KR20030019587A - Use of IL-8 Receptor Antagonists in the Treatment of Virus Infections - Google Patents

Abstract

The present invention relates to novel uses of IL-8 receptor antagonists for treating aggravation of human viral infections and the symptoms associated therewith.

Description

Use of IL-8 Receptor Antagonists in the Treatment of Virus Infections

Human rhinovirus (HRV), the most common cause of common cold, is increasingly associated with more severe sequelae, including asthma, chronic bronchitis, COPD, otitis media and sinusitis. Recently published studies in adults and adolescents, using PCR to assist in virus detection, found that up to 50% to 80% of asthma exacerbations are associated with upper canal virus infection and rhinoviruses are the most common cold virus.

HRV infects nasal epithelial cells. Recent studies suggest that the virus can also infect bronchial epithelium. Pre-cold symptoms are evident within 24 hours after infection, peak at 2 to 5 days, and heal naturally within 7 to 14 days. However, this effect may last longer than in some individuals. The virus can be eliminated, but symptoms often persist. Symptoms are thought to result from the host's response to infection rather than an acute cytotoxic effect, since only a small percentage of upper respiratory epithelial cells are clearly infected and there is minimal epithelial cell damage. Increased intranasal levels of kinin, IL-1, IL-8, IL-6, IL-11 and neutrophils are found in normal individuals infected with rhinoviruses. The correlation between IL-8 concentrations in local nasal secretions and local myeloperoxidase levels and symptoms has been demonstrated in several recent studies. Intranasal concentrations of IL-1 and IL-6 also correlate with the severity of symptoms. Experimental rhinovirus infection immediately elevated allergic and late allergic reactions and increased the infiltration of T lymphocytes and eosinophils into the lower respiratory tract. In atopy and asthma, these effects last up to 2 months after infection. Human bronchial epithelial cell lines have been shown to produce IL-1, IL-6, IL-8, IL-11 and GM-CSF in response to rhinovirus infection. Therefore, early production of cytokines by epithelial cells infected with rhinoviruses can lead to the aggregation of neutrophils, T cells and activated eosinophils into the upper and lower airways.

In addition, IL-1, IL-6 and IL-8 are also produced in response to infection with other respiratory viruses (influenza, respiratory syncytial virus) that can cause common colds and associated sequelae.

Many different names such as neutrophil attractant / activating protein-1 (NAP-1), neutrophil chemotactic factor (MDNCF) derived from monocytes, neutrophil activating factor (NAF) and T-cell lymphocyte chemotactic factor are known to be interleukin-8 (IL -8) has been applied. Interleukin-8 is a chemoattractant for neutrophils, basophils and subgroups of T-cells. Interleukin-8 is exposed to the majority of nucleated cells, including macrophages, fibroblasts, endothelial cells and epithelial cells exposed to TNF, IL-1α or IL-1β or LPS, and to chemotactic factors such as LPS, or FMLP When neutrophils are produced by themselves [M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter, et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992).

GROα, GROβ, GROγ and NAP-2 also belong to the chemokine class. Like IL-8, these chemokines have been called by various names. For example, GROα, β, and γ have been called MGSAα, β and γ (melanoma growth stimulating activity), respectively [Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All chemokines of the α-class with the ELR motif immediately before the CXC motif bind to the IL-8 B receptor (CXCR2).

IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78 stimulate many functions in vitro. While they have all been found to exhibit chemoattraction for neutrophils, IL-8 and GROα exhibit T-lymphocytic and basophilic chemotaxis. In addition, IL-8 can induce histamine release from basophils of both normal and atopic patients. In addition, IL-8 and GROα can induce lysozyme enzyme release and respiratory bursts from neutrophils. IL-8 was also found to increase the surface expression of Mac-1 (CD1 lb / CD18) on neutrophils without de novo protein synthesis.

In vitro, IL-8, GROα, GROβ, GROγ and NAP-2 bind to and activate seven transmembrane G protein binding receptors, in particular IL-8 receptors, particularly the IL-8 β receptor (CXCR2). Binding to neutrophil morphology, chemotaxis, granule release and respiratory burst (Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991) )).

