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1.
AAPS PharmSciTech ; 20(8): 308, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520165

RESUMO

Quantitative structure-property relationship (QSPR) approach has been widely used in predicting physicochemical properties of compounds. However, its application in the estimation of formulation properties based on the polymer used in it to achieve desired formulation characteristics is an extremely challenging process. In the present research, predictive QSPR models were developed by correlating the physicochemical properties of varying grades of cellulose ethers (hydroxypropyl methylcellulose, HPMC) with those of nateglinide (NTG) containing tablets (in vitro and in vivo properties). Sustained release tablets of NTG were prepared by using different grades and concentrations of HPMC and subsequently characterized for in vitro as well as in vivo parameters. Further, QSPR models for individual formulation property were developed by correlating the polymeric physicochemical properties with the formulation characteristics. Subsequently, a true external validation method was used to validate the predictability of developed models. The dissolution study indicated Korsmeyer-Peppas as the best fit model following non-Fickian as drug transport mechanism extending the drug release up to 12 h. In vivo studies showed limited absorption of the NTG. Developed QSPR models showed promising validated predictability for formulation characteristics. The applicability of present work in formulation development could significantly reduce the time and cost expenditure on design trials without actually formulating a delivery system.


Assuntos
Excipientes/química , Derivados da Hipromelose/química , Animais , Simulação por Computador , Preparações de Ação Retardada , Composição de Medicamentos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Modelos Químicos , Nateglinida/administração & dosagem , Nateglinida/química , Nateglinida/farmacocinética , Polimerização , Relação Quantitativa Estrutura-Atividade , Coelhos , Reprodutibilidade dos Testes , Comprimidos
2.
Life Sci ; 235: 116818, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31473193

RESUMO

AIMS: Considering the potential oral administration sequences and role of microbiota for metformin (MET) and berberine (BBR) during anti-diabetic treatments, the current study aimed to investigate the pharmacokinetic interactions between MET and BBR in rats after oral administration at different sequences and impacts of microbiota on such interactions. MAIN METHODS: Sprague-Dawley rats were divided into five groups as per what was orally administered to them: MET (G1)/BBR (G2) at 200 mg/kg, BBR 2-hour (h) after dosing MET (G3), MET 2-h after dosing BBR (G4) or MET with BBR at the same time (G5) followed by monitoring their pharmacokinetic profiles. Further in vitro incubations mimicking the above five treatments in rat intestinal content (G1R-G5R), human fecalase (G1H-G5H) and selected bacteria (G1B-G5B) were conducted for both MET and BBR (10 µg/ml for G1R/H-G5R/H and 50 µM for G1B-G5B) up to 24-h. Concentrations of MET and BBR were analyzed by LC/MS/MS. KEY FINDINGS: Although BBR was barely measurable in vivo, it significantly increased systemic exposure of MET in G3/G4. Consistent with pharmacokinetic findings, sequential in vitro incubations of MET and BBR in both rat intestinal content and human fecalase demonstrated significant increase on MET persisted after 24-h incubation in G3R/H & G4R/H. Moreover, post-dose (G3B) and pre-dose (G4B) of BBR decreased the MET degradation significantly in most selected bacteria. SIGNIFICANCE: Our finding for the first time demonstrated the significant effect of sequential co-administration of BBR and MET on their pharmacokinetic interactions, which could be related to their microbiota mediated metabolisms in gastrointestinal tract (GI).


Assuntos
Bactérias/efeitos dos fármacos , Berberina/farmacocinética , Interações de Medicamentos , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Administração Oral , Animais , Berberina/administração & dosagem , Diabetes Mellitus/tratamento farmacológico , Esquema de Medicação , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Metformina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
3.
Vnitr Lek ; 65(6): 425-432, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31484483

RESUMO

The second part of the review deals in detail with the diagnostics and treatment of toxic alcohols poisoning and management and indication of extracorporeal removal techniques in intoxication with other drugs, theophylline, valproic acid, metformin and metformin associated lactic acidosis, respectively. The extracorporeal treatment enhances the clearance of the toxin and corrects patients metabolic disturbances as well. It is necessary to use this treatment in severe intoxications. Indication of this invasive procedure falls within clinicians and nephrologists competence being advised by a toxicologist. This review could help make fast decisions.


