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BACKGROUND: Although the antidiarrheal loperamide is a potent opiate, it does not produce opioid central nervous system effects at usual doses in patients. On the basis of in vitro studies demonstrating that loperamide is a substrate for the adenosine triphosphate-dependent efflux membrane transporter P-glycoprotein, we postulated that inhibition of P-glycoprotein with quinidine would increase entry of loperamide into the central nervous system with resultant respiratory depression. METHODS: To test this hypothesis, a 16-mg dose of loperamide was administered to eight healthy male volunteers in the presence of either 600 mg quinidine, a known inhibitor of P-glycoprotein, or placebo. Central nervous system effects were measured by evaluation of the respiratory response to carbon dioxide rebreathing as a measure of opiate-induced respiratory depression. RESULTS: Loperamide produced no respiratory depression when administered alone, but respiratory depression occurred when loperamide (16 mg) was given with quinidine at a dose of 600 mg (P < .001). These changes were not explained by increased plasma loperamide concentrations. CONCLUSION: This study therefore demonstrates first the potential for important drug interactions to occur by a new mechanism, namely, inhibition of P-glycoprotein, and second that the lack of respiratory depression produced by loperamide, which allows it to be safely used therapeutically, can be reversed by a drug causing P-glycoprotein inhibition, resulting in serious toxic and abuse potential.
Loperamide inhibits PGE1-induced electrogenic HCO3 secretion in guinea-pig gallbladder. Underlying changes in epithelial cell membrane properties were investigated using intracellular microelectrode techniques in vitro. In the absence of PGE1, mucosal loperamide (10(-4) mol/l) reversibly depolarized both cell membranes by approximately 6 mV. The apparent ratio of membrane resistances (Ra/Rb) remained unchanged and so did voltage responses to luminal Cl removal and Na reduction. The depolarizing response to elevation of luminal K concentration from 5 to 76 mmol/l was decreased from 13 to 8 mV. In the presence of 1 PGE1, the apical membrane is mainly permeable to Cl and HCO3. Under these conditions, loperamide reduced membrane potentials by approximately 10 mV, Ra/Rb remaining constant at approximately 0.4. Effects on voltage responses to changes in luminal Na or K concentration were unchanged. Responses to luminal Cl removal (transient depolarization) were greatly enhanced (from 22 to 42 mV) as predictable from the fall in K permeability that hinders Cl efflux from cell into lumen. Less marked but significant effects were obtained with 10(-5) mol/l (mucosal side) and serosal loperamide (10(-4) mol/l). We suggest that loperamide inhibits electrogenic HCO3 secretion by reducing apical membrane K permeability. The resulting depolarization diminishes the driving force for conductive anion efflux from cell into lumen. This conclusion is supported by the ability of luminal K elevation to mimick loperamide inhibition of the secretory flux of HCO3 (pH-stat experiments).
1. We set out to ascertain the role of tachykinins, neurokinin A and substance P, in castor oil-induced diarrhoea in rats as disclosed by the inhibitory effect of the non-peptide NK1- and NK2-receptor antagonists. SR 140333 and SR 48968, respectively. 2. SR 48968 (0.02 to 20 micrograms kg-1, s.c. or p.o.), and the opioid receptor agonist loperamide (1-10 mg kg-1, p.o.), dose-dependently prevented castor oil effects: % inhibition vs castor oil, diarrhoea 0 to 100, increase in faecal mass 7 to 90 and water content 16 to 90. SR 140333 (0.02 to 20 micrograms kg-1, s.c.) and the platelet activating factor antagonist SR 27417 (5 to 500 micrograms kg-1, p.o.) did not prevent the increase in faecal water content, but reduced faecal mass (35 to 66%) and diarrhoea (0 to 57%). 3. The R-enantiomers of tachykinin NK1 and NK2 receptor antagonists, SR 140603 and SR 48605 (both at 2 or 20 micrograms kg-1, s.c.) had no effect other than reducing faecal mass at the highest dose tested. 4. SR 48968 (20 micrograms kg-1, p.o.) but not loperamide (10 mg kg-1, p.o.) given 24 h before castor oil, still slightly but significantly reduced by 30% the increase of faecal mass output; both treatments significantly reduced (30 to 70%) the effect of castor oil on faecal water content, although the incidence of diarrhoea was only slightly less than in controls. 5. In castor oil-treated rats, naloxone (2 mg kg-1, s.c.) completely blocked the antidiarrhoeal action of loperamide (10 mg kg-1, p.o.) but not of SR 48968 (20 micrograms kg-1, p.o.): a similar result was obtained on faecal mass and water content. 6. Castor oil strongly increased the occurrence of manometrically recorded propulsive giant contractions (500 to 1000% over control values) of transverse and distal colon, this effect being significantly prevented (80 to 100%) by SR 48968 and loperamide and partially by SR 140333 (35% distal colon, 70% transverse colon). 7. In castor oil free rats, loperamide but not SR 48968 or SR 140333 significantly reduced by 50% the gastrointestinal transit of a charcoal test meal, as well as 24 h faecal mass output. Consistently, loperamide, unlike the tachykinin receptor antagonists, had a dramatic effect on manometric recordings of intestinal motility, reducing all kinds of colonic contractions. 8. Our findings suggest that castor oil diarrhoea in rats entails activation of NK1 and NK2 receptors by endogenous tachykinins, whose antagonists may have a potential as antidiarrhoeal agents free from the constipating action of opioids.
Wood creosote, the principal ingredient in Seirogan, has a long history as a known gastrointestinal microbicidal agent. When administered orally, the intraluminal concentration of wood creosote is not sufficiently high to achieve this microbicidal effect. Through further animal tests, we have shown that antimotility and antisecretory actions are the principal antidiarrheal effects of wood creosote. Wood creosote inhibits intestinal secretion induced by enterotoxins by blocking the Cl(-) channel on the intestinal epithelium. Wood creosote also decreases intestinal motility accelerated by mechanical, chemical, or electrical stimulus by the inhibition of the Ca(2+) influx into the smooth muscle cells. In this overview, the antimotility and antisecretory effects of wood creosote are compared with those of loperamide. Wood creosote was observed to inhibit stimulated colonic motility, but not normal jejunal motility. Loperamide inhibits normal jejunal motility, but not stimulated colonic motility. Both wood creosote and loperamide inhibit intestinal secretion accelerated by acetylcholine. Wood creosote was found to have greater antisecretory effects in the colon than loperamide. Based upon these findings, we conclude that the antidiarrheal effects of wood creosote are due to both antisecretory activity in the intestine and antimotility in the colon, but not due to the microbicidal activity as previously thought. Wood creosote was found to have no effects on normal intestinal activity. These conclusions are supported by the results of a recent clinical study comparing wood creosote and loperamide, which concluded that wood creosote was more efficacious in relieving abdominal pain and comparable to loperamide in relieving diarrhea.
KW-5617 (zaldaride maleate), 1,3-dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin -4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one maleate, is a selective calmodulin inhibitor. We studied the effects of KW-5617 on secretory diarrhea and gastrointestinal propulsion in rats, as compared with those of loperamide, a conventional anti-diarrheal drug. Diarrhea was induced in rats either by 16,16-dimethyl prostaglandin E2 (500 microg/kg, i.p.) or by castor oil (1 ml/100 g body weight, p.o.). In the 16,16-dimethyl prostaglandin E2 model, KW-5617 at the doses of 3 mg/kg (p.o.) and higher ameliorated the diarrhea. Similarly, loperamide improved the diarrhea, the activity of loperamide being equivalent to that of KW-5617. In the castor oil model, KW-5617 significantly delayed the onset of diarrhea at the doses of 3 mg/kg (p.o.) and higher, while loperamide delayed the onset of diarrhea at the doses of 0.3 mg/kg (p.o.) and higher. KW-5617 only at the high doses of 30 and 100 mg/kg (p.o.) reduced gastric emptying, small intestinal propulsion, proximal colonic propulsion and distal colonic propulsion. In contrast, loperamide at its anti-diarrheal doses inhibited gastrointestinal propulsion. Our results show that KW-5617, unlike loperamide, at its anti-diarrheal doses does not exert anti-propulsive effects in rats. KW-5617 may be a useful drug for the treatment of diarrhea in terms of less side effects such as constipation.
