El sodio como excipiente de medicamentos y su potencial relación con la elevación de la presión arterial / Sodium as a drug excipient and its potential relationship with blood pressure elevation

Objetivos: Conocer la composición cuantitativa de sodio en las formas farmacéuticas efervescentes y en soluciones de analgésicos, suplementos de calcio y mucolíticos utilizadas crónicamente; evaluar en qué proporción se tiene en cuenta el potencial riesgo a la hora de prescribir estos medicamentos a pacientes hipertensos y analizar si la toma de estas formas farmacéuticas por la población hipertensa se acompañaba de una descompensación de los valores de presión arterial (PA). Métodos: Se calculó el porcentaje de hipertensos tratados con paracetamol, calcio y acetilcisteína efervescentes (bicarbonato y carbonato sódico) en 10 Centros de Atención Primaria. Se realizó un estudio de cohortes retrospectivo con grupo control (ajustado por edad y género) en uno de los centros; seguimiento de un año. Las variables estudiadas fueron: PA sistólica (PAS) y diastólica (PAD) pre-post inicio del tratamiento con las formas farmacéuticas efervescentes, considerando clínicamente relevantes incrementos >5 mmHg; intensificación del tratamiento antihipertensivo.Resultados: Un 7,7% (rango: 5,4%-9,9%) de pacientes hipertensos se trataron con los medicamentos efervescentes estudiados. El porcentaje de hipertensos que mostraron un aumento de PAS relevante fue significativamente superior en el grupo tratado con medicamentos efervescentes en comparación al del grupo control: 35,9% (IC 95% 27,2%-44,6%) vs. 18,8% (IC 95% 12,7%-24,8%) y también respecto a la intensificación del tratamiento antihipertensivo, 46,6% (IC 95% 37,5%-55,6%) vs. 30% (IC 95% 22,9%-37,1%).Conclusiones: La sensibilización al potencial efecto adverso es muy variable. Los medicamentos efervescentes que incluyen carbonato-bicarbonato de sodio pueden incrementar la PA. El uso de las formas farmacéuticas efervescentes, especialmente en pacientes de riesgo, debe evitarse. (AU)

Aim: To know the quantitative composition of sodium in effervescent pharmaceutical forms and in solutions of analgesics, calcium supplements and mucolytics used chronically; to evaluate in what proportion the potential risk is taken into account when prescribing these drugs to hypertensive patients and to analyze whether the taking of these pharmaceutical forms by the hypertensive population was accompanied by a decompensation of blood pressure (BP) values.Methods: The percentage of hypertensive patients treated with effervescent paracetamol, calcium and acetylcysteine (bicarbonate and sodium carbonate) in 10 Primary Care Centers was calculated. A retrospective cohort study with a control group (adjusted for age and gender) was carried out in one of the centers. The follow-up was one year. The study variables were systolic (SBP) and diastolic (DBP) pre-post initiation of treatment with effervescent preparations, considering clinically relevant increases >5 mmHg; intensification of antihypertensive treatment.Results: 7.7% (range 5.4%-9.9%) of hypertensive patients were treated with the study effervescent drugs. The percentage of hypertensive patients who showed a relevant increase in SBP was significantly higher in the group treated with effervescent drugs compared to the control group: 35.9% (95% CI 27.2%-44.6%) vs. 18.8% (95% CI 12.7%-24.8%) and also regarding the intensification of antihypertensive treatment, 46.6% (95% CI 37.5%-55.6%) vs. 30% (95% CI 22.9%-37.1%).Conclusions: Sensitivity to the potential adverse effect is highly variable. Effervescent medications that include sodium carbonate-bicarbonate can increase BP. The use of effervescent pharmaceutical forms, especially in patients at risk, should be avoided. (AU)

Desarrollo y validación de métodos analíticos para la cuantificación de antirretrovirales por HPLC / Development and validation of laboratory methods for antiretroviral quantitation using HPLC

