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1.
Angiol Sosud Khir ; 27(1): 33-38, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33825726

RESUMO

PURPOSE: This study was undertaken to investigate efficacy of apixaban in prevention of haemorrhagic complications during treatment of proximal thromboses of deep veins of the lower extremities using endovascular techniques. PATIENTS AND METHODS: We retrospectively studied the results of treating a total of 50 patients presenting with deep vein thromboses at late stages of the pathological process. The patients were subdivided into 2 statistically homogeneous groups. Group One was composed of 30 patients undergoing treatment consisting in a combination of catheter-guided thrombolysis with urokinase and percutaneous mechanical thrombectomy, with rivaroxaban used for prolonged anticoagulation therapy. Group Two comprised 20 patients subjected to similar endovascular treatment with additional venous stenting. Prolonged 6-month anticoagulation therapy was carried out with apixaban. The results of treatment were assessed after 12 months by means of control ultrasonographic and clinical examination in order to determine the degree of restoration of the lumen of deep veins and severity of venous outflow impairments. RESULTS: After 1 year, in Group One patients there was no evidence of impaired venous outflow in 40% of patients, with a mild degree revealed in 40%, moderate degree in 13.3%, and severe degree in 6.7% of patients. In Group Two patients, there were no symptoms of venous insufficiency in 83.4%, with a mild degree revealed in 16.6%. Neither moderate nor severe impairments of venous outflow were observed. In Group One, manifestations of haemorrhagic syndrome on the background of taking rivaroxaban were noted to occur in 10% of patients and in Group Two on the background of taking apixaban also in 10% of patients. CONCLUSION: The use of apixaban in patients with proximal thromboses of deep veins of lower limbs on the background of treatment by endovascular techniques proved effective and safe.


Assuntos
Procedimentos Endovasculares , Trombose Venosa , Procedimentos Endovasculares/efeitos adversos , Humanos , Pirazóis , Piridonas/efeitos adversos , Estudos Retrospectivos , Terapia Trombolítica , Resultado do Tratamento , Trombose Venosa/diagnóstico , Trombose Venosa/tratamento farmacológico
2.
Artigo em Russo | MEDLINE | ID: mdl-33834728

RESUMO

The article is a short review of an observational study that proves the good efficacy and tolerability of perampanel suspension in the adjunctive treatment of epilepsy in children over 4 years of age. The study demonstrated a high level of 50% responders: 47% with focal seizures, 65% with transition of focal seizures to bilateral tonic-clonic seizures, 65% with primary generalized tonic-clonic seizures. Cessation of seizures was achieved in 12%, 19% and 55% of patients, respectively. The most common side-effects were fatigue (26%), nasopharyngitis (19%), lightheadedness, irritability, fever (13% each), and vomiting (11%). There were no significant clinical negative changes in cognitive functions according to the assessment on the Aldenkamp-Baker scale, both on the total score and subscales. Also, there were no significant changes in laboratory data, vital functions and ECG parameters.


Assuntos
Anticonvulsivantes , Epilepsia Tônico-Clônica , Anticonvulsivantes/efeitos adversos , Criança , Epilepsia Tônico-Clônica/tratamento farmacológico , Humanos , Piridonas/efeitos adversos , Convulsões/tratamento farmacológico , Resultado do Tratamento
3.
Medicine (Baltimore) ; 100(12): e25185, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761699

