Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-09-17
2001-08-14
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S561000, C514S563000, C514S567000
Reexamination Certificate
active
06274564
ABSTRACT:
BACKGROUND OF THE INVNETION
The cobalamin family comprises vitamin B12 (cyanocobalamin) and its axial-ligand substituted congeners, such as hydroxocobalamin, methylcobalamin and adenosylcobalamin, among others. Various cobalamins have been used effectively for the treatment of conditions resulting from cobalamin deficiency, such as hematological abnormalities (e.g., macrocytosis and megaloblastic anemia) and neurological impairments (ranging from neuropathy and demyelination to confusional states, mood shifts, memory loss, dementia and depression). These classical sequelae to chronic vitamin B12 deficiency and their treatment are well known (Schneider and Stroinski,
Comprehensive B
12 (New York: Walter de Gruyter & Co., 1987)). In addition, a number of other diseases or disease states have been characterized by some form of cobalamin deficiency; in many of these cases cobalamin treatment has been reported to result in an amelioration of symptoms or other improvement in the patient's condition. The diseases and disease states studied include anemias of various kinds, autoimmune conditions, disorders of carbohydrate and lipid metabolism such as diabetes and atherosclerosis, neuropathies of various etiologies, mitochondrial disorders and/or deficiencies of cellular bioenergetics, neurodegenerative diseases, mental and psychiatric disorders, endocrine dysfunctions, infertility and reproductive disorders, osteoporosis, immunodeficiencies, AIDS and cancer.
Erythrocyte macrocytosis and macrocytic anemia are often considered to be the classic hematological signs of cobalamin deficiency, especially when found in conjunction with low hemoglobin values. Recently, however, a more complex and varied picture of cobalamin-deficiency anemia has emerged. For example, a surprisingly high rate of incidence of cobalamin deficiency has been detected in sickle cell disease (SCD) patients (Carmel & Johnson, Blood 86, Suppl. 1,644
a
(1995); Al-Momen, J. Intern. Med. 237, 551-555 (1995)), where the sickle cell anemia may mask a coexisting cobalamin deficiency anemia. The frequent association of folate deficiency with SCD further obscures and complicates the clinical picture. In particular, investigators have concluded that the frequency of cobalamin abnormalities is high enough to warrant concern about the indiscriminate use of folate supplements in SCD (Carmel & Johnson, op. cit.), since folate administration in the absence of cobalamin is known to exacerbate the neuropathology of cobalamin deficiency. Thus, cobalamin supplementation may be especially desirable in those SCD patients who are being treated with folate. Furthermore, an increased unsaturated B12 binding capacity has been unexpectedly found in association with iron deficiency anemia (Rosner & Schreiber, Am. J. Med. Sci. 263, 473-480 (1972)) suggesting an increased need for vitamin B12 under these circumstances. Delayed plasma clearance of radiolabeled cobalamin has also been reported in iron deficiency anemia; one explanation proposed for this effect is a decreased uptake of vitamin B12 by tissues as a result of diminished erythropoiesis (Cook & Valberg, Blood 25, 335-344 (1965)). Since ethrythrocytes appear to play a significant role in delivering cobalamin to tissues (Sorrell et al., Am. J. Clin. Nutr. 24 924-929 (1971)), one may conclude that any cause of anemia resulting in diminished erythropoeisis and/or decreased red cell numbers can induce a state of functional cobalamin deficiency. Therefore, cobalamin supplementation may be useful in treating various forms of anemia and especially in treating those cases associated with coexisting folate deficiency, e.g., as in thalassemia (Kumar et al., Am. J. Clin. Pathol. 84,668-671 (1985)) or SCD.
