Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 688
Filtrar
1.
PLoS One ; 14(5): e0217945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31150519

RESUMO

Chemical proteasome inhibition has been a valuable animal model of neurodegeneration to uncover roles for the ubiquitin-proteasome system in the central nervous system. However, little is known about the effects of chemical proteasome inhibitors on retinal integrity. Therefore, we characterized the effects of structurally different chemical proteasome inhibitors on the retinal morphology and the mechanisms of their action in the normal adult rat eyes. Intravitreal injection of MG-262 and other proteasome inhibitors led to inner retinal degeneration. MG-262-induced inner retinal degeneration was accompanied by reduced proteasome activity, increased poly-ubiquitinated protein levels, and increased positive immunostaining of ubiquitin, 20S proteasome subunit and GADD153/CHOP in the retina. Its retinal degenerative effect was also associated with reduced retinal neurofilament light chain gene expression, reflecting retinal ganglion cell death. MG-262-induced neurofilament light chain downregulation was largely resistant to pharmacological modulation including endoplasmic reticulum stress, apoptosis or MAP kinase inhibitors. Thus, this study provides further evidence of roles for the ubiquitin-proteasome system in the maintenance of the retinal structural integrity. Chemical proteasome inhibition may be used as a novel animal model of inner retinal degeneration, including retinal ganglion cell loss, which warrants further analysis of the molecular mechanisms underlying its retinal degenerative effect.


Assuntos
Complexo de Endopeptidases do Proteassoma/genética , Inibidores de Proteassoma/farmacologia , Retina/patologia , Degeneração Retiniana/patologia , Animais , Apoptose/efeitos dos fármacos , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacologia , Modelos Animais de Doenças , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Ratos , Retina/efeitos dos fármacos , Degeneração Retiniana/induzido quimicamente , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Tapsigargina/efeitos adversos , Tapsigargina/farmacologia , Tunicamicina/efeitos adversos , Tunicamicina/farmacologia
2.
Expert Rev Anti Infect Ther ; 16(12): 865-876, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30372359

RESUMO

INTRODUCTION: Complicated urinary tract infections are increasingly caused by multidrug-resistant organisms. Carbapenem-resistant Enterobacteriaceae (CRE) constitute a rising threat among uropathogens with significant morbidity and mortality. Meropenem-vaborbactam is a novel carbapenem and cyclic boronic acid-based beta-lactamase inhibitor combination with potent activity against subtypes of CRE. Areas covered: This article reviews mechanisms of carbapenem resistance, existing treatment options for CRE, and the current evidence to support the use of meropenem-vaborbactam for the treatment of infections caused by subtypes of CRE including complicated urinary tract infections. Expert commentary: Meropenem-vaborbactam is a superior treatment option for infections secondary to Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. It is associated with higher rates of treatment success and lower rates of toxicity than traditional agents and demonstrates a potentially higher barrier to acquired antimicrobial resistance than ceftazidime-avibactam. At present, meropenem-vaborbactam should be regarded as a preferred treatment option for invasive infections secondary to KPC-producing CRE.


Assuntos
Antibacterianos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Meropeném/administração & dosagem , Adulto , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Humanos , Klebsiella pneumoniae/isolamento & purificação , Meropeném/efeitos adversos , Meropeném/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia
3.
Future Microbiol ; 13: 971-983, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29692218

RESUMO

Meropenem-vaborbactam is a fixed-dose combination product of a carbapenem and a cyclic boronic acid ß-lactamase inhibitor with potent in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE). The efficacy of meropenem-vaborbactam for the treatment of complicated urinary tract infections and acute pyelonephritis was demonstrated in a Phase III trial (TANGO I). Preliminary data from TANGO II, a separate Phase III study, support the efficacy of meropenem-vaborbactam for the treatment of infections caused by CRE. Overall, meropenem-vaborbactam appears to be safe and well tolerated. It has favorable toxicity, pharmacokinetic and pharmacodynamic profiles compared with other antibiotics with activity against CRE. Meropenem-vaborbactam is an important addition to the current armamentarium of antimicrobial agents with activity against K. pneumoniae carbapenemase-producing CRE.


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Meropeném/uso terapêutico , Inibidores de beta-Lactamases/uso terapêutico , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/farmacologia , Ensaios Clínicos Fase III como Assunto , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Meropeném/efeitos adversos , Meropeném/farmacocinética , Meropeném/farmacologia , Resultado do Tratamento , Infecções Urinárias/tratamento farmacológico , Inibidores de beta-Lactamases/efeitos adversos , Inibidores de beta-Lactamases/farmacocinética , Inibidores de beta-Lactamases/farmacologia
4.
JAMA ; 319(8): 788-799, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29486041

RESUMO

Importance: Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections. Objective: To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis. Design, Setting, and Participants: Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (≥18 years) with complicated UTI, stratified by infection type and geographic region. Interventions: Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment. Main Outcomes and Measures: Primary end point for FDA criteria was overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-to-treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was -15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95% CIs were calculated. Results: Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%] women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenem-vaborbactam vs 105 of 182 (57.7%) with piperacillin-tazobactam (difference, 9.0% [95% CI, -0.9% to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9% [95% CI, -4.2% to 16.0%]; P < .001 for noninferiority). Adverse events were reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-tazobactam. Conclusions and Relevance: Among patients with complicated UTI, including acute pyelonephritis and growth of a baseline pathogen, meropenem-vaborbactam vs piperacillin-tazobactam resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion. Further research is needed to understand the spectrum of patients in whom meropenem-vaborbactam offers a clinical advantage. Trial Registration: clinicaltrials.gov Identifier: NCT02166476.


Assuntos
Antibacterianos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Ácido Penicilânico/análogos & derivados , Pielonefrite/tratamento farmacológico , Tienamicinas/administração & dosagem , Infecções Urinárias/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Antibacterianos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Meropeném , Pessoa de Meia-Idade , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/efeitos adversos , Piperacilina/administração & dosagem , Piperacilina/efeitos adversos , Combinação Piperacilina e Tazobactam , Guias de Prática Clínica como Assunto , Tienamicinas/efeitos adversos , Urina/microbiologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-29437614

RESUMO

Meropenem-vaborbactam is a fixed combination of the novel ß-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.).


Assuntos
Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Meropeném/efeitos adversos , Meropeném/farmacocinética , Adolescente , Adulto , Método Duplo-Cego , Esquema de Medicação , Interações de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Drugs Today (Barc) ; 53(10): 521-530, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29286054

RESUMO

On August 29, 2017, the United States Food and Drug Administration (FDA) approved meropenem/ vaborbactam fixed combination for the treatment of adults with complicated urinary tract infections (cUTI). The decision was based on substantial preclinical and clinical data, including two recent trials involving hundreds of adults with cUTI. Meropenem/ vaborbactam represents a powerful new treatment option to address antibiotic-resistant pathogens, including Klebsiella pneumoniae carbapenemase-producing bacteria. In this paper, we examine the work that led to FDA approval, with special emphasis on molecular pharmacology, pharmacokinetics, metabolism, efficacy and drug safety. We also look ahead, to explore how this promising new antimicrobial agent might be used in the near future to confront other drug-resistant infections..


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/administração & dosagem , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Tienamicinas/administração & dosagem , Infecções Urinárias/tratamento farmacológico , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/farmacologia , Ensaios Clínicos como Assunto , Interações de Medicamentos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , Meropeném , Tienamicinas/efeitos adversos , Tienamicinas/farmacocinética , Tienamicinas/farmacologia
7.
Leuk Lymphoma ; 58(8): 1872-1879, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28140719

RESUMO

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (ß5/ß1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m2. Dose-limiting toxicities (DLTs) at 2.4 mg/m2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.


Assuntos
Ácidos Borônicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Inibidores de Proteassoma/uso terapêutico , Treonina/análogos & derivados , Idoso , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/efeitos adversos , Recidiva , Retratamento , Treonina/administração & dosagem , Treonina/efeitos adversos , Treonina/uso terapêutico , Resultado do Tratamento
8.
Antimicrob Agents Chemother ; 60(10): 6326-32, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27527080

RESUMO

Vaborbactam (formerly RPX7009) is a member of a new class of ß-lactamase inhibitor with pharmacokinetic properties similar to those of many ß-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single- and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort. Maximum concentrations for vaborbactam were achieved at the end of the 3-h infusion. Vaborbactam exposure (Cmax and area under the concentration-time curve [AUC]) increased in a dose-proportional manner following multiple doses. There was no evidence of accumulation with multiple doses, consistent with the terminal half-life of ∼2 h. Both the volume of distribution (Vss) and plasma clearance were independent of dose. For the 2,000-mg dose, the plasma clearance was 0.17 ± 0.03 liters/h, the AUC from 0 h to infinity (AUC0-∞) was 144.00 ± 13.90 mg · h/liter, and the Vss was 21.80 ± 2.26 mg · h/liter. Urinary recovery was 80% or greater over 48 h across all dose groups. No subjects discontinued the study due to adverse events (AEs), and no serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among the vaborbactam- and placebo-treated subjects, with mild lethargy as the only unique AE reported with the high dose of vaborbactam. Overall, this study revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and formed the basis for advancement into patient studies in combination with meropenem, including treatment of patients with carbapenem-resistant Enterobacteriaceae (CRE) infections. (This study is registered at ClinicalTrials.gov under identifier NCT01751269.).


Assuntos
Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/farmacocinética , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Compostos Heterocíclicos com 1 Anel/farmacocinética , Administração Intravenosa , Adulto , Ácidos Borônicos/efeitos adversos , Feminino , Meia-Vida , Voluntários Saudáveis , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Humanos , Masculino
9.
Braz. j. med. biol. res ; 48(7): 622-628, 07/2015. graf
Artigo em Inglês | LILACS | ID: lil-751346

RESUMO

Posthemorrhagic shock mesenteric lymph (PHSML) is a key factor in multiple organ injury following hemorrhagic shock. We investigated the role of hydrogen sulfide (H2S) in PHSML drainage in alleviating acute kidney injury (AKI) by administering D,L-propargylglycine (PPG) and sodium hydrosulfide hydrate (NaHS) to 12 specific pathogen-free male Wistar rats with PHSML drainage. A hemorrhagic shock model was established in 4 experimental groups: shock, shock+drainage, shock+drainage+PPG (45 mg/kg, 0.5 h prehemorrhage), and shock+drainage+NaHS (28 µmol/kg, 0.5 h prehemorrhage). Fluid resuscitation was performed after 1 h of hypotension, and PHMSL was drained in the last three groups for 3 h after resuscitation. Renal function and histomorphology were assessed along with levels of H2S, cystathionine-γ-lyase (CSE), Toll-like receptor 4 (TLR4), interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-α in renal tissue. Hemorrhagic shock induced AKI with increased urea and creatinine levels in plasma and higher H2S, CSE, TLR4, IL-10, IL-12, and TNF-α levels in renal tissue. PHSML drainage significantly reduced urea, creatinine, H2S, CSE, and TNF-α but not TLR4, IL-10, or IL-12. PPG decreased creatinine, H2S, IL-10, and TNF-α levels, but this effect was reversed by NaHS administration. In conclusion, PHSML drainage alleviated AKI following hemorrhagic shock by preventing increases in H2S and H2S-mediated inflammation.


Assuntos
Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Ácidos Hidroxâmicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pirazinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/efeitos adversos , Intervalo Livre de Doença , Ácidos Hidroxâmicos/efeitos adversos , Pirazinas/efeitos adversos , Resultado do Tratamento
10.
Acta Haematol ; 134(1): 25-31, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25871926

RESUMO

AIMS: To explore the biomarker for predicting the occurrence of adverse events in myeloma patients treated by intravenous bortezomib, we measured proteasome activity in peripheral blood mononuclear cells. METHODS: Samples were obtained from 34 bortezomib-naïve patients. Proteasome activity was measured at pre- and postchemotherapy phase by using a synthetic substrate. RESULTS: Bortezomib injection resulted in a dramatic decrease in proteasome activity, reaching 32.4 ± 18.79% (mean ± SD) of the pretreatment level at 1 h, but it generally recovered at the end of the first course. In total, 6 patients manifested with severe bortezomib-induced peripheral neuropathy (sBIPN) in the second-third course. There was a nonsignificant trend for these patients to have lower levels of the relative proteasome activity at the end of the first course than those without sBIPN (median: 74.03 vs. 103.2%, p = 0.052). Moreover, in all of them, proteasome activity did not recover to the pretreatment level, whereas no patients with complete recovery manifested with sBIPN. Analysis with Fisher's exact test demonstrated that incomplete recovery of proteasome activity is a significant risk factor for sBIPN (p = 0.014). CONCLUSION: Patients with incomplete recovery of proteasome activity are at high risk for developing sBIPN, and the susceptible patients can be indicated by monitoring proteasome activity.


