Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models

Objective: The population pharmacokinetics of amikacin, in neonates, was investigated using the nonlinear mixed effects model (NONMEM). Methods: One hundred and six steady-state amikacin serum levels were obtained from 53 black neonates with a mean gestational age of 35.1 weeks and mean age at the start of treatment of 3.1 days. A one-compartment model was used to fit the data. Results: The final models for clearance (CL) and volume of distribution (V) were:

健康者体内头孢唑林对阿米卡星药动学的影响

采用微量微生物法对阿米卡星（ＡＭＫ）单用及ＡＭＫ与头孢唑林（ＣＥＺ）合用后,健康者体内ＡＭＫ血药浓度进行测定;药时数据用ＭＣＰＫＰ软件经ＩＢＭ计算机处理,并对两组药动学参数进行了统计学处理,结果表明ＣＥＺ对ＡＭＫ的药动学有显著的影响。     

头孢唑林对阿米卡星在兔体内的药动学影响

采用微量微生物法对阿米卡星（ＡＭＫ）单用及与头孢唑林（ＣＥＺ）合用后兔体内ＡＭＫ血药浓度进行测定,药时数据用ＭＣＰＫＰ软件经ＩＢＭ 计算机处理,并对两组药动学参数进行了统计学处理,结果表明ＣＥＺ对ＡＭＫ的药动学有显著的影响。     

国内红细胞载体文献的计量学分析

利用中国知网全文数据库,运用文献计量学方法对1978-01～2007-08国内学术期刊上发表的红细胞载药系统文献进行文献数量、年代、研究内容等方面的统计分析,探讨我国红细胞载体给药技术研究的发展与现状。     

阿米卡星在不同年龄呼吸系统感染病人中的药物动力学

为研究阿米卡星（ＡＭＫ）在不同年龄呼吸系感染病人中的药物动力学特性,采用荧光偏振免疫法（ＦＰＩＡ）测定病人血中ＡＭＫ浓度,根据药－时数据求出药物动力学参数。结果表明,ＡＭＫ在青年病人组和老年病人组中的末端相消除半衰期分别为３．０２±０．６３ｈ和４．４８±１．３９ｈ,老年病人组明显长于青年病人组（Ｐ＜０．０５）。药物峰浓度分别为３８．７０±７．５１ｍｇ／Ｌ和４０．０６±５．３０ｍｇ／Ｌ,两组间无差异。研究证明,在肾功正常的条件下,年龄因素是影响ＡＭＫ消除半衰期的重要因素之一,但不影响药物峰浓度及其它药物动力学参数。因此,老年病人应用ＡＭＫ时应进行血药浓度监测     

高剂量阿米卡星在PICU败血症患儿体内药代动力学的初步研究

目的初步探讨5 mg/kg阿米卡星在PICU患儿体内的药代动力学和血液动力学的关系。方法纳入符合条件的30例革兰阴性败血症患儿进行阿米卡星药物治疗研究,通过非房室模型计算每例患儿的阿米卡星的药代动力学。结果阿米卡星在革兰阴性败血症患儿体内平均药物分布为(0.36±0.07)L/kg,平均血液清除率为(3.88±0.97)m L/(min·kg)。肌酐清除率(CCR)与血清肌酸酐(SCr)相关性差异有统计学意义。结论对PICU患儿应用高剂量阿米卡星(≥25 mg/kg)需要考虑败血症对血液动力学的影响,要密切监测败血症患儿血药浓度变化。     

Renal effects of supernatant from rat peritoneal macrophages activated by microcystin-LR: role protein mediators.

We have demonstrated previously that microcystin-LR promoted some renal alterations using the isolated perfused rat kidney preparation. However, these effects were not proved to be direct or indirect. The aim of the current work is to examine the renal effects promoted by supernatants from rat macrophages stimulated with microcystin-LR and the role of inflammatory mediators. Peritoneal macrophages were collected previously and were incubated for 1h in fresh medium (control) and in medium containing microcystin-LR. Dexamethasone, quinacrine, thalidomide and cycloheximide were administered 30 min before microcystin-LR. Supernatants of macrophages stimulated with or without pharmacological inhibitors were added on the perfused rat kidney model. The infusion of macrophages supernatants stimulated by microcystin-LR caused significant increases in renal vascular resistance (C: 4.93+/-0.33 vs T: 5.15+/-0.21), glomerular filtration rate (C: 0.559+/-0.008 vs T: 0.978+/-0.15) and urinary flow (C: 0.16+/-0.01 vs T: 0.23+/-0.03). Cycloheximide, quinacrine and dexamethasone blocked these effects and thalidomide blocked renal vascular resistance. Macrophages stimulated by microcystin-LR release mediators capable of promoting nephotoxicity in isolated perfused rat kidney. Phospholipase A(2), TNF-alpha and other protein mediators appear to be involved on its renal toxic mechanism.     

神经生长因子对小鼠腹腔巨噬细胞SOD活性、MDA含量的影响

目的 研究神经生长因子（NGF）对正常小鼠、非肥胖性糖尿病（NOD）小鼠腹腔巨噬细胞过氧化物歧化酶（SOD）活性、丙二醛（MDA）含量的影响。方法 实验分对照组和实验组,用黄嘌呤氧化酶、TBA法检测细胞培养液中SOD活性、MDA含量。结果 与正常小鼠比较,NOD小鼠腹腔巨噬细胞SOD活性明显增高（P〈0．05）,MDA含量却明显减小（P〈0．01）;与各自对照组比较,NGF（5ng／ml、10ng／m1）实验组巨噬细胞SOD活性、MDA含量有显著改变。结论 糖尿病在病程的不同时期,SOD活性、MDA含量可以出现不同的变化,NGF对改善细胞代谢可能有一定影响。     

Effect of endosulfan and malathion on lipid peroxidation, nitrite and TNF-alpha release by rat peritoneal macrophages

Endosulfan and malathion are organochlorine and organophosphate insecticides, respectively. The toxicity of both the insecticides are well known on non-target organisms. Both endosulfan and malathion are reported to suppress humoral as well as cellular immune responses. We investigated the possible effect of both these insecticides on lipid peroxidation, nitrite production and TNF-alpha generation in rat peritoneal macrophages under in vitro conditions. Rat peritoneal cells were collected and cultured with or without insecticides and relevant stimulants for lipid peroxidation, generation of nitric oxide and TNF-alpha. FeSO(4) was used as an inducer for lipid peroxidation and LPS was used to induce nitric oxide synthase and release of TNF-alpha. Lipid peroxidation was assayed by estimating MDA; nitric oxide was determined by estimating nitrite and TNF-alpha by using an assay kit in culture supernatants. Both endosulfan and malathion had no effect on lipid peroxidation. Endosulfan did not have any influence on nitrite production, but suppressed the LPS-induced TNF-alpha generation. Malathion, however, showed a direct suppression on nitrite production and suppression of LPS-induced TNF-alpha generation. This study suggests that functional aberrations of macrophages may contribute significantly to the immunomodulation reported for these insecticides.     

Tissue distribution and pharmacokinetics of stable polyacrylamide nanoparticles following intravenous injection in the rat

A variety of polymer nanoparticles (NP) are under development for imaging and therapeutic use. However, little is known about their behavior. This study examined pharmacokinetics, distribution and elimination of stable polyacrylamide (PAA) nanoparticles (~ 31 nm average diameter). PAA NPs and polyethylene glycol-coated PAA NPs were injected into the tail veins of healthy male rats. Blood, tissues and excreta were collected at times ranging from 5 min to 120 h and their radioactive content was quantified. A mathematical model was then applied to analyze the distribution dynamics of both NPs. Elimination from the blood could be accounted for by a quick but finite relocation to the major organs (about 20%, 0.6 to 1.3 h half-lives), and a slower distribution to the carcass (about 70%, 35 to 43 h half-lives). Excreted urinary levels correlated with blood concentrations. Combined cumulative urinary and fecal output accounted for less than 6% of the dose at 120 h. Compared to five other polymeric nanoparticles, the studied particles are at the highest half-lives and Area Under the Curve (4000 to 5000%-h). These two parameters decrease by three orders of magnitude when nanoparticle size increases from the 30 nm range up to 250 nm. For similar sizes, pegylated nanoparticles are more persistent in the blood than non-pegylated ones, but this difference is much smaller in the 30 nm and relatively high dose range than above 100 nm. Persistence of PAA NPs is not associated with acute toxicity signs as measured by typical serum markers of inflammation and cellular damage.     

Selective kinetic determination of amikacin in serum using long-wavelength fluorimetry

A simple and rapid method for the determination of the antibiotic amikacin, involving the use of a long-wavelength fluorophor, namely indocyanine green, (ICG) is presented. The dye is oxidised by cerium(IV) in acidic medium, resulting in a sharp decrease of the fluorescence, but this fluorescence quenching is inhibited in the presence of amikacin, which can be ascribed to the formation of an ion pair between the fluorophor and the analyte. The initial rate of the system is monitored at λ_ex: 765 nm and λ_em: 812 nm as excitation and emission wavelengths, respectively, using the stopped-flow mixing technique, which makes the method applicable to automatic routine analysis. Each measurement is obtained in only 2–3 s. The method presents a detection limit of 0.02 μg m1⁻¹ in standard solutions, which corresponds to 2.5 μg ml⁻¹ in serum samples. The precision is in the range 4.8–6%. The good selectivity of the method allows amikacin to be determined in the presence of other antibiotics, including other aminoglycoside antibiotics, in serum. The recoveries obtained from the analysis of different samples were in the range 89.4–104.7%.     

荧光偏振免疫分析法测定新生儿丁胺卡那霉素血药浓度及药物动力学研究

本文用荧光偏振免疫分析法(Fluorescence Polarization Immunoassay,简称FPIA)测定20例新生儿患者丁胺卡那霉素(Amikacin 下称AMK)血清浓度。剂量按7.5mg/kg 静脉滴注给药,30min 滴毕,经时采样测得数据,用3P87程序处理数据,经分析符合一室模型,并取得药动学参数。平均Vd:0.75±S0.20_1(L/kg)Ke:0.17±0·06(h~(-1))T_(1/2):4.8±S1.8(h)C1:1.9±0.5(ml/min·kg)     

Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages

Spherical and rod-shaped gold nanoparticles with surface poly(ethylene glycol) (PEG) chains were characterized for size, shape, charge, poly dispersity and surface plasmon resonance. The nanoparticles were injected intravenously to 6-8-week-old female nu/nu mice bearing orthotopic ovarian tumors, and their biodistribution in vital organs was compared. Gold nanorods were taken up to a lesser extent by the liver, had longer circulation time in the blood, and higher accumulation in the tumors, compared with their spherical counterparts. The cellular uptake of PEGylated gold nanoparticles by a murine macrophage-like cell line as a function of geometry was examined. Compared to nanospheres, PEGylated gold nanorods were taken up to a lesser extent by macrophages. These studies point to the importance of gold nanoparticle geometry and surface properties on transport across biological barriers.     

红细胞包蔽吗啡的制备及包蔽效果的研究

目的：了解高渗法制备RBC吗啡载体的可行性。方法：①全血与50％GS混合后以血球压积的变化评价RBC的脱水效果；②利用扫描电镜观察RBC包蔽吗啡前后其形态的变化；③采用放免分析(RIA)方法对RBC一吗啡溶液中RBC内外吗啡的浓度进行测定；④HPLE法分析人RBC内Hb与吗啡的结合率。结果：全血与50％GS按1：0．5混合时的脱水效果最显著；RBC脱水后以及包蔽吗啡后其形态由正常圆盘状变为扁平和皱缩，最后又恢复为正常圆盘状；RBC包蔽吗啡剂量为5mg和10mg时RBC内外吗啡浓度之间均无显著差异。Hb与吗啡在不同浓度混合下均具有一定的结合率。结论：高渗法制备RBC吗啡载体具有较好的包蔽效果，Hb与吗啡结合率的存在可能影响吗啡的作用时效。     

糖萜素对小鼠腹腔巨噬细胞产生一氧化氮的影响

目的：探讨糖萜素对小鼠腹腔巨噬细胞产生NO的影响。方法：在饲料中添加不同剂量糖萜素喂养NIH小鼠,以基础饲料为对照,检测环磷酰胺免疫抑制组与非抑制组不同时间段小鼠腹腔巨噬细胞产生NO的含量。结果：含糖萜素饲料组于不同时间测得NO含量均较基础饲料组显著增高（P＜0．05）。免疫抑制状态下,含糖萜素饲料组NO含量也较基础饲料组高（P＜0．05）。体外糖萜素不能直接影响NO的生成。结论：糖萜素能显著提高小鼠体内巨噬细胞产生NO。体外则不能直接影响NO的生成。     

刚果红褪色光度法测定硫酸阿米卡星

在酸性条件下 ,刚果红 (CR)与硫酸阿米卡星 (AMK)反应 ,生成离子缔合物 ,使刚果红溶液褪色 ,最大褪色波长位于 5 6 4 nm,表观摩尔吸光系数 (ε)为 2 .6 1× 10 4 L/ (mol·cm) ;硫酸阿米卡星的浓度在 0～ 1.7× 10 - 5mol/ L 范围内 ,遵从比尔定律。该法用于市售药物中硫酸阿米卡星含量的测定 ,结果满意。     

葎草联合阿米卡星治疗感染性腹泻的疗效研究

目的 探讨葎草联合阿米卡星治疗感染性腹泻的临床疗效.方法 130例感染性腹泻患者,随机分成研究组和对照组各65例,比较2组的总有效率、痊愈率、治疗后主要症状和体征的改善时间等.结果 研究组痊愈率和总有效率分别为83.08%和98.46%,明显高于对照组的40.00和86.15%,差异有统计学意义（P〈0.05）;研究组治疗后大便正常、腹痛和呕吐消失时间均短于对照组,差异有统计学意义（P〈0.05）.结论 葎草煎剂联合阿米卡星治疗感染性腹泻的疗效确切,能够显著缓解病情,缩短腹泻时间.     

头孢吡肟联合阿米卡星治疗克雷伯杆菌引发肺炎的效果研究

目的观察头孢吡肟联合阿米卡星治疗克雷伯杆菌引发肺炎的效果。方法选择2013年1-12月来我院就诊的克雷伯杆菌肺炎患者86例,依据治疗方法的不同将患者分为治疗组和对照组,每组43例。对照组应用头孢哌酮联合庆大霉素治疗,治疗组应用头孢吡肟联合阿米卡星进行治疗。分别于治疗前及获知痰培养药敏结果后,检测患者白细胞计数(WBC)、C反应蛋白(CRP)、动脉血氧分压(PaO2)、尿蛋白、呼吸频率、红细胞沉降速率(ESR)、体温,比较两组呼吸困难、紫绀、寒战及死亡例数。结果治疗前,两组患者的WBC、CRP、PaO2、尿蛋白、呼吸频率、ESR、体温、呼吸困难例数、紫绀例数及寒战例数比较差异无统计学意义(P>0.05)。治疗组患者获知痰培养药敏结果后的WBC、CRP、尿蛋白、呼吸频率、ESR、体温、呼吸困难例数、紫绀例数、寒战例数均明显低于对照组(P<0.05);治疗组、对照组患者的PaO2分别为(82.16±19.21)、(73.24±18.17)mmHg,治疗组明显高于对照组(P<0.05)。结论应用头孢吡肟联合阿米卡星可明显提高克雷伯杆菌肺炎患者的治疗效果,减轻患者的临床症状并降低死亡率。     

硫酸阿米卡星多囊脂质体的制备及评价

目的 制备硫酸阿米卡星多囊脂质体(amikacin sulfate multivesicular liposomes, AMK-MVLs),对其进行质量评 价,并考察了其体外抗菌活性。方法 采用复乳法制备AMK-MVLs混悬液Ⅰ,Box-Behnken效应面法优化筛选最佳处方,采 用生理盐水洗涤后调整药物浓度得AMK-MVLs混悬液。采用光学显微镜、激光粒度仪、差示扫描量热(differential scanning calorimeter,DSC)考察制剂的理化性质,采用透析法考察其体外释放规律,通过微量稀释法初步考察其体外抗菌活性。结 果 优化得到AMK-MVLs混悬液Ⅰ的最佳处方为：大豆磷脂与胆固醇质量比为1.91:1,三油酸甘油酯用量为1.02%,PVA用量为 0.62%。AMK-MVLs呈堆叠有无数囊泡的非同心球状,AMK-MVLs混悬液包封率(87.12±1.55)%,平均粒径为11.93 μm。DSC 结果表明,AMK以无定型状态存在于脂质体内。体外释放结果显示AMK-MVLs混悬液在72 h时释药约80%。体外溶血实验表 明,AMK-MVLs脂质体粒子浓度低于400 μg/mL时无溶血风险。体外抗菌实验结果显示,相较于AMK溶液,AMK-MVLs混悬液对E. coli、 P. aeruginosa、S. aureus 3种细菌具有更好的抗菌效果。结论 成功制备了一种硫酸阿米卡星多囊脂质体,其粒径分布均匀、包 封率高,释药规律符合Higuchi动力学模型,具有增强的抗菌活性。     

阿米卡星脂质体在小鼠体内的组织分布

用微生物测定法对阿米卡星脂质体在小鼠体内各组织中的药物浓度进行测定，研究了给药后组织浓度及分布情况，并将其与游离阿米卡星作比较。结果表明：小鼠单剂量静脉注射５２ｍｇ／ｋｇ游离的或脂质体硫酸阿米卡星后，测定０．５、１、３、７、１２、２４ｈ各组织中药物浓度，以肾脏浓度为最高。与游离药物相比，阿米卡星脂质体明显提高了心（６．２倍）、肝（９．５倍）、脾（２８４倍）、肺（３倍）、脑（１４．７倍）、血清（３倍）中的药物分布，降低了肾脏的分布（１／２）。阿米卡星脂质体不仅改变了该游离药物的体内组织分布，而且延长了半衰期，血药浓度可维持２４ｈ（游离药物仅７ｈ）。说明阿米卡星脂质体具有靶向和缓释的双重作用。