Pharmacokinetics of hydromorphone hydrochloride in healthy dogs.

OBJECTIVE: To assess the pharmacokinetics of hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. STUDY DESIGN: Randomized experimental trial. ANIMALS: Seven healthy male neutered Beagles aged 12.13 +/- 1.2 months and weighing 11.72 +/- 1.10 kg. METHODS: The study was a randomized Latin square block design. Dogs were randomly assigned to receive hydromorphone hydrochloride 0.1 mg kg(-1) or 0.5 mg kg(-1) IV (n = 4 dogs) or 0.1 mg kg(-1) (n = 6) or 0.5 mg kg(-1) (n = 5) SC on separate occasions with a minimum 14-day washout between experiments. Blood was sampled via a vascular access port at serial intervals after drug administration. Serum was analyzed by mass spectrometry. Pharmacokinetic parameters were determined with computer software. RESULTS: Serum concentrations of hydromorphone decreased quickly after both routes of administration of either dose. The serum half-life, clearance, and volume of distribution after IV hydromorphone at 0.1 mg kg(-1) were 0.57 hours (geometric mean), 106.28 mL minute(-1) kg(-1), and 5.35 L kg(-1), and at 0.5 mg kg(-1) were 1.00 hour, 60.30 mL minute(-1) kg(-1), and 5.23 L kg(-1), respectively. The serum half-life after SC hydromorphone at 0.1 mg kg(-1) and 0.5 mg kg(-1) was 0.66 hours and 1.11 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Hydromorphone has a short half-life, suggesting that frequent dosing intervals are needed. Based on pharmacokinetic parameters calculated in this study, 0.1 mg kg(-1) IV or SC q 2 hours or a constant rate infusion of hydromorphone at 0.03 mg kg(-1) hour(-1) are suggested for future studies to assess the analgesic effect of hydromorphone.

Gender and gonadal status differences in zona reticularis expression in marmoset monkey adrenals: Cytochrome b5 localization with respect to cytochrome P450 17,20-lyase activity.

Neonatal marmosets express an adrenal fetal zone comparable to humans. While adult males fail to express a functional ZR, with barely detectable blood DHEA levels, females produce higher levels of DHEA than males in adulthood. We investigated the presence of a putative functional ZR in adult female marmosets. In contrast to males, immunohistochemical analysis showed the ZR marker cytochrome b5 was elevated in the innermost zone in cycling females (compared to testis-intact males), further elevated in the adrenals from anovulatory females, and substantially elevated and continuous in ovariectomized females. As a functional test in vivo, following overnight dexamethasone treatment, cycling and anovulatory females showed higher levels of DHEA relative to males, but DHEA failed to increase in response to ACTH. In direct contrast, while ovariectomized females exhibited lower initial DHEA levels, clear increases were detectable after ACTH administration (p<0.05), suggesting an adrenal origin. The apparent differences in cytochrome b5 expression between groups were also further verified by Western blotting of adrenal microsomes, and compared to 17,20-lyase activity; the two parameters were positively correlated (p<0.01) across multiple treatment groups. We conclude that the cycling female marmoset expresses a rudimentary ZR with at least a capacity for DHEA production that becomes significantly ACTH-responsive after anovulation. Expression of cytochrome b5 in this region may be directly or indirectly controlled by gonadal function, and is, at least in part, a critical determinant in the development of an adrenal ZR that is more defined and significantly ACTH-responsive.

Social suppression of cortisol in female marmosets: role of luteinizing hormone/chorionic gonadotropin.

