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At least 55 records · Page 3Linked to original sources
PubMed2003

Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)-deficient mice.

gamma-Hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), is proposed to function as a neurotransmitter or neuromodulator. gamma-Hydroxybutyrate and its prodrug, gamma-butyrolactone (GBL), recently received increased public attention as they emerged as popular drugs of abuse. The actions of GHB/GBL are believed to be mediated by GABAB and/or specific GHB receptors, the latter corresponding to high-affinity [3H]GHB-binding sites coupled to G-proteins. To investigate the contribution of GABAB receptors to GHB actions we studied the effects of GHB in GABAB(1)-/- mice, which lack functional GABAB receptors. Autoradiography reveals a similar spatial distribution of [3H]GHB-binding sites in brains of GABAB(1)-/- and wild-type mice. The maximal number of binding sites and the KD values for the putative GHB antagonist [3H]6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene acetic acid (NCS-382) appear unchanged in GABAB(1)-/- compared with wild-type mice, demonstrating that GHB- are distinct from GABAB-binding sites. In the presence of the GABAB receptor positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol GHB induced functional GTPgamma[35S] responses in brain membrane preparations from wild-type but not GABAB(1)-/- mice. The GTPgamma[35S] responses in wild-type mice were blocked by the GABAB antagonist [3-[[1-(S)-(3,4dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]-cyclohexylmethyl phosphinic acid hydrochloride (CGP54626) but not by NCS-382. Altogether, these findings suggest that the GHB-induced GTPgamma[35S] responses are mediated by GABAB receptors. Following GHB or GBL application, GABAB(1)-/- mice showed neither the hypolocomotion, hypothermia, increase in striatal dopamine synthesis nor electroencephalogram delta-wave induction seen in wild-type mice. It, therefore, appears that all studied GHB effects are GABAB receptor dependent. The molecular nature and the signalling properties of the specific [3H]GHB-binding sites remain elusive.

4-Butyrolactone↗
PubMed2005

Enzymatic synthesis of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) with CoA recycling using polyhydroxyalkanoate synthase and acyl-CoA synthetase.

We succeeded in developing a novel method for in vitro poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3 HB-co-4 HB)] synthesis with CoA recycling using polyhydroxyalkanoate synthase and an acyl-CoA synthetase. Using this method, the monomer compositions in P(3 HB-co-4 HB)s could be controlled strictly by the ratios of the monomers in the reaction mixtures.

Acyltransferases↗
PubMed2000

Utilization of oxidative pressure for enhanced production of poly-beta-hydroxybutyrate and poly(3-hydroxybutyrate-3-hydroxyvalerate) in Ralstonia eutropha.

Ralstonia eutropha was cultivated under oxidative conditions in the presence of hydrogen peroxide and methyl viologen to stimulate the flux of NADPH to the PHA biosynthesis pathway. The effects of oxidants on the biosynthesis of poly-beta-hydroxybutyrate(PHB) and poly(3-hydroxybutyrate-3-hydroxyvalerate)[P(3HB-3HV)] were investigated. The biosynthesis rate and concentrations of PHB and its copolymer P(3HB-3HV) increased significantly under the oxidative pressure of methyl viologen, meanwhile, the molar fraction of 3HV in P(3HB-3HV) remained constant. The effect of methyl viologen on the flux of the intermediate compounds was investigated by measuring the activity of enzymes related to PHB biosynthesis, glucose 6-phosphate dehydrogenase (G6PD), and NADPH level. The oxidant significantly activated the G6PD of R. eutropha, increasing the NADPH level used for the reduction reaction of acetoacetyl-CoA to beta-hydroxybutyryl-CoA, thereby enhancing the biosynthesis of PHB and P(3HB-3HV).

Journal Article↗
PubMed2007

Feasibility of D-glucuronate to enhance gamma-hydroxybutyric acid metabolism during gamma-hydroxybutyric acid toxicity: pharmacokinetic and pharmacodynamic studies.

Gamma-Hydroxybutyric acid (GHB) is a drug of abuse. Literature studies showed that D-glucuronate acts as an oxidative stimulator of GHB metabolism following in vivo GHB tracer doses. The present proof-of-concept study investigates if D-glucuronate enhances GHB metabolism and inhibits blood-brain barrier (BBB) carrier-mediated transport of GHB for clinically relevant and toxicological concentrations of GHB. In a randomized cross-over study with a 3 day washout period, rats were intravenously administered GHB (200, 400 or 800 mg/kg) with either saline or D-glucuronate (830 mg/kg i.v. bolus followed by a constant infusion of 1.39 g/kg-h). Systemic and renal GHB pharmacokinetics, as well as onset, offset and duration of GHB sedative/hypnotic effects were measured following each GHB dose. In situ brain perfusion was used to determine if D-glucuronate inhibited GHB BBB transport. D-Glucuronate did not alter GHB sedative/hypnotic effects at all three GHB doses. A model independent approach revealed that GHB systemic (AUC, CL(Total), CL(Metabolism), V(SS), T(1/2)) and renal (CL(Renal), f(e)) pharmacokinetic parameters were unaltered by D-glucuronate administration. GHB influx clearance was unaltered by D-glucuronate suggesting a lack of transport inhibition. These observations suggest that although previously shown to be promising at GHB tracer doses, D-glucuronate lacks therapeutic benefit in the treatment of GHB toxicity.

Animals↗
PubMed2001

Application of a convenient extraction procedure to analyze gamma-hydroxybutyric acid in fatalities involving gamma-hydroxybutyric acid, gamma-butyrolactone, and 1,4-butanediol.

The most common chemicals that can be ingested and lead to greater than endogenous levels of gamma-hydroxybutyric acid (GHB) in decedents are salts of GHB, gamma-butyrolactone (GBL), and 1,4-butanediol (BD). Results for three deaths involving the ingestion of one or another of these three chemicals, which led to findings of GHB in the decedents, are presented. An extraction procedure that facilitates the quantitation of GHB was developed. If present in the same specimen, both GHB and GBL can be quantitated. To determine the GBL concentration, the specimen is first analyzed for existing GHB, the GBL is then converted to GHB, and the analysis is repeated. The difference between the results in molarity units can yield the GBL concentration. A separate procedure was utilized for estimating concentrations of BD. Specimens analyzed included urine, blood, ocular fluid, brain, and solutions consumed by the decedents prior to death. The procedures were found to be convenient in as much as they are relatively rapid, precise, and economical.

4-Butyrolactone↗
PubMed1971

Metabolism of poly- -hydroxybutyrate: effect of mild alkaline extraction on native poly- -hydroxybutyrate granules.

Mild alkaline extraction of native poly-beta-hydroxybutyrate (PHB) granules results in the solubilization of a protein fraction. Both the solubilized protein fraction and the extracted granules are essentially devoid of PHB synthetase activity unless recombined. The protein fraction has been separated by chromatography into two components (A-I and A-II). A-I but not A-II can be recombined with extracted granules to give rise to PHB synthetase activity. Extracted granules no longer require pretreatment with activator or trypsin but are directly susceptible to hydrolysis by Rhodospirillum rubrum depolymerase. Addition of A-II or A-I prevents the direct hydrolysis by depolymerase. The inhibition is reversed by activator or trypsin. We conclude that native granules are associated with a protein inhibitor which prevents the hydrolysis of PHB by depolymerase unless the protein is destroyed by trypsin, removed by alkaline extraction, or modified by activator.

Bacillus megaterium↗
PubMed1991

Molecular analysis of the Alcaligenes eutrophus poly(3-hydroxybutyrate) biosynthetic operon: identification of the N terminus of poly(3-hydroxybutyrate) synthase and identification of the promoter.

Molecular methods have been applied to analyze the expression of the Alcaligenes eutrophus poly(3-hydroxybutyrate) (PHB) synthase gene (phbC). The translational initiation codon was identified by analysis of the amino acid sequence of a PHB synthase-beta-galactosidase fusion protein. This protein was purified to almost gel electrophoretic homogeneity by chromatography on DEAE-Sephacel and on aminophenyl-beta-D-thiogalactopyranoside-Sepharose from cells of A. eutrophus which harbored a phbC'-'lacZ fusion gene. A sequence (TTGACA-18N-AACAAT), exhibiting striking homology to the Escherichia coli sigma 70 promoter consensus sequence, was identified approximately 310 bp 5' upstream from the translation initiation codon. An S1 nuclease protection assay mapped the transcription start point of phbC 6 bp downstream from this promoter. The location of the promoter was confirmed by analyzing the expression of active PHB synthase in clones of E. coli harboring 5' upstream deletions of phbC ligated to the promoter of the lacZ gene (lacZp) in a Bluescript vector. Plasmids do181 and do218, which were deleted for the first 108 or 300 bp of the phbC structural gene, respectively, conferred the ability to synthesize large amounts of different truncated PHB synthase proteins to the cells. These proteins contributed to approximately 10% of the total cellular protein as estimated from sodium dodecyl sulfate-polyacrylamide gels. The modified PHB synthase encoded by plasmid do181 was still active. Clones in which the lacZp-'phbC fusion harbored the complete phbC structural gene plus the phbC ribosome binding site did not overexpress PHB synthase.

Acyltransferases↗
PubMed2005

Hydroxyapatite reinforced poly(3-hydroxybutyrate) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) based degradable composite bone plate.

Poly(3-hydroxybutyrate) (P3HB), its co-polymers with 3-hydroxyvalerate (HV) (PHBV8 and PHBV22), and their hydroxyapatite (HAp) containing composites (5 and 15%, w/w) were prepared by injection molding. PHBV bone plates with low valerate contents and 15% (w/w) HAp appear to have better mechanical properties than the others. Flexural strengths of 15% (w/w) HAp-loaded P3HB, PHBV8 and PHBV22 were 78.28, 63.45 and 39.38 MPa, respectively. Tensile strengths of 15% (w/w) HAp-loaded P3HB, PHBV8 and PHBV22 were 18.99, 15.44 and 11.02 MPa, respectively. For the ageing test, bone plates were incubated in phosphate-buffered saline PBS (0.1 M, pH 7.4) at 37 degrees C and at pre-determined time points they were removed and subjected to a three-point bending test. Incubation in PBS caused a sharp decrease in the mechanical properties within the first 24 h, followed either by a gradual decrease or no change for a period of about 1 month. SEM results showed that there was no significant material erosion in the 4-week incubation period. P3HB loaded with 15% HAp appeared to yield the most suitable bone plate, insofar as mechanical properties are concerned with potential for further testing in vivo.

Biocompatible Materials↗
PubMed2002

Oral beta-hydroxybutyrate supplementation in two patients with hyperinsulinemic hypoglycemia: monitoring of beta-hydroxybutyrate levels in blood and cerebrospinal fluid, and in the brain by in vivo magnetic resonance spectroscopy.

In persistent hyperinsulinemic hypoglycemia of infancy, ketone body concentrations are abnormally low at times of hypoglycemia, depriving the brain of its most important alternative fuel. The neuroprotective effect of endogenous ketone bodies is evidenced by animal and human studies, but knowledge about exogenous supply is limited. Assuming that exogenous ketone body compounds as a dietetic food might replace this alternative energy source for the brain, we have monitored the fate of orally supplemented DL sodium beta-hydroxybutyrate (beta-OHB) in two 6-mo-old infants with persistent hyperinsulinemic hypoglycemia for 5 and 7 mo, while on frequent tube-feedings and treatment with octreotide. Near total (95%) pancreatectomy had been ineffective in one patient and was refused in the other. In blood, concentrations of beta-OHB increased to levels comparable to a 16- to 24-h fast while on DL sodium beta-OHB 880 to 1000 mg/kg per day. In cerebrospinal fluid, concentrations of beta-OHB increased to levels comparable to a 24- to 40-h fast, after single dosages of 4 and 8 g, respectively. High ratios of beta-OHB to acetoacetate indicated exogenous origin of beta-OHB. An increase of intracerebral concentrations of beta-OHB could be demonstrated by repetitive single-voxel proton magnetic resonance spectroscopy by a clear doublet at 1.25 ppm. Oral DL sodium beta-OHB was tolerated without side effects. This first report on oral supplementation of DL sodium beta-OHB in two patients with persistent hyperinsulinemic hypoglycemia demonstrates effective uptake across the blood-brain barrier and could provide the basis for further evaluation of the neuroprotective effect of beta-OHB in conditions with hypoketotic hypoglycemia.

3-Hydroxybutyric Acid↗
PubMedDate not supplied

Properties and drug release behaviour of poly(3-hydroxybutyric acid) and various poly(3-hydroxybutyrate-hydroxyvalerate) copolymer microcapsules.

Microcapsules of poly(3-hydroxybutyric acid) [PHB] and its copolymers with hydroxyvalerate [HV] were prepared by the solvent evaporation technique and loaded with a model drug, 2,7-dichlorofluorescein. Microcapsules were also prepared from the same polymers by incorporating a polyphosphate-Ca+2 complex into the membrane. The morphology of the microcapsules varied by the change in the type of polymer used, by the introduction of drug and by the incorporation of the complex. Drug release behaviour, encapsulation efficiency and loading were all found to be influenced by the polymer type. The DSC results revealed that upon incorporation of valerate as the co-monomer, the crystallinity of the polymer decreased, leading to a material with more segmental mobility. This probably was the reason why the loading and encapsulation efficiency of the homopolymer were lower than those of the copolymers. DSC also indicated that the complex became an integral part of the membrane.

Calcium↗
PubMed1980

Gamma-hydroxybutyric acid as hypnotic. Clinical and pharmacokinetic evaluation of gamma-hydroxybutyric acid as hypnotic in man.

Gamma-Hydroxybutyric acid (GOH) was administered to three groups of four patients in 50, 75 or 100 mg/kg dose respectively, and sleep effects were scored, by sleep observation and questionnaire; GOH plasma levels were determined at 75-100 mg/kg, saliva and urine excretion at 100 mg/kg. Sleep induction was rapid and irresistible, subjects awoke at plasma levels of 90 micrograms/ml; sleep scores were good for 75 mg/kg, excellent for 100 mg/kg, notably on mood. For 75 or 100 mg/kg GOH had virtually disappeared from the blood eight hours after intake; twelve hours after intake no more GOH was detectable in urine; no correlation between plasma- and saliva levels was found. Plasma levels for 100 mg/kg dose were not at an anaesthetic level. So, GOH is a safe and good hypnotic at 75 or 100 mg/kg in clinical use.

Humans↗
PubMed1991

The gamma-hydroxybutyrate model of absence seizures: correlation of regional brain levels of gamma-hydroxybutyric acid and gamma-butyrolactone with spike wave discharges.

gamma-Hydroxybutyric acid (GHB) produces a constellation of EEG and behavioral changes when given to animals, which represent an experimental model of generalized absence seizures. gamma-Butyrolactone (GBL), the prodrug of GHB, produces these changes more rapidly and consistently than GHB, such that the rat treated with GBL is a more reproducible and predictable model of absence seizures. The hypothesis that the epileptogenic effects of GBL are due solely to its conversion to GHB was tested. The regional concentration of both compounds in brain was determined in time-course and dose-response studies, as well as at the onset of EEG changes, induced by both GHB and GBL. Also, the EEG and behavioral effects of both drugs were ascertained after intrathalamic injection in the rat. gamma-Butyrolactone produced a rapid onset of bilaterally synchronous spike and wave discharges in the rat, which correlated with a rapid appearance of GHB in brain in the GBL-treated animals. In the GHB-treated animals, EEG changes occurred 20 min after administration of GHB when levels of GHB in the brain were peaking. The threshold concentration of GHB in brain for EEG changes, in both GHB-and GBL-treated animals was 240 x 10(-6) M. The concentration of GBL in brain peaked 1 min after administration of GBL and fell rapidly to undetectable levels within 5 min. Bilateral injection of GHB into thalamus resulted in a brief burst of spike and wave discharges, while GBL, administered into the thalamus, had no effect. The use of GBL as a prodrug for GHB in this model of generalized absence seizures is valid, since GBL itself was inactive.

4-Butyrolactone↗
PubMed2003

A tertiary alcohol analog of gamma-hydroxybutyric acid as a specific gamma-hydroxybutyric acid receptor ligand.

gamma-Hydroxybutyric acid (GHB) shows great promise as a treatment for sleeping disorders but is also increasingly abused. The exact mechanism of action of GHB is yet to be delineated, but it is known to interact with specific GHB binding sites or receptors, to act as a weak agonist at GABA(B) receptors, and that GHB undergoes metabolism to GABA. In drug discrimination studies, GABA(B) agonists, and to a lesser extent GABA(A)-positive modulators, substitute for GHB. To delineate the relative contributions of each receptor system to the profile of GHB, tertiary alcohol analogs of GHB and its homolog, 5-hydroxypentanoic acid (UMB58), were prepared (UMB68 and UMB75, respectively), which cannot be metabolized to GABA-active compounds. Binding studies against [(3)H]NCS-382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) ethanoic acid] showed that the tertiary alcohol analog of GHB (UMB68) has similar affinity to GHB, with the longer chain analogs possessing lower affinity. Against [(3)H]GABA, UMB68 showed no affinity (IC(50) >100 microM) at GABA(A) or GABA(B) receptors. In vivo studies showed that, at behaviorally active doses, rats trained to discriminate GHB did not recognize the novel ligands as GHB. Thus, UMB68 is a selective GHB receptor ligand in binding assays, will not undergo metabolism to GABA-active compounds, and does not show the same effects as GHB in vivo. These data suggest that, although UMB68 binds to the GHB receptor, it does not have the observed GABA receptor-mediated effects of GHB in vivo and could provide a novel tool for studying the pharmacology of the GHB receptor in the absence of complicating GABAergic effects.

Animals↗
PubMed1987

On the biodegradation of poly-beta-hydroxybutyrate (PHB) homopolymer and poly-beta-hydroxybutyrate-hydroxyvalerate copolymers.

The known biodegradability of PHB in certain biological environments has led to its proposed use as a 'biodegradable' implant material. Monofilaments of PHB homopolymer and two PHV-PHB copolymers have been studied in vivo and in vitro and assessed for changes in mechanical properties and topography. In vivo biodegradation was only observed with PHB when pre-degraded by 10.0 Mrad of gamma-irradiation before implantation. High temperature in vitro hydrolysis suggested that PHV copolymer additions retarded the rate of degradation of PHB. Hydration reactions had most effect on the ultimate tensile properties of the materials. In contrast, the elastic properties appeared to be relatively unaffected.

Animals↗
PubMedDate not supplied

Poly(3-hydroxybutyrate) granule-associated proteins: impacts on poly(3-hydroxybutyrate) synthesis and degradation.

Polyhydroxyalkanoates (PHAs) represent a group of biopolymers that are synthesized by many bacteria as storage compounds and deposited as insoluble cytoplasmic inclusions. Because they have many putative technical and medical applications, PHAs may play an important role in human life in the future. Therefore, for academic interest the bacterial PHA metabolism has been studied in much detail. In the past decade much new and unexpected information about the metabolism of PHA in bacteria became available. Aspects of the biogenesis of PHA granules in bacteria become more and more important in the literature. Several enzymes, proteins, and mechanisms of regulation are involved in PHA biosynthesis and PHA granule biogenesis. The intention of this review is to give an overview about our current knowledge of the structure of the PHA granule surface and the PHA granule-associated proteins involved in biogenesis and degradation. The focus is on the PHA synthases, the intracellular PHA depolymerases, the phasins, and the transcriptional regulator PhaR, which are the main actors in biosynthesis and intracellular degradation of PHAs and formation of PHA granules. In addition, putative applications of PHA granules and PHA granule-associated proteins in nanotechnology are discussed.

Acyltransferases↗