ABSTRACT
A 82-year-old woman came to our hospital because of orthopnea and cardiac cachexia. Echocardiography revealed a pressure gradient of 50 mmHg at the left ventricular outflow tract and that of 78 mmHg at the mid-ventricle. Systolic anterior motion of the mitral leaflet caused by mitral annular calcification and severe mitral regurgitation( MR) were observed. On the basis of the patient's age and poor general conditions, we resected abnormal myocardium on the septum from the outflow tract down to the apex via aortic valve and we left the mitral annular calcification. The pressure gradient in the left ventricle, systolic anterior motion and mitral regurgitation were relieved, and her postoperative course was uneventful. Two years after the surgery, she remains in New York Heart Association( NYHA) class â and is well.
Subject(s)
Cardiomyopathy, Hypertrophic , Mitral Valve Insufficiency , Humans , Female , Aged, 80 and over , Mitral Valve Insufficiency/diagnostic imaging , Mitral Valve Insufficiency/etiology , Mitral Valve Insufficiency/surgery , Heart Ventricles/surgery , Mitral Valve/diagnostic imaging , Mitral Valve/surgery , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/surgery , HemodynamicsABSTRACT
The design, synthesis, and biological evaluation of novel 3-aryl-indazole derivatives as peripherally selective pan-Trk inhibitors are described. Three strategies were used to obtain a potent compound exhibiting low central nervous system (CNS) penetration and high plasma exposure: 1) a structure-based drug design (SBDD) approach was used to improve potency; 2) a substrate for an efflux transporter for lowering brain penetration was explored; and 3) the most basic pKa (pKa-MB) value was used as an indicator to identify compounds with good membrane permeability. This enabled the identification of the peripherally targeted 17c with the potency, kinase-selectivity, and plasma exposure required to demonstrate in vivo efficacy in a Complete Freund's adjuvant (CFA)-induced thermal hypersensitivity model.
Subject(s)
Drug Discovery , Indazoles/pharmacology , Pain/drug therapy , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Molecular Structure , Pain/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
An epicardial mesothelial cyst, which can be defined as a mesothelial cyst attached to the epicardium surrounding the heart and the great vessels inside the pericardial sac, is a rare condition. We herein report a case of epicardial cyst, which was attached to the ascending aorta. The patient was a 76-year-old male who underwent coronary artery bypass surgery, and the cyst was found incidentally. It was approximately 5 cm in diameter, and histological examination confirmed mesothelial cell origin. The ascending aorta has not previously been reported as the origin of an epicardial mesothelial cyst. This case gives new insight into the embryology of these cysts.
Subject(s)
Aorta/pathology , Heart Neoplasms/pathology , Heart Neoplasms/surgery , Mesothelioma, Cystic/pathology , Mesothelioma, Cystic/surgery , Pericardium/pathology , Aged , Aorta/surgery , Humans , Incidental Findings , Male , Pericardium/surgery , Treatment OutcomeABSTRACT
We describe a medicinal chemistry approach to generate a series of benzimidazoles bearing thiazolidin-4-one using scaffold hopping from thiazole 1, our previously described thiazole. Our goal was to discover a potent and permeable small-molecule ADAMTS-5 inhibitor. The results suggest that small compound 22 shows promise as a potent small-molecule ADAMTS-5 inhibitor with good permeability.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , ADAM Proteins/metabolism , ADAMTS5 Protein , Benzimidazoles/pharmacokinetics , Drug Design , Humans , Osteoarthritis/drug therapy , Permeability , Structure-Activity RelationshipABSTRACT
A series of thiazole bearing thiazolidin-4-one was discovered via high-throughput screening as non-competitive inhibitors of ADAMTS-5. Compound 31 appeared to give the best ADAMTS-5 inhibition and good selectivity over other metalloproteases.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Thiazoles/pharmacology , ADAM Proteins/metabolism , ADAMTS5 Protein , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
During screening for mammalian DNA polymerase inhibitors, we found and succeeded in isolating a potent inhibitor from a higher plant, Taxus cuspidate. The compound was unexpectedly determined to be taxinine, an intermediate of paclitaxel (taxol) metabolism. Taxinine was found to selectively inhibit DNA polymerase alpha (pol.alpha) and beta (pol.beta). We therefore, tested taxol and other derivatives and found that taxol itself had no such inhibitory effect, and only taxinine could inhibit both pol.alpha and beta. The other compounds used, one derivative, cephalomannine, and five intermediates synthesized chemically inhibited only the pol.alpha activity in vitro. None of the compounds, including taxinine, influenced the activities of the other DNA polymerases, which are reportedly targeted by many pol.beta inhibitors. With both pol.alpha and beta, all of the compounds tested noncompetitively inhibited with respect to both the DNA template-primer and the dNTP substrate.
