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.
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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. intracellular concentrations of cAMP and ccjMP in platelets. Several regions of the brain express PDE2 and rat experi BRIEF DESCRIPTION OF THE DRAWINGS ments indicate that inhibition of PDE2 enhances memory. PDE2 may play a role in regulation of fluid and cell extrava 0015 The novel features of the invention are set forth with sation during inflammatory conditions as PDE2 is localized particularity in the appended claims. A better understanding to microVessels, especially venous capillary and endothelial of the features and advantages of the present invention will be cells, but apparently not to larger vessels. PDE2 may also be obtained by reference to the following detailed description a good pharmacological target for pathological states Such as that sets forth illustrative embodiments, in which the prin sepsis or in more localized inflammatory responses such as ciples of the invention are utilized, and the accompanying thrombin-induced edema formation in the lung. PDE-2 selec drawings of which: tive inhibitors include EHNA (erythro-9-(2-hydroxy-3- 0016 FIG. 1 illustrates the structure of the patient flow of nonyl) adenine), 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4- the clinical trial showing the number and percentage of dimethoxybenzyl)-purin-6-one (PDP), and BAY 60-7750. patients that returned on theophylline treatment. Three hun (0024. The PDE3 family hydrolyzes cAMP and coMP but dred twelve patients began the study on 200 mg. If improved in a manner Suggesting that in Vivo, the hydrolysis of cAMP is <5% patient number indicates progression to next step up in inhibited by c0MP. They also are distinguished by their abil dose (400 mg, 600 mg. 800 mg). Left sided numbers (lines) ity to be activated by several phosphorylation pathways indicate numbers of distant patients who returned for first including the PKA and PI3K/PKB pathways. PDE3A is rela time (see text). Right sided numbers (lines) indicate patient tively highly expressed in platelets, as well as in cardiac numbers who improved <5% and returned on a higher dose. myocytes and oocytes. PDE3B is a major PDE in adipose Difference between right sided numbers and patient numbers tissue, liver, and pancreas, as well as in several cardiovascular who improved <5% (in right boxes) indicate number of tissues. Both PDE3A and PDE3B are highly expressed in patient drop outs at each dose. If improved 25% patient data vascular Smooth muscle cells and are likely to modulate con not included in further step-up doses. traction. 0017 FIG. 2A-B is a comparison of DT and RT values for 0025 PDE3 inhibitors mimic sympathetic stimulation to pyridine (PYRD), nitrobenzene (NO2B), thiophene (THIO) increase cardiac inotropy, chronotropy and dromotropy. and amyl acetate (AA) in 312 patients before treatment and in PDE3 inhibitors also antagonize platelet aggregation, all patients in each group after treatment with oral theophyl increase myocardial contractility, and enhance vascular and line at 200 mg, 400 mg, 600 mg and 800 mg (see Tables II, airway smooth muscle relaxation. PDE3A is a regulator of IV-VII). this process and PDE3 inhibitors effectively prevent aggre 0018 FIG. 3A-B is a comparison of ME and H values for gation. In fact one drug, cilastazol (Pletal), is approved for pyridine (PYRD), nitrobenzene (NO2B), thiophene (THIO) treatment of intermittent claudication. Its mechanism of and amyl acetate (AA) in 312 patients before treatment and in action is thought to involve inhibition of platelet aggregation all patients in each group after treatment with oral theophyl along with inhibition of smooth muscle proliferation and line at 200 mg, 400 mg, 600 mg and 800 mg (see Tables II, vasodilation. PDE3-selective inhibitors include enoximone, IV-VII). milrinone (Primacor), amrinone, cilostamide, cilostazol (Ple tal) and trequinsin. DETAILED DESCRIPTION OF THE INVENTION 0026 PDE4 inhibitors can effectively suppress release of 0019. Numerous PDEs are known with notable PDEs, inflammatory mediators e.g., cytokines, inhibit the produc their inhibitors and uses for these inhibitors listed below. tion of reactive oxygen species and immune cell infiltration. 0020. Theophylline and papaverine are representative PDE4-selective inhibitors include mesembrine, rolipram, members of non-specific PDE inhibitors that are prescribed Ibudilast, a neuroprotective and bronchodilator drug used orally to treat asthma and chronic obstructive pulmonary mainly in the treatment of asthma and stroke, and roflumilast disease (COPD) through the relaxation of smooth muscle in (Daxas) and cilomilast (Airflo), currently in phase III clinical the airways. Theophylline has anti-inflammatory effects on trials for treatment of chronic obstructive pulmonary disease. the airways that is useful to combat the abnormal inflamma Other inflammatory diseases for which PDE4 inhibitors are tion seen in asthmatics. Most importantly, this anti-inflam currently being developed include asthma, arthritis, and pso matory effect is found at levels in the blood well below that riasis. which causes the common side effects seen in most people. 0027 PDE5 is a regulator of vascular smooth muscle con Patients with emphysema and chronic bronchitis can also be traction best known as the molecular target for several well helped with theophylline when their symptoms are partially advertised drugs used to treat erectile dysfunction and pull related to reversible airway narrowing. monary hypertension. In the lung, inhibition of PDE5 US 2010/0022563 A1 Jan. 28, 2010
opposes smooth muscle vasoconstriction, and PDE5 inhibi receptor antagonists, thromboxane synthetase inhibitors, tors are in clinical trials for treatment of pulmonary hyper thromboxane A receptor antagonist, mediator release inhibi tension. tor, antihistamic agent, cytokine inhibitor, prostaglandins, 0028. PDE5-selective inhibitors include Sildenafil, tad forskolin, elastase inhibitor, Steroid, expectorant, or antibac alafil. Vardenafil, udenafil and avanafil. terial agent. The other medicaments can be administered 0029 PDE inhibitors inhibit cellular apoptosis by inhibit simultaneously with, Subsequently to, or prior to administra ing TNFalpha, TRAIL and their metabolites. PDE inhibitors tion of the PDE inhibitors. activate the production and secretion of nitric oxide in all 0036. In one embodiment, the patient is administered a tissues thereby inducing vasorelaxation or vasodilation of all therapeutically effective amount of a PDE inhibitor and a blood vessels including those of the peripheral blood vessels vasoactive agent. A vasoactive agent is any therapeutic agent (inhibiting intermittent claudication), the distal extremities capable of relaxing vascular Smooth muscle. Suitable vaso and in the penile region contributing to penile erection. active agents include, but are not limited to, potassium chan 0030 PDE inhibitors useful in the present invention nel activators (such as, for example, nicorandil, pinacidil, include, for example, filaminast, piclamilast, rolipram, Org cromakalim, minoxidil, aprilkalim, loprazolam and the like); 20241, MCI-154, roflumilast, toborinone, posicar, lixazi calcium blockers (such as, for example, nifedipine, Vera none, Zaprinast, sildenafil, pyrazolopyrimidinones (such as parmil, diltiazem, gallopamil, niludipine, nimodipins, nicar those disclosed in WO98/491.66), motapizone, pimobendan, dipine, and the like); beta-blockers (such as, for example, Zardaverine, siguaZodan, CI-930, EMD 53998, imazodan, butixamine, dichloroisoproterenol, propanolol, alprenolol. saterinone, loprinone hydrochloride, 3-pyridinecarbonitrile bunolol, nadolol, Oxprenolol, perbutolol, pinodolol, Sotalol, derivatives, denbufyllene, albifylline, torbafylline, doxofyl timolol, metoprolol, atenolol, acebutolol, bevantolol, line, theophylline, pentoxofylline, nanterinone, cilostaZol. pafenolol, tolamodol, and the like); long and short acting cilostamide, MS 857, piroximone, milrinone, aminone, alpha-adrenergic receptor antagonist (Such as, for example, tolafentrine, dipyridamole, papaverine, E4021, thienopyrimi phenoxybenzamide, dibenamine, doxazosin, teraZosin, phen dine derivatives (such as those disclosed in WO 98/17668), tolamine, tolazoline, proZosin, trimaZosin, yohimbine, moxi triflusal, ICOS-351, tetrahydropiperazino 1,2-bbeta-carbo Sylyte and the like adenosine, ergot alkaloids (such as, for line-1,4-dione derivatives (such as those disclosed in U.S. example, ergotamine, ergotamine analogs, including, for Pat. No. 5,859,006, WO 97/03985 and WO 97/03675), car example, acetergamine, braZergoline, bromerguride, cianer boline derivatives, (such as those disclosed in WO 97/43287), goline, delorgotrile, disulergine, ergonovine maleate, ergota 2-pyrazolin-5-one derivatives (such as those disclosed in U.S. mine tartrate, etisulergine, lergotrile, lysergide, mesulergine, Pat. No. 5,869,516), fused pyridazine derivatives (such as metergoline, metergotamine, nicergoline, pergolide, propis those disclosed in U.S. Pat. No. 5,849,741), quinazoline ergide, proterguride, terguride); vasoactive intestinal pep derivatives (such as those disclosed in U.S. Pat. No. 5,614, tides (such as, for example, peptide histidine isoleucine, pep 627), anthranilic acid derivatives (such as those disclosed in tide histidine methionine, Substance P, calcitonin gene U.S. Pat. No. 5,714.993), imidazoquinazoline derivatives related peptide, neurokinin A, bradykinin, neurokinin B, and (such as those disclosed in WO 96/26940), and the like. Also the like); dopamine agonists (such as, for example, apomor included are those phosphodiesterase inhibitors disclosed in phine, bromocriptine, testosterone, cocaine, Strychnine, and WO99/21562 and WO99/30697. The disclosures of each of the like); opioid antagonists (such as, for example, naltrex which are incorporated herein by reference in their entirety. In one, and the like); prostaglandins (such as, for example, Some embodiments, the intranasal composition does not alprostadil, prostaglandin E, prostaglandin F misoprostol, comprise a PDE5 selective inhibitor. enprostil, arbaprostil, unoprostone, trimoprostil, carboprost, 0031 Sources of information for the above, and other limaprost, gemeprost, lantanoprost, omoprostil, beraprost, phosphodiesterase inhibitors include Goodman and Gilman, Sulpostrone, rioprostil, and the like); endothelin antagonists The Pharmacological Basis of Therapeutics (9th Ed.). (such as, for example, bosentan, Sulfonamide endothelin McGraw-Hill, Inc. (1995), The Physician's Desk Reference antagonists, BQ-123, SQ 28.608, and the like) and mixtures (49th Ed.), Medical Economics (1995), DrugFacts and Com thereof. parisons (1993 Ed), Facts and Comparisons (1993), and The 0037. In one aspect of the present invention, methods are Merck Index (12th Ed.), Merck & Co., Inc. (1996), the dis provided to prevent or treat diseases associated with or caused closures of each of which are incorporated herein by refer by the increased (pathological) metabolism of cyclic adenos ence in their entirety. ine 3',5'-monophosphate (cAMP) or cyclic guanosine 3',5'- 0032. The following definitions are used throughout the monophosphate (cGMP), including, for example, anoSmia, specification. hyposmia, ageusia, hypogeusia, hypertension, pulmonary 0033 “Phosphodiesterase inhibitor” or “PDE inhibitor” hypertension, congestive heart failure, renal failure, myocar refers to any compound that inhibits a phosphodiesterase dial infraction, stable, unstable and variant (Prinzmetal) enzyme, isozyme or allozyme. The term refers to selective or angina, atherosclerosis, cardiac edema, renal insufficiency, non-selective inhibitors of cyclic guanosine 3',5'-monophos nephrotic edema, hepatic edema, stroke, asthma, bronchitis, phate phosphodiesterases (cGMP-PDE) and cyclic adenosine chronic obstructive pulmonary disease (COPD), cystic fibro 3',5'-monophosphate phosphodiesterases (cAMP-PDE). sis, dementia including Alzheimer's disease, immunodefi 0034) “Patient” refers to animals, preferably mammals, ciency, premature labor, Parkinson's disease, multiple scle more preferably humans. rosis, dysmenorrhoea, benign prostatic hyperplasis (BPH), 0035. Other medicaments may be combined with or bladder outlet obstruction, incontinence, conditions of administered contemporaneously with at least one PDE reduced blood vessel patency, e.g., postpercutaneous translu inhibitors to complement and/or to enhance the prevention or minal coronary angioplasty (post-PTCA), peripheral vascu treatment effect of a PDE inhibitor. These other medicaments lar disease, allergic rhinitis, glaucoma, malignancies and dis include vasoactive agents, anticholinergic agents, leukotriene eases characterized by disorders of gut motility, e.g., irritable US 2010/0022563 A1 Jan. 28, 2010
bowel syndrome (IBS), rheumatoid arthritis, systemic lupus that is effective to achieve its intended purpose. While indi erythematosus, psoriasis, and other autoimmune diseases, vidual patient needs may vary, determination of optimal Huntington's chorea, and Amyotrophic lateral sclerosis ranges for effective amounts of each of the compounds and (ALS), by administering to a patient in need thereof a thera compositions is within the skill of an ordinary practitioner of peutically effective amount of the compounds and/or compo the art. Generally, the dosage required to provide an effective sitions described herein. amount of the composition, and which can be adjusted by one 0038. In some embodiments, the intranasal, pulmonary or of ordinary skill in the art, will vary, depending on the age, lingual administration of a PDE inhibitor can increase cell, health, physical condition, sex, weight, extent of the dysfunc tissue or organ levels of cAMP or cGMP. In some embodi tion of the recipient, frequency of treatment and the nature ments, the increase in cAMP or cGMP levels is at least 10%, and scope of the dysfunction. 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 0043. The amount of a given PDE inhibitor which will be 300%, 400%, 500% or 1000% over the untreated State. In effective in the prevention or treatment of a particular dys other embodiments, cAMP or cGMP levels are increased to at function or condition will depend on the nature of the dys least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, function or condition, and can be determined by standard 100%, 125%, 150%, 200%, 300%, 400%, or 500% of the clinical techniques, including reference to Goodman and Gil levels seen in controls, i.e., normal individuals. In some man, supra: The Physician's Desk Reference, supra; Medical embodiments of the invention, a method is provided for Economics Company, Inc., Oradell, N.J., 1995; and Drug increasing nasal mucus or salivary cAMP or cGMP levels, Facts and Comparisons, Inc., St. Louis, Mo., 1993. The pre wherein an effective amount of a PDE inhibitor is adminis cise dose to be used in the formulation will also depend on the tered intranasally to a patient resulting in an increase in the route of administration, and the seriousness of the dysfunc cAMP or cGMP levels of at least 10%, 20%, 30%, 40%, 50%, tion or disorder, and should be decided by the physician and 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, the patient's circumstances. 500%, or 1000% over the untreated level. In other embodi 0044) The nasal and/or pulmonary administered PDE ments, nasal mucus or salivary cAMP or cGMP levels are inhibitors can be used at dose ranges and overa course of dose increased to at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, regimen that are the same or Substantially equivalent to those 80%, 90%, 100%, 125%, 150%, 200%, 300%, 400%, or used for oral administration. The nasal and/or pulmonary 500% of the levels seen in normal individuals. administered PDE inhibitors can also be used in lower doses 0039. In some embodiments, the administration of an and in less extensive regimens of treatment. The amount of effective amount of a PDE inhibitor by intranasal, lingual or active ingredient that can be combined with one or more pulmonary administration does not produce a detectable carrier material to produce a single dosage form will vary blood level of the PDE inhibitor. In some embodiments, the depending upon the host treated and the particular mode of administration of an effective amount of a PDE inhibitor by administration. intranasal, lingual or pulmonary administration produces 0045 Representative daily intranasal, lingual or pulmo blood concentration of the PDE inhibitor that are less than 5 nary dosages are between about 1.0 g and 2000 mg per day, mg/dl., 2 mg/dl. 1 mg/dl., 500 g/dl., 250 lug/dl. 100 g/dl., 50 between about 1.0 g and 500.0 mg per day, between about 10 ug/dl., 25 g/dl. 10 ug/dl., 5 g/dl., or 1 ug/dl. ug and 100.0 mg per day, between about 10 ug and about 10 0040. In some embodiments, intranasal or lingual admin mg per day, between about 10 ug and 1.0 mg per day, between istration of an effective amount of a PDE inhibitor increases about 10 ug and 500 ug per day or between about 1 lug and 50 taste or Smell acuity. In some embodiments, the increase in ug per day of the active ingredient comprising a preferred taste or smell acuity is at least 5%, 10%, 20%, 30%, 40%, compound. These ranges of dosage amounts represent total 50%, 75%, or 100% compared to the untreated state. In other dosage amounts of the active ingredient per day for a given embodiments, taste or Smell acuity is increased to at least 5%, patient. In some embodiments, the daily administered dose is 10%, 20%, 30%, 40%, 50%, 75%, or 100% of the acuity of less than 2000 mg per day, 1000 mg per day, 500 mg per day, normal individuals. In some embodiments, taste or Smell 100 mg per day, 10 mg per day, 1.0 mg per day, 500g per day, acuity is measured objectively, while in other embodiments 300 ug per day, 200 ug per day, 100 ug per day or 50 ug per taste or Smell acuity is measured Subjectively. day. In other embodiments, the daily administered dose is at 0041. When administered in vivo, the compounds and least 2000 mg per day, 1000 mg per day, 500 mg per day, 100 compositions of the present invention can be administered in mg per day, 10 mg per day, 1.0 mg per day, 500g per day,300 combination with pharmaceutically acceptable carriers and in ug per day, 200 ug per day, 100 ug per day or 50 ug per day. dosages described herein. The compounds and compositions In some embodiments, on a per kilo basis, Suitable dosage of the present invention can be formulated as pharmaceuti levels of the compounds will be between about 0.001 ug/kg cally acceptable neutral (free base) or salt forms. Pharmaceu and about 10.0 mg/kg of body weight per day, between about tically acceptable salts include, for example, those formed 0.5 g/kg and about 0.5 mg/kg of body weight per day, with free amino groups such as those derived from hydro between about 1.0 ug/kg and about 100 ug/kg of body weight chloric, hydrobromic, hydroiodide, phosphoric, Sulfuric, ace per day, and between about 2.0 ug/kg and about 50 ug/kg of tic, citric, benzoic, fumaric, glutamic, lactic, malic, maleic, body weight per day of the active ingredient. In other embodi Succinic, tartaric, p-toluenesulfonic, methanesulfonic acids, ments, the Suitable dosage level on a per kilo basis is less than gluconic acid, and the like, and those formed with free car 10.0 mg/kg of body weight per day, 1 mg/kg of body weight boxyl groups, such as those derived from sodium, potassium, per day, 500 ug/kg of body weight per day, 100 ug/kg of body ammonium, calcium, ferric hydroxides, isopropylamine, tri weight per day, 10ug/kg of body weight per day of the active ethylamine, 2-ethylamino ethanol, histidine, procaine, and ingredient, or 1.0 g/kg of body weight per day of active the like. ingredient. In further embodiments, the suitable dosage level 0042 “Therapeutically effective amount” refers to the on a per kilo basis is at least 10.0 mg/kg of body weight per amount of a PDE inhibitor with or without additional agents day, 1 mg/kg of body weight per day, 500 ug/kg of body US 2010/0022563 A1 Jan. 28, 2010
weight per day, 100 ug/kg of body weight per day, 10ug/kg of electronic nebulizer particularly those modified with the body weight per day of the active ingredient, or 1.0 ug/kg of addition of one-way flow valves, such as for example, the Pari body weight per day of active ingredient. LC PlusTM nebulizer, commercially available from Pari Res 0046. In some embodiments, the individual or single intra piratory Equipment, Inc., Richmond, Va., which delivers up nasal, lingual and/or pulmonary dose of the PDE inhibitors is to 20% more drug than other unmodified nebulizers. less than 10 mg, less than 2 mg, less than 1 mg, less than 500 0053. The pH of the formulation is also important for ug, less than 200 g, less than 100 ug, or less than 50g per aerosol delivery. When the aerosol is acidic or basic, it can dosage unit or application. In other embodiments, the indi cause bronchospasm and cough. The safe range of pH is vidual or single intranasal, lingual and/or pulmonary dose of relative and depends on a patient's tolerance. Some patients the PDE inhibitors is at least 10 mg, 1 mg, 500 ug. 200 ug. 100 tolerate a mildly acidic aerosol, which in others will cause ug, 50 g per dosage unit or application. In further embodi bronchospasm. Typically, an aerosol Solution having a pH ments, the individual or single intranasal, lingual and/or pull less than 4.5 induces bronchospasm. An aerosol Solution hav monary dose of the PDE inhibitors ranges from 1 lug to 10 mg. ing pH between 4.5 and 5.5 will occasionally cause this 10L to 1 mg, 10ug to 500 Lig, 10ug to 250 ug, 10ug to 100 ug, problem. The aerosol solution having a pH between 5.5 and 10 ug to 50g, 25ug to 100g, 25 ug to 250 ug, 50 ug to 500 7.0 is usually considered safe. Any aerosol having pH greater ug, or 100 ug to 1.0 mg than 7.0 is to be avoided as the body tissues are unable to 0047. The number of times per day that a dose is admin buffer alkaline aerosols and result in irritation and broncho istered will depend upon Such pharmacological and pharma spasm. Therefore, the pH of the formulation is preferably cokinetic factors as the half-life of the active ingredient, maintained between 4.5 and 7.0, more preferably between 5.0 which reflects its rate of catabolism and clearance, as well as and 7.0 and most preferably between 5.5 and 6.5 to permit the minimal and optimal blood plasma or other body fluid generation of a PDE inhibitor aerosol that is well tolerated by levels of said active ingredient attained in the patient which patients without any secondary undesirable side effects Such are required for therapeutic efficacy. Typically, the PDE as bronchospasm and cough. The osmolarity of the formula inhibitors are given once, twice, trice, or four times daily. tion can also be adjusted to osmolarities of about 250 to 350 PDE inhibitors may also be administered on a less frequent moSm/L, according to the patient's tolerance. basis, such as every other day, every three, four, five, six or 0054 Drops and Gels seven days. 0055. In some embodiments, the PDE inhibitor is directly 0048. Other factors may also be considered in deciding applied to the nasal or lingual epithelium as a liquid, cream, upon the number of doses per day and the amount of active lotion, ointment or gel. These fluids or semifluids contain at ingredient per dose to be administered. Not the least impor least one therapeutically active PDE inhibitor and may further tant of such other factors is the individual response of the include at least one excipient (e.g., preservatives, viscosity patient being treated. Thus, for example, where the active modifiers, emulsifiers, or buffering agents) that are formu ingredient is used to treat or prevent asthma, and is adminis lated for administration as nose drops, or applied with an tered loco-regionally via aerosol inhalation into the lungs, applicator to the inside of the nasal passages. In some from one to four doses consisting of actuations of a dispens embodiments, the preservative is methylparaben or propylpa ing device, i.e., "puffs' of an inhaler, may be administered raben. The pH of the formulation is preferably maintained each day, with each dose containing from about 10.0 ug to between 4.5 and 7.0, more preferably between 5.0 and 7.0 and about 10.0 mg of active ingredient. most preferably between 5.5 and 6.5. The osmolarity of the 0049 Effective doses can be extrapolated from dose-re formulation can also be adjusted to osmolarities of about 250 sponse curves derived from in vitro or animal model test to 350 mosm/L. systems and are in the same ranges or less than as described 0056 Dry Powder Formulation for the commercially available compounds in the Physician's 0057. As an alternative therapy to aerosol, liquid or gel Desk Reference, supra. delivery, the PDE inhibitor may be administered in a dry 0050 Aerosols powder formulation for efficacious delivery into the nasal 0051. By “aerosol is meant any composition of a PDE cavity and/or endobronchial space. Dry powder formulation inhibitor administered as an aerosolized formulation, includ is convenient because it does not require further handling by ing for example an inhalation spray, inhalation solution, inha a physician, pharmacist or patient Such as diluting or recon lation Suspension, a nebulized solution, or nasal spray. Aero stituting the agent as is often required with nebulizers. Fur Solized formulations can deliver high concentrations of a thermore, dry powder delivery devices are sufficiently small PDE inhibitor directly to the airways with low systemic and fully portable. Dry powder formulations may also be absorption. Solutions for aerosolization typically contain at applied directly on the lingual epithelium. least one therapeutically active PDE inhibitor dissolved or 0058. For dry powder formulations, a PDE inhibitor and/ Suspended in an aqueous solution that may further include or carrier is processed to median diameter ranging from one or more excipients (e.g., preservatives, viscosity modifi 0.001-250 um typically by media milling, jet milling, spray ers, emulsifiers, or buffering agents). The solution acts as a drying, Super-critical fluid energy, or particle precipitation carrier for the PDE inhibitor. In some embodiments, the pre techniques. Particles of a desired size ranges can also be servative is methylparaben or propylparaben. These formu obtained through the use of sieves. Frequently, milled par lations are intended for delivery to the respiratory airways by ticles are passed through one or more sieves to isolate a inspiration. desired size range. In some embodiments intended for pull 0052 A major limitation of pulmonary delivery is the monary administration, the PDE inhibitor and/or carrier has a difficulty of reaching the deep lung. To achieve high concen median diameter ranging from 0.01-25um, 0.1-10 um, 1-10 trations of a PDE inhibitor solution in both the upper and um, 1-5 um, or 2-5 um. In further embodiments intended for lower respiratory airways, the PDE inhibitor solution is pref pulmonary administration, the PDE inhibitor and/or carrier erably nebulized injet nebulizers, a ultrasonic nebulizer, oran has a median diameter ranging less than 20 Jum, 10um, 5um, US 2010/0022563 A1 Jan. 28, 2010
4, um, 3 um, 2 um, or 1 Lum. In some embodiments intended container that is compartmentalized to receive one or more for nasal administration, the PDE inhibitor and/or carrier has blister packs, bottles, tubes, capsules, and the like. In certain a median diameter ranging from 1-250 um, 5-200 um, 10-150 embodiments, the pharmaceutical compositions are pre um, 10-100 um, 10-50 um, 15-100 um, 15-50 um, or 20-60 sented in a pack or dispenser device which contains one or um. In further embodiments intended for nasal administra more unit dosage forms containing a compound provided tion, the PDE inhibitor and/or carrier has a median diameter herein. In other embodiments, the pack contains metal or of less than 250 um, 200 um, 150 um, 100 um, 75um, 60 um, plastic foil. Such as ablister pack. In some embodiments, the 50 um, 40 um or 30 m. In other embodiments intended for pack contains capsules, vials, or tubes. In other embodiments, nasal administration, the PDE inhibitor and/or carrier has a the pack or dispenser device is accompanied by instructions median diameter of at least 20 um, 30 um, 40 um, 50 um, 60 for administration. In some embodiments, the dispenser is um, 75um, 100 um, 150 um or 200 um. disposable or single use, while in other embodiments, the 0059. In some embodiments, a pharmaceutically accept dispenser is reusable. In certain embodiments, the pharma able carrier for the present compositions and formulations ceutical formulations are preloaded into the device. include but are not limited to amino acids, peptides, proteins, 0066. In still other embodiments, the pack or dispenser non-biological polymers, biological polymers, simple Sugars, also accompanied with a notice as required by a governmental carbohydrates, gums, inorganic salts and metal compounds agency regulating the manufacture, use, or sale of pharma which may be present singularly or in combination. In some ceuticals. This notice states that the drug is approved by the embodiments, the pharmaceutically acceptable carrier com agency for human or veterinary administration. Such notice, prises native, derivatized, modified forms, or combinations for example, is the labeling approved by the U.S. Food and thereof. Drug Administration for prescription drugs, or the approved 0060. In some embodiments, useful proteins include, but product insert. Compositions containing a compound pro are not limited to, gelatin or albumin. In some embodiments, vided hereinformulated in a compatible pharmaceutical car useful Sugars that can serve as pharmaceutically acceptable rier are also prepared, placed in an appropriate container, and carriers include, but are not limited to fructose, galactose, labeled for treatment of an indicated condition. glucose, lactitol, lactose, maltitol, maltose, mannitol, melezi 0067. The articles of manufacture provided herein may tose, myoinositol, palatinite, raffinose, stachyose, Sucrose, also contain an administration or dispensing device. trehalose, xylitol, hydrates thereof, and combinations of Examples of administration devices include pulmonary thereof. inhalers and intranasal applicators. Pumps may be provided 0061. In some embodiments, useful carbohydrates that with the inhalers and intranasal devices, or the pumps may be can serve as pharmaceutically acceptable carriers include, but built into the devices. Alternatively, a propellant may be are not limited to starches such as corn starch, potato starch, included with or it may be stored within the devices. amylose, amylopectin, pectin, hydroxypropyl Starch, car 0068. Such kits optionally comprise an identifying boxymethyl starch, and cross-linked starch. In other embodi description or label for the containers. In further embodi ments, useful carbohydrates that can serve as pharmaceuti ments, the label is on a container with letters, numbers or cally acceptable carriers include, but are not limited to other characters forming the label and attached, molded or cellulose, crystalline cellulose, microcrystalline cellulose, etched into the container itself, a label is associated with a C-cellulose, methylcellulose, hydroxypropyl cellulose, car container when it is present within a receptacle or carrier that boxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl also holds the container, e.g., as a package insert. In some cellulose, and cellulose acetate. embodiments, a label is used to indicate that the contents are 0062. In some embodiments, the composition or formula to be used for a specific therapeutic application. In yet other tion includes an excipient. Useful excipients include, but are embodiments, the label also indicates directions for use of the not limited to, fluidizers, lubricants, adhesion agents, Surfac contents, such as in the methods described herein. In some tants, acidifying agents, alkalizing agents, agents to adjust embodiments, a set of instructions may also be included, pH, antimicrobial preservatives, antioxidants, anti-static generally in the form of a package insert. The informational agents, buffering agents, chelating agents, humectants, gel material may contain instructions on how to dispense the forming agents, or wetting agents. Excipients also include pharmaceutical composition, including description of the coloring agents, coating agents, Sweetening, flavoring and type of patients who may be treated, the schedule (e.g., dose perfuming and other masking agents. The compositions and and frequency), and the like. formulations of this invention may include a therapeutic 0069. The invention also relates to a set (kit) consisting of agent with an individual excipient or with multiple excipients separate packs of kits that are frequently assembled for ship in any suitable combination, with or without a carrier. ping or for patient convenience, Such as a weekly, biweekly or 0063. The dry powder formulations of the present inven monthly supply of a medicament. tion may be used directly in metered dose or dry powder inhalers. With dry powder inhalers, the inspiratory flow of the Experimental Section patient accelerates the powder out of the device and into the Example 1 nasal and/or oral cavity. Alternatively, dry powder inhalers may employ an air source, a gas source, or electrostatics, to 0070 Patients with smell loss (hyposmia) reflect a clini deliver the therapeutic agent. The dry powder formulations cally diverse group of patients (1-10). Whereas there is com are temperature stable and have a physiologically acceptable mon agreement that many patients exhibit this clinical prob pH of 4.0-7.5, preferably 6.5 to 7.0. lem, there is no agreement with respect to their treatment. 0064 Kits/Articles of Manufacture Indeed, most groups who evaluate these patients consider that 0065 For use of the therapeutic compositions described there are few, if any, medically relevant treatments for them. herein, kits and articles of manufacture are also described. In 0071. In an attempt to elucidate the biochemical pathology Some embodiments, such kits include a carrier, package, or of hyposmia, total protein fractionation was performed on US 2010/0022563 A1 Jan. 28, 2010
saliva (14, 15) and nasal mucus (16), since these fluids bathe reported as MESEM of correct responses for each odor in both taste buds and olfactory epithelial tissues, respectively, each treatment group; ME was reported in % and results and contain Substances which are critical to maintain these calculated to obtain MESEM for each treatment group for all sense organs (14-16). It was discovered that some patients correct responses using data for the four highest odor concen with smell loss had diminished salivary (17) and nasal mucus trations presented (from 10° an absolute odor concentra (18) levels of the saliva and nasal mucus protein carbonic tion). anhydrase (CA) VI, a putative stem cell growth factor; treat 0076. In addition, each patient graded the hedonic (H) ment of these patients with exogenous Zinc increases both value of each odor presented for these same odor concentra salivary and nasal mucus CAVI (19) leading to an increase in tions (from 10° an absolute odor concentration using a smell acuity (19). These CAVI deficient patients, however, -100-0-100 scale). If they considered the presented odor represent only a fraction of the total patient group (1, 2). pleasant (“they wished to smell the odor again”) they graded 0072 Further investigation revealed many of the non the odor as +1100 with respect to pleasantness; if they CAVI deficient patients exhibited lower than normal levels of considered the odor unpleasant (“they did not wish to smell both cAMP and coMP in their saliva (31) and nasal mucus the odor again”) they graded the odor as -1--100 with (32). When the cAMP and coMP levels in the saliva and in the respect to unpleasantness; if they did not consider the odor nasal mucus of these patients was compared against the sever either pleasant or unpleasant they graded the odor as neutral ity of their smell loss, it was noted that as smell loss severity or 0. Results were obtained by calculating the arithmetical increased (worsened) levels of these cyclic nucleotides in Sum of each correct recognition response for each odor with saliva (34) and nasal mucus (35) decreased. Since these cyclic respect to its pleasantness, unpleasantness or neutrality. nucleotides act as growth factors for several neural tissues Arithmetic MESEM were obtained for each treatment group (36-38) including olfactory tissues (39-45), it was reasoned for each odor presented. that lower than normal levels of cyclic nucleotides may play a role in generation of their hyposmia. To test this hypothesis, 0077 Independently, patients were also required to grade patients were treated with the PDE inhibitor theophylline in their ability to smell daily on a scale from 0-100, with 0 an effort to increase saliva and nasal mucus levels of these reflecting no overall smell function over a 24hour period, 100 cyclic nucleotides. It was found that hyposmia was corrected reflecting normal overall smell function over this period and in many of them as demonstrated by improvement of psycho numbers between 0-100 reflecting their estimation of their physical measurements of hyposmia, (1, 2, 49), by increased overall ability to smell odors over this period. brain activation to several olfactory stimuli through measure (0078 Based upon values for the DT, RT and ME tests, ments of functional magnetic resonance imaging (FMRI) patients were classified with respect to severity of smell loss (48) and associated with changes in serum theophylline (44). into the four types (1, 2) (Table I). Anosmia is the complete loss of smell. Patients with anosmia have DT, RT and ME test 0073. In order to confirm these initial studies, theophylline values of Zero, since they cannot detect, recognize nor grade was given to 312 patients in a fixed design, controlled, open the intensity of any odor including an absolute concentration trial over a period of seven years. These patients exhibited of any odorant (Table I). No patients with anosmia were salivary (32) and nasal mucus (33) levels of cAMP and ccjMP present in the study due to the relative rarity of this condition below the normal mean. Studies were approved by an Insti (1). Patients with Type I hyposmia (96 patients) could detect tutional Review Board and all patients gave informed con Some odors but could not recognize any odor correctly; thus, Sent. DTs for some odors were present, but RTs and MEs for all 0074 The patients ranged in age from 18 to 86 y (55+1 y, odors were Zero since they could neither recognize correctly meant-SEM) and consisted of 178 women, aged 18-85 y nor thereby grade correctly intensity of any odor (Table I). (55+2 y) and 134 men, aged 23-86 y (54+3 y). Patients Patients with Type II hyposmia (208 patients) could detect reported a history of smell loss extending from 2 months to 40 and recognize Some odors, but at levels greater than normal; y (6.5+1.0 y). Etiology of smell loss varied; the major causes thus DTs and RTs were present, but elevated above normal of hyposmia were post influenza-like hyposmia 97 patients, and MEs were present but at levels lower than normal (Table 31.1% of the total (50) and allergic rhinitis 97 patients, I). Patients with Type III hyposmia (8 patients) could detect 31.1% of the total (51) followed by head injury 42 patients, and recognize all odors at normal levels (i.e., normal DT and 13.5% (52) and several other causes, as previously described RT), but ME values for one or more odors were significantly 76 patients, 24.4% (1,2). Levels of CAVI in their saliva and decreased below normal (Table I). Severity of smell loss nasal mucus were within normal levels. graded from most to least severe loss was typed as 0075 Patients initially reported their sensory dysfunction anosmia>hyposmia Type I>Type II>Type III and verified by as either loss of taste (i.e., flavor) and/or smell function. This demonstrating that as Smell loss severity increased levels of Subjective response was documented by objective psycho nasal mucus cAMP and coMP decreased (32. 34). physical measurements of olfactory function administered to each patient by use of a forced-choice, three-stimuli, step TABLE I wise-staircase technique in a fixed, controlled design (1, 53). Efficacy of this technique and results of testing were previ CLASSIFICATION OF SMELL LOSS ously documented in a double-blind clinical trial (53). Four DETECTION RECOGNITION MAGNITUDE odors were used; they were pyridine (dead-fish odor), THRESHOLD THRESHOLD ESTIMATION nitrobenzene (bitter-almond odor), thiophene (petroleum DT in ML RT in ML MEANME in 96 like odor) and amyl acetate (banana-oil odor). Detection NORMALS -- * 248 thresholds (DT), recognition thresholds (RT) and magnitude PATIENTS estimation (ME) values for each odor were determined as previously described (1,53). Thresholds were converted into ANOSMIA do O O O bottle units (BU) as previously described (53) and results US 2010/0022563 A1 Jan. 28, 2010
I0083. Local Patients—Second Return (400 mg. Theophyl TABLE I-continued line) I0084 Patients returned after four to eight months of treat CLASSIFICATION OF SMELL LOSS ment and consisted of patients who previously reported <5% DETECTION RECOGNITION MAGNITUDE improvement on 200 mg of theophylline but also some distant THRESHOLD THRESHOLD ESTIMATION patients who returned on this dose. Blood theophylline was DT in ML RT in ML MEANME in 96 measured as before. All patients independently reported sub HYPOSMIA jective overall changes in Smell function as done previously. TYPE I O O At this visit, smell function was measured as before to deter TYPE II * &48 mine DT, RT, ME and H for all four odors without recourse to prior measurements. + Normal (s.10 for all odorants) +* Normal (s.10’ for all odorants) I0085 Local Patients. Third Return (600 mg. Theophyl O Absent response (co) line) + Present but < normal (>10'
line levels were measured. Smell function was measured 2A-B). H responses were significantly lower (less pleasant) using the Subjective and psychophysical techniques (DT, RT for amyl acetate and nitrobenzene (odors usually considered ME, H) previously described. pleasant) and significantly higher for pyridine and thiophene 0095 Distant Patients Fourth Call In (800 mg. Theo phylline) (less unpleasant—closer to Zero for odors usually considered 0096. At this time, if patients reported either 25% unpleasant) (FIG. 2A-B). Analysis of H data indicate that for improvement or <5% improvement, they were requested to normal Subjects H values for pyridine and thiophene (un return to the study site as soon as possible to reevaluate their pleasant responses) are similar to or slightly higher than ME smell function. At this return, blood theophylline levels were values, whereas H values for nitrobenzene and amyl acetate measured and Smell function were measured using both Sub (pleasant responses) are similar or slightly lower. Ratios of jective and psychophysical techniques with results as shown H:ME in normals for pyridine and thiophene are 1.09 and on Table VII and discussed previously. 1.05 whereas for nitrobenzene and amyl acetate they are 0.94 0097. Since data for all measurements from each patient and 0.96. For untreated patients (patients with Type II and III group (local or distant) on each dose level were combined hyposmia only) these ratios are quite different. For pyridine mean and SEM for each measurement (DT, RT, ME, H) of and thiophene, these ratios are 0.87 and 0.81 whereas for Smell function for each treatment group were calculated on nitrobenzene and amyl acetate they are 0.81 and 0.10. In part, this basis. Differences in measurements between before treat H decreases for nitrobenzene and amyl acetate are related to ment and each treatment level were calculated and signifi decreased patient acuity; however, the major discrepancy is cance of differences estimated using Student t tests (values p<0.05 considered significant). Some patient responses were that about 50% of patients with hyposmia also exhibit dysos also analyzed by use of non-parametric statistics (sign test) mia (1, 2) in which odors usually considered pleasant are and the Spearman rank correlation technique; r-0.05 was considered unpleasant (e.g., banana-oil odor may be consid considered significant related to Smell loss type and treatment ered putrid) and even unpleasant odors may be considered response. Since each patient served as his/her own control pleasant (e.g., pyridine may be considered flowery). These with respect to before and after treatment, paired ttests were distortions in patients comprise a bimodal response for H also calculated; t values <0.05 were considered significant. values (some patients reporting a normal hedonic response These values were not included in the results presented. related to appropriate pleasantness and unpleasantness of the 0098 Results were previously obtained in 150 normal perceived odor whereas others reporting a distortion) which subjects for each of these measurements (1, 53-55) and are reduces the overall arithmetic mean obtained for H for each reported here for comparison. odor.
TABLE II
DIFFERENCES IN SMELL FUNCTION BETWEEN STUDY PATIENTSBEFORE TREATMENT AND NORMAL CONTROLS
SMELL PATIENTS (312 NORMALS (15S
FUNCTIONSODOR PYRD NOB THIO AA PYRD NOB THIO AA
DT 8.5 + 0.28: 9.O. O.2 8.5 O.2 8.9 0.2 4.2 + 0.1 3.90.1 3.60.1 3.7 0.1 RT 10.20.1 1O.S. O.2 10.2-0.2 10.7 - 0.01 7.2. O.1 5.7 O.1 7.1 O.1 6.8 0.1 ME 232 121 162 101 643 514 664 514 H -20 + 2 4 + 1 -13 + 2 11 -743 485 -8O2 54 - 5 () Patient number *Mean SEM DT, detection threshold, in bottle units BU () RT, recognition threshold, in bottle units BU () ME, magnitude estimation, in 96 () H, hedonic estimation, in 96 (+, pleasant, -, unpleasant, O, neutral) PYRD, pyridine: NO2B, nitrobenzene: THIO, thiophene: AA, amyl acetate With respect to normals p < 0.001
0099 Results 0102 Comparison of Smell Function in Patients Classi 0100 Comparison of Smell Function in Normal Subjects fied by Degree of Smell Loss 0103 Categorized by smell loss type, results of each mea and in Untreated Patients with Hyposmia surement indicate that before treatment, patients exhibited a 0101 Results of each measurement (DT, RT ME and H) in consistent pattern of abnormality associated with their loss untreated patients indicated significant impairment of Smell type such that Type I hyposmia>Type II>Type III (Table III). function compared to normal subjects (Table II, FIG. 2A-B). H:ME ratios were closer to those of normals in patients with For DT and RT, patient responses were significantly higher Type III compared to those with Type II hyposmia, as would (less sensitive) than in normals (Table II), ME responses were be expected due to the lesser degree of abnormality in the significantly lower (less sensitive) than in normals (FIG. former patients (Table III). US 2010/0022563 A1 Jan. 28, 2010
TABLE III
COMPARISON OF SMELL FUNCTION BETWEEN UNTREATED PATIENTS WITH TYPES I, II AND III HYPOSMIA
I (96) II (208)
PYRD NOB THIO AA PRYD NOB THIO AA
DT 9.8 0.1* 11.2 + 0.2 10.90.2 11.7 - 0.2 8.8 0.2 8.3 O.2 8.O. O.2 8.2 O.2 RT 11.701 11.8 0.1 11.8 + 0.1 11.8 0.1 9.7- 0.1° 10.1 - 0.2 9.7 O.2 10.4 - 0.2 ME O O O O 292 161 212 13 - 1 H O O O O -2S2 S 1 -16 - 2 1 - 1
III (8)
PRYD NOB THIO AA
DT 4.0 - 0.5 3.4 + 0.6% 3.3 + 0.8° 2.5 + 0.5°-6 RT 5.6+ 0.8 4.0 + 0.9° 3.9 + 0.8° 5.3 + 1.0 ME 42 + 4° 34 + 4- 34 10 40 23-6 H -27 - 14 127 -46 - 13 34 + 6
() Patient number * Mean SEM DT, detection threshold, in BU RT, recognition threshold, in BU ME, magnitude estimation, in 96 H, hedonic estimation, in 96 PYRD, pyridine: NO2B, nitrobenzene: THIO, thiophene: AA, amyl acetate With respect to Type I p < 0.001 With respect to Type II 'p < 0.001
0104 Changes in Smell Function in All Patients Treated 0106 Among the 199 patients (both improved and not with Theophylline, 200 mg Daily improved) who returned on 200 mg. DT and RT for all odors decreased (improved) significantly (Table IV). ME for pyri dine and amyl acetate also increased (improved) significantly 01.05 Changes in smell function in 199 patients with (FIG. 3A-B). H values for pyridine and thiophene decreased hyposmia after treatment with 200 mg daily of theophylline significantly i.e., odors pyridine and thiophene were recog for two-six months are shown in Table IV and in FIG. 3A-B. nized as more unpleasant (FIG. 3A-B) and H values for These patients constituted mainly local patients minus 15 of nitrobenzene increased significantly i.e., the odor of the original 312 who did not return after treatment was initi nitrobenzene was recognized as more pleasant (FIG. 3A). ated. Of the 15 non-returning patients, seven reported >5% While not statistically significant, H values for amyl acetate increased 50% (perceived as more pleasant with improved improvement (46.7%) and one (14.3%) reported a return to odor recognition). On treatment, H:ME ratios did not change normal; eight reported improvement of <5%. With returning significantly since both ME and H values changed to similar patients, 34 patients (17.1%) improved 25% (and were not degrees. No differences in results with respect to age or gen included in Subsequent studies). Among this group nine (26. der of these patients were apparent. At Subsequent visits over 5%) considered their smell function had returned to normal. the next six-36 months with continued treatment on this dose, Two hundred sixty-three patients improved <5% (160 local the 34 patients with initially improved smell function main and 103 distant patients); among this group 36 patients did not tained their increased acuity or improved further. Mean serum continue in the study. theophylline on this treatment was 4.0+0.2 mg/dl. US 2010/0022563 A1 Jan. 28, 2010 11
TABLE IV CHANGES IN SMELL FUNCTION FOLLOWING TREATMENT WITH ORAL THEOPHYLLINE, 200 MGDAILY
SMELL Before Treatment (199 After Treatment (199
FUNCTIONXODOR PYRD NOB THIO AA PYRD NOB THIO AA DT 8.5 + 0.2% 9.0 + 0.2 8.5 + 0.2 8.9 + 0.2 7.6+ 0.2 7.8 + 0.2 7.5 + 0.2 7.9 + 0.2 RT 10.2 + 0.1 10.5 + 0.2 10.2 + 0.2 10.7 - 0.1 9.0 - 0.2 9.5 + 0.2 9.1 - 0.2 9.90.2 ME 23 - 2 121 16 - 2 10 1 282 17 - 2 212 15 + 2 () Patient number *Mean SEM DT, detection threshold, in BU RT, recognition threshold, in BU ME, magnitude estimation, in 96 H, hedonic estimation, in 96 PYRD, pyridine: NOB, nitrobenzene: THIO, thiophene: AA, amyl acetate With respect to before treatment p < 0.001 'p & 0.005 p < 0.01 'p & 0.05
0107 Changes in Smell Function in Patients with odors increased (improved) significantly (Table V) (both Hyposmia Treated with Theophylline 400 mg Daily improved and unimproved patients included). Hedonic val ues also increased significantly for pyridine and thiophene 0108. One hundred twenty patients (97 from the 165 who i.e., odors of pyridine and thiophene were recognized as returned on <5% on 200 mg and 23 who returned for the first more unpleasant (FIG. 2A-B). While not statistically signifi time on 400 mg) were reevaluated after taking 400 mg of cant, H values for nitrobenzene increased 50% (perceived as theophylline for two-six months (Table IV). On this treatment more pleasant); H values for thiophene decreased 40% (per dose, 35 patients (29.2%) improved 25% (and were not ceived as more unpleasant). Overall, H:ME ratios did not included in Subsequent studies). Among this group, three change significantly on treatment. No differences in results (8.6%) considered their smell function had returned to nor with respect to age or gender of these patients were apparent. mal. One hundred ninety-two patients improved <5% (96 Among patients who exhibited improvement at this dose, on local and 96 distant patients). Twenty-five patients of these Subsequent visits over six-36 months, their improvement per 192 did not continue in the study. On this dose, DT and RT for sisted. Mean serum theophylline on this treatment dose was all odors decreased (improved) significantly and ME for all 7.4+0.4 mg/dl.
TABLEV CHANGES IN SMELL FUNCTION FOLLOWING TREATMENT WITH ORAL THEOPHYLLINE, 400 MGDAILY
SMELL Before Treatment (120 After Treatment (120
FUNCTIONXODOR PYRD NOB THIO AA PYRD NOB THIO AA DT 8.4 O.2* 9.O. O.3 8.6 + 0.3 8.9 + 0.3 7.0 + 0.3° 7.2 + 0.3 6.8 + 0.4° 7.1 + 0.3 RT 10.3 O2 10.5 + 0.2 10.5 + 0.2 10.6+ 0.2 8.5 + 0.3° 8.9 + 0.3’ 8.4 + 0.3° 9.3 + 0.3 ME 212 122 14 - 2 101 333 232 26 - 2 18-2 H -19 + 2 4 + 1 -12 + 2 2 - 1 –26 + 3 8 + 3 -19 + 2 3 - 2 () Patient number *Mean SEM DT, detection threshold, in BU RT, recognition threshold, in BU ME, magnitude estimation, in 96 H, hedonic estimation, in 96 PYRD, pyridine: NOB, nitrobenzene: THIO, thiophene: AA, amyl acetate With respect to before treatment p < 0.001 'p & 0.005 p < 0.01 p < 0.05 US 2010/0022563 A1 Jan. 28, 2010
0109 Change in smell function in patients with hyposmia treated with theophylline, 600 mg daily 0110 Changes in smell function in 160 patients after treat ment with 600 mg daily for two-12 months are shown on Table VI. This patient number includes 77 distant patients who returned on this theophylline dose as well as 83 local patients who improved <5% on 400 mg. Among this group, 66 (41.2%) improved 25% and 17 (10.6%) considered their Smell function had returned to normal. On Subsequent visits, over the next six-36 months, improvement on this dose either persisted or improved further. One hundred thirty-seven patients improved <5% and 73 did not continue. On this dose, DT and RT for all odors decreased (improved) significantly and ME for all odors increased (improved) significantly (Table VI) (both improved and unimproved patients included). H values did not change significantly for any odor, although pyridine and thiophene were recognized as more unpleasant (FIG. 3A-B) and nitrobenzene and amyl acetate were recognized as more pleasant (FIG. 3A-B). Overall, H:ME ratios did not change significantly. Again, as noted on the previous theophylline doses, no differences were apparent with respect to age or gender of these patients. Mean serum theophylline on this dose was 9.4+0.38 mg/dl.
TABLE VI
CHANGESIN SMELL FUNCTION FOLLOWING TREATMENT WITHORAL THEOPHYLLINE 600 MGDAILY
SMELL Before Treatment (160 After Treatment (160
FUNCTIONXODOR PYRD NOB THIO AA PYRD NOB THIO AA
DT 8.4 - 0.2* 9.2 + 0.2 8.8 O.2 9.3 O.2 7.4 O.2 7.8 O.3 7.1 O.3 7.8 0.3 RT 10.3-0.2 10.5 + 0.2 10.3 - 0.2 10.8 - 0.2 9.40.2 9.1 - 0.2 9.0 - 0.3 9.6 0.2 ME 192 11 - 1 13 - 2 8 - 1 26 + 2 18 + 2 21 + 2 15 + 2 H -16 + 2 3 - 1 -9 + 2 2 - 1 -192 8 + 2 -14 + 2 4 + 1 () Patient number *Mean SEM DT, detection threshold, in BU RT, recognition threshold, in BU ME, magnitude estimation, in 96 H, hedonic estimation, in 96 PYRD, pyridine: NO2B, nitrobenzene: THIO, thiophene: AA, amyl acetate With respect to before treatment p < 0.001 'p < 0.005 p < 0.01 'p & 0.05
0111 Change in Smell Function in Patients with more unpleasant) and H for nitrobenzene and amyl acetate Hyposmia Treated with Theophylline, 800 mg Daily increased about 50% (became more pleasant). When ana lyzed by paired ttest (data not shown) DT, RT and ME for all 0112 Changes in smell function in 28 patients after treat odors increased significantly, H for pyridine and thiophene ment with 800 mg daily for two-12 months are shown in Table decreased significantly and H for nitrobenzene and amyl VII. Among this group, 15 (53.6%) improved 25% and three acetate increased significantly. Mean serum theophylline on (33%) considered their smell function had returned to normal. this dose was 11.2+0.8 mg/dl. On Subsequent visits over the next two-six months, improve 0113. As drug doses increased mean DT and RT for most ment on this dose persisted or improved further. Thirteen odors decreased (acuity increased) whereas, mean ME for patients improved <5%. At this dose, the study terminated. most odors increased from 200 mg to 400 mg and then DT and RT for all odors increased on treatment, but were remained relatively constant. H also decreased from 200 mg statistically significant only for DT for nitrobenzene, RT for to 400 mg (increased unpleasantness) for pyridine and nitrobenzene and amyl acetate. ME for all odors increased, thiophene and then remained relatively constant as doses but was significant only for amyl acetate. H for both pyridine increased; H for nitrobenzene and amyl acetate (increased and thiophene decreased 55% and 37%, respectively (became pleasantness) increased in a similar manner. US 2010/0022563 A1 Jan. 28, 2010 13
TABLE VII CHANGES IN SMELL FUNCTION FOLLOWING TREATMENT WITH ORAL THEOPHYLLINE, 800 MGDAILY
SMELL Before Treatment (28 After Treatment (28
FUNCTIONXODOR PYRD NOB THIO AA PYRD NOB THIO AA DT 7.9 0.6* 9.3 - 0.7 8.9 O.6 8.8 + 0.7 6.9 + 0.6 7.0 + 0.8 7.2 + 0.7 7.2 + 0.8 RT 10.6 - 0.3 10.1 - 0.6 10.2 - O.S 10.9 + 0.3 8.5 + 0.6°, 7.8 + 0.8 9.6+ 0.6 9.0 + 0.5° ME 184 11 + 4 14 + 4 10 - 4 295 25 6 20 4 242 H -12 + 4 6 - 2 -9 +4 4 + 4 -22 + 6 13 - 7 -15 - 4 85 () Patient number *Mean SEM DT, detection threshold, in BU RT, recognition threshold, in BU ME, magnitude estimation, in 96 H, hedonic estimation, in 96 PYRD, pyridine: NO2B, nitrobenzene: THIO, thiophene: AA, amyl acetate With respect to before treatment p < 0.001 'p & 0.005 p < 0.01 'p & 0.05
0114 Changes in Smell Function and After Treatment with Theophylline in Patients Classified by Hyposmia Type 0115 Type I Hyposmia Treatment. After treatment with either 200 mg. 400 mg. 600 mg or 800 mg, there were sig nificant decreases in DT and RT, increases in ME and changes in H for specific odors consistent with improvement in smell function (Table VIII). Of the 96 patients with Type I hyposmia in the study, 32 (33.3%) reported >5% improvement and 5 (15.6%) reported their smell function had returned to normal.
TABLE VIII
CHANGES IN SMELL FUNCTION IN TYPE IHYPOSMLA PATIENTS FOLLOWING TREATMENT
SMELL Before Treatment (96)
FUNCTIONXODOR PYRD NOB THIO AA PYRD NOB THIO AA After Treatment 200 mg (57)
DT 9.8 0.1* 11.2 + 0.2 10.9 O2 11.20.2 9.5 O.2 10.3 + 0.3° 10.1 + 0.3 10.5 + 0.3 RT 11.701 1180.1 11.8 O1 11.701 11.O. O.2 11.2 + 0.2 11.4 + 0.2 11.3 O2 M E O O O O 11 - 2 S2 62 62 H O O O O -82 42 -32 42 After Treatment 400 mg (33)
8.8 0.5 9.8 O.S 9.8 O.S 10.1 - O.S RT 10.6 - O.4 10.9 + 0.4° 10.8 + 0.4 11.2 + 0.3 M E 123 83 72 73 -73 33 -S 2 S3 After Treatment 600 mg (51)
8.9 + 0.3 9.9 0.4 9.40.4 10.1 - 0.3 RT 10.9 O.3 10.8 + 0.3° 10.9 + 0.3° 11.1 + 0.2° ME 113 62 72 S2 -82 22 -32 -0.4 + 1 After Treatment 800 mg (12)
DT 9.6 O.8 10.1 - 0.8 1.O.O.O.7 10.6 - O.S RT 10.3 1.0 11.3 O.7 11.6 O.2 11.60.4 US 2010/0022563 A1 Jan. 28, 2010 14
TABLE VIII-continued
CHANGES IN SMELL FUNCTION IN TYPE IHYPOSMLA PATIENTS FOLLOWING TREATMENT
SMELL Before Treatment (96
FUNCTIONXODOR PYRD NOB THIO AA PYRD NOB THIO AA ME 104° 43 42 S3 R -115 22 -42 -1 + 4 () Patient number; *Mean SEM DT, detection threshold, in BU RT, recognition threshold, in BU ME, magnitude estimation, in 96 H, hedonic value, in % PYRD, pyridine: NO2B, nitrobenzene: THIO, thiophene: AA, amyl acetate Compared to before treatment p < 0.001 'p < 0.005 p < 0.01 'p & 0.05
0116 Type II Hyposmia Treatment. After treatment with either 200 mg. 400 mg. 600 mg or 800 mg, there were sig nificant decreases in DT and RT, increases in ME and changes in H for specific odor consistent with improvement in smell function (Table IX). Of the 208 patients with Type II hyposmia in the study, 129 (62%) reported >5% improvement and 26 (20.2%) reported their smell function had returned to normal.
TABLE IX
CHANGESIN SMELL FUNCTION IN TYPE IIHYPOSMIA PATIENTS FOLLOWING TREATMENT
SMELL Before Treatment (208)
FUNCTIONXODOR PYRD NOB THIO AA PYRD NOB THIO AA
After Treatment 200 mg (138)
DT 8.8 O2 8.3 O2 8.O.O.2 8.2 + 0.2 6.90.2 6.90.3 6.5 + 0.3 7.00.3 RT 9.7. O.1 10.1 - O2 9.7 O2 10.4 O2 8.2 O2 8.8 0.3 8.20.3 9.30.2 ME 292 16 - 1 212 13 - 1 352 222 272 192 H -252 5 - 1 -16 it 2 1 - 1 -28 - 2 72 -19 + 2 3 - 2 After Treatment 400 mg (85)
DT 6.3 - 0.3 6.3 0.4 5.7 0.4 6.1 + 0.4 RT 7.7 O.3 8.20.4 7.6 04 8.8 O.4 ME 413° 273 313 213 H -34 +3 113 -233 O3 + 2.8 After Treatment 600 mg (105)
DT 6.7 O.3 6.8 O.3 6.1 O.3 6.8 0.3 RT 8.9 O.3 8.4 O.3 8.1 O.3 8.90.3 ME 33 - 2 242 272 192 H -253 112 -20 + 2 72 After Treatment 800 mg (16)
DT 4.7 O.7° 4.6 O.9° 4.9 O.7° 4.6 0.7 RT 7.1 - 0.7° S.1 O.9° 8.01.O 7.10.6 US 2010/0022563 A1 Jan. 28, 2010 15
TABLE IX-continued
CHANGESIN SMELL FUNCTION IN TYPE IIHYPOSMIA PATIENTS FOLLOWING TREATMENT
SMELL Before Treatment (208
FUNCTIONXODOR PYRD NOB THIO AA PYRD NOB THIO AA ME 43 S 42 + 8 33 6 386 H -31 - 9 22, 11 -24 + 8 139 () Patient number DT, detection threshold, in BU RT, recognition threshold, in BU ME, magnitude estimation, in 96 H, hedonic value, in % PYRD, pyridine: NO2B, nitrobenzene: THIO, thiophene: AA, amyl acetate Compared to before treatment & O.OO1 'p & 0.005 p < 0.02
0117 Type III Hyposmia Treatment. After treatment with 0118 Discussion either 200 mg. 400 mg or 600 mg, there were no significant 0119) These results indicate that 157 of the 312 patients in changes in DT or RT, since these values were not significantly the study (50.3%) were responsive to treatment with theo different from normal before treatment. After treatment, there phylline. Of these, 34 (21.7%) considered their smell function were changes in ME and H, but values were variable due to returned to normal levels. Overall, 10.9% of all patients in the the small number of patients in each treatment series (Table study considered their smell function had returned to normal. X). Of the eight patients with Type III hyposmia in the study, Improvement in Smell function, once occurred, persisted and 5 (62.5%) reported >5% improvement and 3 (60%) reported Sometimes continued to improve as long as treatment contin their smell function had returned to normal (see Table X). ued.
TABLE X
CHANGES IN SMELL FUNCTION IN TYPE IIIHYPOSMIA PATIENTS FOLLOWING TREATMENT
SMELL Before Treatment (8
FUNCTIONXODOR PYRD NOB THIO AA PYRD NOB THIO AA After Treatment 200 mg (4)
DT 4.O.O.S 340.6 3.3 O.8 2.5 OS 4.O. O.6 3.8 - 0.7 32 08 2.8 0.5 RT 5.6 O.8 4.O. O.9 39 O.8 5.3 - 1.0 5.2 - O.S S.O. O.6 3.8 - 0.6 5.2 1.6 ME 42 + 4 34 - 4 34 - 10 4O2 45 - 11 33 8 47 - 15 32 - 10 H -27 - 14 127 -46 - 13 34 8 -40 + 13 13 - 12 -40 - 18 1413 After Treatment 400 mg (2)
DT 2.5 1 2 RT 4.0 1 3 ME 79 99 75 H -40 -62 -99 75 After Treatment 600 mg (4)
DT 3.809 3.8 - 0.9 2.O. 10 2.5 1.0 RT 5.5 - 0.9 4.513 3.8 O.9 4.8 1.7 ME 41 - 15 33 - 13 42 - 20 31 - 17 H -26 - 22 12- 16 -35 - 24 28, 19 () Patient number DT, detection threshold, in BU RT, recognition threshold, in BU ME, magnitude estimation, in 96 H, hedonic value, in % PYRD, pyridine: NOB, nitrobenzene: THIO, thiophene: AA, amyl acetate US 2010/0022563 A1 Jan. 28, 2010
0120 Initial studies were made at two-six month intervals acuity, but also sensory distortions. This phenomena was after drug initiation. Subjective responses indicated that observed upon comparison of ME and H values between return of function was both time and dose related; patients untreated patients and normals (Table II). The disparate ratios reported little or no improvement before four-six weeks of of H:ME reflected among the patients not only manifest treatment and reported greater improvement as doses decreased acuity (lowerME) but also the bimodal distribution increased to 400 mg and especially to 600 mg and 800 mg. of H values (as discussed previously). This bimodal distribu 0121 Patients with smell loss exhibited varying degrees of tion becomes more apparent for H values as patients recov loss prior to treatment, however, improvement was noted in ered their sensory acuity (manifested by increased DT, RT patients regardless of degree of loss. Patients with lesser and ME) since there was an even greater divergence of pleas degrees of smell loss (Type II and III hyposmia) exhibited antness-unpleasantness among all odors presented than in more improvement with more patients reporting a return to normals. Thus, H values among some patients in whom sen normal Smell function on treatment than those with a more sory acuity increased, pleasant odors (e.g., nitrobenzene— severe degree of loss (Type I hyposmia). Indeed, in terms of bitter almond or marzipan-like or amylacetate banana-like) percent patients reporting a return to normal function, twice were considered putrid because the distorted aspect of these as many patients with Type II and III hyposmia compared to odors also increased. This type of change may not be as Type I reported a return to normal function. These results are readily apparent with respect to changes in more unpleasant useful since smell loss degree is related to severity of bio odors (e.g., pyridine, thiophene), but may also occur with chemical changes (35) responsible for the loss. This result these unpleasant odors considered Sweet or fruity as part of lends credence to the Smell loss classification previously the distortion. devised (1, 2,56) and alerts physicians treating these patients 0.125. On 200 mg theophylline, ME values for pyridine that patients with a greater degree of smell loss require greater and thiophene increased 6% and 5%, respectively, whereas H care and diligence with respect to Successful treatment values decreased (became less unpleasant) 2%, respectively; responses. Among patients who did not improve (those who ME values for nitrobenzene and amyl acetate increased 5%, responded <5% improvement), increasing the dose of theo respectively, whereas H values increased (became more phylline further to 800 mg improved smell function further. In pleasant) only by 2% (Table IV). This effect is better appre another group of patients who improved <5%, the addition of ciated on 400 mg theophylline with ME increases for pyridine another PDE inhibitor (i.e., cilostazol) to theirdose of 600 mg and thiophene at 12%, respectively, whereas increases in H or 800 mg of theophylline improved smell function in an values were 9% and 7%, respectively; ME for nitrobenzene additional 15% of patients. and amyl acetate increased 11% and 8%, respectively, 0122) When analyzed with respect to changes in objective whereas H values decreased (became more pleasant) only 4% psychophysical measurements of Smell function, mean val and 1%, respectively (Table V). Similar results hold for 600 ues for DT and RT improved significantly for all odors for mg theophylline also (Table VI). each theophylline dose, whether or not subjective improve 0.126 Differences with respect to subjective responses and ment occurred (Tables IV, V, VI). These results indicate that changes measured in DT and RT before and after treatment treatment with theophylline improved standardized threshold may reflect differences in how patients considered their over measurements of sensory function, albeit, not enough to be all improvement on treatment. A response of 25% was cho perceived by the patients as significant. While mean DT and Sen to indicate improvement in Smell function on treatment. RT for all odors improved on treatment, none of these means This apparently Small response number may in actuality be a reached the level of improvement exhibited by normal sub conservative estimate of return of smell function since this jects (cf. Tables III, IV, V, VI). number is a composite of all odors which the patient consid 0123. When analyzed with respect to ME on 200 mg theo ered improved on treatment. Thus, responses to Some strong phylline (Table IV), only responses to pyridine were signifi odors (e.g., gasoline, bleach, ammonia, etc.) may have been cantly greater than prior to treatment. ME for each odor, considered improved by a great deal, but these responses may however, increased with the total mean increase (51%) con have been tempered by the patients' responses to weaker sistent with the overall reported subjective improvement odors (e.g., flowers, perfume, shampoo, etc.) in which no among the Successfully treated patients. On 400 mg theophyl improvement may have occurred. Therefore, the overall com line (Table V), ME for each odor increased significantly with posite which the patient was required to consider, included a total mean increase of 10.4%. On 600 mg theophylline overall improvement in both strong and weak odors. (Table VI), ME for each odor also increased significantly with I0127. Most patients are usually unconcerned whether or a total mean increase of 6.9%. These results are probably not they can detector recognize weak concentrations of odors more consistent with patient Subjective changes, since most (DT or RT), but they are concerned about the intensity (ME) patients are less focused on whether or not they can detect or at which odors are perceived. After treatment with 200 mg recognize weak (threshold) concentrations of odors. Rather, theophylline, the average improvement in ME for all odors they are more concerned about the intensity at which odors was 5.1% consistent with the results reported with respect to are perceived. These results are consistent with the subjective subjective responses to treatment (Table IV). After treatment responses of the patients. with 400 mg, mean ME increased 10.4% consistent with 0.124. In general, as noted before, ME and H values in increased response to this dose (Table V) and after treatment normal Subjects are similar, since Subjects usually equate with 600 mg, mean ME increased 6.9% (Table VI). These pleasantness or unpleasantness of any odor with its intensity, results are more consistent with the Subjective responses of be it pleasant or unpleasant (Table V). For example, pyridine the patients, although data for DT and RT increased signifi odor of 50% intensity is generally considered as 50% cantly. unpleasant whereas amyl acetate odor of 50% intensity is I0128. Side effects of theophylline among patients were generally considered as 50% pleasant. Patients with generally minimal. Patients were required to take the drug in hyposmia, however, may not only manifest decreased sensory divided doses in middle of meals (breakfast and lunch). While US 2010/0022563 A1 Jan. 28, 2010 this technique delayed drug absorption it did not inhibit Anatomical Neuroendocrinology, (Stumpf, W. E., absorption. Thus, the more common and usual side effects of Grant, L. D., Eds.), Karger, A. G., Basel, 1975, pp. nervousness, jitteriness and difficulty in falling asleep were 298-316. obviated. Mild gastrointestinal upset, tachycardia, nausea, 0.142 12. Henkin, R. I. The role of adrenal corticoster diarrhea, headache and insomnia were occasionally reported oids in sensory processes, in Adrenal Gland, (Blaschko, but were usually obviated by temporarily decreasing drug H. Sayers, G., Smith, A. D., Eds.), Handbook of Physi intake for a short period and then increasing drug dose to the ology. Endocrinology, Washington, D.C. Amer. Physiol. required amount. Soc., Sect. 7, Vol. VI, 1975, pp. 209-230. 0129 Treatment with theophylline improved smell func 0.143 13. Henkin, R. I. 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On the antiapoptotic sensory neurons. J. Neurochem. 2005:95:200-9. mechanism of action of theophylline in restoring Smell (0161 31. Henkin R.I., Velicu I., PapathanasiuA. cAMP function inpatients with hyposmia. J. Invest. Med. 2005; and coMP in human parotid saliva: relationships to taste 53 (Suppl. 2):S402. and Smell dysfunction, gender and age. Amer. J. Med. (0178 48. Levy, L. M., Henkin, R.I., Hutter, A. Lin, C. Sci. 2007:334:431-440. S., Schellinger, D. Increased brain activation in response (0162. 32. Henkin, R.I., Velicu, I. cAMP and coMP in to odors in patients with hyposmia after theophylline nasal mucus: relationships to taste and Smell dysfunc treatment demonstrated by fMRI. J. Comp. Asst. tion, gender and age. Clinical Invest. Med. 2008:31: Tomog. 1998:22:760-770. E71-ET7. 0.179 49. Henkin, R.I., Velicu, I., Schmidt, L. Effective 0163. 33. Henkin, R. I. The definition of primary and treatment of smell loss with theophylline. Exper. Biol. accessory areas of olfaction as the basis for a classifica 2008:22:B976.2. tion of decreased olfactory acuity, in Olfaction and Taste 0180 50. Henkin, R. I., Larson, A. L., Powell R. D. II, (Hayashi, T. Ed.), Pergamon Press, London, 1967, pp. Hypogeusia, dysgeusia, hyposmia and dysosmia follow 235-252. ing influenza-like infection. Ann. Otol. Rhin. Laryngol. 0164. 34. Henkin, R. I. Velicu, I. Decreased parotid 1975;84:672–682. salivary cyclic nucleotides related to smell loss severity 0181 51. Church, J. A., Bauer, H., Bellanti, J. A., Sat in patients with taste and smell dysfunction. Metabo terly, R. A., Henkin, R. I. Hyposmia associated with lism. 2009; in press. atopy. Ann. Aller. 1978:40:105-109. (0165 35. Henkin, R.I., Velicu, I. cAMP and coMP in 0182 52. Schechter, P. J., Henkin, R. I. Abnormalities nasal mucus related to severity of Smell loss in patients of taste and smell following head trauma. J. Neurol. with smell dysfunction. Clinical Invest. Med. 2008:31: Neurosurg. Psychiat. 1974:37:802-810. E78-E84. 0183 53. Henkin, R.I., Schecter, P. J., Friedewald, W. 0166 36. Cai, D., Qiu, J., Cao, Z. McAtee, M., Breg T. DeMets, D. L., Raff, M.S. Adouble blind study of the man, B.S., Filben, M.T. Neuronal cyclic AMP controls effects of zinc sulfate on taste and smell dysfunction. the developmental loss in ability of axons to regenerate. Amer. J. Med. Sci. 1976:272: 285-299. J. Neurosci. 2001:21:4731-4739. 018.4 54. Henkin, R.I., Schechter, P. J., Hoye, R. C., 0.167 37. Neumann, S., Bradke, F., Tessier-Lavigne, Mattern, C. F.T. Idiopathic hypogeusia with dysgeusia, M., Basbaum, A. I. Regeneration of sensory axons hyposmia and dysosmia: a new syndrome. J. Amer. Med. within the injured spinal cord induced by intragangli Assoc. 1971:217:434-440. 0185. 55. Schechter, P.J., Friedwald, W.T., Bronzert, D. onic cAMP elevation. Neuron. 2002:34:885-893. A., Raff, M. S., Henkin, R. I. Idiopathic hypogeusia: a (0168 38. Cai, D., Shen, Y., DeBellard, M., Tang, S., description of the syndrome and a single blind study Filben, M. T. Prior exposure to neurotrophins blocks with zinc sulfate, in Internat. Rev. Neurobiol. Suppl. 1. inhibition of axonal regeneration by MAG and myelin (Pfeiffer, C., Ed.), Academic Press, NY, 1972, pp. 125 via a cAMP dependent mechanism. Neuron. 1999:22: 133. 89-101. 0186 56. Henkin, R. I. The definition of primary and 0169. 39. Kurihara, K. Koyama, N. High activity of accessory areas of olfaction as the basis for a classifica adenylyl cyclase in olfactory and gustatory organs. Bio tion of decreased olfactory acuity, in Olfaction and Taste chem. Biophys. Rev. Comm. 1972:48:30-34. II, (Hayashi, T. Ed.), Pergamon Press, London, 1967, pp. (0170 40. Pace, U., Hanski, E., Salomon, Y., Lancet, D. 235-252. Odorant-sensitive adenylate cyclase may mediate olfac tory reception. Nature. 1985:316:255-258. Example 2 0171 41. Moon, C., Simpson, P.J., Cho, H., Ronnett, G. Y. Regulation of intracellular cyclic GMP levels in 0187. Theophylline treatment restored smell function in olfactory sensory neurons. J. Neurochem. 2005:95:205 over 50% of the hyposmic patients in Example 1. This study, 209. however, was an open label clinical trial and not all patients 0172 42. Shepherd, G. M. Sensory transduction enter responded to the drug. These results raise questions about the ing the mainstream of membrane signaling. Cell. 1991; character of the study and the efficacy of the drug to correct 67:845-851. the smell loss. 0173 43. Thompson, W. J. Cyclic nucleotide phos 0188 In an effort to understand more about these results, phodiesterase: pharmacology, biochemistry and func levels of cAMP and cc MP in Saliva before and after theo tion. Pharmacol. Ther. 1991:51:13-33. phylline treatment were studied in patients who participated US 2010/0022563 A1 Jan. 28, 2010 in the clinical study of Example 1. Cyclic nucleotide levels phylline, their dose was increased to 400 mg and they were not assayed until the entire analysis of the clinical trial returned to study site after an additional two-four months of results was completed. treatment. These same measurement processes occurred after (0189 Methods (0190. Thirty-one patients, aged 29-85 y (56+3 y, treatment with 400 mg and 600 mg of theophylline. Mean-SEM) from among the 312 patients who participated 0195 Data for the cyclic nucleotides from these 31 in the open label, fixed design clinical trial treated with theo patients was not analyzed until the entire study of the 312 phylline of Example 1 were studied. There were 13 men, aged patients in Example 1 was assembled and analyzed in its 54+3 y and 18 women, aged 58+4 y. All patients exhibited entirety. After completion of these analyses, all data for hyposmia. Six had Type I hyposmia, 25 had Type II hyposmia parotid saliva cAMP and ccjMP from all patients in whom . Patients had a variety of etiologies for their hyposmia; six salivary cAMP and coMP were obtained were assembled. had PVIL and hypogeusia, thirteen had allergic rhinitis, nine Levels of salivary cyclic nucleotides varied widely. Initially, had a head injury, and three had a variety of the etiologies contributing to their loss including a drug reaction, an idio without external criteria, there was no way to understand pathic cause and post chemotherapy. these disparate data. To assist in understanding these data, 0191 Measurements of smell function were obtained for each data point was independently identified with respect to each patient by use of a standard three stimuli forced choice which patient from whom it was obtained and categorized as technique using four odors (pyridine, nitrobenzene, to whether or not that patient demonstrated improvement or thiophene and amyl acetate as described in Example 1. Sub lack of improvement in both subjective smell function and in jective measurements of Smell function were also obtained objective measurements of smell function (DT, RT, ME, H) for each patient by use of standard technique in which Smell on theophylline treatment. On this basis, 20 patients were acuity was graded on a scale from 0-100 with 0 indicating an identified as having improved smell function and 11 did not absence of overall smell function and 100 indicating normal improve. In a similar manner, measurements of each patient's smell function as described in Example 1. plasma theophylline level at each dosage of theophylline (at 0.192 Parotid saliva was collected from each patient by 200 mg, 400 mg, 600 mg of theophylline) were catagorized. application of a Lashley cup over Stensen's duct with lingual stimulation by placement of concentrated lemon juice. Saliva The two patient groups were also analyzed post hoc with was collected in plastic tubes and stored at -20° C. until respect to type of Smell loss and etiology of Smell loss. assayed. cAMP and coMP were measured in saliva by a (0196) Differences in the characteristics between these two sensitive 96 plate spectrophotometric assay (R&D Systems, patient groups were analyzed with respect to each measure Minneapolis, Minn.). ment obtained (Mean-SEM). Differences between 0193 All patients were placed in a fixed design open label meant-SEM were analyzed using Student t test and X2: dif clinical trial with treatment with oral theophylline. Treatment ferences of ps5% were considered significant. consisted offixed treatment periods of two-eight months with sequential doses of the drug at 200 mg, 400 mg and 600 mg. (0197) Results At termination of each of these intervals, patients returned to (0198 Post hoc analysis demonstrated that initial values of study site for reevaluation. At the end of each interval subjec Subjective Smell function and measurements of Smell func tive responses to treatment were measured with a modifica tion (DT, RT, ME, H) from these two patient groups prior to tion of the 0-100 scale previously used (vs). Subjective theophylline treatment did not differ. At baseline, there were responses to treatment were graded on a sliding scale from also no significant differences in saliva cAMP and ccjMP -100-0-100 with patients recording improvement between improved and unimproved patients (Table XI). Lev (+0-100), no improvement (O) or worsening (0-100) of els of saliva cAMP prior to treatment were consistent with their overall smell function. If overall smell function mean values obtained for saliva cAMP in all 312 patients improved >5% they were considered to improve clinically included in the original study. After treatment with 200 mg of (1). If smell function improved <5% they were considered not theophylline, cAMP levels in the improved patients increased to improve (1). At the end of each interval subjective mea 10% above baseline, albeit not significantly; there was essen surements of smell function, measurements of DT, RT, ME tially no change among the unimproved patients (Table I). and Hand measurements of parotid saliva for levels of cAMP and ccjMP were obtained. In addition, blood plasma was After treatment with 400 mg of theophylline, however, obtained by Venipuncture, placed in ice into zinc free tubes although values were not statistically significant compared to which contained 100 mg zinc free heparin, centrifuged at before treatment, cAMP levels increased 40% over baseline 3000 rpm for 10-20 min, the plasma transferred to plastic in the improved group, whereas there was essentially no PCR tubes and stored at -20°C. until assayed. Theophylline change among the unimproved patients. After treatment with was assayed by a fluorescence polarization assay (Abbott, 600 mg. cAMP levels increased significantly to 67% above Chicago, Ill.), as previously described. initial cAMP values in the improved patients, but there was 0194 At each return visit, if patients noted improvement essentially no change among unimproved patients. After in their overall smell function (see Example 1) they continued treatment with 600 mg, levels of cAMP in the improved on this same drug dose and were not included in any further patients were still below the mean of saliva cAMP reported in data. If smell function did not improve on 200 mg of theo normal Subjects. US 2010/0022563 A1 Jan. 28, 2010 20
TABLE XI
RESULTS FOR PATIENTS WITH IMPROVED SMELL FUNCTION
BEFORE BEFORE TREAT THEOPHYLLINE TREATMENT TREAT THEOPHYLLINE TREATMENT MENT cAMP (pmol/ml MENT cGMP (pmol/ml PLASMA THEOPHYLLINE (pmol/ml) 200 mg 400 mg 600 mg (pmol/ml) 200 mg 400 mg 600 mg (mg/dl) O.87 O.96 O.13 1.22 O.33 1.45 + 0.37 0.08 + 0.016 0.08 + 0.016 0.22 + 0.07 0.27+ 0.09 3.5 + 0.4 6.4 + 1.2 12.41.8 0.14* (20) (16) (12) (9) (20) (15) (12) (10) (13) (12) (9) *Mean SEM () Patient number With respect to no improvement in Smell function 'p & 0.05 'p & 0.025
0199. At baseline, there were no significant differences between ccjMP levels for the two groups of patients (Table XII). Mean values obtained in each patient group were con sistent with values obtained in the total group of 312 patients prior to initiation of the treatment (see Example 1). After treatment with 200 mg of theophylline, there was little dif ference in saliva coMP levels between improved and unim proved patients or compared to pretreatment values. After treatment with 400 mg of theophylline, salivacGMP levels in the improved patients increased significantly to 275% over initial values, whereas there was little change among the unimproved patients. After treatment with 600 mg of theo phylline, c0MP levels improved significantly to 338% over initial values, whereas there was no increase among the unim proved patients. After treatment with 400 mg or 600 mg of theophylline, c0MP mean levels in the improved patients were similar to those obtained in normal Subjects.
TABLE XII
RESULTS FOR PATIENTS WITHUNIMPROVED SMELL FUNCTION
BEFORE BEFORE TREAT THEOPHYLLINE TREATMENT TREAT THEOPHYLLINE TREATMENT MENT cAMP (pmol/ml) MENT cGMP (pmol/ml) PLASMA THEOPHYLLINE (pmol/ml) 200 mg 400 mg 600 mg (pmol/ml) 200 mg 400 mg 600 mg (mg/dl)
1.03 - 0.24 O.78 O.26 O.95 - 0.26 O56 - 0.21 3.71.O 8.6 1.4 8.7 O.6 (11) (9) (5) (9) (11) (4) (5) (9) (5) (9)
*Mean SEM () Patient number
0200 Comparison of blood plasma theophylline between ited Type I hyposmia, indicating that significantly more of the the two groups indicated that there was no difference in mean unimproved patients (with unchanged levels of cAMP and values after treatment with either 200 mg or 400 mg of theo cGMP) had Type I hyposmia, the more severe type of smell phylline (Table XI). After treatment with 600 mg, however, loss (Table XII). although plasma theophylline increased in both groups, com pared to plasma levels seen following treatment with 200 mg TABLE XIII or 400 mg of theophylline, mean theophylline was signifi cantly elevated in the improved group compared to the unim COMPARISON OF CLINICAL CHARACTERISTICS BETWEEN proved group. (Tables XI and XII). IMPROVED AND UNIMPROVED PATIENTS 0201 Classified by smell loss type, there were significant IMPROVED * UNIMPROVED differences between the two groups (Table XIII). Among the SMELL LOSS TYPE I II I II improved patients, 95% of the patients exhibited Type II PATIENT NUMBER 1 19. 4 7 hyposmia, whereas, only one patient had Type I hyposmia. Among the unimproved patients, 57% of the patients exhib US 2010/0022563 A1 Jan. 28, 2010 21
(0208 While levels of blood theophylline increased in both TABLE XIII-continued groups of patients as the dose of theophylline increased (200 mg, 400 mg, 600 mg), levels of blood theophylline were COMPARISON OF CLINICAL CHARACTERISTICS BETWEEN IMPROVED AND UNIMPROVED PATIENTS significantly higher in the improved group compared to the unimproved group after 600 mg of the drug. The blood theo IMPROVED: UNIMPROVED phylline level in the improved group was 12.4 mg/dl whereas ETIOLOGY OF AR PIEHEH HI OTHER AR PIEHEH HI OTHER it was 8.7 mg in the unimproved group (Tables XI and XII). LOSS While the level of theophylline in the improved patients is in PATIENT 8 6 3 3 8 O 3 O the normal range for therapeutic effects of the drug (10-20 NUMBER mg/dl), the level in the unimproved group was not. Previous * Parotid saliva cAMP and coMP concentrations after 600 mg theophylline data Suggest that patients that improve with theophylline were significantly higher in improved than in unimproved patients (see exhibit plasma levels between 2-14 mg/dl, so that it would not Tables I, II) Improved vs Unimproved by Smell Loss Type be reasonable to imply that these differences between these two groups are attributable only to the differences obtained in AR, allergic rhinitis PIHH, post influenza-like hyposmia and hypogeusia serum theophylline. While this is undoubtedly one factor HI, head injury related to drug resistance, as is well known from many other Other (drug reaction, idiopathic, post chemotherapy) studies, this difference may not account for all the differences between these two groups. 0202 Classified by diagnosis, the distribution of etiology of Smell loss among the improved patients was similar to that (0209. The open label trial of theophylline in Example 1 previously reported in several publications. Among the unim demonstrates the usefulness of theophylline in restoring the proved patients, however, there were no patients who had sense of smell in patients with smell loss. The present studies PIHH or “other causes of smell loss. Indeed, only two eti indicate that multiple factors influence Successful treatment ologies comprised the etiology of Smell loss among unim of hyposmic patients and that a thorough work up is required proved patients, either allergic rhinitis or head injury (Table if treatment is to be successful. These factors include testing XII). as to the type and degree of Smell loss, discovering the etiol 0203 Discussion ogy of the patient's Smell loss, analysis of theophylline 0204 The observed results were unexpected. These plasma levels, and analysis of parotid gland secretion of results, however, Suggest that changes incGMP may be more cAMP and coMP. In particular, parotid saliva coMP level relevant to changes in Smell function than measurement of stands out as predictive of clinical response given the unex cAMP since, among the improved patients, levels of c(GMP pected finding that cOMP levels correlate with recovery of the increased into the normal range whereas for cAMP they sense of smell. This observation allows for the development increased, but not into the normal range. of a testing regiment to select for the appropriate therapy. A 0205 These results also suggest that administration of patient can be administered a standard challenge dose of theophylline at the same dose results in differences in smell theophylline or other PDE inhibitor and then the level of improvement, in levels of saliva cAMP or cGMP and in serum parotid saliva coMP is determined. Patients that achieve a theophylline levels in this group of patients. There are no threshold level of c(GMP following the challenge can then be prior studies that would suggest differential effects of drug prescribed the appropriate dose that will achieve the targeted response or biochemical changes related to theophylline steady state plasma level of the PDE inhibitor. Patients whom intake. This type of change, however, has been observed parotid salivacci MP levels fail to achieve the threshold level previously with many drugs and is well known in several can be challenged with a higher dose of the PDE inhibitor, disease states. Indeed, drug resistance has been important to have another PDE inhibitor or other active agent added to the understanding differential drug affects and their influence on dosage of the original PDE inhibitor, or switched to another metabolic processes. Although the patient number in this PDE inhibitor as is clinically warranted. In this way, a phy study is relatively small, apparently this is the first report of sician can determine the optimum PDE inhibitor dosage for a drug resistance to oral administration of theophylline. patient without undertaking the long dose escalation titration 0206 Patients with theophylline resistance appear to have required in the original study detailed in Example 1. specific clinical characteristics by which they can be identi 0210. In some embodiments, a method is provided for fied prior to their treatment and development of this resis screening patients for PDE inhibitor therapy for anosmia or tance. It was discovered that unimproved patients had head hyposmia comprising: administering to a patient a challenge injury and allergic rhinitis. In addition these patients exhibit a dose of a PDE inhibitor; determining the salivary level of preponderance of a severe type of Smell loss (Type I cGMP; and comparing the patient's salivary c0MP level to a hyposmia), one in which they cannot recognize the character threshold value, wherein patients who have acci MP salivary of any odor. level equal to or greater than the threshold value are candi 0207. The data obtained also suggest that this resistance is dates for PDE inhibitor therapy to treat anosmia or hyposmia. present irrespective of drug dose, although it is more obvious In Some embodiments, the challenge dose is 200 mg, 400 mg. at higher doses of the drug. In addition, drug resistance effects 600 mg or 800 mg of theophylline. In some embodiments, the appear to be more robust with respect to levels of salivacciMP threshold value is at least 0.08, 0.10, 0.12, 0.14, 0.16, 0.18, rather than to cAMP. Levels of salivary c0MP among the 0.20, 0.22, 0.24, 0.26, or 0.28 pmol/ml. improved patients returned to levels previously observed in 0211. In some embodiments, the threshold value is equal normal subjects. Saliva cAMP levels increased, significantly to or substantially similar to the mean ccjMP value seen in so at the highest dose of theophylline administered, but they normal individuals following the same challenge dose. In did not increase to levels measured in normal Subjects. other embodiments, the threshold value is not less than 10%, US 2010/0022563 A1 Jan. 28, 2010 22
20%, 30%, 40%, or 50% of the mean salivary c0MP value for at least an equivalent recovery of smell acuity comparable seen in normal individuals following the same challenge to that achieved with orally administered PDE 1 inhibitor or dose. PDE1 C2 inhibitor, avoiding or reducing the side effects caused by higher PDE1 inhibitor or PDE1C2 inhibitorplasma Example 3 levels seen with oral administration. 0212 Hyposmic patients for whom the etiology of smell loss is not associated with head injury or allergic rhinitis are Example 5 enrolled in an open label trial of inhalable theophylline. 0218. For over 60 years, theophylline has been used as a Patients are started at an initial dose of not more than 500 ug bronchodilator in the treatment of asthma and COPD and formulated as a liquid spray or dry powder to be delivered as remains one of the most widely prescribed drugs for the a metered dose. Initially only local patients are enrolled so treatment of airway diseases worldwide. Theophylline that quicker dose titration is achieved. Groups of 5 patients directly relaxes human airways Smooth muscle in vitro and, are started on not more than 500 g of theophylline and like beta-agonists, acts as a functional antagonist, preventing continued for 1 month. and reversing the effects of all bronchoconstrictor agonists. 0213 Patients are tested for improvement in smell acuity Bronchodilatation by theophylline is achieved through PDE using the standard forced choice technique using four odors inhibition, resulting in an increase in cAMP by inhibition of as described in Example 1. Additionally, subjective measure PDE3 and PDE4 and in cyclic guanosine 3',5'-monophos ments of smell function are obtained using a scale from 0-100 phate by inhibition of PDES. The bronchodilator effect of as described in Example 1. Blood samples are also drawn to theophylline in human airways is reduced by charybdotoxin, ascertain blood theophylline level to gauge its relationship to which selectively inhibits large conductance Ca" activated the expected recovery of smell. K" channels (maxi-K channels), suggesting that theophylline 0214 Nasal administration of theophylline provides for opens these maxi-K channels via an increase in cAMP high, initial concentrations of theophylline being deposited 0219. In asthma therapy, theophylline has an increasing on the olfactory epithelium, thereby exposing olfactory neu acute bronchodilator response above plasma concentrations rons and their sensory cilia to higher concentrations of theo of 10 mg/L (55 uM), however, the upper recommended phylline than are achieved through oral administration plasma concentration is 20 mg/L due to unacceptable side through the avoidance of first pass metabolism. Nasal admin effects above this level including nausea and headaches. The istration provides for at least an equivalent recovery of Smell therapeutic range for plasma concentrations is therefore acuity comparable to that achieved with orally administered established at 10 to 20 mg/L, and doses are adjusted in indi theophylline while avoiding or at least reducing the side vidual patients to achieve this range. effects caused by higher theophylline plasma levels seen with 0220. Theophylline has an additional effect on mucocili oral administration. ary clearance through a stimulatory effect on ciliary beat frequency and water transport across the airway epithelium. Example 4 Relatively high doses of theophylline are needed, as this 0215 Hyposmic patients for whom the etiology of smell effect is likely to be due to an increase in cAMP as a result of loss is not associated with head injury or allergic rhinitis are PDE inhibition. enrolled in an open label trial of an inhalable PDE1 inhibitor. 0221) Theophylline also has anti-inflammatory effects in More preferably, a PDE1C2 inhibitor such as ebumamenine asthma. In allergen challenge studies in patients with asthma, 14-carboxylic acid ethyl ester (vinpocetine), 8-methoxym intravenous theophylline inhibits the late response to aller ethyl-1-methyl-3-(2-methylpropyl) xanthine (8MM-IBMX), gen. A similar finding with allergen challenge was reported Zaprinast (M&B 22948), 4-3-(cyclopentyloxy)-4-methox after chronic oral treatment with theophylline. Oral theophyl yphenyl-2-pyrrolidinone (rolipram), 4-(3-butoxy-4-meth line also inhibits the late response to toluene diisocyanate in oxybenzyl)-2-imidazolidinone (RO20-1724), 1,6-dihydro-2- toluene diisocyanate-sensitive individuals with asthma. This methyl-6-oxo-(3,4'-bipyridine)-5-carbonitrile (milrinone), is interpreted as an effect on the chronic inflammatory trequinsin (HL 725), and/or combinations thereof because of response, and this is Supported by a reduced infiltration of the high expression level of PDE1C2 in the olfactory epithe eosinophils and CD4" lymphocytes into the airways after lium. Patients are started at an initial dose of 500 ug formu allergen challenge Subsequent to low doses of theophylline. lated as a liquid spray or dry powder delivered as a metered In patients with nocturnal asthma, low-dose theophylline dose. Initially only local patients are enrolled so that quicker inhibits the influx of neutrophils and, to a lesser extent, eosi dose titration is achieved. Groups of 5 patients are started on nophils in the early morning. In patients with mild asthma, 500 ug of the PDE1 inhibitor or PDE102 inhibitor and con low doses of theophylline (mean plasma concentration ~5 tinued for 1 month. mg/L) reduce the numbers of eosinophils in bronchial biop 0216 Patients are tested for improvement in smell acuity sies, bronchoalveolar lavage, and induced sputum, whereas in using the standard forced choice technique using four odors severe asthma, withdrawal of theophylline results in as described in Example 1. Additionally, subjective measure increased numbers of activated CD4+cells and eosinophils in ments of smell function are obtained using a scale from 0-100 bronchial biopsies. as described in Example 1. Blood samples are also drawn to 0222. In patients with COPD, theophylline reduces the ascertain blood levels of the PDE1 inhibitor or PDE1 C2 total number and proportion of neutrophils in induced spu inhibitor and its relationship to the observed patient response. tum, the concentration of interleukin-8, and neutrophil 0217 Nasal administration of the PDE1 inhibitor or chemotactic responses, suggesting an antiinflammatory PDE102 inhibitor provides higher exposure of the PDE1 effect. This is in sharp contrast to the lack of effect of high inhibitor or PDE1C2 inhibitor to nasal olfactory neurons than doses of inhaled corticosteroids in a similar population of can be achieved through oral administration. This provides patients. US 2010/0022563 A1 Jan. 28, 2010
0223) These anti-inflammatory effects of theophylline in allowed to rest for 20 minutes before baseline measurements asthma and COPD are seen at concentrations that are usually of FEV1 (six recordings) and sGaw (five recordings) are less than 10 mg/L, which is below the dose where significant made. Subjects receive a dry powder dispenser loaded with a clinically useful bronchodilatation is evident. dose of 1 mg IBMX formulated as a dry powder or a dry 0224. Theophylline is a weak and nonselective inhibitor of powder carrier. Subjects are advised that some of the prepa PDEs. In vitro, theophylline relaxes airway smooth muscle by rations may have a bitter taste, while others will not, but that inhibition of PDE activity (PDE3, PDE4, and PDES), but this does not necessarily reflect the presence or degree of relatively high concentrations are needed for maximal relax activity of the drug. After each inhalation, measurements of ation. The degree of PDE inhibition is very small at concen sGaware made at 1, 3, 5, 10, 15, 20, 25, and 30 minutes. After trations of theophylline that are therapeutically relevant with 30 minutes, the sGaw measurement is still 20% above the experiments with human lung extracts demonstrating only 5 baseline measurement, so additional sGaw measurements are to 10% inhibition of total PDE activity at therapeutic concen taken every 15 minutes until baseline is reached at one and a trations. half hours. 0225. Inhalation therapy with neublized solutions of theo 0230. On completion of the last recording, subjects inhale phylline and other methylxanthines was tried to widen the a 200 ug dose of salbutamol from a metered inhaler and a therapeutic index. Inhalation of methylxanthine derivatives further measurement of sGaw mad after 15 minutes. Subjects produce an immediate increase in specific airway resistance are also be monitored for coughing and are questioned about (sGaw) that peaks in 5 minutes, but the effects were no more the taste of the drug. The increase in sGaw produced by the than half the response seen with a standard 200 ug dose of inhaled IBMX is comparable with that produced by salbuta inhaled salbutamol, and dissipated by 30 minutes. Addition mol. Furthermore, the dry powder formulation is without the ally, the nebulized solutions of methylxanthine derivatives unpleasant taste or the induction of coughing associated with have a disagreeable taste and produced a pronounced cough a liquid formulation delivered by a nebulizer. leading the researchers to conclude that inhalation of meth ylxanthines derivatives were unlikely to be of benefit in the Example 7 treatment of asthma. 0226 Applicants believe that this past failure with inhal 0231. Ten patients with hyposmia were selected from able methylxanthine derivatives owes more to the formula among 400 patients with hyposmia to participate in a pilot tion and method of delivery than to the inherent properties of study to determine safety and efficacy of intranasal theophyl the derivatives. To test this theory, asthmatic patients are line for the treatment of hyposmia. These patients were pre enrolled in a dose escalating single blind study. On arrival to viously treated with oral theophylline or were switched from the clinic, subjects are allowed to rest for 20 minutes before oral theophylline to intranasal theophylline at the start of the baseline measurements of FEV1 (six recordings) and sGaw study. Selection for inclusion in the intranasal study was (five recordings) are made. Subjects receive a dry powder based upon several criteria. 1) non-response to oral theophyl dispenser loaded with a dose of 2 mg theophylline or a dry line; 2) severe side effects with oral theophylline that pre powder carrier. Subjects are advised that some of the prepa vented reaching a dose of Sufficient strength to restore Smell rations may have a bitter taste, while others will not, but that function; and/or 3) preference for intranasal medication over this does not necessarily reflect the presence or degree of oral medication. activity of the drug. After each inhalation, measurements of 0232 Through careful evaluation of plasma, saliva and sGaware made at 1, 3, 5, 10, 15, 20, 25, and 30 minutes. After nasal mucus theophylline levels in patients with hyposmia 30 minutes, the sGaw measurement is still 20% above the taking theophylline at doses of 200-800 mg daily, it was baseline measurement, so additional sGaw measurements are determined that a dose of 20 ug theophylline delivered intra taken every 15 minutes until baseline is reached at 1 hour. nasally to each naris (or 40 ug total) was sufficient to produce 0227. On completion of the last recording, subjects inhale localized effects similar to those achieve with oral theophyl a 200 ug dose of salbutamol from a metered inhaler and a line of 200-400 mg daily. Additionally, loco-regional admin further measurement of sGaw is made after 15 minutes. Sub istration of Such a low dose would avoid producing the side jects are also monitored for coughing and are questioned effects seen with oral administration. about the taste of the drug. The increase in sGaw produced by 0233 Intranasal Preparation the inhaled theophylline is comparable to that produced by 0234. A batch of theophylline for intranasal administra salbutamol. Furthermore, the dry powderformulation is with tion at a dose of 20 ug/0.4 ml of was prepared by dissolving out the unpleasant taste or the induction of coughing associ 250 mg of methylparaben powder and 250 mg of propylpa ated with a liquid formulation delivered by a nebulizer. raben powder in 5 ml of propylene glycol. Next 50 mg of Example 6 theophylline, anhydrous powder, was dissolved in a small amount of 0.9% sodium chloride. The dissolved parabens 0228 IBMX, (isobutylmethylxanthine), a non-specific were added to the theophylline solution and mixed well. PDE inhibitor possesses greater potency than theophylline Sufficient 0.9% sodium chloride was added to the mixture to (IC50=2-50 uM). Given IBMX structural similarity to theo bring the total volume to 1000 ml. The solution was sterilized phylline, IBMX shares theophylline's bronchodialation, anti by filtering through a sterile 0.2 um filter. 1 ml syringes were inflammatory, and ciliary beat frequency stimulatory effects loaded with 0.4 ml of the sterile solution and then capped with but is expected to have a wider therapeutic index potentially a tamper evident cap. allowing for the use of lower dosages, thereby reducing side 0235 Representative samples were sent to an independent effects and complaints over disagreeable taste when admin testing laboratory for pH, endotoxin, sterility, and fungal istered through a nebulizer. contamination testing in addition to the determination of the 0229 Asthmatic patients are enrolled in a dose escalating theophylline concentration. The test results demonstrated single blind study. On arrival to the clinic, subjects are that the preparation had 20.716 ug of theophylline per 0.4 ml US 2010/0022563 A1 Jan. 28, 2010 24 with a pH of 5.9. Further, endotoxin was below 1.0 EU/ml and smell function to treatment with 0 indicating no response, 100 the preparation was sterile and free of fungal contamination. indicating return to normal function and intermediate num 0236 Study Design bers indicating an intermediate response. 0237. The purpose, risk and benefits of participating in the (0258 Treatment Technique study were explained to each patient by the study's Supervis 0259. The patients inserted a plastic syringe containing ing physician. Prior to enrollment in the study, each patient 0.4 ml of fluid (20 ug theophylline) into each naris once a day. read and signed an informed consent form. Next, each patient Previous investigation of the Syringe injection technique for was instructed in the proper technique of intranasal adminis intranasal drug administration indicated that a volume of 0.4 tration. ml delivered to each naris was sufficient to deliver the drug 0238 Patients discontinued their use of oral theophylline dose without having the liquid escape out of the nares or either at time of entry into the study (eight patients) or four directly into the pharynx. The drug dose was delivered months prior to study entry (two patients). through a plastic nipple which fitted snugly onto the filled 0239 Changes to smell function was determined at four Syringe which was attached directly to the nipple. One nipple specific periods: was supplied for each set of two syringes in each application 0240 Time 0 at the start of the study. kit. The patient fitted the nipple on one syringe, placed the 0241 Time 1—one week after starting intranasal theo nipple securely into the lower naris and injected the contents phylline of the Syringe directly into the lower vault of one naris accom 0242 Time 2—two weeks after starting intranasal theo panied by a modest inhalation. This technique was then used phylline for the second syringe used for the other naris. The patients 0243 Time 4 four weeks after starting intranasal theo were instructed to administer the drug either seated or stand phylline ing with their head in an erect, vertical position. 0244. After reaching Time 4, the study was discontinued 0260 Patients were supplied with 15 doses on each of two and the patients were returned to their use of oral theophylline occasions with all used syringes returned to the clinic after if indicated. use to insure proper and complete usage. 0245 Study Measurements 0261 Results 0246. At each of the four time periods of the study the 0262 Ten hyposmia patients were enrolled in the study, following battery of tests were performed and samples eight patients have completed all four phases of the study with obtained. the remaining two patients still in process. No side effects of 0247 Objective Test Measurements intranasal use were observed, including, no nasal congestion, 0248 Taste Function Tests nasal pruritus, nasal discomfort, cough or unusual or bitter 0249 Taste function was measured by detection threshold taste. No patient exhibited a further of loss of smell while in (DT), recognition threshold (RT), magnitude estimation the study. This demonstrates that the patients that stopped (ME) and hedonics (H) for four tastants (NaCl, sucrose, HCl, their oral medication at the time of the start of the study, which urea) by use of a standard three stimuli, forced choice stair ranged from 400-800 mg oral theophylline daily, received at case drop technique described in Example 1 and ref 53. least an equivalent localized dose of theophylline to the nasal (0250 Smell Function Tests olfactory epithelium as was achieved with their total oral 0251 Smell function was measured for DT, RT, ME and H dose. for four odorants (pyridine, nitrobenzene, thiophene, amyl 0263. Of the eight patients that completed the study, six acetate) by use of the standard three stimuli, forced choice reported subjective improvement in both taste and smell func staircase sniff technique described in Example 1 and in ref53. tion (>10-20% over prior results with oral theophylline). The 0252 Bodily Fluids plasma theophylline levels for the eight patients was Zero 0253 Blood was obtained by Venipuncture to collect indicating that at most an undetectable fraction of intranasal plasma and red blood cells used to measure trace metals (Cu, theophylline was absorbed systemically. Furthermore, this Zn, Mg), various enzymes, theophylline and other chemical data demonstrates that at the dosage level of 20 ug per naris, moieties. more theophylline is delivered locally to the nasal olfactory 0254 Saliva was collected with a modified Lashley cup as epithelium than is delivered by 200-800 mg of oral theophyl described in Example 2 and used to measure trace metals (Cu, line because the six patients that experienced increased Smell Zn, Mg), various enzymes (cAMP. c6MP, CAVI, etc.), theo acuity with the intranasal theophylline reported that their phylline and other chemical moieties. acuity diminished upon the resumption of their previous oral 0255 Nasal mucus was collected by use of a standard dosage of theophylline. technique and used to measure trace metals (Cu, Zn, Mg), 0264. Overall, of the first eight patients, six (75%) exhib various enzymes (cAMP. c6MP, CA VI, etc.), theophylline ited subjective improvement in smell function in the study and other chemical moieties. Trace metals were measured by with the other two patients reporting maintenance of the atomic absorption spectrophotometry (as previously dec improvement in Smell acuity previously achieved with oral scribed) using a dual beam Thermo-Jarrel Ash atomic absorp theophylline. tion spectrophotometer. CAVI was measured by enzymatic 0265 Discussion analysis of activity of the enzyme by our modification of the 0266 Preliminary results of this trial of intranasal theo method of Richli, et al. Cyclic nucleotides were measured by phylline indicate that patients can administer the drug without a sensitive 96 plate spectrophotometric sensitive ELISA difficulty. Further, no side effects were observed with the assay provided by Applied Biosystems, Minneapolis, Minn. intranasal administration of theophylline. Additionally, all ot 0256 Subjective Test Measurements the patients preferred intranasal administration over oral 0257 Subjective responses to treatment were obtained administration with six of the eight evaluable patients studied independent of any interaction with the clinical staff by using noting significant improvement in taste and Smell function a scale of 0-100 to measure response of taste function and after use of intranasal over that achieved with oral theophyl US 2010/0022563 A1 Jan. 28, 2010
line. All ten patients reported no diminution of their smell thylxanthine) aminophylline, doxophylline, cipamphylline, function using intranasal administration demonstrating that neuphylline, pentoxiphylline, or diprophylline. they are receiving at least an equivalent dose of theophylline 5. The method of claim 3, wherein the methylxanthine by intranasal administration. As the last two patients have not derivative is theophylline or pentoxiphylline. yet completed the study, the number of patients responding to 6. The method of claim 2, wherein the PDE-3 inhibitor is the intranasal therapy may further increase. Furthermore, cilostazol. taste and Smell acuity was stable or improved without pro 7. The method of claim 1, wherein the effective amount of ducing measureable blood theophylline levels. the PDE inhibitor is less than 2 mg. 8. The method of claim 1, wherein PDE inhibitor is formu 0267 One of the patients that achieved an improved sense lated as a liquid or dry powder. of smell did not wish to return the unused portion of the 9. The method of claim 1, wherein PDE inhibitor is admin intranasal theophylline since the methodology also Success istered at least once, twice, or thrice daily. fully enhanced her nasal breathing, nasal homeostasis and 10. The method of claim 1, wherein successful treatment ability to sleep more soundly at night due to improvement in comprises an increase in taste or Smell acuity of at least 5%. nasal function. 11. The method of claim 10, wherein the increase intaste or 0268 While preferred embodiments of the present inven Smell acuity is accompanied by an increase in nasal mucus or tion have been shown and described herein, it will be obvious saliva cAMP or cGMP levels. to those skilled in the art that such embodiments are provided 12. A pharmaceutical composition for intranasal adminis by way of example only. Numerous variations, changes, and tration comprising a phosphodiesterase (PDE) inhibitor, substitutions will now occur to those skilled in the art without wherein the composition comprises less than 1 mg of the PDE departing from the invention. It should be understood that inhibitor and a pharmaceutically acceptable carrier. various alternatives to the embodiments of the invention 13. The composition of claim 12, wherein the PDE inhibi described herein may be employed in practicing the inven tor is selected from the group consisting of non-selective PDE tion. It is intended that the following claims define the scope inhibitors, PDE-1 selective inhibitors, PDE-2 selective of the invention and that methods and structures within the inhibitors, PDE-3 selective inhibitors, PDE-4 selective Scope of these claims and their equivalents be covered inhibitors, and PDE-5 selective inhibitors. thereby. 14. The composition of claim 13, wherein non-selective PDE inhibitor is a methylxanthine derivative. What is claimed is: 15. The composition of claim 13, wherein the methylxan 1. A method for treating anoSmia or hyposmia comprising: thine derivative is caffeine, theophylline, IBMX (3-isobutyl administering to a patient in need thereof, an effective 1-methylxanthine) aminophylline, doxophylline, cipamphyl amount of a phosphodiesterase (PDE) inhibitor, wherein line, neuphylline, pentoxiphylline.or diprophylline. the PDE inhibitor is administered by intranasal admin 16. The composition of claim 13, wherein PDE inhibitor is istration and wherein said anoSmia or hyposmia is a PDE-3 selective inhibitor. treated. 17. The composition of claim 13, wherein the PDE-3 selec 2. The method of claim 1, wherein the PDE inhibitor is tive inhibitor is cilostazol. selected from the group consisting of non-selective PDE 18. The composition of claim 12, wherein the composition inhibitors, PDE-1 selective inhibitors, PDE-2 selective is a dry powder. inhibitors, PDE-3 selective inhibitors, PDE-4 selective 19. The composition of claim 12, wherein the composition inhibitors, and PDE-5 selective inhibitors. is a liquid. 3. The method of claim 2, wherein the non-selective PDE 20. The composition of claim 12, further comprising an inhibitor is a methylxanthine derivative. excipient. 4. The method of claim 3, wherein the methylxanthine derivative is caffeine, theophylline, IBMX (3-isobutyl-1-me