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PubMed2004

Determination of gabapentin-lactam in serum of patients under gabapentin therapy.

Gabapentin (1-(aminomethyl)cyclohexane acetic acid, CAS 601 42-96-3, GBP, Neurontin) and its derivative gabapentin-lactam (8-aza-spiro[5,4]decan-9-one, GBP-L) were determined by HPLC in the serum of patients with focal epilepsy treated with GBP. In patients in whom serum was acquired within 3 h after oral intake, GBP-L could be detected at concentrations up to 8.2 micromol/l. As GBP-L has been previously shown to exert neuroprotective effects in a similar concentration range, this finding suggests that clinically relevant effects of GBP-L may occur in patients treated with GBP. The possible neuroprotective efficacy of GBP-L should be the subject of further preclinical and clinical investigations.

Acetates↗
PubMed1997

Pharmacologic and dietary therapies in epilepsy: conventional treatments and recent advances.

A number of treatment options are currently available for the medical management of epilepsy. Conventional antiepileptic drugs (AEDs) include phenytoin, carbamazepine, valproic acid, ethosuximide, barbiturates, and benzodiazepines. Although these drugs control seizures, they may also cause blood dyscrasias, sedation, and cognitive impairment. Felbamate, gabapentin, lamotrigine, and vigabatrin are new AEDs believed to cause fewer side effects than conventional medications. Felbamate, however, has been linked with substantially increased incidence of aplastic anemia, and the other new AEDs have been studied for relatively short periods of time. Ketogenic diets, comprised of foods high in fat and low in protein and carbohydrate content, have been reported to improve seizure control. However, these diets are widely acknowledged to be unpalatable, making sustained compliance with dietary restrictions difficult. To promote long-term control of seizures, physicians must consider the side effects of therapeutic interventions for epilepsy, as well as their anticonvulsant efficacy.

Acetates↗
PubMed1995

Existence of gamma-aminobutyric acid and its biosynthetic and metabolic enzymes in rat salivary glands.

To obtain more insight into the physiological role of gamma-aminobutyric acid (GABA) in rat salivary glands, we measured the concentration of GABA and the activities of its biosynthetic and metabolic enzymes, glutamate decarboxylase (GAD) and GABA transaminase (GABA-T). The GABA concentrations in rat parotid and submandibular glands were 10.0 and 14.3 nmol/g weight, respectively, which were 0.6-0.8% of the levels in the brain (cerebellum and medulla oblongata), whereas glutamic acid (Glu) was abundant in the two glands. These GABA levels in the two glands were significantly decreased by administration of semicarbazide (200 mg/kg, i.p.), a GAD inhibitor, and increased by gabaculine (50 mg/kg, i.p.), a GABA-T inhibitor. The activities of both GAD and GABA-T were also detected in homogenates of the two salivary glands, but they were lower than those in the brain. However, kinetic analysis showed that the values of Michaelis constants for Glu and GABA in both enzyme reactions in these two glands were similar to those in the brain. These results indicate that GABA and its biosynthetic and metabolic enzymes are present in rat salivary glands as well as the brain.

4-Aminobutyrate Transaminase↗
PubMed1978

Purification and properties of chorismate synthase from Bacillus subtilis.

Chorismatic synthase was purified to apparent homogeneity from Bacillus subtilis. The enzyme required NADPH-dependent flavin reductase, Mg2+, NADPH, and flavin (FMN or FAD) for activity. The molecular weight of chorismate synthase was 24,000 as determined by sodium dedecyl sulfate (SDS)-gel electrophoresis. The enzyme was also isolated in a complex form associated with NADPH-dependent flavin reductase and another enzyme of the aromatic amino acid pathway, dehydroquinate synthase. On SDS-gel electrophoresis, this form was resolved into three bands with molecular weights of 13,000, 17,000, and 24,000. The enzyme complex was easily dissociated and the dissociation resulted in a change in the chromatographic properties of NADPH-dependent flavin reductase which was no longer retained on phosphocellulose whereas chorismate synthase was still adsorbed. Chorismate synthase activity was linear with time and protein concentration, whereas partially purified preparations showed a significant lag period before the reaction took place. Moreover, crude or partially purified enzyme preparations were completely inactivated by dilution and the activity could be recovered by addition of flavin reductase. A possible role of NADPH-dependent flavin reductase in the activation and regulation of chorismate synthase activity is discussed.

