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1.
J Agric Food Chem ; 68(10): 3017-3025, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32059105

RESUMO

Chlorsulfuron has been applied in wheat fields as a recognized herbicide worldwide, yet it was officially banned in China since 2014 for its soil persistence problem. On the basis of our previous research that 5-dimethylamino distinctively accelerated degradation rate in soils, a modified amino moiety (Ia-c) and monosubstituted amino group (Id-e) were introduced onto the fifth position of the benzene ring in sulfonylurea structures, as well as heterocyclic amino substituents (If-g) to seek a suitable soil degradation rate during such an in situ crop rotation system. Referring to the biological data and ScAHAS inhibition and ScAHAS docking results, they turned out to be AHAS inhibitors with high potent herbicidal activities. The various influence on soil degradation rate along with crop safety indicated that different substituents on the fifth position have exerted an apparent impact. Their united study of structure-activity-safety-degradation relationship has great potential to provide valuable information for further development of eco-friendly agrochemicals.


Assuntos
Acetolactato Sintase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Poluentes do Solo/química , Compostos de Sulfonilureia/farmacologia , Acetolactato Sintase/metabolismo , Amaranthus/efeitos dos fármacos , Amaranthus/enzimologia , Brassica/efeitos dos fármacos , Brassica/enzimologia , Inibidores Enzimáticos/química , Herbicidas/química , Cinética , Modelos Moleculares , Proteínas de Plantas/metabolismo , Poluentes do Solo/farmacologia , Relação Estrutura-Atividade , Compostos de Sulfonilureia/química
2.
Plant Mol Biol ; 102(4-5): 403-416, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31898147

RESUMO

KEY MESSAGE: CYP81A P450s armor Echinochloa phyllopogon against diverse and several herbicide chemistries. CYP81A substrate preferences can be a basis for cross-resistance prediction and management in E. phyllopogon and other related species. Metabolism-based herbicide resistance is a major threat to agriculture, as it is unpredictable and could extend resistance to different chemical groups and modes of action, encompassing existing, novel and to-be-discovered herbicides. Limited information on the enzymes involved in herbicide metabolism has hindered the prediction of cross-resistance in weeds. Members of CYP81A subfamily in multiple herbicide resistant (MHR) Echinochloa phyllopogon were previously identified for conferring cross-resistance to six unrelated herbicide classes. This suggests a critical role of CYP81As in endowing unpredictable cross-resistances in E. phyllopogon, thus the functions of all its nine putative functional CYP81A genes to 33 herbicides from 24 chemical groups were characterized. Ectopic expression in Arabidopsis thaliana identified the CYP81As that can confer resistance to multiple and diverse herbicides. The CYP81As were further characterized for their enzymatic functions in Escherichia coli. CYP81A expression in E. coli was optimized via modification of the N-terminus, co-expression with HemA gene and culture at optimal temperature. CYP81As metabolized its herbicide substrates into hydroxylated, N-/O-demethylated or both products. The cross-resistance pattern conferred by CYP81As is geared towards all chemical groups of acetolactate synthase inhibitors and is expanded to herbicides inhibiting photosystem II, phytoene desaturase, protoporphyrinogen oxidase, 4-hydroxyphenylpyruvate dioxygenase, and 1-deoxy-D-xylulose 5-phosphate synthase. Cross-resistance to herbicides pyrimisulfan, propyrisulfuron, and mesotrione was predicted and confirmed in MHR E. phyllopogon. This study demonstrated that the functional characterization of the key enzymes for herbicide metabolism could disclose the cross-resistance pattern and identify appropriate chemical options to manage the existing and unexpected cross-resistances in E. phyllopogon.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Echinochloa/efeitos dos fármacos , Echinochloa/enzimologia , Resistência a Herbicidas/genética , Acetolactato Sintase/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/enzimologia , Cromatografia Líquida , Escherichia coli , Regulação da Expressão Gênica de Plantas , Herbicidas/farmacologia , Plantas Geneticamente Modificadas/efeitos dos fármacos , Sementes , Especificidade por Substrato , Compostos de Sulfonilureia/farmacologia , Espectrometria de Massas em Tandem , Temperatura Ambiente
3.
Curr Top Med Chem ; 20(1): 37-56, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31884929

RESUMO

BACKGROUND: Type 2 diabetes mellitus is a complex progressive endocrine disease characterized by hyperglycemia and life-threatening complications. It is the most common disorder of pancreatic cell function that causes insulin deficiency. Sulfonylurea is a class of oral hypoglycemic drugs. Over the past half century, these drugs, together with the subsequent non-sulfonylureas (glinides), have been the main oral drugs for insulin secretion. OBJECTIVE: Through in-depth study, the medical profession considers it as an important drug for improving blood sugar control. METHODS: The mechanism, characteristics, efficacy and side effects of sulfonylureas and glinides were reviewed in detail. RESULTS: Sulfonylureas and glinides not only stimulated the release of insulin from pancreatic cells, but also had many extrapanular hypoglycemic effect, such as reducing the clearance rate of insulin in liver, reducing the secretion of glucagon, and enhancing the sensitivity of peripheral tissues to insulin in type 2 diabetes mellitus. CONCLUSION: Sulfonylureas and glinides are effective first-line drugs for the treatment of diabetes mellitus. Although they have the risk of hypoglycemia, weight gain and cardiovascular disease, their clinical practicability and safety can be guaranteed as long as they are reasonably used.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Compostos de Sulfonilureia/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Compostos de Sulfonilureia/efeitos adversos , Compostos de Sulfonilureia/uso terapêutico
4.
Int J Nanomedicine ; 14: 6287-6296, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496686

RESUMO

Purpose: We aimed to enhance the solubility, dissolution rate, oral bioavailability, and α-glucosidase inhibition of glimepiride (Glm) by fabricating its nanosuspension using a precipitation-ultrasonication approach. Methods: Glm nanosuspensions were fabricated using optimized processing conditions. Characterization of Glm was performed using Malvern Zetasizer, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. Minimum particle size and polydispersity index (PDI) values were found to be 152.4±2.42 nm and 0.23±0.01, respectively, using hydroxypropyl methylcellulose: 6 cPs, 1% w/v, polyvinylpyrrolidone K30 1% w/v, and sodium lauryl sulfate 0.12% w/v, keeping ultrasonication power input at 400 W, with 15 minutes' processing at 3-second pauses. In vivo oral bioavailability was assessed using rabbits as a model. Results: The saturation solubility of the Glm nanosuspensions was substantially enhanced 3.14-fold and 5.77-fold compared to unprocessed drug in stabilizer solution and unprocessed active pharmaceutical ingredient. Also, the dissolution rate of the nanosuspensions ws substantially boosted when compared to the marketed formulation and unprocessed drug candidate. The results showed that >85% of Glm nanosuspensions dissolved in the first 10 minutes compared to 10.17% of unprocessed Glm), 42.19% of microsuspensions, and 19.94% of marketed tablets. In-vivo studies conducted in animals, i.e. rabbits, demonstrated that maximum concentration and AUC0-24 with oral dosing were twofold (5 mg/kg) and 1.74-fold (2.5 mg/kg) and 1.80-fold (5 mg/kg) and 1.63-fold (2.5 mg/kg), respectively, and compared with the unprocessed drug formulation. In-vitro α-glucosidase inhibition results showed that fabricated nanosuspensions had a pronounced effect compared to unprocessed drug. Conclusion: The optimized batch fabricated by ultrasonication-assisted precipitation can be useful in boosting oral bioavailability, which may be accredited to enhanced solubility and dissolution rate of Glm, ultimately resulting in its faster rate of absorption due to nanonization.


Assuntos
Precipitação Química , Inibidores de Glicosídeo Hidrolases/farmacologia , Nanopartículas/química , Compostos de Sulfonilureia/farmacologia , Ultrassom , alfa-Glucosidases/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Derivados da Hipromelose/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Coelhos , Solubilidade , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacocinética , Suspensões , Difração de Raios X
5.
Diabetes Res Clin Pract ; 157: 107836, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479704

RESUMO

The place of Sulphonylurea based insulin secretagogues in the management of Type 2 diabetes appears as controversial today as it was fifty years ago. Newer therapies are associated with less hypoglycaemia and weight gain than Sulphonylureas but currently cost more and lack assurances which come with long-term exposure. Emergence of recent CVOT data for SGLT-2 inhibitors and GLP-1 receptor agonists is likely to influence therapeutic choices and guidance is now supportive of their earlier use in cases at high risk of cardiovascular disease. Meta-analyses of Sulphonylurea trials have failed to indicate a consistent effect (positive or negative) on cardiovascular disease or mortality, although are limited by the relative scarcity of studies directly reporting these outcomes. The CAROLINA trial is reassuring in demonstrating cardiovascular safety for the Sulphonylurea Glimepiride when compared directly with the DPP-4 inhibitor Linagliptin, suggesting either of these agents would be relatively safe second line options after Metformin in the majority of patients. This review provides a balanced assessment of available Sulphonylurea treatments in the context of current cardiovascular outcome trial data (CVOT) data and hopefully assists informed decision making about the place of these drugs in contemporary glucose lowering practice.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Adulto , Idoso , Doenças Cardiovasculares , Humanos , Hipoglicemiantes/farmacologia , Pessoa de Meia-Idade , Compostos de Sulfonilureia/farmacologia
6.
Eur J Pharmacol ; 861: 172598, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31408647

RESUMO

Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.


Assuntos
Neoplasias , Compostos de Sulfonilureia/química , Animais , Carcinogênese/efeitos dos fármacos , Humanos , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Risco , Compostos de Sulfonilureia/farmacologia , Compostos de Sulfonilureia/uso terapêutico
7.
Mol Biol Rep ; 46(5): 5113-5121, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280423

RESUMO

Acetolactate synthase (ALS)-inhibiting herbicides have been widely used for effective management and control of wild mustard (Sinapis arvensis) biotypes in Iran. The resistance of the ALS inhibitor to weeds is attributed to either target site alteration or enhanced herbicide degradation. Molecular and genetic characterization of the resistance mechanism is relevant to the evolution and management of herbicide resistance. The aims of this research were (a) to characterize the mechanism molecular suspected to Granstar (tribenuron methyl) and Atlantis (Mesosulfuron + Iodosulfuron) resistance in S. arvensis biotypes in the greenhouse and laboratory (b) to investigate the organization of the target-site loci in field selected S. arvensis populations and (c) instantly recognize the mutations that cause resistance to ALS inhibitors. Eighty resistant populations of S. arvensis were carefully collected from fields repeatedly treated with Granstar and Atlantis. The resistance level and pattern of the population were determined through a greenhouse dose-response experiment by applying the above-mentioned herbicides. Extraction of genomic DNA was carried out for PCR and ALS gene analysis. Our results showed that by greenhouse experiment across 80 biotypes suspected to resistance collected in the fields of whole Kermanshah Province, 30 biotypes (37.5%) conferred S. arvensis resistance species reported in the farm. Among 30 biotypes screened in a greenhouse experiment, six biotypes (20%), No. 9, 14, 17, 19, 23 and 28 revealed a mutation in the ALS gene that was detected by PCR-based method. Biotype No. 9 in the position 376 (Asp376-Gly, GAC to GGC), biotypes 14 and 19 in the position 197 (Pro197-Ala, CCT to GCT), biotypes 17, 23 and 28 in the position 574 (Trp574-Leu, TGG to TTG) and biotype No. 23 in the position 122 (Thr-122-Ala, ACA to GCA) showed herbicide resistance. The specific mutation in the position of 122 of the ALS gene in S. arvensis is the first report. Other biotypes showed resistance in the greenhouse but didn't indicate any mutation by PCR-based method. Most of the resistance to Granstar and Atlantis are genetic and are induced by mutations in the ALS gene. The resistance to herbicides may contain a non-mutagenic and non-genetic origin. The reason of herbicide resistance as non-target-site in some of the biotypes may relate to the activity of the herbicide-metabolizing enzyme(s) or transporter proteins that will naturally lead to an increase in herbicide degradation or compartmentation away from its active site.


Assuntos
Acetolactato Sintase/genética , Resistência a Herbicidas , Herbicidas/farmacologia , Mutação Puntual , Sinapis/crescimento & desenvolvimento , Substituição de Aminoácidos , Sulfonatos de Arila/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas de Plantas/genética , Reação em Cadeia da Polimerase , Sinapis/efeitos dos fármacos , Sinapis/genética , Sulfonamidas/farmacologia , Compostos de Sulfonilureia/farmacologia
8.
J Microbiol Biotechnol ; 29(5): 713-720, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31030451

RESUMO

Acanthamoeba castellanii belonging to the T4 genotype may cause a fatal brain infection known as granulomatous amoebic encephalitis, and the vision-threatening eye infection Acanthamoeba keratitis. The aim of this study was to evaluate the antiamoebic effects of three clinically available antidiabetic drugs, Glimepiride, Vildagliptin and Repaglinide, against A. castellanii belonging to the T4 genotype. Furthermore, we attempted to conjugate these drugs with silver nanoparticles (AgNPs) to enhance their antiamoebic effects. Amoebicidal, encystation, excystation, and host cell cytotoxicity assays were performed to unravel any antiacanthamoebic effects. Vildagliptin conjugated silver nanoparticles (Vgt-AgNPs) characterized by spectroscopic techniques and atomic force microscopy were synthesized. All three drugs showed antiamoebic effects against A. castellanii and significantly blocked the encystation. These drugs also showed significant cysticidal effects and reduced host cell cytotoxicity caused by A. castellanii. Moreover, Vildagliptin-coated silver nanoparticles were successfully synthesized and are shown to enhance its antiacanthamoebic potency at significantly reduced concentration. The repurposed application of the tested antidiabetic drugs and their nanoparticles against free-living amoeba such as Acanthamoeba castellanii described here is a novel outcome that holds tremendous potential for future applications against devastating infection.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Anti-Infecciosos/farmacologia , Hipoglicemiantes/farmacologia , Nanoconjugados/química , Amebicidas/química , Anti-Infecciosos/química , Carbamatos/química , Carbamatos/farmacologia , Células HeLa , Humanos , Hipoglicemiantes/química , Nanopartículas Metálicas/química , Piperidinas/química , Piperidinas/farmacologia , Prata/química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Vildagliptina/química , Vildagliptina/farmacologia
9.
Diabetes Res Clin Pract ; 151: 65-73, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30954510

