Pyridostigmine for the Treatment of Constipation in Parkinson Disease

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.

Inclusion Criteria:Age ≥ 18 yearsBe able to provide signed informed consentStated ability and willingness to comply with all study proceduresAble to take oral medicationsFemales 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)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)Meet United Kingdom Parkinson's Disease Society Brain Bank Criteria:A. Diagnosis of a parkinsonism:Bradykinesia, plus at least one of the following:Muscular rigidity4-6 Hz resting tremorPostural stability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunctionB. At least three supportive criteria:Unilateral onset of symptomsRest tremorProgressive symptomsPersistent asymmetry affecting the side of onset mostExcellent response to levodopaSevere levodopa-induced choreaLevodopa response for five years or moreClinical course of 10 years or moreFulfill the ROME IV Criteria for Functional Constipation, with a specific requirement that the patient must have fewer than three defecations per week (criterion Ai):Must include two or more of the following:i. Fewer than three 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 defecationsLoose stools are rarely present without the use of laxativesInsufficient criteria for irritable bowel syndromeCriteria 1-3 must be fulfilled for at least three months with onset of symptoms at least six months prior to diagnosisExclusion Criteria:Diagnosis of atypical parkinsonismDiagnosis of drug-induced parkinsonismDiagnosis of vascular parkinsonismKnown allergy to pyridostigmine bromide or other study drug componentsCurrent or recent (within 90 days of enrollment) use of pyridostigmine for any reasonHistory of any bowel surgeryHistory of bladder or bowel obstructionSevere asthma or chronic obstructive pulmonary diseaseMeet 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 featuresRepeated head injuryDefinite encephalitisOculogyric crisesNeuroleptic treatment at onset of symptomsGreater than one affected relativeSustained remissionStrictly unilateral features after 3 yearsSupranuclear gaze palsyCerebellar signsEarly severe autonomic involvementEarly severe dementiaBabinski signCerebral tumor or communicating hydrocephalusNegative response to large doses of levodopa1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposureSignificant 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 reviewSignificant abnormalities on screening electrocardiogram conducted at the screening visit or within the three months prior if available for reviewPositive pregnancy test (if female of child-bearing age)Antibiotic use within two weeks prior to enrollment