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PubMed1995

Unexpected prosecretory action component of loperamide at mu-opioid receptors in the guinea-pig colonic mucosa in vitro.

1. In a voltage clamp setting (Ussing chamber), the antidiarrhoeal drug, loperamide (Lop) slightly augmented prostaglandin E1 (PGE1) plus theophylline-stimulated net chloride secretion above control values at low concentrations (10(-10) and 10(-9) M) but inhibited it at higher concentrations (10(-6) and 10(-5) M). The apparently weak prosecretory action component of Lop was turned into a clear cut antisecretory effect by pretreatment with 2 x 10(-7) M naloxonazine plus 10(-7) M CTOP-NH2 (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2), two selective mu opioid receptor antagonists. This indicates a prosecretory effect of loperamide at mu opioid receptors. The antisecretory effect of low Lop concentrations, uncovered by mu opioid receptor blockade, was prevented by additional blockade of kappa opioid receptors by 5 x 10(-9) M nor-binaltorphimine (nor-BNI). 2. The nonselective opioid antagonist, naloxone, at 10(-6) M did not significantly reduce either PGE1 plus theophylline-stimulated net chloride secretion in Lop-free controls or the antisecretory action of Lop. By contrast, the partial agonist ethylketocyclazocine (EKC), which activates kappa but blocks mu opioid receptors, concentration-dependently inhibited PGE1 plus theophylline-stimulated net chloride secretion without any consistent prosecretory action component. Nor-BNI at 5 x 10(-8) M significantly blocked the antisecretory action of EKC. 3. It is concluded that, in the guinea-pig colonic mucosa under the present conditions, mu opioid receptors mediate enhancement and kappa opioid receptors inhibition of PGE1-stimulated net chloride secretion by low Lop concentrations. The two opposite actions are largely masked by superimposition. An opioid receptor-independent mechanism of action contributes to the antisecretory effect of Lop at high concentrations.

Alprostadil↗
PubMed1986

Loperamide associated necrotising enterocolitis.

Two cases of necrotising enterocolitis (NEC) occurring in infants beyond the neonatal period were reported. They did not have any predisposing factors to NEC but both had paralytic ileus after loperamide therapy for their mild diarrhoea prior to the onset of NEC. The possible role of loperamide in the pathogenesis of NEC was discussed.

Enterocolitis, Pseudomembranous↗
PubMed2005

Hydrolysis of capecitabine to 5'-deoxy-5-fluorocytidine by human carboxylesterases and inhibition by loperamide.

Capecitabine is an oral prodrug of 5-fluorouracil that is indicated for the treatment of breast and colorectal cancers. A three-step in vivo-targeted activation process requiring carboxylesterases, cytidine deaminase, and thymidine phosphorylase converts capecitabine to 5-fluorouracil. Carboxylesterases hydrolyze capecitabine's carbamate side chain to form 5'-deoxy-5-fluorocytidine (5'-DFCR). This study examines the steady-state kinetics of recombinant human carboxylesterase isozymes carboxylesterase (CES) 1A1, CES2, and CES3 for hydrolysis of capecitabine with a liquid chromatography/mass spectroscopy assay. Additionally, a spectrophotometric screening assay was utilized to identify drugs that may inhibit carboxylesterase activation of capecitabine. CES1A1 and CES2 hydrolyze capecitabine to a similar extent, with catalytic efficiencies of 14.7 and 12.9 min(-1) mM(-1), respectively. Little catalytic activity is detected for CES3 with capecitabine. Northern blot analysis indicates that relative expression in intestinal tissue is CES2 > CES1A1 > CES3. Hence, intestinal activation of capecitabine may contribute to its efficacy in colon cancer and toxic diarrhea associated with the agent. Loperamide is a strong inhibitor of CES2, with a K(i) of 1.5 muM, but it only weakly inhibits CES1A1 (IC(50) = 0.44 mM). Inhibition of CES2 in the gastrointestinal tract by loperamide may reduce local formation of 5'-DFCR. Both CES1A1 and CES2 are responsible for the activation of capecitabine, whereas CES3 plays little role in 5'-DFCR formation.

Antimetabolites, Antineoplastic↗
PubMed1983

Loperamide in severe protracted diarrhoea.

Six infants with severe life-threatening protracted diarrhoea were treated with loperamide. Steady-state perfusion studies of the jejunum showed that in 2 of them the small intestine was in a net secretory state with respect to water, and in the others this was inferred from the fact that the diarrhoea persisted despite nothing by mouth. Loperamide resulted in a prompt and impressive improvement in the condition of each infant. We conclude that this drug has an important role in the management of protracted diarrhoeal states in some infants who are unresponsive to current treatments, and that its effect is related to its antisecretory action.

Child, Preschool↗
PubMed1988

Effect of codeine and loperamide on upper intestinal transit and absorption in normal subjects and patients with postvagotomy diarrhoea.

Patients with chronic severe diarrhoea after truncal vagotomy and pyloroplasty are often difficult to treat using conventional antidiarrhoeal drugs and remain severely disabled. We examined the effect of two drugs, codeine phosphate and loperamide, on upper intestinal transit and carbohydrate absorption, measured non-invasively by serial exhaled breath hydrogen monitoring, in patients with postvagotomy diarrhoea who had previously failed to gain relief from drug therapy. Orocaecal transit was consistently faster in these patients than a group of controls and was associated with malabsorption of glucose. Codeine phosphate 60 mg significantly delayed transit in patients and controls and was associated with a reduction in glucose malabsorption and improvement in symptoms. Loperamide also delayed transit and improved symptoms, but the doses required for this effect (12-24 mg) were higher than usually considered necessary in secretory diarrhoea. These studies indicate that rapid intestinal nutrient transit and associated malabsorption is a factor in the development of diarrhoea postvagotomy and that symptomatic relief can be achieved in most patients by more rational use of existing drugs.

Adult↗
PubMed1990

Small intestinal amyogenesia and dysmyogenesia induced by morphine and loperamide.

We studied the effects of morphine and loperamide on small bowel myoelectric and contractile activity in 12 conscious dogs. After initially producing premature migrating myoelectric complexes, both substances destabilized and obliterated electrical control activity (ECA). The obliteration of ECA occurred mainly in the proximal half of the small intestine. During ECA obliteration, the base line was almost flat at the usual amplification. At higher amplification, the base line exhibited irregular low level fluctuations that could not be related to electrical response activity (ERA) bursts or contractions. The mean time lag for obliteration of ECA in the proximal small intestine decreased at higher doses of morphine infusion. During the destabilization and obliteration of ECA, contractions and ERA bursts occurred in unusual patterns. The ERA bursts and contractions were generally discoordinated. However, in the proximal small intestine some contractions migrated rapidly and uninterrupted at 32 +/- 7 cm/s over long distances (124 +/- 24 cm). ECA destabilization and obliteration were reversed in approximately 15-30 min after the ingestion of a meal or intravenous administration of atropine, hexamethonium, or naloxone. We conclude that during the absence or destabilization of ECA, the ERA bursts and contractions occur in an uncontrolled manner. These two states were called "amyogenesia" and "dysmyogenesia," respectively. The unusual patterns of contractions during small intestinal amyogenesia and dysmyogenesia may be one of the factors in delayed intestinal transit produced by morphine and loperamide.

Animals↗
PubMed1993

Influence of senna, fibre, and fibre + senna on colonic transit in loperamide-induced constipation.

Retarded colonic transit and disturbed defecation are the most prominent pathophysiological mechanisms in constipation. Both may be influenced by bulking agents and by laxatives such as senna. Direct measurements of the influence of such substances on colonic transit are rare mainly because of technical problems. We measured gastric emptying, small and large intestinal transit in 24 healthy volunteers by a newly developed method employing a metal detector. Twelve persons taking a normal diet received loperamide in a dose sufficient to double the individual transit time. All subjects measured gastrointestinal transit time under normal conditions and with Sennatin containing purified sennosides 20 mg, Agiocur (30 g) as a fibre product containing 20 g Plantago ovata seeds/husks, or Agiolax (10 g) as a combination of 5.4 g P. ovata seeds/husks + 1.2 g senna pod with a sennoside content of 30 mg. Colonic transit was reduced by Sennatin and by Agiolax from 39 +/- 4 h to 17 +/- 3 h (p < 0.005). Agiocur did not influence colonic transit (39 +/- 3 h). Loperamide prolonged colonic transit from 27 +/- 0.7 to 72 +/- 12 h. This effect was abolished by Sennatin (30 +/- 5 h) and Agiolax (27 +/- 1 h) (p < 0.005), but not by Agiocur (64 +/- 13 h). The same effects were seen when right and left colonic transit were analyzed separately. Neither gastric emptying nor small intestinal transit were affected by either substance. All of the three study drugs increased stool weight significantly (p < 0.05). When stool frequency and consistency were compared, the effects were less clear.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Loperamide inhibits the enhanced intestinal glucose absorption of cystic fibrosis in vitro.

