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(12) Patent Application Publication (10) Pub. No.: US 2010/0022563 A1 Henkin (43) Pub US 2010.0022563A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0022563 A1 Henkin (43) Pub. Date: Jan. 28, 2010 (54) PHOSPHODIESTERASE INHIBITOR Publication Classification TREATMENT (51) Int. Cl. (76) Inventor: Robert I. Henkin, Bethesda, MD A6II 3/522 (2006.01) (US) A6II 3/47 (2006.01) A6IP27/00 (2006.01) Correspondence Address: WILSON, SONSINI, GOODRICH & ROSATI 650 PAGE MILL ROAD (52) U.S. Cl. .................................... 514/263.34: 514/312 PALO ALTO, CA 94304-1050 (US) (21) Appl. No.: 12/508,530 (57) ABSTRACT (22) Filed: Jul. 23, 2009 Methods and compositions are disclosed for the treatment of diseases or conditions produced by or associated with low Related U.S. Application Data cyclic nucleotide levels. The compositions comprise phos (60) Provisional application No. 61/083,147, filed on Jul. phodiesterase inhibitors and are formulated for intranasal and 23, 2008. pulmonary administration. : *xissists 3rs:xxxx x . 3:23888 &gt; 88: ----------------------------------- 8 8888.88 keigorowed & 88: 38 easixts 8xxx 8.8% : : 8: 28 assets agrew &c: : x is 888 satients retired a : 888 sig. 8: 83883. 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Patent Application Publication Jan. 28, 2010 Sheet 5 of 5 US 2010/0022563 A1 3. i i i : 3 i 3. : I . US 2010/0022563 A1 Jan. 28, 2010 PHOSPHODESTERASE INHIBITOR 0007. In one aspect of the invention, a method is provided TREATMENT for treating anoSmia or hyposmia comprising administering to a patient in need, an effective amount of a PDE inhibitor, CROSS-REFERENCE wherein the blood concentration of the PDE inhibitor does 0001. This application claims the benefit of U.S. Provi not exceed 1 mg/dl. sional Application No. 61/083,147, filed Jul. 23, 2008, incor 0008. In another aspect of the invention, a method is pro porated herein by reference in its entirety. vided for increasing nasal mucus or saliva cyclic adenosine 3',5'-monophosphate (cAMP) or cyclic guanosine 3',5'- BACKGROUND OF THE INVENTION monophosphate (cGMP) levels comprising administering by intranasal administration to a patient in need, an effective 0002 Phosphodiesterases (PDE) are a diverse family of amount of a phosphodiesterase (PDE) inhibitor, whereby the enzymes that hydrolyse cyclic nucleotides resulting in the cAMP or cGMP levels are increased at least 10% over the modulation of intracellular levels of the second messangers untreated level. cAMP and cQMP, and hence, cell function. Numerous dis 0009. In one aspect, a method is provided for increasing eases and conditions result from low levels of cyclic nucle taste or Smell acuity comprising administering to a patient in otides. The use of PDE inhibitors to raise cellular levels of need, an effective amount of a PDE inhibitor, wherein the cyclic nucleotides offers the ability to prevent, treat, or ame PDE inhibitor is administered by intranasal administration liorate diseases, conditions or their symptoms, however, sys and wherein taste or Smell acuity is increased. In some temic administration may not achieve therapeutically effec embodiments, taste or smell acuity is increased at least 5% or tive concentrations due to unacceptable side effects or to 10% over pre-treatment levels. In some embodiments, taste or inability to obtain therapeutic levels in clinically responsive smell acuity is measured objectively, while in other embodi tissues. There is a need for Suitable compositions and meth ments, it is subjectively. In further embodiments, the increase ods of delivery to achieve medically relevant concentrations in taste or Smell acuity is accompanied by an increase in nasal of PDE inhibitors without unacceptable side effects. The mucus or saliva cAMP or cGMP levels. In some embodi present invention addresses these unmet needs. ments, nasal mucus or saliva cAMP or cGMP levels increase at least 10% compared to the untreated state. SUMMARY OF INVENTION 0010. In another aspect, a method is provided for compen 0003. In one aspect of the invention, a method is provided sating for a pathologic rate of cAMP or cGMP metabolism for treating anoSmia, hyposmia, ageusia, or hypogeusia com comprising administering to a patient in need, an effective prising administering by intranasal administration to a amount of a PDE inhibitor, wherein the PDE inhibitor is patient, an effective amount of a phosphodiesterase (PDE) administered by intranasal administration and wherein inhibitor that treats the patient's anoSmia, hyposmia, ageusia, cAMP or cGMP metabolism is decreased. In some embodi or hypogeusia. In one embodiment, the PDE inhibitor is a ments, the blood concentration of