Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity.
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The antihyperalgesic properties of the opiate antidiarrheal agent loperamide (ADL 2-1294) were investigated in a variety of inflammatory pain models in rodents. Loperamide exhibited potent affinity and selectivity for the cloned micro (Ki = 3 nM) compared with the delta (Ki = 48 nM) and kappa (Ki = 1156 nM) human opioid receptors. Loperamide potently stimulated [35S]guanosine-5'-O-(3-thio)triphosphate binding (EC50 = 56 nM), and inhibited forskolin-stimulated cAMP accumulation (IC50 = 25 nM) in Chinese hamster ovary cells transfected with the human mu opioid receptor. The injection of 0.3 mg of loperamide into the intra-articular space of the inflamed rat knee joint resulted in potent antinociception to knee compression that was antagonized by naloxone, whereas injection into the contralateral knee joint or via the i.m. route failed to inhibit compression-induced changes in blood pressure. Loperamide potently inhibited late-phase formalin-induced flinching after intrapaw injection (A50 = 6 microgram) but was ineffective against early-phase flinching or after injection into the paw contralateral to the formalin-treated paw. Local injection of loperamide also produced antinociception against Freund's adjuvant- (ED50 = 21 microgram) or tape stripping- (ED50 = 71 microgram) induced hyperalgesia as demonstrated by increased paw pressure thresholds in the inflamed paw. In all animal models examined, the potency of loperamide after local administration was comparable to or better than that of morphine. Loperamide has potential therapeutic use as a peripherally selective opiate antihyperalgesic agent that lacks many of the side effects generally associated with administration of centrally acting opiates. (+info)
Effect of the 5-hydroxytryptamine3 (5-HT3)-receptor antagonist KB-R6933 on experimental diarrhea models.
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The effects of a 5-hydroxytryptamine3 (5-HT3)-receptor antagonist KB-R6933 (6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-benzimidazole dimaleate) on experimental diarrhea and on intestinal fluid secretion stimulated by cholera toxin were examined and compared with those of ramosetron and loperamide. KB-R6933 and ramosetron (0.03-1 mg/kg, p.o.) inhibited the diarrhea induced by 5-HT, but not that by castor oil or prostaglandin E2 (PGE2), in mice. Loperamide significantly inhibited the diarrhea induced by 5-HT, castor oil and PGE2. All drugs tested inhibited the diarrhea induced by restraint stress and the intestinal fluid secretion stimulated by cholera toxin in rats. The results suggest the possibility that KB-R6933 may have clinical efficacy in the treatment of diarrhea. (+info)
Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of traveler's diarrhea.
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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. (+info)
Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5-fluorouracil induced diarrhea and failure of loperamide treatment.
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BACKGROUND: Diarrhea is one of the most disturbing effects of chemotherapy, affecting quality of life on the one hand and limiting applicable doses on the other. Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are associated with an elevated risk of developing severe diarrhea. Standard therapy consists of high-dose loperamide, but is associated with frequent failure. Other therapeutic regimens are still experimental. Endoscopic examination of a patient with severe loperamide-resistant diarrhea after CPT-11 chemotherapy revealed an inflammation of the ileo-coecal region. Oral therapy with the topical corticosteroid budesonide was immediately effective. This led to a phase I study of budesonide in CPT-11- and 5-FU-induced and loperamide-refractory diarrhea. PATIENTS AND METHODS: Fourteen patients with CPT-11- and seven patients with 5-FU-induced grade 3-4 (NCI/WHO) diarrhea and loperamide failure were enrolled in this study. All patients had metastatic colorectal cancer. RESULTS: In 86% of the CPT-11- and 57% of the 5-FU-treated patients with grade 3-4 diarrhea and loperamide failure, treatment with budesonide resulted in a reduction of diarrhea severity by at least two grades. CONCLUSIONS: The orally administered topical active steroid budesonide is highly effective in the therapy of loperamide-refractory chemotherapy (CPT-11 or 5-FU)-induced diarrhea. (+info)
Effects of racecadotril and loperamide on bacterial proliferation and on the central nervous system of the newborn gnotobiotic piglet.