Enhanced Na(+)-linked nutrient absorption has been demonstrated in the cystic fibrosis bowel and may contribute to the dehydration of the luminal contents. The ability of loperamide to inhibit glucose transport was therefore assessed in jejunal biopsy specimens from children with cystic fibrosis by measuring the increased short-circuit current associated with active glucose absorption using a mini-Ussing chamber technique. The presence of loperamide in the luminal solution reduced the rise in short-circuit current induced by glucose over the range of concentrations tested (2.5 to 40 mmol.L-1). This finding suggests that the enhanced Na+ absorption, which is a feature of cystic fibrosis, is amenable to treatment and can be restored to normal levels. This result may have therapeutic implications for gastrointestinal function and may be applicable to other tissues where similar therapeutic approaches to reduce Na+ and thus water absorption are being pursued.

Adolescent↗
PubMed1996

Effects of atropine and loperamide on the agitating force and GI transit time in dogs in drug absorption studies.

There are difficulties in drug absorption studies using dogs because of different gastrointestinal (GI) conditions between these animals and humans, including shorter intestinal transit time and strong agitation force in the GI tract. We attempted to modify the agitation force and GI transit time using atropine and loperamide. The agitation force was examined based on in vitro/in vivo correlation for two controlled release (CR) formulations of acetaminophen. Atropine treatment considerably reduced the agitating force whereas that of loperamide did not.

Acetaminophen↗
PubMedDate not supplied

Influence of the preparation methods on the drug release behaviour of loperamide-loaded nanoparticles.

Polylactide (PLA) or poly(lactide-coglycolide) (PLGA) nanoparticles containing loperamide (LPM) were prepared by an incorporation or adsorption method with the objective of developing nanoparticles with a rapid drug release. The use of polymers such as PLA with lower molecular weights and the addition of sorbitan fatty acid esters (SFAE) for the incorporation led to an almost complete entrapment of LPM in nanoparticles. Preparation of PLA nanoparticles by adsorption was performed by addition of LPM methanol solution before, during and after evaporation of dichloromethane from the system. The adsorption of LPM onto the nanoparticles with low molecular weight PLA (m.w. 2000) showed an isotherm with a good correlation to the Langmuir equation. A high amount of LPM can be entrapped or adsorbed in nanoparticles only with low molecular weights of PLA or PLGA. In the incorporation method, the addition of SFAEs increased drug entrapment. However, in the adsorption method they had no effect on nanoparticle drug adsorption. The drug-release profiles from both nanoparticles, prepared by the adsorption and incorporation methods, were biphasic with an initial rapid release and a second slower release phase, although their initial extents of release were different. The release rates were almost the same for both the adsorption and incorporation method without SFAEs. The addition of SFAEs to the adsorption system increased the extent of drug release from nanoparticles. In conclusion, a rapid loperamide release from nanoparticles can be achieved by use of PLA or PLGA with low molecular weights and in the adsorption method by the addition of SFAEs.

Adsorption↗
PubMed1975

Loperamide antagonism of castor oil-induced diarrhea in rats: a quantitative study.

The time-course of castor oil-induced diarrhea in fasted rats was quantified by weighing stools every 15 minutes for 8 hours after the challenge and then after 24 hours. Diarrhea began within 1 hour as a series of rapidly occurring evacuations over 20 to 40 minutes. The mean weight of these stools was 5.7 g; later irregular evacuations increased the weight to 9.4 g at 8 hours. The area of individual time-weight diagrams had a median value of 432 units. Pretreatment with 0.16 mg/kg of loperamide, a new antidiarrheal drug, significantly decreased the area of similarly obtained diagrams; 0.31 mg/kg caused a 50% reduction. This antagonism by loperamide of castor oil-induced diarrhea may involve reduction in the severity of inflammatory changes in the intestinal wall.

Animals↗
PubMed2003

[Ileus after the use of loperamide in a child with acute diarrhea].