Objetivo: Desarrollo, validación y caracterización de la funcióndel error de tres métodos analíticos mediante la técnica decromatografía líquida de alta eficacia (HPLC) para el análisis cuantitativode ritonavir, saquinavir y abacavir en plasma humano.Método: Se han indicado los reactivos y aparatos empleados,la preparación de los diferentes estándares de referencia, el procedimientode extracción desde la matriz biológica y las condicionesde análisis ensayadas para la puesta a punto de los tres métodosanalíticos. Además, también se han descrito las metodologías devalidación y de obtención de la función del error analítico.Resultados: Los métodos analíticos desarrollados para ritonavir,saquinavir y abacavir en plasma humano fueron selectivos,lineales (r2 > 0,99), precisos (coeficientes de variación < 15%) yexactos (errores relativos < 15%) en el rango de concentracionesseleccionado. La recuperación fue mayor del 95% en todos losmétodos. Los antirretrovirales estudiados fueron estables en lascondiciones ensayadas de acuerdo con la rutina del laboratorio.La función del error discriminada para cada uno de los métodosanalíticos validados resultó ser lineal en saquinavir (DE = 4,84 +7,14·10-2C) y abacavir (DE = -1,072 + 3,70·10-2C) y no lineal enel caso de ritonavir (DE = 39,98 + 2,40·10-5C2).Conclusiones: Se han desarrollado y posteriormente validadotres métodos analíticos, encontrándose los parámetros de validacióndentro de las especificaciones y atributos de calidad establecidos. Lafunción del error de cada uno de los métodos validados puedeemplearse como método de ponderación heteroscedástica en laestimación de parámetros mediante regresión no lineal en estudiosde farmacocinética clínica de los antirretrovirales ensayados

Objective: Development, validation and error characterizationof three analytical methods, by high performance liquid chromatography(HPLC), for the quantitative analysis of ritonavir,saquinavir and abacavir in human plasma.Method: Reagents and instrumentation used, preparation ofdifferent standards, sample extraction procedure from biologicmatrix, and analytical conditions assayed were detailed to set upthree analytical methods. In addition, the validation and the determinationof analytical error were also described.Results: The analytical methods developed for ritonavir,saquinavir and abacavir in human plasma were selective, linear(r2 > 0.99), precise (coefficients of variation < 15%) and accurate(relative errors < 15%) over the concentration range selected. Therecovery was more than 95% in all methods. Antiretroviral drugswere stable in the storage conditions assayed according to theroutine laboratory. The error function discriminated for each analyticalmethod validated was linear in saquinavir (SD = 4.84 +7.14·10-2C) and abacavir (SD = -1.072 + 3.70·10-2C), and nonlinearin ritonavir (SD = 39.98 + 2.40·10-5C2).Conclusions: Three analytical methods were developed andsubsequently validated, with validation parameters being withinthe specifications and attributes of quality established. The errorfunction characterized for each validated method can be used as aheteroscedastic weighting method in the parameter estimation bynon-linear regression analysis in clinical pharmacokinetic studiesof antiretroviral drugs assayed

[Development and validation of laboratory methods for antiretroviral quantitation using HPLC]. / Desarrollo y validación de métodos analíticos para la cuantificacion de antirretrovirales por HPLC.

OBJECTIVE: Development, validation and error characterization of three analytical methods, by high performance liquid chromatography (HPLC), for the quantitative analysis of ritonavir, saquinavir and abacavir in human plasma. METHOD: Reagents and instrumentation used, preparation of different standards, sample extraction procedure from biologic matrix, and analytical conditions assayed were detailed to set up three analytical methods. In addition, the validation and the determination of analytical error were also described. RESULTS: The analytical methods developed for ritonavir, saquinavir and abacavir in human plasma were selective, linear (r2>0.99), precise (coefficients of variation<15%) and accurate (relative errors<15%) over the concentration range selected. The recovery was more than 95% in all methods. Antiretroviral drugs were stable in the storage conditions assayed according to the routine laboratory. The error function discriminated for each analytical method validated was linear in saquinavir (SD=4.84+7.14.10(-2)C) and abacavir (SD=-1.072+3.70.10(-2)C), and non-linear in ritonavir (SD=39.98+2.40.10(-5)C2). CONCLUSIONS: Three analytical methods were developed and subsequently validated, with validation parameters being within the specifications and attributes of quality established. The error function characterized for each validated method can be used as a heteroscedastic weighting method in the parameter estimation by non-linear regression analysis in clinical pharmacokinetic studies of antiretroviral drugs assayed.

