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1.
AAPS PharmSciTech ; 22(6): 218, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389913

RESUMO

The primary objective of the present research work was to develop nanoparticles incorporating (nanoparticulate) fast dissolving (orodispersible) film evincing enhanced solubility and bioavailability of nitrendipine (NIT). An antisolvent sonoprecipitation method was employed to produce the NIT nanosuspension (NS), which was optimized using the 32 optimal response surface design and then the optimized one was evaluated for various parameters (Gandhi et al., AAPS PharmSciTech 22 (1):1-15, 2021). The NIT nanoparticulate orodispersible film (N-ODF) was prepared utilizing the nanosuspension by the solvent casting method using the Vijay film-forming instrument. The N-ODF was optimized by the 23 full factorial design and was evaluated for several parameters. The optimized NS depicted a particle size of 505.74 ± 15.48 nm with a polydispersity index (PDI) of 0.083 ± 0.006 (Fig. 1b). The NIT nanoparticles showed a striking increment in saturation solubility (26.14 times), when compared with plain NIT (2). The developed NIT N-ODF exhibited thickness (0.148 ± 0.008 mm), folding endurance (280.33 ± 5.51 times), surface pH (6.86 ± 0.05), tensile strength (8.25 ± 0.13 kg/cm2), % elongation (63.5 ± 1.97%), and disintegration time (24.60 ± 1.31 s) to be within the standard intended limit. The in vitro dissolution study unveiled 100.28 ± 2.64% and 100.68 ± 2.50% of NIT release from lyophilized nanocrystals (in 8 min) and N-ODF (in 3.5 min), respectively, whereas the conventional NIT tablet took 30 min to release 99.94 ± 1.57% of NIT (Gandhi et al., AAPS PharmSciTech 22 (1):1-15, 2021). The in vivo pharmacokinetic study in rabbits inferred the achievement of significantly (p < 0.05) higher bioavailability of NIT on release from N-ODF in comparison to the conventional NIT tablet. Thus, the generation of N-ODF can be considered as a propitious move toward improving the efficacy of NIT to treat hypertension and angina pectoris.


Assuntos
Nanopartículas , Nitrendipino , Administração Oral , Animais , Disponibilidade Biológica , Tamanho da Partícula , Coelhos , Solubilidade
2.
AAPS PharmSciTech ; 22(3): 113, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33751276

RESUMO

The present research focuses on the development of a nanoparticulate (nanocrystals-loaded) rapidly dissolving (orodispersible) tablet with improved solubility and bioavailability. The nanosuspension (NS) was prepared by antisolvent sonoprecipitation technique and the optimized NS was lyophilized to obtain nanocrystals (NCs), which were evaluated for various parameters. The nitrendipine (NIT) nanoparticulate orodispersible tablet (N-ODT) was prepared by direct compression method. The optimized N-ODT was evaluated for pre and post compression characteristics, in vivo pharmacokinetic and stability profile. The optimized NS showed a particle size of 505.74 ± 15.48 nm with a polydispersity index (PDI) of 0.083 ± 0.006. The % NIT content in the NCs was found to be 78.4 ± 2.3%. The saturation solubility of NIT was increased remarkably (26.14 times) in comparison to plain NIT, post NCs development. The DSC and p-XRD analysis of NCs revealed the perseverance of the integrity and crystallinity of NIT on lyophilization. The results of micromeritic studies revealed the good flow-ability and compressibility of NCs blend. All the post-compression properties of N-ODT were observed within the standard intended limit. The dispersion, wetting, and disintegration time of the optimized batch of N-ODT was found to be 39 ± 1.13 s, 44.66 ± 1.52 s, and 33.91 ± 0.94 s respectively. The in vitro dissolution study displayed 100.28 ± 2.64% and 100.61 ± 3.3% of NIT released from NCs (in 8 min) and N-ODT (in 6 min) respectively, while conventional NIT tablet took 30 min to release 99.94 ± 1.57% of NIT. The in vivo pharmacokinetic study in rabbits demonstrated significantly (p < 0.05) higher bioavailability of NIT on release from N-ODT than the conventional NIT tablet. Thus, N-ODT could be a promising tool for improving the solubility and bioavailability of NIT and to treat cardiovascular diseases effectively.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Nanopartículas/química , Nanopartículas/metabolismo , Nitrendipino/síntese química , Nitrendipino/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Liberação Controlada de Fármacos/fisiologia , Masculino , Nanopartículas/administração & dosagem , Nitrendipino/administração & dosagem , Tamanho da Partícula , Coelhos , Solubilidade , Difração de Raios X/métodos
3.
Spectrochim Acta A Mol Biomol Spectrosc ; 244: 118894, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32919159

RESUMO

A fixed dose combination of enalapril maleate (EN) and nitrendipine (NT) achieved satisfactory blood pressure control rather than monotherapy. Four accurate spectrophotometric methods utilizing ratio spectra were developed and validated for the simultaneous determination of EN and NT in combined pharmaceutical dosage form (Eneas® tablets). The first method was first derivative ratio spectrophotometric method (1DD) where the amplitudes maxima were measured at 219.2 nm and 233.4 nm for the determination of EN and NT, respectively. The second method was ratio difference spectrophotometric method where EN and NT were estimated by measuring the amplitudes difference between 213 nm and 225 nm on the ratio spectrum of EN and between 241 nm and 227 nm on the ratio spectrum of NT. The third method was ratio subtraction followed by extended ratio subtraction, EN was determined at 210 nm by subtraction of the constant values from the ratio spectrum then multiplication with the divisor (NT spectrum). An extended ratio subtraction method was then applied in order to determine NT at 235 nm by using the zero-order spectrum of EN (10 µg/ml) as a divisor. The fourth method was ratio subtraction coupled with constant multiplication methods. The zero- order absorption spectrum of the laboratory prepared mixture was divided by NT (12 µg/ml) spectrum, subsequently, the value of the constant was multiplied by the divisor to obtain the original spectrum of NT, followed by its subtraction from the laboratory prepared mixture to get the spectrum of EN. EN and NT were determined at 210 nm and 235 nm, respectively. Linearity was ascertained over the concentration ranges of (1-11 µg/ml) for EN and (2-14 µg/ml) for NT, for the first and second methods and (2-13 µg/ml) for EN and (3-20 µg/ml) of NT, for the third and fourth methods. Application of the methods to the determination of the cited drugs in Eneas® tablets gave satisfactory results. Methods validation confirmed their accuracy and selectivity. Statistical comparison of the results with the reported one showed no significant difference, regarding precision and accuracy. Routine analysis of the cited drugs in quality control laboratories could be performed using the developed methods.


Assuntos
Enalapril , Nitrendipino , Espectrofotometria , Comprimidos
4.
Mater Sci Eng C Mater Biol Appl ; 118: 111372, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33254988

RESUMO

To combine the advantages of micelles and biomimetic silica materials, biomimetic micellar mesoporous silica xerogel (BM-SX) was initially established, biomimetic silica xerogel (B-SX) was also studied as control and nitrendipine (NDP) was taken as model drug. The content mainly focused on drug dissolution, systemic stability and cellular transmembrane transport of NDP loaded B-SX and NDP loaded BM-SX. With extra mesopores formed due to HPMC E50 micelles, the mean pore diameter, surface area and pore volume of BM-SX were all larger than B-SX. After loading NDP into the two carriers, crystal NDP changed to amorphous phase, leading to enhanced NDP dissolution. BM-SX presented superior abilities not only for its higher drug dissolution compared to B-SX but also for its capacity in remaining high amorphous drug phase and therefore no drug dissolution reduction can be observed. The dynamic contact angle result confirmed the strong power of HPMC E50 micelles in maintaining amorphous NDP in the carrier to improve high systemic stability. Both B-SX and BM-SX could increase drug absorption permeability and exert function as drug efflux inhibitor to inhibit the efflux effect of p-gp drug pump and promote NDP absorption and transport, and BM-SX was superior owing to micelles in the system.


Assuntos
Nitrendipino , Dióxido de Silício , Biomimética , Portadores de Fármacos , Micelas , Porosidade , Solubilidade
5.
Biomed Chromatogr ; 34(12): e4955, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32706446

RESUMO

Hypertension is a major risk factor for atherosclerosis and ischemic heart disease. Most hypertensive patients need a combination of antihypertensive agents to achieve therapeutic goals. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of enalapril maleate (ENA) and its major metabolite enalaprilat (ENAT), nitrendipine (NIT) and its major metabolite dehydronitrendipine (DNIT), and hydrochlorothiazide (HCT) in human plasma using felodipine as an internal standard (IS). The drugs were extracted from plasma using one-step protein precipitation. Chromatographic separation was performed on a Symmetry C18 column, with water and acetonitrile (10:90, v/v) as mobile phase. The detection was carried out using multiple reaction monitoring mode and coupled with electrospray ionization source. Multiple reaction monitoring transitions were m/z 377.1 → 234.1 for ENA, m/z 349.2 → 206.1 for ENAT, m/z 361.2 → 315.1 for NIT, m/z 359 → 331 for DNIT, m/z 295.9 → 205.1 for HCT, and m/z 384.1 → 338 for felodipine (IS). The method was linear over concentration ranges of 1-200, 20-500, 5-200, 2-100, and 5-200 ng/mL for ENA, ENAT, NIT, DNIT, and HCT, respectively, with r2 ≥ 0.99. Method validation was performed according to U.S. Food and Drug Administration guidelines. The validated method showed good sensitivity and selectivity and could be applied for therapeutic drug monitoring and bioequivalence studies.


Assuntos
Cromatografia Líquida/métodos , Enalapril/sangue , Hidroclorotiazida/sangue , Nitrendipino/sangue , Espectrometria de Massas em Tandem/métodos , Estabilidade de Medicamentos , Enalapril/química , Enalapril/farmacocinética , Humanos , Hidroclorotiazida/química , Hidroclorotiazida/farmacocinética , Modelos Lineares , Nitrendipino/química , Nitrendipino/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray
6.
Drug Dev Ind Pharm ; 46(2): 329-342, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31976777

RESUMO

Objective: The purpose of present research was to develop and statistically optimize nitrendipine nanoemulsion gel for transdermal delivery using box-behnken statistical design.Method: The nanoemulsion formulations bearing nitrendipine were prepared by application of ternary phase diagram and spontaneous emulsification method. Box-behnken design was employed for the optimization of nitrendipine loaded nanoemulsion. The independent variables were oil, surfactant and co-surfactant while globule size, drug content and zeta potential were dependent variables. The optimized nanoemulsion formulation was incorporated into gel and evaluated for in-vitro release, ex-vivo permeation studies, confocal laser scanning microscopy, skin irritation and histopathological studies.Results: The optimized formulation through box-behnken statistical design showed globule size of 20.43 ± 1.50 nm, drug content of 97.05 ± 1.77% and zeta potential of -15.45 ± 0.35 mV. The ex-vivo study confirmed the enhanced delivery of nitrendipine from nanoemulsion gel than compare to drug solution by virtue of better permeation and solubility. Nanoemulsion gel was proved significantly superior by confocal laser scanning microscopy for satisfactory permeation and distribution of gel, deep into the rat skin. The optimized gel was found with no allergic dermal effects and was proved safe by histopathological studies for transdermal application.Conclusions: Results reveals that developed nitrendipine nanoemulsion gel overcomes the limitation of low penetration and accentuate permeation through albino Wistar rat skin. It was concluded that nanoemulsion gel could be utilized as a potential carrier for transdermal delivery of nitrendipine.


Assuntos
Emulsões/química , Géis/química , Nanopartículas/química , Nitrendipino/administração & dosagem , Nitrendipino/química , Administração Cutânea , Animais , Química Farmacêutica/métodos , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Masculino , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Wistar , Pele/metabolismo , Absorção Cutânea/efeitos dos fármacos , Solubilidade/efeitos dos fármacos , Tensoativos/química
7.
AAPS PharmSciTech ; 19(7): 3228-3236, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30187447

RESUMO

In this study, mesoporous SnO2 (MSn) with a three-dimensional mesoporous structure was prepared using MCM-48 as the template in order to increase the oral bioavailability and dissolution rate of insoluble drugs. The model drug, nitrendipine (NDP), was loaded into the MSn by the adsorption method. The structural features of MSn were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and N2 adsorption (desorption) analysis. NDP was existed in the pore channels of MSn in an amorphous state, which was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). MSn showed a good biocompatibility in the cell toxicity assay for Caco-2 cells. In vitro dissolution results suggested that MSn could significantly enhance the dissolution rate of NDP compared with commercial NDP tablets. Pharmacokinetic studies indicated that NDP-MSn tablets effectively enhanced the oral bioavailability of NDP. In conclusion, MSn was found to be a potential carrier for improving the solubility of insoluble drugs.


