RESUMO
Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.
Assuntos
Doença de Chagas/enzimologia , Antagonistas do Ácido Fólico/farmacologia , Tripanossomicidas/farmacologia , Doença de Chagas/tratamento farmacológico , Simulação por Computador , Reposicionamento de Medicamentos , Antagonistas do Ácido Fólico/química , Glipizida/química , Glipizida/farmacologia , Glibureto/química , Glibureto/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Tripanossomicidas/química , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Reactive oxygen species (ROS) have been described in their double physiological function, helping in the maintenance of health as well as contributing to oxidative stress. Diabetes mellitus is a chronical disease nearly related to oxidative stress, whose treatment (in type II variant) consists in the administration of antidiabetic compounds (Andb) such as Gliclazide (Gli) and Glipizide (Glip). In this context, as Andb may be exposed to high ROS concentrations in diabetic patients, we have studied the potential ROS-mediated degradation of Gli and Glip through photosensitized processes, in the presence of Riboflavin (Rf) vitamin. We found that singlet oxygen (O2 (1 ∆g )) participated in the Rf-sensitized photodegradation of both Andb, and also superoxide radical anion in the case of Gli. Two principal products derived from O2 (1 ∆g )-mediated degradation of Gli were identified and their chemical structures characterized, through HPLC mass spectrometry. O2 (1 ∆g )-mediated degradation products and their toxicity was assayed on Vero cell line. These studies demonstrated that neither Gli nor its photoproducts caused cytotoxic effect under the experimental conditions assayed. Our results show strong evidences of ROS-mediated Andb degradation, which may involve the reduction or loss of their therapeutic action, as well as potential cytotoxicity derived from their oxidation products.
Assuntos
Gliclazida/química , Glipizida/química , Hipoglicemiantes/química , Fármacos Fotossensibilizantes/química , Riboflavina/química , Oxigênio Singlete/química , Superóxidos/química , Animais , Biotransformação/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gliclazida/metabolismo , Gliclazida/farmacologia , Glipizida/metabolismo , Glipizida/farmacologia , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Cinética , Luz , Oxirredução , Fotólise , Fármacos Fotossensibilizantes/metabolismo , Riboflavina/metabolismo , Oxigênio Singlete/metabolismo , Soluções , Espectrometria de Fluorescência , Superóxidos/metabolismo , Células VeroRESUMO
AIMS: To examine whether initiation of fibrates or statins in sulfonylurea users is associated with hypoglycaemia, and examine in vitro inhibition of cytochrome P450 (CYP) enzymes by statins, fenofibrate and glipizide. METHODS: We used healthcare data to conduct nested case-control studies of serious hypoglycaemia (i.e. resulting in hospital admission or emergency department treatment) in persons taking glipizide or glyburide, and calculated adjusted overall and time-stratified odds ratios (ORs) and 95% confidence intervals (CIs). We also characterized the in vitro inhibition of CYP enzymes by statins, fenofibrate and glipizide using fluorometric CYP450 inhibition assays, and estimated area under the concentration-time curve ratios (AUCRs) for the drug pairs. RESULTS: We found elevated adjusted overall ORs for glyburide-fenofibrate (OR 1.84, 95% CI 1.37, 2.47) and glyburide-gemfibrozil (OR 1.57, 95% CI 1.25, 1.96). The apparent risk did decline over time as might be expected from a pharmacokinetic mechanism. Fenofibrate was a potent in vitro inhibitor of CYP2C19 (IC50 = 0.2 µm) and CYP2B6 (IC50 = 0.7 µm) and a moderate inhibitor of CYP2C9 (IC50 = 9.7 µm). The predicted CYP-based AUCRs for fenofibrate-glyburide and gemfibrozil-glyburide interactions were only 1.09 and 1.04, suggesting that CYP inhibition is unlikely to explain such an interaction. CONCLUSIONS: Use of fenofibrate or gemfibrozil together with glyburide was associated with elevated overall risks of serious hypoglycaemia. CYP inhibition seems unlikely to explain this observation. We speculate that a pharmacodynamic effect of fibrates (e.g. activate peroxisome proliferator-activator receptor alpha) may contribute to these apparent interactions.
Assuntos
Ácidos Fíbricos/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipoglicemia/etiologia , Compostos de Sulfonilureia/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Estudos de Casos e Controles , Inibidores das Enzimas do Citocromo P-450/efeitos adversos , Inibidores das Enzimas do Citocromo P-450/farmacologia , Interações Medicamentosas , Feminino , Ácidos Fíbricos/farmacologia , Glipizida/efeitos adversos , Glipizida/farmacologia , Glibureto/efeitos adversos , Glibureto/farmacologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Farmacoepidemiologia , Compostos de Sulfonilureia/farmacologia , Adulto JovemRESUMO
In this study we examined the acute in vivo effect and short- and long-term in vitro effects of samples from native and commercial Ilex paraguariensis on glucose homeostasis. Also, the potential effect of I. paraguariensis on serum insulin secretion was investigated. The chemical identification and quantification of methyl xanthines and polyphenols in CH2Cl2, EtOAc and n-BuOH fractions of native I. paraguariensis as well as infusions of green and roasted I. paraguariensis from a commercial source was verified by high-performance liquid chromatography. The results for the serum glucose-lowering indicated that both fractions and both infusions were able to improve significantly the oral glucose tolerance curve. Additionally, both the EtOAc and n-BuOH fractions induced-insulin secretion, but EtOAc induced an early (at 15 min) and late (at 60 min) biphasic peak of insulin secretion similar to glipizide stimulatory effect. Both fractions increased liver glycogen content compared with fasted normal rats. Also, EtOAc and n-BuOH fractions inhibited in vitro disaccharidases activities after an acute treatment. The maximum inhibitory effect of the EtOAc and n-BuOH fractions on maltase activity (at 5 min) was around 35%. The evident reduction of protein glycation by glucose or fructose with EtOAc and n-BuOH fractions increased from 7 to 28 days of in vitro incubation. Inhibition of bovine serum albumin glycation by glucose and fructose, by around 50% and 90%, respectively, was observed. Additionally, the green and roasted mate infusions reduced the formation of AGEs in a characteristic long-term effect. In conclusion, this study shows that I. paraguariensis has an anti-hyperglycemic potential role able to improve the diabetic status and is probably a source of multiple hypoglycemic compounds.
Assuntos
Glicemia/metabolismo , Hipoglicemiantes/farmacologia , Ilex paraguariensis/química , Insulina/sangue , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Xantinas/farmacologia , Animais , Bebidas , Brasil , Bovinos , Cromatografia Líquida de Alta Pressão , Comércio , Dissacaridases/metabolismo , Inibidores Enzimáticos/farmacologia , Frutose/metabolismo , Glipizida/farmacologia , Teste de Tolerância a Glucose , Produtos Finais de Glicação Avançada/metabolismo , Glicogênio/metabolismo , Glicosilação , Homeostase/efeitos dos fármacos , Hipoglicemiantes/análise , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Extratos Vegetais/química , Polifenóis/análise , Proteínas/metabolismo , Ratos , Ratos Wistar , Valores de Referência , Albumina Sérica/metabolismo , Tempo , Xantinas/análise , alfa-Glucosidases/metabolismoRESUMO
The antihyperglycemic effect and mechanism of action of extracts, fractions and compounds from Wilbrandia ebracteata was studied. The crude extract reduced the glycemia, increased glycogen content and serum insulin in hyperglycemic rats. Also, a significant effect was observed with the n-butanol and metanol subfraction. However, the antihyperglycemic effect of the n-butanol fraction was not observed in diabetic rats. The C-glycosylflavones isovitexin and swertisin showed a strong antihyperglycemic action compared with the extracts and fractions. These results show that the extracts, fractions, and isolated C-glycosylflavones have an antihyperglycemic action that was reinforced by the stimulation on in vivo insulin secretion.
Assuntos
Apigenina/farmacologia , Cucurbitaceae/química , Insulina/metabolismo , Animais , Apigenina/química , Glicemia/efeitos dos fármacos , Glipizida/farmacologia , Teste de Tolerância a Glucose , Secreção de Insulina , Masculino , Estrutura Molecular , Ratos , Ratos WistarRESUMO
In this study, the in vivo and in vitro anti-hyperglycemic activity of chalcone derivatives of 3,4-methylenedioxy, with a substituent electron-acceptor nitro group in the A or B ring, was investigated. As expected, the second generation sulfonylurea glipizide stimulated insulin secretion and reduced glycemia over the study period. Also, it was demonstrated for the first time that chalcones are able to increase insulin secretion and this event was coincident with serum glucose-lowering in the oral glucose tolerance test. Additionally, the chalcones studied had a similar effect on insulin secretion and serum glucose-lowering as glipizide. The effect of chalcones in terms of inducing insulin secretion was greater than that of glipizide after 30 min. Moreover, chalcones were not able to stimulate glucose uptake in soleus muscle, either in the presence of insulin or in the absence of this hormone. In addition, the oral treatment with chalcones did not alter glycemia in diabetic rats. These reports indicate that the effect of chalcones on serum glucose-lowering in hyperglycemic-normal rats is mainly a consequence of insulin secretion, highlighting these chalcones as novel compounds with strong anti-hyperglycemic properties.
Assuntos
Glicemia/efeitos dos fármacos , Chalcona/farmacologia , Glipizida/farmacologia , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Administração Oral , Animais , Chalcona/administração & dosagem , Diabetes Mellitus Experimental/sangue , Glipizida/administração & dosagem , Glucose/análise , Teste de Tolerância a Glucose , Secreção de Insulina , Masculino , Ratos , Ratos WistarRESUMO
The possible participation of K(+) channels in the antinociceptive action induced by resveratrol was assessed in the 1% formalin test. Local administration of resveratrol produced a dose-dependent antinociception in the second phase of the test. The antinociception produced by resveratrol was due to a local action as its administration in the contralateral paw was not active. Local pretreatment of the injured paw with glibenclamide, tolbutamide or glipizide (ATP-sensitive K(+) channel inhibitors) did not modify resveratrol-induced antinociception. In contrast, charybdotoxin and apamin (large and small conductance Ca(2+) activated-K(+) channel blockers, respectively), 4-aminopyridine or tetraethylammonium (voltage-dependent K(+) channel inhibitors) dose-dependently prevented resveratrol-induced antinociception. Local peripheral administration of glibenclamide, but not charybdotoxin or apamin, significantly reduced the antinociceptive effect produced by peripheral morphine (positive control). At the highest effective doses, none of the drugs used induced behavioral side effects as revealed by the evaluation of stepping, righting, corneal and pinna reflexes. In addition, when given alone, none of the inhibitors modified the nociceptive behavior induced by 1% formalin. The results suggest that resveratrol opens large and small conductance Ca(2+)-activated K(+) channels, but not ATP-sensitive K(+) channels, in order to produce its peripheral antinociceptive effect in the formalin test. The participation of voltage-dependent K(+) channels was also suggested, but since non-selective inhibitors were used the data awaits further confirmation.