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1.
Am J Physiol Heart Circ Physiol ; 316(3): H743-H750, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30681368

RESUMO

Adenosine is involved in classic preconditioning in most species and acts especially through adenosine A1 and A3 receptors. The aim of the present study was to evaluate whether remote ischemic preconditioning (rIPC) activates adenosine A1 receptors and improves mitochondrial function, thereby reducing myocardial infarct size. Isolated rat hearts were subjected to 30 min of global ischemia and 60 min of reperfusion [ischemia-reperfusion (I/R)]. In a second group, before isolation of the heart, a rIPC protocol (3 cycles of hindlimb I/R) was performed. Infarct size was measured with tetrazolium staining, and Akt/endothelial nitric oxide (NO) synthase (eNOS) expression/phosphorylation and mitochondrial function were evaluated after ischemia at 10 and 60 min of reperfusion. As expected, rIPC significantly decreased infarct size. This beneficial effect was abolished only when 8-cyclopentyl-1,3-dipropylxanthine (adenosine A1 receptor blocker) and NG-nitro-l-arginine methyl ester (NO synthesis inhibitor) were administered during the reperfusion phase. At the early reperfusion phase, rIPC induced significant Akt and eNOS phosphorylation, which was abolished by the perfusion with an adenosine A1 receptor blocker. I/R led to impaired mitochondrial function, which was attenuated by rIPC and mediated by adenosine A1 receptors. In conclusion, we demonstrated that rIPC limits myocardial infarct by activation of adenosine A1 receptors at early reperfusion in the isolated rat heart. Interestingly, rIPC appears to reduce myocardial infarct size by the Akt/eNOS pathway and improves mitochondrial function during myocardial reperfusion. NEW & NOTEWORTHY Adenosine is involved in classic preconditioning and acts especially through adenosine A1 and A3 receptors. However, its role in the mechanism of remote ischemic preconditioning is controversial. In this study, we demonstrated that remote ischemic preconditioning activates adenosine A1 receptors during early reperfusion, inducing Akt/endothelial nitric oxide synthase phosphorylation and improving mitochondrial function, thereby reducing myocardial infarct size.


Assuntos
Precondicionamento Isquêmico Miocárdico , Mitocôndrias Cardíacas , Receptor A1 de Adenosina , Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Trifosfato de Adenosina/biossíntese , Animais , Inibidores Enzimáticos/uso terapêutico , Masculino , Potencial da Membrana Mitocondrial , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroarginina/uso terapêutico , Consumo de Oxigênio , Ratos , Ratos Sprague-Dawley , Xantinas/uso terapêutico
2.
Crit Rev Food Sci Nutr ; 59(16): 2597-2625, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29624433

RESUMO

Methylated xanthines (methylxanthines) are available from a significant number of different botanical species. They are ordinarily included in daily diet, in many extremely common beverages and foods. Caffeine, theophylline and theobromine are the main methylxanthines available from natural sources. The supposedly relatively low toxicity of methylxanthines, combined with the many beneficial effects that have been attributed to these compounds through time, generated a justified attention and a very prolific ground for dedicated scientific reports. Methylxanthines have been widely used as therapeutical tools, in an intriguing range of medicinal scopes. In fact, methylxanthines have been/were medically used as Central Nervous System stimulants, bronchodilators, coronary dilators, diuretics and anti-cancer adjuvant treatments. Other than these applications, methylxanthines have also been hinted to hold other beneficial health effects, namely regarding neurodegenerative diseases, cardioprotection, diabetes and fertility. However, it seems now consensual that toxicity concerns related to methylxanthine consumption and/or therapeutic use should not be dismissed. Taking all the knowledge and expectations on the potential of methylxanthines into account, we propose a systematic look at the past and future of methylxanthine pharmacologic applications, discussing all the promise and anticipating possible constraints. Anyways, methylxanthines will still substantiate considerable meaningful research and discussion for years to come.


Assuntos
Xantinas/história , Xantinas/uso terapêutico , História do Século XX , História do Século XXI , Humanos , Estudos Retrospectivos , Xantinas/química
3.
Pain ; 160(1): 102-116, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30169421

RESUMO

Neuropathic pain is one of the most important types of chronic pain. It is caused by neuronal damage. Clinical and experimental studies suggest a critical role for neuroimmune interactions in the development of neuropathic pain. In this article, we have shown that the cytoplasmic receptor Nod-like receptor-2, NOD2, and its adaptor-signaling molecule RIPK2 participate in the development of neuropathic pain after peripheral nerve injury (spared nerve injury model). The activation of NOD2 signaling in peripheral macrophage mediates the development of neuropathic pain through the production of pronociceptive cytokines (tumor necrosis factor and IL-1ß). This study found that peripheral nerve injury promoted a systemic increase in the NOD2 ligand. These results highlight a previously undetermined role for NOD2 signaling in the development of neuropathic pain, suggesting a new potential target for preventing neuropathic pain.


Assuntos
Macrófagos/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Transplante de Medula Óssea , Carragenina/toxicidade , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Minociclina/uso terapêutico , Neuralgia/genética , Neuralgia/cirurgia , Fármacos Neuroprotetores/uso terapêutico , Proteína Adaptadora de Sinalização NOD2/genética , RNA Interferente Pequeno/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Xantinas/uso terapêutico
4.
Asia Pac J Ophthalmol (Phila) ; 7(6): 405-414, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30338677

RESUMO

The burden associated with the rising prevalence of myopia and high myopia, and the associated vision impairment and sight-threatening complications, has triggered the need to evaluate strategies to control the progression of myopia. We provide an overview of the literature on the use of optical (spectacles, contact lenses, and orthokeratology) and pharmaceutical approaches to slow progress of myopia. The evidence indicates that myopia progression can be slowed by varying degrees using these strategies. All approaches play a role in the management of myopia as needs and requirements of an individual vary based on age, suitability, affordability, safety of the approach, subjective needs of the individual, and rate of progression. This review also identifies and discusses the lack of long-term efficacy data and rebound on discontinuation of myopia control products.


Assuntos
Lentes de Contato , Óculos , Miopia/tratamento farmacológico , Miopia/terapia , Procedimentos Ortoceratológicos , Preparações Farmacêuticas , Atropina/uso terapêutico , Progressão da Doença , Humanos , Agonistas Muscarínicos/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Miopia/prevenção & controle , Pirenzepina/uso terapêutico , Tropicamida/uso terapêutico , Xantinas/uso terapêutico
5.
Naunyn Schmiedebergs Arch Pharmacol ; 391(12): 1361-1371, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30094458

RESUMO

The main goal of the present study was to evaluate the influence of the adenosine A1 receptor (A1R) antagonist - DPCPX - on depressive-like behavior in mice, as well as the effect of DPCPX on the activity of imipramine, escitalopram, and reboxetine, each at non-effective doses. The influence of DPCPX on behavior and its influence on the activity of selected antidepressants was evaluated in the forced swim test (FST) and the tail suspension test (TST) in mice. Locomotor activity was measured to verify and exclude false-positive data obtained in the FST and TST. Moreover, serum and brain concentrations of tested antidepressants were determined using HPLC. DPCPX, at doses of 2 and 4 mg/kg, exhibited antidepressant activity in the FST and TST, which was not related to changes in the spontaneous locomotor activity. Co-administration of DPCPX with imipramine, escitalopram, or reboxetine, each at non-active doses, significantly reduced the immobilization period in the FST and TST in mice, which was not due to the increase in locomotor activity. Both antagonists of 5-HT receptors (WAY 100635 and ritanserin) completely antagonized the effect elicited by DPCPX in the behavioral tests. Results of assessment of the nature of the interaction between DPCPX and test drugs show that in the case of DPCPX and imipramine or reboxetine, there were pharmacodynamic interactions, whereas the DPCPX-escitalopram interaction is at least partially pharmacokinetic in nature. Presented outcomes indicate that an inhibition of A1Rs and an increase of monoaminergic transduction in the CNS may offer a novel strategy for the development of antidepressant drugs.


