天麻素的药理作用及临床应用

天麻为兰科植物天麻(Gastrodia elataBI)的干燥块茎[1],为常用名贵中药,具有平肝熄风止痉之功。天麻素注射液是单体制剂,是天麻的有效成分之一,其化学结构为4-羟甲基苯甲醇-β-D吡喃葡萄糖甙[2]。天麻素具有镇痛、镇静及增加脑血流量,减少脑血流阻力,特别是能增加椎-基底动脉供血,改善迷路动脉及内耳血供[3]。近年药理研究表明,天麻素对中枢神经系统、心血管系统和免疫系统等方面也有较广泛的药理活性[4]。本文就天麻素的药理作用及临床应用作一综述。1药理作用1·1对血管血压的作用血管内皮细胞分泌的缩血管因子内皮素(ET)、内皮衍生舒…     

贵州野生和种植天麻中天麻素的含量比较

目的:比较贵州不同产地野生和种植天麻中天麻素的含量,为人工种植天麻提供科学依据。方法:天麻经微波萃取后采用反相高效液相色谱法测定其中天麻素的含量。结果:野生天麻中天麻素的含量高于种植天麻;不同产地野生天麻中天麻素的含量有差异,而种植天麻之间天麻素的含量差异不显著。结论:野生天麻的质量优于种植天麻。本研究可为天麻的种植提供一定的科学依据。     

合成天麻素注射液应用于神经科临床

天麻(Gastrodia elata Blume)的有效成份为天麻素(Gastrodin,学名:对羟甲基苯—B—D—葡萄吡喃糖甙)和天麻甙元。为了解决天麻药源缺乏的问题,中国科学院昆明植物所人工合成了天麻素,认为对神经衰弱、神经衰弱综合征、血管神经性头痛等有较好疗效。四川医学院附属医院根据临床需要,研制成合成天麻素注射液。1983年经云南省卫生厅批准由昆明制药厂和四川医学院协作、进一步扩大临床试用,现将四川医学院和各协作医疗单位用于神经科临床337例的情况总结如下:     

野生天麻与种植天麻的主要性状鉴别与质量比较

目的通过对野生天麻和种植天麻的主要性状特征及其天麻素含量的比较,以确定两者质量的优劣。方法观察天麻的主要性状特征,如质地、颜色、断面、气味等,区分野生天麻与种植天麻;天麻经乙醇提取后,采用高效液相色谱法测定其中天麻素的含量。结果野生天麻与种植天麻的主要性状特征存在一定的差异;野生天麻中天麻素的含量高于种植天麻。结论野生天麻的质量优于种植天麻。     

天麻有效成分的提取工艺研究

<正>天麻的主要化学成分有天麻素、天麻苷元、香草醛、香草醇、倍半萜类、嘌呤类等,其中天麻素是天麻的最主要成分。天麻有保护神经细胞、抗惊厥、镇静催眠、镇痛、增强免疫及抗炎、抗衰老作用[1,2]。现以天麻素为主要指标考察不同提取条件对天麻素的影响,筛选出能确保制剂质量与疗效的提取工艺。     

11批天麻胶囊中天麻素的含量考察

目的考察11批不同厂家天麻胶囊的天麻素含量。方法采用HPLC法测定天麻胶囊中的天麻素。结果 11批天麻胶囊中天麻素的含量为26.4~235.1μg.粒-1。结论应增加天麻素的含量测定项目,以保证临床用药安全有效。     

微透析和高效液相色谱法测定大鼠脑内天麻素及天麻苷元含量

目的考察不同剂量天麻素皮下及口服给药后大鼠脑内的天麻素及其代谢产物天麻苷元的浓度变化。方法采用脑内微透析技术进行在体动态取样,建立了高效液相-串联四级杆质谱方法测定脑透析液中的天麻素含量,建立了高效液相-二极管阵列检测方法测定脑透析液中的天麻苷元含量。结果两种给药方式大鼠不同脑区内天麻素浓度均较低,天麻苷元脑内浓度明显高于其原型药物天麻素。结论天麻素的血脑屏障透过能力差,但其活性代谢产物天麻苷元能够较好地进入脑内发挥作用。     

