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At least 19 recordsLinked to original sources
PubMed1996

Increased systemic availability of loperamide after oral administration of loperamide and loperamide oxide with cotrimoxazole.

1. The effects of concurrent administration of cotrimoxazole on the plasma concentration-time profiles of loperamide and its oxide were investigated in two separate studies in healthy male volunteers. Cotrimoxazole (960 mg, twice daily) was administered for 24 h before and 48 h after an oral dose of loperamide oxide (4 mg) or loperamide (4 mg). 2. Coadministration of cotrimoxazole with loperamide oxide did not alter the tmax, Cmax and AUC of loperamide oxide, whereas the Cmax (0.32 +/- 0.14 ng ml-1 without cotrimoxazole; 0.45 +/- 0.18 ng ml-1 with cotrimoxazole; P < 0.05) and AUC (8.13 +/- 1.91 ng ml-1 h without cotrimoxazole; 12.50 +/- 4.60 ng ml-1 h with cotrimoxazole; P < 0.005) of loperamide were significantly increased. 3. Coadministration of cotrimoxazole with loperamide significantly increased the Cmax (0.74 +/- 0.22 ng ml-1 without cotrimoxazole; 1.49 +/- 0.81 ng ml-1 with cotrimoxazole; P < 0.01) and AUC (13.40 +/- 3.80 ng ml-1 h without cotrimoxazole; 25.30 +/- 11.10 ng ml-1 h with cotrimoxazole; P < 0.005) of loperamide, whilst its tmax and t1/2,z were not significantly altered. 4. The increase in loperamide AUC, following coadministration of either loperamide oxide or loperamide with cotrimoxazole, may be due to reduced first pass metabolism of loperamide.

Administration, Oral↗
PubMed1995

Gastrointestinal distribution of the prodrug loperamide oxide and its active drug loperamide in the dog.

Loperamide oxide is a prodrug of the effective antidiarrheal loperamide. Administration of this prodrug improves efficacy and tolerability. For better understanding of these effects, the absorption and gastrointestinal distribution of loperamide oxide and of its active drug loperamide were studied. Beagle dogs received a single oral dose of loperamide oxide or loperamide at 0.16 mg/kg. Plasma, gastrointestinal contents and tissues, and some other organs were obtained. Concentrations were determined by specific radioimmunoassays. Loperamide oxide was gradually converted to loperamide in the gastrointestinal tract. After administration of the prodrug, the systemic absorption of the active drug was lower and more delayed than after administration of loperamide itself. As a consequence, more loperamide was available in the contents and the mucosa of the gut, in particular in the lower part of the small intestine and in the large intestine. The higher levels of loperamide in mucosa may cause more pronounced and longer lasting antisecretory effects after administration of loperamide oxide. The results of this study are in line with the hypothesis that loperamide oxide is a site-specific prodrug that acts as a chemically designed controlled-release form of loperamide keeping a higher amount of the active drug for a longer time at the site of action in the gut wall.

Animals↗
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↗
PubMedDate not supplied

Loperamide-simethicone vs loperamide alone, simethicone alone, and placebo in the treatment of acute diarrhea with gas-related abdominal discomfort. A randomized controlled trial.

