• 【药物见解:男性激素避孕的最新进展。】 复制标题 收藏 收藏
    DOI:10.1038/ncpendmet0069 复制DOI
    作者列表:Amory JK,Page ST,Bremner WJ
    BACKGROUND & AIMS: :As there are limitations to current methods of male contraception, research has been undertaken to develop hormonal contraceptives for men, analogous to the methods for women based on estrogen and progestogens. When testosterone is administered to a man, it functions as a contraceptive by suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. Since these hormones are the main stimulatory signals for spermatogenesis, low levels of LH and FSH markedly impair sperm production. After 3-4 months of testosterone treatment, 60-70% of men no longer have sperm in their ejaculate, and most other men exhibit markedly diminished sperm counts. Male hormonal contraception is well tolerated, free of serious adverse side effects, and 95% effective in the prevention of pregnancy. Importantly, male hormonal contraception is reversible, with sperm counts usually recovering within 4 months of the discontinuation of hormone treatment. Because exogenous testosterone administration alone does not completely suppress sperm production in all men, researchers have combined testosterone with second agents, such as progestogens or gonadotropin-releasing-hormone antagonists, to further suppress secretion of LH and FSH and improve suppression of spermatogenesis. Recent trials have used combinations of long-acting injectable or implantable forms of testosterone with progestogens, which can be administered orally, by injection or by a long-acting implant. Such combinations suppress spermatogenesis to zero without severe side effects in 80-90% of men, with near-complete suppression in the remainder of individuals. One of these testosterone and progestogen combination regimens might soon bring the promise of male hormonal contraception to fruition.
    背景与目标: :由于目前男性避孕方法的局限性,已经进行了研究以开发男性荷尔蒙避孕药,类似于基于雌激素和孕激素的女性避孕方法。当男人服用睾丸激素时,它通过抑制垂体促黄体生成激素(LH)和促卵泡激素(FSH)的分泌而起避孕作用。由于这些激素是精子发生的主要刺激信号,因此低水平的LH和FSH明显损害了精子的产生。经过3-4个月的睾丸激素治疗后,60-70%的男性不再有精子射精,其他大多数男性的精子数量也明显减少。男性荷尔蒙避孕药耐受性好,没有严重的不良副作用,并且95%的预防怀孕有效。重要的是,男性荷尔蒙避孕是可逆的,在停止激素治疗后的4个月内,精子数量通常会恢复。由于单独使用外源性睾丸激素并不能完全抑制所有男性的精子产生,因此研究人员已将睾丸激素与第二种药物(如孕激素或促性腺激素释放激素拮抗剂)联合使用,以进一步抑制LH和FSH的分泌并改善对精子发生的抑制作用。最近的试验已将长效可注射或可植入形式的睾丸激素与孕激素结合使用,可以口服,注射或长效植入物给药。这样的组合在80-90%的男性中将精子发生抑制为零而没有严重的副作用,而在其余个体中则几乎完全被抑制。这些睾丸激素和孕激素联合治疗方案之一可能很快会带来雄激素避孕的希望。
  • 【体外药物活性和药代动力学在预测抗分枝杆菌疗法有效性中的价值:一项重要综述。】 复制标题 收藏 收藏
    DOI:10.1097/00000441-199706000-00008 复制DOI
    作者列表:Burman WJ
    BACKGROUND & AIMS: Marked increases in case rates of drug-resistant tuberculosis and nontuberculous mycobacterial infections have brought renewed urgency to the development of new treatment regimens for mycobacterial infections. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of drug-susceptible tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial therapy. In vitro measures of drug activity predict the potency of a drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a drug or the activity of drug combinations. In vitro measures of drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of drug activity but still do not predict sterilizing activity. In contrast, animal models of tuberculosis have predicted relative drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.

    背景与目标: 耐药结核病和非结核分枝杆菌感染的病例率显着增加,这为开发针对分枝杆菌感染的新治疗方案带来了新的紧迫性。临床前数据,例如药物活性和药代动力学的体外测量,用于设计新的治疗方案。这篇综述调查了有关药物敏感性肺结核治疗的广泛发表的临床经验,以评估这些临床前措施在预测抗分枝杆菌治疗的临床结果中的应用。药物活性的体外量度可以预测药物对其他抗分枝杆菌药物产生抗药性的能力,但不能预测药物的灭菌活性或药物组合的活性。药物活性的体外测量不能可靠地预测应将生物体视为抗药性的水平。药物在组织中的渗透和针对细胞内细菌的活性的测定适度地增加了药物活性体外测量的预测价值,但仍不能预测灭菌活性。相反,结核病的动物模型预测了相对的药效(包括杀菌活性),多种药物疗法的疗效以及所需的治疗时间。尽管药代动力学参数表明每天需要多剂量,但每隔一周两次不频繁使用时,所有一线抗结核药物均具有活性。难以预测具有休眠能力的细胞内病原体的治疗效果。需要更好的体外模型,尤其是预测杀菌活性的模型。

  • 【进入三级医院内科病房的患者不良药物反应的直接费用和临床方面】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Tribiño G,Maldonado C,Segura O,Díaz J
    BACKGROUND & AIMS: INTRODUCTION:Adverse drug reactions (ADRs) occur frequently in hospitals and increase costs of health care; however, few studies have quantified the clinical and economic impact of ADRs in Colombia. OBJECTIVES:These impacts were evaluated by calculating costs associated with ADRs in patients hospitalized in the internal medicine ward of a Level 3 hospital located in Bogotá, Colombia. In addition, salient clinical features of ADRs were identified and characterized. MATERIAL AND METHODS:Intensive follow-ups for a cohort of patients were conducted for a five month period in order to detect ADRs; different ways to classify them, according to literature, were considered as well. Information was collected using the INVIMA reporting format, and causal probability was evaluated with the Naranjo algorithm. Direct costs were calculated from the perspective of payer, based on the following costs: additional hospital stay, medications, paraclinical tests, additional procedures, patient displacement to intermediate or intensive care units, and other costs. RESULTS:Of 836 patients admitted to the service, 268 adverse drug reactions were detected in 208 patients (incidence proportion 25.1%, occurence rate 0.32). About the ADRs found, 74.3% were classified as probable, 92.5% were type A, and 81.3% were moderate. The body system most often affected was the circulatory system (33.9%). Drugs acting on the blood were most frequently those ones associated with adverse reactions (37.6%). The costs resulting from medical care of adverse drug reactions varied from COL dollar 93,633,422 (USD dollar 35,014.92) to COL dollar 122,155,406 (USD dollar 45,680.94), according to insurance type, during the study period. CONCLUSIONS:Adverse drug reactions have a significant negative health and financial impact on patient welfare. Because of the substantial resources required for their medical care and the significant proportion of preventable adverse reactions, active programs of institutional pharmacovigilance are highly recommended.
    背景与目标: 简介:药物不良反应(ADR)在医院中经常发生,并增加了医疗保健费用;但是,很少有研究能够量化ADR在哥伦比亚的临床和经济影响。
    目的:通过计算在哥伦比亚波哥大三级医院内科病房住院的患者与ADR相关的费用来评估这些影响。此外,ADR的显着临床特征已得到鉴定和表征。
    材料与方法:对一组患者进行了为期五个月的强化随访,以检测ADR。根据文献,还考虑了不同的分类方法。使用INVIMA报告格式收集信息,并使用Naranjo算法评估因果概率。直接费用是根据以下费用从付款人的角度计算的:额外的住院时间,药物,辅助临床检查,其他程序,将患者转移到中级或重症监护室以及其他费用。
    结果:836例入院患者中,208例患者发生了268例药物不良反应(发生率25.1%,发生率0.32)。关于发现的ADR,有74.3%被归为可能,A型为92.5%,中度为81.3%。受影响最严重的身体系统是循环系统(33.9%)。作用于血液的药物最常见于那些与不良反应有关的药物(37.6%)。根据保险类型,在研究期间,药物不良反应的医疗费用从93,633,422美元(35,014.92美元)到122,155,406美元(45,680.94美元)不等。
    结论:药物不良反应会对患者的健康产生重大的负面健康和财务影响。由于其医疗服务所需的大量资源以及可预防的不良反应的比例很大,因此强烈建议积极进行机构药物警戒计划。
  • 【吸毒规则:古代世界中的葡萄酒和罂粟衍生物。六。罂粟是食物和毒品的来源。】 复制标题 收藏 收藏
    DOI:10.3109/10826089709039375 复制DOI
    作者列表:Nencini P
    BACKGROUND & AIMS: :Poppies were widely used during antiquity as a source of food, therapeutics, and poisons. It is likely that the alimentary value of poppy seeds was known in the Neolithic age, and there is some evidence that the neuropsychopharmacological effects of poppy juice were exploited during the Minoan civilization in the eastern Mediterranean basin. The Minoan civilization dates the attribution to poppies of symbolic meanings connected with rites of agricultural fertility. The persistence throughout antiquity of this symbolism is testified by literary and iconographic evidence of the attribution of poppies to goddesses of fertility, such as Demeter, Aphrodite, and Ceres.
    背景与目标: :在古代,罂粟被广泛用作食物,治疗剂和毒药的来源。罂粟种子的营养价值很可能是在新石器时代就已经知道的,并且有一些证据表明,罂粟汁的神经心理药理作用是在地中海东部的米诺斯文明期间被利用的。米诺斯文明可追溯到象征意义的罂粟的归属,这些象征意义与农业生育的仪式有关。这种象征主义在整个上古时代的持久性通过文学和肖像学证据证明,罂粟归因于狄特耳特,阿芙罗狄蒂和谷神星等生育女神。
  • 【耐药细胞提取物中癌基因依赖性细胞凋亡。】 复制标题 收藏 收藏
    DOI:10.1101/gad.11.10.1266 复制DOI
    作者列表:Fearnhead HO,McCurrach ME,O'Neill J,Zhang K,Lowe SW,Lazebnik YA
    BACKGROUND & AIMS: Many genotoxic agents kill tumor cells by inducing apoptosis; hence, mutations that suppress apoptosis produce resistance to chemotherapy. Although directly activating the apoptotic machinery may bypass these mutations, how to achieve this activation in cancer cells selectively is not clear. In this study, we show that the drug-resistant 293 cell line is unable to activate components of the apoptotic machinery-the ICE-like proteases (caspases)-following treatment with an anticancer drug. Remarkably, extracts from untreated cells spontaneously activate caspases and induce apoptosis in a cell-free system, indicating that drug-resistant cells have not only the apoptotic machinery but also its activator. Comparing extracts from cells with defined genetic differences, we show that this activator is generated by the adenovirus E1A oncogene and is absent from normal cells. We provide preliminary characterization of this oncogene generated activity (OGA) and show that partially purified OGA activates caspases when added to extracts from untransformed cells. We suggest that agents that link OGA to caspases in cells would kill tumor cells otherwise resistant to conventional cancer therapy. As this killing relies on an activity generated by an oncogene, the effect of these agents should be selective for transformed cells.

    背景与目标: 许多遗传毒性剂通过诱导细胞凋亡杀死肿瘤细胞。因此,抑制细胞凋亡的突变产生了对化学疗法的抗性。尽管直接激活凋亡机制可能绕过这些突变,但是如何在癌细胞中选择性地实现这种激活尚不清楚。在这项研究中,我们显示了抗药性293细胞系无法激活凋亡机制的成分(如ICE样蛋白酶(胱天蛋白酶)),随后进行了抗癌药物治疗。值得注意的是,未经处理的细胞提取物会自发激活胱天蛋白酶并在无细胞系统中诱导凋亡,这表明耐药细胞不仅具有凋亡机制,还具有其激活剂。比较具有确定的遗传差异的细胞提取物,我们表明该激活剂是由腺病毒E1A癌基因产生的,而正常细胞中却不存在。我们提供了此致癌基因产生的活性(OGA)的初步表征,并表明当添加到未转化细胞的提取物中时,部分纯化的OGA会激活胱天蛋白酶。我们建议将OGA与细胞中的半胱氨酸蛋白酶连接的药剂会杀死肿瘤细胞,否则它们会对常规癌症治疗产生抵抗力。由于这种杀伤作用依赖于癌基因产生的活性,因此这些药剂对转化细胞的作用应该是选择性的。

  • 【腺病毒对细胞蛋白质合成的抑制作用被药物2-氨基嘌呤阻止。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.87.18.7115 复制DOI
    作者列表:Huang JT,Schneider RJ
    BACKGROUND & AIMS: :Adenovirus infection results in the suppression of cellular protein synthesis, but the mechanism has not been established. In this report we demonstrate that the shut-off of cellular protein synthesis by adenovirus is prevented in cells by treatment with the drug 2-aminopurine. Treatment with 2-aminopurine is shown to prevent suppression of cellular translation without disrupting the normal viral block in the transport of cellular mRNAs from the nucleus to the cytoplasm. We show that viral suppression of cellular protein synthesis occurs concomitant with activation of the interferon-induced double-stranded RNA-activated inhibitor (DAI), a protein kinase, and phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha), but that prevention of host cell shut-off by 2-aminopurine occurs without a decrease in kinase activity or a dephosphorylation of eIF-2 alpha. Results are presented that indicate that activation of DAI kinase and phosphorylation of eIF-2 alpha may be required but are not sufficient to achieve inhibition of cellular protein synthesis during adenovirus infection. We suggest that other events, in particular the modification of additional initiation factors, are likely involved in viral inhibition of cellular translation.
    背景与目标: :腺病毒感染导致细胞蛋白质合成受到抑制,但该机制尚未建立。在本报告中,我们证明了通过用2-氨基嘌呤药物治疗可防止腺病毒关闭细胞蛋白质合成。已显示用2-氨基嘌呤处理可防止细胞翻译受到抑制,而不会破坏细胞mRNA从细胞核到细胞质的运输过程中的正常病毒阻滞。我们显示病毒抑制细胞蛋白质合成的发生与干扰素诱导的双链RNA激活的抑制剂(DAI),蛋白激酶和真核生物起始因子2(eIF-2 alpha)的α亚基的磷酸化的激活同时发生。 ,但可以防止2-氨基嘌呤阻止宿主细胞的关闭,而不会降低激酶活性或eIF-2α的去磷酸化。结果表明,可能需要DAI激酶的激活和eIF-2α的磷酸化,但不足以抑制腺病毒感染期间细胞蛋白质合成。我们建议其他事件,特别是其他起始因子的修饰,可能与细胞翻译的病毒抑制有关。
  • 【开放性扩展研究旨在研究THC / CBD口腔粘膜喷雾剂和口腔粘膜THC喷雾剂在晚期癌症相关疼痛至强阿片类镇痛药难以治疗的患者中的长期安全性和耐受性。】 复制标题 收藏 收藏
    DOI:10.1016/j.jpainsymman.2012.07.014 复制DOI
    作者列表:Johnson JR,Lossignol D,Burnell-Nugent M,Fallon MT
    BACKGROUND & AIMS: CONTEXT:Chronic pain in patients with advanced cancer poses a serious clinical challenge. The Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (U.S. Adopted Name, nabiximols; Sativex(®)) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group. OBJECTIVES:This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer. METHODS:In total, 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing, who had participated in a previous three-arm (THC/CBD spray, THC spray, or placebo), two-week parent randomized controlled trial, entered this open-label, multicenter, follow-up study. Patients self-titrated THC/CBD spray (n=39) or THC spray (n=4) to symptom relief or maximum dose and were regularly reviewed for safety, tolerability, and evidence of clinical benefit. RESULTS:The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for "pain severity" and "worst pain" domains showed a decrease (i.e., improvement) at each visit in the THC/CBD spray patients. Similarly, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scores showed a decrease (i.e., improvement) from baseline in the domains of insomnia, pain, and fatigue. No new safety concerns associated with the extended use of THC/CBD spray arose from this study. CONCLUSION:This study showed that the long-term use of THC/CBD spray was generally well tolerated, with no evidence of a loss of effect for the relief of cancer-related pain with long-term use. Furthermore, patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time, suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit.
    背景与目标: 背景:晚期癌症患者的慢性疼痛提出了严峻的临床挑战。 Δ9-四氢大麻酚(THC)/大麻二酚(CBD)口腔粘膜喷雾剂(美国采用名称,nabiximols;Sativex®)是一种新型大麻素制剂,目前正在接受治疗,作为该治疗组的辅助疗法。
    目的:这项随访研究调查了THC / CBD喷雾剂和THC喷雾剂在缓解晚期癌症患者的疼痛方面的长期安全性和耐受性。
    方法:总共有43例癌症相关疼痛患者尽管使用了阿片类药物长期服用,但仍没有足够的镇痛作用,他们参加了先前的三组试验(THC / CBD喷雾剂,THC喷雾剂或安慰剂),为期两周的父母随机对照试验,参加了这项开放性,多中心的后续研究。患者自行滴定THC / CBD喷雾剂(n = 39)或THC喷雾剂(n = 4)以缓解症状或最大剂量,并定期检查其安全性,耐受性和临床获益证据。
    结果:THC / CBD喷剂患者每次就诊时,“疼痛严重程度”和“最严重疼痛”域的平均简短疼痛清单-简表得分的基线变化的功效终点显示出降低(即改善)。同样,欧洲癌症生活质量研究和治疗组织问卷-C30的得分显示,失眠,疼痛和疲劳程度较基线水平有所降低(即有所改善)。这项研究没有引起与广泛使用THC / CBD喷雾剂相关的新安全隐患。
    结论:这项研究表明,长期使用THC / CBD喷雾剂通常具有良好的耐受性,没有证据表明长期使用THC / CBD喷雾剂可减轻癌症相关疼痛。此外,继续使用研究药物的患者并未寻求随时间增加这种药物或其他缓解疼痛药物的剂量,这表明在与癌症相关的疼痛中辅助使用大麻素可提供有益的益处。
  • 【CHADS2评分与阵发性房颤患者抗心律失常药物治疗疗效之间的关系。】 复制标题 收藏 收藏
    DOI:10.1253/circj.cj-12-0854 复制DOI
    作者列表:Komatsu T,Sato Y,Ozawa M,Kunugita F,Ueda H,Tachibana H,Morino Y,Nakamura M
    BACKGROUND & AIMS: BACKGROUND:The Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] (CHADS(2)) score is a useful scheme for risk stratification of thromboembolism patients, but there is little information about its usefulness for the evaluation of antiarrhythmic drug (AAD) therapy. METHODS AND RESULTS:This study included 459 paroxysmal atrial fibrillation (AF) patients (309 men, mean age 66 ± 12 years, mean follow-up 50 ± 35 months) and prophylactic efficacy was analyzed on the basis of CHADS(2) score. (1) Survival rates free from AF recurrence at 1, 6, 12 and 24 months were, respectively, 89%, 74%, 63% and 47% in score-0 group (n=152); 92%, 68%, 59% and 48% in score-1 group (n=158); 86%, 64%, 56% and 46% in score-2 group (n=84); 81%, 65%, 51% and 35% in score-3 group (n=43); and 68%, 50%, 36% and 18% in ≥ score-4 group (n=22) (P<0.05; score-0, score-1 or score-2 vs. ≥ score-4 group). (2) Survival rates free from progression to chronic AF at 12, 36, 60 and 90 months were, respectively, 95%, 93%, 91% and 89% in score-0 group; 97%, 91%, 89% and 88% in score-1 group; 96%, 93%, 88% and 83% in score-2 group; 91%, 74%, 67% and 60% in score-3 group; and 91%, 82%, 68% and 55% in ≥ score-4 group (P<0.01; score-0, score-1 or score-2 vs. ≥ score-4 group). (3) In multivariate logistic regression analysis adjusted for potentially confounding variables, CHADS(2) score was associated with AF recurrence (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.16-1.81, P<0.001), and progression to chronic AF during AAD therapy (OR 1.64, 95% CI 1.04-2.69, P<0.001). CONCLUSIONS:When using a rhythm control strategy, the CHADS(2) score is a useful scheme for predicting the outcome of AAD treatment of patients with paroxysmal AF.  
    背景与目标: 背景:心脏衰竭,高血压,年龄,糖尿病,中风[加倍](CHADS(2))评分是对血栓栓塞患者进行风险分层的有用方案,但有关其对抗心律不齐药物(AAD)评估的有用性的信息很少) 治疗。
    方法与结果:这项研究纳入459例阵发性房颤(AF)患者(309名男性,平均年龄66±12岁,平均随访50±35个月),并根据CHADS(2)评分分析了其预防性疗效。 (1)得分为0的组在1、6、12和24个月无房颤复发的生存率分别为89%,74%,63%和47%(n = 152);得分1组(n = 158)为92%,68%,59%和48%;得分2组分别为86%,64%,56%和46%(n = 84);得分3组(n = 43)分别为81%,65%,51%和35%; ≥分数4组的患者分别为68%,50%,36%和18%(n = 22)(P <0.05;分数≥0,分数1或得分2与≥分数4组相比)。 (2)在0级评分组中,在12、36、60和90个月无进展为慢性房颤的生存率分别为95%,93%,91%和89%;得分1组分别为97%,91%,89%和88%;得分2组分别为96%,93%,88%和83%;分数3组的比例分别为91%,74%,67%和60%; ≥4分组分别为91%,82%,68%和55%(P <0.01; 0分,1分或2分与≥4分组比较)。 (3)在针对潜在混杂变量进行调整的多因素logistic回归分析中,CHADS(2)评分与房颤复发相关(优势比[OR] 1.45、95%置信区间[CI] 1.16-1.81,P <0.001)和进展到AAD治疗期间的慢性房颤(OR 1.64,95%CI 1.04-2.69,P <0.001)。
    结论:使用节律控制策略时,CHADS(2)评分是预测阵发性房颤患者AAD治疗结果的有用方案。
  • 【将质量和安全纳入医学和护理学校课程并促进共同学习的努力的结果。】 复制标题 收藏 收藏
    DOI:10.1377/hlthaff.2011.0121 复制DOI
    作者列表:Headrick LA,Barton AJ,Ogrinc G,Strang C,Aboumatar HJ,Aud MA,Haidet P,Lindell D,Madigosky WS,Patterson JE
    BACKGROUND & AIMS: :Improvements in health care are slow, in part because doctors and nurses lack skills in quality improvement, patient safety, and interprofessional teamwork. This article reports on the Retooling for Quality and Safety initiative of the Josiah Macy Jr. Foundation and the Institute for Healthcare Improvement, which sought to integrate improvement and patient safety into medical and nursing school curricula. In one academic year, 2009-10, the initiative supported new learning activities (87 percent of which were interprofessional, involving both medical and nursing students) in classrooms, simulation centers, and clinical care settings that involved 1,374 student encounters at six universities. The work generated insights-described in this article-into which learning goals require interprofessional education; how to create clinically based improvement learning for all students; and how to demonstrate the effects on students' behavior, organizational practice, and benefits to patients. A commonly encountered limiting factor for the programs was the lack of a critical mass of clinically based faculty members who were ready to teach about the improvement of care. What's more, the paucity of robust evaluation strategies for such programs suggests a future research agenda that deserves to be funded.
    背景与目标: :医疗保健方面的改进缓慢,部分原因是医生和护士缺乏提高质量,患者安全和跨专业团队合作的技能。本文报道了Josiah Macy Jr. Foundation和医疗保健改善研究所的“质量与安全重组”倡议,该倡议旨在将改善和患者安全纳入医疗和护理学校课程。在2009-10学年的一个学年中,该计划支持了教室,模拟中心和临床护理环境中的新学习活动(其中87%是跨专业的,涉及医学和护理学的学生),涉及六所大学的1,374名学生。这项工作产生了本文中介绍的见解,其中的学习目标需要跨专业的教育;如何为所有学生创建基于临床的改进学习;以及如何证明对学生的行为,组织实践和对患者的好处的影响。该计划的一个普遍遇到的限制因素是缺乏足够数量的临床教师来准备教授改善护理的知识。而且,此类计划缺乏强有力的评估策略,这表明未来的研究议程值得资助。
  • 【手性识别多沙唑嗪对映体在3个靶标中的治疗作用以及在动物实验中的不良药物反应。】 复制标题 收藏 收藏
    DOI:10.1139/y2012-129 复制DOI
    作者列表:Zhao D,Duan LH,Wang FY,Wang M,Lu HG,Wu ZG,Wang X,Ren LM
    BACKGROUND & AIMS: :Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α(1A)-adrenoceptors (in the prostate), α(1D)-adrenoceptors (in the aorta), and an unknown mechanism (in the heart) are involved, respectively. We hypothesized that there is a chiral recognition of doxazosin enantiomers in the 3 targets. Using isolated rat aorta (α(1D)-adrenoceptors) and rabbit prostate (α(1A)-adrenoceptors), we examined pA(2) and pK(B) values of doxazosin enantiomers. We observed chronotropic and inotropic effects of doxazosin enantiomers in isolated rat and rabbit heart tissues. (-)Doxazosin and (+)doxazosin produced a shift to the right of concentration-contraction curves for noradrenalin (aorta) and phenylephrine (prostate smooth muscle). The pA(2) value of (-)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pK(B) values in rabbit prostate were the same. In rat and rabbit heart tissues, (+)doxazosin (3-30 µmol·L(-1)) significantly decreased atrial rate, and produced negative inotropic effects; however, (-)doxazosin did not affect the atrial rate, and produced positive inotropic effects in the atria. Thus, the chiral carbon atom of doxazosin does not affect its activity at the therapeutic target of α(1A)-adrenoceptors in the prostate, but significantly changes its blocking activity against α(1D)-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α(1)-adrenoceptor-independent mechanism.