Análisis y estudio comparativo de la producción científica de los servicios de farmacia de hospital de España y gran bretaña a través del medline (1966-1997) / Analysis and comparative study of the scientific production of the hospital pharmacy services of Spain and Great Britain through the Medline (1966-1997)

En un intento de conocer las aportaciones de los servicios de farmacia de hospital (SFH) localizados en España y Gran Bretaña que pueden favorecer el desarrollo de la práctica basada en la evidencia, se ha realizado un análisis y un estudio comparativo de las líneas de investigación desarrolladas en dichos servicios, a partir de las publicaciones que originan. La base de datos utilizada como fuente de información fue Medline y el período de estudio 1966-1997.Para ello se fijaron tres criterios de inclusión para la selección de un documento indizado en Medline: que se realizara en España o Gran Bretaña, que los autores estuvieran adscritos exclusivamente al SFH y que el tema científico no fuera el económico. El análisis y estudio comparativo se realizó en función del área temática, año y revista de publicación y lugar de realización de los artículos publicados durante el período de estudio. (AU)

A comparative in vitro study of percutaneous penetration of beta-blockers in human skin.

In vitro diffusion experiments with propranolol, oxprenolol, metoprolol and atenolol were carried out using excised human abdominal skin. The main permeation parameters (permeability coefficient, flow and lag time) were calculated and compared as measurement of intrinsic permeability across human skin. A long lag time and a low steady-state flow were found for all drugs assayed. Skin permeability predicted at steady state did not reach therapeutic concentrations, which indicated the need for appropriate chemical penetration enhancers or vehicles to overcome limiting factors. The results, including those of celiprolol and bisoprolol reported previously, correlated with physicochemical properties, especially with lipophilicity, one of the main factors in drug permeability prediction through human skin.

Error structure for the HPLC analysis for atenolol, metoprolol and propranolol: a useful weighting method in parameter estimation.

Three reversed-phase high performance liquid chromatography (HPLC) methods with UV detection were developed and fully validated for the quantification of three beta-blockers: atenolol, metoprolol and propranolol. After validation, error structures for the HPLC analysis were established using a convenient and practical procedure. The mean percentage of relative standard deviation (RSD) of the experimental concentrations (C), were less than 4.29% for proportionality and less than 3.68% for precision for any of the drugs, which allowed the quantitation of beta-blockers assayed at concentrations in the range 25-0.78 micrograms.ml-1. The error structures for the HPLC analysis were: SD (micrograms.ml-1) = 5.02 x 10(-2) C for atenolol, SD (micrograms.ml-1) = 4.55 x 10(-2) + 0.63 x 10(-2) C - 7.58 x 10(-6) C3 for metoprolol and SD (micrograms.ml-1) = 2.73 x 10(-2) C - 3.49 x 10(-4) C2 for propranolol. The reciprocal of the square of the SD of the drug concentrations measured within the calibration curve could be used as weighting methods in parameter estimation by non-linear regression.

Comparative study of different weighting methods in non-linear regression analysis: implications in the parametrization of carebastine after intravenous administration in healthy volunteers.

