wiping them with an absorbent cloth at time t(0), prior to the work session, and at t(1) after three hours of work. For each surface, we calculated the median mass value with respect to the baseline value and the 90th, 75th, 50th and 25th percentiles for each cytotoxin in µg/m(2). Distribution normality was assessed using the Shapiro-Wilk test. Statistical analysis included the Kruskal-Wallis and Mann-Whitney-Wilcoxon tests. Statistical significance was established for values of P<.05. RESULTS: We gathered a total of 90 samples, 30 from each of the studied work surfaces. The mean recorded mass of any of the cytotoxic compounds was higher for S(1) and t(1), with values of P=.017 and P=.004 respectively. The target value for each cytotoxic drug was established at the 25th percentile, where undetectable contamination values were obtained. CONCLUSIONS: Introducing a continuous programme to monitor work surfaces for an array of cytotoxic compounds is fundamental in order to establish acceptable levels of residual contamination and reduce exposure in the workplace.

Modelo predictivo preliminar para la identificación de pacientes con oportunidades de mejora farmacoterapéutica / Preliminary prediction model for identifying patients with the possibility of pharmacotherapy improvement

Objetivo Desarrollar un modelo predictivo para la identificación de pacientes con oportunidades de mejora en la farmacoterapia durante el proceso de validación farmacéutica de la prescripción. Método Estudio transversal de dos meses de duración realizado en los servicios de medicina interna y enfermedades infecciosas. La detección de oportunidades de mejora en la calidad de la farmacoterapia se efectuó mediante validación farmacéutica de la prescripción. A partir de la información obtenida en este proceso se realizó un análisis mediante regresión logística multivariante utilizando como factores pronóstico variables demográficas, farmacoterapéuticas y clínicas relacionadas con la identificación en el paciente de problemas relacionados con la medicación. La validez predictiva del modelo se evaluó mediante la curva de rendimiento diagnóstico y el cálculo de su área. Resultados El modelo predictivo final incluyó las variables edad, fármacos cardiovasculares (digoxina) y fármacos en los que se recomienda el ajuste posológico por insuficiencias orgánicas. El análisis de la curva ROC mostró un área bajo la curva estimada del 84,0% (IC95%: 80,5–87,1), un valor de sensibilidad del 28% (IC95%: 24,07–32,19), un valor de especificidad del 99,10% (IC95%: 97,80–99,73), un valor predictivo para positivos del 77,78% y un valor predictivo para negativos del 92,41%.ConclusiónEl modelo predictivo obtenido permite la detección poblacional del riesgo de seguridad farmacoterapéutica en los pacientes adultos ingresados en los servicios hospitalarios seleccionados. Las variables predictoras manejadas por el modelo son habitualmente utilizadas en la práctica asistencial diaria (AU)

Objective To develop a prediction model for identifying patients with the possibility of improving pharmacotherapy during the process of pharmaceutical validation of the prescription. Method Cross-sectional study over two months, performed in the Internal Medicine and Infectious Disease divisions. Detecting opportunities for improving quality of pharmacotherapy is done by means of a pharmacist's validation of the prescription. Based on the information we obtained through this process, we performed a multivariate logistic regression analysis using as prognostic factors the demographic, pharmacotherapy and clinical variables related to identifying any drug-related problems (DRPs) in the patient. The model's prediction validity was assessed using the diagnostic performance curve and calculating the area under it. Results The final prediction model included the variables age, cardiovascular drugs (digoxin) and drugs for which a dosage adjustment is recommended in the case of organ failures. Analysis of the ROC curve showed an estimated area under the curve AUCROC) of 84.0% (95% CI: 80.5–87.1), a sensitivity value of 28% (95% CI: 24.07–32.19), a specificity value of 99.10% (95% CI: 97.80–99.73), a positive predictive value of 77.78% and a negative predictive value of 92.41%.ConclusionThe resulting prediction model enables population-based detection of pharmacotherapy safety risks in adult patients admitted to the selected hospital units. The predictive variables used by the model are commonly used in daily practice (AU)

[Preliminary prediction model for identifying patients with the possibility of pharmacotherapy improvement]. / Modelo predictivo preliminar para la identificación de pacientes con oportunidades de mejora farmacoterapéutica.

