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(12) Patent Application Publication (10) Pub. No.: US 2011/0171195 A1 Abraham Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0171195 A1 Abraham Et Al US 2011 0171195A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0171195 A1 Abraham et al. (43) Pub. Date: Jul. 14, 2011 (54) METHODS AND COMPOSITIONS FOR A 6LX 3L/7076 (2006.01) TREATING URINARY TRACT INFECTIONS A638/17 (2006.01) USINGAGENTS THAT MIMIC OR ELEVATE A 6LX 3L/739 (2006.01) CYCLICAMP A6II 3/66 (2006.01) A63L/7028 (2006.01) (75) Inventors: Soman N. Abraham, Chapel Hill, A6II 3/448 (2006.01) NC (US); Brian L. Bishop, A6II 3/34 (2006.01) Durham, NC (US); Matthew J. A6II 3/423 (2006.01) Duncan, Duncan, SC (US); K. A6II 3/545 (2006.01) Ranga Rama Krishnan, Chapel A63L/43 (2006.01) Hill, NC (US); Jeongmin Song, A63L/65 (2006.01) Chapel Hill, NC (US); Guojie Li, A6IP3L/04 (2006.01) Charlotte, NC (US); David A. Zaas, A6IP3L/00 (2006.01) Chapel Hill, NC (US) A6IP3/00 (2006.01) (73) Assignee: Duke University, Durham, NC (52) U.S. Cl. ... 424/94.5: 514/766; 514/455; 514/254.11: (US) 514/699; 514/393: 514/654: 514/653: 514/46; 514/24: 514/54: 514/77: 514/25; 514/352; (21) Appl. No.: 12/663,959 514/.461; 514/375; 514/200: 514/192: 514/154 (22) PCT Filed: Jun. 12, 2008 (57) ABSTRACT (86). PCT No.: PCT/USO8/66647 Methods and compositions are provided for treating a urinary tract infection (UTI). The methods involve administering to a S371 (c)(1), subject in need thereof a cAMP elevator or agent that mimics (2), (4) Date: Sep. 21, 2010 cAMP particularly a labdane diterpene such as forskolin or a derivative or analog thereof in a therapeutically effective Related U.S. Application Data amount to treat a UTI. The methods may further include administration of at least one cAMP elevator in combination (60) Provisional application No. 60/944,182, filed on Jun. with one or more additional active compounds from other 15, 2007. classes of therapeutic agents, such as antimicrobial agents or O O cholesterol lowering drugs. Compositions of the invention Publication Classification include pharmaceutical compositions and kits for treating a (51) Int. Cl. UTI in a subject in need thereof that include therapeutically A6 IK 38/45 (2006.01) effective amounts of at least two cAMP elevators, particularly A6 IK3I/05 (2006.01) where one of the cAMP elevators is a labdane diterpene such A6 IK3I/352 (2006.01) as forskolin or a derivative oranalog thereof. In particular, the A6 IK 3/496 (2006.01) compositions and kits may also include at least one cAMP A6 IK3I/II (2006.01) elevator in combination with one or more additional active A6 IK 3/462 (2006.01) compounds from other classes of therapeutic agents. Such as A6 IK3I/37 (2006.01) antimicrobial agents or cholesterol lowering drugs. Patent Application Publication Jul. 14, 2011 Sheet 1 of 19 US 2011/0171195 A1 Patent Application Publication Jul. 14, 2011 Sheet 2 of 19 US 2011/0171195 A1 Figure 2 Patent Application Publication Jul. 14, 2011 Sheet 3 of 19 US 2011/0171195 A1 Figure 3 : 100% : 40% C SS 80% is 30% 3 60% 3. 8E E g a g 20% S R 40% E SRO t 3 10% s gS. S. 20% g & 0% is 0% : Forskolin dibutyryl ionophore E, CO. E. COf E. COlf (100M) cAMP (1 M) + NC + H89 (1 mM) Patent Application Publication Jul. 14, 2011 Sheet 4 of 19 US 2011/0171195 A1 Figure 4 anti-CD63 anti-CD63 The CG Patent Application Publication Jul. 14, 2011 Sheet 5 of 19 US 2011/0171195 A1 Figure 5 a 5 140% b. 3,500 120% as 3,000 100% 5 2,500 is 80% is 2,000 60% 1,500 S 40% 1,000 8 20% soo 5 o. 24 48 72 96 i2O S. SS SS . s s s: Time after invasion (h) s' & y : C S9, d is 140% 14% 120% F429, * 09: 8 is 10% *se - SE 8% ...3 80% 6%% 3.is sor). fig 29, is 20% O3. lii O% s°& N is & - gSNN s&X C oS Patent Application Publication Jul. 14, 2011 Sheet 6 of 19 US 2011/0171195 A1 Figure 6 1509. 1259, 100% S. O 25 Control Bafilomycin NH4C NHCl (1 um) (10pmM (50mM Patent Application Publication Jul. 14, 2011 Sheet 7 of 19 US 2011/0171195 A1 Figure 7 C 5ww. 150% d 50C E 25% 85 i25% Ye-s OO% kiit. OO3: 53. s 75: S 50% Egg 50% g : is 25% 25% O8. CO?tro FSkol- Cotrol F. Ski- Salig Forskoli E. treated Safaria treated EC S. enerica e 150% f 140% 25%. 5re. 20% i s 100% 8 1009: is 8 80% 5 : 75% 32 st s: ass 3. 