Role of taxanes in pancreatic cancer

Pancreatic cancer is one of the most deadly cancers and is characterized by a poor prognosis. Single agent gemcitabine, despite its limited activity and modest impact on disease outcome, is considered as the standard therapy in pancreatic cancer. Most of the combination regimens used in the treatment of this disease, also including the targeted agents, did not improve the outcome of patients. Also, taxanes have been tested as single agent and in combination chemotherapy, both in first line and as salvage chemotherapy, as another possible option for treating pancreatic cancer. The inclusion of taxanes in combination with gemcitabine as upfront therapy obtained promising results. Accordingly, taxanes, and above all, new generation taxanes, appear to be suitable candidates for further testing to assess their role against pancreatic cancer in various clinical settings.     

Benefits and risks of long-term low-dose oral continuous combined hormone therapy

OBJECTIVES: Current recommendations for hormone therapy (HT) are mainly based on findings from studies using standard dose regimens in older women who had a different health profile from those who start HT soon after the onset of menopause. METHODS: We, therefore, reviewed controlled trials assessing the efficacy, safety and tolerability of low-dose oral continuous combined HT (cc-HT) started for treatment of climacteric symptoms. This review is limited to oral cc-HT regimens over sequential regimens as most postmenopausal women prefer not to have a return of uterine bleeding, and to studies of at least 2 years in duration. RESULTS: Low-dose cc-HT is effective in alleviating climacteric symptoms and in maintaining bone density over prolonged periods, although no data were available regarding fracture risk. No increased risk of coronary heart disease, venous thrombo-embolism or stroke during the use of low-dose cc-HT was reported in the long-term studies and no definitive evidence for an increased risk of breast cancer was found. Breakthrough bleeding during the first months of use is less common than with standard dose HT and amenorrhoea is achieved in most women over time. These regimens are safe for the endometrium and are well tolerated, with a low incidence of adverse events compared with standard doses. CONCLUSIONS: Current evidence from controlled trials indicates that low-dose oral cc-HT appears effective and safe. This makes it a good choice for the alleviation of climacteric symptoms, and for this purpose long-term administration of low-dose cc-HT does not seem to impose serious health risks. However, more long-term study data and direct head-to-head comparisons between various low-dose preparations are needed to support or rectify the safety aspects.     

Enhanced in vitro activity of tigecycline in the presence of chelating agents

The lack of availability of novel antibiotic agents and the rise of resistance to existing therapies has led clinicians to utilise combination therapy to adequately treat bacterial infections. Here we examined how chelators may impact the in vitro activity of tigecycline (TIG) against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Minimum inhibitory concentrations (MICs) were determined by broth dilution with and without various combinations of chelators (EDTA and other tetracyclines) and metal ions (i.e. calcium, magnesium). Trimethoprim (TMP) was used as a non-chelating control. Addition of metal ions led to increases in MICs, whilst addition of EDTA led to decreases in MICs. The chelating effects of EDTA were reversed by addition of magnesium and most profoundly calcium. Similar effects of EDTA and calcium were observed for tetracycline (TET) and TMP. When other tetracyclines (TET, oxytetracycline (OXY) and chlortetracycline (CHL)) were used as chelators at concentrations below their MICs, TIG MICs decreased for P. aeruginosa but not for E. coli. Some decreases in TIG MICs were observed for K. pneumoniae when TET and CHL were added. A dose-dependent decrease in TIG MIC was observed for TET and was reversed by the addition of calcium. The presence of effects of EDTA and calcium on TMP MICs indicates that mechanisms outside of TIG chelation likely play a role in enhanced activity. Full characterisation of an unexpected interaction such as TIG–TET with different microorganisms could provide valuable insights into the underlying mechanisms and design of physiologically viable chelators as candidates for future combinations regimens.     

头孢哌酮与β-内酰胺酶抑制剂复方研究进展

头孢哌酮是第三代头孢菌素类抗生素,抗菌谱广,对敏感菌引起的多种感染有良好疗效。随着头孢哌酮在临床上的广泛应用乃至滥用,耐药率逐渐升高。国内外研究表明β-内酰胺抗生素与β-内酰胺酶抑制剂联用是解决临床细菌耐药的有效方法之一。本文阐述国内头孢哌酮复方制剂的情况,对比了不同头孢哌酮复方制剂中联用β-内酰胺酶的配伍比例和用法用量的情况,为临床合理选择使用头孢哌酮复方制剂提供参考。     

Anti-malarial efficacy of pyronaridine and artesunate in combination in vitro and in vivo

Pyronaridine is a Mannich base anti-malarial with demonstrated efficacy against drug resistant Plasmodium falciparum, P. vivax, P. ovale and P. malariae. However, resistance to pyronaridine can develop quickly when it is used alone but can be considerably delayed when it is administered with artesunate in rodent malaria models. The aim of this study was to evaluate the efficacy of pyronaridine in combination with artesunate against P. falciparum in vitro and in rodent malaria models in vivo to support its clinical application. Pyronaridine showed consistently high levels of in vitro activity against a panel of six P. falciparum drug-sensitive and resistant strains (Geometric Mean IC50=2.24 nM, 95% CI=1.20-3.27). In vitro interactions between pyronaridine and artesunate showed a slight antagonistic trend, but in vivo compared to pyronaridine and artesunate administered alone, the 3:1 ratio of the combination, reduced the ED90 of artesunate by approximately 15.6-fold in a pyronaridine-resistant P. berghei line and by approximately 200-fold in an artesunate-resistant line of P. berghei. Complete cure rates were achieved with doses of the combination above or equal to 8 mg/kg per day against P. chabaudi AS. These results indicate that the combination had an enhanced effect over monotherapy and lower daily doses of artesunate could be used to obtain a curative effect. The data suggest that the combination of pyronaridine and artesunate should have potential in areas of multi-drug resistant malaria.     

抗结核药物固定剂量复合制剂隔日疗法临床效果分析

目的 评价国产抗结核药物固定剂量复合制剂（FDC）隔日疗法的临床应用效果,为抗结核FDC隔日疗法的推广应用提供参考依据.方法 根据两组试点市（县）地貌、人口数、总体经济状况、结核科仪器设备和工作人员水平等基本接近的原则,“抗结核药物FDC隔日疗法试点组”（简称“FDC组”）为保定市12个市（县）中纳入的初治活动性肺结核患者,共计1225例;“抗结核药物板式组合药对比观察试点组”（简称“组合药组”）为保定市另11个市（县）中纳入的初治活动性肺结核患者2328例,通过人口容量比率概率法抽取1225例患者.对两组临床治疗完成率,2、3、6个月末痰菌阴转率,疗程末X线实变阴影及空洞改变,以及不良反应等情况,用对照研究的方法进行对比观察.用统计软件包SPSS 13.0进行处理与分析,计数资料的比较采用x2检验,以P＜0.05为差异有统计学意义.结果 治疗完成率抗结核FDC组为94.53％（1158/1225）,组合药组为90.94％（1114/1225）,两组比较差异有统计学意义（x2＝11.73,P＜0.01）;2、3、6个月末痰菌阴转率抗结核FDC组分别为91.29％（262/287）、94.08％（270/287）、97.56 ％（280/287）,组合药组分别为89.05％ （244/274）、93.07％ （255/274）、96.72％（265/274）,两组比较差异均无统计学意义（x2值分别为0.79、0.24、0.36,P值均＞0.05）;FDC组疗程末X线胸片实变阴影有效吸收率及空洞改善率分别为93.06％（845/908）、89.60％（181/202）,组合药组分别为91.99％（781/849）、88.95％（169/190）,两组比较差异均无统计学意义（x2值分别为0.73、0.04,P值均＞0.05）;总不良反应发生率抗结核FDC组为21.35％（237/1110）,组合药组为22.62％（235/1039）,两组比较差异无统计学意义（x2 =0.50,P＞0.05）;实验室检测结果血常规异常、肝功能异常及肾功能异常方面,抗结核FDC组和板式组合药组相比,差异均无统计学意义（x2值分别为1.16、0.00、0.21,P值均＞0.05）.结论 国产抗结核FDC与板式组合药疗效相似,且能提高患者治疗完成率,可作为传统板式组合药的替代品.     

A random set approach to confidence regions with applications to the effective dose with combinations of agents

The effective dose (ED) is the pharmaceutical dosage required to produce a therapeutic response in a fixed proportion of the patients. When only one drug is considered, the problem is a univariate one and has been well‐studied. However, in the multidimensional setting, that is, in the presence of combinations of agents, estimation of the ED becomes more difficult. This study is focused on the plug‐in logistic regression estimator of the multidimensional ED. We discuss consistency of such estimators and focus on the problem of simultaneous confidence regions. We develop a bootstrap algorithm to estimate confidence regions for the multidimensional ED. Through simulation, we show that the proposed method gives 95% confidence regions, which have better empirical coverage than the previous method for moderate to large sample sizes. The novel approach is illustrated on a cytotoxicity study on the effect of two toxins in the leukemia cell line HL‐60 and a decompression sickness study of the effects of the duration and depth of the dive. Copyright © 2014 John Wiley & Sons, Ltd.     

吉西他滨固定剂量率输注联合奥沙利铂一线治疗晚期胰腺癌的Meta分析

背景与目的:有研究提示吉西他滨(Gemcitabine,GEM)固定剂量率(Fixed-dose rate,FDR)输注治疗晚期胰腺癌似有较好的疗效,Meta分析也显示含铂类联合化疗优于GEM单药化疗,本文试图通过Meta分析,探讨GEM FDR输注联合奥沙利铂(GEMOX)一线治疗晚期胰腺癌的地位和价值.方法:通过MEDLINE、EMBASE、ASCO等数据库及论文集检索国内外的相关文献.选择治疗组为GEMOX方案化疗,对照组为标准GEM单药化疗的晚期胰腺癌随机对照试验.由2位评价者分别按上述检索策略收集资料,按纳入标准入选,主要对总生存率及主要不良反应进行Meta分析.结果:从182篇文献中筛选出符合纳入标准的2个随机对照试验,共涉及869例患者.与GEM单药组比较,GEMOX组半年生存率提高9%(95%CI 0.03～0.16,P=0.005),1年生存率提高5%(95%CI-0.01～0.11,P=0.08),客观有效率提高6%(95%CI 0.02～0.10,P=0.006);WHO Ⅲ/Ⅳ度贫血发生率下降5%(95%CI-0.08～-0.01,P=0.01),恶心/呕吐提高13%(95%CI 0.08～0.18,P＜0.001),神经毒性增加14%(95%CI 0.04～0.24,P=0.009),粒细胞减少症、血小板减少症两组相似,差异无统计学意义.结论:现有的证据提示,GEM固定剂量率输注联合奥沙利铂组成的GEMOX方案一线治疗晚期胰腺癌可能有较好的应用前景,值得进行进一步的临床试验.     

Impacto de la edad del donante-receptor en la supervivencia al trasplante cardiaco. Subanálisis del Registro Español de Trasplante Cardiaco

Introduction and objectivesThe age of heart transplant recipients and donors is progressively increasing. It is likely that not all donor-recipient age combinations have the same impact on mortality. The objective of this work was to compare survival in transplant recipients according to donor-recipient age combinations.MethodsWe performed a retrospective analysis of transplants performed between 1 January 1993 and 31 December 2017 in the Spanish Heart Transplant Registry. Pediatric transplants, retransplants and combined transplants were excluded (6505 transplants included). Four groups were considered: a) donor < 50 years for recipient < 65 years; b) donor < 50 years for recipient ≥ 65 years; c) donor ≥ 50 years for recipient ≥ 65 years, and d) donor ≥ 50 years for recipient < 65 years.ResultsThe most frequent group was young donor for young recipient (73%). There were differences in the median survival between the groups (P < .001): a) younger-younger: 12.1 years, 95%CI, 11.5-12.6; b) younger-older: 9.1 years, 95%CI, 8.0-10.5; c) older-older: 7.5 years, 95%CI, 2.8-11.0; d) older-younger: 10.5 years, 95%CI, 9.6-12.1. On multivariate analysis, independent predictors of mortality were the age of the donor and the recipient (0.008 and 0.001, respectively). The worst combinations were older-older vs younger-younger (HR, 1.57; 95%CI, 1.22-2.01; P < .001) and younger-older vs younger-younger (HR, 1.33; 95%CI, 1.12-1.58; P = .001).ConclusionsAge (of the donor and recipient) is a relevant prognostic factor in heart transplant. The donor-recipient age combination has prognostic implications that should be identified when accepting an organ for transplant.Full English text available from: www.revespcardiol.org/en