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PubMed1996

Broad spectrum antiemetic effects of CP-122,721, a tachykinin NK1 receptor antagonist, in ferrets.

The potent, selective, tachykinin NK1 receptor antagonist, CP-122,721 ([(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2- phenylpiperidine]), at 0.01-1 mg/kg, s.c. reduced retching and vomiting elicited by loperamide, copper sulfate, ipecac syrup and cisplatin in a dose-dependent manner. ID50 values after subcutaneous administration ranged from 0.02 mg/kg (loperamide) to 0.08 mg/kg (ipecac). Oral CP-122,721 reduced cisplatin-induced emesis with an ID50 of approximately 0.08 mg/kg. The less active (2R, 3R)-enantiomer, CP-132.687, did not significantly suppress retching or vomiting induced by any of the emetogens. These data support the hypothesis that CP-122,721 blocks emesis by a specific action at tachykinin NK1 receptors. Its broad spectrum of antiemetic activity suggests a central site of action.

Animals↗
PubMed1983

The role of opioids in feeding and reward elicited by lateral hypothalamic electrical stimulation.

We have previously shown that feeding induced by electrical stimulation in the lateral hypothalamus of rats is inhibited by naloxone but not its quaternary analogue. In the present study, effects of morphine and loperamide -an opiate that does not pass the blood-brain barrier- were examined. Loperamide inhibited stimulation-induced feeding; reversal of this effect by quaternary naloxone confirmed the peripheral site of action. A low dose of morphine (1.25 mg/kg) facilitated feeding but higher doses were inhibitory. An inhibitory dose of morphine became facilitory, however, when preceded by quaternary naloxone. It therefore appears that central opioid activity promotes ingestive behavior while peripheral activity inhibits ingestion. To evaluate the function served by the central facilitory process, we exploited the relation that exists between feeding and self-stimulation elicited through a common electrode. It was found that potentiation of self-stimulation by food deprivation is blocked by naloxone. It is concluded that endogenous opioid activity may promote feeding by enhancing the reward value of food as a function of hunger.

Animals↗
PubMed1993

Resinferatoxin, an ultrapotent capsaicin analogue, has anti-emetic properties in the ferret.

Resinferatoxin (100 micrograms/kg, s.c.), the ultrapotent analogue of capsaicin, when given acutely blocked radiation-(200 rads) and copper sulphate (40 mg% 30 ml, p.o.)-induced emesis in ferrets and substantially decreased loperamide (0.5 mg/kg, s.c.)-induced vomiting, without significantly affecting the von Bezold-Jarisch reflex or gag reflex. It also produced a decrease in core temperature as has been reported for capsaicin. The observation that resinferatoxin reduced or blocked emesis induced by both centrally (loperamide) and peripherally (CuSO4, radiation) acting stimuli suggests a novel anti-emetic action that may provide an insight into clinically useful innovative anti-emetics. The mechanism by which resinferatoxin has its anti-emetic effect is at present unknown, although the combination of results from the present study suggest a central site of action involving modulation of release of neurotransmitter, possibly in the nucleus tractus solitarius.

Animals↗
PubMed1989

Central vs. peripheral mediation of opioid effects on alcohol consumption in free-feeding rats.

Although there is considerable evidence that pretreatment with low doses of opioid agonists can enhance, and opioid antagonists can reduce alcohol consumption in rats, little is known about the locus or mechanism of these effects. As a first approximation as to where the effect may occur, we compared the effects of an opioid agonist morphine (1, 3 and 10 mg/kg) and antagonist naltrexone (1, 3 and 10 mg/kg) that are known to act within the brain as well as the periphery, to those of an agonist-like drug loperamide (0.3, 1 and 3 mg/kg) and an antagonist methylnaltrexone (3, 10 and 30 mg/kg) that are known to act peripherally only. Free-feeding rats were initially trained to drink alcohol using a limited access paradigm, and when animals were drinking asymptotic amounts of 12% (w/v) alcohol, increasing doses of one of the four drugs or saline were administered IP to separate groups of rats 30 min prior to the hour-long daily drinking session. The results confirmed that the effects of the opioids on alcohol consumption are indeed mediated within the central nervous system in that morphine enhanced alcohol consumption but loperamide did not, naltrexone reduced alcohol consumption but methylnaltrexone did not, and naltrexone was able to block the morphine effect but methylnaltrexone failed to do so. An unexpected finding was that methylnaltrexone alone also increased alcohol consumption. Possible means by which this could occur, also supporting the idea of a central locus for the effect, as well as possible mechanisms by which opioids could influence alcohol consumption generally, are discussed.

Alcohol Drinking↗
PubMedDate not supplied

Salt formation in solid dispersions consisting of polyacrylic acid as a carrier and three basic model compounds resulting in very high glass transition temperatures and constant dissolution properties upon storage.

The purpose of the study was to investigate the suitability of polyacrylic acid (PAA) as a carrier in solid dispersions, with the aim to delay crystallization of basic drugs and improve their dissolution behaviour. The physicochemical properties were investigated in order to link the physical state of some model compounds to their dissolution properties. Loperamide and two structurally related substances were selected as model compounds. Solid dispersions were prepared by spray drying. The amount of residual solvents and water was determined with gas chromatography (GCS: S: solvent) and thermogravimetric analysis (TGA). The drug loading of the dispersions was determined using high performance liquid chromatography (HPLC). ADSC (alternating or temperature modulated DSC), XRD and FT-IR-spectroscopy were used to evaluate the physical state and in vitro dissolution tests were performed to measure the dissolution properties. IR-measurements demonstrated the formation of a salt between the COOH-groups of the polymer and the amino-groups of the compounds. This phenomenon results in high T(g)-values of the dispersions, suppression of crystallization of the fragment molecules during preparation and an increase of the dissolution rate. Furthermore, the stability study conducted on the dispersions with loperamide showed that both, the amorphous state of the drug and the dissolution behaviour are stable under the applied storage conditions. Hence, from the experimental results it could be concluded that PAA is a suitable carrier in the formulation of stable solid dispersions for the basic compounds that were investigated.

Acrylic Resins↗
PubMed2006

Effect of opioid mu-receptors activation on insulin signals damaged by tumor necrosis factor alpha in myoblast C2C12 cells.

In an attempt to develop a new target for handling of insulin resistance, we investigated the effect of opioid mu-receptor activation on insulin signals in differentiated myoblast C2C12 cells damaged by tumor necrosis factor-alpha (TNFalpha). A marked reduction of insulin-stimulated radioactive 2-deoxyglucose (2-DG) uptake was observed in TNFalpha (10 ng/ml for 1 h)-treated cells. Loperamide (10 micromol/l for 24 h) reversed the inhibition of insulin-stimulated 2-DG uptake by TNFalpha in a manner sensitive to blockade of opioid mu-receptors. Insulin signals damaged by TNFalpha were the impaired expressions of insulin receptor (IR), tyrosine autophosphorylation in IR, and insulin receptor substrate (IRS)-1 protein, as well as a decrease of IRS-1 tyrosine phosphorylation. Also, the signaling defects including an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and Akt serine phosphorylation were observed. Loperamide (10 micromol/l for 24 h) reversed the TNFalpha-induced decrement of insulin signals at same concentration used to raise glucose uptake. In conclusion, activation of opioid mu-receptors may reverse the insulin signals damaged by inflammatory cytokine.

Animals↗
PubMedDate not supplied

Effects of fasting on evaluation of gastrointestinal transit with charcoal meal.

INTRODUCTION: At the present time, most studies investigating gastrointestinal transit time with charcoal are conducted in fasted rats. It seems reasonable to hypothesize that the fasting state of rats could influence the effect a compound had on gastrointestinal transit time. The purpose of this study was to investigate the effects of food on the pharmacological effects on gastrointestinal transit. METHODS: For each drug investigated, two sets of 32 male Sprague-Dawley rats were used. One set was studied after being fasted for approximately 6 h, the second set was studied after free access to food. Each set had 4 groups of animals (n=8/group) that were administered different doses, allowing the assessment of the drug effect after fasting and after free access to food. Animals were administered 0, 10, 25, and 75 mg/kg of morphine; 0, 10, 20, and 40 mg/kg loperamide, or 0, 0.05, 0.5, and 3.0 mg/kg clonidine. At predetermined times, an activated charcoal suspension was administered by oral gavage. Thirty minutes after receiving the charcoal meal, rats were euthanized and the small intestine was removed. The length of the small intestine and the distance traveled by the charcoal were recorded. For each animal, gastrointestinal transit was calculated as the percentage of the distance traveled relative to the total length of the small intestine. RESULTS: Baseline (vehicle dosed animals) gastrointestinal transit was significantly greater in fasted versus fed rats. In fasted rats, morphine did not have a significant effect on transit. In fed rats, 25 and 75 mg/kg morphine caused a significant decrease in transit. In fed and fasted rats, 0.5 and 3 mg/kg clonidine caused a significant decrease in transit. Loperamide did not affect gastrointestinal transit in fed or fasted rats at doses up to 40 mg/kg. DISCUSSION: These data demonstrate that food does not reduce the sensitivity of the gastrointestinal transit time.

Animals↗
PubMed2006

Investigation on the relationship between cannabinoid CB1 and opioid receptors in gastrointestinal motility in mice.

1. This study investigated whether (a) cannabinoid CB(1) receptor knockout (CB(1)(-/-)) mice displayed altered gastrointestinal transit and (b) cannabinoid CB(1) and opioid receptors functionally interact in the regulation of gastrointestinal transit. 2. Gastrointestinal transit was assessed by the Whole Gastrointestinal Transit, measuring the excretion time of an intragastrically administered marker (whole intestine), and the Upper Gastrointestinal Transit, measuring the distance covered by the marker in the small intestine. 3. CB(1)(-/-) and homozygous CB(1)(+/+) (CB(1)(+/+)) mice did not differ in both whole gut and small intestine transit. CB(1)(-/-) and CB(1)(+/+) mice were equally responsive to the inhibitory effect of morphine (10 mg kg(-1)) and loperamide (3 mg kg(-1)) on whole gut transit.4. Additionally, in CD1 mice the cannabinoid CB(1) receptor antagonist, rimonabant (0-0.5 mg kg(-1)), failed to block the inhibitory effect of morphine (0-1.25 mg kg(-1)) and loperamide (0-0.5 mg kg(-1)) on transit in small and whole intestine. Similarly, the opioid receptor antagonists, naloxone (0-1 mg kg(-1)) and naltrexone (0-10 mg kg(-1)), failed to block the inhibitory effect of the cannabinoid WIN 55,212-2 (0-3 mg kg(-1)) on transit in small and whole intestine.5. These results suggest that (a) compensatory mechanisms likely developed in CB(1)(-/-) mice to overcome the lack of inhibitory function of endocannabinoid system; (b) cannabinoid and opioid receptor systems did not interact in regulating gastrointestinal transit in mice.

Animals↗
PubMed2000

Campylobacter jejuni-induced severe colitis--a rare cause of toxic megacolon.

The development of toxic megacolon as a sequel of infectious colitis is rare. We have observed the very rare case of a campylobacter jejuni-induced toxic megacolon. A 28-year-old man was admitted with severe enterocolitis and appearance of blood in stools. He had been treated with loperamide without success. Two days after admission stool cultures revealed campylobacter jejuni and then an oral antibiotic therapy was started. On the fifth day clinical performance deteriorated again with development of toxic megacolon and consecutive subtotal colectomy. Rectoscopy before discharge after 13 days showed a normal mucosa. The unusual course with first improvement and then rapid deterioration despite adequate therapy was observed in 4 other cases, which may also be a hint of ensuing megacolon. Even in usually harmless enterocolitis like campylobacter infection, predisposing factors such as loperamide are known to precipitate toxic megacolon and should be considered in clinical practice.

Adult↗
PubMed1985

Absorption of starch by healthy ileostomates: effect of transit time and of carbohydrate load.

Recently, breath hydrogen studies and intubation techniques have indicated that in excess of 10% of starch in normal foods may be malabsorbed in the small intestine and enter the colon. We evaluated starch absorption in healthy subjects with ileostomy. First, unabsorbed starch was quantified in ileostomy effluent from six ileostomates who ingested constant diets of wheat and potato starch for four days. Daily unabsorbed starch ranged from 1.3% to 5.0% of total ingested starch. Second, starch from a radiolabeled solid meal containing 50 g potato starch was measured under control conditions and after altering transit time with either loperamide, or magnesium citrate. Loperamide significantly decreased the amount of unabsorbed starch in all six ileostomates (p less than 0.05), while magnesium citrate significantly increased starch malabsorption in all six subjects (p less than 0.05). Third, starch absorption was measured after single solid meals containing 25, 50, 75, and 100 g potato starch. There was a linear relationship between starch input and output. Mean output expressed as a percent of input remained constant. We conclude that the degree of starch malabsorption by the small intestine of ileostomates may be less than that estimated by indirect methods in intact humans. The amount of unabsorbed starch is directly related to the quantity ingested and to the small intestinal transit time.

Adult↗
PubMed2003

Peripheral opioids act as analgesics in bone cancer pain in mice.

Previous reports have shown that systemic administration of morphine can prevent the thermal hyperalgesia induced by the development of an osteosarcoma in C3H/HeJ mice after the implantation of NCTC 2472 cells. We show here that this type of hyperalgesia is also abolished by the local administration of morphine given at low doses (10 nmol), or the peripheral acting opioid receptor agonist loperamide (146 nmol). The analgesic effect of loperamide is prevented by the administration of the opioid receptor antagonist naloxone methiodide (10 mg/kg, i.p.), which is unable to cross the blood-brain barrier. These results provide evidence which supports the fact that peripheral opioids could be useful tools in the management of some types of cancer pain.

Analgesics, Opioid↗
PubMed1985

Evaluation of gastrointestinal motility using the hydrogen breath test.

The purpose of the study was to evaluate the validity of a model where intestinal transit is increased and decreased by motility modifying drugs. The measurement of breath hydrogen concentrations after ingestion of lactulose was used to estimate small intestinal transit time. After obtaining base-line values, eight healthy volunteers were pretreated on separate occasions with loperamide, diphenoxylate, metoclopramide and cisapride. Diphenoxylate caused a significant increase in small bowel transit time, whereas both metoclopramide and cisapride significantly shortened it. The H2 breath test therefore seems to accurately reflect the expected transit time. Loperamide did not alter significantly intestinal transit. Possibly this drug counteracts its own delaying influence on small bowel transit by hurrying gastric emptying. Alternatively, not enough time was allowed for it to exert its full effect.

Adult↗
PubMed1986

Effects of amitraz, several opiate derivatives and anticholinergic agents on intestinal transit in ponies.

Amitraz, atropine, glycopyrrolate and morphine (but not its derivatives, meperidine [pethidine], oxymorphone and butorphanol) produced similar effects on clinically observed intestinal functions and significantly prolonged intestinal transit, as assessed with polyethylene glycol (PEG). However, their mechanisms of action, particularly on intestinal transport (fluid movement), may differ widely. Loperamide appeared to exert a preferential action on intestinal transport rather than motility, as there was no significant delay in PEG transit. The action of amitraz in perturbing smooth muscle coordination and enhancing absorption involved, at least partially, an alpha 2 adrenergic component susceptible to yohimbine. Naloxone, an opiate antagonist, did not influence amitraz responses but induced the return of intestinal sounds and defecation after a refractory period in morphine-dosed ponies. The results suggest potential clinical applications in horses for loperamide in diarrhoea therapy, for alpha 2 adrenergic antagonists in obstruction and ileus and, possibly, of amitraz-like agents in reducing fluid losses in diarrhoea.

Animals↗
PubMed1993

Do antidiarrhoeal opiates accumulate in the rat intestinal lumen?

The opiate antidiarrhoeal drugs loperamide (0.6 mg kg-1, i.p.) or difenoxin (0.77 mg kg-1, s.c.), were administered in an anaesthetic mixture (pentobarbitone 60 mg kg-1) to rats. A length of jejunum (approx. 30 cm) was cannulated, washed and then perfused with iso-osmotic saline for 20 min. The perfusion commenced 50 min after drug administration and continued for 20 min. The perfusates were collected for analysis of fluid transport rates and antidiarrhoeal drug content. These doses of the antidiarrhoeals caused marked inhibition of intestinal fluid secretion induced by intra-arterial infusion of vasoactive intestinal peptide. However, neither of the antidiarrhoeal drugs were detected in the intestinal perfusates (< 0.5 ng by HPLC). The results indicate that loperamide and difenoxin have a different pharmacokinetic profile compared with that previously found for morphine under the same conditions.

Absorption↗
PubMed1995

The peristaltic reflex in the rat ileum: evidence for functional mu- and delta-opiate receptors.

The potency order of opiate agonists at decreasing the rate of peristalsis in the rat isolated ileum was: difenoxin > loperamide > DADLE (D-Ala2-D-Leu5-enkephalin) > morphine > DSLET (D-Ser2,Leu5-Thr6-enkephalin). U-50488 (trans 3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl) cyclohexyl) benzeneacetamide methane sulphonate) was inactive at 300 nM. Naloxone (400 nM) caused a significant 1.52-fold increase in the rate of peristaltic contractions and inhibited the effects of the active opiate agonists. The apparent pA2 values of naloxone were similar using difenoxin, loperamide and morphine as agonists, but the value was slightly, though significantly lower when DADLE was the agonist. It is suggested that the previously identified delta-opiate receptors of the rat small intestine have a functional role in suppressing the peristaltic reflex. The same response is subserved by mu-opiate receptors and either of these opiate-receptor subtypes could be activated by endogenous enkephalins.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2004

Nociceptive sensitivity and opioid antinociception and antihyperalgesia in Freund's adjuvant-induced arthritic male and female rats.

The present study was designed to examine sex differences in complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia and sex differences in opioid antinociception and anti-hyperalgesia. Female rats developed inflammation and hyperalgesia faster and exhibited greater peak hyperalgesia than male rats. In arthritic (CFA-treated) rats, lower thresholds were observed during estrus and proestrus, and in nonarthritic (vehicle-treated) rats, lower thresholds were observed during proestrus. Morphine and oxycodone were more potent in male than female arthritic rats, and butorphanol was more potent and effective in male than female arthritic rats. The potency of morphine was increased in arthritic rats, although to a greater magnitude in males. The potency of oxycodone was increased in male but not female arthritic rats. The potency of butorphanol was increased in arthritic male rats and the maximal antinociceptive effect of butorphanol was increased in arthritic female rats, but it did not result in greater than 20% antinociception. Morphine, oxycodone, and butorphanol all produced antihyperalgesic effects (returning thresholds of arthritic rats to the thresholds of nonarthritic rats) with greater potency in males than females. The peripherally acting opioid agonist loperamide produced intermediate levels of antinociception in male and female arthritic rats and no antinociception in nonarthritic rats. Loperamide was more potent in male than female arthritic rats at producing antihyperalgesia. These data demonstrate sex differences in arthritis-induced hyperalgesia and responsiveness to opioid analgesics. In arthritic rats, the antinociceptive effects of opioid agonists are most probably mediated by both central and peripheral opioid receptors, whereas their antihyperalgesic effects are mediated primarily by actions at peripheral opioid receptors.

Analgesics, Opioid↗
PubMed2006

Covalent linkage of apolipoprotein e to albumin nanoparticles strongly enhances drug transport into the brain.

Drug delivery to the brain is becoming more and more important but is severely restricted by the blood-brain barrier. Nanoparticles coated with polysorbates have previously been shown to enable the transport of several drugs across the blood-brain barrier, which under normal circumstances is impermeable to these compounds. Apolipoprotein E was suggested to mediate this drug transport across the blood-brain barrier. In the present study, apolipoprotein E was coupled by chemical methods to nanoparticles made of human serum albumin (HSA-NP). Loperamide, which does not cross the blood-brain barrier but exerts antinociceptive effects after direct injection into the brain, was used as model drug. Apolipoprotein E was chemically bound via linkers to loperamide-loaded HSA-NP. This preparation induced antinociceptive effects in the tail-flick test in ICR mice after i.v. injection. In contrast, nanoparticles linked to apolipoprotein E variants that do not recognize lipoprotein receptors failed to induce these effects. These results indicate that apolipoprotein E attached to the surface of nanoparticles facilitates transport of drugs across the blood-brain barrier, probably after interaction with lipoprotein receptors on the brain capillary endothelial cell membranes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Sodium channel blockers and uridine triphosphate: effects on nasal potential difference in cystic fibrosis mice.

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.

Amiloride↗