Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
2000-08-24
2002-07-23
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
C426S072000, C426S073000, C426S074000, C424S439000, C424S632000, C424S633000, C424S634000, C424S635000, C424S637000, C424S638000, C424S641000, C424S643000, C424S681000, C424S682000, C424S683000, C424S686000, C424S688000, C424S689000, C424S692000, C424S697000, C424S702000, C514S249000, C514S458000, C514S474000, C514S494000, C514S499000, C514S500000, C514S561000, C514S562000, C514S563000, C514S706000, C514S725000, C514S904000, C514S905000
Reexamination Certificate
active
06423349
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of the amino acid glutamine in combination with additional nutrients in a composition for promoting recovery in patients undergoing elective surgery and for treating multiple organ system failure.
2. Description of the Related Art
Schneider et al., U.S. Pat. No. 5,902,829, discloses a method for the amelioration of microcirculatory hypoperfusion, and/or the treatment or prophylaxis or hypoperfusion-reperfusion injury, in patients in need of such amelioration, treatment or prophylaxis, comprising administering preoperatively to a patient undergoing surgery to the patient a composition comprising an effective amount of a nitric oxide donor and/or a substrate of nitric oxide synthetase and/or a precursor of the substrate, for the amelioration, treatment or prophylaxis, and a nutritionally acceptable carrier. Schneider et al. further discloses that the precursor of L-arginine is ornithine or glutamine and that the composition is administered at least one day prior to surgery, but can be initiated between 3-10 days prior to surgery.
Vinnars et al., U.S. Pat. No. 5,646,187, discloses a composition for the treatment of critically ill patients having one or more organ failures or sepsis and a general catabolism which have more than a 50% reduction of the glutamine level in skeletal muscles and under intensive care, in order to improve protein synthesis capacity, maintaining energy level, preserving the lean body mass, wherein the composition consists essentially of a conventional amino acid mixture and more than 25 gl of alpha-ketoglutarate or admixtures of these with at least one member selected from the group consisting of glutamine, L-asparagine, acetoacetate, glucose and fat.
Wilmore, U.S. Pat. No. 5,292,722, discloses a composition for decreasing dehydration and nitrogen loss in a mammal comprising from about 4% to 10% dextrose and from about ½% to 2% glutamine, or glutamine equivalent, wherein said glutamine equivalent is capable of being converted to glutamine by said mammal. Wilmore discloses that the composition can be used in treating dehydration and nitrogen loss which is associated with surgical operations.
3. Discussion of the Background of the Invention
Throughout the world, multiple organ system failure (MOSF) has become the most common cause of death in intensive care units (ICU); the reported mortality rates vary from 30-100% with a mean of 50%, depending on the number of organ systems involved, the patients' ICU stay may last for 6 weeks to many months. As used herein, the term “MOSF or Multiple Organ System Failure” refers to the clinical syndrome of vital organ dysfunction or failure due to tissue injury resulting from SIRS (Systemic Inflammatory Response Syndrome which refers to the excessive and dysfunctional elaboration by a human patient of inflammatory mediators which results in an excessive and injurious inflammatory response). In prior studies, patients with multiple system failure have used nearly 40% of the available ICU days. See, e.g., Carrico et al. Arch. Surg. Vol. 121 page 196(1986). For the last ten years, efforts to improve outcome based upon increasing systemic oxygen delivery have been advocated, but either no effect or increased mortality has been associated with this approach.
Gastric intramucosal pH monitoring has been advocated as a more sensitive endpoint of resuscitation and two clinical studies have suggested improved outcome in selected subsets of patients. See Gutierrez et al., Lancet, vol. 339 page 195 (1992) and Ivatury et al., J. Trauma vol. 39, page 1, (1995). Others have confirmed that failure of splanchnic resuscitation correlates with MOSF and increased length of ICU stay in a hemodynamically unstable trauma patient. See, e.g., Kirton et al., Chest, vol. 108, No. 3, page 104S (1995).
Kirton et al. have studied ICU patients with persistent uncorrected gastric intramucosal pH and who had pulmonary artery catheters to guide resuscitation. See Kirton et al., J. Trauma vol. 39, No. 6, page 1211(1995). Kirton et al. have found that the relative risk of death in patients with a pH
i
of less than 7.32 was 4.5 whereas the relative risk of developing multiple organ system failure was 5.4 in patients having a pH
i
of greater than 7.32. During the study a resuscitation protocol was begun upon ICU admission, which utilized inotropic and vasodilatory agents to optimize systemic and splanchnic O
2
delivery (e.g., dubutamine, isoproterenol, prostaglandin E, nitroglycerin, nitroprusside). The xanthine oxidase inhibitor, folate, and the free radical scavenger, mannitol, were uniformly administered. Drugs causing splanchnic vasoconstriction (e.g., epinephrine, norephinephrine, meosynephrine) were only used to treat severe systemic hypotension. This protocol resulted in a significant reduction in multiple organ system failures per patient and length of ICU and total hospital stay in patients with persistent gastric intramucosal acidosis. The agents administered increased splanchnic perfusion and were intended to prevent free radical damage during reperfusion. The study concluded that the severity of MOSF as judged by defined organ system failures and duration of stay were associated with gastrointestinal intramucosal acidosis related to splanchnic hypoperfusion. However, the problem of reversing the abnormal pH
i
and curtailing the long ICU stay indicated that further improvements are necessary.
Multiple organ system failure is associated with ischemia-reperfusion injury. Oxygen radicals are involved during ischemia followed by reperfusion. Therapy to block xanthine oxidase and thus prevent the generation of free radicals (e.g., superoxicde:O
2
, hydrogen peroxide:H
2
O
2
, and the hydroxyl radical:OH) and promote the generation of radical scavengers to prevent damage when radicals have already been generated are essential to treatment of multiple organ system failure. The oxygen free radicals are capable of causing cellular injury through cellular membrane lipid peroxidation and degradation of nucleic acids, eventually leading to increased membrane permeability and cell-lysis. Certain free radical species, including O
2
—and OH cause polymorphonuclear cells (PMNs) to be attracted to the gastrointestinal tract, adhere, and then be activated. The free radicals are then released and spread systemically, attacking normal tissue through their respiratory burst and causing further tissue injury by releasing intracellular proteases and lipases capable of autodigestion of cellular components. Free radicals also produce arachiodonic acid, leukotrienes, thromboxanes and prostaglandins through lipid peroxidation. The body's natural antioxidant defenses to these free radicals consist principally of glutathione peroxidase, catalase and superoxide dismutase.
Some of the reactions are well known and available agents can be used in combination to either prevent their occurrence or to minimize the adverse affects of the agents produced. The first two abnormalities that occur in the period of ischemia are related to ATP regeneration and xanthine dehydrogenase function.
During normoxia ATP liberates energy for cellular work; in the presence of oxygen, however, ADP combines with hydrogen ion and ATP is re-synthesized. Hypoxanthine combines with NAD
+
, a reaction catalyzed by xanthine dehydrogenase, to produce xanthine and NADH.
During ischemia, however, ATP degrades beyond ADP to AMP, adenosine, inosine and finally to hypoxanthine. Xanthine dehydrogenase is converted to xanthine oxidase.
During reperfusion which reintroduces oxygen, xanthine oxidase catalyzes the transformation of hypoxanthine to xanthine which also results in the production of superoxide and hydrogen peroxide.
Later reactions produce the hydroxyl radical, superoxide, and hydrogen peroxide which create tissue injury through lipid peroxidation, destruction of protein such as ATPase, destruction of nucleic acids and membrane permeability.
Superoxide, through the process of lipid perox
Sherratt J. Dale
Somerville Joann
Baxter International Inc.
Buonaiuto Mark J.
Kowalik Francis C.
Nichols Jeffrey C.
Pak John
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