Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1997-08-28
2001-12-18
Jordan, Kimberly (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06331534
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to methods for alleviating pain.
DESCRIPTION OF THE RELATED ART
The present invention relates to certain steroids, and methods of using these steroids as human vomeropherins in order to alter hypothalamic function, thereby affecting certain consequent behavior and physiology, e.g., the reduction of anxiety. Ohloff, G. et al. (
Helv. Chim. Acta
(1983) 66:192-217), which is incorporated herein by reference, have shown that several steroids (androstenes) have an odor which varies with different isomeric, diastereomeric, and enantiomeric forms. Some members of this group have been reported to act as a pheromone in some mammalian species—for instance, 5&agr;-androst-16-en-3-one and 5&agr;-androst-16-en-3&agr;-ol in pigs (Melrose, D. R., et al.,
Br. vet. J.
(1971) 127:497-502). These 16-androstenes produced by the boar induce mating behavior in estrus sows (Claus, et al.,
Experimentia (
1979) 35:1674-1675).
Some studies have noted that, in some species, various characteristics of certain 16-androstenes (including 5&agr;-Androst-16-en-3&agr;-ol and 5&agr;-Androst-l6-en-3-one), such as concentration, metabolism, and localization, are sexually dimorphic (Brooksbank et al.,
J. Endocr.
(1972) 52: 239-251; Claus, et al.,
J. Endocr.
(1976) 68:483-484; Kwan, et al.,
Med. Sci. Res.
(1987) 15:1443-1444). For instance, 5&agr;-Androst-16-en-3&agr;-ol and 5&agr;-Androst-16-en-3-one, as well as Androsta-4,16-dien-3-one, have been found at different concentrations in the peripheral blood, saliva and axillary secretions of men and of women (Kwan, T. K., et al.,
Med. Sci. Res.
(1987) 15:1443-1444), and their function as a human pheromone, to the extent of affecting choice and judgment, has been suggested (Id.; see also Gower, et al., “The Significance of Odorous Steroids in Axillary Odour”, In,
Perfumery,
pp. 68-72, Van Toller and Dodds, Eds., Chapman and Hall, 1988); Kirk-Smith, D. A., et al.,
Res. Comm. Psychol. Psychiat. Behav.
(1978) 3:379). Androstenol (5&agr;-androst-16-en-3&agr;-ol) has been claimed to exhibit a pheromone-like activity in a commercial men's cologne and women's perfume (Andron™ for men and Andron™ for women by Jövan). Japanese Kokai No. 2295916, refers to perfume compositions containing androstenol and/or its analogues. Androstadien-3&bgr;-ol (and perhaps the 3&agr;-ol) has also been identified in human axillary secretion (Gower, et al., supra, at 57-60). On the other hand, there is little agreement in the literature as to whether or not any putative pheromone actually plays any role in the sexual or reproductive behavior of mammals, particularly of humans. See: Beauchamp, G. K., et al., “The Pheromone Concept in Mammalian Chemical Communication: A Critique”, In:
Mammalian Olfaction, Reproductive Processes and Behavior,
Doty, R. L., Ed., Academic Press, 1976). See also: Gower, et al., supra at 68-73.
The pheromone properties of some estrene steroids for some mammalian species has been described. Michael, R. P. et al.,
Nature
(1968) 218:746 refers to Estrogens (particularly Estradiol) as a pheromonal attractant of male rhesus monkeys. Parrot, R. F.,
Hormones and Behavior
(1976) 7:207-215, reports Estradiol benzoate injection induces mating behavior in ovariectomized rats; and the role of the blood level of Estradiol in make sexual response (Phoenix, C. H.,
Physiol. and Behavior
(1976) 16305-310) and female sexual response (Phoenix, C. H.,
Hormones and Behavior
(1977) 8:356-362) in Rhesus monkeys has been described. On the other hand, there is little agreement in the literature as to whether or not pheromones as such play any role in the reproductive behavior and interpersonal communication of mammals (Beuchamp, G. K., et al., The Pheromone Concept in Mammalian Chemical Communication: A Critique', In:
Mammalian Olfaction, Reproductive Processes, and Behavior,
Doty R. L., Ed., Academic Press, 1976).
