Pyridostigmine for Paralytic Ileus

(PESTI Trial)

Overseen By Stefan D Holubar

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Stefan Holubar MD MS FACS, FASCRS

Must not be taking: Acetylcholine esterase inhibitors, Laxatives

Disqualifiers: Bowel obstruction, Intraabdominal septic complications, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 2 days

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and effectiveness of pyridostigmine, a medication, for treating postoperative ileus—a condition where the bowels temporarily stop working after surgery—in patients who have undergone colorectal surgery. Participants will receive either pyridostigmine (also known as Mestinon or Regonol) or a placebo, alongside standard care, to determine if it helps restore bowel function. Ideal candidates are those who have had colorectal surgery and are experiencing symptoms such as bloating, nausea, or an inability to pass gas or stool for at least 48 hours post-surgery. As a Phase 2 trial, this study measures how well the treatment works in an initial, smaller group of people, offering participants a chance to contribute to important medical research.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including neostigmine, alvimopan, metoclopramide, erythromycin, methylnaltrexone, naloxegol, cisapride, and laxatives or cathartics. If you are currently using any of these, you would need to discontinue them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that pyridostigmine is generally safe to use after certain surgeries. Studies have found that it helps the bowels resume function and is well-tolerated by most patients. In one study, 95% of patients experienced results within the first 24 hours. Safety data from other research indicates that most people experience only minor side effects. These findings suggest pyridostigmine could be a safe option for treating postoperative ileus, a condition where the bowels take longer to start working after surgery. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for ileus?

Most treatments for paralytic ileus focus on supportive care and symptom management, like bowel rest and intravenous fluids. But pyridostigmine bromide works differently, as it specifically targets the underlying issue by enhancing nerve signaling to the gut, helping to stimulate bowel movement. Researchers are excited about this treatment because it leverages pyridostigmine's ability to improve neuromuscular communication, potentially accelerating recovery of bowel function more effectively than existing methods. This could mean quicker relief for patients and a shorter hospital stay, which is a significant improvement over current options.

What evidence suggests that pyridostigmine might be an effective treatment for postoperative ileus?

Research has shown that pyridostigmine, which participants in this trial may receive, can help treat paralytic ileus, a condition where the intestines stop working after surgery. One study found that pyridostigmine was effective in 95% of patients within the first 24 hours, while only 50% of those on standard treatment improved. Pyridostigmine helps the intestines start moving again, speeding up the return to normal bowel function. Patients treated with pyridostigmine passed gas and stool faster, reducing recovery time by up to 47.6 hours. Overall, pyridostigmine appears to be a promising option for quickly restoring bowel function after surgery. ^{1 2 3 6 7}

Who Is on the Research Team?

Stefan D Holubar

Principal Investigator

The Cleveland Clinic

Are You a Good Fit for This Trial?

This trial is for adults who've had colorectal surgery and are now facing a condition called postoperative ileus, where the intestines don't move food properly causing bloating or nausea. Participants need to have normal organ function, not be pregnant or breastfeeding, and can't have other serious health issues like heart failure or bowel obstructions.

Inclusion Criteria

I am not completely bedridden.

I am an adult who had colorectal surgery and now have bloating and can't pass gas or stool for over 48 hours.

Radiographic confirmation of POI diagnosis either via abdominal radiography (KUB), computed tomography abdomen/pelvis (CT A/P), or both

Exclusion Criteria

I do not have uncontrolled illnesses like severe asthma, heart failure, or major organ failure.

I am not currently using any experimental drugs or specific medications for digestion.

I have had infections inside my abdomen like abscesses or leaks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either pyridostigmine or placebo every 12 hours for a maximum of 48 hours

2 days

Daily monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including side effects and bowel function

30 days

Regular follow-up visits

Outcome Assessment

Assessment of re-operation, complications, and re-admission within 30 days post-surgery

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Pyridostigmine Bromide

Trial Overview The study tests if Pyridostigmine Bromide can help with intestinal movement after surgery compared to a placebo. It's a double-blind trial, meaning neither patients nor doctors know who gets the real drug. Everyone continues standard care too.

How Is the Trial Designed?

Group I: Pyridostigmine Experimental Treatment 1 Intervention

Patients randomized to this group will be given 60mg of pyridostigmine bromide orally, every 12 hours. Pyridostigmine will be administered from the time of diagnosis of postoperative ileus until the return of bowel function, or for a maximum of 48 hours.

Group II: Placebo Placebo Group 1 Intervention

Patients randomized to this group will be given starch orally, every 12 hours for a maximum of 48 hours.

Who Is Running the Clinical Trial?

Stefan Holubar MD MS FACS, FASCRS

Lead Sponsor

Trials

2

Recruited

50+

Published Research Related to This Trial

In a case series of children with various gastrointestinal motility disorders, oral pyridostigmine was found to be effective and safe, improving symptoms like abdominal distention and bowel movement frequency.

The effective dosing of pyridostigmine ranged from 0.25 to 2.0 mg/kg/day, and while one patient experienced abdominal cramping, the overall results suggest it is a promising option when other treatments fail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of Pyridostigmine in Pediatric Gastrointestinal Motility Disorders: A Case Series. Manini, ML., Camilleri, M., Grothe, R., et al.[2018]

In a study involving over 100 patients with functional ileus, a treatment combining adrenergic blockade with low doses of stimulants effectively restored intestinal function, particularly in patients resistant to traditional stimulant therapies.

