Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-04-28
2004-03-30
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S059000
Reexamination Certificate
active
06713459
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for preventing and treating tissue injury. More specifically, the invention relates to methods for treating major organ (especially cardiac) tissue damage, particularly when associated with ischemia/reperfusion injury, sepsis, or microbial infection.
DESCRIPTION OF RELATED ART
Worldwide, the World Health Organization estimates that by 2020 up to 40 percent of all deaths will be related to cardiovascular disease. In 1995, cardiovascular disease accounted for almost 15 million deaths. Since 1900, cardiovascular disease has been the number one killer in the United States in every year except 1918 (the year of the influenza pandemic), and medical costs directly related to heart disease are estimated at 30 billion dollars annually. The American Heart Association estimates that approximately 59.7 million Americans have one or more types of cardiovascular disease. Ischemic heart disease and related cardiac myopathies are the major causes of cardiac dysfunction, with ischemic heart disease causing approximately 90% of cardiac mortalities. Myocyte loss, presumably due to apoptosis, is a feature of every known type of cardiomyopathy.
Treatments for ischemic disease include aspirin, adrenoceptor blocking agents, nitrates, and angiotensin converting enzyme (ACE) inhibitors. Heparin has been administered (either intravenously or subcutaneously) in conjunction with a nonspecific fibrinolytic agent such as streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC), or urokinase.
Beta-adrenergic blockers and calcium channel blockers have been shown to have some beneficial effect in the treatment of patients with chronic heart failure, which often follows ischemic cardiac tissue damage. Combinations of thrombolytic therapy and beta-adrenergic blockers, nitroglycerin, heart-rate decreasing calcium antagonists, or angiotension-converting enzyme inhibitors are currently recommended to treat patients with acute myocardial infarction. Combinations of compounds administered for the purpose of constricting arteries, increasing arterial blood pressure, and dilating veins to enhance arterial blood flow to the brain and heart, have been proposed for the treatment of patients experiencing cardiac arrest (U.S. Pat. No. 5,588,422, issued to Lurie and Gold, Dec. 31, 1996). A combination of vasopressin and an adrenergic agent, for administration to a patient suffering from cardiac arrest, has also been shown to have some benefit (U.S. Pat. No. 5,827,893, issued to Lurie and Lindner, Oct. 27, 1998).
Haikala et al. (U.S. Pat. No. 5,968,959, Oct. 19, 1999) describe use of a phospholamban inhibitor to relieve the inhibitory effect of phospholamban on cardiac sarcoplasmic reticulum Ca
2+
-ATPase. Araneo et al. (U.S. Pat. No. 5,977,095, Nov. 2, 1999) describe administration of a dehydroepiandrosterone (DHEA) derivative to prevent or reduce the effects of ischemia. Singh et al. (U.S. Pat. No. 5,912,019, Jun. 15, 1999) described methods of using NO donors, inhibitors of iNOS induction, and endopeptidase inhibitors to reduce ischemia/reperfusion injury. Tomaru et al. (U.S. Pat. No. 5,869,044, Feb. 9, 1999) describe the use of batroxobin (a thrombin-like enzyme derived from snake venom) to prevent or treat ischemia/reperfusion injury. Young et al. (U.S. Pat. No. 5,863,789, Jan. 26, 1999) describe the use of IL-Ira beta polypeptides and polynucleotides for treatment of cardiac ischemia. Neely (U.S. Pat. No. 6,001,842, Dec. 14, 1999) describe methods for preventing or treating ischemia/reperfusion injury in an organ by administration of a composition containing a selective A
1
adenosine receptor antagonist, a P
2x
purinoceptor antagonist, or both.
A variety of compounds derived from red wine or grape seed have also been demonstrated to reduce ischemia/reperfusion injury (Sato, M. et al.
J. Mol. Cell. Cardiol
. (1999) 31(6): 1289-1297).
