ABSTRACT
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 11.7 ng/mL and 50.8 ng/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 5.5 ng/mL and 23.9 ng/mL, respectively. A single-dose, open-label PET study (4-20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [(11)C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [(11)C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30-40 h) 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 1.21 ng/mL, and at doses of greater than 4 mg 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 6.35 ng/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.
Subject(s)
Neurotransmitter Uptake Inhibitors/pharmacology , Neurotransmitter Uptake Inhibitors/pharmacokinetics , Phenyl Ethers/pharmacology , Phenyl Ethers/pharmacokinetics , Piperidines/pharmacology , Piperidines/pharmacokinetics , Adult , Aniline Compounds , Animals , Blood Chemical Analysis , Brain/diagnostic imaging , Brain/drug effects , Brain/metabolism , Half-Life , Humans , Magnetic Resonance Imaging , Male , Models, Biological , Morpholines , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Positron-Emission Tomography , Radiopharmaceuticals , Rats, Sprague-Dawley , Reboxetine , Serotonin Plasma Membrane Transport Proteins/metabolism , Spinal Cord/drug effects , Spinal Cord/metabolism , SulfidesABSTRACT
This paper describes a technical manoeuvre to accommodate an exposed metal implant used in the treatment of a fracture of the tibia within a "turn-over" de-epithelialised fasciocutaneous flap. The need for such a procedure in this particular case is commented upon. A discussion is also included on the nature of the blood supply to the integument based on available information.
