Granted Patent
B2
US 12,298,316 · App. 18/235,474 · Granted May 13, 2025
Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell
Assignee:
Cyrano Therapeutics, Inc.
G01N33/6893A61K9/0043A61K31/197A61K31/352A61K31/44A61K31/4709A61K31/506A61K31/522A61K31/5377A61K31/5575A61K38/26A61K45/06A61P27/00
View Patent ↗
Loading inventors, assignments & file history…
Abstract
Disclosed herein are methods for diagnosing a subject with loss and/or distortion of taste or smell, e.g., hyposmia, dysosmia, anosmia, phantosmia, hypogeusia, dysgeusia, phantogeusia, and/or ageusia. Also disclosed herein are methods and compositions for treating a subject for loss and/or distortion of taste or smell, e.g., hyposmia, dysosmia, anosmia, phantosmia, hypogeusia, dysgeusia, phantogeusia, and/or ageusia.
Claims (17)
1. A method comprising:
(a) measuring a level of sonic hedgehog (SHH) in a biological sample that comprises a nasal mucus, a saliva, or a combination thereof;
(b) identifying, with aid of a computer system comprising a computer processing unit and computer readable medium, a decreased level of SHH, wherein the identifying comprises:
(i) comparing the level of SHH in the biological sample to a SHH reference level, stored at least transiently on the computer readable medium;
(ii) detecting a lower level of SHH in the biological sample, relative to the SHH reference level; and
(iii) communicating a presence of the lower level of SHH based on the detecting of (ii).
2. The method of claim 1 , wherein the biological sample comprises the nasal mucus.
3. The method of claim 1 , further comprising repeating (a) after a time period of about a week after the measuring of (a).
4. The method of claim 1 , wherein the biological sample comprises the saliva.
5. The method of claim 1 , further comprising administering a PDE inhibitor or a salt thereof to a subject when the decreased level of SHH is identified.
6. The method of claim 5 , wherein the PDE inhibitor, or the salt thereof, is a non-selective PDE inhibitor, or a salt thereof.
7. The method of claim 5 , wherein the PDE inhibitor, or the salt thereof, is a selective PDE inhibitor, or a salt thereof.
8. The method of claim 7 , wherein the selective PDE inhibitor, or the salt thereof, is a phosphodiesterase-1 selective inhibitor, or a salt thereof; a phosphodiesterase-2 selective inhibitor, or a salt thereof; a phosphodiesterase-3 selective inhibitor, or a salt thereof; a phosphodiesterase-4 selective inhibitor, a phosphodiesterase-5 selective inhibitor, or a salt thereof, a phosphodiesterase-10 selective inhibitor, or a salt thereof; or any combination thereof.
9. The method of claim 5 , wherein the PDE inhibitor, or the salt thereof, is roflumilast, or a salt thereof; cilostazol, or a salt thereof; or any combination thereof.
10. The method of claim 5 , wherein the PDE inhibitor, or the salt thereof, is theophylline, or a salt thereof.
11. The method of claim 5 , wherein the PDE inhibitor, or the salt thereof, is administered intranasally.
12. The method of claim 1 , wherein the reference level is from a patient without a taste or smell disorder.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 18, 2023
From: HENKIN, ROBERT I.
To: CYRANO THERAPEUTICS, INC.
Reel/Frame 064633/0867 →
CHANGE OF ADDRESS
Recorded Aug 18, 2023
From: CYRANO THERAPEUTICS, INC.
To: CYRANO THERAPEUTICS, INC.
Reel/Frame 064783/0023 →
Continuity (7)
Continuation
15119696
Provisional Application
62075337
· Nov 5, 2014
Provisional Application
62026298
· Jul 18, 2014
Provisional Application
61941199
· Feb 18, 2014
References Cited (296)
US 174915A
· Lorenz
· 1876
[cited by applicant]
US 4066405A
· Henkin
· 1978
[cited by applicant]
US 4146501A
· Henkin
· 1979
[cited by applicant]
US 4368197A
· Shefter
· 1983
[cited by applicant]
US 4444879A
· Foster
· 1984
[cited by applicant]
US 4652521A
· Confer
· 1987
[cited by applicant]
US 4683195A
· Mullis
· 1987
[cited by applicant]
US 4683202A
· Mullis
· 1987
[cited by applicant]
US 4800159A
· Mullis
· 1989
[cited by applicant]
US 4992445A
· Lawter
· 1991
[cited by applicant]
US 5001139A
· Lawter
· 1991
[cited by applicant]
US 5023252A
· Hseih
· 1991
[cited by applicant]
US 5079142A
· Coleman
· 1992
[cited by applicant]
US 5132324A
· Meglasson
· 1992
[cited by applicant]
US 5169849A
· Kiechel
· 1992
[cited by applicant]
US 5384308A
· Henkin
· 1995
[cited by applicant]
US 5525329A
· Snyder
· 1996
[cited by applicant]
US 5591645A
· Rosenstein
· 1997
[cited by applicant]
US 5601986A
· Takacs
· 1997
[cited by applicant]
US 5614627A
· Takase
· 1997
[cited by applicant]
US 5622871A
· May
· 1997
[cited by applicant]
US 5707802A
· Sandhu
· 1998
[cited by applicant]
US 5714993A
· Keoshkerian
· 1998
[cited by applicant]
US 5788967A
· Henkin
· 1998
[cited by applicant]
US 5849741A
· Watanabe
· 1998
[cited by applicant]
US 5859006A
· Daugan
· 1999
[cited by applicant]
US 5869516A
· Arlt
· 1999
[cited by applicant]
US 5993782A
· Gardner
· 1999
[cited by applicant]
US 6207703B1
· Ponikau
· 2001
[cited by applicant]
US 6228660B1
· May
· 2001
[cited by applicant]
US 6387639B1
· Posner
· 2002
[cited by applicant]
US 6462044B2
· Garvey
· 2002
[cited by applicant]
US 6506801B1
· Yee
· 2003
[cited by applicant]
US 6929925B1
· Zuker
· 2005
[cited by applicant]
US 7109042B2
· May
· 2006
[cited by applicant]
US 7144585B1
· Mukai
· 2006
[cited by applicant]
US 7670849B2
· Henkin
· 2010
[cited by applicant]
US 8293489B2
· Henkin
· 2012
[cited by applicant]
US 8506934B2
· Henkin
· 2013
[cited by applicant]
US 8549741B2
· Nelson
· 2013
[cited by applicant]
US 8580801B2
· Henkin
· 2013
[cited by applicant]
US 8663938B2
· Henkin
· 2014
[cited by applicant]
US 8968706B2
· Henkin
· 2015
[cited by applicant]
US 9719988B2
· Henkin
· 2017
[cited by applicant]
US 20030055039A1
· Ikeya
· 2003
[cited by applicant]
US 20040209843A1
· Inoue
· 2004
[cited by applicant]
US 20050288265A1
· Locher
· 2005
[cited by applicant]
US 20060222718A1
· Böhme et al.
· 2006
[cited by applicant]
US 20080029084A1
· Costantino
· 2008
[cited by applicant]
US 20080200484A1
· Liu
· 2008
[cited by applicant]
US 20110023870A1
· Wermeling
· 2011
[cited by applicant]
US 20110137407A1
· Nguyen
· 2011
[cited by applicant]
US 20130144372A1
· Wood
· 2013
[cited by applicant]
US 20130225595A1
· Gillies
· 2013
[cited by applicant]
US 20140053835A1
· Gilbert
· 2014
[cited by applicant]
US 20150297601A1
· Henkin
· 2015
[cited by applicant]
US 20160030435A1
· Henkin
· 2016
[cited by applicant]
US 20190224426A1
· Farina
· 2019
[cited by applicant]
US 20190231785A1
· Henkin
· 2019
[cited by applicant]
US 20220226332A1
· Henkin
· 2022
[cited by applicant]
EP 0967214B1
· 1999
[cited by applicant]
EP 1547592A1
· 2005
[cited by applicant]
EP 1035833B1
· 2005
[cited by applicant]
NL 2031214B1
· 2023
[cited by applicant]
WO 1996026940A1
· 1996
[cited by applicant]
WO 1996041194A1
· 1996
[cited by applicant]
WO 1997003675A1
· 1997
[cited by applicant]
WO 1997003985A1
· 1997
[cited by applicant]
WO 1997043287A1
· 1997
[cited by applicant]
WO 1998017668A1
· 1998
[cited by applicant]
WO 1998049166A1
· 1998
[cited by applicant]
WO 1999001135A1
· 1999
[cited by applicant]
WO 1999021562A1
· 1999
[cited by applicant]
WO 1999030697A2
· 1999
[cited by applicant]
WO 2001048477A1
· 2001
[cited by applicant]
WO 2001082931A1
· 2001
[cited by applicant]
WO 2003025224A1
· 2003
[cited by applicant]
WO 2003025224A3
· 2003
[cited by applicant]
WO 2006085102A1
· 2006
[cited by applicant]
WO 2006119292A2
· 2006
[cited by applicant]
WO 2007044375A2
· 2007
[cited by applicant]
WO 2008141438A1
· 2008
[cited by applicant]
WO 2009003199A1
· 2008
[cited by applicant]
WO 2009115235A1
· 2009
[cited by applicant]
WO 2010147981A1
· 2010
[cited by applicant]
WO 2012016845A3
· 2012
[cited by applicant]
WO 2012016889A3
· 2012
[cited by applicant]
WO 2012154975A3
· 2012
[cited by applicant]
WO 2013021199A2
· 2013
[cited by applicant]
WO 2014055801A1
· 2014
[cited by applicant]
WO 2014059197A1
· 2014
[cited by applicant]
WO 2014143453A1
· 2014
[cited by applicant]
WO 2015126944A1
· 2015
[cited by applicant]
WO 2015136515A1
· 2015
[cited by applicant]
WO 2015194962A1
· 2015
[cited by applicant]
WO 2017095219A1
· 2017
[cited by applicant]
WO 2017095220A1
· 2017
[cited by applicant]
WO 2018026812A1
· 2018
[cited by applicant]
WO 2018034920A1
· 2018
[cited by applicant]
WO 2019006173A1
· 2019
[cited by applicant]
WO 2019136306A1
· 2019
[cited by applicant]
WO 2020160037A1
· 2020
[cited by applicant]
WO 2021194893A1
· 2021
[cited by applicant]
WO 2021255622A1
· 2021
[cited by applicant]
Nakajima, et al. Studies on cyclic nucleotides in brochopulmonary diseases with special reference to CAMP, cGMP in patients with nasal allergy and bronchial asthma. Acta Med. Kinki Univ., 1979, vol. 4, p. 257-272.
[cited by applicant]
Nakamura, et al. Proceedings of the 25th Japanese Symposium on Taste and Smell: 1. Current and Ca influx induced by intracellular cAMP in the newt olfactory receptor. Chem Sense, 1991, vol. 17, p. 85-116.
[cited by applicant]
Neumann, S. et al., Regeneration of Sensory Axons Within the Injured Spinal Cord Induced by Intraganglionic cAMP Elevation. Neuron., 2002, vol. 34, p. 885-893.
[cited by applicant]
Pace, U., Hanski, E., Salomon, Y, et al. Odorant-sensitive adenylate cyclase may mediate olfactory reception. Nature. 1985, vol. 316, p. 255-8.
[cited by applicant]
Papthanassiu, A., Henkin, R.I. cAMP is present in human nasal mucus and may act as a growth factor in cells of the olfactory epithelium. FASEB J. 2002, vol. 16, A1153.
[cited by applicant]
Pelangaris, et al. Oncogenic co-operation in beta-cell tumorigenesis. Endocr Relat Cancer. Dec. 2001, vol. 8(4), p. 307-14.
[cited by applicant]
Philips, et al. Factors determining the appearance of glucose in upper and lower respiratory tract secretions. Intensive Care Med. Dec. 2003, vol. 29(12), p. 2204-10.
[cited by applicant]
Poehling, et al., Accuracy and Impact of a Point of a Care Rapid Influenza Test in Young Children With Respiratory Illnesses, Arch Pediatr Adolsec Med., 2006, vol. 160(7), p. 713-718.
[cited by applicant]
Prakasam et al., Biodegradable Materials and Metallic Implants—A Review, J Funct Biomater, 2017, vol. 8(4), p. 1-15.
[cited by applicant]
Rickli, E.E., et al., Carbonic Anhydrases from Human Erythrocytes, J. Biol. Chem., 1964, vol. 239, p. 1065-1078.
[cited by applicant]
Riste, et al. High prevalence of Type 2 diabetes in all ethnic groups, including Europeans, in a British Inner City. Diabetes Care, 2001, vol. 24, p. 1377-1383.
[cited by applicant]
Rock, et al. Inhibitors of the proteosome block the degradation of most cell proteins and the generation of peptides presented on MHC class 1 molecules. Cell. 1994, vol. 78, p. 761-771.
[cited by applicant]
Rosenweig, S., et al., Possible Novel Mechanism for Bitter Taste Mediated Through cGMP. J. Neurophysiol. 1999, vol. 81, pp. 1661-1665.
[cited by applicant]
Sano, et al. Immuno-PCR: Very sensitive antigen detection by means of specific antibody-DNA conjugates. Science, vol. 258 (1992), p. 120-122.
[cited by applicant]
Schaeffer L.D ., Sproles, A, Krakowski, A Detection of CAMP in parotid saliva of normal individuals. J. Dent. Res. 1973, vol. 52, p. 629.
[cited by applicant]
Schechter P.J., Friedwald, W.T., Bronzert, D.A., Raff, M.S., Henkin, R.I. Idiopathic hypogeusia: a description of the syndrome and a single blind study with zinc sulfate, in Intemat. Rev. Neurobiol. Suppl. 1., (Pfeiffer…
[cited by applicant]
Schechter, P.J. et al., Abnormalities of Taste and Smell Following Head Trauma. J. Neurol. Neurosurg. Psychiat., 1974, vol. 37, p. 802-810.
[cited by applicant]
Schiffman, et al. Methyl xanthines enhance taste: evidence for modulation of taste by adenosine receptor. Pharmacol Biochem Behav, Feb. 1985, vol. 22(2), p. 195-203.
[cited by applicant]
Seal, et al. Point-of-care nucleic acid lateral flow tests. IVD Techology, 2006, pp. 41-51.
[cited by applicant]
Seiden A.M., Duncan, H.J., Smith, D.V. Office management of taste and smell disorders. Otolaryngol. Clin. North Amer. 1992, vol. 25, p. 817-835.
[cited by applicant]
Shepherd Shepherd, G.M. Sensory transduction entering the mainstream of membrane signaling. Cell. 1991; vol. 67, p. 845-851.
[cited by applicant]
Shin, et al. Virus-induced Type 1 IFN stimulates generation of immunoproteasomes at the site of infection. J. Clin. Invest. 2006, vol. 116(11), p. 3006-3014.
[cited by applicant]
Shirley, et al. Olfactory adenylate cyclase of the rat. Stimulation by odorants and inhibition by Ca2+. Biochem J, Dec. 1, 1986, vol. 240(2), p. 605-7.
[cited by applicant]
Shital et al., Development and Evaluation of a Novel Intranasal Spray for the Delivery of Amantadine, Journal of Pharmaceutical Sciences, 2016, vol. 105, p. 1209-1220.
[cited by applicant]
Sklar, et al. The odorant-sensitive adenylate cyclase of olfactory receptor cells. Differential stimulation by distinct classes of odorants. J Biol Chem. Nov. 25, 1986, vol. 261 (33), p. 15538-43.
[cited by applicant]
Sobottka, et al. Disseminated Encephalitozoon (Septata) intestinalis infection in a patient with AIDS: novel diagnostic approaches and autopsy-confirmed parasitological cure following treatment with albendazole. J Clin …
[cited by applicant]
Spivey, et al. Comparative Analysis of Manual Versus Automated Actuation Parameters for Droplet Size Determination by Laser Diffraction for Spray Devices. Catalent Pharma Solutions. 2008. 1 page.
[cited by applicant]
Suzuki. Proceedings of the 21st Japanese Symposium on Taste and Smell: cyclic nucleotides as intracellular messengers in the olfactory transduction process. Chem Sense. 1988, vol. 13, Abstract.
[cited by applicant]
Temmel, A.F.P., et al., Characteristics of Olfactory Disorders in Relation to Major Causes of Olfactory Loss. Arch. Otolaryngol. Head Neck Surg. 2002; vol. 128; pp. 635-641.
[cited by applicant]
The Expert Committee. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003, vol. 26, S5-S20.
[cited by applicant]
Thompson, W.J. Cyclic nucleotide phosphodiesterase: pharmacology, biochemistry and function. Pharmacol. Ther. 1991, vol. 51, p. 13-33.
[cited by applicant]
Vaughan. Second wind for second-messenger research. Bioscience. 1987, vol. 37, p. 642-646.
[cited by applicant]
Velicu, et al. Insulin is present in human saliva and nasal mucus. Journal of Investigative Medicine. 2006, vol. 54, S385.
[cited by applicant]
Velicu, I., et al., On the Antiapoptotic Mechanism of Action of Theophylline in Restoring Smell Function in Patients with Hyposmia, J. Invest. Med., 2005, vol. 53 (Suppl. 2), S402.
[cited by applicant]
Verma et al., Topical gels as drug delivery systems: A review. Int. J. Pharm. Sci. Rev. Res, 2013, vol. 23(2), p. 374-382.
[cited by applicant]
Voegels, et al. Expression of interleukins in patients with nasal polyposis. Otolaryngology—Head and Neck Surgery, 2005, vol. 132, No. 4, p. 613-616.
[cited by applicant]
Washington et al., Determination of baseline human nasal pH and the effect of intranasally administered buffers, International Journal of Pharmaceutics, vol. 198, 2000, p. 139-146.
[cited by applicant]
Weinstock, et al. Olfactory dysfunction in humans with deficient guanine nucleotide-binding protein. Nature, 1986, Aug 14-20, vol. 322(6080), p. 635-6.
[cited by applicant]
Weyer, et al. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest, Sep. 1999, vol. 104(6), p. 787-94.
[cited by applicant]
Will, et al. Cigarette smoking and diabetes mellitus from a large prospective cohort study. Int. J. Epidemiol, 2001, vol. 30, p. 540-546.
[cited by applicant]
Williams, G., Diabetes in Endocrine Disorder. Oxford Testbook of Medicine. Volume 2, 4th Edition, Oxford Univ. Press 2003, p. 317-359.
[cited by applicant]
Wood, et al. Effect of hyperglyaemia on glucose concentration of human nasal secretions. Clin Sci (Lond). May 2004, vol. 106(5), p. 527-33.
[cited by applicant]
Wysocki C.J., Gilbert, A.N. National Geographic Smell Survey: Effects of age are heterogeneous. Ann. NY Acad. Sci. 1989, vol. 561, p. 12-28.
[cited by applicant]
Xi et al., Visualization and Quantification of Nasal and Olfactory Deposition in a Sectional Adult Nasal Airway Cast, Pharm Res, 2016, vol. 33, p. 1527-1541.
[cited by applicant]
Yang et al., Reservoir-based polymer drug delivery systems. Journal of laboratory automation, 2012, vol. 17(1), p. 50-58.
[cited by applicant]
Zhu et al., Delivery of theophylline as dry powder for inhalation, Asian Journal of Pharmaceutical Sciences, 2015, vol. 10, p. 520-527.
[cited by applicant]
Dewey et al., Intranasal Apomorphine Rescue Therapy for Parkinsonian “Off” Periods, Clinical Neuropharmacology, 1996, vol. 19, No. 3, p. 193-201.
[cited by applicant]
Henkin R.I., et al., An Open-Label Controlled Trial of Theophylline for Treatment of Patients with Hyposmia, American Journal of Medical Sciences, vol. 337, No. 6, 2009, p. 396-406.
[cited by applicant]
Henkin R.I. et al., Hypogeusia, dysgeusia, hyposmia and dysosmia following influenza-like infection. Ann. Otol. Rhin. aryngol. 1975, vol. 8, p. 672-682.
[cited by applicant]
Henkin R.I. et al., Decreased parotid salivary cyclic nucleotides related to smell loss severity in patients with taste and smell dysfunction. Metabolism Clinical and Experimental, 2009 p. 1717-1723.
[cited by applicant]
Henkin RI, et al. ‘Intranasal Theophylline Treatment of Hyposmia and Hypogeusia,’ Arch Otolaryngol Head Neck Surg, (2012) vol. 138 No 11, pp. 1064-1070.
[cited by applicant]
Henkin RI, et al., Olfactory Hallucinations Without Clinical Motor Activity: a Comparison of Unirhinal with Birhinal Phantosmia. Brain Sci. 2013, vol. 3, p. 1483-1553.
[cited by applicant]
Henkin RI, et al., Taste and smell function in chronic disease: a review of clinical and biochemical evaluation of taste and smell dysfunction in over 5000 patients at the Taste and Smell Clinic in Washington, DC. Amer.…
[cited by applicant]
Henkin Robert, et al., Rapid changes in taste and semll function following transcranical magnetic stimulation (TCMS) in humans: relationships to CNS plasticity, FASEB J., 2002, vol. 16, A878.
[cited by applicant]
Henkin, et al. Aberrant signaling in the olfactory system: a mechanism for smell loss. FASEB Journal, vol. 18, No. 4-5, pp. Abst. 792.7, 2004.
[cited by applicant]
Henkin, et al. Interleukin 6 in hyposmia. JAMA Otolaryngol Head Neck Surg, Jul. 2013, vol. 139(7), p. 728-34.
[cited by applicant]
Jenkin, et al. Treatment of abnormal chemsensation in human taste and smell. In: Norris DM, ed. Perception of Behavioral Chemicals. Amsterdam, Netherlands: Elsevier/North Holland Biomedical Press, 1981, p. 227-265.
[cited by applicant]
Jenkin, et al., Insulin receptors as well as insulin are present in saliva and nasal mucus. Journal of Investigative Medicine, 2006, vol. 54, (Suppl. 2), S378.
[cited by applicant]
Henkin, R.I. et al., cAMP and cGMP in Nasal Mucus: Relationships to Taste and Smell Dysfunction, Gender and Age. Clinical Invest. Med. 2008, vol. 3, E71-E77.
[cited by applicant]
Henkin, R.I. et al., Effective Treatment of Smell Loss with Theophylline. Exper. Biol., 2008, vol. 22, B976.2.
[cited by applicant]
Henkin, R.I. et al., Is Increased IL-6 the Result or Cause of Smell Loss in Patients with Hyposmia?, FASEB Journal, 2009, vol. 23 (Meeting Abstract Supplement), Abstract 835.1.
[cited by applicant]
Henkin, R.I., et al., A Zinc Protein Isolated from Human Parotid Saliva, Proc. Nat. Acad. Sci. USA, 1975, vol. 72, pp. 488-492.
[cited by applicant]
Henkin. Concepts of therapy in taste and smell dysfunction: repair of sensory receptor function as primary treatment. Olfaction and Taste XI, (Kurihara, K., Suzuki, N., Ogawa, H., Eds.), Springer Verlag, 1994, pp. 568-5…
[cited by applicant]
Huque, et al. Odorant- and guanine nucleotide—stimulated phosphoinositide turnover in olfactory cilia. Biochem Biophys Res Commun. May 2, 19869, 137(1), p. 36-42.
[cited by applicant]
Inthavong, et al., A Numerical Study of Spray Particle Deposition in a Human Nasal Cavity, Aerosol Science and Technology, vol. 40(11), p. 1034-1045.
[cited by applicant]
Kanamori, T. et al., Origin of cyclic adenosine monophosphate in saliva. J. Dent. Res. 1975, vol. 54, p. 535-539.
[cited by applicant]
Khani et al., Potential pharmacologic treatments for COVID-19 smell and taste loss: A compreshensive review, European Journal of Pharmacology, 2021, vol. 912, p. 1-9.
[cited by applicant]
Kim, et al. Defects in the peripheral taste structure and function in the MRL/Ipr mouse model of autoimmune disease. PLoS One, 2012, vol. 7(4), e35588.
[cited by applicant]
Kragelund, et al. N-terminal Pro-B-type natriuretic-peptide and long-term mortality in stable coronary heart disease. New Engl. J. Med. 2006, vol. 252, p. 666-675.
[cited by applicant]
Kublik, et al. Nasal delivery systems and their effect on deposition and absorption. Adv Drug Deliv Rev. Jan. 5, 1998, vol. 29(1-2), p. 157-177.
[cited by applicant]
Kulkarni, et al. Formulation and characterization of nasal sprays. An examination of nasal sprat formulation parameters and excipients and their influence on key in vitro tests. Inhalation, Jun. 2012, p. 10-15.
[cited by applicant]
Kundoor et al., Effect of Formulation- and Administration-Related Variables on Deposition Pattern of Nasal Spray Pumps Evaluated Using a Nasal Cast, Pharm Res, 2011, vol. 28, p. 1895-1904.
[cited by applicant]
Kurihara, K., Koyama, N. High activity of adenylyl cyclase in olfactory and gustatory organs. Biochem. Biophys. Rev. Comm. 1972, vol. 48, p. 30-34.
[cited by applicant]
Kurihara, K., Suzuki, N., Ogawa, H., Eds.), Concepts of Therapy in Taste and Smell Dysfunction: Repair of Sensory Receptor Function as Primary Treatment, Springer Verlag, 1994, pp. 568-573.
[cited by applicant]
Lancet, et al. Molecular transduction in smell and taste. Cold Spring Harb Symp Quant Biol. 1988, vol. 53, Pt 1, p. 343-8.
[cited by applicant]
Law, et al. Distribution of calmodulin in taste buds. Life Sci, 1985, vol. 36, p. 1189-1195.
[cited by applicant]
Law, et al. Zinc deficiency decreases the activity of calmodulin regulated cyclic nucleotide phosphodiesterases in vivo in selected rat tissues. Biol Trace Elem Res, Aug. 1988, vol. 16(3), p. 221-6.
[cited by applicant]
Law, et al., Low parotid saliva calmodulin in patients with taste and smell dysfunction. Biochem Med Metab Biol, Aug. 1986, vol. 36(1), p. 118-24.
[cited by applicant]
Lee, et al. Thiolated chitosan nanoparticles enhance anti-inflammatory effects of intranasally delivered theophylline. Respir Res., Aug. 24, 2006, vol. 7, p. 1-10.
[cited by applicant]
Levine, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. New Engl. J. Medicine. 2006, vol. 355, p. 992-1005.
[cited by applicant]
Levy L.M., Henkin, R.I., Hutter, A, Lin, C.S., Schellinger, D. Increased brain activation in response to odors in patients with hyposmia after theophylline treatment demonstrated by fMRI. J. Comp. Asst. Tomog. 1998, vol…
[cited by applicant]
Lindheimer, et al. Explaining and predicting preeclampsia. New Engl. J. Medicine. 2006, vol. 355, p. 1056-1058.
[cited by applicant]
Liu Hong Xiang et al.: “Multiple Shh Signaling Centers Participate in Fungiform Papilla and Taste Bud Formation and Maintenance”, Developmental Biology, vol. 382, No. 1, Aug. 2, 2013 (Aug. 2, 2013), pp. 82-97.
[cited by applicant]
Liu, et al., “Sonic Hedgehog Exerts Distinct, Stage-Specific Effects on Tongue and Taste Papilla Development”, Development Biology, vol. 276, pp. 280-300, Sep. 25, 2004.
[cited by applicant]
Lowe, et al. Contribution of the ciliary cyclic nucleotide-gated conductance to olfactory transduction in the salamander. J Physiol. Mar. 1993, vol. 462, p. 175-96.
[cited by applicant]
Lu et al., Hydrogen sulfide regulates cAMP homeostasis and renin degranulation in As4.1 and rat renin-rich kidney cells, Cell Physiology, 2012, vol. 302, C59-C66.
[cited by applicant]
Maggi et al., TT Virus in the Nasal Secretions of Children with Acute Respiratory Diseases: Relations to Viremia and Disease Severity, J Virology, Feb. 2003, vol. 77(4), p. 2418-2425.
[cited by applicant]
Maitra, et al. The pancreas in Pathological Basis of Disease. 7th Edition. Elsevier, 2004, p. 1155-1207.
[cited by applicant]
Margolskee, Robert F. Molecular mechanisms of taste transduction. Pure and applied chemistry, 2002, vol. 74(7), p. 1125-1133.
[cited by applicant]
Margolskee. The biochemistry and molecular biology of taste transduction. Curr Opin Neurobiol, Aug. 1993, vol. 3 (4), p. 526-31.
[cited by applicant]
McAuley, et al. Diagnosing insulin resistance in the general population. Diabetes Care. Mar. 2001, vol. 24(3), p. 460-4.
[cited by applicant]
Meret, S., et al., Simultaneous Direct Estimation by Atomic Absorption Spectrophotometry of Copper and Zinc in Serum, Urine, and Cerebrospinal Fluid, Clin. Chem., 1971, vol. 17, pp. 369-373.
[cited by applicant]
Misaka, et al. Taste buds have a cyclic nucleotide-activated channel, CNGgust. J Biol Chem, Sep. 5, 1997, vol. 272 (36), p. 22623-9.
[cited by applicant]
Moharram R., et al., Meeting Abstracts, FASEB J., 2004, 18:A201.
[cited by applicant]
Moon, C. et al., Regulation of Intracellular Cyclic GMP Levels in Olfactory Sensory Neurons. J. Neurochem., 2005, vol. 95, p. 200-9.
[cited by applicant]
MWV Healthcare MK Sprayer. Product Information. 2013. 2 pages.
[cited by applicant]
International Search Report and Written Opinion for PCT/US2013/064416, mailed Dec. 5, 2013.
[cited by applicant]
International Search Report and Written Opinion for PCT/US2021/023283, mailed Jul. 9, 2021.
[cited by applicant]
International Search Report and Written Opinion for PCT/US2022/081622, mailed Jun. 9, 2023.
[cited by applicant]
International Search Report and Written Opinion for PCT/US2022/081646, mailed Jun. 6, 2023.
[cited by applicant]
International Search Report and Written Opinion for PCT/US2023/060164, mailed Apr. 6, 2023.
[cited by applicant]
International Search Report and Written Opinion for PCT/US2023/060165, mailed Jun. 15, 2023.
[cited by applicant]
International Search Report and Written Opinion for PCT/US2023/060168, mailed Jun. 14, 2023.
[cited by applicant]
International Search Report for PCT/US2006/016846, mailed Nov. 14, 2016.
[cited by applicant]
International Search Report Written Opinion for PCT/US2013/063331,mailed Dec. 12, 2013.
[cited by applicant]
International Search Report Written Opinion for PCT/US2014/014940, mailed Apr. 8, 2014.
[cited by applicant]
International Search Report Written Opinion for PCT/US2015/016381, mailed May 29, 2015.
[cited by applicant]
Partial International Search Report and Provisional Opinion for PCT/US2023/060165, mailed Apr. 25, 2023.
[cited by applicant]
Provisional Opinion accompanying Partial Search Report for PCT/US2023/060168, mailed Apr. 20, 2023.
[cited by applicant]
C. Huart et al., Comparison of COVID-19 and common cold chemosensory dysfunction, Rhinology, 2020, vol. 58, No. 6, p. 623-625.
[cited by applicant]
Costantino et al., Intranasal delivery: Physicochemical and therapeutic aspects, ScienceDirect, International Journal of Pharmaceuticals, 2007, vol. 337, p. 1-24.
[cited by applicant]
Agarwal, et al., Bio. Tr. Elem. Res., 1985, vol. 7, pp. 199-208.
[cited by applicant]
Ajani, et al. Alcohol consumption and risk of coronary heart disease by diabetes status. Circulation. Aug. 1, 2000, vol. 102(5), p. 500-505.
[cited by applicant]
Anderson, et al., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002.
[cited by applicant]
Anholt, R.R.H. Molecular neurobiology of olfaction. Crit. Rev. Neurobiol. 1993, vol. 7, p. 1-22.
[cited by applicant]
Asakura, K., Kataura, A cAMP and cGMP in the human parotid saliva. Arch. Otorhinolaryngol. 1980, vol. 226, p. 1529-30.
[cited by applicant]
Atkinson, et al., The pathogenesis of insulin-dependent diabetes mellitus. New Engl. J. Med. 1994, vol. 33, p. 1428-1436.
[cited by applicant]
Bakalyar, et al. Identification of a specialized adenylyl cyclase that may mediate odorant detection. Science. Dec. 7, 1990, vol. 250(4986), p. 1403-6.
[cited by applicant]
Bogardus, et al. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest. Oct. 1984, vol. 4(4), p. 1238-…
[cited by applicant]
Borisy, et al. High-affinity cAMP phosphodiesterase and adenosine localized in sensory organs. Brain Res. May 7, 1993, vol. 610(2), p. 199-207.
[cited by applicant]
Breer. Molecular reaction cascades in olfactory signal transduction. J Steroid Biochem Mol Biol. Oct. 1991, vol. 39 (4B), p. 621-5.
[cited by applicant]
Bromley, S.M. Smell and taste disorders: a primary care approach. Amer. Fam. Physician., 2000, vol. 61, p. 427-436.
[cited by applicant]
Cai, D. et al., Neuronal Cyclic AMP Controls the Developmental Loss in Ability of Axons to Regenerate. J. Neurosci., 2001, vol. 21, p. 4731-4739.
[cited by applicant]
Cai, D. et al., Prior Exposure to Neurotrophins Blocks Inhibition of Axonal Regeneration by MAG and Myelin via a cAMP Dependent Mechanism. Neuron., 1999, vol. 22, p. 89-101.
[cited by applicant]
Carlsson, et al. Alcohol consumption and the increase of Type II diabetes: Finnish twin cohort study. Diabetes Care. 2003, vol. 26, p. 2785-2790.
[cited by applicant]
Cho Hj, et al. ‘Development of Udenafil-Loaded Microemulsions for Intranasal Delivery: In Vitro and in Vivo Evaluations,’ International Journal of Pharmaceutics, (2012) vol. 423, pp. 153-160.
[cited by applicant]
Chou. Wake up and smell the coffee. Caffeine, coffee, and the medical consequences. West J Med. Nov. 1992, vol. 157(5), p. 544-53.
[cited by applicant]
Church J.A., Bauer, H., Bellanti, J.A., Satterly, R.A., Henkin, R.I. Hyposmia associated with atopy. Ann. Aller. 1978, vol. 40, p. 105-109.
[cited by applicant]
Cicinelli, P., et al., Post-stroke reorganization of brain motor output to the hand: a 2-4 month follow-up with focal magnetic transcranial stimulation, Eletroenceph. Clin. Neurophys, 1997, vol. 105, p. 438-450.
[cited by applicant]
Cullen, M., Leopold, D. Disorders of smell and taste. Med. Clin. North Amer. 1999, vol. 83, p. 57-74.
[cited by applicant]
Davidson, T.M., Murphy, C., Jalowayski, A.A Smell impairment: can it be reversed? Postgrad. Med. 1995, vol. 98, pp. 107-109, 112-118.
[cited by applicant]
Deems, D.A., Doty, R.L., Settle, R.G., Moore-Gillon, V., Shaman, P., Mester, A.F., Kimmelman, C.P., Brightman, V.J., Snow, J.B. Jr. Smell and taste disorders, a study of 750 patients from the University of Pennsylvania …
[cited by applicant]
Djordjevic et al., Effects of Perceived and Imagined Odors on Taste Detection, Chem Senses, 2004, vol. 29, p. 199-208.
[cited by applicant]
Doerty, A.E., Matin, B.M., Dai, W.L., Henkin, R.I. Carbonic anhydrase (CA) activity in nasal mucus appears to be a marker for loss of smell (hyposmia) in humans. J. Invest. Med. 1997, vol. 45,237A.
[cited by applicant]
Doty, et al. Human odor intensity perception: correlation with frog epithelial adenylate cyclase activity and transepithelial voltage response. Brain Res. Sep. 10, 1990, vol. 527(1), p. 130-4.
[cited by applicant]
Draheim, et al., Anti-Inflammatory Potential of the Selective Phosphodiesterase 4 Inhibitor N-(3,5-Dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic Acid Amide (AWD 12-281) in Human Cell Preparat…
[cited by applicant]
Elshafeey AH, et al. Intranasal Microemulsion of Sildenafil Citrate: In Vitro Evaluation and In Vivo Pharmacokinetic Study in Rabbits, AAPS PharmSciTech, (2009), vol. 10, No. 2, pp. 361-367.
[cited by applicant]
Firestien B.I., Bredt, D.S. Regulation of sensory neuron precursor proliferation by cyclic GMP—dependent protein kinase. J. Neurochem. 1998, vol. 71, p. 1846-1853.
[cited by applicant]
Firestien S., Zufall, F., Sheperd, G.M. Single odor-sensitive channels in olfactory receptor neurons are also gated by cyclic nucleotides. J. Neurosci. 1991, vol. 11, p. 3565-72.
[cited by applicant]
Franz, et al., Evidence-based nutrition principles and recommendations for diabetes and related complications. Diabetes Care, 2002, vol. 25, 1244-1265.
[cited by applicant]
Gao et al., Factors influencing drug deposition in the nasal cavity upon delivery via nasal sprays, Journal of Pharmaceutical Investigation, 2020, vol. 50, p. 251-259.
[cited by applicant]
Gillespie, et al. Pharmacologic Management of Chronic Rhinosinusitis, Alone or with Nasal Polyposis. Current Allergy and Asthma Reports, 2004, vol. 4, No. 6, pp. 478-485.
[cited by applicant]
Glenert, U., Geisler, A A single assay for cyclic adenosine 3′:5′-monophosphate in human saliva. J. Cyclic Nucleotide Protein Phosphor. Res. 1985, vol. 10, p. 451-461.
[cited by applicant]
Guidance for Industry. Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products—Chemistry, Manufacturing, and Controls Documentation. US Department of Health and Human Services. CDER. Jul. 2002.
[cited by applicant]
Hardwick, et al., The effect of PGI2 and theophylline on the response of platelets subjected to shear stress. Blood. Oct. 1981, vol. 58(4), p. 678-81.
[cited by applicant]
Harris R., Davidson, T.M., Murphy, C., Gilbert, P.E., Chem, M. Clinical evaluation and symptoms of chemosensory impairment: one thousand consecutive cases from the Nasal Dysfunction Clinic in San Diego. Amer. J. Rhinol.…
[cited by applicant]
Henkin et al., Drug-induced taste and smell disorders, Drug safety, vol. 11, p. 310-377, 1994.
[cited by applicant]
Henkin et al., Evaluation and treatment of human olfactory dysfunction, Otolaryngology, 1993, vol. 2, p. 1-64.
[cited by applicant]
Henkin et al., Nasal seroproteins: a new frontier in the exploration of physiology and pathology of nasal and sinus disease, New Frontiers in Immunobiology, 2000, pp. 127-152.
[cited by applicant]
Henkin et al., Taste and Smell Phantoms Revealed by Brain Functional MRI (fMRI), Journal of Computer Assisted Tomography, 2000, vol. 24, No. 1, p. 106-123.
[cited by applicant]
Henkin R.I. Effects of ACTH, adrenocorticosteroids and thyroid hormone on sensory function, in Anatomical Neuroendocrinology, (Stumpf, W.E., Grant, L.D., Eds.), Karger, A.G. , Basel, 1975, pp. 298-316.
[cited by applicant]
Henkin R.I. The definition of primary and accessory areas of olfaction as the basis for a classification of decreased olfactory acuity, in Olfaction and Taste II, (Hayashi, T. Ed.), Pergamon Press, London, 1967, pp. 235…
[cited by applicant]
Henkin R.I. The role of adrenal corticosteroids in sensory processes, in Adrenal Gland, (Blaschko, H., Sayers, G., Smith, A.D., Eds.), Handbook of Physiology. Endocrinology, Washington, DC. Amer. Physiol. Soc., Sect. 7,…
[cited by applicant]
Henkin R.I. Zinc, saliva and taste: Interrelationships of gustin, nerve growth factor, saliva and zinc, in Zinc and Copper in Clinical Medicine, (Hambidge, K.M., Nichols, B.L., Eds.), Spectrum Publ. Inc., Jamaica, NY, 1…
[cited by applicant]
Henkin R.I. et al., Age related changes in cyclic nucleotides in saliva and nasal mucus—possible feedback mechanism in development of gustatory and olfactory receptor function. FASEB J. 2005, vol. 19, A1368.
[cited by applicant]
Henkin R.I. et al., Idiopathic hypogeusia with dysgeusia, hyposmia and dysosmia: a new syndrome. J. Amer. Med. Assoc. 1971, vol. 217, p. 434-440.
[cited by applicant]
Henkin R.I. et al., A Dichotomous changes in cAMP and cGMP in human parotid saliva after oral theophylline. FASEB J. 2003, vol. 17, A1028.
[cited by applicant]
Henkin R.I. et al., cAMP and cGMP in Nasal Mucus Related to Severity of Smell Loss in Patients with Smell Dysfunction. Clinical Invest. Med., 2008, vol. 31, E78-E84.
[cited by applicant]
Jenkin R.I. et al., Decreased parotid saliva gustin/carbonic anhydrase VI secretion: an enzyme disorder manifested by gustatory and olfactory dysfunction. Amer. J. Med. Sci. 1999, vol. 318, p. 380-391.
[cited by applicant]
Henkin R.I. et al., Efficacy of exogenous zinc in treatment of patients with carbonic anhydrase VI deficiency. Amer. J. Med. Sci. 1999, vol. 318, p. 392-404.
[cited by applicant]
Henkin R.I., et al., A double blind study of the effects of zinc sulfate on taste and smell dysfunction, Amer. J. Med. Sci., 1976, vol. 272, p. 285-299.
[cited by applicant]
Chai et al., Two nights of recovery sleep restores hippocampal connectivity but not episodic memory after total sleep deprivation, Scientific Reports, 2020, vol. 10, p. 1-11.
[cited by applicant]
Henkin et al., Improved Smell and Taste Dysfunction with Intranasal Theophylline, American Journal of Otolaryngology and Head and Neck Surgery, Remedy Publications LLC, 2019, vol. 2, Issue 9, Art 1070, p. 1-8.
[cited by applicant]
Henkin et al., Sonic Hedgehog in Nasal Mucus is a Biomarker for Smell Loss in Patients with Hyposmia, Cellular & Molecular Medicine, 2016, vol. 2, p. 1-6.
[cited by applicant]
International Search Report and Written Opinion for PCT/US2024/025817 mailed Sep. 23, 2024.
[cited by applicant]
Last et al., Scaling toward Diminutive MEMS: Dust-Sized Spray Chips for Aerosolized Drug Delivery to the Lung, Advanced Materials, 2023, vol. 8, No. 7, p. 1-8.
[cited by applicant]
Myatt et al., Unlocking further understanding of the atomization mechanism of a pressurized metered dose inhaler, Aerosol Science and Technology, 2022, vol. 56, No. 11, p. 1-11.
[cited by applicant]
Sheng et al., Inhibition of phosphodieterase: A novel therapeutics target for the treatment of mild cognitive impairment and Alzheimer's disease, Front Aging Neurosci., 2022, vol. 14, p. 1-12.
[cited by applicant]
Si et al., Liquid Film Translocation Significantly Enhances Nasal Spray Delivery to Olfactory Region: A Numerical Stimulation Study, Pharmaceuticals, 2021, vol. 13, p. 1-19.
[cited by applicant]
Wall et al., Pentoxifylline or theophylline use in hospitalized COVID-19 patients requiring oxygen support, Clin Respir J., 2021, Viol 15, p. 843-846.
[cited by applicant]