RESUMO
The brewers' spent grain is a by-product generated during brewery process and is a potential source for arabinoxylans (AX) extraction. In the present work, the extraction and characterization of an arabinoxylan-rich fraction from brewers' spent grain (BSG-AX) were performed, and BSG-AX was evaluated as release matrix for caffeine. The BSG-AX showed an AX content of 72% (w/w), a ferulic acid content of 3.52⯵g/mg BSG-AX, an Ara/Xyl ratio of 0.89, an intrinsic viscosity of 41.18â¯mLâ¯g-1, and a molecular weight of 43.80â¯kDa. The studied BSG-AX showed a good antioxidant capacity compared with other polysaccharide gums and was estimated by DPPH (114.41⯵M Trolox equivalent/g BSG-AX) and FRAP (49.01⯵mol Fe2+/g BSG-AX) assays. The partial specific volume (0.63â¯cm3â¯g-1), loss on drying (10.68%), swelling (10.87%), solubility (80.93%) and electrostatic interactions (by zeta potential, -3.44 to -9.17â¯mV) were determined and used to evaluate the application of the BSG-AX as release matrix. A film containing the BSG-AX, glycerol (as plasticizer) and caffeine (target drug) was prepared as release matrix. Glycerol promoted an increase in the extensibility and the surface smoothness of the BSG-AX-caffeine film. The drug was released (≈98%) in about 7â¯h. These results are promising to concern the design and use of BSG-AX based biofilms for the controlled release of bioactive compounds.
Assuntos
Cafeína/química , Estimulantes do Sistema Nervoso Central/química , Portadores de Fármacos , Grão Comestível/microbiologia , Fermentação , Hordeum/microbiologia , Resíduos/análise , Xilanos/química , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Microbiologia de Alimentos , Glicerol/química , Cinética , Plastificantes/química , Solubilidade , Viscosidade , Xilanos/isolamento & purificaçãoRESUMO
BACKGROUND: Benzofurans are heterocyclic compounds with neurotropic activity. Some have been developed for the treatment of acute and degenerative neuronal injuries. OBJECTIVE: The study aimed to evaluate the in silico binding of some promising benzofurans on the GABA receptors, and the in vivo neurotropic activity of benzofuran analogues (BZF 6-10) of gamma-aminobutyric acid (GABA) on a seizure model. METHODS: The ligands with the best physicochemical attributes were docked on two GABA receptors (the alpha-1 subunit of GABAA-R and GBR1 subunit of GABAB-R). Selected benzofuran derivatives were synthesized by a multistep procedure and characterized. To examine the neurotropic effects, mice were pretreated with different concentrations of the compounds prior to PTZ- or 4- AP-induced seizures. We assessed acute toxicity, motor behavior, and the effects on seizures. RESULTS: The tested ligands that complied with Lipinski's rule of five were tested in silico with GABAA-R (ΔG = -5.51 to -5.84 kcal/mol) at the allosteric site for benzodiazepines. They bound to a similar cluster of residues as the reference compound (gaboxadol, ΔG = -5.51 kcal/mol). Synthesis was achieved with good overall yields (42-9.7%). Two compounds were selected for biological tests (BZF-7 and rac-BZF-10) on a mouse model of seizures, induced by pentylenetetrazol (PTZ) or 4-aminopyridine (4-AP). PTZ-induced seizures are associated with GABA receptors, and those 4-AP-induced with the blockage of the delayed rectifier-type potassium channel, which promotes the release of the NMDA-sensitive glutamatergic ionotropic receptor and other neurotransmitters. The biological assays demonstrated that BZF-7 and rac-BZF-10 do not protect against seizures. Indeed, BZF-7 increased the number of PTZ-induced seizures and decreased latency time. The 4-AP model apparently showed a potentiation of seizure effects after administration of the BZF-analogues, evidenced by the incidence and severity of the seizures and reduced latency time. CONCLUSION: The results suggest that the test compounds are GABAergic antagonists with stimulatory activity on the CNS.
