Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-06-20
2002-08-27
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06441041
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to pharmaceutical compositions containing (−)-hydroxycitric acid useful for preventing osteoporosis and other forms of bone loss.
2. Description of Prior Art
Osteoporosis is Latin for “porous bones.” It is a progressive condition in which the bones gradually lose their strength and density. As a living tissue, the bone is continuously “remodeled” as it renews itself, responds to damage, and so forth. It constantly is both releasing and absorbing new calcium. As is true of all other tissues, the bone renews itself with a turnover of its cells over time. Bone loss results when the balance of the constructive and destructive processes is tipped from equilibrium towards a loss of calcium and other bone components. An estimated 1.3 million older Americans suffer broken bones every year because of osteoporosis. Wrists, hips, and spinal vertebrae are the most susceptible areas. Women are far more susceptible than are men and suffer about 80% of the injuries caused by this condition. Nevertheless, as this number indicates, a substantial number of men also suffer from osteoporosis. At least in part, this gender-based disproportion in injuries appears to reflect the fact that males begin with larger and denser bones, hence can lose more bone mass and yet still not suffer damage. Still, there is more to it than this. By the age of 65, men on average have lost approximately 9% of their bone mass, whereas women have lost 26% of their bone mass on reaching this age.
Most discussions of osteoporosis focus on the loss of calcium. In fact, this is a major error in analysis. Although the contemporary public health emphasis in maintaining bone health is always upon calcium because calcium is the major component of the bones, even with regard to the inorganic components of bone, calcium may not be the most important in preventing demineralization. The bone consists of both inorganic mineral components and organic components. Osteomalacia is the technical name for the softening of the bones which results from a lack of calcium in the diet. In osteoporosis, not only calcium and other minerals, but also the non-mineral bone matrix, which consists of collagen and proteins, is disrupted. The consensus is that in postmenopausal women the fall in estrogen levels is a major factor in declining bone mineral density, yet there are good reasons for doubting that this is the whole of the answer. Indeed, estrogen is not even approved for the treatment of osteoporosis because recent clinical studies, namely the Heart and Estrogen/Progestin Replacement Study (HERS) and the Postmenopausal Estrogen/Progestin Interventions (PEPI) did not show any fracture reduction in the treatment groups even though a reduction in the loss in bone mineral density (BMD) was reported. (Hulley S, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605-613; The Writing Group for the PEPI. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA. 1996;276:1389-1396.)
More successful in preventing bone loss, at least in the short term, than hormone replacement therapy (HRT) is treatment with bisphosponates. Randomized clinical trials have demonstrated that vertebral fractures in postmenopausal women are reduced by treatment with the bisphosphonates alendronate, risedronate or raloxifene, and also with nasal calcitonin. The bisphosphonates also reduce the incidence of hip fractures in postmenopausal women and have an additive benefit in subjects receiving calcium and vitamin D supplements. (Black DM, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348:1535-1541; Ettinger B, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-645; Harris S T, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999;282:1344-1352; Chesnut CH 3rd, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med. 2000;109:267-276).
All of the antiresorptive agents currently approved for the treatment of osteoporosis—alendronate, risedronate, raloxifene, and nasal calcitonin—therefore can be said to decrease bone resorption. However, not one of these compounds induces new bone formation. In fact, antiresorptive agents appear to prevent new bone formation; there are grounds to fear that after a period of 3 to 4 years, they actually may increase the fracture rate. (Goodman R L. The effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001 May 31;344(22):1720-1; Mashiba T, et al. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 2001 May;28(5):524-3 1).
Consequently, there is a finite limit to the benefits of antiresorptive agents even under the best circumstances. Moreover, the bisphosphonates can cause serious side effects involving the gastrointestinal tract. (Wallace J L, et al. N-bisphosphonates cause gastric epithelial injury independent of effects on the microcirculation. Aliment Pharmacol Ther. 1999 December;13(12):1675-82.) The bisphosphonates alendronate, risedronate and raloxifene may prove particularly unsafe when used in combination with the nonsteroidal anti-inflammatory drugs so commonly taken by the elderly. (Cappell M S, Schein J R. Diagnosis and treatment of nonsteroidal anti-inflammatory drug-associated upper gastrointestinal toxicity. Gastroenterol Clin North Am 2000 March 29(1):97-124, vi).
The notion that it is the age-related decline in estrogen which is primarily responsible for bone loss in aging women remains strongly entrenched in the medical mind. HRT, treatment with bisphosphonates and recommendations for ever higher levels of calcium intake—a dietary recommendation which has produced clinically significant, but nonetheless unimpressive results—constitute almost the whole of the modem medical arsenal against osteoporosis. Many other alternatives have gone largely unexplored. For instance, it is well-established that bone loss is one of the most devastating side effects of glucocorticoid treatment for rheumatic conditions because these compounds inhibit calcium transport, cause secondary hyperparathyroidism, hypogonadism, and impairment of osteoblast function. (Lukert B P, Raisz L G. Glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am 1994 August 20(3):629-50.) The incidence of osteoporosis in patients receiving long-term glucocorticoid therapy is roughly 50%. Trabecul bone is lost more rapidly than is cortical bone with such treatment. Again, it should be that the cause of glucocorticoid-induced bone loss is multifactorial. The gastrointestinal absorption of calcium falls even as urinary excretion rises; the production of gonadal hormones decreases; and bone formation is inhibited in the presence of glucocorticoids, whereas resorption is enhanced. (Lukert B P. Glucocorticoid-induced osteoporosis. South Med J 1992 August 85(8):2S48-51.)
Endogenous glucocorticoid levels typically increase as humans age and remain chronically elevated and/or dysregulated in comparison with the levels found in young adults. According to various studies, a significant increase of serum cortisol levels during evening- and night-times is found in elderly subjects when compared to y
Clouatre Dallas L.
Dunn James M.
Jogoe Donna
Krass Frederick
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