US 201302037.15A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2013/0203715A1 Hava et al. (43) Pub. Date: Aug. 8,9 2013

(54) USE OF TRP CHANNEL AGONISTS TO A61 K. 3 1/196 (2006.01) TREAT INFECTIONS A61 K. 3 1/()45 (2006.01) (75) Inventors: David L. Hava, Natick, MA (US); A61 K. 3 1/05 (2006.01) Robert W. Clarke, Medfield, MA (US) A61 K. 3 1/513 (2006.01) A61 K 45/06 (2006.01) (73) Assignee: Pulmatrix, Inc., Lexington, MA (US) A61R 31/357 (2006.01) (21) Appl. No.: 13/810,762 (52) U.S. CI. CPC ...... A61K 31/496 (2013.01); A61K 45/06 (22) PCT Filed: Jul. 20, 2011 (2013.01); A61K3I/23 (2013.01); A61 K 86) PCT NO.: PCT/US11/44628 31/495 (2013.01); A61K31/357 (2013.01); (86) O A61K 31/045 (2013.01); A61K3I/05 § 371 (c)(1), (2013.01); A61K31/513 (2013.01); A61 K (2), (4) Date: Mar. 13, 2013 31/196 (2013.01) Related U.S. Application Data USPC 514/171; 514/510; 514/252.13: 514/255.04; (60) Provisional application No. 61/365,840, filed on Jul. 514/450, 514/729; 514/731: 514/274; 514/567 20, 2010. Publication Classification (57) ABSTRACT

51) Int. Cl. (51) ºIK 31/496 (2006.01) Methods are described for treating or preventing a respiratory A6 IK 3 1/23 (2006.01) infection by administering an effective amount of a TRP A6 IK 31/.495 (2006.01) channel agonist. Patent Application Publication Aug. 8, 2013 Sheet 1 of 11 US 2013/0203715 A1

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USE OF TRP CHANNEL AGONISTS TO cium. 2003. 33(5-6):497-507; Hoenderop J G, et al. Homo TREAT INFECTIONS and heterotetrameric architecture of the epithelial Ca2+ chan nels TRPV5 and TRPV6, EMBO J. 2003. 22(4):776-785.) RELATED APPLICATIONS [0006] The TRPM (where “M” represents “melastatin”) channel subfamily takes its name from the observed over [0001] This application claims the benefit of U.S. Provi expression of TRPM1 (MLSN) transcripts in certain meta sional Application No. 61/365,840, filed on Jul. 20, 2010. The static melanomas. TRPM2 (h'?RPC7, LTRPC2) is gated by entire contents of the foregoing application is hereby incor binding of ADP-ribose and NAD (nicotinic adenine dinucle porated by reference. otide) to its C-terminal hydrolase domain. TRPM3 (MLSN2, LTRPC3), like TRPV4, is sensitive to hypotonicity, but there RELATED APPLICATIONS is little homology to suggest a common mechanism of action. [0002] Transient receptor potential (TRP) channels repre TRPM4 (LTRPC4, MLS2s, CAN[4b]) and TRPM5 (Mtrl, sent a large superfamily of homologous membrane proteins. LTRPC5) are the only TRP channels that are monovalent TRP channels are expressed throughout the body, and several cation-selective. TRPM4 is widely expressed, and TRPM4 TRP channel family members can be expressed on a single deficient mice have enhanced anaphylactic responses. cell type. TRP channels are composed of six-transmembrane (Clapham 2003; Clapham 2007) TRPM5 is also widely (6TM) polypeptide subunits that combine to form tetramers. expressed, and plays a role in the taste perception of sweet, These tetramers form pores in the membrane that are perme bitter and umami (amino acid) sensations. (Zhang Y, et al. able to cations (e.g., Caº and Nat). TRP channel activation Coding of sweet, bitter, and umami tastes: different receptor allows for rapid, yet controlled, entry of one or more cations cells sharing similar signaling pathways. Cell. 2003. 112(3): into a cell, and are involved in sensory transduction in 293-301.) TRPM6 (CHAK2) and TRPM7 (CHAK, TRP response to a diverse array of physiological stimuli. PLIK, LTRPC7) contain a functional kinase domain, but this (Clapham D. E. TRP channels as cellular sensors. Nature. domain is not necessary for the channel activity. (Runnels L 2003. 426:517-524.) TRP channels are classified into sub W, et al. The TRPM7 channel is inactivated by PIP(2) families based on sequence homology, which include the hydrolysis. Nat Cell Biol. 2002.4(5):329-336.; Schmitz C, et TRPC, TRPV, TRPM and TRPA1 subfamilies. al. Regulation of vertebrate cellular Mg2+ homeostasis by [0003] TRPC (where “C” represents “classic” or “canoni TRPM7. Cell. 2003. 114(2):191-200.) TRPM7 is thought to cal”) channel subfamily members are G-protein-coupled play a role in monitoring intracellular energy stores by sens receptor (GPCR) or receptor tyrosine kinase activated chan ing Mg-ATP levels. (Nadler M.J, et al. LTRPC7 is a Mg-ATP nels. TRPC1, TRPC4 (CCE2), and TRPC5 (CCE1) are highly regulated divalent cation channel required for cell viability. homologous, are expressed in the central nervous system Nature. 2001. 411:590-595.) TRPM8 (Trp-p8, CMR1) is (CNS) and form homo or heteromeric channels. (Clapham involved in detecting “cooling” and noxious cold sensations 2003) TRPC3, TRPC6, and TRPC7 are also highly expressed from ~8°C. to 28°C. Menthol and icilin are agonists that in smooth and cardiac muscle cells and may beinvolved in the enhance the sensory transduction of TRPM8. (Clapham regulation of vascular tone, airway resistance, and/or cardiac 2003; McKemy D D, et al. Identification of a cold receptor function. (See Clapham 2003; Trebak M, Vazquez G, Bird G reveals a general role for TRP channels in thermosensation. S, Putney, J.W. The TRPC3/6/7 subfamily of cation channels. Nature. 2002. 416:52-58; Peier AM, et al. ATRP channel that Cell Calcium. 2003.33(5-6);451-461.) senses cold stimuli and menthol. Cell. 2002. 108(5):705 [0004] The TRPV (where “V” represents “vanilloid”) 715.) channel subfamily members are more selective for Cat" than [0007] TRPA1 (ANKTM1, P120), (where “A” represents other TRP subfamilies, and TRPV5 and TRPV6 are the most “ankyrin”) is the only member of the TRPA subfamily. Caº selective TRP channels. (Clapham 2003) TRPV1 TRPA1 is activated by temperatures below 15° C. Although (VR1), TRPV2 (VRL1, OTRPC2), TRPV3 (VRL2) and there is no significant homology to TRPM8, TRPA1 is acti TRPV4 (OTRPC4, VR-OAC) are activated by elevated tem vated by the TRPM8 agonist icilin. (Clapham 2007; Story G peratures. M, et al. ANKTM1, a TRP-like channel expressed in nocice [0005] These four TRPV channels are also thought to be ptive neurons, is activated by cold temperatures. Cell. 2003. activated by cell stretching that is likely due to detecting 112(6):819-829.) TRPA1 is usually co-expressed in TRPV1 changes in extracellular tonicity, and specifically hypotonic positive dorsal root ganglion neurons that do not express ity. (Birder LA, et al. Altered urinary bladderfunction in mice TRPM8. (Clapham 2003; Kobayashi K, etal. Distinct expres lacking the vanilloid receptor TRPV1. Nat Neurosci. 2002. sion of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary 5(9):856-860; Iwata Y, et al. A novel mechanism of myocyte afferent neurons with adelta/c-fibers and colocalization with degeneration involving the Ca2+-permeable growth factor trk receptors. J Comp Neurol. 2005. 493(4):596-606.) regulated channel. J Cell Biol. 2003. 161(5):957-967; Hu H [0008] Some TRP channel agonists, such as the vanilloid Z, et al. 2-aminoethoxydiphenylborate is a common activator capsaicin, are known pain relievers. (Tominaga M, Julius D. of TRPV1, TRPV2, and TRPV3.JBiol Chem. 2004.279(34): Capsaicin receptor in the pain pathway. Jpn. J. Pharmacol. 35741-35748.)TRPV5 (ECaC1, CaF2) and TRPV6(ECaC2, 2000. 83(1):20-24; Cortright DN, Szallasi A. TRP channels CaT1) are the only TRPV channels not known to possess and pain. Curr Pharm Des. 2009. 15(15):1736-1749.) thermosensory activity. Both TRPV5 and TRPV6 are [0009| Certain TRPV3 agonists may be useful for treating expressed in the intestines, are constitutively active, and are inflammatory-associated conditions, including asthma and inhibited by intracellular Caº concentrations, which sug inflammatory bowel disorder (See, e.g., WIPO Patent Publi gests a role in calcium absorption. (Clapham D. E. SnapShot: cation WO2008065666) or allergic and non-allergic rhinitis Mammalian TRPChannels. Cell. 2007. 129(1):220; den Dek (See US Patent Publication No. 20090286811). ker E, et al. The epithelial calcium channels, TRPV5 & [0010) Certain TRPV1 agonists might be useful to treat TRPV6: from identification towards regulation. Cell Cal rhinitis and herpes (See U.S. Pat. No. 7,632,519). US 2013/0203715 A1 Aug. 8, 2013

[0011] Current therapies for respiratory tract infections (CBG), THC acid (THC-A), CBD acid (CBD-A), Compound involve the administration of anti-viral agents, anti-bacterial 1 (AMG5445), 4-methyl-N-(2,2,2-trichloro-1-(4-chlorophe agents, or anti-fungal agents for the treatment, prevention, or nylsulfanyl)ethyl]benzamide, N-(2,2,2-trichloro-1-(4-chlo amelioration of viral, bacterial, and fungal respiratory tract rophenylsulfanyl) ethyl]acetamid, AMG9090, AMG5445, infections, respectively. Unfortunately, in some cases, there 1-oleoyl-2-acetyl-sn-glycerol (OAG), carbachol, diacylglyc are no therapies available, infections are refractory to thera erol (DAG), 1,2-Didecanoylglycerol, flufenamate/flufenamic pies, or the occurrence of side effects outweighs the benefits acid, niflumate/niflumic acid, hyperforin, 2-aminoethoxy of the administration of a therapeutic agent. The use of anti diphenyl borate (2-APB), diphenylborinic anhydride viral or anti-bacterial agents for treatment of viral or bacterial (DPBA), delta-9-tetrahydrocannabinol (A*-THC or THC), tract infections may produce side effects or result in the cannabiniol (CBN), 2-APB, O-1821, 11-hydroxy-A*-tetrahy emergence of resistant strains. The administration of anti drocannabinol, nabilone, CP55940, HU-210, HU-211/dex fungal agents may cause renal failure or bone marrow dys anabinol, HU-331, HU-308, JWH-015, WINS 5,212-2, function and may not be effective against fungal infection in 2-Arachidonoylglycerol (2-AG), Arvil, PEA, AM404, patients with suppressed immune systems. Additionally, the O-1918, JWH-133, incensole, incensole acetate, menthol, infection-causing organisms (e.g., a virus, a bacterium, or a eugenol, dihydrocarvedl, carvedl, thymol, vanillin, ethylvan fungus) may be resistant or develop resistance to the admin illin, cinnemaldehyde, 2 aminoethoxydiphenyl borate istered therapeutic agent or combination of therapeutic (2-APB), diphenylamine (DPA), diphenylborinic anhydride agents. In fact, microorganisms that develop resistance to (DPBA), camphor, (+)-borneol, (–)-isopinocampheol, (-) administered therapeutic agents often develop pleiotropic fenchone, (-)-trans-pinocarveol, isoborneol, (+)-cam drug or multidrug resistance, that is, resistance to therapeutic phorquinone, (-)-O-thujone, Cº-pinene oxide, 1,8-cineole/eu agents that act by mechanisms different from the mechanisms calyptol, 6-tert-butyl-m-cresol, carvacrol, p-sylenol, kreosol, of how the administered agents act. Thus, as a result of drug propofol, p-cymene, (–)-isoppulegol, (-)-carvone, (+)-dihy resistance, many infections prove refractory to a wide array of drocarvone, (-)-menthone, (+)-linalool, geraniol, 1-isopro standard treatment protocols. Therefore, new therapies for the pyl-4-methyl-bicyclo[3.1.0]hexan-4-ol, 40 PDD, treatment, prevention, management, and/or amelioration of GSK1016790A, 5'6'Epoxyeicosatrienoic (5'6'-EET), respiratory tract infections and symptoms thereofare needed. 8'9"Epoxyeicosatrienoic (8'9"-EET), APP44-1, RN1747, For mulation Ib WO200602909, Formulation IIb WO200602909, SUMMARY Formulation IIc WO200602929, Formulation IId [0012] The invention relates to a method of treating or WO200602929, Formulation IIIb WO200602929, Formula preventing infections. The method includes administering to tion IIIc WO200602929, arachidonic acid (AA), 12-O-Tet an individual an effective amount of a TRP channel agonist radecanoylphorbol-13-acetate (TPA)/phorbol 12-myristate selected from the group consisting of TRPV2, TRPV3, 13-acetate (PMA), bisandrographalide (BAA), incensole, TRPV4, TRPC6, TRPM6, TRPA1, and combinations incensole acetate, Compound DK WO2010015965, Com thereof. pound X WO2010015965, Compound XI WO2010015965, [0013] In one aspect, the invention is a method of treating or Compound XII WO2010015965, WO2009004071, preventing a respiratory infection, comprising administering WO2006038070, WO2008065666, Formula VII WO2010015965, Formula IV WO2010015965, diben to an individual an effective amount of a TRP channel agonist zoazepine, dibenzooxazepine, Formula I WO2009071631, selected from the group consisting of TRPV2, TRPV3, N-(1S)-1-[({(4R)-1-[(4-chlorophenyl)sulfonyl]-3-oxo TRPV4, TRPC6, TRPM6, TRPA1, and combinations hexahydro-1H-azepin-4-yl)amino)earbonyl]-3-methylbu thereof. In a particular aspect, an agonist of TRPV4 is admin ty1}-1-benzothiophen-2-carboxamide, N-(1S)-1-[({(4R)-1 istered. [(4-fluorophenyl)sulfonyl]-3-oxohexahydro-1H-azepin-4 [0014] In one aspect, the invention relates to a method of treating a respiratory infection, comprising administering to y1}amino)carbonyl]-3-methylbutyl)-1-benzothiophen-2 an individual having a respiratory infection an effective carboxamide, N-(1S)-1-[({(4R)-1-[(2-cyanophenyl) amount of a TRP channel agonist selected from the group sulfonyl]-3-oxohexahydro-1H-azepin-4-yl)amino) consisting of Allyl isothiocyanate (AITC), Benyzl isothiocy carbonyl]-3-methylbutyl)-1-methyl-1H-indole-2 anate (BITC), Phenyl isothiocyanate, Isopropyl isothiocyan carboxamide, and N-(1S)-1-[({(4R)-1-[(2-cyanophenyl) ate, methyl isothiocyanate, diallyl disulfide, acrolein (2-pro sulfonyl]hexahydro-1H-azepin-4-yl)amino)carbonyl]-3 penal), disulfuram (Antabuse R), farnesyl thiosalicylic acid methylbutyl}-1-methyl-1H-indole-2-carboxamide. (FTS), farnesylthioacetic acid (FTA), chlodantoin (Sporosta [0015] In another aspect, the invention relates to a method cinº, topical fungicidal), (15-d-PGJ2), 5,8,11,14 eicosatet of treating a respiratory infection, comprising administering raynoic acid (ETYA), dibenzoazepine, mefenamic acid, to an individual having a respiratory infection an effective fluribiprofen, keoprofen, diclofenac, indomethacin, SC amount of a TRP channel agonist selected from the group alkyne (SCA), pentenal, mustard oil alkyne (MOA), iodoac consisting of Allyl isothiocyanate (AITC), Benyzl isothiocy etamine, iodoacetamide alkyne, (2-aminoethyl) methaneth anate (BITC), Phenyl isothiocyanate, Isopropyl isothiocyan iosulphonate (MTSEA), 4-hydroxy-2-noneal (HNE),4-hy ate, methyl isothiocyanate, diallyl disulfide, acrolein (2-pro droxy xexenal (HHE), 2-chlorobenzalmalononitrile, penal), disulfuram (Antabuse?), farnesyl thiosalicylic acid N-chloro tosylamide (chloramine-T), formaldehyde, isoflu (FTS), farnesylthioacetic acid (FTA), chlodantoin (Sporosta rane, isovelleral, hydrogen peroxide, URB597, thiosulfinate, cinº, topical fungicidal), (15-d-PGJ2), 5,8,11,14 eicosatet Allicin (a specific thiosulfinate), flufenamic acid, niflumic raynoic acid (ETYA), dibenzoazepine (WO9747611), diben acid, carvacrol, eugenol, menthol, gingerol, icilin, methyl zoxazepine (WO9747611), dibenz|b,fl-[1,4]oxazepine (CR), salicylate, arachidonic acid, cinnemaldehyde, super sinnem 11H-dibenz|b,e]azepine, 1,2 naphthoguione, 1,3-dihydrox aldehyde, tetrahydrocannabinol (THC or A*-THC), canna ynaphthalene, 2 methyl-1,4-naphthoguinone, 1-nitronaph bidiol (CBD), cannabichromene (CBC), cannabigerol thalene, hydroquinone, 4-phenyl-1,2-dihydronaphthalene, US 2013/0203715 A1 Aug. 8, 2013

3,5-ditert-butylphenol, 2,4-ditert-butylphenol, 1.3 butadiene, (TPA)/phorbol 12-myristate 13-acetate (PMA), bisan [(3E)-1-phenyl-1,3-pentadienyl]benzene, [(27)-3-phenyl-2 drographalide (BAA), incensole, incensole acetate, Com butenyl]benzene, mefenamic acid, fluribiprofen, keoprofen, pound IX WO2010015965, Compound X WO2010015965, diclofenac, indomethacin, SC alkyne (SCA), pentenal, mus Compound XI WO2010015965, Compound XII tard oil alkyne (MOA), iodoacetamine, iodoacetamide WO2010015965, WO2009004071, WO2006038070, alkyne, (2-aminoethyl) methanethiosulphonate (MTSEA), WO2008065666, Formula VII WO2010015965, Formula IV 4-hydroxy-2-noneal (HNE), 4-hydroxy xexenal (HHE), WO2010015965, dibenzoazepine, dibenzooxazepine, For mula I WO2009071631, N-((1S)-1-[({(4R)-1-[(4-chlo 2-chlorobenzalmalononitrile, N-chloro tosylamide rophenyl)sulfonyl]-3-oxohexahydro-1H-azepin-4 (chloramine-T), aldehyde, acetaldehyde (US2009269280), y1}amino)carbonyl]-3-methylbutyl)-1-benzothiophen-2 formaldehyde, O-anisaldehyde, isoflurane, isovelleral, carboxamide, N-(1S)-1-[({(4R)-1-[(4-fluorophenyl) hydrogen peroxide, URB597, thiosulfinate, Allicin (a specific sulfonyl]-3-oxohexahydro-1H-azepin-4-yl)amino) thiosulfinate), flufenamic acid, niflumic acid, carvacrol, carbonyl]-3-methylbutyl)-1-benzothiophen-2-carboxamide, eugenol, menthol, gingerol, propofol, thymol, 2-tert-butyl-5 N-(1S)-1|({(4R)-1-[(2-cyanophenyl)sulfonyl]-3-oxo methylphenol, icilin, methyl salicylate, arachidonic acid, cin hexahydro-1H-azepin-4-yl)amino)earbonyl]-3-methylbu nemaldehyde, super cinnemaldehyde, 10-hydroxy-2-de ty1}-1-methyl-1H-indole-2-carboxamide, N-((1S)-1-[({ cenoic acid, 10-hydroxydecanoic acid, 4-oxo-2-nonenal (4R)-1-[(2-cyanophenyl)sulfonyl]hexahydro-1H-azepin-4 (4-ONE), 1-chloroacetophenone (CN), bromobenzyl cya y1}amino)carbonyl]-3-methylbutyl)-1-methyl-1H-indole-2 mide, Compounds CA3, 13-19 and 21-27 from Defalco Jet al., carboxamide, N-(4-Hydroxyphenyl)-57.87,11Z,147 Biocrg Med Chem Lett. 2010 2001):276-279, 2-chloroben zylidene malononitrile (CS), morphanthridine, Compounds 6 eicosatetraenamide (AM404) and anandamide. and 32 from Gijsen HJet al., JMed Chem 2010, 53(19):7011 [0016] The respiratory infection can be a bacterial infec 7020, methyl vinyl ketone, mesityl oxide, acrylic acid N-hy tion. For example, the bacterial infection can be caused by droxysuccinimide ester, hydrocinnamic acid N-hydroxysuc Streptococcus pneumoniae, Staphylococcus aureus, Staphy cinimide ester, 3-(2-Pyridyldithio)propionic acid lococcus spp., Streptococcus spp., Streptococcus agalactiae, N-hydroxysuccinimide ester, N-acetyl-p-benzo-quinon Haemophilus influenzae, Klebsiella pneumoniae, Escheri eimine, 1'-acetoxychavicol acetate, piperine, isopiperine, chia coli, Pseudomonas aeruginosa, Moraxella catarrhalis, isochavicine, piperanine, piperolein A, piperolein B, (2E, Chlamydophila pneumoniae, Mycoplasma pneumoniae, 4E)-N-Isobutyl-2,4-decadienamide, nitro-oleic acid (OA Legionella pneumophila, Enterobacter spp., Acinetobacter NO2), 2-chloroacetophenone, styrene, naphthalene, indoli spp., Acinetobacter baumannii, methicillin-resistant Staphy none compounds (US201100.9379), tetrahydrocannabinol lococcus aureus, Stenotrophomonas maltophilia, Burkhold (THC or A*-THC), cannabidiol (CBD), cannabichromene eria spp., Yersinia enterocolitica, Mycobacterium tuberculo (CBC), cannabinol (CBN), cannabigerol (CBG), THC acid sis, Bordetella pertussis, Bordetella bronchiseptica, Brucella (THC-A), tetrahydrocannabivarin (THCVA), CBD acid spp., Brucella abortus, Brucella melitensis, Brucella suis, (CBD-A), Compound 1 (AMG5445), 4-methyl-N-(2,2,2 Chlamydophila psittaci, Clostridium tetani, Streptococcus trichloro-1-(4-chlorophenylsulfanyl)ethyl]benzamide, N-(2, pyogenes, Corynebacterium diphtheriae, Neisseria menin 2,2-trichloro-1-(4-chlorophenylsulfanyl)ethyl]acetamid, gitides, Enterococcus faecalis, Francisella tularensis, Bacil AMG9090, AMG5445, 1-oleoyl-2-acetyl-sn-glycerol lus anthracis, Helicobacter pylori, Leptospira spp., Lep (OAG), carbachol, diacylglycerol (DAG), 1,2-Didecanoylg tospira interrogans, Listeria monocytogenes, Rickettsia lycerol, flufenamate/flufenamic acid, niflumate/niflumic rickettsii, Salmonella spp., Shigella sonnei, Vibrio cholerae, acid, hyperforin, 2-aminoethoxydiphenyl borate (2-APB), or Yersinia pestis. diphenylborinic anhydride (DPBA), delta-9-tetrahydrocan [0017] The respiratory infection can be a viral infection. nabinol (A*-THC or THC), cannabiniol (CBN), 2-APB, For example, the viral infection can be caused by influenza O-1821, 11-hydroxy-A*-tetrahydrocannabinol, nabilone, virus, rhinovirus, parainfluenza virus, respiratory syncytial CP55940, HU-210, HU-211/dexanabinol, HU-331, HU-308, virus (RSV), metapneumovirus, adenovirus, herpes simplex JWH-015, WINS 5,212-2, 2-Arachidonoylglycerol (2-AG), virus, cytomegalovirus (CMV), coronavirus, hantavirus, cox Arvil, PEA, AM404, O-1918, JWH-133, incensole, incensole sackievirus, rhinovirus, enterovirus, or human bocavirus acetate, menthol, eugenol, dihydrocarvedl, carvedl, thymol, (HBoV). vanillin, ethyl vanillin, cinnemaldehyde, 2 aminoethoxy [0018] In some embodiments, the TRP channel agonists is diphenyl borate (2-APB), diphenylamine (DPA), diphenyl administered as an aerosol to the respiratory tract of the borinic anhydride (DPBA), camphor, (+)-borkkkol, (–)-iso individual. pinocampheol, (–)-fenchone, (–)-trans-pinocarveol, [0019. In one embodiment, the method may further com isoborneol, (+)-camphorquinone, (-)-O-thujone, Cº-pinene prise administering one or more co-therapeutic agents oxide, 1,8-cineole/eucalyptol, 6-tert-butyl-m-cresol, carvac selected from the group consisting of mucoactive or muco rol, p-sylenol, kreosol, propofol, p-cymene, (–)-isoppulegol, lytic agents, surfactants, cough suppressants, expectorants, (-)-carvone, (+)-dihydrocarvone, (-)-menthone, (+)-lina steroids, bronchodilators, antihistamines, anti-inflammatory lool, geraniol, farnesyl pyrophosphate, farnesyl diphosphate, agents, antibiotics, and antiviral agents. isopentenyl pyrophosphate, 1-isopropyl-4-methyl-bicyclo[3. [0020) The invention also relates to a method of treating a 1.0]hexan-4-ol, 40 PDD, GSK1016790A, 5'6'Epoxyeicosa respiratory infection, comprising administering to an indi trienoic (5'6'-EET), 8'9"Epoxyeicosatrienoic (8'9"-EET), vidual having a respiratory infection, an effective amount of APP44-1, RN1747, Formulation Ib WO200602909, Formu 4C&PDD. lation IIb WO200602909, Formulation IIc WO200602929, [0021] The invention also relates to a method of treating a Formulation IId WO200602929, Formulation IIIb respiratory infection, comprising administering to an indi WO200602929, Formulation IIIc WO200602929, arachi vidual having a respiratory infection, an effective amount of donic acid (AA), 12-O-T etradecanoylphorbol-13-acetate GSK1016790A. US 2013/0203715 A1 Aug. 8, 2013

[0022] The invention also relates to a method of treating a reduces influenza infection. FIG. 10C is a graph illustrating respiratory infection, comprising administering to an indi that icilin, an agonist of TRPM8 and TRPA1, modestly vidual having a respiratory infection, an effective amount of reduces influenza infection. RN1747. [0036] FIG. 11A is a graph illustrating that flufenamic acid, an agonist of TRPC6 and TRPA1, reduces influenza infection BRIEF DESCRIPTION OF THE DRAWINGS of Calu-3 cells. [0023] FIG. 1 shows graphical illustrations of the effects of [0037] FIG. 11B is a graph illustrating that allicin, an ago two broad-spectrum TRP channel antagonists on the ability of nist of TRPA1, reduces influenza infection of Calu-3 cells. an 8× calcium-sodium (Ca:Na) formulation to reduce influ enza (Influenza A/Panama/2007/99) infection of Calu-3 cells. DETAILED DESCRIPTION Viral infection was measured by quantifying viral titer using a 50% Tissue Culture Infectious Dose (TCIDso) assay. FIG. [0038] As described and exemplified herein, the inventors 1A is a graph illustrating that ruthenium red (RR) abrogates conducted studies into the anti-infective properties of certain the ability of an 8×Ca:Na formulation to reduce influenza calcium-containing formulations, and surprisingly discov infection. FIG. 1B is a graph illustrating that SKF96365 ered that TRP channels are involved in the anti-infective attenuates the ability of an 8×Ca:Na formulation to reduce effect. The invention provides methods for treating or pre influenza infection. venting infections of mucosal surfaces comprising adminis [0024] FIG. 2A is a graph illustrating that RR attenuates the tering an effective amount of a TRP channel agonist to an ability of an 8×Ca:Na formulation to reduce parainfluenza individual in need thereof. The TRP channel agonist can be (hPIV3) infection of Calu-3 cells. administered to the individual by any suitable route of admin [0025] FIG.2B is a graph illustrating that RR attenuates the istration, depending on the mucosal surface to be treated. For ability of an 8×Ca:Na formulation to reduce rhinovirus (Rv") example, mucosal surfaces include a mucosal surface of the infection of Calu-3 cells. alimentary tract, respiratory tract, urogenital tract, eye, eus [0026] FIG. 3 is a graph illustrating that RR attenuates the tation tube, and the like, such as buccal mucosa, esophageal ability of an 8×Ca:Na formulation to reduce influenza infec mucosa, gastric mucosa, intestinal mucosa, nasal mucosa, tion of normal human bronchial epithelial (NHBE) cells. olfactory mucosa, oral mucosa, bronchial mucosa, uterine [0027] FIG. 4A is a graph illustrating that RR attenuates the mucosa, endometrium, urethra and penile mucosa. ability of a dry powder, Formulation I (10% leucine, 58.6% [0039] The inventors further discovered, that agonists of calcium lactate, 31.4% sodium chloride, weight percent), to TRP channels surprisingly have anti-infective activity in reduce influenza infection of Calu-3 cells. models of respiratory tract infections. Methods of treating [0028] FIG. 4B is a graph illustrating that RR attenuates the and preventing respiratory tract infections are described and ability of a dry powder, Formulation II (10% leucine, 39.6% exemplified herein. calcium chloride, 50.4% sodium sulfate, weight percent), to [0040] As used herein, the term “respiratory infection” reduce influenza infection of Calu-3 cells. refers to an infection of the respiratory tract that is caused by [0029] FIG. 5 shows a graphical illustration of the expres a microbial pathogen. Common symptoms of a respiratory sion levels of various TRP channels in Calu-3 and NHBE infection include fever, cough, shortness of breath (dyspnea), cells as assayed by quantitative PCR (qPCR). Cycle threshold and/or wheezing. Clinically, respiratory infections can be (Ct) values for the genes were calculated as the expression diagnosed, for example, by culturing the infecting organism, level of the genes relative to the expression level of a house by clinical exam, or other suitable methods, such as chest keeping gene (GAPDH). x-ray. The diagnosis of a respiratory infection does not [0030] FIG. 6 is a graph illustrating that the Transient require that the presence of an infective pathogen in the res Receptor Potential V4 (TRPV4) antagonist RN1734, in a piratory tract of the individual be confirmed. dose-dependent manner, abrogates the ability of an 8×Ca:Na [0041] The term “respiratory tract” as used herein includes formulation to reduce influenza infection of Calu-3 cells. the upper respiratory tract (e.g., nasal passages, nasal cavity, [0031] FIG. 7 shows graphical illustrations of the effects of throat, pharynx), respiratory airways (e.g., larynx, trachea, three TRPV4 agonists on influenza infection of Calu-3 cells. bronchi, bronchioles) and lungs (e.g., respiratory bronchi FIG. 7A is a graph illustrating that 40 PDD reduces influenza oles, alveolar ducts, alveolar sacs, alveoli). infection. FIG. 7B is a graph illustrating that GSK1016790A [0042] The term “aerosol” as used herein refers to any reduces influenza infection in a dose-dependent manner. FIG. preparation of a fine mist of particles (including liquid and 7C is a graph illustrating that RN1747 reduces influenza non-liquid particles, e.g., dry powders), typically with a vol infection in a dose-dependent manner. ume median geometric diameter of about 0.1 to about 30 [0032] FIG. 8A is a graph illustrating that 40 PDD reduces microns or a mass median aerodynamic diameter of between parainfluenza infection of Calu-3 cells. about 0.5 and about 10 microns. Preferably the volume [0033] FIG. 8B is a graph illustrating that 40 PDD reduces median geometric diameter for the aerosol particles is less rhinovirus infection of Calu-3 cells. than about 10 microns. The preferred volume median geo [0034] FIG. 9 is a graph illustrating that 40 PDD and metric diameter for aerosol particles is about 5 microns. For GSK1016790A reduce influenza infection of NHBE cells. example, the aerosol can contain particles that have a volume [0035] FIG. 10 shows graphical illustrations of the effects median geometric diameter between about 0.1 and about 30 of multiple-target TRP channel agonists on influenza infec microns, between about 0.5 and about 20 microns, between tion of Calu-3 cells relative to the effect of 40 PDD. FIG. 10A about 0.5 and about 10 microns, between about 1.0 and about is a graph illustrating that menthol, an agonist of TRPM8 and 3.0 microns, between about 1.0 and 5.0 microns, between TRPV3, reduces influenza infection. FIG. 10B is a graph about 1.0 and 10.0 microns, between about 5.0 and 15.0 illustrating that carvacrol, an agonist of TRPV3 and TRPA1, microns. US 2013/0203715 A1 Aug. 8, 2013

[0043] Preferably the mass median aerodynamic diameter isothiocyanate, diallyl disulfide, acrolein (2-propenal), disul is between about 0.5 and about 10 microns, between about 1.0 furam (Antabuse R), farnesyl thiosalicylic acid (FTS), farne and about 3.0 microns, or between about 1.0 and 5.0 microns. sylthioacetic acid (FTA), chlodantoin (Sporostacinº, topical [0044] To facilitate the preparation of a clear and concise fungicidal), 15-d-PGJ2, 5, 8, 11, 14 eicosatetraynoic acid specification, the invention is further described with refer (ETYA), dibenzoazepine (WO9747611), dibenzoxazepine ence to preferred embodiments of treating respiratory infec (WO9747611), dibenz|b,fl-[1,4]oxazepine (CR), 11H tions. It is intended and to be understood that the methods can dibenz|b,e]azepine, 1,2 naphthoduione, 1,3-dihydroxynaph be used to treat infections of any mucosal tissue. thalene, 2 methyl-1,4-naphthoguinone, 1-nitronaphthalene, hydroquinone, 4-phenyl-1,2-dihydronaphthalene, 3,5-ditert Methods of Treating Respiratory Infections butylphenol, 2,4-ditert-butylphenol, 1,3 butadiene, [(3E)-1 [0045] In one aspect, the invention provides methods for phenyl-1,3-pentadienyl]benzene, [(27)-3-phenyl-2-butenyl] treating or preventing a respiratory infection that comprises benzene, mefenamic acid, fluribiprofen, keoprofen, administering an effective amount of a TRP channel agonist diclofenac, indomethacin, SC alkyne (SCA), pentenal, mus to an individual in need thereof. The TRP channel agonist can tard oil alkyne (MOA), iodoacetamine, iodoacetamide be administered to the individual by any suitable route of alkyne, (2-aminoethyl)methanethiosulphonate (MTSEA), administration, such as orally, parenterally, by inhalation or 4-hydroxy-2-noneal (HNE), 4-hydroxy xexenal (HHE), other suitable route. Preferably, the TRP channel agonist is 2-chlorobenzalmalononitrile, N-chloro tosylamide administered by inhalation. (chloramine-T), aldehyde, acetaldehyde (US2009269280), [0046] The individual to be treated in accordance with the formaldehyde, O-anisaldehyde, isoflurane, isovelleral, invention may have a diagnosed respiratory infection, such as hydrogen peroxide, URB597, thiosulfinate, Allicin (a specific an infection diagnosed by clinical exam, by diagnostic pro thiosulfinate), flufenamic acid, niflumic acid, carvacrol, cedure (e.g., chest x-ray) and/or confirmed presence of an eugenol, menthol, gingerol, propofol, thymol, 2-tert-butyl-5 infective agent in the respiratory tract of the subject (e.g., methylphenol, icilin, methyl salicylate, arachidonic acid, cin using a suitable microbiological or molecular diagnostic nemaldehyde, super cinnemaldehyde, 10-hydroxy-2-de test). The subject to be treated in accordance with the inven cenoic acid, 10-hydroxydecanoic acid, 4-oxo-2-nonenal tion may be at risk for a respiratory infection. Generally, such (4-ONE), 1-chloroacetophenone (CN), bromobenzyl cya subjects are exposed to infectious agents more frequently mide, Compounds CA3, 13-19 and 21-27 from Defalco Jet al., Biocrg Med Chem Lett. 2010 2001):276-279, 2-chloroben than the general population, or are more susceptible to infec zylidene malononitrile (CS), morphanthridine, Compounds 6 tion than the general population. Individuals at risk for a and 32 from Gijsen HJet al., JMedChem 2010, 53(19):7011 respiratory infection include, for example, health care work 7020, methyl vinyl ketone, mesityl oxide, acrylic acid N-hy ers, individuals with chronic lung diseases (e.g., asthma, droxysuccinimide ester, hydrocinnamic acid N-hydroxysuc chronic bronchitis, emphysema, chronic obstructive pulmo cinimide ester, 3-(2-Pyridyldithio)propionic acid nary disease, cystic fibrosis, bronchiectasis), individuals who N-hydroxysuccinimide ester, N-acetyl-p-benzo-quinon are immunosuppressed, infants, newborns and young (e.g., eimine, 1'-acetoxychavicol acetate, piperine, isopiperine, humans younger than about 12 years of age), and elderly (e.g., isochavicine, piperanine, piperolein A, piperolein B, (2E, humans older that about 65 or 70 years of age). 4E)-N-Isobutyl-2,4-decadienamide, nitro-oleic acid (OA [0047] Accordingly, in some embodiments, the invention is NO2), 2-chloroacetophenone, styrene, naphthalene, indoli a method for the treatment or prevention of respiratory infec none compounds (US201100.9379), tetrahydrocannabinol tion in an individual with a chronic underlying respiratory (THC or A*-THC), cannabidiol (CBD), cannabichromene disease, such as asthma, chronic bronchitis, emphysema, (CBC), cannabinol (CBN), cannabigerol (CBG), THC acid chronic obstructive pulmonary disease, cystic fibrosis, bron (THC-A), tetrahydrocannabivarin (THCVA), CBD acid chiectasis, comprising administering an effective amount of a (CBD-A), Compound 1 (AMG5445), 4-methyl-N-(2,2,2 TRP channel agonist to the individual. trichloro-1-(4-chlorophenylsulfanyl)ethyl]benzamide, N-(2, [0048] The TRP channel agonist administered in accor 2,2-trichloro-1-(4-chlorophenylsulfanyl)ethyl]acetamid, dance with the methods of the invention is preferably an agonist of one or more of TRPV2, TRPV3, TRPV4, TRPC6, AMG9090, AMG5445, and the compounds disclosed in WO TRPM6, and TRPA1. One or more TRP channel agonists can 2009/071631 (e.g., a compound of Formula I). be administered. In some embodiments, two or more agonists [0050] Exemplary agonists of TRPC6 that can be adminis that activate the same or different TRP channels are admin tered in accordance with the method of the invention include istered. Although specific agonists of TRPV2, TRPV3, 1-oleoyl-2-acetyl-sn-glycerol (OAG), carbachol, diacylglyc TRPV4, TRPC6, TRPM6, and TRPA1 may be beneficial in erol (DAG), 1,2-Didecanoylglycerol, flufenamate/flufenamic some instances, the invention does not require the use of acid, niflumate/niflumic acid, hyperforin, and the compounds specific agonists. In some embodiments, the TRP channel disclosed in WO 2010/015965 (e.g., a compound of Formula agonist administered does not activate TRPV1. In other IV, compound IX, compound X, compound XI, compounds embodiments, the TRP channel agonist administered does not XII). activate a TRP channel other than a channel selected from the [0051] Exemplary agonists of TRPM6 that can be admin group consisting of TRPV2, TRPV3, TRPV4, TRPC6, istered in accordance with the method of the invention TRPM6, TRPA1, and combinations thereof. Preferred TRP include 2-aminoethoxydiphenylborate (2-APB). channel agonists are non-toxic when administered to the res [0052] Exemplary agonists of TRPV2 that can be adminis piratory tract. tered in accordance with the method of the invention include [0049| Exemplary agonists of TRPA1 that can be adminis diphenylborinic anhydride (DPBA), delta-9-tetrahydrocan tered in accordance with the method of the invention include nabinol (A*-THC or THC), cannabiniol (CBN), cannabidiol Allyl isothiocyanate (AITC), Benyzl isothiocyanate (BITC), (CBP), 2-APB, probenecid, O-1821, 11-hydroxy-A*-tetrahy Phenyl isothiocyanate, Isopropyl isothiocyanate, methyl drocannabinol, nabilone, CP55940, HU-210, HU-211/dex US 2013/0203715 A1 Aug. 8, 2013

anabinol, HU-331, HU-308, JWH-015, WINS 5,212-2, eria monocytogenes, Rickettsia rickettsii, Salmonella spp., 2-Arachidonoylglycerol (2-AG), Arvil, PEA, AM404, Shigella sonnei, Vibrio cholerae, Yersinia pestis, and combi O-1918, and JWH-133. nations thereof. [0053] Exemplary agonists of TRPV3 that can be adminis [0056] Exemplary viral pathogens that cause respiratory tered in accordance with the method of the invention include infections that may be treated or prevented by the methods of Incensole, incensole acetate, a compound disclosed in WO the invention include, but are not limited to, Orthomyxoviri 2008/065666 (e.g., a compound of Formula I or Formula II, dae (e.g., influenza virus A or B), Paramyxoviridae (e.g., compound IA), menthol, eugenol, dihydrocarvedl, carvedl, respiratory syncytial virus (RSV) and metapneumovirus), thymol, vanillin, ethyl vanillin, cinnemaldehyde, 2 aminoet Adenoviridae (e.g., adenovirus), Herpesviridae (e.g., herpes hoxydiphenylborate (2-APB), diphenylamine (DPA), diphe simplex virus, cytomegalovirus (CMV), and parainfluenza nylborinic anhydride (DPBA), camphor, (+)-borneol, (–)-iso virus), Coronaviridae (e.g., coronavirus (SARS-CoV)), Bun pinocampheol, (–)-fenchone, (–)-trans-pinocarveol, yaviridae (e.g., hantavirus), Picornaviridae (e.g., coxsack isoborneol, (+)-camphorquinone, (-)-O-thujone, Cº-pinene ievirus, rhinovirus, and enteroviruses), Parvoviridae (e.g., oxide, 1,8-cineole/eucalyptol, 6-tert-butyl-m-cresol, carvac human bocavirus (HBoV)), rhinovirus and combinations rol, p-xylenol, kreosol, propofol, p-cymene, (–)-isoppulegol, thereof. In particular embodiments, the subject is infected by (-)-carvone, (+)-dihydrocarvone, (-)-menthone, (+)-lina influenza virus, parainfluenza virus, or rhinovirus. In a more lool, geraniol, farnesyl pyrophosphate, farnesyl diphosphate, particular embodiment, the subject is infected by influenza isopentenyl pyrophosphate, and 1-isopropyl-4-methyl-bicy V11 U.S. [0057] The invention provides a method for treating or clo[3.1.0|hexan-4-ol. preventing a respiratory infection that comprises administer [0054] Exemplary agonists of TRPV4 that can be adminis ing an effective amount of a TRPV2 channel agonist to a tered in accordance with the method of the invention include subject in need thereof. 4C PDD, GSK1016790A, 5'6'Epoxyeicosatrienoic [0058] The invention provides a method for treating or (5'6'-EET), 8'9"Epoxyeicosatrienoic (8'9"-EET), APP44-1, preventing a respiratory infection that comprises administer RN1747, Formulation Ib WO200602909, Formulation IIb ing an effective amount of a TRPV3 channel agonist to a WO200602909, Formulation IIc WO200602929, Formula subject in need thereof. tion IId WO200602929, Formulation IIIb WO200602929, Formulation IIIc WO200602929, arachidonic acid (AA), [0059] The invention provides a method for treating or 12-O-Tetradecanoylphorbol-13-acetate (TPA)/phorbol preventing a respiratory infection that comprises administer 12-myristate 13-acetate (PMA), bisandrographalide (BAA), ing an effective amount of a TRPV4 channel agonist to a and compounds disclosed in WO 2006/029209 (e.g., a com subject in need thereof. pound of Formula I, II, IIa, or III, N-(1S)-1|({(4R)-1-[(4 [0060] The invention provides a method for treating or chlorophenyl)sulfonyl]-3-oxohexahydro-1H-azepin-4 preventing a respiratory infection that comprises administer y1}amino)carbonyl]-3-methylbutyl)-1-benzothiophen-2 ing an effective amount of a TRPC6 channel agonist to a carboxamide, N-(1S)-1-[({(4R)-1-[(4-fluorophenyl) subject in need thereof. sulfonyl]-3-oxohexahydro-1H-azepin-4-yl)amino) [0061] The invention provides a method for treating or carbonyl]-3-methylbutyl}-1-benzothiophen-2-carboxamide, preventing a respiratory infection that comprises administer N-(1S)-1-[({(4R)-1-[(2-cyanophenyl)sulfonyl]-3-oxo ing an effective amount of a TRPM6 channel agonist to a hexahydro-1H-azepin-4-yl)amino)earbonyl]-3-methylbu subject in need thereof. ty1}-1-methyl-1H-indole-2-carboxamide, N-(1S)-1-[({ [0062] The invention provides a method for treating or (4R)-1-[(2-cyanophenyl)sulfonyl]hexahydro-1H-azepin-4 preventing a respiratory infection that comprises administer y1}amino)carbonyl]-3-methylbutyl)-1-methyl-1H-indole-2 ing an effective amount of a TRPA1 channel agonist to a carboxamide), N-(4-Hydroxyphenyl)-57.87,11Z,147 subject in need thereof. eicosatetraenamide (AM404) and anandamide. [0063] The invention provides a method for the treatment [0055] The respiratory infection may becaused by a micro or prevention of respiratory infection in an individual with a bial pathogen, such as bacteria or viruses. Exemplary bacte chronic underlying respiratory disease, such as asthma, rial pathogens that cause respiratory infections that may be chronic bronchitis, emphysema, chronic obstructive pulmo treated or prevented by the methods of the invention include, nary disease, cystic fibrosis, bronchiectasis, comprising but are not limited to, Streptococcus pneumoniae, Staphylo administering an effective amount of a TRPV2 channel ago coccus aureus, Staphylococcus spp., Streptococcus spp., nist to the individual. Streptococcus agalactiae, Haemophilus influenzae, Kleb [0064] The invention provides a method for the treatment siella pneumoniae, Escherichia coli, Pseudomonas aerugi or prevention of respiratory infection in an individual with a nosa, Moraxella catarrhalis, Chlamydophila pneumoniae, chronic underlying respiratory disease, such as asthma, Mycoplasma pneumoniae, Legionella pneumophila, Entero chronic bronchitis, emphysema, chronic obstructive pulmo bacter spp., Acinetobacter, Acinetobacter baumannii, methi nary disease, cystic fibrosis, bronchiectasis, comprising cillin-resistant Staphylococcus aureus, Stenotrophomonas administering an effective amount of a TRPV3 channel ago maltophilia, Burkholderia spp., Yersinia enterocolitica, nist to the individual. Mycobacterium tuberculosis, Bordetella pertussis, Borde [0065] The invention provides a method for the treatment tella bronchiseptica, Brucella spp., Brucella abortus, Bru or prevention of respiratory infection in an individual with a cella melitensis, Brucella suis, Chlamydophila psittaci, chronic underlying respiratory disease, such as asthma, Clostridium tetani, Streptococcus pyogenes, Corynebacte chronic bronchitis, emphysema, chronic obstructive pulmo rium diphtheriae, Neisseria meningitides, Enterococcus nary disease, cystic fibrosis, bronchiectasis, comprising faecalis, Francisella tularensis, Bacillus anthracis, Helico administering an effective amount of a TRPV4 channel ago bacter pylori, Leptospira spp., Leptospira interrogans, List nist to the individual. US 2013/0203715 A1 Aug. 8, 2013

[0066] The invention provides a method for the treatment agent. For example, the co-therapeutic agent can be admin or prevention of respiratory infection in an individual with a istered before, after or substantially concurrently with the chronic underlying respiratory disease, such as asthma, TRP channel agonist. chronic bronchitis, emphysema, chronic obstructive pulmo [0075] Generally, the TRP channel agonist is administered nary disease, cystic fibrosis, bronchiectasis, comprising to an individual as a component of a pharmaceutical compo administering an effective amount of a TRPC6 channel ago sition. nist to the individual. [0067] The invention provides a method for the treatment Modes of Administration or prevention of respiratory infection in an individual with a [0076] The TRP channelagonist can be administered in any chronic underlying respiratory disease, such as asthma, suitable way, such as, parenterally (e.g., intravenous, intra chronic bronchitis, emphysema, chronic obstructive pulmo muscular, intraperotineal, or subcutaneous injection), topi nary disease, cystic fibrosis, bronchiectasis, comprising cally, transdermally, via suppository (e.g., rectal orintravagi administering an effective amount of a TRPM6 channel ago nal administration), orally or by inhalation. The TRP channel nist to the individual. agonist can be administered in a single dose or multiple doses [0068] The invention provides a method for the treatment as indicated. or prevention of respiratory infection in an individual with a [0077] Preferably, the TRP channel agonist is administered chronic underlying respiratory disease, such as asthma, to the respiratory tract (e.g., to the mucosal surface of the chronic bronchitis, emphysema, chronic obstructive pulmo respiratory tract), and can be administered in any suitable nary disease, cystic fibrosis, bronchiectasis, comprising form, such as a solution, a suspension, a spray, a mist, a foam, administering an effective amount of a TRPA1 channel ago a gel, a vapor, droplets, particles, or a dry powder. In more nist to the individual. preferred embodiments, the TRP channel agonist is aero [0069] In a specific embodiment, the invention provides a solized for administration to the respiratory tract. TRP chan method of treating a respiratory infection, comprising admin nel agonists can be aerosolized for administration via the oral istering to an individual having a respiratory infection an airways using any suitable method and/or device, and many effective amount of an agonist of TRPV4, wherein the agonist suitable methods and devices are conventional and well is 40 PDD. In another embodiment, the invention provides a known in the art. For example, TRP channel agonists can be method of treating a respiratory infection, comprising admin aerosolized using a metered dose inhaler (e.g., a pressurized istering to an individual having a respiratory infection an metered dose inhaler (pMDI) including HFA propellant, or a effective amount of an agonist of TRPV4, wherein the agonist non-HFA propellant) with or without a spacer or holding is GSK1016790A. In a further embodiment, the invention chamber, a nebulizer, an atomizer, a continuous sprayer, an provides a method of treating a respiratory infection, com oral spray or a dry powder inhaler (DPI). TRP channel ago prising administering to an individual having a respiratory nists can be aerosolized for administration via the nasal air infection an effective amount of an agonist of TRPV4, ways using a nasal pump or sprayer, a metered dose inhaler wherein the agonist is RN 1747. (e.g., a pressurized metered dose inhaler (pMDI) including HFA propellant, or a non-HFA propellant) with or without a [0070] The invention provides a method for treating or spaceror holding chamber, a nebulizer with or without a nasal preventing a respiratory infection that comprises administer adapter or prongs, an atomizer, a continuous sprayer, or a ing an effective amount of one or more TRP channel agonists DPI. TRP channel agonists can also be delivered to the nasal shown in Table 1 to an individual in need thereof. mucosal surface via, for example, nasal wash and to the oral [0071] The invention provides a method for the treatment mucosal surfaces via, for example, an oral wash. TRP channel or prevention of respiratory infection in an individual with a agonists can be delivered to the mucosal surfaces of the chronic underlying respiratory disease, such as asthma, sinuses via, for example, nebulizers with nasal adapters and chronic bronchitis, emphysema, chronic obstructive pulmo nasal nebulizers with oscillating or pulsatile airflows. nary disease, cystic fibrosis, bronchiectasis, comprising [0078] The geometry of the airways is an important con administering an effective amount of one or more TRP chan sideration when selecting a suitable method for producing nel agonists shown in Table 1 to the individual. and delivering aerosols of TRP channel agonists to the lungs. [0072] In particular embodiments, the methods of the The lungs are designed to entrap particles of foreign matter invention comprise administering the effective amount of a that are breathed in, such as dust. There are three basic mecha TRP channel agonist to the respiratory tract of the individual nisms of deposition: impaction, sedimentation, and Brownian (e.g., a patient with a respiratory infection). Delivery to the motion (J. M. Padfield. 1987. In: D. Ganderton & T. Jones respiratory tractis preferably by inhalation of an aerosol, such eds. Drug Delivery to the Respiratory Tract, Ellis Harwood, as a dry powder aerosol or a nebulized aerosol. Chicherster, U.K.). Impaction in the upper airways occurs when particles are unable to stay within the air stream, par [0073] In preferred embodiments of the methods described ticularly at airway branches. Impacted particles are adsorbed herein, the individual has or is at risk for a viral respiratory onto the mucus layer covering bronchial walls and eventually infection. cleared from the lungs by mucociliary action. Impaction [0074] The methods of the invention can further comprise mostly occurs with particles over 5 pum in aerodynamic diam administering a co-therapeutic agent, such as mucoactive or eter. Smaller particles (those less than about 3 pum in aerody mucolytic agents, surfactants, cough suppressants, expecto namic diameter) tend to stay within the air stream and to be rants, steroids such as a corticosteroid, bronchodilators, anti advected deep into the lungs. Sedimentation often occurs in histamines, anti-inflammatory agents, antibiotics, and antivi the lower respiratory system where airflow is slower. Very rals. Cotherapeutic agents can be administered in any desired small particles (those less than about 0.6 pum) can deposit by way, provided that there is overlap in the pharmacological Brownian motion. Deposition by Brownian motion is gener activity of the TRP channel agonist and the co-therapeutic ally undesirable because deposition cannot be targeted to the US 2013/0203715 A1 Aug. 8, 2013

alveoli (N. Worakul & J. R. Robinson. 2002. In: Polymeric 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), fatty Biomaterials, 2" Ed. S. Dumitriu ed. Marcel Dekker. New alcohols, polyoxyethylene-9-lauryl ether, surface active fatty, York). acids, sorbitan trioleate (Span 85), glycocholate, surfactin, [0079] For administration, a suitable method (e.g., nebuli poloxomers, sorbitan fatty acid esters, tyloxapol, phospholip zation, dry powder inhaler) is selected to produce aerosols ids, alkylated sugars, sodium phosphate, maltodextrin, with the appropriate particle size for preferential delivery to human serum albumin (e.g., recombinant human serum albu the desired region of the respiratory tract, such as the deep min), biodegradable polymers (e.g., PLGA), dextran, dextrin, lung (generally particles between about 0.6 microns and 5 and the like. If desired, the pharmaceutical composition can microns in diameter), the upper airway (generally particles of also contain additives, preservatives, or fluid, nutrient or elec about 3 microns or larger diameter), or the deep lung and the trolyte replenishers (See, generally, Remington’s Pharma upper airway. ceutical Sciences, 17th Edition, Mack Publishing Co., PA, [0080] Some respiratory infections begin as infections of 1985). the upper respiratory airways. For example, influenza virus [0085] The pharmaceutical composition formulation pref typically replicates initially in the upper airways and later in erably contains a concentration of TRP channel agonist that the lung epithelia. Therefore, the TRP channel agonist can be permits convenient administration of an effective amount of delivered to the upper respiratory airway and/or the lung (e.g., the TRP channel agonist to the respiratory tract. For example, deep lung). Delivery to the upper respiratory airways is it is generally desirable that liquid formulations not be so advantageous for prophylaxis or to prevent an early infection dilute so as to require a large amount of the formulation to be from spreading. nebulized in order to deliver an effective amount to the res [0081] In the methods of the invention, an “effective piratory tract of a subject. Long administration periods are amount” of a TRP channel agonist is administered to an disfavored, and generally the formulation should be concen individual in need thereof. An effective amount is an amount trated enough to permit an effective amount to be adminis that is sufficient to achieve the desired therapeutic or prophy tered to the respiratory tract (e.g., by inhalation of aerosolized lactic effect, such as an amount sufficient to reduce respira formulation, such as nebulized liquid or aerosolized dry pow tory infection, to reduce duration of illness, to reduce patho der) in no more than about 120 minutes, no more than about gen burden, to reduce the number of days that infected 90 minutes, no more than about 60 minutes, no more than individuals experience respiratory infection symptoms and/ about 45 minutes, no more than about 30 minutes, no more or to decrease the incidence or rate of respiratory infection. than about 25 minutes, no more than about 20 minutes, no [0082] The clinician of ordinary skill can determine appro more than about 15 minutes, no more than about 10 minutes, priate dosage of TRP channel agonist based on the properties no more than about 7.5 minutes, no more than about 5 min of the particular TRP channel agonist selected and other utes, no more than about 4 minutes, no more than about 3 conventional factors, for example, the individual’s age, sen minutes, no more than about 2 minutes, no more than about 1 sitivity or tolerance to drugs, the particular infection to be minute, no more than 45 seconds, or no more than about 30 treated and the individuals overall well-being, and the treating seconds. clinician’s sound judgment. [0086] If desired, the pharmaceutical composition formu Pharmaceutical Compositions lation may further comprise a co-therapeutic agent. Co-ad ministration of a co-therapeutic agent does not require that [0083) Pharmaceutical compositions that contain a TRP the co-therapeutic agent be included in the same pharmaceu channel agonist for use in the methods described herein con tical formulation as the TRP channel agonist. In some tain at least one TRP channel agonist as an active ingredient, embodiments, the co-therapeutic agent is included in the and a pharmaceutically acceptable carrier or diluent, and can pharmaceutical composition comprising the TRP channel optionally contain additional agents. The pharmaceutical agonist. In other embodiments, the co-therapeutic agent may composition can be in any desired form, such as a solution, be a separate pharmaceutical composition. Exemplary co emulsion, suspension, or a dry powder. Preferred pharmaceu therapeutic agents may include, but are not limited to, muco tical composition, such as solutions and dry powders, can be active or mucolytic agents, surfactants, cough suppressants, aerosolized. The pharmaceutical composition can comprise expectorants, steroids, bronchodilators, antihistamines, anti multiple doses or be a unit dose composition as desired. inflammatory agents, antibiotics, and antivirals. The [0084] The pharmaceutical composition is generally pre co-therapeutic agents may be combined with other co-thera pared in or comprises a physiologically acceptable carrier or peutic agent(s) or with any of the TRP channel agonist(s) excipient. For pharmaceutical composition in the form of described herein. solutions, suspensions or emulsions, any suitable carrier or excipient can be included. Suitable carriers include, for [0087] Examples of suitable mucoactive or mucolytic example, aqueous, alcoholic/aqueous, and alcohol solutions, agents include MUC5AC and MUC5B mucins, DNA-ase, emulsions or suspensions, including water, saline, ethanol/ N-acetylcysteine (NAC), cysteine, nacystelyn, dornase alfa, water solution, ethanol solution, buffered media, propellants gelsolin, heparin, heparin sulfate, P2Y2 agonists (e.g. UTP. and the like. For pharmaceutical composition in the form of INS365), hypertonic saline, and mannitol. dry powders, suitable carrier or excipients include, for [0088] Suitable surfactants include L-alpha-phosphatidyl example, sugars (e.g., lactose, trehalose), sugar alcohols (e.g., choline dipalmitoyl (“DPPC”), diphosphatidyl glycerol mannitol, xylitol, sorbitol), amino acids (e.g., glycine, ala (DPPG), 1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine nine, leucine, isoleucine), dipalmitoylphosphosphatidyl (DPPS), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine choline (DPPC), diphosphatidyl glycerol (DPPG), 1,2-Di (DSPC), 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine palmitoyl-sn-glycero-3-phospho-L-serine (DPPS), 1,2 (DSPE), 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), Dipalmitoyl-sn-glycero-3-phosphocholine (DSPC), 1,2 fatty alcohols, polyoxyethylene-9-lauryl ether, surface active Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), fatty, acids, sorbitan trioleate (Span 85), glycocholate, surfac US 2013/0203715 A1 Aug. 8, 2013 tin, poloxomers, sorbitan fatty acid esters, tyloxapol, phos Immune Globulin), pleconaril, rupintrivir, palivizumab, mot pholipids, and alkylated sugars. avizumab, cytarabine, docosanol, denotivir, cidofovir, and [0089] Suitable cough suppressants include benzonatate, acyclovir. The salt formulation can contain a suitable anti benproperine, clobutinal, diphenhydramine, dextromethor influenza agent, such as zanamivir, oseltamivir, amantadine, phan, dibunate, fedrilate, glaucine, oxalamine, piperidione, or rimantadine. opiods such as codeine and the like. [0096] Suitable cough suppressants include benzonatate, [0090] Suitable expectorants include guaifenesin, guai benproperine, clobutinal, diphenhydramine, dextromethor acolculfonate, ammonium chloride, potassium iodide, tylox phan, dibunate, fedrilate, glaucine, oxalamine, piperidione, apol, antimony pentasulfide and the like. opiods such as codeine and the like. [0091] Suitable steroids include corticosteroids, combina [0097] Suitable brochodilators include short-acting beta, tions of corticosteroids and long-acting beta, agonists agonists, long-acting beta: agonists (LABA), long-acting (LABA), combinations of corticosteroids and long-acting muscarinic anagonists (LAMA), combinations of LABAs muscarinic anagonists (LAMA), and the like. Suitable corti and LAMAs, methylxanthines, short-acting anticholinergic costeroids include budesonide, fluticasone, flunisolide, tri agents (may also be referred to as short acting anti-muscar amcinolone, beclomethasone, mometasone, ciclesonide, inic), long-acting bronchodilators and the like. dexamethasone, and the like. Combinations of corticoster [0098] Suitable short-acting beta, agonists include oids and LABAs include salmeterol with fluticasone, formot albuterol, epinephrine, pirbuterol, levalbuterol, metaproter erol with budesonide, formoterol with fluticasone, formoterol onol, maxair, and the like. with mometasone, indacaterol with mometasone, and the [0099] Examples of albuterol sulfate formulations (also like. called salbutamol) include Inspiryl (AstraZeneca Plc), Salb [0092] Suitable bronchodilators include short-acting beta, utamol SANDOZ (Sanofi-Aventis), Asmasal clickhaler (Vec agonists, long-acting beta, agonists (LABA), long-acting tura Group Plc.), Ventolin R (GlaxoSmithKline Plc), Salbuta muscarinic anagonists (LAMA), combinations of LABAs mol GLAND (GlaxoSmithKline Plc), Airomir R (Teva and LAMAs, methylxanthines, and the like. Suitable short Pharmaceutical Industries Ltd.), ProAir HFA (Teva Pharma active beta, agonists include albuterol, epinephrine, pir ceutical Industries Ltd.), Salamol (Teva Pharmaceutical buterol, levalbuterol, metaproteronol, maxair, and the like. Industries Ltd.), Ipramol (Teva Pharmaceutical Industries Suitable LABAs include salmeterol, formoterol and isomers Ltd), Albuterol sulfate TEVA (Teva Pharmaceutical Indus (e.g. arformoterol), clenbuterol, tulobuterol, vilanterol tries Ltd), and the like. Examples of epinephrine include (Revolair"M), indacaterol, and the like. Examples of LAMAs Epinephine Mist KING (King Pharmaceuticals, Inc.), and the include tiotroprium, glycopyrrolate, aclidinium, ipratropium like. Examples of pirbuterol as pirbuterol acetate include and the like. Examples of combinations of LABAs and Maxair R (Teva Pharmaceutical Industries Ltd.), and the like. LAMAs include indacaterol with glycopyrrolate, indacaterol Examples of levalbuterol include Xopenex R (Sepracor), and with tiotropium, and the like. Examples of methylxanthine the like. Examples of metaproteronol formulations as metap include theophylline, and the like. roteronol sulfate include Alupent R (Boehringer Ingelheim [0093) Suitable antibiotics may include a macrolide (e.g., GmbH), and the like. azithromycin, clarithromycin and erythromycin), a tetracy [0100] Suitable LABAs include salmeterol, formoterol and cline (e.g., doxycycline, tigecycline), a fluoroquinolone (e.g., isomers (e.g. ar?ormoterol), clenbuterol, tulobuterol, gemifloxacin, levofloxacin, ciprofloxacin and mocifloxacin), vilanterol (RevolairTM), indacaterol, carmoterol, isoproter a cephalosporin (e.g., ceftriaxone, defotaxime, ceftazidime, enol, procaterol, bambuterol, milveterol, olodaterol and the cefepime), a penicillin (e.g., amoxicillin, amoxicillin with like. clavulanate, ampicillin, piperacillin, and ticarcillin) option [0101) Examples of salmeterol formulations include sal ally with a fl-lactamase inhibitor (e.g., sulbactam, tazobactam meterol xinafoate as Serevent R (GlaxoSmithKline Plc), sal and clavulanic acid), such as ampicillin-sulbactam, piperacil meterol as Inaspir (Laboratorios Almirall, S.A.), Advair'R lin-tazobactam and ticarcillin with clavulanate, an aminogly HFA (GlaxoSmithKline PLC), Advair Diskus R (Glaxo coside (e.g., amikacin, arbekacin, gentamicin, kanamycin, SmithKline PLC, Theravance Inc), Plusvent (Laboratorios neomycin, netilmicin, paromomycin, rhodostreptomycin, Almirall, S.A.), VR315 (Novartis, Vectura Group PLC) and streptomycin, tobramycin, and apramycin), a penem or car the like. Examples of formoterol and isomers (e.g., arformot bapenem (e.g. doripenem, ertapenem, imipenem and mero erol) include Foster (Chiesi Farmaceutici S.p.A), Atimos penem), a monobactam (e.g., aztreonam), an oxazolidinone (Chiesi Farmaceutici S.p.A, Nycomed Internaional Manage (e.g., linezolid), Vancomycin, glycopeptide antibiotics (e.g. ment), Flutiform R (Abbott Laboratories, SkyePharma PLC), telavancin), tuberculosis-mycobacterium antibiotics and the MFF258 (Novartis AG), Formoterol clickhaler (Vectura like. Group PLC), Formoterol HFA (SkyePharma PLC), Oxis® [0094] The antibiotic may be one for treating infections (Astrazeneca PLC), Oxis pNMDI (Astrazeneca), Foradi18 with mycobacteria, such as Mycobacterium tuberculosis. Aerolizer (Novartis, Schering-Plough Corp, Merck), Suitable agents for treating infections with mycobacteria Foradil R. Certihaler (Novartis, SkyePharma PLC), Sym (e.g., M. tuberculosis) include an aminoglycoside (e.g. bicort?R (AstraZeneca), VR632 (Novartis AG, Sandoz Inter capreomycin, kanamycin, streptomycin), a fluoroquinolone national GmbH), MFF258 (Merck & Co Inc, Novartis AG), (e.g. ciprofloxacin, levofloxacin, moxifloxacin), isozianid Alvesco R. Combo (Nycomed International Management and isozianid analogs (e.g. ethionamide), aminosalicylate, GmbH, Sanofi-Aventis, Sepracor Inc), Mometasome furoate cycloserine, diarylquinoline, ethambutol, pyrazinamide, pro (Schering-Plough Corp), and the like. Examples of clen tionamide, rifampin, and the like. buterol include Ventipulmin(R) (Boehringer Ingelheim), and [0095) Suitable antiviral agents may include oseltamivir, the like. Examples of tulobuterol include Hokunalin Tape zanamavir, amantidine, rimantadine, ribavirin, gancyclovir, (Abbott Japan Co., Ltd., Maruho Co., Ltd.), and the like. valgancyclovir, foscavir, Cytogamº (Cytomegalovirus Examples of vilanterol include RevolairTM (GlaxoSmith US 2013/0203715 A1 Aug. 8, 2013

Kline PLC), GSK64244 (GlaxoSmithKline PLC), and the montelukast sodium SCHERING (Schering-Plough Corp), like. Examples of indacaterol include QAB149 (Novartis AG, MK0476C (Merck & Co Inc), and the like. Examples of SkyePharma PLC), QMF149 (Merck & Co Inc) and the like. masilukast include MCC847 (AstraZeneca PLC), and the Examples of carmoterol include CHF4226 (Chiese Farma like. Examples of zafirlukast (leukotriene D4 and E4 receptor ceutici S.p.A., Mitsubishi Tanabe Pharma Corporation), inhibitor) include Accolate R (AstraZeneca PLC), and the CHF5188 (Chiesi Farmaceutici S.p.A), and the like. like. Examples of pranlukast include Azlaire (Schering Examples of isoproterenol sulfate include Aludrin (Boe Plough Corp). Examples of zileuton (5-LO) include Zyflo'R hringer Ingelheim GmbH) and the like. Examples of pro (Abbott Laboratories), Zyflo CRR (Abbott Laboratories, caterol include Meptin clickhaler (Vectura Group PLC), and the like. Examples of bambuterol include Bambec (AstraZen SkyePharma PLC), Zileuton ABBOTTLABS (Abbott Labo eca PLC), and the like. Examples of milveterol include ratories), and the like. Suitable PDE4 inhibitors include cilo GSK159797C (GlaxoSmithKline PLC), TD3327 (Thera milast, roflumilast, oglemilast, tofimilast, and the like. vance Inc), and the like. Examples of olodaterol include [0113] Examples of cilomilast include Ariflo (GlaxoSmith BI1744CL (Boehringer Ingelheim GmbH) and the like. Kline PLC), and the like. Examples of roflumilast include [0102) Examples of LAMAs include tiotroprium, trospium Daxas R (Nycomed International Management GmbH, Pfizer chloride, glycopyrrolate, aclidinium, ipratropium and the Inc), APTA2217 (Mitsubishi Tanabe Pharma Corporation), like. and the like. Examples of oglemilast include GRC3886 (For [0103] Examples of tiotroprium include Spiriva (Boe est Laboratories Inc), and the like. Examples of tofimilast hringer-Ingleheim, Pfizer), and the like. Examples of glyco include Tofimilast PFIZER INC (Pfizer Inc), and the like. pyrrolate include Robinul R. (Wyeth-Ayerst), Robinul R. Forte (Wyeth-Ayerst), NVA237 (Novartis), and the like. Examples [0114] Other anti-inflammatory agents include omali of aclidinium include Eklira.R. (Forest Labaoratories, Alm zumab (anti-IgE immunoglobulin Daiichi Sankyo Company, irall), and the like. Limited), Zolair (anti-IgE immunoglobulin, Genentech Inc, [0104] Examples of combinations of LABAs and LAMAs Novartis AG, Roche Holding Ltd), Solfa (LTD4 antagonist include indacaterol with glycopyrrolate, formoterol with gly and phosphodiesterase inhibitor, Takeda Pharmaceutical copyrrolate, indacaterol with tiotropium, olodaterol and Company Limited), IL-13 and IL-13 receptor inhibitors (such tiotropium, vilanterol with a LAMA, and the like. as AMG-317, MILR1444A, CAT-354, QAX576, IMA-638, [0105] Examples of combinations of indacaterol with gly Anrukinzumab, IMA-026, MK-6105, DOM-0910, and the copyrrolate include QVA149A (Novartis), and the like. like), IL-4 and IL-4 receptor inhibitors (such as Pitrakinra, Examples of combinations of formoterol with glycopyrrolate AER-003, AIR-645, APG-201, DOM-0919, and the like), include PTO03 (Pearl Therapeutics) and the like. Examples of IL-1 inhibitors such as canakinumab, CRTh2 receptor combinations of olodaterol with tiotropium include BI1744 antagonists such as AZD1981 (CRTh2 receptor antagonist, with Spirva (Boehringer Ingelheim) and the like. Examples of AstraZeneca), neutrophil elastase inhibitor such as AZD9668 combinations of vilanterol with a LAMA include (neutrophil elastase inhibitor, from AstraZeneca), GSK573719 with GSK642444 (GlaxoSmithKline PLC), and GW856553X Losmapimod (P38 kinase inhibitor, Glaxo the like. SmithKline PLC), Arofylline LAB ALMIRALL (PDE-4 [0106] Examples of methylxanthine include aminophyl inhibitor, Laboratorios Almirall, S.A.), ABT761 (5-LO line, ephedrine, theophylline, oxtriphylline, and the like. inhibitor, Abbott Laboratories), Zyflo R (5-LO inhibitor, [0107] Examples of aminophylline include Aminophylline Abbott Laboratories), BTO61 (anti-CD4 mAb, Boehringer BOEHRINGER (Boehringer Ingelheim GmbH) and the like. Ingelheim GmbH), Corns (inhaled lidocaine to decrease eosi Examples of ephedrine include Bronkaidº (Bayer AG), nophils, Gilead Sciences Inc), Prograf (IL-2-mediated T-cell Broncholate (Sanofi-Aventis), Primatene R (Wyeth), Tedral activation inhibitor, Astellas Pharma), Bimosiamose PFIZER SAR, Marax (Pfizer Inc) and the like. Examples of theophyl INC (selectin inhibitor, Pfizer Inc), R411 (o.431/0437 inte line include Euphyllin (Nycomed International Management grin antagonist, Roche Holdings Ltd), Tilade® (inflamma GmbH), Theo-dur (Pfizer Inc, Teva Pharmacetuical Indus tory mediator inhibitor, Sanofi-Aventis), OrenicaR (T-cell tries Ltd) and the like. Examples of oxtriphylline include co-stimulation inhibitor, Bristol-Myers Squibb Company), Choledyl SA (Pfizer Inc) and the like. Soliris R (anti-05, Alexion Pharmaceuticals Inc), Entorken R. [0108] Examples of short-acting anticholinergic agents (Farmacija d.o.o.), Excellair'R' (Syk kinase siRNA, ZabeCor include ipratropium bromide, oxitropium bromide, and Pharmaceuticals, Baxter International Inc), KB003 (anti tiotropium (Spiriva). GMCSF mab, KaloBios Pharmaceuticals), Cromolyn sodi [0109| Examples of ipratropium bromide include Atrovent/ ums (inhibit release of mast cell mediators): Cromolyn Apovent/Inpratropio (Boehringer Ingelheim GmbH), sodium BOEHRINGER (Boehringer Ingelheim GmbH), Ipramol (Teva Pharmaceutical Industries Ltd) and the like. Cromolyn sodium TEVA (Teva Pharmaceutical Industries Examples of oxitropium bromide include Oxivent (Boe Ltd), Intal (Sanofi-Aventis), BI1744CL (oldaterol (B2 hringer Ingelheim GmbH), and the like. adrenoceptor antagonist) and tiotropium, Boehringer Ingel [0110] Suitable anti-inflammatory agents include leukot heim GmbH), NFk-B inhibitors, CXR2 antagaonists, HLE riene inhibitors, phosphodiesterase 4 (PDE4) inhibitors, inhibitors, HMG-CoA reductase inhibitors and the like. other anti-inflammatory agents, and the like. [0115] Anti-inflammatory agents also include compounds [0111] Suitable leukotriene inhibitors include montelukast that inhibit/decrease cell signaling by inflammatory mol (cystinyl leukotriene inhibitors), masilukast, Zafirleukast ecules like cytokines (e.g., IL-1, IL-4, IL-5, IL-6, IL-9, IL-13, (leukotriene D4 and E4 receptor inhibitors), pranlukast, IL-18 IL-25, IFN-O, IFN-?º, and others), CC chemokines zileuton (5-lipoxygenase inhibitors), and the like. CCL-1-CCL28 (some of which are also known as, for [0112| Examples of montelukast (cystinyl leukotriene example, MCP-1, CCL2, RANTES), CXC chemokines inhibitor) include Singulair (Merck & Co Inc), Loratadine, CXCL1-CXCL17 (some of which are also know as, for US 2013/0203715 A1 Aug. 8, 2013

example, IL-8, MIP-2), growth factors (e.g., GM-CSF, NGF, PLC, Sandoz International GmbH), and the like. Other for SCF, TGF-B, EGF, VEGF and others) and/or their respective mulations of fluticasome include fluticasone as Flusonal receptors. (Laboratorios Almirall, S.A.), fluticasone furoate as [0116] Some examples of the aforementioned anti-inflam GW685698 (GlaxoSmithKline PLC, Thervance Inc.), Plus matory antagonists/inhibitors include ABN912 (MCP-1/ vent (Laboratorios Almirall, S.A.), Flutiform R (Abbott CCL2, Novartis AG), AMG761 (CCR4, Amgen Inc), Laboratories, SkyePharma PLC), and the like. Enbrel R (TNF, Amgen Inc, Wyeth), humab OX40L [012.1] Examples of flunisolide include Aerobid R. (Forest GENENTECH (TNF superfamily, Genentech Inc, AstraZen Laboratories Inc), Aerospan R. (Forest Laboratories Inc), and eca PLC), R4930 (TNF superfamily, Roche Holding Ltd), the like. Examples of triamcinolone include Triamcinolone SB683699/Firategrast (VLA4, GlaxoSmithKline PLC), ABBOTTLABS (Abbott Laboratories), Azmacort?R (Abbott CNT0148 (TNFO, Centocor, Inc, Johnson & Johnson, Scher ing-Plough Corp); Canakinumab (IL-13, Novartis); Isra Laboratories, Sanofi-Aventis), and the like. Examples of pa?ant MITSUBISHI (PAF/IL-5, Mitsubishi Tanabe Pharma beclomethasone dipropionate include Beclovent (Glaxo Corporation); IL-4 and IL-4 receptor antagonists/inhibitors: SmithKline PLC), QVARR (Johnson & Johnson, Schering AMG317 (Amgen Inc), BAY1699.96 (Bayer AG), AER-003 Plough Corp, Teva Pharmacetucial Industries Ltd), Asmabec (Aerovance), APG-201 (Apogenix); IL-5 and IL-5 receptor clickhaler (Vectura Group PLC), Beclomethasone TEVA antagonists/inhibitors: MEDI563 (AstraZeneca PLC, (Teva Pharmaceutical Industries Ltd), Vanceril (Schering Medlmmune, Inc), Bosatria R (GlaxoSmithKline PLC), Plough Corp), BDP Modulite (Chiesi Farmaceutici S.p.A.), Cinquil R (Ception Therapeutic), TMC120B (Mitsubishi Clenil (Chiesi Farmaceutici S.p.A), Beclomethasone dipro Tanabe Pharma Corporation), Bosatria (GlaxoSmithKline pionate TEVA (Teva Pharmaceutical Industries Ltd), and the PLC), Reslizumab SCHERING (Schering-Plough Corp); like. Examples of mometasome include QAB149 Mometa MEDI528 (IL-9, AstraZeneca, MedImmune, Inc), IL-13 and some furoate (Schering-Plough Corp), QMF149 (Novartis IL-13 receptor antagonists/inhibitors: TNX650 GENETECH AG), Fomoterol fumarate, mometoasone furoate (Schering (Genetech), CAT-354 (AstraZeneca PLC, MedImmune), Plough Corp), MFF258 (Novartis AG, Merck & Co Inc), AMG-317 (Takeda Pharmaceutical Company Limited), Asmanex R Twisthaler (Schering-Plough Corp), and the like. MK6105 (Merck & Co Inc), IMA-026 (Wyeth), IMA-638 Examples of cirlesonide include Alvesco R (Nycomed Inter Anrukinzumab (Wyeth), MILR1444A/Lebrikizumab (Ge national Management GmbH, Sepracor, Sanofi-Aventis, nentech), QAX576 (Novartis), CNTO-607 (Centocor), Tejin Pharma Limited), Alvesco R. Combo (Nycomed Inter MK-6105 (Merck, CSL); Dual IL-4 and IL-13 inhibitors: national Management GmbH, Sanofi-Aventis), Alvesco R. AIR645/ISIS369645 (ISIS Altair), DOM-0910 (Glaxo HFA (Nycomed Intenational Management GmbH, Sepracor SmithKline, Domantis), Pitrakinra/AER001/Aerovant"M Inc), and the like. Examples of dexamethasone include Dex (Aerovance Inc), AMG-317 (Amgen), and the like. Pak R. (Merck), Decadron R (Merck), Adrenocot, CPC-Cort D, Decaject-10, Solurex and the like. Other corticosteroids [0117| Suitable steroids include corticosteroids, combina tions of corticosteroids and LABAs, combinations of corti include Etiprednol dicloacetate TEVA (Teva Pharmaceutical costeroids and LAMAs, combinations of corticosteroids, Industries Ltd), and the like. LABAs and LAMAs, and the like. [0122) Combinations of corticosteroids and LABAs include salmeterol with fluticasone, formoterol with budes [0118| Suitable corticosteroids include budesonide, fluti onide, formoterol with fluticasone, formoterol with mometa casone, flunisolide, triamcinolone, beclomethasone, sone, indacaterol with mometasone, and the like. mometasone, ciclesonide, dexamethasone, and the like. [0119) Examples of budesonide include Captisol-Enabled [0123] Examples of salmeterol with fluticasone include Budesonide Solution for Nebulization (AstraZeneca PLC), Plusvent (Laboratorios Almirall, S.A.), Advair R HFA Pulmicort?R (AstraZeneca PLC), Pulmicort R. Flexhaler (As (GlaxoSmithKline PLC), Advair R Diskus (GlaxoSmith traZeneca Plc), Pulmicort R. HFA-MDI (AstraZeneca PLC), Kline PLV. Theravance Inc), VR315 (Novartis AG, Vectura Pulmicort Respules R (AstraZeneca PLC), Inflammide (Boe Group PLC, Sandoz International GmbH) and the like. hringer Ingelheim GmbH), Pulmicort R. HFA-MDI (SkyeP Examples of vilanterol with fluticasone include GSK642444 harma PLC), Unit Dose Budesonide ASTRAZENECA (As with fluticasone and the like. Examples of formoterol with traZeneca PLC), Budesonide Modulite (Chiesi Farmaceutici budesonide include Symbicort?R (AstraZeneca PLC), VR632 S.p.A), CHF5188 (Chiesi Farmaceutici S.p.A), Budesonide (Novartis AG, Vectura Group PLC), and the like. Examples of ABBOTT LABS (Abbott Laboratories), Budesonide click formoterol with fluticasone include Flutiform R (Abbott haler (Vestura Group PLC), Miflonide (Novartis AG), Xavin Laboratories, SkyePharma PLC), and the like. Examples of (Teva Pharmaceutical Industries Ltd.), Budesonide TEVA (Teva Pharmaceutical Industries Ltd.), Symbicort?R (Astra formoterol with mometasone include Dulera R/MFF258 (No Zeneca K.K., AstraZeneca PLC), VR632 (Novartis AG, San vartis AG, Merck & Co Inc), and the like. Examples of inda doz International GmbH), and the like. caterol with mometasone include QAB149 Mometasome furoate (Schering-Plough Corp), QMF149 (Novartis AG), [0120) Examples of fluticasone propionate formulations and the like. Combinations of corticosteroids with LAMAs include Flixotide Evohaler (GlaxoSmithKline PLC), Flix otide Nebules (GlaxoSmithKline Plc), Flovent R (Glaxo include fluticasone with tiotropium, budesonide with tiotro SmithKline Plc), Flovent R. Diskus (GlaxoSmithKline PLC), pium, mometasome with tiotropium, salmeterol with tiotro Flovent R. HFA (GlaxoSmithKline PLC), Flovent R. Rotadisk pium, formoterol with tiotropium, indacaterol with tiotro (GlaxoSmithKline PLC), Advair R HFA (GlaxoSmithKline pium, vilanterol with tiotropium, and the like. Combinations PLC, Theravance Inc), Advair Diskus R (GlaxoSmithKline of corticosteroids with LAMAs and LABAs include flutica PLC, Theravance Inc.), VR315 (Novartis AG, Vectura Group some with salmeterol and tiotropium. US 2013/0203715 A1 Aug. 8, 2013

[012.4] Other anti-asthma molecules include: ARD111421 SAR389644 (DP1 receptor antagonist), SAR398171 (VIP agonist, AstraZeneca PLC), AVE0547 (anti-inflamma (CRTH2 antagonist), SSR161421 (adenosine A3 receptor tory, Sanofi-Aventis), AVE0675 (TLRagonist, Pfizer, Sanofi antagonist); Aventis), AVE0950 (Syk inhibitor, Sanofi-Aventis), AVE5883 (NK1/NK2 antagonist, Sanofi-Aventis), AVE8923 [0129] Merck & Co Inc: MK0633, MK0633, MK0591 (tryptase beta inhibitor, Sanofi-Aventis), CGS21680 (adenos (5-LO inhibitor), MK886 (leukotriene inhibitor), BIO1211 ine A2A receptor agonist, Novartis AG), ATL844 (A2B (VLA-4 antagonist); Novartis AG: QAE397 (long-acting cor receptor antagonist, Novartis AG), BAY443428 (tryptase ticosteroid), QAK423, QAN747, QAP642 (CCR3 antago inhibitor, Bayer AG), CHF5407 (M3 receptor inhibitor, nist), QAX935 (TLR9 agonist), NVA237 (LAMA). Chiesi Farmaceutici S.p.A.), CPLA2 Inhibitor WYETH [0130J Suitable expectorants include guaifenesin, guai (CPLA2 inhibitor, Wyeth), IMA-638 (IL-13 antagonist, acolculfonate, ammonium chloride, potassium iodide, tylox Wyeth), LAS100977 (LABA, Laboratorios Almirall, S.A.), apol, antimony pentasulfide and the like. MABA (M3 and 52 receptor antagonist, Chiesi Farmaceutici S.p.A), R1671 (mAb, Roche Holding Ltd), CS003 (Neuroki [0131) Suitable vaccines include nasally inhaled influenza nin receptor antagonist, Daiichi Sankyo Company, Limited), vaccines and the like. DPC168 (CCR antagonist, Bristol-Myers Squibb), E26 (anti [0132) Suitable macromolecules include proteins and large IgE, Genentech Inc), HAE1 (Genentech), IgE inhibitor peptides, polysaccharides and oligosaccharides, and DNA AMGEN (Amgen Inc), AMG853 (CRTH2 and D2 receptor and RNA nucleic acid molecules and their analogs having antagonist, Amgen), IPL576092 (LSAID, Sanofi-Aventis), therapeutic, prophylactic or diagnostic activities. Proteins EPI2010 (antisense adenosine 1, Chiesi Farmaceutici S.p. can include antibodies such as monoclonal antibodies. A.), CHF5480 (PDE-4 inhibitor, Chiesi Farmaceuticis.p.A.), Nucleic acid molecules include genes, antisense molecules KIO4204 (corticosteroid, Abbott Laboratories), SVT47060 such as siRNAs that bind to complementary DNA, RNAi, (Laboratorios Salvat, S.A.), VML530 (leukotriene synthesis inhibitor, Abbott Laboratories), LAS35201 (M3 receptor shRNA, microRNA, RNA, or ribosomes to inhibit transcrip antagonist, Laboratorios Almirall, S.A.), MCC847 (D4 tion or translation. Preferred macromolecules have a molecu receptorantagonist, Mitsubishi Tanabe Pharma Corporation), lar weight of at least 800 Da, at least 3000 Da or at least 5000 MEM1414 (PDE-4 inhibitor, Roche), TA270 (5-LO inhibi Da. tor, Chugai Pharmaceutical Co Ltd), TAK661 (eosinophil [0133] Selected macromolecule drugs for include Ven chemotaxis inhibitor, Takeda Pharmaceutical Company Lim tavis R (Iloprost), Calcitonin, Erythropoietin (EPO), Factor ited), TBC4746 (VLA-4 antagonist, Schering-Plough Corp), DK, Granulocyte Colony Stimulating Factor (G-CSF), Granu VR694 (Vectura Group PLC), PLD177 (steroid, Vectura locyte Macrophage Colony, Stimulating Factor (GM-CSF), Group PLC), KIO3219 (corticosteroid+LABA, Abbott Labo Growth Hormone, Insulin, Interferon Alpha, Interferon Beta, ratories), AMG009 (Amgen Inc), AMG853 (D2 receptor Interferon Gamma, Luteinizing Hormone Releasing Hor antagonist, Amgen Inc); mone (LHRH), follicle stimulating hormone (FSH), Ciliary [0125] AstraZeneca PLC: AZD1744 (CCR3/histamine-1 Neurotrophic Factor, Growth Hormone Releasing Factor receptor antagonist, AZD1419 (TLR9 agonist), Mast Cell (GRF), Insulin-Like Growth Factor, Insulinotropin, Interleu inhibitor ASTRAZENECA, AZD3778 (CCR antagonist), kin-1 Receptor Antagonist, Interleukin-3, Interleukin-4, DSP3025 (TLR7 agonist), AZD1981 (CRTh2 receptor Interleukin-6, Macrophage Colony Stimulating Factor antagonist), AZD5985 (CRTh2 antagonist), AZD8075 (M-CSF), Thymosin Alpha 1, IIb/IIIa Inhibitor, Alpha-1 (CRTh2 antagonist), AZD1678, AZD2098, AZD2392, Antitrypsin, Anti-RSV Antibody, palivizumab, motavi AZD3825 AZD8848, AZD9215, ZD2138 (5-LO inhibitor), zumab, and ALN-RSV, Cystic Fibrosis Transmembrane AZD3199 (LABA); Regulator (CFTR) Gene, Deoxyribonuclase (DNase), Hep [0126] GlaxoSmithKline PLC; GW328267 (adenosine A2 arin, Bactericidal/Permeability Increasing Protein (BPI), receptor agonist), GW559090 (o.4 integrin antagonist), Anti-Cytomegalovirus (CMV) Antibody, Interleukin-1 GSK679586 (mAb), GSK597901 (adrenergic B2 agonist), Receptor Antagonist, and the like. GLP-1 analogs (lira AM103 (5-LO inhibitor), GSK256006 (PDE4 inhibitor), glutide, exematide, etc.), Domain antibodies (dAbs), Pramlin GW842470 (PDE-4 inhibitor), GSK870086 (glucocorticoid tide acetate (Symlin), Leptin analogs, Synagis (palivizumab, agonist), GSK159802 (LABA), GSK256066 (PDE-4 inhibi MedImmune) and cisplatin. tor), GSK642444 (LABA, adrenergic f;2 agonist), GSK64244 and Revolair (fluticasone/vilanterol), [0134] Selected therapeutics helpful for chronic mainte GSK799.943 (corticosteroid), GSK573719 (mAchR antago nance of CF include antibiotics/macrolide antibiotics, bron nist), and GSK573719. chodilators, inhaled LABAs, and agents to promote airway secretion clearance. Suitable examples of antibiotics/mac [0127] Pfizer Inc. PF3526299, PF3893787, PF4191834 rolide antibiotics include tobramycin, azithromycin, ciprof (FLAP antagonist), PF610355 (adrenergic f;2 agonist), loxacin, colistin, aztreonam and the like. Suitable examples CP664511 (o.431/VCAM-1 interaction inhibitor), CP609643 of bronchodilators include inhaled short-acting beta, agonists (inhibitor of o431/VCAM-1 interactions), CP690550 (JAK3 such as albuterol, and the like. Suitable examples of inhaled inhibitor), SAR21609 (TLR9 agonist), AVE7279 (Th1 LABAs include salmeterol, formoterol, and the like. Suitable switching), TBC4746 (VLA-4 antagonist); R343 (IgE recep examples of agents to promote airway secretion clearance tor signaling inhibitor), SEP42960 (adenosine A3 antago include Pulmozyme (dornase alfa, Genetech), hypertonic nist); saline, DNase, heparin and the like. Selected therapeutics [0128] Sanofi-Aventis: MLNG095 (Cr'TH2 inhibitor), helpful for the prevention and/or treatment of CF include SAR137272 (A3 antagonist), SAR21609 (TLR9 agonist), VX-770 (Vertex Pharmaceuticals) and amiloride. US 2013/0203715 A1 Aug. 8, 2013 13

TABLE 1 Agonists of TRP Channels TRPA1 Agonists Allyl isothiocyanate (AITC) (Mustard oil)

Benyzl isothiocyanate (BITC)

Phenyl isothiocyanate

Isopropyl isothiocyanate

Methyl isothiocyanate

Diallyl disulfide

Acrolein (2-propenal)

CH3 Disulfiram (Antabuse (R), Odyssey S Pharmaceuticals) 2 SS Js s^ S

Farnesyl thiosalicylic acid (FTS)

HO S O

HOOCs > S S. Farnesyl thioacetic acid (FTA) S

Chlodantoin (Sporostacin (R) US 2013/0203715 A1 Aug. 8, 2013 14

TABLE 1-continued

Agonists of TRP Channels

15-deoxy-A-12,14-PG.J., (15d-PGJ2) COOH

5, 8, 11, 14 Eicosatetraynoic acid (ETYA)

H3C Dibenzoazepine (WO9747611)

N — O Dibenzoxazepine (WO9747611)

Dibenz|b,fl-[1,4]oxazepine (CR)

1,2 naphthoguione

OH 1,3-dihydroxynaphthalene

Co. OH US 2013/0203715 A1 Aug. 8, 2013 15

TABLE 1-continued Agonists of TRP Channels 2 methyl-1,4-naphthoguinone

1-nitronaphthalene

hydroquinone * () OH 4-phenyl-1,2-dihydronaphthalene

CH3 4-phenyl-1,2-dihydronaphthalene

H 3,5-ditert-butylphenol

2,4-ditert-butylphenol

S2’s 1,3 butadiene [(3E)-1-phenyl-1,3-pentadienyl]benzene [(27)-3-phenyl-2-butenyl]benzene US 2013/0203715 A1 Aug. 8, 2013 16

TABLE 1-continued Agonists of TRP Channels

O OH Mefenamic acid CH3 ..CH3

Fluribiprofen

Ketoprofen

Diclofenac

Cl OH

O

Indomethacin

SC alkyne (SCA)

Pentenal

Mustard oil alkyne (MOA) US 2013/0203715 A1 Aug. 8, 2013 17

TABLE 1-continued Agonists of TRP Channels

Iodoacetamide

Iodoacetamide alkyne

O (2-aminoethyl) methanethiosulphonate | (MTSEA) —S–S

O| \ NH2 ºOH 4-hydroxy-2-noneal (HNE) O 4-hydroxy xexenal (HHE)

*~~OH

Cl 2-chlorobenzalmalononitrile 2^ S | N-chloro tosylamide (chloramine-T) O\/ O

C| H3C J Aldehyde H O Acetaldehyde (US2009269280) | / H–C–C | \ H H

O Formaldehyde II’ | Sir

O H O-anisaldehyde

OCH3 US 2013/0203715 A1 Aug. 8, 2013 18

TABLE 1-continued Agonists of TRP Channels Cl F Isoflurane

Isovelleral

. . . ii II CHO

CHO

H H Hydrogen peroxide * / O—O

O NH2 URB597

ºH O | Thiosulfinate S R’ R^ ^ S …”

Allicin

O OH Flufenamic acid F F H N F

O OH Niflumic acid F F N F | S N 2

Carvacrol OH

CH3O 2. Eugenol

HO US 2013/0203715 A1 Aug. 8, 2013 19

TABLE 1-continued Agonists of TRP Channels

CH3 Menthol

OH

H3C CH3 O CH3 Gingerol

HOºOCH, º Propofol

CH3 Thymol

OH

H3C CH3 CH3 2-tert-butyl-5-methylphenol

OH CH3 H3C CH3

OH NO2 Icilin K . / \ N H O O Methyl salicylate

CºOH Arachidonic acid US 2013/0203715 A1 Aug. 8, 2013 20

TABLE 1-continued

Agonists of TRP Channels

O Cinnemaldehyde

S H

O Super Cinnemaldehyde

O \

O 10-hydroxy-2-decenoic acid

HO *>~~~~

O 10-hydroxydecanoic acid

O 4-oxo-2-nonenal (4-ONE)

*~~~~O O_{C| 1-chloroacetophenone (CN) . Bromobenzyl cyanide Compounds CA3, 13-19 and 21-27 from Defalco Jet al., 2010, Biocrg Med Chem Lett. 2001): 276-279.

Cl 2-chlorobenzylidene malononitrile (CS) US 2013/0203715 A1 Aug. 8, 2013 21

TABLE 1-continued

Agonists of TRP Channels

H morphanthridine

Compounds 6 and 32 from Gijsen HJ et al., 2010, J Med Chem 53(19):7011-702.

O methyl vinyl ketone ~'sO mesityl oxide O Acrylic acid N-hydroxysuccinimide ester O

~JºO

O Hydrocinnamic acid N-hydroxysuccinimide ester O ozº N O

O 3-(2-Pyridyldithio)propionic acid N S hydroxysuccinimide ester

22 S O —N N s^ sº O O º N-acetyl-p-benzo-quinoneimine

OJO’ O ºr 1'-acetoxychavicol acetate US 2013/0203715 A1 Aug. 8, 2013 22

TABLE 1-continued

Agonists of TRP Channels O Piperine

& scº, Isopiperine O O N

& S Isochavicine O S.

O N

Piperanine O r N O O

Piperolein A

Piperolein B

O (2E,4E)-N-Isobutyl-2,4-decadienamide US 2013/0203715 A1 Aug. 8, 2013 23

TABLE 1-continued

Agonists of TRP Channels º Nitro-oleic acid (OA –NO2) N"—O

O

HO o'O 2-chloroacetophenone Cº Styrene CO Naphthalene

R! Indolinone compounds (US201100.9379)

| S R+ O 2">N \ X-R2

Compounds from Perilla frutescens. Bassoli et al., H O 2009, Biorg Med Chem 17(4): 1636-1639.

O

º Cannabinoids Tetrahydrocannabinol (THC or A*-THC) US 2013/0203715 A1 Aug. 8, 2013 24

TABLE 1-continued Agonists of TRP Channels Cannabidiol (CBD)

OH

HO OH Cannabichromene (CBC)

Cannabinol (CBN)

OH

OH Cannabigerol (CBG)

HO THC acid (THC-A)

OH

THC-A COOH CBD acid (CBD-A)

CBD-A COOH Tetrahydrocannabivarin (THCVA) OC US 2013/0203715 A1 Aug. 8, 2013

TABLE 1-continued Agonists of TRP Channels Activates rat TRPA1, antagonizes human TRPA1 NO2 Compound 1 from Chen et al., 2008, O CCl3 J Neuroscience 28(19): 5063-5071. * (AMG5445) H ::

Cl 4-methyl-N-(2,2,2-trichloro-1-(4 chlorophenylsulfanyl)ethyl]benzamide O CCl3 C? (Abbott). Compound 2 from Chen et al., 2008, * J Neuroscience 28(19): 5063-5071. H ::

O CCl3 O N-[2,2,2-trichloro-1-(4-chlorophenylsulfanyl) ethyl]acetamide (Abbott). Compound 3 from Chen et al., 2008, J Neuroscience 28(19): 5063 5071. H ::

Cl AMG9090 (Amgen)

S NH

Cl Cl ?º O AMG909?) Cl AMG5445 (Amgen) O

S NH

Cl º CI C) AMG5445 Cl

EXEMPLIFICATION was removed and ALI cultures were established. NHBE cells were cultured for 4 or more weeks at ALI prior to each Methods experiment. [0136] Prior to each experiment, the apical surface of each [0135] Cell culture models of influenza, rhinovirus or Transwell was washed 3 times with PBS. Where indicated, 10 parainfluenza infection were used to study the role of TRP pull of the specified TRP channel antagonist or agonist (see channels in calcium-sodium formulation inhibition of viral Table 2) was added to the apical surface of cells. As a control, infection. Calu-3 cells (American Type Culture Collection, cells that did not receive the channel antagonist or agonist Manassas, Va.) were cultured on permeable membranes (12 were administered an equal volume of PBS (10 pull). When mm Transwells, 0.4 plm pore size; Corning Lowell, Mass.) appropriate, cells were subsequently exposed to nebulized until confluent (membrane was fully covered with cells) and formulations (see Table 3) with a sedimentation chamber and air-liquid interface (ALI) cultures were established by remov Series 8900 nebulizers (Slater Labs). Immediately after expo ing the apical media and culturing at 37°C./5% CO2. Cells sure, the basolateral media (media on the bottom side of the were cultured for more than 2 weeks at ALI before each Transwell or Millicell) was replaced with fresh media. Rep experiment. Normal human bronchial epithelial (NHBE) licate wells were exposed to each formulation in each test. A cells (Scott Randell, University of North Carolina) were second cell culture plate was exposed to the same formula seeded at passage 2 on permeable membranes (12 mm Mil tions to quantify the delivery of total salt or calcium to cells. licell, 0.4 pum pore size; Millipore Billerica, Mass.) and incu One hour after exposure, cells were infected with either 10 HD bated (37°C., 5% CO2,95% RH) until confluent under liquid of Influenza A/Panama/2007/99 at a multiplicity of infection covered culture conditions. Once confluent, the apical media of 0.1-0.001 (0.1-0.001 virions per cell), 10 pull of rhinovirus US 2013/0203715 A1 Aug. 8, 2013 26

(RV16) at a multiplicity of infection of 0.1-0.01 (0.1-0.01 3). Untreated cells or cells administered each treatment indi virions per cell) or parainfluenza (hPTV3) at a multiplicity of vidually were used as controls. Treatment of cells with the infection of 3-0.3 (3-0.3 virions per cell). Four hours after 8×Ca:Na formulation significantly reduced influenza infec aerosol treatment, the apical surfaces were washed to remove tion (140-fold) compared to the untreated control (FIG. 1; excess formulation and unattached virus. An additional 10 pull p-0.01 compared to untreated control; one-way ANOVA with of the appropriate channel antagonist or agonist was added to Tukey's multiple comparison post-test). When the 8× treat the apical surface of the appropriate Transwells or Millicells ment was administered to cells pretreated with either RR and the plates were incubated overnight. Twenty four hours (FIG. 1A) or SKF96365 (FIG. 1B), the effect on viral infec after viral infection, virus released onto the apical surface of tion was reduced to levels comparable to the untreated control infected cells was collected in culture media or PBS and the cells. Each data point is the mean:standard deviation (SD) of concentration of virus in the apical wash was quantified by a triplicate wells and representative of two independent experi 50% Tissue Culture Infectious Dose assay (TCIDso). The ments with each antagonist. These results suggested that the TCIDso assay is a standard endpoint dilution assay that is inhibition of TRP channels by ruthenium red and SKF96365 used to quantify how much of a given virus is present in a reduced the efficacy of the 8×Ca:Na formulation against sample. influenza.

TABLE 2 B. TRP Channel Inhibition Reduces the Efficacy of a Calcium-Sodium Formulation Against Parainfluenza and TRP Channel Antagonists and Agonists Rhinovirus. Antagonist? TRP channel Working [0138] Ruthenium red was used to determine if inhibition Chemical Name Agonist target Concentrations of TRP channel activity also reduced the previously demon Ruthenium Red Antagonist TRPV1-TRPV6, 1 LIM strated broad-spectrum anti-viral activity of Ca:Na formula TRPM6, TRPA1 tions against other viruses like human parainfluenza virus and SKF96365 Antagonist TRPV2, TRPC6, -10 ||M rhinovirus (see e.g., PCT/US10/28914 filed Mar. 26, 2010, TRPC7 RN1734 Antagonist TRPV4 1 piM-100 piM incorporated herein by reference). Human parainfluenza 4CºPDD Agonist TRPV4 0.01 puM-100 piM virus is a single stranded RNA enveloped virus distinct from GSK1016790A Agonist TRPV4 0.01 mm-1 ||M influenza. Parainfluenza viruses are 150-300 nm in diameter RN1747 Agonist TRPV4 1 nm-10pi M and are covered in hemagglutinin-neuraminidase (HN) Resiniferatoxin Agonist TRPV1 100 nm-100 piM Menthol Agonist TRPM8, TRPV3 100 nm-100 piM spikes and fusion proteins. Unlike influenza virus, the Carvacrol Agonist TRPA1, TRPV3 300 nm-100 piM genome is non-segmented and, following attachment of the Icilin Agonist TRPA1, TRPM8 100 nm-100 piM virus to the target cell via HN tetramers, the virus is believed Flufenamic Acid Agonist TRPC6, TRPA1 100 nm-100 piM to fuse directly with the plasma membrane. Parainfluenza is associated with upper and lower respiratory tract disease and is frequently a cause of an influenza-like illness (ILI) and TABLE 3 acute exacerbations (AEs) in respiratory infection. Human rhinovirus is a single-stranded RNA non-enveloped virus that Liquid Calcium-Sodium Formulations causes the common cold. Among the smallest of viruses, rhinoviruses have a diameter of only about 30 nanometers. CaCl2 CaCl2 NaCl NaCl Human rhinoviruses are composed of a capsid made up of Tonicity (% w/v) (M) (% w/v) (M) four viral proteins (VP1-VP4) that form an icosahedral struc 0.5X 0.59 0.053 0.04 0.007 ture. Rhinovirus preferentially infects the upper respiratory 1X 1.2 0.11 0.08 0.013 (isotonic) tract and enters respiratory epithelial cells through receptor 2X 2.4 0.21 0.16 0.027 mediated (ICAM-1, LDL receptor family) endocytosis. 4X 4.7 0.43 0.31 0.053 [0139| Ruthenium red and the 8×Ca:Na formulation were 8X 9.4 0.85 0.62 0.11 tested against parainfluenza virus and rhinovirus. Calu-3 cells were pretreated with ruthenium red (1 puM in PBS) and sub sequently exposed to an 8×Ca:Na formulation. Untreated Example 1 cells or cells administered each treatment individually were used as controls. Treatment of cells with the 8×Ca:Na formu lation reduced parainfluenza (FIG. 2A) and rhinovirus (FIG. TRP Channel Antagonists Inhibit Calcium-Sodium 2B) infection compared to the untreated control (FIG. 2; Formulation-Mediated Reduction of Viral Infection p-0.01 compared to untreated control; one-way ANOVA with Tukey's multiple comparison post-test). When the 8× treat A. TRP Channel Inhibition Reduces the Efficacy of a ment was administered to cells pretreated with ruthenium red, Calcium-Sodium Formulation Against Influenza. the efficacy of the 8× treatment was reduced (hatched bar in [0137] Calcium-sodium formulations inhibit viral infec FIG. 2) and viral titers were comparable to those in the ruthe tion (see, e.g., PCT/US10/28900 filed Mar. 26, 2010, incor nium red treated controls (grey bar in FIG. 2). Each data point porated herein by reference). To determine if calcium-sodium is the mean:SD of triplicate wells. (Ca:Na) formulations act through TRP channels to reduce viral infection, ruthenium red (RR) and SKF96365, inhibitors C. TRP Channel Inhibition Reduces the Efficacy of a of TRP channel activity (calcium uptake) (see Table 2), were Calcium-Sodium Formulation Against Influenza in Normal employed. Calu-3 cells were pretreated with either 10 pull of Human Bronchial Epithelial Cells. RR (1 mM in PBS) or 10 pil of SKF96365 (10 mM in PBS) and [0140|| Normal human bronchial epithelial (NHBE) cells subsequently exposed to an 8×Ca:Na formulation (see Table were also used to test the effect of TRP channel antagonism US 2013/0203715 A1 Aug. 8, 2013 27 on Ca:Na formulation anti-viral activity. NHBE cell cultures were performed with an initial reverse transcription reaction, are multicellular (ciliated epithelial cells, non-ciliated cells, followed by a second amplification reaction that contained and goblet cells) and are comprised of primary cells cultured SYBR green. The relative expression levels of each gene were from human lung tissue samples. Treatment of NHBE cells determined using arbitrary cut-off points based on the expres with Ca:Na formulations significantly reduced influenza sion of housekeeping genes (GAPDH) and negative control infection and/or replication (see e.g., PCT/US10/28906 filed samples (no reverse transcription). Mar. 26, 2010, incorporated herein by reference). NHBE cells [0144] Of the 25 genes analyzed, 14 had cycle threshold were treated with ruthenium red (1 puM) immediately before (Ct) values of less than 30 in both cell types; thus, these 14 treatment of cells with an 8×Ca:Na formulation. The 8×Ca: TRP channel genes would be predicted to be expressed in Na formulation significantly reduced influenza infection Calu-3 and NHBE cells. Channels with a Cts 30 were: compared to untreated or ruthenium red treated cells in the TRPC1, TRPC6 (NHBE only), TRPV1, TRPV4, TRPV5, absence of Ca:Na treatment (FIG. 3; p-0.001 compared to TRPV6, TRPM2, TRPM4, TRPM6 (Calu-3 only), TRPM7, untreated control; one-way ANOVA with Tukey's multiple TRPM8 (Calu-3 only), TRPP1, TRPP3 and TRPML1 (FIG. comparison post-test). However, treatment of cells with 5). Six additional channels had Ct values between 30 and 35 ruthenium red before treatment with the 8×Ca:Na formula and could possibly be expressed in each cell type. These 6 tion blocked the anti-viral action of the Ca:Na formulation; TRP channels with a Ct between 30 and 35 were TRPC5, viral titers were similar to that of control cells (FIG. 3; p.<0. TRPV2, TRPV3, TRPM3, TRPM5, and TRPML2 (FIG. 5). 001 compared to untreated control; one-way ANOVA with The remaining channels had Ct values greater than 35 and Tukey’s multiple comparison post-test). were likely not expressed at detectable levels. Of the channels that the qPCR analysis identified as being expressed in the D. TRP Channel Inhibition Reduces the Efficacy of a Dry cells, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, TRPV6, Powder Calcium-Sodium Formulation Against Influenza. TRPM6 and TRPA1 have been described as being sensitive to ruthenium red. Thus, the qPCR analysis suggested that the [0141] Dry powder Ca:Na formulations have also been aforementioned channels could be those through which shown to reduce viral infection (see e.g., PCT/US10/28900 Ca:Na formulations were exerting their anti-viral effect. and PCT/US10/28917 filed Mar. 26, 2010, incorporated herein by reference). To test the effect of TRP channel antago Example 3 mists on the ability of dry powder Ca:Na formulations to inhibit viral replication, Calu-3 cells pre-treated with ruthe The TRPV4 Channel is Involved in Ca:Na nium red (1 puM) were subsequently treated with Formulation Formulation Reduction of Viral Infectivity I (10% leucine, 58.6% calcium lactate, 31.4% sodium chlo ride, weight percent) or Formulation II (10% leucine, 39.6% A. TRPV4 Channel Inhibition Reduces Ca:Na Formulation calcium chloride, 50.4% sodium sulfate, weight percent). Efficacy Against Influenza. Three hours later, cells were washed to remove unattached [0145] To test if one of the aforementioned TRP channels virus, and again treated with ruthenium red. The delivered identified above, TRPV4, was involved in mediating Ca:Na dose of Formulation I was 11.6 pig Ca/cm alone and 12.1 p.g formulation anti-viral activity, RN1734, a specific TRPV4 Ca/cm with ruthenium red. The delivered dose of Formula channel antagonist was tested for its ability to inhibit Ca:Na tion II was 11.7 pig Ca/cm alone and 11.8 pig Ca/cm with formulation reduction of viral infection. Calu-3 cells were ruthenium red. Compared to untreated or ruthenium red either untreated or with increasing concentrations of RN1734 treated cells, treatment of cells with Formulation I reduced (1 plm?, 10 puM and 100 puM). Cells were subsequently treated viral titer, and this reduction was attenuated by ruthenium red apically as described previously with an 8×Ca:Na formula (FIG. 4A, p<0.01 compared to untreated control; one-way tion alone, or in wells treated with RN1734 at various con ANOVA with Tukey’s multiple comparison post-test). Simi centrations. One hour later, cells were infected with influenza larly, the reduction of influenza infection by treatment of cells virus and 3 hours after that, washed to remove unattached with Formulation II was attenuated by ruthenium red (FIG. virus, at which point the cells were treated again with 4B; p-0.05 compared to untreated control; one-way ANOVA RN1734. Twenty four hours after infection viral titers were with Tukey’s multiple comparison post-test). Each data point determined from the apical surface of the cultures in a TCIDso is the mean:SD of triplicate wells. assay. RN1734 inhibited the 8×Ca:Na formulation-mediated [0142] Altogether, these data suggested that Ca:Na formu reduction of influenza infection in a dose dependent manner lations act through ruthenium red-sensitive TRP channels to (FIG. 6; p.<0.01 (1 mM, 10 puM RN1734), p<0.001 (100 mM reduce viral infection. RN1734) compared to untreated control; one-way ANOVA with Tukey’s multiple comparison post-test). Each bar Example 2 depicts the mean:SD for each condition and data are pooled from two independent studies, each performed in duplicate. Numerous TRP Channels are Expressed in Calu-3 These data indicated that pretreatment of cells with a TRPV4 and NHBE Cells channel inhibitor blocked the anti-viral action of Ca:Na for [0143] Twenty-eight different TRP channels have been mulations and suggested that TRPV4 is one TRP channel identified in mammals. To determine which TRP channels through which Ca:Na formulations exert their effects. were present and potentially being inhibited by ruthenium red in Calu-3 and NHBE cells, TRP channel gene expression was B. TRPV4 Activation Reduces Viral Infection. analyzed by quantitative PCR (qPCR). Quantitative PCR [0146) Given that Ca:Na formulations appeared to act analysis was performed using total cellular RNA from Calu-3 through TRPV4 channels, activation of TRPV4 with specific and NHBE cells and oligonucleotides specific to each of the agonists should mimic the anti-viral effects of Ca:Na formu indicated channels (see FIG. 5). Two-step PCR reactions lations. TRPV4 agonists 40-Phorbol 12,13-didecanoate US 2013/0203715 A1 Aug. 8, 2013 28

(40 PDD) (Sigma-Aldrich, St. Louis, Mo.), GSK1016790A red treatment were also tested for anti-viral activity using (Sigma-Aldrich, St. Louis, Mo.) and RN1747 (Menai Organ specific TRP channel agonists. Specifically, Calu-3 cells were ics, Gwynedd, UK) were employed in these experiments. The pre-treated with the indicated concentrations of menthol apical surface of Calu-3 cells was treated with 10 pil of each (TRPM8 and TRPV3 agonist) (FIG.10A), carvacrol (TRPV3 TRPV4 agonist diluted to the indicated concentrations in PBS and TRPA1 agonist) (FIG. 10B), icilin (TRPM8 and TRPA1 (see FIG. 7). One hour later, the cells were infected with agonist) (FIG. 10C), flufenamic acid (TRPC6 and TRPA1 Influenza A (H3N2). Three hours after infection, the apical agonist) (FIG. 11A) or allicin (TRPA1 agonist) (FIG. 11B) in surface of the Transwells was washed with PBS to remove 10 pull of PBS. In some studies, cells were also treated with unattached virus and the same concentrations of 40 PDD, 40 PDD (10 pull PBS) to assess the anti-viral activity of the GSK1016790A and RN1747 were added to the apical surface TRP channel agonists relative to that resulting from TRPV4 of the appropriate wells. Twenty-four hours after infection, activation. As described above, cells were infected with influ virus released onto the apical surface of infected cells was enza virus 1 hour after agonist pre-treatment, washed 3 hours collected in culture media or PBS, and the concentration of later with PBS, agonist reapplied at the appropriate concen virus in the apical wash was quantified in a TCIDso assay. The trations and viral titer assayed (TCIDso) 24 hours after infec mean:SD of duplicate or triplicate wells is shown for each tion. The mean:SD of replicate wells is shown for each condition. All the TRPV4 agonists reduced influenza infec condition. Menthol (FIG. 10A), carvacrol (FIG. 10B), flufe tion independent of the presence of Ca:Na formulations with namic acid (FIG. 11A) and allicin (FIG. 11B) all reduced GSK10168790, an extremely potent TRPV4 agonist (Thor influenza titer in a dose responsive manner, although none of neole et al., J Pharm Exp Ther 326:432-442, 2008), demon these agonists were as effective as the TRPV4 agonist strating the highest level of anti-viral efficacy in a dose 40 PDD. Application of icilin resulted in a small, but measur dependent manner. Overall, the data implicated TRPV4 as able reduction of influenza titer (FIG. 10C). The level of potentially mediating the anti-viral effect of the Ca:Na for reduction of influenza infection by the various TRP channel mulations. agonists tested is quantified and summarized in Table 4. C. TPV4 Activation Reduces Parainfluenza and Rhinovirus Infection. TABLE 4 [0147] To determine if TRPV4 activation reduced infection Reduction of Influenza Infection of viruses other than influenza, TRPV4 agonists were also Active Max reduction in tested against parainfluenza and rhinovirus. Experiments Agonist Target concentrations titer (Log10) were performed as described above for influenza virus. Briefly, Calu-3 cells were pretreated with different doses of 4aPDD TRPV4 –9 to —5M 2.9 GSK1016790A TRPV4 —11 to —6M 5.0 40PDD (0.1 mM to 10 puM) in 10 pull PBS or with PBS alone. RN1747 TRPV4 –8 to —4M 2.3 One hour later cells were infected with either parainfluenza Capsacin TRPV1 –8 to —4M 2.2 (hPIV3) or rhinovirus (RV16). Cells were then washed 3 Resiniferatoxin TRPV1 –6 to —4M 3.3 hours after infection to remove unattached virus and 40 PDD Allicin TRPA1 –6 to —4M 1.6 Icillin TRPA1 –6 to —4M 1 reapplied at the appropriate concentrations. Twenty-four Carvacrol TRPA1 –6.5 to —4M 3 hours after infection, viral titers were determined by a TRPM8 TCIDso assay. The average +SD of duplicate or triplicate Menthol TRPV3 –7 to —4M 2.5 wells is shown for each virus. 40 PDD was able to reduce both TRPM8 parainfluenza (FIG. 8A) and rhinovirus (FIG. 8B) infection. Flufenamic acid TRPC6 –6 to —4M 2.5 Thus, these results suggested that TRPV4 activation resulted in a broad-spectrum anti-viral activity. [0150] In all, the data suggested that several TRP channels D. TRPV4 Activation Inhibits Influenza Infection of NHBE were involved in the observed anti-viral activity of Ca:Na Cells. formulations. [0148] The anti-viral effect of TRPV4 activation was fur [0151] While this invention has been particularly shown ther tested in primary cells cultured from human lung tissue and described with references to preferred embodiments samples. NHBE cells were pre-treated with 40 PDD or thereof, it will be understood by those skilled in the art that GSK1016790A diluted in 10 pil of PBS to 1 puM one hour various changes in form and details may be made therein prior to infection with influenza. Cells were washed with PBS without departing from the scope of the invention encom 3 hours after infection to remove unattached virus and ago passed by the appended claims. nists reapplied. After 24 hours, the apical surface of cells was [0152] The teachings of all patent documents cited herein rinsed and influenza viral titer assayed by TCIDso. The are incorporated herein by reference. mean:SD of duplicate wells is shown for each condition. As What is claimed is: seen in Calu-3 cells, treatment of NHBE cells with TRPV4 1. A method of treating or preventing a respiratory infec agonists reduced influenza replication compared to untreated tion, comprising administering to an individual in need (PBS control) cells (FIG. 9; p-0.01 compared to untreated thereof an effective amount of an agonist of a TRP channel control; one-way ANOVA with Tukey's multiple comparison selected from the group consisting of TRPV2, TRPV3, post-test). TRPV4, TRPC6, TRPM6, TRPA1, and combinations Example 4 thereof. 2. The method of claim 1, wherein said respiratory infec Activation of Other TRP Channels Reduces tion is a bacterial infection. Influenza Infection 3. The method of claim 2, wherein said bacterial infection [0149] The activation of other TRP channels identified by comprises infection by a pathogen selected from the group qPCR analysis and those known to be sensitive to ruthenium consisting of Streptococcus pneumoniae, Staphylococcus US 2013/0203715 A1 Aug. 8, 2013 29 aureus, Staphylococcus spp., Streptococcus spp., Streptococ (OAG), carbachol, diacylglycerol (DAG), 1,2-Didecanoylg cus agalactiae, Haemophilus influenzae, Klebsiella pneumo lycerol, flufenamate/flufenamic acid, niflumate/niflumic niae, Escherichia coli, Pseudomonas aeruginosa, Moraxella acid, hyperforin, 2-aminoethoxydiphenyl borate (2-APB), catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneu diphenylborinic anhydride (DPBA), delta-9-tetrahydrocan moniae, Legionella pneumophila, Enterobacter spp., Acine nabinol (A*-THC or THC), cannabiniol (CBN), 2-APB, tobacter spp., Acinetobacter baumannii, methicillin-resistant O-1821, 11-hydroxy-A*-tetrahydrocannabinol, nabilone, Staphylococcus aureus, Stenotrophomonas maltophilia, CP55940, HU-210, HU-211/dexanabinol, HU-331, HU-308, Burkholderia spp., Yersinia enterocolitica, Mycobacterium JWH-015, WIN55,212-2, 2-Arachidonoylglycerol (2-AG), tuberculosis, Bordetella pertussis, Bordetella bronchisep Arvil, PEA, AM404, O-1918, JWH-133, incensole, incensole tica, Brucella spp., Brucella abortus, Brucella melitensis, acetate, menthol, eugenol, dihydrocarvedl, carvedl, thymol, Brucella suis, Chlamydophila psittaci, Clostridium tetani, vanillin, ethyl vanillin, cinnemaldehyde, 2 aminoethoxy Streptococcus pyogenes, Corynebacterium diphtheriae, diphenyl borate (2-APB), diphenylamine (DPA), diphenyl Neisseria meningitides, Enterococcus faecalis, Francisella borinic anhydride (DPBA), camphor, (+)-borneol, (–)-isopi tularensis, Bacillus anthracis, Helicobacter pylori, Lep nocampheol, (–)-fenchone, (–)-trans-pinocarveol, tospira spp., Leptospira interrogans, Listeria monocytogenes, isoborneol, (+)-camphorquinone, (-)-O-thujone, Cº-pinene Rickettsia rickettsii, Salmonella spp. Shigella sonnei, Vibrio oxide, 1,8-cineole/eucalyptol, 6-tert-butyl-m-cresol, carvac cholerae, and Yersinia pestis. rol, p-sylenol, kreosol, propofol, p-cymene, (–)-isoppulegol, 4. The method of claim 1, wherein said respiratory infec (-)-carvone, (+)-dihydrocarvone, (-)-menthone, (+)-lina tion is a viral infection. lool, geraniol, 1-isopropyl-4-methyl-bicyclo[3.1.0]hexan-4 5. The method of claim 4, wherein said viral infection ol, 40 PDD, GSK1016790A, 5'6'Epoxyeicosatrienoic comprises infection by a pathogen selected from the group 8'9"Epoxyeicosatrienoic (8'9"-EET), APP44-1, RN1747, For consisting of influenza virus, rhinovirus, parainfluenza virus, mulation Ib WO200602909, Formulation IIb WO200602909, respiratory syncytial virus (RSV), metapneumovirus, aden Formulation IIc WO200602929, Formulation IId ovirus, herpes simplex virus, cytomegalovirus (CMV), coro WO200602929, Formulation IIIb WO200602929, Formula navirus, hantavirus, coxsackievirus, rhinovirus, enterovirus, tion IIIc WO200602929, arachidonic acid (AA), 12-O-Tet human bocavirus (HBoV). radecanoylphorbol-13-acetate (TPA)/phorbol 12-myristate 6. The method of claim 1, wherein said TRP channel ago 13-acetate (PMA), bisandrographalide (BAA), incensole, nist is administered as an aerosol to the respiratory tract of incensole acetate, Compound DK WO2010015965, Com said individual. pound X WO2010015965, Compound XI WO2010015965, 7. The method of claim 1, further comprising administer Compound XII WO2010015965, WO2009004071, ing one or more co-therapeutic agents selected from the group WO2006038070, WO2008065666, Formula VII WO2010015965, Formula IV WO2010015965, diben consisting of mucoactive or mucolytic agents, surfactants, zoazepine, dibenzooxazepine, Formula I WO2009071631, cough suppressants, expectorants, steroids, bronchodilators, N-(1S)-1-[({(4R)-1-[(4-chlorophenyl)sulfonyl]-3-oxo antihistamines, anti-inflammatory avents, antibiotics, and hexahydro-1H-azepin-4-yl)amino)earbonyl]-3-methylbu antiviral agents. ty1}-1-benzothiophen-2-carboxamide, N-(1S)-1-[({(4R)-1 8. The method of claim 1, wherein an agonist of TRPV4 is [(4-fluorophenyl)sulfonyl]-3-oxohexahydro-1'-1-azepin-4 administered. y1}amino)carbonyl]-3-methylbutyl)-1-benzothiophen-2 9. A method of treating a respiratory infection, comprising carboxamide, N-(1S)-1-[({(4R)-1-[(2-cyanophenyl) administering to an individual having a respiratory infection sulfonyl]-3-oxohexahydro-1H-azepin-4-yl)amino) an effective amount of a TRP channel agonist selected from carbonyl]-3-methylbutyl)-1-methyl-1H-indole-2 the group consisting of Allyl isothiocyanate (AITC), Benyzl carboxamide, and N-(1S)-1-[({(4R)-1-[(2-cyanophenyl) isothiocyanate (BITC), Phenyl isothiocyanate, Isopropyl sulfonyl]hexahydro-1H-azepin-4-yl)amino)carbonyl]-3 isothiocyanate, methyl isothiocyanate, diallyl disulfide, methylbutyl}-1-methyl-1H-indole-2-carboxamide. acrolein (2-propenal), disulfuram (Antabuse?), farnesyl thiosalicylic acid (FTS), farnesylthioacetic acid (FTA), chlo 10. The method of claim 9, wherein said respiratory infec dantoin (Sporostacinº, topical fungicidal), (15-d-PGJ2), 5,8, tion is a bacterial infection. 11,14 eicosatetraynoic acid (ETYA), dibenzoazepine, mefe 11. The method of claim 10, wherein said bacterial infec namic acid, fluribiprofen, keoprofen, diclofenac, tion comprises infection by a pathogen selected from the indomethacin, SC alkyne (SCA), pentenal, mustard oil group consisting of Streptococcus pneumoniae, Staphylococ alkyne (MOA), iodoacetamine, iodoacetamide alkyne, cus aureus, Staphylococcus spp., Streptococcus spp., Strep (2-aminoethyl) methanethiosulphonate (MTSEA), 4-hy tococcus agalactiae, Haemophilus influenzae, Klebsiella droxy-2-noneal (HNE), 4-hydroxy xexenal (HHE), 2-chlo pneumoniae, Escherichia coli, Pseudomonas aeruginosa, robenzalmalononitrile, N-chloro tosylamide (chloramine-T), catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneu formaldehyde, isoflurane, isovelleral, hydrogen peroxide, moniae, Legionella pneumophila, Enterobacter spp., Acine URB597, thiosulfinate, Allicin (a specific thiosulfinate), tobacter spp. Acinetobacter baumannii, methicillin-resistant flufenamic acid, niflumic acid, carvacrol, eugenol, menthol, Staphylococcus aureus, Stenotrophomonas maltophilia, gingerol, icilin, methyl salicylate, arachidonic acid, cinnem Burkholderia spp., Yersinia enterocolitica, Mycobacterium aldehyde, super sinnemaldehyde, tetrahydrocannabinol tuberculosis, Bordetella pertussis, Bordetella bronchisep (THC or A*-THC), cannabidiol (CBD), cannabichromene tica, Brucella spp., Brucella abortus, Brucella melitensis, (CBC), cannabigerol (CBG), THC acid (THC-A), CBD acid Brucella suis, Chlamydophila psittaci, Clostridium tetani, (CBD-A), Compound 1 (AMG5445), 4-methyl-N-(2,2,2 Streptococcus pyogenes, Corynebacterium diphtheriae, trichloro-1-(4-chlorophenylsulfanyl)ethyl]benzamide, N-(2, Neisseria meningitides, Enterococcus faecalis, Francisella 2,2-trichloro-1-(4-chlorophenylsulfanyl)ethyl]acetamid, tularensis, Bacillus anthracis, Helicobacter pylori, Lep AMG9090, AMG5445, 1-oleoyl-2-acetyl-sn-glycerol tospira spp., Leptospira interrogans, Listeria monocytoge US 2013/0203715 A1 Aug. 8, 2013 30 nes, Rickettsia rickettsii, Salmonella spp., Shigella sonnei, Vibrio cholerae, and Yersinia pestis. 12. The method of claim 9, wherein said respiratory infec tion is a viral infection. 13. The method of claim 12, wherein said viral infection comprises infection by a pathogen selected from the group consisting of influenza virus, rhinovirus, parainfluenza virus, respiratory syncytial virus (RSV), metapneumovirus, aden ovirus, herpes simplex virus, cytomegalovirus (CMV), coro navirus, hantavirus, coxsackievirus, rhinovirus, enterovirus, human bocavirus (HBoV). 14. The method of claim 9, wherein said TRP channel agonist is administered as an aerosol to the respiratory tract of said individual. 15. The method of claim 9, further comprising administer ing one or more co-therapeutic agents selected from the group consisting of mucoactive or mucolytic agents, surfactants, cough suppressants, expectorants, steroids, bronchodilators, antihistamines, anti-inflammatory agents, antibiotics, and antiviral agents. 16. A method of treating a respiratory infection, compris ing administering to an individual having a respiratory infec tion an effective amount of an agonist of TRPV4, wherein the agonist is selected from the group consisting of 40 PDD, GSK1016790A, and RN1747. 17.-18. (canceled)