Treating chemosensory dysfunction caused by coronavirus infection

Abstract

Disclosed herein is a method for treating taste and smell disorders caused by a viral infection in a subject, the method comprising administering a phosphodiesterase inhibitor to the subject. Also disclosed herein is a method for treating loss of taste and smell due to COVID-19 by administering a phosphodiesterase inhibitor to a subject in need thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 994,172, filed March 24, 2020, and U.S. Provisional Patent Application No. 63 / 006,489, filed April 7, 2020, each of which is incorporated by reference in its entirety.

[0002] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that a publication, patent, or patent application incorporated by reference conflicts with the disclosure contained herein, the specification is intended to supersede and / or take precedence over any such conflicting material. Summary of the Invention [Means for solving the problem]

[0003] Disclosed herein are methods for treating chemosensory dysfunction in humans, where the chemosensory dysfunction may result at least in part from, or may occur during or after, a coronavirus infection. In some embodiments, the method may include administering a therapeutically effective amount of a phosphodiesterase (PDE) inhibitor or a pharmaceutically acceptable salt thereof to a human to treat the chemosensory dysfunction. In some embodiments, (i) the coronavirus may include SARS-CoV-2 or a variant thereof, (ii) the PDE inhibitor or a pharmaceutically acceptable salt thereof may be administered in a unit dose formulation, or (iii) any combination thereof. In some embodiments, the therapeutically effective amount of the PDE inhibitor or a pharmaceutically acceptable salt thereof may be formulated as a liquid formulation, a solid formulation, or a gel formulation. In some embodiments, the PDE inhibitor or a pharmaceutically acceptable salt thereof may be formulated as a liquid formulation, and administering may include application of the liquid formulation as a nasal wash. In some embodiments, the PDE inhibitor or a pharmaceutically acceptable salt thereof may be formulated as a liquid formulation, and administering may include application of the liquid formulation as an aerosol. In some embodiments, the PDE inhibitor or a pharma- ceutically acceptable salt thereof can be formulated as a solid formulation, and administering can include application of the solid formulation as a powder aerosol. In some embodiments, the PDE inhibitor or a pharma- ceutically acceptable salt thereof can be formulated as a gel formulation, and administering can include application of the gel formulation by contacting at least a portion of the naris with the gel formulation. In some embodiments, administering can include intranasally applying a liquid formulation, solid formulation, or gel formulation to one or both nostrils. In some embodiments, administering can be performed during or after coronavirus infection. In some embodiments, the method can further include a second administering.In some embodiments, the second administering can include remdesivir, chloroquine, lopinavir, ritonavir, favilavir, interferon-beta, antiviral drugs, oxygen, or any combination thereof. In some embodiments, the administering can be at least once, twice, or three times within a 24-hour period. In some embodiments, the chemosensory dysfunction can include anosmia, hyposmia, ageusia, dysosmia, parosmia, phantosmia, or any combination thereof. In some embodiments, the PDE inhibitor or a pharmaceutically acceptable salt thereof can be theophylline or a pharmaceutically acceptable salt thereof, roflumilast or a pharmaceutically acceptable salt thereof, cilostazol or a pharmaceutically acceptable salt thereof, any derivative of these or a pharmaceutically acceptable salt thereof, or any combination thereof. In some embodiments, the therapeutically effective amount can include a practical amount of a PDE inhibitor or a pharma- ceutically acceptable salt thereof of less than about 100 mg, less than about 10 mg, less than about 1 mg, less than about 500 μg, or less than about 100 μg. In some embodiments, administering a PDE inhibitor or a pharma- ceutically acceptable salt thereof can result in a blood concentration of the PDE inhibitor or a pharma- ceutically acceptable salt thereof of less than about 10 mg / dl, less than about 1 mg / dl, or less than about 100 μg / dl during the time course of treating. In some embodiments, the PDE inhibitor or a salt thereof can include theophylline or a pharma- ceutically acceptable salt thereof. In some embodiments, after administering and during the time course of treating, theophylline, theophylline metabolites, N-demethylated theophylline, or any combination thereof can be present in the blood in an amount of less than about 10 mg / dl, less than about 1 mg / dl, or less than about 100 μg / dl.In some embodiments, saliva or nasal mucus cAMP or cGMP levels in a human can be increased by at least about 10% after about 30 days of continuous treatment with a therapeutically effective amount of a PDE inhibitor or a pharma- ceutically acceptable salt thereof, compared to these levels in a human before administration. In some embodiments, smell acuity in a human can be increased by at least about 5% after about 30 days of continuous treatment with a therapeutically effective amount of a PDE inhibitor or a pharma- ceutically acceptable salt thereof, compared to these levels in a human before administration, as measured by detection threshold (DT). In some embodiments, smell acuity in a human can be increased by at least about 5% after about 30 days of continuous treatment with a therapeutically effective amount of a PDE inhibitor or a pharma- ceutically acceptable salt thereof, compared to these levels in a human before administration, as measured by recognition threshold (RT). In some embodiments, the olfactory acuity in a human can be increased by at least about 5% after about 30 days of continuous treatment with a therapeutically effective amount of a PDE inhibitor or a pharma- ceutically acceptable salt thereof, as compared to these levels in the human before administration, as measured by magnitude estimation (ME). In some embodiments, the olfactory acuity in a human can be increased by at least about 5% after about 30 days of continuous treatment with a therapeutically effective amount of a PDE inhibitor or a pharma- ceutically acceptable salt thereof, as compared to these levels in the human before administration, as measured by hedonic method (H). In some embodiments, the chemosensory dysfunction can be diagnosed by detecting sonic hedgehog below a threshold level in a biological sample from a human, by detecting cyclic nucleotide levels below a threshold level in a biological sample from a human, or any combination thereof. In some embodiments, the chemosensory dysfunction can be diagnosed by determining a detection threshold, determining a recognition threshold, and by magnitude estimation for at least one of pyridine, nitrobenzene, thiophene, and amyl acetate. In some embodiments, the formulation can include an excipient. In some embodiments, the excipient may include water.In some embodiments, the PDE inhibitor or a pharma- ceutically acceptable salt thereof can be administered in a formulation in a unit dose form. In some embodiments, the unit dose formulation can be included in a multi-dose nasal spray device that delivers a unit dose in a plume upon actuation. In some embodiments, the plume can have a droplet size distribution. In some embodiments, the droplet size distribution can include: (a) less than about 5% of the droplets in the plume have a size less than about 10 μm; (b) a D10 of greater than 12.5 μm, where about 10% of the droplets in about one plume can have a size less than D10; (c) a D50 of about 30 μm, where about 50% of the droplets in the plume can have a size less than D50; (d) a D90 of about 75 μm to about 100 μm, where about 90% of the droplets in the plume can have a size less than D90; and (e) a span of about 1 to about 6, where the span can be calculated according to (D90-D10) / D50. In some embodiments, the PDE inhibitor or a pharma- ceutically acceptable salt thereof may be theophylline or a pharma- ceutically acceptable salt thereof. In some embodiments, the human may be assigned male or female at birth. In some embodiments, the human may be about 1 month to about 12 months old, about 1 year to about 20 years old, about 15 years to about 50 years old, about 40 years to about 80 years old, or about 60 years to about 110 years old. In some embodiments, the human may have a comorbid condition. In some embodiments, the comorbid condition may be selected from the group consisting of schematic heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, and any combination thereof. In some embodiments, the comorbid condition may be a respiratory disease. In some embodiments, the respiratory disease may be selected from asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, or any combination thereof. In some embodiments, the coronavirus infection may be from a SARS-CoV-2 virus, a SARS-COV virus, a MERS-CoV virus, a HKU1 virus, an OC43 virus, a NL63 virus, a 229E virus, or any combination thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0004] Unless otherwise indicated, open terms such as "contain," "containing," "include," "including," etc. mean comprising.

[0005] Disclosed herein is a method of treatment by administering to a subject a phosphodiesterase (PDE) inhibitor, its salt, or a combination of PDE inhibitors or their salts.As disclosed herein, the term "PDE inhibitor" can refer to a compound that can at least partially inhibit the function of PDE polypeptide, such as PDE1, PDE2, PDE3, PDE4, PDE5 polypeptide, or any combination thereof.

[0006] PDE2 polypeptides can reduce aldosterone secretion. Such a reduction can play an important role in regulating the increase in intracellular concentrations of cAMP and cGMP in platelets. Some areas of the brain can express PDE2, and rat experiments have shown that inhibition of PDE2 can enhance memory. PDE2 can be localized in microvessels, especially venous capillaries and endothelial cells, and therefore may play a role in regulating fluid and cell extravasation during inflammatory conditions. PDE2 may also be a good pharmacological target for pathological conditions such as sepsis, or for more localized inflammatory responses such as thrombin-induced edema formation in the lungs.

[0007] The PDE3 family hydrolyzes cAMP and cGMP, but in a way suggests that in vivo, cAMP hydrolysis can be inhibited by cGMP. They can also be distinguished by their ability to be activated by several phosphorylation pathways, including the PKA and PI3K / PKB pathways. PDE3A can be relatively highly expressed in platelets, as well as in cardiomyocytes and oocytes. PDE3B can be the major PDE in adipose tissue, liver, and pancreas, as well as in some cardiovascular tissues. Both PDE3A and PDE3B can be highly expressed in vascular smooth muscle cells, likely regulating contraction. PDE5 can be a regulator of vascular smooth muscle contraction, best known as the molecular target of several well-publicized drugs used to treat erectile dysfunction and pulmonary hypertension. In the lungs, inhibition of PDE5 can counteract smooth muscle vasoconstriction, and PDE5 inhibitors are in clinical trials for the treatment of pulmonary hypertension.

[0008] Examples of PDE inhibitors include, for example, filaminast, piclamilast, rolipram, Org20241, MCI-154, roflumilast, toborinone, pozicar, lixazinone, zaprinast, sildenafil, pyrazolopyrimidinone, motapizone, pimobendan, zardaverine, siguazodan, CI-930, EMD53998, imazodan, saterinone, loprinone hydrochloride, 3-pyridinecarbonitrile derivatives, denbufilene, albifyline, torbafylline, doxofylline, theophylline, The PDE inhibitors may include pentofylline, nantherinone, cilostazol, cilostamide, MS857, piroximone, milrinone, aminone, trafentrin, dipyridamole, papaverine, E4021, thienopyrimidine derivatives, triflusal, ICOS-351, tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivatives, carboline derivatives, 2-pyrazolin-5-one derivatives, condensed pyridazine derivatives, quinazoline derivatives, anthranilic acid derivatives, imidazoquinazoline derivatives, and the like. In some embodiments, one or more PDE inhibitors, or salts thereof, may be formulated into an intranasal composition. In some embodiments, the composition may include a non-specific PDE inhibitor or a salt thereof. In some embodiments, the composition may include a PDE inhibitor or a salt thereof that is selective for a PDE subtype, such as PDE:1, 2, 3, 4, or 5. In some embodiments, the intranasal composition does not include a PDE5 selective inhibitor. In some embodiments, the composition may be in liquid, power, solid, or gel form. In some embodiments, the PDE inhibitor or salt thereof may be administered in the range of about 0.001 mg to about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the formulation may be in unit dose form. In some embodiments, the formulation may contain a second active ingredient, such as a corticosteroid, or an antihistamine, or a vasoconstrictor, or any combination thereof. In some embodiments, the formulation does not contain a second active ingredient. In some cases, the formulation may be a pharmaceutical composition. In some cases, the composition may be a pharmaceutical composition.

[0009] The PDE inhibitor can be a selective PDE inhibitor or a non-specific PDE inhibitor. The PDE selective inhibitor can include a PDE1 selective inhibitor, a PDE2 selective inhibitor, a PDE3 selective inhibitor, a PDE4 selective inhibitor, or a PDE5 selective inhibitor. In some cases, the selective PDE inhibitor can be specific to one or more of PDE1, PDE2, PDE3, PDE4, and PDE5. The non-specific PDE can include a PDE inhibitor that inhibits at least two, three, four, or five of PDE1, PDE2, PDE3, PDE4, and PDE5.

[0010] PDE inhibitors can inhibit cell apoptosis by inhibiting TNF alpha, TRAIL and their metabolites.PDE inhibitors can activate the production and secretion of nitric oxide in all tissues, thereby inducing vasorelaxation or vasodilation of all blood vessels, including peripheral blood vessels (inhibiting intermittent claudication), distal limbs, and blood vessels in the penile region that contribute to penile erection.

[0011] Non-specific PDE inhibitors may include theophylline, papaverine caffeine, IBMX (3-isobutyl-1-methylxanthine, aminophylline, doxofylline, cipamphylline, theobromine, pentoxifylline (oxpentifylline), and diprophylline. Theophylline is a methylxanthine derivative that, when administered as described herein, may have an anti-inflammatory effect on the airways that may be useful in combating the abnormal inflammation seen in asthma. In some cases, an anti-inflammatory effect may be achieved when theophylline is prescribed or administered at a level that results in systemic levels of theophylline in the blood that are much lower than those that cause side effects. Patients with emphysema and chronic bronchitis may also be helped with theophylline if their symptoms are in part related to reversible airway narrowing.

[0012] Selective inhibitors of PDE1, formerly known as calcium and calmodulin-dependent phosphodiesterase, can include eburnamenine-14-carboxylic acid ethyl ester (vinpocetine). In some cases, vinpocetine can be used to induce vasorelaxation in brain smooth muscle tissue.

[0013] PDE2 selective inhibitors can include EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one (PDP), and BAY60-7750.

