Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing compound doai
Reexamination Certificate
1998-07-10
2001-08-21
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing compound doai
C514S724000, C514S668000
Reexamination Certificate
active
06277891
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention is related to the field of virology. More particularly it relates to the field of human rhinoviruses.
BACKGROUND OF THE INVENTION
Rhinovirus infections are the predominant cause of the common cold (18), the most frequently experienced acute respiratory illness in humans. Recent evidence also implicates rhinovirus infections as an important precipitating factor for exacerbations of asthma (21, 22, 37), chronic bronchitis (35), sinusitis (19, 50), and otitis media (3). Despite the high health care costs associated with rhinovirus infections, the underlying process by which viral infection leads to symptomatology is poorly understood.
The epithelial cell is the primary site of rhinovirus infection (6, 51). In contrast to other respiratory viruses, such as influenza, cytotoxic damage of infected epithelial cells does not appear to play a role in the pathogenesis of rhinovirus infections, since cytotoxicity is not observed either in infected human epithelial cell cultures (49) or in the nasal mucosa of infected individuals (53, 54). In light of this, emphasis has focused on the concept that symptoms may result from the actions of proinflammatory mediators that are generated as a consequence of rhinovirus infection. Support for this hypothesis has come from two lines of evidence: 1) Studies of subjects with experimentally-induced, or naturally-acquired colds have demonstrated increased levels of several mediators, including kinins (36, 41), IL-1 (40), and IL-6 (55) in nasal secretions during symptomatic rhinovirus infections, and 2) infection of purified human respiratory epithelial cell populations with rhinovirus has been shown to induce production of proinflammatory cytokines, including IL-8, IL-6 and GM-CSF (49, 55), that could contribute to disease pathogenesis. To date, however, the specific biochemical events involved in the production of each of these cytokines by rhinoviruses are incompletely understood, and the role of specific cytokines, and other mediators, in the pathogenesis of colds remains to be established.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide methods of alleviating symptoms induced by a rhinoviral infection.
It is another object of the present invention to provide methods of reducing rhinoviral replication.
It is an object of the present invention to provide methods of reducing cytokine production induced by a rhinovirus.
It is still another object of the invention to provide a method for screening to compounds to identify candidate therapeutic or prophylactic agents for rhinoviral infection.
These and other objects of the invention are achieved by providing a method of alleviating symptoms induced by a rhinoviral infection which comprises administering a compound to a human infected with a rhinovirus. The compound releases nitric oxide (NO). An amount is administered which is sufficient to alleviate one or more symptoms associated with the infection.
According to another aspect of the invention a method is provided of reducing rhinoviral replication. The method comprises contacting human respiratory epithelial cells which are infected by a rhinovirus with a compound. The compound is one which releases NO. Sufficient compound is administered to inhibit replication of the rhinovirus.
According to yet another aspect of the invention a method is provided of reducing cytokine production induced by a rhinovirus. The method comprises the step of contacting human respiratory epithelial cells which are infected by a rhinovirus with a compound. The compound is one which releases NO. Sufficient compound is administered to inhibit cytokine production induced by the rhinovirus.
Another embodiment of the invention is a method of alleviating symptoms induced by a rhinoviral infection. The method comprises administering an effective amount of a compound to a human infected with a rhinovirus. The compound induces nitric oxide synthase (NOS) in human respiratory epithelial cells, whereby the symptoms of the infection are alleviated.
Still another embodiment of the invention is provided by a method of reducing rhinoviral replication. The method comprises contacting human respiratory epithelial cells which are infected by a rhinovirus with a compound. The compound induces NOS in the human respiratory epithelial cells. The compound is administered in an amount effective to inhibit replication of the rhinovirus.
Even another aspect of the invention is a method of reducing cytokine production induced by a rhinovirus. The method comprises contacting human respiratory epithelial cells which are infected by a rhinovirus with a compound. The compound is one which induces NOS in the human respiratory epithelial cells. An amount is administered which is effective to inhibit cytokine production induced by the rhinovirus.
Yet another embodiment of the invention is a method for testing compounds to identify candidate agents for therapeutic or prophylactic treatment of a common cold or other disease associated with human rhinoviruses. The method comprises the step of infecting human respiratory epithelial cells with a human rhinovirus; contacting the cells with a test compound; and measuring the amount of at least one proinflammatory or eosinophil-active cytokine produced by the respiratory epithelial cells, wherein a test compound which reduces the amount of the cytokine produced is a candidate agent for prophylactic or therapeutic treatment of human rhinovirus infection.
Another aspect of the invention is another method for testing compounds to identify candidate agents for therapeutic or prophylactic treatment of a common cold or other disease associated with human rhinoviruses. The method comprises the steps of: infecting human respiratory epithelial cells with a human rhinovirus; contacting the cells with a test compound; and measuring the amount rhinoviral genome replicated in the respiratory epithelial cells, wherein a test compound which reduces the amount of the rhinoviral genome replicated is a candidate therapeutic or prophylactic agent for prophylactic or therapeutic treatment of human rhinovirus infection.
According to another aspect of the invention a pharmaceutical composition for treating rhinovirus infections is provided. The composition comprises a liquid formulation comprising a compound which releases NO. The liquid formulation is nose drops.
Another embodiment of the invention is a nose spray- or dropper-bottle for administering a pharmaceutical composition to a human nose. The bottle comprises a liquid formulation comprising a compound which releases NO.
Still another aspect of the invention is an inhaler or nebulizer for delivering an antirhinoviral composition to the respiratory tract of a human. The device comprises a liquid formulation comprising a compound which releases NO.
The invention thus provides the art with compositions, devices, and methods for treating rhinovirus infections as well as methods for identifying additional candidate therapeutic and prophylactic agents.
REFERENCES:
patent: 5455279 (1995-10-01), Lipton
Croen 119CA:115219, 1993.*
Karupiah et al 119 CA: 201499, 1993.*
Mannick et al 125 CA: 25680, 1996.*
Scherer P. Sanders et al. “Nitric Oxide Inhibits Rhinovirus-Induced Cytokine Production and Viral Replication in a Human Respiratory Epithelial Cell Lines” Journal of Virology, Feb. 1998 pp 934-942.
Proud David
Sanders Scherer P.
Banner & Witcoff
The Johns Hopkins University
Travers Russell
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