Selexipag, a selective prostacyclin receptor agonist in pulmonary arterial hypertension: a pharmacology review.

INTRODUCTION: Pulmonary hypertension is defined by a mean pulmonary artery pressure ≥25 mm Hg at rest. Management of pulmonary arterial hypertension (PAH) includes specific drug therapy with calcium channel blockers in vasoreactive patients, or drugs approved for PAH in non-reactive patients that target the endothelin, nitric-oxide and prostacyclin pathways. Areas covered: The review covers receptor selectivity, pharmacokinetics, pharmacodynamics and adverse effects (AEs) of intravenous (IV) epoprostenol (synthetic prostacyclin); the prostacyclin analogs iloprost, beraprost, and treprostinil administered by IV, subcutaneous, inhaled or oral routes; and the oral selective prostacyclin receptor agonist selexipag. Expert commentary: Development of a selective prostacyclin receptor agonist has aimed at identifying compounds with improved pharmacological properties. The high selectivity of selexipag, and its active metabolite ACT-333679, for the prostacyclin receptor, in conjunction with pharmacokinetic properties that reduce peak-trough fluctuations and the up-titration regimen used at the start of treatment, are collectively considered to minimize AEs associated with prostacyclin use. In a large phase 3 study, selexipag-associated AEs were consistent with those observed with drugs that target the prostacyclin pathway, and mainly mild to moderate in severity. The dosing flexibility afforded by oral selexipag may facilitate achieving the maximum therapeutic effect with acceptable tolerability in patients with PAH.

Percepción de los médicos sobre los factores que influyen en la elección de un dicumarínico o de un nuevo anticoagulante oral en pacientes con fibrilación auricular no valvular / Perception of physicians on factors that influence the choice of a dicoumarin or a new oral anticoagulant in patients with non-valvular atrial fibrillation

OBJETIVO: Estudios recientes han demostrado la eficacia y la seguridad de los nuevos anticoagulantes orales (NACO) en la prevención de tromboembolias en pacientes con fibrilación auricular no valvular (FANV). Nuestro objetivo es evaluar qué factores influyen en los médicos para elegir entre dicumarínicos o NACO. DISEÑO: Se analizaron distintas variables, que fueron discutidas y puntuadas siguiendo una metodología Workmat®. EMPLAZAMIENTO: Se realizaron 6 reuniones regionales en España (Levante, Cataluña, Andalucía Extremadura, Madrid, Noroeste y Norte de España). PARTICIPANTES: Participaron 39 especialistas (cardiólogos, neurólogos, hematólogos, internistas y médicos de urgencias y atención primaria). Mediciones: Cada participante puntuó de 1 a 10 (de menor a mayor) el grado de acuerdo con cada variable analizada. RESULTADOS: Se elegiría preferiblemente un NACO en pacientes con fracaso previo del tratamiento dicumarínico (9,7 ± 0,5), riesgo hemorrágico elevado (8,7 ± 1), antecedentes de hemorragia (7,8 ± 1,5) y riesgo trombótico alto (7,7 ± 1,2). Se decantarían por un dicumarínico en casos de disfunción renal grave (1,2 ± 0,4) o moderada (4,2 ± 2,5), buen control con dicumarínicos (2,3 ± 1,5), deterioro cognitivo (3,2 ± 3) y riesgo hemorrágico bajo (4,3 ± 3). La edad, el sexo, el peso, el coste del fármaco, la polimedicación y la existencia de un riesgo trombótico bajo obtuvieron puntuaciones intermedias. CONCLUSIONES: El riesgo trombótico y hemorrágico elevado y el fracaso del tratamiento previo con dicumarínicos predisponen a elegir un NACO. La insuficiencia renal, el deterioro cognitivo, el buen control con dicumarínicos y un riesgo hemorrágico bajo inclinan a decantarse por un dicumarínico clásico

AIMS: Recent studies have demonstrated the efficacy and safety of new oral anticoagulant drugs for the prevention of thromboembolic events in patients with non-valvular atrial fibrillation. Our aim was to evaluate the factors that can influence physicians in their choice between a classic and a new anticoagulant in these patients. DESIGN: Several variables of interest were discussed and analysed using a WorkmatTM methodology. Sites: Six regional meetings were held in Spain (East, Catalonia, Andalusia-Extremadura, Madrid, North-east, and North of Spain). PARTICIPANTS: Meetings were attended by 39 specialists (cardiologists, neurologists, haematologists, internists, and emergency and Primary Care physicians). Measurements: Each participant graded their level of agreement, with a score from 1 to 10, on every analysed variable. RESULTS: A new anticoagulant drug was preferred in patients with previous failure of dicoumarin therapy (9.7 ± 0.5), high haemorrhagic risk (8.7 ± 1), prior bleeding (7.8 ± 1.5), and high thrombotic risk (7.7 ± 1.2). Dicoumarins were preferred in cases of severe (1.2 ± 0.4) or moderate (4.2 ± 2.5) kidney failure, good control with dicoumarins (2.3°æ 1.5), cognitive impairment (3.2 ± 3), and low haemorrhagic risk (4.3 ± 3). Age, sex, weight, cost of drug, polymedication, and low thrombotic risk achieved intermediate scores. There were no differences between the different specialists or Spanish regions. CONCLUSIONS: The presence of a high thrombotic or haemorrhagic risk and the failure of previous dicoumarin therapy lead to choosing a new oral anticoagulant in patients with non-valvular atrial fibrillation, while kidney failure, cognitive impairment, good control with dicoumarins, and a low bleeding risk predispose to selecting a classic dicoumarin anticoagulant

[Perception of physicians on factors that influence the choice of a dicoumarin or a new oral anticoagulant in patients with non-valvular atrial fibrillation]. / Percepción de los médicos sobre los factores que influyen en la elección de un dicumarínico o de un nuevo anticoagulante oral en pacientes con fibrilación auricular no valvular.

AIMS: Recent studies have demonstrated the efficacy and safety of new oral anticoagulant drugs for the prevention of thromboembolic events in patients with non-valvular atrial fibrillation. Our aim was to evaluate the factors that can influence physicians in their choice between a classic and a new anticoagulant in these patients. DESIGN: Several variables of interest were discussed and analysed using a WorkmatTM methodology. SITES: Six regional meetings were held in Spain (East, Catalonia, Andalusia-Extremadura, Madrid, North-east, and North of Spain). PARTICIPANTS: Meetings were attended by 39 specialists (cardiologists, neurologists, haematologists, internists, and emergency and Primary Care physicians). MEASUREMENTS: Each participant graded their level of agreement, with a score from 1 to 10, on every analysed variable. RESULTS: A new anticoagulant drug was preferred in patients with previous failure of dicoumarin therapy (9.7±0.5), high haemorrhagic risk (8.7±1), prior bleeding (7.8±1.5), and high thrombotic risk (7.7±1.2). Dicoumarins were preferred in cases of severe (1.2±0.4) or moderate (4.2±2.5) kidney failure, good control with dicoumarins (2.3±1.5), cognitive impairment (3.2±3), and low haemorrhagic risk (4.3±3). Age, sex, weight, cost of drug, polymedication, and low thrombotic risk achieved intermediate scores. There were no differences between the different specialists or Spanish regions. CONCLUSIONS: The presence of a high thrombotic or haemorrhagic risk and the failure of previous dicoumarin therapy lead to choosing a new oral anticoagulant in patients with non-valvular atrial fibrillation, while kidney failure, cognitive impairment, good control with dicoumarins, and a low bleeding risk predispose to selecting a classic dicoumarin anticoagulant.

[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)

Efecto clase / The class effect

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