RESUMEN
BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. OBJECTIVE: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. MATERIALS AND METHODS: Everolimus was dosed 4.5 mg/m2 /day (titrated to trough 5-15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis-associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. RESULTS: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1-67.7%) in EXIST-1 and 68.2% (58.5-76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41-45%). CONCLUSION: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.
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Angiomiolipoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Astrocitoma/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Everolimus/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Esclerosis Tuberosa/tratamiento farmacológico , Adolescente , Adulto , Angiomiolipoma/etiología , Antineoplásicos/efectos adversos , Astrocitoma/etiología , Neoplasias del Sistema Nervioso Central/etiología , Niño , Preescolar , Everolimus/efectos adversos , Femenino , Humanos , Lactante , Neoplasias Renales/etiología , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/etiología , Esclerosis Tuberosa/complicaciones , Adulto JovenRESUMEN
Tuberous sclerosis complex (TSC) is an important cause of epilepsy and autism, as well as renal and pulmonary disease in adults and children. Affected individuals are subject to hamartomas in various organ systems which result from constitutive activation of the protein kinase mTOR (mammalian target of rapamycin). The clinical course, prognosis and appropriate therapy for TSC patients are often different from that for individuals with epilepsy, renal tumors, or interstitial lung disease, from other causes. Additionally, TSC serves as a model for other conditions in which the mTOR pathways are also up-regulated. This article reviews the molecular pathophysiology and management of neurological, renal and pulmonary manifestations of the disorder. The use of mTOR inhibitors such as rapamycin and everolimus is discussed and recent clinical trials of these drugs in TSC are reviewed.
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Encéfalo/fisiopatología , Riñón/fisiopatología , Pulmón/fisiopatología , Esclerosis Tuberosa/fisiopatología , Adulto , Encéfalo/metabolismo , Encéfalo/patología , Niño , Humanos , Riñón/metabolismo , Riñón/patología , Pulmón/metabolismo , Pulmón/patología , Serina-Treonina Quinasas TOR/metabolismo , Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/patologíaRESUMEN
BACKGROUND: Major sources of morbidity and mortality in patients with tuberous sclerosis who develop subependymal giant cell astrocytomas (SEGAs) relate to tumor growth and resultant hydrocephalus. We describe a modification of a specialized minimal access resection technique in which an operative corridor is formed with balloon dilation over the course of a week prior to tumor resection. METHODS: Three patients with tuberous sclerosis who had an enlarging SEGA and concomitant hydrocephalus underwent surgical resection with this modified technique. A frontal craniotomy was performed and the optimal trajectory for tumor resection was confirmed by image guidance. After initial insertion of the deflated balloon into the ventricle and removal of the peel-away sheath, inflation of the balloon with a 1-mL saline injection sealed the tract. Additional 1-mL saline injections were continued during the next week until the balloon reached a 15-mm diameter, thus creating the operative corridor. One week after the first operation, the balloon was deflated and removed, and the patient underwent tumor resection via the newly formed operative corridor. RESULTS: Three patients with tuberous sclerosis underwent gross total resections of SEGAs and experienced subsequent resolution of ventricular dilation. Postoperative imaging confirmed minimal cortical disruption. CONCLUSIONS: Use of balloon dilation for the gradual formation of an operative corridor eliminated the need for additional retraction during SEGA resection, potentially decreasing injury to the surrounding neural tissue. In our three patients, the dilation tract retained its integrity during the operation and had sealed completely on postoperative imaging.
Asunto(s)
Astrocitoma/cirugía , Neoplasias Encefálicas/cirugía , Cateterismo/métodos , Craneotomía/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Esclerosis Tuberosa/cirugía , Adolescente , Astrocitoma/etiología , Neoplasias Encefálicas/etiología , Niño , Preescolar , Femenino , Humanos , Hidrocefalia/prevención & control , Masculino , Procedimientos Neuroquirúrgicos/métodos , Tomografía Computarizada por Rayos X , Esclerosis Tuberosa/complicacionesRESUMEN
BACKGROUND: Although many lines of evidence suggest an autoimmune etiology, the pathophysiology of opsoclonus-myoclonus syndrome (OMS) remains poorly understood and no immunologic abnormalities have correlated with neurologic severity. Conventional immunotherapies often do not prevent relapse or permanent sequelae. OBJECTIVE: To test the cellular immune hypothesis of OMS in a cross-sectional study and determine if CSF lymphocyte subset analysis provides biomarkers of disease activity. METHODS: The expression of lymphocyte surface antigens was investigated in CSF and blood of 36 children with OMS and 18 control subjects, using a comprehensive panel of monoclonal antibodies to adhesion and activation proteins in combination with anti-CD3 and anti-CD45 antibodies in four-color fluorescence-activated cell sorting. RESULTS: Although most children with OMS had normal CSF cell counts, they exhibited expansion of CD19+ B-cell (up to 29%) and gammadelta T-cell (up to 26%) subsets and a lower percentage of CD4+ T-cells and CD4/CD8 ratio, which persisted even years after disease onset and conventional treatments. The percentage of activated CSF T-cells was also higher. Abnormalities correlated with neurologic severity, as scored blinded from videotapes using a 12-item motor scale, and disease duration. No significant differences were found between tumor and no-tumor groups. In children with neuroblastoma, tumor resection or cancer chemotherapy did not alter immunologic abnormalities. CONCLUSIONS: CSF B- and T-cell recruitment is linked to neurologic signs in pediatric OMS, which may relate to relapses and disease progression.
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Linfocitos B/inmunología , Biomarcadores/líquido cefalorraquídeo , Inmunofenotipificación , Síndromes Paraneoplásicos del Sistema Nervioso/líquido cefalorraquídeo , Linfocitos T/inmunología , Antígenos CD19/inmunología , Antígenos de Superficie/inmunología , Linfocitos B/citología , Progresión de la Enfermedad , Humanos , Activación de Linfocitos , Recuento de Linfocitos , Subgrupos Linfocitarios/citología , Subgrupos Linfocitarios/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Recurrencia , Linfocitos T/citologíaRESUMEN
PURPOSE: Lamotrigine (LTG), a newer antiepileptic drug (AED), has activity against both partial-onset and generalized seizures. Its reported benefits for behavior, and its effectiveness in Lennox-Gastaut syndrome and other forms of refractory epilepsy, make it a logical choice for treatment of epilepsy in tuberous sclerosis complex (TSC). We present our experience with LTG therapy of epilepsy in 57 patients with TSC. METHODS: Patients fulfilled the diagnostic criteria for clinically definite TSC. LTG was initiated and increased until improvement in seizure frequency was noted, intolerable side effects occurred, or maximal doses were reached. Seizure frequency and behavioral changes were recorded during LTG therapy and compared with those prior to the introduction of LTG. RESULTS: Twenty-four (42%) were seizure free, and 21 (37%) had a >50% reduction in seizure frequency. Eighteen (32%) had subjectively improved behavior and/or alertness with daily activities. Thirty-eight (67%) had no change in this regard, whereas one (2%) became worse. Responders were more likely to not have a history of infantile spasms, and to have experienced only partial seizures (p < 0.05). Otherwise no phenotypic correlations with response were apparent. CONCLUSIONS: Among patients with TSC and epilepsy, LTG was effective and well tolerated, including as initial monotherapy. Improved alertness and behavior were apparent in many patients. The incidence of side effects is similar to that reported for other pediatric populations with symptomatic partial epilepsy. The usefulness of LTG in TSC may relate to an underlying defect of glutamatergic neurotransmission in partial epilepsy.
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Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Triazinas/uso terapéutico , Esclerosis Tuberosa/complicaciones , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Epilepsias Parciales/tratamiento farmacológico , Epilepsias Parciales/etiología , Epilepsia/etiología , Femenino , Humanos , Lactante , Lamotrigina , Modelos Logísticos , Masculino , Espasmos Infantiles/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH) produce cystic and nodular disease, respectively, in the lungs of patients with tuberous sclerosis. The objective of this study was to prospectively characterize the prevalence, clinical presentation, and genetic basis of lung disease in TSC. We performed genotyping and computerized tomographic (CT) scanning of the chest on 23 asymptomatic women with tuberous sclerosis complex (TSC). Cystic pulmonary parenchymal changes consistent with LAM were found in nine patients (39%). These patients tended to be older than cyst-negative patients (31.9 +/- 7.6 yr versus 24.8 +/- 11.6 yr, p = 0.09). There was no correlation between presence of cysts and tobacco use, age at menarche, history of pregnancy, or estrogen-containing medications. Three of the cyst-positive patients had a prior history of pneumothorax. Pulmonary function studies revealed evidence of gas trapping but normal spirometric indices in the cyst-positive group. All nine cyst-positive patients had angiomyolipomas (AML), which were larger (p < 0.05) and more frequently required intervention (p = 0.08) than cyst-negative patients (8 of 14 with AMLs, p < 0.05). Ten patients (43%) had pulmonary parenchymal nodules. Pulmonary nodules were more common in women with cysts (78% versus 21%, p < 0.05), and 52% of all patients had either cystic or nodular changes. TSC2 mutations were identified in all cyst-positive patients who were tested (n = 8), whereas both TSC1 and TSC2 mutations were found in patients with nodular disease. Correlation of the mutational and radiographic data revealed one pair of sisters who were discordant for cystic disease, two mother- daughter pairs who were discordant for nodular disease, and no clear association between cyst development and a specific mutational type. This prospective analysis demonstrates that cystic and nodular pulmonary changes consistent with LAM and MMPH are common in women with TSC.
Asunto(s)
Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Linfangiomioma/diagnóstico por imagen , Linfangiomioma/genética , Alveolos Pulmonares/citología , Alveolos Pulmonares/patología , Tomografía Computarizada por Rayos X , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/genética , Adolescente , Adulto , Análisis Mutacional de ADN/métodos , Femenino , Genotipo , Humanos , Hiperplasia , Enfermedades Renales/genética , Persona de Mediana Edad , Linaje , Prevalencia , Estudios Prospectivos , Pruebas de Función Respiratoria , Nódulo Pulmonar Solitario , EspirometríaRESUMEN
Tuberous sclerosis (TSC) is a relatively common hamartoma syndrome caused by mutations in either of two genes, TSC1 and TSC2. Here we report comprehensive mutation analysis in 224 index patients with TSC and correlate mutation findings with clinical features. Denaturing high-performance liquid chromatography, long-range polymerase chain reaction (PCR), and quantitative PCR were used for mutation detection. Mutations were identified in 186 (83%) of 224 of cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. A standardized clinical assessment instrument covering 16 TSC manifestations was used. Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations and was somewhat distinct from patients with TSC1 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as-yet-unidentified locus with a relatively mild clinical phenotype.
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Mutación/genética , Proteínas/genética , Proteínas Represoras/genética , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patología , Adolescente , Adulto , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Exones/genética , Duplicación de Gen , Genotipo , Humanos , Lactante , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutagénesis Insercional/genética , Desnaturalización de Ácido Nucleico , Fenotipo , Eliminación de Secuencia/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de TumorRESUMEN
Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder due to deficiency of the enzyme arylsulfatase A that leads to progressive, diffuse demyelination. The syndrome of nonverbal learning disability has been attributed to white matter abnormality and has been reported in children with this disorder and in some healthy family member carriers of gene. We examined the neuropsychologic profiles and MRIs of eight members of the family of a 7-year-old girl with this disease, all of whom were heterozygous carriers of the mutation and five of whom were also carriers of the MLD pseudodeficiency gene. All had low normal levels of arylsulfatase A, and seven of the eight had average or better profiles across all assessed neuropsychological domains. The patient's younger sister had a profile with features of the syndrome of nonverbal learning disability despite a normal MRI, whereas two members with minor white matter findings did not. This family does not provide evidence for the syndrome of nonverbal learning disability in heterozygous carriers of the gene for MLD, even when associated with the MLD pseudodeficiency gene.
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Encéfalo/patología , Cerebrósido Sulfatasa/deficiencia , Familia/psicología , Discapacidades para el Aprendizaje/genética , Leucodistrofia Metacromática/psicología , Pruebas Neuropsicológicas , Adolescente , Adulto , Niño , Preescolar , Femenino , Genotipo , Heterocigoto , Humanos , Discapacidades para el Aprendizaje/diagnóstico , Discapacidades para el Aprendizaje/enzimología , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/patología , Imagen por Resonancia Magnética , Masculino , Fenotipo , SíndromeRESUMEN
Cardiac complications of the ketogenic diet, in the absence of selenium deficiency, have not been reported. Twenty patients on the ketogenic diet at one institution were investigated. Prolonged QT interval (QTc) was found in 3 patients (15%). There was a significant correlation between prolonged QTc and both low serum bicarbonate and high beta-hydroxybutyrate. In addition, three patients had evidence of cardiac chamber enlargement. One patient with severe dilated cardiomyopathy and prolonged QTc normalized when the diet was discontinued.
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Enfermedades Cardiovasculares/etiología , Dieta/efectos adversos , Estado Epiléptico/dietoterapia , Ácido 3-Hidroxibutírico/sangre , Adolescente , Adulto , Arritmias Cardíacas/sangre , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Cardiomiopatía Dilatada/sangre , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/etiología , Enfermedades Cardiovasculares/diagnóstico , Niño , Preescolar , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Resistencia a Medicamentos , Ecocardiografía , Electrocardiografía , Humanos , Lactante , Masculino , Transaminasas/sangre , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiologíaRESUMEN
Angelman's syndrome, a genetic disorder involving a defect in the DNA coding for subunits of the gamma-aminobutyric acid (GABA) type A receptor, often is associated with intractable epilepsy. Topiramate is a novel anticonvulsant that enhances GABAergic neurotransmission. Five children with Angelman's syndrome and epilepsy were treated with topiramate for clinical indications. The drug was effective and well tolerated, possibly because of its GABAergic properties. Further studies are necessary to confirm and elucidate this observation.
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Síndrome de Angelman/complicaciones , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/etiología , Fructosa/análogos & derivados , Niño , Preescolar , Femenino , Fructosa/efectos adversos , Fructosa/uso terapéutico , Humanos , Masculino , TopiramatoAsunto(s)
Trastorno Autístico/fisiopatología , Cerebelo/patología , Cerebelo/fisiopatología , Esclerosis Tuberosa/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Trastornos del Conocimiento/diagnóstico , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Pruebas NeuropsicológicasRESUMEN
Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder with a high spontaneous mutation rate. Understanding of this disorder has greatly increased in recent years. Two chromosomal loci can produce the TSC phenotype: 9q34 and 16p13. These appear to code for proteins that have a tumor suppressor function. TSC results in hamartomas that affect various organ systems, most commonly brain, skin, heart, and kidney. Previously thought to consist of intractable seizures, facial angiofibromas, and dementia, increasing numbers of persons with less severe involvement have been identified. Diagnostic criteria, various types of lesions, and medical management are reviewed.
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Esclerosis Tuberosa/diagnóstico , Encéfalo/patología , Niño , Aberraciones Cromosómicas/genética , Trastornos de los Cromosomas , Cromosomas Humanos Par 16 , Cromosomas Humanos Par 9 , Diagnóstico por Imagen , Genes Dominantes/genética , Genes Supresores de Tumor/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Fenotipo , Esclerosis Tuberosa/genéticaRESUMEN
The pharmacological properties of centrally acting alpha2-receptor agonists such as clonidine suggest a potentially important role as ideal adjuvants for anesthesia since they produce sedation, analgesia anxiolysis, xerostomia and cardiovascular stability without respiratory depression, development of tolerance or addiction liability. Further clinical experience with this exciting development will undoubtedly establish the ultimate role and optimal use of alpha2 -receptor agonists in anesthetic practice. Beta-blockage can result in significant bradycardia, atrial ventricular conduction problems, bronchospasm and left ventricular contractile dysfunction. Thus, the use of long-acting beta-blockers is of limited value in the perioperative period. Esmolol, because of its ultrashort action, cardioselective properties and titratability, has been shown to be safe and effective for the treatment of tachycardia and hypertension. Doses from 50 to 300 micrograms/kg/min for up to 7 hours in the perioperative period have been shown to cause no apparent cumulative effect. It has been used in the treatment of asthmatic patients with tachycardia and hypertension without significant increases in airway resistance. Studies using esmolol during general anesthesia have demonstrated no significant interaction with several anesthetic regimens.
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Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos beta/farmacología , Clonidina/farmacología , Humanos , Propanolaminas/farmacologíaRESUMEN
The effects of 3 phosphodiesterase inhibitors, aminophylline, isobutylmethylxanthine (IBMX), and RO 20-1724, were tested on descending intraspinal and spinal reflex transmission to sympathetic preganglionic neurons in unanesthetized spinal cats. Sympathetic discharges, recorded from upper thoracic preganglionic white rami, were evoked by stimulation (0.1 Hz) of descending excitatory pathways in the cervical dorsolateral funiculus (intraspinal) or of adjacent intercostal nerves (spinal reflex). Each phosphodiesterase rapidly and markedly enhanced transmission through intraspinal pathways but only slowly and modestly enhanced transmission through spinal reflex pathways. Pretreatment with a methyltyrosine-reserpine combination, chlorpromazine, or prazosin markedly restricted the enhancement of intraspinal transmission by IBMX to levels typically produced on spinal reflex pathways. Clonidine markedly depressed transmission through both pathways and prevented enhancement by the phosphodiesterase inhibitors. Yohimbine or tolazoline antagonized the depressant effects of clonidine and restored the ability of the phosphodiesterase inhibitors to enhance transmission. Somatic spinal reflexes were not affected by the phosphodiesterase inhibitors. The results suggest that descending norepinephrine pathways to sympathetic preganglionic neurons activate adenylate cyclase to generate cyclic AMP which increases neuronal excitability, possibly by phosphorylating membrane proteins. Clonidine appears to depress neuronal excitability by inhibiting adenylate cyclase through activation of alpha 2-adrenergic receptors.
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Clonidina/farmacología , Neuronas/fisiología , Inhibidores de Fosfodiesterasa/farmacología , Médula Espinal/fisiología , Sistema Nervioso Simpático/fisiología , Transmisión Sináptica/efectos de los fármacos , Animales , Catecolaminas/antagonistas & inhibidores , Catecolaminas/metabolismo , Gatos , Estado de Descerebración , Femenino , Ganglios/citología , Ganglios/fisiología , Masculino , Reflejo/efectos de los fármacos , Sistema Nervioso Simpático/citologíaRESUMEN
Two selective inhibitors of central epinephrine synthesis, LY 134046 and SKF 64139 (20 mg/kg, i.v.), gradually but markedly enhanced descending intraspinal transmission to sympathetic preganglionic neurons in spinal cats. Enhancement increased linearly to maximum values of 200% and 250%, respectively, at 4.5-5.5 h. Spinal sympathetic reflexes were not enhanced by either drug. The results support the proposal that bulbospinal epinephrine pathways depress the excitability of sympathetic preganglionic neurons by activating postsynaptic alpha 2-adrenergic receptors.
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Fibras Autónomas Preganglionares/efectos de los fármacos , Benzazepinas/farmacología , Epinefrina/antagonistas & inhibidores , Ganglios Simpáticos/efectos de los fármacos , Isoquinolinas/farmacología , Médula Espinal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Tetrahidroisoquinolinas , Fibras Adrenérgicas/efectos de los fármacos , Animales , Gatos , Relación Dosis-Respuesta a Droga , Potenciales Evocados/efectos de los fármacos , Norepinefrina/metabolismo , Feniletanolamina N-Metiltransferasa/antagonistas & inhibidores , Reflejo/efectos de los fármacosRESUMEN
Unilateral injection of 5,7-dihydroxytryptamine (DHT) into the rat neostriatum markedly reduced not only striatal tryptophan hydroxylase (TPH) activity but also striatal tyrosine hydroxylase (TH) activity and dopamine (DA) concentration measured 10--15 days later. The decrease in striatal TH activity was dose related over the range of 8--32 micrograms of DHT; a dose of 16 micrograms reduced striatal TH activity to 40--50% of control, DA concentration to 38% of control, and TPH activity to 5--20% of control. Intrastriatal injection of 16 micrograms of DHT reduced TH activity in the ipsilateral substantia nigra to 51% of control. Pretreatment with amfonelic acid, a potent DA uptake inhibitor, significantly reduced the effect of DHT on striatal and nigral TH activity and striatal DA concentration without affecting the DHT-induced decrease in striatal TPH activity. Desmethylimipramine (5 and 25 mg/kg) had no effect on the DHT-induced decrease in striatal TH activity. Striatal choline acetyltransferase and glutamic acid decarboxylase activities were not decreased by 16 micrograms of DHT. The results indicate that DHT can alter dopaminergic function in the rat neostriatum through a direct effect of the drug on DA neurons.
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5,7-Dihidroxitriptamina/farmacología , Núcleo Caudado/metabolismo , Dihidroxitriptaminas/farmacología , Dopamina/metabolismo , Putamen/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ácido Nalidíxico/análogos & derivados , Naftiridinas/farmacología , Ratas , Ratas Endogámicas , Factores de Tiempo , Triptófano Hidroxilasa/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Morphine, methadone, meperidine, fentanyl, and clonidine rapidly depressed transmission through sympathetic preganglionic neurons in cats with the spinal cord transected. Naloxone promptly antagonized this effect of the opiates but not that of clonidine which was reversed by alpha 2-adrenergic receptor antagonists. The independent depression of preganglionic neurons by clonidine may contribute to the ability of this drug to depress the symptoms of opiate withdrawal that are characterized by sympathetic hyperactivity.