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PubMed1982

Relationship between anti-diarrheal activity and binding to calmodulin.

Several neuroleptics known to bind to calmodulin were tested for anti-diarrheal activity and were compared with the opiate anti-diarrheals loperamide and diphenoxylate. All inhibited the intestinal fluid secretion induced by 16,16-dimethyl prostaglandin E2 and castor oil-induced diarrhea in rats as a function of dose, the order of potency being loperamide approximately equal to diphenoxylate greater than chlorpromazine greater than promethazine greater than amitriptyline. The opiates loperamide and diphenoxylate were found to compete with [3H]trifluoperazine binding to calmodulin in the presence of calcium. These opiates were approximately 3 times more potent inhibitors of [3H]trifluoperazine binding than chlorpromazine. A positive correlation between calmodulin binding and anti-diarrheal activity was demonstrated.

16,16-Dimethylprostaglandin E2↗
PubMed1986

Human intestinal motor activity and transport: effects of a synthetic opiate.

Effects of opiates on intestinal motor activity and transport of water and electrolytes have been studied separately in previous investigations. The aim of these experiments was to evaluate simultaneously the effects of a synthetic opiate, loperamide, on motor activity and transport in the human intestine. Jejunal, ileal, and colonic perfusions were performed in 9 healthy volunteers. After application of loperamide (12 mg), cyclically recurring migrating motor complexes in the small intestine occurred at a significantly higher frequency than after application of placebo. This was primarily due to a decrease in the duration of irregular motor activity (phase II). Loperamide increased the transit time in the jejunum but not in the ileum or in the colon. Transport rates of water and electrolytes and transmural electrical potential differences were not significantly affected by the drug. These results suggest that opiates exert their constipating effect by inhibiting phase II-related irregular motor activity.

Adult↗
PubMed1988

Evidence for a peripheral action of thyrotropin releasing hormone on gastrointestinal transit in mice.

The effect of the two analogs of thyrotropin-releasing hormone (TRH), namely MK-771 and DN-1417, administered peripherally, on the actions of morphine and loperamide on gastrointestinal transit, was investigated in mice. The actions of naltrexone and methyl naltrexone on these effects were also determined in order to assess the central or peripheral mechanism of action. The administration of morphine sulfate (5 mg/kg) inhibited gastrointestinal transit, as measured by the charcoal meal test. The effect of morphine was potentiated by MK-771 and DN-1417 at the 10 mg/kg dose. The peripheral administration of DN-1417 inhibited gastrointestinal transit but MK-771 had no effect. Naltrexone antagonized the potentiating effect of the peptides on the effect of morphine on gastrointestinal transit. Methyl naltrexone, which crosses the blood-brain barrier with difficulty, also antagonized the potentiating effect of the peptides on the action of morphine on gastrointestinal transit. A subthreshold dose (0.5 mg/kg) of loperamide, a peripherally acting opiate, which had no effect on gastrointestinal transit by itself, when combined with MK-771 or DN-1417 significantly inhibited gastrointestinal transit. The administration of methyl naltrexone had little effect on loperamide-induced inhibition of gastrointestinal transit but antagonized the potentiating effect of MK-771 and DN-1417. It is concluded that the effects of analogs of thyrotropin releasing hormone on gastrointestinal transit involve peripheral sites of action, the effect of DN-1417 was not antagonized by naloxone and that the inhibitory effect of DN-1417 on gastrointestinal transit is not mediated by opiate receptors.

Animals↗
PubMed2004

Variable modulation of opioid brain uptake by P-glycoprotein in mice.

