NAALADase (N‐acetylated‐α‐linked‐acidic dipeptidase; also termed glutamate carboxypeptidase II) is an enzyme that catalyzes hydrolysis of the abundant brain peptide N‐acetyl‐aspartyl‐glutamate (NAAG) ...to N acetyl‐aspartate (NAA) and glutamate. We have synthesized many potent and selective NAALADase inhibitors from distinct chemical classes. In rodents, selective inhibitors have been shown to increase NAAG and decrease glutamate extracellularly and provide therapeutic benefits in animal models of neurological diseases where excess glutamate neurotransmission has been implicated. Specifically, NAALADase inhibitors exhibit neuroprotection in rats following transient middle cerebral artery occlusion, attenuate neuropathic pain following chronic constrictive injury, prevent nerve conduction velocity deficits and sural nerve degeneration following chronic diabetes in STZ and BB/W rats, and delay clinical symptoms and mortality in the mouse SOD transgenic model of ALS. These biological effects are likely mediated by increases in extracellular NAAG and decreases in extracellular glutamate as a consequence of NAALADase inhibition. NAALADase inhibition may be useful in neurological disorders in which excessive excitatory amino acid transmission is pathogenic. Also, NAALADase inhibition may represent a novel glutamate regulating strategy devoid of the side‐effects that have hampered development of postsynaptic glutamate receptor antagonists. A lead NAALADase inhibitor termed GPI 5693 is currently completing Phase I clinical testing.
To assess changes in risk factors of coronary artery disease, examinations which had been performed in 1981 and 1982 were repeated in males aged 40-59, inhabitants of the district "Czechów" in ...Lublin. The study was based on Polish Experiment of Coronary Disease Multifactor Prevention assumptions 112 of 203 males investigated in 1981, 1982 underwent repeated examination (attendance rate - 55%). Statistical analysis was performed only in twice examined subjects. Significant increase of blood pressure, body weight, total serum cholesterol and uric acid concentration was stated in comparison with their respective initial values. Significant decrease of HDL-cholesterol and no changes in serum triglycerides concentration were observed. The only positive stated alteration was a lower percentage of tobacco smokers. Diagnosis of coronary artery disease remained unchanged despite of increased risk factors levels (increase of mean Rose's index score from 5 in initial examination to 6.5 in a control one). This high increase in risk factors occurrence allows an unfavourable prognosis for future incidence of coronary artery disease and also demands to undertake vigorous prevention.
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