Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
1999-11-19
2001-08-07
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
Reexamination Certificate
active
06270764
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to medical science particularly the treatment of viral hemorrhagic fever with protein C.
BACKGROUND OF THE INVENTION
Protein C is a vitamin K dependent serine protease and naturally occurring anticoagulant that plays a role in the regulation of hemostasis by inactivating Factors Va and VIIIa in the coagulation cascade. Human protein C circulates as a 2-chain zymogen, but functions at the endothelial and platelet surface following conversion to activated protein C (aPC) by limited proteolysis with thrombin in complex with the cell surface membrane protein, thrombomodulin.
In conjunction with other proteins, aPC functions as perhaps the most important down-regulator of blood coagulation resulting in protection against thrombosis. In addition to its anti-coagulation functions, aPC has anti-inflammatory effects through its inhibition of cytokine generation (e.g. TNF and IL-1) and also exerts profibrinolytic properties that facilitate clot lysis. Thus, the protein C enzyme system represents a major physiological mechanism of anti-coagulation, anti-inflammation, and fibrinolysis.
Viral hemorrhagic fever is a clinical syndrome associated with significant mortality. Without exception, hemorrhagic fever viruses are enveloped RNA viruses that belong to four viral families: Arenaviridae [Junin, Machupo, Lassa fever], Bunyaviridae [Crimean-Congo hemorrhagic fever, Rift Valley fever, Hantaan and related viruses], Filoviridae [Ebola, Marburg] and Flaviviridae [Dengue, Yellow fever, Omsk hemorrhagic fever, Kyasanur Forest disease], [Cosgriff, T. M.,
Reviews of Infectious Diseases
11(4): S672-S688, 1989]. These agents produce a wide spectrum of disease severity, but the most extreme manifestations include circulatory instability, increased vascular permeability, and diffuse hemorrhage [Lacy, et al.
Advances in Pediatric Infectious Diseases,
12:21-53, 1997].
The underlying mechanism of the bleeding in the hemorrhagic fevers is complex. Possible factors include thrombocytopenia alone, or thrombocytopenia associated with disseminated intravascular coagulation (DIC). Central to the mechanism may well be endothelial cell dysfunction, which has profound implications for both platelets and coagulation. Another possible factor is a decrease in levels of coagulation factors in plasma as the result of either increased consumption or impaired synthesis. Increased consumption occurs in DIC, while impaired synthesis is the likely consequence of liver injury. Liver involvement is a universal occurrence in viral hemorrhagic fever. For example, in Yellow fever, Rift Valley fever and Crimean-Congo hemorrhagic fever, the temporal association of hemorrhage with sever hepatic dysfunction is evident.
Viruses alter hemostasis in two general ways. The first is through direct effect on cellular functions, and the second is through activation of immune and inflammatory pathways. Both mechanisms may lead to variable degrees of cellular injury, including cell death. Activation of coagulation pathways is an important part of immune and inflammatory reactions and accounts for the fibrin deposition that sometimes is observed in these reactions.
Thrombocytopenia is a universal occurrence in viral hemorrhagic fevers. For example, in dengue hemorrhagic fever both changes suggestive of decreased thrombopoiesis and of increased platelet consumption has been determined. This is also the case in hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan and related viruses. Other mechanisms for increased platelet destruction in viral infections include direct interaction of platelets with viruses, DIC, and endothelial injury.
In Ebola and Marburg hemorrhagic fevers, generalized hemorrhages are found in most organs. Focal necrosis without significant inflammation is also widely seen, especially in the lungs, liver, kidneys, and lymphoid organs. DIC is common.
Currently, there is no effective therapy to treat viral hemorrhagic fever. In the absence of viral-specific chemotherapy, management is primarily supportive. Therefore, a need exists for a safe, effective therapy of patients with viral hemorrhagic fever.
The present invention is the first to describe the treatment of viral hemorrhagic fever with protein C. Protein C, with its anticoagulant, anti-inflammatory, and profibrinolytic activities, is useful for the treatment of the hypercoagulable state or protein C deficiency that occurs in viral hemorrhagic fever patients.
SUMMARY OF THE INVENTION
The present invention provides a method of treating a patient suffering from viral hemorrhagic fever which comprises, administering to said patient a pharmaceutically effective amount of protein C.
The present invention further provides a method of treating viral hemorrhagic fever in a patient in need thereof, which comprises administering to said patient a pharmaceutically effective amount of activated protein C such that an activated protein C plasma level of about 2 ng/ml to about 300 ng/ml is achieved.
DETAILED DESCRIPTION OF THE INVENTION
For purposes of the present invention, as disclosed and claimed herein, the following terms are as defined below.
Protein C refers to a vitamin K dependent serine protease with anticoagulant, anti-inflammatory, and profibrinolytic properties which includes, but is not limited to, plasma derived and recombinant produced protein C. Protein C includes and is preferably human protein C although protein C may also include other species or derivatives having protein C proteolytic, amidolytic, esterolytic, and biological (anticoagulant, pro-fibrinolytic, and anti-inflammatory) activities. Examples of protein C derivatives are described by Gerlitz, et al., U.S. Pat. No. 5,453,373, and Foster, et al., U.S. Pat. No. 5,516,650, the entire teachings of which are hereby included by reference.
Zymogen—an enzymatically inactive precursor of a proteolytic enzyme. Protein C zymogen, as used herein, refers to secreted, inactive forms, whether one chain or two chains, of protein C.
Activated protein C or aPC refers to protein C zymogen which has been converted by limited proteolysis to its activated form. aPC includes and is preferably human protein C although aPC may also include other species or derivatives having protein C proteolytic, amidolytic, esterolytic, and biological (anticoagulant or pro-fibrinolytic) activities. Examples of protein C derivatives are noted above in the description of protein C.
HPC—human protein C zymogen.
r-hPC—recombinant human protein C zymogen.
r-aPC—recombinant human activated protein C produced by activating r-hPC in vitro or by direct secretion of the activated form of protein C from procaryotic cells, eukaryotic cells, and transgenic animals or plants, including, for example, secretion from human kidney 293 cells as a zymogen then purified and activated by techniques well known to the skilled artisan and demonstrated in Yan, U.S. Pat. No. 4,981,952, and Cottingham, WO97/20043, the entire teachings of which are herein incorporated by reference.
Plasma derived activated protein C—activated protein C produced by activating plasma HPC as described in Eibl, U.S. Pat. No. 5,478,558, the entire teaching of which is herein incorporated by reference.
Continuous infusion—continuing substantially uninterrupted the introduction of a solution into a vein for a specified period of time.
Bolus injection—the injection of a drug in a defined quantity (called a bolus) over a period of time up to about 120 minutes.
Suitable for administration—a lyophilized formulation or solution that is appropriate to be given as a therapeutic agent.
Unit dosage form—refers to physically discrete units suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
Pharmaceutically effective amount—represents an amount of a compound of the invention that is capable of inhibiting sepsis in human
Fisher Charles Jack
Yan Sau-Chi Betty
Barrett Brian P.
Eli Lilly and Company
Weber Jon P.
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