Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Patent
1995-03-03
1999-07-20
Richter, Johann
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
530351, 514 8, 514 12, A61K 4505
Patent
active
059253444
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the novel use of certain cytokines in the treatment of certain blood disorders, primarily consumptive thrombohemorrhagic disorder.
Consumptive thrombohemorrhagic disorder comprises disseminated intravascular coagulation (DIC), defibrination syndrome and consumptive coagulopathy. A consumptive thrombohemorrhagic disorder is a pathological syndrome, the manifestation of which can in large part be regarded as a consequence of thrombin formation although other features such as blood factor and platelet consumption and fibrinolysis are present. Thrombin catalyses the activation and subsequent consumption of certain coagulant proteins and production of fibrin thrombi or clots. The fibrin thrombus is seen as an indicator of DIC. Microvascular, non adherent thrombi are present in almost all cases of DIC.
The symptoms of consumptive thrombohemorrhagic disorder such as DIC vary with the stage and severity of the consumptive thrombohemorrhagic disorder. Most patients have extensive skin and mucous membrane bleeding and hemorrhage from multiple sites. Occasionally patients have abnormalities in laboratory tests without clinical manifestations. The major manifestations in laboratory tests include thrombocytopenia, prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT) and a reduced fibrinogen plasma level illustrating the consumption of essential coagulation factors. Elevated fibrin degradation products (FDPs or fibrin split products) account for intense secondary fibrinolysis. Other factors such as factors V, VIII and XIII are usually decreased. Such findings can strengthen the diagnosis.
In particular, lowered factor VIII levels may be a sensitive indicator. However, the major manifestation of DIC, which correlates closely with bleeding, is the reduced plasma fibrinogen level. Normally, there is a fine balance in blood between clot-forming and clot-dissolving factors as will be explained in more detail below.
Heretofore, the treatment of consumptive thrombohemorrhagic disorder has been based on the correction of any reversible cause of consumptive thrombohemorrhagic disorder, on measures to control the major symptoms i.e. bleeding and/or thrombosis, and on prophylactic regimens to prevent recurrence of the causes. Treatments vary according to the cause and the clinical presentation but the major issue is the control of bleeding and thrombosis which are often associated. Accordingly, the clinician may supply the patients with plasma coagulation factors, attempt to correct the hypofibrinogenemia and correct the thrombocytopenia by infusing fresh frozen plasma as well as platelet concentrates. Thrombosis is normally counteracted by the administration of heparin, which is a potent antithrombin agent capable of preventing further consumption of coagulation factors. Agents which inhibit the associated fibrinolysis are rarely used because of the difficulty in controlling their secondary thrombotic effects.
Care has to be exercised over the timing of administration of heparin and blood products. Transfusion without prior administration of heparin may actually promote thrombosis without correcting the plasma deficiency state. The clinician has to overcome the paradox of administering an anticoagulant to a patient with bleeding manifestations. Logic dictates that bleeding would be worsened initially by the additive effect of heparin. Once heparin treatment has been instituted, bleeding diathesis needs to be immediately treated by replenishing the depleted (consumed) supply of platelets and clotting factors.
Clearly, there is a need for a relatively simple regimen for the treatment of consumptive thrombohemorrhagic disorder in which the clinician is not faced with the task of balancing the patient's requirements for several substances in order to restore normal hemostasis.
Surprisingly, we have discovered that the administration of interleukin-6 (IL-6) can be used beneficially in combatting consumptive thrombohemorrhagic disorder such as DIC in that it not
REFERENCES:
patent: 5087448 (1992-02-01), Burstein
patent: 5188828 (1993-02-01), Goldberg et al.
patent: 5264209 (1993-11-01), Mikayama et al.
"Induction of Rat Acute-Phase Proteins by Interleukin 6 In Vivo"; Thomas Geiger, Tilo Andus, Jan Klapproth, Toshio Hirano, Tadamitsu Kishimoto and Peter C. Heinrich; Eur. J. Immunol.; 1988.18: 717-721.
"Human Endothelial Cells Produce IL-6--Lack of Responses to Exogenous IL-6.sup.a "; Thomas J. Podor, Frank R. Jirik, David J. Loskutoff, Dennis A. Carson and Martin Lotz; Annals New York Academy of Sciences; 557, 374-85; 1989.
"Dexamethasone and Phorbol Ester, but not Cytokines, Increase the Production of Plasminogen Activator Inhibitor Type-2 in the PL-21 Human Promyeloctyc Leukemia Cell Line"; Kenji Niiya, Tetsuo Takeuchi, Makoto Kobayashi, Isao Miyoshi, Tomohiro Hayashi and Nobuo Sakuragawa; Thrombosis and Haemostasis; 66(2), 232-238; 1991.
"Human HuH-7 Hepatoma Cells Express Urokinase and Plasminogen Activator Inhibitor-1; Identification, Characterization and Regulation by Inflammatory Mediators"; Allan Arndt, Patricai Murphy and David A. Hart; Biochim. et Biophys. Acta; 1138, 149-156; Feb. 14, 1992.
"Type 1 Plasminogen Activator Inhibitor is not an Acute Phase Ractant in Rats--Lack of IL-6 and Hepatocyte-Dependent Synthesis"; Thomas J. Podor, Jack Hirsh, Thomas D. Gelehrter, Ron Zeheb, Diane Torry, Yves Guigoz, Felipe Sierra and Jack Gualdie; J. Immunology; 150(1), 225-235; Jan. 1, 1993.
J. V. Castell et al., "Recombinant Human Interleukin-6 (IL-6/BSF-2/hsf) Regulates the Synthesis of Acute Phase Proteins in Human Hepatocytes", FEBS Letters, vol. 232, No. 2, May 1988, pp. 347-350.
"The Merck Manual of Diagnosis + Therapy" (vol. I, General Medicine Merck + Co., (1987).
P. Wolf, "The importance of Azpha(2)-Antiplasminin in The Defibrination Syndrome" Arch. Intern. Medicine vol. 149, Aug. 1989.
Herodin Francis
Martin Serge
Mestries Jean-Claude
Ythier Armaud
Applied Research Systems ARS Holdings NV
Delaney Patrick R.
Richter Johann
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