BACKGROUND & AIMS: :Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT6R) antagonists resulted in identification of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (5al, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HT6R (Ki = 2.04 nM) and selectivity over 100 target sites which include receptors, enzymes, peptides, growth factors, ion channels, steroids, immunological factors, second messengers, and prostaglandins. It has high selectivity over 5-HT2A receptor. It is orally bioavailable and brain penetrant with robust preclinical efficacy. The combination of 5al, donepezil, and memantine (triple combination) produces synergistic effects in extracellular levels of acetylcholine in the ventral hippocampus. Preclinical efficacy in triple combination and high selectivity over 5-HT2A receptors are the differentiating features which culminated in selection of 5al for further development. The Phase-1 evaluation of safety and pharmacokinetics has been completed, allowing for the initiation of a Phase-2 proof of concept study.

背景与目标： ：新型的3-（哌嗪基甲基）吲哚衍生物作为5-羟基色胺-6受体（5-HT6R）拮抗剂的优化导致1-[（（2-溴苯基）磺酰基] -5-甲氧基-3-[（ 4-甲基-1-哌嗪基）甲基] -1H-吲哚二甲酸酯一水合物（5al，SUVN-502）作为潜在治疗认知障碍的临床候选药物。它对人5-HT6R具有高亲和力（Ki = 2.04 nM），对100个靶位具有选择性，这些靶位包括受体，酶，肽，生长因子，离子通道，类固醇，免疫学因子，第二信使和前列腺素。它对5-HT2A受体具有很高的选择性。它具有口服生物利用度和脑渗透性，并具有强大的临床前功效。 5al，多奈哌齐和美金刚的组合（三联组合）在腹侧海马中的细胞外乙酰胆碱水平上产生协同作用。三联组合的临床前功效和对5-HT2A受体的高选择性是区别特征，最终决定了5al的进一步开发。安全性和药代动力学的第一阶段评估已经完成，从而可以启动第二阶段概念验证研究。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:Attention deficits are often among the most persistent and debilitating impairments resulting from traumatic brain injury (TBI). This study examined the effects of lisdexamfetamine dimesylate (Vyvanse) in treating attention deficits due to moderate-to-severe TBI. It was the first study of lisdexamfetamine dimesylate with this population and, in fact, was the first controlled trial in this area examining a stimulant medication option other than methylphenidate. METHODS:This was a 12-week, randomized, double-blind, placebo-controlled, cross-over trial. A total of 22 rigorously selected cases were enrolled, 13 of whom completed the trial. They were 16-42 years of age and had newly acquired attention deficits persisting for 6-34 months post-injury. They were assessed on a broad range of neuropsychological and behavioural measures at baseline, 6-weeks and at 12-weeks. RESULTS AND CONCLUSIONS:Positive treatment effects were found involving selective measures of sustained attention, working memory, response speed stability and endurance and in aspects of executive functioning. No major problems with safety or tolerability were observed. Some moderating treatment effects were found from a broad range of pre-treatment subject characteristics and injury variables examined. Avenues for further research and treatment applications in this area are discussed.

背景与目标： 背景与目的：注意缺陷通常是由外伤性脑损伤（TBI）引起的最持久和使人衰弱的障碍之一。这项研究检查了赖氨酸安非他明二甲磺酸盐（Vyvanse）在治疗中度至重度TBI引起的注意力缺陷中的作用。这是该人群中赖斯氨苯丙胺二甲磺酸酯的首次研究，事实上，这是该领域中第一个研究了除哌醋甲酯以外的刺激性药物选择的对照试验。
方法：这是一项为期12周的随机，双盲，安慰剂对照，交叉试验。共有22个经过严格筛选的病例入选，其中13个完成了试验。他们的年龄为16-42岁，并且刚获得新的注意力缺陷，受伤后持续6-34个月。在基线，6周和12周时对他们进行了广泛的神经心理学和行为学评估。
结果与结论：发现积极的治疗效果涉及持续关注，工作记忆，反应速度稳定性和耐力以及执行功能方面的选择性测量。没有观察到安全性或耐受性方面的重大问题。从广泛的治疗前受试者特征和所检查的损伤变量中发现了一些适度的治疗效果。讨论了在该领域进一步研究和治疗应用的途径。

BACKGROUND & AIMS: OBJECTIVE:To evaluate stimulant medication on symptoms and functioning for college students with ADHD using double-blind, placebo-controlled, crossover design. METHOD:Participants included 24 college students with ADHD and 26 college students without psychopathology. Lisdexamfetamine dimesylate (LDX) was examined for ADHD participants over five weekly phases (no-drug baseline, placebo, 30-, 50-, and 70-mg LDX per day). Self-report rating scales of functioning and direct assessment of ADHD symptoms, verbal learning/memory, and adverse side effects were collected (baseline only for control students). RESULTS:LDX was associated with large reductions in ADHD symptoms and improvement in executive functioning along with smaller effects for psychosocial functioning. Reduction in ADHD symptoms was found for 86.4% of participants; however, large differences in symptoms and executive functioning remained relative to controls. CONCLUSION:LDX is a safe, efficacious treatment for symptom relief in college students with ADHD. Research documenting medication effects on academic functioning and evaluating psychosocial/educational interventions is needed.

背景与目标： 目的：使用双盲，安慰剂对照，交叉设计评估兴奋性药物对多动症大学生的症状和功能的影响。
方法：参与者包括24名患有ADHD的大学生和26名无精神病理学的大学生。在五个星期的阶段（无药物基线，安慰剂，每天30、50和70 mg LDX）检查了AD参与者中的Lsdexamfetamine dimesylate（LDX）。收集自我功能的评估量表，并直接评估ADHD症状，言语学习/记忆和不良副作用（仅针对对照学生作为基线）。
结果：LDX与ADHD症状的大量减轻和执行功能的改善以及对心理社会功能的影响较小有关。发现86.4％的参与者的ADHD症状有所减轻；但是，与对照组相比，症状和执行功能仍存在较大差异。
结论：LDX是一种治疗ADHD大学生症状的安全，有效的方法。需要研究记录药物对学术功能的影响并评估社会心理/教育干预措施。

BACKGROUND & AIMS: :To assess the safety and pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, this double-blind study enrolled adults with clinically stable schizophrenia who were adherent (≥12 weeks) to antipsychotic pharmacotherapy. The participants received placebo or ascending LDX doses (50, 70, 100, 150, 200, and 250 mg) daily for 5 days at each dose (dose periods, 1-6; days, 1-5). Of the 31 enrolled participants, 27 completed the study (placebo, n = 6; LDX, n = 21). Treatment-emergent adverse events (AEs) were reported by 4 participants receiving placebo and by 23 participants receiving LDX (all doses) with no serious AEs while on active treatment. For all periods, the mean postdose change on day 5 (up to 12 hours postdose) in systolic and diastolic blood pressure and pulse, respectively, ranged from -4.62 to 8.05 mm Hg, -3.67 to 4.43 mm Hg, and -3.57 to 14.43 beats per minute for placebo and -3.83 to 11.25 mm Hg, -1.55 to 5.80 mm Hg, and -0.36 to 21.26 beats per minute for LDX. With ascending LDX dose, the mean (SD) maximum plasma concentration for LDX-derived d-amphetamine ranged from 51.68 (10.28) to 266.27 (56.55) ng/mL. The area under the plasma concentration-time curve for 24 hours ranged from 801.8 (170.2) to 4397.9 (1085.9) ng[BULLET OPERATOR]h/mL. The d-amphetamine maximum plasma concentration and area under the plasma concentration-time curve increased linearly with ascending LDX dose. Antipsychotic agents did not markedly affect d-amphetamine pharmacokinetics. Over a wide range of ascending doses, LDX safety profile in adults with schizophrenia was consistent with previous findings with no unexpected treatment-emergent AEs. Pulse tended to increase with LDX dose; overall, blood pressure did not increase with LDX dose. Consistent with previous studies, pharmacokinetic parameters increased linearly with increasing LDX dose.

背景与目标： ：为评估d-苯异丙胺前药赖氨苯丙胺二甲磺酸酯（LDX）的安全性和药代动力学，该双盲研究招募了坚持抗精神病药物疗法（≥12周）且临床稳定的精神分裂症患者。参与者每天接受安慰剂或递增剂量的LDX（50、70、100、150、200和250 mg），每种剂量持续5天（剂量周期为1-6；第1-5天）。在31名参与者中，有27名完成了研究（安慰剂，n = 6； LDX，n = 21）。在接受积极治疗时，有4名接受安慰剂的受试者和23名接受LDX（所有剂量）的受试者报告了治疗紧急不良事件（AE）。在所有期间，第5天（给药后最多12小时）的平均给药后收缩压和舒张压和脉搏变化范围为-4.62至8.05 mm Hg，-3.67至4.43 mm Hg和-3.57至14.43对于安慰剂，每分钟搏动为-3.83至11.25毫米汞柱，对于-1.55至5.80毫米汞柱，对于LDX为-0.36至21.26每分钟搏动。随着LDX剂量的增加，源自LDX的d-苯异丙胺的平均（SD）最大血浆浓度范围为51.68（10.28）至266.27（56.55）ng / mL。 24小时血浆浓度-时间曲线下的面积范围为801.8（170.2）至4397.9（1085.9）ng [BULLET OPERATOR] h / mL。 d-苯丙胺最大血浆浓度和血浆浓度-时间曲线下的面积随LDX剂量的增加而线性增加。抗精神病药对d-苯异丙胺的药代动力学没有明显影响。在广泛的剂量范围内，成人精神分裂症的LDX安全性与以前的发现一致，没有意外的治疗紧急事件。脉搏随LDX剂量的增加而增加；总体而言，血压并未随LDX剂量而增加。与以前的研究一致，药代动力学参数随LDX剂量的增加而线性增加。

BACKGROUND & AIMS: PURPOSE:Young adults with ADHD have been shown to be at increased risk for impairment in driving behaviors. Although stimulant medications have proven efficacy in reducing ADHD symptomatology, there is limited knowledge as to their effects on driving behavior. The focus of this report is on assessing the impact of lisdexamfetamine dimesylate (LDX) on driving behaviors in young adults with ADHD using a validated driving behavior questionnaire. METHODS:This assessment was carried out in the context of a randomized, double-blind, 6-week, placebo-controlled, parallel-design study of LDX versus placebo. Subjects were 61 outpatients of both sexes, 18-26 years of age, who met Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for ADHD. Subjects were randomized to receive LDX or placebo for 6 weeks. Driving behavior was assessed at baseline and at the end of treatment using a U.S. version of the Manchester Driving Behavior Questionnaire (DBQ). RESULTS:Highly significant improvements were documented on LDX, over placebo, in driving behaviors assessed through the DBQ in measures of driving errors, driving lapses, and a trend toward fewer driving violations. There were no meaningful associations between these DBQ results and previously documented changes in a laboratory driving simulation paradigm or with improvement in symptoms of ADHD assessed through the ADHD rating scale. CONCLUSIONS:LDX treatment was associated with significant improvements in self-reported driving behaviors that were independent of improvement in symptoms of ADHD. These results suggest that LDX may reduce behaviors associated with driving risks in young adults with ADHD.

