Heparin sodium, as as anti-coagulants, belongs to a class of glucans, which can interact with a variety of proteins to produce a variety of biological activities.[1][2] Heparin sodium is routinely use for preventing the deep venous thrombosis in medical and surgical patients[5].
In vitro experiment it demonstrated that SARS-CoV-2 spike protein binds with a much higher affinity to heparin with K D of 55 nM compared to the RBD with K D of 1 μM alone. And heparin has no effect on angiotensin-converting enzyme 2 binding or proteolytic processing of the spike.[6] Moreover, heparin can inhibit the proteolytic activity of Mpro with an inhibition constant Ki of 6.9 nM and a half maximal inhibitory concentrations (IC50) of 7.8 ± 2.6 nM. [7].
In vivo clinical study it shown that treatment with continuous heparin sodium 12 500 U throughout 24 hours with intravenous pump for 5 days in heparin sodium group patients, and with low molecular weight heparin sodium (LMWHS) patients were given LMWHS 2 500 U subcutaneously, twice a day for 5 days, incidence of bleeding during treatment in LMWHS group was remarkably lower than that in heparin sodium group. Moreover, the platelet count in both LMWHS group and heparin sodium group was markedly increased compared with that before treatment; activated partial thromboplastin time also in heparin sodium group was significantly prolonged compared with that before treatment.[3] In the clinical test, there is no obvious difference in the duration of catheter patency or incidence of phlebitis was observed between the adult patients received 1 mL of a heparin sodium 100 units/mL flush solution and adult patients received a 0.9% sodium chloride flush solution by intermittent intravenous devices were randomly assigned.[4] In the clinical trail, treatment with low-dose heparin, patients with diabetes mellitus or chronic renal insufficiency are especially predisposed to hyperkalemia.[5].
参考文献:
[1]Capila I, et al. Heparin-protein interactions. Angew Chem Int Ed Engl. 2002 Feb 1;41(3):391-412.
[2]Hashii N, et al. Heparin identification test and purity test for OSCS in heparin sodium and heparin calcium by weak anion-exchange high-performance liquid chromatography. Biologicals. 2010 Sep;38(5):539-43.
[3]Li Y, et al. [Comparison of the effect of low molecular weight heparin sodium and that of heparin sodium on pre-disseminated intravascular coagulation stage in patients suffering from exertional heat stroke]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2015 Aug;27(8):649-52. Chinese.
[4]Hamilton RA, et al. Heparin sodium versus 0.9% sodium chloride injection for maintaining patency of indwelling intermittent infusion devices. Clin Pharm. 1988 Jun;7(6):439-43.
[5]Edes TE, et al. Heparin-induced hyperkalemia. Arch Intern Med. 1985 Jun;145(6):1070-2.
[6]Liu L, et al. Heparan Sulfate Proteoglycans as Attachment Factor for SARS-CoV-2. ACS Cent Sci. 2021 Jun 23;7(6):1009-1018.
[7]Li J, et al. Heparin interacts with the main protease of SARS-CoV-2 and inhibits its activity. Spectrochim Acta A Mol Biomol Spectrosc. 2022 Feb 15;267(Pt 2):120595.?
肝素钠作为抗凝剂，属于一类葡聚糖，可与多种蛋白质相互作用，产生多种生物活性。[1][2] 肝素钠常规用于预防内科和外科患者的深静脉血栓形成[5]。
体外实验表明，SARS-CoV-2 刺突蛋白与肝素的结合亲和力更高，K D 为 55 nM，而 RBD 单独使用时的 K D 为 1 μM。而肝素对血管紧张素转换酶2的结合或蛋白水解过程无影响。[6]此外，肝素可抑制Mpro的蛋白水解活性，抑制常数Ki为6.9 nM半。最大抑制浓度 (IC50) 为 7.8 ± 2.6 nM。 [7].
体内临床研究显示，肝素钠组患者24小时内连续12500U肝素钠静脉泵治疗5天，低分子肝素钠（LMWHS）患者给予LMWHS 2500U皮下给药，每天两次，连续5天，LMWHS组治疗期间的出血发生率明显低于肝素钠组。此外，LMWHS组和肝素钠组的血小板计数均较治疗前明显升高；肝素钠组活化部分凝血活酶时间也较治疗前显着延长。[3] 临床试验中，导管通畅时间及静脉炎发生率无明显差异在接受 1 mL 肝素钠 100 单位/mL 冲洗液的成年患者和通过间歇静脉装置接受 0.9% 氯化钠冲洗液的成年患者之间随机分配。[4] 在临床试验中、低剂量肝素治疗、糖尿病或慢性肾功能不全患者尤其容易发生高钾血症。[5]。
| Cell experiment [1]: | |
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Cell lines |
Mouse spermatozoa |
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Preparation Method |
Mouse spermatozoa were incubated with various concentrations (0.001-100 μM) of steroids (estrogen and progesterone) and heparin for 15 or 30 min, and then capacitation and AR were assessed using chlortetracycline. |
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Reaction Conditions |
0.001-100 μM; 15 or 30 min |
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Applications |
Steroids (estrogen and progesterone) and heparin studied effectively alter capacitation and/or AR in mouse spermatozoa with different manner. |
| Animal experiment [2]: | |
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Animal models |
Four- to six-week-old Athymic BALB/c-nu/nu female nude mice (14-18 g) |
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Preparation Method |
According to body weight and tumor size, the animals were divided into four experimental groups of five mice each: groups A, B, C, and D, respectively, received through the tail vein injections of 100 μL of saline as control (Group A, n=5), heparin (10 mg/kg, Group B, n=5), DOC-heparin VI (5 mg/kg, Group C, n=5), and DOC-heparin VI (10 mg/kg, Group D, n=5). Each drug was administered twice a week for four weeks after tumor inoculation. |
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Dosage form |
10 mg/kg; i.v. |
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Applications |
Larger antitumor effects of the DOC-heparin VI (8.5 mol of DOC coupled with 1.0 mol heparin) were achieved in animal studies, compared to heparin alone. |
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参考文献: [1]. [1]Park YJ, et al. Xenoestrogenic chemicals effectively alter sperm functional behavior in mice. Reprod Toxicol. 2011 Dec;32(4):418-24. [2]. Cho KJ, et al. Preparation of sodium deoxycholate (DOC) conjugated heparin derivatives for inhibition of angiogenesis and cancer cell growth. Bioconjug Chem. 2008 Jul;19(7):1346-51. |
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