Fluconazole for Vascular Response in Healthy Subjects

Overseen By Jeremy M Kellawan, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Oklahoma

Must not be taking: Amiodarone, Sulphaphenazole, S-warfarin, others

Disqualifiers: Smoking, Hypertension, Cardiometabolic diseases, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Most cardiometabolic diseases are characterized by increased muscle sympathetic nerve activity (MSNA) during rest and exercise which contributes to poor health outcomes. In healthy humans during muscle contraction, there is a blunting of skeletal muscle vascular responsiveness to increases in MSNA. However, the exact mechanisms involved are unknown although, best evidence suggests that the mechanism is endothelium derived, but nitric oxide (NO) and prostaglandin (PG) independent. Endothelium-derived hyperpolarizing factor (EDHF) is a NO and PG independent vasodilator in both cerebral and skeletal muscle circulations, however, it is unknown if EDHF contributes to vascular responsiveness during elevated MSNA. The application of lower body negative pressure (LBNP) is a safe and non-invasive manipulation that can be used to increase MSNA causing vasoconstriction in humans. Therefore, the purpose of this experiment is to determine if acute inhibition of EDHF alters central and peripheral vascular responses to LBNP at rest and during dynamic exercise. Thereby, providing evidence by which EDHF contributes to vascular control in healthy humans and identify it's potential as a therapeutic target for cardiometabolic diseases that are characterized by elevated MSNA

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications, including Amiodarone, Sulphaphenazole, S-warfarin, Tolbutamine, Phenytoin, Lonafarnib, cardiometabolic medications, and sex hormone replacement medications, to participate in this trial.

Is Fluconazole generally safe for humans?

The provided research articles do not contain specific safety data for Fluconazole (also known as Diflucan) in humans. ^{1 2 3 4 5}

How does the drug fluconazole differ from other treatments for vascular response?

Fluconazole is unique in its ability to inhibit cytochrome P450 enzymes, which are involved in the regulation of arterial stiffness and vascular tone through the production of epoxyeicosatrienoic acids, a type of endothelium-derived hyperpolarizing factor. This mechanism is different from other treatments that may focus on nitric oxide pathways or other vascular functions. ^{6 7 8 9 10}

Research Team

Jeremy M Kellawan, PhD

Principal Investigator

University of Oklahoma

Eligibility Criteria

This trial is for healthy individuals with a BMI under 30, no cardiovascular or metabolic diseases, premenopausal women with regular cycles, and normal blood pressure. It excludes pregnant people, those on certain medications like Amiodarone or S-warfarin, hormone replacement therapy users, smokers/tobacco users within the last 6 months, and anyone on cardiometabolic meds.

Inclusion Criteria

Individuals with a BMI under 30 kg/m²

Individuals free of any form of autonomic dysfunction

Normotensive individuals (systolic blood pressure < 130 mmHg and/or diastolic blood pressure < 85 mmHg)

Exclusion Criteria

I am currently taking Amiodarone or Sulphaphenazole.

I am using sex hormone replacement therapy.

Smokers, tobacco users (regular use in the last 6 months)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a placebo or fluconazole to assess the impact of EDHF inhibition on vascular responses during LBNP and exercise

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Fluconazole

Trial Overview The study tests if Fluconazole (150 mg) affects how blood vessels respond to increased nerve activity that causes them to narrow. This response will be observed at rest and during exercise using a technique called lower body negative pressure in healthy participants.

