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1.
Medicine (Baltimore) ; 98(43): e17397, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651842

RESUMO

BACKGROUND: Community-acquired pneumonia (CAP) is a major global disease. Parapneumonic effusions often complicate CAP and range from uninfected (simple) to infected (complicated) parapneumonic effusions and empyema (pus). CAP patients who have a pleural effusion at presentation are more likely to require hospitalization, have a longer length of stay and higher mortality than those without an effusion. Conventional management of pleural infection, with antibiotics and chest tube drainage, fails in about 30% of cases. Several randomized controlled trials (RCT) have evaluated the use of corticosteroids in CAP and demonstrated some potential benefits. Importantly, steroid use in pneumonia has an acceptable safety profile with no adverse impact on mortality. A RCT focused on pediatric patients with pneumonia and a parapneumonic effusion demonstrated shorter time to recovery. The effects of corticosteroid use on clinical outcomes in adults with parapneumonic effusions have not been tested. We hypothesize that parapneumonic effusions develop from an exaggerated pleural inflammatory response. Treatment with systemic steroids may dampen the inflammation and lead to improved clinical outcomes. The steroid therapy and outcome of parapneumonic pleural effusions (STOPPE) trial will assess the efficacy and safety of systemic corticosteroid as an adjunct therapy in adult patients with CAP and pleural effusions. METHODS: STOPPE is a pilot multicenter, double-blinded, placebo-controlled RCT that will randomize 80 patients with parapneumonic effusions (2:1) to intravenous dexamethasone or placebo, administered twice daily for 48 hours. This exploratory study will capture a wide range of clinically relevant endpoints which have been used in clinical trials of pneumonia and/or pleural infection; including, but not limited to: time to clinical stability, inflammatory markers, quality of life, length of hospital stay, proportion of patients requiring escalation of care (thoracostomy or thoracoscopy), and mortality. Safety will be assessed by monitoring for the incidence of adverse events during the study. DISCUSSION: STOPPE is the first trial to assess the efficacy and safety profile of systemic corticosteroids in adults with CAP and pleural effusions. This will inform future studies on feasibility and appropriate trial endpoints. TRIAL REGISTRATION: ACTRN12618000947202 PROTOCOL VERSION:: version 3.00/26.07.18.


Assuntos
Corticosteroides/administração & dosagem , Infecções Comunitárias Adquiridas/tratamento farmacológico , Dexametasona/administração & dosagem , Derrame Pleural/tratamento farmacológico , Pneumonia/tratamento farmacológico , Administração Intravenosa , Adulto , Infecções Comunitárias Adquiridas/complicações , Método Duplo-Cego , Estudos de Viabilidade , Feminino , Humanos , Masculino , Projetos Piloto , Derrame Pleural/microbiologia , Pneumonia/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
2.
Medicine (Baltimore) ; 98(39): e17364, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574883

RESUMO

OBJECTIVE: We performed a meta-analyisis to evaluate the efficacy of maintenance dexamethasone against acute or delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetic risk chemotherapy regimen. METHODS: PubMed, Embase, and Cochrane Library were searched for eligible studies. Data comparing maintenance dexamethasone with single-dose dexamethasone during the acute, delayed, and overall phase of CINV were extracted. Overall risk ratio (RR) was used to estimate the efficacy and adverse effects. RESULTS: Nine studies were included. In delayed phase, maintenance dexamethasone has similar efficacy to single-dose dexamethasone for no emetic episodes (RR, 1.06; 95% confidence interval [CI], 1.00-1.14), complete response (RR, 1.04; 95% CI, 0.98-1.11), complete control (RR, 1.07; 95% CI, 0.98-1.16), and total control (RR, 1.06; 95% CI, 0.91-1.23). In overall phase, maintenance dexamethasone has similar efficacy to single-dose dexamethasone for no emetic episodes (RR, 1.02; 95% CI, 0.94-1.11), complete response (RR, 1.02; 95% CI, 0.95 -1.09), complete control (RR, 1.03; 95% CI, 0.94-1.13), total control (RR, 1.05; 95% CI, 0.90-1.23), and no rescue medication (RR, 1.07; 95% CI, 0.97-1.19). Maintenance dexamethasone was only superior to single-dose dexamethasone for no rescue medication during delayed phase (RR, 1.10; 95% CI, 1.01-1.21, P = .034). The incidence of hiccup was observed higher in maintenance dexamethasone group (RR = 3.16, 95% CI, 1.12-8.92). CONCLUSION: The single-dose dexamethasone regimen offers high and similar overall control of symptoms as the maintenance dexamethasone regimen in this population. Multiple-day dexamethasone was suitable for patients who used rescue medication during the delayed phase.


Assuntos
Antieméticos/administração & dosagem , Antineoplásicos/efeitos adversos , Dexametasona/administração & dosagem , Náusea/prevenção & controle , Vômito/prevenção & controle , Protocolos Clínicos , Humanos , Náusea/induzido quimicamente , Vômito/induzido quimicamente
3.
Toxicol Lett ; 316: 136-146, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520701

RESUMO

Prenatal dexamethasone exposure (PDE) induces developmental toxicities of multiple organs in offspring, but its serum metabolic profile changes before and after birth are unclear. Here, we employed a LC-MS-based metabolomic approach to detect serum metabolites of PDE offspring rats in utero and adulthood, and explore its change characteristics and toxicological significances. Meanwhile, the bodyweight, serum index related to hepatic and renal function were detected. As compared to healthy control rats, PDE reduced offspring birthweight but caused postnatal catch-up growth accompanied by adult liver and kidney function injury. In utero, the differential metabolites in response to PDE were mainly manifested as enhanced glycolysis, increased protein breakdown and disordered lipid metabolism, and multiple metabolic pathways were changed, which displayed gender differences. In adulthood, PDE offspring showed fewer and inconsistent types of differential metabolites compared to those in utero, which exhibited significant gender differences. The main differential metabolites induced by PDE included lactic acid, carnitine, cortexolone, bile acid, phosphatidylcholine, uric acid and platelet activating factor, which may participate in dexamethasone multi-organ toxicities and multi-disease susceptibility. In conclusion, PDE could induce a gender-difference and sustainable multi-organ damage in the offspring rats via serum metabolic profile analysis, which will enhance offspring susceptibility to multiple adult diseases.


Assuntos
Dexametasona/toxicidade , Metabolismo Energético/efeitos dos fármacos , Glucocorticoides/toxicidade , Metabolômica/métodos , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Peso ao Nascer/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Dexametasona/administração & dosagem , Feminino , Glucocorticoides/administração & dosagem , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Gravidez , Ratos Wistar , Medição de Risco , Fatores Sexuais , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Fatores de Tempo
4.
AAPS PharmSciTech ; 20(7): 270, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363872

RESUMO

Currently, there is no specific treatment for acute lung injury (ALI). E-selectin-binding peptide (Esbp), a high-affinity peptide that delivers drugs targeting inflammatory vascular endothelial cells, can bind to E-selectin and act as a targeting ligand for selective drug delivery. In this study, we coupled the thiol groups of Esbp to the amino groups on the surface of bovine serum albumin (BSA) using succinimidyl iodoacetic acid to make Esbp-modified BSA nanoparticles (BSANPs) at the average ratio of 19.3 µg Esbp to 1 mg BSA. The Esbp-modified BSANPs were spherical in shape and had a particle size of 266.7 ± 2.7 nm, polydispersity index of 0.165 ± 0.02, zeta potential of - 33.64 ± 1.23 mV, encapsulation efficiency of 84.3 ± 2.3%, and drug loading of 6.7 ± 0.32%. The cumulative release rate of dexamethasone-loaded Esbp-modified BSANPs was 51.2% within 12 h, significantly lower than that of 88.2% of free drugs. Moreover, Esbp-modified BSANPs could be uptaken in vitro by activated human umbilical vein endothelial cells and in vivo by the lungs of the established ALI mouse model. These results indicated that our Esbp-modified BSANPs delivery system has characteristics of good targeting ability and biocompatibility and is able to inhibit inflammation. Overall, our Esbp-modified BSANPs delivery system has therapeutic potentials as a new targeting drug system for the treatment of ALI in the future.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Dexametasona/administração & dosagem , Selectina E/administração & dosagem , Antígenos HLA-D/administração & dosagem , Nanopartículas/administração & dosagem , Soroalbumina Bovina/administração & dosagem , Lesão Pulmonar Aguda/metabolismo , Animais , Bovinos , Linhagem Celular Tumoral , Dexametasona/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Selectina E/metabolismo , Antígenos HLA-D/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Nanopartículas/metabolismo , Tamanho da Partícula , Soroalbumina Bovina/metabolismo , Resultado do Tratamento
5.
Expert Rev Pharmacoecon Outcomes Res ; 19(5): 505-508, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31379219

RESUMO

Introduction: The analysis was conducted to assess a cost-efficacy analysis of new antiemetic drugs (netupitant plus palonosetron (NEPA)) for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in highly and moderately emetogenic chemotherapy for cancer treatment. Areas covered:The present evaluation was restricted to pivotal phase III randomized controlled trials (RCTs) of NEPA versus (vs.) palonosetron for the prophylaxis of CINV. We calculated the pharmacological costs necessary to get the benefit in complete response (CR), for each trial. Our analysis evaluated 2 RCTs, including 1720 patients. Referring to both highly and moderately emetogenic chemotherapy, NEPA plus DEX was economic superior to palonosetron (PALO) plus DEX, with 13 312 € and 7885 € gain in medical costs every 100 patients treated, respectively. The cost-effectiveness ratios (CERs) (€/CR) in highly emetoge nic risk were 1.24 and 13.23 for the NEPA and PALO group, respectively and 1.49 and 15.20 for the same groups in moderately emetogenic risk. The incremental cost-effectiveness ratio (ICER) between the groups was 1016.18 €/CR and 1024.03 €/CR in highly and moderately emetogenic risk, respectively. Expert opinion:The combination of NEPA plus DEX is cost-effective for preventing CINV in highly and moderately (AC-based) emetogenic cancer treatment.


Assuntos
Antieméticos/administração & dosagem , Palonossetrom/administração & dosagem , Piridinas/administração & dosagem , Antieméticos/economia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Análise Custo-Benefício , Dexametasona/administração & dosagem , Dexametasona/economia , Humanos , Náusea/induzido quimicamente , Náusea/economia , Náusea/prevenção & controle , Neoplasias/tratamento farmacológico , Palonossetrom/economia , Piridinas/economia , Ensaios Clínicos Controlados Aleatórios como Assunto , Vômito/induzido quimicamente , Vômito/economia , Vômito/prevenção & controle
6.
Medicine (Baltimore) ; 98(34): e15852, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441836

RESUMO

BACKGROUND: The purpose of this study was to investigate the benefits and harm of combined administration of tranexamic acid (TXA) and dexamethasone (Dexa) in total knee arthroplasty (TKA). METHODS: A total of 88 consecutive patients undergoing TKA for knee osteoarthritis were stratified in 2 groups. All surgeries were performed under general anesthesia. Brief, patients in the TXA + Dexa group (n = 45) received 10 mg Dexa just after the anesthesia, and repeated at 24 hours after the surgery; and patients in the TXA group (n = 43) received 2 ml of normal saline solution at the same time. The measured outcomes were the C-reactive protein (CRP) and interleukin-6 (IL-6) from preoperatively to postoperatively, and postoperative nausea and vomiting (PONV), fatigue, range of motion (ROM), length of stay (LOS), and the analgesic and antiemetic rescue consumption RESULTS:: The level of CRP and IL-6 in the TXA + Dexa group were lower than that in the TXA group at 24 hours (P < .001, P < .001), 48 hours (P < .001, P < .001), and 72 hours (P < .001, P < .001) after the surgery. The pain scores in the TXA + Dexa group were lower during walking at 24 hours (P < .001), 48 hours (P < .001), and 72 hours (P < .001) and at rest at 24 hours (P = .022) after the surgery. Patients in the TXA + Dexa group had a lower nausea score, the incidence of PONV, fatigue, and the analgesic and antiemetic rescue consumption, and had a greater ROM than that in the TXA group. No significant differences were found in LOS and complications. CONCLUSION: The combined administration of TXA + Dexa significantly reduced the level of postoperative CRP and IL-6, relieve postoperative pain, ameliorate the incidence of POVN, provide additional analgesic and antiemetic effects, reduce postoperative fatigue, and improve ROM, without increasing the risk of complications in primary TKA.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antifibrinolíticos/uso terapêutico , Artroplastia do Joelho/métodos , Dexametasona/uso terapêutico , Ácido Tranexâmico/uso terapêutico , Idoso , Analgésicos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Antieméticos/administração & dosagem , Perda Sanguínea Cirúrgica/prevenção & controle , Proteína C-Reativa/efeitos dos fármacos , Dexametasona/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/biossíntese , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/prevenção & controle , Náusea e Vômito Pós-Operatórios/prevenção & controle , Amplitude de Movimento Articular , Ácido Tranexâmico/administração & dosagem
7.
N Engl J Med ; 381(8): 727-738, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31433920

RESUMO

BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Dexametasona/efeitos adversos , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hidrazinas/efeitos adversos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Triazóis/efeitos adversos , Adulto Jovem
8.
Gene ; 719: 144080, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31454541

RESUMO

Trigeminal neuropathic pain is seen as a huge clinical challenge. Although numerous drugs have been developed to treat the condition, some patients have shown intolerance to the drugs and thus continue to suffer. In the present study, a rat model of trigeminal neuropathic pain was established using incorrectly positioned dental implants, which had various manifestations that were similar to human trigeminal neuropathic pain. Using this model, we investigated the differential regulation of JAK2 and PTEN. Firstly, we examined the expression of JAK2 and PTEN in the medullary dorsal horn. After inhibiting JAK2/PTEN, we evaluated nociception-related behavioral alterations. The rat models were established by replacing the left lower second molar with a mini dental implant. Immunoblot assay and immunofluorescence experiments indicated high expression of JAK2 and PTEN in medullary dorsal horn after the nerve injury, which attained plateau levels on post-operative day (POD) 5-10 and 10-20. Administration of adenovirus-shRNA-JAK2 on POD 1 reduced mechanical allodynia and downstream STAT activation. Meanwhile, the administration of adenovirus-shRNA-PTEN on POD 1 attenuated mechanical allodynia while upregulating AKT. In addition to postoperative JAK2 and PTEN activation, dexmedetomidine treatment (10 mg/kg) also modulated the downstream sensors of these signaling molecules. These data suggest that JAK2 and PTEN are pivotal to the development of trigeminal neuropathic pain, and that JAK2 and PTEN suppression alleviates the neuropathic pain.


Assuntos
Técnicas de Silenciamento de Genes , Janus Quinase 2/genética , Neuralgia/diagnóstico , PTEN Fosfo-Hidrolase/genética , Neuralgia do Trigêmeo/genética , Animais , Implantes Dentários/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Dexmedetomidina/administração & dosagem , Dexmedetomidina/uso terapêutico , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Janus Quinase 2/antagonistas & inibidores , Masculino , Neuralgia/genética , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Medição da Dor , Ratos , Ratos Sprague-Dawley
9.
Lancet Haematol ; 6(9): e459-e469, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327687

RESUMO

BACKGROUND: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual. FINDINGS: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5-10·9). Median progression-free survival was 5·6 months (95% CI 3·7-7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05-2·22; p=0·98). Median overall survival was not reached (95% CI 12·9-not reached) versus 15·2 months (12·7-not reached; HR 1·61; 95% CI 0·91-2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Miocardite/etiologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Recidiva , Síndrome de Stevens-Johnson/etiologia , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
10.
Lancet Haematol ; 6(9): e448-e458, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327689

RESUMO

BACKGROUND: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual. FINDINGS: Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4-9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2-88·1) versus 85·0% (76·8-90·5; hazard ratio [HR] 1·22; 95% CI 0·67-2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Lenalidomida/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Humanos , Lenalidomida/efeitos adversos , Masculino , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Pneumonia/etiologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Resultado do Tratamento
11.
J Cancer Res Clin Oncol ; 145(9): 2343-2355, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280348

RESUMO

PURPOSE: Combinations of bortezomib (Velcade), cyclophosphamide and dexamethasone have shown significant efficacy and safety for patients of newly diagnosed multiple myeloma (NDMM). In this study, we compared the efficacy and safety of modified VCD regimens with novel changes in bortezomib dose and schedule for NDMM. METHODS: Eighty-five NDMM patients from multiple centers were randomly assigned to a high-dose (1.6 mg/m2) (group A) or a low-dose (1.3 mg/m2) (group B) bortezomib, administrated on days 1, 6, 11, and 16 subcutaneously in a 4-week cycle for nine cycles, combined with 40 mg dexamethasone on bortezomib days and cyclophosphamide 300 mg/m2 on days 1-3 intravenously. RESULTS: After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During induction, for patients with R-ISS stage III, the CR or better rate in group A was superior to that in group B (P = 0.01). Of patients < 65, the CR or better rate of group A was superior to that of group B (P = 0.004). Rapid onset of CR occurred in group A (P < 0.01). Meanwhile, rate of 3-4 diarrhea was higher in group A (P = 0.03), which caused higher rate of dose reduction for patients ≥ 65 (P = 0.041). No significant difference between the two groups in PFS and OS. CONCLUSIONS: The studied high-dose VCD as induction regimen had an improved CR rate, especially in patients < 65 or with R-ISS stage III, and is feasible for young and high-risk patients. Trial registration ClinicalTrials.gov: NCT02086942.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Teniposídeo/administração & dosagem , Resultado do Tratamento
12.
Medicine (Baltimore) ; 98(26): e16080, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261519