Two high-affinity human IL-8 receptors (77% homology), i.e. high affinity for GROα, GROβ, GROγ and NAP-2, as well as IL-8RA, and IL-8 that only bind IL-8 with high affinity IL-8RB has been characterized (Holmes et al., Supra; Murphy et al., Science 253, 1280 (1991); Lee et al., J. Biol. Chem. 267,16283 (1992); LaRosa et al., J. Biol. Chem. 267,25402 (1992); and Gayle et al., J. Biol. Chem. 268, 7283 (1993)).

Interfering with the biochemical processes of epithelial cells resulting from viral infection is a living new therapeutic target for IL-8 receptor antagonists. The present invention relates to novel findings for the treatment of this therapeutic target.

Summary of the Invention

The present invention provides a method of treating a disease mediated by chemokine, wherein the chemokine binds to an IL-8A or IL-8B receptor, the method comprising an effective amount of an IL-8 receptor antagonist or a pharmaceutically acceptable thereof. Administering salts. In addition, the present invention is directed to humans in need of treatment, including prevention and inhibition / reduction of severity of the underlying symptoms of viral infections, including human rhinoviruses, enteroviruses, coronaviruses, influenza viruses, parainfluenza viruses, respiratory syncytial viruses, and adenoviruses. The use of an IL-8 receptor antagonist for treatment, including the prevention and suppression / reduction of severity of the underlying symptoms of the viral infection in a method comprising administering to the human an effective amount of an IL-8 receptor antagonist. .

The present invention relates to the use of IL-8, GROα, GROβ, GROγ, NAP-2 and ENA-78 modulators in the treatment of viral infections.

Inhibition of RV or Gro-beta induced calcium mobilization in human neutrophils by CXCR2 antagonist X. FIG.

2-Inhibition of RV-induced chemotaxis of human neutrophils by CXCR2 antagonist X.

Figure 3-RV, groα, groβ and groβ-T induced calcium mobilization in neutrophils.

How to treat

The IL-8 receptor antagonists or pharmaceutically acceptable salts thereof of the present invention are mammalian cells, such as, but not limited to, monocytes and / or macrophages, or IL-, also called type I or type II receptors. Prophylactic or curative treatment of symptoms or sequelae of viral infection in humans or other mammals, aggravated or caused by excessive or unregulated IL-8 cytokine production by other chemokines that bind to 8A or IL-8B receptors It can be used in the manufacture of a medicament for.

Accordingly, the present invention provides a method of treating a viral infection, wherein the chemokine binds to an IL-8A or IL-8B receptor, which method comprises administering an effective amount of an inhibitor of the invention or a pharmaceutically acceptable salt thereof. It includes. In particular, the chemokine is IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78.

In order to use the IL-8 receptor antagonist of the present invention or a pharmaceutically acceptable salt thereof for the treatment, the antagonist or the salt will generally be formulated into a pharmaceutical composition according to standard pharmaceutical practice.

Accordingly, the present invention also relates to pharmaceutical compositions comprising an effective non-toxic amount of the IL-8 receptor antagonist of the present invention and a pharmaceutically acceptable carrier or diluent.

The IL-8 receptor antagonists of the present invention, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same may be used in any conventional route used for drug administration, for example, oral, topical, buccal, parenteral or inhalation. Can be conveniently administered. They may be administered in conventional dosage forms prepared by combining standard pharmaceutical carriers and mixtures of the present invention according to conventional methods. They can also be administered in conventional dosage forms with known second therapeutically active compounds. Such methods may involve mixing, granulating and compacting or dissolving ingredients suitable for the desired formulation. It will be appreciated that the form and nature of the pharmaceutically acceptable carrier or diluent will be determined by the amount of active ingredient formulated therewith, the route of administration and other well known variables. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

Pharmaceutical carriers can be, for example, solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, carriers or diluents may include time delay materials well known in the art, such as glyceryl mono-stearate or glyceryl distearate, used alone or in combination with waxes.

A wide variety of pharmaceutical forms can be used. Thus, when a solid carrier is used, the preparation may be compressed and placed in hard gelatin capsules in the form of powders or pellets, or in the form of troches or lozenges. The amount of solid carrier varies widely but will preferably be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrups, emulsions, soft gelatin capsules, sterile injectable solutions (eg, ampoules or non-aqueous suspensions).