天麻的药理研究——(三)天麻素及天麻甙元的抗惊厥、抗癫痫及对血压的作用

天麻的药理研究,1979—1980年我们曾报导了合成天麻素及天麻甙元的急性毒性实验、亚急性毒性实验、镇静、对心脏及小肠的作用。本文继续报导天麻素及天麻甙元的抗惊厥、抗癫痫及对血压的作用。实验材料与制剂实验所用的天麻素及天麻甙元系昆明植物研究所植物化学研究室供给。天麻素用灭菌蒸馏水按实验配成所需的浓度,但不超过2.5％以免产生混浊现象。天麻甙元不溶于水,用40％丙二醇作溶剂按实验配成所需的浓度。实验方法及结果     

HPLC法测定不同产地天麻中天麻素的含量

目的建立HPLC法,同时测定不同产地天麻中天麻素含量。方法采用DiamonsilTMC18色谱柱(200 mm×4.6 mm,5μm),流动相为甲醇水冰醋酸(体积比为5∶95∶1),流速为1.0 mL.min-1,检测波长为270 nm。结果天麻素质量浓度在20~200 mg.L-1内呈良好的线性关系,平均回收率为98.2%,RSD为2.7%(n=9),4个产地天麻中的天麻素质量百分含量分别为0.381%、0.454%、0.620%、0.332%。结论本法可用于天麻中天麻素的含量测定;样品溶液制备方法比药典方法天麻素提取更完全;4个产地的天麻中天麻素含量有明显差异,四川青川产天麻中天麻素含量最高。     

天麻素注射液药理毒理研究综述

天麻素注射液是天麻素的灭菌水溶液,天麻素(Gastrodin)是名贵药材天麻的有效单体,化学名为4-羟甲基苯-β-D-吡喃葡萄糖苷,用于神经衰弱、神经衰弱综合征及血管神经性头痛等症(如偏头痛、三叉神经痛、枕骨大神经痛等)亦可用于脑外伤性综合征、眩晕症如美尼尔病、药性眩晕、外伤性眩晕、突发性耳聋、前庭神经元炎、椎基底动脉供血不足等。近年来,广大学者对天麻素的药理作用进行了广     

Mechanisms involved in the spasmolytic effect of extracts from sabal serrulata fruit on smooth muscle

• 1.1. The effects of two extracts from Sabal serrulata fruits [total lipidic (L) and saponifiable (S)] on smooth muscle contractions have been assayed.
• 2.2. Both extracts (0.1–1 mg/ml) relaxed the tonic contraction induced by norepinefrine (30 nM) on rat aorta [EC₅₀, 0.53 ± 0.05 mg/ml (L) and 0.5 ± 0.04 mg/ml (S)] and by KCl (60 mM) on rat uterus. The Sabal extracts (0.3–1 mg/ml) also antagonized the dose-response curve of contractions induced by acetylcholine (0.1–100 μM) on urinary bladder.
• 3.3. dL-Propranolol (1 μM) but not the inactive (R)-(+)-propranolol (1 μM) potentiated the Sabal extracts relaxant effect by lowering the EC₅₀ (0.35 ± 0.2 vs 0.20 ± 0.01 mg/ml for L and 0.43 ± 0.02 vs 0.19 ± 0.02 mg/ml, P < 0.01, for S extract).
• 4.4. Cycloheximide (10 μg/ml) antagonized the effect of extracts from Sabal. However, actinomycin D (5 μg/ml) significantly (P ≤ 0.01) antagonized the effect of the total lipidic extract without modifying that of the saponifiable extract.
• 5.5. The relaxant effect of both extracts was not modified by the tyrosine kinase inhibitor genistein (10 μM) or the ornithine decarboxylase inhibitor α-difluoromethyl-ornithine (10 mM).

     

Antiviral activity of Rheum palmatum methanol extract and chrysophanol against Japanese encephalitis virus

Rheum palmatum, Chinese traditional herb, exhibits a great variety of anti-cancer and anti-viruses properties. This study rates antiviral activity of R. palmatum extracts and its components against Japanese encephalitis virus (JEV) in vitro. Methanol extract of R. palmatum contained higher levels of aloe emodin, chrysophanol, rhein, emodin and physcion than water extract. Methanol extract (IC₅₀ = 15.04 μg/ml) exhibited more potent inhibitory effects on JEV plaque reduction than water extract (IC₅₀ = 51.41 μg/ml). Meanwhile, IC₅₀ values determined by plaque reduction assay were 15.82 μg/ml for chrysophanol and 17.39 μg/ml for aloe-emodin, respectively. Virucidal activity of agents correlated with anti-JEV activity, while virucidal IC₅₀ values were 7.58 μg/ml for methanol extract, 17.36 μg/ml for water extract, 0.75 μg/ml for chrysophanol and 0.46 μg/ml for aloe-emodin, respectively. In addition, 10 μg/ml of extract, chrysophanol or aloe emodin caused 90 % inhibition of JEV yields in cells and significantly activated gamma activated sequence-driven promoters. Hence, methanol extract of R. palmatum and chrysophanol with high therapeutic index might be useful for development of antiviral agents against JEV.     

Synthesis and Calcium Antagonistic Activity of 8-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-β-alanyl]-5,6,7,8-tetrahydrothieno[3,2-b][1,4]thiazepine Fumarate

KT-362 is an antiarrhythmic and antihypertensive agent with vasodilating activity. Since it carries a homoveratryl group in the side chain, an obvious relation exists to the verapamil-type calcium antagonists. Replacement of the fused aromatic moiety in KT-362 with thiophene provided 8-[N-[2-(3,4-dimethoxyphenyl)ethyl]-β-analyl]-5,6,7,8-tetrahydrothieno[3,2-b][1,4] thiazepine ( 1 ). Compound 1 shows a negative chronotropic activity in spontaneously beating right atria (IC₅₀ = 23 μM, n = 7), and a negative inotropic effect in papillary muscles (IC₅₀ = 2.7 μM, n = 7) and left atria (IC₅₀ = 4 μM, n = 6) of the guinea-pig heart. The decrease of contractility in papillary muscles could be antagonized by increasing the extracellular calcium concentration. Compound 1 was found to affect high (IC₅₀: 70 ± 5 μM) and low (IC₅₀: 129 ± 34 μM) voltage-activated calcium channel currents as well as voltage-activated sodium channel currents (IC₅₀: 80 ± 13 μM) in chick dorsal root ganglion neurons. In addition, nicotine-induced currents were potently inhibited (IC₅₀: 6 ± 0.7 μM) in bovine chromaffin cells.     

INVESTIGATION OF IN VITRO TOXICITY OF JET FUELS JP-8 AND JET A

The in vitro cytotoxicity and electrophysiological toxicity of Jet Propulsion-8 (JP-8 jet fuel) on four cell types: H4IIE liver cell line, NIH Swiss 3T3 cell line, neuroblastoma × glioma NG108-15 cells, and embryonic hippocampal neurons were investigated. H4IIE cells exposed to Jet A (a commercial fuel) and JP-8 demonstrated identical toxicity with an IC₅₀ of 12.6 ± 0.4 μg/ml for the two fuels. Comparison of H4IIE and NIH/3T3 toxicity to JP-8 revealed that NIH/3T3 cells were more sensitive to JP-8 than H4IIE cells, with an IC₅₀ 8.5 ± 0.1 μg/ml. JP-8 exposure for the hippocampal neurons proved to be highly toxic (IC₅₀ of <2 μg/ml), while in contrast, the NG108-15 cells were much less sensitive. Electrophysiological examination of NG108-15 cells showed that administration of JP-8 at 1 μg/ml did not alter significantly any of the electrophysiological properties. However, exposure to JP-8 at 10 μg/ml during a current stimulus of +46 pA decreased the amplitude of the action potential to 83 ± 7% (n = 4), the rate of rise, dV/dt_MAX to 50 ± 8% (n = 4), and the spiking rate to 25 ± 11% (n = 4) of the corresponding control levels. These results demonstrate JP-8 induced cytotoxic varies among cell types. The possible mechanisms underlying these observations are presented.     

Calcium and depolarization-dependent effect of pregnenolone derivatives on uterine smooth muscle

• 1.1. The effects of several gestagens (pregnenolone [1 to 30 μm], 20α-hydroxypregnenolone [1 to 30 μM]), and 20β-hydroxypregnenolone [1 to 30 μm]) on rat uterine contraction induced by KC1 (60 mM) and CaCl₂ (30 μM to 6 mM) have been assayed.
• 2.2. The three drugs relaxed the tonic contraction induced by KCI in a concentration-dependent way. The respective EC₅₀ values were: 27.6±1.58 μM (pregnenolone), 4.1±0.12 μM (20α-hydroxypregnenolone), and 11.2±1.04 μM (20β-hydroxypregnenolone). CaCl₂ (1 to 10 mM) totally counteracted the relaxing effect of pregnenolone but only partially compared to that of 20α- or 20β-hydroxy-pregnenolone.
• 3.3. CaC1₂ (30 μM to 6 mM) produced concentration-dependent contraction of rat uterus in medium lacking calcium plus 30, 60, or 90 mM of KC1. The EC₅₀ values of CaCl₂ were: 0.38±0.072, 0.183±0.015, and 0.183±0.015 μM in a medium with 30, 60, or 90 mM of KCI, respectively.
• 4.4. Pregnenolone (10 μM) did not significantly modify the EC₅₀ of CaC1₂ in a medium with 30, 60, or 90 mM of KCI. However, 20β-hydroxypregnenolone (10 μM) antagonized, in a noncompetitive manner, the concentration-response curve to CaC1₂.
• 5.5. 20α-Hydroxypregnenolone (4 μM) antagonized the concentration-response curve to CaCl₂ in a competitive manner. This antagonism was directly related to the concentration of KCI in the medium.
• 6.6. Our results suggest a different calcium antagonist effect of the three gestagens assayed.

     

Design,synthesis, and modelling study of new 1,2,3-triazole/chalcone hybrids with antiproliferative action as epidermal growth factor receptor inhibitors

A novel series of 1,2,3-triazole/chalcone hybrids 6a–n was designed and synthesized using a molecular hybridization approach to develop a new cytotoxic agent capable of targeting epidermal growth factor receptor (EGFR) and/or BRAF. The antiproliferative effect of the novel hybrids was investigated against four cancer cells using doxorubicin as a reference. Hybrids 6a , 6d , 6f–h , and 6n have the highest antiproliferative activity (IC₅₀ values 0.95–1.80 μM) compared to doxorubicin (IC₅₀ 1.14 μM). The most potent antiproliferative derivative, compound 6d , was also the most potent EGFR inhibitor with an IC₅₀ of 0.09 ± 0.05 μM, which is comparable to the reference Erlotinib (IC₅₀ = 0.05 ± 0.03 μM). 6d has modest BRAF inhibitory action with an IC₅₀ of 0.90 ± 0.10 μM. The findings were also related to molecular docking studies, which provided models of strong interactions with the EGFR-TK domain for the inhibitors. In cell cycle analysis, hybrid 6d caused a cell cycle arrest at the G1 transition phase.     

Involvement of cAMP and β-adrenoceptors in the relaxing effect elicited by flavonoids on rat uterine smooth muscle

1 The effect of the flavonoids genistein (3–100 μM), kaempferol (3–60 μM) and quercetin (1–100 μM) on KCI (60 mM)-induced tonic contraction in rat smooth muscle was assayed. In the same way, the modification of these effects in the presence of an inhibitor of protein kinase (PKA) (Rp-cAMPS), an inhibitor of phosphodiesterase (papaverine) and β-adrenoreceptor blocking agents (propranolol and atenolol) was studied. 2 The flavonoids totally relaxed the KCI-induced tonic contraction (IC₅₀: genistein 20.2 ± 2.0 μM, n = 11; kaempferol 10.1 ± 1.6 μM, n = 8; quercetin 13.2 ± 1.2 μM, n = 8). 3 The incubation with Rp-cAMPS (10 and 100 μM) 30 min prior to KCI shifted the dose-response curve of the flavonoids to the right, increasing their IC₅₀ up to 27.8 ± 3.8 and 31.9 ± 7.3 μM, respectively, for genistein; 24.7 ± 0.2 and 19.6 ± 4.9 μM, respectively, for kaempferol; 18.8 ± 2.2 and 18.4 ± 1.5 μM, respectively, for quercetin. 4 Papaverine (3–100 μM) also relaxed the contraction induced by KCI and this effect was significantly displaced to the right with Rp-cAMPS (10 μM) (IC₅₀ 12.1 ± 2.2 vs. 16.5 ± 3.1 μM). Papaverine (3 μM) added to the organ bath 15 min before the contractile agent increased the relaxing effect of the flavonoids and significantly decreased their IC₅₀ (genistein 20.2 ± 2.0 vs. 9.8 ± 1.4 μM; kaempferol 10.1 ± 1.6 vs. 6.6 ± 0.7 μM; quercetin 13.2 ± 1.2 vs. 7.8 ± 1.4 μM). 5 The incubation with atenolol (10 μM) did not alter the relaxing effect of the flavonoids. In the same experimental conditions, propranolol (10 μM) did not modify the effect of genistein and kaempferol, but shifted the response curve of quercetin significantly to the right (13.2 ± 1.2 vs. 17.7 ± 3.4 μM). 6 The results suggest that genistein, kaempferol and quercetin produced the relaxation of uterine smooth muscle by increasing intracellular cAMP. β-Adrenoceptors could also be involved in the effect of quercetin.     

