两性霉素B脂质体的制备及药动学

目的:制备两性霉素B脂质体并对其药动学进行研究。方法:采用有机溶剂注入法制备两性霉素B脂质体,用微射流进行整粒,用动态光散射法测定粒径,采用Ultrafree-CL离心超滤管分离游离两性霉素B(F-AMB)与复合两性霉素B(L-AMB)检测包封率,用Wistar大鼠进行药动学研究。结果:两性霉素B脂质体平均粒径为(115±20)nm;包封率>99.9%;大鼠静脉注射,实验药与Amphotec的Cmax,AUC0~168 h和AUC0~∞无显著性差异(P>0.05)。结论:采用有机溶剂注入法制备两性霉素B脂质体具有较高包封率,在大鼠体内的药动学特征与Amphotec一致。     

载两性霉素B的PLA-PEG纳米粒在小鼠体内的分布

采用改良的相分离法制备载有两性霉素B（1）的聚乳酸-聚乙二醇纳米粒，HPLC法检测小鼠脑组织及其它脏器中的药物浓度。以1粉针剂和1脂质体为对照，评价纳米粒的脑靶向作用。在小鼠脑内1粉针剂组未能检测出药物，1脂质体组于3h后能测得微量药物，1纳米粒组小鼠给药30min后脑内浓度达33．5ng／g，12h达最高（160．4ng／g）。     

两性霉素B静脉和雾化联合给药治疗肺曲霉病1例报告

1例47岁男性患者因“肺曲霉病”住院治疗。因抗真菌药敏试验显示耐药或用药后治疗效果欠佳及肝功能异常而先后停用卡泊芬净和伏立康唑。换用两性霉素B脂质体静脉滴注治疗病灶吸收缓慢,且肾功能有受损趋势。给予联合两性霉素B（AmB）雾化吸入治疗,因出现呛咳、咽痛等局部刺激症状而停用。临床药师认为两性霉素B雾化吸入疗效好,安全性高,局部药物浓度维持时间长,虽然局部不良反应发生率较高,但降低吸入药物浓度可以避免或减轻不良反应。建议继续联合雾化吸入两性霉素B。临床医生采纳临床药师意见,减低雾化吸入两性霉素B的浓度,待患者耐受后再逐渐提高浓度和剂量。联合给药2周后,咳嗽症状基本消失。复查纤支镜示支气管腔病灶显著减少。随访肾功能无进一步恶化。     

两性霉素B脂质体和脂质复合体的临床应用

尽管两性霉素B去氧胆酸钠(Fungiz-one,AmB_(DOC)),是选用于多种真菌感染疾病的治疗剂,但由于它的高毒性,应用极大地受到限制,其中毒性包括给药期间急性副作用寒战、发烧、肌痛、血栓性静脉炎,以及低钾血、低镁血、肾毒性等.AmB_(DOC)体外杀真菌活性是强大的,且杀菌活性与浓度成正相关,但却由于它的毒性问题,临床上只能在0.7～1.5mg/kg最大耐受剂量间用药,临床疗效发挥是不充分的,且导致治疗失败率高,特别在中性粒细胞减少症和其它免疫缺损病人更为明显.     

两性霉素B脂质体滴眼液在兔房水中的药动学

目的:探索兔眼局部应用生物黏附性两性霉素B脂质体(AmBL)滴眼液后,房水中的药动学状况。方法:32只新西兰白兔,在角膜上皮完整和刮除时,分别应用0．5％AmBL滴一眼,用0．5％两性霉素B滴眼液(AmBS)滴对侧眼作对照,于用药后0．25,0．5,1,2,3和4 h的6个时点,选取不同的白兔抽取房水,用高效液相色谱法测定房水中AmB的含量。结果:AmBL滴眼后,房水中AmB的有效抑菌浓度可维持2 h,AmBE S滴眼1 h后即近全部消除。角膜上皮完整时,AmBL的AUC和t1/2是AmBS的3．6倍和5倍;角膜上皮刮除后,AmBL的AUC和t1/2是AmBL S的3．9倍和3．2倍。结论:0．5％AmBL滴眼液具有较好的缓释作用和生物利用度,药物浓度较稳定,作用时间较长,是较有前途的局部治疗真菌性角膜炎的新型缓释制剂。     

RMP-7对两性霉素B脂质体跨血脑屏障能力的药效学研究RMP-7对两性霉素B脂质体跨血脑屏障能力的药效学研究

目的研究两性霉素B脑靶向脂质体对小鼠脑膜炎的治疗作用。方法用薄膜超声法制备两性霉素B脂质体和两性霉素B脑靶向脂质体,测定其包封率和浓度;建立小鼠的脑膜炎模型,研究了两性霉素B脂质体的疗效。结果两性霉素B脂质体的包封率为(93.3±1.8)%;脑内注射白色念珠球菌2 h使小鼠形成脑膜炎模型;将两性霉素B制成脑靶向脂质体,能显著延长脑膜炎小鼠的生存期。结论与普通两性霉素B脂质体相比,两性霉素B脑靶向脂质体能显著提高对小鼠脑膜炎的治疗作用,使小鼠的存活期延长一倍。     

两性霉素B雾化吸入治疗老年糖尿病患者下呼吸道真菌感染的临床观察

目的:探讨两性霉素B雾化吸入治疗老年糖尿病患者下呼吸道真菌感染的临床疗效及安全性.方法:将42例老年糖尿病合并下呼吸道真菌感染的患者随机分为观察组和对照组,各21例.观察组选用25 mg两性霉素B溶于20 mL灭菌注射用水中,每次取10～12.5 mg 雾化吸入,氧流量8～10 L*min-1,持续15～20 min,每天2次,疗程10～14 d.对照组予25 mg两性霉素B加于500 mL 5%葡萄糖盐水中静脉滴注,每分钟20～30滴,疗程10～14 d.结果:观察组、对照组有效率分别为66.6%和73.6%,无显著性差异(P>0.05);观察组、对照组不良反应发生率分别为23.8%和80.9%,有显著性差异(P<0.05).结论:两性霉素B雾化吸入治疗老年糖尿病合并下呼吸道真菌感染安全有效,不良反应少,值得临床推广.     

两性霉素B脂质体-微球的制备及工艺优化

目的 应用Box-Behnken响应面分析法优化两性霉素B脂质体-微球的制备条件。方法 采用乳化-相分离法制备包载两性霉素B脂质体的海藻酸钠微球,通过单因素实验确定显著影响微球成球性的因素,利用Box-Behnken响应面分析法考察氯化钙浓度、司盘80用量及搅拌速度对微球粒径、跨距、包封率、1h释放量及72h释放量的影响,筛选最佳制备工艺,并进行体外抑菌试验。结果 最佳制备工艺条件为氯化钙浓度41%,司盘80用量4.3%,搅拌速度678r/min。此优化条件下,制得的两性霉素B脂质体-微球平均粒径为8.0μm,药物包封率大于80%,体外抑菌试验结果显示载药微球具有较好的抑菌能力。结论 Box-Behnken响应面分析法可有效平衡各因素之间的相互影响,适用于两性霉素B脂质体-微球的制备工艺筛选。     

两性霉素B及其脂质体致急性肾损伤的自动监测比较

目的 对比分析住院患者中两性霉素B及其脂质体致急性肾损伤(AKI)的发生特点和临床特征,为临床安全合理用药提供参考。方法 基于医疗机构药物不良事件主动监测与智能评估警示系统(ADE-ASAS)回顾性监测解放军总医院2010年1月1日—2020年1月1日所有使用两性霉素B普通制剂(AmB-D)和脂质体制剂(L-AmB)的住院患者,并根据给药途径将AmB-D分为静脉途径及其他途径2个亚组进行分析,经系统报警、双人盲评、专家审核最终确认AmB-D及L-AmB致AKI阳性病例。结果 AmB-D及L-AmB用药患者分别为2139例次及717例次,AmB-D静脉途径、其他途径及L-AmB致AKI阳性病例分别为53例次(6.92%)、45例次(3.28%)及27例次(3.77%),发生率差异有统计学意义(P<0.01)。AmB-D静脉途径致AKI中位发生时间4(2～6) d,其他途径为3(2～6) d, L-AmB为5(3～6) d,均以1期AKI为主(分别占77.4%,73.3%,55.6%)。2种剂型都以血液科及血液系统疾病患者发生AKI占比最高。静脉用药后血清肌酐(SCr)及峰值SCr均...     

国外两性霉素B新剂型在临床的应用

两性霉素B几乎对绝大部分真菌均有效．耐药菌株少见，价格较低，这使其得以在临床应用40多年仍显示出很高的实用价值，但因其明显的肾毒性和输注相关性毒性（如发热、寒战、恶心等），两性霉素B的推广应用受到了很大限制。为降低不良反应，国外近年来开发了三种脂质体剂型两性霉素B：两性霉素B脂质体、两性霉素B脂质体复合物（ABLC）和两性霉素B胶体分散剂（ABCD）。研究资料表明：此三种剂型药物在提高抗真菌活力的同时，显著减少了两性霉素B的毒性，特别是明显减少了肾毒性的发生率。虽然剂型改造后的两性霉素B在临床上继续发挥着良好作用，但由于价格较昂贵，市场份额相对较低，目前只占3％左右。     

灰色模型在静脉注射药动学研究中的应用

将灰色理论用于药物动力学的研究,通过对静脉注射梓醇后的血药浓度数据进行倒数化生成处理,最终建立了适合于静脉注射途径下药动学研究的灰色模型(grey model)。结果表明灰色模型精度优于传统的房室模型,且计算简单。     

Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe

Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non‐pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5–2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118–127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 μg/kg/hr were applied to antebrachium, and ewes were then given a 2 μg/kg intravenous bolus followed by an intra‐operative 2.5 μg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra‐ and post‐operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep.     

家兔静脉注射左氧氟沙星后的眼内组织分布及其药动学研究

目的:研究家兔静脉注射左氧氟沙星后的眼内组织分布及药动学。方法:27只家兔单剂量静脉注射左氧氟沙星(24mg/kg)后0.125、0.5、1.0、2.0、3.0、4.0、6.0、8.0、12.0h处死并取眼球各组织制备成匀浆,以高效液相色谱法测定眼内各组织中的药物浓度,3p97软件计算药动学参数。结果:给药后房水、角膜、虹膜-睫状体、玻璃体和晶体组织中药物cmax分别为(4.93±0.83)μg/ml,(6.12±0.71)、(6.02±0.55)、(1.98±0.28)、(1.38±0.12)μg/g;tmax分别为(0.50±0.00)、(0.83±0.26)、(0.71±0.71)、(0.52±0.28)、(0.67±0.26)h;t1/2β分别为(2.53±0.65)、(3.20±0.32)、(3.34±0.46)、(2.74±0.78),(2.49±0.45)h;AUC0-12h分别为(11.46±1.42)μg·h/ml,(28.01±1.59)、(26.01±2.34)、(8.16±0.85)、(5.23±0.89)μg·h/g。除房水为二室模型外,其余均呈一室模型分布。结论:家兔单剂量静脉注射左氧氟沙星后在眼内各组织中分布浓度较高,达峰时间较快,但保留时间相对较短。     

Comparative Pharmacokinetics and Interspecies Scaling of Amphotericin B in Several Mammalian Species

This study employed several interspecies scaling methods, to evaluate the applicability of extrapolating to man, pharmacokinetic information obtained from animals for amphotericin B, an anti-fungal drug. Pharmacokinetic parameters from four animal species (mouse, rat, monkey and dog) and man were obtained from the literature or from analysis of data reported in the literature. The allometric relationships (obtained from four animal species) as a function of species body weight (W; kg) for systemic clearance per maximum life span potential (CL_S/MLP), steady-state volume of distribution (V_SS), apparent volume of distribution (V_β) and volume of the central compartment (V_C) were: 5691W^1.096; 2.46W^0.839; 3.08W^0.948 and 1.07W^0.965, respectively. The allometric relationships for half-life (h) and mean residence time (h) did not scale well with body weight. The prediction of pharmacokinetic parameters in man from the allometric equations do not always agree with those reported in the literature which are based upon a limited number of studies with few human subjects. The plasma concentration-time profiles from these animals were adjusted by normalizing the concentration with dose/W^0.948, and re-plotted on different pharmacokinetic time scales. The syndesichrons plot produced an almost superimposable profile of adjusted concentrations as a function of adjusted time among the four species.     

Trimedoxime and HI-6: Kinetic Comparison after Intravenous Administration to Mice

Abstract: The intravenous pharmacokinetics of the oximes HI-6 (pyridinium-1-(((4-carbamoi 1-pyridinio)metoxy)rnethyl)-2-(hydroxyiminomethyl)dichloride monohydrate), (132.54 μmol/kg) and trimedoxime (1,1′-(1,3′-propanedyl)bis((4-hydroxyimino) methyl)-pyridinium dibromide), (55,98 μmol/kg) in mice was investigated. The concentrations of oximes in plasma determined by high pressure liquid chromatography (HPLC) corresponded to a two-compartment pharmacokinetic open model. The oximes were rapidly eliminated from mice plasma, with half-times of 57.93 min. for HI-6 and 108.08 min. for trimedoxime. Although the oximes passed from circulation into the tissues at approximately the same rate, their transport back to the central compartment was two-times slower in the case of trimedoxime: t_1/2k21 was 77.9 min. for trimedoxime and 41.7 min. for HI-6. The total body clearance (CI_tot) of HI-6 was about 25% higher than that of trimedoxime. The central compartment volume of HI-6 distribution (V₁) was greater, whereas the volume of distribution of the peripheral compartment (V₂) was lower for about 35% with respect to the corresponding parameters of trimedoxime. The calculated pharmacokinetic parameters for the oxime HI-6 and trimedoxime show that trimedoxime is eliminated more slowly in mice, and penetrates better into the peripheral comparment where it remains longer.     

Biodistribution and Pharmacokinetics of Dapivirine-Loaded Nanoparticles after Vaginal Delivery in Mice

Purpose

To assess the potential of polymeric nanoparticles (NPs) to affect the genital distribution and local and systemic pharmacokinetics (PK) of the anti-HIV microbicide drug candidate dapivirine after vaginal delivery.

Methods

Dapivirine-loaded, poly(ethylene oxide)-coated poly(epsilon-caprolactone) (PEO-PCL) NPs were prepared by a nanoprecipitation method. Genital distribution of NPs and their ability to modify the PK of dapivirine up to 24 h was assessed after vaginal instillation in a female mouse model. Also, the safety of NPs upon daily administration for 14 days was assessed by histological analysis and chemokine/cytokine content in vaginal lavages.

Results

PEO-PCL NPs (180–200 nm) were rapidly eliminated after administration but able to distribute throughout the vagina and lower uterus, and capable of tackling mucus and penetrate the epithelial lining. Nanocarriers modified the PK of dapivirine, with higher drug levels being recovered from vaginal lavages and vaginal/lower uterine tissues as compared to a drug suspension. Systemic drug exposure was reduced when NPs were used. Also, NPs were shown safe upon administration for 14 days.

Conclusions

Dapivirine-loaded PEO-PCL NPs were able to provide likely favorable genital drug levels, thus attesting the potential value of using this vaginal drug delivery nanosystem in the context of HIV prophylaxis.     

Pharmacokinetics and Pharmacodynamics of Azosemide after Intravenous and Oral Administration to Rats with Alloxan-induced Diabetes Mellitus

Because physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs used to treat the disease, the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg^?1) to control and alloxan-induced diabetes mellitus rats (AIDRs). After intravenous administration of azosemide to the AIDRs, the area under the plasma concentration-time curve (AUC) increased considerably (3120 compared with 2520 μg min mL^?1; P < 0.135) and the total body clearance decreased considerably (3.20 compared with 3.96 mL min^?1 kg^?1; P < 0.0593). The considerable reduction in time-averaged total body clearance in the AIDRs was a result of the significant decrease in renal clearance (1.01 compared with 1.55 mL min^?1 kg^?1) in the AIDRs, the non-renal clearance being comparable between the two groups of rats. After intravenous administration, the 8-h urinary excretion of azosemide (29.5 compared with 40% of intravenous dose; P < 0.0883) and one of its metabolites, M1 (2.15 compared with 2.60% of intravenous dose, expressed in terms of azosemide; P < 0.05) decreased in the AIDRs because of the impaired kidney function. The diuretic, natriuretic, kaliuretic and chloruretic efficiencies increased significantly in the AIDRs. After oral administration of azosemide, AUC decreased significantly in the AIDRs (115 compared with 215 μg min mL^?1) possibly because of the reduced gastrointestinal absorption of azosemide in the AIDRs. After oral administration of azosemide, the 8-h urine output decreased significantly in the AIDRs (9.32 compared with 16.1 mL per 100 g body weight) because of the significantly reduced 8-h urinary excretion of azosemide (3.00 compared with 9.14% of oral dose). After both intravenous and oral administration some pharmacokinetic and pharmacodynamic parameters of azosemide were significantly different in AIDRs.     

小檗碱静脉注射及鼻腔给予在大鼠血浆与海马中的药代动力学研究

初步比较小檗碱静脉注射及鼻腔给予在大鼠血浆和海马组织中的药代动力学参数的差别。120只大鼠随机分为小檗碱静脉注射6 mg/kg和鼻腔给予9 mg/kg组,分别在给药后12个时间点采血和分离海马组织,采用反相高效液相色谱内标法,检测血浆和海马给织中小檗碱含量,并利用DAS软件计算其药代动力学参数。结果表明,小檗碱血药浓度-时间曲线经拟合二房室模型,鼻腔给药的生物利用度3.05,在海马中的直接转运率为52.663%     

Pharmacokinetics of N4-Octadecyl-1-β-d-Arabinofuranosylcytosine in Plasma and Whole Blood after Intravenous and Oral Administration to Mice

N⁴-octadecyl-1-β-d -arabinofuranosylcytosine (NOAC) is a new cytotoxic derivative of cytosine arabinoside with improved cytotoxic activity and stability against deamination. Its pharmacokinetics were studied in mice. The drug was administered intravenously and orally to ICR mice to assess its pharmacokinetic parameters in plasma and whole blood. The lipophilic drug was administered in small unilamellar liposomes 100–400 nm in diameter. The concentrations of NOAC in plasma and erythrocytes were determined by high-performance liquid chromatography (HPLC). When given orally a rather low amount of the delivered NOAC was absorbed as the unchanged drug, resulting in a bioavailability of 11% from the plasma and 12.9% from whole blood. As shown elsewhere, the amount of drug absorbed is sufficient to provide excellent cytotoxic activity in the L1210 leukemia and in human xenograft models after oral administration. The mean residence time of NOAC after intravenous administration was 3.5 h in plasma and 6 h in whole blood giving NOAC a terminal half-life in blood substantially longer than that of cytosine arabinoside. After oral administration the mean residence time was 18 h in plasma and whole blood. In summary, NOAC has a prolonged half-life after intravenous administration compared with cytosine arabinoside. The distribution of NOAC in blood is highly dependent on its mode of administration.