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1.
Arch Osteoporos ; 17(1): 75, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35513573

RESUMO

In many countries, osteoporosis is predominantly managed by primary care physicians; however, management after a fragility fracture has not been widely investigated. We describe osteoporosis care gaps in a real-world patient cohort. Our findings help inform initiatives to identify and overcome obstacles to effective management of patients after fragility fracture. PURPOSE: A fragility fracture is a major risk factor for subsequent fracture in adults aged ≥ 50 years. This retrospective observational study aimed to characterize post-fracture management in Canadian primary care. METHODS: A total of 778 patients with an index fragility fracture (low-trauma, excluding small bones) occurring between 2014 and 2016 were identified from medical records at 76 primary care centers in Canada, with follow-up until January 2018. RESULTS: Of 778 patients (80.5% female, median age [IQR] 73 [64-80]), 215 were on osteoporosis treatment and 269 had osteoporosis diagnosis recorded prior to their index fracture. The median follow-up was 363 (IQR 91-808) days. Of patients not on osteoporosis treatment at their index fracture, 60.2% (n = 339/563) remained untreated after their index fracture and 62.2% (n = 23/37) continued untreated after their subsequent fracture. After their index fracture, fracture risk assessment (FRAX or CAROC) was not performed in 83.2% (n = 647/778) of patients, and 59.9% (n = 466/778) of patients did not receive bone mineral density testing. Of patients without osteoporosis diagnosis recorded prior to their index date, 61.3% (n = 300/489) remained undiagnosed after their index fracture. At least one subsequent fracture occurred in 11.5% (n = 86/778) of patients. CONCLUSION: In the primary care setting, fragility fracture infrequently resulted in osteoporosis treatment or fracture risk assessment, even after multiple fragility fractures. These results suggest a fragility fracture is not recognized as a major risk factor for subsequent fracture and its occurrence does not prompt primary care physicians to intervene. These data urge initiatives to identify and overcome obstacles to primary care physicians' effective management of patients after fragility fractures.


Assuntos
Conservadores da Densidade Óssea , Osteoporose , Fraturas por Osteoporose , Adulto , Conservadores da Densidade Óssea/uso terapêutico , Canadá/epidemiologia , Feminino , Humanos , Masculino , Osteoporose/complicações , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Atenção Primária à Saúde , Estudos Retrospectivos
2.
AAPS J ; 22(6): 140, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33104902

RESUMO

The global regulatory implementation and acceptance of a science and risk-based stability (SRB) strategies for a stable drug product is reviewed. This stability strategy may also be referred to as "lean stability" since it includes a stability protocol reduction in the number of tests and time points than might normally be applied. A product line extension (new solid dosage form) for a well-understood product was used as a test case for this stability strategy. The drug product line extension was filed globally with a proposed reduction to analytical stability tests and frequency. This stability protocol is aligned with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q1A (R2) stability guidelines (ICH: Guideline Q1A(R2), 2003), the World Health Organization (WHO) (WHO INT. [Online], 2020), and most country regulatory guidelines. Although this strategy was not accepted universally, the strategy enabled opportunities to engage in productive dialogs with regulatory authorities in several countries on how the case leveraged product understanding and development knowledge to develop a fit for purpose stability protocol. A persistent and consistent effort from industry to move toward product-specific protocols based on product knowledge and stability risk assessments should lead to further acceptance of science and risk-based stability strategies in all regions.


Assuntos
Ensaios Clínicos como Assunto/organização & administração , Desenvolvimento de Medicamentos/organização & administração , Cooperação Internacional , Gestão de Riscos , Aprovação de Drogas , Humanos , Ciência da Implementação
3.
AAPS J ; 22(1): 2, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31686262

RESUMO

This manuscript discusses global regulatory divergence of dissolution requirements for modified release solid oral dosage forms and the obstacles that must be addressed to be compliant with evolving guidance and legislation. The proliferation of local guidance documents, changing regulatory expectations, and increased legal enforcement has resulted in mismatched country-specific dissolution testing requirements and similarity criteria, and heightens industry's challenges with registration of modified release solid oral dosage forms. The lack of global harmonization and the complexity added by minor regional adaptations contributes to inefficiencies and hinders industry's goal of developing and delivering medicines. Awareness of country-specific similarity requirements and alignment between industry leaders and regulators is needed to facilitate global harmonization which will enable delivering new and improved medicines. The purpose of this manuscript is to compare and contrast in vitro conditions stated in local regulatory guidelines, raise awareness of the need to work toward harmonization of global requirements, and propose an initial study design toward that aspiration.


Assuntos
Liberação Controlada de Fármacos , Controle de Medicamentos e Entorpecentes
4.
Can J Cardiol ; 35(7): 884-891, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292087

RESUMO

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is an important indicator in the development and management of atherosclerotic cardiovascular disease (ASCVD). Herein, we describe the management of LDL-C with lipid-lowering therapy, among patients diagnosed with clinical ASCVD in Alberta, Canada. METHODS: A retrospective study was conducted by linking multiple health system databases to examine clinical characteristics, treatments, and LDL-C assessments. Patients with ASCVD were identified using a specific case definition on the basis of International Classification of Diseases, Ninth Revision, Clinical Modification/International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada codes between 2011 and 2015. LDL-C was assessed at the first measurement (index test) and second measurement (follow-up test) during the study period. LDL-C levels were evaluated on the basis of the 2016 Canadian Cardiovascular Society guideline recommendations for achieving < 2.0 mmol/L or a 50% reduction. Statin therapies were categorized as low-, moderate-, and high-intensity. RESULTS: Among the 281,665 individuals identified with ASCVD during the study period, 219,488 (77.9%) had an index LDL-C test, whereas 120,906 (55.1%) and 144,607 (65.9%) were prescribed lipid-lowering therapy before and after their index test, respectively. Most patients who received any lipid-lowering therapy were receiving moderate-/high-intensity statins (n = 133,029; 60.6%). Among the study cohort who had 2 LDL-C tests (n = 91,841; 32.6%), 48.5% of patients who received any lipid-lowering therapy did not achieve LDL-C levels < 2.0 at index date, whereas 36.6% did not achieve LDL-C levels < 2.0 or a 50% reduction at the follow-up test. CONCLUSIONS: The current study revealed that only two-thirds of patients with ASCVD were receiving pharmacotherapy and of those, a significant proportion did not reach recommended LDL-C levels. A remarkable treatment gap was identified for at-risk ASCVD patients. Further implementation strategies are required to address this undermanagement.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/epidemiologia , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Idoso , Alberta/epidemiologia , Aterosclerose/sangue , Doenças Cardiovasculares/sangue , Prescrições de Medicamentos/estatística & dados numéricos , Dislipidemias/sangue , Feminino , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
J Pharm Sci ; 107(12): 3080-3088, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30145210

RESUMO

Hard gelatin capsule (HGC) shells are widely used to encapsulate drugs for oral delivery but are vulnerable to gelatin cross-linking, which can lead to slower and more variable in vitro dissolution rates. Adding proteolytic enzymes to the dissolution medium can attenuate these problems, but this complicates dissolution testing and is only permitted by some regulatory authorities. Here, we expand the scope of our previous work to demonstrate that canisters containing activated carbon (AC) or polymeric films embedded with AC particles can be used as packaging components to attenuate gelatin cross-linking and improve the dissolution stability of hard gelatin-encapsulated products under accelerated International Council for Harmonisation conditions. We packaged acetaminophen and diphenhydramine HCl HGCs with or without AC canisters in induction-sealed high-density polyethylene bottles and with or without AC films in stoppered glass vials and stored these samples at 50°C/75% relative humidity through 3 months and at 40°C/75% relative humidity for 6 months. Samples packaged with AC canisters or AC films dissolved more rapidly than samples packaged without AC when differences were observed. These results demonstrate that different sources and formats of AC can enhance the dissolution stability of HGCs packaged in bottles and other potential packaging systems such as blister cards.


