Intravenous amoxicillin-sulbactam against Escherichia coli: optimizing the dose, component ratio and infusion time using a human pharmacodynamic model.

Amoxicillin-sulbactam (AMX-SUL) is an aminopenicillin/beta-lactamase inhibitor combination currently available in 29 countries which may be a suitable option for treating intra-abdominal infections. the aim of this study was to identify the optimal dose and ratio between components of this formulation through an ex-vivo human pharmacodynamic model against Escherichia coli. Four volunteers were randomized to receive alternatively a single dose of AMX-SUL infused either over 30 min or 3h in the following ratios (g/g): 1/0.5; 1/1, 2/0.5 and 0/2. time-kill studies were performed with the 0-, 0.5-, 2-, 4-, 6- and 8-h post-dosing sera against E. coli ATCC 25922 (AMX MIC, 2 microg/ml; AMX-SUL MIC, 2 microg/ml) and E. coli ATCC 35218 (AMX MIC, 1024 microg/ml; AMX-SUL MIC, 4-8 microg/ml). AMX-SUL 1g/0.5 g infused over 30 min was only active at 0.5 h after dose, being inferior to both AMX-SUL 1g/1g and AMX-SUL 2g/0.5 g against E. coli ATCC 25922, for which the 2h post-dose serum proved active. When tested against E. coli ATCC 35218, AMX-SUL 1g/0.5 g and AMX-SUL 2g/0.5 g were active only at 0.5 h post-dose, whereas AMX-SUL 1g/1g showed bactericidal activity 0.5h post-dose and was able to inhibit bacterial growth 2 h post-dose. When infused over 3h, the antimicrobial activity of AMX-SUL was better than the 30-min infusion. Moreover, AMX-SUL 1g/1g was able to inhibit, and kill to some extent, the E. coli ATCC 25922 strain at 4h post-dose (i.e. 67% and 50% of a 6- and 8-h dosing interval, respectively). The present study suggests that 1g/1g is the best formulation for AMX-SUL against E. coli. The infusion over 3h optimizes its pharmacodynamic profile, as well as that of the 1g/0.5g combination. These findings encourage the performance of clinical trials to assess the efficacy of this combination, given as an extended infusion, in the treatment of community-acquired intra-abdominal infections.

[The pharmacokinetic study of a daily dose of theophylline]. / Estudio farmacocinético de una dosis diaria de teofilina.

Theophylline pharmacokinetics, administered in tablets containing 600 mg in a sustained-release hydrophilic matrix for a once daily intake, was evaluated after being administered to 6 healthy volunteers during 7 days at 8 pm. Plasmatic levels at -2, 0, 2, 3, 4, 6, 8, 10, 12, 14, 18 and 24 hours in relation with 8 pm intake, were obtained at the 7th day of administration. A plasmatic curve was obtained with a maximum concentration at 12 hours of 10.18 mcg/ml, a minimum concentration of 3.27 mcg/ml and an area under the concentration/time curve of 198.4 mcg.h/ml. These data make it evident that the tablet studied shows a release profile without excessive peaks and an average concentration at steady state within therapeutical range, and suggests its use in asthma.

Estudio farmacocinético de una dosis diaria de teofilina. / [The pharmacokinetic study of a daily dose of theophylline]

Theophylline pharmacokinetics, administered in tablets containing 600 mg in a sustained-release hydrophilic matrix for a once daily intake, was evaluated after being administered to 6 healthy volunteers during 7 days at 8 pm. Plasmatic levels at -2, 0, 2, 3, 4, 6, 8, 10, 12, 14, 18 and 24 hours in relation with 8 pm intake, were obtained at the 7th day of administration. A plasmatic curve was obtained with a maximum concentration at 12 hours of 10.18 mcg/ml, a minimum concentration of 3.27 mcg/ml and an area under the concentration/time curve of 198.4 mcg.h/ml. These data make it evident that the tablet studied shows a release profile without excessive peaks and an average concentration at steady state within therapeutical range, and suggests its use in asthma.

Estudio farmacocinético de una dosis diaria de teofilina. / [The pharmacokinetic study of a daily dose of theophylline]

Theophylline pharmacokinetics, administered in tablets containing 600 mg in a sustained-release hydrophilic matrix for a once daily intake, was evaluated after being administered to 6 healthy volunteers during 7 days at 8 pm. Plasmatic levels at -2, 0, 2, 3, 4, 6, 8, 10, 12, 14, 18 and 24 hours in relation with 8 pm intake, were obtained at the 7th day of administration. A plasmatic curve was obtained with a maximum concentration at 12 hours of 10.18 mcg/ml, a minimum concentration of 3.27 mcg/ml and an area under the concentration/time curve of 198.4 mcg.h/ml. These data make it evident that the tablet studied shows a release profile without excessive peaks and an average concentration at steady state within therapeutical range, and suggests its use in asthma.

[Ambulatory ergometric and pressurometric results with a daily dose of 240 mg of diltiazem in labile hypertensive patients with threshold ergometry]. / Resultados ergométricos y presurométricos ambulatorios con 1 dosis diaria de 240 mg de diltiazem en hipertensos labiles con ergometría limítrofe.

The pharmacological treatment of hypertension raises not only the dilemma of the election of the most suitable drugs given to each patient, but also that of an effective control of the antihypertensive effect as well as undesirable reactions, including an accentuated hypotension. Continuous ambulatory monitoring (CAM) is an effective form of diagnosis and therapeutic control of hypertension. In order to evaluate the efficacy and tolerance of a new concentration of diltiazem (240 mg) in tablets of sustained release, for a single daily intake, a double blind, randomized, crossed study with placebo, was performed in 20 patients with mild to moderate hypertension and a positive ergometric test. Clinical, electrocardiographic, ergometric and CAM controls were carried out. A significant difference was observed for diltiazem monodosis 240 mg in relation to placebo with respect to the reduction of systolic and diastolic pressures, not only in clinical controls but also during the CAM, in both diurnal and nocturnal periods during 24 hours. In ergometric studies, a significant difference was also noted in the following parameters: total time of exercise, burden in kilos, systolic and diastolic blood pressure and the underlevel of ST. It is concluded that diltiazem monodosis, 240 mg, led to a sustained antihypertensive action throughout the 24 hours, with good clinical tolerance, improving ergometry and CAM. We suggest that diltiazem is a first choice drug for there patients in whom the exclusive treatment of hypertension has not prevented, up to now, the occurrence of ischemic cardiopathy.

Resultados ergometricos y presurometricos ambulatorios con 1 dosis diaria de 240 mg de diltiazem en hipertensos labiles con ergometria limitrofe / Ambulatory ergometric and pressurometric results with a daily dose of 240 mg of diltiazem in labile hypertensive patients with threshold ergometry

El monitoreo ambulatorio contínuo (MAC) constituye un eficiente elemento de diagnóstico y control terapéutico de la hipertensión arterial (HA). Con la finalidad de evaluar la eficacia y tolerancia de una nueva concentración de diltiazem (240 mg), en comprimidos de liberación programada para una toma diaria, se realizó un estudio doble ciego en 20 pacientes clínicos, electrocardiográficos, ergométricos y de MAC en los períodos basales, placebo y con droga activa. Se observó una diferencia significativa para diltiazem monodosis 240 mg en relación al placebo, en lo que se refiere al descenso de la presión arterial (PA) sistólica y diastólica, no sólo en los controles clínicos sino también durante el MAC tanto en el período diurno como en el nocturno. Esto ocurrió con el promedio de 24 horas y con el porcentaje de registros anormales. En los estudios ergométricos también se observó una diferencia estadísticamente significativa para diltiazem en los siguientes parámetros: tiempo total de la prueba, carga en Kilos, PA sistólica, y desnivel del ST. Se concluye que el diltiazem monodosis 240 mg fue capaz de mantener una eficaz acción antihipertensiva sostenida a lo largo de las 24 horas, con muy buena tolerancia clínica, induciendo una mejoría evidente en la ergtométría y en el MAC, lo que la hace una droga de primera elección en pacientes en los cuales el tratamiento exclusivo de la hipertensión arterial, hasta, ahora, no ha mejorado el pronóstico de la cardiopatia isquémica

Resultados ergométricos y presurométricos ambulatorios con 1 dosis diaria de 240 mg de diltiazem en hipertensos labiles con ergometría limítrofe. / [Ambulatory ergometric and pressurometric results with a daily dose of 240 mg of diltiazem in labile hypertensive patients with threshold ergometry]

The pharmacological treatment of hypertension raises not only the dilemma of the election of the most suitable drugs given to each patient, but also that of an effective control of the antihypertensive effect as well as undesirable reactions, including an accentuated hypotension. Continuous ambulatory monitoring (CAM) is an effective form of diagnosis and therapeutic control of hypertension. In order to evaluate the efficacy and tolerance of a new concentration of diltiazem (240 mg) in tablets of sustained release, for a single daily intake, a double blind, randomized, crossed study with placebo, was performed in 20 patients with mild to moderate hypertension and a positive ergometric test. Clinical, electrocardiographic, ergometric and CAM controls were carried out. A significant difference was observed for diltiazem monodosis 240 mg in relation to placebo with respect to the reduction of systolic and diastolic pressures, not only in clinical controls but also during the CAM, in both diurnal and nocturnal periods during 24 hours. In ergometric studies, a significant difference was also noted in the following parameters: total time of exercise, burden in kilos, systolic and diastolic blood pressure and the underlevel of ST. It is concluded that diltiazem monodosis, 240 mg, led to a sustained antihypertensive action throughout the 24 hours, with good clinical tolerance, improving ergometry and CAM. We suggest that diltiazem is a first choice drug for there patients in whom the exclusive treatment of hypertension has not prevented, up to now, the occurrence of ischemic cardiopathy.

Resultados ergometricos y presurometricos ambulatorios con 1 dosis diaria de 240 mg de diltiazem en hipertensos labiles con ergometria limitrofe / Ambulatory ergometric and pressurometric results with a daily dose of 240 mg of diltiazem in labile hypertensive patients with threshold ergometry

El monitoreo ambulatorio contínuo (MAC) constituye un eficiente elemento de diagnóstico y control terapéutico de la hipertensión arterial (HA). Con la finalidad de evaluar la eficacia y tolerancia de una nueva concentración de diltiazem (240 mg), en comprimidos de liberación programada para una toma diaria, se realizó un estudio doble ciego en 20 pacientes clínicos, electrocardiográficos, ergométricos y de MAC en los períodos basales, placebo y con droga activa. Se observó una diferencia significativa para diltiazem monodosis 240 mg en relación al placebo, en lo que se refiere al descenso de la presión arterial (PA) sistólica y diastólica, no sólo en los controles clínicos sino también durante el MAC tanto en el período diurno como en el nocturno. Esto ocurrió con el promedio de 24 horas y con el porcentaje de registros anormales. En los estudios ergométricos también se observó una diferencia estadísticamente significativa para diltiazem en los siguientes parámetros: tiempo total de la prueba, carga en Kilos, PA sistólica, y desnivel del ST. Se concluye que el diltiazem monodosis 240 mg fue capaz de mantener una eficaz acción antihipertensiva sostenida a lo largo de las 24 horas, con muy buena tolerancia clínica, induciendo una mejoría evidente en la ergtométría y en el MAC, lo que la hace una droga de primera elección en pacientes en los cuales el tratamiento exclusivo de la hipertensión arterial, hasta, ahora, no ha mejorado el pronóstico de la cardiopatia isquémica (AU)

Niveles plasmáticos y biodisponibilidad de diltiazem en comprimidos de acción prolongada / Plasma levels and diltiazem bioavailability in sustained-release tablets

Se administraron 90 mg de diltiazem -en dosis única- vehiculizados en un comprimido de liberación prolongada (diseñado especialmente en base a la utilización de matrices hidrofílicas) a 8 voluntarios sanos, todos del sexo masculino. Se obtuvieron concentraciones plasmáticas de diltiazem cuyo pico máximo se alcanzó a las 6,37 + ou - 0,93 horas con un valor de 82,8 + ou - 11,3 ng/ml. A las 12 horas la concentración plasmática de diltiazem era de 40,2 + ou - 3,9 ng/ml. El t 1/2 fue de 5,77 siendo el área bajo la curva de 1097 + ou - 141 ng/ml x h. Estos datos permiten suponer razonablemente que, con la administración de 1 comprimido (90 mg) de diltiazem -vehiculizado en este nuevo diseño de comprimido de liberación prolongada- cada 12 horas se obtendrán niveles terapéuticos eficaces, minimizando (al mismo tiempo) la probabilidad de aparición de efectos adversos

Niveles plasmáticos y biodisponibilidad de diltiazem en comprimidos de acción prolongada / Plasma levels and diltiazem bioavailability in sustained-release tablets

Se administraron 90 mg de diltiazem -en dosis única- vehiculizados en un comprimido de liberación prolongada (diseñado especialmente en base a la utilización de matrices hidrofílicas) a 8 voluntarios sanos, todos del sexo masculino. Se obtuvieron concentraciones plasmáticas de diltiazem cuyo pico máximo se alcanzó a las 6,37 + ou - 0,93 horas con un valor de 82,8 + ou - 11,3 ng/ml. A las 12 horas la concentración plasmática de diltiazem era de 40,2 + ou - 3,9 ng/ml. El t 1/2 fue de 5,77 siendo el área bajo la curva de 1097 + ou - 141 ng/ml x h. Estos datos permiten suponer razonablemente que, con la administración de 1 comprimido (90 mg) de diltiazem -vehiculizado en este nuevo diseño de comprimido de liberación prolongada- cada 12 horas se obtendrán niveles terapéuticos eficaces, minimizando (al mismo tiempo) la probabilidad de aparición de efectos adversos (AU)