甲磺酸酚妥拉明的血药浓度测定及其家兔体内的药动学

目的建立一种测定家兔血浆中甲磺酸酚妥拉明含量的方法,并应用于甲磺酸酚妥拉明溶液的药动学研究。方法家兔的给药方式采用溶液灌胃;血药浓度分析采用HPLC内标法。结果甲磺酸酚妥拉明血药浓度测定的线性关系为:y= 0.006 6ρ-0.013 3(r=0.999 7,n=3),线性范围为:5～250μg·L~(-1)。6只家兔药动学参数分别为:ρ_(max)(110.78±24.35)μg·L~(-1),t_(max)(11.67±2.58)min,k(0.46±0.13)h~(-1),t(1/2)(1.60±0.47)h,AUC_(0→6h)(104.50±15.13)μg·h·L~(-1),AUC_(0→∞)(119.12±19.10)μg·h·L~(-1)。结论我们建立的测定方法简便、灵敏、准确,可以用作甲磺酸酚妥拉明在家兔体内的药动学研究。     

头痛宁鼻腔喷雾剂在大鼠体内的药动学及脑靶向研究

目的:研究头痛宁鼻腔喷雾剂经鼻给药后在大鼠体内的药动学及脑靶向情况。方法:84只SD大鼠分为鼻腔给药组和静脉给药组,每组42只,给药剂量均为1.2 mL/kg。分别于给药后5、10、15、30、60、90、120 min于腹主动脉取血5 mL,并取脑组织(每个时间点6只)。采用高效液相色谱-串联质谱法测定各组大鼠血浆和脑组织中升麻素苷、5-O-甲基维斯阿米醇苷的浓度,采用DAS 2.0软件计算药动学参数及脑靶向性指数。结果:鼻腔给药组大鼠血浆中升麻素苷、5-O-甲基维斯阿米醇苷的c_(max)分别为(0.202 4±0.015 8)、(0.373 8±0.085 7)μg/mL,t_(max)均为(10.000 0±0.000 0)min,AUC_(0-∞)分别为(16.542 9±2.110 3)、(27.452 7±5.572 1)μg·h/mL;脑组织中升麻素苷、5-O-甲基维斯阿米醇苷的c_(max)分别为(0.180 2±0.038 4)、(0.320 4±0.027 7)μg/g,t_(max)均为(10.000 0±0.000 0)min,AUC_(0-∞)分别为(17.105 3±2.432 9)、(24.541 6±3.753 4)μg·h/g。静脉给药组大鼠血浆中升麻素苷、5-O-甲基维斯阿米醇苷的c_(max)分别为(0.300 2±0.016 1)、(0.526 7±0.044 1)μg/mL,t_(max)均为(10.000 0±0.000 0)min,AUC_(0-∞)分别为(28.010 5±4.112 8)、(60.294 1±11.290 2)μg·h/mL;脑组织中升麻素苷、5-O-甲基维斯阿米醇苷的c_(max)分别为(0.149 8±0.031 5)、(0.199 8±0.040 1)μg/g,t_(max)均为(15.000 0±0.000 0)min,AUC_(0-∞)分别为(22.643 4±2.883 1)、(36.721 8±14.885 6)μg·h/g。升麻素苷、5-O-甲基维斯阿米醇苷脑靶向性指数分别为2.387 0、2.176 1。结论:头痛宁鼻腔喷雾剂鼻腔给药后一部分药物可经鼻腔吸收直接转运至脑,制成鼻腔喷雾剂科学合理。     

两种阿莫西林片在健康志愿者体内的药物动力学和生物利用度

目的:研究单剂量po阿莫西林咀嚼片和普通片后,阿莫西林在血浆中的药物动力学与相对生物利用度.方法:采用高效液相色谱法测定10名健康男性受试者草剂量po750mg阿莫西林咀嚼片和普通片后,血浆中阿莫西林浓度变化情况;计算药物动力学参数与相对生物利用度.结果:咀嚼片与普通片的药-时曲线均符合一房室模型.主要药物动力学参数分别为t_(max)(70.92±9.38)和(78.01±18.97)min;C_(max)(10.09±2.62)和(9.86±3.14)μg/ml;AUC(2136.53±481.83)和(2182.83±524.12)(min·μg)/ml.咀嚼片的相对生物利用度为97.88%.结论:两种片剂药物动力学参数间无显著性差异(P>0.05);两药具有生物等效性.     

应用液质联用法同时测定新西兰家兔血浆中左炔诺孕酮和炔雌醇浓度及其药动学

目的建立液相色谱-质谱联用法(HPLC-MS/MS)测定新西兰家兔血浆中左炔诺孕酮(LNG)和炔雌醇(EE)浓度的方法,并探讨LNG/EE复方避孕贴多次给药后药动学特征。方法 6只雌性新西兰家兔连续10次给予LNG/EE复方避孕贴(5 cm×4 cm,每贴含LNG 5.35 mg,EE 0.11 mg),每3 d1贴,连续给药30 d,分别于给药后不同时间耳缘静脉采血,血浆样品经丹酰氯衍生化后,采用HPLC-MS/MS测定血浆中LNG和EE浓度,并采用DAS3.0软件计算首末次给药的主要药动学参数。结果 LNG的线性范围为0.10~20.00μg·L~(-1),最低定量限为0.10μg·L~(-1),提取回收率均>78.30%,日内精密度<7.38%、日间精密度<12.89%。首次给药后LNG的主要药动学参数为:峰浓度C_(max)为(8.10±2.38)μg·L~(-1),达峰时间(T_(max))为(2.38±1.45)h,西药浓度-时间曲线下面积(AUC)(0-768)为(142.35±36.99)h·μg·L~(-1);末次给药后LNG的药动学参数:C_(max)为(7.05±1.07)μg·L~(-1),T_(max)为(2.71±1.83)h,AUC(0-768)为(141.95±22.31)h·μg·L~(-1)。EE的线性范围为0.02~5.00μg·L~(-1),最低定量限为0.02μg·L~(-1),提取回收率均>79.99%,日内精密度<3.28%、日间精密度<12.76%。首次给药后EE的药动学参数:C_(max)为(0.18±0.04)μg·L~(-1),T_(max)为(2.50±1.30)h,AUC(0-768)为(2.65±0.56)h·μg·L~(-1);末次给药后EE的药动学参数:C_(max)为(0.17±0.07)μg·L~(-1),T_(max)为(2.17±0.26)h,AUC(0-768)为(2.02±0.82)h·μg·L~(-1)。结论建立的HPLC-MS/MS法准确灵敏,可用于同时测定血浆中LNG和EE的浓度。新西兰家兔给予LNG/EE复方避孕贴后首末次主要药动学参数无显著性差异,且多次给予此避孕贴后体内血药浓度无蓄积。     

高效液相色谱法测定大鼠血浆中伊马替尼浓度及其药动学

目的建立大鼠血浆中伊马替尼的高效液相色谱测定方法,研究伊马替尼在大鼠体内的药动学特征。方法血浆经高氯酸沉淀,以ZORBAX SB-C18(4.6 mm×150 mm,5μm)为色谱柱,流动相为乙腈:0.1%TFA:水=20:36:44(V/V/V),流速为1.0 mL·min^(-1),检测波长为282 nm。测定10只雄性SD大鼠单剂量伊马替尼50 mg/kg(-1),检测波长为282 nm。测定10只雄性SD大鼠单剂量伊马替尼50 mg/kg^(-1)灌胃后的血药浓度经时过程。由DAS2.0程序处理计算药动学参数。结果伊马替尼浓度在0.10(-1)灌胃后的血药浓度经时过程。由DAS2.0程序处理计算药动学参数。结果伊马替尼浓度在0.10²0.00μg·mL20.00μg·mL^(-1)范围内线性关系良好(r=0.999 8),定量下限为0.10μg·mL(-1)范围内线性关系良好(r=0.999 8),定量下限为0.10μg·mL^(-1),日内、日间RSD均小于10%,回收率均大于85%,伊马替尼在大鼠体内峰值浓度p_(max)为(11.8±2.0)μg·mL(-1),日内、日间RSD均小于10%,回收率均大于85%,伊马替尼在大鼠体内峰值浓度p_(max)为(11.8±2.0)μg·mL^(-1),达峰时间t_(max)为(3.0±0.7)h,AUC_(0-∞)为(126±28)μg·mL(-1),达峰时间t_(max)为(3.0±0.7)h,AUC_(0-∞)为(126±28)μg·mL^(-1),AUC_(0-∞)为(128±28)μg·h·mL(-1),AUC_(0-∞)为(128±28)μg·h·mL^(-1),t_(1/2α)为(2.4±0.8)h,t_(1/2β)为(7.8±0.9)h。结论本方法准确可靠、简便快速,适用于大鼠血浆伊马替尼浓度的测定及其药动学研究。     

沙丁胺醇气雾剂在健康受试者体内的药物动力学和相对生物利用度

目的:研究沙丁胺醇气雾剂在健康受试者的药物动力学和生物利用度.方法:十名健康男性志愿者单剂量吸入1.2 mg沙丁胺醇气雾剂或口服沙丁胺醇水溶液.用HPLC法测定人血浆中沙丁胺醇浓度.以非房室模型计算药物动力学参数,计算气雾剂相对水溶液的生物利用度.结果:气雾剂和口服溶液的药物动力学参数如下:T_(max)(0.22±0.07)和(1.8±0.6)h,C_(max)(3.4±1.1)和(3.9±1.4)μg·L~(-1),T_(1/2)(4.5±1.5)和(4.6±1.1)h,AUC_(0-20min)(0.9±0.3)和(0.16±0.10)μg·h·L~(-1).两种给药途径的T_(max)和AUC_(0-20 min)之间差异显著(P<0.01).AUC_(0-20min)(nihal)为 AUC_(0-20 min)(po)的 8倍.沙丁胺醇气雾剂相对口服溶液的生物利用度为 57％±24％.结论:沙丁胺醇气雾剂在人体的吸收过程与口服溶液差异有显著性.     

功劳木提取物中三种生物碱类成分在大鼠体内的药动学研究

目的建立用于同时测定大鼠血浆中药根碱、木兰花碱和巴马汀的LC-MS/MS分析方法,并将该方法用于功劳木提取物在大鼠体内的药动学研究。方法大鼠灌胃给予功劳木提取物后,眼眶静脉丛取血,蛋白沉淀法处理血浆样品,色谱柱为Agilent ZORBAX SB-C18(50 mm×4.6 mm,5μm),流动相采用乙腈-5 mmol·L~(-1)乙酸铵(含体积分数0.2%甲酸),体积比为35∶65等度洗脱,以正离子扫描选择反应监测(SRM)模式进行检测。结果药根碱、木兰花碱和巴马汀质量浓度分别在5.0~320.0、2.0~648.0和2.5~200.0μg·L~(-1)内线性关系良好,日内和日间精密度均小于15.0%,准确度均在±3.9%以内,提取回收率均在70.0%以上。药根碱的主要药动学参数t_(max)、t_(1/2)、ρ_(max)、AUC0-t分别为(0.50±0.16)h、(7.34±4.91)h、(141.11±74.72)μg·L~(-1)、(208.27±95.25)μg·h·L~(-1);木兰花碱的t_(max)、t_(1/2)、ρ_(max)、AUC0-t分别为(0.11±0.04)h、(4.79±4.26)h、(366.60±135.65)μg·L~(-1)、(305.54±176.29)μg·h·L~(-1);巴马汀的t_(max)、t_(1/2)、ρ_(max)、AUC0-t分别为(0.25±0.08)h、(5.16±3.58)h、(56.60±33.75)μg·L~(-1)、(112.60±56.61)μg·h·L~(-1)。结论该方法快速、选择性好,适用于大鼠灌胃给予功劳木提取物后药根碱、木兰花碱和巴马汀在大鼠体内的药动学研究。药根碱、木兰花碱和巴马汀在大鼠体内吸收均较迅速。     

雷公藤甲素与雷公藤红素含药血清对小鼠巨噬细胞一氧化氮分泌的影响

目的研究雷公藤甲素与雷公藤红素抗炎作用量效关系。方法健康雄性Wistar大鼠灌胃给予雷公藤甲素与雷公藤红素的混合液,分别于给药前0h和给药后0.5、1.0、2.0、4.0、6.0、8.0和12.0h收集血清,利用液相色谱-质谱联用法检测大鼠血清中雷公藤甲素和雷公藤红素的浓度;采用小鼠腹腔巨噬细胞线RAW264.7,利用脂多糖(lipopolysaccharide,LPS)作为刺激剂构建炎症模型,向细胞模型中分别加入雷公藤甲素、雷公藤红素药液或含药血清,采用Griess试剂利用紫外分光光度法检测孵化液中一氧化氮(NO)的分泌情况。结果雷公藤甲素质量浓度高于200μg·L-1,即可抑制LPS对RAW264.7细胞的刺激,雷公藤红素药液质量浓度高于80μg·L-1时,也可产生此作用,并呈现浓度依赖关系。血清中雷公藤甲素的质量浓度在0.5和1.0h时高于300μg·L-1,雷公藤红素的血清质量浓度在0.5⁶.0h内维持在200μg·L-1左右。大鼠服用雷公藤甲素和雷公藤红素后0.56.0h内维持在200μg·L-1左右。大鼠服用雷公藤甲素和雷公藤红素后0.5⁶.0h内的含药血清能明显抑制LPS对RAW264.7细胞的刺激作用,6.0h后含药血清抑制效果不显著。结论雷公藤甲素、雷公藤红素药液及大鼠服用雷公藤甲素和雷公藤红素后的含药血清均具有抗炎作用,该作用与这2种化合物体内浓度相关。     

雷公藤甲素在正常大鼠和佐剂性关节炎模型大鼠体内的药动学研究

目的:研究雷公藤多苷片中活性成分雷公藤甲素在正常大鼠和佐剂性关节炎模型大鼠体内的药动学特征,为其临床合理用药提供参考。方法:将12只SD大鼠随机分为正常组和模型组,每组6只。模型组大鼠sc完全弗氏佐剂0.1 m L复制佐剂性关节炎模型,正常组大鼠sc等体积生理盐水。造模14 d后,两组大鼠均ig雷公藤多苷片混悬液96 mg/kg,分别于给药前及给药后10、30、45、60、90、120、150、180、240、300、420 min眼眶取血0.4 m L,采用高效液相色谱法测定雷公藤甲素的血药浓度;采用DAS 2.0药动学软件计算药动学参数,并进行比较。结果:雷公藤甲素在正常组、模型组大鼠体内的c_(max)分别为(1.139±0.114)、(0.916±0.103)μg/m L,t_(max)分别为(2.167±0.606)、(3.083±0.801)h,t_(1/2α)分别为(5.500±3.610)、(5.593±1.795)h,AUC_(0-7 h)分别为(5.052±0.371)、(4.707±0.347)μg·h/m L,MRT_(0-7 h)分别为(3.224±0.119)、(3.429±0.139)h,CL分别为(11.616±2.986)、(11.246±2.638)m L/h。与正常组比较,模型组大鼠c_(max)显著减小,t_(max)和MRT_(0-7 h)显著延长(P<0.05)。结论:佐剂性关节炎会影响大鼠体内雷公藤甲素的药动学特征,其可促进大鼠体内雷公藤甲素的吸收与消除。     

泮托拉唑钠在大鼠体内药动学研究

目的建立HPLC法测定大鼠血浆中泮托拉唑钠对映体,研究泮托拉唑钠在大鼠体内药动学特征。方法血浆用醋酸乙酯提取,以非那西丁为内标,Chiralcel OJ-RH色谱柱(250 mm×4.6 mm,5μm),流动相为20 mmol/L磷酸二氢钠(含0.01%磷酸)–乙腈(78∶22),紫外检测波长为288 nm,体积流量为1.0 m L/min,柱温40℃。大鼠尾iv消旋体16 mg/kg,HPLC-UV法测定血浆中左旋和右旋泮托拉唑钠浓度,并采用DAS 2.0软件计算药动学参数。结果左旋泮托拉唑钠、右旋泮托拉唑钠线性范围均为0.156~40.000μg/m L,定量限为0.156μg/m L。泮托拉唑钠左旋体与右旋体的主要药动学参数分别为:Cmax(38.13±3.33)、(40.52±3.69)μg/L;AUC0-τ(1 688.45±302.38)、(1 399.88±376.44)min·μg/m L;AUC0-∞(1710.61±309.40)、(1 417.29±383.21)min·μg/m L;t1/2(30.92±6.41)、(22.37±7.59)h。结论泮托拉唑钠对映体在大鼠体内的药动学存在立体选择性特征,为临床合理应用手性药物泮托拉唑钠提供参考。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Glycofection: The Ubiquitous Roles of Sugar Bound on Glycoplexes

Glycofection (transfection by using sugar-substituted polylysine) was assessed in order to provide an alternative to viral vectors for the transfer of genes into vascular smooth muscle cells. A rabbit vascular smooth muscle cell line (Rb-1 cells) was selectively transfected by using glycoplexes (glycosylated polylysine/pSV2LUC complexes) in the presence of 10 mu M of the fusogenic peptide GALA. A sugar-specific transfection was obtained when the glycofection was conducted for 1 h with glycoplexes containing either alpha Gal, alpha -Glc, alpha -GalNAc, beta -GlcNAc, or beta -GalNAc residues. The gene expression was high after transfection, with glycoplexes bearing alpha Gal, alpha -GalNAc, or beta -GalNAc residues that were weakly internalized, and low with glycoplexes carrying Lact or Rha residues that were well taken up by cells. These results suggest that 1) glycofection can be a good approach for a selective transfer of genes intovascular smooth muscle cells, 2) an efficient uptake of the glycoplexes is not the unique limiting step for an efficient transfection, and 3) the sugar-dependent trafficking of the glycoplexes inside the cells may account for the transfection efficiency.     

直肠癌下切缘病理组织学分析

目的探讨直肠癌逆向浸润与下切缘的安全距离的关系。方法对36例直肠癌Miles手术和Dixon手术后标本的肿瘤下缘1.0cm、2.0cm、3.0cm的肠壁及对应的系膜病理组织学检查,观察直肠癌逆向浸润或转移的距离。结果36例直肠癌标本距癌肿下缘1.0 cm、2.0cm、3.0cm的肠壁及对应的系膜病理组织学检查均为阴性,结论直肠癌远恻逆向浸润或转移未见超过1.0cm,因此认为保肛手术时切除肿瘤远侧肠管(包括系膜)2.0cm是安全的。