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1.
Eur J Obstet Gynecol Reprod Biol ; 283: 142-148, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36732101

RESUMO

BACKGROUND: We evaluated the safety, efficacy, and acceptability of a new device designed to facilitate uterine compression in women with postpartum haemorrhage (PPH). METHODS: A prospective, phase two clinical device trial with concurrent qualitative study, conducted in a UK consultant obstetric unit. The device was used in addition to standard care in women unresponsive to initial oxytocin therapy. The primary effectiveness outcome was additional blood loss of over 1000mls, whilst safety was assessed through adverse events. Interviews assessed device feasibility and acceptability, and were analysed using framework analysis. RESULTS: We recruited 57 women with clinical PPH after vaginal birth; 67% were primiparous and 47% had undergone operative birth. All but two (96%) had atony as a cause of the haemorrhage; in addition, 30% also had bleeding from lacerations and 11% had retained tissue. After device use, only one woman had additional blood loss over 1000mls, although 3 women (7%) needed a Bakri balloon and 14% received a blood transfusion. All but one clinician felt that the device was easy to use. Clinicians stated that the device assisted management in 85% of cases. All 56 women who responded stated that if they bled in a future birth they would want the device to be used again. There were no serious adverse events related to the device. However, 3 events were judged as 'possibly' being caused by the device - 2 minor vaginal grazes and one postnatal episiotomy infection and breakdown. Lax vaginal tissue complicated the use of the device in three women. In 47 interviews, participants, birth partners, clinician users and attending midwives viewed the device positively. Clinicians found it useful as a way of stopping blood loss and as an aid to diagnose the source of bleeding. CONCLUSIONS: The PPH Butterfly may provide a rapid, acceptable and effective treatment for postpartum haemorrhage. Clinical Trial Registration prospective with ISRCTN15452399 11/09/2017 (www.isrctn.com/ISRCTN15452399).


Assuntos
Hemorragia Pós-Parto , Gravidez , Feminino , Humanos , Hemorragia Pós-Parto/tratamento farmacológico , Estudos Prospectivos , Ocitocina/uso terapêutico , Resultado do Tratamento
2.
Cells ; 11(16)2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-36010603

RESUMO

In nematodes that invade the gastro-intestinal tract of the ruminant, the process of larval exsheathment marks the transition from the free-living to the parasitic stages of these parasites. To investigate the secretome associated with larval exsheathment, a closed in vitro system that effectively reproduces the two basic components of an anaerobic rumen environment (CO2 and 39 °C) was developed to trigger exsheathment in one of the most pathogenic and model gastrointestinal parasitic nematodes, Haemonchus contortus (barber's pole worm). This study reports the use of multimodal untargeted metabolomics and lipidomics methodologies to identify the metabolic signatures and compounds secreted during in vitro larval exsheathment in the H. contortus infective third-stage larva (iL3). A combination of statistical and chemoinformatic analyses using three analytical platforms revealed a panel of metabolites detected post exsheathment and associated with amino acids, purines, as well as select organic compounds. The major lipid classes identified by the non-targeted lipidomics method applied were lysophosphatidylglycerols, diglycerides, fatty acyls, glycerophospholipids, and a triglyceride. The identified metabolites may serve as metabolic signatures to improve tractability of parasitic nematodes for characterizing small molecule host-parasite interactions related to pathogenesis, vaccine and drug design, as well as the discovery of metabolic biomarkers.


Assuntos
Haemonchus , Nematoides , Animais , Larva , Ruminantes , Secretoma
3.
BMC Pregnancy Childbirth ; 22(1): 634, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35948884

RESUMO

BACKGROUND: Around 1 in 150 babies are stillborn or die in the first month of life in the UK. Most women conceive again, and subsequent pregnancies are often characterised by feelings of stress and anxiety, persisting beyond the birth. Psychological distress increases the risk of poor pregnancy outcomes and longer-term parenting difficulties. Appropriate emotional support in subsequent pregnancies is key to ensure the wellbeing of women and families. Substantial variability in existing care has been reported, including fragmentation and poor communication. A new care package improving midwifery continuity and access to emotional support during subsequent pregnancy could improve outcomes. However, no study has assessed the feasibility of a full-scale trial to test effectiveness in improving outcomes and cost-effectiveness for the National Health Service (NHS). METHODS: A prospective, mixed-methods pre-and post-cohort study, in two Northwest England Maternity Units. Thirty-eight women, (≤ 20 weeks' gestation, with a previous stillbirth, or neonatal death) were offered the study intervention (allocation of a named midwife care coordinator and access to group and online support). Sixteen women receiving usual care were recruited in the 6 months preceding implementation of the intervention. Outcome data were collected at 2 antenatal and 1 postnatal visit(s). Qualitative interviews captured experiences of care and research processes with women (n = 20), partners (n = 5), and midwives (n = 8). RESULTS: Overall recruitment was 90% of target, and 77% of women completed the study. A diverse sample reflected the local population, but non-English speaking was a barrier to participation. Study processes and data collection methods were acceptable. Those who received increased midwifery continuity valued the relationship with the care coordinator and perceived positive impacts on pregnancy experiences. However, the anticipated increase in antenatal continuity for direct midwife contacts was not observed for the intervention group. Take-up of in-person support groups was also limited. CONCLUSIONS: Women and partners welcomed the opportunity to participate in research. Continuity of midwifery care was supported as a beneficial strategy to improve care and support in pregnancy after the death of a baby by both parents and professionals. Important barriers to implementation included changes in leadership, service pressures and competing priorities. TRIAL REGISTRATION: ISRCTN17447733 first registration 13/02/2018.


Assuntos
Serviços de Saúde Materna , Tocologia , Morte Perinatal , Estudos de Coortes , Procedimentos Clínicos , Estudos de Viabilidade , Feminino , Humanos , Recém-Nascido , Tocologia/métodos , Morte Perinatal/prevenção & controle , Gravidez , Cuidado Pré-Natal/métodos , Estudos Prospectivos , Medicina Estatal , Natimorto/psicologia
4.
Mol Ther Nucleic Acids ; 28: 87-98, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35356682

RESUMO

Phenylketonuria (PKU) is an inborn error caused by deficiencies in phenylalanine (Phe) metabolism. Mutations in the phenylalanine hydroxylase (PAH) gene are the main cause of the disease whose signature hallmarks of toxically elevated levels of Phe accumulation in plasma and organs such as the brain, result in irreversible intellectual disability. Here, we present a unique approach to treating PKU deficiency by using an mRNA replacement therapy. A full-length mRNA encoding human PAH (hPAH) is encapsulated in our proprietary lipid nanoparticle LUNAR and delivered to a Pah enu2 mouse model that carries a missense mutation in the mouse PAH gene. Animals carrying this missense mutation develop hyperphenylalanemia and hypotyrosinemia in plasma, two clinical features commonly observed in the clinical presentation of PKU. We show that intravenous infusion of LUNAR-hPAH mRNA can generate high levels of hPAH protein in hepatocytes and restore the Phe metabolism in the Pah enu2 mouse model. Together, these data establish a proof of principle of a novel mRNA replacement therapy to treat PKU.

5.
Mol Ther ; 29(6): 1970-1983, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33823303

RESUMO

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4+ T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 µg and 10 µg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Sintéticas/administração & dosagem , Alphavirus/genética , Alphavirus/imunologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Vacinas contra COVID-19/biossíntese , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Feminino , Expressão Gênica , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Transgênicos , Replicon/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/virologia , Transgenes , Resultado do Tratamento , Vacinação/métodos , Vacinas Sintéticas/biossíntese , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas de mRNA
6.
Clin Infect Dis ; 71(8): e323-e330, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31814028

RESUMO

BACKGROUND: Produce-associated outbreaks of Shiga toxin-producing Escherichia coli (STEC) were first identified in 1991. In April 2018, New Jersey and Pennsylvania officials reported a cluster of STEC O157 infections associated with multiple locations of a restaurant chain. The Centers for Disease Control and Prevention (CDC) queried PulseNet, the national laboratory network for foodborne disease surveillance, for additional cases and began a national investigation. METHODS: A case was defined as an infection between 13 March and 22 August 2018 with 1 of the 22 identified outbreak-associated E. coli O157:H7 or E. coli O61 pulsed-field gel electrophoresis pattern combinations, or with a strain STEC O157 that was closely related to the main outbreak strain by whole-genome sequencing. We conducted epidemiologic and traceback investigations to identify illness subclusters and common sources. A US Food and Drug Administration-led environmental assessment, which tested water, soil, manure, compost, and scat samples, was conducted to evaluate potential sources of STEC contamination. RESULTS: We identified 240 case-patients from 37 states; 104 were hospitalized, 28 developed hemolytic uremic syndrome, and 5 died. Of 179 people who were interviewed, 152 (85%) reported consuming romaine lettuce in the week before illness onset. Twenty subclusters were identified. Product traceback from subcluster restaurants identified numerous romaine lettuce distributors and growers; all lettuce originated from the Yuma growing region. Water samples collected from an irrigation canal in the region yielded the outbreak strain of STEC O157. CONCLUSIONS: We report on the largest multistate leafy greens-linked STEC O157 outbreak in several decades. The investigation highlights the complexities associated with investigating outbreaks involving widespread environmental contamination.


Assuntos
Infecções por Escherichia coli , Escherichia coli O157 , Doenças Transmitidas por Alimentos , Escherichia coli Shiga Toxigênica , Surtos de Doenças , Infecções por Escherichia coli/epidemiologia , Escherichia coli O157/genética , Microbiologia de Alimentos , Doenças Transmitidas por Alimentos/epidemiologia , Humanos , Lactuca , Pennsylvania , Escherichia coli Shiga Toxigênica/genética , Estados Unidos/epidemiologia
8.
Sci Rep ; 9(1): 14659, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601898

RESUMO

Eukaryotic multicellularity originated in the Mesoproterozoic Era and evolved multiple times since, yet early multicellular fossils are scarce until the terminal Neoproterozoic and often restricted to cases of exceptional preservation. Here we describe unusual organically-preserved fossils from mudrocks, that provide support for the presence of organisms with differentiated cells (potentially an epithelial layer) in the late Neoproterozoic. Cyathinema digermulense gen. et sp. nov. from the Nyborg Formation, Vestertana Group, Digermulen Peninsula in Arctic Norway, is a new carbonaceous organ-taxon which consists of stacked tubes with cup-shaped ends. It represents parts of a larger organism (multicellular eukaryote or a colony), likely with greater preservation potential than its other elements. Arrangement of open-ended tubes invites comparison with cells of an epithelial layer present in a variety of eukaryotic clades. This tissue may have benefitted the organism in: avoiding overgrowth, limiting fouling, reproduction, or water filtration. C. digermulense shares characteristics with extant and fossil groups including red algae and their fossils, demosponge larvae and putative sponge fossils, colonial protists, and nematophytes. Regardless of its precise affinity, C. digermulense was a complex and likely benthic marine eukaryote exhibiting cellular differentiation, and a rare occurrence of early multicellularity outside of Konservat-Lagerstätten.


Assuntos
Organismos Aquáticos/ultraestrutura , Evolução Biológica , Eucariotos/ultraestrutura , Fósseis/ultraestrutura , Organismos Aquáticos/citologia , Regiões Árticas , Eucariotos/citologia , Microscopia Eletroquímica de Varredura , Noruega
10.
Gigascience ; 8(3)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30534956

RESUMO

BACKGROUND: Taphonomic and palaeoecologic studies of obrution beds often employ conventional methods of investigation such as physical removal and extraction of fossils from their host rock (matrix) by mechanical preparation. This often-destructive method is not suitable for studying mold fossils, which are voids left in host rocks due to dissolution of the original organism in post-depositional processes. FINDINGS: Microcomputed tomography (µCT) scan data of 24 fossiliferous rock samples revealed thousands of Paleozoic echinoderms. Digitally "stitching" together individually µCT scanned rock samples within three-dimensional (3D) space allows for quantifiable taphonomic data on a fossil echinoderm-rich obrution deposit from the Devonian (Emsian) of South Africa. Here, we provide a brief step-by-step guide on creating, segmenting, and ultimately combining sections of richly fossiliferous beds to create virtual models suited for the quantitative and qualitative taphonomic analyses of fossil invertebrate assemblages. CONCLUSIONS: Visualizing the internal features of fossiliferous beds in 3D is an invaluable taphonomic tool for analyzing delicate fossils, accounting for all specimens irrespective of their preservation stages and with minimal damage. This technique is particularly useful for analyzing fossiliferous deposits with mold fossils that prove to be difficult to study with traditional methods, because the method relies on the large density contrast between the mold and host rock.


Assuntos
Fósseis , Sedimentos Geológicos , Paleontologia , Microtomografia por Raio-X , Animais , Equinodermos , Geografia , Processamento de Imagem Assistida por Computador , África do Sul
11.
J Clin Pharmacol ; 58(11): 1452-1460, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29873817

RESUMO

AZD3241 is a potent and selective myeloperoxidase inhibitor potentially for the treatment of a number of neurodegenerative disorders, including multiple system atrophy (MSA). The objectives of this work were to develop a population pharmacokinetic (PopPK) model for AZD3241 and to investigate the correlation between AZD3241 exposure and myeloperoxidase inhibition. The PopPK model was developed using AZD3241 data from one phase 1 study in healthy subjects and one phase 2 study in patients with MSA. A one-compartment model incorporating a gallbladder compartment for enterohepatic circulation, sequential zero-first order absorption, and first-order elimination adequately described the AZD3241 concentration profiles. The apparent clearance and central volume of distribution were 63.1 L/h (interindividual variability: 34.8%) and 121.9 L (interindividual variability: 44.0%), respectively. The enterohepatic circulation model reasonably captured the second peak of AZD3241, and high-fat food increased the absorption rate by 69%. A linear regression model was applied to describe the relationship between AZD3241 exposure and percentage change from baseline in myeloperoxidase-specific activity. The developed PopPK model was consistent with known pharmacokinetic characteristics of AZD3241. This model can be used to estimate AZD3241 exposure in patients with MSA and could be applied to future pharmacokinetic-pharmacodynamic analyses of AZD3241 in clinical development.


Assuntos
Circulação Êntero-Hepática/efeitos dos fármacos , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Peroxidase/antagonistas & inibidores , Pirimidinonas/farmacologia , Pirimidinonas/farmacocinética , Pirróis/farmacologia , Pirróis/farmacocinética , Adulto , Idoso , Bile , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Atrofia de Múltiplos Sistemas/metabolismo , Pirimidinonas/metabolismo , Pirróis/metabolismo , Distribuição Aleatória
12.
Int J Gynecol Cancer ; 25(8): 1476-83, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26244756

RESUMO

OBJECTIVE: Both radical hysterectomy with pelvic lymphadenectomy and primary chemoradiotherapy have been shown to be effective in the management of women with stage IB2 cervical cancer. This study aims to review the outcomes related to each treatment modality and the effects of pathological risk factors on overall survival (OS) and disease-free survival. METHODS: We performed a retrospective study of 92 women with stage IB2 cervical cancer who were treated at the Northern Gynecological Oncology Center (Gateshead, United Kingdom) across a 22-year period between January 1991 and July 2013. Women were divided into those undergoing primary surgery and those undergoing primary radiotherapy/chemoradiotherapy. The main outcome measures were OS and progression-free survival (PFS). Pathological risk factors of survival were assessed using multivariate analysis. RESULTS: Sixty-seven women (72.8%) underwent primary surgery, and 25 women (27.2%) had primary radiotherapy/chemoradiotherapy. Thirty-one of 67 women (46.3%) required adjuvant radiotherapy/chemoradiotherapy after surgery because of positive lymph nodes in 77.4% of cases. The median follow-up was 57.5 months (range, 3-137 months). Thirty-two women (34.8%) had disease recurrence: 6 women (16.7%) in the group undergoing surgery alone, 15 women (48.4%) in the group requiring adjuvant treatment after surgery, and 11 women (44%) in the group having primary radiotherapy/chemoradiotherapy. Overall survival and PFS were higher for women undergoing surgery alone (91.7% and 83.3%) compared with women requiring adjuvant treatment after surgery (54.8% and 51.4%) and those having primary radiotherapy/chemoradiotherapy (60% and 56%) (P = 0.0004 and P = 0.005, respectively). Lymph node metastasis was a significant pathological risk factor of OS and PFS in multivariate analysis. CONCLUSIONS: Most women require adjuvant treatment after surgery because of positive lymph nodes. Because survival outcomes for women requiring dual treatment are similar to those for women undergoing primary chemoradiotherapy, nodal assessment before definitive treatment should guide the management of these women and identify a low-risk group that can be treated with surgery alone.


Assuntos
Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Histerectomia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia Adjuvante , Terapia Combinada , Feminino , Seguimentos , Humanos , Excisão de Linfonodo , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Neoplasias do Colo do Útero/mortalidade , Adulto Jovem
13.
Midwifery ; 31(2): 280-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25575860

RESUMO

INTRODUCTION: maternal obesity [body mass index (BMI)≥30kg/m(2)] is a cause for concern because of increasing rates and risk of associated complications. However, little is known about how to improve the health of women with a BMI≥30kg/m(2). OBJECTIVE AND METHODS: a 10-week antenatal lifestyle programme (The Lifestyle Course - TLC), underpinned by behaviour change theory, was developed in a programme of research which included a prospective, multicentred, feasibility phase (n=227). Participants had a BMI≥30kg/m(2) at the start of their pregnancy, planned to deliver in two areas of Greater Manchester and were aged 18 or over. The objectives were to (1) assess the feasibility of the intervention and (2) to pilot the trial processes and outcome measures. FINDINGS: (1) Trial intervention: only 22% of women in the feasibility phase had received gestational weight advice prior to the study. One or more TLC sessions were attended by 79% of women and 97% said they would recommend TLC to a friend due to the content suitability, perceived personal gains and extra care received. Changes to the TLC were suggested and implemented in the pilot phase. (2) Trial processes: recruitment rates (36%), retention rates (100%) and questionnaire completion rates up to one year (33%) were found. Daily general 'lifestyle' diaries and pedometers were not acceptable data collection tools (response rates of 32% and 16% respectively). However, specific food diaries were acceptable (response rates of 80-81%). The major challenge was the collection of maternal weight data at the follow-up points. CONCLUSIONS AND IMPLICATIONS: the antenatal intervention (TLC) designed for this programme of work appears to suit the needs of women with a BMI≥30kg/m(2). The need for an antenatal intervention is clear from this study and also highlights reflections on effective communication with pregnant women with a BMI≥30kg/m(2). Lessons learnt for designing a future trial include effective ways to communicate with pregnant women with a BMI≥30kg/m(2). TRIAL REGISTRATION: ISRCTN29860479.


Assuntos
Índice de Massa Corporal , Educação em Saúde/métodos , Estilo de Vida , Cuidado Pré-Natal/métodos , Feminino , Humanos , Obesidade/complicações , Obesidade/prevenção & controle , Gravidez , Complicações na Gravidez/prevenção & controle , Cuidado Pré-Natal/estatística & dados numéricos , Cuidado Pré-Natal/tendências , Estudos Prospectivos , Inquéritos e Questionários
14.
Clin J Oncol Nurs ; 18(2): 193-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24675254

RESUMO

Gastrointestinal (GI) cancer is the second most frequent cancer diagnosis in the United States, and the care for patients with GI cancer is multifaceted, with each clinical encounter impacting patients' overall experience. Patients and families often navigate this complicated journey on their own with limited resources and knowledge; therefore, innovative, patient-centered, and quality-focused programs must be developed. The purpose of this article is to discuss the development of GI nurse navigators (NNs) and the important role they have in providing coordinated evidence-based cancer care and in the benchmarking of quality metrics to allow more transparency and improve GI cancer care. This article provides a foundation for developing a GI NN role within the context of a newly developed multidisciplinary GI cancer program, and identifies the importance of tracking specific quality metrics. This innovative model is useful for healthcare organizations and nursing practice because it identifies the importance of a nurse in the navigator role, as well as highlights the numerous functions the NN can provide to the GI multidisciplinary team and patients.


Assuntos
Neoplasias Gastrointestinais/enfermagem , Papel do Profissional de Enfermagem , Humanos , Assistência Centrada no Paciente , Indicadores de Qualidade em Assistência à Saúde
15.
Bioorg Med Chem Lett ; 23(8): 2344-8, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23489629

RESUMO

N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11ß-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11ß-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Aminopiridinas/farmacocinética , Sulfonamidas/farmacocinética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacologia , Glutationa/farmacocinética , Células HEK293 , Humanos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
16.
J Control Release ; 161(1): 124-31, 2012 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-22521595

RESUMO

Polymeric prodrugs are one of the most promising chemotherapeutic agent delivery approaches, displaying unique drug release profiles, serum stability, formulation flexibility, and reduced drug resistance. One of the most important aspects of a polymeric prodrug, albeit a less-extensively studied one, is the polymer's molecular weight, which affects particle formation, drug release and PK/PD profiles, drug stability, and cell uptake; these factors in turn affect the prodrug's maximum tolerated dose and anticancer efficacy. Poly(L-γ-glutamylglutamine) (PGG) is a linear polymer designed to improve the therapeutic index of attached drugs. In this study we selected poly(L-γ-glutamylglutamine)-paclitaxel (PGG­PTX), as a model system for the methodical investigation into the effects of the poly(L-γ-glutamylglutamine) backbone molecular weight on its pharmacological performance. The polymeric prodrug was characterized by NMR, DLS and GPC-MALS, and its anticancer activity in vitro and in vivo was assessed. Herein we present data which provide valuable insight into improving anticancer polymer-based prodrug design and development.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/análogos & derivados , Proteínas/química , Proteínas/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Peso Molecular , Neoplasias/tratamento farmacológico , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Proteínas/farmacocinética
17.
BMC Public Health ; 10: 284, 2010 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-20507580

RESUMO

BACKGROUND: Obesity is a global public health issue. Having a BMI of 30 kg/m2 or more (classifying a person as obese) at the start of pregnancy is a significant risk factor for maternal and fetal morbidity. There is a dearth of evidence to inform suitable interventions to support pregnant women with a BMI of 30 kg/m2 or more. Here we describe a study protocol to test the feasibility of a variety of potential healthy lifestyle interventions for pregnant women with a BMI of 30 kg/m2 or more in a community based programme. METHODS/DESIGN: Four hundred women will be approached to attend a 10-week community lifestyle programme. The programme will be provided as a supplement to standard antenatal care. The programme is multi-faceted, aimed at equipping participants with the skills and knowledge needed to adopt healthy behaviours. The social (cognitive) learning theory will be used as a tool to encourage behaviour change, the behaviour change techniques are underpinned by five theoretical components; self-efficacy, outcome expectancies, goal setting, feedback and positive reinforcement.The main outcomes are pregnancy weight gain and caesarean section rate. Other important outcomes include clinical outcomes (e.g., birth weight) and psychological outcomes (e.g., well-being). Secondary outcomes include women's experience of pregnancy and health care services, amount of physical activity, food intake and the suitability of the intervention components.A prospective study using quantitative and qualitative methods will inform the feasibility of implementing the community lifestyle programme with pregnant women with a BMI of 30 kg/m2 or more. Mixed methods of data collection will be used, including diaries, focus groups/interviews, pedometers, validated and specifically designed questionnaires, a programme register, weight gain during pregnancy and perinatal outcome data. DISCUSSION: Findings from this current feasibility study will inform future interventions and NHS services and add to the evidence-base by providing information about the experiences of pregnant women with a BMI of 30 kg/m2 or more undertaking a community lifestyle programme. The study will lead on to a randomised control trial of a suitable intervention to improve the pregnancy outcomes of this target group.


Assuntos
Estilo de Vida , Obesidade/psicologia , Obesidade/terapia , Complicações na Gravidez/psicologia , Complicações na Gravidez/terapia , Adulto , Terapia Comportamental , Índice de Massa Corporal , Ensaios Clínicos como Assunto , Inglaterra , Estudos de Viabilidade , Feminino , Comportamentos Relacionados com a Saúde , Nível de Saúde , Humanos , Saúde Mental , Gravidez , Estudos Prospectivos , Projetos de Pesquisa
18.
Bioorg Med Chem Lett ; 19(13): 3493-7, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19473839

RESUMO

N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Aminopiridinas/síntese química , Inibidores Enzimáticos/síntese química , Sulfonamidas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Linhagem Celular , Simulação por Computador , Cricetinae , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética
19.
Inorg Chem ; 47(23): 11228-36, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18989922

RESUMO

The syntheses and structures of three new coordinatively unsaturated, monomeric, square-pyramidal thiolate-ligated Fe(III) complexes are described, [Fe(III)((tame-N(3))S(2)(Me2))](+) (1), [Fe(III)(Et-N(2)S(2)(Me2))(py)](1-) (3), and [Fe(III)((tame-N(2)S)S(2)(Me2))](2-) (15). The anionic bis-carboxamide, tris-thiolate N(2)S(3) coordination sphere of 15 is potentially similar to that of the yet-to-be characterized unmodified form of NHase. Comparison of the magnetic and reactivity properties of these reveals how anionic charge build up (from cationic 1 to anionic 3 and dianionic 15) and spin-state influence apical ligand affinity. For all of the ligand-field combinations examined, an intermediate S = 3/2 spin state was shown to be favored by a strong N(2)S(2) basal plane ligand field, and this was found to reduce the affinity for apical ligands, even when they are built in. This is in contrast to the post-translationally modified NHase active site, which is low spin and displays a higher affinity for apical ligands. Cationic 1 and its reduced Fe(II) precursor are shown to bind NO and CO, respectively, to afford [Fe(III)((tame-N(3))S(2)(Me))(NO)](+) (18, nu(NuO) = 1865 cm(-1)), an analogue of NO-inactivated NHase, and [Fe(II)((tame-N(3))S(2)(Me))(CO)] (16; nu(CO) stretch (1895 cm(-1)). Anions (N(3)(-), CN(-)) are shown to be unreactive toward 1, 3, and 15 and neutral ligands unreactive toward 3 and 15, even when present in 100-fold excess and at low temperatures. The curtailed reactivity of 15, an analogue of the unmodified form of NHase, and its apical-oxygenated S = 3/2 derivative [Fe(III)((tame-N(2)SO(2))S(2)(Me2))](2-) (20) suggests that regioselective post-translational oxygenation of the basal plane NHase cysteinate sulfurs plays an important role in promoting substrate binding. This is supported by previously reported theoretical (DFT) calculations.


Assuntos
Hidroliases/química , Ferro/química , Compostos Organometálicos/química , Cristalografia por Raios X , Elétrons , Hidroliases/metabolismo , Magnetismo , Compostos Organometálicos/metabolismo , Oxirredução
20.
Int J Behav Nutr Phys Act ; 5: 9, 2008 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-18269748

RESUMO

OBJECTIVES: This study seeks to determine whether perception of weight status among the overweight has changed with the increasing overweight/obesity prevalence. METHODS: The perception of weight status was compared between overweight participants (BMI between 25.0-29.9 kg/m2) from NHANES III (1988-1994) and overweight participants from NHANES 1999-2004. Perception of weight status was assessed by asking participants to classify their weight as about the right weight, underweight or overweight. Comparisons were made across age groups, genders, race/ethnicities and various income levels. RESULTS: Fewer overweight people during the NHANES 1999-2004 survey perceived themselves as overweight when compared to overweight people during the NHANES III survey. The change in distortion between the survey periods was greatest among persons with lower income, males and African-Americans. CONCLUSION: The increase in overweight/obesity between the survey years (NHANES III and NHANES 1999-2004 has been accompanied with fewer overweight people perceiving themselves as overweight.

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