WO1996005836A2

WO1996005836A2 - Methods of treating cold symptoms using pentoxifylline

Info

Publication number: WO1996005836A2
Application number: PCT/US1995/010840
Authority: WO
Inventors: Ronald B. Turner
Original assignee: Medical University Of South Carolina
Priority date: 1994-08-25
Filing date: 1995-08-25
Publication date: 1996-02-29
Also published as: AU3539795A; WO1996005836A3

Abstract

The invention provides a method of alleviating a symptom of an upper respiratory viral infection in a subject, comprising administering to the subject an effective amount of pentoxifylline or an analog thereof. The invention also provides a method of inhibiting interleukin-8 elaboration in a subject comprising administering to the subject an effective amount of pentoxifylline or an analog thereof. A pharmaceutical composition for alleviating a symptom of an upper respiratory viral infection is also provided, comprising an effective amount of pentoxifylline or an analog thereof in a pharmaceutically acceptable nasal spray carrier.

Description

METHODS OF TREATING COLD SYMPTOMS USING PENTOXIFYLLINE

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

The present invention relates to a method of treating cold symptoms in a subject by administering pentoxifylline and to a method of inhibiting interleukin-8 (IL- 8) production in a subject by administering pentoxifylline.

BACKGROUND ART

Infection with a variety of different upper respiratory pathogens and rhinoviruses in particular, may result in common cold symptoms, such as rhinorrhea, nasal obstruction, sneezing, cough, sore throat, malaise, headache and chills (1). The pathogenesis of the symptoms of these infections is not known, but the host response to the virus may cause at least some of the manifestations. Kinins appear in nasal washes from symptomatic human volunteers with rhinovirus colds (2,3) and challenge of human subjects with bradykinin causes rhinorrhea and nasal obstruction (4). Similarly, an increased level of interleukin-1 β (IL-1 β) has been reported in the nasal secretions of subjects with symptomatic rhinovirus colds (5). In experimental colds in human volunteers, PMNs appear in the nasal mucosa early in the course of infection (6). Examination of nasal secretions during experimental colds revealed an influx of PMNs in rhinovirus-infected volunteers who became ill that was not seen in infected non-ill or uninfected volunteers (2). Although this observed association between PMNs and symptomatic infections does not establish a role for PMNs in the pathogenesis of rhinovirus colds, identification of the mechanism by which PMNs are attracted to the nasal mucosa may provide insight into the pathogenesis of rhinovirus induced symptoms. Interleukin-8 (IL-8) is a proinflammatory, leukocyte derived cytokine with chemoattractant activity for PMNs (7,8). Infection of human respiratory epithelium with respiratory syncytial virus (RSV) or influenza A virus results in increased production of IL-8 (9, 10, 11). Stimulation of respiratory epithelial cells with tumor necrosis factor-alpha (TNF-α), IL-1 β or RSV resulted in a several-fold increase in both IL-8 mRNA expression and secretion into the cell culture medium (9), suggesting that IL-8 elaboration is indirectly induced by these cytokines.

Pentoxifylline [3,7-dimethyl-l-(5-oxohexyl)-xanth-ne] (PFN) (Trental, Hoechst-Roussel Pharmaceuticals, Inc.) is a phosphodiesterase inhibitor which has been found to inhibit certain activities of TNF-α and IL-1 (17,18, U.S. Patent No. 5,272,153).

Efforts to intervene in the common cold have used two general approaches, antiviral therapy, which has been uniformly unsuccessful except as prophylaxis, and symptomatic therapy, which requires combination therapy and is generally of limited efficacy. Thus, there exists a need for an effective therapy to relieve the symptoms of the common cold.

This invention meets this need by providing a method for alleviating common cold symptoms by administering pentoxifylline and a method of inhibiting IL-8 elaboration by administering pentoxifylline.

SUMMARY OF THE INVENTION

The present invention provides a method of alleviating a symptom of an upper respiratory viral infection in a subject, comprising administering to the subject an effective amount of a compound having the structure:

wherein Rι R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C₆H₅-(CH₂),-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl.

In the method of the present invention, a more preferred compound is the structure shown above, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃_C(OH)(CH₃)-

(CH₂)₄-, (CH₃)₂-COH-(CH₂)₄-, CH₃-CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- or HC=CCH₂-; Rj is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂-CH₂-, CH₃- CH₂-O-CH₂-, H, CH₃, C^-O or HC=CCH₂- .

In the method of the present invention, an even more preferred compound is the structure shown above, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃- C(OH)(CH₃HCH₂)₄-, (CH₃)₂-COH-(CH₂)₄- or CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-0-CH₂-, H or CH₃. A still further preferred compound for use in the present method is pentoxifylline.

A pharmaceutical composition for alleviating a symptom of an upper respiratory viral infection is also provided, comprising an effective amount of pentoxifylline or an analog thereof in a pharmaceutically acceptable nasal spray carrier.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to a method of alleviating a symptom of an upper respiratory viral infection in a subject, comprising administering to the subject an effective amount of a compound having the structure:

wherein R_j R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C₆H₅-(CH₂),-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl.

(CH₂)₄-, (CH₃)₂-COH-(CH₂)₄-, CH₃-CCKCH₂)₄-, H, CH₃-CH₂-CH₂- orHC=CCH₂-; R₂ is CH₃, CH_j-CH_j-CH_j-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂-CH₂-, CH₃- CH₂-O-CH₂-, H, CH₃, CβHj-CHa- or HC=CCH₂- .

