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Improvement of fluconazole flowability and its effect on dissolution from tablets and capsules

CONSIGLIERI, Vladi Olga; MOURÃO, Samanta; SAMPAIO, Mauricio; GRANIZO, Patricia; GARCIA, Pedro; MARTINELLO, Valeska; SPRICIGO, Rodrigo; FERRAZ, Humberto Gomes
Fonte: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Publicador: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas
Tipo: Artigo de Revista Científica
ENG
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37.16%
The aim of this work was to improve fluconazole flowability by wet granulation and to study the effect of granulation on drug dissolution from tablets and capsules. Fluconazole was submitted to a process of wet granulation in a high-speed granulator using Plasdone® K29/32 or K90. Flow properties of granules and dissolution profiles for tablets and capsules produced with them were determined. Fluconazole granules demonstrated better flowability, calculated by angle of repose and compressibility index data, compared with powder. Additionally, it was observed that the granulation process improved the dissolution efficiency (ED) of fluconazole from tablets and capsules, which could also suggest an increase in bioavailability. Higher dissolution efficiencies were achieved with Plasdone® K29/32.; O objetivo deste trabalho foi melhorar as características de fluxo do fluconazol com o emprego da granulação úmida e estudar o efeito desse processo na dissolução do fármaco em cápsulas e comprimidos. O fluconazol foi submetido ao processo de granulação úmida num granulador de alta velocidade empregando Plasdone K29/32 e K90. Foram determinadas as propriedades de fluxo dos grânulos e obtidos os perfis de dissolução de cápsulas e comprimidos obtidos com os granulados em estudo. Os grânulos de fluconazol apresentaram melhores características de fluxo após o processamento...

Electrochemical Behavior and Determination of Fluconazole

GIL, Éric de S.; CORDEIRO, Diogo D.; MATIAS, Ana E. B.; SERRANO, Sílvia H. P.
Fonte: Sociedade Brasileira de Química Publicador: Sociedade Brasileira de Química
Tipo: Artigo de Revista Científica
ENG
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37.09%
The electrochemical behavior of fluconazole showed an irreversible oxidation process, with the electrochemical - chemical mechanism being highly dependent on the electrode material. Adsorption of reagent at positive applied potential was observed at Pt electrode while preferential adsorption of the oxidation products was observed at Glassy Carbon surfaces. In pH below 7.0, the anodic current process was intensively decreased. At carbon paste electrode, the fluconazole oxidation current, recorded in phosphate buffer solution (pH 8.0), changed linearly with the fluconazole concentration, Ipa = 5.7×10-5 (mA) × 0.052 [Fluconazol] (μg mL-1), in the range of 48.0 to 250.0 μg mL-1. The detection limit obtained was 6.3 μg mL-1.; O comportamento eletroquímico do fluconazol demonstrou oxidação irreversível com mecanismos eletroquímicos-químicos dependentes do material eletródico. Em eletrodos de Pt observou-se adsorção do reagente sob a aplicação de potenciais positivos, enquanto adsorção preferencial dos produtos foi observada em eletrodo de carbono vítreo. Em valores de pH inferiores a 7,0, a corrente do processo anódico é intensamente diminuída. Em eletrodo de pasta de carbono e tampão fosfato, pH 8,0, a corrente de oxidação variou linearmente com a concentração de fluconazol em solução...

Seven-year trend analysis of nosocomial candidemia and antifungal (fluconazole and caspofungin) use in Intensive Care Units at a Brazilian University Hospital

