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1.
Ann Palliat Med ; 9(2): 579-585, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32156130

RESUMO

Methadone has unique characteristics that make it an attractive agent for the treatment of chronic pain and opioid drug dependence. However, methadone prescription requires more clinical experience and close monitoring of patients to avoid its undesirable side effects. Recently, levorphanol has emerged as "a forgotten opioid" with a similar profile as methadone. Levorphanol has no impact on QTc prolongation and considerably less drug-drug interactions as compared to methadone. Lack of commercial availability, providers' unfamiliarity, and limited clinical data on its effectiveness remain practical issues. The objective of this article is to review and compare the safety considerations for methadone and levorphanol use.


Assuntos
Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Levorfanol/uso terapêutico , Metadona/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Analgésicos Opioides/efeitos adversos , Sistema Nervoso Central/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Levorfanol/efeitos adversos , Metadona/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/etiologia , Equivalência Terapêutica
3.
Integr Cancer Ther ; 19: 1534735419890017, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31906724

RESUMO

The purpose of this essay is to inform others that it is possible to survive breast cancer with brain metastases. The second author is the subject patient and a long-term survivor of systemic metastatic breast cancer with numerous brain metastases (corresponding to 8% survivor group). We credit her survival to a combination of (1) medicine as practiced by an excellent oncologist with whom we developed a partnership to manage the patient's health, (2) our informed exploration of the available scientific knowledge including a review of scientific research articles that go beyond conventional care, and (3) the patient's supplementation with numerous repurposed drugs and other substances reported to have antitumor properties. Alongside her conventional treatment (the medical standard of care), it seems likely that this supplementation has been a key factor in the patient's long-term survival. We also point out that the lack of follow-up magnetic resonance imaging brain scans for early detection of brain metastases poses substantial risks for patients with HER2+ metastatic breast cancer in non-central nervous system locations. Thus, we suggest that research be conducted on such early detection for possible inclusion in the recommendations for the medical standard of care. Finally, medical doctors and also patients with backgrounds in biological science may wish to consider potential options and advantages of repurposed drugs and other substances reported in scientific publications when the medical standard of care has limited options for advanced cancer and other severe chronic health conditions. However, any efforts along this line by patients should be in collaboration with their medical doctors.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/terapia , Carcinoma Ductal/terapia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Sobreviventes de Câncer , Carcinoma Ductal/patologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Induzidas por Radiação , Tomografia por Emissão de Pósitrons , Receptor ErbB-2 , Fatores de Tempo
4.
Eur J Med Chem ; 186: 111893, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761383

RESUMO

The pyrazolone structural motif is a critical element of drugs aimed at different biological end-points. Medicinal chemistry researches have synthesized drug-like pyrazolone candidates with several medicinal features including antimicrobial, antitumor, CNS (central nervous system) effect, anti-inflammatory activities and so on. Meanwhile, SAR (Structure-Activity Relationship) investigations have drawn attentions among medicinal chemists, along with a plenty of analogues have been derived for multiple targets. In this review, we comprehensively summarize the biological activity and SAR for pyrazolone analogues, wishing to give an overall retrospect and prospect on the pyrazolone derivatives.


Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Pirazolonas/farmacologia , Animais , Anti-Infecciosos/química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/química , Sistema Nervoso Central/efeitos dos fármacos , Química Farmacêutica , Humanos , Inflamação/tratamento farmacológico , Pirazolonas/química
5.
DNA Cell Biol ; 39(2): 197-209, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31880481

RESUMO

Propofol is a widely used intravenous agent for the induction and maintenance of anesthesia. An increasing number of studies have shown that propofol modulates autophagy, which is an evolutionarily conserved catabolic process that maintains cellular homeostasis by degrading long-lived proteins and damaged cellular proteins or organelles. Extensive studies have been performed to better understand the regulation of autophagy by propofol, the majority of which have demonstrated that the effects of propofol on autophagy are beneficial to organs and tissues. In this review, we retrospectively analyzed studies to assess the effects of propofol on autophagy in different diseases and evaluated the underlying mechanisms.


Assuntos
Autofagia/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Propofol/farmacologia , Animais , Autofagia/fisiologia , Sistema Nervoso Central/lesões , Humanos , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacos
6.
BMJ ; 367: l6459, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31818811

RESUMO

General anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates. The possibility of anesthetic induced neurotoxicity occurring in children has led to concerns about the safety of pediatric anesthesia. A spectrum of behavioral changes has been documented after general anesthetic exposure in young children, including emergence delirium, which may be evidence of toxicity. Most clinical studies are retrospective; specifics about medications or monitoring are unavailable and many of the outcomes may not be sensitive to detect small neurocognitive deficits. Some of these retrospective studies have shown an association between anesthesia exposure at a young age and neurocognitive deficits, but others have not. Practitioners and families should be reassured that although general anesthetics have the potential to induce neurotoxicity, very little clinical evidence exists to support this.


Assuntos
Anestesia Geral/efeitos adversos , Anestésicos/farmacologia , Sistema Nervoso Central , Transtornos do Neurodesenvolvimento/induzido quimicamente , Síndromes Neurotóxicas/etiologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/crescimento & desenvolvimento , Criança , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Lactente , Fatores de Risco
7.
Cancer Metastasis Rev ; 38(4): 657-671, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31820149

RESUMO

The cure rate of acute lymphoblastic leukemia (ALL), the commonest childhood cancer, has been sharply improved and reached almost 90% ever since the central nervous system (CNS)-directed therapy proposed in the 1960s. However, relapse, particularly in the central nervous system (CNS), is still a common cause of treatment failure. Up to now, the classic CNS-directed treatment for CNS leukemia (CNSL) has been aslant from cranial radiation to high-dose system chemotherapy plus intrathecal (IT) chemotherapy for the serious side effects of cranial radiation. The neurotoxic effects of chemotherapy and IT chemotherapy have been reported in recent years as well. For better prevention and treatment of CNSL, plenty of studies have tried to improve the detection sensitivity for CNSL and prevent CNSL from happening by targeting cytokines and chemokines which could be key factors for the traveling of ALL cells into the CNS. Other studies also have aimed to completely kill ALL cells (including dormant cells) in the CNS by promoting the entering of chemotherapy drugs into the CNS or targeting the components of the CNS niche which could be in favor of the survival of ALL cells in CNS. The aim of this review is to discuss the imperfection of current diagnostic methods and treatments for CNSL, as well as new attempts which could be significant for better elimination of CNSL.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/efeitos da radiação , Infiltração Leucêmica/tratamento farmacológico , Infiltração Leucêmica/radioterapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Sistema Nervoso Central/patologia , Criança , Irradiação Craniana , Humanos , Injeções Espinhais , Infiltração Leucêmica/diagnóstico , Infiltração Leucêmica/patologia
8.
Biomed Res Int ; 2019: 2728952, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886190

RESUMO

Objective: To analyse the short-term adverse effects (AEs) of propranolol in the treatment of infantile hemangiomas (IHs) and their relevant factors, as well as the relationship between child growth and propranolol. Methods: A total of 506 patients with confirmed or suspected IHs were enrolled, and a total of 439 cases were included in the study. Short-term AEs were analysed using single-factor analysis and binary logistic regression. Out of 439 patients, 292 were enrolled to examine the effect of propranolol on 2-year-olds' height and body weight (BW), by comparison with reference range and among groups. Spearman rank correlation analysis was used to determine the relationship between BW, height, and duration of propranolol treatment. Results: Among 439 patients, 70 (16.0%) experienced AEs. Among them, 48 had gastrointestinal (GI) symptoms, 23 had central nervous system (CNS) symptoms, 8 had both symptoms above, and 7 had other symptoms. Most of the AEs occurred on the starting day (day 0), and 6 children's AEs were transient. Starting age of no older than 3 months led to more CNS symptoms, and starting age of older than 3 months was a protective factor against CNS symptoms, with an OR value of 0.303 (0.117-0.783). Height and BW of 292 two-year-old children were no less than the reference levels, although those of 3 females and 1 male were less than the average -2 standard deviation (-2SD). The height and BW of the children at the age of two was not related to the length of time of propranolol treatment. Conclusion: Oral propranolol has a good tolerance in the treatment of IHs. Oral propranolol exerts more adverse effects on the CNS of lower age children, and it has exhibited no effect on the growth of two-year-old children.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Hemiplegia/tratamento farmacológico , Propranolol/administração & dosagem , Estatura/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/patologia , Hemiplegia/complicações , Hemiplegia/patologia , Humanos , Doença Iatrogênica/prevenção & controle , Lactente , Masculino , Propranolol/efeitos adversos , Resultado do Tratamento
9.
Eur J Med Chem ; 183: 111724, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563012

