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1.
J Enzyme Inhib Med Chem ; 35(1): 21-30, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619095

RESUMO

Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Doença de Chagas/tratamento farmacológico , Ciclamatos/farmacologia , Tripanossomicidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Doença de Chagas/metabolismo , Ciclamatos/síntese química , Ciclamatos/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia
2.
J Chem Inf Model ; 58(7): 1331-1342, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29870230

RESUMO

The purpose of this investigation is to contribute to the development of new anticonvulsant drugs to treat patients with refractory epilepsy. We applied a virtual screening protocol that involved the search into molecular databases of new compounds and known drugs to find small molecules that interact with the open conformation of the Nav1.2 pore. As the 3D structure of human Nav1.2 is not available, we first assembled 3D models of the target, in closed and open conformations. After the virtual screening, the resulting candidates were submitted to a second virtual filter, to find compounds with better chances of being effective for the treatment of P-glycoprotein (P-gp) mediated resistant epilepsy. Again, we built a model of the 3D structure of human P-gp, and we validated the docking methodology selected to propose the best candidates, which were experimentally tested on Nav1.2 channels by patch clamp techniques and in vivo by the maximal electroshock seizure (MES) test. Patch clamp studies allowed us to corroborate that our candidates, drugs used for the treatment of other pathologies like Ciprofloxacin, Losartan, and Valsartan, exhibit inhibitory effects on Nav1.2 channel activity. Additionally, a compound synthesized in our lab, N, N'-diphenethylsulfamide, interacts with the target and also triggers significant Na1.2 channel inhibitory action. Finally, in vivo studies confirmed the anticonvulsant action of Valsartan, Ciprofloxacin, and N, N'-diphenethylsulfamide.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Anticonvulsivantes/química , Epilepsia/tratamento farmacológico , Canal de Sódio Disparado por Voltagem NAV1.2/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Anticonvulsivantes/farmacologia , Ciprofloxacino/química , Ciprofloxacino/farmacologia , Bases de Dados de Compostos Químicos , Células HEK293 , Humanos , Losartan/química , Losartan/farmacologia , Masculino , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Valsartana/química , Valsartana/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
3.
J Chem Inf Model ; 57(8): 1868-1880, 2017 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-28708399

RESUMO

Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer and a potential source of drug interactions. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. We have developed a computational nonlinear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers, and data fusion. The best model ensemble consists in averaging the ranking of the 12 decision trees that showed the best performance on the training set, which also demonstrated a good performance for the test set. It was experimentally validated using the ex vivo everted rat intestinal sac model. Five anticonvulsant drugs classified as nonsubstrates for BRCP by the model ensemble were experimentally evaluated, and none of them proved to be a BCRP substrate under the experimental conditions used, thus confirming the predictive ability of the model ensemble. The model ensemble reported here is a potentially valuable tool to be used as an in silico ADME filter in computer-aided drug discovery campaigns intended to overcome BCRP-mediated multidrug resistance issues and to prevent drug-drug interactions.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Biologia Computacional/métodos , Simulação por Computador , Desenho de Drogas , Proteínas de Neoplasias/metabolismo , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Masculino , Ligação Proteica , Ratos , Ratos Wistar , Máquina de Vetores de Suporte
4.
Eur J Pharmacol ; 774: 55-63, 2016 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-26849942

RESUMO

We report herein the design and optimization of a novel series of sulfamides and sulfamates derived from amino esters with anticonvulsant properties. The structures were designed based on the pharmacophoric pattern previously proposed, with the aim of improving the anticonvulsant action. The compounds were obtained by a new synthetic procedure with microwave assisted heating and the use of adsorbents in the isolation process. All the derivatives showed protection against the maximal electroshock seizure test (MES test) in mice at the lowest dose tested (30 mg/kg) but they did not show significant protection against the chemical induced convulsion by pentylenetetrazole. These results verify the ability of the computational model for designing new anticonvulsants structures with anti-MES activity. Additionally, we evaluated the capacity of the synthesized structures to bind to the benzodiazepine binding site (BDZ-bs) of the γ-aminobutiric acid receptor (GABAA receptor). Some of them showed medium to low affinity for the BDZ-bs.


Assuntos
Amidas/química , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/química , Anidrases Carbônicas/metabolismo , Domínio Catalítico , Técnicas de Química Sintética , Ésteres , Masculino , Camundongos , Modelos Moleculares , Convulsões/tratamento farmacológico , Ácidos Sulfônicos/química , Ácidos Sulfônicos/uso terapêutico
5.
Biochem Pharmacol ; 83(2): 253-9, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22056620

RESUMO

A set of sulfamides designed, synthesized and evaluated against maximal electroshock seizure (MES) and pentilenetetrazol (PTZ) tests with promising results, were tested for their affinity for the benzodiazepine binding site of the GABA(A) receptor. The most active compounds, N,N'-dicyclohexylsulfamide (7) and N,N'-diphenethylsulfamide (10), competitively inhibited the binding of [(3)H]-flunitrazepam to the benzodiazepine binding site with K(i)±SEM values of 27.7±4.5µM (n=3) and 6.0±1.2µM (n=3), respectively. The behavioral actions of these sulfamides, i.p. administered in mice, were examined in the plus-maze, hole-board and locomotor activity assays. Compound 7 exhibited anxiolytic-like effects in mice evidenced by a significant increase of the parameters measured in the hole-board test (at 1 and 3mg/kg) and the plus-maze assay (at 1 and 3mg/kg). Compound 10 evidenced anxiolytic activity in the plus-maze and the hole-board tests at 1mg/kg. Locomotor activity of mice was not modified by compound 7 or 10 at the doses tested. Flumazenil, a non selective benzodiazepine binding site antagonist, was able to completely reverse the anxiolytic-like effects of these sulfamides, proving that the GABA(A) receptor is implicated in this action. Anxiety represents a major problem for people with epilepsy. The use of anxiolytic and anticonvulsant sulfamides would be beneficial to individuals who suffer from both disorders.


Assuntos
Ansiolíticos/metabolismo , Anticonvulsivantes/metabolismo , Ansiedade/metabolismo , Benzodiazepinas/metabolismo , Receptores de GABA-A/metabolismo , Sulfonamidas/metabolismo , Animais , Ansiolíticos/química , Ansiolíticos/uso terapêutico , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Flunitrazepam/química , Flunitrazepam/metabolismo , Flunitrazepam/uso terapêutico , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Sulfonamidas/química , Sulfonamidas/uso terapêutico
6.
Arthritis Care Res (Hoboken) ; 62(4): 465-72, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20391500

RESUMO

OBJECTIVE: To validate manual muscle testing (MMT) for strength assessment in juvenile and adult dermatomyositis (DM) and polymyositis (PM). METHODS: Patients with PM/DM (73 children and 45 adults) were assessed at baseline and reevaluated 6-9 months later. We compared Total MMT (a group of 24 proximal, distal, and axial muscles) and Proximal MMT (7 proximal muscle groups) tested bilaterally on a 0-10 scale with 144 subsets of 6 and 96 subsets of 8 muscle groups tested unilaterally. Expert consensus was used to rank the best abbreviated MMT subsets for face validity and ease of assessment. RESULTS: The Total, Proximal, and best MMT subsets had excellent internal reliability (Total MMT r(s) = 0.91-0.98), and consistency (Cronbach's alpha = 0.78-0.97). Inter- and intrarater reliability were acceptable (Kendall's W 0.68-0.76, r(s) = 0.84-0.95). MMT subset scores correlated highly with Total and Proximal MMT scores and with the Childhood Myositis Assessment Scale, and correlated moderately with physician global activity, functional disability, magnetic resonance imaging, and axial and distal MMT scores, and, in adults, with creatine kinase level. The standardized response mean for Total MMT was 0.56 in juveniles and 0.75 in adults. Consensus was reached to use a subset of 8 muscles (neck flexors, deltoids, biceps, wrist extensors, gluteus maximus and medius, quadriceps, and ankle dorsiflexors) that performed as well as the Total and Proximal MMT, and had good face validity and ease of assessment. CONCLUSION: These findings aid in standardizing the use of MMT for assessing strength as an outcome measure for myositis.


Assuntos
Dermatomiosite/diagnóstico , Debilidade Muscular/diagnóstico , Exame Físico , Polimiosite/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miosite/diagnóstico , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
7.
Arthritis Rheum ; 60(11): 3425-35, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19877055

RESUMO

OBJECTIVE: We undertook this study to validate the Myositis Damage Index (MDI) in juvenile and adult myositis, to describe the degree and types of damage and to develop predictors of damage. METHODS: Retrospective MDI evaluations and prospective assessment of disease activity and illness features were conducted. Patients with juvenile-onset disease (n = 143) were evaluated a median of 18 months after diagnosis; 135 patients were assessed 7-9 months later, and 121 were last assessed a median of 82 months after diagnosis. Ninety-six patients with adult-onset dermatomyositis or polymyositis had a baseline assessment a median of 30 months after diagnosis; 77 patients had a 6-month followup evaluation, and 55 had a final assessment a median of 60 months after diagnosis. RESULTS: Damage was present in 79% of juvenile patients and in 97% of adult patients. In juveniles, scarring, contractures, persistent weakness, muscle dysfunction, and calcinosis were most frequent (23-30%) at the last evaluation. In adults, muscle atrophy, muscle dysfunction, and muscle weakness were most frequent (74-84%). MDI severity correlated with physician-assessed global damage, serum creatinine, and muscle atrophy on magnetic resonance imaging, and in juveniles also with functional disability and weakness. MDI damage scores and frequency were highest in patients with a chronic illness course and in adult patients who died. Predictors of damage included functional disability, duration of active disease, disease severity at diagnosis, physician-assessed global disease activity, and illness features, including ulcerations in children and pericarditis in adults. CONCLUSION: Damage is common in myositis after a median duration of 5 years in patients with adult-onset disease and 6.8 years in patients with juvenile-onset disease. The MDI has good content, construct, and predictive validity in juvenile and adult myositis.


Assuntos
Dermatomiosite/fisiopatologia , Miosite/fisiopatologia , Polimiosite/fisiopatologia , Índice de Gravidade de Doença , Adolescente , Adulto , Calcinose/epidemiologia , Calcinose/etiologia , Calcinose/fisiopatologia , Criança , Cicatriz/epidemiologia , Cicatriz/etiologia , Cicatriz/fisiopatologia , Dermatomiosite/complicações , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/epidemiologia , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Atrofia Muscular/epidemiologia , Atrofia Muscular/etiologia , Atrofia Muscular/fisiopatologia , Polimiosite/complicações , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos
8.
J Emerg Med ; 22(4): 385-7, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12113850

RESUMO

Intravenous (IV) colchicine is occasionally prescribed for the treatment of acute gouty arthritis. The Food and Drug Administration (FDA) recently received a report of death in a patient that was associated with inappropriate IV dosing of colchicine. This report prompted further investigation of other deaths associated with IV colchicine use in the FDA Adverse Event Reporting System (AERS) and the medical literature. A total of 20 deaths were identified. Eight patients were females, 11 were males, and the gender was unknown in 1. In all cases, the recommended maximum cumulative dose of 2 to 4 mg during a course of therapy was exceeded. Dose reductions are recommended in patients with renal or hepatic disease and in the elderly. All reported adverse events were associated with colchicine toxicity, including thrombocytopenia, leukopenia, pancytopenia, agranulocytosis, aplastic anemia, acute renal failure, and disseminated intravascular coagulopathy. Death occurred within 1 to 40 days after drug administration. Therapeutic guidelines exist for use of IV colchicine and these guidelines should be followed to prevent serious toxicities and death.


Assuntos
Colchicina/envenenamento , Supressores da Gota/envenenamento , Gota/tratamento farmacológico , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Colchicina/administração & dosagem , Colchicina/uso terapêutico , Overdose de Drogas , Evolução Fatal , Supressores da Gota/administração & dosagem , Supressores da Gota/uso terapêutico , Humanos , Injeções Intravenosas , Masculino , Guias de Prática Clínica como Assunto , Estados Unidos , United States Food and Drug Administration
9.
Arch Intern Med ; 162(6): 713-5, 2002 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-11911727

RESUMO

Rofecoxib is a nonsteroidal anti-inflammatory drug that is reported to act by selectively inhibiting cyclooxygenase-2. A review and analysis of reports sent to the Spontaneous Reporting System of the Food and Drug Administration, Rockville, Md, suggest that aseptic meningitis is associated with rofecoxib use. To our knowledge, there have been no published reports of aseptic meningitis occurring in association with rofecoxib use to date. We report 5 serious cases of aseptic meningitis associated with rofecoxib use.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Lactonas/efeitos adversos , Meningite Asséptica/induzido quimicamente , Adolescente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Síndrome do Túnel Carpal/tratamento farmacológico , Feminino , Humanos , Lactonas/uso terapêutico , Masculino , Meningite Asséptica/diagnóstico , Pessoa de Meia-Idade , Cervicalgia/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Sulfonas
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