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2.
Phys Chem Chem Phys ; 21(40): 22584-22588, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31589235

RESUMO

During molecular processes, protein flexibility is a fundamental property allowing protein-protein interaction. Following structural changes during these interactions is then of crucial interest. Site-Directed Spin Labeling (SDSL) combined to EPR spectroscopy is a powerful technique to follow structural modifications within proteins and during protein-protein interactions. Usual nitroxide labels target cysteine residues and afford a 3-line spectrum, whose shape is informative of the structural environment of the label. However, it is not possible to probe two regions of a protein or two partner proteins at the same time because of the overlapping of EPR signatures. Previously, we reported the design and the characterization of a spin label based on a ß-phosphorylated (PP) nitroxide yielding a 6-line spectrum. Here, we report the use of two labels with different EPR signatures, namely maleimido-proxyl (P) and PP, to follow structural changes during a protein-protein interaction process in one single experiment. As a model system, we chose a disordered protein that undergoes an induced α-helical folding upon binding to its partner. We show that the EPR spectrum of a mixture of labeled interacting proteins can be analyzed in terms of structural changes during the interaction. This study represents an important step forward in the extension of the panoply of SDSL-EPR approaches.

3.
Magn Reson Chem ; 55(8): 714-719, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28078740

RESUMO

Site-directed spin labeling (SDSL) combined with continuous wave electron paramagnetic resonance (cw EPR) spectroscopy is a powerful technique to reveal, at the residue level, structural transitions in proteins. SDSL-EPR is based on the selective grafting of a paramagnetic label on the protein under study, followed by cw EPR analysis. To extract valuable quantitative information from SDSL-EPR spectra and thus give reliable interpretation on biological system dynamics, numerical simulations of the spectra are required. Such spectral simulations can be carried out by coding in MATLAB using functions from the EasySpin toolbox. For non-expert users of MATLAB, this could be a complex task or even impede the use of such simulation tool. We developed a graphical user interface called SimLabel dedicated to run cw EPR spectra simulations particularly coming from SDSL-EPR experiments. Simlabel provides an intuitive way to visualize, simulate, and fit such cw EPR spectra. An example of SDSL-EPR spectra simulation concerning the study of an intrinsically disordered region undergoing a local induced folding is described and discussed. We believe that this new tool will help the users to rapidly obtain reliable simulated spectra and hence facilitate the interpretation of their results. Copyright © 2017 John Wiley & Sons, Ltd.

4.
Eur J Obstet Gynecol Reprod Biol ; 210: 94-101, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27984749

RESUMO

The optimal management of ureteral endometriosis (UE) is not yet well defined. The choice on surgical approach and type of procedure has been based both on surgeons' experience and the location and depth of the lesion. The aim of this study was to review evidence about laparoscopic management of ureteral endometriosis, including preoperative evaluation, surgical details and postoperative follow-up. PubMed Central and SCOPUS databases were searched to identify studies reporting cases of laparoscopically managed ureteral endometriosis and including data regarding preoperative findings, surgical interventions and postoperative follow-up. Two sets of MeSH terms were used: 1) "laparoscopy", "endometriosis" and "ureter"; 2) "laparoscopy", "endometriosis" and "urinary tract". Databases were searched for articles published since 1996, in English, French, Spanish and Portuguese, without restrictions regarding study design. Studies reporting surgical approaches other than conventional laparoscopy were excluded, as were case reports and case studies including fewer than 5 cases. From 327 studies obtained through database searching, 18 articles were finally included in this review, including a total of 700 patients with ureteral endometriosis. 57% of patients had at least one previous surgery for endometriosis. Preoperative evidence of significant hydroureter/hydronephrosis was found in 324 of 671 (48.3%) patients. Dysmenorrhea (81.4%), pelvic pain (70.2%) and dyspareunia (66.4%) were the presenting symptoms more commonly reported by the patients. Most patients presented no symptoms specific to the urinary tract. Ureteral endometriosis was more frequent in the left ureter (53.6%) and it was bilateral in 10.6% of cases. Ureterolysis alone was considered a sufficient procedure in 579 of 668 patients (86.7%), and in the remaining 89 patients ureteral resection was necessary. Rectovaginal and uterosacral involvement was present in 58.8% and 47.9% of patients, respectively. Concomitant ureteral and bladder endometriosis was described in 19.8% of patients. Only 6 studies reported cases of accidental ureteral injuries, in 1-24% of patients. Cases of conversion to laparotomy are reported in only 6 studies, in 3-6,7% of patients. Major postoperative complications occurred in 21 out of 682 patients (3.2%). The need for reoperation during follow-up period because of ureteral endometriosis persistence or recurrence was 3.9%. When performed in specialized centers, laparoscopic ureterolysis showed to be a feasible and safe procedure, with a low risk of complications and with satisfactory long-term results. This conservative approach may be used as the initial treatment option in most patients with ureteral endometriosis.


Assuntos
Endometriose/cirurgia , Procedimentos Cirúrgicos em Ginecologia , Laparoscopia , Doenças Ureterais/cirurgia , Feminino , Humanos
5.
J Antimicrob Chemother ; 67(11): 2725-30, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22833639

RESUMO

OBJECTIVES: Posaconazole is an extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis. The marketed oral suspension should be taken with food to maximize systemic absorption. A new solid oral tablet has been developed with improved bioavailability that can be administered without regard to food. The aim of this study was to evaluate rising single- and multiple-dose pharmacokinetics, safety and tolerability of the new tablet. METHODS: This was a single-centre, randomized, placebo-controlled, Phase I, rising single- and multiple-dose study of healthy subjects aged 18-65 years who received a posaconazole tablet as 200 mg once daily, 200 mg twice daily or 400 mg once daily. The 24 subjects were studied in two cohorts of 12 subjects each (9 active and 3 placebo). RESULTS: After single or multiple oral dose administration of posaconazole tablets (200 and 400 mg), exposure increased in a dose-related manner. Peak posaconazole concentrations were attained at a median T(max) of 4-5 h. Mean half-life was similar for 200 and 400 mg posaconazole doses (25 and 26 h). The accumulation ratio upon multiple doses over 8 days was ∼3 for 200 and 400 mg once daily and ∼5 for 200 mg twice daily. C(avg) values exceeded 1300 ng/mL. The posaconazole oral tablet was safe and well tolerated, although mild, transient elevations in liver function were reported in some patients. CONCLUSIONS: Posaconazole exposure increased in a dose-related manner. The pharmacokinetics of this new solid oral tablet of posaconazole supports the clinical evaluation of once-daily dosing regimens for fungal infections.


Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Comprimidos/administração & dosagem , Triazóis/efeitos adversos , Triazóis/farmacocinética , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Comprimidos/efeitos adversos , Comprimidos/farmacocinética , Triazóis/administração & dosagem
7.
Biophys J ; 98(10): 2170-8, 2010 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-20483325

RESUMO

This article explores the role of some geometrical factors on the electrophoretically driven translocations of macromolecules through nanopores. In the case of asymmetric pores, we show how the entry requirements and the direction of translocation can modify the information content of the blocked ionic current as well as the transduction of the electrophoretic drive into a mechanical force. To address these effects we studied the translocation of single-stranded DNA through an asymmetric alpha-hemolysin pore. Depending on the direction of the translocation, we measure the capacity of the pore to discriminate between both DNA orientations. By unzipping DNA hairpins from both sides of the pores we show that the presence of single strand or double strand in the pore can be discriminated based on ionic current levels. We also show that the transduction of the electrophoretic drive into a denaturing mechanical force depends on the local geometry of the pore entrance. Eventually we discuss the application of this work to the measurement of energy barriers for DNA unzipping as well as for protein binding and unfolding.


Assuntos
Transporte Biológico/fisiologia , DNA de Cadeia Simples/fisiologia , DNA/fisiologia , Desnaturação de Ácido Nucleico/genética , DNA/química , DNA de Cadeia Simples/química , Nanoestruturas , Nanotecnologia , Conformação de Ácido Nucleico , Porosidade
8.
J Acquir Immune Defic Syndr ; 51(4): 437-44, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19623694

RESUMO

BACKGROUND: Patients with HIV/AIDS are at increased risk for opportunistic fungal infections. These patients may require concomitant treatment with antiretrovirals and azole antifungals, and interactions between these classes of drugs should be anticipated. METHODS: A phase 1, open-label, randomized, crossover, drug interaction study was conducted to assess the pharmacokinetic effects of coadministration of posaconazole (400 mg twice daily), with atazanavir (ATV) (300 mg/d alone) and with ritonavir (100 mg/d) or with efavirenz (400 mg/d) in healthy volunteers. RESULTS: Posaconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of ATV by 2.6-fold and 3.7-fold, respectively. Posaconazole increased ATV Cmax and AUC when administered with ritonavir by 1.5-fold and 2.5-fold, respectively. Most subjects who received ATV (with and without ritonavir) and posaconazole experienced clinically relevant increases in total bilirubin. Coadministration of posaconazole and efavirenz resulted in clinically relevant decreases of posaconazole Cmax and AUC of approximately 45% and 50%, respectively. CONCLUSIONS: Frequent monitoring of adverse events and toxicity related to antiviral exposure is recommended in the event of coadministration of posaconazole and ATV with or without ritonavir. In addition, because of decreased posaconazole exposure, coadministration with efavirenz should be avoided unless the benefit to patients outweighs the risk.


Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Benzoxazinas/administração & dosagem , Oligopeptídeos/farmacocinética , Piridinas/farmacocinética , Ritonavir/administração & dosagem , Triazóis/farmacologia , Administração Oral , Adulto , Alcinos , Área Sob a Curva , Sulfato de Atazanavir , Estudos Cross-Over , Ciclopropanos , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Triazóis/administração & dosagem , Triazóis/farmacocinética
9.
Antimicrob Agents Chemother ; 50(2): 658-66, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16436724

RESUMO

The pharmacokinetic profiles, safety, and efficacies of different dosing schedules of posaconazole oral suspension in patients with possible, probable, and proven refractory invasive fungal infection (rIFI) or febrile neutropenia (FN) were evaluated in a multicenter, open-label, parallel-group study. Sixty-six patients with FN and 32 patients with rIFI were randomly assigned to one of three posaconazole regimens: 200 mg four times a day (q.i.d.) for nine doses, followed by 400 mg twice a day (b.i.d.); 400 mg q.i.d. for nine doses, followed by 600 mg b.i.d.; or 800 mg b.i.d. for five doses, followed by 800 mg once a day (q.d.). Therapy was continued for up to 6 months in patients with rIFI or until neutrophil recovery occurred in patients with FN. The 400-mg-b.i.d. dose provided the highest overall mean exposure, with 135% (P = 0.0004) and 182% (P < 0.0001) greater exposure than the 600-mg-b.i.d. and 800-mg-q.d. doses, respectively. However, exposure in allogeneic bone marrow transplant (BMT) recipients (n = 12) was 52% lower than in non-BMT patients. Treatment-related adverse events (occurring in 24% of patients) were mostly gastrointestinal in nature. Twenty-four percent of patients had adverse events leading to premature discontinuation (none were treatment related). In efficacy-evaluable patients, successful clinical response was observed in 43% with rIFI (56% of patients receiving 400 mg b.i.d., 17% receiving 600 mg b.i.d., and 50% receiving 800 mg q.d.) and 77% with FN (74% receiving 400 mg b.i.d., 78% receiving 600 mg b.i.d., and 81% receiving 800 mg q.d.). Posaconazole is well tolerated and absorbed. Divided doses of 800 mg (400 mg b.i.d.) provide the greatest posaconazole exposure.


Assuntos
Antifúngicos/farmacocinética , Febre/tratamento farmacológico , Micoses/tratamento farmacológico , Neutropenia/complicações , Triazóis/farmacocinética , Adulto , Idoso , Transplante de Medula Óssea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Triazóis/efeitos adversos
10.
J Clin Pharmacol ; 45(2): 185-92, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15647411

RESUMO

Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL(CR) = 50-80 mL/min), moderate (CL(CR) = 20-49 mL/min), and severe chronic renal disease (CL(CR) <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400-mg dose of posaconazole oral suspension with a standardized high-fat breakfast. For hemodialysis-dependent subjects, this dose was given on a nonhemodialysis day, and a second 400-mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis-dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, C(max), CL/F, and t1/2 values were not significantly different from zero (P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only approximately 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (approximately 98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single-dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.


Assuntos
Falência Renal Crônica/tratamento farmacológico , Resultado do Tratamento , Triazóis/farmacocinética , Administração Oral , Alanina Transaminase/efeitos dos fármacos , Alanina Transaminase/metabolismo , Área Sob a Curva , Aspartato Aminotransferases/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Disponibilidade Biológica , Creatinina/metabolismo , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacocinética , Esquema de Medicação , Ingestão de Alimentos , Feminino , Meia-Vida , Humanos , Falência Renal Crônica/epidemiologia , Testes de Função Hepática/efeitos adversos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Ligação Proteica/efeitos dos fármacos , Diálise Renal/métodos , Suspensões , Triazóis/administração & dosagem , Triazóis/metabolismo
11.
Gynecol Endocrinol ; 14(4): 245-7, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11075293

RESUMO

Autoimmune progesterone dermatitis is a rare cutaneous disorder characterized by recurrent and cyclic skin eruption with variable morphology, occurring during the luteal phase. A case of autoimmune progesterone urticaria in a 47-year-old woman is reported. An intradermal progestin test revealed a strong reactivity against this hormone. Treatment with tamoxifen and leuprolide acetate induced only a partial remission of urticaria. Bilateral oophorectomy was performed with absolute clearing of cutaneous lesions.


Assuntos
Progesterona/farmacologia , Urticária/induzido quimicamente , Urticária/diagnóstico , Doenças Autoimunes/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Testes Intradérmicos , Pessoa de Meia-Idade , Ovariectomia , Urticária/cirurgia
12.
Arq Gastroenterol ; 24(3-4): 139-45, 1987.
Artigo em Português | MEDLINE | ID: mdl-3505171

RESUMO

The authors present their experience with radionuclide transit in the study of esophageal motility using a very simple and easy technique. They have established a normal pattern and analyse their findings in achalasia and probable diffuse esophageal spasm. They review the literature and submit the method as a very important tool for the diagnosis of esophageal motor disorders.


Assuntos
Acalasia Esofágica/diagnóstico por imagem , Espasmo Esofágico Difuso/diagnóstico por imagem , Esôfago/diagnóstico por imagem , Adulto , Idoso , Junção Esofagogástrica/fisiopatologia , Esôfago/fisiopatologia , Feminino , Trânsito Gastrointestinal , Humanos , Masculino , Pessoa de Meia-Idade , Cintilografia
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