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Cited by 44Parkinson's Disease Mechanisms and TreatmentsGastrointestinal motility and disordersNeurological disorders and treatments

Targeting neurons in the gastrointestinal tract to treat Parkinson's disease

Open access
Hauser, Robert A., Sutherland, Dean, Madrid, Juan A., Rol, Maria Angeles, Frucht, Steven, Isaacson, Stuart, Pagan, Fernando, Maddux, Brian N. +19 more·2019·Clinical Parkinsonism & Related Disorders
DOI 10.1016/j.prdoa.2019.06.001PMC PMC8288812
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Abstract

BACKGROUND: Parkinson's disease (PD) is associated with α-synuclein (αS) aggregation within the enteric nervous system (ENS) and constipation. Squalamine displaces proteins that are electrostatically bound to intracellular membranes and through this mechanism suppresses aggregation of αS monomers into neurotoxic oligomers. OBJECTIVE: We sought to evaluate the safety of ENT-01 oral tablets (a synthetic squalamine salt), its pharmacokinetics, and its effect on bowel function in PD patients with constipation. METHODS: In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum tolerated dose (MTD). In Stage 2, 34 patients received daily doses escalating from 75 to a maximum of 250 mg/day, a dose that induced change in bowel function or MTD, followed by a fixed dose for 7 days, and a 2-week washout. Primary efficacy endpoint was defined as an increase of 1 complete spontaneous bowel movement (CSBM)/week, or 3 CSBM/week over the baseline period, as defined by FDA guidelines for prokinetic agents. Safety was also assessed. RESULTS: ). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was <0.3%. CONCLUSIONS: Orally administered ENT-01 was safe and significantly improved bowel function in PD, suggesting that the ENS is not irreversibly damaged in PD. Minimal systemic absorption suggests that improvements result from local stimulation of the ENS. A double-blind, placebo-controlled study is now ongoing.

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  • The gastrointestinal tract is increasingly viewed as a therapeutic target in Parkinson disease, including approaches that aim to modulate enteric neuronal signaling.

    “The gastrointestinal tract is also increasingly viewed as a therapeutic target in PD, including approaches that aim to modulate enteric neuronal signaling (Hauser et al., 2019).”

    From Autonomic nervous system and gastrointestinal manifestations with an emphasis on gastric dysfunction (2026) · cites this paper as Hauser et al., 2019

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Authors
Hauser, R. A., Sutherland, D., Madrid, J. A., Rol, M. A., Frucht, S., Isaacson, S., Pagan, F., Maddux, B. N., Li, G., Tse, W., Walter, B. L., Kumar, R., Kremens, D., Lew, M. F., Ellenbogen, A., Oguh, O., Vasquez, A., Kinney, W., Lowery, M., Resnick, M., Huff, N., Posner, J., Ballman, K. V., Harvey, B. E., Camilleri, M., Zasloff, M., & Barbut, D.
Affiliations
  • University of South Florida (US)
  • Sarasota Memorial Hospital (US)
  • Universidad de Murcia (ES)
  • NYU Langone Health (US)
  • Riverhills Healthcare (US)
  • MedSol Clinical Research Center (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • University Hospitals of Cleveland (US)
  • Thomas Jefferson University (US)
  • Keck Hospital of USC (US)
  • Quest Research Institute (US)
  • University of Florida (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Cornell University (US)
  • Mayo Clinic (US)
  • MedStar Georgetown University Hospital (US)
Corresponding author
  • Hauser, Robert A.
  • Barbut, Denise
ORCID
Venue
Clinical Parkinsonism & Related Disorders
Publisher
Elsevier BV
Published
2019
Volume
1
Pages
2-7
ISSN
2590-1125 (ISSN-L)
DOI
10.1016/j.prdoa.2019.06.001
PMC
PMC8288812
OpenAlex
W2958864094
Cited by
44
References
43
Citations by year
2026: 1 · 2025: 5 · 2024: 10 · 2023: 8 · 2022: 10 · 2021: 3 · 2020: 6 · 2019: 1
FWCI
3.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Parkinsonism & Related Disorders (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Enterin, Inc.
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
Keywords
Parkinson's disease, squalamine, alpha-synuclein aggregation, enteric nervous system, constipation, bowel function, prokinetic agents, pharmacokinetics, systemic absorption, drug safety, nausea, diarrhea

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