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A Parada

Publications and source records attributed to A Parada.

15 recordsLinked to original sources
PubMed2002

Metabolism of 10,11-dihydro-10-hydroxyimino-5H-dibenz/b, f/azepine-5-carboxamide, a potent anti-epileptic drug.

1. 10,11-Dihydro-10-hydroxyimino-5H-dibenzo/b, f/azepine-5-carboxamide (BIA 2-024) is a new anti-epileptic drug similar to oxcarbazepine (OXC) in structure and efficacy, but with a preferred pharmacodynamic profile. It possesses high in vitro activity, but since oximes are usually metabolized to their corresponding ketones, it is important to know whether its is vivo potency is a result of acting as a prodrug of OXC or if it is acting on its own. 2. The drug was given orally to rats, mice and rabbits, the metabolites identified and pharmacokinetic profiles compared between those species. Furthermore, the pharmacokinetic profile of the main metabolite was established in the rat. The results were compared to in vitro metabolism studies with liver microsomes from different mammalian species and humans. 3. In an atypical reaction for oximes, BIA 2-024 in rats was rapidly (t(max) = 2h) metabolized to the non-active 10-nitro-derivative (BIA 2-254), whereas rabbits and particularly mice oxidized the oxime moiety to a much lower extent. BIA 2-254 was then transformed to OXC and subsequently to the 10-hydroxy derivative and other minor metabolites. 4. In vitro data showed a very similar cross-species behaviour as the in vivo results; human liver microsomes catalysed the oxidation of BIA 2-024 to the nitro metabolite only at a low rate, and the same was observed for the subsequent metabolism to OXC. 5. The results allow prediction of the in vivo metabolism of BIA 2-024 in humans, where this drug is most likely absorbed efficiently and excreted mainly as the parent compound with a relatively low hepatic clearance. With the exception of rat, BIA 2-024 does not act as a prodrug of OXC.

Animals↗
PubMed2001

BIA 3-202, a novel catechol-O-methyltransferase inhibitor, enhances the availability of L-DOPA to the brain and reduces its O-methylation.

1-[3,4-Dihydroxy-5-nitrophenyl]-2-phenyl-ethanone (BIA 3-202) is a new long-acting catechol-O-methyltransferase (COMT) inhibitor with limited access to the brain. The present study evaluated the interference of BIA 3-202 upon levels of L-3,4-dihydroxyphenylalanine (L-DOPA) and metabolites in plasma (3-O-methyl-L-DOPA) and brain [3-O-methyl-L-DOPA, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] in rats orally treated with L-DOPA (20 mg/kg) plus benserazide (30 mg/kg). At different time points (1, 3 and 6 h) after the administration of BIA 3-202 (0, 3, 10 and 30 mg/kg) or L-DOPA plus benserazide, rats were sacrificed and the right striatum was quickly dissected out and stored for the assay of L-DOPA, 3-O-methyl-L-DOPA, dopamine and amine metabolites. Levels of L-DOPA, 3-O-methyl-L-DOPA, dopamine, DOPAC and HVA in the striatum in L-DOPA plus benserazide-treated rats were higher than in vehicle-treated rats. However, this increase in striatal L-DOPA, dopamine, DOPAC and HVA was, in a dose- and time-dependent manner, even higher (P<0.05) in rats given BIA 3-202 (3, 10 and 30 mg/kg). This effect was accompanied by a marked decrease in 3-O-methyl-L-DOPA levels in the striatum of L-DOPA plus benserazide-treated rats. Increases in levels of L-DOPA and decreases in 3-O-methyl-L-DOPA levels in plasma also accompanied the administration of BIA 3-202. BIA 3-202 did not significantly affect levels of DOPAC and HVA in the striatum in vehicle-treated rats. It is concluded that administration of BIA 3-202 enhances the availability of L-DOPA to the brain by reducing its O-methylation in the periphery, which may prove beneficial in parkinsonian patients treated with L-DOPA plus an aromatic amino acid decarboxylase inhibitor.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Synthesis, anticonvulsant properties and pharmacokinetic profile of novel 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide derivatives.

A series of novel derivatives of oxcarbazepine (5), 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide was synthesised and evaluated for their anticonvulsant activity and sodium channel blocking properties. The oxime 8 was found to be the most active compound from this series, displaying greater potency than its geometric isomer 9 and exhibiting also the highest protective index value. Importantly, the metabolic profile of 8 differs from the already established dibenz/b,f/azepine-5-carboxamide drugs such as 1 and 5 which undergo rapid and complete conversion in vivo to several biologically active metabolites. In contrast 8 is metabolised to only a very minor extent leading to the conclusion that the observed anti-convulsant effect is solely attributable to 8. It is concluded that 8 may be as effective as 1 and 5 at controlling seizures and that the low toxicity and consequently high protective index should provide the compound with an improved side-effect profile.

Amides↗
PubMed2001

Metabolism of two new antiepileptic drugs and their principal metabolites S(+)- and R(-)-10,11-dihydro-10-hydroxy carbamazepine.

BIA 2-093 and BIA 2-059 are two stereoisomers under development as new antiepileptic drugs. They act as prodrugs for the corresponding hydroxy derivatives (S(+)- or R(-)-10,11-dihydro-10-hydroxy carbamazepine, respectively) which are known to be the active metabolites of the antiepileptic drug oxcarbazepine (OXC). The purpose of this study was to define the metabolic pathway especially in terms of stereoselectivity, and to estimate the possibility of racemization in humans. For in vivo studies, the rat, mouse and rabbit were chosen as models in order to cover a broad spectrum of metabolic activity. In addition, incubations with liver microsomes from these three species plus dog and monkey were compared to results obtained with human liver microsomes. It was found that both drugs were almost instantly hydrolysed to the corresponding 10-hydroxy compounds in mice, rats and rabbits. Mice and rabbits were not able to oxidize the 10-hydroxy compounds to OXC in significant amounts. In the rat, BIA 2-093 also gave origin to OXC, whereas BIA 2-059 resulted in the formation of OXC and the trans-diol metabolite in equal amounts. It could be shown that the rat is able to reduce the formed OXC in liver to S(+)-10-hydroxy metabolite, resulting in a loss of enantiomeric purity after treatment with BIA 2-059 rather than in the case of BIA 2-093. Human liver microsomes hydrolysed BIA 2-093 and BIA 2-059 to their corresponding 10-hydroxy compounds and to OXC in a very small extent with BIA 2-093 only. Therefore, BIA 2-093 and BIA 2-059 seem to be preferable drugs over OXC since they most likely exhibit a 'cleaner' metabolism. From a therapeutic point of view BIA 2-059 would be less appropriate than BIA 2-093 for the purpose of treating epileptic patients due to its propensity to undergo inactivation to the trans-diol.

Animals↗
PubMed2001

Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine.

PURPOSE: BIA 2-093 [(S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide] is endowed with an anticonvulsant potency similar to that of carbamazepine (CBZ), but produces less cognitive and motor impairment. This study evaluated whether voltage-gated sodium channels (VGSCs) are a primary locus for the action of BIA 2-093. METHODS: We used the whole-cell voltage-clamp technique in the mouse neuroblastoma cell line N1E-115 to investigate the effects of BIA 2-093 and CBZ on VGSCs, displacement of [3H]-batrachotoxinin A 20-alpha-benzoate ([3H]-BTX), and [3H]-saxitoxin to define their relative potency to bind to rat brain sodium channels, and inhibition of uptake of 22Na by rat brain cortical synaptosomes stimulated by veratridine as a measure of sodium entry. RESULTS: The inhibitory potencies of BIA 2-093 and CBZ increased as the holding potential was made less negative (-100, -90, -80, and -70 mV) with median inhibitory concentration (IC50) values (in microM) of, respectively, 4,337, 618, 238, and 139 for BIA 2-093, and 1,506, 594, 194, and 101 for CBZ. BIA 2-093 displayed a similar potency in displacing [3H]-BTX (IC50 values, 222 vs. 361 microM; p > 0.05) and inhibiting the uptake of 22Na (IC50 values, 36 vs. 138 microM; p > 0.05). Both drugs failed to displace [3H]-saxitoxin in concentrations up to 300 microM. CONCLUSIONS: BIA 2-093, like CBZ, inhibits sodium currents in a voltage-dependent way by an interaction predominantly with the inactivated state of the channel and interacts with neurotoxin receptor site 2, but not with receptor site 1. BIA 2-093 displayed a potency blocking VGSCs similar to that of CBZ.

Animals↗
PubMed2000

The dopamine antagonist sch 23390 reverses dizocilpine-induced blockade of cocaine sensitization.

The present work examined the effects of pre-treatment with Sch 23390, a selective D(1) receptor antagonist, on the dizocilpine-induced blockade of sensitization to the locomotor-stimulating effect of cocaine. Rats were given either cocaine [15mgkg(-1)day(-1), intraperitoneally (i.p.)] from day 1 to day 5 (cocaine-experienced rats) or vehicle (cocaine-naïve rats). From day 6 to day 15, animals remained drug-free in their home cages. On day 16 rats received a challenge injection of cocaine (15mgkg(-1)) or vehicle, and were tested for sensitization to the locomotor-stimulating effect of cocaine. In cocaine-naïve rats the acute effect of cocaine was a 1.5 times increase in locomotor activity. In cocaine-experienced rats, the acute effects of cocaine were considerably more pronounced than in cocaine-naïve rats; the stimulating effect of cocaine in these animals was a doubling in locomotor activity. In cocaine-naïve rats, pre-treatment with dizocilpine (100microgkg(-1)), Sch 23390 (100microgkg(-1)) or a combination of the two drugs from day 1 to day 5 changed neither spontaneous locomotor activity nor cocaine stimulant activity. By contrast, cocaine-experienced animals that had been given 100microgkg(-1) dizocilpine from day 1 to day 5 failed to show the increase in locomotor activity when challenged with cocaine on day 16. Pre-treatment with Sch 23390 (100microgkg(-1)day(-1), i.p.) from day 1 to day 5 was found to prevent completely the cocaine anti-sensitization properties of 100microgkg(-1) dizocilpine, but failed to prevent cocaine sensitization. On the other hand, horizontal activity in cocaine-experienced rats that had been given dizocilpine (100microgkg(-1)) 15min before cocaine challenge on day 16 was higher than in corresponding controls. It is concluded that prevention of cocaine sensitization by dizocilpine may be related to the events set into motion by the NMDA antagonist at the level of dopaminergic transmission involving D(1) receptors.

Animals↗
PubMed2000

The O-methylated derivative of L-DOPA, 3-O-methyl-L-DOPA, fails to inhibit neuronal and non-neuronal aromatic L-amino acid decarboxylase.

The present study examined whether the O-methylated derivative of L-DOPA, 3-O-methyl-L-DOPA (3-OM-L-DOPA), inhibits neuronal (brain) and non-neuronal (liver and kidney) aromatic L-amino acid decarboxylase (AADC) activity. The incubation of brain, liver and kidney homogenates with 3-OM-L-DOPA (5 mM) did not result in the formation of 3-methoxytyramine, the compound expected to result from the decarboxylation of 3-OM-L-DOPA. Incubation of tissue homogenates with L-DOPA resulted in a concentration-dependent formation of dopamine, revealing K(m) values (in mM) of similar magnitude for brain (0.8), liver (1.6) and kidney (1.0). Both benserazide and L-5-hydroxytryptophan (L-5-HTP) were found to produce concentration dependent decreases in AADC activity with K(i) values in the microM range. By contrast, 3-OM-L95% reduction) in liver and kidney AADC activity accompanied by a marked decrease (49% reduction) in brain AADC activity. By contrast, the administration of 30 mg/kg (p.o.) 3-OM-L-DOPA, which generates levels in brain, liver and kidney six-fold those in L-DOPA-treated rats, was found to change neither neuronal nor non-neuronal AADC activity. In conclusion, 3-OM-L-DOPA fails to interact with neuronal and non-neuronal AADC, either as substrate or inhibitor.

5-Hydroxytryptophan↗
PubMed1999

Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives.

A series of esters of the major metabolite of oxcarbazepine (2), 10, 11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED(50) values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 0.9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b, f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1 produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6, (R)-7, and racemic alcohol 8, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED(50) value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [(3)H]batrachotoxinin A 20-alpha-benzoate ([(3)H]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and 2 at inhibiting the binding of [(3)H]BTX to sodium channels and the influx of (22)Na(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (S)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.

Amides↗
PubMed1999

Comparison of literature searches on quality and costs for health technology assessment using the MEDLINE and EMBASE databases.

Biomedical databases are an important source of information for health technology assessment. However, there is considerable variation in the costs of accessing commercial databases. We sought to measure the quality, amount of overlap, and costs of information retrieved from two of the main database sources--MEDLINE and EMBASE. Librarians at two health technology assessment agencies ran a total of eight literature searches on various medical technologies, using both databases. All search results were independently reviewed by two researchers. The researchers were asked to identify relevant references and to rank each of these according to a level of evidence scale. The results were tabulated to show the number of references identified by each database, the number of relevant references ranked by level of evidence, and the number of these references that were unique to one or the other database. The cost of retrieving references from each source was also calculated. Each database contained relevant references not available in the other. Because of the longer time lag for indexing in MEDLINE, many of the references that originally appeared to be unique to EMBASE were subsequently available in MEDLINE as well. Since our study was conducted, MEDLINE has been made available worldwide, free of charge, via the Internet. Hence, the cost difference between the databases is now even greater. However, notwithstanding the costs, it appears that literature searches that rely on only one or the other database will inevitably miss pertinent information.

Abstracting and Indexing↗
PubMed1998

Rat liver catechol-O-methyltransferase kinetics and assay methodology.

In mammals, catechol-O-methyltransferase (COMT) is distributed throughout various organs, the highest activities being found in the liver and kidney. However, comparisons of the kinetic parameters are difficult to perform, since the experimental procedures in the enzyme assay vary quite considerably. The present work was aimed at studying the optimal liver COMT assay conditions for determining the kinetics of the enzyme. The COMT assay was performed with liver homogenates from 60 days old male Wistar rats with adrenaline (AD) as the substrate. Time course experiments using 100 microM S-adenosyl-L-methionine (SAMe) and 300 microM AD showed linearity of O-methylation reaction upto 10 min. Using 100 microM SAMe, Vmax (nmol mg protein-1 h-1) and Km (microM) values progressively decreased respectively from 22.1 and 104.8 at 5 min down to 5.8 and 24.62 at 60 min incubation periods. This decrease was not due to end-product inhibition. Using 2500 microM AD, Km values (microM) for the methyl donor SAMe increased progressively from 174 at 5 min upto 1192.5 at 60 min; upto 30 min of incubation Vmax values did not change. When a 5 min incubation period and 500 microM SAMe were used, Vmax and Km values for liver COMT were 63.4 nmol mg protein-1 h-1 and 261.1 microM, respectively. It is concluded that an incubation period of 5 min and a SAMe concentration of 500 microM provide optimal conditions for the liver homogenate COMT assay.

Animals↗
PubMed1997

Studies on the tight-binding nature of tolcapone inhibition of soluble and membrane-bound rat brain catechol-O-methyltransferase.

Catechol-O-methyltransferase (COMT) is an enzyme that plays an important role in the inactivation of catecholamine neurotransmitters. Experimental and clinical data suggest that COMT inhibitors may be useful in Parkinsonian patients. Among COMT inhibitors, nitrocatechol derivatives are the most potent and selective. In this study, we evaluated the kinetics of rat brain COMT, as well as its mechanisms of inhibition by tolcapone. Rat whole-brain homogenates and the corresponding soluble and membrane-bound fractions were evaluated for their epinephrine 3-O-methylating activity. Tolcapone exhibited a very low IC50 in all the three enzyme preparations. In whole-brain homogenates, saturation curves made in the presence of 1 nM tolcapone displayed, when compared with controls, a reduction in Vmax without changes in Km, which suggested a noncompetitive type of inhibition. This was confirmed by experiments in which the IC50 value for tolcapone was not affected by substrate concentration. Nevertheless, this classic kinetic analysis is not suitable for a tight-binding inhibitor. A very low IC50, an inhibition potency that is dependent on the previous contact time of the inhibitor with the enzyme and an enzyme titrating capacity were the three criteria that tolcapone met as a tight-binding inhibitor in the rat brain. In conclusion, our results show that tolcapone is a highly potent tight-binding inhibitor of brain soluble and membrane-bound COMT, but because of difficulties in determining the type of inhibition for this type of compound, we cannot confirm previous claims about the competitive type of COMT inhibition produced by tolcapone.

Animals↗
PubMedDate not supplied

Microstructural characterization of degradation in a high-chromium alloy in the sugar industry.

A new high (24%)-chromium alloy was experimentally manufactured by combining the particular chemical composition of various materials with the use of thermal treatments to produce pump impellers for the sugar industry. The alloy metal was tested in situ in a sugar medium and then evaluated by electrochemical measurements; the two former procedures were associated with a nontraditional method to assess the susceptibility and resistance to corrosion. Potentiostatic and atomic absorption measurements were carried out to characterize the degradation and damage morphology by scanning electron microscopy (SEM) observations. The trials proved a good performance for the new alloy in the sugar medium in spite of nonsignificant localized damages involving erosion-corrosion mechanisms and surface microcrackings of the material.

Journal Article↗
PubMedDate not supplied

[Advices for a better drug prescription].

The prescription of a pharmacological agent concludes most medical visits. The rational basis of drug prescription by the physician relies on numerous pharmacodynamic, pharmacokinetic, pragmatic and economic considerations. However, it is a pity to notice that one patient out of two does not strictly follow the pharmacological treatment as it was prescribed. This article analyses some problems of the patient-doctor relationship, which may reduce medication compliance, and provides practical advice for improving such a situation in order to enhance both efficacy and safety of drug prescribing.

Drug Prescriptions↗