RESUMO
Background: Psychostimulants (methylphenidate and amphetamines) are considered first-line therapy for attention-deficit/hyperactivity disorder (ADHD). Lisdexamfetamine dimesylate (LDX) is a new psychostimulant approved for the treatment of ADHD in Brazil. The pharmacologically active fraction, d-amphetamine, is gradually released by hydrolysis of the LDX prodrug. Objectives: To perform a systematic review of the literature of the efficacy and safety of LDX in the treatment of ADHD in children and adolescents. Methods: Medline/PubMed searches for d-amfetamine, lisdexamfetamine and lisdexamfetamine dimesylate were conducted including articles available from January 2000 to November 2013. Additional references were identified using references listed in those articles. Further data on LDX were requested from its manufacturer. Results: Thirty-one papers were found related to ADHD treatment in children and adolescents. Discussion: The therapeutic benefits of LDX in children with ADHD are achieved as early as 1.5 hours after its administration and last for up to 13 hours, with efficacy comparable or superior to that of other available psychostimulants. The literature also reports efficacy in long-term treatment, with safety and tolerability profiles comparable to those of other stimulants used for the treatment of ADHD. Most of the adverse events associated with LDX are considered to be mild or moderate in severity, with the most common being loss of appetite and insomnia...
Contexto: Psicoestimulantes (metilfenidato e anfetaminas) são considerados como tratamento farmacológico de primeira linha no tratamento do transtorno do déficit de atenção e hiperatividade (TDAH). O dimesilato de anfetamina é um novo psicoestimulante aprovado para uso no Brasil, cuja fração farmacologicamente ativa, a d-anfetamina, é gradualmente liberada por hidrólise da pró-droga. Objetivos Realizar uma revisão sistemática de literatura sobre eficácia e segurança da LDX no tratamento de TDAH de crianças e adolescentes. Métodos: Busca na base Medline/PubMed com os termos d-amfetamine, lisdexamfetamine e lisdexamfetamine dimesilate, de janeiro de 2000 até novembro de 2013. Referências adicionais foram retiradas das referências dos artigos obtidos; dados também foram obtidos do fabricante. Resultados: Trinta e um artigos foram encontrados, relacionados ao tratamento de TDAH em crianças e adolescentes. Conclusões: Os benefícios terapêuticos da LDX são obtidos em até 1,5 hora após administração e se estendem até 13 horas, com eficácia comparável ou superior à dos demais psicoestimulantes disponíveis. A literatura também documenta eficácia em longo prazo, com perfis de segurança e tolerabilidade comparáveis aos dos demais estimulantes usados no tratamento do TDAH. A maioria dos eventos adversos associados à LDX é considerada leve ou moderada quanto à gravidade, sendo os eventos mais comuns perda de apetite e insônia...
Assuntos
Humanos , Criança , Adolescente , Dextroanfetamina/efeitos adversos , Dextroanfetamina/farmacocinética , Eficácia , Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso CentralRESUMO
Adverse experiences early in life may have profound influences on brain development, for example, determining alterations in response to psychostimulant drugs, an increased risk of developing a substance abuse disorder, and individual differences in the vulnerability to neuropsychiatric disorders later in life. Here, we investigated the effects of exposure to an early adverse life event, maternal deprivation, combined with repeated d-amphetamine (AMPH) administration in adulthood, on recognition memory and brain-derived neurotrophic factor (BDNF) levels in rats' brain and serum. Rats were exposed to one of the following maternal rearing conditions from postnatal days 1 to 14: non-deprived (ND) or deprived (D). In adulthood, both groups received injections of saline (SAL) or AMPH (2.0mg/kg, i.p.) for 7 days. In Experiment I (performed 24h after the last AMPH injection), AMPH induced long-term memory (LTM) impairments in ND and D groups. The D+AMPH group also presented short-term memory (STM) impairments, indicating that the effects of AMPH on memory were more pronounced when the animals where maternally deprived. The group exposed to D+SAL (SAL) showed only LTM impairments. In Experiment II (performed 8 days after the last injection), AMPH detrimental effects on memory persisted in ND and D groups. BDNF levels were decreased in the hippocampus of D+SAL rats. In conclusion, AMPH produces severe and persistent recognition memory impairments that were more pronounced when the animals were maternally deprived, suggesting that an early adverse life event may increase the vulnerability of cognitive function to exposure to a psychostimulant later in life.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Dextroanfetamina/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/patologia , Análise de Variância , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Feminino , Masculino , Privação Materna , Gravidez , Ratos , Fatores de TempoRESUMO
BACKGROUND: Acute mania can be modeled in animals using D-amphetamine (AMPH). Acute AMPH injections are associated with monoamine depletion, loss of neurofilaments and neurite degeneration. However, the precise mechanisms underlying AMPH-induced neurotoxicity are still unclear. Several studies have demonstrated that oxidative stress may play a role in the behavioral and neurochemical changes observed after AMPH administration. METHODS: The effects of a single and repeated injections (seven daily injections) of AMPH administered intraperitonially on locomotion and the production of lipid and protein oxidative markers in rat cortex, striatum and hippocampus were assessed. Locomotion was assessed in an open-field task and markers of oxidative stress were assessed in brain tissue. RESULTS: Both single and repeated injections of AMPH increased protein carbonyl formation in rat brain. Repeated exposure to AMPH induced an additional increase in thiobarbituric acid reactive species in brain tissue. CONCLUSIONS: Longer periods of exposure to AMPH were associated with increased oxidative stress in rat brain. This adds to the notion that repeated manic episodes may be associated with greater brain damage and, therefore, poorer outcomes.
Assuntos
Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/fisiopatologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Dextroanfetamina/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Dextroanfetamina/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Injeções Intraperitoneais , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
RATIONALE: Flunarizine is known as a calcium channel blocker commonly used in many countries to treat migraine and vertigo. Parkinsonism has been described as one of its side-effects in the elderly, which is in agreement with its recently characterized moderate D2 receptor antagonism. OBJECTIVES: To perform a pre-clinical evaluation of flunarizine as a potential antipsychotic. METHODS: We evaluated the action of orally administered flunarizine in mice against hyperlocomotion induced by amphetamine and dizocilpine (MK-801) as pharmacological models of schizophrenia, induction of catalepsy as a measure for extrapyramidal symptoms and impairment induced by dizocilpine on the delayed alternation task for working memory. RESULTS: Flunarizine robustly inhibited hyperlocomotion induced by both amphetamine and dizocilpine at doses that do not reduce spontaneous locomotion (3-30 mg/kg). Mild catalepsy was observed at 30 mg/kg, being more pronounced at 50 mg/kg and 100 mg/kg. Flunarizine (30 mg/kg) improved dizocilpine-induced impairment on the delayed alternation test. CONCLUSIONS: These results suggest a profile comparable to atypical antipsychotics. The low cost, good tolerability and long half-life (over 2 weeks) of flunarizine are possible advantages for its use as an atypical antipsychotic. These results warrant clinical trials with flunarizine for the treatment of schizophrenia.
Assuntos
Modelos Animais de Doenças , Flunarizina/farmacocinética , Administração Oral , Animais , Catalepsia/induzido quimicamente , Dextroanfetamina/administração & dosagem , Dextroanfetamina/efeitos adversos , Dextroanfetamina/antagonistas & inibidores , Maleato de Dizocilpina/administração & dosagem , Maleato de Dizocilpina/efeitos adversos , Maleato de Dizocilpina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Flunarizina/administração & dosagem , Flunarizina/efeitos adversos , Haloperidol/administração & dosagem , Haloperidol/efeitos adversos , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Receptores de N-Metil-D-Aspartato/administração & dosagem , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/química , Fatores de TempoRESUMO
BACKGROUND: This study examines the effects of long-term continuous exposure to light on dopaminergic supersensitivity induced by repeated treatment with haloperidol in rats. METHODS: Spontaneous general activity in an open-field (SGA) and stereotyped behavior induced by apomorphine (SB-APO) or amphetamine (SB-AMP) were used as experimental parameters. Rats were allocated to four groups in each experiment: saline-treated animals kept under a 12-hour light/dark cycle (LD) or 24-hour light/light cycle (LL), and 2 mg/kg haloperidol-treated animals kept under the above cycles. Plasma corticosterone concentration was also measured by radioimmunoassay in saline-treated rats kept under a LD or LL cycle. RESULTS: All the behavioral parameters used showed the development of central dopaminergic supersensitivity in rats kept under both cycles. Continuous exposure to light enhanced SGA and SB-AMP in both saline- and haloperidol-treated rats, but did not modify SB-APO. Animals kept under the LL cycle presented an increased plasma corticosterone concentration. CONCLUSIONS: Our results suggest that continuous exposure to light leads to an increase in dopaminergic function in both normal and "supersensitive" rats. This effect seems to be mediated by a presynaptic mechanism possibly involving corticosterone actions.
Assuntos
Antipsicóticos/efeitos adversos , Apomorfina/efeitos adversos , Dextroanfetamina/efeitos adversos , Dopaminérgicos/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Haloperidol/efeitos adversos , Luz/efeitos adversos , Transtorno de Movimento Estereotipado/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Corticosterona/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptores Pré-Sinápticos/metabolismo , Fatores de TempoRESUMO
Se analizaron 84 pacientes con las manifestaciones clínicas características del DAHI (Déficit Atencional con Hiperactividad y Excesiva Impulsividad) en un estudio de observación longitudinal a partir de 1983 hasta 1994 en el sector norte de Santiago. Se decidió incluir en el estudio a los pacientes referidos a la clínica ambulatoria de Neurología del Hospital Roberto del Río, durante el mencionado período, desde los Consultorios de Atención Primaria. En casi todos los casos se empleó dextroanfetamina (en casos justificados se empleó metilfenidato), que era entregada a los pacientes si asistían a los controles periódicamente, observándose un adecuado efecto terapéutico, con efectos adversos en pocos casos y sin evidencias de dependencia o aumento de tolerancia. A pesar de ser pacientes complicados desde el punto de vista biológico, económico y social, el plan terapeútico fue satisfactorio en términos generales, siendo los resultados más efectivos y consistentes en quienes la sintomatología del déficit atencional no se acompañaba de alteraciones conductuales, fueron menos favorables cuando hubo manifestaciones de disfunción cerebral orgánica y más problemáticos en la medida que habían evidencias de disfunción psicosocial en el entorno familiar. Los resultados sugieren que la dextroanfetamina puede ser considerada como favorable en una alta proporción de casos independientemente de las condiciones biológicas y del desarrollo psicomotor, pero fueron fundamentales la continuidad y adherencia al plan terapeútico, tanto el manejo ambiental y al uso adecuado del fármaco por parte del paciente y de la familia