Pharmacological and nutritional therapy of children and adults with chronic intestinal pseudo-obstruction.

INTRODUCTION: Chronic intestinal pseudoobstruction (CIPO) is a rare, heterogenous, and severe form of gastrointestinal dysmotility. AREAS COVERED: Pertinent literature on pediatric and adult CIPO management has been assessed via PubMed, Scopus, and EMBASE from inception to June 2022. Prokinetics, aimed at restoring intestinal propulsion (e.g. orthopramides and substituted benzamides, acetyl cholinesterase inhibitors, serotonergic agents, and others), have been poorly tested and the available data showed only partial efficacy. Moreover, some prokinetic agents (e.g. orthopramides and substituted benzamides) can cause major side effects. CIPO-related small intestinal bacterial overgrowth requires treatment preferably via poorly absorbable antibiotics to avoid bacterial resistance. Apart from opioids, which worsen gut motility, analgesics should be considered to manage visceral pain, which might dominate the clinical manifestations. Nutritional support, via modified oral feeding, enteral, or parenteral nutrition, is key to halting CIPO-related malnutrition. EXPERT OPINION: There have been significant roadblocks preventing the development of CIPO treatment. Nonetheless, the considerable advancement in neurogastroenterology and pharmacological agents cast hopes to test the actual efficacy of new prokinetics via well-designed clinical trials. Adequate dietary strategies and supplementation remain of crucial importance. Taken together, novel pharmacological and nutritional options are expected to provide adequate treatments forthese patients.

Clinical Observation of Treatment Efficacy in Critical Paralytic Ileus Disease with Integrated Traditional Chinese and Western Medicine: A Randomized Controlled Trial.

OBJECTIVE: The study aimed to evaluate the treatment efficacy of the combination of Da-Cheng-Qi Decoction (DCQD) injected into the jejunum and as an enema in patients with critical diseases with paralytic ileus. METHODS: In our double-blind randomized controlled study, 114 critically ill patients with paralytic ileus were divided into 2 groups. The control group received conventional medical treatment, and the DCQD group was treated with integrated traditional Chinese medicine (TCM) and Western medicine. The intra-abdominal pressure (IAP), recovery of gastrointestinal (GI) function, clinical efficacy and intensive care unit (ICU) stay in the 2 groups were recorded and compared. RESULTS: The IAP in the DCQD group was lower than in the control group (P < .05). The recovery of GI function and clinical efficacy rate in the DCQD group were significantly better than in the control group (P < .05, respectively). CONCLUSION: DCQD may be an effective method for treating patients with critical diseases with paralytic ileus and is worthy of clinical application.

Effect of Caffeine Intake on Postoperative Ileus: A Systematic Review and Meta-Analysis.

BACKGROUND: Postoperative ileus prolongs both hospital stay and patients' morbidity, having at the same time a great impact on health care costs. Coffee, a worldwide popular, cheap beverage might have an important effect on the motility of the postoperative bowel. METHODS: PubMed, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched. RESULTS: Four studies met the inclusion criteria of our meta-analysis. A total of 341 patients were included. The postoperative administration of coffee significantly reduces the time to first bowel movement, the time to first flatus and the time to tolerance of solid diet. Safe conclusions could not be drawn regarding the additional use of laxatives, the necessity for reinsertion of nasogastric tube or the need for reoperation as all the aforementioned outcomes did not present any statistically significance. None of the complications were attributed to the administration of coffee. CONCLUSION: The administration of coffee as a postoperative ileus prevention measure can change the way postoperative enhanced recovery is applied. Even though the mechanism of action of coffee is not fully known, currently available literature demonstrates a significant improvement in gastrointestinal motility without having any impact on postoperative morbidity. Studies with higher methodological quality can offer a more careful evaluation of the clinical use of this popular beverage.

The Use of Coffee to Decrease the Incidence of Postoperative Ileus: A Systematic Review and Meta-Analysis.

PURPOSE: To investigate the efficacy of providing coffee to elective abdominal surgery patients, immediately postoperatively, to lessen postoperative ileus. DESIGN: A systematic review with meta-analysis of six randomized controlled trials published since 2012. METHODS: Methodological quality was evaluated using the Cochrane guidelines. The Grading of Recommendations, Assessment, Development, and Evaluations assessment tool evaluated the quality of the evidence. Subgroup analyses were completed if the I2 statistic demonstrated heterogeneity (greater than 50%). FINDINGS: Coffee was statistically significant in shortening the time between surgery and the first passage of stool (mean difference, -9.38; 95% confidence interval, -17.60 to -1.16; P = .03). Although not statistically significant (P = .20), the overall effect favored shorter hospital stays for those patients receiving coffee. CONCLUSIONS: The current systematic review and meta-analysis suggests that coffee given as early as 2 hours postoperatively decreases time to first bowel movement. In addition, patients tolerated solid food faster and were discharged sooner when given coffee immediately postoperatively.

Effect of Daikenchuto (TJ-100) on gastrointestinal symptoms following laparoscopic colectomy in patients with colon cancer: study protocol for a randomized controlled trial.

BACKGROUND: Postoperative paralytic ileus can be a difficult complication for both surgeons and patients. Causes and treatments have been discussed for more than two centuries, but have not yet been fully resolved. Daikenchuto (TJ-100, DKT) is a traditional Japanese herbal medicine. Recently, some beneficial mechanisms of DKT to relieve paralytic ileus have been reported. DKT can suppress inflammation, increase intestinal blood flow, and accelerate bowel movements. Therefore, we have designed a randomized controlled trial to investigate the effects of DKT on postoperative gastrointestinal symptoms following laparoscopic colectomy in patients with left-sided colon cancer at a single institution. METHODS/DESIGN: As primary endpoints, the following outcomes will be evaluated: (i) grade of abdominal pain determined using the numeric rating scale (NRS), (ii) grade of abdominal distention determined using the NRS, and (iii) quality of life determined using the Gastrointestinal Quality Life Index (GIQLI). As secondary endpoints, the following will be evaluated: (i) postoperative nutritional status (Onodera's Prognostic Nutritional Index (PNI) and the Controlling Nutritional Status score (CONUT score)), (ii) duration to initial flatus, (iii) duration to initial defecation, (iv) bowel gas volume, (v) character of stool (Bristol Stool Form Scale), (vi) defecation frequency per day, (vii) postoperative complications (Clavien-Dindo classification), (viii) length of postoperative hospital stay, and (ix) metabolites in the stool and blood. This trial is an open-label study, and needs to include 40 patients (20 patients per group) and is expected to span 2 years. DISCUSSION: To our knowledge, this is the first randomized controlled trial to investigate the effects of DKT on postoperative subjective outcomes (i.e., postoperative quality of life) following laparoscopic colectomy as primary endpoints. Exploratory metabolomics analysis of metabolites in stool and blood will be conducted in this trial, which previously has only been performed in a few human studies. The study aims to guide a future full-scale pragmatic randomized trial to assess the overall effectiveness of DKT to improve the postoperative quality of life following laparoscopic colectomy. TRIAL REGISTRATION: UMIN-CTR (Japan), UMIN000023318 . Registered on 25 July 2016.

Pharmacotherapy for pediatric chronic intestinal pseudo-obstruction: Nationwide survey in Japan.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a rare disabling and life-threatening disorder characterized by severe impairment of gastrointestinal peristalsis. While a number of pharmacotherapeutics have been developed, only a few trials have been carried out for improvement of the pathological condition of CIPO patients. This report describes the results of a nationwide survey on the pharmacotherapy used in pediatric CIPO in Japan. METHODS: In 2012, a nationwide survey was conducted to identify the clinical presentation of CIPO in Japan. Information was gathered on pharmacotherapy. Four categories were created for medicines used in pharmacotherapy: "probiotics", "Japanese herbal medicines (Kampo medicines)", "laxatives", and "prokinetics". RESULTS: Ninety-two responses were collected from 47 facilities. Of the 62 patients who met the diagnostic criteria, 52 were treated with medications, while the remaining 10 were not. Thirty-four patients were given a total of 49 probiotics; 39 were treated with a total of 50 Kampo medicines; 20 were treated with a total of 28 laxatives; and 26 were given a total of 30 prokinetics, 70% of whom were treated specifically with mosapride. CONCLUSION: Traditional Japanese medicines such as Kampo medicines and mosapride are often used to treat CIPO in Japan. Two combinations, that is, probiotics and Kampo medicines; and Kampo medicines and prokinetics, were often used for pediatric CIPO in Japan.

Multicentre, randomised, placebo-controlled trial of extract of Japanese herbal medicine Daikenchuto to prevent bowel dysfunction after adult liver transplantation (DKB 14 Study).

INTRODUCTION: This multicentre randomised controlled clinical trial will aim to determine the ability of an extract (TJ-100) of Daikenchuto (traditional Japanese herbal medicine; Kampo) to prevent bowel dysfunction in at least 110 patients after liver transplantation (LT). METHODS AND ANALYSIS: The following co-primary end points will be evaluated on postoperative day 7: total oral and enteral caloric intake, abdominal distension and abdominal pain. The secondary end points will comprise sequential changes of total oral and enteral caloric intake after LT, sequential changes in numeric rating scales for abdominal distension and pain, elapsed time to the first postoperative passage of stool, quality of life assessment using the Gastrointestinal Symptom Rating Scale score (Japanese version), postoperative liver function, liver regeneration rate, incidence of bacteraemia and bacterial strain, trough level of immunosuppressants, occurrence of acute cellular rejection, discharge or not within 2 months after LT, sequential changes of portal venous flow to the graft and ascites discharge. The two arms of the study will comprise 55 patients per arm. ETHICS AND DISSEMINATION: The study has been conducted according to the CONSORT statement. All participants signed a written consent form, and the study has been approved by the institutional review board of each participating institute and conducted in accordance with the Declaration of Helsinki of 1996. The findings will be disseminated through scientific and professional conferences, and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: The DKB 14 Study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000014326) during 2014.

Personalized drug discovery: HCA approach optimized for rare diseases at Tel Aviv University.

The Cell screening facility for personalized medicine (CSFPM) at Tel Aviv University in Israel is devoted to screening small molecules libraries for finding new drugs for rare diseases using human cell based models. The main strategy of the facility is based on smartly reducing the size of the compounds collection in similarity clusters and at the same time keeping high diversity of pharmacophores. This strategy allows parallel screening of several patient derived - cells in a personalized screening approach. The tested compounds are repositioned drugs derived from collections of phase III and FDA approved small molecules. In addition, the facility carries screenings using other chemical libraries and toxicological characterizations of nanomaterials.

Preclinical toxicity evaluation of erythrocyte-encapsulated thymidine phosphorylase in BALB/c mice and beagle dogs: an enzyme-replacement therapy for mitochondrial neurogastrointestinal encephalomyopathy.

Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) is currently under development as an enzyme replacement therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder caused by a deficiency of thymidine phosphorylase. The rationale for the development of EE-TP is based on the pathologically elevated metabolites (thymidine and deoxyuridine) being able to freely diffuse across the erythrocyte membrane where the encapsulated enzyme catalyses their metabolism to the normal products. The systemic toxic potential of EE-TP was assessed when administered intermittently by iv bolus injection to BALB/c mice and Beagle dogs for 4 weeks. The studies consisted of one control group receiving sham-loaded erythrocytes twice weekly and two treated groups, one dosed once every 2 weeks and the other dosed twice per week. The administration of EE-TP to BALB/c mice resulted in thrombi/emboli in the lungs and spleen enlargement. These findings were also seen in the control group, and there was no relationship to the number of doses administered. In the dog, transient clinical signs were associated with EE-TP administration, suggestive of an immune-based reaction. Specific antithymidine phosphorylase antibodies were detected in two dogs and in a greater proportion of mice treated once every 2 weeks. Nonspecific antibodies were detected in all EE-TP-treated animals. In conclusion, these studies do not reveal serious toxicities that would preclude a clinical trial of EE-TP in patients with MNGIE, but caution should be taken for infusion-related reactions that may be related to the production of nonspecific antibodies or a cell-based immune response.

Effect of the herbal medicine dai-kenchu-to on gastrointestinal motility in patients with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) and chronic idiopathic intestinal pseudo-obstruction (CIIP): report of two cases.

Dai-kenchu-to (DKT), a traditional Japanese herbal medicine (Kampo medicine), composed of zanthoxylum fruit, ginseng root, dried ginger rhizome and malt sugar, is clinically effective for postoperative ileus and chronic constipation. MMIHS and CIIP are severe motility disorder associated with high morbidity. The aim of this study was to evaluate the effect of DKT on functional intestinal obstruction. DKT was clinically effective for gastrointestinal motility in a case with MMIHS, but not effective in one with CIIP. MMIHS and CIIP are speculated to have different pathogenesis regarding gastrointestinal pseudo-obstruction based upon the effect of this drug.

[Effect of combined therapy with Kangyanling and Omeprazole on digestive dysfunction in burned patients].

OBJECTIVE: To observe the curative effects of combined therapy with Kangyanling (KYL, a Chinese herbal preparation) and Omeprazole on post-burn digestive dysfunction. METHODS: Patients with post-burn digestive dysfunction were assigned to two groups, the 32 in the treated group, including 18 with acute stress gastrointestinal mucosal hemorrhagic lesion and 14 with toxic enteroparalysis, were treated by KYL plus Omeprazole, and the 20 patients in the control group, 11 with acute stress gastrointestinal mucosal hemorrhagic lesion and 9 with toxic enteroparalysis were treated with Omeprazole alone. The pH value in gastric mucosa was determined before and 12 h after treatment, the hemostasis effects in 48 h, and the anti-paralysis effects in 72 h were observed as well. RESULTS: The pH value in gastric mucosa of both groups before therapy were all lower than the normal range, it raised after treatment in the treated group (P < 0.05), approaching to the normal range, but with no significant change in the control group. The total hemostatic rate and the anti-paralysis rate was 77.8% and 85.7% respectively in the treated group, and 45.5% and 0% in the control group, all shown statistical significance between groups (P < 0.05). CONCLUSION: Combined therapy with Kangyanling and Omeprazole has obvious curative effects on post-burn gastric dysfunction.

[Chronic intestinal pseudo-obstruction]. / Pseudo-obstrucción intestinal crónica.

Chronic intestinal pseudo-obstruction (CIPO) is a syndrome characterized by the presence of recurrent episodes of clinical intestinal obstruction in the absence of obstructive lesions. Although this syndrome is rare, it causes a high morbidity. It is caused by a disturbance of the intestinal motility, that results in a failure of the progression of the intestinal content. Basically, the failure of the intestinal motility is a consequence of muscular disorder, neurological disorder or both. Usually, CIPO is secondary to other systemic disease; however, in the last years, many cases of primary CIPO have been described. The use of new manometric tecniques and specific histological procedures have allowed to clarify the pathogenesis of some of these entities including mitochondrial diseases and paraneoplasic syndromes. Clinical manifestations of CIPO are diverse, depending on the location and extension of the motility disorder. As the diagnosis of this disease is usually not an easy task, patients frecuently undergo unnecesary surgical interventions, are diagnosed of psyquiatric disorders, or the correct diagnosis is delayed several years after the first symptoms arise. The aims of the treatment are to maintain the nutritional condition and to improve symptoms using nutritional measures, drugs or, eventually, endoscopical or surgical procedures.

Da-Cheng-Qi-Tang promotes the recovery of gastrointestinal motility after abdominal surgery in humans.

In order to examine the effects of Da-Cheng-Qi-Tang (DCQT) on gastrointestinal motility functions after abdominal surgery in humans, 33 patients with abdominal surgeries and 36 patients with cholecystectomies were divided into the DCQT and the control groups at random. Electrogastrography (EGG) and gastroduodenojejunal manometry was performed and the levels of plasma motilin were measured by radioimmunoassay. The results were as follows: (1) on the day of surgery, the ratio of EGG normal frequency in the DCQT group was higher than in the control group (P=0.0016); (2) the power of EGG in the DCQT group was higher than in the control group on the second and third days after surgeries (P=0.0011 and P=0.0215, respectively); (3) the percentage of normal bowel peristalsis was significantly higher in the DCQT group than in the control group (P<0.01); and (4) in the DCQT group, the plasma motilin level reached its peak earlier than in the control group. Our results suggest that DCQT can increase plasma motilin, enhance gastrointestinal motility, improve gastric dysrythmia, and reduce gastroparesis after abdominal surgery.

Neostigmine for the treatment of acute hepatic encephalopathy with acute intestinal pseudo-obstruction in a cirrhotic patient.

We treated a 49-yr-old man with neostigmine, who had liver cirrhosis, acute hepatic encephalopathy, and acute intestinal pseudoobstruction. He was admitted in a state of hepatic confusion. On physical examination, the abdomen was distended; and bowel sound was absent. Plain abdomen film revealed multiple air-fluid levels and distention of bowel loops. Initially, we gave him lactulose enemas every 6 hr for one day without improvement in his mental state. Furthermore, he became to a state of coma. Therefore, we gave him 0.5 mg of neostigmine subcutaneously to improve his peristaltic movement, and 2 L of polyethylene glycol electrolyte solution through a nasogastric tube for 4 hr to reduce the production and absorption of gut-derived toxins of nitrogenous compounds. After these treatments, the venous ammonia level decreased to the normal range within 12 hr, and the coma disappeared after 2 days. We suggest that neostigmine may be one of the most effective treatments to initiate peristaltic movement and bowel cleansing in cirrhotic patients with acute hepatic encephalopathy and acute intestinal pseudoobstruction.

Interstitial glycerol increase in microdialysis after glycerol enema.

Microdialysis allows the measurement of extracellular concentrations of various endogenous substances, such as excitotoxic amino acids or metabolic end products. Recent advances in microdialysis techniques have led to widespread use in patients with brain disorders. Microdialysis has proved to be a useful tool for monitoring cerebral biochemical metabolism and secondary brain damage in severe head injury, subarachnoid haemorrhage, stroke, and epilepsy. In our neurosurgical intensive care unit, microdialysis was performed on 42 patients. Four patients received a glycerol enema for therapy of a paralytic ileus. A glycerol peak was observed in both intracerebral and subcutaneous microdialysis occurring three to four hours after the glycerol enema in all four patients. The highest glycerol value was 1187micromol/l cerebral and 2997micromol/l in the subcutaneous tissue. Our study indicates that besides the measurement of serum osmolality and serum glycerol level, microdialysis may be an additional valuable tool to control glycerol therapy in patients with cerebral oedema and elevated intracranial pressure.

Mechanisms for contractile effect of Dai-kenchu-to in isolated guinea pig ileum.

The mechanisms by which Dai-kenchu-to (TJ-100), a kampo medicine, enhances gastrointestinal motility was investigated using isolated guinea pig ileum. TJ-100 induced contractions accompanied by autonomous contraction at a concentration of more than 3 x 10(-4) g/ml in a dose-related manner. The TJ-100-induced ileal contraction was suppressed by atropine and tetrodotoxin, but not by hexamethonium. This effect was partially suppressed in the presence of high concentrations of ICS 205-930, a serotonin 4 (5-HT4) receptor antagonist. In addition, TJ-100 showed an acetylcholine (ACh)-releasing action in the smooth muscle tissues of ileum. These results suggest that contractile response induced by TJ-100 is partially mediated by ACh released from the cholinergic nerve endings and that 5-HT4 receptors would be involved in the effect of TJ-100.

Amelioration of intestinal dysmotility and stasis by octreotide early after small-bowel autotransplantation in dogs.

BACKGROUND: Intestinal dysmotility and stasis after intestinal transplantation are considered to promote bacterial overgrowth and translocation. Two prokinetic agents, KW5139 (13-leu-motilin) and the somatostatin analogue octreotide acetate, were studied to determine whether they can ameliorate intestinal dysmotility during the early postoperative period. MATERIALS AND METHODS: Motility was recorded by multiple extraluminal strain-gauge transducers in 6 dogs on postoperative days 1, 3, 7, and 14. A barium meal study was performed with a separate group of 8 dogs on postoperative days 3 and 7. RESULTS: The agent KW5139 induced brief, weak contractions in the graft and had little effect on the dilated bowel; however, octreotide induced motor activity that propelled accumulated intestinal contents into the colon and reduced dilation of the transplanted bowel. CONCLUSION: Octreotide, but not KW5139, ameliorates intestinal dysmotility associated with bowel autotransplantation during the early postoperative period. Short-term administration of octreotide may be useful for the treatment of dysmotility following intestinal transplantation.

Treatment of acute colonic pseudoobstruction (Ogilvie's syndrome) with cisapride.

A 73-yr-old white woman admitted with lobar pneumonia and congestive heart failure developed progressive colonic pseudoobstruction (Ogilvie's syndrome) 2 days after admission which was unrelieved by diatrizoate meglumine (Gastrografin, Squibb Canada, Montreal) enema and rectal tube. Cisapride, a new gastrointestinal prokinetic agent, was administered intravenously with full resolution of the syndrome. To the authors' knowledge, this is the first reported case of successful treatment of acute colonic pseudoobstruction with cisapride.