Racecadotril versus loperamide: antidiarrheal research revisited

Racecadotril is an enkephalinase inhibitor, presented as a purely antisecretory agent with advantages over the opiate-receptor agonist loperamide in the treatment of diarrhea. A critical review of the literature and the models used was performed. Although pretreatment with high doses of racecadotril reduced cholera toxin-induced secretion and although clinical efficacy was demonstrated in young infants—a population characterized by 10-fold higher plasma enkephalin concentrations compared with adults, the analysis calls into question the peripheral antisecretory selectivity and relative clinical efficacy. Conversely, loperamide can be proposed as an antisecretory agent at therapeutic concentrations. Its efficacy is well established in acute and chronic diarrhea. Current experimental and clinical comparative studies of both drugs have problems with regard to the selection of the doses, the validity of models, and/or the trial design. The conclusion is that more research is needed before reliable conclusions can be drawn on the place of racecadotril in diarrhea treatment.     

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.     

Loperamide Inhibits Replication of Severe Fever with Thrombocytopenia Syndrome Virus

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV). SFTS is mainly prevalent in East Asia. It has a mortality rate of up to 30%, and there is no approved treatment against the disease. In this study, we evaluated the effect of loperamide, an antidiarrheal and antihyperalgesic agent, on the propagation of SFTSV in a cell culture system. Methods: SFTSV-infected human cell lines were exposed to loperamide, and viral titers were evaluated. To clarify the mode of action of loperamide, several chemical compounds having shared targets with loperamide were used. Calcium imaging was also performed to understand whether loperamide treatment affected calcium influx. Results: Loperamide inhibited SFTSV propagation in several cell lines. It inhibited SFTSV in the post-entry step and restricted calcium influx into the cell. Furthermore, nifedipine, a calcium channel inhibitor, also blocked post-entry step of SFTSV infection. Conclusions: Loperamide inhibits SFTSV propagation mainly by restraining calcium influx into the cytoplasm. This indicates that loperamide, a Food and Drug Administration (FDA)-approved drug, has the potential for being used as a treatment option against SFTS.     

Loperamide improves anal sphincter function and continence after restorative proctocolectomy

The physiological and clinical effects of loperamide treatment versus placebo were investigated in a randomized, double-blind, crossover study in patients operated with restorative proctocolectomy. Sixteen patients operated with endoanal mucosectomy and a handsewn ileal pouch-anal anastomosis and 14 patients operated with abdominal proctocolectomy and stapling of the pouch to the top of the anal canal were studied. While loperamide treatment increased resting anal pressure in both groups of patients by approximately 20% (P<0.05), squeeze pressure was not affected. Loperamide did not affect pouch volume or contractility. Sensory thresholds and the recto/pouch-anal inhibitory reflex were not influenced by loperamide treatment. Clinical function was improved, with a reduced bowel frequency and an improved nighttime continence, with less soiling (P<0.05) as well as need to wear a protective pad.This investigation was supported by grants from the Swedish Medical Research Council (17X-03117), the University of Göteborg, Göteborgs Läkarsällskap, Assar Gabrielssons Fond, AB Skandias 100-årsfond and Ingabritt och Arne Lundbergs Forskningsfond.     

Effects of the prodrug loperamide oxide,loperamide, and placebo on jejunal motor activity

This crossover, double-blind study investigated the effects of single oral doses of the prodrug loperamide oxide, which is reduced gradually to loperamide in the intestine, and loperamide on jejunal motor activity in 12 fasting healthy men. Five minutes after a phase III of the migrating motor complex (MMC), 2 mg loperamide oxide, 4 mg loperamide oxide, 4 mg loperamide, or placebo were administered. Thereafter, motor activity 10–30 cm aborad the ligament of Treitz was recorded with five catheter orifices at 3-cm intervals over 4 hr. Number of contractions and area under curve increased significantly with 4 mg loperamide and 4 mg loperamide oxide, the increases with loperamide oxide occurring more gradually. Placebo and 2 mg loperamide oxide had no discernible effects. With both 4 mg loperamide and 4 mg loperamide oxide, phase I of the MMC was slightly prolonged and phase II and the time from drug administration to the onset of the first phase III slightly shortened. The percentage of aborally propagated contractions in phase II increased with all active treatments, whereas the occurrence of phases III was not altered.Presented in poster form at the European Digestive Disease Week, Vienna, Austria, June 5–9, 1990Supported by Janssen Pharmaceutica, Beerse, Belgium.     

The Effects of Loperamide on Continence Problems and Anorectal Function in Obese Subjects Taking Orlistat

Continence problems during treatment with orlistat (a lipase inhibitor) are caused when susceptible patients are exposed to increased volumes of loose, fatty stool. Aim: To investigate the dose-response effects of loperamide on continence and anorectal function in subjects susceptible to continence problems on orlistat. Method: Ten obese subjects enterred a randomized controlled, double-blind study of loperamide at placebo, 2, 4, and 6 mg/day in a factorial design. Continence problems during orlistat treatment were self-assessed by patient diary. Anorectal function and continence were assessed by barostat, manometry, and retention testing. Results: Loperamide increased stool consistency with dose (p = 0.07) and this effect reduced continence problems during orlistat treatment (p < 0.05). A bell-shaped dose-response relationship was present with anal sphincter function (p < 0.01) and anorectal sensitivity (p < 0.01). Conclusion: Loperamide has beneficial effects on stool consistency and continence in obese subjects taking orlistat. The effect on stool consistency appeared more important than effects on anorectal function.     

Loperamide abolishes exercise-induced orocecal liquid transit acceleration

Previous work in our laboratory has found that mild physical activity accelerates mouth-to-large intestinal transit of lactulose in a mixed liquid meal. Because loperamide is commonly used as an antidiarrheal agent, we wondered if it would blunt the orocecal transit acceleration provoked by mild exercise. We investigated this equation in 12 healthy persons by comparing orocolonic liquid transit at rest and in mild exercise. Each subject ingested 8 mg loperamide 1 hr prior to study under both resting and exercise conditions. With loperamide treatment, exercise (walking at 5.6 km/hr) failed to hasten increased H₂ excretion (mean transit time 72±12 min at rest, 90±15 min in exercise;P=NS). This result contrasts sharply with previously reported controls: loperamide completely abolished exercise-induced orocecal transit acceleration (?23±5 min in controls +18±13 min with loperamide;P<0.05). Compared with these same controls, resting transit was not significantly slowed by the drug, while transit in exercise was retarded (64±5 min in controls, 90±15 min with loperamide;P=0.06). Loperamide left unchanged the heart rate and oxygen uptake rises associated with exercise. In summary, by showing that loperamide blocks an exercise effect on the upper gut, these results suggest that the drug might prove effective in treating some gut symptoms induced by physical activity.     

Stimulation of gastrointestinal motility by loperamide in dogs

The effects of loperamide on gastrointestinal motility were investigated in conscious fasted dogs chronically fitted with strain-gauge transducers on the antrum, the jejunum, and the colon. Oral administration of loperamide (0.1 mg/kg) induced, after a delay of 20–30 min, a long-lasting (8–12 hr) stimulation of gastrointestinal motility associated with a disorganization of the cyclic activity at the three levels investigated. These effects were reproduced by a subcutaneous administration at the same dose and were antagonized by previous intravenous administration of naloxone or a quaternary opiate antagonist. Intracolonic administration (0.1 mg/kg) stimulated, after a delay of 20–30 min, colonic motility only. Intracerebroventricular loperamide (1 g/kg) induced a long-lasting (15–20 hr) inhibition of the gastric motility and a short (2-hr) disorganization of the jejunal motor profile. These data show that oral loperamide stimulates gastrointestinal motility in dogs and involves peripheral opiate receptors.     

Loperamide: studies on its mechanism of action.

