Comparison of the efficacy and tolerability of elobixibat plus sodium picosulfate with magnesium citrate and split-dose 2-L polyethylene glycol with ascorbic acid for bowel preparation before outpatient colonoscopy: a study protocol for the multicentre, randomised, controlled E-PLUS trial.

BACKGROUND: Sodium picosulfate (SP)/magnesium citrate (MC) and polyethylene glycol (PEG) plus ascorbic acid are recommended by Western guidelines as laxative solutions for bowel preparation. Clinically, SP/MC has a slower post-dose defaecation response than PEG and is perceived as less cleansing; therefore, it is not currently used for major bowel cancer screening preparation. The standard formulation for bowel preparation is PEG; however, a large dose is required, and it has a distinctive flavour that is considered unpleasant. SP/MC requires a small dose and ensures fluid intake because it is administered in another beverage. Therefore, clinical trials have shown that SP/MC is superior to PEG in terms of acceptability. We aim to compare the novel bowel cleansing method (test group) comprising SP/MC with elobixibat hydrate and the standard bowel cleansing method comprising PEG plus ascorbic acid (standard group) for patients preparing for outpatient colonoscopy. METHODS: This phase III, multicentre, single-blind, noninferiority, randomised, controlled, trial has not yet been completed. Patients aged 40-69 years will be included as participants. Patients with a history of abdominal or pelvic surgery, constipation, inflammatory bowel disease, or severe organ dysfunction will be excluded. The target number of research participants is 540 (standard group, 270 cases; test group, 270 cases). The primary endpoint is the degree of bowel cleansing (Boston Bowel Preparation Scale [BBPS] score ≥ 6). The secondary endpoints are patient acceptability, adverse events, polyp/adenoma detection rate, number of polyps/adenomas detected, degree of bowel cleansing according to the BBPS (BBPS score ≥ 8), degree of bowel cleansing according to the Aronchik scale, and bowel cleansing time. DISCUSSION: This trial aims to develop a "patient-first" colon cleansing regimen without the risk of inadequate bowel preparation by using both elobixibat hydrate and SP/MC. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT; no. s041210067; 9 September 2021; https://jrct.niph.go.jp/ ), protocol version 1.5 (May 1, 2023).

Efficacy and Safety of Over-the-Counter Therapies for Chronic Constipation: An Updated Systematic Review.

INTRODUCTION: Constipation is commonly treated with over-the-counter (OTC) products whose efficacy and safety remain unclear. We performed a systematic review of OTC therapies for chronic constipation and provide evidence-based recommendations. METHODS: We searched PubMed and Embase for randomized controlled trials of ≥4-week duration that evaluated OTC preparations between 2004 and 2020. Studies were scored using the US Preventive Services Task Force criteria (0-5 scale) including randomization, blinding, and withdrawals. The strengths of evidence were adjudicated within each therapeutic category, and recommendations were graded (A, B, C, D, and I) based on the level of evidence (level I, good; II, fair; or III, poor). RESULTS: Of 1,297 studies identified, 41 met the inclusion criteria. There was good evidence (grade A recommendation) for the use of the osmotic laxative polyethylene glycol (PEG) and the stimulant senna; moderate evidence (grade B) for psyllium, SupraFiber, magnesium salts, stimulants (bisacodyl and sodium picosulfate), fruit-based laxatives (kiwi, mango, prunes, and ficus), and yogurt with galacto-oligosaccharide/prunes/linseed oil; and insufficient evidence (grade I) for polydextrose, inulin, and fructo-oligosaccharide. Diarrhea, nausea, bloating, and abdominal pain were common adverse events, but no serious adverse events were reported. DISCUSSION: The spectrum of OTC products has increased and quality of evidence has improved, but methodological issues including variability in study design, primary outcome measures, trial duration, and small sample sizes remain. We found good evidence to recommend polyethylene glycol or senna as first-line laxatives and moderate evidence supporting fiber supplements, fruits, stimulant laxatives, and magnesium-based products. For others, further validation with more rigorously designed studies is warranted.

Castor Oil and Bisacodyl Versus Sodium Picosulphate Magnesium Citrate for Bowel Cleansing Prior to Colonoscopy in a Limited Resource Setting.

BACKGROUND: The cost and availability are among factors that determine bowel preparation regimen for colonoscopy. AIMS: To assess the efficacy of an alternative bowel preparation regimen of Castor oil/Bisacodyl (CaO/B) for colonoscopy in a limited resource setting. MATERIALS AND METHODS: A retrospective cohort study of patients undergoing colonoscopy in an endoscopy referral centre in Port Harcourt Rivers State Nigeria from June 2014 to September 2019. Patients who had bowel preparation prior to colonoscopy with CaO/B were grouped and compared with a control group of patients that received sodium picosulphate magnesium citrate (SPMC). The variables collated were sociodemographics, primary indication, comorbidities, quality of bowel preparation (Aronchick scale), polyp detection and caecal intubation. Statistical analysis was performed using IBM SPSS version 21. RESULTS: A total of 258 patients undergoing colonoscopy met the inclusion criteria with 118 prepared with CaO/B and 140 patients with SPMC. The mean age of patients in the groups were 53.9 ± 11.2 years and 54.7 ± 12.8 years respectively; a total of 192 males and 66 females with a near even distribution in both groups. Bowel preparation was Excellent/Good in 51 patients using CaO/B and 108 for SPMC (p = <0.0001). No statistical difference was noted in the caecal intubation and polyp detection rates between the 2 groups- p values 0.395 and 0.990 respectively. CONCLUSION: Castor oil/ Bisacodyl regimen is cheap but not consistently associated with adequate bowel preparation for colonoscopy. Expertise of endoscopists and copious lavage are crucial when CaO/B regimen is used for bowel cleansing.

Linker Optimization and Therapeutic Evaluation of Phosphatidylserine-Targeting Zinc Dipicolylamine-based Drug Conjugates.

We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy.

[Assessment of the efficacy of mexidol in the combination with hyperbaric oxygen in acute ischemic stroke]. / Otsenka éffektivnosti primeneniia meksidola v sochetanii s giperbaricheskoi oksigenatsiei u bol'nykh v ostreishem periode ishemicheskogo insul'ta.

To study the efficacy of mexidol in the combination with hyperbaric oxygenation (HBO) in comparison with the standard HBO sessions in patients with acute ischemic stroke. One hundred and twelve patients were examined. In the main group, 48 patients underwent HBO and received treatment with mexidol. The control group consisted of 64 people who underwent the standard HBO sessions only. The use of combination therapy (HBO+mexidol) leads to the significantly more rapid normalization of acute phase indices which are correlated with neurological deficit reduction.

2-Methylpyridine-1-ium-1-sulfonate from Allium hirtifolium: An anti-angiogenic compound which inhibits growth of MCF-7 and MDA-MB-231 cells through cell cycle arrest and apoptosis induction.

Natural products have well been recognized as sources of drugs in cancer treatment. Some medicinal plants contain the constituents with potent anti-angiogenic and anti-cancer effects, which have offered great hopes of being used as drugs for treating various cancers. The present study aims at identifying the anti-angiogenic effects of 2-Methylpyridine-1-ium-1-sulfonate (MPS) isolated from the ethyl acetate extract (EA) of Persian shallot (Allium hirtifolium). In a concentration-dependent manner, the MPS was able to inhibit endothelial cell migration and angiogenesis in both in vivo and in vitro assays, and also significantly suppressed proliferation of MCF-7 and MDA-MB-231 human breast cancer cell lines. Additionally, treatment with MPS showed a significant reduction in the vascular endothelial growth factor (VEGF) secretion level and production/activity of matrix metalloproteinases (MMP-2 and MMP-9) in the studied cells. The flow cytometry analysis indicated that MPS suppressed growth of MCF-7 and MDA-MB-231 cells at G0/G1 and S phases, respectively. Our results indicated that the induction of cell cycle arrest was correlated with the obvious changes in expression of p21, p27 and p53. According to the DNA fragmentation assay, MPS caused apoptosis in both cell lines, which confirms the results obtained with the growth assay. Moreover, the compound-mediated apoptosis accompanied with the increase in the Bax/Bcl-2 ratio and caspase-3 and -9 activities. Molecular docking results indicated that the MPS compound can surprisingly bind to VEGF and VEGF receptors and interacts with their critical amino acids. Finally, compounds with anticancer inhibitory activity (e.g. MPS) are abundant in nature and can be obtained from several sources. So, our data can be clinically developed for treating angiogenesis and cancer significantly.

[Dynamics of eeg and psychophysiological indicators of acute poisoning neurotoxicants on the stage of rehabilitation on the background of different methods of treatment]. / Dinamika elektroentsefalograficheskikh i psikhofiziologicheskikh pokazatelei pri ostrykh otravleniyakh neirotoksikantami na etape reabilitatsii na fone razlichnykh metodov lecheniya.

AIM: To evaluate the dynamics of functional activity of brain structures underlying cognitive functions in patients with encephalopathy due to poisoning with neurotoxicants on the stage of rehabilitation. MATERIAL AND METHODS: Fifty-six patients were examined. The main group consisted of 40 patients treated with intravenous injections with mexidol (n=10), combination of mexidol with non-pharmacological methods - mesodiencephalic modulation (MDM) (n=10), hyperbaric oxygenation (HBO) (n=10) and the combination of MDM and HBO (n=10). The comparison group included 16 people. All patients underwent neurophysiological (EEG, auditory event-related potentials) and neuropsychological examinations. RESULTS: Marked EEG changes were noted in all patients. The domination of disturbances of functional activity on the diencephalic or mesodiencephalic levels was observed. After treatment, positive changes were found in 60% of patients. The positive dynamics was observed in 80% patients when the combination of mexidol, MDM and HBO was used. The negative dynamics was noted in 5 (12,5%) of patients of the main group, in particular when mexidol only was used. The results of the primary neuropsychological study revealed that cognitive impairment of different severity was found in 97,5% of patients of the main group and 100% of patients of the comparison group. After treatment, performance on neuropsychological tests improved by 62,5%, N200 and P300 latencies reduced, while the amplitudes increased, in the patients of the main group. CONCLUSION: The use of mexidol, MDM and HBO in the treatment of patients with encephalopathy due to poisoning with neurotoxicants on the stage of rehabilitation improved the indicators of functional brain activity and cognitive functions.

Management of chronic constipation in patients with diabetes mellitus.

AIM: The aim of this review is to provide an overview of the clinical assessment and evidence-based treatment options for managing diabetes-associated chronic constipation. METHODS: A literature search of published medical reports in English language was performed using the OVID Portal, from PUBMED and the Cochrane Database of Systematic Reviews, from inception to October 2015. A total of 145 abstracts were identified; duplicate publications were removed and 95 relevant full-text articles were retrieved for potential inclusion. RESULTS: Chronic constipation is one of the most common gastrointestinal symptoms in patients with diabetes, and occurs more frequently than in healthy individuals. Treatment goals include improving symptoms and restoring bowel function by accelerating colonic transit and facilitating defecation. Based on guidelines and data from published literature, food and dietary change with exercise and lifestyle change should be the first step in management. For patients recalcitrant to these changes, laxatives should be the next step of treatment. Treatment should begin with bulking agents such as psyllium, bran or methylcellulose followed by osmotic laxatives if response is poor. Lactulose, polyethylene glycol and lactitol are the most frequently prescribed osmotic agents. Lactulose has a prebiotic effect and a carry-over effect (continued laxative effect for at least 6 to 7 days, post cessation of treatment). Stimulants such as bisacodyl, sodium picosulphate and senna are indicated if osmotic laxatives are not effective. Newer agents such as chloride-channel activators and 5-HT4 agonist can be considered for severe or resistant cases. CONCLUSION: The primary aim of intervention in diabetic patients with chronic constipation is to better manage the diabetes along with management of constipation. The physician should explain the rationale for prescribing laxatives and educate patients about the potential drawbacks of long-term use of laxatives. They should contact their physician if short-term use of prescribed laxative fails to provide relief.

