维拉帕米对抗阿霉素的中国仓鼠卵巢上皮细胞抗药性的逆转作用

非细胞毒性剂量的维拉帕米(Ver)3μg/ml,增强阿霉素(ADM)对抗阿霉素的中国仓鼠卵巢上皮细胞(RC₁)的生长抑制达10倍。用集落形成法测定表明:Ver 3μg/ml能降低RC₁的IC₅₀值,即从1.2μg/ml降至0.08μg/ml,逆转抗药性达15倍。由于Ver增强ADM在RC₁细胞的积累,从而增强ADM对RC₁细胞的毒性,用流式细胞光度计,研究Ver逆转抗药性机制,发现Ver与ADM合用,能阻断RC₁细胞在G₂+M期。     

顺铂聚乳酸微球的药物释放特性及肝动脉栓塞研究

对顺铂聚乳酸微球进行了体外药物释放和家犬肝动脉栓塞研究。该微球粒径范围为50～200μm,平均粒径为115.76±35.94μm,顺铂含量为37.16%(W/W);体外药物释放机制符合Higuchi方程;肝动脉栓塞后8h,肝组织顺铂浓度高达21.55±12.18μg/g,明显高于肝动脉灌注顺铂组:3.16±0.09μg/g(P<0.05);肝动脉栓塞组的顺铂血浓峰值、各取血点浓度及曲线下面积AUC皆低于肝动脉灌注顺铂组。可望达到提高栓塞部位的药物疗效,降低全身毒副反应的作用。     

阿霉素与胃癌单克隆抗体交联物的体内外抗肿瘤作用

以氧化葡聚糖法制备了阿霉素(ADM)与胃癌单克隆抗体(MoAb)3H11的交联物3H11-DEX-ADM,ADM与3H11克分子比为73:1。经ELISA法测定,交联物的抗体活性保留86%。体外细胞毒试验显示,3H11-DEX-ADM对胃癌细胞BGC823的杀伤作用比游离ADM明显增强,其IC₅₀分别为1.0μg/ml及3.75μg/ml。在荷瘤裸鼠治疗实验中3H11-DEX-ADM能显著抑制肿瘤生长,抑制率为51.5%(P<0.05),明显高于ADM组及其非特异性抗体交联物(NI gG-DEX-ADM)组,后者的抑制率分别为21%及24%。表明3H11-DEX-ADM对肿瘤具有选择杀伤作用。将3H11-DEX-ADM与丝裂霉素C(MMC)-3H11交联物(3H11-HSA-MMC)联合应用,细胞素实验未能显示协同或相加作用;游离ADM与MMC联合亦呈相似结果。     

胸腺肽α1缓释注射微球的研究

制备胸腺肽α₁(Tα₁)的长效注射微球，并对微球的体外释放特性、体外活性及药效学进行考察。采用复乳法(W/O/W)制备了载Tα₁聚乳酸-羟基乙酸嵌段共聚物(PLGA)的微球；考察微球的粒径大小、外观及包封率等理化特性；以HPLC法测定微球的体外释放速率；采用CCK-8法评价微球制备工艺和体外释放过程中Tα₁的生物学活性；体内药效学研究中采用流式细胞仪检测免疫抑制模型大鼠给予Tα₁微球后所产生的CD₄⁺，CD₈⁺因子的量，根据CD₄⁺/CD₈⁺的比值变化评价体内药效。微球球形圆整，分散性好，两个优选处方(外水相中加入5%氯化钠和10%葡萄糖)的微球包封率分别为87.8%和90.2%；Tα₁微球1个月的体外累积释放可达90%以上。使用含10%葡萄糖的PVA溶液作为外水相，较好地保持了制备工艺过程中的Tα₁生物学活性，在体外释放过程中Tα₁的生物学活性略有下降；Tα₁微球可显著提高免疫抑制模型小鼠的免疫力。用可生物降解的聚合物PLGA作为载体材料，可以将Tα₁制备成缓释1个月的注射微球。     

阿霉素在纳米钴修饰电极上的电化学行为及其应用

采用NaBH₄还原法制备了钴纳米粒，将其固定于氧化铟锡(ITO)电极上，首次制成了纳米钴修饰电极(NpCo/ITO)，并研究了阿霉素(adriamycin，ADM)在NpCo/ITO上的电化学性质。用循环伏安法(CV)、扫描电子显微镜(SEM)和能量色散谱(EDS)等对纳米钴修饰电极表面进行了表征。在纳米钴修饰电极上，阿霉素(ADM)在0.01 mol·L^-1 KH₂PO₄-K₂HPO₄溶液(pH 8.0)中，出现还原峰，峰电位为-0.67 V(vs Ag/AgCl),峰电流与ADM浓度在1.0×10^-8～2.0×10^-6 mol·L^-1呈线性关系，检测限为5.0×10^-9 mol·L^-1。循环伏安法研究表明，该体系属于具有吸附性的不可逆过程，NpCo/ITO对ADM的电化学还原过程产生较大的促进作用。     

阿霉素明胶微球的制备与特性研究

目的 :对动脉栓塞阿霉素明胶微球 (ADM GMS)的制备工艺及特性进行初步研究。方法 :以生物降解材料明胶为载体 ,采用乳化化学交联法制备含阿霉素的明胶微球 ,并进行家兔胃左动脉栓塞 ,分别于术后 1周至 4周内作栓塞观察。结果 :所制备的阿霉素明胶微球外形圆整 ,平均粒径为 6 2 .74μm ,载药量为2 1.78μg·mg-1,包封率为 6 7.43% ,体外释药和动物胃左动脉栓塞基本符合要求。结论 :阿霉素明胶微球有望成为临床用动脉栓塞术治疗胃癌的新给药制剂。     

肝动脉栓塞米托蒽醌乙基纤维素微球的研究

利用正交实验设计法,优选适用于肝动脉栓塞的米托蒽醌乙基纤维素微球制备条件和工艺;采用动态透析法研究了该微球的体外释药规律;根据混悬液的稳定性理论,优选并制备了适于临床肝动脉介导栓塞使用的米托蒽醌乙基纤维素微球混悬注射液。结果表明∶在优化工艺条件下制得的米托蒽醌乙基纤维素微球外形圆整,球径在40～200μm范围内的占总数的91.9%,平均球径为110.24±38.19μm;包封率为55.6%;载药量为12.5%;体外释药符合单指数模型,释药方程为lg(Y_∞-Y)=-0.116t-1.198×10^-3(γ=0.9992,t₅₀=2.6h);其混悬液适于临床应用。用狗进行的实验表明肝血药浓度高,平均驻留时间比注射剂长2.45倍。     

肝靶向米托蒽醌白蛋白微球的研究

用乳化—热固化法制备了米托蒽醌白蛋白微球,并对其形态、大小及其分布、微粉学性质、载药性能、体外释药、稳定性和体内分布进行了研究。结果表明,该载药微球的平均算术径为0.99μm,平均表面径为1.24μm,平均容积径为1.44μm;表观载药量为2.558%±0.101%;有效载药量为1.503%±0.127%;包封率为92.82%±4.60%;体外释药符合双相动力学规律,释药方程为1-Q=0.6428e^-0.2132t+0.3988e^-000150t(γ₁=-0.9951,γ₂=-0.9982);T_1/2α=3.250h,T_1/2β=461.7h;室温放置3个月,微球形态、药物含量等均无明显变化。HPLC测定表明,小鼠尾iv该微球20min内即有77.6%±1.38%的药物浓集于肝脏,具有明显的肝靶向性。提示米托蒽醌白蛋白微球有可能提高米托蒽醌的抗肝癌效果和降低其全身毒副作用。     

阿霉素磁性明胶微球的研究

报告了阿霉素磁性明胶微球（Ａｄｒ－ＭＧ－ｍｓ）的制备与性质，研究了超细氧化铁粒子的合成和磁性明胶微球（ＭＧ－ｍｓ）在狗体内的栓塞效果。阿霉素磁性明胶微球由２％阿霉素（Ａｄｒ）、６８％明胶和３０％的磁铁粒子组成，微球的平均粒径为２２μｍ。在体外实验中，药物释放速度证明微球有缓释的性质。磁铁粒子的平均粒径约为１０ｎｍ，磁性明胶微球与￣（９９ｍ）Ｔｃ标记磁性明胶微球通过导管分别输入狗的肝动脉内进行栓塞，照相和血管造影显示在未加外磁场时磁性明胶微球在左右肝叶分布几乎相等，而在１２００高斯的外磁场作用下，靶部位肝左叶的微球分布是肝右叶的２．２５倍，而甲状腺、脑、心脏的微球很微量，结果表明磁性明胶微球在外磁场作用下是一个很好的治疗肝癌的栓塞剂。     

肺靶向利福平聚乳酸微球的研究

在单因素考察的基础上进行正交试验设计,筛选出肺靶向利福平聚乳酸微球的最佳制备工艺条件;利用桨板法研究了微球的体外释药规律;考察了微球在不同温度下的稳定性;用新西兰兔为实验对象,研究了利福平聚乳酸微球的体内药动学及组织药物分布。结果制得的微球形态圆整,粒径在5～15μm范围内的占总体积的86.54%,微球平均粒径为9.00±4.08μm;包封率为31.9%;载药量为16.0%;体外释药方程为Q=20.77+10.12T_1/2(γ=0.9892);微球在冰箱4℃和室温(20～25℃)条件下性质稳定;体内实验表明微球具有长效和肺靶向双重作用。     

Effects of copper on development of the fathead minnow,Pimephales promelas Rafinesque

Embryos of the fathead minnow, Pimephales promelas Rafinesque, were exposed to total copper concentrations (Cu_T) of 0.6, 61, 113, 204, 338 and 621 μg/l from 5 to 10 h post-fertilization through 2 days post-hatch. A decrease in hatching time was observed with increasing total copper concentration but there was no decrease in embryonic developmental rate. Therefore, embryos hatched at earlier stages of development. Significant (P ≤ 0.05) declines in percent survival and percent total hatch were observed at 621 μg/l Cu_T) but not at 338 μg/l Cu_T or lower concentrations. The percentage of embryos with abnormalities was greater at 338 and 621 μg/l Cu_T than at 204 μg/l Cu_T and lower concentrations.Individuals exposed to copper during early development were then exposed to the same test concentrations for 28 days post-hatch. Survivors at 113 through 338 μg/l Cu_T were at earlier stages of development than were control fish. The percentage of fish surviving decreased with increasing copper concentration over the range 61 through 204 μg/l Cu_T. The percentage of fish surviving at 204 μg/l Cu_T was not significantly different from that at 338 μg/l Cu_T, and there were no survivors at 621 μg/l Cu_T. Surviving larvae at all copper concentrations from 61 through 621 μg/l Cu_T showed decreased length, weight and coefficient of condition compared to controls. The percentage of larvae with abnormalities increased significantly with increasing copper concentration. The calculated 96-h LC₅₀ (larval stage) was 250 μg/l Cu_T and the 28-day LC₅₀ (larval stage) was approximately 123 μg/l Cu_T.     

1H‐1,2,3‐Triazole tethered isatin‐moxifloxacin: Design,synthesis and in vitro anti‐mycobacterial evaluation

A series of novel 1H‐1,2,3‐triazole tethered isatin–moxifloxacin (MXF) hybrids 5a ‐ l with greater lipophilicity compared with the parent MXF were designed, synthesized and screened for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant MTB (MDR–MTB) as well as their cytotoxicity on the VERO cell line. All the synthesized hybrids (MIC: 0.025‐0.78 μg/ml) showed considerable activities against MTB H₃₇Rv and MDR–MTB, and the most active conjugate 5c (MIC: 0.025 and 0.06 μg/ml) was 2 to >2048 times more potent in vitro than the three references MXF (MIC: 0.10 and 0.12 μg/ml), rifampicin (MIC: 0.39 and 32 μg/ml) and isoniazid (MIC: 0.05 and >128 μg/ml) against the two tested strains. All hybrids (CC₅₀: 4‐64 μg/ml) were much more cytotoxic than the parent MXF (CC50: 128 μg/ml), but the most active hybrid 5c (CC₅₀: 32 μg/ml) also displayed acceptable cytotoxicity, warranting further investigation.     

A Pharmacokinetic Model of Intravenously Administered Hyaluronan in Sheep

Hyaluronan (HA; hyaluronic acid) is produced in the interstitium and reaches the blood circulation through the lymph. It is rapidly eliminated by means of specific receptors on liver endothelium. The elimination characteristics of intravenously administered HA were studied in 10 conscious sheep at the normal plasma HA concentration by injection of a ³H-labeled tracer and at a very high concentration by an i.v. infusion of unlabeled HA and simultaneous injection of a tracer dose of ³H-labeled HA. At a normal plasma HA concentration (0.12 ± 0.05 µg/ml; range, 0.072–0.228 µg/ml), the apparent T _1/2 of ³H-HA was 5.3 ± 1.1 min (range, 3.3–6.5 min). At higher plasma concentrations (range, 1.83–3.35 µg/ml), the apparent T _1/2 was considerably prolonged (range, 18.2–43.5 min). A one-compartment, nonlinear model was fitted to data obtained from the bolus-infusion study of unlabeled HA. The Michaelis–Menten constant, K _m , was 0.12 ± 0.04 µg/ml, indicating that a deviation from linear kinetics will occur when the normal plasma concentration is exceeded. The V _max was 0.062 ± 0.009 µg/ml/min. Three-dimensional surface plots showed that the plasma HA concentration and the total hepatic plasma flow influence the apparent metabolic clearance, extraction ratio, turnover, and T _1/2 of intravenously injected hyaluronan. There was a high correlation between T _1/2 as measured by the injected ³H-HA and T _1/2 calculated from the model (r = 0.96).     

Phospholipase inhibition and the mechanism of angiotensin-induced prostacyclin release from rat mesenteric vasculature

Generation of prostaglandins by arterial vasculature of rats was measured by perfusing the isolated mesenteric arterial vascular bed with Krebs-Henseleit solution. The effluent directly superfused bioassay tissues in cascade, and aliquots were collected for subsequent chromatography and radioimmunoassay. Injection of arachidonate (1–10 μg) or angiotensin II (0.1–0.5 μg) through the mesentery caused release of a PGI₂-like substance. After extraction and Chromatographic separation of the mesenteric effluent, it was confirmed by radioimmunoassay that 6-oxo-PGF_1α (the hydration production of PGI₂) is the predominant prostanoid generated from exogenous arachidonate. Release of 6-oxo PGF_1α and PGE₂ from mesentery was also stimulated by injection of angiotensin II (0.05–0.5 μg). Treatment of the mesentery with indomethacin (1 μg/ml) abolished all effects of angiotensin II and arachidonate. Perfusion of the mesentery with dexamethasone (3 μg/ml) or mepacrine (33 μg/ml) both of which have been reported to inhibit phospholipase A₂ activity, reduced PGI₂ release induced by angiotensin II, but did not affect conversion of exogenous arachidonate. It is concluded that PGI₂ is the major prostanoid generated in perfused mesenteric arterial vasculature of rats, and angiotensin II releases PGI₂ by activation of a phospholipase.     

Effect of buccal dwell time on the pharmacokinetic profile of fentanyl buccal tablet

Background: The time fentanyl buccal tablet (FBT) takes to completely dissolve after placement on the buccal mucosa (i.e., ‘dwell time’) could exceed the time to onset of analgesia. Objective: To examine the relationship between FBT dwell time and fentanyl pharmacokinetic parameters. Research design and methods: This was a post hoc exploratory analysis of data from two randomized, open-label, crossover, pharmaco?kinetic studies that were designed to assess dose proportionality within the anticipated therapeutic dose range. Healthy adults received single FBT doses of 200 – 1080 μg in Study 1 (n = 28) and 270 – 1300 μg in Study 2 (n = 42). Main outcome measures: Assessments included buccal dwell time, defined as the duration of FBT presence in the oral cavity, and the following pharmacokinetic measures: maximum serum concentration (C_max), time to C_max (T_max) and area under the concentration–time curve (AUC; exposure) from 0 minutes to median T_max adjusted for the dose (T_max′) (AUC_{0 – Tmax′}). Spontaneously reported adverse events were recorded. Results: Mean buccal dwell time for FBT across the dose range varied from 14 to 25 minutes (range 3 – 62 minutes). There was no evidence of an association between FBT dwell time and values for T_max (medians 45 – 60 minutes), dose-normalized C_max (means 0.42 – 0.66 pg/ml/200 μg) or dose-normalized AUC_{0 – Tmax′} (means 0.24 – 0.38 pg·h/ml/200 μg) over the range of FBT doses delivered. All adverse events reported were mild to moderate; none were unexpected or serious. Conclusion: The pharmacokinetic parameters of FBT did not appear to be related to its buccal dwell time.     

多柔比星纳米微粒-碘油乳剂肝动脉栓塞治疗大鼠肝癌的药效学研究

将多柔比星（ＡＤＭ）纳米微粒（小粒径脂质体与毫微粒）与碘油制成乳剂经肝动脉栓塞治疗大鼠Ｗ２５６ 肝癌模型。结果表明,与同剂量游离ＡＤＭ 及生理盐水对照组相比,ＡＤＭ 纳米微粒－碘油乳剂治疗组对肿瘤生长抑制明显提高（Ｐ＜ ０．０１）,肿瘤坏死彻底,而大鼠的生存延长期则显著延长（Ｐ＜ ０．０１）。高效液相色谱测定结果表明纳米微粒－碘油乳剂治疗组ＡＤＭ 在体内的分布以肝、脾组织为主,说明用ＡＤＭ 纳米微粒－碘油乳剂肝动脉栓塞治疗肝癌能降低毒性,提高治疗效果。     

Pharmacokinetic profile of a new formulation of injection diclofenac designed for intradeltoid use

Objective: Injection diclofenac sodium available at present as a 3-ml formulation is administered intragluteally. Standard needles may not reach the gluteus maximus muscle in many cases, especially in obese patients. Alternative sites like the deltoid have been suggested to be more suitable for these patients. Diclofenac sodium 75 mg/ml was prepared to facilitate intradeltoid adminis-tration. The objective of this study was to determine pharmacokinetic parameters and to compare the bioavailability of the new formulation of injection diclofenac sodium (75 mg/ml), given as an intradeltoid injection, with the reference formulation (75mg/3 ml) given intragluteally. Research design/methods: A single-dose, two-way bioequivalence study was carried out in 18 healthy, Indian, male volunteers with a washout period of 5 days. Blood samples were collected up to 6 h after drug administration and analyzed using a prevalidated HPLC method. Results: The mean C_max and T_max, for the test and reference formulations were 1.95 μg/ml, 1.89 μg/ml and 0.39 h, 0.43 h respectively. AUC values from 0 to last measurable time point ‘t’ observed for test and reference formulations were 3.37 μg.h/ml and 3.28 μg.h/ml respectively. The mean AUC 0 – infinity for test and reference formulations was 3.57 μg.h/ml and 3.52 μg.h/ml. Conclusion: Results suggest that the test and reference formulations of injection diclofenac sodium 75 mg given intradeltoid and intragluteally are bioequivalent. The test formulation would be especially helpful in the management of obese/overweight patients and patients with thick subcutaneous fat in the gluteal region. It would increase the success rate of intramuscular deposition of the medication.     

阿霉素脂质体犬肝动脉栓塞后的体内分布与药代动力学研究

用阿霉素脂质体与碘油混合后对大经导管肝动脉栓塞，用反相高效液相色谱法研究了阿霉素在犬体内的分布及药代动力学。结果显示，阿霉素脂质体－碘油栓塞组大血浆阿霉素浓度显著低于阿霉素灌注组（P＜0.01）和阿霉素－碘油栓塞组（P＜0．05），而其血浆阿霉素消除半衰期和肝组织中阿霉素浓度与后两组相比则显著增加（p＜0．01及p＜0．05）。说明阿霉素脂质体与碘油混合肝动脉栓塞后可显著提高阿霉素对肝脏的靶向性，延长阿霉素消除半衰期．