Differential Adrenoreceptor Mediated Tachyphylaxis and Upregulation - Full Text View

Sponsored by:	University of Dundee
Information provided by:	University of Dundee
ClinicalTrials.gov Identifier:	NCT00487032

Purpose

The investigators wish to evaluate the onset of tolerance to nasal decongestants like oxymetazoline (available over the counter) and the mechanism of tolerance particularly with differential effects on alpha 1 and alpha 2 adrenoreceptors on the nose. The investigators will 'tease' out by using an alpha

1 blocker called Prazosin. The investigators hypothesize that alpha 1 receptors mediate arterial constriction and this will be captured by measuring nasal blood flow. The investigators also hypothesize that alpha 2 receptors mediate venous sinusoid constriction and this the investigators will capture by airflow parameters like Peak Nasal Inspiratory Flow, Rhinomanometry, Oscillometric indices etc.

Condition	Intervention	Phase
Allergic Rhinitis Tachyphylaxis Rhinitis Medicamentosa	Drug: Oxymetazoline 0.05% w/v Drug: Fluticasone propionate 50 micrograms per actuation Drug: Prazosin hydrochloride Drug: Placebo to Prazosin	Phase IV

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Safety/Efficacy Study
Official Title:	A Proof of Concept Study to Evaluate Differential Tachyphylaxis of Alpha 1 and Alpha 2 Adrenoreceptor Mediated Decongestant Response to Oxymetazoline and Its Acute Reversal by Corticosteroid in Healthy Volunteers

Resource links provided by NLM:

Drug Information available for: Phenylephrine Phenylephrine hydrochloride Prazosin Prazosin hydrochloride Fluticasone propionate Fluticasone Oxymetazoline Oxymetazoline hydrochloride

U.S. FDA Resources

Further study details as provided by University of Dundee:

Primary Outcome Measures:

The primary endpoint will be the difference in peak PNIF response to incremental doses of Oxymetazoline [i.e. as a dose response] [ Time Frame: 1 hour ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Active Anterior Rhinomanometry [ Time Frame: 1 hour ] [ Designated as safety issue: No ]
Nasal oscillometric indices [ Time Frame: 1 hour ] [ Designated as safety issue: No ]
Laser Doppler Flowmetry to measure nasal blood flow [ Time Frame: 1 hour ] [ Designated as safety issue: No ]
Systolic, Diastolic blood pressure(measure of alpha blockade) [ Time Frame: 1 hour ] [ Designated as safety issue: Yes ]

Enrollment:	29
Study Start Date:	May 2008
Study Completion Date:	May 2009
Primary Completion Date:	May 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Prazosin 1mg challenge to block alpha 1 adrenoreceptors	Drug: Oxymetazoline 0.05% w/v 2 squirts in each nostril thrice daily Drug: Fluticasone propionate 50 micrograms per actuation 2 Squirts in each nostril twice daily Drug: Prazosin hydrochloride Prazosin 1mg one dose only
2: Placebo Comparator Placebo to Prazosin	Drug: Placebo to Prazosin Placebo 1 tablet one dose only

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Male of Female aged 18-65 years.
Healthy volunteers with a negative history of seasonal or perennial nasal symptoms other than occasional common colds. Atopy will not preclude inclusion into the study as long as patients have no nasal symptoms.
Current non-smokers (ex-smokers for greater than 6 months duration with a total smoking history of less than 5 pack-years will be eligible).
PNIF > 100L/min (best effort of 3) and reversibility with OXY 2 squirts in each nostril (20 min reading) > 20 L/min.
Ability to give a written informed consent.
Ability and willingness to comply with the requirements of the protocol.

Exclusion Criteria:

Recent respiratory tract/sinus infection within the last 2 months.
Pregnancy, planned pregnancy or lactation.
Known or suspected hypersensitivity to any of the IMP's.
Concomitant use of medicines (prescribed, OTC or herbal) like alpha blockers that may interfere with the trial.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00487032

Locations

United Kingdom, Perthshire
Perth Royal Infirmary (Tayside NHS Trust)
Perth, Perthshire, United Kingdom, PH1 1NX
United Kingdom, Tayside
Ninewells Hospital and Medical School (Tayside NHS Trust, University of Dundee)
Dundee, Tayside, United Kingdom, DD1 9SY

Sponsors and Collaborators

University of Dundee

Investigators

Principal Investigator:	Sriram Vaidyanathan, MRCS, DOHNS	University of Dundee
Study Director:	Brian Lipworth, MD, FRCP	University of Dundee

More Information

Publications:

Bousquet J, Van Cauwenberge P, Khaltaev N; Aria Workshop Group; World Health Organization. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001 Nov;108(5 Suppl):S147-334. Review. No abstract available.

Nassef M, Shapiro G, Casale TB; Respiratory and Allergic Disease Foundation. Identifying and managing rhinitis and its subtypes: allergic and nonallergic components--a consensus report and materials from the Respiratory and Allergic Disease Foundation. Curr Med Res Opin. 2006 Dec;22(12):2541-8.

Nolte H, Nepper-Christensen S, Backer V. Unawareness and undertreatment of asthma and allergic rhinitis in a general population. Respir Med. 2006 Feb;100(2):354-62. Epub 2005 Jul 11.

Gupta R, Sheikh A, Strachan DP, Anderson HR. Burden of allergic disease in the UK: secondary analyses of national databases. Clin Exp Allergy. 2004 Apr;34(4):520-6.

Ferguson BJ. Influences of allergic rhinitis on sleep. Otolaryngol Head Neck Surg. 2004 May;130(5):617-29. Review.

Patou J, De Smedt H, van Cauwenberge P, Bachert C. Pathophysiology of nasal obstruction and meta-analysis of early and late effects of levocetirizine. Clin Exp Allergy. 2006 Aug;36(8):972-81.

Hadley JA. Cost-effective pharmacotherapy for inhalant allergic rhinitis. Otolaryngol Clin North Am. 2003 Oct;36(5):825-36. Review.

Graf P. Long-term use of oxy- and xylometazoline nasal sprays induces rebound swelling, tolerance, and nasal hyperreactivity. Rhinology. 1996 Mar;34(1):9-13.

Scadding GK. Rhinitis medicamentosa. Clin Exp Allergy. 1995 May;25(5):391-4. Review. No abstract available.

Ramey JT, Bailen E, Lockey RF. Rhinitis medicamentosa. J Investig Allergol Clin Immunol. 2006;16(3):148-55. Review.

Petruson B. Treatment with xylometazoline (Otrivin) nosedrops over a six-week period. Rhinology. 1981 Sep;19(3):167-72.

Yoo JK, Seikaly H, Calhoun KH. Extended use of topical nasal decongestants. Laryngoscope. 1997 Jan;107(1):40-3.

Watanabe H, Foo TH, Djazaeri B, Duncombe P, Mackay IS, Durham SR. Oxymetazoline nasal spray three times daily for four weeks in normal subjects is not associated with rebound congestion or tachyphylaxis. Rhinology. 2003 Sep;41(3):167-74.

Andersson KE, Bende M. Adrenoceptors in the control of human nasal mucosal blood flow. Ann Otol Rhinol Laryngol. 1984 Mar-Apr;93(2 Pt 1):179-82.

Corboz MR, Rivelli MA, Varty L, Mutter J, Cartwright M, Rizzo CA, Eckel SP, Anthes JC, Hey JA. Pharmacological characterization of postjunctional alpha-adrenoceptors in human nasal mucosa. Am J Rhinol. 2005 Sep-Oct;19(5):495-502.

Michelotti GA, Price DT, Schwinn DA. Alpha 1-adrenergic receptor regulation: basic science and clinical implications. Pharmacol Ther. 2000 Dec;88(3):281-309. Review.

Johannssen V, Maune S, Werner JA, Rudert H, Ziegler A. Alpha 1-receptors at pre-capillary resistance vessels of the human nasal mucosa. Rhinology. 1997 Dec;35(4):161-5.

Wight RG, Cochrane T. A comparison of the effects of xylometazoline on nasal airflow, and on blood flux as measured by laser Doppler flowmetry. Acta Otolaryngol. 1989 Sep-Oct;108(3-4):284-9.

Ruffolo RR Jr, Rosing EL, Waddell JE. Receptor interactions of imidazolines. I. Affinity and efficacy for alpha adrenergic receptors in rat aorta. J Pharmacol Exp Ther. 1979 Jun;209(3):429-36. No abstract available.

Ruffolo RR Jr, Waddell JE. Receptor interactions of imidazolines: alpha-adrenoceptors of rat and rabbit aortae differentiated by relative potencies, affinities and efficacies of imidazoline agonists. Br J Pharmacol. 1982 Sep;77(1):169-76.

Hein P, Michel MC. Signal transduction and regulation: are all alpha1-adrenergic receptor subtypes created equal? Biochem Pharmacol. 2007 Apr 15;73(8):1097-106. Epub 2006 Nov 7. Review.

DeBernardis JF, Winn M, Kerkman DJ, Kyncl JJ, Buckner S, Horrom B. A new nasal decongestant, A-57219: a comparison with oxymetazoline. J Pharm Pharmacol. 1987 Sep;39(9):760-3.

Jaillon P. Clinical pharmacokinetics of prazosin. Clin Pharmacokinet. 1980 Jul-Aug;5(4):365-76. Review.

Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, Molinoff PB, Ruffolo RR Jr, Trendelenburg U. International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev. 1994 Jun;46(2):121-36. Review. No abstract available.

Hallen H, Enerdal J, Graf P. Fluticasone propionate nasal spray is more effective and has a faster onset of action than placebo in treatment of rhinitis medicamentosa. Clin Exp Allergy. 1997 May;27(5):552-8.

Davies AO, Lefkowitz RJ. Regulation of beta-adrenergic receptors by steroid hormones. Annu Rev Physiol. 1984;46:119-30. Review. No abstract available.

Brodde OE, Brinkmann M, Schemuth R, O'Hara N, Daul A. Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen. J Clin Invest. 1985 Sep;76(3):1096-101.

Tan KS, Grove A, McLean A, Gnosspelius Y, Hall IP, Lipworth BJ. Systemic corticosteriod rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients. Am J Respir Crit Care Med. 1997 Jul;156(1):28-35.

Hamamdzic D, Duzic E, Sherlock JD, Lanier SM. Regulation of alpha 2-adrenergic receptor expression and signaling in pancreatic beta-cells. Am J Physiol. 1995 Jul;269(1 Pt 1):E162-71.

Hochban W, Althoff H, Ziegler A. Nasal decongestion with imidazoline derivatives: acoustic rhinometry measurements. Eur J Clin Pharmacol. 1999 Mar;55(1):7-12.

Responsible Party:	University of Dundee ( Dr. Sriram Vaidyanathan )
Study ID Numbers:	VAI03, 2007−003194−82
Study First Received:	June 14, 2007
Last Updated:	June 1, 2009
ClinicalTrials.gov Identifier:	NCT00487032 History of Changes
Health Authority:	United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Dundee:

allergic rhinitis
rhinitis medicamentosa
imidazolines
corticosteroid

Study placed in the following topic categories:

Anti-Inflammatory Agents
Neurotransmitter Agents
Adrenergic Agents
Rhinitis
Healthy
Adrenergic Agonists
Nasal Decongestants
Respiratory Tract Infections
Respiratory Tract Diseases
Prazosin
Phenylephrine
Vasoconstrictor Agents
Fluticasone
Pseudoephedrine

Otorhinolaryngologic Diseases
Adrenergic alpha-Agonists
Anti-Asthmatic Agents
Anti-Allergic Agents
Adrenergic alpha-Antagonists
Cardiovascular Agents
Antihypertensive Agents
Oxymetazoline
Mydriatics
Ephedrine
Adrenergic Antagonists
Peripheral Nervous System Agents
Bronchodilator Agents

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Respiratory System Agents
Neurotransmitter Agents
Adrenergic Agents
Molecular Mechanisms of Pharmacological Action
Cardiotonic Agents
Physiological Effects of Drugs
Rhinitis
Adrenergic Agonists
Nasal Decongestants
Respiratory Tract Infections
Respiratory Tract Diseases
Phenylephrine
Prazosin
Therapeutic Uses

Vasoconstrictor Agents
Fluticasone
Dermatologic Agents
Otorhinolaryngologic Diseases
Adrenergic alpha-Agonists
Sympathomimetics
Anti-Asthmatic Agents
Anti-Allergic Agents
Adrenergic alpha-Antagonists
Cardiovascular Agents
Antihypertensive Agents
Protective Agents
Nose Diseases
Pharmacologic Actions
Oxymetazoline

ClinicalTrials.gov processed this record on July 02, 2009