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1.
Behav Neurosci ; 135(5): 591-600, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34582222

RESUMO

The effects of methylphenidate (MPH), atomoxetine (ATMX), and/or physical exercise (EX) on orienting behavior and social interaction were examined in spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). During the orienting procedure, rats received repeated presentations of a nonreinforced visual stimulus. As observed previously, orienting behavior (rearing up on the hind legs) habituated across trials in normo-active control rats (Wistars) but not in SHRs, suggesting that SHRs have difficulty ignoring irrelevant behavioral stimuli. Treatment with MPH (0.125 mg/kg), ATMX (0.125 mg/kg), or EX (3 weeks of access to a running wheel), alone or in combination, reduced rearing behavior in SHRs to the level observed in the Wistar control group. Similarly, drug treatment and/or EX reduced the number of social interactions exhibited by SHRs, while having no effects on locomotor activity. It is important to note that EX was just as effective as MPH or ATMX in reducing orienting behavior and social interaction. In contrast to the SHRs, neither MPH nor ATMX affected orienting or social behavior in Wistar rats. Together, these findings support the growing literature that EX may be useful as an adjunctive or replacement therapy in ADHD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Catecolaminas/uso terapêutico , Modelos Animais de Doenças , Ratos , Ratos Wistar , Interação Social
4.
Orphanet J Rare Dis ; 16(1): 380, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496899

RESUMO

BACKGROUND: Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Often, patients with SMS are diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations. METHODS AND ANALYSIS: We will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged ≥ 6 years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level. CONCLUSIONS: This study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care. TRIAL REGISTRATION: This study is registered in the Netherlands Trial Register (NTR9125).


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Síndrome de Smith-Magenis , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estimulantes do Sistema Nervoso Central/uso terapêutico , Método Duplo-Cego , Humanos , Metilfenidato/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome de Smith-Magenis/tratamento farmacológico , Resultado do Tratamento
5.
Postepy Biochem ; 67(2): 141-156, 2021 06 30.
Artigo em Polonês | MEDLINE | ID: mdl-34378894

RESUMO

The article describes different groups of psychoactive substances, which are chemical compounds that alter perception. Based on their main effect on the psyche they were classified into four subclasses: stimulants, empathogens, hallucinogens and depressants., Molecular mechanisms of action of different drugs of abuse were described, together with their social and economic issues in Poland and Europe.


Assuntos
Estimulantes do Sistema Nervoso Central , Alucinógenos , Europa (Continente) , Alucinógenos/farmacologia , Humanos , Polônia
6.
BMC Psychiatry ; 21(1): 405, 2021 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-34391396

RESUMO

BACKGROUND: The study aim was to examine the secular trends and regional variations in pharmacotherapy of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in Germany. METHODS: We used nationwide drug prescription data of outpatient care (2009 to 2016). The study population comprised patients aged between 5 and 14 years with the diagnoses "hyperkinetic disorders" (ICD-10 code F90) (e.g. n = 262,766 in 2016). The examined drugs were methylphenidate, amphetamines, atomoxetine and guanfacine. RESULTS: Overall, the proportion of patients received any prescription showed a decreasing trend over years (2010, 51%; 2016, 44%). The proportion of methylphenidate prescription was higher in Western than Eastern federal states. However, atomoxetine was more often prescribed in Eastern than Western federal states. The proportion of methylphenidate prescriptions issued by pediatric psychiatrists increased from 28% (2009) to 41% (2016). CONCLUSION: A decreasing trend in use of pharmacotherapy may be explained by prescription restrictions issued by the Federal Joint Committee in recent years.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Adolescente , Cloridrato de Atomoxetina/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Pré-Escolar , Alemanha , Humanos , Metilfenidato/uso terapêutico
7.
S D Med ; 74(8): 372-375, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34461003

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a commonly encountered diagnosis in the child and adolescent populations, and stimulant medications are often prescribed for their treatment. There are numerous available options in this category, including immediate and extended release formulations. There have been many case reports in the literature involving purposeful overdose on immediate release stimulants, but a relative paucity involving extended release forms. Additionally, they often involve Caucasian and Asian populations. We treated a Native American adolescent who took an overdose of extended-release methylphenidate with the intention of suicide. He developed transient orofacial dyskinesia and upper extremity choreoathetosis as a result which did not abate during his time in the emergency department. Once transferred to our care, he was given a one-time benzodiazepine dose with some benefit. This case report describes objective sequelae of a long-acting methylphenidate overdose as well as treatment for the benefit of treating clinicians with similar patient populations and situations.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Discinesias , Metilfenidato , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Criança , Discinesias/tratamento farmacológico , Humanos , Masculino , Metilfenidato/efeitos adversos , Extremidade Superior
8.
Expert Opin Drug Metab Toxicol ; 17(9): 1125-1138, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34410209

RESUMO

INTRODUCTION: Catha edulis (Vahl) Forssk. ex Endl. (Celestraceae) is used as a recreational drug on daily basis for its euphoric and psychostimulant effects. It is also chewed by individuals who are on medications, raising the possibility of drug-khat interaction. However, limited data are available in the literature, although clinically significant interactions are expected, as khat contains a complex mixture of pharmacologically active constituents. AREAS COVERED: It provides an overview of the phytochemistry, pharmacokinetics, pharmacodynamics, and pharmacogenetics of khat based on the literature mined from PubMed, Google Scholar, and Cochrane databases. It also presents a detailed account of drug-khat interactions with specific examples and their clinical significance. The interactions mainly occur at the pharmacokinetics level and particular attention is paid for the phases of absorption and cytochrome P450 enzyme-mediated metabolism. EXPERT OPINION: Despite the increasing trend of khat chewing with medications among the populace and the potential risk for the occurrence of clinically significant interactions, there is paucity of data in the literature demonstrating the magnitude of the risk. The available data, however, clearly demonstrate that the consequence of drug-khat interaction is dependent on genotype. Genotyping, where feasible, could be used to improve clinical outcome and minimize adverse reactions.


Assuntos
Catha/química , Interações Ervas-Drogas , Extratos Vegetais/farmacologia , Estimulantes do Sistema Nervoso Central/isolamento & purificação , Estimulantes do Sistema Nervoso Central/farmacologia , Genótipo , Humanos , Farmacogenética , Farmacocinética
9.
BMJ Open ; 11(8): e048528, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389573

RESUMO

OBJECTIVE: To assess the 5-year changes in the adult medical use of central nervous system (CNS) stimulants with higher risk of dependence and evaluate the population characteristics of users and their medical and/or neurological conditions. DESIGN: Cross-sectional study. SETTING: Annual US Medical Expenditure Panel Survey, a stratified random sample of approximately 30 000 persons designed to produce national population estimates. It focuses on reported medical spending, medical services used, health status and prescription medications. PARTICIPANTS: Adults age 19 years and older who reported obtaining one or more prescriptions for amphetamine or methylphenidate products during two survey years, 2013 and 2018. MAIN OUTCOMES MEASURES: Prescriptions obtained, the specific stimulant product and annual treatment days of drug supplied. RESULTS: In 2018, an estimated 4.1 million US adults (95% CI 3.4 million to 4.8 million) reported prescriptions for CNS stimulants, having filled a mean of 7.3 (95% CI 6.8 to 7.8) prescriptions with a mean of 226 (95% CI 210 to 242) days' supply. Compared with 2013, the estimated number of adults reporting using CNS stimulants in 2018 increased by 1.8 million (95% CI 1.0 million to 2.7 million) or 79.8%. Most 2018 adult stimulant users reported taking psychoactive medication for one or more mental, behavioural or neurodevelopment disorders. Overall, 77.8% (95% CI 72.6% to 83.0%) reported some medication for adult attention deficit disorder, 26.8% (95% CI 22.2% to 31.5%) took medication for anxiety, 25.1% (95% CI 19.9% to 30.3%) for depression and 15.3% (95% CI 9.8% to 20.8%) indicated drug treatment for other mental or neurological disorders. Adult CNS stimulant use was higher in females, in younger age cohorts and among individuals of white race/ethnicity. CONCLUSIONS: Adult medical use of prescription stimulants increased markedly in 5 years and occurred in a population often reporting multiple mental or neurological disorders. Further action is needed to understand and manage this new resurgence in drugs with high risks of dependence.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Transtornos Relacionados ao Uso de Substâncias , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Estudos Transversais , Prescrições de Medicamentos , Feminino , Humanos , Metilfenidato/uso terapêutico , Adulto Jovem
10.
Nutrients ; 13(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445005