The efflux transporter P-glycoprotein (P-gp) is an important component of the blood-brain barrier (BBB) that limits accumulation of many compounds in brain. Some opioids have been shown to interact with P-gp in vitro and in vivo. Genetic or chemical disruption of P-gp has been shown to enhance the antinociceptive and/or toxic effects of some opioids, although the extent of this phenomenon has yet to be understood. The purpose of this study was to assess quantitatively the influence of mdr1a P-gp on initial brain uptake of chemically diverse opioids in mice. The brain uptake of opioids selective for the mu (fentanyl, loperamide, meperidine, methadone, and morphine), delta (deltorphin II, DPDPE, naltrindole, SNC 121) and kappa (bremazocine and U-69593) receptor subtypes was determined in P-gp-competent (wild-type) and P-gp-deficient [mdr1a(-/-)] mice with an in situ brain perfusion model. BBB permeability of the opioids varied by several orders of magnitude in both mouse strains. The difference in brain uptake between P-gp-competent and P-gp-deficient mice ranged from no detectable effect (meperidine) to >/=8-fold increase in uptake (DPDPE, loperamide, and SNC 121). In addition, loperamide efflux at the BBB was inhibited by quinidine. These results demonstrate that P-gp modulation of opioid brain uptake varies substantially within this class of compounds, regardless of receptor subtype. P-gp-mediated efflux of opioids at the BBB may influence the onset, magnitude, and duration of analgesic response. The variable influence of P-gp on opioid brain distribution may be an important issue in the context of pharmacologic pain control and drug interactions.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Hypothalamic-pituitary-adrenal axis sensitivity to opioids in women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the influence of the opioid system on the hypothalamic-pituitary-adrenal axis in women with polycystic ovary syndrome (PCOS). DESIGN: Controlled clinical study. SETTING: Academic research environment. PATIENT(S): Eight lean and 12 obese women with PCOS, and seven lean and 5 obese control subjects. INTERVENTION(S): Each patient received an i.v. bolus of naloxone at a dose of 125 microgram per kilogram of body weight; 48 hours later, each patient received 16 mg of loperamide p.o. MAIN OUTCOME MEASURE(S): Samples were collected for 2 hours for the naloxone test and for 3 hours for the loperamide test. Levels of adrenocorticotropic hormone (ACTH) and cortisol were measured in all plasma samples. RESULT(S): The obese women with PCOS had a greater ACTH and cortisol response to opiate blockade than either the lean women with PCOS or the control subjects, but there was no difference between the lean or obese control subjects and the lean women with PCOS. There was no difference in the responsiveness of the hypothalamic-pituitary-adrenal axis to loperamide between the PCOS and control groups. CONCLUSION(S): The data indicate that the sensitivity of the hypothalamic-pituitary-adrenal axis to opioids cannot be altered in women with PCOS. However, abnormalities of the hypothalamic-pituitary-adrenal axis in women with PCOS could be central in origin, as suggested by the effects of naloxone administration, and probably are related to the anthropometric characteristics of these hyperandrogenic patients.

Adrenal Glands↗
PubMed2002

Effects of full-thickness burns on nociceptor sensitization in anesthetized rats.

Burn-induced pain is often inadequately managed and its mechanisms, both peripheral and central, are poorly understood. To examine peripheral mechanisms, the effects of full-thickness burns on individual nociceptive fibers in sural nerve of anesthetized rats were studied. Additionally, the study investigated whether topical post-burn treatment with the mu-opioid receptor agonist loperamide ameliorated burn-induced pathologies. Receptive field (RF) properties of C-fibers were determined for 4h before and after producing burns. Burns caused profound tissue damage with edema extending beyond the injury site. Injury located within or proximal to RFs of nociceptors caused rapid decreases in mechanical responsiveness or complete desensitization at the original test site. However, post-burn, RF size frequently grew to include areas of newly sensitized skin. Transient or prolonged periods of ectopic activity was recorded from some nociceptors; this was most prevalent in fibers with RFs proximal to the injury site where burn induced background firing in 60% of the population. In most cases, loperamide significantly increased mechanical thresholds, prevented sensitization of uninjured skin, and reduced discharge.These data indicate that full-thickness burns activate and/or sensitize C-nociceptors, thus probably leading to pain. As loperamide ameliorates nociceptor activation and sensitization, it is an appropriate candidate for burn pain management.

Animals↗
PubMed2000

Relationships between transit time in man and in vitro fermentation of dietary fiber by fecal bacteria.

OBJECTIVE: To assess the effects of drug-induced changes in mean transit time (MTT) on the activity of human fecal flora in vitro. METHODS: The activity of fecal flora was estimated by the ability of a fecal inoculum to ferment a substrate (beet fiber) in vitro in a batch system for 24 h. The inoculum was collected from 8 healthy volunteers studied during three 3-week randomized periods, who received a controlled diet alone (control period) or the same diet with either cisapride or loperamide. Cisapride and loperamide were adjusted in order to halve and double MTT measured during the control period. At the end of each period, the percentage disappearance of the initial added substrate and the concentration and the profile of short-chain fatty acids (SCFAs), were determined. RESULTS: In the control period, the pH of the inoculum and SCFA concentration were inversely related to MTT (P=0.0001). Individual SCFA production was also significantly related to MTT (P<0.01). Cisapride-reduced transit time was associated with a significant rise in the concentrations of total SCFAs (P<0.05), propionic and butyric acids (P<0.05) and the percentage substrate disappearance (P<0.05). Inverse relations were observed during the loperamide period. Moreover, MTT was inversely related to the percentage substrate disappearance (P<0.001), SCFA production (P<0.001) and butyrate production (P<0.0005). CONCLUSION: Changes in MTT alter bacterial activity and modify the bacterial pathways affecting the proportion of individual SCFAs. European Journal of Clinical Nutrition (2000) 54, 603-609

Adult↗
PubMedDate not supplied

Effect of opioid active therapeutics on the ascending reflex pathway in the rat ileum.

