Therapeutic drug monitoring of tumour necrosis factor inhibitors in the management of chronic inflammatory diseases.

Tumour necrosis factor inhibitor therapy has drastically changed the management of chronic inflammatory diseases. Some important drawbacks that can cause loss of response during treatment with these drugs are related to their large individual variability, the disease burden and the formation of antidrug antibodies that increase its clearance. Therapeutic drug monitoring of these drugs is not yet recommended by all scientific societies, and if so, only in patients with inflammatory symptoms. Proactive therapeutic drug monitoring represents a new strategy with many potential clinical benefits, including the prevention of immunogenicity, a reduction in the need for rescue therapy and greater durability of tumour necrosis factor inhibitor treatment. The review is based on a systematic search of the literature for controlled trials, systematic reviews, experimental studies, guideline papers and cohort studies addressing the best practice in tumour necrosis factor inhibitor therapeutic drug monitoring. Although there is ample evidence supporting the use of therapeutic drug monitoring in clinical practice to achieve better outcomes, some challenges have been detected. Many studies are focused on finding solutions for the lack of standardization of analytical methods to measure tumour necrosis factor inhibitor and antidrug antibodies concentrations. Other challenges are development of effective cost-saving proactive algorithms to identify optimal drug concentrations and the research on the role of antidrug antibodies, especially in the management and prevention of loss of response. Therapeutic drug monitoring of tumour necrosis factor inhibitor offers a rational approach to the optimization of the treatment of chronic inflammatory disease. Although prospective controlled trials yield little conclusive evidence of its benefits, there is growing acceptance of its value in clinical practice.

Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients.

BACKGROUND: In anesthesia with propofol, variability persists besides sophisticated effect targeting. Drug formulation may be another factor. We have analyzed, retrospectively, the pharmacokinetics (PK) and pharmacodynamics (PD) in monitored surgery patients anesthetized with one each of five formulations of propofol. METHODS: Propofol 1% ('form' 1: Diprivan(Zeneca Limited, Macclesfield, UK), 2: Recofol(Schering Espana, Madrid, Spain), 3: Ivofol(Juste, Madrid, Spain), 4: Propofol Abbott (Abbott Laboratories, Madrid, Spain), 5: Fresenius (Fresenius Kabi Espana, Barcelona, Spain)) was administered to 77 ASA I-II patients of age [mean (range) 44 (18-65) years]. Induction of anesthesia was with varying propofol doses up to endpoints of either 60 on the Bispectral Index system (BIS) in group I (n = 48, model development) or standard clinical signs in group II (n = 29, validation). Maintenance was with three 10-min infusions of 10, 8 and 6 mg kg(-1) h(-1). Three blood samples were obtained from each subject, immediately after induction, and at 15 and 30 min on maintenance, with BIS and hemodynamic variables recorded at these times also. Total and free blood concentrations (Cb) of propofol were determined with HPLC. Pharmacokinetic and PD models with link equilibration rate ke0, were studied with a mixed-effects procedure (NONMEM). RESULTS: The induction dose (group I) showed large interindividual variability [mean (range) 163 (90-290 mg)] that correlated significantly with age, basal systolic blood pressure and formulation. The PK of propofol (basic model) was described by a one-compartment model with (typical value [interindividual coefficient of variation percent (CV%)]) CL=2.30 l min(-1) (27%) and V=8.40 l (80%). Weight (WT) and formulation, within NONMEM, were found to be significant covariates for CL and V, reducing their CV% to 25% and 74%, respectively. The final PK/PD model, which includes formulation, showed a 50% reduction in the CV% for both the ke0 and the residual error. This PK/PD model was validated in group II with 33% precision and no bias. CONCLUSION: The PK and PD are not equal for all formulations, which contributes to an increase in variability of the observed effect.

