狭叶藜芦中活性成分的化学研究 Ⅲ.β_1-查茄碱的结构和狭叶藜芦碱丙、碱丁的部分结构研究

自狭叶藜芦中首次分离出β_1-查茄碱和两个新碱狭叶藜芦碱丙、碱丁。根据光谱数据和衍生物的制备,测定了β_1-查茄碱的结构,初步推定了狭叶藜芦碱丙和碱丁的部分结构。     

狭叶藜芦中活性成分的化学研究——Ⅱ.新降压活性成分狭叶藜芦碱甲的结构研究

自狭叶藜芦中分离出一种新碱狭叶藜芦碱甲,根据光谱数据和衍生物的制备确定其结构。药理实验表明,该化合物有较强且持久的降压和减慢心律的生理活性。     

狭叶藜芦中活性成分的化学研究——Ⅱ.新降压活性成分狭叶藜芦碱甲的结构研究

自狭叶藜芦中分离出一种新碱狭叶藜芦碱甲,根据光谱数据和衍生物的制备确定其结构。药理实验表明,该化合物有较强且持久的降压和减慢心律的生理活性。     

狭叶藜芦中活性成分的化学研究——Ⅰ.狭叶藜芦碱乙的结构以及其它成分的鉴定

自狭叶藜芦中分离出十四个化合物(Ⅴ₁～Ⅴ₁₄),其中七个分别鉴定为β-谷甾醇(Ⅴ₁),木蜡酸(Ⅴ₂),胡萝卜甙(Ⅴ₅),藜芦酰棋盘花胺(Ⅴ₇),当归酰棋盘花胺(Ⅴ₉),棋盘花胺(Ⅴ₁₁),介藜芦胺(Ⅴ₁₃),并推定Ⅴ₈为etioline,本文报道新生物碱狭叶藜芦碱乙(Ⅴ₆)的结构测定以及八个已知化合物的鉴定工作。     

WB852-β环糊精包合物的研究

环糊精(cyclodextrin,CD)的发现已近百年,其基础和应用方面的研究至今仍相当活跃,由于环糊精优良的理化性质和生物学特性,可使不稳定的药物包含于环糊精分子内,因此在某种程度上切断药物分子与周围化学环境的联系,而提高药物的稳定性。本文就抗癌抗炎新药WB_(852)~((2,3))的环糊精包合物进行研究,以期提高其化学稳定性。     

联合测定非霍奇金淋巴瘤患者血清乳酸脱氢酶及β2-微球蛋白的临床意义

目的 探讨血清乳酸脱氢酶(LDH)和β₂-微球蛋白(β₂-MG)在非霍奇金淋巴瘤(NHL)患者中的水平及临床意义。方法 回顾性分析2009年1月至2014年1月住院治疗的280例初治NHL患者治疗前后血清LDH及β₂-MG动态水平,并组成A组(研究组),另选取门诊同期进行健康体检者270例组成B组(对照组),按淋巴瘤国际预后指数(IPI)评分分为低危及中低危组(0~2分)95例,中高危及高危组(3~5分)185例,对比分析A组和B组血清中LDH及β₂-MG水平。结果 A组血清LDH及β₂-MG水平范围为488.11±222.13U/L和4.48±1.21 mg/L;B组血清LDH及β₂-MG水平范围为116.05±106.51 U/L和1.61±0.37 mg/L;两组比较,A组明显高于B组(P < 0.05);LDH和β₂-MG水平在Ⅲ~Ⅳ期患者高于Ⅰ~Ⅱ期患者(P < 0.05),有全身症状组与无全身症状组以及IPI(3~5分)组与(0~2分)组比较,前者LDH及β₂-MG的范围为(573.71±257.28) U/L和(5.75±0.81) mg/L,后者LDH及β₂-MG的范围为352.81±188.02 U/L和2.8±0.58 mg/L,两者比较,前者明显高于后者(P < 0.05);A组患者治疗后血清中LDH及β₂-MG水平明显低于治疗前,差异均有统计学意义(P < 0.05);血清LDH及β₂-MG水平正常的NHL患者临床疗效优于血清LDH及β₂-MG水平异常患者。结论 血清LDH及β₂-MG水平可作为NHL的辅助诊断及患者分型、分期、疗效的评估和预后判断的一个有效指标。     

辛伐他汀联合辅酶Q10对慢性心衰大鼠心肌转化生长因子β1表达的影响

目的 探讨辛伐他汀联合辅酶Q₁₀对慢性心力衰竭大鼠心肌转化生长因子β₁(transforming growth factor-β₁,TGF-β₁)表达的影响。方法 利用腹主动脉缩窄法制作SD大鼠慢性心力衰竭模型,随机分为模型组、辛伐他汀组、辅酶Q₁₀组、辛伐他汀+辅酶Q₁₀组,另设假手术组,每组8只大鼠,观察各组大鼠血流动力学参数(左室舒张末压、±dp/dt_max) 和左心室心肌组织病理学改变,SP免疫组化检测各组大鼠左心室心肌中TGF-β₁表达情况。结果 与模型组相比,辛伐他汀组、辅酶Q₁₀组和辛伐他汀+辅酶Q₁₀组左室舒张末压显著降低(P<0.01),±dp/dt_max显著升高(P<0.01),左心室肌TGF-β₁阳性表达水平显著降低(P<0.01);联合用药较辛伐他汀组、辅酶Q₁₀改变更为显著(P<0.05)。结论 辛伐他汀与辅酶Q₁₀联合应用较两药单独应用改善心衰大鼠心功能、抑制心室重塑和减少TGF-β₁表达作用明显。     

氟伐他汀对糖尿病肾病患者血清、尿转化生长因子β1的影响及意义

目的观察氟伐他汀对糖尿病肾病（DN）患者血、尿转化生长因子β₁（TGF-β₁）的影响，探讨氟伐他汀治疗DN的机制。方法60例血脂正常的2型糖尿病患者根据尿微量白蛋白排泄率（UAER）分为正常白蛋白尿组（A组）、微量白蛋白尿组（B组）、临床蛋白尿组（C组），分别检测血糖、甘油三酯（TG）、胆固醇（TC）、低密度脂蛋白（LDL）、血肌酐（Cr）UAER、血TGFβ₁、尿TGFβ₁。A、B、C组随机分为氟伐他汀治疗组和常规治疗组。结果糖尿病各组UAER、血、尿TGFβ1水平均显著增高。相关分析表明血TGFβ₁、尿TGFβ₁水平与Cr、UAER呈正相关。氟伐他汀治疗后UAER、血TGFβ₁、尿TGFβ₁均显著降低。结论氟伐他汀对DN患者肾脏有保护作用，这种作用可能与其抑制DN患者TGFβ₁产生有关。     

一个新型α1-去甲肾上腺素受体的光亲和放射性碘探针的母体化合物的合成

A new and high-yielding procedure was described for the synthesis of 4-amino-6,7-dimethoxy-2[4-[4 (4-aminophenyl) butanoyl]-1-piperazinyl]-quinazoline Ⅶ, the key intermedi-ate for the newly designed potential α₁-AR affinity/photoaffinity probes Ⅷa/Ⅸa.     

人参皂苷Rb1抑制β淀粉样蛋白25-35诱导的皮层神经元tau蛋白过度磷酸化

目的探讨人参皂苷Rb1对凝聚态β-AP_25-35诱导的胎鼠皮层神经元tau蛋白过度磷酸化的影响及其可能的作用机制。方法通过蛋白免疫印迹法和免疫细胞化学染色法检测神经元tau蛋白磷酸化水平、总tau蛋白水平和糖原合成酶3β(GSK-3β)的蛋白表达水平。结果凝聚态β-AP_25-35(20 μmol·L^-1)作用于皮层神经元12 h，tau蛋白磷酸化水平和总tau蛋白水平均增高，同时GSK-3β蛋白表达也增多。用人参皂苷Rb1或GSK-3β特异性抑制剂氯化锂预处理后，凝聚态β-AP_25-35诱导的tau蛋白的过度磷酸化受到明显抑制，同时GSK-3β的表达也降低。结论人参皂苷Rb1可通过抑制GSK-3β的表达来抑制凝聚态β-AP_25-35诱导的皮层神经元tau蛋白的过度磷酸化。     

Studies on electroencephalogram (EEG) in rats suggest that moderate doses of cocaine ord-amphetamine activate D1 rather than D2 receptors

The effects of cocaine andd-amphetamine, two psychomotor stimulant drugs with pronounced addictive properties, on the electroencephalogram (EEG) of rats were studied by telemetric recordings from the skull in non-anesthetized, freely moving rats. The electrocorticogram (ECoG) was recorded. Both cocaine (10 mg/kg IP) andd-amphetamine (0.4 mg/kg IP) produced a desynchronization, characterized by a general lowering in power in all of the frequency bands. These effects of both drugs were mimicked by the selective agonist at D₁ receptors SK&F 38393 (3 mg/kg SC) and were reversed by the antagonist at D₁ receptors SCH 23390 (0.2 mg/kg IP) but not influenced by haloperidol (0.1 mg/kg IP) in a dose which is likely to block D₂ rather than D₁ receptors. These doses of cocaine ord-amphetamine did not produce stereotyped behaviour and slight, if any, increases in locomotor activity only. Large doses of cocaine (30 mg/kg IP) ord-amphetamine (4 mg/kg IP) produced stereotyped behaviour and alterations in EEG which are, based on previous own studies, characteristic for additional stimulation of D₂ receptors. This was manifest in a selective increase in power of the alpha-1 band. A similar effect was also produced by the agonist both at D₁ and D₂ receptors, apomorphine (0.5 mg/kg SC). These results suggest that moderate, but probably rewarding doses of cocaine ord-amphetamine mainly activate D₁ dopamine receptors. This activation might be relevant for the rewarding properties of these drugs.     

槲寄生化学成分的研究——Ⅷ.2,3-丁二醇单葡萄糖甙的分离和结构

From the ethanol extract of Viscum coloratum (Kom.) Nakai , a giucoside ofaliphatic diol and three other glucosides were isolated. Based on chemical and spectroscopic analysis,the structures have been elucidated as 2-β-D- glucosyl-3- methylpropanol (Ⅷ), syringin (Ⅸ),eleatheroside E(Ⅹ) and syringenin-4'-O-D-apiosylglucoside (Ⅺ). Ⅷ is a new glucoside of aliphaticdiol and named 3-β-D-glucopyranosyloxy-butanol-2. Three other compounds (Ⅸ～-Ⅺ) were foundfor the first time in this plant.     

Analysis of the beta 1 and beta 2 adrenoceptor interactions of the partial agonist, clenbuterol (NAB365), in the rat jugular vein and atria

Summary The potent bronchodilator, clenbuterol, was compared to other beta adrenoceptor agonists with regard to affinity and efficacy for interaction with beta₁ and beta₂ adrenoceptors in the rat jugular vein and atria. Clenbuterol was a potent partial beta adrenoceptor agonist in both tissues based on the following observations: 1. Maximal relaxation of the jugular vein and increases in atrial rate to clenbuterol were less than maximal responses to other beta adrenoceptor agonists. 2. Clenbuterol antagonized responses to the stronger agonist, isoproterenol, in both tissues and 3. the equilibrium dissociation constant for clenbuterol approximated the ED₅₀ concentration for vascular relaxation and increase in atrial rate, a characteristic of some, but not all, partial agonists. Relative to other beta adrenoceptor agonists, clenbuterol showed high affinity toward both beta₁ and beta₂ adrenoceptors and selectivity toward beta₂ adrenoceptors. Equilibrium dissociation constants were 38 and 6.3 nM for beta₁ and beta₂ adrenoceptors, respectively. The high affinity of clenbuterol toward beta₁ and beta₂ adrenoceptors was coupled to a low relative efficacy of clenbuterol to activate either beta₁ or beta₂ adrenoceptors. Most beta₂ adrenoceptor agonists such as isoproterenol or salbutamol require approximately 1–3% adrenoceptor occupation for 40–50% relaxation of the jugular vein whereas clenbuterol required approximately 100% adrenoceptor occupation for a similar response. Thus, based on our analysis, the high agonist potency of clenbuterol results primarily from the high affinity toward beta adrenoceptors rather than efficient activation of the adrenoceptor as occurs with isoproterenol or salbutamol.     

Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population

Objective The frequency of functionally important mutations and alleles of genes coding for xenobiotic metabolizing enzymes shows a wide ethnic variation. However, little is known of the frequency distribution of the major allelic variants in the Russian population.Methods Using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) genotyping assays and the real-time PCR with fluorescent probes, the frequencies of functionally important variants of the cytochromes P₄₅₀ (CYP) 2C9, 2C19, 2D6, 1A1 as well as arylamine N-acetyltransferase 2 (NAT2) and P-glycoprotein (MDR1) were determined in a sample of 290 Russian volunteers derived from Voronezh area.Results CYP2C9*2 and *3 alleles were found with allelic frequencies of 10.5% and 6.7%, respectively. The novel intron-2 T>C mutation at exon 2 +73 bp occurred in 24.8% of alleles. CYP2C19*2 and *3 alleles occurred in 11.4% and 0.3%, respectively. Six persons (2.1%) carried two of these CYP2C19 alleles responsible for poor metabolizing activity. Of all subjects, 5.9% were CYP2D6 poor metabolizers, whereas 3.4% were addressed to ultra-rapid metabolizers (CYP2D6*1×2/*1). The CYP1A1*2A allele was found in 4.7%, *2B in 5.0%, *4 in 2.6%, and the 5-mutations –3219C>T, –3229G>A, and the novel –4335G>A in 6.0%, 2.9% and 26.0% of alleles, respectively. Genotyping of eight different single nucleotide polymorphisms in the NAT2 gene provided in 58.0% a genotype associated with slow acetylation. The MDR1 triple variants G2677T and G2677A in exon 21 had an allelic frequency of 41.9% and 3.3%, respectively, and the variant C3435T in exon 26 one of 54.3%. Frequencies of functionally important haplotypes were calculated.Conclusion The overview of allele distribution of important xenobiotic-metabolizing enzymes among a Russian population shows similarity to other Caucasians. The data will be useful for clinical pharmacokinetic investigations and for drug dosage recommendations in the Russian population.     

Pharmacology of cloned human 5-HT1D receptor-mediated functional responses in stably transfected rat C6-glial cell lines: further evidence differentiating human 5-HT1D and 5-HT1B receptors

This study was undertaken to investigate the pharmacology of human serotonin (5-HT)_1D receptor sites by measuring two functional cellular responses, inhibition of forskolin-stimulated cAMP formation and promotion of cell growth, using transfected rat C6-glial cell lines and a broad series of 5-HT receptor agonists. Stable and separate transfection of a pcDNA3 or pRcRSV plasmid, each containing a cloned human 5-HT_1D receptor gene, in rat C6-glial cells was confirmed with RT PCR of 5-HT_1D receptor mRNA and radioligand binding with [³H] 5-carboxamidotryptamine (5-CT) and [³H] sumatriptan. The 5-HT_1D receptor density was 350 and 1050 fmol/mg protein for the C6-glial/pcDNA3/5-HT_1D and C6-glial/pRcRSV/5-HT_1D cell line, and forskolin (100 M)-induced cAMP formation was inhibited by 45 and 78% in the presence of 1 M 5-HT, respectively. A comparison of the intrinsic agonist activities for sixteen 5-HT receptor ligands with their corresponding binding affinities for the human 5-HT_1D receptor site showed similar results for both cell lines with the exception of the partial agonist m-trifluoro-phenyl-piperazine (TFMPP). Three classes of compounds were observed: 1. efficacious agonists, such as 5-CT, 5-methoxytryptamine, 5-HT, sumatriptan, bufotenine, 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole (RU 24,969), tryptamine and 8-hydroxy-2(di-n-propilamino)tetralin (8-OH-DPAT), with agonist potency close to their binding affinity; 2. the partial agonists metergoline, 7-trifluoromethyl-4(4-methyl-l-piperazinyl)-pyrolo-(1,2-a) quinoxaline (CGS 12066B), 1-naphthylpiperazine and 2-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide (GR 127,935) with marked intrinsic agonist activity but at concentrations higher than their binding affinity; and 3. the silent antagonists ritanserin, ketanserin and methiothepin, apparently free of intrinsic agonist activity, with antagonist potency close to their binding affinity. The cAMP data were further supported by the observed promotion of cell growth by stimulation of both transfected cell lines with sumatriptan under serum-free conditions; half-maximal stimulation was obtained at 4.4 nM (C6-glial/pcDNA3/5-HT_1D) fully in agreement with its EC₅₀-value (5.7 nM) for inhibition of cAMP formation. This growth promoting effect was antagonised by 1 M methiothepin and not observed in pcDNA3-plasmid-transfected and non-transfected C6-glial cells. A comparative study with a C6-glial/pcDNA3/5-HT_1B cell line expressing a similar amount of cloned human 5-HT_1B receptors (B _max: 360 fmol/mg protein) showed almost no intrinsic agonist activity for metergoline, 1-naphtylpiperazine and GR 127,935. Together with the 5-HT_1D receptor binding selectivity and antagonist activity of ketanserin and ritanserin, the findings define important pharmacological differences between cloned human 5-HT_1D and 5-HT_1B receptor sites.     

