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1.
BMC Psychiatry ; 21(1): 204, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888067

RESUMO

BACKGROUND: The purpose of this study was to evaluate the post-marketing safety and effectiveness of aripiprazole in treating irritability in pediatric patients (6-17 years) with autism spectrum disorder (ASD) in actual clinical sites of Japan. METHODS: In this post-marketing surveillance, patients were enrolled into the multicenter, prospective, non-interventional, observational study for 52 weeks, and were dosed with aripiprazole (1-15 mg/day) under daily clinical settings in Japan. RESULTS: In 510 patients, the continuation rate of aripiprazole treatment was 84.6% at day 168 (week 24) and 78.1% at day 364 (week 52). Adverse drug reactions (ADRs) occurred in 22.7% of patients (n = 116), and the most common ADRs were somnolence (9.4%), followed by weight increased (3.3%). At week 4, the mean change from baseline in the irritability subscale score for the Aberrant Behavior Checklist Japanese version (ABC-J) was - 5.7 ± 6.8 (n = 288). Based on multiple regression analysis, comorbid attention deficit and hyperactivity did not affect the ABC-J irritability subscale score at endpoint. At week 24, the mean change from baseline for the Strengths and Difficulties Questionnaire was - 3.3 ± 4.9 (n = 215) for the total difficulties score and 0.6 ± 1.7 (n = 217) for the prosocial behavior subscale score. CONCLUSIONS: Aripiprazole was well tolerated and effective in the long-term treatment of irritability associated with ASD in Japanese pediatric patients in the real-world clinical practice. TRIAL REGISTRATION: This surveillance was registered with Clinical Trial.gov (no. NCT03179787 ) on June 7, 2017 (retrospectively registered).


Assuntos
Antipsicóticos , Transtorno do Espectro Autista , Adolescente , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Transtorno do Espectro Autista/tratamento farmacológico , Criança , Humanos , Humor Irritável , Japão , Marketing , Vigilância de Produtos Comercializados , Estudos Prospectivos , Resultado do Tratamento
2.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669336

RESUMO

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Encéfalo/metabolismo , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Asseio Animal/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Ansiedade/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas dos Receptores de Dopamina D2/metabolismo , Células HEK293 , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Ligantes , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Receptores Histamínicos H3/metabolismo
3.
Cochrane Database Syst Rev ; 2: CD013457, 2021 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-33583058

RESUMO

BACKGROUND: Symptoms of autism spectrum disorder (ASD) have been associated, in part, with the dysfunction of N-methyl-D-aspartate (NMDA) glutamate receptors at excitatory synapses and glutamate abnormalities. Medications related to glutamatergic neurotransmission, such as D-cycloserine - which is a partial agonist of the NMDA glutamate receptor - are potential treatment options for the core features of ASD. However, the potential effect of D-cycloserine on the social and communication skills deficits of individuals with ASD has not been thoroughly explored and no systematic reviews of the evidence have been conducted. OBJECTIVES: To assess the efficacy and adverse effects of D-cycloserine compared with placebo for social and communication skills in individuals with ASD. SEARCH METHODS: In November 2020, we searched CENTRAL, MEDLINE, Embase, six other databases and two trials registers. We also searched the reference lists of relevant publications and contacted the authors of the included study, Minshawi 2016, to identify any additional studies. In addition, we contacted pharmaceutical companies, searched manufacturers' websites and sources of reports of adverse events.  SELECTION CRITERIA: All randomised controlled trials (RCTs) of any duration and dose of D-cycloserine, with or without adjunct treatment, compared to placebo in individuals with ASD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted relevant data, assessed the risk of bias, graded the certainty of the evidence using the GRADE approach, and analysed and evaluated the data. We provide a narrative report of the findings as only one study is included in this review. MAIN RESULTS: We included a single RCT (Minshawi 2016) funded by the United States Department of Defense. It was conducted at two sites in the USA: Indiana University School of Medicine and Cincinnati Children's Hospital Medical Centre. In the included study, 67 children with ASD aged between 5 and 11 years were randomised to receive either 10 weeks (10 doses) of (50 mg) D-cycloserine plus social skills training, or placebo plus social skills training. Randomisation was carried out 1:1 between D-cycloserine and placebo arms, and outcome measures were recorded at one-week post-treatment. The 'risk of bias' assessment for the included study was low for five domains and unclear for two domains. The study (67 participants) reported low certainty evidence of little to no difference between the two groups for all outcomes measured at one week post-treatment: social interaction impairment (mean difference (MD) 3.61 (assessed with the Social Responsiveness Scale), 95% confidence interval (CI) -5.60 to 12.82); social communication impairment (MD -1.08 (measured using the inappropriate speech subscale of the Aberrant Behavior Checklist (ABC)), 95% CI -2.34 to 0.18); restricted, repetitive, stereotyped patterns of behaviour (MD 0.12 (measured by the ABC stereotypy subscale), 95% CI -1.71 to 1.95); serious adverse events (risk ratio (RR) 1.11, 95% CI 0.94 to 1.31); non-core symptoms of ASD (RR 0.97 (measured by the Clinical Global Impression-Improvement scale), 95% CI 0.49 to 1.93); and tolerability of D-cycloserine (RR 0.32 (assessed by the number of dropouts), 95% CI 0.01 to 7.68).  AUTHORS' CONCLUSIONS: We are unable to conclude with certainty whether D-cycloserine is effective for individuals with ASD. This review included low certainty data from only one study with methodological issues and imprecision. The added value of this review compared to the included study is we assessed the risk of bias and evaluated the certainty of evidence using the GRADE approach. Moreover, if we find new trials in future updates of this review, we could potentially pool the data, which may either strengthen or decrease the evidence for our findings.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Comunicação , Ciclosserina/uso terapêutico , Habilidades Sociais , Criança , Pré-Escolar , Ciclosserina/efeitos adversos , Feminino , Humanos , Indiana , Masculino , Estudos Multicêntricos como Assunto , Ohio , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Comportamento Estereotipado/efeitos dos fármacos
4.
Health Qual Life Outcomes ; 19(1): 33, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33494757

RESUMO

BACKGROUND: The net health benefit of using antipsychotics in children and adolescents with ASD is unclear. This review was performed to provide the evidence necessary to inform the Italian national guidelines for the management of ASD. METHODS: We performed a systematic review of randomized controlled trials (RCTs) comparing antipsychotics versus placebo for the treatment of ASD in children and adolescents. For efficacy, acceptability and safety we considered outcomes evaluated by the guideline panel critical and important for decision-making. Continuous outcomes were analyzed by using standardized mean difference (SMD), and dichotomous outcomes by calculating the risk ratio (RR), with their 95% confidence interval (95% CI). Data were analyzed using a random effects model. We used the Cochrane tool to assess risk of bias of included studies. Certainty in the evidence of effects was assessed according to the GRADE approach. RESULTS: We included 21 RCTs with 1,309 participants, comparing antipsychotics to placebo. Antipsychotics were found effective on "restricted and repetitive interests and behaviors" (SMD - 0.21, 95% CI - 0.35 to - 0.07, moderate certainty), "hyperactivity, inattention, oppositional, disruptive behavior" (SMD - 0.67, 95% CI - 0.92 to - 0.42, moderate certainty), "social communication, social interaction" (SMD - 0.38, 95% CI - 0.59 to - 0.16, moderate certainty), "emotional dysregulation/irritability" (SMD - 0.71, 95% CI - 0.98 to - 0.43, low certainty), "global functioning, global improvement" (SMD - 0.64, 95% CI - 0.96 to - 0.33, low certainty), "obsessions, compulsions" (SMD - 0.30, 95% CI - 0.55 to - 0.06, moderate certainty). Antipsychotics were not effective on "self-harm" (SMD - 0.14, 95% CI - 0.58 to 0.30, very low certainty), "anxiety" (SMD - 0.38, 95% CI - 0.82 to 0.07, very low certainty). Antipsychotics were more acceptable in terms of dropout due to any cause (RR 0.61, 95% CI 0.48 to 0.78, moderate certainty), but were less safe in terms of patients experiencing adverse events (RR 1.19, 95% CI 1.07 to 1.32, moderate certainty), and serious adverse events (RR 1.07, 95% CI 0.48 to 2.43, low certainty). CONCLUSIONS: Our systematic review and meta-analysis found antipsychotics for children and adolescents with ASD more efficacious than placebo in reducing stereotypies, hyperactivity, irritability and obsessions, compulsions, and in increasing social communication and global functioning. Antipsychotics were also found to be more acceptable, but less safe than placebo.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Qualidade de Vida/psicologia , Adolescente , Antipsicóticos/efeitos adversos , Transtornos de Ansiedade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Humanos
5.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333772

