RESUMEN
BACKGROUND: A disturbance in glutamate neurotransmission has been hypothesized in schizophrenia. Hence, the beneficial effects of pharmacological treatment may be related to adaptive changes taking place in this neurotransmitter system. METHODS: In this study, we investigated the modulation of ionotropic and metabotropic glutamate receptors in the rat brain following acute or chronic exposure to the novel antipsychotic olanzapine. RESULTS: In accordance with the clear distinction between classical and atypical drugs, olanzapine did not alter glutamate receptor expression in striatum. Chronic, not acute, exposure to olanzapine was capable of up-regulating hippocampal mRNA levels for GluR-B and GluR-C, two alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-forming subunits. This effect could be relevant for the improvement of schizophrenic alterations, which are thought to depend on dysfunction of the glutamatergic transmission within the hippocampal formation. We also found that the expression of group II glutamate metabotropic receptors was up-regulated in the frontal cortex after chronic exposure to clozapine, and to a lesser extent olanzapine, but not with haloperidol. CONCLUSIONS: The adaptive mechanisms taking place in glutamatergic transmission might prove useful in ameliorating some of the dysfunction observed in the brain of schizophrenic patients.
Asunto(s)
Antipsicóticos/farmacología , Pirenzepina/análogos & derivados , Pirenzepina/farmacología , Receptores de Glutamato/efectos de los fármacos , Animales , Antipsicóticos/administración & dosificación , Benzodiazepinas , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Olanzapina , Pirenzepina/administración & dosificación , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores AMPA/efectos de los fármacos , Receptores AMPA/metabolismo , Receptores de Glutamato/metabolismo , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Evidence for heterodimerization has recently been provided for dopamine D(1) and adenosine A(1) receptors as well as for dopamine D(2) and somatostatin SSTR(5) receptors. In this paper, we have studied the possibility that D(2) and D(3) receptors interact functionally by forming receptor heterodimers. Initially, we split the two receptors at the level of the third cytoplasmic loop into two fragments. The first, containing transmembrane domains (TM) I to V and the N-terminal part of the third cytoplasmic loop, was named D(2trunk) or D(3trunk), and the second, containing the C-terminal part of the third cytoplasmic loop, TMVI and TMVII, and the C-terminal tail, was named D(2tail) or D(3tail). Then we defined the pharmacological profiles of the homologous (D(2trunk)/D(2tail) and D(3trunk)/D(3tail)) as well as of the heterologous (D(2trunk)/D(3tail) and D(3trunk)/D(2tail)) cotransfected receptor fragments. The pharmacological profile of the cross-cotransfected fragments was different from that of the native D(2) or D(3) receptors. In most cases, the D(3trunk)/D(2tail) was the one with the highest affinity for most agonists and antagonists. Moreover, we observed that all of these receptor fragments reduced the expression of the wild type dopamine D(2) and D(3) receptors, suggesting that D(2) and D(3) receptors can form complexes with these fragments and that these complexes bind [(3)H]nemonapride less efficiently or are not correctly targeted to the membrane. In a second set of experiments, we tested the ability of the split and the wild type receptors to inhibit adenylyl cyclase (AC) types V and VI. All of the native and split receptors inhibited AC-V and AC-VI, with the exception of D(3), which was unable to inhibit AC-VI. We therefore studied the ability of D(2) and D(3) to interact functionally with one another to inhibit AC-VI. We found that with D(2) alone, R-(+)-7-hydroxydypropylaminotetralin hydrobromide inhibited AC-VI with an IC(50) of 2.05 +/- 0.15 nm, while in the presence of D(2) and D(3) it inhibited AC-VI with an IC(50) of 0.083 +/- 0.011 nm. Similar results were obtained with a chimeric cyclase made from AC-V and AC-VI. Coimmunoprecipitation experiments indicate that D(2) and D(3) receptors are capable of physical interaction.
Asunto(s)
Receptores de Dopamina D2/química , Adenilil Ciclasas/metabolismo , Animales , Células COS , Membrana Celular/metabolismo , Clonación Molecular , Citoplasma/metabolismo , ADN Complementario/metabolismo , Dimerización , Relación Dosis-Respuesta a Droga , Immunoblotting , Concentración 50 Inhibidora , Pruebas de Precipitina , Unión Proteica , Estructura Terciaria de Proteína , Ratas , Receptores de Dopamina D2/fisiología , Receptores de Dopamina D3 , TransfecciónRESUMEN
An N-terminal dopamine D(2s) receptor clone was constructed and coexpressed in COS-7 cells together with a separate gene fragment coding for the C-terminal sequence of the dopamine D(2s) receptor. The truncated receptor (referred to as D(2trunc)) contained transmembrane domains I-V and the N-terminal portion of the third cytoplasmic loop, whereas the C-terminal receptor fragment (referred to as D(2tail)) contained transmembrane domains VI and VII and the adjacent intra- and extracellular sequences of the dopamine D(2s) receptor. Expression in COS-7 cells of either of these two polypeptides alone did not result in any detectable [3H]methylspiperone binding activity. However, specific [3H]methylspiperone binding could be observed after coexpression of the D(2trunc) and D(2tail) gene constructs; the number of receptors present on the plasma membrane was about 10% with respect to that of the wild type. The binding properties of the coexpressed fragments were similar to those of the wild-type dopamine D(2s) receptor for agonists and antagonists. Functional stimulation of the cotransfected D(2trunc) and D(2tail) fragments with quinpirole resulted in the inhibition of adenylate cyclase activity. Maximal inhibition corresponds to a 28% decrease in forskolin-stimulated adenylate cyclase. The apparent IC(50) of quinpirole was 5.1+/-0.3 mcM. These findings confirm and extend analogous data for other G protein-coupled receptors and indicate that this phenomenon is of general importance for the entire family of these proteins.
Asunto(s)
Fragmentos de Péptidos/fisiología , Receptores de Dopamina D2/fisiología , Animales , Apomorfina/farmacología , Unión Competitiva/efectos de los fármacos , Células COS , Clozapina/farmacología , Colforsina/farmacología , AMP Cíclico/metabolismo , Dopamina/farmacología , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Expresión Génica , Haloperidol/farmacología , Membranas/metabolismo , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/genética , Pergolida/farmacología , Quinpirol/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/fisiología , Espiperona/análogos & derivados , Espiperona/metabolismo , Espiperona/farmacología , Transfección , TritioRESUMEN
Epidemiological studies have shown a reduced incidence of cancer in Parkinson's disease. Since nearly all parkinsonian patients with clinical impairment are treated with L-beta-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine (DA)ergic agonists, a possibility exists that these therapeutic agents can influence the risk of cancer. We studied the antiproliferative effect of these therapeutic agents (and substances structurally correlated) on Chinese hamster ovary (CHO)-K1 cell growth. Among the compounds tested, apomorphine proved to be the most potent inhibitor of CHO-K1 cell growth, with an EC(50) of 3.35 +/- 0.12 micro M. The apomorphine analogues, apocodeine and hydroxyethylnorapomorphine, were less active as inhibitors of CHO-K1 cell growth. The activity of DA, 6-hydroxydopamine (6-OHDA), phenylethylamine (PEA), L-DOPA and bromocriptine as antiproliferative was one order of magnitude lower than that of apomorphine while pergolide was ineffective. To test whether or not the oxidative potential of these compounds was important for their antiproliferative effect, several antioxidants were assayed. Among them glutathione (GSH) and dithiothreitol (DTT) were effective in reversing the anti-proliferative effect of apomorphine, DA, 6-OHDA and PEA, conversely they did not work with bromocriptine. GSH and DTT are sulphydryl-reducing agents; while their effect could explain the efficacy against apomorphine, DA and 6-OHDA, it is difficult to understand why they should have any effect on PEA as this substance does not react with sulphydryl groups. The oxidative potential as a mechanism of action was also questioned by the results obtained with dihydrorhodamine 123, a probe that changes its fluorescent emission wave when oxidized. None of the compounds, with the exception of 6-OHDA, had any effect on the fluorescent emission wave of the probe at the maximal concentrations used to inhibit CHO-K1 cell growth. At concentrations five times higher, apomorphine and DA generated reactive oxygen species but PEA and bromocriptine did not. These data demonstrate that the antiproliferative effect of these compounds is not due to their oxidative potential, but another mechanism must be postulated.
RESUMEN
OBJECTIVES: To determine whether continuous waking day dopaminergic stimulation with the dopamine agonist apomorphine can reduce levodopa induced dyskinesias in Parkinson's disease METHODS: 19 patients with severe unpredictable refractory motor fluctuations and functionally disabling levodopa induced dyskinesias were treated with continuous subcutaneous apomorphine monotherapy for a minimum duration of 2.7 years RESULTS: A mean 65% reduction in dyskinetic severity and a mean 85% reduction in frequency and duration occurred. On discontinuing levodopa a concomitant reduction in off period time was also seen (35% of waking day "off" reduced to 10%) CONCLUSION: Continuous waking day dopaminergic stimulation with apomorphine reset the threshold for dyskinesias and led to a pronounced reduction in their frequency. Apomorphine should be considered as a less invasive alternative to pallidotomy or deep cerebral stimulation in controlling levodopa induced interdose dose dyskinesias.
Asunto(s)
Antiparkinsonianos/efectos adversos , Apomorfina/administración & dosificación , Agonistas de Dopamina/administración & dosificación , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Bombas de Infusión Implantables , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Antiparkinsonianos/administración & dosificación , Apomorfina/efectos adversos , Cronoterapia , Agonistas de Dopamina/efectos adversos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Discinesia Inducida por Medicamentos/etiología , Femenino , Humanos , Inyecciones Subcutáneas , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Examen Neurológico/efectos de los fármacos , Resultado del TratamientoRESUMEN
Previous investigations on the mutual pharmacokinetic influence of L-dopa and dopamine agonists in Parkinson's disease (PD) have shown controversial results. Two studies of the possible clinical and pharmacokinetic interaction between L-dopa and cabergoline were performed in 10 patients with de novo PD and 12 patients with fluctuating PD. In the first study (de novo patients), cabergoline was administered at increasing dosages until the maximum dosage of 2 mg/day once a day for 8 weeks; subsequently L-dopa (250 mg/day) was added. Blood levels of cabergoline were assayed in two different days, before starting L-dopa, and 1 week thereafter. In the second 8-week study (fluctuating patients), cabergoline was added to the current L-dopa therapy (maximum dosage 4 mg/day once a day). Blood levels of L-dopa were measured in two different days, before cabergoline was added, and at the end of the study. In both studies motor performance was evaluated by means of the Unified Parkinson's Disease Rating Scale (motor examination) and the Clinical Global Impression Scale; on-off diaries of daily motor condition also were filled by fluctuating patients. In patients with de novo PD, cabergoline pharmacokinetic parameters were unmodified by the adjunct of L-dopa, except that the time to reach the peak concentration (Tmax) significantly increased after L-dopa. In patients with fluctuating PD, no modification of L-dopa pharmacokinetics was observed before and after cabergoline coadministration. Clinical evaluations confirmed that cabergoline is effective in the treatment of advanced PD as well as in the management of de novo patients.
Asunto(s)
Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapéutico , Ergolinas/farmacocinética , Ergolinas/uso terapéutico , Levodopa/farmacocinética , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Anciano , Cabergolina , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora/efectos de los fármacosRESUMEN
3,4-Dihydroxyphenylacetic acid (DOPAC) is commonly considered to be the main dopamine (DA) metabolite produced by monoamine oxidase (MAO); however, the initial product of DA oxidation is 3,4-dihydroxyphenylacetaldehyde (DOPALD). Owing to technical difficulties in detecting DOPALD from a biological matrix, no studies have so far been performed to measure brain levels of this aldehyde in vivo. In this work, using transstriatal microdialysis in freely moving rats, we identified DOPALD by HPLC coupled to a coulometric detector. In chromatograms obtained from microdialysis samples, DOPALD appeared as a peak with a retention time coincident with that of the standards obtained via enzymatic and chemical synthesis. On the other hand, DOPALD was undetectable ex vivo from rat striatal homogenates. This discrepancy is probably due to the preferential extraneuronal localization together with the high reactivity of the aldehyde, which is rapidly removed by the dialysis probe, whereas the ex vivo procedure allows its condensation and enzymatic conversion. Measurement of DOPALD levels as a routine procedure might represent a reliable tool to evaluate DA oxidative metabolism directly, in vivo. Moreover, parallel detection of DOPALD and DOPAC levels in brain dialysate may make it possible to distinguish between the activity of MAO and aldehyde dehydrogenase. DOPALD, like many endogenous aldehydes, has been shown to be toxic to the cell in which it is formed. Therefore, in vivo measurement of DOPALD levels could highlight new aspects in the molecular mechanisms underlying both acute neurological insults and neurodegenerative diseases.
Asunto(s)
Ácido 3,4-Dihidroxifenilacético/análogos & derivados , Neostriado/metabolismo , Ácido 3,4-Dihidroxifenilacético/análisis , Ácido 3,4-Dihidroxifenilacético/síntesis química , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Dopamina/metabolismo , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Sensibilidad y EspecificidadRESUMEN
Studies on the influence of some dopamine agonists, particularly bromocriptine, on the pharmacokinetics of L-dopa have furnished contrasting results. Thus, any possible pharmacokinetic interaction should be taken into consideration when adding a new dopamine agonist to L-dopa treatment. In 12 Parkinson's disease (PD) patients with motor fluctuations, cabergoline was added in an 8-week study to their usual L-dopa/carbidopa therapy. Cabergoline was administered once a day at increasing doses of 0.5, 1, 2, and 3mg/day for a period of one week per dose, and 4mg/day for three weeks. Motor performance was assessed weekly evaluating the motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS) and the patients' diaries of daily on-off time. Blood levels of both L-dopa and 3-O-methyldopa (3-OMD) were assayed by HPLC in two different days, over an 8-hour period, before initiating cabergoline and at the end of the study. The results of this study confirm that cabergoline is effective in the management of PD motor fluctuations without modifying L-dopa and 3-OMD pharmacokinetics.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Ergolinas/uso terapéutico , Levodopa/farmacocinética , Trastornos del Movimiento/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Análisis de Varianza , Antiparkinsonianos/efectos adversos , Cabergolina , Agonistas de Dopamina/efectos adversos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Ergolinas/efectos adversos , Femenino , Humanos , Levodopa/sangre , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/sangre , Enfermedad de Parkinson/sangre , Resultado del TratamientoRESUMEN
The influence of not occupational factors (smoking, alcohol, coffee, drugs, sport, sex, age and body weight) on hippuric acid excretion was analyzed in two groups of healthy male subjects. A group was constituted of 710 painters occupied in wood and coach workings and the other one of 109 not occupational. The 5 degrees, 50 degrees, 95 degrees percentiles of the two distribution were 208, 605, 1784 and 153, 538, 1700 mg/g creatinine respectively. The analysis of variance undertaken on exposed subjects showed that there was a significative difference between urinary hippuric acid levels of subjects consuming alcohol and the not ones. Multiple regression analysis on hippuric acid excretion values distribution in not exposed group showed that only the variable "coffee consumption" resulted statistically significative (Ln hippuric acid = 5.0287 + 0.8062; R2 = 01221). Coffee consumption increase excretion rate (mg/hour) of hippuric acid likely an exposure to a toluene air concentration of 50 mg/m3. The authors suggest an action of caffeine on endogenous amount of benzoic acid.
Asunto(s)
Hipuratos/orina , Exposición Profesional , Tolueno/efectos adversos , Adolescente , Adulto , Anciano , Consumo de Bebidas Alcohólicas , Peso Corporal , Niño , Café , Quimioterapia , Humanos , Masculino , Persona de Mediana Edad , Ocupaciones , Análisis de Regresión , Fumar , DeportesRESUMEN
The effects of reversible inhibitors of monoamine oxidase-A (moclobemide, Ro 41-1049, both 20 mg/kg, i.p., and brofaromine, 10 mg/kg, i.p.) on the outflow of dopamine (DA) and its metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) as well as of 5-hydroxyindoleacetic acid was investigated by trans-striatal microdialysis in rats. These drugs markedly increased the level of DA in the dialysis fluid by 100% of basal values and concomitantly reduced the output of 3,4-dihydroxy-phenylacetic acid and homovanillic acid by 90%. The presence of tetrodotoxin in the perfusion fluid decreased the basal DA outflow and virtually abolished the rise in DA efflux after moclobemide administration. On the other hand, tetrodotoxin did not counteract the DA outflow induced by Ro 4-1284 (1 mg/kg, i.p.), a tetrabenazine derivative which rapidly releases DA from vesicles and causes a massive increase in the concentration of extravesicular amine. The injection of Ro 4-1284 30 min after moclobemide, brofaromine or Ro 41-1049 induced a 6-fold increase in DA outflow, which was accompanied by a transient increase in 3,4-dihydroxyphenylacetic acid levels. This latter effect was more marked for moclobemide than for the other two reversible inhibitors tested and was not observed in rats given the irreversible inhibitor clorgyline (5 mg/kg, i.p.). These results support the view that a large increase in the concentration of endogenous substrates in the cytosol might displace reversible monoamine oxidase-A inhibitors from the enzyme active sites. Therefore, the microdialysis technique seems to be a reliable in vivo method for assessing the degree of reversibility of monoamine oxidase inhibitors.
Asunto(s)
Benzamidas/farmacología , Núcleo Caudado/efectos de los fármacos , Citosol/metabolismo , Dopamina/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Piperidinas/farmacología , 2-etil-1,3,4,6,7,11b-hexahidro-3-isobutil-9,10-dimetoxi-2H-benzo(a)quinolizin-2-ol/farmacología , Animales , Monoaminas Biogénicas/metabolismo , Núcleo Caudado/metabolismo , Masculino , Moclobemida , Ratas , Serotonina/metabolismo , Tetrodotoxina/farmacologíaRESUMEN
Moclobemide is a reversible inhibitor of monoamine oxidase (MAO) with clear preference for the A type (so-called RIMA). The enzyme inhibition shows complex kinetics, and the molecular mechanism of interaction with the enzyme is not yet clear. Moclobemide increases the extracellular concentration of the monoamines in rat brain and decreases the level of their metabolites. Neither a loss nor a cumulation of activity has been observed after chronic treatment. Reversibility of MAO-A inhibition was demonstrated in vitro as well as in vivo. In various animal behavioral models, in particular in a novel model of stress-induced anhedonia, moclobemide was as effective as standard antidepressants. Moclobemide improves cognitive functions that are impaired in experimental situations. A neuroprotective action is seen in rats subjected to transient global ischemia/-hypoxia. Moclobemide lacks anticholinergic and other effects and only slightly increases the pressor effect of orally administered tyramine. Possible links between MAO-A inhibition and the various effects of moclobemide on brain function are discussed.
Asunto(s)
Benzamidas/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Animales , Antidepresivos/farmacología , Sinergismo Farmacológico , Humanos , Moclobemida , Tiramina/farmacologíaRESUMEN
A reliable high-performance liquid chromatographic (HPLC) method which allows the determination in human urine of two important metabolites of N,N-dimethylformamide (DMF), namely N-methylformamide (MMF) and N-methyl-N-(hydroxymethyl)formamide (DMFOH), is reported. A single-step rapid purification of urine was performed on a C18 solid-phase extraction column and the eluate was injected directly on to the HPLC column. HPLC was carried out isocratically on Aminex Ion Exclusion HPX-87H column using 7.5.10(-4) M sulphuric acid as the mobile phase with ultraviolet detection at 196 nm. The method is specific, accurate, precise and sufficiently sensitive to be applied to the biological monitoring of MMF and DMFOH in workers exposed to DMF.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Dimetilformamida/análogos & derivados , Formamidas/análisis , Dimetilformamida/análisis , Humanos , Exposición Profesional , Reproducibilidad de los Resultados , Espectrofotometría UltravioletaRESUMEN
In this study, the effect of the interaction between the short-acting reserpine-like dopamine (DA) releaser Ro 4-1284 (1 mg/kg IP) and the reversible inhibitors of monoamine oxidase type A (MAO-A), moclobemide (Aurorix) and Ro 41-1049 (20 mg/kg IP, each), on the outflow of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) was investigated by rat transstriatal microdialysis. The injection of Ro 4-1284 after MAO-A inhibitors produced a marked increase of DA concentrations corresponding to a bell-shaped change in DOPAC outflow. This effect was more pronounced in rats treated with moclobemide than with Ro 41-1049. These data support the view that the increment of the endogenous substrate DA might displace moclobemide more rapidly than Ro 41-1049 from MAO-A active sites. The microdialysis method is proposed as a more reliable in vivo technique to investigate the degree of reversibility of the reversible MAO-A inhibitors.
Asunto(s)
Benzamidas/farmacología , Química Encefálica/efectos de los fármacos , Dopamina/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , 2-etil-1,3,4,6,7,11b-hexahidro-3-isobutil-9,10-dimetoxi-2H-benzo(a)quinolizin-2-ol/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Unión Competitiva/efectos de los fármacos , Diálisis , Masculino , Moclobemida , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Endogámicas , Tiazoles/farmacologíaRESUMEN
A random biochemical screening followed by lead optimization culminated in the discovery of Ro 40-7592 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone). Ro 40-7592 was found to inhibit COMT in a competitive fashion both in the CNS and in the periphery (Ki for the liver enzyme = 30 nM). Ro 40-7592 (30 mg/kg p.o.) combined with benserazide (15 mg/kg p.o.) and a low dose of L-DOPA (10 mg/kg p.o.) almost completely blocked (for about 6 h) the formation of 3-O-methyldopa (3-OMD) in brain and plasma, producing a long-lasting increase of L-DOPA in plasma and a parallel marked increase of L-DOPA and dopamine in the brain. Ro 40-7592, combined with peripheral decarboxylase inhibitors and L-DOPA (as in Madopar and Sinemet), will offer substantial advantages in the therapy of Parkinson's disease, i.e. enhanced bioavailability and prolonged plasma half-life of L-DOPA, pronounced DOPA sparing effect and blockade of 3-OMD formation.
Asunto(s)
Benzofenonas/farmacología , Encéfalo/enzimología , Inhibidores de Catecol O-Metiltransferasa , Animales , Benserazida/farmacología , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Catecol O-Metiltransferasa/sangre , Cromatografía Líquida de Alta Presión , Electroquímica , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Semivida , Técnicas In Vitro , Levodopa/metabolismo , Masculino , Nitrofenoles , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas , Tolcapona , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
The effect of reversible inhibitors of the monoamine oxidase type A (MAO-A), moclobemide (Aurorix) and Ro 41-1049 (20 mg/kg i.p. each), as well as of reversible inhibitors of the MAO type B (MAO-B), Ro 19-6327 (1 mg/kg i.p.), on the outflow of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was studied in the rat by transstriatal microdialysis. Reversible MAO-A inhibitors markedly increased the output of DA and concomitantly decreased the output of DOPAC and HVA. These effects were absent with the highly selective MAO-B inhibitor Ro 19-6327.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Benzamidas , Cuerpo Estriado/efectos de los fármacos , Desaminación , Diálisis , Ácido Homovanílico/metabolismo , Masculino , Moclobemida , Ácidos Picolínicos , Ratas , Ratas Endogámicas , TiazolesRESUMEN
Flunarizine (FLU) treatment has proved effective for migraine but there have been reports--though controversial--of depression and/or extrapyramidal signs and symptoms in cases of chronic therapy. It has been suggested that FLU may interfere with the activity of central dopaminergic systems. In this study, prolactin (PRL) secretion was chosen as a parameter for functional exploration of central dopaminergic systems in normal and migraineous women before and after FLU treatment. Five healthy women were given FLU (20 mg) and placebo per os, each for one day. A significance increase of serum PRL levels was found after FLU administration, but not after placebo. Ten women with common migraine underwent TRH stimulation test (200 micrograms i.v.) before and after a 30-day FLU therapy (10 mg per os). Basal PRL levels were not modified by the treatment, but TRH stimulated PRL values were significantly enhanced after a 30-day FLU therapy. These results seem to confirm the hypothesis that FLU interferes with central dopaminergic activity.