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PubMed1987

Ricinoleic acid and loperamide have opposite motor effects in the small and large intestine of the cat.

The actions of laxatives and antidiarrheal agents in the gut are incompletely understood. Therefore, the effects of Na ricinoleate 10(-4)-10(-2) g/kg b. w. and of loperamide 10(-4) g/kg b. w. on myoelectric activity and marker propulsion were studied in the small and large intestine of 7 unanesthetized cats. Intraduodenal application of ricinoleate briefly increased and then decreased spike activity in the small intestine; marker transit was delayed (92 +/- 18 min vs. 55 +/- 14 min in controls). Ricinoleate also initiated spike complexes of 10-215 sec duration. Transit from the right to the left colon was sometimes accelerated and sometimes delayed. The number of uncoupled slow waves was increased to 278% of control. Loperamide accelerated small intestinal transit to 17 +/- 6 min and markedly delayed it in the colon. At the same time it caused a strong and prolonged rise in colonic spike activity. When ricinoleate and loperamide were given together, their effects almost compensated for each other. The resulting net effect was similar to the data in the control experiments. It is concluded that laxatives and antidiarrheal agents alter not only transit, but also myoelectric activity in the small and large intestine. The effects are largely in opposite direction. Loperamide may, therefore, antagonize motor effects of ricinoleate in the gut.

Animals↗
PubMed1995

Loperamide for treatment of acute diarrhoea in infants and young children. A double-blind placebo-controlled trial.

High-dose loperamide reduces stool output and shortens the duration of diarrhoea in infants receiving intravenous fluids for rehydration, but may cause potentially harmful side-effects in a small number of patients. This double-blind placebo-controlled study was undertaken to assess whether loperamide would shorten the hospital stay of dehydrated children in a rehydration unit. Ninety-one patients with acute dehydrating diarrhoea received loperamide and 94 received placebo. The groups were clinically indistinguishable on admission to hospital. There was no difference between groups for the duration of rehydration or the number of treatment failures. The use of loperamide is not recommended in the treatment of infants and young children with acute diarrhoea.

Antidiarrheals↗
PubMed1995

Treatment of travellers' diarrhoea: zaldaride compared with loperamide and placebo.

OBJECTIVE: To compare zaldaride maleate, a calmodulin inhibitor with gastrointestinal antisecretory properties, with loperamide and a placebo in the treatment of travellers' diarrhoea. DESIGN: Randomized, double-blind, double-dummy study. SETTING: Study clinic staffed by European residents on Nile cruise ships. PATIENTS: Tourists (n = 436) who acquired travellers' diarrhoea during the Nile cruise. INTERVENTIONS: (1) Zaldaride 20 mg four times daily, (2) zaldaride 2 x 20 mg as initial loading dose followed by three doses of 20 mg on the first day and four doses of 20 mg on the second day, (3) loperamide 2 x 2 mg loading dose following by a flexible dosage of 2 mg after each unformed stool (maximum of 16 mg daily), (4) placebo. MAIN OUTCOME MEASURES: Number of unformed stools, rate of improvement of patients with diarrhoea, rate of relief from diarrhoea. RESULTS: Among the 331 compliant and fully evaluated patients, the zaldaride with loading dose group showed no significant differences in cure rates from the loperamide group. For most parameters, zaldaride without a loading dose and the placebo resulted in significantly lower cure rates. CONCLUSIONS: A zaldaride regimen including a loading dose was shown to be well tolerated and as effective as loperamide.

Adolescent↗
PubMedDate not supplied

Assessment of pharmacokinetic interaction between theophylline and loperamide in the rat.