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METHODS: The effects of 4 days of oral administration of different doses of two drugs, an enkephalinase inhibitor (the antisecretory agent, racecadotril) and a mu-receptor agonist (loperamide), on intestinal growth of a bacterial nonpathogenic strain (Escherichia coli E 404) and on the central nervous system (CNS) were compared in newborn gnotobiotic piglets. RESULTS: The E. coli content of the proximal jejunum (segment S1) and the E. coli ratio of stomach:segment S1 were similar in the racecadotril (20 mg/kg b.d., n = 5) and control groups. In contrast, in the loperamide group (1 mg/kg b.d., n = 4), the E. coli content of segment S1 and the E. coli ratio stomach:S1 were both significantly higher than with racecadotril or control (P = 0.04 and 0.005, respectively, for E. coli content; P = 0.05 and 0.03, respectively, for stomach:S1). There were no clinical signs of neurotoxicity and no deaths with racecadotril given orally at a high dose of 130 mg/kg b.d. (n = 5)--nearly 60 times the paediatric dosage. In contrast, an equivalent high dose of loperamide (5 mg/kg b.d.) resulted in death in three out of four piglets. CONCLUSIONS: In contrast to loperamide, racecadotril did not induce bacterial overgrowth and did not produce central neurotoxicity. (+info)
Comparison of racecadotril and loperamide in adults with acute diarrhoea.
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METHODS: A multicentre, randomized, double-blind, double-placebo, parallel-group study was carried out to compare the efficacy, tolerability, and safety of racecadotril (100 mg three times daily) and loperamide (2 mg after each diarrhoeic stool) in 157 adults with acute diarrhoea. Patients were treated for 7 days or until recovery, if this took place earlier. RESULTS: Both groups of patients passed similar numbers (mean +/- S.E.M.) of stools before recovery (3.5 +/- 0.5 for racecadotril vs. 2.9 +/- 0.4 for loperamide), and the duration of diarrhoea (mean +/- S.E.M.) was similar in both groups (14.9 +/- 2.0 h for racecadotril and 13.7 +/- 2.2 h for loperamide). Both treatments reduced the incidence of associated symptoms and signs during the study, and both were similarly well tolerated. However, more patients on loperamide reported rebound constipation during treatment (18.7% vs. 9.8% with racecadotril). CONCLUSIONS: The enkephalinase inhibitor, racecadotril, and the intestinal transit inhibitor, loperamide, were similarly and rapidly effective in resolving the symptoms and associated signs of diarrhoea. (+info)
Comparison of racecadotril and loperamide in children with acute diarrhoea.
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METHODS: A multicentre, parallel-group, double-blind, double-placebo study was carried out to compare the efficacy, tolerability, and safety of racecadotril and loperamide in children aged 2 to 10 years who were suffering from acute diarrhoea. Patients received racecadotril (1.5 mg/kg) or loperamide (0.03 mg/kg) three times daily plus matching placebo until recovery. Fifty-two children received racecadotril and 50 loperamide. RESULTS: Patients on racecadotril passed a mean (+/- S.E.M.) of 2.7 +/- 0.4 stools before recovery compared with 2.1 +/- 0.4 stools for loperamide. The duration of diarrhoea was similar with both treatments. The incidence of adverse events was lower with racecadotril than with loperamide (11.5% vs. 22%), and significantly more patients on loperamide suffered from constipation (58% vs. 36.5%; P = 0.03). Moreover, significantly more children receiving loperamide required concomitant medication during the study (38% v 19.2%; P = 0.047). Measurement of abdominal circumference at the final consultation, 6 days after entry to the study, revealed no significant differences between treatments. CONCLUSIONS: Racecadotril and loperamide were equally effective in treating acute diarrhoea in these children, and racecadotril had a superior tolerability and safety profile. (+info)
Sodium channel blockers and uridine triphosphate: effects on nasal potential difference in cystic fibrosis mice.
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Sodium channel inhibitors block the enhanced Na+ reabsorption in cystic fibrosis (CF). Extracellular nucleotides facilitate Cl- secretion via Ca2+ gated Cl- channels. A combination of these effects may produce less viscid secretions in CF which are easier to expectorate. This study examined the effects of combining sodium channel blockers with uridine triphosphate (UTP) on nasal membrane potential difference (PD) in CF insertional null mutant mice (cftr(tm1HGU)), deltaF508 homozygous mice (cftr(tm1Cam)) and matched control animals. Median basal PD in the insertional CF mice and deltaF508 CF mice were -28 and -34 mV respectively. These values were significantly different to the control animals (-20 mV). Amiloride and loperamide reduced the PD in cftr(tm1HGU) CF mice (deltaPD 13 mV & 15 mV respectively) suggesting Na+ blockade. The subsequent addition of UTP in a chloride-free vehicle increased the PD (deltaPD -8- -12.5 mV). DeltaF508 mice showed significantly greater responses compared with CF insertional null mutant mice (p<0.05). The action of UTP was brief and not prolonged by the addition alpha-beta-methylene-adenosine 5' diphosphate. Suramin, a competitive antagonist of P2 purinoceptors blocked the action of UTP. In conclusion, this study demonstrated dose dependant nasal membrane potential changes in differences mice with uridine triphosphate in the presence of sodium channel blockers suggestive of chloride secretion. More stable analogues of uridine triphosphate in combination with long acting sodium channel blockers such as loperamide may have therapeutic potential in cystic fibrosis. (+info)