Assuntos
Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Imipramina/uso terapêutico , Reboxetina/uso terapêutico , Xantinas/uso terapêutico , Animais , Antidepressivos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Citalopram/farmacocinética , Depressão/metabolismo , Interações de Medicamentos , Quimioterapia Combinada , Elevação dos Membros Posteriores , Imipramina/farmacocinética , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Reboxetina/farmacocinética , Antagonistas da Serotonina/farmacologia
6.
Pediatr Res ; 84(3): 333-340, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29983414

RESUMO

Apnea of prematurity (AOP) is a common and pervasive problem in very low birth weight infants. Methylxanthines were reported >40 years ago to be an effective therapy and, by the early 2000s, caffeine had become the preferred methylxanthine because of its wide therapeutic index, excellent bioavailability, and longer half-life. A clinical trial to address unresolved questions and toxicity concerns, completed in 2004, confirmed significant benefits of caffeine therapy, including shorter duration of intubation and respiratory support, reduced incidence of chronic lung disease, decreased need for treatment of patent ductus arteriosus, reduced severity of retinopathy of prematurity, and improved motor and visual function. Cohort studies have now further delineated the benefits of initiation of therapy before 3 days postnatal age, and of higher maintenance doses to achieve incremental beneficial effects. This review summarizes the pivotal and in particular the most recent studies that have established the safety and efficacy of caffeine therapy for AOP and other respiratory and neurodevelopmental outcomes. Caffeine has a very favorable benefit-to-risk ratio, and has become one of the most prescribed and cost-effective pharmacotherapies in the NICU.


Assuntos
Apneia/tratamento farmacológico , Cafeína/uso terapêutico , Doenças do Prematuro/tratamento farmacológico , Recém-Nascido de muito Baixo Peso , Estimulantes do Sistema Nervoso Central/uso terapêutico , Permeabilidade do Canal Arterial/complicações , Enterocolite Necrosante/etiologia , Medicina Baseada em Evidências , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Inflamação , Transtornos Motores/complicações , Segurança do Paciente , Retinopatia da Prematuridade/complicações , Transtornos da Visão/complicações , Xantinas/uso terapêutico
7.
Eur Respir Rev ; 27(148)2018 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-29720510

RESUMO

Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD.


Assuntos
Broncodilatadores/uso terapêutico , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Xantinas/uso terapêutico , Broncodilatadores/efeitos adversos , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Recuperação de Função Fisiológica , Teofilina/análogos & derivados , Teofilina/uso terapêutico , Resultado do Tratamento , Xantinas/efeitos adversos
8.
J Nutr Sci Vitaminol (Tokyo) ; 64(2): 151-160, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29710033

RESUMO

Cacao extract (CE) consumption has beneficial effects on human health, such as lowering the risk of obesity. However, the underlying molecular mechanism for the anti-obesity effect of CE remains incompletely understood. Here, we used a 50% aqueous alcohol extract of cacao mass, which is rich in methylxanthine derivatives (about 11%) and poor in flavan-3-ols (less than 1%), and assessed the suppression effects of this extract on adipocyte differentiation to investigate the anti-obesity mechanism. CE dose-dependently decreased fat accumulation in 3T3-L1 cells without affecting cell viability. CE also dose-dependently decreased the protein and gene expression levels of two adipogenesis-related transcription factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPs). Moreover, CE decreased protein expression levels of sterol regulatory element-binding protein 1 (SREBP1) and its downstream fatty acid synthase (FAS), which was accompanied by the retained localization of SREBP1 in the cytoplasm of 3T3-L1 cells. After ICR mice were fed a diet containing 1% CE for 1 wk, their white adipose tissue weight was lower, whereas their brown adipose tissue weight was higher compared with those of control animals. Additionally, the protein expression levels of PPARγ, C/EBPs, SREBP1, and FAS in the white adipose tissue of these mice were also lower than those in control animals. In contrast, diet supplementation with CE induced higher levels of phosphorylated AMP-activated protein kinase (AMPK) and its downstream acetyl-CoA carboxylase. In conclusion, methylxanthine derivative-rich CE decreases fat accumulation in adipocytes by downregulating the expression of the adipocyte differentiation master regulators through the activation of AMPK.


Assuntos
Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Cacau/química , Obesidade/metabolismo , PPAR gama/metabolismo , Xantinas/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Chocolate , Regulação para Baixo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Obesidade/prevenção & controle , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Xantinas/uso terapêutico
9.
Mini Rev Med Chem ; 18(14): 1168-1174, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29692248

RESUMO

In the past decades, many efforts were undertaken to develop ligands for the adenosine receptors, with the purpose to individuate agonists and antagonists affinity and selectivity for each subtypes, namely A1, A2A, A2B, and A3. These intense studies allowed a deeper knowledge of the nature and, moreover, of the pathophysiological roles of all the adenosine receptor subtypes. In particular, the involvement of the A2A adenosine receptor subtype in some physiological mechanisms in the brain, that could be related to important diseases such as the Parkinson's disease, encouraged the research in this field. Particular attention was given to the antagonists endowed with high affinity and selectivity since they could have a real employment in the treatment of Parkinson's disease, and some compounds, such as istradefylline, preladenant and tozadenant, are already studied in clinical trials. Actually, the role of A2A antagonists in Parkinson's disease is becoming contradictory due to contrasting results in the last studies, but, at the same time, new possible employments are emerging for this class of antagonists in cancer pathologies as much interesting to legitimate further efforts in the research of A2A ligands.


Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/metabolismo , Compostos Bicíclicos com Pontes/uso terapêutico , Cafeína/química , Cafeína/metabolismo , Cafeína/uso terapêutico , Dopaminérgicos/química , Dopaminérgicos/metabolismo , Dopaminérgicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Doença de Parkinson/patologia , Receptor A2A de Adenosina/química , Xantinas/química , Xantinas/metabolismo , Xantinas/uso terapêutico
10.
J Perinatol ; 38(6): 702-707, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29515224

RESUMO

OBJECTIVE: We often encounter infants who developed hypokalaemia following low-dose doxapram for apnea of prematurity (AOP). AIMS: To determine changes in blood potassium (K+) levels after doxapram administration. STUDY DESIGN: We studied infants born before 30 weeks gestation. Doxapram (0.1-0.3 mg/kg/h) in addition to methylxanthines was used to treat AOP refractory to methylxanthines. RESULTS: Twenty-five infants received doxapram were studied. Fifty-two percent developed hypokalemia (<3.0 mEq/L) during doxapram administration. Time after starting doxapram to nadir blood K+ (<3.0 mEq/L) level was 11 days. Blood K+ levels normalized after 5 days of stopping doxapram administration. Data at 10 days before and after and at the time of doxapram administration were, respectively: lowest blood K+ level: 3.9, 3.0, and 3.6 mEq/L; urine aldosterone: 90, 206, and 146 pg/µg creatinine. Blood pH, blood pressure and urine volume were similar. CONCLUSIONS: Doxapram-induced hypokalemia may be due to an inappropriate increase in aldosterone levels.


Assuntos
Aldosterona/urina , Doxapram/efeitos adversos , Hipopotassemia/induzido quimicamente , Recém-Nascido Prematuro , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Xantinas/efeitos adversos , Estudos de Coortes , Creatinina/sangue , Relação Dose-Resposta a Droga , Doxapram/uso terapêutico , Esquema de Medicação , Feminino , Seguimentos , Idade Gestacional , Hospitais Pediátricos , Humanos , Hipopotassemia/epidemiologia , Incidência , Recém-Nascido , Japão , Masculino , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Xantinas/uso terapêutico
11.
Invest Ophthalmol Vis Sci ; 59(1): 472-486, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29368006

RESUMO

Purpose: Previous studies suggest that the adenosine receptor antagonist, 7-methylxanthine (7-MX), retards myopia progression. Our aim was to determine whether 7-MX alters the compensating refractive changes produced by defocus in rhesus monkeys. Methods: Starting at age 3 weeks, monkeys were reared with -3 diopter (D; n = 10; 7-MX -3D/pl) or +3D (n = 6; 7-MX +3D/pl) spectacles over their treated eyes and zero-powered lenses over their fellow eyes. In addition, they were given 100 mg/kg of 7-MX orally twice daily throughout the lens-rearing period (age 147 ± 4 days). Comparison data were obtained from lens-reared controls (-3D/pl, n = 17; +3D/pl, n = 9) and normal monkeys (n = 37) maintained on a standard diet. Refractive status, corneal power, and axial dimensions were assessed biweekly. Results: The -3D/pl and +3D/pl lens-reared controls developed compensating myopic (-2.10 ± 1.07 D) and hyperopic anisometropias (+1.86 ± 0.54 D), respectively. While the 7-MX +3D/pl monkeys developed hyperopic anisometropias (+1.79 ± 1.11 D) that were similar to those observed in +3D/pl controls, the 7-MX -3D/pl animals did not consistently exhibit compensating myopia in their treated eyes and were on average isometropic (+0.35 ± 1.96 D). The median refractive errors for both eyes of the 7-MX -3D/pl (+5.47 D and +4.38 D) and 7-MX +3D/pl (+5.28 and +3.84 D) monkeys were significantly more hyperopic than that for normal monkeys (+2.47 D). These 7-MX-induced hyperopic ametropias were associated with shorter vitreous chambers and thicker choroids. Conclusions: In primates, 7-MX reduced the axial myopia produced by hyperopic defocus, augmented hyperopic shifts in response to myopic defocus, and induced hyperopia in control eyes. The results suggest that 7-MX has therapeutic potential in efforts to slow myopia progression.


