Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 63
Filtrar
1.
N Engl J Med ; 386(15): 1421-1431, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35417637

RESUMO

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).


Assuntos
Inibidores de Proteínas Quinases , Púrpura Trombocitopênica Idiopática , Administração Oral , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Humanos , Contagem de Plaquetas , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Resultado do Tratamento
2.
Bioconjug Chem ; 34(11): 1951-2000, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37821099

RESUMO

Antibody-drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently among the most promising drug classes in oncology, with efforts to expand their application for nononcological indications and in combination therapies. Here we provide a detailed overview of the recent advances in ADC research and consider future directions and challenges in promoting this promising platform to widespread therapeutic use. We examine data from the CAS Content Collection, the largest human-curated collection of published scientific information, and analyze the publication landscape of recent research to reveal the exploration trends in published documents and to provide insights into the scientific advances in the area. We also discuss the evolution of the key concepts in the field, the major technologies, and their development pipelines with company research focuses, disease targets, development stages, and publication and investment trends. A comprehensive concept map has been created based on the documents in the CAS Content Collection. We hope that this report can serve as a useful resource for understanding the current state of knowledge in the field of ADCs and the remaining challenges to fulfill their potential.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Imunoconjugados/uso terapêutico , Antineoplásicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico
3.
Phys Rev Lett ; 130(22): 223401, 2023 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-37327422

RESUMO

We demonstrate the formation of a single RbCs molecule during the merging of two optical tweezers, one containing a single Rb atom and the other a single Cs atom. Both atoms are initially predominantly in the motional ground states of their respective tweezers. We confirm molecule formation and establish the state of the molecule formed by measuring its binding energy. We find that the probability of molecule formation can be controlled by tuning the confinement of the traps during the merging process, in good agreement with coupled-channel calculations. We show that the conversion efficiency from atoms to molecules using this technique is comparable to magnetoassociation.


Assuntos
Eritrócitos , Pinças Ópticas , Movimento (Física) , Probabilidade
4.
J Org Chem ; 88(7): 4031-4035, 2023 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-37026384

RESUMO

Organic synthesis continues to drive a broad range of research advances in chemistry and related sciences. Another clear trend in organic synthesis research is the increasing desire to target improvements in the quality of life of humankind, new materials, and product specificity. Here, a landscape view of organic synthesis research is provided by analysis of the CAS Content Collection. Three emerging research directions, enzyme catalysis, photocatalysis, and green chemistry in organic synthesis, were identified and featured based on the publication trend analysis.

5.
Med J Aust ; 216(1): 43-52, 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-34628650

RESUMO

INTRODUCTION: The absence of high quality evidence for basic clinical dilemmas in immune thrombocytopenic purpura (ITP) underlines the need for contemporary guidelines relevant to the local treatment context. ITP is diagnosed by exclusions, with a hallmark laboratory finding of isolated thrombocytopenia. MAIN RECOMMENDATIONS: Bleeding, family and medication histories and a review of historical investigations are required to gauge the bleeding risk and possible hereditary syndromes. Beyond the platelet count, the decision to treat is affected by individual bleeding risk, disease stage, side effects of treatment, concomitant medications, and patient preference. Treatment is aimed at achieving a platelet count > 20 × 109 /L, and avoidance of severe bleeding. Steroids are the standard first line treatment, with either 6-week courses of tapering prednisone or repeated courses of high dose dexamethasone providing equivalent efficacy. Intravenous immunoglobulin can be used periprocedurally or as first line therapy in combination with steroids. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: There is no consensus on choice of second line treatments. Options with the most robust evidence include splenectomy, rituximab and thrombopoietin receptor agonists. Other therapies include azathioprine, mycophenolate mofetil, dapsone and vinca alkaloids. Given that up to one-third of patients achieve a satisfactory haemostatic response, splenectomy should be delayed for at least 12 months if possible. In life-threatening bleeding, we recommend platelet transfusions to achieve haemostasis, along with intravenous immunoglobulin and high dose steroids.


