某品牌嫩肉粉急性毒性作用研究

目的 确定嫩肉粉半数致死剂量LD50.方法 采用改进寇氏法测定嫩肉粉LD50.结果 嫩肉粉NIH小鼠经口灌胃LD50为8711 mg/kg.bw.结论 根据国家标准评价,嫩肉粉毒性分级属实际无毒级.     

靶控输注丙泊酚复合舒芬太尼在无肌松药行气管插管时EC50的测定

目的探讨在不用肌松药行气管插管术中丙泊酚靶控输注复合舒芬太尼时丙泊酚的半数有效血浆靶浓度(EC50)。方法择期手术患者22例,在舒芬太尼0.5μg/kg推注复合靶控输注(TCI)丙泊酚4min后经口行气管插管,并根据下颌松弛程度、声带位置和对气管插管的反应进行插管评级(优、良、一般和差;优、良认为是临床满意而一般,差看作临床不满意)。丙泊酚的半数有效血浆靶浓度按序贯法确定,相邻血浆靶浓度差为0.5μg/ml。结果当达到临床满意的气管插管条件时丙泊酚的半数有效血浆靶控浓度为6.69μg/ml,95%的可信区间为5.999~7.463μg/ml。结论复合舒芬太尼0.5μg/kg时,在不用肌松药行气管插管术达到插管条件为优良时丙泊酚的半数有效血浆靶浓度是6.69μg/ml。     

Acute toxicity studies of Croton membranaceus root extract

Aim of the study

Croton membranaceus root and leaf extracts are used in the Bahamas to aromatize tobacco, in Nigeria to improve digestion, and in Ghana, for benign prostate hyperplasia. Despite claims of success there is paucity of information on its toxicity. The aim of this study was to determine if Croton membranaceus has acute toxicity properties.

Materials and methods

Roots were air-dried in a solar dryer for one week before milling. The powder was extracted with 96% ethanol, freeze-dried and re-extracted with distilled water and freeze-dried. 15 male Sprague-Dawley rats (180-200 g) were divided equally into 2 treatment groups [low dose (LD) and high dose (HD)], plus a control group (C). LD and HD received 1500 and 3000 mg/kg b.wt. Croton membranaceus aqueous extract, respectively, one time and observed for 14 days. Haematological [Full Blood Count and haemoglobin (Hb)], biochemical [bilirubin, alanine aminotransferase (ALA), aspartate aminotransferase (AST), total protein, albumin, globulin, alkaline phosphatise (ALP), γ-glutamyltranspetidase (GGT), urea, creatinine, creatinine kinase - Muscle and Brain (CK-MB), creatinine kinase - Total (CK-R)] examinations were performed.

Results

Control group's CK-MB (5444 ± 534 U/L) and LD group CK-MB (4014 ± 1016 U/L) were significantly different (p < 0.05). Control and the HD group CK-MB (3955 ± 1135 U/L) were significantly different (p < 0.05). Both LD and HD CK-R levels (697 ± 197 U/L and 732 ± 203 U/L, respectively), were lower than the control (1139 ± 220 U/L) at 48 h and 14 days (p < 0.05, p < 0.05, respectively). γ-GT levels of the HD group was 4.8 ± 0.4 U/L compared to the Control group value of 0.9 ± 0.2 U/L (p < 0.05).

Conclusions

Taking all factors into consideration, Croton membranaceus ingestion does not produce general acute toxicity. However, its creatinine kinase lowering ability could be explored.     

癃闭消颗粒对小鼠的急性毒性作用研究

目的:探讨癃闭消颗粒对小鼠急性毒性作用,为该药安全性评价提供理论依据.方法:急性毒性试验分别采用测定癃闭消颗粒对小鼠的最大耐受量和小鼠LD50,观察结果,确定该药的用药安全范围.结果:测得小鼠单次ig癃闭消最大耐受量>100 g·kg-1,1日多次ig最大耐受量>240 g·kg-1,分别为人体单次po用药剂量的389倍,日用药剂量的311倍.癃闭消颗粒以最大浓度、最大剂量给小鼠灌胃后观察14 d,全部动物存活,未观察到急性毒性的发生.结论:癃闭消颗粒用药安全范围较宽,无毒性作用.     

磷酸川芎嗪纳米脂质体包封率的测定

目的 建立磷酸川芎嗪纳米脂质体包封率的测定方法. 方法 采用Sephadex G-50凝胶柱分离脂质体和游离磷酸川芎嗪,紫外分光光度法测定包封率. 结果 凝胶柱层析能有效分离脂质体与游离磷酸川芎嗪,柱回收率和柱加样回收率分别为99.09%和98.35%. 磷酸川芎嗪线性范围为0.160～24.048 μg&#8226;mL^-1（r＝0.999 8）,测得包封率平均值为36.12%,RSD为1.18%. 结论 该方法简便易行,准确可靠,可用于磷酸川芎嗪纳米脂质体包封率的测定.     

丹红注射液的毒理学研究

目的 观察丹红（倍通）注射液的急慢性毒性，对其进行安全性评价。方法 小鼠连续7d静脉给药，测定药物的半数致死量（LD50）。大鼠连续给药90d后，处死大部动物，取血，做血常规、血液生化指标测定，取主要脏器称重进行病理学检查。余下大鼠在停药继续喂养2周后，处死进行病理组织学检查。结果 小鼠LD50为39．5ml／kg。各实验组大鼠在体质量增加、器官系数、血常规、血液生化指标上基本相似，与对照组比较差异无统计学意义（P〉0．05）。主要脏器的病理组织学检查未见明显异常。结论 急慢性毒性实验的结果表明该药安全可靠。     

3'-Azido-3'-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria

Long-term use of 3'-azido-3'-deoxythymidine (AZT) is associated with various tissue toxicities, including hepatotoxicity and cardiomyopathy, and with mitochondrial DNA depletion. AZT-5'-triphosphate (AZTTP) is a known inhibitor of the mitochondrial DNA polymerase gamma and has been targeted as the source of the mitochondrial DNA depletion. However, in previous work from this laboratory with isolated rat heart and liver mitochondria, AZT itself was shown to be a more potent inhibitor of thymidine phosphorylation (IC50 of 7.0+/-1.0 microM AZT in heart mitochondria and of 14.4+/-2.6 microM AZT in liver mitochondria) than AZTTP is of polymerase gamma (IC50 of >100 microM AZTTP), suggesting that depletion of mitochondrial stores of TTP may limit replication and could be the cause of the mitochondrial DNA depletion observed in tissues affected by AZT toxicity. The purpose of this work is to characterize the nature of AZT inhibition of thymidine phosphorylation in isolated rat heart and rat liver mitochondria. In both of these tissues, AZT was found to be a competitive inhibitor of the phosphorylation of thymidine to TMP, catalyzed by thymidine kinase 2. The inhibition constant (Ki) for heart mitochondria is 10.6+/-4.5 microM AZT, and for liver mitochondria Ki is 14.0+/-2.5 microM AZT. Since AZT is functioning as a competitive inhibitor, increasing thymidine concentrations may be one mechanism to overcome the inhibition and decrease AZT-related toxicity in these tissues.     

Methyl-beta-cyclodextrin enhances the susceptibility of human breast cancer cells to carboplatin and 5-fluorouracil: involvement of Akt, NF-kappaB and Bcl-2

The response rates of extensively used chemotherapeutic drugs, carboplatin (Carb) or 5-fluorouracil (5-FU) are relatively disappointing because of considerable side effects associated with their high-dose regimen. In the present study, we determined whether treatment with a cholesterol depleting agent, methyl-beta-cyclodextrin (MCD), enhances the weak efficacy of low doses of Carb or 5-FU in human breast cancer cells. Data demonstrate that pretreatment with MCD significantly potentiates the cytotoxic activity of Carb and 5-FU in both MCF-7 and MDA-MB-231. Furthermore, we explored the molecular basis of enhanced cytotoxicity, and our data revealed that low-dose treatment with these drugs in MCD pretreated cells exhibited significantly decreased Akt phosphorylation, NF-kappaB activity and down-regulation in expression of anti-apoptotic protein Bcl-2. In addition, MCD pretreated cells demonstrated an increased intracellular drug accumulation as compared to cells treated with drugs alone. Taken together, our data provide the basis for potential therapeutic application of MCD in combination with other conventional cytotoxic drugs to facilitate reduction of drug dosage that offers a better chemotherapeutic approach with low toxicity.     

Monoacylglycerol lipase inhibition by organophosphorus compounds leads to elevation of brain 2-arachidonoylglycerol and the associated hypomotility in mice

Three components of the cannabinoid system are sensitive to selected organophosphorus (OP) compounds: monoacylglycerol (MAG) lipase that hydrolyzes the major endogenous agonist 2-arachidonoylglycerol (2-AG); fatty acid amide hydrolase (FAAH) that cleaves the agonist anandamide present in smaller amounts; the CB1 receptor itself. This investigation considers which component of the cannabinoid system is the most likely contributor to OP-induced hypomotility in mice. Structure-activity studies by our laboratory and others rule against major involvement of a direct toxicant-CB1 receptor interaction for selected OPs. Attention was therefore focused on the OP sensitivities of MAG lipase and FAAH, assaying 19 structurally diverse OP chemicals (pesticides, their metabolites and designer compounds) for in vitro inhibition of both enzymes. Remarkably high potency and low selectivity is observed with three O-alkyl (C1, C2, C3) alkylphosphonofluoridates (C8, C12) (IC50 0.60-3.0 nM), five S-alkyl (C5, C7, C9) and alkyl (C10, C12) benzodioxaphosphorin oxides (IC50 0.15-5.7 nM) and one OP insecticide metabolite (chlorpyrifos oxon, IC50 34-40 nM). In ip-treated mice, the OPs at 1-30 mg/kg more potently inhibit brain FAAH than MAG lipase, but FAAH inhibition is not correlated with hypomotility. However, the alkylphosphonofluoridate-treated mice show dose-dependent increases in severity of hypomotility, inhibition of MAG lipase activity and elevation of 2-AG. Moderate to severe hypomotility is accompanied by 64 to 86% MAG lipase inhibition and about 6-fold elevation of brain 2-AG level. It therefore appears that OP-induced MAG lipase inhibition leads to elevated 2-AG and the associated hypomotility.     

A novel high-throughput neutralization assay for supporting clinical evaluations of human cytomegalovirus vaccines

Neutralizing antibodies are considered an important component of protective immunity against congenital infection of human cytomegalovirus (HCMV), a frequently cited cause of birth defects. An effective HCMV vaccine is desired to induce potent neutralizing antibodies in seronegative females, so that the viral transmission to fetus would be blocked if the women contracted HCMV infections during their pregnancies. We describe a novel microneutralization assay to measure antiviral activities against HCMV in serum samples. The assay is based on detection of a dominant HCMV antigen expressed in cells, using near infrared dye-labeled immune reagents. Since the detection is independent of viral cytopathic effects, this assay format has the appeal of a short turn-around time and a read-out that is not subject to operator experience and judgment, making it a promising platform to support large scale clinical studies. In a serological survey of a cohort of 200 healthy females, we showed that the neutralizing titers measured in this assay are highly comparable to those from a neutralization assay based on an enzyme-linked immunostaining method. Lastly, to demonstrate the utility of this assay to support HCMV vaccine study, we presented the results of neutralizing titers from a rhesus macaque vaccination study.