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1.
J Nanobiotechnology ; 20(1): 471, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36335352

RESUMO

Ovarian cancer is a highly fatal gynecologic malignancy worldwide. Chemotherapy remains the primary modality both for primary and maintenance treatments of ovarian cancer. However, the progress in developing chemotherapeutic agents for ovarian cancer has been slow in the past 20 years. Thus, new and effective chemotherapeutic drugs are urgently needed for ovarian cancer treatment. A reduction-responsive synergetic delivery strategy (PSSP@ART-ISMN) with co-delivery of artesunate and isosorbide 5-mononitrate was investigated in this research study. PSSP@ART-ISMN had various effects on tumor cells, such as (i) inducing the production of reactive oxygen species (ROS), which contributes to mitochondrial damage; (ii) providing nitric oxide and ROS for the tumor cells, which further react to generate highly toxic reactive nitrogen species (RNS) and cause DNA damage; and (iii) arresting cell cycle at the G0/G1 phase and inducing apoptosis. PSSP@ART-ISMN also demonstrated excellent antitumor activity with good biocompatibility in vivo. Taken together, the results of this work provide a potential delivery strategy for chemotherapy in ovarian cancer.


Assuntos
Nanopartículas , Neoplasias Ovarianas , Feminino , Humanos , Artesunato , Espécies Reativas de Oxigênio , Polímeros , Dinitrato de Isossorbida/metabolismo , Dinitrato de Isossorbida/farmacologia , Dinitrato de Isossorbida/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico
2.
Drug Deliv ; 26(1): 107-119, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30744434

RESUMO

The present study aimed to evaluate the penetration activity of O-acylterpineol derivatives both in vitro and in vivo, and to investigate the enhancing mechanism of O-acylterpineol derivatives which were synthesized by α-terpineol and fatty acid. The promoting activities on the isosorbide dinitrate patch were tested across full thickness rabbit skin both in vitro and in vivo. In order to elucidate the permeation mechanism, attenuated total reflection Fourier transform infrared spectroscopy, molecular modeling, and confocal laser scanning microscopy were introduced to investigate the regulation of enhancers in the skin permeability and biophysical properties. With in vitro cytotoxicity test and in vivo erythema model, the skin irritation of enhancers was also evaluated. Permeation studies showed 2-(4-methylcyclohex-3-en-l-yl) propan-2-yl tetradecanoate produced the obvious enhancement activity for ISDN both in vitro and in vivo from patches. These results were supported by ATR-FTIR, molecular modeling, and CLSM studies which revealed that O-acylterpineol could decrease the order of the alkyl chains in the skin lipids. Additionally, it was found that TER-C14 produced a relatively low skin irritation, compared with the TER which was assumed to be a safe compound. The present research suggested that some newly designed acylterpineol derivatives are shown to be suitable permeation enhancers for transdermal drug delivery, and the chain length of C14 seem to be safe and more favorable for the penetration of ISDN from DIA patches.


Assuntos
Dinitrato de Isossorbida/análogos & derivados , Modelos Moleculares , Absorção Cutânea/fisiologia , Terpenos/metabolismo , Animais , Células Cultivadas , Sinergismo Farmacológico , Humanos , Dinitrato de Isossorbida/administração & dosagem , Dinitrato de Isossorbida/química , Dinitrato de Isossorbida/metabolismo , Masculino , Microscopia Confocal/métodos , Técnicas de Cultura de Órgãos , Permeabilidade/efeitos dos fármacos , Coelhos , Absorção Cutânea/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Terpenos/administração & dosagem , Terpenos/química
3.
Drug Dev Ind Pharm ; 42(8): 1365-74, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26716771

RESUMO

Isosorbide dinitrate-polyvinylpyrrolidone (ISDN-PVP) electrospinning fibers were formulated and explored as potentially sublingual membrane. The addition of polyethylene glycol (PEG) to the formulation improved flexibility and reduced fluffiness of the fiber mat. The scanning electron microscopy (SEM) demonstrated that the fibers tended to be cross-linking, and the crosslinking degree increased with the increase of PEG amount. The differential scanning calorimetry (DSC) indicated that ISDN existed in non-crystalline state in the fibers (except at the highest drug content). The infrared spectroscopy suggested that ISDN had better compatibility with the ingredients owing to the hydrogen bonding (or hydrophobic interactions). The fibers were highly favorable for the fabrication of sublingual membrane due to neutral pH, large folding endurance and rapid drug release (complete dissolution within 120 s). The permeation study of ISDN through both dialysis membrane (DM) and porcine sublingual mucosa (SM) were carried out. A significant relationship of drug permeation rate through DM and SM was built up, which indicated that DM could be used to partly simulate SM and assess formulation. The pharmacokinetic study in rats demonstrated that the electrospinning fiber membrane had a higher Cmax and lower Tmax compared to the reference preparation, and the relative bioavailability of the fiber membrane was 151.6%.


Assuntos
Dinitrato de Isossorbida/química , Dinitrato de Isossorbida/metabolismo , Soalho Bucal/metabolismo , Povidona/química , Povidona/metabolismo , Tecnologia Farmacêutica/métodos , Administração Sublingual , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Liberação Controlada de Fármacos/fisiologia , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Masculino , Permeabilidade , Polietilenoglicóis/química , Ratos , Ratos Wistar , Suínos
4.
Biol Pharm Bull ; 35(2): 192-202, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22293349

RESUMO

The purpose of this study was to clarify the influence of skin thickness on the in vitro permeabilities of 3 model drugs with different physicochemical properties (nicorandil (NR), isosorbide dinitrate (ISDN) and flurbiprofen (FP)) through Sprague-Dawley rat (rat) or Yucatan micropig (YMP) skin. Intact, dermis-split, stratum corneum-stripped or stratum corneum-stripped and dermis-split rat or YMP skin (rat skin thickness: approximately 0.4, 0.9 or 1.2 mm; YMP skin thickness: approximately 0.4, 0.9, 1.8 or 2.8 mm) were set in Franz-type diffusion cells to determine the permeation rate, lag time and resistance ratio of the viable epidermis and dermis against whole skin (R(ved)/R(tot)) of the drugs. The YMP skin permeabilities of the drugs decreased with an increase in the skin thickness, and significant differences were observed in the permeation rates and lag times between intact and dermis-split (0.4 mm) YMP skins. The decreases in the permeabilities of the drugs through the YMP skin were larger than those through the rat skin. The influence of resistances of ISDN and FP through the dermis-split rat or YMP skin was greater at 0.9 mm skin thickness than 0.4 mm skin thickness. The R(ved)/R(tot) values for the YMP skins were relatively large for lipophilic drugs (ISDN and FP), and these ratios increased with an increase in the dermis thickness. These results suggest that in vitro skin permeation studies must be done using dermis-split (0.4 mm) skin with the thinnest dermis for predicting in vivo human percutaneous absorption rate.


Assuntos
Permeabilidade , Pele/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Feminino , Flurbiprofeno/metabolismo , Técnicas In Vitro , Dinitrato de Isossorbida/metabolismo , Masculino , Nicorandil/metabolismo , Ratos , Ratos Sprague-Dawley , Pele/anatomia & histologia , Absorção Cutânea , Suínos , Espectrometria de Massas em Tandem
5.
Int J Pharm ; 397(1-2): 59-66, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20599486

RESUMO

The objective of this work was to study the influence of different absorption enhancers on the intranasal absorption of isosorbide dinitrate (ISDN). First of all, an in situ nasal perfusion technique in rats was used to investigate the effect of pH, concentration of drug solution and different absorption enhancers on the intranasal absorption of ISDN. The absorption enhancers investigated include hydroxypropyl-beta-cyclodextrin (HP-beta-CD), chitosans (CS) of different molecular weight, and poloxamer 188. All of them enhanced the intranasal absorption of ISDN remarkably. It was found that poloxamer 188 had better permeation enhancing effect than that of HP-beta-CD and CS of the same concentration. Thereafter, in vivo behaviors of the selected formulations were studied in rats and the pharmacokinetic parameters were calculated and compared with that of intravenous injection. Both in situ and in vivo studies demonstrated that poloxamer 188 played a key role in promoting intranasal absorption of ISDN. In nasal ciliotoxicity test, all the absorption enhancers investigated showed good safety profiles. Taking both enhancing effect and safety into account, we suggest poloxamer 188 is the most promising as an intranasal absorption enhancer.


Assuntos
Quitosana , Dinitrato de Isossorbida/farmacocinética , Mucosa Nasal/metabolismo , Poloxâmero , Vasodilatadores/farmacocinética , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Absorção , Administração Intranasal , Animais , Química Farmacêutica , Quitosana/análogos & derivados , Concentração de Íons de Hidrogênio , Dinitrato de Isossorbida/administração & dosagem , Dinitrato de Isossorbida/sangue , Dinitrato de Isossorbida/metabolismo , Masculino , Ratos , Ratos Wistar , Vasodilatadores/administração & dosagem , Vasodilatadores/sangue , Vasodilatadores/metabolismo
6.
Dev World Bioeth ; 8(2): 82-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19143085

RESUMO

This paper discusses the link between pharmacogenetics and race, and the global justice issues that the introduction of pharmacogenetics in pharmaceutical research and clinical practice will raise. First, it briefly outlines the likely impact of pharmacogenetics on pharmaceutical research and clinical practice within the next five to ten years and then explores the link between pharmacogenetic traits and 'race'. It is shown that any link between apparent race and pharmacogenetics is problematic and that race cannot be used as a proxy for pharmacogenetic knowledge. The final section considers the implications of the development of pharmacogenetics for health care systems in low- and middle-income countries.


Assuntos
Atenção à Saúde/normas , Países em Desenvolvimento , Internacionalidade , Farmacogenética , Grupos Raciais , Justiça Social , Negro ou Afro-Americano/genética , Combinação de Medicamentos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Humanos , Hidralazina/metabolismo , Hidralazina/farmacocinética , Hidralazina/uso terapêutico , Dinitrato de Isossorbida/metabolismo , Dinitrato de Isossorbida/farmacocinética , Dinitrato de Isossorbida/uso terapêutico , Estados Unidos , United States Food and Drug Administration
7.
Int J Pharm ; 352(1-2): 92-103, 2008 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-18053661

RESUMO

To develop more effective compounds as enhancers, O-acylmenthol derivatives which were expected to be enzymatically hydrolyzed into nontoxic metabolites by esterases in the living epidermis were synthesized from l-menthol and pharmaceutical excipient acids (lactic acid, cinnamic acid, salicylic acid and oleic acid) in this study. Their promoting activity on the percutaneous absorption of five model drugs, 5-fluorouracil (5-FU), isosorbide dinitrate (ISDN), lidocaine (LD), ketoprofen (KP), and indomethacin (IM), which were selected based on their lipophilicity represented by log K(O/W), were tested in vitro across full thickness rat skin with each of the evaluated drugs in saturated donor solution. 2-Isopropyl-5-methylcyclohexyl 2-hydroxypanoate (M-LA) provided the highest increase of accumulation of 5-FU (3.74-fold) and LD (4.19-fold) in the receptor phase while 2-isopropyl-5-methylcyclohexyl cinnamate (M-CA) was ineffective for most of the drugs; Both 2-isopropyl-5-methylcyclohexyl 2-hydroxybenzoate (M-SA) and (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate (M-OA) had better promoting effects on the drugs with low water-solubility. The four O-acylmenthol enhancers produced parabolic relationship between the lipophilicity (log K(O/W)) of the model drugs (5-FU, ISDN, KP, IM) and their enhancement ratio of the permeation coefficient (ER(P)), indicating that the lipophilicity of the penetrants has significant effect on the permeation results, r = 0.989 (P=0.144) for M-LA, r = 0.965 (P = 0.216) for M-CA, r = 0.786 (P = 0.630) for M-SA, and r = 0.996 (P = 0.088) for M-OA.


Assuntos
Ácidos Carbocíclicos/farmacologia , Mentol/farmacologia , Ácidos Oleicos/farmacologia , Preparações Farmacêuticas/metabolismo , Absorção Cutânea/efeitos dos fármacos , Pele/efeitos dos fármacos , Ácidos Carbocíclicos/química , Administração Cutânea , Animais , Química Farmacêutica , Cinamatos/farmacologia , Cultura em Câmaras de Difusão , Composição de Medicamentos , Fluoruracila/metabolismo , Hidrólise , Indometacina/metabolismo , Dinitrato de Isossorbida/metabolismo , Cetoprofeno/metabolismo , Cinética , Lactatos/farmacologia , Lidocaína/metabolismo , Masculino , Mentol/análogos & derivados , Mentol/química , Ácidos Oleicos/química , Permeabilidade , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Ratos , Ratos Wistar , Salicilatos/farmacologia , Pele/metabolismo , Tecnologia Farmacêutica/métodos
8.
Clin Cancer Res ; 13(7): 2199-206, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17404104

RESUMO

PURPOSE: Hypoxia contributes to drug resistance in solid cancers, and studies have revealed that low concentrations of nitric oxide (NO) mimetics attenuate hypoxia-induced drug resistance in tumor cells in vitro. Classic NO signaling involves activation of soluble guanylyl cyclase, generation of cyclic GMP (cGMP), and activation of cGMP-dependent protein kinase. Here, we determined whether chemosensitization by NO mimetics requires cGMP-dependent signaling and whether low concentrations of NO mimetics can chemosensitize tumors in vivo. EXPERIMENTAL DESIGN: Survival of human prostate and breast cancer cells was assessed by clonogenic assays following exposure to chemotherapeutic agents. The effect of NO mimetics on tumor chemosensitivity in vivo was determined using a mouse xenograft model of human prostate cancer. Drug efflux in vitro was assessed by measuring intracellular doxorubicin-associated fluorescence. RESULTS: Low concentrations of the NO mimetics glyceryl trinitrate (GTN) and isosorbide dinitrate attenuated hypoxia-induced resistance to doxorubicin and paclitaxel. Similar to hypoxia-induced drug resistance, inhibition of various components of the NO signaling pathway increased resistance to doxorubicin, whereas activation of the pathway with 8-bromo-cGMP attenuated hypoxia-induced resistance. Drug efflux was unaffected by hypoxia and inhibitors of drug efflux did not significantly attenuate hypoxia-induced chemoresistance. Compared with mice treated with doxorubicin alone, tumor growth was decreased in mice treated with doxorubicin and a transdermal GTN patch. The presence of GTN and GTN metabolites in plasma samples was confirmed by gas chromatography. CONCLUSION: Tumor hypoxia induces resistance to anticancer drugs by interfering with endogenous NO signaling and reactivation of NO signaling represents a novel approach to enhance chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Experimentais/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/fisiologia , Animais , Neoplasias da Mama/metabolismo , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , GMP Cíclico/metabolismo , Feminino , Humanos , Dinitrato de Isossorbida/metabolismo , Dinitrato de Isossorbida/farmacologia , Masculino , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Doadores de Óxido Nítrico/sangue , Doadores de Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Nitroglicerina/sangue , Nitroglicerina/metabolismo , Nitroglicerina/farmacologia , Neoplasias da Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Drug Metab Pharmacokinet ; 22(1): 15-9, 2007 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-17329906

RESUMO

Nitric oxide (NO) biotransformation from NO-aspirin (NCX-4016) is not clearly understood. We have previously reported that cytochrome P450 (P450) plays important role in NO generation from other organic nitrates such as nitroglycerin (NTG) and isosorbide dinitrate (ISDN). The present study was designed to elucidate the role of human cytochrome P450 isoforms in NO formation from NCX-4016, using lymphoblast microsomes transfected with cDNA of human P450 or yeast-expressed, purified P450 isoforms. CYP1A2 and CYP2J2, among other isoforms, were strongly related to NO production from NCX-4016. In fact, these isoforms were detected in human coronary endothelial cells. These results suggest that NADPH-cytochrome P450 reductase and the P450 system participate in NO formation from NCX-4016, as well as other organic nitrates.


Assuntos
Aspirina/análogos & derivados , Sistema Enzimático do Citocromo P-450/metabolismo , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Animais , Aspirina/metabolismo , Vasos Coronários/enzimologia , Vasos Coronários/metabolismo , DNA Complementar/biossíntese , DNA Complementar/genética , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Isoenzimas/metabolismo , Dinitrato de Isossorbida/metabolismo , Masculino , Microssomos/enzimologia , Microssomos/metabolismo , Miocárdio/enzimologia , Miocárdio/metabolismo , Ratos , Saccharomyces cerevisiae/enzimologia
10.
Diabetologia ; 48(12): 2563-6, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16283243

RESUMO

AIMS/HYPOTHESIS: The beta cell metabolism of glucose, and some other fuels, initiates insulin secretion by closure of ATP-sensitive K+ channels and amplifies the secretory response via unknown metabolic intermediates. The aim of this study was to further characterise the mechanism responsible for the metabolic amplification of insulin secretion. MATERIALS AND METHODS: Pancreatic islets were isolated from albino mice by collagenase digestion. Insulin secretion in perifused islets was determined by ELISA. Bioluminometry was used to determine the ATP and ADP content of the incubated islets. RESULTS: After perifusing islets for 60 min with 2.7 micromol/l glipizide (closing all ATP-sensitive K+ channels) in the absence of any fuel, perifusion with a test medium containing 2.7 micromol/l glipizide plus 30 mmol/l glucose did not enhance insulin secretion. However, test media supplemented with 2.7 micromol/l glipizide plus either 10 mmol/l alpha-ketoisocaproate or 10 mmol/l 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid amplified the glipizide-induced insulin secretion. In pancreatic islets preincubated for 60 min with 2.7 micromol/l glipizide in the absence of any fuel, 40 min incubations in the presence of 2.7 micromol/l glipizide plus 30 mmol/l glucose or plus 10 mmol/l alpha-ketoisocaproate produced an increase in the ATP content, no change in the ADP content and a rather small increase in the ATP:ADP ratio. The corresponding effects of glucose and alpha-ketoisocaproate were similar. CONCLUSIONS/INTERPRETATION: These results suggest that metabolic amplification of fuel-induced insulin secretion is not mediated by changes in the beta cell content of ATP and ADP, but might be due to export of citrate cycle intermediates to the beta cell cytosol.


Assuntos
Glipizida/farmacologia , Glucose/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Difosfato de Adenosina/análise , Trifosfato de Adenosina/análise , Aminoácidos Cíclicos/farmacologia , Animais , Citratos/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/química , Dinitrato de Isossorbida/metabolismo , Cetoácidos/farmacologia , Masculino , Camundongos , Camundongos Mutantes , Mitocôndrias/metabolismo , Succinatos/farmacologia
11.
Int J Immunopathol Pharmacol ; 17(3): 317-30, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15461866

RESUMO

Brain inflammation is an underlying factor in the pathogenesis of Alzheimers disease (AD). We investigated, in vivo, whether differences exist in the anti-inflammatory and neuroprotective actions of flurbiprofen and its two nitric oxide-donor derivatives, HCT-1026 and NCX-2216, and the ability of these two derivatives to release nitric oxide in the brain. In adult rats injected into the nucleus basalis with preaggregated Abeta(1-42) we investigated glia reaction, the induction of inducible nitric oxide synthase (iNOS), the activation of p38 mitogen-activated protein kinase (p38MAPK) pathway and the number of choline acetyltransferase (ChAT)-positive neurons and, in naive rats we investigated, by microdialysis, cortical extracellular levels of nitrite. Injection of Abeta(1-42) induced iNOS and activation of p38MAPK 7 days after injection and an intense microglia and astrocyte reaction along with a marked reduction in the number ChAT-positive neurons, persisting up to at least 21 days. Flurbiprofen, HCT-1026 and NCX-2216 (15 mg/kg) significantly attenuated the Abeta(1-42)-induced glia reaction, iNOS induction and p38MAPK activation 7 days after treatment and astrocytes reaction 21 days after treatment. On an equimolar basis, HCT-1026 resulted the most active agent in reducing the Abeta(1-42)-induced microglia reaction. The cholinergic cell loss was also significantly reduced by 21 days of HCT-1026 treatment. No differences in body weight were found between the animals treated for 21 days with 15 mg/kg of either HCT-1026 or NCX-2216 and the controls. Oral administration of HCT-1026 (15 mg/kg) or NCX-2216 (100 mg/kg) to naive rats was followed by significant and long lasting increases in cortical nitrite levels. These findings indicate that the addition of a nitric oxide donor potentiates the anti-inflammatory activity of flurbiprofen in a model of brain inflammation.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Anti-Inflamatórios não Esteroides/farmacologia , Encefalite/patologia , Flurbiprofeno/análogos & derivados , Flurbiprofeno/farmacologia , Dinitrato de Isossorbida/análogos & derivados , Neurônios/patologia , Fragmentos de Peptídeos/toxicidade , Animais , Anticorpos Monoclonais/farmacologia , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Peso Corporal/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Dinitrato de Isossorbida/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Biochem Biophys Res Commun ; 324(1): 417-23, 2004 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-15465035

RESUMO

Adaptation to hypoxia and maintenance of O(2) homeostasis involve a wide range of responses that occur at different organizational levels in the body. One of the most important transcription factors that activate the expression of O(2)-regulated genes is hypoxia-inducible factor 1 (HIF-1). Nitric oxide (NO) mediates a variety of biological effects including relaxation of blood vessels and cytotoxicity of activated macrophages. We investigated the effect of the clinically used nitrates nitroglycerin (NTG), isosorbide dinitrate (ISDN), and sodium nitroprusside (SNP) on HIF-1-mediated transcriptional responses to hypoxia. We demonstrate that among the three nitrates, only SNP inhibits HIF-1 activation in response to hypoxia. In contrast, NTG or ISDN does not affect HIF-1 activity. SNP inhibits the accumulation of HIF-1alpha, the regulatory subunit of HIF-1, and the transcriptional activation of HIF-1alpha via a mechanism that is not dependent on either NO or soluble guanylate cyclase.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/metabolismo , Proteínas de Ligação a DNA/genética , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/metabolismo , Guanilato Ciclase , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Imidazóis/química , Imidazóis/metabolismo , Dinitrato de Isossorbida/metabolismo , Doadores de Óxido Nítrico/metabolismo , Nitroglicerina/metabolismo , Nitroprussiato/metabolismo , Proteínas Nucleares/genética , Oxigênio/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Guanilil Ciclase Solúvel , Fatores de Transcrição/genética , Transcrição Gênica , Vasodilatadores/metabolismo
15.
Exp Biol Med (Maywood) ; 228(5): 529-34, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12709581

RESUMO

Pentaerithrityl tetranitrate (PETN) is a long-acting donor of nitric oxide (NO) and has recently been characterized as an antianginal agent that, in contrast with other nitric acid esters, does not induce oxidative stress and is therefore free of tolerance. Moreover, animal experiments have revealed that PETN actively reduces oxygen radical formation in vivoand specifically prevents atherogenesis and endothelial dysfunction. Because heme oxygenase-1 (HO-1) has been described as an antiatherogenic and cytoprotective gene in the endothelium, our aim was to investigate the effect of the active PETN metabolite pentaerithrityl trinitrate (PETriN) on HO-1 expression and catalytic activity in endothelial cells. Endothelial cells derived from human umbilical vein were incubated with PETriN (0.01-1 mM) for 8 hr. PETriN increased HO-1 mRNA and protein levels in a concentration-dependent fashion up to 3-fold over basal levels. Elevation of HO-1 protein was accompanied by a marked increase in catalytic activity of the enzyme as reflected by enhanced formation of both carbon monoxide and the endogenous antioxidant, bilirubin. Pretreatment of endothelial cells with PETriN or bilirubin at low micromolar concentrations protected endothelial cells from hydrogen peroxide-mediated toxicity. HO-1 induction and endothelial protection by PETriN were not mimicked by isosorbide dinitrate, another long-acting nitrate. The present study demonstrates that the active PETN metabolite, PETriN, stimulates mRNA and protein expression as well as enzymatic activity of the antioxidant defense protein, HO-1, in endothelial cells. Increased HO-1 expression and ensuing formation of bilirubin and carbon monoxide may contribute to and explain the specific antioxidant and antiatherogenic actions of PETN.


Assuntos
Bilirrubina/metabolismo , Monóxido de Carbono/metabolismo , Endotélio Vascular/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Tetranitrato de Pentaeritritol/análogos & derivados , Tetranitrato de Pentaeritritol/farmacologia , Animais , Antioxidantes/metabolismo , Sobrevivência Celular/fisiologia , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase-1 , Humanos , Dinitrato de Isossorbida/metabolismo , Proteínas de Membrana , Doadores de Óxido Nítrico/metabolismo , S-Nitroso-N-Acetilpenicilamina/metabolismo
16.
J Pharmacol Exp Ther ; 293(2): 569-77, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10773030

RESUMO

The flavoprotein inhibitor, diphenyleneiodonium (DPI), inhibits the action of glyceryl trinitrate (GTN) and the D-enantiomer of isoidide dinitrate (IIDN), but not the L-enantiomer (L-IIDN), in isolated rat aorta via inhibition of the bioactivation of these prodrugs. Paradoxically, a vascular NAD(P)H oxidase, which also is inhibited by DPI, has been proposed to generate superoxide that quenches nitric oxide (NO) produced during GTN biotransformation, and increased oxidase levels are proposed to contribute to the phenomenon of organic nitrate tolerance. We examined the effect of DPI on isolated rat aorta using an in vivo model of organic nitrate tolerance. The EC(50) values for GTN-, D-IIDN-, and L-IIDN-induced relaxation of aorta from GTN-tolerant rats were increased 4.5- to 7.5-fold. Treatment of blood vessels with DPI (0.3 microM) increased the EC(50) values for GTN and D-IIDN by the same magnitude in control and tolerant aortae, a result that would not be predicted if DPI and GTN tolerance affected common targets. The expression of NADPH-cytochrome P450 reductase (CPR) during in vivo tolerance was assessed by NADPH-dependent cytochrome c reductase activity of aortic microsomes, immunoblotting, and Northern analysis. By all three determinants, CPR expression was unchanged in aorta from GTN-tolerant rats. Superoxide dismutase-inhibitable NADPH-dependent cytochrome c reductase activity (a measure of superoxide generation) of tolerant rat aortic microsomes was not different from that of controls. Superoxide dismutase-inhibitable NADH-dependent cytochrome c reductase activity was detected only in microsomes from tolerant animals. DPI caused a modest increase in the sensitivity for relaxation by the NO donor DEA NONOate to an equal extent in tolerant and nontolerant tissues, whereas the superoxide scavenger, 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), had no effect on the sensitivity for relaxation by GTN. These results would not be expected if tolerance-induced increases in superoxide were a causative factor for the reduced relaxation response in tolerance. We conclude that neither reduced flavoprotein-dependent metabolic activation of organic nitrates, such as that mediated by CPR, nor increased superoxide due to increased NAD(P)H oxidase activity can account for the development of in vivo tolerance to GTN.


Assuntos
Inibidores Enzimáticos/farmacologia , Flavoproteínas/antagonistas & inibidores , Nitratos/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Oniocompostos/farmacologia , Vasodilatadores/antagonistas & inibidores , Animais , Aorta Torácica/efeitos dos fármacos , Biotransformação , Northern Blotting , Tolerância a Medicamentos , Glutationa/análogos & derivados , Glutationa/farmacologia , Dinitrato de Isossorbida/antagonistas & inibidores , Dinitrato de Isossorbida/metabolismo , Dinitrato de Isossorbida/farmacologia , Masculino , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Nitratos/metabolismo , Nitratos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitroglicerina/antagonistas & inibidores , Nitroglicerina/metabolismo , Nitroglicerina/farmacologia , Compostos Nitrosos/farmacologia , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Ratos , Ratos Sprague-Dawley , S-Nitrosoglutationa , Estereoisomerismo , Superóxidos/metabolismo , Vasodilatadores/metabolismo , Vasodilatadores/farmacologia
17.
Pol Merkur Lekarski ; 7(38): 64-6, 1999 Aug.
Artigo em Polonês | MEDLINE | ID: mdl-10522420

RESUMO

UNLABELLED: The aim of this study was to investigate the bioavailability of isosorbide mononitrate (IS-5MN) after oral administration of Monocard 20 mg-capsules, made in "Synteza" â Pharmaceutical-Chemical Company in Poznan. Effox 20 mg, coated tablets from Schwarz Pharma, was used as an counterpart of Monocard 20 mg. The concentrations of IS-5MN in healthy volunteers' plasma were determined by using Hewlett Packard gas chromatography. CONCLUSIONS: The bioavailability of IS-5MN after oral administration of Monocard 20 mg is the same as after oral administration of Effox 20 mg, whose clinical efficacy was tested before. This conclusion confirms the same value of AUC, tmax, cmax and other pharmacokinetic parameters of Monocard 20 mg and Effox 20 mg.


Assuntos
Dinitrato de Isossorbida/análogos & derivados , Propranolol/farmacologia , Vasodilatadores/farmacocinética , Adulto , Disponibilidade Biológica , Feminino , Humanos , Dinitrato de Isossorbida/metabolismo , Dinitrato de Isossorbida/farmacocinética , Masculino
18.
Am J Physiol ; 274(5): G857-62, 1998 05.
Artigo em Inglês | MEDLINE | ID: mdl-9612266

RESUMO

Recently, in vivo electron paramagnetic resonance (EPR) spectroscopy and imaging have been widely used to investigate free radical distribution and metabolism in tissues, organs, and whole body of small animals. Endogenous nitric oxide (NO) is an attractive target of this method. In the present study, NO production from a nitrovasodilator, isosorbide dinitrate (ISDN), in live mice was investigated by in vivo EPR spectroscopy and imaging combined with the spin-trapping technique. A highly water-soluble Fe complex with N-(dithiocarboxy)sarcosine (DTCS) was used as an NO-trapping agent. Mice received [14N]-ISDN, and the Fe-DTCS complex subcutaneously exhibited the characteristic triplet EPR signal of the NO adduct [14NO-Fe(DTCS)2]2-. Using [15N]ISDN instead of [14N]ISDN, we were able to observe that the doublet EPR signal stemmed from the 15NO adduct, which directly demonstrated that NO was produced from ISDN. The three-dimensional EPR images of the upper abdomen of living mice showed that the NO adducts were distributed in the liver and the kidneys. This EPR image combined with the ex vivo EPR measurements of the blood suggested that NO production from ISDN occurred in the liver in this experimental condition.


