Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 409
Filtrar
1.
Eur Rev Med Pharmacol Sci ; 26(23): 8893-8902, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36524509

RESUMO

OBJECTIVE: To investigate the effects of octreotide and nateglinide on ovarian follicle count, ovarian tissue damage, biochemical parameters and free radical scavenging system in letrazole-induced rat model of PCOS. MATERIALS AND METHODS: Forty-two female Sprague-Dawley rats were divided into six groups. Group 1 (Control Group): after localizing the ovaries and the uterine horns, the abdominal wall was closed without any surgical procedure. Group 2 (PCOS Group): PCOS was induced by administrating Letrozole orally for 21 successive days. At the end of 21 days, rats underwent ovarian biopsies. The experimental PCOS model was considered successful in the presence of atretic follicles without granulosa cell stratification. Group 3 (PCOS + Nateglinide Group): Nateglinide was administered by oral dropper for 30 days to the rats in which PCOS model was created. Group 4 (Nateglinid only Group): 30 days of NG was applied to the rats without PCOS. Group 5 (PCOS+Octreotide Group): 0.1 mg/kg/day Octreotide was given intraperitoneally for 4 weeks to the rats in which PCOS model was created. Group 6 (Octreotide only Group): animals without PCOS given 0.1 mg/kg/day Octreotide at the end of the treatment, bilateral oophorectomy was performed and blood samples were collected from all groups. Ovarian tissue was stained immunohistochemically with TLR-4 in addition to conventional staining. In addition to follicle classification, ovarian damage was graded. Serum insulin, FSH and LH, TNF-α, IL-6, SHBG, SOD, IGF-1, MDA and GSH levels were also measured. RESULTS: The cystic and degenerated follicle density of PCOS group was high compared with the other groups. Both cystic and degenerated follicles were significantly reduced in PCOS+NG and PCOS+OC groups compared to PCOS group. There was no difference between the groups in terms of serum LH, FSH and insulin levels (p>0.05). Serum testosterone level was significantly higher in the PCOS group compared to the other groups (p<0.01). Adding OC or NG to PCOS groups did not cause significant changes in testosterone levels. TNF-α and IL-6 levels were high in PCOS group (p<0.03). IGF-1 and MDA levels were higher in PCOS than in other groups (p<0.03, p<0.01 respectively). Adding OC or NG to the treatment normalized IGF-1 and MDA levels. Serum GSH levels were significantly lower in the PCOS group (p<0.05). Adding NG to the treatment increased GSH levels. CONCLUSIONS: Both NG and OCT reverses atretic and degenerate follicle damage due to PCOS through TLR-4, antioxidant and anti-inflammatory pathways.


Assuntos
Insulinas , Nateglinida , Octreotida , Síndrome do Ovário Policístico , Animais , Feminino , Ratos , Modelos Animais de Doenças , Hormônio Foliculoestimulante/química , Radicais Livres , Fator de Crescimento Insulin-Like I , Interleucina-6 , Nateglinida/farmacologia , Nateglinida/uso terapêutico , Octreotida/farmacologia , Octreotida/uso terapêutico , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/patologia , Ratos Sprague-Dawley , Testosterona , Receptor 4 Toll-Like/química , Fator de Necrose Tumoral alfa/química , Letrozol/farmacologia
2.
Pharmacol Rep ; 74(5): 1083-1091, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35932448