OBJECTIVE: To develop a prediction model for identifying patients with the possibility of improving pharmacotherapy during the process of pharmaceutical validation of the prescription. METHOD: Cross-sectional study over two months, performed in the Internal Medicine and Infectious Disease divisions. Detecting opportunities for improving quality of pharmacotherapy is done by means of a pharmacist's validation of the prescription. Based on the information we obtained through this process, we performed a multivariate logistic regression analysis using as prognostic factors the demographic, pharmacotherapy and clinical variables related to identifying any drug-related problems (DRPs) in the patient. The model's prediction validity was assessed using the diagnostic performance curve and calculating the area under it. RESULTS: The final prediction model included the variables age, cardiovascular drugs (digoxin) and drugs for which a dosage adjustment is recommended in the case of organ failures. Analysis of the ROC curve showed an estimated area under the curve AUCROC) of 84.0% (95% CI: 80.5-87.1), a sensitivity value of 28% (95% CI: 24.07-32.19), a specificity value of 99.10% (95% CI: 97.80-99.73), a positive predictive value of 77.78% and a negative predictive value of 92.41%. CONCLUSION: The resulting prediction model enables population-based detection of pharmacotherapy safety risks in adult patients admitted to the selected hospital units. The predictive variables used by the model are commonly used in daily practice.

Predicting risk of acute rejection in patients with kidney transplants.

OBJECTIVE: Create a model to predict the risk of acute rejection of kidney transplant considering variables related to the immunosuppressant agent used, the receiver, the donor and the transplanted organ. METHODS: Cohort study in a population of 68 patients with kidney transplants being treated with tacrolimus triple therapy. Predicting the risk of acute rejection was carried out with a logistic regression analysis using age, sex, re-transplant status, number of HLA incompatibilities, cold ischaemia time, acute tubular necrosis, induction with basiliximab or thymoglobulin and treatment type as explanatory variables. The contribution of variables associated with determining the blood concentration of tacrolimus was also evaluated; these variables include the average blood concentration, the number of values below and included in the pre-defined therapeutic interval, and the time during which those values remained within that interval. RESULTS: The logistic regression analysis indicates that the risk of acute rejection depends on the acute tubular necrosis (OR: 3; CI 95%, 0.7 to 13.2) and on the time that the blood concentrations of tacrolimus remains within the therapeutic interval (OR: 0.8; CI 95%, 0.7 to 0.9). The final model presents an optimal discrimination power (AUCROC: 77%; CI 95%, 62% to 92%). For the selected cut-off point (probability greater than or equal to 0.24) the model shows a sensitivity of 83% (CI 95%, 74 to 90%) and a specificity of 71% (CI 95%, 61 to 80%). CONCLUSIONS: In patients with kidney transplants, the presence of acute tubular necrosis, together with the time the blood concentration of tacrolimus remained within the predetermined therapeutic interval, permitted the identification of patients with a higher probability of having an acute rejection episode during the first two weeks following the transplant.

Predicción de riesgo de rechazo agudo en pacientes con trasplante renal / Predicting risk of acute rejection in patients with kidney transplants

Objetivo: Construir un modelo para predecir el riesgo de rechazo agudo al trasplante renal considerando variables relacionadas con el tratamiento inmunosupresor instaurado, el receptor, el donante y el órgano trasplantado. Método: Estudio de cohortes en una población de 68 pacientes con trasplante renal en tratamiento con tacrolimus en triple terapia. La predicción del riesgo de rechazo agudo se realizó mediante un análisis de regresión logística utilizando como variables explicativas la edad, sexo, presencia de retrasplante, número de incompatibilidades HLA, tiempo de isquemia fría, necrosis tubular aguda, inducción con basiliximab o timoglobulina y tipo de tratamiento. También se evaluó la contribución de variables asociadas a la determinación de la concentración sanguínea de tacrolimus, entre ellas la media de la concentración sanguínea, el número de valores por debajo e incluidos en el intervalo terapéutico predefinido, y el tiempo que dichos valores permanecían en las condiciones referidas. Resultados: El análisis de regresión logística indica que el riesgo de rechazo agudo depende de la necrosis tubular aguda (odds ratio [OR] = 3; intervalo de confianza [IC] del 95 %, 0,7 a 13,2) y del tiempo que las concentraciones sanguíneas de tacrolimus permanecen dentro del intervalo terapéutico (OR = (..) (AU)