RESUMO

Osteoporosis is a common problem, especially among postmenopausal women. Postmenopausal women with osteoporosis have major risk factors for osteoporotic fractures. The abuse of epidural steroid injections (ESIs) or the misunderstanding of their proper use could cause osteoporotic fractures. Therefore, we aimed to investigate whether ESIs are associated with osteoporotic fractures in postmenopausal women with low back pain and osteoporosis. Furthermore, we aimed to provide evidence on whether ESIs could be used in postmenopausal women with osteoporosis who are at high risk for osteoporotic fractures.We reviewed the medical records of postmenopausal women with osteoporosis but no fractures. A total of 172 postmenopausal women were divided into 2 groups. Group 1 comprised patients receiving medications and Group 2 comprised patients receiving ESIs. All participants received medications for treating osteoporosis. Each patient's age, bone mineral density, body mass index, medical history, and status with respect to smoking, drinking, physical activity, and exercise were obtained using a questionnaire and medical records.The mean total number of ESIs was 6.2, and the mean cumulative administered dose of glucocorticoids (dexamethasone) was 31 mg. The incidences of fractures in the medication and ESI groups were 22% and 24%, respectively, in the thoracolumbar spine, and 2% and 5%, respectively, in the hip joint.There was no significant difference in the incidences of osteoporotic fractures at the thoraco-lumbar spine and hip joint in postmenopausal women with osteoporosis between those who received ESIs (a mean of 6.2 ESIs, a cumulative dexamethasone dose of 31 mg) and those who did not, with both groups taking anti-osteoporotic medications for low back pain. Our data suggest that ESI treatment using a mean of 6.2 ESIs to deliver a maximum cumulative dexamethasone dose of 31 mg could be safely used in postmenopausal women with osteoporosis, without any significant impact on the their risk for osteoporotic fractures.


Assuntos
Glucocorticoides/administração & dosagem , Osteoporose Pós-Menopausa/epidemiologia , Fraturas por Osteoporose/epidemiologia , Esteroides/administração & dosagem , Idoso , Dexametasona/administração & dosagem , Feminino , Fraturas do Quadril/epidemiologia , Humanos , Incidência , Injeções Epidurais , Dor Lombar/tratamento farmacológico , Dor Lombar/epidemiologia , Pós-Menopausa , Prevalência , Estudos Retrospectivos , Fraturas da Coluna Vertebral/epidemiologia
14.
Indian J Ophthalmol ; 67(7): 1236-1238, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31238480

RESUMO

A 10-year-old girl presented to us with inferonasally displaced, non-axial proptosis of oculus dexter (OD), with ipsilateral, painless massive cervical lymphadenopathy of ten weeks duration. After a detailed hematological work-up and imaging, the histological evidence obtained on cervical lymph node biopsy established the diagnosis of Rosai-Dorfman disease. Although, Rosai-Dorfman disease of unilateral lacrimal gland is extremely infrequent, a high degree of suspicion is warranted in a case of young patient presenting with unilateral isolated lacrimal gland swelling and associated lymphadenopathy, wherein no other cause is found. Treatment protocol should be individualized as per the extent of systemic involvement and functional disability.


Assuntos
Tratamento Conservador/métodos , Dexametasona/administração & dosagem , Histiocitose Sinusal/complicações , Doenças do Aparelho Lacrimal/terapia , Aparelho Lacrimal/diagnóstico por imagem , Biópsia por Agulha Fina , Criança , Diagnóstico Diferencial , Edema/diagnóstico , Edema/etiologia , Edema/terapia , Feminino , Glucocorticoides/administração & dosagem , Histiocitose Sinusal/diagnóstico , Humanos , Injeções Intravenosas , Doenças do Aparelho Lacrimal/diagnóstico , Doenças do Aparelho Lacrimal/etiologia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X
16.
Artigo em Chinês | MEDLINE | ID: mdl-31163529

