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• Anticoagulant drug

  Heparin sodium salt, used as an anticoagulant, is a mucopolysaccharide substance, is the sodium salt form of glucosamine sulfate extracted from the intestinal mucosa of pigs, cattle, and sheep. It is secreted by mast cells to be naturally presented the blood inside the human bodies. Heparin can prevent platelet aggregation and destruction, inhibit the conversion from fibrinogen to fibrin monomers, inhibit the formation of thromboplastin and fight against the pre-formed thromboplastin, and also prevent the conversion of prothrombin to thrombin and counteract the antithrombin.
  Heparin sodium salt can delay or prevent blood coagulation in vitro and in vivo. Its mechanism of action is very complicated which involves many processes of coagulation process. Its role is to: 1. inhibit the formation and function of thromboplastin, thus preventing the conversion of prothrombin into thrombin; 2. Inhibit the thrombin and other coagulation factors at relative high concentrations, preventing the conversion of fibrinogen to fibrous proteins; 3. prevent platelet aggregation and destruction. In addition, the anticoagulant effect of Heparin sodium salt is still related to the negatively charged sulfate inside its molecule. Positively charged alkaline substance such as protamine or toluidine blue can all neutralize its negative charge, thus inhibiting its anticoagulant effect. Because heparin can be activated in vivo and release lipoprotein lipase, hydrolyzing the triglycerides and low-density lipoprotein in chylomicrons, so it also has a lipid-lowering effect.
  Heparin sodium salt can be used for the treatment of acute thromboembolic disease and disseminated intravascular coagulation (DIC). In recent years, it was found that heparin has an effect on blood lipid clearance. Intravenous or deep intramuscular injection (or subcutaneous) for 5,000 to 10,000 units per time is suitable. Heparin sodium salt has a low toxicity with spontaneous bleeding tendency as the major danger of the excessive use of heparin. Oral administration is invalid. Administration by injection is demanded. Intramuscular or subcutaneous injection is highly irritating with allergic reactions occur sometimes. Excess amount can even cause cardiac arrest; occasionally a transient hair loss and diarrhea occurs. In addition, it can also cause spontaneous fractures. Long-term use can sometimes cause thrombosis which may be the consequence of anticoagulation enzyme-III depletion. Patients of bleeding tendency, severe liver and kidney dysfunction, severe hypertension, hemophilia, intracranial hemorrhage, peptic ulcer, pregnant and postpartum, visceral tumors, trauma and post-surgery are not allowed to use Heparin sodium salt.
  The above information is edited by the Chemicalbook of Dai Xiongfeng.;

• Chemical and physical property

  Heparin sodium salt is white or almost off-white powder, odorless, hygroscopic; soluble in water; insoluble in ethanol, acetone and other organic solvents. It has a strong negative charge in aqueous solution and can binds to a number of cationic molecules to become molecules complex. Its aqueous solution is stable at pH 7.0. ;

• The molecular structure of heparin

  Heparin sodium salt is a sulfate group-containing acidic mucopolysaccharide and is a natural anti-clotting substance. Heparin is the collection of a cluster of acidic mucopolysaccharide of different molecular weight. It is a linear chain molecule containing six or eight saccharide repeating unit with molecular weight being between 3,000 to 30,000 and an average molecular weight of about 15,000.
  Heparin sodium salt formula consists of two main structural units:
  Structure unit 1: GlcNHR-6-OSO3-GlcA-GlcNSO3-3,6-2-OSO3-IdoA-2-OSO3-GlcNSO3-6-OSO3.
  Structure unit 2: IdoA-2-OSO3-GlcNSO3-6-OSO3.
  Heparin sodium salt, together with other glycosaminoglycans, forms protein complexes inside the tissue. Thereby heparin preparation process comprises of two steps: extracting heparin-protein complex, and the separation and purification of the heparin.
  Heparin molecule contain sulfate groups and carboxyl groups, which is a strong acidic polyanion, and capable of reacting with a cationic salt. These cations include metal cations: Ca2 +, Na +, K +, long-chain pyridine compounds of organic base such as cetyl pyridinium chloride (CPC), strychnine, basic dyes-Azure A, cationic surfactants ( long chain quaternary ammonium salts) such as cetyl trimethyl ammonium bromide; cation exchanger and positively charged proteins such as protamine 0 protein. The N-sulfate groups in Heparin structure are closely related with the anti-clotting effect which will be reduced if the N-sulfate groups are disrupted. N-sulfate group is susceptible to acid hydrolysis and is quite stable under alkaline conditions. The free hydroxyl groups in heparin molecule are esterified whose sulfation will also reduce the anticoagulant. However, acetylation does not affect the anticoagulant activity.
  
