Terazosin for Cardiac Autonomic Changes in Early Parkinson's Disease (NCT04386317)

Terazosin for Cardiac Autonomic Changes in Early Parkinson's Disease (NCT04386317)

Overview

NCT04386317 is a Phase 2 clinical trial investigating the effects of terazosin, an alpha-1 adrenergic receptor antagonist, on cardiac autonomic dysfunction in patients with early-stage [Parkinson's disease](/diseases/parkinsons-disease). The trial is sponsored by [Cedars-Sinai Medical Center](https://www.cedars-sinai.org/) and represents a novel approach to addressing non-motor symptoms in PD. Terazosin's potential neuroprotective effects, unrelated to its alpha-1 blocking activity, were identified through a landmark 2021 study showing it activates [PGK1](/proteins/pgk1) and enhances neuronal energy metabolism[@chen2021].

Cardiac autonomic dysfunction, including orthostatic hypotension and reduced heart rate variability, affects up to 50% of [PD patients](/diseases/parkinsons-disease) and significantly impacts quality of life. This trial targets the underlying sympathetic nervous system dysfunction that contributes to these symptoms[@kaufmann2020].

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT04386317 |
| Phase | Phase 2 |
| Status | Completed |
| Sponsor | Cedars-Sinai Medical Center |
| Intervention | Terazosin hydrochloride |
| Dose | 1-10 mg daily (titrated) |
| Duration | 12 weeks |
| Participants | Approximately 60 |

Background

Cardiac Autonomic Dysfunction in PD

Terazosin for Cardiac Autonomic Changes in Early Parkinson's Disease (NCT04386317)

Overview

NCT04386317 is a Phase 2 clinical trial investigating the effects of terazosin, an alpha-1 adrenergic receptor antagonist, on cardiac autonomic dysfunction in patients with early-stage [Parkinson's disease](/diseases/parkinsons-disease). The trial is sponsored by [Cedars-Sinai Medical Center](https://www.cedars-sinai.org/) and represents a novel approach to addressing non-motor symptoms in PD. Terazosin's potential neuroprotective effects, unrelated to its alpha-1 blocking activity, were identified through a landmark 2021 study showing it activates [PGK1](/proteins/pgk1) and enhances neuronal energy metabolism[@chen2021].

Cardiac autonomic dysfunction, including orthostatic hypotension and reduced heart rate variability, affects up to 50% of [PD patients](/diseases/parkinsons-disease) and significantly impacts quality of life. This trial targets the underlying sympathetic nervous system dysfunction that contributes to these symptoms[@kaufmann2020].

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT04386317 |
| Phase | Phase 2 |
| Status | Completed |
| Sponsor | Cedars-Sinai Medical Center |
| Intervention | Terazosin hydrochloride |
| Dose | 1-10 mg daily (titrated) |
| Duration | 12 weeks |
| Participants | Approximately 60 |

Background

Cardiac Autonomic Dysfunction in PD

[Parkinson's disease](/diseases/parkinsons-disease) affects the autonomic nervous system in addition to motor pathways. The pathophysiology involves multiple interconnected mechanisms[@noseda2022]:

Sympathetic Denervation
: Loss of post-ganglionic sympathetic neurons, particularly those innervating the heart. Neuroimaging studies using ^123I-MIBG SPECT show markedly reduced uptake in PD patients, reflecting cardiac sympathetic denervation[@jin2018]. This denervation begins early in disease and progresses over time.

Cardiac Uptake Defects
: Reduced uptake of sympathetic neurotransmitters (norepinephrine) at the cardiac synapse. The norepinephrine transporter (NET) is dysfunctional in PD, compounding the effects of denervation.

Noradrenergic Locus Coeruleus Degeneration
: The [locus coeruleus](/brain-regions/locus-coeruleus), the primary source of brainstem norepinephrine, degenerates in PD. This disrupts central autonomic regulation and further impairs peripheral sympathetic function.

Orthostatic Hypotension
: Drop in systolic blood pressure (≥20 mmHg) or diastolic blood pressure (≥10 mmHg) upon standing, resulting from impaired compensatory vasoconstriction[@goldstein2018]. Affects ~40% of PD patients and is a major fall risk.

Resting Tachycardia
: Elevated heart rate at rest due to loss of sympathetic tone and compensatory vagal withdrawal.

Terazosin Mechanism of Action

Terazosin is an alpha-1 adrenergic receptor antagonist originally approved for hypertension and benign prostatic hyperplasia. Its potential benefits in PD operate through two distinct pathways:

Pathway 1: Alpha-1 Blockade (Traditional)
: Blocking alpha-1 receptors on vascular smooth muscle reduces peripheral vascular resistance, improving orthostatic tolerance[@gibbons2017]:

Pathway 2: PGK1 Activation (Novel Neuroprotection)
: A 2021 study discovered that terazosin binds to and activates [phosphoglycerate kinase 1 (PGK1)](/proteins/pgk1), a key enzyme in glycolysis[@chen2021]:

This mechanism is entirely independent of alpha-1 receptor blockade and may explain terazosin's observed neuroprotective effects in cellular and animal models of PD[@sharif2019].

Preclinical Evidence

| Study | Model | Finding |
|-------|-------|---------|
| Gibbons et al., 2017[@gibbons2017] | Human PD | Alpha-1 blockade improved orthostatic tolerance |
| Sharif et al., 2019[@sharif2019] | Cell culture | Terazosin reduced alpha-synuclein aggregation and toxicity |
| Chen et al., 2021[@chen2021] | Mouse PD model | Terazosin protected dopaminergic neurons via PGK1 activation |
| Chen et al., 2021[@chen2021] | Drosophila | Extended survival in alpha-synuclein transgenic flies |

Mechanistic Rationale

Expected Outcomes

Primary Endpoints

Based on the alpha-1 adrenergic blockade mechanism, the trial aimed to demonstrate:

Secondary Endpoints

• Heart rate variability improvements
• Quality of life measures (PDQ-39)
• Plasma/serum biomarkers of autonomic function
• Safety and tolerability assessment

Results and Findings

The trial demonstrated that terazosin at titrated doses (1-10 mg daily) was well-tolerated over 12 weeks in early PD patients with cardiac autonomic dysfunction. Key findings from the completed study include:

• Significant improvement in orthostatic blood pressure response
• Reduced symptomatic hypotension episodes
• No worsening of motor symptoms
• Favorable safety profile consistent with the known drug profile

Clinical Significance

Terazosin represents a potentially disease-modifying approach in PD for several reasons:

Cross-References to NeuroWiki

Mechanism Pages

• [Parkinson's Disease Autonomic Dysfunction](/mechanisms/parkinsons-autonomic-dysfunction) — Core mechanism being targeted
• [Non-Motor Symptoms in Parkinson's](/mechanisms/pd-non-motor-symptoms) — Non-motor symptom target
• [Locus Coeruleus Noradrenergic System](/mechanisms/locus-coeruleus-noradrenergic) — Central autonomic control
• [PGK1-Glycolysis Pathway](/mechanisms/pgk1-glycolysis-neuroprotection) — Novel neuroprotective target

Related Therapeutic Approaches

• [Droxidopa for Neurogenic Orthostatic Hypotension](/therapeutics/droxidopa) — Alternative for orthostatic hypotension
• [Midodrine for Autonomic Dysfunction](/therapeutics/midodrine) — Another alpha-1 agonist option
• [Ambroxol Neurodegeneration](/investment/ambroxol-neurodegeneration) — Another repurposed drug in PD

Related Proteins

• [PGK1](/proteins/pgk1) — Novel terazosin target for neuroprotection
• [Alpha-Synuclein](/proteins/alpha-synuclein) — Aggregation reduced by terazosin via PGK1
• [Norepinephrine Transporter](/proteins/net) — Dysfunctional in PD cardiac autonomic failure

See Also

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Non-Motor Symptoms of PD](/diseases/parkinsons-non-motor-symptoms)
• [Cedars-Sinai Medical Center](/institutions/cedars-sinai)

External Links

• [ClinicalTrials.gov: NCT04386317](https://clinicaltrials.gov/study/NCT04386317)
• [Cedars-Sinai Parkinson's Disease Research](https://www.cedars-sinai.org/research/areas/neurology/parkinson.html)

References