Antagonists of the invention may be administered topically, i.e. non-systemically. This administration includes external application of the compound of the invention to the epidermis or the oral cavity so that the compound of the invention rarely enters the bloodstream, and the infusion of the compound into the ears, eyes and nose slowly. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include, for example, liquid and semi-liquid formulations suitable for penetration into the inflammatory site through the skin, such as topical medicines, lotions, creams, ointments or pastes, drops suitable for administration to the eyes or nose, And solutions or suspensions suitable for inhalation. For topical administration, the active ingredient may be included at 0.001% to 10% by weight, for example 1% to 2% by weight of the formulation. However, the active ingredient may be included in as much as 10% by weight of the formulation, but preferably will be included in less than 5% by weight of the formulation, more preferably from 0.1% to 1% by weight of the formulation.

Lotions according to the present invention include lotions suitable for application to the skin or eyes. Eye lotions may optionally include sterile aqueous solutions containing fungicides and may be prepared by methods analogous to the preparation of the preparation. Lotions or smears for application to the skin may include substances that promote drying and cool the skin, such as alcohol or acetone, and / or moisturizers such as glycerol or oils (eg, castor oil or arachis oil). have.

Creams, ointments or pastes according to the invention are semisolid preparations of the active ingredient for external application. They can be prepared by using a suitable machine to mix the active ingredients in finely divided or powdered form alone or in a solution or suspension in an aqueous or non-aqueous liquid with a smooth or non-smooth substrate. The substrate may be selected from hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, metal soaps; mucilage; Oils of natural origin such as almond, corn, arachis, castor or olive oil; Woolen or derivatives thereof or fatty acids (eg, stearic or oleic acid) used with alcohols such as propylene glycol or macrogels. The formulation may comprise any suitable surface active agent such as anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural rubber, cellulose derivatives or inorganic materials (eg, siliceous silica), and other ingredients such as lanolin may also be included.

Appropriate preparations according to the invention may comprise sterile aqueous or oily solutions or suspensions, and the active ingredient is contained in a suitable aqueous solution containing fungicides, fungi and / or any other suitable preservatives and preferably comprising a surface active agent. It can manufacture by dissolving. The resulting solution is then clarified by filtration and transferred to a suitable container, which is then sterilized by sealing and autoclaving or holding at 98-100 ° C. for 1 hour 30 minutes. Alternatively, the solution can be filtered and sterilized and transferred to the container by aseptic technique. Examples of fungicides and fungi suitable for inclusion in the preparation are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions include glycerol, diluted alcohol and propylene glycol.

Antagonists of the invention may be administered by parenteral administration, ie intravenous, intramuscular, subcutaneous, intranasal, rectal, intravaginal or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Suitable dosage forms for such administration can be prepared by conventional techniques. Antagonists of the invention may also be administered by inhalation, i.e. nasal and oral inhalation administration. Suitable dosage forms for inhalation administration, such as aerosol formulations or inhalers in which the dosage is metered, can be prepared by conventional techniques.

For all methods of use disclosed herein for the antagonists of the invention, the daily oral dosage will preferably be from about 0.01 to about 80 mg per kg of total body weight. The daily parenteral dosage will be from about 0.001 to about 80 mg per kg of total body weight. The daily topical dose will preferably be between 0.1 mg and 150 mg and will be administered 1 to 4, preferably 2 or 3 times daily. The daily inhalation dose will preferably be from about 0.01 mg / kg to about 1 mg / kg per day. In addition, the person skilled in the art will know that the optimal amount and individual dose of the antagonist or pharmaceutically acceptable salt thereof of the present invention will be determined by the nature and extent of the condition to be treated, the dosage form, the route of administration and the site of administration, and the particular patient to be treated. It will be appreciated that such optimal conditions can be determined by conventional techniques. Those skilled in the art will also recognize that the optimal duration of treatment, i.e. the number of administrations, of a compound of the invention or a pharmaceutically acceptable salt thereof administered per day for a defined period of time may be determined by one skilled in the art using conventional procedures of treatment determination testing. something to do.

While the invention will be described in conjunction with the following biological examples, the examples are illustrative only and are not intended to limit the scope of the invention.

Biological Example

The IL-8 and GRO-α chemokine inhibitory effects of the compounds of the present invention are measured by the following in vitro assays.

