Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
2000-10-20
2004-12-07
Bugaisky, Gabriele (Department: 1653)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C424S094100, C424S094600, C424S236100, C424S239100, C424S247100, C512S012000, C512S002000
Reexamination Certificate
active
06827931
ABSTRACT:
BACKGROUND
The present invention relates to methods for treating endocrine disorders. In particular, the present invention relates to methods for treating endocrine disorders by intracranial administration of a neurotoxin.
The pituitary gland (the hypophysis) is a relatively small weighing only about 600 mg. The pituitary can be divided into an anterior lobe (the adenohypohysis) and a posterior lobe (the neurohypophysis). The functions of both lobes of the pituitary are heavily influenced by vascular and/or neural connections with the hypothalamus. The anterior pituitary makes six major hormones and stores two others. These are growth hormone (GH) which regulates growth and has important functions on intermediary metabolism; prolactin (PRL) which is necessary for lactation and which can suppress menstruation; luteinizing hormone (LH) and follicle stimulating hormone (FSH) both of which influence gonadal activity in men and women; thyroid stimulating hormone (TSH) which regulates thyroid function, and; adrenocorticotropin (corticotropin (ACTH) which controls glucocorticoid function of the adrenal cortex. Vasopresin (AVP, also called antidiuretic hormone, ADH) and oxytocin are produced in neurons of the hypothalamus and stored in the posterior lobe of the pituitary. AVP controls water conservation by the kidneys, while oxytocin is necessary for milk let-down during lactation and may aid in parturition.
The hypothalamus weighs about 4 grams and is the ventral and medial region of the diencephalon forming the walls of the ventral half of the third ventricle. It is delineated from the thalamus by the hypothalamic sulcus (a shallow groove between the dentate gyrus and the parahippocsmpal gyrus), lying medial to the internal capsule and subthalamus, continuous with the precommissural septum anteriorly and with the mesencephalic tegmentum and central gray substance posteriorly. The ventral surface of the hypothalamus can be identified by, proceeding from front to back along the ventral surface of the hypothalamus, the optic chiasma the unpaired infundibulum which extends by way of the infundibular stalk into the posterior lobe of the hypophysis and the paired mamillary bodies. Hypothalamus neurons have been grouped into various nuclei on the basis of functional characteristics. These hypothalamic nuclei include the supraoptic paraventricular, lateral preoptic, lateral hypothalamic, tuberal, anterior hypothalamic, ventmmedial, dorsomedial, arcuate, posterior hypothalamic, and premamillary nuclei and the mamilliary body.
The hypothalamus has afferent nerve fiber connections with the mesencephalon, limbic system, cerebellum and efferent fiber connections with the same structures and with the posterior lobe of hypophysis. Functional connection of the hypothalamus with the anterior lobe of the hypophysis is established by the hypothalmohypophysial portal system. The hypothalamus is prominently involved In the functions of the autonomic nervous system and, through its vascular link with the anterior lobe of the hypophysis, in endocrine mechanisms. The hypothalamus may also play a role in neural mechanisms underlying moods and motivational states. With regard to the endocrine hypothalamus, it is known that the arcuate nucleus of the hypothalamus is the major site of gonadotropin hormone releasing hormone (GnRH) production.
A single hypothalamic regulatory factor, GnRH, stimulates synthesis and secretion from the anterior pituitary of both FSH and LH in males and females. FSH and LH are collectively referred to as the gonadotropins. Other hypothalamic regulatory factors stimulate pituitary secretion of ACTH, TSH and GH, but inhibit the release of PRL from the anterior pituitary.
Vascular connection of the hypothalamus to the hypophysis is established when the neurosecretory neurons of the hypothalamus release regulatory (releasing and inhibiting) factors which reach the adenohypophysis through the portal circulation of the capillary plexus located in the median eminence region of the hypothalamus. These neurohemoral hypothalamic regulatory factors are small peptide neurohormones which, by influencing the secretion of adenohypophysial hormones, serve as the main functional link between the brain and the adenohypohysis. The hypothalamus is itself influenced by higher brain regions which employ various neurotransmitters, including dopamine, norepinephine, serotonin and acetylcholine to act upon the hypothalamus.