The subject invention concerns the non-systemic administration to the vomeronasal organ (VNO) of certain steroids to alleviate pain. Administration provides for contacting neurochemical receptors in the VNO (also known as “Jacobson's organ”), with one or more steroid(s) or with compositions containing the steroid(s). This organ is accessed through the nostrils of most higher animals—from snakes to humans, and has been associated, inter alia, with pheromone reception in certain species (see generally Muller-Schwarze & Silverstein,
Chemical Signals,
Plenum Press, New York (1980)). The axons of the neuroepithelia of the vomeronasal organ, located supra palatinal, form the vomeronasal nerve and have direct synaptic connection to the accessory olfactory bulb and indirect input from there to the cortico-medial amygdaloid basal forebrain and hypothalamic nuclei of the brain. The distal axons of terminalis nerve neurons may also serve as neurochemical receptors in the VNO. Stensaas, L. J., et al.,
J. Steroid Biochem. and Molec. Biol.
(1991) 39:553. This nerve has direct synaptic connection with the hypothalamus.
Johnson, A. et al. (
J. Otolaryngology
(1985) 14:71-79) report evidence for the presence of the vomeronasal organ in most adult humans, but conclude that the organ is probably non-functional. Contravening results which suggest that the VNO is a functional chemosensory receptor are reported by Stensaas, L., et al., supra; and by Moran, D. T., et al., Garcia-Velasco, J. and M. Mondragon; Monti-Bloch, L. and B. Grosser all in
J. Steroid Biochem. and Molec. Biol.
(1991) 39.
This invention relates to the unexpected discovery that, when administered into the VNO of human subjects, certain neurochemical ligands, particularly steroids, and related compounds, specifically bind to chemoreceptors of certain nasal neuroepithelial cells and this binding generates a series of neurophysiological responses resulting in alleviating pain. An effect via the VNO on the hypothalamus can affect the function of the autonomic nervous system and a variety of behavioral-or physiological phenomena which include, but are not limited to the following: anxiety, premenstrual stress, fear, aggression, hunger, blood pressure, and other behavioral and physiological functions normally regulated by the hypothalamus. See Otto Appenzeller,
The Autonomic Nervous System. An Introduction of basic and clinical concepts
(1990); Korner, P. I.
Central nervous control of autonomic cardiovascular function,
and Levy, N. M. and Martin, P. J.
Neural control of the heart,
both in
Handbook of Physiology; Section
2;
Cardiovascular System—the heart,
Vol. I, Washington D.C., 1979, American Physiological Society; Fishman, A. P., et al. editors,
Handbook of Physiology. Section
3:
Respiratory System. Vol. II. Control of breathing,
Bethesda Md., 1986. American Physiological Society.
Patients diagnosed with premenstrual dysphoric disorder (PMDD, commonly referred as premenstrual syndrome or PMS), show negative changes in mood together with physical symptoms, during the luteal phase of the menstrual cycle (see Table I). The symptoms are severe enough to cause physical or emotional distress, and they remit shortly after the onset of menstruation. However, they are not unique or diagnostic for this disease. Several surveys show that 30% of women have classical premenstrual dysphoric disorder symptoms, 2% to 10% being severely affected (Woods et al.,
Am. J. Pub. Health,
72:1257-62, 1982; Van Keep et al., “The Premenstrual Syndrome—An Epidemiologic and Statistical Exercise”, Van Keep, P. A. and Utian, W. H., Eds.,
The Premenstrual Syndrome, MTP Press Ltd.,
Lancaster, England, 1981; and Andersch et al., J. Psychomsom. Obstet. Gyn. 5:39-46, 1986). It is also reported that PMDD is not a disease of just older women since teenagers and young women have symptomatology as frequently as older women (Rivera-Tovar et al., Am. J. Psychiatry, 147:1634-43, 1990).
Many patients that seek treatment for PMDD may be found to suffer from a generalized psychiatric disorder. However, the main feature distinguishing PMDD from chronic psychiatric di
Berliner David L.
Monti-Bloch Luis
Heller Ehrman White & McAuliffe LLP
Jordan Kimberly
Pherin Pharmaceuticals, Inc.
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