Impact assessment of tail-vein injection in mice using a modified anaesthesia induction chamber versus a common restrainer without anaesthesia.

Intravenous (IV) administration in mice is predominantly performed via the lateral tail veins. The technique requires adequate training before it can be used safely and routinely. A novel anaesthesia induction chamber has been developed to simplify the treatment and to facilitate IV injection in mice, particularly for untrained personnel. We have assessed the benefits of the chamber in refining IV injection in isoflurane-anaesthetized mice in direct comparison with the common restrainer method on conscious animals. The body weight, nesting behaviour and concentrations of faecal corticosterone metabolites were taken as indicative of distress induced by the various procedures. The results suggest that both methods of tail-vein injection induce similar levels of momentary stress in the animals, revealed by a short-term increase in the levels of stress hormone metabolites in faeces. A temporary reduction of body weight was observed after IV injection under isoflurane anaesthesia but not for conscious mice injected in the common restrainer. We conclude that the severity of tail-vein injection in mice is 'mild' for both methods. There was no evidence that refining the procedure by using isoflurane anaesthesia in the induction chamber was associated with any benefit.

Selective glucocorticoid receptor modulation inhibits cytokine responses in a canine model of mild endotoxemia.

Selective glucocorticoid receptor modulators (GRMs) promise to reduce adverse events of glucocorticoids while maintaining anti-inflammatory potency. The present study tested the anti-inflammatory activity of two novel non-steroidal GRMs (GRM1: BI 607812 BS, GRM2: BI 653048 BS*H3PO4) in comparison to prednisolone in a canine model of low dose endotoxemia. This study compared the anti-inflammatory and pharmacokinetic profile of escalating daily oral doses of GRM1 (1, 2.5, 5 and 10mg/kg) and GRM2 (0.1, 0.25 and 1mg/kg) with prednisolone (0.25 and 0.5mg/kg) and placebo after intravenous infusion of endotoxin (0.1µg/kg) to Beagle dogs. This was followed by a 14-day evaluation study of safety and pharmacokinetics. Endotoxin challenge increased TNF-α ∼2000-fold and interleukin-6 (IL-6) 100-fold. Prednisolone and both GRMs suppressed peak TNF-α and IL-6 by 71-82% as compared with placebo. The highest doses of GRM1 and GRM2 reduced the mean body temperature increase by ∼30%. The endotoxin-induced rise in plasma cortisol was strongly suppressed in all treatment groups. Pharmacokinetics of both GRMs were non-linear. Adverse effects of endotoxemia such as vomiting were mitigated by GRM2 and prednisolone, indicating an antiemetic effect. During the 14-day treatment period, the adverse event profile of both GRMs appeared to be similar to prednisolone. Both GRMs had anti-inflammatory effects comparable to prednisolone and showed good safety profiles. Compounds targeting the glucocorticoid receptor selectively may provide an alternative to traditional glucocorticoids in the treatment of inflammatory disease.