Compound 21 for Preeclampsia

Recruiting in Palo Alto (17 mi)

Overseen by Anna Reid-Stanhewicz, PhD

Age: 18 - 65

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: Anna Stanhewicz, PhD

Must not be taking: Antihypertensives, Statins

Disqualifiers: Hypertension, Metabolic disease, Gestational diabetes, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

Women who develop preeclampsia during pregnancy are more likely to develop and die of cardiovascular disease later in life, even if they are otherwise healthy. The reason why this occurs is unclear but may be related to impaired endothelial function and dysregulation of the angiotensin system that occurs during the preeclamptic pregnancy and persists postpartum, despite the remission of clinical symptoms. The purpose of this investigation is to determine the mechanisms contributing to this lasting blood vessel damage caused by reduced endothelial function in women who have had preeclampsia compared to women who had a healthy pregnancy. Identification of these mechanisms and treatment strategies may lead to better clinical management of cardiovascular disease risk in these women. The purpose of this study is to examine the microvascular differences in women who have had preeclampsia following activation of protective angiotensin receptors in the skin. This will help increase understanding of the mechanisms of angiotensin II receptors in these women, and how activation of these receptors may restore microvascular function. In this study, the investigators use the blood vessels in the skin as a representative vascular bed for examining mechanisms of microvascular dysfunction in humans. Using a minimally invasive technique (intradermal microdialysis for the local delivery of pharmaceutical agents) the investigators examine the blood vessels in a dime-sized area of the skin.

Will I have to stop taking my current medications?

If you are currently taking antihypertensive or cholesterol-lowering medications, you cannot participate in this trial. The protocol does not specify about other medications, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Compound 21 for treating preeclampsia?

Research suggests that targeting the angiotensin receptors, like those affected by Compound 21, may have potential in treating preeclampsia. The angiotensin system is involved in blood pressure regulation, and variations in angiotensin receptor genes have been linked to preeclampsia, indicating that drugs affecting these receptors could be beneficial. ^{1 2 3 4 5}

Is Compound 21 generally safe for humans?

Compound 21, also known as an Angiotensin II Type 2 Receptor Agonist, has been studied for its ability to lower blood pressure, but specific safety data for humans is not detailed in the available research. ^{1 2 4 6 7}

How does Compound 21 differ from other drugs for preeclampsia?

Compound 21 is unique because it targets GPCRs (G protein-coupled receptors), which are promising candidates for treating preeclampsia, unlike other treatments that focus on different pathways. This approach could offer a new way to manage the condition by addressing specific receptor targets involved in the disease. ^{1 2 4 5 8}

Research Team

Anna Reid-Stanhewicz, PhD

Principal Investigator

University of Iowa

Eligibility Criteria

This trial is for women aged 18-45 who experienced preeclampsia between 12 weeks and 5 years ago. It's also open to those who had healthy pregnancies. Participants should not be currently pregnant, planning pregnancy, have a history of hypertension or metabolic disease before pregnancy, use tobacco, or take certain medications like antihypertensives or statins.

Inclusion Criteria

Women who had preeclampsia and women who did not have preeclampsia

I gave birth between 12 weeks and 5 years ago.

I am between 18 and 45 years old.

Exclusion Criteria

Known allergy to study drugs

Body mass index less than 18.5 kg/m2

I have a skin condition.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo intradermal microdialysis for the local delivery of compound 21 and L-NAME to the cutaneous microvasculature

1 hour

1 visit (in-person)

Follow-up

Participants are monitored for changes in microvascular blood flow response and angiotensin receptor expression

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Compound 21 (Angiotensin II Receptor Agonist)

Trial Overview The study tests Compound 21 on the microvascular function in the skin of women post-preeclampsia. Researchers are investigating if activating angiotensin II receptors can repair blood vessel damage caused by preeclampsia and reduce future cardiovascular disease risk.

Participant Groups

Group I: assessment of microvascular function Experimental Treatment 1 Intervention

The investigators use intradermal microdialysis to deliver compound 21 and L-NAME to the cutaneous microvasculature

Who Is Running the Clinical Trial?

Anna Stanhewicz, PhD

Lead Sponsor

Trials

12

Recruited

460+

Findings from Research

Preeclampsia affects about 5% of women after the 20th week of pregnancy and currently has no specific therapy or cure, highlighting the need for new treatment options.

The review identifies several promising G protein-coupled receptor (GPCR) targets, such as the calcitonin receptor-like receptor and angiotensin receptors, which could lead to new therapeutic strategies for managing preeclampsia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPCRs as potential therapeutic targets in preeclampsia. McGuane, J., Conrad, K.[2021]

A study involving 168 women (84 with early-onset preeclampsia and 84 controls) found that certain genetic variations in the angiotensin II receptor genes (AT1R and AT2R) are associated with a higher risk of developing early-onset preeclampsia, particularly in those with three mutant receptor combinations.

The presence of these genetic variants could help predict susceptibility to early-onset preeclampsia and may guide future research on targeted treatments for hypertensive disorders in pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of maternal angiotensin II type 1 and type 2 receptor combination genotypes with susceptibility to early-onset preeclampsia. Satra, M., Samara, M., Alatsathianos, G., et al.[2022]

The soluble forms of the type-1 receptor for vascular endothelial growth factor (sFlt1) and endoglin (sEng) are promising biomarkers for preeclampsia, as they significantly increase in maternal blood weeks before clinical symptoms appear, potentially aiding in early identification of high-risk women.

Defective placental steroidogenesis and altered angiotensin-2 receptor tolerance are implicated in the pathophysiology of preeclampsia, suggesting these pathways could lead to new biomarkers and therapeutic strategies, although more research is needed in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New markers in preeclampsia. Hertig, A., Liere, P.[2015]

Pravastatin has emerged as a promising candidate for preventing preeclampsia, showing beneficial effects in preclinical studies and early clinical trials, with several large prevention trials currently underway to confirm its efficacy.

Other potential treatments, including proton-pump inhibitors, metformin, and natural compounds, are also being evaluated for their ability to target the underlying mechanisms of preeclampsia, indicating a broad interest in repurposing existing drugs and exploring new therapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia. Tong, S., Kaitu'u-Lino, TJ., Hastie, R., et al.[2022]

Preeclampsia is primarily caused by systemic maternal vascular dysfunction due to oxidative stress and excessive anti-angiogenic factors from a dysfunctional placenta, leading to hypertension and other complications during pregnancy.

Currently, the only definitive treatment for preeclampsia is the delivery of the placenta, often resulting in preterm birth, highlighting the urgent need for new therapies that specifically target the underlying vascular dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the vascular dysfunction: Potential treatments for preeclampsia. Marshall, SA., Cox, AG., Parry, LJ., et al.[2019]

The PI2 Trial is a phase II clinical study involving 150 women with preterm pre-eclampsia, testing the efficacy of extended-release metformin compared to a placebo, with the primary goal of delaying delivery by at least 5 days.

Metformin is already known to be safe during pregnancy and may provide a new therapeutic option to manage preterm pre-eclampsia, potentially improving outcomes for both mothers and their babies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol. Cluver, C., Walker, SP., Mol, BW., et al.[2023]

Activation of AT2 receptors (AT2Rs) by Compound 21 (C-21) in rats significantly increased urinary sodium excretion by 10-fold, demonstrating its efficacy in promoting natriuresis without affecting renal blood flow.

C-21 not only induced natriuresis but also lowered blood pressure in a model of hypertension, suggesting that targeting AT2Rs could be a promising strategy for treating conditions related to fluid retention and high blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AT₂ receptor activation induces natriuresis and lowers blood pressure. Kemp, BA., Howell, NL., Gildea, JJ., et al.[2021]

Preeclampsia affects 3-8% of pregnancies and is a major cause of complications for mothers and babies, highlighting the urgent need for effective treatments.

Therapies that improve endothelial function, such as PDE-5 inhibitors and endothelin type A receptor antagonists, may offer promising options to manage preeclampsia and improve outcomes for both mothers and infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging drugs for preeclampsia--the endothelium as a target. Sasser, JM., Murphy, SR., Granger, JP.[2018]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

GPCRs as potential therapeutic targets in preeclampsia. [2021]

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

Association of maternal angiotensin II type 1 and type 2 receptor combination genotypes with susceptibility to early-onset preeclampsia. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

New markers in preeclampsia. [2015]

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

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia. [2022]

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

Targeting the vascular dysfunction: Potential treatments for preeclampsia. [2019]

6. England pubmed.ncbi.nlm.nih.gov

A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol. [2023]

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

AT₂ receptor activation induces natriuresis and lowers blood pressure. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Emerging drugs for preeclampsia--the endothelium as a target. [2018]