The effects of loperamide on net solute and water absorption, and prostaglandin E2 (PGE2) and cholera toxin-induced secretion were studied in the rat jejunum using an in vivo steady-state perfusion technique. Loperamide stimulated absorption of fluid, electrolytes, and glucose and reversed PGE2 and cholera toxin-induced secretion to absorption; this opiate analogue had no effect on cholera toxin stimulation of adenylate cyclase activity or the rise of tissue cyclic AMP (cAMP) concentrations. The opiate antagonist, naloxone, reduced the antisecretory effects of loperamide without affecting tissue levels of cAMP. These results indicate that loperamide inhibits PGE2 and cholera toxin-induced secretion, and that this phenomenon is independent of any direct effect that cholera toxin has on the adenylate cyclase system. The action of naloxone suggests, but does not prove, that loperamide exerts its effect via opiate receptors.     

Oral naloxone antagonizes loperamide-induced delay of orocecal transit

Orocecal transit time was determined by the lactulose hydrogen breath test in nine healthy volunteers after administration of placebo, loperamide (16 mgper os), and loperamide (16 mgper os) followed by oral naloxone at doses of 16 and 32 mg. The four tests were performed in double-blind conditions and in random sequences. Transit time (mean,sd) after loperamide (128.8 min, 32.9) was significantly increased (P<0.05) compared with placebo (85.5 min, 35.7), loperamide followed by naloxone 16 mg (88.8 min, 46.2), and loperamide followed by naloxone 32 mg (84.4 min, 40.6). These results show that the peripheral opioid agonist loperamide delays orocecal transit in healthy subjects and that naloxoneper os at adequate doses antagonizes this effect.     

Loperamide has antisecretory activity in the human jejunum in vivo

We investigated the possibility that loperamide might influence absorption and secretion in the human jejunum in vivo. Using a triple lumen tube perfusion technique in healthy normal volunteers we showed that loperamide did not affect net absorption of water or electrolytes under basal condition. When secretion was induced by prostaglandin E2, however, loperamide significantly reduced that secretion and in three out of six subjects secretion was abolished. Loperamide was effective when it was given either before or after secretion had been initiated. The results lend support to the suggestion that the antidiarrhoeal activities of loperamide may include an antisecretory effect.     

Randomized trial of loperamide versus dose escalation of octreotide acetate for chemotherapy-induced diarrhea in bone marrow transplant and leukemia patients

This study compares maximal daily doses of loperamide to escalating doses of continuous intravenous (Cl) octreotide acetate in bone marrow transplant (BMT) and leukemia patients. A total of 36 patients were enrolled in the study. Of these, all were evaluable for intention to treat, and 31 were evaluable for initial response. Based on intent to treat at the initial 48 hr, patients receiving loperamide had a higher complete response rate (86% vs. 45%, P = 0.033) than did those who received octreotide. By treatment analysis (patients who actually received the drug), patients receiving loperamide had a higher complete response rate (92% vs. 56%, P = 0.0448) than did those who received octreotide at the 150 μg dosage level. Additional octreotide patients eventually achieved a CR at a higher dosage level (78%). Loperamide at maximal doses of 4 mg po q6h is more effective than octreotide 150 μg Cl in treating diarrhea following chemotherapy in BMT and leukemia patients. Higher doses of octreotide may be required in a significant number of patients not responding to lower doses. Following chemotherapy, BMT and leukemia patients who developed ≧600 ml of stool volume in a 24-hr period were randomized to receive loperamide 4 mg po q6h or octreotide 150 μg mixed in hyperalimentation solution or normal saline and administered Cl. Patients were assessed at 48 hr intervals for decrease in stool volume from baseline. Complete response (CR) was defined as ≧50% from baseline stool volume (BSV). Patients receiving octreotide who did not achieve a CR at 48 hr were dose escalated by doubling the dose to a maximum of 2,400 μg with evaluations at 48 hr intervals. Patients receiving loperamide who did not achieve a CR at 48 hr had treatment discontinued.     

Loperamide therapy in a patient with diarrhea and resistant hypertension

A 65-year-old man was admitted to our hospital for resistant essential hypertension. He had a past history of bowel resections due to Crohn’s disease. We assumed that in this patient insufficient drug absorption might be a cause of resistant hypertension and that even increased antihypertensive regimens would fail to decrease blood pressure. We administered loperamide, which may increase drug absorption from the residual intestine. Blood pressure was successfully decreased, with a concomitant increase in blood concentration of antihypertensive drugs. In patients with impaired drug absorption, we should make an effort to restore drug obstruction before considering increased drug regimens.     

Subcutaneous Loperamide Prevents Gastric Lesions Induced by Necrotizing Agents in Rats

The effects of subcutaneous loperamide ongastric lesions induced by necrotizing agents wereinvestigated in the rat. Loperamide produced adose-dependent increase of gastric fluid volume andinhibition of gastric lesions caused by 0.6 N HCl orabsolute ethanol. Pretreatment with naloxone almostcompletely blocked both fluid pooling effect and mucosalprotective effect of loperamide. Omeprazole reduced the acidity of the gastric fluid in ratstreated with loperamide without significantly decreasingthe fluid volume. Various volumes of acid, given orallyimmediately before 0.6 N HCl, volume-dependently prevented gastric lesions. We conclude thatsubcutaneous loperamide protects the gastric mucosaagainst necrotizing agents through luminal dilution ofirritants, which is mediated by naloxonesensitive opiate receptors.     

Effect of Loperamide on Lower Oesophageal Sphincter Pressure in Idiopathic Achalasia

Penagini R, Bartesaghi B, Negri G, Bianchi PA. Effect of loperamide on lower oesophageal sphincter pressure in idiopathic achalasia. Scand J Gastroenterol 1994;29:1057-1060.

Background: We have recently shown that in achalasia patients morphine has a striking inhibitory action on resting lower oesophageal sphincter (LOS) pressure, which is mediated by opioid receptors. The aim of this study was to investigate the effect of a peripheral opioid agonist, loperamide, administered at a dose of 16 mg, on resting LOS pressure in nine patients with untreated idiopathic achalasia.

Methods: All patients underwent two experiments after oral administration of placebo and loperamide, respectively, on separate days and in randomized order. At the end of the placebo experiment we also tested the effect of loperamide as compared with distilled water, both infused intraluminally at the level of the LOS. In the loperamide experiment, after a 60-min basal period, naloxone, 40 μg/kg, was injected intravenously, and recordings continued for a further 10min.

Results: Loperamide administered orally decreased (p<0.01) LOS pressure by 10 ± 2mmHg (37 ± 7%) compared with placebo, and naloxone intravenously failed to block the effect. LOS pressure was not affected by infusion of either distilled water or loperamide at the level of the LOS.

Conclusions: Our findings indicate that in patients with idiopathic achalasia oral administration of loperamide at a high dose markedly decreases resting LOS pressure. This may not occur through opioid receptor stimulation and requires intestinal absorption of the drug. The possible effect of combining a small dose of loperamide with the traditional achalasia drugs awaits further evaluation.     

Effects of seirogan (wood creosote) on propulsive colonic motility and stool characteristics in ambulatory mini-pigs

Our goal was to determine whether Seirogan, an herbal medicine used as an antidiarrheal agent, modifies colonic function, including motility. Experiments were performed on four female Yucatan mini-pigs with established permanent cecal fistulas providing direct access to the colon. Long-term recordings of proximal colonic motility were accomplished by a solid-state probe (six pressure ports 10 cm apart), and a motility index was calculated. Stool viscosity was also measured. The laxative bisacodyl (15 mg/kg) was used to induce colonic motility (increase in motility index) and stool softening, prior to investigating the effect of Seirogan (2–15 mg/kg per os twice a day) or a vehicle control. Seirogan (15 mg/kg), but not the placebo, reversed the bisacodyl-induced stool softening and restored the motility index to normal values by reducing the number of propagating contractions. Taken together the results suggest that inhibition of proximal colonic motility by Seirogan may contribute to its antidiarrheal action.