Assuntos
Transfusão de Plaquetas/normas , Guias de Prática Clínica como Assunto , Púrpura Trombocitopênica Idiopática/terapia , Esplenectomia/normas , Adulto , Austrália , Consenso , Quimioterapia Combinada/normas , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Nova Zelândia , Preferência do Paciente , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Rituximab/uso terapêutico
6.
Platelets ; 33(3): 329-338, 2022 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-34166171

RESUMO

Aspirin, an antiplatelet drug, is commonly used at low doses for numerous indications, including prophylaxis of cardiovascular, neurovascular, and venous thromboembolic events. Due to review articles suggesting that aspirin resistance may result in poorer outcomes, interest in assessing platelet function is increasing. Despite this, platelet function tests are rarely used as part of routine clinical practice and therefore, a basic understanding of these tests may be lacking. Although aspirin resistance can be categorized as clinical or laboratory resistance, determining laboratory resistance is the only way to determine resistance before treatment failure occurs. Therefore, knowledge of platelet assays to determine aspirin resistance is of importance. The following review aims to provide a framework for clinicians to understand the main principles of platelet function tests. This includes comparison of the most frequently used platelet assays to diagnose aspirin resistance, including the basic mechanism, methodology, reference ranges, inter-assay comparison, and their respective clinical considerations when using.


Assuntos
Aspirina/uso terapêutico , Bioensaio/métodos , Resistência a Medicamentos/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária/métodos , Aspirina/farmacologia , Humanos , Inibidores da Agregação Plaquetária/farmacologia
7.
Bioconjug Chem ; 32(12): 2457-2479, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34846126

RESUMO

Bioorthogonal chemistry is a set of methods using the chemistry of non-native functional groups to explore and understand biology in living organisms. In this review, we summarize the most common reactions used in bioorthogonal methods, their relative advantages and disadvantages, and their frequency of occurrence in the published literature. We also briefly discuss some of the less common but potentially useful methods. We then analyze the bioorthogonal-related publications in the CAS Content Collection to determine how often different types of biomolecules such as proteins, carbohydrates, glycans, and lipids have been studied using bioorthogonal chemistry. The most prevalent biological and chemical methods for attaching bioorthogonal functional groups to these biomolecules are elaborated. We also analyze the publication volume related to different types of bioorthogonal applications in the CAS Content Collection. The use of bioorthogonal chemistry for imaging, identifying, and characterizing biomolecules and for delivering drugs to treat disease is discussed at length. Bioorthogonal chemistry for the surface attachment of proteins and in the use of modified carbohydrates is briefly noted. Finally, we summarize the state of the art in bioorthogonal chemistry and its current limitations and promise for its future productive use in chemistry and biology.


Assuntos
Azidas , Azidas/química , Reação de Cicloadição
8.
Blood ; 131(16): 1809-1819, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29449276

RESUMO

Much focus has been on the interaction of programmed cell death ligand 1 (PD-L1) on malignant B cells with programmed cell death 1 (PD-1) on effector T cells in inhibiting antilymphoma immunity. We sought to establish the contribution of natural killer (NK) cells and inhibitory CD163+ monocytes/macrophages in Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). Levels of PD-1 on NK cells were elevated in cHL relative to DLBCL. Notably, CD3-CD56hiCD16-ve NK cells had substantially higher PD-1 expression relative to CD3-CD56dimCD16+ cells and were expanded in blood and tissue, more marked in patients with cHL than patients with DLBCL. There was also a raised population of PD-L1-expressing CD163+ monocytes that was more marked in patients with cHL compared with patients with DLBCL. The phenotype of NK cells and monocytes reverted back to normal once therapy (ABVD [doxorubicin 25 mg/m2, bleomycin 10 000 IU/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2, all given days 1 and 15, repeated every 28 days] or R-CHOP [rituximab 375 mg/m2, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 (2 mg maximum) IV, prednisone 100 mg/day by mouth days 1-5, pegfilgrastim 6 mg subcutaneously day 4, on a 14-day cycle]) had commenced. Tumor-associated macrophages (TAMs) expressed high levels of PD-L1/PD-L2 within diseased lymph nodes. Consistent with this, CD163/PD-L1/PD-L2 gene expression was also elevated in cHL relative to DLBCL tissues. An in vitro functional model of TAM-like monocytes suppressed activation of PD-1hi NK cells, which was reversed by PD-1 blockade. In line with these findings, depletion of circulating monocytes from the blood of pretherapy patients with cHL and patients with DLBCL enhanced CD3-CD56hiCD16-ve NK-cell activation. We describe a hitherto unrecognized immune evasion strategy mediated via skewing toward an exhausted PD-1-enriched CD3-CD56hiCD16-ve NK-cell phenotype. In addition to direct inhibition of NK cells by the malignant B cell, suppression of NK cells can occur indirectly by PD-L1/PD-L2-expressing TAMs. The mechanism is more prominent in cHL than DLBCL, which may contribute to the clinical sensitivity of cHL to PD-1 blockade.