Objective: Create a model to predict the risk of acute rejection of kidney transplant considering variables related to the immunosuppressant agent used, the receiver, the donor and the transplanted organ. Methods: Cohort study in a population of 68 patients with kidney transplants being treated with tacrolimus triple therapy. Predicting the risk of acute rejection was carried out with a logistic regression analysis using age, sex, re-transplant status, number of HLA incompatibilities, cold ischaemia time, acute tubular necrosis, induction with basiliximab or thymoglobulin and treatment type as explanatory variables. The contribution of variables associated with determining the blood concentration of tacrolimus was also evaluated; these variables include the average blood concentration, the number of values below and included in the pre-defined therapeutic interval, and the time during which those values remained within that interval. Results: The logistic regression analysis indicates that the risk of acute rejection depends on the acute tubular necrosis (OR: 3; CI 95 %, 0.7 to 13.2) and on the time that the blood concentrations of tacrolimus remains within the therapeutic interval (OR: 0.8; CI 95 %, 0.7 to 0.9).The final model presents an optimal discrimination power (AUCROC:77 %; CI 95 %, 62 % to 92 %). For the selected cut-off point (probability greater than or equal to 0.24) the model shows a sensitivity of 83 % (CI 95 %, 74 to 90 %) and a specificity of 71 % (CI 95 %, 61 to 80 %).Conclusions: In patients with kidney transplants, the presence of acute tubular necrosis, together with the time the blood concentration of tacrolimus remained within the predetermined therapeutic interval, permitted the identification of patients with a higher probability of having an acute rejection episode during the first two weeks following the transplant (AU)

[Therapeutic exchange of angiotensin II receptor antagonists in patients hospitalised in a traumatology unit]. / Intercambio terapéutico de antagonistas del receptor de angiotensina II en pacientes hospitalizados en una unidad de traumatología.

OBJECTIVE: To analyse the proportion of patients whose blood pressure values have remained within the established therapeutic aim, so as to reduce cardiovascular risk following therapeutic exchange of angiotensin II receptor antagonists (AIIRA.) METHODS: Analytical, observational, prospective, longitudinal study with pre-post analysis. Patients undergoing AIIRA treatment who were not included in the hospital's pharmaco-therapeutic guide were included in the study over those who had undergone a normalised therapeutic exchange of AIIRA. Variable response: proportion of patients whose blood pressure levels (BP levels) remained within the established therapeutic aim for the prevention of cardiovascular accidents. Other variables: systolic and diastolic blood pressure values (SBP and DBP) in the month prior to hospitalisation and after therapeutic exchange, antihypertensive medication, comorbidities. RESULTS: 37 patients were included in the study. Following therapeutic exchange, 81.08 % maintained BP values within the range established by the European Society of Hypertension-European Society of Cardiology Committee. SBP difference: 4.82 (confidence interval [CI] 95 %: 1.09 to 10.74; p = 0.107); DBP difference: 0.15 (CI 95 %: 3.27 to 2.97; p = 0.924), and therefore not clinically significant. CONCLUSIONS: The normalised procedure for therapeutic exchange of AIIRA is effective and safe for patients in terms of maintaining BP, which allows for adequate control of BP during the hospital stay.

Intercambio terapéutico de antagonistas del receptor de angiotensina II en pacientes hospitalizados en una unidad de traumatología / Therapeutic exchange of angiotensin II receptor antagonists in patients hospitalised

Objetivo: Analizar la proporción de pacientes que mantiene los valores de presión arterial (PA) dentro del objetivo terapéutico establecido para reducir el riesgo cardiovascular tras el intercambio terapéutico de antagonistas del receptor de angiotensina II (ARA-II). Métodos: Estudio observacional, analítico, prospectivo y longitudinal, con análisis pre-post. Se incluyeron pacientes en tratamiento con ARA-II no incluidos en la guía farmacoterapéutica del hospital en los que se realizó un intercambio terapéutico normalizado de ARA-II. Variable respuesta: proporción de pacientes que mantienen los valores de PA dentro del objetivo terapéutico establecido para la prevención de accidentes cardiovasculares. Otras variables: valores de PA sistólica (PAS) y diastólica (PAD) el mes previo al ingreso y tras el intercambio terapéutico, medicamentos antihipertensivos, comorbilidades. Resultados: Se incluyó a 37 pacientes. Tras el intercambio terapéutico el 81,08 % de los pacientes mantiene los valores de PA dentro del objetivo establecido por la European Society of Hypertension-European Society of Cardiology Committee. Diferencia PAS: 4,82 (intervalo de confianza [IC] del 95 %, ¿1,09 a 10,74; p = 0,107); diferencia PAD: ¿0,15 (IC del 95 %, ¿3,27 a 2,97; p = 0,924) y, por tanto, sin significación clínica. Conclusiones: El procedimiento normalizado para intercambio terapéutico de ARA-II es efectivo y seguro para los pacientes en términos de mantenimiento de la PA, permitiendo un adecuado control de la PA durante la estancia hospitalaria (AU)

Objective: To analyse the proportion of patients whose blood pressure values have remained within the established therapeutic aim, so as to reduce cardiovascular risk following therapeutic exchange of angiotens in II receptor antagonists (AIIRA.)Methods: Analytical, observational, prospective, longitudinal study with pre-post analysis. Patients undergoing AIIRA treatment who were not included in the hospital’s pharmaco-therapeutic guide were included in the study over those who had undergone a normalised therapeutic exchange of AIIRA. Variable response: proportion of patients whose blood pressure levels (BP levels) remained within the established therapeutic aim for the prevention of cardiovascular accidents. Other variables: systolic and diastolic blood pressure values (SBP and DBP) in the month prior to hospitalisation and after therapeutic exchange, antihypertensive medication, comorbidities. Results: 37 patients were included in the study. Following therapeutic exchange, 81.08 % maintained BP values within the range established by the European Society of Hypertension-European Society of Cardiology Committee. SBP difference: 4.82 (confidence interval [CI] 95 %: —1.09 to 10.74; p = 0.107); DBP difference: —0.15 (CI 95 %: —3.27 to 2.97; p = 0.924), and therefore not clinically significant. Conclusions: The normalised procedure for therapeutic exchange of AIIRA is effective and safe for patients in terms of maintaining BP, which allows for adequate control of BP during the hospital stay (AU)

[Mycophenolate mofetil and cyclosporine in the treatment of steroid-dependent nephrotic syndrome with frequent relapses]. / Micofenolato de mofetilo y ciclosporina en el tratamiento del síndrome nefrótico dependiente de corticoides con recaídas frecuentes.

We describe the case of an 8-year-old patient, with steroid-dependent minimal lesion nephrotic syndrome, with frequent relapses despite treatment with cyclosporine. After the switch to mycophenolate mofetil the patient had new relapses, and there was difficulty in controlling the disease. The reintroduction of cyclosporine combined with mycophenolate mofetil obtained an optimal response, with a longer relapse-free time. Due to their kinetic variability, the blood levels of both drugs were closely monitored during follow-up.

Micofenolato de mofetilo y ciclosporina en el tratamiento del síndrome nefrótico dependiente de corticoides con recaídas frecuentes / Mycophenolate mofetil and cyclosporine in the treatment of steroid-dependent nephrotic syndrome with frequent relapses

Describimos el caso de un paciente de 8 años de edad, con síndrome nefrótico por lesiones mínimas dependiente de corticoides, con recaídas frecuentes a pesar del tratamiento con ciclosporina. Tras la conversión a micofenolato de mofetilo, el paciente sufre nuevas recaídas, con una situación de difícil control de la enfermedad. La reincorporación de la ciclosporina asociada al tratamiento con micofenolato de mofetilo consiguió una remisión de la enfermedad, con un tiempo libre de recaída superior a los obtenidos hasta ese momento, siendo necesario un adecuado seguimiento de las concentraciones sanguíneas de ambos fármacos debido a su variabilidad en el comportamiento cinético

We describe the case of an 8-year-old patient, with steroid-dependent minimal lesion nephrotic syndrome, with frequent relapses despite treatment with cyclosporine. After the switch to mycophenolate mofetil the patient had new relapses, and there was difficulty in controlling the disease. The reintroduction of cyclosporine combined with mycophenolate mofetil obtained an optimal response, with a longer relapse-free time. Due to their kinetic variability, the blood levels of both drugs were closely monitored during follow-up

Evolución temporal de la respuesta farmacoterapéutica: integración de modelos farmacocinéticos y farmacodinámicos (II) / The curse of pharmacotherapeutic response: integration pharmacokinetic and pharmacodynamic models (II)

En la primera parte de este artículo de revisión, se han presentado los modelos farmacodinámicos básicos cuyo conocimiento es imprescindible para establecer las bases de la modelización farmacocinética-farmacodinámica. En esta segunda parte, se inicia la presentación de los modelos PK/PD. Cuando el efecto farmacológico máximo se presenta diferido en el tiempo respecto al que se alcanza la concentración plasmática máxima, los modelos farmacodinámicos directos, no son capaces de describir el comportamiento dinámico de los fármacos. En estos casos, el modelo del compartimento del efecto y/o los modelos de respuestas indirectas entre otros pueden utilizarse para integrar el conocimiento cinético y dinámico del fármaco

Nowadays, the integration of pharmacokinetics and pharmacodynamics concepts is considered as an essential tool to increase the efficiency of clinical trial and a strategy to improve the rational use of medicines. This review presents a description of pharmacokinetics- pharmacodynamics compartimental models that can describe the time course of the clinical endpoints and surrogate markers in subjects receiving pharmacological treatment. In the first part of this review the basic pharmacokinetic models that directly relate drug concentrations to clinical effect are presented together with examples. In the second part we described the pharmacokinetic-pharmacodynamic models used to model the delay observed between plasma concentrations and clinical response. In particular, effect compartment model and basic models of indirect responses are presented with examplesIn the first part of this review, the basic pharmacokinetic models that directly relate drug concentrations to clinical effect were presented. They are essentials to lay the foundations of pharmacokinetic-pharmacodynamic models. In this second part, we describe the PK/PD models when a delay between plasma concentrations and clinical response exits. In this situation, direct pharmacodynamics models are not aplicable and the effect compartment model and/or the basic models of indirect responses has been used to integrated the pharmacokinetic and pharmacodynamic knowledge

[Therapeutic interchange standardization for antiotensin II receptor antagonists in the treatment of hypertension in the hospital setting]. / Normalización del intercambio terapéutico de antagonistas del receptor de la angiotensina-II para el tratamiento de la hipertensión en el medio hospitalario.

INTRODUCTION: Standardization of the therapeutic inter change process in the hospital setting by the establishment and spreading of standard criteria has been defined as an activity conducent to increased health care quality, and hence improved patient care. OBJECTIVE: To establish standardized therapeutic swapping for angiotensin II receptor antagonists (ARA-II) in the treatment of blood hypertension, and to evaluate the suitability of therapeutic interchange in an integrated individualized drug dispensation system. MATERIAL AND METHODS: Standardized therapeutic inter-change was performed based on therapeutic equivalence criteriafor ARA-Ils such as candesartan, eprosartan, irbesartan, losartan,olmesartan, telmisartan, and valsartan, according to the pharmacodynamic characteristics, dosage recommendations, pharmacokinetic characteristics and interactions of each one of them. The suitability of therapeutic interchange was assessed in terms of standardization or adaptation to this practice developed by using percentage adherence in the previous 12 months (period A) and during the 12 months following its implementation and spread(period B). RESULTS: The only ARA-II included in the hospital's pharmacotherapeutic guide is losartan, on which standardized therapeutic interchange for initial and maintenance doses of any drug within this class was based. The overall number of interchanges per-formed was 417-216 during period A and 201 during period B. Implementing therapeutic swapping has significantly increased adherence to explicitly established criteria by 35.2% (95% CI:25.9 to 44.5%). Similarly, during period B a reduction in the variability of therapeutic interchanges among various pharmacists was observed regarding losartan dosage. DISCUSSION: The standardization of therapeutic interchange procedures for ARA-lls allowed a reduction of the variability seen in this process, and hence the potential for medication-related problems. Another benefit of the spread of therapeutic swapping has been an increased adjustment of medical prescriptions to the hospital's pharmacotherapeutic guide.

Evolución temporal de la respuesta farmacoterapéutica: integración de modelos farmacocinéticos y farmacodinámicos (I) / The curse of pharmacotherapeutic response: integration pharmacokinetic and pharmacodynamic models (I)

Actualmente la integración de los conceptos farmacocinéticos y farmacodinámicos no sólo se considera como una herramienta necesaria e imprescindible para incrementar la eficiencia de los ensayos clínicos en humanos sino también como una estrategia de mejora continuada de la utilización de los medicamentos. Los artículos que constiluyen esta revisión presentan una descripción de los modelos farmacocinéticos y farmacodinámicos que desde una perspecliva compartimental permiten describir la evolución de la respuesta clínica de los pacienles en tratamiento farmacológico. En la primera parte de este artículo se describen los modelos farmacodinámicos básicos pues constituyen la base metodológica para modelizar los efectos farmacológicos directamente relacionados con la concentración plasmática. En la segunda parte se introducen los principales modelos farmacocinéticos y farmacodinámicos ampliamente utilizados para modelar el desequilibrio existente entre las concentraciones plasmáticas y la respuesta clínica observada. Así se describe el modelo del compartimento de efecto y el modelo básico de respuestas indirectas

Nowadays, the integration of pharmacokinetics and pharmacodynamics concepts is considered as an essential tool to increase the efficiency of clinical trial and a strategy to improve the rational use of medicines. This review presents a description of pharmacokinetics- pharmacodynamics compartimental models that can describe the time course of the clinical endpoints and surrogate markers in subjects receiving pharmacological treatment. In the first part of this review the basic pharmacokinetic models that directly relate drug concentrations to clinical effect are presented together with examples. In the second part we described the pharmacokinetic-pharmacodynamic models used to model the delay observed between plasma concentrations and clinical response. In particular, effect compartment model and basic models of indirect responses are presented with examplesIn the first part of this review, the basic pharmacokinetic models that directly relate drug concentrations to clinical effect were presented. They are essentials to lay the foundations of pharmacokinetic-pharmacodynamic models. In this second part, we describe the PK/PD models when a delay between plasma concentrations and clinical response exits. In this situation, direct pharmacodynamics models are not aplicable and the effect compartment model and/or the basic models of indirect responses has been used to integrated the pharmacokinetic and pharmacodynamic knowledge

Normalización del intercambio terapéutico de antagonistas del receptor de la angiotensina-II para el tratamiento de la hipertensión en el medio hospitalario / Therapeutic interchange standardization for angiotensin II receptor antagonists in the treatment of hypertension in the hospital setting

Introducción: La normalización del proceso de intercambio terapéutico de medicamentos en el medio hospitalario, mediante el establecimiento y difusión de criterios normalizados, se ha definido como una actividad que conduce a un incremento en la calidad asistencial y, consecuentemente, a una mejora en el cuidado del paciente. Objetivo: Establecer un intercambio terapéutico normalizado para los antagonistas del receptor de angiotensina-II (ARA-II) en el tratamiento de la hipertensión arterial y, evaluar la idoneidad de los intercambios terapéuticos realizados en un sistema integral de dispensación individualizada de medicamentos. Material y métodos: El intercambio terapéutico normalizado se realizó a partir de los criterios de equivalencia terapéutica establecidos para los ARA-II, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan y valsartan, basándose en las características farmacodinámicas, recomendaciones posológicas, características farmacocinéticas e interacciones y, efectos adversos de cada uno de ellos. Se evaluó la idoneidad del intercambio terapéutico, en términos de normalización o adecuación al intercambio terapéutico desarrollado, mediante el cálculo del porcentaje de adherencia al intercambio terapéutico, durante los 12 meses anteriores (periodo A) y los 12 meses posteriores a la implantación y difusión del mismo (periodo B). Resultados: El único ARA-II incluido en la guía farmacoterapéutica del hospital es el losartan, sobre el que se estableció el intercambio terapéutico normalizado para las dosis de inicio y mantenimiento de cualquier fármaco de este grupo terapéutico. El número global de intercambios realizados fue de 417; 216 en el periodo A y 201 en el periodo B. La implantación del intercambio terapéutico ha supuesto un incremento significativo de la adherencia a los criterios explícitos establecidos del 35,2% (IC 95%: 25,9 a 44,5%). Asimismo, durante el periodo B, se ha observado una reducción en la variabilidad de los intercambios terapéuticos realizados entre los distintos farmacéuticos con relación a la posología de losartan. Discusión: La normalización de los procedimientos para el intercambio terapéutico de ARA-II ha permitido reducir la variabilidad observada en este proceso y, con ello, la potencialidad de problemas relacionados con la medicación. Otra ventaja derivada de la difusión de este intercambio terapéutico ha sido el incremento en la adecuación de la prescripción médica a la guía farmacoterapéutica del hospital

Introduction: Standardization of the therapeutic interchange process in the hospital setting by the establishment and spreading of standard criteria has been defined as an activity conducent to increased health care quality, and hence improved patient care. Objective: To establish standardized therapeutic swapping for angiotensin II receptor antagonists (ARA-II) in the treatment of blood hypertension, and to evaluate the suitability of therapeutic interchange in an integrated individualized drug dispensation system. Material and methods: Standardized therapeutic interchange was performed based on therapeutic equivalence criteria for ARA-IIs such as candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan, according to the pharmacodynamic characteristics, dosage recommendations, pharmacokinetic characteristics and interactions of each one of them. The suitability of therapeutic interchange was assessed in terms of standardization or adaptation to this practice developed by using percentage adherence in the previous 12 months (period A) and during the 12 months following its implementation and spread (period B). Results: The only ARA-II included in the hospital's pharmacotherapeutic guide is losartan, on which standardized therapeutic interchange for initial and maintenance doses of any drug within this class was based. The overall number of interchanges performed was 417-216 during period A and 201 during period B. Implementing therapeutic swapping has significantly increased adherence to explicitly established criteria by 35.2% (95% CI: 25.9 to 44.5%). Similarly, during period B a reduction in the variability of therapeutic interchanges among various pharmacists was observed regarding losartan dosage. Discussion: The standardization of therapeutic interchange procedures for ARA-IIs allowed a reduction of the variability seen in this process, and hence the potential for medication-related problems. Another benefit of the spread of therapeutic swapping has been an increased adjustment of medical prescriptions to the hospital's pharmacotherapeutic guide

[Cyclosporin pharmacokinetic modeling in renal transplant patients]. / Modelado farmacocinético de ciclosporina en pacientes con trasplante renal.

AIM: To characterize the pharmacokinetic behavior of oral cyclosporin (CsA) in renal transplant patient, based on through blood concentration (C0) value, and to develop and to evaluate a Bayesian method for the individualized adjustment of CsA daily dose (DD). METHODS: Sixty-seven renal allograft recipients (42 men and 25 women) who had been treated with CsA (Sandimmun Neoral) associated with mycophenolate mofetil (2g daily) and prednisone (0,5-1 mg/kg daily) were randomly divided into two groups. Group A (N=48) was used to characterize CsA pharmacokinetic behavior and Group B (N=19) to evaluate Bayesian predictive performance for the model developed. We evaluated different structural models using non linear mixed effects modeling implemented in the NONMEN computer program in order to quantify the relationship between DD and C0. Accuracy and precision were evaluated by the mean standardized prediction error and its standard deviation. RESULTS: The Michaelis-Menten model was found to be optimum for quantifying the relationship between DD and C0. This model includes time-dependent parameters such as the Michaelis-Menten constant (Km) and daily maximum dose (Dmax) as well as first order autoregressive terms DD and C0 included in the structural model in an additive way. In the final model, the Dmax parameter is affected by plasmatic urea values and shows a half-life stabilization time of 90.90 days (95% CI: 52.60 to 250 days). Plasmatic urea values of 50 mg/dL are related to an initial Dmax value of 3 mg/kg daily (95% CI: 1.81 to 4.19 mg/kg daily) which decreases exponentially throughout the post-transplant period until it reaches a constant value of 2.16 mg/kg daily (95% CI: 1.41 to 2.91 mg/kg daily) In the same way, the Km parameter presents a central tendency value of 93.60 ng/mL (95% CI: 28.60 to 158.60 ng/mL) and the half-life necessary for its stabilization is 12.70 days (95% CI: 9.80 to 17.90 days). The residual variability of the model is 8.2%. The mean value of standardized prediction errors for populations and its standard deviation, as well as its confidence intervals of 95%, confirm the appropriate accuracy and precision of both a priori and a posteriori predictions with this model. Also, it reached between 70 and 100% a posteriori sequential predictions with prediction errors below 10%. CONCLUSION: The characterization of the pharmacokinetic behavior of CsA requires us to consider parameters such as Dmax and Km as non lineal functions of time, while the first order autoregressive terms DD and C0 must also be incorporated into the model.

[Pharmacy Department standard procedures for clinical trial development]. / Procedimientos normalizados del Servicio de Farmacia para el desarrollo de los ensayos clínicos.

INTRODUCTION: Regulations on good clinical practice in the execution of clinical trials require the establishment and compliance of normalised working procedures by the hospital Pharmacy Department. These procedures must indicate precisely each one of the processes involved in their development, e.g. the reception, custody, storage, preparation and dispensing of research samples. OBJECTIVE: The aim of the present study is to analyse the information included in clinical trial protocols involved in the circulation of drug samples during the research stage and, based on the results obtained, to develop normalised working procedures for our hospital Pharmacy Department in order to carry out these clinical trials. MATERIAL AND METHODS: Eleven items were defined in order to describe key processes involved in identification, storage, receipt, preparation, dispensation, administration, maintenance and return of research samples, as well as those related to the beginning and end or closing of a clinical trial. Information included in 39 clinical trial protocols that had been sent to the Hospital Ethics Committee for evaluation between January and August of 2002 and was analysed in terms of the items previously defined. RESULTS: 46% of the protocols included data from the monitor or person representing the sponsor. 64% adequately described conservation and storage conditions of the research samples; but in 39% of the studied cases external labelling descriptions did not comply with legislation. Only 15% of the cases included clear instructions on research sample reception and its acknowledgement. 25.6% reported correct handling and/or preparation instructions for research samples with parenteral administration. Sample dispensation procedures were correctly described in no more than 5.1% of the protocols analyzed. 41% included information for patients, relatives or nurses on administration and handling of research samples, but none of them included specific information pamphlets or three-page leaflets. Procedures for either returning research samples to the sponsor or for their maintenance and replacement were not specified in the 71.8 and 100% of the cases, respectively. Likewise, trial ending or closing dates as well as procedures that must be followed by the Hospital Pharmacy Department during these processes were not stated in 89.7% of the protocols. Finally, only 30.8% of the cases explicitly cite the hospital Pharmacy Department. CONCLUSION: These results support and justify the need to improve clinical trial protocols in order for them to be performed in a secure, effective and efficient way. Besides, they have been the starting point to devise the normalised working procedures of the hospital Pharmacy Department for the development of the clinical trials.

Análisis de la calidad de las determinaciones de ciclosporina mediante inmunofluorescencia polarizada indirecta / Analysis of the quality of cyclosporine determinations by indirect polarized immunofluorescence

El objetivo del presente trabajo es optimizar la determinación de CsA en sangre total mediante inmunofluorescencia polarizada indirecta con la finalidad de asegurar la calidad de la información obtenida en la monitorización de este fármaco. El análisis de la calidad de la determinación de CsA en sangre total mediante la técnica de inmunofluorescencia polarizada indirecta se ha realizado mediante la valoración de la precisión y la exactitud en la determinación de concentraciones conocidas de CsA (controles). La optimización de la calidad de la determinación de CsA se ha realizado mediante el establecimiento y la validación de los límites de alerta y de invalidación asociados a los controles de forma individual (precisión) y poblacional (exactitud). Finalmente se procedió a la caracterización del modelo de error de la técnica analítica empleada. El análisis de los límites de precisión evidencia una similitud entre los límites de invalidación obtenidos en nuestro laboratorio y los recomendados por el laboratorio fabricante. Resulta de gran utilidad práctica disponer de límites de alerta con el fin de determinar con mayor sensibilidad la presencia de valores de concentraciones de referencia sesgados. No obstante, definir un intervalo de alerta más estrecho que el intervalo de invalidación permite equiparar dos determinaciones consecutivas fuera de los límites de alerta con una determinación fuera de los límites de invalidación. El análisis global de la exactitud exige la utilización de la media móvil con el fin de evidenciar tendencias sistemáticas en la determinación de los fármacos. El modelo de error para la determinación de CsA mediante inmunofluorescencia polarizada indirecta en nuestra unidad de farmacocinética clínica es un modelo proporcional con un coeficiente de variación inferior a 6 por ciento (AU)