1,721,120 research outputs found
Integration of monoclonal antibodies and immunoconjugates into the treatment of acute myeloid leukemia..
No full textMonoclonal antibodies and immunoconjugates in acute myeloid leukemia
No full textThe use of monoclonal antibodies for patients with acute myeloid leukemia is based on targeting cell-surface antigens preferentially expressed on leukemic blasts while sparing normal cells and tissues. The majority of studies performed to date have used antibodies reactive with the CD33 antigen. Phase II studies have demonstrated antileukemic responses with all agents, although less so with unlabeled antibodies. The most promising results have been obtained in the treatment of minimal residual disease in patients with acute promyelocytc leukemia. Antibody-targeted chemotherapy with gemtuzumab ozogamicin has also shown significant activity in patients with relapsed acute myeloid leukemia. Radioimmunotherapy with Î2-particle emitters may be most effective for the treatment of bulky disease or as part of a conditioning regimen for hematopoietic stem-cell transplantation, whereas radioimmunotherapy with α-particle emitters may be better suited to the treatment of small-volume or minimal residual leukemia. Whether or not monoclonal antibody therapy will improve disease outcome compared with conventional treatment regimens remains to be demonstrated by well-designed clinical trials. © 2006 Elsevier Ltd. All rights reserved
Biologic aspects of thrombopoietin and the development of novel thrombopoietic agents for clinical use
No full textThrombocytopenia is a frequent finding in several clinical settings, including bone marrow failure associated with various disorders, immune-mediated thrombocytopenia, and chronic liver diseases. Currently, there is an unmet need for thrombopoietic agents to treat this condition. Thrombopoietin (TPO) is the key cytokine involved in thrombopoiesis, and is the endogenous ligand for the thrombopoietin receptor that is expressed on the surface of megakaryocytes and megakaryocytic precursors. Although clinical trials with first generation thrombopoietic agents were abruptly discontinued after the development of TPO autoantibodies had been observed, non-antigenic second generation thrombopoietic growth factors with unique pharmacological properties have been developed. These include TPO peptide mimetics (AMG 531 and Fab59), TPO nonpeptide mimetics (eltrombopag, NIP-004, and AKR-501) and TPO agonist antibodies. All of these bind to and activate the TPO receptor in different ways but all via JAK2/STAT signalling pathways, producing a dose-dependent rise in platelet counts. In view of their use as therapeutic agents, nonpeptide agonists seem to have an advantage over peptide agonists, in that they could be orally bioavailable. The aim of the present review is to illustrate the biology of TPO and its receptor, and to describe the structure and function of the new thrombopoietic agents. © 2007 Bentham Science Publishers Ltd
Long-Term Outcome of Otherwise Healthy Individuals with Incidentally Discovered Borderline Thrombocytopenia.
No full textBACKGROUND: The long-term outcome of individuals with mild degrees of thrombocytopenia is unknown. METHODS AND FINDINGS: In a prospective study conducted between August 1992 and December 2002, 260 apparently healthy individuals with incidentally discovered platelet counts between 100 x 10(9)/l and 150 x 10(9)/l were monitored for 6 mo to determine whether their condition persisted. The monitoring period was completed in 217 cases, of whom 191 (88%) maintained stable platelet counts. These 191 individuals were included in a long-term follow-up study to gain knowledge of their natural history. With a median time of observation of 64 mo, the thrombocytopenia resolved spontaneously or persisted with no other disorders becoming apparent in 64% of cases. The most frequent event during the study period was the subsequent development of an autoimmune disease. The 10-y probability of developing idiopathic thrombocytopenic purpura (ITP), as defined by platelet counts persistently below 100 x 10(9)/l, was 6.9% (95% confidence interval [CI]: 4.0%-12.0%). The 10-y probability of developing autoimmune disorders other than ITP was 12.0% (95% CI: 6.9%-20.8%). Most of the cases (85%) of autoimmune disease occurred in women. CONCLUSIONS: Healthy individuals with a sustained platelet count between 100 x 10(9)/l and 150 x 10(9)/l have a 10-y probability of developing autoimmune disorders of 12%. Further investigation is required to establish whether this risk is higher than in the general population and whether an intensive follow-up results in an improvement of prognosis
Novel thrombopoietic agents: A review of their use in idiopathic thrombocytopenic purpura