BACKGROUND: Chronic functional diarrhea is an embarrassing symptom, causing the impairment of the quality of life. AIM: We looked for the effect of two antidiarrheal drugs, diosmectite and loperamide on the psychosocial adjustment to illness, a predictor for the health-related quality of life, in chronic functional diarrhea. METHODS: Prospective controlled randomized trial including 50 consecutive patients with chronic functional diarrhea. They received either diosmectite 3 g b.i.d (n=25, 11M/14F, age 43+/-12 years) or loperamide 2 mg b.i.d. (n=25, 12M/13F, 47+/-11 years) for 2 weeks. Diarrhea and four other digestive symptoms were evaluated on a 0-16 scale, as well as patient's satisfaction (scale 1-10) and physician's satisfaction (scale 0-4). Psychosocial adjustment to illness was assessed with the PAIS-SR scale. RESULTS: Symptom score for diarrhea was reduced from 10.5+/-5.7 to 2.6+/-1.2 (mean+/-SD), p<0.001 by diosmectite and from 8.5+/-4.2 to 1.2+/-0.6, p<0.0001 by loperamide. Diosmectite had a stronger effect than loperamide on accompanying pain (p<0.05) and bloating (p<0.01), but not on nausea, anorexia and emesis. The overall ratings of the patient's satisfaction (8.7+/-0.9 vs. 8.2+/-1.1, NS) and physician's satisfaction (3.2+/-0.3 vs. 3.1+/-0.4, NS) were similar. Psychological adjustment to illness was not changed for following items: health care orientation and domestic environment. Diosmectite improved more than loperamide the psychological distress (from 12.7+/-3.8 to 7.7+/-2.1 vs. 11.8+/-3.3 to 9.05+/-2.2, p<0.05), vocational environment (from 3.2+/-1.1 to 2.2+/-1.2 vs. 3.3+/-1.2 to 3.4+/-1.5, p<0.05) and sexual relationship scores (from 6.4+/-2.2 to 3.0+/-1.5 vs. 7.2+/-2.2 to 5.5+/-2.1, p<0.05). Both drugs similarly improved the items: family relationship and social environment. CONCLUSIONS: Diosmectite and loperamide are both potent drugs for chronic functional diarrhea. Diosmectite has better effects on associated symptoms and some items of psychosocial adjustment to illness (distress, sexual activity and vocational environment).
Pharmacological studies were performed to investigate the interaction of SC-27166 (2-[3-(5-methyl-1,3,4--oxadiazol-2-yl)-3,3-diphenylpropyl]-2-azabicyclo[2.2.2]octane), a new antidiarrheal agent, with opiate receptor sites in vitro and in vivo. Morphine, loperamide and SC-27166 inhibited the binding of [3H]naloxone to homogenates of guinea-pig brain and myenteric plexus and the inhibition was diminished in the presence of 100 mM Na+. Unlike that of morphine and [3H]naloxone itself, the binding of loperamide and SC-27166 was complex and Scatchard plots indicated the presence of low and high affinity sites for both compounds. Morphine, loperamide and SC-27166 inhibited the contractions of electrically driven longitudinal muscle from guinea-pig ileum and naloxone antagonized these effects. In the anesthetized dog, i.v. administration of morphine and SC-27166 enhanced the contractile activity of circular muscle in proximal and distal duodenum and distal ileum but duodenal longitudinal muscle was relaxed; these effects were completely reversed by subsequent administration of naloxone. In the rat, p.o. administration of loperamide and SC-27166 inhibited intestinal propulsion at doses considerably lower than were necessary to produce activity in the hot plate test; this specificity of action was not seen with morphine. In the rat, p.o. administration of loperamide and SC-27166 inhibited diarrhea at doses considerably lower than were necessary to produce withdrawal symptoms. The authors concluded that both loperamide and SC-27166 are specific antidiarrheal agents that produce both their central and antidiarrheal effects by binding to opiate receptor sites.
