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At least 19 recordsLinked to original sources

PubMed1992

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

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

Administration, Oral↗

PubMed1990

Comparison of the antisecretory effects of loperamide and loperamide oxide in the jejunum and the colon of rats in-vivo.

The antidiarrhoeal effect of loperamide is caused by its antimotility and antisecretory properties. In-vivo experiments in the rat jejunum and colon have been performed to compare the antisecretory effect of loperamide with the effect of its prodrug, loperamide oxide. Both loperamide and loperamide oxide administered intraluminally, equally and dose dependently (2 to 250 micrograms mL-1) reduced PGE2-induced net fluid secretion (32 ng min-1 i.a.) in the jejunum and colon. The antisecretory effect of both drugs is blocked by naloxone (1 mg kg-1 s.c.). It is concluded that loperamide oxide administered intraluminally is reduced to loperamide and has the same antisecretory potency as loperamide in jejunum and colon. The effect appears to be mediated via opiate receptors. The observation that loperamide cannot be detected in the colonic lumen two h after oral administration suggests that the drug is delivered from the blood stream to the site of action after absorption in the small intestine.

Administration, Oral↗

PubMed1978

[Pharmacological studies of loperamide, an anti-diarrheal agent. III. Interaction between loperamide and various agonists in the guinea pig intestine (author's transl)].

To clarify the mode of action of loperamide, the interaction with various agonists was investigated in guinea pig intestines. The following results were obtained. Prostaglandin E1 (0.1 microgram) or acetylcholine (1 approximately 3 microgram) injection into the mesenteric artery at 10 min intervals caused a constant rise of intraluminal pressure of the intestinal loop in situ. Loperamide (0.01 approximately 0.1 mg/kg i.v.) markedly suppressed the response induced by prostaglandin E1. Morphine (0.1 approximately 1.0 mg/kg i.v.) and atropine (0.01 mg/kg i.v.) also suppressed the response. The intestinal response induced by acetylcholine was inhibited markedly by atropine and slightly by loperamide (0.1 mg/kg i.v.) but not by morphine. Contractions of the isolated ileum induced by coaxial stimulation, BaCl2, nicotine and serotonin were suppressed by loperamide (10(-9) approximately 2 X 10(-7) g/ml). Morphine, methadone and codeine showed the same effect as loperamide but the activity was weaker than that of loperamide. Contractions of isolated ileum induced by acetylcholine, histamine and bradykinin, and Ca-contraction in the depolarized taenia coli were inhibited by relatively high concentrations of loperamide (2 X 10(-7) g/ml or above). These results suggest that loperamide suppresses the function of cholinergic neurons in the intestines.

Acetylcholine↗

PubMed1992

Influence of loperamide and loperamide oxide on the anal sphincter. A manometric study.

The objective of this study was to investigate the effects of the opioid loperamide and its recently synthesized pharmacologically inactive prodrug loperamide oxide on the anal sphincter. In a double-blind, placebo-controlled crossover study, anorectal manometry was performed in 12 healthy volunteers five hours after oral bolus application of 10 mg of loperamide, loperamide oxide, or placebo. Loperamide significantly increased the threshold volumes for minimal perception and urgency to defecate (P less than 0.05) and raised the volume required to abolish recovery of the rectoanal inhibitory reflex (P less than 0.05). These findings suggest that loperamide has a specific continence-improving action on the anal sphincter. However, anal resting pressure and maximal squeeze pressure were unaffected in our study and do not seem to be responsible for this effect. The effects under loperamide oxide showed a similar tendency but were without statistical significance.

Adult↗

PubMed1992

Dose proportionality study of loperamide following oral administration of loperamide oxide.

The pharmacokinetics of loperamide, after oral administration of increasing doses (1 to 16 mg) of loperamide oxide, has been investigated in 10 healthy male volunteers, using a randomised cross-over design. Comparison of the maximum plasma loperamide concentration and AUC demonstrated that the bioavailability of loperamide was proportional to the dose of loperamide oxide administered.

Administration, Oral↗

PubMed1990

Effect of increasing oral doses of loperamide on gallbladder motility in man.

1. Loperamide, a peripherally acting opiate receptor agonist with antidiarrhoeal action, inhibits ileal and colonic motor function. To determine the effect of loperamide on gallbladder motility, we have pretreated five healthy volunteers with 2 mg oral loperamide 24 h, 20, 12 and 2.5 h before; six healthy volunteers with 16 mg oral loperamide 2.5 h before; and eight healthy volunteers with 16 mg oral loperamide 12 and 2.5 h before intravenous infusion of a 'physiological dose' of 12.5 pmol kg-1 cholecystokinin (CCK) for 1 h to stimulate gallbladder contraction. All subjects served as their own controls. Gallbladder volume was measured by ultrasonography and plasma CCK by radioimmunoassay until 90 min after start of the CCK infusion. 2. Infusion of CCK resulted in plasma CCK concentrations similar to those after intraduodenal fat. Integrated gallbladder contraction after 4 X 2 mg loperamide (4600 +/- 891% min) was similar to that without pretreatment (5270 +/- 1037% min; NS). Integrated gallbladder contraction after 1 X 16 mg loperamide diminished from 5458 +/- 412% min without to 2632 +/- 816% min with loperamide (P less than 0.05), and was completely abolished to -596 +/- 762% min (P less than 0.0005 vs without loperamide) after 2 X 16 mg loperamide. 3. It is concluded that loperamide inhibits gallbladder contraction in response to a physiological dose of cholecystokinin in a dose-dependent manner.

Adult↗

PubMed1992

Effects of loperamide on the human hypothalamo-pituitary-adrenal axis in vivo and in vitro.

Loperamide, an opiate agonist of high specificity for mu-receptors, was recently reported to suppress ACTH and cortisol levels in normal subjects, but not in patients with proven ACTH-dependent Cushing's disease. However, there is little information on the site of action of loperamide in the hypothalamo-pituitary-adrenal axis of man. We investigated the effect of loperamide on pituitary hormone secretion in vivo and in vitro. In seven normal subjects, basal ACTH plasma levels were significantly suppressed 3 h after loperamide administration (16 mg, orally) from 5 +/- 1 to 2 +/- 0 pmol/L (P less than 0.0001). After the combined pituitary stimulation test (100 micrograms human CRH, 100 micrograms GnRH, 100 micrograms GH-releasing hormone, and 200 micrograms TRH), the ACTH peak (maximum increase at 30 min) was significantly blunted by loperamide from 9 +/- 1 to 4 +/- 1 pmol/L (P less than 0.001) and the area under the curve of ACTH from 0-120 min was reduced from 35 +/- 5 to 23 +/- 4 pmol/L.2 h (P less than 0.05). In the insulin-hypoglycemia test (0.15 IU/kg BW), neither the ACTH peak nor the area under the curve of ACTH was affected by loperamide. In six patients with Cushing's disease and one patient with secondary adrenal insufficiency due to hypothalamic failure, neither basal ACTH and cortisol levels nor CRH-stimulated levels were influenced by loperamide. In four cultured human corticotropic adenomas, loperamide was not able to reduce basal and CRH-induced ACTH secretion. In summary, loperamide is able to reduce basal and CRH-induced ACTH and cortisol levels in normal subjects, but not in patients with Cushing's disease or secondary adrenal failure of hypothalamic origin. Loperamide has no significant effect on insulin-hypoglycemia-induced ACTH and cortisol levels and, therefore, no effect on stress-induced elevation of cortisol levels. Loperamide might act at a suprapituitary site in man in vivo, but, nevertheless, a pituitary site cannot be excluded.

Adenoma↗

PubMed1991

Effect of loperamide on jejunal electrolyte and water transport, prostaglandin E2-induced secretion and intestinal transit time in man.

Jejunal perfusion was performed in 12 healthy volunteers to evaluate the dose dependent effects of loperamide on intestinal absorption, stimulated secretion and transit. In 6 volunteers intestinal perfusion of the jejunal segment with isotonic NaCl solution was followed by addition of loperamide in increasing doses (2-8 mg.l-1). The volunteers were pretreated with 1 mg.l-1 prostaglandin E2 (PgE2) in the perfusate before addition of 4 mg.l-1 loperamide. Phenolsulphonphtalein (PSP) boluses (2 ml) were given to measure mean transit time (MTT). Loperamide 2 mg.l-1 converted the minor secretion after perfusion with the standard solution (water -145 ml.min-1, Na -0.09 and Cl -0.04 mmol.min-1) to absorption (water 0.93 ml.min-1, Na 0.23, Cl 0.25 mmol.min-1) within 15 min. Higher doses of loperamide did not increase absorption. The addition of PgE2 induced net secretion of water (-4.48 ml.min-1) and electrolytes (Na -0.57, Cl -0.51 mmol.min-1). Loperamide 4 mg.l-1 significantly diminished the PgE2-induced net secretion by approximately 50%. Loperamide dose dependently increased the MTT from 6 (2 mg.l-1) to 13.3 min (8 mg.l-1). MTT was still delayed 60 min after a wash out period (10.5 min). It is concluded that loperamide had a dual effect or intestinal activities stimulating absorption and prolonging intestinal transit time with rising doses.

Adolescent↗

PubMed1976

Loperamide binding to opiate receptor sites of brain and myenteric plexus.

Loperamide, a new antidiarrheal agent, was tested to determine whether its biological activity involves binding to opiate receptor sites. Loperamide and morphine competitively inhibited 3H-naloxone binding to homogenates a guinea-pig brain and myenteric plexus. The Kp values obtain in the presence of Na+ were: morphine, 9.60-10(-9) M (brain), 1.66-10(-7) M (myenteric plexus); loperamide, 7.20-10(-9) M (brain), 1.33-10(-7) M (myenteric plexus); naloxone, 4.78-10(-10) M (brain), 1.27-10(-9) M (myenteric plexus. In the absence of Na+, binding a loperamide and morphine to brain homogenate was enhanced while the binding of naloxone was reduced. Morphine (IC50 = 7.5-10(-8) M) and loperamide (IC50 = 6.9-10(-9) M) inhibited the electrically induced contractions of longitudinal muscle from guinea-pig ileum, and naloxone competitively antagonized these effects. The Kd value calculated for the interaction of naloxone with binding sites associated with the contracting muscle was between 0.98-10(-9) M and 1.85-10(-9) M. In the mouse hot plate test, subcutaneous administration of morphine (minimal effective dose = 6.6 mugmol/kg) and loperamide (minimal effective dose = 78 mugmol/kg) delayed the response to heat stimuli and this effect was completely blocked by prior administration of naloxone. In the anesthetixed dog, intravenous administration of morphine (100 mug/kg) and loperamide (100 mug/kg) enhanced the contractile activity of circular muscle in proximal and distal duodenum, distal ileum and proximal colon but duodenal longitudinal muscle was relaxed; these effects were completely reversed by subsequent administration of naloxone. It is concluded that loperamide binds to opiate receptor sites and possesses opiate agonist activity both in vivo and in vitro.

Analgesics, Opioid↗

PubMed1990

Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea.

An open-label, parallel comparison of loperamide hydrochloride (Imodium A-D) and bismuth subsalicylate (Pepto-Bismol) was conducted using nonprescription dosages in adult students with acute diarrhea (three or more unformed stools in the preceding 24 hours plus at least one additional symptom of enteric infection). For the two-day study period, the daily dosage was limited to 8 mg (40 ml) for loperamide-treated subjects and to 4.9 g for bismuth subsalicylate-treated subjects. At these dosages, loperamide significantly reduced the average number of unformed bowel movements relative to bismuth subsalicylate. Following the initial dose of treatment, control of diarrhea was maintained significantly longer with loperamide than with bismuth subsalicylate. Time to last unformed stool was significantly shorter with loperamide than with bismuth subsalicylate. In providing overall subjective relief, subjects rated loperamide significantly better than bismuth subsalicylate at the end of the 24 hours. Both treatments were well tolerated, and none of the minor adverse effects reported resulted in discontinuation of therapy. It was concluded that loperamide is effective at a daily dosage limit of 8 mg (40 ml) for the treatment of acute nonspecific diarrhea and provides faster, more effective relief than bismuth subsalicylate.

