黄花石蒜的催吐与祛痰作用及其机制

用昆明产黄花石蒜(Lycoris aurea Herb.)的干燥鳞茎制成流浸膏及盐酸石蒜碱作药理实验,结果证明本品对犬、鸽有催吐作用,其机制不仅有末梢性反射作用,而且也有中枢作用参与,氯丙嗪、异丙嗪、苯海拉明、阿託品及东茛菪碱均不能对抗黄花石蒜所引起的呕吐作用.用兔作祛痰实验,以本品0.1克/公斤的剂量灌胃,在用药后第1小时内,呈明显的祛痰作用.将黄花石蒜给小白鼠灌胃,测得LD₅₀为26.42克/公斤.     

抗肿瘤药物的研究 Ⅷ.几种药物对Sb-71毒性及疗效的影响

1.皮下注射二巯基丁二酸钠500毫克/公斤,BAL-glucoside 1167毫克/公斤,BAL30毫克/公斤或半胱氨酸1000毫克/公斤,对接受中毒剂量Sb-71的小鼠均有明显的保护作用,使小鼠不发生死亡或减少死亡。2.二巯基丁二酸钠1500毫克/公斤,BAL-glucoside 2000毫克/公斤,BAL 40毫克/公斤或半胱氨酸1000毫克/公斤可分别将Sb-71的急性LD₅₀剂量由40毫克/公斤提高至232,76,68和87毫克/公斤。3.二巯基丁二酸钠,BAL-glucoside和BAL也可对抗Sb-71对Ehrlich腹水瘤的抑制作用;前二者在Sb-71剂量增加时,疗效又可出现。半胱氨酸在500毫克/公斤时可以减少Sb-71的毒性,但对其疗效则无明显影响。     

青藤碱的药理作用Ⅲ.对中枢神经系统的作用

本文继续报导对青藤碱(sinomenine)的药理作用的研究.(1)腹腔注射育藤碱40毫克/公斤无明显延长小白鼠戊巴比妥钠引起的睡眠时间.(2)腹腔注射青藤碱25毫克/公斤明显减少小白鼠自发活动,剂量增加到50毫克/公斤作用非常显著,作用最强是在给药后20-60分钟,至120分钟恢复正常.(3)青藤碱使士的宁的惊厥阈降低,但对五甲烯四氮唑的惊厥没有影响.(4)青藤碱略有催吐作用,对注射去水吗啡引起的呕吐无影响.(5)对大白鼠腹腔注射青藤碱60毫克/公斤时,于给药后30-60分钟有一定降温作用.(6)青藤碱对小白鼠皮下注射的半数致死量为535±41.9毫克/公斤.     

石蒜碱对子宫的作用

石蒜碱(lycorine)从黄花石蒜的干燥鳞茎中提得,熔点为278—280℃,用其盐酸盐(熔点为205—207℃)实验。结果,本品对家兔原位子宫及子宫瘘子宫、家兔和豚鼠的离体子宫均有兴奋作用。对大白鼠离体子宫小剂量呈兴奋作用,大剂量呈抑制作用。盐酸石蒜碱对小白鼠的LD_(50)为42毫克/公斤。     

石蒜碱对动物垂体促肾上腺皮质激素分泌的刺激作用

作者用幼小鼠胸腺萎缩法、家兔肾上腺抗坏血酸含量降低及蟾蜍嗜酸性白血球减少等方法,证实石蒜碱具有刺激动物肾上腺皮质功能的作用;当用去除垂体蟾蜍作试验对象时,证明石蒜碱的这一作用系通过垂体而实现.此外,石蒜碱对家兔甲酸性关节炎及大鼠蛋白性关节炎显示明显的抗炎作用.     

石蒜碱对动物垂体促肾上腺皮质激素分泌的刺激作用

作者用幼小鼠胸腺萎缩法、家兔肾上腺抗坏血酸含量降低及蟾蜍嗜酸性白血球减少等方法,证实石蒜碱具有刺激动物肾上腺皮质功能的作用;当用去除垂体蟾蜍作试验对象时,证明石蒜碱的这一作用系通过垂体而实现.此外,石蒜碱对家兔甲酸性关节炎及大鼠蛋白性关节炎显示明显的抗炎作用.     

青藤碱的药理作用 Ⅱ.毒性及一般药理

青藤碱(sinomenine)对小白鼠口服半数致死量为580±51毫克/公斤;大白鼠一次口服694毫克/公斤无不良反应;犬及猴分别口服45及95毫克/公斤有显著镇静作用及轻度胃肠反应;但静脉给药于犬及猴(5—13.5毫克/公斤)立即出现高度衰弱、血压下降、心率增速、呼吸困难,此种严重反应于一小时许恢复(猴);犬及猴无论口服或静脉给药后,肝、肾功能均无变化;大白鼠亚急性毒性试验表明,该药40及80毫克/公斤/日腹腔注射,连续二周,对动物体重、食欲、血象、内脏病理切片均无明显改变.青藤碱静脉给药可使麻醉兔、犬的血压显著降低,剂量愈大,作用愈显著,其降压作用与M-胆碱反应系统无关,亦无直接扩张血管作用;高浓度抑制离体蛙心的收缩,此外,该药抑制离体肠肌,并对抗毛果芸香碱、组织胺及乙酰胆碱对离体肠肌的作用;本药不延长硫喷妥钠的作用时间.     

长春花生物碱部分之一 AC-875的抗肿瘤作用及毒性

木文对长春花(Catharanthus roseus Linn.G.Don)中分离提出的生物碱AC-875进行了毒性及抗癌作用的实验研究.试验结果表明AC-875在20-42毫克/公斤时,对小鼠Ehrlich腹水癌及腹水型肝癌均有明显的抑制作用.当剂量为10毫克/公斤时,对大鼠腹水型吉田肉瘤也有较好的疗效.在实体瘤的治疗中,注射35毫克/公斤,对小鼠S-180仅有轻度抑制作用,且不太稳定.对小鼠网织细胞瘤、Ehrlich腹水癌实体瘤、大鼠Jensen肉瘤及Walker癌等则无抑制作用.给小鼠腹腔注射AC-875的急性LD₅₀为170毫克/公斤,亚急性LD₅₀为61毫克/公斤.给大白鼠腹腔注射AC-875的意性及亚急性LD₅₀分别为122毫克/公斤及18毫克/公斤.给家兔静脉注射8毫克/公斤AC-875时,心电图无明显变化.静脉注射AC-875 1毫克/公斤、2.5毫克/公斤或皮下注射5毫克/公斤,对狗的肝、肾功能、尿常规、红血细胞、血红蛋白及体重均无明显影响,但2.5和5毫克/公斤组,狗的白细胞有下降现象.     

牡丹皮水溶性成分的药理学研究

本文探讨牡丹皮水溶性成分(MC)的一般药理作用及降血糖作用。ICR种系雄性小鼠皮下注射100、200毫克/公斤MC,自发运动量分别减少25、75％,分别延长己巴比妥钠(100毫克/公斤,腹腔)睡眠时间11、13分钟。皮下注射100～200毫克/公斤MC,对戊四唑(130毫克/公斤,皮下),士的宁(175毫克/公斤,皮下)的小鼠致死时间分别延长1.3～2.5分,0.9～1.2分。给乌拉坦麻醉兔静注20～50毫克/公斤MC     

青藤碱的药理作用Ⅵ.抗炎作用机制的研究

实验发现青藤碱能降低大鼠肾上腺内维生素C的含量,对用戊巴比妥钠麻醉的大鼠却无此种作用,对切除肾上腺或垂体的大鼠,青藤碱无抗炎作用.在预先切除肾上腺的小鼠青藤碱的LD₅₀较未切除肾上腺的小鼠明显降低.青藤碱并不降低大鼠腹部皮肤组织胺的含量,皮下注射多粘菌素B(5毫克/公斤)可使皮肤中组织胺含量显著减少;但后者并无对抗蛋白性“关节炎”的作用.上述结果表明,青藤碱的抗炎作用机制可能是通过下丘脑影响垂体-肾上腺系统所致,而与青藤碱释放组织胺作用无关.     

Electrophysiologic effects of flecainide relative to serum and tissue concentrations in rabbits after chronic drug administration