Assuntos
Nitrendipino/química , Compostos de Estanho/química , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Portadores de Fármacos , Humanos , Nitrendipino/farmacocinética , Porosidade , Coelhos , Solubilidade
8.
Mol Pain ; 14: 1744806918765806, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29580153

RESUMO

Background Following peripheral nerve chronic constriction injury, the accumulation of the α2δ-1 auxiliary subunit of voltage-gated Ca2+ channels in primary afferent terminals contributes to the onset of neuropathic pain. Overexpression of α2δ-1 in Xenopus oocytes increases the opening properties of Cav1.2 L-type channels and allows Ca2+ influx at physiological membrane potentials. We therefore posited that L-type channels play a role in neurotransmitter release in the superficial dorsal horn in the chronic constriction injury model of neuropathic pain. Results Whole-cell recording from lamina II neurons from rats, subject to sciatic chronic constriction injury, showed that the L-type Ca2+ channel blocker, nitrendipine (2 µM) reduced the frequency of spontaneous excitatory postsynaptic currents. Nitrendipine had little or no effect on spontaneous excitatory postsynaptic current frequency in neurons from sham-operated animals. To determine whether α2δ-1 is involved in upregulating function of Cav1.2 L-type channels, we tested the effect of the α2δ-1 ligand, gabapentin (100 µM) on currents recorded from HEK293F cells expressing Cav1.2/ß4/α2δ-1 channels and found a significant decrease in peak amplitude with no effect on control Cav1.2/ß4/α2δ-3 expressing cells. In PC-12 cells, gabapentin also significantly reduced the endogenous dihydropyridine-sensitive calcium current. In lamina II, gabapentin reduced spontaneous excitatory postsynaptic current frequency in neurons from animals subject to chronic constriction injury but not in those from sham-operated animals. Intraperitoneal injection of 5 mg/kg nitrendipine increased paw withdrawal threshold in animals subject to chronic constriction injury. Conclusion We suggest that L-type channels show an increased contribution to synaptic transmission in lamina II dorsal horn following peripheral nerve injury. The effect of gabapentin on Cav1.2 via α2δ-1 may contribute to its anti-allodynic action.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Subunidades Proteicas/metabolismo , Substância Gelatinosa/metabolismo , Transmissão Sináptica , Aminas/farmacologia , Animais , Bovinos , Constrição Patológica , Ácidos Cicloexanocarboxílicos/farmacologia , Di-Hidropiridinas/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Gabapentina , Células HEK293 , Humanos , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Masculino , Nitrendipino/farmacologia , Células PC12 , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Xenopus , Ácido gama-Aminobutírico/farmacologia
9.
AAPS PharmSciTech ; 18(7): 2737-2743, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28321695

RESUMO

The aim of the present study was to ascertain the solubility of nitrendipine (NP), an antihypertensive drug in six different pure solvents such as water, ethyl acetate (EA), ethanol, isopropyl alcohol (IPA), polyethylene glycol-400 (PEG-400), and Transcutol at temperature from 298.15 to 318.15 K under atmospheric pressure (p) of 0.1 MPa. Experimental solubility data of NP was fitted with Apelblat and ideal models. The mole fraction solubility of NP was found maximum in PEG-400 (6.85 × 10-2 at 318.15 K) followed by Transcutol (4.65 × 10-2 at 318.15 K), EA (1.68 × 10-2 at 318.15 K), ethanol (2.83 × 10-3 at 318.15 K), IPA (2.69 × 10-3 at 318.15 K), and water (1.29 × 10-7 at 318.15 K). The dissolution activity of NP was observed as an endothermic, spontaneous, and an entropy-driven in most of studied pure solvents. The solubility data of NP obtained in the present study could be useful in purification, recrystallization, and dosage forms design of NP.


Assuntos
Anti-Hipertensivos/química , Nitrendipino/química , Termodinâmica , Polietilenoglicóis/química , Solubilidade , Solventes/química , Temperatura
10.
J Hypertens ; 35(4): 886-892, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27977472

RESUMO

OBJECTIVES: The objective of this article is to compare blood pressure (BP)-lowing effects of nitrendipine and hydrochlorothiazide and nitrendipine and metoprolol, and estimate the economic effect of these therapies on hypertension. METHODS: Outpatients (N = 793) 18-70 years of age with stage 2 or severe hypertension (SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg) were recruited from four randomly selected rural community health centers in Beijing and Jilin. After drug wash out, they were randomly divided into nitrendipine and hydrochlorothiazide group or nitrendipine and metoprolol group. The costs of drug treatment for hypertension were calculated and general estimation, whereas effectiveness was measured as a reduction in SBP and DBP at the end of a 24-week study period. RESULTS: Overall, 623 patients were eligible for the study and after a 24-week follow-up, SBP and DBP were 131.2/82.2 mmHg for the nitrendipine and hydrochlorothiazide group and 131.4/82.9 mmHg for the nitrendipine and metoprolol group and these were not significantly different (P = 0.7974 SBP and P = 0.1166 DBP). Comparing with nitrendipine and metoprolol, the cost of nitrendipine and hydrochlorothiazide was less, and its effectiveness was similar. The cost/effect ratio (US$/mmHg) was 1.4 for SBP and 2.8 for DBP for the nitrendipine and hydrochlorothiazide group, and 1.9 and 3.8 for the nitrendipine and metoprolol group's SBP and DBP values, respectively. The incremental cost per patient for achieving target BP was 5.1. Adverse events were mild or moderate and there were no differences between treatment groups. CONCLUSION: Treating hypertension with nitrendipine and hydrochlorothiazide was cost-effective than nitrendipine and metoprolol, and these data will allow more reasonable and efficient allocation of limited resources in low-income countries.


Assuntos
Anti-Hipertensivos/uso terapêutico , Centros Comunitários de Saúde , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Metoprolol/uso terapêutico , Nitrendipino/uso terapêutico , Serviços de Saúde Rural , Adolescente , Adulto , Idoso , Anti-Hipertensivos/economia , Pequim , Pressão Sanguínea/efeitos dos fármacos , Análise Custo-Benefício , Quimioterapia Combinada/economia , Feminino , Custos de Cuidados de Saúde , Humanos , Hidroclorotiazida/economia , Hipertensão/fisiopatologia , Masculino , Metoprolol/economia , Metoprolol/farmacologia , Pessoa de Meia-Idade , Nitrendipino/economia , Estudos Prospectivos , Adulto Jovem
11.
Eur J Pharm Sci ; 85: 68-83, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-26827925

RESUMO

Three isostructural 1,4-dihydropyridines (DHPs), namely, nifedipine, nitrendipine and nimodipine were selected to characterize their structure, intermolecular interactions and molecular dynamics. The studied samples were analyzed using powder X-ray diffraction (XRD), neutron (INS) and infrared spectroscopy (FT-IR) as well as solid-state nuclear magnetic resonance (NMR), where each technique was supported by the state-of-the-art theoretical calculations for solid-state. By combining multiple experimental techniques with advanced theoretical calculations we were able to shed light on the mutual relation between the structure, stabilizing intermolecular interactions and their spectral response. For the first time, unambiguous computationally-supported assignment of the most prominent spectral features in DHPs is presented to give a valuable support for polymorph screening and drug control. Molecular motions were interpreted in details, revealing that a dynamic reservoir of each compound is dominated by intra-molecular reorientations of methyl groups and large-amplitude oscillations in terminal chains. Our study successfully validates the realm of applicability of first-principles solid-state calculations in search of the mutual relation between the structure and spectroscopy in this important class of drugs. Such approach gives a first necessary step to gather combined structure-dynamics data on functionalized DHPs, which are of importance to better understand crystallization and binding tendency. The NMR relaxation experiments reveal that nitro groups significantly hinder the reorientation of methyl rotors and provide the first evidence of low-temperature methyl-group tunneling in DHPs, an intriguing quantum-effect which is to be further explored.


Assuntos
Bloqueadores dos Canais de Cálcio/química , Cristalização/métodos , Di-Hidropiridinas/química , Espectroscopia de Ressonância Magnética/métodos , Simulação de Dinâmica Molecular , Nifedipino/química , Nimodipina/química , Nitrendipino/química , Teoria Quântica , Espectrofotometria Infravermelho/métodos , Difração de Raios X/métodos
12.
Environ Toxicol ; 31(11): 1293-1306, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25758670

RESUMO

Smoking increases the risk of cardiovascular disorders and leads to damage caused by inflammation and oxidative stress. The actin cytoskeleton is a key player in the response to inflammatory stimuli and is an early target of cellular oxidative stress. The purpose of this study was to investigate the changes in actin cytoskeleton dynamics in human endothelial EA.hy926 cells exposed to cigarette smoke extract (CSE). Immunostaining revealed that CSE exposure resulted in modification of the actin cytoskeleton and led to cell rounding in a dose- and time-dependent manner. In addition, the intracellular calcium concentration was increased by treatment with CSE. Pretreatment with antioxidants (lipoic acid, glutathione, N-acetyl cysteine, aminoguanidine, α-tocopherol, and vitamin C) significantly attenuated the CSE-induced actin cytoskeleton reorganization and cell rounding. Calcium ion chelators (EGTA, BAPTA-AM AM) and a potent store-operated calcium channel inhibitor (MRS 1845) also reduced CSE-induced intracellular calcium changes and attenuated actin cytoskeleton reorganization and cell morphology change. Moreover, the CSE-induced intracellular calcium increase was suppressed by pretreatment with the inositol trisphosphate receptor (IP3R) inhibitor xestospongin C, the phospholipase C (PLC) inhibitor U-73122, and the protein kinase C (PKC) inhibitor GF109203X. These results suggest that reactive oxygen species production and intracellular calcium increase play an essential role in CSE-induced actin disorganization and cell rounding through a PLC-IP3-PKC signaling pathway. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1293-1306, 2016.


Assuntos
Citoesqueleto de Actina/metabolismo , Sinalização do Cálcio , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Fumaça , Tabaco/química , Acetilcisteína/farmacologia , Citoesqueleto de Actina/efeitos dos fármacos , Antioxidantes/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Quelantes/farmacologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Estrenos/farmacologia , Glutationa/metabolismo , Humanos , Indóis/farmacologia , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Compostos Macrocíclicos/farmacologia , Maleimidas/farmacologia , Microscopia de Fluorescência , Nitrendipino/análogos & derivados , Nitrendipino/farmacologia , Oxazóis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Pirrolidinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tabaco/metabolismo , Fosfolipases Tipo C/antagonistas & inibidores , Fosfolipases Tipo C/metabolismo
13.
Artif Cells Nanomed Biotechnol ; 44(7): 1684-93, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26375758

RESUMO

CONTEXT: Vesicular transdermal delivery can enhance the bioavailability of a drug especially affected by first-pass metabolism, e.g. nitrendipine. However effective transdermal delivery employs permeation enhancer, e.g oleic acid (OA) with ceramide 2, stearic acid, behenic acid, and cholesteryl sulfate lipid complex. OBJECTIVE: This study investigated the preparation, characterization of physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential in rats, of nitrendipine-loaded nanovesicles of ceramide 2, stearic acid, behenic acid and cholesteryl sulfate containing oleic acid gel (NOVG). MATERIALS AND METHODS: The nanovesicles were made using film hydration method and characterized for physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential. RESULTS: Nitrendipine-loaded nanovesicles of ceramide-2 containing oleic acid (NOV-5) have shown fluxes in the range of 4.88-24.72 µg/cm(2)/h nitrendipine oral suspension (NOS) at equal dose. NOVG-5 has shown almost 33% reduction in blood pressure in the first hour and a further decrease of 25% in the second hour to restore the normal pressure. DISCUSSION: The permeation increases with increase in OA content. OA gets integrated in vesicle wall and enhances its permeability, whereas ceramide content makes sure that skin does not become damaged even after permeation. CONCLUSION: NOVG-5 has shown the most favorable physicochemical properties and good permeation through skin providing good management of hypertension during crucial initial hours.


Assuntos
Nanocápsulas/química , Nitrendipino , Absorção Cutânea/efeitos dos fármacos , Animais , Ceramidas/química , Ceramidas/farmacocinética , Ceramidas/farmacologia , Ésteres do Colesterol/química , Ésteres do Colesterol/farmacocinética , Ésteres do Colesterol/farmacologia , Ácidos Graxos/química , Ácidos Graxos/farmacocinética , Ácidos Graxos/farmacologia , Feminino , Humanos , Masculino , Nitrendipino/química , Nitrendipino/farmacocinética , Nitrendipino/farmacologia , Ácido Oleico/química , Ácido Oleico/farmacocinética , Ácido Oleico/farmacologia , Ratos , Ratos Wistar , Ácidos Esteáricos/química , Ácidos Esteáricos/farmacocinética , Ácidos Esteáricos/farmacologia
14.
Pharm Dev Technol ; 21(6): 749-54, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26166407

RESUMO

Starch macrocellular foam (SMF), a novel natural bio-matrix material, was prepared by the hard template method in order to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. Nitrendipine (NDP) was chosen as a model drug and was loaded into SMF by the solvent evaporation method. SMF and the loaded SMF samples (NDP-SMF) were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro drug release studies showed that SMF significantly increased the dissolution rate of NDP. In vivo studies showed that the NDP-SMF tablets clearly increased the oral bioavailability of NDP in comparison with the reference commercial tablets. All the results obtained demonstrated that SMF was a promising carrier for the oral delivery of poor water-soluble drugs.


Assuntos
Nitrendipino/farmacocinética , Amido/farmacocinética , Substâncias Viscoelásticas/farmacocinética , Água/metabolismo , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacocinética , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Nitrendipino/administração & dosagem , Nitrendipino/química , Coelhos , Distribuição Aleatória , Solubilidade , Amido/química , Substâncias Viscoelásticas/administração & dosagem , Substâncias Viscoelásticas/química , Água/química , Difração de Raios X
15.
Arch Orthop Trauma Surg ; 134(12): 1739-44, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25362529

RESUMO

INTRODUCTION: Matrix metalloproteinases (MMPs) are involved in physiological events such as restructuring of the tissue, morphogenesis, wound healing and normal developmental process. Use of diclofenac sodium following rotator cuff repair can disrupt healing of tendon through acting on MMPs. MATERIALS AND METHODS: Supraspinatus tendons of rats (n = 84) were detached from their insertion on humerus, and repaired to anatomic footprint. Rats were divided into study group (n = 42) and control group (n = 42). Study group received a dose of 1 mg/kg daily diclofenac sodium subcutaneously. The rats were killed at weeks 1, 3 and 6, and seven rats from each groups were included in biomechanical and immunohistological examinations. Immunohistological staining of MMP-2, MMP-3 and MMP13 were used. RESULTS: Maximum load was reduced in the study group at the end of week 1 (8.76 vs. 5.28 N) (p = 0.01). MMP-3 level was statistically significantly lower in the study group at the end of week 1. MMP-13 level and stiffness decreased towards week 6 in the study group while in the control group the level of MMP-2 decreased towards week 6. CONCLUSION: Diclofenac has an impact on the levels of MMP-2, MMP-3 and MMP-13, which are needed for normal healing process, and it can also lead to disruption of tendon healing.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diclofenaco/farmacologia , Metaloproteinases da Matriz/metabolismo , Manguito Rotador/enzimologia , Cicatrização/efeitos dos fármacos , Animais , Imuno-Histoquímica , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Nitrendipino , Ratos Wistar , Manguito Rotador/fisiopatologia , Manguito Rotador/cirurgia , Tendões/cirurgia , Cicatrização/fisiologia
16.
Cardiovasc Res ; 104(1): 183-93, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25100767

RESUMO

AIMS: Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca(2+) channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure. METHODS AND RESULTS: We compared the effects of cilnidipine, a dual N- and L-type Ca(2+) channel blocker, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A ß-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B(+/-) mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B(+/+) mice. CONCLUSIONS: Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure.


Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Sistema Nervoso Autônomo/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/efeitos dos fármacos , Morte Súbita Cardíaca/prevenção & controle , Di-Hidropiridinas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Coração/inervação , Antagonistas Adrenérgicos beta/farmacologia , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Sistema Nervoso Autônomo/metabolismo , Sistema Nervoso Autônomo/fisiopatologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo N/genética , Canais de Cálcio Tipo N/metabolismo , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Morte Súbita Cardíaca/etiologia , Modelos Animais de Doenças , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Camundongos Knockout , Camundongos Transgênicos , Nitrendipino/farmacologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos
17.
Drug Metab Dispos ; 42(9): 1540-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25005602

RESUMO

The accurate prediction for the body clearance of a novel drug candidate by humans during the preclinical stage contributes to its successful development. To improve the predictability of human hepatic clearance, we focused on CYP3A4, which is involved in the metabolism of more than 50% of all currently marketed drugs. In this study, we investigated the validity of the in vivo model using transgenic mice carrying the human CYP3A4 gene and lacking their own Cyp3a genes (CYP3A4-Tg mice). The CYP3A4 activity toward its substrates in liver microsomes was similar in CYP3A4-Tg mice and humans. As for the clearance, six CYP3A4 substrates (alprazolam, felodipine, midazolam, nifedipine, nitrendipine, and quinidine) were given intravenously to CYP3A4-Tg mice, and their hepatic intrinsic clearance (CLint,h) was evaluated. A regression analysis of the data obtained indicated that the CLint,h values of six substrates in CYP3A4-Tg mice were highly correlated with those in humans (R(2) = 0.95). This correlation could be improved by correcting the CLint,h values by the relative contribution of artificially expressed CYP3A4 to the overall metabolism in the mice. From these findings, it is reasonable to expect that the CLint,h of a particular drug in humans is predictable by applying the CLint,h obtained in CYP3A4-Tg mice to a regression line prepared in advance. The variance of the CLint,h prediction by this method was evaluated and found to be within a range of 2-fold of the regression value. These results suggest that the CYP3A4-Tg mouse model has the potential to accurately predict the human hepatic clearance of CYP3A4 substrates.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Microssomos Hepáticos/metabolismo , Alprazolam/metabolismo , Animais , Felodipino/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Midazolam/metabolismo , Nifedipino/metabolismo , Nitrendipino/metabolismo , Quinidina/metabolismo
18.
Pharmacol Rep ; 66(1): 74-80, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24905310

RESUMO

BACKGROUND: In this study, we investigated the in vitro effects of calcium channel blockers (nifedipine, nitrendipine, isradipine, and amlodipine besylate) on the activity of paraoxonase-1 (PON1). METHODS: PON1 was purified from human serum using simple chromatographic methods, including DEAE-Sephadex anion-exchange and Sephadex G-200 gel filtration chromatography. RESULTS: The calcium channel blockers decreased the in vitro PON1 activity. The inhibition mechanism of amlodipine besylate was noncompetitive, whereas nifedipine, nitrendipine, and isradipine were competitive inhibitors. CONCLUSIONS: Our results showed that calcium channel blockers exhibit inhibitory effects on PON1 at low concentrations. The IC(50) values for nifedipine, nitrendipine, isradipine, and amlodipine besylate were determined to be 0.121 mM, 0.130 mM, 0.255 mM, and 0.304 mM, respectively, and the K(i) constants were calculated to be 0.222 ± 0.049 mM, 0.151 ± 0.067 mM, 0.286 ± 0.137 mM, and 0.321 ± 0.002 mM, respectively.


Assuntos
Arildialquilfosfatase/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Anlodipino/farmacologia , Arildialquilfosfatase/antagonistas & inibidores , Humanos , Isradipino/farmacologia , Nifedipino/farmacologia , Nitrendipino
19.
Respirology ; 19(5): 763-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24850215

RESUMO

The cause of airway smooth muscle (ASM) hypercontractility in asthma is not fully understood. The relationship of spontaneous intracellular calcium oscillation frequency in ASM to asthma severity was investigated. Oscillations were increased in subjects with impaired lung function abolished by extracellular calcium removal, attenuated by caffeine and unaffected by verapamil or nitrendipine. Whether modulation of increased spontaneous intracellular calcium oscillations in ASM from patients with impaired lung function represents a therapeutic target warrants further investigation.


Assuntos
Asma/fisiopatologia , Sinalização do Cálcio/fisiologia , Músculo Liso/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Músculos Respiratórios/fisiopatologia , Índice de Gravidade de Doença , Adulto , Idoso , Biópsia , Cafeína/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Nitrendipino/farmacologia , Músculos Respiratórios/efeitos dos fármacos , Músculos Respiratórios/patologia , Verapamil/farmacologia , Capacidade Vital/fisiologia
20.
Eur J Drug Metab Pharmacokinet ; 39(4): 277-81, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24092617

RESUMO

Silibinin, a major constituent of silymarin, is widely used for its hepatoprotective effects. This study investigated the effect of silibinin on the pharmacokinetics of oral nitrendipine in rabbits. In first set of experiment, male New Zealand rabbits were pretreated with silibinin (50 mg/kg, PO) for 7 days and on last day nitrendipine (10 mg/kg, PO) was administered. In second set, both silibinin and nitrendipine were coadministered to examine acute effect of silibinin on nitrendipine pharmacokinetics. The plasma concentration of nitrendipine was estimated by high performance liquid chromatography and different pharmacokinetic parameters were calculated using WinNonlin(®) software. Coadministration of silibinin had no significant effect on pharmacokinetics of nitrendipine when compared to control group. However, a 1.89-1.57-fold increase in area under the concentration-time curve and peak plasma concentration (C max), respectively, of nitrendipine was observed in silibinin pretreated group. The mean C max was 0.034 ± 0.005 µg/mL (nitrendipine alone) and 0.054 ± 0.006 µg/mL (nitrendipine after pretreatment with silibinin). The time to reach C max, elimination rate constant and elimination half-life of nitrendipine were not significantly different among control and silibinin treated groups. This study demonstrates that silibinin increase plasma concentration of nitrendipine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing nitrendipine to the patients already taking silymarin.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacocinética , Nitrendipino/farmacocinética , Silimarina/farmacologia , Animais , Área Sob a Curva , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Masculino , Coelhos , Silibina
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