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• Heparin

  Heparin is a mucopolysaccharide sulfuric acid ester type. According to their molecular weight, it can be divided into ordinary heparin and low molecular-weight heparin. Common heparin, namely Heparin sodium salt can be used to make calcium heparin by ion exchange process. Heparin sodium salt has a physical and chemical property of a strong negative charge, and can interfere with multiple aspects of the clotting process. It has anti-clotting effect both in vivo and in vitro. It mainly binds to antithrombin III and enhanced its inhibition effect on activated clotting factor II, IX, X, XI and XII. The consequences involve preventing platelet aggregation and damage; blocking the formation of thromboplastin; preventing the conversion of prothrombin to thrombin; inhibiting thrombin and thereby preventing fibrinogen from becoming fibrin. If sulfate groups are hydrolyzed or neutralized by the strong positive charged protamine, it would lose anticoagulant activity immediately. Moreover, topical application of heparin also has anti-inflammatory and analgesic effects.
  The pharmacological effect of calcium heparin is similar with that of Heparin sodium salt. However, the role of anti-clotting factor II a slightly stronger; the role of anti-Factor Xa is weak. Calcium heparin also has pharmacological effects are such as adjusting blood lipid, anti-inflammatory, anti-complement, anti-allergy and immune regulation.
  Low molecular weight heparin preparation has a antithrombin III-dependent anti-factor Xa activity. It has inhibitory effects on in vivo and in vitro thrombosis, and the formation of both arterial and venous thrombosis. It can stimulate endothelial cells to release the inhibitor of coagulation pathway of tissue factor and also release the fibrinolysis plasminogen activator. It has little effect on platelet function when exerting its antithrombotic effect, and thus reducing the incidence of bleeding complications.
  Reference: Licensed Pharmacist Association, Shanghai, the Shanghai Association of Integrative Medicine organized the compilation; Zhang Yao years, Li Duan, Wang Wenjian as major editor. ;

• Low molecular weight heparin

  Low molecular weight heparin is a low molecular-weight dextran sulphate and is a new anticoagulant drug as a short-chain heparin preparation of a variety of depolymerization composition. It has effects of anticoagulant, antithrombotic, anti-inflammatory, anti-tumor and inhibiting the proliferation of mesangial cell and matrix. Major products in current market include dalteparin, enoxaparin sodium, and nadroparin calcium. They are anticoagulant and antithrombotic drugs, usually as a colorless or light yellow transparent liquid.
  low molecular weight Heparin sodium salt generally refers to the fraction of heparin with a molecular weight less than 10,000. Compared with the standard heparin, low molecular weight heparin has a strong role of anti-clotting factor X but has a very weak role of anticoagulant II factor and inhibiting the action of thrombin. Thereby this product has a strong antithrombotic effect with less bleeding complications. In addition, there are low molecular weight Heparin sodium salts which have pro-fibrinolytic activity for dissolving the formed fresh thrombus. This kind of drug has a slight inhibition on platelet aggregation and has an antithrombotic effect on the human body. In usual doses, it neither causes significant changes in the overall coagulation index nor prolongs the bleeding time. There is only a small possibility of the reduction of blood platelets. There is also no change in fibrinogen binding. Compared with standard heparin, low molecular weight heparin preparations increased the bioavailability and half-life. Subcutaneous injection can lead to rapid absorption.
  Low molecular weight heparin having a significant and long-lasting antithrombotic effect. Its antithrombotic activity is stronger than the anticoagulant activity. Thus there is a relative small risk of simultaneously occurrence of antithrombotic effect and bleeding. Clinical used for:
  1. Prevention of deep vein thrombosis and pulmonary embolism.
  2. Treatment of acute deep vein thrombosis.
  3. Upon hemodialysis or hemofiltration, prevent the occurrence of thrombosis or blood clotting in vitro circulation system.
  4. Low molecular weight heparin is suitable for the prevention and treatment of thrombosis of surgery. ;

• Drug Interactions

  Heparin should not be combined with double coumarin, nonsteroidal anti-inflammatory drug, dipyridamole, dextran, corticosteroids, uric acid, and urokinase which can exacerbate bleeding; Combination with methimazole and propylthiouracil has a synergistic effect. This product has incompatibility with cefotaxime pyridine, cephalothin, daunorubicin, azithromycin, erythromycin, hyaluronidase, aminoglycoside antibiotics, polymyxin B, vancomycin, hydrocortisone, chlorpromazine, and promethazine. ;

