Simultaneous determination of diosmin and diosmetin in human plasma by ion trap liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry: Application to a clinical pharmacokinetic study.

Diosmetin (3',5,7-trihydroxy-4'-methoxyflavone) is the aglycone of the flavonoid glycoside diosmin (3',5,7-trihydroxy-4'-methoxyflavone-7-ramnoglucoside). Diosmin is hydrolyzed by enzymes of intestinal micro flora before absorption of its aglycone diosmetin. A specific, sensitive, precise, accurate and robust HPLC assay for the simultaneous determination of diosmin and diosmetin in human plasma was developed and validated. Plasma samples were incubated with beta-glucuronidase/sulphatase. The analytes were isolated by liquid-liquid extraction with tert-butyl methyl ether at pH 2, and separated on a C(18) reversed-phase column using a mixture of methanol/1% formic acid (58:42, v/v) at a flow rate of 0.5ml/min. APCI in the positive ion mode and multiple reaction monitoring (MRM) method was employed. The selected transitions for diosmin, diosmetin and the internal standard (7-ethoxycoumarin) at m/z were: 609.0-->463.0, 301.2-->286.1 and 191, respectively. A good linearity was found in the range of 0.25-500ng/ml (R(2)>0.992) for both compounds. The intra-batch assay precision (CV) for diosmin and diosmetin ranged from 1.5% to 11.2% and from 2.8% to 12.5%, respectively, and the inter-batch precision were from 5.2% to 11.5% and 8.5% to 9.8%, respectively. The accuracy was well within the acceptable range the accuracies (from -2.7% to 4.2% and -1.6% to 3.5% for diosmin and diosmetin, respectively). The mean recoveries of diosmin, diosmetin and the internal standard were 87.5%, 89.2% and 67.2%. Stability studies showed that diosmin and diosmetin were stable in different conditions. Finally, the method was successfully applied to the pharmacokinetic study of diosmin in healthy volunteers following a single oral administration (Daflon).

Absceso intraabdominal posquirúrgico con bacteriemia por Propionibacterium acnes / No disponible

No disponible

Tenofovir: farmacología e interacciones / Tenofovir: pharmacology and interactions

Tenofovir es un análogo de los nucleótidos y, por ello, presenta un mecanismo de acción diferente al de los análogos a los nucleósidos. Se administra por vía oral en forma de éster disoproxil, que es desesterificado para alcanzar una biodisponibilidad, que supera el 20%, y que aumenta ligeramente si el fármaco se ingiere con grasas. Presenta una distribución tisular amplia, facilitada por el pequeño tamaño de la molécula y su escasa fijación a proteínas, y se elimina en su práctica totalidad en forma activa por la orina, a través de filtración glomerular y secreción tubular activa. Esta circunstancia obliga a realizar un ajuste de la dosis cuando hay insuficiencia renal. De forma característica, presenta una semivida intracelular que supera en más de 10 veces a la plasmática. Su perfil farmacocinético le configura como un fármaco con poco potencial de producir o de presentar interacciones con otros fármacos. Así, dentro de los antirretrovirales se ha descrito un aumento de la biodisponibilidad de didanosina que conlleva la recomendación de utilizarlo en dosis inferior a la habitual, mientras que puede utilizarse sin ajustes con otros inhibidores análogos y no análogos. Tampoco parece alterar la farmacocinética de los fármacos inhibidores de la proteasa, aunque éstos pueden producir un aumento ligero de la biodisponibilidad de tenofovir que parece tener escasa trascendencia clínica. Se ha señalado la ausencia de interacciones con otros fármacos no antirretrovirales(AU)

Tenofovir is a nucleotide analogue and consequently its mechanism of action differs from that of nucleoside analogues. This drug is administered orally in the form of disoproxil ester, which is deesterified to achieve a bioavailability of more than 20%. This bioavailability slightly increases if tenofovir is taken with a fat-rich meal. This drug has broad tissue distribution, aided by its small molecular size and very low protein binding, and is eliminated as unchanged drug in the urine through glomerular filtration and active tubular secretion. Because of this latter characteristic, dosage adjustments are required in patients with renal insufficiency. The intracellular half-life of tenofovir is more than 10 times greater than the plasma half-life. Because of the pharmacokinetic profile of tenofovir, interactions with other drugs are scarce. Within the class of antiretroviral agents, an increase in the bioavailability of didanosine has been described, leading to the recommendation that the dose of didanosine be reduced when used in combination with tenofovir. Tenofovir can be used without adjustments with other nucleoside and nonnucleoside reverse transcriptase inhibitors. Equally, tenofovir seems to have no effect on the pharmacokinetics of protease inhibitors although these latter agents may produce a slight increase in the bioavailability of tenofovir, which seems to be of little clinical relevance. The absence of interactions with other non-antiretroviral agents has been reported(AU)

