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Diarrhoeal diseases are the major cause of infant mortality in developing countries. Dehydration is the most common complication of diarrhoea, and severe dehydration causes up to 80% of diarrhoeal fatalities. For more than 100 years, physicians focused the treatment of diarrhoeal diseases on the symptom diarrhoea, and there were many 'antidiarrhoeal' drugs, such as water adsorbents (kaolin and pectin) and antiperistaltics (opium, paregoric elixir, diphenoxylate hydrochloride with atropine sulphate and loperamide). This approach focused on a non-dangerous symptom and diverted attention from the real killer, dehydration. A few decades ago, only severely dehydrated patients were treated by intravenous therapy. This treatment was prescribed by a group of professional health workers, administered intravenously by skilled nurses, and reserved for the few patients resident near health facilities. Oral rehydration therapy (ORT), developed 20 years ago, has several advantages over intravenous therapy; it can be administered at home, at health clinics or in modern hospitals, by parents or by nurses or physicians. Most serum disturbances in dehydrated neonates, infants, children, adults and the elderly are resolved by this treatment.
Dried whole plant parts of Ludwigia hyssopifolia were subjected to successive cold extraction with n-hexane, ethylacetate and methanol. The methanol extract (LHM), obtained as 1% yield, showed significant antidiarrheal property by reducing diarrheal episodes in castor oil and serotonin induced diarrhea in laboratory mice at a dose of higher than 100 mg/kg body weight as compared to standard drug loperamide given at a dose of 66.67 microg/kg body weight. The percent reduction in diarrheal episode by 56.32 and 89.66 after castor oil challenge and 59.09 and 86.36 in serotonin induced diarrhea was observed at doses of 200 mg/kg and 400 mg/kg body weight of the extract respectively. The extract LHM was also found to reduce the gastrointestinal motility by 53.8% at a dose of 100 mg/kg body weight as compared to control, while no remarkable inhibition of gastrointestinal motility was seen at a dose of 50 mg/kg body weight of the extract.
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We searched the Cochrane Incontinence Group Specialised Register of Trials, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE in process, and handsearching of journals and conference proceedings (searched 21 June 2012) and the reference lists of relevant articles.
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We investigated the possibility that loperamide might influence absorption and secretion in the human jejunum in vivo. Using a triple lumen tube perfusion technique in healthy normal volunteers we showed that loperamide did not affect net absorption of water or electrolytes under basal condition. When secretion was induced by prostaglandin E2, however, loperamide significantly reduced that secretion and in three out of six subjects secretion was abolished. Loperamide was effective when it was given either before or after secretion had been initiated. The results lend support to the suggestion that the antidiarrhoeal activities of loperamide may include an antisecretory effect.
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Infectious diarrhea is among the most common medical problems associated with military deployments and has been reported as a frequent problem for troops currently deployed to Iraq and Afghanistan. Lacking is information describing clinical presentation, risk behaviors, and treatment of travelers' diarrhea in this population.
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Preoperative demographics were similar between 2 groups in age (13.5 ± 3.5 years -Ostomy, 14.3 ± 3 years +Ostomy), serum albumin (3.6 ± 0.7 -Ostomy, 3.6 ± 0.7 +Ostomy), body mass index (20.8 ± 6.9 -Ostomy, 21.3 ± 8.6 +Ostomy), and daily corticosteroid dose (22.4 ± 17.7 mg -Ostomy, 23.5 ± 13.7 mg +Ostomy). Operating time was less in -Ostomy with mean times of 6:22 ± 2:04 vs 9:07 ± 2:57. The -Ostomy group required fewer ileoanal anastomotic dilations per patient (0.4 ± 0.8 vs 1.4 ± 1.9). Functional outcomes were not significantly different regarding pouchitis episodes per patient (0.6 ± 1.1 -Ostomy, 0.6 ± 1.1 +Ostomy), daily bowel movements (5.5 ± 1.9 -Ostomy, 6.7 ± 4.0 +Ostomy), and daily postoperative loperamide dose (8.4 ± 4.3 mg -Ostomy, 6.8 ± 4.0 mg +Ostomy).
P-glycoprotein (P-gp) is a membrane-bound efflux pump that limits the distribution of drugs to several organs of the body. At the blood-brain barrier, P-gp blocks the entry of both loperamide and its metabolite, N-desmethyl-loperamide (N-dLop), and thereby prevents central opiate effects. Animal studies have shown that (11)C-dLop, compared with (11)C-loperamide, is an especially promising radiotracer because it generates negligible radiometabolites that enter the brain. The purposes of this study were to determine whether (11)C-dLop is a substrate for P-gp at the blood-brain barrier in humans and to measure the distribution of radioactivity in the entire body to estimate radiation exposure.
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Enhanced sensitivity for determination of basic drugs in body fluids was achieved by in-line coupling of extraction across supported liquid membrane (SLM) to large electrokinetic injection and transient isotachophoresis-capillary zone electrophoresis (tITP-CZE) in commercial CZE instrument. Twelve cm long tITP plug of 300mM ammonium acetate was formed in the separation capillary just before the electrokinetic injection of acceptor solution containing nortriptyline, haloperidol and loperamide extracted across the SLM. The tITP plug ensured efficient stacking and preconcentration of the injected basic drugs due to the tITP action of ammonium and the drugs were then separated by CZE using 5.2M acetic acid as background electrolyte. No interferences were observed from highly-abundant body fluid species (NaCl and human serum albumin) due to the excellent clean-up properties of SLMs and analytical sensitivity increased up to 340 times compared to SLM extractions coupled in-line to CZE with standard hydrodynamic injections. The SLM-tITP-CZE method was characterized by good repeatability (RSDs of peak areas below 7.8%), linearity over two orders of magnitude (r(2) better than 0.994) and limits of detection (defined as 3×S/N) between 3 and 45μg/L. Interfacing of SLM extractions to CZE instrumentation was achieved by low-cost, disposable micro-extraction devices, which can be routinely prepared in every analytical laboratory. These devices eliminated sample carry-over, minimized the need for manual sample handling and ensured fully automated determination (including extraction, injection, preconcentration and separation) of the three basic drugs in 20μL of untreated body fluids.
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The efflux transporter P-glycoprotein, expressed at high levels at the blood-brain barrier, exerts a profound effect on the disposition of various therapeutic compounds in the brain. A rapid and efficient modulation of this efflux transporter could enhance the distribution of its substrates and thereby improve central nervous system pharmacotherapies. This study explored the impact of the intravenous coadministration of two P-glycoprotein modulators, tariquidar and elacridar, on the pharmacokinetics and brain distribution of loperamide, a P-glycoprotein substrate probe, in rats. After 1 hour postdosing, tariquidar and elacridar, both at a dose of 1.0 mg/kg, increased loperamide levels in the brain by 2.3- and 3.5-fold, respectively. However, the concurrent administration of both P-glycoprotein modulators, each at a dose of 0.5 mg/kg, increased loperamide levels in the brain by 5.8-fold and resulted in the most pronounced opioid-induced clinical signs. This phenomenon may be the result of a combined noncompetitive modulation by tariquidar and elacridar. Besides, the simultaneous administration of elacridar and tariquidar did not significantly modify the pharmacokinetic parameters of loperamide. This observation potentially allows the concurrent use of low but therapeutic doses of P-gp modulators to achieve full inhibitory effects.
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Comparatively little attention has been given to the role of gastrointestinal motility in the pathogenesis and treatment of diarrhoea. Here the relationship between motor activity and absorption in the small intestine has been assessed, as has that between small intestinal secretion and motility, and between colonic salvage and motility. It is suggested that diarrhoea should be considered as a disturbance of intestinal flow, involving disturbances in both motility and transport. The role of antimotility agents (particularly opiate-like agents such as loperamide) is reviewed. The most successful antidiarrhoeal agents are those that combine a reversal of epithelial secretion with an action on motility.
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Several neuroleptics known to bind to calmodulin were tested for anti-diarrheal activity and were compared with the opiate anti-diarrheals loperamide and diphenoxylate. All inhibited the intestinal fluid secretion induced by 16,16-dimethyl prostaglandin E2 and castor oil-induced diarrhea in rats as a function of dose, the order of potency being loperamide approximately equal to diphenoxylate greater than chlorpromazine greater than promethazine greater than amitriptyline. The opiates loperamide and diphenoxylate were found to compete with [3H]trifluoperazine binding to calmodulin in the presence of calcium. These opiates were approximately 3 times more potent inhibitors of [3H]trifluoperazine binding than chlorpromazine. A positive correlation between calmodulin binding and anti-diarrheal activity was demonstrated.
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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels underlie the pacemaker currents in neurons (I(h)) and cardiac (I(f)) cells. As such, the identification and characterization of novel blockers of HCN channels is important to enable the dissection of their function in vivo. Using a new IonWorks HT electrophysiology assay with human HCN1 and HCN4 expressed stably in cell lines, four HCN channel blockers are characterized. Two blockers known for their activity at opioid/Ca(2+) channels and K(+) channels, loperamide and CP-339,818 (respectively), are described to block HCN1 more potently than HCN4. The known HCN blocker ZD7288 was also found to be more selective for HCN1 over HCN4, while the HCN blocker DK-AH269 was equipotent on HCN4 and HCN1. Partial replacement of the intracellular Cl(-) with gluconate reduced the potency on both channels, but to varying degrees. For both HCN1 and HCN4, ZD7288 was most sensitive in lower Cl(-) solutions, while the potency of loperamide was not affected by the differing solutions. The block of HCN1 for all compounds was voltage-dependent, being relieved at more negative potentials. The voltage-dependent, Cl(-) dependent, HCN1 preferring compounds described here elaborate on the current known pharmacology of HCN channels and may help provide novel tools and chemical starting points for the investigation of HCN channel function in natively expressing systems.
A total of 139 patients were randomly assigned, most of whom received fluorouracil- and oxaliplatin-containing chemotherapy regimens. The rate of diarrhea was 76.1% in the experimental group (n = 68) and 78.9% in the control group (n = 71). Treatment with octreotide LAR did not prevent or reduce the severity of CID. Treatment choices for diarrhea management included loperamide in the majority of patients. No benefit from octreotide LAR was identified in terms of need for diarrhea treatment, opioids, or intravenous hydration or in the rate of hospitalization or quality of life.
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In a double-blind randomized placebo-controlled study, including 70 patients treated with radiotherapy of localized malignancies in the pelvis, the effects of prophylactic sucralfate in preventing bowel discomfort were evaluated. Radiotherapy was delivered in a conventional manner with high-energy photons in a total dose of 62-66 Gy (target dose, 1.8-2.2 Gy) during 6.5 weeks. Dose granules of sucralfate or placebo were given 2 weeks after irradiation started and continued for 6 weeks. All analyses were performed blindly. The patients in the sucralfate group had significantly less problems with acute (5 weeks) and chronic (66 weeks) bowel discomfort. The consumption of loperamide was also reduced in the sucralfate group, and the weight decrease was less pronounced. No adverse effects were seen. Thus, sucralfate seems to be beneficial in minimizing the problems of bowel discomfort during and after irradiation of malignancies in the pelvis. These results are discussed in relation to other related observations.
Constipation was induced by oral administration of loperamide (3 mg/kg body weight) while the control rats received normal saline. The constipated rats were treated with 50, 100 and 200 mg/kg body weight/day of the extract for 7 days during which the feeding characteristics, body weight, fecal properties and gastrointestinal transit ratio were monitored.
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Of 64 patients evaluated, 33 were reconstructed using the double stapling technique (DST) and 31 were reconstructed using the intersphincteric resection (ISR) technique. The median Visual Analogue Scale at ISR was improved from 7 to 1.5 at 1 year after surgery. The median Wexner scores were 6.0, 6.0, 5.0 and 5.0 for DST and 14.5, 12.0, 10.0 and 8.0 for ISR for the first 4 years, respectively. The only independent predictor of a poor bowel function (Wexner score >10) according to a multivariate analyses was pelvic infection (OR 3.994, 95% CI 1.235-13.52, p = 0.021), while ISR was not a predictor.
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To evaluate therapies available for the treatment of irritable bowel syndrome, and provide consensus recommendations for their use, a total of 51 double-blind clinical trials using bulking agents, prokinetics, antispasmodics, alosetron, tegaserod and antidepressants were selected. The quality of studies was assessed using 5-point scale. Meta-analyses were performed on all studies, and on 'high-quality studies'. The efficacy of fibre in the global irritable bowel syndrome symptoms relief (OR: 1.9; 95% CI:1.5-2.4) was lost after exclusion of low-quality trials (OR: 1.4; 95% CI: 1.0-2.0, P = 0.06). When excluding the low-quality trials, an improvement of global irritable bowel syndrome symptoms with all antispasmodics (OR: 2.1; 95% CI:1.8-2.9) was maintained only for octylonium bromide, but on the basis of only two studies. Antidepressants were effective (OR: 2.6, 95% CI: 1.9-3.5), even after exclusion of low-quality studies (OR: 1.9, 95% CI: 1.3-2.7). Alosetron (OR: 2.2; 95% CI: 1.9-2.6) and tegaserod (OR: 1.4; 95% CI: 1.2-1.5) showed a significant effect in women. We recommend the use of tegaserod for women with irritable bowel syndrome with constipation and alosetron for women with severe irritable bowel syndrome with diarrhoea. Antidepressants can be beneficial for irritable bowel syndrome with diarrhoea patients with severe symptoms. Loperamide can be recommended in painless diarrhoea. Evidence is weak to recommend the use of bulking agents in the treatment of irritable bowel syndrome with constipation.
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Short bowel syndrome most commonly results after bowel resections for Crohn's disease. The normal human small intestinal length ranges from about 3 to 8 m, thus if the initial small intestinal length is short, a relatively small resection of the intestine may result in the problems of a short bowel. Two types of patient with a short bowel are encountered in clinical practice: those with their jejunum anastomosed to a functioning colon, and those with a jejunostomy. Both types of patient have problems absorbing adequate macronutrients, and both need long-term vitamin B12 therapy. Patients with a jejunostomy also have major problems with large stomal losses of water, sodium, and magnesium. This high-volume jejunostomy output is treated by restricting oral fluids, giving a glucose-saline solution to drink, and using drugs that either reduce gastrointestinal motility (loperamide or codeine phosphate) or secretions (H2 antagonists, proton pump inhibitors, or octreotide). Patients whose jejunal length is less than 100 cm, and whose stomal output is greater than their oral intake, benefit most from antisecretory drugs. In patients with a retained colon, bacterial fermentation of unabsorbed carbohydrate in the colon results in energy being salvaged. However, they have increased oxalate absorption and a 25% chance of developing calcium oxalate renal stones. Thus patients with a colon are advised to eat a high-energy diet rich in carbohydrate but low in oxalate. Patients with a jejunostomy need a high-energy iso-osmolar diet with added salt. Both patient types have a 45% prevalence of gallstones. With current therapy most patients with a short bowel have a normal body mass index and a good quality of life.
We examined the laxative effect of propolis on stool frequency by administering orally an ethanol extract of propolis (EEP) or a water extract of propolis (WEP) at 10, 50, 100, or 500 mg/kg to normal mice. We then investigated the effects of propolis using constipation model mice induced by two types of drugs, loperamide (a μ opioid receptor agonist) and clonidine (an α-2 adrenergic receptor agonist). We also investigated the effects of WEP on gastrointestinal transit and contractional tension of the ileum to uncover the mechanism of action of WEP.
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36 volunteers completed the study. WGTT increased in those receiving loperamide and decreased in those receiving senna. The decrease in WGTT was not significant in those receiving wheat bran. Diets did not change. There were no changes in TBARS, cholesterol, triglyceride or TBARS adjusted for cholesterol and triglyceride, during any intervention.
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Cellular uptake and transcellular transport were determined after exposure to various concentrations of loperamide (2-50 microM) with and without the presence of active efflux protein inhibitors. Loperamide was detected at 214 nm using high-performance liquid chromatography (HPLC) protocols.
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The review describes gastrointestinal receptors which are of therapeutic interest for the treatment of motility disorders. It updates the present knowledge on muscarinic, adrenergic, dopamine, opioid and dihydropyridine receptors, their subtypes, cellular sites and functional role as drug targets. On the basis of this pharmacological receptor concept, drugs like bethanechol, clonidine, lidamidine, metoclopramide, domperidone, cisapride, loperamide and nifedipine are evaluated in proven and potential indications. In view of the very complex regulation of motility, our understanding of receptors is still fragmentary and our tools to treat motility disorders do not fulfil all therapeutic requirements. This review tries to point out the areas of particular need for further basic research and the prospects of further drug development.