南五味子多糖急性毒性及对小鼠肝损伤保护作用的研究

摘 要 目的：研究南五味子多糖的急性毒性及对四氯化碳（CCl4）致小鼠肝损伤的保护作用。方法: 采用经典的急性毒性实验方法,测定南五味子多糖的最大给药量（MLD）,并观察其急性毒性反应;采用0.5% CCl4致小鼠急性肝损伤模型,将60只小鼠随机分为空白对照组、CCl4模型对照组、联苯双酯组及南五味子多糖高（1 388 mg·kg^-1）、中（694 mg·kg^-1）、低（347 mg·kg^-1）剂量组,每组10只,连续给药6 d,检测血清中AST和ALT水平,观察肝脏的损伤程度。结果: 急性毒性实验中对小鼠的一般行为、体质量变化及各脏器检查均未见异常,南五味子多糖毒性症状不显著;与模型对照组比较,南五味子多糖3个剂量组的ALT水平显著降低（P<0.05或P<0.01）,南五味子多糖高、中剂量组的AST水平显著降低（P<0.01）,一定程度上改善了肝脏组织损伤。结论:南五味子多糖无显著毒性,对CCl4致小鼠急性肝损伤具有一定的保护作用。     

木鳖子提取物对小鼠急性毒性实验研究

摘 要 目的：研究木鳖子提取物对小鼠急性毒性的影响,进行木鳖子的急性毒性观察与评价,为安全用药提供依据。方法: 按照小鼠急性毒性经典实验方法,对木鳖子提取物不同给药途径的小鼠急性毒性实验进行比较研究,以概率单位法（Bliss法）计算木鳖子口服和腹腔注射时半数致死量（LD50）,给药后连续观察小鼠状态7 d,实验结束后处死小鼠,观察重要脏器是否存在病理改变。结果: 小鼠口服木鳖子提取物半数致死量LD50=4.03 g·kg^-1,95%置信区间（CI））为3.29～4.92 g·kg^-1;小鼠腹腔注射木鳖子提取物半数致死量LD50=146.17 mg·kg^-1,95%CI为118.92～177.31 mg·kg^-1。结论: 实验表明木鳖子药材具有一定的毒性,与文献和药典报道相符。通过木鳖子小鼠急性毒性实验研究,有利于进行木鳖子的毒性研究与评价,为临床安全用药提供实验依据。     

苦参素胶囊对BALB/c小鼠人肝癌细胞株SMMC 7721体外种植瘤的影响

摘 要 目的：观察苦参素胶囊对BALB/c小鼠人肝癌细胞株SMMC 7721体外种植瘤的影响。方法: 采用体外传代培养人肝癌SMMC 7721细胞株,建立体外种植瘤小鼠肝癌模型。随机分为模型组、氟尿嘧啶（5 Fu）组（25 mg·kg^-1）、苦参素胶囊高剂量组（90 mg·kg^-1）、苦参素胶囊低剂量组（45 mg·kg^-1）,另设空白对照组。每组10只,连续给药14 d后。眼球取血,分离血清,Elisa法测定IL 2水平。摘取瘤株,称量湿质量,计算抑制率;HE染色,观察肿瘤组织的病理改变。结果: 与模型组比较,苦参素胶囊高、低剂量组可显著升高小鼠血清IL 2含量（P<0.01或P<0.05）;抑制体外种植瘤生长（P<0.001或P<0.05）;高剂量组上述作用与5 Fu组相比无明显差异（P>0.05）。HE染色可见小鼠肿瘤细胞核染色变浅,肿瘤细胞数量减少。结论: 苦参素胶囊对BALB/c小鼠人肝癌细胞株体外种植瘤有一定的抑制作用。     

前列康和非那雄胺治疗良性前列腺增生的对比研究

摘 要 目的： 比较前列康和非那雄胺治疗大鼠良性前列腺增生的疗效。方法: 36只Wistar大鼠随机分成3组,去势14 d后皮下注射丙酸睾丸酮5 mg·kg^-1,前列康组按成人剂量10倍剂量灌胃给药,非那雄胺组按0.1 mg·kg^-1灌胃给药,对照组给予等量的蒸馏水,21 d后处死,称取前列腺湿质量,量取前列腺体积,光镜观察前列腺组织病理学改变。结果: 前列康和非那雄胺组大鼠前列腺湿质量分别为 （0.467±0.061）g,（0.408±0.058）g;大鼠前列腺体积分别为（0.371±0.059）ml,（0.365±0.054）ml,均显著低于对照组大鼠（P＜0.05）。结论: 前列康能显著抑制模型大鼠的良性前列腺增生,其机制可能是通过抑制前列腺细胞的增殖而实现的。     

糖止丸的急性与亚急性毒性试验研究

目的 通过糖止丸的急性毒性、最大耐受量以及亚急性毒性试验，为临床安全用药提供依据。方法 急性毒性试验中设定3个剂量组，首次给药1次，连续观察7 d，记录糖止丸对小鼠体质量及进食量的影响；最大耐受量试验中将糖止丸按照最大溶解度配置成225 mg·mL^-1溶液，按小鼠最大给药体积40 mL·kg^-1灌胃给药，观察和记录中毒症状及死亡情况；亚急性毒性试验中将糖止丸分别按2.25，1.50，1.00 g·kg^-1配置成高、中、低3个剂量组溶液，10 mL·kg^-1灌胃，观察大鼠的亚急性毒性反应。结果 糖止丸急性毒性试验单次给药后观察7 d未见小鼠死亡，无法测出其LD₅₀。按照毒理学评价标准，LD₅₀>1 g·kg^-1属无毒性物质，最大耐受量试验中给药剂量增加到9 g·kg^-1仍未出现毒性，表明糖止丸对小鼠安全无毒。亚急性毒性试验，在高、中、低3个剂量连续用药30 d后，大鼠体征和各生理指标与空白对照组比较差异无统计学意义。结论 糖止丸安全性良好，可进一步用于治疗糖尿病的新药开发。     

白假丝酵母菌阴道炎小鼠模型的构建

摘 要 目的：构建白假丝酵母菌阴道炎小鼠模型,探索最佳成模条件,以提供经济实用的白假丝醇母菌性阴道炎动物模型。方法: 采用昆明雌性小鼠,预先连续灌胃给予低、中、高剂量（0.001 5,0.015,0.15 mg/10 g）的戊酸雌二醇7 d后接种白假丝酵母菌建立阴道炎模型,并进行阴道灌洗液真菌载量和阴道组织病理观察。结果: 戊酸雌二醇低、中、高剂量组阴道灌洗液的菌落计数分别为124.67±19.01、217.67±22.50、282.00±27.87,高剂量组与中、低剂量组比较差异有统计学意义（P<0.05或P<0.01）。HE染色和PAS染色结果显示,戊酸雌二醇高剂量组有较多多形核粒细胞（PMNs）浸润及紫红色线状菌丝。结论: 戊酸雌二醇高剂量组造模方式为昆明小鼠白假丝酵母菌阴道炎模型的最佳造模条件。     

翻白草胶囊的毒理安全性试验

目的 研究翻白草胶囊的急性毒性及长期毒性。方法 采用最大耐受量法进行小鼠急性毒性试验,30 g/kg翻白草胶囊ig给予小鼠,间隔6 h给药2次,观察体质量、进食情况、外观情况、行为活动、是否出现死亡现象等,连续观察1周;将清洁级别的80只大鼠随机分为对照组和翻白草胶囊高、中、低剂量（4.8、2.4、1.2 g/kg）组,每天ig给药1次,每周给药6次,连续给药90 d,并停药观察15 d,观察大鼠外观体征、饮食、体质量等情况,并进行一般形态学、血液学、脏器形态学、血液生化学、组织病理学检测。结果 急性毒性试验期间内无小鼠死亡现象,小鼠对药物的最大耐受量为30 g/kg,相当于人临床用药剂量的320倍。长期毒性试验结果表明,翻白草胶囊高剂量组在给药初期,部分动物出现精神萎靡、厌食、大便偶见溏稀化、口周出现青紫状斑点等现象,连续给药后可自行缓解;与对照组比较,翻白草胶囊组血液学、脏器形态学、血液生化学指标均未出现剂量相关性的显著变化,无明显药物毒性反应;给药90 d后,翻白草胶囊高剂量肺组织切片光镜下偶见局部出现点状炎症细胞,卵巢偶见炎症细胞并伴有脓细胞,停药15 d后症状消失。结论 在本实验条件下,翻白草胶囊对受试动物无明显毒性反应,安全剂量范围大,在有效剂量下,长期用药安全。     

蛞蝓胶囊大鼠长期毒性实验研究

目的 观察大鼠对蛞蝓胶囊的长期毒性反应,为临床研究提供依据。方法 按照成人每日用量,将给药组大鼠分为低剂量组175.0 mg·kg^-1、中剂量组553.0 mg·kg^-1、高剂量组1 750.0 mg·kg^-1和对照组。连续灌胃给药26周,停药恢复4周,对一般情况进行观察,对体质量、进食量进行称量比较,对血液学指标、血液生化指标、尿常规进行检测,对脏器进行病理学检查和脏器系数比较。结果 给药组与对照组比较,大鼠的一般状况、行为活动、进食量、体质量变化、外周血象、尿常规指标、血液生化指标、脏器系数以及病理组织学等均无统计学差异。结论 蛞蝓胶囊大鼠长期毒性实验未见毒性反应,提示临床拟用剂量安全。     

葡聚糖硫酸钠自由饮用与灌胃诱导小鼠溃疡性结肠炎模型的对比研究

摘 要 目的：比较葡聚糖硫酸钠（DSS）自由饮用与灌胃两种给药方式诱导小鼠溃疡性结肠炎（UC）疾病相关指标的差异,为优化UC小鼠造模方法提供实验参考。方法: 将C57BL/6小鼠随机分为正常对照组、自由饮用组和灌胃组3组,每组10只,分别自由饮水、自由饮用3% DSS溶液及4 g·kg^-1·d^-1灌胃DSS,连续7 d,建立UC模型。以疾病活动指数（DAI）、小鼠结肠的组织学损伤评分及髓过氧化物酶（MPO）活性为评价指标,比较两种给药方式的各指标均数及变异系数的差异。结果: 自由饮用组造模过程中有2只小鼠死亡,造模结束后存活小鼠的DAI值为（8.8±1.6）分,灌胃组无小鼠死亡,其DAI值为（9.0±0.8）分,两组间差异无统计学意义（P＞0.01）,但自由饮用组的变异系数高于灌胃组（18.7 vs. 8.6）。自由饮用组与灌胃组结肠组织学损伤评分分别为（24.8±4.2）,（27.0±2.8）分,均呈典型性炎症改变,两组间差异无统计学意义（P＞0.05）,但自由饮用组的变异系数高于灌胃组（16.9 vs. 10.4）。正常对照组、自由饮用组与灌胃组结肠组织MPO分别为（0.41±0.03）,（2.32±0.34）,（2.05±0.18）U·g^-1,与正常对照组相比,自由饮用组与灌胃组的MPO差异有统计学意义（P＜0.01）,自由饮用组与灌胃组两组间MPO差异无统计学意义（P＞0.05）,但自由饮用组的变异系数高于灌胃组（14.7 vs. 8.8）。结论:自由饮用组与灌胃组均可成功诱导小鼠UC模型。与自由饮用组相比,灌胃组各项指标数据的变异系数小,离散度低,采用灌胃法制备溃疡性结肠炎小鼠模型,动物表现更均一。     

耳复康口服液对小鼠微循环障碍的影响

摘 要 目的：观察耳复康口服液对肾上腺素致急性血瘀症小鼠微循环障碍的影响。方法: 将小鼠随机分为模型组,脑得生片组（1.35 g·kg^-1）,高(30 ml·kg^-1)、中(15 ml·kg^-1)、低(7.5 ml·kg^-1)剂量耳复康口服液组,用微循环仪观察正常小鼠给药1 h后毛细血管开放数。尾静脉注射肾上腺素造成耳廓微循环障碍,观察造模后2 min小鼠的毛细血管开放数及血流情况。结果:和模型组相比,高、中、低剂量耳复康口服液对正常小鼠耳廓毛细血管开放数无明显影响(P＞0.05);与模型组相比,高、中剂量耳复康口服液可显著改善肾上腺素致小鼠耳壳微循环障碍模型微循环血流情况(P＜0.05或P<0.01),可明显对抗肾上腺素所致小鼠耳壳微循环障碍模型毛细血管网开放数的减少(P<0.05)。结论:耳复康口服液有改善微循环障碍的作用。     

某区2006年至2008年放射工作人员个人剂量监测结果分析

目的调查某区放射工作人员个人的受照剂量及程度,为采取防护辐射措施提供基础数据。方法采用热释光剂量仪检测某区2006年至2008年1688人次的放射工作人员个人年剂量,统计各年监测人数、4组剂量组的人数频数分布及人均年当量剂量,并按不同工种进行分类统计和比较。结果个人剂量低水平所占的比例较大,人均年当量剂量呈现较明显的下降趋势,但总体剂量水平较高;不同工种当中,正电子发射型计算机断层显像（PET）和医用诊断X射线工种人均年当量剂量较高。结论某区各医疗单位总体剂量水平较高,应进一步加强防护意识;PET放射诊断和放射介入工作人员须采取措施降低照射剂量对身体的危害。     

Evaluation of a proposed method for phenytoin maintenance dose prediction following an intravenous loading dose

Summary A large clinical study, designed to investigate the induction of theophylline metabolism by phenytoin, provided the opportunity to test a previously proposed method for estimating dose requirements of phenytoin. This method involves prediction of the oral maintenance dosage from data obtained following the administration of an intravenous loading dose.In 30 subjects, trough plasma concentration at steady-state were 12.0±4.9 µg·ml^–1 (mean ±SD) and differed by –2.7±39.3% from a mean target plasma concentration of 12.5±1.5µg·ml^–1.A Bayesian regression programme was used to forecast an estimate of each subject's individual pharmacokinetics. These were then used to predict the steady-state plasma concentrations which would be expected from a standard dosing regimen (4 mg per kg per day). When compared to the results expected from the use of this standard dosage, the proposed method gave acceptable steady-state plasma phenytoin concentrations with significant reductions in deviations from target concentrations.This method for the rapid individualization of phenytoin dosage requirements provides an improvement over more traditional methods of choosing an arbitrary dose adjusted for body weight followed by dosage adjustments based on achieved plasma concentration.     

A statistical evaluation of toxicity study designs for the estimation of the benchmark dose in continuous endpoints.

The benchmark approach is gaining attention as an alternative to the No-Observed-Adverse-Effect-Level (NOAEL) approach. However, current guidelines for the design of toxicity tests are based on assessing a NOAEL. It has been suggested that the current study design may not be optimal for assessing a Benchmark Dose (BMD). To further investigate this we performed three simulation studies in which a large number of designs were compared, focusing on continuous endpoints. Four fictitious endpoints were considered, their underlying dose-response curves having a linear, sublinear, supralinear, or sigmoidal shape. In each simulation run the BMD was derived from a model fitted to the generated data, where the selection of the model was based on that particular data set (according to a formal likelihood ratio test procedure). Thus, the model used for deriving the BMD in a single generated data set may not be the same as the one used for generating the data. In this way, model uncertainty is taken into account as well. The results show that the performance of a design is, first of all, determined by the total number of animals used. Distributing them over more dose groups does not result in a poorer performance of the study, despite the smaller number of animals per dose group. Dose placement is another crucial factor, and to minimize the risk of inadequate dose placement, the use of multiple dose studies is favorable. As a concomitant advantage, the use of multiple doses mitigates the disturbing effect of potential systematic errors in single dose groups. However, for endpoints with large residual variation (CV > or = 18%) there is a substantial probability of not detecting the overall dose-response, and this probability increases in designs with increasing number of dose groups. In such situations, six dose groups may be used as a compromise. Designs with high dose levels (i.e., associated with relatively high effects) are helpful in estimating doses with smaller effects (such as the benchmark dose), and it appears bad practice to omit higher dose groups to improve the fit at lower doses. The typical 28-day study design of four dose groups with five animals (per sex) may not be adequate to assess endpoints with large residual variation (CV > or = 18%), both in assessing a benchmark dose and in assessing a NOAEL.     

High Dose versus Moderate Dose Methadone Maintenance: Is There a Better Outcome?

ABSTRACT

Methadone dosing has been an issue of controversy among clinicians for a long time. Few recent studies reported that doses above 100 mg daily seem promising in better control of illicit opiate use for some patients, but more research is needed to support that notion. A retrospective chart review for patients maintained on methadone at Atlanta Veterans Affairs Medical Center was conducted. Patients were categorized into two groups: patients on a methadone dose of 60 to 100 mg daily (n = 34) and patients on a methadone dose greater than 100 mg daily (n = 25). Those charts were compared for urine drug screens for opiates and cocaine (first four from admission and most recent four screens), retention or drop out from the program, and Addiction Severity Index (ASI) composite score at admission and most recent score. The results of the first and last four urine drug screens for opiates showed that the moderate dose group was positive 23% and 17%, respectively. However, the high dose group was positive 14% and 8%, respectively. These results showed statistical significance (Chi-Square = 8.04, df = 3 and p =.03). ASI scores for drugs did not show statistically significant improvement for the moderate dose group (p =.19) but showed statistically significant improvement for the high dose group (p =.0002) when the result of the first and last ASI scores among each group were compared. The ASI scores for family problems showed statistically significant improvement for the moderate dose group (p =.03). High doses of methadone greater than100 mg daily may provide a better outcome for illicit opiate use among some patients who would not respond to moderate doses.     

应用基准剂量法探讨氯蜱硫磷的参考剂量

目的应用基准剂量(BMD)法探讨氯蜱硫磷(毒死蜱)的参考剂量。方法 80只清洁级成年雌性SD大鼠,ig给予氯蜱硫磷0.25,0.5,1,2,4,8和16 mg.kg-1,每天1次,连续21 d。21 d后处死大鼠测定大鼠大脑皮质、海马和血清中乙酰胆碱酯酶(AChE)活性,观察氯蜱硫磷的未观察到损害作用剂量。采用R语言的PROAST28.1软件包计算BMD及其下限值,将BMD下限值除以安全系数100得到氯蜱硫磷的参考剂量。结果 与正常对照组相比,氯蜱硫磷4,8和16 mg.kg-1使大鼠海马中AChE活性明显降低(P<0.01);氯蜱硫磷2,4,8和16 mg.kg-1使大鼠皮质中AChE活性明显降低(P<0.01);而氯蜱硫磷1,2,4,8和16 mg.kg-1使大鼠血清中AChE活性明显降低(P<0.01)。随着氯蜱硫磷染毒剂量的增加,大鼠海马、皮质和血清中的AChE活性表现出下降趋势。以AChE活性作为指标,海马、皮质和血清中氯蜱硫磷的未观察到损害作用剂量分别为低于2.0,1.0,0.5 mg.kg-1的剂量,BMD分别为0.81,0.90和0.41 mg.kg-1,参考剂量分别为5.5,4.6和3.6μg.kg-1;为人类膳食安全,将氯蜱硫磷的参考剂量定为3.6μg.kg-1。结论 BMD法可制定比未观察到损害作用剂量法更加安全的参考剂量,并可以进一步应用于膳食暴露风险评估。     

Aerosol Profile Extracted from Spacers as a Determinant of Actual Dose

No HeadingPurpose. We propose a novel method to evaluate the efficacy of a pressurized metered dose inhaler (pMDI) in combination with a spacer, by not only considering the total dose extractable from the spacer but also the dependence of dose on the volume available for aerosol inhalation.Methods. We studied volume-dependence of aerosol concentration during extraction from two commonly used plastic spacers (150 ml AerochamberPlus; 750 ml Volumatic) after a single puff of a 100 g salbutamol pMDI (HFA-Ventolin), using laser photometric measurements.Results. After a delay of 1s in each spacer, the aerosol peak dose for AerochamberPlus was 2-fold that for Volumatic (p < 0.001), with the peak appearing well within the first 0.5 L even for the largest spacer. The opposite dose relationship is reached when considering total cumulative dose, which was 2-fold higher for Volumatic than for AerochamberPlus (p < 0.001); >95% of total cumulative dose was extracted well within 3 L for the largest spacer. The 2-fold cumulative dose relationship was confirmed by chemical assay on an absolute filter [AerochamberPlus: 21.4 ± 3.2 (SD) g; Volumatic: 43.8 ± 9.1 (SD) g].Conclusions. Actual aerosol dose available to patients during inhalation via spacers can only be done on the basis of a quantification of aerosol peak dose and cumulative dose as a function of extracted volume.     

Time-Dependent Absorption of Phenprobamate Following Multiple Dosing in Rats

Unusual serum profiles of phenprobamate, a centrally skeletal muscle relaxant, were observed in Sprague Dawley rats receiving multiple doses of phenprobamate suspension. The concentrations of phenprobamate were higher after the morning doses than after the evening doses, synchronizing with the day–night pattern of drug administration. Crossover studies were conducted to investigate the apparent time-dependent kinetics of phenprobamate. Phenprobamate emulsion was orally administered as a single dose to a group of six rats at 0900 hr and again, after a washout period of 3 days, at 2100 hr. Another group of six rats was treated similarly with intraperitoneal drug administration. Blood samples were collected at various times for 12 hr. The AUCs were 146.56 ± 31.77 µg · hr/ml for the morning oral dose and 111.31 ± 21.32 µg · hr/ml for the evening oral dose (P < 0.001). Administered intraperitoneally, the AUCs were 179.89 ± 37.50 and 185.58 ± 28.51 µg · hr/ml for the morning and evening doses, respectively, the difference of which was not significant. The paired t test indicated a significant morning–evening difference in AUC following oral but not intraperitoneal drug administration. This suggests the absorption rather than metabolism as a contributing factor to the time-dependent kinetics of phenprobamate in rats.     

A pharmacokinetic model-independent approach for estimating dose required to give desired steady-state trough concentrations of drug in plasma

A maintenance dose designed to give a desired minimum concentration of drug in plasma at steady-state can be determined in a model-independent manner assuming that concentration-time data needed for the calculation are obtained after absorption and distribution are complete. Using a few concentration-time points obtained after the first dose, numerical values of and Z, a parameter consisting of different pharmacokinetic parameters for different models, can be obtained. An administration interval () can be chosen based on . Using the values of , Z, and , a maintenance dose is calculated. This approach will allow calculation of a maintenance dose when drug is present in plasma at the time the first monitored dose is given.