The influence of different weighting methods in non-linear regression analysis was evaluated in the pharmacokinetics of carebastine after a single intravenous dose of 10 mg in 8 healthy volunteers. Plasma concentrations were measured by HPLC using an on-line solid-phase extraction method and automated injection. The analytical method was fully validated and the function of the analytical error subsequently determined. The parametric approach was performed using different weighting methods, including the homoscedastic method (W = 1) and heteroscedastic methods using weights of 1/C, 1/C2, and the inverse of the concentration variance calculated through the analytical error function (1/V), and the results were statistically evaluated according to the normal distribution. Statistically significant differences were observed in the representative parameters of the disposition kinetics of carebastine. The use of a multiple comparison test for statistical analysis of all differences among group means indicated that differences were generated between the homoscedastic method (W = 1) and the heteroscedastic methods (1/C, 1/C2, and 1/V). The results obtained in the present study confirmed the utility of the analytical error function as a weighting method in non-linear regression analysis and reinforced the importance of the correct choice of weights to avoid the estimation of imprecise or erroneous pharmacokinetic parameters.

Pentoxifylline, ciprofloxacin and prednisone failed to prevent transplant-related toxicities in bone marrow transplant recipients and were associated with an increased incidence of infectious complications.

TNF-alpha (Tumor necrosis factor-alpha) is involved in many immunological and inflammatory processes, and might be expected to play an important role in the development of BMT-related complications. Triple therapy (pentoxifylline, ciprofloxacin and prednisone) with known anti-TNF activity was tested in 37 patients undergoing a hematopoietic progenitor transplant (HPT). A control group of 16 patients with similar characteristics was selected among consecutive patients receiving a HTP in a neighboring center who did not receive anti-TNF prophylaxis. Major transplant-related complications were registered (VOD, acute GVHD, infectious episodes, renal failure and mucositis) and survival status. TNF plasma concentrations were determined by ELISA, and pentoxifylline plasma concentrations were determined by HPLC. Among patients treated with pentoxifylline (PTX), ciprofloxacin and steroids, no difference in the mean survival time was observed compared with the control group. The incidence of procedure-related death up to day +35 was 11% in the study group and 6% in the control group. In spite of a tendency to a lower incidence of mucositis there was a higher incidence of infections (positive blood cultures) in the study group (49%) than in the control group (16.7%) (P = 0.16). This difference achieved statistical significance in patients receiving an allogeneic HPT (P = 0.05). It is likely that the use of steroids in the early period after transplant increases infectious episodes and makes control of GVHD difficult. The combined administration of steroids with pentoxifylline and ciprofloxacin has not proved beneficial in preventing mucositis, renal failure, VOD or GVHD, or in improving patient survival.

Parametrization by nonlinear regression analysis of the active acid metabolite of ebastine using different weighting methods.

The study of the analytical error function has been applied to evaluate the pharmacokinetics of ebastine active acid metabolite after a single oral dose of 10 mg of metabolite in 6 healthy volunteers. Plasma concentrations were measured using an automated solid phase extraction method. The analytical method was fully validated and the function of the analytical error subsequently determined. The parametric approach was performed by nonlinear regression analysis comparing the results obtained after the application of different weighted least square methods including the homoscedastic method (W = 1) and heteroscedastic methods using weights of 1/C, 1/C2 and the inverse of the concentration variance calculated through the function of the analytical error. The results obtained in the study showed no influence of the different weighting methods used on the estimation of the pharmacokinetic parameters of ebastine acid metabolite.

Determination of analytical error function for beta-blockers as a possible weighting method for the estimation of the regression parameters.

Three analytical methods have been developed and validated for the quantification of beta-blockers (celiprolol, bisoprolol and oxprenolol) using high performance liquid chromatography (HPLC) with UV detection. The methods were determined to be linear, precise and accurate (RSDs were lower than 5%), which allowed the quantitation of beta-blockers assayed at concentrations in the range 25-0.78 micrograms ml-1. After validation of reversed-phase HPLC methods, their analytical error functions were established by a rapid, simple and economical procedure. The discrimination of the best function for each active principle was performed by an appropriate polynomial statistical analysis, yielding SD (microgram ml-1) = 0.0295 + 0.0124C - 3.88 x 10(-4)C2 for celiprolol, 0.0199 + 0.011C - 1.27 x 10(-5)C3 for bisoprolol; and 0.0183 + 0.0089C - 9.68 x 10(-6)C3 for oxprenolol. These analytical error functions are an alternative to the weighting methods used in parameter estimation of beta-blockers.

