RESUMEN
BACKGROUND: Causes of death of patients with the 3243A>G mutation have been described in case reports or case series with a limited number of subjects. METHODS: Eighty-two maternally related sibships of 11 families with 3243A>G were included in this survey. The lifespan of each subject in these families was compared with the life expectancy of the general population, adjusted with respect to year of birth and gender. Causes of death were determined among 3243A>G carriers and their first-degree maternal relatives. RESULTS: We identified 123 deceased subjects in families with 3243A>G and found an excess mortality during the early years of life and young adulthood. The median age at death for 3243A>G carriers and their first-degree maternal relatives was significantly lower than that of the general population. Neurological and cardiovascular diseases made up one-third of the causes of death. Sudden and unexpected death was not uncommon in patients with cardiovascular diseases, diabetes and epilepsy. CONCLUSIONS: 3243A>G carriers and their first-degree maternal relatives died younger than was predicted by their life expectancy at birth. Neurological disease was the most common cause of death.
Asunto(s)
Nucleótidos de Adenina/genética , Causas de Muerte , Nucleótidos de Guanina/genética , Enfermedades Mitocondriales/mortalidad , Proteínas Mitocondriales/genética , Fenotipo , Aminoacil-ARN de Transferencia/genética , Adolescente , Adulto , Secuencia de Bases , Cardiomiopatías/genética , Cardiomiopatías/mortalidad , Niño , Preescolar , Análisis Mutacional de ADN , ADN Mitocondrial/genética , Muerte Súbita/epidemiología , Diabetes Mellitus/genética , Diabetes Mellitus/mortalidad , Femenino , Finlandia , Tamización de Portadores Genéticos , Insuficiencia Cardíaca/mortalidad , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Esperanza de Vida , Masculino , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/mortalidad , Estado Epiléptico/genética , Análisis de SupervivenciaRESUMEN
BACKGROUND: Previous studies suggest that obese women taking valproate (VPA) for epilepsy are insulin resistant. OBJECTIVE: To assess the effects of antiepileptic drugs on serum insulin and lipid levels in men with epilepsy. METHODS: Body mass index (BMI) and fasting serum concentrations of insulin and lipids were measured in 102 men with epilepsy who were treated with VPA, carbamazepine (CBZ), or oxcarbazepine (OXC) monotherapy. Thirty-two healthy men served as control subjects. RESULTS: Obesity was not more common among VPA-treated men than among other men with epilepsy or the control subjects. However, the obese VPA-treated men had higher serum insulin levels (p < 0.001) than the obese control subjects despite similar BMI. CBZ and OXC did not have any significant effect on any of the measurements. Fasting serum insulin concentrations above the normal range were observed in seven obese VPA-treated patients (35%) but in only one obese control subject (5%). Five obese VPA-treated patients (25%) and one obese control subject (5%) had serum triglyceride levels above the normal range, and a low high-density lipoprotein/total cholesterol ratio was observed in two obese VPA-treated patients (10%). CONCLUSIONS: Obese valproate-treated men have high serum insulin levels, indicating insulin resistance. Moreover, some of the valproate-treated men cluster cardiovascular risk factors such as obesity, hyperinsulinemia, and elevated serum triglyceride concentrations. CBZ and OXC do not seem to have any significant effects on serum insulin or lipid levels in men with epilepsy.
Asunto(s)
Carbamazepina/análogos & derivados , Epilepsia/sangre , Ayuno/sangre , Insulina/sangre , Lípidos/sangre , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Índice de Masa Corporal , Carbamazepina/uso terapéutico , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Humanos , Hiperinsulinismo/sangre , Hiperinsulinismo/complicaciones , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Obesidad/sangre , Obesidad/complicaciones , Oxcarbazepina , Valores de Referencia , Factores de Riesgo , Triglicéridos/sangre , Ácido Valproico/efectos adversos , Ácido Valproico/uso terapéuticoRESUMEN
PURPOSE: Antiepileptic drugs (AEDs) may affect serum thyroid hormone concentrations. This study aimed to evaluate thyroid function in men taking carbamazepine (CBZ), oxcarbazepine (OCBZ), or valproate (VPA) for epilepsy. METHODS: Ninety men with epilepsy (40 taking CBZ, 29 taking OCBZ, and 21 taking VPA monotherapy) and 25 control subjects participated in the study. After clinical examination, a blood sample for hormone, gamma-glutamyl-transferase (GGT) and antibody (ab) assays was obtained. RESULTS: Serum thyroxine (T4) and free thyroxine (FT4) concentrations were low in men taking CBZ or OCBZ. Forty-five percent of men taking CBZ and 24% of men taking OCBZ had serum T4 and/or FT4 levels below the reference range. However, no correlations were found between T4 or FT4 and GGT concentrations in men taking CBZ or OCBZ. Thirteen percent of men taking CBZ, 17% of men taking OCBZ, and 6% of control men had increased levels of thyroid peroxidase (TPO)-ab and/or thyroglobulin (TG)-ab, but these were not associated with altered serum thyroid hormone concentrations. Serum triiodothyronine and thyrotropin levels in men taking CBZ or OCBZ were normal. In men taking VPA, the concentrations of thyroid hormones, thyrotropin, and antithyroid ab were normal. CONCLUSIONS: Serum thyroid hormone concentrations are low in CBZ- or OCBZ-treated men. However, these low levels do not seem to be due to liver enzyme induction or activation of immunologic mechanisms. Therefore, interference with hypothalamic regulation of thyroid function by CBZ and OCBZ seems possible. VPA does not have any significant effects on thyroid function.
Asunto(s)
Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Pruebas de Función de la Tiroides/estadística & datos numéricos , Glándula Tiroides/efectos de los fármacos , Adolescente , Adulto , Anticonvulsivantes/sangre , Carbamazepina/análogos & derivados , Carbamazepina/sangre , Carbamazepina/farmacología , Carbamazepina/uso terapéutico , Inducción Enzimática/efectos de los fármacos , Inducción Enzimática/fisiología , Epilepsia/sangre , Humanos , Yoduro Peroxidasa/inmunología , Hígado/enzimología , Masculino , Persona de Mediana Edad , Oxcarbazepina , Radioinmunoensayo , Factores Sexuales , Tiroglobulina/inmunología , Glándula Tiroides/fisiología , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangre , Ácido Valproico/sangre , Ácido Valproico/farmacología , Ácido Valproico/uso terapéutico , gamma-Glutamiltransferasa/sangreRESUMEN
BACKGROUND: Recent observations have indicated that reproductive endocrine disorders are common among women taking valproate (VPA) for epilepsy, but it is not known whether respective abnormalities develop in men taking VPA for epilepsy. Carbamazepine (CBZ) may induce endocrine disorders in men with epilepsy, but the endocrine effects of oxcarbazepine (OXC) are not known. METHODS: Reproductive endocrine function was evaluated in 90 men taking VPA (n = 21), CBZ (n = 40), or OXC (n = 29) as monotherapy for epilepsy and in 25 healthy control men. RESULTS: Twelve men (57%) taking VPA had increased serum androgen levels. The mean serum level of androstenedione was high in patients taking VPA. Serum levels of dehydroepiandrosterone sulfate were low, and serum concentrations of sex hormone-binding globulin (SHBG) were high in men taking CBZ. The endocrine effects of OXC seemed to be dose-dependent, because serum hormone levels were normal in patients with low OXC doses (< 900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose > or = 900 mg. CONCLUSIONS: VPA increases serum androgen concentrations in men with epilepsy. The endocrine effects of CBZ and OXC were different, because CBZ appears to decrease the bioactivity of androgens, whereas OXC does not.
Asunto(s)
Anticonvulsivantes/efectos adversos , Carbamazepina/efectos adversos , Epilepsia Generalizada/tratamiento farmacológico , Hiperandrogenismo/inducido químicamente , Ácido Valproico/efectos adversos , Adolescente , Adulto , Androstenodiona/sangre , Carbamazepina/análogos & derivados , Sulfato de Deshidroepiandrosterona/sangre , Epilepsias Parciales/tratamiento farmacológico , Disfunción Eréctil/sangre , Disfunción Eréctil/inducido químicamente , Humanos , Hiperandrogenismo/sangre , Masculino , Persona de Mediana Edad , Oxcarbazepina , Estudios Retrospectivos , Globulina de Unión a Hormona Sexual/metabolismo , Disfunciones Sexuales Psicológicas/sangre , Disfunciones Sexuales Psicológicas/inducido químicamente , Testosterona/sangreRESUMEN
The aim of this study was to evaluate cardiovascular responses as a marker of autonomic nervous system (ANS) disturbances in patients with untreated Parkinson's disease (PD) and to assess the relationship between them and the clinical characteristics of PD. The ANS functions were investigated in 50 patients with PD and 55 healthy subjects by measuring standard cardiovascular autonomic reflexes and heart rate variability (HRV) at rest using spectral analysis (the autoregressive model and the fast Fourier transformation), the percentage of the counts of beat-to-beat variation greater than 50 ms and the fractal dimension. Significantly attenuated HRV and deficient blood pressure reaction to tilting were found in the PD patient group. The patients with hypokinesia/rigidity as the initial symptom of PD had a more pronounced HRV deficit than those with tremor onset. Untreated PD patients suffer significant failure in cardiovascular nervous system regulation, and in patients with hypokinesia/rigidity as their initial disease manifestation the risk of this ANS dysfunction is high. However, in the early stages of PD these changes did not reach significance at individual level.
Asunto(s)
Frecuencia Cardíaca/fisiología , Enfermedad de Parkinson/fisiopatología , Adulto , Anciano , Sistema Nervioso Autónomo/fisiopatología , Presión Sanguínea/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Pruebas de Mesa Inclinada , Maniobra de ValsalvaRESUMEN
OBJECTIVES: Stroke often causes physical, cognitive and psychomotor dysfunction, which markedly decreases the driving ability of stroke patients. The aim of this study was to evaluate the driving ability of stroke patients using multidisciplinary clinical evaluation and driving-related laboratory tests. MATERIALS AND METHODS: A neurologist evaluated the driving ability of 20 male stroke patients on the basis of his own clinical examination and the observations and measurements of a neurological multidisciplinary rehabilitation team. After that a traffic psychologist evaluated the patients' driving ability on the basis of the driving-related cognitive and psychomotor laboratory tests. The patients themselves also evaluated their driving ability, as did their spouses. All the evaluations were carried out independently using the same 10-point scale. The control group consisted of 20 healthy males, matched by age and driving experience, who went through the same laboratory test package as the patients did. RESULTS: The stroke patients had more deficiencies in all tested driving related cognitive and psychomotor functions than the controls. The neurologist and the psychologist together evaluated 12 (60%) of the 20 stroke patients being unable to drive; 8 patients out of 11 with non-dominant hemisphere lesion and 4 in the dominant group. The patients themselves and their spouses had a clear tendency to overestimate driving ability compared to the estimates of the neurologist and the psychologist. The hit-rate of the evaluations of the neurologist and traffic psychologist (75%) was high. CONCLUSION: Stroke patients form a risk group as drivers due to their decreased cognitive and psychomotor abilities, and driving ability should always be evaluated after stroke. The results suggest that multidisciplinary neurological teams are able to evaluate the driving ability of stroke patients reliably. A careful evaluation of driving ability without a driving test requires assessment of cognitive and psychomotor functions critical in driving, which is not feasible for physicians without the support of a multidisciplinary team and/or traffic-related laboratory tests.
Asunto(s)
Conducción de Automóvil , Examen Neurológico/métodos , Trastornos Psicomotores/diagnóstico , Accidente Cerebrovascular , Atención/fisiología , Conducción de Automóvil/psicología , Estudios de Casos y Controles , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Diagnóstico por Computador , Humanos , Juicio/fisiología , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Distribución Normal , Trastornos de la Percepción/diagnóstico , Trastornos de la Percepción/etiología , Trastornos Psicomotores/etiología , Tiempo de Reacción/fisiología , Autoevaluación (Psicología) , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/psicologíaRESUMEN
Abnormal beta-adrenergic receptor (betaAR) density in the brains of suicide victims has been reported, although results of studies are inconsistent. Ethanol modifies betaAR-mediated signal transduction. Moreover abnormal betaAR function has been implicated in alcoholism. BetaAR antagonists, which were used as ligands in previous betaAR binding studies, also bind to 5-HT1B/1Dbeta receptors; hence, their estimates of betaAR density are confounded by binding to 5-HT1B/1Dbeta receptors. More importantly, previous studies did not examine betaAR agonist affinity or coupling efficiency to Gs protein. We investigated agonist affinity and coupling efficiency of betaAR to Gs protein in the brains of ten suicide victims, six subjects with alcoholism, and eight controls. There were no differences in betaAR density in either the frontal cortex or hippocampus of suicide victims or alcoholic subjects compared to controls. Preliminary results indicate betaAR supercoupling in suicide victims in both brain regions and uncoupling in alcoholic subjects in the frontal cortex. These results are discussed in view of the existing literature on the role of betaAR in suicide and alcoholism and the mechanism of action of antidepressants.
Asunto(s)
Alcoholismo , Corteza Cerebral/química , Subunidades alfa de la Proteína de Unión al GTP Gs/análisis , Hipocampo/química , Receptores Adrenérgicos beta/análisis , Suicidio , Antagonistas Adrenérgicos beta/análisis , Adulto , Anciano , Alcoholismo/metabolismo , Corteza Cerebral/metabolismo , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Hipocampo/metabolismo , Humanos , Yodocianopindolol/análisis , Masculino , Persona de Mediana Edad , Receptores Adrenérgicos beta/metabolismoAsunto(s)
Trastornos Cerebrovasculares/genética , ADN Mitocondrial/genética , Haplotipos/genética , Síndrome MELAS/genética , Trastornos Migrañosos/complicaciones , Hueso Occipital , Mutación Puntual/genética , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Most ligands which have been employed to investigate the regulation of beta-adrenergic receptors (betaAR) under pathophysiological conditions and in response to pharmacological manipulations have also been shown to have affinity for 5-HT1B receptors. We examined the effects of serotonin and metergoline (10 microM) on 125I-iodocyanopindolol (ICYP, 5-100 pM) binding to betaAR in rat frontal cortex and hippocampus membranes. In both brain regions, the presence of either serotonin or metergoline significantly lowered iodocyanopindolol dissociation constant (Kd) and maximum binding capacity (Bmax). Isoproterenol displacement curves showed that the decrease in receptor density was primarily due to a significant decrease in the receptors in the low-conformational state. Thus, a significant fraction of the apparent ICYP binding to betaAR in the low-conformational state was due to binding to 5-HT1B receptors. Neither serotonin nor metergoline had an effect on the agonist isoproterenol dissociation constant from betaAR in either conformational state.
Asunto(s)
Química Encefálica/efectos de los fármacos , Metergolina/farmacología , Pindolol/análogos & derivados , Receptores Adrenérgicos beta/metabolismo , Antagonistas de la Serotonina/farmacología , Serotonina/farmacología , Animales , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Guanosina Trifosfato/farmacología , Guanilil Imidodifosfato/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Yodocianopindolol , Masculino , Pindolol/farmacocinética , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/efectos de los fármacosRESUMEN
The efficacy and safety of tolfenamic acid and oral sumatriptan in the acute treatment of migraine was studied at five neurological centers in Finland. One hundred forty-one patients experiencing 289 migraine attacks, fulfilling the diagnostic criteria for migraine with or without aura as defined by the International Headache Society, were randomized. For first attacks, 77% of patients receiving tolfenamic acid experienced a reduction of the initial severe or moderate headache to mild or no headache after 2 hours, as compared to 79% in the sumatriptan group and 29% in the placebo group. No significant difference was found between active treatments (P = 0.85, 95% CI [-22%, 18%]), however, both active treatments were significantly better than placebo; P = 0.001, 95% CI (26%, 69%) for tolfenamic acid and P = 0.001, 95% CI (28%, 71%) for sumatriptan. For second attacks, results were similar with 70% of patients receiving tolfenamic acid experiencing relief, as compared to 64% in the sumatriptan group and 39% in the placebo group. No significant differences were observed in accompanying symptoms. Both drugs were well tolerated with the frequency of adverse events; 30% for tolfenamic acid and 41% for sumatriptan, a nonsignificant difference. In this study, tolfenamic acid and oral sumatriptan are comparably effective in the acute treatment of migraine. When comparably effective, factors like individual effect, tolerance, and cost of treatment should be considered when prescribing migraine medication.
Asunto(s)
Trastornos Migrañosos/tratamiento farmacológico , Antagonistas de Prostaglandina/uso terapéutico , Agonistas de Receptores de Serotonina/uso terapéutico , Sumatriptán/uso terapéutico , ortoaminobenzoatos/uso terapéutico , Enfermedad Aguda , Adulto , Formas de Dosificación , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Driving is a complex form of activity involving especially cognitive and psychomotor functions. These functions may be impaired by Parkinson's disease. The relation between Parkinson's disease and driving ability is still obscure and clinicians have to make decisions concerning the driving ability of their patients based on insufficient information. Until now no studies have compared different methods for evaluating the driving ability of patients with Parkinson's disease. METHODS: The driving ability of 20 patients with idiopathic Parkinson's disease and 20 age and sex matched healthy control subjects was evaluated by a neurologist, psychologist, vocational rehabilitation counsellor, and driving instructor using a standard 10 point scale. The patients and controls also evaluated their own driving ability. Cognitive and psychomotor laboratory tests and a structured on road driving test were used for evaluating the subjects' driving ability. RESULTS: The patients with Parkinson's disease performed worse than the controls both in the laboratory tests and in the driving test. There was a high correlation between the laboratory tests and driving test both in the patient group and in the control group. Disease indices were not associated with the driving test. The neurologist overestimated the ability of patients with Parkinson's disease to drive compared with the driving ability evaluated by the structured on road driving test and with the driving related laboratory tests. Patients themselves were not capable of evaluating their own ability reliably. CONCLUSION: Driving ability is greatly decreased in patients with even mild to moderate Parkinson's disease. The evaluation of patients' driving ability is very difficult to carry out without psychological and psychomotor tests and/or a driving test.
Asunto(s)
Examen de Aptitud para la Conducción de Vehículos , Conducción de Automóvil/psicología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/psicología , Desempeño Psicomotor , Adulto , Anciano , Sesgo , Estudios de Casos y Controles , Cognición , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Reproducibilidad de los Resultados , Índice de Severidad de la EnfermedadRESUMEN
Both ethanol and desipramine influence beta-adrenoceptor regulation. We reported previously that ethanol partially counteracted desipramine's effects on beta-adrenoceptor. Previous studies utilized beta-adrenoceptor radioligands that also bind to 5-HT1B receptors, thus, changes in 5-HT1B receptors could have confounded the results. The effects of chronic ethanol, desipramine and ethanol/desipramine treatment on beta-adrenoceptor coupling efficiency to Gs protein in rat brain were examined using 125I-iodocyanopindolol after blocking binding to 5-HT1B receptors. In the frontal cortex, ethanol uncoupled beta-adrenoceptor from GS. Desipramine decreased beta-adrenoceptor density, particularly in the high-conformational state, with no effect on coupling. In combined treatment, desipramine prevented ethanol-induced uncoupling. In the hippocampus, desipramine enhanced beta-adrenoceptor coupling, but ethanol had no effect. In combination with desipramine, ethanol enhanced desipramine-induced decrease in beta-adrenoceptor density in the high-conformational state, but uncoupled beta-adrenoceptors, an effect not observed with ethanol alone. These results suggest a complex interplay between ethanol and antidepressants in modulating beta-adrenoceptor function.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Encéfalo/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Desipramina/farmacología , Etanol/farmacología , Receptores Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Unión Competitiva , Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Interacciones Farmacológicas , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Yodocianopindolol/farmacología , Isoproterenol/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/efectos de los fármacosRESUMEN
The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) may present with symptoms that resemble a stroke. The strokelike episodes most commonly involve the posterior part of the cerebrum. We identified retrospectively 38 patients with an occipital stroke between ages 18 to 45 years during a 19-year period in a hospital serving as the only neurologic center for a specific population. The common MELAS mutation at the base pair 3243 (A3243G) of the mitochondrial DNA (mtDNA) was analyzed in blood samples. We found four patients (10%) with a clinical or molecular diagnosis of a mitochondrial disorder. Two of the patients carried the A3243G mutation, suggesting frequencies of 6% among patients younger than 45 years of age and 14% among patients younger than 30 years for this mutation. Furthermore, we identified two patients with a clinically definite mitochondrial disorder, and sequencing of the 22 transfer RNA genes revealed the mtDNA mutation A12308G in one patient. Clinical evaluation revealed that occipital stroke was part of a more complex syndrome in these four patients. These population-based findings demonstrate that the A3243G mutation in the mtDNA, and mitochondrial disorders are not uncommon among young patients with occipital stroke.
Asunto(s)
Infarto Cerebral/genética , ADN Mitocondrial/genética , Síndrome MELAS/genética , Lóbulo Occipital/patología , Mutación Puntual , Adolescente , Adulto , Infarto Cerebral/etiología , Infarto Cerebral/mortalidad , Estudios de Cohortes , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Estudios de Seguimiento , Humanos , Síndrome MELAS/complicaciones , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Selegiline (L-deprenyl), a selective inhibitor of monoamine oxidase type B, is an established adjuvant to levodopa therapy in Parkinson's disease (PD). To evaluate whether selegiline also effects the severity and progression of autonomic nervous system dysfunction in PD, we studied autonomic functions by measuring cardiovascular responses to normal breathing, deep breathing, the Valsalva maneuver, the tilting test, and the isometric contraction test prospectively in 52 PD patients receiving either selegiline (n = 27) or placebo (n = 25) in randomized order in a double-blind parallel trial. The study also continued double-blind after the introduction of levodopa. Recordings of cardiovascular responses were carried out annually, with the median follow-up period being 6 years. Cardiovascular autonomic reflexes were diminished in the patient groups compared with those of healthy control subjects (n = 45). There was no progression (except age-related) in dysautonomia in patients on placebo, but there was a decrease in cardiovascular responses in the selegiline group. The heart rate variability in normal breathing, in the Valsalva maneuver, and in the tilting test was clearly diminished during the selegiline treatment. In addition, in the tilting test, the fall in diastolic blood pressure immediately after tilting and in systolic blood pressure 2 minutes after standing up was more pronounced in the selegiline group than in the placebo group. Levodopa treatment had no effect on the measured autonomic responses. In the isometric contraction test, the two treatment groups showed no difference. We conclude that selegiline treatment diminishes autonomic responses, especially those of the sympathetic division. This sympatholytic effect may signal an increased risk of orthostatic hypotension.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Enfermedades Cardiovasculares/prevención & control , Inhibidores de la Monoaminooxidasa/uso terapéutico , Enfermedad de Parkinson/complicaciones , Selegilina/uso terapéutico , Análisis de Varianza , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/prevención & control , Enfermedades Cardiovasculares/etiología , Electrocardiografía , Femenino , Estudios de Seguimiento , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Inhibidores de la Monoaminooxidasa/farmacología , Estudios Prospectivos , Reflejo/efectos de los fármacos , Selegilina/farmacología , Pruebas de Mesa InclinadaRESUMEN
Ethanol may downregulate G-protein-coupled beta-adrenoreceptors (beta AR). beta AR may also be dysregulated in panic disorder (PD). In clinical samples, many patients have comorbid alcohol dependence (AD) and PD. Therefore, we investigated beta AR coupling in patients with these disorders. We harvested polymorphonuclear leukocytes from 24 healthy volunteers (Vs), and from 22 abstinent AD patients, 7 PD patients, and 9 patients with comorbid AD/PD. beta AR were assayed using saturation and agonist-displacement experiments. Group differences were tested using one-way analysis of variance (ANOVA). All beta AR binding parameters were similar in AD patients and Vs. The ratio of the agonists' dissociation constant from the receptor in the low affinity state (KL) to that in the high affinity state (KH) was significantly higher in PD patients than in AD patients and Vs (930.97 +/- 440.80 vs. 226.2 +/- 94.47 vs. 197.05 +/- 61.03, respectively, p < .01). This finding suggests that beta AR are supercoupled to GS in patients with PD. There was a trend for higher total receptor density (RT) in AD/PD and PD patients (Vs = 39.06 +/- 42.57 vs. AD = 27.93 +/- 23.07 vs. AD/PD = 66.85 +/- 79.02 vs. PD = 68.36 +/- 49.20, p < .08). There were no differences between AD/PD and PD patients, who combined had a significantly higher RT than Vs and AD patients (Vs = 38.95 +/- 8.81 vs. AD = 29.63 +/- 5.07 vs. AD/PD = 67.51 +/- 17.00, fmol/mg protein, p < .04). Finally, AD/PD patients had a significantly higher receptor density in the low-affinity conformational state than Vs and AD patients, but not PD patients (25.96 +/- 11.59 vs. 10.69 +/- 1.53 vs. 7.62 +/- 1.08 vs. 17.07 +/- 5.26 fmol/mg protein, respectively, p < .005). beta AR function in polymorphonuclear leukocytes is normal in abstinent alcoholics. The previously reported abnormal beta AR regulation in alcoholism may be state dependent. The higher RT and KL/KH ratio in AD/PD and PD, but not in AD patients, suggest that increased beta AR function may be important in the pathophysiology of PD.
Asunto(s)
Alcoholismo/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Trastorno de Pánico/metabolismo , Receptores Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/metabolismo , Adulto , Alcoholismo/complicaciones , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Femenino , Humanos , Técnicas In Vitro , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Trastorno de Pánico/complicaciones , Escalas de Valoración PsiquiátricaRESUMEN
The present study investigated the effects of early postnatal handling and temporary maternal isolation, between the 5th and 20th postnatal days, on various behaviors related to stress measured in adulthood in male Wistar rats. In addition, beta-adrenoceptor binding in the brain was measured. The handling consisted of daily 3-min sessions during which a pup was gently held by an investigator. The isolated rat pups were kept separated from their nursing mothers for 1 h daily. Subsequently, it was found that the time spent immobile in Porsolt's swim test was shortened, and voluntary alcohol (5% v/v) consumption was reduced in the handled rats, as compared with the non-handled and isolated animals. No differences in the measure of anxiety--food consumed in a novel environment--or the time spent in social, aggressive and defensive behaviors in a resident-intruder paradigm, were noted. Neither did the density or affinity of beta-adrenoceptors in the frontal cortex or hippocampus differ significantly between the groups. The results indicate that short-lasting maternal separation does not cause sustained effects on behavior in the rat. Early postnatal handling leads to shortened immobility in the swim test and reduced voluntary alcohol consumption, suggesting that handled rats show an improved ability to cope with stress.
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Animales Recién Nacidos/fisiología , Conducta Animal/fisiología , Encéfalo/metabolismo , Manejo Psicológico , Receptores Adrenérgicos alfa/metabolismo , Estrés Fisiológico/fisiopatología , Consumo de Bebidas Alcohólicas , Animales , Ingestión de Alimentos , Femenino , Privación Materna , Ratas , Ratas Endogámicas , Estrés Fisiológico/metabolismo , NataciónRESUMEN
The effect of chronic ethanol exposure alone or in combination with desipramine on agonist and antagonist binding to beta-adrenoceptors was studied in membrane preparations from rat frontal cortex and hippocampus. Ten day exposure of animals to ethanol vapor (25 mg/l) in inhalation chambers had no effect on binding properties of antagonist iodocyanopindolol (ICYP) in either brain region. However, ethanol in combination with chronic desipramine treatment prevented the reduction of beta-adrenoceptor density in frontal cortex produced by desipramine administration. Similar to its effects on antagonist binding, chronic ethanol exposure did not change the agonist isoproterenol binding characteristics measured in membranes from either rat frontal cortex or hippocampus. However, the combination of ethanol plus desipramine reduced the dissociation constant of the low affinity state of the receptor (KL) in frontal cortex from 23.1 +/- 3.7 microM in controls to 11.2 +/- 1.7 microM. Moreover, ethanol plus desipramine produced a greater decrease in the percentage of cortical receptors in the high affinity state for agonist (%RH) than did desipramine alone. This suggests that ethanol enhances desipramine-induced desensitization of beta-adrenoceptors in frontal cortex in spite of the prevention of reduction in density of the receptors. In hippocampal membranes, ethanol together with desipramine prevented desipramine-induced changes in agonist binding characteristics, i.e. the decrease in KH (dissociation constant from high affinity state of the receptor) and the consequent enhancement in KL/KH ratio. Thus, chronic exposure to relatively low concentrations of ethanol partially prevents effects of desipramine on beta-adrenoceptors.
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Química Encefálica/efectos de los fármacos , Desipramina/farmacología , Etanol/farmacología , Receptores Adrenérgicos beta/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Proteínas de Unión al GTP/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Técnicas In Vitro , Isoproterenol/farmacología , Cinética , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Ratas , Ratas Endogámicas , Receptores Adrenérgicos beta/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The action of chronic desipramine administration on agonist and antagonist binding to beta-adrenoceptors was investigated in rat frontal cortex and hippocampus. Ten day treatment with desipramine (10 mg/kg per day i.p.) resulted in a significant 34% decrease in the density of beta-adrenoceptors in membranes from rat frontal cortex but not hippocampus. The KD values for antagonist (iodocyanopindolol) did not change in either tissue after the desipramine treatment. Desipramine had no effect on the affinity of the agonist isoproterenol in frontal cortex. The percentage of receptors in the high affinity state for isoproterenol (% RH) decreased by 11% in the membranes from frontal cortex after desipramine administration. In contrast, in hippocampal membranes, desipramine treatment produced a decrease in KH (dissociation constant for isoproterenol binding to the high affinity state) and consequently a 137% increase in the ratio of dissociation constants for isoproterenol to the low and high affinity conformations (KL/KH; an putative index of coupling). This observation is new and suggests possible supercoupling of beta-adrenoceptors in hippocampus during desipramine treatment. Thus, in addition to desensitization of beta-adrenoceptors in rat frontal cortex ten day administration of desipramine causes a change compatible with supercoupling of beta-receptors in hippocampal membranes.
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Desipramina/farmacología , Hipocampo/efectos de los fármacos , Receptores Adrenérgicos beta/metabolismo , Animales , Unión Competitiva , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Fenómenos Químicos , Química , Desipramina/administración & dosificación , Hipocampo/metabolismo , Isoproterenol/metabolismo , Masculino , Ratas , Ratas Endogámicas , Receptores Adrenérgicos beta/efectos de los fármacosRESUMEN
The autonomic nervous system (ANS) function of patients with Parkinson's disease (PD) was investigated in 30 patients with PD, and in 21 healthy subjects of similar age by utilizing cardiovascular reflex measurements as indicators. In deep breathing, in the Valsalva manoeuvre, and in the tilting test the heart rate variability (R-R variation) differed significantly between the patients and the controls: the beat-to-beat variation was clearly decreased in patients with PD. Responses in diastolic pressure to isometric work were also clearly diminished. However, no significant differences in any measured ANS indices were found between the patients who were treated with levodopa and those who were not. Similarly, anticholinergics did not seem to affect the results.