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PubMed1998

Sensitive high-performance liquid chromatographic method with fluorometric detection for the simultaneous determination of gabapentin and vigabatrin in serum and urine.

Serum concentrations of the antiepileptic drug gabapentin (GBP) are usually determined by high-performance liquid chromatography (HPLC) using UV photometric detection after pre-column derivatization with 2,4,6-trinitrobenzenesulphonic acid. Vigabatrin levels in serum are determined by HPLC using fluorescence detection. Like vigabatrin (VGB), gabapentin has also a primary amine group that easily reacts with o-phthaldialdehyde reagent and produces a fluorescing substance. By the use of fluorometric detection, GBP can be determined more simply, sensitively and simultaneously with VGB. The day-to-day coefficient of variation for the determination of GBP in a pooled serum was 4.0% (n=17; serum concentration, 13.8 micromol/l) and forVGB was 3.1% (n=21; serum concentration, 26.4 micromol/l). The lower limit of detection is 0.5 micromol/l for both drugs and the method is linear up to 500 micromol/l for GBP and 1300 micromol/l for VGB.

Acetates↗
PubMed1988

gamma-Aminobutyric acid release from synaptosomes prepared from rats treated with isonicotinic acid hydrazide and gabaculine.

The potassium-stimulated release of gamma-aminobutyric acid (GABA) from synaptosomes was determined in preparations from control rats and from rats treated with a convulsant agent [isonicotinic acid hydrazide (INH)] and an anticonvulsant agent (gabaculine). INH treatment brought about a significant decrease in Ca2+-dependent release of GABA with no effect on Ca2+-independent release, whereas gabaculine caused an increase in Ca2+-independent release with no effect on Ca2+-dependent release of GABA. Thus, the anticonvulsant action of gabaculine was not a simple reversal of the effects of INH on GABA release. The results indicate that there are at least two pools of GABA in nerve endings and support the hypothesis that exogenous GABA is taken up first into a pool that supplies GABA for Ca2+-independent release and then is transferred to a second pool (Ca2+-dependent releasable), where it mixes with newly synthesized GABA.

Animals↗
PubMed1984

Use of an antifibrinolytic agent (tranexamic acid) and lateral sutures with laser conization of the cervix.

One hundred forty patients who underwent laser conization and 220 patients who underwent laser miniconizations were prospectively randomized into two study groups. One treatment group was given antifibrinolytic therapy in the form of tranexamic acid (Cyklokapron, KabiVitrum, Sweden) intraoperatively and for 14 days postoperatively. The other group did not receive antifibrinolytic therapy. In the group of 68 patients with laser conizations who were given antifibrinolytic therapy, no postoperative hemorrhages occurred, whereas there were eight such hemorrhages in 72 conizations (11%) in the untreated patients. This difference is statistically significant (P = .004, Fisher exact test for two proportions). Also, for laser miniconization, the frequency of postoperative hemorrhage was almost halved, from 9.1% in 110 patients not receiving antifibrinolytic therapy to 5.5% in the 110 treated patients. The use of lateral cervical sutures did not reduce the frequency of postoperative hemorrhage at laser conization in the present study.

Carcinoma in Situ↗
PubMed2005

The plmS2-encoded cytochrome P450 monooxygenase mediates hydroxylation of phoslactomycin B in Streptomyces sp. strain HK803.

Streptomyces sp. strain HK803 produces six analogues of phoslactomycin (Plm A through Plm F). With the exception of Plm B, these analogues contain a C-18 hydroxyl substituent esterified with a range of short-alkyl-chain carboxylic acids. Deletion of the plmS(2) open reading frame (ORF), showing high sequence similarity to bacterial cytochrome P450 monooxygenases (CYPs), from the Plm biosynthetic gene cluster has previously resulted in an NP1 mutant producing only Plm B (N. Palaniappan, B. S. Kim, Y. Sekiyama, H. Osada, and K. A. Reynolds, J. Biol. Chem. 278:35552-35557, 2003). Herein, we report that a complementation experiment with an NP1 derivative (NP2), using a recombinant conjugative plasmid carrying the plmS(2) ORF downstream of the ermE* constitutive promoter (pMSG1), restored production of Plm A and Plm C through Plm F. The 1.2-kbp plmS(2) ORF was also expressed efficiently as an N-terminal polyhistidine-tagged protein in Streptomyces coelicolor. The recombinant PlmS(2) converted Plm B to C-18-hydroxy Plm B (Plm G). PlmS(2) was highly specific for Plm B and unable to process a series of derivatives in which either the lactone ring was hydrolyzed or the C-9 phosphate ester was converted to C-9/C-11 phosphorinane. This biochemical analysis and complementation experiment are consistent with a proposed Plm biosynthetic pathway in which the penultimate step is hydroxylation of the cyclohexanecarboxylic acid-derived side chain of Plm B by PlmS(2) (the resulting Plm G is then esterified to provide Plm A and Plm C through Plm F). Kinetic parameters for Plm B hydroxylation by PlmS(2) (K(m) of 45.3 +/- 9.0 microM and k(cat) of 0.27 +/- 0.04 s(-1)) are consistent with this step being a rate-limiting step in the biosynthetic pathway. The penultimate pathway intermediate Plm G has less antifungal activity than Plm A through Plm F and is not observed in fermentations of either the wild-type strain or NP2/pMSG1.

Cytochrome P-450 Enzyme System↗
PubMed1987

Clinical pharmacology of tranexamic acid.

Tranexamic acid (AMCA) is a potent antifibrinolytic drug occurring in two isomeric forms; the antifibrinolytic potency resides in the transisomeric form. The main action of AMCA is blocking of the lysine-binding sites of the plasminogen molecule, which are of importance for the binding to fibrin. This prevents activation of plasminogen by plasminogen activator also absorbed to fibrin. AMCA can be administered perorally or intravenously and is excreted into the urine. It enters tissues and fluids in various concentrations and crosses the placenta. There is no evidence of a thrombogenic effect of AMCA, but in accordance with its action, it prolongs dissolution of fibrin deposits already formed. AMCA is a drug of high clinical value for the treatment of bleedings due to both systemic and local fibrinolysis.

Animals↗
PubMedDate not supplied

An open label study of gabapentin in the treatment of acute mania.

Recent anecdotal single case reports have suggested that the new antiepileptic drug gabapentin might be effective in the treatment of manic episodes and in the prophylaxis of bipolar disorder. In the present open trial, 14 patients with acute mania were treated for up to 21 days with gabapentin in a dose range from 1200 to 4800 mg/day. Six patients were treated with gabapentin as add-on medication and 8 patients were treated with a high dose of gabapentin alone. Gabapentin was both efficacious and safe when applied in combination with other drugs such as lithium and valproic acid. All patients in the add-on group and 4/8 patients on gabapentin monotherapy finished the 21 day protocol. Analysis of the scores of the Bech-Rafaelsen Mania Assessment Scale (BRMAS) of these patients showed that the mean BRMAS score declined from 37.7 to 7.8 on day 21 in the add-on group and from 27.8 to 9.0 in 4/8 patients finishing 21 days in the monotherapy group. It is suggested that gabapentin monotherapy might be useful in selected patients to treat modest but not severe manic states. In addition, gabapentin in conjunction with other effective mood stabilisers seems to be safe and efficacious in the treatment of severe mania.

Acetates↗
PubMed2002

Bipolar disorders and the effectiveness of novel anticonvulsants.

The discovery that valproic acid is helpful in the management of patients with rapid-cycling bipolar disorder led to an explosion of research culminating in the third-generation anticonvulsants. Refractory depressive phases are frequent in bipolar disorders. No studies to date have shown that gabapentin is effective in bipolar mania or hypomania. Lamotrigine may have a role in treating bipolar depressive episodes, but it is not a particularly effective antimanic agent. Topiramate has shown encouraging results in both depressed and manic bipolar patients, and it may also promote weight loss. The new anticonvulsants are promising agents for the treatment of bipolar disorders, but they are heterogeneous with regard to their efficacy, target symptoms, and adverse event profiles.

Acetates↗
PubMed1990

[Endoscopic hemostasis in hemorrhagic peptic ulcer. A review and pilot study of local thrombin injection combined with systemic fibrinolysis inhibition (with tranexamic acid)].

Today, most upper GI-haemorrhages can be handled without surgery. We discuss the available endoscopic haemostatic methods. Injection therapy seems to be as effective as laser-, heater probe- and bipolar electrocoagulation, and is often preferred because the equipment is inexpensive. In a pilot study of 37 patients with haemorrhage from peptic ulcer (13 with active bleeding and 24 with stigmata of recent hemorrhage) we injected thrombin in the ulcer base and treated the patients systemically with an antifibrinolytic drug (tranexamic acid) for five days. Endoscopic follow-up revealed stigmata of recent haemorrhage in 23 patients on day 1 and in eight patients on day 5. "Blood in stomach" was seen in eight patients on day 1 and in two patients on day 5. Four patients had clinical signs of rebleeding, but only one of them needed operation (definite hemostasis 97%). There were no obvious side effects of the treatment. Contrary to other endoscopic methods, local injection of thrombin does not damage the normal mucosa. However, the method has not been sufficiently explored as yet, and cannot be recommended without strict control and follow-up measures. Early control endoscopy seems to be a sensitive way of monitoring haemostasis.

Cyclohexanecarboxylic Acids↗
PubMed2002

Gabapentin and vigabatrin increase GABA in the human neocortical slice.

The effects of antiepileptic drugs, gabapentin and vigabatrin, on gamma-aminobutyric acid (GABA) concentrations were studied in human (n=14) and rat (n=6) neocortical slice preparations. In this study, neocortical slices were incubated with gabapentin, vigabatrin or no drugs for 3 h in an oxygenated environment. Proton magnetic resonance spectroscopy (MRS) of perchloric acid (PCA) extracts was used to measure GABA concentrations. Vigabatrin increased cellular GABA concentrations in both human and rat neocortical slices by 62% (P<0.001) and 88% (P<0.03), respectively. Gabapentin significantly increased GABA concentrations by 13% (P<0.02) in human neocortical slices made from tissue resected during epilepsy surgery. However, in the rat neocortical slice exposed to the same conditions as the human tissue, gabapentin did not increase GABA significantly. These results confirm our MRS studies in vivo that gabapentin increases GABA levels in epileptic patients, but has minimal or no effect in a healthy rodent model. Caution must be used in extrapolating negative results obtained in rodent models to the human condition.

Acetates↗
PubMed1998

Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study.

A novel paired transcranial magnetic stimulation (TMS) paradigm with a suprathreshold first and a subthreshold second stimulus was used in healthy volunteers to investigate the acute effects of a single oral dose of various CNS-active drugs on short-interval motor evoked potential (MEP) facilitation. MEPs were recorded from the relaxed abductor digiti muscle. Three peaks of MEP facilitation were consistently observed at interstimulus intervals of 1.1-1.5 ms, 2.3-2.7 ms, and 3.9-4.5 ms. The size of these MEP peaks was transiently suppressed by drugs which enhance gamma-aminobutyric acid (GABA) function in the neocortex (lorazepam, vigabatrin, phenobarbital, ethanol), while the GABA-B receptor agonist baclofen, anti-glutamate drugs (gabapentin, memantine), and sodium channel blockers (carbamazepine, lamotrigine) had no effect. The interstimulus intervals effective for the production of the MEP peaks remained unaffected by all drugs. The MEP peaks are thought to be due to a facilitatory interaction of I-(indirect) waves in the motor cortex. Therefore, the present results indicate that the production of I-waves is primarily controlled by GABA related neuronal circuits. The potential relevance of this non-invasive paired TMS protocol for the investigation of I-waves in patients with neurological disease will be discussed.

Acetates↗
PubMed1981

The inactivation of gamma-aminobutyric acid transaminase in dissociated neuronal cultures from spinal cord.

It had previously been shown that dissociated cell cultures from chick embryo spinal cord have a high affinity uptake system for the neurotransmitter gamma-aminobutyric acid (GABA) and make functional inhibitory synaptic contacts as determined by electrophysiology (Farb et al., 1979). It is shown here that these cultures can synthesize GABA from added glutamate in a glutamate decarboxylase-dependent reaction. Furthermore, these cultures have a functional GABA transaminase that degrades the neurotransmitter. This enzyme can be specifically and irreversibly blocked with gabaculine. A 15 min incubation with 10(-6) M-gabaculine completely inactivates the enzyme. The inactivation of the enzyme leads to an increase in GABA levels. Long-term incubation (16 days) of gabaculine in the medium does not appear to alter high affinity GABA transport, suggesting that the drug is not toxic to cells capable of accumulating GABA.

4-Aminobutyrate Transaminase↗
PubMed1982

Effect of 1-methyl cyclohexane carboxylic acid on electrical activity of Purkinje cells in the rat: evidence for a potentiation of intracerebellar inhibition.

The effect of an anticonvulsant compound (Simiand, Ferrandes, Lacolle and Eymard, 1979), 1-methyl cyclohexane carboxylic acid (CCA), upon the electrical activity of Purkinje cells (PCs) was studied in the cerebellar cortex of the rat in vivo. Cyclohexane carboxylic acid (200-400 mg/kg i.v.) decreased the spontaneous simple spike (SS) activity of the Purkinje cells tested without modifying the complex spike (CS) frequency. Two effects of CCA upon intracortical inhibition were observed: (1) the decrease in firing rate that followed surface stimulation of the parallel fibres (LOC stimulation) was enhanced after injection of CCA; (2) the depression of the antidromic field potential of Purkinje cells by a conditioning stimulation was also enhanced after injection of CCA. This latter effect was suppressed in a reversible manner by injection of bicuculline. These results strongly suggest that the effect of CCA upon electrical activity of Purkinje cells is related to an enhancement of the inhibition exerted on Purkinje cells by GABAergic, cerebellar interneurones. The possible mechanisms of action of CCA are discussed.

Animals↗
PubMed1970

Organization of polyaromatic biosynthetic enzymes in a variety of photosynthetic organisms.

Sucrose density gradient centrifugation was used to estimate the molecular weights and determine possible physical aggregation of the enzymes catalyzing steps 2 to 6 in pre-chorismic acid polyaromatic biosynthesis in Anabaena variabilis, Chlamydomonas reinhardi, Euglena gracilis, Nicotiana tabacum, and Physcomitrella patens. In A. variabilis, the five enzymes are separable. Similar results were obtained for P. patens, N. tabacum, and C. reinhardi extracts, except that dehydroshikimate reductase and dehydroquinase were not separable by this method. Evidence is presented for an enzyme aggregate containing five activities, with a molecular weight of approximately 120,000 in E. gracilis; dissociation of this aggregate into components corresponding to molecular weight of ca. 60,000 is also observed. Preliminary evidence concerning the enzymatic composition of the 60,000-molecular-weight components is presented and discussed. Similarities between the E. gracilis polyaromatic aggregate and that of Neurospora crassa are discussed.

Alcohol Oxidoreductases↗
PubMed1987

Effects of the gamma-aminobutyrate transaminase inhibitors gabaculine and gamma-vinyl GABA on gamma-aminobutyric acid release from slices of rat cerebral cortex.

The release of [3H]gamma-aminobutyric acid (GABA) from pre-loaded slices of rat cerebral cortex was investigated in the presence and absence of the GABA-transaminase inhibitors gabaculine and gamma-vinyl GABA. In the experiments carried out without an inhibitor, an ion-exchange column chromatographic technique was used to separate [3H]GABA from tritiated metabolites released with it into the superfusate. The presence of gabaculine (5 microM) substantially reduced the Ca2+-dependence of the release of [3H]GABA evoked by a 4 min 30 mM K+ pulse, whereas this was not appreciably reduced by the presence of gamma-vinyl GABA (2 mM or 10 mM). Nevertheless, the characteristics of [3H]GABA release were not identical in the presence and absence of either inhibitor.

4-Aminobutyrate Transaminase↗
PubMed1975

Muscle protein biosynthesis in the tumour-bearing rat. A defect in a post-initiation stage of translation.

1. The decreased ability of polysomes isolated from the gastrocnemius of rats bearing the Walker 256 carcinoma to incorporate L-[14C]leucine into protein persisted in the presence of 5-10-5 M aurin tricarboxylic acid and 1-10-2 M NaF. 2. Poly(U)-directed phenylalanine incorporation by such polysome preparations was less than that of similar preparations from normal rats. 3. The ability of gastrocnemius polysomes from tumour-bearing rats to react with puromycin was markedly decreased. Cycloheximide inhibited peptidyl puromycin formation by polysome preparations from both normal and tumour-bearing rats. 4. The ability of recombined 60 S and 40 S subunits prepared from polysomes of tumour-bearing rats to carry out poly(U)-directed polyphenylalanine synthesis was much reduced when assayed over a wide range of magnesium concentrations. Cross-over experiments with subunits from normal and tumour-bearing animals suggested that this was due to a defect in the smaller ribosomal subunit.

Animals↗
PubMed1979

Gas chromatographic method for the determination of valproic acid in human plasma.

A gas chromatographic method has been developed for the routine monitoring of valproic acid (VPA) in human plasma samples. Two compounds, 2-ethylpentanoic acid (EPA) and 2-propylhexanoic acid (PHA), were synthesized and evaluated as internal standards together with cyclohexane carboxylic acid (CHCA), a commonly employed internal standard. Crystalline barium salts of VPA, EPA, and PHA were prepared, which enabled preparation of standard solutions of high accuracy for use in calibration experiments and in daily intra-laboratory quality control tests. The extraction scheme was designed on the basis of the solvent partitioning properties of VPA. Solvent transfers are required in the extraction scheme, but solvent evaporations are not. Studies were made of the performances of EPA, PHA, and CHCA as internal standards in the VPA assay at different lifetimes of the 10% SP-1000 chromatography column. As judged by these studies, EPA or CHCA is a better choice than PHA as an internal standard, provided that certain guidelines are followed in the use of CHCA.

Chromatography, Gas↗
PubMed1976

Pulmonary damage following pulmonary microembolism in the dog. Effect of various types of treatment.

In the present study the pathogenesis of the pulmonary damage following infusion of thrombin in combination with a fibrinolysis inhibitor, AMCA, in the dog was elucidated. An important mechanism in the development of the pulmonary damage following infusion of thrombin and AMCA seems to be an increased vascular permeability in the pulmonary microvasculature leading to pulmonary oedema. The question whether this pulmonary damage can be prevented by antihistamine (mepyramine maleate), antiserotonins (methysergide, reserpine) antiprostaglandins (acetylsalicylic acid, indomethacin, polyphloretin phosphate), 'anti-inflammatory agents' (methylprednisolone, calcium) or an anti-adrenergic agent (phenoxybenzamine) was investigated. None of these agents did prevent the lung damage following thrombin and AMCA. In order to study the possible role of bronchoconstriction, the complement system and the kinin system for this damage dogs were also artificially ventilated with an increased end-expiratory pressure, decomplemented with cobra venom factor or treated with Trasylol respectively. Neither were these treatments effective in preventing the pulmonary damage. The findings of the present study suggest that the permeability increasing substance involved in the pathogenesis of the pulmonary damage following thrombin and AMCA is not histamine, serotonin, prostaglandins or bradykinin. Therefore another, still unknown factor, may be of greater importance for this damage.

Animals↗
PubMed1980

Different assessment of plasmin with different substrates. In vitro alteration of plasmin, influence of epsilon-aminocaproic acid and tranexamic acid upon its activity.

The alteration of human and porcine plasmin and the influence of EACA and AMCHA on their activity were investigated. Solutions of both plasmins undergo storage induced alteration, which is best recorded by Chromozym PL, whereas the other chromogenic substrates, S-2251 and S-2302, and casein are less sensitive, and the fibrin plate inadequate. Plasmin amidolytic and fibrinolytic activity is maximally enhanced at 7.6 x 10(-3) M EACA and 6.4 x 10(-4) M AMCHA, and decay through storage is reversed. The caseinolytic activity seems slightly inhibited at the same EACA and AMCHA concentrations. Our results show: 1. The quotient: plasmin activity towards Chromozym PL/Activity towards S-2251 is a useful indicator of "plasmin quality". The quotient decreases markedly upon storage of plasmin solutions. 2. Plasmin stability is improved in the presence of AMCHA. 3. It is valueless to add EACA or AMCHA to inhibit plasmin in amidolytic assays since the chosen concentration enhances the amidolytic activity of already formed plasmin.

Aminocaproates↗