CONTEXT: Acute diarrhea with gas-related abdominal discomfort is a common, usually self-limited disorder with substantial social and economic impact. OBJECTIVE: To compare the efficacy and safety of a loperamide hydrochloride-simethicone combination product with those of loperamide alone, simethicone alone, and placebo in treating acute diarrhea with gas-related abdominal discomfort. DESIGN: Randomized, placebo-controlled, double-blind trial of 48 hours' duration. SETTING: A primary care, ambulatory practice in Acapulco, Mexico. PATIENTS: A total of 493 outpatient adults aged 18 to 63 years, with acute nonspecific diarrhea with at least moderately severe abdominal discomfort. INTERVENTIONS: Each patient was randomly assigned to receive 2 chewable tablets containing loperamide hydrochloride, 2 mg, and simethicone, 125 mg (n = 124); loperamide hydrochloride, 2 mg (n = 123); simethicone, 125 mg (n = 123); or placebo (n = 123). This was followed by 1 tablet after each unformed stool, up to 4 tablets in any 24-hour period. MAIN OUTCOME MEASURES: Time to last unformed stool and time to complete relief of gas-related abdominal discomfort were the protocol-specified primary outcomes. Secondary outcomes included time to complete relief of diarrhea, number of unformed stools, and patient-assessed variables at the end of the study (overall illness relief, diarrhea relief, and abdominal discomfort relief). RESULTS: Patients who received loperamide-simethicone had significantly (P < .001) shorter time to last unformed stool and faster relief of gas-related abdominal discomfort than patients who received loperamide, simethicone, or placebo alone. Loperamide-simethicone was significantly (P < or = .01) more effective than the other 3 treatments for all end-of-study patient-assessed outcomes and all clinically important secondary outcomes. No significant differences in adverse events were found among treatment groups. CONCLUSIONS: The loperamide-simethicone combination chewable product provides faster and more complete relief of acute nonspecific diarrhea and associated gas-related abdominal discomfort (gas pain, cramps, gas pressure, and bloating) than either of its components or placebo. The combination is well tolerated.

Abdominal Pain↗
PubMed2004

LC-MS determination and bioavailability study of loperamide hydrochloride after oral administration of loperamide capsule in human volunteers.

The purpose of the present study was to develop a standard protocol for loperamide hydrochloride bioequivalence testing. For this purpose, a simple rapid and selective LC-MS method utilizing a single quadrupole mass spectrometer was developed and validated for the determination of loperamide hydrochloride in human plasma, and we followed this with a bioavailability study. Methyl tert-butylether (MTBE) was used to extract loperamide hydrochloride and ketoconazole (internal standard (IS)) from an alkaline plasma sample. LC separation was performed on a Zorbax RX C18 column (5 microm, 2.1 mm x 150 mm) using acetonitrile-water-formic acid (50:50:0.1 (v/v)) as a mobile phase. The retention times of loperamide hydrochloride and IS were 1.2 and 0.8 min, respectively. Quadrupole MS detection was by monitoring at m/z 477 (M + 1) corresponding to loperamide hydrochloride and at m/z 531 (M + 1) for IS. The described assay method showed acceptable precision, accuracy, linearity, stability, and specificity. The bioavailability of loperamide hydrochloride was evaluated in eight healthy male volunteers. The following pharmacokinetic parameters were elucidated after administering a single dose of four 2mg capsules of loperamide: the area under the plasma concentration versus time curve from time 0 to 72 h (AUC72 h) 19.26 +/- 7.79 ng h/ml; peak plasma concentration (Cmax) 1.18 +/- 0.37 ng/ml; time to Cmax (Tmax) 5.38 +/- 0.74 h; and elimination half-life (t1/2) 11.35 +/- 2.06 h. The developed method was successfully used to study the bioavailability of a low dose (8 mg) of loperamide hydrochloride.

Adult↗
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↗
PubMed1993

Comparison of the effects of loperamide and loperamide oxide on absorptive processes in rat small intestine.

Mucosal loperamide inhibited the absorption of glycine by everted sacs of rat small intestine over 10-, 30- or 60-min incubation periods, but loperamide oxide was without effect. In stripped intestinal sheets, loperamide inhibited the rise in short-circuit current associated with Na(+)-linked glucose absorption, but this effect was not observed with loperamide oxide. It is concluded that although there is evidence that loperamide oxide is converted to loperamide in the intestinal lumen, the rate at which free loperamide appears is not sufficient to inhibit absorptive processes.

Animals↗
PubMed1993

Antisecretory activities of orally administered loperamide and loperamide oxide on intestinal secretion in rats.

In-vivo experiments in the rat jejunum have been performed to compare the antisecretory effect of orally administered loperamide with the effect of its pro-drug, loperamide oxide. Both loperamide and loperamide oxide, administered orally, reduced the secretory effect of prostaglandin E2 (32 ng min-1, intra-arterially) in the jejunum and the colon. Differences between the two drugs as to time course and dose response can be seen. Loperamide oxide shows its antisecretory effect in the jejunum, and at a dose of 2 mg kg-1 also shows its effect in the colon 1 h after administration. The effect was maximal after 2 h and decreased after 4 h. A dose-response relationship was demonstrated at 2 h in the jejunum and the colon. In comparison, the effect of loperamide started later, and a good dose-response relationship was not observed in the jejunum or in the colon, higher doses always appearing less effective than lower doses.

