| Compositions and methods for delivering carbon monoxide (co) and nitric oxide (no) to tissue using heme proteins as carriers -> Monitor Keywords |
|
|
  Compositions and methods for delivering carbon monoxide (co) and nitric oxide (no) to tissue using heme proteins as carriersUSPTO Application #: 20060234915Title: Compositions and methods for delivering carbon monoxide (co) and nitric oxide (no) to tissue using heme proteins as carriers Abstract: The present invention relates to compositions and methods for delivering nitric oxide (NO) or carbon monoxide (CO) to cells using heme proteins as carriers. In one embodiment, the present invention relates to the use of modified hemoglobin to deliver NO or CO to cells (end of abstract)
Agent: Gordon & Rees LLP - San Diego, CA, US Inventor: Robert M. Winslow USPTO Applicaton #: 20060234915 - Class: 514006000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Heavy Metal Containing (e.g., Hemoglobin, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20060234915. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to compositions and methods for delivering nitric oxide (NO) or carbon monoxide (CO) to red blood cells and tissues using heme proteins as carriers. In one embodiment, the present invention relates to the use of modified hemoglobin to deliver NO or CO to cells. BACKGROUND OF THE INVENTION [0002] The delivery of oxygen in higher organisms is carried out by the protein hemoglobin. In mammals, hemoglobin has a molecular weight of approximately 64,000 Da and is composed of about 6% heme and 94% globin. Heme is a type of porphyrin molecule that coordinates to Fe(II) using its four nitrogen atoms as electron-pair donors. In coordination with globin (i.e. the globular polypeptide portion (if hemoglobin), the heme binds O.sub.2, and can also bind NO and CO. In its native form, mammalian hemoglobin contains four subunits (i.e., it is a tetramer), each containing a heme group and a globin polypeptide chain. In other animals, the structure of hemoglobin is somewhat different. For example, insects have dimeric hemoglobin consisting of only two heme groups and two globin chains. In contrast, other organisms such as annelids (such as earthworms) have giant hemoglobins consisting of over 100 heme-globin complexes. Mammals also have a monomeric heme protein called myoglobin, which is found mainly in muscle tissue where it serves as an intracellular storage site for oxygen. [0003] In mammals, hemoglobin is found in red blood cells. Interestingly, free hemoglobin in the bloodstream is actually harmful, because of its vasoactivity. The vasoactivity of substances in the bloodstream can take the form of either vasoconstriction or vasodilation. Vasodilation is a physical change in a blood vessel, which results in an increased blood capacity through the blood vessel; and leads to decreased resistance and increased flow through the vessel. Vasodilation can either be active vasodilation or passive vasodilation. Active vasodilation is caused by a decrease in the tonus of smooth muscle in the wall of the vessel, whereas passive vasodilation is caused by increased pressure in the lumen of the vessel. [0004] Pulmonary hypertension is a condition that commonly benefits from the use of vasodilators. Pulmonary hypertension results from an elevation of pulmonary arterial pressure over normal levels. For an adult human, a typical mean pulmonary arterial pressure is approximately 12-15 mm Hg. Pulmonary hypertension is said to exist when the pulmonary arterial pressure increases by at least 5 to 10 mm Hg over normal levels. [0005] One form of pulmonary hypertension is hypoxia-induced pulmonary hypertension. Other examples include pulmonary hypertension resulting from disease states such as interstitial lung diseases with fibrosis, e.g., sarcoidosis and puemoconioses. Pulmonary hypertension can also result from emboli, from parasitic diseases such as shistosomiasis or filariasis, from multiple pulmonary vasculature occlusion associated with sickle cell disease, from cardiac disease, and from ischemic and valvular heart disease. [0006] Attempts have been made to treat pulmonary hypertension by administering drugs with known systemic vasodilatory effects, such as calcium channel blockers, hydralazine, and nitroprusside. Although these drugs may be successful in lowering the pulmonary blood pressure, they typically also decrease systemic blood pressure, which may result in dangerous pooling of the blood in the venous circulation. This can lead to hypotension, ischemia and consequent heart failure. [0007] Nitric oxide (NO) is one compound that plays an important role in regulating pulmonary blood flow. This vasodilator activates guanylate cyclase in pulmonary vascular muscle cells, with a subsequent increase in cyclic guanosine monophosphate and a decrease in intracellular calcium, leading to smooth muscle relaxation. Experimental studies on the physiological effects of NO have been facilitated by the development of a wide variety of organic compounds that spontaneously release NO and can be easily acquired to reproduce a physiological or pathophysiological function of NO. [0008] Carbon monoxide (CO) also functions as a vasodilator. CO is a colorless, odorless and tasteless gas which is formed in many chemical reactions and in the thermal or incomplete decomposition of many organic materials. In the atmosphere, the average global levels are estimated to be 0.19 parts per million (p.p.m.), 90% of which comes from natural sources including ocean microorganism production, and 10% of which is generated by human activity. Thus, inhalation of even small quantities of CO is inevitable for living organisms. [0009] The use of CO as a therapeutic agent has been explored. For example, Beutler administered CO as an inhalant at a concentration of 1000-2000 PPM to two patients suffering from Sickle Cell Disease. In both patients, anti-sickling was observed (E. Beutler, Blood 46:253-259 (1975). In addition, the effects of CO inhalation in a lung ischemia/reperfusion model were studied and shown to confer a benefit (C. Thiemermann, Nature Medicine 7:535-536 (2001)). However, in both studies, it was concluded that the dangers of CO inhalation outweighed