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1.
J Pediatr Gastroenterol Nutr ; 78(6): 1342-1354, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38644678

RESUMO

BACKGROUND: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. METHODS: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. FINDINGS: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. INTERPRETATION: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.


Assuntos
Antivirais , Carbamatos , Combinação de Medicamentos , Hepatite C Crônica , Compostos Heterocíclicos de 4 ou mais Anéis , Sofosbuvir , Humanos , Sofosbuvir/uso terapêutico , Sofosbuvir/farmacocinética , Sofosbuvir/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Criança , Carbamatos/uso terapêutico , Carbamatos/farmacocinética , Carbamatos/efeitos adversos , Carbamatos/administração & dosagem , Masculino , Pré-Escolar , Feminino , Antivirais/uso terapêutico , Antivirais/farmacocinética , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Adolescente , Hepatite C Crônica/tratamento farmacológico , Resultado do Tratamento , Hepacivirus/genética , Hepacivirus/efeitos dos fármacos , Resposta Viral Sustentada , Genótipo , Benzimidazóis , Benzopiranos
2.
J Allergy Clin Immunol ; 151(6): 1646-1654, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36716825

RESUMO

BACKGROUND: Increased prevalence of autoantibody Fab glycosylation has been demonstrated for several autoimmune diseases. OBJECTIVES: To study whether elevated Fab glycosylation is a common feature of autoimmunity, this study investigated Fab glycosylation levels on serum IgG and its subclasses for autoantibodies associated with a range of different B cell-mediated autoimmune diseases, including rheumatoid arthritis, myasthenia gravis subtypes, pemphigus vulgaris, antineutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, anti-glomerular basement membrane glomerulonephritis, thrombotic thrombocytopenic purpura, and Guillain-Barré syndrome. METHODS: The level of Fab glycosylated IgG antibodies was assessed by lectin affinity chromatography and autoantigen-specific immunoassays. RESULTS: In 6 of 10 autoantibody responses, in 5 of 8 diseases, the investigators found increased levels of Fab glycosylation on IgG autoantibodies that varied from 86% in rheumatoid arthritis to 26% in systemic lupus erythematosus. Elevated autoantibody Fab glycosylation was not restricted to IgG4, which is known to be prone to Fab glycosylation, but was also present in IgG1. When autoimmune diseases with a chronic disease course were compared with more acute autoimmune illnesses, increased Fab glycosylation was restricted to the chronic diseases. As a proxy for chronic autoantigen exposure, the investigators determined Fab glycosylation levels on antibodies to common latent herpes viruses, as well as to glycoprotein 120 in individuals who are chronically HIV-1-infected. Immunity to these viral antigens was not associated with increased Fab glycosylation levels, indicating that chronic antigen-stimulation as such does not lead to increased Fab glycosylation levels. CONCLUSIONS: These data indicate that in chronic but not acute B cell-mediated autoimmune diseases, disease-specific autoantibodies are enriched for Fab glycans.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Miastenia Gravis , Humanos , Autoanticorpos , Imunoglobulina G , Autoantígenos
3.
J Med Internet Res ; 22(5): e15895, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32412424

RESUMO

BACKGROUND: With the global rise in chronic health conditions, health care is transforming, and patient empowerment is being emphasized to improve treatment outcomes and reduce health care costs. Patient-centered innovations are needed. We focused on patients with chronic myeloid leukemia (CML), a chronic disease with a generally good long-term prognosis because of the advent of tyrosine kinase inhibitors. However, both medication adherence by patients and guideline adherence by physicians are suboptimal, unnecessarily jeopardizing treatment outcomes. OBJECTIVE: The aim of this study was to develop a patient-centered innovation for patients with CML using a design thinking methodology. METHODS: The 5 phases of design thinking (ie, empathize, define, ideate, prototype, and test) were completed, and each phase started with the patient. Stakeholders and end users were identified and interviewed, and observations in the care system were made. Using tools in human-centered design, problems were defined and various prototypes of solutions were generated. These were evaluated by patients and stakeholders and then further refined. RESULTS: The patients desired (1) insights into their own disease; (2) insights into the symptoms experienced, both in terms of knowledge and comprehension; and (3) improvements in the organization of care delivery. A web-based platform, CMyLife, was developed and pilot-tested. It has multiple features, all targeting parts of the bigger solution, including a website with reliable information and a forum, a guideline app, personal medical records with logs of symptoms and laboratory results (including a molecular marker and linked to the guideline app), tailored feedback based on the patients' symptoms and/or results, screen-to-screen consulting, delivery of medication, and the collection of blood samples at home. CONCLUSIONS: The multifeatured innovation, CMyLife, was developed in a multidisciplinary way and with active patient participation. The aim of developing CMyLife was to give patients the tools to monitor their results, interpret these results, and act on them. With this tool, they are provided with the know-how to consider their results in relation to their personal care process. Whether CMyLife achieves its goal and the evaluation of the added value will be the focus of future studies. CML could become the first malignancy for which patients are able to monitor and manage their disease by themselves.


Assuntos
Gerenciamento Clínico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Assistência Centrada no Paciente/métodos , Telemedicina/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
4.
Pharm Res ; 36(7): 93, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044267

RESUMO

INTRODUCTION: In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab. METHODS: 578 subjects were randomized to ibrutinib or placebo with BR (6 cycles). Ibrutinib PK samples and tumor measurements were obtained from all subjects; a subset was evaluated for bendamustine and rituximab PK. Population rituximab PK was assessed using nonlinear mixed-effects modeling. RESULTS: Dose-normalized plasma concentration-time bendamustine data were comparable between the arms. Systemic rituximab exposure was higher with BR-I versus BR; mean trough serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher subsequently. No relevant safety differences were observed. In the modeling, including treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall rituximab clearance significantly improved fitting of the data. CONCLUSIONS: BR-I led to higher dose-normalized systemic rituximab exposure versus BR and more rapid steady-state achievement. The modeling data suggest that rituximab disposition is, at least in part, target mediated. Determining the clinical significance of these findings requires further assessments. TRIAL REGISTRATION: This study is registered at https://clinicaltrials.gov/ct2/show/NCT01611090 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cloridrato de Bendamustina/farmacocinética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/metabolismo , Pirimidinas/metabolismo , Rituximab/farmacocinética , Adenina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/efeitos adversos , Cloridrato de Bendamustina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Piperidinas , Resultado do Tratamento
5.
Ophthalmologica ; 241(3): 143-153, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30227415

RESUMO

PURPOSE: This prospective case series is aimed at exploring optical coherence tomographic angiography (OCT-A) as a treatment monitoring tool in patients treated for retinal angiomatous proliferation (RAP). METHODS: Twelve treatment-naïve RAP patients were included, with a median age of 79 years (range 65-90). Patients were imaged with an experimental 1,040-nm swept-source phase-resolved OCT-A instrument before and after treatment. Treatment consisted of either intravitreal bevacizumab or triamcinolone injections with or without photodynamic therapy (PDT). Abnormal blood flow after treatment was graded as increased, unchanged, decreased, or resolved. RESULTS: OCT-A images before and after treatment could be obtained in 9 patients. The median follow-up period was 10 weeks (range 5-19). After various treatments, the RAP lesion resolved in 7 patients, in 1 patient the OCT-A depicted decreased flow in the lesion, and 1 patient showed unchanged abnormal blood flow. Monotherapy with intravitreal bevacizumab injections resolved RAP in 1 out of 2 patients. Combined therapy of bevacizumab with PDT resolved RAP in 6 out of 7 patients. CONCLUSIONS: OCT-A visualized resolution of abnormal blood flow in 7 out of 9 RAP patients after various short-term treatment sequences. OCT-A may become an important noninvasive monitoring tool for optimizing treatment strategies in RAP patients.


Assuntos
Bevacizumab/administração & dosagem , Angiofluoresceinografia/métodos , Degeneração Macular/tratamento farmacológico , Fotoquimioterapia/métodos , Neovascularização Retiniana/tratamento farmacológico , Tomografia de Coerência Óptica/métodos , Triancinolona/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Fundo de Olho , Glucocorticoides/administração & dosagem , Humanos , Injeções Intravítreas , Degeneração Macular/diagnóstico , Masculino , Fármacos Fotossensibilizantes/uso terapêutico , Estudos Prospectivos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Retina/patologia , Neovascularização Retiniana/diagnóstico , Resultado do Tratamento , Acuidade Visual
6.
Invest New Drugs ; 36(3): 476-486, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29177975

RESUMO

Purpose Trabectedin is metabolized by the liver and has been associated with transient, noncumulative transaminase elevation. Two recent studies further characterize hepatic tolerability with trabectedin therapy: a phase 1 pharmacokinetic study (Study #1004; NCT01273493) in patients with advanced malignancies and hepatic impairment (HI), and a phase 3 study (Study #3007; NCT01343277) of trabectedin vs. dacarbazine in patients with advanced sarcomas and normal hepatic function. Methods In Study #1004, patients received a single 3-h intravenous (IV) infusion of trabectedin: control group, trabectedin 1.3 mg/m2; HI group (baseline total bilirubin >1.5 and ≤3× upper limit of normal [ULN]; AST and ALT ≤2.5× ULN), trabectedin 0.58 or 0.9 mg/m2. In Study #3007, the trabectedin group received 1.5 mg/m2 by 24-h IV infusion every 3 weeks until disease progression or unacceptable toxicity. Results In Study #1004, dose-normalized trabectedin exposure was higher in HI patients (n = 6) versus controls (n = 9) (geometric mean ratios [90% CI] AUClast: 1.97 [1.20; 3.22]). In Study #3007, following trabectedin administration, 90% of patients had elevated ALT (32% grade 3-4) and 84% had elevated AST (17% grade 3-4). Transaminase elevations were transient and noncumulative. Progression-free survival was similar in patients with grade 3-4 hepatotoxicity (n = 109) versus grade 0-2 hepatotoxicity (n = 231) (median [95% CI]: 4.63 [4.01, 5.85] months versus 3.55 [2.73, 4.63] months; P = 0.545, HR = 0.91 [0.68-1.23]). Conclusion Trabectedin treatment of patients with HI results in higher plasma exposures. Hepatotoxicity in patients with normal liver function can be effectively addressed through dose reductions and delays.


Assuntos
Fígado/patologia , Trabectedina/efeitos adversos , Trabectedina/farmacocinética , Adulto , Idoso , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Trabectedina/sangue
7.
Hematol Oncol ; 36(1): 238-244, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28626947

RESUMO

This phase 4, single-arm, non-randomized, open-label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (≥20 years) with measurable secretory multiple myeloma (serum monoclonal IgG ≥10, IgA/IgE ≥5, IgD ≥0.5 g/L, IgM present [regardless of level], and urine M protein of ≥200 mg/24 h) received intravenous bortezomib 1.3 mg/m2 , twice weekly for 2 weeks, followed by a 10-day resting phase (days 12 to 21). Pharmacokinetics and safety were assessed at pre-specified time points. All enrolled patients (n = 18, men: 11; women: 7) completed the study. Mean (SD) Cmax (maximum observed plasma concentration) on day 11 was 266 (77.5) ng/mL, approximately 60% higher compared with non-Asian patients receiving a similar bortezomib regimen but with overlapping ranges. Because of the protracted terminal phase, half-life (t1/2 ), area under the plasma concentration-time curve from time 0 to infinity (AUC∞ ), volume of distribution (Vz ), and systemic clearance were not assessable. All patients experienced treatment-emergent adverse events (TEAEs); 78% were drug-related. Most commonly reported TEAEs were thrombocytopenia (n = 11 [61%]), neutropenia (n = 9 [50%]), leukopenia (n = 6 [33%]), and diarrhoea (n = 6 [33%]); the most common serious adverse event was pneumonia (n = 2 [11%]). One patient had a dose reduction due to a TEAE of thrombocytopenia. Overall, bortezomib exposure (AUC) in Taiwanese patients (AUClast [SD]: 230 [147] ng·h/mL) with twice weekly intravenous administration was comparable with non-Asian population (AUClast [SD]: 241 [82] ng·h/mL). Bortezomib treatment was associated with manageable toxicity profile and did not limit the continuity of therapy.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Bortezomib/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Taiwan
8.
Eur J Haematol ; 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30058149

RESUMO

OBJECTIVES: To obtain insight into patients' reasons for medication (non)adherence in chronic myeloid leukaemia (CML) and needs and wishes regarding information and communication. METHODS: A mixed-method study on the basis of a questionnaire and semi-structured interviews. The CML patient advocacy group asked patients to participate. RESULTS: Sixty-one patients (54 ± 12 years, 43% male) using imatinib, dasatinib or nilotinib participated. Fifteen patients (25%) reported to miss an intake at least once a month. Most were not worried about missing an intake and did not discuss missed intakes with their healthcare provider (HCP). Social activities disturbing daily routines and the wish to avoid side effects resulted in nonadherence. Patients wanted extensive and understandable information provided timely on all aspects of CML treatment, in particular on side effects, and a more supportive HCP attitude. CONCLUSIONS: Nonadherence to CML medication does not cause concern in all patients and is not discussed pro-actively. HCP have a clear role in supporting medication adherence in CML and must be aware that social activities disturbing daily routines contribute to nonadherence. HCP should discuss (non)adherence in a direct manner, motivate patients to play an active role in managing their medication and timely provide extensive and understandable information on all aspects of CML.

9.
Eur J Immunol ; 46(3): 762-71, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26626052

RESUMO

Inefficient clearance of apoptotic cells and the subsequent exposure of the immune system to nuclear contents are crucially involved in the pathogenesis of systemic lupus erythematosus (SLE). Factor VII-activating protease (FSAP) is activated in serum upon contact with dead cells, and releases nucleosomes from late apoptotic cells into the extracellular environment. We investigated whether FSAP-mediated nucleosome release from late apoptotic cells is affected in SLE patients. Nucleosome release in sera of 27 SLE patients and 30 healthy controls was investigated by incubating late apoptotic Jurkat cells with serum and analyzing the remaining DNA content by flow cytometry. We found that nucleosome release in sera of SLE patients with high disease activity was significantly decreased when compared with that in SLE sera obtained during low disease activity or from healthy individuals. Upon removal of IgG/IgM antibodies from SLE sera, nucleosome release was restored. Similarly, monoclonal antinuclear antibodies inhibited nucleosome release in healthy donor serum or by plasma-purified FSAP. This inhibition was lost when Fab fragments were used, suggesting that antigen cross-linking is involved. In conclusion, FSAP-mediated nucleosome release from late apoptotic cells is greatly impaired in SLE patient sera, possibly hampering the clearance of these cells and thereby propagating inflammation.


Assuntos
Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Nucleossomos/metabolismo , Serina Endopeptidases/fisiologia , Adolescente , Adulto , Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais/imunologia , Apoptose/fisiologia , Feminino , Humanos , Imunoglobulina G , Imunoglobulina M/deficiência , Inflamação/etiologia , Inflamação/imunologia , Células Jurkat , Masculino , Pessoa de Meia-Idade , Nucleossomos/imunologia , Serina Endopeptidases/imunologia , Soro/química , Adulto Jovem
10.
Ophthalmology ; 124(10): 1510-1522, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28499747

RESUMO

PURPOSE: Traditionally, preoperative posturing consisting of bed rest and positioning is prescribed to patients with macula-on retinal detachment (RD) to prevent RD progression and detachment of the fovea. Execution of such advice can be cumbersome and expensive. This study aimed to investigate if preoperative posturing affects the progression of RD. DESIGN: Prospective cohort study. PARTICIPANTS: Ninety-eight patients with macula-on RD were included. Inclusion criteria were volume optical coherence tomography (OCT) scans could be obtained with sufficient quality; and the smallest distance from the fovea to the detachment border was 1.25 mm or more. METHODS: Patients were admitted to the ward for bed rest in anticipation of surgery and were positioned on the side where the RD was mainly located. At baseline and before and after each interruption for meals or toilet visits, a 37°×45° OCT volume scan was performed using a wide-angle Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany). The distance between the nearest point of the RD border and fovea was measured using a custom-built measuring tool. MAIN OUTCOME MEASURES: The RD border displacement and the average RD border displacement velocity moving toward (negative) or away (positive) from the fovea were determined for intervals of posturing and interruptions. RESULTS: The median duration of intervals of posturing was 3.0 hours (interquartile range [IQR], 1.8-14.0 hours; n = 202) and of interruptions 0.37 hours (IQR, 0.26-0.50 hours; n = 197). The median RD border displacement was 2 µm (IQR, -65 to +251 µm) during posturing and -61 µm (IQR, -140 to 0 µm) during interruptions, a statistically significant difference (P < 0.001, Mann-Whitney U test). The median RD border displacement velocity was +1 µm/hour (IQR, -21 to +49 µm/hour) during posturing and -149 µm/hour (IQR, -406 to +1 µm/hour) during interruptions, a statistically significant difference (P < 0.001). CONCLUSIONS: By making use of usual interruptions of preoperative posturing we were able to show, in a prospective and ethically acceptable manner, that RD stabilizes during posturing and progresses during interruptions in patients with macula-on RD. Preoperative posturing is effective in reducing progression of RD.


Assuntos
Repouso em Cama , Fóvea Central/patologia , Postura , Cuidados Pré-Operatórios/métodos , Descolamento Retiniano/diagnóstico , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Descolamento Retiniano/cirurgia , Recurvamento da Esclera , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia
11.
Br J Clin Pharmacol ; 81(2): 235-45, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26382728