Assuntos
Antígeno B7-H1/imunologia , Doença de Hodgkin/imunologia , Células Matadoras Naturais/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Macrófagos/imunologia , Modelos Imunológicos , Monócitos/imunologia , Proteínas de Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral , Adulto , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Células Matadoras Naturais/patologia , Linfonodos/imunologia , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Macrófagos/patologia , Masculino , Monócitos/patologia , Prednisona/administração & dosagem , Rituximab , Vimblastina/administração & dosagem , Vincristina/administração & dosagem
9.
Am J Hematol ; 95(6): 643-651, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32129511

RESUMO

Romiplostim self-administration by patients or caregivers may offer time/cost savings to healthcare professionals (HCPs) and convenience for patients who avoid weekly clinic visits. We performed an integrated analysis of five clinical trials to evaluate the efficacy and safety of romiplostim self-administration. Data were analyzed from adults with immune thrombocytopenia (ITP) who received weekly romiplostim via self-administration or from an HCP. Patients who achieved a stable romiplostim dose for ≥3 weeks (HCP group ≥5 weeks to provide an appropriate index date to enable comparisons with the self-administration group) with platelet counts ≥50 × 109 /L were eligible. In the self-administration (n = 621) vs HCP (n = 133) groups, respectively, median age was 53 vs 58 years, median time since primary ITP diagnosis was 3.7 vs 2.5 years, and median baseline platelet count at ITP diagnosis was 19.0 vs 20.0 × 109 /L. In the self-administration and HCP-dosed groups, median romiplostim treatment duration was 89 vs 52 weeks and median total number of doses was 81 vs 50, respectively. In the self-administration and HCP groups, respectively: 95.0% and 100.0% of patients achieved ≥1 platelet response (defined as weekly platelet count ≥50 × 109 /L without rescue medication in previous 4 weeks); the median percentage of weeks with a response was 94.5% and 95.9%; and rescue medication was used in 36.7% and 39.8% of patients. Self-administration did not adversely affect safety; duration-adjusted rates for all treatment-emergent adverse events (TEAEs) and bleeding TEAEs were numerically lower with self-administration. Romiplostim self-administration appears effective and well tolerated in eligible patients with ITP.


Assuntos
Bases de Dados Factuais , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Trombopoetina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Proteínas Recombinantes de Fusão/efeitos adversos , Autoadministração , Trombopoetina/efeitos adversos
10.
Platelets ; 31(3): 285-290, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31269407

RESUMO

Thrombocytopenia is a common reason for referral to hematologists in community and hospital practice. A broad differential diagnosis, combined with the potentially life-threatening nature of some presentations necessitates a rapid evaluation of the situation and potential need for emergency intervention; followed by further comprehensive investigation to confirm the diagnosis and institution of longer term management. This review offers an approach to the initial assessment, diagnosis, and referral. We then highlight aspects of the clinical history, examination and laboratory investigations which may provide critical insights into the most likely diagnosis. ITP is the commonest cause of severe isolated thrombocytopenia in the general community and is the most common cause of thrombocytopenia in patients referred to our hematology service. It remains a diagnosis of exclusion and a high degree of vigilance for alternative diagnoses should be maintained, particularly if presentations are atypical or expected response to treatment is not seen. Adult presentation of hereditary thrombocytopenia syndromes can mimic new onset thrombocytopenia, however, improving access to genetic testing will facilitate accurate diagnosis and avoid unnecessary treatment.


