Pyridostigmine for the Treatment of Constipation in Parkinson Disease

Inclusion Criteria:

1. Age ≥ 18 years

2. Be able to provide signed informed consent

3. Stated ability and willingness to comply with all study procedures

4. Able to take oral medications

5. Females of reproductive potential who are sexually active must be willing to use twoof the following highly effective methods of contraception for the duration of studyparticipation and for an additional 28 days after the end of study drugadministration: barrier contraception (female condom, diaphragm, cervical capwith/without spermicide), hormonal contraception, or intrauterine device; OR one ofthe previously mentioned methods AND partner must use barrier contraception (malecondom with/without spermicide)

6. Males of reproductive potential who are sexually active must be willing to use thefollowing highly effective methods of contraception for the duration of studyparticipation and for an additional 28 days after the end of study drugadministration: barrier contraception (male condom with/without spermicide) ANDpartner must be postmenopausal, use hormonal contraception, have an intrauterinedevice, or use barrier contraception (female condom, diaphragm, cervical capwith/without spermicide)

7. Meet United Kingdom Parkinson's Disease Society Brain Bank Criteria:

A. Diagnosis of a parkinsonism:

• Bradykinesia, plus at least one of the following:

• Muscular rigidity

• 4-6 Hz resting tremor

• Postural stability not caused by primary visual, vestibular, cerebellar orproprioceptive dysfunction

B. At least three supportive criteria:

• Unilateral onset of symptoms

• Rest tremor

• Progressive symptoms

• Persistent asymmetry affecting the side of onset most

• Excellent response to levodopa

• Severe levodopa-induced chorea

• Levodopa response for five years or more

• Clinical course of 10 years or more

8. Fulfill the ROME IV Criteria for Functional Constipation, with a specificrequirement that the patient must have three or fewer defecations per week (criterion Ai):

• Must include two or more of the following: i. Three or fewer defecations per week ii. Straining during > 25% ofdefecations iii. Lumpy or hard stools in > 25% of defecations iv. Sensation ofincomplete evacuation for > 25% of defecations v. Sensation of anorectalobstruction/blockage for > 25% of defecations vi. Manual maneuvers tofacilitate > 25% of defecations

• Loose stools are rarely present without the use of laxatives

• Insufficient criteria for irritable bowel syndrome

• Criteria 1-3 must be fulfilled for at least three months with onset of symptomsat least six months prior to diagnosis

Exclusion Criteria:

1. Diagnosis of atypical parkinsonism

2. Diagnosis of drug-induced parkinsonism

3. Diagnosis of vascular parkinsonism

4. Known allergy to pyridostigmine bromide or other study drug components

5. Current or recent (within 90 days of enrollment) use of pyridostigmine for anyreason

6. History of any bowel surgery

7. History of bladder or bowel obstruction

8. Severe asthma or chronic obstructive pulmonary disease

9. Meet exclusion criteria noted in the UK Parkinson's Disease Society Brain BankCriteria, at the PI's discretion: A.Exclusion of any of the following:

• Repeated strokes with stepwise progression of parkinsonian features

• Repeated head injury

• Definite encephalitis

• Oculogyric crises

• Neuroleptic treatment at onset of symptoms

• Greater than one affected relative

• Sustained remission

• Strictly unilateral features after 3 years

• Supranuclear gaze palsy

• Cerebellar signs

• Early severe autonomic involvement

• Early severe dementia

• Babinski sign

• Cerebral tumor or communicating hydrocephalus

• Negative response to large doses of levodopa

• 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure

10. Significant abnormalities on laboratory analysis (complete blood count,comprehensive metabolic panel, thyroid stimulating hormone) conducted at thescreening visit or within the three months prior if available for review

11. Significant abnormalities on screening electrocardiogram conducted at the screeningvisit or within the three months prior if available for review

12. Positive pregnancy test (if female of child-bearing age)

13. Antibiotic use within two weeks prior to enrollment