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
2002-11-19
Spivack, Phyllis G. (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
06482858
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to pharmaceutical compositions containing (−)-hydroxycitric acid useful for wound healing and immunomodulation, especially by means of correcting the dysregulation of glucocorticoid and melatonin metabolism.
2. Description of Prior Art
The immune system is the body's ultimate defense against attack by external pathogens, such as bacteria and viruses, and against internal mistakes in replication, such as cancer. Modern medicine for the most part seeks to bolster this defense in only two ways. First, it employs a wide range of supplements to the body's own protective mechanisms in the form of drugs and therapies. Antibiotics, chemotherapy and radiation therapy all attempt to aid or even to replace the body's own defenses when these prove inadequate. Second, medicine uses vaccinations to bolster the immune system's specific abilities, usually in advance of exposure to a pathogen or as an aid to help the body target specific pathogens which the immune system either does not recognize or does not react strongly enough against.
More recently, researchers have begun to reproduce elements of the immune system and to use these against diseases, especially cancer. For instance, genetically engineered bacteria can now produce interferon, which can be harvested and then injected into the patient's blood or even directly into a tumor. To date, the results of such methods have been promising, but clinical trials have yielded many fewer complete successes than originally had been hoped for. The reasons for this are not entirely understood, but apparently exogenous sources of immune elements, such as interferon or interleukin-1, are rapidly cleared from the body. Moreover, the immune system is homeostatic—in a healthy immune system, the elements are always in balance with one another. The increase in one aspect of the system typically suppresses some other part of the system. Similarly, the use of antibiotics and other drugs which are powerful supplements to and even substitutes for the body's own functions is medically recognized to suppress natural immunity, in some cases to the point of complete failure.
The quality of the immune response makes itself known in a variety of ways, some of which are readily observable. For instance, one way of looking at the skin is as an immune organ which is in need of constant maintenance and repair. An obvious example of this is to be seen in the case of a cut or scratch. The better the immune system, the faster the healing, but what does healing mean to the skin? It means both preventing infection and returning to its previous condition. Hence, the immune system not only attacks external invaders, but also activates the skin cells called fibroblasts, which are responsible for production of the precursors of collagen, elastin and other elements of the skin and connective tissues. Either improper immune activation or suppression may lead to undesirable effects upon the body's external immune barrier. In the case of the skin, as in other areas of the body, proper immune metabolism is always an issue of balance.
Immune imbalance is readily apparent in conditions such as diabetes mellitus. Diabetics are often troubled by non-healing skin ulcers. Indeed, nonhealing wounds constitute a major problem which plagues approximately 15% of all patients with diabetes despite proper insulin treatment and following a prescribed diet. Faulty wound healing contributes to more inpatient hospital days than any other complication associated with diabetes and is a factor in 81% of diabetic lower extremity amputations. Experimental and clinical studies using various models of wound healing reveal that diabetes is accompanied by a derangement in tissue repair involving almost every element of wound healing, including inflammation, cellular proliferation, and angiogenesis. In addition, reduced collagen formation and lower tensile strength have also been reported in surgical diabetic wounds. (Bitar M S, et al. Glucocorticoid-Dependent Impairment of Wound Healing in Experimental Diabetes: Amelioration by Adrenalectomy and RU 486. Journal of Surgical Research 1999;82:234-243.)
Data from various studies show that therapeutic doses of glucocorticoids (GCs) reduce wound healing potential in human and experimental models of wound repair. This inhibition is linked to a delay in the appearance of inflammatory cells and to a reduction in fibroplasia, with a similar delay in the appearance of new connective tissue matrix, collagen synthesis and deposition. An inverse relationship has been shown to exist between wound healing potential and stress, a source of endogenous CGs. Moreover, other findings support the hypothesis that hypercortisolemia is a common feature in both human and experimental diabetes. Blockading GC receptors with the receptor blocker mifepristone (RU486) has shown therapeutic potential in reversing the GC-induced wound healing impairment. (Bitar M S, et al. 1999; Bitar M S, et al. Insulin and glucocorticoid-dependent suppression of the IGF-I system in diabetic wounds. Surgery 2000;127:687-95.)
As in diabetic wound healing deficiency, studies have demonstrated that psychological stress perturbs cutaneous (skin) permeability barrier homeostasis. Research supports the concept that psychological stress is an important determinant of the onset and severity of skin diseases such as psoriasis and adult atopic dermatitis. An increase in endogenous glucocorticoid production, which is deleterious to barrier function, is essential for the barrier abnormalities that occur in response to psychological stress. (Denda M, et al. Stress alters cutaneous permeability barrier homeostasis. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 2000;278:R367-R372.)
A great deal of evidence, again, supports the contention that the actions of glucocorticoids extend far beyond the inhibition of wound healing, the inhibition of fibroblasts, the loss of collagen and connective tissue, and interference with other elements operative at levels beyond that of the skin. An array of findings now indicate that glucocorticoids and catecholamines—the end-products of the stress system—and histamine—a product of activated mast cells—might selectively suppress cellular immunity and favor humoral immune responses. This is mediated by a differential effect of stress hormones and histamine on T helper 1 (Th1)/Th2 patterns and type 1/type 2-cytokine production. Systemic stress appears to induce a Th2 shift, and under certain conditions, it might induce pro-inflammatory activities through neural activation of the peripheral corticotropin-releasing factor-mast cell-histamine axis. Through these mechanisms, stress may influence the onset and/or course of infectious, autoimmune/inflammatory, allergic and neoplastic diseases. (Elenkov I J. Stress, cytokine patterns and susceptibility to disease. Bailliére's Clinical Endocrinology and Metabolism 1999;13,4:583-595.)
The administration of exogenous glucocorticoids clearly dysregulates the physiologic axis involving melatonin, ACTH and cortisol. (Kos-Kudla B, et al. Diurnal Rhythm of Serum Melatonin, ACTH And Cortisol In Asthma Patients with Long Term Glucocorticoid Treatment. Endocrine Regulations 1997;31:47-54.) Interactions between the hypothalamic-pituitary-adrenocortical (HPA) system and melatonin secretion have been demonstrated repeatedly. Unfortunately, most research in this area has been upon melatonin, and only the effects of melatonin on the activity of the HPA system have been studied extensively in man. Evidence to date suggests that the impact of glucocorticoids upon melatonin secretion may be indirect rather than direct. For example, corticotropin-releasing hormone (CRH), which is thought to be involved in HPA abnormalities in depressed patients, can suppress melatonin secretion in healthy in normal volunteers. (Kellner M, et al. Corticotropin-releasing hormone inhibits melatonin secretion in healthy volunteers—a potential link t
Clouatre Dallas L
Dunn James M
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