G.J. Pesman

Safety of glucocorticoids can be improved by lower yet still effective dosages of liposomal steroid formulations in murine antigen-induced arthritis: comparison of prednisolone with budesonide

UNLABELLED The goal of this study was to compare the effects of liposomal and free glucocorticoid formulations on joint inflammation and activity of the hypothalamic-pituitary-adrenal (HPA) axis during experimental antigen-induced arthritis (AIA). A dose of 10mg/kg liposomal prednisolone phosphate (PLP) gave a suppression of the HPA-axis, as measured by plasma corticosterone levels in mice with AIA and in naïve mice. In a subsequent dose-response study, we found that a single dose of 1mg/kg liposomal prednisolone phosphate (PLP) was still equally effective in suppressing joint inflammation as 4 repeated once-daily injections of 10mg/kg free PLP. Moreover, the 1mg/kg liposomal PLP dose gave 22% less suppression of corticosterone levels than 10mg/kg of liposomal PLP at day 14 of the AIA. In order to further optimize liposomal glucocorticoids, we compared liposomal PLP with liposomal budesonide phosphate (BUP) (1mg/kg). At 1 day after treatment, liposomal BUP gave a significantly stronger suppression of joint swelling than liposomal PLP (lip. BUP 98% vs. lip. PLP 79%). Both formulations also gave a strong and lasting suppression of synovial infiltration in equal amounts. However, at day 21 after AIA, liposomal PLP still significantly suppressed corticosterone levels, whereas this suppression was not longer statistically significant for liposomal BUP. CONCLUSION Liposomal delivery improves the safety of glucocorticoids by allowing for lower effective dosing. The safety of liposomal glucocorticoid may be further improved by encapsulating BUP rather than PLP.

Serial plasma concentrations of atrial natriuretic peptide, plasma renin activity, aldosterone, and antidiuretic hormone in neonates on extracorporeal membrane oxygenation.

To obtain information on water and salt regulating hormones and volume homeostasis during neonatal extracorporeal membrane oxygenation (ECMO), serial determinations of atrial natriuretic peptide (ANP), plasma renin activity (PRA), aldosterone (Aldo), antidiuretic hormone (ADH), colloid-osmotic pressure (COP), osmolality (Osmol), and central venous pressure (CVP) before, during, and after neonatal ECMO in 10 neonates with meconium aspiration syndrome (MAS) were carried out. Mean gestational ages and birth weights were 41+3 weeks (39+6 - 42+4) and 4,063 gm (3,500–4700), respectively; mean age at start and duration of ECMO 29.3 (14–69) and 152.6 hr (92–267), respectively. Plasma ANP (mean ± SD) was 67.8 ± 69.1 pmol/L before, decreased to 33.3 ± 22.1 (not significant) pmol/L during, and significantly increased to 274.6 ± 131.8 pmol/L after ECMO (p < 0.05). ANP correlated positively with CVP (r = 0.63;p < 0.001). Pre-ECMO PRA, Aldo, and ADH were comparable to those described earlier in normal neonates, decreased during (p < 0.001 for Aldo;p < 0.05 for PRA and ADH) and either remained elevated (PRA, p < 0.001; Aldo, p < 0.05) or decreased (ADH) after ECMO. COP and Osmol remained unchanged. Neonatal ECMO for MAS is characterized by circulatory and osmotic equilibrium. It is suggested that circulating volume contracts during and expands after neonatal ECMO for MAS.

Dopamine susceptibility of APO-SUS rats is not per se coupled to HPA-axis activity

A synergistic relationship is thought to exist between hypothalamic-pituitary-adrenal (HPA) axis activity and dopamine neurotransmission. To test whether a high response to dopamine indeed implies a hyperactive HPA-axis, we here used Wistar rats that were selected twice independently (original and replicate lines) for a high or low susceptibility to the dopamine receptor agonist apomorphine (so-called APO-SUS and APO-UNSUS rats, respectively). The APO-SUS rats from the original line displayed a hyperactive HPA-axis in that higher basal and stress-induced adrenocorticotropic hormone (ACTH) levels, and lower basal free-corticosterone levels were observed than those found in the original APO-UNSUS rats. In contrast, the activity of the HPA-axis in the APO-SUS rats from the replicate line did not differ from that in the replicate APO-UNSUS rats. Thus, in the APO-SUS/APO-UNSUS rat model the level of HPA-axis activity is not necessarily causally linked to dopamine responsiveness, implying that a hyperactive HPA-axis is not a prerequisite for a high dopaminergic response.

Plasma Concentrations of Atrial Natriuretic Peptide (ANP), Plasma Renin Activity (PRA), Aldosterone (Aldo) and Arginine-Vasopressin (AVP) in Neonates on Extracorporeal Membrane Oxygenation (ECMO)

Plasma Concentrations of Atrial Natriuretic Peptide (ANP), Plasma Renin Activity (PRA), Aldosterone (Aldo) and Arginine-Vasopressin (AVP) in Neonates on Extracorporeal Membrane Oxygenation (ECMO)