Administration, Oral↗
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↗
PubMed1999

Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of traveler's diarrhea.

Eighty United States students in Mexico received either loperamide (an initial dose of 4 mg, followed by 2 mg after passage of each unformed stool, up to 8 mg/d; 40 patients) or loperamide (at the same dosage schedule) plus an oral rehydration therapy (ORT) preparation (500 mL initially, followed by 250 mL after each subsequently passed unformed stool, up to 1,000 mL per 24 hours; 40 patients). The ORT preparation was a modification of the World Health Organization-recommended solution, adjusted to a sodium concentration of 60 mEq/L. All treatments were given for 48 hours. The study demonstrated equivalent clinical responses with regard to diminishment of diarrhea or subjective findings such as abdominal pain/cramps, headache, dry mouth, dizziness, or thirst. Stool number (by form) and specific gravity of urine postenrollment were similar in the groups. Administration of loperamide plus ORT for the management of traveler's diarrhea, in cases in which subjects were encouraged to drink ad libitum, offered no benefit over administration of loperamide alone.

Administration, Oral↗
PubMedDate not supplied

First-line treatment in acute non-dysenteric diarrhoea: clinical comparison of loperamide oxide, loperamide and placebo. UK Janssen Research Group of General Practitioners.

The use of antimicrobial agents for the treatment of acute diarrhoea has become more common with the introduction of quinolone compounds, which are active against most types of bacterial pathogens. Despite the fact that such drugs have been used for empirical therapy or even for prophylaxis, current opinion would restrict their use to specific groups of patients who are likely to show particular benefit from them. Non-specific therapy seems a more appropriate initial treatment for cases of acute, non-dysenteric diarrhoea. Clinical trial data are presented here comparing the effects of loperamide oxide 1 and 2 mg to those of placebo and loperamide 2 mg in this condition. All the drug preparations were significantly superior to placebo, in particular reducing the time to complete relief of symptoms to about 24 hours, as opposed to 45 hours on placebo treatment. Of these preparations, loperamide oxide 1 mg is to be preferred, as it produces fewer constipation-like episodes after treatment. The introduction of loperamide oxide 1 mg represents a useful advance in the non-specific treatment of acute, non-dysenteric diarrhoea.

Acute Disease↗
PubMed2000

Quantitation of loperamide and N-demethyl-loperamide in human plasma using electrospray ionization with selected reaction ion monitoring liquid chromatography-mass spectrometry.

We report here the development and validation of an LC-MS method for quantitation of loperamide (LOP) and its N-demethyl metabolite (DMLOP) in human plasma. O-Acetyl-loperamide (A-LOP) was synthesized by us for use as an internal standard in the assay. After addition of the internal standard, the compounds of interest were extracted with methyl tert.-butylether and separated by HPLC on a C18 reversed-phase column using an acetonitrile-water gradient containing 20 mM ammonium acetate. The three compounds were well separated by HPLC and no interfering peaks were detected at the usual concentrations found in plasma. Analytes were quantitated using positive electrospray ionization in a triple quadrupole mass spectrometer operating in the MS-MS mode. Selected reaction monitoring was used to quantify LOP (m/z 477-266), DMLOP (m/z 463-->252) and A-LOP (m/z 519-->266) on ions formed by loss of the 4-(p-chlorophenyl)-4-hydroxy-piperidyl group upon low energy collision-induced dissociation. Calibration curves, which were linear over the range 1.04 to 41.7 pmol/ml (LOP) and 1.55 to 41.9 pmol/ml (DMLOP), were run contemporaneously with each batch of samples, along with low (4.2 pmol/ml), medium (16.7 pmol/ml) and high (33.4 pmol/ml) quality control samples. The lower limit of quantitation (LLQ) of LOP and DMLOP was about 0.25 pmol/ml in plasma. The extraction efficiency of LOP and DMLOP from human plasma was 72.3+/-1.50% (range: 70.7-73.7%) and 79.4+/-12.8% (64.9-88.8%), respectively. The intra- and inter-assay variability of LOP and DMLOP ranged from 2.1 to 14.5% for the low, medium and high quality control samples. The method has been used successfully to study loperamide pharmacokinetics in adult humans.

