Twenty six-week repeat dose oral rat toxicity study of cizolirtine, a substance-P and calcitonin gene-related peptide release modulator.

Cizolirtine, a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence, was orally administered for 26-weeks to rats at dosages of 20, 60 and 200 mg/kg/day. Clinical signs were limited to post-dosing salivation and brown staining on head and muzzle. There were slight decreases in bodyweight gain and slight increases in water consumption among cizolirtine-treated animals. Slight increases in plasma alkaline phosphatase activity, and cholesterol and phospholipid concentrations were observed in mid- and/or high-dose animals. Low urinary volume, pH and sodium and potassium outputs were observed after 12-weeks, and low urinary pH, low sodium and high potassium outputs at end of treatment. Increased relative (to bodyweight) liver weight was observed in high-dose animals. Treated males and high-dose females showed a dose-related increase in the incidence and severity of periacinar hepatocytic hypertrophy and midzonal/periacinar hepatocytic fat vacuolization. Increased incidences of hepatic clear cell foci were observed in all cizolirtine-treated male groups and, to a lesser extent, in treated females. Ovaries of treated females showed a dose-dependent increased incidence of absent corpora lutea and, occasionally, follicular cysts. The dosages of 20 and 60 mg/kg/day were considered as the No-Observed-Adverse-Effect Levels for males and females, respectively.

Legacy data sharing to improve drug safety assessment: the eTOX project.

The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through the Innovative Medicines Initiative to explore this possibility.

Costo-efectividad de la resincronización biventricular como alternativa de tratamiento de la insuficiencia cardiaca / Cost-effectiveness of the biventricular resynchronization as an alternative therapy for heart failure

La evolución final de la mayoría de las enfermedades cardiovasculares es el síndrome de insuficiencia cardiaca, su tratamiento puede abordarse de diferentes formas. Para aquellos pacientes refractarios a tratamiento farmacológico, uno de los más recientemente utilizados es la resincronización biventricular. Identificar los costos y el grado de efectividad de la resincronización biventricular como una opción en el tratamiento de enfermos con insuficiencia cardiaca refractaria y bloqueo de la rama izquierda del haz de His. Se realizó una evaluación económica del tipo costo-efectividad según la clasificación de Drummond y otros. Fue considerado un horizonte temporal que osciló entre seis meses y cinco años. Las alternativas consideradas fueron: la resincronización biventricular y la terapia farmacológica como alternativa teórica de la no resincronización. El universo lo integraron 30 enfermos con insuficiencia cardiaca refractaria a tratamiento. La variable de efectividad considerada fue: muerte evitada. El 76,6 por ciento de los enfermos eran del sexo masculino y el 23,4 por ciento del sexo femenino. La mortalidad fue de 36,6 por ciento en el período de seguimiento. La efectividad del proceder alcanzó el 63,4 por ciento, con 19 muertes evitadas. El costo efectividad incremental fue de 33 805, 00 pesos. La introducción en Cuba de la alternativa de tratamiento de la insuficiencia cardiaca, conocida como resincronización biventricular resulta costo-efectiva(AU)

The final evolution of most of cardiovascular diseases is the heart failure syndrome and there are several ways to treat it. For those patients refractory to drug therapy, one of the most recent methods is biventricular resyncronization. To identify costs and level of effectiveness of biventricular resynchronization as a choice of treatment of refractory heart failure patients with His´bundle left branch blocking. A cost-effectiveness type economic assessment was made following Drummond et al´s classification. The considered period of time was 6 months to one year. The analyzed alternatives were biventricular resynchronization and drug therapy as theoretical alternative to non-resynchronization. The universe of study was 30 patients suffering heart failure refractory to treatment. The effectiveness variable was prevented death. In this group, 76,6 percent of patients were males and 23.4 percent were females. Mortality rate was 36,6 percent in the follow-up period. The effectiveness of the procedure was 63,4 percent representing 19 prevented deaths. The incremental cost-effectiveness was $ 33 805, 00 pesos. The introduction of therapeutic option known as biventricular resynchronization to treat heart failure was cost-effective(AU)

Costo-efectividad de la resincronización biventricular como alternativa de tratamiento de la insuficiencia cardiaca / Cost-effectiveness of the biventricular resynchronization as an alternative therapy for heart failure