Assuntos
Carvão Vegetal/química , Reagentes de Ligações Cruzadas/química , Gelatina/química , Preparações Farmacêuticas/administração & dosagem , Administração Oral , Cápsulas/química , Composição de Medicamentos/métodos , Embalagem de Medicamentos , Humanos , Umidade , Preparações Farmacêuticas/química , Solubilidade , Temperatura
6.
J Pharm Sci ; 105(7): 2027-31, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27262203

RESUMO

Formaldehyde and formic acid are reactive impurities found in commonly used excipients and can be responsible for limiting drug product shelf-life. Described here is the use of activated carbon in drug product packaging to attenuate formaldehyde-induced and formic acid-induced drug degradation in tablets and cross-linking in hard gelatin capsules. Several pharmaceutical products with known or potential vulnerabilities to formaldehyde-induced or formic acid-induced degradation or gelatin cross-linking were subjected to accelerated stability challenges in the presence and absence of activated carbon. The effects of time and storage conditions were determined. For all of the products studied, activated carbon attenuated drug degradation or gelatin cross-linking. This novel use of activated carbon in pharmaceutical packaging may be useful for enhancing the chemical stability of drug products or the dissolution stability of gelatin-containing dosage forms and may allow for the 1) extension of a drug product's shelf-life when the limiting attribute is a degradation product induced by a reactive impurity, 2) marketing of a drug product in hotter and more humid climatic zones than currently supported without the use of activated carbon, and 3) enhanced dissolution stability of products that are vulnerable to gelatin cross-linking.


Assuntos
Carvão Vegetal/química , Formas de Dosagem , Formaldeído/química , Formiatos/química , Gelatina/química , Cápsulas , Reagentes de Ligações Cruzadas , Contaminação de Medicamentos , Embalagem de Medicamentos , Estabilidade de Medicamentos , Excipientes , Comprimidos , Vareniclina/química
8.
AAPS J ; 18(1): 15-22, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26428517

RESUMO

The objective of this article is to compare and contrast the international expectations associated with the model-independent similarity factor approach to comparing dissolution profiles. This comparison highlights globally divergent regulatory requirements to meet local dissolution similarity requirements. In effect, experiments customized to meet the current international regulatory expectations for dissolution and drug release unnecessarily increase manufacturing costs, hinder science and risk-based approaches, increase collective regulatory burden, reduce continuous improvement and innovation, and potentially delay patient access to urgently needed medication. Comparative assessment of regulatory differences in applying dissolution to demonstrate product similarity is crucial to reduce non-scientifically justified experiments and foster collaborative harmonization among global regulatory health authorities and the pharmaceutical industry.


Assuntos
Química Farmacêutica/normas , Legislação de Medicamentos , Solubilidade , Algoritmos , Indústria Farmacêutica/normas , União Europeia , Humanos , Cooperação Internacional , Estados Unidos
9.
BMJ Open ; 5(6): e007200, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26033942

RESUMO

INTRODUCTION: While the risk of adverse events following surgery has been identified, the impact of nursing care on early detection of these events is not well established. A systematic review of the evidence and an expert consensus study in post-anaesthetic care identified essential criteria for nursing assessment of patient readiness for discharge from the post-anaesthetic care unit (PACU). These criteria were included in a new nursing assessment tool, the Post-Anaesthetic Care Tool (PACT), and incorporated into the post-anaesthetic documentation at a large health service. The aim of this study is to test the clinical reliability of the PACT and evaluate whether the use of PACT will (1) enhance the recognition and response to patients at risk of deterioration in PACU; (2) improve documentation for handover from PACU nurse to ward nurse; (3) result in improved patient outcomes and (4) reduce healthcare costs. METHODS AND ANALYSIS: A prospective, non-randomised, pre-implementation and post-implementation design comparing: (1) patients (n=750) who have surgery prior to the implementation of the PACT and (2) patients (n=750) who have surgery after PACT. The study will examine the use of the tool through the observation of patient care and nursing handover. Patient outcomes and cost-effectiveness will be determined from health service data and medical record audit. Descriptive statistics will be used to describe the sample and compare the two patient groups (pre-intervention and post-intervention). Differences in patient outcomes between the two groups will be compared using the Cochran-Mantel-Haenszel test and regression analyses and reported as ORs with the corresponding 95% CIs. CONCLUSIONS: This study will test the clinical reliability and cost-effectiveness of the PACT. It is hypothesised that the PACT will enable nurses to recognise and respond to patients at risk of deterioration, improve handover to ward nurses, improve patient outcomes, and reduce healthcare costs.


Assuntos
Período de Recuperação da Anestesia , Análise Custo-Benefício/economia , Análise Custo-Benefício/métodos , Alta do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/prevenção & controle , Análise Custo-Benefício/estatística & dados numéricos , Feminino , Humanos , Masculino , Alta do Paciente/economia , Complicações Pós-Operatórias/economia , Estudos Prospectivos , Reprodutibilidade dos Testes , Risco
10.
BMC Public Health ; 12: 843, 2012 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-23035666

RESUMO

BACKGROUND: Well managed diabetes requires active self-management in order to ensure optimal glycaemic control and appropriate use of available clinical services and other supports. Peer supporters can assist people with their daily diabetes self-management activities, provide emotional and social support, assist and encourage clinical care and be available when needed. METHODS: A national database of Australians diagnosed with type 2 diabetes is being used to invite people in pre-determined locations to participate in community-based peer support groups. Peer supporters are self-identified from these communities. All consenting participants receive diabetes self-management education and education manual prior to randomization by community to a peer support intervention or usual care. This multi-faceted intervention comprises four interconnected components for delivering support to the participants. (1) Trained supporters lead 12 monthly group meetings. Participants are assisted to set goals to improve diabetes self-management, discuss with and encourage each other to strengthen linkages with local clinical services (including allied health services) as well as provide social and emotional support. (2) Support through regular supporter-participant or participant-participant contact, between monthly sessions, is also promoted in order to maintain motivation and encourage self-improvement and confidence in diabetes self-management. (3) Participants receive a workbook containing diabetes information, resources and community support services, key diabetes management behaviors and monthly goal setting activity sheets. (4) Finally, a password protected website contains further resources for the participants. Supporters are mentored and assisted throughout the intervention by other supporters and the research team through attendance at a weekly teleconference. Data, including a self-administered lifestyle survey, anthropometric and biomedical measures are collected on all participants at baseline, 6 and 12 months. The primary outcome is change in cardiovascular disease risk using the UKPDS risk equation. Secondary outcomes include biomedical, quality of life, psychosocial functioning, and other lifestyle measures. An economic evaluation will determine whether the program is cost effective. DISCUSSION: This manuscript presents the protocol for a cluster randomized controlled trial of group-based peer support for people with type 2 diabetes in a community setting. Results from this trial will contribute evidence about the effectiveness of peer support in achieving effective self-management of diabetes. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR); ACTRN12609000469213.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Promoção da Saúde/métodos , Grupo Associado , Autocuidado/psicologia , Grupos de Autoajuda , Adulto , Idoso , Australásia , Análise por Conglomerados , Diabetes Mellitus Tipo 2/psicologia , Seguimentos , Humanos , Pessoa de Meia-Idade , Avaliação de Programas e Projetos de Saúde , Projetos de Pesquisa , Apoio Social
11.
Acad Pediatr ; 12(3): 171-80, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22583631

RESUMO

OBJECTIVE: Universal newborn hearing screening for bilateral permanent congenital hearing impairment is standard practice in many developed economies, but until there is clear evidence of cost-effectiveness, it remains a controversial use of limited health care resources. We conducted a formal systematic review of studies of newborn hearing screening that considered both costs and outcomes to produce a summary of the available evidence and to determine whether there was a need for further research. METHODS: A search was conducted of medical and nursing databases and gray literature websites by the use of multiple keywords. The titles and abstracts of studies were examined for preliminary inclusion if reference was made to newborn hearing screening, and to both costs and outcomes. Studies of potential relevance were independently assessed by 2 health economists for final inclusion in the review. Studies that met inclusion criteria were appraised by the use of existing guidelines for observational studies, economic evaluations and decision analytic models, and reported in a narrative literature review. RESULTS: There were 22 distinct observational or modeled evaluations of which only 2 clearly compared universal newborn hearing screening to risk factor screening for bilateral permanent congenital hearing impairment. Of these, the single evaluation that examined long-term costs and outcomes found that universal newborn hearing screening could be cost-saving if early intervention led to a substantial reduction in future treatment costs and productivity losses. CONCLUSIONS: There are only a small number of economic evaluations that have examined the long-term cost-effectiveness of universal newborn hearing screening. This is partly attributable to ongoing uncertainty about the benefits gained from the early detection and treatment of bilateral permanent congenital hearing impairment. There is a clear need for further research on long-term costs and outcomes to establish the cost-effectiveness of universal newborn hearing screening in relation to other approaches to screening, and to establish whether it is a good long term investment.


Assuntos
Perda Auditiva Bilateral/diagnóstico , Testes Auditivos/economia , Triagem Neonatal/economia , Análise Custo-Benefício , Intervenção Médica Precoce , Perda Auditiva Bilateral/congênito , Humanos , Recém-Nascido
12.
Am J Physiol Renal Physiol ; 303(2): F266-78, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22573382

RESUMO

Renal proximal tubule injury is induced by agents/conditions known to cause endoplasmic reticulum (ER) stress, including cyclosporine A (CsA), an immunosuppressant drug with nephrotoxic effects. However, the underlying mechanism by which ER stress contributes to proximal tubule cell injury is not well understood. In this study, we report lipid accumulation, sterol regulatory element-binding protein-2 (SREBP-2) expression, and ER stress in proximal tubules of kidneys from mice treated with the classic ER stressor tunicamycin (Tm) or in human renal biopsy specimens showing CsA-induced nephrotoxicity. Colocalization of ER stress markers [78-kDa glucose regulated protein (GRP78), CHOP] with SREBP-2 expression and lipid accumulation was prominent within the proximal tubule cells exposed to Tm or CsA. Prolonged ER stress resulted in increased apoptotic cell death of lipid-enriched proximal tubule cells with colocalization of GRP78, SREBP-2, and Ca(2+)-independent phospholipase A(2) (iPLA(2)ß), an SREBP-2 inducible gene with proapoptotic characteristics. In cultured HK-2 human proximal tubule cells, CsA- and Tm-induced ER stress caused lipid accumulation and SREBP-2 activation. Furthermore, overexpression of SREBP-2 or activation of endogenous SREBP-2 in HK-2 cells stimulated apoptosis. Inhibition of SREBP-2 activation with the site-1-serine protease inhibitor AEBSF prevented ER stress-induced lipid accumulation and apoptosis. Overexpression of the ER-resident chaperone GRP78 attenuated ER stress and inhibited CsA-induced SREBP-2 expression and lipid accumulation. In summary, our findings suggest that ER stress-induced SREBP-2 activation contributes to renal proximal tubule cell injury by dysregulating lipid homeostasis.


Assuntos
Apoptose/fisiologia , Retículo Endoplasmático/fisiologia , Túbulos Renais Proximais/fisiopatologia , Metabolismo dos Lipídeos/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Estresse Fisiológico/fisiologia , Animais , Apoptose/efeitos dos fármacos , Biópsia , Células Cultivadas , Ciclosporina/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Homeostase/fisiologia , Humanos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Ligação a Elemento Regulador de Esterol 2/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Tunicamicina/farmacologia
13.
Expert Rev Mol Med ; 13: e4, 2011 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-21288373

RESUMO

Cellular cholesterol homeostasis is a fundamental and highly regulated process. Transcription factors known as sterol regulatory element binding proteins (SREBPs) coordinate the expression of many genes involved in the biosynthesis and uptake of cholesterol. Dysregulation of SREBP activation and cellular lipid accumulation has been associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). This review will provide an overview of ER stress and the UPR as well as cholesterol homeostasis and SREBP regulation, with an emphasis on their interaction and biological relevance.


Assuntos
Colesterol/metabolismo , Retículo Endoplasmático/metabolismo , Metabolismo dos Lipídeos , Resposta a Proteínas não Dobradas/fisiologia , Animais , Colesterol/biossíntese , Retroalimentação Fisiológica , Humanos , Transtornos do Metabolismo dos Lipídeos/etiologia , Transtornos do Metabolismo dos Lipídeos/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Ativação Transcricional , Resposta a Proteínas não Dobradas/genética
14.
FASEB J ; 25(2): 576-89, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20966213

RESUMO

Endoplasmic reticulum (ER) stress causes macrophage cell death within advanced atherosclerotic lesions, thereby contributing to necrotic core formation and increasing the risk of atherothrombotic disease. However, unlike in advanced lesions, the appearance of dead/apoptotic macrophages in early lesions is less prominent. Given that activation of the unfolded protein response (UPR) is detected in early lesion-resident macrophages and can enhance cell survival against ER stress, we investigated whether UPR activation occurs after monocyte to macrophage differentiation and confers a cytoprotective advantage to the macrophage. Human peripheral blood monocytes were treated with monocyte colony-stimulating factor to induce macrophage differentiation, as assessed by changes in ultrastructure and scavenger receptor expression. UPR markers, including GRP78, GRP94, and spliced XBP-1, were induced after macrophage differentiation and occurred after a significant increase in de novo protein synthesis. UPR activation after differentiation reduced macrophage cell death by ER stress-inducing agents. Further, GRP78 overexpression in macrophages was sufficient to reduce ER stress-induced cell death. Consistent with these in vitro findings, UPR activation was observed in viable lesion-resident macrophages from human carotid arteries and from the aortas of apoE(-/-) mice. However, no evidence of apoptosis was observed in early lesion-resident macrophages from the aortas of apoE(-/-) mice. Thus, our findings that UPR activation occurs during macrophage differentiation and is cytoprotective against ER stress-inducing agents suggest an important cellular mechanism for macrophage survival within early atherosclerotic lesions.


Assuntos
Aterosclerose/metabolismo , Diferenciação Celular/fisiologia , Macrófagos/metabolismo , Monócitos/fisiologia , Resposta a Proteínas não Dobradas/fisiologia , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Sobrevivência Celular , Chaperona BiP do Retículo Endoplasmático , Feminino , Regulação da Expressão Gênica , Humanos , Macrófagos/ultraestrutura , Camundongos , Camundongos Knockout , Monócitos/citologia
16.
Int J Biochem Cell Biol ; 39(10): 1843-51, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17604677

RESUMO

BACKGROUND: Sterol regulatory element binding protein-2 (SREBP-2) is a membrane-bound transcription factor that upon proteolytic processing can activate the expression of genes involved in cholesterol biosynthesis and uptake. We as well as others have demonstrated that the accumulation of misfolded proteins within the endoplasmic reticulum (ER), a condition known as ER stress, can dysregulate lipid metabolism by activating the SREBPs. The purpose of this study was to determine the mechanism by which ER stress induces SREBP-2 activation. METHODS AND RESULTS: HeLa and MCF7 cells were treated with ER stress-inducing agents to determine the effect of ER stress on SREBP-2 cleavage and subsequent cholesterol accumulation. Cells treated with thapsigargin (Tg) exhibit proteolytic cleavage of SREBP-2. Proteolytic cleavage of SREBP-2 induced by Tg occurred independently of caspase activation and was inhibited by the site-1 protease inhibitor AEBSF, suggesting that Tg-induced SREBP-2 cleavage occurs through the conventional site-1/-2 pathway. Treatment of HeLa cells with Tg also led to the accumulation of free cholesterol as measured by Filipin staining. CONCLUSIONS: These results imply that ER stress-induced SREBP-2 activation occurs through the conventional pathway that normally regulates SREBP in accordance with intracellular sterol concentration.


Assuntos
Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Caspase 3/fisiologia , Colesterol/metabolismo , Inibidores Enzimáticos/farmacologia , Expressão Gênica , Células HeLa , Humanos , Processamento de Proteína Pós-Traducional , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Sulfonas/farmacologia , Tapsigargina/farmacologia , Transfecção , Células Tumorais Cultivadas
17.
Clin Colorectal Cancer ; 6(6): 442-6, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17531108

RESUMO

The aim of this review is to discuss the basic science of tumor angiogenesis and recent clinical trial results with angiogenic inhibitors. Colorectal cancer (CRC) continues to be a major cause of all new cancer cases and cancer-related deaths in North America. Although advances in chemotherapy have increased overall survival for patients suffering from metastatic CRC, the survival rate continues to be poor. In order to develop new and more effective therapies for advanced CRC, it is important to understand the basic biologic processes that govern tumor growth. This review will focus on pathways involved in stimulating tumor growth and angiogenesis. Recent excitement has been generated by the clinical efficacy of targeted antiangiogenic therapy against growth factors important in angiogenesis and tumor proliferation. By presenting the basic biology of tumor growth and angiogenesis, we will attempt to explain the therapeutic effects of different angiogenesis inhibitors and speculate how combination treatments with these agents might be beneficial.


Assuntos
Neoplasias Colorretais/enzimologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/enzimologia , L-Lactato Desidrogenase/metabolismo , Neovascularização Patológica/enzimologia , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/tratamento farmacológico , Humanos
19.
J Org Chem ; 71(24): 9045-50, 2006 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-17109528

RESUMO

Aqueous phosphoric acid (85 wt %) is an effective, environmentally benign reagent for the deprotection of tert-butyl carbamates, tert-butyl esters, and tert-butyl ethers. The reaction conditions are mild and offer good selectivity in the presence of other acid-sensitive groups, including CBZ carbamates, azetidine, benzyl and methyl esters, TBDMS, and methyl phenyl ethers. The mildness of the reaction is further demonstrated in the synthesis of clarithromycin derivative, in which a tert-butyl ester is removed in the presence of cyclic carbamate, lactone, ketal, acetate ester, and epimerizable methyl ketone functionalities. The reaction preserves the stereochemical integrity of the substrates. The reactions are high yielding, and the workup is convenient.


Assuntos
Carbamatos/química , Ésteres/química , Éteres/química , Indicadores e Reagentes/química , Ácidos Fosfóricos/química , Espectroscopia de Ressonância Magnética , Água
20.
J Cell Physiol ; 208(1): 229-37, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16575906

RESUMO

Chronic exposure of the skeletal muscle microcirculation to elevated shear stress-induces angiogenesis. Previous studies observed that shear stress-induced capillary growth involves luminal sprouting, or internal division, of the capillaries, which is characterized by a minimal proliferative response and the retention of an intact basement membrane. Matrix metalloproteinases (MMPs) are associated with the process of abluminal sprouting angiogenesis, but may not be required for the process of luminal division during capillary growth. We analyzed the production of MMP-2, using both the in vivo model of prazosin-induced angiogenesis in rat skeletal muscle, and cultured microvascular endothelial cells exposed to laminar shear stress. We found that MMP-2 was not elevated in capillaries of shear stress-stimulated skeletal muscle, despite a significant increase in capillary number in response to a shear stress stimulus. In cultured microvascular endothelial cells, MMP-2 mRNA and protein levels were attenuated significantly in response to shear stress exposure. This effect on MMP-2 was reversed by nitric oxide (NO) synthase inhibition using LNNA. In contrast, exposure of static cultures of endothelial cells to NO donors significantly reduced MMP-2 production. Shear stress exposure and NO donors both modified phosphorylation levels of several members of the MAPK family. Treatment of shear stress-exposed cells with the p38 MAPK inhibitor, SB203580, abolished the shear stress-mediated reduction in MMP-2 mRNA. Thus, our data provide strong evidence that elevated shear stress inhibits MMP-2 production in microvascular endothelial cells, an effect that is mediated by signal pathways involving both production of NO and activation of p38 MAPK.


Assuntos
Endotélio Vascular/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Ácido Nítrico/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Animais , Western Blotting , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Células Endoteliais/fisiologia , Endotélio Vascular/química , Endotélio Vascular/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Imidazóis/farmacologia , Masculino , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 2 da Matriz/genética , Neovascularização Fisiológica/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/farmacologia , Fosforilação , Prazosina/farmacologia , Piridinas/farmacologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Mecânico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
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