[THE STUDY OF THE EFFECTS OF ANXYOLYTIC, ANTIOXIDANT, IMMUNOCORRECTOR AND HYPERBARIC OXYGENATION ON THE DYNAMICS OF MAIN BLOOD GAS AND ELECTROLYTE INDICES AND BEHAVIORAL RESPONSE IN EXPERIMENTAL STRESS MODEL].

Experiments on the model of immobilization stress in albino mice showed that a combination of mexidol, thymogen, and hyperbaric oxygenation reduced adverse effects of diazepam on behavioral response of animals in the black-and-white chamber and elevated cross maze tests and led to optimization of the blood gas composition as manifested by increased oxygen tension, normalization of the partial pressure of carbon dioxide, and restoration of the acid-base balance and blood bicarbonate level. The proposed combined treatment can be recommended for the treatment of patients with stress-induced pathology.

Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile.

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.

[Bowel preparation for colonoscopy. Any significant progress on the horizon?]. / Preparación para colonoscopia. ¿Algún avance significativo en el horizonte?

Colonoscopy is the method of choice for colorectal cancer screening. To be effective, screening colonoscopy must have high quality standards. The key element is the quality of the preparation. However, up to 20% of patients are inadequately prepared and, at present, anterograde washing is the least tolerated part of the procedure. In the choice of preparation, safety is a prerequisite and efficacy is a priority. Tolerance is a secondary but nevertheless influential factor in the quality of preparation and has consequently been the primary focus of many recent studies. In the last few years, a rapidly increasing number of studies have evaluated new drugs, dosages and adjuvant therapies to improve efficacy and tolerability. These studies have collaterally shown that inadequate preparation and lack of adherence to the prescribed regimen can be partially predicted, making it essential to identify this patient subgroup and invest the necessary effort in their instruction. New individualized and flexible approaches are expected for the different clinical scenarios. The search for the ideal colonoscopy preparation, which would be tolerable, safe and above all effective, remains open.

Systematic review of stimulant and nonstimulant laxatives for the treatment of functional constipation.

BACKGROUND: Constipation is an uncomfortable and common condition that affects many, irrespective of age. Since 1500 BC and before, health care practitioners have provided treatments and prevention strategies to patients for chronic constipation despite the significant variation in both medical and personal perceptions of the condition. OBJECTIVE: To review relevant research evidence from clinical studies investigating the efficacy and safety of commercially available pharmacological laxatives in Canada, with emphasis on studies adopting the Rome criteria for defining functional constipation. SEARCH METHODS: PubMed, Medline, Embase and Evidence-Based Medicine Reviews databases were searched for blinded or randomized clinical trials and meta-analyses assessing the efficacy of nonstimulant and stimulant laxatives for the treatment of functional constipation. RESULTS: A total of 19 clinical studies and four meta-analyses were retrieved and abstracted regarding study design, participants, interventions and outcomes. The majority of studies focused on polyethylene glycol compared with placebo. Both nonstimulant and stimulant laxatives provided better relief of constipation symptoms than placebo according to both objective and subjective measures. Only one study compared the efficacy of a nonstimulant versus a stimulant laxative, while only two reported changes in quality of life. All studies reported minor side effects due to laxative use, regardless of treatment duration, which ranged from one week to one year. Laxatives were well tolerated by both adults and children.

[The distribution of mexidol in the rat's brain and its subcellular fractions].