The effects of chronic treatment with flecainide on the cellular electrophysiology and the relationship of the electrophysiologic effects to serum and myocardial flecainide concentrations were determined in rabbit ventricular myocardium. Two groups of rabbits were administered flecainide at doses of 7.5 mg/kg body weight (dose I) and 20 mg/kg body weight (dose II) intraperitoneally (i.p.) twice daily for 12-14 days; a third group received saline. Serum and myocardial flecainide concentrations with dose II (0.44 +/- 0.15 micrograms/ml and 3.0 +/- 1.4 micrograms/g, respectively) were significantly (p less than 0.01) higher than with dose I (0.19 +/- 0.11 micrograms/ml and 0.81 +/- 0.15 micrograms/g, respectively). At 1.0-Hz stimulation, only the high dose produced significant changes in transmembrane action potentials of right ventricular myocardial fibers, which showed a 17.6% (n = 6, p less than 0.05) decrease in maximal upstroke velocity (Vmax) of phase 0 and 19.5% (n = 6, p less than 0.05) prolongation of effective refractory period (ERP). Repetitive stimuli led to an exponential decline in Vmax with both dosage regimens. The magnitude of Vmax decrease was frequently dependent and was greater with the higher dose. The rate of decrease of Vmax per action potential (AP) during train of stimuli in rabbits treated with dose II was 0.037 +/- 0.012 (n = 5) at 2.0-Hz stimulation, and the recovery time constant from use-dependent block at 4.0-Hz stimulation increased significantly from 12.6 +/- 3.6% decrease in Vmax with the low dose to 35.6 +/- 7.1% decrease with the high dose. The data show that sodium channel inhibition by chronic flecainide administration is a function of dose, serum, and myocardial flecainide concentrations.     

The effects of intraperitoneal administration of the GABA(B) receptor agonist baclofen on food intake in CFLP and C57BL/6 mice

The effects of the GABA(B) receptor agonist baclofen were investigated on food intake in non-deprived CFLP and C57BL/6 mice. In Experiment 1, baclofen (1-8 mg /kg) administered i.p. to CFLP mice, produced a dose-related increase in food intake. The 4 and 8 mg/kg doses produced significant increases in cumulative feeding when measure 120 min after administration (at least P < 0.05, in each case). In Experiment 2, baclofen (1-10 mg/kg), administered intraperitoneally (i.p.) to C57BL/6 mice, also produced a dose-related increase in food intake. The 4 mg/kg dose of baclofen significantly increased cumulative food intake at 60 min (P < 0.05), while the 2 and 4 mg/kg doses significantly increased cumulative food intake at 120 min (P < 0.01, in each case). The 10mg/kg dose was without effect. These data show that systemic administration of the GABA(B) agonist baclofen produces an increase in food consumption in two different strains of mice and extend previous observations made in rat to another rodent species.     

General pharmacology of beraprost sodium. 1st communication: effect on the central nervous system

Beraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is an orally active epoprostenol (prostaglandin I2, PGI2) analogue. Its effect on the central nervous system (CNS) was studied. 1. When orally administered in mice, beraprost sodium at 0.3 mg/kg caused a flush of skin, a suppression of spontaneous motility, and a fall of body temperature. At 1 mg/kg and more, it showed obvious sedation, prolongation of hexobarbital hypnosis, and analgesic action in acetic acid-induced writhing test. However, even at 3 mg/kg beraprost sodium neither induced ataxia nor had anticonvulsant activity. Hypothermia was also observed in rabbits at 1 mg/kg (p.o. and i.v.). 2. When intravenously administered, beraprost sodium exerted long-lasting action on the CNS, while its pharmacological effects resembled those of PGI2. 3. Oral administration of beraprost sodium did not inhibit aggregation toxicity induced by methamphetamine (20 mg/kg i.p.) in mice. Beraprost sodium at doses higher than 1 mg/kg enhanced aggregation toxicity induced by methamphetamine (5 mg/kg i.p.), while intracerebral ventricular administration of beraprost sodium failed to enhance it. 4. In rat spinal reflex, intravenous administration of beraprost sodium (0.1 mg/kg) slightly enhanced monosynaptic reflex and at a high dose (1 mg/kg) suppressed polysynaptic reflex. 5. In the rabbit EEG, intravenous administration of beraprost sodium at a high dose (1 mg/kg) showed some effects such as the continuous pattern of wakefulness and a fall in power of the EEG.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of the anxiolytic-like effects of fluvoxamine, milnacipran and risperidone in mice using the conditioned fear stress paradigm