[0014] PDE3 selective inhibitors may include enoximone, milrinone (Primacor), amrinone, cilostamide, cilostazol (Pletal), and trexin. When administered as described herein, PDE3 inhibitors can produce sympathetic stimulation to increase cardiac contractility (inotropy), heart rate (chronotropy) and impulse conduction velocity (dromotropy). When administered as described herein, PDE3 inhibitors can also antagonize platelet aggregation, increase myocardial contractility, and enhance vascular and airway smooth muscle relaxation. PDE3A may be a regulator of this process. When administered as described herein, PDE3 inhibitors can effectively prevent aggregation. Cilastazol (Pletal) is approved for the treatment of intermittent claudication. Its mechanism of action may involve inhibition of platelet aggregation along with inhibition of smooth muscle proliferation and vasodilation.

[0015] PDE4 selective inhibitors may include mesembrine, rolipram, ibudilast (i.e., neuroprotectants and bronchodilators that can be used to treat asthma and stroke), and roflumilast (Daxas) and cilomilast (Airflo) (i.e., PDE4 selective inhibitors that can be administered to treat chronic obstructive pulmonary disease).PDE4 selective inhibitors can at least partially suppress the release of inflammatory mediators, such as cytokines, or at least partially inhibit the production of reactive oxygen species and immune cell infiltration.PDE4 inhibitors can also be used to treat asthma, arthritis, and psoriasis.

[0016] PDE5 selective inhibitors can include sildenafil, tadalafil, vardenafil, udenafil, and avanafil.

[0017] definition The singular forms "a," "an," and "the" are used herein to include plural referents unless the context clearly dictates otherwise. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this application are approximations that may vary depending upon the desired properties to be obtained.

[0018] As used herein, the term "about" or "approximately" can mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, "about" can mean plus or minus 10%, as is customary in the art. Alternatively, "about" can mean a range of plus or minus 20%, plus or minus 10%, plus or minus 5%, or plus or minus 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold of a value. When a particular value is described in the present application and claims, unless otherwise stated, the term "about" should be assumed to mean within an acceptable error range for the particular value. Also, when a range and / or sub-range of values ​​is provided, the range and / or sub-range can include the endpoints of the range and / or sub-range. As used herein, the term "substantially" can refer to a value that approaches 100% of a given value. In some cases, the term can refer to an amount that may be at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 99.99% of the total. In some cases, the term can refer to an amount that may be about 100% of the total.

[0019] The terms "administer", "administering", "administration" and the like, as used herein, can refer to methods that can be used to enable delivery of a compound or its salt or composition to a desired site of biological action. Delivery can include direct application to affect a tissue or area of ​​the body. The compositions provided herein can be administered by any method. The administration method can be by inhalation, intraarterial injection, intracerebroventricular injection, intracisternal injection, intramuscular injection, intraorbital injection, intraparenchymal injection, intraperitoneal injection, intraspinal injection, intrathecal injection, intravenous injection, intraventricular injection, stereotactic injection, subcutaneous injection, or any combination thereof. Delivery can include parenteral administration (including intravenous, subcutaneous, intrathecal, intraperitoneal, intramuscular, intravascular, or infusion), oral administration, nasal administration, inhalation administration, intraduodenal administration, rectal administration. Delivery can include topical administration (lotion, cream, gel, liquid, solid, powder, ointment, etc.) to the external surface such as the skin. In some cases, the subject can administer the compound, its salt, or composition in the absence of supervision. In some cases, the subject can administer the composition under the supervision of a medical professional (e.g., a doctor, a nurse, a physician's assistant, a hospital attendant, a hospice worker, etc.). In some cases, a medical professional can administer the composition. In some cases, a cosmetic professional can administer the composition.

[0020] As used herein, "treating" a chemosensory dysfunction can include one or more of reducing the frequency or severity of one or more symptoms, eliminating one or more symptoms or their underlying causes, or ameliorating or repairing damage. For example, treating a chemosensory dysfunction can include increasing the acuity of smell and taste from a patient suffering from a coronavirus infection, such as a COVID-19 patient, and / or causing regression or elimination of a chemosensory dysfunction.

[0021] "Therapeutically effective amount" can refer to the amount of a compound or its salt, with or without additional agents, that is effective to achieve its intended purpose. The needs of individual patients may vary. In general, the dosage required to provide an effective amount of a compound, its salt, or a composition containing one or both of them, and can be adjusted by those skilled in the art, will vary according to the age, health, physical condition, sex, weight, degree of functional impairment of the recipient, frequency of treatment, and the nature and extent of the functional impairment.

[0022] The terms "subject," "host," "individual," and "patient" are used interchangeably herein to refer to an animal, typically a mammal. Any suitable mammal can be administered a compound, salt, or composition described herein or treated by the methods described herein. Non-limiting examples of mammals include humans, non-human primates (e.g., apes, gibbons, chimpanzees, orangutans, monkeys, macaques, etc.), domestic animals (e.g., dogs and cats), livestock (e.g., horses, cows, goats, sheep, pigs), and laboratory animals (e.g., mice, rats, rabbits, guinea pigs). The mammal can be of any age or at any stage of development, for example, the mammal can be a neonate, infant, adolescent, adult, or in utero. In some embodiments, the mammal is a human. The human can be about: 1, 2, 5, 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or greater than about 120 years old. The human can be less than about: 1, 2, 5, 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or greater than about 120 years old. In some cases, the human can be less than about 18 years old. In some cases, the human can be greater than about 18 years old. The mammal, e.g., human, can be male or female.

[0023] As used herein, a reference to a PDE inhibitor generally, or to a specific PDE inhibitor, includes a reference to any salt, solvate, ester, or polymorph of the PDE inhibitor. "Salt" can include pharma- ceutically acceptable salts. Examples of pharma- ceutically acceptable salts include salts prepared by reaction of a compound disclosed herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bitartrate, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, etc. Acid salts include, for example, acid salts, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.Additionally, the compounds disclosed herein can be used to dissolve the free base form of the compounds in an aqueous solution of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, as well as in an aqueous solution of acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene ... The compounds may be prepared as pharmaceutically acceptable salts formed by reacting with pharmaceutically acceptable inorganic or organic acids, including, but not limited to, organic acids such as benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-sodium-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Other acids, such as oxalic acid, may be used in the preparation of salts that are not themselves pharmaceutically acceptable but are useful as intermediates in obtaining pharmaceutically acceptable acid addition salts. In some embodiments, the compounds disclosed herein that may contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates, ammonia, or pharma- ceutically acceptable organic primary, secondary, or tertiary amines of pharma- ceutically acceptable metal cations. Representative alkali or alkaline earth salts may include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N. + (C 1~4Examples of suitable base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. Representative organic amines useful for the formation of base addition salts may include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It may be understood that the compounds disclosed herein may also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products may be obtained by such quaternization. The compounds disclosed herein may be prepared as pharma-ceutically acceptable salts formed when acidic protons present in the parent compound may be replaced by metal ions, e.g., alkali metal ions, alkaline earth ions, or aluminum ions, or may be coordinated with an organic base. In some embodiments, base addition salts may also be prepared by reacting the free acid form of the compounds disclosed herein with a pharma-ceutically acceptable inorganic or organic base, including, but not limited to, organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Additionally, the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.

