Vascular Function in Pulmonary Arterial Hypertension

Overseen By Maydeen Ogara

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Russell Richardson

Disqualifiers: Severe COPD, Myocardial infarction, Renal disease, others

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

Compensation: Varies

Number of Visits: 2

Duration: 6-8 weeks

420 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how blood flow and muscle health can improve in people with certain conditions and as they age. It tests various treatments, including Acetylcholine, to assess their effects on blood flow during activities like exercise. Participants include those with mild to moderate COPD, pulmonary arterial hypertension, heart failure, or high blood pressure, as well as healthy volunteers. Individuals dealing with any of these conditions and interested in exploring new treatment options may find this trial suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that many treatments in this study have undergone safety testing in humans. For example, Vitamin C and Vitamin E are widely used and recognized as safe. As antioxidants, they help protect the body from damage. Studies indicate they can benefit heart health and other conditions.

Fexofenadine, found in allergy medications, has a strong safety record. It usually doesn't cause drowsiness because it doesn’t significantly affect the brain. Reports show that most people tolerate it well.

Valsartan is often used to treat high blood pressure. Long-term studies have not identified any new major side effects, making it a relatively safe choice.

MitoQ is an antioxidant that targets mitochondria, the energy centers of cells. Early studies suggest it supports heart and blood vessel health. While promising, more research is needed to fully understand its safety.

Phentolamine is used to manage high blood pressure in specific situations, and its safety is well-documented. It's considered effective for short-term use.

For treatments like Acetylcholine, Angiotensin-II, and others that may lack extensive safety data, it's important to note that this study is in its early phase. These early studies focus carefully on monitoring safety. While some risks may exist, the early phase ensures treatments are tested cautiously to protect participant safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pulmonary arterial hypertension because they explore a diverse range of mechanisms and potential benefits that are not fully addressed by current options. Unlike standard treatments that primarily focus on dilating blood vessels, this trial investigates the effect of antioxidants like MitoQ and α-Lipoic Acid, which may reduce oxidative stress and improve vascular function. Additionally, the combination of agents like BQ-123 and L-NMMA targets specific pathways involved in blood vessel constriction and relaxation, offering a more comprehensive approach. This multi-faceted exploration could lead to more effective management of blood flow and tissue metabolism, potentially improving outcomes for patients with this challenging condition.

What evidence suggests that this trial's treatments could be effective for pulmonary arterial hypertension?

Research has shown that several treatments studied in this trial may improve blood flow and reduce symptoms for people with pulmonary arterial hypertension (PAH). Participants may receive L-NMMA, which safely enhances heart function by affecting nitric oxide, helping to relax blood vessels. Vitamin C might lower high blood pressure in the lungs, as seen in some animal studies and patient cases. Vitamin E, known for its antioxidant benefits, is linked to heart health and may reduce risks related to PAH. BQ-123, a medicine that blocks certain receptors, has effectively lowered lung blood pressure and improved heart function. Lastly, MitoQ, an antioxidant targeting cell structures, has shown potential in reducing damage from oxidative stress, though more research is needed to confirm its benefits for PAH. These treatments are being explored for their potential to improve health by addressing different factors involved in blood flow and pressure. ^{6 7 8 9 10}

Who Is on the Research Team?

Russell Richardson, Ph.D.

Principal Investigator

George E Wahlen VA Medical Center

Are You a Good Fit for This Trial?

This trial is for healthy young adults (18-30), older adults (65+), and patients with mild to moderate COPD, Group 1 pulmonary arterial hypertension, or Class I-III heart failure. Excluded are those with severe diseases like unstable angina, significant renal disease, severe COPD requiring oxygen, recent heart attacks or surgeries, pregnant women, and anyone at risk from MRI.

Inclusion Criteria

I have been diagnosed with mild to moderate COPD.

I have Group 1 pulmonary arterial hypertension that is idiopathic or heritable.

I am over 65 and healthy with no conditions affecting study participation.

Exclusion Criteria

I have a history of variant angina.

I have had a heart attack before.

Subject has physical ailments (other than COPD, PAH, HF, or hypertension) that would prevent them from study participation in the judgment of the investigator

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo various pharmacologic interventions and exercise tests to assess vascular function and metabolic demand

6-8 weeks

Weekly visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Open-label extension (optional)

Participants may opt into continuation of treatment long-term to further assess vascular function

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Acetylcholine
• Angiotensin-II
• BH4
• BQ-123
• Fexofenadine
• L-NMMA
• MitoQ
• Norepinephrine
• Phentolamine
• Ranitidine
• Sodium Nitroprusside
• Valsartan
• Vitamin C
• Vitamin E
• α-Lipoic Acid and L-Ascorbate

Trial Overview The study investigates how blood supply meets tissue demand during exercise in aging and diseases like COPD. It tests the effects of various substances on vascular function: BH4, L-NMMA, vitamins C & E; α-Lipoic Acid; Fexofenadine; Ranitidine; Angiotensin-II; Valsartan; BQ-123; MitoQ through maximum exercise tests and drug responses.