Participant Groups

Group I: fluconazole Experimental Treatment 1 Intervention

fluconazole tablet/pill 150 mg, single acute dose

Group II: Placebo Placebo Group 1 Intervention

250 mg pill microcrystalline Cellulose, single acute dose

Fluconazole is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Diflucan for:

• Candidiasis
• Cryptococcosis
• Histoplasmosis
• Coccidioidomycosis

Approved in United States as Diflucan for:

• Vaginal candidiasis
• Oropharyngeal candidiasis
• Esophageal candidiasis
• Cryptococcal meningitis

Approved in Canada as Diflucan for:

• Vaginal candidiasis
• Oropharyngeal candidiasis
• Esophageal candidiasis
• Cryptococcal meningitis

Approved in Japan as Diflucan for:

• Candidiasis
• Cryptococcosis
• Histoplasmosis
• Coccidioidomycosis

Approved in China as Diflucan for:

• Vaginal candidiasis
• Oropharyngeal candidiasis
• Esophageal candidiasis
• Cryptococcal meningitis

Who Is Running the Clinical Trial?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

Findings from Research

The PM-1 automated perfusion myograph is a new in vitro model that allows researchers to test how drugs affect vascular function, including their impact on blood vessel relaxation and permeability.

In experiments, the myograph demonstrated that Ivermectin enhanced blood vessel relaxation, while L-NAME inhibited it, showcasing the model's ability to predict drug effects on vascular responses and potentially identify adverse reactions early in drug development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel system for the investigation of microvascular dysfunction including vascular permeability and flow-mediated dilatation in pressurised human arteries. Moss, E., Lynagh, S., Smith, D., et al.[2013]

In resistance arteries from cardiovascular disease patients, the effectiveness of the vasodilator bradykinin (BK) is influenced by the type of contractile stimulus, with enhanced relaxation observed in the presence of endothelin-1 (ET-1).

The study found that in ET-1-contracted arteries, the relaxing effect of BK shifts from relying on nitric oxide (NO) to hydrogen peroxide (H2O2), suggesting a potential mechanism for endothelial dysfunction in conditions with elevated ET-1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelin-1 shifts the mediator of bradykinin-induced relaxation from NO to H2 O2 in resistance arteries from patients with cardiovascular disease. Leurgans, TM., Bloksgaard, M., Brewer, JR., et al.[2021]

The study identified that bradykinin induces vasodilation in human and porcine intramyocardial coronary micro-arteries through hyperpolarization of smooth muscle cells, rather than relying on nitric oxide, highlighting a unique mechanism of blood flow regulation.

The presence of longitudinally-arranged smooth muscle cells (l-SMCs) in the coronary artery wall facilitates rapid intercellular signaling, enhancing the coordination of blood flow in the coronary microvasculature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Signaling and structures underpinning conducted vasodilation in human and porcine intramyocardial coronary arteries. Dora, KA., Lin, J., Borysova, L., et al.[2023]

Increased shear stress in the coronary microcirculation promotes the production of nitric oxide (NO), which helps limit vasoconstriction, particularly in small arteries, as shown in a study measuring microvascular diameter and flow velocity during vasoconstriction with endothelin or vasopressin.

The study found that inhibiting NO production with L-NMMA enhanced vasoconstriction, indicating that NO plays a crucial role in moderating constriction in response to shear stress, with small arteries being more responsive to this regulation than larger arterioles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitric oxide limits coronary vasoconstriction by a shear stress-dependent mechanism. Stepp, DW., Merkus, D., Nishikawa, Y., et al.[2020]

Trelagliptin, a DPP-4 inhibitor, induces vasodilation in rabbit aortic rings in a dose-dependent manner, primarily through the activation of Kv7.X potassium channels and the SERCA pump.

The study suggests caution when prescribing trelagliptin to patients with hypotension and diabetes, as its vasodilatory effects could exacerbate low blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anti-diabetic drug trelagliptin induces vasodilation via activation of Kv channels and SERCA pumps. Heo, R., Seo, MS., An, JR., et al.[2021]

In a randomized double-blind, placebo-controlled trial involving 52 obese male smokers, 3 months of treatment with calcium dobesilate showed no significant effects on endothelial function, blood pressure, or markers of oxidation compared to placebo.

