Compound 21 for Preeclampsia
Recruiting in Palo Alto (17 mi)
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.
12345Is 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.
12467How 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.
12458Eligibility 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.
+7 more
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)
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: assessment of microvascular functionExperimental Treatment1 Intervention
The investigators use intradermal microdialysis to deliver compound 21 and L-NAME to the cutaneous microvasculature
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of IowaIowa City, IA
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Who Is Running the Clinical Trial?
Anna Stanhewicz, PhDLead Sponsor
References
GPCRs as potential therapeutic targets in preeclampsia. [2021]Preeclampsia is an important obstetric complication that arises in 5% of women after the 20(th) week of gestation, for which there is no specific therapy and no cure. Although much of the recent investigation in this field has focused on soluble forms of the angiogenic membrane receptor tyrosine kinase Flt1 and the transforming growth factor β co-receptor Endoglin, there is significant clinical potential for several GPCR targets and their agonists or antagonists in preeclampsia. In this review, we discuss several of the most promising candidates in this category, including calcitonin receptor-like receptor / receptor activity modifying protein 1 complexes, the angiotensin AT1, 2 and Mas receptors, and the relaxin receptor RXFP1. We also address some of the controversies surrounding the roles and therapeutic potential of these GPCRs and their (ant)agonists in preeclampsia.
Association of maternal angiotensin II type 1 and type 2 receptor combination genotypes with susceptibility to early-onset preeclampsia. [2022]Allelic variations affecting the activity of the maternal renin-angiotensin system may play a role in the development of hypertensive disorders of pregnancy like preeclampsia, its more severe early-onset form, and intrauterine growth restriction. We examined the association of common allelic variants of angiotensin II type 1 and type 2 receptor genes (AT1R and AT2R) sorted in five AT1R/AT2R receptor combination genotype groups with susceptibility to early-onset preeclampsia (EOP). The occurrence of AT1R (A1166C) and A2TR (C3123A) alleles in wild type (AA, CC), heterozygous (A/C, C/A), and homozygous (C/C, A/A) states was recorded in 84 women with a history of EOP and 84 age-matched controls sorted in five AT1R/AT2R receptor combination genotype (wild type: AA/CC, one mutant: AA/CA, AC/CC, two mutant: AC/CA, AA/AA, CC/CC, three mutants: AC/AA, CC/CA and four mutant: CC/AA) groups, by polymerase chain reaction-RFLP analysis. Three mutant receptor combination genotype carriers were more common in women with a history of EOP than in controls (26.18% vs. 4.76%, p = 0.003, OR = 8.25). Receptor combination genotyping may be of clinical value in: (a) maternal prediction of susceptibility to EOP, (b) disease subtyping for directed studies with receptor signaling antagonists, (c) the broader study of hypertension.
New markers in preeclampsia. [2015]Preeclampsia (PE) is one of the most common diseases worldwide, complicating ~5% of all pregnancies. Although no major progress has been achieved in the treatment of PE, our ability to identify women at high-risk has increased considerably during the past decade. Thus, the soluble form of the type-1 receptor of vascular endothelial growth factor (sFlt1) and of endoglin (sEng), an endothelial receptor for transforming growth factor beta, have been shown to increase dramatically in the maternal blood of the women affected some weeks before the onset of clinical symptoms. A relative concomitant fall in VEGF and placental growth factor (PlGF) has also been reported. In 2010, they are the most promising biomarkers for PE. The extent to which they are involved in the pathophysiology of the maternal syndrome and of the primary placental disorder responsible for PE is being actively investigated. In parallel, defective placental steroidogenesis, as well as the loss of tolerance towards the angiotensin-2 receptor have also been found to be critically involved in mouse models of PE. Although there is not much data to support their role in human PE, these two biological pathways are a potential future source of both new biomarkers, and new therapeutic strategies. The aim of this review is to compare the likely value of these molecules at the bedside, and to discuss their implication in the pathophysiology of what used to be known as "the disease of theories".
Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia. [2022]There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.
Targeting the vascular dysfunction: Potential treatments for preeclampsia. [2019]Preeclampsia is a pregnancy-specific disorder, primarily characterized by new-onset hypertension in combination with a variety of other maternal or fetal signs. The pathophysiological mechanisms underlying the disease are still not entirely clear. Systemic maternal vascular dysfunction underlies the clinical features of preeclampsia. It is a result of oxidative stress and the actions of excessive anti-angiogenic factors, such as soluble fms-like tyrosine kinase, soluble endoglin, and activin A, released by a dysfunctional placenta. The vascular dysfunction then leads to impaired regulation and secretion of relaxation factors and an increase in sensitivity/production of constrictors. This results in a more constricted vasculature rather than the relaxed vasodilated state associated with normal pregnancy. Currently, the only effective "treatment" for preeclampsia is delivery of the placenta and therefore the baby. Often, this means a preterm delivery to save the life of the mother, with all the attendant risks and burdens associated with fetal prematurity. To lessen this burden, there is a pressing need for more effective treatments that target the maternal vascular dysfunction that underlies the hypertension. This review details the vascular effects of key drugs undergoing clinical assessment as potential treatments for women with preeclampsia.
A double blind, randomised, placebo-controlled trial to evaluate the efficacy of metformin to treat preterm pre-eclampsia (PI2 Trial): study protocol. [2023]Pre-eclampsia is a major complication of pregnancy, globally responsible for 60 000 maternal deaths per year, and far more fetal losses. There is no definitive treatment other than delivery. A therapeutic that could quench the disease process would be useful to treat preterm pre-eclampsia, as it could allow these pregnancies to safely continue to a gestation where fetal outcomes are significantly improved. We have published preclinical data to show that metformin, a drug known to be safe in pregnancy and commonly used to treat gestational diabetes, has potent biological effects making it another promising candidate to treat pre-eclampsia. Here, we describe a phase II clinical trial to examine whether administering extended-release metformin may be effective in treating women with preterm pre-eclampsia (PI2 Trial).
AT₂ receptor activation induces natriuresis and lowers blood pressure. [2021]Compound 21 (C-21) is a highly selective nonpeptide AT2 receptor (AT2R) agonist.
Emerging drugs for preeclampsia--the endothelium as a target. [2018]Preeclampsia, the development of new onset hypertension and proteinuria during pregnancy, affects ∼ 3 - 8% of all pregnancies and is a leading cause of maternal and perinatal morbidity and mortality. Despite the potentially devastating effects of this disease on the mother and the baby and the recent advances in understanding some of the pathological mechanisms responsible for the progression of preeclampsia, there are still few therapies available to manage the disease. The maternal syndrome of preeclampsia is characterized by systemic endothelial dysfunction; therefore, agents that improve endothelial function may hold promise to alleviate the symptoms of preeclampsia, delay the necessity for preterm delivery and improve neonatal outcomes. This brief review will focus on two therapies that are already approved for use in the US for other indications: PDE-5 inhibition to preserve nitric oxide - cGMP signaling to promote vasodilation and inhibition of the endothelin type A receptor to reduce vascular contraction.