新生儿静脉营养液中邻苯二甲酸二(2-乙基)己酯含量检测

目的建立气相色谱-质谱联用(GC-MS)法测定新生儿静脉营养液中邻苯二甲酸二(2-乙基)己酯(DEHP)的含量。方法收集放置不同时间段的新生儿静脉营养液,采用GC-MS进行定性定量,考察其DEHP的含量及其变化。结果新生儿静脉营养液中DEHP量随软袋放置时间延长而增加,测得放置24 h DEHP为3.23 mg·L-1。结论新生儿静脉营养液中放置24 h,溶出的DEHP量低于新生儿耐受摄入量,但也对新生儿带来危害。     

GC-MS法测定一次性使用静脉营养输液器中增塑剂DEHP的溶出量

目的:建立测定一次性使用静脉营养输液器中增塑剂邻苯二甲酸二(2-乙基己基)酯(DEHP)溶出量的方法。方法:采用气相色谱-质谱联用(GC-MS)法,以邻苯二甲酸二丁酯为内标,使用一次性使用静脉营养输液器制备营养液,测定室温放置和模拟临床输液24 h后营养液中DEHP的溶出量。采用Rtx-5 MS色谱柱;进样口温度:300℃;载气:氦气;程序升温模式:起始温度200℃,15℃/min升温至280℃,维持5 min;EI离子源,离子源温度:250℃,接口温度:280℃;采集模式:选择离子监测模式(SIM):质荷比(m/z)149。结果:DEHP检测质量浓度的线性范围为0.2³0μg/m(lr=0.999 8),检测限为0.01μg/ml,定量限为0.04μg/ml,平均回收率为102.4%,RSD为4.23%(n=3),精密度试验RSD为2.7%(n=5)。室温放置24 h营养液中DEHP溶出量为0.54730μg/m(lr=0.999 8),检测限为0.01μg/ml,定量限为0.04μg/ml,平均回收率为102.4%,RSD为4.23%(n=3),精密度试验RSD为2.7%(n=5)。室温放置24 h营养液中DEHP溶出量为0.547¹7.400 mg,模拟临床输液24 h后营养液中DEHP溶出量为8.77917.400 mg,模拟临床输液24 h后营养液中DEHP溶出量为8.779¹0.620 mg,均小于成人的耐受摄入量(30 mg)。结论:本法简单、快速、准确,可用于一次性使用静脉营养输液器中DEHP溶出量的测定。     

紫杉醇注射液配套输液器中邻苯二甲酸二辛酯的溶出性考察

目的:考察紫杉醇注射液配套输液器及聚氯乙烯(PVC)输液器中邻苯二甲酸二辛酯(DEHP)的溶出情况,评价紫杉醇临床用输液器的安全性。方法:收集重庆市9家"三甲"医院紫杉醇包装中配备的输液器,模拟临床紫杉醇输注的浓度、时间,用8种(其中7种为配套输液器)不同输液器滴注3h,用高效液相色谱法测定收集液中DEHP的峰面积,计算含量;并考察时间对DEHP溶出的影响。结果:紫杉醇通过8种输液器的DEHP溶出总量分别为1408、9393、6576·5、2412·6、8194·4、0、8477·2、8037·4μg;输注时间越长,DEHP溶出越多。结论:目前临床使用的紫杉醇配套输液器绝大部分为PVC输液器,由于DEHP溶出后可直接进入人体,不能保证紫杉醇的用药安全,故应高度重视其危害性。     

静脉营养输液袋中DEHP的溶出量研究

目的:建立测定一次性使用静脉营养输液袋中增塑剂邻苯二甲酸二-(2-乙基己基)酯(DEHP)溶出量的方法。方法:采用气相色谱-质谱联用仪对一次性使用静脉营养输液袋DEHP溶出量进行定量分析,优化了色谱与质谱实验条件。结果:用该法测定出了一次性使用静脉营养输液袋DEHP溶出量小于3 mg.套-1。结论:本方法灵敏度高,重复性好,简便可行,可用于静脉营养输液袋的质量控制。     

PVC软输液袋对紫杉醇稳定性的影响及其中DEHP溶出量考察

目的考察聚氯乙烯(PVC)软输液袋对紫杉醇稳定性的影响及其中增塑剂邻苯二甲酸二(2-乙基)己酯(DEHP)的溶出情况。方法模拟临床使用紫杉醇的条件,用高效液相色谱法测定整个使用过程中紫杉醇的浓度变化和DEHP的溶出量。结果紫杉醇浓度随时间的延长而下降,DEHP的溶出量随温度的升高和时间的延长而增大。结论目前临床使用的紫杉醇配套输液袋绝大多数为PVC袋,由于紫杉醇浓度下降且溶出的DEHP可直接进入人体,不能保证用药安全,故应高度重视PVC软输液袋的危害性。     

常用注射剂表面活性剂对聚氯乙烯输液器中邻苯二甲酸二辛酯溶出的试验研究

目的:考察常用的5种注射剂表面活性剂对聚氯乙烯(PVC)输液器中邻苯二甲酸二辛酯(DEHP)溶出的影响。方法:分别配制吐温-80、吐温-40、吐温-20、聚氧乙烯蓖麻油、卵磷脂溶液,加入5%葡萄糖注射液中,模拟临床输注方式,用PVC输液器滴注,以高效液相色谱法测定收集液中DEHP峰面积,计算含量,以此考察加入表面活性剂的种类、浓度、输液时间及输液管长度对DEHP溶出的影响。结果:5种表面活性剂对DEHP的溶出能力为吐温-80>吐温-40>吐温-20>聚氧乙烯蓖麻油>卵磷脂,卵磷脂未见溶出DEHP。在表面活性剂种类一定的情况下,DEHP的溶出与其浓度、输液时间以及输液管长度成正相关。结论:本研究可为含有表面活性剂的注射剂选择安全的输液器及药厂生产注射剂时选择表面活性剂提供参考。     

克林霉素磷酸酯注射液对一次性输液器中邻苯二甲酸二（2-乙基）己酯的溶出研究

摘要：目的:考察克林霉素磷酸酯注射液对一次性使用输液器中苯二甲酸二（2-乙基）己酯（DEHP）的溶出规律。方法:模拟临床使用克林霉素磷酸酯注射液经一次性输液器静脉滴注,UPLC-MS/MS法测定流出液中DEHP的溶出量。同时考察药物浓度和滴注时间对于DEHP溶出的影响,确定克林霉素磷酸酯注射液促进DEHP溶出的因素。结果:克林霉素磷酸酯注射液中的苯甲醇是促进一次性输液器中DEHP溶出的主要因素,并且随着苯甲醇浓度升高和滴注时间的延长,DEHP的溶出量相应增加。结论:苯甲醇促进了一次性输液器中DEHP的溶出,溶出量与苯甲醇浓度和滴注时间呈正相关。     

医疗器械中增塑剂的应用和安全性研究进展

目的了解并总结医疗器械中增塑剂应用现状及其安全性研究的最新进展。方法列举常用医疗器械中增塑剂的种类，简要说明塑料医用器械在临床上的应用，搜集并整理已有的增塑剂毒性的研究资料，以归纳医疗器械中最常用的增塑剂对人体的潜在风险，最后对增塑剂安全性评价策略进行总结。结果塑料医疗器械临床应用广泛，其中加入的增塑剂，如DEHP存在潜在风险并会产生以生殖毒性和肝毒性为主的不良反应。对塑料医疗器械的风险评估主要对医疗器械中增塑剂的释放量和摄入量这两个方面进行评价。结论医疗增塑剂的应用和安全性研究的讨论对医用增塑剂的风险评估及今后发展新型增塑剂具有指导意义。     

自制与原研头孢克肟胶囊在4种介质中的体外溶出度比较

目的:评价自制与原研头孢克肟胶囊体外溶出行为的相似性。方法:依据2010年版《中国药典》(二部)和日本《医疗用医药品品质情报集》(橙皮书)中的溶出度试验条件,采用高效液相色谱法测定;分别以水、p H 1.2盐酸溶液、p H 6.8磷酸盐缓冲液(PBS)、p H 7.5 PBS为溶出介质,采用桨法(加沉降篮),转速为50 r/min进行溶出度测定;通过相似因子f2法评价2种产品溶出曲线的相似性。结果:自制胶囊在4种介质中溶出曲线f2值均大于50。结论:2种产品的体外溶出曲线相似,提示自制头孢克肟胶囊处方合理、质量稳定可靠。     

自制恩替卡韦片与上市对照制剂体外溶出度对比研究

目的:比较自制恩替卡韦片与对照制剂体外溶出行为。方法:参照日本《医疗用药品品质情报集》中的溶出度试验条件,分别考察自制制剂与对照制剂在pH1.2的人工胃液、pH4.0的醋酸盐缓冲液、pH6.8的磷酸盐缓冲液及水中的体外溶出行为,溶出方法为桨法,转速为50r.min-1。结果:自制制剂与对照制剂在4种不同的溶出介质中溶出曲线均相似。结论:自制制剂与对照制剂体外溶出度基本一致。     

Di-(2-ethylhexyl)-phthalate migration from irradiated poly(vinyl chloride) blood bags for graft-vs-host disease prevention

Irradiation with 20-25 kGy is a process commonly used for sterilizing poly(vinyl chloride) (PVC) medical devices. Moreover, whole blood and blood components undergo additional irradiation with 25-50 Gy to inhibit the proliferative capacity of lymphocytes and reduce the risk of transfusion-associated graft-vs-host disease (GVHD). Di-(2-ethylhexyl)-phthalate (DEHP) plasticized PVC is extensively used for the production of flexible medical devices including blood bags, but since DEHP is not covalently bound to PVC, it tends to migrate and leach out of the medical device, with harmful consequences for the patients. In this study, the effects of different doses of gamma irradiation on DEHP migration from PVC blood bags was investigated using differential scanning calorimetry (DSC) analysis. Our findings indicate that irradiation with 25-100 Gy reduces the ability of DEHP to migrate from the blood bags, and in the case of a primary container a correlation between the doses of gamma ray irradiation was also observed. In particular, a decrease in DEHP leachability was obtained by increasing the dose of gamma ray irradiation.     

The validation of column-switching LC/MS as a high-throughput approach for direct analysis of di(2-ethylhexyl) phthalate released from PVC medical devices in intravenous solution

Health Canada reported recently that medical devices containing di(2-ethylhexyl) phthalate (DEHP) should not be used in the clinical treatment of infants, young boys, pregnant women, and nursing mothers. The risk assessment of DEHP released from PVC medical devices is an important issue for hospitalized patients. In this study, a simple, accurate, low-contamination and high-throughput analytical technique for the determination of DEHP in intravenous (IV) solution was developed using column-switching liquid chromatography/mass spectrometry (LC/MS) with an extraction mini-column. The sample preparation for on-line extraction involved simply mixing IV solution with internal standard as DEHP-d₄ in LC glass vials. The IV fat emulsion drug sample cannot be analyzed directly, hence this sample spiked with DEHP-d₄ solution was extracted by hexane and measured by column-switching LC/MS yielding an average recovery of 92.2% (C.V.=7.8%, n=5). A linear response was found for a variety of drugs tested within the validated range of 0.1 or 0.5–10 μg/ml with correlation coefficients (r) greater than 0.99. These results suggest that this method can assay background exposure to DEHP released from PVC medical devices in the patients. The method was applied to various IV solution samples to establish the first screening method for DEHP released from medical devices with respect to their safety.     

Simulated neonatal exposure to DEHP and MEHP from PVC enteral nutrition products

The leaching of di(2-ethylhexyl)phthalate (DEHP) and mono(2-ethylhexyl)phthalate (MEHP) from medical products made of polyvinyl-chloride (PVC) to enteral nutrition (EN) for neonatal patients was determined in a simulated study. The study simulated a typical case of EN administration to a neonatal patient (body weight, 3 kg) in a neonatal care unit (temperature, 25 degrees C); the medical products used were an irrigator and catheter containing DEHP (9.1-31.8%, w/w) as a plasticizer. The worst-case daily exposures of the neonatal patient to DEHP and MEHP by the administration of EN were estimated to be 148 and 3.72 microg/(kg day), respectively, as assessed from the levels of these compounds leaching from the medical products to the EN. The use of DEHP-free medical products reduced the exposure of DEHP and MEHP to the minimum levels contained in the EN at preparation. A transition to DEHP-free medical products for neonatal patients would be effective in reducing the exposure of neonatal patients to DEHP via EN administration.     