RESUMO

BACKGROUND: Nateglinide is a meglitinide used for the treatment of type 2 diabetes mellitus. Individual studies demonstrated the association of CYP2C9, SLCO1B1, and MTNR1B variants with the safety and efficacy of nateglinide. The current study aimed to develop a pharmacogenomic algorithm to optimize nateglinide therapy. METHODS: Multiple linear regression (MLR) and classification and regression tree (CART) were used to develop a pharmacogenomic algorithm for nateglinide dosing based on the published nateglinide pharmacokinetic data on the area under the curve data (AUC) and Cmax (n = 143). CYP2C9 metabolizer phenotype, SLCO1B1, MTNR1B genotypes, and CYP2C9 inhibitor usage were used as the input variables. The results and associations were further confirmed by meta-analysis and in silico studies. RESULTS: The MLR models of AUC and Cmax explain 87.4% and 59% variability in nateglinide pharmacokinetics. The Bland and Altman analysis of the nateglinide dose predicted by these two MLR models showed a bias of ± 26.28 mg/meal. The CART algorithm was proposed based on these findings. This model is further justified by the meta-analysis showing increased AUCs in CYP2C9 intermediate metabolizers and SLCOB1 TC and CC genotypes compared to the wild genotypes. The increased AUC in SLCO1B1 mutants is due to decreased binding affinity of nateglinide to the mutant affecting the influx of nateglinide into hepatocytes. MTNR1B rs10830963 G-allele-mediated poor response to nateglinide is attributed to increased transcriptional factor binding causing decreased insulin secretion. CONCLUSION: CYP2C9, SLCO1B1, and MTNR1B genotyping help in optimizing nateglinide therapy based on this algorithm and ensuring safety and efficacy.


Assuntos
Hidrocarboneto de Aril Hidroxilases , Diabetes Mellitus Tipo 2 , Humanos , Nateglinida , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Farmacogenética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Hipoglicemiantes , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Cicloexanos/farmacologia , Fenilalanina/metabolismo , Fenilalanina/farmacologia , Área Sob a Curva , Algoritmos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo
3.
Angew Chem Int Ed Engl ; 61(41): e202210312, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-35972406

RESUMO

Amides are ubiquitous in physical and life sciences. Given the significant abundance of arenes, dearomative aminocarbonylation of arenes would lead to a large and underexplored chemical space for amide discovery. However, such reactions are challenging due to the high degree of resonance stabilization and selectivity issues. Herein, we disclose an unprecedented dearomative trifluoromethylative aminocarbonylation of arenes via bifunctional coordination to chromium, providing a modular platform for the construction of amides possessing trifluoromethyl (CF3 ) groups and three-dimensional rings. Its versatility further enabled a switchable difluoromethylation or trifluoromethylation aminocarbonylation of arene C-H bonds. A possible mechanism was proposed based on control experiments. Finally, the synthetic utility was well demonstrated by diverse applications in the total synthesis of CF3 -functionalized amide-type drugs, including praziquantel, nateglinide, maraviroc and alloyohimbane.


Assuntos
Cromo , Praziquantel , Amidas/química , Catálise , Maraviroc , Nateglinida
4.
Biol Pharm Bull ; 45(6): 803-805, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35650107

RESUMO

Nateglinide (NAT) is used to treat diabetes, stimulating pancreatic islet ß-cells with residual insulin secretory capacity to increase insulin secretion. NAT has been reported to bind to human serum albumin (HSA), but the detail is still unclear. In the current study, we investigated the location and the affinity for the binding of NAT to HSA. Quantitative analysis data from the ultrafiltration experiment indicated that NAT binds strongly to a primary site on HSA with a high affinity. The presence of diazepam (DZP) or ibuprofen (IB), the specific site II ligands of HSA, decreased the binding constants of NAT respectively, without the significant changes in the number of binding sites. Whereas warfarin (WF), a site I specific ligand, did not affect the binding of NAT. Fluorescent replacement experiment showed that NAT replaced dansylsarcosine (DNSS), a site II probe of HSA, but not WF. An increasing level of myristate and uremic toxins, indoxyl sulphate (IS), indoxyl acetate (IA) and p-cresyl sulphate (PCS), during renal disease significantly increased the concentration of unbound NAT. These findings suggest that NAT specifically binds to site II of HSA and the binding capacity and pharmacokinetics of NAT change in renal diseases.


