Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1999-06-28
2002-08-06
Kemmerer, Elizabeth (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
C424S198100, C514S002600, C514S012200, C530S300000, C530S303000, C530S350000, C530S399000
Reexamination Certificate
active
06428781
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compounds and methods for elevating endogenous insulin-like growth factors and their activities in living bodies.
BACKGROUND ART
Insulin-like growth factors (hereinafter “IGF”) are found in two distinct molecular forms called IGF-I and IGF-II, respectively. Human IGF-I and IGF-II are 70 and 67 amino acids in length, respectively. Compared to IGF-II, IGF-I has three more amino acids at the site corresponding to the C peptide, which is a partial structure of insulin. The amino acid sequence homology between IGF-I and IGF-II is about 60% while that between IGF-I and insulin is about 40%. Although the liver and kidney are the major sites of production for IGF-I in living bodies, northern blot analysis of MRNA has revealed that IGF-I is produced by almost all tissues in the body (D'Ercole, A. J., et al., Proc.
Natl. Acad. Sci. USA. 81, 935 (1984); Humbel, R. E., et al., Eur. J. Biochem., 190, 445 (1990)). IGF-I is considered to act not only as an endocrine factor but also as paracrine or autocrine factor.
IGF-I and IGF-II bind to distinct and specific receptors; an IGF-I receptor and an IGF-II/cation-independent mannose-6-phosphate receptor, respectively. However, since IGF-II has also been shown to bind to the IGF-I receptor, the various biological activities associated with IGF-II are thought to occur mainly through the IGF-I receptor located on cell surface (Casella, S. J., et al., J. Biol. Chem., 261, 9268 (1986); Sakano, K., et al., J. Biol. Chem., 266, 20626 (1991)).
The IGF-I receptor shares a high degree of amino acid sequence homology with the insulin receptor and the two molecules resemble each other in their intracellular signal transduction mechanism (Shemer, J., et al., J. Biol. Chem., 262, 15476 (1987); Myers, M. G. Jr., et al., Endocrinology, 132,. 1421 (1993)). IGFs regulate glucose metabolism predominantly in the peripheral tissue, which is different from insulin, as shown in animal model studies. The receptors for IGFs and insulin are differentially localized in tissues, and this may explain why the biological effect of IGFs in the body is distinguishable from insulin's effect (Laager, R., et al., J. Clin. Invest., 92, 1903 (1993)).
The blood of an average adult human contains about 100 nM of IGF and about 100 pM of insulin (Baxter, R. C., in Modern Concepts of Insulin-Like Growth Factors (Spencer, E. M., ed) pp.371, Elsevier Science Publishing Co., New York-Amsterdam (1991)). Most IGFs found in living bodies form complexes with an IGF-binding protein (hereinafter “IGFBP”). It appears that a specific binding protein exists for each IGF. The hypoglycemic effect of free IGF or unbound IGF is about 5 to 10% of that of insulin (Guler, H. P. et al., New Engl. J. Med., 317, 137 (1987)), indicating that insulin-like growth factors are at concentrations of about 50 to 100-fold greater than insulin (Baxter, R. C., in Modern Concepts of Insulin-Like Growth Factors (Spencer, E. M., ed) pp.371, Elsevier Science Publishing Co., New York-Amsterdam (1991)).
The World Health Organization has classified the disease, Diabetes mellitus, into roughly three categories on the basis of their distinct clinical patterns:
(1) Insulin-dependent diabetes mellitus (hereinafter “IDDM”)
(2) Non insulin dependent diabetes mellitus (hereinafter “NIDDM”)
(3) Other diabetes mellitus (derived from pancreato-pathy diseases or endocrinopathy)
A method for treating IDDM involves insulin therapy, while diet therapy, kinesitherapy, or treatment with an oral hypoglycemic agent or with insulin is mainly used in the treatment of NIDDM. In recent years, IGF-I therapy has been considered as an alternative treatment for insulin-dependent diabetes mellitus in cases where administration of insulin alone is not effective (Kuzuya, H., et al. Diabetes 42, 696 (1993)). Also for NIDDM, effects of IGF have been under investigation (Zenobi, P. D., et al., J. Clin. Invest., .90,. 2234 (1992); Moses, A. C., et al. , Diabetes, 45, 91(1996)).
