Effects of the oxazolidinedione anticonvulsants trimethadione and dimethadione and the barbiturate homolog 5,5-dimethylbarbituric acid onN-nitrosodiethylamine-initiated renal and hepatic carcinogenesis in the F344/NCr rat

The oxazolidinedione anticonvulsant trimethadione (3,5,5-trimethyl-2,4-oxazolidinedione, TMO) as well as its major metabolite, dimethadione (5,5-dimethyl-2,4-oxazolidinedione, DMO), and a structural analog from the barbiturate series, 5,5-dimethylbarbituric acid (DMB), were fed to F344/NCr male rats previously given a single initiating injection of N-nitrosodiethylamine (NDEA). The known promoter, phenobarbital (5-ethyl-5-phenylbarbituric acid, PB), was employed in this study as a positive control. At dosage levels equimolar to 500 ppm PB, none of the three compounds promoted development of hepatocellular adenomas or carcinomas, in contrast to PB. The two oxazolidinedione analogs and DMB caused minimal or no induction of cytochrome P450 isozyme 2B1 (CYP2B1)-mediated alkoxyresorufin O-dealkylase activities following short-term (2 weeks) feeding to separate groups of 6-week-old male F344/NCr rats, in contrast to the dramatic induction caused by PB. Promotion of neither thyroid nor renal neoplasia was observed following prolonged feeding of any of the tested compounds, although a significantly higher frequency of premalignant renal cortical tubular lesions (dysplasias) was seen in rats exposed to TMO following NDEA initiation than in those treated with NDEA alone. These studies provide important additional data on structure/liver tumor promoting activity relationships, and yield further evidence that within this group of structurally related anticonvulsants, it is possible to separate anticonvulsant activity from tumor promoting activity in the rat liver.     

An operant determination of the behavioral mechanism of benzodiazepine enhancement of food intake

Rationale A recent review paper by Cooper (Appetite 44:133–150, 2005) has pointed out that a role for benzodiazepines as appetite stimulants has been largely overlooked. Cooper’s review cited several studies that suggested the putative mechanism of enhancement of food intake after benzodiazepine administration might involve increasing the perceived pleasantness of food (palatability).Objectives The present study examined the behavioral mechanism of increased food intake after benzodiazepine administration.Materials and methods The cyclic-ratio operant schedule has been proposed as a useful behavioral assay for differentiating palatability from regulatory effects on food intake (Ettinger and Staddon, Physiol Behav 29:455–458, 1982 and Behav Neurosci 97:639–653, 1983). The current study employed the cyclic-ratio schedule to determine whether the effects on food intake of chlordiazepoxide (CDP) (5.0 mg/kg), sodium pentobarbital (5.0 mg/kg), and picrotoxin (1.0 mg/kg) were mediated through palatability or regulatory processes.Results The results of this study show that both the benzodiazepine CDP and the barbiturate sodium pentobarbital increased food intake in a manner similar to increasing the palatability of the ingestant, and picrotoxin decreased food intake in a manner similar to decreasing the palatability of the ingestant.Conclusions These results suggest that the food intake enhancement properties of benzodiazepines are mediated through a mechanism affecting perceived palatability.     

The stimulatory effects of secobarbital and pregnanolone on the GABAA receptor can be blocked selectively

The stimulatory effects of secobarbital and pregnanolone on GABA receptor binding could be distinguished by their sensitivity to blockade by phenobarbital, avermectin B_1a and picrotoxinin. Phenobarbital (1 mM) and avermectin (10⁻⁹−10⁻⁶ M) inhibited the stimulation of [³H]muscinol binding to pig brain menbranes caused by secobarbital but not that caused by pregnanolone. In contrast, enhancement of [³H]muscimol binding by pregnanolone showed a greater sensitivity to the inhibitory effects of picrotoxinin. These results, together with data demonstrating an additivity of barbiturate- and steroid-induced effects, indicate that these two classes of modulators may interact with the GABA_A receptor through different sites.     

体液中29种中枢神经系统药物的高效毛细管电泳系统分析方法

建立了高效毛细管电泳系统分析法,分析体液样品中29种CNS药物,作为CNS药物中毒的快速的初筛方法。血、尿样品用有机溶剂萃取,胃液直接进样。用酸、弱碱和中性3组缓冲液体系进行电泳分离。以组分与电渗流迁移时间之比的相对迁移时间和紫外吸收光谱为定性指标。最低检测浓度0.5～5μg·mL^-1。在此法基础上可增加分析品种。通用的提取方法可避免漏检,广谱分离条件便于分类,专一分离条件便于定性。本法用于实际中毒样品分析,证实所建方法操作简便、分析时间短、杂质干扰小。     

Reevaluation of Potency and Pharmacokinetic Properties of some Lipid-soluble Barbiturates with an EEG-threshoJd Method

Abstract: Five lipid-soluble anaesthetic barbiturates amobarbital, (pentymalum NFN), hexobarbital (en-hexymalum NFN), pentobarbital (mebumalum NFN), thiopental (thiomebumalum NFN), methohexital (enallynymalum NFN) were investigated for potency and kinetic properties with an EEG-threshold method. By constant infusion of barbiturate at different dose rates to a well specified EEG-criterion, the “silent second”, a dose rate curve can be made. This curve has a minimum, “optimal dose rate”, and the amount of barbiturate used to reach the criterion at this dose rate can be used as an accurate measure of potency. The dose to reach the “silent second” at the optimal dose rate was highly correlated to brain concentrations at the criterion for the barbiturates in contrast to the plasma concentrations. This measure of potency is superior to other used measures such as anaesthesia times or AD50, since it is less affected by differences in pharmacokinetic properties. The anaesthesia times after threshold determinations show large variations between different barbiturates which can be dependent both on dose administered and on dose rate. The quotient between brain concentration at the EEG-criterion and at the time of return of righting reflex for these barbiturates shows variations that can be due to differences in acute tolerance.     

Effects of sodium pentabarbital on matching behavior in the pigeon

Nine pigeons in a matching-to-sample task with 5 alternative stimuli were exposed to 4 dose levels of sodium pentobarbital. Each drug session alternated with a control session, and 6 determinations were made at each dose level. Dose-response curves were obtained, and drug effects are described for position-specific and stimulus-specific behaviors. These results suggest that the drug effect is to weaken control by the sample stimulus and shift control to properties of the comparison stimuli.     

A sensitive method for gas-chromatographic assay of barbiturates in body fluids

The Authors present a gas-chromatographic method which allows for the rapid identification and assay of barbiturates and antiepileptics in body fluids. The Kupferberger procedure for extraction is used. The identification is obtained on two different columns: 10% Dexil 300 GC on Chromosorb W-HP and 3% OV 17 on Chromosorb G AW-DMCS (80–100 mesh). A considerable and interesting reduction of the barbiturates adsorption in the columns is obtained by preliminary conditioning with tetraethylorthosilicate. In this way, phenobarbital and cyclobarbital may also be assayed up to 1 g/ml in blood. For the simultaneous assay of therapeutic levels of phenobarbital and hydantoins methylderivates are better employed: blood concentrations as low as 0.1 /ml are easily detected.

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Zusammenfassung Eine sensible Methode zur gaschromatographischen Identifizierung von Barbituraten und Körperflüssigkeiten.Die Verfasser berichten über eine gaschromatographische Methode, die eine rasche Identifizierung von Barbituraten und Antiepileptica in Körperflüssigkeiten erlaubt. Zur Extraktion wird die Kupferberger Methode verwendet. Die Identifizierung erfolgt auf zwei verschiedenen Säulen: 10% Dexil 300 GC in Chromosorb W-HP und 3% OV 17 in Chromosorb G AW-DMCS (80–100 mesh). Man kann eine erhebliche und interessante Reduktion der Barbituratabsorption auf den Säulen erzielen, indem man im voraus mit Tetraäthylorthosilicat konditioniert. Es ist so möglich, direkt das Vorhandensein sowohl von Phenobarbital als auch von Cyclobarbital bis zu 1 g/ml festzustellen. Zur gleichzeitigen Feststellung von therapeutischen Mengen von Phenobarbital und Hydantoin werden Methylderivate verwendet: Blutkonzentrationen von 0,1 g/ml sind leicht zu identifizieren.

     

Drugs and taste aversion

The literature on the effects of drugs on the acquisition and the magnitude of taste aversion is reviewed and discussed. Then, the results of a series of experiments on the effects of phenobarbital and related drugs on taste aversion are reported. A standard taste aversion model was used in all experiments; test drugs were injected prior to drinking in a one bottle situation on the first test day following the taste aversion treatment. Phenobarbital in doses ranging from 20 to 80 mg/kg significantly attenuated taste aversion induced by lithium chloride (LiCl) and x-radiation, the maximal effect occurred with the 60 mg/kg dose. The attenuating effect was found to be dependent upon the magnitude of the aversion to the sapid solution. Phenobarbital completely abolished aversion produced by 0.375 mEq LiCl while the attenuation effect decreased linearly with higher doses of LiCl. Results also indicate that phenobarbital's attenuating effect cannot be solely attributed to its dipsogenic characteristic or to its state dependent learning effect. Attenuation of LiCl aversion to a saccharin solution was also observed following single doses of amobarbital, 30 mg/kg, pentobarbital, 15 mg/kg, and chlorpromazine, 0.75 mg/kg. Taste aversion was not affected by other doses of those drugs or by hexobarbital, barbital, and chlordiazepoxide. Phenobarbital's attenuating effect on taste aversion is discussed in relation to other known behavioral and neurophysiological effects of the drug.     

Identification of barbiturates by computerized mass spectrometry

Summary A computer has been used for rapid and exact identification of mass spectra for the barbiturates presently on sale in Sweden. The compounds were isolated from blood, or liver from intoxicated persons in suicide cases and a small part of the chloroform extracts were analyzed on a gas chromatograph-mass spectrometer instrument. The mass spectra were recorded on a digital tape off line system and the tape was evaluated and processed by the computer. The amount of tissue or blood was in the magnitude of less than 50 mg in these cases.

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Zusammenfassung Es wurde ein Computer für eine schnelle und exakte Identifizierung der Massenspektren zum Nachweis von Barbituraten, die zur Zeit im Verkauf in Schweden angeboten werden, angewandt. Aus Blut- oder Leberproben der Personen, die Selbstmorde durch Vergiftung begangen haben, wurden Substanzen isoliert und eine geringe Menge der Chloroformextrakte mit Hilfe der Gaschromatografie-Massenspektrometrie(GC-MS)-Apparatur analysiert. Die Massenspektren wurden auf einem Digitalband aufgezeichnet und danach durch den Computer bewertet und wiedergegeben. Das Gewicht der Gewebe und des Blutes in den untersuchten Fällen lag unter 50 mg.

     

Effects of various psychoactive drugs on the metabolism of Δ1-tetrahydrocannabinol by rats in vitro and in vivo

Metabolism of ¹⁴C-tetrahydrocannabinol (¹⁴C-THC) by rat liver microsomal preparations in vitro was studied in the absence and presence of other psychoactive drugs. Disappearance of ¹⁴C-THC, and changes in metabolite patterns as shown by thin layer chromatography, were studied. SKF 525-A, pentobarbital, phenobarbital and amphetamine all produced an apparently non-competitive inhibition of THC metabolism. The inhibition produced by meprobamate was at least partly competitive. Morphine and mescaline had no evident effect. SKF 525-A and the barbiturates markedly decreased the concentrations of all the major THC metabolites found in the incubation media.In contrast, none of the drugs tested in vivo, with the exception of SKF 525-A, had any effect on the biliary ¹⁴C-excretion or metabolite pattern, or on final tissue levels of ¹⁴C, when administered in doses comparable to those used for studies of interaction with THC in vivo. SKF 525-A, however, did markedly decrease the excretion of total ¹⁴C and alter the pattern of THC metabolites in the bile, and increased the final tissue ¹⁴C levels.It is concluded that in vivo interactions between THC and other psychoactive drugs are probably not explainable primarily on the basis of altered THC metabolism.