RESUMEN
AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced ß cell stress, and promoted ß cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.
Asunto(s)
Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Compuestos Heterocíclicos/farmacología , Homeostasis , Animales , Glucemia/efectos de los fármacos , Presión Sanguínea , Cardiomegalia , Enfermedades Cardiovasculares , Glucógeno/metabolismo , Corazón , Holoprosencefalia/prevención & control , Humanos , Resistencia a la Insulina , Células Secretoras de Insulina , Anomalías Maxilomandibulares/prevención & control , Metformina/uso terapéutico , Ratones , Ratones Obesos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Ratas , Volumen SistólicoRESUMEN
BACKGROUND: There are few independent, population-based reports that estimate the risk of hospitalization of respiratory syncytial virus (RSV)-infected infants before and during the palivizumab era. We present figures from the greater Stockholm area during the three seasons after the introduction of palivizumab and relate them to data based on 1400 hospitalizations for RSV disease in the same population area during 1987 through 1998. METHODS: The number of births, neonatal complications and palivizumab prescriptions was obtained. We retrieved information about all infant hospitalizations for confirmed RSV infections with risk factors and complications. Chronic lung disease (CLD) in preterm infants was defined as oxygen dependency beyond 36 weeks of postconceptional age. RESULTS: Eight hundred eighteen infants (1.3% of the population) were hospitalized for confirmed RSV infection. The hospitalization rates were 3.7% (24 of 642) among preterm infants with gestational age <33 weeks without CLD and 7.2% (14 of 195) in those with CLD. Palivizumab had been given to 235 infants, usually those with CLD and in need of continuous oxygen or steroid treatment or the <6 month-old infants with extremely preterm birth (gestational age <26 weeks). The risk of hospitalization for RSV disease was low, but this was the case also before the introduction of palivizumab. CONCLUSIONS: In countries with a low baseline risk of hospitalization for RSV infection, the benefit of palivizumab might not justify the cost of its widespread use. We advocate defining more rigorous prescription criteria.