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PubMed1983

Mechanisms of action of loperamide.

The beneficial effect of loperamide in some children with severe protracted diarrhoea which persisted when nil by mouth, made us suspect that loperamide may have an antisecretory action. Using a steady-state perfusion technique in rat jejunum we showed that loperamide inhibits cholera toxin induced secretion of water, sodium and chloride (p less than 0.001). This antisecretory action was blocked by naloxone and not mediated via an effect on tissue cyclic AMP level or adenylate cyclase activity. More recently we have studied the effect of loperamide on secretion of water in the rat jejunum induced by other agents with differing mechanisms of action. The first set of observations suggest that loperamide's antisecretory effect is mediated via opiate receptors either distal to, or separate from the adenylate cyclase/cyclic AMP pathway. Our more recent studies support the notion that loperamide has an effect on specific transport systems rather than non-specific passive diffusional processes.

Animals↗
PubMed1981

Effect of loperamide, a peripheral opiate agonist, on circulating glucose, free fatty acids, insulin, C-peptide and pituitary hormones in healthy man.

The effect of acute oral administration of loperamide (4, 8 and 16 mg), a peripheral opiate agonist used in the treatment of diarrhoea, on several metabolic and endocrine variables has been evaluated in healthy volunteers in comparison with placebo. Plasma glucose was significantly raised by all three doses, whereas serum IRI and C-peptide were decreased and serum FFA was significantly increased only after loperamide 8 and 16 mg; serum PRL, GH, LH and FSH did not change. The data suggest that opiates may be involved in the regulation of glycaemia, probably by modifying islet hormone secretion by acting at a peripheral site, since loperamide does not cross the blood-brain barrier. Although the precise mechanism of these actions is unknown, it is suggested that the effects of loperamide are mediated either by stimulation of opiate receptors per se, or by suppression of acetylcholine release from cholinergic nerve endings. The lack of change in pituitary hormone secretion by loperamide is in agreement with previous observations indicating that opiate effects on PRL, GH and gonadotropins occur at the level of the central nervous system.

Adult↗
PubMed1993

Loperamide. Survey of studies on mechanism of its antidiarrheal activity.

In castor oil challenged rats, low doses of loperamide inhibit diarrhea and normalize intestinal propulsion. Unlike other opioids, loperamide is devoid of central opiate-like effects, including blockade of intestinal propulsion, up to the highest subtoxic oral dose. Nevertheless, the antidiarrheal action of loperamide can be considered to be mu-opiate receptor mediated, only a few in vitro effects at rather high concentrations being not naloxone-reversible. There is little evidence that interactions with intestinal opiate receptors directly change epithelial cell function. When secretory stimuli increase mucosal tension, however, loperamide may reverse the elevated hydrostatic tissue pressure that opposes normal absorption. This antisecretory effect at the mucosal level is accompanied by motor effects when loperamide reaches the myenteric mu-opiate receptors. At therapeutic doses for the treatment of acute diarrhea, it is likely that the mucosal effect prevails.

Animals↗
PubMed1984

Local inhibition of myoelectrical activity of human colon by loperamide.

In order to study whether the antidiarrheal effects of loperamide are largely brought about by a local inhibition of the drug, we applied doses of 0.2 mg directly on the mucosa of the descending and sigmoid colon of 33 healthy volunteers. Loperamide decreased BER frequencies and reduced spike activity to 6.6 +/- 0.3% of time vs 11.3 +/- 0.7% in the control recorded from 3 cm aside and to 5.8 +/- 0.4% vs 12.7 +/- 0.9% in the descending and sigmoid colon, respectively. The same effects became apparent when spike activity was stimulated by neostigmine. Loperamide also reduced the occurrence of groups of spikes to 3.8 +/- 0.4/hr vs 10.3 +/- 0.6 and to 3.6 +/- 0.4/hr vs 14.6 +/- 0.7 in the descending and sigmoid colon, respectively. Groups of spikes are thought to be the equivalent of propulsive movements. Thus, loperamide is active locally and exhibits inhibitory effects on the motor activity of the colon. Clinical studies seem warranted to examine the effectiveness of loperamide enemas in motility disturbances of the anorectum.