Pernicious anemia, the prototypical disorder of cobalamin absorption, is generally characterized by gastric atrophy and autoimmune attack on the parietal cells of the gastric fundus, with consequent depletion or impairment of intrinsic factor. Suggestively, an increased prevalence of other autoimmune disorders, such as vitiligo, Graves' disease, Hashimoto's thyroiditis, Type I diabetes, Sjogren's syndrome and rheumatoid arthritis, is found among pernicious anemia patients; the resulting pattern of coexisting autoimmune disease is referred to by the term polyglandular autoimmune syndrome (Leshin, Am. J. Med. Sci. 290, 77-88 (1985)). Many autoimmune disorders, whether components of a polyglandular autoimmune syndrome or not, are associated with abnormal cobalamin metabolism. For example, cases of Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and autoimmune hemolytic anemia have been associated with elevated levels of apo-transcobalamin II, the unbound form of the B12-binding protein which carries cobalamin from serum to cells, thus suggesting an increased demand for vitamin B12 in these conditions (Gimsing et al., Scand. J. Rheumatol. 11, 1-4 (1982); Frater-Schroder et al., Lancet 2, 238-239 (1978)). Furthermore, cobalamin deficiencies have been noted in both synovial fluid (Ono et al., J. Vitaminol. 18, 1-2 (1972)) and serum (Vreugdenhil et al., Ann. Rheum. Dis. 49, 93-98 (1990)) of patients with rheumatoid arthritis, and in the sera of patients with systemic lupus erythematosus (Molad et al., Am. J. Med. 88, 141-144 (1990)), inclusion body myositis and Sjogren's syndrome (Khraishi et al., J. Rheumatol. 19, 306-309 (1992)). A number of these conditions have been shown to be responsive to cobalamin therapy. For example, methylcobalamin has been reported efficacious in the treatment of rheumatoid arthritis (Yamashiki et al., J. Clin. Lab. Immunol. 37, 173-182 (1992)). Likewise, some cases of multiple sclerosis are associated with cobalamin deficiency (Reynolds et al., Arch. Neurol. 48, 808-811 (1991); Baig & Qureshi, Biogenic Amines 11, 479-485 (1995)), and improvement in some patients has been noted upon treatment with cyanocobalamin (Levin, Am. J. Digest. Dis. 22, 96-97 (1955)) or methylcobalamin (Kira et al., Intern. Med. 33, 82-86 (1994)). Both psoriasis and lupus erythematosus have been successfully treated with cyanocobalamin (Stingily, Miss. Doctor 32, 222-223 (1955)), while cases of vitiligo have responded to treatment with vitamin B12 combined with other vitamins (Montes et al., Cutis 50, 39-42 (1992)).
Several distinct lines of evidence connect cobalamin deficiency with diabetes mellitus and other disorders of carbohydrate metabolism. In animals rendered experimentally diabetic, a significant decrease in both serum and tissue cobalamins has been shown to accompany the induction of ketosis (Nath & Nath, J. Vitaminol. 15, 174-177 (1969)). Elevated levels of unsaturated B12 binding capacity (UBBC), a measure of apo-transcobalamins in serum, have been noted in diabetic patients with hyperglycemia, with UBBC normalizing upon restitution of glycemic control (Takahashi et al., Diabetes Res. Clin. Pract. 25, 13-17 (1994)). Moreover, it has long been known that insulin resistance is common among patients presenting with both diabetes and pernicious anemia (Adams, Med. Clin. N. Amer. 8, 1163-1170 (1925); Wright, Clifton Med. Bull. 12, 64-67 (1926)), whereas vitamin B12 administration is effective in increasing insulin sensitivity in some diabetics (Ralli et al., J. Clin. Endocrinol. Metab. 15, 898 (1955)). Likewise, treatment of pernicious anemia patients with cyanocobalamin is known to improve glucose tolerance, an effect attributed to the regulatory influence of vitamin B12 on carbohydrate metabolism (Panzram, Schweiz. Med. Wschr. 91, 234-240 (1961)). Vitamin B12 has also been reported effective in restoring the impaired glucose tolerance induced by thyroid hormone, corticosteroids and by various disease processes (Hadnagy et al., Int. Z. Vitaminforsch. 33, 141-150 (1963)). Since Type II diabetes, obesity, hypertension, coronary artery disease and age-related glucose intolerance have all been associated with increased insulin resistance (Reaven, Diabetes 37, 1595-1607 (1988); Jackson, Diabetes Care 13, Suppl. 2, 9-19 (1990)),
Brennan Thomas F.
Sarill William J.
Lahive & Cockfield LLP
Travers Russell
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