RESUMO

Caffeine, a natural stimulant, is known to be effective for weight loss. On this basis, we screened the arousal-inducing effect of five dietary supplements with a weight loss effect (Garcinia cambogia, Coleus forskohlii, Camellia sinensis L., Irvingia gabonensis, and Malus pumila M.), of which the G. cambogia peel extract (GC) showed a significant arousal-inducing effect in the pentobarbital-induced sleep test in mice. This characteristic of GC was further evaluated by analysis of electroencephalogram and electromyogram in C57L/6N mice, and it was compared to that of the positive control, caffeine. Administration of GC (1500 mg/kg) significantly increased wakefulness and decreased non-rapid eye movement sleep, similar to that of caffeine (25 mg/kg), with GC and caffeine showing a significant increase in wakefulness at 2 and 6 h, respectively. Compared to that of caffeine, the shorter duration of efficacy of GC could be advantageous because of the lower possibility of sleep disturbance. Furthermore, the arousal-inducing effects of GC (1500 mg/kg) and caffeine (25 mg/kg) persisted throughout the chronic (3 weeks) administration study. This study, for the first time, revealed the arousal-inducing effect of GC. Our findings suggest that GC might be a promising natural stimulant with no side effects. In addition, it is preferential to take GC as a dietary supplement for weight loss during the daytime to avoid sleep disturbances owing to its arousal-inducing effect.


Assuntos
Nível de Alerta/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Eletroencefalografia , Garcinia cambogia , Extratos Vegetais/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Encéfalo/fisiologia , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/isolamento & purificação , Frutas , Garcinia cambogia/química , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Pentobarbital/farmacologia , Extratos Vegetais/isolamento & purificação , Sono/efeitos dos fármacos
11.
J Pharm Biomed Anal ; 205: 114317, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34419812

RESUMO

Amphetamine-type stimulants (ATS) like amphetamine ('speed'), methamphetamine ('crystal meth') and 3,4-methylenedioxy-N-methylamphetamine (MDMA, 'ecstasy') represent some of the most frequently abused drugs worldwide. Another less frequently abused ATS is 4-fluoroamphetamine (4-FA). The enantiomers of these four compounds exhibit different pharmacokinetic and pharmacodynamic properties. According to the free drug theory, the pharmacological properties of a substance are dependent on its plasma protein binding (PPB). However, data on PPB of stimulant enantiomers in humans are rare or non-existent. Human plasma samples were spiked with racemic mixtures of the stimulants and subjected to ultrafiltration to extract the unbound fraction. Enantioselective liquid chromatography - tandem mass spectrometry (LC-MS/MS) methods were applied using a chiral Phenomenex® Lux3 µm AMP column. Method validation showed satisfactory selectivity, linearity (0.5 250 ng/mL), accuracy and precision. Enantiomers were quantified before and after ultracentrifugation to determine PPB. For all analytes, low to medium plasma protein binding was found. For (R)-amphetamine a slightly but significantly higher PPB was found compared to the (S)-enantiomer (31.7 % vs 29.0 %). (R)-MDMA also showed only slightly but significantly significantly higher PPB than (S)-MDMA, although the mean difference was negligible (21.6 % vs 21.3 %). For the enantiomers of methamphetamine and 4-FA, no significant differences in PPB were found. In summary, there were no or only minor differences in PBB for the enantiomers of all investigated compounds. The different pharmacological properties of the stimulant enantiomers can therefore not be explained by differences in PPB.


Assuntos
Estimulantes do Sistema Nervoso Central , Drogas Ilícitas , Anfetamina , Cromatografia Líquida , Humanos , Ligação Proteica , Estereoisomerismo , Espectrometria de Massas em Tandem
12.
J Consult Clin Psychol ; 89(7): 615-625, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34383534

RESUMO

Objective: Although attention deficit hyperactivity disorder (ADHD) is associated with cognitive deficits, there is considerable heterogeneity and only a minority of individuals with the disorder demonstrate a deficit in any cognitive domain. Recent studies indicate that the relationships between ADHD symptoms and cognition are complex with a dissociation between medication responses across these two domains. Method: We examined whether methylphenidate (MPH) differentially impacts on cognition in those with and without pretreatment cognitive deficits in a 4-week randomized controlled crossover of high (0.6 mg/kg/dose) and low (0.3 mg/kg/dose) dose MPH and placebo in 75 medication-naive boys with ADHD. Cognition was assessed using tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Confirmatory factor analysis (CFA) was used to form latent cognitive factors of executive functioning, visual memory, and reaction time, as well as a general cognition factor. Results: Compared to placebo, both high and low MPH doses significantly improved performance on pattern recognition (PR), spatial recognition (SR), and simple reaction time. The low, but not the high, dose improved performance on the Stockings of Cambridge (SOC) and delayed matching-to-sample tasks. Both doses also significantly improved performance on the executive functioning, visual memory, reaction time skills, and general cognitive latent variables. There were however no differences in the effects of MPH on cognition between those with and without a baseline cognitive deficit, for either the observed task values or the latent cognitive factor scores. Conclusions: We conclude that MPH can enhance executive functioning, visual memory, reaction time, and general cognitive function in boys with ADHD. These improvements are not dependent on baseline cognitive performance. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Cognição/efeitos dos fármacos , Metilfenidato/farmacologia , Metilfenidato/uso terapêutico , Adolescente , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Estudos Cross-Over , Método Duplo-Cego , Humanos , Masculino , Testes Neuropsicológicos
13.
Exp Clin Psychopharmacol ; 29(3): 288-293, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34264739

RESUMO

The lack of a consensus on empirically supported and clinically meaningful outcome measures for stimulant use disorders (SUDs) continues to undermine the development and evaluation of effective behavioral and pharmacological treatment options. The aim of this study was to evaluate the clinical relevance of four stimulant use treatment outcome measures (longest duration of abstinence [LDA], percent of negative urinalysis submitted, abstinent in the last 2 weeks of treatment, and three or more weeks of continuous abstinence) by exploring their utility via association with stimulant and alcohol use, employment and legal problems, and severity of psychiatric symptomatology collected at follow-up. Data used in these secondary analyses came from a multisite randomized contingency management treatment trial for SUDs (n = 441) conducted through the NIDA Clinical Trials Network. Multiple regression analyses were conducted to explore the association of four stimulant use treatment outcome measures and eight 3-month follow-up outcomes. The percent of negative urinalysis outcomes showed the most consistent performance compared to alternative outcomes, being significantly associated with better responses in all eight 3-month follow-up outcomes (ß range: -169 to -241, p < .01). Both dichotomous outcome measures showed similar performances being significantly associated with four follow-up outcomes (ß range: -159 to -203, p < .01). All outcome measures were consistently associated with better outcome responses at the 3-month follow-up, adding support to their clinical relevance and their adoption in SUD treatment trials. The two dichotomous outcome measures are reliable candidates to be used as endpoint outcomes, as recommended by the U.S. Food and Drug Administration (FDA). (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Adulto , Estimulantes do Sistema Nervoso Central/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Resultado do Tratamento
14.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281286

RESUMO

Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane ß2-adrenergic receptors (ARs). Evidence indicates that ß2-ARs activation restores autophagy, which is impaired by Meth administration. This occurs via restoration of the autophagy flux and, as assessed by ultrastructural morphometry, by preventing the dissipation of microtubule-associated protein 1 light chain 3 (LC3) from autophagy vacuoles to the cytosol, which is produced instead during Meth toxicity. These findings may have an impact in a variety of degenerative conditions characterized by NE deficiency along with autophagy impairment.


Assuntos
Metanfetamina/antagonistas & inibidores , Metanfetamina/toxicidade , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Norepinefrina/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Adrenérgicos/farmacologia , Animais , Autofagia/efeitos dos fármacos , Compartimento Celular/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/antagonistas & inibidores , Estimulantes do Sistema Nervoso Central/toxicidade , Desipramina/farmacologia , Relação Dose-Resposta a Droga , Metanfetamina/administração & dosagem , Microscopia Eletrônica de Transmissão , Modelos Neurológicos , Neurônios/ultraestrutura , Fármacos Neuroprotetores/farmacologia , Norepinefrina/metabolismo , Células PC12 , Ratos , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo , Vacúolos/ultraestrutura
15.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207724

RESUMO

Selective antagonists of thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2), in order to enable a better understanding of this peptide's central functions, have not been identified. Using pGlu-Glu-Pro-NH2 ([Glu2]TRH) as a lead peptide and with modification at its central residue, our studies focused on some of its analogues synthesized as potential functional antagonists of TRH in the rodent brain. Among the peptides studied, the novel isomeric analogue [ß-Glu2]TRH was found to suppress the analeptic and antidepressant-like pharmacological activities of TRH without eliciting intrinsic effects in these paradigms. [ß-Glu2]TRH also completely reversed TRH's stimulation of acetylcholine turnover in the rat hippocampus without a cholinergic activity of its own, which was demonstrated through in vivo microdialysis experiments. Altogether, [ß-Glu2]TRH emerged as the first selective functional antagonist of TRH's prominent cholinergic actions, by which this endogenous peptide elicits a vast array of central effects.


Assuntos
Antidepressivos , Estimulantes do Sistema Nervoso Central , Hipocampo/metabolismo , Peptídeos , Hormônio Liberador de Tireotropina/antagonistas & inibidores , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/patologia , Masculino , Camundongos , Peptídeos/química , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Hormônio Liberador de Tireotropina/metabolismo
16.
Molecules ; 26(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198510

RESUMO

Antimicrobial resistance is a major healthcare threat globally. Xanthines, including caffeine and pentoxifylline, are attractive candidates for drug repurposing, given their well-established safety and pharmacological profiles. This study aimed to analyze potential interactions between xanthines and aromatic antibiotics (i.e., tetracycline and ciprofloxacin), and their impact on antibiotic antibacterial activity. UV-vis spectroscopy, statistical-thermodynamical modeling, and isothermal titration calorimetry were used to quantitatively evaluate xanthine-antibiotic interactions. The antibacterial profiles of xanthines, and xanthine-antibiotic mixtures, towards important human pathogens Staphylococcus aureus, Enterococcus faecium, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter cloacae were examined. Caffeine and pentoxifylline directly interact with ciprofloxacin and tetracycline, with neighborhood association constant values of 15.8-45.6 M-1 and enthalpy change values up to -4 kJ·M-1. Caffeine, used in mixtures with tested antibiotics, enhanced their antibacterial activity in most pathogens tested. However, antagonistic effects of caffeine were also observed, but only with ciprofloxacin toward Gram-positive pathogens. Xanthines interact with aromatic antibiotics at the molecular and in vitro antibacterial activity level. Given considerable exposure to caffeine and pentoxifylline, these interactions might be relevant for the effectiveness of antibacterial pharmacotherapy, and may help to identify optimal treatment regimens in the era of multidrug resistance.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Cafeína/farmacologia , Compostos Heterocíclicos/química , Pentoxifilina/farmacologia , Antibacterianos/química , Bactérias/crescimento & desenvolvimento , Cafeína/química , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacologia , Interações Medicamentosas , Testes de Sensibilidade Microbiana , Pentoxifilina/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia
17.
Molecules ; 26(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199192