Adult↗
PubMed1984

Role of loperamide and placebo in management of irritable bowel syndrome (IBS).

Symptom scores, stool data, and the transit of a standard, solid meal were measured in 28 patients with irritable bowel syndrome (IBS) during baseline conditions and after five weeks of treatment with placebo and loperamide, given as a flexible dosage regime in the form of a double-blind, cross-over trial. All patients had undergone a comprehensive series of diagnostic investigations and had failed to respond to dietary supplementation with coarse wheat bran (10-30 g daily). Loperamide treatment accelerated gastric emptying, compared with placebo (1.2 +/- 0.1 vs 1.5 +/- 0.1 hr; P less than 0.001) and delayed both small bowel (6.2 +/- 0.3 vs 4.3 +/- 0.3 hr; P less than 0.001) and whole gut transit (56 +/- 5 vs 42 +/- 4 hr; P less than 0.01). Eighteen patients said they felt better taking loperamide compared with placebo and, at follow up, 15 of these patients remained satisfied with the effects of the drug. Most symptoms improved significantly on placebo compared with the baseline period, but three of these [diarrhea (P less than 0.01), urgency (P less than 0.01) and borborygmi (P less than 0.05)] showed a further significant improvement on loperamide. Improvement in diarrhea was not associated with any change in stool weight but was associated with reductions in stool frequency (P less than 0.001), passage of unformed stools (P less than 0.01), and incidence of urgency (P less than 0.001). Urgency was the only symptom that was significantly more common in the success group, compared with the group who did not feel better on loperamide.

Adult↗
PubMed1991

Effect of loperamide and delay of bowel motility on bile acid malabsorption caused by late radiation damage and ileal resection.

Selenium-75 homocholic acid conjugated with taurine (75Se-HCAT) was used during loperamide administration in seven patients suspected of having bile acid malabsorption due to late radiation damage and small-bowel resection in order to document the aetiology of ileal dysfunction and to adjust therapeutic management. In two patients with ileal resection up to 50 cm and in one patient without resection, a reduction of bowel motility by loperamide resulted in marked normalization of the 75Se-HCAT retention measurements. Sequential scintigraphic 75Se-HCAT imaging demonstrated a significant improvement in the 75Se-HCAT reabsorption and recirculation, accompanied in one case by prolongation of colonic retention of the radiopharmaceutical. In four patients with more than 80 cm resection, the 75Se-HCAT test was abnormal during loperamide administration. In two of these patients for whom baseline values were available, no improvement in the pattern of 75Se-HCAT absorption was observed. In conclusion, the first results of loperamide 75Se-HCAT in patients suspected of having bile acid malabsorption and abnormal baseline 75Se-HCAT are promising. Intervention with loperamide is easy and seems to improve the clinical value of the test with direct therapeutic implications. Sequential 75Se-HCAT imaging is essential for interpreting changes in the 75Se-HCAT retention measurements.

Abdomen↗
PubMed2001

Control of irinotecan-induced diarrhea by octreotide after loperamide failure.

Diarrhea is a well-recognized side effect of chemotherapy, which affects the quality of life and when refractory is potentially life threatening. Irinotecan (CPT-11) is associated with an elevated incidence of chemotherapy-induced diarrhea and subsequent morbidity. Standard antidiarrheal treatment is based on high-dose loperamide, but this agent is associated with a significant failure rate. Octreotide is active against chemotherapy-induced diarrhea caused by fluoropyrimidines and irinotecan, with a distinct mechanism of action. We administered octreotide in a phase I trial in 37 patients who received irinotecan and experienced loperamide-refractory diarrhea, 23 of whom experienced grade III-IV diarrhea and were treated with loperamide. The 13 patients in whom to loperamide failed to control diarrhea received octreotide, with a high response rate (92%). We conclude that octreotide is effective against loperamide-refractory diarrhea resulting from irinotecan-based chemotherapy.

Adult↗
PubMed1979

Effects of loperamide on the guinea pig taenia coli.