Assuntos
Anisometropia/tratamento farmacológico , Modelos Animais de Doenças , Emetropia/efeitos dos fármacos , Miopia/tratamento farmacológico , Antagonistas de Receptores Purinérgicos P1/uso terapêutico , Xantinas/uso terapêutico , Administração Oral , Animais , Animais Recém-Nascidos , Anisometropia/fisiopatologia , Biometria , Emetropia/fisiologia , Hiperopia/fisiopatologia , Macaca mulatta , Miopia/fisiopatologia , Antagonistas de Receptores Purinérgicos P1/administração & dosagem , Xantinas/administração & dosagem
12.
Eur J Pharmacol ; 819: 9-15, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-28974348

RESUMO

In the right atrium (RA), adenosine and acetylcholine inhibit the pacemaker function of the sinoatrial node and induce cardiac arrest. Pre-incubation of receptor antagonists is known to inhibit the cardiac arrest induced by these agonists; however, the effect of antagonist administration after established cardiac arrest has not been described. Therefore, we assessed whether specific receptor antagonists could revert cardiac arrest induced by adenosine and muscarinic receptors activation. RA isolated from adults Wistar rats were mounted in an organ bath containing Krebs solution. Cardiac arrest was induced by adenosine or ATP (1mM), the A1 adenosine receptor agonist CPA (0.1-1µM), and muscarinic receptor agonists, carbachol (0.3-1µM) and acetylcholine (1mM). After establishing the cardiac arrest, the A1 adenosine receptor antagonist DPCPX (0.3-30µM), the muscarinic receptor antagonist atropine (10nM to 100µM) or the phosphodiesterase inhibitor IBMX (10-300µM) were incubated in order to check for the return of spontaneous contractions. DPCPX reversed the cardiac arrest induced by adenosine, ATP and CPA. In addition, atropine reversed the cardiac arrest induced by carbachol. Unexpectedly, DPCPX also reversed the cardiac arrest induced by carbachol. Similarly to DPCPX, the phosphodiesterase inhibitor IBMX reversed the cardiac arrest induced by adenosine, CPA and carbachol. The antagonism of adenosine and acetylcholine receptors activation, as well as phosphodiesterase inhibition, are able to revert cardiac arrest. DPCPX restore spontaneous contractions via the selective antagonism of A1 adenosine receptor and through a secondary mechanism likely related to phosphodiesterase inhibition.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/tratamento farmacológico , Agonistas Muscarínicos/farmacologia , Receptor A1 de Adenosina/metabolismo , Receptores Muscarínicos/metabolismo , Xantinas/farmacologia , Animais , Carbacol/farmacologia , Masculino , Ratos , Ratos Wistar , Xantinas/uso terapêutico
13.
Brain Res ; 1682: 14-23, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29274881