For a long time therapeutic agents that interact with opioid receptors have been used in antidiarrheal therapy. The action of the opioid active substances on motility and transit have already been characterized; however, their effects on myenteric reflexes and their possible luminal action have not yet been investigated. Loperamide, fedotozine and beta-casomorphin-4, as well as the casomorphin-analogue beta-CM-4027, are, or have been, suggested as therapeutic agents and were studied in the isolated rat ileum for their effect on the ascending reflex pathway. beta-CM-4027 > fedotozine > loperamide > beta-casomorphin-4 caused a concentration-dependent inhibition of the ascending contractile reflex response with an IC(50)of 1.4x10(-7)M, 1.5x10(-6)M, 4.1x10(-6)M and 4.5x10(-6)M respectively. At the same time as the oral contractile reflex response was inhibited, all four opioid agonists (CM-4027 > beta-casomorphin-4 > fedotozine > loperamide) increased the latency of the reflex response. Both effects were blocked by naloxone, indicating the involvement of opioid receptors. These results demonstrate that opioid-active drugs and substances modify the peristaltic reflex by reducing the efficacy of the reflex response and modulating the timing of the reflex pathway. In a second series of experiments, luminal application of opioid-active drugs was compared with serosal application. beta-casomorphine-4 caused a concentration-dependent inhibition of the oral reflex response with an IC(50)of 3x10(-3)M which was 750 times higher than after serosal application. In contrast, a stable and highly selective kappa opioid agonist (U-50,488), which caused potent inhibition upon serosal application (IC(50): 2.3x10(-7)M), showed no inhibitory effect after luminal application up to a concentration of 10(-2)M. Thus casomorphins could have a local effect on the gut wall with no need for systemic absorption. This might be used for a possible therapeutic application.

Animals↗
PubMedDate not supplied

Worldwide efficacy of bismuth subsalicylate in the treatment of travelers' diarrhea.

So far four randomized studies, three of them double-blind and placebo-controlled, have investigated the role of bismuth subsalicylate (BSS) in the treatment of travelers' diarrhea. When compared with placebo BSS significantly reduced the number of unformed stools and increased the proportion of patients free of symptoms at the end of the trial. In the two studies that compared BSS with loperamide, the latter agent brought significantly faster relief. Diarrhea accompanied by dysenteric symptoms was influenced most favorably by administration of systemic antimicrobial agents. In all four studies only minor adverse effects were noted with BSS or the other active agents. One may include loperamide and a systemic antimicrobial agent in one's travel kit; however, loperamide should not be used for dysentery, and the antimicrobial agent should not be used in uncomplicated cases. As an alternative, although it is less effective, BSS has the unique advantage of being safe enough to use for all patients with travelers' diarrhea.

Adolescent↗
PubMed1995

Effect of lactose, lactulose and bisacodyl on gastrointestinal transit studied by metal detector.

AIM AND METHODS: To study the effect of 45 g lactose, 30 g lactulose and 10 mg bisacodyl on gastrointestinal transit in 30 healthy volunteers by metal detector and Hinton marker method. The first set of measurements were performed under standard conditions. In a second stage, transit was slowed to twice the original value by loperamide to simulate constipation conditions. RESULTS: Bisacodyl drastically accelerated small and large intestinal transit. Colonic transit was shortened to 23% and to 31% of control values, without and with loperamide. Bisacodyl increased stool weight and decreased stool consistency in all persons. Lactulose marginally shortened small intestinal transit (P = 0.08) but significantly increased stool weight and decreased stool consistency. The accelerating effect of lactose on small intestinal transit was abolished by loperamide. Lactose did not influence colonic transit, stool weight or stool consistency. Results of metal detector and Hinton marker method corresponded well (r = 0.75), the metal detector method measuring slightly shorter transit times than the Hinton marker method. CONCLUSIONS: With the dose chosen in this trial, lactose did not have any laxative effect in lactose tolerant persons. Laxative effect was mild with lactulose and most pronounced with bisacodyl.

Adult↗
PubMed2006

Synthesis and pharmacological activity of 2-(substituted)-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-ones.

Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.

Animals↗
PubMed1978

The effect of some anti-diarrhoeal drugs on intestinal transit and faecal excretion of water and electrolytes in the horse.

The effect of morphine, Tinct. opii, loperamide, pethidine and atropine on intestinal transit and the faecal and urinary excretion of water and electrolytes was studied in ponies. The rate of passage of a particulate marker was slowed by morphine, hastened then slowed by loperamide and Tinct. opii, and hastened by atropine. The liquid marker was slowed by Tinct. opii and hastened then slowed by the other drugs. Only loperamide decreased the faecal sodium excretion. This drug also decreased faecal water and weight; it appeared worthy of clinical trial in diarrhoea. Tinct. opii decreased by morphine, pethidine and atropine increased faecal water.

Animals↗
PubMed1996

P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs.

The mouse mdr1a (also called mdr3) P-GP is abundant in the blood-brain barrier, and its absence in mdr1a (-/-) mice leads to highly increased levels of the drugs ivermectin, vinblastine, digoxin, and cyclosporin A in the brain. We show here that the drugs loperamide, domperidone, and ondansetron are transported substrates for the mouse mdr1a P-GP and its human homologue MDR1. Phenytoin is a relatively weaker substrate for each, and the drugs haloperidol, clozapine, and flunitrazepam are transported hardly or not at all. Tissue distribution studies demonstrated that the relative brain penetration of radiolabeled ondansetron and loperamide (and their metabolites) is increased four- and sevenfold, respectively, in mdr1a (-/-) mice. A pilot toxicity study with oral loperamide showed that this peripherally acting antidiarrheal agent gains potent opiatelike activity in the central nervous system of mdr1a (-/-) mice. mdr1a (-/-) mice also showed increased sensitivity to neurolepticlike side effects of oral domperidone. These results point to the possible role that the drug-transporting P-GP(s) may play in the clinical use of many drugs, especially those with potential targets in the central nervous system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment.

PURPOSE: Irinotecan (CPT-11), a camptothecin derivative, has shown efficacy against colorectal cancer. Delayed-onset diarrhea is its main limiting toxicity. The aim of this study was to determine the pathophysiology of CPT-11-induced delayed-onset diarrhea and assess the efficacy of combined antidiarrheal medication in a phase II, prospective, successive-cohorts, open study. PATIENTS AND METHODS: Twenty-eight patients with advanced colorectal cancer refractory to fluorouracil (5-FU) therapy received CPT-11 350 mg/m2 every 3 weeks. The first cohort of 14 consecutive patients explored for the mechanism of diarrhea received acetorphan (a new enkephalinase inhibitor) 100 mg three times daily; the second 14-patient cohort received, in addition to acetorphan, loperamide 4 mg three times daily. Before treatment, and if late diarrhea occurred, patients underwent colon mucosal biopsies for CPT-11 and topoisomerase I levels; intestinal transit time; fecalogram; fat and protein excretion; alpha1-antitrypsin clearance; D-xylose test; blood levels for vasoactive intestinal polypeptide, glucagon, gastrin, somatostatin, prostaglandin E2, and carboxylesterase; CPT-11/SN-38 and SN-38 glucuronide pharmacokinetics; and stool cultures. RESULTS: Delayed-onset diarrhea occurred during the first three treatment cycles in 23 patients (82%). Electrolyte fecal measurements showed a negative or small osmotic gap in nine of nine patients and an increased alpha1-antitrypsin clearance in six of six patients. There were no modifications in stool cultures or hormonal dysfunction. Four of 11 patients (36%) with delayed-onset diarrhea in the first cohort responded to acetorphan, whereas nine of 10 patients (90%) responded to the combination of acetorphan and loperamide (P < .02). CONCLUSION: CPT-11-induced delayed-onset diarrhea is caused by a secretory mechanism with an exudative component. Early combined treatment with loperamide and acetorphan seems effective in controlling the diarrheal episodes.

Adult↗
PubMed2000

Effect of zaldaride maleate, an antidiarrheal compound, on fecal pellet output induced by hyperpropulsion in gastrointestine of rats.