The effect of loparamide (1 mgkg-1, p.o.) on the pharma-cokinetics of theophylline was studied in the rat. Theophylline (as aminophylline-25 mgkg-1, p.o.) was administered either alone, in combination with, or 1 hr after loperamide. Plasma levels of theophylline were serially measured over a period of 12 hr using HPLC. The disposition kinetics of theophylline was markedly altered by loperamide. This was evident from the significant differences obtained between the control and drug combination groups in most of the parameters studied (Cpmax, tmax, Ka, t1/2 and AUC). Allowing for the limitations of single dose studies, the data presented here suggest that pharma-cokinetic interaction between theophylline and loperamide is possible during their concomitant use.

Animals↗
PubMed2001

[Loperamide abuse in anxiety disorder].

Anxiety disorders often accompany somatic correlates of anxiety such as abdominal trouble and diarrhoea. Nevertheless, misuse of antidiarrhoeals has been described only once. We report on a 34-year-old woman who abused loperamide for over 10 years, taking up to 16 mg per day. Loperamide is an opioid that stimulates opioid receptors in the gastrointestinal tract, thereby inhibiting intestinal secretion and propulsive peristalsis, probably without affecting the central nervous system. As our patient's digestive trouble was a consequence of her states of anxiety, diazepam application helped against her diarrhoea as well. This second strategy of self-medication gained particular importance for her, when even high doses of loperamide stopped having an effect. So she developed a benzodiazepine dependence. As soon as she began treatment as an inpatient, her feelings of anxiety became less and the diarrhoea disappeared.

Adult↗
PubMed2005

Activation of opioid mu-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells.

AIMS/HYPOTHESIS: This study investigated the role of opioid mu-receptor activation in the improvement of insulin resistance. METHODS: Myoblast C2C12 cells were cultured with IL-6 to induce insulin resistance. Radioactive 2-deoxyglucose (2-DG) uptake was used to evaluate the effect of loperamide on insulin-stimulated glucose utilisation. Protein expression and phosphorylation in insulin-signalling pathways were detected by immunoblotting. RESULTS: The insulin-stimulated 2-DG uptake was reduced by IL-6. Loperamide reversed this uptake, and the uptake was inhibited by blockade of opioid mu-receptors. Insulin resistance induced by IL-6 was associated with impaired expression of the insulin receptor (IR), IR tyrosine autophosphorylation, IRS-1 protein content and IRS-1 tyrosine phosphorylation. Also, an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase, Akt serine phosphorylation and the protein of glucose transporter subtype 4 were observed in insulin resistance. Loperamide reversed IL-6-induced decrement of these insulin signals. CONCLUSIONS/INTERPRETATION: Opioid mu-receptor activation may improve IL-6-induced insulin resistance through modulation of insulin signals to reverse the responsiveness of insulin. This provides a new target in the treatment of insulin resistance.

Animals↗
PubMed2001

Does loperamide affect motor activity after proctocolectomy and ileal pouch-anal anastomosis? An experimental study in dogs.

This study investigated the effect of loperamide on the motor function of small intestine and J-pouch. Proctocolectomy and ileal pouch-anal anastomosis were performed in four dogs. Motility was recorded by serosal electrodes and strain gauge transducers. The intestinal transit time was determined radiologically. Multiple measurements were performed before and during chronic administration of loperamide. This treatment led to a significant decrease in median stool frequency from 11 (10-13) to 9 stools/day (8-12) and a tendential increase in intestinal transit time from 60 (50-105) to 70 min (60-90). This was not accompanied by significant changes in fasted or postprandial motility. There were no significant differences in the characteristics of the migrating myoelectric complex or in the fed pattern, either in the small intestine or in the pouch. Loperamide thus does not significantly affect intestinal motility after ileal pouch-anal anastomosis. The reduction in stool frequency seems to be due to antisecretory effects in the first line.

Animals↗
PubMed1985

Vagally mediated reflex and cardiac slowing induced by loperamide in rats.