GIRAO, E.; LEVIN, A. S.; BASSO, M.; GOBARA, S.; GOMES, L. B.; MEDEIROS, E. A. S.; COSTA, S. F.
Fonte: INFORMA HEALTHCARE Publicador: INFORMA HEALTHCARE
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
37.26%
Candidemia is associated with high morbidity and mortality resulting in significant increases in the length of patients` hospitalization and in healthcare costs. Critically ill patients are at particular risk for candidemia because of their debilitated condition and frequent need for invasive procedures. The aim of this study was to characterize the incidence and epidemiology of candidemia over a seven-year period in intensive care units (ICUs) and the use of fluconazole and caspofungin in a large university-affiliated hospital. All cases of candidemia were identified by surveillance, using the Centers for Diseases Control and Prevention criteria. Demographic variables, use of antifungal (fluconazole and caspofungin) and patient outcomes were evaluated. The 2 test for linear trend was employed to evaluate the distribution of Candida spp. and the use of fluconazole and caspofungin by defined daily dose (DDD) per 1,000 patients-days during the study period. One hundred and eight episodes of candidemia were identified. The overall incidence of candidemia (P=0.20) and incidence of non-Candida albicans Candida infections (P=0.32) remained stable over the study period and ranged from 0.3-0.9 episodes per 1,000 catheter-days and 0.39-0.83 episodes per 1...

Avaliação da bioequivalência de formulações do mercado nacional contendo fluconazol; Evaluation of the bioequivalence of capsules containing 150 mg of fluconazole

Porta, Valentina
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 19/11/1999 PT
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O fluconazol é um fármaco antifúngico utilizado na prevenção e tratamento de infecções micóticas. Atualmente, no mercado brasileiro, vários laboratórios farmacêuticos comercializam produtos a base de fluconazol na forma de cápsulas de 150 mg. Estes produtos são considerados similares e, portanto, teoricamente intercambiáveis, por conterem o mesmo princípio ativo nas mesmas dosagem e forma farmacêutica. No entanto, não existem estudos atestando a bioequivalência entre eles. Pretendeu-se, nesse trabalho, realizar avaliação biofarmacotécnica in vitro (cinética de dissolução) e in vivo (bioequivalência) de duas formulações do mercado nacional contendo fluconazol: Zoltec® 150 mg (laboratórios Pfizer Ltda.), considerado produto referência (R) e Flunazol® 150 mg (Laboratórios Sintofarma S.A.), considerado produto teste (T). Inicialmente, desenvolveu-se método para a análise da cinética de dissolução, já que não existe teste oficial de dissolução para formas farmacêuticas contendo fluconazol. Após padronização do método, avaliou-se a cinética de dissolução de cápsulas de fluconazol provenientes de dois lotes de R e dois lotes de T por meio dos parâmetros ks (constante de velocidade de dissolução) e t85% (tempo necessário para dissolução de 85% do fármaco presente na forma farmacêutica)...

Identificação e análise de mutações no gene ERG11 de isolados de Candida susceptíveis e resistentes ao fluconazol; Identification and analyses of ERG11 gene mutations from fluconazole-susceptible and fluconazole-resistant Candida isolates

Carvalho, Vagner Oliveira
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 31/05/2011 PT
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Por muitos anos o fluconazol tem sido uma opção usual para tratamento de infecções por Candida. Entretanto, o uso indiscriminado desta terapia antimicótica tem favorecido o surgimento de microrganismos resistentes. A redução da afinidade da enzima alvo dos antifúngicos, 14--demetilase (ERG11p), tem sido descrita como um importante mecanismo de resistência, caracterizado por mutações em seu gene codificante ERG11. Neste estudo, foi investigada a suscetibilidade ao fluconazol de 87 isolados de C. albicans, C. tropicalis, C. parapsilosis, C. krusei e C. glabrata, com valores de MIC determinados através do método de microdiluição em caldo M27-A3 (CLSI, 2008); verificou-se que dezessete isolados apresentavam decréscimo da suscetibilidade ao fluconazol. A triagem de mutações foi realizada através da amplificação de quatro regiões do gene ERG11 com primers específicos delineados neste estudo, para cada espécie de Candida, seguida de análise pela técnica de eletroforese SSCP e seqüenciamento automatizado. Foram identificadas 217 mutações, incluindo 185 silenciosas e 32 por troca de sentido (que altera o aminoácido resultante). Estas últimas foram observadas em 19 isolados e 17 resíduos distintos, sendo 7 deles ainda não descritos anteriormente: L321F em C. albicans; K53M em C. krusei; Y221F...