The antipropulsive activity of a series of opioids in the charcoal test was compared with their antidiarrheal activity in the castor oil test and their analgesic activity in the tail withdrawal test. The obtained antipropulsive/antidiarrheal potency ratios varied from 0.71 to greater than 552 [pethidine (oral ED50's in mg/kg: 21.5/30.2), fentanyl (0.77/0.49), dextromoramide (5.39/2.90), methadone (14.2/6.38), codeine (98.4/10.8), morphine (56.6/5.21), diphenoxylate (8.15/0.54), nufenoxole (74.7/1.72), difenoxin (7.10/0.16), loperamide oxide (greater than 160/0.34) and loperamide (greater than 160/0.29)]. The above ratios correlated with the gut selectivity of the compounds as defined by their analgesic/antidiarrheal potency ratios (r = 0.92, P less than 0.001). Furthermore, inhibition of propulsion was found to correlate with central analgesic activity (r = 0.93, P less than 0.001) but not with protection from diarrhea (r = 0.023, P greater than 0.05). Indeed, gut-selective opioids such as loperamide and loperamide oxide failed to affect propulsion up to doses more than 450 times their antidiarrheal doses. In contrast, alpha 2-adrenoceptor agonists delayed propulsion at doses comparable to their antidiarrheal doses [clonidine (0.085 vs 0.021), lidamidine (2.35 vs 1.66)] and anticholinergics inhibited propulsion even at doses many times below their antidiarrheal doses [atropine (0.26 vs 9.30), dexetimide (0.13 vs 5.03) and isopropamide (0.78 vs 74.6)]. The present results indicate that the in vivo inhibition of gastrointestinal propulsion by opioids in rats is mediated by a central action. Effects on intestinal fluid transport or, alternatively, on motility events distal to the ileocecal junction rather than effects on propulsion through the small intestine, seem to be the primary mechanism of antidiarrheal action of gut-selective opioids such as loperamide and loperamide oxide.
OBJECTIVE: The antidiuretic effect of desmopressin is widely utilized in the treatment of neurogenic diabetes insipidus and nocturnal enuresis in children. The objective of the present study was to assess how changes in gastrointestinal motility, induced by erythromycin and loperamide, influence the pharmacokinetics of orally administered desmopressin. METHODS: This study was conducted using an open randomized, three-period, three-treatment design in 18 healthy subjects. On each study day a single oral dose of 400 microg desmopressin was administered in the morning. The desmopressin dose was either given alone (reference) or after pretreatment with either loperamide tablets (4 mg at -24, -12 h and -1 h) or erythromycin capsules (250 mg q.i.d, with the first dose in the morning 3 days before the study day and the last dose at -1 h). On each study day, blood was sampled up to 8 h after dosing for assessment of desmopressin concentration. RESULTS: Compared with administration of 400 microg of desmopressin alone, pretreatment with loperamide produced significantly (P < 0.05) altered pharmacokinetics of desmopressin as the endpoints; area under the curve up to infinity (AUC), area up to the last determinable plasma concentration (AUCt) and maximum plasma concentration (Cmax) increased 3.1-fold (95% CI 2.3-4.2), 3.2 (2.3-4.4) and 2.3 (1.6 3.2), respectively. Although the estimates were lower, pretreatment with erythromycin did not result in any significant changes in these endpoints. There were no significant changes observed between the three treatments regarding the terminal elimination half-life (t1/2). However, significant (P < 0.05) changes in the time to reach Cmax (tmax) values (median and range) were observed as, compared with administration of desmopressin alone (1.3 h and 0.5-4.0), it was longer after pretreatment with loperamide (2.0 h and 0.5-3.0) and shorter following pre-treatment with erythromycin (0.9 h and 0.5-1.3). CONCLUSION: Presumably due to slower gastrointestinal motility, pretreatment with loperamide significantly increases the gastrointestinal absorption of desmopressin. Except for a shortening of tmax pretreatment with erythromycin did not significantly influence absorption of the drug.
Opioids play an important role in the regulation of glucose homeostasis. In the previous report, we showed that activation of opioid mu-receptors produced a plasma glucose lowering effect in diabetic rats lacking insulin. In the present study, we found that the response of opioid mu-receptor is more sensitive in streptozotocin-induced diabetic rats (STZ-diabetic rats) than in normal rats. Intravenous injection of loperamide, an agonist of opioid mu-receptors, induced a dose-dependent decrease of plasma glucose from 3 microg/kg to 60 microg/kg in fasting STZ-diabetic rats. However, loperamide decreased the plasma glucose of normal fasting rats at the doses of 0.3 mg/kg to 1.5 mg/kg, which were much higher than those needed to produce the same effect in diabetic rats. The plasma glucose-lowering action of loperamide at the dose effective in normal rats disappeared in opioid mu-receptor knockout mice, while the plasma glucose-lowering response to loperamide was still observed in wild-type mice. This opens the possibility of mediation through opioid mu-receptor in the plasma glucose-lowering action of loperamide. Moreover, the mRNA level of opioid mu-receptor in the liver markedly increased in STZ-diabetic rats compared to normal rats. Normalization of plasma glucose concentrations in STZ-diabetic rats with exogenous insulin or phlorizin reversed mRNA and protein levels of opioid mu-receptor in the liver after 4 days of treatment. This shows that correction of hyperglycemia in STZ-diabetic rats may reverse the higher gene expression of opioid mu-receptor. These results suggest that hyperglycemia is responsible for increase of opioid mu-receptor in STZ-diabetic rats.