The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anaesthetized rats. Both effects were inhibited by the opiate antagonists naloxone and MRZ 2266 BS. Bilateral vagotomy also inhibited both effects whereas atropine only reduced the bradycardia, but the combination of atropine and tertatolol suppressed the bradycardia. A high dose of loperamide induced bradycardia in pithed rats. This effect was prevented by MRZ 2266 BS but not by naloxone. It is concluded that loperamide can elicit a vagally mediated reflex involving vagal and sympathetic mechanisms and could stimulate cardiac opiate receptors, probably kappa, both effects leading to bradycardia.

Animals↗
PubMed1991

Loperamide but not morphine has anti-secretory effects in human colon, in vitro.

Isolated preparations of human colonic mucosa were set up in Ussing chambers. Noradrenaline reduced basal short-circuit current, morphine did not nor did loperamide except at the highest concentration tested. Electrically evoked increases in short-circuit current were unaffected by morphine but reduced by loperamide, by a naloxone-insensitive mechanism. Unidirectional fluxes of 22sodium and 36chloride were unaffected by morphine. It is concluded that loperamide but not morphine has an anti-secretory effect on human colonic mucosa.

Colon↗
PubMed1986

Effect of lidamidine hydrochloride and loperamide on gastric emptying and transit of the small intestine. A double-blind study.

We performed a double-blind randomized study in 24 healthy volunteers, to evaluate the effects of two doses of lidamidine hydrochloride, loperamide, and placebo on transit of the small intestine and gastric emptying. Transit time of the small intestine was determined by measuring the rise in breath hydrogen excretion after ingestion of lactulose. Although there was a trend for prolonged intestinal transit time in both lidamidine groups, this difference was not significant compared with that in the placebo group. Loperamide significantly slowed transit when compared with placebo or lidamidine (p less than 0.001). Gastric emptying was assessed by using a solid-phase radiolabeled meal. Three parameters of gastric emptying were analyzed: half-emptying time, area under the gastric emptying curve, and beta. Although there was a trend for a longer half-emptying time in the group that received 12 mg of lidamidine, this difference approached, but did not reach, statistical significance (p = 0.06) compared with placebo. The area under the gastric emptying curve, a potentially more sensitive parameter for measuring gastric emptying, was significantly increased in the group receiving 12 and 18 mg of lidamidine (p less than 0.05) compared with the group receiving loperamide or placebo. In summary, lidamidine significantly delayed gastric emptying but had no significant effect on small bowel transit. These data suggest that the antidiarrheal properties of lidamidine are the result of enhanced absorption or inhibition of secretion of fluid and electrolytes.

Adolescent↗
PubMed1995

Spectrofluorimetric and derivative absorption spectrophotometric techniques for the determination of loperamide hydrochloride in pharmaceutical formulations.

Simple, sensitive and rapid spectrofluorimetric and derivative absorption spectrophotometric procedures are described for the accurate determination of loperamide hydrochloride. The spectrofluorimetric method involves the measurement of the fluorescence of the compound in an ethanol-sulphuric acid mixture (90:10, v/v) using either the direct or the synchronous modes of measurement. Optimum conditions for maximum fluorescence are described. The derivative spectrophotometric method involves the measurement of either the second derivative peak amplitude (crest to trough, i.e. maximum to minimum) between 258 and 263 nm or the second derivative peak height (i.e. maximum to zero line) at 224 nm of an ethanolic solution of the drug. The proposed methods have been used for the determination of loperamide in pharmaceutical formulations. Compared to the pharmacopoeial method, the proposed methods give equally accurate (t-test) and precise (f-test) results. The proposed methods have the advantages of being highly sensitive for the determination of small concentrations of loperamide, a weak UV-absorbing compound prescribed in low doses.

Chromatography, High Pressure Liquid↗
PubMed2004

[Loss of consciousness in a child due to loperamide].

Loperamide is an antidiarrheal peripheral opiate agonist, with rare neurological secondary effects. We report the case of a 26-month-old child who had impaired consciousness under treatment by loperamide, and was treated successfully with naloxone. Limitations of the use of loperamide in young children are underlined. Naloxone may be used in case of impaired consciousness, for a diagnostic as well as therapeutic purpose.

