Pharmacological Basis for the Antidiarrheal and Antispasmodic Effects of Cuminaldehyde in Experimental Animals: In Silico, Ex Vivo and In Vivo Studies.

BACKGROUND: Medicinal herbs are frequently used for the management of gastrointestinal disorders because they contain various compounds that can potentially amplify the intended therapeutic effects. Cuminaldehyde is a plant-based constituent found in oils derived from botanicals such as cumin, eucalyptus, myrrh, and cassia and is responsible for its health benefits. Despite the utilization of cuminaldehyde for several medicinal properties, there is currently insufficient scientific evidence to support its effectiveness in treating diarrhea. Hence, the present investigation was carried out to evaluate the antidiarrheal and antispasmodic efficacy of cuminaldehyde, with detailed pharmacodynamics explored. METHODS: An in vivo antidiarrheal test was conducted in mice following the castor oil-induced diarrhea model, while an isolated small intestine obtained from rats was used to evaluate the detailed mechanism(s) of antispasmodic effects. RESULTS: Cuminaldehyde, at 10 and 20 mg/kg, exhibited 60 and 80% protection in mice from episodic diarrhea compared to the saline control group, whereas this inhibitory effect was significantly reversed in the pretreated mice with glibenclamide, similar to cromakalim, an ATP-dependent K+ channel opener. In the ex vivo experiments conducted in isolated rat tissues, cuminaldehyde reversed the glibenclamide-sensitive low K+ (25 mM)-mediated contractions at significantly higher potency compared to its inhibitory effect against high K+ (80 mM), thus showing predominant involvement of ATP-dependent K+ activation followed by Ca++ channel inhibition. Cromakalim, a standard drug, selectively suppressed the glibenclamide-sensitive low K+-induced contractions, whereas no relaxation was observed against high K+, as expected. Verapamil, a Ca++ channel inhibitor, effectively suppressed both low and high K+-induced contractions with similar potency, as anticipated. At higher concentrations, the inhibitory effect of cuminaldehyde against Ca++ channels was further confirmed when the preincubated ileum tissues with cuminaldehyde (3 and 10 mM) in Ca++ free medium shifted CaCl2-mediated concentration-response curves (CRCs) towards the right with suppression of the maximum peaks, similar to verapamil, a standard Ca++ ion inhibitor. CONCLUSIONS: Present findings support the antidiarrheal and antispasmodic potential of cuminaldehyde, possibly by the predominant activation of ATP-dependent K+ channels followed by voltage-gated Ca++ inhibition. However, further in-depth assays are recommended to know the precise mechanism and to elucidate additional unexplored mechanism(s) if involved.

Racecadotril Versus Loperamide in Acute Radiation Enteritis: A Randomized, Double-Masked, Phase 3, Noninferiority Trial.

PURPOSE: There is currently no gold standard for the management of acute radiation enteritis. We compared the efficacy and safety of Racecadotril, an anti-hypersecretory drug, versus Loperamide, an anti-motility agent, in acute radiation enteritis. METHODS AND MATERIALS: We conducted a randomized, double-masked, non-inferiority trial at a single research institute. Patients receiving curative radiation for pelvic malignancies, who developed grade 2 or 3 diarrhea (as per Common Terminology Criteria for Adverse Events, v 4.0) were included in the study. Patients in the intervention arm received Racecadotril and placebo. Patients in the control arm received Loperamide and placebo. The primary outcome was the resolution of diarrhea, 48 hours after the start of treatment. RESULTS: 162 patients were randomized between 2019 and 2022. On intention-to-treat analysis, 68/81 patients, 84%, (95% CI, 74.1%-91.2%) in the Racecadotril arm and 70/81, 86.4%, (95% CI, 77.0%-93.0%) in the Loperamide arm improved from grade 2 or 3 diarrhea to grade 1 or 0, (P= .66, χ2 test). The difference in proportion was 2.4% (95% CI: -8.5% to 13.4%). Since the upper boundary of the 95% CI crossed our non-inferiority margin of 10% (13.4%) we could not prove the non-inferiority of Racecadotril over Loperamide. Rebound constipation was more in the Loperamide arm compared to Racecadotril (17.3% vs 6.2%; P = .028) CONCLUSIONS: The non-inferiority of Racecadotril to Loperamide in acute radiation enteritis could not be demonstrated. However, Racecadotril can be the preferred drug of choice in acute radiation enteritis because Racecadotril does not affect bowel motility, achieved a high clinical success rate similar to that of Loperamide, and was associated with lesser side effects.