Addition of acetylcholine to anterior pituitary tissue incubated with hypothalamic fragments can result in the release of LH by the pituitary tissue and this LH release can be blocked by atropine (a muscarinic acetylcholine receptor (post synaptic) antagonist). Prostigmine, an acetylcholinesterase inhibitor, can also stimulate LH release in this system. Fiorindo R. P. et al.,
Evidence for a Cholinergic Component in the Neuroendocrine Control of Luteinizing Hormone Secretion,
Neuroendocrinology 18: 322-332,1975.
Additionally, while as expected, FSH levels Increased upon addition of hypothalamic fragments to incubated anterior pituitary tissue, a further increase of pituitary FSH release is produced by acetylcholine. This enhanced FSH release is antagonized by atropine. Simonovic I, et al.,
Acetylcholine and the Release of Follicle Stimulating Hormone Releasing Factor
, Endocrinology 95: 1371,1974.
Furthermore, cholinergic agents can stimulate release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which is blocked by atropine. GNRH acts in turn upon the anterior pituitary to promote the release of LH and FSH. Richardson S B, et al.,
Acetylcholine, Melatonin, and Potassium Depoladzation Stimulate Release of Luteinizing Hormone
-
Releasing Hormone From Rat Hypothalamus in Vitro
, Proc Natl Acad Aci U.S.A. 79 (8): 268-9,1982. In intact rats, injection of acetylcholine into the lateral ventricle stimulates LH release. This can be blocked with atropine or enhanced with prostigmine.
Notably, hemicastration (removal of one ovary) in the female rat normally results in gonadotropin-mediated hypertrophy of the remaining ovary and this effect be blocked by atropine implants into the anterior hypothalamus. Monti J. M. et al.,
Inhibition of Ovarian Compensatory Hypertophy by Implants of Atropine in the Hypothalamus
, Eperientia 26: 1263-1264,1970. Similar implants also blocked the post-orchidectomy rise in LH and FSH in male rats. Libertun C. et al.,
Blockade of the Postorchidectomy Increase in Gonadotropin by Implants of Atropine into the Hypothalamus
, Proc Soc Exp Biol Med 152: 143-146,1976. These data are consistent with the existence of a muscarinic cholinergic mechanism mediating GnRH release in the hypothalamus, clearly indicating therefore a stimulatory cholinergic influence over hypothalamic activity.
Additional studies have indicated that the net effect of acetylcholinesterase inhibition or acetylcholine administration to the hypothalamus stimulates gonadotropin secretion. See e.g. Blake C A.,
Parallelism and Divergence in Luteinizing and Follicle Stimulating Hormone Release in Nicotine
-
Treated Rats
, Proc Soc Exp Biol Med 145: 716-720, 1974; Kanematsu S. et al.,
Inhibition of the Progesterone
-
Advanced LH Surge at Proestrus
, Proc Soc Exp Biol Med 143: 1183-5,1973; Blake C. A., et al.,
Nicotine Delays the Ovulatory Surge of Luteinizing Hormone in the Rat
, Proc Soc Exp Biol Med 141: 1014-1016,1972; Blake C. A. et al.,
Localization of the Inhibitory Actions of Estrogen and Nicotine on Release of Luteinizing Hormone in Rats
, Neuroendocrinology 16: 22-35,1974, and; Blake C. A. et al.,
Effects of Hypothalamic Deafferentation and Ovarian Steroids on Pituitary Responsiveness to LH
-
RH in Female Rats
. In Gual and Rosemberg, eds,
Hypothalamic Hypophysiotropic Hormones
. Excerpta Medica, Amsterdam, 1973, pp. 33-38.
With few exceptions (testosterone in men, progesterone in men and women) hormone excess causes pathological effects. Thus, excessive secretion of growth hormone or GHRH causes acromegaly in adults or gigantism in adolescents, if the excessive secretion s
Allergan Inc.
Baran Robert J.
Bugaisky Gabriele
Fisher Carlos A.
Voet Martin A.
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