Behaviorally subordinate female common marmosets (Callithrix jacchus) undergo suppression of ovulation and chronic reductions in basal plasma cortisol concentrations. Indirect evidence suggests that hypophyseal chorionic gonadotropin (CG; the major pituitary luteinizing gonadotropin in marmosets) may elevate cortisol concentrations in female marmosets, and therefore that social suppression of CG may contribute to diminution of cortisol in subordinates. To test this hypothesis, we determined whether pharmacological inhibition of pituitary CG release decreases basal and adrenocorticotropin (ACTH)-stimulated cortisol secretion. We characterized cortisol and reproductive hormone concentrations in six ovary-intact and six ovariectomized marmosets during long-term treatment with leuprolide acetate, a gonadotropin-releasing hormone (GnRH) agonist, and vehicle. Leuprolide suppressed basal plasma CG concentrations, abolished the CG response to exogenous GnRH, and, in intact animals, blocked ovarian cyclicity. During treatment with vehicle, plasma cortisol concentrations were elevated during the periovulatory phase in intact females, compared to the follicular phase, the luteal phase, and ovariectomized females. Leuprolide suppressed basal cortisol concentrations of intact females as compared to the periovulatory phase, but did not affect basal cortisol in ovariectomized animals and did not alter responses to exogenous ACTH. These findings suggest that elevations in circulating CG concentrations are associated with elevated cortisol concentrations in female marmosets, and that this relationship requires simultaneous increases in ovarian hormones that occur only during the periovulatory period. Thus, suppression of CG release in anovulatory subordinate females may not play an important role in socially induced diminution of cortisol.

Hypoestrogenism does not mediate social suppression of cortisol in subordinate female marmosets.

Behaviorally subordinate female marmosets undergo social suppression of ovulation and hypoestrogenism, as well as chronic reductions in circulating basal cortisol concentrations. Because estrogen elevates hypothalamic-pituitary-adrenal axis activity and circulating glucocorticoid levels in other species, we tested the hypothesis that socially induced hypoestrogenism contributes to cortisol reductions in subordinate female marmosets. We characterized morning basal plasma cortisol levels, as well as cortisol responses to exogenous adrenocorticotropic hormone (ACTH; 0, 1, or 10 microg/kg), in seven anovulatory subordinate females and six ovariectomized, non-subordinate females under two conditions: during long-term treatment with estradiol (E2) and control. Circulating E2 and cortisol levels were compared to those of six dominant females undergoing ovulatory cycles. Basal cortisol concentrations in the control condition were significantly lower in subordinates than in both dominant and ovariectomized females. E2 treatment elevated circulating E2 levels of subordinate and ovariectomized females into the range seen in dominant females but did not increase either mean basal or ACTH-stimulated cortisol levels. To the contrary, E2 treatment caused a decline in basal cortisol levels over time, especially in ovariectomized animals. These results indicate that treatment with exogenous estrogen does not elevate circulating cortisol levels in previously hypoestrogenemic female marmosets and, correspondingly that socially induced hypoestrogenism does not diminish cortisol levels in subordinate females.

Diminished cortisol levels in subordinate female marmosets are associated with altered central drive to the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Female marmosets offer a promising primate model of stress-related hypocortisolism, as they undergo chronic reductions in circulating cortisol after becoming subordinate in a social group. In this study, we treated dominant and subordinate female marmosets with the cortisol synthesis inhibitor metyrapone and corticotropin-releasing factor (CRF) to characterize the effects of subordination on central regulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Seven dominant and six subordinate female marmosets received CRF (6 microg/kg, intravenous [IV]), following pretreatment with metyrapone (75 mg/kg, by mouth [PO]) or water. Plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were determined before metyrapone or water treatment and before, 1 hour after, and 2 hours after CRF treatment. RESULTS: Following metyrapone treatment, subordinates had similar cortisol levels to dominants but significantly higher ACTH levels. During CRF challenges, cortisol concentrations were lower and ACTH concentrations higher in subordinates, although net integrated responses to CRF did not differ. Cortisol-to-ACTH ratios were consistently lower in subordinates. CONCLUSIONS: These results confirm previous findings of low cortisol concentrations and blunted adrenal responsiveness in subordinates and suggest that when differences in cortisol levels are eliminated, subordinates exhibit exaggerated hypothalamic drive to the pituitary. These neuroendocrine alterations in subordinate marmosets resemble those in posttraumatic stress disorder patients and adult survivors of child abuse.