The effects of an antidiarrhoeal agent, loperamide, were studied using isolated guinea pig taenia coli. Loperamide in concentrations ranging from 10(-7) M inhibited the cholinergic, contractile responses induced by electrical transmural stimulation, nicotine and serotonin, and the nonadrenergic, relaxing responses induced by electrical transmural stimulation and nicotine. However, the adrenergic response to perivascular nerve stimulation was not affected by these concentrations. The inhibitory effects of loperamide were not reversed by washing with a drug-free solution. Morphine (10(-6 M to 10(-5) M) also inhibited both cholinergic and nonadrenergic responses, but the effect was reversible. Naloxone (1o(-6) M) attenuated the inhibitory effects of both drugs. Unlike morphine, loperamide in concentrations higher than 5 x 10(-6) M relaxed the strips and reduced the contractile response to acetylcholine noncompetitively, and these effects were not blocked by naloxone. These results suggest that loperamide at low concentrations acts selectively on the opiate receptors located in both cholinergic and nonadrenergic nerves and at higher concentrations also acts directly on smooth muscle thus producing relaxation of the intestinal tone.

Acetylcholine↗
PubMed1982

Increase of plasma corticosterone induced by loperamide in rats.

Loperamide given intracerebroventricularly and intraperitoneally to rats provoked, like morphine, a plasma corticosterone increase 60 min after injection. Loperamide intracerebroventricularly was 3.73 times less active than morphine, while intraperitoneally it was 10.13 times more potent. This increase, associated with a significant elevation in the plasma ACTH concentration, was antagonized by naloxone (10 mg/kg i.p.) injected 30 min before loperamide. In hypophysectomized rats loperamide intraperitoneally did not affect the plasma corticosterone levels. We conclude that loperamide can stimulate corticosterone secretin from the adrenal gland via the opiate receptors and that this effect is mediated by a direct or indirect induction of ACTH release.

Adrenocorticotropic Hormone↗
PubMed1988

Action of loperamide on neuronally mediated and Ca2+- or cAMP-mediated secretion in rat colon.

The action of loperamide on the ion secretion evoked in rat colon descendens by electric field stimulation of enteric neurons, on the Ca2+-dependent secretion due to carbachol, and on the cAMP-mediated secretion elicited by forskolin was studied. Loperamide blocked all three types of secretion, but about 10 times higher concentrations of the drug were necessary to block the secretion caused by forskolin than to block the secretion mediated neuronally or by Ca2+. All the effects of loperamide were mimicked by trifluoperazine, a calmodulin antagonist. Neither morphine nor the Ca2+ channel blocker, verapamil, mimicked the effects of loperamide on ion transport. Therefore it seems reasonable to conclude that the antisecretory action of loperamide in the rat colon is caused by a block of the calmodulin system.

Animals↗
PubMed1989

Inhibition by loperamide of mucus secretion in the rat colon in vivo.

The effect of loperamide on mucus secretion and the net transport of fluid, sodium and potassium was investigated in the perfused rat colon in vivo. Prostaglandin E2 (PGE2, 1 mg/kg per h intraarterially) and deoxycholic acid (2 mM intraluminally) were used as secretagogues. Mucus secretion was determined as the total amount of protein-bound hexose in the effluent. Under basal conditions, loperamide (6 mg/kg subcutaneously) slightly decreased mucus secretion and increased the absorption of fluid and sodium. PGE2 and deoxycholic acid stimulated mucus secretion about 4- and 9-fold, respectively. Loperamide abolished the mucus secretory response to PGE2 and reduced the response to deoxycholic acid by 50%. It also reduced the fluid secretion following PGE2 but did not affect the diminished fluid absorption following deoxycholic acid. Potassium secretion was not significantly influenced by loperamide and therefore was independent of the secretion of mucus. The data suggest that loperamide is a potent inhibitor of colonic mucus secretion, a property that possibly contributes to the antidiarrheal effect of this opiate analogue.

Animals↗
PubMed1994

Absence of emetic effects of morphine and loperamide in Suncus murinus.

