<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01713179</url>
  </required_header>
  <id_info>
    <org_study_id>2011-07-63</org_study_id>
    <nct_id>NCT01713179</nct_id>
  </id_info>
  <brief_title>Effects of Oral Mucolytics on Tear Film and Ocular Surface</brief_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hallym University Kangnam Sacred Heart Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hallym University Kangnam Sacred Heart Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Ambroxol is a metabolite of bromhexine and possesses mucokinetic and secretolytic properties&#xD;
      that are also found in mucolytic agents.1 Ambroxol has been used for decades for the&#xD;
      treatment of respiratory disorders associated with excessive mucus, including chronic&#xD;
      inflammatory pulmonary conditions, bronchitis, and pneumonia.2,3 The drug changes the&#xD;
      biophysical properties of secretions by degrading the mucin polymers, deoxyribonucleic acid,&#xD;
      fibrin in airway secretions, and by generally decreasing viscosity.4 In addition, ambroxol&#xD;
      increases cyclic nucleotide (cAMP or cGMP),5 which can theoretically increase tear&#xD;
      secretion.6 Many systemic medications, such as antihistamines, antidepressants, diuretics,&#xD;
      acne drugs, and certain blood pressure medicines can cause or exacerbate a dry eye.7,8 On the&#xD;
      other hand, several topical medications, including mucolytics such as ambroxol and&#xD;
      bromhexine, may be used to treat tear-deficient dry eyes by promoting lacrimal gland&#xD;
      function.9 However, the effects of mucoactive agents on the tear film have not been&#xD;
      investigated systemically, and mucoactive agents may have a disturbing effect on the tear&#xD;
      film because they modify mucin.10,11 The tear film is composed of 3 unique layers, including&#xD;
      the outermost lipid layer, the middle aqueous layer, and the innermost mucus layer; this&#xD;
      structure enables it to perform many functions.12 The lipid layer acts as a barrier to&#xD;
      prevent tear film evaporation, and the aqueous layer supplies oxygen and important nutrients&#xD;
      to the cornea.13 The mucin layer, secreted mostly by conjunctival goblet cells, coats the&#xD;
      corneal surface rendering it hydrophilic, and anchors the tear film to the corneal surface.14&#xD;
      Deficiencies in the amount of tear production or alteration in tear composition can lead to&#xD;
      ocular surface disease.15 Although many studies have focused on aqueous-deficient dry eye&#xD;
      syndrome,16-18 the effect of mucin layer defects on the tear film has not been thoroughly&#xD;
      studied. Furthermore, very few reports have determined the effects of oral mucolytic agents&#xD;
      on the tear film and ocular surfaces, although a study has reported that filamentary&#xD;
      keratopathy was treated with debridement of filaments and application of topical mucolytic&#xD;
      agents such as acetylcysteine eyedrops. In the present study, we investigated the effects of&#xD;
      oral ambroxol on tear film and ocular surface.&#xD;
&#xD;
      Reference&#xD;
&#xD;
        1. Malerba M, Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update.&#xD;
           Expert Opin Drug Metab Toxicol 2008;4:1119-1129.&#xD;
&#xD;
        2. Rubin BK. Mucolytics, expectorants, and mucokinetic medications. Respir Care&#xD;
           2007;52:859-865.&#xD;
&#xD;
        3. Rogers DF. Mucoactive agents for airway mucus hypersecretory diseases. Respir Care&#xD;
           2007;52:1176-1193.&#xD;
&#xD;
        4. Gupta PR. Ambroxol - Resurgence of an old molecule as an anti-inflammatory agent in&#xD;
           chronic obstructive airway diseases. Lung India 2010;27:46-48.&#xD;
&#xD;
        5. Anfossi G, Russo I, Massucco P, et al. Adenosine increase human platelet levels of cGMP&#xD;
           through nitric oxide: possible role in its antiaggregating effect. Thromb Res&#xD;
           2002;105:71-78.&#xD;
&#xD;
        6. Gilbard JP, Rossi SR, Heyda KG, et al. Stimulation of tear secretion by topical agents&#xD;
           that increase cyclic nucleotide levels. Invest Ophthalmol Vis Sci 1990;31:1381-1388.&#xD;
&#xD;
        7. Gayton JL. Etiology, prevalence, and treatment of dry eye disease. Clin Ophthalmol&#xD;
           2009;3:405-412.&#xD;
&#xD;
        8. Terry MA. Dry eye in the elderly. Drugs Aging 2001;18:101-107.&#xD;
&#xD;
        9. Calonge M. The treatment of dry eye. Surv Ophthalmol 2001;45:227-239.&#xD;
&#xD;
