BACKGROUND & AIMS: These experiments were designed to determine whether glycogenolysis was influenced by the glycogen concentration of vascular smooth muscle. Segments of hog carotid artery smooth muscle were allowed to synthesize variable amounts of 1-[13C]glucosyl units of glycogen. Artery segments were then isometrically contracted in the presence of 2-[13C]glucose. Prior to and after isometric contraction, measurements were made of tissue glycogen content and superfusate glucose and lactate concentrations. 2-[13C]Lactate and 3-[13C]lactate peak intensities in the superfusate were measured using 13C-NMR spectroscopy. The tissue glycogen content decreased exponentially during the 4.5 h of isometric contraction (R2 = 0.990), despite more than a 3-fold range of glycogen concentration prior to contraction. The extent of glycogen utilization during a 3 h isometric contraction varied linearly with the precontraction glycogen concentration (R2 = 0.727). Lactate production specifically from glycogen breakdown increased with an increase in precontraction glycogen concentration (R2 = 0.620). During a 3 h isometric contraction neither the glucose utilization (R2 = 0.007) nor lactate production specifically produced from glucose (R2 = 0.00002) varied with the precontraction glycogen concentration. It is concluded that the rate of glycogenolysis is determined by the content of glycogen during prolonged contractions. In addition, precontraction glycogen levels influence the pathway for glycogen utilization but not the pathway for glucose utilization. Therefore, glycolysis and glycogenolysis behave independently in vascular smooth muscle.

背景与目标： 这些实验旨在确定糖原分解是否受血管平滑肌糖原浓度的影响。允许猪颈动脉平滑肌段合成可变量的1-[13C] 糖原葡萄糖单元。然后在2-[13C] 葡萄糖存在下等距收缩动脉段。在等距收缩之前和之后，测量组织糖原含量和超融合物葡萄糖和乳酸浓度。使用13C-NMR光谱测量超融合物中的2-[13C] 乳酸和3-[13C] 乳酸峰强度。组织糖原含量在等距收缩的4.5小时内呈指数下降 (R2 = 0.990)，尽管收缩前糖原浓度超过3倍。在3 h等距收缩期间糖原利用的程度随收缩前糖原浓度线性变化 (R2 = 0.727)。糖原分解产生的乳酸产量随着收缩前糖原浓度的增加而增加 (R2 = 0.620)。3小时的等距收缩葡萄糖利用率 (R2 = 0.007) 和特别由葡萄糖产生的乳酸产量 (R2 = 0.00002) 都不随收缩前糖原浓度而变化。结论是糖原分解速率由长期收缩期间糖原含量决定。此外，收缩前糖原水平会影响糖原利用的途径，但不会影响葡萄糖利用的途径。因此，糖酵解和糖原分解在血管平滑肌中独立运作。

BACKGROUND & AIMS: :Orphan medicinal products (OMPs) are targeted at the diagnosis, prevention or treatment of rare diseases and have a special status in European law. This status brings incentives for pharmaceutical companies to invest in OMP development. The goal of the legislation is to encourage the development of more treatments for life-threatening rare disorders, but increased availability of OMPs raises important issues surrounding the public funding of very expensive treatments by national health services. In this article we review OMPs and the incentives for their development and discuss the challenges presented by funding these treatments.

背景与目标： : 孤儿药品 (OMPs) 针对罕见疾病的诊断，预防或治疗，在欧洲法律中具有特殊地位。这种状态为制药公司投资OMP开发带来了动力。该立法的目标是鼓励为危及生命的罕见疾病开发更多的治疗方法，但是omp的可用性增加引发了围绕国家卫生服务机构为非常昂贵的治疗提供公共资金的重要问题。在本文中，我们回顾了omp及其发展的诱因，并讨论了资助这些治疗带来的挑战。

BACKGROUND & AIMS: The involvement of antigen-specific T cells in the pathogenesis of collagen diseases is still controversial. The final stages of collagen diseases are usually characterized by the dominance of inflammation. Therefore, antigen non-specific factors, such as inflammatory cytokines, probably play an important role in this process. On the other hand, the methods available to analyze the antigen-specific aspects of the immune response are still limited. Here we review our novel system of T cell clonality analysis based on the idea that activated antigen-specific T cells should form accumulating clones among the lymphocyte population. Using this method, dynamic changes of clonal accumulation of T cells could be evaluated during antigenic stimulation in vivo and in vitro. The significance of antigen-specific T cell clones in collagen diseases is discussed using data obtained from patients with rheumatoid arthritis and systemic lupus erythematosus.

背景与目标： 抗原特异性T细胞参与胶原疾病的发病机理仍存在争议。胶原蛋白疾病的最后阶段通常以炎症为主。因此，抗原非特异性因子 (如炎性细胞因子) 可能在这一过程中起重要作用。另一方面，用于分析免疫应答的抗原特异性方面的方法仍然有限。在这里，我们基于激活的抗原特异性T细胞应在淋巴细胞群体中形成累积克隆的想法，回顾了我们的新型T细胞克隆分析系统。使用该方法，可以在体内和体外评估抗原刺激过程中T细胞克隆积累的动态变化。使用类风湿关节炎和系统性红斑狼疮患者获得的数据讨论了抗原特异性T细胞克隆在胶原疾病中的意义。

BACKGROUND & AIMS: :The aim of this study is to find out the causes of skin diseases in one-third of the staff of a perfume factory, in which 10 different perfume sprays were being manufactured. Site inspection, dermatological examination and patch testing of all 26 persons at risk with 4 perfume oils and 30 ingredients of them. The results showed 6 bottlers were found suffering from allergic contact dermatitis, 2 from irritant contact dermatitis, 12 workers showed different strong reactions to various fragrances. The main causes of allergic contact dermatitis were 2 perfume oils (12 cases) and their ingredients geraniol (12 cases), benzaldehyde(9), cinnamic aldehyde (6), linalool, neroli oil, terpenes of lemon oil and orange oil (4 each). Nobody was tested positive to balsam of Peru. Job changes for office workers, packers or printers to other rooms, where they had no longer contact with fragrances, led to a settling. To conclude, automation and replacement of glass bottles by cartridges from non-fragile materials and using gloves may minimize the risk.

背景与目标： : 这项研究的目的是找出3分之1一家香水工厂的工作人员的皮肤病的原因，该工厂生产了10种不同的香水喷雾剂。现场检查，皮肤科检查和所有26名有风险的人使用4种香料油和30种成分进行贴剂测试。结果显示，6名装瓶工人患有过敏性接触性皮炎，2名来自刺激性接触性皮炎，12名工人对各种香料表现出不同的强烈反应。过敏性接触性皮炎的主要病因为香精油2种 (12例)，其成分为香叶醇 (12例)，苯甲醛 (9例)，肉桂醛 (6例)，芳樟醇，橙花油，柠檬油和橙油的萜烯 (4例)。没有人对秘鲁的香脂测试呈阳性。办公室工作人员，包装工或打印机的工作变更到其他房间，他们不再与香水接触，导致了定居。总而言之，用非易碎材料和使用手套的墨盒自动化和更换玻璃瓶可以最大程度地降低风险。

BACKGROUND & AIMS: :Seventy-two patients with tumor and ten with non-neoplastic colon disease were studied for the presence of estrogen receptors (ER) by three different methods. Only seven specimens (six primary adenocarcinomas and one recurrent cancer) had an ER concentration above 3 fm/mg of cytosolic protein, with no sex, age and tumor stage correlation. Our results suggest that the large bowel does not contain a cytosolic receptor for estradiol.

背景与目标： : 通过三种不同的方法研究了72例肿瘤患者和10例非肿瘤性结肠疾病的雌激素受体 (ER) 的存在。只有7个标本 (6个原发性腺癌和1个复发性癌症) 的ER浓度高于3 fm/mg的胞质蛋白，没有性别，年龄和肿瘤分期的相关性。我们的结果表明，大肠不含雌二醇的胞质受体。

BACKGROUND & AIMS: INTRODUCTION:STDs are a significant cause of illness throughout the world. Female sex workers (FSWs) are commonly perceived as belonging to a social group which may engage in high-risk behaviour for acquiring or transmitting HIV and other STDs. The number of immigrant women engaged in sex work has increased in Catania, Sicily, over the last 10 years. This study aims to estimate the prevalence of HIV, HBV, HCV and syphilis among Colombian and Dominican FSWs. METHODS:In total 118 (63.78%) of the FSWs contacted in the course of the project agreed to participate in the study. All women enrolled were counselled on STDs/HIV, safer sex practices and the use of condoms. Blood samples were taken and tested for HIV, HBV, HCV and syphilis. RESULTS:Of the 118 FSWs enrolled, all were negative for both HIV and HCV infection. Two women (1.6%) were positive for hepatitis B (HbsAg). Syphilis testing by VDRL showed three positive results (2.5%), which was confirmed by TPHA. DISCUSSION:This study showed that HIV, HBV, HCV and syphilis seroprevalence among Colombian and Dominican FSWs remains low or very rare. It also indicates that these women were healthy when they arrived in Italy and that condom use with clients is high.

背景与目标：

BACKGROUND & AIMS: :Go/Gi coupled G-protein receptor mediated transactivation is critical in the activation of receptor tyrosine kinases (RTK). Here we show that mu opioid receptor (MOR) transactivates Flk1 and platelet-derived growth factor-beta (PDGF-beta) receptors and its agonist morphine stimulates pro-angiogenic and survival-promoting signaling in mouse retinal endothelial cells (mREC). Morphine stimulates mREC proliferation in a dose dependent fashion and promotes survival to the same extent as vascular endothelial growth factor164 (VEGF164). Morphine stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt phosphorylation in a time dependent manner like VEGF in mREC. Moreover, analogous to VEGF, morphine stimulates oncogenic signal transducer and activator of transcription 3 (STAT3) signaling. Morphine as well as VEGF-induced phospho-STAT3 and phospho-Flk1 immunoprecipitated with MOR-associated proteins. In addition morphine also stimulated MOR associated PDGF-beta receptor phosphorylation. Consistent with the relationship between VEGF and MOR we found that VEGF upregulates MOR protein and RNA expression in mREC. These data suggest that MOR associates and transactivates RTKs for Flk1 and PDGF-beta, which may have a compounding effect on angiogenic signaling in endothelium. Therefore, G-Protein coupled receptors including MOR provide novel targets to develop anti-angiogenic agents.

背景与目标： : Go/Gi偶联的g蛋白受体介导的反式激活在受体酪氨酸激酶 (RTK) 的激活中至关重要。在这里，我们显示mu阿片受体 (MOR) 反式激活Flk1和血小板衍生的生长因子-β (pdgf-β) 受体及其激动剂吗啡刺激小鼠视网膜内皮细胞 (mREC) 中的促血管生成和促进存活的信号。吗啡以剂量依赖性方式刺激mREC增殖，并以与血管内皮生长因子164 (VEGF164) 相同的程度促进存活。吗啡以时间依赖性方式刺激丝裂原激活的蛋白激酶/细胞外信号调节激酶 (MAPK/ERK) 和Akt磷酸化，如mREC中的VEGF。此外，与VEGF类似，吗啡刺激致癌信号转导和转录激活因子3 (STAT3) 信号传导。吗啡以及VEGF诱导的phospho-STAT3和phospho-Flk1用MOR相关蛋白免疫沉淀。此外，吗啡还刺激MOR相关的PDGF-β 受体磷酸化。与VEGF和MOR之间的关系一致，我们发现VEGF上调了MOR蛋白和RNA在mREC中的表达。这些数据表明，MOR关联并反式激活了Flk1和PDGF-β 的RTKs，这可能对内皮中的血管生成信号传导具有复合作用。因此，包括MOR在内的g蛋白偶联受体为开发抗血管生成剂提供了新的靶标。

BACKGROUND & AIMS: OBJECTIVE:To compare prostate carcinoma, with and with no lymph node metastasis, to benign prostatic hyperplasia (BPH) tissue for lymphatic vessel density (LVD) and the expression of the lymph-endothelial specific growth factor, vascular endothelial growth factor C (VEGF-C), to determine their role in lymphogenic metastasis. PATIENTS, MATERIALS AND METHODS:Lymphatic vessels were stained using lymphatic vessel endothelial hyaluronan receptor 1 and assessed in standard areas. The expression of VEGF-C was assessed by the number of positive epithelial cells. The data were compared with the clinical staging. RESULTS:The lowest LVD was found in tumorous areas as opposed to periphery and nontumorous tissue (P = 0.007; P < 0.001). The highest LVD was in BPH tissue (P < 0.001). There was no correlation with clinical staging. There was more VEGF-C staining in pN1 than in pN0 and in BPH specimens (P = 0.002). CONCLUSION:LVD is not a prognostic variable for the process of lymphogenic metastasis in prostate cancer. VEGF-C is up-regulated in prostate cancer and its correlation with lymph node status suggests a role for the development of lymph node metastasis, e.g. via an increased permeability of lymphatic vessels.

背景与目标：

BACKGROUND & AIMS: OBJECTIVES:To describe the prevalence of oral diseases and their impact on oral-health-related quality of life in people with severe mental illness undertaking community-based psychiatric care. METHODS:A survey was conducted at eight outpatient psychiatric care clinics in Tower Hamlets, London, UK. One hundred and twelve consecutive patients with mental illness were invited to participate in this study. They were clinically examined and asked to complete the oral health impact profile (OHIP) questionnaire. RESULTS:The response rate was 79% (n = 89); 57 (64%) males and 58 persons over 45 years of age (65%) participated in this survey. Overall OHIP score was 25.4 (95% CI 23.3, 27.4), 70 (78%) were smokers and 45 (51%) had been to the dentist in the last two years. Forty-seven (53%) respondents had caries in at least one tooth, 60 (67%) had 21 teeth and more, and 14 (16%) used dentures. Advanced periodontal treatment was indicated in 42 (55%) of patients and 52.8% (n = 47) patients reported current pain. CONCLUSION:Overall, this survey found that oral health has a great impact on patients with severe mental illness being treated in the community setting and their oral health is poorer than the national adult general population. Future research should consider the causes that relate to the poorer oral health in this population and potential health promotion mechanisms in this population to encourage an upstream approach to health.

背景与目标：

BACKGROUND & AIMS: :Thrombosis is the main cause of failure of small-diameter synthetic vascular grafts when used for by-pass procedures. The development of bioresorbable vascular scaffolds with localized and sustained intra-luminal antithrombotic drug release could be considered a desirable improvement towards a valuable solution for this relevant clinical need. For this aim, we present the fabrication and characterization of aspirin-loaded electrospun poly(ε-caprolactone) tubular scaffolds as a vascular drug-delivery graft. Three different drug concentrations were considered (i.e., 1, 5 or 10 % w/w). Although a fibrous structure was clearly observed for all the collected scaffolds, aspirin content was directly implied in the final microstructure leading to a bimodal fiber diameter distribution and fused fibers at crossing-points (5 or 10 % w/w). Mechanical response highlighted a direct relationship for modulus and stress at break with the aspirin content, while the elongation at break was not remarkably different for the investigated cases. The temporal drug release was strongly dependent from the amount of loaded aspirin, reaching a steady state release after about 50 h. Finally, the adhesion assay confirmed the capability of the electrospun scaffolds to reduce platelet adhesion/aggregation onto aspirin loaded polymeric fibers. Aspirin-loaded electrospun tubular scaffold could represent a feasible candidate to develop a novel bioresorbable drug-releasing graft for small-diameter vessel replacements.

背景与目标： : 血栓形成是用于旁路手术时小直径合成血管移植物失败的主要原因。开发具有局部和持续的腔内抗血栓药物释放的生物可吸收血管支架可被认为是针对此相关临床需求的有价值解决方案的理想改进。为此，我们介绍了负载阿司匹林的电纺聚 (ε-己内酯) 管状支架作为血管药物递送移植物的制备和表征。考虑三种不同的药物浓度 (即1、5或10% w/w)。尽管对于所有收集的支架都清楚地观察到纤维结构，但在最终微结构中直接隐含阿司匹林含量，导致双峰纤维直径分布和在交叉点处的融合纤维 (5或10% w/w)。机械响应强调了模量和断裂应力与阿司匹林含量的直接关系，而断裂伸长率在所研究的情况下没有显着差异。暂时的药物释放强烈依赖于阿司匹林的载量，约50小时后达到稳定状态释放。最后，粘附试验证实了电纺支架减少血小板粘附/聚集在阿司匹林负载的聚合物纤维上的能力。阿司匹林负载的电纺管状支架可能是开发用于小直径血管置换的新型生物可吸收药物释放移植物的可行候选者。

BACKGROUND & AIMS: :From 1982 to 1987, 2,433 lesions of the thyroid gland in 1,796 patients were examined by fine needle aspiration (FNA). Cytopathology classified 66.91% of the aspirates as benign, 10.76% as thyroiditis, 4.89% as suspected (unspecified) neoplasia, 1.31% as positive for malignancy and 16.11% (392) as unsatisfactory. The histologic diagnoses in 257 cases were compared with cytologic diagnoses to determine the accuracy of FNA cytology of thyroid lesions, yielding a sensitivity of 71.43%, a specificity of 100% and an accuracy of 95.09%. This data strongly supports thyroid FNA as an important preoperative diagnostic tool. Follicular carcinomas were difficult to cytologically differentiate from nonmalignant follicular neoplasms, and papillary thyroid carcinomas less than 2 cm in diameter in elderly patients were frequently misdiagnosed or diagnosed only as "suspect lesion."

背景与目标： : 从1982个1987年中，通过细针穿刺 (FNA) 检查了1,796例患者的2,433个甲状腺病变。细胞病理学将66.91% 抽吸物分类为良性，10.76% 为甲状腺炎，4.89% 为疑似 (未指定) 肿瘤，1.31% 为恶性肿瘤阳性，16.11% (392) 为不满意。将257例的组织学诊断与细胞学诊断进行比较，以确定甲状腺病变的FNA细胞学检查的准确性，从而产生71.43% 的敏感性，100% 的特异性和95.09% 的准确性。该数据强烈支持甲状腺FNA作为重要的术前诊断工具。滤泡癌在细胞学上很难与非恶性滤泡肿瘤区分开来，而老年患者直径小于2厘米的甲状腺乳头状癌经常被误诊或仅被诊断为 “可疑病变”。

BACKGROUND & AIMS: :Mutations in the senataxin (SETX) gene can cause amyotrophic lateral sclerosis 4 (ALS4), an autosomal dominant form of juvenile onset amyotrophic lateral sclerosis, or result in autosomal recessive ataxia with oculomotor apraxia type 2. Great caution regarding the possible disease causation, especially of missense variations, has to be taken. Here, we evaluated the significance of all previously reported SETX missense mutations as well as six newly identified variations in 54 patients suspected of having ALS4. Yet, epidemiologic and in silico evidence indicates that all newly identified variations and two previously published ALS4-related missense variations (C1554G and I2547T) are most likely non-pathogenic, demonstrating the problems of interpretation of SETX missense alleles in the absence of functional assays.

背景与目标： : senataxin (SETX) 基因的突变可导致肌萎缩性侧索硬化症4 (ALS4)，这是一种常染色体显性遗传形式的少年性肌萎缩性侧索硬化症，或导致常染色体隐性遗传性共济失调并伴有动眼失用2型。对于可能的疾病原因，尤其是错义变异，必须谨慎行事。在这里，我们评估了所有先前报道的SETX错义突变以及54例怀疑患有als4的患者中新发现的六个变异的重要性。然而，流行病学和计算机证据表明，所有新发现的变异和两个先前发表的ALS4-related错义变异 (C1554G和I2547T) 最有可能是非致病性的，证明了在缺乏功能测定的情况下解释SETX错义等位基因的问题。

BACKGROUND & AIMS: :Spontaneous intracranial hemorrhage is a debilitating form of stroke, often leading to death or permanent cognitive impairment. Many of the causative genes and the underlying mechanisms implicated in developmental cerebral-vascular malformations are unknown. Recent in vitro and in vivo studies in mice have shown inhibition of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway to be effective in stabilizing cranial vessels. Using a combination of pharmacological and genetic approaches to specifically inhibit the HMGCR pathway in zebrafish (Danio rerio), we demonstrate a requirement for this metabolic pathway in developmental vascular stability. Here we report that inhibition of HMGCR function perturbs cerebral-vascular stability, resulting in progressive dilation of blood vessels, followed by vessel rupture, mimicking cerebral cavernous malformation (CCM)-like lesions in humans and murine models. The hemorrhages in the brain are rescued by prior exogenous supplementation with geranylgeranyl pyrophosphate (GGPP), a 20-carbon metabolite of the HMGCR pathway, required for the membrane localization and activation of Rho GTPases. Consistent with this observation, morpholino-induced depletion of the β-subunit of geranylgeranyltransferase I (GGTase I), an enzyme that facilitates the post-translational transfer of the GGPP moiety to the C-terminus of Rho family of GTPases, mimics the cerebral hemorrhaging induced by the pharmacological and genetic ablation of HMGCR. In embryos with cerebral hemorrhage, the endothelial-specific expression of cdc42, a Rho GTPase involved in the regulation of vascular permeability, was significantly reduced. Taken together, our data reveal a metabolic contribution to the stabilization of nascent cranial vessels, requiring protein geranylgeranylation acting downstream of the HMGCR pathway.

背景与目标： 自发性颅内出血是中风的一种衰弱形式，通常导致死亡或永久性认知障碍。与发育性脑血管畸形有关的许多致病基因和潜在机制尚不清楚。最近在小鼠中进行的体外和体内研究表明，抑制3-羟基-3-甲基戊二酰-coa还原酶 (HMGCR) 途径可有效稳定颅骨血管。使用药理学和遗传学方法相结合的方法来特异性抑制斑马鱼 (Danio rerio) 中的HMGCR途径，我们证明了这种代谢途径在发育血管稳定性中的需求。在这里，我们报告了HMGCR功能的抑制会干扰脑血管的稳定性，导致血管进行性扩张，然后血管破裂，模仿人和鼠模型中的脑海绵状畸形 (CCM) 样病变。通过事先补充香叶基焦磷酸 (GGPP) (HMGCR途径的20碳代谢产物) 来挽救脑部出血，这是Rho GTPases膜定位和激活所必需的。与该观察结果一致，吗啉代诱导的香叶基转移酶I (GGTase I) 的 β 亚基耗竭，该酶促进了GGPP部分翻译后转移到Rho gtp酶家族的C末端，模拟了HMGCR的药理和遗传消融引起的脑出血。在脑出血的胚胎中，参与调节血管通透性的Rho GTPase cdc42的内皮特异性表达显着降低。总之，我们的数据揭示了对新生颅骨血管稳定的代谢贡献，需要在HMGCR途径下游起作用的蛋白质香叶基。

BACKGROUND & AIMS: INTRODUCTION:Databases are useful tools in clinical settings. The authors review the benefits and challenges associated with the development and implementation of an efficient electronic database for the multidisciplinary Vascular Birthmark Clinic at the Alberta Children's Hospital, Calgary, Alberta. METHODS:The content and structure of the database were designed using the technical expertise of a data analyst from the Calgary Health Region. Relevant clinical and demographic data fields were included with the goal of documenting ongoing care of individual patients, and facilitating future epidemiological studies of this patient population. After completion of this database, 10 challenges encountered during development were retrospectively identified. Practical solutions for these challenges are presented. RESULTS:THE CHALLENGES IDENTIFIED DURING THE DATABASE DEVELOPMENT PROCESS INCLUDED: identification of relevant data fields; balancing simplicity and user-friendliness with complexity and comprehensive data storage; database expertise versus clinical expertise; software platform selection; linkage of data from the previous spreadsheet to a new data management system; ethics approval for the development of the database and its utilization for research studies; ensuring privacy and limited access to the database; integration of digital photographs into the database; adoption of the database by support staff in the clinic; and maintaining up-to-date entries in the database. CONCLUSIONS:There are several challenges involved in the development of a useful and efficient clinical database. Awareness of these potential obstacles, in advance, may simplify the development of clinical databases by others in various surgical settings.

背景与目标：

BACKGROUND & AIMS: :The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release. For reconfirming the findings of the animal studies when administering 1 to healthy human volunteers, a phase I clinical trial was conducted. Apart from further information regarding the pharmacokinetic and pharmacodynamic characteristics of 1, it was demonstrated that dual inhibition of p38α MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.

背景与目标： : p38丝裂原活化蛋白激酶 (MAPK) 抑制剂的抗炎潜力被巧合地扩展为对p38α MAPK和磷酸二酯酶4 (PDE4) 的双重抑制，并且两种炎症相关酶的阻断所产生的潜在益处被彻底研究。在对啮齿动物，狗和猴子施用1之后，在体外实验以及体外和体内临床前研究中相继评估了最有希望的化合物CBS-3595 (1)。所得数据清楚地表明有效抑制了肿瘤坏死因子 α 的释放。为了在向健康的人类志愿者施用1时再次确认动物研究的结果，进行了I期临床试验。除了有关1的药代动力学和药效学特征的进一步信息外，还证明了p38α MAPK和PDE4的双重抑制能够协同减弱过度的抗炎反应。