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Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders | Schultz M.,Foundation Care | Minnick-Poppe L.,St. Louis College of Pharmacy
Archives of Otolaryngology - Head and Neck Surgery | Year: 2012

Objective: To determine whether intranasal theophylline methylpropyl paraben can correct hyposmia and hypogeusia. Design: We performed an open-label pilot study in patients with hyposmia and hypogeusia under the following 3 conditions: (1) before treatment, (2) after oral theophylline anhydrous treatment, and (3) after intranasal theophylline treatment. Under each condition, we performed subjective evaluations of taste and smell functions, quantitative measurements of taste (gustometry) and smell (olfactometry), and measurements of serum theophylline level and body weight. Setting: The Taste and Smell Clinic in Washington, DC. Patients: Ten patients with hyposmia and hypogeusia clinically related to the effects of viral illness, allergic rhinitis, traumatic brain injury, congenital hyposmia, and other chronic disease processes were selected. Interventions: Oral theophylline anhydrous, 200 to 800 mg/d for 2 to 12 months, was administered to each patient. This treatment was discontinued for 3 weeks to 4 months when intranasal theophylline methylpropyl paraben, 20 μg/d in each naris, was administered for 4 weeks. Main Outcome Measures: At termination of each condition, taste and smell function was determined subjectively, by means of gustometry and olfactometry, with measurement of serum theophylline levels and body weight. Results: Oral theophylline treatment improved taste and smell acuity in 6 patients after 2 to 12 months of treatment. Intranasal theophylline treatment improved taste and smell acuity in 8 patients after 4 weeks, with improvement greater than after oral administration. No adverse effects accompanied intranasal drug use. Body weight increased with each treatment but was greater after intranasal than after oral administration. Conclusions: Intranasal theophylline treatment is safer and more effective in improving hyposmia and hypogeusia than oral theophylline anhydrous treatment. ©2012 American Medical Association. All rights reserved.


Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders | Levy L.M.,George Washington University | Fordyce A.,Center for Molecular Nutrition and Sensory Disorders
American Journal of Otolaryngology - Head and Neck Medicine and Surgery | Year: 2013

Purpose To describe systematic methods developed over 40 years among over 5000 patients at The Taste and Smell Clinic in Washington, DC to evaluate taste and smell dysfunction. Materials and Methods A tripartite methodology was developed. First, methods to determine clinical pathology underlying the multiple disease processes responsible for taste and smell dysfunction were developed. Second, methods to determine biochemical parameters responsible for these pathologies were developed. Third, methods to implement these techniques were developed to form a unified basis upon which treatment strategies can be developed to treat these patients. Results Studies were performed in 5183 patients. Taste loss was present in 62% of patients, smell loss in 87%. Most patients with taste loss (52%) exhibited Type II hypogeusia; most patients with smell loss (56%) exhibited Type II hyposmia. Sensory distortions were present in 60%. Four common diagnostic entities were found: post influenza-type hyposmia and hypogeusia (27% of patients), idiopathic causes (16%), allergic rhinitis (15%) and post head injury (14%). Regardless of clinical diagnosis the major biochemical abnormality found in most patients (~ 70%) was diminished parotid salivary and nasal mucus secretion of cAMP and cGMP. Conclusions Taste and smell dysfunctions are common clinical problems associated with chronic disease processes. These symptoms require a systematic, integrated approach to understand their multiple and complex components. The approach presented here can and has led to effective treatment. © 2013 Elsevier Inc.


Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders
Nutrition | Year: 2014

Objective: Smell loss (hyposmia) inhibits flavor perception and influences food intake. To compensate for flavor loss, some patients with hyposmia appear to increase salt usage. The purpose of this study was to compare self-reported salt usage in patients with hyposmia with that in normal volunteers. Methods: Salt usage was compared in 56 patients with hyposmia but with normal taste function with that in 27 normal volunteers. Salt usage was formulated with respect to 1) a standard quantitative salt intake scale, 2) salt addition related to food intake, 3) intake of foods and beverages with high salt content, and 4) salt intake related to presence or absence of hypertension. Results: Eighteen (32%) of the 56 patients self-reported increased salt usage they were labeled "increased users." The other 38 hyposmic patients (68%) did not report increased salt usage they were labeled "non-changers." Increased users estimated their salt usage rose an average 2.8 times that experienced before their hyposmia onset. They also reported adding salt to their food before tasting it and ate more highly salted foods than did the non-changers. Salt usage was not increased further among increased users with hypertension but was increased further among non-changers with hypertension. Conclusions: Salt usage is increased among some patients with hyposmia presumably to enhance flavor perception to compensate for diminished flavor perception related to loss of smell. © 2014 Elsevier Inc.


Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders
Nutrition | Year: 2010

Background: After discovery of insulin as a hypoglycemic agent in 1921 various routes of administration to control blood glucose were attempted. These included subcutaneous, oral, rectal, sublingual, buccal, transdermal, vaginal, intramuscular, intrapulmonary and intranasal delivery systems. While each delivery system controlled hyperglycemia the subcutaneous route was given priority until 2006 when the Federal Drug Administration (FDA) approved the first commercially available pulmonary inhaled insulin. Methods: A review of major publications dealing with intrapulmonary administration of insulin was made to understand the physiological basis for its use, its efficacy in controlling hyperglycemia, its side effects and a comparison of its efficacy with other delivery methods. Results: The large surface area of the lung, its good vascularization, capacity for solute exchange and ultra thin membranes of alveolar epithelia are unique features that facilitate pulmonary insulin delivery. Large lung surface area (∼75 m2) and thin alveolar epithelium (∼0.1-0.5 μm) permit rapid drug absorption. First pass metabolism avoids gastrointestinal tract metabolism. Lung drug delivery depends upon a complex of factors including size, shape, density, charge and pH of delivery entity, velocity of entry, quality of aerosol deposition, character of alveoli, binding characteristics of aerosol on the alveolar surface, quality of alveolar capillary bed and its subsequent vascular tree. Many studies were performed to optimize each of these factors using several delivery systems to enhance pulmonary absorption. Availability was about 80% of subcutaneous administration with peak activity within 40-60 min of administration. Intranasal insulin delivery faces a smaller surface area (∼180 cm2) with quite different absorption characteristics in nasal epithelium and its associated vasculature. Absorption depends upon many factors including composition and character of nasal mucus. Absorption of intranasal insulin resulted in a faster absorption time course than with subcutaneous insulin. Interpretation: After many studies the FDA approved Pfizer's product, Exubera, for intrapulmonary insulin delivery. While the system was effective its expense and putative side effects caused the drug company to withdraw the drug from the marketplace. Attempts by other pharmaceutical companies to use intrapulmonary insulin delivery are presently being made as well as some minor attempts to use intranasal delivery systems. © 2010 Elsevier Inc. All rights reserved.


Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders
Nutrition | Year: 2010

Background: Intranasal insulin has proven useful to control hyperglycemia in diabetics but its mechanism of action has not been well defined. We attempted to understand several aspects of human insulin metabolism by measurement of and interaction of insulin and its associated moieties in nasal mucus, saliva and blood plasma under various physiological and pathological conditions. Methods: Insulin, insulin receptors, insulin-like growth factor 1 (IGF1) and insulin-like growth receptor 3 (IGFR3) were measured in nasal mucus, saliva and blood plasma in normal subjects, in thin and obese subjects and in diabetics under fasting and fed conditions. Results: There are complex relationships among each of these moieties in each biological fluid. Insulin and its associated moieties are present in both nasal mucus and saliva. These moieties in nasal mucus and saliva report on physiological and pathological changes in glucose metabolism as do these moieties in plasma. Indeed, insulin and its associated moieties in nasal mucus may offer specific data on how insulin enters the brain and thereby play essential roles in control of insulin metabolism. Interpretation: These data support the concept that insulin is synthesized not only in parotid glands but also in nasal serous glands. They also support the concept that insulin enters the brain following intranasal administration either 1) by direct entry through the cribriform plate, along the olfactory nerves and into brain parenchyma, 2) by entry through specific receptors in blood-brain barrier and thereby into the brain or 3) some combination of 1) and 2). Conversely, data also show that insulin introduced directly into the brain is secreted out of brain into the peripheral circulation. Data in this study demonstrate for the first time that insulin and its associated moieties are present not only in saliva but also in nasal mucus. How these complex relationships among nasal mucus, saliva and plasma occur are unclear but results demonstrate these relationships play separate yet interrelated roles in physiology and pathology of human insulin metabolism. © 2010 Elsevier Inc.


Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders | Velicu I.,Center for Molecular Nutrition and Sensory Disorders
Journal of Oral Pathology and Medicine | Year: 2011

We previously described some of the moieties in human saliva and nasal mucus including cyclic nucleotides. However, comparison of levels of these latter moieties in saliva and nasal mucus has not been performed and meaning of differences found has not been discussed. Purpose: To compare the levels of cAMP and cGMP in saliva and nasal mucus and to describe the differences in their concentrations and function. Methods: cAMP and cGMP in saliva and nasal mucus were compared in normal subjects and patients with taste and smell dysfunction by use of a spectrophotometric colorimetric ELISA. Results: Both cAMP and cGMP were present in saliva and nasal mucus of normals and patients with levels of both moieties lower in patients than in normals. In normals, cAMP is 61/2 times higher in saliva than in nasal mucus whereas cGMP in nasal mucus is 21/2 times higher than in saliva. In patients, these differences persist but are less robust. In normals, within saliva, cAMP is 91/2 times higher than cGMP whereas within nasal mucus cAMP is half the level of cGMP. In patients, within saliva, these differences persist but at variable differences. Conclusions: Both saliva and nasal mucus cAMP and cGMP play roles in taste and smell function, and differences in their concentrations may offer insight into these roles. In nasal mucus, cGMP may be more relevant than cAMP in activity of olfactory epithelial cell function. In saliva, cAMP may be more relevant as a growth factor in taste bud function than cGMP. © 2010 John Wiley & Sons A/S.


Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders | Velicu I.,Center for Molecular Nutrition and Sensory Disorders | Schmidt L.,Center for Molecular Nutrition and Sensory Disorders
American Journal of the Medical Sciences | Year: 2011

Introduction: Oral treatment with the phosphodiesterase inhibitor theophylline in an open-label fixed-design clinical trial in 312 patients with hyposmia improved smell function in >50%. Before treatment, all patients had lower than normal levels of nasal mucus cAMP and cGMP. The purpose of this study was to study relationships among changes in smell function, theophylline levels and nasal mucus cAMP and cGMP among patients whose smell function improved (responders) and those who did not improve (nonresponders) on oral theophylline treatment. Methods: After all data analysis from the clinical trial was completed, data from each of the 31 of the 312 patients in whom nasal mucus cAMP and cGMP and theophylline levels were available before and after theophylline treatment at several drug doses were evaluated. At initiation and at termination of each treatment, dose smell function, nasal mucus cAMP and cGMP and plasma theophylline were analyzed. Results: On the same theophylline dose, although serum theophylline increased among both responders and nonresponders, serum levels were consistently higher among responders. Nasal mucus cAMP and cGMP were also higher among responders than nonresponders. At higher theophylline doses, cGMP reached normal levels among responders, whereas it did not change significantly among nonresponders. Conclusions: Some patients with hyposmia with initially low nasal mucus cAMP and cGMP levels may be relatively resistant to oral theophylline treatment. This result may offer a mechanism of response lack among some patients whose smell function did not improve after oral theophylline treatment although other factors may influence their response lack. © 2011 Lippincott Williams & Wilkins.


Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders
Therapeutic Drug Monitoring | Year: 2012

Background: Theophylline, used in the treatment for various pulmonary pathologies, is usually given orally with drug levels measured primarily in blood serum and occasionally in saliva. Although theophylline treatment is now not commonly used it has been effective to correct smell loss (hyposmia). This is important because 21 million people in the United States exhibit hyposmia and oral theophylline has corrected hyposmia in about 50% of these patients. This result suggests that oral theophylline may result in the drug not only appearing in the serum but also in nasal mucus, thereby playing a role in correcting hyposmia. No prior report of theophylline in nasal mucus has been made and no comparison of levels in nasal mucus, blood serum, or saliva has been previously reported. Purpose: The aim was to determine, after oral theophylline treatment, if it is present in nasal mucus and, if present, to compare the levels with those in serum and saliva. Methods: Oral theophylline was given to 23 hyposmic patients at daily doses of 200, 300, 400, 600, and 800 mg for periods of 2-10 months. During each period, blood serum, saliva, and nasal mucus were collected and theophylline measured in each fluid. Results: Theophylline was found in nasal mucus and in saliva and blood serum at each drug dose in each patient to whom it was given. The mean level of theophylline in nasal mucus was 74% that of serum; mean level in saliva was 67% of serum; mean level in nasal mucus was 111% that in saliva. Conclusions: Theophylline is present in nasal mucus after oral administration. Levels in nasal mucus reflect blood and saliva levels in a consistent manner and offer a simple convenient noninvasive method to monitor theophylline doses of the oral drug. © 2012 Lippincott Williams & Wilkins.


Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders | Velicu I.,Center for Molecular Nutrition and Sensory Disorders
Archives of Oral Biology | Year: 2012

Objective: We previously demonstrated that parotid saliva cAMP and cGMP were lower in patients with taste and smell dysfunction than in normal subjects. We subsequently demonstrated parotid saliva cAMP and cGMP were inversely correlated with smell loss degree such that as smell loss severity increased parotid saliva cAMP and cGMP decreased proportionately. To learn more about these relationships we studied parotid saliva cAMP and cGMP with respect to aetiology of sensory loss in these patients. Design: Parotid saliva cAMP and cGMP in patients with smell loss (hyposmia) who participated in an open label fixed design controlled clinical trial with treatment with oral theophylline were evaluated with respect to their initial etiological diagnosis. Levels of cyclic nucleotides in each etiological category were compared to each other, to the entire patient group and to normal subjects. Results: Mean cAMP and cGMP in all patients combined were below those in normals, as previously described. However, categorized by aetiology, there was a stratification of levels of both cyclic nucleotides; some levels were below the normal mean and some were at or above the normal mean. Conclusions: Parotid saliva cyclic nucleotides characterised in hyposmic patients by aetiology indicate (1) there are differential alterations in these nucleotides related to aetiology of sensory dysfunction and (2) these moieties measured prior to treatment indicate which patient groups may benefit from treatment with phosphodiesterase (PDE) inhibitors which increase levels of these moieties and thereby correct their sensory dysfunction. © 2012 Elsevier Ltd. All rights reserved.


Henkin R.I.,Center for Molecular Nutrition and Sensory Disorders | Gouliouk V.,Center for Molecular Nutrition and Sensory Disorders | Fordyce A.,Center for Molecular Nutrition and Sensory Disorders
Archives of Oral Biology | Year: 2012

Objective: Burning mouth syndrome (BMS) is a complex of clinical symptoms defined by burning sensations in the oral cavity without observed oral pathology. Clinically two patient groups within BMS were distinguished, one with burning limited to the anterior tongue (glossopyrosis) and the other with burning in multiple mouth regions, including tongue, lips, palate, gums and cheeks (oropyrosis). Biochemical differences between these two groups could assist in distinguishing them. Design: Eighty-three patients with BMS, 47 with oropyrosis and 31 with glossopyrosis were studied. Measurements of zinc, copper, magnesium and calcium in blood plasma, erythrocytes and parotid saliva were obtained in patients and in normal subjects and mean levels were compared. Results: Clinical history differentiated patients into categories of oropyrosis and glossopyrosis. Erythrocyte and saliva levels of magnesium were significantly lower in patients with glossopyrosis than in patients with oropyrosis or in normal volunteers whereas levels of zinc and calcium were similar. Conclusions: These data suggest that patients with glossopyrosis not only differ clinically from those with oropyrosis but also exhibit magnesium deficiency as manifested by lower than normal magnesium levels in saliva and erythrocytes. Lingual burning in patients with glossopyrosis is consistent with hyperalgesia and neurogenic inflammation observed in patients and animals with magnesium deficiency and in magnesium deficient tissues. These results suggest a possible biochemical mechanism for pyrosis in patients with glossopyrosis. © 2011 Elsevier Ltd All rights reserved.

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