Antidiarrheals↗
PubMed2005

Analgesic effects of morphine and loperamide in the rat formalin test: interactions with NMDA receptor antagonists.

To reveal peripheral components of opiate analgesia, effects of loperamide, opioid agonist which does not penetrate the blood-brain barrier, were examined in formalin and acute thermal pain tests in comparison with morphine. Formalin administration induces pain behaviour such licking/biting of injected paw expressed as two phases. The first phase is caused by C-fibre activation due to peripheral stimulation, the second phase attributed to ongoing input from peripheral site, leading to spinal hyperexcitability, which is dependent on N-methyl-D-aspartate (NMDA) receptor activation. Loperamide (3-10 mg/kg) and morphine (6 mg/kg) reduced formalin-induced nociceptive behaviours and these effects were reversed by naloxone methiodide (0.03-10 mg/kg), opioid receptor antagonist which poorly penetrates the blood-brain barrier. Loperamide action was enhanced only by centrally active NMDA receptor antagonists memantine (3 mg/kg) and CGP 37849 (3 mg/kg), but not by NMDA/glycineB receptor antagonists showing weak or no central nervous system (CNS) activity. Present results suggest that central NMDA receptor blockade may be necessary to enhance analgesia induced through peripheral opioid mechanisms in formalin-evoked nociception.

Analgesics, Opioid↗
PubMed2004

Effect of finite doses of propylene glycol on enhancement of in vitro percutaneous permeation of loperamide hydrochloride.

We hypothesised that the depletion of propylene glycol from topical formulations applied at clinically relevant doses (approximately mg/cm2) would limit its penetration enhancement effect. The in vitro percutaneous permeation of a model drug-loperamide hydrochloride-in formulations containing propylene glycol was therefore investigated under finite dose conditions. The flux of loperamide and propylene glycol across dermatomed human skin was measured. The first study examined the effect of topical loading of a gel containing 12% propylene glycol. The second study investigated the effect of propylene glycol content in creams containing 15 and 40%. Both studies showed a correlation between the amount of propylene glycol dosed on the skin and the amount of drug that had permeated. The substantial permeation of propylene glycol and relatively small permeation of loperamide, strongly suggests, that the time dependent permeation of the drug was due to the depletion of propylene glycol at the skin surface and not to the depletion of the drug itself. As often doses applied in in vitro skin permeation experiments do not match the intended clinical dosage-they are usually much greater-this study suggests that the penetration enhancement effect of propylene glycol can be overestimated in in vitro studies.

Administration, Cutaneous↗
PubMed2004

Liquid chromatography-tandem mass spectrometry determination of loperamide and its main metabolite desmethylloperamide in biological specimens and application to forensic cases.

A liquid chromatographic mass spectrometric (LC/MS/MS) method has been developed for the determination of loperamide in whole blood and other biological specimens. The procedure involves liquid-liquid extraction of loperamide, desmethylloperamide and methadone-D3 (internal standard) with butyl acetate. Confirmation and quantification was done by positive electrospray ionisation with a triple quadrupole mass spectrometer operating in multiple reaction-monitoring (MRM) mode. Two MRM transitions of each compound were established and identification criteria were set up based on the ratio of the responses between the two MRM transitions of each compound. The standard curves were linear over a working range of 0.1-500 microg/kg for all transitions. The limit of quantification was 0.1 microg/kg in whole blood. The repeatability and reproducibility within the laboratory expressed by relative standard deviation were less than 5 and 11%, respectively, and the accuracy was better than 9%. The method was developed to examine a feces sample from a child whose mother was suspected of Münchausen syndrome by proxy and it proved to be suitable for forensic cases being simple, selective and reproducible. The method was also applied for a case investigation involving a overdose of loperamide.

Antidiarrheals↗
PubMed2001

Early pregnancy termination with vaginal misoprostol combined with loperamide and acetaminophen prophylaxis.

