Potentiation of the Antiepileptic Activity of Phenobarbital by Nicotinamide

Nicotinamide is a ligand of the benzodiazepine receptor and has been reported to have anticonvulsant activity. In addition, our previous clinical experience has raised the possibility that it may also potentiate the action of barbiturates. Therefore, we have examined the anticonvulsant activity and neurotoxicity of nicotinamide alone and in combination with phenobarbital in mice. Nicotinamide had its maximal anticonvulsant effect 15 min and its maximal sedative effect 45 min after intraperitoneal injection. At 15 min, the median effective dose was 586.5 mg/kg against bicuculline and 2,019 mg/kg against pentylenetetrazol. Nicotinamide was ineffective against maximal electroshock. It had a sedative effect, with a median toxic dose of 874.8 mg/kg by the Rotorod Toxicity Test at 45 min. At doses that were ineffective by themselves (0.01 effective dose) nicotinamide potentiated the anticonvulsant activity of phenobarbital against bicuculline and pentylenetetrazol, but the toxicity was not potentiated and therefore the therapeutic index of phenobarbital was improved by nicotinamide. These results suggest that nicotinamide may be useful as a therapeutic adjunct for the treatment of epilepsy with phenobarbital or primidone.     

Analysis of drug effects on multiple fixed ratio 33-Fixed interval 5 min in pigeons

Summary Several drugs were tested for their effects on the performance of pigeons in a schedule of positive reinforcement (Multiple Fixed Ratio 33-Fixed Interval 5 min). The experiments consisted of three successive cross-over designs, each involving a pair of drugs: amphetamine versus scopolamine; phenobarbital versus chlordiazepoxide; chlorpromazine versus haloperidol. Diazepam was tested alone at the end of the experiments.Amphetamine induced an enhancement of overall FI response rates at lower doses, while higher doses were followed by a reduction or a reversal of effect in most animals. The response enhancement was not necessarily associated to an alteration of the characteristic FI scalloped pattern (quantified by means of quarter-life measurements), while higher doses caused a marked enhancement of responding in the early portion of the interval.Scopolamine provoked a dose-dependent reduction of response rate and of quarter-life. Marked effects on the latter appeared, in general, at doses higher than those sufficient to depress response rate. Nevertheless, this drug was the most potent of all agents tested in regard to attenuation of the FI curvature. On the other hand, the discrimination between the FI and FR components of the schedule, based on visual stimuli, was unaffected.Phenobarbital provoked a marked dose-dependent enhancement of response rate and a reduction of quarter-life. Chlordiazepoxide gave a clear-cut, dose-dependent reduction of response rate in some animals, while negligible or non-systematic changes were observed in others. Diazepam provoked a wide variety of changes in opposite directions. With both benzodiazepine derivatives no significant average deviations of response rates from control baselines were obtained, while significant changes in quarter-life were observed. Again, the latter were in the direction of an increased proportion of early responses.The well-known properties of chlorpromazine, which gives a reduction of response rate and of quarter-life, were confirmed. However, a rather large dose (5 mg/kg) was necessary to obtain clear-cut, significant effects. On the contrary, haloperidol gave a major depression of response rate already at a dose of 0.05 mg/kg, but left the response distribution unaffected at all doses tested (0.05–0.4 mg/kg).We wish to acknowledge the expert technical assistance of Mr. Luigi de Acetis.     

Diphenylhydantoin and phenobarbital in the relief of psychoneurotic symptoms

This study is a double-blind comparison of the clinical effects of diphenylhydantoin (DPH) and phenobarbital among 80 adult psychoneurotic, non-epileptic outpatients. Patients were assigned at random to eight weeks of treatment with DPH 300 mg or phenobarbital 90 mg daily. During this time, patients were followed in brief bi-weekly interviews by one of two treating psychiatrists.At each visit, the patient's clinical condition was evaluated by the patient's ratings of distress on a factored list of 65 common psychoneurotic symptoms, on a mood adjective checklist, on the Psychiatric Evaluation Profile and on a global scale of change, and by the doctor's ratings on several global scales of change. Each criterion was analyzed with respect to initial score, medication, doctor and the medication by doctor interaction. The one doctor's patients responded better than the other doctor's patients.The results suggested that DPH and phenobarbital in the doses employed had similar effects on psychoneurotic symptoms. More extensive analyses of one patient rating and one doctor rating were performed to look for characteristics of the patient or the treatment situation that might affect medication responses. No useful predictors of differential response to the two medications appeared. Patients with brief illnesses, no prior psychiatric care and no previous phenothiazines or antidepressants responded better than their counterparts to both medications.Some patients who terminated prematurely reported very marked improvement—even more than most patients who completed the prescribed course of treatment. This observation challenges the usual assumption that drop-outs represent treatment failures. The equivocal results with regard to medication effects point up the potential value of studies designed to produce dose-response information.This investigation was supported by research grants from the Dreyfus Medical Foundation and by Research Scientist Development Award No. 2-K3-MH-18611 from the National Institute of Mental Health. Computations were performed at the Computing Center of the Johns Hopkins Medical Institutions, which is supported by grant No. FR-00004 from the Division of Research Resources of the National Institutes of Health, and at the Biomedical Computation Facilities of the University of Chicago, which are supported by grant No. FR-00013 from the Division of Research Resources of the National Institutes of Health.Miss Jil Culver, Miss Elizabeth Grether, Mrs. Mark Hollander, Mr. Clay Kallman, Mrs. Helen Russell, and Mrs. Marie Stephens provided technical assistance.     

Influence of isolation and of fighting on adrenal tyrosine hydroxylase and phenylethanolamine-N-methyltransferase activities in three strains of mice

Mice (BALB/C or NIH, C57 BR/cdJ and A/HeJ) were isolated for 2 weeks then exposed to another mouse for 10 min daily for 1 week. Isolated, unexposed and grouped controls were also studied. Aggression, defined as stereotyped attack behavior, was produced only in the NIH mice which were subsequently used as aggressors. When attacked, the victims, C57 BR/cdJ mice defended themselves whereas A/HeJ mice remained submissive.Isolation alone did not alter adrenal medullary levels of tyrosine hydroxylase (TOH), phenylethanolamine-N-methyltransferase (PNMT) or catecholamines. NIH mice showed an increase in TOH but not in PNMT when they fought with NIH or C57 BR/cdJ mice, whereas both victims showed increases in TOH and PNMT. It was concluded therefore that fright or active fighting induces increases in adrenal medullary enzymes.Drugs were injected into C57 BR/cdJ mice at doses which did not impair their defense behavior, using untreated NIH mice as aggressors. Phenobarbital fully inhibited both TOH and PNMT rise while chlorpromazine only partly suppressed PNMT increase. Methamphetamine was less effective than phenobarbital. Tranylcypromine increased both enzymes in control animals and partly suppressed TOH rise induced by defense.Thus, a reliable model of mild stress was produced which appears suitable for screening psychoactive drugs.     

Phenobarbital and d-amphetamine effects on discrimination performance of rats and juvenile baboons

Hungry rats in Skinner boxes were trained to select the right or left lever as correct as a function of the presence of a tone or light stimulus, respectively. Correct responses produced liquid food rewards. Acute intraperitoneal administration of d-amphetamine or phenobarbital did not affect accuracy of performance, but decreased the percent trials attempted and lengthened response times as a function of increasing doses. The mean extra responses during the delay intervals generally decreased under phenobarbital and increased under d-amphetamine. Juvenile baboons were trained to respond on a delayed match-to-sample task in order to obtain banana pellet rewards. Acute intramuscular administration of phenobarbital produced a dose-related increase in errors, a decrease in mean extra responses and an increase in response times. A slight reduction in the percent trials attempted occured only at the highest dose of the drug. Acute intramuscular d-amphetamine did not increase errors even at dose levels that increased reaction times, decreased extra responses and reduced the percent trials attempted.     

Discriminative,disinhibitory, and depressant effects of several anticonvulsants

The discriminative attributes of drugs were used to assess the degree to which several anticonvulsants have behavioral effects resembling those of pentobarbital. Rats were trained to make alternative responses to obtain water, depending on whether they had been injected IP with pentobarbital (10 mg/kg) or saline 10 min before the session. The pentobarbital response was chosen in tests with phenobarbital, dimethylphenobarbital, or methsuximide in the anticonvulsant dosage range. Increasing doses increased the percentage pentobarbital choice. Response rate was generally increased by doses that increased percentage of pentobarbital choice. The rats predominantly chose the saline response when administered phenytoin, primidone, or phenylethylmalondiamide, even at doses that were sufficiently high to reduce the response rate. The results suggest that different types of depressant effects are associated with the anticonvulsants tested.     

Stimulierung der Oxydation von Fremdstoffen in Nierenmikrosomen durch Phenobarbital

Summary Pretreatment of rats and rabbits with Phenobarbital (80 mg/kg and 60 mg/kg respectively) caused a 30% increase in the liver weight relative to body weight. There was a smaller increase in the kidney weight (7% in rats and 10% in rabbits) which was not statistically significant. The yields of microsomes per gram of liver was also increased by about 90% and 60% in rats and rabbits respectively, but only a slight increase was observed for kidneys (12% and 18% respectively).Pretreatment with Phenobarbital, 3,4-Benzpyrene or Chlorophenothane neither significantly increased the cytochromes of rat kidney microsomes, nor the oxidative drug metabolism. However, in the kidneys of rabbits the cytochrome-b₅-and P₄₅₀-concentrations and drug metbolism were 2–3 fold higher after Phenobarbital. The correlation between P₄₅₀ content and drug oxidase activity in the kidney microsomes of untreated and Phenobarbital treated rabbits was low.Suspensions of rabbit kidney microsomes revealed the same spectral changes after addition of Hexobarbital or Aniline as those reported for liver microsomes.

Teilweise vorgetragen bei der Tagung der Britischen und Deutschen Pharmakologischen Gesellschaften in Cambridge, 6.–8. Sept. 1967 (Abstr. Uehleke u. Greim, 1968).     

Comparison of ethanol,pentobarbital, and phenobarbital using drug vs. drug discrimination training

Rats learned drug vs. drug (D vs. D) or drug vs. no drug (D vs. N) discriminations in a T-maze shock-escape task with various doses of pentobarbital, phenobarbital, or ethanol. Dose-effect curves were obtained for each drug using D vs. N training. After D vs. N training with any one of these drugs, rats made D choices during substitution tests with the other two drugs, suggesting drug interchangeability. D vs. D training also showed that pentobarbital and phenobarbital were virtually indistinguishable from one another. However, ethanol was readily discriminated from pentobarbital, showing that the two drugs differed. The results show the utility of D vs. D training as a method for studying drug differences that may be too small to detect with substitution tests.     

HPLC法测定镇静催眠类中成药中非法添加化学药物成分

目的：建立快速、准确、高灵敏度的测定镇静催眠类中成药中非法添加巴比妥、司可巴比妥钠、异戊巴比妥、苯巴比妥、氯美扎酮的分析方法。方法：色谱柱：Kromasil C18（150mm×4．6mm,5μm）,流动相：乙腈-0．2％（v／v）醋酸溶液（25：75）,流速：1 ml·min^-1,检测波长：210nm,柱温：35℃,选样量：20μl。结果：5种化学镇静催眠药相互之间分离良好,检出限为1．43～4．26ng;回收率为97．29％-101．48％,RSD为0．9％～1．5％。结论：该方法灵敏准确,可作为镇静催眠类中成药中巴比妥、司可巴比妥钠、异戊巴比妥、苯巴比妥、氯关扎酮的有效检测方法。