Role of Epoxy-eicosatrienoic Acids in Post-occlusive Hyperemia and Thermal Hyperemia

Study Overview
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Brief Summary
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The objective of this proof of concept study is to assess the involvement of epoxy-eicosatrienoic acids (EETs) in post-occlusive hyperemic and thermal hyperemia responses, and the interaction between nitric oxide (NO) and EETs, using the latest methods for the study of functional microcirculation.

Detailed Description
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The EETY study is a single-center proof of concept study in healthy volunteers. The main objective is to study the involvement of epoxy-eicosatrienoic acids (EETs) in the reactivity of cutaneous microcirculation during post-occlusive hyperemia and thermal hyperemia, by studying the response to microdialysis of fluconazole (an inhibitor of EETs) versus control, on the forearm. Response is measured by the amplitude of the post-occlusive hyperemia and thermal hyperemia peaks (maximum amplitude as a percentage of maximal vasodilation and areas under the curve: AUC) during the injection of fluconazole compared to an intradermal injection of solvent (NaCl 9 ‰). The subjects are healthy volunteers of both sexes, aged between 18 and 35, non-smokers and in good health. Over two years, 30 subjects will be included in the study for 6 to 13 weeks.

Official Title
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Role of Epoxy-eicosatrienoic Acids in Post-occlusive Hyperemia and Thermal Hyperemia

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Microdialysis of fluconazole, vehicle and N(G)-nitro-L-arginine-methyl ester (L-NMMA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 35 years Affiliated to the French social security system or beneficiary a similar regime In good health Exclusion Criteria: Active smoker Pregnant, parturient, breast-feeding Person deprived of civil liberties by judicial or administrative measure; person under legal protection, Minor less than 18 years Within period exclusion for other clinical research studies Person has exceeded the annual compensation for participation in trials Person with active disease or with prolonged treatment, excluding oral contraceptives and paracetamol Asthma, urticaria, angioedema, known drug allergy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 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

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vehicle without ANESDERM (lidocaine, prilocaine)<br> | Drug: Microdialysis of fluconazole, vehicle and N(G)-nitro-L-arginine-methyl ester (L-NMMA)<br>* At the first three visits, volunteers will receive fluconazole (650µmol/L and 6.5mmol/L) and vehicle (NaCl 0.9%), and at the fourth, these plus L-NMMA (10mmol/L), delivered by microdialysis in the forearm, with or without anesthesia. Then post-occlusive hyperemia and thermal hyperemia are performed.<br>|
| Active Comparator: Vehicle with ANESDERM (lidocaine, prilocaine)<br> | Drug: Microdialysis of fluconazole, vehicle and N(G)-nitro-L-arginine-methyl ester (L-NMMA)<br>* At the first three visits, volunteers will receive fluconazole (650µmol/L and 6.5mmol/L) and vehicle (NaCl 0.9%), and at the fourth, these plus L-NMMA (10mmol/L), delivered by microdialysis in the forearm, with or without anesthesia. Then post-occlusive hyperemia and thermal hyperemia are performed.<br>|
| Active Comparator: Fluconazole without ANESDERM (lidocaine, prilocaine)<br> | Drug: Microdialysis of fluconazole, vehicle and N(G)-nitro-L-arginine-methyl ester (L-NMMA)<br>* At the first three visits, volunteers will receive fluconazole (650µmol/L and 6.5mmol/L) and vehicle (NaCl 0.9%), and at the fourth, these plus L-NMMA (10mmol/L), delivered by microdialysis in the forearm, with or without anesthesia. Then post-occlusive hyperemia and thermal hyperemia are performed.<br>|
| Active Comparator: Fluconazole with ANESDERM (lidocaine, prilocaine)<br> | Drug: Microdialysis of fluconazole, vehicle and N(G)-nitro-L-arginine-methyl ester (L-NMMA)<br>* At the first three visits, volunteers will receive fluconazole (650µmol/L and 6.5mmol/L) and vehicle (NaCl 0.9%), and at the fourth, these plus L-NMMA (10mmol/L), delivered by microdialysis in the forearm, with or without anesthesia. Then post-occlusive hyperemia and thermal hyperemia are performed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amplitude of the post-occlusive hyperemia and thermal hyperemia following the injection by intradermal microdialysis of fluconazole compared with injection of vehicle (NaCl 9 ‰) | maximum amplitude as a percentage of maximal vasodilation and area under the curve: AUC | 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amplitude of the post-occlusive hyperemia and thermal hyperemia following the injection by intradermal microdialysis of fluconazole, at 2 concentrations, or vehicle (NaCl 9 ‰) | maximum amplitude expressed as percentage of maximal vasodilation and AUC | 2 hours | 
| Amplitude of the post-occlusive hyperemia and thermal hyperemia following the injection by intradermal microdialysis of fluconazole or vehicle (NaCl 9 ‰), with and without ANESDERM ® (lidocaine, prilocaine) | maximum amplitude expressed as percentage of maximal vasodilation and AUC | 2 hours | 
| Amplitude of the post-occlusive hyperemia and thermal hyperemia following the injection by intradermal microdialysis of fluconazole or vehicle (NaCl 9 ‰), with and without N(G)-nitro-L-arginine-methyl ester (L-NMMA) | maximum amplitude expressed as percentage of maximal vasodilation and AUC | 2 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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epoxy-eicosatrienoic acid, Laser Doppler, Endothelium derived hyperpolarizing factor, cutaneous microcirculation, post-occlusive hyperaemia, thermal hyperemia, intradermal microdialysis, fluconazole