背景与目标： 目的：已证明患有多动症的年轻成年人驾驶行为受损的风险增加。尽管刺激性药物已被证明能有效减轻ADHD症状，但对其驾驶行为的影响知之甚少。本报告的重点是使用经过验证的驾驶行为调查表评估赖氨苯丙胺二甲磺酸酯（LDX）对患有ADHD的年轻成年人的驾驶行为的影响。
方法：本评估是在LDX与安慰剂进行的随机，双盲，6周，安慰剂对照，平行设计研究的背景下进行的。受试者为61名年龄在18-26岁之间的男女门诊患者，均符合《精神障碍诊断和统计手册》（第四版）中关于多动症的标准。受试者随机接受LDX或安慰剂治疗6周。使用美国版的曼彻斯特驾驶行为问卷（DBQ）在基线和治疗结束时评估驾驶行为。
结果：与安慰剂相比，LDX记录了通过DBQ评估的驾驶行为（衡量驾驶错误，驾驶失误以及减少驾驶违规的趋势）的显着改善。这些DBQ结果与先前记录的实验室驾驶模拟范式变化或通过ADHD评分量表评估的ADHD症状改善之间没有有意义的关联。
结论：LDX治疗与自我报告的驾驶行为显着改善有关，而自我报告的驾驶行为与ADHD症状的改善无关。这些结果表明，LDX可以减少与多动症年轻成年人驾驶风险相关的行为。

BACKGROUND & AIMS: BACKGROUND:Amphetamine analogs have been demonstrated to have some efficacy in reducing use in cocaine dependent individuals. However, these agents also have potential for abuse. Lisdexamfetamine (LDX), a lysine+dextroamphetamine formulation, has been approved for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and as a prodrug, has less abuse potential. OBJECTIVE:This pilot study sought to evaluate the safety, tolerability, and efficacy of LDX as a candidate treatment for cocaine dependence. METHODS:A randomized, double-blind, placebo-controlled parallel group study served to evaluate LDX in 43 cocaine-dependent individuals: (1) placebo (PBO; 0mg, n=21), (2) LDX (70mg, n=22). Participants received medication for 14 weeks. Cocaine use was determined based on urine analysis for benzoylecgonine (BE; a cocaine metabolite). RESULTS:Retention rates were higher though not significantly different in the PBO (71.4%) than the LDX condition (57.1%). Compared to those in the PBO condition, those receiving LDX were more likely to report experiencing (ps<0.05) diarrhea (45.5% vs. 14.3%), headaches (45.5% vs. 9.5%), and anxiety (31.8% vs. 4.8%). No differences in medication conditions were observed for blood pressure, heart rate, or body weight. In the randomized sample, no differences in cocaine use were seen. Those receiving LDX reported significantly less craving for cocaine than participants receiving PBO. CONCLUSIONS:LDX did not significantly reduce cocaine use compared to PBO in the randomized sample.

背景与目标： 背景：苯丙胺类似物已被证明在减少可卡因依赖者的使用方面具有一定功效。但是，这些代理也有可能被滥用。赖氨酸右苯丙胺制剂Lisdexamfetamine（LDX）已被批准用于治疗注意力缺陷/多动症（ADHD），并且作为前药，滥用潜力较小。
目的：本试验研究旨在评估LDX作为可卡因依赖治疗的候选药物的安全性，耐受性和疗效。
方法：一项随机，双盲，安慰剂对照的平行组研究用于评估43位可卡因依赖者的LDX：（1）安慰剂（PBO; 0mg，n = 21），（2）LDX（70mg，n = 22） ）。参与者接受了14周的药物治疗。根据尿液中苯甲酰芽子碱（BE；可卡因代谢物）的分析确定可卡因的使用。
结果：PBO的保留率更高（71.4％），与LDX的保留率（57.1％）没有显着差异。与PBO情况相比，接受LDX的人更容易出现腹泻（ps <0.05）（45.5％比14.3％），头痛（45.5％比9.5％）和焦虑症（31.8％比4.8）。 ％）。血压，心率或体重在用药条件上未见差异。在随机样本中，可卡因的使用没有差异。与接受PBO的参与者相比，接受LDX的人对可卡因的渴望显着减少。
结论：与PBO相比，随机样本中LDX并未显着减少可卡因的使用。

BACKGROUND & AIMS: OBJECTIVES:The purpose of this study was to assess long-term improvement in quality of life (QOL) in adolescents with attention-deficit/hyperactivity disorder (ADHD) treated with lisdexamfetamine dimesylate (LDX). METHODS:Adolescents with ADHD treated for ≥3 weeks in a 4 week, placebo-controlled study entered a 1 year, open-label study. After the 4 week dose optimization (30, 50, and 70 mg/day LDX) period, treatment was maintained for 48 additional weeks. Change from baseline (of prior study) to week 52/early termination (ET) (of open-label study) in ADHD Rating Scale IV (ADHD-RS-IV) assessed effectiveness, and the Youth QOL-Research Version (YQOL-R) assessed participant-perceived QOL. Post-hoc analyses described effectiveness and QOL for participants with self-perceived poor QOL at baseline (≥1 SD below the mean) versus all others, and for study completers versus study noncompleters. RESULTS:These post-hoc analyses included 265 participants. Participants with baseline self-perceived poor QOL (n=32) versus all others (n=232) exhibited robust YQOL-R perceptual score changes (improvement) with LDX, emerging by week 28 and maintained to week 52/ET. Week 52/ET mean change score ranged from +9.8 to +17.6 for participants with baseline self-perceived poor QOL and +0.4 to +5.1 for all others; week 52/ET improvements in ADHD-RS-IV total scores were similar, regardless of baseline YQOL-R total score. At week 52/ET, study completers had greater YQOL-R improvements than did noncompleters; ADHD-RS-IV total score changes were also numerically larger at week 52/ET for completers than for noncompleters. CONCLUSION:Participant-perceived QOL and ADHD symptoms improved from baseline with LDX in adolescents with ADHD; greatest improvements occurred among participants with baseline self-perceived poor QOL.

背景与目标： 目的：本研究的目的是评估使用赖氨苯丙胺二甲磺酸酯（LDX）治疗的患有注意力缺陷/多动症（ADHD）的青少年的生活质量（QOL）的长期改善。
方法：在4周的安慰剂对照研究中，接受ADHD治疗的青少年≥3周进入了为期1年的开放标签研究。经过4周的剂量优化（30、50和70μmg/天LDX /天）后，治疗又维持了48周。从ADHD评分量表IV（ADHD-RS-IV）评估的有效性和青年QOL研究版本（YQOL-R）从基线（先前研究）到第52周/（开放标签研究）提前终止（ET）的变化）评估参与者感知的QOL。事后分析描述了基线时自我感知的QOL差（均值低于1 SD）与所有其他参与者，研究完成者与研究未完成者的有效性和QOL。
结果：这些事后分析包括265名参与者。基线自我感觉较差的QOL（n = 32）与其他所有参与者（n = 232）的受试者在LDX上表现出强劲的YQOL-R感知得分变化（改善），在第28周时出现并维持至52 / ET周。基线自我感觉较差的QOL的参与者在52周/ ET的平均变化评分范围从9.8到17.6，其他所有参与者的平均变化得分在0.4到5.1之间；不管基线YQOL-R总得分如何，第52周/ ET在ADHD-RS-IV总得分中的改善都是相似的。在第52周/东部时间，研究完成者的YQOL-R改善比未完成者大。在52 / ET周，ADHD-RS-IV总成绩的变化也比未完成者大。
结论：与ADX青少年相比，LDX改善了参与者感知的QOL和ADHD症状；基线自我感觉较差的生活质量的参与者中最大的改善发生了。

BACKGROUND & AIMS: BACKGROUND:Despite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD. METHODS:In a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an "optimal" LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission. RESULTS:Four hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits. CONCLUSION:In the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months. TRIAL REGISTRATION:Clinical Trial Numbers: NCT00334880 and NCT01070394CLINICAL TRIAL REGISTRY: clinicaltrials.gov.

背景与目标： 背景：尽管总体上对药物疗法的反应程度很高，但在治疗患有注意力不足/多动症（ADHD）的成人时如何判断临床反应或确定最佳治疗/缓解方面尚无共识。这项研究在2项多动症成人AD的赖氨苯丙胺二甲磺酸盐（LDX）的分析中检查了临床反应和症状缓解。
方法：在一项为期4周的双盲，强制剂量试验中，ADHD成人被随机分为LDX 30、50和70 mg / d（mg / d）或安慰剂。在第二项开放标签的后续试验中，将为期4周的研究的成年人调整为“最佳” LDX剂量（30 mg / d [n = 44]，50 mg / d [n = 112]）。和70毫克/天[n = 171]），持续4周，并再维持11个月。具有成人提示的ADHD评分量表IV（ADHD-RS-IV）和临床总体印象改善（CGI-I）量表评估了疗效。事后的临床反应定义为：ADHD-RS-IV和CGI-I分级为1或2较基线降低≥30％；症状缓解定义为ADHD-RS-IV总分≤18。对数秩分析及时检查了治疗组对应答或缓解的总体意义。
结果：4周研究中有414名参与者，开放标签扩展研究中有345名参与者被纳入疗效人群。在两项研究中，所有LDX组的ADHD-RS-IV和CGI-I得分均得到改善。在为期4周的研究中（n = 414），LDX（所有剂量）缓解率达69.3％，缓解率达45.5％。安慰剂缓解率为37.1％，缓解率为16.1％；中位临床反应（所有LDX剂量）的治疗时间（95％CI）为15.0（15.0，17.0）天，缓解时间为31.0（28.0，37.0）天（总体P <0.0001）。在开放标签研究中，采用LDX（所有剂量），在327位具有可评估的维持阶段数据的受试者中，分别有313名（95.7％）和278名（85.0％）达到了缓解和缓解的标准。在为期12个月的研究中，完成剂量优化的参与者中，仍有75.2％的患者有反应，而65.7％的患者仍处于缓解状态。总体上，在345位参与者中，有285位（82.6％）和227位（65.8％）在他们的最终访问中分别是响应者和缓解者。
结论：在长期研究中，通过开放标签，剂量优化的LDX治疗，大多数患有ADHD的成年人均达到了临床反应和/或症状缓解。在剩余的11个月中，几乎三分之二的患者保持了症状缓解。
试验注册：临床试验编号：NCT00334880和NCT01070394临床试验注册：clinicaltrials.gov。