No full textThe underlying problem in idiopathic thrombocytopenic purpura (ITP) has traditionally been-recognized as accelerated platelet destruction. However, recent studies have provided evidence that the pathophysiology of ITP is more complex, and impaired platelet production has emerged as one of the mechanisms contributing to the thrombocytopenia. On these grounds, second-generation thrombopoietic agents have been used in clinical trials to stimulate platelet production in ITP patients who are not responsive to standard treatments. These new molecules bear no structural resemblance to thrombopoietin (TPO) but still bind and activate the TPO receptor. Studies have been completed for two TPO receptor agonists: romiplostim (formerly AMG 531) and eltrombopag (formerly SB497115). Romiplostim is a recombinant protein defined as a peptibody. Results of phase I-II trials published recently demonstrated that romiplostim given as a weekly subcutaneous injection for 1-6 weeks results in doubling of platelet counts and an increase to > 50 x 10(9)/L in most treated patients with minimal adverse effects. Eltrombopag is an orally available, small organic compound. In a randomized, double-blind, placebo-controlled phase III trial, ITP patients were given daily oral treatment with placebo or eltrombopag 50 mg. Platelet responses were observed in 59% of eltrombopag-treated patients and in 16% of patients in the placebo arm. No significant adverse events were seen. Other thrombopoietic agents in development, such as AKR-501 (formerly YM 477), appear promising in healthy volunteers. Ongoing phase III clinical trials will reveal the potential of these agents in the management of ITP prior to splenectomy and for long-term maintenance therapy, as well as their relative benefit compared with standard of care treatment
Evaluation of mixed mode ventilation cooling energy saving potential in nZEB: A case study in Southern Italy
No full textIn recent decades, reducing the energy demand of the building sector has become a major goal of global policies. Proper design of the building-plant system is hence strategic to achieve nearly zero energy building (NZEB) target. This paper reports the results of modeling the building-plant system of an NZEB in Southern Italy. The case study is a multi-family complex of eight dwellings located in Bari, in the Apulia region. The building project originates from the energy refurbishment of a former industrial shed that was demolished and rebuilt for residential use. The planned HVAC system foresees the combined use of primary ventilation with fan-coil units fed by two ground source heat pumps (GSHP) supplied by eight vertical probes. Three hybrid ventilation strategies have been compared to evaluate the potential cooling energy saving: the first one examines an earth-to-air heat exchanger (EAHX), the second one proposes night hybrid ventilation from 10 pm to 6 am, and the last considers the adoption of free cooling in mechanical ventilation. Economic and energy comparisons among these three approaches are reported. Using EAHX, the cooling consumption saving reached about 20.7% The use of night ventilation combined with MVS can reduce the cooling energy demand for 14.4%, while free cooling in MVS produces a less effective decrease in the electricity consumption for cooling of about 7.7%. All three strategies generate major benefits in the middle-season
A Multi-criteria Optimization Framework for the Residential Hot Water Network Emphasizing on the Role of Control Strategy
No full textCutting-edge technologies and optimization frameworks for energy efficiency enhancement of the entire domestic hot water (DHW) chain are crucial to fulfill the ambitious goals of the future building regulations. In this context, the present study establishes a multi-objective optimization framework for the DHW network in a typical residential building, in which the hot water is supplied by a PV-BESS driven air source heat pump system relying on the thermal energy storage (TES) to decouple energy production and demand. Emphasizing on the role of in-building control strategies and user behavior, the optimization algorithm employs the response surface methodology (RSM) with central composite design (CCD). It seeks to simultaneously minimize the total energy use for DHW production and total heat loss from the DHW network, while maximizing the temperature of delivered hot water to users as well as the TES mean temperature. To examine interactions in components of the DHW network, dynamic simulations are carried out by developing a TRNSYS model coupled to a MATLAB code. The latter generates the hourly DHW consumption profiles using Gaussian distribution. It is shown that the developed optimization framework strikes a balance between conflictive design factors to meet the targets of multi-criteria optimization. The variable TES set-point is found to be the most influential factor in terms of providing hot water at a higher temperature to users. Furthermore, adjusting the activation time (and flow rate) of recirculating loop and the TES charging time slots in accordance with the user behavior (draw-off) and peak consumption timespans demonstrate a significant impact on minimizing either the total energy use or thermal loss
