title: New synthetic peptide with efficacy for heparin reversal and low toxicity and immunogenicity in comparison to protamine sulfate.
abstract: Protamine sulfate (PS), the only clinically approved antidote to unfractionated heparin (UFH), is widely used for cardiopulmonary surgery or other extracorporeal circulation situations. However, the applications of PS have accompanied various severe side-effects. In this study, we presented a novel synthesized peptide compound (RRRRR-RRRRR-RRRRR-sulfate, R15S) served as a safer UFH antidote. Comparison studies were conducted between PS and R15S on efficacy and safety, aided by heparin neutralization studies, drug toxicity studies and anaphylactic analysis. Our research demonstrated that R15S contained comparable UFH neutralization activity in vitro and in rats in vivo as to active partial thromboplastin time (APTT) and anti-FXa assays. There was no cytotoxicity for R15S at 60 μg mg(-1) or below and the median lethal dose (LD50) of R15S in mice was 35.4 mg kg(-1), both of which were similar to that of PS. Furthermore, R15S exhibited no immunogenicity while it was obvious in guinea pigs immunized with PS. The level of cross-reactivity to anti-PS antibodies of R15S was about 30%. Both of which indicated much safer properties of R15S than PS. In conclusion, we presented a promising candidate R15S for UFH reversal, which is effective in neutralizing UFH and potentially safer in use.
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gan
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Ruolan
authors.initials: R
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Zhuona
authors.initials: Z
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Taoyun
authors.initials: T
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Han
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China.
authors.forename: Su
authors.initials: S
authors.lastname: Han
authors.affiliation: State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China. Electronic address: douguifang@vip.sina.com.
authors.forename: Guifang
authors.initials: G
authors.lastname: Dou
mesh_terms: D000818:Animals; D005260:Female; D006493:Heparin / Q000378:metabolism*; D008297:Male; D010455:Peptides / Q000494:pharmacology* / Q000633:toxicity; D011479:Protamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010455:Peptides; D011479:Protamines; D006493:Heparin
keywords: Cross-reactivity; Heparin neutralization; Immunogenicity; Protamine; Protamine toxicity