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At least 19 recordsLinked to original sources
PubMed2000

Phenobarbital prior to preterm birth for preventing neonatal periventricular haemorrhage.

BACKGROUND: Preterm infants are at risk of periventricular haemorrhage. This can damage the brain and lead to neurodevelopmental abnormalities, including cerebral palsy. Phenobarbital might prevent ischaemic injury or reduce fluctuations in blood pressure and blood flow in the brain. OBJECTIVES: The objective of this review was to assess the benefits and harms of giving phenobarbital to women at risk of imminent very preterm birth with the primary aim of preventing periventricular haemorrhage in the infant. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register and bibliographies. Date of last search: December 1998. SELECTION CRITERIA: Randomised trials with reported data which compare outcomes, such as neonatal mortality, neonatal neurological and other morbidity, longterm neurodevelopment and maternal morbidity, following prenatal exposure to phenobarbital, with outcomes in controls with or without placebo. DATA COLLECTION AND ANALYSIS: Assessments of trial eligibility, quality and data extractions were done by the two authors independently. Eligible trials were included in the initial analysis and prespecified sensitivity analyses done to evaluate the effect of trial quality. MAIN RESULTS: Over 1600 women were entered into the eight trials included. Analyses showed a significant reduction in the rates of all grades of periventricular haemorrhage (PVH) (relative risk 0.75, 95% confidence interval 0.65 to 0.88) and severe grades PVH (3 and 4) (relative risk 0.49, 95% confidence interval 0.32 to 0.74) in infants whose mothers had been given prenatal phenobarbital. These results were influenced by the earlier trials which were of poorer quality and contributed excessive weight in the analysis due to their higher rates of severe PVH. Over time, and with improved trial quality, these beneficial effects disappeared. No difference was found in the incidence of neurodevelopmental abnormalities at paediatric follow-up assessed between 18-36 months of age. Maternal sedation was more likely in women receiving phenobarbital. REVIEWER'S CONCLUSIONS: Phenobarbital administration to women prior to preterm birth cannot be recommended for routine clinical practice. Any future trials should examine the effects of phenobarbital prior to preterm birth at gestational ages with a high risk of PVH, stratify for gestational age and ensure minimal exclusions after randomisation. Neurodevelopmental status at follow-up should be measured as the most important outcome.

Central Nervous System Agents↗
PubMed1997

High-performance liquid chromatographic analysis of phenobarbital and phenobarbital metabolites in human urine.

A HPLC assay using UV detection and post-column alkalinization was developed to quantify possible urinary excretion products of phenobarbital in human urine. After filtration the urine was injected directly onto the HPLC column for analysis of phenobarbital, p-hydroxyphenobarbital, phenobarbital N-glucosides and phenobarbital N-glucuronides. The accuracy and precision of the assay were within +/- 15% and the limit of detection (LOD) was 1 microM, suitable for pharmacokinetic studies. Phenobarbital was administered orally to five male subjects and urine was collected for a period of 96-108 h. Phenobarbital, p-hydroxyphenobarbital, and phenobarbital N-glucosides were detected and quantified in the urine of all five subjects. The phenobarbital N-glucuronides were not detected in the urine. This assay provides a rapid method with improved selectivity to analyze urine for phenobarbital and its metabolites.

Adult↗
PubMed1995

Identification of phenobarbital N-glucuronides as urinary metabolites of phenobarbital in mice.

Mice were evaluated for their ability to form phenobarbital N-glucuronides. Following oral administration of [14C]phenobarbital to mice, a radiolabeled phenobarbital metabolite cochromatographed with synthetic standards of phenobarbital N-glucuronides. The phenobarbital N-glucuronides were partially purified from the mouse urine as phenobarbital N-methylglucuronates. The phenobarbital N-methylglucuronates isolated from mouse urine had similar chromatographic and spectroscopic properties as synthetic standards. The diastereomers of phenobarbital N-glucuronides and phenobarbital N-glucosides accounted for 7.8 +/- 2.3% and 1.6 +/- 0.6%, respectively, of the radioactivity excreted in mouse urine in the first 48 hr after dosing. This study indicates that the mouse may be a suitable species to study both N-glucosidation and N-glucuronidation simultaneously as metabolic pathways for barbiturates.

Animals↗
PubMed1999

Phenobarbital in comparison with carbon tetrachloride and phenobarbital-induced cirrhosis in rat liver regeneration.

BACKGROUND: The simultaneous administration of carbon tetrachloride (CCl4) and phenobarbital in the rat produces one of the most common experimental models of liver cirrhosis. As phenobarbital also has a hepatotrophic effect, its role in liver regeneration following partial hepatectomy (HTX) is not elucidated. PURPOSE: To examine the effect of long-term administration of phenobarbital in liver regeneration after HTX with regard to CCl4-induced cirrhotic rat model. Materials and Methods. The liver regeneration following HTX in phenobarbital-treated rats (PB rats) was compared to that seen in cirrhotic rats (LC rats), induced by oral gavage of CCl4 and phenobarbital, and normal rats. The effect of the withdrawal of phenobarbital was also examined. Liver regeneration was estimated 24 h after the HTX by measuring the liver weight, the DNA content in the liver, and [3H]thymidine incorporation into the DNA. RESULTS: Treatment with CCl4 and phenobarbital caused liver deformity, and the highest percentage of liver weight regeneration was seen in LC rats with this deformity, even though [3H]thymidine incorporation into the DNA was impaired in this group. Phenobarbital had a hepatotrophic effect, but its withdrawal caused a decrease in liver mass and cessation of body weight gain. The change in the DNA content 24 h after HTX was negative in PB rats. CONCLUSIONS: Liver regeneration could not be estimated using liver or body weight in the PB or LC rat model. [3H]Thymidine incorporation into the DNA was reliable indicator of liver regeneration in the different liver states during the early stage after HTX. Although the DNA content with respect to total liver mass was obscured due to liver inflation in PB rats, [3H]thymidine incorporation into the DNA between PB rats and normal rats was similar.

Animals↗
PubMed1997

Phenobarbital alters protein binding to the CYP2B1/2 phenobarbital-responsive unit in native chromatin.

Phenobarbital is a classical inducer of the drug metabolizing cytochrome P450 genes, but the molecular mechanism of induction has not been elucidated. Functional analyses have identified a phenobarbital-responsive unit in the rat CYP2B1/2 and mouse Cyp2b10 genes about -2.3 kilobase pairs from the transcriptional start site, but little or no changes in protein binding to this region were observed in vitro. To examine the role of chromatin structure, protein binding to the phenobarbital-responsive unit assessed by in vitro DNase I footprinting was compared with that assessed by DNase I in vivo footprints in native chromatin. A region centered on a putative nuclear factor-1 site was the major protected region in in vitro footprints, and there were no detectable differences in binding between extracts from control and phenobarbital-treated animals. In contrast, phenobarbital treatment dramatically altered the protection pattern in native chromatin. In control samples a core region of about 25 base pairs (bp) centered on the nuclear factor-1 site was protected. However, after phenobarbital treatment, the protection of this core region was increased, and more dramatically the region of protection was extended 20 bp to either side so that a total of about 60 bp were protected. These results provide the first evidence that phenobarbital treatment alters the composition or architecture of proteins binding to the phenobarbital-responsive unit region and indicate that chromatin structure is important in this process. Because proteins are bound to the region in the untreated animal, the mechanism of induction involves the activation of proteins bound to the region and possibly recruitment of additional regulatory proteins rather than conversion of a closed chromatin structure to an open one that can bind regulatory factors.

Animals↗
PubMed1991

Identification of phenobarbital N-glucosides as urinary metabolites of phenobarbital in mice.

Previously, the N-glucosylation of phenobarbital had been observed only in humans. The results of a species screen (mouse, rat, guinea pig, rabbit, cat, dog, pig, and monkey) found that only mice excreted the N-glucosides of phenobarbital in urine after ip administration of sodium phenobarbital. The major diastereomer excreted by the mouse had the R configuration at the C-5 position of the barbiturate ring. The N-glucoside metabolites accounted for a small percentage of the dose (approximately 0.5%). Following ip dosing of the mouse with the phenobarbital N-glucosides, free phenobarbital could be detected in the urine. Upon ip or intercerebroventricular (icv) injection of the phenobarbital N-glucosides, minimal CNS activity was observed in the mouse.

Animals↗
PubMed1986

Regulation of cytochrome P-450p by phenobarbital and phenobarbital-like inducers in adult rat hepatocytes in primary monolayer culture and in vivo.

Treatment of rats with phenobarbital increases the hepatic concentration of P-450p, a form of cytochrome P-450 believed to be controlled primarily by a mechanism that stereospecifically recognizes glucocorticoids like dexamethasone and anti-glucocorticoids like pregnenolone-16 alpha-carbonitrile [Schuetz, E.G., & Guzelian, P.S. (1984) J. Biol. Chem. 259, 2007]. To test the possibility that phenobarbital induces P-450p indirectly by increasing the availability of endogenous glucocorticoids in the liver, we added phenobarbital and phenobarbital-like inducers to primary monolayer cultures of adult rat hepatocytes incubated in serum-free medium without glucocorticoids and found stimulated de novo synthesis of P-450p measured as increased incorporation of [3H]leucine into immunoprecipitable P-450p protein. With some of the inducers, notably the organochlorine pesticides chlordane and trans-nonachlor, there was a greater accumulation of P-450p measured on quantitative immunoblots than could be accounted for by the increase in P-450p synthesis. "Pulse-chase" experiments confirmed that these compounds significantly lengthen the half-life of P-450p up to 60 h as compared to the values in control (11 h) or dexamethasone-treated (10 h) cultures. Treatment of rats with chlordane, trans-nonachlor, or other cyclodiene organochlorine pesticides confirmed that these agents increase the concentration of P-450p in liver microsomes analyzed on immunoblots of two-dimensional electrophoretic gels. The time courses of induction in trans-nonachlor-treated rats of P-450p protein and of P-450PB proteins induced by phenobarbital were similar as were the amounts of P-450PB mRNA and P-450p mRNA measured by hybridization to cloned cDNA probes. However, analysis of structure-activity relationships among polychlorinated biphenyls revealed that isomers with two ortho chlorinated positions maximally induced P-450PB whereas isomers with three and four ortho chlorines maximally induced P-450p in rats and in hepatocyte culture, respectively. We conclude that P-450p is induced by the phenobarbital class of inducers through direct contact with the hepatocytes involving decreased degradation of the protein and stimulation of its synthesis in a manner similar but not identical with that of P-450PB.

Animals↗
PubMed1998

The CYP2B2 phenobarbital response unit contains an accessory factor element and a putative glucocorticoid response element essential for conferring maximal phenobarbital responsiveness.

Hepatic cytochrome P450s play a critical role in the metabolism of hydrophobic xenobiotics. One of the major unsolved problems in xenobiotic metabolism is the molecular mechanism whereby phenobarbital induces hepatic enzymes, particularly CYP2B1 and CYP2B2 in rat liver. By using primary rat hepatocytes for transfection analyses, we previously identified in the CYP2B2 5'-flank a 163-base pair Sau3AI fragment that confers phenobarbital inducibility on a cat reporter gene and that has the properties of a transcriptional enhancer. Transfection experiments with sub-regions of the Sau3AI fragment now indicate that a central core together with an upstream or downstream accessory element within the fragment can confer phenobarbital responsiveness. One such accessory element, AF1, was identified and localized. DNase I footprinting analysis revealed the presence of a footprint overlapping this AF1 element. It also identified three other major protected regions, two of which are putative recognition sites for known transcription factors. Site-directed mutagenesis indicated that a putative glucocorticoid response element as well as a nuclear factor 1 site and an associated nuclear receptor hexamer half-site are essential for conferring maximal phenobarbital inducibility. Taken together, the results indicate that phenobarbital induction of CYP2B2 requires interactions among multiple regulatory proteins and cis-acting elements constituting a phenobarbital response unit.

Animals↗
PubMed2000

Tissue-specific chromatin structure of the phenobarbital-responsive unit and proximal promoter of CYP2B1/2 and modulation by phenobarbital.

Phenobarbital induction of transcription of CYP2B genes is mediated by an enhancer, termed a phenobarbital responsive unit (PBRU), approximately 2000 bp 5' of the transcription start site. To further delineate the mechanism of phenobarbital induction, protein binding in native chromatin and the nucleosomal structure of the PBRU and proximal promoter were examined in liver and kidney, in which the CYP2B1/2 genes are expressed and not expressed, respectively. Protein binding to the PBRU in kidney chromatin was not detected even though in vitro DNase I footprints were not detectably different with nuclear extracts from liver and kidney. Likewise, protein binding to regulatory motifs was not detected in the proximal promoter region in kidney chromatin. In liver chromatin, however, DNase I hypersensitivity and partial protection of the regulatory motifs from DNase I digestion or reaction with dimethyl sulfate was observed and phenobarbital treatment increased the hypersensitivity but only modestly affected protection. Low resolution Southern analysis of micrococcal nuclease-digested chromatin from untreated rats revealed micrococcal nuclease hypersensitive regions in the proximal promoter and PBRU regions in liver, but not in kidney. Phenobarbital treatment increased hyper-sensitivity in liver in both regions. Micrococcal nuclease hypersensitivity in the PBRU was largely restricted to a linker region between phased nucleosomes while in the proximal promoter hypersensitivity extended over approximately 200 bp suggesting disruption of a nucleosome in this region. These data indicate that in liver phenobarbital treatment substantially alters protein binding to regulatory motifs in the PBRU, while not greatly affecting such binding in the proximal promoter, and substantially alters chromatin structure in both regions, presumably as a result of chromatin modifying factors recruited to the PBRU. In the kidney, chromatin is probably in a closed conformation that prevents binding of regulatory factors.

Animals↗
PubMed1985

Biopharmaceutical investigation of rectal suppositories. Part 2(1): Pharmaceutical and biological availability of phenobarbital and phenobarbital-sodium.

The influence of the suppository base and drug solubility on the release an absorption of phenobarbital and phenobarbital-sodium from model suppositories was investigated. It was established that the pharmaceutical and biological availability of phenobarbital is higher from a hydrophilic base because of its improved solubility. The rate and the degree of release of phenobarbital-sodium are more significant from lipophilic bases. The bioavailability of two drug forms-phenobarbital and phenobarbital-sodium--is almost equal after rectal and oral administration.

Animals↗
PubMed1996

Phenobarbital induction of hepatic CYP2B1 and CYP2B2: pretranscriptional and post-transcriptional effects of gender, adult age, and phenobarbital dose.

Chemical induction of hepatic monooxygenases should not be viewed as an extracorporal process but rather as one that is liable to be influenced by numerous endogenous factors. In this regard, we examined the interactions of gender, adult age, and barbiturate dose on the course of phenobarbital induction of hepatic CYP2B1 and CYP2B2. We observed that femaleness and youth were associated with the greatest inhibition, so that both the rate and initiation of CYP2B1 and CYP2B2 induction were suppressed most in the young adult (65 days of age) females, followed by the mature adult (150 days of age) females and then by the young adult males, with the mature adult males exhibiting the least suppression of phenobarbital induction. The differential expression rates of hepatic CYP2B1 mRNA in the young and mature male and female rats, similarly reflected at the protein level, suggest that gender- and age-dependent suppression of CYP2B1 occurs at a pretranscriptional or transcriptional level. In contrast, transcript levels of CYP2B2 were unaffected by gender or age. However, accumulation of cytochrome P450 (P450) 2B2 protein was affected by the animal's age and gender, suggesting regulation of a post-transcriptional event. Highly selective (androstenedione 16beta-hydroxylase) as well as nonspecific (total P450 and hexobarbital hydroxylase) P450 2B1- and 2B2-dependent catalytic activities were in agreement with protein levels. Determination of gender- and age-dependent circulating growth hormone profiles indicates that the continuous secretion of the hormone characteristic of the female is more suppressive of CYP2B induction than the episodic pattern growth hormone secretion found in males. The considerably elevated growth hormone pulse amplitudes observed in the young rats of both genders seem to be an additional inhibitory signal antagonizing phenobarbital induction of CYP2B1 and CYP2B2. Phenobarbital administration did not interfere with the normal gender- and age-dependent growth hormone secretory profiles. Last, although as little as 1 mg/kg phenobarbital increased CYP2B1 mRNA concentrations by 100%, there was no translation into detectable levels of protein. In contrast, the same low dose of barbiturate inducing an equal percent increase in CYP2B2 mRNA did result in an expression of protein. Unlike use of the 10 mg/kg dose, CYP2B1 and CYP2B2 induction by phenobarbital at 1 mg/kg was unaffected by age or gender.

Age Factors↗
PubMedDate not supplied

Immunofluorescence of phenobarbital inducible cytochrome P-450 in the hepatic lobule of normal and phenobarbital-treated rats.

The localization of the form of cytochrome P-450 that is induced by phenobarbital was studied by direct immunofluorescence in the hepatocytes of rats pretreated with phenobarbital in comparison with saline-treated rats. Specific fluorescence was seen in the hepatocyte cytoplasm in saline- and phenobarbital-treated rats; a more concentrated halo of fluorescence was detected surrounding the nuclei in the centrilobular zones after phenobarbital treatment. In the saline-treated rats, fluorescence was barely discernible but slightly more intense in the centrilobular than perilobular zones. In phenobarbital-treated rats, fluorescence was much more intense, with a similar but much greater difference between the centrilobular and perilobular zones. The tissue distribution and induction site of this component of the cytochrome P-450-dependent microsomal system may be relevant to the site of drug toxicity and the development of chemical carcinogenesis.

Animals↗
PubMed1982

Drug release from non-aqueous suspensions. I. Release of phenobarbital and phenobarbital sodium from paraffin suspensions.

The rate at which phenobarbital and phenobarbital sodium, suspended in liquid paraffin, are released to buffers pH = 3.0, 7.4 and 10.0 has been studied. The release rate of phenobarbital depends on its solubility and hence on the pH, whereas the initial release rate of phenobarbital sodium is governed by sedimentation and hence is independent of the pH. However, when phenobarbital sodium is released to buffer pH = 3.0, it crystallizes in the interfacial layer after an initial release time. The release process in the release apparatus used cannot be described by a theory based on forced convection [i.e. the (E)SCRD-theory], but has to be regarded as a natural convection process.

Chemistry, Pharmaceutical↗
PubMed1983

Late phase of liver restoration following partial hepatectomy in phenobarbital-treated rats. I. Effect of preoperative and postoperative phenobarbital treatment on organ weight, protein and DNA content of the normal and the regenerating liver.

Rats were treated with phenobarbital (50 mg/kg) for 7 days prior to or after partial hepatectomy. Liver weight, protein, DNA, and RNA content were determined in liver tissue removed at operation as well as in regenerating liver 7 days later at the time of death. When rats were treated with phenobarbital in the preoperative period an increase in liver weight secondary to cell hyperplasia was observed as compared to livers of rats treated with sodium chloride. The weight of regenerating liver of preoperatively treated rats did not differ from the controls, but protein concentration was significantly higher (P less than or equal to 0.001). When phenobarbital was applied only in the postoperative period, a highly significant (P less than or equal to 0.001) enlargement of the regenerating liver tissue was found secondary to cell hypertrophy without hyperplasia, whereas protein concentration was unchanged. An increased RNA/DNA ratio, however, suggests that further protein synthesis is enhanced. The results show that both preoperative and postoperative phenobarbital treatment aids in hepatic tissue enlargement, though by a different mechanism.

Animals↗
PubMed1997

Phenobarbital molecularly imprinted polymer selectively binds phenobarbital.

Molecularly imprinted polymer (MIP) was prepared against phenobarbital using methacrylic acid as the functional monomer and ethylene glycol dimethacrylate as the cross linking monomer. We analyzed the recognition properties of the phenobarbital MIP. In some organic solvents, imprinted polymer showed selective binding to phenobarbital. Two dissociation constants of binding were calculated by Scatchard plot analyses; Kd values were 1.8, 121.7 microM, and the number of binding sites was 8.3, 92.3 mumol/g MIP in toluene-heptane-acetic acid (25 : 75 : 1, v/v), respectively. The relationship between the binding affinity to phenobarbital MIP and the polarity of the solvent system, as well as the structure of the template molecule is also discussed.

Cross-Linking Reagents↗