In the method of the present invention, an even more preferred compound is the structure shown above, wherein R_t is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃- C(OH)(CH₃HCH₂)₄-, (CH₃)₂-COH-(CH₂)₄- or CH₃-CO-(CΑ^₄-, R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H or CH₃. A still further preferred method of alleviating the symptoms of an upper respiratory infection uses the compound with the above structure, wherein Rι is CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃.

The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, /-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. Preferred alkyl groups herein contain from 1 to 12 carbon atoms, even more preferably from 1 to 6 carbon atoms. The term "lower alkyl" intends an alkyl group of from one to six carbon atoms, preferably from one to four carbon atoms.

The term "alkene" as used herein intends an unsaturated hydrocarbon group of 2 to 24 carbon atoms, preferably from 2 to 12 carbon atoms, even more preferably from 1 to 6 carbon atoms, having one or more double bonds. Asymmetric structures such as (AB)C=C(CD) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkene is present, or it may be explicitly indicated by the bond symbol — .

The term "alkyne" as used herein refers to an unsaturated hydrocarbon group of from 2 to 24 carbon atoms, preferably from 2 to 12 carbon atoms, even more preferably from 1 to 6 carbon atoms, having the structural formula C_rtH_2n-₃ ^anc' containing a triple bond.

Preferred species include Propentofylline, Torbafylline, Albifylline and

Pentoxifylline (Meskini et al. Biochemical Pharmacology 47(5):781-788, 1994); 3- Propylxanthine (emprofylline), 3-isobutyl-l-methyl-xanthine, 1,3,7-Trimethylxanthine (caffeine) and l,3-Dipropyl-7-methylxanthine (Ukena et al. Biochemical Pharmacology 45(4):Z47-S5\, 1993); 1,3-Dimethylxanthine, l-(5-Hydroxyhexyl)-3,7- dimethylxanthine, 7-Propyl-l-(5-hydroxy-5-methy-hexyl)-3-methylxanthine (Semmler et al. Immunology 78:520-525, 1993); and 1,3,7-Tripropargyl, 1,3,7- Tripropargylxanthine, l,7-DiMe-3-propargylxanthine, 3,7-DiMe-l-propargylxanthine, 7-Benzyl-IBMX, l,7-DiMe-3-propylxanthine, l,3-DiMe-7-propylxanthine and 1,3- Dipropylxanthine (Choi et al. Life Sciences 43:387-398, 1988).

The present invention provides a method of alleviating a symptom of an upper respiratory viral infection in a subject comprising administering to the subject an effective amount of PFN or an analog thereof as provided herein. Analogs of PFN are defined as chemical compounds comprising the core structure of a xanthine as shown above, having R_b R₃ and R₇ groups which render the compound chemically stable and having the activity of inhibiting elaboration of IL-8. Analogs of PFN can be obtained commercially or synthesized according to well known chemical methods. For example, a synthesis method is described in Mohler and Sόder (21). The analogs can then be routinely tested for efficacy in the present methods, by the in vitro and in vivo assays described in the Examples. Examples of such analogs are provided herein.

The upper respiratory viral infection can be a rhinovirus infection, an influenza A virus infection or a respiratory syncytial virus infection. As used herein, "effective amount" means that amount of PFN which is determined to alleviate a symptom of an upper respiratory viral infection. PFN can be used to treat the symptoms of colds or upper respiratory viral infections. The determination of effectiveness can be made, for example, in the protocol for human administration as described herein. As used herein, "alleviating or alleviate" means to inhibit, lessen, reduce or relieve a symptom of an upper respiratory viral infection. Also as used herein, "a symptom of an upper respiratory viral infection" means a symptom or symptoms manifested in a subject who has been infected with an upper respiratory viral pathogen. These symptoms comprise rhinorrhea, nasal obstruction, sneezing, cough, sore throat, malaise, headache and chills. The ordinary skilled clinician applying the present method can use the typical measures of the severity of the cold symptoms to tailor the therapy to the individual subject. An example of a measure of severity of symptoms or a measure of relief of symptoms is the scoring method provided below in the description of the detection of IL-8 in rhinovirus-challenged human subjects.

The present invention also provides the use of an effective amount of a compound having the structure:

wherein R_j R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, CJΛ₅- CH^)_Λ-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, in the manufacture of a medicament for the treatment of a symptom of an upper respiratory viral infection in a human subject. In this embodiment, a more preferred compound is the structure shown above, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃.C(OH)(CH₃)-(CH₂)₄-, (CH₃)₂-COH-(CH₂)₄-, CH₃-CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- or HC=CCH₂-; R₂ is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂- O-CH₂-, H, CH₃, C₆H₅-CH₂- or HC=CCH₂- .

An even more preferred compound in this embodiment is the structure shown above, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃-C(OH)(CH₃)-(CH₂)₄-, (CH₃)₂- COH-(CH₂)₄- or CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O- CH₂-, H or CH₃. A still further preferred compound for use in the manufacture of a medicament for the treatment of a symptom of an upper respiratory infection is the compound with the above structure, wherein R, is CH₃-CO-(CH₂)₄-; R is CH₃; and R₃ is CH₃.