The house musk shrew Suncus murinus recently has been introduced for the study of emesis. We investigated the emetic effects of the opioids morphine (0.1-21.5 mg/kg i.p.) and loperamide (0.01-10 mg/kg i.p.) and found a complete lack of emetogenic potential. Nicotine, however, dose dependently induced vomiting in the Suncus with an ED50 of 8.8 mg/kg s.c. and a 100% incidence at 20 mg/kg. This drug-induced vomiting was reduced by morphine or loperamide: ED50 values obtained were 1.2 mg/kg i.p. for morphine and 0.7 mg/kg i.p. for loperamide. Naloxone (2 mg/kg s.c.) antagonised the inhibitory effect of morphine (2 mg/kg i.p.) or loperamide (10 mg/kg i.p.). Serotonin (20 mg/kg s.c.) had less reliable emetogenic potency than nicotine in the Suncus with incidences between 50 and 100%. However, the serotonin-induced vomiting was abolished by morphine and loperamide and this inhibition was antagonised by naloxone. These results suggest that systemically administered opioids are pure antiemetics in Suncus murinus in contrast to other animal models and man. Naloxone antagonism indicates that this antiemetic effect is mediated by opioid receptors.

Animals↗
PubMed1987

Influence of loperamide on the internal anal sphincter in the opossum.

The objective of this study was to examine the influence of the commonly used antidiarrheal agent loperamide on the internal anal sphincter of anesthetized opossums. Loperamide caused a rise in internal anal sphincter pressures, and a decrease in the rectal distention-induced internal anal sphincter relaxation. To define the mechanism of decrease in the rectal distention response of the internal anal sphincter, we examined the effects of sacral efferent nerve stimulation, local intramural stimulation, and ganglionic stimulant (which acts at the postganglionic inhibitory neuron). Loperamide caused a significant decrease in the internal anal sphincter relaxation caused by sacral nerve stimulation, but not in that caused by local intramural stimulation and nicotine. These effects of loperamide on the internal anal sphincter were antagonized by naloxone. These findings suggest that the therapeutic effects of loperamide on the internal anal sphincter as an antidiarrheal agent are due to a rise in the tone of the sphincter and the inhibition of its relaxation in response to rectal distention. Both of these actions are mediated by activation of opioid receptors. The inhibition of internal anal sphincter relaxation induced by rectal distention (which mimicks recto-anal reflex) is due to inhibition of release of neurotransmitter from the preganglionic sacral nerve fibers.

Anal Canal↗
PubMed1994

Comparative effects of loperamide hydrochloride on prostaglandin E1-induced contraction in isolated fundus and ileum of guinea pigs.

The tension of isolated preparations of the fundus and the ileum of guinea pigs was measured isometrically to study the specific effect of loperamide hydrochloride on prostaglandin E1-induced contraction. Prostaglandin E1 caused concentration-dependent contraction in both the fundus and the ileum, and there was no significant difference between the fundus and the ileum. Loperamide hydrochloride inhibited prostaglandin E1-induced contraction in the fundus and the ileum. From the pD'2 value, loperamide hydrochloride caused greater inhibition of the contraction in the ileum than in the fundus. In a Ca(2+)-free solution containing 0.1 mM EGTA, prostaglandin E1-induced contraction in the ileum was almost eliminated, whereas 58% of the contraction in the fundus still remained. In Ca(2+)-free solution, loperamide hydrochloride and verapamil hydrochloride had no influence on prostaglandin E1-induced contraction, but markedly inhibited Ca(2+)-induced contraction. These results suggest that loperamide hydrochloride shows regional differences between gastrointestinal smooth muscles contracted by prostaglandin E1, and this may reflect one of the mechanisms in its antidiarrheal action through the suppression of peristalsis.

Alprostadil↗
PubMed2005

Study of the physicochemical properties and stability of solid dispersions of loperamide and PEG6000 prepared by spray drying.