Despite these many and varied methods of treatment, however, significant cardiac tissue damage occurs as a result of ischemia followed by reperfusion, placing the health of thousands of individuals at risk each year. Thus, there is clearly a need for more effective agents to prevent and treat cardiac tissue injury, especially cardiac tissue injury resulting from ischemia/reperfusion.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a method for reducing cardiac tissue damage in a mammalian subject, particularly a human subject, comprising administering to the subject a therapeutic dosage of a (1-3)-&bgr;-D-glucan. In the method of the present invention, the therapeutic dosage is administered prior to onset of ischemia, prior to onset of symptoms of viral or bacterial infection, subsequent to onset of ischemia, or subsequent to onset of symptoms of viral or bacterial infection, particularly septicemia. The method is particularly useful for bacterial infection associated with septic sequelae. The method of the present invention is also useful for preventing or treating cardiac tissue damage resulting from infection with a virus, such as human immunodeficiency virus (HIV) or human adenovirus (Ad).
In the method of the present invention, the therapeutic dosage can be administered by standard means, including orally, parenterally, intraperitoneally, and intravenously.
The invention also provides a method for treating ischemia/reperfusion injury in a body organ of a mammalian subject, comprising administering to the subject a therapeutic dosage of a (1-3)-&bgr;-D-glucan. The organ may be a heart, lung, liver, or other major organ. The ischemia/reperfusion injury may result from, for example, myocardial infarction, pulmonary embolism, or traumatic injury resulting in blood loss.
In one embodiment, the invention provides an emergency care or other kit for treating ischemia/reperfusion injury in a mammalian subject, comprising a therapeutic dosage of a (1-3)-&bgr;-D-glucan and a pharmaceutically acceptable carrier. The therapeutic dosage can be packaged as single dosage units or bulk packaged, and the pharmaceutically acceptable carrier can be chosen from among a tablet, caplet, capsule, intravenous fluid, or other carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1
illustrates results of scanning densitometry of autoradiograms derived from gel shift assays. Tissue samples were harvested 3 hours subsequent to cecal ligation and puncture (CLP) performed in ICR/HSD (Harlan Sprague-Dawley, Indianapolis, Ind.) mice, with n=4 per group. NF-&kgr;KB and NF-IL6 nuclear binding activity in liver and lung tissue were decreased in mice pretreated with glucan phosphate (50 mg/kg, injected intraperitoneally). Results are shown as normalized integrated intensity for binding activity in liver and lung tissue taken from mice subjected to CLP and to laparotomy only (LO).
FIG. 2
illustrates results of scanning densitometry of autoradiograms derived from gel shift assays. Tissue samples were harvested 3 hours subsequent to CLP. NF-&kgr;B and NF-IL6 nuclear binding activity in liver and lung tissue were decreased in mice pretreated with scleroglugan (50 mg/kg, injected intraperitoneally). Results are shown as normalized integrated intensity for binding activity in liver and lung tissue taken from mice subjected to CLP and to laparotomy only (LO).
FIG. 3
illustrates survival rate, expressed as percentage surviving (Y axis) over time course (X axis), of mice subjected to CLP with or without glucan pretreatment (n≧20). Glucans were administered intraperitoneally (50 mg/kg) 1 hour prior to CLP surgery. Results are shown for control (CLP with no glucan treatment), glucan phosphate (glucan phosphate pretreatment followed by CLP), and scleroglucan (pretreatment with scleroglucan, followed by CLP).
FIG. 4
illustrates normalized integrated intensity for mRNA levels assessed by RT-PCR and quantified by scanning densitometry. Tissue samples were harvested 3 hours after CLP or LO. TNF-&agr; and IL-6 mRNA levels were measured in liver and lung tissue of ICR/HSD mice (n=4) pretreated with glucan phosphate (5
Li Chuanfu
Williams David L.
East Tennessee State University
Maier Leigh C.
Wilson James O.
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