Pharmacological properties of MM-706, a new prostacyclin derivative

• 1.1. In human platelet-rich plasma, platelet aggregation induced in vitro by collagen (10 μg/ml) or thrombin (50 mU/ml) was dose-dependently inhibited by increasing concentrations of prostacyclin or of the new derivative (±)(5E)-13,14-didehydro-ω-hexanor(1-hydroxycyclohexyl)-9a-carbaprostacyclin (MM-706) with an IC₅₀ of 20–50 nM and 250–500 nM, respectively. In human platelets loaded with fura-2, the intracellular rise of [Ca²⁺] induced by thrombin was dose-dependently inhibited by MM-706 with an approximate IC₅₀ of 100 μM.
• 2.2. In rabbit isolated femoral artery, MM-706 (10nM–10μM) was completely ineffective in relaxing the vessel, which was different to prostacyclin which was able to relax vessels at the same concentrations.
• 3.3. In in vitro guinea-pig ileum, prostacyclin produced a contractile effect in the concentration range 1 nM-10μM, but the derivative MM-706 was ineffective at the same concentrations. Preventive addition of MM-706 did not inhibit prostacyclin contraction.
• 4.4. On isolated guinea-pig tracheal preparation, prostacyclin induced a concentration-dependent contraction but the new compound MM-706 showed a lower activity, in the concentration range 10nM–10μM. The activity of prostacyclin was not affected by the contemporary presence of MM-706.
• 5.5. It is concluded that MM-706 is a prostacyclin analogue with antiaggregating properties but without evident effects on smooth muscle of different regions.

     

Effects of Mercuric Chloride and Methyl Mercury on Cholinergic Neuromuscular Transmission in the Guinea-Pig Ileum

Abstract: The effects of mercuric chloride (HgCl₂) and methyl mercury (MeHg) were examined on basal mechanical activity and electrically-induced neurogenic cholinergic contractions (twitch contractions) in longitudinal muscle-myenteric plexus strips from guinea-pig distal ileum. Both compounds at 0.3-3 μM slightly enhanced the amplitude of twitch contractions in ~50% preparations. This effect was probably due to facilitation of acetylcholine (ACh) release since 0.1 and 1 μM mercurials increased electrically-evoked tritium outflow from [³H]choline preloaded muscle layer with attached myenteric plexus. Conversely, higher mercury concentrations inhibited twitch contractions (HgCl₂ IC₅₀=21.3±6.4 μM; MeHg IC₅₀=45.1±5.5 μM), as well as contractions to exogenous ACh (0.1 μM) in resting preparations, and concomitantly increased the basal tone. The former effects possibly reflected an antimuscarinic activity of mercury, while the latter was related to alterations of calcium homeostasis in the effector cells. Indeed, the effect of HgCl₂ on basal tone was antagonized by the Ca²⁺ entry blocker nifedipine (3, 10, 30 nM), indicating Hg-induced facilitation of Ca²⁺ influx through voltage-dependent channels. On the whole, our results suggest that cholinergic neuromuscular transmission and Ca²⁺-dependent mechanisms underlying smooth muscle contractility are targets for mercury toxicity in the intestine.