BACKGROUND & AIMS: :Young adults with Attention Deficit Hyperactivity Disorder (ADHD) have been shown to be at increased risk for impairment in driving behaviors. While stimulant medications have proven efficacy in reducing ADHD symptomatology, there is limited knowledge as to their effects on driving impairment. The main aim of this study was to assess the impact of lisdexamfetamine dimesylate (LDX) on driving performance in young adults with ADHD using a validated driving simulation paradigm. This was a randomized, double-blind, 6-week, placebo-controlled, parallel-design study of LDX vs. a placebo on driving performance in a validated driving simulation paradigm. Subjects were sixty-one outpatients of both sexes, 18-26 years of age, who met DSM-IV criteria for ADHD. Subjects were randomized to receive LDX or placebo after a baseline driving simulation and completed a second driving simulation six weeks after beginning drug or placebo. Examination of reaction time across five surprise events at post-treatment showed a significant positive effect of medication status. LDX treatment was also associated with significantly fewer accidents vs. placebo. LDX treatment was associated with significantly faster reaction times and a lower rate of simulated driving collisions than placebo. These results suggest that LDX may reduce driving risks in young adults with ADHD.

背景与目标： ：患有注意力缺陷多动障碍（ADHD）的年轻人已显示出驾驶行为受损的风险增加。虽然兴奋剂已被证明能有效减少ADHD症状，但对其对驾驶障碍的影响知之甚少。这项研究的主要目的是使用经过验证的驾驶模拟范例来评估赖氨苯丙胺二甲磺酸酯（LDX）对ADHD年轻人的驾驶性能的影响。这是LDX与安慰剂在一项经过验证的驾驶模拟范例中进行的一项随机，双盲，为期6周，安慰剂对照，并行设计的研究。受试者为六十一名年龄在18-26岁之间的男女门诊患者，均符合DSM-IV的ADHD标准。在基线驾驶模拟后将受试者随机接受LDX或安慰剂，并在开始药物或安慰剂治疗六周后完成第二次驾驶模拟。治疗后五个意外事件中反应时间的检查显示出药物状态的显着积极影响。与安慰剂相比，LDX治疗还减少了事故。与安慰剂相比，LDX治疗与显着更快的反应时间和更低的模拟驾驶碰撞率相关。这些结果表明，LDX可以降低患有ADHD的年轻人的驾驶风险。

BACKGROUND & AIMS: :The purpose of this work was to assess the pharmacokinetics and safety of lisdexamfetamine dimesylate (LDX) delivered and released regionally in the gastrointestinal (GI) tract. In this open-label, randomized, crossover study, oral capsules and InteliSite delivery capsules containing LDX (50 mg) with radioactive marker were delivered to the proximal small bowel (PSB), distal SB (DSB), and ascending colon (AC) during separate periods. Gamma scintigraphy evaluated regional delivery and GI transit. LDX and d-amphetamine in blood were measured postdose (≤72 h). Treatment-emergent adverse events (TEAEs) were assessed. Healthy males (n = 18; 18-48 years) were enrolled. Mean (S.D.) maximal plasma concentration (C(max)) was 37.6 (4.54), 40.5 (4.95), 38.7 (6.46), and 25.7 (9.07) ng/ml; area under the concentration-time curve to the last measurable time point was 719.1 (157.05), 771.2 (152.88), 752.4 (163.38), and 574.3 (220.65) ng · h · ml⁻¹, respectively, for d-amphetamine after oral, PSB, DSB, and AC delivery of LDX. Median time to C(max) was 5, 4, 5, and 8 h, respectively. Most TEAEs were mild to moderate. No clinically meaningful changes were observed (laboratory, physical examination, or electrocardiogram). LDX oral administration or targeted delivery to small intestine had similar d-amphetamine systemic exposure, indicating good absorption, and had reduced absorption after colonic delivery. The safety profile was consistent with other LDX studies.

背景与目标： ：这项工作的目的是评估在胃肠道（GI）区域局部递送和释放的赖氨苯丙胺二甲磺酸酯（LDX）的药代动力学和安全性。在这项开放标签，随机，交叉研究中，口服胶囊和包含带有放射性标记物的LDX（50毫克）的InteliSite递送胶囊在治疗期间被递送至近端小肠（PSB），远端SB（DSB）和升结肠（AC）分开的时期。伽玛闪烁显像术评估了区域传递和胃肠道过境。用药后（≤72小时）测量血液中的LDX和d-苯异丙胺。评估治疗紧急不良事件（TEAE）。纳入健康男性（n = 18； 18-48岁）。平均（S.D.）最大血浆浓度（C（max））为37.6（4.54），40.5（4.95），38.7（6.46）和25.7（9.07）ng / ml;口服后d-苯异丙胺的浓度-时间曲线下到最后一个可测量时间点的面积分别为719.1（157.05），771.2（152.88），752.4（163.38）和574.3（220.65）ng·h·ml -1。 ，PSB，DSB和LDX的AC交付。 C（max）的中位时间分别为5、4、5和8 h。多数TEAE为轻度至中度。没有观察到具有临床意义的变化（实验室检查，体格检查或心电图检查）。口服LDX或靶向小肠给药具有相似的d-苯异丙胺全身暴露，表明其吸收良好，并且在结肠给药后吸收降低。安全性与其他LDX研究一致。