Assuntos
Secretagogos , Albumina Sérica Humana , Ácidos Graxos , Humanos , Insulina , Insulina Regular Humana , Ligantes , Nateglinida , Albumina Sérica/metabolismo , Toxinas Urêmicas , Varfarina
5.
J Vasc Nurs ; 40(1): 47-53, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35287834

RESUMO

INTRODUCTION: Claudication is the most usual symptom of peripheral artery disease, it is described as painful contractions in the leg when walking and alleviated upon resting. People with claudication have an added risk of cardiocerebrovascular events, amputation, and death. Adherence to medical treatment and changes in lifestyles can lower this risk, but this secondary prevention therapy requires engagement, participation, and adherence from the patient. OBJECTIVE: To explore patients' experiences of participating in a 1-year multicentre clinical trial with two follow-up programs evaluating a nurse-led, patient-centered health-promoting programme after surgical treatment for claudication, the FASTIC study. METHODS: A descriptive design with qualitative semi-structured interviews was used among participants in the FASTIC study. The study was conducted at two centres for vascular surgery in the city of Stockholm, Sweden. In all, 17 patients (nine men and eight women) who had completed the FASTIC study participated. Data was analysed using qualitative content analysis with an inductive approach. RESULTS: Two main categories were identified, 'Patient-Professional collaboration' and 'Experience of one´s health', which were associated with four subcategories: facing opportunities and obstacles, cooperating based on the illness experience, increasing awareness of one's own health, and maintaining a healthy lifestyle. CONCLUSIONS: Patients' participation in follow-up programs after surgical treatment for claudication is highly valuable for an increased awareness of one's own health. A person-centered care with patient-professional collaboration is experienced as important for maintaining a health-promoting lifestyle.


Assuntos
Claudicação Intermitente , Doença Arterial Periférica , Feminino , Seguimentos , Humanos , Claudicação Intermitente/cirurgia , Masculino , Nateglinida , Doença Arterial Periférica/cirurgia , Caminhada
6.
Anticancer Res ; 42(3): 1333-1338, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35220224

RESUMO

BACKGROUND/AIM: Nitric oxide (NO) has antitumor activity against various solid tumor cell types in addition to its vasodilatory effect. In the current study, we investigated the effect and mechanism of the synthetic nitrated form (NO2-NAT) of nateglinide, a hypoglycemic agent, on the induction of cell death in human pancreatic cancer cells. MATERIALS AND METHODS: NO production was evaluated by measuring nitrite (NO2) and nitrate (NO3) (NOx). Apoptotic cell numbers were determined using annexin V. RESULTS: NO2-NAT released nitrate and nitrite ions immediately upon dissolving in aqueous solution. NO2-NAT caused significant extracellular leakage of lactate dehydrogenase (LDH) in the human pancreatic cancer cell lines AsPC1 and BxPC3, and increased annexin-positive cells in a time- and concentration-dependent manner. NO2-NAT also significantly increased the activity of caspases 3 and 7. Exposure to Z-VAD-FMK, a caspase inhibitor, significantly suppressed NO2-NAT-induced cell death. CONCLUSION: These results indicated that NO2-NAT induces apoptosis in human pancreatic cancer cells and may serve as a new NO-based chemotherapeutic agent for the treatment of pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Nateglinida/farmacologia , Doadores de Óxido Nítrico/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Humanos , Nateglinida/análogos & derivados , Nateglinida/metabolismo , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Transdução de Sinais
7.
Clin Pharmacol Ther ; 111(1): 218-226, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34312836

RESUMO

Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Insulina/agonistas , Secretagogos/efeitos adversos , Demandas Administrativas em Assistência à Saúde , Idoso , Idoso de 80 Anos ou mais , Carbamatos/efeitos adversos , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Interações Medicamentosas , Feminino , Glipizida/efeitos adversos , Glibureto/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Medicaid , Metformina/efeitos adversos , Pessoa de Meia-Idade , Nateglinida/efeitos adversos , Farmacoepidemiologia , Piperidinas/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Estados Unidos
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 268: 120712, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-34896681

RESUMO

Selective and straightforward kinetic spectrophotometric methods were developed to quantify nateglinide (NTG) in pharmaceutical dosage forms. Fixed time (ΔA) and the equilibrium methods utilized the reaction of NTG with 1-chloro-2,4-dinitrobenzene (CDNB) in dimethyl sulfoxide (DMSO) with heating at 80 °C for 25 min to form a stable yellow-coloured Meisenheimer complex, which absorbs maximally at 421 nm. The optimization was achieved by utilizing the Box-Behnken experimental design (BBD) combined with response surface methodology (RSM). In which three significant factors were studied, namely, CDNB volume (A), heating temperature (B) and heating time (C) against the absorbance as a response. Method validation presented the International Conference on Harmonisation (ICH) parameters such as specificity, selectivity, linearity, precision, accuracy, limit of detection (LOD), limit of quantitation (LOQ), robustness and solution stability. The LOD and LOQ values were 0.48, 1.46, and 0.21, 0.62 µg/ml, respectively, for a fixed time (ΔA) and equilibrium methods with the linear dynamic range of 1-15 µg/ml. Furthermore, Youden's robustness test using factorial combinations of the selected analytical parameters was performed and investigated its influence with alternative conditions. All results were reproducible and quickly adopted for routine analysis of NTG in pharmaceutical formulations and laboratory preparations.


Assuntos
Projetos de Pesquisa , Composição de Medicamentos , Cinética , Nateglinida , Espectrofotometria
9.
BMC Med Genomics ; 14(1): 267, 2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34772419

RESUMO

BACKGROUND: Genetic polymorphisms in the PPARD and NOS1AP is associated with type 2 diabetes mellitus (T2DM); however, there is no evidence about its impact on the therapeutic efficacy of nateglinide. This study was designed to investigate a potential association of PPARD rs2016520 (T/C) and NOS1AP rs12742393 (A/C) polymorphisms with efficacy of nateglinide in newly diagnosed Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: Sixty patients with newly diagnosed T2DM were enrolled to identify PPARD rs2016520 and NOS1AP rs12742393 genotypes using the polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). All subjects were treated with nateglinide (360 mg/day) for 8 weeks. Anthropometric measurements, clinical laboratory tests were obtained at baseline and after 8 weeks of nateglinide treatment. RESULTS: After nateglinide treatment for 8 consecutive weeks, patients with at least one C allele of PPARD rs2016520 showed a smaller decrease in post plasma glucose (PPG), homeostasis model assessment for beta cell function (HOMA-B) than those with the TT genotype did (P < 0.05). In patients with the AA genotype of NOS1AP rs12742393, the drug showed better efficacy with respect to levels of fasting plasma glucose (FPG), fasting serum insulin (FINS), HOMA-B and homeostasis model assessment for insulin resistance (HOMA-IR) than in patients with the AC + CC genotype (P < 0.05). NOS1AP rs12742393 genotype distribution and allele frequency were associated with responsiveness of nateglinide treatment (P < 0.05). CONCLUSIONS: The PPARD rs2016520 and NOS1AP rs12742393 polymorphisms were associated with nateglinide monotherapy efficacy in Chinese patients with newly diagnosed T2DM. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR13003536, date of registration: May 14, 2013.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Nateglinida/uso terapêutico , PPAR delta/genética , Polimorfismo de Nucleotídeo Único , China , Feminino , Genótipo , Humanos , Masculino , Resultado do Tratamento
10.
J Diabetes Res ; 2021: 5534387, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34222493

RESUMO

BACKGROUND: To assess the association of metformin monotherapy with the risk of all-cause deaths and cardiovascular deaths and events in type 2 diabetes patients in real clinical practice. METHODS: This retrospective, observational study comprised patients with type 2 diabetes initially treated with metformin or nonmetformin monotherapy over 2011-2016. Data were extracted from the National Healthcare Big Data database in Fuzhou, China. Propensity score matching (PSM) was performed, matching each patient on metformin to one on nonmetformin in terms of a set of covariates. The primary endpoint was all-cause death, and secondary endpoints were cardiovascular death, heart failure, and heart failure hospitalization. Covariate-adjusted associations of metformin use with all the endpoints were assessed by Cox proportional hazards models. RESULTS: Among 24,099 patients, 5491 were initially treated with metformin and 18,608 with nonmetformin. PSM yielded 5482 patients in each cohort. During a median follow-up of 2.02 years, we observed 110 and 211 deaths in the metformin and nonmetformin groups, respectively. Metformin was significantly associated with reduced risk of all-cause death (adjusted hazard ratio (aHR) 0.52, 95% confidence interval (CI) 0.39-0.69), cardiovascular death (aHR 0.63, 95% CI 0.43-0.91), and heart failure (aHR 0.61, 95% CI 0.52-0.73), whereas the reduced risk in heart failure hospitalization was not statistically significant (aHR 0.70, 95% CI 0.47-1.02). CONCLUSIONS: In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications.


Assuntos
Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Mortalidade , Idoso , Benzamidas/uso terapêutico , Carbamatos/uso terapêutico , Causas de Morte , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Nateglinida/uso terapêutico , Piperidinas/uso terapêutico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Compostos de Sulfonilureia/uso terapêutico , Tiazolidinedionas/uso terapêutico
11.
J Pharm Biomed Anal ; 201: 114097, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33933705

RESUMO

During diabetes human serum albumin (HSA), an important drug transport protein, can be modified by agents such as glyoxal (Go) and methylglyoxal (MGo) to form advanced glycation end-products. High-performance affinity microcolumns and zonal elution competition studies were used to compare interactions by the anti-diabetic drugs repaglinide and nateglinide with normal and Go- or MGo-modified HSA at Sudlow sites I and II of this protein. Both drugs had their strongest binding at Sudlow site II for the normal and modified forms of HSA. The association equilibrium constants at this site for repaglinide and nateglinide with normal HSA were 6.1 (± 0.2) × 104 M-1 and 7.1 (± 0.8) × 105 M-1, respectively, at pH 7.4 and 37°C; these values increased by up to 3.6-fold for repaglinide and decreased by up to 45-55 % for nateglinide when HSA was modified by Go or MGo at levels seen in prediabetes or diabetes. Both drugs were also found to bind at Sudlow site I, with association equilibrium constants at this site on normal HSA of 4.2 (± 0.3) × 104 M-1 for repaglinide and 5.0 (± 0.1) × 104 M-1 for nateglinide. The binding strength for repaglinide at Sudlow site I increased by 1.3- to 1.7-fold with the Go-modified HSA and decreased slightly (i.e., up to 19 %) for the MGo-modified HSA, while nateglinide showed only a small or insignificant change in binding with the same modified HSA samples. These results indicated that binding by repaglinide and nateglinide with HSA can be altered significantly by modification of this protein with Go or MGo, making these modifications of potential interest in the treatment of patients with these drugs during diabetes.


Assuntos
Glioxal , Aldeído Pirúvico , Carbamatos , Cromatografia de Afinidade , Glicosilação , Humanos , Nateglinida , Piperidinas , Ligação Proteica , Albumina Sérica/metabolismo , Albumina Sérica Humana/metabolismo
12.
Pharmacology ; 106(7-8): 418-425, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33866315

RESUMO

INTRODUCTION: Nateglinide or N-(trans-4-isopropylcyclohexyl-1-carbonyl)-D-phenylalanine is a drug with a rapid hypoglycemic effect that is mainly used in the treatment of type 2 diabetes. Very few studies have assessed bioequivalence based on feeding status. This study aimed to assess the pharmacokinetic bioequivalence and safety of nateglinide-containing tablets (0.12 g) in healthy Chinese volunteers under fasting and fed conditions. METHODS: The studies were performed in 2017-2018 in the Phase I Clinical Trial Ward of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China. Eligible Chinese volunteers received a single 0.12-g dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. Blood samples were collected at various time intervals, and plasma nateglinide concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Then, the adverse events, laboratory test results, vital signs, and physical exam findings were compared between the 2 groups. RESULTS: The ratios of the geometric means of Cmax, AUC0-t, and AUC0-inf of the tested to reference preparations under fasting conditions were 105.03% (90% confidence interval [CI]: 99.53-110.83%), 104.02% (90% CI: 101.37-106.74%), and 104.04% (90% CI: 101.38-106.77%), respectively. The same ratios under fed conditions were 96.55% (90% CI: 85.80-108.65%), 103.08% (90% CI: 100.07-106.18%), and 103.07% (90% CI: 100.21-106.01%), respectively. The 90% CI values for Cmax, AUC0-t, and AUC0-inf fell within the accepted range of bioequivalence (80.00-125.0%). Common adverse events included hypoglycemia, heart rate increase, palpitation, sweating, dizziness, and diarrhea. CONCLUSIONS: The test formulation (0.12 g) met the CFDA's regulatory definition for bioequivalence to the reference formulation. Both formulations were well tolerated by healthy Chinese subjects. TRIAL REGISTRATION: This trial has been registered in the Chinese Clinical trial registry (ChiCTR2000030694), March 10, 2020.


Assuntos
Medicamentos Genéricos/farmacocinética , Hipoglicemiantes/farmacocinética , Nateglinida/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Jejum , Feminino , Interações Alimento-Droga , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nateglinida/administração & dosagem , Nateglinida/efeitos adversos , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto Jovem
13.
Biol Pharm Bull ; 44(1): 96-102, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390555

RESUMO

The effects of inflammation on hypoglycemic agents were evaluated in male rats with acute peripheral inflammation (API). Nateglinide (NTG) was utilized as a model compound, since it is a hepatically-metabolized compound and its metabolism is mainly mediated by CYP 2C11 enzyme. In the experiments, rats were subjected to carrageenan injection into their hind paws for API induction, and the plasma concentration profiles of NTG were then examined. In addition, pooled liver microsomes were prepared from control and API rats, and the hepatic drug-metabolizing activity toward NTG and the hepatic expression of CYP2C11 protein were evaluated. It was shown that the plasma concentration of NTG following its intravenous administration decreases at a slower rate in API rats than that in control rats. It was also indicated in the incubation study with the liver microsomes that the hepatic drug-metabolizing activity toward NTG decreases in API rats. Additionally, it was revealed in Western immunoblotting that the hepatic expression of CYP2C11 protein decreases in API rats. These findings suggest that inflammation occurring in peripheral tissues brings about a decrease in hepatic NTG metabolism by suppressing the hepatic expression of CYP2C11 protein, causing an alteration of the plasma concentration profile of NTG with its impaired elimination.


Assuntos
Hipoglicemiantes/sangue , Inflamação/sangue , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Nateglinida/sangue , Animais , Carragenina/toxicidade , Hipoglicemiantes/farmacologia , Inflamação/induzido quimicamente , Masculino , Nateglinida/farmacologia , Ratos , Ratos Wistar
14.
Curr Drug Saf ; 16(2): 207-216, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33106149

RESUMO

Meglitinides are a group of oral hypoglycemic medications currently approved for the treatment of type 2 diabetes mellitus (T2DM). Two meglitinide molecules, Repaglinide and Nateglinide, are presently in use. Repaglinide is preferred because of its superior glycemic efficacy. They have modest efficacy with a mean decrement of glycosylated haemoglobin (HbA1c) ranging between -0.2 to -1.50% with individual therapy. Additional HbA1c reduction can occur with combination therapy with other oral hypoglycemics. This class of drugs is effective in controlling postprandial hyperglycemia with minimal risk of hypoglycemia. It is also useful in patients with variable meal timings, especially in the elderly, and in patients with renal failure. There are a dearth of long-term studies on meglitinides to assess cardiovascular outcomes or mortality in T2DM, although the Nateglinide and Valsartan in Impaired Glucose ToleranceOutcomes Research (NAVIGATOR) study showed no difference between Nateglinide and placebo with regard to the core composite cardiovascular outcomes. Based on a PubMed literature search using key words: 'meglitinides', 'repaglinide', 'nateglinide', 'HbA1c', 'glycated haemoglobin', 'cardiovascular safety', 'cardiovascular events', 'cardiovascular outcome trials', 'type 2 diabetes mellitus' and heart failure, and combining the search terms using Boolean operators 'AND', 'OR' and 'NOT' as needed we compiled current evidence for use of these oral hypoglycemic agents in clinical use. This article is an attempt to review the efficacy and cardiovascular (CV) safety of Meglitinides to help clinicians to use this class of oral hypoglycaemic agents prudently.


Assuntos
Diabetes Mellitus Tipo 2 , Idoso , Benzamidas , Glicemia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/efeitos adversos , Nateglinida
15.
J Chromatogr Sci ; 59(3): 297-304, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33275653

RESUMO

A validated method for preconcentration and determination of nateglinide in plasma was developed using vortex-assisted dispersive liquid-liquid microextraction. Different variables that affect extraction efficiency were studied and optimized, including type and volume of extractant, type and volume of disperser, pH of diluent, salt addition effect, centrifugation and vortex time. Nateglinide was extracted using 30 µL of 1-octanol as an extractant and 200 µL of methanol as a disperser. The enrichment factor reached 330 under the optimum conditions. High-performance liquid chromatography/ultraviolet was used for detection using phosphate buffer (pH 2.5, 10 mM): acetonitrile (45:55, v/v) as a mobile phase at a flow rate of 1 mL/min. The method was linear over the range of 50-20,000 ng/mL with a limit of detection of 15 ng/mL (signal-to-noise ratio = 3). Intra- and inter-day precision had %relative standard deviation <6% (n = 3) and the %recoveries were found to be between 102.5 and 105.9%. The proposed method is simple, sensitive, eco-friendly, cost-effective and powerful for microextraction of nateglinide from human plasma samples.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Microextração em Fase Líquida/métodos , Nateglinida/sangue , Humanos , Limite de Detecção , Modelos Lineares , Nateglinida/isolamento & purificação , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta
16.
Drug Dev Ind Pharm ; 46(10): 1676-1683, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32892654

RESUMO

OBJECTIVE: The aim of this work was to investigate dry co-grinding of nateglinide with meglumine for enhanced dissolution rate of nateglinide. The study was extended to investigate the effect of this dissolution enhancement on the hypoglycemic effect of the drug in diabetic rats. METHODS: Nateglinide was subjected to dry co-grinding with increasing proportions of meglumine to prepare products containing the drug with meglumine at 1:1, 1:2, and 1:3 molar ratios. These products were evaluated using combined instrumental analysis which employed Fourier transform infrared spectroscopy (FTIR), differential thermal analysis (DTA), and X-ray diffraction (XRD). Drug dissolution was also monitored before and after processing with and without meglumine. The optimum ratio was used to assess the effect of dissolution enhancement on the hypoglycemic effect of nateglinide on diabetic rats. The unprocessed nateglinide was used as control. RESULTS: Co-grinding of nateglinide resulted in changes in the FTIR spectral patterns of nateglinide and meglumine. The changes suggested the formation of amide bond between both compounds at 1:1 molar ratio. The new species was confirmed by DTA and XRD. This species exhibited fast dissolution of nateglinide after incorporation of higher proportions of meglumine. Co-grinding was essential as indicated from slower dissolution from physical mixture containing the highest proportion of meglumine. Enhanced dissolution was reflected in vivo as improved rate and extent of hypoglycemia. CONCLUSION: Dry co-grinding of nateglinide with meglumine developed new species which liberated nateglinide rapidly and enhanced the rate and extent of hypoglycemia of nateglinide.


Assuntos
Diabetes Mellitus Experimental , Meglumina , Nateglinida/química , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Ratos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
17.
Inflammation ; 43(2): 401-416, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31863220

RESUMO

Ischemic stroke is a major cause of death and motor disabilities all over the world. It is a muti-factorial disorder associated with inflammatory, apoptotic, and oxidative responses. Nateglinide (NAT), an insulinotropic agent used for the treatment of type 2 diabetes mellitus, recently showed potential anti-inflammatory and anti-apoptotic effects. The aim of our study was to elucidate the unique neuroprotective role of NAT in the middle cerebral artery occlusion (MCAO)-induced stroke in rats. Fifty-six male rats were divided to 4 groups (n = 14 in each group): the sham-operated group, sham receiving NAT (50 mg/kg/day, p.o) group, ischemia/reperfusion (IR) group, and IR receiving NAT group (50 mg/kg/day, p.o). MCAO caused potent deficits in motor and behavioral functions of the rats. Significant increase in inflammatory and apoptotic biomarkers has been observed in rats' hippocampi. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was significantly stimulated causing activation of series inflammatory biomarkers ending up neuro-inflammatory milieu. Pretreatment with NAT preserved rats' normal behavioral and motor functions. Moreover, NAT opposed the expression of hypoxia-inducible factor-1α (HIF-1α) resulting in downregulation of more inflammatory mediators namely, NF-κB, tumor necrosis factor-ß (TNF-ß), and the anti-survival gene PMAIP-1. NAT stimulated caveolin-1 (Cav-1) which prevented expression of oxidative biomarkers, nitric oxide (NO), and myeloperoxidase (MPO) and hamper the activation of apoptotic biomarker caspase-3. In conclusion, our work postulated that NAT exhibited its neuroprotective effects in rats with ischemic stroke via attenuation of different unique oxidative, apoptotic, and inflammatory pathways.


Assuntos
Isquemia Encefálica/metabolismo , Caveolina 1/biossíntese , Hipocampo/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Nateglinida/uso terapêutico , Receptores de Superfície Celular/metabolismo , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/prevenção & controle , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Nateglinida/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Ratos , Ratos Wistar , Receptores de Superfície Celular/antagonistas & inibidores , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
18.
J Chromatogr Sci ; 58(4): 309-322, 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31836899

RESUMO

Nateglinide (NAT) and Pioglitazone (PIO) are an antidiabetic drugs combination and currently under clinical trial in countries like Japan. In this study, an alternative, a simple, sensitive high-performance liquid chromatography method has been developed (limit of detection: 15 ng/mL and limit of quantification: 50 ng/mL) for simultaneous estimation of this drug combination in rat plasma. Most remarkably, bioavailability of NAT has been increased markedly on coadministration with PIO, than when it was administered alone. Thus, PIO is assumed to retard the catabolism of NAT by inhibiting metabolic liver-microsomal enzyme, especially CYP2C9. Using a Waters Nova-Pak C 18 column (150 × 3.9 mm, 4 µm) and a mobile phase of acetonitrile: 10 mM KH2PO4 (60: 40, V/V (volume by volume)) pH 3.5, the analysis was performed at 210 nm with a flow rate of 1.5 mL/min. In silico docking via molecular dynamics simulation revealed that NAT-CYP2C9 binding affinity may be reduced after PIO attachment, presumably due to the binding site overlapping of the two drugs. Thus, it has been proposed that NAT and PIO may be an efficient synergistic fixed dose combination against diabetes mellitus, and the above method can foster a simple but highly sensitive bioanalytical estimation for routine analysis.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Nateglinida/farmacocinética , Pioglitazona/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Estabilidade de Medicamentos , Sinergismo Farmacológico , Hipoglicemiantes/farmacocinética , Limite de Detecção , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Nateglinida/administração & dosagem , Nateglinida/sangue , Nateglinida/química , Pioglitazona/administração & dosagem , Pioglitazona/sangue , Pioglitazona/química , Ratos , Reprodutibilidade dos Testes
19.
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
20.
Clin Pharmacol Ther ; 106(6): 1346-1352, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31216051

RESUMO

This nested case-control study evaluated the potential interaction between repaglinide and clopidogrel. Cases were defined by inpatient admissions or emergency department visits due to hypoglycemia. Concomitant use of repaglinide and clopidogrel within 3 days before the hypoglycemic event was the exposure of interest. For each case, up to four controls were randomly selected and matched by age, sex, type of glinide used (repaglinide or nateglinide), and time since cohort entry to the index date. Hypoglycemic risk was estimated by conditional logistic regressions. Concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone (adjusted odds ratio: 2.42; 95% confidence interval: 1.75-3.35). No significant associations were found with the two negative control object drug concomitants: nateglinide and clopidogrel and repaglinide and aspirin (without clopidogrel use). Our study suggests drug interaction between clopidogrel and repaglinide is clinically relevant and could increase the risk for hypoglycemia.


Assuntos
Carbamatos/efeitos adversos , Clopidogrel/efeitos adversos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Piperidinas/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Idoso , Aspirina/uso terapêutico , Estudos de Casos e Controles , Interações Medicamentosas , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nateglinida/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...