Pharmacological treatment for cerebral ischemia and cerebral vasospasm following subarachnoid hemorrhage (SAH) cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. We recently developed a liposomal drug delivery system for intrathecal application that can maintain effective concentrations of cerebral vasodilator, fasudil, in the CSF. A single intrathecal injection of liposomal fasudil could maintain a therapeutic drug concentration in the CSF over a period time due to their sustained-release property, significantly decreasing infarct size in a rat model of acute ischemia and reducing vasoconstriction of the rat and dog basilar artery in a model of SAH. In this review, we are introducing our new less-invasive intrathecal drug delivery system that provides an alternative and safe method to deliver therapeutic agents.
with pulmonary atresia associated with various other congenital anomalies in whom the central pulmonary artery originally gave rise to right and left pulmonary arteries. Twenty one patients who had not been treated surgically form the present study group. They range in age from 11 days to 21 years (median 4 years). Eight are males and 13 are females (Table). All were investigated by cross sectional echocardiography and angiocardiography. The morphology of the central pulmonary artery (pulmonary trunk and main branches) was studied by biplane cut-film or cine angiography. After ventriculography or aortography, selective pulmonary angiography was performed by catheterisation of the persistent ductus arteriosus, except in one patient (case 6) in whom the ductus arteriosus was not patent and in five patients under the age of 1 year (cases 1, 2, 7, 8, and 16). In case 6 the entire central pulmonary artery was visualised by pulmonary vein wedge angiography. In the five infants the central pulmonary artery was clearly visualised by aortography. In six patients (cases 16-21) the proximal left pulmonary artery was atretic and angiography through the ductus arteriosus showed only the distal left pulmonary artery. In three (cases 17, 18, and 20) of these six patients a right pulmonary arteriogram was obtained by injection of contrast medium into the right pulmonary vein wedge position.
A culture of smooth muscle cells obtained from monkey middle cerebral arteries was developed to allow quantitative assessment of intracellular calcium and immunofluorescence analysis after various periods of exposure to oxyhemoglobin. Intracellular calcium concentration was examined for up to 7 days after a single exposure to oxyhemoglobin. Intracellular calcium concentrations were measured with the fluorescent dye fura-2 and were significantly elevated for 7 days after exposure to oxyhemoglobin (P less than 0.01). Less than 2 minutes after application of oxyhemoglobin, there was marked elevation of intracellular calcium from the control value of 75 +/- 2 nmol/L to 240 +/- 28 nmol/L (P less than 0.01 by analysis of variance). Intracellular calcium concentration of cells exposed for 24 hours to oxyhemoglobin and then grown in normal oxyhemoglobin-free medium fell close to normal levels on Days 3 and 7. On Day 3, the increase in intracellular calcium that followed repeated daily exposure to oxyhemoglobin was greater than that resulting from a single application of oxyhemoglobin (P less than 0.01 by Student's t test), but by Day 7 the elevation produced by these different approaches was similar. Smooth muscle cells exposed to oxyhemoglobin showed a reduction in immunoreactivity to alpha-actin. These data support the hypothesis that disruption of intracellular calcium regulation and calcium overloading may be important in the process of cell injury, which results in vasoconstriction and sometimes cell death, after exposure to oxyhemoglobin.
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