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Pharmacokinetics and behavioral effects of liposomal hydromorphone suitable for perioperative use in rhesus macaques.

ABSTRACT: This study aims to evaluate the pharmacokinetic, behavioral, and motor effects of a liposomal preparation of hydromorphone hydrochloride (LE-hydro) in rhesus monkeys. We administered either 2 mg/kg of LE-hydro (n?=?8) subcutaneous (s.c.) or 0.1 mg/kg of standard pharmaceutical hydromorphone HCl (hydro) preparation either intravenous (i.v.; n?=?4) or s.c. (n?=?5).Serial blood samples were drawn after injection and analyzed for serum hydro concentration by liquid chromatography/mass spectrometry. Following s.c. injection of 0.1 mg/kg hydro or 2 mg/kg LE-hydro, behavioral evaluations were conducted in groups of rhesus monkeys (n?=?10/group) in the presence of a compatible stimulus animal and motor skills were also evaluated (n?=?10/group). The motor skills test consisted of removing a food reward (carrot ring) from either a straight peg (simple task) or a curved peg (difficult task).LE-hydro (MRT(0-INF)?=?105.9 h) demonstrated extended-release pharmacokinetics compared to hydro when administered by either i.v. (MRT(0-INF) =1.1 h) or s.c. (MRT(0-INF) =1.3 h) routes. Hydro did not affect motor performance of the simpler task, but the monkeys' performance deteriorated on the more difficult task at 0.5 and 1 h after injection. LE-hydro had no effect on motor skills in either the simpler or more difficult task.The results of these studies indicate that LE-hydro has a pharmacokinetic and behavioral side effects profile consistent with an analgesic that could be tested for surgical use in animals. Our studies also expand the use of rhesus monkeys as a translational behavioral pharmacodynamics model for testing extended-release opioid medication.

SUBMITTER: Krugner-Higby L

PROVIDER: S-EPMC3142292 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Pharmacokinetics and behavioral effects of liposomal hydromorphone suitable for perioperative use in rhesus macaques.

Krugner-Higby Lisa L KuKanich Butch B Schmidt Brynn B Heath Timothy D TD Brown Carolyn C

Psychopharmacology 20110315 4

<h4>Introduction</h4>This study aims to evaluate the pharmacokinetic, behavioral, and motor effects of a liposomal preparation of hydromorphone hydrochloride (LE-hydro) in rhesus monkeys. We administered either 2 mg/kg of LE-hydro (n = 8) subcutaneous (s.c.) or 0.1 mg/kg of standard pharmaceutical hydromorphone HCl (hydro) preparation either intravenous (i.v.; n = 4) or s.c. (n = 5).<h4>Materials and methods</h4>Serial blood samples were drawn after injection and analyzed for serum hydro concent ...[more]

PMID: 21404039

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Project description:A subset of serotonin (5-HT) pathway polymorphisms has been shown to confer risk for psychological dysfunction, particularly in individuals who experience early adversity. Understanding the developmental processes underlying these Gene x Environment interactions will strengthen the search for risk factors for behavioral dysfunction. We investigated the combined influence of two serotonin pathway polymorphisms and species-atypical, and possibly adverse, rearing (nursery rearing [NR]) on two dimensions of behavioral stress response in infant rhesus macaques. We hypothesized that the experience of NR and possession of both "high-risk" genotypes (genotypes that are thought to confer low 5-HT function) would predict the greatest behavioral stress response to maternal/social separation. Using a matched-pair design, the impact of early experience and the serotonin transporter (rh5-HTTLPR) and monoamine oxidase A (rhMAO-A-LPR) promoter polymorphisms on behavioral reactivity of 136 infant rhesus macaques (90-120 days of age) during a 25-hr social separation/relocation procedure was assessed. Each pair included one infant reared with mother in a large, outdoor field enclosure (field rearing) and one infant reared in a nursery (NR). Pairs were matched for putative gene activity of each polymorphism, sex, age, and weight at testing. Behavioral responses in a "human intruder" test were recorded, and activity and emotional reactivity composites were created to detect different aspects of psychological adaptation to stress. Our hypothesis that high-risk groups would be the most reactive to stress was not entirely borne out. Rh5-HTTLPR x rhMAOA-LPR interactions predicted emotional reactivity and tended to predict behavioral activity scores. Carriers of the two "low-risk" alleles exhibited the lowest behavioral activity, as might be predicted, but carriers of both "high-risk" alleles were two of four genotype groups exhibiting the highest observed Emotional Reactivity. Gene x Gene interactions were exacerbated by the experience of nursery rearing, as predicted, however. Finally, we suggest that genetic or environmental factors may mitigate the risk for behavioral dysregulation illustrated in the patterns of behavioral activity and emotional reactivity displayed by infants.

Dataset Information

Pharmacokinetics and behavioral effects of liposomal hydromorphone suitable for perioperative use in rhesus macaques.

Publications

Pharmacokinetics and behavioral effects of liposomal hydromorphone suitable for perioperative use in rhesus macaques.

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