Assuntos
Trombocitopenia/diagnóstico , Trombocitopenia/terapia , Diagnóstico Diferencial , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Trombocitopenia/epidemiologia , Trombocitopenia/etiologia
12.
Aust N Z J Psychiatry ; 53(5): 403-412, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30864459

RESUMO

BACKGROUND: In most countries, clozapine can only be prescribed with regular monitoring of white blood cell counts because of concerns that clozapine has a stronger association with neutropenia than other antipsychotics. However, this has not been previously demonstrated conclusively with meta-analysis of controlled studies. METHODS: The aim of this study was to assess the strength of the association between clozapine and neutropenia when compared to other antipsychotic medications by a meta-analysis of controlled studies. An electronic search of Medline (1948-2018), PsycINFO (1967-2018) and Embase (1947-2018) using search terms (clozapine OR clopine OR clozaril OR zaponex) AND (neutropenia OR agranulocytosis) was undertaken. Random-effects meta-analysis using Mantel-Haenszel risk ratio was used to assess the strength of the effect size. RESULTS: We located 20 studies that reported rates of neutropenia associated with clozapine and other antipsychotic medications. The risk ratio was not significantly increased in clozapine-exposed groups compared to exposure to other antipsychotic medications (Mantel-Haenszel risk ratio = 1.45, 95% confidence interval = [0.87, 2.42]). This also applied to severe neutropenia (absolute neutrophil count < 500 per µL) when compared to other antipsychotics (Mantel-Haenszel risk ratio = 1.65, 95% confidence interval = [0.58, 4.71]). The relative risk of neutropenia associated with clozapine exposure was not significantly associated with any individual antipsychotic medication. CONCLUSION: Data from controlled trials do not support the belief that clozapine has a stronger association with neutropenia than other antipsychotic medications. This implies that either all antipsychotic drugs should be subjected to haematological monitoring or monitoring isolated to clozapine is not justified.


Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Ensaios Clínicos Controlados como Assunto , Neutropenia/induzido quimicamente , Humanos
13.
Platelets ; 29(8): 793-800, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29090586

RESUMO

MYH9-related disorders (MYH9-RDs) caused by mutation of the MYH9 gene which encodes non-muscle myosin heavy-chain-IIA (NMMHC-IIA), an important motor protein in hemopoietic cells, are the most commonly encountered cause of inherited macrothrombocytopenia. Despite distinguishing features including an autosomal dominant mode of inheritance, giant platelets on the peripheral blood film accompanied by leucocytes with cytoplasmic inclusion bodies (döhle-like bodies), these disorders remain generally under-recognized and often misdiagnosed as immune thrombocytopenia (ITP). This may result in inappropriate treatment with corticosteroids, immunosupressants and in some cases, splenectomy. We explored the efficacy of next generation sequencing (NGS) with a candidate gene panel to establish the aetiology of thrombocytopenia for individuals who had been referred to our center from hematologists in the Australasian region in whom the cause of thrombocytopenia was suspected to be secondary to an inherited condition but which remained uncharacterized despite phenotypic investigations. Pathogenic MYH9 variants were detected in 15 (15/121, 12.4%) individuals and the pathogenecity of a novel variant of uncertain significance was confirmed in a further two related individuals following immunofluorescence (IF) staining performed in our laboratory. Concerningly, only one (1/17) individual diagnosed with MYH9-RD had been referred with this as a presumptive diagnosis, in all other cases (16/17, 94.1%), a diagnosis was not suspected by referring clinicians, indicating a lack of awareness or a failing of our diagnostic approach to these conditions. We examined the mean platelet diameter (MPD) measurements as a means to better identify and quantify platelet size. MPDs in cases with MYH9-RDs were significantly larger than controls (p < 0.001) and in 91% were greater than a previously suggested threshold for platelets in cases of ITP. In addition, we undertook IF staining in a proportion of cases and confirm that this test and/or NGS are satisfactory diagnostic tests. We propose that fewer cases of MYH9-RDs would be missed if diagnostic algorithms prioritized IF and/or NGS in cases of thrombocytopenia associated with giant platelets, even if döhle-like bodies are not appreciated on the peripheral blood film. Finally, our report describes the long-term use of a thrombopoietin agonist in a case of MYH9-RD that had previously been diagnosed as ITP, and demonstrates that treatment with these agents may be possible, and is well tolerated, in this group of patients.


