Differential Adrenoreceptor Mediated Tachyphylaxis and Upregulation

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

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.

Allergic rhinitis affects upto 25% of the worldwide population and is associated with asthma. Furthermore, nonallergic rhinitis accounts for more than 50% of Rhinitis sufferers. Patients with Allergic Rhinitis, Nonallergic Rhinitis and Common cold have nasal blockage as their principal symptom. Nasal blockage can affect sleep quality and impairs daytime performance. It is a major cause of sickness absenteeism and has been shown to adversely affect quality of life. The most efficacious class of drugs for this symptom are the nasal decongestants (sympathomimetics acting on alpha receptors). Unfortunately prolonged use of these sprays can result in a condition of tolerance (reduced efficacy), rebound nasal congestion and nasal hyperreactivity called Rhinitis Medicamentosa. It is a poorly understood condition and the mechanism of action is unclear. What is also not clear is the time to onset of tolerance. Finally many research studies have demonstrated that use of these nasal sprays for many weeks did not result in any side effects. Although evidence for this is conflicting, in vitro studies have shown that adrenoreceptors are known to develop tolerance within days of agonist use. Moreover beta adrenoreceptors in the lung can be upregulated (i.e., tolerance can be reversed) by use of corticosteroids. We have also seen over many years of clinical practise that concomitant use of steroid sprays and decongestants does not result in tolerance or rebound. Finally, research has shown that rebound congestion can be treated by stopping the decongestant spray and starting steroid sprays. We are not studying rebound congestion which takes years of decongestant abuse to develop. What we would like to demonstrate is the onset of tolerance (which precedes rebound) and its reversal by steroids. We would also find out if one of the two alpha receptors is responsible for this, which may lead to a selective alpha 1 or alpha 2 agonist being used safely in the nose.We, therefore propose to conduct a proof of concept study to evaluate the onset of tolerance by nasal decongestant Oxymetazoline (OXY, its differential effects on alpha 1 and alpha 2 adrenoreceptors by an alpha 1 blocker Prazosin and finally the reversal of this process by intranasal steroid (Fluticasone). We are recruiting 31 patients (38 to complete 31) according to previous research studies and PNIF as an outcome measure if the true difference between the two arms is 10L/min. There would be a total of 7 visits to the Asthma and Allergy group at Ninewells Hospital, Dundee and Perth Royal Infirmary. Healthy Volunteers from 18-65 years of age will attend for a screening visit. Their Peak Nasal Inspiratory Flow (PNIF) must be more than 100L/min (best of three). All patients who satisfy the inclusion criteria and none of the exclusion criteria will be included in the trial. They will be issued a Peak Nasal Inspiratory Flow diary and a symptom diary. This they will record at home each morning before and 20 min after using their nasal sprays and repeated before bedtime. They will be issued with Oxymetazoline nasal spray to be used according to the recommended dose of 2 squirts in each nostril three times daily (can be used upto four times daily), on waking up, after lunch and before bedtime. The first visit will include a baseline nasal blood flow and airflow tests. The order of the tests will be as follows: Firstly, nasal peak inspiratory flow (PNIF), secondly, active anterior rhinomanometry, thirdly, nasal impulse oscillometry, and finally, nasal blood flow using Laser Doppler Flowmetry. They will also have lying/standing blood pressure measurements. This will be followed by the administration of 1mg of oral Prazosin/Placebo in a supine position. 3 hours later a dose response curve (DRC) will be constructed with OXY at 20 minute intervals using cumulative sequential doses of 50 µg [1 squirt] , 100 µg[+ 1 squirt ] and 200 µg per nostril[+ 2 squirts].After 1st dose and 2nd dose, only PNIF and Rhinomanometry will be performed 10 minutes after each dose administration . After the last dose, the order of tests will be again PNIF, active anterior rhinomanometry, nasal impulse oscillometry, and laser Doppler flowmetry. For the first 2 hours lying/standing BP will be measured at ½ hourly intervals; hourly thereafter. They will be asked to lie down till the end of the visit (4 hours down) or until no postural drop in blood pressure is recorded whichever comes first. There is very rarely a drop in blood pressure on giving Prazosin called 'First Dose Hypotension'. This happens in hypertensive patients who take a high dose of an alpha blocker like Prazosin. Therefore the British National Formulary will advise patients to be given a dose of say 0.5 milligrammes thrice daily with the first dose at bedtime and them slowly increased to upto a maximum daily dose of 20 milligrammes. We are within this dose range. Moreover, in clinical practise, doses of upto 5 milligrammes have been prescribed and in previous research trials upto 10 milligrammes have been given to Healthy Volunteers who have a lesser risk of this first dose effect. Moreover, according to previous pharmacokinetic and pharmacodynamic studies within 4-6 hours Prazosin effect on Blood Pressure wanes. Therefore we would conduct the Prazosin challenge test and the OXY dose response in a supine position and no patient will be discharged till the postural BP change is within normal limits. Laser Doppler Flowmetry is a noninvasive test designed to measure blood flow through the nose. Rhinomanometry is another noninvasive test measuring nasal resistance and flow. Oscillometry is another parameter measured on the Rhinomanometry machine itself.PNIF is a noninvasive measure of airflow which is basically a peak flow meter reversed. Thus no invasive measures will be used. This order of tests will be performed on Day 1 and repeated on Day 14 to compare acute with chronic agonist use. On day 14 Fluticasone nasal spray 2 squirts twice daily will be issued and on Day 17 the same order of tests will be performed. As this is a cross over study the patients receiving placebo will have prazosin in the second arm following a weeks washout in between. The same procedure for Prazosin/Placebo challenge will be followed throughout.

The primary endpoint will be the difference in peak PNIF response to incremental doses of Oxymetazoline [i.e. as a dose response]

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.

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