Assuntos
Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Leucócitos Mononucleares , Mieloma Múltiplo , Proteínas de Neoplasias/metabolismo , Doenças do Sistema Nervoso Periférico , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirazinas/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Bortezomib , Suscetibilidade a Doenças , Feminino , Seguimentos , Humanos , Leucócitos Mononucleares/enzimologia , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/enzimologia , Doenças do Sistema Nervoso Periférico/patologia , Pirazinas/administração & dosagem
11.
J Biol Regul Homeost Agents ; 29(1): 115-24, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25864747

RESUMO

The proteasome inhibitor bortezomib is an antineoplastic drug mainly used for the treatment of multiple myeloma (MM). Despite its effectiveness, bortezomib clinical use is often limited by the onset of peripheral neuropathy (BiPN). To better understand the mechanisms of BiPN several rat and mice models have been proposed, but no studies in MM-bearing animals allowing to test the antitumor activity of the selected schedules and the role of MM by itself in peripheral nervous system damage have been reported to date. Here, we carried out a study using immunodeficient C.B-17/Prkdcscid (SCID) mice injected with RPMI8266 human MM cells and treated with bortezomib 1 mg/kg once a week for five weeks. Animals were assessed with neurophysiological, behavioral and pathological methods and tumor volume measurement was performed along the study. At the end of the study BiPN was evident in bortezomib-treated animals, and this neurotoxic effect was evident using a schedule able to effectively prevent tumor growth. However, neurophysiological and pathological evidence of MM induced peripheral nervous system damage was also reported. This model based on MM-bearing animals is more reliable in the reproduction of the clinical setting and it is, therefore, more suitable than the previously reported models of BiPN to study its pathogenesis. Moreover, it represents an optimal model to test the efficacy of neuroprotective agents and at the same time their non-interference with bortezomib antineoplastic activity.


Assuntos
Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Pirazinas/efeitos adversos , Animais , Bortezomib , Modelos Animais de Doenças , Humanos , Camundongos SCID , Mieloma Múltiplo/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
N Engl J Med ; 372(10): 944-53, 2015 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-25738670

RESUMO

BACKGROUND: The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma. METHODS: In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival. RESULTS: After a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group. CONCLUSIONS: VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Ácidos Borônicos/efeitos adversos , Bortezomib , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Pirazinas/efeitos adversos , Rituximab , Vincristina/uso terapêutico
15.
Rinsho Ketsueki ; 56(1): 44-7, 2015 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-25745969

RESUMO

We report an 81-year-old woman with multiple myeloma who developed acute cardiac injury after receiving bortezomib. The patient received weekly intravenous bortezomib. She developed shortness of breath and bilateral pedal edema on day 19. Electrocardiography showed no ST-T changes but the cardio-thoracic ratio was increased, the ejection fraction was decreased, the ventricular septum showed hypokinesis and mitral regurgitation was noted. We stopped bortezomib and started acute congestive heart failure treatment. ST-T changes were detected after the patient's condition improved. There was no evidence of coronary stenosis on CT angiography. Acute cardiac injury is rare during bortezomib administration, but patients should be monitored carefully during treatment.


Assuntos
Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/efeitos adversos , Doença Aguda , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Bortezomib , Eletrocardiografia , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Pirazinas/administração & dosagem
16.
Drug Resist Updat ; 18: 18-35, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25670156

RESUMO

Over the past decade, the proteasome inhibitor bortezomib (Velcade) has not only gained a cornerstone position in the treatment of hematological malignancies, particularly multiple myeloma and mantle cell lymphoma, but also in experimental therapeutics of acute leukemia. However, the therapeutic efficacy of bortezomib is hampered by the emergence of acquired resistance, for which multifactorial mechanisms have been identified. This review summarizes the current status of the molecular mechanisms underlying resistance to proteasome inhibitors that emerged in preclinical therapeutic studies, and discusses these findings in the clinical perspective of novel therapeutic modalities of hematological malignancies. The specific topics that will be addressed in the current review include the recently established mechanisms of resistance to proteasome inhibitors: the role of constitutive and immunoproteasomes, mutations in proteasome subunits, unfolded protein response, XBP1 and MARCKS proteins, multidrug efflux transporters, aggresomes and autophagy, as well as the impact of pro-survival signaling pathways and bone marrow microenvironment. The growing knowledge of the determinants that confer bortezomib resistance and/or toxicity has provided the basis for the rational development of second generation proteasome inhibitors, some of which were recently approved or that are undergoing clinical evaluation as novel strategies to overcome bortezomib resistance as well as to enhance clinical therapeutic efficacy along with minimal side effects. Collectively, these combined approaches should enhance therapeutic efficacy and outcome in patients with hematological malignancies.


