Differential blockade of bicuculline convulsions by neuroleptics.

Haloperidol, pimozide, sulpiride and metoclopramide blocked bicuculline-induced convulsions in mice. Chlorpromazine and thioridazine exhibited this effect at low doses whereas at higher doses (e.g. 1 mg/kg i.p. chlorpromazine) this activity was no longer apparent. A dose of phenoxybenzamine which was inactive alone (7.5 mg/kg i.p.) completely blocked the anti-bicuculline effect of sulpiride and antagonized that of haloperidol. These data are interpreted as indicating that intact noradrenergic systems are necessary for the anti-bicuculline effect of the neuroleptics.     

Increase of 3-methoxy-4-hydroxyphenylethylene glycol in rat brain by neuroleptic drugs

The potency of various neuroleptic drugs in increasing the content of endogenous 3-methoxy-4-hydroxyphenyl-ethylene glycol (MOPEG) in rat brain decreased in the order methiothepin, haloperidol, clozapine, thioridazine, chlorpromazine, pimozide. The neuroleptics, except pimozide and chlorpromazine, also caused a slight to moderate diminution of the endogenous cerebral noradrenaline (NA).Based on these and earlier findings it is concluded that (a) changes in brain NA turnover induced by neuroleptics can be estimated, in a relatively simple way, by measuring cerebral MOPEG; (b) these drugs markedly differ in their ability to activate noradrenergic neurons; and (c) the activation of noradrenergic neurons by neuroleptics does not seem to parallel that of dopaminergic neurons.     

Evaluation of health status in epilepsy using the EQ-5D questionnaire: a prospective,observational, 6-month study of adjunctive therapy with anti-epileptic drugs

ABSTRACT

Aims: The aims of this project were to evaluate the impact of adjunctive treatment with an anti-epileptic drug (AED) on the health status of people with epilepsy and to investigate how seizure frequency affects their health status.

Methods: Adult epilepsy patients, refractory to current treatment, were included in this prospective observational study. Patients commencing adjunctive therapy with one of five AEDs (topiramate, lamotrigine, gabapentin, clobazam, vigabatrin) were eligible for inclusion. The study took place at the outpatient clinics of the National Hospital for Neurology and Neurosurgery, Queen Square, London. Patients completed the EQ-5D, a generic health status measure, at baseline and again after 3 and 6 months. Information was also collected on medications and seizure frequency.

Results: In total, 125 patients entered the study and were followed up for 6 months. Patients treated with topiramate had a significant increase (?p < 0.05) in EQ-5D score from baseline, indicating an improvement in their health status whereas scores for lamotrigine, clobazam and gabapentin all showed a non-significant decline. When the data were analysed according to seizure frequency, only patients who became seizure-free on adjunctive treatment had a significant increase in their health status. The group who had a 50% reduction in seizure frequency did not have increased health status.

Conclusions: In summary, adjunctive treatment with topiramate significantly increased health status as measured by the EQ-5D. These data also suggest that achievement of seizure-freedom is the key to improving health status in this patient group.     

Effects of neuroleptic drugs,clonidine and lithium on the expression of conditioned behavioral excitation in rats

Rats with a history of daily (21 days) amphetamine (2.5 mg/kg) treatment showed enhanced activity when under placebo in their amphetamine-associated environment. We found that this conditioned effect was reduced by haloperidol (0.06; 0.125; 0.25 mg/kg), pimozide (0.25; 0.5 mg/kg) and sulpiride (8; 16; 32 mg/kg) but only at doses similar to or, in the case of pimozide, higher than those required to antagonize the unconditioned stimulant effects of amphetamine (2.5 mg/kg). Conversely, we observed that clonidine (7; 15; 30; 60 g/kg) or lithium regimen (between days 15 and 21) leading to lithium plasma levels of 1.3±0.1 mEq/1, abolished amphetamine-conditioned hyperactivity but did not affect the unconditioned stimulation of amphetamine or locomotor activity in control rats. Moreover, we found that hyperactivity induced by the daily anticipation of food delivery shared identical pharmacological sensitivity with the behavioural excitation produced by a conditioning history with amphetamine. In light of the antimanic properties of lithium and clonidine and the ability of this latter drug to reduce noradrenergic transmission, our findings raise the posibility that incentive activity may model noradrenergic-dependent aspects of mania.     