The present invention further provides the use of an effective amount of a compound having the structure:

wherein R_j R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C₆H₅-(CH₂)_a-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, for the treatment of a symptom of an upper respiratory viral infection in a human subject. In this embodiment, a more preferred compound is the structure shown above, wherein R. is CH₃, CH₃-CHOH- (CH₂)₄-, CH₃.C(OH)(CH₃HCH₂)₄-, (CH₃)₂-COH-(CH₂)₄-, CH₃-CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- or HC=CCH₂-; R₂ is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H, CH₃, CeHs-CHj- or HC=CCH₂- .

An even more preferred compound in this embodiment is the structure shown above, wherein R_j is CH₃, CH_rCHOH-(CΑ^₄-, CH₃-C(OH)(CH₃)-(CH₂)₄-, (CH₃)₂- COH-(CH₂)₄- or CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O- CH₂-, H or CH₃. A still further preferred form of the above compound for treatment of a symptom of an upper respiratory infection is the compound with the above structure, wherein K. is CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃.

In another embodiment, the present invention provides a method of inhibiting interleukin-8 elaboration in a subject comprising administering to the subject an effective amount of a compound having the structure:

wherein R, R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C₆H₅-(CH₂)_β-, wherem a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl.

A preferred method of inhibiting IL-8 uses the compound with the above structure, wherein Ri is CH₃, CH₃-CHOH-(CH₂)₄-,

(CH₃)₂-COH-(CH₂)₄-, CH₃-CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- or HC=CCH₂-; R₂ is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂- O-CH₂-, H, CH₃, C₆H₅-CH₂- or HC=CCH₂- . An even more preferred method of inhibiting IL-8 uses the compound with the above structure, wherein R, is CH₃, CH₃-CHOH-(CH₂) -, CH₃-C(OH)(CH₃)-(CH₂)₄-, (CH₃)₂-COH-(CH₂)₄- or CH₃-CO-(CH^₄- R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃- CH₂-O-CH₂-, H or CH₃.. A still further preferred method of inhibiting IL-8 uses the compound with the above structure, wherein K_{ is CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃.

The elaboration can be induced by an upper respiratory viral infection. "Elaboration" as used herein means the production or expression of IL-8 by cells or the release of IL-8 from cells. The inhibition of elaboration is distinct from the mere inhibition of one or more of the known activities of IL-8. However, it is understood that inhibition of elaboration can result in inhibition of activity. Such inhibition of elaboration can result , for example, in the reduction of side effects of upper respiratory viral infection.

Another embodiment of the invention provides the use of an effective amount of a compound having the structure:

wherein K. R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C₆H₅-(CH₂),-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, in the manufacture of a medicament for inhibiting interleukin-8 elaboration in a human subject.

A preferred use of the above compound employs the above structure, wherein

R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃.C(OH)(CH₃)-(CH₂)₄-, (CH₃)₂-COH-(CH₂)₄-, CH₃-CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- or HC=CCH₂-; R₂ is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H, CH₃, C^- CH₂- or HC=CCH₂- .

An even more preferred use employs the above compound wherein R, is CH₃,

CH₃-CHOH-(CH₂)₄-, CH₃-C(OH)(CH₃HCH₂)₄-, (CH₃)₂-COH-(CH₂)₄- or CH₃-CO- (CH₂)₄-; R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H or CH₃.. A still further preferred use is the compound with the above structure, wherein Ri is CH₃- CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃.

In an additional embodiment, the present invention provides the use of an effective amount of a compound having the structure:

wherein R_j R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, CgH_j^CH^.-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, for inhibiting interleukin-8 elaboration in a human subject.

A preferred use of the above compound employs the above structure, wherein

R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃.C(OH)(CH₃)-(CH₂)₄-, (CH₃)-,-COH-(CH₂)₄-, CH₃-CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- or HC=CCH₂-; R₂ is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H, CH₃, C₆H₅- CH₂- or HC=CCH₂- .

An even more preferred use employs the above compound wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃-C(OH)(CH₃MCH₂)₄-, (CH₃)₂-COH-(CH₂)₄- or CH₃-CO- (CH₂)₄-; R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H or CH₃. A still further preferred use is the compound with the above structure, wherein K. is CH₃- CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃.

In another embodiment, the present invention provides a pharmaceutical composition for alleviating a symptom of an upper respiratory viral infection, comprising an effective amount of a compound having the structure:

wherein Rj R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =0, alkene, alkyne, C₆H_s-(CH₂)_a-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, in a pharmaceutically acceptable nasal spray carrier.

A preferred form of the above compound is the above structure, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-,

(CH₃)₂-COH-(CH₂)₄-, CH₃- CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- orHC=CCH₂-; R₂ is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H, CH₃, C^-O or HC=CCH₂- .

An even more preferred form is the above compound, wherein R, is CH₃, CH₃- CHOH-(CH₂)₄-, CH₃-C(OH)(CH₃)-(CH₂)₄-, (CH₃)₂-COH-(CH₂)₄- or CH₃-CO- (CH₂)₄-; R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H or CH₃. A still further preferred form is the compoimd with the above structure, wherein Ri is CH₃- CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃. In another embodiment, the present invention provides a pharmaceutical composition for alleviating a symptom of an upper respiratory viral infection, comprising an effective amount of PFN or an analog thereof in a pharmaceutically acceptable carrier. The carrier can be a nasal spray, for example, a composition comprising compounds typically used for administration through the nares. One example of such a carrier includes a composition comprising sodium chloride, citric add, benzethenium chloride, purified water and sodium hydroxide or hydrochloric acid to pH 5.0. Another example of a carrier can include Dristan* Saline Spray (Whitehall Laboratories, New York, NY), which comprises water, sodium chloride, benzyl alcohol, hydroxypropyl methylcellulose, sodium phosphate, disodium phosphate, benzalkonium chloride and disodium EDT A. The carrier can also include additional compounds which may provide relief from cold symptoms. For example, the carrier may include the compounds of Ponaris (Jamol Laboratories, Emerson, NJ), a nasal mucosal emollient, comprising essential oils of pine, eucalyptus, peppermint, cajeput and cottonseed as iodized organic salts.

