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1.
Drug Saf ; 43(7): 657-660, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32495148

RESUMO

INTRODUCTION: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. OBJECTIVE: The present study was undertaken to investigate the reality of this putative drug-drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. METHODS: Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/non-case study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. RESULTS: Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as 'fatal outcomes'. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9-139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6-13.8). CONCLUSION: Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.


Assuntos
Infecções por Coronavirus , Interações Medicamentosas , Quimioterapia Combinada , Hidroxicloroquina , Metformina , Pandemias , Pneumonia Viral , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/mortalidade , Feminino , Humanos , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/uso terapêutico , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/farmacocinética , Metformina/uso terapêutico , Pessoa de Meia-Idade , Farmacovigilância , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia
2.
Aging (Albany NY) ; 12(10): 8760-8765, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: covidwho-401312

RESUMO

Pathological signaling in the lung induced by particulate matter (PM) air pollution partially overlaps with that provoked by COVID-19, the pandemic disease caused by infection with the novel coronavirus SARS-CoV-2. Metformin is capable of suppressing one of the molecular triggers of the proinflammatory and prothrombotic processes of urban PM air pollution, namely the mitochondrial ROS/Ca2+ release-activated Ca2+ channels (CRAC)/IL-6 cascade. Given the linkage between mitochondrial functionality, ion channels, and inflamm-aging, the ability of metformin to target mitochondrial electron transport and prevent ROS/CRAC-mediated IL-6 release might illuminate new therapeutic avenues to quell the raging of the cytokine and thrombotic-like storms that are the leading causes of COVID-19 morbidity and mortality in older people. The incorporation of infection rates, severity and lethality of SARS-CoV-2 infections as new outcomes of metformin usage in elderly populations at risk of developing severe COVID-19, together with the assessment of bronchial/serological titers of inflammatory cytokines and D-dimers, could provide a novel mechanistic basis for the consideration of metformin as a therapeutic strategy against the inflammatory and thrombotic states underlying the gerolavic traits of SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus , Inflamação/metabolismo , Metformina , Pandemias , Pneumonia Viral , Transdução de Sinais/efeitos dos fármacos , Trombose , Idoso , Betacoronavirus/fisiologia , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Reposicionamento de Medicamentos/métodos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-6/imunologia , Metformina/farmacocinética , Metformina/uso terapêutico , Material Particulado/imunologia , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Espécies Reativas de Oxigênio/imunologia , Trombose/tratamento farmacológico , Trombose/metabolismo
3.
Aging (Albany NY) ; 12(10): 8760-8765, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32463794

RESUMO

Pathological signaling in the lung induced by particulate matter (PM) air pollution partially overlaps with that provoked by COVID-19, the pandemic disease caused by infection with the novel coronavirus SARS-CoV-2. Metformin is capable of suppressing one of the molecular triggers of the proinflammatory and prothrombotic processes of urban PM air pollution, namely the mitochondrial ROS/Ca2+ release-activated Ca2+ channels (CRAC)/IL-6 cascade. Given the linkage between mitochondrial functionality, ion channels, and inflamm-aging, the ability of metformin to target mitochondrial electron transport and prevent ROS/CRAC-mediated IL-6 release might illuminate new therapeutic avenues to quell the raging of the cytokine and thrombotic-like storms that are the leading causes of COVID-19 morbidity and mortality in older people. The incorporation of infection rates, severity and lethality of SARS-CoV-2 infections as new outcomes of metformin usage in elderly populations at risk of developing severe COVID-19, together with the assessment of bronchial/serological titers of inflammatory cytokines and D-dimers, could provide a novel mechanistic basis for the consideration of metformin as a therapeutic strategy against the inflammatory and thrombotic states underlying the gerolavic traits of SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus , Inflamação/metabolismo , Metformina , Pandemias , Pneumonia Viral , Transdução de Sinais/efeitos dos fármacos , Trombose , Idoso , Betacoronavirus/fisiologia , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Reposicionamento de Medicamentos/métodos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-6/imunologia , Metformina/farmacocinética , Metformina/uso terapêutico , Material Particulado/imunologia , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Espécies Reativas de Oxigênio/imunologia , Trombose/tratamento farmacológico , Trombose/metabolismo
4.
Life Sci ; 253: 117651, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32304764

