ABSTRACT
Background: Self-assembling peptides (TDMs) comprise synthetic amphipathic peptides that immediately react to changes in pH and/or inorganic salts to transform into a gelatinous state. The first generation of these peptides (TDM-621) is currently used as a hemostatic agent in Europe. However, TDM-621 exhibits slow gel-formation and low retention capabilities on tissue surfaces. The second generation (TDM-623) was therefore developed to encourage faster gel-formation and better tissue-sealing capabilities. Aim: The aim of this study was to verify the efficacy of TDM-623 in terms of its hemostatic effect in endoscopic surgery. Materials and methods: Evaluation of the hemostatic effect in endoscopic surgery (animal study) was performed using eight porcine in spine position. Following systemic heparinization, we established a "bleeding model" by endoscopic grasping forceps on the anterior walls of the stomach and duodenum. In the hemostasis method, an endoscope with a distal hood was brought into contact with the bleeding point, and 1 ml TDM-623 was applied to the wound. After TDM-623 gelation, the endoscope was removed, and the acute hemostatic effect (after 2 min) was confirmed. Result: In the endoscopic bleeding model, 17 of the 23 cases (74%) showed complete hemostatic effects on the anterior wall of the stomach, and 18 of the 20 cases (80%) on the anterior wall of the duodenum, respectively. None of the applied gels were displaced from the anterior walls of the stomach and duodenum. Conclusion: The new self-assembling peptide (TDM-623) showed high hemostatic effects. TDM-623 had potential usefulness for upper gastrointestinal endoscopic surgery.
ABSTRACT
Introduction: Self-assembling peptides are synthetic, amphipathic peptides that may serve as new hemostatic agents. The first-generation hemostat TDM-621 has been used in clinical practice in a limited capacity. The second-generation hemostat TDM-623 was developed for faster gel formation and better tissue-sealing capability. We compared the physical properties and hemostatic effects of TDM-621 and TDM-623.Material and methods: First, we evaluated the physical properties of both materials in a bench test setting, including the external appearance of the gel, rheological properties in sol/gel forms, and local self-weight pressure. We then performed a randomized preclinical trial using swine. Bleeding wounds were created on the liver surface, and randomized application of 1 mL of either TDM-621 or TDM-623 was performed. The hemostatic effects were evaluated two and five minutes after application. Resected specimens were histologically evaluated.Results: In the bench test setting, TDM-623 showed higher gel height, higher sol viscosity, and higher local self-weight pressure than TDM-621. In the preclinical setting, TDM-623 showed significantly greater hemostatic effects at two and five minutes after application than TDM-621. Histological examination showed no inflammatory reaction in either group.Conclusions: TDM-623 has greater hemostatic capability than TDM-621 and is therefore promising as a new hemostatic agent.
Subject(s)
Hemostatics , Animals , Hemorrhage/therapy , Hemostasis, Surgical , SwineABSTRACT
An aza-cycloisodityrosine analogue of RA-VII, 3, was designed and synthesized. The key aza-cycloisodityrosine unit was prepared by copper(II)-acetate-mediated intramolecular phenylamine/arylboronic acid coupling of dipeptide followed by connection with the tetrapeptide segment to afford a hexapeptide. Subsequent macrocyclization of the hexapeptide with EDC · HCl and HOOBt under dilute conditions gave 3. Analogue 3 showed significant cytotoxic activity against human promyelocytic leukemia HL-60 cells and human colon carcinoma HCT-116 cells, but its activity was weaker than that of parent peptide RA-VII (1).
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Peptides, Cyclic/chemistry , Peptides/chemistry , Tyrosine/analogs & derivatives , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/toxicity , Aza Compounds/chemistry , Crystallography, X-Ray , HCT116 Cells , HL-60 Cells , Humans , Molecular Conformation , Peptides/chemical synthesis , Peptides/toxicity , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/toxicity , Rubia/chemistry , Rubia/metabolism , Tyrosine/chemical synthesis , Tyrosine/chemistry , Tyrosine/toxicityABSTRACT
An analogue of an antitumor bicyclic hexapeptide RA-VII was prepared, in which the Ala-2 and Tyr-3 residues of RA-VII were replaced by a cycloisodityrosine unit. In the crystalline state, the peptide backbone structures and the side-chain conformations at Tyr-3, Tyr-5, and Tyr-6 of this analogue and of RA-II were very similar. This analogue, however, showed much weaker cytotoxicity against P-388 leukemia cells than parent RA-VII.