• Precautions

  1. Heparin overdose can cause spontaneous bleeding, manifested as mucosal bleeding (hematuria, gastrointestinal bleeding), hemarthrosis and wound bleeding. Thereby, it should be measured for the clotting time or partial thromboplastin time (PTT) during the treatment, coagulation time> 30 minutes or PTT> 100 sec indicates overdose. Immediately stop taking the drugs upon spontaneous bleeding. Upon severe bleeding, we can intravenously inject protamine sulfate to neutralize the Heparin sodium salt sodium with injection speed not exceeding 20mg per minute or injecting 50 mg within 10 minutes being appropriate. Typically, 1mg of protamine in the body can neutralize 100 units of heparin.
  2. Intramuscular or subcutaneous injection is highly irritating. Use fine needle in the deep muscle or subcutaneous adipose tissue injection; intramuscular injection can cause local hematoma, should consider to plus 2% procaine hydrochloride solution.
  3. Be contraindicated in disease including hemorrhagic diathesis and associated slow-down in blood clotting; be cautious when applying to animals of renal insufficiency, pregnant livestock, postpartum, miscarriage, trauma and post-operative animals.
  4. Blood containing Heparin sodium salt cannot be used in the similar agglutination, complement and red blood cell fragility test.
  5. Combination with sodium bicarbonate, sodium lactate can promote the anticoagulant effect of Heparin sodium salt. ;

• Calcium Heparin

  Calcium heparin has the same role as Heparin sodium salt. Because heparin ultimately take effects in the form of calcium salt in the body, it is more suitable for the physiological property of human to apply calcium salts. Together with its stronger anti-renin activity and anti-aldosterone activity than heparin, as well as the advantage of overcoming the adverse reactions caused by subcutaneous injection of heparin such as bleeding, bruising, local pain, this product will serve as a new alternative for heparin preparations. Its usage and dosage is similar with Heparin sodium salt. High-dose therapy is applied to treatment of acute pulmonary embolism and abnormal elevated acute coagulation, Use a dosage of 30,000 U of intravenous infusion per day with dilution at 5% glucose saline or Ringer's solution. Inject subcutaneously 8,000 to 10,000 U per time and once every 8 hours. Medium dose therapy is suitable for treating disseminated intravascular coagulation or thromboembolic disease. Apply 20000 U daily with intravenous or subcutaneous injection. Inject once every 8 to 12 hours. For the above two kinds of treatments, detection blood clotting time is necessary to determine the heparin dose and frequency of administration. Low-dose therapy is suitable for coronary heart disease, unstable angina, hyperlipidemia, and correcting hyper-coagulation state. The daily amount should be around 5,000 to 10,000 U. Apply subcutaneous injection with 5000 U every 12 hours or 24 hours or 7500 daily. Adverse reactions and precautions are similar with heparin. 1 ml Injection each contains 5000U (40mg), 7500U (60mg), 1 Wan U (80mg). Keep shading and store it at cool places. ;

• Chemical property

  White or gray-brown amorphous powder, odorless, tasteless, and hygroscopic. Specific rotation [α] 25D + 47 ° (1.5%, water); easily soluble in water; insoluble in organic solvents such as alcohol, ether, acetone and benzene; LD50 (rat, intravenously) 354mg/kg. ;

• Uses

  1. Biochemical studies; used for preventing the conversion of prothrombin into thrombin; has blood anti-thrombosis effect.
  2. For the delay and prevention of blood clotting.
  3. Heparin sodium salt is a mucopolysaccharides biochemical medicine extracted from porcine small intestinal mucosa with strong anticoagulant activity. Mclcan found it from the liver tissue of dog in the study of the clotting mechanism. Brinkous et al proved that heparin having anticoagulant activity. After the first application of heparin as an anticoagulant in clinical filed, it has drawn worldwide attention. With a strong anticoagulant effect, heparin is the primary choice for prevention and treatment of deep vein thrombosis and other thrombotic diseases. Although has more than 60 years of clinical history, so far people haven’t develop a complete substitute of it and thereby it is still the most important anticoagulant and antithrombotic drug of biochemistry. It has a wide application in pharmacy where it is used for the treatment of acute myocardial infarction and toxin-hepatitis. Combination with ribonucleic acid can further increase the its efficacy on treating hepatitis B. Combined with chemotherapy, it helps prevent the formation of blood clots, lower blood fat and enhance immunity. Low molecular weight heparin has anticoagulant Factor Xa activity. Pharmacodynamic studies have shown that low molecular weight heparin has inhibitory effect on both in vivo and in vitro thrombosis and arterial-venous thrombosis but has less impact on blood coagulation and fibrinolysis system. There is a low possibility of bleeding when it produces antithrombotic effect. Ordinary heparin is a mixture containing a variety of amino dextran glycosides. It can delay or prevent blood coagulation both in vitro and in vivo. Its anticoagulant mechanism is very complicated, and has a role in all processes of blood coagulation including inhibiting the conversion of prothrombin into thrombin; inhibition of thrombin activity; prevent conversion of fibrinogen into fibrin; prevent platelet aggregation and destruction. Heparin can also reduce cholesterol, lower LDL and VLDL, increase HDL, change blood viscosity, protect vascular endothelial cells, prevent atherosclerosis, boost blood flow, and improve coronary circulation. ;

• Production method

  Extract the intestinal mucosa of pigs, sheep, and cattle, refine to obtain it. ;

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