Avaliação da terapia com B(1-3) glucana associada ao fluconazol na criptococose experimental; Evaluation of ß (1-3) glucan therapy associated with fluconazole in experimental cryptococcosis

Faria, Renata Osório de
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Tese de Doutorado Formato: application/pdf
POR
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A Criptococose é uma enfermidade micótica sistêmica, subaguda ou crônica, que acomete a cavidade nasal, tecidos paranasais e pulmões do homem, animais domésticos e silvestres, podendo disseminar-se para o sistema nervoso central, olhos, pele e outros órgãos. Considerando as dificuldades terapêuticas no tratamento da micose em pequenos animais, incluindo toxicidade, desenvolvimento de resistência aos antifúngicos tradicionalmente utilizados e longos períodos de tratamento da enfermidade, o estudo objetivou avaliar a eficácia do imunomodulador ß (1-3) glucana isoladamente e em associação ao fluconazol no tratamento da criptococose experimental. Foram utilizados 100 camundongos (Mus musculus), cepa UFPel, albinos, os quais foram divididos em cinco grupos de 20 animais. O tratamento dos animais com criptococose experimental foi iniciado sete dias após a inoculação. O grupo Controle (G1) foi tratado com 0,1 ml de água destilada estéril, o grupo Fluconazol (G2) com 5 mg/kg de fluconazol, o grupo Fluconazol associado a ß (1-3) glucana (G3) com 5 mg/kg de fluconazol associado a 0,5 mg de ß (1-3) glucana, o grupo Glucana dose I (G4) com 0,5 mg de ß (1-3) glucana e o grupo Glucana dose II (G5) recebeu 0,25 mg de ß (1-3) glucana. Após acompanhamento clínico durante as seis semanas de tratamento os animais foram eutanasiados e necropsiados para avaliação anatomopatológica dos órgãos...

Review of Fluconazole Properties and Analytical Methods for Its Determination

Ruela Correa, Josilene Chaves; Salgado, Hérida Regina Nunes
Fonte: Taylor & Francis Inc Publicador: Taylor & Francis Inc
Tipo: Revisão Formato: 270-279
ENG
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Fluconazole, alpha-(2.4-diflurofenil)-alpha-(1H-triazol-1-methyl)-1H-1,2,4-triazol-1-ethanol, is an antifungal of the triazoles class. It shows activity against species of Candida sp. and it is indicated in cases of oropharyngeal candidiasis, esophageal, vaginal, and deep infection. Fluconazole is a selective inhibitor of ergosterol, a steroid exclusive of the cell membrane of fungal cells. Fluconazole is highly absorbed by the gastrointestinal tract and spreads easily by body fluids. The main adverse reactions related to the use of fluconazole are nausea, vomiting, headache, rash, abdominal pain, diarrhea, and alopecia in patients undergoing prolonged treatment with a dose of 400 mg/day. In the form of raw material, pharmaceutical formulations, or biological material, fluconazole can be determined by methods such as titration, spectrophotometry, and thin-layer, gas, and liquid chromatography. This article discusses the pharmacological and physicochemical properties of fluconazole and also the methods of analysis applied to the determination of the drug.