The approach, which focuses on countering adrenergic inhibition rather than merely stimulating the intestines, demonstrated a low risk of complications and significant efficacy in treating functional ileus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of functional ileus: adrenergic blockade and stimulation (author's transl)]. Grund, KE.[2013]

Pyridostigmine, an oral anti-cholinesterase drug, has been successfully used to treat a young child with chronic intestinal pseudo-obstruction, enhancing gut motility by increasing acetylcholine levels.

The treatment led to significant improvements, including reduced abdominal distension, decreased reliance on parenteral nutrition, and better oral feeding, suggesting that pyridostigmine is an effective and well-tolerated option for managing this rare pediatric condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pyridostigmine in Pediatric Intestinal Pseudo-obstruction: Case Report of a 2-year Old Girl and Literature Review. Di Nardo, G., Viscogliosi, F., Esposito, F., et al.[2020]

In a double-blind clinical trial with 26 patients, ceruletide was found to be significantly more effective than metroclopramide in restoring intestinal movement after abdominal surgery, with a statistically significant result (P < 0.05).

This suggests that ceruletide may be a better treatment option for patients experiencing intestinal paralysis post-surgery, highlighting its potential efficacy in improving gastrointestinal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceruletide vs. metoclopramide in postoperative intestinal paralysis. A double-blind clinical trial. Lykkegaard-Nielsen, M., Madsen, PV., Nielsen, OV.[2019]

In a pilot study involving 15 patients who underwent elective colorectal surgery, oral pyridostigmine was found to be safe, with no adverse effects directly linked to its use and no signs of excessive parasympathetic activity.

The median time to recovery of gastrointestinal function, measured by the GI-2 score, was 2 days, suggesting potential benefits in GI motility, but further research with larger sample sizes is necessary to confirm its efficacy in preventing postoperative ileus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PyRICo-Pilot: pyridostigmine to reduce the duration of postoperative ileus after colorectal surgery - a phase II study. Dudi-Venkata, NN., Kroon, HM., Bedrikovetski, S., et al.[2021]

In a study of 40 patients, oral pyridostigmine (60 mg) significantly reduced the time to pass gas and stool after abdominal surgery, with mean times of 5.4 hours and 4.9 hours, respectively, compared to 32.4 hours and 36.2 hours in the control group.

Pyridostigmine was effective in 95% of patients within the first 24 hours, while only 50% of the control group responded, highlighting its potential as a simple and effective treatment for postoperative ileus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the Effect of Oral Pyridostigmine on the Ileus after Abdominal Surgery: A Blinded Randomized Clinical Trial. Maleknejad, A., Khazaei, A., Bouya, S.[2020]

Acetylcholinesterase inhibitors, specifically neostigmine and pyridostigmine, may significantly reduce the time it takes for gastrointestinal function to return after abdominal surgery, with some studies showing a reduction of 17 to 47.6 hours in time to flatus or stool among 703 patients across 8 randomized controlled trials.

Despite the promising results, the current evidence is limited and potentially biased, highlighting the need for further research to confirm these findings and explore the integration of these inhibitors into enhanced recovery protocols, particularly for colorectal surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of acetylcholinesterase inhibitors in reducing time to gastrointestinal function recovery following abdominal surgery: A systematic review. Traeger, L., Dudi-Venkata, N., Bedrikovetski, S., et al.[2023]

Neostigmine effectively improved bowel transit in two cases of drug-induced ileus, allowing for successful whole bowel irrigation after overdoses, indicating its potential as a treatment in similar situations.

No significant adverse events were reported with neostigmine administration, suggesting it is a safe option for facilitating gut decontamination in cases of ileus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of neostigmine for the management of drug induced ileus in severe poisonings. Chan, B., Whyte, I., Dawson, A., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5977143/

Evaluation of the Effect of Oral Pyridostigmine on the Ileus ... The overall results of the study indicate a positive effect of oral pyridostigmine as a simple and effective treatment of the ileus colon; ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05334485

Pyridostigmine Efficacy and Safety for Treatment of Ileus ... Pyridostigmine will be administered from the time of diagnosis of postoperative ileus until the return of bowel function, or for a maximum of 48 hours.

3. withpower.com withpower.com/trial/phase-2-and-3-ileus-3-2022-2c09e

Pyridostigmine for Paralytic Ileus (PESTI Trial) Pyridostigmine was effective in 95% of patients within the first 24 hours, while only 50% of the control group responded, highlighting its potential as a simple ...

4. karger.com karger.com/dsu/article/41/1/12/871684/Use-of-Acetylcholinesterase-Inhibitors-in-Reducing

Use of Acetylcholinesterase Inhibitors in Reducing Time to ... Five studies showed a significant reduction in time to flatus and/or stool by 17–47.6 h. Methodological variations, differing procedure types, ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38743864/

Pyridostigmine to Reduce the duration of postoperative ... Pyridostigmine resulted in a quicker return of GI-2 and was well tolerated. Larger multicentre studies are required to determine the optimal ...

6. ovid.com ovid.com/journals/clrcd/pdf/10.1111/codi.15748~pyricopilot-pyridostigmine-to-reduce-the-duration-of

Pilot: pyridostigmine to reduce the duration of ... in patients undergoing abdominal surgery [25], the safety and efficacy data appeared promising, with a 1- day reduction in time to first pas-.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34021689/

pyridostigmine to reduce the duration of postoperative ileus ... Conclusion: Oral pyridostigmine appears to be safe to use after elective colorectal surgery in a select group of patients. However, considering this is a pilot ...