the PDE inhibitor does not non-selective PDE inhibitor, PDE-1 selective inhibitor, exceed 1 mg/dl. PDE-2 selective inhibitor, PDE-3 selective inhibitor, PDE-4 0011. In one aspect of the invention, a method is provided selective inhibitor, or a PDE-5 selective inhibitor. In another for screening patients for suitability for PDE inhibitor therapy embodiment, the non-selective PDE inhibitor is a methylx for anoSmia, hyposmia, ageusia or hypogeusia by adminis anthine derivative. In a further embodiment the methylxan tering to a patient a challenge dose of a PDE inhibitor; deter thine derivative is caffeine, theophylline, IBMX (3-isobutyl mining the nasal mucus or salivary level of c(3MP; and com 1-methylxanthine) aminophylline, doxophylline, paring the patient's coMP level to a threshold value, wherein cipamphylline, neuphylline, pentoxiphylline, or diprophyl patients who have acci MP level equal to or greater than the line. In a particular embodiment, the methylxanthine deriva threshold value are candidates for PDE inhibitor therapy to tive is theophylline or pentoxiphylline. In one embodiment treat anoSmia, hyposmia, ageusia or hypogeusia. the PDE-3 inhibitor is ciloStaZol. 0012. In another aspect of the invention, a pharmaceutical 0004. In some embodiments, the effective amount of the composition for intranasal administration is provided com PDE inhibitor is less than 2 mg. In other embodiments, the prising a phosphodiesterase (PDE) inhibitor, wherein the effective amount is less than 1 mg, 500 ug. 250L, or 100 ug. In composition comprises less than 1 mg of the PDE inhibitor one embodiment, the effective amount is 40 ug. and a pharmaceutically acceptable carrier. In some embodi 0005. In some embodiments, the PDE inhibitor is formu ments, the PDE inhibitor is selected from the group consisting lated as a liquid, while in other embodiments it is formulated of non-selective PDE inhibitors, PDE-1 selective inhibitors, as a dry powder. In some embodiments, the PDE inhibitor is PDE-2 selective inhibitors, PDE-3 selective inhibitors, administered as a liquid, gel, ointment, cream, spray, aerosol, PDE-4 selective inhibitors, and PDE-5 selective inhibitors. In or dry powder. In other embodiments, the PDE inhibitor is some embodiments, the PDE inhibitor is a non-selective PDE administered at least once, twice, or thrice daily. inhibitor, while in other embodiments, the non-selective PDE 0006. In some embodiments, successful treatment of inhibitor is a methylxanthine derivative. In further embodi anoSmia or hyposmia increases a patient's taste or Smell acu ments, the methylxanthine derivative is caffeine, theophyl ity by at least 5%. In other embodiments, taste or smell acuity line, IBMX (3-isobutyl-1-methylxanthine) aminophylline, is measured objectively, while in other embodiments, acuity doxophylline, cipamphylline, neuphylline, pentoxiphylline, is measured Subjectively. In some embodiments, the increase or diprophylline. In one embodiment, the methylxanthine in taste or Smell acuity is accompanied by an increase in nasal derivative is theophylline or pentoxiphylline. In a further mucus or saliva cAMP or cGMP levels. In further embodi embodiment, the PDE inhibitoris a PDE-3 selective inhibitor. ments, the increase in salivary or nasal mucus cAMP or In a still further embodiment, the PDE-3 selective inhibitor is cGMP level is at least 10% over the untreated level. cilostazol. US 2010/0022563 A1 Jan. 28, 2010 0013. In some embodiments the composition is a dry pow 0021. Theophylline is a methylxanthine derivative; other der. In other embodiments, the dry powder composition fur non-selective phosphodiesterase inhibitors in this class ther comprises an excipient. In further embodiments, the include caffeine, IBMX (3-isobutyl-1-methylxanthine, ami composition is a liquid. In some embodiments, the liquid nophylline, doxophylline, cipamphylline, theobromine, pen composition further comprises an excipient. In further toxifylline (oxpentifylline) and diprophylline. embodiments, the excipient is a preservative. 0022 PDE1 selective inhibitors formerly known as cal cium- and calmodulin-dependent phosphodiesterases include INCORPORATION BY REFERENCE eburnamenine-14-carboxylic acid ethyl ester (vinpocetine), 0014 All publications and patent applications mentioned used to induce vasorelaxtion on cerebral Smooth muscle tis in this specification are herein incorporated by reference to SU the same extent as if each individual publication or patent 0023 PDE2 decreases aldosterone secretion and is sug application was specifically and individually indicated to be gested to play an important role in the regulation of elevated incorporated by reference.
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