Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-04
2004-01-06
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
56
Reexamination Certificate
active
06673823
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout the application, various publications are referenced in parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in the application in order to more fully describe the state of the art to which this invention pertains.
1. Field of the Invention
The present invention is related to the medical arts, in particular to the treatment of pituitary tumors.
2. Discussion of the Related Art
The pituitary gland is divided into two primary regions, a larger anterior region (adenohypophysis), which constitutes 80 percent of the pituitary by weight, and a smaller posterior region (neurohypophysis). This gland connects to a region of the brain called the hypothalamus near the pituitary stalk. Because of its close proximity to major intracranial nerves and blood vessels, as well as the vital hormonal control the pituitary gland provides, disorders of the pituitary can cause a wide spectrum of symptoms, both hormonal and neurological. In most instances, pituitary disorders result in the secretion of either too much or too little of one or more hormones typically secreted by the pituitary gland.
The importance of the pituitary gland is amply illustrated by the numerous hormones it produces, i.e., hormones such as Thyroid Stimulating Hormone (TSH), Growth Hormone (GH), Adrenocorticotrophic Hormone (ACTH), Antidiuretic Hormone (ADH), Luteinizing Hormone (LH), Prolactin (PRL), Follicle Stimulating Hormone (FSH), Melanocyte-Stimulating Hormone (MSH), and Oxytocin.
The cells of the anterior lobe synthesize and release several protein hormones necessary for normal growth and development and also stimulate the activity of several target glands. Deviations above or below normal hormone levels of the hormones produced by the anterior lobe can result in any one of a number of disease conditions. For example, excess amounts of the hormone ACTH can result in Cushing's syndrome; an excess production of TSH causes hyperthyroidism; and hypersecretion of GH can result in either acromegaly or gigantism. Conversely, reduced amounts of GH can cause growth hormone deficiency syndrome in adults and children, (characterized by short stature in children). Other hormones controlled by the anterior lobe include LH and FSH, which when affected by a tumor can give rise to sexual symptoms in men and women. Increased production of prolactin can cause abnormal milk production, irregular menses and infertility in women; for men, increased prolactin levels can cause impotence, infertility, feminization and lactation. Tumors affecting the posterior lobe disrupt production of ADH, which may lead to diabetes insipidus; the hormone oxytocin is also secreted from the posterior lobe.
Some pituitary disorders have exhibited a familial predisposition, including, e.g., multiple endocrine neoplasia, Carney complex, and McCune Albright syndrome. (See Larsson, C., et al., M. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma, Nature 322:85-87 [1988]; Chandrasekharappak, S. C., et al., Positional cloning of the gene for multiple endocrine neoplasia- type 1, Science 276:404-406 [1997]; Stratakis, C. A., et al., Carney complex, familial multiple neoplasia and lentiginosis syndrome. Analysis of kindreds and linkage to the short arm of chromosome 2, J. of Clin. Invest. 97:699-705 [1996]; Lyons J., et al., Two G protein oncogenes in human endocrine tumors, Science 249:655-659 [1990]).
One genre of pituitary disorders is pituitary tumors. A pituitary tumor (adenoma) is a non-cancerous growth that typically affects different hormone-producing regions, depending on its specific location. Pituitary tumors account for about 15% of intracranial tumors, and are associated with significant morbibity due to local compressive effects, hormonal hypersecretion, or treatment-associated endocrine deficiency (Heaney A. P., et al.: Molecular Pathogenesis of Pituitary Tumors. In: Oxford Textbook of Endocrinology, Wass J. A. H. and Shalet S. M., (Eds.), Oxford University Press, Oxford, 2002 (in press)). The great majority of pituitary adenomas are benign, not malignant, and are relatively slow growing. (See UCLA Neurosurgery web site at <www.neurosun.medsch.ucla.edu>). Pituitary tumors may lead to overproduction of one or more of the pituitary hormones. In other instances, pituitary tumors are non-functioning or “endocrine-inactive,” meaning that they do not produce excessive hormones.
Non-functioning adenomas are the most commonly encountered pituitary tumors. These tumors fail to secrete hormones, are generally macroadenomas (≧1 centimeter), and cause high morbidity and ultimately mortality due to visual field loss, headache, and pituitary dysfunction (Shimon, I., et al., Management of Pituitary Tumors, Ann. Intern. Med. 129:472-483 [1998]). Some non-functioning pituitary tumors express dopamine and/ or somatostatin receptors, but response to treatment with dopamine agonists and/ or somatostatin is poor, and their use has largely been discontinued (Nobels, F. R., et al., Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma. Eur. J. Endocrinol. 143:615-21 [2000]) and effective drug therapies for non-functioning pituitary tumors do not currently exist. As pituitary tumors enlarge, compression of normal pituitary tissue can occur, resulting in decreased or absent hormone production. This condition is called hypopituitarism and may also result from brain trauma, surgery, bleeding into the pituitary or from radiation therapy to the pituitary.
Examples of pituitary tumors that lead to pituitary hormone hypersecretion are PRL- and GH-secreting pituitary tumors. Dopamine agonists and somatostatin analogs effectively suppress PRL and GH hypersecretion, respectively, and control tumor growth or induce tumor shrinkage in most, but not all, PRL-and GH-secreting pituitary tumors (Shimon, I., et al., Management of Pituitary Tumors, Ann. Intern. Med. 129:472-83 [1998]; Giustina, A., et al., Criteria for cure of acromegaly: a consensus statement, J. Clin. Endocrinol. Metab. 85:526-9 [2000]). A subset of patients with PRL- and GH-secreting pituitary tumors do not respond to such drug treatments or are intolerant of side-effects from these drugs. For unresponsive GH- and PRL-secreting, and non-functioning pituitary tumors, surgery with or without adjuvant radiation is the treatment mainstay, and portends a 50-60% overall control rate in specialized centers (Bevan, J. S., et al., Non-functioning pituitary adenomas do not regress during bromocriptine therapy but possess membrane-bound dopamine receptors which bind bromocriptine, Clin. Endocrinol. 25:561-72 [1986]; Colao, A., et al., New medical approaches in pituitary adenomas, Horm. Res. 53:76-87 [2001]). Although 70% of pituitary microadenomas are successfully resected by transsphenoidal approaches, 25% of PRL-secreting, and 90% of GH-secreting and non-functioning tumors are >1 cm in diameter, and surgical “cure” rates for these macroadenomas are achieved in about a third of patients in specialized centers (Colao, A., et al., New medical approaches in pituitary adenomas, Horm. Res. 53:76-87 [2001]). Tumor recurrence requires pituitary-directed radiation to suppress tumor growth and hormonal levels, but radiation effects may not be manifest for several years, and are ultimately associated with pituitary damage and dysfunction in most patients (Kreutzer J., et al., Surgical management of GH-secreting pituitary adenomas: an outcome study using modern remission criteria, J. Clin. Endocrinol. Metab. 86:4072-7 [2001]).
Another such pituitary tumor that leads to pituitary hormone hypersecretion is an ACTH-secreting pituitary tumor. About 90% of ACTH-secreting pituitary tumors are microadenomas (<1 cm diameter), and cavernous sinus invasion or optic chiasm compression are uncommonly encountered (Ross, E.
Heaney Anthony P.
Melmed Shlomo
Cedars-Sinai Medical Center
Reamer James H
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