Methacholine, Long-acting M-cholinolytic and beta2-agonist on the Activity of Beta-receptors in Healthy Volunteers

Study Overview
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Brief Summary
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Interventional open-labeled study in parallel groups is aimed to evaluate changes of beta receptors in healthy volunteers under the influence of inhaled metacholine, long-acting anticholinergics and beta-agonists using modified radioligand method.

Detailed Description
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Long-acting beta2-agonists and anticholinergics are main drugs in therapy of chronic obstructive pulmonary disease . Beta-agonists exert their bronchodilatory effects via β2 adrenoceptors located on airway smooth muscle cells. Anticholinergics block mainly M3-cholinoreceptors located in the airways, thus inhibiting bronchoconstriction. Metacholine blocks M2-cholinoreceptors thus inducing bronchoconstriction. It is known, that muscarine and beta-receptors interact with each other, but the detailed mechanism is unknown. For evaluating the binding activity of beta-receptors after inhalation of these drugs the modified radioligand method was used.

Official Title
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Effect of Methacholine, Long-acting M-cholinolytic and beta2-agonist on the Binding Activity of Beta-receptors in Healthy Volunteers

Conditions
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Health, Subjective, Hyperreactivity, Bronchial

Intervention / Treatment
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* Drug: Formoterol
* Drug: Tiotropium Bromide
* Diagnostic Test: metacholine test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1 Provision of signed and dated informed consent form 2. Healthy male or female, aged 18-60 years Exclusion Criteria: Participants unable to perform spirometry Exacerbation respiratory infection within the previous four weeks Hypersensitivity or allergy to formoterol, metacholine or tiotropium bromide Females who are currently pregnant and lactating major surgery in the last 6 months Refusal to participate Currently participating in another clinical study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: There are two groups: the first group is smokers, the second group is non - smokers. The participants of both groups will receive metacholine on the first visit, formoterol 12 micrograms on the second visit, then tiotropium bromide 18 mkg on the third visit.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: smoking<br>Healthy smoking volunteers | Drug: Formoterol<br>* The participants will receive inhalation of formoterol 12 micrograms<br>Drug: Tiotropium Bromide<br>* The participants will receive inhalation of tiotropium bromide 18 mkg once<br>Diagnostic Test: metacholine test<br>* The participants will receive inhalation of metacholine once<br>|
| Experimental: non-smoking<br>Healthy non-smoking volunteers | Drug: Formoterol<br>* The participants will receive inhalation of formoterol 12 micrograms<br>Drug: Tiotropium Bromide<br>* The participants will receive inhalation of tiotropium bromide 18 mkg once<br>Diagnostic Test: metacholine test<br>* The participants will receive inhalation of metacholine once<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline beta-receptor binding activity at 60 min after the inhalation of formoterol or tiotropium. | Beta-receptor binding activity will be measured with modified radioligand method before and after 60 min after the inhalation of formoterol or tiotropium | Baseline (pre-dose), 60 minutes | 
| Change from baseline beta-receptor binding activity at 40 min after the challenge test with metacholine. | Beta-receptor binding activity will be measured with modified radioligand method before and after 40 min after the challenge test with metacholine. | Baseline (pre-dose), 40 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of beta-receptor binding activity measured with modified radioligand after formoterol and tiotropium. | Difference of change of beta-receptor binding activity measured with modified radioligand method before and after 60 min after the inhalation of formoterol and tiotropium. | Baseline (pre-dose), 60 minutes | 
| Comparison of beta-receptor binding activity measured with modified radioligand method after formoterol or tiotropium in smokers and non-smokers. | Difference of change of beta-receptor binding activity measured with modified radioligand method before and after 60 min after the inhalation of formoterol or tiotropium in smokers and non-smokers. | Baseline (pre-dose), 60 minutes | 
| Comparison of beta-receptor binding activity measured with modified radioligand after metacholine | Difference of change of beta-receptor binding activity measured with modified radioligand method before and after inhalation of metacholine | Baseline (pre-dose), 40 minutes | 
| Comparison of beta-receptor binding activity measured with modified radioligand method after inhalation of metacholine in smokers and non-smokers. | Difference of change of beta-receptor binding activity measured with modified radioligand method before and after inhalation of metacholine | Baseline (pre-dose), 40 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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beta-receptors, metacholine, formoterol, tiotropium