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PubMed1983

Loperamide: evidence of interaction with mu and delta opioid receptors.

Loperamide was tested on electrically-evoked contractions using a series of "in vitro" isolated preparations, in comparison with morphine, met-enkephalin, beta-endorphin, ethylketocyclazocine used as representative agonists of mu, delta, epsilon, kappa receptors respectively. The IC50 of loperamide on myenteric plexus longitudinal muscle of guinea pig ileum was found to be 1.90 X 10(-7)M and equal to that of morphine. The IC50 on mouse vas deferens was found to be 13.02 X 10(-7)M. In this tissue, loperamide resulted as active as morphine, but 54 times less active than met-enkephalin (IC50 0.24 X 10(-7)M). On the rat vas deferens where, as expected, beta-endorphin was strongly active (IC50 1.38 X 10(-7)M), morphine exerted a stimulatory action within the range 10(-5)M-10(-4)M and loperamide was only poorly depressive. The Ke value of naloxone, a specific mu receptor antagonist, against loperamide in the guinea pig ileum was 3.83 nM, and in the mouse vas deferens was 82.87 nM indicating that loperamide in the guinea pig ileum acts on mu receptors while in the mouse vas deferens on another opiate receptor.

Animals↗
PubMed1998

Central analgesic actions of loperamide following transient permeation of the blood brain barrier with Cereport (RMP-7).

The bradykinin analog, Cereport (RMP-7), was designed to increase permeability of the blood brain barrier (BBB). Over the past several years it has been developed primarily as a means of increasing permeability of the blood brain tumor barrier, where early evidence indicated a particularly robust and reliable effect. The present series of experiments were intended to determine whether Cereport might also be used to increase delivery of pharmacological agents across the normal (i.e., non-tumor) BBB. This was accomplished by testing the ability of Cereport to enhance delivery of the peripherally acting opiate agonist, loperamide, to the brain, as evidenced by induction of a centrally mediated analgesic effect. Intravenous administration of a combination of Cereport and loperamide produced a significant analgesic effect (2-fold increase in response times) when animals were tested on a hotplate apparatus. Loperamide alone did not produce analgesia. An analysis of the time course of analgesia revealed a graded onset of analgesia which peaked at 30 min, maintained asymptote at 60 min, and began to diminish by 120 min following Cereport and loperamide administration. Finally, the analgesic effects of combining Cereport and loperamide were completely blocked when animals were pre-treated with the opiate antagonist naloxone, demonstrating that the analgesia was mediated through opiate receptors. Collectively, these results suggest that Cereport was able to increase delivery of loperamide across the BBB, allowing it to gain access to opiate receptors in the CNS to produce a centrally mediated analgesic effect. They therefore provide clear evidence that safe and well-tolerated doses of Cereport can increase permeability of the normal (i.e., non-tumor) BBB. Moreover, they provide the first evidence of a pharmacological effect specifically enabled by controlled (i.e., receptor-mediated) modulation of the BBB.

Analgesics↗
PubMed1990

Effect of loperamide on stool output and duration of acute infectious diarrhea in infants.

This study was designed to assess the effect of loperamide, given to infants in higher than recommended doses, on the severity and duration of acute diarrhea. Thirty infants with acute diarrhea and dehydration were given loperamide (0.8 mg/kg/day), in addition to standard fluid therapy, for 48 hours after admission to the hospital. The stool output in grams per kilograms of body weight per day and the duration of diarrhea in these infants were compared with those in 30 matched control infants receiving only standard fluid therapy. Two infants given loperamide had to be withdrawn from the trial because ileus developed in one and the other had persistent severe vomiting. In four other infants receiving loperamide, drowsiness developed but resolved rapidly on discontinuation of the drug. Infants receiving loperamide had a shorter duration of diarrhea (median 2.5 vs 6.0 days) and lower daily stool output than the control subjects had. The study confirmed the efficacy of loperamide in reducing the duration and severity of diarrhea but raised doubts regarding its safety in the treatment of young infants.

Administration, Oral↗
PubMed2003

Analgesic action of loperamide, an opioid agonist, and its blocking action on voltage-dependent Ca2+ channels.