RESUMO

AIMS: To directly compare the effectiveness and safety between two distinct sodium-glucose co-transporter 2 (SGLT2) inhibitors, empagliflozin and dapagliflozin, as part of a quadruple oral antidiabetic agents (OADs) in patients with inadequately controlled type 2 diabetes (T2D). METHODS: This study was an open-labeled, prospective, 52-week study conducted in T2D patients with glycated hemoglobin (HbA1c) ranging 7.5-12.0% with metformin, glimepiride and dipeptidyl peptidase-4 inhibitors. Patients were divided into either empagliflozin (25 mg/day) or dapagliflozin (10 mg/day). The outcome measures included changes in HbA1c, fasting plasma glucose (FPG), and cardiometabolic variables and the safety profiles. RESULTS: In total, 350 patients were enrolled with empagliflozin (n = 176) and dapagliflozin (n = 174), respectively. After 52 weeks, both groups showed significant reductions in HbA1c and FPG, but the reduction was greater in the empagliflozin group (P < 0.001). Both groups showed significantly decreased blood pressure and body weight and high-density lipoprotein cholesterol levels were increased in the empagliflozin (between groups, P = 0.035). Both groups showed similar safety profiles. CONCLUSIONS: Our study demonstrated that SGLT2 inhibitors can be effectively used as a fourth OAD in T2D patients who are treated with three other OADs. More specifically, empagliflozin was more effective in reducing HbA1c and improving other cardiometabolic parameters than dapagliflozin. Clinical Trial Number NCT03748810 (ClinicalTrials.gov).


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada/métodos , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos Benzidrílicos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Método Duplo-Cego , Feminino , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Estudos Prospectivos , Compostos de Sulfonilureia/farmacologia , Adulto Jovem
10.
PLoS One ; 14(3): e0214458, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913269

RESUMO

Herbicide-resistant weeds, especially Palmer amaranth (Amaranthus palmeri S. Watson), are problematic in row-crop producing areas of the United States. The objectives of this study were to determine if chlorimuron-ethyl, fomesafen, and glyphosate applied separately and in mixtures control A. palmeri and confirm the presence of various genotypes surviving two- and three-way herbicide mixtures. Fifteen percent of A. palmeri treated with the three-way herbicide mixture survived. Mixing fomesafen with chlorimuron-ethyl or fomesafen with glyphosate to create a two-way mixture reduced A. palmeri survival 22 to 24% and 60 to 62% more than glyphosate and chlorimuron-ethyl alone, respectively. Previously characterized mutations associated with A. palmeri survival to chlorimuron-ethyl, fomesafen, and glyphosate Trp574Leu, a missing glycine codon at position 210 of the PPX2L gene (ΔG210), and 5-enolpyruvylshikimate-3-phosphase synthase (EPSPS) gene amplification; respectively, were present in surviving plants. However, 37% of plants treated with chlorimuron-ethyl did not contain heterozygous or homozygous alleles for the Trp574Leu mutation, suggesting alternative genotypes contributed to plant survival. All surviving A. palmeri treated with fomesafen or glyphosate possessed genotypes previously documented to confer resistance. Indiana soybean [Glycine max (L.) Merr] fields infested with A. palmeri possessed diverse genotypes and herbicide surviving plants are likely to produce seed and spread if alternative control measures are not implemented.


Assuntos
3-Fosfoshikimato 1-Carboxiviniltransferase/genética , Amaranthus/genética , Benzamidas/farmacologia , Amplificação de Genes , Glicina/análogos & derivados , Resistência a Herbicidas/genética , Pirimidinas/farmacologia , Compostos de Sulfonilureia/farmacologia , Amaranthus/efeitos dos fármacos , Amaranthus/enzimologia , Códon/genética , Genótipo , Glicina/farmacologia , Mutação
11.
Pestic Biochem Physiol ; 155: 126-131, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30857622

RESUMO

Tausch's goatgrass (Aegilops tauschii Coss.) is one of the most troublesome weeds in winter wheat-growing regions of China. In recent years, the recommended field rate of mesosulfuron-methyl failed to control the Tausch's goatgrass population in Shanxi province (SX), China. Experiments were conducted to characterize the herbicide resistance level and investigate the basis of mesosulfuron-methyl resistance in Tausch's goatgrass. Whole-plant dose-response tests showed that the SX population exhibited 11.42-fold resistance to mesosulfuron-methyl than the susceptible HN population, and the resistance level in the SX population could be significantly reduced by malathion, a cytochrome P450 inhibitor. The SX population also exhibited cross-resistance to imazethapyr, pyroxsulam and bispyribac­sodium. Acetohydroxyacid synthase (AHAS) sequencing and enzyme activity assays demonstrated that the mesosulfuron-methyl resistance was not conferred by target-site substitution. A sensitive AHAS, together with the malathion revisable resistance, suggested that herbicide metabolism likely plays a main role in the mechanism of mesosulfuron-methyl resistance in the SX population. To our knowledge, this is the first report elucidating the mesosulfuron-methyl resistance in Tausch's goatgrass.


Assuntos
Aegilops/efeitos dos fármacos , Herbicidas/farmacologia , Compostos de Sulfonilureia/farmacologia , Acetolactato Sintase/metabolismo , Aegilops/metabolismo , Benzoatos/farmacologia , Ácidos Nicotínicos/farmacologia , Pirimidinas/farmacologia
12.
Diabetes Res Clin Pract ; 150: 331-341, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30772385

RESUMO

AIMS: Adding lixisenatide to basal insulin (BI) instead of sulfonylurea (SU), versus continuing SU + BI was assessed in people with type 2 diabetes mellitus (T2DM) who intended to fast during Ramadan 2017. METHODS: LixiRam (NCT02941367) was a phase 4, randomized, open-label, 12-22-week study in people with T2DM insufficiently controlled with SU + BI ±â€¯1 oral anti-diabetic. Endpoints included the percentage of participants with ≥1 documented symptomatic hypoglycemia event (plasma glucose ≤70 mg/dL; primary endpoint) and any hypoglycemia during Ramadan fasting. RESULTS: A numerically lower percentage of participants with lixisenatide + BI (3.3%, 3/91) versus SU + BI (8.9%, 8/90) had ≥1 documented symptomatic hypoglycemia event (intent-to-treat visit 4) during Ramadan fasting (OR: 0.34; 95% CI 0.09, 1.35; proportion difference -0.06, 95% CI -0.13, 0.01); the difference was statistically significant for the 'any hypoglycemia' category (lixisenatide + BI: 4.3%, 4/92; SU + BI: 17.4%, 16/92; OR: 0.22; 95% CI 0.07, 0.68; proportion difference -0.13, 95% CI -0.22, -0.04; intent-to-treat). No new treatment-emergent adverse events occurred. CONCLUSIONS: Compared with SU + BI, lixisenatide + BI provided lower rates of any hypoglycemia in people with T2DM during Ramadan fasting. Lixisenatide + BI therapy may be a suitable treatment option during fasting.


Assuntos
Quimioterapia Combinada/métodos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Peptídeos/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Adulto , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Islamismo , Masculino , Pessoa de Meia-Idade , Peptídeos/farmacologia , Compostos de Sulfonilureia/farmacologia
13.
Cell Physiol Biochem ; 52(1): 16-26, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30790502

RESUMO

BACKGROUND/AIMS: Diabetes affects the entire vascular system and accelerates atherosclerosis and ischemia. Percutaneous transluminal angioplasty with or without stenting is the main therapeutic strategies; however, the restenosis rate is high in diabetics. Sulfonylureas (SUs) are widely prescribed agents for the treatment of type 2 diabetes (T2DM) and function by interacting with sulfonylurea receptors (SURs), which also exists in vascular smooth muscle cells (VSMCs), give rise to the potential that SUs influence VSMCs. The proliferation and migration of VSMCs play important roles in the formations of primary stenosis and restenosis, especially the latter. However, there are no data about the exact effects of SUs on these processes. METHODS: Human aortic smooth muscle cells (HASMCs) were exposed to SUs prior to exposure to 30mM glucose. Cell proliferation was detected by CCK8 assay. Cell migration was detected by wound healing assay and transwell assay. Protein expression was determined by immunofluorescence and western blot. Diazoxide was used to evaluate the role of KATP channel in these processes. RESULTS: The proliferation and migration of HASMCs were significantly aggravated by glibenclamide and glimepiride, and their effects were reversed by diazoxide. In contrast, above characteristics of HASMCs were apparently inhibited by gliclazide, and this was maintained after opening the KATP channel. CONCLUSION: These results imply that KATP channels play an important part in proliferation and migration of VSMCs induced by glibenclamide and glimepiride. In contrast, the inhibitory effect of gliclazide on VSMCs appeared to have more potential for the prevention of vascular obstructive diseases in T2DM.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Compostos de Sulfonilureia/farmacologia , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia
14.
Diabetes Res Clin Pract ; 149: 47-63, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30710655

RESUMO

BACKGROUND: The first treatment approach for type 2 diabetes mellitus is lifestyle change and metformin, but it is usually not sufficient. For some time, the anti-hyperglycemic classes of sulfonylureas and dipeptidyl peptidase-4 (DPP-4) inhibitors were considered second-line of treatment, since they show similar efficacy effect. However, the recent ADA-EASD consensus gives the preference to DPP-4 inhibitors compared to sulfonylureas, except if cost is a major problem. We performed a meta-analysis for safety and tolerability profile to comprehend which treatment has less adverse events. METHODS: PUBMED and EMBASE databases were searched from inception until July 2017 to retrieve RCT studies comparing DPP-4 inhibitors and sulfonylureas treatments in adult type 2 diabetes patients. There was no language restriction. We extracted and combined data from studies comparison that reported safety profile and weight change. A random effect, meta-analytic model was applied to all calculations. Cochrane collaboration tool was used to assess quality and bias of the included studies. Trial registered with PROSPERO (CRD42017075823). FINDINGS: Out of 1472 articles identified in our search and screened for eligibility, 36 studies comparing DPP-4 inhibitors and sulfonylureas were identified. DPP-4 inhibitors in combination with metformin had less overall adverse events (RR: 0·90; 95% CI, 0·86-0·94; p < 0·0001; I2 = 83%; 17 studies), cardiovascular events (RR: 0·54; 95% CI, 0·37-0·79; p = 0·002; I2 = 0%; 6 studies), hypoglycemia (RR: 0·17; 95% CI, 0·13-0·22; p < 0·00001; I2 = 76%; 17 studies) and severe hypoglycemic events (RR: 0·10; 95% CI, 0·05-0·19; p < 0·00001; I2 = 0%; 12 studies). The mean difference of the weight change was 1·92 kg in favor of DPP-4 inhibitors in combination with metformin in relation to sulfonylureas in combination with metformin. Monotherapy with DPP-4 inhibitors also had less rates of hypoglycemia (RR: 0·31; 95% CI, 0·24-0·41; p < 0·00001; I2 = 0%; 8 studies) and severe hypoglycemic events (RR: 0·26; 95% CI, 0·10-0·66; p = 0·004; I2 = 0%; 8 studies) and patients did not gain 1·19 kg. INTERPRETATION: These results suggest better safety profile for DPP-4 inhibitors than sulfonylureas for both comparisons, and it is more notable when the treatment regimen includes metformin. FUNDING: This study was funded by Takeda Pharmaceuticals, Brazil.


Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada/métodos , Compostos de Sulfonilureia/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Humanos , Masculino , Compostos de Sulfonilureia/farmacologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-30605064

RESUMO

BACKGROUND: Sulphonylureas (SU) are known to cause weight gain. Some investigators have reported increased insulin sensitivity with some sulphonylurea agents. OBJECTIVE: To review available evidence of SU agents having PPARγ agonist activity. METHODS: We searched online databases of PubMed®, Embase®, Google Scholar® and Web of Science® as per current guidance, published in English, between 1st January 1970 and 31st December 2017. The search found 6 articles. RESULTS: None of the 1st generation SU drugs have any demonstrable PPARγ agonist activity. Most of the 2nd generation SU agents had a positive correlation between their concentration and PPARγ agonist activity except Gliclazide. The demonstrated PPARγ agonist activity was maximum in experiments with Glimepiride and Gliquidone and was seen in these in-vitro experiments at concentrations which were pharmacologically achievable in-vivo. The PPARγ agonist activity may be responsible for some sideeffect of the SU agents as weight gain. On the contrary, the clinical efficacy of the thiazolidinediones could theoretically be reduced when used in combination with the SUs with significant PPARγ agonist activity. CONCLUSION: The PPARγ agonist activity demonstrated in vitro experiments may have clinical connotations.


Assuntos
Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Compostos de Sulfonilureia/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina/fisiologia , PPAR gama/metabolismo , Compostos de Sulfonilureia/uso terapêutico
16.
Metabolism ; 97: 87-91, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30615948

RESUMO

BACKGROUND: We have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets and mice through induction of ER chaperone BIP. Therefore, we investigated if PI would have the same effects in a diabetic condition as well. METHODS: GSK2606414 was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. To generate a mouse model of type 2 diabetes mellitus (DM), male C57BL/6J mice were fed with high-fat diet and injected with streptozotocin. Several doses (6-16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. RESULTS: High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40 nM which decreased PERK phosphorylation by 40% significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain and prominent hyperglycemia were induced, PI at 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. CONCLUSION: PI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Secreção de Insulina/efeitos dos fármacos , Insulina/metabolismo , eIF-2 Quinase/antagonistas & inibidores , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Modelos Animais de Doenças , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Indóis/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Palmitatos/farmacologia , Compostos de Sulfonilureia/farmacologia
17.
Pest Manag Sci ; 75(1): 204-214, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29808621

RESUMO

BACKGROUND: Shortawn foxtail (Alopecurus aequalis Sobol.) is a competitive grass weed infesting winter wheat- and canola-growing fields in China. In May 2016, a suspected A. aequalis resistant population AHTC-06 that survived fenoxaprop-P-ethyl and mesosulfuron-methyl applied at their field-recommended rates was collected from a wheat field in Jinji County, Anhui Province, China. This study aimed to determine the resistance profile of this AHTC-06 population to ACCase- and ALS-inhibitors, and to investigate its mechanisms of resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl. RESULTS: Two mutations, a common Ile-2041-Asn (ACCase gene) and a very rare Pro-197-Tyr (ALS1 gene), were both identified in resistant individual plants. The homozygous subpopulation AHTC-06F1 for the two mutations was generated, and it showed broad-spectrum resistance to APPs, DENs, and ALS-inhibiting herbicides of all five chemical families tested, with resistance index (RI) values that ranged from 2.2 to 36.5. In vitro ALS activity assays showed the ALS from the resistant population was insensitive to all the tested ALS inhibitors, with RI values ranging from 3.10 to 22.51. Pre-treatment with piperonyl butoxide (PBO) and malathion significantly (P < 0.05) reversed the weed's resistance to fenoxaprop-P-ethyl and mesosulfuron-methyl, respectively. Two P450 genes, c21190_g1 and c43350_g3, were constitutively overexpressed and mesosulfuron-methyl-induced upregulated in resistant plants, for which c43350_g3 was also fenoxaprop-P-ethyl-induced upregulated. CONCLUSION: This study confirms the first case of a grass weed featuring broad-spectrum resistance to ALS-inhibiting herbicides due to a Pro-197-Tyr mutation in the ALS gene. Fenoxaprop-P-ethyl and mesosulfuron-methyl resistances in AHTC-06 plants were conferred by target site mutations and P450s-based metabolism. © 2018 Society of Chemical Industry.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Oxazóis/farmacologia , Proteínas de Plantas/genética , Poaceae/genética , Propionatos/farmacologia , Compostos de Sulfonilureia/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Mutação , Proteínas de Plantas/metabolismo , Poaceae/efeitos dos fármacos , Poaceae/fisiologia
18.
Exp Clin Endocrinol Diabetes ; 127(4): 226-233, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29396966

RESUMO

Sulfonylureas are insulin secretagogues which act in pancreatic ß cells by blocking the KATP channels encoded by KCNJ11 and ABCC8 genes. In the present study, a pharmacoepigenetic approach was applied for the first time, investigating the correlation of KCNJ11 and ABCC8 gene promoter methylation with sulfonylureas-induced mild hypoglycemic events as well as the KCNJ11 E23K genotype. Sodium bisulfite-treated genomic DNA of 171 sulfonylureas treated T2DM patients previously genotyped for KCNJ11 E23K, including 88 that had experienced drug-associated hypoglycemia and 83 that had never experienced hypoglycemia, were analyzed for DNA methylation of KCNJ11 and ABCC8 gene promoters via quantitative Methylation-Specific PCR. KCNJ11 methylation was detected in 19/88 (21.6%) of hypoglycemic and in 23/83 (27.7%) of non-hypoglycemic patients (p=0.353), while ABCC8 methylation in 6/83 (7.2%) of non-hypoglycemic and none (0/88) of the hypoglycemic patients (p=0.012). Methylation in at least one promoter (KCNJ11 or ABCC8) was significantly associated with non-hypoglycemic patients who are carriers of KCNJ11 EK allele (p=0.030). Our data suggest that ABCC8 but not KCNJ11 methylation is associated to hypoglycemic events in sulfonylureas-treated T2DM patients. Furthermore, it is demonstrated that the KCNJ11 E23K polymorphism in association to either of the two genes' DNA methylation may have protective role against sulfonylurea-induced hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Hipoglicemiantes/farmacologia , Farmacogenética , Canais de Potássio Corretores do Fluxo de Internalização , Compostos de Sulfonilureia/farmacologia , Receptores Sulfonilureia , Idoso , Metilação de DNA/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/genética , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/genética , Hipoglicemia/metabolismo , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Compostos de Sulfonilureia/efeitos adversos , Receptores Sulfonilureia/genética , Receptores Sulfonilureia/metabolismo
19.
Pharm Dev Technol ; 24(5): 539-549, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30259768

RESUMO

Glimepiride (Gmp) a third generation of sulphonylurea is a weakly acidic hypoglycemic drug that belongs to Biopharmaceutical Classification System (BCS) class II. It suffers from poor solubility as well as erratic and variable therapeutic effect. The authors investigated the feasibility of utilizing two nontoxic and biodegradable biopolymers (casein (CA) and chitosan (CT)) as a new in-situ gelling tablet matrix to circumvent this limitation. Both polymers in different ratios were combined with constant dose of the drug and compressed by direct compression to produce constant weights of different tablet matrices. Basic tromethamine (Tris) was also included in each matrix as a pH modifier. Swelling indices, rheological properties of the swollen matrices, and their in-vitro drug release in simulating gastric fluid were assessed. The higher the ratio of casein in the tablet matrix, the lower its swelling index and the higher its viscosity indicate a shear thickening property. Intuitively, zero order drug diffusion in 0.1 N HCl prevailed for more than 8 hours from this gelled matrix. Both reduction of blood glucose level up till 11 hours and x-ray imaging of the selected tablets in the GIT of rabbits correlated well with the shear thickening properties. These findings propose a new stable, simple and affordable price matrix with large versatility.


Assuntos
Caseínas/química , Quitosana/química , Preparações de Ação Retardada/química , Géis/química , Hipoglicemiantes/farmacocinética , Compostos de Sulfonilureia/farmacocinética , Animais , Disponibilidade Biológica , Glicemia/análise , Liberação Controlada de Fármacos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Masculino , Coelhos , Solubilidade , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/farmacologia , Comprimidos , Viscosidade
20.
Fundam Clin Pharmacol ; 33(3): 277-285, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30451327

RESUMO

There is a growing number of epidemiological and molecular studies which suggest that diabetes is associated with an increased risk of Parkinson's disease (PD). Hence, in this study, the effect of glimepiride (GPD), a sulphonylurea (antidiabetic) on paraquat (PQT)-induced Parkinsonism was evaluated in mice. Thirty-six mice were randomly divided into six groups (n = 6) and treated orally for 21 consecutive days as follows: Group 1: vehicle (10 mL/kg), Group 2: PQT (10 mg/kg, i.p., twice per week for 3 weeks), Group 3-5: GPD (1, 2 or 4 mg/kg) + PQT (10 mg/kg, i.p., twice per week for 3 weeks), Group 6: GPD (4 mg/kg, p.o.). The effects of the treatment on motor coordination were evaluated using the rotarod performance, bar and open field tests while working memory was assayed using Y-maze test. Paraquat injection induced significant decrease in falling time, number of crosses and percentage alternation behaviour with a concomitant increase in the duration of cataleptic behaviour in the rotarod, open field, Y-maze and bar tests, respectively, which was ameliorated by GPD treatment. PQT also increased lipid peroxidation, peroxynitrite and TNF-α generations as well as deficit in superoxide dismutase and GSH activities in the midbrain. PQT-induced oxidative stress and neuroinflammation was attenuated by GPD treatment. Findings from this study showed that GPD prevents PQT-induced motor dysfunction, memory impairment, oxidative stress and neuroinflammation through enhancement of antioxidant defense system and inhibition of pro-inflammatory cytokine release. Thus, GPD could be a potential adjunct in the management of Parkinsonism.


Assuntos
Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Compostos de Sulfonilureia/farmacologia , Animais , Antioxidantes/metabolismo , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Inflamação/patologia , Inflamação/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/fisiopatologia , Transtornos da Memória/prevenção & controle , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Paraquat/toxicidade , Transtornos Parkinsonianos/fisiopatologia , Compostos de Sulfonilureia/administração & dosagem , Superóxido Dismutase/metabolismo
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