Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-12-14
2003-01-21
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S568000, C514S575000, C514S922000, C514S630000
Reexamination Certificate
active
06509380
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for reducing iron levels and/or levels of other toxic metals or elements in mammals. In a particular aspect, the present invention relates to methods for reducing free iron ion levels and/or excess and toxic levels of other elements in mammals, and to the removal of excess iron or excesses of other metals/elements stored in the organs by administration of acetaminophen and/or structural or chemical analogues or derivatives thereof. These compounds may scavenge excess iron or free iron ions in hosts undergoing anthracycline chemotherapy, as well as hosts suffering from iron overload or non-iron overload diseases and/or conditions, such as hereditary hemochromatosis, blood-transfusion related anemias and hemolytic anemias such as thalassemia, hemodialysis, stroke, and rheumatoid arthritis. Acetaminophen is particularly preferred in this regard. In a further aspect, the present invention relates to compositions and formulations useful in the methods disclosed herein.
BACKGROUND OF THE INVENTION
Iron is crucial for maintaining normal structure and function of virtually all mammalian cells (see, for example, Voest et al., in
Ann. Intern. Med.,
120:490-499 (1994) and Kontoghiorghes, G. J., in
Toxicol. Letters,
80:1-18 (1995), the contents of which are hereby incorporated by reference in their entirety). Iron and its binding proteins have immunoregulatory properties. Adult humans contain 3-5 g of iron, mainly in the form of hemoglobin (58%), ferritin/hemosiderin (30%), myoglobin (9%) and other heme or nonheme enzyme proteins (Harrison and Hoare, in
Metals in Biochemistry,
Chapman and Hall, New York, 1980, the contents of which is hereby incorporated by reference in its entirety). Approximately 10 to 15 mg of dietary iron is normally consumed per day by each individual in the U.S. About 1 to 2 mg of iron in the Fe (II) form is absorbed each day chiefly through villi in the duodenum to compensate for the 1 to 2 mg daily body loss of iron. Normal men absorb about 1 mg iron per day, menstruating women 2 mg iron per day, and hemachromotosis patients 2 to 5 mg iron per day.
Total iron levels in the body are regulated mainly through absorption from the intestine and the erythropoietic activity of the bone marrow. Upon absorption, iron is transported to various tissues and organs by the serum protein transferrin. Once transported to the target tissue or organ, iron is transported and stored intracellularly in the form of ferritin/hemosiderin. Under normal conditions, transferrin is about 30% saturated with iron in healthy individuals, and an equilibrium is maintained between the sites of iron absorption, storage and utilization. The presence of these homeostatic controls ensures the maintenance of physiological levels of not only iron, but also other essential metal ions such as copper, zinc and cobalt. The control of iron absorption may be genetic with complex interactions with intestinal mucosal cells, dietary factors, and other influences.
Iron is absorbed both as heme and non-heme iron chiefly in the duodenum and the proximal jejunum. Iron in meat, primarily heme iron, is better absorbed than non-heme iron. The absorption of heme iron is not influenced by dietary composition or luminal factors as is the absorption of non-heme iron.
Breakdown of these controls could result in metal imbalance and metal overload, causing iron overloading toxicity and possibly death in many groups of patients, especially those with idiopathic hemochromatosis (see, for example, Guyader et al., in
Gastroenterol.,
97:737-743 (1989), the contents of which is hereby incorporated by reference in its entirety). Shifting of immunoregulatory balances by iron excess or deficiency may produce severe, deleterious psychological effects.
Iron, particularly in the form of free iron ions, can promote the generation of reactive oxygen species through the iron-catalyzed Fenton and Haber-Weiss reactions (Haber and Weiss, in Proc R Soc Ser A 1934;147:332) as follows:
Fe
3+
+.O
2
+
__________→Fe
2+
+O
2
Fe
2+
+H
2
O
2
__________→Fe
3+
+.OH+OH— (Fenton reaction)
The Haber-Weiss reaction is shown below:
O
2
—+H
2
O
2
__________→.OH+OH—
(. designates a free radical, in this case an oxygen free radical)
(modified from U.S. Pat. No. 5,922,761)
The Haber-Weiss and Fenton reactions are seen to produce the hydroxyl radical (.OH), a highly potent oxidant which is capable of causing oxidative damage to lipids, proteins, and nucleic acids (Lai and Piette. Biochem Biophys Res-Commun 1977;78:51-9, and Dizdaroglu and Bergtold. Amal Biochem 1986;156:182).
Effects of iron overload include decreased antibody-mediated and mitogens-stimulated phagocytosis by monocytes and macrophages, alterations in T-lymphocyte subsets, and modification of lymphocyte distribution in different compartments of the immune system. Accordingly, among its toxic effects, iron is known to mediate a repertoire of oxygen related free radical reactions (see, for example, Halliwell and Gutteridge, in Halliwell and Gutteridge, Free Radicals in Biology and Medicine, 2nd edition. Oxford: Clarendon Press, 15-19 (1989), the contents of which is hereby incorporated by reference in its entirety).
The importance of iron in regulating the expression of T-lymphocyte cell surface markers, influencing the expansion of different T-cell subsets, and affecting immune cell functions can be demonstrated in vitro and in vivo. The poor ability of lymphocytes to sequester excess iron in ferritin may help to explain the immune system abnormalities in iron-overloaded patients.
In particular, hemochromatosis is a disease of excessive iron storage leading to tissue damage and fibrosis. Both genetic, or hereditary, hemochromatosis, which can affect 1 in 500 of some populations, and the form of this disease which occurs as a secondary consequence of the hemoglobinopathy, homozygous &bgr;-thalassemia, with 40 million carriers worldwide, have a common pathology. The cardiotoxicity and hepatoxicity, which occurs with this disease, have never been produced experimentally in other species. Hemochromatosis of the liver in man is caused when the iron burden exceeds a threshold in the region of 22 &mgr;mol/g liver dry weight.
Genetic hemochromatosis, a life-long disease, is probably the most common autosomal recessive disorder found in white Americans, of whom about 5/1,000 (0.5 percent) are homozygous for the associated gene. The hemochromatosis gene is probably located close to the HLA-A locus on the short arm of chromosome 6. Homozygous individuals may develop severe and potentially lethal hemochromatosis, especially after age 39.
Hereditary hemochromatosis involves an increased rate of iron absorption from the gut with subsequent progressive storage of iron in soft organs of the body. Excessive iron storage eventually produces pituitary, pancreatic, cardiac, spleen, epidermal, and liver and/or hepatic failure or cancer. Damage to these organs may be characterized by elevated liver enzyme values and hepatomegaly often with cirrhosis which may develop into hepatocellular carcinoma, splenomegaly, pancreatic fibrosis leading to diabetes mellitus, hyperpigmentation of the skin, pituitary insufficiency, hypogonadism, occasional hypothyroidism, cardiac abnormalities such as arrythmias and/or congestive heart failure, and arthritis/arthropathy. Early diagnosis can prevent these excess iron-induced problems. Iron overload owing to HLA-linked hereditary hemochromatosis can be distinguished from other causes of hemochromatosis by liver biopsies and interpretations.
Iron overload as seen in hereditary hemochromatosis patients enhances suppressor T-cell (CD8) numbers and activity, decreases the proliferative capacity, numbers, and activity of helper T cells (CD4) with changes in CD8/CD4 ratios, impairs the generation of cytotoxic T cells, and alters immunoglobulin secretion when compared to treated hereditary hemochromatosis patients or controls. A correlation has rece
Goldberg Joshua B.
Juneau Todd L.
Krass Frederick
Marshall University Research Corporation
Nath Gary M.
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