Antagonism of seizures induced by the administration of the endogenous convulsant quinolinic acid into rat brain ventricles

Summary The effect of pretreatment with drugs on generalized clonic-tonic seizures induced by intracerebroventricular (i.c.v.) administration of the endogenous convulsant quinolinic acid (QUIN, 50g) was studies in rats. Of the inhibitory amino acids tested, only l-glycine (50 and 100g, i.c.v.) diminished the number of animals with seizures while taurine and GABA were ineffective. Of the kynurenine metabolites, only kynurenic acid (50g, i.c.v.) prevented seizures and lethality. Picolinic acid, nicotinic acid and nicotinamide were ineffective. The standard anticonvulsants phenobarbital, diphenylhydantoin and primidone were effective antagonists of QUIN-induced seizures at doses which did not influence pentylenetetrazol seizures. However, the only drug which completely prevented QUIN-induced seizures was diazepam (10 mg/kg). It also prevented pentylenetetrazol seizures in rats in a four times lower dose. The GABA derivatives sodium hydroxybutyrate and phenibut (beta-phenyl-GABA), which are effective QUIN-antagonists in mice, were found to be ineffective in rats. Species differences between rats and mice in the efficacy of antagonists QUIN are discussed.Reported at the 162nd Meeting of Leningrad Pharmacological Society (March 9, 1982).     

A randomized comparison of midazolam and diazepam injectable emulsion in cataract surgery

The purpose of this study was to compare the psychomotor recovery of patients sedated with either midazolam or Diazemuls using the digit symbol substitution test and the Trieger test. Sixty patients were allocated in random double-blind fashion to receive either midazolam or diazepam in oil emulsion (Diazemuls) as intravenous sedation for cataract surgery. Both groups received fentanyl 0.5 μg· kg^?1 IV. Tests of cognition were performed by the patients prior to sedation and at half-hourly intervals for three hours after cataract surgery. In a dose ratio of 1:4, midazolam was found to produce better sedation but more prolonged recovery than Diazemuls. Anterograde amnesia was comparable in the two groups, while more patients in the Diazemuls group developed episodes of apnoea and venous irritation.     

Effect of serotoninergic drugs on stress-induced hyperthermia (SIH) in mice

Summary 8-OH-DPAT (2.5–10 mg/kg) and buspirone (10 mg/kg) but not 5,7DHT (200 g/mouse), pCPA (75 and 150 mg/kg, three times), ritanserin (0.1 and 0.2 mg/kg), LY 53857 (1.5 and 3 mg/kg), GR 38032 F (0.1–100 g/kg), TFMPP (5 and 20 mg/kg) and mCPP (2.5 and 5 mg/kg) antagonized the rise in body temperature that occurs to the last mice removed from their group housing, which was termed as stress-induced hyperthermia (SIH). Ro 15-1788, at a dose which blocked the effect of diazepam on SIH, did not reverse the anxiolytic effect of buspirione. Instead, when cerebral 5-HT content was reduced to 50% by 5,7-DHT-induced lesion, the effect of buspirone on SIH was decreased. TFMPP 5 mg/kg did not shorten significantly the onset of SIH as could have been expected by an anxiogenic drug, while the dose of 20 mg/kg did not modify the pattern of SIH at all. The lower dose of TFMPP evoked a hyperthermic and the higher a hypothermic response.Abbreviations TFMPP m-trifluoromethylphenylpiperazine - mCPP m-chlorophenylpiperazine - pCPA P-chlorophenylalanine - 5,7 DHT 5,7 dihydroxytryptamine - 8-OH-DPAT 8-hydroxy-2-(di-N-propylamino)tetralin - 5-HT serotonin     

Recall of intraoperative events after general anaesthesia and cardiopulmonary bypass