Adult↗
PubMed2001

A scintigraphic study to investigate the potential for altered gut distribution of loperamide from a loperamide-simethicone formulation in man.

A loperamide simethicone combination formulation has recently been demonstrated to have significant clinical advantages compared to loperamide alone in the relief of diarrhoea and related symptoms. The product visualisation technique of gamma scintigraphy has been used to investigate the interaction of the formulation with the heterogenous environment of the human gut in a group of 12 healthy volunteers. The results suggest that changes in the intestinal kinetics of loperamide from the combination product, e.g. jejunal coating, could be contributing to the improved efficacy.

Antidiarrheals↗
PubMed1995

Reduction of the prodrug loperamide oxide to its active drug loperamide in the gut of rats, dogs, and humans.

Loperamide oxide (LOPOX) is a prodrug of loperamide (LOP). The reduction of LOPOX to LOP was investigated to provide a pharmacokinetic basis for the pharmacodynamics and improved side effect profile of the prodrug. Reduction of LOPOX was studied in vitro in gut contents, gut flora, intestinal cells, and hepatocytes. In vivo pharmacokinetics and metabolism of LOPOX and LOP were compared in the dog. LOPOX could be efficiently reduced in the gut contents of rats, dogs, and humans, with the most extensive reduction found in cecal contents. Reduction was diminished to 13% of the anaerobic LOPOX reductase activity in the presence of oxygen and to 2.5% of the original activity by heat treatment of the contents. In human ileal effluents, LOPOX reductase activity was similar in oxygen and heat sensitivity. In the rat, the cecum contained on average 89.2% of the total activity in the contents of the upper part of the intestine. In the dog, there was a gradual increase in LOPOX reductase activity from the proximal small intestine toward the cecum. In germ-free rats, the cecum contained < 1% of the activity of the small intestine. Isolated intestinal microflora of rat and dog was able to reduce LOPOX to LOP under anaerobic conditions, indicating that the microflora was primarily involved in the reduction. In its absence (i.e. in germ-free rats), reduction could still be conducted by other unknown components of the gut contents. In isolated intestinal cells, the initial rate of drug uptake was approximately 3-10 times faster for LOP than for LOPOX.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers.

Loperamide (LOP) is a peripherally acting opioid receptor agonist used for the management of chronic diarrhea through the reduction of gut motility. The lack of central opioid effects is partly due to the efflux activity of the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier. The protease inhibitors are substrates for P-gp and have the potential to cause increased LOP levels in the brain. Because protease inhibitors, including tipranavir (TPV), are often associated with diarrhea, they are commonly used in combination with LOP. The level of respiratory depression, the level of pupil constriction, the pharmacokinetics, and the safety of LOP alone compared with those of LOP-ritonavir (RTV), LOP-TPV, and LOP-TPV-RTV were evaluated in a randomized, open-label, parallel-group study with 24 healthy human immunodeficiency virus type 1-negative adults. Respiratory depression was assessed by determination of the ventilatory response to carbon dioxide. Tipranavir-containing regimens (LOP-TPV and LOP-TPV-RTV) caused decreases in the area under the concentration-time curve from time zero to infinity for LOP (51% and 63% decreases, respectively) and its metabolite (72% and 77% decreases, respectively), whereas RTV caused increases in the levels of exposure of LOP (121% increase) and its metabolite (44% increase). In vitro and in vivo data suggest that TPV is a substrate for and an inducer of P-gp activity. The respiratory response to LOP in combination with TPV and/or RTV was not different from that to LOP alone. There was no evidence that LOP had opioid effects in the central nervous system, as measured indirectly by CO2 response curves and pupillary response in the presence of TPV and/or RTV.

Adult↗