RESUMO

AIMS: To investigate the combination of dimerization and PEGylation to enhance the receptor activation and in vivo stability of Oxyntomodulin (OXM). MAIN METHODS: All LDM peptides were produced by using standard method of solid phase synthesis. The in vitro effects of LDM peptides were assessed by glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GcgR) binding test and Proteolytic stability test. Subsequently, saline, Liraglutide and three doses of LDM-3 treated groups were subjected to the evaluation of aute and long-term efficacy. KEY FINDINGS: Five long-acting OXM conjugates, termed LDM-1 to LDM-5, were designed using cysteine (Cys)-specific modification reaction including the activated PEG, bisMal-NH2, and OXM-Cys, and all prepared with high purity. LDM-3 exhibited greater GLP-1R and GcgR activation and ameliorative serum stability. In addition, LDM-3 was identified with enhanced insulinotropic and glycemic abilities in the gene knockout mice. The prolonged glucose-lowering effects of the LDM-3 were proved by hypoglycemic duration test and multiple oral glucose tolerance tests (OGTTs) in the diet-induced obesity (DIO) mice. Furthermore, the pharmacokinetic tests in Sprague Dawley (SD) rat and cynomolgus monkey exhibited the lifespans of LDM-3 at 90 nmol·kg-1 were 101.5 h and 119.4 h, respectively. Nevertheless, consecutive 8-week administration of LDM-3 improved the cumulative body weight gain, food intake, % HbA1c, glucose tolerance and the pancreatic of the obese mice. SIGNIFICANCE: LDM-3, as a dual GLP-1R and GcgR agonist, holds potential to be developed as a promising therapeutic candidate for both diabetes and obesity.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipoglicemiantes/química , Oxintomodulina/química , Receptores de Glucagon/metabolismo , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus/metabolismo , Dimerização , Glucagon/metabolismo , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacocinética , Macaca fascicularis , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Obesidade/metabolismo , Oxintomodulina/farmacocinética , Polietilenoglicóis/química , Ratos Sprague-Dawley , Técnicas de Síntese em Fase Sólida , Perda de Peso/efeitos dos fármacos
5.
Diabetes ; 69(6): 1140-1148, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32217610

RESUMO

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this "glucose effectiveness" is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). KATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the KATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.


Assuntos
Glicemia/fisiologia , Glucose/metabolismo , Canais KATP/metabolismo , Adulto , Animais , Diazóxido/administração & dosagem , Diazóxido/farmacocinética , Diazóxido/farmacologia , Interações Medicamentosas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Técnica Clamp de Glucose , Glibureto/administração & dosagem , Glibureto/farmacocinética , Glibureto/farmacologia , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Canais KATP/genética , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Adulto Jovem
7.
Int J Nanomedicine ; 15: 1129-1148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110012

RESUMO

Introduction: Solid lipid nanoparticles (SLNs) are considered a promising system in enhancing the oral bioavailability of poorly water-soluble drugs; owing to their intrinsic ability to increase the solubility together with protecting the incorporated drugs from extensive metabolism. Objective: Exploiting such properties, SLNs loaded with gliclazide (GLZ) were developed in an attempt to improve the oral bioavailability and the anti-diabetic action of GLZ, together with prolonging its duration of action for better glycemic control. Methods: SLNs were prepared by ultra-sonication technique using glyceryl behenate (Compritol®888 ATO) as a lipid matrix and poloxamer 188 (PLX) as a stabilizer. A 2*3 asymmetrical factorial design was adopted to study the effect of different stabilizer concentrations at different sonication times on the shape, and size of the particles, PDI and drug loading. The selected optimum formulation was then freeze dried using trehalose di-hydrate as a cryo-protectant in different ratios with respect to glyceryl behenate concentration. After freeze drying, the formulation was tested for in-vitro drug release, pharmacokinetics, and pharmacodynamics. Safety of the selected formula was established after carrying out a subacute toxicity study. Results: The factorial design experiment resulted in an optimum formulation coded 10F2 (150 mg PLX/10 min sonication). Scanning electron micrographs showed spherical particles with smooth surface, whereas a ratio of 2:1 cryo-protectant:lipid was found to be optimum with particle size of 245.9 ± 26.2 nm, polydispersity index of 0.482 ± 0.026, and biphasic in-vitro release with an initial burst effect, followed by a prolonged release phase. On the other hand, the selected SLNs exhibited prolonged drug release when compared with the GLZ commercial immediate release (IR) tablets (Diamicron®). Pharmacokinetics study showed about 5-fold increase in GLZ oral bioavailability loaded in SLNs when compared with raw GLZ powder. Pharmacodynamics study on a diabetic rat model confirmed the better anti-diabetic action of GLZ loaded SLNs when compared to raw GLZ powder. Subacute toxicity study indicated the safety of SLNs upon repetitive oral administration.


Assuntos
Gliclazida/farmacocinética , Hipoglicemiantes/farmacocinética , Nanopartículas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Diabetes Mellitus Experimental/tratamento farmacológico , Liberação Controlada de Fármacos , Ácidos Graxos/química , Liofilização , Gliclazida/administração & dosagem , Gliclazida/toxicidade , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/toxicidade , Lipídeos/química , Masculino , Nanopartículas/química , Tamanho da Partícula , Poloxâmero/química , Ratos Wistar , Solubilidade , Comprimidos/química , Testes de Toxicidade Subaguda
8.
J Med Chem ; 63(6): 2958-2973, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32077280

RESUMO

Autoimmune deficiency and destruction in either ß-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting ß-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human ß-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).


Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/química , Indóis/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Compostos Aza/farmacocinética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Indóis/farmacocinética , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
9.
Pharmacol Rep ; 72(1): 254-259, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016844

RESUMO

BACKGROUND: Diabetes reduces the activity of CYP3A4 and may increase the exposure for the drugs metabolized by the isoenzyme. Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI), used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. The TKI undergoes CYP3A4-dependent oxidative transformation, which may be influenced by hyperglycaemia. The aim of the study was to compare the oxidation for sorafenib between healthy and streptozotocin-induced diabetic rats. Additionally, the effect of sorafenib on glucose levels was investigated. METHODS: The rats were assigned to the groups: streptozotocin-induced diabetic (DG, n = 8) or healthy (HG, n = 8). The rats received sorafenib orally as a single dose of 100 mg/kg. The plasma concentrations of sorafenib and its metabolite N-oxide were measured with the validated high-performance liquid chromatography with ultraviolet detection. RESULTS: The difference between groups in Cmax and AUC0-t values for sorafenib were significant (p = 0.0004, p = 0.0104), and similarly for the metabolite (p = 0.0008, p = 0.0011). Greater exposure for the parent drug and analysed metabolite was achieved in diabetic group. However, the Cmax, AUC0-t, and AUC0-∞ ratios between the metabolite and sorafenib were similar in both groups. The significant reduction of glycaemia was observed only in the diabetic animals. CONCLUSION: The findings of the study provide evidence that diabetes significantly influence on the exposition for sorafenib and its metabolite, but similar ratios N-oxide/sorafenib for AUC and Cmax in healthy and diabetic animals suggest that oxidation of the TKI is rather unchanged. Additionally, sorafenib-associated hypoglycaemia was confirmed in diabetic animals.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Administração Oral , Animais , Área Sob a Curva , Glicemia/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Masculino , Oxirredução , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Ratos Wistar , Sorafenibe/administração & dosagem , Sorafenibe/farmacocinética , Estreptozocina
10.
Food Funct ; 11(2): 1560-1571, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32003379

RESUMO

Previously, we have reported the opposite effects of compounds isolated from Lagerstroemia speciosa leaves on a glucose transport (GLUT4) assay. Ellagitannins from L. speciosa activated GLUT4, while ellagic acid derivatives showed an inhibitory effect. As part of our continuing research on anti-diabetic nutritional supplements, we herein compared the anti-diabetic effects of several extracts (LE1-8) from leaves of L. speciosa using different manufacturing processes based on the contents of ellagitannins and ellagic acid derivatives. Their anti-diabetic effects were evaluated through glucose uptake and adipocyte differentiation in 3T3-L1 cells in vitro as well as alloxan induced diabetic mice in vivo. These extracts were given to mice by gavage at doses of 0.25, 1.0, and 4.0 g per kg body weight once a day for 21 consecutive days. Results showed that LE1 (1.0 g kg-1), LE3 (1.0 or 4.0 g kg-1), LE4 (1.0 or 4.0 g kg-1), LE5 (0.25 or 1.0 or 4.0 g kg-1) and LE7 (1.0 or 4.0 g kg-1) showed significant anti-diabetic effects in alloxan-induced diabetic mice as indicated by the decreased levels of fasting blood glucose, body weight, serum biomarkers, tissue weight and body fat, and increased final insulin levels. LE8 (1.0 g kg-1) showed a moderate anti-diabetic effect as illustrated by the reduced fasting blood glucose level while LE2 and LE6 showed slight effects in alloxan-induced diabetic mice. The potential correlation of the content of ellagitannins, ellagic acid derivatives, and corosolic acid with the anti-diabetic activity was discussed.


Assuntos
Ácido Elágico , Taninos Hidrolisáveis , Hipoglicemiantes , Lagerstroemia/química , Extratos Vegetais , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Ácido Elágico/química , Ácido Elágico/farmacocinética , Ácido Elágico/farmacologia , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/farmacocinética , Taninos Hidrolisáveis/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia , Folhas de Planta/química
11.
J Pharmacol Exp Ther ; 372(3): 256-263, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900320

RESUMO

Excess intramyocellular lipid (IMCL) deposition in skeletal muscle is closely associated with insulin resistance. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 offers a promising approach to treat insulin resistance through stimulation of mitochondrial fatty acid oxidation (FAO) and reduction of IMCL deposition. Previously reported experimental ACC2 inhibitors exhibited plasma glucose-lowering effects in diabetic rodents. However, their antidiabetic action may be potentially biased by off-target effects on triglyceride metabolism or by neurologic side effects. In this study, we investigated a safety profile, target dependency of its action, and antidiabetic efficacy of compound 2e, a novel olefin derivative potent ACC2 selective inhibitor. Four-day administration of suprapharmacological dose of compound 2e did not exhibit any obvious side effects in Sprague-Dawley rats. In db/db mice, single administration of compound 2e led to significantly elevated FAO and reduced IMCL deposition in skeletal muscle. In ACC2 knockout mice, treatment with pharmacological doses of compound 2e did not reduce plasma triglyceride levels, whereas A-908292, a previously reported ACC2 inhibitor, caused a significant triglyceride reduction, showing that compound 2e was devoid of off-target triglyceride-lowering activity. Chronic treatment of db/db mice with compound 2e improved hyperglycemia but did not decrease plasma triglyceride levels. Additionally, compound 2e showed significant improvements of whole-body insulin resistance in the clamp study and insulin tolerance test. Collectively, compound 2e demonstrated a good safety profile and significant antidiabetic effects through inhibition of ACC2-dependent pathways. These findings provide further evidence that selective inhibition of ACC2 is an attractive strategy against insulin resistance and type 2 diabetes. SIGNIFICANCE STATEMENT: This study shows that pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 leads to significant improvements in whole-body glucose homeostasis, independently of off-target metabolic pathways and toxicity, which were observed in previously reported ACC2 inhibitors. These findings support the concept that ACC2-selective inhibitors will be a novel remedy for treatment of type 2 diabetes.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Acetil-CoA Carboxilase/genética , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipoglicemiantes/toxicidade , Insulina/metabolismo , Camundongos Knockout , Músculo Esquelético/enzimologia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Ratos Sprague-Dawley , Testes de Toxicidade , Triglicerídeos/sangue
12.
Talanta ; 209: 120514, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31892045

RESUMO

In this study, sandwich-structured magnetic graphene composites with Zn metal-organic framework layer coated on both two sides (denoted as magG@Zn-MOFs) were synthesized. The composites have large specific surface of 114 m2 g⁻1, uniform porous structure and rapid magnetic separation within 10 s. The magG@Zn-MOFs composites were used for extraction of acarbose in plasma prior to its quantitative analysis by LC-MS/MS. The established method has good linearity (10-1000 ng mL-1), satisfactory recovery (94.3-107.5%), low detection limit (as low as 2.5 ng mL-1), good intra-day precision (RSD 3.5-5.3%) and inter-day precision (RSD 6.3-8.1%). Finally, the method was successfully applied to pharmacokinetic study of acarbose in rats.


Assuntos
Acarbose/sangue , Grafite/química , Estruturas Metalorgânicas/química , Zinco/química , Acarbose/farmacocinética , Animais , Cromatografia Líquida , Óxido Ferroso-Férrico/química , Inibidores de Glicosídeo Hidrolases/sangue , Inibidores de Glicosídeo Hidrolases/farmacocinética , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Limite de Detecção , Masculino , Estruturas Metalorgânicas/síntese química , Microesferas , Ratos Sprague-Dawley , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem
13.
Scand J Med Sci Sports ; 30(5): 858-864, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31975547

RESUMO

Exercise is widely accepted as having therapeutic effects; thus, it is important to know whether it interacts with medications. The aim of the present pilot study was to examine the effect of high-intensity interval exercise (known to have antidiabetic action) on key pharmacokinetic parameters related to absorption of metformin (the first-line medication against type 2 diabetes). Ten healthy men participated in two sessions, spaced one to two weeks apart in random, counterbalanced order. In both sessions, participants received 1000 mg of metformin orally, 1-1.5 hours after breakfast. Then, they either ran for 60 minutes at alternating intensity, starting at 40 minutes after metformin administration, and rested without food consumption over the next 3 hours or they rested without food consumption during the entire testing period. Venous blood samples were collected before and at 0.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after metformin administration for metformin determination by liquid chromatography-mass spectrometry. Capillary blood samples were also collected for lactate and glucose measurements. Data from the two sessions were compared through Wilcoxon or Student's t test, as appropriate. Maximum plasma concentration of metformin (Cmax ) was higher at exercise compared to rest (P = .059). Time to reach Cmax (Tmax ) decreased with exercise (P = .009), and the area under the metformin concentration vs time curve was higher at exercise (P = .047). The addition of exercise to metformin administration did not cause hypoglycemia or lactic acidosis. In conclusion, our results provide the first evidence that pharmacokinetic values related to metformin absorption are affected by exercise.


Assuntos
Treinamento Intervalado de Alta Intensidade/métodos , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Adulto , Glicemia , Voluntários Saudáveis , Humanos , Hipoglicemiantes/sangue , Ácido Láctico/sangue , Masculino , Metformina/sangue , Projetos Piloto
14.
Drug Metab Pharmacokinet ; 35(1): 160-164, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974043

RESUMO

Polymorphisms in SLC22A1 lead to variability in metformin clinical efficacy. Sixty-three Lebanese patients with type 2 diabetes who administered metformin, were followed up for six months and genotyped for rs622342A>C. The area under the plasma concentration-time curve and the maximum concentration of metformin was highest in CC patients (P ≤ 0.03). There was a significant difference between groups in the percentage decrease in fasting blood sugar (FBS) and glycated hemoglobin (HbA1c). Going into the same direction, rs622342C was associated with decrease in FBS levels after three and six months of treatment (P ≤ 0.02), whereas with HbA1c, the decrease was noticed after six months (ß = -2.78; P = 0.03). In contrast, the serum levels of lactate and creatinine did not vary significantly according to rs622342A>C genotypes. The rs622342A>C in SLC22A1 may be associated with metformin pharmacokinetics and variability in therapeutic efficacy.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Transportador 1 de Cátions Orgânicos/metabolismo , Adulto , Idoso , Creatinina/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Ácido Láctico/sangue , Masculino , Metformina/administração & dosagem , Metformina/sangue , Pessoa de Meia-Idade , Transportador 1 de Cátions Orgânicos/genética , Polimorfismo Genético/genética
15.
Clin Ther ; 42(2): 295-304, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31992459

RESUMO

PURPOSE: Coadministration of lobeglitazone and dapagliflozin is expected to result in a blood glucose-lowering effect, followed by a gradual increase, in clinical usage; however, combining drugs could cause negative interactions. This study aimed to evaluate the effect of the coadministration of lobeglitazone and dapagliflozin on their individual pharmacokinetic properties at steady state in healthy male volunteers in the fasted state. METHODS: This study consisted of 2 parts, each of which was a randomized, open-labeled, multiple-dose, 2-way crossover study in 20 healthy male volunteers in each part. Blood samples were taken periodically over a 48-h period after dosing to derive total plasma lobeglitazone and dapagliflozin pharmacokinetic properties; safety profile was evaluated throughout the study. FINDINGS: When the pharmacokinetic properties of dapagliflozin were evaluated following its administration alone and in combination with lobeglitazone, point estimate and 90% CI of the geometric mean ratio of dapagliflozin AUCτ were entirely within the conventional bioequivalence range of 80%-125%. However, although it was not clinically meaningful, its Css,max was ~8% lower in subjects receiving multiple doses of dapagliflozin and lobeglitazone than that in those administered dapagliflozin alone. The pharmacokinetic properties of lobeglitazone were evaluated following its administration alone and in combination with dapagliflozin. The geometric mean ratios and 90% CIs of the lobeglitazone Css,max and AUCτ were within the conventional bioequivalence range of 80%-125%. IMPLICATIONS: Coadministration of lobeglitazone and dapagliflozin had no apparent clinically relevant effects on the pharmacokinetic properties of either drug. Based on these findings, it is anticipated that lobeglitazone and dapagliflozin can be coadministered without dose adjustment. ClinicalTrials.gov identifier: NCT03616392.


Assuntos
Compostos Benzidrílicos/farmacocinética , Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Pirimidinas/farmacocinética , Tiazolidinedionas/farmacocinética , Adulto , Estudos Cross-Over , Interações Medicamentosas , Jejum , Voluntários Saudáveis , Humanos , Masculino , Equivalência Terapêutica , Adulto Jovem
16.
Int J Pharm ; 576: 119019, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31911116

RESUMO

Combination therapy in Type 2 Diabetes Mellitus is necessary to achieve tight glycaemic control and reduce complication risk. Current treatment plans require patients to take several drugs concomitantly leading to low therapy adherence. This study describes the development and characterisation of a stable parenteral co-formulation of a sodium glucose co-transporter 2 inhibitor (dapagliflozin) and a therapeutic lipidated peptide, using hydroxypropyl-ß-cyclodextrin as an enabling excipient. Using NMR, calorimetry, computational modelling and spectroscopic methods, we show that besides increasing the solubility of dapagliflozin, cyclodextrin prevents self-association of the peptide through interaction with the lipid chain and amino acids prone to aggregation including aromatic groups and ionisable residues. While those interactions cause a dramatic secondary structure change, no impact on potency was seen in vitro. A subcutaneous administration of the co-formulation in rat showed that both drugs reach exposure levels previously shown to be efficacious in clinical mono-therapy studies. Interestingly, a faster absorption rate was observed for the peptide formulated within the cyclodextrin vehicle with respect to the buffer vehicle, which could trigger an earlier onset of action. The cyclodextrin based co-formulation is therefore a promising approach to develop a fixed dose combination of a therapeutic peptide and a small molecule drug for increased patient adherence and better blood glucose control.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Compostos Benzidrílicos/farmacocinética , Glicemia/efeitos dos fármacos , Excipientes/química , Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Peptídeos/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Animais , Compostos Benzidrílicos/química , Glicemia/metabolismo , Células CHO , Cricetulus , Combinação de Medicamentos , Composição de Medicamentos , Absorção Gastrointestinal , Glucosídeos/química , Hipoglicemiantes/química , Injeções Subcutâneas , Masculino , Peptídeos/administração & dosagem , Peptídeos/química , Agregados Proteicos , Estrutura Secundária de Proteína , Ratos , Inibidores do Transportador 2 de Sódio-Glicose/química , Solubilidade
17.
Am J Ther ; 27(1): e42-e51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31876563

RESUMO

BACKGROUND: Biosynthetic human insulins and analogs have replaced animal insulins and permitted structural modifications to alter the rate of absorption, duration of action, improve reproducibility of effects, and modulate relative efficacy in various target tissues. Several forms of rapidly acting insulins nearly achieve rapid pharmacokinetics and pharmacodynamics similar to first-phase insulin release. There is need for even faster-acting analogs to mimic normal physiology and improve control of postprandial glycemic excursions. Two biosynthetic insulin analogs have sufficiently long duration of action for use as once-daily basal insulins; controversy persists regarding their respective risks of hypoglycemia and relative glycemic variability. RESULTS: Basal-bolus therapy and insulin pump therapy, including closed-loop automated insulin delivery, require rapid-acting insulin analogs. The longer acting insulins can provide stable, reproducible basal insulin with reduced rates of hypoglycemia, particularly nocturnal hypoglycemia, greater efficacy in reducing mean glucose and glucose variability while increasing time in glucose target range. Inhalable human insulin provides very rapid action. Premixture of rapid-acting analogs with protamine has been useful for some patients with type 2 diabetes. An insulin analog with preferential efficacy at the liver has been developed and tested clinically but not marketed. Current research is aimed at developing even faster-acting insulin analogs. Long-acting basal insulins coformulated with GLP-1 receptor agonists or with a rapidly acting insulin analog have valuable clinical applications. Excipients, chaperones, local heating of the infusion site, and hyaluronidase have also been used to accelerate the absorption of insulin analogs. CONCLUSIONS: Biosynthetic human insulins have radically revolutionized management of both type 1 and type 2 diabetes worldwide. The ability to manipulate the structure and formulation of insulin provides for more physiologic pharmacokinetics and pharmacodynamics, enabling improved glycemic control, reduced risk of hypoglycemia, and reduced rates of long-term complications.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/análogos & derivados , Insulina/uso terapêutico , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobina A Glicada , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Insulina/administração & dosagem , Insulina/farmacocinética , Sistemas de Infusão de Insulina , Insulina de Ação Prolongada/farmacocinética , Insulina de Ação Prolongada/uso terapêutico , Insulina Regular de Porco/administração & dosagem
18.
J Ethnopharmacol ; 248: 112268, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31593813

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus emblica Linn. (Syn. Emblica officinalis Gaertn.), has been used to cure many ailments of human beings. Literature survey demonstrates that it has many pharmacological activities i.e. antidiabetic, antioxidant, anti-microbial, antifungal, antiallergic, antiviral, and anticancer properties. AIM OF THE STUDY: The present study aimed to identify the novel plant-derived antidiabetic compounds from P. emblica to understand the molecular basis of antidiabetic activities. MATERIAL AND METHODS: Text mining analysis of P. emblica and its disease association was carried out using server DLAD4U. Due to the highest score of P. emblica with diabetes, the virtual screening of a phytochemical library of P. emblica against three targets of diabetes was carried out. After that FAF-Drug4, admetSAR and DruLiTo servers were used for drug-likeness prediction. Additionally, pharmacophore modeling was also carried out to understand the antidiabetic activity of screened compounds. RESULTS: The docking scores, drug-likeness and pharmacophore studies found that Ellagic acid, Estradiol, Sesamine, Kaempferol, Zeatin, Quercetin, and Leucodelphinidin are potential antidiabetic compounds. CONCLUSIONS: Our study shows that phytochemicals of P. emblica are very potential antidiabetic candidates. Using the modern techniques these molecules could be used to develop an effective antidiabetic drugs from a natural resource.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/farmacologia , PPAR gama/metabolismo , Phyllanthus emblica , Compostos Fitoquímicos/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Simulação por Computador , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Modelos Biológicos , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/farmacocinética , Fitoterapia
19.
Pak J Pharm Sci ; 32(5): 2025-2031, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31813867

RESUMO

Metformin is one of the most common medicines for the treatment of type 2 diabetes, however, recent studies suggest that concomitant antihyperglycemic agents should be administered for better efficacy. Yukmijihwang-tang (YMJHT) is a nephroprotective polyherb prescribed for renal disorders or diabetic mellitus in traditional Korean medicine. Therefore, the pharmacokinetics between metformin and YMJHT were examined for their coadministration. Rats were orally coadministered with metformin and YMJHT as a combination group or metformin and distilled water as the corresponding control. Then, the metformin concentration in plasma and its pharmacokinetic parameters including maximum concentration (Cmax) and area under the plasma concentration time curve (AUC) were analyzed. There were no interactions between metformin and YMJHT in the single coadministration at intervals within 5 min. However, pretreatments with YMJHT for 6 days increased the metformin concentration and its Cmax and AUC (p<0.05). The repeated coadministration for 8 days increased the Cmax of metformin (p<0.05). Conversely, when the combination was coadministered at 2h -intervals, there were no interactions between metformin and YMJHT after a single dosing or repeated dosing of coadministration for 7 days. These results of the present study will help structure proper dosing regimens for the concomitant therapy of metformin and YMJHT.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas/fisiologia , Metformina/farmacocinética , Plantas Medicinais/efeitos adversos , Animais , Área Sob a Curva , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Quimioterapia Combinada/efeitos adversos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Ratos , Ratos Sprague-Dawley
20.
AAPS PharmSciTech ; 21(2): 35, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31879830

RESUMO

The present work embarks upon increasing the dissolution rate and the bioavailability of model anti-diabetic drug, gliquidone, a sulfonylurea class drug used for treating diabetes mellitus type 2. The gliquidone nanoparticles were prepared by using anti-solvent precipitation technique in which, gliquidone solution in acetone was added at a controlled rate to an aqueous solution containing polyvinylpyrrolidone K25 (PVP K25) as stabilizer. The effect of drug concentration (X1), polymer concentration (X2) and solvent to anti-solvent ratio (X3) on particle size and dissolution was studied using Box-Behnken design. The results revealed that by decreasing the drug concentration and by increasing the stabilizer concentration and solvent/anti-solvent ratio, reduction in the size of the particles was observed. The mentioned parameters were optimised and particle of size about 175 nm was achieved. The relative dissolution rate of prepared gliquidone nanoparticles in phosphate buffer pH 7.4 was ~ 4.7 times faster than original drug at t = 45 min. Further, the gliquidone nanoparticles were characterized by scanning electron microscope (SEM), Fourier transform-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD). The particles revealed to be oval in shape with stabilizer molecules on surface and exhibited decreased crystalline nature when compared to free gliquidone. Finally, the in vivo studies using gliquidone nanoparticles revealed ~ 2.5-fold increase in Cmax when taken orally in the form of hard gelatin capsules in comparison to free gliquidone. Thus, overall investigation suggests that the developed strategy of gliquidone nanoparticles possess a keen potential for exhibiting anti-diabetic effect.


Assuntos
Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Nanopartículas/química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacocinética , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Técnicas In Vitro , Masculino , Microscopia Eletrônica de Varredura , Difração de Pó , Coelhos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier
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