Bacillus subtilis↗
PubMed2003

Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations.

The effects of antiepileptic drugs, gabapentin, pregabalin and vigabatrin, on brain gamma-aminobutyric acid (GABA), glutamate and glutamine concentrations were studied in Long Evans rats using proton magnetic resonance spectroscopy (MRS) of perchloric acid extracts. Cellular glutamate concentrations significantly decreased by 7% (P<0.05) 2 hours after intraperitoneal injection of 100mg/kg gabapentin and 4% (P<0.05) with 1000 mg/kg. No differences were observed in cellular GABA and cellular glutamine concentrations in rats treated with gabapentin. Pregabalin, an analogue of gabapentin, significantly decreased cellular glutamate concentrations by 4% (P<0.05), while no effect was observed on cellular GABA or glutamine concentrations in the healthy rat forebrain. Vigabatrin, used as a positive control to increase GABA levels, produced a 50% increase in cellular GABA compared to saline treated rats (P<0.003). Although, gabapentin and pregabalin are anticonvulsants designed to mimic GABA, these drugs do not raise cellular GABA levels acutely but modestly decreased cellular glutamate levels in our healthy rat forebrain model.

Acetates↗
PubMedDate not supplied

Nuclear magnetic resonance spectroscopic determination of dicyclomine hydrochloride in tablet, capsule, and injection dosage forms.

A rapid and specific nuclear magnetic resonance (NMR) spectroscopic method was developed for determining dicyclomine hydrochloride in tablet, capsule, and injection dosage forms. The method consists of an extraction step with chloroform, evaporation of the solvent, addition of maleic acid as an internal standard, dissolution of the mixture in deuterated chloroform-deuterated acetone (40 + 60), NMR spectral determination, and integration of the peaks of interest. The concentration of dicyclomine hydrochloride in the dosage form was calculated from the integral values for the peaks of the test compound and the internal standard. The average recovery value +/- the standard deviation (n = 5) of dicyclomine hydrochloride added to synthetic samples was 99.7 +/- 0.9% (coefficient of variation 0.9%). The assay values for various commercial tablets, capsules, and injectables analyzed by using the proposed method differed in all cases by less than 1% from those obtained by using the USP XX titrimetric method. There was no interference from stearate, an excipient found in tablets and capsules, or from chloral hydrate, a preservative found in injectables .

Capsules↗
PubMed1982

Effect of GABA and isogabaculine on ornithine decarboxylase and putrescine metabolism.

Isogabaculine (3-amino-1,3-cyclohexadienyl carboxylic acid; RMI 71,932), an irreversible inhibitor of GABA transaminase, when added to mouse neuroblastoma cells in spinner culture at the time of induction of cell proliferation, increased ornithine decarboxylase (ODC) activity threefold above that of normal control cells and twofold above that of GABA (gamma-aminobutyric acid)-treated cells. Isogabaculine did not affect ODC activity of rat glioma (C6) or rat hepatoma (HTC) cells. As determined by half-life measurements of ODC and intracellular GABA concentrations, isogabaculine apparently has a direct stabilizing effect on ODC in neuroblastoma cells that is unrelated to the accumulation of GABA due to GABA transaminase inhibition. Putrescine metabolism to GABA or spermidine was determined in C6, HTC, and neuroblastoma cells in the presence or absence of isogabaculine and/or GABA. Neither GABA nor isogabaculine treatment dramatically altered the metabolism of putrescine to GABA or spermidine in neuroblastoma, C6 glioma, or HTC cells. However, the appreciable amount of labeled GABA formed from putrescine indicated that this metabolic route may be more important than was previously thought.

Animals↗
PubMed1996

The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy.

Gabapentin has come into clinical use as adjunctive therapy in the treatment of epilepsy. Designed to mimic gamma-aminobutyric acid (GABA), its mechanism of action remains elusive. In vivo measurements of GABA in human brain were made using 1H magnetic resonance spectroscopy. We used a 2.1-T magnetic resonance imager-spectrometer and an 8-cm surface coil to measure a 13.5-cm3 volume in the occipital cortex. GABA levels were measured in 14 patients enrolled in an open-lbel trial of gabapentin. GABA was elevated in patients taking gabapentin compared with 14 complex partial epilepsy patients, matched for antiepileptic drug treatment. Brain GABA levels appeared to be higher in patients taking high-dose gabapentin (3,300-3,600 mg/day) than in those taking standard doses (1,200-2,400 mg/day). Gabapentin appears to increase human brain GABA levels.

Acetates↗
PubMed1981

Antagonism of calcium-induced contraction in potassium-depolarized rabbit detrusor muscle strips by dicyclomine hydrochloride and rociverine.

The musculotropic action of dicyclomine hydrochloride in bladder muscle has been attributed to its local anesthetic activity. In this study rabbit detrusor strips were depleted of calcium by incubation in Ca2+-free solution containing ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA). Contractions elicited by replacement of Ca2+ during depolarization with 80 mM K+ were only slightly affected by atropine or scopolamine but were antagonized in a noncompetitive manner by dicyclomine and rociverine (pD2' = 4.89 and 4.61, respectively). These contractions were also blocked with greater potency by nifedipine (pD2' = 8.50) and with lesser potency by lidocaine (pD2' = 2.52). Procaine was ineffective up to 1 mM. Comparison of the antagonism produced by dicyclomine and rociverine with that produced by nifedipine or lidocaine did not help to define the mechanism of the musculotropic drugs. However, as rociverine is not a local anesthetic and procaine was not effective, it appears that the "local anesthetic" property is not sufficient to explain the action of these musculotropic drugs.

Animals↗
PubMed1976

Treatment of hereditary angioneurotic edema with tranexamic acid and cinnarizine.

Six out of 7 Finnish patients suffering from hereditary angioneurotic edema were helped during attacks, by treatment with tranexamic acid (AMCA, Cyklokapron, Kabi) in doses of 1.5 g 3 times daily, follow-up time 3-25 months. 3 of these patients also had continuous AMCA treatment, in the course of which 2 remained nearly symptom-free on a dosage of 1 g 2-3 times daily. Even the third one had shorter and milder attacks. One patient, however, had to stop taking AMCA after 6 weeks' treatment, because of fatigue and nausea. Follow-up time for the others was 9-11 months. For comparative purposes, 3 patients were given continuous treatment with an antihistamine, cinnarizine in a dosage of 20-30 mg daily. Two of the patients were helped by it, one becoming nearly symptom-free and the other having fewer and milder attacks; follow-up time 9-10 months.

Adult↗
PubMed1995

The anticonvulsant gabapentin enhances promoted release of GABA in hippocampus: a field potential analysis.

The mechanism of action of the recently developed anticonvulsant gabapentin (GBP) used for treatment of partial seizures [12] is largely unknown. Rat hippocampal slices were maintained in vitro and the effects of microapplication of nipecotic acid (NPA), which promotes the release and blocks uptake of GABA, on the synaptically-evoked population excitatory postsynaptic potential (EPSP) were assessed before and after 1 h bath application of GBP. GBP treatment did not alter the population EPSP amplitude to paired or multiple stimuli, but nearly doubled the shunting effects of NPA on the EPSP with no effect on the presynaptic volley. The NPA-induced shunting of the EPSP was bicuculline-sensitive, indicating its mediation by GABAA receptor activation. These results suggest that GBP may increase free GABA levels in hippocampal cells, the release of which may be enhanced under conditions of promoted GABA release. Moreover, the study presents a methodology to electrophysiologically assess relative free GABA levels using field potential analysis in the adult rat brain.

Acetates↗
PubMed1996

Antimyoclonic effect of gabapentin in a posthypoxic animal model of myoclonus.

The antimyoclonic property of the novel antiepileptic drug, gabapentin (1-(aminomethyl) cyclohexane acetic acid), was tested in cardiac arrest-and p,p'-DDT(1,1,1-trichloro-2,2-bis (p-chlorophenyl)ethane)-induced animal models of myoclonus. Gabapentin dose-dependently attenuated myoclonus in posthypoxic rats for more than 3 h. The drug was also found to be effective in controlling the early stages of seizures following the anoxic insult. In contrast, the drug was ineffective in controlling either myoclonus or seizures in p,p'-DDT-treated animals. These results suggest that gabapentin can be used used as an effective therapeutic agent in an acute hypoxia/ischemia-induced neurological disorder. The data further indicate that distinct neurological mechanisms may be operating in the expression of myoclonus among posthypoxic and p,p'-DDT-induced animal models.

Acetates↗
PubMed1980

Studies on the kinetics and stoichiometry of inactivation of Pseudomonas omega-amino acid:pyruvate transaminase by gabaculine.

A homogeneous pyruvate-requiring omega-amino acid transaminase from Pseudomonas species F-126 has been examined for its behavior with gamma-aminobutyrate (GABA) as omega-amino acid substrate and for its susceptibility to the cyclic dihydroaromatic GABA analogue, gabaculine, a known suicide substrate for alpha-ketoglutarate-requiring GABA transaminases (Biochemistry 16, 4604-4610, 1977). One isomer of DL-gabaculine serves as a completely efficient titrant (no product molecules released) for this omega-amino acid transaminase by the anticipated mechanism of bound pyridoxal 5'-phosphate (PLP) derivitization. Stoichiometric titration with [2-3H]gabaculine reveals full inactivation at 0.45 labels/enzyme tetramer (see below), consistent with the subsequent demonstration that there is only 0.45 PLP molecule, bound as phenylhydrazine-titratable aldehyde form, per tetramer. Spectroscopic monitoring of inactivation also agrees with formation, on full inactivation, of 0.45 mol of m-anthranilyl-PNP adduct as the species quantitatively responsible for enzyme inactivation. Incubation of enzyme with excess PLP at 60 degrees C allows loading of enzyme with coenzyme to an average level of approximately 1 PLP/subunit, but even in this case activity is only increased up to 1.5-fold, and 1 to 1.5 molecules of gabaculine/tetramer cause complete inactivation. These data may indicate negative cooperativity between subunits.

Cyclohexanecarboxylic Acids↗
PubMed1971

Phenylalanine and tyrosine biosynthesis in Escherichia coli K-12: mutants derepressed for 3-deoxy-D-arabinoheptulosonic acid 7-phosphate synthetase (phe), 3-deoxy-D-arabinoheptulosonic acid 7-phosphate synthetase (tyr), chorismate mutase T-prephenate dehydrogenase, and transaminase A.

Mutant strains of Escherichia coli have been isolated in which the synthesis of 3-deoxy-d-arabinoheptulosonic acid 7-phosphate (DAHP) synthetase (phe) is derepressed, in addition to those enzymes of tyrosine biosynthesis previously shown to be controlled by the gene tyrR. The major enzyme of the terminal pathway of phenylalanine biosynthesis chorismate mutase-prephenate dehydratase is not derepressed in these strains. Genetic analysis of the mutants shows that the mutation or mutations causing derepression map close to previously reported tyrR mutations. A study of one of the mutations has shown it to be recessive to the wild-type allele in a diploid strain. It is proposed that the tyrR gene product is involved in the regulation of the synthesis of DAHP synthetase (phe) as well as the synthesis of DAHP synthetase (tyr), chorismate mutase-prephenate dehydrogenase, and transaminase A.

Aldehyde-Lyases↗
PubMed2006

Neurochemical evidence that supraspinally administered gabapentin activates the descending noradrenergic system after peripheral nerve injury.

We have previously demonstrated that gabapentin supraspinally activates the descending noradrenergic system to produce analgesic effects after peripheral nerve injury. To further establish the neurochemical basis for its supraspinally mediated analgesic action, concentrations of spinal noradrenaline, 4-hydroxy-3-methoxyphenylglycol (MHPG), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and dopamine were measured using high-performance liquid chromatography in a murine neuropathic pain model that was prepared by partial ligation of the sciatic nerve (the Seltzer model). Intracerebroventricularly (i.c.v.) administered gabapentin (100 and 300 microg) increased the spinal MHPG concentration and the MHPG/noradrenaline ratio and alleviated mechanical hypersensitivity, whereas the concentrations of noradrenaline, 5-HT, 5-HIAA and dopamine were unchanged. By contrast, i.c.v. gabapentin neither affected the spinal MHPG concentration and MHPG/noradrenaline ratio nor exhibited analgesic effects in animals subjected to a sham operation. In addition, spinal monoamine levels in ligated animals were not changed after intrathecal administration of gabapentin which however generated analgesic effects. Thus, the supraspinally mediated analgesic effects of gabapentin are correlated with an increase in spinal noradrenaline turnover.

Amines↗
PubMed2002

trans-3-Ethyl-cis-2,6,6-trimethyl-4-oxocyclohexanecarboxylic acid: an intermediate in the synthesis of a highly potent estrogen.

The title compound, C(12)H(20)O(3), (IV), the ethyl ester of which is an intermediate in the synthesis of a compound reported to be highly estrogenic, has been prepared. After the initial steps reported for the synthesis of this ester intermediate were followed, it was converted into the crystalline acid, (IV), for X-ray analysis. It was verified that (IV) was racemic when prepared. X-ray analysis showed that anti-hydrogenation of the double bond had occurred in the synthesis, making the orientation of the carboxyl group cis to the 2-methyl group and trans to the 3-ethyl group. NMR spectroscopy showed that the stereochemistry of (IV) was identical with that of its ester precursor. While the earlier report did not note the stereochemistry of this ester, it pointed out that the estrogenic product derived from it possessed the opposite carboxyl-2-methyl orientation, i.e. trans, although no X-ray analysis was performed. In the light of these results and the importance of correlating biological activity with compound structure, the unequivocal characterization of the highly estrogenic compound is warranted.

Cyclohexanecarboxylic Acids↗
PubMed1980

A simple rapid method for isolating soluble fibrin complexes from fibrinogen by treatment with thrombin and t-AMCHA.

Using treatment with thrombin associated with trans-aminomethylcyclohexane carboxylic acid (t-AMCHA), a simple and rapid method for isolating soluble fibrin complexes (SFC) from fibrinogen in the plasma was developed. By this procedure, the recovery rates of SFC and early FDP (mainly X) increased according to the concentration of t-AMCHA, reaching a maximum at 286 mM t-AMCHA. On the other hand, the recovery rate of fibrinogen remained below 1.5% and that of late FDP was almost 100% at all concentrations of t-AMCHA. These results suggested that SFC and FDP could be isolated from fibrinogen by thrombin and t-AMCHA (286 MM) treatment. Moreover, it was possible to isolate SFC from FDP using gel filtration after treatment with thrombin and t-AMCHA. The SFC could be quantified by assay of the eluted fractions containing SFC by the staphylococcal clumping test.

Aprotinin↗
PubMed2003

Cellular and molecular action of the putative GABA-mimetic, gabapentin.

Gabapentin was originally designed as an anti-convulsant gamma-aminobutyric acid (GABA) mimetic capable of crossing the blood-brain barrier. In the present review we show that although gabapentin is not a GABA mimetic, it has great utility as an add-on therapy for epilepsy and as a first-line treatment for neuropathic pain. We summarise the studies that have been performed which demonstrate that gabapentin appears to interact with a novel binding site expressed at high density within the central nervous system (CNS), namely the alpha2delta voltage-dependent calcium channel subunit. The review continues by examining the effects of gabapentin on calcium channel function and neurotransmitter release before, in the latter part of the review, summarising the more recently discovered actions of gabapentin in relation to intracellular signalling.

Acetates↗