前庭刺激对红细胞和脑乙醚胆硷酯酶活性的影响

观察了２１名海员在海上航行平稳和颠簸明显时期红细胞乙酰胆硷酯酶活性的变化。结果表明颠簸所造成的前庭刺激可引起该酶活性降低（Ｐ＜０．０５）。动物实验发现，大鼠接受正负交变加速度旋转刺激后，红细胞和丘脑、延脑内乙酰胆硷酯酶活性均明显降低（Ｐ＜０．０１）。结果表明，人和动物机体受到异常前庭刺激时红细胞与中枢某些部位的乙酰胆硷酯酶活性发生的变化类似。     

[1—~3H]-1,2,2-三甲基丙氧基甲膦酰氟及其衍生物的合成

由于1,2,2-三甲基丙氧基甲膦酰氟是一个强烈的胆硷酯酶抑制剂,而其膦酰化的胆硷酯酶又极易脱落1,2,2-三甲基丙基,变成难以重活化的“老化”酶,因此,需要研究其反应机制。本文合成了[1-~3H]-1.2.2-三甲基丙氧基甲膦酰氟(Ⅰ)及其衍生物甲膦酸(O-[1-~3H]-1,2,2-三甲基丙基-O′-对-硝基     

千里光B硷的中枢抗胆硷能作用和抗毒效应

峨眉千里光(Senecio fuberi Hemsl)是筛选出来的防治有机磷神经毒有效的中草药。其有效结晶为饱和及不饱和的单环双酯双稠吡咯啶生物硷(Pyrollizidine alkaloid)。饱和者无肝毒,称之为千里光B硷。经分析其理化性质及结构式一如自高加索红苦菜提出的红苦菜硷。苏联药典将红苦菜硷列为一种作用于外周的抗胆硷能药。文献中既未看到红苦菜硷有中枢性抗胆硷能作用,更未见用它来防治神经毒的报导。     

茜草双酯的β-环糊精包合物

目的 考察茜草双酯与β-环糊精(β-CD)及羟丙基-β-环糊精(HP-β-CD)的包合作用.方法 采用紫外分光光度法测定茜草双酯的含量,相溶解度法研究了2种环糊精(CDs)对茜草双酯的包合作用、增溶作用及包合过程中热力学参数变化.结果 茜草双酯的溶解度随着CDs浓度的增加而呈线性增加,相溶解度图呈AL-型,茜草双酯与2种CDs在包合过程中的吉布斯自由能变化(△G)、焓变(△H)均为负值.茜草双酯与β-CD在包合过程中的熵变(△S)为正值,而与HP-β-CD包合过程中的△S为负值.结论 茜草双酯与2种CDs在水溶液中均可自发形成1∶1(物质的量的比例)可溶性包合物,从而增加其溶解度.选择适宜的包合温度有利于包合过程的进行.     

Effect of single-nucleotide polymorphisms -705T/C and -603T/A in P1 promoter region of human insulinlike growth factor-Ⅰ Gene on promoter activity

目的 探讨人胰岛素样生长因子-I(ICF-I)基因P1启动子区域单核苷酸多态性(SNP)-Y05T＞C和-603T＞A对启动子活性的影响.方法 招募152名健康志愿者参与本研究,取静脉血样品,使用基因组DNA提取试剂盒从血样中提取全基因组DNA.通过限制片段长度多态性分析(RFLP),对每名志愿者的SNP-705T＞C和-603T＞A进行基因分型,统计各基因型的频率.使用PHASE v2.1软件程序分析P1启动子单体型的类型和频率.通过荧光素酶报告基因测定不同P1启动子单体型的活力差异.结果 成功提取了每名志愿者的全基因组DNA并测定了SNP -705T＞C和-603T＞A的基因型.基因型-70ST/T、705T/C、-705C/C的频率分别与-603T/T、-603T/A、-603A/A相同,分别为43.4％、45.4％、11.2％.等位基因-705T、-705C的频率分别与-603T、-603A相同,分别为66.1％、33.9％.SNP -705T＞C和-603T＞A之间存在完全的连锁不平衡,其组成的P1启动子单体型只有-705T/-603T和-705C/-603A两种,频率分别为66.1％和33.9％.报告基因分析结果表明,P1启动子-705C/-603A单体型的活力显著高于-705T/-603T单体型.结论 人IGF-Ⅰ基因P1启动子区域SNP -705T/C和-603T/A能够影响P1启动子的活性.     