Acute Disease↗

PubMed1978

[Pharmacological studies of loperamide, an anti-diarrheal agent. II. Effects on peristalsis of the small intestine and colon in guinea pigs (author's transl)].

Effects of loperamide on peristalsis in the guinea pig intestines were investigated in comparison with those of morphine and atropine. The following results were obtained. The ejection of intraluminal fluid produced by the peristaltic contraction of the isolated ileum was suppressed by loperamide at a concentration of 10(-8) or 2 X 10(-8) g/ml. Peristalsis in the intestinal loop of anesthetized guinea pigs was inhibited by i.v. administration of loperamide at a dose of 0.03 mg/kg. Morphine (0.03 mg/kg i.v.) and atropine (0.05 mg/kg i.v.) also inhibited the peristaltic contraction. The effect of loperamide continued longer than that of morphine. Peristalsis in the colonic loop of anesthetized guinea pigs was inhibited by i.v. administration of loperamide at a dose of 0.01 or 0.03 mg/kg. Morphine (0.1 mg/kg i.v.) and atropine (0.03 mg/kg i.v.) also inhibited the peristaltic contraction of the colonic loop. Loperamide (0.01 or 0.03 mg/kg i.v.) and morphine (0.1 mg/kg i.v.) caused a slight and temporary increase of resting level of intraluminal pressure with inhibition of peristalsis in the colonic loop. These results suggest that loperamide suppresses the peristaltic contraction caused by distension of the intestinal lumen.

Animals↗

PubMed1991

Treatment of travelers' diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin alone. A placebo-controlled, randomized trial.

OBJECTIVE: To compare the safety and efficacy of loperamide used in combination with ciprofloxacin or ciprofloxacin alone for the treatment of travelers' diarrhea. DESIGN: Double-blind, placebo-controlled, randomized clinical trial. SETTING: United States Army hospital in Egypt. PARTICIPANTS: United States military personnel with travelers' diarrhea (n = 104) during a military exercise in November 1989. Persons who were noncompliant, had bloody diarrhea, or had received antidiarrheal medications before entry into the study were excluded. INTERVENTIONS: All participants with travelers' diarrhea were treated with ciprofloxacin, 500 mg twice daily for 3 days. Fifty of these patients were randomly assigned to receive loperamide, a 4-mg first dose and 2 mg for every loose stool (as much as 16 mg/d), and 54 were randomly assigned to receive placebo. MEASUREMENTS: Enterotoxigenic Escherichia coli was isolated from 57% of patients; Shigella and Salmonella, seen in 4% and 2% of patients, respectively, were not common. MAIN RESULTS: After 24 hours, the symptoms of 82% of patients in the ciprofloxacin and loperamide group compared with 67% in the ciprofloxacin and placebo group had improved or fully recovered (odds ratio, 2.3; 95% CI, 0.8 to 6.3; P = 0.08). After 48 hours, the symptoms of 90% of both groups had improved or fully recovered. The mean number of stools for those receiving loperamide was not much lower than those who did not receive loperamide after 24 hours (1.9 +/- 0.2 [SE] compared with 2.6 +/- 0.2) or 48 hours (3.1 +/- 0.3 compared with 4.0 +/- 0.3) of treatment (P = 0.19). CONCLUSIONS: In a region where enterotoxigenic E. coli was the predominant cause of travelers' diarrhea, loperamide combined with ciprofloxacin was not better than treatment with ciprofloxacin alone. Loperamide appeared to have some benefit in the first 24 hours of treatment in patients infected with enterotoxigenic E. coli. Both regimens were safe.

Ciprofloxacin↗

PubMed1976

Loperamide in chronic diarrhea and after ileostomy: a placebo-controlled double-blind cross-over study.