RESUMO

Neuroinflammation is a physiological response aimed at maintaining the homodynamic balance and providing the body with the fundamental resource of adaptation to endogenous and exogenous stimuli. Although the response is initiated with protective purposes, the effect may be detrimental when not regulated. The physiological control of neuroinflammation is mainly achieved via regulatory mechanisms performed by particular cells of the immune system intimately associated with or within the nervous system and named "non-neuronal cells." In particular, mast cells (within the central nervous system and in the periphery) and microglia (at spinal and supraspinal level) are involved in this control, through a close functional relationship between them and neurons (either centrally, spinal, or peripherally located). Accordingly, neuroinflammation becomes a worsening factor in many disorders whenever the non-neuronal cell supervision is inadequate. It has been shown that the regulation of non-neuronal cells-and therefore the control of neuroinflammation-depends on the local "on demand" synthesis of the endogenous lipid amide Palmitoylethanolamide and related endocannabinoids. When the balance between synthesis and degradation of this bioactive lipid mediator is disrupted in favor of reduced synthesis and/or increased degradation, the behavior of non-neuronal cells may not be appropriately regulated and neuroinflammation exceeds the physiological boundaries. In these conditions, it has been demonstrated that the increase of endogenous Palmitoylethanolamide-either by decreasing its degradation or exogenous administration-is able to keep neuroinflammation within its physiological limits. In this review the large number of studies on the benefits derived from oral administration of micronized and highly bioavailable forms of Palmitoylethanolamide is discussed, with special reference to neuroinflammatory disorders.


Assuntos
Amidas/administração & dosagem , Amidas/metabolismo , Etanolaminas/administração & dosagem , Etanolaminas/metabolismo , Inflamação/dietoterapia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Ácidos Palmíticos/administração & dosagem , Ácidos Palmíticos/metabolismo , Doença de Alzheimer/dietoterapia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Esclerose Amiotrófica Lateral/dietoterapia , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/metabolismo , Animais , Transtorno do Espectro Autista/dietoterapia , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Endocanabinoides/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Redes e Vias Metabólicas , Esclerose Múltipla/dietoterapia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Doenças do Sistema Nervoso/dietoterapia , Doenças do Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/dietoterapia , Doenças Neurodegenerativas/metabolismo , Dor/dietoterapia , Dor/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo
6.
Sci Rep ; 10(1): 22173, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335150

RESUMO

Autism spectrum disorder (ASD) is a continuum of neurodevelopmental disorders and needs new therapeutic approaches. Recently, oxytocin (OXT) showed potential as the first anti-ASD drug. Many reports have described the efficacy of intranasal OXT therapy to improve the core symptoms of patients with ASD; however, the underlying neurobiological mechanism remains unknown. The OXT/oxytocin receptor (OXTR) system, through the lateral septum (LS), contributes to social behavior, which is disrupted in ASD. Therefore, we selectively express hM3Dq in OXTR-expressing (OXTR+) neurons in the LS to investigate this effect in ASD mouse models developed by environmental and genetic cues. In mice that received valproic acid (environmental cue), we demonstrated successful recovery of impaired social memory with three-chamber test after OXTR+ neuron activation in the LS. Application of a similar strategy to Nl3R451C knock-in mice (genetic cue) also caused successful recovery of impaired social memory in single field test. OXTR+ neurons in the LS, which are activated by social stimuli, are projected to the CA1 region of the hippocampus. This study identified a candidate mechanism for improving core symptoms of ASD by artificial activation of DREADDs, as a simulation of OXT administration to activate OXTR+ neurons in the LS.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Expressão Gênica , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de Ocitocina/genética , Septo do Cérebro/metabolismo , Comportamento Social , Animais , Ansiedade , Transtorno do Espectro Autista/tratamento farmacológico , Comportamento Animal , Modelos Animais de Doenças , Imunofluorescência , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Células Piramidais/metabolismo , Receptores de Ocitocina/antagonistas & inibidores
7.
Pediatrics ; 146(5)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33093139

RESUMO

Autism spectrum disorder (ASD) is the most common disability-causing neurodevelopmental disorder in childhood. Although inborn errors of metabolism (IEM) are rare causes of ASD, they are significant for several reasons, including implications in genetic counseling and determination of prognosis. In this article, we present a 6-year-old boy who presented to us with ASD and was diagnosed with creatine transporter deficiency. Physical and neurologic examination of this patient had not previously raised suspicion of IEM, but twin pregnancy, prematurity, NICU stay due to necrotizing enterocolitis, transient infantile hypotonia, gross-motor delay, breath-holding spells, and a single febrile seizure complicated the history. MRI revealed mild T2-hyperintensity in posterior periventricular white matter. Further evaluation with magnetic resonance spectroscopy, which showed a decreased creatine peak, led to diagnostic investigations for disorders of creatine metabolism, revealing increased urinary creatine:creatinine ratio and a de novo, novel hemizygous frameshift variant in SLC6A8 Clinicians are advised to maintain a high index of suspicion for IEM and to evaluate patients with ASD for syndromic features. Although current guidelines from relevant organizations differ in their recommendations regarding the necessity and the extent of metabolic screening in ASD, there is a growing trend toward screening for treatable IEM. In this case report, we present challenges and pitfalls in the diagnostic journey for creatine transporter deficiency and underline the significance of a thorough history and physical examination in the evaluation of a child with ASD.