Differential effects of fluphenazine-N-mustard,on calmodulin activity and on D1 and D2 dopaminergic responses

Fluphenazine-N-mustard (FNM) has been shown to irreversibly block dopaminergic receptor sites and inhibit certain dopaminergically-mediated behaviors. In this study we measured whether FNM has any differential effects on D₁ and D₂ dopaminergic events. Accordingly, we examined the relative effects of FNM on rotational behavior induced by SKF 38393 (D₁ agonist) and Ly 171555 (D₂ agonist) in mice with unilateral, 6-hydroxydopamine-induced lesions of the striatum and the effects of FNM on the binding of [³H]Sch 23390 (D₁ ligand) and [³H]spiroperidol (D₂ ligand) to mouse striatal membranes. FNM inhibited rotational behavior induced by Ly 171555 at doses 10-fold lower than those required to block rotations induced by SKF 38393 (ID₅₀ values: Ly 171555=1.8 mole/kg, IP; SKF 38393=16 mole/kg, IP). The inhibitory effect of high doses of FNM (20 mole/kg) on rotational behavior was overcome by increasing the dose of SKF 38393 and apomorphine, a nonselective dopaminergic agonist. By contrast, the inhibitory effect of FNM was not overcome by Ly 171555, even when given in doses more than 100 times its ED₅₀. Using striatal homogenates in vitro, FNM inhibited the specific binding of [³H]spiroperidol at concentrations about 10-fold lower than those required to inhibit the binding of [³H]Sch 23390 (IC₅₀ values: [³H]spiroperidol=90 nM; [³H]Sch 23390=840 nM). Considerably higher concentrations of FNM were needed to irreversibly inhibit calmodulin activity in striatal homogenates (IC₅₀=10 M). In vivo, FNM inhibited the binding of [³H]spiroperidol measured ex vivo (ID₅₀=4 mole/kg), but did not inhibit the binding of [³H]Sch 23390, even when given in doses as high as 100 mole/kg. These studies indicate that FNM was approximately 10 times more potent at inhibiting D₂-than D₁-mediated behavior and at displacing D₂ versus D₁ ligands and suggest that FNM may be useful for studying and differentiating D₂- and D₁-mediated events.     

中药商陆有效成分的研究——Ⅱ.商陆皂甙戊、己的分离与鉴定

从商陆科(Phytolaccaceae)植物商陆(Phytolacca esculenta Van Houtte)中分离得到四种结晶,根据化学性质和光谱(UV,IR、NMR,¹³CNMR和MS)分析,确定结晶Ⅰ为2-羟基商陆酸(2-hydroxyl esculentic acid),结晶Ⅱ为3-O-β-D-吡喃木糖-2-羟基商陆酸,称为商陆皂甙戊,结晶Ⅲ为3-O-(β-D-吡喃葡萄糖-β-D-吡喃木糖)_1→4-2-羟基商陆酸,称为商陆皂甙己;结晶Ⅳ的结构正在鉴定中。2-羟基商陆酸有抗炎作用。商陆皂甙戊在本植物中系首次分得,商陆皂甙己为新化合物。     

中药附子成分研究——Ⅰ.去甲猪毛菜碱(salsolinol)的分离及其结构测定

From the lateral root of Aconitum carmichaeli Debx., Fu-Zi, which has long been used as one of the most important herbs as a heart stimulant in Chinese medicine, a cardiac and hypertensive principle Ⅱ was isolated and identified as salsolinol, 1-methyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, from its spectral data and by comparison with synthesized authentic sample.