WO2004112795A1

WO2004112795A1 - Ltb4 compositions for treating tract infections

Info

Publication number: WO2004112795A1
Application number: PCT/CA2004/000910
Authority: WO
Inventors: Jean Gosselin; Louis Flamand; Pierre Borgeat
Original assignee: Ltb4 Sweden Ab
Priority date: 2003-06-25
Filing date: 2004-06-18
Publication date: 2004-12-29

Abstract

The present invention relates to leukotriene B4 (LTB4) intra-respiratory tract compositions and to the uses of leukotriene B4 (LTB4) intra-respiratory administration for the treatment and/or prophylaxis of respiratory tract infection.

Description

LTB4 COMPOSITIONS FOR TREATING RESPIRATORY TRACT INFECTIONS

BACKGROUND OF THE INVENTION (a) Field ofthe Invention

The invention relates to leukotriene B4 (LTB4) intra-respiratory tract compositions and to the uses of leukotriene B4 (LTB4) intra-respiratory administration for the treatment and/or prophylaxis of respiratory tract infection, (b) Description of Prior Art Many important infectious diseases afflicting mankind are caused by viruses. Some are important because they are frequently fatal; among such are rabies, smallpox, poliomyelitis, hepatitis, yellow fever, immune deficiencies and various encephalitic diseases. Others are also important because they are very contagious and create acute discomfort such as influenza, measles, mumps and chickenpox, as well as respiratory-gastrointestinal disorders. Others such as rubella and cytomegalovirus can cause congenital abnormalities. Finally, there are viruses, known as oncoviruses, that can cause tumors and cancer in humans and animals.

Primary viral infections are often associated with a viremic phase in the blood, which distributes viruses to most organs ofthe body. Certain viral infections however, have a much more restricted infected tissue distribution with viral replication taking place in one or a few selected tissues. One organ that is often the site of viral infections is the lung. The lungs, as they are in continuously exposed to the outside world through the air we inhale, represent a major entry point for infectious agents, including viruses. The lung tissue relies on a variety of effector mechanisms that help clear the infectious invaders. Such mechanisms are made up of physical barriers such as mucus secretion and by the antimicrobial activity of specialized cells of the immune system, the alveolar macrophages (AM). AM patrol the alveolar surface in search of pathogens that they engulf and destroy. In the majority of cases, the infections are efficiently controlled and the host makes a successful recovery. Unfortunately, impairment of these defenses can compromise viral clearance and predispose to pneumonia. Significance of Viral Pneumonia

Respiratory viral infections have a major impact on health. Acute respiratory illnesses, caused largely by viruses, are the most common illnesses experienced by otherwise healthy adults and children. Data from the USA suggest that such illnesses are experienced at a rate of 85.6 illnesses per 100 persons per year and account for 54% of all acute conditions exclusive of injuries (Department of Health and Human Services. 1994. Current estimates form the National Health Interview Survey, 1992. DHHS publication (PHS) 94-1517 ed. Department of Health and Human Services, Hyattsville, MD.). Forty-four % of these illnesses require medical attention and result in 287 days of restricted activity, 94.4 days lost from work, and 182 days lost from school per 100 persons per year.

Acute respiratory infection is a major cause of childhood mortality in developing countries and it is estimated that 4.5 million children younger than 5 years of age die annually from acute respiratory infections (Berman, S. 1991, Rev. Infect. Dis. 13:S454-S462). In healthy adults, viral infections account for approximately 8% of acute pneumonia cases with the majority of cases associated with Influenza virus infection. Individuals with diminished host immunity may develop severe, life-threatening pulmonary infections from the entire spectrum of RNA and DNA viruses, including viruses that typically cause lower respiratory tract diseases in normal and immunocompromised hosts. For example, infections by cytomegalovirus (CMV), a DNA herpesvirus, cause severe pneumonitis in immunocompromised individuals, particularly transplant recipients. Other Herpesviruses such as Herpes simplex and Varicella-zoster viruses are also an important cause of pneumonia. RNA viruses have also received increasing recognition as significant causes of morbidity and mortality in immunocompromised individuals, with respiratory syncytial virus (RSV) infections being the most common (Sable, CA. and F.G. Hayden. 1995, Infect. Transplant. 9: 987-1003). Another RNA virus that is gaining increasing medical attention is the coronavirus (CoV) associated with the Severe Acute Respiratory Syndrome (SARS) (SARS-CoN). Infection with SARS-CoN is usually characterized by fever, followed a few days later by a dry, non-productive cough and shortness of breath. Death from progressive respiratory failure occurs in about 3% to nearly 10% of cases. Besides SARS-CoV, human coronaviruses (HcoV) are responsible for approximately 30% of mild upper respiratory tract illnesses. Current Therapy

Therapy of viral pneumonia is dependent on the severity of disease, the age and immune status of the host, and the specific causative viral agent. A number of therapeutic agents are available for the treatment of influenza virus infection, including the M2 inhibitors amantadine and rimantadine and the neurammidase inhibitors zanamivir and oseltamivir. The only option available for the other RNA viruses is ribavirin, but there is little evidence of efficacy of this agent for treating established viral pneumonia. Pneumonia associated with herpesvirus infection can be treated with nucleoside analogues (acyclovir, ganciclovir) or non-nucleoside viral DNA polymerase inhibitor such as foscarnet. Although recent years have witnessed a significant increase in the spectrum and potency of available agents, drug therapy of viral pneumonia remains burdened by the toxicity of drugs, the development of antiviral resistance, and the complex pathogenesis of many viral syndromes in which viral replication is only part of the disease process. What is needed is a means for enhancing pulmonary defense capabilities that either requires no antiviral drugs or can be used to augment antiviral treatment. The enhancement means should be efficacious in the treatment and prevention of viral respiratory infections in those patients who are especially susceptible thereto, should have a rapid onset of action, and should not elicit imniunological reactions in the recipients. It would be highly desirable to be provided with leukotriene B4 (LTB4) intra-respiratory tract compositions and to the uses of leukotriene B4 (LTB4) intra- respiratory administration for the treatment and/or prophylaxis of respiratory tract infection. SUMMARY OF THE INVENTION

One aim of the present invention is to provide leukotriene B4 ( TB4) intra-respiratory tract compositions and to the uses of leukotriene B4 (LTB4) intra- respiratory administration for the treatment and/or prophylaxis of respiratory tract infection. hi accordance with one aspect ofthe invention there is provided the use of an intra-respiratory tract administration of a leukotriene B4 (LTB4) agent for the treatment and/or prophylaxis of a respiratory tract infection in a patient, wherein the leukotriene B4 (LTB4) agent is in association with a pharmacologically acceptable carrier for administration into the respiratory tract.

In accordance with another aspect of the invention there is provided an intra-respiratory tract pharmaceutical composition for the treatment and/or prophylaxis of a respiratory tract infection in a patient, comprising a therapeutically effective amount of a LTB4 agent, in association with a pharmaceutically acceptable carrier for administration into the respiratory tract.

The respiratory tract infection may be caused by a virus. Such a virus includes, without limitation, coronaviridae (a family of virus causing Severe Acute Respiratory Syndrome (SARS)), orthomyxoviridae (for example, influenza types A and B), paramyxoviridae (for example, para-influenza types 1, 2 and 3, respiratory syncytial virus and measles virus), picornaviridae (for example, rhmovirus and enterovirus), adenoviridae et herpesviridae (for example, cytomegalo virus).

The term "patient" is intended to mean any mammal, preferably a human.

The expression "intra-respiratory tract administration" is intended to mean any administration route for delivery of a pharmaceutically effective amount of leukotriene B4 (LTB4) agent to the upper, middle and lower airways, including, without limitation, intranasally, intrarespiratory, and by inhalation. Suitable pharmaceutically acceptable carriers for such intra-respiratory tract administration are described in US patent No. 5,190,029 issued on March 2, 1993 in the names of Byron et al., the content of which is hereby incorporated by reference. The preferred LTB agent is leukotriene B4[5S,12R-6,8,10,14- (Z,E,E,Z)-eicosatetraenoic acid]. hi accordance with another aspect of the invention, LTB4 agent is administered in association with one or several different antiviral agents, such as but not restricted to interferon-α, -β, -γ, tumor necrosis factor , ganciclovir, acyclovir, vidarabine, idoxuridine, famciclovir, 3TC, crixivan, nevarepine, prostaglandins, prostaglandin analogs and AZT, amantadine, rimantadine, ribavirin, zanamivir and oseltamivir.

The term "LTB4 agent" includes, without limitation, any of the following:

LTB4, 14,15-dihydro-LTB₄, . 17,18-dehydro-LTB₄, 19-hydroxy-LTB , 20-hydroxy-LTB4 and 5(R)-hydroxy, 5-keto, 5(S)hydroperoxy, 5(R)-hydroperoxy and 5-deoxy analogs thereof; leukotriene A4 ("LTA4¹'); 14,15-dihydro-LTA4, 17,18-dehydro-LTA4; 5(S)-hydroxy-6,8,l l,14(E,Z,Z,Z)-eicosatetraenoic acid ("5-HETE"), 14,15-dihydro-5-HETE, 17,18-dehydro-5-HETE, and 5(R)-hydroxy, 5-keto, 5(S)-hydroperoxy, 5(R)-hydroperoxy analogs thereof; 12(R)-hydroxy- 5,8,10,14(Z,Z,E,Z)-eicosatetraenoic acid ("12-HETE"), 5,6-dihydro-12-HETE, 14,15-dihydro-12-HETE, 17,18-dehydro-12-HETE and 12(S)-hydroxy, 12-keto, 12(S)-hydroperoxy and 12(R)-hydroperoxy analogs thereof; and 12-oxo- 5,8,10(Z,Z,E)-dodecatrienoic acid, 15(S)-hydroxy-5,8,l l,13(Z,Z,Z,E)- eicosatetraenoic acid ("15-HETE"), 5,6- dihydro-15-HETE, 17,18-dehydro-15- HETE and 15(R)-hydroxy, 15-keto, 15(S)-hydroperoxy, and 15(R)-hydroperoxy analogs thereof; 12(S)-hydroxy-5,8,10(Z,E,E)-heptadecatrienoic acid; leukotrienes C4, D4 and E4 and 14,15-dihydro or 17,18-dehydro analogs thereof; N-acyl or N- alkyl derivatives of leukotrienes C4, D4 and E4, and 14,15-dihydro or 17,18- dehydro analogs thereof; 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid, isomers thereof and 14,15-dihydro or 17,18-dehydro analogs thereof; 5,6-dihydroxy- 7,9,11,14-eicosatetraenoic acid, isomers thereof and 14,15-dihydro or 17,18- dehydro analogs thereof; 5,15-dihydroxy-6,8,ll,13-eicosatetraenoic acid, 5(S),15(S)-dihydroxy-6,8,10,13(E,Z,Z,E)-eicosatetraenoic acid, isomers thereof and 17,18-dehydro analogs thereof; 8-hydroxy-ll(12)-epoxy-5,9,14-eicosatrienoic acid, hepoxilin A3₅ isomers thereof and 5,6-dihydro or 14,15-dihydro or 17,18- dehydro analogs thereof; 10-hydroxy-ll(12)-epoxy-5,8,14-eicosatrienoic acid, hepoxilin B3, isomers thereof and 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs thereof; 8,ll,12-trihydroxy-5,9,14-eicosatrienoic acid, trioxilin A3₅ isomers thereof and 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs thereof; 10,ll,12-trihydroxy-5,8,14-eicosatrienoic acid, trioxilin B3, isomers thereof and 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs thereof; ll(12)-epoxy-5,7,9,14-eicosatetraenoic acid, isomers thereof and 14,15-dihydro or 17,18-dehydro analogs thereof; l l,12-dihydroxy-5,7,9,14-eicosatetraenoic acid, isomers thereof and 14,15-dihydro or 17,18-dehydro analogs thereof; 8(9)-epoxy- 5,10,12,14-eicosatetraenoic acid, isomers thereof and 5,6-dihydro or 17,18-dehydro analogs thereof; 8,9-dihydroxy-5,10,12,14-eicosatetraenoic acid, isomers thereof and 5,6-dihydro or 17,18-dehydro analogs thereof; 8,15-dihydroxy-5,9,ll,13- eicosatetraenoic acid, isomers thereof and 5,6-dihydro or 17,18-dehydro analogs thereof; 14(15)-epoxy-5,8,10,12-eicosatetraenoic acid, isomers thereof and 5,6- dihydro or 17,18-dehydro analogs thereof; 14,15-dihydroxy-5,8,10,12- eicosatetraenoic acid, isomers thereof and 5,6-dihydro or 17,18-dehydro analogs thereof; 5-hydroxy-14(15)-epoxy-6,8,10,12-eicosatetraenoic acid, isomers thereof and 17,18-dehydro analogs thereof; 5,14,15-trihydroxy-6,8,10,12-eicosatetraenoic acid, lipoxin B4, isomers thereof and 17,18-dehydro analogs thereof; 5,6,15- trihydroxy-7,9,11,13 -eicosatetraenoic acid, lipoxin A4, isomers thereof and 17,18- dehydro analogs thereof; 5(6)-epoxy-15-hydroxy-7,9,l l,13-eicosatetraenoic acid, isomers thereof and 17,18-dehydro analogs thereof; 5-hydroxy-6,8, 11,14- eicosatetraenoic acid, isomers thereof and 14,15-dihydro or 17,18-dehydro analogs thereof; 8-hydroxy-5,9,l l,14-eicosatetraenoic acid, isomers thereof and 5,6- dihydro or 14,15-dihydro or 17,18-dehydro analogs thereof; 9-hydroxy-5,7, 11,14- eicosatetraenoic acid, isomers thereof and 14,15-dihydro or 17,18-dehydro analogs thereof; ll-hydroxy-5,8,12,14-eicosatetraenoic acid, isomers thereof and 5,6- dihydrό or 17,18-dehydro analogs thereof; 12-hydroxy-5,8,10,14-eicosatetraenoic ^■ 1

acid, isomers thereof and 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs thereof; 15-hydroxy-5,8,ll,13-eicosatetraenoic acid, isomers thereof and 5,6- dihydro or 17,18-dehydro analogs thereof; 9-hydroxy-10,12-octadecadienoic acid and isomers thereof; 13-hydroxy-9,ll-octadecadienoic acid and isomers thereof; 12(R)-hydroxy-5,8,14(Z,Z,Z)-eicosatrienoic acid and isomers thereof; 5(6)oxido- or 5,6-dihydroxy-8,ll,14-eicosatrienoic acid, isomers thereof and 14,15-dihydro or 17,18-dehydro analogs thereof; 8(9)-oxido- or 8,9-dihydroxy-5, 11,14- eicosatrienoic acid, isomers thereof and 5,6-dihydro or 14,15-dihydro or 17,18- dehydro analogs thereof; ll(12)-oxido- or ll,12-dihydroxy-5,8,14-eicosatrienoic acid, isomers thereof and 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs thereof; 14(15)-oxido- or 14,15-dihydroxy-5,8,l l-eicosatrienoic acid, isomers thereof and 5,6-dihydro or 17,18-dehydro analogs thereof; 20,20,20- trifluoromethyl-LTB4; 19-methyl-LTB4, 19,19-dimethyl-LTB4, 19-fluoro-LTB4, 19,19-difluoro-LTB4, 18,20-difluro-LTB4, 20-fluoro-LTB4; 3-thio-LTB4, 3-hydroxy-LTB4, 3-methyl-LTB4, 3,3-dimethyl-LTB4, 3-fluoro-LTB4, 3,3- difluoro-LTB4, 2,3-difluoro-LTB4, LTB4 methylsulfonylamide, LTB4 methylamide, 1-tetrazide LTB4; sodium or potassium salts ofthe LTB4 agent; and ester or ether derivatives ofthe LTB4 agent; and isomers and analogs thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates the effects of intranasal administration of LTB4 on pulmonary CMV viral loads infection in lungs of mice; following intranasal CMV infection of mice.

Fig. 2 illustrates the effects of intravenous administration of LTB4 on pulmonary CMV viral loads infection in lungs of mice; following intravenous CMV infection of mice.

Fig. 3 illustrates the effects of intranasal administration of LTB4 on influenza infection in lungs of mice. DETAILED DESCRIPTION OF THE INVENTION i) LTB₄

The leukotriene B4 (LTB4) agent of the present invention is either LTB4 or certain structurally related polyunsaturated fatty acids, or substances structurally unrelated to fatty acids, which stimulate the synthesis of LTB4 or other LTB4 agents by cells, or mimic their biological activity. They are either natural substances or analogs of such natural substances. All of the LTB4 agents can be obtained by chemical synthesis by methods described in the literature and most are commercially available. As used herein, the term "LTB4 agent" means one or more of the following polyunsaturated fatty acids, which in addition to LTB4 itself, are analogs of LTB4, or precursors or metabolites of LTB4 or LTB4 analogs: LTB4, 14,15-dihydro-LTB4, 17,18-dehydro-LTB4, 19-hydroxy-LTB4, 20-hydroxy-LTB and their 5(R)-hydroxy, 5-keto, 5(S)hydroperoxy, 5(R)-hydroperoxy and 5-deoxy analogs; LTA4; 14,15-dihydro-LTA , 17,18-dehydro-LTA ; 5(S)-hydroxy- 6,8,1 l,14(E,Z,Z,Z)-eicosatetraenoic acid ("5-HETE"), 14,15-dihydro-5-HETE, 17,18-dehydro-5-HETE, and their 5(R)-hydroxy, 5-keto, 5(S)-hydroperoxy, 5(R)- hydroperoxy analogs; 12(R)-hydroxy-5,8,10,14(Z,Z,E,Z)-eicosatetraenoic acid ("12-HETE"), 5,6-dihydro-12-HETE, 14,15-dihydro-12-HETE, 17,18- dehydro- 12-HETE and their 12(S)-hydroxy, 12-keto, 12(S)-hydroρeroxy and 12(R)-hydroperoxy analogs and 12-oxo-5,8,10(Z,Z,E)-dodecatrienoic acid, 15(S)- hydroxy-5,8,ll,13(Z,Z,Z,E)-eicosatetraenoic acid ("15-HETE"), 5,6- dihydro-15- HETE, 17,18-dehydro-15-HETE and their 15(R)-hydroxy, 15-keto, 15(S)- hydroperoxy, and 15(R)-hydroperoxy analogs. The term LTB4 agent also includes other derivatives of polyunsaturated fatty acids; some are derived from the cyclooxygenase pathways, the lipoxygenase pathways (5-, 12- and 15-lipoxygenases) or the cytochrome P450 pathways; others are isomers, analogs or derivatives of naturally formed compounds: 12(S)-hydroxy- 5,8,10(Z,E,E)-heptadecatrienoic acid; leukotrienes C4, D4 and E4 and their 14,15- dihydro or 17,18-dehydro analogs; N-acyl or N-alkyl derivatives of leukotrienes C4, D4 and E4, and their 14,15-dihydro or 17,18-dehydro analogs; all isomeric 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acids and their 14,15-dihydro or 17,18- dehydro analogs; all isomeric 5,6-dihydroxy-7,9,l l,14-eicosatetraenoic acids and their 14,15-dihydro or 17,18-dehydro analogs; all isomeric 5,15-dihydroxy- 6,8,11,13 -eicosatetraenoic acids (including 5(S),15(S)-dihydroxy-

6,8,10,13(E,Z,Z,E)-eicosatetraenoic acid) and their 17,18-dehydro analogs; all isomeric 8-hydroxy-ll(12)-epoxy-5,9,14-eicosatrienoic acids (including hepoxilin A3) and their 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs; all isomeric 10-hydroxy-l l(12)-epoxy-5,8,14-eicosatrienoic acids (including hepoxilin B3) and their 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs; all isomeric 8,11,12- trihydroxy-5,9,14-eicosatrienoic acids (including trioxilin A3) and their 5,6- dihydro or 14,15-dihydro or 17,18-dehydro analogs; all isomeric 10,11,12- trihydroxy-5,8,14-eicosatrienoic acids (including trioxilin B3) and their 5,6- dihydro or 14,15-dihydro or 17,18-dehydro analogs; all isomeric l l(12)-epoxy- 5,7,9, 14-eicosatetraenoic acids and their 14,15-dihydro or 17,18-dehydro analogs; all isomeric l l,12-dihydroxy-5,7,9, 14-eicosatetraenoic acids and their 14,15- dihydro or 17,18-dehydro analogs; all isomeric 8(9)-epoxy-5, 10,12,14- eicosatetraenoic acids and their 5,6-dihydro or 17,18-dehydro analogs; all isomeric 8,9-dihydroxy-5,l 0,12, 14-eicosatetraenoic acids and their 5,6-dihydro or 17,18- dehydro analogs; all isomeric 8,15-dihydroxy-5,9,l l,13-eicosatetraenoic acids and their 5,6-dihydro or 17,18-dehydro analogs; all isomeric 14(15)-epoxy-5, 8,10,12- eicosatetraenoic acids and their 5,6-dihydro or 17,18-dehydro analogs; all isomeric 14,15-dihydroxy-5,8,10,12-eicosatetraenoic acids and their 5,6-dihydro or 17,18- dehydro analogs; all isomeric 5-hydroxy-14(15)-epoxy-6,8,10,12-eicosatetraenoic acids and their 17,18-dehydro analogs; all isomeric 5,14,15-trihydroxy-6,8,10,12- eicosatetraenoic acids (including lipoxin B4) and their 17,18-dehydro analogs; all isomeric 5,6,15-trihydroxy-7,9,ll,13-eicosatetraenoic acids (including lipoxin A4) and their 17,18-dehydro analogs; all isomeric 5(6)-epoxy-15-hydroxy-7,9,ll,13- eicosatetraenoic acids and their 17,18-dehydro analogs; all isomeric 5-hydroxy- 6,8,11, 14-eicosatetraenoic acids and their 14,15-dihydro or 17,18-dehydro analogs; all isomeric 8-hydroxy-5,9,ll, 14-eicosatetraenoic acids and their 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs; all isomeric 9-hydroxy-5,7, 11, 14- eicosatetraenoic acids and their 14,15-dihydro or 17,18-dehydro analogs; all isomeric ll-hydroxy-5,8,12,14-eicosatetraenoic acids and their ^• 5,6-dihydro or 17,18-dehydro analogs; all isomeric 12-hydroxy-5,8,10,14-eicosatetraenoic acids and their 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs; all isomeric 15- hydroxy-5,8,ll,13-eicosatetraenoic acid and their 5,6-dihydro or 17,18-dehydro analogs; all isomeric 9-hydroxy-10,12-octadecadienoic acids; all isomeric 13- hydroxy-9,l l-octadecadienoic acids; 12(R)-hydroxy-5,8,14(Z,Z,Z)-eicosatrienoic acid; all isomeric 5(6)oxido- or 5,6-dihydroxy-8,ll,14-eicosatrienoic acids and their 14,15-dihydro or 17,18-dehydro analogs; all isomeric 8(9)-oxido- or 8,9- dihydroxy-5,ll,14-eicosatrienoic acids and their 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs; all isomeric ll(12)-oxido- or l l,12-dihydroxy-5,8,14- eicosatrienoic acids and their 5,6-dihydro or 14,15-dihydro or 17,18-dehydro analogs; all isomeric 14(15)-oxido- or 14,15-dihydroxy-5,8,ll-eicosatrienoic acids and their 5,6-dihydro or 17,18-dehydro analogs.

The term LTB4 also includes variants which are non-covalently modified fatty acids such as the sodium or the potassium salts Ofthe LTB4 agents. The term LTB4 agent also includes variants where a modification is introduced into the molecule by reacting targeted functional groups ofthe fatty acid with an organic derivatizing agent that is capable of reacting with the selected functional group (yielding for example, ester and ether derivatives of LTB4 agent) or to cause intramolecular rearrangement (such as the formation of lactones with hydroxylated fatty acids). The resulting compounds may have altered biological activity and/or bioavailability. Thus, the covalently modified fatty acid can be a pro-drug with reduced biological activity which upon in vivo administration is slowly transformed into a more active molecule (underivatized LTB4 agent). Variants may also be metabolically stable and biologically active analogs of LTB4 agents altered in a way that will result in retarded disposition of the compound (decreased metabolism and/or elimination). Variants with modifications at the omega end (such as 20,20,20-trifluoromethyl-LTB4) show increased resistance to omega-oxidation (a catabolic process of unsaturated fatty acids); other variants with modification at the omega end at the level of carbons 13 to 20 (such as 19- methyl-LTB₄ or 19,19-dimethyl-LTB₄ or 19-fluoro-LTB₄ or 19,19-difluoro-LTB₄ or 18,20-difluro-LTB4 or 20-fluoro-LTB4) may show increased resistance to omega-oxidation and variants with modifications at the carboxylic end, at the level of carbon 1, 2, 3 or 4 (for example, 3-thio-LTB4, 3-hydroxy-LTB4, 3-methyl-LTB4 or 3,3-dimethyl-LTB4 or 3-fluoro-LTB4 or 3,3-difluoro-LTB4 or 2,3-difluoro- LTB4, LTB4 methylsulfonylamide, LTB4 methylamide, 1-tetrazide LTB4), may show increased metabolic resistance to beta-oxidation and/or to elimination (such as uptake by probenecide-sensitive organic acid transporter). Other variants with modification(s) at carbon 12, such as 12(R)-methyl-LTB4, may show increased resistance to reduction of the 11,12 double bond (a metabolic pathway of LTB4). Other variants are analogs of LTB4 agents with structural changes, such as changes in chain length (chain length increased or decreased by up to 4 carbons), addition of double bond(s), saturation of double bond(s), changes in double bond(s) geometry (cis to trans or vice versa), change of double bond(s) for triple bond(s), change in the configuration of one or several functional group(s) (R to S or S to R), or where one or several functional group(s) or substituent(s) are either removed, added or changed for other functional groups or substituents (including but not limited to hydroperoxyl, carbonyl, sulfhydryl, sulfoxide, sulfone, cysteinyl, glutathionyl, cysteinyl-glycine, methyl, isopropyl, benzyl, chloro, fluoro), or where the positions of one or several functional groups and/or one or several double bonds has been moved by one, two or three carbons relative to the omega end. The LTB4 agent may be a variant carrying one or several of the above mentioned structural modifications.

The LTB4 agents and variants of LTB4 agents are structurally related to LTB4 and bind or may bind with different affinities to either the cell surface binding sites of LTB4 (or other related eicosanoids, including but not limited to 5- HETE, LTD4, lipoxin A4) present on various leukocytes (and other cell types), or to the nuclear binding site of LTB4, the transcription factor PPARα (peroxisome proliferator-activated receptor alpha) (Devchand P.R., et al., Nature 384:39, 1996), or to other unknown binding sites of LTB4, resulting in the expression of the biological activities of LTB4 and LTB4 agents. The LTB4 agents and variants show or may show biological activities qualitatively similar to that of LTB4 (but may be more or less active than LTB4 itself) and thus can be expected to exert an antiviral activity similar to that of LTB4. The LTB4 agents and variants thereof are included within the scope of this invention.

The teπn LTB4 agent also includes agents not structurally related to LTB4 including but not limited to the chemotactic peptide formyl-met-leu-phe (fMLP) (and analogs such as N-formyl-nle-leu-phe, N-formyl-met-leu-phe- benzylamide, N-formyl-met-leu-phe-methyl-ester and N-formyl-Nle-leu-phe-nle- tyr-lys), the complement fragment C5a and analogs, and the biologically active phospholipid platelet-activating factor, l-0-hexadecyl-2-0-acetyl-sn-glycero-3- phosphό-choline (and analogs such as l-0-octadecyl-2-0-sn-glycero-3- phosphocholine and l-0-hexadecyl-2-N-methyl-carbamyl-sn-glycero-3- phosphocholine) that stimulate or may stimulate the release of unsaturated fatty acids in cells (mainly arachidonic acid) and consequently the formation of one or several LTB4 agents, and may therefore exhibit an antiviral activity similar to that of LTB4. The above-mentioned LTB4 agents not structurally related to LTB4 are thus included within the scope of this invention.

The term LTB4 agent also includes formulations of compounds which might contain a mixture of two or several LTB4 agents or an LTB4 agent and one or several equally or less active isomer(s) of the LTB4 agent (positional, geometrical or optical isomers). ii) Dose Ranges

The therapeutically effective amount of the LTB4 agent to be administered will vary with the particular LTB4 agent used, the type or mode of administration, the concurrent use of other active compounds, host age and size, type, severity and spread of infection, response of individual patients, and the like. In the case of LTB4, it will be administered in doses ranging from about 0.05 μg/kg to about 100 μg/kg as suggested by the doses of LTB4 found to be effective in terms of antiviral activity. An effective dose amount of the LTB4 agent is thus be determined by the clinician after a consideration of all the above-mentioned criteria. In the case of LTB4 agents other than LTB4 which have a different biological activity, the effective dose required may be different, for instance up to 10 mg/kg. iii) Pharmaceutical Compositions

Any suitable intra-respiratory means of administration may be employed for providing an effective dosage of a LTB4 agent of the present invention to the lung of a patient. Dosage forms include powders, solutions, dispersions, suspensions, and aerosols.

The pharmaceutical compositions of the present invention comprise a LTB4 agent as an active ingredient, and a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.

The LTB4 agent may be used in combination with other agents including, but not limited to, antiviral agents.

The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.

EXAMPLE I

Effect of LTB₄ administration on human coronavirus infection in lungs of mice

The antiviral effect of LTB₄ in controlling pneumonia caused by coronavirus was evaluated in an in vivo model using C57BL/6 mice (8 day old).

Mice were infected (n=6/group) intranasally with 10 μl of coronavirus suspension

(10 PFU, strain HCoV-OC43). Twenty-four hours post-infection, mice were treated intranasally with a placebo or with varying doses of LTB₄ (5 ng/dose or 50 ng/dose). Mice were treated once a day during 5 days, and were sacrificed and autopsied on day 6. Lungs of mice were surgically removed and the viral load was titrated on HRT-18 cell line. The results obtained indicate that LTB₄ significantly reduces the number of coronavirus particles in lungs of mice (Table 1).

TABLE 1

Effects of intranasal administration ofLTU₄ on human coronavirus infection in lungs of mice

* PFU/lungs

N.D. = below detection limit of 32 TCTDso/lungs EXAMPLE II

Effect of intranasal administration of LTB on viral loads in the lungs of mice following intranasal CMV infection

To support the role of LTB₄ as agent for the treatment of pulmonary infection, other experiments were performed by infecting airways of mice with CMV. BALB/c mice (6-8 week old) were infected intranasally (n=6/group) with 8.6x10 PFU (Smith strain) of murine CMV. At day 1 post-infection, mice were treated with a placebo or with varying doses of LTB₄ (10 ng/dose and 100 ng/dose) delivered intranasally. Mice were treated once a day during 7 days. On the 8^th day post-infection, mice were sacrificed and CMV viral loads in the lungs were determined by standard plaque assay on murine embryonic fibroblasts. Results presented in Fig. 1 clearly show that LTB significantly causes a reduction of CMV viral loads of infected mice following local administration of LTB₄.

EXAMPLE IH Effect of intranasal administration of LTB₄ on viral loads in the lungs of mice following intravenous CMV infection

To further support the role of LTB4 in the treatment of airway infections, six to eight week old female BALB/c mice were infected (n=8/group) by intravenous injection with 10³ PFU (Smith strain) of murine CMV to cause a systemic infection that reaches the lungs between days 6 and 10 post-infection. On days 1, 3, 5 and 7 following infection, mice were treated with a placebo or varying doses of LTB₄ by intranasal administration. On the 8^th day following infection, all mice were sacrificed and the CMV viral loads in the lungs determined by standard plaque assay on murine embryonic fibroblasts. The results show (Fig. 2) that significant reductions in lung viral loads were obtained following intranasal administrations of LTB doses ranging between 10-1000 ng/mouse. P values were calculated using the Mann Whitney test. EXAMPLE IV

Effect of LTB on influenza infection in lungs of mice

The efficacy of LTB to reduce influenza infection in lungs of mice was also demonstrated. BALB/c mice (6-8 week old) were infected (n=6/group) by delivering 10 PFU of influenza virus (strain A/Pr/8/34) in the nasal cavity. On days 1 to 5 post-infection, mice were treated intranasally with a placebo or with varying doses of LTB (1, 10 and 100 ng/dose). On the 6^th day post-infection, all mice were sacrificed and influenza viral loads in lungs were determined using the MDCK cell line. The results (Fig. 3) show that influenza titers in the lungs were significantly decreased in mice that have received LTB₄ locally in the airways.

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope ofthe appended claims.

Claims

WHAT IS CLAIMED IS:

1. Use of an intra-respiratory tract administration of a leukotriene B4 (LTB4) agent for the treatment and/or prophylaxis of a respiratory tract infection in a patient, wherein said leukotriene B4 (LTB4) agent is in association with a pharmacologically acceptable carrier for administration into the respiratory tract.

2. The use according to claim 1, wherein said infection is caused by a virus.

3. The use according to claim 2, wherein said virus is selected from the group consisting of coronaviridae, orthomyxoviridae, paramyxoviridae, picornaviridae, adenoviridae and herpesviridae.

4. The use according to claim 3, wherein said patient is a mammal.

5. The use according to claim 4, wherein said mammal is a human.

6. The use according to claim 2, wherein said intra-respiratory tract administration is effected by one administration route selected from the group consisting of intranasally, intrarespiratory, and by inhalation.

7. The use according to claim 1, wherein said LTB4 agent is leukotriene B4[5S,12R-6,8,10,14-(Z,E,E,Z)-eicosatetraenoic acid] ("LTB4").

8. The use according to claim 1, wherein said LTB4 agent is administered in association with one or several different antiviral agents.

9. The use according to claim 8, wherein said different antiviral agents are selected from the group consisting of interferon-α, -β, -γ, tumor necrosis factor α, ganciclovir, acyclovir, vidarabine, idoxuridine, famciclovir, 3TC, crixivan, nevarepine, prostaglandins, prostaglandin analogs and AZT, ribavirin, amantadine, rimantadine, zanamivir and oseltamivir.

10. The use according to claim 1, wherein said LTB4 agent is selected from the group consisting of:

14,15-dihydro-LTB ("LTB3"), 17,18-dehydro-LTB₄ ("LTB5"), 19-hydroxy- LTB4, 20-hydroxy-LTB4 and 5(R)-hydroxy, 5-keto, 5(S)hydroperoxy, 5(R)-hydroperoxy and 5-deoxy analogs thereof.

11. The use according to claim 1, wherein said LTB4 agent is selected from the group consisting of:

5-keto, 5(R)-hydroxy and 5(R)-hydroperoxy analogs of said LTB4 agent.

12. The use according to claim 1, wherein said LTB4' agent is selected from the group consisting of: > leukotriene A4 ("LTA4"); 14,15-dihydro-LTA₄ ("LTA3"), 17,18-dehydro-LTA₄ ("LTA₅").

13. The use according to claim 1, wherein said LTB4 agent is selected from the group consisting of:

14,15-dihydro-LTA4 methyl ester and LTB4 methyl ester.

14. The use according to claim 1, wherein said LTB4 agent is selected from the group consisting of:

5(S)-hydroxy-6,8,ll,14(E,Z,Z,Z)-eicosatetraenoic acid ("5-HETE"), 14,15- dihydro-5-HETE, 17,18-dehydro-5-HETE, and 5(R)-hydroxy, 5-keto, 5(S)- hydroperoxy and 5(R)-hydroperoxy analogs thereof.

15. The use according to claim 1, wherein said LTB4 agent is selected from the group consisting of: leukotrienes C4, D4 and E4 and 14,15-dihydro or 17,18-dehydro analogs thereof; N-acyl or N-alkyl derivatives of leukotrienes C4, D4 and E4, and 14,15-dihydro or 17,18-dehydro analogs thereof.

16. The use according to claim 1, wherein said LTB4 agent is selected from the group consisting of:

5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid, 5-hydroxy-6,8,ll, 14- eicosatetraenoic acid and isomers thereof.

17. The use according to claim 1, wherein said LTB4 agent is selected from the group consisting of:

20,20,20-trifluoromethyl-LTB₄; 19-methyl-LTB₄, 19,19-dimethyl-LTB , 19- fluoro-LTB , 19,19-difluoro-LTB4, 18,20-difluro-LTB , 20-fluoro-LTB₄ and isomers and analogs thereof.

18. . The use according to claim 1, wherein said LTB4 agent is selected from the group consisting of:

3-thio-LTB4, 3-hydroxy-LTB4, 3-methyl-LTB4, 3,3-dimethyl-LTB4, 3-fiuoro- LTB4, 3,3-difluoro-LTB4, 2,3-difluoro-LTB4 and isomers and analogs thereof.

19. The use according to claim 1, wherein said LTB4 agent is selected from the group consisting of:

LTB4 methylsulfonylamide, LTB4 methylamide, 1-tetrazide LTB4 and isomers and analogs thereof.

20. An intra-respiratory tract pharmaceutical composition for the treatment and/or prophylaxis of a respiratory tract infection in a patient, comprising a therapeutically effective amount of a LTB4 agent, in association with a pharmaceutically acceptable carrier for administration into the respiratory tract.

21. The composition according to claim 20, wherein said infection is caused by a virus.

22. The composition according to claim 21, wherein said virus is selected from the group consisting of coronaviridae, orthomyxoviridae, paramyxoviridae, picornaviridae, adenoviridae and herpesviridae.

23. The composition according to claim 22, wherein said patient is a mammal.

24. The composition according to claim 23, wherein said- mammal is a human.

25. The composition according to claim 24, wherein said intra-respiratory tract administration is effected by one administration route selected from the group consisting of intranasally, intrarespiratory, and by inhalation.

26. The composition according to claim 20, wherein said LTB4 agent is leukotriene B4[5S,12R-6,8,10,14-(Z,E,E,Z)-eicosatetraenoic acid].

27. The composition according to claim 20, wherein said LTB4 agent is administered in association with one or several different antiviral agents.

28. The composition according to claim 27, wherein said different antiviral agents are selected from the group consisting of interferon-α, -β, -γ, tumor necrosis factor α, ganciclovir, acyclovir, vidarabine, idoxuridine, famciclovir, 3TC, crixivan, nevarepine, prostaglandins, prostaglandin analogs and AZT, ribavirin, amantadine, rimantadine, zanamivir and oseltamivir.

29. The composition according to claim 20, wherein said LTB4 agent is selected from the group consisting of:

B4[5S,12R-6,8,10,14-(Z,E,E,Z)-eicosatetraenoic acid] ("LTB4"),

14,15-dihydro-LTB₄ ("LTB3"), 17,18-dehydro-LTB₄ ("LTB5"), 19-hydroxy- LTB4, 20-hydroxy-LTB4 and 5(R)-hydroxy, 5-keto, 5(S)hydroperoxy, 5(R)-hydroperoxy and 5-deoxy analogs thereof, 5-keto, 5(R)-hydroxy and 5(R)- hydroperoxy analogs of said LTB4 agent, leukotriene A4 ("LTA4"); 14,15-dihydro-LTA ("LTA3"), 17,18-dehydro-LTA ("LTA5"),

14,15-dihydro-LTA4 methyl ester and LTB4 methyl ester, 5(S)-hydroxy- 6,8,1 l,14(E,Z,Z,Z)-eicosatetraenoic acid ("5-HETE"), 14,15-dihydro-5-HETE, 17,18-dehydro-5-HETE, and 5(R)-hydroxy, 5-keto, 5(S)- hydroperoxy and 5(R)- hydroperoxy analogs thereof, leukotrienes C4, D4 and E4 and 14,15-dihydro or 17,18-dehydro analogs thereof; N-acyl or N-alkyl derivatives of leukotrienes C4, D4 and E4, and 14,15-dihydro or 17,18-dehydro analogs thereof, 5,12-dihydroxy- 6,8, 10, 14-eicosatetraenoic acid, 5-hydroxy-6, 8, 11, 14-eicosatetraenoic acid and isomers thereof, 20,20,20-trifluoromethyl-LTB4; 19-methyl-LTB₄, 19,19- dimethyl-LTB₄, 19-fluoro-LTB₄, 19,19-difluoro-LTB₄, 18,20-difluro-LTB , 20- fluoro-LTB4 and isomers and analogs thereof, 3-thio-LTB4, 3-hydroxy-LTB4, 3- methyl-LTB4, 3,3-dimethyl-LTB4, 3-fluoro-LTB4, 3,3-difluoro-LTB4, 2,3- difluoro-LTB4 and isomers and analogs thereof, LTB4 methylsulfonylamide, LTB4 methylamide, 1-tetrazide LTB4 and isomers and analogs thereof.