RESUMO
1. It has previously been demonstrated that metabolism of drugs via a single enzymatic pathway, particularly CYP3A4, is associated with increased risk for drug-drug interactions (DDI). Quantitative experimental systems as well as integrated prediction models to assess such risk during the preclinical phase are highly warranted. 2. The present study was designed to systematically investigate the performance of human cryopreserved hepatocytes in suspension to predict fraction metabolized via CYP3A (fmCYP3A) by assessing the ketoconazole sensitive intrinsic clearance (CLint) for five prototypical CYP3A substrates with varying degree of CYP3A dependent CLint in twelve individual hepatocyte batches. 3. We demonstrate that in contrast to well predicted mean hepatic metabolic clearance (CLH) and mean fmCYP3A data, the variability in CYP3A contribution for compounds having multiple metabolic pathways cannot be predicted from inhibition experiments using ketoconazole as inhibitor. Instead, data in the present paper indicate that the variability is larger after inhibition of CYP3A for compounds having multiple metabolic pathways. 4. It is therefore recommended to estimate the average CLint and fmCYP3A for a given test compound in a series (n = 10) of individual human hepatocyte batches.
Assuntos
Criopreservação/métodos , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas/fisiologia , Hepatócitos/metabolismo , Redes e Vias Metabólicas/fisiologia , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Cromatografia Líquida de Alta Pressão , Humanos , Espectrometria de MassasRESUMO
The air-dried stems and ripe fruit of Drypetes inaequalis Hutch. (Euphorbiaceae) were studied. Four triterpene derivatives, characterized as lup-20(29)-en-3beta,6alpha-diol, 3beta-acetoxylup-20(29)-en-6alpha-ol, 3beta-caffeoyloxylup-20(29)-en-6alpha-ol and 28-betad-glucopyranosyl-30-methyl 3beta-hydroxyolean-12-en-28,30-dioate along with 10 known compounds were isolated from the whole stems. One triterpene, characterized as 3alpha-hydroxyfriedelan-25-al along with six known compounds were isolated from the ripe fruit. Their structures were established on the basis of spectroscopic analysis and chemical evidence. The triterpenes were tested for antimicrobial activity against some Gram-positive and Gram-negative bacteria, and two of them appeared to be modestly active.
Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Magnoliopsida/química , Triterpenos/química , Triterpenos/farmacologia , Anti-Infecciosos/isolamento & purificação , Frutas/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Caules de Planta/química , Triterpenos/isolamento & purificaçãoRESUMO
The CH(2)Cl(2)/MeOH extract of the stem bark of Erythrina vogelii (Fabaceae) from Nigeria has yielded two novel isoflavones, 7,4'-dihydroxy-8-(gamma,gamma-dimethylallyl)-2''zeta-(4''-hydroxyisopropyl)dihydrofurano[1'',3'':5,6]isoflavone (vogelin H) (1) and 7,4'-dihydroxy-8-[(2'''zeta,3'''-dihydroxy-3'''-methyl)butyl]-2'',2''-dimethyl-3'',4''-dehydropyrano[1'',4'':5,6]isoflavone (vogelin I) (2), a novel flavone, 7,4'-dihydroxy-2'',2''-dimethyl-3'',4''-dehydropyrano[1'',4'':5,6]flavone (vogelin J) (3), and eight known flavonoids.
Assuntos
Erythrina/química , Flavonas/química , Isoflavonas/química , Flavonas/isolamento & purificação , Isoflavonas/isolamento & purificação , Espectroscopia de Ressonância Magnética , Nigéria , Casca de Planta/química , Caules de Planta/químicaRESUMO
Two prenylated xanthone derivatives, named globulixanthones C and D and one bis-xanthone, designated globulixanthone E, have been isolated from the root bark of Symphonia globulifera. The structures of these compounds were elucidated by a detailed spectroscopic analysis. They have been shown to exhibit in vitro significant antimicrobial activity against a range of micro-organisms.
Assuntos
Casca de Planta/química , Raízes de Plantas/química , Árvores/química , Xantenos/química , Xantenos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Xantenos/isolamento & purificaçãoRESUMO
A new prenylated xanthone, named allanxanthone A, was isolated from the stem bark of Allanblackia floribunda in addition to known compounds, 1,5-dihydoxyxanthone, 1,5,6-trihydroxy-3,7-dimethoxyxanthone, stigmasterol and stigmasteryl-3-O-beta-D-glucopyranoside. The structure of the new compound was assigned as 1,3,5-trihydroxy-2-(3-methylbut-2-enyl)-4-(1,1-dimethylprop-2-enyl) xanthone, by means of spectroscopic analysis. The 13C NMR spectral data of 1,5-dihydroxyxanthone is reported here for the first time as well as the in vitro cytotoxic activity of xanthone metabolites against the KB cell line.
Assuntos
Plantas Medicinais/química , Xantenos/química , Xantonas , Camarões , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células KB/efeitos dos fármacos , Espectroscopia de Ressonância Magnética/métodos , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Caules de Planta/química , Prenilação de Proteína , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Xantenos/isolamento & purificação , Xantenos/toxicidadeRESUMO
The study of the chemical constituents of the root bark and the nut of Calophyllum inophyllum has resulted in the isolation and characterization of a xanthone derivative, named inoxanthone, 3, together with 12 known compounds: caloxanthones A, 4 and B, 5, macluraxanthone, 6, 1,5-dihydroxyxanthone, 7, calophynic acid, 8, brasiliensic acid, 9 inophylloidic acid, 10, friedelan-3-one, 11, calaustralin, 12, calophyllolide, 13, inophyllums C, 14 and E, 15. Their structures were established on the basis of spectral evidence. Their in vitro cytotoxicity against the KB cell line and their antibacterial activity and potency against a wide range of micro organisms were evaluated.
Assuntos
Antibacterianos/química , Antineoplásicos Fitogênicos/química , Calophyllum/química , Antibacterianos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Bactérias/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Células KB , Estrutura Molecular , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sementes/química , Xantonas/química , Xantonas/isolamento & purificaçãoRESUMO
In 2340 adult patients above the age of 26 years with rheumatic valvular disease (RHD) seen since 1987, injection benzathine penicillin (once in 3 weeks) was discontinued and the patients were followed for evidence of rheumatic fever for a period of one to nine years (mean of 3 years). Recurrence of rheumatic fever was seen in 5 patients (0.21%). This study confirms that recurrence of rheumatic fever in patients with RHD above 26 years of age is very low and hence we recommend long term chemoprophylaxis to the patients above the age of 26 on an individual basis.
Assuntos
Doenças das Valvas Cardíacas/prevenção & controle , Penicilina G Benzatina/uso terapêutico , Penicilinas/uso terapêutico , Febre Reumática/prevenção & controle , Adolescente , Adulto , Feminino , Humanos , Masculino , RecidivaRESUMO
BACKGROUND/OBJECTIVES: The value of preoperative nutritional support in liver resection remains questionable. The aim of the present study was to compare the incidence of postoperative complications after liver resection between those patients that received preoperative immunonutrition versus those patients without preoperative nutritional support. SUBJECTS/METHODS: Patients undergoing elective liver resection between 9 November 2007 and 14 May 2013 were considered for the study: 84 with preoperative immunonutrition (Oral-Impact, Nestle, 3 × 237 ml per day for seven days at home) and 63 control patients without preoperative nutritional support. To reduce selection bias, propensity score matching was performed. Primary endpoint was the overall complication rate. Secondary endpoints were infectious and major complications. RESULTS: Ninety-eight patients could be matched (49 in each group). Seventy-seven patients (78.6%) had a minor and 21 patients (21.4%) a major liver resection. The two groups were balanced for age, gender distribution, American Society of Anesthesiology score ⩾3, NRS 2002 score, weight loss>10%, cirrhosis, steathosis, preoperative chemotherapy, pathology, major liver resection and extrahepatic procedures. No significant differences were observed in the overall complication rate (53.0% versus 51.0%), infectious complications (38.7% versus 28.5%) and major complications (12.2% versus 10.2%) for the immunonutrition and control group, respectively. CONCLUSIONS: The present study did not permit to demonstrate an impact of preoperative immunonutrition with Oral-Impact on postoperative complications after minor liver resection.
Assuntos
Procedimentos Cirúrgicos Eletivos , Nutrição Enteral , Fígado/cirurgia , Complicações Pós-Operatórias , Cuidados Pré-Operatórios/métodos , Idoso , Estudos de Casos e Controles , Fígado Gorduroso/cirurgia , Feminino , Humanos , Cirrose Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/prevenção & controle , Prevalência , Pontuação de PropensãoAssuntos
Angina Pectoris/terapia , Angioplastia Coronária com Balão/instrumentação , Estenose das Carótidas/terapia , Stents , Angina Pectoris/diagnóstico por imagem , Angina Pectoris/etiologia , Angioplastia Coronária com Balão/métodos , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
Bioassay-guided fractionation of the stem bark of Symphonia globulifera has yielded three known xanthones, ugaxanthone (1), mbarraxanthone (2) and gentisein (3), two biflavonoid derivatives named GB2 (4) and manniflavanone GB3 (5), and one new polyoxygenated xanthone with an isoprenoid group, named globulixanthone F (6). The structures of these compounds were elucidated by means of spectroscopic methods. The spectral data of 1 and 2 are reported here for the first time, as well as the antimicrobial activity of globulixanthone F against a range of microorganisms. We also report the total synthesis of the xanthone skeleton.
Assuntos
Anti-Infecciosos/química , Clusiaceae/química , Flavonoides/química , Flavonoides/farmacologia , Casca de Planta/química , Xantonas/química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Biologia MolecularRESUMO
Two new coumestan glycosides, coumestoside C (1) and coumestoside D (2), were isolated from the stem bark of Cylicodiscus gabunensis Harms. Their structures were established by spectroscopic means and chemical transformations as 9-O-alpha-L-rhamnopyranosyl-3-hydroxy-4-(5'-hydroxy-3'-methylbut-2'E-enyl) coumestan (1) and 9-O-beta-D-galactopyranosyl-3-O- prenyl-4-hydroxycoumestan. Coumestoside C exhibited antimicrobial activity against Proteus vulgaris.
Assuntos
Cumarínicos/química , Fabaceae/química , Glicosídeos/química , Carboidratos/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Glicosídeos/isolamento & purificação , Hidrólise , Testes de Sensibilidade Microbiana , Casca de Planta/química , Extratos Vegetais/química , Caules de Planta/química , Proteus vulgaris/efeitos dos fármacos , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
A 21-year-old female developed severe unremitting intravascular hemolysis following closure of a large patent ductus arteriosus using an Amplatzer duct occluder. Percutaneous deployment of fibered platinum coils within the nitinol wire cage of the Amplatzer duct occluder abolished the residual shunt through the device and resulted in cessation of intravascular hemolysis and reversal of its adverse sequelae.
Assuntos
Cateteres de Demora/efeitos adversos , Permeabilidade do Canal Arterial/complicações , Permeabilidade do Canal Arterial/cirurgia , Hemólise , Adulto , Falha de Equipamento , Feminino , Humanos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Índice de Gravidade de DoençaRESUMO
Thirty-three X-press cementless stems (Depuy) manufactured according to standardized X-rays were inserted from 1992 to 1994. The patients' mean age was 49 (range 15-79) years with a mean follow-up of 32 (+/-6) months. A characteristic radiographic pattern of aseptic loosening with erosion of the medial cortex by the tip of the stem occurred in 28 patients and a valgus shift of the implant in 14 cases. A radiolucent line with increased sclerosis below the tip (zone Gruen 4) was observed in 17 cases. Four stems were revised due to histologically confirmed aseptic loosening. Biomechanical investigation of one of the revised stems with the typical pattern of valgus angulation and medial cortex erosion included photoelasticity and finite-element analysis. The intertrochanteric fit and fill obviously resulted in an unfavorable distribution of contact areas, including peaks of high stress on the medial tip of the stem. These experimental findings are even evident for a postulated rotational stability. The clinical and radiographic results of the cementless X-press stems do not seem to support the fixation concept of intertrochanteric fit and fill of femoral components.
Assuntos
Análise de Elementos Finitos , Prótese de Quadril , Falha de Prótese , Adolescente , Adulto , Idoso , Elasticidade , Humanos , Pessoa de Meia-Idade , Estresse MecânicoRESUMO
The acute response of pig skin to treatment with high energy carbon ions (plateau region) at the Gesellschaft für Schwerionenforschung (GSI, Darmstadt, Germany) was compared with changes after 200 kV x-irradiation. Carbon doses isoeffective to the x-ray doses were computed with a recently established model for calculation of the biological effect of heavy ions. Clinical changes and physiological symptoms (blood flow, erythema, trans-epidermal water loss, skin hydration) were scored. The parameters analyzed were maximum and mean values of each symptom during days 24 to 70 after irradiation, and the quantal endpoints for the establishment of dose effect curves were the median values of these. With exception of the maximum change in the red blood cell concentration (p < 0.02) no significant differences could be found in the response to x-rays and RBE-corrected heavy ions. These results indicate that the model is valid for the calculation of biological effects of 12C-ions (plateau region) and may at least for epidermis be applied to treatment planning.
Assuntos
Lesões Experimentais por Radiação/etiologia , Dermatopatias/etiologia , Pele/efeitos da radiação , Animais , Carbono , Relação Dose-Resposta à Radiação , Íons , Reprodutibilidade dos Testes , Suínos , Porco MiniaturaRESUMO
Bioassay-guided fractionation of a root bark extract of Symphonia globulifera has yielded, in addition to stigmasterol, two new xanthones with isoprenoid units, named globulixanthones A (1) and B (2). The structures of these compounds have been elucidated by spectroscopic means. They possess significant cytotoxicity in vitro against the KB cell line.