[0024] Treatment method Disclosed herein is a method for treating chemosensory dysfunction in a human. In some cases, the chemosensory dysfunction may result at least in part from, during or after a coronavirus infection, such as SARS-CoV-2. In some cases, the method may include administering to the human a therapeutically effective amount of a phosphodiesterase (PDE) inhibitor or a pharmaceutically acceptable salt thereof to treat the chemosensory dysfunction. In some cases, the coronavirus may include SARS-CoV-2 or a mutated form thereof, which may cause the disease COVID-19. In some cases, the PDE inhibitor or a pharmaceutically acceptable salt thereof may be administered in a formulation in a unit dose form.

[0025] Disclosed herein are methods of treating a condition by administering a PDE inhibitor or salt thereof described herein. In some cases, administering can include administering a PDE inhibitor or salt thereof in a unit dosage form. In some embodiments, a representative daily intranasal, lingual or pulmonary dosage is about 1.0 μg to 2000 mg per day, about 1.0 μg to 500.0 mg per day, about 10 μg to 100.0 mg per day, about 10 μg to about 10 mg per day, about 10 μg to 1.0 mg per day, about 10 μg to 500 μg per day, or about 1 μg to 50 μg per day of the compound (i.e., PDE inhibitor). These dosage ranges represent the total dosage of active ingredient per day for a given patient. In some embodiments, the daily dosage can be less than about: 2000 mg per day, 1000 mg per day, 500 mg per day, 100 mg per day, 10 mg per day, 1.0 mg per day, 500 μg per day, 300 μg per day, 200 μg per day, 100 μg per day, or 50 μg per day. In some embodiments, the daily dosage can be at least about: 2000 mg per day, 1000 mg per day, 500 mg per day, 100 mg per day, 10 mg per day, 1.0 mg per day, 500 μg per day, 300 μg per day, 200 μg per day, 100 μg per day, or 50 μg per day. In some embodiments, suitable dosage levels of the compound per kilogram may be about 0.001 μg / kg to about 10.0 mg / kg of body weight per day, about 0.5 μg / kg to about 0.5 mg / kg of body weight per day, about 1.0 μg / kg to about 100 μg / kg of body weight per day, and about 2.0 μg / kg to about 50 μg / kg of body weight per day. In some embodiments, suitable dosage levels per kilogram may be about: 10.0 mg / kg of body weight per day, 1 mg / kg of body weight per day, 500 μg / kg of body weight per day, 100 μg / kg of body weight per day, 10 μg / kg of body weight per day, or less than 1.0 μg / kg of body weight of the compound per day.In some embodiments, suitable dosage levels per kilogram may be at least about: 10.0 mg / kg of body weight per day, 1 mg / kg of body weight per day, 500 μg / kg of body weight per day, 100 μg / kg of body weight per day, 10 μg / kg of body weight per day of active ingredient, or 1.0 μg / kg of body weight of the compound per day.

[0026] In some cases, the amount administered may be the same as that administered to treat a particular disease, or may be less than that administered to treat that particular disease. The dosage may be administered once a day, or several or multiple times a day. For example, the PDE inhibitor or its salt may be administered twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, or more times a day. In some cases, the composition may be administered once, twice, or three times in a 24-hour period. In some cases, the PDE inhibitor or its salt may be administered for about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, or lifelong. The amount of drug administered in the practice of this invention will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. The dosages used to practice this invention can produce the desired therapeutic or prophylactic effect without causing serious side effects.

[0027] In some embodiments, administration of an effective amount of a PDE inhibitor by intranasal, lingual, or pulmonary administration does not result in detectable blood levels of the PDE inhibitor. In some embodiments, administration of an effective amount of a PDE inhibitor by intranasal, lingual, or pulmonary administration results in a blood concentration of the PDE inhibitor that is less than about: 5 mg / dl, 2 mg / dl, 1 mg / dl, 500 μg / dl, 250 μg / dl, 100 μg / dl, 50 μg / dl, 25 μg / dl, 10 μg / dl, 5 μg / dl, or 1 μg / dl. In some embodiments, administration of an effective amount of a PDE inhibitor by intranasal, lingual, or pulmonary administration results in a blood concentration of the PDE inhibitor that is greater than about: 2 mg / dl, 1 mg / dl, 500 μg / dl, 250 μg / dl, 100 μg / dl, 50 μg / dl, 25 μg / dl, 10 μg / dl, 5 μg / dl, or 1 μg / dl.

[0028] In some embodiments, administration of an effective amount of a PDE inhibitor or salt thereof can increase saliva and / or nasal mucus cAMP or cGMP levels in a human by at least about: 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or about 50% compared to these levels in the human prior to administration of a therapeutically effective amount of a PDE inhibitor or a pharma- ceutical acceptable salt thereof. In some cases, an increase in saliva and / or nasal mucus cAMP or cGMP levels is observed after about 1 to about 10 days, about 15 to about 45 days, or about 30 days of continuous treatment with a therapeutically effective amount of a PDE inhibitor or a pharma- ceutical acceptable salt thereof.

[0029] Methods of treatment include, by way of example only, oral administration, transmucosal administration, buccal administration, intranasal administration such as inhalation, parenteral administration, intravenous, subcutaneous, intramuscular, sublingual, transdermal administration, and rectal administration. In some embodiments, the composition may be administered as a liquid nasal wash, an aerosol, a powder aerosol, or a combination thereof. In some cases, administering may include intranasal application in one or both nostrils. In some embodiments, a gel composition may be administered to the nares. In some embodiments, a liquid composition may be administered as a nasal wash. In some cases, administering the composition may occur during, after, or both during and after coronavirus infection.

[0030] In some cases, the compositions described herein can be administered with one or more additional therapeutic agents. For example, the PDE inhibitor or its salt can be administered with a second therapy. In some cases, the second therapy can be administered simultaneously or sequentially. In some cases, the additional therapeutic agent can include remdesivir, chloroquine, lopinavir, ritonavir, favivir, interferon-beta, antiviral drugs, oxygen, or any combination thereof. In some cases, the additional therapeutic agent can include nitric oxide, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or any combination thereof.

[0031] In some cases, the subject may be diagnosed (e.g., diagnosed with chemosensory dysfunction) before treatment with a PDE inhibitor or salt thereof. In some cases, the treatment method may include diagnosing chemosensory dysfunction in the subject. In some cases, diagnosing may include an in vitro assay. In some cases, chemosensory dysfunction may be diagnosed by detecting sonic hedgehog below a threshold level in a biological sample from a human. In some cases, the sample may be a nasal sample or a saliva sample. In some cases, chemosensory dysfunction may be diagnosed by detecting cyclic nucleotide levels below a threshold level in a biological sample from a human. In some cases, chemosensory dysfunction may be diagnosed by determining a detection threshold, determining a recognition threshold, and by magnitude estimation for at least one of pyridine, nitrobenzene, thiophene, and amyl acetate.

[0032] In some embodiments, the method of treatment is by nasal administration or inhalation. Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may include suitable pharma- ceutically acceptable excipients as described above. The compositions may be administered by oral or nasal respiratory routes for local or systemic effect. Compositions, preferably in pharma- ceutically acceptable solvents, may be nebulized by the use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner. In some cases, the device may be a nasal spray device.

[0033] In some embodiments, the subject may be a human. In some embodiments, the subject may have or be suspected of having a disease or condition. The subject may be a patient, such as a patient being treated for a condition or disease, such as heart disease, high blood pressure, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, coronavirus infection, pneumonia, pleural effusion, or any combination thereof. The subject is prone to be at risk for developing a condition or disease, such as a respiratory disease. The subject may be in remission from a condition or disease, such as a cancer patient. The subject may be healthy.

[0034] In some embodiments, intranasal or lingual administration of an effective amount of a PDE inhibitor increases taste or smell acuity. In some embodiments, the increase in taste or smell acuity can be at least about: 5%, 10%, 20%, 30%, 40%, 50%, 75%, or 100% compared to an untreated state. In some embodiments, taste or smell acuity is increased to at least about: 5%, 10%, 20%, 30%, 40%, 50%, 75%, or 100% of that of a normal individual. In some cases, the increase in taste or smell acuity can be measured after about 10 to about 20 days, about 15 to about 30 days, 25 to about 50 days, 1 month to about 6 months, or about 6 months to about 3 years. In some embodiments, the increase in taste or smell acuity can be measured after about 30 days. In some embodiments, taste or smell acuity can be measured objectively. In some embodiments, taste or smell power can be measured subjectively. In some cases, smell power can be measured by detection threshold, recognition threshold, hedonic methods, magnitude estimation, or any combination thereof.

[0035] When administered in vivo, the compounds, salts thereof, and compositions may be administered in combination with one or more pharma- ceutically acceptable carriers or excipients, and in dosages as described herein. The compounds, salts thereof, and compositions may be formulated as pharma- ceutically acceptable neutral (free base) or salt forms.

[0036] In some embodiments, pharma- ceutically acceptable carriers may include, but are not limited to, amino acids, peptides, proteins, nonbiological polymers, biological polymers, monosaccharides, carbohydrates, gums, inorganic salts, and metal compounds, which may be present alone or in combination. In some embodiments, pharma- ceutically acceptable carriers may include natural, derivatized, modified, or combinations thereof.

[0037] In some embodiments, the composition or formulation can include an excipient. The excipient can include, but is not limited to, one or more of water, flow agents, lubricants, adhesives, surfactants, acidifiers, alkalinizers, agents for adjusting pH, antimicrobial preservatives, antioxidants, antistatic agents, buffers, chelating agents, humectants, gel-forming agents, or humectants. The excipient can also include colorants, coating agents, sweeteners, flavors and fragrances, or masking agents. The composition and formulation can include a therapeutic agent with individual excipients, with or without a carrier, or with multiple excipients in any suitable combination. In some cases, the excipient can include glycerol.

[0038] Therapeutically effective amount can refer to the amount of PDE inhibitor or its salt with or without additional agents that are effective to achieve its intended purpose.The needs of individual patients may vary.In general, the dosage required to provide an effective amount of the compound, its salt, or a composition containing one or both of them, and can be adjusted by those skilled in the art, will vary according to age, health, physical condition, sex, weight, degree of functional disorder of the recipient, frequency of treatment, and nature and extent of functional disorder.Dosage can be in unit dosage form.

[0039] The PDE inhibitor or salt thereof described herein can be formulated as an aerosol. An "aerosol" can be any composition of the PDE inhibitor administered in an aerosolized formulation, including, for example, an inhalation spray, an inhalation solution, an inhalation suspension, a nebulized solution, or a nasal spray. Aerosolized formulations can deliver high concentrations of the PDE inhibitor directly to the airways or one or more nasal passages, in some cases with low systemic absorption. Solutions for aerosolization typically contain at least one therapeutically effective PDE inhibitor or salt thereof dissolved or suspended in an aqueous solution that may further include one or more excipients (e.g., preservatives, viscosity modifiers, emulsifiers, or buffers). The solution can act as a carrier for the PDE inhibitor or salt thereof. In some embodiments, the preservative can include methylparaben or propylparaben. These formulations can deliver the PDE inhibitor to the respiratory tract, for example, one or both nostrils, for example, by inhalation.

[0040] In some embodiments, the PDE inhibitors can be applied directly to the nasal or lingual epithelium as a liquid, cream, lotion, ointment, or gel. These can include at least one therapeutically effective PDE inhibitor or a salt thereof. In some cases, the formulation can further include at least one excipient (e.g., a preservative, a viscosity modifier, an emulsifier, or a buffering agent) that can be formulated for administration, such as a nasal drop, or application by an applicator to at least a portion of one or more nasal cavities. In some embodiments, the preservative can be methylparaben or propylparaben. The pH of the formulation can be maintained at about 4.5 to about 7.0, or about 5.0 to about 7.0, or about 5.5 to about 6.5. The osmolality of the formulation can also be adjusted to an osmolality of about 250 to about 350 mosm / L.

[0041] In some embodiments, the phosphodiesterase inhibitor or pharma- ceutically acceptable salt may be administered using a multi-dose nasal spray device that delivers a dosage unit in a plume upon actuation. The dosage unit includes an effective amount of a phosphodiesterase inhibitor, a pharma- ceutically acceptable salt, an excipient, or any combination thereof. The taste or smell disorder may be a chemosensory dysfunction, anosmia, hyposmia, ageusia, hypogeusia, dysomia, phantosmia, or a combination thereof. The dosage unit may include a PDE inhibitor or a pharma- ceutically acceptable salt thereof, such as theophylline or a pharma- ceutically acceptable salt thereof, roflumilast or a pharma- ceutically acceptable salt thereof, cilostazol or a pharma- ceutically acceptable salt thereof, any derivative thereof (e.g., solvate, isomer, ester, amide, etc.) or a pharma- ceutically acceptable salt thereof, or any combination thereof. The plume can have a droplet size distribution, where (a) less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9% of the droplets in the plume can have a size less than about 10 μm, and (b) the droplets have a D greater than about 12.5 μm. 10 and about 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the droplets in the plume have a D 10 (c) the droplets have a size of about 30 μm D 50 and about 40%, 45%, 50%, 55%, or 60% of the droplets in the plume have a diameter of D 50 (d) the droplets have a size of about 75 to about 100 μm D 90 and about 80%, 85%, 90%, 95%, or 99% of the droplets in the plume have a diameter of D 90 (e) the span of the droplet size distribution can be from about 1 to about 6, the span being (D 90 -D 10 ) / D 50 It is calculated according to "D 10 ", "D 50 ", "D 90" and "span" are measurements of the droplet or particle size distribution of the plume.

[0042] As used herein, "Magnitude Estimation" or "ME" can refer to the measurement of a subject's ability to determine the intensity of a stimulus, such as an odorant or taster.

[0043] As used herein, "recognition threshold" or "RT" can refer to a measurement of a subject's ability to recognize the identity of a stimulus substance, such as an odorant or taster.

[0044] As used herein, "detection threshold" or "DT" can refer to a measurement of a subject's ability to perceive exposure to a stimuli, such as an odorant or taster, as pleasant or unpleasant.

[0045] As used herein, "hedonic" value or "H" value can refer to a measurement of a subject's response to a stimuli, such as an odorant or taste, as being unpleasant or unpleasant.

[0046] In some cases, administering a PDE inhibitor described herein can be used to prevent or treat a disease associated with or caused by a coronavirus. Such diseases can include, for example, anosmia, ageusia, anosmia, anosmia, dysosmia, parosmia, chemosensory dysfunction, cough, fever, fever, fatigue, dyspnea, runny nose, sore throat, stuffy nose, or any combination thereof. Coronavirus infections can be caused by alphacoronavirus, betacoronavirus, gammacoronavirus, deltacoronavirus, 229Ecoronavirus, NL63coronavirus, OC43coronavirus, HKU1coronavirus, MERS-CoV, SARS-CoV, SARS-CoV-2, mutated forms thereof, or any combination thereof. In some cases, viruses such as coronaviruses can have mutations. For example, coronaviruses have approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 108, 109, 109, 110, 111, 112, 113, 114, 115, 116, 1 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or more than 100 nucleotide variations. In some cases, the coronavirus comprises a genome having greater than about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a reference sequence.In some cases, the coronavirus comprises a genome having less than about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a reference sequence. In some cases, the reference sequence can be a reference sequence from the National Center for Biotechnology Information.

[0047] In some cases, administering the PDE inhibitors described herein can be used in patients with comorbidities, such as hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infarction, stable angina, unstable angina, variant (Prinsmetal) angina, atherosclerosis, cardiac edema, heart disease, renal failure, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, dementia (including Alzheimer's disease), immunodeficiency, premature birth, Parkinson's disease, multiple sclerosis, dysmenorrhea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, reduced vascular patency (e.g., For example, the co-morbidities may include post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, respiratory disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, allergic rhinitis, glaucoma, malignant diseases characterized by impaired intestinal motility, such as irritable bowel syndrome (IBS), rheumatoid arthritis, bacterial infections, fungal infections, parasitic infections, viral infections, HIV, systemic lupus erythematosus, psoriasis, other autoimmune diseases, Huntington's chorea, and amyotrophic lateral sclerosis (ALS), or any combination thereof. Treatment of the co-morbidities may be achieved by administering a therapeutically effective amount of the compounds and / or compositions described herein to a patient in need of treatment.

[0048] Also disclosed herein are methods of making the compositions described herein. The methods of making the compositions may include contacting a compound or salt thereof described herein with other components (e.g., carriers, diluents, excipients, etc.) described herein.

[0049] Example 1 Patients diagnosed with or previously diagnosed with COVID-19 with at least partial loss of smell or taste associated with COVID-19 are treated with a formulation containing theophylline administered intranasally, where the theophylline is administered once daily in each nostril for about 30, 60, or 90 days.

[0050] Administration of the formulation results in an increase in the patient's sonic hedgehog or cyclic nucleotide levels for about 30, 60, or 90 days, which in turn results in a significant increase in the patient's ability to taste and smell, thus at least partially ameliorating the loss of smell and taste.

[0051] Example 2 A multi-dose nasal spray device that delivers a dosage unit in a plume upon actuation is used to treat anosmia in a subject who has recovered from COVID-19, where the anosmia is caused by COVID-19 and persists despite recovery from COVID-19. The multi-dose spray device is configured to provide a dosage unit of theophylline, roflumilast, cilostazol, or a combination thereof when administered intranasally by the device. The dosage unit comprises an effective amount of theophylline, roflumilast, cilostazol, or a combination thereof in a pharma- ceutically acceptable carrier that includes one or more excipients. The plume has a droplet size distribution, where (a) less than about 5% of the droplets in the plume have a size less than about 10 μm, and (b) the D is greater than about 12.5 μm. 10 (where approximately 10% of the droplets in the plume are D 10 (c) having a size of about 30 μm D 50 (where approximately 50% of the droplets in the plume are D 50(d) having a size of about 75 to about 100 μm D 90 (where approximately 90% of the droplets in the plume are D 90 (e) a span of about 1 to about 6, where the span is (D 90 -D 10 ) / D 50 (Calculated according to

[0052] After administration of the dosage units using the multi-dose device, the patient is examined and re-treated for 30, 60, or 90 days, and the treatment of anosmia is monitored using an increase in recognition threshold compared to before the first administration.

[0053] Example 3 Patients reported sensory dysfunction initially as either taste disturbance (i.e., loss of flavor) and / or olfactory function. This subjective response was recorded using a three-stimulus, graded stepwise technique with forced selection in a fixed, controlled design, with objective psychophysical measures of olfactory function administered to each patient (1, 2). The validity of this technique and the test results were previously documented in a double-blind clinical trial (2). Four odors were used: pyridine (dead fish odor), nitrobenzene (bitter almond odor), thiophene (petroleum-like odor), and amyl acetate (banana oil odor). Detection threshold (DT) and recognition threshold (RT) values ​​for each odor were determined as previously described (1, 2). Thresholds were converted to bottle units (BU) as previously described (2), and results were reported as M of correct responses for each odor in each treatment group. References: (1) Henkin, RIEvaluation and treatment of human olfactory dysfunction, in Otolaryngology (English, GM Ed.), Lip pincott, Philadelphia, 1993, Vol. 2, pp. 1-86. (2) Henkin, RI, Schecter, PJ, Friedewald, WT, DeMets, DL, Raff, MSA double blind study of the effects of zinc sulfate on taste and smell dysfunction. Amer. J. Med. Sci. 1976;272:285-299.

[0054] Patients with loss of taste and smell due to COVID-19 were administered theophylline. A formulation containing 80 μg of theophylline was administered once daily via two actuations from a nasal spray device. A baseline olfactory test was performed before the first dose of theophylline. A follow-up olfactory test was performed 3 months after the first dose. No adverse events were reported. The results are shown in Table 1. The patients' detection thresholds (DT) and recognition thresholds (RT) for pyridine (Pyr), nitrobenzene (NO2B), thiophene (Thio) and amyl acetate (AA) were determined before (pre) and after (3M) treatment. For all four odor tests, the patients' detection and recognition thresholds improved. An improvement of one bottle unit means that the patient can detect and / or recognize odors that were 10 times lower in concentration compared to baseline. For example, the recognition threshold (RT) for AA improved by 8 bottle units, which is also equivalent to an improvement of 8 orders of magnitude. In this case, the patient could detect and / or recognize odors that were 10 times lower in concentration. 8 Low AA concentrations could be detected; the number of bottle units below 5 is considered to be in the normal range. [Table 1]

[0055] While exemplary embodiments have been shown and described herein, such embodiments are by way of example only. Many variations, changes, and substitutions may be made in the exemplary embodiments. It is to be understood that various alternatives to the embodiments described herein may be employed. The present invention provides, for example, the following items. (Item 1) 1. A method for treating a chemosensory dysfunction in a human, wherein the chemosensory dysfunction results at least in part from, or occurs during or after, a coronavirus infection, the method comprising administering to the human a therapeutically effective amount of a phosphodiesterase (PDE) inhibitor or a pharmaceutically acceptable salt thereof to treat the chemosensory dysfunction; (i) the coronavirus comprises SARS-CoV-2 or a mutated form thereof; (ii) the PDE inhibitor or a pharma- ceutically acceptable salt thereof is administered in a formulation in unit dosage form; or (iii) any combination thereof. (Item 2) 2. The method of claim 1, wherein the therapeutically effective amount of the PDE inhibitor or the pharma- ceutically acceptable salt thereof is formulated as a liquid, solid, or gel formulation. (Item 3) 3. The method of claim 2, wherein the PDE inhibitor or the pharma- ceutically acceptable salt thereof is formulated as a liquid formulation and the administering comprises application of the liquid formulation as a nasal wash. (Item 4) 3. The method of claim 2, wherein the PDE inhibitor or the pharma- ceutically acceptable salt thereof is formulated as a liquid formulation and the administering comprises application of the liquid formulation as an aerosol. (Item 5) 3. The method of claim 2, wherein the PDE inhibitor or the pharma- ceutically acceptable salt thereof is formulated as a solid formulation and the administering comprises application of the solid formulation as a powder aerosol. (Item 6) 3. The method of claim 2, wherein the PDE inhibitor or the pharma- ceutically acceptable salt thereof is formulated as a gel formulation and the administering comprises application of the gel formulation by contacting at least a portion of the naris with the gel formulation. (Item 7) 3. The method according to item 2, comprising intranasal application of said liquid, solid or gel formulation in one or both nostrils. (Item 8) 2. The method of claim 1, wherein the administering is performed during or after the coronavirus infection. (Item 9) 9. The method of item 8, further comprising a second administering, wherein the second administering comprises remdesivir, chloroquine, lopinavir, ritonavir, favilavir, interferon-beta, an antiviral drug, oxygen, or any combination thereof. (Item 10) 2. The method of claim 1, wherein the administering is at least once, twice, or three times within a 24 hour period. (Item 11) 2. The method of claim 1, wherein the chemosensory dysfunction comprises anosmia, hyposmia, ageusia, dysosmia, parosmia, phantosmia, or any combination thereof. (Item 12) 2. The method according to item 1, wherein the PDE inhibitor or a pharma- ceutically acceptable salt thereof is theophylline or a pharma- ceutically acceptable salt thereof, roflumilast or a pharma- ceutically acceptable salt thereof, cilostazol or a pharma- ceutically acceptable salt thereof, any of their derivatives or a pharma- ceutically acceptable salt thereof, or any combination thereof. (Item 13) 2. The method of claim 1, wherein the therapeutically effective amount comprises an amount of the PDE inhibitor or a pharma- ceutically acceptable salt thereof that is less than about 100 mg, less than about 10 mg, less than about 1 mg, less than about 500 μg, or less than about 100 μg. (Item 14) 2. The method of claim 1, wherein said administering of said PDE inhibitor or said pharma- ceutically acceptable salt thereof results in a blood concentration of said PDE inhibitor or said pharma- ceutically acceptable salt thereof of less than about 10 mg / dl, less than about 1 mg / dl, or less than about 100 μg / dl during the time course of said treating. (Item 15) 2. The method of claim 1, wherein the PDE inhibitor or salt thereof comprises theophylline or a pharma- ceutically acceptable salt thereof, and during the time course of the treating after the administering, the theophylline, theophylline metabolites, N-demethylated theophylline, or any combination thereof, is present in the blood in an amount of less than about 10 mg / dl, less than about 1 mg / dl, or less than about 100 μg / dl. (Item 16) 2. The method of claim 1, wherein saliva or nasal mucus cAMP or cGMP levels in the human are increased by at least about 10% after about 30 days of continuous treatment with the therapeutically effective amount of a PDE inhibitor or a pharma- ceutical acceptable salt thereof, compared to these levels in the human prior to the administration. (Item 17) The method of claim 1, wherein smell acuity is increased by at least about 5% in the human after about 30 days of continuous treatment with the therapeutically effective amount of a PDE inhibitor or a pharma- ceutical acceptable salt thereof, as measured by detection threshold (DT), compared to these levels in the human prior to the administering. (Item 18) The method of claim 1, wherein olfactory acuity is increased by at least about 5% in the human after about 30 days of continuous treatment with the therapeutically effective amount of a PDE inhibitor or a pharma- ceutical acceptable salt thereof, as measured by recognition threshold (RT), compared to these levels in the human prior to the administering. (Item 19) The method of claim 1, wherein olfactory ability is increased by at least about 5% in the human after about 30 days of continuous treatment with the therapeutically effective amount of a PDE inhibitor or a pharma- ceutically acceptable salt thereof, as measured by magnitude estimation (ME), compared to levels in the human prior to the administering. (Item 20) The method of claim 1, wherein olfactory ability is increased by at least about 5% in the human after about 30 days of continuous treatment with the therapeutically effective amount of a PDE inhibitor or a pharma- ceutically acceptable salt thereof, as compared to these levels in the human prior to said administering, as measured by hedonic methods (H). (Item 21) 2. The method of claim 1, wherein the chemosensory dysfunction is diagnosed by detecting a threshold level or less of Sonic Hedgehog in a biological sample from a human, by detecting a threshold level or less of cyclic nucleotides in a biological sample from a human, or by any combination thereof. (Item 22) Item 13. The method of item 1, wherein the chemosensory dysfunction is diagnosed by determining a detection threshold, determining a recognition threshold, and by magnitude estimation for at least one of pyridine, nitrobenzene, thiophene, and amyl acetate. (Item 23) 2. The method of claim 1, wherein the formulation comprises an excipient. (Item 24) 24. The method of claim 23, wherein the excipient comprises water. (Item 25) The PDE inhibitor or pharma- ceutically acceptable salt thereof is administered in the formulation in a unit dose form, the unit dose formulation being contained within a multi-dose nasal spray device that upon actuation delivers the unit dose in a plume, the plume having a droplet size distribution comprising: (a) less than about 5% of the droplets in the plume having a size less than about 10 μm; (b) a D of greater than about 12.5 μm; 10 and about 10% of the droplets in the plume are 10 having a size less than D 10 , (c) D of about 30 μm 50 and about 50% of the droplets in the plume are 50 having a size less than D 50 (d) D of about 75 μm to about 100 μm 90 and about 90% of the droplets in the plume are within the D 90 and (e) a span of about 1 to about 6, the span being less than (D 90 -D 10 ) / D 50 2. The method of claim 1, further comprising: (Item 26) 26. The method according to item 25, wherein the PDE inhibitor or a pharma- ceutically acceptable salt thereof is theophylline or a pharma- ceutically acceptable salt thereof. (Item 27) 2. The method of claim 1, wherein the human is assigned male or female at birth. (Item 28) 28. The method according to item 27, wherein the human is about 1 month to about 12 months old, about 1 year to about 20 years old, about 15 years to about 50 years old, about 40 years to about 80 years old, or about 60 years to about 110 years old. (Item 29) 28. The method of claim 27, wherein the human has a comorbidity. (Item 30) 30. The method of claim 29, wherein the comorbidity is selected from the group consisting of schematic heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, and any combination thereof. (Item 31) 31. The method of claim 30, wherein the comorbidity is a respiratory disease, and the respiratory disease is selected from asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, or any combination thereof. (Item 32) 2. The method of claim 1, wherein the coronavirus infection is caused by a SARS-CoV-2 virus, a SARS-COV virus, a MERS-CoV virus, a HKU1 virus, an OC43 virus, a NL63 virus, a 229E virus, or any combination thereof.

Claims

1. A formulation for the treatment of olfactory dysfunction in a human, comprising a phosphodiesterase (PDE) inhibitor or a pharma- ceutically acceptable salt thereof, wherein the olfactory dysfunction results at least in part from, or occurs during or after, a coronavirus infection; (i) the coronavirus comprises SARS-CoV-2 or a mutated form thereof; and (ii) a therapeutically effective amount of the PDE inhibitor or the pharma- ceutically acceptable salt thereof is administered intranasally, the formulation is administered in a unit dose form, and the PDE inhibitor or the pharma- ceutically acceptable salt thereof is theophylline or a pharma- ceutically acceptable salt thereof. formulation.

2. The formulation of claim 1 , wherein the formulation is formulated as a liquid formulation.

3. The formulation of claim 2 , wherein the liquid formulation is administered as an aerosol.

4. 3. The formulation of claim 2, wherein the formulation is administered intranasally in one or both nostrils.

5. 10. The formulation of claim 1, wherein the formulation is administered during or after the coronavirus infection.

6. 6. The formulation of claim 5, wherein the formulation is administered in combination with remdesivir, chloroquine, lopinavir, ritonavir, favilavir, interferon-beta, an antiviral drug, oxygen, or any combination thereof.

7. 10. The formulation of claim 1, wherein the formulation is administered at least once, at least twice, or at least three times within a 24 hour period.

8. 2. The formulation of claim 1, wherein the olfactory dysfunction comprises anosmia, hyposmia, dysosmia, parosmia, phantosmia, or any combination thereof.

9. 2. The formulation of claim 1, wherein the therapeutically effective amount comprises an amount of the PDE inhibitor or a pharma- ceutically acceptable salt thereof that is less than 100 mg, less than 10 mg, less than 1 mg, less than 500 μg, or less than 100 μg.

10. The formulation of claim 1, wherein saliva or nasal mucus cAMP or cGMP levels in the human are increased by at least 10% after 30 days of continuous treatment with the formulation compared to these levels in the human prior to administration of the formulation.

11. 2. The formulation of claim 1, wherein smell acuity is increased by at least 5% in the human after 30 days of continuous treatment with the formulation, as measured by detection threshold (DT), compared to these levels in the human prior to administration of the formulation.

12. The formulation of claim 1, wherein olfactory acuity is increased by at least 5% in the human after 30 days of continuous treatment with the formulation, as measured by recognition threshold (RT), compared to these levels in the human prior to administration of the formulation.

13. The formulation of claim 1, wherein the olfactory dysfunction is diagnosed by detecting Sonic Hedgehog at or below a threshold level in a biological sample from a human, by detecting cyclic nucleotide levels at or below a threshold level in the biological sample from the human, or by any combination thereof.

14. 2. The formulation of claim 1, wherein the olfactory dysfunction is diagnosed by determining a detection threshold, determining a recognition threshold, and by determining a magnitude estimate for at least one of pyridine, nitrobenzene, thiophene, and amyl acetate.

15. The formulation of claim 1 , wherein the formulation further comprises an excipient.

16. The formulation of claim 15, wherein the excipient comprises water.

17. The formulation is administered in a unit dose form, the unit dose formulation being contained within a multi-dose nasal spray device that upon actuation delivers the unit dose in a plume, the plume having a droplet size distribution comprising: (a) less than 5% of the droplets in the plume having a size less than 10 μm; (b) less than 5% of the droplets in the plume having a size greater than 12.5 μm; １０ 10% of the droplets in the plume are １０ D １０ , (c) 30 μm D ５０ 50% of the droplets in the plume are ５０ D ５０ , (d) D of 75 μm to 100 μm ９０ 90% of the droplets in the plume are ９０ and (e) a span from 1 to 6, the span having a size less than (D ９０ -D １０ ) / D ５０ The formulation of claim 1, comprising a span calculated according to:

18. The formulation of claim 1 , wherein the human is assigned male or female at birth.

19. 20. The formulation of claim 18, wherein the human is between 1 month and 12 months of age, between 1 year and 20 years of age, between 15 years and 50 years of age, between 40 years and 80 years of age, or between 60 years and 110 years of age.

20. 20. The formulation of claim 18, wherein the human has a comorbidity.

21. 21. The formulation of claim 20, wherein the comorbidity is selected from the group consisting of schematic heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, and any combination thereof.

22. 22. The formulation of claim 21, wherein the comorbidity is a respiratory disease, and the respiratory disease is selected from asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, or any combination thereof.

23. 23. The formulation of any one of claims 1 to 22, wherein the daily dose of the PDE inhibitor is from about 10 μg to about 10 mg per day.

24. 24. The formulation of claim 23, wherein the daily dose of the PDE inhibitor is from about 10 μg to about 2 mg per day.

25. The formulation of any one of claims 1 to 24, wherein the PDE inhibitor is administered for at least 3 months.

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