OBJECTIVE: To study the penetration of mexidol through the blood-brain barrier into different brain compartments and cell mitochondria. MATERIAL AND METHODS: The study was carried out on adult male Wistar rats using the drug mexidol ("Farmasoft" Russia). The penetration of mexidol into different compartments of the brain (the cortex, cerebellum, thalamus and medulla) and distribution between mitochondrial and cytoplasmic fractions of the cerebral cortex was studied. The concentration of mexidol in blood plasma and brain tissues was measured using HPLC. RESULTS AND CONCLUSION: Mexidol penetrated through the blood-brain barrier into brain compartments of rats with the maximal accumulation in the cortex. In the brain cortex cells, mexidol was identified in the cytoplasmic and mitochondrial fractions.

[Effect of intravenous laser irradiation on some blood biochemical indicators in the acute stage of lacunar infarcts].

OBJECTIVE: To investigate the dynamics of lipid metabolism, C-reactive protein (CRP), lipid peroxidation and antioxidant system in lacunar infarction (LI) in chronic cerebral ischemia. MATERIAL AND METHODS: Two groups of patients were studied. The main group included 31 patients who received intravenous laser irradiation of blood (ILIB) with semiconductor laser (wavelength - 0.67 microns, the power output - 3-2 mW) in addition to standard treatment. Patients of the control group (n=22) received only standard treatment. RESULTS: A statistically significant decrease in total cholesterol levels to normal values due to the significant reduction of the content of antiatherogenic fraction of cholesterol (high-density lipoprotein and atherogenic low-density lipoprotein cholesterol) was found in the main group after treatment. The reduction in atherogenic cholesterol fractions in both groups was associated with the decrease in apolipoprotein B level. The level of CRP was higher than normal in the main and control groups of patients before and after treatment, which indicated the risk of vascular diseases in patients with LI. After treatment, superoxide dismutase activity returned to normal values. In patients of the main group, the catalase activity increased while the level of reduced glutathione did not change and lipid peroxidation products remained on the high level. CONCLUSION: Additional antioxidant therapy is needed for these patients.

Pediatric constipation in the emergency department: evaluation, treatment, and outcomes.

OBJECTIVES: Limited knowledge exists surrounding the pharmacologic management of pediatric constipation in the emergency department (ED) setting and the success of interventions. Our primary objective was to determine whether enema administration is associated with 7-day ED revisits for persistent symptoms. Secondary objectives focused on assessing other predictors of ED revisits. METHODS: We conducted a retrospective cohort study of children <18 years old, diagnosed as having constipation (International Classification of Diseases-10 codes F98.1 nonorganic encopresis, K59.0 constipation) in a pediatric ED in Toronto, Canada, between November 2008 and October 2010. RESULTS: A total of 3592 visits were included; 6% (n = 225) were associated with a revisit. Children with revisits more frequently had vomiting (28% vs 17%, P = 0.001), more pain (5.7 ±â€Š3.6 vs 4.6-3.6 of 10, P = 0.01), and underwent more blood tests (19% 05, 11%, 95% confidence interval [CI] of the difference 3%-14%] and diagnostic imaging (62% vs 47%, 95% CI of the difference 9%-22%). Children administered an enema were 1.54 times more likely to revisit the ED than those who did not receive an enema (8.6% vs 5.5%, 95% CI of the difference 1.1%-5.2%, P = 0.001). Type of enema administered varied by age (P < 0.001). Regression analysis identified the following independent predictors of revisits: diagnostic imaging (odds ratio [OR] 1.54, 95% CI 1.15-2.06), vomiting (OR 1.45, 95% CI 1.07-1.98), enema administration (OR 1.40, 95% CI 1.05-1.88), and significant medical history (OR 1.26, 95% CI 1.04-1.53). CONCLUSIONS: Enema administration and diagnostic imaging are associated with revisits in children diagnosed with constipation. Their role in the ED management of pediatric constipation requires further evaluation.

Antithrombogenic activity of antioxidant compounds.

