RESUMEN
Striatal adenylyl cyclase activity from autopsied human brain is selectively stimulated by low concentrations of dopamine. Under the experimental conditions used, norepinephrine was about three times less potent than dopamine. Histamine and serotonin were ineffective. The stimulation by dopamine was competitively inhibited by haloperidol. There was no difference between the basal adenylyl cyclase activity or its level after dopamine stimulation between nine control subjects without a psychiatric history and seven patients with chronic schizophrenia.
Asunto(s)
Adenilil Ciclasas/metabolismo , Núcleo Caudado/enzimología , Dopamina/farmacología , Esquizofrenia/enzimología , Adenosina Trifosfato/metabolismo , Animales , Autopsia , Radioisótopos de Carbono , Antagonistas de Dopamina , Haloperidol/farmacología , Histamina/farmacología , Humanos , Norepinefrina/farmacología , Ratas , Serotonina/farmacologíaRESUMEN
Methionine-enkephalin, substance P, and homovanillic acid concentrations were measured in the CSF of subjects not affected by neurologic disorders (group 1), and in parkinsonian patients who had a slight or moderate (group 2) or severe (group 3) disability. Homovanillic acid and substance P concentrations in the CSF of groups 2 and 3 were respectively lower and higher than in group 1. On the contrary, an increase in CSF methionine-enkephalin content was found only in group 2. Our results confirm in humans the close relation between the dopaminergic and peptidergic transmissions in the nigrostriatal system that has been observed in experimental animals.
Asunto(s)
Encefalina Metionina/líquido cefalorraquídeo , Ácido Homovanílico/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Fenilacetatos/líquido cefalorraquídeo , Sustancia P/líquido cefalorraquídeo , Adulto , Anciano , Dopamina/fisiología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We tested the efficacy of coenzyme Q10 (ubidecarenone, CoQ10) therapy in patients with Kearns-Sayre syndrome and other mitochondrial myopathies with chronic progressive external ophthalmoplegia (CPEO). We treated seven patients for 1 year with daily oral administration of 120 mg of CoQ10. Throughout the treatment most of our patients showed a progressive reduction of serum lactate and pyruvate levels following standard muscle exercise and generally improved neurologic functions. The ECG and echocardiogram showed no significant changes in our patients. None of our patients showed any improvement in ptosis and CPEO.
Asunto(s)
Síndrome de Kearns-Sayre/tratamiento farmacológico , Mitocondrias Musculares , Enfermedades Musculares/tratamiento farmacológico , Oftalmoplejía/tratamiento farmacológico , Ubiquinona/análogos & derivados , Adolescente , Adulto , Coenzimas , Femenino , Humanos , Síndrome de Kearns-Sayre/patología , Masculino , Mitocondrias Musculares/ultraestructura , Enfermedades Musculares/patología , Ubiquinona/uso terapéuticoRESUMEN
The effect of the inhibition of aminopeptidase and enkephalinase A on the pain threshold of mice and rats was investigated, using bestatin and thiorphan as selective peptidase inhibitors. The results indicate that both enzymes are relevant to the catabolism of enkephalins in vivo; however, their simultaneous activation requires particular conditions. These conclusions are based on the following observations: (1) Only concomitant intracerebral treatment with both inhibitors led to an increase in the threshold of animal pain, whereas, in the presence of exogenous peptides, the concomitant injection of both inhibitors in mice elicited an analgesic response greater than the sum of the effects of each single inhibitor. (2) This response could be seen only after acute trauma; in fact, when the drugs were injected through a plastic cannula, only enkephalinase A inhibition was effective in increasing analgesia induced by exogenous peptides.
Asunto(s)
Aminopeptidasas/metabolismo , Endopeptidasas/metabolismo , Dolor/fisiopatología , Aminopeptidasas/antagonistas & inhibidores , Animales , Encefalina Leucina/farmacología , Leucina/análogos & derivados , Leucina/farmacología , Masculino , Ratones , Neprilisina , Inhibidores de Proteasas , Ratas , Ratas Endogámicas , Umbral Sensorial/efectos de los fármacos , Umbral Sensorial/fisiología , Especificidad de la Especie , Tiorfan , Tiopronina/análogos & derivados , Tiopronina/farmacologíaRESUMEN
A series of N-(4-isoxazolylthiazol-2-yl)oxamic acid derivatives was synthesized and tested on the passive cutaneous anaphylaxis (PCA) model in rats to verify its potential antianaphylactic activity. These compounds were prepared by reaction of an appropriate bromoacetylisoxazole with thiourea to give the corresponding aminothiazole and subsequent condensation with an oxalic acid monoester chloride to yield, following the usual process, the oxamic acid derivatives. Most of the new compounds exhibited, by intraperitoneal route in rats, a very potent antianaphylactic activity on PCA response, higher than that of the reference compound disodium cromoglycate (DSCG). The new derivatives, in contrast with DSCG, were effective on PCA even by oral route. The most interesting derivative of the new series was N-[4-(3-methyl-5-isoxazolyl)-2-thiazolyl]oxamic acid 2-ethoxyethyl ester (49), which was also active and more potent than DSCG in experimental models involving either IgE- or IgG-mediated anaphylactic responses at bronchopulmonary level.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Isoxazoles/síntesis química , Ácido Oxámico/análogos & derivados , Administración Oral , Animales , Fenómenos Químicos , Química , Cromolin Sódico/farmacología , Femenino , Cobayas , Antagonistas de los Receptores Histamínicos/farmacología , Isoxazoles/farmacología , Masculino , Ácido Oxámico/síntesis química , Ácido Oxámico/farmacología , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Ratas , Ratas Endogámicas , SRS-A/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Opioids' modulation of beta-receptors' density and function has been investigated in a cultured cell line system. Rat C6 glioma cells do not have opioid receptors or, at least, the number of these receptors is very low, but cell exposure to desmethylimipramine (DMI) causes expression of functional opioid receptors as indicated by the increased [3H]DHM binding and by the acquired ability of opioids to inhibit ISO-stimulated cAMP accumulation. Cell exposure to DMI also causes beta-receptors' down-regulation as indicated by the decline in [3H]DHA binding coupled to a reduced ability of isoproterenol (ISO) to stimulate cAMP accumulation in intact cells. In the present paper we show that cell exposure to opioid agonists during DMI treatment counteracted DMI-induced beta-receptor loss. Similarly, opioid agonists added at the beginning of ISO exposure in DMI-pretreated cells, inhibited ISO-induced beta-receptor tachyphylaxis. These results suggest that opioids may exert a protective effect on beta-receptor function and this appears to be a common mechanism which is operant when overstimulation of beta-receptors takes place.
Asunto(s)
Desipramina/farmacología , Receptores Adrenérgicos beta/metabolismo , Receptores Opioides/metabolismo , Animales , Línea Celular , Membrana Celular/metabolismo , AMP Cíclico/metabolismo , Glioma , Isoproterenol/farmacología , Cinética , Morfina/farmacología , Naloxona/farmacología , Ratas , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores Opioides/efectos de los fármacosRESUMEN
A case of human parkinsonism, due to n-hexane exposure, was recently described. On the basis of this observation, we treated mice and rats with n-hexane and its principle toxic metabolite 2,5-hexanedione. The mice underwent a chronic treatment intraperitoneum, the rats were treated stereotaxically into the substantia nigra. At biochemical analysis of the striata, dopamine and homovanillic acid levels were significantly lower compared with control animals; norepinephrine, serotonin, 5-hydroxindolacetic acid levels were unchanged. The rats treated with 2,5-hexanedione showed an apomorphine-induced rotational behavior significantly higher compared to controls. Since n-hexane and its metabolites are environmental contaminants and by-products of endogenous metabolic pathways, we propose that they may play a role in inducing parkinsonism in humans.
Asunto(s)
Cuerpo Estriado/metabolismo , Hexanos/toxicidad , Enfermedad de Parkinson Secundaria/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Hexanonas/farmacología , Ácido Homovanílico/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas , Valores de Referencia , Serotonina/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismoRESUMEN
The specific binding of broxaterol, a potent new orally active antiasthmatic drug, to beta 1- and beta 2-adrenoceptors was characterized by receptor binding studies with rat heart and lung membrane preparations. Broxaterol showed high affinity and selectivity for the beta 2-component of [3H]dihydroalprenolol binding in both lung (58% beta 2-sites, Ki = 130 nM) and heart membranes (19% beta 2-sites, Ki = 98 nM), whereas the binding to the beta 1-component was at lower affinity (42% beta 1-sites, Ki = 4100 nM in the lung and 81% beta 1-sites, Ki = 3460 mM in the heart). The influence of temperature changes on the binding properties of broxaterol towards beta-adrenoceptors was also investigated. A marked increase in the affinity of broxaterol for lung beta-receptors was observed on lowering the assay temperature, whereas the affinity for heart beta-receptors was little affected by temperature changes. Thermodynamic analysis of the binding data showed that the binding of broxaterol as well as isoproterenol to lung beta-receptors was associated with a large decrease in enthalpy, which correlates well with the full agonistic properties of this compound at beta 2-receptors.
Asunto(s)
Agonistas Adrenérgicos beta/metabolismo , Isoxazoles/metabolismo , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Dihidroalprenolol/farmacología , Técnicas In Vitro , Pulmón/metabolismo , Masculino , Miocardio/metabolismo , Propranolol/farmacología , Ratas , Ratas Endogámicas , TermodinámicaRESUMEN
We investigated the effect of bestatin, a specific inhibitor of aminopeptidase and thiorphan, a specific inhibitor of enkephalinase A, on the analgesic effect induced by the intracerebral injection of heptapeptide [Met5]enkephalin-Arg6-Phe7 (MEAP) in cannulated rats. In contrast with the results obtained when [Met5]enkephalin (ME) was used, bestatin clearly potentiated the analgesic effect of MEAP, but thiorphan was totally ineffective. These observations indicate that the predominant inactivating mechanism for MEAP is the action of an aminopeptidase whereas this enzyme seems to be little involved in the catabolism of ME. The existence of two different catabolic pathways for MEAP and ME suggests that MEAP may act not only as a precursor of ME but also as an independent neuromodulator.
Asunto(s)
Aminoácidos Sulfúricos/farmacología , Aminopeptidasas/antagonistas & inhibidores , Analgesia , Encefalina Metionina/análogos & derivados , Leucina/análogos & derivados , Inhibidores de Proteasas , Tiopronina/farmacología , Animales , Encefalina Metionina/farmacología , Leucina/farmacología , Masculino , Neprilisina , Ratas , Ratas Endogámicas , Tiorfan , Tiopronina/análogos & derivadosRESUMEN
Evidence has been obtained suggesting that cathinone-induced analgesia depends upon stimulation of alpha-adrenoceptors, followed by release of opioid peptides and by activation of serotonergic pathways. This hypothesis is supported by the following. (1) Cathinone potentiated morphine analgesia and the whole effect was antagonized by naloxone whereas onto the cathinone potentiation was counteracted by phenoxybenzamine. (2) Bestatin potentiated cathinone-induced analgesia and this effect was sensitive to both naloxone and phenoxybenzamine blockade. (3) The analgesic effect of cathinone + bestatin was further potentiated by the serotonin uptake inhibitor citalopram.
Asunto(s)
Alcaloides/farmacología , Analgésicos , Aminas Biogénicas/fisiología , Endorfinas/fisiología , Psicotrópicos/farmacología , Animales , Masculino , Ratones , Naloxona/farmacología , Fenoxibenzamina/farmacologíaRESUMEN
Interleukin 1 (IL-1) induces a series of metabolic and endocrine effects. Activation of the hypothalamus-pituitary-adrenal axis, inhibition of food and water intake, elevation of serum interleukin-6 (IL-6) concentration and hypoglycemia are some of the effects induced by IL-1. The purpose of this study was to compare the sensitivity of these effects following central and peripheral administration of IL-1 beta. Different doses of IL-1 beta (0.1-1000 ng/mouse) were centrally (ICV) or peripherally (IP) injected to male mice two hours prior to sacrifice. The ICV administration was more efficacious than the IP injection in elevating serum corticosterone and IL-6 concentrations, whereas no difference was evident in the IL-1 beta-induced hypoglycemia. Central IL-1 beta administration was also more potent than IP injection in inhibiting overnight food and water intake. A dose-dependent effect was evident in all these cases. In summary, our data compare effects elicited by central or peripheral administration of different doses of IL-1 beta. This comparison suggests that the IL-1 beta stimulation of serum corticosterone and IL-6 and inhibition of food and water intake are events more centrally mediated than the IL-1 beta-induced hypoglycemia.
Asunto(s)
Glucemia/metabolismo , Ventrículos Cerebrales/fisiología , Corticosterona/sangre , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Interleucina-1/farmacología , Interleucina-6/sangre , Animales , Ventrículos Cerebrales/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Interleucina-1/administración & dosificación , Masculino , Ratones , Ratones Endogámicos ICR , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Privación de AguaRESUMEN
The synthesis of new 2-(3-substituted-5-isoxazolyl)-2-methoxyiminoacetic acids and their condensation derivatives with a suitable cephalosporanic nucleus, is reported. Their antibacterial properties were tested in vivo and in vitro also against beta-lactamase producer microorganisms; particularly the oral bioavailability of some of these new derivatives was studied.
Asunto(s)
Antibacterianos , Cefalosporinas/síntesis química , Isoxazoles/síntesis química , Oxazoles/síntesis química , Animales , Infecciones Bacterianas/tratamiento farmacológico , Disponibilidad Biológica , Cefalosporinas/análisis , Cefalosporinas/uso terapéutico , Isomerismo , Isoxazoles/análisis , Isoxazoles/uso terapéutico , Pruebas de Sensibilidad Microbiana , Ratas , Relación Estructura-ActividadRESUMEN
The bactericidal properties of normal serum are an important feature in host defence; it has been suggested that they are depressed by cigarette smoke. The aim of the present study was to investigate the in vitro depressant effect of cigarette smoke on antibacterial activity of rabbit serum and its interaction with the well-known antioxidant agent, N-acetylcysteine. Escherichia coli was used to study the bactericidal activity of the complement-dependent system and Staphylococcus aureus was used to study the thermostable bactericidal system. It was found that exposure of serum and bacteria to cigarette smoke significantly decreased the bactericidal powder of serum; when N-acetylcysteine was added to the incubation mixture, however, a marked inhibitory effect on the toxic action of smoke on rabbit serum was observed.
Asunto(s)
Acetilcisteína/farmacología , Escherichia coli/inmunología , Humo/efectos adversos , Animales , Sangre/efectos de los fármacos , Supervivencia Celular , Escherichia coli/efectos de los fármacos , Plantas Tóxicas , Conejos , Staphylococcus aureus/efectos de los fármacos , NicotianaRESUMEN
The synthesis of new 2-(3-bromo-5-isoxazolylideneamino-oxy)acetic acids and their condensation derivatives with suitable beta-lactam nuclei is reported. Their antibacterial properties have been tested in vitro. An interesting activity against Gram-positive bacteria including beta-lactamase-producing microorganisms was found among the cephalosporanic acid derivatives.
Asunto(s)
Antibacterianos/síntesis química , Isoxazoles/síntesis química , Antibacterianos/farmacología , Cefalosporinas/síntesis química , Cefalosporinas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/enzimología , Isoxazoles/farmacología , Pruebas de Sensibilidad Microbiana , Penicilinas/síntesis química , Penicilinas/farmacología , beta-Lactamasas/biosíntesis , beta-Lactamas/síntesis química , beta-Lactamas/farmacologíaRESUMEN
Fourty four patients with mitochondrial myopathies were treated with Ubidecarenone (CoQ10) for six months in an open multicentric trial. No side effects due to the drug administration were observed. Sixteen patients showing at least 25% decrease of post exercise lactate levels were selected as responders. Responsiveness was apparently not related to CoQ10 level in serum and platelets or to the presence or absence of mtDNA deletions. The responders were further treated for 3 months with CoQ10 or placebo in the second blind part of the trial; no significant differences between the 2 groups were observed. It is not clear why CoQ10 had therapeutic effects in some patients and not in others with the same clinical presentation and biochemical defect, and we failed to identify candidate responders before treatment. At the dosage of CoQ10 used in the study (2 mg/kg/day) the therapy requires long administration time before a response is demonstrable.