We investigated the relationship between the antinociceptive effect of the opiate agonist loperamide at the spinal level and its inhibitory effect on calcium influx. Intrathecal administration of loperamide showed a significant antinociceptive effect in the formalin test, which was not prevented by naloxone. On the other hand, no significant effects were observed by nicardipine, an L-type specific blocker, or by BAY K8644, an L-type specific agonist, suggesting no significant role of L-type calcium channels in nociceptive signal transduction. Loperamide suppressed the calcium influx in dorsal root ganglion neurons. As the antinociceptive effect of loperamide was not affected by naloxone or other calcium channel blocking toxins, and loperamide showed a direct inhibitory effect on calcium-influx, the analgesic effect of intrathecally injected loperamide might be due to its blockade of the voltage-dependent calcium channels at the terminals of the primary afferent fibers.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Determination of loperamide in rat plasma and bovine serum albumin by LC.

A rapid, isocratic liquid chromatographic (LC) method was developed for the determination of loperamide (Lop) in solutions of bovine serum albumin (BSA) and rat plasma. Prior to LC analysis, BSA solutions or rat plasma samples were treated with metaphosphoric acid to precipitate protein. Supernatant was directly injected onto a C18 reverse phase column and loperamide was monitored by a UV detector set at 195 nm. The concentrations of Lop in both rat plasma and BSA solution samples were determined by comparison with their calibration curves, which were generated from the peak area ratio of Lop to internal standard, clomipramine versus loperamide concentration. The calibration curves were linear in the range 0-3.0 microg ml(-1) of Lop for the BSA solution sample and 0-1.0 microg ml(-1)for the rat plasma sample. Overall recoveries of loperamide added to BSA and rat plasma samples were 101.4 and 95.5%, respectively. The method is simple (no extraction), rapid (22 min separation time), sensitive (the detection limit of loperamide is 50 ng ml(-1) for the BSA solution sample and 100 ng ml(-1) for the rat plasma sample), reproducible (within-day R.S.D. of 2.59-7.11%, among-day R.S.D. of 1.25-5.97%), and suitable for routine analysis of loperamide in rat plasma and BSA solution samples.

Animals↗
PubMed1999

Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5-fluorouracil induced diarrhea and failure of loperamide treatment.

BACKGROUND: Diarrhea is one of the most disturbing effects of chemotherapy, affecting quality of life on the one hand and limiting applicable doses on the other. Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are associated with an elevated risk of developing severe diarrhea. Standard therapy consists of high-dose loperamide, but is associated with frequent failure. Other therapeutic regimens are still experimental. Endoscopic examination of a patient with severe loperamide-resistant diarrhea after CPT-11 chemotherapy revealed an inflammation of the ileo-coecal region. Oral therapy with the topical corticosteroid budesonide was immediately effective. This led to a phase I study of budesonide in CPT-11- and 5-FU-induced and loperamide-refractory diarrhea. PATIENTS AND METHODS: Fourteen patients with CPT-11- and seven patients with 5-FU-induced grade 3-4 (NCI/WHO) diarrhea and loperamide failure were enrolled in this study. All patients had metastatic colorectal cancer. RESULTS: In 86% of the CPT-11- and 57% of the 5-FU-treated patients with grade 3-4 diarrhea and loperamide failure, treatment with budesonide resulted in a reduction of diarrhea severity by at least two grades. CONCLUSIONS: The orally administered topical active steroid budesonide is highly effective in the therapy of loperamide-refractory chemotherapy (CPT-11 or 5-FU)-induced diarrhea.

Administration, Oral↗
PubMed1997

Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles.

PURPOSE: The possibility of using polysorbate 80-coated nanoparticles for the delivery of the water insoluble opioid agonist loperamide across the blood-brain barrier was investigated. The analgesic effect after i.v. injection of the preparations was used to indicate drug transport through this barrier. METHODS: Loperamide was incorporated into PBCA nanoparticles. Drug-containing nanoparticles were coated with polysorbate 80 and injected intravenously into mice. Analgesia was then measured by the tail-flick test. RESULTS: Intravenous injection of the particulate formulation resulted in a long and significant analgesic effect. A polysorbate 80 loperamide solution induced a much less pronounced and very short analgesia. Uncoated nanoparticles loaded with loperamide were unable to produce analgesia. CONCLUSIONS: Polysorbate 80-coated PBCA nanoparticles loaded with loperamide enabled the transport of loperamide to the brain.

Analgesics↗
PubMed2003

Loperamide increases glucose ultilization in streptozotocin-induced diabetic rats.

