老年原发性高血压患者血尿β2微球蛋白及尿微白蛋白的变化

目的 探讨老年原发性高血压（ＥＨ）血、尿β２微球蛋白（β２－ＭＣ）及尿微白蛋白（Ｍ－Ａ１ｂ）的变化。方法 对血尿素氮（ＢＵＮ）、肌酐（Ｃｒ）正常的老年ＥＨ患者７７例对照组２４例测定血、尿β２－ＭＣ及尿Ｍ－Ａ１ｂ水平,进行对照分析。结果 ＥＨⅠ级对照组无差异（Ｐ〉０．０５）;ＥＨⅡ级组血、尿β２－ＭＧ及尿Ｍ－Ａ１ｂ均明显高于对照组（Ｐ〈０．０５）;ＥＨⅢ级组与对照组有显著性差异（Ｐ〈０．０１）,且明     

2－甲基－5－巯基－1，3，4－噻二唑的合成

２－甲基－５－巯基－１，３，４－噻二唑的合成李敬芬，王旭，黄剑（佳木斯医学院药学系黑龙江１５４００２）ＳＹＮＴＨＥＳＩＳＯＦ２－ＭＥＴＨＹＬ－５－ＭＥＲＣＡＰＴＯ－１，３，４－ＴＨＩＡＤＩＡＺＯＬＥ￥ＬＩＪｉｎｇ－Ｆｅｎ；ＷＡＮＧＸｕ；ＨＵＡＮＧＪｉ...     

老年冠心病可溶性白细胞介素2受体和免疫球蛋白水平的研究

检测了５０例老年冠心病（ＣＨＤ）和２０例健康老年人（ＮＣ）血清可溶性白细胞介素２受体（ＳＩＬ—２Ｒ）和ＩｇＧ、ＩｇＡ、ＩｇＭ水平。ＣＨＤ组ＳＩＬ—２Ｒ较ＮＣ组明显升高（Ｐ＜０．０１），且不同类型冠心病，ＳＩＬ—２Ｒ水平不同，随心肌损伤明显而增高；ＣＨＤ组ＩｇＧ水平高于ＮＣ组（Ｐ＜０．０５），ＩｇＡ、ＩｇＭ在两组间无明显差异（Ｐ＞０．０５）；心肌梗塞病人ＩｇＧ高于ＮＣ组，心绞病者与ＮＣ组相比则无差别。提示老年冠心病患者ＳＩＬ－－２Ｒ、ＩｇＧ水平增高，免疫功能损伤在老年冠心病发生中有意义，且随病情严重程度加重而增高。     

不同剂量的阿米卡星对小儿尿β2-微球蛋白的影响

目的：监测阿米卡星的肾毒性并探讨其安全剂量和疗程。方法：对１２０例感染性疾病患儿分别使用阿米卡星７．５,１０,１５ｍｇ·ｋｇ－１·ｄ－１,治疗３ｄ及７ｄ后用放射免疫分析法测尿β２微球蛋白（β２ＭＧ）,及血β２ＭＧ（ｎ＝３６）,用速率法测尿素氮（ＢＵＮ）,肌酐（Ｃｒ）（ｎ＝３６）。结果：尿β２ＭＧ升高率,１５ｍｇ·ｋｇ－１·ｄ－１组显著高于７．５ｍｇ·ｋｇ－１·ｄ－１组（Ｐ＜０．０１）;１０ｍｇ·ｋｇ－１·ｄ－１组与７．５ｍｇ·ｋｇ－１·ｄ－１组差异无显著性（Ｐ＞０．０５）。三组血β２ＭＧ、ＢＵＮ、Ｃｒ的均数与健康对照组相比,差异无显著性（Ｐ均＞０．０５）。结论：尿β２ＭＧ是评价阿米卡星肾毒性特异的敏感的指标,儿童阿米卡星的安全剂量是７．５～１０ｍｇ·ｋｇ－１·ｄ－１。     

氢氯噻嗪对大鼠主动脉收缩及^86Rb外流的影响

氢氯噻嗪（ＨＣＴ）０．１，０．３ｍｍｏｌ·Ｌ＾－１可抑制低浓度ＫＣＬ（〈４０ｍｍｏｌ·Ｌ＾－１），ＮＥ和５－ＨＴ所致大鼠主动脉条收缩，对高Ｋ＾＋（８０ｍｍｏｌ·Ｌ＾－１）去极化时ＣａＣｌ２所致收缩无影响。ＨＣＴ对低浓度ＫＣＬ所致收缩的抑制作用可被ＢａＣｌ２和ＴＥＡ拮抗，不被Ｇｌｉ拮抗。ＨＣＴ３ｍｍｏｌ·Ｌ＾－１可使＾８６Ｒｂ外流增加，此作用可这ＢａＣｌ２拮抗，不被Ｇｌｉ拮抗。ＨＣＴ抑制大鼠主动脉…     

人参皂苷抗海马培养细胞缺氧损伤的作用

观察人参皂苷抗脑细胞缺氧损伤的作用。将１２ｄ培龄的海马细胞置于９５％Ｎ２＋５％ＣＯ２中４－２４ｈ，比较人参皂苷组和照组细胞形态学。存活率及ＬＤＨ和Ｋ＾＋流出的变化。缺氧２４ｈ后，对照细胞存活率从缺氧前９２％±４％降至１．０％±２．０％；ＬＤＨ和Ｋ＾＋漏出量分别由２．３±０．６ＵＬ＾－１和５．５６±０．１６ｍｍｏｌ／Ｌ＾－１增至３６±５ＵＬ＾－１和８．５±０．８ｍｍｌｏｌＬ＾－１；此时，人参皂苷组细     

小诺米星在新生儿的药物动力学

本文报告２０例患儿（男性１２例，女性８例；日龄１５±ｓ８ｄ）应用小诺米星，Ａ组１０例以４ｍｇ／（ｋｇ·ｄ），Ｂ组１０例以５ｍｇ／（ｋｇ·ｄ），均ｂｉｄ，静脉滴注，观察其药物动力学与肾毒性。单剂０．５ｈ滴毕。结果：血药峰值分别为４．５与４．７μｇ／ｍＬ（Ｐ＞０．０５）。２组药物动力学参数（Ｖｄ，Ｃｌ，ＡＵＣ）与肾毒性参数（β２－ＭＧ，ＢＵＮ）差别均无显著意义（Ｐ＞０．０５）。提示该药用于新生儿，且剂量增至５ｍｇ／（ｋｇ·ｄ）于１ｗｋ内应用是安全的。     

多剂量口服5-单硝酸异山梨酯缓释片及普通片的药代动力学和生物利用度研究

对１０名健康男性受试者连续６ｄ多剂量交叉ｐｏＩＳ５ＭＮ缓释片和普通片的药代动力学性质和相对生物利用度进行了研究。结果表明：ＩＳ５ＭＮ缓释片和普通片的Ｔｍａｘ分别为５０ｈ和１４ｈ（Ｐ＜００５），前者的缓释效果十分明显；ＡＵＣ经对数转换后的多种统计分析表明，ＩＳ５ＭＮ缓释片（４０ｍｇ）与ＩＳ５ＭＮ普通片（２０ｍｇ×２）生物等效；ＩＳ５ＭＮ缓释片的相对生物利用度为１０８９５％；ＩＳ５ＭＮ缓释片和普通片的Ｃｍｉｎ分别为７４２０ｎｇ·ｍｌ－１和１３４４２ｎｇ·ｍｌ－１（Ｐ＜００５），而两种制剂的其他药代动力学参数如Ｃｍａｘ，ＡＵＣ２４０，ＡＵＣ∞０，Ｋｅ，Ｔ１／２以及波动系数（ＦＩ）等均无显著性差异（Ｐ＜００５）。多次给药后两种制剂都无明显的蓄积。     

Detection of DNA damage in peripheral lymphocytes by 7 compounds using comet assay

目的：检测过氧化氢（Ｈ２Ｏ２）、甲磺酸乙酯（ＥＭＳ）、丝裂霉素Ｃ（ＭＭＣ）、二甲基亚硝胺（ＤＭＮＡ）、苯并（ａ）芘（ＢａＰ）、２氨基芴（２ＡＦ）和环磷酰胺（ＣＰ）诱发小鼠、大鼠及人外周血淋巴细胞ＤＮＡ单链断裂．方法：体外单细胞微量凝胶碱性电泳试验（慧星试验）．结果：除ＥＭＳ０９７ｍｍｏｌ·Ｌ－１在小鼠淋巴细胞，ＭＭＣ３０μｍｏｌ·Ｌ－１在小鼠、人淋巴细胞中呈阴性外，其余均为阳性．最低可检测浓度分别为Ｈ２Ｏ２１μｍｏｌ·Ｌ－１，ＥＭＳ０４８ｍｍｏｌ·Ｌ－１，ＢａＰ５０μｍｏｌ·Ｌ－１，ＣＰ２０ｍｍｏｌ·Ｌ－１，ＭＭＣ１０μｍｏｌ·Ｌ－１，ＤＭＮＡ２７３ｍｍｏｌ·Ｌ－１，２ＡＦ６２５μｍｏｌ·Ｌ－１．ＣＰ、ＢａＰ、２ＡＦ需经Ｓ９Ｍｉｘ代谢活化才显示毒性．结论：彗星试验检测出ＭＭＣ诱导大鼠，ＥＭＳ诱导大鼠和人，以及Ｈ２Ｏ２、ＤＭＮＡ、ＢａＰ、ＣＰ和２ＡＦ诱导小鼠、大鼠和人外周血淋巴细胞ＤＮＡ单链断裂损伤．     

苯胺衍生物对肝细胞毒性构效关系的量子化学研究

应用ＣＮＤＯ／２量子化学方法计算２８个苯胺衍生物分子的电子结构,探讨了药物分子的电子结构对肝细胞毒性三项指标的关系,结果得到了三个反映苯胺衍生物对肝细胞毒性的定量构效关系（ＱＳＡＲ）的回归方程：ｐＴＣ５０＝５．４１７＋０．６７９ＥＨＯＭＯ;ｐＳＤＨ＝－５．３８９－１．３５３ＳＱＲ－０．３４６ＥＨＯＭＯ;ｐＬＤＨ＝－６．０９４－１．５５６ＳＱＲ－０．３０６ＥＨＯＭＯ。根据所得的ＱＳＡＲ方程可预测化合     

alpha-Difluoromethylornithine effects on nitrosourea-induced cytotoxicity and crosslinking in a methylation excision repair positive (MER+) human cell line

We investigated the cytotoxic effects of nitrosoureas with and without a 42-hr preincubation with the ornithine decarboxylase (EC 4.1.1.17) inhibitor alpha-difluoromethylornithine (DFMO, 1 mM) in a MER+ (methylation excision repair positive) human cell line. DFMO combined with a chloroethyl nitrosourea [1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) or 1-(2-chloroethyl)-1-nitrosourea (CNU)] yielded increased toxicity with D37 ratios of 1.9 and 3.3 respectively. There was no enhanced toxicity with the monofunctional nitrosourea 1-ethyl-1-nitrosourea (ENU). BCNU or CNU did not induce DNA-DNA interstrand crosslinks in cells with or without a DFMO pretreatment. DNA single-strand breakage was not increased by addition of DFMO. BCNU-induced DNA-protein crosslinking was decreased in cells pretreated with DFMO. These findings are similar to those in MER- cells in that the chloroethyl carbonium alkylating species is required for the enhanced cytotoxicity seen with DFMO. The ability to form DNA interstrand crosslinks, however, does not appear to be necessary for this toxicity enhancement.     

An analysis of 1-(2-chloroethyl)-1-nitrosourea activity at the cellular level

The effect of five different 1-(2-chloroethyl)-1-nitrosoureas on the growth of cultured P388 cells has been analyzed in terms of physical, chemical, and kinetic parameters that are related to the mechanism of action of this class of cancer chemotherapeutic agent. This study correlates structure with activity at the cellular level by using a dose function that is related to the amount of active species, the (2-chloroethyl)diazonium ion, that is formed during the period of exposure of cells to drug rather than to the initial drug dose. 1-(2-Chloroethyl)-1-nitrosourea analogues that rapidly enter the P388 cells are shown to have the same activity relative to the amount of active species formed. When analyzed in this way, activity is not influenced by the structure of the N-3 substituent, lipophilicity, or carbamoylating activity. The agents 1-(2-chloroethyl)-1-nitrosourea (CNU), 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) all produce a 50% cell growth inhibition at 6 to 7 microM active species formed per cell volume. Chlorozotocin required a twofold higher effective dose to produce the same toxic effect. This decreased activity is attributed to the slow uptake of the water-soluble chlorozotocin into P388 and L1210 cells relative to the rate of chlorozotocin conversion to active species in medium. The yields to 2-chloroethanol from CNU, BCNU, and chlorozotocin were shown to be the same, indicating that these agents generate the same yield of alkylating intermediate at 37 degrees C and pH 7.4.     

BCNU-loaded poly(D,L-lactide-co-glycolide) wafer and antitumor activity against XF-498 human CNS tumor cells in vitro

Implantable polymeric device that can release chemotherapeutic agent directly into central nervous system (CNS) has had an impact on malignant glioma therapy. The purpose of our study was to develop an implantable polymeric device, which can release intact 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for long-term period over 1 month, and to evaluate its cytotoxicity against XF 498 human CNS tumor cells in vitro. BCNU was incorporated into biodegradable poly(D,L-lactide-co-glycolide) (PLGA), by using spray-drying method. BCNU-loaded PLGA microparticles were characterized by scanning electron microscopy (SEM), powder X-ray diffraction, and differential scanning calorimetry. SEM observation of the microparticles showed that the microparticles were spherical, i.e. microspheres. Homogeneous distribution of BCNU in PLGA microsphere was confirmed by significant reduction of crystallinity of BCNU. Microspheres were fabricated into wafers with flat and smooth surface by direct compression method. In vitro release of BCNU in pH 7.4 phosphate buffered saline was prolonged up to 8 weeks after short initial burst period. Antitumor activity of BCNU-loaded PLGA wafer against XF 498 human CNS tumor cells continued over 1 month and, PLGA only did not affect the growth of the cells. Meanwhile, the cytotoxic activity of BCNU powder disappeared within 12 h. These results strongly suggest that the BCNU/PLGA formulations increase release period of carmustine in vivo and also be useful in the development of implantable polymeric device for malignant glioma.     

Inhibition of carboxyethylphosphoramide mustard formation from 4-hydroxycyclophosphamide by carmustine

It has been reported that the toxicity of carmustine (BCNU) cyclophosphamide (CY)/etoposide regimen (when BCNU is split into 4 doses) is less than that of BCNU/CY/cisplatin regimen (when the same amount of BCNU is administered as a single dose). We hypothesized that this might in part be due to the inhibition of aldehyde dehydrogenase 1 (ALDH1) by BCNU or its degradation product, 2-chloroethyl isocyanate, which is likely to be more pronounced at the higher BCNU dose. The effects of BCNU and 2-chloroethyl isocyanate on the formation of carboxyethylphosphoramide mustard (CEPM) from 4-hydroxycyclophosphamide (HCY) was evaluated in human liver cytosol incubations. We found that CEPM formation from HCY was inhibited strongly by BCNU and weakly by 2-chloroethyl isocyanate. The mechanism of inhibition of ALDH1 activity by BCNU was elucidated using indole-3-acetaldehyde (IAL) as the probe substrate in ALDH1 prepared from human erythrocytes. BCNU was a competitive inhibitor of ALDH1 activity with a K_i of 1.95 μM. The inhibition was independent of preincubation time and reversible by dialysis. The calculated %inhibition of ALDH1 activity by acrolein and BCNU in patients receiving BCNU in 4 split doses with CY was 81%, and it increased to 92% in single dose BCNU regimen. Thus, the calculation indicates that residual operating ALDH1 activity is halved in the presence of single-dose BCNU compared to split-dose BCNU. The inhibition of ALDH1 may contribute to the observed lower incidence of toxicity when BCNU was split into 4 doses compared with single dose and coadministered with CY although dose-dependent effects of BCNU on glutathione and glutathione reductase are also likely to contribute.     

Metoclopramide as a sensitizer of 1,3-bis(2-chloroethyl)-1-nitrosourea treatment of brain tumors in the rat.

RG2 glioma-like cells grown in in vitro culture can be inoculated into rat brains using stereotactic surgical procedures to produce tumors with a diameter of 12-16 mm2 in 20-21 days. This system has been used to evaluate if metoclopramide (MCA) could sensitize the tumor toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU alone (15 mg/kg, intravenously), and MCA alone (2 mg/kg, intraperitoneally), and these drug treatments in combination, were administered so that BCNU alone was given as a single dose on day 3 after inoculation of the RG2 cells, MCA alone was given on day 3 at 0 and 3 h followed by five or six treatments per week beginning 24 h after the 3 h dose, and BCNU plus MCA were given according to the combined schedule where the first MCA treatment was scheduled 30 min prior to the BCNU infusion. The design of this study required the drug treated animals to be matched to untreated animals (controls) at the time of inoculation of the RG2 cells. Under these experimental conditions, BCNU alone and MCA alone had no effect on tumor growth, whereas BCNU plus MCA significantly retarded brain tumor growth. The normal tissue toxicity induced by BCNU treatment, evaluated by measurement of body weight and survival, was not potentiated by the combination of BCNU plus MCA. These data extend the previous findings of MCA as a radio- and chemosensitizer to include the sensitization of another cytotoxic agent (BCNU) and of another type of tumor (malignant glioma).     

Application of lipid microspheres for the treatment of cancer

Lipid microspheres can act as a carrier for antitumor agents. We incorporated a lipophilic antitumor agent, l,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) into microspheres by homogenizing a soybean oil solution of BCNU with egg yolk lecithin. Lipid microsphere-encapsulated BCNU showed a significantly enhanced antitumor activity with reduced toxicity in mice with L1210 leukemia when compared to the corresponding dose of free BCNU. Lipid nanospheres, smaller particles containing BCNU with an average size of 50 nm, also showed a similar level of in vivo antitumor activity. An in vitro study showed that [¹⁴C]triolein uptake by tumor cells was increased by incorporation into microspheres. The in vitro uptake of small microspheres was lower than that of standard microspheres. However, the in vivo half-life of small microspheres was longer, they avoided capture by the reticuloendothelial system and showed higher accumulation at tumor sites. Thus, lipid microspheres may be useful for delivering various lipophilic chemotherapy agents.     

Effect of cations on the formation of DNA alkylation products in DNA reacted with 1-(2-Chloroethyl)-1-nitrosourea.

The purpose of this study was to examine the influence of cations on the formation of the individual DNA alkylation products derived from 1-(2-chloroethyl)-1-nitrosourea (CNU). Reaction of calf-thymus DNA with [(3)H]CNU in 10 mM triethanolamine buffer produced 13 DNA adducts. Seven of these adducts were identified as N7-(2-hydroxyethyl)guanine, N7-(2-chloroethyl)guanine, 1, 2-(diguan-7-yl)ethane, N1-(2-hydroxyethyl)-2-deoxyguanosine, 1-(N1-2-deoxyguanosinyl)-2-(N3-2-deoxycytidyl)ethane, O(6)-(2-hydroxyethyl)-2-deoxyguanosine, and phosphotriesters. The ratios of the individual products indicated that the chloroethyl and hydroxyethyl adducts are derived from different alkylating intermediates. The influence of cations on the formation of these DNA alkylation products was investigated by the addition of either NaCl, MgCl(2), or spermine. The results demonstrated that (1) the levels of DNA alkylation were inversely proportional to ionic strength, (2) the extent of inhibition was dependent on the alkylation product, and (3) the order of relative effectiveness of inhibition of DNA alkylation by these cations was as follows: spermine > Mg > Na. These results support a model whereby reactions which proceed via an S(N)2 mechanism are more sensitive to the effects of ionic strength than reactions which proceed via an S(N)1 mechanism. In 9L cells treated with CNU, the same alkylation products were formed as in purified DNA; however, the product distribution was different. We interpret this to indicate that within cells, cations modify the reaction of intermediates derived from CNU with DNA.     

Nucleoside analogues: 7. Effect on colon, breast and lung tumours in mice of 5-fluorouracil/nitrosourea molecular combinations incorporating alkoxy and oxidized sulphur functions

This study considers further changes in the carrier moiety of molecular combinations of the pyrimidine antimetabolite 5-fluorouracil (5-FU) and the alkylating group chloroethylnitrosourea (CNU). Detailed chemical syntheses are described of compounds incorporating (a) a simpler alkoxy group in the 'sugar' fragment, (b) attachment of the 5-FU residue to the C-X-C-C chain on the side of the heteroatom X distal from the CNU group, and (c) higher oxidation states of the sulphur atom in the prototypical compound B.3839. Anti-tumour activity of these analogues against a series of experimental murine colon, lung and mammary tumours is described. The pattern of activity reveals that the carrier moiety is important but further pharmacokinetics and metabolism studies are required to determine structure-activity relationships.     

1,3-(2-Chloroethyl)-1-nitrosourea potentiates the toxicity of acetaminophen both in the phenobarbital-induced rat and in hepatocytes cultured from such animals

The toxicity of acetaminophen was studied in hepatocytes cultured from phenobarbital-induced male rats. Such cells were less sensitive to acetaminophen than similar ones cultured from animals induced with 3-methylcholanthrene. In both cases, the toxicity of acetaminophen depended on its metabolism. Inhibition of glutathione reductase with 1,3-(2-chloroethyl)-1-nitrosourea (BCNU) potentiated the toxicity of acetaminophen in the presence or absence of 100 mM acetone, an agent that activates the mixed function oxidation of the toxin. BCNU enhanced the rate and extent of the depletion of GSH in the presence or absence of acetone. Pretreatment of the hepatocytes with the ferric iron chelator deferoxamine or addition to the culture medium of the antioxidant N,N'-diphenyl-p-phenylenediamine prevented the toxicity of acetaminophen in the presence of BCNU whether or not there was acetone in the cultures. BCNU similarly potentiated the hepatotoxicity of acetaminophen in the intact, phenobarbital-induced rat. These data indicate that the mechanism of the killing of hepatocytes induced with phenobarbital is similar to that reported previously with hepatocytes prepared from animals induced with 3-methylcholanthrene. In both cases it would seem that the liver cells are killed by acetaminophen as a result of an oxidative stress that accompanies the metabolism of this hepatotoxin.     

A quantitative structure-activity relationship (QSAR) analysis of the effects of aromatic substitution on the anticonvulsant activity and toxicity of arylsuccinimides.

Anticonvulsant activity and toxicity of 20 arylsuccinimides were quantitatively correlated with the hydrophobic, electronic and steric parameters of the substituents in the benzene ring and at the nitrogen atom. The activity was highest when the benzene ring substituents X were characterized by hydrophobic fragmental constants fx lying in the 1.0-1.7 range, though toxicity increased with fx.