The study measured various vascular responses, including vasodilation and capillary recruitment, and found no meaningful differences, indicating that calcium dobesilate does not improve vascular function in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of calcium dobesilate on vascular endothelial function, blood pressure, and markers of oxidation in obese male smokers: a placebo-controlled randomised clinical trial. Schram, MT., Stam, F., de Jongh, RT., et al.[2019]

In a study involving healthy volunteers, it was found that increased blood flow from hand skin heating led to decreased arterial stiffness, indicating that the endothelium plays a crucial role in regulating arterial tone during changes in blood flow.

The regulation of arterial stiffness was shown to involve both nitric oxide (NO) and cytochrome-derived epoxyeicosatrienoic acids, with specific inhibitors demonstrating that these factors work together to modulate arterial compliance and stiffness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arterial stiffness is regulated by nitric oxide and endothelium-derived hyperpolarizing factor during changes in blood flow in humans. Bellien, J., Favre, J., Iacob, M., et al.[2022]

The study demonstrated that both nitric oxide (NO) and calcium-activated potassium (K(Ca)) channels play a crucial role in regulating the diameter of human peripheral conduit arteries, as shown by significant changes in radial artery diameter when these pathways were inhibited.

The combined inhibition of NO synthesis and cytochrome P-450 (CYP) led to a greater reduction in artery diameter than either inhibitor alone, indicating an interaction between NO and a CYP-related endothelium-derived hyperpolarizing factor (EDHF) that helps maintain artery diameter in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence for a basal release of a cytochrome-related endothelium-derived hyperpolarizing factor in the radial artery in humans. Bellien, J., Joannides, R., Iacob, M., et al.[2020]

In a study involving 14 untreated essential hypertensive patients and 14 normotensive controls, it was found that epoxyeicosatrienoic acids (EETs) do not help regulate artery diameter in hypertensive patients as they do in healthy individuals, indicating a potential dysfunction in this compensatory mechanism.

While the inhibition of NO synthase reduced artery diameter in both groups, the combination of inhibiting both EETs and NO synthase did not further decrease artery diameter in hypertensive patients, suggesting that EETs are ineffective in compensating for altered NO availability in these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impaired role of epoxyeicosatrienoic acids in the regulation of basal conduit artery diameter during essential hypertension. Bellien, J., Remy-Jouet, I., Iacob, M., et al.[2022]

Endothelium-derived hyperpolarizing factors, which activate K(+)(Ca) channels, play a significant role in maintaining resting blood flow and vasodilation, especially in individuals with multiple cardiovascular risk factors, as shown in a study involving 174 subjects.

In conditions where nitric oxide availability is reduced, such as hypercholesterolemia, these hyperpolarizing factors help compensate for the loss of vasodilatory function, indicating their importance in vascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease. Ozkor, MA., Murrow, JR., Rahman, AM., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

A novel system for the investigation of microvascular dysfunction including vascular permeability and flow-mediated dilatation in pressurised human arteries. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Endothelin-1 shifts the mediator of bradykinin-induced relaxation from NO to H2 O2 in resistance arteries from patients with cardiovascular disease. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Signaling and structures underpinning conducted vasodilation in human and porcine intramyocardial coronary arteries. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Nitric oxide limits coronary vasoconstriction by a shear stress-dependent mechanism. [2020]

5. Netherlands pubmed.ncbi.nlm.nih.gov

The anti-diabetic drug trelagliptin induces vasodilation via activation of Kv channels and SERCA pumps. [2021]

6. Ireland pubmed.ncbi.nlm.nih.gov

The effect of calcium dobesilate on vascular endothelial function, blood pressure, and markers of oxidation in obese male smokers: a placebo-controlled randomised clinical trial. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Arterial stiffness is regulated by nitric oxide and endothelium-derived hyperpolarizing factor during changes in blood flow in humans. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Evidence for a basal release of a cytochrome-related endothelium-derived hyperpolarizing factor in the radial artery in humans. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Impaired role of epoxyeicosatrienoic acids in the regulation of basal conduit artery diameter during essential hypertension. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease. [2021]