RESUMO
BACKGROUND: There are few approved therapies for adults with attention-deficit/hyperactivity disorder (ADHD) in Europe. Lisdexamfetamine (LDX) is an effective treatment for ADHD; however, no clinical trials examining the efficacy of LDX specifically in European adults have been conducted. Therefore, to estimate the efficacy of LDX in European adults we performed a meta-regression of existing clinical data. METHODS: A systematic review identified US- and Europe-based randomized efficacy trials of LDX, atomoxetine (ATX), or osmotic-release oral system methylphenidate (OROS-MPH) in children/adolescents and adults. A meta-regression model was then fitted to the published/calculated effect sizes (Cohen's d) using medication, geographical location, and age group as predictors. The LDX effect size in European adults was extrapolated from the fitted model. Sensitivity analyses performed included using adult-only studies and adding studies with placebo designs other than a standard pill-placebo design. RESULTS: Twenty-two of 2832 identified articles met inclusion criteria. The model-estimated effect size of LDX for European adults was 1.070 (95% confidence interval: 0.738, 1.401), larger than the 0.8 threshold for large effect sizes. The overall model fit was adequate (80%) and stable in the sensitivity analyses. CONCLUSION: This model predicts that LDX may have a large treatment effect size in European adults with ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Dimesilato de Lisdexanfetamina/administração & dosagem , Adulto , Atenção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Europa (Continente) , Feminino , Seguimentos , Humanos , Masculino , Metilfenidato/administração & dosagem , Análise de Regressão , Resultado do TratamentoAssuntos
Hipocampo/fisiologia , Sinapses/fisiologia , Doença de Alzheimer/fisiopatologia , Animais , Axônios/fisiologia , Comportamento Animal/fisiologia , Encéfalo/fisiologia , Sobrevivência Celular , Eletrofisiologia , Sistema Límbico/citologia , Sistema Límbico/fisiologia , Regeneração Nervosa , Neurônios/fisiologia , Receptores Purinérgicos P1/fisiologia , RoedoresRESUMO
The perforant path is the major excitatory cortical projection to the hippocampal dentate gyrus. Field potentials from the medial perforant path exhibit paired-pulse depression when evoked at interstimulus intervals of 40 to 800 msec. We found that an early component of paired-pulse depression recorded at interstimulus intervals of 40 to 100 msec from slices of rat hippocampus was reduced by L-2-amino-4-phosphonobutanoic acid (L-AP4) (20 microM) without a change in the size of the first field potential in the pair. Paired-pulse depression evoked at intervals of 200 to 800 msec was not reduced. 1S,3R-1-Aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), DL-2-amino-3-phosphonopropionic acid and carbachol also reduced paired-pulse depression in a manner similar to L-AP4. Picrotoxin, phaclofen, theophylline or atropine did not reduce paired-pulse depression. Furthermore, paired-pulse depression (40-100 msec) does not appear to involve glutamate uptake or N-methyl-D-aspartate receptors as L-alpha-aminoadipate did not alter paired-pulse depression and neither trans-L-pyrrolidine-2,4-dicarboxylate and L-alpha-aminoadipate nor D-2-amino-5-phosphonopropionic acid blocked the effect of L-AP4 on paired-pulse depression. 4-Aminopyridine inhibits a potassium current that has a similar time course to the L-AP4-induced reduction of paired-pulse depression, however, paired-pulse depression was increased with exposure to 4-aminopyridine. These results indicate that the mechanism underlying paired-pulse depression consists of two components, the early component being reduced by L-AP4, 1S,3R-ACPD, DL-2-amino-3-phosphonopropionic acid and carbachol.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Aminobutiratos/farmacologia , Cicloleucina/análogos & derivados , Hipocampo/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Animais , Atropina/farmacologia , Baclofeno/análogos & derivados , Baclofeno/farmacologia , Carbacol/farmacologia , Cicloleucina/farmacologia , Depressão Química , Glutamatos/metabolismo , Ácido Glutâmico , Hipocampo/anatomia & histologia , Hipocampo/fisiologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Vias Neurais/fisiologia , Inibidores da Captação de Neurotransmissores/farmacologia , Picrotoxina/farmacologia , Canais de Potássio/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Teofilina/farmacologiaRESUMO
The molecular layer of the dentate gyrus exhibits extensive circuit and receptor reorganization after entorhinal lesions and in Alzheimer's disease, including decreased adenosine (A1) receptor binding in the terminal zone of damaged perforant path fibers. We examined the adenosine-sensitivity of evoked synaptic activity recorded from the rat dentate gyrus molecular layer in hippocampal slices prepared after electrolytic lesions were placed in approximately the middle third of the entorhinal cortex. Extracellular field potentials (EFPs) recorded in slices prepared from animals two days post-lesion were small, upward-going, and exhibited paired-pulse potentiation, but by two weeks post-lesion EFPs had recovered to large, downward-going responses that exhibited paired-pulsed depression. EFPs recorded from two week post-lesion slices were about 2-fold more sensitive (P < or = 0.05) to exposure to adenosine when compared to EFPs recorded from slices from unlesioned animals. Adenosine-induced reduction of paired-pulse depression was similar between unlesioned and post-lesion slices. AChE histochemistry performed after recording revealed dense staining in the dentate gyrus molecular layer of post-lesion slices as compared to slices from unlesioned animals, confirming that sprouting of cholinergic fibers occurred as expected from previous entorhinal lesion studies. Autoradiography performed on adjacent slices showed a decrease in binding to A1-adenosine receptors in the dentate gyrus molecular layer in post-lesion slices as compared to slices from unlesioned animals, indicating that there was a loss of presynaptically located A1-adenosine receptors on damaged perforant pathway terminals. These results indicate that, in addition to the recovery of the major excitatory signal to the hippocampus after entorhinal cell loss, this signal is more sensitive to modulation by adenosine, suggesting an increase in A1-adenosine receptor efficacy in the reinnervated region.
Assuntos
Adenosina/farmacologia , Córtex Cerebral/fisiologia , Hipocampo/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Autorradiografia , Denervação , Eletrofisiologia , Potenciais Evocados/fisiologia , Espaço Extracelular/fisiologia , Hipocampo/metabolismo , Histocitoquímica , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos/efeitos dos fármacos , Receptores Purinérgicos/fisiologia , Sinapses/fisiologia , Xantinas/farmacologiaRESUMO
Paired-pulse potentiation of the glutamate-mediated excitatory postsynaptic potential (EPSP) recorded in the dentate gyrus molecular layer is thought to be mediated presynaptically. It is known that the activation of adenosine (A1) and GABAB receptors results in the reduction of glutamate release in the dentate molecular layer via presynaptic mechanisms. To examine possible modulatory roles of these receptors on paired-pulse potentiation, we examined the effects of adenosine and baclofen (a GABAB agonist) on paired-pulse potentiation using extracellular recording from the lateral perforant path in rat hippocampal slices maintained in vitro. We compared these effects with those of L-alpha-amino-4-phosphonobutyric acid (L-AP4) over a wide range of interstimulus intervals (ISIs). L-AP4 enhanced paired-pulse potentiation over the full range of ISIs tested (40-800 ms), whereas adenosine enhanced paired-pulse potentiation only at ISIs of 40-100 ms. In contrast, baclofen reduced paired-pulse potentiation only at ISIs of 400-800 ms. Furthermore, baclofen increased the amplitude of lateral perforant path field potentials, previously reported to be baclofen-insensitive. These results suggest that paired-pulse potentiation can be modulated through the activation of adenosine and baclofen receptors, indicate that this modulation is dependent on ISI, and show that there are at least two pharmacologically separable components of paired-pulse potentiation in the dentate gyrus.
Assuntos
Adenosina/farmacologia , Aminobutiratos/farmacologia , Baclofeno/farmacologia , Hipocampo/fisiologia , Animais , Cálcio/fisiologia , Dendritos/fisiologia , Estimulação Elétrica , Potenciais Evocados/efeitos dos fármacos , Glutamatos/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Junção Neuromuscular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Receptores Purinérgicos/efeitos dos fármacos , Receptores Purinérgicos/fisiologia , Estimulação Química , Sinapses/fisiologiaRESUMO
Research over the past 15 years has led to a comprehensive description of the processes of axonal sprouting and synaptic reorganization in the hippocampus. Previous studies on axonal sprouting have now been supplemented with recent studies on excitatory amino acid receptor plasticity. These and related studies pave the way to research strategies which detail the molecular mechanisms of the sprouting response. The re-expression of the fetal form of alpha-tubulin mRNA in rat after entorhinal lesions was found to be similar to the re-expression of the human fetal form of alpha-tubulin in Alzheimer's brain. This result suggests that the sprouting process may involve a reactivation of certain developmental mechanisms and that this may possibly contribute to the etiology of Alzheimer's disease.
Assuntos
Doença de Alzheimer/fisiopatologia , Axônios/fisiologia , Encéfalo/fisiologia , Regeneração Nervosa , Doença de Alzheimer/patologia , Animais , Encéfalo/citologia , Encéfalo/fisiopatologia , Humanos , RatosRESUMO
Excitatory amino acids and their receptors play an important role in both normal synaptic transmission and excitotoxic-mediated neuronal death. In the present investigation we have prepared a series of glutamate analogs and examined the pharmacological specificity with which they interact with excitatory amino acid receptors. Included within this group of compounds is a potent excitotoxic amino acid, beta-N-oxalyl-L-alpha, beta-diaminopropionic acid (beta-L-ODAP). This excitotoxin is of particular interest because it has been identified as a major causative agent of human neurolathyrism, a disease characterized by permanent spastic paralysis. The site of action of beta-L-ODAP was delineated with both electrophysiological recordings in hippocampal slices and radioligand binding assays in synaptic plasma membranes. We report that beta-L-ODAP is a potent agonist at the non-N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor. beta-L-ODAP interacts most potently with the quisqualate class of non-NMDA receptors (IC50 = 1.3 microM), less potently with the kainate receptor (IC50 = 17 microM), and very weakly with NMDA receptors. The specificity of this binding was consistent with physiological experiments that demonstrated that beta-L-ODAP-induced depolarizations were potently blocked by the newly identified non-NMDA receptor antagonist, CNQX, but were not affected by the NMDA antagonist D-AP5. These results extend recent studies that have focused on the contribution of NMDA receptors to excitotoxicity and highlight the potential involvement of non-NMDA receptors in excitotoxic-mediated cell death.
Assuntos
Diamino Aminoácidos/farmacologia , Receptores de Superfície Celular/fisiologia , Diamino Aminoácidos/metabolismo , Animais , Eletrofisiologia , Ácido Ibotênico/análogos & derivados , Ácido Ibotênico/antagonistas & inibidores , Ácido Ibotênico/metabolismo , Ácido Caínico/metabolismo , Masculino , Oxidiazóis/metabolismo , Ácido Quisquálico , Ratos , Ratos Endogâmicos , Receptores de Aminoácido , Receptores de Superfície Celular/metabolismo , Relação Estrutura-Atividade , Membranas Sinápticas/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiônicoRESUMO
The effects of applications of carbachol on evoked synaptic responses recorded in the dentate gyrus of guinea pig hippocampal slices were examined. Carbachol depressed potentials recorded extracellularly in the medial perforant path terminal zone, but did not significantly alter field potentials recorded in the lateral perforant path terminal zone. Carbachol-induced depression was reversed by applications of the muscarinic antagonists, atropine or pirenzepine. It was suggested that the difference observed in carbachol-induced depression of medial versus lateral perforant path field potentials may be due to regional differences in acetylcholine receptor distribution in the molecular layer of the dentate gyrus.