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At least 19 recordsLinked to original sources
PubMed1991

Barbital N-glucoside is not detected as a urinary excretion product of barbital in humans.

A study was undertaken to determine if humans excreted barbital N-glucoside as a urinary metabolite following oral administration of barbital. A liquid chromatography method using gradient elution was developed for detecting and quantifying barbital N-glucoside and barbital in urine. Following a single oral dose of barbital to male caucasian and oriental subjects that had previously been shown to excrete amobarbital and phenobarbital N-glucosides, no barbital N-glucoside conjugate was observed in the urine. This result indicates that N-glucosylation of barbiturates is not a general pathway for the biodisposition of barbiturates in man.

Administration, Oral↗
PubMed1985

Development of tolerance to chronic barbital treatment in the cerebellar cyclic guanosine monophosphate system and its response to subsequent barbital abstinence.

Female Sprague-Dawley rats were placed on a 6-week barbital feeding regimen, previously documented to result in drug tolerance and dependence. Groups of animals were sacrificed on the 2nd and 5th day of each week, up to week 5, or at various time points following drug withdrawal. Cerebellae and cerebral cortices were collected for cyclic GMP (cGMP) measurements. Initial suppressions of cGMP were seen in both the cerebellum and cerebral cortex during early weeks of the feeding regimen. These gradually returned essentially to control levels by the end of 5 weeks, a finding consistent with the development of tolerance to chronic barbiturates in the cGMP system. Barbital was withdrawn after 6 weeks of chronic administration. Four hours after withdrawal, a dramatic elevation of cerebellar cGMP was seen. This elevation was coincident with a significant decline in serum barbital levels and preceded the onset of weight loss, spontaneous seizures and locomotor depression. The elevation of cGMP was less dramatic but still apparent at 72 hr postwithdrawal when all other evaluated parameters had returned to control values. Alterations of cGMP during chronic barbital treatment and subsequent to abrupt barbital withdrawal may reflect aberrations in the function of neurotransmitter pathways involved in regulating cGMP in the cerebellum. Further, the elevation of cGMP after barbiturate withdrawal may itself play a functional role in the manifestation of barbital abstinence.

Animals↗
PubMed1994

Comparative hyaline droplet nephropathy in male F344/NCr rats induced by sodium barbital and diethylacetylurea, a breakdown product of sodium barbital.

Hyaline droplet nephropathy in male rats due to alpha 2u-globulin accumulation in proximal tubules is caused by chemicals from several chemical classes. We have previously shown that the well-known sedative/hypnotic barbiturate, sodium barbital, and its breakdown product, diethylacetylurea, are renal toxins and renal tumor promoters. To determine comparative induction of hyaline droplets in renal tubules by sodium barbital and diethylacetylurea, male F344/NCr rats, 6 weeks of age, were given diets containing 0, 170, 341, 500, or 1000 ppm of diethylacetylurea or containing 500, 1000, or 4000 ppm of sodium barbital for periods of 2 or 10 weeks. Rats were terminated at 2 or 10 weeks and the histology of the kidney was evaluated using light microscopy with hematoxylin and eosin staining and staining by the Heidenhain method. Quantitative analysis showed dose responses for the degree of droplet accumulation in the P2 and P3 segments of the proximal tubules. Diethylacetylurea was more potent. Immunohistochemistry and ultrastructural evaluation revealed the nature of the droplets. Western blotting confirmed the presence of alpha 2u-globulin. Renal tubular necrosis, regeneration, and increased levels of cell proliferation using proliferating cell nuclear antigen immunohistochemistry were also found. Female rats similarly exposed to each chemical did not show tubule droplet accumulations nor renal lesions. We confirm for the first time that these two chemicals can be added to the enlarging list of nephrotoxic chemicals inducing alpha 2u-globulin nephropathy and possessing tumor promoting and renal carcinogenic properties.

Animals↗
PubMed1982

Induction time measurement of barbital tolerance in mice given recurrent subhypnotic dosage of barbital.

A procedure designed to estimate the degree of development of neuronal tolerance to barbiturates is described. With this technique, it has been shown that a subhypnotic (125 mg/kg) peritoneal dose of barbital sodium, given twice daily, over the course of either five or 10 consecutive days, can produce significant elevation in tolerance over that found for analogous groups of saline control animals. Mean tolerances were considerably lower (about 20 percent) than those obtained when the recurrent barbital sodium dosages were at the hypnotic (300 mg/kg) level given once per day for 10 days. The results obtained support the proposition that the method employed is sufficiently sensitive to estimate neuronal tolerance developed as a result of recurrent administrations of subhypnotic dosages of barbiturates when given at adequate frequency and duration.

Animals↗
PubMed1990

Amelioration of sodium barbital-induced nephropathy and regenerative tubular hyperplasia after a single injection of streptozotocin does not abolish the renal tumor promoting effect of barbital sodium in male F344/NC4 rats.

The renal tumor promoting activity of barbital sodium (BBNa) and the role of renal tubular cell hyperplasia in tumor promotion following initiation with streptozotocin (STZ) was investigated. Six week old male F344/NCr rats were given STZ as a single i.p. injection of 50 mg/kg body wt and beginning 2 weeks later were fed diets containing 0 or 4000 p.p.m. of BBNa until they were killed at 33, 52 or 72 experimental weeks for histological evaluation and determination of levels of renal DNA synthesis by bromodeoxyuridine (Brdu) immunohistochemistry. A promoting effect on renal carcinogenesis was found by 72 weeks, but not at 33 or 52 weeks, confirming that prolonged administration of BBNa is necessary to promote renal tubular cell neoplasms. The promoting effect was evident as a higher incidence of large renal tubular tumors after 52 weeks, rather than an increase in number of dysplastic tubules, putative preneoplastic lesions. These findings suggest that the targets for the promoting activity of BBNa may be dysplastic lesions which may progress to tumors. Detailed examination by the step section technique through the entire kidneys revealed that STZ or BBNa administration induced a high incidence of putative preneoplastic renal tubular lesions (dysplasias) which seemed to be derived from the P1 or P2 segment of the nephron, also a site of high Brdu labeling index (LI) associated with BBNa toxicity. STZ administration was also associated with attenuation of BBNa-induced nephropathy and with diabetes from pancreatic islet degeneration and atrophy. The reduction in severity of nephropathy was correlated with a reduction in the LI of the renal cortical and medullary tubules, but not with the renal tumor incidence. These results indicate that decreased DNA synthesis in target cells does not eliminate tumor promoting activity in renal tubular epithelium. In addition, BBNa alone induced papillomas of the transitional epithelium of the renal pelvis and renal tubular cell adenomas.

Adenoma↗
PubMed1980

[On the Polymorphism of barbiturates in powders and tablets. Part 4: the dissolution of barbital B and barbital A (modifications I and III and their release from tablets (author's transl)].

Two commercial brands of barbital (A: German Democratic Republic, modification III; B: Hungarian Peopl's Republic, modification I) were used to study the solubility and dissolution of the modifications. Crystals of these two substances were brought into the shape of tablets, the physical parameters and textural properties of which were determined. The effect of polymorphism on the release of these substances is discussed in the light of the results obtained from this investigation. The discussion will be continued and summarized in a subsequent paper, including further modifications.

Barbital↗
PubMed1980

Continuous administration of barbital by pellet implantation.

Mice were continuously administered with barbital by the sc implantation of 16 mg barbital pellet (acid form). Serum and brain barbital levels were assessed at different times after pellet implantation. After 3 days of implantation the barbital pellet was removed and the mice were observed for a 96 hr period. A 30% decrease in sleeping time was observed 72 hr after pellet removal when mice were challenged with 400 mg/kg of barbital ip. Brain and serum barbital levels upon awakening were also assessed with a dose of sodium barbital, 400 mg/kg ip, administered 72 hr after removal of either a barbital or placebo pellet. It was observed that serum and brain barbital concentrations were significantly higher in barbital treated animals than in controls. The effect of barbital pellet implantation on pentobarbital (75 mg/kg, ip) sleeping times was also assessed. Cross tolerance to pentobarbital was observed 24, 48, and 72 hr after barbital pellet implantation. The results demonstrated that barbital pellet implantation enhanced hepatic drug metabolism as evidenced by significant increases in hepatic microsomal N-demethylase and hydroxylase activities. CNS hyperexcitability, an indication of dependence, was assessed by the method of pentylenetetrazol (PTZ) induced convulsions (60 mg/kg, sc). At 48 and 72 hr after pellet removal, PTZ induced convulsions increased by 41% and 35%, respectively, over control values. Index of dependence was also substantiated by a decrease in threshold for electroshock. These studies substantiate the validity of this experimental model for the assessment of the development of tolerance to and physical dependence on barbiturates.

Animals↗
PubMed1995

Neuron transplantation into mice hippocampus alters sensitivity to barbital narcosis.

The role of several hippocampal innervations in the sensitivity to barbital-induced narcosis was studied in selected mice strains. The outbred and inbred mouse strains HS/lgb, SABRA/HUC, C57BL, CBA/LAC, and BALB/c were tested for barbital-induced sleep (315 mg/kg). The relatively short sleeping HS/lbg (HS) and the longest sleeping BALB/c (BALB) were chosen for further investigation. Cholinergic (ACh), serotonergic (5-HT), and noradrenergic (NE) innervations were studied in HS strain; whereas BALB, which possesses both an unusually high sensitivity to barbital and unique NE innervations in the cortex and hippocampus, was employed in a detailed study of the NE innervations. Transplantation of embryonic NE cells from the mouse embryo into the hippocampus of adult HS mice increased barbital narcosis by 65% (p < 0.05), whereas transplantation of 5-HT cells decreased barbital narcosis by 54% (p < 0.001). Transplantation of ACh cells had no significant effect on barbital-induced narcosis. BALB mice were subjected to NE cell transplantation into the hippocampus and cortex. Similarly to HS, BALB receiving NE transplants into their hippocampus slept 34% longer than control after barbital challenge (p < 0.025). Noradrenergic cell transplantation into frontal cortex had no effect on barbital sleep. The results suggest that (a) enhancement by neural grafting of the NE innervation to the hippocampus accentuates and enhancement of the 5-HT innervations attenuates the sensitivity to barbital narcosis, whereas ACh innervations have no effect on the sensitivity to barbital narcosis, and (b) the unusually high sensitivity of BALB mice to barbital may not be related to its unique NE innervations.

Acetylcholine↗
PubMed1984

The effects of chronic oral administration of barbital on cerebellar cyclic GMP.

Female Sprague-Dawley rats received increasing dosages of barbital mixed with ground LabBlox for 7 weeks. At the end of this period, the rats were given doses of barbital acutely, and the effects of this treatment on levels of cyclic guanosine monophosphate (cGMP) in the cerebellum were determined. Chronic administration of barbital resulted in a slight depression of cGMP compared to control values. The acute injections of barbital produced a dramatic, dose-related decrease in levels of cerebellar cGMP in both control (C) and barbital-dependent (BD) animals. This depression of cGMP is of particular interest because the barbital-dependent animals had considerably higher levels of serum barbital than matched controls. The overall effect of chronic administration of barbital was right shift in the dose-response curve for levels of cGMP following acute injections of barbital. No differences in motor activity were noted between the dependent and control animals. It is believed that these results indicate that a high degree of tolerance is developed in the cGMP system of the cerebellum after chronic oral administration of barbital. Further investigation of this neurochemical parameter may provide useful information in the study of mechanisms mediating the dependence and the abstinence syndrome to barbiturates.

Administration, Oral↗
PubMed1993

Effects of flunarizine and diltiazem on physical dependence on barbital in rats.

The effects of flunarizine and diltiazem both on development of physical dependence on barbital and on barbital withdrawal signs in rats were examined using the drug-admixed food (DAF) method. Rats were chronically treated with barbital or barbital in combination with flunarizine (fixed at 1.5 mg/g of food) or diltiazem (fixed at 0.75 mg/g of food)-admixed food on the schedule of gradually increasing doses of barbital. Motor incoordination during the treatment was potentiated by coadministration of flunarizine, but not by coadministration of diltiazem. After the termination of drug treatment, the body weight loss and withdrawal scores were significantly suppressed in the group coadministered flunarizine, but not in that coadministered diltiazem. There were no significant differences in plasma barbital levels after the withdrawal between groups. In the substitution test, flunarizine (20 and 40 mg/kg, IP) significantly suppressed the body weight loss and withdrawal scores after the withdrawal, but diltiazem (20 mg/kg, IP) did not. These results indicated that flunarizine suppressed both the development of physical dependence on barbital and barbital withdrawal signs, mainly according to the suppression of convulsions, but not diltiazem, which is known to poorly penetrate into the brain. Therefore, the present findings suggest that central calcium channels may be involved in both the development of physical dependence on barbital and the appearance of barbital withdrawal signs.

Animals↗
PubMed1983

Effects of propranolol on barbital dependence formation and withdrawal signs.

We studied the involvement of beta-adrenoceptors in the physical dependence formation of barbital. 1. Propranolol (at a dose of 0.5 or 1.0 mg/g food) and barbital were applied simultaneously as a mixture with animal food (barbital-propranolol combination). Barbital was applied on a schedule of gradually increasing dosages from 0.5-and-1.0 to 6-and-8 mg/g food over 36 days. Only the animals dosed with barbital exhibited severe withdrawal signs such as spontaneous withdrawal convulsions. The animals dosed with propranolol alone showed no changes even on withdrawal of the drug. The formation of physical dependence on barbital was obviously inhibited by the combination of barbital and propranolol. 2. Cross-application of propranolol (30 and 60 mg/kg, p.o., and 10 and 30 mg/kg, i.p.) following withdrawal of barbital resulted in the inhibition of the spontaneous withdrawal convulsions, muscle rigidity and hyperirritability. It also inhibited significantly tranylcypromine-induced convulsions, while it failed to inhibit similarly induced hyperthermia. These results including previous findings of effects of monoamine-related compounds on barbital withdrawal convulsions suggest that the balance of activities of noradrenergic neurons, especially that of alpha- and beta- receptors, has great influence on both the formation of physical dependence on barbital and the manifestation of withdrawal convulsions.

Animals↗
PubMedDate not supplied

Demonstration of neurochemical tolerance following chronic barbital treatment.

Control rats (C) and rats rendered barbital dependent (BD) by the consumption of barbital chronically in their food for 6 weeks were treated with saline or 1 of 3 acute dosages of barbital 16 minutes before killing. Cyclic guanosine monophosphate (cGMP) levels and circulating levels of barbital were measured. Significantly higher circulating levels of barbital were required to produce a comparable suppression of cerebellar cGMP in the BD as opposed to the C rats. These data provide evidence for the development of tolerance to barbital in the cerebellar cGMP system during chronic barbital treatment. When barbital was abruptly withdrawn from BD rats, a profound elevation of cerebellar cGMP was observed to precede and outlast behavioral manifestations of barbital abstinence. Further understanding of the withdrawal induced aberrations in the mechanisms regulating cerebellar cGMP may give insight into the pathways involved in the manifestation of the barbital abstinence syndrome.

Animals↗