Sigmund E. Lasker

Low-Molecular-Weight Derivative of Heparin that is Orally Active in Mice

An important characteristic of heparin as a therapeutic anticoagulant or a prophylactic agent for deep venous thrombosis is its rapid onset of action. The need for parenteral injection, however, severely limits its use as a long-term therapeutic agent. An orally active heparin-like compound could find wide application.

PMR AND 13C STUDIES OF SOME SULFATED POLYSACCHARIDES

Our interest in the structure and function of sulfatei pc.,fsacchariL,s of mammalian origin is motivated by the continued successful use of these compounds in clinical medicine. Although these polymers have been available for several decades, knowledge of their structural detail and precise mechanisms of action is lacking, particularly in the case of polymers of glucosamine and uronic acid. Some of these polysaccharides have important clinical application because of their unusual biological properties. When injected, heparin can function in living systems with minimal toxicity as a potent inhibitor of blood clotting and can stimulate the production of the enzymic clearing factor, which is capable of hydrolyzing the fatty acid esters. These properties of some sulfated polysaccharides are of current clinical interest. Their role in triglyceride and cholesterol metabolism and in blood coagulation in myocardial infarction is presently being explored. Compounds that inhibit the clotting mechanism or interact with enzymes involved in clotting or that alter the blood level of triglycerides are currently being used clinically as experimental prophylactics in large scale trials. The heparins that are used commercially have been isolated from the cellular substance of liver, lung, or intestines of beef or pork. These polysaccharides are also found in abundance in the organs of the whale and man. Heparinoids with anticoagulant activity have also been isolated from clam muscle, mast cell tumors of man, dog, and mouse, as well as from the scales of the carp. We present here a preliminary report on our continuing nmr studies of this class of compounds.

N-ethyl-N-nitrosourea induced brain tumors in rats monitored by nuclear magnetic resonance imaging, plasma proton nuclear magnetic resonance spectroscopy and microscopy ☆

Characteristic slow growing brain gliomas were induced in rats by a single subcutaneous injection of N-ethyl-N-nitrosourea (ENU) within 24 h of birth. A parallel control group of rats was injected with saline. Seven treated rats developed gliomas within 2 years. Periodic nuclear magnetic resonance imaging (MRI) of the brain in 3-mm slices at 1.5 Tesla and monthly plasma sampling for proton magnetic resonance spectroscopy (MRS) at 360 MHz were started 6 months after the injection of ENU. In the MRS experiments, the Fossel index, average of the line widths of the methylene and methyl peaks at 360 MHz, was determined from half-line widths of methyl and methylene peaks at 0.8 ppm and 1.3 ppm. In five of the ENU injected animals that developed histologically verified brain tumors, these were also observed by MRI without contrast agents. There was no consistent correlation between the imaged tumors and the Fossel index obtained through MRS during the course of the study where repeated observations were performed on individual animals, nor was there any consistent statistical difference in the Fossel index between ENU-treated and control animals. The results of this study demonstrate that slowly developing carcinogen-induced brain tumors in rats can be successfully and reliably monitored noninvasively by MRI but not by MRS of plasma.

Light scattering dissymmetry studies of systems containing fibrinogen and thrombin or bothrops atrox venom

Abstract The changes in the dissymmetry of light-scattering which occur during the coagulation of fibrinogen in the presence of thrombin are described. The data are interpreted with regard to polymerization and gelation of the coagulation process and presented, in part, in a novel tabular fashion. In light scattering experiments, in which the conversion of purified fibrinogen to fibrin by thrombin is performed with different additives, characteristics dissymmetry curves are obtained. At pH 8.4, as well as in the presence of 0.2 M LiBr, μ=0.34, pH 7.4, three breaks and three slopes can be seen. The second slope represents a fast increase in particle size, whereas the third slope is a negative one, leading to a steady dissymetry value. The use of a coagulant enzyme preparation from Bothrops atrox venom, instead of thrombin, produces two distinct breaks and two slopes. The second slope, brought about at pH∼7 by fibrinogen, thrombin and Ca++, is decreased by heparin, depending on its concentration, and is increased by the addition of the BaSO4 plasma. This addition also produces a larger particle size within 2 min, leading to a gel. This gel is only partially insoluble after 20 min and is completely insoluble after 40 min in urea solution. Thus, the gelation-promoting or geloplastic effect appears to be independent of transamidase present in the same plasma.