The effect of zaldaride, a calmodulin inhibitor, on fecal pellet output in rats was compared with that of loperamide, an antidiarrheal drug. 5-Hydroxytryptamine (10 mg/kg, s.c.), neostigmine (0.3 mg/kg, s.c.) and nicotine (1.0 mg/kg, s.c.) increased fecal pellet output. Zaldaride (> or = 30 mg/kg, p.o.) reduced these increases in fecal pellet outputs. Loperamide (10 mg/kg, p.o.) inhibited fecal pellet output induced by 5-hydroxytryptamine and neostigmine but not nicotine. Under normal conditions, zaldaride and loperamide did not affect fecal pellet output at doses used in these studies. In conclusion, zaldaride may inhibit increases in fecal pellet output induced by hyperpropulsion of the gastrointestinal tract without causing constipation as a side effect.

Animals↗
PubMed2000

Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials.

PURPOSE: To evaluate the efficacy of pharmacologic agents for the irritable bowel syndrome. DATA SOURCES: Electronic literature search of MEDLINE (1966 to 1999), EMBASE (1980 to 1999), PsycINFO (1967 to 1999), and the Cochrane controlled trials registry and a manual search of references from bibliographies of identified articles. STUDY SELECTION: Randomized, double-blind, placebo-controlled, parallel, or crossover trials of a pharmacologic intervention for adult patients that reported outcomes of improvement in global or irritable bowel-specific symptoms. DATA EXTRACTION: Qualitative and quantitative data reported on study groups, interventions, treatment outcomes, and trial methodologic characteristics. DATA SYNTHESIS: 70 studies met the inclusion criteria. The most common medication classes were smooth-muscle relaxants (16 trials), bulking agents (13 trials), prokinetic agents (6 trials), psychotropic agents (7 trials), and loperamide (4 trials). The strongest evidence for efficacy was shown for smooth-muscle relaxants in patients with abdominal pain as the predominant symptom. Loperamide seems to reduce diarrhea but does not relieve abdominal pain. Although psychotropic agents were shown to produce global improvement, the evidence is based on a small number of studies of suboptimal quality. Psychotropic drugs, 5-hydroxytryptamine (5-HT)-receptor antagonists, peppermint oil, and Chinese herbal medicine require further study. CONCLUSIONS: Smooth-muscle relaxants are beneficial when abdominal pain is the predominant symptom. In contrast, the efficacy of bulking agents has not been established. Loperamide is effective for diarrhea. Evidence for use of psychotropic agents is inconclusive; more high-quality trials of longer duration are needed. Evidence for the efficacy of 5-HT-receptor antagonists seems favorable, although more studies are needed.

Antidiarrheals↗
PubMed1983

Alterations in intestinal fluid movement.

Fluid loss in diarrhoea is caused by alterations in the basic mechanisms of transport both in the small intestine and in the colon. The role of blood flow is discussed with reference to anatomy and blood flow distribution, fluid transport, luminal pressure and intestinal motility. The control of intestinal fluid transport and of absorption and secretion processes by intracellular and extracellular mediators is reviewed. Treatment of disorders of fluid transport consist of fluid replacement therapy or the use of antidiarrhoeal agents with high specificity and safety, such as loperamide. The effects of interactions between loperamide and bacterial toxins, theophylline and prostaglandins on the antisecretory activity of loperamide are detailed.

Acetylcholine↗
PubMed1978

The control of acute diarrhea in a large industrial plant.

Diarrhea causes considerable absenteeism and loss of working time among employees in the United States. One hundred employees with acute diarrhea at a Ford Motor Company plant were studied for four months to determine if loperamide hydrochloride treatment would control diarrheal symptoms, reduce absenteeism due to the condition, and be well-tolerated. Diarrhea was controlled with a median dosage of three capsules (6 mg total dose) and a range of two to 12 capsules. Ninety-six percent of the subjects were controlled after the first day, 98% by the third day. A statistically significant number were symptom free at their last clinical visits. Side effects were generally minor in nature. Substantially more than 1,000 man-hours of lost time were saved because of the treatment. Known drug dependents did not suffer from CNS effects or "highs". Loperamide acts directly on the intestinal wall to inhibit excessive peristalsis, thereby providing prompt, effective relief, with normal bowel patterns observed in these patients. The simple, individualized dosage is patient-oriented, rather than based on a fixed regimen. Because of its rapid onset of action, effective control of symptoms, low dosage, and being well-tolerated, loperamide meets the criteria for an effective antidiarrheal agent in industry.

Absenteeism↗