       10. Yamada T, Takemura Y, Niisato N, et al. Action of N-acylated ambroxol derivatives on&#xD;
           secretion of chloride ions in human airway epithelia. Biochem Biophys Res Commun&#xD;
           2009;380:586-590.&#xD;
&#xD;
       11. Hasegawa I, Niisato N, Iwasaki Y, et al. Ambroxol-induced modification of ion transport&#xD;
           in human airway Calu-3 epithelia. Biochem Biophys Res Commun 2006;343:475-482.&#xD;
&#xD;
       12. Antti H, Tuulikki S, Matej O. Human tear fluid lipidome: from composition to function.&#xD;
           PLoS One 2011;6:e19553.&#xD;
&#xD;
       13. Ohashi Y, Dogru M, Tsubota K. Laboratory findings in tear fluid analysis. Clin Chim Acta&#xD;
           2006;396:17-28.&#xD;
&#xD;
       14. Davidson HJ, Kuonen VJ. The tear film and ocular mucins. Vet Ophthalmol 2004;7:71-77.&#xD;
&#xD;
       15. Bhavsar AS, Bhavsar SG, Jain SM. A review on recent advances in dry eye: pathogenesis&#xD;
           and management. Oman J Ophthalmol 2011;4:50-56.&#xD;
&#xD;
       16. Patel S, Farrell J, Blades KJ, et al. The value of a phenol red impregnated thread for&#xD;
           differentiating between the aqueous and non-aqueous deficient dry eye. Ophthalmic&#xD;
           Physiol Opt 1998;18:471-476.&#xD;
&#xD;
       17. Lin H, Li W, Dong N, et al. Changes in corneal epithelial layer inflammatory cells in&#xD;
           aqueous tear-deficient dry eye. Invest Ophthalmol Vis Sci 2010;51:122-128.&#xD;
&#xD;
       18. Yokoi N, Yamada H, Mizukusa Y, et al. Rheology of tear film lipid layer spread in normal&#xD;
           and aqueous tear-deficient dry eye. Invest Ophthalmol Vis Sci 2008;49:5319-5324.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2011</start_date>
  <completion_date type="Actual">October 2011</completion_date>
  <primary_completion_date type="Actual">October 2011</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Visual analog pain score</measure>
    <time_frame>1 day</time_frame>
    <description>Visual analog pain score Subjective discomfort or pain was graded numerically using the VAS. The scale range was 0 (absence of pain) to 10 (maximal pain). Subjects were asked to describe their symptoms using the VAS.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Fluorescein staining</measure>
    <time_frame>1 day</time_frame>
    <description>Corneal fluorescein staining was examined with a biomicroscope under blue-light illumination after fluorescein instillation into the tear film. The corneal surface was divided into 5 areas (1 center zone and 4 peripheral zones). Corneal erosion staining was recorded using a standardized grading system of 0 to 3 for each of the 5 areas.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tear break up time</measure>
    <time_frame>1 day</time_frame>
    <description>Fluorescein was placed in the lower conjunctival sac using a fluorescein strip (HAAG-STREIT, Köniz, Switzerland), and the time between the last blink and the first appearance of a dark spot was measured using the cobalt blue light of a slit lamp. This procedure was repeated 3 times, and the average value was recorded.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Fluorescein clearance test</measure>
    <time_frame>1 day</time_frame>
    <description>After applying 1 drop of 0.5% proparacaine hydrochloride to each eye, the inferior fornix was carefully dried with tissue paper. Fluorescein was then applied to the inferior fornix of each eye. The patient continued to sit in the examination room under ambient light and was asked to blink normally. After 10 minutes had elapsed, as determined by a timer, a Schirmer paper strip was inserted into the inferior fornix of each eye at a position approximately one-third lateral to the temporal caruncle. This maneuver was repeated for 3 times over a period of 30 minutes at 10-minute intervals.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Schirmer's test</measure>
    <time_frame>1 day</time_frame>
    <description>One drop of 0.5% proparacaine hydrochloride (Alcaine, Alcon, Forth Worth, TX, USA) was instilled in the conjunctival sac for topical anesthesia. In a silent room, filter paper (Color Bar, EagleVision, Memphis, TN, USA) was placed in the inferolateral one-third of the lower lid. Care was taken to prevent the paper from contacting the cornea. After 5 minutes, the level of strip wetting (in millimeters) was measured.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>In the Present Study, we Investigated the Effects of Oral Ambroxol on Tear Film and Ocular Surface.</condition>
  <arm_group>
    <arm_group_label>ambroxol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ambroxol hydrochloride (Mucopect®, trans-4[2-amino-3.5-dibrombenzylamino]-cyclohexanhydro-chloride, 60 mg, Boehringer Ingelheim) was administered orally to subjects in the ambroxol group immediately after initial examination (10 AM).&#xD;
one dose for one day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ambroxol hydrochloride (Mucopect®, 60 mg, Boehringer Ingelheim)</intervention_name>
    <arm_group_label>ambroxol</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Twenty healthy male volunteers aged between 25 and 29 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects with dry eye symptoms within the previous 6 months were excluded from the&#xD;
             study.&#xD;
&#xD;
          -  Subjects have any systemic diseases such as systemic lupus, rheumatoid arthritis,&#xD;
             Sjögren's syndrome or a history of ocular disease.&#xD;
&#xD;
          -  Subjects have disorder of lid margin, nasolacrimal duct, and cornea.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>25 Years</minimum_age>
    <maximum_age>29 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Hallym University, Kangnam Sacred Heart Hospital</name>
      <address>
        <city>Seoul</city>
        <zip>150-950</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>August 2016</verification_date>
  <study_first_submitted>October 22, 2012</study_first_submitted>
  <study_first_submitted_qc>October 23, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 24, 2012</study_first_posted>
  <last_update_submitted>August 29, 2016</last_update_submitted>
  <last_update_submitted_qc>August 29, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 30, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hallym University Kangnam Sacred Heart Hospital</investigator_affiliation>
    <investigator_full_name>Young Joo Shin</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ambroxol</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01713179
org study id: 2011-07-63
nct id: NCT01713179
lead sponsor: 
has dmc: No
Ambroxol is a metabolite of bromhexine and possesses mucokinetic and secretolytic properties
      that are also found in mucolytic agents.1 Ambroxol has been used for decades for the
      treatment of respiratory disorders associated with excessive mucus, including chronic
      inflammatory pulmonary conditions, bronchitis, and pneumonia.2,3 The drug changes the
      biophysical properties of secretions by degrading the mucin polymers, deoxyribonucleic acid,
      fibrin in airway secretions, and by generally decreasing viscosity.4 In addition, ambroxol
      increases cyclic nucleotide (cAMP or cGMP),5 which can theoretically increase tear
      secretion.6 Many systemic medications, such as antihistamines, antidepressants, diuretics,
      acne drugs, and certain blood pressure medicines can cause or exacerbate a dry eye.7,8 On the
      other hand, several topical medications, including mucolytics such as ambroxol and
      bromhexine, may be used to treat tear-deficient dry eyes by promoting lacrimal gland
      function.9 However, the effects of mucoactive agents on the tear film have not been
      investigated systemically, and mucoactive agents may have a disturbing effect on the tear
      film because they modify mucin.10,11 The tear film is composed of 3 unique layers, including
      the outermost lipid layer, the middle aqueous layer, and the innermost mucus layer; this
      structure enables it to perform many functions.12 The lipid layer acts as a barrier to
      prevent tear film evaporation, and the aqueous layer supplies oxygen and important nutrients
      to the cornea.13 The mucin layer, secreted mostly by conjunctival goblet cells, coats the
      corneal surface rendering it hydrophilic, and anchors the tear film to the corneal surface.14
      Deficiencies in the amount of tear production or alteration in tear composition can lead to
      ocular surface disease.15 Although many studies have focused on aqueous-deficient dry eye
      syndrome,16-18 the effect of mucin layer defects on the tear film has not been thoroughly
      studied. Furthermore, very few reports have determined the effects of oral mucolytic agents
      on the tear film and ocular surfaces, although a study has reported that filamentary
      keratopathy was treated with debridement of filaments and application of topical mucolytic
      agents such as acetylcysteine eyedrops. In the present study, we investigated the effects of
      oral ambroxol on tear film and ocular surface.

      Reference

        1. Malerba M, Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update.
           Expert Opin Drug Metab Toxicol 2008;4:1119-1129.

        2. Rubin BK. Mucolytics, expectorants, and mucokinetic medications. Respir Care
           2007;52:859-865.

        3. Rogers DF. Mucoactive agents for airway mucus hypersecretory diseases. Respir Care
           2007;52:1176-1193.

        4. Gupta PR. Ambroxol - Resurgence of an old molecule as an anti-inflammatory agent in
           chronic obstructive airway diseases. Lung India 2010;27:46-48.

        5. Anfossi G, Russo I, Massucco P, et al. Adenosine increase human platelet levels of cGMP
           through nitric oxide: possible role in its antiaggregating effect. Thromb Res
           2002;105:71-78.

        6. Gilbard JP, Rossi SR, Heyda KG, et al. Stimulation of tear secretion by topical agents
           that increase cyclic nucleotide levels. Invest Ophthalmol Vis Sci 1990;31:1381-1388.

        7. Gayton JL. Etiology, prevalence, and treatment of dry eye disease. Clin Ophthalmol
           2009;3:405-412.

        8. Terry MA. Dry eye in the elderly. Drugs Aging 2001;18:101-107.

        9. Calonge M. The treatment of dry eye. Surv Ophthalmol 2001;45:227-239.

       10. Yamada T, Takemura Y, Niisato N, et al. Action of N-acylated ambroxol derivatives on
           secretion of chloride ions in human airway epithelia. Biochem Biophys Res Commun
           2009;380:586-590.

       11. Hasegawa I, Niisato N, Iwasaki Y, et al. Ambroxol-induced modification of ion transport
           in human airway Calu-3 epithelia. Biochem Biophys Res Commun 2006;343:475-482.

       12. Antti H, Tuulikki S, Matej O. Human tear fluid lipidome: from composition to function.
           PLoS One 2011;6:e19553.

       13. Ohashi Y, Dogru M, Tsubota K. Laboratory findings in tear fluid analysis. Clin Chim Acta
           2006;396:17-28.

       14. Davidson HJ, Kuonen VJ. The tear film and ocular mucins. Vet Ophthalmol 2004;7:71-77.

       15. Bhavsar AS, Bhavsar SG, Jain SM. A review on recent advances in dry eye: pathogenesis
           and management. Oman J Ophthalmol 2011;4:50-56.

       16. Patel S, Farrell J, Blades KJ, et al. The value of a phenol red impregnated thread for
           differentiating between the aqueous and non-aqueous deficient dry eye. Ophthalmic
           Physiol Opt 1998;18:471-476.

       17. Lin H, Li W, Dong N, et al. Changes in corneal epithelial layer inflammatory cells in
           aqueous tear-deficient dry eye. Invest Ophthalmol Vis Sci 2010;51:122-128.

       18. Yokoi N, Yamada H, Mizukusa Y, et al. Rheology of tear film lipid layer spread in normal
           and aqueous tear-deficient dry eye. Invest Ophthalmol Vis Sci 2008;49:5319-5324.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Health Services Research
masking: Single (Participant)
measure: Visual analog pain score
time frame: 1 day
description: Visual analog pain score Subjective discomfort or pain was graded numerically using the VAS. The scale range was 0 (absence of pain) to 10 (maximal pain). Subjects were asked to describe their symptoms using the VAS.
measure: Fluorescein staining
time frame: 1 day
description: Corneal fluorescein staining was examined with a biomicroscope under blue-light illumination after fluorescein instillation into the tear film. The corneal surface was divided into 5 areas (1 center zone and 4 peripheral zones). Corneal erosion staining was recorded using a standardized grading system of 0 to 3 for each of the 5 areas.
measure: Tear break up time
time frame: 1 day
description: Fluorescein was placed in the lower conjunctival sac using a fluorescein strip (HAAG-STREIT, Köniz, Switzerland), and the time between the last blink and the first appearance of a dark spot was measured using the cobalt blue light of a slit lamp. This procedure was repeated 3 times, and the average value was recorded.
measure: Fluorescein clearance test
time frame: 1 day
description: After applying 1 drop of 0.5% proparacaine hydrochloride to each eye, the inferior fornix was carefully dried with tissue paper. Fluorescein was then applied to the inferior fornix of each eye. The patient continued to sit in the examination room under ambient light and was asked to blink normally. After 10 minutes had elapsed, as determined by a timer, a Schirmer paper strip was inserted into the inferior fornix of each eye at a position approximately one-third lateral to the temporal caruncle. This maneuver was repeated for 3 times over a period of 30 minutes at 10-minute intervals.
measure: Schirmer's test
time frame: 1 day
description: One drop of 0.5% proparacaine hydrochloride (Alcaine, Alcon, Forth Worth, TX, USA) was instilled in the conjunctival sac for topical anesthesia. In a silent room, filter paper (Color Bar, EagleVision, Memphis, TN, USA) was placed in the inferolateral one-third of the lower lid. Care was taken to prevent the paper from contacting the cornea. After 5 minutes, the level of strip wetting (in millimeters) was measured.
arm group label: ambroxol
arm group type: Experimental
description: Ambroxol hydrochloride (Mucopect®, trans-4[2-amino-3.5-dibrombenzylamino]-cyclohexanhydro-chloride, 60 mg, Boehringer Ingelheim) was administered orally to subjects in the ambroxol group immediately after initial examination (10 AM).
one dose for one day
arm group label: control
arm group type: No Intervention
intervention type: Drug
intervention name: Ambroxol hydrochloride (Mucopect®, 60 mg, Boehringer Ingelheim)
arm group label: ambroxol
criteria: 
gender: Male
minimum age: 25 Years
maximum age: 29 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: Hallym University Kangnam Sacred Heart Hospital
investigator full name: Young Joo Shin
investigator title: Assistant Professor
mesh term: Ambroxol