Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-11-01
2002-03-19
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06358925
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns a method for the treatment of higher mammals having or being at substantial risk of developing osteoporosis in cortical bone, the treatment comprising the administration of insulin-like growth factor I (IGF-I). Hence, the invention is directed to the fields of bone growth and degeneration, to IGF-I, and to compositions thereof for use as pharmaceuticals.
BACKGROUND OF THE INVENTION
Osteoporosis encompasses a broad range of clinical syndromes having varying etiologies. In postmenopausal women, for example, two distinct types of osteoporsis have been identified. Type I osteoporosis occurs mainly in the early postmenopausal period from about age 50-65. It is characterized by excessive resorption, primarily in trabecular bone. Vertebral fractures are common. If given prior to significant bone loss, treatment which decreases or prevents bone resorption (such as with estrogen or calcitonin) is considered effective therapy.
Type II osteoporosis (a.k.a. senile osteoporosis) occurs essentially in all aging women and, to a lesser extent, in men. It is characterized by proportionate loss of cortical bone as well as trabecular bone. Here decreased bone formation plays a major role, if not a more important role than increased bone resorption. Fractures of the hip are characteristic of this type of osteoporosis.
Currently approved therapeutic agents for osteoporosis are antiresorptives. As such, while they may prevent further loss in patients with Type I osteoporosis, they are not as effective in reversing osteoporosis of either Type I or Type II or in halting Type II osteoporsis. See The American Journal of Medicine, Vol. 91 (Suppl 5B) 37S-41S; The American Journal of Medicine, Vol. 91 (Suppl 5B) 10S-13S; and The American Journal of Medicine, Vol. 91 (Suppl 5B) 23S-28S. In addition, the most widely accepted preventive agent for osteoporosis currently in use is estrogen therapy, which is not really an acceptable therapeutic agent for women with a history of or at risk for breast or endometrial cancers (estrogen dependent tumors) or for men with osteoporosis.
Insulin-like Growth Factor I (IGF-I) is a 70 amino acid peptide belonging to a family of compounds under the class name somatomedins and retains some structural and biologically similarities to insulin. The somatemedins' activity lie on a spectrum from hypoglycemic effects similar to insulin to growth promoting effects which are exemplified by growth hormone. IGF-I predominately induces growth and cell proliferation. IGF-I has also been demonstrated to specifically bind to receptors on rat osteoblast-like bone cells (Bennett et al, Endocrin. 115(4):1577-1583, 1984). IGF-I is routinely fabricated in the liver and released for binding to carrier proteins in the plasma (Schwander et al, Endocrin. 113(1):297-305, 1983), which bound form is inactive. In addition, there is a biofeedback regulating loop involving the somatomedins and growth hormone such that higher somatomedin concentrations inhibit growth hormone release which results in lesser production of endogenous IGF-I.
IGF-I infused into rats has been shown to result in markedly greater increases in body weight gain compared to controls, with increases in tibial epiphyseal width and thymidine incorporation into costal cartilage (Nature 107: 16-24, 1984) and directly stimulate osteoblasts to result in a greater number of functional osteoblasts. IGF-I is also mentioned as the vehicle through which growth hormone's effects on bone is mediated in Simpson, Growth Factors Which Affect Bone, Physiol. 235, TIBS, December 1984.
Nevertheless, it is important to note that the foregoing pre-clinical studies were conducted with fetal or newborn rat cells. It is highly likely that such “young” cells are more responsive to IGF-I (as well as other influences) than older cells, especially those in the elderly with established osteoporosis or those with drug induced or environmentally induced defects leading to reduced bone density. Furthermore, in J. Bone and Mineral Res., Vol 6, Suppl 1, Abstr. 549, p. S-221, August 1991, the authors report that IGF-I has virtually no effect on cortical bone of oovariectomized rats.
OBJECTS OF THE INVENTION
Accordingly, an object of the present invention is to provide a method of treatment of osteoporosis in higher mammals exhibiting decreased cortical bone mineral density and preventing osteoporosis due to cortical bone mineral density reduction in such mammals clinically prone to such cortical bone density reductions.
Another object of the invention is to provide pharmaceutical compositions useful in achieving the foregoing object.
SUMMARY OF THE INVENTION
Surprisingly, these and other objects of the invention have been achieved with the finding that IGF-I is useful in the treatment of osteoporosis in higher mammals exhibiting decreased cortical bone mineral density and those exposed to drugs or environmental conditions which tend to result in cortical bone mineral density reduction and potentially to a cortical bone osteoporotic condition.
DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns osteoporosis treatment and prevention, which osteoporosis is associated with decreased cortical bone mineral density in mammals generally, but is especially suited for the treatment and prevention of such osteoporosis in humans.
For the present invention purposes, mammals includes all mammals within the taxonomic orders of Primates, Carnivora, Perissodactyla and Artiodactyla. This includes, without limitation, Old World monkeys, New World monkeys, great apes, humans, cats, dogs, horses, pigs, cattle, sheep, and goats. Preferably mammals are selected from the taxonmic orders of Primates, Carnivora, Perissodactyla, and Artiodactyla, more preferably Primates, cats, dogs, sheep, goats, horses, pigs and cattle,still more preferably Primates, most preferably humans.
IGF-I is a naturally occurring protein that can be obtained from a number of sources. Preferably, IGF-I from the same species (or its synthetic twin) as the species being treated therewith is employed, but IGF-I from one species may be used to treat another species if the immune response elicited is slight or non-existent. In addition, fragments and analogs of IGF-I having IGF-I activity, particularly IGF-I anti-osteoporosis activity, are also suitably employed in the invention. As used within the context of the present invention IGF-I includes such fragments and analogs unless the text clearly states otherwise. Where weights of IGF-I are presented, that weight of IGF-I or an approximately equipotent weight of such analogs and fragments are intended absent clear direction to the contrary. Where no type of IGF-I is indicated, reference is to human-IGF-I (meaning the structure, not the species source), unless the reasonable reading of the text requires otherwise.
IGF-I analogs and fragments of IGF-I or its analogs are commonly known in the art as can be seen from Proc. Natl. Acad. Sci. USA, Vol 83, pp.4904-4907, July, 1986; Biochemical and Biophysical Research Communications, Vol 149, No.2, pp.398-404, Dec. 16, 1987; Biochemical and Biophysical Research Communications, Vol. 149, No. 2, pp.672-679, Dec. 16, 1987; Endocrinology, Vol. 123, No. 1, pp.373-381; The Journal of Biological Chemistry, Vol. 263, No. 13, pp. 6233-6239, May 5, 1988; and Biochemical and Biophysical Research Communications, Vol. 165, No. 2, pp. 766-771, Dec. 15, 1989.
IGF-I can be synthetically produced, chemically or by recombinant techniques, as well as extracted from tissues. Recombinant manufacture is preferred. One such recombinant technique is disclosed in EP 123,228, incorporated herein by reference.
An effective amount of IGF-I for the present invention is an amount sufficient to slow, stop, or reverse the cortical bone mineral density reduction rate in a patient exhibiting cortical bone mineral density reduction. Throughout the specification where values are given for non-cortical bone tissue they are for purposes of exemplifying the osteoporotic state generally. In
Bhatia Satish
Guler Hans-Peter
Ferraro Gregory D.
Novartis Corp.
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