BACKGROUND & AIMS: :p38α mitogen-activated protein kinase (MAPK) is activated in cancer cells in response to environmental factors, oncogenic stress, radiation, and chemotherapy. p38α MAPK phosphorylates a number of substrates, including MAPKAP-K2 (MK2), and regulates the production of cytokines in the tumor microenvironment, such as TNF-α, interleukin-1β (IL-1β), IL-6, and CXCL8 (IL-8). p38α MAPK is highly expressed in human cancers and may play a role in tumor growth, invasion, metastasis, and drug resistance. LY2228820 dimesylate (hereafter LY2228820), a trisubstituted imidazole derivative, is a potent and selective, ATP-competitive inhibitor of the α- and β-isoforms of p38 MAPK in vitro (IC(50) = 5.3 and 3.2 nmol/L, respectively). In cell-based assays, LY2228820 potently and selectively inhibited phosphorylation of MK2 (Thr334) in anisomycin-stimulated HeLa cells (at 9.8 nmol/L by Western blot analysis) and anisomycin-induced mouse RAW264.7 macrophages (IC(50) = 35.3 nmol/L) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc ≤ 10 μmol/L. LY2228820 also reduced TNF-α secretion by lipopolysaccharide/IFN-γ-stimulated macrophages (IC(50) = 6.3 nmol/L). In mice transplanted with B16-F10 melanoma, tumor phospho-MK2 (p-MK2) was inhibited by LY2228820 in a dose-dependent manner [threshold effective dose (TED)(70) = 11.2 mg/kg]. Significant target inhibition (>40% reduction in p-MK2) was maintained for 4 to 8 hours following a single 10 mg/kg oral dose. LY2228820 produced significant tumor growth delay in multiple in vivo cancer models (melanoma, non-small cell lung cancer, ovarian, glioma, myeloma, breast). In summary, LY2228820 is a p38 MAPK inhibitor, which has been optimized for potency, selectivity, drug-like properties (such as oral bioavailability), and efficacy in animal models of human cancer.

背景与目标： ：p38α丝裂原激活蛋白激酶（MAPK）在癌细胞中被激活，以响应环境因素，致癌性应激，放射和化学疗法。 p38αMAPK磷酸化许多底物，包括MAPKAP-K2（MK2），并调节肿瘤微环境中细胞因子的产生，例如TNF-α，白介素-1β（IL-1β），IL-6和CXCL8（IL -8）。 p38αMAPK在人类癌症中高表达，并可能在肿瘤生长，侵袭，转移和耐药性中发挥作用。 LY2228820二甲磺酸酯（以下称LY2228820）是三取代的咪唑衍生物，是体外有效的p38 MAPKα和β亚型的ATP竞争性抑制剂（IC（50）分别为5.3和3.2 nmol / L） 。在基于细胞的分析中，LY2228820有效地和选择性地抑制了由茴香霉素刺激的HeLa细胞（蛋白印迹分析为9.8 nmol / L）和由茴香霉素诱导的小鼠RAW264.7巨噬细胞（IC（50）= 35.3）中MK2（Thr334）的磷酸化（nmol / L），但p38αMAPK，JNK，ERK1 / 2，c-Jun，ATF2或c-Myc≤10μmol/ L的磷酸化没有变化。 LY2228820还通过脂多糖/IFN-γ刺激的巨噬细胞（IC（50）= 6.3 nmol / L）减少了TNF-α的分泌。在移植有B16-F10黑色素瘤的小鼠中，LY2228820以剂量依赖性方式抑制肿瘤磷酸化MK2（p-MK2）[阈值有效剂量（TED）（70）= 11.2 mg / kg]。单次口服10 mg / kg剂量后，显着抑制靶标（p-MK2降低40％以上）。 LY2228820在多种体内癌症模型（黑色素瘤，非小细胞肺癌，卵巢癌，神经胶质瘤，骨髓瘤，乳腺癌）中产生了显着的肿瘤生长延迟。总之，LY2228820是一种p38 MAPK抑制剂，已针对人类癌症动物模型的效价，选择性，类药物特性（例如口服生物利用度）和功效进行了优化。

BACKGROUND & AIMS: BACKGROUND:There are few approved therapies for adults with attention-deficit/hyperactivity disorder (ADHD) in Europe. Lisdexamfetamine (LDX) is an effective treatment for ADHD; however, no clinical trials examining the efficacy of LDX specifically in European adults have been conducted. Therefore, to estimate the efficacy of LDX in European adults we performed a meta-regression of existing clinical data. METHODS:A systematic review identified US- and Europe-based randomized efficacy trials of LDX, atomoxetine (ATX), or osmotic-release oral system methylphenidate (OROS-MPH) in children/adolescents and adults. A meta-regression model was then fitted to the published/calculated effect sizes (Cohen's d) using medication, geographical location, and age group as predictors. The LDX effect size in European adults was extrapolated from the fitted model. Sensitivity analyses performed included using adult-only studies and adding studies with placebo designs other than a standard pill-placebo design. RESULTS:Twenty-two of 2832 identified articles met inclusion criteria. The model-estimated effect size of LDX for European adults was 1.070 (95% confidence interval: 0.738, 1.401), larger than the 0.8 threshold for large effect sizes. The overall model fit was adequate (80%) and stable in the sensitivity analyses. CONCLUSION:This model predicts that LDX may have a large treatment effect size in European adults with ADHD.

背景与目标： 背景：在欧洲，针对成人注意力不足/多动障碍（ADHD）的成人认可的疗法很少。 Lisdexamfetamine（LDX）是治疗ADHD的有效方法；但是，尚未进行过专门研究LDX在欧洲成人中的疗效的临床试验。因此，为了评估LDX在欧洲成人中的疗效，我们对现有临床数据进行了荟萃回归。
方法：系统评价确定了基于美国和欧洲的LDX，阿托西汀（ATX）或渗透释放口服哌醋甲酯（OROS-MPH）在儿童/青少年和成人中的随机疗效试验。然后使用药物，地理位置和年龄组作为预测因子，将荟萃回归模型拟合到已发布/计算出的效应量（Cohen d）。欧洲成年人的LDX效应大小是从拟合模型中推算出来的。进行的敏感性分析包括仅使用成人的研究，以及使用标准药丸-安慰剂设计以外的安慰剂设计进行的研究。
结果：2832篇已鉴定文章中有22篇符合纳入标准。欧洲成年人LDX的模型估计效应大小为1.070（95％置信区间：0.738、1.401），大于大效应大小的0.8阈值。总体模型拟合良好（80％），灵敏度分析稳定。
结论：该模型预测LDX在欧洲成人ADHD中可能具有较大的治疗效果。

BACKGROUND & AIMS: OBJECTIVE:This study examined the time course of efficacy-related endpoints for lisdexamfetamine dimesylate (LDX) versus placebo in adults with protocol-defined moderate to severe binge-eating disorder (BED). METHODS:In two 12-week, double-blind, placebo-controlled studies, adults meeting DSM-IV-TR BED criteria were randomized 1:1 to receive placebo or dose-optimized LDX (50 or 70 mg). Analyses across visits used mixed-effects models for repeated measures (binge eating days/week, binge eating episodes/week, Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [Y-BOCS-BE] scores, percentage body weight change) and chi-square tests (Clinical Global Impressions-Improvement [CGI-I; from the perspective of BED symptoms] scale dichotomized as improved or not improved). These analyses were not part of the prespecified testing strategy, so reported p values are nominal (unadjusted and descriptive only). RESULTS:Least squares mean treatment differences for change from baseline in both studies favored LDX over placebo (all nominal p values <  .001) starting at Week 1 for binge eating days/week, binge-eating episodes/week, and percentage weight change and at the first posttreatment assessment (Week 4) for Y-BOCS-BE total and domain scores. On the CGI-I, more participants on LDX than placebo were categorized as improved starting at Week 1 in both studies (both nominal p values <  .001). Across these efficacy-related endpoints, the superiority of LDX over placebo was maintained at each posttreatment assessment in both studies (all nominal p values <  .001). DISCUSSION:In adults with BED, LDX treatment appeared to be associated with improvement on efficacy measures as early as 1 week, which was maintained throughout the 12-week studies.

背景与目标： 目的：本研究探讨了方案定义为中度至重度暴饮暴食症（BED）的成年人中，赖氨酸安非他明二甲磺酸盐（LDX）与安慰剂的疗效相关终点的时程。
方法：在两项为期12周，双盲，安慰剂对照的研究中，将符合DSM-IV-TR BED标准的成年人按1：1随机接受安慰剂或剂量优化的LDX（50或70 mg）。两次访问之间的分析使用混合效果模型进行重复测量（暴饮暴食天/周，暴饮暴食发作/周，针对暴饮暴食[Y-BOCS-BE]评分修改的耶鲁-布朗强迫症量表，体重变化百分比）和平方检验（临床总体印象改善[CGI-I；从BED症状的角度看]分为改善或未改善的量表。这些分析不是预先指定的测试策略的一部分，因此报告的p值为标称值（未经调整且仅用于描述）。
结果：在两项研究中，偏方均值表示从基线开始改变的治疗差异（LDX优于安慰剂（所有标称p值均＜.001））始于第1周的暴饮暴食日/周，暴饮暴食发作/周，体重变化百分比和在第一次后处理评估（第4周）中获得Y-BOCS-BE总分和领域分数。在CGI-I上，两项研究中，从第1周开始，与安慰剂相比，更多的LDX参与者被归类为改善的（名义p值均<0.001）。跨越这些与功效相关的终点，在两项研究的每次治疗后评估中，LDX均优于安慰剂（所有标称p值均<0.001）。
讨论：在患有BED的成人中，LDX治疗似乎最早可在1周时改善疗效，并在整个12周的研究中一直保持这种状态。

BACKGROUND & AIMS: BACKGROUND:A 12-month, open-label extension study assessed the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in adults with binge eating disorder (BED). METHODS:Adults (aged 18-55 y) with BED who completed 1 of 3 antecedent studies were enrolled in a 52-week, open-label extension study (dose optimization, 4 weeks [initial titration dose, 30-mg LDX; target doses, 50- or 70-mg LDX]; dose maintenance, 48 weeks). Safety evaluations included the occurrence of treatment-emergent adverse events (TEAEs), vital sign and weight assessments, and Columbia-Suicide Severity Rating Scale responses. RESULTS:Of the 604 enrolled participants, 599 (521 women and 78 men) comprised the safety analysis set, and 369 completed the study. Mean (SD) LDX exposure was 284.3 (118.84) days; cumulative LDX exposure duration was 12 months or longer in 344 participants (57.4%). A total of 506 participants (84.5%) reported TEAEs (TEAEs leading to treatment discontinuation, 54 [9.0%]; severe TEAEs, 42 [7.0%]; serious TEAEs, 17 [2.8%]). Treatment-emergent adverse events reported in greater than or equal to 10% of participants were dry mouth (27.2%), headache (13.2%), insomnia (12.4%), and upper respiratory tract infection (11.4%). Mean (SD) changes from antecedent study baseline in systolic and diastolic blood pressure, pulse, and weight at week 52/early termination (n = 597) were 2.19 (11.043) and 1.77 (7.848) mm Hg, 6.58 (10.572) beats per minute, and -7.04 (7.534) kg, respectively. On the Columbia-Suicide Severity Rating Scale, there were 2 positive responses for any active suicidal ideations; there were no positive responses for suicidal behavior or completed suicides. CONCLUSIONS:In this 12-month, open-label, extension study, the long-term safety and tolerability of LDX in adults with BED were generally consistent with its established profile for attention-deficit/hyperactivity disorder.