60% - 50%: al 40% 25% i. 2O, O% O' Salie Forskol Saline Foskolin Salie Forskoli Before treatlet 18 after treatmelt Patent Application Publication Jul. 14, 2011 Sheet 8 of 19 US 2011/0171195 A1 Figure 8 5 Patent Application Publication Jul. 14, 2011 Sheet 9 of 19 US 2011/0171195 A1 Figure 9 OOOOO OOOOO DOD) OOO i OO O -a-V- - - - - - - Contro - - - - - - - - - - - - - - - - - - - - - - - - -: IPFskp Fsk catheter FskFisk - - - - - - - ---------- Series A2OOO 1653 Patent Application Publication Jul. 14, 2011 Sheet 10 of 19 US 2011/0171195 A1 Figure 10 Utreated TLR4 ligand (LPS) Patent Application Publication Jul. 14, 2011 Sheet 11 of 19 US 2011/0171195 A1 Figure 11 Forskoin W Caffeine s s s se* treate M foskir Caffeire fSKO Caffere Patent Application Publication Jul. 14, 2011 Sheet 12 of 19 US 2011/0171195 A1 Figure 12 Forskolin wi Papaverine as E s as--- E.i Patent Application Publication Jul. 14, 2011 Sheet 13 of 19 US 2011/0171195 A1 Figure 13 Forskoi w BMX s 8. s treated Of fisk in Ly BX OO M forskor 5 y BMX Patent Application Publication Jul. 14, 2011 Sheet 14 of 19 US 2011/0171195 A1 Figure 14 Forski w EHNA 35 as 's Untreated 1 Oji forskirt a y EHNA forskoli 20 EHA Patent Application Publication Jul. 14, 2011 Sheet 15 of 19 US 2011/0171195 A1 Figure 15 Forskolin wi Rolipram as {Css -9 's Untreated 1 OOM forskolin 40DuM roljpram 1 OUM fori 400 M r Patent Application Publication Jul. 14, 2011 Sheet 16 of 19 US 2011/0171195 A1 Figure 16 Forskolin wi Zaprinast as in so 's ritreated M foski 2 Zapirast frSkif M Zaprinas Patent Application Publication Jul. 14, 2011 Sheet 17 of 19 US 2011/0171195 A1 Figure 17 C lostami de -PDE3 inhibitor 40%|OJ?uOO Patent Application Publication Jul. 14, 2011 Sheet 18 of 19 US 2011/0171195 A1 Figure 18 PMA-PKC activator 120 . OO 80 60 40 20 Untreated 1UM PMA 2uM PMA 4M PMA Patent Application Publication Jul. 14, 2011 Sheet 19 of 19 US 2011/0171195 A1 Figure 19 4OO oh wu 35O O O 3OO () re O) 250 o 2OO SSup 150 O Ce O X o D O Li US 2011/0171195 A1 Jul. 14, 2011 METHODS AND COMPOSITIONS FOR Such embodiment, the other class of therapeutic agents TREATING URINARY TRACT INFECTIONS includes any agent in use or in development to treat a UTI. USINGAGENTS THAT MIMIC OR ELEVATE including antimicrobial agents such as, for example, antibi CYCLICAMP otics, and drugs that block bacterial adherence to the bladder wall. In another embodiment, the other class of therapeutic FEDERALLY SPONSORED RESEARCHOR agents includes cholesterol lowering drugs. DEVELOPMENT 0007 Compositions of the invention include pharmaceu 0001. This invention was made with government support tical compositions and kits for treating a UTI in a subject in under grant number R37 DK50814 awarded by the National need thereof. In some embodiments, the pharmaceutical com Institutes of Health. The United States government has cer positions and kits include therapeutically effective amounts of at least two cAMP elevators or agents that mimic cAMP. tain rights in the invention. and optionally one or more additional active compounds from FIELD OF THE INVENTION other classes of therapeutic agents. In other embodiments, the pharmaceutical compositions and kits include one or more 0002 The presently disclosed subject matter relates to cAMP elevator or agent that mimics cAMP in combination methods and compositions to treat urinary tract infections with at least one additional active compound from other using agents that mimic or elevate intracellular levels of classes of therapeutic agents. cAMP. BRIEF DESCRIPTION OF THE DRAWINGS BACKGROUND 0008 FIG. 1 shows transmission electron micrographs of 0003 Urinary tract infections (UTIs) represent one of the uropathogenic E. coli (UPEC) invading superficial bladder most common bacterial infections in humans. Each year at epithelial cells (BECs) through fusiform canals. (A) Unin least 4 million patients (mostly women) seek treatment for fected bladder epithelium showing scalloped plaques in the UTIs, and approximately $1.6 billion will be spent in the lumenal surface as well as in intracellular fusiform vesicles diagnosis and treatment of UTIS. Frequent recurrences in (scale bars-2 um). (B and C) Attachment of E. coli CI5 to healthy adult females after an initial bout of UTI continue to Scalloped plaques of the BEC lumenal Surface appear to asso frustrate clinicians. Patients with recurrent UTIs are often ciate with fusion of fusiform vesicles at the attachment site subjected to sustained “suppressive' antibiotic therapy, (arrows) (scale bars-4 um). (D) E. coli CI5 were found in which can be toxic to various organs of the body. Addition tubular, scallop-shaped canals within Superficial BECs (the ally, constant use of antibiotics can result in the development tubular canal retains a scalloped appearance as sequestered of multiresistant bacteria. bacteria are no longer in direct contact with the lumenal 0004 To date, most treatment strategies for UTIs have surface of the bladder; scale bars-4 um).
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