灭吐灵对人体血浆胆碱酯酶的影响

体外试验已证实灭吐灵可明显抑制人体血浆胆硷酯酶活性。我院对40例病人静注灭吐灵前后进行了血浆胆硷酯酶活性测定,现将结果报告如下。 选40例肝肾功能正常的择期手术病人,年龄16～59岁,体重46～80kg。其中男23例,女17例。包括胆囊、胃、髋关节、上下肢等手术。术前常规     

N-取代氨乙基硫代磷酸酯和硫代硫酸酯的合成

本文报道了S-2-(芳氧烷氨基)-乙基,S-2-(芳基烷氨基)-乙基硫代磷酸酯和硫代硫酸酯的合成.所台成的6个化合物在小鼠上进行了辐射防护作用的研究.初筛结果表明,部分化合物有不同程度的防护作用,其中S-2-(4-(3-甲基-5-甲氧基苯基)-丁氨基)-乙基硫代硫酸酯(8a)效果最好.     

气道平滑肌神经支配的新见解

根据以往的认识,气道平滑肌完全是受胆硷能和肾上腺素能两种神经的支配.胆硷能神经兴奋时其神经末梢释放乙酰胆硷使气道平滑肌收缩,肾上腺素能神经兴奋时则释放肾上腺素类物质作用于气道平滑肌β受体使其舒张.正常生理情况下,两者处于平衡状态,以保持适度的肌张力.近年由于气道内第三神经系统(即非肾上腺素能非胆硷能神经,Non-adrenergic,non-cholinergic,简称NANC神经)的发现,对上述观点提出了新的见解.本文就气道平滑肌内NANC神经的发现、NANC神经的递质、NANC神经的生理学作用及其与临床的关系概述如下.     

5-单硝酸异山梨酯缓释片在健康中国人体内的药代动力学及相对生物利用度

 目的评价5-单硝酸异山梨酯的缓释效果及与普通片相比的生物等效性.方法采用反相高效液相法测定血浆中5-单硝酸异山梨酯的含量,用3 P 97软件处理数据.结果单次及多次口服5-单硝酸异山梨酯缓释片后的相对生物利用度分别为107%和102%;单次给药后缓释片和普通片的浓度值分别为(573.24±163.99)mg/ml和(892.06±329.13)mg/ml,时间值分别为(3.54±0.50(h和(1.57±0.32)h;多次给药达稳态后,缓释片和普通片峰谷波动系数分别为(1.55±0.16)和(1.83±0.12).结论5-单硝酸异山梨酯缓释片具有缓释效果,缓释片与普通片相比具有生物等效性.     

甲氧酶抑宁的终板受体增敏作用及其对抗梭曼中毒的横纹肌麻痹

A.Arnold等合成了一系列具有抗胆硷酯酶作用的二羧酸氨基烃酰胺的季铵盐(Quaternary salts of amino alkyamides of dicarboxylic acid)。酶抑宁(Win8077、Mytelase Ambenoniurn)是代表性的高效化合物,用于治疗重症肌无力。经实验证明:酶抑宁的药理作用与抗胆硷酯酶强度无平行关系。     

Spectroscopic and crystallographic characterization of two cathinone derivatives: 1-(4-fluorophenyl)-2-(methylamino)pentan-1-one (4-FPD) hydrochloride and 1-(4-methylphenyl)-2-(ethylamino)pentan-1-one (4-MEAP) hydrochloride

Purpose

In this study, we performed identification and physicochemical characterization of two cathinone derivatives, 4-FPD and 4-MEAP, found in market-available materials.

Methods

The compounds were characterized by electrospray ionization ion trap mass spectrometry (MS) in MS² and MS³ modes, gas chromatography–MS, infrared, Raman and ultraviolet-visible spectroscopies, X-ray crystallography, differential scanning calorimetry and nuclear magnetic resonance spectroscopy.

Results

We could obtain detailed and comprehensive physicochemical characterization of 4-FPD and 4-MEAP—new cathinone derivatives available on the designer drugs market.

Conclusions

Dynamic growth in the number of psychoactive substances available on the designer drug markets makes it compulsory to obtain analytical data allowing unequivocal identification of these drugs in the fastest possible way. In this study we presented analytical data useful in quick identification of the investigated compounds.

     

Identification and characterization of novel synthetic cannabinoid ethyl-2-(1-(5-fluoropentyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate (5F-EDMB-PICA)

Forensic Toxicology - The purpose of the current study was to evaluate an analytical characterization of a novel synthetic cannabinoid...     

In vivo evaluation of [123I]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine,an iodinated SPECT tracer for imaging the P-gp transporter

IntroductionP-glycoprotein (P-gp) is an energy-dependent transporter that contributes to the efflux of a wide range of xenobiotics at the blood–brain barrier playing a role in drug-resistance or therapy failure. In this study, we evaluated [¹²³I]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine ([¹²³I]-FMIP) as a novel single photon emission computed tomography (SPECT) tracer for imaging P-gp at the brain in vivo.MethodsThe tissue distribution and brain uptake as well as the metabolic profile of [¹²³I]-FMIP in wild-type and mdr1a (?/?) mice after pretreatment with physiological saline or cyclosporin A (CsA) (50 mg/kg) was investigated. The influence of increasing doses CsA on brain uptake of [¹²³I]-FMIP was explored. μSPECT images of mice brain after injection of 11.1 MBq [¹²³I]-FMIP were obtained for different treatment strategies thereby using the Milabs U-SPECT-II.ResultsModulation of P-gp with CsA (50 mg/kg) as well as mdr1a gene depletion resulted in significant increase in cerebral uptake of [¹²³I]-FMIP with only minor effect on blood activity. [¹²³I]-FMIP is relative stable in vivo with >80% intact [¹²³I]-FMIP in brain at 60 min p.i. in the different treatment regiments. A dose-dependent sigmoidal increase in brain uptake of [¹²³I]-FMIP with increasing doses of CsA was observed. In vivo region of interest-based SPECT measurements correlated well with the observations of the biodistribution studies.ConclusionsThese findings indicate that [¹²³I]-FMIP can be applied to assess the efficacy of newly developed P-gp modulators. It is also suggested that [¹²³I]-FMIP is a promising SPECT tracer for imaging P-gp at the blood-brain barrier.     

N,N-dimethyl-2-(2-amino-4-(18)F-fluorophenylthio)-benzylamine (4-(18)F-ADAM): an improved PET radioligand for serotonin transporters.

There has been considerable interest in the development of PET radioligands that are useful for imaging serotonin transporter (SERT) in the living human brain. For the last decade, (11)C-(+)McN5652 has been the most promising PET agent for studying SERT in humans. However, this agent has some limitations. Recently, a new promising SERT PET radioligand, 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile, has been reported. We recently reported the synthesis of a new (18)F-labeled SERT PET radioligand, N,N-dimethyl-2-(2-amino-4-(18)F-fluorophenylthio)benzylamine (4-(18)F-ADAM), which may have advantages over (11)C-labeled radioligands. The purpose of this study was to evaluate this newly developed (18)F-labeled PET radioligand as a promising agent for studying SERT in the living human brain. METHODS: This agent was evaluated by studying its in vitro binding to different monoamine transporters, its in vivo biodistributions in rats, its integrity and pharmacologic profiles in rat brain, and its distribution in a female baboon brain. RESULTS: In vitro binding assays showed that 4-F-ADAM displayed high affinity to SERT sites (inhibition constant = 0.081 nmol/L, using membrane preparations of LLC-PK1 cells expressing the specific transporter) and showed more than 1,000- and 28,000-fold selectivity for SERT over norepinephrine transporter and dopamine transporter, respectively. Biodistribution of 4-(18)F-ADAM in rats showed a high initial uptake and slow clearance in the brain (2.13%, 1.90%, and 0.95% injected dose per organ at 2, 30, and 60 min after intravenous injection, respectively), with the specific binding peaking at 2 h after injection (hypothalamus/cerebellum = 12.49). The uptake in blood, muscle, lung, kidney, and liver was also initially high but cleared rapidly. The radioactivity in the femur increases with time for 4-(18)F-ADAM, indicating that in vivo defluorination may occur. In vivo metabolism studies in rats showed that 4-(18)F-ADAM was not metabolized in rat brain (>96% of radioactivity was recovered as parent compound at 1 h after injection). However, it metabolized rapidly in the blood. Less than 7% of the radioactivity recovered from plasma was the parent compound, with the majority of radioactivity in the plasma not extractable by ethyl acetate. Blocking studies showed significant decreases in the uptake of 4-(18)F-ADAM in the brain regions (hypothalamus, hippocampus, and striatum) where SERT concentrations are high when rats were pretreated with (+)McN5652 (2 mg/kg 5 min before intravenous injection of 4-(18)F-ADAM). However, changes in the uptake of 4-(18)F-ADAM in these brain regions were less significant when rats were pretreated with either methylphenidate or nisoxetine. The baboon study showed that uptake of 4-(18)F-ADAM in the midbrain peaked at approximately 1 h after injection and then declined slowly. The ratios of the radioactivity in the midbrain to that in the cerebellum (where the concentration of SERT is low) at 2 and 3 h after injection were 3.2 and 4.2, respectively. CONCLUSION: 4-(18)F-ADAM is suitable as a PET radioligand for studying SERT in the living brain. Further characterization of this new radioligand in humans is warranted.     

Nicotinic α4β2 receptor imaging agents. Part IV. Synthesis and Biological Evaluation of 3-(2-(S)-3,4-dehydropyrrolinyl methoxy)-5-(3′-18F-Fluoropropyl)pyridine (18F-Nifrolene) using PET

Imaging agents for nicotinic α4β2 receptors in the brain have been under way for studying various CNS disorders. Previous studies from our laboratories have reported the successful development of agonist, ¹⁸F-nifene. In attempts to develop potential antagonists, ¹⁸F-nifrolidine and ¹⁸F-nifzetidine were previously reported. Further optimization of these fluoropropyl derivatives has now been carried out resulting in 3-(2-(S)-3,4-dehydropyrrolinylmethoxy)-5-(3′-Fluoropropyl)pyridine (nifrolene) as a new high affinity agent for nicotinic α4β2 receptors. Nifrolene in rat brain homogenate assays – labeled with ³H-cytisine – exhibited a binding affinity of 0.36 nM. The fluorine-18 analog, ¹⁸F-nifrolene, was synthesized in approximately 10%–20% yield and specific activity was estimated to be > 2000 Ci/mmol. Rat brain slices indicated selective binding to anterior thalamic nuclei, thalamus, subiculum, striata, cortex and other regions consistent with α4β2 receptor distribution. This selective binding was displaced > 90% by 300 μM nicotine. Thalamus to cerebellum ratio (> 10) was the highest for ¹⁸F-nifrolene with several other regions showing selective binding. In vivo rat PET studies exhibited rapid uptake of ¹⁸F-nifrolene in the brain with specific retention in the thalamus and other brain regions while clearing out from the cerebellum. Thalamus to cerebellum ratio value in the rat was > 4. Administration of nicotine caused a rapid decline in the thalamic ¹⁸F-nifrolene suggesting reversible binding to nicotinic receptors. PET imaging studies of ¹⁸F-nifrolene in anesthetized rhesus monkey revealed highest binding in the thalamus followed by regions of the lateral cingulated and temporal cortex. Cerebellum showed the least binding. Thalamus to cerebellum ratio in the monkey brain was > 3 at 120 min. These ratios of ¹⁸F-nifrolene are higher than measured for ¹⁸F-nifrolidine and ¹⁸F-nifzetidine. ¹⁸F-Nifrolene thus shows promise as a new PET imaging agent for α4β2 nAChR.     

The synthesis and evaluation of radioiodinated 14-(iodophenyl)-3-(R,S)methyltetradecanoic acid

Radiohalogenated fatty acids (FA) labelled with gamma-emitting isotopes have a potentially important application in studies of impaired myocardial perfusion and metabolism. Evaluation of straight-chain fatty acids radiolabelled in different positions on the FA chain has been reported by many groups. In this paper we extended our recent studies using the betamethyl branched-chain fatty acid. The synthesis, labelling and preliminary evaluation of 131I- and 123I-14-(iodophenyl)-3-(R,S)methyltetradecanoic acid (I-PBMTA) are reported. This radiolabel concentrates in the mouse myocardium with 16% injected dose g-1 and 11% injected dose g-1 at 15 and 30 min, respectively. The images of the canine heart postinjection indicate a high myocardial extraction of the label with activity retained over an hour. The rate of washout of the activity from the heart was very low. This analogue is a potential agent for myocardial imaging studies.     

(R)-N-Methyl-3-(3-(125)I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

Alterations in serotonin and norepinephrine neuronal functions have been observed in patients with major depression. Several antidepressants bind to both serotonin transporters and norepinephrine transporters (NET). The ability to image NET in the human brain would be a useful step toward understanding how alterations in NET relate to disease. In this study, we report the synthesis and characterization of a new series of derivatives of iodonisoxetine, a known radioiodinated probe. The most promising, (R)-N-methyl-3-(3-iodopyridin-2-yloxy)-3-phenylpropylamine (PYINXT), displayed a high and saturable binding to NET, with a K(d) value of 0.53+/-0.03 nM. Biodistribution studies of (R)-N-methyl-3-(3-(125)I-pyridin-2-yloxy)-3-phenylpropan-1-amine in rats showed moderate initial brain uptake (0.54% dose/organ at 2 min) with a relatively fast washout from the brain (0.16% dose/organ at 2 h) as compared to [(125)I]INXT. The hypothalamus (a NET-rich region)-to-striatum (a region devoid of NET) ratio was found to be 2.14 at 4 h after intravenous injection. Preliminary results suggest that this improved iodinated ligand, when labeled with (123)I, may be useful for mapping NET-binding sites with single photon emission computed tomography in the living human brain.     

Juliana Littbrand-Denekamp (1943-2000)

Purpose: The aim of this study was to evaluate the effect of microwaves modulated at different frequencies on human electroencephalographic (EEG) rhythms.

Materials and methods: Thirteen healthy volunteers were exposed to microwaves (450 MHz) pulse-modulated at frequencies of 7, 14 and 21 Hz. The field power density at the scalp was 0.16 mW/cm². Our experimental protocol consisted of two five-cycle (1 min on and 1 min off) series of exposures at fixed modulation frequencies. A relative change in the EEG power with and without exposure was used as a quantitative measure. EEG frequencies recorded in the theta (4 – 6.8 Hz), alpha (8 – 13 Hz), beta1 (15 – 20 Hz), and beta2 (22 – 38 Hz) bands were analyzed.

Results: Modulated microwaves caused an increase in the average EEG alpha (17%) and beta (7%) power but the theta rhythm remained unaffected. Increases in the EEG alpha and beta power were statistically significant during the first half-period of the exposure interval (30 s) at the modulation frequencies of 14 and 21 Hz. Differences were found in individual sensitivity to exposure. Increases in the EEG beta power appeared statistically significant in the case of four subjects.

Conclusions: Our findings suggest that the effect of the 450 MHz microwave radiation modulated at 7, 14 and 21 Hz varies depending on the modulation frequency. The microwave exposure modulated at 14 and 21 Hz enhanced the EEG power in the alpha and beta frequency bands, whereas no enhancement occurred during exposure to the modulation frequency of 7 Hz.