RESUMO

BACKGROUND: Dual anti-platelet therapy (DAPT) with aspirin and clopidogrel has been the mainstay of treatment for patients with acute coronary syndrome (ACS). However, the recurrence of thrombotic events, potential aspirin and clopidogrel hypo-responsiveness, and other limitations of DAPT have led to the development of newer oral anti-thrombotic drugs. Apixaban, a new non-vitamin K antagonist, has been approved for use. In this meta-analysis, we aimed to compare the bleeding outcomes observed with the addition of apixaban to DAPT for the treatment of patients with ACS. METHODS: Online databases including EMBASE, Cochrane Central, http://www.ClinicalTrials.gov, MEDLINE and Web of Science were searched for English based publications comparing the use of apixaban added to DAPT for the treatment of patients with ACS. Different categories of bleeding events and cardiovascular outcomes were assessed. The analysis was carried out by the RevMan software version 5.4. Odds ratios (OR) with 95% confidence intervals (CI) were used to represent the data following analysis. RESULTS: This research analysis consisted of 4 trials with a total number of 9010 participants. Thrombolysis in myocardial infarction (TIMI) defined major bleeding (OR: 2.45, 95% CI: 1.45-4.12; P = .0008), TIMI defined minor bleeding (OR: 3.12, 95% CI: 1.71-5.70; P = .0002), International society of thrombosis and hemostasis (ISTH) major bleeding (OR: 2.49, 95% CI: 1.80-3.45; P = .00001) and Global Use of Strategies to Open Occluded Arteries (GUSTO) defined severe bleeding (OR: 3.00, 95% CI: 1.56-5.78; P = .01) were significantly increased with the addition of apixaban to DAPT versus DAPT alone in these patients with ACS. However fatal bleeding (OR: 10.96, 95% CI: 0.61-198.3; P = .11) was not significantly different. CONCLUSIONS: Addition of the novel oral anticoagulant apixaban to the DAPT regimen significantly increased bleeding and therefore did not show any beneficial effect in these patients with ACS. However, due to the extremely limited data, we apparently have to rely on future larger studies to confirm this hypothesis.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Anticoagulantes/efeitos adversos , Aspirina/efeitos adversos , Clopidogrel/efeitos adversos , Hemorragia/induzido quimicamente , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Quimioterapia Combinada , Humanos , Fatores de Risco
4.
J Med Case Rep ; 15(1): 109, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653337

RESUMO

BACKGROUND: Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors. CASE PRESENTATION: A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAFV600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography-computed tomography (PET-CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib-trametinib withdrawal, the patient developed tumor progression with significant clinical worsening. CONCLUSIONS: This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.


Assuntos
Enfisema/diagnóstico por imagem , Imidazóis/efeitos adversos , Enteropatias/diagnóstico por imagem , Oximas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias da Base do Crânio/tratamento farmacológico , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia , Enfisema/induzido quimicamente , Feminino , Humanos , Enteropatias/induzido quimicamente , Radioisótopos do Iodo/uso terapêutico , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/genética , Neoplasias da Base do Crânio/secundário , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/secundário
5.
Medicine (Baltimore) ; 100(11): e25216, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33726018

RESUMO

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have been widely used for stroke prevention in atrial fibrillation (AF) and the treatment and prevention of venous thromboembolism. There is an issue with safety, especially in clinically relevant bleeding. We performed a network meta-analysis to evaluate the risk of major gastrointestinal (GI) bleeding associated with NOACs. METHODS: Interventions were warfarin, enoxaparin, apixaban, dabigatran, edoxaban, and rivaroxaban. The primary outcome was the incidence of major GI bleeding. A subgroup analysis was performed according to the following indications: AF, deep venous thrombosis/pulmonary embolism, and postsurgical prophylaxis. RESULTS: A total of 29 randomized controlled trials (RCTs) and 4 large observation population studies were included. Compared with warfarin, apixaban showed a decreased the risk of major GI bleeding (relative risk [RR] 0.54, 95% confidence interval [CI] 0.25-0.76), and rivaroxaban tended to increase this risk (RR 1.40, 95% CI 1.06-1.85). Dabigatran (RR 1.25, 95% CI 0.98-1.60), edoxaban (RR 1.07, 95% CI 0.69-1.65), and enoxaparin (RR 1.24, 95% CI 0.63-2.43) did not significantly increase the risk of GI bleeding than did warfarin. In the subgroup analysis, according to indications, apixaban showed a decreased risk of major GI bleeding (RR 0.50, 95% CI 0.34-0.74) than did warfarin in AF studies. Dabigatran (RR 2.36, 95% CI 1.55-3.60, and rivaroxaban (RR 1.75, 95% CI 1.10-6.41) increased the risk of major GI bleeding than did apixaban. An analysis of studies on venous thromboembolism or pulmonary embolism showed that no individual NOAC or enoxaparin was associated with an increased risk of major GI bleeding compared to warfarin. CONCLUSION: Individual NOACs had varying profiles of GI bleeding risk. Results of analyses including only RCTs and those including both RCTs and population studies showed similar trends, but also showed several differences.