Receptor binding assay :

[ ¹²⁵ I] IL-8 (human recombinant) with a specific activity of 2000 Ci / mmol was purchased from Amersham Corp. (Arlington Heights, IL). GRO-α was purchased from NEN-New England Nuclear. All other chemicals are of analytical grade. Highly recombinant human IL-8 type α and β receptors were individually expressed in Chinese hamster ovary cells described in Holmes, et al., Science, 1991, 253, 1278. Chinese hamster ovary membrane, homogenization buffer was lO mM Tris-HCL buffer (1 mM MgSO ₄ , 0.5 mM EDTA (ethylene-diaminetetraacetic acid), 1 mM PMSF (α-toluenesulfonyl fluoride), 0.5 mg / L Homogenized according to Haour, et al., J. Biol. Chem., 249 pp 2195-2205 (1974), except for the change to peptin, pH 7.5). Membrane protein concentration was measured using a microanalysis kit (Pierce Co.) using bovine serum albumin as a standard. All analyzes were performed in 96-well microplate format. Each reaction mixture was ¹²⁵ I IL-8 (0.25 nM) in 20 mM bis-trispropane and 0.4 mM Tris HC1 buffer (containing pH 8.0, 1.2 mM MgSO ₄ , 0.1 mM EDTA, 25 mM Na and 0.03% CHAPS). Or ¹²⁵ I GRO-α and 0.5 μg / ml IL-8Rα or 1.0 μg / ml IL-8Rβ membrane. In addition, the drug or compound of interest previously dissolved in DMSO was added to a final concentration of 0.01 nM to 100 μM. Assays were initiated by the addition of ¹²⁵ I-IL-8. After 1 hour at room temperature, the plates were collected using a Tomtec 96-well harvester on a glass fiber filter mat blocked with 1% polyethyleneimine / 0.5% BSA, and buffered (25 mM NaCI, 10 mM TrisHCl, 1 mM MgSO _4). , 0.5 mM EDTA, 0.03% CHAPS, pH 7.4). The filter was then dried and counted on a betaplate liquid scintillation counter. Recombinant IL-8 Rα or type I receptors are also referred to herein as non-acceptable receptors, and recombinant IL-8 Rβ or type II receptors are also called acceptable receptors.

Chemotaxis Analysis:

In vitro inhibition of these compounds was determined in the neutrophil chemotaxis assay described in Current Protocols in Immunology, vol. I, Suppl 1, Unit 6.12.3., Which is hereby incorporated by reference in its entirety. Neutrophils were isolated from human blood as described in Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1, which is hereby incorporated by reference in its entirety. Chemoattractants IL-8, GRO-α, GRO-β, GRO-γ and NAP-2 were placed in the bottom chamber of 48 multiwell chambers (Neuro Probe, Cabin John, MD) at concentrations from 0.1 to 100 nM. The two chambers are separated by 5 μM polycarbonate filter. When the compounds of the present invention were tested, the compounds were mixed with cells (0.001-1000 nM) just before adding the cells to the upper chamber. Incubation was for about 45-90 minutes in a 37 ° C., humid incubator with 5% CO ₂ . At the end of the incubation, the polycarbonate membrane was separated, the top was washed and the membrane was stained using the Diff Quick staining protocol (Baxter Products, McGaw Park, IL, USA). Cells showing chemotaxis to chemokines were visually counted using a microscope. In general, four fields per each sample were counted and these cell numbers were averaged to determine the average number of migrated cells. Each sample was tested three times and each compound was repeated four or more times. Certain cells (positive control cells) to which no compound is added show the maximum chemotactic response of the cells. If a negative control (not stimulated) was needed, no chemokine was added to the bottom chamber. The difference between the positive control and the negative control indicates the chemotactic activity of the cells.

Elastase Release Assay:

Compounds of the invention were tested for their ability to interfere with the release of elastase from human neutrophils. Neutrophils are described in Current Protocols in Immunology Vol. I, isolated from human blood as described in Suppl 1 Unit 7.23.1). Each 50-well volume of 0.88 x 10 ⁶ PMN cells suspended in Ringer's solution ((NaCl 118, KCl 4.56, NaHC0 ₃ 25, KH ₂ PO ₄ 1.03, glucose 11.1, HEPES 5 mM, pH 7.4) was added to each well of a 96 well plate. 50 μl volume of test compound (0.001-1000 nM), 50 μl volume of cytocalasin B (20 μg / ml) and 50 μl volume of Ringer buffer were added to the plate. After warming up (37 ° C., 5% CO ₂ , 95% RH), IL-8, GROα, GROβ, GROγ or NAP-2 was added to a final concentration of 0.01-1000 nM. After centrifugation, the 96 well plate was centrifuged (800 × g, 5 min) to obtain 100 μl of supernatant, which was added to a second 96 well plate and then the artificial elastase substrate (MeOSuc-Ala-Ala). -Pro-Val-AMC, Nova Biochem, La Jolla, Calif.) Was dissolved in phosphate buffered saline to a final concentration of 6 μg / ml Immediately, the plates were plated with fluorescent 96 wells. The data were collected in a reader (Cytofluor 2350, Millipore, Bedford, Mass.) And collected at 3 minute intervals according to the method of Nakajima et al J. Biol. Chem. 254 4027 (1979). The amount of agent was calculated by measuring the MeOSuc-Ala-Ala-Pro-Val-AMC degradation rate.

Renovirus method:

Cell line and rhinovirus serotype 39 were purchased from American Type Culture Collection (ATCC). BEAS-2B cells were cultured according to the instructions provided by ATCC using BEGM (Bronch Epithelial Growth Medium) purchased from Clonetics Corp. HELA cell cultures used for detection and titration of virus were maintained in Eagles minimal essential medium (MEM) containing 10% fetal bovine serum, 2 mM 1-glutamine and 10 mM HEPES buffer.

A variation of the method reported by Subauste et al., For in vitro infection of human bronchial epithelial cells with rhinoviruses was used in this study. BEAS-2B cells (2 × 10 ⁵ / well) were incubated in collagen coated wells for 24 hours and then infected with linovirus. After rhinovirus serotype 39 was added to the cell culture for 1 hour incubation at 34 ° C., the inoculum was replaced with fresh medium and the culture was further incubated at 34 ° C. for 72 hours. Supernatants collected 72 hours after infection were analyzed for cytokine protein concentration by ELISA using a commercially available kit (R & D system). Virus yield was also determined from the culture supernatants using microtiter assays in HELA cell cultures (Subauste et al., Supra. In cultures treated with IL-8 inhibitors, drugs were added 30 minutes after infection. Compound stocks were prepared in DMSO (10 mM drug) and stored at -20 ° C.

To detect IL-8R inhibition, cultures were incubated in basal medium without growth factors and additives to reduce the intrinsic concentration of activated IL-8. Supernatants were collected and concentrated at various time points after linovirus addition. The concentrate was fractionated on Sepharose 6 column. The supernatant was concentrated to more than 50 times using an Amicon concentrator (representing 5,000 molecular weight cutoff).

A single injection (0.5 ml) was applied to the Superros 6 size fractionation column eluting at a single flow rate (0.2 ml / min). 0.5 ml fractions were pooled and analyzed for Ca ²⁺ mobilization activity in instant isolated human PMN loaded with FURA-2.

result:

Characterization of Chemokines Produced from RAS-infected BEAS-2B Human Epithelial Cells

Under dormant conditions, BEAS-2B human epithelial cells produced three or more known small amounts of human chemokines, namely Groα, IL-8 and ENA-78. When these cells were infected with rhinoviruses, the production of three ELR chemokines was increased 6.6 to 20-fold higher than under dormant conditions (Table 1).

Production of ELR chemokines from BEAS-2B epithelial cells under dormant and infectious conditions (n = 6) process Groα (pg / ml) IL-8 (pg / ml) ENA-78 (pg / ml) Control 1568 ± 402 143 ± 86 164 ± 33 HRV-39 12135 ± 3599 2870 ± 645 1083 ± 194

When epithelial cell supernatants infected with HRV-39 were size exclusion fractionated on a Superros 6 column, the supernatants were recruited to Ca ²⁺ when analyzed using human neutrophils (FIG. 3) or cell lines transfected with CXCR1 or CXCR2 receptors. A single peak of activity is shown. Mobilization of Ca ²⁺ in neutrophils occurs in the same fraction as the elution of chemokines IL-8, ENA-78 and Groα.

To determine if other chemokines are produced from BEAS-2B cells infected by HRV-39 (since we do not have an ELISA kit), other instantaneous expression of various chemokine receptors including CCR1, CCR2, CCR3 and CCR5 BEAS-2B supernatants were analyzed on isolated human peripheral cells. When the active fractions derived from BEAS-2B epithelial cells were analyzed for Ca ²⁺ recruitment using Fura-2 loaded eosinophils or peripheral blood mononuclear cells (PBL), no fraction recruited Ca ²⁺ . It was. This means that chemokines except IL-8, Groα and ENA-78 are not present at such concentrations as to facilitate Ca ²⁺ recruitment.

In order to determine the possibility of other chemokines that activate PMN, and the possibility that IL-8 activates PMN through CXCR2, the inventors of the present invention have superimposed Groβ, concentrated BEAS-2B supernatant, or Fura-2 loaded PMN. The ability of IL-8 receptor antagonists to inhibit Ca ²⁺ recruitment induced by active fractions derived from Ross 6 column separation was measured. As can be seen from FIG. 1, Compound-X completely inhibited dose dependently the RV concentrated supernatant, and the chemokine containing fractions obtained from the Superrose 6 column with an IC ₅₀ of 1.7 to 2 nM. This IC ₅₀ was similar to the IC ₅₀ (IC ₅₀ = 5 nM) obtained using only Groβ, meaning that all Ca ²⁺ mobilization activity contained in the concentrate or fractions acts through the CXCR2 receptor.

To determine whether the RV supernatant acts alone through the CXCR2 receptor, we found a high correlation between a number of selective CXCR2 antagonists and the ability of the antagonists to inhibit Ca ²⁺ mobilization induced by concentrated RV supernatants and Groβ. Check if there is a relationship. There is a very high correlation between the various sets of CXCR2 antagonists and the ability of these antagonists to inhibit Ca ²⁺ mobilization induced by RV and Groβ, indicating that Ca ²⁺ mobilization activity of the RV supernatant is entirely through the CXCR2 receptor on PMN. Means that.

Inhibition of PMN chemotaxis was also measured in both concentrated and fractionated RV samples. Chemotaxis was inhibited by the specific CXCR2 antagonist described in FIG. 2.

These results demonstrate that a variety of ELR chemokines are produced by BEAS-2B cells that act through the CXCR2 receptor and can be blocked by selective CXCR2 antagonists. Although IL-8 is present in the supernatant, IL-8 is also completely blocked by CXCR2 antagonists. IL-8 is unlikely, but may act at its low level compared to Groα.

All documents, including but not limited to patents and patent applications cited herein, are incorporated herein as if each individual document were specifically and individually described to be incorporated herein as if the entire document had been described.

The foregoing description fully discloses the present invention, including the preferred embodiment. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest extent. Therefore, the embodiments herein are for illustrative purposes only and are not intended to limit the scope of the invention in any way. Embodiments of the present invention for which exclusive ownership or privilege are claimed are defined as follows.

IL-8 and other cytokines affect a wide variety of cells and tissues, and these cytokines and other leukocyte derived cytokines are important and critical inflammatory mediators responsible for the symptoms of many viral infections. Inhibition of these cytokines is beneficial in controlling, alleviating and alleviating many of these symptoms of respiratory viral infections. The invention also relates to the treatment of symptoms caused by viral infections in humans caused by human rhinoviruses, other enteroviruses, coronaviruses, herpesviruses, influenza viruses, parainfluenza viruses, respiratory syncytial viruses or adenoviruses. . The invention also relates to respiratory viral infections that exacerbate underlying chronic symptoms such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, otitis media and sinusitis. It should also be noted that the respiratory viral infections treated herein may be associated with secondary bacterial infections such as otitis media, sinusitis or pneumonia.

The present invention demonstrates that the IL-8 receptor antagonist is useful for the treatment of symptoms associated with respiratory viral infections, and in particular for the inhibition / severity of exacerbation of underlying symptoms, including asthma, otitis media, COPD, sinusitis, chronic bronchitis, and the like. will be.

Suitable IL-8 inhibitors are well known in the art and assays for measuring IL-8 inhibition are readily available. See, for example, US Pat. Nos. 5886044, 5780483, 6005008, 5929250, 6015908 and 5919776; U.S. Patent Application Nos. 09/111663, 09/125279, 09/240354, 09/202570, 09/202586, 09/202569, 09/202568, 09/230120 , 09/230290, 09/230952, 09/230977, 09/230981, 09/230980, 09/242187, 09/341378, 09/341382, 09 09/341262, 09/463673, 09/508039 and 09/486986; WO99 / 65310, WO0012489, WO0009511, WO9942464, WO9942463, WO9942461, WO00 / 05216, WO99 / 36069, WO99 / 36070 and WO00 / 06557; PCT / US99 / 23776 and PCT / US99 / 29940; And US Provisional Application Nos. 60/134728, 60/136666, 60/136665, 60/136717, 60/136667, 60/139675, 60/139680, 60/139678 60/139673, 60/140024, 60/139677, 60/139674, 60/140025, 60/145756, 60/164350, 60/186239, 60 60/186183, 60/186182, 60/188410, 60/188243, 60/189176, 60/189175, 60/189848, 60/192132 and 60 / See 196022].

IL-8 receptor antagonists can also be administered in conjunction with a second therapeutic agent. The second therapeutic agent may be an antiviral agent such as ribavirin, amantidine, rimantidine, rerenza, tamilflu, BTA 188, RWJ-270210 (BCX-1812), sICAM-1, tICAM453, flaconanyl or AG 7088, and Bena Antihistamines such as drill, chlorpheneramine and salts thereof, bromfeneramine or salts thereof, and the like; Decongestants such as phenylpropanolamine and salts thereof, pseudoephedrine or salts thereof; Steroids such as dexamethasone, prednisone or prednisolone; Various antibiotics such as quinolone, cephalosporin, β-lactamase inhibitors, and the like; Anti-inflammatory agents such as CSAIDS, COX-1 or COX-2 inhibitors, ASA or indomethacin and the like.

Claims (13)

Effective amounts of IL-8 receptor antagonists include human rhinoviruses, other enteroviruses, herpesviruses, coronaviruses, influenza viruses, parainfluenza viruses, respiratory cells A method of treating a common cold symptom caused by said viral infection in said human, comprising administering to a human being in need of treatment of a common cold symptom caused by a respiratory syncytial virus or adenovirus infection. The method of claim 1, wherein said respiratory virus infection exacerbates asthma. The method of claim 1, wherein the respiratory viral infection exacerbates chronic bronchitis. The method of claim 1, wherein the respiratory viral infection exacerbates chronic obstructive pulmonary disease. The method of claim 1, wherein the respiratory viral infection exacerbates otitis media. The method of claim 1, wherein said respiratory viral infection exacerbates sinusitis. The method of claim 1, wherein the respiratory viral infection is associated with a second bacterial infection such as otitis media, sinusitis or pneumonia. 8. The method of claim 1, wherein the IL-8 receptor antagonist is administered in conjunction with a second therapeutic agent. 9. The method of claim 1, wherein the second therapeutic agent is selected from the group consisting of antiviral agents, antihistamines, decongestants, steroids, antibiotics and anti-inflammatory agents. 10. The method of any one of claims 1-9, wherein the therapeutic agent is administered orally, orally, topically (intranasally) or inhaled (aerosol), or via both topical and inhalation. The method of claim 10, wherein the compound is administered with a second therapeutic agent. The method of claim 11, wherein the second therapeutic agent is selected from the group consisting of antiviral agents, antihistamines, decongestants, steroids, antibiotics and anti-inflammatory agents. The method of claim 1, wherein the IL-8 receptor antagonist is disclosed in US Pat. Nos. 5886044, 5780483, 6005008, 5929250, 6015908 and 5919776; U.S. Patent Application Nos. 09/111663, 09/125279, 09/240354, 09/202570, 09/202586, 09/202569, 09/202568, 09/230120 , 09/230290, 09/230952, 09/230977, 09/230981, 09/230980, 09/242187, 09/341378, 09/341382, 09 09/341262, 09/463673, 09/508039 and 09/486986; WO99 / 65310, WO0012489, WO0009511, WO9942464, WO9942463, WO9942461, WO00 / 05216, WO99 / 36069, WO99 / 36070 and WO00 / 06557; PCT / US99 / 23776 and PCT / US99 / 29940; And US Provisional Application Nos. 60/134728, 60/136666, 60/136665, 60/136717, 60/136667, 60/139675, 60/139680, 60/139678 60/139673, 60/140024, 60/139677, 60/139674, 60/140025, 60/145756, 60/164350, 60/186239, 60 60/186183, 60/186182, 60/188410, 60/188243, 60/189176, 60/189175, 60/189848, 60/192132 and 60 / Selected from the compounds disclosed in 196022.