Fifteen patients (20 to 66 years) with long-standing chronic diarrhea of varying etiology were selected for an open trial of loperamide 2 mg capsules. The optimal daily dose for substantial reduction of the diarrhea ranged from two to seven capsules. Eleven patients showed a significant improvement in stool consistency and stool frequency, and a decrease of abdominal cramps. Loperamide appeared to be ineffective in two patients with cholerrheic diarrhea, and in one patient with laxative-induced diarrhea, and in one patient with diarrhea of unknown etiology. The eleven successfully treated patients then entered a double-blind placebo-controlled trial for ten days or until relapse, the daily dose being identical to the optimal one previously determined in the open phase. The investigator was able to guess the code correctly in ten out of eleven cases. Twenty ileostomy patients (ages 25 to 73 years) volunteered for the evaluation of the inhibitory activity on small intestinal peristalsis by loperamide in a double-blind placebo-controlled cross-over study. Mean daily ileostomy output decreased by 22% in the loperamide period, as compared with the drug-free study phase (P less than 0.001). Of the 20 patients, 16 were able to guess their code correctly, whereas four were uncertain, although their fecal weights were lower with loperamide. Many patients noticed an increased urinary production and experienced an improvement in their ileostomy care during loperamide treatment. Because of its effectiveness, its low side-effect liability and its lack of toxicity, loperamide is considered a promising drug in the symptomatic treatment of chronic diarrhea, and as a reliable agent in the treatment of ileostomy patients.

Adult↗

PubMed1979

Human pharmacokinetics and comparative bioavailability of loperamide hydrochloride.

A pharmacokinetic study of the antidiarrheal agent loperamide hydrochloride (Imodium) was conducted in six male subjects. The study utilized a random crossover design and employed a 2-mg capsule and a 0.2-mg/ml syrup formulation. Each treatment consisted of a single oral dose of 8 mg loperamide HCl followed by a two-week interval before the next treatment. Serum and urine samples obtained at various times after drug administration were assayed for loperamide using a radioimmunoassay specific for the drug. The mean biologic half-life, calculated from the elimination phase of the log serum concentration-versus-time data, was 10.8 +/- 0.6 hours for the overall study, 10.2 +/- 0.6 hours for the syrup formulation, and 11.2 +/- 0.8 hours for the capsules. The loperamide from the syrup was absorbed more rapidly than from the capsule formulation, with the peak serum levels observed at a mean time of 2.4 +/- 0.7 hours for the syrup and 5.2 +/- 0.3 hours for the capsule formulation. The relative areas under the serum loperamide concentration-versus-time curves suggested that the two formulations have comparable physiologic availability. The maximum observed serum concentrations were also similar, indicating the safety of the syrup formulation. Excretion of approximately 1 per cent of the dose in the urine as unchanged loperamide after seven days was observed independent of the particular dosage form that was administered.

Adult↗

PubMed1990

Naloxone-insensitive transport effects of loperamide in guinea-pig gallbladder epithelium.

The effects of the antidiarrheal drug, loperamide, on HCO3 and Na transport across guinea-pig gallbladder epithelium were investigated using Ussing-chamber methods. Under basal conditions, mucosal loperamide (10(-4) mol/l) moderately lowered both the absorptive (JHCO3ms) and the secretory HCO3 flux (JHCO3sm) (pH-stat method), most likely by changing paracellular HCO3 flow. Exposure to serosal prostaglandin E1 (10(-6) mol/l) abolished Na absorption and turned HCO3 secretion electrogenic. The associated short-circuit current (Isc) was inhibited by loperamide in a concentration-dependent manner; mucosal addition (threshold at 3 x 10(-6) mol/l) of the drug was more effective. Inhibition of Isc was related to a decrease in JHCO3sm, but exceeded the drop in JHCO3net. The effects on JHCO3sm and Isc were mimicked by [Met5]enkephalin. Naloxone (10(-6) mol/l) was unable to influence the effects of loperamide and [Met5]enkephalin on Isc. There were no pro-absorptive effects of loperamide on unidirectional Na fluxes. We conclude that antisecretory properties of loperamide are solely due to inhibition of electrogenic HCO3 secretion, an effect unrelated to opiate receptor binding.

Alprostadil↗

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↗

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↗