| Biodegradable glucosamine-muramyl peptides for apoptosis modulation -> Monitor Keywords |
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  Biodegradable glucosamine-muramyl peptides for apoptosis modulationRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Glycoprotein (carbohydrate Containing)The Patent Description & Claims data below is from USPTO Patent Application 20060241025. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation application claiming priority of U.S. patent application Ser. No. 10/409,846 filed 9 Apr. 2003, which is incorporated herein in its entirety by this reference. FIELD OF THE INVENTION [0002] The present invention relates to apoptosis modulating glucosamine-muramyl-peptides, obtained by specific endopeptidase digestion of gram positive bacteria, methods of preparation of thereof and medical food compositions for management and treatment of conditions caused by TNF alpha cytotoxicity. BACKGROUND OF THE INVENTION [0003] Apoptosis, or programmed cell death, is a naturally occurring process that plays a strong role in ensuring the development and maintenance of multicellular organisms by eliminating unwanted cells. However, if this process goes over stimulated, cell loss and degenerative disorders such as rheumatoid arthritis, chronic heart, liver and renal failure, adult respiratory distress syndrome, cachexia caused by cancer, stroke, heart attack and heart failure can result. (Sharma, R., et al, Int. J. Cardiol., 2002, 85:161-171, Argiles, J. M. et al., Int. J. Biochem. Cell Biol., 2003, 35:405-409, Castellanos, M, et al., Stroke, 33:982-987, Cusack, M. R., et al., Amer. Coll. Cardiol., 2002, 39:1917-23, Agnoletti, L., et al, Circulation, 1999, 100:1983-1991). [0004] Mediators, which can trigger apoptosis include TNF alpha, Fas and transforming growth factor beta, neurotransmitters, growth factor withdrawal, loss of extracellular matrix attachment and extreme fluctuations in intracellular calcium levels (Afford and Randhawa, Mol. Pathol., 2000, 53:55-63). Among them TNF alpha killing pathways are considered as a most common route of apoptosis signaling. This cytokine is also involved in cancer related fatigue, leucopenia, anemia, and thrombocytopenia (Kurzrock, R., Cancer, 2001, 92: 1684-8). TNF alpha is also implicated in the development of the neurodegenerative disorders such as Alzheimer's and Parkinson's disease, ALS, rhinitis pigmentosa and multiple sclerosis (McGuire S O et al., Exp. Neurol., 2001, 169:219-230). Its pathogenetic role is crucial in the development of the extensive brain, lung, and heart damage (Barone F. C., et al, Stroke, 1997, 28:1233-1244; Armstrong, L. et al., Thorax, 1997, 52:442-446). Plasma concentrations of TNF alpha are persistently elevated among patients after myocardial infarction (Ridker, P., et al, Circulation, 2000, 101:2149-2153) [0005] With the identification of the systemic TNF alpha response as a major component in the pathogenesis of the septic shock syndrome (Jaecshke H., et al J. Immunol., 1998, 160:3480-3486), much of the recent work has focused on modulating of this response. High-flow haemofiltration was offered to clean both endotoxin and cytokines (Sharma, V. K., et al., Expert Opin. Investig. Drugs, 2003, 12:139-152). Hypotensive and proinflammotory effects of TNF alpha were inhibited by soluble receptors/receptor antagonists and anti-inflammatory cytokines such as interleukine10. The current experimental therapies involve transforming growth factor-beta, granulocyte colony-stimulating factor, interferon phi and anti TNF alpha antibody (Stamm, C., et al, Circulation, 101, Suppl. 1, 350-351). Moreover, less known cytokines such as macrophage migration inhibitory factor and high mobility group I protein will be clinically tested (Zanotti, S., et al., Expert Opin. Investig. Drugs, 2002, 11:1061-75). [0006] Another preliminary study has demonstrated that recombinant GM-CSF upregulates HLA-DR expression on monocytes, thus reversing the immunoparalysis in patients with severe sepsis. Moreover, there was a concurrent increase of whole blood TNF response. (Nierhaus, A., et al., Intensive Care Med, 2003, 21). [0007] The same situation was noticed in rats with burn shock. Nonsurvival group had lower levels of serum G-CSF and higher content of TNF alpha compared with survival. Supplement of GM-CSF could significantly