Antithrombotic activities of enoxifol, a new antioxidant with antiaggregant activity demonstrated in vitro and in vivo, and antioxidant mexidol were compared on the rat model of arterial thrombosis induced by application of 50% ferric chloride. Acetylsalicylic acid (antiaggregant) served as the reference drug. All drugs exhibited dose-dependent antithrombotic activity. Enoxifol was more effective than mexidol, both drugs being more active than the reference drug (acetylsalicylic acid). Taking into account the pathogenesis of the thrombosis in this experimental model, we can hypothesize that the pronounced antithrombotic effect of enoxifol was due to its antiaggregant and antioxidant activities.

[Endoscopic treatment of chemical burns to the stomach with mucosa ulceration and necrosis].

The prevalence of acute poisoning with caustic substances in Russia is higher than in other countries and is reported by different authors as accounting for 10-32% cases among the patients admitted to acute poisoning treatment centres. Especially unfavorable prognosis is considered for necrotizing burns to the stomach that increase the risk of severe complications leading to disability of patients. The study aimed at improving the treatment of necrotizing chemical burn to the stomach by the infusion of a 5% Mexidole solution into the edges of a burn lesion at different stages of the treatment course. The paper presents the outcomes of patients who sustained chemical burns to the stomach with mucosa ulceration and necrosis, and provides an assessment of early endoscopic treatment effect.

[Myocardial cytoprotectors, a reserve therapeutic modality for patients with stable angina of effort].

The study included 1418 patients with FC I-IV stable angina of effort (42.4% men and 57.6% women, mean age 74.6 +/- 1.2 years). The possibility to supplement standard therapy with myocardial cytoprotectors (trimetasidin, mexidol, qudesan) was estimated in 4 groups of patients from the severity of pain syndrome, chronic cardiac insufficiency, and heart rhythm disturbances.

[Pharmacological neuroprotection against brain damage in ischemiai/reperfusion experiment].

Experiment carried out on laboratory animals (rats) were aimed at comparative evaluation of the effect of several neuroprotective drugs under the conditions of model brain ischemia-reperfusion. The experimental methods included staining of brain tissue sections by hematoxiline-eosine, Nissl staining, and expression of NOS1, NOS3, TRAIL by imunnohistological means. The intensity of damage in various parts of brain and the nature of apoptosis without neuroprotection and with popular neuroprotectors (cytoflavin, actovegin, mexidol) and a test drug at the stage ofpreclinical trial (AKF-90-7) were evaluated. Characteristic cytotoxic (coagulative pycnomorphic and colliquative necrosis of neurons) and vascular (hemostasia, erythropedesis) changes were revealed. The neuroprotective effectof drugs decreases in the following order: AKF-90-7 > cytoflavin > actovegin > mexidol.

Evidence-based recommendations for bowel cleansing before colonoscopy in children: a report from a national working group.

BACKGROUND: There are no current recommendations for bowel cleansing before colonoscopy in children. The Israeli Society of Pediatric Gastroenterology and Nutrition (ISPGAN) established an iterative working group to formulate evidence-based guidelines for bowel cleansing in children prior to colonoscopy. METHOD: Data were collected by systematic review of the literature and via a national-based survey of all endoscopy units in Israel. Based on the strength of evidence, the Committee reached consensus on six recommended protocols in children. Guidelines were finalized after an open audit of ISPGAN members. RESULTS: Data on 900 colonoscopies per year were accrued, which represents all annual pediatric colonoscopies performed in Israel. Based on the literature review, the national survey, and the open audit, several age-stratified pediatric cleansing protocols were proposed: two PEG-ELS protocols (polyethylene-glycol with electrolyte solution); Picolax-based protocol (sodium picosulphate with magnesium citrate); sodium phosphate protocol (only in children over the age of 12 years who are at low risk for renal damage); stimulant laxative-based protocol (e. g. bisacodyl); and a PEG 3350-based protocol. A population-based analysis estimated that the acute toxicity rate of oral sodium phosphate is at most 3/7320 colonoscopies (0.041 %). Recommendations on diet and enema use are provided in relation to each proposed protocol. CONCLUSION: There is no ideal bowel cleansing regimen and, thus, various protocols are in use. We propose several evidence-based protocols to optimize bowel cleansing in children prior to colonoscopy and minimize adverse events.