the benefits. Thus, more recently, a carrier for CO has been proposed U.S. Patent Publication No. 2003/0064114 describes the therapeutic delivery of carbon monoxide by metal carbonyls to enhance vasodilation. [0010] In the body, CO is the product of metabolic breakdown of heme by heme oxygenase. Since all higher organisms use heme proteins for oxygen transport, CO itself is ubiquitous. CO binds to hemoglobin at the heme iron site with an affinity about 250 times higher than that of O.sub.2 (J. W. Severinghaus, et al., "Oxygen Dissociation Curve Analysis at 98.7%-99.6% Saturation, in "Oxygen Affinity of Hemoglobin and Red Cell Acid Base Status", P. Astrup and M. Rorth, Eds., Academic Press, New York, N.Y. (1972)). CO can also bind to myoglobin with a very high affinity. The fact that CO is not converted to CO.sub.2, and is instead eliminated from the body as CO, was established over 25 years ago (F. J. W. Roughton, Am. J. Physiol. 145:239-252 (1945)). Because of its high affinity for CO, the hemoglobin molecule switches to its high affinity form (i.e. the relaxed or "R" form) at very low CO saturation levels, which effectively increases its affinity for O.sub.2. This effect is the presumed basis for the favorable effect of CO on reversing sickled cells in Sickle Cell Disease (E. Beutler, Blood, 46:253-255 (1975)). [0011] CO shares some of the biological effects of NO, the endothelium-derived vasodilator. Thus, CO also induces cyclic GMP (cGMP) synthesis by activation of soluble guanylate cyclase (sGC). In addition to activation of sGC, CO promotes vasorelaxation through mechanisms that involve stimulation of calcium-activated potassium channels or diminished synthesis of constrictor mediators, such as endothelin and 20-HETE (F. Zhang, et al., Am. J. Hypertens. 14:62S-67S (2001)). Recent studies have indicated that CO can reduce restenosis when administered prior to angioplasty, suppress endothelial cell apoptosis, reduce xenotransplant rejection, and reduce hypoxia-induced vasoconstriction. (See L. E. Otterbein, et al., Nat. Med. 9:183-190 (2003); S. Brouard, et al., J. Exp. Med. 192:1015-1026 (2000); Y. Lin, et al., J. Immunol. 164:4883-4892 (2001); and R. J. Gonzales, et al., Am. J. Physiol. Heart Circ. Physiol. 282:H30-H37 (2002)). [0012] While the use of CO in clinical applications appears to be promising, its administration must be carefully controlled, since it is a poison. COHb levels of 16% predictably cause clinical symptoms, and as little as 10% can cause headaches. Levels of 70% are associated with seizures. Levels of as little as 5-10% can cause exertional angina in patients with underlying cardiovascular disease. [0013] Accordingly, there is a need to develop carriers for delivering vasodilators such as NO and CO as therapeutic agents that facilitate controlled administration so that a clinical benefit can be achieved without the risk of toxicity or undesirable side effects. The present invention relates to the use of heme proteins such as hemoglobin as just such a carrier. SUMMARY OF THE INVENTION [0014] The present invention relates to compositions and methods for delivering CO or NO to cells. The method is performed by first preparing a CO-- or NO-hemoglobin (Hb) complex; and thereafter contacting the cells with the XO-Hb complex. The Hb may be modified, such as by surface modification with, for example, maleimidyl-activated polyethylene glycol (MalPEG). [0015] In one embodiment, the CO-- and NO-Hb complexes are formed by first preparing an aqueous solution of Hb, and thereafter introducing gasous NO or CO into the solution. The Hb may previously be modified to block free sulfhydryl groups, which may involve mixing the Hb with an excess amount of MalPEG to form surface modified Hb, or MalPEG-Hb. [0016] The compositions of the present invention comprise the CO-- or NO-Hb complexes as described above in a pharmaceutically acceptable carrier, which is usually adapted for administration to a mammal. [0017] The compositions are useful for preventing and treating a variety of different conditions known to involve CO and NO metabolism, such as: hypertension, radiation damage, endotoxic shock, inflammation, autoimmune diseases (e.g., rheumatoid arthritis), vascular restenosis, sickle cell disease, apoptosis, xenotransplant rejection, Alzheimer's Disease, hypoxia, hyperoxia-induced injury, cancer, transplant rejection, post-operative ileus, arteriosclerosis, post-ischemic organ damage, myocardial infarction, angina, hemorrhagic shock, sepsis, penile erectile dysfunction, adult respiratory distress syndrome, hepatic cirrhosis, cardiac hypertrophy, heart failure, ulcerative colitis, and stroke. [0018] Other aspects of the invention are described throughout the specification and claims. BRIEF DESCRIPTION OF THE DRAWINGS [0019] FIG. 1 depicts the hematologic changes after infusion of an exemplary composition, COMP4; hematocrit (Hct), total hemoglobin (Hb) and plasma hemoglobin (Plas Hb). [0020] FIG. 2 depicts the hemodynamic changes after infusion of COMP4; mean arterial pressure (MAP), heart rate (HR), and cardiac contraction force (dP/dt). [0021] FIG. 3 depicts the changes in percent COHb in RBCs and plasma after infusion of COMP4. Continue reading... Full patent description for Compositions and methods for delivering carbon monoxide (co) and nitric oxide (no) to tissue using heme proteins as carriers Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Compositions and methods for delivering carbon monoxide (co) and nitric oxide (no) to tissue using heme proteins as carriers patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Compositions and methods for delivering carbon monoxide (co) and nitric oxide (no) to tissue using heme proteins as carriers or other areas of interest. ### Previous Patent Application: Oral insulin therapy Next Patent Application: Cardioprotective agent Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Compositions and methods for delivering carbon monoxide (co) and nitric oxide (no) to tissue using heme proteins as carriers patent info. IP-related news and info Results in 0.32945 seconds Other interesting Feshpatents.com categories: Qualcomm , Schering-Plough , Schlumberger , Seagate , Siemens , Texas Instruments , |
||