RESUMO

It is well-known that the health properties attributed to several fruits, herbs, seeds and their processed foods/beverages are due to an important group of natural polyphenols classified as hydrolysable tannins (HT) named ellagitannins (ETs), that encompass both one or more gallic acid (GA) units and one or more hexahydroxydiphenoic acid (HHDP) units, ester-connected with a sugar residue. In vivo, ETs are rather not absorbed and in gastrointestinal tract (GIT), they are hydrolysed providing mainly ellagic acid (EA). Due to its trivial water-solubility, first pass effect, metabolism in GIT, or irreversible binding to cellular DNA and proteins, EA has a very low bioavailability. Some authors are studying methods to increase EA water-solubility and thus to improve its bioavailability. At the same, EA metabolism to urolithins (UROs), whose concentration and activity is inter-individual and intra-individual dependent, is still under study and not completely elucidate. Numerous in vitro and in vivo studies have been carried out to define the molecular and cellular events underlying the beneficial effects that this compound and its metabolites exert in pathological conditions. The anti-inflammatory and the antioxidant properties of EA attracted the interest of researchers for its potential health benefits in humans, including anti-cancer, anti-diabetes activities and cardio-protection. Nevertheless, lately the attention paid to EA is focusing on its potential protective action towards several neurodegenerative disorders. Thus, EA is investigated as a potential "lead compound" endowed with multi-target pharmacological properties on CNS. Since the identification of the pharmacophore(s) responsible for both health benefits and collateral effects of this compound is crucial in drug discovery, this review aims to provide an all-round updated analysis of the literature concerning EA involvement in several CNS disorders, hoping that such information will be useful to researchers involved in multi-target drug design for CNS.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Descoberta de Drogas , Ácido Elágico , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Ácido Elágico/química , Ácido Elágico/farmacologia , Ácido Elágico/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico
10.
Food Chem Toxicol ; 133: 110802, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31493462

RESUMO

The aim of this study was to characterize the central effects of the Hyptis martiusii leaf essential oil (OEHM) and 1,8-cineole (eucalyptol) using behavioral animal models. Gas chromatography coupled to mass spectrometry (GC/MS) was used to characterize the chemical compounds present in the OEHM. For the behavioral tests, female Swiss mice treated with the OEHM (25, 50, 100 and 200 mg/kg, i.p.) and 1,8-cineole (50 mg/kg, i.p.) were used and subjected to the following tests: open field, elevated cross maze, rotarod, sodium pentobarbital- or ethyl ether-induced sleep time, pentylenetetrazol-induced convulsions, haloperidol-induced catalepsy, and ketamine-induced hyperkinesia. GC/MS analysis identified 20 constituents with the majority of them being monoterpenes and sesquiterpenes, with eucalyptol (1,8-cineol), the major sample compound (25.93%), standing out. The results showed the OEHM (25, 50 100 and 200 mg/kg, i.p.) and its major compound (50 mg/kg, i.p.) reduced animal motility in the open field test, increased pentobarbital- and ethyl ether-induced sleep time, as well as death latency in the pentylenetetrazole-induced convulsion model. However, the tested compounds were devoid of anxiolytic-like and myorelaxant activity. In addition, the OEHM (100 and 200 mg/kg, i.p.) and 1,8-cineole (50 mg/kg, i.p.) potentiated haloperidol-induced catalepsy and reduced ketamine-induced hyperkinesia. Taken together, the results suggest the OEHM has important hypnotic-sedative and antipsychotic-like effects, which appear to be due to the monoterpene 1,8-cineole, the major compound identified in the essential oil.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Eucaliptol/farmacologia , Hyptis/química , Óleos Voláteis/farmacologia , Animais , Eucaliptol/toxicidade , Feminino , Hipercinese/tratamento farmacológico , Ketamina , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Óleos Voláteis/toxicidade , Folhas de Planta/química , Sono/efeitos dos fármacos
11.
Pharmacol Rev ; 71(4): 520-538, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31530573

RESUMO

Chromosome conformation capture methods have revealed the dynamics of genome architecture which is spatially organized into topologically associated domains, with gene regulation mediated by enhancer-promoter pairs in chromatin space. New evidence shows that endogenous hormones and several xenobiotics act within circumscribed topological domains of the spatial genome, impacting subsets of the chromatin contacts of enhancer-gene promoter pairs in cis and trans Results from the National Institutes of Health-funded PsychENCODE project and the study of chromatin remodeling complexes have converged to provide a clearer understanding of the organization of the neurogenic epigenome in humans. Neuropsychiatric diseases, including schizophrenia, bipolar spectrum disorder, autism spectrum disorder, attention deficit hyperactivity disorder, and other neuropsychiatric disorders are significantly associated with mutations in neurogenic transcriptional networks. In this review, we have reanalyzed the results from publications of the PsychENCODE Consortium using pharmacoinformatics network analysis to better understand druggable targets that control neurogenic transcriptional networks. We found that valproic acid and other psychotropic drugs directly alter these networks, including chromatin remodeling complexes, transcription factors, and other epigenetic modifiers. We envision a new generation of CNS therapeutics targeted at neurogenic transcriptional control networks, including druggable parts of chromatin remodeling complexes and master transcription factor-controlled pharmacogenomic networks. This may provide a route to the modification of interconnected gene pathways impacted by disease in patients with neuropsychiatric and neurodegenerative disorders. Direct and indirect therapeutic strategies to modify the master regulators of neurogenic transcriptional control networks may ultimately help extend the life span of CNS neurons impacted by disease.


Assuntos
Redes Reguladoras de Genes/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiologia , Cromatina/efeitos dos fármacos , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética , Genoma Humano/efeitos dos fármacos , Humanos , Receptores de Neurotransmissores/agonistas , Receptores de Neurotransmissores/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
Eur J Med Chem ; 182: 111643, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31514017

RESUMO

Developing drugs for CNS related diseases continues to be one of the most challenging endeavors in drug discovery. This is at least in part related to the existence of the Blood Brain Barrier (BBB), a complex multicellular organization that provides selective access to required nutrients and hormones, while removing waste and restricting exposure to potential harmful toxins, pathogens, and xenobiotics. Consequently, designing and selecting molecules that can overcame this protection system are unique and critical aspects of the CNS drug discovery. Here we review modern CNS pharmacokinetic concepts and methods suitable for early drug discovery, and medicinal chemistry strategies towards molecules with optimal CNS exposure.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Descoberta de Drogas , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/química , Sistemas de Liberação de Medicamentos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
13.
Psychiatr Danub ; 31(Suppl 3): 530-533, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488786

RESUMO

Major depressive disorder (MDD) is a recurrent, incapacitating psychiatric illness which will be the second most disabling disease worldwide by the year 2020. There is a rising promise in a N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, which may be used in the treatment of resistant depression. Many of the studies are in favor of the drug, even in single dose application, with effects appearing in minutes to hours from administration. However, there is a need to evaluate the benefits and risks regarding psychomimetic, psychiatric, neurologic, and cognitive adverse effects of ketamine administration. The most distressing symptoms which appear most frequently during ketamine administration are dissociative symptoms, which can be quantified as a CNS adverse drug reaction. Results generally show that a single infusion of ketamine is efficacious and well-tolerated, while dissociative symptoms tend to abate within 2 hours after ketamine administration. As studies show single doses of ketamine should be definitely considered as an option in TRD patients with/without suicidal thoughts, even though it could not provide remission, or the effect could be temporary, but improving patients' quality of life by reducing depressive symptomatology should be a major asset while considering this particular procedure, particularly in inpatients.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Depressão/tratamento farmacológico , Humanos , Qualidade de Vida
14.
Int J Mol Sci ; 20(19)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554165

RESUMO

The increase in the incidence of neurodegenerative diseases, in particular Alzheimer's Disease (AD), is a consequence of the world's population aging but unfortunately, existing treatments are only effective at delaying some of the symptoms and for a limited time. Despite huge efforts by both academic researchers and pharmaceutical companies, no disease-modifying drugs have been brought to the market in the last decades. Recently, several studies shed light on Carbonic Anhydrases (CAs, EC 4.2.1.1) as possible new targets for AD treatment. In the present review we summarized preclinical and clinical findings regarding the role of CAs and their inhibitors/activators on cognition, aging and neurodegeneration and we discuss future challenges and opportunities in the field.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Anidrases Carbônicas/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Biomarcadores , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/genética , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo/efeitos dos fármacos
15.
Ecotoxicol Environ Saf ; 185: 109680, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31546204

RESUMO

The freshwater planarian mostly lives in the upper reaches of springs and rivers. Generally, it is realized as a suitable warning indicator of environmental toxicants. The freshwater planarian Dugesia japonica has a powerful regenerative capability and can regenerate a new individual including a complete central nervous system in one week. Rapamycin is an inhibitor of mammalian TORC1 (target of rapamycin complex-1) and used in the treatment of some diseases like cancer, cardiovascular and neurological diseases. However, the roles of rapamycin in the regulation of planarian regeneration remain to be elucidated. In present study, freshwater planarians D. japonica were firstly treated with 1 µM rapamycin for 18 h exposures and the expression patterns of Djtor was analyzed by the whole-mount in situ hybridization (WISH). Our results indicated rapamycin could strongly inhibit Djtor expression in planarian D. japonica and cause asymmetric blastemas and neuronal defects in planarians. Furthermore, knockdown of Djtor gene in planarians using RNA interference resulted in the suppression of downstream autophagy genes. These findings suggested that rapamycin might regulate freshwater planarian regeneration via Djtor signaling pathway.


Assuntos
Planárias/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Sirolimo/toxicidade , Serina-Treonina Quinases TOR/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Sistema Nervoso Central/efeitos dos fármacos , Neurônios , Planárias/genética , Planárias/crescimento & desenvolvimento , Planárias/metabolismo , Interferência de RNA , Regeneração/fisiologia , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
16.
Environ Res ; 177: 108641, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31421445

RESUMO

Lead (Pb) is a worldwide environmental contaminant that even at low levels influences brain development and affects neurobehavior later in life; nevertheless it is only a small fraction of the neurotoxicant (NT) exposome. Exposure to environmental Pb concurrent with other NT substances is often the norm, but their joint effects are challenging to study during early life. The aim of this review is to integrate studies of Pb-containing NT mixtures during the early life and neurodevelopment outcomes of children. The Pb-containing NT mixtures that have been most studied involve other metals (Mn, Al, Hg, Cd), metalloids (As), halogen (F), and organo-halogen pollutants. Co-occurring Pb-associated exposures during pregnancy and lactation depend on the environmental sources and the metabolism and half-life of the specific NT contaminant; but offspring neurobehavioral outcomes are also influenced by social stressors. Nevertheless, Pb-associated effects from prenatal exposure portend a continued burden on measurable neurodevelopment; they thus favor increased neurological health issues, decrements in neurobehavioral tests and reductions in the quality of life. Neurobehavioral test outcomes measured in the first 1000 days showed Pb-associated negative outcomes were frequently noticed in infants (<6 months). In older (preschool and school) children studies showed more variations in NT mixtures, children's age, and sensitivity and/or specificity of neurobehavioral tests; these variations and choice of statistical model (individual NT stressor or collective effect of mixture) may explain inconsistencies. Multiple exposures to NT mixtures in children diagnosed with 'autism spectrum disorders' (ASD) and 'attention deficit and hyperactivity disorders' (ADHD), strongly suggest a Pb-associated effect. Mixture potency (number or associated NT components and respective concentrations) and time (duration and developmental stage) of exposure often showed a measurable impact on neurodevelopment; however, net effects, reversibility and/or predictability of delays are insufficiently studied and need urgent attention. Nevertheless, neurodevelopment delays can be prevented and/or attenuated if public health policies are implemented to protect the unborn and the young child.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/toxicidade , Chumbo/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Feminino , Humanos , Lactente , Gravidez , Qualidade de Vida
17.
Regul Toxicol Pharmacol ; 107: 104421, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31299268

RESUMO

Acute central nervous system (CNS) depression is the most sensitive toxicological effect associated with aliphatic hydrocarbon exposure. No observed effect levels for the CNS effects of aliphatic constituents decrease with increasing carbon number to C10 (Lammers et al., 2011; McKee et al., 2011), whereas constituents with carbon numbers > C10 do not produce CNS effects at maximally attainable vapor concentrations (Nilsen et al., 1988). Accordingly, as n-decane appeared to be the "worst case" for acute CNS effects among aliphatic hydrocarbon solvent constituents, experimental studies were conducted to more precisely define the no effect level. Rats were exposed for 8 h to n-decane, either constantly at 3000 mg/m3 or at higher levels using a discontinuous exposure protocol to assess the influence of fluctuating exposures. Neurobehavioral testing methods including visual discrimination performance and motor activity were used to assess performance, and concentrations of n-decane in blood and brain were measured to obtain pharmacokinetic data. No statistically significant differences were observed in the neurobehavioral tests, establishing 3000 mg/m3 as the no effect level for CNS effects in rats. These data support the recommended guidance value of 1050 mg/m3 for C9-C15 aliphatic hydrocarbons for use in calculating occupational exposure levels for complex hydrocarbon solvents and provide empirical evidence that advice from the ACGIH® that within a working day there should be no more than 3 fluctuations, not longer than 15 min and not exceeding 3 times the Threshold Limit Value (TLV®), is reasonable for this group of substances.


Assuntos
Alcanos/toxicidade , Sistema Nervoso Central/efeitos dos fármacos , Solventes/toxicidade , Administração por Inalação , Alcanos/sangue , Alcanos/farmacocinética , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Solventes/farmacocinética , Níveis Máximos Permitidos
18.
Nutrients ; 11(7)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284389

RESUMO

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS). The etiology of this multifactorial disease has not been clearly defined. Conventional medical treatment of MS has progressed, but is still based on symptomatic treatment. One of the key factors in the pathogenesis of MS is oxidative stress, enhancing inflammation and neurodegeneration. In MS, both reactive oxygen and nitrogen species are formed in the CNS mainly by activated macrophages and microglia structures, which can lead to demyelination and axon disruption. The course of MS is associated with the secretion of many inflammatory and oxidative stress mediators, including cytokines (IL-1b, IL-6, IL-17, TNF-α, INF-γ) and chemokines (MIP-1a, MCP-1, IP10). The early stage of MS (RRMS) lasts about 10 years, and is dominated by inflammatory processes, whereas the chronic stage is associated with neurodegenerative axon and neuron loss. Since oxidative damage has been known to be involved in inflammatory and autoimmune-mediated processes, antioxidant therapy could contribute to the reduction or even prevention of the progression of MS. Further research is needed in order to establish new aims for novel treatment and provide possible benefits to MS patients. The present review examines the roles of oxidative stress and non-pharmacological anti-oxidative therapies in MS.


Assuntos
Antioxidantes/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/efeitos adversos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Esclerose Múltipla/dietoterapia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Estado Nutricional , Transdução de Sinais , Resultado do Tratamento
19.
Molecules ; 24(13)2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31277214

RESUMO

Ginseng is a group of cosmopolitan plants with more than a dozen species belonging to the genus Panax in the family Araliaceae that has a long history of use in traditional Chinese medicine (TCM). Among the bioactive constituents extracted from ginseng, ginseng saponins are a group of natural steroid glycosides and triterpene saponins found exclusively throughout the plant. Studies have shown that these ginseng saponins play a significant role in exerting multiple therapeutic effects. This review covers their chemical structure and classification, as well as their pharmacological activities, including their regulatory effects on immunomodulation, their anticancer effects, and their functions in the central nervous and cardiovascular systems. The general benefits of ginseng saponins for boosting physical vitality and improving quality of life are also discussed. The review concludes with fruitful directions for future research in the use of ginseng saponins as effective therapeutic agents.


Assuntos
Panax/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Saponinas/química , Saponinas/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Carboidratos/química , Sistema Nervoso Central/efeitos dos fármacos , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
20.
Expert Opin Pharmacother ; 20(16): 1961-1970, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31355689

RESUMO

Introduction: Given our improved understanding of the role of central sensitization (CS) in many patients with chronic pain, it seems rational to account for CS during treatment. Areas covered: First, the treatment rationale based on the complex mechanisms underlying CS in patients having chronic pain is presented. Second, emphasis is given to explaining the concept of CS when providing treatment, as well as why patients and clinicians should focus on long-term rather than short-term treatment effects. Third, possible pharmacological and non-pharmacological treatment options are discussed. Expert opinion: Centrally acting drugs such as tricyclic compounds, serotonin-norepinephrine reuptake inhibitors, and α2δ ligands each target mechanisms that are often dysfunctional in patients having chronic pain and CS, but decades of clinical practice and clinical trials have not resulted in satisfactory outcomes. This comes as no surprise; CS comprises complex psycho-neuro-immunological interactions, while each of the tested drugs targets one or two of those mechanisms from a purely biomedical viewpoint. Clinicians willing to take CS into account should design an individually tailored multimodal treatment plan comprising pain neuroscience education, cognition-targeted exercise therapy, sleep management, stress management, and/or dietary intervention.


Assuntos
Dor Crônica/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Dor Crônica/metabolismo , Dor Crônica/patologia , Humanos , Inibidores de Captação de Serotonina/farmacologia
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