Racecadotril for the treatment of acute gastroenteritis in children received outpatient care in Qatar

Introduction: Acute gastroenteritis is a clinical syndrome often defined by increased stool frequency (eg, ≥3 loose or watery stools in 24 hours, also it is one of the most common causes of morbidity and mortality in children under 5 years in the developing world. Racecadotril is an antisecretory agent that can prevent fluid/electrolyte depletion from the bowel as a result of acute diarrhea without affecting intestinal motility. Research question or hypothesis: To investigate whether prescribing Racecadotril plus oral rehydrating solution in outpatient care helps to decrease the hospital revisit rate within 72 hours due to acute gastroenteritis in comparison with oral rehydrating solution alone. Study design: Retrospective cohort study. Methods: Pediatric patients aged 3 months to 14 years visited Al Wakra Pediatric emergency department due to acute gastroenteritis for outpatient care in the period between 1/1/2022 till 30/06/2022 were included. Case group was defined as patients who prescribed oral rehydrating solution plus Racecadotril upon their initial visit. Control group was defined as patients who prescribed only oral rehydrating solution upon their initial visit. Results: 2505 pediatric patients were included, 520 patients were enrolled in the control group, and 1985 patients were included in the case group. Most patients in both groups were 1 to 5 years old (67% in control group, and 59% in case group). The hospital revisit rate within 72 hours due to gastroenteritis was slightly less in case group 7.1% in comparison with 7.5% in control group (Relative risk 0.95, 95% CI 0.68 to 1.34). Most patients (88%) who revisited the hospital due to gastroenteritis within 72 hours showed no or mild signs of clinical dehydration in their initial visit (77% in control group, and 93% in case group) Conclusion: Racecadotril was found to have insignificant impact on hospital revisit rate in acute pediatric gastroenteritis managed at outpatient setting. (AU)

Ethanol Extract of Glycyrrhiza uralensis Fisch: Antidiarrheal Activity in Mice and Contraction Effect in Isolated Rabbit Jejunum.

OBJECTIVE: To evaluate the antidiarrheal effect of ethanol extract of Glycyrrhiza uralensis Fisch root (GFR) in vivo and jejunal contraction in vitro. METHODS: In vivo, 50 mice were divided into negative control, positive control (verapamil), low-, medium- and high-dose GFR (250, 500, 1,000 mg/kg) groups by a random number table, 10 mice in each group. The antidiarrheal activity was evaluated in castor oil-induced diarrhea mice model by evacuation index (EI). In vitro, the effects of GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) on the spontaneous contraction of isolated smooth muscle of rabbit jejunum and contraction of pretreated by Acetylcholine (ACh, 10 µmol/L) and KCl (60 mmol/L) were observed for 200 s. In addition, CaCl2 was accumulated to further study its mechanism after pretreating jejunal smooth muscle with GFR (1 and 3 g/L) or verapamil (0.03 and 0.1 µmol/L) in a Ca2+-free-high-K+ solution containing ethylene diamine tetraacetic acid (EDTA). RESULTS: GFR (500 and 1,000 mg/kg) significantly reduced EI in castor oil-induced diarrhea model mice (P<0.01). Meanwhile, GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) inhibited the spontaneous contraction of rabbit jejunum (P<0.05 or P<0.01). Contraction of jejunums samples pretreated by ACh and KCl with 50% effective concentration (EC50) values was 1.05 (0.71-1.24), 0.34 (0.29-0.41) and 0.15 (0.11-0.20) g/L, respectively. In addition, GFR moved the concentration-effect curve of CaCl2 down to the right, showing a similar effect to verapamil. CONCLUSIONS: GFR can effectively against diarrhea and inhibit intestinal contraction, and these antidiarrheal effects may be based on blocking L-type Ca2+ channels and muscarinic receptors.

Ethanol Extract of Glycyrrhiza uralensis Fisch: Antidiarrheal Activity in Mice and Contraction Effect in Isolated Rabbit Jejunum / 中国结合医学杂志

OBJECTIVE@#To evaluate the antidiarrheal effect of ethanol extract of Glycyrrhiza uralensis Fisch root (GFR) in vivo and jejunal contraction in vitro.@*METHODS@#In vivo, 50 mice were divided into negative control, positive control (verapamil), low-, medium- and high-dose GFR (250, 500, 1,000 mg/kg) groups by a random number table, 10 mice in each group. The antidiarrheal activity was evaluated in castor oil-induced diarrhea mice model by evacuation index (EI). In vitro, the effects of GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) on the spontaneous contraction of isolated smooth muscle of rabbit jejunum and contraction of pretreated by Acetylcholine (ACh, 10 µmol/L) and KCl (60 mmol/L) were observed for 200 s. In addition, CaCl2 was accumulated to further study its mechanism after pretreating jejunal smooth muscle with GFR (1 and 3 g/L) or verapamil (0.03 and 0.1 µmol/L) in a Ca2+-free-high-K+ solution containing ethylene diamine tetraacetic acid (EDTA).@*RESULTS@#GFR (500 and 1,000 mg/kg) significantly reduced EI in castor oil-induced diarrhea model mice (P<0.01). Meanwhile, GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) inhibited the spontaneous contraction of rabbit jejunum (P<0.05 or P<0.01). Contraction of jejunums samples pretreated by ACh and KCl with 50% effective concentration (EC50) values was 1.05 (0.71-1.24), 0.34 (0.29-0.41) and 0.15 (0.11-0.20) g/L, respectively. In addition, GFR moved the concentration-effect curve of CaCl2 down to the right, showing a similar effect to verapamil.@*CONCLUSIONS@#GFR can effectively against diarrhea and inhibit intestinal contraction, and these antidiarrheal effects may be based on blocking L-type Ca2+ channels and muscarinic receptors.

Effects of probiotics on loperamide-induced constipation in rats.

The role of probiotics in mitigating constipation, gut immunity, and gut microbiota has not been well studied. We aimed to evaluate the effects of probiotics on loperamide (LP)-induced constipation in Sprague-Dawley rats. Altogether, 150 male Sprague-Dawley rats (age 8 weeks) were used in the experiments following a 12-day acclimatisation period and were randomly divided into three treatment groups (groups 1, 2, and 3). Spastic constipation was induced via oral LP administration (3 mg/kg) for 6 days, 1 h before administering each test compound in groups 1 and 2. A probiotic solution (4 mL/kg body weight) was orally administered once a day for 6 days in group 2. In group 1, a phosphate buffer solution was orally administered once a day for 6 days, 1 h after each LP administration. In group 3, a phosphate buffer solution was orally administered once a day for 6 days. In the probiotic group, faecal parameters improved; faecal n-butyric acid, acetic acid, and IgA concentrations were increased; intestinal transit time was shortened; and disturbance of intestinal microbiota was inhibited. Our findings suggest that this probiotic was useful in improving various symptoms caused by constipation.

Loperamide Toxicity Revealing Apical Hypertrophic Cardiomyopathy.

Loperamide, a µ-opioid receptor agonist, can cause cardiotoxicity by inhibiting the potassium ion channel and slowing cardiomyocyte repolarization. This, in turn, can lead to frequent early afterdepolarizations, the most common mechanism of drug-induced long QT syndrome and torsades de pointes. Apical hypertrophic cardiomyopathy (AHCM) is a nonobstructive hypertrophic cardiomyopathy rarely associated with malignant arrhythmias. We present a case of loperamide-induced malignant ventricular arrhythmia revealing underlying AHCM in a 25-year-old woman with a history of sudden cardiac arrest (SCA) and opioid use. It is important to evaluate for structural heart disease in all patients presenting with SCA, regardless of presumed etiology such as drug-induced cardiotoxicity, to prevent missed opportunities for adequate treatment. Furthermore, the diagnosis of AHCM in SCA warrants further genetic evaluation for variances with a predilection for malignant arrhythmias.

A Case Report of Torsade de Pointes and Brugada Pattern Associated with Loperamide Misuse and Supratherapeutic Loperamide Concentrations.

BACKGROUND: Loperamide, commonly sold under the brand name Imodium® (Johnson & Johnson, Fort Washington, PA), is a widely available, over-the-counter antidiarrheal medication that possesses µ-opioid agonist properties and can have catastrophic cardiac events when misused or abused. Since the start of the opioid epidemic in the United States, there has been an increasing number of case reports and deaths linking loperamide abuse with cardiac events such as torsades de pointes (TdP) and Brugada syndrome. CASE REPORT: This case report presents a 22-year-old man who presented in cardiac arrest from polymorphic ventricular tachycardia consistent with TdP and a Type 1 Brugada pattern after intentional loperamide abuse. We discuss this patient's management and the proposed pathophysiology of these two cardiotoxicities, of which, to our knowledge, no previously published case report has displayed both in the same patient after a supratherapeutic loperamide ingestion. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As the prevalence of opioid dependency and misuse has increased, so, too, has the misuse of un-scheduled medications such as loperamide to achieve central nervous system opioid effects. It is important for the emergency physician to know about and understand loperamide-associated cardiotoxicities such as prolongation of the QRS, unmasking of Brugada patterns, QT prolongation, or ventricular dysrhythmias such as TdP to be able to recognize and treat it.

A Case Report of Loperamide-Induced Ventricular Storm.

Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.

Is Lanreotide Really Useful in High Output Stoma? Comparison between Lanreotide to Conventional Antidiarrheal Treatment Alone.

BACKGROUND: The incidence of high-output stoma (HOS) was reported to be approximately 3 to 16% in the literature, and HOS can cause dehydration. This complication is often severe enough to warrant hospital readmission and may result in renal failure. The aim of this study was to show a decrease of 50% in ileostomy output in the experimental arm using lanreotide treatment. METHODS: Patients with an ileostomy output ≥ 1.5 l/24 hours were included in this prospective, open, multicentre randomized trial. Patients were randomly allocated between treatment arms with either lanreotide (LAN) and antidiarrhoeal treatments (TAD) (LAN-TAD group) or antidiarrhoeal treatments only (TADS group). The primary outcome was ileostomy output after 72 days. The secondary endpoints were ileostomy output during the first 6 days, blood urea and creatinine values, hospital length of stay and serious adverse events. RESULTS: In the per-protocol analysis, there were nine patients in the control group (TADS) and six patients in the experimental group (TAD-LAN group). The stoma outputs at Day 3 (D3) in the experimental and control groups were 1,900 ± 855.7 mL and 1,728.6 ± 845.5 mL, respectively (p = 0.2). No differences were found concerning stoma output at D6, renal function, or hospital length of stay between the two groups. CONCLUSION: The trial was prematurely stopped due to the low number of patients included. The question of the usefulness of somatostatin analogues in HOS persists, especially as the cost of this treatment is high, and there is a lack of evidence of its effectiveness.

Chitosan oligosaccharides attenuate loperamide-induced constipation through regulation of gut microbiota in mice.

This study was designed to explore the improvement of chitosan oligosaccharides (COS) on constipation through regulation of gut microbiota. Here, we proved that COS treatment profoundly boosted intestinal motility, restrained inflammatory responses, improved water-electrolyte metabolism and prevented gut barrier damage in constipated mice induced by loperamide. By 16S rDNA gene sequencing, the disbalanced gut microbiota was observed in constipated mice, while COS treatment statistically reversed the abundance changes of several intestinal bacteria at either phylum, family and genus levels, which partly led to the balance in production of intestinal metabolites including bile acids, short-chain fatty acids and tryptophan catabolites. In addition, COS failed to relieve the constipation in mice with intestinal flora depletion, confirming the essentiality of gut microbiota in COS-initiated prevention against constipation. In summary, COS can ameliorate the development of loperamide-induced constipation in mice by remodeling the structure of gut microbial community.

Lower-Dose Zinc for Childhood Diarrhea - A Randomized, Multicenter Trial.

BACKGROUND: The World Health Organization recommends 20 mg of zinc per day for 10 to 14 days for children with acute diarrhea; in previous trials, this dosage decreased diarrhea but increased vomiting. METHODS: We randomly assigned 4500 children in India and Tanzania who were 6 to 59 months of age and had acute diarrhea to receive 5 mg, 10 mg, or 20 mg of zinc sulfate for 14 days. The three primary outcomes were a diarrhea duration of more than 5 days and the number of stools (assessed in a noninferiority analysis) and the occurrence of vomiting (assessed in a superiority analysis) within 30 minutes after zinc administration. RESULTS: The percentage of children with diarrhea for more than 5 days was 6.5% in the 20-mg group, 7.7% in the 10-mg group, and 7.2% in the 5-mg group. The difference between the 20-mg and 10-mg groups was 1.2 percentage points (upper boundary of the 98.75% confidence interval [CI], 3.3), and that between the 20-mg and 5-mg groups was 0.7 percentage points (upper boundary of the 98.75% CI, 2.8), both of which were below the noninferiority margin of 4 percentage points. The mean number of diarrheal stools was 10.7 in the 20-mg group, 10.9 in the 10-mg group, and 10.8 in 5-mg group. The difference between the 20-mg and 10-mg groups was 0.3 stools (upper boundary of the 98.75% CI, 1.0), and that between the 20-mg and 5-mg groups was 0.1 stools (upper boundary of the 98.75% CI, 0.8), both of which were below the noninferiority margin (2 stools). Vomiting within 30 minutes after administration occurred in 19.3%, 15.6%, and 13.7% of the patients in the 20-mg, 10-mg, and 5-mg groups, respectively; the risk was significantly lower in the 10-mg group than in the 20-mg group (relative risk, 0.81; 97.5% CI, 0.67 to 0.96) and in the 5-mg group than in the 20-mg group (relative risk, 0.71; 97.5% CI, 0.59 to 0.86). Lower doses were also associated with less vomiting beyond 30 minutes after administration. CONCLUSIONS: Lower doses of zinc had noninferior efficacy for the treatment of diarrhea in children and were associated with less vomiting than the standard 20-mg dose. (Funded by the Bill and Melinda Gates Foundation; ZTDT ClinicalTrials.gov number, NCT03078842.).

Loperamide Abuse and Its Sequelae.

INTRODUCTION: Loperamide is an opioid available over the counter and in prescription form. Loperamide functions as a µ-agonist within the enteric nervous system to slow intestinal motility. Its antidiarrheal properties and primarily peripheral activity make loperamide an important tool in the management of inflammatory bowel disease. CASE REPORT: A 42-year-old man was found unconscious in cardiac arrest, and emergency medical personnel restored normal sinus rhythm. Family reported complaints of abdominal pain and that he "went through a lot" of loperamide. In the emergency department, the patient exhibited symptoms consistent with an opioid overdose. Mental status improved after administration of naloxone, an opioid antagonist. An electrocardiogram revealed a prolonged QTc interval, which progressed into Torsades de Pointes rhythm during admission. The patient succumbed from hypoxic brain injury, and there was evidence of acute pancreatitis at autopsy. Loperamide and desmethylloperamide (loperamide metabolite) were detected in blood samples. Cause of death was ruled loperamide toxicity. DISCUSSION: Because of reduced central nervous system activity and associated euphoria at therapeutic doses, loperamide abuse is rarely reported. This case demonstrates that an overdose on loperamide can occur in patients seeking symptom alleviation, and may mimic the presentation of opioid overdose.

Antidiarrheal pill in the airway.

