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1.
Ann Oncol ; 31(8): 1030-1039, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32339648

RESUMO

BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Anticorpos Monoclonais Humanizados , Axitinibe , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Sunitinibe/uso terapêutico
2.
Dis Esophagus ; 31(1): 1-7, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29155982

RESUMO

The inpatient burden of dysphagia has primarily been evaluated in patients with stroke. It is unclear whether dysphagia, irrespective of cause, is associated with worse clinical outcomes and higher costs compared to inpatients with similar demographic, hospital, and clinical characteristics without dysphagia. The aim of this study is to assess how a dysphagia diagnosis affects length of hospital stay (LOS), costs, discharge disposition, and in-hospital mortality among adult US inpatients. Annual and overall dysphagia prevalence, LOS, hospital charges, inpatient care costs, discharge disposition, and in-hospital mortality were measured using the AHRQ Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (2009-2013). Patients aged 45 years or older with ≤180 days of stay in hospital with and without dysphagia were included. Multivariable survey regression methods with propensity weighting were used to assess associations between dysphagia and different outcomes. Overall, 2.7 of 88 million (3.0%) adult US inpatients had a dysphagia diagnosis (50.2% male, 72.4% white, 74.6% age 65-90 years) and prevalence increased from 408,035 (2.5% of admissions) in 2009 to 656,655 (3.3%) in 2013. After inverse probability of treatment weighting adjustment, mean hospital LOS in patients with dysphagia was 8.8 days (95% CI 8.66-8.90) compared to 5.0 days (95% CI 4.97-5.05) in the non-dysphagia group (P < 0.001). Total inpatient costs were a mean $6,243 higher among those with dysphagia diagnoses ($19,244 vs. 13,001, P < 0.001). Patients with dysphagia were 33.2% more likely to be transferred to post-acute care facility (71.9% vs. 38.7%, P < 0.001) with an adjusted OR of 2.8 (95% CI 2.73-2.81, P < 0.001). Compared to non-cases, adult patients with dysphagia were 1.7 times more likely to die in the hospital (95% CI 1.67-1.74). Dysphagia affects 3.0% of all adult US inpatients (aged 45-90 years) and is associated with a significantly longer hospital length of stay, higher inpatient costs, a higher likelihood of discharge to post-acute care facility, and inpatient mortality when compared to those with similar patient, hospital size, and clinical characteristics without dysphagia. Dysphagia has a substantial health and cost burden on the US healthcare system.


Assuntos
Efeitos Psicossociais da Doença , Transtornos de Deglutição/economia , Transtornos de Deglutição/mortalidade , Custos de Cuidados de Saúde/estatística & dados numéricos , Mortalidade Hospitalar , Hospitalização/economia , Idoso , Feminino , Preços Hospitalares/estatística & dados numéricos , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia
3.
Clin Pharmacol Ther ; 102(6): 1006-1016, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28480503

RESUMO

Aggregate data model-based meta-analysis is a regression approach to compare the dose-response and/or time-course across different treatments using summary level data from the literature. Literature search and systematic review following the Cochrane approach yielded 912 sources for investigational and approved treatments for psoriasis. In addition, data for tofacitinib were obtained from an internal database. Tofacitinib is an oral Janus kinase inhibitor. Two mathematical models were developed for Psoriasis Area and Severity Index (PASI) response in moderate to severe psoriasis patients to quantify the time to maximum effect for PASI75 and to evaluate the dose-response relationship for PASI responders (PASI50, PASI75, PASI90, PASI100) at Week 12. Body weight exhibited an inverse effect on the placebo component of both models, suggesting that body weight affects the overall PASI response regardless of drug. This analysis provides a quantitative framework for efficacy comparisons across psoriasis treatments.


Assuntos
Modelos Estatísticos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Psoríase/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
4.
CPT Pharmacometrics Syst Pharmacol ; 6(5): 322-330, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28317328

RESUMO

Tofacitinib is an oral Janus kinase inhibitor. An integrated analysis was conducted to evaluate dosage optimality for tofacitinib in patients with moderate-to-severe plaque psoriasis and the impact of body weight on optimality in this patient population. Data were pooled from one phase IIb trial (2, 5, and 15 mg twice daily (b.i.d.)) and four phase III trials (5 and 10 mg b.i.d.). A longitudinal exposure-response model for Psoriasis Area and Severity Index (PASI) improvement (percent change from baseline) was established. Body weight influenced potency; heavier subjects require higher doses to achieve comparable benefit to lighter subjects. Disease severity, sex, and prior biologic usage were also predictive of response. The 10 and 5 mg doses were predicted to achieve 81% and 65%, respectively, of the maximum effect based on a 75% improvement in PASI. The greater efficacy of 10 mg over 5 mg was clinically meaningful.


Assuntos
Relação Dose-Resposta a Droga , Inibidores de Janus Quinases/administração & dosagem , Modelos Biológicos , Piperidinas/administração & dosagem , Psoríase/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Administração Oral , Peso Corporal , Método Duplo-Cego , Feminino , Humanos , Inibidores de Janus Quinases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Resultado do Tratamento
5.
Clin Pharmacol Ther ; 101(6): 745-753, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27859030

RESUMO

Extended-release (XR) formulations enable less frequent dosing vs. conventional (e.g., immediate release (IR)) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model-informed, exposure-response (E-R) approach to translate controlled trial data from one formulation to another without a phase III trial, using a tofacitinib case study. Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). E-R analyses were conducted using validated clinical endpoints from phase II dose-response and nonclinical dose fractionation studies of the IR formulation. Consistent with the delay in clinical response dynamics relative to PK, average concentration was established as the relevant PK parameter for tofacitinib efficacy and supported pharmacodynamic similarity. These evaluations, alongside demonstrated equivalence in total systemic exposure between IR and XR formulations, provided the basis for the regulatory approval of tofacitinib XR once daily by the US Food and Drug Administration.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Janus Quinases/antagonistas & inibidores , Modelos Biológicos , Neoplasias/tratamento farmacológico , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Administração Oral , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Área Sob a Curva , Preparações de Ação Retardada , Esquema de Medicação , Aprovação de Drogas , Humanos , Janus Quinases/metabolismo , Masculino , Taxa de Depuração Metabólica , Modelos Animais , Neoplasias/enzimologia , Neoplasias/patologia , Piperidinas/química , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirimidinas/farmacocinética , Pirróis/química , Pirróis/farmacocinética , Ratos Sprague-Dawley , Equivalência Terapêutica , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
6.
Langmuir ; 32(34): 8748-58, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27443165

RESUMO

The classic chemical garden experiment is reconstructed to produce protein-intercalated silicate-phosphate tubules that resemble tubular sponges. The constructs were synthesized by seeding calcium chloride into a solution of sodium silicate-potassium phosphate and gelatin. Sponge-mimetic tubules were fabricated with varying percentages of gelatin (0-15% w/v), in diameters ranging from 200 µm to 2 mm, characterized morphologically and compositionally, functionalized with biomolecules for cell adhesion, and evaluated for cytocompatibility. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy analysis (EDS) experiments showed that the external surface of the tubules was relatively more amorphous in texture and carbon/protein-rich in comparison to the interior surface. Transmission electron microscopy (TEM) images indicate a network composed of gelatin incorporated into the inorganic scaffold. The presence of gelatin in the constructs was confirmed by infrared spectroscopy. Powder X-ray diffraction (XRD) was used to identify inorganic crystalline phases in the scaffolds that are mainly composed of Ca(OH)2, NaCl, and Ca2SiO4 along with a band corresponding to amorphous gelatin. Bioconjugation and coating protocols were developed to program the scaffolds with cues for cell adhesion, and the resulting constructs were employed for 3D cell culture of marine (Pyrocystis lunula) and mammalian (HeLa and H9C2) cell lines. The cytocompatibility of the constructs was demonstrated by live cell assays. We have successfully shown that these biomimetic materials can indeed support life; they serve as scaffolds that facilitate the attachment and assembly of individual cells to form multicellular entities, thereby revisiting the 350-year-old effort to link chemical gardens with the origins of life. Hybrid chemical garden biomaterials are programmable, readily fabricated and could be employed in tissue engineering, biomolecular materials development, 3D mammalian cell culture and by researchers investigating the origins of multicellular life.


Assuntos
Materiais Biocompatíveis/química , Materiais Biomiméticos/química , Gelatina/química , Fosfatos/química , Silicatos/química , Alicerces Teciduais , Animais , Materiais Biocompatíveis/farmacologia , Materiais Biomiméticos/farmacologia , Cloreto de Cálcio/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dinoflagellida/efeitos dos fármacos , Dinoflagellida/fisiologia , Células HeLa , Humanos , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/fisiologia , Poríferos/anatomia & histologia , Poríferos/química , Ratos , Engenharia Tecidual
7.
Ann Rheum Dis ; 74(6): 1311-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25398374

RESUMO

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. METHODS: A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). RESULTS: Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. CONCLUSIONS: Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. TRIAL REGISTRATION NUMBER: NCT00976599.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Janus Quinase 1/efeitos dos fármacos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , Fatores de Transcrição STAT/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Adulto , Idoso , Antirreumáticos/farmacologia , Artrite Reumatoide/metabolismo , Quimiocinas/efeitos dos fármacos , Quimiocinas/genética , Quimiocinas/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Janus Quinase 1/metabolismo , Masculino , Metaloproteinase 1 da Matriz/efeitos dos fármacos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/efeitos dos fármacos , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , RNA Mensageiro/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/metabolismo , Resultado do Tratamento
9.
Clin Pharmacol Ther ; 93(6): 502-14, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23588322

RESUMO

The pharmaceutical industry continues to face significant challenges. Very few compounds that enter development reach the marketplace, and the investment required for each success can surpass $1.8 billion. Despite attempts to improve efficiency and increase productivity, total investment continues to rise whereas the output of new medicines declines. With costs increasing exponentially through each development phase, it is failure in phase II and phase III that is most wasteful. In today's development paradigm, late-stage failure is principally a result of insufficient efficacy. This is manifested as either a failure to differentiate sufficiently from placebo (shown for both novel and precedented mechanisms) or a failure to demonstrate sufficient differentiation from existing compounds. Set in this context, this article will discuss the role model-based drug development (MBDD) approaches can and do play in accelerating and optimizing compound development strategies through a series of illustrative examples.


Assuntos
Descoberta de Drogas/métodos , Modelos Biológicos , Ensaios Clínicos como Assunto/economia , Ensaios Clínicos como Assunto/métodos , Simulação por Computador , Descoberta de Drogas/economia , Indústria Farmacêutica/economia , Indústria Farmacêutica/métodos , Humanos
10.
Anticancer Agents Med Chem ; 13(10): 1469-76, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23387970

RESUMO

The concept of Ayurvedic expert guided drug discovery and development is defined and put to test systematically for the first time in literature. Western Science has explored only ~5% of the approximately 25,000 species of higher plants for drug leads. The ancient medical science of Ayurveda has however employed a much larger spectrum of plants for clinical treatment. Clerodendrum viscosum (CV), a commonly growing weed in the Indian subcontinent has been employed by S. Nirmalananda (Ayurvedic expert) for the treatment of cervical cancer. Here we isolate and characterize a water extract fraction (Cv-AP) from the root of CV and evaluate its anticervical cancer cell bioactivity. Our results indicate that Cv-AP possesses pro-apoptotic, anti-proliferative, and anti-migratory activity in a dose-dependent fashion against cervical cancer cell lines. In contrast, primary fibroblasts (control healthy cells), when exposed to similar concentrations of this extract, fail to undergo apoptosis and remain relatively unaffected. These findings suggest that Clerodendrum viscosum (CV) is a readily available source of components with potent anti-cancer activity and selective bioactivity against cervical cancer cells. The major component in CV-AP was identified as a glycoprotein via SDS Page and Concanavalin-A binding studies. This study serves to illustrate that systematic collaboration with Ayurveda is a practical and powerful strategy in drug discovery and development.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Clerodendrum/química , Glicoproteínas/isolamento & purificação , Extratos Vegetais/farmacologia , Proteínas de Plantas/isolamento & purificação , Plantas Medicinais/química , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Concanavalina A/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Glicoproteínas/química , Células HeLa , Humanos , Ayurveda , Especificidade de Órgãos , Extratos Vegetais/química , Proteínas de Plantas/química , Raízes de Plantas/química , Cultura Primária de Células , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
11.
Br J Dermatol ; 167(3): 668-77, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22924949

RESUMO

BACKGROUND: Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis. OBJECTIVES: This Phase 2b, 12-week, dose-ranging study (A3921047, NCT00678210) aimed to characterize the exposure-response, efficacy and safety of tofacitinib vs. placebo in patients with moderate-to-severe chronic plaque psoriasis. METHODS: One hundred and ninety-seven patients were randomized. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12. RESULTS: At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25·0% (2 mg; P < 0·001), 40·8% (5 mg; P < 0·0001) and 66·7% (15 mg; P < 0·0001), compared with placebo (2·0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure-response over the 0-15 mg tofacitinib twice-daily dose range was successfully characterized. PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22·4% (2 mg twice daily), 20·4% (5 mg twice daily), 36·7% (15 mg twice daily) and 32·0% (placebo). Discontinuations due to AEs were 6·0%, 2·0%, 4·1% and 6·1% of patients in the placebo, and 2, 5 and 15 mg twice-daily tofacitinib groups, respectively. Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed. CONCLUSION: Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Janus Quinase 3/antagonistas & inibidores , Psoríase/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Administração Oral , Adulto , Doença Crônica , Fármacos Dermatológicos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Piperidinas , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Resultado do Tratamento
12.
Am J Transplant ; 12(9): 2446-56, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22682022

RESUMO

In this Phase 2b study, 331 low-to-moderate risk de novo kidney transplant patients (approximately 60% deceased donors) were randomized to a more intensive (MI) or less intensive (LI) regimen of tofacitinib (CP-690, 550), an oral Janus kinase inhibitor or cyclosporine (CsA). All patients received basiliximab induction, mycophenolic acid and corticosteroids. Primary endpoints were: incidence of biopsy-proven acute rejection (BPAR) with a serum creatinine increase of ≥0.3 mg/dL and ≥20% (clinical BPAR) at Month 6 and measured GFR at Month 12. Similar 6-month incidences of clinical BPAR (11%, 7% and 9%) were observed for MI, LI and CsA. Measured GFRs were higher (p < 0.01) at Month 12 for MI and LI versus CsA (65 mL/min, 65 mL/min vs. 54 mL/min). Fewer (p < 0.05) patients in MI or LI developed chronic allograft nephropathy at Month 12 compared with CsA (25%, 24% vs. 48%). Serious infections developed in 45%, 37% and 25% of patients in MI, LI and CsA, respectively. Anemia, neutropenia and posttransplant lymphoproliferative disorder occurred more frequently in MI and LI compared with CsA. Tofacitinib was equivalent to CsA in preventing acute rejection, was associated with improved renal function and less chronic allograft histological injury, but had side-effects at the doses evaluated.


Assuntos
Imunossupressores/uso terapêutico , Janus Quinase 3/antagonistas & inibidores , Transplante de Rim , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Piperidinas , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirróis/efeitos adversos , Pirróis/farmacocinética
13.
Eur J Pediatr Surg ; 22(1): 80-4, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21879464

RESUMO

PURPOSE: The Global Paediatric Surgery Network (GPSN) website was launched in May 2010, with the following goals: to serve as a clearing house for pediatric surgery volunteer work performed worldwide, to provide online resources for surgeons working in areas of limited medical resources, and to provide practical and educational information for surgeons who wish to volunteer. The purpose of this study was to assess use of the website over the first year since its launch (May 6, 2010-May 5, 2011). METHODS: The GPSN website was examined for number of pages, number of listings in Past Work, Present Work, and Help Needed categories, as well as number of volunteers available. The online tool Google Analytics was used to assess parameters that measure use of the website, such as number of visits, number of page views, number of visitors, time on the website, and geographic origin of visitors. RESULTS: The GPSN website consists of 30 pages. There are 9 listings in Past Work, 23 listings in Present Work, and 13 listings in Help Needed categories. 118 people have registered as willing to volunteer, and 96 have indicated that they are able to work in times of a natural disaster. There were 8437 visits to the website, with 28 916 page views by 5170 visitors from 145 countries, with an average number of page views of 3.43 and an average time on the website of 4:05 min. The most visited pages were the homepage, the meetings page, and the pediatric surgery organizations page. 4 websites of pediatric surgery organizations have links to the GPSN website. CONCLUSIONS: Based on early website use, we conclude that there is an interest in the GPSN. We speculate that participation in the GPSN will continue to grow, but that there is a continued need to promote the website in the global pediatric surgery community.


Assuntos
Internet/estatística & dados numéricos , Sistemas On-Line/estatística & dados numéricos , Pediatria/estatística & dados numéricos , Humanos , Especialidades Cirúrgicas , Voluntários
14.
Am J Transplant ; 8(8): 1711-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18557720

RESUMO

CP-690 550 inhibits Janus kinase 3 with nanomolar potency. In this dose-escalation study, we assessed the safety, tolerability, effects on lymphocyte subsets, and pharmacokinetics of CP-690 550 when coadministered with mycophenolate mofetil in stable renal allograft recipients for 28 days. Twenty-eight patients were enrolled. Six patients received CP-690 550 5 mg twice daily (BID), 6 patients received 15 mg BID, 10 patients received 30 mg BID, and 6 patients received placebo. The most frequent adverse events were infections and gastrointestinal (abdominal pain, diarrhea, dyspepsia, and vomiting). CP-690 550 15 mg BID and 30 mg BID were associated with a mean decrease in hemoglobin from baseline of 11% and a mean decrease in absolute natural killer cell counts of 50%. CP-690 550 30 mg BID was also associated with a mean increase in absolute CD19(+) B-lymphocytes of 130%. There were no changes in the number of neutrophils, total lymphocytes, platelets, or CD4(+) or CD8(+) T cells; clinical chemistry; vital signs; or electrocardiograms from the pretreatment baseline. Administration of CP-690 550 without a concomitant calcineurin inhibitor resulted in CP-690 550 exposures consistent with previous studies in nontransplant subjects. Additional dose-ranging studies are warranted to evaluate the safety and efficacy of CP-690 550 in renal transplant recipients over longer treatment duration.


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Janus Quinase 3/metabolismo , Linfócitos/efeitos dos fármacos , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/farmacocinética , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/análogos & derivados , Piperidinas , Transplante Homólogo
15.
Chem Commun (Camb) ; (34): 4315-7, 2005 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-16113733

RESUMO

The Cu(I)-catalyzed ATRP and azide-alkyne cycloaddition reactions together provide a versatile method for the synthesis of end-functionalized glycopolymers and their attachment to a suitably modified viral protein scaffold.


Assuntos
Alcinos/química , Azidas/química , Cobre/química , Glucose/química , Proteínas Virais/química , Catálise , Ciclização , Hemaglutinação , Lectinas , Polímeros/síntese química
16.
Int J Clin Pharmacol Ther ; 43(3): 117-22, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15792395

RESUMO

OBJECTIVE: Reports characterizing the pharmacokinetics of inhaled fluticasone propionate (FP) using compartmental approaches have suggested that the absorption of FP into the systemic circulation is rapid with a half-life of approximately 10 min. We believe that this is a classical case of misassignment of the pharmacokinetic parameter estimates, a problem often encountered while modeling pharmacokinetic data. The objective of this study was to illustrate and analyze this problem using actual blood level data of FP obtained in 14 healthy subjects. MATERIALS AND METHODS: Serum concentration-time data of FP were obtained from a double-blind, randomized study involving single and multiple twice-daily inhalations of 500 microg via a dry powder device, Diskus. The profiles were fitted using one- and two-compartment pharmacokinetic models with first order absorption. Various permutations of the resulting exponential rate constants were analyzed to determine the combination that was most consistent with the underlying physical process. RESULTS: The two-compartment body model with first order absorption gave excellent fits for the observed FP concentrations after both single and multiple dosing. Even though peak levels were reached relatively early (30 - 90 min) after inhalation, the combination that most appropriately described the underlying process was alpha > Ka > beta, i.e. slow absorption, rapid distribution and slower elimination kinetics. The absorption, distribution and elimination half-lives resulted to be 3.8 h, 9.9 min and 13.6 h, respectively, consistent with the high lipophilicity and sustained dissolution characteristics observed in vitro. CONCLUSIONS: Analysis of FP pharmacokinetics after inhalation represents a classical case of potential misassignment of the exponential rate constants, which if ignored, could lead to erroneous interpretations regarding the underlying process. The study also elucidates the pitfall of using t(max) to calculate absorption rate.


Assuntos
Androstadienos/farmacocinética , Broncodilatadores/farmacocinética , Absorção , Administração por Inalação , Androstadienos/administração & dosagem , Androstadienos/sangue , Área Sob a Curva , Disponibilidade Biológica , Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Fluticasona , Meia-Vida , Humanos , Modelos Biológicos , Reprodutibilidade dos Testes , Distribuição Tecidual
18.
Biomacromolecules ; 4(3): 472-6, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12741758

RESUMO

Cowpea mosaic virus was derivatized with poly(ethylene glycol) to give well-controlled loadings of polymer on the outer surface of the coat protein assembly. The resulting conjugates displayed altered densities and immunogenicities, consistent with the known chemical and biological properties of PEG. These studies make CPMV potentially useful as a tailored vehicle for drug delivery.


Assuntos
Comovirus/química , Polietilenoglicóis/química , Polímeros/química , Animais , Comovirus/genética , Feminino , Camundongos , Camundongos Endogâmicos C57BL
19.
J Environ Radioact ; 67(1): 69-90, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12634002

RESUMO

238U and (232)Th concentrations and the extent of (238)U-(234)U-(230)Th radioactive equilibrium have been measured in a suite of Precambrian carbonates and black shales from the Lesser Himalaya. These measurements were made to determine their abundances in these deposits, their contributions to dissolved uranium budget of the headwaters of the Ganga and the Indus in the Himalaya and to assess the impact of weathering on (238)U-(234)U-(230)Th radioactive equilibrium in them. (238)U concentrations in Precambrian carbonates range from 0.06 to 2.07 microg g(-1). The 'mean' U/Ca in these carbonates is 2.9 ng U mg(-1) Ca. This ratio, coupled with the assumption that all Ca in the Ganga-Indus headwaters is of carbonate origin and that U and Ca behave conservatively in rivers after their release from carbonates, provides an upper limit on the U contribution from these carbonates, to be a few percent of dissolved uranium in rivers. There are, however, a few streams with low uranium concentrations, for which the carbonate contribution could be much higher. These results suggest that Precambrian carbonates make only minor contributions to the uranium budget of the Ganga-Indus headwaters in the Himalaya on a basin wide scale, however, they could be important for particular streams. Similar estimates of silicate contribution to uranium budget of these rivers using U/Na in silicates and Na* (Na corrected for cyclic and halite contributions) in river waters show that silicates can contribute significantly (approximately 40% on average) to their U balance. If, however, much of the uranium in these silicates is associated with weathering resistant minerals, then the estimated silicate uranium component would be upper limits. Uranium concentration in black shales averages about 37 microg g(-1). Based on this concentration, supply of U from at least approximately 50 mg of black shales per liter of river water is needed to balance the average river water U concentration, 1.7 microg L(-1) in the Ganga-Indus headwaters. Data on the abundance and distribution of black shales in their drainage basin are needed to test if this requirement can be met. (234)U/(238)U activity ratios in both carbonates and black shales are at or near equilibrium, thus preferential mobilization of (234)U from these deposits, if any, is within analytical uncertainties. (230)Th is equivalent to or in excess of (238)U in most of the carbonates. (230)Th/(238)U>1 indicates that during weathering, uranium is lost preferentially over Th. (232)Th concentrations in carbonates are generally quite low, <0.5 microg g(-1), though with a wide range, 0.01-4.8 microg g(-1). The variation in its concentrations seem to be regulated by aluminosilicate content of the carbonates as evident from the strong positive correlation between (232)Th and Al.


Assuntos
Tório/análise , Urânio/análise , Poluentes Radioativos da Água/análise , Carbonatos/química , Monitoramento Ambiental , Fenômenos Geológicos , Geologia , Índia , Solubilidade
20.
Bioconjug Chem ; 14(1): 38-43, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12526690

RESUMO

Nonenveloped viruses provide the chemist with large, preassembled polyvalent protein scaffolds for modification. These structures are typically porous to small molecules but not to large ones. The solution-phase structures and reactivities of such assemblies may be substantially different than indicated by X-ray crystal structures. Here, the attachment of organic compounds to either the inside or outside surface of the cowpea mosaic virus (CPMV) coat protein was verified with an indicating antibody-antigen interaction. Antibody binding was subsequently blocked by the installation of poly(ethylene glycol) chains. These results typify the type of site-specific control that is available with CPMV and related virus building blocks.


Assuntos
Proteínas do Capsídeo/química , Comovirus/química , Compostos Orgânicos/química , Anticorpos Antivirais/imunologia , Reações Antígeno-Anticorpo , Proteínas do Capsídeo/imunologia , Corantes Fluorescentes , Modelos Moleculares , Polietilenoglicóis/química , Vírus/química
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