Targeting neurons in the gastrointestinal tract to treat Parkinson's disease
| Autor: | Karla V. Ballman, Alberto Vasquez, Juan Antonio Madrid, Denise Barbut, Steven J. Frucht, Matt Lowery, Brian E. Harvey, Michael Zasloff, Maria Resnick, Mark F. Lew, William A. Kinney, Nicole Huff, Robert A. Hauser, Aaron Ellenbogen, Dean Sutherland, Maria Angeles Rol, Winona Tse, Odinachi Oguh, Rajeev Kumar, Brian N. Maddux, Daniel Kremens, Jerry Posner, Benjamin L. Walter, Michael Camilleri, Stuart Isaacson, George Li, Fernando Pagan |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_specialty
Parkinson's disease Constipation Nausea ENT-01 Gastroenterology lcsh:RC346-429 chemistry.chemical_compound Pharmacokinetics Internal medicine medicine Adverse effect lcsh:Neurology. Diseases of the nervous system Synuclein Squalamine business.industry General Medicine medicine.disease Treatment Diarrhea chemistry Non-motor Defecation Original Article medicine.symptom business |
| Zdroj: | Clinical Parkinsonism & Related Disorders, Vol 1, Iss, Pp 2-7 (2019) Clinical Parkinsonism & Related Disorders |
| ISSN: | 2590-1125 |
| Popis: | 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 Over 80% of patients achieved the primary efficacy endpoint, with the mean number of CSBM/week increasing from 1.2 at baseline to 3.6 during fixed dosing (p = 1.2 × 10−7). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was 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. |
| Databáze: | OpenAIRE |
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