Assuntos
Transtorno do Espectro Autista/genética , Encefalopatias Metabólicas Congênitas/genética , Creatina/deficiência , Doenças em Gêmeos/genética , Mutação da Fase de Leitura , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Criança , Creatina/genética , Creatinina/metabolismo , Doenças em Gêmeos/diagnóstico , Doenças em Gêmeos/tratamento farmacológico , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Espectroscopia de Prótons por Ressonância Magnética
8.
Paediatr Drugs ; 22(5): 473-483, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32686015

RESUMO

Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition affecting an estimated one in 36 children. Youth with ASD may have severe behavioral disturbances including irritability, aggression, and hyperactivity. Currently, there are only two medications (risperidone and aripiprazole) approved by the US Food and Drug Administration (FDA) for the treatment of irritability associated with ASD. Pharmacologic treatments are commonly used to target ASD-associated symptoms including irritability, mood lability, anxiety, and hyperactivity. However, evidence for the efficacy of many commonly used treatments is limited by the lack of large placebo-controlled trials of these medications in this population. Research into the pathophysiology of ASD has led to new targets for pharmacologic therapy including the neuroimmune system, the endocannabinoid system, and the glutamatergic neurotransmitter system. The goal of this review is to provide an overview of the current evidence base for commonly used treatments, as well as emerging treatment options for common behavioral disturbances seen in youth with ASD.


Assuntos
Comportamento do Adolescente/efeitos dos fármacos , Antipsicóticos/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Comportamento Infantil/efeitos dos fármacos , Adolescente , Agressão/efeitos dos fármacos , Ansiedade/tratamento farmacológico , Transtorno do Espectro Autista/psicologia , Criança , Humanos , Hipercinese/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Transtornos do Sono-Vigília/tratamento farmacológico
9.
Curr Top Behav Neurosci ; 45: 167-208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468495

RESUMO

Abnormalities of cholinergic nuclei, cholinergic projections, and cholinergic receptors, as well as abnormalities of growth factors involved in the maturation and maintenance of cholinergic neurons, have been described in postmortem brains of persons with autism spectrum disorder (ASD). Further, microdeletions of the 15q13.3 locus that encompasses CHRNA7, the gene coding the α7 nicotinic acetylcholine receptor (α7 nAChR), are associated with a spectrum of neurodevelopmental disorders, including ASD. The heterozygous 15q13.3 microdeletion syndrome suggests that diminished or impaired transduction of the acetylcholine (ACh) signal by the α7 nAChR can be a pathogenic mechanism of ASD. The α7 nAChR has a role in regulating the firing and function of parvalbumin (PV)-expressing GABAergic projections, which synchronize the oscillatory output of assemblies of pyramidal neurons onto which they project. Synchronous oscillatory output is an electrophysiological substrate for higher executive functions, such as working memory, and functional connectivity between discrete anatomic areas of the brain. The α7 nAChR regulates PV expression and works cooperatively with the co-expressed NMDA receptor in subpopulations of GABAergic interneurons in mouse models of ASD. An evolving literature supports therapeutic exploration of selectively targeted cholinergic interventions for the treatment of ASD, especially compounds that target the α7 nAChR subtype. Importantly, development and availability of high-affinity, brain-penetrable, α7 nAChR-selective agonists, partial agonists, allosteric agonists, and positive allosteric modulators (PAMs) should facilitate "proof-of-principle/concept" clinical trials. nAChRs are pentameric allosteric proteins that function as ligand-gated ion channel receptors constructed from five constituent polypeptide subunits, all of which share a common structural motif. Importantly, in addition to α7 nAChR-gated Ca2+ conductance causing membrane depolarization, there are emerging data consistent with possible metabotropic functions of this ionotropic receptor. The ability of α7-selective type II PAMs to "destabilize" the desensitized state and promote ion channel opening may afford them therapeutic advantages over orthosteric agonists. The current chapter reviews historic and recent literature supporting selective therapeutic targeting of the α7 nAChR in persons affected with ASD.