RESUMO

The beneficial effects of coffee on human diseases are well documented, but the molecular mechanisms of its bioactive compounds on cancer are not completely elucidated. This is likely due to the large heterogeneity of coffee preparations and different coffee-based beverages, but also to the choice of experimental models where proliferation, differentiation and immune responses are differently affected. The aim of the present study was to investigate the effects of one of the most interesting bioactive compounds in coffee, i.e., caffeine, using a cellular model of melanoma at a defined differentiation level. A preliminary in silico analysis carried out on public gene-expression databases identified genes potentially involved in caffeine's effects and suggested some specific molecular targets, including tyrosinase. Proliferation was investigated in vitro on human melanoma initiating cells (MICs) and cytokine expression was measured in conditioned media. Tyrosinase was revealed as a key player in caffeine's mechanisms of action, suggesting a crucial role in immunomodulation through the reduction in IL-1ß, IP-10, MIP-1α, MIP-1ß and RANTES secretion onto MICs conditioned media. The potent antiproliferative effects of caffeine on MICs are likely to occur by promoting melanin production and reducing inflammatory signals' secretion. These data suggest tyrosinase as a key player mediating the effects of caffeine on melanoma.


Assuntos
Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Simulação por Computador/estatística & dados numéricos , Melaninas/metabolismo , Melanoma/tratamento farmacológico , Monofenol Mono-Oxigenase/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Biologia Computacional/métodos , Bases de Dados Genéticas , Regulação da Expressão Gênica , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia
18.
Curr Sports Med Rep ; 20(7): 338-344, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34234088

RESUMO

ABSTRACT: Creatine is a popular and widely used ergogenic dietary supplement among athletes, for which studies have consistently shown increased lean muscle mass and exercise capacity when used with short-duration, high-intensity exercise. In addition to strength gains, research has shown that creatine supplementation may provide additional benefits including enhanced postexercise recovery, injury prevention, rehabilitation, as well as a number of potential neurologic benefits that may be relevant to sports. Studies show that short- and long-term supplementation is safe and well tolerated in healthy individuals and in a number of patient populations.


Assuntos
Atletas , Creatina/farmacologia , Suplementos Nutricionais , Substâncias para Melhoria do Desempenho/farmacologia , Anaerobiose/efeitos dos fármacos , Desempenho Atlético , Composição Corporal/efeitos dos fármacos , Concussão Encefálica/prevenção & controle , Concussão Encefálica/terapia , Cafeína/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Cognição/efeitos dos fármacos , Carboidratos da Dieta/farmacologia , Exercício Físico , Tolerância ao Exercício/efeitos dos fármacos , Humanos , Força Muscular/efeitos dos fármacos , Treinamento de Força , Valeratos/farmacologia
19.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299015

RESUMO

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity.


Assuntos
Alcaloides/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzodioxóis/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pentanonas/farmacologia , Pirrolidinas/farmacologia , Ácido gama-Aminobutírico/metabolismo
20.
Am J Cardiol ; 154: 86-91, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34233837

RESUMO

Methamphetamine-associated cardiomyopathy (MACM) in an increasingly prevalent disease yet presenting clinical characteristics have not been well studied. We studied consecutive patients with MACM presenting between June 2018 and March 2020 who were interviewed for drug use and medical history. We retrospectively identified an age- and gender-matched cohort of Non-MACM (NMACM) patients and compared clinical characteristics. 140 patients (70 MACM and 70 NMACM) were studied. MACM patients were young (49.6 ± 10 years) and predominantly male (94%). Compared to NMACM, MACM patients were more likely to be Caucasian (21% vs 6%, p = 0.007) and homeless (47% vs 7%, p = 0.001). MACM was characterized by lower left ventricular ejection fraction (EF) (p <0.001) and greater LV end diastolic volume (LVEDV) (p = 0.024). Right ventricular (RV) dilation was present more often (p = s0.001) and was more often severe (p = 0.03). Among MACM cases, half of the cohort developed MACM within 5 years of starting MA (18% within 1 year). There was no apparent relationship between frequency or amount of MA used weekly with time until heart failure onset. Drug use patterns were not clearly related to the degree of LV structural change however there were more consistent, significant associations with RV and right atrial (RA) size parameters. In conclusion, patients with MACM have more severe myocardial impairment with lower EF, greater LVEDV and RV dilation. Drug use patterns do not clearly impact degree of LV structural changes by echocardiography however may be related to RV and RA size.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Cardiomiopatias/fisiopatologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Administração Intranasal , Adulto , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/epidemiologia , Cardiotoxicidade , Estudos de Casos e Controles , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumar , Volume Sistólico , Disfunção Ventricular Esquerda
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