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1.
Clin Neurol Neurosurg ; 185: 105492, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31470359

RESUMO

Neurological complications of Epstein Barr virus (EBV) infection are infrequent and may include occasionally encephalitis, usually with a benign evolution. We here report on an aggressive case of EBV encephalitis in a 14-year-old boy with extensive basal ganglia involvement, and to a lesser degree of brain cortex who presented atypically with akinetic mutism and non-convulsive status epilepticus, requiring intensive care but showed a favorable outcome. EBV encephalitis is uncommon and its best management is unclear. Its pathophysiology is not well understood but could include autoimmunity. Onconeuronal and synaptic antibodies were negative in serum and cerebrospinal fluid, including the dopamine D2 receptor. To the best of our knowledge, this is the first report to evaluate antibodies to D2 receptors in EBV encephalitis. Corticosteroid therapy is usually recommended but the use of acyclovir is controversial. Intensive care is required in severe cases to assure a favorable outcome.


Assuntos
Afasia Acinética/fisiopatologia , Doenças dos Gânglios da Base/fisiopatologia , Encefalite Viral/fisiopatologia , Infecções por Vírus Epstein-Barr/fisiopatologia , Estado Epiléptico/fisiopatologia , Adolescente , Afasia Acinética/diagnóstico por imagem , Afasia Acinética/imunologia , Afasia Acinética/terapia , Anticonvulsivantes/uso terapêutico , Autoanticorpos/imunologia , Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/imunologia , Doenças dos Gânglios da Base/terapia , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/imunologia , Edema Encefálico/fisiopatologia , Edema Encefálico/terapia , Cromonar , Eletroencefalografia , Encefalite Viral/diagnóstico , Encefalite Viral/imunologia , Encefalite Viral/terapia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/terapia , Glucocorticoides/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Receptores de Dopamina D2/imunologia , Recuperação de Função Fisiológica , Estado Epiléptico/imunologia , Estado Epiléptico/terapia
2.
J Med Internet Res ; 21(6): e10838, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31165710

RESUMO

BACKGROUND: Web-based self-directed mental health applications are rapidly emerging to address health service gaps and unmet needs for information and support. OBJECTIVE: The aim of this study was to determine if a multicomponent, moderated Web-based mental health application could benefit individuals with mental health symptoms severe enough to warrant specialized mental health care. METHODS: A multicenter, pragmatic randomized controlled trial was conducted across several outpatient mental health programs affiliated with 3 hospital programs in Ontario, Canada. Individuals referred to or receiving treatment, aged 16 years or older, with access to the internet and an email address, and having the ability to navigate a Web-based mental health application were eligible. A total of 812 participants were randomized 2:1 to receive immediate (immediate treatment group, ITG) or delayed (delayed treatment group, DTG) access for 3 months to the Big White Wall (BWW), a multicomponent Web-based mental health intervention based in the United Kingdom and New Zealand. The primary outcome was the total score on the Recovery Assessment Scale, revised (RAS-r) which measures mental health recovery. Secondary outcomes were total scores on the Patient Health Questionnaire-9 item (PHQ-9), the Generalized Anxiety Disorder Questionnaire-7 item (GAD-7), the EuroQOL 5-dimension quality of life questionnaire (EQ-5D-5L), and the Community Integration Questionnaire. An exploratory analysis examined the association between actual BWW use (categorized into quartiles) and outcomes among study completers. RESULTS: Intervention participants achieved small, statistically significant increases in adjusted RAS-r score (4.97 points, 95% CI 2.90 to 7.05), and decreases in PHQ-9 score (-1.83 points, 95% CI -2.85 to -0.82) and GAD-7 score (-1.55 points, 95% CI -2.42 to -0.70). Follow-up was achieved for 55% (446/812) at 3 months, 48% (260/542) of ITG participants and 69% (186/270) of DTG participants. Only 58% (312/542) of ITG participants logged on more than once. Some higher BWW user groups had significantly greater improvements in PHQ-9 and GAD-7 relative to the lowest use group. CONCLUSIONS: The Web-based application may be beneficial; however, many participants did not engage in an ongoing way. This has implications for patient selection and engagement as well as delivery and funding structures for similar Web-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02896894; https://clinicaltrials.gov/ct2/show/NCT02896894 (Archived by WebCite at http://www.webcitation.org/78LIpnuRO).


Assuntos
Serviços de Saúde Mental/estatística & dados numéricos , Saúde Mental/normas , Adulto , Cromonar , Feminino , Humanos , Masculino , Qualidade de Vida/psicologia , Inquéritos e Questionários , Resultado do Tratamento
3.
J Neurosci Methods ; 256: 184-97, 2015 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-26363189

RESUMO

Our recently published analytic toolbox (Cacioppo et al., 2014), running under MATLAB environment and Brainstorm, offered a theoretical framework and set of validation studies for the automatic detection of event-related changes in the global pattern and global field power of electrical brain activity. Here, we provide a step-by-step tutorial of this toolbox along with a detailed description of analytical plans (aka the Chicago Electrical Neuroimaging Analytics, CENA) for the statistical analysis of brain microstate configuration and global field power in within and between-subject designs. Available CENA functions include: (1) a difference wave function; (2) a high-performance microsegmentation suite (HPMS), which consists of three specific analytic tools: (i) a root mean square error (RMSE) metric for identifying stable states and transition states across discrete event-related brain microstates; (ii) a similarity metric based on cosine distance in n dimensional sensor space to determine whether template maps for successive brain microstates differ in configuration of brain activity, and (iii) global field power (GFP) metrics for identifying changes in the overall level of activation of the brain; (3) a bootstrapping function for assessing the extent to which the solutions identified in the HPMS are robust (reliable, generalizable) and for empirically deriving additional experimental hypotheses; and (4) step-by-step procedures for performing a priori contrasts for data analysis. CENA is freely available for brain data spatiotemporal analyses at https://hpenlaboratory.uchicago.edu/page/cena, with sample data, user tutorial videos, and documentation.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Eletroencefalografia/métodos , Software , Acesso à Informação , Cromonar , Potenciais Evocados , Humanos , Modelos Biológicos , Atividade Motora/fisiologia , Teste de Stroop , Interface Usuário-Computador , Percepção Visual/fisiologia , Adulto Jovem
4.
Molecules ; 15(1): 270-9, 2010 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-20110890

RESUMO

A series of 6-halo-3-hydroxyphenylcoumarins (resveratrol-coumarins hybrid derivatives) was synthesized in good yields by a Perkin reaction followed by hydrolysis. The new compounds were evaluated for their vasorelaxant activity in intact rat aorta rings pre-contracted with phenylephrine (PE), as well as for their inhibitory effects on platelet aggregation induced by thrombin in washed human platelets. These compounds concentration-dependently relaxed vascular smooth muscle and some of them showed a platelet antiaggregatory activity that was up to thirty times higher than that shown by trans-resveratrol and some other previously synthesized derivatives.


Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Vasodilatadores/síntese química , Vasodilatadores/farmacologia , Animais , Cromonar/química , Cumarínicos/química , Feminino , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Masculino , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Ratos , Ratos Wistar , Resveratrol , Estilbenos/química , Vasodilatação/efeitos dos fármacos , Vasodilatadores/química , Varfarina/química
5.
Invest Ophthalmol Vis Sci ; 50(8): 3846-52, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19279317

RESUMO

PURPOSE: Retinal microvascular cells play a crucial role in the pathogenesis of diabetic retinopathy. The endothelial effects of cloricromene, a novel coumarin derivative, on diabetic retinopathy induced by streptozotocin (STZ) in the rat were investigated. METHODS: Cloricromene (10 mg/kg intraperitoneally) was administered daily in diabetic rats, and 60 days later eyes were enucleated for localization of nitrotyrosine, ICAM-1, VEGF, ZO-1, occludin, claudin-5, and VE-cadherin by immunohistochemical analysis. The effect of treatment was also evaluated by TNFalpha, ICAM-1, VEGF, and eNOS protein levels measurement in the retina with the respective ELISA kits. Blood-retinal barrier (BRB) integrity was also evaluated by Evans blue. RESULTS: Increased amounts of cytokines, adhesion molecule, and nitric oxide synthase were observed in retina. Cloricromene treatment significantly lowered retinal TNFalpha, ICAM-1, VEGF, and eNOS. Furthermore, immunohistochemical analysis for VEGF, ICAM-1, nitrotyrosine (a marker of peroxynitrite), and tight junctions revealed positive staining in the retina from STZ-treated rats. The degree of staining for VEGF, ICAM-1, nitrotyrosine, and tight junctions was markedly reduced in tissue sections obtained from diabetic rats treated with cloricromene. Treatment with cloricromene suppressed diabetes-related BRB breakdown by 45%. CONCLUSIONS: This study provides the first evidence that the new coumarin derivative cloricromene attenuates the degree of inflammation preserving the BRB in diabetic rats.


Assuntos
Cromonar/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Animais , Antígenos CD/metabolismo , Barreira Hematorretiniana/efeitos dos fármacos , Western Blotting , Caderinas/metabolismo , Cromonar/uso terapêutico , Claudina-5 , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Injeções Intraperitoneais , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ocludina , Fosfoproteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteína da Zônula de Oclusão-1
6.
J Ocul Pharmacol Ther ; 23(3): 257-63, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17593009

RESUMO

PURPOSE: The aim of this study was to evaluate the retina and plasma distribution of cloricromene, a coumarin derivative, and its active metabolite (MET) after an oral administration in rabbits and rats. METHODS: A single dose of cloricromene was orally administered to rabbits (10 or 100 mg/kg) and to rats (100 mg/kg). Retina and plasma samples were collected at 15, 30, 60, and 90 min following administration. Drug concentrations in the retina and plasma were measured by high-performance liquid chromatography. RESULTS: As anticipated, only the active metabolite was found in all samples. The retina and plasma showed the same T(max); peak levels of the drug were achieved at 15 min in rats and at 30 min in rabbits. In rabbits, MET exposure was approximately dose-proportional in both retina and plasma between the 10- and 100-mg/kg dose. Substantial retinal exposure was observed in both the rat and rabbit, at exposures approximately nine- to sixteenfold lower in the retina than in plasma. CONCLUSIONS: The results showed that the active metabolite of cloricromene reached the retina after a single oral dose with exposures proportional to those in plasma. These data, along with the previously published potency data for cloricromene, suggest that cloricromene could be potentially useful in ischemic-retinal diseases where amelioration of blood flow and inflammation is desirable.


Assuntos
Cromonar/análogos & derivados , Inibidores da Agregação Plaquetária/farmacocinética , Pró-Fármacos/farmacocinética , Retina/efeitos dos fármacos , Administração Oral , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Cromonar/administração & dosagem , Cromonar/farmacocinética , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Isquemia/tratamento farmacológico , Masculino , Inibidores da Agregação Plaquetária/administração & dosagem , Pró-Fármacos/administração & dosagem , Coelhos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Retina/metabolismo , Doenças Retinianas/tratamento farmacológico , Especificidade da Espécie , Distribuição Tecidual
7.
J Pharm Pharmacol ; 58(7): 1001-5, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16805962

RESUMO

The pharmacokinetics of a lipophilic alkylamino acid (LAA) prodrug of cloricromene (AD6), name CLOR-C4, was studied in rat plasma and brain. In particular, we observed that the intraperitoneal administration of CLOR-C4 to rats was able to provide a slight but statistically significant higher concentration of the active drug metabolite (cloricromene acid) in the brain compared with the parent drug administered by the same way. The correlation between pharmacokinetic data and calculated partition (LogP) and brain distribution coefficients (LogBB) supported the hypothesis that the amphiphilic nature of the LAA promoiety could be responsible for a better penetration into the brain, more than the simple increase of lipophilicity gained with respect to the parent drug.


Assuntos
Encéfalo/metabolismo , Cromonar/análogos & derivados , Portadores de Fármacos/química , Lipídeos/química , Pró-Fármacos/farmacocinética , Animais , Disponibilidade Biológica , Cromonar/sangue , Cromonar/química , Cromonar/farmacocinética , Masculino , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
8.
AAPS PharmSciTech ; 7(1): E27, 2006 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-16584158

RESUMO

The purpose of this study was to improve the stability of cloricromene (AD6) in ophthalmic formulations and its drug availability at the ocular level. To this end, AD6-loaded polymeric nanoparticle suspensions were made using inert polymer resins (Eudragit RS100 and RL100). We modified the quasi-emulsion solvent diffusion technique by varying some formulation parameters (the drug-to-polymer ratio, the total drug and polymer amount, and the stirring speed). The chemical stability of AD6 in the nanosuspensions was assessed by preparing some formulations using (unbuffered) isotonic saline or a pH 7 phosphate buffer solution as the dispersing medium. The formulations were stored at 4 degrees C, and the rate of degradation of AD6 was followed by high performance liquid chromatography (HPLC). The obtained nanosuspensions showed mean sizes and a positive surface charge (zeta-potential) that make them suitable for an ophthalmic application; these properties were maintained upon storage at 4 degrees C for several months. In vitro dissolution tests confirmed a modified release of the drug from the polymer matrixes. Nanosuspensions prepared with saline solution and no or lower amounts of surfactant (Tween 80) showed an enhanced stability of the ester drug for several months, with respect to an AD6 aqueous solution. Based on the technological results, AD6-loaded Eudragit Retard nanoparticle suspensions appear to offer promise as a means to improving the shelf life and bioavailability of this drug after ophthalmic application.


Assuntos
Resinas Acrílicas/administração & dosagem , Cromonar/análogos & derivados , Olho/metabolismo , Nanoestruturas , Química Farmacêutica , Cromonar/administração & dosagem , Cromonar/química , Cromonar/farmacocinética , Estabilidade de Medicamentos , Tamanho da Partícula , Solubilidade , Suspensões
9.
Naunyn Schmiedebergs Arch Pharmacol ; 373(1): 51-9, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16572308

RESUMO

Recent studies have demonstrated that cloricromene, a coumarin derivative, exerts protective effects in models of inflammation and shock. Tumour necrosis factor plays a pivotal role in the induction of genes involved in physiological processes, as well as in the response to inflammation. We investigated the effect of cloricromene in a rat model of periodontitis. Periodontitis was induced in rats by placing a 2/0 braided silk ligature around the lower left first molar. At day 8 the gingivomucosal tissue encircling the mandibular first molar was removed for evaluation of tumour necrosis factor production, neutrophil infiltration, tissue permeability, nitrotyrosine formation, poly (ADP-ribose) polymerase activation, radiography and histology. Ligation significantly induced an increased tumour necrosis factor production, neutrophil infiltration and a positive staining for nitrotyrosine formation and poly (ADP-ribose) polymerase activation. Ligation significantly increased Evans blue extravasation in gingivomucosal tissue and alveolar bone erosion as evaluated by radiography analysis. Intraperitonal injection of cloricromene (10 mg/kg daily for 8 days) significantly decreased all of the parameters of inflammation as described above. This suggests that cloricromene treatment, which reduced tumour necrosis factor production, may be of benefit in the treatment of periodontitis.


Assuntos
Cromonar/análogos & derivados , Periodontite/prevenção & controle , Animais , Permeabilidade Capilar/efeitos dos fármacos , Cromonar/farmacologia , Cromonar/uso terapêutico , Masculino , Infiltração de Neutrófilos , Periodontite/metabolismo , Periodontite/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Tirosina/análogos & derivados , Tirosina/biossíntese
10.
Life Sci ; 78(8): 785-94, 2006 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-16126232

RESUMO

Since alterations of tryptophan metabolism have been reported in diabetes and atherosclerosis, it was thought of interest to investigate any role of cloricromene through the influence on the oxidative metabolism of the amino acid by using diabetic/hyperlipidemic rabbits. Male 4-month-old New Zealand white rabbits, fed a diet enriched with 1% cholesterol and 10% corn oil, were made diabetic with alloxan. During the hyperlipidemic diet, a group of rabbits was treated with cloricromene (10 mg/kg/day subcutaneously plus 1.5 mg/kg/day intravenously, for 5 weeks). The other group received saline. Normometabolic New Zealand rabbits fed standard diet, treated or not with cloricromene, were used as control. The specific activities of liver tryptophan 2,3-dioxygenase and small intestine indole 2,3-dioxygenase were not significantly changed by the drug treatment. Also the specific activities of other enzymes of the kynurenine pathway in the liver and kidneys, specifically kynurenine 3-monooxygenase, kynureninase and kynurenine-oxoglutarate transaminase, did not show any significant difference in both tissues between the two groups of rabbits. On the contrary, 3-hydroxyanthranilate 3,4-dioxygenase activity in the liver of diabetic/hyperlipidemic rabbits and control rabbits treated with cloricromene showed a slight increase in comparison with untreated animals. Conversely, the specific activity of the enzyme in kidneys was not affected by the drug treatment in diabetic/hyperlipidemic animals but was reduced in controls. Aminocarboxymuconate-semialdehyde decarboxylase specific activity remained unchanged in the liver following cloricromene treatment, instead the specific activity of the enzyme in the kidneys of the diabetic/hyperlipidemic rabbits was significantly increased by the drug, with a value more than double in comparison to untreated animals. The activity of the scavenger enzyme Cu/Zn superoxide dismutase (Cu/Zn SOD) in the small intestine was also determined and found significantly increased of about twice as much in the group of diabetic/hyperlipidemic rabbits treated with cloricromene. In conclusion, in diabetic/hyperlipidemic rabbits, cloricromene appeared to influence the enzymes involved in the last steps of tryptophan oxidative metabolism through the kynurenine pathway. This, together with the antioxidant action through the activation of Cu/Zn SOD, might deserve further investigation for evaluating any link between the observed experimental findings at the level of the kynurenine pathway and the clinical effect of the drug.


Assuntos
Cromonar/análogos & derivados , Diabetes Mellitus Experimental/enzimologia , Hiperlipidemias/enzimologia , Niacina/metabolismo , Oxigenases/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Triptofano/metabolismo , Animais , Colesterol na Dieta/administração & dosagem , Cromonar/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Sequestradores de Radicais Livres/metabolismo , Hiperlipidemias/tratamento farmacológico , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Oxirredução , Coelhos
11.
Naunyn Schmiedebergs Arch Pharmacol ; 370(2): 140-5, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15322736

RESUMO

In this study we investigated, for the first time in vivo, the effect of cloricromene, a cumarine derivative, on NF-kappaB activation in endotoxin-treated rats. Endotoxemia was induced in male rats by the intravenous injection of Salmonella typhosa lipopolysaccharide (LPS; 2 mg/kg/i.v.). In vivo treatment with cloricromene (2 mg/kg/i.v.) 30 min before lipopolysaccharide administration reversed the LPS-induced loss in tone of the aortic rings, improved their reactivity to phenylephrine, decreased both nitric oxide (NO) and TNF-alpha serum levels by inhibiting LPS-induced inducible NO synthase and TNF-alpha mRNA expression, and interestingly inhibited LPS-induced NF-kappaB activation. Our data suggest that cloricromene protects rats from LPS by blocking LPS-induced NF-kappaB activation, leading to inhibition of NO and TNF-alpha overproduction and thereby reversing the LPS-induced vascular hyporeactivity.


Assuntos
Cromonar/análogos & derivados , Cromonar/uso terapêutico , Endotoxemia/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Salmonella typhi , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Ensaio de Desvio de Mobilidade Eletroforética , Endotoxemia/metabolismo , Endotoxemia/fisiopatologia , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , NF-kappa B/genética , NF-kappa B/metabolismo , Nitratos/sangue , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Nitritos/sangue , Fenilefrina , RNA Mensageiro/antagonistas & inibidores , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética
12.
J Pharm Pharmacol ; 56(7): 841-6, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15233861

RESUMO

A Eudragit RL100 polymer nanoparticle system loaded with cloricromene was prepared and characterized on the basis of physicochemical properties, stability and drug release features. To investigate the ocular bioavailability of cloricromene after inclusion in the polymer matrix, the new nanoparticle system was topically administered in the rabbit eye and compared with an aqueous solution of the same drug. The nanoparticle system showed interesting size distribution and surface charge values, suitable for ophthalmic application. The results indicated that the dispersion of cloricromene within Eudragit RL100 polymer nanoparticles increased its ocular bioavailability and enhanced the biopharmaceutical profile. The new cloricromene-loaded nanoparticle system described here may be useful in clinical practice.


Assuntos
Resinas Acrílicas/química , Cromonar/análogos & derivados , Cromonar/administração & dosagem , Cromonar/química , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/química , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Cromonar/farmacocinética , Vias de Administração de Medicamentos , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Masculino , Nanotecnologia , Tamanho da Partícula , Inibidores da Agregação Plaquetária/farmacocinética , Coelhos , Solubilidade , Propriedades de Superfície , Tecnologia Farmacêutica
13.
Int J Pharm ; 278(1): 133-41, 2004 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-15158956

RESUMO

Cloricromene (AD6), an anti-ischemic drug, is rapidly metabolised into a stable and active metabolite (cloricromene acid, AD6-acid) poorly soluble in water and less lipophilic than cloricromene. The aim of this study was to evaluate which of the two forms has more possibility to be efficiently encapsulated in nanoparticles based on poly(D,L-lactide) and prepared using the nanoprecipitation method. Increasing the theoretical loading of AD6, an increase in drug actual loading and in the mean particle size occurred, while no formation of nanoparticles was observed when the highest theoretical loading (50 mg) was employed. Changing the pH of the aqueous phase the drug content dramatically increased. However, at a pH value of 11 a more rapid hydrolysis of AD6 occurred. When AD6-acid was embedded in the nanoparticles, suitable results concerning both drug content and encapsulation efficiency were achieved. A good control in the release of AD6 from the AD6-loaded nanoparticles was observed while the liberation of AD6-acid from the AD6-acid-loaded nanoparticles was faster than the dissolution of the AD6-acid free. These results confirm that the most easy encapsulable form in nanoparticles is AD6-acid probably owing to its poor water solubility. Further studies will be carried out in order to evaluate if the increase in the liberation of AD6-acid by nanoencapsulation may have outcomes in its bioavaibility in vivo.


Assuntos
Cromonar/análogos & derivados , Lipídeos/química , Nanotecnologia/métodos , Poliésteres/química , Água/química , Cromonar/química , Cromonar/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Concentração de Íons de Hidrogênio , Lipídeos/farmacocinética , Microscopia Eletrônica de Varredura , Poliésteres/farmacocinética , Solubilidade/efeitos dos fármacos
14.
Life Sci ; 74(22): 2749-56, 2004 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-15043989

RESUMO

Biologic therapies, namely antibodies against tumor necrosis factor-alpha (TNF- alpha) or its receptors, have been recently introduced for the treatment of patients with inflammatory bowel disease (IBD). In the present study the effects of cloricromene, an agent with known antithrombotic actions and with demonstrated anti-TNF- alpha activity were investigated in a rat model of experimental colitis induced with dinitrobenzenesulphonic acid (DNB)/ethanol. We investigated three experimental groups: (i) sham-colitis with vehicle-treatment (controls, n = 6), (ii) colitis with vehicle-treatment (saline, 0.1 ml s.c., daily) (DNB-V, n = 7), (iii) colitis with cloricromene-treatment (10 mg/kg/day s.c.; DNB-C, n = 8). After 7 days, the weight gain, colon wet weight, macroscopic damage score, coagulation parameters, colon mucosal myeloperoxidase activity (MPO), and tissue concentrations of TNF- alpha and of macrophage inhibitory peptide-2 (MIP-2) were assessed. The macroscopic damage scores, colon wet weights, and tissue MIP-2 levels were significantly increased in untreated and in cloricromene-treated rats compared with controls. Cloricromene treatment was associated with a minor body weight loss (p < 0.025) and significantly reduced tissue concentrations of MPO and TNF-alpha (p < 0.02, both). Blood coagulation parameters were not affected by treatment. In the DNB-model treatment with cloricromene effectively reduces tissue levels of TNF- alpha and of myeloperoxidase, whereas MIP-2 concentrations were not influenced. Blood coagulation parameters remained unchanged indicating safety of treatment. Since biological therapies frequently fail to improve disease course of IBD, other therapies with similar targets should be further investigated.


Assuntos
Cromonar/análogos & derivados , Cromonar/uso terapêutico , Colite/prevenção & controle , Colo/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Animais , Benzenossulfonatos , Peso Corporal/efeitos dos fármacos , Quimiocina CXCL2 , Cromonar/administração & dosagem , Colite/induzido quimicamente , Colite/patologia , Colo/enzimologia , Colo/patologia , Injeções Subcutâneas , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Monocinas/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Peroxidase/metabolismo , Inibidores da Agregação Plaquetária/administração & dosagem , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
15.
Drug Deliv ; 10(4): 245-50, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14612340

RESUMO

This article describes the development of solid lipid nanoparticles (SLN) as colloidal carriers for cloricromene. Nanoparticles were prepared by the microemulsion or precipitation technique. In vitro drug release profile from SLN was studied under various experimental conditions mimicking some body fluids. The drug release rate of drug at pH 7.4 and human plasma is high. In plasma, after 15 min, about 70% of drug was released. The cloricromene that was not released within 4 hr was found in the SLN. This result suggests that this colloidal system could be useful for targeted drug delivery to the central nervous system after intravenous administration.


Assuntos
Cromonar/análogos & derivados , Cromonar/síntese química , Lipídeos/síntese química , Nanotecnologia/métodos , Cromonar/farmacocinética , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Humanos , Lipídeos/farmacocinética
16.
Invest Ophthalmol Vis Sci ; 44(3): 1178-84, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12601047

RESUMO

PURPOSE: To investigate the effects of cloricromene, a coumarin derivative, in rats subjected to endotoxin-induced uveitis (EIU). METHODS: Endotoxin uveitis was induced in male Lewis rats by a single footpad injection of 200 microg lipopolysaccharide (LPS). Cloricromene was topically applied to the rat eye twice at 1 hour before and 7 hours after injection of LPS. A separate group of animals was treated with vehicle. Rats were killed 16 hours after injection and the eyes enucleated for histologic examination and immunohistochemical analysis. The effect of treatment was also evaluated by slit lamp examination, by the number of intraocular inflammatory cells on histologic sections, and by measuring the protein and TNFalpha levels in the aqueous humor. Nitrite and nitrate production was also measured in the aqueous humor. RESULTS: The histopathology of the iris-ciliary body included inflammatory cell infiltration and nuclear modification of vessel endothelial cells. Cloricromene treatment reduced the inflammatory cell infiltration and improved histologic status of the ocular tissue. Immunohistochemical analysis for P-selectin, intracellular adhesion molecule (ICAM)-1, nitrotyrosine, and poly(ADP-ribose) synthetase (PARS) revealed a positive staining in inflammatory cell infiltration from LPS-treated rats. The degree of staining for P-selectin, ICAM-1, nitrotyrosine, and PARS was markedly reduced in tissue sections obtained from LPS-recipient rats that had received cloricromene. Cloricromene strongly inhibited cell infiltration, protein exudation, TNFalpha production, and nitrite-nitrate formation. CONCLUSIONS: This study provides the first evidence that cloricromene, a coumarin derivative, attenuates the degree of inflammation and tissue damage associated with EIU in rats.


Assuntos
Cromonar/análogos & derivados , Cromonar/administração & dosagem , Lipopolissacarídeos , Inibidores da Agregação Plaquetária/administração & dosagem , Salmonella , Tirosina/análogos & derivados , Uveíte Anterior/prevenção & controle , Administração Tópica , Animais , Humor Aquoso/metabolismo , Corpo Ciliar/efeitos dos fármacos , Corpo Ciliar/metabolismo , Corpo Ciliar/patologia , Ensaio de Imunoadsorção Enzimática , Técnica Indireta de Fluorescência para Anticorpo , Molécula 1 de Adesão Intercelular/metabolismo , Iris/efeitos dos fármacos , Iris/metabolismo , Iris/patologia , Masculino , Nitratos/metabolismo , Nitritos/metabolismo , Soluções Oftálmicas , Selectina-P/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ratos , Ratos Endogâmicos Lew , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/metabolismo , Uveíte Anterior/induzido quimicamente , Uveíte Anterior/metabolismo , Uveíte Anterior/patologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-11863286

RESUMO

A rapid and simple method was developed for the simultaneous separation and quantification of cloricromene, a coumarine derivative, and its active metabolite, cloricromene acid, in rabbit aqueous humor. The analyses were performed by high-performance liquid chromatography using a C18 reversed-phase column (Hypersil ODS) with UV detection at 318 nm. The mobile phase consisted of acetonitrile-water containing 1% triethylamine pH 3.5, adjusted with orthophosphoric acid. An acetonitrile gradient was necessary to achieve good separation within 13 min. Timolol was found to be a suitable internal standard. The retention times ranged from 5.72 to 11.25 min. A simple pre-treatment with acetonitrile containing 0.6% HCIO4 was used to deproteinize aqueous humor samples. The limit of quantitation ranged between 10 and 20 ng/ml. The recovery was >90%. The relationship between peak areas and concentration was linear over the range between 0.01 and 3.8 microg/ml, with r2 > 0.99. The assay provided good reproducibility and accuracy for both analytes and proved to be suitable for pharmacokinetic studies of cloricromene.


Assuntos
Humor Aquoso/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Cromonar/análogos & derivados , Cromonar/metabolismo , Animais , Masculino , Coelhos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta
18.
Therapie ; 56(4): 403-7, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11677863

RESUMO

Local pharmacological intradermal infiltration is a therapy being used more and more thanks to the positive results achieved, particularly for all those therapies acting on the microcirculation. In trying to better the results obtained with medical therapy for tinnitus sufferers, to assess the effect of a vasoactive drug, the method of administration by the intradermal route, which allows a strengthening of the pharmacological effect, has been added. The present study comprised 120 tinnitus sufferers who underwent intradermal auricle infiltration with a vasoactive drug. The control group includes 115 tinnitus sufferers who underwent systemic vasoactive therapy with the same drug. Forty-five days after beginning intradermal treatment the symptom improved and continued to do so following further infiltrations which patients underwent every 15 days. In the control group we noticed a moderate improvement 45 days after the beginning of oral therapy; thereafter the results reached a plateau by the 60th day. Intradermal vasoactive therapy for idiopathic tinnitus seems to be a new success, which will be an interesting progression in the therapy of this kind of symptom.


Assuntos
Cromonar/análogos & derivados , Cromonar/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Zumbido/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Percepção Auditiva , Cromonar/uso terapêutico , Orelha Externa , Feminino , Humanos , Injeções Intradérmicas , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Zumbido/fisiopatologia , Resultado do Tratamento
19.
Am J Physiol Heart Circ Physiol ; 281(3): H1407-12, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11514313

RESUMO

Estrogen replacement therapy reduces risk of cardiovascular events by altering coronary vasoregulation and distribution of blood flow. Vessel reactivity and blood flow distribution were assessed in anesthetized female rabbits in the following groups: 1) sham, 2) ovariectomy, 3) ovariectomy + 17beta-estradiol, and 4) ovariectomy + dehydroepiandrosterone. After a 2-wk treatment, cardiac hemodynamics, vascular reserve, and blood flow were evaluated during the following infusions: 1) NaCl, or vehicle (0.5 ml/min), 2) acetylcholine (2 mg/kg), 3) isoproterenol (2 mg. kg(-1). min(-1)), and 4) chromonar (8 mg/kg). In hearts from ovariectomized rabbits, autoregulatory blood flow was preserved despite lower diastolic perfusion pressures (55 +/- 8 vs. 64 +/- 8 mmHg in sham) and rate-pressure product (14.4 +/- 0.8 vs. 19.3 +/- 0.8 beats/min. mmHg x 10(-3)). Estrogen replacement therapy restored coronary pressure and reserve, and all drugs increased vascular conductance. In conclusion, in hearts from ovariectomized rabbits, vascular reserve declined because coronary pressure was lower; however, blood flow was preserved at a higher level than expected for oxygen demand. Estrogen replacement therapy restores myocardial oxygen supply-demand indices and returns coronary pressure-flow data to levels observed in animals with intact ovaries.


Assuntos
Circulação Coronária/efeitos dos fármacos , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Acetilcolina/farmacologia , Anestesia , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/farmacologia , Cromonar/farmacologia , Circulação Coronária/fisiologia , Desidroepiandrosterona/farmacologia , Feminino , Isoproterenol/farmacologia , Ovariectomia , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Coelhos , Vasodilatadores/farmacologia
20.
Eur J Pharmacol ; 418(3): 231-7, 2001 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-11343695

RESUMO

Cloricromene decreases myocardial infarct size after ischemic-reperfusion injury in vivo, and it has been suggested that this is due to inhibition of tumor necrosis factor-alpha (TNF-alpha). The purpose of this work was to characterize the mechanism of cloricromene-induced inhibition of TNF-alpha in rat macrophages. Cloricromene inhibited lipopolysaccharide-induced TNF-alpha release in a dose-dependent manner (IC(50)=5.9 +/- 0.8 microM). This was not due to cytotoxicity, as cloricromene was well tolerated up to 500 microM. Cloricromene inhibited lipopolysaccharide-induced expression of TNF-alpha mRNA, which suggests a pre-transcriptional effect. We then investigated the early signal transduction pathway triggered by lipopolysaccharide. The binding of lipopolysaccharide to its receptor CD14 activates protein kinase C and nuclear factor-kappaB (NF-kappaB). Cloricromene inhibited NF-kappaB activation in a dose-dependent manner, but affected protein kinase C translocation only slightly. We then established that cloricromene inhibited lipopolysaccharide-induced cellular oxidative activity, which is important for NF-kappaB activation. Our results show that cloricromene interferes with the early signal transduction pathway triggered by lipopolysaccharide.


Assuntos
Cromonar/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Cromonar/análogos & derivados , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/citologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transcrição Genética/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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