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1.
Mater Sci Eng C Mater Biol Appl ; 104: 109917, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500044

RESUMO

In this work, nanofibers based on hydrophilic poly(vinylpyrrolidone) (PVP) and hydrophobic ethyl cellulose (EC) were generated via electrospinning. A model antibiotic, ciprofloxacin (CIF), was also incorporated into the fibers. Fibers were collected on both a foil substrate and a commercial gauze, the latter in the interests of developing a smart fabric. Electron microscopy images revealed that the fibers collected on both foil and fabric were homogeneous and cylindrical. Infrared spectroscopy, X-ray diffraction and differential scanning calorimetry demonstrated that CIF was successfully loaded into the fibers and present in the amorphous physical form. In vitro drug release tests were conducted to simulate drug release from the formulations into a wound site, and as expected the hydrophilic fibers showed much faster release than their hydrophobic analogues. CIF was released through a combined mechanism of polymer erosion and drug diffusion, and the EC nanofibers displayed close to zero-order release over three days. Fibroblast cells are able to grow and proliferate on the fibers. Finally, inhibition zone assays revealed that the growth of both Gram positive and Gram negative bacteria could be effectively inhibited as a result of the presence of CIF in the fibers. There were no marked differences between the fibers collected on foil and on gauze, and electrospinning can be performed directly onto a gauze substrate to prepare a smart fabric.


Assuntos
Bandagens , Celulose/análogos & derivados , Ciprofloxacino/farmacologia , Nanofibras/química , Povidona/química , Engenharia Tecidual/métodos , Cicatrização/efeitos dos fármacos , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Varredura Diferencial de Calorimetria , Sobrevivência Celular/efeitos dos fármacos , Celulose/química , Derme/citologia , Liberação Controlada de Fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Cinética , Testes de Sensibilidade Microbiana , Nanofibras/ultraestrutura , Difração de Raios X
3.
J Am Geriatr Soc ; 66(5): 924-929, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29676777

RESUMO

OBJECTIVES: To explore the effect of the presence and timing of a do-not-resuscitate (DNR) order on short-term clinical outcomes, including mortality. DESIGN: Retrospective cohort study with propensity score matching to enable direct comparison of DNR and no-DNR groups. SETTING: Large, academic tertiary-care center. PARTICIPANTS: Hospitalized medical patients aged 65 and older. MEASUREMENTS: Primary outcome was in-hospital mortality. Secondary outcomes included discharge disposition, length of stay, 30-day readmission, restraints, bladder catheters, and bedrest order. RESULTS: Before propensity score matching, the DNR group (n=1,347) was significantly older (85.8 vs 79.6, p<.001) and had more comorbidities (3.0 vs 2.5, p<.001) than the no-DNR group (n=9,182). After propensity score matching, the DNR group had significantly longer stays (9.7 vs 6.0 days, p<.001), were more likely to be discharged to hospice (6.5% vs 0.7%, p<.001), and to die (12.2% vs 0.8%, p<.001). There was a significant difference in length of stay between those who had a DNR order written within 24 hours of admission (early DNR) and those who had a DNR order written more than 24 hours after admission (late DNR) (median 6 vs 10 days, p<.001). Individuals with early DNR were less likely to spend time in intensive care (10.6% vs 17.3%, p=.004), receive a palliative care consultation (8.2% vs 12.0%, p=.02), be restrained (5.8% vs 11.6%, p<.001), have an order for nothing by mouth (50.1% vs 56.0%, p=.03), have a bladder catheter (31.7% vs 40.9%, p<.001), or die in the hospital (10.2% vs 15.47%, p=.004) and more likely to be discharged home (65.5% vs 58.2%, p=.01). CONCLUSION: Our study underscores the strong association between presence of a DNR order and mortality. Further studies are necessary to better understand the presence and timing of DNR orders in hospitalized older adults.


Assuntos
Mortalidade Hospitalar/tendências , Hospitalização , Pontuação de Propensão , Ordens quanto à Conduta (Ética Médica) , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo
4.
J Am Geriatr Soc ; 66(1): 70-75, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29052224

RESUMO

BACKGROUND/OBJECTIVES: Whereas opiate prescribing patterns have been well described in outpatient and emergency department settings, they have been less defined in hospitalized older adults. The objective was to describe patterns of opiate prescribing and associated outcomes in hospitalized older adults. DESIGN: Retrospective cohort study. SETTING: Tertiary care facility. PARTICIPANTS: Hospitalized medical patients aged 65 and older (N = 9,245; mean age 80.3, 55.2% female, 72.3% white, 90.8% non-Hispanic). MEASUREMENTS: Opiate exposure and duration of action, concurrent use of potentially inappropriate medications (PIMs), adverse events, discharge disposition, length of stay (LOS), and 30-day readmissions. RESULTS: There was no difference in sex, race, ethnicity, or Charlson Comorbidity Index between opiate exposure groups. Participants who had never received opiates had a significantly shorter mean LOS than prior and new opiate users (5.2, 6.8, 7.7 days; P < .001) and were more likely to be discharged home (88.6%, 82.8%, 82.5%; P < .001) and significantly less likely to be readmitted within 30-days (19.6%, 25.0%, 22.3%; P < .001). Participant who had never been exposed to opiates had a significantly shorter mean LOS than those receiving short- and long-acting opiates (5.2, 7.3, 8.6 days; P < .001) and were more likely to be discharged home (88.6%, 82.6%, 82.4%; P < .001) and significantly less likely to be readmitted within 30-days (19.6%, 27.7%, 28.9%; P < .001). CONCLUSION: Opiate use is widespread during hospitalization and is associated with significant negative clinical outcomes and quality metrics. There is an urgent need to develop innovative pain management alternatives to opiate use.


Assuntos
Analgésicos Opioides/uso terapêutico , Hospitalização/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Manejo da Dor/métodos , Idoso de 80 Anos ou mais , Analgésicos Opioides/efeitos adversos , Feminino , Humanos , Prescrição Inadequada , Masculino , Alta do Paciente/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Estudos Retrospectivos
5.
Inorg Chem ; 56(3): 1558-1573, 2017 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-28124561

RESUMO

Molybdenum solubility is a limiting factor to actinide loading in nuclear waste glasses, as it initiates the formation of water-soluble crystalline phases such as alkali molybdates. To increase waste loading efficiency, alternative glass ceramic structures are sought that prove resistant to internal radiation resulting from radioisotope decay. In this study, selective formation of water-durable CaMoO4 in a soda lime borosilicate is achieved by introducing up to 10 mol % MoO3 in a 1:1 ratio to CaO using a sintering process. The resulting homogeneously dispersed spherical CaMoO4 nanocrystallites were analyzed using electron microscopy, X-ray diffraction (XRD), Raman and electron paramagnetic resonance (EPR) spectroscopies prior to and post irradiation, which replicated internal ß-irradiation damage on an accelerated scale. Following 0.77 to 1.34 GGy of 2.5 MeV electron radiation CaMoO4 does not exhibit amorphization or significant transformation. Nor does irradiation induce glass-in-glass phase separation in the surrounding amorphous matrix, or the precipitation of other molybdates, thus proving that excess molybdenum can be successfully incorporated into a structure that it is resistant to ß-irradiation proportional to 1000 years of storage without water-soluble byproducts. The CaMoO4 crystallites do however exhibit a nonlinear Scherrer crystallite size pattern with dose, as determined by a Rietveld refinement of XRD patterns and an alteration in crystal quality as deduced by anisotropic peak changes in both XRD and Raman spectroscopy. Radiation-induced modifications in the CaMoO4 tetragonal unit cell occurred primarily along the c-axis indicating relaxation of stacked calcium polyhedra. Concurrently, a strong reduction of Mo6+ to Mo5+ during irradiation is observed by EPR, which is believed to enhance Ca mobility. These combined results are used to hypothesize a crystallite size alteration model based on a combination of relaxation and diffusion-based processes initiated by added energy from ß-impingement and second-order structural modifications induced by defect accumulation.

6.
J Psychol ; 151(1): 1-4, 2017 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-28001965
7.
JAMA Surg ; 150(9): 841-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26200995

RESUMO

IMPORTANCE: The Denver criteria grade blunt cerebrovascular injuries (BCVIs) but fail to capture many patients with indeterminate findings on initial imaging. OBJECTIVE: To evaluate outcomes and clinical significance of indeterminate BCVIs (iBCVIs). DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of all patients treated for BCVIs at our institution from January 1, 2007, through July 31, 2014, was completed. Patients were divided into 2 groups: those with true BCVIs as defined by the Denver criteria and those with iBCVIs, which was any initial imaging suggestive of a cerebrovascular arterial injury not classifiable by the Denver criteria. MAIN OUTCOMES AND MEASURES: Primary outcomes were rate of resolution of iBCVIs, freedom from cerebrovascular accident (CVA) or transient ischemic attack (TIA), and 30-day mortality. RESULTS: We identified 100 patients with 138 BCVIs: 79 with true BCVIs and 59 with iBCVIs. With serial imaging, 23 iBCVIs (39.0%) resolved and 21 (35.6%) remained indeterminate, whereas 15 (25.4%) progressed to true BCVI. The rate of CVA or TIA in the iBCVI group was 5.1% compared with 15.2% in the true BCVI group (P = .06). Of the 15 total CVAs or TIAs, 11 (73.3%) resulted from carotid injury and 4 (26.7%) from vertebral artery occlusion (P = .03). By Kaplan-Meier analysis, there was no difference in freedom from CVA or TIA for the 2 groups (P = .07). Median clinical follow-up was 91 days. Overall and 30-day mortality for the entire series were 17.4% and 15.2%, respectively. There was no difference in long-term or 30-day mortality between true BCVI and iBCVI groups. CONCLUSIONS AND RELEVANCE: Detection of iBCVI has become a common clinical conundrum with improved and routine imaging. Indeterminate BCVI is not completely benign, with 25.4% demonstrating anatomical progression to true BCVI and 5.1% developing cerebrovascular symptoms. We therefore recommend serial imaging and antiplatelet therapy for iBCVI.


Assuntos
Traumatismo Cerebrovascular/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Ferimentos não Penetrantes/diagnóstico , Adulto , Traumatismo Cerebrovascular/mortalidade , Feminino , Humanos , Escala de Gravidade do Ferimento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Estudos Retrospectivos , Ferimentos não Penetrantes/mortalidade
8.
Pain Med ; 16(12): 2277-83, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25917518

RESUMO

OBJECTIVE: In recent years, there has been increased attention to pain management after surgery in the hospital setting along with financial enticement from the US government. The aim of this study is to evaluate the current efficacy of postoperative pain management. METHODS: In a prospective study, patients in an academic private nonprofit medical center were asked the same questions about their postoperative pain as in a previously published 2003 survey. Questionnaires on 1) pain intensity on a verbal categorical scale and 2) patient satisfaction with pain medication were completed in the patient's room before hospital discharge, and followed-up by telephone interviews at 1 and 2 weeks later. Numerical Pain Scale (NRS) pain scores were obtained at the same time points. Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) results for pain management were obtained at bedside interview along with standard mailed HCAHPS survey obtained by Press Ganey. RESULTS: Based on 441 surgical inpatients (Orthopedic, General, Neurosurgery, Gynecological) 12% of patients had "Severe-to-Extreme" pain and 54% had "Moderate-to-Extreme" pain at discharge. During the first 2 weeks after discharge, 13% of patients had "Severe-to-Extreme" pain and 46% had "Moderate-to-Extreme" pain. Pain scores at discharge and after discharge were negatively correlated with patient satisfaction with pain medication (P < 0.0001), indicating that increased pain intensity was associated with decreased patient satisfaction. For the HCAHPS question "how often was your pain well controlled?," 66% answered "Always" in the Press Ganey report versus 51% at bedside (P < 0.0001). CONCLUSIONS: The incidence of severe-to-extreme pain in patients before and after discharge following inpatient surgery is 12-13%, and this is a reduction from 10 years ago.


Assuntos
Cirurgia Geral/estatística & dados numéricos , Medição da Dor/estatística & dados numéricos , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/prevenção & controle , Satisfação do Paciente/estatística & dados numéricos , Índice de Gravidade de Doença , Atividades Cotidianas , Adulto , Distribuição por Idade , Idoso , Chicago/epidemiologia , Autoavaliação Diagnóstica , Feminino , Pesquisas sobre Serviços de Saúde , Hospitalização , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/diagnóstico , Estudos Prospectivos , Fatores de Risco , Distribuição por Sexo , Adulto Jovem
9.
Pract Midwife ; 16(9): 31-4, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24358598

RESUMO

Birth injuries are frequently seen in newborn infants. Clavicular fractures are the most commonly encountered bony injuries seen in clinical practice. The incidence of clavicle fracture ranges from 0.35 per cent to 2.9 per cent of births and remains undetected at the time of discharge from hospital in up to 40 per cent of cases. Clinical suspicion of fractured clavicle may be raised from history (shoulder dystocia) or clinical examination (spongy feeling or crepitus on palpation). This should be confirmed with imaging studies. Parents should have the diagnosis explained and be reassured that healing without residual deformity will occur without any medical intervention. Careful documentation of any confirmed clavicle fracture is important from medico-legal aspects. We present the case of a newborn clavicular fracture associated with shoulder dystocia, following a vaginal birth,.


Assuntos
Traumatismos do Nascimento/enfermagem , Clavícula/lesões , Distocia/enfermagem , Fraturas Ósseas/enfermagem , Complicações do Trabalho de Parto/enfermagem , Ombro , Traumatismos do Nascimento/etiologia , Distocia/etiologia , Feminino , Fraturas Ósseas/etiologia , Humanos , Recém-Nascido , Gravidez
10.
Surg Obes Relat Dis ; 9(4): 559-68, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22608055

RESUMO

BACKGROUND: Bariatric surgery improves arterial hypertension and renal function; however, the underlying mechanisms and effect of different surgical procedures are unknown. In the present prospective study, we compared the 12-month follow-up results after Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, and laparoscopic sleeve gastrectomy on weight loss, hypertension, renal function, and inflammatory status. METHODS: A total of 34 morbidly obese patients were investigated before, one and 12 months after Roux-en-Y gastric bypass (n = 10), laparoscopic adjustable gastric banding (n = 13), and laparoscopic sleeve gastrectomy (n = 11) for hypertension, kidney function, urinary and serum cytokine levels of macrophage migration inhibitory factor, monocyte chemotactic protein-1, and chemokine ligand-18. RESULTS: At 12 months after surgery, the patients in all 3 treatment arms showed a significant decrease in the mean body mass index, mean arterial pressure, and urinary and serum inflammatory markers (all P < .001). The reduction in urinary and serum cytokine levels correlated directly with body weight loss (P < .05). Patients with impaired renal function at baseline (corresponding to serum cystatin C >.8 mg/L) had a marked improvement in renal function 12 months after surgery (P < .05). CONCLUSION: Surgically induced weight loss is associated with a marked decrease in renal and systemic inflammation and arterial hypertension and improvement in renal function in patients with pre-existing renal impairment. These effects appear to be independent of surgical procedure. The improvement in renal inflammation could be 1 of the mechanisms contributing to the beneficial effects of bariatric surgery on arterial blood pressure, proteinuria, and renal function.


Assuntos
Gastrectomia/métodos , Derivação Gástrica/métodos , Gastroplastia/métodos , Hipertensão/cirurgia , Laparoscopia/métodos , Obesidade Mórbida/cirurgia , Adulto , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Creatinina/metabolismo , Cistatina C/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Inflamação/fisiopatologia , Inflamação/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrite/fisiopatologia , Nefrite/cirurgia , Obesidade Mórbida/fisiopatologia , Estudos Prospectivos , Perda de Peso/fisiologia
11.
Phys Med Rehabil Clin N Am ; 23(2): 271-303, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22537693

RESUMO

Rehabilitation medicine is practiced in a variety of settings. Physiatrists are an integral part of the care provided in many of these settings and are often consulted to provide diagnostic and therapeutic services and expertise to individuals with a variety of diagnoses. In this role, it is imperative that physiatrists have a working knowledge of various medications as well as the principles of medication safety. This article provides a foundation in the general and specific aspects of medication safety as they apply to the practice of rehabilitation medicine.


Assuntos
Analgésicos Opioides/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticoagulantes/efeitos adversos , Hipnóticos e Sedativos/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Reabilitação , Acidentes por Quedas , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Interações de Medicamentos , Humanos , Erros de Medicação , Reconciliação de Medicamentos , Dor/tratamento farmacológico , Educação de Pacientes como Assunto , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
12.
Phys Med Rehabil Clin N Am ; 23(2): 441-56, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22537705

RESUMO

Cancer patients receive rehabilitation services in acute hospitalizations, rehabilitation wards, outpatient rehabilitation facilities, and home settings. Given the complexity and acuity of their medical care coupled with the long-term effects of the cancer and its treatments, patient safety is a significant concern in the delivery of rehabilitation services for this population. Cancer survivorship is growing in importance as a significant number of adults and children diagnosed with cancer are surviving beyond the 5-year mark. The goal of this article is to provide an overview to rehabilitation clinicians on the topic of patient safety in the rehabilitation of cancer patients.


Assuntos
Comunicação Interdisciplinar , Neoplasias/complicações , Neoplasias/reabilitação , Humanos , Anamnese , Neoplasias/patologia , Neoplasias/terapia , Exame Físico , Medição de Risco
13.
J Med Chem ; 53(9): 3814-30, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20405922

RESUMO

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.


Assuntos
Hidantoínas/farmacocinética , Fatores Imunológicos/química , Antígeno-1 Associado à Função Linfocitária/efeitos dos fármacos , Ácidos Nicotínicos/farmacocinética , Humanos , Hidantoínas/farmacologia , Antígeno-1 Associado à Função Linfocitária/química , Antígeno-1 Associado à Função Linfocitária/imunologia , Ácidos Nicotínicos/toxicidade , Relação Estrutura-Atividade
14.
J Med Chem ; 52(23): 7360-3, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-19778024
15.
J Med Chem ; 51(19): 5897-900, 2008 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-18763755

RESUMO

We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Piridonas/administração & dosagem , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Benzimidazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Transplante de Neoplasias , Receptor de Pregnano X , Inibidores de Proteínas Quinases/química , Piridonas/química , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/metabolismo , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Pharm Res ; 25(7): 1511-20, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18185985

RESUMO

PURPOSE: Since the first demonstration of PAMPA, the artificial membrane has been traditionally prepared by impregnating a porous filter with a solution of lipid mixture. While the lipid solution-based method is simple and seems to provide good predictability for many compounds, it is challenged by several shortcomings including reproducibility, stability, mass retention and the incorrect prediction of a group of highly permeable compounds including caffeine and antipyrine. Here we present the validation of a novel artificial membrane formed by constructing a lipid/oil/lipid tri-layer in the porous filter. METHODS: Permeability values obtained from traditional and new artificial membrane were compared for their correlation with Caco-2 and human absorption values. Mass retention, stability and organic solvent compatibility of the new artificial membrane were studied. RESULTS: The new artificial membrane correctly predicts the permeability of the traditionally under-predicted compounds and improves the correlation with Caco-2 and human absorption values. Furthermore, the new artificial membrane reduces the mass retention of compounds that are highly retained by the traditional artificial membrane. The new artificial membrane is also found to be robust enough to sustain long term storage and has good compatibility with organic solvents. CONCLUSIONS: The new artificial membrane provides an improved PAMPA model.


Assuntos
Membranas Artificiais , Modelos Químicos , Absorção , Algoritmos , Tampões (Química) , Células CACO-2 , Desenho de Drogas , Humanos , Lipídeos/química , Permeabilidade , Preparações Farmacêuticas/química , Solventes
17.
Arch Pharm Res ; 30(4): 507-18, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17489369

RESUMO

The purpose of this study was to investigate the utility of stably transfected MDCK-hPepT1 cells for identifying peptide transporter substrates in early drug discovery and compare the characteristics of this cell line with Caco-2 cells. MDCK-hPepT1, MDCK-mock, and Caco-2 cells grown to confluence on 24-well Transwell were used for this study. Expression levels of different transporter proteins (PepT1, PepT2, P-gp) in these cell lines were assessed by qRT-PCR. Permeability studies were conducted in parallel in all the cells with a diverse set of peptide substrates using the optimized experimental condition: 100 microM, apical pH 6.0, basolateral pH 7.4, 2 hr incubation at 37 degrees C. Permeability studies were also conducted with classical P-gp substrates (tested in bi-directional mode) and paracellularly absorbed probes to investigate the differences between the cell lines. As expected, MDCK-hPepT1 cells express significantly higher level of PepT1 mRNA compared to both Caco-2 and MDCK-mock cells. Efflux transporter, P-gp, was expressed adequately in all the cell lines. Permeability studies demonstrated that classical peptide substrates had significantly higher permeability in stably transfected MDCK-hPepT1 cells compared to MDCK-mock and Caco-2 cells. The transfected MDCK-hPepT1 cells were qualitatively similar to Caco-2 cells with respect to functional P-gp efflux activity and paracellular pore activity. Stably transfected MDCK-hPepT1 cells have been demonstrated as a viable alternative to Caco-2 cells for estimating the human absorption potential of peptide transporter substrates. These cells behave similar to Caco-2 cells with regards to P-gp efflux and paracellular pore activity but demonstrate greater predictability of absorption values for classical peptide substrates (for which Caco-2 cells under-estimate oral absorption).


Assuntos
Absorção Intestinal , Simportadores/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Células CACO-2 , Cães , Humanos , Transportador 1 de Peptídeos , Permeabilidade , Transfecção
18.
J Med Chem ; 49(24): 6946-9, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-17125246

RESUMO

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.


Assuntos
Antígeno-1 Associado à Função Linfocitária/metabolismo , Compostos de Espiro/síntese química , Tiofenos/síntese química , Animais , Adesão Celular/efeitos dos fármacos , Cristalografia por Raios X , Cães , Rejeição de Enxerto/prevenção & controle , Humanos , Antígeno-1 Associado à Função Linfocitária/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia , Transplante Homólogo
19.
Hum Nat ; 17(2): 169-89, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26181413

RESUMO

Growing evidence suggests mothers invest more in girls than boys and fathers more in boys than girls. We develop a hypothesis that predicts preference for girls by the parent facing more resource constraints and preference for boys by the parent facing less constraint. We test the hypothesis with panel data from the Tsimane', a foraging-farming society in the Bolivian Amazon. Tsimane' mothers face more resource constraints than fathers. As predicted, mother's wealth protected girl's BMI, but father's wealth had weak effects on boy's BMI. Numerous tests yielded robust results, including those that controlled for fixed effects of child and household.

20.
Eur J Pharm Biopharm ; 58(1): 99-105, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15207543

RESUMO

The use of Caco-2 cells for screening of discovery compounds for their permeability characteristics and P-glycoprotein interactions is well established and used routinely in pharmaceutical industries world-wide. The screening model involves growing cells on 12 or 24 well transwell format. In this manuscript, we report the use of Caco-2 cells grown on 96 well transwell plates for screening compounds for their potential to interact with P-gp. Bi-directionality studies were performed with known P-gp substrates such as saquinavir, indinavir, vinblastine, vincristine, verapamil, digoxin and taxol. P-gp inhibition studies were also conducted using radiolabeled digoxin as the probe. The results demonstrated that P-gp substrates had efflux ratios (Pc (B to A)/Pc (A to B)) in the 96 well format that were comparable to the ratios seen in 12 and 24 well format. Inhibition of digoxin efflux transport in presence of the test compounds (P-gp substrates) demonstrated that 96 well cells express adequate amounts of efflux transporters and perform as well as the 12 and 24 well Caco-2 cells. Thus, the 96 well Caco-2 cell set-up presents a higher throughput permeability model capable of identifying compounds that interact with P-gp and has the potential to significantly increase the efficiency of P-gp screening in early drug discovery.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos/instrumentação , Avaliação Pré-Clínica de Medicamentos/métodos , Preparações Farmacêuticas/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Humanos
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