A 2-year-old girl was diagnosed as having acute gastroenteritis with severe diarrhoea, for which she was prescribed a loperamide solution. Following this she developed paralytic ileus. She was then treated conservatively and was administered fluid and electrolytes parenterally. She started to recover after 48 hours. In young children with acute diarrhoea there usually is no place for medicinal treatment, and certainly not with antimotility drugs such as loperamide.

Antidiarrheals↗
PubMed1992

Influence of cisapride, metoclopramide and loperamide on gastric emptying of normal volunteers as measured by means of the area under the curve of the cumulative fraction absorbed-time profiles of paracetamol.

The present study with paracetamol was designed to compare the effects of 40 mg cisapride, 20 mg metoclopramide and 4 mg loperamide given orally on gastric emptying under fasting conditions in normal volunteers. The well known bioavailability parameters of absorption and the area under the curve of the fractional absorbed time profiles up to 30 min were used as an index of gastric emptying. As reflected by the AUC of the fractional absorbed time profiles, it was concluded that pretreatment with cisapride speeded up the gastric emptying under fasting conditions. Tmax was the only normal bioavailability parameter that showed any significant change after cisapride treatment. Pretreatment with therapeutic doses of loperamide and metoclopramide did not significantly modify stomach emptying.

Acetaminophen↗
PubMed1991

[The efficacy of smectite in acute infantile diarrhea, compared to a placebo and loperamide].

Fifty-six infants (aged 2 months to two years) with moderate to severe diarrhea were entered in a comparative therapeutic trial of smectite versus placebo or loperamide. Results showed that diarrhea resolved faster under smectite than under placebo and at least as fast under smectite as under loperamide. Tolerance of smectite is excellent as a result of the lack of any effect on intestinal motility.

Dehydration↗
PubMed1991

Effect of loperamide and bisacodyl on intestinal transit time, fecal weight and short chain fatty acid excretion in the rat.

We analyzed the effect of drugs that modify the colonic motility on rat intestinal transit time (ITT) (measured with radiopaque markers), fecal weight (FW) and fecal concentration of short chain fatty acids (FSCFA) (assayed by gas liquid chromatography), over a four-week period. Bisacodyl was used to accelerate and Loperamide to retard the intestinal transit in rats maintained on a conventional diet. The first and 3rd week were drug-free control periods. The mean values of these periods were: ITT = 28.9h +/- 1.9 FW: 9.2 +/- 1.2 g/24 h and FSCFA = 60.6 +/- 17.9 mmol/g. After loperamide administration, we observed an increase in the mean ITT as compared to the control period (40.4 +/- 8.0h) and decrease in FW (4.8 +/- 3.6 g/24h) and in FSCFA = 32.2 +/- 5.6 mmol/g). After bisacodyl administration, we found a shorter ITT in relation to controls (24.8 +/- 2.5h), and increases in FW (27.5 +/- 3.6g/24h) and in FSCFA (108.2 +/- 39.9 mmol/g). There was a negative correlation between ITT and FW (R = 0.67 p less than 0.01) and a positive correlation between total SCFA concentration and FW (R = 0.71 p less than 0.01). The concentration of acetic, propionic and butyric acids increased with progressive increments in fecal weight, whereas concentrations of isovaleric and caproic acids decreased. The results of this study show that the FW and the FSCFA may be influenced by modifications in the intestinal transit time.

Animals↗
PubMed1990

[Small intestinal perforation as complication of loperamide treatment of Salmonella typhimurium infection].

A patient is described with an acute gastroenteritis, after ingestion of French fries and a raw egg and the simultaneous use of loperamide, due to an infection with Salmonella typhimurium phage type 10. As a complication multiple perforations of the ileum developed which needed surgical resection. This is the first report of this complication in the literature. The simultaneous use of loperamide is suspected to be the promoting factor in the development of this complication.

Adolescent↗
PubMed1986

A multicenter double-blind controlled trial comparing lidamidine HCl and loperamide in the symptomatic treatment of acute diarrhoea.

The efficacy of 1-(2,6-dimethylphenyl)-3-methyl-amidinourea hydrochloride (lidamidine HCl, WHR-1142 A) an aryl-substituted amidinourea recently synthesized, was compared with that of loperamide in 32 patients with acute diarrhoea. The results of the study show that lidamidine HCl and loperamide had comparable effects in the pharmacological treatment of acute non-specific diarrhoea. Lidamidine HCl was also shown to be well tolerated; side-effects were generally minor and self-limiting.

Acute Disease↗