Taiwan food scandal: The illegal use of phthalates as a clouding agent and their contribution to maternal exposure

In 2011 the Taiwan Food and Drug Administration reported that plasticizers di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP), endocrine disruptors, were illegally added to clouding agents used in foods and beverages. 965 products were found contaminated, of which 206 were exported to 22 countries. This study’s purpose was to obtain English names for 28 contaminated products for which DEHP levels were reported, calculate estimated average daily intake (mg/kg/day) for a 50 kg woman consuming one portion, and compare to U.S. and E.U. guidelines for daily intake. We found that drinking just one bottle (500 ml) of sports drinks would result in an average DEHP intake of 0.14 mg/kg bw/day (range 0.091–0.341), which exceeds by several fold government guidelines (0.02–0.06 mg/kg bw/day). One (2 g) serving from 4/14 samples of contaminated dietary supplements exceeds the guideline of 0.02 mg/kg bw/day. In conclusion, consuming even one portion of tainted drinks and some powders would lead to daily intake of DEHP that greatly exceeds established safety guidelines, raising concerns about potential adverse effects, particularly reproductive tract development in the male fetus. Global distribution of DEHP-contaminated and other adulterated products should prompt governments to become proactive in food safety regulations and chemical testing.     

In vitro and in silico hormonal activity studies of di‐(2‐ethylhexyl)terephthalate,a di‐(2‐ethylhexyl)phthalate substitute used in medical devices,and its metabolites

Plasticizers added to polyvinylchloride used in medical devices can be released into patients’ biological fluids. The substitution of di‐(2‐ethylhexyl)phthalate (DEHP) by alternative plasticizers is essential but their safety must be demonstrated. DEHP, di‐(2‐ethylhexyl)terephthalate (DEHT) and their metabolites were investigated using level 2 Organization for Economic Co‐operation and Development bioassays to screen for in vitro hormonal changes. Differences between the DEHP and DEHT metabolites were observed. Albeit weak, the hormonal activities of DEHT‐derived metabolites, e.g., 5‐OH metabolite of mono‐(ethylhexyl)terephthalate (5‐OH‐MEHT), were detected and the results of docking experiments performed on estrogen receptor alpha and androgen receptor agreed with the biological results. A co‐stimulation of human estrogen receptor alpha and human androgen receptor was also observed. With regard to steroidogenesis, a 16‐fold increase in estrogen synthesis was measured with 5‐OH‐MEHT. Therefore, even if DEHT remains an interesting alternative to DEHP because of its low migration from medical devices, it seems important to verify that multi‐exposed patients in neonatal intensive care units do not have urinary levels of oxidized metabolites, in particular 5‐OH‐MEHT, suggesting a potential endocrine‐disrupting effect.     

Di(2-ethylhexyl) phthalate promotes hepatic fibrosis by regulation of oxidative stress and inflammation responses in rats

Di(2-ethylhexyl) phthalate (DEHP) is an environmental pollutant that is widely used in medical and consumer products. An epidemiological study has suggested that a large daily intake of DEHP from phthalate-contaminated food may be a risk factor for liver dysfunction. Long-term exposure to DEHP is associated with liver disease and exacerbates the progression of chronic liver injury. However, the effect of DEHP on hepatic fibrosis is rarely studied. In the present study, we sought to determine the effect of DEHP on carbon tetrachloride (CCl4)-induced liver fibrosis, and to further examine the molecular mechanisms. We found that DEHP exposure remarkably promoted liver inflammation, necrosis and fibrosis, and increased expression of the protein associated with liver inflammation and fibrogenesis, including α-SMA, COL-Ⅰ, COL-Ⅲ, TGF-β1, P-Smad2, P-Smad3, P-p38 and P-p65. The similar trend was observed in the LX-2 cells. Furthermore, DEHP exposure induced oxidative stress and inflammatory cytokine production. Taken together, DEHP might play a fibrotic role in hepatic fibrosis rats and TGF-β1-stimulated LX-2 cells in vitro which was related to TGF-β1/Smad and p38MAPK/NF-κB signal pathway.