Use of autologous fibrin glue in the treatment of splenic trauma: an experimental study.

There is little doubt that preserving the spleen will contribute to a much more favourable outcome in patients undergoing splenic surgery, as a result of avoiding the well known risks of splenectomy. Among many operative methods described for splenic salvage, application of autologous fibrin glue (AFG) is particularly promising because of its unique characteristics. The use of AFG has been evaluated and its efficacy and tissue compatibility assessed in the treatment of splenic trauma in 15 partially splenectomized New Zealand White rabbits. The application of the AFG to the resected splenic surface achieved complete haemostasis in all animals. The animals were divided into four groups and were killed at varying intervals ranging from 24 h to 10 weeks. During re-exploration there was no evidence of recurrent bleeding and histopathological examination revealed progressive absorption of the AFG with a minimal inflammatory response. It is concluded that AFG is an effective haemostatic agent with good systemic and local compatibility and can be used in splenic salvage, which thereby avoids the use of non-autologous products with their risks of disease transmission.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.