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.     

Injection drug use among street-involved youth in a Canadian setting

Background  

Street-involved youth contend with an array of health and social challenges, including elevated rates of blood-borne infections and mortality. In addition, there has been growing concern regarding high-risk drug use among street-involved youth, in particular injection drug use. We undertook this study to examine the prevalence of injection drug use and associated risks among street-involved youth in Vancouver, Canada.     

Improving surveillance of intimate partner violence by use of multiple data sources

BACKGROUND: Intimate partner violence (IPV) is a significant public health problem in the United States. Estimates of incidence and prevalence vary widely, depending on the data source used. Combining information from different sources can enhance our understanding of IPV. METHODS: In this paper, we used 1998 data from the Rhode Island (RI) Department of Health Violence Against Women Public Health Surveillance System to describe the prevalence of IPV reported to police, the demographic characteristics and help-seeking efforts of women reporting IPV, and characteristics of IPV incidents. We used data from the 1998 RI Department of Health Behavioral Risk Factor Surveillance System survey to examine associations between health care use and health outcomes of victims and nonvictims of IPV, and to explore the correlates of IPV. We also discuss the use of both narrow and broad definitions of IPV. RESULTS: Our findings show that the definition of IPV and the source used to identify IPV victims can produce a markedly different picture of IPV victims, and that combining information from different data sources can enhance our understanding of IPV. An important finding for health care providers is that IPV victims do not appear to be significantly different from nonvictims in their access to and utilization of routine health care, and that more than 60% of victims at highest risk for injury reported seeing a health care provider because of IPV. CONCLUSIONS: Our findings underscore the importance of health care providers addressing IPV and its consequences among their patients.     

石杉碱甲类似物的研究Ⅲ．N－甲基吡啶酮石杉碱甲类似物的合成

石杉碱甲（１）是从中草药石杉属植物千层塔（ＬｙｃｏｐｏｄｉｕｍｓｅｒｒａｔｕｍＴｈｕｎｂ．）中分得的一种高效可逆的乙酰胆碱酯酶抑制剂，临床试验证实它对早老性痴呆症有显著疗效。本文报道Ｎ－甲基吡啶酮石杉碱甲类似物２和３的合成。２－甲氧基－５－甲氧羰基－１１－亚甲基－５，９－甲撑环辛－７－烯并吡啶（９）在乙腈中用三甲基氯硅烷和碘化钠选择性脱保护以定量的产率得吡啶酮１０，再用甲醇钠和碘甲烷甲基化得Ｎ－甲基吡啶酮１１，１１经碱性水解，Ｃｕｒｔｉｕｓ重排和氨基的脱保护得Ｎ－甲基吡啶酮石杉碱甲类似物２。通过类似的途径从中间体２－甲氧基－５－甲氧羰基－７－甲基－１１－酮－５，９－甲撑环辛－７－烯并吡啶（１４）合成了类似物３。类似物２和３的乙酰胆碱酯酶抑制活性均低于天然石杉碱甲。     

Individual,Social, and Environmental Factors Associated with Initiating Methamphetamine Injection: Implications for Drug Use and HIV Prevention Strategies

The purpose of this study was to determine the incidence and predictors of initiating methamphetamine injection among a cohort of injection drug users (IDU). We conducted a longitudinal analysis of IDU participating in a prospective study between June 2001 and May 2008 in Vancouver, Canada. IDU who had never reported injecting methamphetamine at the study’s commencement were eligible. We used Cox proportional hazards models to identify the predictors of initiating methamphetamine injection. The outcome was time to first report of methamphetamine injection. Time-updated independent variables of interest included sociodemographic characteristics, drug use patterns, and social, economic and environmental factors. Of 1317 eligible individuals, the median age was 39.9 and 522 (39.6%) were female. At the study’s conclusion, 200 (15.2%) participants had initiated injecting methamphetamine (incidence density: 4.3 per 100 person-years). In multivariate analysis, age (adjusted hazard ratio [aHR]: 0.96 per year older, 95%CI: 0.95–0.98), female sex (aHR: 0.58, 95%CI: 0.41–0.82), sexual abuse (aHR: 1.63, 95%CI: 1.18–2.23), using drugs in Vancouver’s drug scene epicentre (aHR: 2.15 95%CI: 1.49–3.10), homelessness (aHR: 1.43, 95%CI: 1.01–2.04), non-injection crack cocaine use (aHR: 2.06, 95%CI: 1.36–3.14), and non-injection methamphetamine use (aHR: 3.69, 95%CI: 2.03–6.70) were associated with initiating methamphetamine injection. We observed a high incidence of methamphetamine initiation, particularly among young IDU, stimulant users, homeless individuals, and those involved in the city’s open drug scene. These data should be useful for the development of a broad set of interventions aimed at reducing initiation into methamphetamine injection among IDU.