RESUMO

BACKGROUND: Neuropathic pain is relatively common and occurs in approximately 6-8% of the population. It is associated with allodynia and hyperalgesia. Thus, non-pharmacological treatments, such as transcranial direct current stimulation (tDCS) may be useful for relieving pain. OBJECTIVES: This study aimed to investigate the antiallodynic effect of tDCS in a mice model of neuropathic pain, and the underlying neurotransmission systems that could drive these effects. METHODS: Male, Swiss mice, weighing 25-35 g, were subjected to partial sciatic nerve ligation (PSNL). Allodynia was assessed using a Von Frey filament (0.6 g). First, the behavioral time-course of these mice was assessed after 5, 10, 15 and 20 min of tDCS (0.5 mA). Second, the mice that underwent PSNL were assigned to either the tDCS (0.5 mA, 15 min) or tDCS sham group, and further assigned to receive either saline or a drug (i.e., naloxone, yohimbine, a-methyl-p-tyrosine, q-chlorophenylalanine methyl ester, caffeine, 1,3-dipropyl-8-cyclopentylxanthine, AM281, AM630, flumazenil, MK-801, or lidocaine). RESULTS: The antiallodynic effect of tDCS lasted 2 h and 4 h, after 10 min and 15 or 20 min of treatment, respectively (P < .001, P < .01, and P < .05, respectively). The antiallodynic effect of tDCS was associated with all the systems that were analyzed, i.e., the opioidergic (P < .01), adenosinergic (P < .001), serotonergic (P < .01), noradrenergic (P < .001), cannabinoid (P < .001), GABAergic, and glutamatergic (P < .001) systems. Lidocaine did not reverse the antiallodynic effect of tDCS (P > .05). CONCLUSION: The antiallodynic effect of tDCS was associated with different neurotransmitters systems; the duration of these after-effects depended on the time exposure to tDCS.


Assuntos
Hiperalgesia/etiologia , Hiperalgesia/terapia , Neuralgia/complicações , Neuralgia/terapia , Limiar da Dor/fisiologia , Estimulação Transcraniana por Corrente Contínua/métodos , Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Animais , Cafeína/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Modelos Animais de Doenças , Maleato de Dizocilpina/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Flumazenil/uso terapêutico , Moduladores GABAérgicos/uso terapêutico , Masculino , Camundongos , Morfolinas/uso terapêutico , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Estimulação Física/efeitos adversos , Pirazóis/uso terapêutico , Xantinas/uso terapêutico
14.
J Inorg Biochem ; 181: 104-110, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29150325

RESUMO

Ilex paraguariensis, yerba mate is a native plant from the southern region of Brazil. Studies showed that yerba mate has an antioxidant potential, which could help to reduce the risk of developing neurodegenerative diseases, as Alzheimer's Disease (AD). It's known that I. paraguariensis grows in acid soils with aluminium (Al), which is bioavailable in these soils. Al has a neurotoxic potential related with the progression of neurological disorders. This study aim was to evaluate the potential of I. paraguariensis in the etiology of AD using strains of Caenorhabditis elegans and the concentration of Al and antioxidants in the yerba mate extract. The results of the I. paraguariensis infusions made at 65°C and at 75° C show that there was no significant difference between both temperatures when preparing the tea infusion in relation to the presence of Al, methylxanthines, phenolic compounds and flavonoids. Additionally, in the case of Al, there was no difference between the extracts prepared at both temperatures. The behavioral parameters of C. elegans were altered after a long-term exposure to both factors: I. paraguariensis extract and Al. Through the antioxidant levels results along with the Al content on the Acetylcholinesterase (AChE) activity it is possible to observe that the acute and chronic exposure to Al and I. paraguariensis leaves extract are very similar to wild-type worms. Moreover, we can observe that the results in both the transgenic strains long-term exposed to I. paraguariensis leaves extract and to the Al concentrations presented an increase in the AChE activity.


Assuntos
Alumínio/toxicidade , Doença de Alzheimer/etiologia , Modelos Animais de Doenças , Contaminação de Alimentos , Ilex paraguariensis/química , Poluentes do Solo/toxicidade , Chás de Ervas/efeitos adversos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Alumínio/análise , Doença de Alzheimer/prevenção & controle , Animais , Animais Geneticamente Modificados , Antioxidantes/análise , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Brasil , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/agonistas , Proteínas de Caenorhabditis elegans/metabolismo , Flavonoides/análise , Flavonoides/uso terapêutico , Ilex paraguariensis/crescimento & desenvolvimento , Síndromes Neurotóxicas/fisiopatologia , Fenóis/análise , Fenóis/uso terapêutico , Folhas de Planta/química , Folhas de Planta/crescimento & desenvolvimento , Poluentes do Solo/análise , Chás de Ervas/análise , Testes de Toxicidade Aguda , Testes de Toxicidade Crônica , Xantinas/análise , Xantinas/química , Xantinas/uso terapêutico
15.
Emerg Med Pract ; 19(10 Suppl): S1-S2, 2017 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-29068643

RESUMO

Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a clinical diagnosis that is based on changes in dyspnea, cough, and/or sputum production in a COPD patient; however, patients presenting with an acute exacerbation may be undiagnosed or have a variety of comorbid conditions that can complicate diagnosis. This issue presents strategies and algorithms for the early use of evidence-based interventions, including appropriate use of antibiotics, bronchodilators, and corticosteroids, along with noninvasive ventilation with capnography, to minimize morbidity and mortality associated with this disease. [Points & Pearls is a digest of Emergency Medicine Practice.].