improve animal survival with burn wound infection following severe burn shock (Yan R., et al. Zhonghua Zhen Xing Shao Shang Wai Ke Za Zi, 1997, 13:368-372). Serum TNF alpha was also elevated after soft tissue trauma and hemorrhagic shock, which leads to the acute respiratory distress syndrome (ARDS) {Jarrar D, et al. Am. J. Physiol. Lung Cell Mol. Physiol., 2002, 283:799-805}. [0008] Ischemia/reperfusion (I/R) induces a cytokines response and production of reactive oxygen species, which affects the organs remote to the sites of I/R. Yet, hepatic TNF alpha was implicated in playing major role in the liver damage during renal surgery (Serteser, M., et. al., J. Surg. Res. 2002, 107:234-40). [0009] Intravenous injection of whole lactobacillus reduced tachyarrhythmia significantly and improved recovery of the ischemized rat heart (Oxman, T., et al, Am. J. Physiol. Heart. Circ. Physiol., 278, H1717-H1724). [0010] However, a broad variety of biodegradable glucosaminemuramyl peptides were not isolated and tested for cytoprotective effects. SUMMARY OF INVENTION [0011] The present invention is based on the discovery that hydrolysis of the peptide bonds and peptide cross link of the gram positive bacteria leads to release of the novel glucosamine muramyl peptides, with strong potency towards inhibition of TNF alpha cytotoxicity. Consequently, in one aspect the invention provides new biodegradable glucosaminemuramyl tri, tetra-, penta-, hexa-, and octapeptides, which possess apoptosis modulating properties and are useful for treating all conditions with elevated serum lactate dehydrogenase activity. Examples of such conditions are ischemic reperfusion injury, atherosclerosis, heart attack, cerebral infarction, and chronic heart failure. Applicants also demonstrated that enhanced cytoprotective properties of these muramyl peptides are caused by the presence of two and more D-amino acids covalently bound L-amino acids. [0012] Another aspect of the present invention is to provide a method for isolation of high purity biodegradable glucosaminemuramyl peptides, which comprises the bacterial wall isolation with subsequent lysozyme and endopeptidase hydrolysis and purification with preparative high pressure liquid chromatography (HPLC). [0013] Yet, another aspect of this invention is a preparation of the medical food for dietary management of all conditions caused by elevation of TNF alpha and LDH. Novel medical food consisting of the hydrolyzed bacterial wall or whole bacteria can be used for reduction of the systemic cytokine toxicity, which leads to elevation of LDH and cachexia. Such medical food may be used to reduce LDH associated malignancy and damage caused by radiation therapy and chemotherapy. Specifically, the present food may be recommended for those patients who suffer from common postchemotherapy toxicity such as leukocytopenia, thrombocytopenia, and high bilirubin with elevated liver enzymes. Further, the present invention provides nutrition for reducing cancer fatigue and muscle dystrophy. [0014] In a related aspect, the present invention provides a food useful for treating patients suffering from hepatotoxicity caused by chemicals, anesthetics, drugs, and alcohol. Glucopeptide fortified food and drink may be especially beneficial for people with concurrent liver cirrhosis, thus preventing severe fatigue and brain damage caused by ammonia. Furthermore, presented invention provides the food for metabolic detoxifications of the cancerogenic chemicals and mutagens. [0015] Still another aspect of the present invention includes dietary methods of inhibiting dermal apoptosis, thereby reducing clinical symptoms of psoriasis. [0016] While another aspect of this invention is to provide a method of lung protection in the patients with pulmonary diseases such as adult respiratory distress syndrome, fibrosis, and cardiogenic lung edema. BRIEF DESCRIPTION OF THE DRAWINGS [0017] For further details, reference is made to the discussion which follows, in light of the accompanying drawings, wherein: [0018] FIG. 1 illustrates the cytoprotective potency of the novel GMHP in comparison with GMDP. [0019] FIG. 2. demonstrates inhibition of TNF alpha cytotoxicity by D-amino acids in combination with the same concentration of N-acetyl-glucosamine. Continue reading... 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