Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-04
2002-04-30
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S318000
Reexamination Certificate
active
06380201
ABSTRACT:
BACKGROUND OF THE INVENTION
Since the discovery of serotonin (5-hydroxytryptamine, 5-HT) over four decades ago, the cumulative results of many diverse studies have indicated that serotonin plays a significant role in the functioning of the mammalian body, both in the central nervous system and in peripheral systems as well. Morphological studies of the central nervous system have shown that serotonergic neurons, which originate in the brain stem, form a very diffuse system that projects to most areas of the brain and spinal cord. R. A. O'Brien,
Serotonin in Mental Abnormalities,
1:41 (1978); H. W. M. Steinbusch, Handbook of Chemical Neuroanatomy, Volume 3, Part II, 68 (1984); N. E. Anden, et al.,
Acta Physiologica Scandinavia,
67:313 (1966). These studies have been complemented by biochemical evidence that indicates large concentrations of 5-HT exist in the brain and spinal cord. H. W. M. Steinbusch, supra.
With such a diffuse system, it is not surprising that 5-HT has been implicated as being involved in the expression of a number of behaviors, physiological responses, and diseases which originate in the central nervous system. These include such diverse areas as sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, 221 (1982); D. J. Boullin, Serotonin in Mental Abnormalities 1:316 (1978); J. Barchas, et al.,
Serotonin and Behavior,
(1973).
Serotonin plays an important role in peripheral systems as well. For example, approximately 90% of the body's serotonin is synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system provides another example of a peripheral network that is very sensitive to serotonin. Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophhrenia, autism, neurodegenerative disorders, such as Alzheimer's disease, Parkinsonism, and Huntington's chorea, and cancer chemotherapy-induced vomiting. M. D. Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al.,
Journal of Cardiovascular Pharmacology,
15:Supplement 7 (1990).
Serotonin produces its effects on cellular physiology by binding to specialized receptors on the cell surface. It is now recognized that multiple types of receptors exist for many neurotransmitters and hormones, including serotonin. The existence of multiple, structurally distinct serotonin receptors has provided the possibility that subtype-selective pharmacologic agents can be produced. The development of such compounds could result in new and increasingly selective therapeutic agents with fewer side effects, since activation of individual receptor subtypes may function to affect specific actions of the different parts of the central and/or peripheral serotonergic systems.
An example of such specificity can be demonstrated by using the vascular system as an example. In certain blood vessels, stimulation of 5-HT
1
-like receptors on the endothelial cells produces vasodilation while stimulation of 5-HT
2
receptors on the smooth muscle cells produces vasoconstriction.
Currently, the major classes of serotonin receptors (5-HT
1
, 5-HT
2
, 5-HT
3
, 5-HT
4
, 5-HT
5
, 5-HT
6
, and 5-HT
7
) contain some fourteen to eighteen separate receptors that have been formally classified based on their pharmacological or structural differences. [For an excellent review of the pharmacological effects and clinical implications of the various 5-HT receptor types, see Glennon, et al.,
Neuroscience and Behavioral Reviews,
14:35 (1990).]
Pollen has long been recognized as a cause of allergic rhinitis commonly called “hay fever”. Pollen contains proteases which induce the release of mediators from mast cells, thereby stimulating IgE biosynthesis. The granulation of mast cells by IgE results in the release of histamines which leads to an inflammatory response which causes congestion, itching, and swelling of sinuses. Many eosinophils are present in allergic patients with nasal mucus and neutrophils are present in patients with infected mucus.
Antihistamines are drugs commonly utilized which, when taken orally, frequently have a sedative effect. Alternatively, nasal sprays containing cromolyn sodium have been effective as cromolyn acts by clocking the reaction of the allergen with tissue mast cells. Cromolyn is not entirely effective, however, as it apparently does not bind to some of the mediators of inflammation or the activators of IgE biosynthesis that stimulate the degranulation of mast cells and the production of histamines from the mast cells.
Inflammation is a non-specific response of tissues to diverse stimuli or insults and results in the release of materials at the site of inflammation that induce pain. It is now recognized that mast cells, neutrophils, and T-cells are implicated in the pathophysiology of inflammatory skin conditions as well as in other physiological disorders. Mast cells provide the greatest source of histamines in acute inflammation, as well as chymases, after degranulation by IgE.
The “common cold” is a time honored phrase used by both physicians and lay persons alike for the identification of acute minor respiratory illness. Since the identification of rhinovirus in 1956, a considerable body of knowledge has been acquired on the etiology and epidemiology of common colds. It is known that the common cold is not a single entity, but rather is a group of diseases caused by members of several families of viruses, including parainfluenza viruses, rhinoviruses, respiratory syncytial viruses, enteroviruses, and coronaviruses. Much work has been performed in characterizing viruses which cause the common cold. In addition, the molecular biology of rhinoviruses, the most important common cold viruses, is understood in great detail. In contrast, progress on the treatment of common colds has been slow despite these advances. While there are now large numbers of compounds that have been found to exhibit antiviral activity against cold viruses in cell culture, antiviral compounds have had limited effectiveness in patients.
Because of the widespread dissatisfaction with the currently marketed treatments for the common cold and allergic rhinitis within the affected population, there exists a need for a more efficacious and safe treatment.
SUMMARY OF THE INVENTION
This invention provides methods for the treatment or amelioration of the symptoms of the common cold or allergic rhinitis in a mammal which comprise administering to a mammal in need thereof an effective amount of a composition having serotonin 5-HT
1F
agonist activity.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
The term “allergic rhinitis” as employed herein is understood to include rhinitis medicamentosa, rhinitis sicca, and atrophic rhinitis.
Many serotonin binding receptors have been identified. These receptors are generally grouped into seven classes on the basis of their structure and the pharmacology of the receptor as determined by the binding efficiency and drug-related characteristics of numerous serotonin receptor-binding compounds. In some of the groups several subtypes have been identified. [For a relatively recent review of 5-hydroxytryptamine receptors, see, E. Zifa and G. Fillion,
Pharamcological Reviews,
44:401-458 (1992); D. Hoyer, et al.,
Pharamcological Reviews,
46:157-203 (1994). The Hoyer, et al., reference describes for each class or subtype one or more compounds which have efficacy as antagonists or agonists f
Johnson Kirk Willis
Phebus Lee Alan
Eli Lilly and Company
Titus Robert D.
Travers Russell
Tucker R. Craig
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