Introducción La evolución final de la mayoría de las enfermedades cardiovasculares es el síndrome de insuficiencia cardiaca, su tratamiento puede abordarse de diferentes formas. Para aquellos pacientes refractarios a tratamiento farmacológico, uno de los más recientemente utilizados es la resincronización biventricular. Objetivos Identificar los costos y el grado de efectividad de la resincronización biventricular como una opción en el tratamiento de enfermos con insuficiencia cardiaca refractaria y bloqueo de la rama izquierda del haz de His. Métodos Se realizó una evaluación económica del tipo costo-efectividad según la clasificación de Drummond y otros. Fue considerado un horizonte temporal que osciló entre seis meses y cinco años. Las alternativas consideradas fueron: la resincronización biventricular y la terapia farmacológica como alternativa teórica de la no resincronización. El universo lo integraron 30 enfermos con insuficiencia cardiaca refractaria a tratamiento. La variable de efectividad considerada fue: muerte evitada. Resultados El 76,6 por ciento de los enfermos eran del sexo masculino y el 23,4 por ciento del sexo femenino. La mortalidad fue de 36,6 por ciento en el período de seguimiento. La efectividad del proceder alcanzó el 63,4 por ciento, con 19 muertes evitadas. El costo efectividad incremental fue de 33 805,00 pesos. Conclusiones La introducción en Cuba de la alternativa de tratamiento de la insuficiencia cardiaca, conocida como resincronización biventricular resulta costo-efectiva.

Introduction The final evolution of most of cardiovascular diseases is the heart failure syndrome and there are several ways to treat it. For those patients refractory to drug therapy, one of the most recent methods is biventricular resyncronization. Objectives To identify costs and level of effectiveness of biventricular resynchronization as a choice of treatment of refractory heart failure patients with His´bundle left branch blocking. Methods A cost-effectiveness type economic assessment was made following Drummond et al´s classification. The considered period of time was 6 months to one year. The analyzed alternatives were biventricular resynchronization and drug therapy as theoretical alternative to non-resynchronization. The universe of study was 30 patients suffering heart failure refractory to treatment. The effectiveness variable was prevented death. Results In this group, 76.6 percent of patients were males and 23.4 percent were females. Mortality rate was 36.6 percent in the follow-up period. The effectiveness of the procedure was 63.4 percent representing 19 prevented deaths. The incremental cost-effectiveness was $ 33 805.00 pesos. Conclusions The introduction of therapeutic option known as biventricular resynchronization to treat heart failure was cost-effective.

Evaluation of the genotoxic potential of three phenyltetrahydropyridinyl butylazole-derived sigma-receptor ligand drug candidates.

Three structurally related phenyltetrahydropyridinyl butylazole (PTHPB)-derived drug candidates with sigma receptor-binding properties were evaluated for genotoxic potential in the ICH standard battery of genetic toxicology assays. These comprised an Ames test, a mouse-lymphoma assay, and a mouse bone-marrow micronucleus test. The maximum test concentrations in the in vitro assays were determined by the solubility and/or the cytotoxicity of the compounds. In the mouse micronucleus assay, the compounds were administered orally at three levels up to the maximum tolerated dose (MTD). Negative results were obtained for all three drug candidates in the Ames test and in the mouse-lymphoma assay, both in the absence or presence of metabolic activation. In the mouse micronucleus test, there was no effect on the frequency of micronucleated polychromatic erythrocytes (MNPCE) in bone marrow after oral administration of any of the three test compounds, at any dose level or sampling time (24 and 48h). Administration of all three compounds at the MTD induced a clear decrease in mouse body-temperature of 3.1-4.8 degrees C below normal; the temperature returned to normal within 8h of dose administration. The produced mild hypothermia and absence of micronucleus induction was in contrast to the induction of MNPCE secondary to marked hypothermia reported for a structurally similar PTHPB-derived sigma-receptor ligand, the antipsychotic compound E-5842. The results obtained in the current series of studies suggest that exposure to the three tested PTHPB-derived drug candidates would not pose a genotoxic risk under clinical conditions.

Separación de la tríada de zoapatanol y montanol obtenida de Montanoa tomentosa s.s.p. tomentosa por cromatografía de líquidos de alta exactitud en fase inversa / Separation of \"triplet\" zoapatanol and montanol obtained from Montanoa tomentosa s.s.p. tomentosa by revers-plase high perfomance liquid chromatography

Se ha aislado a partir de hojas y flores de Montanoa tomentosa s.s.p. tomentosa un material homogéneo biológicamente activo conocido como "tríada"; en este artículo se describe la separación de los tres componentes por cromatografía líquida de alta presión. Este método es más sencillo, rápido y barato que cualquier otro publicado hasta la fecha. Este procedimiento permite la separación preparativa de zoapatanol y montanol. También se comprueba que la "tríada" está formada por zoapatanol, montanol y otro compuesto estrechamente relacionado con el último