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1.
Rinsho Ketsueki ; 60(10): 1449-1454, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31695006

RESUMO

The clinical course of chronic lymphocytic leukemia (CLL) is often complicated by autoimmune cytopenia (AIC). Here we report a case of a 69-year-old woman with CLL complicated by monoclonal immunoglobulin deposition disease (MIDD) and AIC. The patient was diagnosed with CLL at the age of 63 years and treated with chemotherapy including rituximab and/or fludarabine owing to the development of anemia, multiple lymphadenopathy, and B symptoms at the age of 66 years. Furthermore, pancytopenia and renal failure developed at the age of 68 years. Consequently, the patient was admitted owing to dyspnea. Because of no apparent signs of CLL progression, we concluded that pancytopenia was due to AIC (autoimmune granulocytopenia and thrombocytopenia) and renal anemia. MIDD was diagnosed based on renal histology and detection of IgM and λ chain immunoglobulin deposits on glomeruli and tubules, which were presumed to be derived from CLL cells. The patient was treated with ibrutinib in order to reduce monoclonal protein levels. AIC improved concurrently with IgM reduction 1 month later. Supportive care, involving transfusion and granulocyte colony-stimulating factor, was not required approximately 3 months after initiating ibrutinib treatment. In contrast, MIDD did not improve and maintenance hemodialysis was required. Owing to its antitumor and immunomodulatory effects, ibrutinib may contribute to improve CLL-associated AIC.


Assuntos
Anticorpos Monoclonais , Doenças Autoimunes/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/complicações , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Feminino , Humanos , Rituximab
2.
Rinsho Ketsueki ; 60(10): 1462-1467, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31695008

RESUMO

The Richter syndrome (RS) is defined as a histologically diagnosed diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. A standard treatment for RS has not yet been established. Most patients with RS are treated with combination chemotherapy regimens used for de novo DLBCL or HL. Recently, the Bruton's tyrosine kinase inhibitor, ibrutinib (IBR), has shown remarkable efficacy in CLL; however, limited evidence exists regarding its single agent efficacy in RS. We encountered two patients with RS in whom CLL transformed to DLBCL, confirmed by G-banding/spectral karyotyping analysis. Both patients achieved durable responses for 12 and 10 months, with IBR alone. Hemorrhagic cystitis due to adenovirus occurred in one patient at an initial dose of 420 mg/day, but a dose reduction to 280 mg/day made long-term continuation of IBR possible. Interestingly, retreatment with IBR alone achieved disease control again for 5.5 and 2 months, after these patients underwent salvage chemotherapies for aggressive relapse.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Humanos
3.
Zhonghua Xue Ye Xue Za Zhi ; 40(9): 750-754, 2019 Sep 14.
Artigo em Chinês | MEDLINE | ID: mdl-31648477

RESUMO

Objective: To improve the knowledge and experience of ibrutinib combined with CAR-T cells in the treatment of high-risk chronic lymphoblastic leukemia (CLL) patients or small lymphocytic lymphoma (SLL) with TP53 gene aberration. Methods: One case of del (17p) CLL patients with BCL-2 inhibitor resistance was treated with ibrutinib combined with CAR-T cells, successfully bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT) , and the relative literatures were reviewed. Results: The patient was a young female with superficial lymph node enlarging at the beginning of the onset. Lymph node biopsy was confirmed as small lymphocytic lymphoma (SLL) without del (17p) . The disease progressed rapidly to CLL/SLL with del (17p) and bone marrow hematopoietic failure 2 years later. Firstly, the patient was treated with BCL-2 inhibitor (Venetoclax) , and the enlarged lymph nodes shrank significantly 2 months later. After 3 months, the disease progressed rapidly. The spleen was enlarged to 16 cm below the ribs, the neck lymph nodes was rapidly enlarged, and the superior vena cava syndrome appeared, which were mainly attributed to venetoclax resistance; so BTK inhibitor (ibrutinib) was used continuously after venetoclax discontinuation. Partial remission (PR) was achieved without lymphocytosis after 2 months, then ibrutinib was combined with CAR-T cells targeting CD19 antigen. Grade 1 of cytokine release syndrome (CRS) appeared after CAR-T cells infusion, and the complete remission (CR) was achieved after 1 month both in bone marrow and peripheral blood, with minimal residual disease (MRD) negative, then bridging allo-HSCT after 2 months of combined therapy. Conclusion: CLL/SLL patients with TP53 aberration have poor prognosis because of rapid progression, drug resistance, etc. Ibrutinib combined with CAR-T cell therapy can quickly achieved complete remission.


Assuntos
Leucemia Linfocítica Crônica de Células B , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/terapia , Proteínas Proto-Oncogênicas c-bcl-2 , Recoverina , Linfócitos T
4.
Gan To Kagaku Ryoho ; 46(10): 1595-1597, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31631147

RESUMO

Tropomyosin-related kinase(TRK)fusion proteins are oncogenic drivers in multiple tumors in adults and children.Larotrectinib, an orally administered selective TRK inhibitor approved in the US, exhibits inhibitory activity against tumors harboring TRK fusions and is well tolerated.Here, we report the case of an 8-year-old female child with recurrence of an NTRK fusion low-grade sarcoma treated with larotrectinib monotherapy.The patient previously underwent resection of low-grade sarcoma in the right brachialis at 6 years of age, but local recurrence occurred after 16 months.As re-operation likely required amputation, larotrectinib was commenced at a dose of 100 mg BID.Complete radiographic remission was achieved after 3 months.There were no adverse events attributed to larotrectinib treatment.After dosing for 6 months, we performed local resection, confirming pathological complete remission.The drug was stopped, and the patient showed no evidence of relapse at 4 months after resection.In this case, larotrectinib was obtained using Single Patient Expanded Access under the FDA.In this paper, we also discuss the issues faced while accessing unapproved drugs in the precision medicine era in Japan.


Assuntos
Recidiva Local de Neoplasia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sarcoma , Criança , Feminino , Fusão Gênica , Humanos , Japão , Lamina Tipo A , Receptor trkA , Sarcoma/tratamento farmacológico
5.
J Assoc Physicians India ; 67(10): 14-19, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31571445

RESUMO

Background: Teneligliptin is widely prescribed dipeptidyl peptidase-4 inhibitor (DPP-4i) in India because of its economical pricing. However, there is no headto-head trial comparing teneligliptin with any other DPP-4i in Indian setting. We evaluated the efficacy and safety of teneligliptin versus sitagliptin as add-on to metformin and/or sulfonylureas in patients with type 2 diabetes mellitus (T2DM). Methods: This prospective, open-label, randomized, active-controlled study enrolled 76 patients (1:1) at 2 centres. Patients received teneligliptin 20 mg or sitagliptin 100 mg orally once daily for 12 weeks as add-on to ongoing metformin or sulfonylurea therapy. Primary endpoint was mean change in glycosylated hemoglobin (HbA1c) from baseline at week 12. Results: Both arms were comparable (p>0.05) at baseline in terms of age, gender, metformin daily dose, sulfonylurea use, HbA1c, fasting and postprandial blood glucose (FBG and PPBG). At the end of 12 weeks, statistically significant reductions were observed in both teneligliptin and sitagliptin arms in HbA1c (-1.19 ± 1.16% p<0.0001 and -0.92 ± 0.95%, p<0.0001), in FBG (-28.3 ± 63.0 mg/dL, p= 0.01 and -22.9 ± 47.4 mg/dL, p=0.006) and PPBG (-41.3 ± 85.4 mg/dL, p=0.006 and -54.7 ± 85.6 mg/dL, p=0.0005). The reductions in all glycemic parameters were similar between the arms. Both gliptins were well-tolerated with no difference in the number of adverse events. There was no change in QT/QTc intervals or other ECG parameters at week 12 in both arms. In post-hoc comparison, percentage of patients achieving target HbA1c <7% (as per American Diabetes Association guidelines) at week 12 favored teneligliptin arm over sitagliptin arm (33.3% vs. 19.4% patients). Conclusion: Teneligliptin provided similar glycemic control as compared to sitagliptin and reduced HbA1c, FBG and PPBG values significantly within 12 weeks of treatment. Both gliptins were found to be safe and well-tolerated in Indian patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Pirazóis/uso terapêutico , Fosfato de Sitagliptina/uso terapêutico , Tiazolidinas/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Índia , Estudos Prospectivos
7.
Int Heart J ; 60(5): 1137-1141, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31484878

RESUMO

Current therapeutic methods for chronic thromboembolic pulmonary hypertension (CTEPH) can improve hemodynamic status and are expected to improve prognoses. However, some patients experience dyspnea during effort and continue supplemental oxygenation despite their hemodynamic status being fully improved. Considering the pathogenesis of CTEPH, the dead space and intrapulmonary shunt are assumed to be responsible for hypoxia in CTEPH, but their contributions are unclear. It is also unclear whether they are improved after treatment. The aim of this study was to investigate the implications of the dead space ratio (DSR) and the intrapulmonary shunt ratio (ISR) for hypoxia in CTEPH and treatment for CTEPH.We retrospectively measured the DSR and ISR of 23 consecutive patients with CTEPH. For 11 of these 23 (10 were treated by balloon pulmonary angioplasty, one with riociguat), we also measured these parameters before and after CTEPH treatments. Overall, the DSR and ISR were abnormally elevated (DSR: 0.63 ± 0.06; ISR: 0.20 ± 0.05). After treatment, mean pulmonary artery pressure was improved (from 40.3 ± 8.1 to 25.5 ± 2.7 mmHg). Although atrial oxygen saturation (SaO2), DSR and ISR were improved (SaO2: from 90.2 ± 3.2 to 93.7 ± 1.8%; DSR: from 0.64 ± 0.06 to 0.58 ± 0.05; ISR: from 0.20 ± 0.04 to 0.18 ± 0.02), these improvements were slight compared with that of mean pulmonary artery pressure.The DSR and ISR were abnormally elevated in patients with CTEPH and their improvement by treatment was limited. Only DSR can be a useful marker for normalization of hypoxia in CTEPH.


Assuntos
Angioplastia com Balão/métodos , Hipertensão Pulmonar/terapia , Embolia Pulmonar/terapia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Espaço Morto Respiratório/efeitos dos fármacos , Adulto , Idoso , Doença Crônica , Feminino , Hemodinâmica/fisiologia , Hospitais Universitários , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/mortalidade , Japão , Masculino , Pessoa de Meia-Idade , Oxigenoterapia/métodos , Prognóstico , Circulação Pulmonar/fisiologia , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/mortalidade , Espaço Morto Respiratório/fisiologia , Testes de Função Respiratória , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Taxa de Sobrevida , Resultado do Tratamento
8.
Rinsho Ketsueki ; 60(8): 953-959, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31484895

RESUMO

Graft-versus-host-disease (GvHD) is a major complication and leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids remain the standard initial therapy for GvHD; however, patients frequently become steroid-refractory (SR) or remain steroid dependent. Cytokine inhibition appears to be a potential option; however, blockade of any single cytokine may not be sufficient probably because of the redundant effects of multiple cytokines. The Jak1/2 inhibitor ruxolitinib can simultaneously inhibit the signaling pathway of multiple cytokines with relevance for GvHD, such as interferon (IFN-γ), IL-2, and IL-6. A recent retrospective survey reported that ruxolitinib produced a high response rate for SR-GvHD, leading to better survival odds. A prompt and sustained ruxolitinib response contributes to the steroid-sparing effect; however, accumulating evidence showed that ruxolitinib exerts substantial myelosuppression and immunosuppressive activity in patients with myelofibrosis (MF). Additionally, serious adverse events following discontinuation of ruxolitinib treatment, characterized by acute relapse of the disease and/or GvHD, have been recognized. Herein we discuss the advantages and disadvantages of ruxolitinib as treatment for GvHD in patients with MF.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Pirazóis/uso terapêutico , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Mielofibrose Primária/complicações , Estudos Retrospectivos
10.
Drugs Today (Barc) ; 55(8): 495-501, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31461086

RESUMO

Erdafitinib is the first Food and Drug Administration (FDA)-approved oral pan-fibroblast growth factor receptor (FGFR) kinase inhibitor that binds to four FGFRs (FGFR-1 to -4), leading to decreased cell signaling and cellular apoptosis. Erdafitinib also binds to RET, colony-stimulating factor 1 receptor (CSF-1R), platelet-derived growth factor receptor α and ß (PDGFR-α and PDGFR-ß), Fms-related tyrosine kinase 4 (FLT4), KIT and vascular endothelial growth factor receptor 2 (VEGFR-2), exhibiting additional antitumor mechanisms resulting in cell kill. In this article, we provide a comprehensive review of the preclinical and clinical activity of erdafitinib, which has been recently approved in the U.S. for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3/FGFR2 genetic alterations following progression during or after at least one line of platinum-containing chemotherapy and within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Erdafitinib is the first oral treatment option for patients with urothelial carcinoma.


Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias Urológicas/tratamento farmacológico , Urotélio/patologia , Humanos
11.
Hematol Oncol ; 37(4): 392-400, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420873

RESUMO

Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death-1 (PD-1) on total CD4+ (P < .01), total CD8+ (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on total CD4+ (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C-X-C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death-ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal ß2-macroglobulin (ß2-MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA-4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal ß2-MG, normal LDH, IGHV-mutated and wild-type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/farmacologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunofenotipagem , Células Matadoras Naturais/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos
12.
Rinsho Ketsueki ; 60(7): 755-760, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391362

RESUMO

We retrospectively analyzed 30 patients with myelofibrosis who had been treated with ruxolitinib at our hospital. Although dose reduction was required for 13 patients due to anemia or thrombocythemia, it was later possible to increase the dose of ruxolitinib in 10 patients (77%). A total of five patients became transfusion dependent. Among them, one patient who continued ruxolitinib therapy exhibited subsequent symptom improvement and reduction in splenomegaly while also becoming transfusion independent. Four patients whose platelet counts were <50×109/l were also treated with ruxolitinib, one of whom was able to continue ruxolitinib therapy for 25 months with some response. For one patient, ruxolitinib therapy was withdrawn due to non-response. However, upon reintroduction of ruxolitinib after 5 months without treatment, spleen size and LD levels decreased, which lasted for around 5 months. This retrospective study supports the current understanding on ruxolitinib therapy for Japanese patients with cytopenia.


Assuntos
Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Humanos , Estudos Retrospectivos , Resultado do Tratamento
13.
Presse Med ; 48(7-8 Pt 1): 832-841, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31444019

RESUMO

Lymphoplasmocytic lymphona with monoclonal lgM, rare. Median age at diagnosis 70 years old, frail population. Heterogenous clinic presentation. Molecular diagnosis with MYD88. Treatment required for symptomatic WM patients only. 1st line therapy: DRC. Input of targeted therapies (ibrutinib) for frail patients, maintenance effect.


Assuntos
Macroglobulinemia de Waldenstrom , Idade de Início , Idoso , Análise Mutacional de DNA/métodos , Idoso Fragilizado , Humanos , Técnicas de Diagnóstico Molecular/métodos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Fator 88 de Diferenciação Mieloide/genética , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/epidemiologia , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/terapia
14.
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
16.
Clin Adv Hematol Oncol ; 17(4): 223-233, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31188814

RESUMO

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Antígenos CD20/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Ensaios Clínicos como Assunto , Previsões , Neoplasias Gastrointestinais/induzido quimicamente , Hemorragia/induzido quimicamente , Humanos , Fatores Imunológicos/administração & dosagem , Linfocitose/induzido quimicamente , Linfoma de Célula do Manto/enzimologia , Terapia de Alvo Molecular/efeitos adversos , Infecções Oportunistas/induzido quimicamente , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Terapia de Salvação
17.
BMC Vet Res ; 15(1): 193, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186043

RESUMO

BACKGROUND: Pedobarographic analyses detect pressure redistribution among limbs and within limbs in humans, equids and dogs. The main objective of this study was to assess the usefulness of a set of pedobarographic parameters for the detection of lameness, as well as for its suitability for assessing the effects of therapies against osteoarthritis in dogs. With this purpose, eleven large-breed lame dogs with unilateral osteoarthritis due to elbow dysplasia were evaluated using a pressure platform prior to (D0) and after 3 months (D90) of treatment with mavacoxib, a COX-2 selective NSAID. The obtained parameters were: pressure distribution between lame and sound limbs, as well as paw area, mean pressure, and peak pressure of both lame and sound limbs. RESULTS: The results showed statistical differences in all these parameters between lame and sound limbs at D0; however, at D90, differences were significantly decreased as result of the treatment, indicating a substantial functional recovery under the study design conditions. CONCLUSIONS: The provided data prove the suitability of this novel technique in canine models for the quantitative and objective assessment of lameness, but also for the evaluation of treatments for lameness caused by articular pain.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças do Cão/tratamento farmacológico , Osteoartrite/veterinária , Pirazóis/uso terapêutico , Animais , Doenças do Cão/diagnóstico , Cães , Feminino , Marcha , Artropatias/diagnóstico , Artropatias/tratamento farmacológico , Artropatias/veterinária , Coxeadura Animal/diagnóstico , Masculino , Osteoartrite/diagnóstico , Osteoartrite/tratamento farmacológico , Pressão
18.
Oncology ; 97(2): 102-111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31230047

RESUMO

BACKGROUND: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. METHODS: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. RESULTS: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). CONCLUSIONS: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética
19.
J Dermatol ; 46(8): 724-730, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237712

RESUMO

Alopecia areata (AA) is a relatively common disease, but no satisfactory treatment has yet been developed. Recently, research progress has been made in the pathogenesis of AA, revealing that autoreactive cytotoxic T cells are important and that the Janus kinase (JAK) pathway is involved. Therefore, the potential of JAK inhibitors as therapeutic agents for AA is attracting attention. Several single-arm clinical trials and retrospective studies demonstrated that oral JAK inhibitors are effective and tolerable treatments for moderate to severe AA. Although JAK inhibitors are emerging as an innovative treatment for AA, further placebo-controlled clinical trials are required to confirm their efficacy and long-term safety.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Administração Oral , Alopecia em Áreas/imunologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Pessoa de Meia-Idade , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
20.
Int J Mol Sci ; 20(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174329

RESUMO

Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu2 and M4 subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu2 and M4 receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu2 receptor, and VU152100 (0.25-0.5 mg/kg), a positive allosteric modulator of the M4 receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug-drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M4 and mGlu2 receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Benzamidas/uso terapêutico , Memória de Curto Prazo/efeitos dos fármacos , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Comportamento Social , Sulfonamidas/uso terapêutico , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Maleato de Dizocilpina/toxicidade , Quimioterapia Combinada , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Agonistas de Aminoácidos Excitatórios/farmacologia , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/toxicidade , Masculino , Camundongos , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Receptor Muscarínico M4/efeitos dos fármacos , Receptores de Glutamato , Esquizofrenia/etiologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia
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