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存在局限性，因此已经进行了研究以开发针对男性的激素避孕药，类似于基于雌激素和孕激素的女性避孕方法。当向男性施用睾丸激素时，它通过抑制垂体的促黄体激素 (LH) 和促卵泡激素 (FSH) 的分泌而起到避孕作用。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个月的睾酮治疗后，60-70% 的男性射精中不再有精子，大多数其他男性的精子数量明显减少。男性激素避孕耐受性良好，无严重不良副作用，95% 有效预防妊娠。重要的是，男性激素避孕是可逆的，精子数量通常在停止激素治疗后4个月内恢复。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 (例如孕激素或促性腺激素释放激素拮抗剂) 结合使用，以进一步抑制LH和FSH的分泌并改善精子发生的抑制。最近的试验使用了长效可注射或可植入形式的睾丸激素与孕激素的组合，可以口服，注射或长效植入物给药。在80-90% 的男性中，这种组合将精子发生抑制为零，而没有严重的副作用，在其余个体中几乎完全抑制。这些睾丸激素和孕激素联合疗法之一可能很快就会实现男性激素避孕的希望。

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，为开发新的分枝杆菌感染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结核病治疗的广泛已发表的临床经验，以评估这些临床前措施在预测抗细菌治疗临床结果中的应用。药物活性的体外测量可以预测药物的效力，以防止对其他抗细菌药物的耐药性出现，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无法可靠地预测生物体应被认为具有抗性的水平。药物在组织中的渗透和对细胞内杆菌的活性的测定适度增加了药物活性的体外测量的预测值，但仍不能预测灭菌活性。相反，结核病的动物模型已经预测了相对的药物效力 (包括灭菌活性)，多药疗法的功效以及所需的治疗持续时间。尽管药代动力学参数表明每天需要多次剂量，但所有一线抗结核药物在每周两次的情况下均具有活性。很难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，尤其是可以预测灭菌活性的模型。

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：

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： : 罂粟在上古时期被广泛用作食物，疗法和毒药的来源。罂粟种子的营养价值很可能在新石器时代就已为人所知，并且有证据表明，在地中海东部盆地的米诺斯文明期间，罂粟汁的神经心理药理作用已被利用。米诺斯文明将其归因于与农业生育仪式有关的象征意义的罂粟。这种象征主义在整个古代的持久性通过文学和图像证据证明了罂粟花归因于生育女神，例如得墨忒耳，阿芙罗狄蒂和谷神星。

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： 许多遗传毒性药物通过诱导凋亡来杀死肿瘤细胞; 因此，抑制凋亡的突变会产生对化学疗法的抵抗力。尽管直接激活凋亡机制可能会绕过这些突变，但如何选择性地在癌细胞中实现这种激活尚不清楚。在这项研究中，我们表明抗药性293细胞系在用抗癌药物治疗后无法激活凋亡机制的成分-冰样蛋白酶 (caspases)。值得注意的是，来自未处理细胞的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，而且具有其激活剂。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，而正常细胞中不存在。我们提供了这种癌基因产生的活性 (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与细胞中的胱天蛋白酶联系起来的药物会杀死原本对常规癌症治疗具有抗性的肿瘤细胞。由于这种杀灭依赖于癌基因产生的活性，因此这些药物的作用应对转化细胞具有选择性。

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的抑制，但机制尚未建立。在本报告中，我们证明了通过用药物2-氨基嘌呤处理可防止细胞中腺病毒对细胞蛋白质合成的切断。显示用2-氨基嘌呤处理可防止抑制细胞翻译，而不会破坏细胞mrna从细胞核到细胞质转运中的正常病毒阻滞。我们显示，细胞蛋白合成的病毒抑制与干扰素诱导的双链RNA激活抑制剂 (DAI)，蛋白激酶的激活以及真核起始因子2 (eIF-2 α) 的 α 亚基的磷酸化同时发生，但是，通过2-氨基嘌呤阻止宿主细胞关闭而不会降低激酶活性或eIF-2 α 的去磷酸化。结果表明DAI激酶的活化和eIF-2 α 的磷酸化可能是必需的，但不足以在腺病毒感染期间实现细胞蛋白合成的抑制。我们建议其他事件，尤其是其他起始因子的修饰，可能与病毒对细胞翻译的抑制有关。

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：

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： : 多沙唑嗪用于良性前列腺增生具有引起低血压和心力衰竭风险的副作用。分别涉及 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个目标。我们假设在3个靶标中存在多沙唑嗪对映体的手性识别。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。我们观察到多沙唑嗪对映体在分离的大鼠和兔心脏组织中的变时性和正性肌力作用。(-) 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。在大鼠主动脉中 (-) 多沙唑嗪 (8.625 ± 0.053) 的pA(2) 值小于 () 多沙唑嗪 (9.503 ± 0.051)，但它们在兔前列腺中的pK(B) 值相同。在大鼠和兔心脏组织中，() 多沙唑嗪 (3-30 µ mol·L(-1)) 显着降低了心房速率，并产生了负性肌力作用; 但是，(-) 多沙唑嗪不影响心房速率，并在心房中产生了正性肌力作用。因此，多沙唑嗪的手性碳原子不会影响其在前列腺中 α(1A)-肾上腺素受体的治疗靶标上的活性，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，并通过不依赖 α(1)-肾上腺素受体的机制在心房中产生相反的正性肌力作用。

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： : 进行了大规模研究，以确定药房中抗肿瘤药物的污染水平，并调查定期擦拭样品监测的适用性和效果。开发了一个特定的研究设计。将130家参与的药房分为研究组和对照组，分别进行了五个和两个擦拭采样周期。使用问卷调查对工作实践进行了分析，以确定影响污染水平的因素。从1269擦拭样品中，774 (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减少。药房擦拭采样方法的监测效果研究已被证明是控制污染的可靠且负担得起的工具。根据污染值的第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)。

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： : 本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颗粒 (psn) 的组合制备水飞蓟宾 (72 h-SLB) 的72 h释放制剂，并研究体外/体内相关性 (IVIVCs)。扫描电子显微镜和N(2) 吸附结果表明，空psn具有球形，高度多孔结构，大的比表面积 (385.89 ± 1.12 m(2)/g) 和小的孔径 (平均2.74 nm)。72 h-SLB和水飞蓟宾负载的psn在不同浓度 (0.01，0.06和0.08M) 的Na(2)CO(3) 溶液表明，0.06 M Na(2)CO(3) 溶液是最佳介质，其中水飞蓟宾可以从72 h-SLB中释放，具有一级释放动力学和psn。具有Higuchi动力学。此外，还建立了beagle犬中72 h-SLB和水飞蓟宾psn的ivvc。使用0.06 M Na(2)CO(3) 溶液作为体外溶出介质，对于72 h-SLB和水飞蓟宾负载的psn都可以实现良好的线性关系。研究结果支持以下事实: 72 h-SLB (由固体分散体，规则凝胶基质和psn组成) 与Na(2)CO(3) 溶液一起作为体外溶出介质，可以开发为具有良好的IVIVC可溶性药物的有希望的制剂。

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：

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) 是一种持续的进行性神经退行性疾病，导致进行性虚弱，最终导致死亡。尽管进行了积极的研究，但导致神经元死亡的途径尚不完全清楚。利鲁唑是唯一经临床证实可提高ALS患者生存率的药物，但其作用机制尚不清楚。在本文中，对ALS的拟议病理生理学进行了综述，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药物研究以及有希望的当前ALS药物研究，重点是从替补席到患者床边的这些研究的进展。

BACKGROUND & AIMS: :Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens.