Assuntos
Transtorno do Espectro Autista , Transtornos Cromossômicos , Receptores Nicotínicos , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Humanos , Camundongos , Agonistas Nicotínicos , Convulsões , Receptor Nicotínico de Acetilcolina alfa7
10.
Sci Rep ; 10(1): 5822, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242086

RESUMO

Autism Spectrum Disorder (ASD) is one of the most common neurodevelopmental disorders with no drugs treating the core symptoms and no validated biomarkers for clinical use. The multi-functional phytochemical sulforaphane affects many of the biochemical abnormalities associated with ASD. We investigated potential molecular markers from three ASD-associated physiological pathways that can be affected by sulforaphane: redox metabolism/oxidative stress; heat shock response; and immune dysregulation/inflammation, in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with ASD. We first analyzed the mRNA levels of selected molecular markers in response to sulforaphane ex vivo treatment in PBMCs from healthy donors by real-time quantitative PCR. All of the tested markers showed quantifiability, accuracy and reproducibility. We then compared the expression levels of those markers in PBMCs taken from ASD patients in response to orally-delivered sulforaphane. The mRNA levels of cytoprotective enzymes (NQO1, HO-1, AKR1C1), and heat shock proteins (HSP27 and HSP70), increased. Conversely, mRNA levels of pro-inflammatory markers (IL-6, IL-1ß, COX-2 and TNF-α) decreased. Individually none is sufficiently specific or sensitive, but when grouped by function as two panels, these biomarkers show promise for monitoring pharmacodynamic responses to sulforaphane in both healthy and autistic humans, and providing guidance for biomedical interventions.


Assuntos
Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/tratamento farmacológico , Isotiocianatos/uso terapêutico , Leucócitos Mononucleares/metabolismo , Transtorno do Espectro Autista/metabolismo , Células Cultivadas , Criança , Citocinas/sangue , Citocinas/metabolismo , Humanos , Inflamação/sangue , Inflamação/metabolismo , Leucócitos/metabolismo , Masculino
11.
Health Qual Life Outcomes ; 18(1): 101, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32299432

RESUMO

INTRODUCTION: Some recent randomized controlled trials (RCTs) assessed the efficacy and safety of polyunsaturated fatty acids (PUFAs) for the treatment of autism spectrum disorder (ASD). To optimally inform the Italian guideline for the management of ASD in children and adolescents, we reviewed the impact on equity, acceptability and feasibility for developing a pilot recommendation for PUFAs. METHODS: We performed a rapid systematic review of observational and experimental studies on PUFAs for children and adolescents with ASD, extracting data on resources required, equity, acceptability, and feasibility of PUFAs. We followed the framework provided by the grading of recommendations assessment, development and evaluation (GRADE) methodology, and we assessed risk of bias and methodological quality of included studies. Results were synthesized both narratively and quantitatively to address clinically relevant questions on equity, acceptability, and feasibility. RESULTS: We found 14 papers related to equity. PUFAs did not seem to impact equity importantly. We did not find variation in effectiveness across subgroups and in a base case scenario, the cost of a 12 weeks cycle of therapy with 1.155 g/day of PUFAs was €65.51 euro. The acceptability of PUFAs was evaluated in 17 studies, 9 of which were RCTs. PUFAs were widely used among children and adolescents with ASD (18 to 51%), and 50% of parents considered nutritional supplementation as useful. Difficulty in swallowing capsules and bad taste were identified as possible causes of poor compliance, but treatment adherence, when measured in included RCTs, was judged to be good to excellent. Discontinuation due to any cause for PUFAs could not differ from placebo (low certainty of evidence). The feasibility of using PUFAs was assessed in 12 studies. PUFAs were probably sustainable, and no particular critical issue emerged from the feasibility assessment. However, the evidence appeared scarce and indirect. CONCLUSIONS: We found the administration of PUFAs in children and adolescents with ASD to be potentially equitable, acceptable and feasible. These results are limited by the limited number and quality of retrieved documents, and need to be viewed in light of efficacy and safety data to formulate clinical recommendations.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Ácidos Graxos Insaturados/uso terapêutico , Adolescente , Criança , Ácidos Graxos Insaturados/economia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Psychiatry Res ; 287: 112900, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32179209

RESUMO

Autism spectrum disorder (ASD) is characterized by impaired social communication and restricted repetitive behaviors and interests. There are no FDA-approved medications for these core symptoms, and there are limited data regarding pharmacological management of ASD in adults. Here, the literature was reviewed in an effort to develop an algorithm for pharmacological management of core symptoms of ASD in adults. The literature search was conducted using PubMed. It was very difficult to distil a plausible algorithm from these data. Not included in this review are behavioral strategies, which are first-line. For instances when medication is being considered for management of core ASD symptoms in adults, the authors suggest starting with fluvoxamine as first-line, with possible consideration of a second SSRI trial if there is an inadequate or no response to fluvoxamine. The next step, if there is comorbid irritability, is to consider a second-generation antipsychotic. If there is no comorbid irritability, in the final step of the tentative algorithm, there are possible augmenting agents: propranolol, memantine, d-cycloserine, and oxytocin. Management of the symptoms of ASD requires a comprehensive treatment approach, and treatment planning must be individualized. Treatment of core ASD symptoms is not always desired. Further studies are needed to develop a stronger evidence base to support pharmacological management of core symptoms.


Assuntos
Algoritmos , Antipsicóticos/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Avaliação de Sintomas/métodos , Adulto , Transtorno do Espectro Autista/psicologia , Regras de Decisão Clínica , Comorbidade , Feminino , Fluvoxamina/uso terapêutico , Humanos , Humor Irritável/efeitos dos fármacos , Masculino , Psicofarmacologia
13.
BMC Psychiatry ; 20(1): 121, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164636

RESUMO

BACKGROUND: This paper is a systematic review and meta-analysis of the efficacy of available medications for the treatment of restricted/repetitive behavior (RRBs) in Autism Spectrum Disorder (ASD). METHOD: We searched MEDLINE, Embase, PsycINFO, The Cochrane Library (Cochrane Database of Systematic Reviews (CDRS), the Cochrane Central Register of Controlled Trials (CENTRAL), database of Abstracts of Reviews of Effects (DARE)), Scopus, Epistimonikos, Clinicaltrials.gov, and included all randomized controlled trials published after 1993 that were directed at RRBs in patients with ASD of all ages. We extracted the relevant data from the published studies with a predefined data extraction form and assessed the risk of bias. The primary outcomes were change in restricted/repetitive behavior. We performed a meta-analysis using the random effect model and included studies with given mean and standard deviation. This study is registered with PROSPERO number CRD42018092660). RESULTS: We identified 14 randomized controlled trials that met initial inclusion criteria. After closer inspection, nine trials - involving 552 patients in total - were included in the final analysis. The meta-analysis found no significant difference between medications (including fluvoxamine, risperidone, fluoxetine, citalopram, oxytocin, N-Acetylcysteine, buspirone) and placebo in the treatment of RRBs in ASD (P = 0.20). Similarly, the sub-group meta-analysis also showed no significant difference between Selective Serotonin Reuptake Inhibitor (SSRIs) and placebo in the treatment of RRBs in ASD (P = 0.68). There was no evidence of publication bias. CONCLUSION: This meta-analysis finds little support for the routine use of medications to treat restricted/repetitive behaviors in Autism Spectrum Disorder. Further research of large, balanced trials with precise assessment tools and long-term follow-up are needed. TRIAL REGISTRATION: The study protocol is registered in PROSPERO (Reference number: CRD42018092660).


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/psicologia , Comportamento/efeitos dos fármacos , Humanos , Inibidores de Captação de Serotonina/uso terapêutico
14.
Health Qual Life Outcomes ; 18(1): 28, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066439

RESUMO

BACKGROUND: Recent randomized controlled trials (RCTs) claimed PUFAs to be effective for autism spectrum disorder (ASD) but international guidelines have not considered yet this body of evidence. Our aim was to assess the effectiveness of PUFAs in children and adolescents with ASD, for the Italian national guidelines on the management of ASD in children and adolescents. METHODS: We performed a systematic review and meta-analysis of RCTs comparing PUFAs versus placebo or a healthy diet for the treatment of ASD in children and adolescents. The outcomes considered were deemed by the guideline panel to be highly relevant to children and adolescents with ASD and to their caregivers. The outcomes included hyperactivity, quality of sleep, self-harm, aggression, irritability, anxiety, attention, adaptive functioning, social interaction, restricted and repetitive interests and behavior, communication, hyperactivity and disruptive behaviors coexistent with core symptoms. The risk of bias of the included studies was assessed with the Cochrane tool, and the rating of the confidence in the effect estimates according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included 9 studies with 405 participants. The strength of evidence ranged from low to very low. Six studies included preschoolers and school-age children, three studies included both children and adolescents. The majority of participants were males (83.8%), with a mean age of 6.7 years. PUFAs were superior compared to placebo in reducing anxiety in individuals with ASD (SMD -1.01, 95% CI - 1.86 to - 0.17; very low certainty of evidence). Moreover, PUFAs worsened quality of sleep compared to a healthy diet (SMD 1.11, 95% CI 0.21 to 2.00; very low certainty of evidence). PUFAs were not better than placebo in reducing aggression, hyperactivity, adaptive functioning, irritability, restricted and repetitive interests and behaviors and communication. Effects on some critical outcomes such as sleep, self-harm and disruptive behavior are currently unknown. The main limitations were the small number of participants included in the RCTs and the dosage which varied greatly (from 200 mg/day to 1540 mg/day), making it difficult to address causal inference. CONCLUSIONS: PUFAs did not show evidence of effect in children and adolescents with ASD and the certainty of evidence as measured with the GRADE was low to very low. Further research is needed on this topic because the available evidence is inconclusive.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Ácidos Graxos Insaturados/administração & dosagem , Transtorno do Espectro Autista/complicações , Criança , Dieta Saudável , Feminino , Humanos , Masculino , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
15.
Neurology ; 94(9): 392-404, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32051244

RESUMO

OBJECTIVE: To review pharmacologic and nonpharmacologic strategies for treating sleep disturbances in children and adolescents with autism spectrum disorder (ASD) and to develop recommendations for addressing sleep disturbance in this population. METHODS: The guideline panel followed the American Academy of Neurology 2011 guideline development process, as amended. The systematic review included studies through December 2017. Recommendations were based on evidence, related evidence, principles of care, and inferences. MAJOR RECOMMENDATIONS LEVEL B: For children and adolescents with ASD and sleep disturbance, clinicians should assess for medications and coexisting conditions that could contribute to the sleep disturbance and should address identified issues. Clinicians should counsel parents regarding strategies for improved sleep habits with behavioral strategies as a first-line treatment approach for sleep disturbance either alone or in combination with pharmacologic or nutraceutical approaches. Clinicians should offer melatonin if behavioral strategies have not been helpful and contributing coexisting conditions and use of concomitant medications have been addressed, starting with a low dose. Clinicians should recommend using pharmaceutical-grade melatonin if available. Clinicians should counsel children, adolescents, and parents regarding potential adverse effects of melatonin use and the lack of long-term safety data. Clinicians should counsel that there is currently no evidence to support the routine use of weighted blankets or specialized mattress technology for improving disrupted sleep. If asked about weighted blankets, clinicians should counsel that the trial reported no serious adverse events with blanket use and that blankets could be a reasonable nonpharmacologic approach for some individuals.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/terapia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/terapia , Adolescente , Transtorno do Espectro Autista/complicações , Criança , Humanos , Distúrbios do Início e da Manutenção do Sono/complicações
16.
Adv Neurobiol ; 24: 601-614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32006376

RESUMO

Autism is a complex neurodevelopmental disorder that is evident in early childhood and can persist throughout the entire life. The disease is basically characterized by hurdles in social interaction where the individuals demonstrate repetitive and stereotyped interests or patterns of behavior. A wide number of neuroanatomical studies with autistic patients revealed alterations in brain development which lead to diverse cellular and anatomical processes including atypical neurogenesis, neuronal migration, maturation, differentiation, and degeneration. Special education programs, speech and language therapy, have been employed for the amelioration of behavioral deficits in autism. Although commonly prescribed antidepressants, antipsychotics, anticonvulsants, and stimulants have revealed satisfactory responses in autistic individuals, adverse side effects and increased risk of several other complications including obesity, dyslipidemia, diabetes mellitus, thyroid disorders, etc. have compelled the researchers to turn their attention toward herbal remedies. Alternative approaches with natural compounds are on continuous clinical trial to confirm their efficacy and to understand their potential in autism treatment. This chapter aims to cover the major plant-based natural products which hold promising outcomes in the field of reliable therapeutic interventions for autism.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Medicina Herbária , Fitoterapia , Transtorno Autístico/tratamento farmacológico , Humanos
17.
Adv Neurobiol ; 24: 661-678, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32006379

RESUMO

Autism spectrum disorder (ASD) is a developmental disorder that influences communication and behavior. Numerous researches propose that genes can act together with manipulations from the environment to affect development in ways that lead to ASD. The broad range of issues facing people with ASD means that there is no single proper drug and treatment for ASD. Numerous shortcomings associated with the present conventional therapeutic strategies have forced researchers to venture into alternative natural sources for effective compounds. The marine environment has emerged as an alternate search environment due to its versatile conditions where organisms employ various biodefense mechanisms for their survival. Ascidians are an excellent source for unique bioactive compounds with nutritive and therapeutic content and it still holds credit for being an underused source from marine animals. Bioactive compounds isolated from ascidians have various commendable biomedical applications due to their unique chemical structures. The present chapter will focus on the potential of bioactive compounds derived from ascidians for the treatment of the neurologic disorder-ASD.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Urocordados/química , Animais , Humanos
18.
Curr Pharm Biotechnol ; 21(7): 555-565, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31914909

RESUMO

BACKGROUND: Probiotics and their nutrient sources (prebiotics) have been shown to have positive effects on different organs of the host. The idea of their potential benefits on Central Nervous Systems (CNS) and the incidence of Anxiety, Schizophrenia, Alzheimer, Depression, Autism, and other mental disorders has proposed a new category of medicines called "psychobiotic" which is hoped to be of low-side effect anti-inflammatory, antidepressant, and anti-anxiety constitutes. OBJECTIVE: In the current review, we present valuable insights into the complicated interactions between the GI microbiota (especially in the colon), brain, immune and central nervous systems and provide a summary of the main findings of the effects of pro- and prebiotics on important mental disorders from the potential mechanisms of action to their application in clinical practice. METHODS: Google Scholar, Pub Med, Scopus, and Science Direct databases were searched using following key words: "probiotics", "prebiotics", "mental disorders", "psychological disorders", "depression", "anxiety", "stress", "Alzheimer" and "autism spectrum". The full text of potentially eligible studies was retrieved and assessed in detail by the reviewers. Data were extracted and then summarized from the selected papers. RESULTS: The results of the provided evidence suggest that probiotic and prebiotics might improve mental function via several mechanisms. The beneficial effects of their application in Depression, Anxiety, Alzheimer and autism spectrum diseases have also been supported in clinical studies. CONCLUSION: Pro and prebiotics can improve mental health and psychological function and can be offered as new medicines for common mental disorders, however, more clinical studies are necessary to conduct regarding the clinical significance of the effects and their bioequivalence or superiority against current treatments.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Transtorno do Espectro Autista/tratamento farmacológico , Depressão/tratamento farmacológico , Prebióticos , Probióticos/uso terapêutico , Doença de Alzheimer/microbiologia , Ansiedade/microbiologia , Transtorno do Espectro Autista/microbiologia , Depressão/microbiologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Humanos , Saúde Mental , Microbiota/efeitos dos fármacos
19.
J Med Chem ; 63(4): 1511-1525, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31951127

RESUMO

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Benzodiazepinas/uso terapêutico , Piridinas/uso terapêutico , Receptores de Vasopressinas/metabolismo , Triazóis/uso terapêutico , Adolescente , Adulto , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Transtorno do Espectro Autista/metabolismo , Benzodiazepinas/síntese química , Benzodiazepinas/farmacocinética , Encéfalo/metabolismo , Criança , Ensaios Clínicos como Assunto , Descoberta de Drogas , Feminino , Humanos , Masculino , Mamíferos , Piridinas/síntese química , Piridinas/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética
20.
Pediatr Emerg Care ; 36(2): e96-e98, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31929391

RESUMO

Radiopaque densities can be observed on imaging after the ingestion of either foreign bodies or some medications. Our case report discusses an 11-year-old boy with autism spectrum disorder and attention deficient disorder who presented to the emergency department because of concerns for constipation and dehydration. Incidentally, an abdominal x-ray showed numerous radiopaque densities throughout his intestines in addition to his constipation. He was admitted, and his home regimen was reviewed to attempt to identify a potential source for these radiopaque densities. This case presented an interesting teaching opportunity in the identification of the radiopaque densities and review of pharmacokinetics.


Assuntos
Abdome/diagnóstico por imagem , Bezoares/diagnóstico por imagem , Corpos Estranhos/diagnóstico por imagem , Fumarato de Quetiapina/efeitos adversos , Abdome/patologia , Dor Abdominal/diagnóstico por imagem , Dor Abdominal/etiologia , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/tratamento farmacológico , Bezoares/complicações , Criança , Constipação Intestinal/complicações , Diagnóstico Diferencial , Corpos Estranhos/complicações , Humanos , Dimesilato de Lisdexanfetamina/efeitos adversos , Dimesilato de Lisdexanfetamina/uso terapêutico , Masculino , Fumarato de Quetiapina/uso terapêutico , Radiografia Abdominal , Tomografia Computadorizada por Raios X
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