Opiate agonist action of antidiarrheal agents in vitro and in vivo?Findings in support for selective action

Wüster, Michael; Herz, A.

doi:10.1007/bf00507036

Cited by 85 publications

(25 citation statements)

References 16 publications

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“…Loperamide does not produce opiate-like discriminative stimulus effect in rats (Colpaert et al 1975) or subjective effects in humans (Jaffe et al 1980). This lack of CNS effects is presumed to result from pharmacokinetic limitations of loperamide to cross the blood-brain barrier (Wuster and Herz 1978;Niemegeers et al 1979;Yanagita et al 1980).…”

Section: Discussionmentioning

confidence: 98%

“…Evidence that the peripheral effects of loperamide are similar to those of heroin (at these doses) comes from several sources. Loperamide binds to both central and peripheral opioid receptors (Wuster and Herz 1978) and exhibits an opioid-like profile in tissue bioassays (e.g. guinea pig ileum and mouse vas deferens; Gliagnoni et al 1983), antidiarrheal tests (Awouters et al 1993) and antinociceptive tests (Takasuna et al 1994).…”

Section: Discussionmentioning

confidence: 98%

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Smoked heroin self-administration in rhesus monkeys

Mattox

Carroll

1996

Psychopharmacology

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The purpose of the present study was to evaluate behavioral and pharmacological determinants of smoked heroin self-administration. Eight rhesus monkeys were trained to self-administer smoked heroin under a chained fixed-ratio, (FR, 64-1024) for lever presses, FR 5 for inhalations schedule during daily experimental sessions. Demand for heroin was determined by plotting consumption (smoke deliveries) as a function of price which was varied by increasing the FR lever press requirement from 64 to 1024. The heroin demand curve was compared to that obtained with smoked cocaine base. Dose-effect determinations were obtained by varying the unit dose of heroin from 0.025 to 1.6 mg/kg per delivery. Pretreatment with naloxone (0.01-1.0 mg/kg IM, 10 min presession) and substitution tests with the peripherally acting opioid loperamide (0.1 mg/kg per delivery) were also conducted. Deliveries of smoked heroin decreased, but lever responding per delivery increased as the FR increased. Demand for heroin was elastic and comparable to demand for smoked cocaine base. Varying the dose of heroin available for self-administration resulted in an asymptotic dose-effect curve. Naloxone pretreatment produced dose-dependent decreases in heroin self-administration. Substitution of loperamide for heroin produced extinction-like responding within one or two sessions, with the total smoke deliveries decreasing by 80% of heroin levels within 8-15 days. Reinstatement of heroin resulted in a rapid return to baseline levels of self-administration. These data suggest that rhesus monkeys will readily and reliably self-administer heroin via the inhalation route, and behavioral and pharmacological manipulations indicate that smoked heroin functioned as a positive reinforcer.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Smoked heroin self-administration in rhesus monkeys

Mattox

Carroll

1996

Psychopharmacology

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“…The C max of loperamide in healthy volunteers following a single 16-mg dose has been reported as 7.8 to 8.6 nM (Doser et al, 1995;Tayrouz et al, 2001). However, loperamide is also a potent P-glycoprotein substrate (Wandel et al, 2002), and studies in laboratory animals have shown that it accumulates in the small intestine (Wuster and Herz, 1978;Lavrijsen et al, 1995). Therefore, CES2 in the intestinal epithelium may be exposed to a higher and potentially inhibitory concentration of loperamide.…”

Section: Discussionmentioning

confidence: 99%

Hydrolysis of Capecitabine to 5′-Deoxy-5-fluorocytidine by Human Carboxylesterases and Inhibition by Loperamide

Quinney

Sanghani

Davis

et al. 2005

J Pharmacol Exp Ther

163

117

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Capecitabine is an oral prodrug of 5-fluorouracil that is indicated for the treatment of breast and colorectal cancers. A three-step in vivo-targeted activation process requiring carboxylesterases, cytidine deaminase, and thymidine phosphorylase converts capecitabine to 5-fluorouracil. Carboxylesterases hydrolyze capecitabine's carbamate side chain to form 5Ј-deoxy-5-fluorocytidine (5Ј-DFCR). This study examines the steady-state kinetics of recombinant human carboxylesterase isozymes carboxylesterase (CES) 1A1, CES2, and CES3 for hydrolysis of capecitabine with a liquid chromatography/mass spectroscopy assay. Additionally, a spectrophotometric screening assay was utilized to identify drugs that may inhibit carboxylesterase activation of capecitabine. CES1A1 and CES2 hydrolyze capecitabine to a similar extent, with catalytic efficiencies of 14.7 and 12.9 min Ϫ1 mM Ϫ1

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“…The carboxylic acid metabolite is somewhat more potent than the parent drug (as assessed using a rat brain homogenate binding assay), and systemic concentrations of the metabolite are greater than for the parent (Karim et al, 1972). The target of action is the gut, so it cannot be necessarily stated that the metabolite bears the greater role in activity since the effect could be due to local exposures to parent drug upon oral administration (Wüster and Herz, 1978). In a comparison, dosing the metabolite directly to humans showed that five-times less was needed to achieve a constipatory effect the same as the parent ester (Rubens et al, 1972).…”

Section: A Drugs With Active Metabolites That Dominate the Activitymentioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

137

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Opiate agonist action of antidiarrheal agents in vitro and in vivo?Findings in support for selective action

Cited by 85 publications

References 16 publications

Smoked heroin self-administration in rhesus monkeys

Smoked heroin self-administration in rhesus monkeys

Hydrolysis of Capecitabine to 5′-Deoxy-5-fluorocytidine by Human Carboxylesterases and Inhibition by Loperamide

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

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