1. Loperamide has an ability to lower the plasma glucose concentration in streptozotocin (STZ)-induced diabetic rats. In the present study, we investigated the molecular mechanisms by which loperamide regulates plasma glucose concentrations in the absence of insulin. 2. Loperamide, at a dose sufficient (17.6 microg/kg) to activate mu-opioid receptors, significantly decreased plasma glucose levels in STZ-diabetic rats. The mRNA and protein levels of glucose transporter 4 (GLUT-4) in soleus muscle, detected by northern and western blotting, respectively, were increased after repeated intravenous administration of loperamide (17.6 micro g/kg) to STZ-diabetic rats over 3 days. Moreover, similar treatment with loperamide (17.6 microg/kg) for 3 days reversed the elevated mRNA and protein levels of phosphoenolpyruvate carboxykinase (PEPCK) in the liver of STZ-diabetic rats to near the levels seen in normal rats. 3. These results suggest that activation of mu-opioid receptors by loperamide can increase glucose utilization in peripheral tissues and/or reverse the higher gene expression of PEPCK to inhibit hepatic gluconeogenesis, thereby lower plasma glucose in diabetic rats lacking insulin.

Animals↗
PubMed2004

Signals in the activation of opioid mu-receptors by loperamide to enhance glucose uptake into cultured C2C12 cells.

In an attempt to understand the signal pathways of opioid mu-receptors for glucose metabolism, we used loperamide to investigate the glucose uptake into the myoblast C2C12 cells. Loperamide enhanced the uptake of radioactive deoxyglucose into C2C12 cells in a concentration-dependent manner that was abolished in cells pre-incubated with naloxone or naloxonazine at concentrations sufficient to block opioid mu-receptors. Pharmacological inhibition of phospholipase C (PLC) by U73122 resulted in a concentration-dependent decrease in loperamide-stimulated uptake of radioactive deoxyglucose into C2C12 cells. This inhibition of glucose uptake by U73122 was specific since the inactive congener, U73343, failed to modify loperamide-stimulated glucose uptake. Moreover, both chelerythrine and GF 109203X diminished the action of loperamide at concentrations sufficient to inhibit protein kinase C (PKC). The obtained data suggest that an activation of opioid mu-receptors in C2C12 cells by loperamide may increase glucose uptake via the PLC-PKC pathway.

Animals↗
PubMed2001

Antisecretory effect of loperamide in colon epithelial cells by inhibition of basolateral K+ conductance.

BACKGROUND: The mechanism of the antisecretory effect of loperamide was investigated in cultured highly differentiated colon epithelial cells (HT-29/B6). METHODS: Chloride secretion was stimulated via cAMP by forskolin (FSK, 10(-5) M), via Ca2+ by the muscarinic agonist carbachol (CCh, 10(-4) M), and via protein kinase C by the phorbol ester PMA (5 x 10(-9) M). Stimulated Cl- secretion was quantified as short circuit current (I(SC)) of HT-29/B6 monolayers mounted in Ussing-type chambers. RESULTS: Loperamide (5 x 10(-5) M) inhibited I(SC) stimulated by FSK, CCh and PMA. The antisecretory action of loperamide was unaffected by preincubation with naloxone (10(-5) M). Furthermore, loperamide strongly inhibited basolateral 86Rb efflux. Like loperamide, the calmodulin antagonist trifluoperazine (10(-4) M) inhibited I(SC) induced by FSK, CCh or PMA. The Ca2+ channel blocker verapamil (5 x 10(-5) M), on the other hand, inhibited only PMA-stimulated I(SC),but had no effect on FSK or CCh-induced I(SC) CONCLUSIONS: Loperamide exerts a direct antisecretory action on chloride secretion of colon epithelial cells independently of the respective stimulatory signal transduction pathway. This antisecretory effect is not mediated by opiate receptors and reflects inhibition of basolateral K+ conductance.

Antidiarrheals↗
PubMed1987

Review: loperamide--a potent antidiarrhoeal drug with actions along the alimentary tract.

The synthetic opioid, loperamide, reduces stool weight, frequency of bowel movements, urgency and faecal incontinence in acute and chronic diarrhoea. In man, the mechanism of action of loperamide is primarily the retardation of small-intestinal transit, and the stimulation of anal sphincter pressure and of faecal continence. This mechanism increases mucosal contact time, allowing more complete absorption of electrolytes and water. Studies in animals have demonstrated inhibitory effects of opiates and opioids, including loperamide, on fluid and electrolyte secretion induced by various secretagogues. By comparison, opiates have smaller if any antisecretory or pro-absorptive actions in man. The discrepancies between the results obtained in animal and human experiments are most certainly due to the large differences between drug doses used. Besides its opiate-receptor binding and stimulating activity, loperamide also behaves as a calcium-calmodulin antagonist and as a calcium channel blocker. These two other mechanisms might contribute to loperamide's antidiarrhoeal activity. Loperamide is more effective and safer than other opiates or opioid drugs in the treatment of both infantile and adult diarrhoea of various causes, although adequate fluid and electrolyte replacement remain the prime need.

Animals↗
PubMed2000

Prospective, controlled, multicentre study of loperamide in pregnancy.

BACKGROUND: Loperamide is a synthetic piperidine derivative used for the treatment of both acute and chronic diarrhea. Little is known about its safety and risk in pregnancy. Human data are limited to one surveillance study of Michigan Medicaid patients, with 108 women exposed in the first trimester. In this study there were six major birth defects, three of which were cardiovascular anomalies. OBJECTIVES: To determine whether loperamide use in pregnancy is associated with an increased risk of major malformations. The secondary end points were rates of minor malformations, spontaneous and therapeutic abortions, and premature births, and mean birth weights. PATIENTS AND METHODS: Women counselled by five teratogen information centres on the safety and risk of loperamide in pregnancy were followed after delivery and compared with a similar group of women matched for age, smoking, alcohol and other exposures. RESULTS: One hundred and five follow-ups were completed; 89 of the women were exposed to loperamide in the first trimester of pregnancy. There were no statistically significant differences between the study group and the control group in any of the end points that were analyzed. However, of women who took loperamide throughout their pregnancy, 21 of 105 had babies who were 200 g smaller than babies in the control group. CONCLUSIONS: The results of this study suggest that the use of loperamide during pregnancy is not associated with an increased risk of major malformations.

Abnormalities, Drug-Induced↗
PubMed1978

[Pharmacological studies of loperamide, an anti-diarrheal agent. I. Effects on diarrhea induced by castor oil and prostaglandin E. (author's transl)].

Effects of loperamide on diarrhea induced by castor oil and prostaglandin E1 were investigated in rats and mice and compared with those of narcotic analgesics, atropine, mecamylamine and local anesthetics. The following results were obtained. Loperamide markedly suppressed the appearance of diarrhea induced by oral administration of castor oil in rats and the ED50 values for 1 and 2 hr protection was 0.082 and 0.42 mg/kg p.o., respectively. Loperamide markedly suppressed the appearance of diarrhea induced by i.v. administration of prostaglandin E1 and the ED50 value for 2 hr protection was 0.24 mg/kg p.o. in rats. The ID120 min value of loperamide which was calculated on the basis of the dose producing a 20% or more inhibition of the charcoal transport in the small intestine for 120 min was 0.8 mg/kg p.o. in mice and this activity was 9.2 times more potent than that of morphine. The analgesic ED50 value (Haffner's method) and LD50 value of loperamide was 149 and 249 mg/kg p.o., respectively. These results suggest that loperamide has a potent anti-diarrheal activity and specificity to the gastrointestinal tract and inhibits the effect of prostaglandin E1 and ricinoleic acid on the intestinal tract in rats.

Analgesics↗
PubMed1978

Loperamide: a review of its pharmacological properties and therapeutic efficacy in diarrhoea.

Loperamide, a butyramide derivative is a new agent for use in symptomatic control of acute non-specific diarrhoea and chronic diarrhoea. Unlike diphenoxylate or codeine, loperamide does not appear to exert opiate activity in man at normal therapeutic doses. In acute diarrhoea, loperamide provides more rapid control of symptoms than diphenoxylate when given in a flexible dosage according to unformed bowel movements, and in single dose studies 4mg loperamide has a much longer duration of effect than 5mg diphenoxylate. Loperamide is probably superior to diphenoxylate in providing symptomatic control of chronic diarrhoea such as that associated with chronic inflammatory bowel disease or following gastrointestinal surgery. It has been used for up to 3 years in such conditions without evidence of tolerance. The possibility of once daily dosage of loperamide in chronic diarrhoea is an advantage. Side-effects have not proved a problem.

Acute Disease↗
PubMed1996

A double-blind placebo-controlled trial with loperamide in irritable bowel syndrome.

BACKGROUND: Loperamide has a relaxing effect on localized and segmental large-bowel spasms. On the basis of previously observed effects on pain and stool habits in patients with diarrhoea, the present trial intended to examine the regulating effect in an unselected cohort of patients with the irritable bowel syndrome (IBS). The symptoms in IBS are dependent on variations in motility initiated by different mechanisms. Therefore, when examining the effect of treatment, characterization of the patient material is important. METHODS: Ninety patients were included in this prospective double-blind trial comparing loperamide with placebo over 5 weeks. The two groups were characterized and compared with healthy controls (n = 33), matched by age and sex. Demographic, clinical, and biochemical data were recorded. RESULTS: Clinical variables and social and personal relationships were similar for the loperamide group (n = 35), the placebo group ( n = 34), the dropouts (n = 21), and controls. Somatic diseases and mental disturbances were increased in the patients compared with the controls. Throughout the 5 weeks of treatment an improved stool consistency (32%), reduced defecation frequency (36%), and reduced intensity of pain (30%) were found in the loperamide group. An increase in nightly pain was observed in the loperamide group. CONCLUSIONS: This trial lends support to a multifactorial aetiology in IBS. Treatment must be individualized with regard to both the effect and the risk of constipation and abdominal pain. The trial shows a benefit of loperamide in an unselected cohort of IBS patients with regard to stool frequency, stool consistency, and the overall pain intensity, but with increased abdominal pain during the night. It should be recommended that the patients take the medication in divided daily doses.

Adult↗
PubMed1987

[Effects of loperamide on the fecal flora in children in severe diarrheas].

Loperamide has been recently indicated in the management of infants with severe protracted diarrhea. The purpose of this study was to determine the effect of loperamide on fecal flora in severe protracted diarrheas. 19 children aged 1 to 36 months, with severe protracted diarrhea were studied: 14 received loperamide (0.5 mg/kg/d) and 5 were without loperamide treatment. Criteria analysed were: clinical tolerance (vomiting and abdominal distention); efficacy (number of stools, transit time and Na+/K+ in stools) and effect on fecal flora, with differential qualitative and quantitative analysis method (complete identification and counts of aerobic and strict anaerobic bacteria in fresh fecal samples before and 4 to 8 days after the beginning of loperamide). Parenteral and/or oral alimentation remain constant during the study. Results show a rapid (24 h) efficacy in 9/14. Although important changes in specific fecal flora counts was noticed for streptococcus D and Proteus as compared to five controls, no bacterial overgrowth appeared or was increased during loperamide treatment.

Child, Preschool↗
PubMed1986

Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea.

Loperamide hydrochloride was compared with bismuth subsalicylate for the treatment of acute nondysenteric travelers' diarrhea in 219 students visiting seven countries in Latin America. Subjects whose condition was not improved with therapy could elect to take trimethoprim-sulfamethoxazole. Persons receiving loperamide passed fewer unformed stools when compared with the bismuth subsalicylate group during the first four hours of therapy, from four to 24 hours, and from 24 to 48 hours after therapy was initiated. Among subjects with disease due to enterotoxigenic Escherichia coli, Shigella sp, other pathogens, and unknown agents, fewer unformed stools were passed by the loperamide-treated subjects than the bismuth subsalicylate-treated subjects for all time periods studied. No significant prolongation of disease was seen in subjects with shigellosis treated with loperamide. Eight of the loperamide-treated subjects experienced constipation compared with one in the bismuth subsalicylate-treated group; otherwise, there was no difference in minor side effects experienced between both treatment groups. We conclude that loperamide is a safe and effective alternative to bismuth subsalicylate for the treatment of nondysenteric travelers' diarrhea.

Acute Disease↗
PubMed1985

Different actions of 2 antidiarrheal agents, lidamidine and loperamide, on motility of the isolated cat colon muscle.

Besides their action on intestinal absorption and secretion antidiarrheal agents may affect gastrointestinal motility. Little is known about motor actions in the large intestine. Therefore, the effects of loperamide and lidamidine on contractile and myoelectrical activity were studied in strips of the circular muscle of the cat colon in vitro. Both drugs caused a concentration dependent increase in spontaneous contractions, but the potency of loperamide was greater than that of lidamidine and the efficacy of lidamidine greater than that of loperamide. The corresponding EC50 were 2.9 X 10(-9) M and 1.4 X 10(-5) M, respectively, and the EC100 2.7 X 10(-7) M and 10(-4) M, respectively. In the myoelectrical tracings loperamide stimulated predominantly spike activity, lidamidine oscillatory potentials. The effect of loperamide was antagonized by naloxone, thus indicating an action on opiate receptors. The effect of lidamidine was not inhibited by a variety of drugs. Tetrodotoxin and alpha-adrenergic inhibitors even exaggerated the lidamidine effect, probably by a suppression of tonic nervous inhibition. The receptor for the lidamidine action has yet to be determined. In conclusion, the motor effects may play an important role in the antidiarrheal action of loperamide, but probably not in that of lidamidine, at least not within the range of clinically used doses.

Animals↗