Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bladder motility recordings were performed in anaesthetized rats and the effect of the peripherally active opiate agonist loperamide on urinary bladder function was studied. Regional intra-arterial administration of loperamide (0.01-2 mg kg-1) induced weak bladder contraction per se. Loperamide caused an effective dose-dependent inhibition of bladder motility induced by regional injection of the receptor agonists acetylcholine (ACh) and substance P (SP), as well as by peripheral motor nerve stimulation (PNS). Pretreatment with naloxone (0.5 mg kg-1) partially antagonized the inhibitory action of loperamide on the nerve-mediated detrusor contraction. However, the depression of the motor responses induced by the receptor agonists ACh and SP was not influenced. It is suggested that the demonstrated inhibitory effect of loperamide on bladder motility is partially mediated by peripheral opioid receptors. The main non-opioid part of the inhibition might be a direct smooth muscle action.
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PMID:In vivo motor effects of loperamide on the rat urinary bladder. 138 Feb 2

Using a radiolabelling technique it was possible to measure changes of cholinergic nerve activity in human isolated taenia coli muscle. Loperamide (1.9-97.3 microM) depressed release of acetylcholine produced by electrical field stimulation to a greater degree than morphine (0.13-130 microM). The effect of loperamide was only partially sensitive to naloxone. Loperamide (7.8 microM) demonstrated calcium channel blocking-like properties as shown by its antagonism of CaCl2-induced contractions of depolarised muscle. Although an established calcium channel antagonist, verapamil, was also able to depress cholinergic nerve activity, the concentration was considerably greater than required for antagonism of CaCl2 contractions. The depression of acetylcholine release by loperamide may contribute to its anti-diarrhoeal properties.
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PMID:Opioid and non-opioid actions of loperamide on cholinergic nerve function in human isolated colon. 285 Feb 1

This review summarizes the clinical evidence to support current therapies in irritable bowel syndrome (IBS). Fibre is indicated at a dose of at least 12 g per day in patients with constipation-predominant IBS. Loperamide (and probably other opioid agonists) are of proven benefit in diarrhoea-predominant IBS; loperamide may also aid continence by enhancing resting anal tone. In general, smooth muscle relaxants are best used sparingly, on an 'as needed' basis, as their overall efficacy is unclear. Psychotropic agents are important in relieving depression and of proven benefit for pain and diarrhoea in patients with depression associated with IBS. Further trials with selective serotonin reuptake inhibitors (SSRIs) are awaited. Psychological treatments including hypnotherapy are less widely available, but may play an important role in relief of pain. In summary, current therapies targeted on the predominant symptoms in IBS are moderately successful. New therapies are needed to more effectively relieve this syndrome, not just symptoms.
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PMID:Review article: clinical evidence to support current therapies of irritable bowel syndrome. 1042 40

This article reviews briefly the evidence to support current therapies in irritable bowel syndrome (IBS) and the novel therapeutic approaches on the threshold of clinical application. Fiber is indicated at a dose of at least 12 grams per day in patients with constipation-predominant IBS. Loperamide (and probably other opioid agonists) are of proven benefit in diarrhea-predominant IBS; loperamide may also aid continence by enhancing resting anal tone, but there is no evidence that it results in pain relief. In general, smooth muscle relaxants are best used sparingly, on an as-needed basis, because their overall efficacy is unclear. The 5-HT3 antagonist, alosetron, results in adequate relief of pain and improvements in bowel function in female nonconstipated patients with IBS. Psychotropic agents are important in relieving depression and are of proven benefit for pain and diarrhea in patients with depression associated with IBS. Further trials with selective serotonin reuptake inhibitors are awaited. Psychological treatments including hypnotherapy are less widely available but may play an important role in the relief of pain. In summary, current therapies targeted on the predominant symptoms in IBS are moderately successful. As the bowel sensorimotor and limbic system disturbances of IBS are more clearly understood, we should anticipate other pharmacologic approaches in the near future, including alpha-adrenergic agonists and 5-HT4 agonists. New therapies directed at treatment of the syndrome, rather than relief of symptoms, are needed.
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PMID:Therapeutic approach to the patient with irritable bowel syndrome. 1058 70

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.
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PMID:Loperamide inhibits tachykinin NK3-receptor-triggered serotonin release without affecting NK2-receptor-triggered serotonin release from guinea pig colonic mucosa. 1594 25

Loperamide (LOP) is a peripherally acting opioid receptor agonist used for the management of chronic diarrhea through the reduction of gut motility. The lack of central opioid effects is partly due to the efflux activity of the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier. The protease inhibitors are substrates for P-gp and have the potential to cause increased LOP levels in the brain. Because protease inhibitors, including tipranavir (TPV), are often associated with diarrhea, they are commonly used in combination with LOP. The level of respiratory depression, the level of pupil constriction, the pharmacokinetics, and the safety of LOP alone compared with those of LOP-ritonavir (RTV), LOP-TPV, and LOP-TPV-RTV were evaluated in a randomized, open-label, parallel-group study with 24 healthy human immunodeficiency virus type 1-negative adults. Respiratory depression was assessed by determination of the ventilatory response to carbon dioxide. Tipranavir-containing regimens (LOP-TPV and LOP-TPV-RTV) caused decreases in the area under the concentration-time curve from time zero to infinity for LOP (51% and 63% decreases, respectively) and its metabolite (72% and 77% decreases, respectively), whereas RTV caused increases in the levels of exposure of LOP (121% increase) and its metabolite (44% increase). In vitro and in vivo data suggest that TPV is a substrate for and an inducer of P-gp activity. The respiratory response to LOP in combination with TPV and/or RTV was not different from that to LOP alone. There was no evidence that LOP had opioid effects in the central nervous system, as measured indirectly by CO2 response curves and pupillary response in the presence of TPV and/or RTV.
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PMID:Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers. 1630 51

P-glycoprotein is considered to be a major factor impeding effective drug therapy for many diseases of the central nervous system (CNS). Thus, efforts are being made to gain a better understanding of P-glycoprotein's role in drug distribution to brain parenchyma and cerebrospinal fluid (CSF). The goal of this study was to validate and introduce a novel P-glycoprotein-deficient (ABCB1-1Delta) canine model for studying P-glycoprotein-mediated effects of drug distribution to brain tissue and CSF. CSF concentrations of drug are often used to correlate efficacy of CNS drug therapy as a surrogate for determining drug concentration in brain tissue. A secondary goal of this study was to investigate the validity of using CSF concentrations of P-glycoprotein substrates to predict brain tissue concentrations. Loperamide, an opioid that is excluded from the brain by P-glycoprotein, was used to confirm a P-glycoprotein-null phenotype in the dog model. ABCB1-1Delta dogs experienced CNS depression following loperamide administration, whereas ABCB1 wild-type dogs experienced no CNS depression. In summary, we have validated a novel P-glycoprotein-deficient canine model and have used the model to investigate transport of the P-glycoprotein substrate (99m)Tc-sestamibi at the blood-brain barrier and blood-CSF barrier.
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PMID:P-glycoprotein contributes to the blood-brain, but not blood-cerebrospinal fluid, barrier in a spontaneous canine p-glycoprotein knockout model. 1833 85

Opioids like morphine produce antinociception after intrathecal administration. Being hydrophilic in nature, morphine also spreads rostrally which leads to respiratory depression. Loperamide has been reported to produce antinociception after both intracisternal and intrathecal administration. It is also hydrophobic, which could restrict its diffusion in the spinal canal. However, the mechanism of its antinociceptive action after intrathecal administration is not definitely known. In the present study, the antinociceptive effect of loperamide was evaluated by the formalin test. It significantly inhibited Phase II flinching behavior. This antinociceptive effect was reversed by pre-administration of naloxone indicating that it was predominantly due to activation of opioid receptors.
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PMID:Spinal antinociceptive action of loperamide is mediated by opioid receptors in the formalin test in rats. 1897 91

Thirty-three Collies (14 male and 19 female) were used in a dose-escalation study to determine the impact of ABCB1 genotype on loperamide pharmacokinetics (PK) and pharmacodynamics (PD). Loperamide was orally administered in four ascending doses (0.01, 0.05, 0.1, or 0.2 mg/kg) over a 4-wk period to fasted Collies. Comparisons were made within each dose to genotype, phenotype, and whether Collies received three (3D) or four (4D) loperamide doses. The 3D and 4D groupings had statistically significant differences in systemic drug exposure (defined by the area under the concentration-versus-time profile estimated from time zero to the last quantifiable drug concentration, AUC0-last). In contrast, statistical differences in AUC0-last only occurred in the comparison between wild-type (WT) Collies versus homozygous mutant (Mut) Collies administered 0.1 mg/kg. Statistical differences in the proportionality relationship were observed when comparing 3D to 4D Collies, and the WT to Mut Collies. Intersubject variability in drug exposure tended to be twice as high between Mut and WT Collies. Associations were observed between systemic drug exposure and ataxia or depression but not between systemic drug exposure and mydriasis or salivation. Thus, Collies expressing the greatest sensitivity to CNS-associated effects of loperamide (Mut) tended to have higher drug exposure compared with those less sensitive to the adverse effects of loperamide. Genotype and phenotype only partially explained differences in loperamide PK and PD, suggesting this relationship may not be straightforward and that other factors need to be considered. Accordingly, the PD and PK of one P-glycoprotein substrate only partially predicted the likelihood of adverse responses to unrelated substrates.
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PMID:Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study. 2615 74

Loperamide, a common over-the-counter antidiarrheal drug and opioid derivative, is formulated to act upon intestinal opioid receptors. However, at high doses, loperamide crosses the blood-brain barrier and reaches central opioid receptors in the brain, leading to central opiate effects including euphoria and respiratory depression. We report the case of a young man found dead in his residence with a known history of drug abuse. At autopsy, the only significant findings were a distended bladder and bloody oral purge. Drug screening found nontoxic levels of alprazolam, fluoxetine, and marijuana metabolites. Liquid chromatography time-of-flight mass spectrometry found an unusual set of split isotope peaks consistent with chlorine. On the basis of autopsy and toxicological findings, loperamide toxicity was suspected because of its opioid properties and molecular formula containing chlorine. A sample of loperamide was analyzed by liquid chromatography time-of-flight mass spectrometry, resulting in a matching mass and retention time to the decedent's sample. Subsequently, quantitative testing detected 63 ng/mL of loperamide or more than 6 times of therapeutic peak concentration. Cause of death was determined as "toxic effects of loperamide with fluoxetine and alprazolam." Because of its opioid effects and easy accessibility, loperamide is known as "poor man's methadone" and may go undetected at medical and forensic drug screening.
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PMID:Poor Man's Methadone: A Case Report of Loperamide Toxicity. 2635 52


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