Review of Fluconazole Properties and Analytical Methods for Its Determination

Ruela Correa, Josilene Chaves; Salgado, Hérida Regina Nunes
Fonte: Taylor & Francis Inc Publicador: Taylor & Francis Inc
Tipo: Revisão Formato: 124-132
ENG
Relevância na Pesquisa
37.26%
Fluconazole, -(2.4-diflurofenil)--(1H-triazol-1-methyl)-1H-1,2,4-triazol-1-ethanol, is an antifungal of triazoles class. It shows activity against species of Candida sp., and it is indicated in cases of oropharyngeal candidiasis, esophageal, vaginal, and deep infection. Fluconazole is a selective inhibitor of ergosterol, a steroid exclusive of the cell membrane of fungal cells. Fluconazole is highly absorbed by the gastrointestinal tract, and it spreads easily by body fluids. The main adverse reactions related to the use of fluconazole are nausea, vomiting, headache, rash, abdominal pain, diarrhea, and alopecia in patients undergoing prolonged treatment with a dose of 400 mg/day. In the form of raw material, pharmaceutical formulations, or biological material, fluconazole can be determined by methods such as titration, spectrophotometry, and thin-layer, gas, and liquid chromatography. This article discusses the pharmacological and physical-chemical properties of fluconazole and also the methods of analysis applied to the determination of the drug.

The resistance to fluconazole in patients with esophageal candidiasis

Wilheim,Ana Botler; Miranda-Filho,Demócrito de Barros; Nogueira,Rodrigo Albuquerque; Rêgo,Rossana Sette de Melo; Lima,Kedma de Magalhães; Pereira,Leila Maria Moreira Beltrão
Fonte: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE ; Colégio Brasileiro de Cirurgia Digestiva - CBCD ; Sociedade Brasileira de Motilidade Digestiva - SBMD ; Federação Brasileira de Gastroenterologia - FBG; Sociedade Brasileira de Hepatologia - SBH; Sociedade Brasileira de Endoscopia Digestiva - SOBED Publicador: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia - IBEPEGE ; Colégio Brasileiro de Cirurgia Digestiva - CBCD ; Sociedade Brasileira de Motilidade Digestiva - SBMD ; Federação Brasileira de Gastroenterologia - FBG; Sociedade Brasileira de Hepatologia - SBH; Sociedade Brasileira de Endoscopia Digestiva - SOBED
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/03/2009 EN
Relevância na Pesquisa
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CONTEXT: Esophageal candidiasis is often observed in patients with risk factors for its development and fluconazole is the therapeutic choice for the treatment of this disease. OBJECTIVES: To determine its frequency, by performing upper digestive endoscopy; to determine Candida species involved in its pathogenesis and verify their distribution according with the predisposing factors and to determine susceptibility to fluconazole in the samples. METHODS: From March 2006 to April 2007, all patients submitted to esophagogastroduodenoscopy at the Digestive Endoscopy Unit in the Oswaldo Cruz University Hospital, Recife, PE, Brazil, were eligible for the study. Samples were collected from patients who presented lesions consistent with esophageal candidiasis in order to identify Candida species and verify their susceptibility to fluconazole. The predisposing factors for the occurrence of esophageal candidiasis were described. RESULTS: Of 2,672 patients referred to upper endoscopy at the Digestive Endoscopy Unit, 40 (1.5%) had endoscopic findings compatible with esophageal candidiasis. The average age was 49.1 years. Twenty one patients (52.5%) were less than 50 years old, of which 82.6% were infected with HIV. Most of them (52.5%) were males and 65.0% were inpatients. Diseases were identified in 90% of the patients and 21 (52.5%) were HIV positive. Concerning endoscopic findings...

The effects of fluconazole and cytokines on human mononuclear cells

Fidan,Isil; Yuksel,Sevgi; Imir,Turgut; Kalkanci,Ayse; Kustimur,Semra; Ilhan,Mustafa N
Fonte: Instituto Oswaldo Cruz, Ministério da Saúde Publicador: Instituto Oswaldo Cruz, Ministério da Saúde
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/03/2007 EN
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Candida infections are common infections and fluconazole is one of the most frequently administered antifungal agents in their treatment. The resistance developed against antifungal agents has necessitated the improvement of new treatments. This study focuses on the investigation of the effect of fluconazole and cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF) on chemokine production and anticandidal activity of human monocytes. In the study it was observed that GM-CSF caused an increase in candidacidal activity of monocytes. Anticandidal activity of GM-CSF + IFN-gamma combination was not found to be more effective than GM-CSF or IFN-gamma alone. The presence of cytokine and fluconazole caused an increase in the levels of CCL3 and CCL4 chemokines. Accordingly, it was considered that chemokines could contribute to the efficacy of fluconazole in C. albicans infections. Besides, in order to strengthen the immune system some cytokines might be used in addition to antifungal agents for the treatment.

Fluconazole susceptibility of Brazilian Candida isolates assessed by a disk diffusion method

Colombo,Arnaldo L.; Matta,Daniel da; Almeida,Leila Paula de; Rosas,Robert
Fonte: Brazilian Society of Infectious Diseases Publicador: Brazilian Society of Infectious Diseases
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2002 EN
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The increasing magnitude of antifungal resistance as well as the advent of new antifungal drugs has generated a renewed interest in fungal susceptibility testing. We used a previously described disk diffusion method to evaluate the susceptibility profile of a large collection of recent clinical Candida spp. isolates against fluconazole. A total of 1,784 yeast isolates were tested, including the following species: Candida albicans (1,036), C. tropicalis (279), C. parapsilosis (202), C. glabrata (119), C. guilliermondii (90), C. krusei (32), C. lusitaniae (7), Candida spp. (14) and other yeasts (5). Susceptibility ranking to fluconazole obtained with all yeasts tested was: C. parapsilosis @ C. tropicalis @ C. guilliermondii > C. glabrata > C. krusei. The majority (94%) of all yeast isolates tested were susceptible to fluconazole. Isolates of C. glabrata and C. krusei exhibited the highest rate of DDS/resistance among all isolates tested but they represented only 9% of all yeasts routinely sent to our lab. Careful periodical surveillance is needed in order to identify any changes in the susceptibility patterns of fluconazole with the increased use of this antifungal agent in Brazilian tertiary care hospitals.

In vitro activities of antifungal agents alone and in combination against fluconazole-susceptible and -resistant strains of Candida dubliniensis

Scheid,Liliane Alves; Mario,Débora Alves Nunes; Kubiça,Thaís Felli; Santurio,Janio Morais; Alves,Sydney Hartz
Fonte: Brazilian Society of Infectious Diseases Publicador: Brazilian Society of Infectious Diseases
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/2012 EN
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In the present study we used two groups of Candida dubliniensis strains: one containing fluconazole-susceptible clinical isolates and another containing fluconazole-resistant laboratory derivative from the former to examine the changes on susceptibility accompanying the development of resistance to fluconazole. Our findings confirmed the ability of C. dubliniensis isolates to become resistant to fluconazole and indicated that this resistance was crossed with ketoconazole, itraconazole, ravuconazole and terbinafine. We also tested combinations of terbinafine, amphotericin B, itraconazole and voriconazole against both groups of isolates in a checkerboard assay. Surprisingly, most combinations evidenced indifferent interactions, and the best synergism appeared when terbinafine and itraconazole were combined against the fluconazole-resistant group.

Mutants with heteroresistance to amphotericin B and fluconazole in Candida

Claudino,A.L.R.; Peixoto Junior,R.F.; Melhem,M.S.C.; Szeszs,M.W.; Lyon,J.P.; Chavasco,J.K.; Franco,M.C.
Fonte: Sociedade Brasileira de Microbiologia Publicador: Sociedade Brasileira de Microbiologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2009 EN
Relevância na Pesquisa
37.29%
Several studies have reported the occurrence of infections caused by Candida yeasts as well as the increasing prevalence of non albicans species. The aim of the present work is focused on the obtaining of heteroresistance to amphotericin B and fluconazole in Candida species using two distinct methodologies: selection and induction. Resistant samples were obtained by selective pressure using a medium with fluconazole for growth, followed by growth in a medium with amphotericin B. The selective pressure was also created beginning with growth in amphotericin B medium followed by growth in fluconazole medium. Concomitantly, samples were submitted to the induction of resistance through cultivation in increasing concentrations of fluconazole, followed by cultivation in increasing concentrations of amphotericin B. Subsequently, the induction began with amphotericin B followed by fluconazole. Three samples resistant to fluconazole and amphotericin B were obtained, two by induction (C. glabrata and C. tropicalis) and one by selection (C. tropicalis). Both C. tropicalis originated from the same wild sample. After successive transfers for drug free medium, only the sample obtained by selection was able to maintain the resistance phenotype. These results suggest that the phenotype of heteroresitance to fluconazole and amphotericin B can be produced by two methodologies: selection and induction.

Improvement of fluconazole flowability and its effect on dissolution from tablets and capsules

Consiglieri,Vladi Olga; Mourão,Samanta; Sampaio,Mauricio; Granizo,Patricia; Garcia,Pedro; Martinello,Valeska; Spricigo,Rodrigo; Ferraz,Humberto Gomes
Fonte: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Publicador: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/03/2010 EN
Relevância na Pesquisa
37.16%
The aim of this work was to improve fluconazole flowability by wet granulation and to study the effect of granulation on drug dissolution from tablets and capsules. Fluconazole was submitted to a process of wet granulation in a high-speed granulator using Plasdone® K29/32 or K90. Flow properties of granules and dissolution profiles for tablets and capsules produced with them were determined. Fluconazole granules demonstrated better flowability, calculated by angle of repose and compressibility index data, compared with powder. Additionally, it was observed that the granulation process improved the dissolution efficiency (ED) of fluconazole from tablets and capsules, which could also suggest an increase in bioavailability. Higher dissolution efficiencies were achieved with Plasdone® K29/32.

Rapid detection of ERG11 gene mutations in clinical Candida albicans isolates with reduced susceptibility to fluconazole by rolling circle amplification and DNA sequencing

Wang, H.; Kong, F.; Sorrell, T.; Wang, B.; McNicholas, P.; Pantarat, N.; Ellis, D.; Xiao, M.; Widmer, F.; Chen, S.
Fonte: BioMed Central Ltd. Publicador: BioMed Central Ltd.
Tipo: Artigo de Revista Científica
Publicado em //2009 EN
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BACKGROUND Amino acid substitutions in the target enzyme Erg11p of azole antifungals contribute to clinically-relevant azole resistance in Candida albicans. A simple molecular method for rapid detection of ERG11 gene mutations would be an advantage as a screening tool to identify potentially-resistant strains and to track their movement. To complement DNA sequencing, we developed a padlock probe and rolling circle amplification (RCA)-based method to detect a series of mutations in the C. albicans ERG11 gene using "reference" azole-resistant isolates with known mutations. The method was then used to estimate the frequency of ERG11 mutations and their type in 25 Australian clinical C. albicans isolates with reduced susceptibility to fluconazole and in 23 fluconazole-susceptible isolates. RCA results were compared DNA sequencing. RESULTS The RCA assay correctly identified all ERG11 mutations in eight "reference" C. albicans isolates. When applied to 48 test strains, the RCA method showed 100% agreement with DNA sequencing where an ERG11 mutation-specific probe was used. Of 20 different missense mutations detected by sequencing in 24 of 25 (96%) isolates with reduced fluconazole susceptibility, 16 were detected by RCA. Five missense mutations were detected by both methods in 18 of 23 (78%) fluconazole-susceptible strains. DNA sequencing revealed that mutations in non-susceptible isolates were all due to homozygous nucleotide changes. With the exception of the mutations leading to amino acid substitution E266D...

Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI Standardized Disk Diffusion

Pfaller, M.; Diekema, D.; Gibbs, D.; Newell, V.; Bijie, H.; Dzierzanowska, D.; Klimko, N.; Letscher-Bru, V.; Lisalova, M.; Muehlethaler, K.; Rennison, C.; Zaidi, M.; Ellis, D.
Fonte: Amer Soc Microbiology Publicador: Amer Soc Microbiology
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
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Fluconazole in vitro susceptibility test results for 256,882 isolates of Candida spp. were collected from 142 sites in 41 countries from June 1997 to December 2007. Data were collected for 197,619 isolates tested with voriconazole from 2001 to 2007. A total of 31 different species of Candida were isolated. Increased rates of isolation of the common non-albicans species C. glabrata (10.2% to 11.7%), C. tropicalis (5.4% to 8.0%), and C. parapsilosis (4.8% to 5.6%) were noted when the time periods 1997 to 2000 and 2005 to 2007 were compared. Investigators tested clinical isolates of Candida spp. by the CLSI M44-A disk diffusion method. Overall, 90.2% of Candida isolates tested were susceptible (S) to fluconazole; however, 13 of 31 species identified exhibited decreased susceptibility (<75% S), similar to that seen with the resistant (R) species C. glabrata and C. krusei. Among 197,619 isolates of Candida spp. tested against voriconazole, 95.0% were S and 3% were R. About 30% of fluconazole-R isolates of C. albicans, C. glabrata, C. tropicalis, C. rugosa, C. lipolytica, C. pelliculosa, C. apicola, C. haemulonii, C. humicola, C. lambica, and C. ciferrii remained S to voriconazole. An increase in fluconazole resistance over time was seen with C. parapsilosis...

In vitro-in vivo extrapolation predicts drug-drug interactions arising from inhibition of codeine glucuronidation by dextropropoxyphene, fluconazole, ketoconazole, and methadone in humans

Raungrut, P.; Uchaipichat, V.; Elliot, D.; Janchawee, B.; Somogyi, A.; Miners, J.
Fonte: Amer Soc Pharmacology Experimental Therapeutics Publicador: Amer Soc Pharmacology Experimental Therapeutics
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
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Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro–in vivo extrapolation approaches were used to identify potential drug–drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant (Km) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S50 values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean Km observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for dextropropoxyphene (3.5 μM)...

Cyclodextrin-crosslinked poly(acrylic acid): Adhesion and controlled release of diflunisal and fluconazole from solid dosage forms

Kutyla, M.; Boehm, M.; Stokes, J.; Shaw, P.; Davies, N.; McGeary, R.; Tuke, S.; Ross, B.
Fonte: Springer New York LLC Publicador: Springer New York LLC
Tipo: Artigo de Revista Científica
Publicado em //2013 EN
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The controlled release of diflunisal and fluconazole from tablets made of novel polymers, poly(acrylic acid) (PAA) crosslinked with either β-cyclodextrin (βCD) or hydroxypropyl-βCD (HPβCD), was investigated and Carbopol 934P (Carbopol) was used as a highly crosslinked PAA for comparison. Diflunisal strongly associates with βCD-PAA and HPβCD-PAA polymers (Ka of 486 and 6,055 M(-1) respectively); thus, it was physically mixed into the conjugates and also precomplexed to identify whether decomplexation has any influence on release kinetics. Fluconazole has poor complexing ability (Ka of 34 M(-1) with HPβCD-PAA); thus, it was only tested as a physical mixture. Swelling and adhesion studies were conducted on all tablet combinations and adhesivity of the CD-PAA polymer tablets was maintained. Diflunisal release was much slower from HPβCD-PAA tablets than from βCD-PAA, suggesting that a higher degree of complexation retards release. The precomplexed diflunisal release was also slower than the physically mixed diflunisal of the corresponding conjugate. The release closely followed zero-order kinetics for HPβCD-PAA, but was more sigmoidal for βCD-PAA and especially Carbopol. Conversely, poorly associating fluconazole released in almost exactly the same way across both polymers and Carbopol...

Einfluss der Fluconazol-Resistenz vermittelnden Expression von MDR1 auf die Expression und Sekretion von Sekretorischen Aspartylproteinasen in Candida albicans; Does Expression of MDR1, important for Resistance against Fluconazole, influences the Expression and Secretion of Secretory Aspartyl Proteinases in Candida albicans?

Schäffler, Holger Dirk
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
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Die Zahl von invasiven Candida albicans Infektionen ist in den letzten Jahren erheblich angestiegen. Die parallel dazu zu beobachtende Resistenzentwicklung insbesondere gegen das gut verträgliche und in Prophylaxe und Therapie breit eingesetzte Fluconazol ist in diesem Zusammenhang von großer klinischer Bedeutung. Für den Erfolg einer Fluconazol-Therapie sind aber nicht allein die MHK-Werte eines Isolates entscheidend, sondern darüber hinaus auch die Virulenz charakterisierende Faktoren. Den wichtigsten Pathogenitätsfaktor von C. albicans stellt die aus 10 Isoenzymen bestehende Familie der Sekretorischen Aspartylproteinasen (SAPs) dar. Ziel dieser Arbeit war es, einen Zusammenhang zwischen Fluconazol-Resistenz vermittelt durch Überexpression des Effluxpumpengens MDR1 und den SAPs sowohl auf RNA-Ebene (Genexpression) als auch auf Protein-Ebene (Enzymaktivität) zu untersuchen. Es wurden sensible Wildtypstämme, durch konstitutive und chemisch induzierte MDR1-Expression resistente Isolate sowie isogene MDR1-negative Mutanten vergleichend geprüft. Die Expression der Zielgene wurde durch RT-PCR bestimmt sowie die extrazelluläre SAP-Aktivität in einem Proteinase-Assay gemessen. Es konnte ein Zusammenhang sowohl zwischen der konstitutiven als auch chemisch induzierten MDR1-Expression und der Expression von Sekretorischen Aspartylproteinasen Typ 1 (SAP1) dargestellt werden. Die sowohl durch konstitutive als auch durch chemisch induzierte MDR1-Expression verstärkte Transkription von SAP1-Genen weist auf eine gemeinsame Regulation der beiden Gene MDR1 und SAP1 durch einen übergeordneten Transkriptionsfaktor hin. Ein Einfluss des Mdr1p auf Transkription und Sekretion von SAP1 konnte dagegen ausgeschlossen werden. Die verschiedenen SAPs werden im Verlaufe einer Infektion zu unterschiedlichen Zeitpunkten produziert und unterliegen einer differenzierten Regulation. Eine veränderte Expression von SAP1 bedingt daher nicht zwangsläufig eine gesteigerte Virulenz eines MDR1-exprimierenden...

Improvement of fluconazole flowability and its effect on dissolution from tablets and capsules

Consiglieri, Vladi Olga; Mourão, Samanta; Sampaio, Mauricio; Granizo, Patricia; Garcia, Pedro; Martinello, Valeska; Spricigo, Rodrigo; Ferraz, Humberto Gomes
Fonte: Universidade de São Paulo. Faculdade de Ciências Farmacêuticas Publicador: Universidade de São Paulo. Faculdade de Ciências Farmacêuticas
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; ; Formato: application/pdf
Publicado em 01/03/2010 ENG
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O objetivo deste trabalho foi melhorar as características de fluxo do fluconazol com o emprego da granulação úmida e estudar o efeito desse processo na dissolução do fármaco em cápsulas e comprimidos. O fluconazol foi submetido ao processo de granulação úmida num granulador de alta velocidade empregando Plasdone K29/32 e K90. Foram determinadas as propriedades de fluxo dos grânulos e obtidos os perfis de dissolução de cápsulas e comprimidos obtidos com os granulados em estudo. Os grânulos de fluconazol apresentaram melhores características de fluxo após o processamento, demonstradas por meio das determinações do ângulo de repouso e do índice de compressibilidade, comparativamente à matéria-prima. Adicionalmente, observou-se que o processo de granulação melhorou a eficiência de dissolução (ED) do fluconazol nos comprimidos e cápsulas.; The aim of this work was to improve fluconazole flowability by wet granulation and to study the effect of granulation on drug dissolution from tablets and capsules. Fluconazole was submitted to a process of wet granulation in a high-speed granulator using Plasdone® K29/32 or K90. Flow properties of granules and dissolution profiles for tablets and capsules produced with them were determined. Fluconazole granules demonstrated better flowability...