Medications for Cerebral Blood Flow Regulation

(Gas Challenge Trial)

Overseen By Shawn E Bolin, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Wisconsin, Madison

Must not be taking: Cardiovascular, Hormonal birth control

Disqualifiers: Obesity, Diabetes, Hypertension, Smoking, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how men and women regulate blood flow to the brain differently, especially under stress conditions like low oxygen or high carbon dioxide. Researchers believe that sex hormones play a role and will test this with specific medications, including estradiol topical, ganirelix acetate, ketorolac tromethamine, L-NMMA, and testosterone transdermal product, while monitoring brain activity with an MRI. The trial seeks healthy individuals aged 18 to 40 with normal blood pressure, who are not obese, and do not have conditions like diabetes or sleep apnea. Participants should also not be on certain medications or smoke regularly. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a unique opportunity to contribute to groundbreaking scientific discovery.

Will I have to stop taking my current medications?

If you are taking cardiovascular medications or hormonal birth control, you will need to stop, as these are not allowed in the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that indomethacin, one of the treatments being tested, can alter blood flow in the brain. Studies have found that it decreases cerebral blood flow by about 22% to 30%, similar to changes seen with aging. In some cases, it also lowers intracranial pressure.

Regarding safety, indomethacin is usually well-tolerated but can cause side effects like headaches, dizziness, or stomach issues. This drug is already used for other conditions, indicating its safety when used properly.

This trial is in its early stages, so information on the safety of these treatments for this specific use is limited. However, researchers are carefully monitoring the trial to ensure participant safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments being explored for cerebral blood flow regulation because they involve novel uses of hormones and other substances to potentially improve blood flow to the brain. Unlike traditional treatments that may focus on dilating blood vessels, these treatments use drugs like Estradiol and Testosterone transdermal products, which could harness hormonal pathways to influence cerebral circulation. This trial also includes L-NMMA, which inhibits nitric oxide production, offering a new angle on managing blood flow. These approaches could lead to more effective or faster-acting interventions for conditions that affect cerebral blood flow, offering hope for better management of such conditions.

What evidence suggests that this trial's treatments could be effective for cerebral blood flow regulation?

Research has shown that transdermal estradiol, one of the treatments in this trial, might improve blood flow and energy use in the brain, potentially benefiting brain health. Ganirelix acetate, another treatment option, helps control hormone levels and may influence blood flow regulation in the brain. Ketorolac, also under study, can increase blood flow in the skin by blocking an enzyme that typically narrows blood vessels. L-NMMA, which inhibits nitric oxide, is part of this trial and does not affect brain blood flow during stress in healthy individuals, suggesting other factors might be involved. Testosterone patches, another treatment in this trial, support brain health by protecting and encouraging nerve growth. Each of these treatments works differently, potentially aiding the brain in managing blood flow. ^{6 7 8 9 10}

Who Is on the Research Team?

William Schrage, PhD

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

Healthy adults aged 18-40 with normal blood pressure, body mass index (BMI) between 19-25, regular menstrual cycles for women, and good cholesterol levels. Excluded are those with a history of stroke, diabetes, kidney or blood diseases, obesity, sleep apnea; smokers; users of hormonal birth control or cardiovascular meds; pregnant women; and anyone unable to undergo MRI.

Inclusion Criteria

I have a regular menstrual cycle without any interventions.

Your blood pressure is lower than 125/80 mm Hg (millimeters of mercury).

Your blood sugar level should be normal (less than 100 mg/dL).

Exclusion Criteria

I have had a stroke in the past.

You smoke cigarettes regularly.

Your current blood pressure is higher than 130/85 mmHg.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1

Participants undergo MRI and pharmacologic testing to study CBF control mechanisms under hypoxia and hypercapnia conditions.

Up to 14 days

Multiple visits (in-person)

Phase 2

Participants repeat Phase 1 procedures with sex hormone suppression and single hormone replacement to study the impact on CBF control.

Up to 14 days

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Estradiol Topical
• Ganirelix Acetate
• Ketorolac Tromethamine
• L-NMMA
• Testosterone Transdermal Product

Trial Overview The study is examining how men and women regulate brain blood flow at rest and under stress from low oxygen or high carbon dioxide. It involves infusions of Ganirelix Acetate, L-NMMA, Ketorolac Tromethamine along with Estradiol Topical for women and Testosterone Transdermal Product for men while using advanced MRI to measure changes in cerebral blood flow.

How Is the Trial Designed?

Group I: Male NOS Experimental Treatment 4 Interventions

Males visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Group II: Male COX Experimental Treatment 4 Interventions

Males visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Group III: Female NOS Experimental Treatment 4 Interventions

Females visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Group IV: Female COX Experimental Treatment 4 Interventions

Females visit MRI twice. Once for indomethacin visit (hypoxia + hypercapnia), and once for placebo visit (hypoxia + hypercapnia). These 2 MRI visits are conducted in a double-blind placebo controlled design. CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Raloxifene, a selective estrogen receptor modulator (SERM), effectively relaxes rat cerebral arteries by inhibiting calcium influx through L-type calcium channels, indicating a potential therapeutic role in cerebrovascular health.

The relaxation effect of raloxifene occurs independently of the endothelium, suggesting that it may provide cardiovascular benefits without the carcinogenic risks associated with traditional estrogen therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Raloxifene relaxes rat cerebral arteries in vitro and inhibits L-type voltage-sensitive Ca2+ channels. Tsang, SY., Yao, X., Essin, K., et al.[2016]

In a long-term study involving 1694 men with prostate cancer, transdermal oestradiol (tE2) patches showed no significant difference in cardiovascular morbidity or mortality compared to luteinising hormone releasing hormone agonists (LHRHa), suggesting tE2 is a safe alternative for androgen suppression.

The study also found that tE2 patches resulted in fewer adverse effects like gynaecomastia and hot flushes compared to LHRHa, indicating a potentially better tolerability profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. Langley, RE., Gilbert, DC., Duong, T., et al.[2023]

In a study involving a once-weekly transdermal estradiol patch applied to either the buttocks or abdomen, the buttock application resulted in significantly higher estradiol levels, with a 125.1% peak concentration compared to the abdomen.

The buttocks provided better bioavailability of estradiol, which may benefit women experiencing menopausal symptoms, as it maintained higher hormone levels throughout the week.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of site of application on the transcutaneous absorption of 17-beta estradiol from a transdermal delivery system (Climara). Taggart, W., Dandekar, K., Ellman, H., et al.[2019]

In female rats, the combination of vitamin D deficiency and testosterone treatment led to significant changes in the anterior cerebral arteries, including decreased lumen size and increased wall thickness, indicating potential risks for cerebrovascular health.

In male rats, vitamin D deficiency alone caused similar adverse effects on the cerebral arteries, suggesting that both hyperandrogenism and vitamin D deficiency can negatively impact vascular health and increase stroke risk, with gender differences in how these factors interact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gender, hyperandrogenism and vitamin D deficiency related functional and morphological alterations of rat cerebral arteries. Pál, É., Hadjadj, L., Fontányi, Z., et al.[2020]

In a study involving 24 healthy women, the contraceptive patch delivered steady-state levels of norelgestromin (NGMN) and ethinyl estradiol (EE) consistently over three cycles, indicating effective and reliable hormone delivery.

The treatment was well tolerated with excellent patch adhesion, and there was minimal accumulation of the hormones over time, suggesting a safe profile for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Abrams, LS., Skee, DM., Natarajan, J., et al.[2019]

In a study involving 18 healthy postmenopausal women, intranasal administration of 17beta-estradiol significantly increased cerebral blood flow (CBF) volume compared to a placebo.

The increase in CBF volume was attributed to the vasodilatatory effects of 17beta-estradiol on the internal carotid and vertebral arteries, although no changes were observed in flow velocities or pulsatility indices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Aerodiol administration on cerebral blood flow volume in postmenopausal women. Acar, M., Cevrioglu, AS., Haktanir, A., et al.[2016]

Intracarotid infusion of estrogen did not increase cerebral blood flow (CBF) in rabbits, indicating that systemic estrogen may not enhance blood flow under steady-state conditions.

Topical application of estradiol on pial arterioles did cause vasodilation, but only at specific concentrations, and this effect was blocked by the antiestrogen tamoxifen, highlighting the role of estrogen receptors in this process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of estrogen on cerebral blood flow and pial microvasculature in rabbits. Littleton-Kearney, MT., Agnew, DM., Traystman, RJ., et al.[2020]

In a study involving 23 postmenopausal women, 17 beta-oestradiol was found to significantly induce vasodilation in femoral arteries, increasing their diameter by an average of 6.4% and blood flow by 30%, indicating its efficacy in improving vascular function.

The study suggests that the vasodilatory effects of 17 beta-oestradiol may play a role in reducing the risk of cardiovascular diseases in postmenopausal women, highlighting its potential therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular responses to 17 beta-oestradiol in postmenopausal women. Riedel, M., Oeltermann, A., Mügge, A., et al.[2019]

The transdermal therapeutic system of estrogen (Estraderm) is effective in relieving hot flushes and vaginal atrophy, showing similar efficacy to oral estrogen treatments while maintaining bone health.

The patch is well tolerated with minimal side effects, such as low incidence of endometrial hyperplasia and breast tenderness, and patients generally prefer this method over oral administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with transdermal estradiol in the treatment of the climacteric. Utian, WH.[2013]

Menorest is a new transdermal patch that delivers 17 beta-estradiol in a microfine suspension, making it thinner and more cosmetically appealing than older patches.

It effectively maintains plasma estradiol levels at or above the target of 40 pg/ml for the entire 80-hour dosing period, demonstrating consistent and reliable hormone delivery across various doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New trends in transdermal technologies: development of the skin patch, Menorest. Marty, JP.[2016]

In a study of 93 transgender women and gender nonbinary adults, sublingual 17β-estradiol tablets resulted in significantly higher estrone concentrations compared to transdermal or injectable forms, indicating differences in hormone absorption and metabolism based on the delivery method.

Estradiol levels above 200 pg/mL were linked to higher estrone levels in those using sublingual tablets, but this association was not observed with transdermal or injectable forms, suggesting that the method of administration may influence hormone interactions and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sublingual Estradiol Is Associated with Higher Estrone Concentrations than Transdermal or Injectable Preparations in Transgender Women and Gender Nonbinary Adults. Cirrincione, LR., Winston McPherson, G., Rongitsch, J., et al.[2021]

Transdermal testosterone patches are being developed for women, particularly for treating sexual dysfunction in menopausal women, and are currently in phase III clinical trials.

Preliminary phase II studies indicate that the testosterone matrix patch is effective and safe for women with sexual dysfunction, showing promise as a new method for androgen therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal testosterone for women: a new physiological approach for androgen therapy. Mazer, NA., Shifren, JL.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3227781/

Vascular Effects of Estrogenic Menopausal Hormone Therapy After approximately 4.1 years of follow-up, HERS found no difference in secondary CVD outcome (nonfatal MI and CVD death), even though MHT reduced LDL-c and ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0303720714000197

Estrogen and cerebrovascular regulation in menopause Studies report diminished neuroprotection with declining E2 levels, corresponding with higher incidence of cerebrovascular and neurological disease.

3. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2000/20323S23lbl.pdf

Vivelle® - accessdata.fda.gov Vivelle contains estradiol. When applied to the skin as directed below, the Vivelle system releases estradiol, which flows through the skin into the bloodstream ...

4. rupahealth.com rupahealth.com/post/estradiol-patches-timeline-for-effectiveness-and-what-to-expect

Estradiol Patches: Timeline for Effectiveness and What to ... A study conducted over 12 months found vasomotor symptoms of menopause (hot flashes, night sweats, heart palpitations, changes in blood pressure) improved by 73 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3302351/

Short-term Hormone Therapy with Transdermal Estradiol ... Findings from clinical studies suggest that, in addition to improving cognition, HT enhances cerebral blood flow and glucose utilization [64–67]. The results ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/10439431/

Indomethacin: a review of its cerebral blood flow effects ... Case series involving severe TBI patients suggest that IND i.v. boluses of 30-50 mg reduce ICP by 37%-52%, reduce CBF by 22%-26%, with a modest 14% increase in ...

7. physoc.onlinelibrary.wiley.com physoc.onlinelibrary.wiley.com/doi/10.1113/JP280118

Indomethacin markedly blunts cerebral perfusion and ... Indomethacin reduces cerebral perfusion to a similar extent as occurs with healthy ageing (i.e. ∼30%) (Ainslie et al. 2008). Indomethacin ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4358685/

Indomethacin-induced impairment of regional cerebrovascular ... INDO-induced blunting of cerebrovascular flow responsiveness (CVR) to CO 2 was unrelated to variability in ventilatory sensitivity during hyperoxic hypercapnia.

9. nature.com nature.com/articles/s41598-020-72461-1

Neuroprotective effect of indomethacin in normal perfusion ... The administration of indomethacin was associated with raised MAP and CPP, as well as decreased ICP. Sodium fluorescein extravasation was slight ...

10. clinicaltrials.gov clinicaltrials.gov/study/NCT04265053

NCT04265053 | Human Cerebral Blood Flow Regulation CBF measured via MRI sequences, and hemodynamics monitored for safety/research. Intervention/Treatment, Drug : Indomethacin 25 MG/50 MG. Indomethacin ...