How Is the Trial Designed?

Group I: Pulmonary Arterial Hypertension patients Experimental Treatment 7 Interventions

Patients with idiopathic or heritable Group 1 pulmonary arterial hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Group II: Hypertension patients Experimental Treatment 7 Interventions

Patients with chronic high blood pressure, but with less than severe hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Group III: Heart Failure patients Experimental Treatment 7 Interventions

Patients with Class I - III New York Heart Association symptoms of Heart Failure who are not anemic or taking medications that affect blood clotting, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Group IV: Healthy Young Volunteers (18-30 years) Experimental Treatment 7 Interventions

Healthy volunteers between the ages of 18 and 30 years with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Group V: Healthy Older Controls (over 65 years) Experimental Treatment 7 Interventions

Healthy volunteers 65 years of age or older with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Group VI: Coronary Angiography patients Experimental Treatment 7 Interventions

Patients undergoing routine coronary angiography, but who do not require intracoronary procedures or have history of myocardial disease, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Group VII: Chronic Obstructive Pulmonary Disease patients Experimental Treatment 7 Interventions

Patients diagnosed with mild to moderate COPD, but not severe COPD patients, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Who Is Running the Clinical Trial?

Russell Richardson

Lead Sponsor

Trials

1

Recruited

420+

Published Research Related to This Trial

In a study of 43 children with idiopathic pulmonary arterial hypertension (IPAH), the pulmonary flow reserve (PFR) in response to acetylcholine was found to be significantly related to the severity of the disease and clinical outcomes, with a mean PFR of 1.58.

A PFR of less than 1.4 was identified as a strong predictor of serious cardiovascular events, such as lung transplantation or death, highlighting its potential as a valuable prognostic tool in managing IPAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of pulmonary endothelial function during invasive testing in children and adolescents with idiopathic pulmonary arterial hypertension. Apitz, C., Zimmermann, R., Kreuder, J., et al.[2014]

In a study involving 30 participants (15 healthy and 15 hypertensive), it was found that calcium antagonists like nifedipine can improve endothelial function in hypertensive patients by restoring nitric oxide (NO) availability, likely due to their antioxidant properties.

After 3 months of nifedipine treatment, hypertensive patients showed increased vasodilation in response to acetylcholine, indicating improved endothelial function, while vitamin C's role diminished, suggesting that nifedipine's effects are more significant in enhancing NO availability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. Taddei, S., Virdis, A., Ghiadoni, L., et al.[2019]

Nitrovasodilators like sodium nitroprusside and SIN-1 effectively relax the pulmonary artery in sheep, indicating their potential use in managing pulmonary hypertension.

Reducing agents such as ascorbic acid enhance nitric oxide-induced vasodilation, suggesting they could improve vascular function under oxidative stress, while oxidizing agents inhibit this effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of oxidizing and reducing agents on ovine pulmonary artery responses to nitric oxide donors, sodium nitroprusside and 3-morpholino-sydnonimine. Sardar, KK., Sarkar, SN., Bawankule, DU., et al.[2013]

The combination of Bosentan and Sildenafil showed the greatest improvement in exercise capacity (measured by the 6-minute walking distance) for patients with pulmonary artery hypertension, indicating effective short-term treatment options.

Safety profiles for combination therapies were comparable to monotherapy, with no significant increase in adverse events, suggesting that these combinations can be safely used in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of endothelin receptor antagonists combined with phosphodiesterase 5 inhibitor in the treatment of pulmonary arterial hypertension: a network meta-analysis]. Fu, WH., Chen, PL., Xia, JL., et al.[2022]

In a study of 96 participants (47 normotensive and 49 hypertensive), it was found that endothelium-dependent vasodilation, measured by the response to acetylcholine, was significantly lower in hypertensive patients compared to normotensive individuals, indicating a dysfunction in the endothelial system related to hypertension.

Aging was associated with a decline in endothelium-dependent vasodilation in both groups, but the antioxidant vitamin C improved vasodilation in older hypertensive patients, suggesting that oxidative stress plays a role in age-related endothelial dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age-related reduction of NO availability and oxidative stress in humans. Taddei, S., Virdis, A., Ghiadoni, L., et al.[2022]

Selexipag is a newly approved oral medication that acts as an IP receptor agonist, targeting the prostacyclin pathway to treat pulmonary arterial hypertension (PAH) by promoting pulmonary vasodilation and improving right ventricular function.

