抗点燃药物对小鼠自主活动的影响

目的观察几种抗点燃药物对小鼠自主活动的影响。方法用光电法测定抗点燃药物托吡酯、唑尼沙铵、丙戊酸钠、卡马西平、苯妥英钠及尼可地尔用药后6h内各时间点小鼠自主活动敷。结果研究显示托吡酯、唑尼沙铵、丙戊酸钠（P〈0.01）和苯妥英钠（P〈0.05）可以减少小鼠的自主活动次数，而卡马西平及尼可地尔未见此作用。结论抗点燃药物托吡酯、唑尼沙铵、丙戊酸钠、苯妥英钠、卡马西平及尼可地尔时小鼠自发运动的影响不一，其中托吡酯、唑尼沙铵、丙戊酸钠和苯妥英钠有中枢镇静作用，而卡马西平及尼可地尔无此作用。     

Contribution of social factors to opiate-induced activation in the mouse

Adult male Swiss-Webster mice of varying group size (single, or in groups of 2, 3, or 4) were injected with vehicle, or 25 or 50 mg/kg of morphine sulfate. In comparison with vehicle, morphine-injected mice showed heightened behavioral activity consisting mainly of stereotyped forward locomotion. This motor response was disproportionately enhanced by the presence of conspecifics. This suggests that morphine-induced activation of grouped animals reflects both individual activation responses and the further influence of social factors.     

Antinociceptive effects of sodium channel-blocking agents on acute pain in mice

The effects of various sodium channel blocking agents on acute thermal and mechanical nociception, as assessed using the plantar and tail pressure tests, respectively, were compared with the effects of morphine. The drugs used were mexiletine, lidocaine, carbamazepine, phenytoin, eperisone, tolperisone, and zonisamide. The sodium channel blocking agents exhibited a rather preferential elevation of the threshold for thermal nociception. By contrast, morphine produced similar analgesic effects on thermal and mechanical nociception. In the sciatic nerve isolated from mice, mexiletine, lidocaine, eperisone, and tolperisone impaired the propagation of low frequency action potentials (evoked at 0.2 Hz). Carbamazepine, phenytoin, and zonisamide generated a more frequency-dependent local anesthetic action with their obvious effects on higher frequency action potentials (evoked at 5 and/or 10 Hz). Our results show that sodium channel blocking agents have a preferential antinociceptive action against thermal stimulation that is likely to be attributed to their local anesthetic action.     

Behavioral interactions between opiate and antiepileptic drugs in the mouse

Morphine and related opioid compounds are known to possess proconvulsant activity based upon both electroencephalographic and behavioral criteria. The present authors previously suggested that opiate-related seizures were behaviorally inhibitory, and this was further investigated in the present study. The effects of pretreatment with three pharmacologically distinct compounds (sodium valproic acid, trimethadione, taurine) upon normal behavioral activation to systemic morphine were examined in the mouse. Morphine consistently increased activity levels in comparison with vehicle. Each of the three experimental compounds itself was behaviorally inhibitory; nonetheless both sodium valproate and trimethadione facilitated behavioral responses to morphine. The effects of the same drugs upon activation produced by central administration of a long-lasting enkephalin analog (d-ala²-leu-enkephalinamide) were investigated, with similar results. These findings confirm a behavioral interaction between opiate and anticonvulsant drugs, although it may be selective for certain classes of anticonvulsant compounds.     

Chronically administered fluoxetine enhances the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock model

Interactions between chronically administered fluoxetine and valproate, carbamazepine, phenytoin, or phenobarbital were studied in the maximal electroshock test in mice. Fluoxetine administered for 14 days at doses up to 20 mg/kg failed to affect the electroconvulsive threshold. Nevertheless the drug (at 15 and 20 mg) enhanced the anticonvulsant activity of valproate, carbamazepine, and phenytoin. When applied at 20 mg/kg, it potentiated the protective action of phenobarbital. Fluoxetine, antiepileptic drugs, and their combinations did not produce significant adverse effects evaluated in the chimney test (motor coordination) and passive-avoidance task (long-term memory). Chronically applied fluoxetine significantly increased the brain concentrations of valproate, carbamazepine, phenobarbital and phenytoin, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. In conclusion, long-term treatment with fluoxetine exhibited some favorable effects on the anticonvulsant properties of conventional antiepileptic drugs, resulting, however, from pharmacokinetic interactions.     

Synthetic cannabinoid WIN 55,212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshock-induced seizures in mice

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN — a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, and valproate) in the mouse maximal electroshock seizure (MES) model. The results indicate that WIN (10 mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test in mice. WIN (5 mg/kg) potentiated the anticonvulsant action of carbamazepine and valproate, but not that of phenytoin or phenobarbital in the MES test in mice. However, WIN administered alone and in combination with carbamazepine, phenytoin, phenobarbital and valproate significantly reduced muscular strength in mice in the grip-strength test. In the passive avoidance task, WIN in combination with phenobarbital, phenytoin and valproate significantly impaired long-term memory in mice. In the chimney test, only the combinations of WIN with phenobarbital and valproate significantly impaired motor coordination in mice. In conclusion, WIN enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test. However, the utmost caution is advised when combining WIN with classical antiepileptic drugs due to impairment of motor coordination and long-term memory and/or reduction of skeletal muscular strength that might appear during combined treatment.     

Design, anticonvulsive and neurotoxic properties of retrobenzamides. N-(Nitrophenyl)benzamides and N-(aminophenyl)benzamides

Design, anticonvulsant properties in maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentetrazole (scPtz), and neurotoxicity of retrobenzamides (N-(nitrophenyl)benzamides and N-(aminophenyl) benzamides are reported. These data are further compared with those on carbamazepine, phenytoin, ameltolide and other reference compounds. Studies on retrobenzamides in mice dosed intraperitoneally point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity for corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were, however, less active in the MES test than in mice dosed intraperitoneally. Differences between experimental animal species and administration routes lead to hypothesize rapid metabolization of compounds, reduced intestinal resorption and increased removal from body. The presence of a methyl substitution on the N-phenyl moiety of aminoretrobenzamides attenuated these discrepancies between mice and rats. Present results indicate that pharmacological values--including the dose offering anticonvulsant protection in 50% of tested animals (ED50) and protective indices--obtained on some retrobenzamides may compete with phenytoin and carbamazepine values. By contrast with phenytoin, some retrobenzamides further exhibit activity in the scPtz test.     

Influence of retigabine on the anticonvulsant activity of some antiepileptic drugs against audiogenic seizures in DBA/2 mice

Retigabine (D-2319, 0.5-20 mg/kg i.p.) antagonised dose dependently audiogenic seizures in DBA/2 mice. Retigabine at 0.5 mg/kg i.p., a dose that per se did not affect the occurrence of audiogenic seizures significantly, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The degree of additivity for the effect induced by retigabine was greatest for diazepam, phenobarbital, phenytoin and valproate, less for carbamazepine and lamotrigine and least for felbamate. The increase in anticonvulsant activity was usually associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment (drugs plus retigabine), was more favourable than the same drug plus vehicle. Since retigabine had no significant influence on the total and free plasma levels of the anticonvulsant drugs, pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that retigabine modifies the clearance of the anticonvulsant drugs from the brain cannot be excluded. Retigabine had no significant effect on the hypothermic effects of the anticonvulsants tested. In conclusion, retigabine showed an additive effect when administered in combination with classical anticonvulsants, most notably diazepam, phenobarbital, phenytoin and valproate.     

Strain difference in morphine-induced increase in plasma cyclic AMP and cyclic GMP levels in relation to locomotor activity in male mice

The effects of morphine on plasma cyclic nucleotide levels and on locomotor activity were investigated in four inbred strains of male mice. Morphine increased both cyclic AMP and cyclic GMP levels as well as locomotor activity in C57BL/6N mice. In BALB/cAnN mice, morphine increased plasma cyclic AMP levels and motor activity without changes in plasma cyclic AMP levels. In C3H/HeN mice, morphine increased plasma cyclic GMP levels without changing cyclic AMP levels and motor activity, but neither plasma cyclic nucleotide levels nor motor activity were increased by morphine in DBA/2N mice. Epinephrine and carbachol increased plasma cyclic AMP and cyclic GMP levels, respectively, in both C57BL and DBA mice. These results show that there is a significant strain difference in the effects of morphine on plasma cyclic nucleotide levels as well as motor activity. The major cause of strain difference in the effects of morphine on cyclic nucleotide levels is unlikely to be due to the difference in the regulation of adenylate cyclase linked to adrenoceptors or that of guanylate cyclase connected with cholinoceptors.     

Morphine self-administration in µ-opioid receptor-deficient mice

Morphine-induced place preference was demonstrated recently in wild-type mice, whereas this conditioned behaviour was not observed in mu-opioid receptor-deficient mice. In the present study, we investigated locomotor effects of subcutaneously (s.c.) injected morphine as well as intracerebroventricular (i.c.v.) morphine self-administration in mu-opioid receptor-knockout mice. After s.c. morphine injection, locomotor activity significantly increased in wild-type animals. As expected, in the self-administration test the rate of self-administration constantly increased in wild-type mice reflecting reward effects of morphine. This increase was independent of locomotor/motor activity. In contrast, self-administration rates and locomotor/motor activity significantly decreased in the receptor-deficient animals. It was shown that this aversive effect might partly be due to kappa-opioid receptor interaction.     

Effect of p-isopropoxyphenylsuccinimide monohydrate on the anticonvulsant action of carbamazepine,phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model

This study was designed to determine the effects of p-isopropoxyphenylsuccinimide monohydrate (IPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure model.Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that IPPS administered intraperitoneally (ip) at doses of 75 and 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. IPPS at lower doses of 18.75 and 37.5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, 37.5 mg/kg IPPS significantly enhanced the anticonvulsant activity of phenytoin and valproate, but not that of carbamazepine or phenobarbital, in the maximal electroshock seizure test in mice. IPPS (18.75 mg/kg) had no impact on the antiseizure action of phenytoin and valproate against maximal electroshock-induced seizures in mice. Pharmacokinetic experiments revealed that IPPS did not alter total brain concentrations of phenytoin or valproate in mice.In conclusion, the enhanced anticonvulsant action of phenytoin and valproate by IPPS in the mouse maximal electroshock-induced seizure model and lack of pharmacokinetic interactions make the combinations of IPPS with phenytoin and valproate of pivotal importance for further experimental and clinical studies. The combinations of IPPS with carbamazepine and phenobarbital are neutral from a preclinical viewpoint.     

Behavioral cross-sensitization between morphine-induced locomotion and sodium depletion-induced salt appetite

In general terms, sensitization refers to the capacity of a repetitive stimulus of fixed strength to produce a progressive increase in the magnitude of a response with each stimulation. In the addiction literature cross-sensitization is the capacity of an agent with abuse potential to sensitize a behavioral response induced by another stimulus. In the present experiments we examined the effects of morphine pretreatment on furosemide-induced saline intake and conversely sodium appetite induction on morphine-induced locomotion. In an initial experiment rats were pretreated with morphine (10 mg/kg, s.c.) or vehicle for 5 days. The rats were then sodium or sham depleted and 24 h later given a sodium appetite test. Sodium depleted rats pretreated with morphine increased saline intake compared to depleted rats initially pretreated with vehicle. In a second experiment rats that were previously depleted and repleted of sodium as compared to sham depleted animals showed enhanced locomotor activity in an open field test when challenged with morphine (1 mg/kg, s.c.). These studies demonstrate that the behavioral responses induced by sodium deficiency and morphine treatment cross-sensitize with one another and suggest that common neural substrates underlie the sensitization of behaviors associated with states induced by morphine and sodium appetite.     

Effects of some centrally active drugs on the allopregnanolone synthesis in rat brain

Effects of antidepressants (desipramine, amitriptyline), anticonvulsants (phenytoin, diazepam, carbamazepine) and addictive drugs (amphetamine, morphine), used at a concentration of 100 microM on the conversion of [14C]-progesterone to 5alpha-pregnane-3,20-dione and allopregnanolone in slices of the frontal cortex and olfactory bulb from rat brain were studied. The synthesis of 5alpha-pregnane-3,20-dione and allopregnanolone was stronger in the olfactory bulb than in the frontal cortex. The biosynthesis of allopregnanolone in the frontal cortex was higher by 74, 109 and 187% when stimulated by amitriptyline, desipramine and carbamazepine, respectively, and, to a lesser degree, by phenytoin and morphine. Desipramine and morphine decreased the concentration of 5alpha-pregnane-3,20-dione. In the olfactory bulb, only carbamazepine enhanced allopregnanolone production, but none of the tested drugs had any effect on 5alpha-pregnane-3,20-dione synthesis. It is concluded that some psychotropic drugs may increase allopregnanolone synthesis by stimulating the activity of the enzyme, 3alpha-hydroxysteroid dehydrogenase, in the frontal cortex, and that this neurosteroid may be partly involved in the mechanism of action of the drugs under study.     

Topiramate potentiates the antiseizure activity of some anticonvulsants in DBA/2 mice

Topiramate (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in DBA/2 mice in a dose-dependent manner. Topiramate at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by topiramate was greatest for diazepam, phenobarbital and valproate, less for lamotrigine and phenytoin and not significant for carbamazepine and felbamate. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of the combination of all drugs+topiramate was more favourable than that of antiepileptics+ saline, with the exception of carbamazepine or felbamate+topiramate. Since topiramate did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that topiramate can modify the clearance from the brain of the anticonvulsant drugs studied cannot be excluded. In addition, topiramate did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, topiramate showed an additive effect when administered in combination with some classical anticonvulsants, most notably diazepam, phenobarbital, lamotrigine, phenytoin and valproate.     

Effect of acutely and chronically administered venlafaxine on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock model

The influence of acute and chronic treatments with intraperitoneal venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor, on the anticonvulsant activity of selected antiepileptic drugs was studied in the maximal electroshock test in mice. Venlafaxine (12.5 and 25 mg/kg), given either acutely or chronically, significantly increased the electroconvulsive threshold. Moreover, both acute and chronic venlafaxine, applied at the highest subprotective dose of 6.25 mg/kg, enhanced the anticonvulsant effect of valproate, without affecting the protective action of carbamazepine, phenobarbital and phenytoin. The antidepressant did not affect brain concentration of valproate, indicating that the interaction between the two drugs seems pharmacodynamic in nature. Despite the lack of effect on the antielectroshock action of the remaining antiepileptics, acute venlafaxine increased the brain concentration of phenobarbital, while chronic venlafaxine reduced the brain level of phenytoin. In terms of adverse effects, acute/chronic venlafaxine and antiepileptic drugs alone, as well as their combinations, did not produce significant motor or long-term memory deficits in mice. Summing up, it seems that venlafaxine may be considered as a safe drug for the clinical use in patients with epilepsy and depressive disorders.     

Anticonvulsant potency of common antiepileptic drugs in the gerbil

In gerbils, 'minor' (myoclonic) and 'major' (clonic-tonic) seizures were induced by blowing at the animals with compressed air. The anticonvulsant ED50 of the following drugs was determined after oral administration against both types of seizures: phenytoin, phenobarbital, carbamazepine, sodium valproate, ethosuximide, and diazepam. Valproate, ethosuximide, and diazepam were most potent against 'minor' seizures which could not or only partially be suppressed by phenytoin or carbamazepine, respectively. The 'grand mal' drugs phenytoin, phenobarbital, and carbamazepine were, on the other hand, more potent against 'major' than against 'minor' seizures. When phenobarbital was administered for several days, a strong induction of hepatic microsomal enzymes occurred.     

病毒性脑膜炎引发癫痫持续状态患者的用药监护

一名病毒性脑炎继发癫痫的患者,在控制病毒感染的同时,联合运用苯妥英钠、苯巴比妥、丙戊酸钠和卡马西平以控制癫痫症状,但由于治疗期间停用丙戊酸钠和卡马西平致使癫痫症状加重。随后调整用药,在密切监测苯妥英钠和苯巴比妥血药浓度的情况下,加大这两种药物的用量,最终患者癫痫得到了控制,而且意识得到恢复。在整个治疗期间,临床药师与医师共同商讨治疗药物方案,医师听取并采纳了药师的合理用药建议。     

The role of beta-endorphin in the acute motor stimulatory and rewarding actions of cocaine in mice

Rationale Opioid receptor antagonists have been shown to attenuate the rewarding and addictive effects of cocaine. Furthermore, cocaine has been shown to cause the release of beta-endorphin, an endogenous opioid peptide. Objective We assessed whether this neuropeptide would play a functional role in cocaine-induced motor stimulation and conditioned place preference (CPP). Materials and methods Mice lacking beta-endorphin and their wild-type littermates were habituated to motor activity chambers for 1 h, then injected with cocaine (0, 15, 30, or 60 mg/kg, intraperitoneally) or morphine (0, 5, or 10 mg/kg, subcutaneously), and motor activity was recorded for 1 h. In the CPP paradigm, mice were tested for baseline place preference on day 1. On days 2 and 3, mice received an alternate-day saline/cocaine (15, 30, or 60 mg/kg) or saline/morphine (10 mg/kg) conditioning session and then tested for postconditioning place preference on day 4. Results Cocaine-induced motor stimulation and CPP were both reduced in mice lacking beta-endorphin. On the other hand, motor stimulation and CPP induced by morphine were not altered in mutant mice. Conclusion The present results demonstrate that the endogenous opioid peptide beta-endorphin plays a modulatory role in the motor stimulatory and rewarding actions of acute cocaine.     

Influence of high fat diet (butter) on pharmacokinetics of phenytoin and carbamazepine

The study was carried out to evaluate the effect of butter on the pharmacokinetics of phenytoin and carbamazepine. In a crossover study, phenytoin 30 mg/kg and carbamazepine 56 mg/kg were given orally to New Zealand white rabbits (n = 8 for each drug). Blood samples were drawn at different time intervals from 0-24 h from the marginal ear vein after drug administration. After a washout period of 7 days, butter (5 mg/kg) was administered for 7 days to the animals. On the 8th day, butter and phenytoin or carbamazepine were administered simultaneously and the blood samples were withdrawn at the same time points. Plasma was separated and stored at -20 degrees C until assayed for phenytoin and carbamazepine by HPLC and different pharmacokinetic parameters were calculated. Butter increased the absorption of both phenytoin and carbamazepine, as there was a significant increase in the Cmax and AUC(0-alpha) of both drugs after butter administration. No significant difference in Tmax was observed. In this study, it was found that a high fat diet increases the bioavailability of phenytoin and carbamazepine in New Zealand white rabbits.     

Evidence for a common site of action of lidocaine and carbamazepine in voltage-dependent sodium channels

The finding that the development of lidocaine-kindled seizures is blocked by carbamazepine suggests an interaction of carbamazepine with local anesthetic mechanisms. To study the site of interaction, the effects of lidocaine, carbamazepine and another anticonvulsant drug, phenytoin on scorpion venom-enhanced specific binding of [3H]batrachotoxinin A 20-alpha-benzoate to the sodium channel gating complex were examined in vitro in a rat brain hippocampus preparation. Lidocaine shifted the concentration inhibition curve of carbamazepine to the right and vice versa. Carbamazepine shifted the concentration inhibition curve of phenytoin to the right and vice versa. The experimentally determined apparent dissociation constants were in a good agreement with the dissociation constants calculated for a one-site model, suggesting that the interaction occurs because lidocaine shares a common binding site with carbamazepine and phenytoin in the voltage-dependent sodium channels.