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1.
Nat Commun ; 12(1): 5525, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535664

RESUMO

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.


Assuntos
Descoberta de Drogas , Fígado/patologia , Modelos Biológicos , Animais , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Quimioprevenção , Estudos de Coortes , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Hepacivirus/fisiologia , Hepatite C/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Vigilância Imunológica/efeitos dos fármacos , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Knockout , Nizatidina/farmacologia , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/genética
2.
J Biomol Struct Dyn ; 38(5): 1375-1387, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30955446

RESUMO

Nizatidine is a histamine H2 receptor antagonist which act by inhibiting the production of stomach acid, thereby, finds its application in treating various diseases related to the gastrointestinal tract. Studying albumin-drug interaction is important for understanding the pharmacokinetics and pharmacodynamics of therapeutic candidates. In the present work, the interaction of nizatidine with BSA was investigated by employing multi-spectroscopic and computational studies. The formation of BSA-nizatidine complex was characterised by UV-visible and fluorescence based-spectroscopic studies. Steady-state fluorescence demonstrated the static mode of quenching of BSA by nizatidine. The interaction was spontaneous and nizatidine binds to BSA with a stoichiometry of 1:1. Forster resonance energy transfer calculations revealed that there was a high possibility of energy transfer between nizatidine and BSA. The resultant secondary structural change in BSA on the addition of nizatidine was studied by circular dichroism spectroscopy. Moreover, synchronous and three-dimensional fluorescence spectroscopy was used to determine the conformational changes occurred in the structure of albumin on the binding of nizatidine. Competitive-site marker experiments suggested that nizatidine binds in the Sudlow site II of BSA. Additionally, the effect of ß-cyclodextrin as an inclusion compound on the interaction was studied. Furthermore, molecular modelling and simulation studies were performed to corroborate the results obtained above.Communicated by Ramaswamy H. Sarma.


Assuntos
Nizatidina , beta-Ciclodextrinas , Sítios de Ligação , Dicroísmo Circular , Simulação de Acoplamento Molecular , Ligação Proteica , Albumina Sérica , Soroalbumina Bovina/metabolismo , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Termodinâmica
3.
J Food Drug Anal ; 27(4): 915-925, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31590763

RESUMO

The liability of the H2-receptor antagonist nizatidine (NZ) to nitrosation in simulated gastric juice (SGJ) and under WHO-suggested conditions was investigated for the first time. For monitoring the nitrosatability of NZ, a hydrophilic interaction liquid chromatography (HILIC) method was optimized and validated according to FDA guidance. A Cosmosil HILIC® column and a mobile phase composed of acetonitrile: 0.04 M acetate buffer pH 6.0 (92:8, v/v) were used for the separation of NZ and its N-nitroso derivative (NZ-NO) within 6 min with LODs of 0.02 and 0.1 µg/mL, respectively. NZ was found highly susceptible to nitrosation in SGJ reaching 100% nitrosation in 10 min, while only 18% nitrosation was observed after 160 min under the WHO-suggested conditions. The chemical structure of NZ-NO was clarified by ESI+/MS. In silico toxicology study confirmed the mutagenicity and toxicity of NZ-NO. Experiments evidenced that ascorbic acid strongly suppresses the nitrosation of NZ suggesting their co-administration for protection from potential risks. In addition, the impacts of the HILIC method on safety, health, and environment were favorably evaluated by three green analytical chemistry metrics and it was proved that, unlike the popular impression, HILIC methods could be green to the environment.


Assuntos
Simulação de Acoplamento Molecular , Neoplasias/induzido quimicamente , Compostos Nitrosos/efeitos adversos , Nizatidina/efeitos adversos , Animais , Cromatografia Líquida de Alta Pressão , Humanos , Conformação Molecular , Compostos Nitrosos/síntese química , Compostos Nitrosos/química , Nizatidina/síntese química , Nizatidina/química , Software , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
4.
Drug Dev Ind Pharm ; 45(4): 651-663, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30638411

