RESUMO
Therapeutic hypothermia is the standard treatment for hypoxic-ischemic encephalopathy (HIE), but despite its widespread use, the rates of mortality and neurodevelopmental impairment for moderate to severe HIE remain around 30%. Methylxanthines, such as caffeine and aminophylline, have potential neuroprotective effects in the setting of hypoxic-ischemic injury. However, data on the safety and efficacy of methylxanthines in the setting of therapeutic hypothermia for HIE are limited. This retrospective multicenter study examined in-hospital outcomes in 52 infants with HIE receiving methylxanthines and therapeutic hypothermia. The frequency of mortality and in-hospital morbidities were similar to those of infants enrolled in clinical trials undergoing therapeutic hypothermia without adjunctive therapies. Clinical trials of methylxanthines for neuroprotection in HIE are needed to determine safety and efficacy and should explore optimal dosing and timing of methylxanthine administration.
Assuntos
Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Fármacos Neuroprotetores , Xantinas , Humanos , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Estudos Retrospectivos , Masculino , Feminino , Xantinas/uso terapêutico , Recém-Nascido , Fármacos Neuroprotetores/uso terapêutico , Hipotermia Induzida/métodos , Cafeína/uso terapêutico , Cafeína/administração & dosagem , Lactente , Resultado do Tratamento , Aminofilina/uso terapêutico , Aminofilina/administração & dosagemRESUMO
Effects of the Adenosine A1 blockade using 8-cyclopentyl-1,3-diprophyxanthine (DPCPX) nanoconjugate on inducing recovery of the hemidiaphragm paralyzed by hemisection have been thoroughly examined previously; however, the toxicology of DPCPX nanoconjugate remains unknown. This research study investigates the therapeutic efficacy and toxicology of the nanoconjugate DPCPX in the cervical spinal cord injury (SCI) rat model. We hypothesized that a single injection of nanoconjugate DPCPX in the paralyzed left hemidiaphragm (LDH) of hemisected rats at the 2nd cervical segment (C2Hx) would lead to the long-term recovery of LDH while showing minimal toxicity. Adult male rats underwent left C2Hx surgery and the diaphragms' baseline electromyography (EMG). Subsequently, rats were randomized into a control group and four treated subgroups. Three subgroups received a single intradiaphragmatic dose of either 0.09, 0.15, or 0.27 µg/kg, and one subgroup received 0.1 mg/kg of native DPCPX two times per day intravenously (i.v.) for 3 days (total 0.6 mg/kg). Rats were monitored for a total of 56 days. Compared with control, the treatment with nanoconjugate DPCPX at 0.09 µg/kg, 0.15 µg/kg, and 0.27 µg/kg doses elicited significant recovery of paralyzed LDH (i.e., 67% recovery at 8 wk) (P < 0.05). DPCPX nanoconjugate-treated rats had significant weight loss for first 2 wk but recovered significantly by day 56 (P < 0.05). The levels of gold in the blood and body tissues were below the recommended levels. No sign of weakness, histology of tissue damage, or organ abnormality was observed. A dose of DPCPX nanoconjugate can induce long-term diaphragm recovery after SCI without observed toxicity.NEW & NOTEWORTHY The intradiaphragmatic administration of nanoconjugate is safe and has the promise to significantly reduce the therapeutic dosage for the treatment and achieve long-term and possibly permanent recovery in respiratory muscle dysfunction after SCI. No toxicity of nanoconjugate was found in any of the experimental animals.
Assuntos
Nanoconjugados , Traumatismos da Medula Espinal , Xantinas , Animais , Diafragma , Masculino , Nanoconjugados/uso terapêutico , Nanoconjugados/toxicidade , Ratos , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/tratamento farmacológico , Xantinas/uso terapêutico , Xantinas/toxicidadeRESUMO
Inhaled therapy remains the cornerstone of chronic obstructive pulmonary disease pharmacologic care, but some systemic treatments can be of help when the burden of the disease remains high. Azithromycin, phosphodiesterase-4 inhibitors, and mucoactive agents can be used in such situations. The major difficulty remains in the identification of the optimal target populations. Another difficulty is to determine how these treatments should be positioned in the global treatment algorithm. For instance, should they be prescribed in addition to other antiinflammatory agents or should they replace them in some cases? Research is ongoing to identify new therapeutic targets.
Assuntos
Corticosteroides/uso terapêutico , Macrolídeos/uso terapêutico , Morfina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Teofilina/uso terapêutico , alfa 1-Antitripsina/uso terapêutico , Administração Oral , Animais , Azitromicina/uso terapêutico , Humanos , Estresse Oxidativo , Resultado do Tratamento , Xantinas/metabolismo , Xantinas/uso terapêuticoRESUMO
6-Hydroxydopamine (6-OHDA) is the most used toxin in experimental Parkinson's disease (PD) models. 6-OHDA shows high affinity for the dopamine transporter and once inside the neuron, it accumulates and undergoes non-enzymatic auto-oxidation, promoting reactive oxygen species (ROS) formation and selective damage of catecholaminergic neurons. In this way, our group has established a 6-OHDA in vitro protocol with rat striatal slices as a rapid and effective model for screening of new drugs with protective effects against PD. We have shown that co-incubation with guanosine (GUO, 100 µM) prevented the 6-OHDA-induced damage in striatal slices. As the exact GUO mechanism of action remains unknown, the aim of this study was to investigate if adenosine A1 (A1R) and/or A2A receptors (A2AR) are involved on GUO protective effects on striatal slices. Pre-incubation with DPCPX, an A1R antagonist prevented guanosine effects on 6-OHDA-induced ROS formation and mitochondrial membrane potential depolarization, while CCPA, an A1R agonist, did not alter GUO effects. Regarding A2AR, the antagonist SCH58261 had similar protective effect as GUO in ROS formation and mitochondrial membrane potential. Additionally, SCH58261 did not affect GUO protective effects. The A2AR agonist CGS21680, although, completely blocked GUO effects. Finally, the A1R antagonist DPCPX, and the A2AR agonist CGS21680 also abolished the preventive guanosine effect on 6-OHDA-induced ATP levels decrease. These results reinforce previous evidence for a putative interaction of GUO with A1R-A2AR heteromer as its molecular target and clearly indicate a dependence on adenosine receptors modulation to GUO protective effect.
Assuntos
Guanosina/farmacologia , Doenças Mitocondriais/prevenção & controle , Neostriado/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Receptor A1 de Adenosina/efeitos dos fármacos , Receptor A2A de Adenosina/efeitos dos fármacos , Explosão Respiratória/efeitos dos fármacos , Antagonistas do Receptor A1 de Adenosina/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Xantinas/uso terapêuticoRESUMO
Some evidence suggests that caffeine, theophylline, and theobromine, as natural methylxanthines (MTXs), possess anti-cancer effects. We systematically reviewed the animal and human studies investigating the effect of (or association between) dietary natural MTXs on (and) colorectal cancer (CRC) and performed a meta-analysis of epidemiological studies. Relevant studies were identified by searching MEDLINE, Embase, Scopus, and Web of Knowledge through September 2020. The overall relative risk (RR) and confidence interval (CI) were determined using a random-effects model. Eight animal and eight epidemiological investigations met our inclusion criteria. Animal studies indicated detrimental effects of high levels of caffeine intake on the initiation and promotion of CRC, while showing beneficial or non-significant effects at lower doses. The meta-analysis of six epidemiological studies found no association between dietary caffeine intake and the risk of CRC (RR = 0.98 (95% CI = 0.88-1.10)). Subgroup analysis revealed a direct association between caffeine intake and risk of CRC only in the studies with a moderate risk of bias and a lack of adjustment for smoking. The results of the only epidemiological study investigating the association between the serum levels of MTXs and the risk of CRC showed an inverse association. In conclusion, some animal studies underlined the beneficial effects of caffeine, at regular doses consumed by humans, on CRC. However, current epidemiological evidence does not support an association between caffeine intake and the risk of CRC.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Dieta , Xantinas/uso terapêutico , Animais , Cafeína/administração & dosagem , Bases de Dados Factuais , HumanosRESUMO
The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.
Assuntos
Carcinogênese/genética , Proteínas de Membrana/genética , Neoplasias/genética , Nucleotidiltransferases/genética , Terapia Biológica/tendências , Carcinogênese/imunologia , Humanos , Imunoterapia/tendências , Interferon Tipo I/genética , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Transdução de Sinais/genética , Xantinas/uso terapêuticoRESUMO
COVID-19 pandemic presents an unprecedented challenge to identify effective drugs for treatment. Despite multiple clinical trials using different agents, there is still a lack of specific treatment for COVID-19. Having the potential role in suppressing inflammation, immune modulation, antiviral and improving respiratory symptoms, this review discusses the potential role of methylxanthine drugs like pentoxifylline and caffeine in the management of COVID-19 patients. COVID-19 pathogenesis for clinical features like severe pneumonia, acute lung injury (ALI) / acute respiratory distress syndrome (ARDS), and multi-organ failures are excessive inflammation, oxidation, and cytokine storm by the exaggerated immune response. Drugs like pentoxifylline have already shown improvement of the symptoms of ARDS and caffeine has been in clinical use for decades to treat apnea of prematurity (AOP) in preterm infants and improve respiratory function. Pentoxifylline is well-known anti-inflammatory and anti-oxidative molecules that have already shown to suppress Tumor Necrosis Factor (TNF-α) as well as other inflammatory cytokines in pulmonary diseases, and this may be beneficial for better clinical outcomes in COVID-19 patients. Pentoxifylline enhances blood flow, improves microcirculation and tissue oxygenation, and caffeine also efficiently improves tissue oxygenation, asthma, decreases pulmonary hypertension and an effective analgesic. There are significant shreds of evidence that proved the properties of pentoxifylline and caffeine against virus-related diseases as well. Along with the aforementioned evidences and high safety profiles, both pentoxifylline and caffeine offer a glimpse of considerations for future use as a potential adjuvant to COVID-19 treatment. However, additional clinical studies are required to confirm this speculation.
Assuntos
Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pentoxifilina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Xantinas/farmacologia , Xantinas/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , COVID-19 , Cafeína/farmacologia , Cafeína/uso terapêutico , Infecções por Coronavirus/complicações , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Inflamação/tratamento farmacológico , Inflamação/etiologia , Pentoxifilina/farmacologia , Pneumonia Viral/complicações , Tratamento Farmacológico da COVID-19RESUMO
Inflammation is pivotal for the development of gastrointestinal cancer and linked to poor survival and limited therapeutic options. In this study, six structurally different carotenoids were isolated and identified from the methanolic extract of Exiguobacterium acetylicum S01 namely lycopene (Car-I), diapolycopenedioic-acid-diglucosyl-ester (Car-II), ß-carotene (Car-III), zeaxanthin (Car-IV), astaxanthin (Car-V), and keto-myxocoxanthin glucoside-ester (Car-VI). Further, their anti-cancer, anti-inflammatory, and antioxidant potentials were evaluated. The MTT assay was used to determine the effect of carotenoids on viability of colorectal cancer (HT-29) as well as peripheral blood mononuclear cells (PBMCs). Results revealed that all the six carotenoids were demonstrated a significant inhibition of HT-29 cells viability in a dose-dependent manner whereas there was no cytotoxic effect in PBMCs. The study also recorded that six carotenoids considerably inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production, tumor necrosis factor-alpha (TNF-α), and lipid peroxidation in PBMCs. Moreover, antioxidant potentials of Car-II and Car-VI were significantly (p = 0.001) higher than ascorbic acid as determined by a 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay. Therefore, our results ascertained the role of carotenoids derived from E. acetylicum S01 in developing potential therapeutic agents for inflammation-associated cancer.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Carotenoides/uso terapêutico , Xantinas/uso terapêutico , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Carotenoides/farmacologia , Exiguobacterium/química , Humanos , Estresse Oxidativo , Xantinas/farmacologiaRESUMO
Background: Methylxanthines and leukotriene receptor antagonists (LTRA) are not a first-line medical treatment for chronic obstructive pulmonary disease (COPD) but are frequently prescribed despite limited evidence. We aimed to elucidate the real prescribing status and clinical impacts of these agents in early COPD patients. Methods: Patients with mild-to-moderate COPD (FEV1>50%) were selected from the Korean National Health and Nutrition Examination Survey data between 2007 and 2012. Besides analyzing the prescription status of methylxanthines and LTRA and the contributing factors to the prescription, we evaluated the clinical impacts of these drugs on the exacerbation, hospitalization, and medical costs. Results: Of 2269 patients with mild-to-moderate COPD, 378 patients (16.7%) were under medical treatments, and the users of methylxanthines and/or LTRA were 279 patients (12.3%); however, only 139 patients (6.1%) were inhaler users. The contributing factors for the prescription of methylxanthines were a comorbidity of asthma or allergic disease, poor lung function, low quality of life, prescribing doctor from the specialty of internal medicine, and an institution type of private hospital. The prescription of LTRA was associated with the comorbidity of allergic disease. The methylxanthine and/or LTRA users had more hospital utilization but did not have significant differences in acute exacerbations and medical cost for hospital utilization, compared with the non-users. Conclusion: Methylxanthines and LTRA were used in a significant proportion of patients with mild-to-moderate COPD in real fields without favorable impacts on the exacerbations, hospitalizations, or medical costs. The use of more effective inhaled medications should be encouraged.
Assuntos
Broncodilatadores/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Pulmão/efeitos dos fármacos , Padrões de Prática Médica/tendências , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Xantinas/uso terapêutico , Idoso , Broncodilatadores/efeitos adversos , Broncodilatadores/economia , Progressão da Doença , Custos de Medicamentos , Prescrições de Medicamentos , Uso de Medicamentos/tendências , Feminino , Volume Expiratório Forçado , Custos Hospitalares , Hospitalização , Humanos , Antagonistas de Leucotrienos/efeitos adversos , Antagonistas de Leucotrienos/economia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/economia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , República da Coreia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Xantinas/efeitos adversos , Xantinas/economiaRESUMO
OBJECTIVES: Propentofylline is a xanthine phosphodiesterase inhibitor and adenosine reuptake blocker with neuroprotective effects linked to anti-inflammatory and antiexcitatory properties. This is a double-blind, placebo-controlled trial investigating the potential beneficial effects of propentofylline, as an adjunctive treatment with risperidone, on the severity and behavioral abnormalities of autism spectrum disorder (ASD). METHODS: A total of 48 children with ASD were randomly allocated into 2 groups of risperidone (initiating at 0.5 mg/d) plus propentofylline (initiating at 300 mg/d) and risperidone plus placebo. The Aberrant Behavior Checklist-Community (ABC-C) and Childhood Autism Rating Scale (CARS) were used for the evaluation of ASD severity and behavioral disruptions at baseline, week 4, and week 10. Primary outcome measure of the study was ABC-C irritability subscale score, whereas CARS score along with other 4 subscales of ABC-C (lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech subscales) were considered as secondary outcome measures. RESULTS: Results from the general linear model repeated measures analysis demonstrated significant time-treatment interaction on irritability subscale (F1.55 = 3.45; P = 0.048) and CARS (F1.41 = 4.08; P = 0.034) scores. Compared with the placebo group, children receiving propentofylline showed greater improvements in the CARS score (P = 0.037) from baseline to the study endpoint. Our results found no significant time-treatment effect on other subscales of ABC-C. Two trial groups were comparable based on the frequency of adverse effects. CONCLUSIONS: Our findings demonstrated that adjunctive treatment with propentofylline is effective in alleviating disease severity and improving irritability in ASD patients. However, larger studies with longer durations are required to confirm these results.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Risperidona/uso terapêutico , Xantinas/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/uso terapêutico , Risperidona/efeitos adversos , Resultado do Tratamento , Xantinas/efeitos adversosRESUMO
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 terapêuticoRESUMO
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 Quinase 2 de Interação com Receptor , 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 terapêuticoRESUMO
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/químicaRESUMO
BACKGROUND: Methylxanthines have cardiac stimulant effects. The current study aimed to compare acute hemodynamic changes between caffeine and aminophylline in ≤34 weeks' preterm neonates. METHODS: The study was performed using information on echocardiography measurements from preterm neonates recruited for apnea of prematurity (75 of 240) and preventing extubation failure (113 of 156) studies. The neonates were randomized either to the caffeine or aminophylline groups. Neonates with no maintenance followed by loading doses with both the methylxanthines (caffeine and aminophylline) and incomplete echocardiography examination were excluded. RESULTS: Cardiac parameters were found to be similar between groups. The heart rate was higher among the aminophylline-treated neonates (p < 0.001) than among the caffeine-treated ones. End-systolic volume was higher among both caffeine- (p < 0.001) and aminophylline-treated neonates (p = 0.001) when compared with pretreatment values. End-diastolic volume was statistically higher in both groups' neonates (p = 0.01). The odds of increase in cardiac output was higher; however, increase in ejection fraction was less in caffeine-treated small-for-gestation-age neonates. CONCLUSION: Caffeine has similar effects on cardiac parameters as aminophylline; however, caffeine-treated small-for-gestation stratification gave rise to significant cardiac variations.
Assuntos
Aminofilina/uso terapêutico , Apneia/tratamento farmacológico , Cafeína/uso terapêutico , Doenças do Prematuro/tratamento farmacológico , Desmame do Respirador/métodos , Xantinas/uso terapêutico , Apneia/diagnóstico , Cafeína/sangue , Relação Dose-Resposta a Droga , Ecocardiografia , Feminino , Idade Gestacional , Frequência Cardíaca/efeitos dos fármacos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Resultado do TratamentoRESUMO
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 terapêuticoRESUMO
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 Medicamentosas , Quimioterapia Combinada , Elevação dos Membros Posteriores , Imipramina/farmacocinética , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Reboxetina/farmacocinética , Antagonistas da Serotonina/farmacologiaRESUMO
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 terapêuticoRESUMO
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 1â 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 adversosRESUMO
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 terapêuticoRESUMO
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.