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.     

Glucagonoma syndrome presenting as psoriasis

Sir, The cutaneous eruption of glucagonoma is described as a distinctclinical entity, but in the early stages of this disease, clinicalsigns may be subtle. We present a patient who presented withpsoriasis and subsequently was diagnosed as having glucagonomasyndrome. A 40-year-old man presented in June 1998 with a year historyof an erythematous scaling seborrhoeic dermatosis, diagnosedclinically and histologically as     

老年人血浆溶血磷脂酸和磷脂酸水平综合干预后的效果比较

目的:通过对老年人进行血浆溶血磷脂酸和磷脂酸的筛检,从而认识血浆溶血磷脂酸和磷脂酸在血栓预防中的作用。方法:对2004-04/07期间的1657名和2005-04/07期间的1748名离休干部进行血浆溶血磷脂酸和磷脂酸含量测定,并对溶血磷脂酸>3.0μmol/L和磷脂酸>5.0μmol/L的阳性人员进行药物干预。同时,选择2004年溶血磷脂酸和/或磷脂酸阳性人员119人,随机分为两组:①干预组(n=72):男63人,女9人,平均年龄78岁。口服阿司匹林100mg/d,持续1个月。②对照组(n=47):男42人,女5人,平均年龄76岁。干预后,测定两组血浆中溶血磷脂酸和磷脂酸的含量。结果:纳入对象全部进入结果分析。2005年磷脂酸及血浆溶血磷脂酸 磷脂酸阳性率均明显低于2004年(P<0.01),尤其是磷脂酸的阳性率降低的更为明显。2005年血浆溶血磷脂酸和磷脂酸的平均值均明显低于2004年(P<0.01)。干预组干预后血浆溶血磷脂酸和磷脂酸明显低于干预前及对照组(P<0.01)。结论:①血浆溶血磷脂酸和磷脂酸的测定可作为血栓预警和了解抗血栓药物疗效的一种手段。②阿司匹林干预后,血浆溶血磷脂酸和磷脂酸的含量均降低,可作为一种降低缺血性疾病发生率的有效途径。