RESUMO

OBJECTIVE: The main objective of this research is to formulate, optimize, and evaluate raft-forming chewable tablets of Nizatidine. Various raft-forming agents were used in preliminary screening. Sodium alginate showed maximum raft strength, so tablets were prepared using sodium alginate as the raft forming agent, along with calcium carbonate (CaCO3) as antacid and raft strengthening agent, and sodium bicarbonate (NaHCO3) as a gas generating agent. RESEARCH DESIGN AND METHODS: Raft forming chewable tablets containing Nizatidine were prepared by direct compression and wet granulation methods, and evaluated for drug content, acid neutralization capacity, raft strength, and in-vitro drug release in 0.1 N HCl. Box-Behnken design was used for optimization. RESULTS: Two optimized formulations were predicted from the design space. The first optimized recommended concentrations of the independent variables were predicted to be X1 = 275.92 mg, X2 = 28.60 mg, and X3 = 202.14 mg for direct compression technique and the second optimized recommended concentrations were predicted to be X1 = 253.62 mg, X2 = 24.60 mg, and X3 = 201.77 mg for wet granulation technique. Optimized formulations were stable at accelerated environmental testing for six months at 35 °C and 45 °C with 75% relative humidity. X-Ray showed that the raft floated immediately after ingestion and remained intact for ∼3 h. CONCLUSION: Raft was successfully formed and optimized. Upon chewing tablets, a raft is formed on stomach content. That results in rapid relief of acid burning symptoms and delivering the drug into systemic circulation with enhanced bioavailability.


Assuntos
Carbonato de Cálcio/administração & dosagem , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Nizatidina/administração & dosagem , Administração Oral , Alginatos/química , Antiácidos/administração & dosagem , Antiácidos/farmacocinética , Disponibilidade Biológica , Carbonato de Cálcio/farmacocinética , Estudos Cross-Over , Combinação de Medicamentos , Gastroenteropatias/tratamento farmacológico , Voluntários Saudáveis , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Humanos , Nizatidina/farmacocinética , Bicarbonato de Sódio/química , Comprimidos
5.
J Labelled Comp Radiopharm ; 60(13): 600-607, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28833386

RESUMO

Nizatidine has been labeled using [125 I] with chloramine-T as oxidizing agent. Factors such as the amount of oxidizing agent, amount of substrate, pH, reaction temperature, and reaction time have been systematically studied to optimize the iodination. Biodistribution studies indicate the suitability of radioiodinated nizatidine as a novel tracer to image stomach ulcer. Radioiodinated nizatidine may be considered a highly selective radiotracer for peptic ulcer imaging.


Assuntos
Halogenação , Radioisótopos do Iodo/química , Nizatidina/química , Nizatidina/farmacocinética , Úlcera Péptica/diagnóstico por imagem , Animais , Marcação por Isótopo , Camundongos , Traçadores Radioativos , Radioquímica , Estômago/diagnóstico por imagem , Distribuição Tecidual
6.
J Chromatogr Sci ; 55(8): 818-831, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28486578

RESUMO

A comparative force degradation high performance thin layer chromatography (HPTLC) method was developed and validated for some H2-receptor antagonists. The studied H2-receptor antagonists were ranitidine (RAN), nizatidine (NIZ) and famotidine (FAM). The degradation behaviors of the studied H2-receptor antagonists were studied under different stress conditions (hydrolytic, thermal and oxidative) conditions as well as storage conditions according to International Conference on Harmonization (ICH) recommendations. A stability-indicating HPTLC method was optimized in order to separate the analyte from the degradation products formed under various stress conditions. Full separation of the drugs from their degradation products was successfully achieved on an HPTLC precoated silica gel plates. Densitometric measurements were carried out using a Camag TLC Scanner III in the absorbance mode at 320 nm for RAN and NIZ, and 280 nm for FAM. The limits of detection and limits of quantitation range were 5.47-9.37 and 16.30-31.26 ng/band, respectively, for all investigated drugs. The validation studies were performed according to ICH requirements. The developed method was simple, rapid and reliable hence it could be applied for routine quality control analysis of the investigated H2-receptor antagonists in dosage forms. The kinetic behavior, degradation rate constants and half-lives of the degradation of the investigated drugs were studied and compared at different stress conditions. The present study provides, for the first time, a new vision to compare the degradation kinetics of H2-receptor antagonists at the same degradation procedures.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Delgada/métodos , Antagonistas dos Receptores H2 da Histamina/análise , Antagonistas dos Receptores H2 da Histamina/química , Densitometria , Estabilidade de Medicamentos , Famotidina/análise , Famotidina/química , Limite de Detecção , Modelos Lineares , Nizatidina/análise , Nizatidina/química , Ranitidina/análise , Ranitidina/química , Reprodutibilidade dos Testes
7.
Eur J Pharm Sci ; 99: 147-151, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27916696

RESUMO

The dielectric properties of two pharmaceuticals nizatidine and perphenazine were investigated in the supercooled liquid and glassy states by broadband dielectric spectroscopy. Two relaxation processes were observed in both the pharmaceuticals. The relaxation process observed above the glass transition temperature is the structural alpha relaxation and below the glass transition temperature is the gamma relaxation of intramolecular origin. The Johari-Goldstein beta relaxation coming from the motion of the entire molecule is found to be hidden under the structural relaxation peak in both the pharmaceuticals.


Assuntos
Nizatidina/química , Perfenazina/química , Preparações Farmacêuticas/química , Espectroscopia Dielétrica/métodos , Vidro/química , Movimento (Física) , Temperatura , Temperatura de Transição
8.
Mediators Inflamm ; 2016: 9862496, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27872516

RESUMO

Purpose. It has been confirmed that inflammatory cytokines are involved in the progression of pterygium. Histamine can enhance proliferation and migration of many cells. Therefore, we intend to investigate the proliferative and migratory effects of histamine on primary culture of human pterygium fibroblasts (HPFs). Methods. Pterygium and conjunctiva samples were obtained from surgery, and toluidine blue staining was used to identify mast cells. 3-[4, 5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) was performed to evaluate the proliferative rate of HPFs and human conjunctival fibroblasts (HCFs); ki67 expression was also measured by immunofluorescence analysis. Histamine receptor-1 (H1R) antagonist (Diphenhydramine Hydrochloride) and histamine receptor-2 (H2R) antagonist (Nizatidine) were added to figure out which receptor was involved. Wound healing model was used to evaluate the migratory ability of HPFs. Results. The numbers of total mast cells and degranulated mast cells were both higher in pterygium than in conjunctiva. Histamine had a proliferative effect on both HPFs and HCFs, the effective concentration (10 µmol/L) on HPFs was lower than on HCFs (100 µmol/L), and the effect could be blocked by H1R antagonist. Histamine showed no migratory effect on HPFs. Conclusion. Histamine may play an important role in the proliferation of HPFs and act through H1R.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Histamina/farmacologia , Pterígio/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Túnica Conjuntiva/citologia , Difenidramina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Nizatidina/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Soro/fisiologia
9.
J Pharm Sci ; 105(12): 3573-3584, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27773524

RESUMO

The slow molecular mobility in the amorphous solid state of 3 active pharmaceutical drugs (cimetidine, nizatidine, and famotidine) has been studied using differential scanning calorimetry and the 2 dielectric-related techniques of dielectric relaxation spectroscopy and thermally stimulated depolarization currents. The glass-forming ability, the glass stability, and the tendency for crystallization from the equilibrium melt were investigated by differential scanning calorimetry, which also provided the characterization of the main relaxation of the 3 glass formers. The chemical instability of famotidine at the melting temperature and above it prevented the preparation of the amorphous for dielectric studies. In contrast, for cimetidine and nizatidine, the dielectric study yielded the main kinetic features of the α relaxation and of the secondary relaxations. According to the obtained results, nizatidine displays the higher fragility index of the 3 studied glass-forming drugs. The thermally stimulated depolarization current technique has proved useful to identify the Johari-Goldstein relaxation and to measure τßJG in the amorphous solid state, that is, in a frequency range which is not easily accessible by dielectric relaxation spectroscopy.


Assuntos
Química Farmacêutica/métodos , Cimetidina/química , Famotidina/química , Nizatidina/química , Varredura Diferencial de Calorimetria/métodos , Cimetidina/metabolismo , Famotidina/metabolismo , Nizatidina/metabolismo , Fatores de Tempo
10.
Molecules ; 21(9)2016 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-27608003

RESUMO

The histamine H2-receptor antagonists cimetidine, famotidine and nizatidine are individually encapsulated by macrocyclic cucurbit[7]uril (CB[7]), with binding affinities of 6.57 (±0.19) × 10³ M(-1), 1.30 (±0.27) × 104 M(-1) and 1.05 (±0.33) × 105 M(-1), respectively. These 1:1 host-guest inclusion complexes have been experimentally examined by ¹H-NMR, UV-visible spectroscopic titrations (including Job plots), electrospray ionization mass spectrometry (ESI-MS), and isothermal titration calorimetry (ITC), as well as theoretically by molecular dynamics (MD) computation. This study may provide important insights on the supramolecular formulation of H2-receptor antagonist drugs for potentially enhanced stability and controlled release based on different binding strengths of these host-guest complexes.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Cimetidina/química , Famotidina/química , Antagonistas dos Receptores H2 da Histamina/química , Imidazóis/química , Simulação de Dinâmica Molecular , Nizatidina/química
11.
Chemosphere ; 146: 154-61, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26714298

RESUMO

Nitro-based compounds are the direct precursors of trichloronitromethane during chlorination disinfection. Two nitro-based pharmaceuticals ranitidine and nizatidine were selected as model compounds to assess the effect of oxidation on the removal of nitro-based pharmaceuticals, as well as the reduction of their trichloronitromethane formation potentials (TCNMFPs). The four oxidants were ozone (O3), chlorine (Cl2), chlorine dioxide (ClO2) and potassium permanganate (KMnO4). The changes in pharmaceuticals and their TCNMFPs during oxidation using various oxidants and dosages were quantified. The relationships between oxidation product structures and TCNMFP changes were also analyzed. The results showed that oxidation with Cl2 and KMnO4 were more effective than ClO2 and O3 in removing the nitro-based pharmaceuticals. Meanwhile, decreased TCNMFPs by KMnO4 oxidation but increased TCNMFPs by Cl2, ClO2 and O3 oxidation were observed. The results of product analysis indicated that chlorine transfer products had higher TCNMFPs, while oxygen transfer products made little contribution to TCNMFPs after oxidation. In addition, one possible reaction pathway leading TCNMFP increase was that chloro-nitromethane or nitromethane, which was a better TCNM precursor, formed when double bond was attacked by oxidants.


Assuntos
Hidrocarbonetos Clorados/análise , Nizatidina/química , Oxidantes/química , Ranitidina/química , Poluentes Químicos da Água/química , Purificação da Água , Desinfetantes/química , Monitoramento Ambiental , Oxirredução , Preparações Farmacêuticas/química
12.
J Chromatogr Sci ; 54(3): 419-28, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26538490

RESUMO

A simple, efficient and reliable ion-pair chromatography (IPC) method was developed and validated for the determination of some H2 receptor antagonists including ranitidine (RAN), nizatidine (NIZ) and famotidine (FAM). The use of IPC separations provided improved peak resolution with good peak shape in short analysis time and augmented method selectivity compared with the frequently used RP-C18 methods. A simple isocratic mode with mobile phase containing acetonitrile and 20 mM acetate buffer (50 : 50, v/v) containing 20 mM sodium dodecyl sulfate was used for separation. The flow rate was set at 1.0 mL min(-1), and the effluent was monitored by UV detector at 280 nm FAM and 320 nm for NIZ and RAN. The method was validated in accordance with International Conference on Harmonization guidelines and shown to be suitable for intended applications. The limits of detections and quantitations were 0.008-0.011 and 0.025-0.033 µg mL(-1), respectively. The proposed IPC method was successfully applied for the determination of pharmaceutical dosage forms without prior need for separation. Additionally, the developed method was applied for the determination of RAN in rabbit plasma using NIZ as the internal standard. The method entailed direct injection of the plasma samples after deproteination using methanol. Finally, the proposed IPC method was applied successfully in a pharmacokinetic study for RAN in rabbits after a single oral dose of RAN.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Famotidina/farmacocinética , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Nizatidina/farmacocinética , Ranitidina/farmacocinética , Acetonitrilas , Administração Oral , Animais , Tampões (Química) , Cromatografia Líquida de Alta Pressão/normas , Famotidina/sangue , Feminino , Antagonistas dos Receptores H2 da Histamina/sangue , Humanos , Limite de Detecção , Nizatidina/sangue , Coelhos , Ranitidina/sangue , Dodecilsulfato de Sódio , Solventes
13.
Clin Pharmacokinet ; 55(4): 495-506, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26507723

RESUMO

BACKGROUND AND OBJECTIVES: In the proximal tubule, basic drugs are transported from the renal cells to the tubule lumen through the concerted action of the H(+)/organic cation antiporters, multidrug and toxin extrusion (MATE) 1 and MATE2K. Dual inhibitors of the MATE transporters have been shown to have a clinically relevant effect on the pharmacokinetics of concomitantly administered basic drugs. However, the clinical impact of selective renal organic cation transport inhibition on the pharmacokinetics and pharmacodynamics of basic drugs, such as metformin, is unknown. This study sought to identify a selective MATE2K inhibitor in vitro and to determine its clinical impact on the pharmacokinetics and pharmacodynamics of metformin in healthy subjects. METHODS: Strategic cell-based screening of 71 US Food and Drug Administration (FDA)-approved medications was conducted to identify selective inhibitors of renal organic cation transporters that are capable of inhibiting at clinically relevant concentrations. From this screen, nizatidine was identified and predicted to be a clinically potent and selective inhibitor of MATE2K-mediated transport. The effect of nizatidine on the pharmacokinetics and pharmacodynamics of metformin was evaluated in 12 healthy volunteers in an open-label, randomized, two-phase crossover drug-drug interaction (DDI) study. RESULTS: In healthy volunteers, the MATE2K-selective inhibitor nizatidine significantly increased the apparent volume of distribution, half-life, and hypoglycemic activity of metformin. However, despite achieving unbound maximum concentrations greater than the in vitro inhibition potency (concentration of drug producing 50% inhibition [IC50]) of MATE2K-mediated transport, nizatidine did not affect the renal clearance (CLR) or net secretory clearance of metformin. CONCLUSION: This study demonstrates that a selective inhibition of MATE2K by nizatidine affected the apparent volume of distribution, tissue concentrations, and peripheral effects of metformin. However, nizatidine did not alter systemic concentrations or the CLR of metformin, suggesting that specific MATE2K inhibition may not be sufficient to cause renal DDIs with metformin.


Assuntos
Metformina/farmacologia , Metformina/farmacocinética , Nizatidina/farmacologia , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Adolescente , Adulto , Linhagem Celular , Estudos Cross-Over , Interações Medicamentosas , Feminino , Células HEK293 , Meia-Vida , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Artigo em Inglês | MEDLINE | ID: mdl-26197435

RESUMO

We developed and validated a high performance liquid chromatographic method coupled with triple quadrupole mass spectrometry for analysis of nizatidine in human plasma and urine. The biological samples were precipitated with methanol before separation on an Agilent Eclipse Plus C18 column (100mm×46mm, 5µm) with a mixture of methanol and water (95:5, plus 5mM ammonium formate) as the mobile phase at 0.5mL/min. Detection was performed using multiple reaction monitoring modes via electrospray ionization (ESI) at m/z 332.1→155.1 (for nizatidine) and m/z 335.1→155.1 (for [(2)H3]-nizatidine, the internal standard). The linear response range was 5-2000ng/mL and 0.5-80µg/mL for human plasma and urine, with the lower limits of quantification of 5ng/mL and 0.5µg/mL, respectively. The method was validated according to the biological method validation guidelines of the Food and Drug Administration and proved acceptable. This newly developed analytical method was successfully applied in a pharmacokinetic study following single oral administration of a 150mg nizatidine capsule in to 16 healthy Chinese subjects. Maximum and endpoint concentrations in plasma and urine were quantifiable, suggesting our method is appropriate for routine pharmacokinetic analysis.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Antagonistas dos Receptores H2 da Histamina/sangue , Antagonistas dos Receptores H2 da Histamina/urina , Nizatidina/sangue , Nizatidina/urina , Espectrometria de Massas em Tandem/métodos , Adulto , Feminino , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Humanos , Masculino , Nizatidina/farmacocinética , Sensibilidade e Especificidade , Adulto Jovem
16.
Drug Deliv ; 22(3): 306-11, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-24601855

RESUMO

BACKGROUND: The purpose of the present study was to formulate and characterize Nizatidine-encapsulated microballoons for enhancing bioavailability and increasing the residence time of drug in the gastrointestinal tract. METHODS: Microballoons were prepared using emulsion solvent diffusion method using Eudragit S-100 and HPMC as the polymer. The formulation process was optimized for polymer ratio, drug: polymer ratio, emulsifier concentration, stirring speed, stirring time. Optimized formulation was subjected to scanning electron microscopy, drug entrapment, buoyancy studies, in-vitro drug release and in-vivo floating efficiency (X-ray) study. In-vivo antiulcer activity was assessed by ethanol-induced ulcer in murine model. RESULTS: The microballoons were smooth and spherical in shape and were porous in nature due to hollow core. A sustained release of drug was observed for 12 h. Examination of the sequential X-ray images taken during the study clearly indicated that the optimized formulation remained buoyant and uniformly distributed in the gastric contents for a period of 12 h. In ethanol-induced ulcer model, drug-loaded Microballoon-treated group showed significant (p < 0.01) ulcer protection index as compared to free drug-treated group. CONCLUSION: Nizatidine-loaded floating microballoons may serve as a useful drug delivery system for prolonging the gastric residence time and effective treatment of gastric ulcers.


Assuntos
Antiulcerosos/química , Antiulcerosos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Nizatidina/química , Nizatidina/uso terapêutico , Úlcera Gástrica/tratamento farmacológico , Animais , Antiulcerosos/administração & dosagem , Antiulcerosos/farmacocinética , Química Farmacêutica , Preparações de Ação Retardada , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Feminino , Masculino , Microscopia Eletrônica de Varredura , Microesferas , Nizatidina/administração & dosagem , Nizatidina/farmacocinética , Ratos , Propriedades de Superfície
17.
J Pharm Biomed Anal ; 106: 85-91, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25498149

RESUMO

A new extraction medium was proposed for liquid-liquid extraction of the histamine H2 receptor antagonists ranitidine (RNT) and nizatidine (NZT). The ionic liquids with low vapor pressure and favorable solvating properties for a range of compounds such as 1-butyl-3-methylimidazolium hexafluorophosphate [C4mim][PF6] and 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [C4mim][Tf2N] were tested for isolation of analytes. The extraction parameters of RNT and NZT, namely, amount of ionic liquid, pH of sample solution, shaking and centrifugation time were optimized. The isolation processes were performed with 1 mL of the ionic liquids. The extracted samples (pH values near 4) were shaken at 1750 rpm. The influence of interfering substances on the efficiency of extraction process was also studied. Methods for the histamine H2 receptor antagonists (ranitidine and nizatidine) determination after their separation using imidazolium ionic liquids by high performance liquid chromatography (HPLC) combined with UV spectrophotometry were developed. The application of ionic liquids in extraction step allows for selective isolation of analytes from aqueous matrices and their preconcentration. The above methods were applied to the determination of RNT and NZT in environmental samples (river water and wastewater after treatment).


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Nizatidina/análise , Ranitidina/análise , Espectrofotometria Ultravioleta/métodos , Água Doce/análise , Antagonistas dos Receptores H2 da Histamina/análise , Imidazóis/química , Líquidos Iônicos/química , Extração Líquido-Líquido/métodos , Águas Residuárias/análise , Poluentes Químicos da Água/análise
18.
Oncology ; 87(6): 351-63, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25195536

RESUMO

OBJECTIVE: The aim of this study was to identify alternative compounds to the tumor suppressor miR-375 using the connectivity map (CMAP) and to validate the antitumor effects of the identified drugs in esophageal squamous cell carcinoma (ESCC). METHODS: Gene profiling of miR-375-treated TE2 and T.Tn cells was applied in order to search the CMAP database. Among the compounds identified using the CMAP, we focused on 8 drugs [(-)-epigallocatechin-3-gallate, metformin, rosiglitazone among others], excluding 2 drugs among the top 10 compounds. We evaluated whether these compounds possess tumor-suppressive functions in ESCC. RESULTS: A cytotoxicity assay showed that the sensitivity of TE2 and T.Tn cells treated with the 8 compounds was evaluated based on IC50 values of 42.9 µM to 3.8 mM. A cell cycle analysis revealed that the percentage of TE2 and T.Tn cells incubated with 6 compounds in the G0/G1 phase or the G2/M phase increased by approximately 40-80%. A TUNEL assay showed that the percentages of apoptotic cells treated with almost all compounds were significantly increased (p < 0.05) compared with the control cells. CONCLUSION: The CMAP database is a useful tool for identifying compounds affecting the same molecular pathways, particularly products that are difficult to apply via practical approaches, such as microRNAs.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Citotoxinas/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , MicroRNAs/efeitos dos fármacos , Proteínas Supressoras de Tumor/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Benzocaína/farmacologia , Betazol/farmacologia , Catequina/análogos & derivados , Catequina/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Ácido Quenodesoxicólico/farmacologia , Primers do DNA , Humanos , Marcação In Situ das Extremidades Cortadas , Metformina/farmacologia , MicroRNAs/metabolismo , Nizatidina/farmacologia , Organofosfatos/farmacologia , Prolina/análogos & derivados , Prolina/farmacologia , Análise Serial de Proteínas , Reação em Cadeia da Polimerase em Tempo Real , Rosiglitazona , Tiazolidinedionas/farmacologia , Transcriptoma , Transfecção , Proteínas Supressoras de Tumor/genética
19.
Hum Vaccin Immunother ; 10(2): 461-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24253609

RESUMO

Nizatidine (NIZ), closely related to Cimetidine, is a histamine H2 receptor inverse agonist used primarily as an anti-acid drug. Recent studies showed that this class of compounds may also modulate immune responses. To evaluate adjuvant effects of NIZ on vaccine immune modulation, we formulated NIZ with a H5N1 killed viral antigen and tested in vitro and in vivo. NIZ activated DC maturation and stimulated Th1 and Th2 immune responses to H5N1 vaccine. As a result, it enhanced both antibody and T cell-mediated immune responses. We also observed that a single immunization into C57BL/6 mice blocked IL-10 upregulation and potentiated Th1/Th2 dual polarization. Importantly, the inoculation of H5N1 vaccine with NIZ significantly improved protection of animals from death after challenge and reduced virus loads in the lung tissues. Considering its water-soluble nature, compared with Cimetidine, Nizatidine may be a better choice to use as a vaccine adjuvant.


Assuntos
Adjuvantes Imunológicos/farmacologia , Imunidade Celular/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Nizatidina/farmacologia , Infecções por Orthomyxoviridae/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Antivirais/sangue , Modelos Animais de Doenças , Feminino , Vacinas contra Influenza/administração & dosagem , Camundongos Endogâmicos C57BL , Nizatidina/administração & dosagem , Infecções por Orthomyxoviridae/imunologia , Análise de Sobrevida , Linfócitos T/imunologia , Células Th1/imunologia , Células Th2/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia
20.
Mov Disord ; 29(4): 562-6, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24375669

RESUMO

BACKGROUND: The objective of this work was to perform an open trial of the effects of nizatidine (NZT), a selective histamine H2-receptor antagonist and a cholinomimetic, on gastroparesis in Parkinson's disease (PD) patients, using objective parameters given by a gastric emptying study using a (13) C-sodium acetate expiration breath test. METHODS: Twenty patients with PD were enrolled in the study. There were 13 men and 7 women; aged 68.0 ± 7.72 years; disease duration 5.50 ± 3.62 years. All patients underwent the breath test and a gastrointestinal questionnaire before and after 3 months of administration of NZT at 300 mg/day. Statistical analysis was performed by Student t test. RESULTS: NZT was well tolerated by all patients and none had abdominal pain or other adverse effects. NZT significantly shortened Tmax ((13) C) (the peak time of the (13) C-dose-excess curve) (P < 0.05). CONCLUSIONS: Although this is a pilot study, we found a significant shortening of gastric emptying time after administration of NZT in PD patients.


Assuntos
Gastroparesia/tratamento farmacológico , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Nizatidina/uso terapêutico , Doença de Parkinson/complicações , Idoso , Feminino , Gastroparesia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento
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