Assuntos
Benzofuranos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-B/farmacologia , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/toxicidade , Estimulantes do Sistema Nervoso Central/síntese química , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/toxicidade , Antagonistas de Receptores de GABA-A/síntese química , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/toxicidade , Antagonistas de Receptores de GABA-B/síntese química , Antagonistas de Receptores de GABA-B/química , Antagonistas de Receptores de GABA-B/toxicidade , Humanos , Ligantes , Masculino , Camundongos , Simulação de Acoplamento Molecular , Receptores de GABA-A/química , Receptores de GABA-B/químicaRESUMO
Caffeine is the most consumed psychoactive substance in the world; in general, it is not associated to potentially harmful effects. Nevertheless, few studies were performed attempting to investigate the caffeine addiction. The present review was mainly aimed to answer the following question: is caffeine an abuse drug? To adress this point, the effects of caffeine in preclinical and clinical studies were summarized and critically analyzed taking account the abuse disorders described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). We concluded that the diagnostic criteria evidenced on DSM-V to intoxication-continued use and abstinence are not well supported by clinical studies. The fact that diagnostic criteria is not widely supported by preclinical or clinical studies may be due specially to a controversy in its exactly mechanism of action: recent literature point to an indirect, rather than direct modulation of dopamine receptors, and auto-limitant consumption due to adverse sensations in high doses. On the other hand, it reports clear withdrawal-related symptoms. Thus, based on a classical action on reward system, caffeine only partially fits its mechanism of action as an abuse drug, especially because previous research does not report a clear effect of dopaminergic activity enhance on nucleus accumbens; despite this, there are reports concerning dopaminergic modulation by caffeine on the striatum. However, based on human and animal research, caffeine withdrawal evokes signals and symptoms, which are relevant enough to include this substance among the drugs of abuse.
Assuntos
Cafeína , Estimulantes do Sistema Nervoso Central , Drogas Ilícitas , Adenosina/metabolismo , Animais , Cafeína/química , Cafeína/farmacocinética , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacocinética , Estimulantes do Sistema Nervoso Central/farmacologia , Fissura , Dopamina/metabolismo , Humanos , Drogas Ilícitas/química , Drogas Ilícitas/farmacocinética , Drogas Ilícitas/farmacologiaRESUMO
In this work, we carried out a theoretical investigation regarding amphetamine-type stimulants, which can cause central nervous system degeneration, interacting with human DNA. These include amphetamine, methamphetamine, 3,4-Methylenedioxymethamphetamine (also known as ecstasy), as well as their main metabolites. The studies were performed through molecular docking and molecular dynamics simulations, where molecular interactions of the receptor-ligand systems, along with their physical-chemical energies, were reported. Our results show that 3,4-Methylenedioxymethamphetamine and 3,4-Dihydroxymethamphetamine (ecstasy) present considerable reactivity with the receptor (DNA), suggesting that these molecules may cause damage due to human-DNA. These results were indicated by free Gibbs change of bind (ΔGbind) values referring to intermolecular interactions between the drugs and the minor grooves of DNA, which were predominant for all simulations. In addition, it was observed that 3,4-Dihydroxymethamphetamine (ΔGbind = -13.15 kcal/mol) presented greater spontaneity in establishing interactions with DNA in comparison to 3,4-Methylenedioxymethamphetamine (ΔGbind = -8.61 kcal/mol). Thus, according with the calculations performed our results suggest that the 3,4-Methylenedioxymethamphetamine and 3,4-Dihydroxymethamphetamine have greater probability to provide damage to human DNA fragments.
Assuntos
Anfetamina/efeitos adversos , DNA/química , Metanfetamina/efeitos adversos , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos , Anfetamina/química , Anfetamina/metabolismo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Estimulantes do Sistema Nervoso Central/química , DNA/metabolismo , Humanos , Metanfetamina/química , Metanfetamina/metabolismo , Simulação de Acoplamento Molecular , N-Metil-3,4-Metilenodioxianfetamina/química , N-Metil-3,4-Metilenodioxianfetamina/metabolismoRESUMO
Oral, intraperitoneal, or intravenous have been the common routes of administration used to study the behavioral and neurochemical pharmacology of caffeine, one of the most widely used psychoactive substances worldwide. We have reported that caffeine is an active adulterant frequently found in coca-paste (CP)-seized samples, a highly addictive form of smokable cocaine. The role of caffeine in the psychostimulant and neurochemical effects induced by CP remains under study. No preclinical animal studies have been performed so far to characterize the effects of caffeine when it is administered through the pulmonary inhalation route. Caffeine (10, 25, and 50 mg) was volatilized and rats were exposed to one inhalation session of its vapor. The stimulant effect was automatically recorded and plasmatic levels of caffeine were measured. Caffeine capability (50 mg) to increase extracellular dopamine (DA) levels in nucleus accumbens shell was also studied by in vivo microdialysis in non-anesthetized animals. A dose-dependent stimulant effect induced by volatilized caffeine was observed and this effect was directly related with caffeine plasmatic levels. A significant increase in the extracellular DA was achieved after 50 mg of volatilized caffeine exposure. This is the first report showing pharmacological acute effects of caffeine through the pulmonary inhalation route of administration and suggests that this could be a condition under which caffeine can elevate its weak reinforcing effect and even enhance the psychostimulant effect and abuse liability of smokable adulterated psychostimulant drugs.
Assuntos
Cafeína/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Dopaminérgicos/administração & dosagem , Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Administração por Inalação , Animais , Cafeína/sangue , Cafeína/química , Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/química , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Dopaminérgicos/sangue , Dopaminérgicos/química , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Masculino , Modelos Animais , Atividade Motora/efeitos dos fármacos , Ratos Wistar , VolatilizaçãoRESUMO
Yerba-mate (Ilex paraguariensis St. Hil.) is the most used beverage in Latin America with approximately 426 thousand of tons consumed per year. Considering the broad use of this plant, we aimed to investigate the anxiety-like and stimulant activity of both the hydroethanolic (HE) and aqueous (AE) extracts from leaves of I. paraguariensis. Swiss mice were treated with I. paraguariensis HE or AE chronically or acutely, respectively, followed by evaluation in the elevated plus-maze (EPM; anxiety-like paradigm), open field (OF; locomotor activity) or the step-down avoidance task (memory assessment). Following behavioral protocols the brains were collected for evaluation of acetylcholinesterase (AChE) activity ex vivo. Chronic treatment with HE induced an anxiolytic-like effect and increased motor activity besides augmented AChE activity. Additionally, acute treatment with AE prevented the scopolamine-induced memory deficit in the step-down avoidance task. Overall, our results indicate the importance of the I. paraguariensis-induced CNS effects, since it is a widely used nutraceutical. We have reported anxiolytic, stimulant and neuroprotective effects for this plant species. These effects are potentially modulated by the cholinergic system as well as by caffeine.
Assuntos
Ansiolíticos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Ilex paraguariensis , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta , Acetilcolinesterase/metabolismo , Animais , Ansiolíticos/química , Ansiedade/tratamento farmacológico , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Cafeína/química , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/química , Colinérgicos/química , Colinérgicos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Ilex paraguariensis/química , Masculino , Transtornos da Memória/prevenção & controle , Camundongos , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fototerapia , Extratos Vegetais/química , Folhas de Planta/química , EscopolaminaRESUMO
Brazil is one of the countries most affected by abuse of stimulant medications by professional drivers, especially fenproporex, amfepramone and mazindol. Even though their sale is banned, they can be found in illegal markets, such as those located on the country's borders. The use of oral fluid to monitor drug levels has many advantages over plasma and urine because it is noninvasive, easier to collect and more difficult to adulterate. The aim of this study was to develop and validate a sensitive and specific method to quantify mazindol in human oral fluid by liquid chromatography-mass spectrometry (LC-MS). The LC system consisted of an LC-MS system operated in selected ion monitoring mode. The mobile phase was composed of water at pH 4.0, acetonitrile and methanol (60:15:25 v/v/v) at a flow rate of 1.0 mL/min and propranolol was used as internal standard. Total running time was 10 min. The lower limit of quantification was 0.2 ng/mL and the method exhibited good linearity within the 0.2-20 ng/mL range (r = 0.9987). A rapid, specific, sensitive, linear, precise and accurate method was developed for determination of mazindol in human oral fluid according to European Medicines Agency guidelines, and is suitable for monitoring mazindol levels in oral fluid of professional drivers.
Assuntos
Estimulantes do Sistema Nervoso Central/análise , Cromatografia Líquida de Alta Pressão/métodos , Mazindol/análise , Saliva/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Condução de Veículo , Brasil , Estimulantes do Sistema Nervoso Central/química , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Masculino , Mazindol/química , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: This study examines whether Mexico's controls on ephedrine and pseudoephedrine, the two precursor chemicals that yield the most potent form of methamphetamine, d-methamphetamine, impacted the prevalence/availability of less potent types of methamphetamine in the United States-types associated with the alternative precursor chemical P2P. METHOD: Using ARIMA-intervention time series analysis of monthly drug exhibits (a prevalence/availability indicator) from the System to Retrieve Information from Drug Evidence (STRIDE), we tested whether Mexico's controls, which began in 2005, were associated with growth/decline in d-methamphetamine and growth/decline in P2P-associated, less potent l-methamphetamine, racemic methamphetamine (a 50:50 ratio of d- and l-isomers), and mixed isomer methamphetamine (an unequal ratio of d- and l-isomers). Heroin, cocaine and marijuana exhibits were used for quasi-control (01/2000-04/2011). RESULTS: Mixed-isomer exhibits constituted about 4% of the methamphetamine exhibits before Mexico's controls, then rose sharply in association with them and remained elevated, constituting about 37% of methamphetamine exhibits in 2010. d-Methamphetamine exhibits dropped sharply; l-methamphetamine and racemic methamphetamine exhibits had small rises. d-Methamphetamine exhibits partially recovered in the US West, but little recovery occurred in the US Central/South. Quasi-control series were generally unaffected. CONCLUSION: The US methamphetamine market changed. Widespread emergence of less potent methamphetamine occurred in conjunction with Mexico's controls. And prevalence/availability of the most potent type of the drug, d-methamphetamine, declined, a partial recovery in the West notwithstanding. Granting that lower potency drugs typically engender less dependence and attendant problems, these findings suggest that, following Mexico's controls, the potential harm of a sizeable amount of the US methamphetamine supply decreased.