A pilot dose-finding study of Terazosin in humans

Jordan L Schultz; Phillip E Gander; Craig D Workman; Laura L Ponto; Stephen Cross; Christopher S Nance; Christopher L Groth; Eric B Taylor; Sarah E Ernst; Jia Xu; Ergun Y Uc; Vincent A Magnotta; Michael J Welsh; Nandakumar S Narayanan

doi:10.1101/2024.05.22.24307622

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A pilot dose-finding study of Terazosin in humans

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A pilot dose-finding study of Terazosin in humans

Jordan L Schultz, Phillip E Gander, Craig D Workman, Laura L Ponto, Stephen Cross, Christopher S Nance, Christopher L Groth, Eric B Taylor, Sarah E Ernst, Jia Xu, …

medRxiv : the preprint server for health sciences

Cold Spring Harbor Laboratory

05/22/2024

DOI: 10.1101/2024.05.22.24307622

PMCID: PMC11142298

PMID: 38826433

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https://doi.org/10.1101/2024.05.22.24307622View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Parkinson's disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects. Eighteen healthy men and women (60 - 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, Phosphorous magnetic resonance spectroscopy for brain ATP levels, F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics. Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response. TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ's efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.

Details

Title: Subtitle: A pilot dose-finding study of Terazosin in humans
Creators: Jordan L Schultz
Phillip E Gander
Craig D Workman
Laura L Ponto
Stephen Cross
Christopher S Nance
Christopher L Groth
Eric B Taylor
Sarah E Ernst
Jia Xu
Ergun Y Uc
Vincent A Magnotta
Michael J Welsh
Nandakumar S Narayanan
Resource Type: Preprint
Publication Details: medRxiv : the preprint server for health sciences
DOI: 10.1101/2024.05.22.24307622
PMID: 38826433
PMCID: PMC11142298
Publisher: Cold Spring Harbor Laboratory; United States
Language: English
Date posted: 05/22/2024
Academic Unit: Neurology; Psychiatry; Pharmacy Practice and Science; Otolaryngology; Roy J. Carver Department of Biomedical Engineering; Radiology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neurosurgery; Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9984632118702771

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