Assuntos
Plaquetas/metabolismo , Perda Auditiva Neurossensorial/genética , Mutação , Cadeias Pesadas de Miosina/genética , Púrpura Trombocitopênica Idiopática/genética , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/congênito , Trombopoetina/uso terapêutico , Adulto , Australásia , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Tamanho Celular , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Genes Dominantes , Perda Auditiva Neurossensorial/sangue , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Corpos de Inclusão/efeitos dos fármacos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Volume Plaquetário Médio , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/sangue , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/genética
15.
Aust N Z J Psychiatry ; 51(10): 980-989, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28747065

RESUMO

BACKGROUND: Clozapine is the most effective medication for treatment-refractory schizophrenia; however, its use is contraindicated in people who have had previous clozapine-induced neutropenia. Co-prescription of granulocyte-colony stimulating factor may prevent recurrent neutropenia and allow continuation or rechallenge of clozapine. OBJECTIVE AND METHODS: Systematic review of literature reporting the use of granulocyte-colony stimulating factor to allow rechallenge or continuation of clozapine in people with previous episodes of clozapine-induced neutropenia. The efficacy of granulocyte-colony stimulating factor and predictors of successful rechallenge will be determined to elucidate whether evidence-based recommendations can be made regarding the use of granulocyte-colony stimulating factor in this context. RESULTS: A total of 17 articles were identified that reported on clozapine rechallenge with granulocyte-colony stimulating factor support. In all, 76% of cases were able to continue clozapine at median follow-up of 12 months. There were no clear clinical or laboratory predictors of successful rechallenge; however, initial neutropenia was more severe in successful cases compared to unsuccessful cases. Cases co-prescribed lithium had lower success rates of rechallenge (60%) compared to those who were not prescribed lithium (81%). The most commonly reported rechallenge strategy was use of filgrastim 150-480 µg between daily to three times a week. There were no medication-specific side effects of granulocyte-colony stimulating factor reported apart from euphoria in one case. Three cases who failed granulocyte-colony stimulating factor had bacterial infection at time of recurrent neutropenia. No deaths were reported. CONCLUSION: Preliminary data suggest granulocyte-colony stimulating factor is safe and effective in facilitating rechallenge with clozapine. Clinical recommendations for use are discussed.


Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos
17.
Br J Haematol ; 168(4): 576-82, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25271366

RESUMO

The myelodysplastic syndromes (MDS) are a group of disorders characterized by ineffective haematopoiesis, bone marrow dysplasia and cytopenias. Failure of red cell production often results in transfusion dependency with subsequent iron loading requiring iron chelation in lower risk patients. Consistent with previous reports, we have observed haematopoietic improvement in a cohort of patients treated with the oral iron chelator deferasirox (DFX). It has been postulated that MDS patients have a pro-inflammatory bone marrow environment with increased numbers of activated T cells producing elevated levels of tumour necrosis factor (TNF), which is detrimental to normal haematopoiesis. We demonstrate that DFX inhibits nuclear factor (NF)-κB dependent transcription without affecting its proximal activation, resulting in reduced TNF production from T cells stimulated in vitro. These results suggest that the haematopoietic improvement observed in DFX-treated patients may reflect an anti-inflammatory effect, mediated through inhibition of the transcription factor NF-κB and support the therapeutic targeting of this pathway, which is aberrantly activated in a large proportion of haematological malignancies.


Assuntos
Anemia Aplástica/genética , Benzoatos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Síndromes Mielodisplásicas/genética , NF-kappa B/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos , Triazóis/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Anemia Aplástica/tratamento farmacológico , Animais , Benzoatos/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Linhagem Celular , Células Cultivadas , Deferasirox , Desferroxamina/farmacologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Síndromes Mielodisplásicas/tratamento farmacológico , RNA Longo não Codificante , Triazóis/uso terapêutico , Fator de Necrose Tumoral alfa/genética
18.
Eur J Haematol ; 94(2): 169-76, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25039799

