RESUMEN
This 9-month randomised, parallel, double-blind, single-centre, placebo-controlled study (PROBE, ISRCTN18030882) assessed the impact of probiotic supplementation on bodyweight. Seventy overweight Bulgarian participants aged 45-65 years with BMI 25-29.9 kg/m2 received a daily dose of the Lab4P probiotic comprising lactobacilli and bifidobacteria (50 billion cfu/day). Participants maintained their normal diet and lifestyle over the duration of the study. The primary outcome was change from baseline in body weight and secondary outcomes included changes in waist circumference, hip circumference and blood pressure. A significant between group decrease in body weight (3.16 kg, 95% CI 3.94, 2.38, p < 0.0001) was detected favouring the probiotic group. Supplementation also resulted in significant between group decreases in waist circumference (2.58 cm, 95% CI 3.23, 1.94, p < 0.0001) and hip circumference (2.66 cm, 95% CI 3.28, 2.05, p < 0.0001) but no changes in blood pressure were observed. These findings support the outcomes of a previous shorter-term Lab4P intervention study in overweight and obese participants (PROMAGEN, ISRCTN12562026). We conclude that Lab4P has consistent weight modulation capability in free-living overweight adults.
Asunto(s)
Suplementos Dietéticos , Sobrepeso/dietoterapia , Probióticos/uso terapéutico , Pérdida de Peso/efectos de los fármacos , Bifidobacterium , Presión Sanguínea/efectos de los fármacos , Tamaño Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Bulgaria , Método Doble Ciego , Femenino , Humanos , Lactobacillus , Masculino , Persona de Mediana Edad , Circunferencia de la Cintura/efectos de los fármacosRESUMEN
The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Cre-positive (SM22α)CaSR(Δflox/Δflox) [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca(2+)) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-l-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca(2+) concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR.
Asunto(s)
Presión Sanguínea , Señalización del Calcio , Calcio/metabolismo , Hipotensión/metabolismo , Músculo Liso Vascular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Vasoconstricción , Vasodilatación , Animales , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Bradicardia/genética , Bradicardia/metabolismo , Bradicardia/fisiopatología , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/genética , Relación Dosis-Respuesta a Droga , Predisposición Genética a la Enfermedad , Frecuencia Cardíaca , Hipotensión/genética , Hipotensión/fisiopatología , Arterias Mesentéricas/metabolismo , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiopatología , Miocitos Cardíacos/metabolismo , Fenotipo , Receptores Sensibles al Calcio , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Vasoconstricción/efectos de los fármacos , Vasoconstricción/genética , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/genética , Vasodilatadores/farmacología , Remodelación VentricularRESUMEN
The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with other serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drugtreated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk.
Asunto(s)
1-Naftilamina/análogos & derivados , Antidepresivos/toxicidad , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidad , 1-Naftilamina/administración & dosificación , 1-Naftilamina/toxicidad , Administración Oral , Animales , Antidepresivos/administración & dosificación , Pruebas de Carcinogenicidad , Enfermedad Hepática Inducida por Sustancias y Drogas , Perros , Evaluación Preclínica de Medicamentos , Inducción Enzimática/efectos de los fármacos , Femenino , Inyecciones Intraperitoneales , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Ratones , Pruebas de Mutagenicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal , Conejos , Ratas , Reproducción/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Sertralina , Especificidad de la EspecieRESUMEN
The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drug-treated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk.