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1.
Cardiovasc Drugs Ther ; 36(6): 1047-1059, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34309798

RESUMO

PURPOSE: This research was designed to investigate the effects and mechanisms of flavocoxid (FCX) on vascular calcification (VC) in rats. METHODS: Vitamin D3 and nicotine were administered to Wistar rats, which then received FCX (VC-FCX group) or its vehicle (VC group) for 4 weeks. Control and FCX groups served as controls. Systolic (SBP) and diastolic (DBP) blood pressures, heart rate (HR), and left ventricular weight (LVW)/BW were measured. Serum concentrations of calcium, phosphate, creatinine, uric acid, and alkaline phosphatase were determined. Moreover, aortic calcium content and aortic expression of runt-related transcription factor (Runx2), osteopontin (OPN), Il-1ß, α-smooth muscle actin (α-SMA), matrix metalloproteinase-9 (MMP-9), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α) were assessed. Oxidative status in aortic homogenates was investigated. RESULTS: Compared to untreated VC rats, FCX treatment prevented body weight loss, reduced aortic calcium deposition, restored normal values of SBP, DBP, and HR, and attenuated LV hypertrophy. FCX also improved renal function and ameliorated serum levels of phosphorus, calcium, and ALP in rats with VC. FCX abolished aortic lipid peroxidation in VC rats. Moreover, VC-FCX rats showed marked reductions in aortic levels of Il-1ß and osteogenic marker (Runx2) and attenuated aortic expression of TNF-α, iNOS, and MMP-9 proteins compared to untreated VC rats. The expression of the smooth muscle lineage marker α-SMA was greatly enhanced in aortas from VC rats upon FCX treatment. CONCLUSION: These findings demonstrate FCX ability to attenuate VDN-induced aortic calcinosis in rats, suggesting its potential for preventing arteiocalcinosis in diabetic patients and those with chronic kidney disease.


Assuntos
Nicotina , Calcificação Vascular , Ratos , Animais , Nicotina/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Ratos Sprague-Dawley , Metaloproteinase 9 da Matriz/metabolismo , Cálcio , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos Wistar , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/prevenção & controle , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo
2.
Eur J Pharm Sci ; 156: 105580, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33010420

RESUMO

This study was undertaken to investigate the possible ameliorative influences of febuxostat (FEB) on vitamin D3 plus nicotine (VDN)-induced vascular calcification (VC) in Wistar rats. VDN rats received a single dose of vitamin D3 (300.000 IU/kg, I.M) and two oral doses of nicotine (25 mg/kg) on day 1. They were then administrated FEB, in two doses (10 and 15 mg/kg/day, orally), or the drug vehicle, for 4 weeks. Age-matched normal rats served as control. At the end of the experiment, body weight, kidney function parameters, serum ionic composition, cardiovascular measures, aortic calcium deposition and aortic levels of oxidative stress markers, interleukin 1ß (IL-1ß), runt-related transcription factor 2 (Runx2) and osteopontin (OPN) were determined. Aortic immunoexpressions of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP-9) and α-smooth muscle actin (α-SMA) were evaluated. FEB significantly restored body weight loss, ameliorated kidney function and diminished serum disturbances of calcium and phosphorus in VDN rats. Moreover, FEB reduced VDN-induced elevations in aortic calcium deposition, SBP and DBP. FEB (15 mg/kg) markedly decreased left ventricular hypertrophy and bradycardia in VDN group. Mechanistically, FEB dose-dependently improved oxidative damage, decreased levels of IL-1ß and Runx2, lessened expression of TNF-α, iNOS and MMP-9 and enhanced expression of OPN and α-SMA in VDN aortas relative to controls. These findings indicate that FEB, mainly at the higher administered dose (15 mg/kg), successfully attenuated VDN-induced VC. FEB may be useful in reducing VC in patients at high risk, including those with chronic kidney disease and diabetes mellitus.


Assuntos
Colecalciferol , Calcificação Vascular , Animais , Febuxostat , Humanos , Nicotina , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/tratamento farmacológico
3.
Environ Toxicol Pharmacol ; 50: 175-182, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28189063

RESUMO

Acute hepatic dysfunction associating sepsis is mediated mainly by toll-like receptor-4 (TLR-4)/nuclear factor kappa-B (NF-κB) inflammatory pathway. This study explores potential hepatoprotective effect of the NF-κB inhibitor celastrol in cecal ligation and puncture (CLP) model in rats. Protective effect of celastrol (1mg/kg, i.p., 1h before CLP) was illustrated after 24h by preventing CLP-induced hepatic histopathological changes and elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB) and gamma aminotransferase (γ-GT)] without affecting mortality. Celastrol anti-inflammatory effect was illustrated by inhibiting increased serum and hepatic mRNA expression of interleukin-6 (IL-6) without affecting IL-10 elevation. Furthermore, celastrol inhibited CLP-induced elevations in hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), TLR-4, 5-lipoxygenase (5-LOX) and prevented NF-κB/p65 nuclear translocation and activation. In conclusion, celastrol prevented CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by attenuating NF-κB activation, TLR-4 and 5-LOX expression with subsequent reduction in pro-inflammatory IL-6.


Assuntos
Anti-Inflamatórios/administração & dosagem , Hepatopatias/prevenção & controle , NF-kappa B/antagonistas & inibidores , Triterpenos/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Ceco/cirurgia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-6/sangue , Interleucina-6/genética , Hepatopatias/etiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Masculino , Triterpenos Pentacíclicos , Ratos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Triterpenos/farmacologia
4.
Naunyn Schmiedebergs Arch Pharmacol ; 390(4): 361-368, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28035464

RESUMO

Sepsis is a systemic inflammatory response associating severe infection leading to multi-organ failure, such as hepatic dysfunction. This study investigates the possible hepatoprotective effect of the lipoxin A4 agonist (BML-111) in cecal ligation and puncture (CLP) model in rats. Pretreatment with BML-111 (1 mg/kg, i.p., 1 h before CLP) protected against CLP-induced mortality after 24 h. BML-111 prevented marked inflammatory cells in liver tissues and decreased elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), gamma-glutamyl transferase (γ-GT)] induced by CLP. Additionally, BML-111 attenuated elevated serum level of interleukin-6 (IL-6) and downregulated hepatic IL-6 mRNA expression. Meanwhile, BML-111 further increased serum IL-10 and upregulated hepatic IL-10 mRNA expression, while it downregulated hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), toll-like receptor-4 (TLR-4), and 5-lipooxygenase (5-LOX). Moreover, BML-111 prevented NF-κB/p65 nuclear translocation and activation. In conclusion, BML-111 attenuated CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by decreasing NF-κB activity, TLR-4, and 5-LOX expression with subsequent decrease in pro-inflammatory IL-6 and elevation in anti-inflammatory IL-10.


Assuntos
Ácidos Heptanoicos/uso terapêutico , Lipoxinas/agonistas , Hepatopatias/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Alanina Transaminase/sangue , Animais , Araquidonato 5-Lipoxigenase/genética , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Ceco/lesões , Ceco/cirurgia , Ácidos Heptanoicos/farmacologia , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-6/sangue , Interleucina-6/genética , Ligadura , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética , gama-Glutamiltransferase/sangue
5.
Eur J Med Chem ; 101: 584-94, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26197162

RESUMO

New curcumin analogues have been synthesized and their antioxidant activities were investigated by measuring their free radical scavenging capacities. The in vitro and in vivo antitumor activities of the synthesized compounds on Ehrlich ascites carcinoma (EAC) cell line were evaluated. 4-(4-Chlorophenyl)-2-(5-ethyl-7-(4-methoxybenzylidene)-3-(4-methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c] pyridin-2-yl)thiazole 7h showed excellent antineoplastic activity in both in vitro and in vivo studies more than that of tested compounds and reference drug, cisplatin. Different molecular modeling studies were performed, where docking of compound 7h into telomerase active site suggested that it could exert its antitumor potential by telomerase inhibition.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Curcumina/análogos & derivados , Animais , Antineoplásicos/química , Antioxidantes/química , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/síntese química , Curcumina/química , Curcumina/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade
6.
Chem Biol Interact ; 207: 81-91, 2014 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-24144775

RESUMO

This study was designed to investigate the potential effects of omega-3, olmesartan and their combination on established hepatic fibrosis in the carbon tetrachloride (CCl4) rat model. Male Wistar rats received subcutaneous injections of CCl4 twice weekly for 12weeks, as well as daily oral treatments of olmesartan (1 and 3mg/kg), omega-3 (75 and 150mg/kg) and their combination during the last 4weeks of intoxication. Our results indicated that omega-3 and, to a lesser extent, olmesartan dose-dependently blunted CCl4-induced necroinflammation scoring and elevation of liver injury parameters in serum. Besides, omega-3 and, to a lesser extent, olmesartan treatments in a dose dependent manner attenuated CCl4-induced liver fibrosis, as demonstrated by hepatic histopathology scoring and 4-hydroxyproline content. The mechanisms behind these beneficial effects of both omega-3 and olmesartan were also elucidated. These include (1) counteracting hepatic oxidative stress and augmenting hepatic antioxidants; (2) preventing the activation of hepatic stellate cells (HSCs), as denoted by reducing α-smooth muscle actin (α-SMA) expression in the liver; (3) inhibiting the proliferation and chemotaxis of HSCs, as evidenced by downregulating platelet-derived growth factor receptors-ß (PDGFR-ß) expression in the liver; and (4) inhibiting the fibrogenesis response of HSCs, as indicated by inhibiting the secretion of transforming growth factor-ß1 (TGF-ß1). Unexpectedly, when olmesartan was co-administered with omega-3, it interfered with the hepatoprotective and anti-fibrotic activities of omega-3. In conclusion, this study introduces the first evidence regarding the pronounced anti-fibrotic activity of omega-3 and suggests that it may be beneficial in the treatment of hepatic fibrosis in humans.


Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Imidazóis/uso terapêutico , Cirrose Hepática Experimental/tratamento farmacológico , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Tetrazóis/uso terapêutico , Actinas/metabolismo , Animais , Biomarcadores/metabolismo , Tetracloreto de Carbono , Quimioterapia Combinada , Ácidos Graxos Ômega-3/farmacologia , Hidroxiprolina/metabolismo , Imidazóis/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática Experimental/sangue , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Ratos , Ratos Wistar , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Tetrazóis/farmacologia , Fator de Crescimento Transformador beta1/metabolismo
7.
Inflammopharmacology ; 19(6): 343-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22081121

RESUMO

The aim of the present study was to investigate the effect of MMR vaccine on inflammation which was induced by complete Freund's adjuvant (CFA) in male Sprague-Dawley rats. Rats were randomly divided into the control, CFA, MMR and CFA + MMR groups. Inflammatory symptoms such as paw oedema was measured in CFA-injected rats' paw. Body weight changes and alterations in some haematological parameters and oxidative stress markers following CFA injection were checked. In CFA-inflammed rats, there was a significant increase in rat paw thickness and decrease in body weight increment. MMR exhibited a significant anti-inflammatory effect as manifested by reduction in paw thickness and normal gain in body weight when administered 1 week prior to induction of inflammation. The altered haematological parameters (TLC) and oxidative stress markers (MDA, GSH, SOD) in the inflammed rats were significantly brought back to near normal by MMR treatment. In conclusion, MMR vaccine showed a reduction in rat paw thickness and it could significantly normalize the haematological and biochemical abnormalities in CFA-induced inflammatory pain model in rats. Our data suggested that MMR could be a potential protective agent against certain types of inflammatory pain. Further histopathological and radiological studies are required to confirm the possibility of developing novel therapeutic vaccines against some forms of arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Adjuvante de Freund/toxicidade , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Vacina contra Sarampo-Caxumba-Rubéola/farmacologia , Animais , Artrite/tratamento farmacológico , Artrite/metabolismo , Peso Corporal/efeitos dos fármacos , Edema/metabolismo , Glutationa/sangue , Inflamação/induzido quimicamente , Inflamação/metabolismo , Contagem de Leucócitos/métodos , Masculino , Malondialdeído/sangue , Estresse Oxidativo/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
8.
Chemotherapy ; 57(4): 321-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21893983

RESUMO

BACKGROUND: Cisplatin is an effective chemotherapeutic agent successfully used in the treatment of a wide range of tumors. Nevertheless, nephrotoxicity has restricted its clinical use. Recent studies have strongly suggested that inflammatory mechanisms may play an important role in the pathogenesis of cisplatin nephrotoxicity. Celecoxib, a selective cyclooxygenase-2 inhibitor used as anti-inflammatory, may therefore have a protective effect on cisplatin-induced renal injury. METHODS: In the present study, rats were injected intraperitoneally with a single dose of cisplatin (7 mg/kg) and/or celecoxib (30 mg/kg) for 5 days. RESULTS: Nephrotoxicity manifested biochemically by elevations in serum creatinine, blood urea nitrogen, and proteinuria, and an increase in kidney weight as a percentage of total body weight. In addition, a marked decrease in serum albumin was observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde level and glutathione content, which were increased and depleted, respectively. Administration of celecoxib with cisplatin attenuated cisplatin-induced changes in kidney function parameters and oxidative stress markers. Histopathological examination of the kidney confirmed these results. CONCLUSION: In conclusion, this study indicates that celecoxib may be a promising drug for clinical use as a nephroprotectant against cisplatin-induced nephrotoxicity.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Celecoxib , Creatinina/sangue , Modelos Animais de Doenças , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Testes de Função Renal , Masculino , Malondialdeído/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
9.
Eur J Med Chem ; 44(6): 2379-91, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18950904

RESUMO

The synthesis of some new 2-thieno-4(3H)-quinazolinone derivatives and their biological evaluation as antitumor agents using the National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Compounds 2-(2-thienylcarbonylamino)-5-iodo-N-(4-hydroxyphenyl)-benzamide (16), 2-(2-thieno)-6-iodo-3-phenylamino-3,4-dihydro-quina-zolin-4-one (26), and 2-(2-thieno)-4-[4-sulfonamidobenzylamino]-6-iodo-quinazoline (42), with GI(50) values of 12.7, 10.3, 16.9 microM, respectively, proved to be the most active members in this study, as compared to the known drug 5-FU. Conformational analysis of the most active molecules using molecular modeling and QSAR techniques enabled the understanding of the pharmacophoric requirements for 2-thieno-quinzolinone derivatives as antitumor agents. These three quinazolinone analogs (16, 26, 42) could be considered as useful templates for future development to obtain more potent antitumor agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Relação Quantitativa Estrutura-Atividade , Quinazolinas/síntese química , Estereoisomerismo
10.
Arch Med Res ; 39(2): 155-61, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18164958

RESUMO

BACKGROUND: In human coronary smooth muscle cells (HCSMCs), we tested the proatherogenic/proliferative potential of the reactive oxygen species (ROS), hydrogen peroxide (HP), and the ability of the polyphenol stilbene resveratrol (RSVL) to protect against such effects. METHODS: Activity for ERK1/2 and the kinase-G cascade were determined and correlated with HCSMC count before and after treatment with HP and/or RSVL. RESULTS: HP evoked concentration-dependent cell proliferation and stimulated ERK1/2 phosphorylation at active sites. Pretreatment with the MEK-ERK inhibitor (PD98059) reversed these effects of HP. RSVL (1-100 microM) elicited more prominent inhibition of HP-evoked cell proliferation and ERK1/2 activation. In addition, RSVL markedly enhanced cGMP formation, a response that was insensitive to the soluble guanylyl-cyclase (sGC) inhibitor (ODQ, 10 microM) but was obliterated with the phorbol ester, (PMA, 0.1 microM), a desensitizer of the pGC enzyme. Likewise, the RSVL-evoked cytostatic and ERK inhibitory effects were significantly reversed by the kinase-G-inhibitor, KT-5823 (10 microM). CONCLUSIONS: Collectively, RSVL activates the kinase-G system to counteract HP-induced ERK1/2 activation and coronary arterial proliferation. These effects for RSVL remain functional in endothelium-disrupted arteries, scenarios that commonly occur in advanced coronary heart disease.


Assuntos
Vasos Coronários/enzimologia , Peróxido de Hidrogênio/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos de Músculo Liso/enzimologia , Oxidantes/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Proliferação de Células , Vasos Coronários/citologia , Relação Dose-Resposta a Droga , Flavonoides/farmacologia , Humanos , Peróxido de Hidrogênio/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Miócitos de Músculo Liso/citologia , Oxidantes/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Resveratrol , Estilbenos/farmacologia
11.
Arch Pharm (Weinheim) ; 341(2): 81-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18214840

RESUMO

The synthesis and biological evaluation of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepin-3-carboxylate (HIE-124, 4), as a member of a new generation of ultra-short acting hypnotics is described. HIE-124 4 exhibited potent in-vivo activity with a very rapid onset of action and a shorter duration of action with no acute tolerance or noticeable side effects than thiopental sodium. The rat in-vivo and in-vitro metabolic profile of 4 is also described. Urine was pooled from a number of animals and analyzed using electrospray liquid chromatography mass spectrometry (ESI LC-MS). HIE-124 4 was incubated with rat-liver microsomal and rat-liver hepatocyte preparations then similarly analyzed. The only metabolic product of both in-vitro and in-vivo experiments is the carboxylic acid derivative 5. HIE-124 4 has the potential use not only as a pre-anesthetic medication and as anesthesia inducer but also has the potential to be used with thiopental sodium to maintain anesthesia for longer duration.


Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Azepinas/metabolismo , Ácidos Carboxílicos/metabolismo , Cromatografia Líquida , Relação Dose-Resposta a Droga , Feminino , Hepatócitos/metabolismo , Hipnóticos e Sedativos/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Tiazóis/metabolismo
12.
Bioorg Med Chem Lett ; 18(1): 72-7, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18023180

RESUMO

Ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepin-3-carboxylate (HIE-124, 4) is a member of a new generation of ultra-short acting hypnotics. HIE-124 (4) exhibited potent in vivo activity with a rapid onset of action and a short duration of action, with no acute tolerance or noticeable side effects. The metabolic profile of 4 is also performed. HIE-124 (4) has the potential use as a preanesthetic medication, anesthesia inducer, and could be used with thiopental sodium to maintain anesthesia for longer duration.


Assuntos
Azepinas/metabolismo , Azepinas/farmacologia , Ácidos Carboxílicos/metabolismo , Ácidos Carboxílicos/farmacologia , Hipnóticos e Sedativos/metabolismo , Hipnóticos e Sedativos/farmacologia , Tiazóis/metabolismo , Tiazóis/farmacologia , Animais , Azepinas/farmacocinética , Ácidos Carboxílicos/farmacocinética , Relação Dose-Resposta a Droga , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/farmacocinética , Camundongos , Tiazóis/farmacocinética
13.
J Biochem Mol Toxicol ; 16(6): 273-8, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12481302

RESUMO

The effect and possible mechanism of action of vanadate on the isolated pulmonary arterial rings of normal rats were studied. Pulmonary arterial rings contracted in response to vanadate (0.1-1 mM) in a concentration-dependent manner. Preincubation of the pulmonary arterial rings with 1 mM melatonin significantly reduced the contractile effect of vanadate by more than 60%. Furthermore, addition of hydrogen peroxide (50 microM) or enzymatic generation of hydrogen peroxide by the addition of glucose oxidase (10 U/mL) to the medium containing glucose produced remarkable increases in the pulmonary arterial tension, 46.2 +/- 7.3 and 78.7 +/- 9.7 g tension/g tissue, respectively. Similarly, incubation of the pulmonary arterial rings with 1 mM melatonin significantly reduced the contractile responses of the arterial rings to hydrogen peroxide and glucose/glucose oxidase to 25.7 +/- 2.9 and 24.7 +/- 4.4 g tension/g tissue, respectively. Vanadate, in vitro, significantly stimulated the oxidation of NADH by xanthine oxidase, and the rate of oxidation was increased by increasing either time or vanadate concentration. Similarly, addition of melatonin to a reaction mixture containing xanthine oxidase and vanadate significantly inhibited the rate of NADH oxidation in a concentration-dependent fashion. The results of the present study indicated that vanadate induced contraction in the isolated pulmonary arterial rings, which was significantly reduced by melatonin. Furthermore, the contractile effect of vanadate on the pulmonary arterial rings may be attributed to the intracellular generation of hydrogen peroxide.


Assuntos
Peróxido de Hidrogênio/farmacologia , Melatonina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Vanadatos/antagonistas & inibidores , Animais , Interações Medicamentosas , Glucose/metabolismo , Glucose Oxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Técnicas In Vitro , Cinética , Músculo Liso Vascular/fisiologia , NAD/metabolismo , Oxirredução , Artéria Pulmonar/fisiologia , Ratos , Ratos Wistar , Vanadatos/farmacologia , Xantina Oxidase/metabolismo
14.
Pharmacol Res ; 45(6): 461-7, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12162946

RESUMO

The effects of Ginkgo biloba extract (EGb 761) and L-carnitine on bleomycin (BLM)-induced lung fibrosis were studied in rats. BLM (cumulative dose of 180 mgkg(-1)) was given intraperitoneally (i.p.) three times weekly for 4 consecutive weeks. Treatment with BLM enhanced the responsiveness of isolated pulmonary arterial rings to serotonin (5-HT), significantly increased the normal serum level of tumour necrosis factor (TNF-alpha) by approximately 105% and markedly elevated the level of lipid peroxide (LPO) and collagen content in the lung homogenates by 34 and 83%, respectively. EGb 761 (100 mgkg(-1) ), given in drinking water for the whole study period, totally abolished the BLM-induced alterations in the measured biochemical and pharmacological parameters. Meanwhile, L-carnitine (500 mg kg(-1) ), administered in drinking water, significantly decreased the BLM-induced elevations of serum TNF-alpha, LPO level in lung tissues and the enhanced responsiveness of pulmonary arterial rings to 5-HT. However,L-carnitine did not reduce the increase in the collagen content produced by BLM. The results of the present study indicate the beneficial effects of EGb 761 and L-carnitine against lung toxicity induced by BLM treatment. Furthermore, the present data shows the advantageous use of EGb 761 as a protective agent in BLM-induced lung fibrosis under the experimental circumstances.


Assuntos
Bleomicina/toxicidade , Carnitina/uso terapêutico , Ginkgo biloba , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Fibrose Pulmonar/prevenção & controle , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Peróxidos Lipídicos/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Artéria Pulmonar/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/fisiopatologia , Ratos , Ratos Wistar , Serotonina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Vasoconstrição/efeitos dos fármacos
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