An assessment of two gastric transport models currently used in safety                 pharmacology testing

Baldrick, Paul; Bamford, D. G.; Tattersall, M. L.

doi:10.1177/096032719801700101

Cited by 6 publications

(2 citation statements)

References 20 publications

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“…-Opioid agonists have a well known propensity to reduce GI motility, an effect quantifiable in animal models. The mouse upper GI transit test was conducted to evaluate the effects of JNJ-20788560 as well as -and ␦-opioid reference compounds on the movement of chyme in the mouse small intestine (Nagakura et al, 1996;Baldrick et al, 1998). Thirty minutes after compound dosing, a carmine dye solution was orally administered as a marker.…”

Section: Side Effect Studiesmentioning

confidence: 99%

JNJ-20788560 [9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic Acid Diethylamide], a Selective Delta Opioid Receptor Agonist, Is a Potent and Efficacious Antihyperalgesic Agent That Does Not Produce Respiratory Depression, Pharmacologic Tolerance, or Physical Dependence

Codd

Carson²,

Colburn³

et al. 2009

J Pharmacol Exp Ther

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ABSTRACT-Opioid analgesics are a mainstay in the treatment of acute and chronic pain of multiple origins, but their side effects, such as constipation, respiratory depression, and abuse liability, adversely affect patients. The recent demonstration of the upregulation and membrane targeting of the ␦-opioid receptor (DOR) following inflammation and the consequent enhanced therapeutic effect of ␦-opioid agonists have enlivened the search for ␦-opioid analgesic agents. JNJ-20788560 [9-(8-azabicyclo-[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide] had an affinity of 2.0 nM for DOR (rat brain cortex binding assay) and a naltrindole sensitive DOR potency of 5.6 nM (5Ј-O-(3-[ 35 S]thio)triphosphate assay). The compound had a potency of 7.6 mg/kg p.o. in a rat zymosan radiant heat test and of 13.5 mg/kg p.o. in a rat Complete Freund's adjuvant RH test but was virtually inactive in an uninflamed radiant heat test.In limited studies, tolerance was not observed to the antihyperalgesic or antinociceptive effects of the compound. Unlike ibuprofen, JNJ-20788560 did not produce gastrointestinal (GI) erosion. Although morphine reduced GI motility at all doses tested and reached nearly full effect at the highest dose, JNJ-20788560 did not retard transit at the lowest dose and reached only 11% reduction at the highest dose administered. Unlike morphine, JNJ-20788560 did not exhibit respiratory depression (blood gas analysis), and no withdrawal signs were precipitated by the administration of opioid ( or ␦) antagonists. Coupled with the previously published lack of self-administration behavior of the compound by alfentanil-trained primates, these findings strongly recommend ␦-opioid agonists such as JNJ-20788560 for the relief of inflammatory hyperalgesia.The -opioid receptor (MOR) is the core target of marketed opioid analgesics, but the side effect profile and abuse liability propensity of these compounds impels the search for better and safer analgesic agents. Although the ␦-opioid receptor (DOR) has long been known to mediate at least a modest level of antinociception (Heyman et al., 1986;Rodriguez et al., 1986), recent work on its regulation during inflammation has provided new impetus to its targeting for the relief of inflammatory pain. Under basal conditions, DOR is located predominantly intracellularly, whereas MOR is localized Article, publication date, and citation information can be found at

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Section: Side Effect Studiesmentioning

confidence: 99%

JNJ-20788560 [9-(8-Azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic Acid Diethylamide], a Selective Delta Opioid Receptor Agonist, Is a Potent and Efficacious Antihyperalgesic Agent That Does Not Produce Respiratory Depression, Pharmacologic Tolerance, or Physical Dependence

Codd

Carson²,

Colburn³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…This is accomplished through the pharmacodynamic characterization of the new drug on central (peripheral) nervous (Haggerty 1991;Mattsson et al 1996;Moser 1991;Porsolt et al 2002;Ross et al 1998), cardiovascular (Bunting & Siegl 1994;Lacroix & Provost 2000;Kinter & Johnson 2003), and respiratory (Murphy 1994(Murphy , 2002Sarlo & Clark 1995) systems (safety pharmacology core battery studies), and other major organ systems (supplemental studies; e.g., gastrointestinal Baldrick et al 1998;Kinter 2003;Mojaverian 1996 andrenal, Chiu 1994;Kinter 2003) as appropriate based on concern for human safety.…”

Section: Ib2 Practice Of Safety Pharmacology (Ich S7a)mentioning

confidence: 99%