Recombinant human granulocyte-macrophage colony-stimulating factor plus erythropoietin for the treatment of cytopenias in patients with myelodysplastic syndromes
No full textIn vitro studies have indicated that granulocyte-macrophage colony-stimulating factor (GM-CSF) synergizes with erythropoietin (EPO) for the production of erythroid precursors in patients with myelodysplastic syndrome (MDS). We performed a clinical trial to evaluate whether the combination of these growth factors was effective in relieving the cytopenias associated with MDS. 31 anaemic patients with low and intermediate-risk primary MDS were enrolled in a 12-week study, Therapy was initiated with GMCSF at 1 mu g/kg/d.s.c., and then adjusted to either normalize or double the absolute neutrophil count, EPO was given subcutaneously on alternate days starting from day 2. The EPO dose was initiated at 150 U/kg and increased to 300 U/ kg if after 6 weeks there was no or suboptimal erythroid response. 26 patients completed the study treatment. All evaluable cases had a neutrophil response, Clinically significant erythroid responses with increases of haemoglobin levels of at least 1 g/dl and/or reduction of transfusion needs were seen in 9/26 (34.6%), five patients improving their response after dose escalation of EPO, Treatment had no apparent effect on mean platelet counts, a single case displaying a trilineage response. An elevated bone marrow erythroid infiltration and low concentrations of circulating tumour necrosis factor-alpha were the only predictors of haemoglobin response both in univariate and in multivariate analysis. We conclude that the combination GM-CSF+EPO can abrogate neutropenia and substantially relieve transfusion requirements in a large proportion of patients with low and intermediate risk MDS. However, in vivo synergy between these growth factors for the production of erythroid precursors is not supported by our data
Should rituximab be used before or after splenectomy in patients with immune thrombocytopenic purpura?
No full textPurpose of review The anti-CD20 monoclonal antibody rituximab has been used to treat patients with chronic immune I thrombocytopenic purpura. This review discusses whether the optimal timing for this therapy is before splenectomy, or after failure of splenectomy. Recent findings No study has directly compared rituximab to splenectomy in I patients with chronic immune thrombocytopenic purpura. Rituximab produces an initial response in approximately 60% of cases, with no significant difference between splenectomized and nonsplenectomized patients. Long-term complete responses are observed in 15-20% of cases. Adverse events related to the drug were usually mild or moderate, with a low incidence of infections. Long-term safety data, however, are still lacking. Deaths have been reported for 2.9% of immune thrombocytopenic purpura cases treated with rituximab, but they could not be attributed to the study drug. Summary Both the response rate and the response duration appear lower following rituximab than following splenectomy. Although the side effects may be fewer, there is insufficient evidence to support the replacement of splenectomy with rituximab as a second-line treatment of chronic immune thrombocytopenic purpura outside a clinical trial. At the present time, the use of immunotherapy before splenectomy can be recommended only in patients at high risk for splenectomy and in those not willing to undergo surgery
Infliximab chimaeric anti-tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes
No full textTumour necrosis factor alpha (TNF-alpha) is believed to play a major role in apoptotic death of bone marrow cells in myelodysplastic syndromes (MDS). We explored the efficacy and safety profile of infliximab chimaeric anti-TNF-alpha monoclonal antibody treatment in two MDS patients. They both had low-/intermediate-risk MDS, isolated anaemia and elevated circulating levels of TNF-alpha. Infliximab produced no adverse side-effects and resulted in sustained erythroid responses, one major and one minor. Laboratory studies indicated a remarkable decrease in the percentage of apoptotic stein cells in the bone marrow. This preliminary report indicates that infliximab may have an application as MDS therapy and warrants further investigation
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