    背景与目标: :多沙唑嗪用于前列腺增生症具有引起低血压和心力衰竭风险的副作用。 α(1A)-肾上腺素受体(在前列腺中),α(1D)-肾上腺素受体(在主动脉中)和未知机制(在心脏中)的3个靶点分别涉及。我们假设在3个靶标中有手性识别多沙唑嗪对映体。使用分离的大鼠主动脉(α(1D)-肾上腺素受体)和兔前列腺(α(1A)-肾上腺素受体),我们检查了多沙唑嗪对映体的pA(2)和pK(B)值​​。我们观察到了多沙唑嗪对映异构体在离体大鼠和兔心脏组织中的变时性和变力作用。 (-)多沙唑嗪和()多沙唑嗪使去甲肾上腺素(主动脉)和去氧肾上腺素(前列腺平滑肌)的浓度-收缩曲线向右移动。大鼠主动脉中(-)恶唑烷的pA(2)值(8.625±0.053)小于()恶唑烷(9.503±0.051),但它们在兔前列腺中的pK(B)值​​相同。在大鼠和兔子的心脏组织中,()多沙唑嗪(3-30 µmol·L(-1))显着降低心房率,并产生负性变力作用;然而,(-)doxazosin不会影响心房率,并在心房产生正性肌力作用。因此,多沙唑嗪的手性碳原子不影响其对前列腺中α(1A)-肾上腺素受体治疗靶点的活性,但会显着改变其对主动脉中α(1D)-肾上腺素受体的阻断活性,并产生相反的正性肌力作用通过独立于α(1)-肾上腺素受体机制的心房。
  • 【药房中抗肿瘤药污染水平的常规环境监测的应用和评估-MEWIP项目。】 复制标题 收藏 收藏
    DOI:10.1093/annhyg/mes081 复制DOI
    作者列表:Kiffmeyer TK,Tuerk J,Hahn M,Stuetzer H,Hadtstein C,Heinemann A,Eickmann U
    BACKGROUND & AIMS: :A large-scale study was carried out in order to determine the contamination level of antineoplastic drugs in pharmacies and to investigate the suitability and effects of wipe sample monitoring at regular intervals. A specific study design was developed. The 130 participating pharmacies were divided into a study and a control group, carrying out five and two wipe sampling cycles, respectively. The work practice was analyzed using questionnaires to identify factors that influence the contamination level. From 1269 wipe samples, 774 (61%) were contaminated with at least one of the analyzed cytotoxic drugs: cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, methotrexate, and paclitaxel. A significant decrease of the contamination with cyclophosphamide and 5-fluorouracil was observed in the study group. The Monitoring-Effect Study of Wipe Sampling in Pharmacies method has proven to be a reliable and affordable tool for contamination control. Based on the 90th percentile of the contamination values, a substance-independent performance-based guidance value of 0.1ng cm(-2) has been derived.
    背景与目标: :进行了一项大规模研究,以确定药房中抗肿瘤药的污染水平,并定期调查擦拭样品监测的适用性和效果。开发了具体的研究设计。将130家参与活动的药店分为研究组和对照组,分别进行了5次和2次擦拭采样。使用调查表对工作实践进行了分析,以找出影响污染水平的因素。从1269个擦拭样品中,有774个(61%)被至少一种分析的细胞毒性药物污染:环磷酰胺,多西他赛,依托泊苷,5-氟尿嘧啶,吉西他滨,异环磷酰胺,甲氨蝶呤和紫杉醇。在研究组中观察到环磷酰胺和5-氟尿嘧啶的污染显着降低。药房擦拭采样的监测效果研究方法被证明是一种可靠且负担得起的污染控制工具。基于污染值的第90个百分位数,得出了与物质无关的基于性能的指导值0.1ng cm(-2)。
  • 【基于多孔二氧化硅纳米粒子的难溶性水飞蓟宾的72小时释放制剂:比格犬的体外释放动力学和体内/体外相关性。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejps.2012.10.012 复制DOI
    作者列表:Cao X,Deng W,Fu M,Zhu Y,Liu H,Wang L,Zeng J,Wei Y,Xu X,Yu J
    BACKGROUND & AIMS: :The objective of this study was to prepare a 72 h-release formulation of silybin (72 h-SLB) using a combination of solid dispersion, gel matrix and porous silica nanoparticles (PSNs) and to investigate the in vitro/in vivo correlations (IVIVCs). The results of scanning electron microscopy and N(2) adsorption demonstrated that empty PSNs possessed a spherical shape, a highly porous structure, a large specific surface area (385.89 ± 1.12 m(2)/g) and a small pore size (2.74 nm on average). The in vitro dissolution profiles of both 72 h-SLB and silybin-loaded PSNs in different concentrations (0.01, 0.06 and 0.08M) of Na(2)CO(3) solutions revealed that 0.06 M Na(2)CO(3) solution was the optimal medium in which silybin could be released from 72 h-SLB with first-order release kinetics and from PSNs with Higuchi kinetics. Furthermore, the IVIVCs of 72 h-SLB and silybin-loaded PSNs in beagle dogs were also established. Using 0.06 M Na(2)CO(3) solution as the in vitro dissolution medium, a good linear relationship could be achieved for both 72 h-SLB and silybin-loaded PSNs. The findings support the fact that the 72 h-SLB (consisting of solid dispersion, regular gel matrix and PSNs) together with Na(2)CO(3) solution as an in vitro dissolution medium can be developed into a promising formulation for poorly soluble drugs, which enjoys a good IVIVC.
    背景与目标: :这项研究的目的是使用固体分散体,凝胶基质和多孔二氧化硅纳米粒子(PSN)的组合制备水飞蓟宾(72 h-SLB)的72 h释放制剂,并研究体内/体外相关性( IVIVC)。扫描电子显微镜和N(2)吸附的结果表明,空的PSN具有球形,高度多孔的结构,较大的比表面积(385.89±1.12 m(2)/ g)和较小的孔径(2.74 nm)一般)。 Nah(2)CO(3)解决方案中不同浓度(0.01、0.06和0.08M)的72 h-SLB和水飞蓟宾加载的PSNs的体外溶出曲线显示0.06 M Na(2)CO(3)解决方案是最佳的培养基,其中水飞蓟宾可以从72 h-SLB中以一级释放动力学释放,而从PSN中以Higuchi动力学释放。此外,还建立了比格犬中72 h-SLB和水飞蓟宾的PSN的IVIVC。使用0.06 M Na(2)CO(3)解决方案作为体外溶出介质,可以为72 h-SLB和水飞蓟宾加载的PSNs都实现良好的线性关系。这些发现支持以下事实:72 h-SLB(由固体分散体,规则的凝胶基质和PSN组成)与Na(2)CO(3)解决方案一起作为体外溶出介质,可以开发为溶解性较差的有前途的制剂药物,享有良好的IVIVC。
  • 【在晚期前列腺癌的早期药物开发中测试生物学假设的新策略。】 复制标题 收藏 收藏
    DOI:10.1373/clinchem.2012.185157 复制DOI
    作者列表:Ferraldeschi R,Attard G,de Bono JS
    BACKGROUND & AIMS: BACKGROUND:Major advances in our understanding of the underlying biology of prostate cancer have helped to herald a new era in the treatment of castration-resistant prostate cancer (CRPC), with 5 new agents having shown a survival advantage in the last 3 years and an impressive number of promising novel agents now entering the clinic. CONTENT:We discuss the challenges facing drug development for CRPC and strategies to meet these challenges, with a focus not only on the development of predictive and intermediate endpoint biomarkers, but also on novel hypothesis-testing, biomarker-driven clinical trial designs. SUMMARY:With several promising agents now entering the clinic, there is increasing pressure to rethink drug development for CRPC to ensure that novel agents are appropriately evaluated and that patients and resources are appropriately allocated. We envision that biomarker-driven, reiterative clinical trials will have a major impact on CRPC treatment through the testing of robust scientific hypotheses with rationally designed drugs and drug combinations administered to selected patients.
    背景与目标: 背景:我们对前列腺癌基础生物学的认识的重大进步帮助开创了去势抵抗性前列腺癌(CRPC)治疗的新时代,最近5年中有5种新药显示出生存优势,并且数量惊人的有希望的新型药物进入临床。
    内容:我们讨论了针对CRPC的药物开发面临的挑战以及应对这些挑战的策略,不仅着眼于预测性和中间终点生物标志物的开发,还着重于新的假设检验,生物标志物驱动的临床试验设计。
    简介:随着一些有前途的药物进入临床,对CRPC进行药物开发的重新思考的压力越来越大,以确保对新型药物进行适当评估,并适当分配患者和资源。我们设想,通过对合理设计的药物和给药于选定患者的药物进行可靠的科学假设测试,生物标记物驱动的重复性临床试验将对CRPC治疗产生重大影响。
  • 【肌萎缩性侧索硬化症:从板凳到床边的药物治疗。】 复制标题 收藏 收藏
    DOI:10.1055/s-0032-1329193 复制DOI
    作者列表:Gibson SB,Bromberg MB
    BACKGROUND & AIMS: :Amyotrophic lateral sclerosis (ALS) is an unrelenting progressive neurodegenerative disease causing progressive weakness, ultimately leading to death. Despite aggressive research, the pathways leading to neuronal death are incompletely understood. Riluzole is the only drug clinically proven to enhance survival of ALS patients, but its mechanism of action is not clearly understood. In this article, the proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death. Based on these mechanisms, past major ALS drug studies will be reviewed as well as promising current ALS drug studies, focusing on the advancement of these studies from the bench to the patient's bedside.
    背景与目标: 肌萎缩性侧索硬化症(ALS)是一种持续不断的进行性神经退行性疾病,会导致进行性无力,最终导致死亡。尽管进行了积极的研究,导致神经元死亡的途径仍未完全了解。利鲁唑是临床上唯一被证明可提高ALS患者生存率的药物,但其作用机理尚不清楚。在本文中,对ALS的拟议病理生理进行了综述,包括谷氨酸兴奋性毒性,氧化应激,线粒体功能障碍,自身免疫机制,蛋白质聚集,SOD1积累和神经元死亡。基于这些机制,将回顾过去的主要ALS药物研究以及有前途的当前ALS药物研究,重点是这些研究从实验台到患者床边的进展。
  • 【12,390名神经外科患者的“团队超时”和外科手术安全性经验。】 复制标题 收藏 收藏
    DOI:10.3171/2012.8.FOCUS12261 复制DOI
    作者列表:Oszvald Á,Vatter H,Byhahn C,Seifert V,Güresir E
    BACKGROUND & AIMS: OBJECT:Quality and safety are basic concerns in any medical practice. Especially in daily surgical practice, with increasing turnover and shortened procedure times, attention to these topics needs to be assured. Starting in 2007, the authors used a perioperative checklist in all elective procedures and extended the checklist in January 2011 according to the so-called team time-out principles, with additional assessment of patient identity and the planned surgical procedure performed immediately before skin incision, including the emergency cases. METHODS:The advanced perioperative checklist includes parts for patient identification, preoperative assessments, team time-out, postoperative treatment, and imaging controls. All parts are signed by the responsible physician except for the team time-out, which is performed and signed by the theater nurse on behalf of the surgeon immediately before skin incision. RESULTS:Between January 2007 and December 2010, 1 wrong-sided bur hole in an emergency case and 1 wrong-sided lumbar approach in an elective case (of 8795 surgical procedures) occurred in the authors' department. Using the advanced perioperative checklist including the team time-out principles, no error occurred in 3595 surgical procedures (January 2011-June 2012). In the authors' department all team members appreciate the chance to focus on the patient, the surgical procedure, and expected difficulties. The number of incomplete checklists and of patients not being transferred into the operating room was lowered significantly (p = 0.002) after implementing the advanced perioperative checklist. CONCLUSIONS:In the authors' daily experience, the advanced perioperative checklist developed according to the team time-out principles improves preoperative workup and the focus of the entire team. The focus is drawn to the procedure, expected difficulties of the surgery, and special needs in the treatment of the particular patient. Especially in emergency situations, the team time-out synchronizes the involved team members and helps to improve patient safety.
    背景与目标: 对象:质量和安全性是任何医学实践中的基本问题。尤其是在日常外科手术中,随着人员流动的增加和手术时间的缩短,需要确保对这些主题的关注。从2007年开始,作者根据所谓的小组超时原则在所有选修程序中使用了围手术期检查表,并于2011年1月扩展了检查表,另外对患者的身份进行了评估,并计划在切开皮肤之前进行手术计划,包括紧急情况。
    方法:围手术期高级检查清单包括患者识别,术前评估,团队超时,术后治疗和影像控制的部分。除团队超时外,所有部件均由负责的医生签名,团队超时是由手术室护士在皮肤切开之前代表外科医生执行并签名的。
    结果:在2007年1月至2010年12月之间,在提交人的科室中发生了1例紧急情况下的错牙钻洞和1例选择性情况下的腰椎错位入路手术(共8795次手术)。使用包括团队超时原则在内的高级围手术期检查表,在3595例外科手术中没有发生错误(2011年1月至2012年6月)。在作者部门,所有团队成员都很高兴有机会专注于患者,手术程序和预期的困难。实施高级围手术期检查清单后,不完整检查清单的数量和未转移到手术室的患者的人数显着降低(p = 0.002)。
    结论:根据作者的日常经验,根据团队超时原则制定的高级围手术期检查清单可以改善术前检查和整个团队的工作重点。重点是手术程序,手术的预期困难以及对特定患者进行治疗的特殊需要。尤其是在紧急情况下,团队超时可以同步参与团队的成员,并有助于提高患者的安全性。

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