The elementary mass action rate constants of P-gp transport for a confluent monolayer of MDCKII-hMDR1 cells.
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The human multi-drug resistance membrane transporter, P-glycoprotein, or P-gp, has been extensively studied due to its importance to human health and disease. Thus far, the kinetic analysis of P-gp transport has been limited to steady-state Michaelis-Menten approaches or to compartmental models, neither of which can prove molecular mechanisms. Determination of the elementary kinetic rate constants of transport will be essential to understanding how P-gp works. The experimental system we use is a confluent monolayer of MDCKII-hMDR1 cells that overexpress P-gp. It is a physiologically relevant model system, and transport is measured without biochemical manipulations of P-gp. The Michaelis-Menten mass action reaction is used to model P-gp transport. Without imposing the steady-state assumptions, this reaction depends upon several parameters that must be simultaneously fitted. An exhaustive fitting of transport data to find all possible parameter vectors that best fit the data was accomplished with a reasonable computation time using a hierarchical algorithm. For three P-gp substrates (amprenavir, loperamide, and quinidine), we have successfully fitted the elementary rate constants, i.e., drug association to P-gp from the apical membrane inner monolayer, drug dissociation back into the apical membrane inner monolayer, and drug efflux from P-gp into the apical chamber, as well as the density of efflux active P-gp. All three drugs had overlapping ranges for the efflux active P-gp, which was a benchmark for the validity of the fitting process. One novel finding was that the association to P-gp appears to be rate-limited solely by drug lateral diffusion within the inner monolayer of the plasma membrane for all three drugs. This would be expected if P-gp structure were open to the lipids of the apical membrane inner monolayer, as has been suggested by recent structural studies. The fitted kinetic parameters show how P-gp efflux of a wide range of xenobiotics has been maximized. (+info)
Meta-analysis: The treatment of irritable bowel syndrome.
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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. (+info)
Acute colitis induction by oil of mustard results in later development of an IBS-like accelerated upper GI transit in mice.
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Oil of mustard (OM) is a potent neuronal activator that promotes allodynia and hyperalgesia within minutes of application. In this study, OM was used to induce an acute colitis. We also investigated whether intracolonic OM-induced inflammation alters gastrointestinal (GI) function over a longer time frame as a model of postinflammatory irritable bowel syndrome (PI-IBS). Mice given a single administration of 0.5% OM developed a severe colitis that peaked at day 3, was reduced at day 7, and was absent by day 14. At the peak response, there was body weight loss, colon shrinkage, thickening and weight increases, distension of the proximal colon, and diarrhea. Macroscopic inspection of the distal colon revealed a discontinuous pattern of inflammatory damage and occasional transmural ulceration. Histological examination showed loss of epithelium, an inflammatory infiltrate, destruction of mucosal architecture, edema, and loss of circular smooth muscle architecture. OM administration increased transit of a carmine dye bolus from 58% of the total length of the upper GI tract in untreated age-matched controls to as high as 74% when tested at day 28 post-OM. Mice in the latter group demonstrated a significantly more sensitive response to inhibition of upper GI transit by the mu-opioid receptor agonist loperamide compared with normal mice. OM induces a rapid, acute, and transient colitis and, in the longer term, functional changes in motility that are observed when there is no gross inflammation and thereby is a model of functional bowel disorders that mimic aspects of PI-IBS in humans. (+info)
A blind, randomized comparison of racecadotril and loperamide for stopping acute diarrhea in adults.
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AIM: Racecadotril is a specific enkephalinase inhibitor that exhibits intestinal antisecretory activity without affecting intestinal transit. Loperamide is an effective anti-diarrheal agent, but it usually induces constipation. This study is to compare the efficacy, safety, and tolerability of racecadotril versus loperamide in the outpatient treatment of acute diarrhea in adults. METHODS: A two-center, randomized, parallel-group, single-blind study was carried out to compare the efficacy, tolerability, and safety of racecadotril (100 mg thrice daily) and loperamide (2.0 mg 2 twice daily) in 62 adult patients suffering from acute diarrhea. The main efficacy criterion used was the duration of diarrhea after beginning the treatment (in hours). Other signs and symptoms were also evaluated. RESULTS: The clinical success rates for these anti-diarrheal treatments were 95.7% and 92.0% for racecadotril and loperamide respectively. Patients on racecadotril had a median duration of diarrhea of 19.5 h compared with a median of 13 h for patients on loperamide. Rapid improvement in anal burn and nausea was found for each drug. However, more patients on loperamide suffered from reactive constipation (29.0% vs 12.9%). Itching, another adverse event was notably higher in the racecadotril group (28.6% vs 0%). With regard to other adverse events, the two medications showed similar occurrence rates and similar concomitant medication usage rates. CONCLUSION: Racecadotril and loperamide are rapid, equally effective treatments for acute diarrhea in adults, but loperamide treatment is associated with a higher incidence of treatment-related constipation. (+info)
Antidiarrheal effects of L-histidine-supplemented rice-based oral rehydration solution in the treatment of male adults with severe cholera in Bangladesh: a double-blind, randomized trial.
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BACKGROUND: Because of the antisecretory potential of L-histidine in the intestinal tract, its antidiarrheal effects were determined in cholera. METHODS: In a double-blind trial of 126 adult male patients with cholera, L-histidine (2.5 g/L) was mixed with a rice-based oral rehydration solution (ORS) and administered to 62 patients; 64 patients received the same ORS without L-histidine. All patients received ciprofloxacin at a dosage of 500 mg every 12 h for 72 h. Fluid output (of stool, urine, and vomit) and intake (of ORS, water, and intravenous fluid) were determined every 8 h for 72 h. RESULTS: Administration of ORS with L-histidine significantly (P<.05) reduced the frequency of stool output during 32-64 h after initiation of ORS treatment, compared with that in patients given ORS without L-histidine ([all data are means+/-SD] 32-48 h, 11.5+/-6.9 mL/kg vs. 18.8+/-16.0 mL/kg; 40-48 h, 6.7+/-4.4 mL/kg vs. 11.5+/-9.7 mL/kg; and 56-64 h, 6.3+/-5.8 mL/kg vs. 7.8+/-4.1 mL/kg). An overall reduction of 22% in the volume of stool was observed in patients given ORS without L-histidine. The amount of required unscheduled intravenous fluid was lower in patients given ORS with L-histidine, compared with that in patients given ORS without L-histidine (0-24 h, 82.5+/-44.4 mL/kg vs. 158.6+/-72.2 mL/kg [P<.01]; and 24-48 h, 41.6+/-40.4 mL/kg vs. 52.5+/-22.1 mL/kg [P>.05]). Administration of ORS with L-histidine also significantly reduced (P<.05) the intake of ORS and the duration of illness. No adverse effects were observed in these patients. CONCLUSIONS: L-histidine reduces the weight of stool and the frequency of stool output in cholera and could be a useful and safe adjunct treatment that will increase the success rate of ORS and antibiotic therapy in cholera. (+info)
Control of muscle tone in the human colon.
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Human colonic muscle tone varies diurnally and postprandially in predictable ways. Increased tone reduces the capacity of the colon to store contents after a meal, whereas increased distensibility (lesser tone) during sleep enlarges the storage capabilities and may slow transit. We tested the hypothesis that antidiarrhoeal drugs would also alter tone which, in turn, might reduce diarrhoea by facilitating the storage and salvage of fluids. Using a colonic barostat to create low pressure, isobaric colonic distension in healthy volunteers, we found that intravenous atropine (0.01 mg/kg) relaxed the colon during fasting, reduced the postprandial increase in tone, and enhanced relaxation in the late (1-2 hour) postprandial period. Intravenous morphine (0.1 mg/kg) caused variable effects soon after injection but, in fasting subjects, the descending colon relaxed 70-90 minutes after morphine. These changes in colonic motility were not always obvious by conventional manometric recording. Colonic distensibility is increased by antidiarrhoeal drugs and this effect may contribute to their efficacy in slowing colonic transit and augmenting absorption. (+info)
Loperamide inhibits tachykinin NK3-receptor-triggered serotonin release without affecting NK2-receptor-triggered serotonin release from guinea pig colonic mucosa.
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The effect of loperamide on tachykinin NK(2)- and NK(3)-receptor-mediated 5-HT outflow from guinea pig colonic mucosa was investigated in vitro. The selective tachykinin NK(2)-receptor agonist [beta-Ala(8)]-neurokinin A(4-10) (betaAla-NKA) or the selective NK(3)-receptor agonist senktide elicited an increase in 5-HT outflow from whole colonic strips, but not from mucosa-free muscle layer preparations. The enhancing effect of betaAla-NKA and senktide was prevented by the selective NK(2)-receptor antagonist GR94800 or the selective NK(3)-receptor antagonist SB222200. Loperamide concentration-dependently suppressed the senktide-evoked 5-HT outflow, but failed to affect the betaAla-NKA-evoked 5-HT outflow. The kappa-opioid receptor antagonist nor-binaltorphimine or the delta-opioid receptor antagonist naltrindole displaced the concentration-response curve for the suppressant action of loperamide to the right without significant depression of the maximum. However, the mu-opioid receptor antagonist CTOP did not affect the suppressant effect of loperamide. We concluded that the NK(3) receptor-triggered 5-HT release from colonic mucosa is suppressed by loperamide-sensitive mechanisms, whereas the NK(2)-receptor-triggered 5-HT release is loperamide-insensitive. Our data also suggest that the suppressant effect of loperamide is probably mediated by the activation of kappa- and delta-opioid receptors located on intrinsic neurons. (+info)
Anti-diarrhoeal potential of Asparagus racemosus wild root extracts in laboratory animals.
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PURPOSE: Asparagus racemosus Wild root has been used traditionally in Ayurveda for the treatment of diarrhoea and dysentery. However, the claims of Ayurveda need to be validated by a suitable experimental model. Therefore, the present study was undertaken to evaluate the effect of ethanol and aqueous extracts of Asparagus racemosus for its antidiarrhoeal potential against several experimental models of diarrhoea in Albino Wistar rats. METHODS: The antidiarrhoeal activity of ethanol and aqueous extracts of Asparagus racemosus root was evaluated using castor oil-induced diarrhoea model in rats. Further, we evaluated the effect of ethanol and aqueous extracts on gastrointestinal tract motility after charcoal meal administration and PGE2 induced intestinal fluid accumulation (enteropooling). Loperamide was used as positive control. RESULTS: The plant extracts showed significant (P < 0.05) inhibitor activity against castor oil induced diarrhoea and PGE2 induced enteropooling in rats when tested at 200 mg/kg. Both extracts also showed significant (P < 0.001) reduction in gastrointestinal motility in charcoal meal test in rats. CONCLUSION: The results point out the possible anti-diarrhoeal effect of the plant extracts and substantiate the use of this herbal remedy as a non-specific treatment for diarrhoea in folk medicine. (+info)