BACKGROUND & AIMS: :The Management Academy for Public Health is a team-based training program jointly offered by the School of Public Health and the Kenan-Flagler Business School at the University of North Carolina at Chapel Hill. This 9-month program teaches public health managers how to better manage people, information, and finances. Participants learn how to work in teams with community partners, and how to think and behave as social entrepreneurs. To practice and blend their new skills, teams develop a business plan that addresses a local public health issue. This article describes the program and explains the findings of the process evaluation, which has examined how best to structure and deploy a team-based method to create more effective, more entrepreneurial public health managers. Findings indicate that recruitment and retention are strong, program elements are relevant to learners' needs, and learners are satisfied with and value the program. Several specific benefits of the program model are identified, as well as several elements that support business plan success and skills' application on the job. On the basis of these findings, four success factors critical for developing similar programs are identified.

背景与目标： ：公共卫生管理学院是一项基于团队的培训计划，由北卡罗来纳大学教堂山分校的公共卫生学院和Kenan-Flagler商学院联合提供。这个为期9个月的课程向公共卫生经理讲授如何更好地管理人员，信息和财务。参与者学习如何与社区合作伙伴一起工作，以及如何思考和表现为社会企业家。为了练习和融合他们的新技能，团队制定了解决当地公共卫生问题的商业计划。本文介绍了该程序，并说明了过程评估的结果，该过程评估了如何最好地构建和部署基于团队的方法来创建更有效，更具创业精神的公共卫生经理。调查结果表明，招聘和留住人才的能力很强，计划要素与学习者的需求相关，学习者对计划感到满意和重视。确定了计划模型的几个特定优点，以及支持业务计划成功和技能在工作中应用的几个要素。根据这些发现，确定了开发类似程序的四个成功因素。

BACKGROUND & AIMS: :The study demonstrates the application of QbD based on historical data for a product at a later development stage - retrospective QbD (rQbD). More specifically, it is investigated the root-cause for the observed slower drug release in Orodispersible Films (ODFs) during storage. Risk assessment tools were used to identify parameters affecting ODFs critical quality attributes, namely percent drug release and residual water content. The parameters room temperature, room relative humidity, drying temperature and mixing equipment were used in the statistical modeling of the available data. The estimated models were then used to define the feasible working region. Statistical modeling indicates that initial residual water content of the ODFs is mainly affected by 2nd order interactions of room temperature, room relative humidity and drying temperature, while the stability of drug release profile is mostly influenced by room temperature and an interaction between room relative humidity and drying temperature. Depending on the drying temperature employed the effect of room temperature and room relative humidity change significantly. This work shows that it is possible to apply rQbD to achieve a greater understanding of the manufacturing process of ODFs and to define a proper design space.

背景与目标： ：研究证明了基于历史数据的QbD在后期产品开发中的应用-回顾性QbD（rQbD）。更具体地说，研究了在储存过程中观察到的较慢的药物在口腔分散膜（ODF）中释放的根本原因。风险评估工具用于确定影响ODF关键质量属性的参数，即药物释放百分比和残留水分。在可用数据的统计模型中，使用了室温，室内相对湿度，干燥温度和混合设备等参数。然后，将估计的模型用于定义可行的工作区域。统计模型表明，ODFs的初始残留水含量主要受室温，室温相对湿度和干燥温度的二阶相互作用影响，而药物释放曲线的稳定性主要受室温以及室温相对湿度与干燥温度之间相互作用的影响。干燥温度。取决于所采用的干燥温度，室温和室内相对湿度的影响会显着变化。这项工作表明，有可能应用rQbD来更好地理解ODF的制造过程并定义适当的设计空间。

BACKGROUND & AIMS: :A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.