RESUMO

Objective:To explore the relationships between glucocorticoid (GC) sensitivity and the prognosis of refractory sudden sensorineural hearing loss (SSNHL), and to analyze the related factors being affected the prognosis of SSNHL. Method:Ninety-one refractory SSNHL patients were enrolled in the present investigation. Peripheral blood mononuclear cells (PBMCs) from the refractory SSNHL were extracted to conduct GC proliferation dexamethasone (DEX) inhibition experiments. All patients accepted comprehensive treatment with methylprednisolone. Result:Total effective rate was 40.66% in refractory SSNHL patients. Gender, number of affected ear, age, accompanying with vertigo, tinnitus or not and the procedure of methylprednisolone treatment were irrelevant to the efficacy. Only the inhibitory rate of DEX and the time from onset to visit were related to GC treatment effect, especially for inhibitory rate of DEX. The DEX inhibition rate of the effective group was higher than that of the ineffective group. Conclusion:DEX inhibition rate can predict GC sensitivity and prognosis of SSNHL. GC sensitivity and the time from onset to treatment are two important factors affecting the prognosis of refractory SSNHL patients..


Assuntos
Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Anti-Inflamatórios/administração & dosagem , Dexametasona/administração & dosagem , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Súbita/complicações , Perda Auditiva Súbita/diagnóstico , Humanos , Leucócitos Mononucleares , Prognóstico , Zumbido , Vertigem
17.
Ann Hematol ; 98(9): 2139-2150, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31240472

RESUMO

The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator's assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/administração & dosagem , Depsipeptídeos/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Talidomida/administração & dosagem
18.
Pan Afr Med J ; 32: 105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223395

RESUMO

Haemophagocytic lymphohistiocytosis (HLH) in Human Immunodeficiency Virus (HIV) infected individuals can either be due to the disease itself or due to associated infections/malignancies. The treatment for HLH requires immunosuppressive therapy but administering immunosuppressive therapy to an already immunosuppressed patient (HIV infection) is complex. We present two such cases of HLH in patients infected with HIV. In the first case, no alternate cause for HLH was found even after extensive investigations and it was attributed to the uncontrolled HIV replication. Patient was started on dexamethasone for the same but succumbed to hospital acquired pneumonia. The second patient was diagnosed with Hodgkin's lymphoma but he succumbed to his illness before initiating immunosuppressive therapy for HLH. We report these cases to highlight the dilemma and a need for further research in this direction.


Assuntos
Infecções por HIV/complicações , Imunossupressores/efeitos adversos , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Adulto , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Infecções por HIV/imunologia , Humanos , Imunossupressores/administração & dosagem , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Pessoa de Meia-Idade
19.
Expert Rev Clin Pharmacol ; 12(7): 661-680, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31194593

RESUMO

Introduction: The addition of neurokinin-1 receptor antagonists (NK1RAs) to standard prophylaxis of 5-hydroxytryptamine-3 RA (5-HT3RA) plus dexamethasone more effectively prevents chemotherapy-induced nausea and vomiting (CINV) associated with highly and moderately emetogenic chemotherapy. Areas covered: This review presents the evidence base for the use of oral and intravenous (IV) NK1RAs, focusing on the pharmacologic and clinical properties as a class, and highlighting differences between agents. A PubMed literature search was conducted from 2000 to 2018. Expert opinion: Adherence to international antiemetic guidelines remains a clinical challenge. Strategies to simplify antiemetic regimens and facilitate their administration may improve compliance and treatment outcomes. The use of fixed-combination antiemetics offers clinical utility, in combining an NK1RA with a 5-HT3RA in a single oral dose. The use of long-lasting NK1RAs and administering CINV prophylaxis closer to the time of chemotherapy may also assist with guideline and treatment compliance, diminishing the need for home-based administration, and potentially reducing resource utilization. The availability of IV and oral formulations of NK1RAs and NK1RA-5-HT3RA fixed combinations offers further utility, particularly for those patients unsuited for oral administration. However, safety considerations with respect to injection site toxicity and hypersensitivity reactions of the new NK1RA IV formulations deserve close attention.


Assuntos
Náusea/prevenção & controle , Antagonistas do Receptor de Neuroquinina-1/administração & dosagem , Vômito/prevenção & controle , Adulto , Antieméticos/administração & dosagem , Antieméticos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Dexametasona/administração & dosagem , Quimioterapia Combinada , Fidelidade a Diretrizes , Humanos , Náusea/induzido quimicamente , Antagonistas do Receptor de Neuroquinina-1/efeitos adversos , Guias de Prática Clínica como Assunto , Fatores de Tempo , Vômito/induzido quimicamente
20.
Lancet ; 394(10192): 29-38, 2019 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171419

RESUMO

BACKGROUND: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. METHODS: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. FINDINGS: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10-5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). INTERPRETATION: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Quimioterapia Adjuvante , Terapia Combinada , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/uso terapêutico , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
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