背景与目标： 背景：一项为期12个月的开放标签扩展研究评估了成人暴食症（BED）的患者使用赖氨苯丙胺二甲酸酯（LDX）的长期安全性和耐受性。
方法：完成了三项前期研究之一的BED成人（18-55岁）参加了一项为期52周的开放标签扩展研究（剂量优化，为期4周[初始滴定剂量，30 mg LDX；目标剂量] ，50或70毫克LDX]；维持剂量48周。安全性评估包括紧急治疗不良事件（TEAE）的发生，生命体征和体重评估以及哥伦比亚－自杀严重性等级量表的反应。
结果：在604名参与者中，有599名（521名女性和78名男性）进行了安全性分析，其中369名完成了研究。平均（SD）LDX暴露时间为284.3（118.84）天； 344名参与者（57.4％）的累积LDX暴露持续时间为12个月或更长时间。共有506位参与者（84.5％）报告了TEAE（导致治疗中断的TEAE，占54 [9.0％]；严重的TEAE，占42 [7.0％]；严重的TEAE，占17 [2.8％]）。大于或等于10％的参与者报告的治疗紧急不良事件为口干（27.2％），头痛（13.2％），失眠（12.4％）和上呼吸道感染（11.4％）。在第52周/早期终止时（n = 597），收缩压和舒张压，脉搏和体重的平均（SD）变化为2.19（11.043）和1.77（7.848）mm Hg，每变化6.58（10.572）次分钟和-7.04（7.534）公斤。在《哥伦比亚自杀严重性等级量表》中，对任何积极的自杀观念有2个积极的回应。没有任何关于自杀行为或完全自杀的积极反应。
结论：在这项为期12个月的开放标签扩展研究中，LDX在BED成人中的长期安全性和耐受性通常与其针对注意力缺陷/多动障碍的既定特征相一致。

BACKGROUND & AIMS: :Lisdexamfetamine dimesylate is a novel prodrug approved in North America, Europe and Brazil for treating attention deficit hyperactivity disorder (ADHD). It undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine. Following our previous work comparing lisdexamfetamine with d-amphetamine, the neurochemical and behavioural profiles of lisdexamfetamine, methylphenidate and modafinil were compared by dual-probe microdialysis in the prefrontal cortex (PFC) and striatum of conscious rats with simultaneous locomotor activity measurement. We employed pharmacologically equivalent doses of all compounds and those that spanned the therapeutically relevant and psychostimulant range. Lisdexamfetamine (0.5, 1.5, 4.5 mg/kg d-amphetamine base, per os (po)), methylphenidate (3, 10, 30 mg/kg base, po) and modafinil (100, 300, 600 mg/kg base, po) increased efflux of dopamine and noradrenaline in PFC, and dopamine in striatum. Only lisdexamfetamine increased 5-hydroxytryptamine (5-HT) efflux in PFC and striatum. Lisdexamfetamine had larger and more sustained effects on catecholaminergic neurotransmission than methylphenidate or modafinil. Linear correlations were observed between striatal dopamine efflux and locomotor activity for lisdexamfetamine and methylphenidate, but not modafinil. Regression slopes revealed greater increases in extracellular dopamine could be elicited without producing locomotor activation by lisdexamfetamine than methylphenidate. These results are consistent with clinical findings showing that lisdexamfetamine is an effective ADHD medication with prolonged duration of action and good separation between its therapeutic actions and stimulant side-effects.

背景与目标： Lisdexamfetamine dimesylate是在北美，欧洲和巴西批准用于治疗注意力缺陷多动障碍（ADHD）的新型前药。它受到红细胞的限速水解，产生d-苯异丙胺。继我们之前的研究结果之后，通过双探针微透析在有意识大鼠的前额叶皮层（PFC）和纹状体中进行了同时运动功能的测量，比较了赖斯地非胺与d-苯异丙胺，赖斯地非胺，哌醋甲酯和莫达非尼的神经化学和行为特征。我们采用了所有化合物的药理等效剂量以及跨越治疗相关和精神兴奋剂范围的药物。 Lisdexamfetamine（0.5，1.5，4.5 mg / kg d-苯异丙胺碱，口服（po）），哌醋甲酯（3，10，30 mg / kg碱，口服）和莫达非尼（100，300，600 mg / kg碱，口服） ）PFC中多巴胺和去甲肾上腺素的流出量增加，纹状体中多巴胺的流出量增加。仅赖氨苯丙胺增加了PFC和纹状体中的5-羟色胺（5-HT）外排。 Lisdexamfetamine对儿茶酚胺能神经传递的作用大于哌醋甲酯或莫达非尼。观察到纹状体多巴胺外排与赖氨酸安非他明和哌醋甲酯的运动活性之间存在线性相关性，但莫达非尼则无此相关性。回归斜率显示，与哌醋甲酯相比，赖氨酸安非他明可引起更大的细胞外多巴胺增加而不会产生赖斯安非他明产生运动活化。这些结果与临床结果一致，该结果表明赖氨苯丙胺是一种有效的ADHD药物，具有延长的作用持续时间，并且在其治疗作用和刺激性副作用之间具有良好的分离性。