Guler et al. observed that the intravenous injection of IGF-I into adult humans in an amount of 100 &mgr;g/kg resulted in the lowering of blood glucose levels with the lowest level occurring after 20 minutes (Guler, H. P., et al., New Engl. J. Med., 317, 137 (1987))
Takano et al. observed that hypoglycemic activity was observed in adult humans following the subcutaneous injection of IGF-I in an amount of 60 to 120 &mgr;g/kg, and that administration of IGF-I every 6 days in an amount of 100 &mgr;g/kg lowered the uric acid and creatinine levels in blood (Takano, K., et al., Endocrinol. Jpn., 37, 309. (1990)).
In addition, there are reports on the lowering of free fatty acid levels in blood (Turkalj. I., et al., J. Clin. Endocrinol. Metab., 75, 1186 (1992)), the lowering of neutral fats such as triglyceride (Turkalj. I., et al., J. Clin. Endocrinol. Metab. 75, 1186 (1992); Zenobi, P. D. , et al. , J. Clin. Invest., 90, 2234 (1992)), and the lowering in total cholesterol level (Zenobi, P. D., et al., Diabetologia 36, 465 (1993)). Increases in renal blood flow and glomerular filtration rate (Elahi, D., et al., in Modern Concepts of Insulin-Like Growth Factors (Spencer, E. M., ed) pp2l9, Elsevier Science Publishing Co., New York-Amsterdam (1991)), have been reported for IGF-I.
There is also a report that the administration of IGF-II was effective for intractable diabetes mellitus (Usara, A., et al., Diabetes, 44, Suppl. 1, 33A, 1995)). Results from animal model studies suggest the effectiveness of IGF-I in the reduction of conditions associated with stress including glucose metabolism at the time of hemorrhagic shock, the alleviation of side effects caused by sugar infusion (Unexamined Japanese Patent Publication (KOKAI) No. Hei 7-242565).
Administering IGF to animals has helped to identify the numerous biological activities of IGF including hypoglycemic activity, induction of proliferation, cell differentiation, and anobolic activity. Local administration of IGF-I to the injured peripheral nervous system results in the proliferation of non-neural cells while stimulating neurons. It is reported that IGF-I receptors are present on spinal cells and that administration of IGF-I decreases cell death of motor neurons. In addition, it is recognized that the administration of IGF increases the muscular end plate, promotes the functional recovery of a damaged sciatic nerve and prevents peripheral motor paralysis observed during chemotherapy (Sjoberg, J., et al., Brain Res. 485, 102 (1989).
Based on these foregoing experimental observations in the peripheral nervous sytem, clinical tests using IGF-I in the treatment of amyotrophic lateral sclerosis and degenerative diseases of the motor neuron have been conducted (Lewis, M. E., et al., Exp. Neurol., 124, 73(1993)). Similarly, the use of IGF in promoting the survival of neuronal cells is recognized as being important in the treatment of Alzheimer's disease, apoplexy, amyotrophic lateral sclerosis, Parkinson's disease and the like (Unexamined Japanese Patent Publication (KOHYO) No. Hei 6-510305). In addition, the effectiveness of IGF-I in the treatment of muscular dystrophy has also been reported (Vlachopapadopoulou, E., et al., J. Clin. Endocrinol. Metab., 80, 3715 (1995)).
The effects of IGF on diabetic neuropathy have also been studied. In an IDDM rat model (STZ-rat: streptozotocin-diabetic rat model), alleviation of diabetic neuropathy was observed when IGF was administered at concentrations that did not lower blood glucose levels (Zhuang, H-X, et al., Exp. Neurol., 140, pp198-205 (1996)). It has also been reported that administration of IGF in an NIDDM rat model (diabetic obese Zucker (fa/fa) rat), reduced the level of IGF-II mRNA in the sciatic nerve, spinal nerves and brain nerves, and alleviated the diabetic neuropathy when used at a concentration that did not result in lowering of blood glucose levels (Zhuang, H-X, et al., J. Pharmacol. Exp. Ther., 283, pp366-374 (1997)). These findings suggest that IGF is effective in the treatment of diabetic neuropathy.
The effects of IG
Hashimoto Ryuji
Higashihashi Nobuyuki
Sakano Katsuichi
Bunner Bridget E.
Daiichi Pharmaceutical Co. Ltd.
Kemmerer Elizabeth
Sughrue & Mion, PLLC
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