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Streptokinase (SK) is a potent clot dissolver but lacks fibrin clot specificity as it activates human plasminogen (HPG) into human plasmin (HPN) throughout the system leading to increased risk of bleeding. Another major drawback associated with all thrombolytics, including tissue plasminogen activator, is the generation of transient thrombin and release of clot-bound thrombin that promotes reformation of clots. In order to obtain anti-thrombotic as well as clot-specificity properties in SK, cDNAs encoding the EGF 4,5,6 domains of human thrombomodulin were fused with that of streptokinase, either at its N- or C-termini, and expressed these in Pichia pastoris followed by purification and structural-functional characterization, including plasminogen activation, thrombin inhibition, and Protein C activation characteristics. Interestingly, the N-terminal EGF fusion construct (EGF-SK) showed plasmin-mediated plasminogen activation, whereas the C-terminal (SK-EGF) fusion construct exhibited ‘spontaneous’ plasminogen activation which is quite similar to SK i.e. direct activation of systemic HPG in absence of free HPN. Since HPN is normally absent in free circulation due to rapid serpin-based inactivation (such as alpha-2-antiplasmin and alpha-2-Macroglobin), but selectively present in clots, a plasmin-dependent mode of HPG activation is expected to lead to a desirable fibrin clot-specific response by the thrombolytic. Both the N- and C-terminal fusion constructs showed strong thrombin inhibition and Protein C activation properties as well, and significantly prevented re-occlusion in a specially designed assay. The EGF-SK construct exhibited fibrin clot dissolution properties with much-lowered levels of fibrinogenolysis, suggesting unmistakable promise in clot dissolver therapy with reduced hemorrhage and re-occlusion risks. [ABSTRACT FROM AUTHOR]

99m Tc-labeled dimercaptosuccinic acid ( 99m Tc-DMSA) imaging is a well-established and highly sensitive method for the diagnosis of several renal cortical disorders affecting children and adults. Beginning in 2014, 99m Tc-DMSA availability was severely impaired when it was added to the Drug Shortages List of the U.S. Food and Drug Administration and was commercially unavailable thereafter. The agent shortage negatively impacted practitioners' ability to evaluate renal cortical defects in children and adults and changed renal imaging practice. A survey among pediatric nuclear medicine clinicians confirmed the clinical need for 99m Tc-DMSA. Finally, in early 2023 the Food and Drug Administration again approved 99m Tc-DMSA in the United States. During the 99m Tc-DMSA shortage, established practitioners may not have had the opportunity of using 99m Tc-DMSA as they were accustomed in their experience. Also, newer imaging specialists and referring physicians and technologists may not have benefited from having 99m Tc-DMSA in their training. Therefore, it is time to bring back 99m Tc-DMSA into the armamentarium of imaging methods available to evaluate regional cortical renal function., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)