The safety of anticholinergic bronchodilators for the treatment of chronic obstructive pulmonary disease

Introduction: Poorly absorbable quaternary ammonium-inhaled muscarinic antagonists both as the short-acting ipratropium and as long-acting (12 – 24 h) agents (tiotropium, glycopyrronium, aclidinium and umeclidinium) have all demonstrated statistically and clinically significant efficacy in chronic obstructive pulmonary disease compared with placebo. However, controversy has arisen concerning the safety of this class of agents principally regarding their association with both fatal and nonfatal cardiovascular toxicity.

Areas covered: The safety of both ipratropium and the long-acting muscarinic antagonists is reviewed with a major emphasis on potential cardiovascular toxicity, based on published clinical trials data and results of analyses of pooled data, meta-analyses, and observational studies. Since glycopyrronium, aclidinium, and umeclidinium have become available only relatively recently, more emphasis will be placed on the more extensive literature concerning the safety of the older anticholinergic compounds, the short-acting ipratropium, and the long-acting tiotropium in its dry powder formulation, as well as its newer soft mist inhaler delivery device.

Expert opinion: Pooled analyses and meta-analyses of randomized controlled trials (RCTs) of tiotropium in both its dry powder and soft mist formulations, as well as some observational studies, have implicated this agent as increasing the risk of nonfatal and fatal cardiovascular events. However, the most robust evidence based on large-scale randomized controlled trials (RCTs) of relatively long duration specifically designed to evaluate the cardiovascular safety of tiotropium have not confirmed these safety concerns. Because of the relatively limited amount of safety data for the newer long-acting muscarinic antagonists compared to the far more extensive experience with tiotropium, it will be important to accumulate additional safety information from post-marketing pharmacovigilance for these newer agents.     

Contrast medium precipitation during abdominal CT

Abdominal computed tomography (CT) scans of 55 patients who had ingested Gastrografin (meglumine diatrizoate and diatrizoate sodium) diluted to 2% with tap water and flavored with a commercial fruit juice base were reviewed. Twenty patients (36%) demonstrated intraluminal precipitation of Gastrografin shown by focal areas of markedly increased attenuation within the gastric lumen or trapped within gastric folds. Beam-hardening artifact produced by precipitation was observed, which limited the diagnostic value of some examinations. In vitro CT scans of the same Gastrografin solution titrated with hydrochloric acid or sodium hydroxide showed that by raising the pH of the solution, precipitation was virtually eliminated. Fifty-one CT scans of the abdomen using a buffered Gastrografin solution demonstrated precipitation in only five patients. Properly buffered dilute oral Gastrografin solutions should significantly decrease the prevalence of precipitation during abdominal CT examinations.     

高剂量美罗培南在肺炎囊性纤维化病人体内的药物动力学

目的 研究美罗培南在肺炎囊性纤维化病人体内的药物动力学.方法6例成年肺炎囊性纤维化住院病人,静脉滴注给予美罗培南2 g q8 h,用HPLC法测定血药浓度.采用3P87程序统计矩方法求算药代动力学参数.结果美罗培南的体内过程符合二室开放模型,其药物动力学参数分别为tmax=(0.574 2±0.020 7) h,cmax=(141.7±40.48) μg/ml,AUC=(148.7±23.42) μg*h*ml-1,t1/2β=(1.168±0.278) h,与常规剂量一致.结论肺炎囊性纤维化病人应用高剂量美罗培南时,具有良好的安全性和很好的临床疗效.     

CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen

Introduction

Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic CYP2D6 gene. CYP2D6 variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment CYP2D6 gene testing assay is available. However, evidence from published studies evaluating CYP2D6 variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of CYP2D6 testing. We investigated the association of CYP2D6 variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen.

Methods

This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis.

Results

In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups.

Conclusions

CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.     

MR findings of primary Ewing's sarcoma of greater wing of sphenoid

Primary Ewing's sarcoma of the skull is a very rare entity. We report MRI findings in a case of Ewing's sarcoma of the greater wing of sphenoid in a 4‐year‐old patient. Magnetic resonance imaging showed markedly heterogenous signal intensity with areas of haemorrhage and necrosis. It also demonstrated the exact extent of tumour due to its multiplanar capabilities and was, therefore, helpful in planning surgery.