Tenofovir: farmacología e interacciones / Tenofovir: pharmacology and interactions

Tenofovir es un análogo de los nucleótidos y, por ello, presenta un mecanismo de acción diferente al de los análogos a los nucleósidos. Se administra por vía oral en forma de éster disoproxil, que es desesterificado para alcanzar una biodisponibilidad, que supera el 20%, y que aumenta ligeramente si el fármaco se ingiere con grasas. Presenta una distribución tisular amplia, facilitada por el pequeño tamaño de la molécula y su escasa fijación a proteínas, y se elimina en su práctica totalidad en forma activa por la orina, a través de filtración glomerular y secreción tubular activa. Esta circunstancia obliga a realizar un ajuste de la dosis cuando hay insuficiencia renal. De forma característica, presenta una semivida intracelular que supera en más de 10 veces a la plasmática. Su perfil farmacocinético le configura como un fármaco con poco potencial de producir o de presentar interacciones con otros fármacos. Así, dentro de los antirretrovirales se ha descrito un aumento de la biodisponibilidad de didanosina que conlleva la recomendación de utilizarlo en dosis inferior a la habitual, mientras que puede utilizarse sin ajustes con otros inhibidores análogos y no análogos. Tampoco parece alterar la farmacocinética de los fármacos inhibidores de la proteasa, aunque éstos pueden producir un aumento ligero de la biodisponibilidad de tenofovir que parece tener escasa trascendencia clínica. Se ha señalado la ausencia de interacciones con otros fármacos no antirretrovirales

Tenofovir is a nucleotide analogue and consequently its mechanism of action differs from that of nucleoside analogues. This drug is administered orally in the form of disoproxil ester, which is deesterified to achieve a bioavailability of more than 20%. This bioavailability slightly increases if tenofovir is taken with a fat-rich meal. This drug has broad tissue distribution, aided by its small molecular size and very low protein binding, and is eliminated as unchanged drug in the urine through glomerular filtration and active tubular secretion. Because of this latter characteristic, dosage adjustments are required in patients with renal insufficiency. The intracellular half-life of tenofovir is more than 10 times greater than the plasma half-life. Because of the pharmacokinetic profile of tenofovir, interactions with other drugs are scarce. Within the class of antiretroviral agents, an increase in the bioavailability of didanosine has been described, leading to the recommendation that the dose of didanosine be reduced when used in combination with tenofovir. Tenofovir can be used without adjustments with other nucleoside and nonnucleoside reverse transcriptase inhibitors. Equally, tenofovir seems to have no effect on the pharmacokinetics of protease inhibitors although these latter agents may produce a slight increase in the bioavailability of tenofovir, which seems to be of little clinical relevance. The absence of interactions with other non-antiretroviral agents has been reported

[New therapeutic strategies for multiple myeloma. Efficacy and cost-effectiveness analyses]. / Nuevas estrategias terapéuticas en el tratamiento del mieloma múltiple. Análisis de su eficacia y coste-efectividad.

The objective of the present article is the review of the most important therapeutic innovations in the treatment of multiple myeloma in terms of efficacy and cost-effectiveness. Besides autologous transplant with peripheral-blood stem-cell, thalidomide establishes as one of the most powerful therapeutic tools in induction and maintenance treatment and together with lenalidomide and bortezomib as therapy for relapsing/refractory multiple myeloma. Considering, the last named situation thalidomide can be an adequate therapeutical option in combination with dexamethasone. Under a strictly pharmacoeconomic point of view, lenalidomide and bortezomib seem to be additional alternatives in patients previously treated with thalidomide.

Nuevas estrategias terapéuticas en el tratamiento del mieloma múltiple. Análisis de su eficacia y coste-efectividad / New therapeutic strategies for multiple myeloma. Efficacy and cost-effectiveness analyses

El objetivo del presente artículo es revisar las principales innovaciones terapéuticas en el tratamiento del mieloma múltiple, desde el punto de vista de su eficacia y coste-efectividad. Aparte del autotrasplante de progenitores hematopoyéticos, la talidomida se establece como uno de los principales recursos terapéuticos en el tratamiento de inducción y de extensión de la respuesta, conjuntamente con la lenalidomida y el bortezomib en el tratamiento de rescate en el mieloma múltiple refractario/recidivante. Con respecto al tratamiento de este último, la talidomida puede ser una opción adecuada en combinación con la dexametasona. Desde un punto de vista estrictamente farmacoeconómico, la lenalidomida y el bortezomib constituyen alternativas especialmente válidas en pacientes tratados previamente con talidomida

The objective of the present article is the review of the most important therapeutic innovations in the treatment of multiple myeloma in terms of efficacy and cost-efectiveness. Besides autologous transplant with peripheral-blood stem-cell, thalidomide establishes as one of the most powerful therapeutic tools in induction and maintenance treatment and together with lenalidomide and bortezomib as therapy for relapsing/refractory multiple myeloma. Considering, the last named situation thalidomide can be an adequate therapeutical option in combination with dexamethasone. Under a strictly pharmacoeconomic point of view, lenalidomide and bortezomib seem to be additional alternatives in patients previously treated with thalidomide (AU)

Granulicatella adiacens breast implant-associated infection.

The 1st reported case of breast implant-associated infection due to Granulicatella adiacens, formerly known as nutritionally variant streptococci, Streptococcus adiacens, and Abiotrophia adiacens is presented. Microbiology and previously reported cases of infections by this organism are reviewed.

Efectos adversos e interacciones de los nuevos antibióticos activos frente a cocos grampositivos / Adverse effects and interactions of the new antibiotics active against Gram-positive cocci

Linezolid, tigeciclina, daptomicina y dalvabancina sonnuevos antibacterianos con un perfil peculiar de efectosadversos (EA) y en algunos casos de interacciones. Elprimero de los citados destaca por la excelente toleranciaen tratamientos de corta duración, mientras que suutilización resulta más problemática cuando la duración seprolonga en el tiempo y parece que las 4 semanas puedenser la barrera que marque, de algún modo, las diferencias.En cualquier caso, ninguno de los EA más problemáticos(neuritis, alteraciones de la médula ósea y acidosis láctica)parece presentarse bruscamente, por lo que la vigilanciade la presencia de síntomas precoces y/o alteraciones enel hemograma se convierte en relevante en este caso. Enreferencia a las interacciones, la peculiaridad pareceubicarse en su ligera capacidad de producir cierto efectoIMAO que conlleva un potencial de suma de efectosserotoninérgicos al asociarse con antidepresivos queelevan la actividad de este mismo neurotransmisor. Denuevo la precaución de reducir la dosis del antidepresivo yla de vigilar la presencia de síntomas precoces (digestivos,musculares y neurológicos) se convierte en la estrategiamás acertada.Tigeciclina muestra un perfil conocido porque lo comparteen su práctica totalidad con el de las tetraciclinas; lasprecauciones y las contraindicaciones de éstas se repiten enel caso de tigeciclina que, además, destaca por su potencialpara producir náuseas y vómitos. Aparentemente parecenfrecuentes, aunque el fármaco se administre cada 12 h. Lano asociación de estos efectos con concentracionesplasmáticas altas facilitaría su uso en una dosis únicadiaria más elevada que la actual, lo que además supondríaconseguir concentraciones plasmáticas superiores(AU)

Daptomicina también presenta un perfil peculiar: laelevación en sangre de las enzimas musculares y,concretamente, de las cifras de creatincinasa, que parecenrelacionarse muy directamente con la acumulación delfármaco en el músculo, por lo que resultan muy pocofrecuentes si el intervalo de administración evita lamencionada acumulación. El uso de dosis adecuadas, peroen única administración diaria ajustada si hay disfunciónrenal, parece que es la solución definitiva de esteproblema, siempre que se tenga la precaución de vigilar posibles signos de miopatía, especialmente si el pacienteestá siendo tratado con otros fármacos que puedanproducir este mismo problema.Es todavía muy pronto para terminar de definir el perfilreal de EA de dalvabancina, ya que la información de losensayos clínicos es todavía escasa, pero aparentemente setrata de un fármaco con buen perfil de tolerancia(AU)

Linezolid, tigecycline, daptomycin and dalbavancin arenew antibacterial agents with a peculiar adverse eventand, in some cases, interactions profile. Linezolid isnotable for its excellent tolerance in short-lastingtreatments; however the use of this drug for more than4 weeks seems to be more problematic. None of the mostproblematic adverse events (neuritis, bone marrowalterations and lactic acidosis) seem to be of brusqueonset and consequently close monitoring for the presenceof early symptoms and/or hemogram abnormalities isimportant. The peculiarity of interactions with linezolidseems to lie in this drug’s relatively weak monoamineoxidase inhibitor (MAOI) effect, which may enhanceserotoninergic effects when combined withantidepressants, increasing the activity of serotonin. Themost appropriate strategy is to reduce the dose of theantidepressant and remain vigilant for the presence ofearly symptoms (gastrointestinal, muscular neurological).Tigecycline has a well-known profile because it is sharedby almost all tetracyclines and the precautions andcontraindications of these drugs are repeated in the caseof tigecycline which, moreover, is notable for its potentialto produce nausea and vomiting. These adverse effectsseem to be frequent, even when the drug is administeredevery 12 hours. The fact that these effects do not seem tobe associated with high plasma concentrations wouldfacilitate use of this drug in a higher single daily dose thanthat currently used, which would also achieve higherplasma concentrations. Daptomycin also has a peculiarprofile, consisting of elevation in blood of muscularenzymes and specifically of CPK counts, which seem to be directly related to accumulation of the drug in muscle;consequently these effects are infrequent if the interval ofadministration avoids this accumulation(AU)

The use of appropriate doses, but in an adjusted single daily dose ifthere is renal dysfunction, seems to be the definitivesolution to this problem, as long as possible signs ofmyopathy are monitored, especially if the patient is alsounder treatment with other drugs that could produce thesame problem. It is still too soon to define the definitiveadverse event profile of dalbavancin, since data fromclinical trials is scarce; however, the drug seems to be welltolerated(AU)

Efectos adversos e interacciones de los nuevos antibióticos activos frente a cocos grampositivos / Adverse effects and interactions of the new antibiotics active against Gram-positive cocci

Linezolid, tigeciclina, daptomicina y dalvabancina sonnuevos antibacterianos con un perfil peculiar de efectosadversos (EA) y en algunos casos de interacciones. Elprimero de los citados destaca por la excelente tolerancia en tratamientos de corta duración, mientras que su utilización resulta más problemática cuando la duración se prolonga en el tiempo y parece que las 4 semanas pueden ser la barrera que marque, de algún modo, las diferencias. En cualquier caso, ninguno de los EA más problemáticos (neuritis, alteraciones de la médula ósea y acidosis láctica) parece presentarse bruscamente, por lo que la vigilancia de la presencia de síntomas precoces y/o alteraciones en el hemograma se convierte en relevante en este caso. En referencia a las interacciones, la peculiaridad parece ubicarse en su ligera capacidad de producir cierto efectoIMAO que conlleva un potencial de suma de efectosserotoninérgicos al asociarse con antidepresivos queelevan la actividad de este mismo neurotransmisor. Denuevo la precaución de reducir la dosis del antidepresivo y la de vigilar la presencia de síntomas precoces (digestivos, musculares y neurológicos) se convierte en la estrategia más acertada (...)

Linezolid, tigecycline, daptomycin and dalbavancin arenew antibacterial agents with a peculiar adverse eventand, in some cases, interactions profile. Linezolid isnotable for its excellent tolerance in short-lastingtreatments; however the use of this drug for more than4 weeks seems to be more problematic. None of the mostproblematic adverse events (neuritis, bone marrowalterations and lactic acidosis) seem to be of brusqueonset and consequently close monitoring for the presenceof early symptoms and/or hemogram abnormalities isimportant. The peculiarity of interactions with linezolidseems to lie in this drug’s relatively weak monoamineoxidase inhibitor (MAOI) effect, which may enhanceserotoninergic effects when combined withantidepressants, increasing the activity of serotonin. The most appropriate strategy is to reduce the dose of the antidepressant and remain vigilant for the presence of early symptoms (gastrointestinal, muscular neurological). Tigecycline has a well-known profile because it is shared by almost all tetracyclines and the precautions andcontraindications of these drugs are repeated in the case of tigecycline which, moreover, is notable for its potential to produce nausea and vomiting. These adverse effects seem to be frequent, even when the drug is administered every 12 hours. The fact that these effects do not seem to be associated with high plasma concentrations would facilitate use of this drug in a higher single daily dose thanthat currently used, which would also achieve higherplasma concentrations. Daptomycin also has a peculiarprofile, consisting of elevation in blood of muscularenzymes and specifically of CPK counts, which seem to be (...)

[Tenofovir: pharmacology and interactions]. / Tenofovir: farmacología e interacciones.

Tenofovir is a nucleotide analogue and consequently its mechanism of action differs from that of nucleoside analogues. This drug is administered orally in the form of disoproxil ester, which is deesterified to achieve a bioavailability of more than 20%. This bioavailability slightly increases if tenofovir is taken with a fat-rich meal. This drug has broad tissue distribution, aided by its small molecular size and very low protein binding, and is eliminated as unchanged drug in the urine through glomerular filtration and active tubular secretion. Because of this latter characteristic, dosage adjustments are required in patients with renal insufficiency. The intracellular half-life of tenofovir is more than 10 times greater than the plasma half-life. Because of the pharmacokinetic profile of tenofovir, interactions with other drugs are scarce. Within the class of antiretroviral agents, an increase in the bioavailability of didanosine has been described, leading to the recommendation that the dose of didanosine be reduced when used in combination with tenofovir. Tenofovir can be used without adjustments with other nucleoside and nonnucleoside reverse transcriptase inhibitors. Equally, tenofovir seems to have no effect on the pharmacokinetics of protease inhibitors although these latter agents may produce a slight increase in the bioavailability of tenofovir, which seems to be of little clinical relevance. The absence of interactions with other non-antiretroviral agents has been reported.

[Pharmacology of azoles]. / Farmacología de los azoles.

Azole antifungals have different pharmacokinetic characteristics: complete oral absorption for Voriconazole, and to a lesser extent for fluconazole. The absorption of posaconazole and itraconazole increases with food intake. All of them have high tissue distribution with low plasma concentrations, especially low in the case of posaconazole and itraconazole. Posaconazole and itraconazole have high plasmatic protein binding and consequently both have a very low free fraction. Elimination of azole antifungals is through a metabolic pathway with CYP450 isoenzymes, and has a non linear pharmacokinetics with a high risk of interation with other drugs since azoles have the ability of CYP450 isoenzymes inhibition. Possibly the parameter that defines more precisely their efficacy is AUIC with an optimum value near 20, although cut-off values must be defined since some azoles may have difficulty to reach this value.

Stereoselective pharmacokinetic analysis of tramadol and its main phase I metabolites in healthy subjects after intravenous and oral administration of racemic tramadol.

The kinetics of tramadol enantiomers are stereoselective when doses of the racemic drug are given orally. To document whether the route of administration determines the stereoselective kinetics of tramadol enantiomers, healthy volunteers received 100 mg oral or intravenous doses of racemic tramadol, and serial blood samples were obtained to assay tramadol enantiomers and their main phase I metabolites, O-demethyltramadol and N-demethyltramadol. To assess accurately the involvement of their metabolites in the pharmacokinetics of tramadol, it is essential to determine the rate and extent of the formation of the enantiomers of these metabolites. A simultaneous pharmacokinetic model describing the plasma concentration-curves of the generated metabolites and the parent compounds after intravenous and oral drug administration is developed and presented. Tramadol and O-demethyltramadol were the major compounds detected in plasma after intravenous administration. Nevertheless, the N-demethylation of tramadol showed a significant increase when the oral route was used. After both oral and intravenous doses, the kinetics of the tramadol enantiomers were stereoselective. The AUC for (R )-(+)-tramadol was greater than the AUC for (S)-(-)-tramadol. The formation of N-demethyltramadol also was enantioselective after oral administration of racemic tramadol, with a greater AUC for (R)-(+)-N-demethyltramadol than for (S)-(-)-N-demethyltramadol. In the opposite form, (S)-(-)-O-demethyltramadol was formed faster than (R)-(+)-O-demethyltramadol. The metabolism of tramadol was also route-dependent with a different enantiomeric ratio for tramadol and its main phase I metabolites after intravenous and oral administration. The disposition of N-demethyltramadol was concentration-dependent.

Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype.

OBJECTIVE: Our objective was to evaluate the effect of CYP2D6 phenotype in the enantioselective metabolism of tramadol in Spanish healthy human volunteers. METHODS: A single oral 100mg dose of racemic tramadol was administered to five subjects who were poor metabolizers (PMs) and 19 subjects who were extensive metabolizers (EMs), whose phenotypes were determined by the use of the racemic tramadol metabolic rate. The pharmacokinetic parameters were estimated from plasma concentrations of the enantiomers of tramadol and their main phase I metabolites, O-desmethyltramadol (M1) and N-desmethyltramadol (M2). Epinephrine plasma concentrations were also determinated. RESULTS: The plasma concentrations of both tramadol enantiomers were consistently higher in PMs than in EMs of CYP2D6, with 1.98- and 1.74-fold differences in the mean area under the plasma concentration-time curves (AUC), respectively. The values for oral clearance of (+)- and (--)-tramadol were 1.91- and 1.71-fold greater in PMs, which were related to differences in both O-desmethylation and N-desmethylation in the two CYP2D6 metabolizer phenotypes. The mean AUC values of (+)-M1 and (--)-M1 were 4.33- and 0.89-fold greater in EMs, and it was related to similar differences in the formation rate constant. On the other hand, the differences were 7.40- and 8.69-fold greater in PMs for M2 enantiomers due to the involvement of CYP2D6 in their subsequent biotransformation. The time course of epinephrine systemic concentrations was completely different between both groups of metabolizers. In EMs plasma concentrations of epinephrine increased after tramadol administration whereas in PMs no effect was observed. CONCLUSIONS: The polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol enantiomers. The N-desmethylation pathway was indirectly affected by CYP2D6 phenotypic differences. Epinephrine showed a good correlation with the pharmacokinetics of the opioid component of tramadol, (+)-M1 and was found to be useful for its pharmacodynamic profiling.

Farmacología de los azoles / Pharmacology of azoles

Los azoles presentan características farmacocinéticas diferenciadas, con unaabsorción oral completa de voriconazol, menor de fluconazol y menosimportante y que aumenta con alimentos en el caso de posaconazol eitraconazol. Todos presentan una distribución tisular elevada, que semanifiesta por concentraciones plasmáticas muy reducidas, especialmente enel caso de posaconazol e itraconazol. Estos dos últimos fármacos presentanuna fracción libre reducida al circular en plasma unidos a proteínas enproporción elevada. La eliminación es en todos los casos a través demetabolismo con intervención de diversas isoenzimas CYP450, a las que soncapaces de inhibir, lo que condiciona una farmacocinética no lineal y unelevado riesgo de interacciones con otros fármacos. Es posible que elparámetro que mejor defina la eficacia sea el AUIC con un valor óptimo de 20.Si esta circunstancia se concreta, debe valorarse el punto de corte para lasensibilidad puesto que algunos de estos fármacos pueden tener dificultadespara alcanzar este valor(AU)

Azole antifungals have different pharmacokinetic characteristics: complete oralabsorption for Voriconazole, and to a lesser extent for fluconazole.The absorption of posaconazole and itraconazole increases with food intake.All of them have high tissue distribution with low plasma concentrations,especially low in the case of posaconazole and itraconazole. Posaconazoleand itraconazole have high plasmatic protein binding and consequently bothhave a very low free fraction. Elimination of azole antifungals is through ametabolic pathway with CYP450 isoenzymes, and has a non linearpharmacokinetics with a high risk of interation with other drugs since azoleshave the ability of CYP450 isoenzymes inhibition. Possibly the parameter thatdefines more precisely their efficacy is AUIC with an optimum value near 20,although cut-off values must be defined since some azoles may have difficultyto reach this value(AU)

[Fosfomycin trometamol: multiple-dose regimen for the treatment of lower urinary tract infections]. / Fosfomicina trometamol. Dosis múltiples como pauta larga en el tratamiento de las infecciones urinarias bajas.

INTRODUCTION: A short antibiotic regimen is recommended for the treatment of uncomplicated lower urinary tract infection. Nevertheless, the treatment to follow in other situations is not so clearly defined. When the person affected by lower urinary tract infection is not a young woman, it is recommended to treat at least 7 days, and quinolones or cotrimoxazole are the antibiotics most often used. However, because of the frequency of drug resistance in this type if infection, it is advisable to apply antibiotics with lower rates of resistance, such as fosfomycin trometamol, for longer treatment periods than the often-used single dose. METHODS: Using the data on urinary elimination of fosfomycin after a single dose obtained in a prior study in healthy volunteers, we simulated the urinary concentrations of this antibiotic following administration of two doses. In addition, we calculated the interval of administration required to achieve urinary concentrations greater than 16 mg/L, the critical concentration of sensitivity for Escherichia coli, one of the most commonly implicated microorganisms in these infections. RESULTS: Fosfomycin concentrations in urine persisted above the defined cut-off for 161 hours after administration of two 3-g doses of fosfomycin trometamol, 72 hours apart. This implied an efficacy time of 66% in a period of 7 days. CONCLUSION: From the pharmacokinetic viewpoint, the optimum dosage of fosfomycin trometamol to achieve appropriate urinary concentrations along 7 days is administration of two 3-g doses, 72 hours apart.

Fosfomicina trometamol. Dosis múltiples como pauta larga en el tratamiento de las infecciones urinarias bajas / Fosfomycin trometamol: Multiple-dose regimen for the treatment of lower urinary tract infections

Introducción. El tratamiento de las infecciones urinarias del tracto inferior no complicadas se realiza con pautas de tratamiento cortas. En otras circunstancias no está tan clara la pauta que hay que seguir. Cuando la infección urinaria del tracto inferior no se produce en una mujer joven, la recomendación terapéutica es la utilización de antibióticos durante al menos 7 días, y son las quinolonas y el cotrimoxazol los antibióticos utilizados con mayor frecuencia. Pero debido al porcentaje de resistencias de los microorganismos implicados en este tipo de infecciones, es aconsejable evaluar otras pautas de tratamiento, de forma que habría que evaluar, entre otros, el uso de antibióticos con un menor índice de resistencias como fosfomicina trometamol, en períodos de tratamiento más largos que el uso tan extendido en dosis única. Métodos. Desde los datos de eliminación urinaria de fosfomicina obtenidos en voluntarios sanos en un estudio previo, se han simulado las concentraciones de este antibiótico en orina tras la administración de 2 dosis. Se ha calculado el intervalo más idóneo para mantener concentraciones urinarias por encima del punto de corte de Escherichia coli para fosfomicina (16 mg/l), uno de los microorganismos implicados con mayor frecuencia en este tipo de infecciones. Resultados. Las concentraciones de fosfomicina en orina se mantienen por encima del punto de corte durante 161 h cuando se administran 2 dosis de 3 g de fosfomicina trometamol separadas 72 h. Éste supone un tiempo de eficacia del 96% en un período total de 7 días. Conclusión. La pauta teórica, desde el punto de vista farmacocinético, para conseguir concentraciones de fosfomicina en orina por encima del punto de corte de E. coli es la administración de 2 dosis de 3 g de fosfomicina trometamol separadas 72 h (AU)

Introduction. A short antibiotic regimen is recommended for the treatment of uncomplicated lower urinary tract infection. Nevertheless, the treatment to follow in other situations is not so clearly defined. When the person affected by lower urinary tract infection is not a young woman, it is recommended to treat at least 7 days, and quinolones or cotrimoxazole are the antibiotics most often used. However, because of the frequency of drug resistance in this type if infection, it is advisable to apply antibiotics with lower rates of resistance, such as fosfomycin trometamol, for longer treatment periods than the often-used single dose. Methods. Using the data on urinary elimination of fosfomycin after a single dose obtained in a prior study in healthy volunteers, we simulated the urinary concentrations of this antibiotic following administration of two doses. In addition, we calculated the interval of administration required to achieve urinary concentrations greater than 16 mg/L, the critical concentration of sensitivity for Escherichia coli, one of the most commonly implicated microorganisms in these infections. Results. Fosfomycin concentrations in urine persisted above the defined cut-off for 161 hours after administration of two 3-g doses of fosfomycin trometamol, 72 hours apart. This implied an efficacy time of 66% in a period of 7 days. Conclusion. From the pharmacokinetic viewpoint, the optimum dosage of fosfomycin trometamol to achieve appropriate urinary concentrations along 7 days is administration of two 3-g doses, 72 hours apart (AU)

A comparative study of the pharmacokinetics of ibuprofen arginate versus dexibuprofen in healthy volunteers.

OBJECTIVE: Ibuprofen arginate is a salt formulation of ibuprofen designed to reach target concentrations rapidly. The primary objective of this study was to compare the 12-h pharmacokinetic profile of S(+)-ibuprofen following administration of single doses of ibuprofen arginate (600 mg) and dexibuprofen (400 mg) in healthy volunteers. METHODS: Twenty-four volunteers were recruited into an open-label, randomised, two-period, single-centre study with crossover design. RESULTS: Both treatments were well tolerated. Ibuprofen arginate and dexibuprofen showed similar bioavailability for S(+)-ibuprofen. Compared with dexibuprofen, ibuprofen arginate demonstrated a 45% higher maximum concentration (C(max)), and a time to peak concentration (T(max)) 2 h sooner. CONCLUSION: Ibuprofen arginate approaches maximum concentrations of S(+)-ibuprofen faster and higher than dexibuprofen.

Effects of a 250-mL enema containing sodium phosphate on electrolyte concentrations in healthy volunteers: An open-label, randomized, controlled, two-period, crossover clinical trial.

BACKGROUND: Enemas are used by individuals with constipation and are often required before certain medical diagnostic procedures and surgical interventions. However, abnormalities in serum electrolyte concentrations have been associated with enema use. OBJECTIVE: The aim of this study was to determine the changes in serum electrolyte concentrations (phosphorus, calcium, sodium, and potassium) and urinary phosphorus elimination after the administration of a sodium phosphate enema. METHODS: Healthy volunteers aged 35 to 70 years were eligible for this open-label, randomized, controlled, 2-period, crossover clinical trial at the Clinical Research Unit of the University Hospital of Navarra, Pamplona, Spain. The study comprised 2 one-day periods separated by a 7-day washout. All subjects were randomly assigned in a 1:1 ratio to 1 of 2 study sequences: (1) a single dose of Enema Casen® 250 mL in the first period followed by no treatment (control) in the second period, or (2) no treatment in the first period followed by a single dose of the study drug in the second period. The sequence of treatment was assigned using a randomization table that was prepared before the beginning of the study. Serum concentrations of phosphorus, sodium, potassium, and calcium were measured in both periods. Urinary phosphorus elimination was measured for 12 hours after enema administration (Ae0-12) in a subset of the subjects in the second period. Adverse events (AEs) were monitored by the investigators throughout the study. Normal ranges for the electrolytes were as follows: phosphorus, 2.5 to 5 mg/dL; calcium, 8.5 to 10.5 mg/dL; sodium, 135 to 145 mEq/L; and potassium, 3.5 to 5 mEq/L. RESULTS: Twenty-four subjects (12 men, 12 women; mean [SD] age, 47.8 [9.6] years [range, 36-68 years]) participated in the study. All of the subjects were white and none were smokers. Twelve hours after enema administration, mean serum phosphorus and sodium concentrations increased by a mean of 1.18 mg/dL and 1.32 mEq/L, respectively (both, P < 0.001). Mean serum phosphorus concentrations were above the upper limit of normal (5 mg/dL) at 30 and 60 minutes after enema administration. In all subjects the values returned to normal within 4 hours after enema administration; a meal was provided after a 3-hour fast. Four subjects (16.7%) had ≥1 serum phosphorus concentration measurement ≥7 mg/dL, a value that is considered serious hyperphosphatemia. A statistically significant correlation was found between phosphorus Cmax and enema retention time (r (2) = 0.452; P < 0.001). No abnormal serum concentrations were obtained for the other electrolytes measured. Phosphorus Ae0-12 was increased after enema administration by 86% (P < 0.001). No serious AEs were observed, although 13 AEs were reported in 9 subjects. None of the changes in serum electrolyte concentrations were associated with clinical symptoms. CONCLUSIONS: Administration of an enema containing 250 mL of sodium phosphate was associated with serum phosphorus concentrations of ≥7 mg/dL in 16.7% of the healthy subjects who participated in the study; however, none of those subjects experienced hypocalcemia. Enema retention time was significantly correlated with the degree of phosphatemia.