The objectives of this prospective non-concurrent cohort study were to confirm the efficacy of vaginal misoprostol for early pregnancy termination and to determine whether the incidence of side effects is lower with prophylactic loperamide and acetaminophen. Two-hundred women with an intrauterine pregnancy < or =56 days gestational age seeking medical pregnancy termination in an ambulatory research clinic were enrolled in the study. One-hundred participants (group 1) ingested 4 mg of loperamide and 500 mg of acetaminophen before the vaginal placement of 800 mirog of misoprostol moistened with 2 mL of saline. If abortion had not occurred, the same regimen was repeated every 24 h (maximum three doses). One-hundred participants (group 2) from the same clinic who previously underwent the same misoprostol regimen without prophylactic medication served as a control group for comparison with respect to abortion success and the incidence of side effects. The rate of successful abortion was not statistically significantly different between the two groups (group 1 93%, group 2 89%). The incidence of opiate analgesic use was significantly less in group 1 (4%) compared with group 2 (16%) (OR 0.22, 95% CI 0.06-0.73, p = 0.01). There was a significantly lower incidence of diarrhea in group 1 (23%) compared with group 2 (44%) (OR 0.38, 95% CI 0.20-0.73, p = 0.003). There was no difference in the incidence of fever/chills or the incidence of emesis between the two groups. Vaginal misoprostol is effective for termination of pregnancy < or = 56 days and the incidence of diarrhea and the use of opiate analgesia is significantly reduced with prophylactic loperamide and acetaminophen.

Abortifacient Agents, Nonsteroidal↗
PubMed2002

Antipruritic and antihyperalgesic actions of loperamide and analogs.

Loperamide and three of its analogs were evaluated for their ability to inhibit binding to cloned human opioid receptor subtypes and to produce antipruritus and antinociception following local s.c. administration to rodents. All four compounds were fully efficacious agonists with affinities of 2 to 4 nM for the cloned human mu opioid receptor. Local s.c. injection of loperamide, ADL 01-0001 or ADL 01-0002 at the same site as the introduction of the pruritogenic compound 48/80 resulted in antipruritic activity in a mouse model of itch. Similarly, i.paw or i.pl. administration of compounds ADL 01-0001, ADL 01-0002 and ADL 01-0003 to inflamed paws caused potent antinociception, inhibiting late phase formalin-induced flinching, Freund's adjuvant-induced mechanical hyperalgesia and tape stripping-induced mechanical hyperalgesia. Loperamide and its analogs were efficacious in animal models of itch and inflammatory pain, and may have potential therapeutic utility as antipruritic and antihyperalgesic agents.

Analgesics↗
PubMed2003

Potential roles of P-gp and calcium channels in loperamide and diphenoxylate transport.

This study examined the accumulation and transport of two related systemic opioids used as antidiarrhoeal drugs and compared their rates of transport with known P-glycoprotein (P-gp) substrates used in our in vitro environment. Cellular uptake and efflux and transcellular transport were all determined using Caco-2 cells after exposure to loperamide or diphenoxylate, with or without a range of efflux inhibitors. Bidirectional transport studies of 5 microM loperamide showed efflux to be fivefold higher than influx (42 x 10(-6) compared to 8 x 10(-6) cm/s); however, this decreased to twofold at 10 microM and was abolished using 100 microM loperamide. An uptake pathway was also discovered when P-gp was inhibited which, in the presence of Ca(2+) channel blockers, was amplified, providing a potential mechanism for central nervous system effects to be increased upon blockage of L-type calcium channels, quite separate from any P-gp inhibition. Diphenoxylate transport, however, showed little sign of P-gp-mediated efflux. Diphenoxylate accumulated readily within cells, yet transport through cells was very low. Additionally, efflux inhibitors had little impact on transport or accumulation, suggesting that diphenoxylate was not a substrate for an efflux mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