Effects of thiourea on pulmonary edema, pleural and peritoneal effusions and toxicity in rats pretreated with actinomycin D

Intraperitoneal (i.p.) injections of toxic amounts of thiourea result in pulmonary edema and pleural effusions. Following i.p. injections of sublethal doses a predominance of pleural effusion over pulmonary edema is demonstrated.Pleural effusion resulting from a sublethal dose of thiourea was seen at 6 h, reached a maximum at 12 h, remained constant until 24 h, and disappeared entirely by 48 h. Administration of 2 doses of Actinomycin D (Act D) (100 μg/kg i.p. 12 h apart) was found to produce profuse pleural and peritoneal effusions without causing pulmonary edema. This was in distinct contrast to intratracheal instillation (50 μg/kg 24 h apart) which produced a large amount of pulmonary edema and little pleural effusion.In general, the effects of thiourea in rats pretreated with Act D i.p. were the development of a greater degree of pleural effusion and a lesser degree of pulmonary edema. In addition, a dose-related reduction in the formation of peritoneal effusion was noticed in these rats. Rats pretreated i.p. with Act D were 4 times more sensitive to the lethal effect of thiourea than controls. It is postulated that Act D pretreatment somehow increases capillary permeability which enhances thiourea toxicity.     

Deoxyribonucleoside triphosphate pools in human diploid fibroblasts and their modulation by hydroxyurea and deoxynucleosides

Deoxyribonucleoside triphosphate (dNTP) pool levels were examined in synchronized and unsynchronized log phase cultures and in quiescent cultures of human diploid foreskin fibroblasts. dNTP levels were in good agreement with those previously published for human HeLa and lymphoblastic leukemia cells. dCTP and dGTP levels showed only a modest lowering in quiescent as compared to log-phase cells, but dATP and dTTP levels were reduced dramatically in quiescent cultures. Cells synchronized by serum starvation and assayed at the peak DNA synthetic phase (18-21 hr post release) showed substantially higher pools of all four dNTPs. Hydroxyurea treatment reduced only purine dNTPs in both log phase and confluent cells while increasing dTTP and dCTP pools. The effects of deoxynucleosides on dNTP pools were also examined and are discussed in light of current models regarding regulation of purified ribonucleotide reductase formulated from in vitro studies.     

美国学校药物滥用预防(禁毒)教育的理念、内容、特点及其启示

D.A.R.E项目是美国最成功的学校药物滥用预防教育项目,在大麻、阿片类毒品、处方/非处方药物、酒精、电子烟等药物滥用课程理念、内容、实施、评价等方面积累了丰富经验,通过文献和调查研究,本文阐释了D.A.R.E药物滥用项目科学化、循证式的设计理念,介绍了小学、中学、大学药物滥用预防教育的分层次、多元化课程内容、互动式、网络化的教学方法以及多方参与的课程评价模式,对我国探索去中心化的药物滥用尤其是禁毒教育管理机制,建构毒品、酒精等药物滥用教育共同体课程设计理念,实现健康、可持续性的药物滥用教育课程体系等方面提出了建设性意见。对我国建构新时代科学化的学校药物滥用预防教育机制和课程模式,推进青少年学生的身心健康教育,促进和谐校园建设具有重要意义。     

The effects of indomethacin upon physiological indices of gastric mucosal integrity

Indomethacin was studied for its effects on three indices of gastric mucosal integrity in anesthetized cats. Following intragastric administration of the compound under conditions of constant stomach acidity and electrolyte concentrations, the transgastric potential difference declined in a gradual, linear fashion during the 210 min of the experimental period. These changes, which were dose related over the range of 1.25-5 mg/kg of indomethacin, were accompanied by increased concentrations of luminal pepsin and blood. The results suggest that the transgastric potential difference is a sensitive indicator of gastric mucosal integrity under the conditions of this study.     

The effects of metalloporphyrins, porphyrins and metals on the activity of delta-aminolevulinic acid synthase in monolayers of chick embryo liver cells

The effect of various metals, porphyrins and metalloporphyrins on the activity of delta-aminolevulinate synthase (ALAS) was measured in monolayers of chick embryo liver cells in order to determine whether the metal moiety of heme or heme itself is the regulator of ALAS activity. Iron, magnesium, zinc, copper, manganese and nickel did not decrease ALAS activity in non-induced and in cells induced by allyl-isopropylacetamide (AIA). Cobalt decreased both non-induced and induced activity. Porphyrins inhibited ALAS, apparently only after having been converted into metalloporphyrins. Almost all the metalloporphyrins examined decreased ALAS activity. None of the substances, at the concentrations used, was toxic to the cells. These observations indicate that probably heme and not iron is the regulator of ALAS activity in monolayers of chick embryo liver cells.     

Biochemical and cytotoxic properties of the isomeric forms of N,N'-bis[N-2-chloroethyl)-N-nitrosocarbamoyl] cystamine

Three isomeric forms of a cystamine-containing chloroethylnitrosourea, N,N'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl]cystamine (CNCC), have been identified and separated by high pressure liquid chromatography. Isomer S, 3,3'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl] ethyl disulfide, was significantly less cytotoxic than isomer C, 1,1'-bis [N-(2-chloroethyl)-N-nitrosocarbamoyl] ethyl disulfide, or isomer M, 1,3'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl] ethyl disulfide, in either a human Namalva lymphoblastoid or a rat Walker 256 carcinoma cell line. Both isomers S and C inhibited DNA synthesis at a 50 microM concentration. A structural analysis of the isomeric forms suggested that bioreduction of the disulfide bond would permit both isomers to produce isocyanate moieties which would carbamoylate intracellular proteins and depress nucleic acid synthesis. The reduced cytotoxic potential of isomer S is consistent with a prolongation in the half-life of production of alkylating carbonium species that lack the capacity to cross-link macromolecules. Overall, the relative position of the NH group within each of the nitrosourea isomers appears critical to the biological properties of the drug.     

Teratogenicity and lethality of hydantoin derivatives in the mouse: Structure-toxicity relationships

The teratogenicities and the lethalities of hydantoin (H), ethotoin (E), mephenytoin (M), phenytoin (P), and phenacemide (PA) were examined in the CD-1 mouse. The outcome of pregnancy was observed following single daily ip administrations on Days 8, 9, and 10 using at least three dose levels for each compound. For comparison, a limited number of dose groups were run on Days 11, 12, and 13. Adult lethality was estimated using female nonpregnant animals following the same 3-day dosing schedule. Dose-response (D-R) relationships were examined by probit analysis. The lethal potency of the compounds varied from an LD50 of 53.7 mmol/kg/day for H to 0.32 mmol/kg/day for P. Slopes of the lethality D-R lines were not significantly different for E, M, and P. There was a strong correlation (R² = 0.94) between the LD50s of the five compounds and their octanol-water partition coefficients (log P). H, E, P, and PA were teratogenic over both treatment schedules while M showed no evidence of dose-related increases in malformations and was embryolethal only at maternally lethal doses. All compounds reduced fetal weights, over both dose schedules. Malformation profiles were similar for H, E, P, and PA, most commonly skeletal and cardiovascular anomalies, exencephaly, and cleft palate for Days 8, 9, and 10 and cleft palate and cardiovascular defects for Days 11, 12, and 13. Teratogenic potency varied from a tD05 (dose required to induce 5% malformations, Days 8, 9, 10 data) of 30.2 mmol/kg/day for H to 0.17 mmol/kg/day for P. For each compound, the slope of the teratogenicity D-R was different from their lethality slope; however, there were no significant differences between the teratogenicity slopes of H, E, and P. Again, there was a correlation between tD05 and log P (R² = 0.89) for H, E, P, and PA. The relative teratogenic index ($\text{RTI =}\text{LD01}\text{tD05}$) was calculated as an indicator of teratogenic hazard. The compounds can be ranked in order of increasing hazard: mephenytoin, <0.9; hydantoin, 1.27; ethotoin, 1.39; phenytoin, 1.62; phenacemide; 3.32. These data suggest a common mechanism of teratogenicity for the closed-ring hydantoins, H, E, and P, and of lethality for the substituted hydantoins E, M, and P. Lethal and teratogenic potencies seem to be determined primarily by lipid solubility but the physiochemical properties which determine relative teratogenic hazard have yet to be identified.     

Correction of drug binding defects in uremia in vitro by anion exchange resin treatment

Serum protein binding of weakly acidic drugs is impaired in uremia, but that of basic drugs tends to be normal. Treatment of uremic serum with anion exchange resin (Amberlite CG-400, acetate form) corrected binding defects for three acidic drugs (nafcillin, salicylate and sulfamethoxazole) but did not affect the binding of two basic drugs (trimethoprim and quinidine). Resin treatment of normal human serum did not alter the binding of these five drugs. Extraction of the acetate buffer eluate from resin exposed to uremic serum with n-butyl chloride at acidic pH (3.0) resulted in a fraction that could induce similar binding defects in normal human serum. The factor(s) responsible for binding defects in uremia appears to be lipid soluble, weakly acidic, and dialyzable. It is believed to be tightly bound to albumin at physiologic pH, but dissociates from it at acidic pH. These findings further support the previously proposed hypothesis that drug-binding defects in uremia are due to accumulation of certain endogenous metabolic product(s).     

参照美国Pharm. D.模式的临床药学教学模式探索

目的：探索我国药学本科生临床药学课程的教学、培养模式。方法：参照美国Pharm. D.教学模式,向31名药学本科生授课并以案例分析实践形式进行强化训练,课后以问卷形式调查学生对学习效果与教学方式的反馈。结果：学生在课堂上有较好的互动,对课堂内容掌握程度较高。问卷调查结果显示,学生自认为学习效果一般(3.47/5)而对于教学方法的认可度较高(4.13/5)。结论：理论学习结合案例学习的教学方式可行性高,值得推广。     

Pulmonary responsiveness to methacholine and disodium hexachloroplatinate (Na2PtCl6) aerosols in cynomolgus monkeys (Macaca fascicularis)

Hyperreactivity of the airways is a common finding in human asthma, and responsiveness to inhaled methacholine aerosols is routinely used for assessing airway irritability. Workers in precious metal refineries demonstrate pulmonary signs suggestive of asthma, presumably related to exposure to soluble platinum salts. In these workers, evidence of physiologic dysfunction precedes immunologic evidence (skin test) of disease, suggesting an initial pharmacologic mechanism. With a primate animal model for the screening of occupational asthmogens, 24 Cynomolgus monkeys were evaluated for their comparative pulmonary responsiveness to inhaled aerosols of methacholine and sodium hexachloroplatinate (Na2PtCl6). Average pulmonary flow resistance (RL), dynamic compliance (CLdyn), maximum expiratory flow volume (MEFV), and respiratory frequency changes were evaluated after bronchoprovocation challenge. Both agents produced dose-dependent increases in RL, dose-dependent decreases in CLdyn and MEFV, and no effect on respiratory rates. Analyses of the correlation between concentration effects of the two agents showed no association between cholinergic airway irritability status and Na2PtCl6-induced bronchoconstriction. Na2PtCl6 bronchoprovocation produced significantly greater flow impairment at lower lung volumes when compared to methacholine concentrations with equipotent effects on RL and CLdyn. These compounds have differential effects on peripheral airway function. The lack of respiratory rate change seen on bronchoprovocation with these compounds, in comparison to the rapid shallow breathing in anesthetized monkeys following irritant or histamine challenge, indicates that neither aerosol stimulated pulmonary irritant receptors.     

Effects of flavonoids and transitional metal cations on antigen-induced histamine release from human basophils

Structure-activity relationship studies have been performed on the inhibition of antigen-induced histamine release from human basophils by various naturally occurring flavonoids. Quercetin was the most active compound. Of the transitional metal ions, Cu2+ most effectively blocked the inhibitory activity of quercetin, possibly through a chelation mechanism.     

Role of red cell membrane lipid peroxidation in hemolysis due to phenylhydrazine

Although red cell membrane lipid peroxidation has been identified as a consequence of certain oxidizing hemolytic drugs, the relative contribution of lipid peroxidation to red cell damage leading to hemolysis is unclear. This has been evaluated by studying the response to phenylhydrazine of vitamin E-deficient rats as compared to vitamin E-supplemented rats. Following repetitive phenylhydrazinc injections, a lower hematocrit was observed in the vitamin E-deficient group which was associated with higher levels of lipid peroxidation, as indicated by the fluorescence of lipid-containing red cell extracts. However, no significant difference in the initial extent of hemolysis following phenyl-hydrazine injection was observed. Evidence was also obtained suggesting that malonaldehyde, a decomposition product of polyunsaturated fatty acids, is capable of cross-linking hemoglobin to the red cell membrane. These findings suggest that red cell membrane lipid peroxidation is of relatively minor consequence in the acute response to phenylhydrazine but may be of importance in chronic hemolysis due to this oxidizing drug.     

薯蓣属植物化学成分的研究——Ⅱ.叉蕊薯蓣中甾体皂甙的分离和鉴定

从叉蕊薯蓣(D.collettii HooK.f.)根茎的乙醇提取物分离到四个甾体皂甙,根据理化性质、光谱数据,推定化学结构为3-O-(β-D-葡萄吡喃糖)-约莫皂甙元(3-O-(β-D-glucopyranosyl)-yamogenin)[Ⅰ];3-O-[α-L-鼠李吡喃糖(1→4)-β-D-葡萄吡喃糖]-约莫皂甙元(3-O-[α-L-rahmnopyranosyl(1→4)-β-D-glucopyranosyl]-yamogenin)[Ⅱ];3-O-{α-L-鼠李吡喃糖(1→4)-[α-L-鼠李吡喃糖(1→2)]-β-D-葡萄吡喃糖}-约莫皂甙元(3-O-{α-L-rhamnopyranosyl(1→4)-[α-L-rhamnopyranosyl(1→2)]-β-D-glucopranosyl}-yamogenin)[Ⅲ];3-O-{β-D-葡萄吡喃糖(1→3)-[α-L-鼠李吡喃糖(1→2)3-β-D-葡萄吡喃糖}-约莫皂甙元(3-O-{β-D-glucopyranosyl(1→3)-[α-L-rhamnopyranosyl(1→2)]-β-D-glucopyranosyl}-yamogenin)[Ⅳ]。其中Ⅰ为已知物,Ⅱ、Ⅲ、Ⅳ为首次从植物界得到的新甾体皂甙。     

发霉叉蕊薯蓣中的甾体皂甙元

前报报道了从国产野生叉蕊薯蓣(Dioscorea collettii Hook.f.)根茎的水解物中分得了10个甾体化合物,其中约莫皂甙元(yamogenin)和薯蓣皂甙元(diosgenin)为主要成分。从根茎中还分得4个约莫皂甙元的甾体皂甙。在研究国产野生薯蓣属植物化学成分的工作中,我们曾观察到一些薯蓣属植物的根茎长时间发霉后可生成表丝兰皂甙元(epi-smilagenin)和丝兰皂甙元酮(smilagenone)。这些皂甙元的存在造成薯蓣皂甙元产品的熔点降低,质     

研究生学位论文选题对培养质量的贡献

1970年代，药物化学制进入了全新时代。在新的时代背景下，药物化学研究生学位论文选题对培养质量有重要贡献。产权性、开放性和创新性是制约论文选题的三个基本元素，在这三元素中，创新性原则具有第一位重要性。指导教师在协调考虑研究内容、技术路线和研究目标的创新性时，总是把选题看作所在学科特定发展空间的特定事件、看作所在领域特定发展时段的特定事件、看作所在研究组生命延续特定步骤的特定事件。在确定论文选题时，指导教师应完成包括以拟定的技术路线实施拟定的研究内容可以构成的数据组、数据组如何独立及相互呼应作为论据为研究目标服务、正常情况下可以构成的创新、创新可以达到的杂志的IF值等在内的思考。     

The optimization test in the guinea pig in relation to other predictive sensitization methods

The allergenicity of various compounds was tested by means of the optimization procedure in the guinea-pig. Results with antibiotics, preservatives, fragrance raw materials and miscellaneous contactants are reported. Their relevance is critically discussed in relation to other animal sensitization methods (Draize, Bühler, open epicutaneous and maximization tests). Predictive animal tests are compared with those used in human allergy (Shelanski & Shelanski; maximization test). The importance of animal methods entailing the use of adjuvants is underlined.     

Glucose metabolism of oxidatively stressed human red blood cells incubated in plasma or medium containing physiologic concentrations of lactate,pyruvate and ascorbate

Red cells suspended in either defined medium or buffered plasma were oxidatively stressed by incubation in the presence of 1, 4-naphthoquinone-2-sulfonate at concentrations which caused less than 50% methemoglobin accumulation, stimulation of the hexose monophosphate shunt to less than 15% of capacity, and about a 30% increase in flux through glycolysis. Normal plasma concentrations of lactate and pyruvate in either defined medium or buffered plasma allowed increased contribution of reducing equivalents from glycolysis in response to oxidative stress. Increased utilization of reducing equivalents by the red cell was observed as increased accumulation of pyruvate, whereas accumulation of lactate represented storage of reducing equivalents. Exogenous lactate or pyruvate did not serve as a net electron source or sink since the total content in red cell suspensions of both lactate and pyruvate was increased during exposure to oxidative stress. If exogenous lactate had been used as a net source of reducing equivalents, the lactate concentration would have decreased during incubation of red cell suspensions. Plasma ascorbate or other constituents did not alter the qualitative response of glycolysis to oxidative stress (decreased lactate accumulation, increased pyruvate accumulation, and increased total flux through glycolysis), but plasma constituents did raise significantly the dose of oxidant agent required to elicit a given quantitative response. At levels of oxidative stress likely to be encountered in vivo, glycolysis and the hexose monophosphate shunt may be equal in importance as aerobic/antioxidant pathways.     

Varying effects of sulfhydryl nucleophiles on acetaminophen oxidation and sulfhydryl adduct formation

The effects of glutathione, cysteine, N-acetylcysteine, cysteamine, α-mercaptopropionylglycine and methionine on the NADPH-dependent metabolism and covalent binding of acetaminophen have been examined in mouse liver microsomal incubations. With the exception of methionine, all of the nucleophiles decreased covalent binding by forming adducts with the electrophilic metabolite of acetaminophen. The adducts were measured quantitatively by high pressure liquid chromatography. In contrast to glutathione, N-acetylcysteine and α-mercaptopropionylglycine, both cysteamine and cysteine in high concentrations also decreased covalent binding of acetaminophen through another mechanism, inhibition of the formation of the reactive acetaminophen metabolite. These results indicate that both inhibition of metabolite formation and detoxification of metabolite by sulfhydryl adduct formation are mechanisms that can be important in reducing acetaminophen toxicity in overdosed patients treated with these nucleophiles.     

Effects of physiologic concentrations of lactate, pyruvate and ascorbate on glucose metabolism in unstressed and oxidatively stressed human red blood cells

Glucose metabolism was studied in human red blood cells incubated in the presence of physiologic concentrations of ascorbate (0.1 mM) and/or lactate (2 mM) plus pyruvate (0.1 mM). The total flux through glycolysis, as measured by 14C-labeling of glycolytic intermediates, was increased about 15% by ascorbate, 30% by lactate plus pyruvate, and 40% by ascorbate plus lactate plus pyruvate. We found, however, that physiologic concentrations of ascorbate and/or lactate plus pyruvate had no effect on flux of glucose or recycling of pentoses through the hexose monophosphate shunt. Increased formation of lactate accounted for most of the observed increase in glycolysis with little change in pyruvate formation, indicating that the increased flux of reducing equivalents from glucose was stored as lactate rather than being consumed by red cell metabolism. In all experiments, there was a net increase with time in the absolute amount of both lactate and pyruvate in red cell suspensions, indicating that lactate or pyruvate present at zero time did not function as a stoichiometric source or sink for reducing equivalents. There was little effect on steady-state levels of ATP or 2,3-diphosphoglycerate. Equilibration of ascorbate between red cells and the medium was complete before the addition of 14C-labeled glucose to the medium. Glucose metabolism prevented net oxidation of ascorbate in the incubation medium. Physiologic concentrations of ascorbate, lactate and pyruvate appear to increase flux through glycolysis by increasing the turnover of ATP and/or 2,3-diphosphoglycerate. Red cells were exposed to mild oxidative stress by incubation with 0.27 mM 6-hydroxydopamine, 0.27 mM 6-aminodopamine, 0.13 mM 1,4-naphthoquinone-2-sulfonic acid or 0.27 mM phenylhydrazine. The metabolic response to oxidative stress was determined by measuring the formation of methemoglobin, pyruvate, lactate and CO2 in the presence and absence of physiologic concentrations of lactate, pyruvate and ascorbate. Lactate, pyruvate and ascorbate had no effect on the net methemoglobin accumulation but rather on the distribution of the metabolic sources of reducing equivalents and on the flux of reducing equivalents to oxygen. Physiologic lactate and pyruvate allowed increased flow of reducing equivalents from glycolysis to methemoglobin and ultimately oxygen without the necessity of increased flux through glycolysis. This was accomplished by a decrease in the ratio of newly formed lactate to newly formed pyruvate with no increase in total lactate plus pyruvate.(ABSTRACT TRUNCATED AT 400 WORDS)