Aspectos psicológicos y psiquiátricos relacionados con el cáncer de mama / Psychological and psychiatric aspects related to the breast cancer

Introducción: El cáncer de mama representa la enfermedad maligna diagnosticada más frecuentemente en las mujeres y la segunda causa de muerte relacionada con el cáncer tras la ocasionada por la de pulmón. Aunque la enfermedad ha alcanzado proporciones epidémicas, el pronóstico de la enfermedad sigue siendo variable y la mortalidad no ha descendido como se esperaba. A pesar de que los factores pronósticos mejor conocidos son los que derivan de las propias características tumorales, se está especulando últimamente que las características psico-psiquátricas de las pacientes también influyen en la forma de afrontar la enfermedad por parte de las mujeres que padecen este proceso. Objetivos: Realizar una revisión bibliográfica sobre los trabajos publicados acerca de lo que se conoce sobre los aspectos psiquiátricos y psicológicos relacionados con el cáncer de mama y realizar un estudio de campo para determinar la repercusión psicológica que provoca en las mujeres la realización de un control mamográfico como despistaje de la enfermedad tumoral mamaria. Material y métodos: Para la revisión de los trabajos publicados al respecto se utilizó el sistema Med-Line y para el estudio de campo se seleccionaron a las pacientes que durante 2 meses acudían a la consulta de Cirugía General del Hospital de Jove de Gijón para someterse a la realización de una mamografía. Como escalas validadas se utilizó la escala Hamilton para la depresión y el inventario STAI para la ansiedad. Resultados: La edad media fue de 52,62 años; el 25,9 por ciento de las mujeres tenían antecedentes familiares de cáncer de mama. Un 96,29 por ciento había realizado con anterioridad alguna mamografía. El 51,9 por ciento había presentado en algún momento un trastorno depresivo, y el 44,4 por ciento tomaban en el momento del estudio medicación antidepresiva/ansiolítica. Se encontró una asociación estadísticamente significativa entre la edad de las pacientes y la puntuación obtenida en la escala Hamilton, así como con la parte del inventario STAI que evaluaba la ansiedad como estado. Existió una diferencia estadísticamente significativa entre el número de mamografías realizadas por las pacientes y el resultado que las mujeres esperaban de la prueba (a mayor número de pruebas complementarias realizadas, mejor era el resultado esperado). La puntuación obtenida en el inventario STAI se relaciona de forma estadísticamente significativa con el resultado esperado de la prueba. Existe una relación estadísticamente significativa entre la edad y el haber padecido un episodio depresivo previo. El haber padecido uno de estos episodios influye desfavorablemente en el resultado esperado; de esta forma, las mujeres con antecedentes psiquiátricos previos, esperan un resultado mamográfico malo, o al menos contemplan la posibilidad de que así sea, con respecto a las que nunca habían presentado este tipo de trastornos. Conclusiones: Es necesario un enfoque más global de la enfermedad tumoral mamaria, en el que además de los factores propios de la enfermedad, se tengan en cuenta variables psicológicas y psiquiátricas que influyen de forma directa tanto en el tratamiento, como en el pronóstico y aceptación de la enfermedad por parte de las mujeres que la padecen. Son necesarios más estudios que complementen a este estudio preliminar dada la limitación de la muestra (AU)

Population pharmacokinetics of high dose ibuprofen in cystic fibrosis.

AIMS: To evaluate ibuprofen population pharmacokinetics in a large series of data collected in children with cystic fibrosis (CF) treated with high doses of ibuprofen (59 patients; 2-18 years), and to identify the main causes responsible for the considerable interindividual variability in ibuprofen serum levels. METHODS: Blood samples were collected during routine clinical care; serum ibuprofen concentrations were determined by HPLC. Fitting of the concentration/time data to a one compartment kinetic population model was performed by a non-linear mixed effect regression method. RESULTS: Body weight, dose, and ibuprofen dosage form (lysinate salt or the free acid form), for elimination clearance (CL/F); and body weight, dose, and fasting status for the apparent distribution volume (Vd/F) proved to be the covariates with influence in the model. The four factors identified helped to explain part of the interindividual variability observed, but the remaining unexplained variability made therapeutic drug monitoring absolutely essential.

Utilidad clínica de los marcadores tumorales séricos / Clinical utility of serous tumoural markers

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[Expression and clinical significance of collagenase-3 (MMP-13) in gastric cancer]. / Expresión y significación clínica de la MMP-13 (colagenasa-3) en el cáncer gástrico.