Solid dispersions of PEG6000 and loperamide-a poorly water-soluble agent-were prepared by spray drying. Their physicochemical properties were evaluated immediately after preparation. The dissolution was higher than that of pure crystalline loperamide. DSC- and XRD-measurements revealed that in the dispersions, loperamide is partially present in the crystalline state. A eutectic state diagram was obtained. The samples containing 20% loperamide were stored under different conditions (40 degrees C and 0% RH, 25 degrees C and 52% RH, 4 degrees C and 0% RH) to investigate their stability as a function of time. The dissolution properties deteriorate upon storage at high temperature (40 degrees C and 0% RH) and in conditions of higher relative humidity (25 degrees C and 52% RH). The DSC-curves clearly indicate an increase in the amount of crystalline compound under these conditions. From these observations it could be concluded that loperamide, which is partially crystalline and partially amorphous in the freshly prepared samples, continues to crystallize under these conditions, resulting in progressively poorer dissolution properties.

Chemical Phenomena↗
PubMed2004

Phase behaviour analysis of solid dispersions of loperamide and two structurally related compounds with the polymers PVP-K30 and PVP-VA64.

The purpose of the present study was to investigate the influence of the structure of a poorly water soluble model drug (loperamide) on the phase behaviour in solid dispersions with PVP-K30. Dispersions with PVP-VA64, a less hydrophilic polymer, were investigated as well in order to study the influence of differences in polymer structure and water content of the samples. The solid dispersions of PVP-K30 or PVP-VA64 with loperamide as well as with two fragments of this molecule were prepared by spray drying. The amount of residual solvents and water was determined with GC and thermogravimetric analysis (TGA). The drug loading of the dispersions was determined using high performance liquid chromatography (HPLC). The solid state properties were evaluated using powder-XRD, IR-spectroscopy and MT-DSC. All mixtures containing loperamide proved to be completely amorphous, whereas the dispersions containing the fragments are only amorphous in case the polymer content is high. The phase diagrams that were constructed clearly show that loperamide exhibits a different behaviour in the solid dispersions than its two building blocks. They also point to the presence of specific intermolecular compound--polymer interactions in the dispersions of one of the fragments with the two polymers. This was confirmed by the IR-results. Despite structural similarities, interactions in dispersions containing loperamide are far less important. In dispersions containing high concentrations of the other fragment, the DSC curves give indications for polymorphism whereas IR and XRD-spectra point towards inclusion of solvent in these samples.

Loperamide↗
PubMed1999

Activation of opioid mu-receptor by loperamide to lower plasma glucose in streptozotocin-induced diabetic rats.

We investigated the effect of loperamide, a selective agonist of opioid mu-receptor, on the plasma glucose in diabetic rats induced by an intravenous injection of streptozotocin (STZ; 60 mg/kg). Intravenous injection of loperamide induced a dose-dependent decrease of plasma glucose in fasting STZ-diabetic rats at 30 min later, but did not modify the plasma glucose level in Wistar rats. Plasma glucose lowering effect of loperamide was abolished by the pretreatment with naloxone or naloxonazine at the dose sufficient to block opioid mu-receptor. In isolated skeletal muscle, loperamide enhanced the glucose uptake into soleus muscles in a concentration-dependent manner. Blockade of this action by naloxonazine indicated the mediation of opioid mu-receptor. These results suggest that an activation of opioid mu-receptor by loperamide can increase the utilization of glucose in peripheral tissue to lower the plasma glucose in STZ-diabetic rats.

Animals↗
PubMed1997

Subcutaneous loperamide prevents gastric lesions induced by necrotizing agents in rats.

The effects of subcutaneous loperamide on gastric lesions induced by necrotizing agents were investigated in the rat. Loperamide produced a dose-dependent increase of gastric fluid volume and inhibition of gastric lesions caused by 0.6 N HCl or absolute ethanol. Pretreatment with naloxone almost completely blocked both fluid pooling effect and mucosal protective effect of loperamide. Omeprazole reduced the acidity of the gastric fluid in rats treated with loperamide without significantly decreasing the fluid volume. Various volumes of acid, given orally immediately before 0.6 N HCl, volume-dependently prevented gastric lesions. We conclude that subcutaneous loperamide protects the gastric mucosa against necrotizing agents through luminal dilution of irritants, which is mediated by naloxone-sensitive opiate receptors.

Animals↗