We wished to identify patients able to recall intraoperative events after general anaesthesia involving cardiopulmonary bypass (CPB). A balanced anaesthetic technique consisting of benzodiazepines, low dose fentanyl (15.9 ± 8.5 μg· kg^{− 1}) and a volatile agent was employed. Perioperative recall was sought utilizing a structured interview on the fourth or fifth postoperative day. During 20 mo 837 patients underwent CPB. Seven hundred patients (84%) were able to respond to a structured postoperative interview. A detailed chart review was performed in patients with recall and in 60 randomly selected patients without recall. Eight patients (1.14%) reported recall of intraoperative events. We were unable to identify any differences between the two groups with respect to narcotic, benzodiazepine dosage or usage of inhalational agents. The incidence of recall in patients undergoing cardiac surgery was less in our group than previously reported. It is, however, higher than the 0.2% incidence recently reported in patients undergoing non-cardiac surgery. This is probably due to patient characteristics and intraoperative factors which make it difficult to avoid periods of relatively light anaesthesia during cardiac surgery. L’objectif de ce travail est d’identifier les patients capables de se rappeler des événements survenus pendant la chirurgie sous circulation extracorporelle (CEC). L’anesthésie consiste en des benzodiazépines, du fentanyl à faibles doses (15,9 ± 8,5 μg· kg^{− 1}), et un agent volatile. On recherche la mémoire évocative périopératoire lors d’une interview au quatrième ou cinquième jour postopératoire. Sur une période de 20 mois, 837 patients ont subi une CEC. De ceux-ci, 700 (84%) sont capables de répondre à une interview postopératoire. Une révision du dossier d’anesthésie est effectuée chez les patients avec mémoire évocative et chez 60 patients sans mémoire évocative. Huit patients (1,14%) se rappellent certains événements périopératoires. Il n’y a pas de différence entre les deux groupes au regard de la posologie opiacée, des benzodiazépines ou de la concentration anesthésique. L’incidence de la mémoire évocative chez nos patients de chirurgie cardiaque est moindre que celle d’études antérieures. Elle est toutefois plus élevée que l’incidence de 0,2% récemment rapportée chez des patients de chirurgie autre que cardiaque. Selon toute probabilité, cette différence est due aux caractéristiques des malades et à des facteurs peropératoires qui ne permettent pas d’éviter pendant la chirurgie cardiaque des périodes d’anesthésie légère.

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Presented in part at the Canadian Anaesthetists’ Society 49th Annual Meeting in Toronto, June 1992.     

氯氟乙酯(25例)和地西泮(23例)治疗焦虑障碍的疗效和安全性比较

目的 :评价氯氟乙酯治疗焦虑障碍的疗效和安全性。方法 :采用双盲、双模拟、随机、平行对照研究。完成 4wk治疗的病人共 4 8例。其中试验组 (氯氟乙酯组 ) 2 5例 ,对照组 (地西泮组 ) 2 3例。试验组早、午餐后服氯氟乙酯安慰剂及地西泮安慰剂各 1片 ,晚餐后服氯氟乙酯 2mg及地西泮安慰剂各 1片 ;对照组早、午、晚餐后服氯氟乙酯安慰剂及地西泮 2 .5mg各 1片 ,疗程为 4wk。结果 :治疗 4wk后 ,试验组的HAMA总分显著降低 ,HAMA减分率达 (5 9± 2 5 ) % ,临床总有效率达72 % ,与对照组相比无显著意义 (P >0 .0 5 )。试验组的不良反应的发生率为 8% ,与对照组相比无显著意义 (P >0 .0 5 )。结论 :氯氟乙酯治疗焦虑障碍的疗效 ,与地西泮相似 ,无明显不良反应。     

安定对兔离体气管平滑肌收缩力的影响

为了对有气道高反应的患者选用理想的镇静安定药提供参考依据,采用研究不同浓度的安定对氯化钾、乙酰胆碱、电脉冲3种刺激因素诱发兔离体气管子滑肌收缩影响的方法。结果：0．018mmol／L的安定无明显抑制作用（P＞0．05）,0．18mmol／L和0．36mmol／L的安定可显著抑制这3种刺激因素诱发的气管平滑肌收缩（P＜0．05或P＜0．01）,β受体阻滞剂普萘乐尔和中枢性苯二氮受体阻滞剂氟马西尼不能拮抗安定对气管平滑肌收缩的抑制作用。结论：安定对兔离体气管平滑肌张力有显著的抑制作用,其部分作用机制与抑制外钙内流和内钙释放及抑制蛋白激酶C（PKC）信号传导系统有关。     

Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor

1. The responses of the electrically-driven right ventricle strip of the guinea-pig heart to diazepam were recorded in the absence and in the presence of different selective cyclic nucleotide phosphodiesterase (PDE) inhibitors.
2. Diazepam, at concentrations ranging from 1 μM to 100 μM, was devoid of effect on the contractile force in this preparation.
3. Conversely, diazepam (5 μM–100 μM) produced a consistent positive inotropic response in the presence of a concentration (1 μM), that was without effect in the absence of diazepam, of either of the selective PDE 3 inhibitors milrinone or SK&F 94120, but not in the presence of the selective PDE 4 inhibitor rolipram.
4. This effect of diazepam was not γ-aminobutyric acid (GABA)-dependent, since it was neither mimicked nor potentiated by GABA, and was not affected by either a high concentration (5 μM) of the antagonists of the benzodiazepine/GABA/channel chloride receptor complex, picrotoxin, flumazenil and β-carboline-3-carboxylic acid methyl ester (βCCMe), or by the inverse agonists, β-carboline-3-carboxylic acid N-methylamide (βCCMa) and methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM, 0.1 μM). Furthermore, a specific antagonist of the peripheral benzodiazepine receptors, PK 11195 (5 μM), did not influence the effect of diazepam.
5. Biochemical studies with isolated PDEs, confirmed that diazepam selectively inhibits type 4 PDE from guinea-pig right ventricle rather than the other PDEs present in that tissue. The compound inhibited this enzyme in a non-competitive manner. Diazepam was also able to inhibit PDE 5, the cyclic GMP specific PDE absent from cardiac muscle, with a potency close to that shown for PDE 4.
6. Diazepam displaced the selective type 4 PDE inhibitor, rolipram from its high affinity binding site in rat brain cortex membranes, and also potentiated the rise in cyclic AMP levels induced by isoprenaline in guinea-pig eosinophils, where only type 4 PDE is present.
7. The PDE inhibitory properties of diazepam were shared, although with lower potency, by other structurally-related benzodiazepines, that also displaced [³H]-rolipram from its high affinity binding site. The order of potency found for these compounds in these assays was not related to their potencies as modulators of the GABA receptor through its benzodiazepine binding site.
8. The pharmacological and biochemical data presented in this study indicate that diazepam behaves as a selective type 4 PDE inhibitor in cardiac tissue and this effect seems neither to be mediated by the benzodiazepine/GABA/channel chloride receptor complex nor by peripheral type benzodiazepine receptors.

     

短程地西泮预防热性惊厥373例临床研究

目的探讨短程间歇性应用地西泮对预防热性惊厥复发的临床疗效。方法对来源于多中心的复杂性热性惊厥和／或反复单纯性热性惊厥的373例患儿口服地西泮（O．3～0．5mg／kg）,动态观察地西泮干预前、后患儿发热及热性惊厥发生的临床特点以及药物不良反应等指标。结果患儿发热及出现热性惊厥发作的高峰月份为每年的11和12月份,疾病以急性上呼吸道感染为主,热性惊厥发作形式主要为单纯性（82．37％～84．95％）。地西泮干预对热性惊厥复发的防治率达81．27％,同干预前比较有差异有统计学意义（X^2=680．06,P〈0．05）,而不良反应轻微并可自行缓解。结论短程间歇性应用地西泮预防热性惊厥复发具有疗效显著及不良反应轻微的优点,适宜在基层医疗机构推行。     

布洛芬-安定混合溶液与安定溶液直肠给药治疗小儿惊厥的比较研究

目的以安定为对照，探讨布洛芬-安定混合溶液（BU—DZP）直肠给药治疗小儿惊厥的实用价值。方法在52例儿童中对比观察直肠注入布洛芬一安定混合溶液与安定溶液的吸收速度和对脑电活动的影响，并比较两药治疗小儿惊厥的疗效。结果布洛芬一安定混合溶液与安定溶液均能从直肠迅速吸收，分别于2-6min及3-8min对脑电活动产生显著影响，明显抑制癫痫样波发放。结论布洛芬一安定混合溶液与安定溶液直肠给药，均能作为小儿惊厥抢救的有效措施。     

Systemic administration of GMP induces anxiolytic-like behavior in rats

The glutamatergic system has received considerable attention over the last few years as potential target to develop anxiolytic drugs. Guanine based purines (GBPs) play an important neurmodulatory effect in the glutamatergic system. Several studies have shown the ability of the GBPs to reduce glutamatergic activity. In the present study, we investigated the anxiolytic effect of GBPs — by Guanosina Monophosphate (GMP) administration — in rodents. Adult male Wistar rats were pretreated with GMP (10, 25, 50, 100 and 150 mg/kg: i.p.); or saline (NaCl 0.9%; i.p.) (control); or, diazepam (2 mg/kg: i.p.) (positive control). One hour after the injection, the anxiety-related behaviors for each animal was evaluated in the light/dark, elevated plus-maze, and open field tasks. Additionally, purines concentration in the cerebrospinal fluid (CSF) was verified. The administration of 25 and 50 mg/kg GMP was able to promote anxiolytic-like behavior, in the light/dark and elevated plus-maze task, similar to diazepam effect. However, no changes in the open field task, or CSF purines concentration were found for either GMP or diazepam treated animals, when compared with saline group. Thus, this study suggests that acute administration of GMP was able to decrease the levels of anxiety in classical behavioral tasks.