It has been known that rodents exhibit the immobility when tested in the same environment in which they had been previously exposed to aversive stimuli. This behavior is called conditioned fear stress-induced freezing behavior, and has been used as a model of anxiety. Using this animal model, the present study tried to characterize the anxiolytic-like effects of fluvoxamine, a selective serotonin reuptake inhibitor, milnacipran, a serotonin noradrenaline reuptake inhibitor and risperidone, an atypical antipsychotic in mice. Fluvoxamine (1.25-10 mg/kg, intraperitoneally (i.p.)) and milnacipran (0.5-4 mg/kg, i.p.) each dose-dependently and significantly suppressed the conditioned fear stress-induced freezing behavior in mice, an indicator of anxiety, and milnacipran had a weaker effect than fluvoxamine. While risperidone also significantly suppressed freezing behavior at a low dose (0.01 mg/kg, i.p.), a high dose (0.04 mg/kg, i.p.) decreased spontaneous motor activity. On the contrary, sulpiride, a typical antipsychotic (2-8 mg/kg, i.p.), did not affect freezing behavior. In a combination study, the suppressive effect of a low dose of risperidone (0.01 mg/kg, i.p.) on freezing behavior was significantly antagonized by the co-administration of low/middle doses of fluvoxamine (1.25 and 2.5 mg/kg, i.p.), whereas a high dose of fluvoxamine (10 mg/kg, i.p.) was unaffected. Additionally, the co-administration of milnacipran (0.5-2 mg/kg, i.p.) also tended to inhibit the suppressive effect of risperidone (0.01 mg/kg, i.p.). These findings indicate that fluvoxamine, milnacipran and risperidone may each be clinically effective at treating anxiety disorders, but their effects may be attenuated in combination with other medications.     

Evidence for GABA-BZ receptor modulation in short-term memory passive avoidance task paradigm in mice

The possible involvement of gamma-aminobutyric acid/benzodiazepine (GABA-BZ) receptor modulation in scopolamine-induced short-term memory deficit was investigated in mice. Passive avoidance step-down task behavior was observed. Latency of mice to reach shock-free zone (SFZ) and number of mistakes the animal made in 15 min were used as separate parameters for acquisition and memory retention, respectively. Scopolamine (0.3 mg/kg) caused a delay in reaching SFZ and an increased number of mistakes. Physostigmine reversed the scopolamine-induced increase in number of mistakes; however, it caused a delay in the time to reach SFZ. Subeffective dose of GABA, when combined with physostigmine, further delayed the latency to reach SFZ, but reduced the number of mistakes very significantly. GABA (50, 75 and 100 mg/kg, i.p.) and GABA agonists sodium valproate (30 and 60 mg/kg, i.p.), fengabine (5 and 10 mg/kg, i.p.), (+/-)baclofen (0.25, 0.5 and 1.0 mg/kg, i.p.) and (-)baclofen (0.25 and 0.5 mg/kg i.p.) reversed the scopolamine-induced effect; however, sodium valproate at higher dose delayed time to reach SFZ. Combined administration of lower dose (+/-)baclofen and subeffective dose of GABA showed significant decrease in latency and number of mistakes in scopolamine-treated animals. The specific benzodiazepine antagonist flumazenil (Ro-15-1788) (5 and 10 mg/kg, i.p.) and inverse agonist FG-7142 (10 mg/kg, i.p.) very significantly reversed scopolamine-induced increase in number of mistakes, but Ro-15-1788 failed to show any effect on latency per se and in scopolamine-treated experiments, as well.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of MK-801 on clozapine-induced potentiation of excitatory synaptic responses in the perforant path-dentate gyrus pathway in chronically prepared rabbits

We previously found that the atypical antipsychotic drug, clozapine, when intraperitoneally (i.p.) injected, long-lastingly potentiated excitatory synaptic responses elicited in the dentate gyrus by single electrical stimulations to the perforant path in chronically prepared rabbits, and called this phenomenon 'clozapine-induced potentiation'. In the present study, we likewise examined whether clozapine-induced potentiation is caused by NMDA receptor-mediated neurotransmission in the perforant path-dentate gyrus pathway of chronically prepared rabbits. The non-competitive NMDA receptor antagonist - 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imino hydrogen maleate (MK-801; 1.0 mg/kg, i.p.) - completely prevented the potentiation of synaptic responses induced by subsequent administration of 20 mg/kg clozapine, whereas the 0.5 mg/kg dose had virtually no effect on the potentiation. These results suggest that the effect of clozapine requires NMDA receptor activation.     

Paracetamol-induced hepatotoxicity: Lack of enhancement of the hepatoprotective effect of N-acetylcysteine by sodium sulphate

The potential role of sodium sulphate in possible enhancement of the hepatoprotective action of N-acetylcysteine (NAC) in paracetamol (PCM) overdose was examined. The effects of sodium sulphate (200 mg/kg) in combination with NAC (400 mg/kg) administered intraperitoneally 2 h post-PCM dose, on mortality rate and plasma activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were investigated in mice 24 h after receiving a single oral dose of 400 mg/kg PCM. In addition, the effect on the mortality rate of PCM-treated animals of co-administering 400 mg/kg sodium sulphate with NAC (200 or 400 mg/kg) was also studied. NAC alone caused a marked reduction in the mortality rate of PCM-treated mice and a sharp drop in their plasma AST and ALT activities to near normal values. However, no additional reduction in plasma levels of AST and ALT was observed when sodium sulphate was co-administered with NAC. Similarly, sodium sulphate (200 mg/kg) administered alone to PCM-treated mice had no effect on the high mortality rate or the elevation in plasma AST and ALT activities observed in these animals. Furthermore, increasing the dose of sodium sulphate to 400 mg/kg did not influence the mortality rate. It is therefore concluded that sodium sulphate neither protects against paracetamol-induced hepatotoxicity nor enhances the hepatoprotective action of N-acetylcysteine.     

Screening for antagonistic agents to the lethal toxicity of neocarzinostatin. II. Effects of various drugs in inhibiting the toxicity of neocarzinostatin in vivo

In clinical chemotherapy with neocarzinostatin (NCS) against cancers, side effects such as leukopenia, anorexia, vomiting and nausea were mainly observed when parenteral administration was used. To prevent these adverse side effects without changing the anticancer activity of the drug, we attempted to apply the two-route-infusion chemotherapy using NCS and antidotes for the NCS treatment devised by Baba. This report presents the results of our study on effects of some antidotes on the acute toxicity of NCS in mice and also on the antitumor activity of NCS against Sarcoma-180 in mice (ICR-JCL strain) when used with tiopronin. The results are summarized as follows. 1. LD50 values of NCS administered via intravenous route increased 2.3- to 3.2-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered subcutaneously together with NCS, 1.3- to 1.4-fold when 50 or 100 mg/kg of sodium thioglycolate was used. When antidotes were given prior to the administration of NCS, 1.8- to 5.4-fold increase in LD50 values of NCS resulted with 300, 500 or 1,000 mg/kg of tiopronin administered 1 hour prior to NCS, 2.3-fold increase resulted with 2,000 mg/kg reduced glutathione, 1.2-fold increase with 100 mg/kg of sodium thioglycolate and 1.9-fold increase with 1,000 mg/kg of L-cysteine monohydrochloride monohydrate. Furthermore, 4.8- to 13.1-fold increase in LD50 of NCS occurred when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered 15 minutes prior to NCS. When these antidotes were administered 1 hour after the administration of NCS, however, no changes in the LD50 value occurred. 2. The LD50 value of NCS given intraperitoneally increased 1.6- to 5.8-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered intravenously at the same time as NCS, 1.4- to 1.6-fold when tiopronin was given 1 hour prior to NCS, intraperitoneally and 1.3- to 1.7-fold when it was given 1 hour after NCS. 3. It was recognized that the acute toxicity of NCS was the most effectively reduced by tiopronin, but only slightly by glutathione, sodium thioglycolate or L-cysteine monohydrochloride monohydrate. The action of tiopronin was the most effective when it was given subcutaneously 15 minutes prior to NCS administered intravenously. 4. The combination chemotherapy on Sarcoma-180 in mice using NCS intraperitoneally and tiopronin intravenously was markedly effective when these agents were given simultaneously.     

The influence of ethanol pretreatment on the effects of nine hepatotoxic agents

The hepatotoxic effects of carbon tetrachloride (0.01 ml/kg i.p.), thioacetamide (50 mg/kg intraperitoneally), paracetamol (0.5 g/kg intraperitoneally), and allyl alcohol (0.05 ml/kg intraperitoneally) as estimated by determination of serum enzyme activities (GOT, GPT, SDH) were enhanced in mice treated with one oral dose of 4.8 g/kg ethanol 16 hrs. previously. Pretreatment of mice with ethanol did not increase the hepatotoxic actions of bromobenzene (0.25 ml/kg intraperitoneally), phalloidin (1.5 mg/kg intraperitoneally), alpha-amanitin (0.75 mg/kg intraperitoneally), and praseodymium (12 mg/kg intravenously) though there was a trend to higher enzyme activities in the case of bromobenzene. In guinea-pigs ethanol also aggravated CCl4-induced liver damage, but only strengthened the hepatotoxic activity of D-galactosamine (150 mg/kg intraperitoneally). Treatment with 4.8 g/kg ethanol did not influence liver glutathione levels in mice but increased aniline hydroxylation in the 9000 x g liver homogenate supernatant of mice and guinea-pigs. A dose of 2.4 g/kg ethanol, on the other hand, neither increased aniline hydroxylase activity nor enhanced carbon tetrachloride-induced hepatotoxicity in mice. It is assumed that the enhanced sensitivity to hepatotoxic agents after treatment with ethanol may be due to an enhanced microsomal activation of these substances.