BACKGROUND: MMP-13 (collagenase-3) is a metalloproteinase with potent degradative activity against a variety of elements of the extracellular matrix. Its expression has been described in some human carcinomas, where it seems to play a role in tumor progression and metastasis. The objective of this study was to investigate the expression and clinical significance of MMP-13 in gastric carcinomas. PATIENTS AND METHOD: MMP-13 expression was analyzed by immunohistochemistry in resected specimens from 44 patients with gastric adenocarcinoma. The mean ( standard error) follow-up period was 21.4 3.2 months. RESULTS: A total of 14 gastric carcinomas (31.8%) showed positive immunostaining for MMP-13. The percentage of MMP-13-positive tumors was significantly (p = 0.009) higher in stage IV carcinomas (69.2%) than in lower stages (I: 22.2%; II: 12.5%; and III: 14.3%), as well as in nonresectable tumors (R1 and R2) (61.5%) than in resectable carcinomas (R0) (19.4%) (p = 0.017). Likewise, MMP-13 tumor expression was significantly associated with shortened overall survival in both the entire group of patients (p = 0.0006) and in the subgroup of patients with resectable tumors (p = 0.018). CONCLUSIONS: Our results suggest that, in patients harboring gastric adenocarcinoma, MMP-13 tumor expression is associated with higher tumor aggressiveness and a poor prognosis.

Population pharmacokinetics of digoxin in pediatric patients.

Digoxin pharmacokinetics were studied in a pediatric population with an age range of 6 days to 1 year using the population pharmacokinetic approach. Digoxin data were analyzed by mixed-effects modeling according to a one-compartment steady-state pharmacokinetic model using NONMEM software. The final model selected for the population prediction of digoxin clearance in pediatric patients was as follows: [equation: see text] Individual empirical Bayesian estimates were generated on the basis of the population estimates and were used to correlate the optimum dose of digoxin and patient age according to the following equation: [equation: see text] This equation and its derived nomogram may be used for the initial dosing of digoxin in children aged between 0 and 1 year. The use of this nomogram in routine monitoring requires further pharmacokinetic and clinical validation.

Digoxin pharmacokinetics in patients with high serum digoxin concentrations.

Digitalis intoxication is a frequent iatrogenic effect in patients on treatment with digoxin. In the present study we evaluated the pharmacokinetic behaviour of digoxin and the factors responsible for intoxication by this drug in monitored patients exhibiting clinical signs of overdosing with serum levels > 2 ng/ml. A control group of patients was used as a reference whose population pharmacokinetic parameters obtained by a maximum likelihood method were: Vd = 542.92 +/- 274.53 (litre); Cl = 8.73 +/- 1.55 (litre/h) (mean +/- SD). Statistically significant differences (P < 0.001) were found between the mean Cl values in both groups of patients. The difference between the dose-level ratios established in both populations studied also proved to be significant (P < 0.001). Calculation of the optimum dose for each patient showed that the doses recommended in intoxicated patients should be three times lower than those used in the control population. A good correlation was found between the concentrations observed 24 h after administration and the mean concentrations observed at steady state predicted for both population groups. Multiple regression analysis showed that the variables with the greatest predictive value for clearance in intoxicated patients were age and renal function. The modifications observed in the pharmacokinetic behaviour and in the response to digoxin in this type of patient suggest systematic monitoring using pharmacokinetic and clinical criteria jointly.

Interaction between digoxin and propafenone.

The pharmacokinetic and pharmacodynamic interactions between digoxin and propafenone were investigated in 10 hospitalized patients with heart disease and cardiac arrhythmias. During steady state (0.25 mg/day) the glycoside was combined with 600 mg of propafenone daily for 1 week. The mean +/- SD serum digoxin concentration (SDC) was 0.97 +/- 0.29 ng/ml before and 1.54 +/- 0.65 ng/ml (p less than 0.003) during propafenone administration. Propafenone induced a mean decrease in 31.1 and 31.7% in total and renal digoxin clearances, respectively. The increase in SDCs was accompanied by a decrease in heart rate (HR) and shortening of QTC (QT interval corrected for HR). In patients receiving digoxin and propafenone simultaneously, the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity.