ABSTRACT
In this paper we describe the synthesis, structure-activity relationship (SAR), and biochemical characterization of N-(4-phenylthiazol-2-yl)benzenesulfonamides as inhibitors of kynurenine 3-hydroxylase. The compounds 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide 16 (IC50 = 37 nM, Ro-61-8048) and 4-amino-N-[4-[2-fluoro-5-(trifluoromethyl)phenyl]-thiazol-2-yl] benzenesulfonamide 20 (IC50 = 19 nM) were found to be high-affinity inhibitors of this enzyme in vitro. In addition, both compounds blocked rat and gerbil kynurenine 3-hydroxylase after oral administration, with ED50's in the 3-5 mumol/kg range in gerbil brain. In a microdialysis experiment in rats, 16 dose dependently increased kynurenic acid concentration in the extracellular hippocampal fluid. A dose of 100 mumol/kg po led to a 7.5-fold increase in kynurenic acid outflow. These new compounds should allow detailed investigation of the pathophysiological role of the kynurenine pathway after neuronal injury.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Mixed Function Oxygenases/antagonists & inhibitors , Neuroprotective Agents/chemical synthesis , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Animals , Brain/drug effects , Brain/enzymology , Brain/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Extracellular Space/chemistry , Gerbillinae , Kidney/drug effects , Kidney/enzymology , Kinetics , Kynurenic Acid/metabolism , Kynurenine 3-Monooxygenase , Liver/drug effects , Liver/enzymology , Mitochondria/drug effects , Mitochondria/metabolism , Mixed Function Oxygenases/metabolism , Molecular Structure , Neuroprotective Agents/pharmacology , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
The authors participated in the European multicenter investigation, ESPRIT, organized by the Wellcome Research Laboratories. Thrombolytic treatment by intravenous tissue plasminogen activator was performed in 25 patients with early (less than 6h) myocardial infarction. The efficacy of the treatment was controlled by repeat coronary arteriography at 60 minutes, at 90 minutes and at 24 hours of the tpA treatment. The infarct related artery was reperfused in 9/25 patients at 60 minutes, in 16/25 at 90 minutes and 17/18 at 24 hours. Four patients died after unsuccessful treatment or reocclusion. In two patients significant bleeding occurred at the puncture site but no transfusion was required. No other untoward effect was registered. The left ventricular function did not change significantly during the first day of infarction. It is concluded, that tpA is a safe thrombolytic agent in myocardial infarction. Its thrombolytic efficacy is similar to that of streptokinase.
Subject(s)
Coronary Disease/drug therapy , Myocardial Infarction/drug therapy , Plasminogen Activators/therapeutic use , Thrombolytic Therapy/methods , Europe , Humans , International CooperationABSTRACT
Direct cardiac effects of ionic diatrizoate (Uromiro) and non-ionic iopamidol (Iopamiro) were investigated in "in situ" heart-lung preparation of 19 vagotomized dogs. Diatrizoate was found to induce considerably greater alteration in plasma osmolality and subsequent dehydration of the myocardium compared with iopamidol. Myocardial dehydration resulted in a decrease of left ventricular compliance and in that of cardiac performance. Diatrizoate was shown to influence the myocardium not only by its hyperosmolarity but also by a direct action. Heart rate was reduced by both contrast media.
Subject(s)
Diatrizoate/pharmacology , Heart/drug effects , Iopamidol/pharmacology , Animals , Blood/drug effects , Blood Pressure/drug effects , Cardiac Output/drug effects , Dogs , Female , Heart Ventricles/drug effects , MaleABSTRACT
The molecular species of the major phospholipids from the marine sponges Parasperella psila and Microciona prolifera were studied using chemical hydrolysis, enzymatic degradation and capillary gas chromatography (GC), high performance liquid chromatography (HPLC), desorption chemical ionization (DCI), fast atom bombardment (FAB) combined with collisionally activated decomposition (CAD) mass spectrometry. Two new solvent systems were developed for the isolation of these species from the sponges. Our investigations indicated the existence of unusual symmetrical phospholipids as major components. 1,2-Di-(5Z,9Z)-5,9-hexacosadienoyl-sn-glycero-3-phosph oethanolamine was found in both organisms, while 1,2-di(5Z,9Z,19Z)-5,9,19-hexacosatrienoyl-sn-gly cero-3-phosphoethanolamine was present in M. prolifera, 1,2-Di-(4Z,7Z,10Z,13Z,16Z,19Z)-4,7,1 0,13,16,19-docosahexaenoyl-sn-glycero-3- phosphocholine was the major molecular species in the PC fraction of M. prolifera.
Subject(s)
Phospholipids , Animals , Chromatography, High Pressure Liquid/methods , Fatty Acids/analysis , Mass Spectrometry/methods , Phospholipids/isolation & purification , Porifera/analysis , Structure-Activity RelationshipABSTRACT
A 48-year-old man sustained an inferior myocardial infarction resulting in a left ventricular aneurysm, ventricular septal defect and mitral regurgitation. Aneurysmectomy, closure of the ventricular septal defect, mitral valve replacement and coronary artery bypass were successfully performed.
Subject(s)
Coronary Artery Bypass , Heart Aneurysm/surgery , Heart Septal Defects, Ventricular/surgery , Heart Valve Prosthesis , Mitral Valve Insufficiency/surgery , Myocardial Infarction/complications , Blood Vessel Prosthesis , Cardiac Catheterization , Combined Modality Therapy , Graft Occlusion, Vascular/diagnostic imaging , Humans , Male , Middle Aged , Mitral Valve/surgery , Myocardial Infarction/surgery , Postoperative Complications/diagnostic imaging , Radiography , Saphenous Vein/transplantationABSTRACT
Left ventriculography and coronary arteriography were performed in 47 patients with hyperacute myocardial infarction prior to recanalization of the infarct-related vessel. Mitral regurgitation was found in ten patients. After successful recanalization, left ventriculography was repeated in eight of the ten patients with mitral incompetence, and the mitral regurgitation had disappeared in seven. Selective intracoronary thrombolysis resulted in improved left ventricular function and disappearance of mitral incompetence.
Subject(s)
Coronary Circulation/drug effects , Fibrinolytic Agents/therapeutic use , Myocardial Infarction/complications , Streptokinase/therapeutic use , Adult , Aged , Angiography , Female , Heart/physiopathology , Heart Ventricles , Humans , Male , Middle Aged , Mitral Valve Insufficiency , Motion Pictures , Myocardial Infarction/physiopathologyABSTRACT
A case of enormous Chiari's network in a 7-year-old girl is described. It formed a parachute or spinnaker-like sack which moved freely into the pulmonary artery causing mild pulmonic stenosis. The preoperative diagnosis was believed to be myxoma of the right ventricle. The real condition was recognized during the operation. This is the seventh reported case of correction of so-called cor triatriatum dextrum.