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1.
Lancet Oncol ; 21(9): 1188-1200, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888452

RESUMO

BACKGROUND: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. METHODS: CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. FINDINGS: Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma). INTERPRETATION: 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche and AbbVie.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Clorambucila/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Clorambucila/efeitos adversos , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sulfonamidas/efeitos adversos , Resultado do Tratamento
2.
Lancet Haematol ; 7(10): e724-e736, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32896301

RESUMO

BACKGROUND: Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukaemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine that has shown promising results in patients with high-risk AML in phase 2 trials. We hypothesised that venetoclax with 10-day decitabine could have improved activity in patients with newly diagnosed AML and those with relapsed or refractory AML, particularly in high-risk subgroups. METHODS: This single centre, phase 2 trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). The study enrolled older patients (aged >60 years) with newly diagnosed AML, not eligible for intensive chemotherapy; secondary AML (progressed after myelodysplastic syndrome or chronic myelomonocytic leukaemia); and relapsed or refractory AML. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or less, white blood cell count less than 10 × 109 per L, and adequate end-organ function. Patients with favourable-risk cytogenetics (eg, t[15;17] or core-binding factor AML) or who had received previous BCL2-inhibitor therapy were excluded. Patients received decitabine 20 mg/m2 intravenously for 10 days with oral venetoclax 400 mg daily for induction, followed by decitabine for 5 days with daily venetoclax for consolidation. The primary endpoint was overall response rate. The secondary endpoints analysed within this report include safety, overall survival, and duration of response, in keeping with recommendations of European LeukemiaNet 2017 guidelines. All patients who received at least one dose of treatment were eligible for safety and response assessments. The trial was registered on ClinicalTrials.gov (NCT03404193) and continues to accrue patients. FINDINGS: Between Jan 19, 2018, and Dec 16, 2019, we enrolled 168 patients; 70 (42%) had newly diagnosed AML, 15 (9%) had untreated secondary AML, 28 (17%) had treated secondary AML, and 55 (33%) had relapsed or refractory AML. The median age was 71 years (IQR 65-76) and 30% of patients had ECOG performance status of 2 or higher. The median follow-up for all patients was 16 months (95% CI 12-18; actual follow-up 6·5 months; IQR 3·4-12·4). The overall response rate was 74% (125 of 168 patients; 95% CI 67-80) and in disease subgroups were: 89% in newly diagnosed AML (62 of 70 patients; 79-94), 80% in untreated secondary AML (12 of 15 patients; 55-93), 61% in treated secondary AML (17 of 28 patients; 42-76), and 62% in relapsed or refractory AML (34 of 55 patients; 49-74). The most common treatment-emergent adverse events included infections with grades 3 or 4 neutropenia (n=79, 47%) and febrile neutropenia (n=49, 29%). 139 (83%) of 168 patients had serious adverse events, most frequently neutropenic fever (n=63, 38%), followed by pneumonia (n=17, 10%) and sepsis (n=16, 10%). The 30-day mortality for all patients was 3·6% (n=6, 95% CI 1·7-7·8). The median overall survival was 18·1 months (95% CI 10·0-not reached) in newly diagnosed AML, 7·8 months (2·9-10·7) in untreated secondary AML, 6·0 months (3·4-13·7) in treated secondary AML, and 7·8 months (5·4-13·3) relapsed or refractory AML. The median duration of response was not reached (95% CI 9·0-not reached) in newly diagnosed AML, 5·1 months (95% CI 0·9-not reached) in untreated secondary AML, not reached (95% CI 2·5-not reached) in previously treated secondary AML, and 16·8 months (95% CI 6·6-not reached) in relapsed or refractory AML. INTERPRETATION: Venetoclax with 10-day decitabine has a manageable safety profile and showed high activity in newly diagnosed AML and molecularly defined subsets of relapsed or refractory AML. Future larger and randomised studies are needed to clarify activity in high-risk subsets. FUNDING: US National Institutes of Health and National Cancer Institute.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento
3.
N Engl J Med ; 383(7): 617-629, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32786187

RESUMO

BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively. CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Azacitidina/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Pneumonia/etiologia , Recidiva , Indução de Remissão , Sulfonamidas/efeitos adversos , Trombocitopenia/induzido quimicamente
4.
Ann Hematol ; 99(10): 2343-2349, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32833105

RESUMO

Ibrutinib-based therapy represents a recent success in managing high-risk CLL patients with 17p/TP53 deletion. However, a subset of CLL patients are resistant to therapy. Deletion of lipoprotein lipase (LPL) has been postulated as a potential evasion mechanism to ibrutinib-based therapy. In this study, we assessed for LPL deletion by fluorescence in situ hybridization in 176 consecutive CLL patients with 17p/TP53 deletion. LPL deletion was detected in 35 (20%) of CLL patients. Patients with LPL deletion (del) showed a higher frequency of CD38 expression but have comparable frequencies of somatic hypermutation and ZAP-70 expression compared with patients with normal (nml) LPL. Gene mutation analysis showed that TP53 was mutated in 68% of LPL-del versus 91% of LPL-nml patients. The overall response to ibrutinib-based therapy was 57%, including 37% complete remission (CR) and 20% partial remission (PR) in patients with LPL-del versus 90% (56% CR and 34% PR) in patients with LPL-nml (p < 0.001). LPL-del patients also showed a poorer overall survival (OS) compared with patients with LPL-nml (median OS, 236 months versus undefined, p < 0.001). In summary, the data presented establish an association between LPL deletion, resistance to ibrutinib-based therapy, and poorer overall survival in TP53-deleted CLL patients. We suggest that LPL deletion might be utilized as a biomarker for risk stratification and to predict therapeutic response in this high-risk group of CLL patients.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , Leucemia Linfocítica Crônica de Células B/genética , Lipase Lipoproteica/deficiência , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Feminino , Genes p53 , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Lipase Lipoproteica/genética , Lipase Lipoproteica/fisiologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Modelos de Riscos Proporcionais , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Medição de Risco , Rituximab/administração & dosagem , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Proteína Supressora de Tumor p53/deficiência , Proteína-Tirosina Quinase ZAP-70/biossíntese , Proteína-Tirosina Quinase ZAP-70/genética
5.
Bull Cancer ; 107(5S): eS22-eS27, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620212

RESUMO

BACKGROUND: The nivolumab-ipilimumab combination provides an overall response rate of 42% in first-line metastatic treatment of clear cell renal carcinoma (mccRCC). To date, there is no robust predictive biomarker of response to immune checkpoint inhibitor (ICI). In addition, severe autoimmune disorders occur more frequently with ICI combination than with ICI alone. The objective of this study is to compare the efficacy of ICI alone or in combination in patients according to tumor molecular characteristics. METHODS: Using a 35-gene expression mRNA signature, patients were divided into 4 molecular groups (1 to 4). Patients in groups 1 and 4 were randomized to receive nivolumab alone (arms 1A and 4A) or nivolumab plus ipilimumab for 4 injections followed by nivolumab alone (arms 1B and 4B). Patients in groups 2 and 3 were randomized to receive nivolumab plus ipilimumab followed by nivolumab alone (arms 2B and 3B) or a tyrosine kinase inhibitor (sunitinib or pazopanib at the investigator's choice (arms 2C and 3C)). The main objective is the overall response rate by treatment and molecular group. DISCUSSION: BIONIKK is the first trial in mccRCC to study the personalization of treatment with ICI or TKI according to tumor molecular characteristics in mccRCC. This trial is the most appropriate to prospectively identify biomarkers of response to nivolumab used alone or in combination or TKI monotherapy in patients with mccRCC. NCT02960906.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ensaios Clínicos Fase II como Assunto/métodos , Ipilimumab/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Nivolumabe/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Sulfonamidas/administração & dosagem , Sunitinibe/administração & dosagem , Biomarcadores Tumorais , Quimioterapia Combinada , Humanos , Neoplasias Renais/patologia , Metástase Neoplásica , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
6.
Lancet Oncol ; 21(8): 1110-1122, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32702309

RESUMO

BACKGROUND: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. METHODS: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. FINDINGS: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. INTERPRETATION: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. FUNDING: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.


Assuntos
Antineoplásicos/administração & dosagem , Quimiorradioterapia/métodos , Terapia Neoadjuvante/métodos , Pirimidinas/administração & dosagem , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adolescente , Adulto , Antineoplásicos/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Pirimidinas/efeitos adversos , Radioterapia Adjuvante , Sarcoma/radioterapia , Neoplasias de Tecidos Moles/radioterapia , Sulfonamidas/efeitos adversos , Adulto Jovem
7.
Int Heart J ; 61(4): 799-805, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32728000

RESUMO

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.


Assuntos
Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Fenilpropionatos/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Idoso , Bosentana/administração & dosagem , Estudos de Casos e Controles , Antagonistas dos Receptores de Endotelina/administração & dosagem , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenilpropionatos/administração & dosagem , Inibidores da Fosfodiesterase 5/uso terapêutico , Placebos/administração & dosagem , Prostaglandinas I/uso terapêutico , Hipertensão Arterial Pulmonar/fisiopatologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Piridazinas/administração & dosagem , Pirimidinas/administração & dosagem , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos
8.
Ann Hematol ; 99(9): 2193-2195, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621180
9.
Lancet ; 396(10246): 255-266, 2020 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711801

RESUMO

BACKGROUND: Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis. METHODS: In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060. FINDINGS: Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p<0·0001). Of the patients with available data for the coprimary endpoints at week 12, compared with the placebo group, the proportion of patients who had achieved an EASI-75 response was significantly higher in the abrocitinib 100 mg group (62 [40%] of 156 patients vs nine [12%] of 76 patients; p<0·0001) and abrocitinib 200 mg group (96 [63%] of 153 patients vs nine [12%] of 76 patients; p<0·0001). Adverse events were reported in 108 (69%) of 156 patients in the abrocitinib 100 mg group, 120 (78%) of 154 patients in the abrocitinib 200 mg group, and 44 (57%) of 77 patients in the placebo group. Serious adverse events were reported in five (3%) of 156 patients in the abrocitinib 100 mg group, five (3%) of 154 patients in the abrocitinib 200 mg group, and three (4%) of 77 patients in the placebo group. No treatment-related deaths were reported. INTERPRETATION: Monotherapy with oral abrocitinib once daily was effective and well tolerated in adolescents and adults with moderate-to-severe atopic dermatitis. FUNDING: Pfizer.


Assuntos
Dermatite Atópica/tratamento farmacológico , Eczema/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adolescente , Adulto , Idoso , Austrália/epidemiologia , Canadá/epidemiologia , Estudos de Casos e Controles , Criança , Dermatite Atópica/patologia , Método Duplo-Cego , Eczema/patologia , Grupos Étnicos , Europa (Continente)/epidemiologia , Feminino , Humanos , Janus Quinase 1/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Segurança , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Estados Unidos/epidemiologia
10.
Lancet Gastroenterol Hepatol ; 5(9): 839-849, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32682494

RESUMO

BACKGROUND: Glecaprevir-pibrentasvir results in high rates of sustained virological response in patients with chronic hepatitis C virus (HCV) genotype 1-6 infection. Data for glecaprevir-pibrentasvir in non-Japanese Asian patients have been minimal. The aim of these studies was to assess the efficacy and safety of glecaprevir-pibrentasvir in treatment-naive and treatment-experienced Asian patients with chronic HCV genotype 1-6 infection without cirrhosis (VOYAGE-1) and with compensated cirrhosis (VOYAGE-2). METHODS: We did two phase 3 studies in treatment-naive and treatment-experienced patients with chronic HCV genotype 1-6 infection. VOYAGE-1 was a randomised, double-blind, placebo-controlled study that recruited patients without cirrhosis at 47 sites across China, South Korea, and Singapore. Randomisation was 2:1 with a fixed block size of three and stratified by geographical region and HCV genotype. Investigators, study site personnel, the study sponsor, and patients were masked to treatment allocation. VOYAGE-2 was a single-arm, open-label study that recruited patients with compensated cirrhosis at 34 sites across China and South Korea. Glecaprevir (300 mg) and pibrentasvir (120 mg) or placebo (VOYAGE-1, 2:1 ratio), administered as three tablets daily, was given for 8 weeks in patients without cirrhosis and for 12 weeks in those with cirrhosis (and for 16 weeks in treatment-experienced patients with genotype 3). The primary efficacy endpoint was the proportion of patients with a sustained virological response, defined as HCV RNA below the lower limit of quantification 12 weeks after the last dose of glecaprevir-pibrentasvir. We analysed efficacy and safety in all patients who received at least one dose of the study drug. These trials are registered with ClinicalTrials.gov, NCT03222583 (VOYAGE-1) and NCT03235349 (VOYAGE-2); both trials have been completed. This Article reports the results of the primary analysis for each study, undertaken when all patients who received glecaprevir-pibrentasvir (during the double-blind period in VOYAGE-1) had been followed up for 12 weeks following their last dose of study drug. Data from the double-blind period for placebo patients in VOYAGE-1 are also summarised. FINDINGS: Between Oct 4, 2017, and April 20, 2018, 546 patients with chronic HCV without cirrhosis were randomly assigned to treatment (363 to glecaprevir-pibrentasvir, 183 to placebo) in VOYAGE-1. One patient withdrew consent and did not receive treatment with glecaprevir-pibrentasvir. 352 of 362 patients who received glecaprevir-pibrentasvir achieved SVR12 (97·2% [95% CI 95·5-98·9]). Of 160 patients with compensated cirrhosis who were enrolled in VOYAGE-2 between Sept 29, 2017, and June 14, 2018, 159 of 160 achieved SVR12 (99·4%, 95% CI 98·2-100·0). 20 patients with HCV genotype 3b across both trials received glecaprevir-pibrentasvir; six of these patients were among the 11 patients who did not achieve SVR12. Upper respiratory tract infection was the most common adverse event (35 [10%] of 362 receiving glecaprevir-pibrentasvir and 18 [10%] of 183 receiving placebo in VOYAGE-1; 19 [12%] of 160 in VOYAGE-2). For patients receiving glecaprevir-pibrentasvir, serious adverse events occurred in three (<1%) of 362 patients in VOYAGE-1 and five (3%) of 160 patients in VOYAGE-2. Grade 3-4 adverse events in patients receiving glecaprevir-pibrentasvir occurred in five (1%) of 362 patients in VOYAGE-1 and six (4%) of 160 patients in VOYAGE-2; each type of event was experienced by at most one patient within a study. One patient with cirrhosis discontinued study drug because of an adverse event. INTERPRETATION: Glecaprevir-pibrentasvir showed high efficacy and an acceptable safety profile in these studies although responses were less common in the few patients with HCV genotype 3b. The results support the use of glecaprevir-pibrentasvir in these Asian populations. FUNDING: AbbVie.


Assuntos
Benzimidazóis/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Ásia/epidemiologia , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Estudos de Casos e Controles , Método Duplo-Cego , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/epidemiologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Prevalência , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Infecções Respiratórias/induzido quimicamente , Infecções Respiratórias/epidemiologia , Segurança , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Resultado do Tratamento
11.
Leukemia ; 34(8): 2225-2229, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601378
12.
Rev. int. androl. (Internet) ; 18(2): 55-62, abr.-jun. 2020. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-193760

RESUMO

INTRODUCTION AND OBJECTIVES: Testicular ischemia/reperfusion (I/R) injury develops after torsion and following detorsion of the testis. Reactive oxygen species were produced and oxidative damage begins to occur due to I/R process. Nimesulide, which is a specific cyclooxygenase-2 inhibitor drug, have antioxidant, antiinflammatory, analgesics and antipyretic effects. We aimed to investigate biochemically and histopathologically effect of nimesulide on testis I/R injury in rats induced by the testicular torsion-detorsion. MATERIAL AND METHODS: In this study, 24 albino Wistar male rats were divided into four groups (6 rats in each group): ischemia/reperfusion applied+50mg/kg nimesulide administrated (NIM-50), ischemia/reperfusion applied+100mg/kg nimesulide administrated (NIM-100), ischemia/reperfusion applied (IR) and Sham surgery (SS) groups. Nimesulide was administered to NIM-50 and NIM-100 groups at the 50mg/kg and 100mg/kg doses before 2h applied I/R procedures. The IR group were applied only I/R procedures, no drug treatment was applied. Animals were sacrificed under high dose anesthesia and left testes were extracted. Testes were examined biochemically and histopathologically. RESULTS: Total glutathione (tGSH) and cyclooxygenase-1 (COX-1) levels were increased in the NIM-50 and NIM-100 groups compared to IR group. The levels of COX-2, malondialdehyde (MDA), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were lower in the NIM-50 and NIM-100 groups than in the IR group. Some histopathological changes seen in IR group. This findings were decreased in NIM-50 group and prevented in NIM-100 group. CONCLUSION: Nimesulide prevented inflammation and oxidative stress. Our results suggest that nimesulide may be have a protective effect on testicular I/R injury


INTRODUCCIÓN Y OBJETIVOS: La lesión de isquemia y reperfusión testicular (I/R) se desarrolla después de la torsión y la consiguiente detorsión del testículo. Se produjeron especies reactivas de oxígeno y el daño oxidativo comienza a producirse debido al proceso de I/R. La nimesulida, que es un fármaco inhibidor específico de la ciclooxigenasa 2, tiene efectos antioxidantes, antiinflamatorios, analgésicos y antipiréticos. El objetivo fue investigar el efecto bioquímico e histopatológico de la nimesulida sobre la lesión testicular I/R en ratas inducida por la torsión-detorsión testicular. MATERIAL Y MÉTODOS: En este estudio se dividió a 24 ratas albinas Wistar macho en 4 grupos (6 ratas en cada grupo): isquemia y reperfusión aplicada+50mg/kg de nimesulida administrada (NIM-50), isquemia y reperfusión aplicada+100mg/kg de nimesulida administrada (NIM-100), isquemia y reperfusión aplicada (IR) y cirugía simulada (SS). La nimesulida se administró a los grupos NIM-50 y NIM-100 a las dosis de 50 y 100mg/kg, respectivamente, 2h antes de aplicar los procedimientos de I/R. Al grupo IR se aplicó solo procedimientos I/R, no se aplicó tratamiento farmacológico. Los animales se sacrificaron con anestesia a dosis altas y se extrajeron los testículos izquierdos. Los testículos se examinaron bioquímicamente e histopatológicamente. RESULTADOS: Los niveles totales de glutatión (tGSH) y ciclooxigenasa-1 (COX-1) aumentaron en los grupos NIM-50 y NIM-100 en comparación con el grupo IR. Los niveles de COX-2, malondialdehído (MDA), interleucina 1β (IL-1β) y factor de necrosis tumoral-α (TNF-α) fueron menores en los grupos NIM-50 y NIM-100 que en el grupo IR. Se vieron algunos cambios histopatológicos en el grupo IR. Estos hallazgos disminuyeron en el grupo NIM-50 y se evitaron en el grupo NIM-100. CONCLUSIÓN: La nimesulida previno la inflamación y el estrés oxidativo. Nuestros resultados sugieren que la nimesulida puede tener un efecto protector sobre la lesión testicular I/R


Assuntos
Animais , Masculino , Camundongos , Traumatismo por Reperfusão/prevenção & controle , Anti-Inflamatórios não Esteroides/administração & dosagem , Sulfonamidas/administração & dosagem , Ratos Wistar , Modelos Animais de Doenças , Traumatismo por Reperfusão/patologia
13.
Pharmacotherapy ; 40(8): 843-856, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32542785

RESUMO

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib's immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients' immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.


Assuntos
Azetidinas/farmacologia , Azetidinas/uso terapêutico , Infecções por Coronavirus/complicações , Inflamação/tratamento farmacológico , Inflamação/etiologia , Janus Quinases/antagonistas & inibidores , Pneumonia Viral/complicações , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Área Sob a Curva , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Betacoronavirus , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Interações Medicamentosas , Humanos , Interferon Tipo I/biossíntese , Taxa de Depuração Metabólica , Pandemias , Peptidil Dipeptidase A/biossíntese , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
14.
Cancer Sci ; 111(9): 3303-3312, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579783

RESUMO

Alveolar soft part sarcoma (ASPS), epithelioid sarcoma (ES), and clear cell sarcoma (CCS) are known to be chemoresistant tumors. The aim of this study was to investigate the effect of pazopanib on these chemoresistant tumors. This study is designed as a single-arm, multicenter, investigator-initiated phase II trial. Patient enrollment was undertaken between July 2016 and August 2018 at 10 hospitals participating in the Japanese Musculoskeletal Oncology Group. The primary end-point is the CBR (CBR, including complete or partial response and stable disease) at 12 weeks after treatment with pazopanib according to RECIST. Eight patients were enrolled within the period. The histological subtypes were 5 ASPS, 2 ES, and 1 CCS. The median follow-up period was 22.2 (range, 4.9-24.9) months. All patients initially received pazopanib 800 mg once daily. The CBRs were 87.5% (7 of 8) and 75.0% (6 of 8) according to RECIST and Choi criteria at 12 weeks after pazopanib treatment, respectively. The CBRs at 12 weeks according to RECIST were 80.0%, 100.0%, and 100.0% in ASPS, ES, and CCS, respectively. Partial response was observed in 1 ASPS according to RECIST and 3 ASPS and 1 ES according to Choi criteria at 12 weeks after pazopanib treatment. This study documented antitumor activity of pazopanib, especially in ASPS. These results support the frontline use of pazopanib for ASPS. Prospective data collection is desired using both RECIST and Choi criteria for these rare chemoresistant tumors.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Pirimidinas/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Feminino , Humanos , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sarcoma/terapia , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Adulto Jovem
15.
Life Sci ; 253: 117747, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376270

RESUMO

AIMS: Multiple sclerosis (MS) whose pathogenesis is still unclear is a chronic progressive disease in the central nervous system. Gut microbiota can directly or indirectly affect the immune system through the brain gut axis to engage in the occurrence and development of the disease. MATERIALS AND METHODS: C57BL/6 mice which were immunized by MOG35-55 to prepare experimental autoimmune encephalomyelitis (EAE) animal models were treated with rapamycin and MCC950 (CP-456773) in combination or separately. After sequencing the 16S rRNA V4 region of gut microbiota, the species, abundance and composition of gut microbiota were analyzed by Alpha diversity, Bata diversity and LEfSe analysis. The pathological changes and the expression of CD4 and CD8 of brain, large intestine and spleen were detected. KEY FINDINGS: The results showed that rapamycin and MCC950 could alleviate the progression of the disease by inducing autophagy and inhibiting the immune response. The Alpha diversity of EAE model group was no significant difference compering to control group while the number of OTUs was decreased. After the treatment by rapamycin and MCC950, the abundance and composition of gut microbiota was relatively recovered, which was close to that of normal mice. SIGNIFICANCE: Inhibiting immune cell-mediated inflammation and restoring the composition of gut microbiota may help to alleviate the clinical symptoms of multiple sclerosis. Furthermore, to research the regulatory effect between immune response and gut microbiota may be a new strategy for the prevention and treatment of multiple sclerosis.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Furanos/farmacologia , Microbioma Gastrointestinal/imunologia , Esclerose Múltipla/tratamento farmacológico , Sirolimo/farmacologia , Sulfonamidas/farmacologia , Animais , Encéfalo/imunologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/microbiologia , Feminino , Furanos/administração & dosagem , Inflamação/imunologia , Inflamação/patologia , Intestino Grosso/imunologia , Intestino Grosso/patologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , RNA Ribossômico 16S , Sirolimo/administração & dosagem , Baço/imunologia , Baço/patologia , Sulfonamidas/administração & dosagem
16.
Lancet Gastroenterol Hepatol ; 5(7): 649-657, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389183

RESUMO

BACKGROUND: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors. METHODS: HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log10IU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV. INTERPRETATION: Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors. FUNDING: Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ezetimiba/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/prevenção & controle , Adulto , Idoso , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Canadá/epidemiologia , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Ezetimiba/efeitos adversos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Quinoxalinas/uso terapêutico , Vírus de RNA/genética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Doadores de Tecidos/estatística & dados numéricos , Transplantados/estatística & dados numéricos , Transplantes/virologia , Carga Viral/estatística & dados numéricos
18.
Gastroenterol Clin North Am ; 49(2): 253-277, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32389362

RESUMO

The World Health Organization has called for the elimination of hepatitis C virus (HCV) as a public health threat by 2030. Highly effective direct-acting antiviral agents provide the therapeutic tools required for elimination. In the absence of a vaccine, HCV elimination will require enhanced primary prevention and an increase in the proportions of people diagnosed and treated. Given that globally only 20% of people with chronic HCV are diagnosed, and around 5% have initiated HCV treatment, the task ahead is enormous. But, global public health needs optimism, and countries currently on track for HCV elimination provide a pathway forward.


Assuntos
Antivirais/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/prevenção & controle , Anilidas/administração & dosagem , Antivirais/economia , Benzofuranos/administração & dosagem , Carbamatos/administração & dosagem , Quimioterapia Combinada , Saúde Global , Custos de Cuidados de Saúde , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/economia , Humanos , Imidazóis/administração & dosagem , Sofosbuvir/administração & dosagem , Sulfonamidas/administração & dosagem , Uracila/administração & dosagem , Uracila/análogos & derivados , Organização Mundial da Saúde
19.
Pharmacotherapy ; 40(5): 416-437, 2020 05.
Artigo em Inglês | MEDLINE | ID: covidwho-38302

RESUMO

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.


Assuntos
Antivirais/administração & dosagem , Antivirais/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Imunomodulação , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Corticosteroides , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/análogos & derivados , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Betacoronavirus , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Infecções por Coronavirus/terapia , Combinação de Medicamentos , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Imunização Passiva , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Lopinavir/administração & dosagem , Lopinavir/efeitos adversos , Nelfinavir/administração & dosagem , Nelfinavir/efeitos adversos , Pandemias , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos
20.
Pharmacotherapy ; 40(5): 416-437, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32259313

RESUMO

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.


Assuntos
Antivirais/administração & dosagem , Antivirais/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Imunomodulação , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Corticosteroides , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/análogos & derivados , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Betacoronavirus , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Infecções por Coronavirus/terapia , Combinação de Medicamentos , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Imunização Passiva , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Lopinavir/administração & dosagem , Lopinavir/efeitos adversos , Nelfinavir/administração & dosagem , Nelfinavir/efeitos adversos , Pandemias , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos
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