AIMS: Stress hormones might be involved in motion sickness. The influence of loperamide on kinetosis-induced nausea and stress hormone release was investigated in a placebo-controlled, cross-over study. METHODS: Standardized rotation around the vertical axis combined with head movements was used to induce nausea 3 h after 16 mg loperamide or placebo (n = 8). Plasma antidiuretic hormone (ADH), adrenocorticotropic hormone (ACTH) and nausea ratings were investigated. RESULTS: After loperamide nausea was significantly lower (P < 0.02). ACTH (P < 0.05) and ADH levels (P < 0.02) increased significantly in both settings, but were lower after loperamide. CONCLUSIONS: The susceptibility to develop kinetosis-induced nausea and stress hormone release is decreased by loperamide, although the site of action remains speculative.
Experimental antidiarrheal activity of a traditionally used medication, Salicairine, was demonstrated in comparison to loperamide by significant inhibition of castor oil-induced diarrhea in mice (increases in hard faeces/total faeces ratio of 38 and 54 and 5 and 54% with respect to controls, at 0.5 and 1 mL/kg and 1 and 2 mg/kg, respectively) and bisacodyl-induced increase in large intestine transit in rats (125 and 280 and 210% with respect to controls, at 0.4 and 2 mL/kg Salicairine and 5 mg/kg loperamide, respectively). Salicairine was able to reduce contractions of isolated rat duodenum induced by barium chloride and acetylcholine, although not completely (that is about 60%) as seen with loperamide. Also, it did not change normal gastrointestinal transit in mice at doses of 0.5 to 1 mL/kg, conversely to loperamide which had a significant effect (decrease of 50%) at 2 mg/kg. Finally, Salicairine at 0.01 mL/mL, like loperamide at 0.2 mg/mL, significantly increased net fluid absorption in rat colon, either in basal conditions (30 and 64% respectively) or after a prostaglandin E1-induced increase in net fluid secretion (41 and 35%, respectively). The antidiarrheal activity of Salicairine is possibly related, at least in part, to an increase in colon net fluid absorption or a decrease in net fluid secretion.
Cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for phase I drug metabolism of many anticancer agents. It is also a major route for metabolism of many drugs used by patients to treat the symptoms caused by cancer and its treatment as well as their other illnesses, for example, cardiovascular disease. To assess the ability to inhibit CYP3A4 of drugs most commonly used by our patients during cancer therapy, we have made in silico predictions based on the crystal structures of CYP3A4. From this set of 33 common comedicated drugs, 10 were predicted to be inhibitors of CYP3A4, with the antidiarrheal drug loperamide predicted to be the most potent. There was significant correlation (r(2) = 0.75-0.66) between predicted affinity and our measured IC(50) values, and loperamide was confirmed as a potent inhibitor (IC(50) of 0.050 +/- 0.006 microM). Active site docking studies predicted an orientation of loperamide consistent with formation of the major (N-demethylated) metabolite, where it interacts with the phenylalanine cluster and Arg-212 and Glu-374; experimental evidence for the latter interaction comes from the approximately 12-fold increase in K(M) for loperamide observed for the Glu-374-Gln mutant. The commonly prescribed drugs loperamide, amitriptyline, diltiazem, domperidone, lansoprazole, omeprazole, and simvastatin were identified by our in silico and in vitro screens as relatively potent inhibitors of CYP3A4 that have the potential to interact with cytotoxic agents to cause adverse effects, highlighting the likelihood of drug-drug interactions affecting chemotherapy treatment.