Modulation of GABA-A Receptors in Parkinson Disease-Clarithromycin Arm

This study focuses on neurochemical changes in the brain that occur in Parkinson's disease.
In particular we will be looking a neurotransmitter called GABA. In some Parkinson's disease
patients we see too much GABA activity in the brain. There is emerging in vitro and in vivo
evidence that clarithromycin, an FDA-approved and orally available macrolide antibiotic, can
act as a negative allosteric modulator of brain GABA-A receptors. This target engagement
study examines the target engagement effect of GABA-A receptor modulation by clarithromycin.
[11C]-flumazenil Positron Emission Tomography (PET) imaging results will be used to assess
for possible GABA-A receptor target engagement effects of clarithromycin.

Inclusion Criteria:

1. Parkinson's disease (PD): PD diagnosis will follow the UK Parkinson's Disease Society
Brain Bank Research Center (UKPDSBRC) clinical diagnostic criteria for PD.

2. Hoehn and Yahr stages 2-4

3. Absence of dementia confirmed by cognitive testing.

4. Abnormal 11C-Dihydrotetrabenazine ([11c]-DTBZ) PET study to demonstrate nigrostriatal
dopaminergic denervation

Exclusion Criteria:

1. PD with Dementia (PDD) or dementia with Lewy bodies (DLB).

2. Other disorders which may resemble PD, such as vascular dementia, normal pressure
hydrocephalus, multiple system atrophy, corticobasal ganglionic degeneration, or toxic
causes of parkinsonism. Prototypical cases have distinctive clinical profiles, like
early and severe dysautonomia or appendicular apraxia, which may differentiate them
from idiopathic PD. The use of the UKPDSBRC clinical diagnostic criteria for PD will
mitigate the inclusion of subjects with atypical parkinsonism.

3. Subjects on benzodiazepine, GABAB-ergic medications (baclofen, tizanidine),
neuroleptic, anticholinergic (trihexphenidyl, benztropine), or cholinesterase
inhibitor drugs.

4. Evidence of a mass lesion on structural brain imaging (MRI).

5. Participants in whom MRI is contraindicated including, but not limited to, those with
a pacemaker, presence of metallic fragments near the eyes or spinal cord, chest, or
cochlear implant.

6. Severe claustrophobia precluding MR or PET imaging.

7. Subjects limited by participation in research procedures involving ionizing radiation.

8. Pregnancy (urine or serum pregnancy test within 48 hours of each PET session) or
breastfeeding.

9. History of seizures

10. Significant anxiety or history of panic disorder.

11. History of recent suicide attempt or overdose of tricyclic antidepressants or other
medications

12. Any other medical history determined by investigators to preclude safe participation.

Exclusion criteria specific for clarithromycin arm of the study

1. Allergy or hypersensitivity to clarithromycin, other macrolide antibiotics, or similar
medicines such as azithromycin, erythromycin or telithromycin.

2. History of significant atrial or ventricular arrhythmias.

3. Significant liver or kidney disease.

4. Corrected QT interval (QTc) prolongation.

5. Subjects taking digoxin, colchicine, pimozide, cisapride, quetiapine, astemizole,
terfenadine, ergotamine, or dihydroergotamine.