Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals.

Buprenorphine is absorbed following sublingual administration, which would be a low-stress delivery route in foals. However, the pharmacokinetics/pharmacodynamics are not described in foals. Six healthy foals <21 days of age participated in a blinded, randomized, 3-period, 5-sequence, 3-treatment crossover prospective study. Foals received 0.01-0.02 mg/kg buprenorphine administered SL or IV with an equivalent volume of saline administered by the opposite route. Blood was collected from the cephalic vein for pharmacokinetic analysis. Physiologic parameters (HR, RR, body temperature, GI sounds), locomotion (pedometer), and behavioral data (activity level, nursing time, response to humans) were recorded. Plasma concentration of buprenorphine exceeded a presumed analgesic level (0.6 ng/ml) in five foals in the IV group and one in the SL group but only for a very brief time. Pharmacokinetic analysis following IV administration demonstrated a short elimination half-life (t1/2ß 1.95 ± 0.7 hr), large volume of distribution (6.46 ± 1.54 L/kg), and a high total clearance (55.83 ± 23.75 ml/kg/min), which differs from adult horses. Following SL administration, maximum concentrations reached were 0.61 ± 0.11 ng/ml and bioavailability was 25.1% ± 10.9%. In both groups, there were minor statistical differences in HR, RR, body temperature, locomotion, and time spent nursing. However, these differences were clinically insignificant in this single dose study, and excitement, sedation, or colic did not occur.

Increased intracellular, cell surface, and secreted inducible heat shock protein 70 responses are triggered during the monocyte to dendritic cell (DC) transition by cytokines independently of heat stress and infection and may positively regulate DC growth.

Physiologic triggers and functional consequences of endogenous heat shock protein (HSP) responses in dendritic cells (DC) are poorly defined. In this study, we show that even in the absence of heat stress and infection, a specific cohort of DC/proinflammatory cytokines (IL-4-IL-13/IL-6/GM-CSF) institutes an enhanced inducible (i)HSP70 intracellular and extracellular response in human monocyte-derived DC, especially during the monocyte to DC transition. Interestingly, whereas heat stress alone initiated an intracellular iHSP70 response in monocyte DC precursors, it did not promote cell surface or secreted iHSP70 responses, both of which were induced by cytokines independently of heat. The cytokine-induced iHSP70 response, which did not occur in lymphocytes, or monocytes-macrophages generated with M-CSF, was instituted within 48 h of cytokine exposure, and peaked upon commitment to DC growth at 72 h. Although a return to baseline levels was noted after this period, a distinct rise in iHSP70 occurred again during terminal DC maturation. Chemical inhibition of the iHSP70 response with either triptolide or KNK-437 was coupled with inhibition of DC differentiation and yielded cells displaying features of monocytes-macrophages. Exogenously supplied riHSP70 amplified events associated with cytokine-advanced DC differentiation/maturation, most notably the up-regulation of antiapoptotic proteins (Bcl-x(L)). Engaging the HSP receptor CD40 with CD40L produced identical results as extracellular riHSP70, and, moreover, an enhanced iHSP70 response. Thus, distinct iHSP70 and HSP receptor-mediated responses are triggered by cytokines irrespective of heat stress and infection in monocyte-derived DC and may function to positively regulate monocyte-derived DC, especially during critical periods of their growth.