RESUMO

AIMS: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is used in the treatment of mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib undergoes extensive rapid oxidative metabolism mediated by cytochrome P450 3A both at the level of first pass and clearance, which might result in low oral bioavailability. The present study was designed to investigate the absolute bioavailability (F) of ibrutinib in the fasting and fed state and assess the effect of grapefruit juice (GFJ) on the systemic exposure of ibrutinib in order to determine the fraction escaping the gut (Fg ) and the fraction escaping hepatic extraction (Fh ) in the fed state. METHODS: All participants received treatment A [560 mg oral ibrutinib, under fasting conditions], B (560 mg PO ibrutinib, fed, administered after drinking glucose drink) and C (140 mg oral ibrutinib, fed, with intake of GFJ before dosing). A single intravenous (i.v.) dose of 100 µg (13) C6 -ibrutinib was administered 2 h after each oral dose. RESULTS: The estimated 'F' for treatments A, B and C was 3.9%, 8.4% and 15.9%, respectively. Fg and Fh in the fed state were 47.0% and 15.9%, respectively. Adverse events were mild to moderate in severity (Grade 1-2) and resolved without sequelae by the end of the study. CONCLUSION: The absolute oral bioavailability of ibrutinib was low, ranging from 3.9% in the fasting state to 8.4% when administered 30 min before a standard breakfast without GFJ and 15.9% with GFJ. Ibrutinib was well tolerated following a single oral and i.v. dose, under both fasted and fed conditions and regardless of GFJ intake status.


Assuntos
Antineoplásicos/farmacocinética , Citrus paradisi/química , Interações Alimento-Droga , Sucos de Frutas e Vegetais , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Adenina/análogos & derivados , Administração Oral , Adolescente , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Área Sob a Curva , Disponibilidade Biológica , Isótopos de Carbono , Estudos Cross-Over , Relação Dose-Resposta a Droga , Jejum , Feminino , Voluntários Saudáveis , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Piperidinas , Pirazóis/administração & dosagem , Pirazóis/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Fatores de Tempo , Adulto Jovem
12.
Retina ; 36(5): 914-25, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26807631

RESUMO

PURPOSE: Current management of submacular hemorrhage (SMH) favors vitrectomy and gas with subretinal administration of recombinant tissue plasminogen activator (rtPA) over mere intravitreal rtPA injections and gas. In this study, we aimed to compare the effectiveness of both treatment modalities to displace submacular blood. METHODS: Twenty-four patients with SMH secondary to age-related macular degeneration were included. The SMH had to exist ≤14 days at time of surgery and SMH thickness had to be between 250 µm and 1,250 µm. Patients were randomized to either intravitreal injections of rtPA, perfluoropropane (C3F8) gas, and bevacizumab (n = 12) or vitrectomy with subretinal rtPA administration, intravitreal C3F8 gas, and bevacizumab (n = 12). The SMH volume change was measured on spectral domain optical coherence tomography postoperatively within a 2.5-mm cylinder centered at the fovea. RESULTS: Median relative volume reduction of subretinal blood at 6 weeks postoperatively was 97% (95% confidence interval: 91-99%) in the intravitreal rtPA group and 100% (95-100%) in the subretinal rtPA group and did not differ significantly between groups (P = 0.56). CONCLUSION: Both treatment modalities effectively displaced SMH in this exploratory clinical trial. To more definitely study the noninferiority of intravitreal rtPA with gas to subretinal rtPA, vitrectomy with gas, a larger clinical trial would be necessary.


Assuntos
Tamponamento Interno , Fibrinolíticos/administração & dosagem , Fluorocarbonos/administração & dosagem , Hemorragia Retiniana/terapia , Ativador de Plasminogênio Tecidual/administração & dosagem , Degeneração Macular Exsudativa/terapia , Doença Aguda , Terapia Combinada , Humanos , Injeções Intraoculares , Injeções Intravítreas , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Hemorragia Retiniana/diagnóstico , Hemorragia Retiniana/etiologia , Hemorragia Retiniana/fisiopatologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Vitrectomia , Degeneração Macular Exsudativa/complicações , Degeneração Macular Exsudativa/diagnóstico , Degeneração Macular Exsudativa/fisiopatologia
13.
J Cardiothorac Vasc Anesth ; 30(5): 1190-5, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27493093

RESUMO

OBJECTIVE: This study investigated postoperative hemostasis of patients subjected to conventional protamine dosing compared with protamine dosing based on a pharmacokinetic (PK) model following cardiopulmonary bypass. DESIGN: Retrospective case-control study. SETTING: Tertiary university hospital. PARTICIPANTS: Patients undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: In 56 patients, protamine was dosed in a fixed ratio (CD), while 62 patients received protamine based on the PK model. MEASUREMENTS AND MAIN RESULTS: There was no difference in heparin administration (414±107 mg (CD) v 403±90 mg (PK); p = 0.54), whereas protamine dosing was considerably different with a protamine-to-heparin dosing ratio of 1.1±0.3 for the CD group and 0.5±0.1 for the PK group (p<0.001). The changes in activated coagulation time (ΔACT) values (ACT after protamine minus preoperative ACT;+17±77 s v+6±15 s; p = 0.31) were equal between groups. Yet, the thromboelastometric intrinsically activated coagulation test clotting time (CT; 250±76 s v 203±44 s; p<0.001) and intrinsically activated coagulation test without the heparin effect CT (275±105 v 198±32 s; p<0.001) were prolonged in the CD group. Median packed red blood cell transfusion (0 [0-2] v 0 [0-0]), fresh frozen plasma transfusion (1 [0-2] v 0 [0-0]), and platelet concentrate transfusion (0 [0-1] v 0 [0-0]) were different between the fixed ratio and PK group, respectively (all p<0.001). CONCLUSIONS: This study showed that patient-tailored protamine dosing based on a PK model was associated with a reduction in protamine dosing, with better hemostatic test results when compared with fixed-ratio protamine dosing.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Antagonistas de Heparina/farmacocinética , Cuidados Pós-Operatórios/métodos , Protaminas/farmacocinética , Idoso , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea/estatística & dados numéricos , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Estudos Retrospectivos , Tromboelastografia/efeitos dos fármacos
14.
J Virol ; 88(5): 2844-57, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24371052

RESUMO

UNLABELLED: Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. These viruses evolve continuously by reassortment and genomic evolution. Antigenic drift is the cause for the need to update influenza vaccines frequently. Using two data sets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that influenza A(H3N2) virus evolution can be mapped to 13 antigenic clusters. Here we analyzed the full genomes of 286 influenza A(H3N2) viruses from these two data sets to investigate the genomic evolution and reassortment patterns. Numerous reassortment events were found, scattered over the entire period of virus circulation, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Furthermore, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including those of the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitutions were most pronounced for the hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1, and nonstructural protein 1. This study of genotype in relation to antigenic phenotype throughout the period of circulation of human influenza A(H3N2) viruses leads to a better understanding of the evolution of these viruses. IMPORTANCE: Each winter, influenza virus infects approximately 5 to 15% of the world's population, resulting in significant morbidity and mortality. Influenza A(H3N2) viruses evolve continuously by reassortment and genomic evolution. This leads to changes in antigenic recognition (antigenic drift) which make it necessary to update vaccines against influenza A(H3N2) viruses frequently. In this study, the relationship of genetic evolution to antigenic change spanning the entire period of A(H3N2) virus circulation was studied for the first time. The results presented in this study contribute to a better understanding of genetic evolution in correlation with antigenic evolution of influenza A(H3N2) viruses.


Assuntos
Evolução Molecular , Genoma Viral , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/epidemiologia , Vírus Reordenados/genética , Substituição de Aminoácidos , Códon , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , História do Século XX , História do Século XXI , Humanos , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/história , Fases de Leitura Aberta , Filogenia , Vírus Reordenados/imunologia , Recombinação Genética , Seleção Genética , Proteínas Virais/genética , Proteínas Virais/imunologia
15.
Drug Metab Dispos ; 43(2): 289-97, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25488930

RESUMO

The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of ¹4C-labeled ibrutinib. The mean (S.D.) cumulative excretion of radioactivity of the dose was 7.8% (1.4%) in urine and 80.6% (3.1%) in feces with <1% excreted as parent ibrutinib. Only oxidative metabolites and very limited parent compound were detected in feces, and this indicated that ibrutinib was completely absorbed from the gastrointestinal tract. Metabolism occurred via three major pathways (hydroxylation of the phenyl (M35), opening of the piperidine (M25 and M34), and epoxidation of the ethylene on the acryloyl moiety with further hydrolysis to dihydrodiol (PCI-45227, and M37). Additional metabolites were formed by combinations of the primary metabolic pathways or by further metabolism. In blood and plasma, a rapid initial decline in radioactivity was observed along with long terminal elimination half-life for total radioactivity. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) for total radioactivity were higher in plasma compared with blood. The main circulating entities in blood and plasma were M21 (sulfate conjugate of a monooxidized metabolite on phenoxyphenyl), M25, M34, M37 (PCI-45227), and ibrutinib. At Cmax of radioactivity, 12% of total radioactivity was accounted for by covalent binding in human plasma. More than 50% of total plasma radioactivity was attributed to covalently bound material from 8 hours onward; as a result, covalent binding accounted for 38% and 51% of total radioactivity AUC(0-24 h) and AUC(0-72 h), respectively. No effect of CYP2D6 genotype was observed on ibrutinib metabolism. Ibrutinib was well-tolerated by healthy participants.


Assuntos
Antineoplásicos/farmacocinética , Absorção Intestinal , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Adenina/análogos & derivados , Adenina/análise , Adenina/sangue , Adenina/urina , Administração Oral , Adulto , Tirosina Quinase da Agamaglobulinemia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/análise , Biotransformação , Radioisótopos de Carbono , Fezes/química , Meia-Vida , Humanos , Hidrólise , Hidroxilação , Eliminação Intestinal , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Oxirredução , Piperidinas , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/análise , Proteínas Tirosina Quinases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/análise , Pirazóis/sangue , Pirazóis/urina , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/análise , Eliminação Renal
16.
Transfusion ; 55(4): 832-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25394209

RESUMO

BACKGROUND: Anti-SSA autoantibodies are among the most frequently detected autoantibodies and have traditionally been associated with Sjögren's syndrome (SjS) and systemic lupus erythematosus. The unexpected finding of anti-SSA antibodies in a patient with common variable immunodeficiency disorder (CVID) treated with intravenous immunoglobulin (IVIG), who developed discoid lupus erythematosus, prompted us to investigate the presence of anti-SSA antibodies in IVIG preparations. Since anti-SSA antibodies may be present in apparently healthy individuals without overt autoimmune features, IVIG preparations may also contain anti-SSA antibodies. STUDY DESIGN AND METHODS: IVIG consists of polyclonal immunoglobulin G isolated from the plasma of more than 1000 blood donors. Several IVIG batches from different suppliers and serum samples of patients receiving these IVIG products were tested for the presence of anti-nuclear antibodies (ANAs) and extractable nuclear antibodies (ENAs). In addition, we tested several plasma pools for the presence of anti-SSA and subsequent serum samples of individual donors. RESULTS: Several CVID-patients receiving IVIG tested positive for ANA and anti-SSA. The IVIG products administered also contained clearly detectable concentrations of these antibodies. The frequency of apparently healthy blood donors with anti-SSA positivity was 0.69% and one of 1894 donors (0.05%) showed a very high titer of anti-SSA of more than 10,000 U/mL. CONCLUSION: Anti-SSA is present in IVIG products and in blood donors without clinical symptoms. IVIG replacement can interfere with ANA and ENA serology by passive transfer of autoantibodies. We hypothesize that such autoantibodies may be causally related to disease manifestations in some recipients.


Assuntos
Anticorpos Antinucleares/sangue , Autoantígenos/imunologia , Doadores de Sangue , Imunodeficiência de Variável Comum/terapia , Imunoglobulinas Intravenosas/efeitos adversos , Lúpus Eritematoso Discoide/etiologia , Ribonucleoproteínas/imunologia , Adulto , Idoso , Feminino , Humanos , Imunoglobulinas Intravenosas/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Transgend Health ; 9(1): 46-52, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38312459

RESUMO

Purpose: Transgender women are disproportionately affected by HIV and are underutilizing preexposure prophylaxis (PrEP). The lower uptake of PrEP by transgender women may be, in part, owing to the perception that taking PrEP may lower the efficacy of gender-affirming hormone therapy (GAHT) or to provider concerns that GAHT may lower the efficacy of PrEP. Methods: DISCOVER was a randomized, double-blind, noninferiority trial comparing emtricitabine (FTC, F) and tenofovir alafenamide (F/TAF) versus emtricitabine and tenofovir disoproxil fumarate (F/TDF) as PrEP among transgender women and cisgender men who have sex with men (MSM). This nested substudy of the DISCOVER trial compared the exposure of the active intracellular metabolites of FTC and tenofovir (TFV), FTC triphosphate (FTC-TP) and TFV diphosphate (TFV-DP), in peripheral blood mononuclear cells (PBMC) among transgender women receiving GAHT versus MSM within the F/TAF and F/TDF groups. Results: Our results demonstrate that TFV-DP and FTC-TP levels in PBMC were comparable between transgender women on GAHT and MSM receiving F/TAF, and between transgender women on GAHT and MSM receiving F/TDF. TFV-DP concentrations remained above the EC90 of 40 fmol/106 cells across all groups. No clinically significant drug-drug interactions of GAHT were observed with either F/TAF or F/TDF in this subanalysis. Conclusions: These findings are consistent with the clinical pharmacology of GAHT, FTC, TDF, and TAF reported in previous studies, and support the continued use of F/TAF and F/TDF for PrEP in transgender women.Clinicaltrials.gov registration number: NCT02842086.

18.
Int J Lang Commun Disord ; 48(4): 382-93, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23889834

RESUMO

Both children with specific language impairment (SLI) and children who acquire a second language (L2) make errors with verb inflection. This overlap between SLI and L2 raises the question if verb inflection can discriminate between L2 children with and without SLI. In this study we addressed this question for Dutch. The secondary goal of the study was to investigate variation in error types and error profiles across groups. Data were collected from 6-8-year-old children with SLI who acquire Dutch as their first language (L1), Dutch L1 children with a typical development (TD), Dutch L2 children with SLI, and Dutch L1 TD children who were on average 2 years younger. An experimental elicitation task was employed that tested use of verb inflection; context (3SG, 3PL) was manipulated and word order and verb type were controlled. Accuracy analyses revealed effects of impairment in both L1 and L2 children with SLI. However, individual variation indicated that there is no specific error profile for SLI. Verb inflection use as measured in our study discriminated fairly well in the L1 group but classification was less accurate in the L2 group. Between-group differences emerged furthermore for certain types of errors, but all groups also showed considerable variation in errors and there was not a specific error profile that distinguished SLI from TD.


Assuntos
Transtornos do Desenvolvimento da Linguagem/diagnóstico , Testes de Linguagem , Multilinguismo , Fonética , Semântica , Criança , Linguagem Infantil , Diagnóstico Diferencial , Feminino , Humanos , Idioma , Masculino , Fala , Vocabulário
19.
Case Rep Ophthalmol ; 14(1): 546-554, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37901641

RESUMO

The surgical treatment of intraretinal juxtapapillary retinal hemangioblastomas (JRHs) was previously contraindicated because of the significant risk of collateral damage to the macula and optic nerve. This case report discusses the effectiveness and safety of a novel surgical technique using intraocular bipolar diathermy forceps to coagulate feeder and draining blood vessels of an intraretinal JRH. The patient suffered from bilateral retinal hemangioblastomas with loss of visual function in one eye and the development of an intraretinal JRH in the other eye. Despite intensive treatment with intravitreal bevacizumab and subconjunctival triamcinolone acetonide, growth of the intraretinal JRH continued, macular exudation worsened, and visual acuity decreased. Surgical treatment was undertaken in which, first, the feeder and draining vessels of the JRH were identified by comparing the retinal imaging of the JRH with the imaging before the emergence of the JRH 4 years earlier. Then, retinal incisions were made above the blood vessels and parallel to the nerve fibers during a pars plana vitrectomy. Lastly, these vessels were lifted above the retinal surface and coagulated using intraocular diathermy forceps. Postoperatively, macular edema reduced, and visual acuity increased and remained stable for about 6 months. Using intraocular diathermy forceps, this case report demonstrates effective and safe intraretinal JRH blood vessel coagulation above the retinal surface. This novel surgical approach was able to delay the deterioration of visual acuity due to tumor growth and exudation in this patient. This suggests that coagulation with intraocular diathermy forceps can be considered an additional surgical treatment option for JRHs, especially those with an intraretinal growth pattern.

20.
Mol Microbiol ; 81(6): 1433-45, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21815946

RESUMO

Mushrooms represent the most conspicuous structures of fungi. Their development is being studied in the model basidiomycete Schizophyllum commune. The genome of S. commune contains 472 genes encoding predicted transcription factors. Of these, fst3 and fst4 were shown to inhibit and induce mushroom development respectively. Here, we inactivated five additional transcription factor genes. This resulted in absence of mushroom development (in the case of deletion of bri1 and hom2), in arrested development at the stage of aggregate formation (in the case of c2h2) and in the formation of more but smaller mushrooms (in the case of hom1 and gat1). Moreover, strains in which hom2 and bri1 were inactivated formed symmetrical colonies instead of irregular colonies like the wild type. A genome-wide expression analysis identified several gene classes that were differentially expressed in the strains in which either hom2 or fst4 was inactivated. Among the genes that were downregulated in these strains were c2h2 and hom1. Based on these results, a regulatory model of mushroom development in S. commune is proposed. This model most likely also applies to other mushroom-forming fungi and will serve as a basis to understand mushroom formation in nature and to enable and improve commercial mushroom production.


Assuntos
Agaricales/crescimento & desenvolvimento , Agaricales/genética , Regulação Fúngica da Expressão Gênica , Schizophyllum/crescimento & desenvolvimento , Schizophyllum/genética , Fatores de Transcrição/metabolismo , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Genes Fúngicos , Modelos Biológicos , Fatores de Transcrição/genética
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