背景与目标： : 恩替卡韦是美国食品药品监督管理局批准的用于治疗慢性乙型肝炎病毒 (HBV) 感染的药物，据信不抑制临床相关剂量的人类免疫缺陷病毒1型 (HIV-1) 的复制。我们观察到恩替卡韦导致HIV-1 RNA在三个HIV-1和HBV共感染的人一致的1-log(10) 减少，我们获得了支持的体外证据，恩替卡韦是HIV-1复制的有效部分抑制剂。详细分析显示，在其中一名患者中，恩替卡韦单药治疗导致拉米夫定耐药突变M184V的HIV-1变异体积累。体外实验表明，M184V具有对恩替卡韦的抗性。直到更多关于HIV-1-resistance模式及其恩替卡韦的选择，需要谨慎使用恩替卡韦与HIV-1和HBV合并感染谁没有接受完全抑制抗逆转录病毒方案的人。

BACKGROUND & AIMS: :Patients taking tricyclic antidepressants (TCA) can experience toxicity or severe side effects. As a rapid and less technically demanding alternative to quantitative serum analysis, most laboratories offer qualitative immunoassays to assist in the evaluation of a suspected TCA overdose. However, the relationship between quantitative serum and qualitative urine levels of TCA-related compounds and their metabolites has not been comprehensively studied. Serum high-performance liquid chromatography results were compared to the qualitative urine results using the Syva Rapid Test and the Biosite Triage. Serum concentrations of amitriptyline, desipramine, doxepin, imipramine, and nortriptyline ranging from subtherapeutic to toxic triggered a positive response on both urine immunoassay devices. On the other hand, neither immunoassay uniformly detected clomipramine, even at serum levels greater than the therapeutic range. False positives due to cyclobenzaprine were more common with the Biosite assay. For virtually all positive urine TCA findings, it was not possible to determine whether the positive results corresponded to subtherapeutic, therapeutic, supratherapeutic, or toxic serum concentrations. Because urine immunoassays are the only option for many laboratories analyzing specimens for TCAs (especially in an emergency setting), clinicians must understand the limitations and interpret results in conjunction with clinical findings and/or quantitation of serum levels.

背景与目标： : 服用三环类抗抑郁药 (TCA) 的患者会出现毒性或严重的副作用。作为定量血清分析的快速且技术要求较低的替代方法，大多数实验室提供定性免疫测定，以帮助评估可疑的TCA过量。然而，尚未全面研究TCA相关化合物及其代谢产物的定量血清和定性尿液水平之间的关系。使用Syva快速测试和Biosite分诊将血清高效液相色谱结果与定性尿液结果进行比较。阿米替林，地昔帕明，多塞平，丙咪嗪和去甲替林的血清浓度从亚治疗性到毒性，在两种尿液免疫测定设备上都产生了阳性反应。另一方面，即使在血清水平大于治疗范围的情况下，也没有免疫测定方法能均匀检测到氯米帕明。由于环苯扎林引起的假阳性在生物矿测定中更为常见。对于几乎所有尿液TCA阳性结果，无法确定阳性结果是否对应于亚治疗，治疗，超治疗或毒性血清浓度。由于尿液免疫测定是许多实验室分析TCAs标本的唯一选择 (尤其是在紧急情况下)，因此临床医生必须了解局限性并结合临床发现和/或血清水平定量来解释结果。

BACKGROUND & AIMS: BACKGROUND:Recent studies show that patients with multiple nonsteroidal anti-inflammatory drug (NSAID) intolerance are frequently characterized by autoreactivity; this can be detected by autologous serum skin test (ASST). OBJECTIVE:To assess whether the autologous plasma skin test (APST), a test that was recently shown to be more sensitive than ASST, may be usefully employed as a predictive test for multiple NSAID intolerance in patients with a history of single NSAID intolerance. METHODS:Thirty otherwise normal adults with a history of acute urticaria following the ingestion of one single NSAID underwent an APST before being challenged with a COX-1-inhibiting NSAID other than the offending drug. RESULTS:Sixteen patients experienced urticaria following the ingestion of the alternative NSAID and were therefore classified as multiple NSAID reactors; all 16 (100%) scored positive on APST. In contrast only 3/14 patients finally classified as single NSAID reactors were positive on APST (p < 0.001). The positive and negative predictive value of APST for multiple NSAID intolerance were 86 and 100%, respectively. CONCLUSION:In patients with a history of acute urticaria induced by a single NSAID APST can be usefully employed to detect patients that are prone to react to NSAID other than the original offending one.

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