9005-49-6 Usage
Description
Heparin is a complex organic acid (mucopolysaccharide) present in mammalian tissues and is a strong inhibitor of blood coagulation. It is a dextrorotatory polysaccharide built up from hexosamine and hexuronic acid units containing sulfuric acid ester groups. Parnaparin sodium is a low molecular weight heparin obtained from bovine mucosal heparin by chemical depolymerization, which has more potent antithrombotic and profibrinolytic activity than heparin.
Uses
Used in Medicine:
Heparin is used as an anticoagulant for preventing blood clotting. It inhibits the formation of thrombin from prothrombin, thereby preventing the clotting of blood. It is effective in improving the venous blood outflow of lower limbs in deep vein thrombosis (DVT) patients, in addition to preventing DVT following orthopaedic surgery, reportedly without causing bleeding complications. Parnaparin has also shown efficacy in inflammatory occlusive complications of postphlebitic syndrome and in acute myocardial infarction.
Used in Biochemical Research:
Heparin is used in biochemical research for its antithrombotic and profibrinolytic properties, as well as its ability to inhibit factor Xa and reduce plasma activity of platelet activator inhibitor.
Used in Rodenticides:
Heparin is used in rodenticides to prevent blood clotting in rodents, leading to their death.
Chemical Properties:
Heparin is a white or pale-colored amorphous powder that is nearly odorless and hygroscopic. It is soluble in water but insoluble in alcohol, benzene, acetone, chloroform, and ether. The pH in a 17% solution is between 5.0 and 7.5.
Brand Names:
Liquaemin Sodium (Organon); Panheprin (Hospira); Fluxum.
Originator
Opocrin (Italy)
Manufacturing Process
5,000 pounds of beef intestine was introduced into a stainless steel reactor,
jacketed with thermostated water and steam. 200 gallons of water and 10
gallons of chloroform were added. The mixture was agitated, the temperature
was raised to 90°F and the agitation stopped. 5 gallons of toluene was added
and the vessel closed. Autolysis was continued for 17 hours.
The extractant solution, consisting of 30 gallons of glacial acetic acid, 35 gallons of 30% aqueous ammonia, 50% sodium hydroxide to adjust the pH to
9.6 at 80°F and water to make 300 gallons, was added to the tissue. With
agitation, the temperature was raised to 60°C and held there for 2 hours.
Then steam was applied and the temperature was raised to boiling. 200
pounds of coarse filter aid (perlite) was added and the mixture filtered
through a string discharge vacuum filter. The cake was washed with 200
gallons of hot water on the filter.
The filtrate was allowed to stand overnight and the fat skimmed off the top.
After cooling to 100°F, the filtrate was transferred to a tank with thermostated
water and the temperature set at 95° to 100°F. 24 gallons of pancreatic
extract, prepared as described above, was added in 4-gallon increments every
12 hours for 3 days. The batch was brought to a boil and cooled to room
temperature.
The batch was then filtered into a vessel and assayed for heparin content.
40,000,000 units were found in 1,000 gallons of filtrate. 20 kg of noctylamine was added and 105 pounds of glacial acetic acid was added to
bring the pH to 6.5. 20 gallons of methyl isobutyl ketone was added and the
whole mixture was vigorously agitated for 1 hour. The mixture was then
allowed to stand overnight. The clear, aqueous phase was drained off and
discarded. The grayish-brown interphase was then removed, together with a
small amount of the ketone phase, and transferred into a small kettle. The
interphase volume was 7 gallons.
30 gallons of methanol was added and the mixture warmed to 120°F and then
the pH was adjusted to 9.0. The mixture was then allowed to settle overnight.
The solids were collected with vacuum and washed with 5 gallons of
methanol. The cake was then suspended in 5 gallons of water and the heparin
precipitated with 10 gallons of methanol. The solids were collected under
vacuum. The dry weight of the cake was 1,000 grams and the total units were
38,000,000, according to US Patent 2,884,358.
Therapeutic Function
Anticoagulant
Biological Functions
Heparin (heparin sodium) is a mixture of highly electronegative
acidic mucopolysaccharides that contain
numerous N- and O-sulfate linkages. It is produced by
and can be released from mast cells and is abundant in
liver, lungs, and intestines.
Hazard
May cause internal bleeding.
Mechanism of action
The anticoagulation action of heparin depends on
the presence of a specific serine protease inhibitor (serpin)
of thrombin, antithrombin III, in normal blood.
Heparin binds to antithrombin III and induces a conformational
change that accelerates the interaction of
antithrombin III with the coagulation factors. Heparin
also catalyzes the inhibition of thrombin by heparin cofactor
II, a circulating inhibitor. Smaller amounts of
heparin are needed to prevent the formation of free
thrombin than are needed to inhibit the protease activity
of clot-bound thrombin. Inhibition of free thrombin
is the basis of low-dose prophylactic therapy.
Pharmacology
The physiological function of heparin is not completely
understood. It is found only in trace amounts in
normal circulating blood. It exerts an antilipemic effect
by releasing lipoprotein lipase from endothelial cells;
heparinlike proteoglycans produced by endothelial
cells have anticoagulant activity. Heparin decreases
platelet and inflammatory cell adhesiveness to endothelial
cells, reduces the release of platelet-derived growth
factor, inhibits tumor cell metastasis, and exerts an antiproliferative
effect on several types of smooth muscle.
Therapy with heparin occurs in an inpatient setting.
Heparin inhibits both in vitro and in vivo clotting of
blood. Whole blood clotting time and activated partial
thromboplastin time (aPTT) are prolonged in proportion
to blood heparin concentrations.
Pharmacokinetics
The pharmacokinetic profiles of heparin and LMWHs are quite different. Whereas heparin is only
30% absorbed following subcutaneous injection, 90% of LMWH is systemically absorbed. The
binding affinity of heparin to various protein receptors, such as those on plasma proteins,
endothelial cells, platelets, platelet factor 4 (PF4), and macrophages, is very high and is related to
the high negative-charged density of heparin. This high nonspecific binding decreases
bioavailability and patient variability. Additionally, heparin's nonspecific binding may account for
heparin's narrow therapeutic window and heparin-induced thrombocytopenia (HIT), a major limitation
of heparin. These same affinities are quite low, however, in the case of LMWHs. These parameters
explain several of the benefits of the LMWH's. The favorable absorption kinetics and low protein
binding affinity of the LMWHs results in a greater bioavailability compared with heparin. The
lowered affinity of LMWHs for PF4 seems to correlate with a reduced incidence of HIT. Heparin is
subject to fast zero-order metabolism in the liver, followed by slower first-order clearance from the
kidneys. The LMWHs are renally cleared and follow first-order kinetics. This makes the
clearance of LMWHs more predictable as well as resulting in a prolonged half-life. Finally, the
incidence of heparin-mediated osteoporosis is significantly diminished with use of LMWHs as opposed to heparin.
Clinical Use
#N/A
Side effects
The major adverse reaction resulting from heparin
therapy is hemorrhage. Bleeding can occur in the urinary
or gastrointestinal tract and in the adrenal gland.
Subdural hematoma, acute hemorrhagic pancreatitis,
hemarthrosis, and wound ecchymosis also occur. The
incidence of life-threatening hemorrhage is low but variable. Heparin-induced thrombocytopenia of immediate
and delayed onset may occur in 3 to 30% of patients.
The immediate type is transient and may not involve
platelet destruction, while the delayed reaction
involves the production of heparin-dependent antiplatelet
antibodies and the clearance of platelets from
the blood. Heparin-associated thrombocytopenia may
be associated with irreversible aggregation of platelets
(white clot syndrome). Additional untoward effects of
heparin treatment include hypersensitivity reactions
(e.g., rash, urticaria, pruritus), fever, alopecia, hypoaldosteronism,
osteoporosis, and osteoalgia.
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: increased risk of bleeding with NSAIDs
- avoid concomitant use with IV diclofenac;
increased risk of haemorrhage with ketorolac -
avoid.
Nitrates: anticoagulant effect reduced by infusions of
glyceryl trinitrate.
Use with care in patients receiving oral
anticoagulants, platelet aggregation inhibitors, aspirin
or dextran.
Metabolism
Heparin is prescribed on a unit (IU) rather than milligram
basis. The dose must be determined on an individual
basis. Heparin is not absorbed after oral administration
and therefore must be given parenterally.
Intravenous administration results in an almost immediate
anticoagulant effect. There is an approximate 2-hour
delay in onset of drug action after subcutaneous administration.
Intramuscular injection of heparin is to be
avoided because of unpredictable absorption rates, local
bleeding, and irritation. Heparin is not bound to
plasma proteins or secreted into breast milk, and it does
not cross the placenta.
Heparin’s action is terminated by uptake and metabolism
by the reticuloendothelial system and liver and
by renal excretion of the unchanged drug and its depolymerized
and desulfated metabolite. The relative
proportion of administered drug that is excreted as unchanged
heparin increases as the dose increases. Renal
insufficiency reduces the rate of heparin clearance from
the blood.
Purification Methods
Most likely contaminants are mucopolysaccharides including heparin sulfate and dermatan sulfate. Purify heparin by precipitation with cetylpyridinium chloride from saturated solutions of high ionic strength. [Cifonelli & Roden Biochemical Preparations 12 12 1968, Wolfrom et al. J Org Chem 29 540 1946, Huggard Adv Carbohydr Chem 10 336-368 1955]
Check Digit Verification of cas no
The CAS Registry Mumber 9005-49-6 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 9,0,0 and 5 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 9005-49:
(6*9)+(5*0)+(4*0)+(3*5)+(2*4)+(1*9)=86
86 % 10 = 6
So 9005-49-6 is a valid CAS Registry Number.
InChI:InChI=1/C26H41NO34S4/c1-4(28)27-7-9(30)8(29)6(2-52-63(43,44)45)53-24(7)56-15-10(31)11(32)25(58-19(15)21(36)37)55-13-5(3-62(40,41)42)14(60-64(46,47)48)26(59-22(13)38)57-16-12(33)17(61-65(49,50)51)23(39)54-18(16)20(34)35/h5-19,22-26,29-33,38-39H,2-3H2,1H3,(H,27,28)(H,34,35)(H,36,37)(H,40,41,42)(H,43,44,45)(H,46,47,48)(H,49,50,51)/t5-,6+,7+,8+,9+,10+,11+,12-,13-,14+,15-,16-,17+,18+,19-,22-,23?,24+,25+,26-/m0/s1
9005-49-6Relevant articles and documents
A new radiochemical method to investigate ion binding with polyelectrolytes
Kijewska, Ilona,Hawlicka, Ewa
, p. 1185 - 1191 (2005)
A new method for investigating the binding of ions with polyelectrolytes has been developed. This method, based on Donnan equilibrium and an isotope exchange between the electrolyte and polyelectrolyte, can distinguish territorial from specific binding of ions and can determine fractions of ions bound with the polyion. This method can determine ion binding with polyelectrolytes in a wide range of polyelectrolyte concentrations in multicomponent solutions. The method was tested with radioactive tracers 22Na+, 36Cl- and heparin sodium salt. The influence of the ionic strength on the Na+ binding with heparin was investigated at 310 K. In the limit of zero ionic strength, all Na+ ions are bound to heparin, but only 45% of them are exchangeable. Thus Na+ ions can be bound both territorially and specifically. The fraction of bound ions decreases rapidly with increasing ionic strength. The fraction of the specifically bound ions becomes negligible when the ionic strength exceeds 0.01 M, whereas the fraction of territorially bound ions can be neglected at ionic strengths higher than 0.45 M.
INDUCER FOR DIFFERENTIATION OF EMBRYO STEM CELLS INTO ECTODERMAL CELLS, METHOD OF OBTAINING THE SAME AND USE THEREOF
-
, (2008/06/13)
A method for obtaining a solution having activity to induce differentiation of an embryonic stem cell into an ectodermal cell or ectoderm-derived cell, which comprises culturing a stromal cell in a culture comprising a polyanionic compound and recovering the culture; a solution having activity to induce differentiation of an embryonic stem cell into an ectodermal cell or ectoderm-derived cell, which is obtainable by the method; and an agent for inducing differentiation of an embryonic stem cell into an ectodermal cell or ectoderm-derived cell.
Polymeric X-ray compositions containing iodinated polymeric beads
-
, (2008/06/13)
Disclosed are x-ray contrast compositions for oral or retrograde examination of the gastrointestinal tract comprising a polymeric material in combination with a divalent cation capable of forming a coating on the gastrointestinal tract and iodinated polymeric, water-insoluble beads having a particle size of from about 0.01 to about 1000μ wherein said iodinated polymeric beads comprise a polymer containing repeating units of the formula (I) STR1 wherein A is a repeating organic unit in the backbone chain of the polymer; and X is an organic moiety containing or iodinated eromatic group and a hydrophilic group, said moiety having an iodine content within the range of from about 40 to about 80 weight percent based or the molecular weight of X, in a pharmaceutically acceptable carrier.