While selexipag shows promise as a treatment option for PAH, its effectiveness as a first-line therapy is uncertain, and it is likely to be used in combination with other PAH-specific medications rather than as a standalone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of pulmonary arterial hypertension. Richter, MJ., Gall, H., Grimminger, J., et al.[2018]

Small pulmonary arteries (100-300 microns) and large pulmonary arteries (1-2 mm) in rats exhibit different mechanical and pharmacological properties, with maximum contractile function achieved at a lower pressure (30 mmHg) compared to systemic vessels, reflecting the unique low pressure of the pulmonary circulation.

Noradrenaline is a strong vasoconstrictor in large pulmonary arteries but not in small ones, while small arteries show greater sensitivity to bradykinin and other agents, indicating distinct responses based on arterial size that could influence treatment strategies for pulmonary conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the pharmacological and mechanical properties in vitro of large and small pulmonary arteries of the rat. Leach, RM., Twort, CH., Cameron, IR., et al.[2019]

In a study using a sheep model of pulmonary hypertension, Prostaglandin E1 was found to be the most effective pulmonary vasodilator, significantly reducing pulmonary artery pressure from 33 to 23 mmHg.

While all tested drugs (nitroglycerin, sodium nitroprusside, hydralazine, and Prostaglandin E1) lowered pulmonary artery pressure, they exhibited different hemodynamic profiles, indicating that the choice of vasodilator should consider individual patient factors like heart rate and cardiac output.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vasodilator therapy in vasoconstrictor-induced pulmonary hypertension in sheep. Prielipp, RC., Rosenthal, MH., Pearl, RG.[2019]

LA-419, a hybrid organic nitrate, effectively prevents and treats pulmonary arterial hypertension in rats by reducing pulmonary pressure and improving heart and artery health, even when administered after the condition develops.

The treatment not only reduced mortality rates but also demonstrated antioxidant effects similar to vitamin E, suggesting that LA-419's mechanism involves a combination of nitric oxide donation and antioxidant properties, making it a promising candidate for treating severe pulmonary hypertension in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with LA-419 prevents monocrotaline-induced pulmonary hypertension and lung injury in the rat. Mourelle, M., Martin, MT., Giménez, F.[2013]

Recent treatments for pulmonary arterial hypertension (PAH) have shown improvements in exercise capacity, with various new medications tested in over 1,100 patients, but none have demonstrated a significant effect on mortality.

While new therapies like terbogrel, treprostinil, and bosentan have improved walking distance in patients, they come with unpredictable side effects, highlighting the need for personalized treatment approaches based on individual patient profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging medical therapies for pulmonary arterial hypertension. Galiè, N., Manes, A., Branzi, A.[2018]

Recent clinical trials involving over 1,100 patients have shown that new treatments for pulmonary arterial hypertension, such as prostacyclin analogues and endothelin receptor antagonists, can improve exercise capacity as measured by the 6-minute walk test, although none have demonstrated a direct impact on mortality.

While these new therapies offer potential benefits, they also come with unpredictable side effects that require careful management, emphasizing the need for personalized treatment plans based on each patient's specific circumstances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The new clinical trials on pharmacological treatment in pulmonary arterial hypertension. Galiè, N., Manes, A., Branzi, A.[2021]

In a 5-year follow-up study of 11 patients with severe pulmonary arterial hypertension (PAH) who transitioned from intravenous prostacyclin to oral bosentan, most patients experienced prolonged stable functional class and walking distance, indicating a potential quality of life improvement.

Despite the transition, 64% of patients required resumption of prostacyclin therapy due to clinical deterioration, highlighting the need for careful monitoring and management in PAH treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of pulmonary hypertension subjects transitioned from intravenous prostacyclin to oral bosentan. Safdar, Z.[2018]

Acetylcholine (ACh) causes a dose-dependent increase in pulmonary arterial pressure (PAP) in isolated rabbit lungs, indicating that it can have significant effects on pulmonary circulation, unlike its known vasodilatory effects in systemic circulation.

The increase in PAP from ACh can be prevented or reversed by the muscarinic receptor antagonist atropine, suggesting that ACh's effects are mediated through these receptors, while the response is also influenced by prostaglandin synthesis, as indicated by the abolishment of the PAP response when using cyclooxygenase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetylcholine in the pulmonary circulation of rabbits. Catravas, JD., Buccafusco, JJ., El Kashef, H.[2018]

In a study involving stroke-prone spontaneously hypertensive rats, treatment with vitamins C and E significantly prevented the progression of hypertension and improved vascular function over 6 weeks.

Both vitamins reduced oxidative stress by decreasing the activity of NADPH oxidase and increasing superoxide dismutase activity, leading to better blood vessel health and lower blood pressure compared to control rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Chen, X., Touyz, RM., Park, JB., et al.[2022]

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