Cross-Enzyme Inhibition by Gabexate Mesylate: Formulation and Reactivity Study

Abstract

Gabexate mesylate (GM; commercialized under the brand name FOY) is a nonantigenic synthetic inhibitor of plasmatic and pancreatic serine proteinases that is used therapeutically in the treatment of pancreatitis and disseminated intravascular coagulation and as a regional anticoagulant for hemodialysis. The inhibitory effect of GM on nitric oxide synthase as well as serine proteinases and swine kidney copper amine oxidase, all acting on cationic substrates, has been investigated. On the basis of the available X-ray crystal structures of the enzymes considered, the possible binding mode(s) of GM has(have) been analyzed. The enzyme cross-inhibition by GM suggests that the use of this drug should be under careful control. With the aim to improve the scarce plasma stability of GM, the positively charged drug has been complexed to the surface of preformed anionic liposomes. The liposome-complexed GM half-life increases about five-fold, indicating the protective effect of liposomes on GM degradation. Moreover, the GM complexation with liposomes does not alter its inhibitory activity on NOS-I and porcine pancreatic trypsin.

Targeting Mast Cells Tryptase in Tumor Microenvironment: A Potential Antiangiogenetic Strategy

“…Gabexate mesylate (GM) is a synthetic inhibitor of trypsin-like serine proteases [95–97] that shows an antiproteinase activity on various kinds of plasma proteases, such as thrombin, plasmin, trypsin, kallikrein, C1 esterase in the complement system, and factor Xa in the coagulation cascade. Accordingly, GM has been therapeutically used for disseminated intravascular coagulation (DIC) and acute pancreatitis [95] in Japan, Italy, Korea, and Taiwan.…”

Clonidine Displacement from Type 1 Imidazoline Receptor by p ‐Aminobenzamidine, the Prototype of Trypsin‐Like Serine Protease Inhibitors

“…As a whole, present results clearly indicate that p-aminobenzamidine interacts with I 1 -R showing a very high efficacy in displacing [ 3 H]clonidine and being, at the same doses, as effective as the putative endogenous ligands, agmatine and N-amidino-2-hydroxypyrrolidine. In this perspective, p-aminobenzamidine and structurally related drugs, such as gabexate mesylate applied clinically to treat acute pancreatitis and disseminated intravascular coagulation (31), might interfere with the cardioprotective and antihypertensive effects of clonidine (1,6,9). Therefore, trypsin-like serine protease inhibitors structurally related to p-aminobenzamidine should be administrated under careful control.…”

Combined derivatization and high‐performance liquid chromatography with fluorescence and ultraviolet detection for simultaneous analysis of octreotide and gabexate mesylate metabolite in human pancreatic juice samples

“…Protease are widely distributed in the human body and may be involved in several diseases, especially acute pancreatitis. Activated trypsin autodigests the pancreas and acts on kininogen to liberate bradykinin, which activates plasma kallikerin (Cortesi et al ., ). The liberation of kinin gives rise to systemic shock and pain.…”