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1.
Crit Care ; 18(1): R17, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24428878

RESUMO

INTRODUCTION: Pseudomonas aeruginosa frequently causes nosocomial pneumonia and is associated with poor outcome. The purpose of this study was to assess the prevalence and clinical outcome of nosocomial pneumonia caused by serotype-specific P. aeruginosa in critically ill patients under appropriate antimicrobial therapy management. METHODS: A retrospective, non-interventional epidemiological multicenter cohort study involving 143 patients with confirmed nosocomial pneumonia caused by P. aeruginosa. Patients were analyzed for a period of 30 days from time of nosocomial pneumonia onset. Fourteen patients fulfilling the same criteria from a phase IIa studyconducted at the same time/centers were included in the prevalence calculations but not in the clinical outcome analysis. RESULTS: The prevalence of serotypes was: O6 (29%), O11 (23%), O10 (10%), O2 (9%), and O1 (8%). Serotypes with a prevalence of less than 5% were found in 13% of patients, 8% were classified as not typeable. Across all serotypes, 19% mortality, 70% clinical resolution, 11% clinical continuation, and 5% clinical recurrence were recorded. Age and higher APACHE II (Acute Physiology and Chronic Health Evaluation II) were predictive risk factors associated with probability of death and lower clinical resolution for P. aeruginosa nosocomial pneumonia. Mortality tends to be higher with O1 (40%) and lower with O2 (0%); clinical resolution tends to be better with O2 (82%) compared to other serotypes. Persisting pneumonia with O6 and O11 was, respectively, 8% and 21%; clinical resolution with O6 and O11 was, respectively, 75% and 57%. CONCLUSIONS: In P. aeruginosa nosocomial pneumonia, the most prevalent serotypes were O6 and O11. Further studies including larger group sizes are needed to correlate clinical outcome with virulence factors of P. aeruginosa in patients with nosocomial pneumonia caused by various serotypes; and to compare O6 and O11, the two serotypes most frequently encountered in critically ill patients.


Assuntos
Infecção Hospitalar/sangue , Pneumonia Bacteriana/sangue , Infecções por Pseudomonas/sangue , Pseudomonas aeruginosa/isolamento & purificação , Adulto , Idoso , Estudos de Coortes , Infecção Hospitalar/diagnóstico , Infecção Hospitalar/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Bacteriana/diagnóstico , Pneumonia Bacteriana/mortalidade , Prevalência , Infecções por Pseudomonas/diagnóstico , Infecções por Pseudomonas/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
2.
J Med Microbiol ; 63(Pt 4): 508-517, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24430251

RESUMO

Pseudomonas aeruginosa is a common cause of nosocomial infections and is associated with high rates of mortality. In order to facilitate rapid and sensitive identification of the most prevalent serotypes of P. aeruginosa, we have developed a 4-valent real-time PCR-based assay using oligonucleotides specific for open-reading frames constituting the O-antigen-specific lipopolysaccharide loci of P. aeruginosa. The assay simultaneously detects and differentiates between each of the four serotypes IATS-O1, -O6, -O11 and serogroup 2 (IATS-O2, -O5, and -O16) with high sensitivity and specificity in a single-tube reaction. No cross-reactivity was observed with other serotypes of P. aeruginosa or other microbial species, and reproducibility was demonstrated regardless of template, i.e. purified DNA, bacterial culture and clinical specimens (broncho-alveolar lavage). The limit of detection of the assay was approximately 100 copies per reaction for IATS-O1, -O2 and -O11, and 50 copies per reaction for IATS-O6. Comparison of the assay specificity with a commercially available slide agglutination kit showed consistent results; however, the number of non-typable isolates was reduced by 15 % using the genotyping assay. Use of the 4-valent genotyping assay in the context of a clinical trial resulted in identification of pneumonia patients positive for the IATS-O11 serotype, and hence eligible for therapy with panobacumab (an investigational monoclonal antibody against the O-polysaccharide of serotype IATS-O11).


Assuntos
Técnicas Bacteriológicas/métodos , Técnicas de Diagnóstico Molecular/métodos , Pneumonia Bacteriana/diagnóstico , Infecções por Pseudomonas/diagnóstico , Pseudomonas aeruginosa/classificação , Pseudomonas aeruginosa/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Genótipo , Humanos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/genética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
3.
PLoS One ; 8(9): e73396, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24023870

RESUMO

Pseudomonas aeruginosa (P. aeruginosa) infections are associated with considerable morbidity and mortality in immunocompromised patients due to antibiotic resistance. Therefore, we investigated the efficacy of the anti-P. aeruginosa serotype O11 lipopolysaccharide monoclonal antibody Panobacumab in a clinically relevant murine model of neutropenia induced by cyclophosphamide and in combination with meropenem in susceptible and meropenem resistant P. aeruginosa induced pneumonia. We observed that P. aeruginosa induced pneumonia was dramatically increased in neutropenic mice compared to immunocompetent mice. First, Panobacumab significantly reduced lung inflammation and enhanced bacterial clearance from the lung of neutropenic host. Secondly, combination of Panobacumab and meropenem had an additive effect. Third, Panobacumab retained activity on a meropenem resistant P. aeruginosa strain. In conclusion, the present data established that Panobacumab contributes to the clearance of P. aeruginosa in neutropenic hosts as well as in combination with antibiotics in immunocompetent hosts. This suggests beneficial effects of co-treatment even in immunocompromised individuals, suffering most of the morbidity and mortality of P. aeruginosa infections.


Assuntos
Anticorpos Antibacterianos/farmacologia , Anticorpos Monoclonais/farmacologia , Neutropenia/complicações , Pneumonia/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/imunologia , Tienamicinas/farmacologia , Doença Aguda , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anticorpos Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Meropeném , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/complicações , Pseudomonas aeruginosa/fisiologia , Tienamicinas/uso terapêutico
4.
Respir Med ; 107(10): 1558-67, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23867808

RESUMO

BACKGROUND: QVA149 is an inhaled, once-daily fixed-dose dual bronchodilator combination of the long-acting ß2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium (NVA237) for the treatment of chronic obstructive pulmonary disease (COPD). We investigated the safety and efficacy of QVA149 over 52 weeks. METHODS: This 52-week, multicenter, double-blind, parallel-group, placebo-controlled study randomized (2:1) patients with moderate-to-severe COPD to once-daily QVA149 (110 µg indacaterol/50 µg glycopyrronium) or placebo delivered via the Breezhaler device. Primary endpoint was safety and tolerability for treatment-emergent adverse events (AEs). Secondary endpoints included safety based on vital signs, electrocardiograms (ECGs), laboratory evaluations, and pre-dose forced expiratory volume in 1 s (FEV1). RESULTS: Of 339 patients randomized, QVA149 [n = 226], placebo [n = 113]; 76.9% male, mean age: 62.6 years, post-bronchodilator FEV1: 57.4% predicted, 83.5% completed study. A smaller percentage of patients discontinued in the QVA149 group (14.2%) compared with placebo (21.2%). Overall incidence of AEs was similar in the QVA149 (57.8%) and placebo (56.6%) groups, with most AEs being mild to moderate in severity. The numerical differences in some AEs observed could be at least in part explained by differences in baseline patient characteristics. No clinically relevant differences were observed between treatment groups for vital signs or ECG parameters. The five deaths reported were unrelated to study medication (QVA149, n = 4 [1.8%]; placebo, n = 1 [0.9%]). QVA149 demonstrated rapid and clinically meaningful bronchodilation sustained over 52 weeks versus placebo. CONCLUSION: QVA149 demonstrated a good safety and tolerability profile, providing rapid and sustained bronchodilation over 52 weeks in patients with moderate-to-severe COPD. ClinicalTrials.gov identifier: NCT01120717.


Assuntos
Broncodilatadores/uso terapêutico , Glicopirrolato/análogos & derivados , Indanos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Idoso , Broncodilatadores/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Glicopirrolato/efeitos adversos , Glicopirrolato/uso terapêutico , Humanos , Indanos/efeitos adversos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinolonas/efeitos adversos , Espirometria , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacos
5.
J Antimicrob Chemother ; 66(5): 1110-6, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21398296

RESUMO

OBJECTIVES: Nosocomial Pseudomonas aeruginosa pneumonia remains a major concern in critically ill patients. We explored the potential impact of microorganism-targeted adjunctive immunotherapy in such patients. PATIENTS AND METHODS: This multicentre, open pilot Phase 2a clinical trial (NCT00851435) prospectively evaluated the safety, pharmacokinetics and potential efficacy of three doses of 1.2 mg/kg panobacumab, a fully human monoclonal anti-lipopolysaccharide IgM, given every 72 h in 18 patients developing nosocomial P. aeruginosa (serotype O11) pneumonia. RESULTS: Seventeen out of 18 patients were included in the pharmacokinetic analysis. In 13 patients receiving three doses, the maximal concentration after the third infusion was 33.9 ±â€Š8.0 µg/mL, total area under the serum concentration-time curve was 5397 ±â€Š1993 µg h/mL and elimination half-life was 102.3 ±â€Š47.8 h. Panobacumab was well tolerated, induced no immunogenicity and was detected in respiratory samples. In contrast to Acute Physiology and Chronic Health Evaluation II (APACHE II) prediction, all 13 patients receiving three doses survived, with a mean clinical resolution in 9.0 ±â€Š2.7 days. Two patients suffered a recurrence at days 17 and 20. CONCLUSIONS: These data suggest that panobacumab is safe, with a pharmacokinetic profile similar to that in healthy volunteers. It was associated with high clinical cure and survival rates in patients developing nosocomial P. aeruginosa O11 pneumonia. We concluded that these promising results warrant further trials.


Assuntos
Anticorpos Antibacterianos/efeitos adversos , Infecção Hospitalar/tratamento farmacológico , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/farmacocinética , Pneumonia Bacteriana/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/administração & dosagem , Estado Terminal , Feminino , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pseudomonas aeruginosa/imunologia
9.
Antimicrob Agents Chemother ; 54(6): 2338-44, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20308370

RESUMO

Pseudomonas aeruginosa infection in ventilator-associated pneumonia is a serious and often life-threatening complication in intensive care unit patients, and new treatment options are needed. We used B-cell-enriched peripheral blood lymphocytes from a volunteer immunized with a P. aeruginosa O-polysaccharide-toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individual P. aeruginosa lipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/kappa antibody that binds P. aeruginosa of International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 x 10(7) M(-1) +/- 2.8 x 10(7) M(-1)) without cross-reacting with other serotypes. KBPA101 specifically opsonized the P. aeruginosa of IATS O11 serotype and mediated complement-dependent phagocytosis in vitro by the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml). In vivo evaluation of KBPA101 demonstrated a dose-response relationship for protection against systemic infections in a murine burn wound sepsis model, where 70 to 100% of animals were protected against lethal challenges with P. aeruginosa at doses as low as 5 microg/animal. Furthermore, a high efficacy of KBPA101 in protection from local respiratory infections in an acute lung infection model in mice was demonstrated. Preclinical toxicology evaluation on human tissue, in rabbits, and in mice did not indicate any toxicity of KBPA101. Based on these preclinical findings, the first human clinical trials have been initiated.


Assuntos
Anticorpos Antibacterianos/imunologia , Anticorpos Monoclonais/imunologia , Imunoglobulina M/imunologia , Pseudomonas aeruginosa/imunologia , Animais , Anticorpos Antibacterianos/uso terapêutico , Anticorpos Antibacterianos/toxicidade , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/toxicidade , Afinidade de Anticorpos , Especificidade de Anticorpos , Sequência de Bases , Linhagem Celular , Proteínas do Sistema Complemento/metabolismo , Primers do DNA/genética , Modelos Animais de Doenças , Células HL-60 , Humanos , Hibridomas/imunologia , Imunoglobulina M/uso terapêutico , Imunoglobulina M/toxicidade , Técnicas In Vitro , Camundongos , Fagocitose , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/prevenção & controle , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/prevenção & controle , Infecções por Pseudomonas/terapia , Pseudomonas aeruginosa/classificação , Pseudomonas aeruginosa/genética , Coelhos , Sepse/imunologia , Sepse/prevenção & controle , Sepse/terapia , Sorotipagem
10.
J Pharm Biomed Anal ; 51(5): 1084-90, 2010 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-20005064

RESUMO

IgM aggregates in biotechnologically produced preparations have been reported, however, in vitro characteristics and in vivo activity of IgM aggregates have not been well studied. We separated two species of the human monoclonal IgM antibody KBPA-101 by size-exclusion chromatography. Molecular weight determination indicated the presence of dipentameric and pentameric forms. We present here the results of a comparative characterization of these IgM species, including in vitro and in vivo effector function against Pseudomonas aeruginosa. Dipentameric (IgM)(2) species were observed to dissociate into pentameric IgM at 37 degrees C, suggesting a dynamic equilibrium, in which the pentameric species is the predominant form. In vitro antigen binding (P. aeruginosa LPS) and IgM-mediated complement-dependent phagocytosis of labeled bacterial cells did not differ significantly between the dipentameric (IgM)(2) and pentameric IgM species. Furthermore, the in vivo efficacy of dipentameric and pentameric IgM in protecting mice from a lethal dose of P. aeruginosa through passive immunization was nearly equivalent. In conclusion, low concentrations of dipentameric (IgM)(2) may contain an additional but equally active component of the principal biological form. The data presented in this work support the conclusion that the pentameric form of IgM directed against the O-polysaccharide moiety of P. aeruginosa serotype IATS-O11 and dipentameric (IgM)(2) are functionally equivalent.


Assuntos
Antibacterianos/farmacologia , Anticorpos Monoclonais/farmacologia , Queimaduras/microbiologia , Imunoglobulina M/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Afinidade de Anticorpos , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células HL-60 , Humanos , Hibridomas , Imunoglobulina M/química , Imunoglobulina M/uso terapêutico , Camundongos , Peso Molecular , Antígenos O/imunologia , Fagocitose/efeitos dos fármacos , Multimerização Proteica , Estabilidade Proteica , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/imunologia
16.
Prim Care Respir J ; 12(1): 16-20, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31700337

RESUMO

Chronic obstructive pulmonary disease (COPD) is a major global problem and its prevalence is increasing; yet under- or misdiagnosis is widespread, possibly due to clinical misinterpretation of symptoms, or lack of symptom reporting by patients. Increasing awareness of COPD, and the implementation of effective screening programmes and treatment strategies in primary care could significantly improve management of the disease.

17.
J Immunol ; 169(6): 3242-9, 2002 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12218143

RESUMO

High-risk human papillomaviruses are linked to several malignancies including cervical cancer. Because human papillomavirus-infected women do not always mount protective antiviral immunity, we explored the interaction of human papillomavirus with Langerhans cells, which would be the first APCs the virus comes into contact with during infection. We determined that dendritic cells, normally targeted by vaccination procedures and Langerhans cells, normally targeted by the natural virus equally internalize human papillomavirus virus-like particles. However, in contrast to dendritic cells, Langerhans cells are not activated by human papillomavirus virus-like particles, illustrated by the lack of: up-regulating activation markers, secreting IL-12, stimulating T cells in an MLR, inducing human papillomavirus-specific immunity, and migrating from epidermal tissue. Langerhans cells, like dendritic cells, can display all of these characteristics when stimulated by proinflammatory agents. These data may define an intriguing immune escape mechanism used by human papillomavirus and form the basis for designing optimal vaccination strategies.


Assuntos
Células de Langerhans/imunologia , Células de Langerhans/virologia , Papillomaviridae/imunologia , Vírion/imunologia , Animais , Antígenos CD/biossíntese , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/ultraestrutura , Células Dendríticas/virologia , Células Epidérmicas , Epiderme/imunologia , Epiderme/virologia , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Interleucina-12/metabolismo , Células de Langerhans/metabolismo , Células de Langerhans/ultraestrutura , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/ultraestrutura , Monócitos/virologia , Técnicas de Cultura de Órgãos , Papillomaviridae/genética , Papillomaviridae/metabolismo , Papillomaviridae/ultraestrutura , Fagocitose/imunologia , Subunidades Proteicas , Proteínas Recombinantes de Fusão/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Regulação para Cima/imunologia , Vírion/genética , Vírion/metabolismo , Vírion/ultraestrutura
18.
Nat Med ; 8(9): 979-86, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12185362

RESUMO

Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wild-type Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.


Assuntos
Transformação Celular Neoplásica/genética , Proteínas de Membrana/metabolismo , Receptores de Superfície Celular , Transdução de Sinais/genética , Fatores de Transcrição , Proteínas ras/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Células Cultivadas , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Camundongos , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fenótipo , Presenilina-1 , Receptor Notch1 , Regulação para Cima , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno , Proteínas ras/genética
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