Constipation is a common and debilitating non-motor symptom of Parkinson disease (PD) that often precedes the onset of classic motor symptoms by decades. There is no standardized algorithm for managing constipation in this patient population, nor are there dedicated treatments. Studies suggest that constipation can affect quality of life to a significant degree, in many cases just as much as motor symptoms. There is an unmet need for effective treatment options for constipation in this patient population. The goal of this study is to determine the efficacy and safety of pyridostigmine as a treatment for chronic constipation in patients with PD.

This is a 13-15 week open-label, dose escalation trial of pyridostigmine 60-180mg three times a day (TID) for the treatment of constipation in patients with 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 two of the following highly effective methods of contraception for the duration of study participation and for an additional 28 days after the end of study drug administration: barrier contraception (female condom, diaphragm, cervical cap with/without spermicide), hormonal contraception, or intrauterine device; OR one of the previously mentioned methods AND partner must use barrier contraception (male condom with/without spermicide)

6. Males of reproductive potential who are sexually active must be willing to use the following highly effective methods of contraception for the duration of study participation and for an additional 28 days after the end of study drug administration: barrier contraception (male condom with/without spermicide) AND partner must be postmenopausal, use hormonal contraception, have an intrauterine device, or use barrier contraception (female condom, diaphragm, cervical cap with/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 or proprioceptive 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 specific requirement 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% of defecations iii. Lumpy or hard stools in > 25% of defecations iv. Sensation of incomplete evacuation for > 25% of defecations v. Sensation of anorectal obstruction/blockage for > 25% of defecations vi. Manual maneuvers to facilitate > 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 symptoms at 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 any reason

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 Bank Criteria, 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 the screening visit or within the three months prior if available for review

11. Significant abnormalities on screening electrocardiogram conducted at the screening visit 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