背景与目标： ：设计，合成和评估了一系列新型白藜芦醇衍生物，作为治疗阿尔茨海默氏病的潜在治疗剂。在这些化合物中，化合物7l，（E）-5-（4-（异丙基氨基）苯乙烯基）苯-1,3-二醇表现出强力的β-淀粉样蛋白聚集抑制活性，这可通过ThT荧光测定法证实（71.65％在20μM）和透射电子显微镜（TEM）。化合物7-1也表现出良好的抗氧化活性（在氧自由基吸收能力测定中为4.12 Trolox当量，并且在10μM下细胞中的活性氧减少了37％）。化合物7f，7i，7j和7l的细胞毒性分析表明，在60μM浓度下，这些化合物的毒性低于白藜芦醇。

BACKGROUND & AIMS: :Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.

背景与目标： ：利用X射线晶体结构分析，设计了（3S，5R）-5- [4-（2-氯苯基）-2,2-二甲基-5-氧哌嗪-1-基]哌啶-3-甲酰胺，并确定为肾素抑制剂。最有效的化合物15在大鼠中显示出良好的药代动力学和药效学特征。

BACKGROUND & AIMS: OBJECT:The purpose of this study was to provide an evidence-based algorithm for the design, development, and implementation of a new checklist for the response to an intraoperative neuromonitoring alert during spine surgery. METHODS:The aviation and surgical literature was surveyed for evidence of successful checklist design, development, and implementation. The limitations of checklists and the barriers to their implementation were reviewed. Based on this review, an algorithm for neurosurgical checklist creation and implementation was developed. Using this algorithm, a multidisciplinary team surveyed the literature for the best practices for how to respond to an intraoperative neuromonitoring alert. All stakeholders then reviewed the evidence and came to consensus regarding items for inclusion in the checklist. RESULTS:A checklist for responding to an intraoperative neuromonitoring alert was devised. It highlights the specific roles of the anesthesiologist, surgeon, and neuromonitoring personnel and encourages communication between teams. It focuses on the items critical for identifying and correcting reversible causes of neuromonitoring alerts. Following initial design, the checklist draft was reviewed and amended with stakeholder input. The checklist was then evaluated in a small-scale trial and revised based on usability and feasibility. CONCLUSIONS:The authors have developed an evidence-based algorithm for the design, development, and implementation of checklists in neurosurgery and have used this algorithm to devise a checklist for responding to intraoperative neuromonitoring alerts in spine surgery.

背景与目标： 目的：本研究的目的是提供一种基于证据的算法，用于设计，开发和实施针对脊柱手术中对术中神经监测警报的反应的新清单。
方法：对航空和外科文献进行了调查，以获取成功设计，开发和实施清单​​的证据。审查了清单的局限性以及实施清单的障碍。在此基础上，开发了神经外科检查清单创建和实现的算法。使用此算法，一个多学科团队调查了文献，以了解如何对术中神经监测警报做出反应的最佳实践。然后，所有利益相关者都对证据进行了审查，并就列入清单的项目达成了共识。
结果：设计了对术中神经监测警报反应的清单。它强调了麻醉师，外科医生和神经监测人员的具体作用，并鼓励团队之间的沟通。它着重于对识别和纠正神经监测警报的可逆原因至关重要的项目。在初步设计之后，检查清单草稿经过了利益相关者的意见审查和修订。然后在小规模试验中对清单进行评估，并根据可用性和可行性进行修订。
结论：作者开发了一种基于证据的算法，用于神经外科检查清单的设计，开发和实施，并已使用该算法设计了对脊柱手术中术中神经监测警报做出反应的检查清单。

BACKGROUND & AIMS: :Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40 000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice.

背景与目标： ：人类有两个谷氨酰胺酶基因，GLS（GLS1）和GLS2，每个都有两个替代转录物：GLS的肾脏同种型（KGA）和谷氨酰胺酶C（GAC），肝脏同种型（LGA）和谷氨酰胺酶B（GAB）适用于GLS2。初始命中化合物（Z）-5-（（（1-（4-溴苯基）-2,5-二甲基-1H-吡咯-3-基）亚甲基）噻唑烷-2,4-二酮（2），噻唑烷-2通过对KGA筛选40000种化合物的高通量筛选获得了4-4-二酮。随后，合成了一系列噻唑烷-2,4-二酮衍生物。发现其中大多数可抑制KGA和GAC的活性相当，对GAB的抑制作用较弱，并且对GLS1的选择性比对GLS2的中等。研究了化学结构，活性和选择性之间的关系。发现获得的先导化合物（1）提供体外细胞活性以抑制细胞生长，克隆形成和细胞谷氨酸生成；（2）通过药代动力学研究显示血浆中高浓度暴露；（3）减小肿瘤大小小鼠体内异种移植人胰腺AsPC-1癌细胞的表达。

BACKGROUND & AIMS: BACKGROUND:Outcome in stroke trials is often based on a 3-month modified Rankin scale (mRS). How 3-month mRS relates to longer-term outcomes will depend on late recovery, delayed stroke-related deaths, recurrent strokes, and nonstroke deaths. We evaluated 3-month mRS and death/disability at 1 and 5 years in a population-based cohort study. METHODS AND RESULTS:In 3-month survivors of ischemic stroke (Oxford Vascular Study; 2002-2014), we related 3-month mRS to disability (defined as mRS >2) at 1 and 5 years and/or death rates (age/sex adjusted). Accrual of disability and index-stroke-related and nonstroke deaths in each poststroke year was categorized according to 3-month mRS. Among 1606 patients with acute ischemic stroke, 181 died within 3 months, but 126 index-stroke-related deaths and 320 other deaths occurred during the subsequent 4866 patient-years of follow-up up to 5 years. Although 69/126 (54.8%) post-3-month index-stroke-related deaths occurred after 1 year, mRS>2 at 1 year strongly predicted these deaths (adjusted hazard ratio=21.94, 95%CI 7.88-61.09, P<0.0001). Consequently, a 3-month mRS >2 was a strong independent predictor of death at both 1 year (adjusted hazard ratio=6.67, 95%CI 4.16-10.69, P<0.0001) and 5 years (adjusted hazard ratio=2.93, 95%CI 2.38-3.60, P<0.0001). Although mRS improved by ≥1 point from 3 months to 1 year in 317/1266 (25.0%) patients with 3-month mRS ≥1, improvement in mRS after 1 year was limited (improvement by ≥1 point: 91/858 [10.6%]; improvement to mRS ≤2: 13/353 [3.7%]). CONCLUSIONS:Our results reaffirm use of the 3-month mRS outcome in stroke trials. Although later recovery does occur, extending follow-up to 1 year would capture most long-term stroke-related disability. However, administrative mortality follow-up beyond 1 year has the potential to demonstrate translation of early disability gains into additional reductions in long-term mortality without much erosion by non-stroke-related deaths.

背景与目标： 背景：中风试验的结果通常基于3个月的改良兰金量表（mRS）。 3个月的mRS与长期结果的关系将取决于晚期康复，中风相关的延迟死亡，中风复发和非中风死亡。在一项基于人群的队列研究中，我们评估了3个月的mRS和1年和5年时的死亡/残疾。
方法和结果：在3个月的缺血性中风幸存者中（牛津血管研究; 2002-2014），我们将3个月的mRS与1岁和5岁时的残疾（定义为mRS> 2）和/或死亡率（年龄/性别调整）。根据每个月的3个月mRS对残疾的累积以及与卒中相关的卒中和非卒中死亡进行分类。在1606例急性缺血性中风患者中，有3个月内有181例死亡，但在随后的4866个患者年的随访中（长达5年）发生了126例与中风相关的死亡，还有320例其他死亡。尽管1年后发生69/126（54.8％）的3个月后与指数卒中相关的死亡，但1年时的mRS> 2强烈预测了这些死亡（调整后的危险比= 21.94，95％CI 7.88-61.09，P < 0.0001）。因此，在1年（调整后的危险比= 6.67，95％CI 4.16-10.69，P <0.0001）和5年（调整后的危险比= 2.93，95％）下，三个月的mRS> 2是死亡的强有力的独立预测因子。 CI 2.38-3.60，P <0.0001）。尽管317/1266（35.0％）3个月mRS≥1的患者在3个月至1年间mRS改善了≥1点，但1年后mRS的改善是有限的（≥1点的改善：91/858 [10.6 ％]； mRS≤2的改善：13/353 [3.7％]）。
结论：我们的研究结果重申了在卒中试验中使用3个月的mRS结果。尽管确实会出现稍后的康复，但将随访延长至1年将捕获大多数与中风相关的长期残疾。但是，对1年以上的行政死亡率进行随访，有可能证明将早期残疾的增加转化为长期死亡率的进一步降低，而不会因非中风相关的死亡而受到很大的侵蚀。

BACKGROUND & AIMS: :Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I-IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.

背景与目标： ：胃蛋白酶是天冬氨酸蛋白酶，参与宿主细胞血红蛋白的降解，被疟原虫用作食物来源。纤溶酶作为药物靶标非常有前途，特别是与抑制也与血红蛋白分解代谢有关的falcipains结合使用时。在这篇综述中，我们鉴于对过渡态模拟物作为潜在的潜在铅化合物的发展感兴趣，讨论了纤溶酶I-IV的机制。概述了针对纤溶酶II的抑制剂的开发以及相关的晶体结构，以便对该领域进行概述。计算技术的应用，特别是通过线性相互作用能法的结合亲和力预测，在疟疾纤溶酶抑制剂的开发中已经取得了很大的成功，并进行了详细的讨论。均相建模和分子对接在当前的抑制剂设计项目中非常有用，并且分析了这些方法与结合自由能计算的结合。

BACKGROUND & AIMS: :The purpose of this study was to evaluate the outcome of patients who underwent glenoid bone grafting and implantation of a reverse design prosthesis in 1 or 2 stages for the treatment of glenoid bone loss and rotator cuff insufficiency. Indications for the reverse prosthesis in this series included cuff tear arthropathy and revision arthroplasty. Nine patients were reviewed clinically and radiographically with a minimum 2-year follow-up (range, 24-41 months). Despite a low postoperative functional score (mean Constant score, 53 points [range, 22-79 points]), most patients were satisfied with their results primarily because of pain relief. (The mean pain score increased from 3 points preoperatively to 12.5 points postoperatively.) Radiographic evaluation did not demonstrate component loosening or evidence of graft failure. Six patients had radiographic evidence of an inferior scapular notch, which may be of concern in the future. Early results of this procedure are encouraging, but further clinical and radiologic assessment is necessary.

背景与目标： ：本研究的目的是评估接受关节盂骨移植并在1或2个阶段植入反向设计假体以治疗关节盂骨丢失和肩袖功能不全的患者的预后。本系列反向假体的适应症包括袖套撕裂性关节炎和翻修置换术。对9例患者进行了临床和影像学检查，至少随访2年（范围24-41个月）。尽管术后功能评分较低（平均恒定评分为53分[范围，22-79分]），但大多数患者对他们的结果感到满意的主要原因是疼痛减轻。 （平均疼痛评分从术前的3分增加到术后的12.5分。）影像学评估未显示组件松动或移植失败的迹象。六例患者的放射学证据显示肩s骨下凹，将来可能会引起关注。该方法的早期结果令人鼓舞，但需要进一步的临床和放射学评估。

BACKGROUND & AIMS: :The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells. Eighteen of the new compounds had cytotoxicity mean-graph midpoint (MGM) GI50 values in the submicromolar (0.033-0.630 μM) range. Compounds 16b and 17b are the most potent in human cancer cell cultures with MGM GI50 values of 0.063 and 0.033 μM, respectively. Possible binding modes to Top1 and TDP1were investigated by molecular modeling.

背景与目标： ：7-氮杂茚并异喹啉是细胞毒性拓扑异构酶I（Top1）抑制剂。以前报道的代表带有一个3-硝基基团。本报告记录了潜在的具有遗传毒性的3-硝基被3-氯和3-氟取代基取代，从而导致在人类癌细胞培养中具有高Top1抑制活性和强细胞毒性的化合物，并降低了动物模型的致死率。一些新的Top1抑制剂还具有对酪氨酰DNA磷酸二酯酶1（TDP1）和酪氨酰DNA磷酸二酯酶2（TDP2）的中等抑制活性，这两种酶都参与了由Top1抑制剂引起的DNA损伤修复，并且它们产生的DNA明显更多。在癌细胞中的损伤要比正常细胞中的损伤大。 18种新化合物的细胞毒性平均图中点（MGM）GI50值在亚微摩尔（0.033-0.630μM）范围内。化合物16b和17b在人类癌细胞培养物中最有效，其MGM GI50值分别为0.063和0.033μM。通过分子建模研究了与Top1和TDP1可能的结合模式。

BACKGROUND & AIMS: :We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b', which were obtained by Simmons-Smith cyclopropanation of ethylester 3a and silyl ether 3b'. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner.

背景与目标： ：我们最近报道了八氢吡咯并[1,2-a]吡嗪A作为凋亡蛋白（IAP）拮抗剂抑制剂的先导化合物的发现。为了开发具有良好PK谱的IAP拮抗剂，我们基于A与细胞的共晶体结构分析，设计了新颖的三环化合物，八氢-1H-环丙[4,5]吡咯并[1,2-a]吡嗪1和2。 IAP-1（cIAP-1）。额外的环丙烷部分用于封闭化合物A的预测代谢位点，而不会损害对cIAP的结合亲和力。经由中间体4a和5b'立体选择性地合成化合物1和2，所述中间体通过乙酯3a和甲硅烷基醚3b'的Simmons-Smith环丙烷化获得。与A相比，化合物1和2在MDA-MB-231乳腺癌细胞中显示出强大的生长抑制作用，并改善了代谢稳定性。化合物2在剂量方面具有显着的体内PD效应，从而增加了肿瘤坏死因子-αmRNA的表达。

BACKGROUND & AIMS: :A series of 1-methyl-3,5-diphenyl-4,5-dihydro-1H-pyrazoles (3a-k and 4a-u) were designed, synthesized, and evaluated for their inhibitory efficacy towards the two hMAO isoforms. Most of the derivatives were found to be potent and selective hMAO-B inhibitors. In particular, derivative 3g showed greater hMAO-B affinity than selective inhibitor selegiline coupled with high selectivity index (SI=145). The most selective hMAO-B inhibitor was the 3-methyl analogue 3f with an SI higher than 909.

背景与目标： ：设计，合成了一系列1-甲基-3,5-二苯基-4,5-二氢-1H-吡唑（3a-k和4a-u），并评估了它们对两种hMAO同工型的抑制作用。发现大多数衍生物是有效的和选择性的hMAO-B抑制剂。特别是，衍生物3g与选择性抑制剂司来吉兰相比具有更高的hMAO-B亲和力，并具有高选择性指数（SI = 145）。最具选择性的hMAO-B抑制剂是3-甲基类似物3f，SI高于909。

BACKGROUND & AIMS: :Walking outdoors is often difficult or impossible for many seniors and people with disabilities during winter. We present a novel approach for conducting winter accessibility evaluations of commonly used pedestrian facilities, including sidewalks, street crossings, curb ramps (curb cuts and dropped curbs), outdoor stairs and ramps, building and transit entrances, bus stops, and driveways. A total of 183 individuals, aged 18-85 completed our survey. The results show that cold weather itself had little impact on the frequency of outdoor excursions among middle-aged and older adults while the presence of snow and/or ice on the ground noticeably kept people, especially older adults at home. The survey found that the key elements decreasing winter accessibility were icy sidewalks and puddles at street crossings and curb ramps. While communities have recognized the need to improve snow and ice removal, little attention has been paid to curb ramp design which is especially ineffective in winter when the bottom of the ramps pool with rain, snow, and ice, making it hazardous and inaccessible to nearly all users. We conclude that investigations of alternative designs of curb ramp are needed.

背景与目标： ：在冬天，对于许多老年人和残疾人来说，户外散步通常很困难或不可能。我们提出了一种新颖的方法，用于对常用的行人设施进行冬季可达性评估，包括人行道，人行横道，路缘坡道（路缘削减和掉落的路缘），室外楼梯和坡道，建筑物和公交入口，公交车站和车道。共有183位年龄在18-85岁之间的人完成了我们的调查。结果表明，寒冷的天气本身对中年和老年人的户外旅行的频率几乎没有影响，而地面上积雪和/或冰的存在则使人们尤其是老年人更加留在家里。调查发现，影响冬季通行能力的关键因素是人行横道，路口和路缘坡道上的水坑。尽管社区已经认识到需要改善除冰和除冰的必要性，但很少有人关注遏制坡道的设计，这种设计在冬季坡道池底部积有雨，雪和冰的情况下尤其无效，这使得它几乎是危险的并且难以接近所有用户。我们得出结论，需要研究路缘坡道的替代设计。

BACKGROUND & AIMS: :Purine-binding proteins are of critical importance to all living organisms. Approximately 13% of the human genome is devoted to coding for purine-binding proteins. Given their importance, purine-binding proteins are attractive targets for chemotherapeutic intervention against a variety of disease states, particularly cancer. Modern computational and biophysical techniques, combined together in a structure-based drug design approach, aid immensely in the discovery of inhibitors of these targets. This review covers the process of modern structure-based drug design and gives examples of its use in discovery and development of drugs that target purine-binding proteins. The targets reviewed are human purine nucleoside phosphorylase, human epidermal growth factor receptor kinase, and human kinesin spindle protein.

背景与目标： ：嘌呤结合蛋白对所有生物至关重要。人类基因组中约有13％专门用于编码嘌呤结合蛋白。鉴于其重要性，嘌呤结合蛋白是针对多种疾病尤其是癌症的化学疗法干预的有吸引力的靶标。现代的计算和生物物理技术，结合以基于结构的药物设计方法，极大地帮助发现了这些靶标的抑制剂。这篇综述涵盖了基于现代结构的药物设计过程，并举例说明了其在发现和开发针对嘌呤结合蛋白的药物中的应用。审查的目标是人嘌呤核苷磷酸化酶，人表皮生长因子受体激酶和人驱动蛋白纺锤体蛋白。

BACKGROUND & AIMS: :The purpose of the present research is to establish a novel nanosizing technique starting from wet nano-milling, named "dry nanosuspension" technique for poorly water-soluble drugs. The spray freeze-drying (SFD) method was applied instead of the spray-drying one previously developed. Drug particles were milled in the aqueous solution of dispersing agents using an oscillating beads-milling apparatus. The milled nanosuspension was sprayed to the surface of liquid nitrogen, and the resultant iced droplets were freeze-dried to obtain the powdery product. The loading ratio of a dispersing agent was investigated to enhance its redispersing property. Dry nanosuspension, which could be spontaneously dispersed into original nanosuspension in water, was obtained by SFD process. It was assumed that self dispersion property would be attributed to its structure with porous network, in which the primary milled drug crystals were embedded. Such unique structure contributed greatly to immediate release behaviors of the drug in gastrointestinal buffered media. These pharmaceutical properties were enhanced by increasing the ratio of the dispersing agent to the drug and the solid content in suspension to be sprayed. The present technique via wet milling and spray freeze-drying processes would be a novel dissolution-enhanced technology for poorly water-soluble drugs.

背景与目标： ：本研究的目的是建立一种从湿法纳米研磨开始的新型纳米技术，该技术被称为“干纳米悬浮”技术，用于水溶性差的药物。应用喷雾冷冻干燥（SFD）方法代替先前开发的喷雾干燥方法。使用振荡珠磨设备在分散剂的水溶液中研磨药物颗粒。将研磨后的纳米悬浮液喷雾至液氮表面，并将所得的冰滴冷冻干燥，以获得粉状产物。为了提高分散剂的再分散性，对分散剂的负载率进行了研究。通过SFD工艺获得了可以自发分散在水中的纳米悬浮液的干燥纳米悬浮液。假定自分散性归因于其具有多孔网络的结构，其中嵌入了原始研磨的药物晶体。这种独特的结构极大地促进了药物在胃肠缓冲介质中的立即释放行为。通过增加分散剂与药物的比例和待喷雾悬浮液中的固体含量，可以提高这些药物的性能。通过湿磨和喷雾冷冻干燥方法的本技术将是用于水溶性差的药物的新型溶解增强技术。