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PubMed1977

Hemorrhage induced by intrauterine devices: control by local proteinase inhibition.

The intrauterine application of proteinase inhibitors, tranexaminc acid and the pancreatic trypsin inhibitor (Trasylol), reduces or eliminates menorrhagia and intermenstrual bleeding (spotting) produced by an intrauterine device (IUD). A decrease in pain and vaginal (cervical) discharge is also frequently observed. A single application is usually sufficient, more than three never being required. The effect lasts for an average of three cycles. In addition to the clinical use of these agents for the treatment of uterine hemorrhage, the slow release of proteinase inhibitors from an IUD may well be useful in minimizing its side effects without interfering with its contraceptive activity.

Administration, Topical↗
PubMed1997

Mechanisms of action of gabapentin.

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.

Acetates↗
PubMed1988

Purification and partial characterization of 4-aminobutyrate:2-oxoglutarate aminotransferase from sheep brain and locust ganglia.

We report here the first purification to homogeneity of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19) (GABA-T) from an invertebrate source (locust) and its initial comparison with that of GABA-T from mammalian brain (sheep). The enzyme from both organisms was found to be a dimer of similar-sized subunits, with a native Mr of approx. 97,000. The pI of GABA-T from the locust was 6.7 and that of the sheep enzyme was 5.5. Michaelis constants for 4-aminobutyric acid (GABA) and 2-oxoglutarate were respectively 0.79 +/- 0.16 mM and 0.27 +/- 0.08 mM for the locust enzyme and 2.2 +/- 0.24 mM and 0.22 +/- 0.11 mM for the sheep enzyme. 5-(Aminomethyl)-3-isoxazolol (muscimol) was a competitive inhibitor of both enzymes, whereas 5-amino-1,3-cyclohexadienylcarboxylic acid (gabaculine) acted as a potent suicide substrate. However, 3-aminopropane-1-sulphonic acid, diaminobutyric acid, 1,2,3,4-tetrahydro-1-methyl-3-pyridinecarboxylic acid (isoguvacine), beta-(aminomethyl)-4-chlorobenzenepropanoic acid (baclofen), bicuculline and picrotoxin did not inhibit either enzyme at concentrations below 100 mM. Polyclonal antisera raised against GABA-T from the sheep failed to cross-react with the enzyme from locust in either an Ouchterlony immunodiffusion plate or a competitive enzyme-linked immunosorbent assay. The purification procedures differed considerably. Ion-exchange chromatography, which was found suitable for the purification of GABA-T from the sheep, was ineffective with locust enzyme, which was finally purified by hydrophobic-interaction chromatography and chromatofocusing.

4-Aminobutyrate Transaminase↗
PubMed2003

The role of GABA in anxiety disorders.

Anxiety stems from and perpetuates dysregulation of neurobiological systems, but the exact mechanisms of anxiety disorders are still only partially understood. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter known to counterbalance the action of the excitatory neurotransmitter glutamate. Several pharmacologic agents target the GABA system and modulate the overall effect of GABA. This article highlights multiple neurobiological interactions that play a role in anxiety and reviews selected studies of plasma neurosteroid levels, plasma GABA levels, and benzodiazepine binding site sensitivity and density in patients with anxiety disorders. The article concludes with further support for the role of the GABA system in anxiety by summarizing the current evidence supporting the use of novel GABAergic agents including tiagabine in the treatment of anxiety disorders.

Acetates↗
PubMed1991

Regulation of the GABAA receptor/ion channel complex by intracellular GABA levels.

Synaptosomes and synaptoneurosomes were prepared from the cerebral cortex of control rats and of rats treated with gabaculine, gamma-vinylGABA (GVG), hydrazine and isonicotinic acid hydrazide (INH). An inverse relationship was observed between the GABA content of the synaptoneurosomes and the muscimol-stimulated chloride ion uptake by the organelles. The relationship held over an extensive range of experimental conditions including different drugs, different dosage levels of the same drug, different time intervals after administration of the same drug, and both single and multiple injections of drugs. The results indicated that the phenomenon was associated with the neurosome component of the preparation, and raised the possibility that GABA levels within the postsynaptic cell might regulate the functioning of the GABAA receptor complex.

Aminocaproates↗
PubMed2000

Antinociception and (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid antagonism by gabapentin in the rat spinal cord in vivo.

Gabapentin, a novel anticonvulsant and analgesic with an unknown mechanism of action, was tested on spinal dorsal horn neurone activity evoked by iontophoretically applied N-methyl-D-aspartic acid (NMDA) and (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and on nociceptive responses of single motor units (SMU) in anaesthetised rats. Gabapentin (10-215 mg/kg, i.v.) dose-dependently and selectively inhibited AMPA-evoked neuronal responses (ED50 106+/-24 mg/kg); no effect on NMDA-evoked activity was observed. In the same dose-range, gabapentin (10-215 mg/ kg, i.v.) dose-dependently reduced SMU responses to noxious electrical and mechanical stimulation. We conclude that gabapentin acts as an AMPA antagonist in the rat spinal cord, and that this mechanism is likely to substantially contribute to the antinociceptive effect of the drug.

Acetates↗
PubMed2005

Chain-length-dependent helical motifs and self-association of beta-peptides with constrained side chains.

Homo-oligomers constructed by using trans-2-aminocyclohexanecarboxylic acid monomers without protecting groups were studied. Both ab initio theory and NMR measurements showed that the tetramer tends to adopt a 10-helix motif, while the pentamer and hexamer form the known 14-helix. It was concluded that the conformationally constrained backbone is flexible enough to afford both 10-helical and 14-helical motifs, this observation in turn providing evidence of the true folding process. Self-association of the helical units was also detected, and the results of variable-temperature diffusion NMR measurements strongly suggested the presence of helical bundles in methanol solution.

Circular Dichroism↗
PubMed2003

[Clinical and neurochemical aspects of diaphragmatic myoclonus].

The case of a 35-year-old woman with diaphragmatic myoclonus of four year duration is presented. The myoclonus deteriorated with anxiety, menstruation and orthostatism. It was frequently accompanied by urinary retention or incontinence. Several pharmacologic agents were shown to be ineffective until the myoclonus was suppressed with a combination of gabapentin and tiagabine. In this article, the respiratory center is proposed as the original focus of the myoclonus, a deficit of gamma-aminobutyric acid (GABA) in brainstem structures as its neurochemical substrate, and GABAergic enhancement as an effective therapeutic measure. The clinical manifestations, etiology, ancillary studies and treatment of diaphragmatic myoclonus are reviewed. Experimental evidence on the anatomical localization, physiology and neurochemistry of the respiratory center is examined. The authors try to relate some of the patient's clinical findings to the experimental data found in the medical literature. The action mechanisms of gabapentin and tiagabine are examined and these drugs are proposed as effective means of enhancing GABAergic neurotransmission and treating diseases with increased inspiratory drive.

Acetates↗
PubMed2004

Sample preparation and determination of gabapentin in venous and capillary blood using liquid chromatography-tandem mass spectrometry.

An analytical method for the determination of gabapentin in serum obtained from venous blood samples has been developed using high-performance liquid chromatography (HPLC)-tandem mass spectrometry. In addition, a comparative study between capillary plasma samples and venous serum samples was carried out. This demonstrates the potential for the use of the described analytical system using very small amounts of blood. As internal standard (S)-(+)-alpha-amino-cyclohexane-propionic acid hydrate was used. Gabapentin and the internal standard are structural isomers, but have different m/z values for the fragments after collision induced dissolution. Gabapentin has 172-->154 and 172-->136 transitions and amino-cyclohexane-propionic acid hydrate has a 172-->126 transition which can be detected in tandem MS. Analysis of gabapentin was carried out on a C8 HPLC column using an isocratic mobile phase consisting of ammonium acetate (pH 3.0; 5mM)-methanol (96:4, v/v). The analytical method was validated for venous serum samples. Limit of detection was 1.6ng/ml and lower limit of quantification was 7.5ng/ml. R.S.D. values and bias values were within the range of acceptance for all concentration levels. The method developed for venous serum samples is being used in a gabapentin monitoring study using population pharmacokinetic modeling.

Acetates↗
PubMed1997

Neurochemical actions of gabapentin in mouse brain.

Gabapentin (GBP) is a recently licensed antiepileptic, drug whose mode of action remains to be fully elucidated. The following studies were designed to investigate the effects of GBP on several gamma-aminobutyric acid (GABA) related neurochemical parameters in mouse brain. GBP (0-75 mg/kg) was administered by intraperitoneal injection either as a single dose or twice daily for 8 days. Animals were sacrificed 4 h after the final administration and their brains removed and analysed for concentrations of GABA, glutamate and glutamine and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). Single dose GBP increased brain GABA-T activity and glutamine concentration but was without effect on GAD activity or the concentrations of GABA and glutamate. Following repeated treatment with GBP, brain GABA-T activity was consistently decreased and there was also a decrease in brain glutamate concentration. Repeated drug treatment was without effect on the activity of GAD or on the concentrations of GABA and glutamine. These results suggest that GBP has effects on the GABAergic system which may contribute to its antiepileptic and/or neuroprotective actions.

Acetates↗
PubMed1999

Stereoselective synthesis of a conformationally defined cyclohexyl carnitine analogue that binds CPT-1 with high affinity.

Carnitine (1, 3-hydroxy-4-trimethylammoniobutyrate) is important in mammalian tissue as a carrier of acyl groups. In order to explore the binding requirements of the carnitine acyltransferases for carnitine, we designed conformationally defined cyclohexyl carnitine analogues. These diastereomers contain the required gauche conformation between the trimethylammonium and hydroxy groups but vary the conformation between the hydroxy and carboxylic acid groups. Here we describe the synthesis and biological activity of the all-trans diastereomer (2), which was prepared by the ring opening of trans-methyl 2,3-epoxycylohexanecarboxylate with NaN3. Racemic 2 was a competitive inhibitor of neonatal rat cardiac myocyte CPT-1 (K(i) 0.5 mM for racemic 2; K(m) 0.2 mM for L-carnitine) and a noncompetitive inhibitor of neonatal rat cardiac myocyte CPT-2 (K(i) 0.67 mM). These results suggest that 2 represents the bound conformation of carnitine for CPT-1.

Animals↗
PubMed2000

Anorgasmia in a patient with bipolar disorder type 1 treated with gabapentin.

Gabapentin is a relatively new anticonvulsant indicated for adjunctive therapy in the treatment of partial seizures, with and without secondary generalization, in adults with epilepsy. Overall, it has a minimal side effect profile compared with other anticonvulsant agents. Postmarketing surveillance is needed to further delineate the spectrum of adverse events that may be experienced by patients treated with this medication. This is a case report of a 25-year-old man with a 10-year history of mood swings that progressively worsened and resulted in a suicide attempt 8 months before his first appointment. A diagnosis of bipolar disorder was established, and a clinical interview ruled out other mental disorders. The patient was administered gabapentin 300 mg/day, and the dose was titrated upward to 900 mg/day. A follow-up appointment revealed improved control of his bipolar symptoms. However, the patient reported that he could not have an orgasm during sexual intercourse. The medication was changed to valproic acid 250 mg three times daily. His bipolar symptoms remained under control and the anorgasmia resolved. This was maintained at the next follow-up appointment. The side effect profile and therapeutic monitoring requirements of gabapentin are favorable when compared with those of other anticonvulsant agents. However, because this agent is relatively new, especially for use in the treatment of bipolar disorder, a more thorough development of its side effect profile is needed. Observing, recording, and reporting atypical adverse events and side effects are critical to postmarketing surveillance and enhance the clinician's ability to make rational therapeutic decisions.

Acetates↗
PubMed1994

Gabapentin increases GABA-induced depolarization in rat neonatal optic nerve.

Membrane potential changes of rat neonatal optic nerves were studied in a sucrose-gap chamber. Nipecotic acid (NPA), which blocks uptake and promotes release of GABA, resulted in a bicuculline-sensitive depolarization (3.08 +/- 0.3 mV, n = 5). Pretreatment of the nerves with the anticonvulsant gabapentin (100 microM for 1 h) resulted in a near doubling of the NPA-induced depolarization (6.64 +/- 0.54 mV, n = 5). Gabapentin itself did not alter membrane potential, nor did brief applications of gabapentin enhance the NPA- or GABA-induced depolarization. Thus, gabapentin appears to enhance the releasable pool of GABA in this CNS neural system. These results have implications for the mechanism of the anticonvulsant properties of gabapentin.

Acetates↗
PubMed1977

Bullous keratopathy (Fuchs' endothelial dystrophy) treated systemically with 4-trans-amino-cyclohexano-carboxylic acid.

Twenty patients with bullous keratopathy (Fuchs' endothelial dystrophy) were treated systemically with the antifibrinolytic drug tranexamic acid. The effect was evaluated by slit-lamp biomicroscopy, measurement of central corneal thickness and determination of visual acuity. The patients subjective complaints were also registered. The duration of the treatment varied from 3 to 16 months. In most cases the treatment was given over several periods with intervening free intervals. In all cases the central corneal thickness decreased and slit-lamp biomicroscopy revealed an improvement. The visual acuity improved and all patients became free of pain. A possible mechanism involving the complement system is discussed and preliminary studies on the composition of the aqueous humour in cases of bullous keratopathy are mentioned.

Aged↗
PubMed1995

[New antiepileptic medications].

Progress made in the development of new antiepileptics (AEs) is justified by the high percentage of refractory patients to the available medical therapy (25%), although only a minority of cases are deemed suitable for surgical therapy. Yet, the ideal AE, that is, with a well-known mechanism of action, effective in monotherapy for all epileptic fits, with a perfect pharmacokinetic profile, with no adverse or teratogenic effects, with no drug interactions and available under many formulations, is far from being developed. The new AEs arise either from modification of already marked drug molecules or clinical formulations or from the effectiveness on the excitatory/inhibitory balance of the major neurotransmitters involved in the pathogenesis of seizures, the gamma-amino-butyric acid (GABA) as the inhibitory, and the glutamate (GLU) as the excitatory one. However, the mechanism remains unknown in a few of them. Those new AEs already marketed in Portugal (Vigabatrin), soon to be (Lamotrigine, Oxcarbazepine) or available abroad only (Gabapentin, Zonisamide) are review with special emphasis on their pharmacokinetic profile, side effects, interaction with other AEs, and clinical use. In conclusion, these new drugs have brought a very important advancement in the management of refractory patients, but the development of well-designed comparative trials involving both monotherapy and polytherapy has become important in order to develop useful strategies in the drug management of epilepsy.

Acetates↗
PubMed1970

Mechanism and stereochemistry of 5-dehydroquinate synthetase.

3-Deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP) labeled at C-7 randomly or stereospecifically with tritium and at C-1 with (14)C was converted enzymically to 5-dehydroquinate. Tritium of all three substrates was completely retained in 5-dehydroquinate, in accord with formation of a non-ketonizing 6,7-enol intermediate. The 5-dehydroquinates were dehydrated to 5-dehydroshikimate by 5-dehydroquinate dehydratase, which is known to catalyze a cis-elimination. Only 5-dehydroquinate derived from [7-(3)H](7R)-DAHP lost its tritium in this dehydration, indicating that the configuration at C-7 was inverted in the conversion of DAHP to 5-dehydroquinate.

Carbon Isotopes↗
PubMed2006

Mechanisms of the antinociceptive action of gabapentin.

Gabapentin, a gamma-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABA(B) receptors consisting of GABA(B1a) and GABA(B2) subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-alpha-amino acid transporter, activating ATP-sensitive K(+) channels, activating hyperpolarization-activated cation channels, and modulating Ca(2+) current by selectively binding to the specific binding site of [(3)H]gabapentin, the alpha(2)delta subunit of voltage-dependent Ca(2+) channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the alpha(2)delta subunit of spinal N-type Ca(2+) channels is very likely the analgesic action target of gabapentin.

Amines↗
PubMed1972

Polypeptide chain initiation in eukaryotes: functional identity of supernatant factor from various sources.

Eukaryotic cells contain polypeptide chain initiation factors that, like the prokaryotic initiation factor IF-2, promote the AUG-dependent binding of fMet-tRNA(f) to the small ribosomal subunit. The bound amino-acyl-tRNA is directly convertible to fMet-puromycin upon addition of 60S subunit. The reaction is sensitive to initiation inhibitors such as aurintricarboxylic acid and edeine but, unlike its prokaryotic counterpart, it does not require GTP. Factors that catalyze the binding and fMet-puromycin reactions with ribosomal subunits from Artemia salina embryos are present in postribosomal supernatants of Artemia, mouse fibroblasts (L cells), and rat liver, as well as in salt washes of rabbit reticulocyte ribosomes. However, whereas all three supernatant factors, like Escherichia coli IF-2, are sensitive to SH-binding reagents, the reticulocyte factor is not. The rat liver and Artemia factors function indiscriminately with Artemia or rat liver ribosomes, but the Artemia factor and E. coli initiation factor IF-2 are not interchangeable.

Animals↗