Assuntos
Ácidos Borônicos/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Pirazinas/farmacologia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Ácidos Borônicos/efeitos adversos , Bortezomib , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hematológicas/patologia , Humanos , Pirazinas/efeitos adversos
17.
Support Care Cancer ; 23(5): 1431-45, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25646616

RESUMO

PURPOSE: Recent therapeutic advancements have significantly improved overall survival of patients with multiple myeloma (MM). As a result, the impact of disease- and treatment-related symptoms must be managed effectively to improve patient quality of life, given prolonged survival after diagnosis. This review discusses current MM treatment options, effective symptom management approaches, and practical strategies for supportive care. METHODS: A literature search was performed using MEDLINE/PubMed and scientific congress databases, focusing on clinical trials, review articles, clinical practice guidelines, and other guidance documents on treatment paradigms and supportive care strategies in MM. Additionally, clinical practice worksheets were developed from published sources, and nursing "pearls of wisdom" were gathered from practical experience in the clinic. RESULTS: Current therapeutic regimens for relapsed/refractory MM include proteasome inhibitors (i.e., bortezomib, carfilzomib) and immunomodulatory agents (i.e., thalidomide, lenalidomide, pomalidomide), alone or in combination with chemotherapy or corticosteroids. Toxicities associated with agents and combination regimens used in the treatment of MM include myelosuppression, venous thromboembolism, peripheral neuropathy, infections, fatigue, gastrointestinal disorders, and/or cardiac events. Treatment-specific tools and clinical assessments can be useful for optimizing dosing and schedule adjustments to increase therapy duration, and implementing supportive care strategies (e.g., growth factors, transfusional support, intravenous hydration, bisphosphonates, antiviral therapies) to manage treatment-related symptoms. CONCLUSIONS: Improved survival after MM diagnosis has led to increased patient susceptibility to other diseases and comorbidities due to advanced age. In addition to appropriate drug dosing and administration, effective supportive care and health maintenance are crucial for maximizing quality of life and disease control.


Assuntos
Antineoplásicos/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Antineoplásicos/uso terapêutico , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/uso terapêutico , Bortezomib , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Imunomodulação , Lenalidomida , Oligopeptídeos/efeitos adversos , Oligopeptídeos/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Qualidade de Vida , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Talidomida/uso terapêutico
18.
Am J Hematol ; 90(4): 314-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25557740

RESUMO

This analysis, using data from the bortezomib-melphalan-prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant-ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m(2); this was selected as the cut-off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (≥39 mg/m(2)) versus lower (<39 mg/m(2)) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age-adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Pirazinas/administração & dosagem , Pirazinas/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/efeitos adversos , Bortezomib , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Pirazinas/efeitos adversos , Análise de Sobrevida
20.
Am J Hematol ; 90(4): E60-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25580702

RESUMO

Bortezomib and lenalidomide are increasingly used in patients with AL amyloidosis, but long term data on their use as primary therapy in AL amyloidosis are lacking while early mortality remains significant. Thus, we analyzed the long term outcomes of 85 consecutive unselected patients, which received primary therapy with bortezomib or lenalidomide and we prospectively evaluated a risk adapted strategy based on bortezomib/dexamethasone to reduce early mortality. Twenty-six patients received full-dose bortezomib/dexamethasone, 36 patients lenalidomide with oral cyclophosphamide and low-dose dexamethasone and 23 patients received bortezomib/dexamethasone at a dose and schedule adjusted to the risk of early death. On intent to treat, 67% of patients achieved a hematologic response (24% hemCRs) and 34% an organ response; both were more frequent with bortezomib. An early death occurred in 20%: in 36% of those treated with full-dose bortezomib/dexamethasone, in 22% of lenalidomide-treated patients but only in 4.5% of patients treated with risk-adapted bortezomib/dexamethasone. Activity of full vs. adjusted dose bortezomib/dexamethasone was similar; twice weekly vs. weekly administration of bortezomib also had similar activity. After a median follow up of 57 months, median survival is 47 months and is similar for patients treated with bortezomib vs. lenalidomide-based regimens. However, risk adjusted-bortezomib/dexamethasone was associated with improved 1-year survival vs. full-dose bortezomib/dexamethasone or lenalidomide-based therapy (81% vs. 56% vs. 53%, respectively). In conclusion, risk-adapted bortezomib/dexamethasone may reduce early mortality and preserve activity while long term follow up indicates that remissions obtained with lenalidomide or bortezomib may be durable, even without consolidation with alkylators.


Assuntos
Amiloidose/tratamento farmacológico , Ácidos Borônicos/uso terapêutico , Cadeias Leves de Imunoglobulina , Pirazinas/uso terapêutico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/metabolismo , Amiloidose/mortalidade , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina , Lenalidomida , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/uso terapêutico , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA