Primary objectiveTo evaluate the mechanism of AITC-induced vasodilationSecondary objectivesTo evaluate the tolerability of local AITC administrationTo evaluate the effect of whole-body heat on generation of NOTo evaluate the effect of AITC and whole…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Vasodilation, Pain
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Laser speckle basal flow (AU) after
* AITC administration
* AITC in combination with whole body heating
Secondary outcome
* Treatment-emergent (serious) adverse events ((S)AEs) throughout the study at
every study visit
* Concomitant medication throughout the study at every study visit
* VAS pain and itch scores
* Serum nitrite, nitrate and peroxynitrite concentrations
* Multispectral camera parameters
* Clinician Erythema Assessment scale
* Skin colorimetry parameters
* Cold pain detection threshold (PDT)
* Heat PDT
* Pressure PDT
Background summary
The nitric oxide (NO) system is involved in a wide range of physiological
processes and pathology. NO is produced by three isoforms of nitric oxide
synthase (NOS). Endothelial NOS (eNOS) and neuronal NOS (nNOS) are expressed
constitutively in respectively endothelial cells and neurons. eNOS is mainly
responsible for endothelium-dependent vasodilation and peripheral
cardiovascular homeostasis and has vasoprotective and anti-atherosclerotic
effects. nNOS is implicated in synaptic plasticity and central regulation of
blood pressure. The third form of NOS, inducible NOS (iNOS), is expressed in a
wide variety of cells, especially immune cells, upon inflammatory stimuli.
Given the wide variety of functions and locations of NOS isoforms, models
separating the physiological pathways of NO function are an attractive target
for development of pharmacological compounds targeting the NO system.
Allyl isothiocyanate (AITC), also known as *mustard oil*, is a transient
receptor potential cation channel A1 (TRPA1)-agonist used in pain models in
preclinical studies. Previous preclinical studies have shown that AITC induces
a significant increase in local skin perfusion as measured using laser speckle
contrast imaging (LSCI). In preclinical studies, this vasodilation is mediated
by TRPA1 channel activation causing Ca2+ influx and production of nitric oxide
(NO) by nitric oxide synthase (NOS). In this study, LSCI assessment of AITC
induced vasodilation will be combined with a whole-body heat stress (WBHS)
challenge. The WBHS response is partially dependent on nNOS. In addition,
nitrate, nitrite and peroxynitrite (reaction products of NO) production can be
measured in blood. The combination of the challenges and measurements allows
targeted assessment of NO pathways. The present study aims to develop NOS
isoform specific measurements as well as validate the AITC challenge model for
further use in development of medicinal compounds.
Next to its use in preclinical context, AITC is also administered in human
experimental pain studies to induce pain, sensitization, and neurogenic
inflammation through activation of TRPA1. Readouts in previous studies
completed by other research groups include thermal pain (heat and cold
allodynia) and mechanical pain. (To validate the use of AITC as pain model at
CHDR, pain will be assessed using the heat- and cold pain paradigms, (using the
QSense TSAII device) and mechanical pain paradigm (using the AlgoMed device)
following application of AITC on designated 3x3 cm area on the upper back. A
non-stimulated area contralateral to that of application will serve as control.
Reproducibility of results will be evaluated by having subjects report to the
clinical unit for two identical study periods that are divided by at least one
week.
Study objective
Primary objective
To evaluate the mechanism of AITC-induced vasodilation
Secondary objectives
To evaluate the tolerability of local AITC administration
To evaluate the effect of whole-body heat on generation of NO
To evaluate the effect of AITC and whole body heat on visual erythema and skin
colorimetry
To evaluate the effect of AITC on heat pain thresholds, cold pain thresholds
and mechanical (pressure) pain thresholds
Study design
Interventional and open-label study.
Intervention
Challenge drugs
25 *L of 15% allyl isothiocyanate solution in mineral oil applied topically to
the skin within an O-ring or using a silicone square mall (3x3 cm, for
applications on the back) for 30 seconds.
Study burden and risks
AITC is expected to induce pain at the application site. Symptoms such as
redness, pain, swelling, and inflammation are also expected side-effects. AITC
has been used in human subjects before as an inflammatory challenge agent.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Healthy male subjects *18 and *65 years of age.
2. Signed informed consent before any study procedures.
Exclusion criteria
1. Evidence of any active or chronic disease or condition that could interfere
with, or for which the treatment of might interfere with, the conduct of the
study, or that would pose an unacceptable risk to the subject in the opinion of
the investigator (following a detailed medical history, physical examination,
vital signs (systolic and diastolic blood pressure, pulse rate, body
temperature) and12-lead electrocardiogram (ECG)). Minor deviations from the
normal range may be accepted, if judged by the Investigator to have no clinical
relevance.
2. Clinically significant abnormalities, as judged by the investigator, in
laboratory test results (including hepatic and renal panels, complete blood
count, chemistry panel and urinalysis). In the case of uncertain or
questionable results, tests performed during screening may be repeated before
randomization to confirm eligibility or judged to be clinically irrelevant for
healthy subjects.
3. Systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and
diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg at
screening.
4. Use of any medications (prescription or over the counter [OTC]), within 14
days of study drug administration, or less than 5 half-lives (whichever is
longer). Paracetamol (up to 4 g/day) and ibuprofen (up to 1g/day) are not
allowed within 2 days before screening and before each study drug
administration. Exceptions will only be made if the rationale is clearly
documented by the investigator.
5. Use of any vitamin, mineral, herbal, and dietary supplements within 7 days
of study drug administration, or less than 5 half-lives (whichever is longer).
Exceptions will only be made if the rationale is clearly documented by the
investigator.
6. Participation in other investigational drug or device study (last dosing of
previous study was within 90 days prior to first dosing of this study or dosed
>3 times in the year prior to first dosing of this study).
7. History of abuse of addictive substances (alcohol, illegal substances) or
current use of more than 21 units alcohol per week, drug abuse, or regular user
of sedatives, hypnotics, tranquillizers, or any other addictive agent
8. Positive test for drugs of abuse at screening.
9. Alcohol will not be allowed from 24 hours before screening or study days.
10. Smoking (i.e., smoking of any cigarettes within 3 months of study
participation). Minor deviations may be accepted if judged by the investigator
to have no clinical relevance.
11. Excess of caffeine consumption (more than eight cups of coffee or
equivalent per day)
12. Known allergy to mustard oil, or any confirmed significant allergic
reactions (urticaria or anaphylaxis) against any drug or food component, or
multiple drug allergies (non-active hay fever is acceptable), or (history of)
contact allergies, or history of atopic dermatitis, or history of food
allergies.
13. Loss or donation of blood over 500 mL within three months prior to
screening or intention to donate blood or blood products during the study.
14. Any known factor, condition, or disease that might interfere with treatment
compliance, study conduct or interpretation of the results such as drug or
alcohol dependence or psychiatric disease.
15. Any skin disorders, excessive hair growth, tattoos, or other physical
characteristics on the forearms or back that may interfere with study conduct.
16. Any current, clinically significant, known medical condition that would
affect sensitivity to cold (such as atherosclerosis, Raynaud*s
disease, urticaria, hypothyroidism) or pain (i.e., disease that
causes pain, hypesthesia, hyperalgesia, allodynia, paraesthesia,
neuropathy).
17. Participants indicating pain tests intolerable at screening.
18. History or presence of post-inflammatory hyperpigmentation
19. Participant is unable to remain in a warm water bath of 40°C for at least
20 minutes
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL79322.056.21 |