RESUMO

OBJECTIVE: This post hoc analysis evaluated romiplostim self-administration (SA group) vs. romiplostim administration by a healthcare provider in a clinical setting (HCP group) in patients with chronic immune thrombocytopenia (ITP). METHODS: Outcomes from 3 ITP trials allowing self-administration in patients achieving a stable romiplostim dose for ≥3 consecutive weeks were compared. Evaluations were conducted for 12-wk treatment intervals. Efficacy endpoints included percentage of patients and weeks with platelets within the target range of 50-200 × 10(9) /L and safety. RESULTS: Baseline characteristics suggested less severe disease in the SA groups (n = 563) than in the HCP groups (n = 241). The SA groups had greater proportions of patients achieving the target platelet range (55-58% vs. 40-52%) and greater proportions of weeks with a platelet response (75-88% vs. 47-76%) than the HCP groups. The rate of romiplostim discontinuation was twofold to fivefold lower in the SA groups than in the HCP groups. Rates of duration-adjusted adverse events (AEs), serious AEs and treatment-related AEs were also lower in the SA groups. CONCLUSIONS: In conclusion, in adults with ITP receiving romiplostim, self-administration was comparable to healthcare provider administration in terms of efficacy and safety profiles, suggesting that self-administration of romiplostim is a feasible option for certain patients with ITP.


Assuntos
Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Doença Crônica , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Púrpura Trombocitopênica Idiopática/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Fc/administração & dosagem , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Autoadministração , Trombopoetina/administração & dosagem , Trombopoetina/efeitos adversos , Resultado do Tratamento
19.
Acta Haematol ; 134(4): 215-28, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26066765

RESUMO

Romiplostim is recommended for the second- and third-line treatment of primary immune thrombocytopenia (ITP). We conducted a large, single-arm study (clinicaltrials.gov; NCT00508820) with broad entry criteria to evaluate the safety of romiplostim in adult ITP. Patients (n = 407) with ITP lasting 0.03-57.14 years and low platelet counts (median 14.0 × 10 9 /l) or uncontrolled bleeding received romiplostim for up to 4 years. The rates of treatment-related, serious adverse events, serious hemorrhage events, thromboembolic events and fatal events were similar to those reported in previous romiplostim trials (0.2, 0.4, 0.2 and 0.1/100 patient-weeks, respectively). Bone marrow reticulin was observed in 4 patients, but biopsies were not routinely performed so the true incidence of this event cannot be determined. Type I collagen (nonserious, unrelated) was reported in 1 patient who likely had myelodysplastic syndrome. No new class of adverse events was reported. Platelet responses were achieved by >90% of the patients, typically within 1-2 weeks of the initiation of romiplostim treatment. From week 8, median platelet counts were >100 × 10 9 /l; 47% of the patients received rescue medications (the use decreased over time). This study confirms and extends the tolerability/efficacy findings of previous romiplostim clinical studies. It was performed on a large ITP population, which is likely more representative of clinical practice.


Assuntos
Hemorragia/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Trombopoetina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hemorragia/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/sangue , Proteínas Recombinantes de Fusão/efeitos adversos , Índice de Gravidade de Doença , Trombopoetina/efeitos adversos , Fatores de Tempo
20.
ACS Infect Dis ; 10(5): 1483-1519, 2024 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-38691668

RESUMO

The development of effective antibacterial solutions has become paramount in maintaining global health in this era of increasing bacterial threats and rampant antibiotic resistance. Traditional antibiotics have played a significant role in combating bacterial infections throughout history. However, the emergence of novel resistant strains necessitates constant innovation in antibacterial research. We have analyzed the data on antibacterials from the CAS Content Collection, the largest human-curated collection of published scientific knowledge, which has proven valuable for quantitative analysis of global scientific knowledge. Our analysis focuses on mining the CAS Content Collection data for recent publications (since 2012). This article aims to explore the intricate landscape of antibacterial research while reviewing the advancement from traditional antibiotics to novel and emerging antibacterial strategies. By delving into the resistance mechanisms, this paper highlights the need to find alternate strategies to address the growing concern.


Assuntos
Antibacterianos , Infecções Bacterianas , Farmacorresistência Bacteriana , Antibacterianos/farmacologia , Antibacterianos/química , Humanos , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Bactérias/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA