Impact of nutritional status on the pharmacokinetics of erlotinib in rats.

Malnourishment is a complex condition in which physiopathological changes take place in multiple systems as a result of energy, protein and nutrient deficiency. The purpose of this study was to evaluate, using an experimental animal model, the impact of nutritional status on the pharmacokinetic profile of erlotinib, a reversible, highly selective, human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Two groups of rats -WN (well-nourished) and UN (undernourished) - were fed with different diets for 23-26 days. Rats were assigned randomly to one of three erlotinib treatments (n = 42) consisting of a single dose administered intravenously (i.v.), via oral solution or via oral suspension. Blood samples were assayed for erlotinib concentration. A population pharmacokinetic model was developed and pharmacokinetic parameters obtained in UN rats were compared with those in WN rats. Erlotinib clearance suffered a 5% decrease in the mild-undernutrition status. Moreover, when the drug was administered orally as a suspension, the extent and rate of absorption underwent a 20% increase in UN rats. The results of this study might help to explain, at least in part, the variability of erlotinib treatment and could represent the first step towards establishing new dosage guidelines for the treatment of undernourished cancer patients. Copyright © 2015 John Wiley & Sons, Ltd.

Development and application to clinical practice of a validated HPLC method for the analysis of ß-glucocerebrosidase in Gaucher disease.

The main objective of our study is to develop a simple, fast and reliable method for measuring ß-glucocerebrosidase activity in Gaucher patients leukocytes in clinical practice. This measurement may be a useful marker to drive dose selection and early clinical decision making of enzyme replacement therapy. We measure the enzyme activity by high-performance liquid chromatography with ultraviolet detection and 4-nitrophenyl-ß-d-glucopyranoside as substrate. A cohort of eight Gaucher patients treated with enzyme replacement therapy and ten healthy controls were tested; median enzyme activity values was 20.57mU/ml (interquartile range 19.92-21.53mU/ml) in patients and mean was 24.73mU/ml (24.12-25.34mU/ml) in the reference group, which allowed the establishment of the normal range of ß-glucocerebrosidase activity. The proposed method for leukocytes glucocerebrosidase activity measuring is fast, easy to use, inexpensive and reliable. Furthermore, significant differences between both populations were observed (p=0.008). This suggests that discerning between patients and healthy individuals and providing an approach to enzyme dosage optimization is feasible. This method could be considered as a decision support tool for clinical monitoring. Our study is a first approach to in depth analysis of enzyme replacement therapy and optimization of dosing therapies.

[Measurement of continuous improvement in the safety of oncologic patients]. / Medida de la mejora continua en la seguridad del paciente oncológico.

OBJECTIVE: To analyze continuous improvement in the safety of oncologic patients through the change of quality indicators established with the implementation of a quality management system (QMS) according to the ISO 9001-2008 regulation at a oncologic pharmacy unit (OPU). METHOD: Prospective and observational study carried out between January of 2008 and December of 2011. The ISO 9001-2008 certification of the OPU included the proceedings of electronic prescription,validation, preparation, delivery, and administration of the antineoplastic therapy. The following quality indicators were established: medication errors (ME), preparation and delivery errors not reaching the patient, and ME reaching the patient. The indicators were calculated quarterly through the Farmis-Oncofarm® software; the adherence standard was defined at ≤ 1 ME per one thousand and the follow-up was done through control graphs. One « post-implementation ¼ period (2008-2011) and one « pre-implementation ¼ period (2007) were established and the U Mann Whitney test was used to compare the median of the indicator for both periods.The differences between the two periods were considered to be statistically significant when the p value was p ≤ 0.05. RESULTS: 140,440 preparations were made at the OPU, for 4,770 patients, corresponding to 52,906 patients-day. The adherence to the standard during the first one-year period allowed reducing the three indicators to ≤ 0,5 ME per one thousand. For preparation ME an abnormal value was identified; the causes were analyzed and improvement measures were proposed. In the post-implementation period, ME were reduced during the post-implementation period as compared to the pre-implementation period (p<0.05). CONCLUSIONS: The follow-up of the quality indicators allows measuring and assessing the pharmaco-therapy safety in the oncologic patient. After the implementation of the QMS at the OPU, the number of ME has been reduced.

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.

Aceptación de recomendaciones en el paciente con oportunidades de mejora farmacoterapéutica / Doctors’ acceptance of recommendations for patients with the opportunity for pharmacotherapy improvement

Objetivo: Identificar y cuantificar la influencia de diferentes variables en la implantación de medidas de optimización farmacoterapéutica en pacientes ingresados. Método Estudio descriptivo, transversal. Período: 2000–2007. Ámbito: hospital general universitario público (25.000 pacientes ingresados/año).El Programa de Mejora de la Calidad de la Farmacoterapia y la Seguridad del Paciente implantado da cobertura al 30% de los pacientes. A partir de los registros del aplicativo Atefarm® Farmis, se analizaron las recomendaciones farmacoterapéuticas (RF) realizadas por los farmacéuticos al médico. Las variables seleccionadas fueron las siguientes: riesgo del medicamento (problema relacionado con el medicamento [PRM]) (0, bajo; 1, alto), categoría del PRM, (0, indicación; 1, efectividad; 2, seguridad), gravedad potencial (escala 1–5), impacto de la RF (0, efectividad; 1, seguridad; 2, eficiencia) e implantación de la RF (sí/no).Se calculó la frecuencia (%) y el intervalo de confianza del 95% (IC95%) de las variables categóricas y se realizó un análisis de regresión logística multivariante para identificar el grado de influencia de las variables en la implantación de las RF. Resultados Se identificaron 7.920 PRM en 4.680 pacientes. En el 85% (6.762) de los PRM se realizó una RF, que se implantó en el 83% (IC95%: 74,2–89,8). La gravedad potencial del PRM superior o igual a 2 (OR: 1,57; IC95%: 1,27–1,94) y la categoría del PRM de efectividad y seguridad (OR: 1,19; IC95%: 1,02–1,39) se manifestaron como determinantes de la implantación de la RF en el paciente. Conclusiones La probabilidad de implantación de RF en el paciente está relacionada con la gravedad potencial y la categoría del PRM identificado. Así, las recomendaciones orientadas a mejorar la efectividad de la farmacoterapia o la seguridad del paciente, y con consecuencias clínicas potenciales presentan mayor éxito en su aplicación al paciente(AU)

Objective: To identify and quantify the influence of different variables on the implementation of pharmacotherapy optimisation measures in hospitalised patients. Method: Descriptive transversal study. Period: 2000—2007. Environment: public university general hospital (25,000 patients admitted/year).The Programme implemented to improve pharmacotherapy quality and patient safety covers30% of all patients. Using records from the Atefarm®Farmis application, we analysed pharmacotherapy recommendations (PRs) made by pharmacists to doctors. The selected variables were the following: Risk of the medication for ADE (1-high, 0-low), ADE category, (0-indication, 1-effectiveness, 2-safety), potential severity (scale of 1 to 5), impact of the PR (0-effectiveness,1-safety, 2-efficiency) and implementation of the PR (yes/no).We calculated the frequency (%) and 95% CI for the categorical variables and performeda multivariate logistical regression analysis to identify the variables’ degree of influence onimplementing the PRs. Results: We identified 7920 ADEs in 4680 patients. A PR was issued in 85% of the cases (6762),and it was implemented in 83% (95% CI 74.2—89.8). Potential severity of the ADE ≥2 (OR 1.57;95% CI 1.27—1.94), and ADE category for effectiveness and safety (OR 1.19; 95% CI 1.02—1.39)were shown to be determining factors for implementing the PR for the patient. Conclusions: The probability that a PR will be implemented for a patient is related to the potential severity and the category of the identified ADE. Therefore, recommendations intended to improve effectiveness of pharmacotherapy or patient safety, and those with potential clinical consequences have a greater chance of being applied to a patient (AU)

Animal model of undernutrition for the evaluation of drug pharmacokinetics.

BACKGROUND: Protein energy malnutrition is a public health problem affecting a great number of people. Pathophysiological imbalances in malnourished individuals have a profound impact on drug pharmacokinetics. OBJECTIVE: To develop an animal model of undernutrition using male Wistar rats to be used to assess, in further studies, the impact of nutritional status on the oral bioavailability and pharmacokinetics of drugs. DESIGN: [corrected] Animals were randomly assigned to one of two groups and fed different diets for 26 days: WN (well-nourished/regular diet, N = 61) and UN (under-nourished/protein-calorie restricted diet, N = 72). Assessment of the animals' nutritional status was performed taking into account serum albumin, total cholesterol level and total body weight. A kinetic model incorporating population kinetic analysis (NONMEM) was developed to analyze body weight versus time profiles in the adaptation period following administration of the two aforementioned diets. RESULTS: Serum albumin plasma levels were lower than 2.3 g/dL in 80% (60/72) of malnourished animals at the end of the adaptation period. The range of the total serum cholesterol was similar in both groups at the end of the adaptation period. Total body weight in all cases was less than 230 g for malnourished animals and higher than 240 g for well-nourished animals. The kinetic model assayed was confirmed to be an expansion module characterized by linear weight gain and a decline module characterized by exponential weight loss, where the weight loss rate constant is an exponential function of time. The bootstrap resampling method confirmed the stability of the model eventually selected. CONCLUSIONS: The animal model developed in this study is reliable and could be of use in evaluating the impact of nutritional state on the pharmacokinetics of drugs. The proposed mathematical model allows the body weight of animals to be predicted at a given time taking into account the diet followed in the experimental period.

Doctors' acceptance of recommendations for patients with the opportunity for pharmacotherapy improvement.

OBJECTIVE: To identify and quantify the influence of different variables on the implementation of pharmacotherapy optimisation measures in hospitalised patients. METHOD: Descriptive transversal study. PERIOD: 2000-2007. ENVIRONMENT: public university general hospital (25,000 patients admitted/year). The Programme implemented to improve pharmacotherapy quality and patient safety covers 30% of all patients. Using records from the Atefarm(®) Farmis application, we analysed pharmacotherapy recommendations (PRs) made by pharmacists to doctors. The selected variables were the following: Risk of the medication for ADE (1-high, 0-low), ADE category, (0-indication, 1-effectiveness, 2-safety), potential severity (scale of 1 to 5), impact of the PR (0-effectiveness, 1-safety, 2-efficiency) and implementation of the PR (yes/no). We calculated the frequency (%) and 95% CI for the categorical variables and performed a multivariate logistical regression analysis to identify the variables' degree of influence on implementing the PRs. RESULTS: We identified 7,920 ADEs in 4,680 patients. A PR was issued in 85% of the cases (6,762), and it was implemented in 83% (95% CI 74.2-89.8). Potential severity of the ADE ≥2 (OR 1.57; 95% CI 1.27-1.94), and ADE category for effectiveness and safety (OR 1.19; 95% CI 1.02-1.39) were shown to be determining factors for implementing the PR for the patient. CONCLUSIONS: The probability that a PR will be implemented for a patient is related to the potential severity and the category of the identified ADE. Therefore, recommendations intended to improve effectiveness of pharmacotherapy or patient safety, and those with potential clinical consequences have a greater chance of being applied to a patient.

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)

Genetic polymorphisms and individualized tacrolimus dosing.

BACKGROUND: Genetic polymorphisms of metabolism enzymes or intestinal drug transporters may affect pharmacokinetic responses to immunosuppressive drugs in renal transplant recipients. We sought to identify the frequency of genetic polymorphisms and their importance for individualization of tacrolimus doses. PATIENTS AND METHODS: We performed an observational study in 35 renal transplant recipients treated with tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus concentrations were determined by immunoanalysis (IMx method; Abbott Diagnostics, Abbott Park, Ill), on 11 blood samples per patient during the first 6 weeks after renal transplantation. For each patient, we calculated the mean value and its standard error (SEM) of the concentration/dose ratio (ng/mL/mg) of tacrolimus. The pharmacogenetic analysis included single nucleotide polymorphisms (SNPs) in the CYP3A5 (CYP3A5*3 (A6986G), CYP3A5*6 (G14690A), MDR1 (C3435T and G2677T/A) and PXR (C-25385T) genes. RESULTS: Of the patients, 62.8% (n=22) were men and the overall mean age was 55 years (95% confidence interval, 48.7-62.7). The SNP distribution was: CYP3A5*3: G/G=82.9%, A/G=17.1%; CYP3A5*6: G/G=88.6%, G/A=11.4%; MDR1 C3435T: C/C=25.7%, C/T=62.9%, T/T=11.4%; for MDR1 G2677T/A: G/G=22.9%, G/T=65.7%, T/T=11.4% and for PXR: C/T=85.7%, T/T=14.3%. Tacrolimus concentration/dose ratios in heterozygote patients for CYP3A5*3 genotypes was >120% lower than for the homozygote CYP3A5*3 genotype (0.65±0.04 vs 1.45±0.05; P<.0001). Wild-type MDR1 (3435 C/C) genotype patients showed up to 40% lower concentration/dose ratios compared with heterozygote and homozygote genotypes (C/C; 1±0.07 vs C/T; 1.4±0.06 vs T/T; 1.37±0.09; P<.0001). CONCLUSION: Intestinal absorption and metabolism of tacrolimus was significantly affected by the SNPs in the CYP3A5 and MDR1 genes, which may offer a useful tool to optimize tacrolimus dosing after renal transplantation.

[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.

[Antineoplastic oral agents and drug-nutrient interactions: a sistematic review]. / Interacción de los antineoplásicos orales con los alimentos: revisión sistemática.

INTRODUCTION: Studies on bioavailability are part of the clinical development of drugs for oral use in order to identify potential drug-food interactions. For oral antitumor drugs, their clinical importance is currently recognized although regrettably the information available presents variability concerning the scientific evidence. OBJECTIVES: To review the available scientific evidence about oral anti-tumor medications and establish the recommendations for their administration with foods. METHODS: We carried out a bibliographic search in Medline and The Cochrane Library for the period January of 1966 to March of 2008, focused on identifying those publications about drug-food interactions with oral antitumor medications. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles in which the title or their content did not correspond with the objective settled; during the second phase, we deleted all the references duplicated in both databases. The inclusion criteria to select the articles were: design (systematic reviews, meta-analysis, Phase I and Phase II randomized clinical trials), population (adult patients; >19 years of age), intervention evaluated (administration of oral anti-tumor drugs under fasting conditions or with food) and measurement of the iFA results (calculation of the 90% CI of the odds ratio between the geometric mean of the values under the curve of the plasma concentrations (ABC) or the maximal plasma concentration (Cmax) with and without foods). We excluded those publications that did not make reference to the bioequivalence dictamen established by the Food and Drugs Administration (FDA) in their outcomes measurement. A critical appraisal of the selected articles was done according to the recommendations that the FDA established to be met by these studies. RESULTS: At the initial search we obtained 850 references (98.5% Medline + and 1.4% Cochrane). During the first phase, we excluded 87.7% (746) of the articles, 100% of them corresponding to the search in Medline. During the second phase, 40 studies remained (5.2% of the initial ones) for full-text critical appraisal, to which four studies were added not indexed in Medline. From the critical appraisal of the 44 final articles, 25 were excluded (20 original articles, 4 short communications, and 1 meta-analysis) because they did not include as an outcome measure the bioequivalence dictamen. The 19 (2.2%) remaining articles provided information on 19 oral anti-tumor drugs in 210 patients and 146 healthy volunteers. Of these 19 drugs, 63% did not present drug-food interactions, with the possibility of administering them either with or without food; 21% have to be administered with foods and only 16% present drug-food interactions, so they have to be administered without foods. DISCUSSION: Currently, the clinical importance of drug-food interactions with oral anti-tumor drugs is identified more directly with the patient's safety than with the efficacy of the therapy. Given the development of these oral agents, their incorporation into the oncologic strategy displacing parenteral therapy, with monthly costs of thousands of Euros, it is necessary to perform well-designed studies on pharmacokinetics and pharmacodynamics. Their goal has to be comparing their bioavailability in the presence or absence of foods with the clinical response. In the meanwhile, to establish recommendations for their administration in relation to foods is inconsistent for some of these drugs and their results is uncertain given the lack of studies based on the FDA bioequivalence dictamen.

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.

Management of returned anti-neoplastic treatments and their reuse in oncology patients.

OBJECTIVE: Analyse the profile of parenteral preparation and treatment (anti-neoplastic and supplementary) that were dispensed and returned to the Pharmacy Department, the reasons why they were not administered, their reuse and the associated direct costs. METHOD: Longitudinal study over eight months (October 2004-May 2005) in a tertiary hospital with centre for preparing anti-neoplastic agents (including supplementary treatment) in its Pharmacy Department. The variables studied, downloaded from the Oncofarm® application, are as follows: (a) patients and diagnostics; (b) returned treatments, classified by reason returned, pharmaco-therapeutic scheme, cycle and day; (c) returned preparations (anti-neoplastic and supplementary) that were reused; and (d) direct costs. Data is presented with its absolute and relative frequencies and confidence intervals of 95% normalised at 1000 patients/day. RESULTS: 84 treatments were returned by 66 patients for a total of 139 preparations corresponding to 3,429 patients/day. This figure represents 24.5 (CI 95%, 19.6 to 30.2) treatments that were prepared and not administered per 1,000 patients/day, mainly due to clinical causes (n = 47). Colon neoplasia and treatment with 5-fluorouracil and levofolinic acid presented the highest number of returns. The returned preparations made up 1.45 % (CI 95%, 1.2 to 1.7) of those produced. The percentage of reuse is 98%, which results in savings of euro 10,432.55 (90% of the cost of the treatments that are returned). CONCLUSIONS: The application of quality, effectiveness and safety criteria to anti-neoplastic treatments that are prepared and returned to the Pharmacy Department allows a more efficient preparation process.

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)

Gestión de la devolución de tratamientos antineoplásicos y de su reutilización en pacientes oncológicos / Management of returned anti-neoplastic treatments and their reuse in oncology patients

Objetivo: Analizar el perfil de tratamientos y preparaciones parenterales (antineoplásicas y de soporte) dispensados y devueltos al servicio de farmacia, las causas de no administración, su reutilización y los costes directos asociados. Método: Estudio longitudinal, prospectivo, durante 8 meses (octubre 2004-mayo 2005) en un hospital terciario con centralización de la preparación de esquemas antineoplásicos (incluye tratamiento de soporte) en el servicio de farmacia. Las variables estudiadas, descargadas del aplicativo Oncofarm®, fueron: a) pacientes y diagnósticos; b) tratamientos devueltos, diferenciando por causa, esquema farmacoterapéutico, ciclo y día; c) preparaciones devueltas (antineoplásicos y soporte) y reutilizadas, y d) costes directos. Los datos se presentan con sus frecuencias absolutas, relativas e intervalos de confianza (IC) del 95 %, normalizado a 1.000 pacientes/día. Resultados: 84 tratamientos devueltos de 66 pacientes con un total de 139 preparaciones correspondientes a 3.429 pacientes/día. Este dato representa 24,5 (IC del 95 %, 19,6 a 30,2) de tratamientos preparados y no administrados por 1.000 pacientes/día, debido, mayoritariamente, a causas clínicas (n = 47). La neoplasia de colon y el esquema de 5-fluorouracilo y ácido levofolínico presentan el mayor número de devoluciones. Las preparaciones devueltas suponen el 1,45 % (IC del 95 %, 1,2 a 1,7) de las elaboradas. El porcentaje de reutilización es del 98 %, con un coste ahorrado que asciende a 10.432,55 (90 % del coste de los tratamientos devueltos).Conclusiones: La aplicación de criterios de calidad, eficacia y seguridad a los tratamientos antineoplásicos preparados y devueltos al servicio de farmacia permite incrementar la eficiencia en el proceso de preparación (AU)

Objective: Analyse the profile of parenteral preparation and treatment (anti-neoplastic and supplementary) that were dispensed and returned to the Pharmacy Department, the reasons why they were not administered, their reuse and the associated direct costs. Method: Longitudinal study over eight months (October 2004-May 2005) in a tertiary hospital with centre for preparing anti-neoplastic agents (including supplementary treatment) in its Pharmacy Department. The variables studied, downloaded from the Oncofarm® application, are as follows: a) patients and diagnostics; b) returned treatments, classified by reason returned, pharmaco-therapeutic scheme, cycle and day; c) returned preparations (anti-neoplastic and supplementary) that were reused; and d) direct costs. Data is presented with its absolute and relative frequencies and confidence intervals of 95 % normalised at 1000 patients/day. Results: 84 treatments were returned by 66 patients for a total of 139 preparations corresponding to 3,429 patients/day. This figure represents 24.5 (CI 95 %, 19.6 to 30.2) treatments that were prepared and not administered per 1,000 patients/day, mainly due to clinical causes (n = 47). Colon neoplasia and treatment with 5-fluorouracil and levofolinic acid presented the highest number of returns. The returned preparations made up 1.45 % (CI 95 %, 1.2 to 1.7) of those produced. The percentage of reuse is 98 %, which results in savings of € 10,432.55 (90 % of the cost of the treatments that are returned).Conclusions: The application of quality, effectiveness and safety criteria to anti-neoplastic treatments that are prepared and returned to the Pharmacy Department allows a more efficient preparation process (AU)

Cisplatin preparation error; patient management and morbidity.

INTRODUCTION: Antineoplastic drug therapy errors represent a high iatrogenic potential due to antineoplastic drugs narrow therapeutic ranges and the complexity of chemotherapy regimens that may increase the risk of morbidity and mortality for oncology patients. SETTING: We report a 57-year-old man with head and neck cancer who mistakenly received 180 mg/ m(2) of cisplatin overdose despite the safety measures and validations carried out during preparation. The patient developed moderate nausea and vomiting, acute renal failure, hearing difficulty (tinnitus), and severe myelodepression. PATIENT MANAGEMENT: Prophylactic and symptomatic treatments were applied in order to prevent and correct toxicity during the 9 days stay at hospital. RESULT: He recovered with mild tinnitus and mild renal impairment as the only sequelae. This case presents a hospital stay and treatment quite different to others used to reverse all cisplatin overdose toxicity and it shows the benefits of prompt management.

Estabilidad de haloperidol-butilescopolamina-midazolamen sistemas de infusión continua de 24 horas / No disponible

Objetivo: determinar la estabilidad de la mezcla ternaria haloperidolbutilescopolamina-midazolam para establecer su validez terapéutica. Material y método: se estudiaron mezclas ternarias de haloperidol, butilescopolamina (Br), y midazolam, utilizando como vehículo glucosa 5%, a concentraciones de 0,2 y 0,8 mg/ml para haloperidol. Para los otros dos componentes la concentración (1,2 mg/ml) permaneció invariable. El estudio se realizó bajo condiciones asépticas, a temperatura ambiente, sin fotoprotección, por duplicado y durante un periodo de 84 horas. Como criterios de compatibilidad física: cambio de color, aparición de opalescencia, variación de peso y pH. La estabilidad química de los componentes se evaluó mediante cromatografía líquida de alta resolución ultravioleta-visible. Como parámetro de validez clínica se empleó el T90, considerando para su cálculo el valor obtenido al interpolar el límite inferior del intervalo de confianza del 95% de la recta representativa de la cinética lineal, para una concentración del 90% de la concentración inicial de los componentes. Resultados: los valores de las concentraciones de los componentes se ajustaron a una cinética de orden uno. El valor de T90 obtenido no fue inferior a 72 horas en las mezclas estudiadas. Durante las 84 horas que duró el ensayo ninguna de las mezclas presentó cambio de color, aparición de opalescencia, variación de peso ni de pH. Conclusión: las mezclas intravenosas a las concentraciones estudiadas de haloperidol (hasta 0,8 mg/ml), butilescopolamina (Br) (1,2 mg/ml) y midazolam (1,2 mg/ml), preparadas en glucosa 5%, en sistemas de infusión elastoméricos portátiles, son físicamente compatibles y químicamente estables durante al menos 72 horas (AU)

Objective: to determine the stability of ternary mixtures of haloperidol, midazolam, and scopolamine in order to establish their therapeutic validity. Material and methods: ternary mixtures of haloperidol, scopolamine, and midazolam were prepared in 5% glucose as vehicle at concentrations of 0.2 and 0.8 mg/mL for haloperidol. Concentration (1.2 mg/mL) remained invariable for the other two components. The study was conducted under aseptic conditions, at room temperature, without photoprotection, in duplicate, and during a period of 84 hours. Chemical stability was evaluated by high pressure liquid chromatography, and physical compatibility by changes in colour, development of opalescence, and changes in weight and pH. The T90 parameter was used to establish clinical validity, and was calculated for each drug in the mixture by considering the time at which the 95% one-sided confidence limit for the mean curve intersects 90% of the drug's initial concentration. Results: concentrations were adjusted to a first-order kinetic equation. The value of T90 was obtained after no less than 72 hours in the mixtures studied. During the 84-hour test none of the mixtures developed changes in colour, opalescence, or changes in weight or pH. Conclusion: the intravenous mixtures studied, consistent of haloperidol (up to 0.8 mg/mL), scopolamine (1.2 mg/mL), and midazolam (1.2 mg/mL) prepared in 5% glucose within elastomeric portable infusion systems, are physically compatible and chemically stable for at least 72 hours (AU)