The composition can comprise PFN and an analog of PFN, or it can comprise more than one analog of PFN. The composition can also comprise PFN and/or one or more analogs of PFN in combination with other compounds which inhibit elaboration or activity of IL-8 or inhibit elaboration or activity of other proinflammatory cytokines. For example, such compounds may include adrenocorticosteroids, interleukin-4 (IL-4) and inter leukin- 10 (EL-10). The combinations can then be routinely tested for efficacy in the present methods, by the in vitro and in vivo assays described in the Examples.

In the present invention, PFN, an analog of PFN, or a pharmaceutical composition can be administered by topical intranasal administration. As used herein, "topical intranasal administration" means delivery of the PFN into the nose and nasal passages through one or both of the nares and can comprise delivery by a spraying mechanism or droplet mechanism. The PFN or analog thereof may also be administered orally, parenteraUy (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, topically, transdermally, or the like, although topical intranasal administration is typically preferred. The exact amount of such compounds required may vary from subject to subject, depending on the age, weight and general condition of the subject, the severity of the infection that is being treated, the particular compound used, its mode of administration and the like. Thus, it is not possible to specify an exact amount. However, an appropriate amount may be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. Generally, the dosage will approximate that which is typical for the administration of PFN (20). Preferably, the dosage will be in the range of about 1000 mg/day to 1500 mg/day, which can be administered intranasally in smaller doses (e.g., approximately 200-500 mg) several times a day during the course of treatment. Alternatively, a range of dosages between 500 and 1000 mg day can be routinely tested for efficacy given the teachings herein. Administration of PFN, an analog of PFN, or a pharmaceutical composition can be continued for as long as the symptoms persist.

Depending on the intended mode of administration, the compounds of the present invention can be in pharmaceutical compositions in the form of solid, semisolid or liquid dosage forms, such as, for example, tablets, pills, capsules, powders, liquids, suspensions, lotions, sprays, creams, gels, or the like, preferably in unit dosage form suitable for single administration of a precise dose. The compositions will include, as noted above, an effective amount of the selected compound in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc. By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject along with the selected compound without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

For intranasal administration, a nebulizer or aerosolizing apparatus can be used to administer a fluid or powder. For oral administration, fine powders or granules may contain diluting, dispersing, and/or surface active agents, and may be presented in water or in a syrup, in capsules or sachets in the dry state, or in nonaqueous solution or suspension wherein suspending agents may be included, or in a suspension in water or a syrup. Where desirable or necessary, flavoring, preserving, suspending, thickening, or emulsifying agent may be included. Tablets and granules are preferred oral administration forms, and these may be coated.

For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid, pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitol monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art, for example, see Remington's Pharmaceutical Sciences (16).

Parenteral administration, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system, such that a constant dosage level is maintained. See, e.g., U.S. Patent No. 3,710,795, which is incorporated by reference herein.

A mixture of PFN and one or more analogs of PFN, a mixture of analogs of

PFN, or a mixture of PFN and/or one or more analogs of PFN in combination with other compounds which inhibit elaboration or activity of IL-8 or inhibit elaboration or activity of other proinfiammatory cytokines can be administered in the methods described herein.

The present invention is more particularly described in the following examples which are intended as illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art.

EXAMPLES Elaboration of IL-8 in virus-challenged human volunteers

The concentration of cytokines in nasal washes from rhinovirus infected human volunteers was determined in specimens collected from placebo treated subjects who were participating in a clinical trial of symptomatic therapy. In this trial, subjects with a serum neutralizing antibody titer of <1 :4 were challenged with rhinovirus (Hanks strain) on study day 1. Nasal wash specimens were collected at 24 hour intervals for six consecutive days beginning just prior to the virus challenge. Each specimen was diluted 3:1 (v:v) with viral collecting broth consisting of 2% EMEM and antibiotics. On each study day, the subjects were assigned a symptom score of 0-4 corresponding to a severity of " absent," "mild," "moderate," "severe" or "very severe," respectively, for the symptoms of rhinorrhea, nasal obstruction, sneezing, cough, sore throat, malaise, headache and chills. The daily symptom score for each symptom was the symptom severity reported on a given day minus the baseline severity reported for that symptom on day 1, prior to virus challenge. The total daily symptom score was the sum of the daily symptom scores for all symptoms. Volunteers who had a symptom score of at least 6 during the five days following virus challenge and who had either at least three days of rhinorrhea or the subjective impression that they had a cold were considered ill. Volunteers who had the study vims isolated from a nasal wash specimen or who had at least a four-fold rise in neutralizing antibody titer to the study virus were considered infected.

Nineteen human volunteer subjects were challenged with rhinovirus and treated with placebo in the clinical trial. Fifteen (79%) of the 19 were both infected and ill. Nine (60%) of the 15 subjects had detectable IL-8 in nasal wash prior to virus challenge, 14 (93%) of 15 had IL-8 in nasal washes collected on study days 3, 4 and 5. The mean (± SD) IL-8 concentration on day 3 was 795 ± 877 pg ml compared to 312 ± 507 pg/ml in washes collected before virus challenge on day 1 (p=0.01). There was only one infected subject who did not meet criteria for illness among the placebo treated subjects in this study. This subject had IL-8 concentrations of 0, 0, 0, 7, 441, and 151 pg/ml in nasal washes collected on study days 1-6, respectively.

Elaboration of IL-8 by virus-infected fibroblast cells

Human embryonic lung fibroblast cells (MRC-5) (ATCC Accession No. CCL- 171) (BioWhittaker, Walkersville, Maryland) were used at passages 20-25. Cells were grown in 24-well cell culture plates in Eagle's minimum essential medium (EMEM) supplemented with 10% fetal bovine serum, vancomycin (20 μg/ml), gentamicin (20 μg/ml) and amphotericin B (2 μg/ml). When the cells were confluent they were changed to maintenance medium (EMEM with 2% fetal bovine serum and antibiotics) and used within three days. The cells were inoculated with rhinovirus, type 39 (RV39) (ATCC Accession No. VR-340) in 0.5 ml of media (MOI=10 TdD₅₀/cell), and incubated at 33 °C in a 5% CO₂ atmosphere for one hour. The wells were then washed X3 with 2% EMEM and the cells were fed with 2 ml of 2% EMEM. One milliliter aliquots were removed at the specified time periods for the cytokine assays and replaced with fresh media. Cell monolayers handled in an identical fashion, except that they were sham inoculated, were used as uninfected controls. Experiments involving rhinovirus, type 2 (RV2) (ATCC Accession No. VR-482) and coronavirus 229E (ATCC Accession No. VR-740) were performed in a similar manner.

Four hours after challenge of human embryonic lung fibroblast cells with RV39, the IL-8 concentration in the media was 2022 ± 1142 pg/ml (mean ± SD), compared with 431 ± 453 pg/ml in media from control cells (p<0.0001). Similar results were seen in fibroblast cells challenged with RV2 or coronavirus 229E. The EL-8 concentration in media collected six hours after fibroblast cells were challenged with RV2 was 446 ± 179 pg/ml compared with 229 ± 220 pg/ml in media from control cells (p=0.05). The IL-8 concentration in media from cells challenged with coronavirus 229E was 892 ± 487 pg/ml compared with 302 ± 179 pg/ml in media from control cells (p=0.01). After 24 hours of incubation in this experiment, the RV39, coronavirus 229E and control media contained 16.2 ± 6.3, 13.3 ± 1.7, and 4.6 ± 1.7 ng/ml of IL-8, respectively.

Elaboration of IL-8 in virus-challenged human adenoid tissue

Adenoids removed for surgical indications were transported to the laboratory in cold saline. After warming to room temperature, the adenoid was examined under a dissecting microscope for functioning cilia. If visibly beating cilia were observed, the epithelial surfaces of the adenoid were cut into fragments approximately 5 X 5 mm that were then placed into the wells of a 24- well tissue culture plate and covered with 1 ml of 10% EMEM with antibiotics. The adenoid explants were used for experiments within 24 hours. For all experiments adenoid explants from the same adenoid were paired for virus challenge and control. RV39 was added to the wells containing the explants to be challenged with virus such that the final concentration of virus was 10 TCID₅₀/well in 2 ml of media. The plates were then incubated at 33 °C for 30 minutes. The medium was then removed from the well and the explant washed with three changes of medium and the medium was replaced with 2 ml of 10% EMEM. One-half miliiliter aliquots were collected from the wells at specified time periods for the cytokine assays and replaced with fresh media.

Virus challenge of human adenoid tissue also resulted in stimulation of IL-8 expression. Two hours after virus inoculation, media from human adenoid tissue challenged with virus contained 2194 ± 898 pg/ml of IL-8 compared with 168 ± 97 pg/ml in media from sham-challenged adenoid tissue (p=0.05). Media collected from sham-challenged adenoid tissue at later time points contained high concentrations of IL-8 that by eight hours after inoculation were equivalent to the IL-8 concentrations in virus-challenged tissue. Purification of rhinovirus

RV39 was purified on metrizimide density gradients as previously described by Abraham and Colonno (14). MRC-5 cell monolayers in 24-well plates were challenged in triplicate with either the purified RV39 (MOI=0.1 TCID₅₀/cell) or sham-challenged with buffer. After incubation at 33 °C for 1.5 hours, the monolayers were washed with PBS three times and the medium was replaced with fresh 2% EMEM. The cell cultures were incubated at 33° C for 24 hours and aliquots of all cell culture supernatants were collected for determination of IL-8 concentration. All virus- challenged cell culture monolayers developed viral cytopathic effect within seven days of the virus challenge.

Fibroblast cells were challenged with RV39 that had been purified on a metrizimide density gradient to confirm that the IL-8 elaborated from the challenged cells was in feet a response specifically to the presence of virus. Media collected from fibroblast cells 24 hours after virus challenge contained 661 ± 30 pg/ml of IL-8 compared with 120 ± 11 pg/ml in control cells.