Assuntos
Gerenciamento Clínico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/terapia , Broncodilatadores/farmacologia , Broncodilatadores/uso terapêutico , Tosse/etiologia , Diagnóstico Diferencial , Dispneia/etiologia , Eletrocardiografia/métodos , Humanos , Magnésio/farmacologia , Magnésio/uso terapêutico , Oximetria/métodos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Espirometria/métodos , Escarro/microbiologia , Esteroides/farmacologia , Esteroides/uso terapêutico , Xantinas/farmacologia , Xantinas/uso terapêutico
16.
Cell Physiol Biochem ; 43(2): 733-742, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28950257

RESUMO

BACKGROUND/AIMS: The adenosine A1 receptor (A1R) has been reported to be involved in the pathogenesis of various cancers, and the effects of A1R on different cancers are pleiotropic. However, the role of A1R in renal cell carcinoma (RCC) remains not well-known. METHODS: The expression of A1R in RCC cells was detected by quantitative real-time PCR and Western blotting analysis. Cell proliferation was detected using an MTT assay and a colony formation assay. Tumor growth was also evaluated in nude mice. Cell invasion and migration were evaluated using a wound healing assay and a transwell assay. Cell cycle distribution and apoptosis rates were analyzed by flow cytometry. RESULTS: A1R was the main subtype of ARs and was up-regulated in 786-O and ACHN cells. Functionally, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an A1R antagonist, inhibited RCC cell proliferation in vitro and tumor growth in vivo. Furthermore, DPCPX inhibited RCC cell migration, while N6-Cyclopentyladenosine (CPA), a selective A1 agonist, was able to rescue RCC cell migration. In addition, DPCPX promoted 786-O and ACHN cell apoptosis and induced an S phase cell cycle arrest. Finally, we demonstrated that DPCPX inhibited tumor progression in part via the ERK/JNK pathway. CONCLUSION: These findings suggest the potentially important role of DPCPX in the control of RCC cell proliferation and migration by regulating the ERK/JNK signaling pathway.


Assuntos
Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Rim/efeitos dos fármacos , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Xantinas/uso terapêutico , Animais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor A1 de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Cell Signal ; 39: 55-65, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28754627

RESUMO

Intracellular cyclic AMP and/or cyclic GMP are characterized in the 1960th. These second messengers, hydrolysed specifically by cyclic nucleotide phosphodiesterase (PDE), play a major role in intracellular signalling. Natural products have been a rich source of drug discovery, Theophylline and Methylxanthine originated from tea leaves used for asthma treatment, whereas, Papaverine, a natural isoquinolein originated from Papaver somniferum traditionally used in impotency, altogether as caffeine where firstly described as PDE-inhibiting compounds. Since that time, the knowledge in PDE field has been drastically increased, allowing the design and development of new therapeutic drugs acting against different pathologies in the nanomolar range. During this period some natural compounds have been identified as PDE inhibitors and used in that context to investigate their therapeutic potential effects. The aim of this literature review is to point out the reported data and demonstrating the contribution of natural characterized molecules as PDE inhibitors in various pathologies that can open new fields of research for drug discovery, notably in epigenetic regulation.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Descoberta de Drogas , Epigênese Genética/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Animais , Asma/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Camundongos , Neovascularização Patológica/tratamento farmacológico , Papaverina/farmacologia , Papaverina/uso terapêutico , Teofilina/farmacologia , Teofilina/uso terapêutico , Xantinas/farmacologia , Xantinas/uso terapêutico
18.
Cardiovasc Drugs Ther ; 31(3): 281-293, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28656542

