异丙酚抑制长效酰胺类局麻药致大鼠中毒惊厥作用的比较

目的:比较异丙酚抑制左旋布比卡因、罗哌卡因和布比卡因所致惊厥的作用。方法:64只Wistar大鼠随机分为对照组(C组)、左旋布比卡因组(L组)、罗哌卡因组(R组)和布比卡因组(B组),4组内再分为实验(EG)和异丙酚处理(PG)2个亚组(n=8)。L组、R组和B组分别经尾静脉泵入0.75%相应局麻药,速度均为2mg·kg-1·min-1,PG各亚组在出现惊厥反应后静脉注射2mg/kg异丙酚。C(EG)组泵入生理盐水,C(PG)组泵入生理盐水后静脉注射异丙酚。惊厥2h后,测定海马CA1区c-fos阳性细胞数、NO水平和一氧化氮合酶(NOS)活性表达。结果:除C组外各组均有惊厥发生。异丙酚处理组在给予异丙酚后很快抑制惊厥。与C(EG)组比较,L(EG)、R(EG)及B(EG)组海马CA1区c-fos阳性细胞数、NO含量以及NOS活性表达均显著增加(P<0.01)。L(PG)、R(PG)和B(PG)组海马CA1区c-fos阳性细胞数、NO含量以及NOS活性表达较对应的L(EG)、R(EG)及B(EG)组均明显减少(P<0.01)。L组与R组较B组c-fos阳性细胞数、NO水平和NOS活性表达的K值明显减小(P<0.01)。结论:异丙酚能在一定程度上抑制左旋布比卡因、罗哌卡因和布比卡因引起的惊厥,且对布比卡因致惊厥的抑制作用强于左旋布比卡因和罗哌卡因。     

Antihypertensive Action of Geraniin in Rats

Abstract— The effects of geraniin, one of the ellagitannins purified from the leaves of Sapium sebiferum, on blood pressure were investigated in the spontaneously hypertensive rat (SHR). A single intravenous bolus injection of geraniin into anaesthetized SHRs lowered the arterial mean blood pressure in a dose-dependent manner without affecting the heart rate. A similar action was also observed in the normotensive (WKY) rat that received this compound at a higher dose. Geraniin did not modify the baroflex sensitivity in the phenylephrine-challenged SHR. This tannin reduced the plasma noradrenaline in a dose-dependent fashion which was not influenced by adrenalectomy. Failure of the antagonists, idazoxan and yohimbine for α₂-adrenoceptors as well as haloperidol and domperidone for dopamine receptors, to reverse the antihypertensive actions of geraniin ruled out the possible mediation of these receptors. Moreover, geraniin attenuated the pressor responses to exogenous noradrenaline and Bay K 8644 to a similar degree, indicating the direct effect of this compound on vascular activity in rats. These results suggest that geraniin possesses the ability to lower systemic blood pressure through the reduction of noradrenaline release or by direct vasorelaxation.     

Pharmacokinetics and Anticonvulsant Effect of a New Hypnotic,CL 284,846, in Rats

Purpose. CL 284,846 (CL846) is an investigational non-benzodiazepine agent with hypnotic, anxiolytic, myorelaxant and anticonvulsant properties. This study assessed the pharmacokinetics and anticonvulsant action of CL846 in female Sprague-Dawley rats. Methods. CL846 pharmacokinetics were examined after either an iv bolus dose (2.5 mg/kg) or a 6-hr infusion (0.4 mg/kg/hr). CL846 pharmacodynamics were evaluated with a pentylenetetrazol (PTZ) infusion 5 min after a CL846 in bolus dose (0 to 10 mg/kg). CL846 and the derived metabolite CL 284,859 (CL859) concentrations in serum and brain tissue were determined by HPLC with fluorescence detection. Results. Both the steady-state volume of distribution (1636 ± 162 and 1804 ± 293 ml/kg, after bolus and infusion administration, respectively) and systemic clearance (19.1 ± 7.1 and 22.2 ± 4.3 ml/min/kg for bolus and infusion administration, respectively) were high. No differences in pharmacokinetic parameters were noted between the two modes of administration. The relationship between anticonvulsant effect and brain/serum concentrations was well described by an E_max model. CL846 was as effective as triazolam in antagonizing PTZ-induced seizures. Conclusions. Under the conditions of the present study, CL846 pharmacokinetics were linear and stationary. Further evaluation of the anticonvulsant properties of CL846 is warranted, including the potential development of tolerance, which is well known for benzodiazepines.     

Increased Sensitivity to the Anticonvulsant Effect of Valproate in Aging BN/BiRij Rats

The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.5 mg/min/kg. The infusion was terminated when the anticonvulsant effect intensity had reached the maximum attainable level or at a total infusion time of three hours. A nonlinear relationship between valproate concentration and anticonvulsant effect intensity was observed with no maximal effect in the concentration range up to 1200 mg · L^–1. With increasing age a parallel shift in the concentration versus anticonvulsant effect relationships toward lower concentrations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.Suzanne Hovinga: Deceased January 30, 1991.     

