Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Phosphorus or phosphorus compound
Reexamination Certificate
1999-03-01
2001-10-16
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Phosphorus or phosphorus compound
C424S602000, C424S603000, C424S604000, C424S605000, C424S606000, C424S682000
Reexamination Certificate
active
06303155
ABSTRACT:
FIELD OF THE INVENTION
The present invention is generally in the field of endocrinology and treatment of conditions associated with impairment in normal hormone levels. More specifically, the present invention provides a composition and method for increasing the level of the parathyroid hormone (PTH) in a needy subject. In accordance with a preferred embodiment, the method and composition are used for the treatment of osteoporosis.
PRIOR ART
The following is a list of prior art believed to be relevant as a background of the invention:
1. Rodan, G. A., Mechanical loading, estrogen deficiency, and the coupling of bone formation to bone resorption,
J. Bone Miner. Res.,
6:527-530, 1991.
2. Juppner, H., Abou-Samra, A. B., Freeman, M., Kong, X. F., Schipani, E., Richards, J., Kolakowski, L. F., Hock, J., Potts, J. T., Kronenberg, H. M., and Segre, G. V., A G-protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide,
Science,
254:1024-1026, 1991.
3. Mosekilde, Li, Danielsen, C. C., Sogaard, C. H., McOsker, J. E., and Wronski, T. J., The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strength-assessed in a sexually mature, ovariectomized rat model,
Bone,
16:223-230, 1995.
4. Reeve, J., Meunier, P. J., Parsons, J. A., Bernat, M., Bilvoet, O. L. M., Courpron, P., Edouard, C., Klenerman, L., Neer, R. M., Renier, J. C., Slovik, D., Vismans, F. J. F. E., and Potts, J. T., Anabolic effects of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: A multicentre trial,
Br. Med. J.,
280:1340-1344, 1980.
5. Dempster, D. W., Cosman, F., Parisien, M., Shen, V., and Lindsay, R., Anabolic actions of parathyroid hormone on bone,
Endocrine Rev.,
14:690-709, 1993.
6. Finkelstein, J. S., Klibanski, A., Schaeffer, E. H., Hornstein, M. D., Schiff, I., and Neer, R. M., Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency,
New Eng. J. Med.,
331:1618-1623, 1994.
7. Prank, S., Nowlan, S. J., Harms, H. M., Kloppstech, M., Brabant, G., Hesch, R. D., and Sejnowski, T. J., Time series prediction of plasma hormone concentration. Evidence for differences in predictability of parathyroid hormone secretion between osteoporotic patients and normal controls,
J. Clin. Invest.,
95:2910-2919, 1995.
Acknowledgement of the above references herein will be made by indicating their number from the above list.
BACKGROUND OF THE INVENTION
Osteoporosis results in bone fractures in about 50% of postmenopausal women and is a leading cause of disability in an aging population. Current therapies include an adequate calcium and vitamin D intake as well as specific treatment with compounds such as estrogens, calcitonin and the bisphosphonates
(1)
. However, each of these treatments has either troubling side effects or limited efficacy. Women fear the small increase in breast cancer due to estrogens despite the dramatic reduction in myocardial infarctions and reduction in bone resorption. Calcitonin has a limited effect and is a protein and therefore needs to be injected or inhaled which is inconvenient. The new bisphosphonates such as alendronate have had encouraging results with an increase in bone density and decrease in fractures with few side effects. Current research for new compounds has concentrated on the systemic administration of bone anabolic compounds such as parathyroid hormone (PTH) or fragments of PTH or locally acting cytokines or bone growth factors such as bone morphogenic proteins. The appeal of PTH is that there are specific PTH receptors in bone
(2)
and it is well established in both experimental animal
(3)
and patient studies that intermittent doses of injected PTH is the most effective agent known to increase bone formation and bone strength
(4-6)
. This effect is additive to that of estrogens. The problem with the administration of PTH is that it is a peptide and must therefore be given by injection. Women with osteoporosis have intact but inadequately functioning parathyroids and an alternative approach is to stimulate their own parathyroids to synthesize and secrete more PTH. It has been evidenced in experimental animals that this is eminently practicable and this is the basis of this present patent application.
Postmenopausal osteoporotic women do not have the appropriate increase in nocturnal serum PTH levels. In osteoporotic women, careful and repeated measurements of serum PTH, and analysis by time series prediction of plasma hormone concentration has shown that there are differences in the predictability of parathyroid hormone secretion between postmenopausal osteoporotic patients and postmenopausal non-osteoporotic controls
(7)
.
SUMMARY OF THE INVENTION
It is the object of the present invention to provide a method and composition for increase in PTH levels in needy subjects.
It is an object in accordance with a preferred embodiment of the invention to provide such a method allowing to restore a circadian rhythm of PTH serum levels similar to that existing in normal individuals.
It is an objection in accordance with another preferred embodiment of the invention to provide a composition and method for the treatment of osteoporosis.
These and other objects of the invention will become clear from the description below.
In accordance with the present invention, it has been found that administration of phosphate results in an increase in PTH levels. Furthermore, in accordance with the invention, the phosphate is preferably administered to individuals in the evening or at night, giving rise to increase in PTH levels during night time, as is the case in normal individuals.
The present invention thus provides novel means for the treatment of individuals suffering from conditions resulting from impairment in PTH levels, by the administration of phosphate. The treatment has utility both in human and veterinary medicine.
The present invention thus provides a method of treatment of conditions resulting from impairment in parathyroid hormone (PTH) levels, comprising administering to a subject in need an effective amount of phosphate.
The present invention also provides a composition for use in treatment of conditions in subjects resulting from impairment in parathyroid hormone (PTH) levels, such as osteoporosis comprising an effective amount of phosphate together with a physiologically acceptable carrier.
The present invention still further provides use of phosphate for the preparation of compositions for the treatment of conditions in subjects resulting from impairment in PTH levels.
In accordance with a preferred embodiment of the invention, the phosphate is administered to individuals at night, and this administration forms part of a combined treatment involving also a timed administration of an effective amount of an auxiliary agent, e.g. calcium, which is capable of decreasing the PTH level during day time. Such an agent may typically be administered to the individual in the morning, and also once again during the day. As a result of such a combined treatment, PTH will have a low level during day time and a higher level during night time, giving rise to a circadian profile of PTH levels, similar to that existing in normal individuals.
The term “effective amount” used above, should be understood as meaning an amount of an active ingredient, i.e. phosphate or an auxiliary agent, which is capable of exerting a desired therapeutic effect. In the case of phosphate, an effective amount is an amount sufficient to cause an increase in the PTH levels; in the case of said auxiliary agent, an effective amount is an amount sufficient to cause a decrease in PTH levels. As will be clear, an effective amount may at times vary between different groups of individuals depending on the factors such as age, type of treated condition, etc., as will no doubt be clear to the artisan.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel means for the treatment of conditions associated with reduction in PTH levels. Such conditions include in particular osteoporosis. In the follow
Browdy and Neimark
Choi Frank
Dees Jose′ G.
Hadasit Medical Research Services and Development Company Ltd.
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