RESUMO

BACKGROUND: Over the last 50 years, clinical trials of novel interventions for acute heart failure (AHF) have, with few exceptions, been neutral or shown harm. We hypothesize that this might be related to a differential response to pharmacological therapy. METHODS: We studied the magnitude of treatment effect of rolofylline across clinical characteristics and plasma biomarkers in 2033 AHF patients and derived a biomarker-based responder sum score model. Treatment response was survival from all-cause mortality through day 180. RESULTS: In the overall study population, rolofylline had no effect on mortality (HR 1.03, 95% CI 0.82-1.28, p = 0.808). We found no treatment interaction across clinical characteristics, but we found interactions between several biomarkers and rolofylline. The biomarker-based sum score model included TNF-R1α, ST2, WAP four-disulfide core domain protein HE4 (WAP-4C), and total cholesterol, and the score ranged between 0 and 4. In patients with score 4 (those with increased TNF-R1α, ST2, WAP-4C, and low total cholesterol), treatment with rolofylline was beneficial (HR 0.61, 95% CI 0.40-0.92, p = 0.019). In patients with score 0, treatment with rolofylline was harmful (HR 5.52, 95% CI 1.68-18.13, p = 0.005; treatment by score interaction p < 0.001). Internal validation estimated similar hazard ratio estimates (0 points: HR 5.56, 95% CI 5.27-7-5.87; 1 point: HR 1.31, 95% CI 1.25-1.33; 2 points: HR 0.75, 95% CI 0.74-0.76; 3 points: HR 1.13, 95% CI 1.11-1.15; 4 points, HR 0.61, 95% CI 0.61-0.62) compared to the original data. CONCLUSION: Biomarkers are superior to clinical characteristics to study treatment heterogeneity in acute heart failure.


Assuntos
Biomarcadores/metabolismo , Diuréticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Xantinas/uso terapêutico , Doença Aguda , Idoso , Feminino , Humanos , Masculino
20.
Acta Pharmacol Sin ; 38(5): 638-650, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28239158

RESUMO

We previously identified AG-690/11026014 (6014) as a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor that effectively prevented angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. In the present study, we reported a new synthesis route for 6014, and investigated its protective effects on Ang II-induced cardiac remodeling and cardiac dysfunction and the underlying mechanisms in mice. We designed a new synthesis route to obtain a sufficient quantity of 6014 for this in vivo study. C57BL/6J mice were infused with Ang II and treated with 6014 (10, 30, 90 mg·kg-1·d-1, ig) for 4 weeks. Then two-dimensional echocardiography was performed to assess the cardiac function and structure. Histological changes of the hearts were examined with HE staining and Masson's trichrome staining. The protein expression was evaluated by Western blot, immunohistochemistry and immunofluorescence assays. The activities of sirtuin-1 (SIRT-1) and the content of NAD+ were detected with the corresponding test kits. Treatment with 6014 dose-dependently improved cardiac function, including LVEF, CO and SV and reversed the changes of cardiac structure in Ang II-infused mice: it significantly ameliorated Ang II-induced cardiac hypertrophy evidenced by attenuating the enlargement of cardiomyocytes, decreased HW/BW and LVW/BW, and decreased expression of hypertrophic markers ANF, BNP and ß-MHC; it also prevented Ang II-induced cardiac fibrosis, as implied by the decrease in excess accumulation of extracellular matrix (ECM) components collagen I, collagen III and FN. Further studies revealed that treatment with 6014 did not affect the expression levels of PARP-1, but dose-dependently inhibited the activity of PARP-1 and subsequently restored the activity of SIRT-1 in heart tissues due to the decreased consumption of NAD+ and attenuated Poly-ADP-ribosylation (PARylation) of SIRT-1. In conclusion, the novel PARP-1 inhibitor 6014 effectively protects mice against AngII-induced cardiac remodeling and improves cardiac function. Thus, 6014 might be a potential therapeutic agent for heart diseases..


Assuntos
Cardiomegalia/terapia , Cardiotônicos/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Tioglicolatos/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Xantinas/uso terapêutico , Angiotensina II/farmacologia , Animais , Cardiomegalia/induzido quimicamente , Cardiotônicos/síntese química , Fibrose/induzido quimicamente , Fibrose/terapia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Sirtuína 1/metabolismo , Tioglicolatos/síntese química , Xantinas/síntese química
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