Effects of CYP2D6 polymorphisms on neuroleptic malignant syndrome

Objective Neuroleptic malignant syndrome (NMS) is one of the most serious adverse reactions to antipsychotic medications. We accumulated data on Japanese NMS patients and, in a study designed to examine the effects of drug metabolism on the occurrence of NMS, tested the possibility of association between NMS and CYP2D6 polymorphisms. Methods We studied 53 patients who had experienced NMS and 112 healthy individuals. We determined what drugs the patients with NMS had been given and retrospectively identified candidates for drugs causing NMS. We screened the prevalence of CYP2D6 genotypes using polymerase chain reaction and restriction fragment length polymorphism analyses. Results The prevalence of *5 alleles in the group of all patients with NMS was higher than that in the controls, though this difference was not statistically significant (10.4% vs. 5.4%; P = 0.107; odds ratio (OR) 2.05; 95% confidence interval (CI) 0.87–4.80). No association was found between the frequency of *10 alleles and the occurrence of NMS. We found *4 and duplicated alleles in only one patient each among the patients with NMS. A total of 29 patients appeared to have developed NMS as a result of having taking CYP2D6 substrates. The prevalence of *5 alleles in these 29 patient was significantly higher than that in the controls (15.5% vs. 5.4%; P = 0.020; OR 3.25; 95% CI 1.30–8.13). Conclusion Our findings suggest that the CYP2D6*5 allele is likely to affect vulnerability to development of NMS.     

The efficacy and tolerability of perampanel and other recently approved anti-epileptic drugs for the treatment of refractory partial onset seizure: a systematic review and Bayesian network meta-analysis

Abstract

Objectives:

This paper compares the efficacy and tolerability of perampanel (PER) relative to other recently approved anti-epileptic drug (AEDs) – lacosamide (LCS), retigabine (RTG), and eslicarbazepine (ESL) for the adjunctive treatment of partial onset seizures with or without secondary generalization and specifically in the secondary generalization subgroup.     

Effects of drugs affecting the noradrenergic system on convulsions in the quaking mouse

Summary Handling-induced convulsions in the quaking mouse can be blocked by: phenobarbital, pentobarbital or phenytoin; postsynaptic alpha-adrenoceptor agonists (noradrenaline, phenylephrine, CRL 40028); presynaptic alpha-adrenoceptor blockers (yohimbine, mianserine); catecholamine liberating agent (amphetamine); noradrenaline reuptake inhibitors (cocaine, imipramine, desipramine).Moreover, the protective effect of yohimbine was antagonized by clonidine, prazosin or alpha-methylparatyrosine, and the protective effect of CRL 40028 was antagonized by prazosin but not by alpha-methyltyrosine. Drugs acting by other mechanisms (pilocarpine, atropine, trihexyphenidyl, (–)-5-HTP, methysergide, pimozide, clonidine, alpha-methyl DOPA, prazosin, isoprenaline, salbutamol) did not protect against convulsions. A slight protection was obtained with high doses of apomorphine and also with (±)-propranolol. This effect is probably not related, to blockade of betaadrenoceptors because the same effect was obtained with (+)propranolol. In young quaking mice, where susceptibility to convulsions is low, both postsynaptic alpha-adrenoceptor blockers and presynaptic alpha-adrenoceptor antagonist lowered the convulsive threshold. Thus, this seems to constitute an interesting model for the in vivo study of substances which affect the central alpha-adrenoceptors either pre- or postsynaptically.     

抗癫痫药物对癫痫患儿的骨代谢影响研究

目的分析抗癫痫药物对癫痫患儿骨代谢相关指标及生活质量的影响。方法选取2013年1月至2015年2月在我院接受抗癫痫药物治疗的癫痫患儿42例为观察组,另选取同时期未接受癫痫药物治疗的癫痫患儿36例为对照组,对比两组患儿治疗前后血清碱性磷酸酶(ALP)、血钙(Ca~(2+))、血磷(P)、骨密度(BMD)、磷酸酶(BAP)等骨代谢相关指标,并应用生活质量评估量表(QOLIE-31)对治疗前后两组患儿的生活质量进行评价。结果治疗后,观察组患儿的Ca~(2+)水平显著降低,BAP水平显著升高,差异均有统计学意义(P<0.05),ALP、P及BMD均无显著变化(P>0.05);观察组患儿的Ca2+水平低于对照组,BAP水平显著高于对照组,差异有统计学意义(P<0.05);对照组患儿各项骨代谢指标无显著变化(P>0.05)。治疗前,两组患儿的生活质量评分比较差异无统计学意义(P>0.05),治疗后,观察组患儿生活质量评分升高,且高于对照组,差异均有统计学意义(P<0.05)。结论抗癫痫药物能够提高癫痫患儿的生活质量,其对癫痫患儿的骨代谢具有一定的影响,对BAP的影响最显著。BAP可以作为指导正确应用癫痫药物的指标。     

Modulation of long-term potentiation: effects of adrenergic and neuroleptic drugs

A variety of drugs which either mimic or antagonize the effects of norepinephrine and dopamine were tested for their ability to modulate long-term potentiation (LTP) in the rat hippocampus in vitro. Neither administration of norepinephrine, amphetamine or adrenergic antagonists, nor pretreatment with reserpine or DSP4 (which selectively destroys noradrenergic afferents to the hippocampus) had any significant effect on the magnitude of LTP. Isoproterenol, a beta-adrenergic receptor agonist, was able to partially block LTP, but this did not appear to be due to a direct action of isoproterenol on LTP. Neuroleptic drugs such as trifluoperazine were able to block LTP almost completely; however, this action was not stereospecific. Other dopamine antagonists such as sulpiride had no effect on LTP. The ability of neuroleptics to antagonize LTP was more closely related to their ability to block calmodulin than to their relative potencies as dopamine antagonists. It would appear that neither norepinephrine nor adrenergic antagonists influence the amount of LTP elicited by repetitive stimulation; however, drugs which have been shown to interfere with calmodulin-mediated cellular processes do antagonize this phenomenon.     

Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity.

Apomorphine and the putative dopamine agonist, 2-(N, N-dipropyl)-amino-5, 6-dihydroxytetralin induced dose-dependent climbing behaviour in the mouse which was measured in wire mesh lined cages as the percentage of time spent climbing in the 30 min period following the first climb and as the maximum time spent in a single climb throughout the drug effect. These These two measures were generally found to parallel excepting when the interacting agent caused muscular hypotonia. All potential interacting agents were given as pretreatments to determine changes in motor function which may interfere with the climbing induced by 1.0 mg/kg s.c. apomorphine. The possibility of a change in the apomorphine response to a sterotyped biting, which would also interfere with climbing, was also considered. Excluding these non-specific changes, climbing behaviour was shown to be antagonised, dose-dependently, by low doses of typical and atypical neuroleptic agents (haloperidol, fluphenazine, loxapine, pimozide, oxiperomide, clozapin, thioridazine, sulpiride, tiapride and metoclopramide) but not specifically by other psychoactive agents. Climbing behaviour was modified by serotonergic agents; the agonist quipazine reduced or abolished, whilst the antagonists, methysergide and cyproheptadine, enhanced the response. Picrotoxin specifically reduced climbing behaviour but sodium valproate exerted non-specific effects, precluding conclusions as to a GABA involvement. Cholinergic and noradrenergic involvements with climbing were also apparently eliminated by the ineffectiveness of atropine, aceperone, piperoxan and propranolol. The involvement of serotonin with climbing was extended to the actions of the neuroleptics: the antagonistic effects of typical neuroleptics (haloperidol, fluphenazine, loxapine) were markedly enhanced by combination with methysergide or cyproheptadine whilst the effects of clozapine, sulpiride and thioridazine were significantly reduced. The actions of metoclopramide, oxiperomide, pimozide and tiapride were not generally modified by such combinations. These differences are discussed in terms of differential abilities to induce extrapyramidal disturbances and the mouse climbing model is forwarded as a test with potential to detect antipsychotic agents of different activity spectra.     

Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins

There is accumulating evidence that most beta-lactam antibiotics (i.e., cephalosporins and penicillins) have some degree of convulsive activity, both in laboratory animals as well as in clinical settings. The proposed mechanism is suppression of inhibitory postsynaptic responses, mainly mediated by gamma-amino butyric acid (GABA)(A)-receptors (GABA(A)-R). However, comprehensive studies on the convulsive activities of various beta-lactam antibiotics in vivo and in vitro have not been performed. We have therefore examined the convulsive activities of seven different cephalosporins using both in vivo and in vitro models: intracerebroventricular (ICV) administration in mouse; [(3)H]muscimol binding assay (BA) in mouse brain synaptosome; and inhibition of recombinant mouse alpha1beta2gamma2s GABA(A)-Rs in Xenopus oocyte (GR). The rank orders of convulsive activities in mouse (cefazolin>cefoselis>cefotiam>cefpirome>cefepime>ceftazidime>cefozopran) correlated with those of inhibitory potencies on [(3)H]muscimol binding and GABA-induced currents of GABA(A)-R in vitro, with correlation coefficients of ICV:GR, ICV:BA and BA:GR of 0.882, 0.821 and 0.832, respectively. In contrast, none of the antibiotics had affinities for N-methyl-D-aspartate (NMDA) receptors nor facilitatory actions on NMDA receptor-mediated current in oocytes. These results clearly demonstrate that the mechanism of cephalosporin-induced convulsions is mediated predominantly through the inhibition of GABA(A)-R function and not through NMDA receptor modulation.     

Alterations in [Met]- and [Leu]enkephalin and neurotensin content in basal ganglia induced by the long-term administration of dopamine agonist and antagonist drugs to rats

Treatment of rats for 18 months with trifluoperazine increased [Met⁵]- and [Leu⁵]enkephalin and neurotensin content in striatum and nucleus accumbens. However, in substantia nigra the content of [Met⁵]enkephalin was decreased, [Leu⁵]enkephalin unchanged and that of neurotensin increased. Administration of L-DOPA plus carbidopa, bromocriptine or pergolide for 12 months decreased [Met⁵]enkephalin (except bromocriptine) and neurotensin, but not [Leu⁵]enkephalin, levels in striatum. L-DOPA decreased and bromocriptine increased neurotensin levels in substantia nigra. But neurotensin levels in nucleus accumbens were unaffected.     

Effects of etomidate,ketamine or propofol,and their combinations with conventional antiepileptic drugs on amygdala-kindled convulsions in rats

Ketamine, etomidate and propofol modified behavioral and electrographic correlates of kindled seizures in rats. In detail, ketamine (5 mg/kg) and propofol (15 mg/kg) significantly increased afterdischarge threshold, reduced seizure severity and shortened seizure and afterdischarge durations. Etomidate (7.5 mg/kg) was effective in terms of seizure and afterdischarge durations. Moreover, the combinations of ketamine (2.5 mg/kg) with carbamazepine (15 mg/kg) or valproate (50 mg/kg; all drugs at their subeffective doses), reduced the severity and duration of kindled seizures. The antiseizure potency of the ketamine/carbamazepine combination was comparable to that of carbamazepine alone administered at 20 mg/kg, while the effect of ketamine/valproate was comparable to the efficacy of valproate alone at 100 mg/kg. However, the combinations of ketamine with phenobarbital or diphenylhydantoin did not exert any protective action. Propofol and etomidate entirely failed to interact with conventional antiepileptics. The combinations of ketamine with carbamazepine or valproate did not induce any significant motor impairment in the chimney test or memory deficit in the passive avoidance task. A pharmacokinetic interaction, at least in plasma, can be excluded, because ketamine (2.5 mg/kg) did not affect the free plasma concentrations of carbamazepine or valproate. Results of the present study may suggest that there may be no risk of negative interactions between injectable anesthetics and antiepileptics in cases of partial epilepsy.     

Effects of chlorprothixene, haloperidol, and trifluoperazine on the delayed-matching-to-sample performance of pigeons

The effects of chlorprothixene (4,6,8, and 10 mg/kg), haloperidol (0.13, 0.25, 0.38, and 0.5 mg/kg), and trifluoperazine (0.5, 1,2, and 3 mg/kg) were examined in pigeons responding under a delayed-matching-to-sample procedure in which delays of 0.5-, 1-, 2-, 4-, and 8-sec duration were arranged during each experimental session. Both chlorprothixene and trifluoperazine typically reduced accuracy (percent correct responses); the magnitude of this effect was generally largest at the longest delay values. Chlorprothixene was associated with an increased rate of responding to the sample stimulus in two of three subjects, whereas trifluoperazine almost always decreased response rate. Haloperidol at high doses decreased response rate, but failed to consistently impair accuracy at any dose or delay value.     

Evidence against serotonin involvement in the tonic component of electrically induced convulsions and in carbamazepine anticonvulsant activity

Intraventricular injection of 5,7-dihydroxytryptamine, selective destruction of descending serotoninergic neurons by 5,6-dihydroxytryptamine or electrolytic and chemical lesions of the nucleus raphe dorsalis did not affect the electroconvulsive threshold in rats. No effect was observed after the systemic administration of drugs known to increase central serotonin transmission, such as quipazine, m-chlorophenylpiperazine, and moderate doses of d-fenfluramine, whereas p-chlorophenylalanine, an inhibitor of serotonin synthesis, decreased seizure susceptibility. The anticonvulsant activity of carbamazepine was not modified in animals with the same experimental lesions. The results, in relation to the high selectivity of the experimental procedures employed to deplete brain and spinal cord serotonin, do not bear out any involvement of serotonin in the tonic component of electrically induced convulsions or in the action of carbamazepine.     

非心血管药物所致尖端扭转型室性心动过速的分类与处理

目的：介绍引起QT间期延长及尖端扭转型室性心动过速（简称室速）的非心血管药物的种类和致病机制，以引起临床医生的重视。方法：对国内外相关文献进行综合、归纳。结果：许多非心血管药物可引起QT间期延长及尖端扭转型室速，包括抗微生物药、抗组胺药、三环类抗抑郁药、抗精神病药和胃肠动力药等。结论：了解导致这种较为罕见且严重的心带失常药物的种类及发病机制，对预防和正确治疗极为重要。     

Multiunit activity from the A9 and A10 areas in rats following chronic treatment with different neuroleptic drugs

Effects of repeated twice daily i.p. administration of haloperidol (0.5 mg/kg), clozapine (3.0 mg/kg) and prothipendyl (1.0 mg/kg) on spontaneous A9 and A10 cell activity were studied using extracellular multiunit recording in rats, which offers relatively rapid access to neural activity in a large number of cells. Two cell types were identified, which probably represent the putative dopaminergic and non-dopaminergic neurons. Repeated neuroleptic treatment reduced the number of spontaneously active type 1 A10 cells per track. The effect of haloperidol was more pronounced than that of clozapine or prothipendyl. A9 cells were affected by haloperidol only. The frequency and amplitude of A9 and A10 active cells remained quite stable, except for a clozapine-induced increase of their values for type 1 A10 cells. Stability of spontaneously active type 1 A10 cells was significantly reduced by the chronic neuroleptic treatment. Collectively the activity of type 2 cells was not altered. Prothipendyl was classified as an atypical neuroleptic drug with potency comparable to clozapine.     

Evaluation of cytochrome P450 inductions by anti-epileptic drug oxcarbazepine, 10-hydroxyoxcarbazepine,and carbamazepine using human hepatocytes and HepaRG cells

1. Anti-epileptic drug oxcarbazepine is structurally related to carbamazepine, but has reportedly different metabolic pathway. Auto-induction potentials of oxcarbazepine, its pharmacologically active metabolite 10-hydroxyoxcarbazepine and carbamazepine were evaluated by cytochrome P450 (CYP) 1A2, CYP2B6 and CYP3A4 mRNA levels and primary metabolic rates using human hepatocytes and HepaRG cells.

2. For the CYP1A2 the induction potential determined as the fold change in mRNA levels was 7.2 (range: 2.3–11.5) and 10.0 (6.2–13.7) for oxcarbazepine and carbamazepine, respectively, while 10-hydroxyoxcarbazepine did not induce. The fold change in mRNA levels for CYP2B6 was 11.5 (3.2–19.3), 7.0 (2.5–10.8) and 14.8 (3.1–29.1) for oxcarbazepine, 10-hydroxyoxcarbazepine and carbamazepine, respectively. The fold change for CYP3A4 induction level by oxcarbazepine, 10-hydroxyoxcarbazepine and carbamazepine was 3.5 (1.2–7.4), 2.7 (0.8–5.7) and 8.3 (3.5–14.5), respectively. The data suggest lower induction potential of oxcarbazepine and 10-hydroxyoxcarbazepine relative to carbamazepine. The results in HepaRG cells showed similar trend as the human hepatocytes.

3. After incubation for 72?h in hepatocytes and HepaRG cells, auto-induction was evident for only carbamazepine metabolism. The 10-keto group instead of double bond at C10 position is evidently a determinant factor for limited auto-induction of P450 enzymes by oxcarbazepine.

     

The effect of anticonvulsant drugs on convulsions triggered by direct stimulation of the brainstem

Brainstem-triggered convulsions are generalized convulsive seizures produced by direct electrical stimulation of the mesencephalic reticular formation. Four anticonvulsant drugs, phenobarbital, phenytoin, trimethadione, and ethosuximide, were tested against brainstem-triggered convulsions in the rat using a standard pharmacological dose-response paradigm. All four drugs proved to be active in small, subtoxic doses, producing a response profile similar to that previously reported for maximal pentylenetetrazol seizures. These results appear consistent with the hypotheses that: (1) the brainstem plays an important role in the production of generalized convulsions; and (2) that anticonvulsant drugs exert major therapeutic effects at the brainstem level.