Pill aspiration depicts an unusual type of foreign body aspiration necessitating a discrete diagnostic and therapeutic approach.1 Some pills may remain intact in the endobronchial tree for many years without causing much harm, whereas others may dissolve2 The clinical outcomes may also vary, from an asymptomatic granuloma to severe, life-threatening airway complications, depending upon the chemical properties of the pill. We report a compelling case of pill aspiration in a healthy patient.

Colloidal Silicon Dioxide in Tablet form (Carbowhite) Efficacy in Patients with Acute Diarrhea: Results of Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study.

The acute diarrhea is a wide-spread disease. The prescription of enterosorbents is appropriate as a primary measure for the treatment of the acute diarrhea for effective prevention of the fluid and electrolyte loss, as well as method for symptom relief of the attack of the disease. Aim of the study - the antidiarrheal efficacy and safety study of high-dispersion silicon dioxide enterosorbent in tablet dosage form in patients with acute diarrhea. This was randomized, double-blind, placebo-controlled, 4-center study. Acute diarrhea was defined as three and more episodes of watery stool per day either during 48 hours or less before study entry in the patients having normal stool recently. It has been postulated that symptoms and signs of acute diarrhea have to be caused by direct infection of the gastrointestinal tract and did not associated with moderate-to-severe systemic states. 144 patients with established acute diarrhea were randomized into treatment group (enterosorbent "Carbowhite", n = 120) or placebo group. Date collection including severity diarrhea, systemic symptoms was performed at baseline and daily during 7 days. Stool examination and serological assay were performed at baseline. The primary end points were declared as time to complete recovery from acute diarrhea. It has been found that the use of the siliceous enterosorbent ("Carbowhite") allowed to reduce (p < 0.001) the treatment period averagely for 0.9 days (95% confidence interval 0.5-1.2 days) in comparison with placebo. Data of safety monitoring has revealed that both patient groups had negative stool culture, while initiation of antibiotic treatment was run more frequently in placebo group (8.3%) compared to investigational product group (4.1%, P = 0.044). The siliceous enterosorbent "Carbowhite" was well tolerated and reduced the recovery time of the acute episode of the diarrhea in the clinically significant form.

Comparative Study of Constipation Exacerbation by Potassium Binders Using a Loperamide-Induced Constipation Model.

Patients on dialysis are frequently administered high doses of potassium binders such as calcium polystyrene sulfonate (CPS) and sodium polystyrene sulfonate (SPS), which exacerbate constipation. Here, we compare the degree of constipation induced by CPS and SPS using a loperamide-induced constipation model to identify the safer potassium binder. Constipation model was created by twice-daily intraperitoneal administration (ip) of loperamide hydrochloride (Lop; 1 mg/kg body weight) in rats for 3 days. Rats were assigned to a control group, Lop group, Lop + CPS group or Lop + SPS group, and a crossover comparative study was performed. Defecation status (number of feces, feces wet weight, fecal water content and gastrointestinal transit time (GTT)) was evaluated. In the Lop + CPS group, GTT was significantly longer, and fecal water content was reduced. In the Lop + SPS group-although the fecal water content and GTT were unaffected-the number of fecal pellets and the fecal wet weight improved. Thus, SPS was less likely to cause constipation exacerbation than CPS. Considering the high frequency of constipation in dialysis patients with hyperkalemia, preferentially administering SPS over CPS may prevent constipation exacerbation.

[Torsade de pointes following repeated massive loperamide ingestions]. / Livsfarligt missbruk av receptfria diarréläkemedlet loperamid.

The anti-diarrheal drug loperamide is a mu-opioid agonist with poor systemic bioavailability at standard doses. However, at very high doses bioavailability increases, due to saturation of P-glycoprotein and first-pass metabolism, leading both to opioid effects on the central nervous system and possible systemic side effects. There have been several reports in the literature recently regarding life-threatening cardiovascular symptoms after longstanding daily intake of massive loperamide doses. We hereby describe a patient with syncope who displayed wide QRS complexes and prolonged QTc intervals on ECG upon arrival to hospital. The patient developed typical bursts of torsade de pointes during a prolonged hospital course.