Sites of First-Pass Bioactivation (Hydrolysis) of Orally Administered Zofenopril Calcium in Dogs

The relative contribution of the gut, liver, and lungs as sites of first-pass bioactivation (hydrolysis) of the orally administered ester prodrug, zofenopril calcium (SQ 26,991), to the active angiotensin converting enzyme (ACE) inhibitor, SQ 26,333, was determined. With a five-way study design, two dogs each received a single 1.6-mg/kg dose of zofenopril [as its soluble potassium salt (SQ 26,900)] via the following routes of administration: intraarterial, intravenous, intraportal, and oral. Each dog also received an equimolar oral dose of zofenopril calcium (1.5 mg/kg). Concentrations of zofenopril in plasma were quantitated with a GC/MSD assay. Extraction ratios (E) for zofenopril by the gut, liver, and lungs were calculated based on the ratios of the area under the curve (AUC) values of zofenopril in arterial plasma after administration by the various routes. As individual eliminating organs, the gut and liver each had a high intrinsic capability to hydrolyze zofenopril; E values ranged from 45 to 89%. The lungs were found to have low, but measurable, hydrolytic activity with estimated E values that ranged from 5 to 26%. Overall, about 95% of the orally administered dose of zofenopril calcium was hydrolyzed during the first pass. Because the prodrug is sequentially exposed to the gut, liver, and lungs, the contribution of the gut to the overall first-pass hydrolysis (ca. 87%) was estimated to be significantly greater than that of the liver (<10%) or lungs (<2%). Zofenopril was rapidly eliminated after parenteral administration; mean residence time values were 2 min and the elimination half-life values (intraarterial route only) were 9 min. The total-body clearance (Cl_total) of zofenopril, determined after intraarterial injection, was rapid (ca. 25 ml/min/kg) and was similar to the Cl_total value reported previously for fosinopril sodium, another prodrug ACE inhibitor. Although the E _lungs value was relatively low, the lungs receive 100% of cardiac output and were estimated to contribute significantly to systemic bioactivation of zofenopril. The major sites of systemic bioactivation appear to be the lungs (ca. 44 to 65%) and liver (ca. 31%), whereas the hydrolysis of zofenopril by the blood per se does not apparently contribute to Cl_total.     

Regional microvascular anatomy of the rabbit ciliary body

Vascular luminal castings of rabbit eyes were microdissected and studied with the scanning electron microscope to delineate the anatomy of the ciliary body microvasculature. We found regional microvascular differences corresponding to well known gross topographical and ultrastructural differences that may indicate regional functional specialization. The major arterial circle of the iris, derived solely from the long posterior ciliary arteries, supplies the ciliary body via two types of arterioles: anterior and posterior. Spiral iridial process capillaries arise from the anterior (iris) arterioles, are radially arranged along the back of the iris and drain directly into the iris veins. Arterioles from the posterior (ciliary) arterioles enter the head of the process, supplying its tortuous capillaries, some of which drain back into the iris veins. Other capillaries turn posteriorly to form relatively straight, parallel capillaries within the process leaf that drain into the choroidal system via marginal process veins. More posterior arterioles supply capillaries to the base of major processes, to the interprocess ciliary web, and to minor processes. The presence of a dual arteriolar supply to the ciliary processes has also been found in primates and suggests that the rabbit may represent a suitable animal model for the study of factors governing regional ciliary process perfusion.     

Scintigraphic evaluation of brain death: significance of sagittal sinus visualization

Radiotracer scintigraphy has been commonly used in this country to confirm and document the clinical diagnosis of brain death. Whether the presence of radiotracer activity in the region of sagittal venous sinus (SVS) represents actual blood flow to the brain in the absence of demonstrable cerebral arterial flow remains a controversial issue. Our retrospective study was performed to review the significance of such sagittal tracer activity. Of the 53 patients showing no cerebral arterial flow, 26 showed tracer activity in the region of SVS. The clinical status, EEG findings, and outcome of all 53 patients were the same irrespective of the presence or absence of SVS tracer activity. We conclude that the mere presence of SVS in the absence of demonstrable cerebral arterial flow activity is not clinically significant and does not contradict the diagnosis of brain death.     

Intraperikaryal Neurofilamentous Accumulations in a Subset of Retinal Ganglion Cells in Aged Mice That Express a Human Neurofilament Gene

Neurofilamentous changes in select groups of neurons are associated with the degenerative changes of many human age-related neurodegenerative diseases. To examine the possible effects of aging on the neuronal cytoskeleton containing human proteins, the retinas of transgenic mice expressing the gene for the human middle-sized neurofilament triplet were investigated at 3 or 12 months of age. Transgenic mice developed tangle-like neurofilamentous accumulations in a subset of retinal ganglion cells at 12 months of age. These neurofilamentous accumulations, which also involved endogenous neurofilament proteins, were present in the perikarya and proximal processes of large ganglion cells and were predominantly located in peripheral retina. The presence of the human protein may thus confer vulnerability of the cytoskeleton to age-related alterations in this specific retinal cell type and may serve as a model for similar cellular changes associated with Alzheimer's disease and glaucoma.     

Posterior cortical atrophy in Alzheimer's disease: analysis of a new case and re-evaluation of a historical report

Summary Disturbances of visual function are not uncommon in Alzheimer's disease and several cases with complex impairment of visuospatial abilities have been described. For instance, posterior cortical atrophy has been demonstrated in cases displaying Balint's syn-drome as the first symptom of the dementing illness. Such cases showed very high lesion counts in the occipital cortex, as well as in visual association regions in the posterior parietal and posterior cingulate cortex, whereas the prefrontal cortex was consistently less severely involved than usually observed in Alzheimer's disease. This suggests that the distribution of the lesions had been shifted to specific elements of the visual system. In the present study; we report the quantitative analysis of a new case of Alzheimer's disease with possible Balint's syndrome and re-evaluate a case originally described in 1945. The distribution of lesions in these two cases parallels previous observations of Alzheimer's disease cases with early visual impairment. Both cases displayed very high densities of neurofibrillary tangles and senile plaques in the primary visual cortex, secondary visual cortex, visual association areas of the dorsal occipital and posterior parietal lobe and in the posterior cingulate cortex, whereas the prefrontal and inferior temporal regions were comparatively less affected. These cases may define clinical subgroups of Alzheimer's disease and suggest that the breakdown of corticocortical projections that is known to occur in dementia may involve select components of specific functional systems in certain cases. In particular, path-ways that subserve motion detection and visuospatial analysis appear to be dramatically affected in these cases presenting with Balint's syndrome. Thus, Alzheimer's disease may be a more heterogeneous disorder than previously thought, and refined neuropsychological testing as well as detailed neuropathological evaluation may be of value to detect possible clinical variants of this dementing conditon.Supported by the Brookdale Foundation, and NIH grants AG06647 and AG05138 (to P.R.H. and J.H.M.), and by funds from the Robert H. and Monica Cole Foundation and Alzheimer's Disease Research, a program of the American Health Assistance Foundation (to A.P.O.)     

Developmental outcome of epilepsy surgery in tuberous sclerosis complex.

In Tuberous sclerosis complex (TSC), neurological dysfunction, usually in association with epilepsy, is responsible for the greatest degree of disease-related disability. Epilepsy surgery is increasingly recognized as a therapeutic option given the often medication-resistant nature of the disease. Seven subjects with medically refractory epilepsy associated with TSC, who underwent surgery at a tertiary care epilepsy center and in whom both preoperative and postoperative neuropsychological data were available, were examined. The Vineland Adaptive Behavior Scales, and in one case, the WISC-III were utilized. Postoperatively, the composite standard scores declined in six of the seven subjects, although for the most part this decline was quite modest (8 points or less in 5/6 subjects). The mean overall developmental/intellectual quotients were comparable across assessments (preoperative M = 55, SD = 20.3; postoperative M = 49 SD = 16.6). Good outcomes appeared to be related to seizure relief. Age estimates of developmental level indicated developmental progress in the majority of subjects in the current sample, and may yield greater clinical information for individuals with developmental delay than do standard scores.     

Effects of the autoimmune uterine/maternal environment upon cortical ectopias, behavior and autoimmunity.

NZB and BXSB mice develop autoimmune disease and learn poorly on avoidance tasks. In addition, many of these mice have ectopic collections of neurons, which occur prenatally, in layer I of the cerebral neocortex. The purpose of these experiments was to evaluate the contribution of the uterine/maternal environment upon these variables by transferring fertilized ova to an autoimmune or a non-autoimmune maternal host. In Experiment 1 fertilized DBA ova were transferred into the uteri of BXSB maternal recipients. Later, these animals and conventionally reared DBAs were tested for paw preference, swimming rotation, water escape learning, and shuttlebox avoidance learning. Blood was taken for measurement of immune parameters, and their brains were examined for cortical ectopias. As compared to conventional DBAs, the ova transfer mice had greater amounts of anti-dsDNA autoantibodies, poorer avoidance learning, and poorer water escape learning; in addition, the females had greater paw asymmetry. There was only 1 ectopia in the 81 ova transfer animals, and none in the 78 control mice. In Experiment 2 fertilized NZB ova were transferred into the uteri of non-autoimmune hybrid females and the same procedures were followed as in Experiment 1. Ova transfer mice had lesser amounts of anti-dsDNA autoantibodies, better avoidance learning scores, and females had less paw asymmetry; in addition, within the ova transfer group males were clockwise swimmers whereas females swam counterclockwise. There were 4 ectopics out of 17 ova transfer mice (23.5%), which did not differ from the 40.5% of the control group. In both experiments the uterine environment did not affect the occurrence of ectopias.(ABSTRACT TRUNCATED AT 250 WORDS)