Does N-Acetylcysteine Decrease Spontaneous Oxidation of Central Neural Dopamine in Parkinson's Disease?

NCT03104725 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 17007617-N-0076
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Parkinsons disease (PD) causes slow movement, stiffness, and poor balance. Many symptoms are due to the loss of brain cells that make the brain chemical dopamine. The cells may be damaged by the breakdown of dopamine by a process called oxidation. The drug N-acetylcysteine (NAC) can act as an antioxidant. Researchers want to test if NAC can decrease the oxidation of brain dopamine in people with PD. Objective: To look at the effect of NAC on brain chemistry in people with PD. Eligibility: People ages 18 and older with PD that were diagnosed within the past 5 years. They must be taking a monoamine oxidase inhibitor. Healthy volunteer participants ages 18 and older. Design: Participants will be screened with: Medical history Physical exam Blood and urine tests Participants will be hospitalized for 4 to 8 days. On day 1, participants will have blood and urine tests. For several hours, they cannot eat or drink anything but water and their medications. Late in the morning they will have a meal. About 2 hours later they will have a spinal tap (lumbar puncture). For this, a numbing medicine is injected into the back. A needle is inserted between the bones in the back to remove a small amount of fluid. The spinal tap may use x-rays to see inside the body. After the spinal tap, they will start taking NAC by mouth. They will take NAC twice a day for 2 more days. On the next day, they will not eat until a meal in the late morning. They will take a final NAC dose. About 2 hours later they will have a second spinal tap. Healthy Volunteer (HV) participants will receive a spinal tap on day one, followed by a second spinal tap 48 hours after the first spinal tap. HV participants will not receive NAC.

Conditions

Parkinson Disease; Cerebrospinal Fluid

Keywords

5-S-Cysteinyldopamine; Cerebrospinal Fluid; PARKINSONS DISEASE; MONOAMINE OXIDASE INHIBITOR

Outcome Measures

Primary Outcomes (1)

• The Mean Percent Change in Cerebrospinal Fluid (CSF) Concentration of 5-S-cysteinyl-dopamine (Cys-DA) Pre and Post-N-acetylcysteine (NAC) Treatment

  Patients with Parkinson's Disease (PD) who took N-acetylcysteine (NAC), and healthy volunteers who did not take NAC, each had two separate lumbar punctures (LP 1 and LP 2) to obtain spinal fluid. The spinal fluid samples were used to measure the amount of a brain chemical called 5-S-cysteinyl-dopamine (Cys-DA). The primary outcome measure is the mean change in CSF Cys-DA levels between pre and post-NAC treatment, which is calculated as the difference of CSF Cys-DA levels at pre-treatment (LP 1) and post-treatment (LP 2) divided by CSF Cys-DA at pre-treatment (LP 1). A greater percent decrease in Cys-DA levels in the brain would suggest that NAC may contribute to a reduction in the oxidation of brain dopamine, while a smaller percent decrease would suggest that NAC had no effect on the oxidation of brain dopamine.

  All participants underwent a baseline LP. For PD participants, the second LP occurred approximately 2 hours after the participant had taken NAC the last NAC dose. For HV participants the second LP takes place approximately 48 hours after the first LP.

Secondary Outcomes (2)

• Mean Ratio of Cys-DA/DOPAC Pre and Post-treatment Lumbar Puncture With and Without N-acetylcysteine (NAC)

  All participants underwent a baseline LP. For PD participants, the second LP occurred approximately 2 hours after the participant had taken NAC the last NAC dose. For HV participants the second LP takes place approximately 48 hours after the first LP.

• Mean Percent Change in Cys-DA/DOPAC Between Pre and Post-treatment Lumbar Puncture With and Without N-acetylcysteine (NAC)

  All participants underwent a baseline LP. For PD participants, the second LP occurred approximately 2 hours after the participant had taken NAC the last NAC dose. For HV participants the second LP takes place approximately 48 hours after the first LP.

Study Arms (2)

Healthy Volunteers

EXPERIMENTAL

HVs who undergo 2 LPs as inpatients, with 48 hours between LPs and no NAC treatment

Procedure: Lumbar Puncture; Radiation: Fluoroscopy

PD Patients

EXPERIMENTAL

Patient undergoes a lumbar puncture (LP) as an inpatient at the NIH Clinical Center to obtain cerebrospinal fluid (CSF) for assays of Cys-DA, 3,4- dihydroxyphenylacetic acid (DOPAC), and related biochemicals. The second LP is done after the patient has taken at least 5 doses of NAC (2 grams orally twice per day).

Drug: N-Acetylcysteine; Procedure: Lumbar Puncture; Radiation: Fluoroscopy

Interventions

N-Acetylcysteine DRUG

Oral

PD Patients

Lumbar Puncture PROCEDURE

Each participant undergoes a baseline lumbar puncture (LP 1) as an inpatient at the NIH Clinical Center to obtain cerebrospinal fluid (CSF) for assays of Cys-DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and related biochemicals. The second LP (LP 2) is completed after the PD participant has taken at least 5 doses of NAC (2 grams orally twice per day) and approximately 2 hours after the last NAC dose. For the HV participant, LP 2 occurs approximately 48 hours after LP 1 (no NAC administered).

Healthy Volunteers; PD Patients

Fluoroscopy RADIATION

If needed for lumbar puncture

Healthy Volunteers; PD Patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• PD diagnosed within the past 5 years
• Taking a monoamine oxidase (MAO) inhibitor
• Able to provide consent
• At least18 years old

You may not qualify if:

• Taking levodopa in any form
• Known allergy to NAC
• Already taking an anti-oxidant dietary supplement (e.g., Olive Leaf Extract, MitoQ)
• A condition that would increase risk from a lumbar puncture (e.g., symptomatic spinal stenosis or myoclonus)
• History of a post-spinal headache that required treatment with a blood patch
• On a prescribed anti-coagulant (e.g., Coumadin, Plavix)
• Pregnant or breast-feeding
• History of alcohol or drug abuse
• Any medical condition thatcould put subjects at increased risk. Potential participants are excluded who have evidence of bone marrow, liver, or kidney failure based on abnormal screening lab results.

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Goldstein DS, Holmes C, Sullivan P, Jinsmaa Y, Kopin IJ, Sharabi Y. Elevated cerebrospinal fluid ratios of cysteinyl-dopamine/3,4-dihydroxyphenylacetic acid in parkinsonian synucleinopathies. Parkinsonism Relat Disord. 2016 Oct;31:79-86. doi: 10.1016/j.parkreldis.2016.07.009. Epub 2016 Jul 20.

  PMID: 27474472 BACKGROUND

• Goldstein DS, Kopin IJ, Sharabi Y. Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders. Pharmacol Ther. 2014 Dec;144(3):268-82. doi: 10.1016/j.pharmthera.2014.06.006. Epub 2014 Jun 16.

  PMID: 24945828 BACKGROUND

• Goldstein DS, Jinsmaa Y, Sullivan P, Holmes C, Kopin IJ, Sharabi Y. Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells. J Pharmacol Exp Ther. 2016 Feb;356(2):483-92. doi: 10.1124/jpet.115.230201. Epub 2015 Nov 16.

  PMID: 26574516 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Parkinson Disease

Interventions

Acetylcysteine; Spinal Puncture

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Biopsy; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Neurological; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques

Results Point of Contact

• Title: Dr. David Goldstein
• Organization: National Institutes of Health/NINDS

goldsteind@ninds.nih.gov

301-496-2103

Study Officials

• David S Goldstein, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 4, 2017
• First Posted: April 7, 2017
• Study Start: September 25, 2017
• Primary Completion: February 27, 2020
• Study Completion: February 27, 2020
• Last Updated: November 4, 2021
• Results First Posted: May 19, 2021

Record last verified: 2020-03

Locations

US (1)