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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. 相似文献Aims: To estimate naming latencies for the 175 items on the PNT, and assess the utility of psycholinguistic variables and naming latencies for predicting item difficulty.
Methods and Procedures: Using a speeded picture naming task we estimated mean naming latencies for the 175 items of the PNT in 44 cognitively healthy adults. We then re-estimated the model reported by Swiderski et al (2016) with the new naming latency data.
Outcomes and Results: The predictor variables described above accounted for a substantial proportion of the variance in the item difficulty parameters (Adj. R2 = .692).
Conclusions: In this study we demonstrated that word length, age of acquisition, lexical frequency, and naming latency from neurotypical young adults usefully predict picture naming item difficulty in people with aphasia. These variables are readily available or easily obtained and the regression model reported may be useful for estimating confrontation naming item difficulty without the need for collection of response data from large samples of people with aphasia. 相似文献