Bioavailability of Phenytoin and Anticonvulsant Activity after Oral Administration of Phenytoin-bis-hydroxyisobutyrate to Rats

Pharmaceutical Research -     

Developmental Toxicity Studies in Mice, Rats, and Rabbits with the Anticonvulsant Gabapentin

The developmental toxicity of the anticonvulsant agent gabapentinwas evaluated in mice, rats, and rabbits treated by gavage throughoutorganogenesis. Mice received 500, 1000, or 3000 mg/kg on gestationdays (GD) 6–15 and rats and rabbits received 60, 300,or 1500 mg/kg on GD 6–15 (rats) or 6–18 (rabbits).Additional groups received an equivalent volume of the vehicle,0.8% methylcellulose, or remained untreated. All dams were observeddaily for clinical signs of toxicity. In mice, body weightsand food consumption were recorded on GD 0, 6, 12, 15, and 18while in rats and rabbits these parameters were evaluated daily.Near term (mouse, GD 18; rat, GD 20; and rabbit, GD 29) eachfemale was euthanatized, necropsies were performed, and litterand fetal data were collected. Live fetuses were examined forexternal, visceral, and skeletal variations and malformations.No adverse maternal or fetal effects were observed in mice orrats given doses up to 1500 or 3000 mg/kg, respectively. Notreatment-related maternal or fetal effects were apparent inrabbits given 60 or 300 mg/kg. At 1500 mg/kg, one rabbit died,four others aborted, and reduced food consumption and body weightgain were observed. No other reproductive, litter, or fetalparameters were affected, except that the incidence of visceralvariations in rat fetuses was slightly but statistically significantlyincreased at 1500 mg/kg due to a slight increase in the incidenceof dilated renal pelvis. This finding was not considered biologicallysignificant because this degree of variability has been seenin this strain of rats. In conclusion, no evidence of teratogenicitywas found for gabapentin at doses up to 3000 mg/kg in the mouseand up to 1500 mg/kg in the rat and rabbit.     

Anticonvulsant Activity of Novel Derivatives of 2- and 3-Piperidinecarboxylic Acid in Mice and Rats

The relative ability of derivatives of 2-piperidinecarboxylic acid (2-PC; pipecolic acid) and 3-piperidinecarboxylic acid (3-PC; nipecotic acid) to block maximal electroshock (MES)-induced seizures, elevate the threshold for electroshock-induced seizures and be neurotoxic in mice was investigated. Protective index (PI) values, based on the MES test and rotorod performance, ranged from 1.3 to 4.5 for 2-PC benzylamides and from <1 to >7.2 for 3-PC derivatives. PI values based on elevation of threshold for electroshock-induced seizures and rotorod performance ranged from >1.6 to >20 for both types of derivatives. Since preliminary data indicated that benzylamide derivatives of 2-PC displace [³H]1-[1-(2-thienyl)-cyclohexyl]piperidine (TCP) binding to the phencyclidine (PCP) site of the N-methyl- -aspartate (NMDA) receptor in the micromolar range and such low affinity uncompetitive antagonists of the NMDA receptor-associated ionophore have been shown to be effective anticonvulsants with low neurological toxicity, the 2-PC derivatives were evaluated in rat brain homogenates for binding affinity to the PCP site. Although all compounds inhibited [³H]TCP binding, a clear correlation between pharmacological activity and binding affinity was not apparent. Select compounds demonstrated minimal ability to protect against pentylene-tetrazol-,4-aminopyridine- and NMDA-induced seizures in mice. Corneal and amygdala kindled rats exhibited different sensitivities to both valproic acid and the nonsubstituted 2-PC benzylamide, suggesting a difference in these two models. Enantiomers of the -methyl substituted benzylamide of 2-PC showed some ability to reduce seizure severity in amygdala kindled rats. © 1997 Elsevier Science Ltd. All rights reserved.     

Anticonvulsant Profile of 4-Amino-(2-methyl-4-aminophenyl)benzamide in Mice and Rats

Abstract: An original ameltolide analogue 4-amino-(2-methyl-4-aminophcnyl)benzamide, in which a second amino group has been introduced, was synthesized and evaluated for anticonvulsant activity. After intraperitoneal administration to mice, 4-amino-(2-methyl-4-aminophenyl)benzamide was found active in the maximal electroshock seizure test and against the tonic seizures elicited either by bicuculline or 3-mercaptopropionic acid. 4-amino-(2-methyl-4-arainophenyl)benzamidc (4A-2M4A-PB) gave anti maximal electroshock seizures ED₅₀, of 63 umol/kg (15.4 mg/kg) and a TD₅₀ of 676 μmol/kg (163 mg/kg), yielding a PI of 10.7: the potency is similar to that of the 4-amino-(2-rnethyl-3-aminophenyl)phthalimide (4-A-2M3A-PP), superior to that of 4-amino-(2,6-dimethylphenyl)phlhaiimide (4A-2,6-DMPP), close to that of phenytoin and carbamazepine and inferior to that of ameltolide. 4A-2M4A-PB with an ED₅₀ of 41 [28-60] μmol/kg (9.9 mg/kg) is as active after oral administration to rats as carbamazepine, more active than ameltolide, 4-A-2M3A-PP and phenytoin and slightly less active than the 4A-2,6-DMPP. The introduction of a second amino group on the substituted phenyl ring does not affect drastically the anticonvulsant potency after intraperitoneal administration to mice; moreover, it seems to enhance the activity after oral administration. 4A-2M4A-PB is a good candidate both for further pharmacokinetic studies and for the study of the precise mechanism of action.     

Relationship Between Receptor Occupancy at 37°C and the Anticonvulsant Effect of Flunitrazepam in Rats

In this investigation an attempt was made to evaluate quantitatively the relationship between benzo-diazepine receptor occupancy and the anticonvulsant effect of flunitrazepam in rats. A graded measure of anticonvulsant effect was obtained on the basis of an elevation of pentylenetetrazol (PTZ) threshold concentrations. The concentration–anticonvulsant effect relationship could be described by the E _max model with an EC₅₀ in cerebrospinal fluid of 2.9 ± 0.8 µg/liter and an E _max of 227 ± 22 mg/liter PTZ (mean ± SE). In vitro receptor occupancy was determined in a crude brain homogenate at 0 and 37°C, which yielded K _D values of 2.2 ± 0.2 and 26 ± 2 µg/liter, respectively. The results obtained in both experiments were combined by focusing on free flunitrazepam concentrations. This strategy resulted in a nonlinear relationship between receptor occupancy and anticonvulsant effect of flunitrazepam, with 90% of the maximum response achieved at a degree of receptor occupancy of approximately 50% at 37°C.     

巯甲丙脯酸对实验性高血压大鼠心肌缺血-再灌注损伤的保护作用

为探讨巯甲丙脯酸（ｃａｎｔｏｐｒｉｌ）对高血压肥大心肌缺血－丙灌注的影响,本实验以造成大鼠腹主动脉狭窄的方法复制高血压模型,观察了应用巯甲丙脯酸的高血压大鼠肉体心脏缺血－再灌注的变化。结果显示未用药的高血压大鼠,离体心脏在缺血－再灌注后出现心肌细胞乳酸脱氢酶的漏出和丙二醛生成增加及组织钙含量增加等损伤性变化,而预先应用巯甲丙脯酸处理的高血压大鼠,乳酸脱氢酶和丙二醛增高的情况明显减轻,避免了钙在心肌内过多积聚。表明巯甲丙脯酸具有抗高血压肥大心肌缺血－再灌注损伤的作用。     

Development of new antiepileptics. II. Anticonvulsant effect of hydantoin derivatives

From a series of N-substituted hydantoin derivatives, 1-phenyl-3-(o-chloro-p-sulfonamide-phenyl)-hydantoin was found to exhibit the best anticonvulsant activity against electroshock seizures. This substance showed also a weak activity against pentylenetetrazole seizures, as well as minor analgesic and sedative effects. The toxic effects are negligible; the lethal dose in mice was higher than 5000 mg/kg p.o. The other tested hydantoin derivatives showed much weaker anticonvulsant activities.     

Prostaglandin D2 Induced Potentiation of the Anticonvulsant Actions of Phenobarbitone and Phenytoin in Rats. Role of Serotonin

Prostaglandin D₂ (PGD₂) produced a dose-related potentiation of the anticonvulsant actions of sub-effective doses of phenobarbitone and phenytoin against maximal electroshock-induced seizures in rats. PDG₂-induced potentiation of phenobarbitone and phenytoin was significantly attenuated following pretreatment with centrally administered 5,6-dihydroxytryptamine, a selective neurotoxin for serotonergic neurones, p-chlorophenylalanine, a specific inhibitor of serotonin biosynthesis, and methysergide, a serotonin receptor antagonist, indicating that the potentiation was serotonin-mediated.     

On the Mechanism of Detoxicating Action of Acid Polysaccharides in Lead-Poisoned Rats

Pharmaceutical Chemistry Journal -     

塞隆骨对骨缺失大鼠的作用研究

In order to probe into the action of Sailong bone's strengthening the muscles and bones in bony deficiency rats, the restoration speed in bony deficiency rats and the therapeutic action in osteoporotic rats were studied.METHODThe femur coloboma was man-ma