Assuntos
Espectroscopia de Ressonância de Spin Eletrônica , Dinitrato de Isossorbida/metabolismo , Óxido Nítrico/biossíntese , Animais , Feminino , Camundongos , Camundongos Endogâmicos ICR , Detecção de Spin , Distribuição Tecidual
19.
Infect Immun ; 65(10): 4030-7, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9317003

RESUMO

Increased interest has recently been focused on nitric oxide (NO) due to its several biological roles. Apart from being a potential antimicrobial defense and a mediator of autoimmune diseases, NO also appears to be a strong mediator of T-cell responses. In this report, we have characterized the effect of NO on T-cell function. For this purpose, we analyzed in vivo T-cell responses to the bacterial superantigen produced by Staphylococcus aureus, staphylococcal enterotoxin B (SEB), in mice treated with an NO donor (isosorbide dinitrate [ISO]). We show that ISO partially prevents SEB-triggered activation-induced cell death of spleen and lymph node CD4Vbeta8+ T cells but not of CD8Vbeta8+ T cells. SEB-promoted thymic deletion is not abolished by ISO; however, a rapid recovery of thymocyte numbers due to increased double-positive (DP) CD4+ CD8+ thymocyte proliferation was clearly observed in ISO-treated, SEB-injected mice but not in controls (untreated SEB-injected mice). It was also found that ISO inhibits the early SEB-induced cell proliferation (i.e., that found 12 h after SEB injection), accelerating the clonal anergy usually observed 3 days after SEB injection. Inhibition of T-cell proliferation by the NO donor does not appear to be due to inhibition of cytokine production. These results show that NO interferes with apoptosis and facilitates thymic proliferation of DP thymocytes, although it inhibits peripheral T-cell proliferation.


Assuntos
Enterotoxinas/imunologia , Ativação Linfocitária/imunologia , Óxido Nítrico/farmacologia , Superantígenos/imunologia , Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Deleção Clonal , Interferon gama/biossíntese , Interleucina-4/biossíntese , Dinitrato de Isossorbida/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Antígenos de Linfócitos T alfa-beta , Baço/citologia , Baço/imunologia , Staphylococcus aureus/imunologia , Linfócitos T/efeitos dos fármacos
20.
Br J Pharmacol ; 116(2): 1829-34, 1995 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8528567

RESUMO

1. The effect of the nitric oxide (NO)-producing nitrovasodilators isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) were assessed on (a) the in vivo model of angiogenesis of the chick chorioallantoic membrane (CAM) and (b) on the growth and metastatic properties of the Lewis Lung carcinoma (LLC) in mice. 2. Isosorbide 5-mononitrate (ISMN) and isosorbide dinitrate (ISDN), inhibited angiogenesis in the CAM dose-dependently. ISMN was more potent in inhibiting this process. Both compounds were capable of completely reversing the angiogenic effect of alpha-thrombin. These effects of ISMN and ISDN on angiogenesis were comparable to those previously observed with sodium nitroprusside which generates NO non-enzymatically. 3. Mice, implanted intramuscularly with LLC, received daily i.p. injections of ISMN for 14 days resulting in a significant decrease in the size of the primary tumour and a reduction in the number and size of metastatic foci in the lungs. ISDN had a similar but less pronounced effect than that observed with ISMN. 4. Addition of ISMN or ISDN to cultures of bovine, rabbit and human endothelial cells and to cultures of LLC cells had no effect on their growth characteristics. 5. These results indicate that ISMN and ISDN inhibit angiogenesis and tumor growth and metastasis in an animal tumour model. The possibility should therefore be considered that these nitrovasodilators which are widely used therapeutically and have well characterized pharmacological profiles, may also possess antitumour properties in the clinic.


Assuntos
Carcinoma/tratamento farmacológico , Dinitrato de Isossorbida/análogos & derivados , Neovascularização Patológica/tratamento farmacológico , Vasodilatadores/metabolismo , Vasodilatadores/farmacologia , Animais , Bovinos , Células Cultivadas/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Dinitrato de Isossorbida/metabolismo , Dinitrato de Isossorbida/farmacologia , Masculino , Camundongos , Metástase Neoplásica , Óxido Nítrico/metabolismo , Coelhos
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