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1.
Medicine (Baltimore) ; 98(33): e16915, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415440

RESUMO

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a rare hematological malignancy classified in the non-Hodgkin's lymphoma category. Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor has been approved for use in the treatment of CLL. This drug has shown beneficial effects including a higher overall response rate, sustained remissions, and a tolerable toxicity level. In this meta-analysis, we aimed to compare the adverse drug events which were associated with the use of ibrutinib for the treatment of patients with CLL. METHODS: A careful search was carried out through the Cochrane Central, EMBASE, MEDLINE (PubMed), and through www.ClinicalTrials.com. The following criteria for inclusion were considered: Both randomized trials and observational cohorts; Studies comparing the adverse drug events observed with the use of ibrutinib versus a control group for the treatment of CLL. The RevMan software (version 5.3) was used to carry out this analysis and the analyzed data were represented by risk ratios (RR) and 95% confidence intervals (CI). RESULTS: A total number of 2456 participants with CLL were included in this analysis. One thousand one hundred thirteen participants were treated with ibrutinib whereas the remaining 1343 participants were assigned to the control (non-ibrutinib) group. Results of this current analysis showed Ibrutinib not to be associated with significantly higher risk of anemia (RR: 0.90, 95% CI: 0.67-1.21; P = .49), thrombocytopenia (RR: 0.61, 95% CI: 0.32-1.14; P = .12), neutropenia (RR: 0.50, 95% CI: 0.25-1.00; P = .05), and febrile neutropenia (RR: 0.89, 95% CI: 0.32-2.49; P = .83) in these patients with CLL. The risk for respiratory tract infection was also similarly manifested (RR: 1.01, 95% CI: 0.78-1.30; P = .96). However, ibrutinib was associated with a high risk of abdominal manifestations in comparison to the control group (RR: 1.62, 95% CI: 1.32-2.00; P = .00001). The risk for diarrhea was also significantly higher in the Ibrutinib group (RR: 2.14, 95% CI: 1.44-3.17; P = .0002). CONCLUSIONS: During the treatment of CLL, ibrutinib was not associated with significantly higher risks of anemia, thrombocytopenia, or neutropenia compared to the control group. However, abdominal manifestations were significantly higher with ibrutinib. Advanced phase trials should further confirm this hypothesis.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Dor Abdominal/induzido quimicamente , Constipação Intestinal/induzido quimicamente , Diarreia/induzido quimicamente , Feminino , Humanos , Masculino , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Vômito/induzido quimicamente
2.
N Engl J Med ; 381(5): 432-443, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31365801

RESUMO

BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited. METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis. RESULTS: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001). CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Rituximab/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Rituximab/efeitos adversos , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados
4.
N Engl J Med ; 381(4): 338-348, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31340094

RESUMO

BACKGROUND: Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with FGFR alterations. METHODS: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified FGFR alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival. RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths. CONCLUSIONS: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).


Assuntos
Antineoplásicos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Quinoxalinas/administração & dosagem , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/tratamento farmacológico , Intervalo Livre de Progressão , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/efeitos adversos , Quinoxalinas/efeitos adversos , Resultado do Tratamento , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Urotélio
5.
Drugs ; 79(12): 1305-1319, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292909

RESUMO

Eltrombopag is an orally available thrombopoietin receptor agonist indicated for the treatment of immune thrombocytopenia (ITP). Beyond the effect on megakaryopoiesis, the drug also showed a stimulating effect on the hematopoietic stem cell with consistent clinical efficacy in aplastic anemia (AA) and myelodysplastic syndromes (MDS). Eltrombopag is highly effective in ITP and less so in AA and MDS. This observation underlines the importance of residual normal hematopoiesis, which is maximal in ITP, minimal/absent in AA, and dysregulated in MDS. In ITP, the drug at 50-75 mg daily induced up to 85% responses both in clinical trials and real-life studies, with the possibility of tapering and discontinuation. In AA, eltrombopag at 150 mg daily was effective in about 40% of cases relapsed/refractory to standard immunosuppression or ineligible for bone marrow transplant. In MDS, the drug seems less effective, with responses in about a quarter of patients at various schedules. The efficacy of eltrombopag in ITP, AA, and MDS suggests the existence of common immune-pathological mechanisms in these diseases, including autoimmunity against peripheral blood cells and bone marrow precursors, as well as a possible evolution of one condition into the other. Additional mechanisms of action emerging from the clinical use of eltrombopag include modulation of T-regulatory cells, restoration of Fc-γ receptor balance in phagocytes, and an iron-mobilizing effect. In this review, we analyzed the most recent literature on eltrombopag use and efficacy in patients with ITP, AA, and MDS, exploring the basis for different dosing, combined treatments, and discontinuation in each context.


Assuntos
Anemia Aplástica/tratamento farmacológico , Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Megacariócitos/imunologia , Síndromes Mielodisplásicas/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Imunomodulação , Imunossupressão , Púrpura Trombocitopênica Idiopática/imunologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Receptores de Trombopoetina/agonistas
6.
N Engl J Med ; 381(6): 509-519, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31199090

RESUMO

BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/administração & dosagem , Benzaldeídos/administração & dosagem , Hemoglobina Falciforme/efeitos dos fármacos , Hemoglobinas/metabolismo , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Adolescente , Adulto , Anemia Falciforme/sangue , Antidrepanocíticos/efeitos adversos , Antidrepanocíticos/uso terapêutico , Benzaldeídos/efeitos adversos , Biomarcadores/sangue , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina Falciforme/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Hidroxiureia/uso terapêutico , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Polimerização/efeitos dos fármacos , Pirazinas/efeitos adversos , Pirazóis/efeitos adversos , Adulto Jovem
8.
Gynecol Oncol ; 154(1): 95-101, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31118140

RESUMO

BACKGROUND: Improved treatment for advanced cervical cancer is needed; currently, treatment options include combined chemotherapy and bevacizumab or pembrolizumab monotherapy for PD-L1 positive disease. PIK3CA and KRAS mutations have been reported in cervical cancers; this study therefore tested dual inhibition of PI3K and RAS signaling by combining the MEK inhibitor trametinib and the AKT inhibitor GSK2141795 in recurrent cervical cancer. METHODS: This was an investigator-initiated phase II study combining trametinib and GSK2141795 in patients with recurrent cervical cancer. Primary endpoint was best tumor response; secondary endpoints included progression free survival, overall survival, and safety assessment. Translational objectives included characterization of molecular alterations in PI3K and RAS signaling pathway genes. RESULTS: Planned accrual was 35 patients; 14 patients were enrolled and received at least one dose of study drug before the study was terminated due to discontinuation of GSK2141795 development. There were no confirmed responses; 1 patient had an unconfirmed PR, 8 had stable disease, 3 had progression as best response, and 2 were unevaluable. Toxicities were mostly grade 1 and 2, although 57% of patients experienced grade 3/4 adverse events and 50% patients required a dose reduction. CONCLUSIONS: The combination of trametinib and GSK2141795 was feasible but required dose holds and modifications for adverse events; however, anti-cancer activity was minimal, even in patients with PI3K or RAS pathway alterations. Although the study was terminated early after GSK2141795 development was halted, the findings in these 14 patients do not support further development of this combination in cervical cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Diaminas/administração & dosagem , Diaminas/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/antagonistas & inibidores , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/enzimologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/enzimologia
9.
N Engl J Med ; 380(22): 2095-2103, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31141631

RESUMO

BACKGROUND: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. METHODS: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10-4). RESULTS: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. CONCLUSIONS: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fibrilação Atrial/induzido quimicamente , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução , Leucemia Linfocítica Crônica de Células B/genética , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Neutropenia/induzido quimicamente , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Indução de Remissão , Sulfonamidas/efeitos adversos
10.
Ann Hematol ; 98(7): 1611-1616, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31093708

RESUMO

Recent evidence suggests that renal dysfunction may be a direct consequence of primary myelofibrosis (PMF). We performed a retrospective analysis of 100 patients with previously untreated PMF, receiving frontline treatment with single agent ruxolitinib, and compared them to 105 patients, receiving frontline treatment with a non-ruxolitinib-based therapy, matched by age, sex, DIPSS plus, and estimated glomerular filtration rate (eGFR). Use of ruxolitinib associated with a significantly higher rate of renal improvement (RI) > 10% (73% vs 50%, p = 0.01) confirmed on multivariate analysis (MVA) [odds ratio 3, 95% confidence interval (CI) 1.6-5.5, p < 0.001]. After a median follow-up of 41 months (range, 1-159 months), median failure-free survival (FFS) was 14 months (range, 1-117 months). Achievement of a RI > 10% maintained its independent association with prolonged FFS on MVA (hazard ratio 1.4, 95% CI 1.1-2, p = 0.02). Ruxolitinib can significantly improve renal function in patients with PMF, significantly impacting failure-free survival.


Assuntos
Bases de Dados Factuais , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim , Mielofibrose Primária , Pirazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Mielofibrose Primária/mortalidade , Mielofibrose Primária/fisiopatologia , Estudos Retrospectivos , Taxa de Sobrevida
11.
Adv Mater ; 31(27): e1901103, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31112631

RESUMO

Ionic liquids (ILs) and deep eutectic solvents have shown great promise in drug delivery applications. Choline-based ILs, in particular choline and geranic acid (CAGE), have been used to enhance the transdermal delivery of several small and large molecules. However, detailed studies outlining the design principles of ILs for transdermal drug delivery are still lacking. Using two model drugs of differing hydrophilicities, acarbose and ruxolitinib and 16 ILs, the dependence of skin penetration on the chemical properties of ILs is examined. First, the impact of ion stoichiometry on skin penetration of drugs is assessed using CAGE, which evidences that a molar ratio of 1:2 of choline to geranic acid yields the highest delivery. Subsequently, variants of CAGE are prepared using anions with structural similarity to geranic acid and cations with structural similarity to choline at a ratio of 1:2. Mechanistic studies reveal that the potency of ILs in enhancing transdermal drug delivery correlates inversely with the inter-ionic interactions as determined by 2D NMR spectroscopy. Using this understanding, a new IL is designed, and it provides the highest delivery of ruxolitinib of all ILs tested here. Overall, these studies provide a generalized framework for optimizing ILs for enhancing skin permeability.


Assuntos
Acarbose/administração & dosagem , Ácidos Carboxílicos/química , Portadores de Fármacos/química , Líquidos Iônicos/química , Pirazóis/administração & dosagem , Administração Cutânea , Animais , Colina/química , Cobaias , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Permeabilidade , Pele/metabolismo , Solventes/química , Terpenos/química
13.
Biomed Res Int ; 2019: 8163780, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30956985

RESUMO

Objective: Steroid-resistant graft-versus-host disease (GvHD) is a major challenge after allogeneic stem cell transplantation and associated with significant morbidity and mortality. There is no therapeutic standard defined beyond calcineurin inhibitors (CNI) and steroids. Furthermore, some patients may have contraindications against CNI or high-dose steroids. Efficacy of ruxolitinib against GvHD has been described recently. Methods: Ruxolitinib was used for treatment of acute or chronic GvHD in eight patients. The patients either needed intensification of therapy or had contraindications against use of CNI or high-dose steroids. Results: Supplementation of therapy in acute GvHD with severe diarrhea with ruxolitinib was unsuccessful. All these patients died from acute GvHD. Introduction of ruxolitinib into therapy and relapse prophylaxis in other patients was successful in 4/4 cases (CR=3, PR=1). Indications for ruxolitinib were contraindications against CNI due to aHUS in two cases and the need for steroid sparing in two other cases. None of these patients suffered from diarrhea at the initiation of ruxolitinib. Conclusion: Ruxolitinib was effective for therapy of acute and chronic GvHD in higher lines in patients without severe diarrhea. Ruxolitinib could replace successfully CNI and high-dose steroids. Further investigations are necessary to define the position of ruxolitinib in GvHD-therapy.


Assuntos
Resistência a Medicamentos/efeitos dos fármacos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Pirazóis/administração & dosagem , Doença Aguda , Adulto , Idoso , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Esteroides/administração & dosagem , Esteroides/efeitos adversos
14.
Chem Pharm Bull (Tokyo) ; 67(3): 224-235, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828000

RESUMO

Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure-activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Simulação por Computador , Cristalografia por Raios X , Meia-Vida , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Miosite Ossificante/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Espectroscopia de Prótons por Ressonância Magnética , Pirazóis/administração & dosagem , Pirazóis/química , Pirazóis/farmacocinética , Solubilidade , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
15.
Vasc Endovascular Surg ; 53(5): 408-410, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30913995

RESUMO

INTRODUCTION: Venous thromboembolism (VTE) of the lower extremities frequently occurs after surgery. It is unknown whether the complication of renal vein thrombosis (RVT) develops after an open repair (OR) for abdominal aortic aneurysm (AAA). Furthermore, anticoagulation therapy with apixaban, a direct oral anticoagulant (DOAC), has not been described as treatment for RVT in such cases. CASE: A 64-year-old man underwent OR for AAA. Postoperative computed tomography revealed RVT in the left renal vein. Apixaban (5 mg twice a day) therapy was initiated. Six months later, we discontinued anticoagulation therapy and observed no recurrence. Following OR, our patient developed RVT for which DOACs were very useful. CONCLUSION: Thus, RVT can manifest as VTE after OR and direct anticoagulants can be considered as a therapeutic option.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Inibidores do Fator Xa/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Veias Renais/efeitos dos fármacos , Grau de Desobstrução Vascular/efeitos dos fármacos , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Trombose Venosa/tratamento farmacológico , Administração Oral , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aortografia/métodos , Angiografia por Tomografia Computadorizada , Humanos , Masculino , Pessoa de Meia-Idade , Flebografia/métodos , Veias Renais/diagnóstico por imagem , Veias Renais/fisiopatologia , Resultado do Tratamento , Ultrassonografia Doppler em Cores , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/etiologia
16.
Vet Parasitol ; 270 Suppl 1: S12-S18, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30914264

RESUMO

The efficacy of a single application of a new topical formulation containing selamectin plus sarolaner (Revolution® Plus / Stronghold® Plus, Zoetis) was evaluated against fleas and ticks infesting cats enrolled as veterinary patients in two field studies conducted in Japan and against Haemaphysalis longicornis ticks on cats in a laboratory study. In the laboratory study, sixteen cats were ranked based on pre-treatment tick counts and allocated randomly to treatment on Day 0 with either selamectin plus sarolaner or placebo. Cats were infested with adult H. longicornis on Days -2, 5, 12, 19, 26 and 33. Efficacy relative to placebo was based on live attached tick counts conducted 48 h after treatment and subsequent re-infestations. Selamectin plus sarolaner reduced live, attached H. longicornis counts by 96.4% within 48 h of treatment, and by ≥91.7% within 48 h of weekly re-infestation for 35 days, based on arithmetic means. In the field studies, 67 client-owned cats harboring six or more live fleas and 63 cats harboring four or more live attached ticks were enrolled to evaluate selamectin plus sarolaner for efficacy and safety compared with a registered product. Cats were allocated randomly to treatment with selamectin plus sarolaner or fipronil plus (S)-methoprene based on order of presentation. Treatment was administered once on Day 0 and efficacy was assessed by parasite counts conducted on Days 14 and 30 compared to the pre-treatment count. In the flea field study, live flea counts on Days 14 and 30 were reduced by 99.5% and 99.9% in the selamectin plus sarolaner group, and by 97.6% and 98.6% in the fipronil plus (S)-methoprene group, based on least squares mean percentage reductions. Clinical signs typically associated with flea allergy dermatitis improved following treatment. In the tick field study, live tick counts on Days 14 and 30 were reduced by 97.5% and 97.7% in the selamectin plus sarolaner group, and by 91.5% and 93.4% in the fipronil plus (S)-methoprene group, based on least squares mean percentage reductions. Selamectin plus sarolaner was determined to be non-inferior to fipronil plus (S)-methoprene in both field studies. There were no treatment-related adverse events in any study. A single topical dose of Revolution® Plus / Stronghold® Plus providing a minimum dosage of 6.0 mg/kg selamectin and 1.0 mg/kg sarolaner was confirmed to be effective against H. longicornis ticks on cats for one month and safe and effective in the treatment of fleas and ticks on cats enrolled as veterinary patients in Japan.


Assuntos
Azetidinas/administração & dosagem , Doenças do Gato/tratamento farmacológico , Infestações por Pulgas/veterinária , Ivermectina/análogos & derivados , Compostos de Espiro/administração & dosagem , Controle de Ácaros e Carrapatos , Infestações por Carrapato/veterinária , Acaricidas/administração & dosagem , Administração Tópica , Animais , Doenças do Gato/prevenção & controle , Gatos , Composição de Medicamentos/veterinária , Feminino , Infestações por Pulgas/tratamento farmacológico , Infestações por Pulgas/prevenção & controle , Inseticidas/administração & dosagem , Ivermectina/administração & dosagem , Japão , Masculino , Metoprene/administração & dosagem , Pirazóis/administração & dosagem , Distribuição Aleatória , Sifonápteros/efeitos dos fármacos , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/prevenção & controle , Carrapatos/efeitos dos fármacos , Resultado do Tratamento
19.
Yakugaku Zasshi ; 139(3): 461-467, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30828024

RESUMO

Direct oral anticoagulants (DOACs) are safe and efficacious when compared to warfarin for patients with venous thromboembolism (VTE). However, bleeding is a major side effect of anticoagulant therapy in VTE patients. Discontinuation of the DOACs associated to adverse events such as bleeding. The HAS-BLED score predicts warfarin-associated hemorrhage. However, little is known about risk factors for DOAC-associated minor bleeding in VTE patients. We aimed to identify risk factors for minor bleeding in VTE patients that were treated with edoxaban, rivaroxaban, or apixaban. We retrospectively evaluated the data of 212 VTE patients who received treatment with a DOAC. The study endpoint was defined as the occurrence of minor bleeding. Logistic regression analysis was used to determine risk factors that were significantly associated with minor bleeding. A total of 36 (17.0%) patients experienced minor bleeding, with rates of 15.7%, 0%, and 21.3% for edoxaban, rivaroxaban, and apixaban, respectively. In the multivariate analysis, bleeding history or predisposition [odds ratio (OR) 6.083, 95% confidence interval (CI) 2.131-17.364, p=0.001] and cancer (OR 6.397, 95% CI 2.858-14.317, p<0.001) were significantly associated with minor bleeding. Bleeding history or predisposition and cancer were the most important risk factors for DOAC-induced minor bleeding in VTE patients in this study. To continue anticoagulant therapy of the DOACs, further management systems by minor bleeding risk factors for patients with VTE will be required.


Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/etiologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
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