Drug – bio-affecting and body treating compositions – Fermentate of unknown chemical structure – Having a known elemental analysis
Patent
1983-12-28
1987-07-14
Rosen, Sam
Drug, bio-affecting and body treating compositions
Fermentate of unknown chemical structure
Having a known elemental analysis
A61K 3514, A61K 3516, A61K 3518, A61K 3528
Patent
active
046801774
DESCRIPTION:
BRIEF SUMMARY
This invention concerns blood products and the processes of their production from mammalian blood or its precursor tissue, bone marrow.
Whole blood is an extremely complex biological fluid and its components undergo a variety of changes in response to changes in the blood environment: coagulation or clotting is one phenomenon that is normally exhibited by shed blood and is the consequence of various complex changes in the blood constituents in response to an environmental change. The clotting mechanism is imperfectly understood but is believed to depend upon the presence in the whole blood of certain constitutents or Factors such as prothrombin and Factors V, VIII and IX and other blood coagulant proteins.
The prevention or delaying of clotting is accomplished by the use of anticoagulants, while clotting can be induced, e.g. in the treatment of haemophilia, by administration of whole blood containing the clotting factors or by the administration of a blood fraction or extract believed to contain the clotting factors.
Whole blood and its components and derivatives have many uses in medical science and its application. All procedures involving the use of shed blood, whether for subsequent transfusion or for processing to obtain blood products, involve an initial treatment to inhibit the clotting mechanism and the literature is replete with descriptions of various materials useful as anticoagulants. However, because for at least one hundred years it has been almost universally believed that the presence of calcium ions, in free or appropriately bound form, in blood was a requirement for coagulation, the anticoagulant materials most commonly used have been those designed to prevent calcium exerting its coagulating effect, as by binding free calcium ions to some structure that inhibits their coagulating action in the blood. Thus for example salts such as fluorides, oxalates, citrates and salts of ethylenediamine tetraacetic acid (EDTA) are to be found in conventional anticoagulants.
There have been a few reports in the literature of the anticoagulant effect of certain neutral salts which do not bind calcium ions, but in general, because this is contrary to conventional wisdom, the use of such neutral salts as anticoagulants has not been explored to any signficant extent in practice.
Thus, for example, Horne in J. Physiology (1896) 19 356/371 reported that blood coagulation was inhibited by the addition of ionic barium, strontium or calcium, with effectiveness in that order, and that the inhibition was reversed by dilution of the anticoagulated blood with water. Horne also reported that the coagulation-inhibiting effect of the divalent cations was enhanced by the presence of sodium chloride and potassium chloride.
Zarday in Folio Haematologica (1934) 52 33-39 established that divalent calcium had a specific anticoagulant effect and that its action was not just due to an increase in ionic strength.
Greville & Lehmann in J. Physiology (1944) 103 175-184 established a true antagonism between calcium and magnesium ions. They showed that calcium ions in a low concentration, less than 5 mM, antagonises the anticoagulant effect of other divalent cations such as strontium, barium and magnesium and reported that the anticoagulation of blood by magnesium chloride "may possibly be of practical value for the storage of blood". They describe the addition of two parts of blood to one part of M/7 magnesium chloride (143 mM) so that the anticoagulated blood exhibits a magnesium chloride concentration of 47.7 mM.
Lovelock & Porterfield in J. Biochem. (1951) 50 415 showed that below a total ionic strength of 0.01, plasma does not clot. The optimal ionic strength for coagulation is 0.03 and high ionic strength inhibits coagulation.
Zucker in a paper from the 1960 Symposium in Philadelphia, U.S.A. on "Metal-binding in Medicine" mentions that adding magnesium chloride to EDTA anticoagulated plasma preserves Factor V and Factor VIII. However she does not mention anticoagulation ab initio with magnesium chloride for this purpose, alth
REFERENCES:
patent: 2196199 (1940-04-01), Dyckerhoff
patent: 2532348 (1950-12-01), Szent-Gyorgyi
Sole--Chem. Abst., vol. 55 (1961), p. 4689d.
Shulman et al.-Chem. Abst., vol. 47 (1953), pp. 11280i to 11281a.
Menghini-Chem. Abst., vol. 43(1949), p. 4378a.
Crawford Neville
Gray Charles R. W.
British Postgraduate Medical Federation
Rosen Sam
The Royal College of Surgeons of England
Trustees of the Garfield Weston Trust for Research into Heart Su
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