Characterization of regional left ventricular contraction by curvature difference analysis

Summary A method which characterizes the contraction of the left ventricle (LV) by changes in the LV endocardial contour curvatures is presented. A normalized curvature difference function (NCDF) is defined by the difference between the (normalized) curvature functions of end diastolic (ED) and end systolic (ES) contours. Unlike wall-motion based procedures, NCDF is independent of any reference system and of the method used for ED-ES shape alignment.Normal and pathological diagnosis criteria were first established based on right anterior oblique (RAO) projection ventriculograms of a study group which included 58 normal and 28 abnormal patients. Patients with an infarcted myocardial region differed from the characteristic NCDF pattern of normals and exhibited regionally defined irregularities. The diagnosis criteria were then applied to a total of 159 patients in two groups in two independent laboratories. One group (in Israel) included 49 cases (20 normals, 29 abnormals); the second (in France) included 108 cases (48 normals, 60 abnormals). These two groups yielded similar sensitivity (97% and 97%) and specificity (90% and 100%) in detection of abnormality of the ventricle. When tested against other quantitative wall motion techniques, the NCDF shows a regional sensitivity of 95%, indicating that curvature difference analysis is a potential tool for the automatic and objective diagnosis of regional LV function abnormalities.     

Synthesis and structure-activity relationships of beta- and alpha-piperidine sulfone hydroxamic acid matrix metalloproteinase inhibitors with oral antitumor efficacy

alpha-Piperidine-beta-sulfone hydroxamate derivatives were explored that are potent for matrix metalloproteinases (MMP)-2, -9, and -13 and are sparing of MMP-1. The investigation of the beta-sulfones subsequently led to the discovery of hitherto unknown alpha-sulfone hydroxamates that are superior to the corresponding beta-sulfones in potency for target MMPs, selectivity vs MMP-1, and exposure when dosed orally. alpha-Piperidine-alpha-sulfone hydroxamate 35f (SC-276) was advanced through antitumor and antiangiogenesis assays and was selected for development. Compound 35f demonstrates excellent antitumor activity vs MX-1 breast tumor in mice when dosed orally as monotherapy or in combination with paclitaxel.