Assuntos
Anticoagulantes/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Hemorragia Gastrointestinal/induzido quimicamente , Embolia Pulmonar/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Adulto , Idoso , Fibrilação Atrial/complicações , Dabigatrana/efeitos adversos , Enoxaparina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Estudos Observacionais como Assunto , Embolia Pulmonar/complicações , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Piridonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/efeitos adversos , Tromboembolia Venosa/complicações , Varfarina/efeitos adversos
7.
AIDS ; 35(2): 213-218, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33394669

RESUMO

OBJECTIVES: Osteopenia is frequent in HIV-infected patients treated with antiretroviral therapy (ART) and has been linked to increased osteoclastogenesis. Little is known about the effects of ART on osteogenesis. DESIGN: We investigated the effect on human mesenchymal stem cells (hMSC) and osteoblasts of Darunavir and Dolutegravir, the most highly used as anchor drugs within a three-drug regimen, and Atazanavir, which was widely utilized in the past. RESULTS: We found that Atazanavir and Dolutegravir delay the osteogenic differentiation of hMSC, impair the activity of osteoblasts and inhibit their conversion into osteocytes, whereas Darunavir exerts no effect. CONCLUSION: Atazanavir and Dolutegravir impair osteogenesis. It is essential to diagnose impaired osteogenesis early and to devise effective therapeutic interventions to preserve bone health in ART-treated HIV patients, putting it in the context of a correct antiretroviral combination.


Assuntos
Fármacos Anti-HIV , Sulfato de Atazanavir/efeitos adversos , Doenças Ósseas Metabólicas , Darunavir/efeitos adversos , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Sulfato de Atazanavir/uso terapêutico , Doenças Ósseas Metabólicas/induzido quimicamente , Darunavir/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Osteogênese , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico
8.
Lancet HIV ; 8(1): e33-e41, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387477

RESUMO

BACKGROUND: Dolutegravir has been widely available in Brazil since 2017. Following the signal that infants born to women with dolutegravir exposure at conception in Botswana had a higher risk of neural tube defects (NTDs), public health leaders initiated a national investigation to evaluate periconception dolutegravir exposure among all pregnant Brazilian women with HIV and its potential association with risk of NTDs, stillbirth, or miscarriage before 22 weeks (also called spontaneous abortion). METHODS: In this retrospective, observational, national, cohort study, we identified all women with pregnancies and possible dolutegravir exposure within 8 weeks of estimated date of conception between Jan 1, 2017, and May 31, 2018, and approximately 3:1 matched pregnant women exposed to efavirenz between Jan 1, 2015, and May 31, 2018, using the Brazilian antiretroviral therapy database. We did detailed chart reviews for identified women. The primary outcomes were NTD and a composite measure of NTD, stillbirth, or miscarriage. NTD incidences were calculated with 95% CI. The composite outcome was examined with logistic regression using propensity score matching weights to balance confounders. FINDINGS: Of 1427 included women, 382 were exposed to dolutegravir within 8 weeks of estimated date of conception. During pregnancy, 183 (48%) of 382 dolutegravir-exposed and 465 (44%) of 1045 efavirenz-exposed women received folic acid supplementation. There were 1452 birth outcomes. There were no NTDs in either dolutegravir-exposed (0, 95% CI 0-0·0010) or efavirenz-exposed groups (0, 95% CI 0-0·0036). There were 23 (6%) stillbirths or miscarriages in 384 dolutegravir-exposed fetuses and 28 (3%) in the 1068 efavirenz-exposed fetuses (p=0·0037). Logistic regression models did not consistently indicate an association between dolutegravir exposure and risk of stillbirths or miscarriages. After study closure, two confirmed NTD outcomes in fetuses with periconception dolutegravir exposure were reported to public health officials. An updated estimate of NTD incidence incorporating these cases and the estimated number of additional dolutegravir-exposed pregnancies between Jan 1, 2015 and Feb 28, 2019, is 0·0018 (95% CI 0·0005-0·0067). INTERPRETATION: Neither dolutegravir nor efavirenz exposure was associated with NTDs in our national cohort; incidence of NTDs is probably well under 1% in dolutegravir-exposed HIV-positive women but still slightly above HIV-uninfected women (0·06%) in Brazil. FUNDING: The Brazilian Ministry of Health and the United States' National Institutes of Health.


Assuntos
Infecções por HIV/complicações , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Defeitos do Tubo Neural/etiologia , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversos , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Brasil/epidemiologia , Comorbidade , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/epidemiologia , Oxazinas/administração & dosagem , Oxazinas/uso terapêutico , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Gravidez , Resultado da Gravidez , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Estudos Retrospectivos , Natimorto , Adulto Jovem
9.
BMC Infect Dis ; 21(1): 5, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33446115

RESUMO

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Oxazinas/administração & dosagem , Oxazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Adolescente , Peso Corporal , Criança , Pré-Escolar , Estudos de Coortes , Cálculos da Dosagem de Medicamento , Europa (Continente)/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Masculino , RNA Viral/genética , África do Sul/epidemiologia , Tailândia/epidemiologia , Resultado do Tratamento , Uganda/epidemiologia , Carga Viral/efeitos dos fármacos , Organização Mundial da Saúde , Zimbábue/epidemiologia
11.
Cancer Sci ; 112(3): 1123-1131, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33492746

RESUMO

BACKGROUND: Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B-cell non-Hodgkin-type lymphoma (B-NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity. METHODS: Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28-day/cycle manner. Tazemetostat dose-limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations. RESULTS: As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B-cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59-85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment-related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment-related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment. CONCLUSIONS: Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B-NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzamidas/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Morfolinas/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Piridonas/efeitos adversos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Humanos , Japão , Linfoma de Células B/genética , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piridonas/administração & dosagem , Piridonas/farmacocinética , Resultado do Tratamento
13.
Lancet ; 396(10267): 1994-2005, 2021 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-33308425

RESUMO

BACKGROUND: Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing. METHODS: ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing. FINDINGS: Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34-50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI -0·6-2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred. INTERPRETATION: The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1. FUNDING: ViiV Healthcare and Janssen.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Piridonas/administração & dosagem , Rilpivirina/administração & dosagem , Adulto , Alanina Transaminase/sangue , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Preparações de Ação Retardada , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Piridonas/efeitos adversos , Piridonas/sangue , RNA Viral/sangue , Rilpivirina/efeitos adversos , Rilpivirina/sangue , Carga Viral
14.
AIDS ; 35(1): 91-99, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33048879

RESUMO

OBJECTIVE: To evaluate changes in weight and BMI in adults with HIV-1 at 1 and 2 years after starting an antiretroviral regimen that included doravirine, ritonavir-boosted darunavir, or efavirenz. DESIGN: Post-hoc analysis of pooled data from three randomized controlled trials. METHODS: We evaluated weight change from baseline, weight gain at least 10%, and increase in BMI after 48 and 96 weeks of treatment with doravirine, ritonavir-boosted darunavir, or efavirenz-based regimens. Risk factors for weight gain and metabolic outcomes associated with weight gain were also examined. RESULTS: Mean (and median) weight changes were similar for doravirine [1.7 (1.0) kg] and ritonavir-boosted darunavir [1.4 (0.6) kg] and were lower for efavirenz [0.6 (0.0) kg] at week 48 but were similar across all treatment groups at week 96 [2.4 (1.5), 1.8 (0.7), and 1.6 (1.0) kg, respectively]. No significant differences between treatment groups were found in the proportion of participants with at least 10% weight gain or the proportion with BMI class increase at either time point. Low CD4 T-cell count and high HIV-1 RNA at baseline were associated with at least 10% weight gain and BMI class increase at both timepoints, but treatment group, age, sex, and race were not. CONCLUSION: Weight gains over 96 weeks were low in all treatment groups and were similar to the average yearly change in adults without HIV-1. Significant weight gain and BMI class increase were similar across the treatment groups and were predicted by low baseline CD4 T-cell count and high baseline HIV-1 RNA.


Assuntos
Fármacos Anti-HIV , Índice de Massa Corporal , Infecções por HIV , Piridonas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Piridonas/efeitos adversos , Ritonavir/uso terapêutico , Resultado do Tratamento , Triazóis/efeitos adversos , Carga Viral
15.
PLoS One ; 15(12): e0242710, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362248

RESUMO

INTRODUCTION: The use of patient-reported outcomes (PROs) to systematically quantify adverse events (AE) will assist in the improvement of medical care and the QoL of patients living with HIV (PLWH). The aim of this study was to investigate the associations between self-reported side effects and other PROs, demographics and laboratory data, and further evaluate the Health Questionnaire (HQ) as a tool for following trends in patient-reported side effects over time in relation to trends in prescribed third agent in ART. MATERIALS AND METHODS: The Swedish National Registry InfCareHiv includes an annual self-reported nine-item HQwhich is used in patient-centered HIV care in all Swedish HIV units. In this study, the experience of side effects was addressed. We analyzed 9,476 HQs completed by 4,186 PLWH together with details about their prescribed ART and relevant biomarkers collected during 2011-2017. Data were analyzed using descriptive statistics, Pearson's correlation coefficient and mixed logistic regression. RESULTS: The cross-sectional analysis of the HQs showed that the frequency of reported side effects decreased from 32% (2011) to 15% (2017). During the same period, there was a shift in ART prescription from efavirenz (EFV) to dolutegravir (DTG) (positive correlation coefficient r = 0.94, p = 0.0016). Further, PLWH who reported being satisfied with their physical health (OR: 0.47, p = <0.001) or psychological health (OR: 0.70, p = 0.001) were less likely to report side effects than those less satisfied. CONCLUSIONS: Self-reported side effects were found to have a close relationship with the patient's ratings of their overall health situation and demonstrated a strong correlation with the sharp decline in use of EFV and rise in use of DTG, with reported side effects being halved. This study supports the feasibility of using the HQ as a tool for longitudinal follow up of trends in PROs.


Assuntos
Alquinos/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Benzoxazinas/efeitos adversos , Ciclopropanos/efeitos adversos , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversos , Qualidade de Vida/psicologia , Sistema de Registros , Adulto , Alquinos/administração & dosagem , Fármacos Anti-HIV/administração & dosagem , Artralgia/induzido quimicamente , Artralgia/diagnóstico , Artralgia/fisiopatologia , Benzoxazinas/administração & dosagem , Estudos Transversais , Ciclopropanos/administração & dosagem , Disfunção Erétil/induzido quimicamente , Disfunção Erétil/diagnóstico , Disfunção Erétil/fisiopatologia , Feminino , HIV/efeitos dos fármacos , Infecções por HIV/fisiopatologia , Infecções por HIV/psicologia , Infecções por HIV/virologia , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/diagnóstico , Náusea/fisiopatologia , Oxazinas/administração & dosagem , Medidas de Resultados Relatados pelo Paciente , Piperazinas/administração & dosagem , Piridonas/administração & dosagem , Suécia
16.
PLoS Med ; 17(12): e1003397, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33315863

RESUMO

BACKGROUND: Rising resistance of HIV-1 to non-nucleoside reverse transcriptase inhibitors (NNRTIs) threatens the success of the global scale-up of antiretroviral therapy (ART). The switch to WHO-recommended dolutegravir (DTG)-based regimens could reduce this threat due to DTG's high genetic barrier to resistance. We used mathematical modeling to predict the impact of the scale-up of DTG-based ART on NNRTI pretreatment drug resistance (PDR) in South Africa, 2020 to 2040. METHODS AND FINDINGS: We adapted the Modeling Antiretroviral drug Resistance In South Africa (MARISA) model, an epidemiological model of the transmission of NNRTI resistance in South Africa. We modeled the introduction of DTG in 2020 under 2 scenarios: DTG as first-line regimen for ART initiators, or DTG for all patients, including patients on suppressive NNRTI-based ART. Given the safety concerns related to DTG during pregnancy, we assessed the impact of prescribing DTG to all men and in addition to (1) women beyond reproductive age; (2) women beyond reproductive age or using contraception; and (3) all women. The model projections show that, compared to the continuation of NNRTI-based ART, introducing DTG would lead to a reduction in NNRTI PDR in all scenarios if ART initiators are started on a DTG-based regimen, and those on NNRTI-based regimens are rapidly switched to DTG. NNRTI PDR would continue to increase if DTG-based ART was restricted to men. When given to all men and women, DTG-based ART could reduce the level of NNRTI PDR from 52.4% (without DTG) to 10.4% (with universal DTG) in 2040. If only men and women beyond reproductive age or on contraception are started on or switched to DTG-based ART, NNRTI PDR would reach 25.9% in 2040. Limitations include substantial uncertainty due to the long-term predictions and the current scarcity of knowledge about DTG efficacy in South Africa. CONCLUSIONS: Our model shows the potential benefit of scaling up DTG-based regimens for halting the rise of NNRTI resistance. Starting or switching all men and women to DTG would lead to a sustained decline in resistance levels, whereas using DTG-based ART in all men, or in men and women beyond childbearing age, would only slow down the increase in levels of NNRTI PDR.


Assuntos
Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Modelos Teóricos , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Substituição de Medicamentos , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/provisão & distribução , HIV-1/patogenicidade , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/provisão & distribução , Humanos , Masculino , Oxazinas/efeitos adversos , Oxazinas/provisão & distribução , Piperazinas/efeitos adversos , Piperazinas/provisão & distribução , Piridonas/efeitos adversos , Piridonas/provisão & distribução , África do Sul/epidemiologia , Fatores de Tempo , Resultado do Tratamento
17.
Kardiologiia ; 60(9): 102-109, 2020 Oct 14.
Artigo em Russo | MEDLINE | ID: mdl-33131481

RESUMO

Aim To compare efficacy and safety of direct oral anticoagulants (DOACs) for prevention of stroke in patients with nonvalvular atrial fibrillation and reduced creatinine clearance.Material and methods Systematic search for literature and indirect comparison of DOACs were performed.Results The indirect comparison included five randomized clinical trials. The DOACs were comparable by the efficacy of preventing stroke and systemic embolism. The safety profiles had differences. Apixaban significantly decreased the relative risk of major bleeding compared to rivaroxaban by 27 % (relative risk (RR) 0.73; 95 % confidence interval (CI): 0.55-0.98). The apixaban advantage was even greater in the group of patients with a creatinine clearance <50 ml/min: RR was reduced by 48 % compared to rivaroxaban (RR=0.52; 95 % CI: 0.32-0.84), by 50 % compared to dabigatran 300 mg/day (RR=0.50; 95 % CI: 0.31-0.81), and by 48 % compared to dabigatran 220 mg/day (RR=0.52; 95 % CI: 0.32-0.85)Conclusion The indirect comparison of DOACs showed that their efficacy was comparable. With respect of safety, apixaban is the preferrable DOAC for patients with atrial fibrillation and creatinine clearance below 50 ml/min.


Assuntos
Fibrilação Atrial , Insuficiência Renal Crônica , Acidente Vascular Cerebral , Administração Oral , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/uso terapêutico , Humanos , Piridonas/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento
18.
Lancet Oncol ; 21(11): 1433-1442, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33035457

RESUMO

BACKGROUND: Activating mutations of EZH2, an epigenetic regulator, are present in approximately 20% of patients with follicular lymphoma. We investigated the activity and safety of tazemetostat, a first-in-class, oral EZH2 inhibitor, in patients with follicular lymphoma. METHODS: This study was an open-label, single-arm, phase 2 trial done at 38 clinics or hospitals in France, the UK, Australia, Canada, Poland, Italy, Ukraine, Germany, and the USA. Eligible patients were adults (≥18 years) with histologically confirmed follicular lymphoma (grade 1, 2, 3a, or 3b) that had relapsed or was refractory to two or more systemic therapies, had an Eastern Cooperative Oncology Group performance status of 0-2, and had sufficient tumour tissue for central testing of EZH2 mutation status. Patients were categorised by EZH2 status: mutant (EZH2mut) or wild-type (EZH2WT). Patients received 800 mg of tazemetostat orally twice per day in continuous 28-day cycles. The primary endpoint was objective response rate based on the 2007 International Working Group criteria for non-Hodgkin lymphoma, assessed by an independent radiology committee. Activity and safety analyses were done in patients who received one dose or more of tazemetostat. This study is registered with ClinicalTrials.gov, NCT01897571, and follow-up is ongoing. FINDINGS: Between July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2mut cohort and 54 in the EZH2WT cohort) were enrolled in the study. At data cutoff for the analysis (Aug 9, 2019), the median follow-up was 22·0 months (IQR 12·0-26·7) for the EZH2mut cohort and 35·9 months (24·9-40·5) for the EZH2WT cohort. The objective response rate was 69% (95% CI 53-82; 31 of 45 patients) in the EZH2mut cohort and 35% (23-49; 19 of 54 patients) in the EZH2WT cohort. Median duration of response was 10·9 months (95% CI 7·2-not estimable [NE]) in the EZH2mut cohort and 13·0 months (5·6-NE) in the EZH2WT cohort; median progression-free survival was 13·8 months (10·7-22·0) and 11·1 months (3·7-14·6). Among all 99 patients, treatment-related grade 3 or worse adverse events included thrombocytopenia (three [3%]), neutropenia (three [3%]), and anaemia (two [2%]). Serious treatment-related adverse events were reported in four (4%) of 99 patients. There were no treatment-related deaths. INTERPRETATION: Tazemetostat monotherapy showed clinically meaningful, durable responses and was generally well tolerated in heavily pretreated patients with relapsed or refractory follicular lymphoma. Tazemetostat is a novel treatment for patients with follicular lymphoma. FUNDING: Epizyme.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Benzamidas/administração & dosagem , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma Folicular/tratamento farmacológico , Piridonas/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Piridonas/efeitos adversos , Resultado do Tratamento
19.
Lancet Oncol ; 21(11): 1423-1432, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33035459

RESUMO

BACKGROUND: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. METHODS: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing. FINDINGS: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. INTERPRETATION: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941). FUNDING: Epizyme.


Assuntos
Benzamidas/administração & dosagem , Piridonas/administração & dosagem , Proteína SMARCB1/genética , Sarcoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Piridonas/efeitos adversos , Piridonas/farmacocinética , Sarcoma/genética , Sarcoma/patologia , Resultado do Tratamento , Adulto Jovem
20.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 148-157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093778

RESUMO

Background: Patients with idiopathic pulmonary fibrosis (IPF) often do not tolerate pirfenidone in the recommended dose of 2400 mg/day. The proportion of patients requiring dose reduction and its impact on survival in the real-world remain unclear. Methods: Consecutive subjects with IPF were enrolled between March 2017 and June 2019. The maximum tolerated dose of pirfenidone (primary outcome) and adverse drug reactions (ADRs) were recorded. A post hoc logistic regression analysis was performed to evaluate the predictors of drug discontinuation due to ADRs. We also compared survival between the full-dose (2400 mg/day), reduced-dose (< 2400 mg/day), and the no-pirfenidone groups, with age and percentage of the predicted forced vital capacity (%pred FVC) as covariates. Results: Of the 128 subjects (mean age, 67.4 years; 77.3% men) included, 115 were initiated on pirfenidone. Forty-nine (42.6%) and 51 (44.3%) subjects tolerated the full dose and reduced doses, respectively. Ninety-six (83.5%) subjects developed at least one ADR; anorexia dyspepsia, and nausea being the most common. Twenty-two subjects discontinued the drug; 15 of them due to ADRs. Body mass index < 20 kg/m2 was the only predictor of drug discontinuation due to ADRs. Among subjects newly initiated on treatment during the study period (n = 80), survival was longer (hazard ratio [interquartile range], 0.19 [0.04-0.96]; p = 0.045) in the full-dose but not the reduced-dose group (p = 0.08) compared with the no-pirfenidone group, after adjusting for covariates. Conclusion: Pirfenidone was tolerated in the full dose in a minority of patients with IPF and appears to improve survival only with the full dose. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 148-157).


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Piridonas/administração & dosagem , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/fisiopatologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Prospectivos , Piridonas/efeitos adversos , Recuperação de Função Fisiológica , Resultado do Tratamento , Capacidade Vital
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