Cytotoxicity assays

The toxicity of 100 μg ml of PFN to the confluent monolayers of MRC-5 cells was determined by observation of the cells for cytopathic effect and estimates of cell death by trypan blue dye exclusion. The ability of the cells to support rhinovirus replication in the presence of PFN was determined by inoculation of confluent MRC-5 cell monolayers with RV39 (MOI=l TC-D50/cell) in the presence of PFN at concentrations of 0, 50, 100, 150, and 200 μg/ml. Three wells were inoculated at each PFN concentration. After incubation of the virus inoculum with the cells for four hours at 33 °C, the cell monolayers were washed X3 and the medium was replaced with fresh PFN supplemented medium at the appropriate concentrations. At 24, 48 and 72 hours after virus challenge, aliquots of medium were collected for virus titration.

The toxicity of PFN was also determined by assessing the effect of various concentrations of PFN on the growth of MRC-5 cells in culture. The cell growth assays were performed by seeding the wells of five 24-well plates with MRC-5 cells (pass 24) at a concentration of 104 cells/ml of media. After 24 hours of incubation in growth medium at 37°C, triplicate wells in each plate were exposed to PFN at concentrations of 0, 25, 50, 100, 200, 400 μg/ml by incorporating the PFN into the growth media. On days 0, 1, 3, 7, and 10 after incubation with PFN, one 24 well plate was trypsinized and the cell concentration in each well was determined. An identical procedure was followed in a second experiment with the exception that the starting concentration of cells was 105 cells/ml of medium and the cell concentrations were determined on days 0, 1, 2, 6, and 10 after addition of PFN to the medium.

Exposure of MRC-5 cells to 100 μg/ml of PFN had no apparent cytotoxic effect on confluent monolayers. No cytopathic effect was evident in these cells and the cells were >98% viable by trypan blue exclusion after 24, 48 and 72 hours of incubation in the presence of PFN.

Virus growth was also not affected by PFN. The geometric mean virus titer was IO²⁶ TCID₅₀/2O μl in media collected at 24 hours from wells incubated with 0 and 100 μg/ml of PFN and titers were IO^{6 8} and IO⁶⁰ TCID^O μl in media collected at 72 hours from wells incubated with 0 and 100 μg/ml of PFN, respectively. Thus, PFN administered at concentrations which inhibit IL-8 production does not appear to enhance viral replication.

Pentoxifylline did have an apparent inhibitory effect on cell growth. With a starting concentration of IO⁴ cells/ml of media, the cell count at day 10 for cells grown in the presence of 100 μg/ml of PFN was only 43% of the count in control wells. With a starting concentration of 10 cells/ml of media, the cell count at day 10 for cells grown in the presence of 100 μg/ml of PFN was 68% of the control count.

IL-8 production in response to challenge with inactivated virus

To determine whether viral infection of the cell monolayer was necessary for elaboration of IL-8, RV39 was inactivated by exposure to ultraviolet light for one hour. The inactivated virus was then inoculated onto monolayers of MRC-5 cells and incubated at 33 °C. Control monolayers that had been inoculated with infectious virus or with uninfected cell culture medium were handled in an identical manner. At specified time intervals, medium from the experimental and the control monolayers was collected and replaced with fresh medium as described above. All samples were then assayed for cytokines. The adequacy of the viral inactivation was confirmed by the absence of viral cytopathic effect in the challenged monolayers after ten days.

The role of virus replication in the elaboration of IL-8 was determined by comparing the stimulation of IL-8 from fibroblast cells challenged with infectious RV39 with that from cells challenged with UV inactivated virus. After incubation for six hours, the IL-8 concentrations were 1098 ± 255 and 950 ± 266 pg/ml in the media from cells challenged with infectious and inactivated vims, respectively.

Effect of antibody to ϋL-lα or TNF-α on virus-induced IL-8 elaboration

The potential role of interieukin-1 α (IL-1 α) or TNF-α in the elaboration of IL-8 from vims-challenged MRC-5 cells was tested by including goat anti-human IL- 1 α antibody (lot AL02, R&D Systems, Minneapolis, Minnesota) or goat anti-human TNF-α antibody (lot AJl 1, R&D Systems, Minneapolis, Minnesota) in the cell culture medium. Each antibody was diluted 1 : 1000, for a final concentration of antibody of 1 μg/ml, in cell culture medium. Cell monolayers, in triplicate, were washed X3 with maintenance medium and then fed with medium containing antibody to either IL-1 α or TNF-α. The wells were then inoculated with RV39 as described above, incubated at 33 °C for six hours and then the medium was collected for cytokine assays. Triplicate wells with antibody containing medium and cells which were not challenged with vims and wells with cells which were challenged with vims in the absence of antibody were included as controls. Examination of the weUs after seven days of incubation at 33 °C revealed no apparent effect of the HL-lα or TNF-α antibody on vims growth. The possibility that TNF-α or IL-1 α might play an intermediate role in the IL-8 response to viral challenge was examined in two ways. Quantitative assays revealed no detectable IL-lα in the media collected from fibroblast cells 0.5, 1, 2, and 4 hours after vims inoculation or in media collected from adenoid tissue two and four hours after vims inoculation. Similarly, TNF-α could not be detected in media collected from fibroblast cells 0.5, 1, 2, 4, and 8 hours after vims inoculation or in media collected from adenoid tissue 2, 4 and 6 hours after inoculation.

Antibody to IL-1 α or TNF-α had no effect on IL-8 elaboration from fibroblast cells following challenge with RV39. Media collected from cells challenged with rhino vims in the presence of antibody to IL-lα and TNF-α had concentrations of IL-8 of 71.2 ± 10 and 78.4 ± 3 ng/ml respectively. Media from cells challenged in the absence of any antibody had an IL-8 concentration of 78.5 ± 15 ng/ml.

Effect of pentoxifylline on IL-8 elaboration

Seven experiments were done on confluent monolayers of MRC-5 cells in 24- well plates. One set of wells in each experiment was incubated at 37° with maintenance medium containing 100 μg/ml of PFN for 24 hours before inoculation with RV39 while the control wells were incubated in fresh maintenance medium with no added PFN. Following this incubation, the medium was removed from all wells and replaced with either PFN-supplemented medium or control medium containing RV39 (MOI=10 TC-D_jo/cell). The cells were incubated in the presence of RV39 for one hour at 33 °C, the monolayers were washed X3 and then the medium was replaced with either PFN-supplemented or control medium as appropriate. Aliquots of medium from all wells were collected four hours after the monolayers were washed (five hours after vims challenge) for determination of IL-8 concentrations. In five of the experiments, the effect of exposure of the cells to PFN coincident with the vims challenge was tested in a third set of wells that were preincubated with control maintenance medium but had PFN-supplemented medium used for all subsequent steps. Each experiment included a minimum of three replicates. Pentoxifylline, at a concentration of 100 μg/ml, significantly reduced the elaboration of IL-8 by MRC-5 cells. This effect was seen on both RV39-induced and constitutive production of IL-8 (Table 1). The effect of PFN added coincident with the vims challenge was similar to that of preincubation of the cells with PFN.

Effect of the combination of PFN with interferon α-2b (IFN)

The effect of the combination of PFN with interferon α-2b (IFN) was also determined in confluent monolayers of MRC-5 cells in 24-well plates. The two drugs were studied in a checkerboard assay using concentrations of IFN of 0, 0.25, 0.5, and 1 U/ml and concentrations of PFN of 0, 12.5, 25, 50, 100, and 200 μg/ml. The appropriate concentrations of the PFN and IFN were added, each well was challenged with RV39 (MOI=10 TdD₅₀ cell), and the plates were incubated at 33 °C. After incubation for six hours, an aliquot of medium was collected from each well for determination of IL-8 concentration. After incubation for 24 hours the medium was collected from the wells for vims titration and the cells were fed with fresh medium and observed daily for seven days for the development of viral cytopathic effect.

The addition of IFN to PFN had no synergistic or additive effect on the inhibition of IL-8 elaboration from rhinovirus-challenged MRC-5 cells.

Virus titrations

All vims titrations were done in 96-well microtiter plates (Falcon Labware, Oxnard, California). Serial 10-fold dilutions of each specimen were made and then 2 x IO⁴ MRC-5 cells were added to each well. The plates were incubated at 33 °C for seven days and then examined for viral cytopathic effect. The vims titers were calculated by the method of Reed and Muench (13).

Cytokine assays

The IL-8, TNF-α and IL-1 α concentrations in the cell culture supernatants were determined by ELISA using commercially available assays (R&D Systems,

Minneapolis, Minnesota). All assays were done in duplicate on an automated spectro- photometric plate reader (Anthos HT11, Anthos Labtec Instruments Co., Salzburg, Germany).

Statistics The mean IL-8 concentrations in medium from RV39-challenged MRC-5 cells and controls were compared by a two-sided paired t test. Samples from RV2- challenged and coronavirus 229E-challenged cells and controls and from human subjects on different days were compared by a two-sided Mann-Whitney U test. IL-8 concentrations in paired specimens from RV39-challenged adenoid explants and controls were compared by the Wilcoxon Signed Rank test. All statistical calculations were performed using commercial software (NWA Statpak; Northwest Analytical, Inc., Portland, OR). The effect of pentoxifylline on rhinovims-induced IL-8 elaboration was compared to control by the Wilcoxon Rank Sum test. Statistical calculations were performed with commercial software (NWA Statpak; Northwest Analytical, Inc., Portland, Oregon).

Administration of PFN to human subjects manifesting a symptom of an upper respiratory viral infection

In a clinical setting, for the purpose of alleviating a symptom of an upper respiratory viral infection, between 1000 mg and 1500 mg of PFN is administered per day intranasally upon manifestation of a symptom to be treated. Administration of PFN is continued for as long as the symptom to be treated persists. More specifically, a dose of PFN of approximately 300 to 400 mg is administered to human subjects intranasally three times a day. The subject is monitored for symptom severity and improvement in a scoring protocol such as that described above. For example, alleviation of a symptom of an upper respiratory infection can be indicated by a reduction in one or more of the symptom scores. For subjects whose condition improves at 300 to 400 mg three times a day, no increase in dosage is necessary. For those subjects not showing clinical improvement at this dosage, more PFN can be administered. In any case, the dose should not exceed a level at which symptoms of toxicity arise, such as localized inflammation (e.g., redness and swelling) or nausea. If, at any dose, a subject exhibits symptoms of toxicity, the dosage is simply decreased below toxic levels and evaluated for efficacy in alleviating symptoms of an upper respiratory viral infection.

To determine a minimum toxic dose, the amount of PFN administered is increased in a stepwise manner until symptoms of toxicity are manifested, such as localized inflammation and nausea.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

Although the present process has been described with reference to specific details of certain embodiments thereof) it is not intended that such details should be regarded as limitations upon the scope of the invention except as and to the extent that they are included in the accompanying claims.

Table 1. Effect of PFN on IL-8 elaboration

Cell Culture Medium MRC-5 Cells Challenged with:

Pre-challenge Post-Challenge RV39 Control

EMEM-PFN^* EMEM-PFN 858 ± 324** 52 ± 59

EMEM EMEM-PFN 1012 ± 317 172 ± 303

EMEM EMEM 2166 ± 1064 449 ± 418

Cell culture maintenance medium with 100 μg/ml of PFN IL-8 concentration (pg/ml), mean ± SD

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12. Turner, RB. 1988. Rhinovirus infection of human embryonic lung fibroblasts induces the production of a chemoattractant for polymorphonuclear leukocytes. J Infect Dis 157:346-350.

13. Reed, L.J., and H. Muench. 1938. A simple method of estimating fifty per cent endpoints. Am J Hygiene 27:493-497.

14. Abraham, G., and RJ. Colonno. 1984. Many rhinovirus serotypes share the same cellular receptor. J Virol 51 :340-345.

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Claims

What is claimed is:

1. A method of alleviating a symptom of an upper respiratory viral infection in a subject, comprising administering to the subject an effective amount of a compound having the structure:

wherein Ri R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =0, alkene, alkyne, C₆H_S-(CH _Λ-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl.

2. The method of claim 1, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH_j. C(OH)(CH^(CH₂)₄-, (CH₃)₂-COH-(CH2)₄-, CH₃-CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- or HC=CCH₂-; R₂ is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂- CH₂-, CH₃-CH₂-O-CH₂-, H, CH₃, C l₅-CH₂- or HC=CCH₂- .

3. The method of claim 1, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃- C(OH)(CH₃)-(CH₂)₄-, (CH₃)2-COH-(CH₂)₄- or CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H or CH₃.

4. The method of claim 1, wherein R_j is CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃.

5. The method of claim 4, wherein the upper respiratory viral infection is a rhino vims infection.

6. The method of claim 4, wherein the administration is by topical nasal administration.

7. A method of inhibiting interleukin-8 elaboration in a subject comprising administering to the subject an effective amount of a compound having the structure:

wherein Ri R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C₆H₅-(CH₂)_β-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl.

8. The method of claim 7, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃. C(0HXCH_J)-(CH₂)₄-, (CH₃)₂-COH-(CH₂)₄-, CH₃-CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- or HC=CCH₂-; R₂ is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂- CH₂-, CH₃-CH₂-O-CH₂-, H, CH₃, C₆H₅-CH₂- or HC=CCH₂- .

9. The method of claim 7, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃- C(OH)(CH₃MCH₂)₄-, (CH^-COH CH_j or CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H or CH₃.

10. The method of claim 7, wherein R, is CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃.

11. A pharmaceutical composition for alleviating a symptom of an upper respiratory viral infection, comprising an effective amount of pentoxifylline or analog thereof in a pharmaceutically acceptable nasal spray carrier.

12. The use of an effective amount of a compound having the structure:

wherein R, a and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C₆H₅-(CH₂)_a-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, in the manufacture of a medicament for the treatment of a symptom of an upper respiratory viral infection in a human subject.

13. The use of an effective amount of a compound having the structure:

wherein Ri R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and or =O, alkene, alkyne, C₆H₅-(CH₂)_β-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, in the manufacture of a medicament for inhibiting interleukin-8 elaboration in a human subject.

14. The use of an effective amount of a compound having the structure:

wherein R_j R-> and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C^^CH^,-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, for the treatment of a symptom of an upper respiratory viral infection in a human subject.

15. The use of an effective amount of a compound having the structure.

wherein R, R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C₆H₅-(CH₂)_a-, wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, for inhibiting interleukin-8 elaboration in a human subject.

16. A pharmaceutical composition for alleviating a symptom of an upper respiratory viral infection, comprising an effective amount of a compound having the structure:

wherein R_j R₂ and R₃ are independently hydrogen, alkyl, unsubstituted or substituted with hydroxy and/or =O, alkene, alkyne, C₆H_s-(CR _Λ-_t wherein a is an integer of from 0 to 6 or lower alkyl-O-lower alkyl, in a pharmaceutically acceptable nasal spray carrier.

17. Claim 12, 13, 14, 15 or 16, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CHa. C(OH)(CH₃)-(CH₂)₄-, (CH₃)₂-COH-(CH₂)₄-, CH₃-CO-(CH₂)₄-, H, CH₃-CH₂-CH₂- or HC=CCH₂-; R₂ is CH₃, CH₃-CH₂-CH₂-, isobutyl- or HC=CCH₂-; and R₃ is CH₃-CH₂- CH₂-, CH₃-CH₂-O-CH₂-, H, CH₃, C^-CH_j- or HC=CCH₂- .

18. Claim 12, 13, 14, 15 or 16, wherein R, is CH₃, CH₃-CHOH-(CH₂)₄-, CH₃- C(OH)(CH₃)-(CH₂)₄-, (CH₃)₂-COH-(CH₂)₄- or CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃-CH₂-CH₂-, CH₃-CH₂-O-CH₂-, H or CH₃.

19. Claim 12, 13, 14, 15, or 16, wherein K. is CH₃-CO-(CH₂)₄-; R₂ is CH₃; and R₃ is CH₃.

20. Claim 12, 14 or 16, wherein the upper respiratory viral infection is a rhinovims infection.