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.     

肿瘤干细胞的研究与进展

目的:作为"种子细胞"的肿瘤干细胞对研究肿瘤发生及其临床治疗具有重要意义。总结近年来肿瘤干细胞的研究进展,对肿瘤干细胞的概念、特性及应用进行综述。资料来源:应用计算机检索Medline数据库1980-01/2006-12期间的相关文章,检索词为"cancer stem cells",限定文章语言种类为English。资料选择:对资料进行初审,并查看每篇文献后的引文。纳入标准:肿瘤干细胞的研究进展及临床价值。排除标准:重复研究。资料提炼:共收集到106篇相关文献,30篇文献符合纳入标准,排除的76篇文献为内容陈旧或重复。符合纳入标准的30篇文献中,分别涉及肿瘤干细胞的定义及来源、研究进展、临床治疗价值等内容。资料综合:肿瘤干细胞具有分裂增殖、自我更新以及分化成其他细胞的能力,目前已证实其存在于白血病、乳腺癌、脑癌、前列腺肿瘤等肿瘤组织中。目前的抗肿瘤治疗方法主要针对的是大多数已经分化的肿瘤细胞,而不能影响到肿瘤干细胞,即治标不治本。肿瘤的复发、转移以及耐药等特征都很可能与肿瘤干细胞有关,因此肿瘤治疗的关键应是针对肿瘤干细胞进行灭杀,又要保护正常干细胞,但此两种细胞表型极为相似,故应找到更为特异的靶点。结论:肿瘤干细胞不仅已经从血液系统的恶性肿瘤中成功分离出来,在大量实体瘤中也证实了肿瘤干细胞的存在,其耐药机制之一是表达一种或多种药物运载蛋白,对于肿瘤的发生及治疗提供了更多的思路和方向。     

Surgical revascularization in patients with end-stage renal disease: results using a new paradigm in outcomes assessment

Studies evaluating the outcome of surgical revascularization (SR) for critical limb ischemia in patients who have end-stage renal disease (ESRD) have differed widely in their findings and conclusions. Differences in definitions of success are largely responsible for the varying outcomes. We developed a method of outcomes assessment that incorporates four all-inclusive endpoints to define success. These include primary graft patency to the point of wound healing, postoperative survival of at least 6 months, limb salvage of at least 1 year, and maintenance of ambulatory status of at least 6 months. The purpose of this study was to use this novel method of defining success to determine the outcome of SR in patients with ESRD. From 1998 to 2004, 40 patients (52 limbs) with ESRD and tissue loss underwent SR for limb salvage. Secondary graft patency and limb salvage rates at 36 months were 54.7 per cent and 53 per cent, respectively. When considering each of the four components used to define success separately, success encouragingly ranged between 60 per cent (patent graft until wound healing) and 87.5 per cent (survival for 6 months). However, if all parameters were combined, clinical success was achieved in only 40 per cent (16/40) of patients. Coronary artery disease was the only factor found to significantly reduce success (P = 0.04). In conclusion, using this multiparameter definition of success, which combines four rather modest outcome milestones, favorable outcome occurred in the minority of cases. This study challenges our current method of analyzing success and questions our therapeutic approach to patients with critical limb ischemia and ESRD.     

Contemporary outcomes of iliofemoral bypass grafting for unilateral aortoiliac occlusive disease: a 10-year experience

Current treatment of complex aortoiliac occlusive disease (AIOD) includes the aortobifemoral bypass or the femoral-femoral bypass. However, because of bilateral groin exposure and associated risks, there is a significant morbidity associated with these procedures. In appropriate patients with unilateral AIOD, the iliofemoral bypass graft (IFBPG) via a lower abdominal retroperitoneal incision can be an acceptable alternative. The purpose of this study is to review the safety and efficacy as well as long-term outcomes of IFBPG in patients with unilateral AIOD. From July 1997 through June 2006, 40 patients (64.3 +/- 11.2-years-old, range 41-89-years-old, 57.5% critical limb ischemia, 70% male, 95% smokers) with unilateral AIOD were treated with IFBPG. Perioperative complications and symptom resolution were measured and Kaplan-Meier life table analysis was used to analyze outcomes of primary and secondary patency, survival, limb salvage, contralateral intervention, and maintenance of ambulation and independent living status. The perioperative complication rate was 12.5 per cent (n = 5) including one patient who developed atrial-fibrillation and one who developed acute renal failure. Both patients experienced resolution of these symptoms before discharge. Other complications included one limb thrombosis and two wound infections. There were no perioperative deaths. Secondary patency was 97.5 per cent and 93.3 per cent at 1 and 5 years. Limb salvage in patients with critical limb ischemia (CLI) was 85.1 per cent and 79.1 per cent at 1 and 5 years. Limb amputation occurred due to infection (n = 2), or failed IFBPG (n = 2). Thirty-one patients (77.5%) experienced symptom resolution including 15 (88.2%) of the patients treated for claudication. Two patients (5%) required contralateral iliac intervention. Patient survival was 97.5 per cent and 64.5 per cent at 1 and 5 years. Greater than 90 per cent of patients maintained their functional independence at 5 years. IFBPG achieved excellent technical and functional outcomes, particularly in patients treated for vasculogenic claudication. This procedure is relatively safe and efficacious in a population of patients with complex unilateral AIOD and can be an acceptable alternative to the aortobifemoral bypass or fem-fem procedure.