Open-loop feedback control of serum bentazepam concentrations and Bayesian estimation in multiple dosage regimens in patients.

The time course of serum levels of bentazepam was studied in 10 patients receiving anxiolytic agent orally at a dose of 25 mg on multiple dosage regimens with dosage intervals of 8 and 12 h. Using the methods of "open-loop feedback control", no linear regression programs and Bayesian estimation, it was possible to establish the best estimates of the pharmacokinetic parameters corresponding to the single-compartment model for each patient from all their data relating to the serum levels obtained after the first dose and after multiple dosing with different regimens. The application of the Kruskal Wallis test showed that there were only statistical differences for the absorption constant, determined with and without Bayesian estimation. However, no statistically significant differences were found on comparing the experimentally obtained serum levels with the corresponding theoretical values calculated independently for each patient from the parameters established with and without Bayesian estimation. As population pharmacokinetic parameters of bentazepam, the following were established: Ka = 2.330 +/- 0.665 l/h; Vd = 1.209 +/- 0.546 l/Kg and Ke = 0.160 +/- 0.118 l/h, corresponding to a mean value for the elimination half-life of 4.33 h.

Adaptive and bayesian control of digoxin in geriatric patients.

The study was carried out in a total of 22 patients classified in two groups: Group "A" (n = 12) was constituted by geriatric patients with cardiac failure diagnostic and with digoxin treatment previously to start our study. Group "B" (n = 10) was also constituted by geriatric patients, but with arteriosclerosis diagnostic and without prior digoxin treatment. Doses of 0.25 mg of digoxin was administered by oral route in a multiple dosage regimen with dosification at times of 0, 24, 48, 72 and 96 h. Samples of blood were obtained at 0, 0.5, 1.75, 7, 24, 49.75, 72 and 168 h after the first administration. The classics one and two-open kinetic model were considered. The elimination constant (Ke) was estimated in function of creatinine clearance (Clcr) according to the following expression: Ke = Kslope * Clcr. The mean value of kinetic parameters established were: For one-compartment kinetic model: Ka = 15.2 and 15.7 h-1, Vd = 5.4 and 4.5 l/Kg and Kslope 0.0006 and 0.0001 min/ml * h for groups "A" and "B", respectively. For two-compartment kinetic model: Ka = 11.5 and 3.6 h-1, K12 = 0.7 and 0.8 h-1, k21 = 0.2 and 0.2 h-1, Vc = 2.7 and 1.9 l/Kg and Kslope 0.0002 and 0.0002 min/ml * h for groups "A" and "B", respectively.

Disposition of phosphomycin in patients with pleural effusion.

The pharmacokinetics of phosphomycin were studied in seven patients with pleural effusion of varied etiologies. All patients received a single intravenous bolus of 30 mg of antibiotic per kg. Phosphomycin levels in plasma and pleural fluid were determined simultaneously. Antibiotic levels in plasma followed a two-compartment open kinetic model. In the pleural fluid, maximum concentrations of phosphomycin, 42.63 +/- 16.03 micrograms/ml (mean +/- standard deviation), were reached at 3.69 +/- 1.08 h after administration of the antibiotic. The disappearance constant of the antibiotic from the pleural fluid was significantly smaller (0.16 +/- 0.06 h-1) than the elimination constant determined from the levels of drug in plasma (0.73 +/- 0.26 h-1). Phosphomycin persisted in antibacterial concentrations in the pleural fluid for a considerable period of time. The low accessibility of phosphomycin observed in one of the patients in the study, with a maximum concentration value of 2.16 micrograms of phosphomycin per ml of pleural fluid, could be due to the existence of pachypleuritis in that patient; this was later confirmed in clinical and histological studies done after the research described here.