Assuntos
Acidose Láctica , Overdose de Drogas , Hipoglicemiantes , Metformina , Overdose de Drogas/terapia , Humanos , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Diálise Renal , Teofilina
4.
Medicina (B Aires) ; 79(4): 241-250, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31487242

RESUMO

Type 2 diabetes is a chronic, progressive disease with increasing prevalence and still late diagnostic. This leads to an increase in the incidence of chronic complications, with signifi cantly increasing health costs. There is also a delay in the onset of insulin therapy in patients with type 2 diabetes for causes related to both patients and physicians. Despite advances in treatment, a low proportion of patients achieve adequate glycemic control. The high hypoglycemia prevalence, consequence of insulin, has led to the development of a new generation long-acting basal insulins to achieve a more stable and prolonged action profile, reducing the variability and risk of hypoglycemia. The EDITION program evaluated the efficacy and safety of glargine U300 compared to glargine U100 in patients with type 1 and 2 diabetes at different stages of the disease. Gla-300 is a new formulation of insulin glargine which has a more stable and prolonged pharmacokinetic and pharmacodynamic profile. Gla-300 demonstrated efficacy and tolerability comparable to glargine U100, with a significant decrease in the risk of hypoglycemia, at night and in 24 hours, providing greater flexibility in the injection schedule, with a window of 6 hours. No increase in weight was observed compared to glargine U100. Bright study (2018) compared glargine U300 vs. degludec U100, demonstrating greater benefit in relation to the risk of hypoglycemia with Gla-300 during titration period. Gla-300 is a last-generation basal insulin, available to improve metabolic control, with a lower risk of hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina Glargina/administração & dosagem , Insulina Glargina/farmacocinética , Medicina Baseada em Evidências , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Insulina Glargina/efeitos adversos
5.
Comput Methods Programs Biomed ; 178: 1-9, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31416537

RESUMO

BACKGROUND AND OBJECTIVE: Type 2 diabetes (T2D) is rapidly increasing in incidence and has significant social and economic costs. Given the increasing cost of complications, even relatively short delays in the onset of T2D can significantly reduce long-term complications and costs. Equally, recent studies have shown the onset of T2D can be delayed by use of long-acting insulin, despite the risk and concomitant low adherence. Thus, there is a strong potential motivation to develop models of long-acting insulin analogues to enable safe, effective use in model-based dosing systems. In particular, there are no current models of long-acting insulin Detemir and its unique action for model-based control. The objective of this work is to develop a first model of insulin Detemir and its unique action, and validate it against existing data in the literature. METHODS: This study develops a detailed compartment model for insulin Detemir. Model specific parameters are identified using data from a range of published clinical studies on the pharmacokinetic of insulin Detemir. Model validity and robustness are assessed by identifying the model for each study and using average identified parameters over several dose sizes and study cohorts. Comparisons to peak concentration, time of peak concentration and overall error versus measured plasma concentrations are used to assess model accuracy and validity. RESULTS: Almost all studies and cohorts fit literature data to within one standard deviation of error, even when using averaged identified model parameters. However, there appears to be a noticeable dose dependent dynamic not included in this first model, nor reported in the literature studies. CONCLUSIONS: A first model of insulin Detemir including its unique albumin binding kinetics is derived and provisionally validated against clinical pharmacokinetic data. The pharmacokinetic curves are suitable for model-based control and general enough for use. While there are limitations in the studies used for validation that prevent a more complete understanding, the results provide an effective first model and justify the design and implementation of further, more precise human trials.


Assuntos
Simulação por Computador , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina Detemir/farmacocinética , Adulto , Algoritmos , Biologia Computacional/métodos , Feminino , Humanos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Adulto Jovem
6.
Drug Metab Rev ; 51(4): 408-427, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31456442

RESUMO

Diabetes is a major health problem worldwide. Glycemic control is the main goal in the management of type 2 diabetes. While many anti-diabetic drugs and guidelines are available, almost half of diabetic patients do not reach their treatment goal and develop complications. The glucose-lowering response to anti-diabetic drug differs significantly between individuals. Relatively little is known about the factors that might underlie this response. The identification of predictors of response to anti-diabetic drugs is essential for treatment personalization. Unfortunately, the evidence on predictors of drugs response in type 2 diabetes is scarce. Only a few trials were designed for specific groups of patients (e.g. patients with renal impairment or older patients), while subgroup analyses of larger trials are frequently unreported. Physicians need help in picking the drug which provides the maximal benefit, with minimal side effects, in the right dose, for a specific patient, using an omics-based approach besides the phenotypic characteristics.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Acarbose/farmacocinética , Acarbose/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Metformina/uso terapêutico , Medicina de Precisão , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Ann Pharm Fr ; 77(5): 374-381, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255239

RESUMO

INTRODUCTION: Fasting has no adverse effects on healthy Muslims during Ramadan. However, it can induce serious complications for patients with type 2 diabetes (T2D). We aimed to follow the variation of some biochemical and clinical parameters in T2D patients before and after Ramadan; and to determine the incidence of fasting on hypoglycaemia and lactic acidosis associated with antidiabetic agents such as metformin. MATERIALS AND METHODS: This work is a prospective study conducted during Ramadan on 150 patients, recruited 2 to 3 weeks prior to the start. These patients were sensitized about the Ramadan lifestyle and diet as well as the medications to take. RESULTS: This study results indicated a significant decrease of glycated haemoglobin (from 8.06% to 7.42%) and a similar trend in the fasting plasma glucose (from 1.81 to 1.36g/L) before and after Ramadan respectively. The serum lipid profile showed significant variations during the study period, and antidiabetic medications was associated with low serum lactate. The plasma creatinine and uric acid were reduced but remained insignificant. DISCUSSION AND CONCLUSION: Based on data from our study, we concluded that a safe fasting with a lower risk hypoglycaemia, can be achieved in a well-controlled patients, under antidiabetic drugs. However, the diabetes medication was associated with a small increase in serum lactate levels that seemed to be dose-independent and not affected by treatment duration.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Jejum/fisiologia , Índice Glicêmico , Hipoglicemiantes/uso terapêutico , Acidose Láctica/urina , Adulto , Idoso , Glicemia/análise , Creatinina/sangue , Diabetes Mellitus Tipo 2/sangue , Jejum/efeitos adversos , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/farmacocinética , Islamismo , Ácido Láctico/sangue , Masculino , Metformina/farmacocinética , Metformina/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Ácido Úrico/urina , Adulto Jovem
8.
Clin Drug Investig ; 39(10): 967-978, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321631

RESUMO

BACKGROUND: Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE: To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS: We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS: In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS: Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER: NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER: JapicCTI-152878.


Assuntos
Atorvastatina/farmacocinética , Benzamidas/farmacocinética , Ciclopropanos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipoglicemiantes/farmacocinética , Oxidiazóis/farmacocinética , Receptores Acoplados a Proteínas-G/agonistas , Rosuvastatina Cálcica/farmacocinética , Adulto , Atorvastatina/administração & dosagem , Benzamidas/administração & dosagem , Estudos Cross-Over , Ciclopropanos/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Interações de Medicamentos/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipoglicemiantes/administração & dosagem , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Oxidiazóis/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem
9.
Expert Opin Pharmacother ; 20(14): 1679-1687, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31335214

RESUMO

Introduction: A growth in the market for anti-diabetic drugs, along with an ever-increasing population suffering from type 2 diabetes mellitus (T2DM), requires a critical re-evaluation of anti-diabetic drugs used for a long time, in order to provide up-to-date practical prescribing information for clinicians. Alogliptin benzoate was firstly approved in 2010 in Japan for T2DM, both as a monotherapy or in combination with other anti-diabetic drugs. Areas covered: This article provides a comprehensive review of the latest data on alogliptin benzoate, including hypoglycemic activity and safety. Expert opinion: The cumulative evidence for alogliptin benzoate is robust with regards to glycemic efficacy and safety. Low hypoglycemia risks and weight changes support its consideration as a first-line medication for T2DM, either as a monotherapy or in combination therapy with other anti-diabetic drugs such as metformin. Ongoing trials will look to better analyze and address its safety and efficacy in pediatric patients and expand our clinical knowledge of this medication.


Assuntos
Benzoatos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Piperidinas/uso terapêutico , Uracila/análogos & derivados , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Meia-Vida , Humanos , Hipoglicemia/patologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Uracila/efeitos adversos , Uracila/farmacocinética , Uracila/uso terapêutico
10.
Mater Sci Eng C Mater Biol Appl ; 103: 109753, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349477

RESUMO

Type 1 diabetes mellitus (DM) is a metabolic disorder associated with impaired carbohydrate metabolism. We present a promising bioinspired approach against type 1 DM using yeast microcapsule (YMC). The glucan component in the outer shell of baker's yeast undergoes receptor-mediated uptake by phagocytic cells through M cell-mediated endocytosis. Thus, a drug can be expected to be delivered to the systemic circulation via lymphatic transport if it is attached to the surface of YMC. For the first time, this possibility has been explored by surface loading of insulin onto YMC. The electrostatic interaction between oppositely charged YMC and insulin resulted in the formation of insulin-loaded yeast microcapsule (IYMC) which was confirmed by fluorescence imaging. Alginate coating provided to IYMC protects YMC from the harsh environment of the gastrointestinal tract and prevents the degradation of insulin in IYMC. Cellular uptake of FITC conjugated IYMC by RAW macrophages confirmed the proposed mechanism of insulin uptake. Moreover, an in vitro method using YMC-imprinted gel was developed for insulin release study from the bioinspired system. Molecular docking studies proved the interaction of insulin with ß-glucan and alginate. A significant hypoglycemic effect was observed after oral administration of the alginate coated insulin-loaded yeast microcapsule (AL-IYMC) in diabetic rats. The AL-IYMCs could serve as a promising approach towards the oral delivery of insulin.


Assuntos
Cápsulas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Insulina/administração & dosagem , Insulina/farmacocinética , Saccharomyces cerevisiae , Administração Oral , Alginatos , Animais , Cápsulas/química , Diabetes Mellitus Experimental/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/análise , Hipoglicemiantes/farmacocinética , Insulina/análise , Intestinos/efeitos dos fármacos , Intestinos/patologia , Camundongos , Simulação de Acoplamento Molecular , Imagem Molecular , Tamanho da Partícula , Células RAW 264.7 , Ratos Sprague-Dawley , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/citologia , Espectroscopia de Infravermelho com Transformada de Fourier
11.
Biopharm Drug Dispos ; 40(7): 225-233, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31215040

RESUMO

The study examined the effect of doxorubicin (DOX) on the hepatic expression of CYP2C and its activity for metabolizing tolbutamide (TB), a specific CYP2C substrate, in rats and whether the pharmacokinetics of tolbutamide were altered by doxorubicin exposure. The expression level of hepatic CYP2C11 was depressed 1 day after doxorubicin administration (day 1), and this effect on CYP2C11 was augmented on day 4. However, the expression level of hepatic CYP2C6 remained unchanged. The activity of tolbutamide 4-hydroxylation in hepatic microsomes was decreased with time following doxorubicin administration. Regarding the enzyme kinetic parameters for tolbutamide 4-hydroxylation on day 4, the maximum velocity (Vmax ) was significantly lower in the DOX group than that in the control group, while the Michaelis constant (Km ) was unaffected. On pharmacokinetic examination, the total clearance (CLtot ) of tolbutamide on day 4 was increased, despite the decreased metabolic capacity. On the other hand, the serum unbound fraction (fu ) of tolbutamide was elevated with a reduced serum albumin concentration in the DOX group. Contrary to CLtot , CLtot /fu , a parameter approximated to the hepatic intrinsic clearance of unbound tolbutamide, was estimated to be significantly reduced in the DOX group. These findings indicate that the metabolic capacity of CYP2C11 in the liver is depressed time-dependently by down-regulation after doxorubicin exposure in rats, and that the decreased enzyme activity of TB 4-hydroxylation in hepatic microsomes reflects the pharmacokinetic change of unbound tolbutamide, not total tolbutamide, in serum.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Hipoglicemiantes/farmacocinética , Tolbutamida/farmacocinética , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Família 2 do Citocromo P450/metabolismo , Interações de Medicamentos , Hidroxilação/efeitos dos fármacos , Hipoglicemiantes/sangue , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos Sprague-Dawley , Albumina Sérica/metabolismo , Esteroide 16-alfa-Hidroxilase/metabolismo , Tolbutamida/sangue
12.
Drugs ; 79(10): 1135-1146, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31236801

RESUMO

Dapagliflozin (Forxiga®) is a highly potent, reversible and selective sodium-glucose cotransporter-2 inhibitor indicated worldwide for the treatment of type 2 diabetes (T2D). In the EU, oral dapagliflozin once daily is approved for use as monotherapy (in patients who are intolerant of metformin) and as add-on combination therapy (with other glucose-lowering agents, including insulin) for T2D when diet and exercise alone do not provide adequate glycaemic control. In numerous well-designed clinical studies and their extensions, dapagliflozin as monotherapy and combination therapy with other antihyperglycaemic agents provided effective glycaemic control and reduced bodyweight and blood pressure (BP) across a broad spectrum of patients. Dapagliflozin reduced the rate of cardiovascular (CV) death or hospitalization for heart failure (HHF), did not adversely affect major adverse CV events (MACE) and possibly reduced progression of renal disease relative to placebo in patients with established atherosclerotic CV disease (CVD) or multiple risk factors for CVD. Dapagliflozin was generally well tolerated, with a low risk of hypoglycaemia; diabetic ketoacidosis (DKA), although rare, and genital infections were more common with dapagliflozin than placebo. Given its antihyperglycaemic, cardioprotective and possibly renoprotective properties and generally favourable tolerability profile, dapagliflozin provides an important option for the management of a broad patient population, regardless of the history of CVD.


Assuntos
Compostos Benzidrílicos/farmacocinética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Aprovação de Drogas , Quimioterapia Combinada/métodos , Europa (Continente) , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Humanos , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Insulina/farmacologia , Gravidez , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
13.
Curr Drug Deliv ; 16(7): 672-686, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31250754

RESUMO

BACKGROUND: In this study, four nanoparticle formulations (F1 to F4) comprising varying ratios of alginate, Pluronic F-68 and calcium chloride with a constant amount of insulin and chitosan as a coating material were prepared using polyelectrolyte complexation and ionotropic gelation methods to protect insulin against enzymatic degradation. METHODS: This study describes the formulation design, optimisation, characterisation and evaluation of insulin concentration via oral delivery in rats. A reversed-phase high-performance liquid chromatography (HPLC) method was developed and validated to quantify insulin concentration in rat plasma. The proposed method produced a linear response over the concentration range of 0.39 to 50 µg/ml. RESULTS: In vitro release study showed that dissolution of insulin in simulated gastric juice of pH 1.2 was prevented by alginate core and chitosan coating but rapidly released in simulated intestinal fluid (pH 6.8). Additionally, Formulation 3 (F3) has a particle size of 340.40 ± 2.39 nm with narrow uniformity exhibiting encapsulation efficiency (EE) of 72.78 ± 1.25 % produced highest absorption profile of insulin with a bioavailability of 40.23 ±1.29% and reduced blood glucose after its oral administration in rats. CONCLUSION: In conclusion, insulin oral delivery system containing alginate and chitosan as a coating material has the ability to protect the insulin from enzymatic degradation thus enhance its absorption in the intestine. However, more work should be done for instance to involve human study to materialise this delivery system for human use.


Assuntos
Alginatos/administração & dosagem , Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Alginatos/química , Alginatos/farmacocinética , Animais , Glicemia/efeitos dos fármacos , Quitosana/química , Quitosana/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Suco Gástrico/química , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Insulina/sangue , Insulina/química , Insulina/farmacocinética , Absorção Intestinal , Secreções Intestinais/química , Masculino , Nanopartículas/química , Ratos Sprague-Dawley
14.
Drugs ; 79(10): 1157-1161, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31201711

RESUMO

Remogliflozin, a selective sodium-glucose co-transporter subtype 2 (SGLT2) inhibitor, which is to be administered as remogliflozin etabonate (Remo™, Remozen™), the prodrug for remogliflozin, recently received its first approval as a treatment for type 2 diabetes mellitus (T2DM) in India. This article summarizes the milestones in the development of remogliflozin etabonate leading to this first approval for T2DM.


Assuntos
Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Pirazóis/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2 , Aprovação de Drogas , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Índia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
15.
Top Curr Chem (Cham) ; 377(4): 19, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165274

RESUMO

This review is an effort to summarize recent developments in synthesis of O-glycosides and N-, C-glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the O-glycosides used in the treatment of diabetes are presented, followed by the N-glycosides and finally the C-glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing potential drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order. C-Glycosyl compounds mimicking O-glycosides structure, exhibit the best features in terms of pharmacodynamics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various C-glycosides. Also N-glycosides such as N-(ß-D-glucopyranosyl)-amides, N-(ß-D-glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidiabetic agents. In order to indicate which of the compounds presented in the given sections have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect. 5. In Sect. 6, biological mechanisms of action of the glycosides and patents of marketed drugs are described.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Descoberta de Drogas/métodos , Glicosídeos/química , Glicosídeos/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus/enzimologia , Diabetes Mellitus/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/metabolismo , Glicosídeos/farmacocinética , Glicosídeos/uso terapêutico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/química , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Relação Estrutura-Atividade
16.
Eur J Pharm Sci ; 136: 104950, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173870

RESUMO

BACKGROUND: Yogliptin is a novel xanthine dipeptidyl peptidase-4 (DPP-4) inhibitor targeting type 2 diabetes. After promising preclinical pharmacological studies, the first human trial of yogliptin was designed. METHODS: A randomized, double-blind, parallel, placebo-controlled phase I single-dose escalation study was designed to evaluate the pharmacokinetics, pharmacodynamics, and tolerability after single oral doses of yogliptin in healthy Chinese subjects. Healthy subjects were assigned to nine cohorts, which received a single dose of yogliptin at 2.5, 5, 10, 25, 50, 100, 200, 400, or 600 mg. Two subjects in each cohort received placebo. Blood samples were collected before dosing and up to 192 h afterwards. Urine samples were collected until 120 h after dosing. Plasma and urine drug concentrations were determined using liquid chromatography coupled with tandem mass spectrometry, and DPP-4 activity was measured using a semi-quantitative, fluorescence-based kinetic assay. RESULTS: A total of 104 subjects were enrolled, 103 of whom completed the study (mean age, 25.3 years; mean weight, 58.8 kg; mean BMI, 21.8 kg/m2). A total of 27 adverse events (AEs) occurred in 25 of 86 yogliptin subjects (29.1%), and 3 AEs occurred in 3 of 18 placebo subjects (16.7%). Yogliptin was absorbed with a median time of maximum observed concentration (Tmax) of 3.0 h and was eliminated slowly with a t1/2 of 25.45-43.84 h. The maximum observed concentration (Cmax) and area under the curve (AUC) varied slightly more than dose-proportionally over the dose range from 2.5 to 400 mg. The fraction of drug excreted in urine ranged from 8.39% to 24.77%. Mean DPP-4 inhibition at 24 h after dosing ranged from 97.7% to 99.5%, and DPP-4 inhibition was >80% for 72 h at doses from 25 to 400 mg. DPP-4 inhibition was >80% for 1 week in the group receiving 400 mg. CONCLUSION: Yogliptin was well tolerated in healthy subjects, with no dose-limiting toxicity observed in the range from 2.5 to 600 mg. Yogliptin inhibited plasma DPP-4 activity for 72 h at single doses of 25-200 mg and for 1 week at 400 mg, suggesting that once-weekly dosing of yogliptin is possible in type 2 diabetes patients. TRIAL REGISTRATION: ChiCTR-IIR-17010311 (Chictr.org).


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Adolescente , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Glicemia/efeitos dos fármacos , Estudos de Coortes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidase 4/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Masculino
17.
Drug Des Devel Ther ; 13: 1623-1632, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190741

RESUMO

Purpose: The aims of this study was to investigate the mutual pharmacokinetic interactions between steady-state atorvastatin and metformin and the effect of food on the fixed-dose combined (FDC) tablet of atorvastatin and metformin extended release (XR). Subjects and methods: Study 1, an open-labeled, fixed sequence, multiple-dose pharmacokinetic drug-drug interaction study, was divided into 2 parts. Atorvastatin (40 mg) or metformin (1,000 mg) XR tablets were administered once daily via mono- or co-therapy for 7 days. Plasma levels of atorvastatin and 2-OH-atorvastatin, were quantitatively determined for 36 h in part A (n=50) while metformin plasma concentration was measured up to 24 h in part B (n=16) after the last dosing. Study 2, a randomized, open-labeled, single-dose, two-treatment, two-period, two-sequence crossover study, involved 27 healthy subjects to investigate the impact of food intake on the pharmacokinetics of a combined atorvastatin/metformin XR 20/500 mg (CJ-30056 20/500 mg) tablet. Results: After multiple doses of mono- or co-therapy of atorvastatin (40 mg) and metformin (1,000 mg) XR, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the peak plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve during the dosing interval at steady state (AUCτ,ss) were 1.07 (0.94-1.22) and 1.05 (0.99-1.10) for atorvastatin, 1.06 (0.96-1.16) and 1.16 (1.10-1.21) for 2-OH-atorvastatin, and 1.00 (0.86-1.18) and 0.99 (0.87-1.13) for metformin, respectively. Food delayed time to reach maximum concentration (tmax), decreased atorvastatin Cmax by 32% with a GMR (90% CI) of 0.68 (0.59-0.78), and increased metformin AUCt by 56% with a GMR (90% CI) of 1.56 (1.43-1.69). Conclusion: No clinically relevant pharmacokinetic interaction was seen when atorvastatin was co-administered with metformin. Food appeared to change the absorption of atorvastatin and metformin from an FDC formulation. These alterations were in accordance with those described with the single reference drugs when ingested with food.


Assuntos
Atorvastatina/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Administração Oral , Adulto , Atorvastatina/administração & dosagem , Atorvastatina/sangue , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Interações Alimento-Droga , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Masculino , Metformina/administração & dosagem , Metformina/sangue , Pessoa de Meia-Idade , Comprimidos , Equivalência Terapêutica , Adulto Jovem
18.
AAPS PharmSciTech ; 20(5): 195, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31119403

RESUMO

The main aim of this work was to 3D print metformin HCl-loaded PVA (ML-PVA) tablets by fused deposition modeling. A modified solvent diffusion approach was used to improve drug loading. PVA filaments were placed in metformin HCl solution in ethanol containing low water content (10%(v/v)) to enhance the drug's solubility. The physicochemical properties of ML-PVA filaments were characterized before and after printing. Lastly, ML-PVA filaments were printed into channeled tablet designs to increase their surface area available for dissolution. The loading of metformin HCl onto PVA filament has significantly increased from 0.08 ± 0.02% in metformin HCl solution in absolute ethanol to 1.40 ± 0.02% in ethanol-water (9:1). The IR spectra of PVA filament soaked in ethanol-water depicted higher peak intensity at 1138 cm-1, indicating higher degree of crystallinity. Thermal analysis of the soaked PVA filaments showed higher melting enthalpies yet lower melting temperature (Tm) compared to unprocessed PVA. ML-PVA filaments were successfully printed into round-channeled tablets (10% infill) with higher surface area and area/volume ratios compared with the solid ones. The inclusion of channels in the tablet design modified their printing pattern causing an unexpected increase in their mass. The dissolution profiles of ML-PVA tablets were mainly dependent on their area/mass ratios. Our results show a simple approach to increase metformin HCl loading onto PVA and reveal the significance of tablet design, infill percentage, and printing pattern as they dictate the area, volume, and the mass of the tablet which impact its dissolution rate.


Assuntos
Desenho de Drogas , Hipoglicemiantes/química , Metformina/química , Impressão Tridimensional , Tecnologia Farmacêutica/métodos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Solubilidade , Comprimidos/química , Comprimidos/farmacocinética
19.
Nanomedicine (Lond) ; 14(8): 989-1009, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31088322

RESUMO

Aim: This study aimed to explore the effect of nanoparticles loaded with exenatide in overcoming the mucus barrier and improving intestinal targeting efficiency, to improve the oral bioavailability. Materials & methods: Low molecular weight protamine (LMWP)-dextran-poly(lactic-co-glycolic acid) was used to create LMWP-dextran-poly(lactic-co-glycolic acid)-nanoparticles (LDPs) encapsulating exenatide-Zn2+ complex.Results & conclusion: LDPs showed improved penetration of the mucus barrier, and LMWP was helpful for mediating cell translocation through protein transduction domains. The absorption sites and distribution rates of LDPs were verified by intestinal localization experiments and in vivo distribution experiments. Cell uptake and transmembrane experiments confirmed the absorption efficiency in the intestinal epithelium. Furthermore, the relative bioavailability after oral administration of exenatide-Zn2+-LDPs was 8.4%, with a significant hypoglycemic effect on Type 2 diabetic mice.


Assuntos
Portadores de Fármacos/química , Exenatida/administração & dosagem , Hipoglicemiantes/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Protaminas/química , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular , Dextranos/química , Exenatida/farmacocinética , Humanos , Hipoglicemiantes/farmacocinética , Absorção Intestinal , Masculino , Muco/metabolismo , Nanopartículas/química , Ratos Sprague-Dawley
20.
Nat Commun ; 10(1): 2172, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092829

RESUMO

Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities. It exhibits insulin-independent antidiabetic effects in multiple animal models of type I and type II diabetes and antisteatotic effects in fatty liver models. These beneficial effects can be explained by the improvement of glucose metabolism and enhancement of energy expenditure by OPC-163493 in the liver. Moreover, OPC-163493 treatment lowered blood pressure, extended survival, and improved renal function in the rat model of stroke/hypertension, possibly by enhancing NO bioavailability in blood vessels and reducing mitochondrial ROS production. OPC-163493 is a liver-localized/targeted mUncoupler that ameliorates various complications of diabetes.


Assuntos
Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Desacopladores/farmacologia , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Cricetulus , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Modelos Animais de Doenças , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Feminino , Células Hep G2 , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Hipertensão/mortalidade , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Análise de Sobrevida , Desacopladores/farmacocinética , Desacopladores/uso terapêutico
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