Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury

<p>Abstract</p> <p>Background</p> <p>Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD), a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome.</p> <p>Methods</p> <p>Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50–150 mg/kg body weight/day; injected subcutaneously) and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue.</p> <p>Results</p> <p>Prophylactic treatment with an optimal dose of sildenafil (2 × 50 mg/kg/day) significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH).</p> <p>Conclusion</p> <p>Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary inflammatory response, fibrin deposition and RVH, and stimulates alveolarization. Initiation of sildenafil treatment after hyperoxic lung injury and continued during room air recovery improves alveolarization and restores pulmonary angiogenesis and RVH in experimental BPD.</p

Changes in electrocardiographic morphology reflect instantaneous changes in left ventricular volume and output in cardiac surgery patients

We examined the relation between changes in R-to-T wave amplitude ratios (R:T) and left ventricular (LV) performance as cardiac output was rapidly varied by inferior vena caval occlusion in 6 subjects prior to cardiopulmonary bypass. To assess the influence of contractility, paired studies before and after bypass were performed in 4 subjects. Stroke volume and cardiac output were assessed by aortic flow probe, and transesophageal echocardiographic LV area measures using the automated border-detection method were used to give LV stroke area, stroke force, maximal LV area, fractional area change, end-systolic elastance, and preload recruitable stroke force. Data were collected on computer and analyzed by linear regression. Significant changes in R:T and measured LV variables during the inferior vena caval occlusion were stroke volume (r = 0.81), LV stroke area (r = 0.77), LV stroke force (r = 0.81), maximal LV area (r = 0.78), and cardiac output (r = 0.80). However, R:T varied inconsistently in relation to fractional area change. After cardiopulmonary bypass, the linear relation between R:T with LV stroke force, LV stroke volume, and maximal LV area persisted, but at a lesser slope. Although absolute pre-inferior vena caval occlusion R:T did not correlate with end-systolic elastance or preload recruitable stroke force, the change in the slope of these linear relations correlated well with the change in end-systolic elastance after surgery (r = 0.92). Instantaneous changes in electrocardiographic morphology reflect changes in LV preload-dependent variables, whereas long-term changes in electrocardiographic morphology may also reflect changes in contractile state. © 1995

Levodopa pharmacokinetic-pharmacodynamic modeling and 6-[F-18]levodopa positron emission tomography in patients with Parkinson's disease

Objective: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with levodopa tagged with 6-fluorine 18, an established imaging method for striatal dopaminergic neurons. Methods. Twenty-three patients in different disease stages (Hoehm. and Yahr stage 2.5-5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427-42]; median duration, 12 years) were studied. PK-PD modeling followed a single oral dose of levodopa/benserazide. The sum score of the Columbia Rating Scale (CURS Sigma) was used for clinical assessments. A nonparametric effect compartment approach assuming a sigmoidal E-max model was applied to the PK-PD analysis of plasma levodopa concentrations and corresponding CURS Sigma. Thereafter 6-[F-18]levodopa PET was performed, and the influx rate constants (k(c)) for the putamen and the caudatus region were correlated with the median effective concentration (EC50) and the equilibrium half-life (T-eq) of the PK-PD model. Results: (1) A significant correlation was observed between PK-PD parameters or with k(c) putamen as the dependent variable and the duration of the disease as the independent variable, which explains 33% of the variability of the EC50, 42% of the variability of T-eq, and 36% of the variability of k(c). (2) Significant correlations were observed between k(c) and either EC50 or T-eq, yielding the closest correlation for the putamen region (r = -0.47, P <.05; and r = 0.55, P <.01; respectively). Conclusions: Our findings show that key parameters of a PK-PD model of levodopa were in fairly close agreement with imaging of dopaminergic neurons by 6-[F-18]levodopa PET. However, although PK-PD modeling of levodopa has been proven as a useful investigation of approaches aimed to restore dopaminergic deficits or to monitor disease progression, this modeling cannot serve as a pathomorphologic surrogate for the loss of striatal dopaminergic neurons

Administrative und technische Moeglichkeiten zur Eindaemmung der Oelverschmutzung der Nordsee Abschlussbericht

TIB: FR 3634+a+b / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman